A Novel Cervical Cancer Screen-and-Treat Demonstration Project With HPV Self-testing and Thermocoagulation for Women in Lilongwe Malawi
Phase: NA
Conditions: HPV Infection, Cervical Cancer, HIV Infections
Sponsor: UNC Lineberger Comprehensive Cancer Center

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R 
L C C C 1 9 0 5 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M 
Dec 1 8, 2 0 2 0 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L 
L C C C 1 9 0 5: A n o vel cer vic al c a ncer scree n - a n d-tre at de m o nstr ati o n pr oject wit h 
H P V self-testi n g a n d t her m oc o a g ul ati o n f or w o me n i n Lil o n g we, M al a wi 
Pri nci p al I n vesti g at or 
La mec k C hi n ula, M B B S, F C O G, M M E D 
U ni versit y of N ort h Car oli na ( U N C) Pr oject- Mala wi 
Ti dzi we Ce nter 
Ka m uz u Ce ntral H os pital 
P/ Ba g A 1 0 4 
Lil o n g we,
 
Mala wi
  
E mail: la mec k _c hi n ula @ me d. u nc.e d u  
C o-I n vesti g at or(s) 
Je n nifer Ta n g, M D, M S C R  
Ta mi we T o m o ka, M B B S, F C Pat h 
Je n nifer S. S mit h, P h D 
A ma n da Varela, M P H 
Fri da y Sai di, M B B S, M M E D 
Si o b ha n Marie O’ C o n n or, M D 
Bi ost atistici a n  
Ma ga niz o C ha g o mera na, P h D 
S p o ns or : U N C Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter 
F u n di n g S o urce : U. S. Nati o nal I nstit utes of Healt h, Bet hes da, M D, U S A 
     U N C Li ne ber ger C om pre he nsi ve Ca ncer Ce nter  
Versi o n D ate: 1 8 Dec 2 0 2 0  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R 
L C C C 1 9 0 5 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
  
Dec 1 8, 2 0 2 0 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L 
 
L C C C 1 9 0 5: A n o vel cer vic al c a ncer scree n - a n d-tre at de m o nstr ati o n pr oject wit h 
H P V self-testi n g a n d t her m oc o a g ul ati o n f or w o me n i n Lil o n g we, M al a wi 
 
Pri nci p al I n vesti g at or 
La mec k C hi n ula, M B B S F C O G M M E D 
U N C Pr oject- Mala wi 
Ti dzi we Ce nter 
Ka m uz u Ce ntral H os pital 
P/ Ba g A 1 0 4 
Lil o n g we, Mala wi   
 
P h o ne: + 2 6 5 1 7 5 0 6 1 0 
Cell:
 
+ 2 6 5 8 8 2 4 8 3 2 2 0
  
 
 
 
 
E mail: la mec k _c hi n ula @ 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 ul at 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:  La mec k C hi n ula _ 
 
PI Si g n at ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
Versi o n D ate: 1 8 Dec 2 0 2 0  
 

L C C C 1 9 0 5 
 
C O N FI D E N TI A L 
PI: L a mec k C hi n ul a 
  
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/ D ate: 5. 0, 1 8 Dec 2 0 2 0 
 
Dec 1 8, 2 0 2 0 
 
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T A B L E O F C O N T E N T S 
1. 0  ..................................................................... B A C K G R O U N D A N D R A TI O N A L E
.............................................................................................................................................. 1 
1. 1  
St u d y S y n o psis ..................................................................................................... 1  
1. 2  
Bac k gr o u n d .......................................................................................................... 1  
1. 3  
P ur p ose a n d Rati o nale .......................................................................................... 2  
2. 0  ............................................................ S T U D Y O B J E C TI V E S A N D E N D P OI N T S
.............................................................................................................................................. 4 
2. 1  
Pri mar y O bjecti ves ............................................................................................... 4  
2. 2  
Sec o n dar y O bjecti ves ........................................................................................... 4  
3. 0  ........................................................................................ P A TI E N T E LI GI BI LI T Y
.............................................................................................................................................. 5 
3. 1  
I ncl usi o n Criteria ................................................................................................. 5 
3. 2  
E xcl usi o n Criteria ................................................................................................ 5  
4. 0  .......................................................................................................... S T U D Y P L A N
.............................................................................................................................................. 6 
4. 1  
Sc he ma ................................................................................................................. 6  
4. 2  
D urati o n of St u d y ................................................................................................. 7  
4. 3  
St u d y Details ........................................................................................................ 8  
4. 4  
E x pecte d Ris ks ................................................................................................... 1 1  
4. 5  
Partici pa nt Rete nti o n .......................................................................................... 1 3  
4. 6  
Re m o val of Patie nts fr o m Pr ot oc ol .................................................................... 1 4 
5. 0  ................................................................................. TI M E A N D E V E N T S T A B L E
............................................................................................................................................ 1 5 
5. 1  
Sc he d ule of st u d y pr oce d ures ............................................................................ 1 5  

L C C C 1 9 0 5 
 
C O N FI D E N TI A L 
PI: L a mec k C hi n ul a 
  
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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6. 0  ..................................................................... S T A TI S TI C A L C O N SI D E R A TI O N S
............................................................................................................................................ 1 6 
6. 1  
St u d y Desi g n ...................................................................................................... 1 6  
6. 2  
Sa m ple Size a n d Accr ual ................................................................................... 1 6  
6. 3  
Data A nal ysis Pla ns ........................................................................................... 1 7  
6. 4  
Data Ma na ge me nt/ A u dit .................................................................................... 2 2  
7. 0  ....................................................................................... S T U D Y M A N A G E M E N T
............................................................................................................................................ 2 2 
7. 1  
I nstit uti o nal Re vie w B oar d (IR B) A p pr o val a n d C o nse nt ................................. 2 3  
7. 2  
Re q uire d D oc u me ntati o n ................................................................................... 2 3  
7. 3  
A d here nce t o t he Pr ot oc ol .................................................................................. 2 4  
7. 4  
Data Safet y M o nit ori n g ...................................................................................... 2 9  
7. 5  
A me n d me nts t o t he Pr ot oc ol .............................................................................. 3 0  
7. 6  
Rec or d Rete nti o n ............................................................................................... 3 0  
7. 7  
O bli gati o ns of I n vesti gat ors ............................................................................... 3 0  
8. 0  ........................................................................................................ R E F E R E N C E S
............................................................................................................................................ 3 1 
9. 0  .......................................................................................................... A P P E N DI C E S
............................................................................................................................................ 3 4 
9. 1  
I nf or me d C o nse nt F or m: L C C C 1 9 0 5:  A N o vel Cer vical Ca ncer Scree n-a n d-
Treat De m o nstrati o n Pr oject wit h H P V Sel f-testi n g a n d T her m oc oa g ulati o n f or W o me n 
i n Mala wi Versi o n 2. 0 date d 0 6 Se pt 2 0 1 9 ( E n glis h a n d C hic he wa versi o ns). ............. 3 4 
9. 2  
I n- De pt h I nter vie w I nf or me d C o nse nt F or m Versi o n 2. 0 date d 0 6 Se pt 2 0 1 9 
( E n glis h a n d C hic he wa versi o ns) ................................................................................... 3 4 
9. 3  
I n- De pt h I nter vie w G ui de Versi o n 1. 0 date d 0 6 Se pt 2 0 1 9 ( E n glis h a n d 
C hic he wa versi o ns) ........................................................................................................ 3 4  
9. 4  
I n- De pt h I nter vie w Q uesti o n naire Versio n 1. 0 date d 0 6 Se pt 2 0 1 9 ( E n glis h a n d 
C hic he wa versi o ns) ........................................................................................................ 3 4  

L C C C 1 9 0 5 
 
C O N FI D E N TI A L 
PI: L a mec k C hi n ul a 
  
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/ D ate: 5. 0, 1 8 Dec 2 0 2 0 
 
Dec 1 8, 2 0 2 0 
 
1 
 
 
 
1. 0  
B A C K G R O U N D A N D R A TI O N A L E 
1. 1  
St u d y S y n o psis 
We pr o p ose a pr os pecti ve st u d y t o assess c o m pleti o n a n d perf or ma nce of t he 
f oll o wi n g n o vel i n vasi ve cer vical ca ncer (I C C) scree n-a n d-treat al g orit h m a m o n g 
6 2 5 HI V- p ositi ve w o me n a n d 6 2 5 HI V- ne gati ve  w o me n i n Lil o n g we, Mala wi: 1) 
ra pi d testi n g of self-c ollecte d va gi nal br us h f or pri mar y hi g h ris k ( hr)- h u ma n 
pa pill o ma vir us ( H P V), 2) sa me- da y vis ual i ns pecti o n wit h acetic aci d ( VI A) f or 
w o me n w h o are hr- H P V p ositi ve, a n d 3) t her m oc oa g ulati o n f or VI A 
p ositi ve/a blati o n-eli gi ble ( b y cer vical c ol p osc o p y) w o me n. T his i n n o vati ve 
strate g y li n ks t w o ne w tec h n ol o gies ( X pert H P V a n d t her m oc oa g ulati o n) wit h 
self-c ollecte d br us h. It has n ot bee n ri g or o usl y e val uate d a m o n g w o me n, 
i ncl u di n g HI V- p ositi ve w o me n at hi g hest ris k f or I C C. We h y p ot hesize t hat 
> 9 0 % of w o me n w h o are H P V- p ositi ve wi ll ha ve VI A perf or me d sa me- da y a n d 
t hat > 9 0 % of w o me n w h o are VI A- p ositi ve/a blati o n-eli gi ble ( b y c ol p osc o p y) will 
ha ve t her m oc oa g ulati o n pe rf or me d t he sa me da y. 
1. 2  
B ac k gr o u n d 
I n vasi ve cer vical ca ncer (I C C) is t he 2 n d m ost c o m m o n ca ncer a m o n g w o me n 
li vi n g i n l o w-a n d- mi d dle-i nc o me c o u ntries ( L MI Cs)1, w here 8 4 % of t he 4 4 5, 0 0 0 
ne w cases dia g n ose d i n 2 0 1 2 occ urre d. 2 T hat sa me year, 2 7 0, 0 0 0 w o me n die d 
fr o m I C C, wit h > 8 5 % of t hese deat hs occ urri n g i n L MI Cs. I C C is pre ve nta ble 
wit h H P V vacci nati o n, cer vical ca ncer sc ree ni n g, a n d treat me nt of cer vical 
d ys plasia. 3 H o we ver, L MI Cs ha ve relati vel y p oor utilizati o n of t hese pre ve nti o n 
strate gies beca use t he y are diffic ult t o access a n d i m ple me nt, a n d re q uire trai ne d 
pr o vi ders i n setti n gs w here maj or s h orta ge s of s kille d healt hcare w or kers alrea d y 
e xist. T hese c halle n ges are c o m p o u n de d i n S u b- Sa hara n Africa ( S S A), t he 
e pice nter of t he HI V e pi de mic, si nce HI V- p ositi ve w o me n ha ve > 2 0-f ol d 
i ncrease d ris k of I C C t ha n HI V- ne gati ve w o me n.4 I C C is t he m ost c o m m o n 
ca ncer a m o n g w o me n i n S S A a n d Mala wi , wit h t he b ur de n dis pr o p orti o natel y 
b or ne b y HI V- p ositi ve w o me n. 2, 5 
 
Mala wi has t he w orl d’s hi g hest I C C m ortal it y a n d is o ne of t he w orl d’s p o orest 
c o u ntries. 2, 6 Mala wi’s esti mate d HI V pre vale nce is 1 1 % a m o n g fe males a ge 1 5-
4 9 years, a n d H P V pre vale nce a m o n g HI V- p ositi ve w o me n is esti mate d at 3 9 %. 7, 8 
D ue t o t he c halle n ges of i m ple me nti n g a n H P V vacci nati o n pr o gra m, t he H P V 
vacci ne is n ot rea dil y a vaila ble i n p u blic  pr o gra ms i n Mala wi. E ve n if wi des prea d 
H P V vacci nati o n of girls is ac hie ve d i n Mala wi, milli o ns of Mala wia n fe males 
will re mai n u n vacci nate d or a g e i neli gi ble si nce o nl y girls a ge d 9- 1 3 years will be 
vacci nati o n-eli gi ble, 9 a n d a s u bse q ue nt decli ne i n I C C i nci de nce will n ot occ ur f or 
deca des, lea vi n g milli o ns of Mala wia n  w o me n v ul nera ble t o de vel o pi n g I C C. 

L C C C 1 9 0 5 
 
C O N FI D E N TI A L 
PI: L a mec k C hi n ul a 
  
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/ D ate: 5. 0, 1 8 Dec 2 0 2 0 
 
Dec 1 8, 2 0 2 0 
 
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1. 3  
P ur p ose a n d R ati o n ale 
F or L MI Cs, t he W orl d Healt h Or ga nizati o n ( W H O) prefere ntiall y rec o m me n ds a n 
I C C scree ni n g a p pr oac h of: 1) hr- H P V testi n g, 2) tria ge of hr- H P V p ositi ve 
w o me n b y VI A, a n d 3) cr y ot hera p y treat m e nt f or VI A p ositi ve/a blati o n-eli gi ble 
w o me n (see defi niti o n bel o w). 1 0 Mala wi a d o pte d a n a p pr oac h of VI A scree ni n g 
a n d cr y ot hera p y treat me nt i n 2 0 0 4, si nce ra pi d a n d i ne x pe nsi ve hr- H P V testi n g 
was n ot yet a vaila ble. 1 1 Cr y ot hera p y has bee n c hallen gi n g t o i m ple me nt, wit h 
< 2 5 % VI A ce nters wit h esta blis he d cr y ot hera p y a n d > 5 0 % of w o me n w h o re q uire 
treat me nt n ot recei vi n g it, lar gel y d ue t o t he hi g h c ost of refri gera nt gas a n d hea v y 
gas c yli n der, w hic h are diffic ult t o o btai n a n d tra ns p ort. 1 2 L oss-t o-f oll o w- u p f or 
VI A- p ositi ve w o me n referre d t o ce nters wit h cr y ot hera p y has als o bee n a 
c halle n ge. A scree n-a n d-treat a p pr oac h, i.e.  sa me da y scree ni n g a n d treat me nt at 
t he sa me site, greatl y re d uces l oss-t o-f oll o w- u p.  
 
