A Double-blind, Single-center, Randomized, Placebo- and Positive-controlled, Parallel-group Trial With a Nested Crossover Part on the Electrocardiographic Effects 100 and 400 mg Pritelivir Per Day in Healthy Subjects: a Thorough QT/QTc Trial
Phase: PHASE1
Conditions: Healthy Subjects
Sponsor: AiCuris Anti-infective Cures AG

 
C o nfi de nti alit y St ate me nt  
T he i nf or mati o n c o ntai ne d herei n is c o nfi de ntial a n d t he s ole pr o pert y of Ai C uris. A n y u na ut h orize d use 
or discl os ure of s uc h i nf or mati o n wit h o ut t he pri or writte n a ut h orizati o n of Ai C uris is strictl y pr o hi bite d.  
Cli ni c al Tri al Pr ot o c ol  
AI C 3 1 6 -0 3 -I-0 7  
A d o u ble -bli n d, si n gle -ce nter, r a n d o mize d, pl ace b o - a n d p ositi ve -c o ntr olle d, p ar allel-gr o u p 
tri al wit h a neste d cr oss o ver p art o n t he electr oc ar di o gr a p hic effects of 1 0 0 a n d 4 0 0 m g  
priteli vir per d a y i n he alt h y s u bjects: a t h or o u g h Q T/ Q Tc tri al  
 
Pr o d uct/f or m ulati o n  
Priteli vir 1 0 0  m g  ta blets 
P hase  
P hase 1  
I n dicati o n 
N ot a p plica ble  
E u dra C T n u m b er  
2 0 2 2 -0 0 0 2 0 3 -1 2  
S p o ns or  
Ai C uris A nti -i nfecti ve C ures A G 
Frie dric h -E bert -Stras se 4 7 5 
4 2 1 1 7 W u p pertal, Ger ma n y  
 
 
Pri nci pal  I n vesti gat or 
Dr J or g Ta u bel, M D, F F P M, F E S C  
Ric h m o n d P har mac ol o g y Lt d.  
Trial Ce nter  
Ric h m o n d P har mac ol o g y Lt d.  
1a Ne wc o me n Street,  
L o n d o n Bri d ge,  
L o n d o n S E 1 1 Y R,  
U nite d Ki n g d o m  
Res p o nsi ble Me dical Direct or  
Dir k Kr o peit , M D, P h D 
Ai C uris A nti -i nfecti ve C ures A G 
 
 
Versi o n  
V 2 . 0 
Date  
2 5 N o v 2 0 2 2  
 

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
2 of 7 6  
 
A P P R O V A L SI G N A T U R E P A G E  
 
I ha ve rea d a n d a gree wit h t his pr ot oc ol a n d will f oll o w t he descri be d pr oce d ures. 
I a gree t o c o n d uct t he trial acc or di n g t o t he pr ot oc ol i n c o m plia nce wit h t he c urre nt acce pte d 
Declarati o n of Helsi n ki a n d t he I C H - G C P g ui deli nes. T he I n vestigat or(s) a gree(s) t o pr o vi de 
direct access t o s o urce data a n d trial -relate d d oc u me nts f or trial-relate d m o nit ori n g a n d a u diti n g 
b y t he S p o ns or a n d i ns pecti o n b y t he a p pr o priate re g ulat or y a ut h orities. 
 
Dr J or g Ta u bel, M D, F F P M, F E S C  
Pri nci pal I n vesti gat or  
Ric h m o n d P har mac ol o g y Lt d.  
 
 
Date, Si g nat ure  
Dir k Kr o peit, M D, P h D  
Ai C uris Res p o nsi ble P h ysicia n  
Ai C uris A nti -i nfecti ve C ures A G 
 
 
Date, Si g nat ure  
Res p o nsi ble Bi ostatisticia n  
Ric h m o n d P har mac ol o g y Lt d.  
 
 
Date, Si g nat ure  
P har mac o vi gila nce Ma na ger  
Ai C uris A nti -i nfecti ve C ures A G 
 
 
Date, Si g nat ure  
Res p o nsi ble P har mac o ki netics Ma na ger  
La b orat or y Hea d of P har mac o ki netics a n d P har mac o metrics  
Ai C uris A nti -i nfecti ve C ures A G 
 
 
Date, Si g nat ure  
 
2 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
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I N V O L V E D P A R TI E S 
 
I n v e sti g at or s 
T his will be a si n gle -ce nter trial. T he Pri nci pal I n vesti gat or will be:  
Dr J or g Ta u bel, M D, F F P M 
C hief E xec uti ve Officer  
Ric h m o n d P har mac ol o g y Lt d. 
1a Ne wc o me n Street,  
L o n d o n Bri d ge,  
L o n d o n, S E 1 1 Y R,  
U nite d Ki n g d o m 
   
 
  
S p o n s or  
P ositi o n  
N a me, Title  
Ai C uris Res p o nsi ble P h ysicia n  
Dir k Kr o peit, M D, P h D  
Hea d of Earl y Cli nical De vel o p me nt  
Ai C uris A nti -i nfecti ve C ures A G 
P har mac o ki netics Ma na ger  
 
La b orat or y Hea d of P har mac o ki netics a n d P har mac o metrics  
Ai C uris A nti -i nfecti ve C ures A G 
P har mac o vi gila nce Ma na ger  
 
 
P har mac o vi gila nce Ma na ger  
Ai C uris A nti -i nfecti ve C ures A G 
Cli nical Trial Ma na ger  
 
 
Cli nical Trial Ma n a ger 
Ai C uris A nti -i nfecti ve C ures A G 
Bi oa nal ytics C o or di nat or  
 
Bi oa nal ytical C o or di nat or  
Ai C uris A nti -i nfecti ve C ures A G 
Me dical Writi n g  
R
 
E xter nal Me dical Writi n g C o ns ulta nt f or  
Ai C uris A nti -i nfecti ve C ures A G 
 
 
 
3 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
4 of 7 6  
 
C o ntr a ct R e s e ar c h Or g a ni z ati o n( s)  
P ositi o n  
N a me, Title  
C o- I n vesti gat or 
 
Me dical Direct or  
Ric h m o n d P har mac ol o g y Lt d.  
1a Ne wc o me n Street  
L o n d o n Bri d ge  
L o n d o n , S E 1 1 Y R  
U nite d Ki n g d o m  
M o nit ori n g Pr oject C o or di nati o n  
A M S A d va nce d Me dical Ser vices Lt d.  
2 6 -2 8 Ha m mers mit h Gr o ve  
L o n d o n W 6 B A  
U nite d Ki n g d o m   
Pr oject Ma na ge me nt at cli nical trial 
site 
Direct or of St u d y Ma na ge me nt  
Ric h m o n d P har mac ol o g y Lt d.  
1a Ne wc o me n Street  
L o n d o n Bri d ge  
L o n d o n, S E 1 1 Y R  
U nite d Ki n g d o m  
Researc h P h ysicia n  
Lea d S pecialit y Researc h P h ysicia n  
Ric h m o n d P har mac ol o g y Lt d.  
1a Ne wc o me n Street  
L o n d o n Bri d ge  
L o n d o n , S E 1 1 Y R  
U nite d Ki n g d o m  
Res p o nsi ble Bi ostatisticia n  
Se ni or Bi os tatisticia n 
Ric h m o n d P har mac ol o g y Lt d.  
1a Ne wc o me n Street  
L o n d o n Bri d ge  
L o n d o n , S E 1 1 Y R  
U nite d Ki n g d o m   
C o ns ulta nt Statisticia n f or E C G 
a nal yses 
Statisti k Ge or g Fer ber G m b H,  
Rie he n,  
S witzerla n d  
Data Ma na ge me nt  
Hea d of Data Ma na ge me nt  
Ric h m o n d P har mac ol o g y Lt d.  
1a Ne wc o me n  Street  
L o n d o n Bri d ge  
L o n d o n , S E 1 1 Y R  
U nite d Ki n g d o m  
4 of 1 3 6

 
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V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
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P ositi o n  
N a me, Title  
P har mac o ki netic e val uati o n  
Ve n n Life Scie nces E D  
La ge M oste n 2 9  
N L -4 8 2 2 N K Bre da  
T he Net herla n ds  
Safet y la b orat or y  
T he D oct ors La b orat or y  
T he Hal o B uil di n g  
1 Ma ble d o n Place  
L o n d o n, W C 1 H 9 A X  
U nite d Ki n g d o m  
S A R S -C o V -2 p ol y merase c hai n 
reacti o n testi n g 
Ric h m o n d P har mac ol o g y Lt d.  
1a Ne wc o me n Street  
L o n d o n Bri d ge  
L o n d o n , S E 1 1 Y R  
U nite d Ki n g d o m  
Bi oa nal ytics  
A & M La b or f ür A nal yti k u n d Meta b olis m usf orsc h u n g Ser vice 
G m b H  
K o per ni k usstra ße 2 5  
5 0 1 2 6 Ber g hei m,  
Ger ma n y  
P har mac o ge n o mics  
I M G M La b orat ories G m b H 
L oc h ha mer Str. 2 9a  
Marti nsrie d,  
Ger ma n y  
P har mac o vi gila nce ( S A E re p orti n g)  
I Q VI A 
East p oi nt B usi ness Par k, Fair vie w  
D u bli n 3, Irela n d  
 
 
 
5 of 1 3 6

 
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C O N FI D E N TI A L  
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I N C A S E O F E M E R G E N C Y 
 
F or ur ge nt me dical a d vice t he Ai C uris Me dical E x pert o n d ut y is a vaila ble 2 4  h per da y u n der 
t he f oll o wi n g: 
2 4 h e mer ge nc y n u m ber  
N u m ber: 
 
 
F or re p orti n g of seri o us a d verse e ve nts, please f oll o w t he pr oce d ures descri be d i n 
Secti o n  6. 6. 4. 1. 8 . T he occ urre nce of S A Es will be n otifie d b y t he I n vesti gat or t o I Q VI A 
i m me diatel y, wit h o ut u n d ue dela y (at least wit hi n 2 4 h o urs) after bec o mi n g a ware of t heir 
occ urre nce b y c o m pleti n g t he c orres p o n di n g A E/ S A E e C R F w hic h ge nerates a n alert n otificati o n 
t o I Q VI A. If n o tra ns missi o n via e C R F/i nter net is p ossi ble, t he c o m plete d S A E f or m m ust be 
se nt t o t he f oll o wi n g: 
2 4 h S A E re p orti n g  
Free -F a x N u m ber: 
 
Or  
E m ail: 
 
 
 
6 of 1 3 6

 
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V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
7 of 7 6  
 
1 
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
Ai C uris A nti -i nfecti ve C ures A G 
Title of t he tri al: 
A d o u ble -bli n d, si n gle -ce nter, ra n d o mize d, place b o - a n d p ositi ve-c o ntr olle d, parallel -gr o u p trial wit h a 
neste d cr oss o ver part o n t he electr ocar di o gra p hic effects of 1 0 0 a n d 4 0 0  m g  priteli vir per da y i n 
healt h y s u bjects: a t h or o u g h Q T/ Q Tc trial  
Pri nci p al  I n vesti g at or: 
Dr. J or g Ta u bel  
St u d y ce nter(s):  
Ric h m o n d P har mac ol o g y  
Pl a n ne d tri al peri o d ( ye ars):  
Q 4 2 0 2 2  t o Q 2 2 0 2 3 
P h ase of de vel o p me nt:  
P hase 1  
O bjecti ves:  
Pri mar y o bjecti ve  
•  
t o defi ne t he effects of priteli vir o n t he Q TcF i nter val deri ve d fr o m 1 2 -lea d E C Gs i n c o m paris o n 
wit h place b o i n male a n d fe male s u bjects  
Sec o n dar y o bjecti ves  
•  
t o assess p har mac o ki netic pr o perties of m ulti ple d oses of priteli vir a n d t o e xa mi ne t he c orrelati o ns 
bet wee n priteli vir plas ma c o nce ntrati o n a n d its effects, if a n y, o n t he Q Tc F i nter val  
•  
t o e val uate a d diti o nal electr ocar di o gra p hic effects of priteli vir 
•  
t o s h o w t he trial’s assa y se nsiti vit y b y assessi n g t he effects of m o xifl o xaci n ( p ositi ve c o ntr ol vs. 
place b o) o n t he Q Tc F i nter val  
•  
t o i n vesti gate t he safet y a n d t olera bilit y of priteli vir 
Tri al desi g n  
S u bjects will be i n -h o use fr o m Da y -2 t o Da y 2 0 a n d will be ra n d o mize d t o o ne of t he 2  parallel 
treat me nt gr o u ps (as part of t he bli n d, b ot h gr o u ps will recei ve t he sa me n u m ber of ta blets a n d ca ps ules 
at t he sa me ti me p oi nts, t h o u g h s o me will be  ver u m a n d s o me will be  place b o  de pe n di n g o n t he 
ra n d o mize d re gi me n). Gr o u p 1 will recei ve a t hera pe utic a n d a s u pra -t hera pe utic d ose of priteli vir pl us 
m o xifl o xaci n place b o. Gr o u p 2 will recei ve priteli vir place b o as well as m o xifl o xaci n a n d matc hi n g 
place b o ( neste d cr oss o ver: Gr o u p 2a a n d Gr o u p 2 b). 1 2 -lea d E C G tri plicates will be rec or de d fr o m t he 
be dsi de 1 2 -lea d E C G o n t he Da y s -1, 1, 2, 6, 1 6, a n d 1 7 a n d will be a nal y ze d after war ds i n eac h gr o u p 
f or t hese 6 da ys of d oc u me ntati o n b y a bli n de d rea der. 
It is of n ote t hat H olter E C G data will be c ollecte d i n parallel at S cree ni n g t o e xcl u de a n y o ne wit h pre-
e xisti n g car diac a b n or malities as well as o n Da ys -1, 1, 2, 6, 1 6, a n d 1 7  as a bac k -u p f or t he be dsi de 
1 2 -lea d E C Gs. 
I n Gr o u p 1, 3 2 male a n d fe male s u bjects (at least 1 2 s u bjects per se x) will recei ve a l oa di n g d ose of 
4 0 0  m g  priteli vir o n Da y 1. After war ds t he y will recei ve 1 0 0  m g  priteli vir q d fr o m Da y  2 t o 6 a n d 
4 0 0  m g  priteli vir q d fr o m Da y 7 t o 1 6. F urt her m ore, t hese s u bjects will recei ve matc hi n g m o xifl o xaci n  
place b o o n t he Da ys 2 a n d 1 7.  
I n Gr o u p 2, 3 2 male a n d fe male s u bjects (at least 1 2 s u bjects per se x) will recei ve t he res pecti ve 
a m o u nts of ta blets of matc hi n g priteli vir  place b o fr o m Da y 1 t o Da y 1 6 i n Gr o u p 2 as ver u m ta blets i n 
Gr o u p 1 . F urt her m ore, s u bjects i n Gr o u p 2a ( 1 6 male a n d fe male s u bjects) will recei ve 4 0 0 m g  
m o xifl o xaci n o n Da y 2 a n d matc hi n g m o xifl o xaci n  place b o o n Da y 1 7 a n d s u bjects i n Gr o u p 2 b  ( 1 6 
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C O N FI D E N TI A L  
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male a n d fe male s u bjects) will recei ve 4 0 0  m g  m o xifl o xaci n o n Da y 1 7 a n d matc hi n g m o xifl o xaci n  
place b o o n Da y 2.  
T o  mai ntai n d o u ble -bli n di n g t he f oll o wi n g meas ures will be nee de d,  a n d data e val uati o ns ge nerate d f or 
Gr o u p 1 a n d Gr o u p  2: 
•  
1 2 -lea d te n sec o n d E C G tri plicates will be di gitall y rec or de d a n d a nal y ze d (fr o m t he be dsi de 1 2 -
lea d-E C G de vices ) i n s u bjects of b ot h gr o u ps o n t he Da ys -1, 1, 2, 6, 1 6 a n d 1 7.  
•  
P K sa m ples will be c ollecte d fr o m s u bjects of b ot h gr o u ps o n t he Da ys 1, 6, a n d 1 6 f or priteli vir 
a n d t he meta b olites AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 as well as f or m o xifl o xaci n o n t he Da ys 2 a n d 1 7.  
•  
O ver -e nca ps ulate d m o xifl o xaci n - a n d matc hi n g place b o will be use d . 
N u m ber o f s u bjects ( pl a n ne d): 
6 4  ( 3 2 s u bjects per gr o u p; at least 1 2 of eac h se x i n eac h gr o u p) 
Di a g n osis a n d m ai n criteri a f or i ncl usi o n:  
A d ult healt h y male a n d fe male s u bjects of a n y et h nic ori gi n ( 1 8 t o 4 5 y ears i ncl usi v e). 
Test pr o d uct, d ose,  a n d m o de of a d mi nistr ati o n:  
•  
Priteli vir 1 0 0  m g  ta blet, oral a d mi nistrati o n   
D ur ati o n of tre at me nt:  
S u bjects will be i n -h o use fr o m Da y -2 t o Da y 2 0.  
Refere nce t her a p y, d ose,  a n d m o de of a d mi nistr ati o n  
•  
Priteli vir place b o ta blets  
•  
M o xifl o xaci n  4 0 0  m g  ca ps ule, oral a d mi nistrati o n 
•  
Matc hi n g m o xifl o xaci n place b o ca ps ule, oral a d mi nistrati o n 
Criteri a f or e v al u ati o n:  
Efficac y  
N ot a p plica ble  
E C G varia bles  
T he f oll o wi n g para meters will be a nal yze d after bei n g deri ve d fr o m t he be dsi de 1 2 -lea d E C G 
meas ure me nts ( 1 0 -sec o n d tri plicate rec or di n gs): 
Pri mar y varia ble (relate d t o t he pri mar y e n d p oi nt)  
•  
Q Tc usi n g Fri dericia c orrecti o n met h o d ( Q Tc F)  
Sec o n dar y varia bles  
•  
Heart rate  
•  
P R i nter val  
•  
Q R S i nter val  
•  
U nc orrecte d Q T  i nter val 
•  
C ha n ge i n E C G m or p h ol o gical patter ns  
P har mac o ki netics  
T he f oll o wi n g para meters of priteli vir a n d its meta b olites AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 will be 
deter mi ne d:  
•  
C 0 h (tr o u g h le vels) of priteli vir, AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 o n t he Da ys 1 t o 5 a n d 1 3 t o 1 5, 
•  
A U C τ, Cma x , tma x , tlag, C L/ F, Vd/ F, M R T of priteli vir i n plas ma o n Da y 1, 
•  
A U C τ,ss, Css, ma x, Cmi n , Css,a v, tma x , C Lss/ F, Vd,ss/ F, M R T of priteli vir i n plas ma o n Da ys 6 a n d 1 6, 
•  
A U C τ, Cma x , tma x , tla g, M R T of meta b olites AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 i n plas ma o n Da y 1. 
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•  
A U C τ,ss, Cma x,ss , Cmi n , Css,a v, tma x , M R T of meta b olites AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 i n plas ma o n 
Da ys  6 a n d 1 6.  
M o xifl o xaci n plas ma c o nce ntrati o ns will be meas ure d usi n g a vali date d assa y f or t he p ur p ose of t he 
c o nce ntrati o n -effect a nal ysis t o de m o nstrate assa y se nsiti vit y. O nl y  c o nce ntrati o ns will be re p orte d, b ut 
n o p har mac o ki netic  a nal ysis will be re p orte d . 
P har mac o ge n o mics/ ge ne e x pressi o n  
P ost -h oc a nal ysis of alleles ass ociate d wit h altere d dr u g meta b olis m/ dis p ositi o n ma y be perf or me d. 
Safet y a n d tolera bilit y  
•  
O vera ll t olera bilit y 
•  
Nat ure, fre q ue nc y, d urati o n, i nte nsit y, seri o us ness, a n d ca usalit y of a d verse e ve nts  
•  
P h ysical e xa mi nati o n, vital si g ns, a n d b o d y te m perat ure  
•  
Cli nical la b orat or y para meters: ser u m c he mistr y, he mat ol o g y a n d c oa g ulati o n para meters, 
uri nal ysis  
•  
Sta n dar d 1 2 -lea d E C G c ollecte d usi n g a 1 2-lea d E C G de vice  
Date of pr ot oc ol : 2 5N o v 2 0 2 2  
 