Cer vical t her m oc oa g ulati o n (a ka c ol d c o a g ulati o n) is a n alter nati ve a blati ve 
treat me nt f or hi g h- gra de cer vical d ys plasia, k n o w n as cer vical i ntrae pit helial 
ne o plasia ( CI N) gra de 2 + (i.e. CI N 2 or  m ore se vere), w hic h i ncl u des CI N 2/ 3, 
carci n o ma i n sit u ( CI S), t he prec urs ors t o  I C C. It was first i ntr o d uce d i n 1 9 6 6 a n d 
use d i n t he U nite d Ki n g d o m i n t he 1 9 8 0s. 1 3 – 1 5 T her m oc oa g ulati o n uses 
t her m os o u n d pr o bes, w hic h are a p plie d seriall y t o destr o y cer vical lesi o ns, usi n g 
pre-selecte d te m perat ures of u p t o 1 2 0° C . I n c o ntrast t o electr o diat her m y, it 
pr o d uces n o s m o ke, a n d t heref or e, n o s mell. A meta-a nal ysis o n t he efficac y of 
t her m oc oa g ulati o n s h o we d t hat cer vical d ys plasia c ure rates were c o m para ble t o 
ot her e xcisi o nal a n d a blati ve trea t me nt met h o ds i n use w orl d wi de.1 6 Des pite 
re p orts of efficac y a gai nst all gra des of cer vical d ys plasia a n d i nfre q ue nt mi ni mal 
si de effects, t her m oc oa g ulati o n has bee n i nfre q ue ntl y use d si nce t he 1 9 8 0s 
beca use it was re place d b y e x cisi o nal met h o ds t hat are rea dil y a vaila ble i n hi g h-
i nc o me c o u ntries, a n d its use was ne ver e x pa n de d t o L MI Cs.1 6 I n t he sa me meta-
a nal ysis, 1 6 n o ne of t he st u dies were fr o m S S A, a n d all st u dies e val uate d t he use of 
t her m oc oa g ulati o n a m o n g p h ysicia ns, m ostl y g y nec ol o gists, w hic h is i m practical 
f or c o u ntries s uc h as Mala wi, w hic h has less t ha n 2 0 trai ne d g y nec ol o gists f or a 
c o u ntr y of 1 9 milli o n. 6 H o we ver, t her m oc oa g ulati o n is t he m ost i m ple me nta ble 
treat me nt m o dalit y f or CI N 2/ 3 f or L MI C, d ue t o ease of use b y mi d-le vel 
pr o vi ders, a n d t he pre vi o usl y- me nti o ne d c halle n ges face d wit h cr y ot hera p y. 1 7 
C urre ntl y, sec o n d- ge nerati o n Li ger T her m oc o a g ulat or ( Le hi, U T), a ha n d hel d a n d 
batter y- o perate d t her m oc o a g ulati o n de vice t hat ca n treat ar o u n d 2 0 – 3 0 w o me n 
per batter y life a n d w hic h ta kes 2 0- 4 0 s ec o n ds per treat me nt ma ki n g it m o bile a n d 
attracti ve f or use i n L MI Cs is a vaila ble. H o we ver, t here are li mite d data o n t he 
efficac y of t her m oc oa g ulati o n i n S S A, w here treat me nt is t y picall y d o ne b y mi d-
le vel pr o vi ders (rat her t ha n g y nec ol o gists), a n d w here HI V pre vale nce is hi g h. 
Des pite t his, S S A c o u ntries i ncl u di n g Mala wi ha ve starte d a d o pti n g 
t her m oc oa g ulati o n f or treat me nt of cer vical d ys plasia, d ue t o c halle n ges wit h 
cr y ot hera p y, w hic h are li miti n g a vaila bil it y of treat me nt f or w o me n w h o scree n 
p ositi ve. 

L C C C 1 9 0 5 
 
C O N FI D E N TI A L 
PI: L a mec k C hi n ul a 
  
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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T he X pert H P V Assa y ( Ce p hei d, I nc., S u n n y vale, C A), is a q ualitati ve real-ti me 
p ol y merase c hai n reacti o n assa y t hat uses  dis p osa ble cartrid ges t o detect D N A 
fr o m 1 4 differe nt hr- H P V strai ns.1 8, 1 9 T he assa y is r u n o n t he Ce p hei d Ge ne X pert 
S yste m, w hic h is a scala ble i nstr u me nt platf or m t hat ca n r u n si m ulta ne o us b ut 
as y nc hr o n o us assa ys f or t he sa me or diffe re nt assa ys, de pe n di n g o n t he cartri d ge. 
U nli ke pre vi o us H P V assa ys, w hic h re q uire d s kille d la b orat or y pers o n nel, 
batc hi n g of m ulti ple sa m ples, a n d se veral h o urs t o c o m plete, t he X pert H P V 
Assa y all o ws f or a si n gle sa m ple t o be r u n, wit h res ults wit hi n 1- 2 h o urs of 
testi n g.1 8 T he Ce p hei d Ge ne X pert S yste m ca n be use d f or p oi nt- of-care testi n g f or 
H P V, t u berc ul osis ( T B), tric h o m o na s, g o n orr hea, c hla m y dia, a n d gr o u p B 
stre pt oc occ us. Gi ve n its m ulti ple uses a n d ra pi d t ur nar o u n d ti me, t he Ce p hei d 
Ge ne X pert mac hi nes ha ve rece ntl y bec o me wi del y a vaila ble i n S S A i ncl u di n g 
Mala wi, w here it is c urre ntl y use d f or p oi nt- of-care T B testi n g. Perf or ma nce of 
t he X pert H P V Assa y i n b ot h ge neral scree ni n g p o p ulati o ns a n d HI V- p ositi ve 
p o p ulati o ns is c o m para ble t o ot her c o m m erciall y-a vaila ble H P V assa ys, wit h 
si milar se nsiti vit y a n d s pecificit y, e ve n a m o n g self-c ollecte d br us h. 1 7- 1 9, 1 9 – 2 1. 
F urt her m ore H P V testi n g o n self- or cli nicia n-c ollecte d va gi nal sa m ples is m ore 
se nsiti ve t ha n VI A f or t he detecti o n of CI N 2 +, a n d I C C. 2 2 I ntr o d ucti o n a n d scale-
u p of H P V scree ni n g tests is n o w o ne pr i orit y acti o n i n t he I nter nati o nal 
Fe derati o n of G y nec ol o g y a n d O bstetrics  ( FI G O) Gl o bal Declarati o n o n cer vical 
ca ncer eli mi nati o n. 2 3 C o m bi ni n g t he use of X pert H P V ra pi d testi n g a n d n o vel 
strate g y of self-c ollecte d va gi nal s peci me n f or H P V testi n g c o ul d i m pr o ve 
w o me n’s scree ni n g partici pati o n as it a v oi ds a n i nitial  pel vic e xa m, all o ws f or 
sa me- da y H P V res ults, wit h si milar sensiti vit y a n d s pecificit y as pr o vi der-
c ollecte d va gi nal s peci me n f or detecti o n of CI N 2 +,2 2, 2 4 a n d is i n li ne wit h t he 
FI G O gl o bal declarati o n o n cer vical ca ncer eli mi nati o n. 2 3 
 
Ot her n o vel scree ni n g met h o ds ma y als o all o w f or sa me- da y  scree n-a n d-treat 
a p pr oac hes.  Rece ntl y, H P V D N A testi n g of  uri ne sa m ples has bee n i n vesti gate d 
as a p ossi ble scree ni n g m o dalit y. C ollecti n g uri ne sa m ples is less i n vasi ve t ha n 
cer vic o va gi nal sa m ples a n d uri ne H P V res ults  see m t o be c orrelate d wit h cer vical 
H P V res ults a n d pat h ol o g y fi n di n gs. 2 5, 2 6 T here is li mite d e x perie nce wit h X pert 
H P V testi n g of uri ne sa m ples. 2 7, 2 8 Be y o n d D N A testi n g, met h ylati o n le vels of 
se veral h u ma n ge nes a n d H P V ge n ot y pes ha ve bee n f o u n d t o be str o n gl y 
ass ociate d wit h t he de vel o p me nt of CI N 2/ 3 or I C C. 2 9 T heref ore, meas uri n g 
met h ylati o n le vels has p ote ntial use as b ot h a pri mar y scree ni n g met h o d as well as 
a tria ge met h o d t o i m pr o ve t he s pecificit y  a n d p ositi ve pre dicti ve val ue ( P P V) f or 
CI N 2 + detecti o n i n H P V- p ositi ve w o me n. 2 9 T he S 5 D N A met h ylati o n classifier 
c o m bi nes testi n g f or met h ylati o n of tar g et re gi o ns of t he h u ma n t u m or s u p press or 
ge ne E P B 4 1 L 3 a n d t he viral late ge ne re gi o ns of o nc o ge nic H P V t y pes 1 6, 1 8, 3 1, 
a n d 3 3. 3 0 T o date, t he S 5 has bee n vali date d as a tria ge met h o d f or H P V- p ositi ve 
w o me n a m o n g lar gel y HI V- ne gati ve w o me n, wit h pr o misi n g fi n di n gs. 2 9- 3 2 T he S 5 

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classifier has n ot bee n vali date d wit h ur i ne sa m ples, w hic h as disc usse d are less 
i n vasi ve t o c ollect.  
 
M o bile O D T E V A s yste m de vel o pe d b y M o bile O ptical Detecti o n Tec h n ol o gies 
c o m bi nes t he f u ncti o nalities of a c ol p os c o p y a n d di gital ca mera. T he E V A s yste m 
is use d f or vis ual e xa mi nati o ns a n d d oc ume ntati o n i n m ulti ple cli nical setti n gs 
i ncl u di n g e xa mi nati o n of t he cer vi x. T he E V A s yste m all o ws t he st ora ge of 
i nf or mati o n ca pt ure d b y t he de vice i n a n o nli ne sec ure d, a n d Healt h I ns ura nce 
P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A) ( HI P P A A)-c o m plia nt cl o u d st ora ge 
w hic h is h oste d b y A maz o n we b ser vices. T he E V A s yste m is e ncr y pte d u p o n set-
u p, a n d a PI N n u m ber or pass w or d is use d t o access t he p h o ne. T he s yste m 
pr o vi des a platf or m f or e xter nal q ualit y ass ura nce f or fi n di n gs i de ntifie d d uri n g 
vis ual e xa mi nati o n of t he cer vi x. 3 3 
 
We t heref ore pla n t o e val uate a n o vel scree n-a n d-treat al g orit h m a m o n g w o me n, 
i ncl u di n g HI V p ositi ve w o me n, i n Lil o n g we, Mala wi f or t he detecti o n a n d 
treat me nt of hi g h- gra de cer vical d ys plasia wit h t he f oll o wi n g c o m bi nati o n of 
strate gies: 1) ra pi d testi n g of self-c ollecte d va gi nal br us h f or hr- H P V, 2) sa me- da y 
VI A f or w o me n w h o are hr- H P V p ositi ve, a n d 3) t her m oc oa g ulati o n f or VI A-
p ositi ve/a blati o n-eli gi ble ( b y c ol p osc o p y wit h M o bile O D T E V A s yste m) w o me n. 
T his i n n o vati ve a p pr oac h has n ot yet b ee n ri g or o usl y e val uate d a m o n g w o me n, 
i ncl u di n g t h ose li vi n g wit h HI V. T heref ore, t his st u d y will pr o vide esse ntial data 
t o i nf or m nati o nal p olic y i n Mala wi an d ot her L MI Cs w here b ot h HI V a n d I C C 
pre vale nce are hi g h. If s uccessf ul, o ur a p pr oac h is ar g ua bl y t he m ost br oa dl y-
scala ble strate g y t o o pti mize I C C scree ni n g i n c o u ntries  w here t he pr o p orti o n of 
w o me n scree ne d re mai ns l o w a n d I C C pre vale nce is hi g h. 
 
2. 0  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S  
2. 1  
Pri m ar y O bjecti ves 
2. 1. 1. T o assess c o m pleti o n of a n o ve l I C C scree n-a n d-treat strate g y a m o n g 
w o me n i n Lil o n g we, Mala wi, usi n g self -c ollecte d va gi nal br us h f or hr- H P V 
testi n g, f oll o we d b y sa me- da y VIA a n d t her m oc oa g ulati o n f or H P V-
p ositi ve/ VI A- p ositi ve/a blati o n-eli gi ble ( b y c ol p osc o p y) w o me n.  
2. 1. 2. T o deter mi ne t he 2 4- wee k effic ac y of t her m oc oa g ulati o n a m o n g w o me n, 
i ncl u di n g HI V- p ositi ve w o me n, wit h CI N 2/ 3. 
2. 2  
Sec o n d ar y O bjecti ves 
2. 2. 1. T o e val uate perf or ma nce of t h e pr o p ose d I C C scree n-a n d-treat strate g y 
a m o n g w o me n, i ncl u di n g HI V- p ositi ve w o me n, b y esti mati n g o vertreat me nt f or 
w o me n w h o are H P V- p ositi ve/ VI A- p ositi ve/a blati o n-eli gi ble, a n d u n dertreat me nt 
a m o n g H P V- p ositi ve/ VI A- ne gati ve w o me n.  

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3. 2. 7. Partici pa nts w h o are less t ha n 1 2 wee ks p ost part u m. 
3. 2. 8. Partici pa nts wit h ot her ill nesse s t hat w o ul d li mit c o m plia nce wit h st u d y 
re q uire me nts or i n t he o pi ni o n of t he i n vesti gat or or desi g nee, ha ve a pr o ble m t hat 
w o ul d ma ke partici pati o n i n  t he st u d y u nsafe, or c o m plicate i nter pretati o n of 
st u d y fi n di n gs.  
 
4. 0  
S T U D Y P L A N 
4. 1  
Sc he m a 
 
 
 
 

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T his is a si n gle ar m, pr os pecti ve st u d y of 1, 2 5 0 w o me n, c o m prisi n g of 6 2 5 HI V-
p ositi ve a n d 6 2 5 HI V- ne gati ve w o me n, i n Lil o n g we, Mala wi. T he pri mar y 
p ur p ose of t his st u d y is t o assess c o m pleti o n a n d perf or ma nce of a n o vel I C C 
scree n-a n d-treat strate g y a m o n g w o me n i n Lil o n g we, Mala wi, usi n g self-c ollecte d 
va gi nal br us h f or hr- H P V testi n g, f oll o we d b y sa me- da y VI A a n d 
t her m oc oa g ulati o n f or H P V- p ositi ve/ VI A- p ositi ve/a blati o n-eli gi ble ( b y 
c ol p osc o p y) w o me n. We a ntici pate t hat al l partici pa nts will be e nr olle d o ver 1 2 
m o nt hs a n d t hat acti ve partici pati o n will c o nti n ue f or u p t o 3 0 wee ks at m ost.  
4. 2  
D ur ati o n of St u d y 
St u d y partici pa nts will ha ve f o ur sc he d ule d st u d y visits: Scree ni n g/ E nr oll me nt, 
Wee k 4, Wee k 2 4, a n d Wee k 2 8. At Sc ree ni n g/ E nr oll me nt, w o me n will c o m plete 
a n i nter vie wer-a d mi nistere d baseli ne q uesti o n naire, uri ne pre g na nc y testi n g, HI V 
ra pi d fi n ger stic k testi n g, a n d bl o o d f or C D 4 + T cell c o u nt a n d HI V- 1 R N A 
testi n g f or HI V p ositi ve partici pa nts, a n d will self-c ollect a va gi nal br us h f or hr-
H P V testi n g. Uri ne c ollecte d f or pre g na nc y testi n g will als o be se nt f or hr- H P V 
a n d S 5 met h ylati o n testi n g (f or resear c h p ur p oses o nl y). H P V- p ositi ve w o me n 
a n d e ver y 1 0 t h c o nsec uti ve H P V- ne gati ve w o ma n will c o m plete sa me- da y VI A 
wit h c ol p osc o picall y- directe d cer vical bi o ps y a n d e n d ocer vical c uretta ge ( E C C) 
(if lesi o n see n), a n d t her m oc oa g ulati o n if a blati o n-eli gi ble b y c ol p osc o p y. If n o 
lesi o n is see n o n c ol p osc o p y, t he w o ma n will ha ve a cer vical pa p s mear a n d E C C 
c ollecte d, a n d n o t her m oc oa g ulati o n will be perf or me d. Fi nall y, w o me n w h o are 
s us pici o us f or ca ncer at VI A will u n derg o c ol p osc o picall y- directe d cer vical 
N B: I n t hese fi g ures, N = 6 2 5 is t he o nly n u m be r t h at is fixe d. T he rest of t he n u m bers 
are ass u m pti o ns b ase d o n very li mite d d at a w here av ail a ble. 

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bi o psies. All w o me n w h o u n der g o s pec ul u m e xa m will u n der g o pr o vi der-
c ollecte d cer vical s wa b, w hic h will be se nt  f or hr- H P V a n d S 5 met h ylati o n testi n g 
(f or researc h p ur p oses o nl y). 
 
All w o me n w h o ha d cer vical bi o ps y or cer vical pa p s mear a n d E C C d o ne at 
Scree ni n g/ E nr oll me nt will ret ur n at Wee k 4 f or hist ol o g y a n d/ or c yt ol o g y res ults. 
All w o me n w h o ha d CI N 1, CI N 2, or CI N 3 a n d u n der we nt t her m oc oa g ulati o n will 
be as ke d t o ret ur n f or a f oll o w- u p visit at Wee k 2 4 p ost-treat me nt t o assess f or 
res ol uti o n of t heir H P V a n d cer vical d ys plasia. At Wee k 2 8 visit, w o me n will 
recei ve t heir hist ol o g y a n d/ or c yt ol o g y res ults a n d be referre d as necessar y. 
4. 3  
St u d y Det ails 
St u d y site 
T he st u d y will be c o n d ucte d at U N C Pr oject- Mala wi Ti dzi we Ce ntre.  
 
Recr uit me nt 
We will recr uit w o me n fr o m Fa mil y Pla n ni n g cli nics, U n der- 5 Cli nics, O ut patie nt 
De part me nts,  a n d  A R T  cli nics  (f or  HI V- p ositi ve  partici pa nts)  at  facilities  i n  
Lil o n g we b y c o n d ucti n g e d ucati o nal tal ks a b o ut cer vical ca ncer a n d t he st u d y i n 
t heir waiti n g areas. We will sc he d ule a scree ni n g a n d e nr oll me nt visit f or p ote ntial 
partici pa nts i ntereste d i n j oi ni n g t he st u d y at U N C Pr oject- Mala wi, w hic h is wit hi n 
a 1 5- 3 0 mi n ute dri ve fr o m t he tar gete d cli n ics. T here, w o me n will be as ke d t o 
pr o vi de writte n i nf or me d c o ns e nt a n d scree ne d f or eli gi bilit y t o partici pate i n t he 
st u d y. U p t o t hirt y w o me n will be recr uite d f or i n- de pt h i nter vie ws (I DIs) a b o ut 
t heir e x perie nces wit h t he pr o p ose d scree n-a n d-treat strate g y . T he H P V- ne gati ve 
w o me n will be recr uite d at t he Scree ni n g/ E nr oll me nt visit w hile t he H P V- p ositi ve 
w o me n ma y be recr uite d at t he Scree ni n g/ E nr oll me nt visit or t he Wee k 4 visit.  
Tra ns p ort rei m b urse me nt will be pr o vi de d t o partici pa nts  atte n di n g st u d y visits t o 
miti gate partici pa nts’ e x pe nses  f or t he st u d y-relate d visits.  
 
Scree ni n g & E nr oll me nt 
W o me n will be e nr olle d i n Lil o n g we, Mala wi, a cit y wit h a p o p ulati o n of 9 0 0, 0 0 0. 3 4 
Partici pa nts will c o m plete a n i nter vie we r-a d mi nistere d baseli ne q uesti o n naire t o 
c ollect s oci o- de m o gra p hic data a n d cer vical  ca ncer ris k fact ors. Baseli ne e val uati o n 
will i ncl u de uri ne pre g na nc y testi n g, HI V ra pi d fi n ger stic k testi n g, a n d bl o o d f or 
C D 4 + T cell c o u nt a n d HI V- 1 R N A testi n g f or HI V- p ositi ve w o me n. Uri ne sa m ples 
c ollecte d  f or  pre g na nc y  testi n g  will  als o  u n der g o  X pert  H P V  testi n g  a n d  S 5  
met h ylati o n testi n g. T hese uri ne tests are o nl y f or researc h p ur p oses a n d res ults will 
n ot i nfl ue nce patie nt ma na ge me nt. 
 
 W o me n will recei ve si m ple i nstr ucti o ns o n h o w t o self-c ollect a cer vic o va gi nal 
sa m ple wit h va gi nal br us h f or hr- H P V testi n g i n t he researc h cli nic, usi n g well-
vali date d,  fiel d-teste d  ill ustrate d  i nstr ucti o ns  t hat  are  c o m pre he nsi ble  t o  l o w-
literac y w o me n.3 5, 3 6 T he self-c ollecti o n kit will c o ntai n a va gi nal br us h a n d vial of 

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sa m ple preser vati o n s ol uti o n. Partici pa nts will t he n c ollect t his br us h, w hic h will 
be teste d o nsite usi n g X pert H P V testi n g.  H P V- ne gati ve w o me n will be a d vise d t o 
c o nti n ue wit h r o uti ne I C C scree ni n g per Mala wi Cer vical Ca ncer G ui deli nes. 1 1 
H P V- p ositi ve w o me n will c o m plete sa me- da y  VI A, usi n g 3- 5 % acetic aci d o n t he 
cer vi x  f or  at  least  1  mi n ute,  t he n  o bs er vi n g  f or  c ol or  c ha n ges  i n dicati n g  t he  
prese nce of a lesi o n, as descri be d i n t he W H O I A R C Ma n ual. 3 7 We will als o 
perf or m  sa me- da y  VI A  o n  e ver y  1 0t h  c o nsec uti ve  w o ma n  f o u n d  t o  be  H P V-
ne gati ve t o assess f or p os si ble u n derscree ni n g wit h self- H P V testi n g. 
 
All w o me n w h o u n der g o s pec ul u m e xa m wi ll ha ve a pr o vi der-c ollecte d s wa b 
perf or me d, w hic h will be se nt f or hr- H P V a n d S 5 met h ylati o n testi n g. T he res ults 
fr o m t hese tests will be use d t o hel p e valuate t he vali dit y of uri ne hr- H P V a n d S 5 
testi n g; t he y will n ot be use d t o i nfl ue nce patie nt ma na ge me nt. 
 
F or all w o me n w h o u n der g o VI A, we will deter mi ne if a w o ma n is VI A- p ositi ve 
a n d a blati o n-eli gi ble usi n g c ol p osc o p y wit h M o bile O D T E V A s yste m. W o me n 
w h o  are  VI A- p ositi ve  will  u n der g o  c ol p osc o picall y- directe d  bi o psies  of  t he  
acet o w hite lesi o n, wit h at least 2 a n d u p t o 4 bi o psies ta ke n, as well as a n E C C. If 
t he w o ma n is still c o nsi dere d t o be a blati o n-eli gi ble b y c ol p osc o p y, s he will t he n 
u n der g o  t her m oc oa g ulati o n.  W o me n  w h o  are  VI A- ne gati ve  will  als o  u n der g o  
c ol p osc o p y, a n d at least 2 a n d u p t o 4 cer vi cal bi o psies a n d E C C if a lesi o n is see n 
at c ol p osc o p y. T her m oc oa g ulati o n will als o be perf or me d o n t hese w o me n if t he y 
are f o u n d t o ha ve a n a blati o n-eli gi ble lesi o n o n c ol p os c o p y. If n o lesi o n is see n o n 
c ol p osc o p y, t he w o ma n will ha ve cer vic al pa p s mear a n d E C C c ollecte d, a n d n o 
t her m oc oa g ulati o n will be perf or me d. W o me n w h o are s us pici o us f or ca ncer at 
VI A will u n der g o c ol p osc o picall y- directe d cer vical bi o psies. W he ne ver bi o ps y is 
i n dicate d, we will perf or m at least 2 cervical bi o psies o n w o me n beca use pre vi o us 
st u dies ha ve s h o w n t hat cer vical bi o ps y is m ost se nsiti ve w he n at least 2 bi o psies 
are ta ke n. 3 3 D uri n g c ol p osc o p y, i ma ges of t he cer vi x ma y be ca pt ure d wit h t he E V A 
s yste m. T hese i ma ges will be st ore d o nl y i n pass w or d- pr otecte d a n d de-i de ntifie d 
st u d y data bases, li n ke d o nl y t o t he st u d y partici pa nt PI D. T he i ma ges will be use d 
f or i nter nal q ualit y ass ura nce a n d ma y als o be s har e d wit h t he s p o ns or or ot her 
parties f or researc h p ur p oses. 
 
F or w o me n t o u n der g o t her m oc oa g ulati o n, we will c o nsi der t he m t o be a blati o n-
eli gi ble if t he f oll o w i n g criteria are met at c ol p osco p y: 1) cer vical lesi o ns are n ot 
s us pici o us f or I C C; 2) cer vical lesi o ns are l ocate d e ntirel y o n t he ect ocer vi x; 3) 
cer vical lesi o ns are n o m ore t ha n 2- 3 m m i n t o t he e n d ocer vical ca nal; 4) t he e ntire 
s q ua m oc ol u m nar j u ncti o n ( S CJ) ca n be vis ualize d; a n d 5) all visi ble lesi o ns are 
dee me d a p pr o priate f or t her m oc oa g ulati o n b y t he treati n g pr o vi der. 1 0 W o me n wit h 
s us pecte d e n d ocer vical d ys plasia, CI S, or I C C will be referre d f or treat me nt at t he 
Ka m uz u  Ce ntral  H os pital  ( K C H),  a  p u bl ic  tertiar y  a n d  teac hi n g  h os pital  
C ol p osc o p y Cli nic o n w hic h ca m p us U N C Pr oject- Mala wi is sit uate d. 
 

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F or t he I DIs, u p t o 3 0 w o me n will be e nr o lle d at eit her t he Scree ni n g/ E nr oll me nt 
visit or Wee k 4 visit (if t he y are H P V- p ositi ve). H P V- ne gati ve w o me n will o nl y be 
e nr olle d if t he y were n ot selecte d t o u n der g o VI A. Partici pa nts  will be c o nse nte d 
f or t he I DIs se paratel y fr o m t heir mai n c o nse nt f or t he st u d y. W o me n will pri maril y 
be recr uite d at c hec k- o ut a n d all i nter v ie ws will be c o n d ucte d after w o me n ha ve 
c o m plete d t he scree n-a n d-treat al g orit h m. T he I DIs will be c o n d ucte d i n t he l ocal 
la n g ua ge, C hic he wa, i n pri vate r o o ms at U N C Pr oject Mala wi. W o me n will be 
offere d t he c h oice t o ha ve t he i nter vie w c o n d ucte d off site (e. g., i n t he c o mf ort of 
t heir h o me or s o me pri vate off site place, if t he y prefer). T he i nter vie w will i ncl u de 
use of a n i nter vie wer-a d mi nistere d q ue sti o n naire e val uati n g w o me n’s rati n g of 
t heir  pri vac y,  e m barrass me nt,  disc o mf ort,  pai n,  a n d  c o nfi de nce  d uri n g  t he  
scree ni n g/treat me nt  pr ocess.  T he  I DIs  will  c o ver  pri or  k n o wle d ge  of  cer vical  
ca ncer,  e x perie nce  wit h  t he  self-sa m pli n g,  u n dersta n di n g  of  t he  res ults,  a n d  
i nte nti o n t o s hare t heir scree ni n g e x perie nce wit h ot hers. 
 
Wee k 4 
All w o me n w h o ha d cer vical bi o psies or cer vical pa p s mear, a n d E C C d o ne at 
Scree ni n g/ E nr oll me nt will ret ur n f or hist ol o g y a n d/ or c yt ol o g y res ults at Wee k 4. 
H P V- p ositi ve/ VI A- ne gati ve w o me n wit h o ut  CI N or I C C o n hist ol o g y a n d t h ose 
wit h n or mal c yt ol o g y will be a d vise d t o c o nti n ue wit h r o uti ne I C C scree ni n g per 
g ui deli nes.  W o me n  w h o  u n der we nt  t her m o c oa g ulati o n  will  be  e val uate d  f or  
i nter val me dical hist or y or p ost-treat me nt a d verse e ve nts d uri n g t his visit. H P V-
p ositi ve/ VI A- ne gati ve  w o me n  wit h  CI N 2 +  o n  E C C  or  a b n or mal  c yt ol o g y  o n  
cer vical  pa p  s mear  will  be  referre d  t o  K C H  C ol p osc o p y  Cli nic  f or  f urt her  
ma na ge me nt.  
 
H P V- p ositi ve/ VI A- p ositi ve  w o me n  w h o  ha d  CI N  detecte d  at  baseli ne  cer vical  
bi o ps y, a n d u n der we nt t her m oc oa g ulati o n will be f oll o we d u p at Wee k 2 4 p ost- 
treat me nt. W o me n w h o ha d CI N a n d visi ble cer vical lesi o n t hat was n ot a blati o n-
eli gi ble b y c ol p osc o p y or ha d I C C will be  referre d t o K C H C ol p osc o p y cli nic f or 
f urt her ma na ge me nt. 
 