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S C H E M A TI C O V E R VI E W O F T H E T RI A L D E SI G N  
 
 
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S C H E D U L E O F T RI A L P R O C E D U R E S  
Peri o d  
Scree ni n g  
Tre at me nt Peri o d  
E o T 
D a y  
-2 1  
t o -3  
- 2 
- 1 
1 
2 
3 
t o 5 
6 
7 
t o 1 5 
1 6  
1 7  
1 8  
t o 1 9 
2 0  
3 0  
t o 3 7 
A d missi o n t o P hase 1 u nit  
 
X 
 
 
 
 
 
 
 
 
 
 
 
I nf or me d c o nse nt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Me dical hist or y  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hei g ht a n d wei g ht  
X  
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
C hec k o n lifest yle a n d ha bits  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Uri ne test f or dr u g a b use  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Alc o h ol breat h test  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
P h ysical e xa mi nati o n  
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
B o d y te m perat ure  
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Ser ol o g y  1) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
S A R S - C O V- 2 m o nit ori n g  
X  2) 
 
Ser u m β- H C G  3 ) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Uri ne β- H C G  3 ) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
F S H test  4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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Cli nical Trial Pr ot oc ol 
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V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
1 2  of 7 6  
 
Peri o d  
Scree ni n g  
Tre at me nt Peri o d  
E o T 
D a y  
-2 1  
t o -3  
- 2 
- 1 
1 
2 
3 
t o 5 
6 
7 
t o 1 5 
1 6  
1 7  
1 8  
t o 1 9 
2 0  
3 0  
t o 3 7 
Vital si g ns  5 ) 6 ) 
X 
X 
X 
 
 
 
X  5 ) 
 
X  5 ) 
 
 
X 
X 
1 2 -lea d E C G 5 ) 7 ) 
X 
X 
X 
X  5 ) 
X 
 
X  5 ) 
 
X  5 ) 
X 
 
X 
X 
H olter - E C G 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
 
Safet y la b orat or y  5), 8) 
X 
X 
 
 
 
 
X  5) 
 
X  5) 
 
 
X 
X 
P har mac o ge n o mics sa m ple  
 
 
 
X  9)  
 
 
 
 
 
 
 
 
 
D osi n g : 
P riteli vir 4 0 0 m g  ( Gr o u p 1)  
O R  
M atc hi n g place b o ( Gr o u p 2)  
 
 
 
X  
 
 
 
X  
X  
 
 
 
 
D osi n g : 
P riteli vir 1 0 0  m g  ( Gr o u p 1) 
O R  
M atc hi n g place b o ( Gr o u p 2)  
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
D osi n g : 
M o xifl o xaci n ( Gr o u p 2 o nl y) 
O R  
M atc hi n g place b o ( Gr o u ps 1 
a n d 2) 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
1 2 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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C O N FI D E N TI A L  
1 3  of 7 6  
 
Peri o d  
Scree ni n g  
Tre at me nt Peri o d  
E o T 
D a y  
-2 1  
t o -3  
- 2 
- 1 
1 
2 
3 
t o 5 
6 
7 
t o 1 5 
1 6  
1 7  
1 8  
t o 1 9 
2 0  
3 0  
t o 3 7 
P K bl o o d sa m ples f or plas ma 
priteli vir a n d meta b olites 
P K  5) 
 
 
 
X  5 ) 
Tr o u g h 
sa m ple 
D 2  
Tr o u g h 
sa m ples 
D 3 - 5 
X  5 ) 
Tr o u g h 
sa m ples 
D 1 3 - 1 5 
X  5 ) 
Tr o u g h 
sa m ple 
D 1 7  
 
 
 
P K bl o o d sa m ples f or 
m o xifl o xaci n deter mi nati o n  5) 
 
 
 
 
X  5) 
 
 
 
 
X  5) 
 
 
 
A d verse e ve nts 
q uesti o ni n g  1 0 ) 
 
X 
X 
X   
X   
X   
X   
X   
X   
X   
X 
X 
X 
C o nc o mita nt me dicati o n  1 1 ) 
X 
X 
X 
X   
X   
X   
X   
X   
X   
X   
X 
X 
X 
Disc har ge fr o m P hase 1 u nit  
 
 
 
 
 
 
 
 
 
 
 
X 
 
β -H C G = beta -h u ma n c h ori o nic g o na d otr o pi n ; E C G =electr ocar di o gra m; E o T = E n d of Trial; F S H =f ollical sti m ulati n g h or m o ne; P K = p har mac o ki netics; 
S A R S -C O V - 2 =se vere ac ute res pirat or y s y n dr o me c or o na vir us 2 
1)  HI V -I- a n d HI V -II-anti b o dies , H B s A g, a nti-H Bc (I g G + I g M), a n d a nti -H C V  
2)  C O VI D -1 9 tests will be carrie d o ut at re g ular i nter vals, pri or t o e ntr y i n t he u nit a n d t hr o u g h o ut t he resi de ntial peri o d as per t h e latest Ric h m o n d 
P har mac ol o g y  C O VI D -1 9 I nfecti o n C o ntr ol G ui del i nes a n d pre-e ntr y al g orit h ms.  
3)  W o me n  o nl y  
4)  W o me n of n o n -c hil d beari n g p ote ntial w h o ha ve a hist or y of n o me nses of at least 2 4 m o nt hs  
5)  Detaile d ti mi n gs of i n di vi d ual P K sa m ples, safet y la b sa m ples, vital si g n meas ure me nts  a n d s u pi ne ti mes, E C Gs , a n d meals are  gi ve n i n  ta ble Ti mi n g of 
re peat meas ure sa m ples. 
6)  Vital si g ns i ncl u de bl o o d press ure  a n d p ulse rate  t hat will be meas ure d after a s u pi ne ti me of at least 5 mi n utes.  
7)  1 2 -lea d E C G will be meas ure d i n tri plicate after a rest peri o d of at least 1 0 mi n utes. 
8)  Ser u m c he mistr y, he mat ol o g y a n d c oa g ulati o n para meters, uri nal ysis  
9)  Pre -d ose  
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C O N FI D E N TI A L  
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1 0)  S ki n reacti o n c hec ks i ncl u de d  
1 1)  O n d osi n g da ys, t he  c o nc o mita nt me dicati o n s h o ul d al wa ys be c hec ke d pre -d ose  
 
 
1 4 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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C O N FI D E N TI A L  
1 5  of 7 6  
 
TI MI N G O F R E P E A T M E A S U R E S A M P L E S  
St u d y 
D a y  
Ti me ( h)  
P K s a m pli n g 1  a) 
( pl as m a) 
P K s a m pli n g 2  b) 
( pl as m a) 
Me als
 c) 
Vit al Si g ns  d) 
E C G  e) 
He m at ol o g y/  
Bi oc he mistr y/  
C o a g ul ati o n  
D a y  - 1 
- 1 
 
 
 
 
X 
 
-4 0  mi ns  
 
 
 
 
X  
 
-2 0  mi ns  
 
 
 
 
X 
 
0 
 
 
 
X 
 
 
1 5  mi ns  
 
 
 
 
X 
 
3 0  mi ns  
 
 
 
 
X 
 
4 5  mi ns  
 
 
 
 
X 
 
1  
 
 
 
 
X  
 
1. 5  
 
 
 
 
 
 
2 
 
 
 
X 
X 
 
3 
 
 
 
 
X 
 
4 
 
 
X  c) 
X 
X 
 
5 
 
 
 
 
X 
 
6 
 
 
 
 
X 
 
7  
 
 
 
 
X  
 
8 
 
 
X  
 
X  f) 
 
1 5 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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C O N FI D E N TI A L  
1 6  of 7 6  
 
St u d y 
D a y  
Ti me ( h)  
P K s a m pli n g 1  a) 
( pl as m a) 
P K s a m pli n g 2  b) 
( pl as m a) 
Me als
 c) 
Vit al Si g ns  d) 
E C G  e) 
He m at ol o g y/  
Bi oc he mistr y/  
C o a g ul ati o n  
1 0  
 
 
 
 
 
 
1 1  
 
 
 
 
 
 
1 2  
 
 
X 
X 
X 
 
D a y  1 
- 1 
 
 
 
 
X 
 
-4 0  mi n s 
 
 
 
 
X 
 
-2 0  mi n s 
 
 
 
 
X 
 
Pre- d ose  ( 0 h)  
X 
 
 
 
 
 
1 5  mi ns  
X 
 
 
 
X 
 
3 0  mi ns  
X  
 
 
 
X  
 
4 5  mi ns  
X 
 
 
 
X 
 
1 
X 
 
 
 
X 
 
1. 5  
X 
 
 
 
 
 
2 
X 
 
 
 
X 
 
3 
X 
 
 
 
X 
 
4 
X 
 
X  c) 
 
X 
 
5  
X  
 
 
 
X  
 
6 
X 
 
 
 
X 
 
1 6 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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C O N FI D E N TI A L  
1 7  of 7 6  
 
St u d y 
D a y  
Ti me ( h)  
P K s a m pli n g 1  a) 
( pl as m a) 
P K s a m pli n g 2  b) 
( pl as m a) 
Me als
 c) 
Vit al Si g ns  d) 
E C G  e) 
He m at ol o g y/  
Bi oc he mistr y/  
C o a g ul ati o n  
7 
X 
 
 
 
X 
 
8  
X  
 
X  
 
X  f) 
 
1 0  
X 
 
 
 
 
 
1 1  
 
 
 
 
 
 
1 2  
X 
 
X 
 
X 
 
D a y  2 
- 1 
 
 
 
 
X 
 
-4 0  mi n s 
 
 
 
 
X 
 
-2 0  mi n s 
 
 
 
 
X 
 
Pre -d ose ( 0  h)  
X  
X  
 
 
 
 
1 
 
X 
 
 
X 
 
2 
 
X 
 
 
X 
 
3 
 
X 
 
 
X 
 
4 
 
X 
X  c) 
 
X 
 
5 
 
X 
 
 
X 
 
6 
 
X 
 
 
X 
 
7  
 
X  
 
 
X  
 
8 
 
X 
X 
 
X  f) 
 
1 7 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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C O N FI D E N TI A L  
1 8  of 7 6  
 
St u d y 
D a y  
Ti me ( h)  
P K s a m pli n g 1  a) 
( pl as m a) 
P K s a m pli n g 2  b) 
( pl as m a) 
Me als
 c) 
Vit al Si g ns  d) 
E C G  e) 
He m at ol o g y/  
Bi oc he mistr y/  
C o a g ul ati o n  
1 2 
 
 
X 
 
 
 
Da y  3  
Pre -d ose ( 0  h)  
X  
 
 
 
 
 
1 
 
 
X 
 
 
 
Da y  4 
Pre- d ose ( 0  h)  
X 
 
 
 
 
 
1 
 
 
X 
 
 
 
Da y  5 
Pre- d ose ( 0  h)  
X 
 
 
 
 
 
1 
 
 
X 
 
 
 
D a y  6 
- 1 
 
 
 
 
X 
 
-4 0  mi n s 
 
 
 
 
X  
 
-2 0  mi n s 
 
 
 
 
X 
 
Pre- d ose ( 0  h)  
X 
 
 
X 
 
X 
1 5  mi ns  
X 
 
 
 
 
 
3 0  mi ns  
X 
 
 
 
 
 
4 5  mi ns  
X 
 
 
 
 
 
1 
X 
 
 
 
X 
 
1. 5  
X  
 
 
 
 
 
2 
X 
 
 
X 
X 
 
1 8 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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C O N FI D E N TI A L  
1 9  of 7 6  
 
St u d y 
D a y  
Ti me ( h)  
P K s a m pli n g 1  a) 
( pl as m a) 
P K s a m pli n g 2  b) 
( pl as m a) 
Me als
 c) 
Vit al Si g ns  d) 
E C G  e) 
He m at ol o g y/  
Bi oc he mistr y/  
C o a g ul ati o n  
3 
X 
 
 
 
X 
 
4  
X  
 
X  c) 
X  
X  
 
5 
X 
 
 
 
X 
 
6 
X 
 
 
 
X 
 
7 
X 
 
 
 
X 
 
8 
X 
 
X 
 
X  f) 
 
1 0  
X 
 
 
 
 
 
1 1  
 
 
 
 
 
 
1 2  
X  
 
X  
X  
X  
 
Da y  7 
2 4  
X 
 
 
 
X 
 
Da y  1 3  
Pre- d ose ( 0  h)  
X 
 
 
 
 
 
1 
 
 
X 
 
 
 
Da y  1 4  
Pre- d ose ( 0  h)  
X 
 
 
 
 
 
1 
 
 
X 
 
 
 
Da y  1 5  
Pre- d ose ( 0  h)  
X 
 
 
 
 
 
1  
 
 
X  
 
 
 
D a y  1 6  
- 1 
 
 
 
 
X 
 
1 9 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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C O N FI D E N TI A L  
2 0  of 7 6  
 
St u d y 
D a y  
Ti me ( h)  
P K s a m pli n g 1  a) 
( pl as m a) 
P K s a m pli n g 2  b) 
( pl as m a) 
Me als
 c) 
Vit al Si g ns  d) 
E C G  e) 
He m at ol o g y/  
Bi oc he mistr y/  
C o a g ul ati o n  
-4 0  mi n s 
 
 
 
 
X 
 
-2 0  mi n s 
 
 
 
 
X  
 
Pre- d ose ( 0  h)  
X 
 
 
X 
 
X 
1 5  mi ns  
X 
 
 
 
 
 
3 0  mi ns  
X 
 
 
 
 
 
4 5  mi ns  
X 
 
 
 
 
 
1 
X 
 
 
 
X 
 
1. 5  
X 
 
 
 
 
 
2  
X  
 
 
X  
X  
 
3 
X 
 
 
 
X 
 
4 
X 
 
X  c) 
X 
X 
 
5 
X 
 
 
 
X 
 
6 
X 
 
 
 
X 
 
7 
X 
 
 
 
X 
 
8 
X 
 
X 
 
X  f) 
 
1 0  
X  
 
 
 
 
 
1 1  
 
 
 
 
 
 
2 0 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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C O N FI D E N TI A L  
2 1  of 7 6  
 
St u d y 
D a y  
Ti me ( h)  
P K s a m pli n g 1  a) 
( pl as m a) 
P K s a m pli n g 2  b) 
( pl as m a) 
Me als
 c) 
Vit al Si g ns  d) 
E C G  e) 
He m at ol o g y/  
Bi oc he mistr y/  
C o a g ul ati o n  
1 2  
X 
 
X 
X 
X 
 
D a y  1 7  
-1  
 
 
 
 
X  
 
-4 0  mi n s 
 
 
 
 
X 
 
-2 0  mi n s 
 
 
 
 
X 
 
Pre- d ose ( 0  h)  
X 
X 
 
 
 
 
1 
 
X 
 
 
X 
 
2 
 
X 
 
 
X 
 
3 
 
X 
 
 
X 
 
4  
 
X  
X  c) 
 
X  
 
5 
 
X 
 
 
X 
 
6 
 
X 
 
 
X 
 
7 
 
X 
 
 
X 
 
8 
 
X 
X 
 
X  f) 
 
1 1  
 
 
 
 
 
 
1 2  
 
 
X 
 
 
 
2 4  
 
 
 
 
 
 
2 1 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
2 2  of 7 6  
 
St u d y 
D a y  
Ti me ( h)  
P K s a m pli n g 1  a) 
( pl as m a) 
P K s a m pli n g 2  b) 
( pl as m a) 
Me als
 c) 
Vit al Si g ns  d) 
E C G  e) 
He m at ol o g y/  
Bi oc he mistr y/  
C o a g ul ati o n  
Da y  2 0  
M or ni n g  
 
 
 
X 
X 
X 
a) P K sa m ple 1: p riteli vir a n d meta b olites i n plas ma. 
b)  P K sa m ple 2:  mo xifl o xaci n i n plas ma.  
c) O n D -1 a n d d osi n g da ys, t he first meal will be l u nc h gi ve n at H  4 p ost d ose. After n o o n s nac k will be gi ve n at H  7 a n d di n ner at H  1 1.  
d)  Vital si g ns i ncl u de bl o o d press ure, p ulse rate, will be meas ure d after a s u pi ne ti me of at least 5 mi n.  
e) 1 2 -lea d E C G will be meas ure d i n tri plicate after a rest peri o d of at least 1 0 mi n. 
f) 
Li g ht e xercise t o be u n derta ke n after H  8 E C G (F urt her details t o be i ncl u de d i n S t u d y O perati o ns M a n ual [S O M ]) 
2 2 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
2 3  of 7 6  
 
T A B L E O F C O N T E N T S  
A p pr o val si g nat ure pa ge ................................................................................................................. 2 
I n v ol ve d parties ............................................................................................................................... 3 
I n case of e mer ge nc y ...................................................................................................................... 6 
1  
S y n o psis .................................................................................................................. 7  
Sc he matic o ver vie w of t he trial desi g n  ......................................................................................... 1 0 
Sc he d ule of trial pr oce d ures  .......................................................................................................... 1 1 
Ti mi n g of re peat meas ure sa m ples  ............................................................................................... 1 5 
Ta ble of c o nte nts ........................................................................................................................... 2 3  
List of a b bre viati o ns ..................................................................................................................... 2 6  
2  
I ntr o d ucti o n ........................................................................................................... 3 0 
2. 1  
Bac k gr o u n d i nf or mati o n ................................................................................ 3 0 
2. 2  
Rati o nale f or t he trial  ..................................................................................... 3 0 
2. 3  
Ris k/ be nefit assess me nt  ................................................................................. 3 0 
3  
Trial o bjecti ves ...................................................................................................... 3 3  
4  
Trial desi g n  ........................................................................................................... 3 3 
4. 1  
O verall tr ial desi g n ........................................................................................ 3 3 
4. 2  
Disc ussi o n of desi g n a n d c h oice of c o ntr ol gr o u ps ....................................... 3 4  
5  
Selecti o n of trial p o p ulati o n .................................................................................. 3 5  
5. 1  
I ncl usi o n criteria ............................................................................................ 3 5 
5. 2  
E xcl usi o n criteria  ........................................................................................... 3 6 
5. 3  
E n d of trial ..................................................................................................... 3 8  
6  
I n vesti gati o nal pla n a n d pr oce d ures ...................................................................... 3 8 
6. 1  
Trial pr oce d ures  ............................................................................................. 3 8 
6. 1. 1  
Scree ni n g  ................................................................................................ 3 8 
6. 1. 2  
Treat me nt P hase  ..................................................................................... 3 8 
6. 1. 3  
E n d of Trial e xa mi nati o n ( Da y 3 0- 3 7)  ................................................... 3 8 
6. 1. 4  
Earl y Ter mi nati o n  ................................................................................... 3 9 
6. 1. 5  
Criteria f or wit h dra wal  ........................................................................... 3 9 
6. 1. 6  
St o p pi n g criteria ..................................................................................... 4 0  
6. 2  
Treat me nts  ..................................................................................................... 4 0 
6. 2. 1  
R o ute a n d a d mi nistrati o n  ........................................................................ 4 0 
6. 2. 2  
Selecti o n of d oses ................................................................................... 4 1  
6. 2. 3  
Descri pti o n of i n vesti gati o nal pr o d uct ................................................... 4 2  
6. 2. 4  
C o nc o mita nt me dicati o ns  ....................................................................... 4 5 
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Cli nical Trial Pr ot oc ol 
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C O N FI D E N TI A L  
2 4  of 7 6  
 