W o me n w h o are H P V- p ositi ve ma y be e nr olle d i n a n d c o nse nte d f or I DIs at t heir 
Wee k 4 visit. T hese i nter vie ws will be c o n d ucte d si milarl y t o t h ose d o ne at t he 
Scree ni n g/ E nr oll me nt visit b ut t he y will als o c o ver w o me n’s e x perie nces s hari n g 
t heir scree ni n g res ults wit h ot hers a n d a bstai ni n g fr o m se x f or t he rec o m me n de d 
i nter val after bi o ps y/t her m oc oa g ulati o n. 
 
Wee k 2 4 
All w o me n treate d b y t her m oc oa g ulati o n a n d ha d CI N 1 + detect e d b y baseli ne 
cer vical bi o ps y will ret ur n at Wee k 2 4 f or c ol p osc o p y t o assess f or res ol uti o n of 
cer vical d ys plasia after t her m oc oa g ulati o n. H P V testi n g o n a pr o vi der-c ollecte d 
va gi nal br us h will als o be perf or me d at W ee k 2 4 t o assess f or H P V res ol uti o n after 
t her m oc oa g ulati o n. If t he c ol p osc o p y s h o ws n o visi ble lesi o ns at t his Wee k 2 4 visit, 

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cer vical pa p s mear a n d E C C will be c ollecte d. If a lesi o n is o bser ve d d uri n g 
c ol p osc o p y, at least 2 b ut n ot m ore t ha n  4 directe d bi o psies a n d E C C will be 
perf or me d. I ma ges ma y be ca pt ure d via t h e E V A S yste m. T hese i ma ges will be 
st ore d o nl y i n pass w or d- pr otecte d a n d de-ide ntifie d st u d y data bases, li n ke d o nl y t o 
t he st u d y partici pa nt PI D. T he i ma ges will be use d f or i nter nal  q ualit y ass ura nce 
a n d p ossi bl y s hare d i n de-i de ntifie d f or m f or f ut ure researc h. All w o me n w h o still 
ha ve CI N 2/ 3 or ha ve de vel o pe d CI S or I C C at Wee k 2 4 will be referre d t o K C H 
f or a d diti o nal ma na ge me nt. W o me n will als o be e val uate d f or c ha n ges i n t heir 
i nter val me dical hist or y a n d p ost-treat me nt a d verse e ve nts d uri n g t his visit. Fi nall y, 
all w o me n w h o were referre d t o K C H C o l p osc o p y Cli nic will be f oll o we d u p at 
t his visit t o e ns ure t hat t he y recei ve d t he care t he y re q uire d. 
 
Wee k 2 8 
All w o me n w h o ha d cer vical bi o ps y or cer vical pa p s mear, a n d E C C d o ne at Wee k 
2 4 will be as ke d t o ret ur n at t his visit f o r hist ol o g y a n d/ or c yt ol o g y res ults a n d a n y 
necessar y f oll o w- u p referrals t o K C H C ol p osc o p y Cli nic.  
 
Q u alit y Ass ur a nce  
Dr. Si o b ha n O’ C o n n or, a pat h ol o gist at U N C- C ha pel Hill, will re-re vie w all bi o ps y 
s peci me ns o btai ne d d uri n g t he st u d y as a q ualit y ass ura nce meas ure. S he will h ol d 
calls  as  nee de d  wit h  pat h ol o g y  staf f  at  U N C  Pr oject- Mala wi  t o  disc uss  
discre pa ncies bet wee n t heir s peci me n re vie ws. 
 
S a m ple st or a ge 
Partici pa nts’ st u d y-ass ociate d sa m ples will be  st ore d i n t he researc h la b orat or y at 
U N C Pr oject- Mala wi f or f ut ure researc h o n H P V i nfecti o n a n d ot her bi o mar kers of 
cer vical ca ncer t o i m pr o ve wa y t o scree n w o me n f or cer v ical ca ncer f or a ma xi m u m 
peri o d  of  1 5  years.  Sa m ples  will  be  st ore d  de-i de ntified  usi n g  o nl y  st u d y  
i de ntificati o n n u m ber wit h n o pers o nal i nf or mati o n. 
4. 4  
E x pecte d Ris ks 
T he f oll o wi n g are p ossi ble ris ks d ue t o partici pa nt e nr oll me nt i nt o o ur st u d y:  
 
4. 4. 1 Sa m ple c ollecti o n: Ris ks t o st u d y pa rtici pa nt i ncl u de t he p h ysical ris ks fr o m 
bl o o d dra w, va gi nal a n d cer vical sa m ple c o llecti o n, cer vical bi o psies, a n d E C C. 
Partici pa nts ca n e x perie nce pai n, blee di n g,  a n d s o meti mes i nfecti o n, a n d da ma ge 
t o tiss ue at t he site of t he sa m ple c ollecti o n. H o we ver, all t hese sa m ple c ollecti o ns 
are  d o ne  as  part  of  r o uti ne  cli nical  e v al uati o ns  w he n  i n dicate d  i n  w o me n  of  
re pr o d ucti ve a ge a n d are c o nsi dere d t o be mi ni mal ris ks.  
 
4. 4. 2 Treat me nt wit h t her m oc oa g ulati o n: Ri s ks i ncl u de pai n, i nfecti o n, a n d da ma ge 
t o  tiss ue  at  t he  site  of  treat me nt  a p plicati o n,  i.e.,  t he  cer vi x.  T hese  ris ks  are  
c o nsi dere d  mi ni mal.  T her m oc oa g ulati o n  is  n ot  ass ociate d  wit h  f ut ure  fertilit y  
c o m pr o mise
 or
 a d verse
 pre g na nc y
 o utc o mes
 i n
 f ut ure
 pre g na ncies.
 

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T her m oc oa g ulati o n  is  use d  f or  treati n g  VI A- p ositi ve  w o me n  i n  s o me  cer vical  
ca ncer scree ni n g pr o gra m s i ncl u di n g Mala wi. 
 
4. 4. 3 Ps yc h ol o gical ris ks mi g ht arise if a partici pa nt’s peer or part ner fi n ds o ut 
a b o ut her st u d y partici pati o n a n d d oes n ot a p pr o ve of it. I n a d diti o n, partici pa nts 
mi g ht als o ha ve s o me e m barrass me nt or disc o mf ort pr o vi di n g uri ne sa m ples; or 
a ns weri n g se nsiti ve q uesti o ns d uri n g t he s ur ve y, b ut t he y ca n o pt n ot t o a ns wer 
s uc h  q uesti o ns.  W o me n  w h o  partici pate  i n  t he  I DIs  ma y  ha ve  f urt her  ris k  of  
e m barrass me nt or disc o mf ort a b o ut a ns wer i n g se nsiti ve q uesti o ns, b ut t he y ca n o pt 
n ot t o a ns wer a n d t he y will be ass ure d t hat  d oi n g s o will n ot affect t heir a bilit y t o 
re mai n i n t he st u d y or recei ve necessar y healt h care. 
 
T o a d dress t hese ris ks, i nf or me d c o nse nt f or ms will be a d mi nistere d i n C hic he wa, 
t he l ocal nati o nal la n g ua ge t hat partici pa nts a n d st u d y staff are fl ue nt i n, a n d o nl y 
partici pa nts w h o de m o nstrate c o m pre he nsi o n t hr o u g h a sta n dar d c o m pre he nsi o n 
c hec klist will be e nr olle d i n t he st u d y after pr o vi di n g writte n i nf or me d c o nse nt. 
D uri n g t he i nf or me d c o nse nt pr ocess, partici pa nts will be c o u nsele d a b o ut t he 
p ote ntial ris ks, be nefits a n d si de effe cts of st u d y pr oce d ures. O nl y st u d y staff 
trai ne d i n t he Bi o me dical Researc h a n d G o o d Cli nical Practices will be i n v ol ve d i n 
t he  st u d y.  St u d y  pr oce d ures,  ris ks,  a n d  benefits  will  be  disc usse d  wit h  st u d y  
partici pa nts, a n d st u d y staff will a ns wer all q uesti o ns pri or t o o btai ni n g c o nse nt. 
Eac h w o ma n will be f ull y i n f or me d re gar di n g t he reas o na bl y f oreseea ble i m pact of 
t he researc h o n her circ u msta nces. 
 
P h ysical  ris ks  will  be  mi ni mize d  b y  ha vi n g  q ualifie d  a n d  e x perie nce d  staff  
c o n d ucti n g st u d y pr oce d ures. Ster ile tec h ni q ues will be ap plie d t o mi ni mize ris ks 
of i nfecti o n. T he St u d y C o or di nat or/ P h ysicia n a n d t he PI, w ill als o be a vaila ble t o 
ma na ge a n y c o m plicati o ns t hat ma y ar ise fr o m st u d y pr oced ures. Ps yc h ol o gical 
ris ks will be mi ni mize d b y e nc o ura gi n g p ote ntial partici pa nts t o discl ose t heir st u d y 
partici pati o n t o t heir part ners a n d b y mi ni mizi n g p h ysical traci n g of partici pa nts 
u nless it is u na v oi da ble, i n w hic h case we  will o nl y be usi n g i nf or mati o n t hat we 
recei ve d per missi o n fr o m t he partici pa nts t o use, partic ularl y w he n t here are safet y 
c o ncer ns. Pri or t o t he i nter vie wer-a d mi niste re d q uesti o n naire, partici pa nts will be 
i nstr ucte d t hat t he y ca n ch o ose n ot t o a ns wer a n y q uesti o ns t he y are n ot c o mf orta ble 
wit h. We will als o pr o vi de a p pr o priate c o u nseli n g f or HI V, se x uall y tra ns mitte d 
i nfecti o ns, a n d uri ne pre g na nc y testi n g t o mi ni mize a n y ris ks ass ociate d wit h t hese. 
Referral f or f urt her ser vices will als o be use d w here necessar y. 
 
I n a d diti o n, t he c o nfi de ntialit y of all st u d y rec or ds will be safe g uar de d t o t he e xte nt 
le gall y p ossi ble. All la b orat or y s peci me ns, re p orts, st u d y data, a n d data c ollecti o n 
f or ms will be i de ntifie d b y a partici pa nt I D n u m ber o nl y t o mai ntai n partici pa nt 
c o nfi de ntialit y.  All  data bases  will  be  sec ure d  wit h  pass w or d- pr otecte d  access  
s yste ms, a n d c o m p uter e ntries will be i de ntifie d b y partici pa nt I D o nl y. C o nse nts, 
t he  partici pa nt  I D  l o g  li n k,  a n d  a n y  ot her  data  f or ms  t hat  li n k  partici pa nt  I D  

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n u m bers  t o  ot her  i de ntif yi n g  i nf or mati o n  will  be  st ore d  i n  a  se parate,  l oc ke d  
ca bi net. T he I DIs will be a u di o-rec or de d after o btai ni n g i nf or me d c o nse nt fr o m t he 
partici pa nt f or t he i nter vie ws t o be rec or de d. T he rec or di n gs will be u pl oa de d t o a 
pass w or d- pr otecte d c o m p uter, a n d Data Ass o ciates will tra nscri be  a n d tra nslate t he 
rec or di n g i nt o a Micr os oft W or d d oc u me nt, w hic h will als o be pass w or d- pr otecte d.  
A n y di gital cer vical i ma ges  ca pt ure d d uri n g c ol p osc o p y will be st ore d o nl y i n 
pass w or d- pr otecte d a n d de-i de ntifie d st u d y data bases, li n ke d o nl y t o t he st u d y 
partici pa nt PI D. As me nti o ne d a b o ve, t hese i ma ges ma y be s hare d wit h s p o ns ors or 
part ners f or f ut ure researc h i n t o cer vical lesi o n dia g n ostics. 
 
All data a nal ysis will be d o ne o n datasets w hic h ha ve o nl y t he partici pa nt I D as a 
u ni q ue  i de ntifier.  Cli nical  i nf or mati o n  w it h  i n di vi d ual  i de ntifiers  will  n ot  be  
release d  wit h o ut  t he  written  per missi o n  of  t h e  partici pa nt.  We  e x pect  t hese  
pr oce d ures t o a de q uatel y pr otect partici p a nt c o nfi de ntialit y. H o we ver, it is p ossi ble 
t hat  a  partici pa nt’s  st u d y  partici pati o n, HI V  or  ca ncer  scree ni n g  stat us  c o ul d  
bec o me  k n o w n  t o  pe o ple  i n  t he  c o m m u n it y  a n d  ma y  res ult  i n  sti g ma  or  
discri mi nati o n. S h o ul d t hat occ ur, st u d y staff will w or k wit h t he partici pa nt a n d 
his/ her  fa mil y  as  a p pr o priate  t o  res ol v e  t he  sit uati o n  i n  w hate ver  ma n ner  is  
preferre d. All st u d y pr oce d ur es carr y mi ni mal ris ks. 
 
Data c ollecti o n f or ms, electr o nic data bases,  a n d pri nte d data will o nl y be s u p plie d 
t o a p pr o priate st u d y staff o n a n as- nee de d basis. A n y p u bli cati o n a b o ut t his researc h 
st u d y will o mit na mes a n d a n y ot her pers o nall y i de ntifia ble i nf or mati o n. H o we ver, 
i n di vi d uall y i de ntifia ble pri vate i nf or mati o n ma y be re vie we d b y t he f oll o wi n g 
gr o u ps t o m o nit or t he c o n d uct of t he st u d y a n d partici pa nt safet y: T he Mi nistr y of 
Healt h  of  Mala wi,  t he  Mala wi  Nati o nal  Healt h  Scie nces  Researc h  C o m mittee  
( N H S R C), a n d t he U N C I R B. 
4. 5  
P artici p a nt Rete nti o n 
O nce a partici pa nt is e nr olle d, st u d y staff will ma ke e ver y eff ort t o retai n t he 
partici pa nt f or t he pr ot oc ol-s pecifie d d urati o n of f oll o w- u p t here b y mi ni mizi n g 
p ote ntial biases ass ociate d wit h l oss t o f oll o w- u p. O nl y partici pa nts w h o 
de m o nstrate u n dersta n di n g t hr o u g h t he c o m pre he nsi o n assess me nt c o n d ucte d 
d uri n g t he i nf or me d c o nse nt pr ocess, i ncl u di n g w hat wi ll be e x pecte d of t he m 
d uri n g st u d y partici pati o n, w ill be e nr olle d i n t he st u d y. 
 
T o mi ni mize l oss-t o-f oll o w- u p, all partic i pa nts w h o re q uire f oll o w- u p visits will 
be pr o vi de d wit h a n a p p oi nt me nt car d w it h a date of t heir ne xt visit a n d t he 
c o ntact n u m bers of o ur st u d y staff. We will c o nti n u o usl y c o u nsel partici pa nts 
a b o ut t he i m p orta nce of a d heri n g t o t hei r sc he d ule d visits i n t he st u d y. T o 
facilitate a d here nce, we will als o pr o vi de tra ns p ort rei m b urse me nt (i n acc or da nce 
wit h N H S R C re q uire me nts) a n d refres h me nts i n t he waiti n g area at t he st u d y 
cli nic. D uri n g t heir waiti n g ti me at t he researc h cli nic, we will als o pr o vi de s o me 
e d ucati o nal materials a n d e ntertai n me nt t hr o u g h t he tele visi o n t hat is i n t he 

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c orri d ors of o ur researc h cli nics. O ver t he years, we ha ve n ote d t hat t his 
mi ni mizes b ore d o m a m o n g partici pa nts w hile waiti n g f or t h eir st u d y visit a n d 
res ults. 
 
We pla n t o c o ntact partic i pa nts b y p h o ne or p h ysical traci n g a fe w da ys bef ore 
t heir sc he d ule d f oll o w- u p visits t o re mi n d t he m of t heir visits. We will use a 
sta n dar dize d l ocat or f or m t o rec or d essential partici pa nt traci n g i nf or mati o n ( wit h 
partici pa nt per missi o n), i ncl u di n g p h o ne n u m bers f or t h e partici pa nt a n d fa mil y 
me m bers/frie n ds, la n d mar ks cl ose t o t he partici pa nt’s h o me (c h urc hes, sc h o ols, 
s h o ps, etc.), dra w n ma ps of t he partici pa nt’s h o me a n d villa ge, t he na me of t he 
villa ge c hief a n d ot her c o ntacts, a n d G P S c o or di nates (if a partici pa nt is trace d 
a n d f o u n d t o be at h o me). F or misse d  sc he d ule d f oll o w u p visit, a st u d y 
c o m m u nit y n urse or e d ucat or will ma ke e ver y eff ort t o bri n g bac k t he partici pa nt 
f or t he f oll o w u p visit e xce pt w here partici pa nt wit h dra ws c o nse nt or w here it is 
n ot feasi ble d ue t o u n pla n ne d rel ocati o n. T he st u d y c o m m u nit y n urse or e d ucat or 
will c o ntact partici pa nt wit hi n 1- 3 da ys of missi n g t heir visit, t hr o u g h p h o ne or 
p h ysical traci n g t o fi n d o ut t he reas o n  f or missi n g t he visits a n d offer re-
sc he d uli n g of t he visits. We will kee p trac k of o ur rete nti o n rates o n a wee kl y 
basis a n d disc uss a n y rete nti o n iss ues e x perie nce d d uri n g t he c o n d uct of t he st u d y 
d uri n g t he st u d y tea m’s wee kl y meeti n g.  
4. 6  
Re m o v al of P atie nts  fr o m Pr ot oc ol  
Re gar dless of t he partici pa nt rete nti o n pr oce d ures refere nce d a b o ve, if a 
partici pa nt i n dicates t hat s he n o l o n ger wi s hes t o partici pate i n t he st u d y, s he will 
be all o we d t o wit h dra w fr o m t he st u d y wit h o ut l osi n g a n y of her access t o 
sta n dar d care. Partici pa nts ma y als o be wit h dra w n fr o m t he st u d y b y t he 
i n vesti gat or or desi g nee u n der t he f oll o wi n g circ u msta nces: 
 Partici pa nt re-l ocates a w a y fr o m t he st u d y site or is ot her wise deter mi ne d 
t o be l ost-t o-f oll o w- u p after e x ha usti n g traci n g eff orts 
 I n vesti gat or or desi g nee deter mi nes t hat c o nti n ue d partici pati o n i n t he 
st u d y w o ul d be u nsafe or ot her wise n ot i n t he best i nterest of t he 
partici pa nt 
 T he st u d y is st o p pe d or ca ncele d b y t he s p o ns ors, g o ver n me nt or 
re g ulat or y a ut h orities, or site I R Bs/ E Cs 
 
F or a n y partici pa nt w h o is wit h dra w n fr o m t he st u d y pri or t o sc he d ule d 
c o m pleti o n of f oll o w- u p, st u d y staff will d oc u me nt t he r eas o n f or t he wit h dra wal 
i n detail a n d will ma ke e ver y eff ort t o c o m plete fi nal e val uati o ns as is all o wa ble 
b y t he partici pa nt at t he ti me. I n t he e ve n t t hat t he circ u msta nces t hat le d t o a 
partici pa nt’s wit h dra wal c h a n ge w hile t he st u d y is still u n der wa y (e. g., s he ret ur ns 
t o t he st u d y site area after ha vi n g re-l ocate d pre vi o usl y), t he site i n vesti gat or or 
desi g nee mi g ht c o nsi der o pti o ns f or res u m pti o n of f oll o w- u p. 
 

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¹ F or t h ose wit h disc or da nt HI V ra pi d tests. 
2F or HI V- p ositi ve partici pa nts o nl y  
3F or all hr- H P V + a n d f or e ver y 1 0t h w o ma n w h o is hr- H P V-.  
4Cer vical bi o ps y a n d E C C if lesi o n see n at c ol p osc o p y; Cer vi cal pa p s mear a n d E C C if n o lesi o n see n at c ol p osc o p y   
5F or w o me n wit h a blati o n-eli gi ble cer vical lesi o n at c ol p osc o p y.  
6F or f oll o w- u p of cer vical hist ol o g y a n d/ or c yt ol o g y res ults fr o m Scree ni n g/ E nr oll me nt a n d t o assess f or a n y c ha n ge i n hist or y o r 
a d verse e ve nts fr o m t her m oc oa g ulati o n (if t her m oc oa g ulati o n was perf or me d).    
 
 
6. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S 
6. 1  
St u d y Desi g n 
T his is a si n gle ar m, pr os pecti ve st u d y of 1, 2 5 0 w o me n ( 6 2 5 HI V- p ositi ve a n d 
6 2 5 HI V- ne gati ve) recr uite d fr o m o ut patie nt cli nics i n Lil o n g we, Mala wi. T he 
pri mar y o bjecti ves of t his st u d y are t o assess c o m pletio n of a n o vel I C C scree n-
a n d-treat strate g y a m o n g w o me n, i ncl u di n g HI V- p ositi ve w o me n, i n Lil o n g we, 
Mala wi, usi n g self-c ollecte d  va gi nal br us h f or hr- H P V testi n g, f oll o we d b y sa me-
da y VI A a n d t her m oc oa g ulati o n f or H P V- p ositi ve/ VI A- p ositi ve/a blati o n-eli gi ble 
( b y c ol p osc o p y) w o me n, a n d t o deter mi ne t he 2 4- wee k efficac y of 
t her m oc oa g ulati o n a m o n g w o me n wit h CI N 2/ 3. T he sec o n dar y o bjecti ves will be 
t o e val uate t he perf or ma nce of t he IC C scree n-a n d-treat strate g y b y esti mati n g 
o vertreat me nt f or w o me n w h o are H P V- p ositi ve/ VI A- p ositi ve/a blati o n-eli gi ble, 
a n d u n dertreat me nt a m o n g H P V- p ositi ve/ VI A- ne gati ve w o me n, a n d t o e x pl ore 
w o me n’s e x perie nces wit h t he pr o p o se d scree n-a n d-treat al g orit h m.  
 
6. 2  
S a m ple Size a n d Accr u al 
We a ntici pate e nr olli n g 6 2 5 w o me n o ver a p pr o xi matel y 2 6 0 da ys. T his 
e nr oll me nt tar get ass u mes a scree ni n g t o  e nr oll me nt rati o of 1 0 t o 9, wit h 2- 3 
w o me n e nr olle d/ da y, w hic h is ver y feasi ble a n d all o ws a de q uate ti me f or 
i nf or me d c o nse nti n g, sa me- da y scree ni n g wit h hr- H P V testi n g, tria ge wit h VI A, 
a n d t her m oc oa g ulati o n f or VI A p ositi ve, a blati o n-eli gi ble ( b y c ol p osc o p y) 
w o me n, a n d als o s ufficie nt ti me f or sc he d ule d f oll o w- u p visits f or alrea d y-
e nr olle d w o me n. Base d o n pri or st u dies d o ne a m o n g HI V- p ositi ve w o me n i n 
S S A, we ass u me t hat at least 5 0 % ( n = 3 1 3) of t he 6 2 5 HI V- p ositi ve w o me n will 
be p ositi ve f or hr- H P V 4 a n d t hat at least 2 0 % of t hese 3 1 3 w o me n will ha ve 
CI N 2/ 3, 3 9, 4 0 w hic h gi ves us at least 6 3 HI V-p ositi ve w o me n wit h CI N 2/ 3 i n o ur 
c o h ort. A m o n g HI V- ne gati ve w o me n, we ass u me t hat at least 2 0 % ( n = 1 2 5) of t he 
6 2 5 HI V- ne gati ve w o me n will be p ositi ve f or hr- H P V 4 1, 4 2 a n d t hat at least 1 0 % of 
t hese w o me n will ha ve CI N 2/ 3,4 2 w hic h gi ves us at least 1 3 HI V- ne gati ve w o me n 
wit h CI N 2/ 3 i n o ur c o h ort. 
 

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We ass u me t hat 5 % of t he 7 6 w o me n wit h CI N 2/ 3 will be l ost-t o-f oll o w- u p after 
2 4 wee ks ( 9 5 % is t he t y pical  rate of rete nti o n f or stu dies d o ne at U N C Pr oject-
Mala wi at 6- m o nt h f oll o w- u p). T heref ore,  we will be a ble t o deter mi ne t he 2 4-
wee k efficac y of t her m oc oa g ulati o n a m o n g a p pr o xi matel y 7 2 w o me n, i ncl u di n g 
6 0 HI V- p ositi ve w o me n, wit h CI N 2/ 3. T his sa m ple size of 7 2 CI N 2/ 3 w o me n, 6 0 
of w h o m are HI V- p ositi ve, is c o m para ble wit h ot her st u dies i ncl u de d i n a meta-
a nal ysis t hat e val uate d t he efficac y of  t her m oc oa g ulati o n f or treati n g CI N 2/ 3.1 6 
Ass u mi n g treat me nt efficac y of 9 0 % o ver 2 4- wee ks f oll o w- u p, we s h o ul d ha ve 
> 9 5 % c o nfi de nce t o meas ure t he efficac y wit hi n ± 8 % f or t he o verall sa m ple a n d 
t he HI V- p ositi ve s u b- gr o u p. 
 
F or t he I DIs, u p t o 3 0 w o me n will be recr uite d at Scree ni n g/ E nr ol me nt Visit or 
Wee k 4 Visit. T he I DIs will e x pl ore part ici pa nts’ e x perie nces wit h t he pr o p ose d 
I C C scree n-a n d-treat strate g y a m o n g w o men. We e x pect t o reac h t he matic 
sat urati o n wit h t his sa m ple size, base d o n pri or w or k s h o wi n g t hat fe w ne w 
t he mes are esta blis he d after t he first 1 8 i nter vie ws.4 3 We e x pect si g nifica nt 
o verla p i n t he mes bet wee n t he H P V- p ositi ve a n d H P V- ne gati ve gr o u ps. 
6. 3  
D at a A n al ysis Pl a ns 
Pri mar y o bjecti ve I: T o assess c o m pleti o n of a n o vel I C C scree n-a n d-treat 
strate g y a m o n g w o me n i n Lil o n g we, Mala wi, usi n g self-c ollecte d va gi nal br us h 
f or hr- H P V testi n g, f oll o we d b y sa me- da y VI A a n d cer vical t her m oc oa g ulati o n 
f or H P V- p ositi ve/ VI A- p ositi ve/a blati o n-eli gi ble ( b y c ol p osc o p y) w o me n. 
 
Data a nal ysis f or pri mar y o bjecti ve I: We  will calc ulate t he f oll o wi n g pr o p orti o ns 
wit h c orres p o n di n g 9 5 % C o nfi de nce I nter vals ( CIs) f or t hese t w o pri mar y 
o utc o mes: a) t he pr o p orti o n of w o me n w h o are H P V p ositi ve w h o ha ve VI A 
perf or me d sa me- da y, a n d b) t he pr o p orti o n of w o me n w h o are VI A 
p ositi ve/a blati o n-eli gi ble ( b y c ol p osc o p y) w h o ha ve t her m oc oa g ulati o n perf or me d 
t he sa me- da y. We h y p ot hesize t hat > 9 0 % of w o me n w h o are H P V- p ositi ve will 
ha ve VI A perf or me d sa me- da y a n d t hat > 9 0 % of w o me n w h o are VI A-
p ositi ve/a blati o n-eli gi ble ( b y c ol p osc o p y) will ha ve t her m oc oa g ulati o n perf or me d 
t he sa me da y. 
 