6. 2. 5  
Dietar y a n d ot her restricti o ns  ................................................................. 4 5 
6. 2. 6  
Treat me nt c o m plia nce  ............................................................................ 4 6 
6. 3  
Assi g n me nt of s u bjects t o treat me nt gr o u ps .................................................. 4 7  
6. 4  
Bli n di n g ......................................................................................................... 4 7  
6. 4. 1  
Mai nte na nc e of ra n d o mizati o n c o de bli n di n g  ........................................ 4 7 
6. 4. 2  
Pr oce d ure f or u n bli n di n g i n di vi d ual ra n d o mizati o n c o des ..................... 4 8  
6. 5  
E x pecte d d urati o n of s u bject partici pati o n .................................................... 4 8  
6. 6  
Trial assess me nt met h o ds  .............................................................................. 4 8 
6. 6. 1  
De m o gra p hics a n d s u bject c haracteristics  .............................................. 4 9 
6. 6. 2  
Efficac y  ................................................................................................... 4 9 
6. 6. 3  
P har mac o ki netics .................................................................................... 4 9  
6. 6. 4  
Safet y  ...................................................................................................... 5 2 
6. 6. 5  
A p pr o priate ness of meas ure me nts  .......................................................... 6 2 
6. 7  
Data ha n dli n g ................................................................................................. 6 3  
6. 7. 1  
Rec or ds a n d re p orts ................................................................................ 6 3  
6. 7. 2  
M o nit ori n g .............................................................................................. 6 4  
6. 8  
C ha n ges i n t he c o n d uct of t he trial ................................................................ 6 4  
7  
Data Ma na ge me nt  ................................................................................................. 6 4 
8  
Statisti cs ................................................................................................................ 6 5 
8. 1  
Deter mi nati o n of sa m ple size  ........................................................................ 6 5 
8. 2  
Defi niti o n of trial p o p ulati o ns  ....................................................................... 6 5 
8. 2. 1  
Safet y Set  ................................................................................................ 6 5 
8. 2. 2  
P har mac o ki netics Set  .............................................................................. 6 5 
8. 2. 3  
E C G Set  .................................................................................................. 6 6 
8. 2. 4  
A nal ysis set f or c o nce ntrati o n -Q T a nal ysis  ............................................ 6 6 
8. 3  
E n d p oi nts ....................................................................................................... 6 6  
8. 4  
A nal yses  ......................................................................................................... 6 7 
8. 4. 1  
E C G varia bles  ......................................................................................... 6 7 
8. 4. 2  
P h ar mac o ki netic a nal yses  ....................................................................... 6 8 
8. 4. 3  
Safet y a nal yses  ....................................................................................... 6 9 
9  
A d mi nistrati ve Pr oce d ures  .................................................................................... 6 9 
9. 1  
Et hics C o m mittee a n d Re g ulat or y A ge nc y a p pr o val ..................................... 6 9  
9. 2  
G C P c o m plia nce  ............................................................................................ 7 0 
9. 3  
Re g ulat or y a p pr o val  ....................................................................................... 7 0 
9. 4  
Et hical c o n d uct of t he trial ............................................................................. 7 0  
9. 5  
S u bject i nf or mati o n a n d i nf or me d c o nse nt .................................................... 7 0  
9. 6  
Pre mat ure ter mi nati o n or disc o nti n uati o n of t he trial .................................... 7 1  
9. 7  
C o nfi de ntialit y  ............................................................................................... 7 1 
1 0  
A d mi n istrati ve res p o nsi bilities ............................................................................. 7 2 
1 0. 1  
Pr ot oc ol a d here nce a n d I n vesti gat or a gree me nt  ............................................ 7 2 
1 0. 2  
Et hics  ............................................................................................................. 7 2 
2 4 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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C O N FI D E N TI A L  
2 5  of 7 6  
 
1 0. 3  
I n de m nit y/lia bilit y a n d i ns ura nce .................................................................. 7 3 
1 0. 4  
Pr ot oc ol ma na ge me nt .................................................................................... 7 3  
1 0. 5  
E n d of trial n otificati o n  .................................................................................. 7 3 
1 0. 6  
D oc u me ntati o n a n d rete nti o n of rec or ds ........................................................ 7 3  
1 0. 7  
M o nit ori n g ..................................................................................................... 7 3  
1 0. 8  
Data ma na ge me nt  .......................................................................................... 7 3 
1 0. 9  
Statistics  ......................................................................................................... 7 3 
1 0. 1 0  
Re p ort writi n g  ................................................................................................ 7 3 
1 0. 1 1  
P osti n g or s u b missi o n of s u m mar y of cli nical trial re p ort t o c o m pete nt 
a ut h orities of me m ber states c o ncer ne d a n d E Cs  .......................................... 7 4 
1 0. 1 2  
Q ualit y ass ura nce  ........................................................................................... 7 4 
1 0. 1 3  
Fi na nci n g a n d i ns ura nce ................................................................................ 7 4  
1 0. 1 4  
P u blicati o n of res ults  ..................................................................................... 7 4 
Refere nces   
............................................................................................................................... 7 5 
1 1  
S u m mar y of c ha n ges ............................................................................................. 7 6  
1 1. 1  
Pr ot oc ol Versi o n 2 ......................................................................................... 7 6  
A p pe n di x 1  
Di visi o n of AI D S ( D AI D S) Ta ble f or Gra di n g t he Se verit y of A d ult a n d 
Pe diatric A d verse E ve nts ( C o rrecte d Versi o n 2. 1, J ul y 2 0 1 7) ............................. 7 7 
A p pe n di x 2  
R ules i n t he e ve nt of a dr u g- relate d A E ................................................................ 7 8 
A p pe n di x 3  
Ris k miti gati o n ta ble  ............................................................................................. 7 9 
A p pe n di x 4  
A da pti ve feat ures of trial desi g n  ........................................................................... 8 0 
A p pe n di x 5  
F D A res p o nse t o T Q T trial desi g n ........................................................................ 8 1  
A p pe n di x 6  
Data pr ocessi n g sc he d ule t o t he pr ot oc ol .............................................................. 8 2  
 
2 5 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
2 6  of 7 6  
 
LI S T O F A B B R E VI A TI O N S 
A b bre vi ati o n  
E x pl a n ati o n  
A E  
a d verse e ve nt  
AI D S  
ac q uire d i m m u ne deficie nc y s y n dr o me  
A U C  
area u n der t he a nal yte c o nce ntrati o n -ti me c ur ve  
β- H C G  
beta h u ma n c h ori o nic g o na d otr o pi n  
B MI 
b o d y mass i n de x  
C A 
C o m pete nt A ut h orit y  
C a v 
a vera ge plas ma c o nce ntrati o n  
C K 
creati ne ki nase  
C L/ F  
t otal a p pare nt cleara nce  
C ma x  
m a xi m u m o bser ve d a nal yte plas ma c o nce ntrati o n  
C mi n  
mi ni m u m o bser ve d a nal yte plas ma c o nce ntrati o n  
C O VI D -1 9  
c or o na vir us disease 2 0 1 9  
C R O 
C o ntract Researc h Or ga nizati o n  
C Y P  
c yt oc hr o me P is oe nz y me  
D AI D S  
D i visi o n of AI D S  
D B P  
diast olic bl o o d press ure  
D DI  
dr u g -dr u g i nteracti o ns  
D H P  
Data Ha n dli n g Pr ot oc ol  
D N A  
de o x yri b o n ucleic aci d  
E C  
Et hics C o m mittee  
E C G 
electr ocar di o gra m 
e C R F 
electr o nic case re p ort f or m  
E D C  
electr o nic data ca pt ure  
E o T  
E n d of T rial 
F D A  
( U nite d States) F o o d a n d Dr u g A d mi nistrati o n 
F S H  
f ollicle sti m ulati n g h or m o ne 
G C P  
G o o d  Cli nical Practice  
G M P  
G o o d Ma n ufact uri n g  Practice  
G P  
Ge neral Practiti o ner  
H Bc  
he patitis B c ore a nti ge n  
H Bs A g  
he patitis B s urface a nti ge n  
H B V  
he patitis B vir us  
H C V  
he patitis C vir us  
h E R G 
h u ma n  et her-à-g o -g o -relate d ge ne  
HI V  
h u ma n i m m u n o deficie nc y vir us  
2 6 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
2 7  of 7 6  
 
A b bre vi ati o n  
E x pl a n ati o n  
H R  
heart rate  
H S V  
her pes si m ple x vir us  
I C5 0 
c o nce ntrati o n at half -ma xi mal i n hi biti o n  
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u ma n Use  
I g( M/ G) 
i m m u n o gl o b uli n (class M/class G)  
I M P 
I n vesti gati o nal Me dici nal Pr o d uct 
I S F 
I n vesti gat or Site File 
M D M A  
3, 4 -met h yle ne di o x y met ha m p heta mi ne  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M R T 
mea n resi de nce ti me  
M T S  
Master Treat me nt Sc he d ule  
N H S  
( U K) Nati o nal Healt h Ser vice 
P G x  
p har mac o ge n o mics  
PI  
Pri nci pal I n vesti gat or  
P K  
p har mac o ki netics  
P K/ P D  
p har mac o ki netics/ p har mac o d y na mics  
P K S  
p har mac o ki netic set  
q d 
o nce dail y  
Q P  
Q ualifie d Pers o n  
Q Tc F  
c orrecte d Q T i nter val usi n g Fri dericia’s f or m ula  
R A 
Re g ulat or y A ut h orit y  
R P  
Researc h P h ysicia n  
R T -P C R  
re verse tra nscri ptase p ol y merase c hai n reacti o n  
S A E  
seri o us a d verse e ve nt 
S A R  
seri o us a d verse reacti o n 
S A R S - C o V- 2 
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2  
S B P 
s yst olic bl o o d press ure 
S O C  
S yste m Or ga n Class  
S O M  
St u d y O perati o ns Ma n ual  
S P C  
S u m mar y of Pr o d uct C haracteristics  
ss 
stea d y state 
S T W  
Sc he d uli n g Ti me Wi n d o ws  
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
t1/ 2z 
ter mi nal eli mi nati o n half-life  
tla g 
ti me peri o d bet wee n t he ti me of d osi n g a n d t he ti me of t he first o bser vati o n wit h a 
meas ura ble n o n -zer o c o nce ntrati o n  
2 7 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
2 8  of 7 6  
 
A b bre vi ati o n  
E x pl a n ati o n  
tma x  
ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n 
T Q T  
t h or o u g h Q T (trial) 
U K  
U nite d Ki n g d o m  
V d/ F 
ap pare nt v ol u me of distri b uti o n  
W H O -D R U G  
W orl d Healt h Or ga nisati o n Dr u g Dicti o nar y  
 
2 8 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
2 9  of 7 6  
 
LI S T O F T A B L E S  
Ta ble 2 - 1 
B y -s pecies m ulti ples- of-e x p os ure f or N O A E Ls vs h u ma n stea d y state at 
4 0 0 m g/ da y d ose .............................................................................................. 3 1  
Ta ble 6 - 1  
I M P or place b o f or eac h a ntici pate d d ose le vel ............................................... 4 7 
Ta ble 6 - 2 
La b orat or y para meters  ..................................................................................... 5 9 
 
 
 
LI S T O F FI G U R E S  
N ot a p plica ble.  
 
2 9 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
3 0  of 7 6  
 
2 
I N T R O D U C TI O N 
2. 1  
B a c k gr o u n d i nf or m ati o n  
Priteli vir  
Priteli vir is a n o vel a nti- her pes si m ple x vir us ( H S V) i n hi bit or a n d bel o n gs t o t he helicase-
pri mase i n hi bit ors, w hic h ha ve a m o de of acti o n t hat is disti nct t o t hat of a nti viral n ucle osi de 
a nal o gs c urre ntl y i n cli nical use. Priteli vir is acti ve a gai nst b ot h H S V t y pes , H S V- 1 a n d H S V- 2, 
a n d pre ve nts de n o v o s y nt hesis of vir us de o x yri b o n ucleic aci d ( D N A) t hr o u g h i n hi biti o n of t he 
viral helicase -pri mase c o m ple x w hereas t he n ucle osi de a nal o gs ter mi nate o n g oi n g D N A c hai n 
el o n gati o n t hr o u g h i n hi biti o n of viral D N A p ol y merase . Priteli vir d oes n ot re q uire acti vati o n b y 
viral t h y mi di ne ki nase. Priteli vir is acti ve a gai nst n ucle osi de -a nal o g resista nt vir us strai ns.  
N o ncli nical safet y p har mac ol o g y st u dies i n Bea gle d o gs s h o we d n o a d verse car diac effects: t here 
was n o i n dicati o n of effects u p o n s yst olic, diast olic a n d mea n peri p heral arterial bl o o d press ure, 
heart rate, car diac o ut p ut, str o ke v ol u me, s yst olic left ve ntric ular press ure, ma xi m u m d p/ dt, 
ce ntral ve n o us press ure as well as res pirat or y rate a n d v ol u me, bl o o d p H, a n d bl o o d gases. N o 
e vi de nce was n ote d f or a pr ol o n gati o n of t he Q T i nter val. 
I n vitr o st u dies usi n g w h ole-cell patc h-cla m p tec h ni q ue was use d t o i n vesti gate t he effects of 
priteli vir o n h E R G p otassi u m c ha n nels i n sta bl y tra nsfecte d H E K 2 9 3 cells ( h u ma n e m br y o nic 
ki d ne y cells) re veale d a c o nce ntrati o n - de pe n de nt i n hi biti o n of h E R G-me diate d tail c urre nt 
a m plit u de (I C 5 0 ~ 1 5 6 µ M). T he i n hi bit or y effect of priteli vir was si g nifica nt at 1 0  µ M 
(re mai ni n g c urre nt 8 2 ± 1 0 %) b ut still far a wa y fr o m bei n g c o m plete at t he s ol u bilit y li mit of 
a b o ut 5 0 µ M (re mai ni n g c urre nt 7 5  ± 9 %) a n d at least partiall y re versi ble u p o n was h - o ut. 
H o we ver, si nce t he I C 5 0 ( h E R G) is m ore t ha n 1 0 0-f ol d greater t ha n t he mea n t hera pe utic Cma x  
val ues w he n c orrecte d f or free fracti o n (fr o m 1 0 9 -f ol d f or t he 4 0 0 m g / da y t o 3 5 5-f ol d f or t he 
1 0 0 m g / da y d ose gr o u p at stea d y state), t he i nteracti o n bet wee n priteli vir a n d h E R G is of 
ne gli gi ble cli nical rele va nce i n h u ma ns. 
M o xifl o x aci n 
M o xifl o xaci n is n or mall y use d t o treat a variet y of bacterial i nfecti o ns a n d bel o n gs t o t he class of 
q ui n ol o ne a nti bi otics. T he r ole of m o xifl o xaci n i n t his trial is t o de m o nstrate t he trial’s a bilit y t o 
detect a s mall effect o n t he Q T i nter val (assa y se nsiti vit y), si nce m o xifl o xaci n is k n o w n t o ha ve a 
mil d Q T pr ol o n gi n g effect t hat has bee n use d i n t he maj orit y of t h or o u g h Q T / Q Tc trials [ 1, 2]. 
F urt her i nf or mati o n o n m o xifl o xaci n ca n be o btai ne d fr o m t h e c urre nt S P C.  
2. 2  
R ati o n al e f or t h e tri al 
As rec o m me n de d b y t he I nter nati o nal C o nfere nce f or H ar m o nisati o n (I C H)  E 1 4 G ui da nce f or 
I n d ustr y [ 3, 4] t he prese nt t h or o u g h Q T/ Q Tc trial is desi g ne d t o i n vesti gate t he p ote ntial of 
priteli vir t o ca use Q T/ Q Tc pr ol o n gati o n.  
2. 3  
Ri s k/ b e n efit  a s s e s s m e nt  
T he c urre nt ris k/ be nefit assess me nt f or a t hera pe utic d ose of 1 0 0 m g / da y priteli vir is gi ve n i n 
Secti o n 6 “ G ui da nce f or t he I n vesti gat or” of t he I n vesti gat or’s Br oc h ure. As i n t he c urre nt trial a 
s u prat hera pe utic d ose of 4 0 0 m g / da y d ose of priteli vir is a d mi nistere d, a s pecific Ris k/ Be nefit is 
d isc usse d bel o w i n t his secti o n.  
3 0 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
3 1  of 7 6  
 