We will als o s yste maticall y m o nit or a n d a nal yze i n dicat ors f or t he c o m pleti o n of 
t his n o vel I C C scree n-a n d-treat strate g y, as f oll o ws: 
 
N u m b er ( a n d %) of w o m e n w h o r e c ei v e d s elf- c oll e cti o n kit a n d w h o r et ur n e d a s elf- s a m pl e 
N u m b er ( a n d %) of H P V p o siti v e, n e g ati v e, i n s uffi ci e nt, a n d mi s si n g r e s ult s fr o m s elf- c oll e cti o n  
N u m b er ( a n d %) of w o m e n w h o r e c ei v e t h eir H P V r e s ult s t h e s a m e d a y a s c oll e cti o n 
N u m b er ( a n d %) of H P V- p o siti v e w o m e n i n vit e d f or VI A  
C o m pl eti o n p oi nt 1:  
N u m b er ( a n d %) of w o m e n wit h H P V- p o siti v e r e s ult s w h o r e c ei v e VI A s a m e- d a y  

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N u m b er ( a n d %) of H P V- p o siti v e w o m e n w h o r e c e i v e VI A o n a n ot h er d a y (i n st e a d of s a m e- d a y) 
N u m b er ( a n d %) of H P V- p o siti v e w o m e n w h o n e v er r e c ei v e VI A (l o s s t o f oll o w- u p) 
N u m b er ( a n d %) of H P V- p o siti v e w o m e n wit h VI A p o siti v e r e s ult s  
N u m b er ( a n d %) of H P V- p o siti v e w o m e n wit h VI A- p o sit i v e r e s ult s w h o ar e eli gi bl e f or t h er m o c o a g ul ati o n b y 
c ol p o s c o p y; n ot eli gi bl e f or t h er m o c o a g ul ati o n b ut L E E P eli gi bl e; or r ef err e d f or s u s p e ct e d c a n c er 
C o m pl eti o n p oi nt 2:  
N u m b er  ( a n d  %)  of  w o m e n  wit h  VI A  p o siti v e  r e s ult s  a n d  ar e  a bl ati o n- eli gi bl e  b y  c ol p o s c o p y  w h o  r e c ei v e  
t h er m o c o a g ul ati o n s a m e- d a y 
N u m b er ( a n d %) of w o m e n wit h VI A p o siti v e r e s ult s a n d ar e a bl ati o n- eli gi bl e w h o r e c ei v e t h er m o c o a g ul ati o n o n 
a f oll o wi n g d a y 
N u m b er ( a n d %) of H P V- p o siti v e w o m e n wit h c er vi c a l bi o p s y or c er vi c al p a p s m e ar, a n d E C C p erf or m e d, a n d N 
( %) wit h hi st ol o g y a n d/ or c yt ol o g y r e a d 
N u m b er ( a n d %) of CI N 2 +, CI N 1, or n or m al at S cr e e ni n g/ E nr oll m e nt 
N u m b er ( a n d %) of tr e at e d w o m e n w h o r et ur n f or W e e k 2 4 f oll o w u p vi sit. 
N u m b er ( a n d %) of tr e at e d w o m e n w h o r et ur n f or W e e k 2 4 f oll o w u p vi sit a n d ar e f o u n d t o h a v e r e s ol v e d v er s u s 
p er si st e nt hr- H P V 
N u m b er ( a n d %) of tr e at e d w o m e n w h o r et ur n f or W e e k 2 4 f oll o w u p vi siti n g t h at ar e f o u n d t o h a v e r e s ol v e d 
CI N 1 
N u m b er ( a n d %) of tr e at e d w o m e n w h o r et ur n f or W e e k 2 4 f oll o w u p vi sit t h at ar e f o u n d t o h a v e r e s ol v e d CI N 2 + 
N u m b er ( a n d %) of tr e at e d w o m e n w h o r et ur n f or W e e k 2 4 f oll o w u p vi sit t h at ar e f o u n d t o h a v e p er si st e nt CI N 1 + 
N u m b er ( a n d %) of tr e at e d w o m e n w h o r et ur n f or W e e k 2 4 f oll o w u p vi sit t h at ar e f o u n d t o h a v e p er si st e nt CI N 2 + 
N u m b er ( a n d %) of tr e at e d w o m e n w h o r et ur n f or W e e k 2 4 f oll o w u p vi sit t h at ar e f o u n d t o h a v e r e s ol v e d CI N 1 
N u m b er ( a n d %) of w o m e n r ef err e d f or f urt h er m a n a g e m e nt w h o h a v e r e c ei v e d a p pr o pri at e m a n a g e m e nt b y 
W e e k 2 4 
 
 
We will als o calc ulate t he me dia n ti me  nee de d t o c o m plete t he pr o p ose d H P V 
testi n g, VI A tria ge, a n d treat me nt casca de b y rec or di n g t he ti mes f or eac h of t he 
f oll o wi n g ste ps.  
1) Ti me t hat t he partici pa nt recei ve d t he self- H P V c ollecti o n br us h  
2) Ti me t hat t he partici pa nt ret u r ne d t he self- H P V c ollecti o n br us h 
3) Ti me t hat t he H P V test was i nitiate d i n t he X pert mac hi ne 
4) Ti me t hat t he H P V test was c o m plete d i n t he X pert mac hi ne 
5) Ti me t hat t he partici pa nt recei ve d her H P V res ult 
6) Ti me t hat t he partici pa nt ha d her VI A c o m plete d (if a p plica ble) 
7) Ti me t hat t he partic i pa nt ha d her c ol p osc o p y c om plete d (if a p plica ble) 
8) Ti me t hat t he partici p a nt ha d cer vical bi o psies or  cer vical c yt ol o g y, a n d E C C 
c o m plete d (if a p plica ble) 
9) Ti me t hat t he partici pa nt ha d her t h er m oc oa g ulati o n c o m plete d (if a p plica ble) 
 
L o gistic re gressi o n m o dels will be use d t o assess fact ors ass ociate d wit h 
c o m pleti n g t he pr o p ose d testi n g a n d tr eat me nt casca de f or b ot h H P V- p ositi ve a n d 
H P V- ne gati ve w o me n, s uc h as HI V stat us, le n gt h of ti me o n A R T, tra vel ti me t o 

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atte n d i n-cli nic a p p oi nt me nts, k n o wle d ge of s o me o ne wit h a n y ca ncer, HI V- 1 
R N A l oa d, a n d C D 4 + T cell c o u nt. T his o bjec ti ve is lar gel y descri pti ve a n d, t h us, 
f or mal p o wer calc ulati o ns are n ot ma de. 
 
Pri mar y o bjecti ve II: T o deter mi ne t he 2 4- wee k efficac y of t her m oc oa g ulati o n 
a m o n g w o me n, i ncl u di n g HI V- p ositi ve w o me n, wit h CI N 2/ 3. W o me n w h o 
u n der g o t her m oc oa g ulati o n will ha ve f oll o w- u p at 2 4- wee ks p ost-treat me nt f or 
c ol p osc o p y, pr o vi der c ollecte d cer vic o va gi nal br us h f or hr- H P V testi n g, E C C, 
c ol p osc o p y- directe d cer vical bi o ps y a n d E C C (if lesi o n n ote d) or cer vical 
c yt ol o g y a n d E C C (if n o lesi o n n ote d at c ol p osc o p y). We h y p ot hesize t hat > 9 0 % 
wit h CI N 2/ 3 o n pre-treat me nt bi o ps y will ha ve ≤CI N 1 at t heir 2 4- wee k bi o ps y. 
 
Data a nal ysis f or pri mar y o bjecti ve II: F or efficac y of t her m oc oa g ulati o n, we will 
c o m pare o ur 2 4- wee k c ure ra tes f or CI N 2/ 3 wit h t her m oc oa g ulati o n t o hist oric 
c ure rates f or CI N 2/ 3 w it h cr y ot hera p y ( 8 5- 9 5 %),4 4 t he rec o m me n de d a blati ve 
treat me nt m o dalit y f or CI N 2/ 3 f or res o urce li mite d c o u ntries.1 0 We will perf or m 
e x pl orat or y a nal ysis t o deter mi ne t he f oll o wi n g: 
a) 2 4- wee k efficac y f or CI N 1, b y calc u lati n g t he pr o p orti o n of w o me n w h o ha d 
CI N 1 at Scree ni n g/ E nr oll me nt a n d t he n were f o u n d t o ha ve n o cer vical d ys plasia 
at Wee ks 2 4 after t her m oc oa g ulati o n treat me nt;  
b) hr- H P V cleara nce i n H P V- p ositi ve w o me n treate d wit h t her m oc oa g ulati o n, b y 
calc ulati n g t he pr o p orti o n wit h n o hr- H P V at Wee ks 2 4; a n d  
c) Ris k fact ors f or CI N 2 + a m o n g H P V- p os iti ve w o me n (i.e., a ge, a ge at first 
se x ual i nterc o urse, n u m ber of se x ual part ners, HI V stat us, le n gt h of ti me o n A R T, 
HI V- 1 R N A l oa d, C D 4 + c o u nt) via m ult i varia ble l o gistic re gressi o n.  
 
Wit h a n e x pecte d 7 6 CI N 2/ 3 lesi o ns a m o n g o ur partici pa nts a n d 9 0 % hr- H P V 
p ositi vit y at ti me of treat me nt, we es ti mate t hat 6 8/ 7 6 w o me n w h o u n der g o 
t her m oc oa g ulati o n at Scree ni n g/ E nr oll me nt will be hr- H P V p ositi ve. Acc o u nti n g 
f or 5 % l oss t o f oll o w u p b y wee k 2 4, we will ha ve a sa m ple of 6 5 w o me n w h o 
were hr- H P V p ositi ve at ti me of treat me nt pr ese nt f or re peat hr- H P V testi n g. Wit h 
t hese 6 5 w o me n, we will ha ve 9 9. 9 % p o wer t o detect a differe nce bet wee n hr-
H P V p ositi vit y pre- a n d p ost-treat me nt, ass u mi n g 1 0 0 % hr- H P V p ositi vit y pre- 
a n d 3 5 % hr- H P V p ositi vit y at 2 4 wee ks p ost-treat me nt. We ass u me t hat 3 5 % will 
still be hr- H P V- p ositi ve base d o n a rece nt s yste matic re vie w, fi n di n g t hat 3 5 % of 
w o me n were still hr- H P V- p ositi ve after cr y ot hera p y; n o s uc h esti mates are 
a vaila ble f or t her m oc oa g ulati o n. 4 5 I n a d diti o n, n o esti mates are c urre ntl y-
a vaila ble f or t he 2 4- wee k f or CI N 1 as t h er m oc oa g ulati o n has n ot bee n use d t o 
treat l o w- gra de d ys plasia. Hr- H P V res ults at t he Wee k 2 4 visit f or n o n- CI N- 2/ 3 
cases at e nr oll me nt will be i n vesti gate d i n e x pl orat or y a nal yses, stratifie d b y 
baseli ne CI N 1 a n d n or ma l/cer vicitis stat us.  
 
Sec o n dar y o bjecti ve I: T o e val uate perf o r ma nce of I C C scree n-a n d-treat strate g y 
a m o n g w o me n, i ncl u di n g HI V- p ositi ve w o me n, b y esti mati n g o vertreat me nt f or 

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w o me n w h o are H P V p ositi ve/ VI A p ositi ve/ a blati o n-eli gi ble, a n d u n dertreat me nt 
a m o n g H P V p ositi ve/ VI A ne gati ve w o me n. All H P V p ositi ve w o me n a n d e ver y 
1 0t h c o nsec uti ve H P V- ne gati ve w o ma n will u n der g o VI A. D uri n g VI A, we will 
deter mi ne if a w o ma n is VI A- p ositi ve a n d a blati o n-eli gi ble. W o me n w h o are 
VI A- p ositi ve will u n der g o c ol p osc o picall y - directe d cer vical bi o psies a n d 
e n d ocer vical c urretti n gs ( E C C). If t he w o ma n is still c o nsi dere d t o be a blati o n-
eli gi ble b y c ol p osc o p y, s he will t he n u n der g o t her m oc oa g ulati o n. W o me n w h o 
are VI A- ne gati ve will als o u n der g o c ol p osc o p y, b ut t he y will o nl y ha ve cer vical 
bi o psies a n d E C C perf or me d if a lesi o n is  see n o n c ol p osc o p y. F oll o wi n g VI A, 
we will c ollect directe d cer vical bi o psies a n d E C C fr o m VI A p ositi ve w o me n 
pri or t o t her m oc oa g ulati o n treat me nt if a blati o n-eli gi ble b y c ol p osc o p y, or 
cer vical pa p s mear a n d E C C fr o m VI A ne ga ti ve w o me n if n o lesi o n is see n at 
c ol p osc o p y. If a lesi o n is see n at c o l p osc o p y, VI A ne gati ve will als o u n der g o 
c ol p osc o picall y- directe d cer vical bi o ps y a n d E C C. We h y p ot hesize t hat < 2 5 % of 
H P V p ositi ve/ VI A p ositi ve w o me n w o ul d ha ve bee n o vertreate d ( n o CI N 2 +, b ut 
treate d) a n d t hat < 3 0 % of H P V p ositi ve/ VI A ne gati ve w o me n w o ul d ha ve bee n 
u n dertreate d ( CI N 2 +, b ut u ntreate d).   
 
Data a nal ysis f or sec o n dar y o bjecti ve I: O vertreat me nt will be calc ulate d as t he 
pr o p orti o n of H P V p ositi ve/ VI A p ositi ve/ a blati o n-eli gi ble w o me n w h o w o ul d 
ha ve bee n treate d wit h t her m oc oa g ulat i o n base d o n t heir H P V a n d VI A fi n di n gs 
al o ne ( wit h o ut c ol p osc o p y), b ut were f o u n d t o ha ve n o CI N 2 + o n 
c ol p osc o picall y- directe d cer vical bi o ps y or E C C at Scree ni n g/ E nr oll me nt. T his 
pr o p orti o n will re prese nt t he w o me n wit h n o lesi o ns or l o w- gra de lesi o ns ( CI N 1) 
w h o w o ul d ha ve bee n u n necessaril y treate d if we base d t he decisi o n t o perf or m 
t her m oc oa g ulati o n o n H P V an d VI A testi n g al o ne.  
 
U n dertreat me nt will be calc ulate d as  t he pr o p orti o n of w o me n wit h CI N 2 + at 
Scree ni n g/ E nr oll me nt w h o were n ot tr eate d or referre d via o ur scree ni n g 
al g orit h m d ue t o a ne gati ve H P V a n d/ or VI A res ult. T his pr o p orti o n will re prese nt 
t he w o me n wit h CI N- 2 + w h o were missed b y o ur H P V-a n d- VI A- base d al g orit h m. 
F or u n dertreat me nt, we will als o e val uate t he pr o p orti o n of w o me n w h o 
u n der we nt t her m oc oa g ulati o n b ut were E C C p ositi ve f or e n d ocer vical CI N 2 +, 
a n d t heref ore nee de d t o be referr e d f or f urt her ma na ge me nt si nce 
t her m oc oa g ulati o n d oes n ot a de q uatel y treat e n d ocer vical d ys plasia. We ha ve 
base d o ur h y p ot heses o n a rece nt re vie w, w hic h f o u n d t hat t he p o ole d esti mates 
f or VI A se nsiti vit y a n d s pecificit y were 0. 6 9 ( 9 5 % CI 0. 5 4- 0. 8 1) a n d 0. 8 7 ( 9 5 % 
CI 0. 7 9- 0. 9 2), res pecti vel y, 4 6 as well as fr o m t he hi g h false p ositi ve rate f or VI A 
f o u n d i n o ur pil ot st u d y wit h n urses a n d cli nicia ns i n Mala wi. T hese perf or ma nce 
meas ures, h o we ver, were f or pri mar y sc ree ni n g, rat her t ha n as referral t o 
treat me nt a m o n g H P V p ositi ve w o me n.  
 
I n a d diti o n, t o assess t he p ote ntial f or u n dertreat me nt of H P V- p ositi ve w o me n, we 
will c o n d uct VI A at Scree ni n g/ E nr oll me nt  f or e ver y 1 0t h w o me n w h o is hr- H P V 

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7. 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 
Pri or t o st u d y i nitiati o n, t he PI will e ns u re re vie w a n d a p pr o val of t his pr ot oc ol 
a n d t he i nf or me d c o nse nt f or m as re q uire d, b y t he Mala wi N H S R C, w hic h is 
res p o nsi ble f or o versi g ht of researc h co n d ucte d i n Mala wi, a n d t he U N C I R B, i n 
acc or da nce wit h 4 5 C F R 4 6. Bef ore be gi n ni n g t he st u d y, a p pr o val will als o be 
s o u g ht fr o m l ocal a ut h orities a n d t he Lil o n g we District He alt h Office. Partici pa nts 
a n d st u d y staff me m bers will ta ke part i n a t h or o u g h i nf or me d c o nse nt pr ocess. 
T he st u d y staff will ma ke eff orts t o mi ni mize ris ks t o partici pa nts.  
 
S u bse q ue nt t o i nitial re vie w a n d a p pr o va l, I R Bs/ E Cs m ust re vie w t he st u d y at 
least a n n uall y. T he PI will pr o vi de a n n ual pr o gress re p orts as re q uire d t o t he 
I R B/ E C. T hese re p orts will i ncl u de t he t otal n u m ber of partici pa nts e nr olle d i n t he 
st u d y, t he n u m ber of partici pa nts w h o c o m plete d t he st u d y, a n y c ha n ges i n t he 
researc h acti vities, a n d all u na ntici pate d pr o ble ms i n v ol vi n g ris ks t o h u ma n 
s u bjects. 
 
 
 
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 t he st u d y a n d will be gi ve n t he o p p ort u nit y t o re vie w t he c o nse nt 
f or m. Eac h c o nse nt f or m will i ncl u de all t he rele va nt ele me nts i n acc or da nce wit h 
4 5 C F R 4 6 a n d a n y l ocal or state 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 ve sti gat or 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 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 
f or m. 
 
Pri or t o a patie nt’s partici pati o n i n t he trial, 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 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. T he i nf or me d c o nse nt pr ocess will 
als o a d dress t he f oll o wi n g:  
 T he p ur p ose of t he st u d y  
 T he p ote ntial ps yc h ol o gical a n d s o cial har ms ass ociate d wit h st u d y 
partici pati o n (a n d w hat t o d o if s uc h har ms are e x perie nce d)  
 T he p ossi ble be nefits t o ta ki n g part i n t his st u d y 
 T he ri g ht t o wit h dra w or n ot a ns wer s o me q uesti o ns i n t he st u d y at a n y 
ti me 
7. 2  
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 d oc u me ntati o n will be 
pr o vi de d t o t he Cli nical Pr ot oc ol Offi ce ( C P O) at t he U ni versit y of N ort h 
Car oli na. 
 A c o p y of t he official I R B a p pr o val le tter f or t he pr ot oc ol a n d i nf or me d 
c o nse nt 
 C Vs a n d me dical lice ns ure f or t he pr i nci pal i n vesti gat or a n d a n y c o-
i n vesti gat ors w h o will be i n v ol ve d i n t he st u d y 

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 A c o p y of t he I R B-a p pr o ve d c o nse nt f or m 
7. 3  
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 pr otecti o n, safet y, 
a n d well- bei n g of t he st u d y patie nt re q uire s alter nati ve treat me nt, t he st u d y s hall 
be c o n d ucte d e xactl y as descri be d i n t he a p pr o ve d pr ot oc ol.   
7. 3. 1  E mer ge nc y M o dific ati o ns 
U N C 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 pr ot oc ol 
t o eli mi nate a n i m me diate hazar d(s) t o trial s u bjects wit h o ut pri or U N C I R B 
a p pr o val or res pecti ve i nstit uti o n’s I R B/I E C a p pr o val/fa v ora ble o pi ni o n. 
 
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 m o dificati o n 
f or m will 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 
of ma ki n g t he c ha n ge.   
7. 3. 2  Si n gle P atie nt/ S u bject E xce pti o ns 
Eli gi bilit y si n gle s u bject e xce pti o ns are n ot per mitte d f or Li ne ber ger 
C o m pre he nsi ve Ca ncer Ce nter I n ves ti gat or I nitiate d Trials u n der a n y 
circ u msta nces. Ot her t y pes of si n gle s u bj ect e xce pti o ns ma y be all o we d if pr o per 
re g ulat or y re vie w has bee n c o m plete d i n acc or da nce wit h Li ne ber ger 
C o m pre he nsi ve Ca ncer Ce nter’s Si n gle S u bject E xce pti o ns P olic y. 
7. 3. 3  A d verse E ve nt a n d Pr ot oc ol De vi ati o ns/ E v al u ati o ns Re p orti n g 
7. 3. 3. 1. Defi niti o ns: 
a)  A dverse eve nt ( A E)  - a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), s y m pt o m, or  disease te m p orall y ass ociate d wit h 
t he use of a me dical treat me nt or proce d ure re gar dless of w het her it is 
c o nsi dere d relate d t o t he me dical tr eat me nt or pr oce d ur e (attri b uti o n of 
u nrelate d, u nli kel y, p ossi ble, pr o ba ble, or defi nite). Eac h A E will be assesse d 
f or relate d ness, se verit y a n d attri buti o n t o t he st u d y i nter ve nti o n or 
partici pati o n. T he C T E P Versi o n 5. 0 of t he N CI C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E ve nts ( C T C A E) w ill be utilize d f or A E re p orti n g. T he 
C T E P Versi o n 5. 0 of t he C T C A E is i d e ntifie d a n d l ocate d o n t he C T E P 
we bsite at 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic a p plicati o ns/ctc. ht m . 
 
b)  Seri o us A dverse Eve nts ( S A Es)  - a n y e ve nt te m p orall y ass ociate d wit h t he 
s u bject’s partici pati o n i n researc h t hat meets a n y of t he f oll o wi n g criteria: 
 Res ults i n deat h 
 Is life-t hreate ni n g at t he ti me of t he e ve nt ( places t he s u bject at 
i m me diate ris k of deat h fr o m t he e ve nt as it occ urre d) 
 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 

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 Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y 
 Is a c o n ge nital a n o mal y/ birt h defect or  
 A n y ot her A E t hat, base d u p o n a p pr o priate me dical j u d g me nt, ma y 
je o par dize t he s u bject’s healt h a n d ma y re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt o ne of o utc o mes liste d a b o ve.  
 
c) U ne x pecte d A Es  – a n y A E occ urri n g i n o ne or m ore s u bjects partici pati n g i n 
a researc h pr ot oc ol, t he nat ure, se ve rit y, or fre q ue nc y of w hic h is n ot 
c o nsiste nt wit h eit her: 
•  
T he k n o w n or f oreseea ble ris k of A Es ass ociate d wit h t he pr oce d ures 
i n v ol ve d i n t he researc h 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-a p pr o ve d researc h 
pr ot oc ol, a n y a p plica ble i n vesti g at or br oc h ure, a n d t he c urre nt 
I R B-a p pr o ve d i nf or me d c o nse nt, a n d 
 t he e x pecte d nat ural pr o gressio n of a n y u n derl yi n g disease, 
dis or der, or c o n diti o n of t he s u bject(s) e x perie nci n g t he a d verse 
e ve nt a n d t he s u bject’s pre dis p osi n g ris k fact or pr ofile f or t he 
a d verse e ve nt. 
 
d)  Rel ate d t o t he rese arc h  – a n i nci de nt, e x perie nce, or o utc o me t hat is li kel y t o 
ha ve res ulte d fr o m partici pati o n i n t he researc h st u d y. 
 P ossi bl y Relate d t o t he researc h – t he reas o na ble p ossi bilit y t hat t he A E, 
i nci de nt, e x perie nce, or o utc o me may ha ve bee n ass ociate d wit h t he 
pr oce d ures i n v ol ve d i n t he researc h. Reas o na ble p ossi bilit y mea ns t hat t he 
e ve nt is m ore li kel y t ha n n ot relate d t o  partici pati o n i n t he researc h or, i n 
ot her w or ds, t here is a > 5 0 % li keli h o o d t hat t he e ve nt is relate d t o t he 
researc h pr oce d ures. 
 
e) U n a ntici p ate d pr o ble ms i nv olvi n g ris k  t o s u bjects or ot hers ( U PI R S O) – a n y 
i nci de nt, e x perie nce, or o utc o me t hat 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: 
 t he researc h 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-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 t he c haracteristics of t he 
partici pa nt p o p ulat i o n bei n g st u die d; 
 Relate d or p ossi bl y relate d t o a s u bject’s partici pati o n i n t he researc h; a n d 
 Seri o us or 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 (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) t ha n was pre vi o usl y k n o w n or rec o g nize d. 
 
f) Pr ot oc ol Devi ati o n  – 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 
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:  
 Is ge nerall y n ote d or rec o g nize d after it occ urs 
 Has n o s u bsta nti ve effect o n t he ri s ks t o researc h partici pa nts 

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 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 c ollecte d  
 Di d n ot res ult fr o m willf ul or k n o w i n g misc o n d uct o n t he part of t he 
i n vesti gat or(s).  
 
A n u n pla n ne d pr ot oc ol varia nce is c o nsi d ere d a vi olati o n if  t he varia nce meets 
a n y of t he f oll o wi n g criteria:  
 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. 
 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. 
 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). 
 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, a varia nce fr o m t he a ppr o ve d st u d y pr ot oc ol. E xa m ples 
i ncl u de st u d y visits or pr oce d ures c o n d ucte d o utsi de of t he visit wi n d o w, 
i nc o m plete st u d y visits as a res ult of err or b y t he st u d y staff, a n d l o gistical 
or a d mi nistrati ve pr o ble ms.   Pr ot oc ol de viati o ns m ust be d oc u me nte d. 
 
g)  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 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 re p ort U PI R S O.   
 
7. 3. 3. 2. Pr oce d ures f or Re p orti n g I nci de nts 
1.  All st u d y staff are res p o nsi ble f or re p orti n g k n o w n or s us pecte d a d verse 
e ve nts ( A E), pr ot oc ol de viati o ns, or U PI R S O i m me diatel y (t he sa me da y of 
t he i nci de nt or disc o ver y of t he i nci de nt) t o t he St u d y C o or di nat or. 
 
2.  If a n i nci de nt i n v ol ves har m or i nj ur y t o a pers o n, t he ne xt ste p is t o eli mi nate 
i m me diate hazar d t o t he s u bject(s) or ot hers. I m me diate c orrecti o ns d o n ot 
re q uire I R B a p pr o val pri or t o i nitiatio n, b ut s h o ul d be descri be d i n t he 
I nci de nt Re p ort.  
 
3.  R o uti ne re p orti n g of A E: all A E will  be s o urce d oc u me nte d. T he f oll o wi n g 
will be re p orte d o n a case re p ort f or m: 
 
a) All ge nital A E re gar dless of gra de a n d se verit y, 
b)  All A Es wit h gra de > 3. 
 
4.  T he St u d y C o or di nat or m ust deter mi ne if t he i nci de nt re q uires pr o m pt 
re p orti n g t o t he I R Bs. If s o, t he St u d y Co or di nat or m ust re p ort t he i nci de nt 
i m me diatel y (t he sa me da y of t he i nci de nt or disc o ver y of t he i nci de nt) t o t he 
PI s o t hat he ca n n otif y t he I R Bs wit hi n 7 cale n dar da ys of n otificati o n. 
 
5.  T he f oll o wi n g i nci de nts re q uire pr o m pt re p orti n g t o t he I R Bs:  

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a. A Es t hat are:  
 U ne x pecte d,  
 Relate d or P ossi bl y Relate d t o partici pati o n i n t he researc h a n d 
are gra de > 3, a n d  
 Seri o us or s u g gest t hat t here ar e ne w or i ncrease d ris k(s) t o 
s u bjects. 
 
b.  I nteri m a nal ysis, data a n d safet y m o nit ori n g re p ort, fi n di n gs fr o m 
ot her st u dies, fi n di n gs fr o m a ni mal or i n- vitr o testi n g, or ot her 
fi n di n g(s) t hat i n dicate: ( 1) t here are ne w or i ncrease d ris ks t o s u bjects 
or ot hers, or ( 2) s u bjects are less li ke l y t o recei ve a n y direct be nefits 
fr o m t he researc h. 
 
c. Pr ot oc ol de viati o ns t hat har me d s u bject(s) or ot hers or place d 
s u bject(s) or ot hers at i ncrease d ris k of har m. 
 
d.  Pr ot oc ol de viati o ns t hat are ma de t o eli mi nate a n im me diate hazar d t o 
a s u bject wit h o ut I R B a p pr o val. 
 
e. I nte nti o nal or u ni nte nti o nal fail ure t o f oll o w a p plica ble fe deral h u ma n 
s u bject pr otecti o n re g ulati o ns, t he re q uire me nts or deter mi nati o ns of t he 
I R B, t he I R B-a p pr o ve d st u d y pr ot oc ol, or U ni versit y p olicies w he n t hat 
fail ure a d versel y affects t he ri g hts or welfare of partici pa nts, s uc h as: 
 C o n d ucti n g h u ma n s u bjects resear c h wit h o ut a n I R B-a p pr o ve d 
pr ot oc ol or e xe m pti o n  
 Starti n g researc h pri o r t o meeti n g t he c o n diti o ns re q uire d b y t he 
I R B a n d recei vi n g a n I R B n otificati o n of a p pr o val, or c o n d ucti n g 
researc h d uri n g a la pse i n a p pr o val  
 Fail ure t o o btai n i nf or me d c o nse nt  
 De viati n g fr o m t he i nf or me d c o nse nt or recr uit me nt pr ocess 
a p pr o ve d b y t he I R B  
 Fail ure t o pr o vi de a partici pa nt wit h ne w i nf or m ati o n a b o ut st u d y 
ris ks or pr oce d ures t hat ma y affect t he partici pa nt’s willi n g ness 
t o c o nti n ue/ partici pate i n t he st u d y (i.e., b y n ot rec o nse nti n g 
partici pa nts or b y usi n g a n ol d versi o n of a c o nse nt d oc u me nt t o 
c o nse nt a ne w partici pa nt)  
 I nitiati n g c ha n ges t o t he pr otoc ol wit h o ut I R B a p pr o val, 
i ncl u di n g usi n g u na p pr o ve d materials (e. g., fact or i nf or mati o n 
s heets, recr uit me nt materials, q uesti o n naires, f oc us gr o u p g ui des, 
scri pts, or ot her materials pr o vi de d t o partici pa nts)  
 Fail ure t o c o m plete I R B- or i nstit uti o nall y-re q uire d h u ma n 
s u bjects pr otecti o n trai ni n g pri or t o e n ga gi n g i n h u ma n s u bjects 
researc h  

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 E nr oll me nt of partici pa nts be y o n d w hat has bee n a p pr o ve d b y 
t he I R B i n a st u d y t hat is greater t ha n mi ni mal ris k  
 
f. Breac h or p ote ntial breac h of s u bject c o nfi de ntialit y 
 
g. C o m plai nt b y or o n be half of  a researc h su bject t hat:  
 
 i n dicates t hat t he ri g hts, welfare, or safet y of t he s u bject has bee n 
a d versel y affecte d, or  
 ca n n ot be res ol ve d b y t he i n vesti g at or. S u bject c o m plai nts a b o ut 
pa y me nt s h o ul d be res ol ve d b y t he st u d y tea m. 
 
h. Alle gati o n of n o nc o m plia nce 
 
i. I nstit uti o n-, i n vesti gat or-, or s p o ns or-i nitiate d h ol d or earl y cl os ure as a 
res ult of safet y c o ncer ns. 
 