T he selecte d d oses of priteli vir  pla n ne d f or t his trial are classifie d t o be hi g h e n o u g h f or t he 
i n vesti gati o n of a p ossi ble i nfl ue nce of priteli vir  o n t he Q T/ Q Tc i nter val. T he c h oice of d oses is 
e x plai ne d i n Secti o n  6. 2. 2 . 
N o effect o n a n y E C G para meter, i ncl u di n g Q T a n d Q Tc F, c o ul d be detecte d i n cli nical trials b y 
classical 1 2 -lea d safet y E C Gs s o far f or d oses u p t o 4 0 0 m g  priteli vir per da y. F urt her m ore, 
p riteli vir has n ot s h o w n a n y rele va nt effect o n E C Gs i n Bea gle d o gs (safet y p har mac ol o g y) or o n 
t he h E R G c ha n nel. 
A b y -s pecies s u m mar y of m ulti ples- of-e x p os ure ( M o Es) f or N O A E Ls vs t he h u ma n stea d y-state 
at 4 0 0 m g / da y d ose is gi ve n i n Ta ble 2- 1 . T he M o Es f or t otal A U C a n d Cma x  are cl ose t o  1 or 
a b o ve f or all s pecies; t he M o Es are bel o w 1 f or u n b o u n d A U C a n d Cma x  es peciall y i n rats, d o gs , 
a n d m o n ke ys.  
T a ble 2- 1 
B y -s pecies m ulti ples -of -e x p os ure f or N O A E Ls vs h u m a n ste a d y st ate at 
4 0 0 m g / d a y d ose 
S pecies  
D ur ati o n of 
e x p os ure 
N O A E L 
(m g/ k g/ d a y ) 
C m a x  at 
N O A E L 
(µ g/ m L ) 
M o E 
a) f or 
C m a x  
(t ot al/free) 
A U C at 
N O A E L 
(µ g· h/ m L ) 
M o E 
a) f or 
A U C  
(t ot al/free) 
Ge n der 
( T K) 
M o use  
1 3 wee ks  
1 0 0  
1 0 1  
5/ 1. 8  
1, 3 8 0  
4/ 1. 5  
m 
1 1 4  
6/ 2. 0  
1, 5 8 0  
5/ 1. 7  
f 
1 0 8  
5/ 1. 9  
1, 4 8 0  
4/ 1. 6  
m +f  
Rat  
2 6 wee ks  
1 0  
2 4. 2  
1. 2/ 0. 5  
2 3 4  
0. 7/ 0. 3  
m 
3 5. 4  
1. 7/ 0. 8  
3 2 9  
1. 0/ 0. 4  
f 
2 9. 8  
1. 5/ 0. 6  
2 8 2  
0. 8/ 0. 4  
m +f  
Rat Se g I  
1 3  wee ks  
5 0  
5 4. 9  
2. 7/ 1. 2  
6 8 1  
2. 0/ 0. 9  
m 
D o g  
1 3 wee ks  
3 0 b) 
3 9. 1  
1. 9/ 0. 7  
6 2 8  
1. 9/ 0. 7  
m 
4 9. 7  
2. 4/ 0. 9  
6 8 3  
2. 0/ 0. 8  
f 
4 4. 4  
2. 2/ 0. 8  
6 5 5  
1. 9/ 0. 7  
m +f  
M o n ke y  
3 9 wee ks  
2 5  
4 2. 0  
2. 0/ 0. 6  
7 6 6  
2. 3/ 0. 6  
m 
2 6. 8  
1. 3/ 0. 4  
4 6 1  
1. 4/ 0. 4  
f 
3 4. 4  
1. 7/ 0. 5  
6 1 4  
1. 8/ 0. 5  
m +f  
A U C =area u n der t he plas ma c o nce ntrati o n ti me c ur ve; C ma x = ma xi m u m o bser ve d plas ma c o nce ntrati o n; 
L O A E L =l o west o bser ve d a d verse effects le vel; M o E = m ulti ple of e x p os ure; N O A E L = n o o bser ve d a d verse effect 
le vel; T K =t o xic o ki netic 
N ote: Uri nar y h y per plasia is a k n o w n r o de nt -s pecific effect a n d it has o nl y bee n o bser ve d i n r o de nts. T heref ore, 
uri nar y h y per plasia is n ot c o nsi dere d rele va nt f or t he calc ulati o n of safet y mar gi ns, ie, M o Es  
a) M o Es calc ulate d vs o bser ve d h u ma n ( male) e x p os ure at 4 0 0  m g / da y d ose i n trial AI C 3 1 6-0 1 -I-0 5  
b)  L O A E L was use d si nce N O A E L was n ot i de ntifie d  
 
T he a d verse effects detecte d at t he d ose le vels a b o ve t he N O A E L i n t he res pecti ve s pecies 
s h o we d e x p os ures lea di n g t o M o Es of 1 a n d a b o ve e ve n f or u n b o u n d A U C a n d C ma x . Ke y 
fi n di n gs a b o ve t hese d ose le vels were uri nar y h y per plasia, i m paire d male fertilit y, he mat ol o gical 
c ha n ges, li ver effects a n d cataracts  i n r o de nts, he mat ol o gical c ha n ges i n d o gs, a n d he mat ol o gical 
3 1 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
3 2  of 7 6  
 
a n d s ki n fi n di n gs i n m o n ke ys ; t hese are disc usse d f urt her i n Secti o n 4. 3. 2 of t he I n vesti gat or’s 
Br oc h ure. T he fi n di n gs occ urre d after a m uc h l o n ger treat me nt peri o d t ha n pla n ne d i n t he c urre nt 
cli nical trial a n d t he y were, wit h o ne e xce pti o n (s ki n fi n di n gs; see bel o w), n ot detecte d i n a 
cli nical trial i n w hic h 4 0 0  m g  priteli vir was a d mi nistere d o nce dail y u p t o 1 6 da ys. 
T he hi g hest d ose of 4 0 0 m g  q d priteli vir (s u prat hera pe utic d ose) i n t he prese nt t h or o u g h Q T/ Q Tc 
trial has alrea d y bee n i n vesti gate d i n male s u bjects i n trial AI C 3 1 6 - 0 1-I- 0 5. I n t his trial, 
v ol u nteers were treate d wit h 2 0 0  m g  o nce dail y ( 2 1 da ys) or 4 0 0 m g  o nce dail y ( u p t o 1 6 da ys); 
priteli vir was well t olerate d i n t he 2 0 0  m g  d osi n g gr o u p a n d als o well t olerate d u p t o Da y 1 0 i n 
t he 4 0 0 m g  d osi n g gr o u p, h o we ver, t he trial was st o p pe d pre mat urel y d ue t o t he occ urre nce of 
A Es bel o n gi n g t o t he S O C s ki n a n d s u bc uta ne o us tiss ue dis or ders; t hese were o nl y o bser ve d i n 
t he 4 0 0 m g  d ose gr o u p; 5 of 1 6 s u bjects ( 4 of 1 2 s u bjects ( 3 3. 3 %) e x p ose d t o priteli vir, 1 of 
4 s u bjects ( 2 5. 0%) e x p ose d t o place b o) de vel o pe d a mac ular or mac ul o- pa p ular s ki n reacti o n 
(e xa nt he ma or er u pti o n), mai nl y bet wee n Da y 1 1 t o 1 4 of treat me nt . T hese mil d s ki n reacti o ns 
were n ot acc o m pa nie d b y f or mati o n of b ullae, p ust ules or alterati o ns of li ver f u ncti o n tests or 
e osi n o p hilia. A viral i nfecti o n c o ul d ha ve bee n t he ca use b ut als o a n effect of priteli vir c o ul d n ot 
be c o m pletel y r ule d o ut.  
It is of n ote t hat o nl y male s u bjects partici pate d i n t he a b o ve-me nti o ne d trial AI C 3 1 6 - 0 1-I- 0 5, 
b ut i n t he T Q T trial, fe male s u bjects will als o be i ncl u de d. H o we ver, base d o n data fr o m t he 
first-i n- h u ma n trial AI C 3 1 6- 0 1-I-0 1, t he D DI trial AI C 3 1 6 - 0 3-I-0 1 as well as P hase 2 trials, 
si milar e x p os ures ca n be e x pecte d i n me n a n d w o me n i n t his T Q T trial. 
T he ris k miti gati o n meas ures f or p ote ntial ris ks are gi ve n i n A p pe n di x 3 . 
T his trial will be c o n d ucte d i n a s pecialize d earl y p hase Cli nical P har mac ol o g y U nit wit h o nsite 
res uscitati o n e q ui p me nt a n d me dicati o n, i n a d diti o n t o access t o a n ac ute h os pital wit h Critical 
Care facilities, t h us e ns uri n g direct access t o e q ui p me nt a n d staff f or res uscitati n g a n d sta bilizi n g 
s u bjects i n ac ute me dical c o n diti o ns a n d e mer ge ncies. T he trial is c o n d ucte d b y a PI a n d well 
trai ne d me dical a n d tec h nical staff wit h a m ple e x perie nce i n t he c o n d uct of earl y p hase cli nical 
trials. T he trial is desi g ne d t o cl osel y m o nit or, treat a n d c o m m u nicate p ote ntial e x pecte d a d verse 
reacti o ns as well as p ote ntial u ne x pecte d a d verse e ve nts. 
T he i n di vi d ual s u bjects i n t his cli nical trial will n ot be nefit fr o m t he treat me nt. I ncl usi o n a n d 
e xcl usi o n criteria ha ve bee n c h ose n t o e na ble a u nif or m trial sa m ple of s u bjects a n d t o mi ni mize 
p ossi ble ris ks d ue t o a d mi nistrati o n of priteli vir . T he trial is desi g ne d t o cl osel y m o nit or, treat 
a n d c o m m u nicate p ote ntial e x pecte d a d verse reacti o ns as well as p ote ntial u ne x pecte d a d verse 
e ve nts. T o e ns ure t he safet y of t he s u bjects, a d verse e ve nts, vital si g ns, p h ysical  e xa mi nati o ns, 
electr ocar di o gra p hic varia bles, a n d la b orat or y para meters will be m o nit ore d. S u bjects will 
re mai n u n der me dical s u per visi o n o n t he war d d uri n g t he w h ole priteli vir/ place b o treat me nt 
peri o d u ntil 4 da ys after last treat me nt.   
I n t he u nli kel y case t hat a d verse e ve nts fr o m S O C s ki n a n d s u bc uta ne o us tiss ue dis or ders  occ ur 
t o s uc h a n e xte nt or se verit y t hat s u bjects ha ve t o be wit h dra w n fr o m t he trial, t he 
s u prat hera pe utic d ose ma y be re d uce d t o 2 0 0 m g / da y priteli vir  i) i n a n i n di vi d ual s u bject f or t he 
rest of t he d osi n g p hase, or ii) it ma y e ve n be deci de d t o s us pe n d f urt her d osi n g of all s u bjects 
(see A p pe n di x 2 ). A ge neral re d ucti o n of t he t hera pe utic d ose t o 2 0 0 m g/ da y f or all f oll o wi n g 
s u bjects will be deci de d b y t he S p o ns or a n d t he Pri nci pal I n vesti gat or a n d re q uires re g ulat or y 
a p pr o val via a s u bs ta ntial a me n d me nt b y R A  a n d E C . 
3 2 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
3 3  of 7 6  
 
I n s u m mar y, p ote ntial ris ks were i de ntifie d d uri n g t he n o ncli nical de vel o p me nt of priteli vir. 
N o ne of t hese p ote ntial ris ks ha ve bee n o bser ve d i n cli nical trials wit h s u prat hera pe utic d oses u p 
t o 2 0 0 m g / da y f or 2 1 da ys or, wit h t he e xce pti o n of s ki n fi n di n gs, u p t o 4 0 0  m g / da y f or u p t o 
1 6 da ys. It re mai ns u n k n o w n w het her t he s ki n a n d s u bc uta ne o us tiss ue dis or der e ve nts were 
ca use d b y priteli vir, h o we ver, if s uc h e ve nts w o ul d occ ur, ris k miti gati o n w o ul d be perf or me d as 
descri be d a b o ve.  
I n c o ncl usi o n, t he e x pecte d hi g hest priteli vir  e x p os ure i n t his T Q T trial after 4 0 0  m g  q d priteli vir  
d osi n g at stea d y state is alrea d y c o vere d b y pre vi o us cli nical trial- a n d n o ncli nical data.  
3 
T RI A L O B J E C TI V E S  
Pri m ar y o bjecti ve 
•  t o defi ne t he effects of priteli vir o n t he Q Tc i nter val deri ve d fr o m 1 2-l ea d E C Gs i n 
c o m paris o n wit h place b o i n male a n d fe male s u bjects . 
Sec o n d ar y o bjecti ves  
•  t o assess p har mac o ki netic pr o perties of m ulti ple d oses of priteli vir a n d t o e xa mi ne t he 
c orrelati o ns bet wee n priteli vir plas ma c o nce ntrati o n a n d its effects, if a n y, o n t he Q Tc F 
i nter val, 
•  t o e val uate a d diti o nal electr ocar di o gra p hic effects of priteli vir, 
•  t o s h o w t he trial’s assa y se nsiti vit y b y assessi n g t he effects of m o xifl o xaci n ( p ositi ve c o ntr ol 
vs. place b o) o n t he Q Tc F i nter val, 
•  t o i n vesti gate t he safet y a n d t olera bilit y of priteli vir. 
4 
T RI A L D E SI G N  
4. 1  
O v er all tri al d e si g n  
T his P hase 1 cli nical trial is a d o u ble - bli n d, si n gle-ce nter, ra n d o mize d, place b o - a n d p ositi ve-
c o ntr olle d, parallel - gr o u p, ‘ neste d cr oss o ver’ trial wit h m ulti ple oral d ose a d mi nistrati o n of 
priteli vir or matc hi n g place b o as well as a si n gle oral a d mi nistrati o n of m o xifl o xaci n ( p ositi ve 
c o ntr ol) a n d c orres p o n di n g matc hi n g place b o i n healt h y male a n d fe male s u bjects. 
S u bjects wi ll be i n- h o use fr o m Da y - 2 t o Da y 2 0 a n d will be ra n d o mize d t o o ne of t he 2 parallel 
treat me nt gr o u ps: Gr o u p 1 will recei ve a t hera pe utic a n d a s u pra-t hera pe utic d ose of priteli vir 
pl us m o xifl o xaci n place b o. Gr o u p 2 will recei ve priteli vir place b o as well as m o xifl o xaci n a n d 
matc hi n g place b o ( neste d cr oss o ver: Gr o u p 2a a n d Gr o u p 2 b). 1 2- lea d E C G tri plicates will be 
rec or de d fr o m t he be dsi de 1 2-lea d- E C G o n t he Da ys - 1, 1, 2, 6, 1 6, a n d 1 7 a n d will be a nal yze d 
after war ds i n eac h gr o u p f or t hese 6 da ys of d oc u me ntati o n b y a bli n de d rea der. 
It is of n ote t hat H olter E C G data will be c ollecte d i n parallel at scree ni n g t o e xcl u de a n y o ne 
wit h pre -e xisti n g car diac pr o ble ms as well as o n Da ys - 1, 1, 2, 6, 1 6, a n d 1 7 as a bac k- u p f or t he 
be dsi de 1 2- lea d-E C G s.  
I n Gr o u p 1, 3 2 male a n d fe male s u bjects (at least 1 2 s u bjects per se x) will recei ve a l oa di n g d ose 
of 4 0 0 m g  priteli vir o n Da y 1. After war ds t he y will recei ve 1 0 0  m g  priteli vir q d fr o m Da y  2 t o 6 
3 3 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
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V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
3 4  of 7 6  
 
a n d 4 0 0 m g  priteli vir q d fr o m Da y 7 t o 1 6. F urt her m ore, t hese su bjects will recei ve matc hi n g 
m o xifl o xaci n place b o o n t he Da ys 2 a n d 1 7. 
I n Gr o u p 2, 3 2 male a n d fe male s u bjects (at least 1 2 s u bjects per se x) will recei ve t he res pecti ve 
a m o u nts of t a blets of matc hi n g priteli vir place b o fr o m Da y 1 t o Da y 1 6 i n Gr o u p 2 as ver u m 
ta blets i n Gr o u p 1. F urt her m ore, s u bjects i n Gr o u p 2a ( 1 6 male a n d fe male s u bjects) will recei ve 
4 0 0 m g  m o xifl o xaci n o n Da y 2 a n d matc hi n g m o xifl o xaci n place b o o n Da y 1 7 a n d s u bjects i n 
Gr o u p 2 b ( 1 6 male a n d fe male s u bjects) will recei ve 4 0 0 m g  m o xifl o xaci n o n Da y 1 7 a n d 
matc hi n g m o xifl o xaci n  place b o o n Da y 2. 
Differe nt meas ures will be nee de d, a n d data e val uati o ns ge nerate d f or Gr o u p 1 a n d Gr o u p 2, 
h o we ver, t o mai ntai n d o u ble bli n di n g bet wee n Gr o u p 1 a n d Gr o u p 2; 
•  1 2- lea d E C G tri plicates will be rec or de d a n d a nal yze d fr o m t he be dsi de 1 2 -lea d-E C G de vices 
i n s u bjects of b ot h gr o u ps o n t he Da ys - 1, 1, 2, 6, 1 6 a n d 1 7. 
•  P K sa m ples will be c ollecte d fr o m s u bjects of b ot h gr o u ps o n t he Da ys 1, 6, a n d 1 6 f or 
priteli vir a n d t he meta b olites AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 as well as f or m o xifl o xaci n o n t he 
Da ys 2 a n d 1 7. 
•  O ver -e nca ps ulate d m o xifl o xaci n- a n d matc hi n g place b o will be use d . 
If A Es i nterfere wit h a de q uate E C G rec or di n g, a Ris k Be nefit  C o m mittee ( partici pa nts fr o m 
Ai C uris as well as t he P ri nci pal I n vesti gat or) mi g ht deci de t o l o wer t he (s u pra-t hera pe utic) d ose 
i n i n di vi d ual s u bjects. 
Ris k  Be nefit C o m mittee  
A Ris k  Be nefit C o m mittee  ( R B C) c o nsisti n g of at least t he Pri nci pal I n vesti gat or , Ai C uris 
Res p o nsi ble P h ysicia n , a n d t he P har mac o vi gila nce Ma na ger will meet t o deci de i n cases w here 
( n o n-e mer ge nc y) u n bli n di n g or re d ucti o ns i n s u prat hera pe utic d ose le vels ma y be necessar y, or 
a n y ot her case w here t he S p o ns or or PI c o nsi der t his necessar y.  
4. 2  
Di s c u s si o n of d e si g n a n d c h oi c e of c o ntr ol gr o u p s  
Acc or di n g t o t he re q uire me nts of t he I C H E 1 4- G ui da nce o n Q T/ Q Tc i nter val pr ol o n gati o n [ 3, 4] 
c o ncer ni n g t he desi g n of ‘t h or o u g h Q T/ Q Tc st u dies’ i n healt h y v ol u nteers, a de q uate met h o ds of 
trial c o ntr ol i ncl u di n g d o u ble- bli n de d a d mi nistrati o n usi n g matc hi n g place b os, ra n d o mizati o n, 
a n d c o nc urre nt use of a p ositi ve c o ntr ol gr o u p are e nf orce d t o re d uce bias pr o d uce d b y s u bjects’ 
a n d I n vesti gat ors’ e x pectati o ns. T heref ore, t he prese nt trial is desi g ne d as a d o u ble- bli n d, si n gle-
ce nter, ra n d o mize d, place b o- a n d p ositi ve-c o ntr olle d, parallel- gr o u p trial wit h a neste d cr oss o ver 
part o n electr ocar di o gra p hic effects of 1 0 0 a n d 4 0 0 m g  priteli vir per da y i n healt h y male a n d 
fe male s u bjects. It will be a nal yze d t o deter mi ne w het her oral priteli vir has a p ote ntial ris k of 
ca usi n g Q T/ Q Tc pr ol o n gati o n after a m ulti ple- d ose a d mi n istrati o n of priteli vir a n d a si n gle d ose 
a d mi nistrati o n of m o xifl o xaci n ( p ositi ve c o ntr ol) as well as t he c orres p o n di n g matc hi n g 
place b os.  
T he m ulti ple - d ose re gi me n was c h ose n t o ac hie ve a n a de q uate e x p os ure of priteli vir ( Gr o u p 1) 
wit h a parallel -gr o u p c o m paris o n vers us place b o ( Gr o u p 2) d ue t o a k n o w n l o n g half- life of 
priteli vir. T he p ositi ve c o ntr ol usi n g m o xifl o xaci n ( Gr o u p 2) will ser ve f or t he de m o nstrati o n of 
assa y se nsiti vit y a n d will acc o u nt f or se q ue nce effects base d o n a ‘ neste d’, place b o -c o ntrolle d, 
3 4 of 1 3 6

 
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V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
3 5  of 7 6  
 
cr oss o ver desi g n wit hi n Gr o u p 2 (ie, 2a vs. 2 b). Bli n di n g will be mai ntai ne d b y t he use of t he 
res pecti ve matc hi n g place b os t o t he I M Ps a n d t he c o n d uct of i de ntical pr oce d ures i n eac h 
treat me nt gr o u p. 
T he pr o p ose d trial desi g n has bee n disc usse d wit h t he F D A w h o pr o vi de d s o me a d diti o nal p oi nts 
f or c o nsi derati o n. T he F D A fee d bac k is attac he d t o t he pr ot oc ol i n A p pe n di x 5 . 
5 
S E L E C TI O N O F T RI A L P O P U L A TI O N  
A d ult healt h y male a n d fe male s u bjects of a n y et h nic ori gi n ( 1 8 t o 4 5 years i ncl usi ve). 
5. 1  
I n cl u si o n crit eri a 
S u bjects meeti n g t he f oll o wi n g criteria will be c o nsi dere d f or i ncl usi o n i nt o t he trial:  
1.  S u bject has bee n i nf or me d b ot h ver ball y a n d i n writi n g a b o ut t he o bjecti ves of t he cli nical 
trial, t he met h o ds, t he a ntici pate d be nefits a n d p ote ntial ris ks a n d t he disc o mf ort t o w hic h 
t he y ma y be e x p ose d a n d has gi ve n writte n c o nse nt t o partici pati o n i n the trial pri or t o trial 
start a n d a n y trial-relate d pr oce d ure. 
2.  Healt h y male a n d fe male s u bjects of a n y et h nic ori gi n, a ge d bet wee n 1 8 a n d 4 5 years 
(i ncl usi ve). Assesse d as healt h y base d o n a Scree ni n g e xa mi nati o n i ncl u di n g me dical hist or y, 
p h ysical e xa mi nati o n, bl o o d press ure, p ulse rate, E C G assess me nt, a n d cli nical la b orat or y 
res ults. 
3.  Male s u bjects  n ot pla n ni n g t o fat her or t o d o nate s per ms f or i n vitr o fertilizati o n d uri n g t he 
trial a n d f or at least 3 m o nt hs after d osi n g of trial me dicati o n . A de q uate c o ntrace pti o n (see 
bel o w) m ust be use d d uri n g se x ual i nterc o urse wit h w o me n of c hil d beari n g p ote ntial t o ma ke 
s ure t he fat heri n g of a c hil d will be r ule d o ut d uri n g t he trial a n d d uri n g t he 3 m o nt hs after 
d osi n g of trial me dicati o n. 
W o me n of c hil d beari n g p ote ntial ha ve t o perf or m a de q uate c o ntrace pti o n. T he y s h o ul d als o 
n ot d o nate o va d uri n g t he trial a n d f or at least 3 m o nt hs after d osi n g of trial me dicati o n. 
A de q u ate c o ntr ace pti o n  is defi ne d as a c o m bi nati o n of a hi g hl y effecti ve met h o d of birt h 
c o ntr ol a n d a d diti o nal barrier c o ntrace pti o n.  
Hi g hly effective met h o d  of birt h c o ntr ol is defi ne d as f oll o ws: c o m bi ne d (estr o ge n a n d 
pr o gester o ne) oral c o ntrace pti ves, c o m bi ne d h or m o nal va gi nal ri n gs, h or m o ne i m pla nts, 
h or m o ne i njecta bles, or i ntra uteri ne de vice t hat nee d t o be i n place f or a peri o d of at least 
2 m o nt hs pri or t o Scree ni n g a n d c o nti n ue f or at least 3 m o nt hs after d osi n g of trial 
me dicati o n . 
A d diti o n al b arrier c o ntr ace pti o n  (t he f oll o wi n g met h o ds are all o we d: c o n d o m of t he male, 
dia p hra g m wit h s per mici de, cer vical  ca p wit h s per mici de) m ust be use d f or t he d urati o n of 
t he trial, defi ne d as fr o m t he ti me of Scree ni n g t o t he E n d of Trial e xa mi nati o n, a n d f or at 
least 3 m o nt h s after d osi n g of trial me dicati o n. A si n gle barrier met h o d al o ne or a bsti ne nce 
al o ne is n ot acce pta ble. H o m ose x ual fe male s u bjects w h o refrai n fr o m heter ose x ual 
i nterc o urse f or at least 3 m o nt hs pri or t o Scree ni n g ma y be i ncl u de d wit h o ut a c o ntrace pti ve 
met h o d if t he y a gree t o f urt her ref rai n fr o m heter ose x ual i nterc o urse u ntil t he E n d of Trial 
e xa mi nati o n, a n d f or at least 3 m o nt hs after d osi n g of trial me dicati o n. 
W o me n of n o n -c hil d beari n g p ote ntial ma y be i ncl u de d if s ur gicall y sterile ( d oc u me nte d 
c o m plete h ysterect o m y, s u pracer vical h y sterect o m y or bi-t u bal li gati o ns; partial 
h ysterect o m y is n ot s ufficie nt) or if p ost me n o pa usal ( w h o ha ve a hist or y of n o me nses of at 
least 2 4 m o nt hs at scree ni n g a n d p ost me n o pa usal stat us c o nfir me d b y F S H test at scree ni n g).  
3 5 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
3 6  of 7 6  
 
4.  I n w o me n, ne gati ve ser u m β -H C G ( beta - h u ma n c h ori o nic g o na d otr o pi n) test at Scree ni n g 
a n d ne gati ve uri ne β- H C G test o n Da y - 2. 
5.  S u bject a grees t o p har mac o ge n o mic bl o o d sa m pli n g. 
6.  S u bject m ust be willi n g a n d a ble t o s wall o w u p t o 4 ta blets ( priteli vir or matc hi n g place b o) 
a n d 1 ca ps ule ( o ver-e nca ps ulate d m o xifl o xaci n or  matc hi n g place b o) at least t wice d uri n g t he 
trial. 
7.  N or mal b o d y wei g ht as e vi de nce d b y a B o d y Mass I n de x ( B MI) ≥1 8. 0 a n d ≤2 5. 0 k g/ m 2, a n d 
a b o d y wei g ht ≥5 0. 0 k g at Scree ni n g. 
8.  S u bjects m ust ha ve a ne gati ve test res ult f or HI V -I- a n d -II-a nti b o d y, H Bs A g, a nti-H Bc (I g G 
+ I g M) a n d a nti- H C V at Scree ni n g.  
9.  S u bjects m ust ha ve ne gati ve uri ne tests f or dr u gs of a b use ( be nz o diaze pi nes, o piates, 
a m p heta mi nes, met ha d o ne, c ocai ne, ca n na bi n oi ds, bar bit urates, c oti ni ne) a n d ne gati ve breat h 
alc o h ol tests at Scree ni n g a n d A d missi o n f or t he i n- h o use p hase ( Da y - 2). 
1 0.  N or mal tri plicate 1 2 -lea d E C G meas ure d after 1 0 mi n utes i n t he s u pi ne p ositi o n at scree ni n g 
a n d o n a d missi o n o n Da y - 2 s h o wi n g re g ular si n us r h yt h m wit h a well- defi ne d e n d of T.  
1 1.  N or mal 2 4- h o ur 1 2- lea d E C G at scree ni n g.  
5. 2  
E x cl u si o n crit eri a  
A s u bject will n ot be eli gi ble f or i ncl usi o n if a n y of t he f oll o wi n g criteria a p plies:  
1.  Hist or y or c urre nt e vi de nce of cli nicall y rele va nt aller gies or i di os y ncras y t o dr u gs or f o o d. 
2.  Hist or y of a ny m o derate or se vere aller g y or a n y k n o w n aller g y t o a n y acti ve or i nacti ve 
i n gre die nt(s) of m o xifl o xaci n I M P, priteli vir I M P, or t heir res pecti ve matc hi n g place b os . 
3.  A n y s pecial dietar y re q uire me nts t hat w o ul d pre ve nt t he c o ns u m pti o n of sta n dar dize d meals. 
4.  Hist or y or c urre nt e vi de nce of a n y cli nicall y rele va nt car di o vasc ular, p ul m o nar y, he patic, 
re nal, gastr oi ntesti nal, he mat ol o gic, e n d ocri ne, meta b olic, ne ur ol o gical, ps yc hiatric, or ot her 
disease s us pecte d t o i nfl ue nce p har mac o ki netics or safet y of t he I M P . 
5.  Hist or y or a n y c urre nt e vi de nce of a der mat ol o gical c o n diti o n re q uiri n g treat me nt b y a G P or 
s pecialist ( wit h t he e xce pti o n of b ur ns, f u n gal i nfecti o ns, a n d/ or warts) . 
6.  A n y ot her si g nifica nt disease or dis or der w hic h, i n t he o pi ni o n of t he I n vesti gat or, m a y eit her 
p ut t he s u bject at ris k beca use of partici pati o n i n t he trial, or ma y bias t he res ult of t he trial or 
t he s u bject's a bilit y t o partici pate i n t he trial. 
7.  Hist or y of mali g na nc y. 
8.  Has vital si g ns c o nsiste ntl y o utsi de of n or mal ra n ge at scree ni n g or Da y -1. Acce pta ble 
n or mal ra n ge is as f oll o ws:  
•  s u pi ne H R 4 0 - 1 0 0 b p m (after at least fi ve mi n utes of s u pi ne rest) 
•  s u pi ne bl o o d press ure (after at least fi ve mi n utes of s u pi ne rest):  
o  s yst olic bl o o d press ure: 9 0 - 1 3 0 m m H g  
o  diast olic bl o o d press ure: 4 0 - 9 0 m m H g 
9.  T he hist or y or prese nce of a n y of t he f oll o wi n g car diac c o n diti o ns: k n o w n str uct ural car diac 
a b n or malities; fa mil y hist or y of l o n g Q T s y n dr o me; car diac s y nc o pe or rec urre nt, i di o pat hic 
s y nc o pe; e xercise-relate d cli nicall y si g nifica nt car diac e ve nts; k n o w n car di o vasc ular disease. 
1 0.  C o nsiste nt a b n or mal i nter val rea di n gs f or P R, Q R S a n d Q Tc i nter vals ( P R < 1 2 0 ms or 
> 2 1 0 ms, Q R S > 1 2 0 ms or Q Tc F > 4 5 0 ms f or males a n d > 4 7 0 ms f or fe males).  
3 6 of 1 3 6