6.   All ot her i nci de nts d o n ot re q uire pr o mpt re p orti n g t o t he I R Bs a n d will be 
s u b mitte d as nee de d t o t he I R Bs d uri n g t he a n n ual c o nti n ui n g re vie w. 
 
7.   All i nci de nts s h o ul d be pr o m ptl y rec or de d i n t he a p pr o priate l o g b y t he St u d y 
C o or di nat or, w h o will t he n se n d t h e u p date d l o g t o PI f or re vie w. 
 
8. F or all Pr ot oc ol De viati o ns, U PI R S O a n d re p orta ble A Es, t he St u d y 
C o or di nat or will als o se n d t he PI a n u p date d L o g or U na ntici pate d Pr o ble m 
Re p ort a b o ut t he i nci de nt, w hic h s h o ul d c o ntai n t he f oll o wi n g, i n acc or da nce wit h 
U N C I R B g ui deli nes: 
a) Detaile d i nf or mati o n a b o ut  t he e ve nt of iss ue, i ncl u di n g rele va nt dates. 
T he re p ort s h o ul d i de ntif y t he affecte d s u bjects b y t heir PI Ds a n d n ot b y 
t heir na mes or ot her pers o nal i de ntifiers. 
b) A n assess me nt of w het her a n y s u bject s or ot hers were place d as ris k or 
s uffere d a n y har m (e. g., p h ysical, s ocial, fi na ncial, le gal, or ps yc h ol o gical) 
as a res ult of t he i nci de nt. 
 
c) If t he e ve nts i n v ol ve n o nc o m plia nce,  descri be t he r o ot ca use a nal ysis, 
w hic h s h o ul d a ns wer t he f oll o wi n g q uesti o ns: 
i. W hat was t he err or? 
ii. H o w di d t he err or occ ur? 
iii. H o w wi des prea d is t he err or? 
i v. W h y di d t he err or occ ur? Kee p as ki n g w h y u ntil y o u i de ntif y t he r o ot 
ca use. 
 
d) A n y c orrecti ve a n d pre ve nti ve ac ti o n ( C A P A), pla n ne d or alrea d y 
ta ke n, w hic h s h o ul d i ncl u de: 

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i. Acti o n t y pe (c orrecti ve or pre ve nti ve)  
ii. Acti o n descri pti o n 
iii. Pers o n nel w h o are res p o nsi ble f or t he i m ple me ntati o n of t he acti o ns. 
i v. Date(s) o n w hic h t he acti o n(s) were ta ke n or are pla n ne d. 
v. Pla n f or effecti ve ness c hec k 
vi. O utc o me of effecti ve ness c hec k 
vii. If a p plica ble, a me n d me nts t o t he C A P A 
 
e) If t he re p ort ca n n ot be c o m plete d i n its e ntiret y wit hi n t he re q uire d ti me 
peri o d, t he re p ort s h o ul d descri be w h at i nf or mati o n is still nee de d a n d 
w he n t he i n vesti gat or a ntici pates t hat a f oll o w- u p re p ort will be s u b mitte d. 
A f oll o w- u p re p ort will t he n nee d t o be s u b mitte d t o t he I R Bs o nce all 
i nf or mati o n is a vaila ble. 
 
9. T he St u d y C o or di nat or a n d PI will disc uss eac h re p orta ble i nci de nt a n d assess 
w het her t he pr ot oc ol or st u d y pr oce d ures n ee d t o be m o difie d. If t he y deci de t hat 
t he pr ot oc ol nee ds m o dificati o n, t he PI or desi g nee c o or di nates t he s u b missi o n of 
t he pr ot oc ol a me n d me nt. 
 
7. 4  
D at a S afet y M o nit ori n g 
a) O ver vie w 
Gi ve n t hat t he trial will i n v ol ve use of Li ger T her m oc o a g ulat or t hat was desi g ne d 
a n d is use d f or treati n g cer vical d ys plasia, e xce pt t hat t hat t here is li mite d data of 
its effecti ve ness i n HI V- p ositi ve w o me n, a n d c ollecti n g cer vical bi o ps y a n d E C C 
w hic h are r o uti ne g y nec ol o gic pr oce d ures  d o ne w he n cli nicall y i n dicate d, n o 
f or mal Data Safet y M o nit ori n g B oar d ( D M S B) will be esta blis he d. H o we ver, we 
will a d here t o t he Data Safet y M o nit ori n g Pla n ( D S M P) as o utli ne d bel o w: 
 
T he Pri nci pal I n vesti gat or ( PI), Dr. La mec k  C hi n ula, will pr o vi de o versi g ht of all 
recr uit me nt a n d st u d y pr oce d ures a n d q ualit y ass ura nce c hec ks will be c o n d ucte d 
as s pecifie d u n der t he directi o n of a 7- me m ber D S M P C o m mittee c o m p ose d of 
t he st u d y’s C o-I n vesti gat ors a n d Ot her Si g nifica nt Co ntri b ut ors: Dr. Je n nifer 
Ta n g, Dr. Je n nifer S mit h, Dr. Ma ga niz o C ha g o mera na, Dr. Ta mi we Ta m o ka, Dr. 
Be nja mi n C hi, a n d Dr. Si o b ha n O’ C o n n or . T he C o m mittee will meet t wice per 
year a n d a d diti o nall y as nee de d, eit her i n pers o n or via c o nfere nce call.  T he 
c o m mittee will disc uss t he pr oject, re vie w its pr o gress, re vie w st u d y 
m o dificati o ns, a n d m o nit or c o m plia nce wit h I R B r ules a n d h u ma n s u bjects’ 
pr oce d ures, as well as u na ntici pate d pr o bl e ms a n d a d verse e ve nts. T h us, t here will 
be o n g oi n g re vie w of t he st u d y’s pr ot oc ol  a n d its i m ple me ntati o n a n d bia n n ual 
re vie ws perf or me d b y t he f ull D S M P steeri n g c o m mittee. I n a d diti o n, o versi g ht of 
data safet y a n d m o nit ori n g will be ac hi e ve d t hr o u g h writte n re p orts prese nte d 
a n n uall y t o t he t w o i n de pe n de nt a n d n o n- o verla p pi n g U N C I R B at U N C a n d t he 
Mala wi Nati o nal Healt h Scie nce Researc h C o m mittee ( N H S R C).  

L C C C 1 9 0 5 
 
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PI: L a mec k C hi n ul a 
  
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/ D ate: 5. 0, 1 8 Dec 2 0 2 0 
 
Dec 1 8, 2 0 2 0 
 
3 0 
 
 
 
 
T he PI will mai ntai n a hi g h de gree of o versi g ht re gar di n g data ma na ge me nt, 
partici pa nt safet y, a n d pr oject i nte grit y. T h e PI will w or k cl osel y wit h t he researc h 
staff t o m o nit or partici pa nts’ safet y an d mi ni mize t he ris ks t o partici pa nts. I n 
a d diti o n, st u d y pr oce d ures are desi g ne d t o ma xi mize t he c o nfi de ntialit y a n d 
i nte grit y of partici pa nts’ data.   
 
7. 5  
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 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.  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 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.   
 
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, will be se nt 
t o b ot h U N C’s I R B a n d Mala wi N H S R C f or re vie w a n d a p pr o val pri or t o 
i m ple me ntati o n.   
7. 6  
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 or 
q ueries, s o urce d oc u me nts, S p o ns or-I n ve sti gat or c orres p o n de nce, 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 an 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 n e d patie nt c o nse nt f or ms). 
 
S o urce 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 a n d rec or d s 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. 
 
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 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. St u d y d oc u me nts will be ke pt o n file u ntil 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. 
7. 7  
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 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 
Declarati o n of Helsi n ki.  T he Pri nci pal I n vesti gat or is res p o ns i ble f or pers o nall y 
o verseei n g t he treat me nt of all st u d y patie nt s.  T he Pri nci pal I n vesti gat or m ust 
ass ure t hat all st u d y site pers o n nel, i n cl 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 pr otoc 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 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 ns tit uti o n or site will be 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 

L C C C 1 9 0 5 
 
C O N FI D E N TI A L 
PI: L a mec k C hi n ul a 
  
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/ D ate: 5. 0, 1 8 Dec 2 0 2 0 
 
Dec 1 8, 2 0 2 0 
 
3 1 
 
 
 
Re p ort F or ms. Peri o dicall y, m o nit ori n g vis its will be c o n d ucte d a n d t he Pri nci pal 
I n vesti gat or will pr o vi de access t o his/ her ori gi nal rec or ds t o per mit verificati o n 
of pr o per e ntr y of data. 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 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 acc urac y of t he data. 
8. 0  
R E F E R E N C E S 
            
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L C C C 1 9 0 5 
 
C O N FI D E N TI A L 
PI: L a mec k C hi n ul a 
  
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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3 9.   S mit h J S, Sa n usi B, S warts A, et al. A ra n d o mize d cli nical tr ial c o m pari n g cer vical 
d ys plasia treat me nt wit h cr y ot hera p y vs l o o p electr os ur gical e xcisi o n pr oce d ure i n 
HI V-ser o p ositi ve w o me n fr o m J o ha n nes b ur g, S o ut h Africa. A m J O bstet Gy nec ol . 
2 0 1 7. d oi: 1 0. 1 0 1 6/j.aj o g. 2 0 1 7. 0 3. 0 2 2 
4 0.   
K o hler R E, Ta n g J, G o pal S, et al . Hi g h rates of cer vical ca ncer a m o n g HI V-

L C C C 1 9 0 5 
 
C O N FI D E N TI A L 
PI: L a mec k C hi n ul a 
  
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/ D ate: 5. 0, 1 8 Dec 2 0 2 0 
 
Dec 1 8, 2 0 2 0 
 
3 4 
 
 
 
i nfecte d w o me n at a referral h os pital i n Mala wi. I nt J S T D AI D S. 2 0 1 6; 2 7( 9). 
d oi: 1 0. 1 1 7 7/ 0 9 5 6 4 6 2 4 1 5 5 9 2 9 9 9 
4 1.  
C u bie H A, M ort o n D, Ka w o n ga E, et  al. H P V pre vale nce i n w o me n atte n di n g 
cer vical scree ni n g i n r ural Mala wi  usi n g t he cartri d ge- base d X pert®  H P V assa y. J 
Cli n Vir ol. 2 0 1 7. d oi: 1 0. 1 0 1 6/j.jc v. 2 0 1 6. 1 1. 0 1 4. 
4 2.  
Tra n P L, Ke nfac k B, Ti nc h o F o g ue m E T, et al. Efficac y of  t her m oa blati o n i n 
treati n g cer vical preca ncer o us lesio ns i n a l o w-res o urce setti n g. I nt J W o me ns 
He alt h. 2 0 1 7. d oi: 1 0. 2 1 4 7/IJ W H. S 1 4 2 9 1 1. 
4 3.  
A n d o H, C o usi ns R, Y o u n g C. Ac hie v i n g sat urati o n i n t he matic a nal ysis: 
de vel o p me nt a n d refi ne me nt of a c o de b o o k. C o m p Psyc h ol o gy . 2 0 1 4. d oi: 
1 0. 2 4 6 6/ 0 3. C P. 3. 4. 
4 4.   Sa u va get C, M u w o n ge R, Sa n kara nara ya na n R. Meta-a nal ysis of t he effecti ve ness 
of cr y ot hera p y i n t he treat me nt of cer vical i ntrae pit helial ne o plasia. I nt J Gy nec ol 
O bstet . 2 0 1 3. d oi: 1 0. 1 0 1 6/j.ij g o. 2 0 1 2. 1 0. 0 1 4 
4 5.   
H off ma n S R, Le T, L oc k hart A, et al . Patter ns of persiste nt H P V i nfecti o n after 
treat me nt f or cer vical i ntrae pit helial neo plasia ( CI N): A s yste matic re vie w. I nt J 
C a ncer . 2 0 1 7. d oi: 1 0. 1 0 0 2/ijc. 3 0 6 2 3 
4 6.   
M ustafa R A, Sa ntess o N, K hati b R, et al. S yste matic re vie ws a n d meta-a nal yses of 
t he acc urac y of H P V tests, vis ual i ns pecti o n wit h acetic aci d, c yt ol o g y, a n d 
c ol p osc o p y. I nt J Gy nec ol O bstet. 2 0 1 6. d oi: 1 0. 1 0 1 6/j.ij g o. 2 0 1 5. 0 7. 0 2 4 
4 7.   
Z h o u X h ua. Ma xi m u m li keli h o o d esti mat ors of se nsiti vit y a n d s pecificit y 
c orrecte d f or verificati o n bias. C o m m u n St at - T he ory Met h o ds . 1 9 9 3. 
d oi: 1 0. 1 0 8 0/ 0 3 6 1 0 9 2 9 3 0 8 8 3 1 2 0 9  
 
9. 0  
A P P E N DI C E S 
9. 1  
I nf or me d C o nse nt F or m: L C C C 1 9 0 5:  A N o vel Cer vical Ca ncer Scree n-
a n d- Treat De m o nstrati o n Pr ojec t wit h H P V Self-testi n g a n d 
T her m oc oa g ulati o n f or W o me n i n Ma la wi Versi o n 4. 0 date d 0 6 Fe b 2 0 2 0 
( E n glis h a n d C hic he wa versi o ns). 
9. 1 
St ore d S peci me ns I nf or me d C o nse n t F or m Versi o n 4. 0 date d 0 6 Fe b 2 0 2 0 
( E n glis h a n d C hic he wa versi o ns) 
9. 2  
I n- De pt h I nter vie w I nf or me d C o nse nt F or m Versi o n 5. 0 date d 1 8 Dec 
2 0 2 0 ( E n glis h a n d C hic he wa versi o ns) 
9. 3  
I n- De pt h I nter vie w G ui de Versi o n 1. 0 date d 0 6 Se pt 2 0 1 9 ( E n glis h a n d 
C hic he wa versi o ns) 
9. 4  
I n- De pt h I nter vie w Q uesti o n naire Versi o n 1. 0 date d 0 6 Se pt 2 0 1 9 
( E n glis h a n d C hic he wa versi o ns)