 
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1 1.  Tra nsie nt fascic ular bl oc ks, u n d ue ect o pic b ur de n, j u ncti o nal r h yt h m a n d a n y ot her E C G 
fi n di n gs w hic h ma y i n t he o pi ni o n of t he I n vesti gat or ma ke a s u bject u ns uita ble f or i ncl usi o n 
i n t his cli nical trial.  
1 2.  C hr o nic or cli nicall y rele va nt ac ute i nfecti o ns or fe brile ill ness wit hi n 5 da ys pri or t o 
a d mi nistrati o n of t he I M P. 
1 3.  Cli nicall y rele va nt a b n or malities i n ser u m c he mistr y, hae mat ol o g y a n d c oa g ulati o n 
para meters, uri nal ysis. S pecificall y:  
•  Partici pa nts wit h tra nsa mi nases ( A S T/ A L T) a b o ve U L N or t otal bilir u b i n x 1. 5 U L N, 
at Scree ni n g.  
•  He m o gl o bi n bel o w L L N at Scree ni n g.  
•  Platelet c o u nt bel o w L L N at Scree ni n g.  
•  W hite Bl o o d C o u nt a b o ve U L N at Scree ni n g.  
•  Partici pa nts wit h uri nal ysis i n dicati ve of u n derl yi n g i nfecti o n/ pat h ol o g y at Scree ni n g.  
1 4.  Ma g nesi u m or p otassi u m o utsi de n or mal ra n ge i n safet y la b orat or y 
1 5.  S u bject is lactati n g or breastfee di n g.  
1 6.  S u bject has recei ve d or is pla n ni n g t o recei ve a C O VI D-1 9 vacci nati o n wit hi n 4  wee ks 
bef ore first d ose a d mi nistrati o n, or wit hi n o ne wee k after trial c o m pleti o n . 
S u bject m ust als o c o m pl y wit h t he latest C O VI D -1 9 safet y meas ures/testi n g 
a p plica ble at t he site at t hat ti me, f or e ntr y i nt o t he u nit a n d d uri n g i n - h o use sta ys. 
N ote: C O VI D -1 9 tests will be carrie d o ut at re g ular i nter vals, pri or t o e ntr y i n t he u nit 
a n d t hr o u g ho ut t he resi de ntial peri o d as per t he latest R ic h m o n d P har mac ol o g y 
C O VI D - 1 9 I nfecti o n C o ntr ol G ui deli nes a n d pre-e ntr y al g orit h ms.  
1 7.  Use of a n y me dicati o n (i ncl. o ver- t he-c o u nter me dicati o n) wit hi n 2 wee ks bef ore d osi n g o n 
Da y  1 or wit hi n less t ha n 1 0 ti mes t he eli mi nati o n half-life of t he res pecti ve dr u g, or 
a ntici pate d c o nc o mita nt me dicati o n d uri n g t he treat me nt peri o d. E xce pti o ns ma y be t he use 
of h or m o nal c o ntrace pti o n a n d h or m o ne re place me nt t hera p y as well as si n gle i nta ke of a 
dr u g if j u d ge d b y t he I n vesti gat ors t o ha ve n o cli nical rele va nce a n d n o rele va nce f or t he trial 
o bjecti ves. E g, li mite d a m o u nts of paraceta m ol are all o we d t o treat pai nf ul i nterc urre nt 
a d verse e ve nts (e g, hea dac he, mi grai ne).  
1 8.  C o ns u m pti o n of met h yl xa nt hi ne-c o ntai ni n g be vera ges or f o o d (c offee, tea, c ola, c h oc olate, 
“ p o wer dri n ks” ) fr o m 2 4 h bef ore d osi n g o n Da y -1 u ntil disc har ge.  
1 9.  C o ns u m pti o n of alc o h ol a n d t o bacc o pr o d ucts wit hi n 4 8 h pri or t o a d missi o n t o t he cli nic 
u ntil disc har ge. 
2 0.  Diseases or s ur ger y of t he gastr oi ntesti nal trac t w hic h ma y i nterfere wit h dr u g a bs or pti o n 
( n ote: t his is n ot a p plica ble f or mi n or a b d o mi nal s ur ger y s uc h as e g, a p pe n dect o m y a n d 
her ni ot o m y). 
2 1.  Treat me nt wit h a n i n vesti gati o nal dr u g wit hi n 9 0  da ys or 5 half -li ves prece di n g t he first d ose 
of trial me dicati o n ( or as deter mi ne d b y t he l ocal re q uire me nt, w hic he ver is t he l o n ger). 
2 2.  D o nati o n of bl o o d or bl o o d pr o d ucts (e xcl u di n g plas ma) wit hi n 9 0 da ys pri or t o trial 
me dicati o n a d mi nistrati o n. 
2 3.  S m o ki n g of m ore t ha n 1 0  ci garettes/ci gars/ pi pes per da y a n d/ or i na bilit y  t o refrai n fr o m 
s m o ki n g d uri n g c o nfi ne me nt. 
2 4.  Hist or y or cli nical e vi de nce of s u bsta nce a n d/ or alc o h ol a b use wit hi n t he 2 years bef ore 
scree ni n g. Alc o h ol a b use is defi ne d as re g ular wee kl y i nta ke of m ore t ha n 1 4 u nits (f or b ot h 
males a n d fe males), usi n g t he  f oll o wi n g N H S alc o h ol trac ker 
htt ps:// w w w . n hs. u k/ o ne y o u/f or- y o ur- b o d y/ dri n k-less/ k n o w- y o ur-alc o h ol-u nits/  
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2 5.  Has a n y fi n di n g t hat, i n t he vie w of t he I n vesti gat or, w o ul d c o m pr o mise t he s u bject’s safet y 
re q uire me nts or t heir a bilit y t o c o m pl y wit h all t he trial re q uire me nts. 
2 6.  N ot a ble t o c o m m u nicate mea ni n gf ull y wit h t he I n vesti gat or a n d site staff. 
2 7.  Lac k of a bilit y or willi n g ness t o gi ve i nf or me d c o nse nt. 
2 8.  Partici pati o n i n a n earlier cli nical trial wit h priteli vir.  
2 9.  V ul nera ble s u bjects (e g, pers o ns ke pt i n dete nti o n)  
5. 3  
E n d of tri al  
T he e n d of t he trial will be defi ne d as t he last s u bject last visit.  
6 
I N V E S TI G A TI O N A L P L A N A N D P R O C E D U R E S  
6. 1  
Tri al p r o c e d ur e s 
6. 1. 1  
S cr e e ni n g  
“Scree ni n g ” is defi ne d as assess me nts t o be ma de wit hi n 3 wee ks pri or t o first a d mi nistrati o n of 
t he I M P t o deter mi ne eli gi bilit y of a partic ular s u bject f or e ntr y i nt o t his trial. 
S u bject I nf or me d C o nse nt m ust  be si g ne d bef ore Scree ni n g e xa mi nati o ns start. 
A ca ps ule of si milar size c o m pare d t o o ver -e nca ps ulate d m o xifl o xaci n will be s h o w n t o t he 
s u bjects t o e val uate t heir willi n g ness a n d a bilit y t o s wall o w a relati vel y bi g ca ps ule t wice d uri n g 
t he trial. 
T he Scree ni n g e xa mi nati o n is descri be d i n t he Sc he d ule of trial pr oce d ures. 
S u bjects w h o are eli gi ble f or t he trial base d o n t he Scree ni n g e xa mi nati o ns will ret ur n t o t he 
war d i n t he after n o o n of Da y - 2 f or a d missi o n. 
A d diti o nal s u bjects will be scree ne d as reser ve s u bjects. Reser ve s u bjects w h o are eli gi ble f or 
e nr oll me nt will als o be a d mitte d t o t he cli nical  facilit y t o e ns ure e n o u g h eli gi ble s u bjects are 
a vaila ble t o fill t he res pecti ve c o h ort. 
6. 1. 2  
Tr e at m e nt P h a s e  
If eli gi bilit y f or t he trial is c o nfir me d, s u bjects will c o nti n ue t he i n- h o use sta y u ntil disc har ge o n 
Da y  2 0. 
A s u m mar y of trial pr oce d ures t o be per f or me d d uri n g t he Treat me nt P hase is pr o vi de d i n t he 
Sc he d ule of trial pr oce d ures.  
N ote: Dietar y a n d ot her restricti o ns ( be y o n d t h ose gi ve n i n t he i ncl usi o n/e xcl usi o n criteria) are 
detaile d i n Secti o n  6. 2. 5 .  
6. 1. 3  
E n d of Tri al e x a mi n ati o n ( D a y 3 0-3 7)  
T he E n d of Trial e xa mi nati o n ( E o T) will be perf or me d 1 4 t o 2 1 da ys after last d osi n g, o n Da y  3 0 
u p t o Da y  3 7. 
Ai m of t he E n d of Trial e xa mi nati o n is t o g uara ntee t he well- bei n g of s u bjects a n d t o verif y t hat 
all val ues teste d d uri n g t he Pre- trial e xa mi nati o n ha ve re mai ne d wit hi n a cli nicall y acce pta ble 
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ra n ge. Val ues t hat are o ut- of-ra n ge a n d cli nicall y si g nifica nt will be f oll o we d u p u ntil t he y ret ur n 
t o t he refere nce ra n ge or u ntil t here is a n a de q uate e x pla nati o n. 
A n y Aes will be f oll o we d u p u ntil t he c o n diti o n is res ol ve d or t here is a n a de q uate e x pla nati o n. 
If t he s u bject ref uses t o f oll o w t he i nstr ucti o ns of t he I n vesti gat or, t he latter is release d fr o m 
res p o nsi bilit y. 
6. 1. 4  
E arl y T er mi n ati o n  
I n case of a n Earl y Ter mi nati o n, pr oce d ures will be perf or me d as defi ne d f or t he E o T 
e xa mi nati o n. Wit h t he s u bject’s a gree me nt, t he In vesti gat or a n d/ or S p o ns or ma y re q uest 
a d diti o nal ( or fe wer) assess me nts i n acc or da nce wit h A p pe n di x 4 . 
If n ot sc he d ule d o n t he da y of earl y ter mi nati o n a n d if p ossi ble, a P K sa m ple s h o ul d be c ollecte d. 
6. 1. 5  
Crit eri a f or wit h dr a w al  
A s u bject ma y ter mi nate partici pati o n i n t he trial at a n y ti me wit h o ut pr o vi di n g a reas o n a n d 
wit h o ut a n y pers o nal disa d va nta ge. A d diti o nall y, t he I n vesti gat or ma y disc uss t he re m o val of a 
s u bject wit h t he Ai C uris Res p o nsi ble P h ysicia n at a n y ti me. S u bjects w h o are wit h dra w n fr o m 
t he trial are n ot all o we d t o re-e nter at a later date. 
A s u bject ma y be wit h dra w n fr o m t he trial u n der t he f oll o wi n g circ u msta nces:  
•  S u bject’s decisi o n  
o  Wit h dra wal of c o nse nt at a n y ti me, wit h o ut t he nee d f or e x pla nati o n 
•  I n vesti gat or’s decisi o n 
o  F or a n y reas o n c o nsi dere d t o be i n t he best i nterest f or t he safet y of t he i n di vi d ual or 
i n t he safet y i nterest of t he ot her s u bjects 
•  S p o ns or’s / Ris k Be nefit C o m mittee’s  (R B C ) decisi o n  
o  Pr ot oc ol vi olati o n  
o  A d mi nistrati ve reas o ns 
o  A n y ot her vali d a n d et hical reas o n 
o  Ter mi nati o n of t he trial  
A d diti o nal wit h dra wal criteria i ncl u de:  
•  A E warra nti n g wit h dra wal  
•  Use of/ nee d f or a pr o hi bite d me dicati o n w hic h i n t he o pi ni o n of t he S p o ns or or I n vesti gat or 
ma y je o par dize t he trial res ults or re prese nt a ris k t o t he s u bject  
•  Pre g na nc y (i n t his case, t he s u bject is t o be f oll o we d u p u ntil deli ver y or a b orti o n) 
•  I n case of n o n -c o m plia nce wit h trial pr oce d ures or restricti o ns.  
•  S u bject meets t he i n di vi d ual r ules criteria (see  A p pe n di x 2 ) 
If a s u bject wit h dra ws c o nse nt, n o f urt her i n vesti gati o n or treat me nt ma y be perf or me d. T he 
I n vesti gat or will e x plai n t o t he s u bject t hat data alrea d y c ollecte d will be a nal yze d. 
T he E o T e val uati o ns are t o be perf or me d t o e ns ure s u bject safet y (see Secti o n 6. 1. 3 ). If p ossi ble, 
w he n trial me dicati o n is wit h dra w n, b ut t he s u bject has n ot wit h dra w n c o nse nt fr o m trial 
partici pati o n, all sc he d ule d visits s h o ul d c o nti n ue t o be perf or me d as pla n ne d, a n d all S A Es m ust 
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be re p orte d u ntil t he E o T Visit. All d oc u me ntati o n c o ncer ni n g t he s u bject m ust be as c o m plete as 
p ossi ble. 
T he reas o n f or disc o nti n uati o n of trial me dicati o n or wit h dra wal fr o m t he trial m ust be clearl y 
d oc u me nte d i n t he e C R F. 
Wit h dra wals d ue t o n o n- atte n da nce must be f oll o we d u p b y t he I n vesti gat or t o o btai n t he reas o n 
f or n o n-atte n da nce. 
I n a d diti o n, t he I n vesti gat or m ust pre pare a detaile d writte n e x pla nati o n f or Ai C uris/ a n d t he 
Et hics C o m mittee ( E C) w here a p plica ble. Ai C uris m ust be i nf or me d as s o o n as p ossi ble a b o ut 
t he wit h dra wal of a s u bject fr o m t he trial. 
6. 1. 6  
St o p pi n g crit eri a  
Pre m at ure ter mi n ati o n of t he tri al  
T he S p o ns or has t he ri g ht t o cl ose t his trial at a n y ti me. T he Pri nci pal I n vesti gat or is a ut h orize d 
t o set t he trial o n h ol d at a n y p oi nt of ti me if t he safet y of s u bjects is e n da n gere d. S pecificall y, 
t he trial will be ter mi nate d pre mat urel y if: 
•  Ne w t o xic o l o gical or p har mac ol o gical fi n di n gs or S A Es i n vali date t he earlier p ositi ve 
be nefit- ris k-assess me nt  
•  A E s occ ur i n s uc h pr o mi ne nce (ie, i nte nsit y a n d fre q ue nc y) t hat a c o nti n uati o n of t he trial is 
n o l o n ger j ustifie d , see als o A p pe n di x 2 . 
•  T he S p o ns or deci des t o disc o nti n ue t he cli nical trial. 
6. 2  
Tr e at m e nt s  
T here are 4 I M Ps i n t his cli nical trial:  
•  Priteli vir 1 0 0  m g  ta blets 
•  Matc hi n g place b o t o Priteli vir 1 0 0 m g  ta blets 
•  E nca ps ulate d m o xifl o xaci n ta blets 4 0 0  m g  
•  Matc hi n g place b o t o e nca ps ulate d m o xifl o xaci n ta blets 4 0 0 m g  
6. 2. 1  
R o ut e a n d  a d mi ni st r ati o n 
Priteli vir  
Priteli vir will be a d mi nistere d orall y as Priteli vir 1 0 0  m g  ta blets. 
I n Gr o u p 1: A l oa di n g d ose of 4 0 0 m g  o n Da y 1, f oll o we d b y a o nce dail y 1 0 0 m g  d ose re gi me n 
fr o m Da y 2 t o Da y 6, f oll o we d b y a o nce dail y 4 0 0 m g  d ose re gi me n fr o m Da y 7 t o Da y 1 6. 
Priteli vir pl ace b o  
Priteli vir place b o will be a d mi nistere d orall y as Priteli vir place b o ta blets.  
I n Gr o u p 2: T he sa me n u m ber of c orres p o n di n g priteli vir place b o ta blets will be a d mi nistere d 
fr o m Da y 1 t o Da y 1 6 i n Gr o u p 2 as ver u m ta blets i n Gr o u p 1. 
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M o xifl o x aci n a n d m o xifl o x aci n pl ace b o  
A si n gle oral d ose of m o xifl o xaci n place b o will be a d mi nistere d i n Gr o u p 1 o n Da ys 2 a n d 1 7 as 
well as o n Da y 1 7 i n Gr o u p 2a a n d Da y 2 i n Gr o u p 2 b. 
A si n gle oral d ose of 4 0 0 m g  m o xifl o xaci n will be a d mi nistere d i n Gr o u p 2a o n Da y 2 a n d i n 
Gr o u p 2 b o n Da y 1 7. 
O ver -e nca ps ulate d m o xifl o xaci n- a n d matc hi n g place b o will be use d t o mai ntai n d o u ble-
bli n d ness.  
6. 2. 2  
S el e cti o n of d o s e s  
Priteli vir  
T he m ost c urre nt I C H E 1 4 g ui deli ne ‘ Cli nical E val uati o n of Q T/ Q Tc I nter val Pr ol o n gati o n a n d 
Pr oarr h yt h mic P ote ntial f or N o n -A ntiarr h yt h mic Dr u gs’ [ 3, 4] states t he f oll o wi n g: “If n ot 
precl u de d b y c o nsi derati o ns of safet y or t olera bilit y d ue t o a d verse effects, t he dr u g s h o ul d be 
teste d at s u bsta ntial m ulti ples of t he a ntici pate d ma xi m u m t hera pe utic e x p os ure”. T h us, a hi g h 
s u pra-t hera pe utic d ose of priteli vir, w hic h res ults i n a n e x p os ure i n e xcess of w hat w o ul d be 
o bser ve d i n patie nts, will be use d i n t his T Q T trial. I n a d diti o n, a d ose t h at pr o d uces a 
t hera pe utic e x p os ure will be i n vesti gate d. 
T hera pe utic d ose:  
Priteli vir has alrea d y e ntere d P hase 3 de vel o p me nt sta ge a n d t he t hera pe utic d ose f or priteli vir  i n 
t he c urre ntl y o n g oi n g P hase 3 trial is 1 0 0 m g / da y. T heref ore, t his is als o t he pl a n ne d t hera pe utic 
d ose f or t his T Q T trial.  
D ue t o t he l o n g ter mi nal eli mi nati o n half-life, a l oa di n g d ose of 4 0 0 m g  will be a d mi nistere d o n 
Da y 1 t o reac h stea d y -state c o n diti o ns i m me diatel y. T his will als o g uara ntee stea d y-state 
c o n diti o ns o n t he pla n ne d P K - a n d E C G-Da y 6. 
S u pra-t hera pe utic d ose: 
F oll o wi n g t he e x p os ure t o 4 0 0 m g  priteli vir  o n Da y 1 a n d 1 0 0 m g  q d f or t he ne xt 5 da ys, d osi n g 
of 4 0 0 m g  q d priteli vir  f or 1 0 f urt her da ys ( Da y 7 t o Da y 1 6) is s ufficie nt ( base d o n res ults of 
trial AI C 3 1 6- 0 1-I- 0 5) t o reac h stea d y-state c o n diti o ns f or t he pla n ne d p har mac o ki netic sa m pli n g 
a n d E C G Da y  1 6.  
O verall, a d osa ge of 4 0 0 m g  q d priteli vir  is c o nsi dere d t o be t he s u pra-t hera pe utic d ose beca use 
of a la g of a bs or pti o n at d oses hi g her t ha n 4 0 0 m g  priteli vir , ie, n o hi g her e x p os ures ca n be 
reac he d b y i ncreasi n g t he d ose w he n a d mi nisteri n g priteli vir o nce dail y. 
After si n gle - a n d m ulti ple-d ose a d mi nistrati o n, t here was a d ose -pr o p orti o nal i ncrease of t he area 
u n der t he plas ma c o nce ntrati o n- ti me c ur ve fr o m ti me zer o t o i nfi nit y ( A U C0- ∞) bet wee n 5 m g  
a n d 4 8 0 m g  a n d i n pea k plas ma c o nce ntrati o n ( Cma x ) bet wee n 5 m g  a n d 4 0 0 m g . Hi g her d oses of 
priteli vir di d n ot f urt her i ncrease s yste mic e x p os ure, s u g gesti n g t hat t he lac k of d ose 
pr o p orti o nalit y ma y be relate d t o ca pacit y-li mite d a bs or pti o n (as o p p ose d t o n o n- li nearit y i n 
eli mi nati o n). A n a b o ut 4-f ol d hi g her e x p os ure after 4 0 0 m g  q d d osi n g c o m pare d t o t he 
t hera pe utic e x p os ure after 1 0 0 m g  q d d osi n g is als o c o nsi dere d t o c o ver i ntrinsic a n d e xtri nsic 
fact ors t hat ma y i ncrease priteli vir e x p os ure after a t hera pe utic d ose of 1 0 0 m g  priteli vir is gi ve n 
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o nce dail y. D ue t o priteli vir’s mai n meta b olis m pat h wa y ( h y dr ol ysis), p ote ntial dr u g- dr u g-
i nteracti o n effects t o i ncrease priteli vir e x pos ure  e g, b y i n hi biti n g C Y Ps are ne gli gi ble. F urt her, 
f o o d has n o rele va nt effect o n A U C 0-l ast a n d lea ds o nl y t o a mil d i ncrease i n Cma x . M ore o ver, t he 
a bs or pti o n fr o m g ut ca n n ot be i ncrease d m uc h as t he a bs ol ute bi oa vaila bilit y is alrea d y hi g h 
( > 7 0 %). T he  i nfl ue nce of he patic a n d re nal i m pair me nt is c urre ntl y u n der i n vesti gati o n i n 
parallel cli nical trials, b ut n o rele va nt effects are e x pecte d.  
Safet y wise , t he 4 0 0 m g  o nce dail y d ose is disc usse d i n t he ris k/b e nefit assess me nt,  Secti o n 2. 3 .  
M o xifl o x aci n 
A si n gle d ose of 4 0 0 m g  m o xifl o xaci n will be a d mi nistere d i n t his trial t o de m o nstrate t he trial’s 
a bilit y t o detect a s mall effect o n t he Q T i nter val (assa y se nsiti vit y) . T his d ose is t he sta n dar d 
d ose i n T Q T trials [ 1]. 
6. 2. 3  
D e s cri pti o n of i n v e sti g ati o n al pr o d u ct  
Priteli vir  1 0 0  m g  t a blets 
Priteli vir 1 0 0  m g  ta blets are pr o vi de d as fil m-c oate d ta blets f or oral a d mi nistrati o n.  
Priteli vir 1 0 0  m g  ta blets were ma n ufact ure d i n acc or da nce wit h G o o d Ma n ufact uri n g Practice 
b y: 
R otte n d orf P har ma G m b H  
Oste nfel der Str. 5 1 - 6 1, 
5 9 3 2 0 E n ni gerl o h, Ger ma n y 
Priteli vir  1 0 0  m g  ta blets are te m p oraril y st ore d, b y: 
Al mac Cli nical Ser vices Li mite d  
Sea g oe I n d ustrial Estate 9  
C harlest o w n R oa d Crai ga v o n  
N ort her n Irela n d  
B T 6 3 5 P W, U nite d Ki n g d o m 
Priteli vir  1 0 0  m g  ta blets are pac ke d, st ore d a n d Q P released b y : 
Ric h m o n d P har mac ol o g y Lt d 
1 A Ne wc o me n Street  
L o n d o n Bri d ge 
L o n d o n S E 1 1 Y R  
Priteli vir pl ace b o  t a blets 
Priteli vir place b o ta blets are pr o vi de d as fil m -c oate d ta blets f or oral a d mi nistrati o n.  
Priteli vir place b o ta blets were ma n ufact ure d i n acc or da nce wit h G o o d Ma n ufact uri n g Practice 
( G M P) b y: 
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V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
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R otte n d orf P har ma G m b H  
Oste nfel der Str. 5 1 - 6 1, 
5 9 3 2 0 E n ni gerl o h, Ger ma n y 
Priteli vir  place b o is te m p oraril y st ore d, b y: 
Al mac Cli nical Ser vices Li mite d  
Sea g oe I n d ustrial Estate 9  
C harlest o w n R oa d Crai ga v o n  
N ort her n Irela n d  
B T 6 3 5 P W, U nite d Ki n g d o m 
Priteli vir  place b o are pac ke d, st ore d a n d Q P release d b y: 
Ric h m o n d P har mac ol o g y Lt d 
1 A Ne wc o me n Street  
L o n d o n Bri d ge 
L o n d o n S E 1 1 Y R  
M o xifl o x aci n c a ps ules 
M o xifl o xaci n is c o m mer ciall y a vaila ble as 4 0 0  m g  ta blets a n d will be pr oc ure d a n d e nca ps ulate d 
i n gelati n ca ps ules f or oral a d mi nistrati o n. T he e nca ps ulate d m o xifl o xaci n f or m ulati o n was 
ma n ufact ure d i n acc or da nce wit h G M P b y: 
Pat he o n b y T her m o Fis her Scie ntific ,  
1 5 1 Br o o k Dri ve, 
Milt o n Par k,  
A bi n g d o n, O xf or ds hire,  
O X 1 4 4 S D, U nite d Ki n g d o m 
E nca ps ulate d m o xifl o xaci n t a blets 4 0 0 m g  are pac ke d, st ore d a n d Q P release d b y: 
Ric h m o n d P har mac ol o g y Lt d 
1 A Ne wc o me n Street  
L o n d o n Bri d ge 
L o n d o n S E 1 1 Y R 
M atc hi n g pl ace b o t o e nc a ps ul ate d m o xifl o x aci n t a blets 4 0 0 m g  
M o xifl o xaci n place b o is a n i de ntical ca ps ule size (t o t hat of M o xifl o xaci n e nca ps ulate d ta blets) 
c o ntai ni n g o ne of t he e xci pie nts prese nt i n t he M o xifl o xaci n ta blet.  T he place b o ta blet will be 
c o m p ose d of 7 5 % M C C P H 2 0 0 a n d 2 5 % Dicalci u m p h os p hate ( A- Ta b)  a n d e nca ps ulate d  i n 
gelati n ca ps ules . 
Matc hi n g place b o t o e nca ps ulate d m o xifl o xaci n ta blets 4 0 0 m g  was ma n ufact ure d i n acc or da nce 
wit h G M P b y: 
Pat he o n b y T her m o Fis her Scie ntific,  
1 5 1 Br o o k Dri ve, 
Milt o n Par k,  
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A bi n g d o n, O xf or ds hire,  
O X 1 4 4 S D, U nite d Ki n g d o m 
Matc hi n g place b o t o e nca ps ulate d m o xifl o xaci n ta blets 4 0 0 m g  are pac ke d, st ore d a n d Q P 
release d b y: 
Ric h m o n d P har mac ol o g y Lt d 
1 A Ne wc o me n Street  
L o n d o n Bri d ge 
L o n d o n S E 1 1 Y R  
6. 2. 3. 1   
Dr u g a c c o u nt a bilit y 
A Dr u g Acc o u nta bilit y F or m will be de vel o pe d f or use wit hi n t he trial w hic h will all o w t he 
acc urate a n d relia ble tr ac ki n g of trial me dicati o n.  
T he I n vesti gat or’s d uties f or dr u g acc o u nta bilit y ma y be desi g nate d t o a n a p pr o priate p har macist 
or a n ot her a p pr o priate i n di vi d ual w h o is u n der s u per visi o n of t he I n vesti gat or. 
T he I n vesti gat or or a p pr o priate desi g nee is o bli ge d t o kee p d oc u me ntati o n (e g, site s pecific dr u g 
acc o u nta bilit y l o g, trial me dicati o n dis pe nsi n g l o g) of t he deli ver y, use, a n d destr ucti o n or ret ur n 
of u n use d, use d or partiall y use d, pac ka ges of trial me dicati o n. T he d oc u me ntati o n m ust i ncl u de 
dates, q ua ntities, l ot/ batc h/serial n u m bers or ot her i de ntificati o n n u m bers, a n d t he mea ns t o 
i de ntif y t he s u bject t o w h o m a s pecific trial me dicati o n was dis pe nse d, e g, s u bject n u m ber. 
Bef ore a n y trial me dicati o n is destr o ye d or ret ur ne d b y t he site t o a ce ntral faci lit y, t he 
I n vesti gat or m ust all o w t he Cli nical Researc h Ass ociate t o perf or m dr u g rec o nciliati o n. E ntries 
i n t he electr o nic data ca pt ure ( E D C) a n d ot her acc o u nta bilit y rec or ds will be c o m pare d wit h t he 
ret ur ne d a n d resi d ual trial me dicati o n, wit h clarificati o n of a n y discre pa ncies or i nc o nsiste ncies. 
I M P m ust n ot t o be use d f or a n y p ur p ose ot her t ha n t he prese nt trial. Re mai ni n g I M P m ust be 
destr o ye d b y t he site at t he e n d of t he trial. 
6. 2. 3. 2  
St or a g e c o n diti o n s a n d st a bilit y  
Priteli vir  1 0 0  m g  t a blets 
At all st ora ge l ocati o ns d uri n g pac ka gi n g, la beli n g a n d distri b uti o n, te m perat ure l o gs a n d 
d oc u me ntati o n a b o ut t he recei pt a n d s hi p me nt of trial me dicati o n will be mai ntai ne d. 
Priteli vir 1 0 0  m g  ta blets will be st ore d i n a sec ure l ocati o n wit h restricte d access at r o o m 
te m perat ure bet wee n 1 5 a n d 3 0° C . T he st ora ge c o n diti o ns at t he i n vesti gati o nal sites will be 
rec or de d dail y, a n d d oc u me ntati o n a b o ut dr u g acc o u nta bilit y (recei pt a n d dis pe nse) will be 
mai ntai ne d. 
Priteli vir pl ace b o  t a blets 
At all st ora ge l ocati o ns d uri n g pac ka gi n g, la beli n g a n d distri b uti o n, te m perat ure l o gs a n d 
d oc u me ntati o n a b o ut t he recei pt a n d s hi p me nt of trial me dicati o n will be mai ntai ne d. 
Priteli vir place b o ta blets will be st ore d i n a sec ure l ocati o n wit h restricte d access at r o o m 
te m perat ure bet wee n 1 5 a n d 3 0° C. T he st ora ge c o n diti o ns at t he i n vesti gati o nal site will be 
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rec or de d dail y, a n d d oc u me ntati o n a b o ut dr u g acc o u nta bilit y (recei pt a n d dis pe nse) will be 
mai ntai ne d. 
M o xifl o x aci n c a ps ules 
M o xifl o xaci n ca ps ules  ( 4 0 0 m g) will be st ore d acc or di n g t o t he l ocal p har mac y pr oce d ures a n d 
t he S u m mar y of Pr o d uct C haracteristics. T he e nca ps ulate d  ta blets will be st ore d bet wee n 1 5 a n d 
2 5° C. 
M o xifl o x aci n m atc hi n g pl ace b o  c a ps ules 
M o xifl o xaci n place b o ca ps ules will be st ore d acc or di n g t o t he l ocal p har mac y pr oce d ures a n d 
t he S u m mar y of Pr o d uct C haracteristics. T he e nca ps ulate d ta blets will be st ore d bet wee n 1 5 a n d 
2 5° C. 
6. 2. 4  
C o n c o mit a nt m e di c ati o n s  
C o nc o mita nt me dicati o n is pr o hi bite d t hr o u g h o ut t he trial, e xce pt f or h or m o nal c o ntrace pti o n 
a n d h or m o ne re place me nt t hera p y as well as si n gle i nta ke of a dr u g if j u d ge d b y t he I n vesti gat ors 
t o ha ve n o cli nical rele va nce a n d n o rele va nce f or t he trial o bjecti ves. Li mite d a m o u nts of 
paraceta m ol ( n ot e xcee di n g 2 g per da y) are all o we d o n de ma n d t o treat pai nf ul i nterc urre nt 
a d verse e ve nts (e g, hea dac he, mi grai ne).  T he nee d f or ot her me dicati o n ma y lea d t o s u bject’s 
wit h dra wal fr o m t he trial. I n a n y case, t he I n vesti gat or will i nf or m t he S p o ns or a b o ut t he 
c o nc urre nt me dicati o n gi ve n.  
Details of all pri or a n d c o nc o mita nt me dicati o ns s h o ul d be rec or de d b y t he I n vesti gat or o n t he 
eC R F a n d s o urce rec or d.  
R estricti o ns c o ncer ni n g pre -trial or c o nc o mita nt me dicati o n use are gi ve n i n t he e xcl usi o n 
criteria i n Secti o n 5. 2 . 
6. 2. 5  
Di et ar y a n d ot h er r e stri cti o n s  
Diet ar y restric ti o ns 
W he ne ver s u bjects are c o nfi ne d i n t he war d, o nl y t he dri n ks a n d meals pr o vi de d b y t he trial 
pers o n nel will be all o we d. 
F or w h ole Da y - 1 ti me p oi nts, t he y s h o ul d be a p pr o xi matel y t he sa me as t he pla n ne d ti me f or 
E C Gs o n Da ys 1, 2, 6, 1 6 a n d 1 7. 
Meals  
•  O n Da ys - 1, 1, 2, 6, 1 6 a n d 1 7, i n or der t o o mit t he effect of f o o d s u bjects will fast fr o m at 
least 1 0 h bef ore u ntil 4 h after d osi n g t o ha ve t he sa me c o n diti o ns o n all H olter- E C G da ys. 
O n all ot her da ys bet wee n Da y  3 a n d 1 5 (e xce pt Da y  6), s u bjects will be d ose d 2 h after a 
sta n dar dize d c o nti ne ntal brea kfast. O n Da ys 1 8 t o 2 0 s u bjects will recei ve a sta n dar dize d 
c o nti ne ntal brea kfast i n t he m or ni n g.  
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•  O n Da ys - 1, 1, 2, 6, 1 6 a n d 1 7, t he sa me meal will be ser v e d (a n i de ntical perce nta ge  of fat, 
pr otei ns, a n d car b o h y drates) f or all s u bjects: l u nc h 4 h ( 6 0 0- 8 0 0 cal ories), after n o o n s nac k 
7 h, a n d di n ner 1 1 h after dr u g a d mi nistrati o n. O n t he ot her da ys bet wee n Da y  - 1 a n d 1 7, 
sta n dar dize d meals will be ser ve d (l u nc h 4 h, after n o o n s nac k 7 h, di n ner 1 1 h p ost- d ose). O n 
Da ys 1 8 t o 1 9 l u nc h, after n o o n s nac k, a n d di n ner will be ser ve d at a c o m para ble ti me t o t hat 
of Da ys - 1 t o 1 7. 
Fl ui ds 
•  O n Da ys - 1, 1, 2, 6, 1 6 a n d 1 7, i nta ke of a n y fl ui ds ot her t ha n t h ose pr o vi de d b y t he trial 
pers o n nel f or dr u g a d mi nistrati o n will n ot be all o we d fr o m at least 1 h o ur bef ore u ntil 4 h 
after d osi n g. Fr o m 4 t o 2 4 h after dr u g a d mi nistrati o n n o n- car b o nate d/car b o nate d water at 
r o o m or refri gerat or te m perat ure is all o we d i n a t otal a m o u nt o ver 2 4 h p ost- d ose of u p t o 
2. 5 L.  
•  O n t he Da ys 3 t o 5 a n d 7 t o 1 5, o nl y fl ui d i nta ke of n o n- car b o nate d/car b o nate d water at r o o m 
or refri gerat or te m perat ure  u p t o a t otal a m o u nt o ver 2 4  h of 2. 5 L is all o we d, w hic h will be 
pr o vi de d b y t he trial pers o n nel. 
T here will be n o restricti o ns wit h re gar d t o t he a m o u nt of fl ui ds d uri n g Da ys 1 8 t o 2 0. 
H o we ver, e nz y me acti vit y i nfl ue nci n g fl ui ds or be vera ges (e g, b ut n ot li mite d t o gra pefr uit 
j uice a n d t o nic water) are n ot all o we d d uri n g t he i n- h o use peri o d. 
Alc o h ol 
•  S u bjects will n ot be all o we d t o c o ns u me alc o h ol wit hi n 2 da ys bef ore c o nfi ne me nt u ntil 
disc har ge a n d wit hi n 2 da ys pri or t o t he p ost-trial e xa mi nati o n ( 1 4 t o 2 1 da ys after last 
d osi n g). 
F urt her details are pr o vi de d i n t he S O M. 
Ot her restricti o ns  
•  S u bjects will n ot be all o we d  t o perf or m e x ha usti n g e xercise (e g, c o m petiti ve s p orts or 
wei g htlifti n g) wit hi n 4 da ys bef ore c o nfi ne me nt u ntil t he E n d of Trial e xa mi nati o n 
•  S u bjects will n ot be all o we d t o s m o ke d uri n g t he i n- h o use peri o d. 
•  D uri n g t he i n - h o use peri o ds s u bjects will prefera bl y re mai n i nsi de t he war d b uil di n g. Li g ht 
o utsi de acti vities u n der s u per visi o n of site staff, e g, g oi n g f or a wal k, will be per mitte d, 
h o we ver. 
F urt her restricti o ns are gi ve n i n t he e xcl usi o n criteria i n Secti o n 5. 2  
6. 2. 6  
Tr e at m e nt c o m pli a n c e  
All trial me dicati o n a d mi nistrati o ns will be perf or me d b y t he I n vesti gat or or a p pr o priatel y 
trai ne d desi g nee (f or e xa m ple a  Researc h P h ysicia n)  a n d t he d osi n g will be verifie d b y a n ot her 
me m ber of t he I n vesti gat or’s staff. After oral a d mi nistrati o n, a t h or o u g h ha n d a n d m o ut h c hec k 
will be perf or me d t o e ns ure pr o per oral i n gesti o n of t he trial me dicati o n.  
T he bl o o d c o nce ntrati o ns of priteli vir a n d m o xifl o xaci n will ser ve as a n a d diti o nal meas ure of 
treat me nt c o m plia nce. 
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Priteli vir , m o xifl o xaci n a n d res pecti ve place b o are pla n ne d t o be a d mi nistere d orall y as detaile d 
i n Ta ble 6- 1 . 
T a ble 6- 1 
I M P or pl ace b o f or e ac h a ntici p ate d d ose le vel 
C o h ort  
Tre at me nt  
I M P/ Pl ace b o d is pe nse d 
A d mi nistr ati o n  
Gr o u p 1  
4 0 0  m g  or 
1 0 0  m g  priteli vir  
4 or 1 x 1 0 0  m g  priteli vir ta blet  
St u d y treat me nts will be 
a d mi nistere d t o eac h 
partici pa nt wit h 2 4 0  m L 
of water  
M o xifl o xaci n 
place b o  
1 x matc he d place b o t o 
m o xifl o xaci n ca ps ule  
Gr o u p 2a a n d 2 b  
Priteli vir place b o  
4 or 1 x matc he d place b o t o 
priteli vir ta blet(s)  
4 0 0  m g  
M o xifl o xaci n  
1 x 4 0 0  m g  m o xifl o xaci n 
ca ps ule  
M o xifl o xaci n 
place b o  
1 x matc he d place b o t o 
m o xifl o xaci n ca ps ule  
 
Detaile d i nstr ucti o ns f or d ose a d mi nistrati o n will be i ncl u de d i n t he S O M. 
6. 3  
A s si g n m e nt of s u bj e ct s t o tr e at m e nt gr o u p s  
S u bjects will be ra n d o ml y assi g ne d t o Gr o u p 1, Gr o u p 2a, or Gr o u p 2 b at a 2: 1: 1 rati o.  All 
s u bjects i n t his trial will be assi g ne d t o a treat me nt re gi me n acc or di n g t o a ra n d o mizati o n 
sc he d ule ge nerate d b y a statisticia n usi n g P R O C Pla n.  
Details re gar di n g t he u ni q ue scree ni n g a n d s u bject n u m be r will be i ncl u de d i n t he S O M. 
6. 4  
Bli n di n g  
S u bjects a n d all trial pers o n nel , e xce pt f or p har mac y staff at R ic h m o n d P har mac ol o g y, a n d 
A & M f or assi g n me nt of bi oa nal ytical sa m ples, will  be bli n de d wit h res pect t o t he assi g n me nt t o 
gr o u p 1 ( priteli vir) a n d 2 ( matc he d place b o t o priteli vir) as well as t he treat me nt se q ue nce of 
m o xifl o xaci n a n d res pecti ve matc hi n g place b o i n gr o u p 2. T o mai ntai n bli n di n g, matc hi n g 
place b os ( priteli vir or m o xifl o xaci n, as a p pr o priate) will be use d at e q ui vale nt ti me p oi nts t o 
ver u m treat me nt i n ot her treat me nt se q ue nces, s o t hat all s u bjects recei ve t he sa me n u m ber of 
ta blets or ca ps ules, wit h t he sa me a p peara nce, at e q ui vale nt ti me p oi nts i n t heir res pecti ve 
treat me nt se q ue nce. 
6. 4. 1  
M ai nt e n a n c e of r a n d o mi z ati o n c o d e  bli n di n g  
T he p har mac y staff pre pari n g t he I M P will n ot be bli n de d t o trial dr u g assi g n me nt. D uri n g t he 
trial, t he i n di vi d ual ra n d o mizati o n c o des will be ke pt i n t he site’s cli nical trials p har mac y, 
accessi ble t o t he p har mac y pers o n nel o nl y. U p o n c o m pleti o n of t he trial, after t he data base l oc k 
a n d after t he bli n d is re veale d, t he ra n d o mizati o n list will be file d i n t he Trial Master File.  
A d mi nistrati ve a n d o perati o nal staff of t he trial  site, i ncl u di n g Pri nci pal I n vesti gat or a n d trial 
ma na ger as well as m o nit ors, Ai C uris staff a n d data ma na gers will re mai n  bli n de d d uri n g t he 
c o urse of t he trial u ntil D ata base L oc k a n d fi nalizati o n of t he S tatistical A nal ysis P la n. 
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6. 4. 2  
Pr o c e d ur e f or u n bli n di n g  i n di vi d u al r a n d o mi z ati o n c o d e s 
I n t he e ve nt of a n e mer ge nc y, a n e n vel o pe f or eac h s u bject c o ntai ni n g his/ her trial dr u g 
assi g n me nt will be a vaila ble i n t he p har mac y at t he cli nical trial site. U n bli n di n g s h o ul d o nl y be 
c o nsi dere d f or t he safet y of t he s u bject. If u n bli n di n g is dee me d necessar y b y t he I n vesti gat or, 
t he I n vesti gat or or desi g nee ca n u n bli n d t he s u bject’s treat me nt all ocati o n usi n g t he e n vel o pe 
a vaila ble fr o m t he p har mac y. T he I n vesti gat or or desi g nee m ust n ote t he date, ti me, a n d reas o n 
f or u n bli n di n g a n d i nf or m t he S p o ns or of u n bli n di n g as s o o n as practica bl y p ossi ble. 
6. 5  
E x p e ct e d d u r ati o n of s u bj e ct p arti ci p ati o n 
T he ma xi m u m t otal peri o d of s u bject partici pati o n i n t he trial will be 5 8 da ys fr o m Scree ni n g, 
t hr o u g h A d missi o n, i n patie nt treat me nt peri o d, o ut patie nt treat me nt peri o d a n d u p t o t he E o T 
safet y f oll o w- u p visit: 
Scree ni n g pe ri o d 
Da y  - 2 1 t o Da y  - 1 
2 1 da ys  
Treat me nt peri o d  (i n patie nt) 
Da y  1 t o Da y  2 0  
2 0  da ys  
F oll o w -u p peri o d (t o E o T)  
U p t o Da y  3 0  t o 3 7  
1 7  da ys  
T otal d urati o n of partici pati o n  
 
5 8  da ys  
 
6. 6  
Tri al a s s e s s m e nt m et h o d s  
N ote :  Ti mes relati ve t o trial treat me nt a d mi nistrati o n refer t o t he ti me of ta blet /ca ps ule 
a d mi nistrati o n. 
C o nsi deri n g pri orities a n d or der of pr oce d ures, t he desi g n of t he Master Treat me nt Sc he d ule 
( M T S) re q uires sc he d uli n g ti me wi n d o ws f or t h ose tas ks t hat occ ur at t he sa me pr ot oc ol ti me 
p oi nt b ut nee d t o be perf or me d bef or e or after t he pri orit y tas k. T he per mitte d ti me wi n d o ws are 
set o ut i n t he Data Ha n dli n g Pr ot oc ol f or Sc he d uli n g Ti me Wi n d o ws ( D H P S T W). 
Cli nical assess me nts s h o ul d be perf or me d e xactl y at t he ti me prescri be d i n t he M T S.  
De v i ati o ns: 
•  De viati o n fr o m sc he d ule d ti me i n M T S: If t he ti me of cli nical assess me nt de viates fr o m t he 
ti me prescri be d i n t he M T S, a cli nical c o m me nt s h o ul d be ma de i n t he a p pr o priate s o urce 
data/ e C R F s pace t hat a de viati o n fr o m t he M T S occ urre d. T he f oll o wi n g de viati o ns fr o m t he 
M T S d o n ot re q uire a c o m me nt: 
All Pr oce d ures ± 2 mi ns  
•  De viati o n fr o m sc he d uli n g ti me wi n d o w i n D H P S T W: If t he ti me of cli nical assess me nt 
de viates fr o m t he sc he d uli n g ti me wi n d o w i n t he D H P S T W, t his will be c o nsi dere d a 
pr ot oc ol de vi ati o n. T hese de viati o ns will be i de ntifie d, classifie d ( mi n or, maj or, critical), a n d 
ma na ge d i n acc or da nce wit h t he D H P S T W.  
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Se q ue nce of pr oce d ures  
W he n t he pr ot oc ol’s S c he d ule of assess me nts  re q uires t hat m ulti ple pr oce d ures occ ur at t he sa me 
ti me p oi nt, P K bl o o d sa m pli n g ta kes pri orit y a n d is t o be sc he d ule d at t he e xact ti me p oi nt 
defi ne d i n t he S c he d ule of assess me nts . 
If 2 or m ore meas ures or acti o ns c oi nci de, t he y s h o ul d be perf or me d acc or di n g t o t he preferre d 
se q ue nce:  
Pre -d ose i n - h o use 
1.  E C G ( meas ure d after rest of at least 1 0 mi n utes i n s u pi ne p ositi o n) 
2.  Vital Si g ns ( meas ure d after rest of at least 5 mi n utes i n s u pi ne p ositi o n)  
3.  Bl o o d Sa m ples ( P K > cli nical c he mistr y a n d he mat ol o g y) 
4.  P G x sa m ple 
5.  Brea kfast  
P ost -d ose i n - h o use 
1.  E C G ( meas ure d after rest of at least 1 0 mi n utes i n s u pi ne p ositi o n) 
2.  Vital Si g ns ( meas ure d after rest of at least 5 mi n utes i n s u pi ne p ositi o n)  
3.  Bl o o d Sa m ples ( P K (e xactl y o n ti me) >cli nical c he mistr y a n d he mat ol o g y) 
4.  F o o d 
P ost - d ose o ut patie nts 
1.  E C G ( meas ure d after rest of at least 1 0 mi n utes i n s u pi ne p ositi o n) 
2.  Vital Si g ns ( meas ure d after rest of at least 5 mi n utes i n s u pi ne p ositi o n)  
3.  Bl o o d Sa m ples ( o n ti me) ( P K > cli nical che mistr y a n d he mat ol o g y) 
6. 6. 1  
D e m o gr a p hi c s a n d s u bj e ct c h a r a ct eri sti c s 
T he f oll o wi n g de m o gra p hic para meters will be rec or de d f or t he de m o gra p hic assess me nts: a ge, 
se x, hei g ht, wei g ht, a n d et h nicit y (i ncl u di n g race). 
F urt her, i nf or mati o n o n lifest yle a n d ha bits (e g, s m o ki n g, alc o h ol c o ns u m pti o n) a n d me dical 
hist or y rec or ds will be pr o vi de d. 
6. 6. 2  
Effi c a c y  
N ot a p plica ble. 
6. 6. 3  
P h ar m a c o ki n eti c s  
Detaile d i nstr ucti o ns o n sa m ple c ollecti o n a n d pr ocessi n g are descri be d i n t he s pecific la b orat or y 
ma n ual. 
Act ual sa m pli n g ti mes will be rec or de d i n t he e C R Fs.  
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Bl o o d s a m pli n g  
U nless i n d icate d, a n y sa m ple ta ke n o utsi de t he acce pta ble bl o o d sa m pli n g ti me wi n d o ws liste d 
a b o ve will be  c o nsi dere d a ti me de viati o n e ve n if t he de viati o n s h o ul d be p har mac o ki neticall y 
irrele va nt. 
Eac h bl o o d sa m ple will be la bele d t o i n dicate t he trial c o de, s u bject n u m ber, a n d n o mi nal 
sa m pli n g ti me. 
T he t otal v ol u me of bl o o d pla n ne d t o be wit h dra w n fr o m eac h s u bject is u nli kel y t o e xcee d 
3 0 0 m L  o ver t he d urati o n of t he trial (i ncl u di n g safet y la b orat or y, P K sa m pli n g, ge n ot y pi n g 
sa m pli n g) b ut will i n a n y e ve nt be less t ha n sta n dar d bl o o d d o nati o n. 
6. 6. 3. 1  
C oll e cti o n a n d h a n dli n g of pl a s m a s a m pl e s  
Priteli vir a n d met a b olites i n pl as m a  
F or deter mi nati o n of priteli vir  (t otal), as well as t he meta b olites AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5, 
3 m L of bl o o d will be dra w n b y ve n o us p u nct ure or i n d welli n g ve n o us cat heter i nt o a p pr o priate 
bl o o d c ollecti o n t u bes t o pre pare plas ma sa m ple deter mi nati o ns.  
Bl o o d sa m pli n g f or deter mi nati o n of priteli vir, AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 c o nce ntrati o ns i n 
plas ma will be carrie d o ut o n:  
•  Da y  1: pre- d ose, 0. 2 5, 0. 5, 0. 7 5, 1, 1. 5, 2, 3, 4, 5, 6, 7, 8, 1 0, 1 2, a n d 2 4 h p ost- d ose 
(ie, Da y  2 pre- d ose) 
•  Da y 3 t o 5: pre- d ose (tr o u g h),  
•  Da y  6: pre- d ose, 0. 2 5, 0. 5, 0. 7 5, 1, 1. 5, 2, 3, 4, 5, 6, 7, 8, 1 0, 1 2, a n d 2 4 h p ost- d ose 
(ie, Da y  7 pre- d ose), 
•  Da y  1 3 t o 1 5: pre- d ose (tr o u g h), 
•  Da y  1 6: pre- d ose, 0. 2 5, 0. 5, 0. 7 5, 1, 1. 5, 2, 3, 4, 5, 6, 7, 8, 1 0, 1 2, a n d 2 4 h p ost- d ose 
(ie, Da y  1 7 pre- d ose). 
M o xifl o x aci n i n pl as m a 
F or deter mi nati o n of m o xifl o xaci n i n plas ma, 2. 7 m L of bl o o d will be dra w n b y ve n o us p u nct ure 
or i n d welli n g ve n o us cat heter i nt o a p pr o priate bl o o d c ollecti o n t u bes t o pre pare plas ma sa m ple 
deter mi nati o ns . 
Bl o o d sa m pli n g f or deter mi nati o n of m o xifl o xaci n plas ma c o nce ntrati o ns will be carrie d o ut o n: 
•  Da y  2: pre- d ose, 1, 2, 3, 4, 5, 6, 7 a n d 8 h p ost-d ose,  
•  Da y  1 7: pre- d ose, 1, 2, 3, 4, 5, 6, 7 a n d 8 h p ost-d ose.  
6. 6. 3. 2  
A n al yti c al m et h o d s  
Vali date d met h o ds will be use d t o deter mi ne t he c o nce ntrati o ns of t he a nal ytes: priteli vir, 
AI C 0 9 0 0 1 5, AI C 0 9 0 1 0 5, a n d m o xifl o xaci n. 
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6. 6. 3. 3  
P h ar m a c o ki n eti c p ar a m et er s  
Plas ma c o nce ntrati o ns will be deter mi ne d b y A & M  a n d c o m m u nicate d t o Ve n n Life Scie nces f or 
deri vati o n of p har mac o ki netic para meters b y a n o n- c o m part me ntal a nal ysis. Ve n n Life Scie nces 
will pr o vi de t he calc ulate d P K para meters t o Ric h m o n d P har mac ol o g y f or inc or p orati o n i nt o t he 
fi nal data set, as well as t o Ai C uris f or preli mi nar y e val uati o n. 
T he p har mac o ki netic a nal ysis will be perf or me d u n der t he res p o nsi bilit y of t he S p o ns or 
acc or di n g t o Ai C uris Sta n dar d O perati n g Pr oce d ure “ A nal ysis of p har mac o ki netic da ta”. 
T he P K varia bles will be deri ve d base d o n t he plas ma c o nce ntrati o ns of t he a nal ytes (see 
Secti o n  6. 6. 3. 1 ) a n d t he act ual sa m pli n g ti mes, usi n g n o n-c o m part me ntal met h o ds. 
T he P K e n d p oi nts are defi ne d i n Secti o n 8. 3 . A d diti o nal P K para meters ma y be e xa mi ne d as 
dee me d necessar y.  
6. 6. 3. 3. 1  
D efi niti o n s a n d c al c ul ati o n s of p h ar m a c o ki n eti c v ari a bl e s  
T he defi niti o ns a n d met h o ds of calc ulati o n of t he p har mac o ki netic para meters are as f oll o ws: 
C ma x  
Ma xi mal o bser ve d a nal yte c o nce ntrati o n  
C ma x,ss  
Ma xi mal o bser ve d a nal yte c o nce ntrati o n at stea d y state  
C mi n  
Mi ni m u m o bser ve d a nal yte c o nce ntrati o n  
C a v,ss 
A vera ge c o nce ntrati o n at stea d y state, calc ulate d as:   
A U C τ,ss/τ 
C 0 h 
Dr u g c o nce ntrati o n o bser ve d at t he last pla n ne d ti me p oi nt pri or t o d osi n g  
tma x   
Ti me t o reac h t he ma xi mal o bser ve d a nal yte c o nce ntrati o n  
tla g 
Ti me peri o d bet wee n t he ti me of d osi n g a n d t he ti me of t he first 
meas ura ble c o nce ntrati o n  
A U C τ 
Area u n der t he a nal yte vs. ti me c o nce ntrati o n c ur ve o ver a d osi n g 
i nter val τ after t he starti n g d ose d uri n g m ulti ple d osi n g, calc ulate d 
b y li near u p/l n d o w n s u m mati o n.  
A U C τ,ss 
Area u n der t he a nal yte vs. ti me c o nce ntrati o n c ur ve o ver a d osi n g 
i nter val τ at stea d y-state (ss), calc ulate d b y li near u p/l n d o w n s u m mati o n.  
C L/ F  
T otal a p pare nt cleara nce of dr u g f oll o wi n g si n gle  e xtra vasc ular  d os e 
a d mi nistrati o n calc ulate d as:  
C L/ F = D ose /  A U C 0- ∞ 
C L ss/ F 
A p pare nt cleara nce of dr u g at stea d y sta te f oll o wi n g e xtra vasc ular 
d osi n g , calc ulate d as:  
C L ss/ F = D ose / A U C τ,ss 
t1/ 2z 
T he a p pare nt ter mi nal eli mi nati o n half -life calc ulate d as:  
t1/ 2z = 0. 6 9 3 /  λ z  
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λ z  
T he a p pare nt ter mi nal eli mi nati o n rate c o nsta nt, deter mi ne d b y li near 
re gressi o n of ter mi nal p oi nts of t he l n-li near a nal yte c o nce ntrati o n-ti me 
c ur ve. 
V d/ F  
A p pare nt v ol u me of distri b uti o n after a si n gle d ose e. v. a d mi nistrati o n 
calc ulate d as: 
V d/ F = D osee.v. / (λ z · A U C 0- ∞) 
V d,ss 
T he a p pare nt v ol u me of distri b uti o n at stea d y state of distri b uti o n , 
calc ulate d as:  
V d,ss/ F = M R T · C Lss. / F 
M R T  
Mea n resi de n ce ti me is t he ti me c orres p o n di n g t o t he ti me (a vera ge ti me) 
t he n u m ber of m olec ules a bs or be d resi de i n t he b o d y, calc ulate d b y : 
M R T = A U M C / A U C   
T he f oll o wi n g re q uire me nts are t o be met f or a n acce pta ble calc ulati o n of t 1/ 2z, λz, A U C0- ∞, C L/ F, 
V d/ F a n d M R T: 
a. at least 3 data p oi nts are use d i n t he calc ulati o n ( n ot i ncl u di n g C ma x ), ot her wise t1/ 2z, λz, a n d 
(c o nse q ue ntl y) A U C0- ∞, C L/ F, V d/ F a n d M R T are n ot assessa ble ( N A)  
b.  c oefficie nt of deter mi nati o n ( r2 a dj) is at least 0. 8 5 0 
c. t he s pa n of ti me p oi nts ( λz u p per - λz l o wer) use d i n t he calc ulati o n is at least t wice t he 
calc ulate d t 1/ 2z 
If re q uire me nt b or c is not met, λ z, t1/ 2z, A U C0- ∞, C L/ F, C Lss/ F, Vd/ F, Vd,ss/ F a n d M R T will be 
re p orte d as a p pr o xi mati o ns a n d will be e xcl u de d fr o m t he descri pti ve statistics.  
A U C 0- ∞ (a n d c o nse q ue ntl y C L/ F, C Lss/ F, Vd/ F, Vd,ss/ F a n d M R T) will als o be re p orte d as 
a p pr o xi mati o ns i n case t he A U C 0- ∞,e x  (t he part of A U C0- ∞ t hat is calc ulate d b y e xtra p olati o n) 
e xcee ds 2 0 . 0 0%, b ut will be e xcl u de d fr o m t he descri pti ve statistics a n d fr o m statistical a nal ysis.  
6. 6. 4  
S af et y  
6. 6. 4. 1  
A d v er s e e v e nt s  
S u bjects will be i nter vie we d b y trai ne d cli nic pers o n nel usi n g n o n- lea di n g q uesti o ns (e g, “ H o w 
d o y o u feel?”) t o elicit i nf or mati o n o n p ossi ble a d verse e ve nts wit hi n 3 0 mi n utes pri or t o 
a d mi nistrati o n or assess me nt at:  
•  Scree ni n g: Da y  - 2, - 1, 
•  Da ys 1 t o 1 7 ( pre- d ose),  
•  Da y  1 8 t o 2 0, a n d 
•  E o T.  
S p o nta ne o usl y re p orte d a n d i n q uire d a d verse e ve nts will be rec or de d i n a n A E l o g. I n case of 
a d verse e ve nts, t he I n vesti gat or ma y deci de t o re peat a cli nical e xa mi nati o n a n d/ or la b orat or y 
test. 
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6. 6. 4. 1. 1  
D efi niti o n of a d v er s e e v e nt  
A n A E is a n y u nt o war d me dical occ urre nce i n a p atie nt or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.  
A n A E ca n t heref ore be a n y u nfa v 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, f or e xa m ple), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a n I M P, 
w het her or n ot c o nsi dere d relate d t o t he I M P.  
D uri n g a trial, a n A E ca n als o occ ur at ti mes w he n I M P (s) is (are) n ot ta ke n, e g, d uri n g was h - o ut 
peri o ds or d uri n g a place b o r u n-i n. 
6. 6. 4. 1. 2  
D efi niti o n of a d v er s e dr u g r e a cti o n  
I n t he pre-a p pr o val cli nical e x perie nce wit h a ne w me dici nal pr o d uct or its ne w usa ges, 
partic ularl y as t he t hera pe utic d ose(s) ma y n ot be esta blis he d: all n o xi o us a n d u ni nte n de d 
res p o nses t o a me dici nal pr o d uct relate d t o a n y d ose s h o ul d be c o nsi dere d a d verse dr u g 
reacti o ns. 
T he p hrase “res p o nses t o a me dici nal pr o d uct” mea ns t hat a ca usal relati o ns hi p bet wee n a 
me dici nal pr o d uct a n d a n A E  is at least a reas o na ble p ossi bilit y, ie, t he relati o ns hi p ca n n ot be 
r ule d o ut.  
6. 6. 4. 1. 3  
D efi niti o n of s eri o u s a d v er s e e v e nt s or s eri o u s a d v er s e dr u g r e a cti o n s  
A n S A E or seri o us a d verse dr u g reacti o n ( S A R, w hic h is a n S A E t hat ha s bee n assesse d as bei n g 
ca usall y relate d t o I M P) is a n y u nt o war d me dical occ urre nce t hat at a n y d ose:  
•  Res ults  i n deat h 
•  Is life-t hreate ni n g 1 
•  Re q uires h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 2 
•  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 
•  Is a n ot her me dicall y i m p orta nt e ve nt or reacti o n 3 
6. 6. 4. 1. 4  
D efi niti o n of i nt e n sit y of a d v er s e e v e nt s  
T he f oll o wi n g cate g ories will be use d f or t he rati n g of i nte nsit y acc or di n g t o t he Di visi o n of 
AI D S ( D AI D S) Ta ble f or Gra di n g t he Se verit y of A d ult a n d Pe diatric A d verse E ve nts 
                                                 
1  T he ter m “life-t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h t he s u bject was at ris k of 
deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt, w hic h h y p ot heticall y mi g ht ha ve ca use d deat h if it 
was m ore se vere .  
2  D oes n ot i ncl u de t he f oll o wi n g h os pital a d missi o ns: u n der 2 4 h o urs, u nrelate d t o a n a d verse e ve nt ( e g, f or la b or 
a n d deli ver y, c os metic s ur ger y, s ocial or a d mi nistrati ve f or te m p orar y place me nt [f or lac k of a place t o slee p]), 
pr ot oc ol -s pecifie d, a n d f or dia g n osis or t hera p y of a c o n diti o n t hat e xiste d bef ore t he recei pt of I M P a n d w hic h 
has n ot i ncrease d i n se verit y or fre q ue nc y.  
3  Me dical a n d scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her e x pe dite d re p orti n g is a p pr o priate i n 
ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life -t hreate ni n g or res ult i n deat h 
or h os pitalizati o n b ut ma y je o par dize t he s u bject or ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her 
o utc o mes liste d i n t he defi niti o ns a b o ve. T hese s h o ul d als o  be c o nsi dere d seri o us  
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( C orrecte d Versi o n 2. 1, J ul y 2 0 1 7, see A p pe n di x 1 ). I n a d diti o n, all deat hs relate d t o a n A E are 
t o be classifie d as Gra de 5. 
P ar a meter  
Gr a de 1  
Mil d  
Gr a de 2  
M o der ate  
Gr a de 3  
Se vere  
Gr a de 4  
P ote nti all y l ife-
t hre ate ni n g 
Cli nical a d verse 
e ve nt N O T 
i de ntifie d 
else w here i n t he 
gra di n g ta ble  
Mil d s y m pt o ms 
ca usi n g n o or 
mi ni mal 
i nterfere nce wit h 
us ual s ocial & 
f u ncti o nal 
acti vities wit h 
i nter ve nti o n n ot 
i n dicate d 
M o derate 
s y m pt o ms ca usi n g 
greater t ha n 
mi ni mal 
i nterfere nce wit h 
us ual s ocial & 
f u ncti o nal 
acti vities wit h 
i nter ve nti o n 
i n dicate d 
Se vere s y m pt o ms 
ca usi n g i na bilit y t o 
perf or m us ual s ocial 
& f u ncti o nal 
acti vities wit h 
i nter ve nti o n or 
h os pitalizati o n 
i n dicate d 
P ote ntiall y life -
t hreate ni n g s y m pt o ms 
ca usi ng i na bilit y t o 
perf or m basic self -care 
f u ncti o ns wit h 
i nter ve nti o n i n dicate d t o 
pre ve nt per ma ne nt 
i m pair me nt, persiste nt 
disa bilit y, or deat h  
 
6. 6. 4. 1. 5  
D efi niti o n of a d v er s e e v e nt c a u s alit y  
A deter mi nati o n of t he relati o ns hi p bet wee n a n A E a n d t he I M P m ust be ma de after d ue 
c o nsi derati o n b y t he I n vesti gat or f or eac h A E. 
T he assess me nt of t he relati o ns hi p of a n A E t o t he a d mi nistrati o n of I M P is a cli nical decisi o n 
base d o n all a vaila ble i nf or mati o n at t he ti me of a n d after t he occ urre nce of t he e ve nt. T he 
fact ors whic h ma y be c o nsi dere d w he n e val uati n g t he relati o ns hi p of a n A E t o t he I M P, i ncl u de: 
ti me fr o m e x p os ure t o I M P u ntil o nset of t he e ve nt; rec o ver y or i m pr o ve me nt o n disc o nti n uati o n 
of I M P; a vaila bilit y of alter nati ve e x pla nati o ns s uc h as u n derl yi n g or i nte rc urre nt diseases; 
c o nc o mita nt me dicati o ns or treat me nts; p har mac ol o g y a n d p har mac o ki netic of t he I M Ps; k n o w n 
res p o nse patter n f or t his class of dr u g; rec urre nce o n rei ntr o d ucti o n of t he I M P. 
T he relati o ns hi p of a d verse e ve nts t o t he I M P will be assesse d a cc or di n g t o t he f oll o wi n g 
cate g ories: 
•  “ defi nite ” : A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h a reas o na ble 
te m p oral relati o ns hi p t o dr u g a d mi nistrati o n. A E ca n n ot be e x plai ne d b y c o nc o mita nt 
diseases or ot her dr u gs or c he micals. Res p o nse o n dr u g wit h dra wal m ust be cli nicall y 
e x plica ble. A E m ust be p har mac ol o gicall y or p he n o me n ol o gicall y u na m bi g u o us; a 
satisfact or y rec halle n ge pr oce d ure mi g ht be use d. 
•  “ pr o b a ble ” : A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y i n a reas o na ble ti me 
se q ue nce t o a d mi nistrati o n of t he dr u g. A E is u nli kel y t o be attri b ute d t o c o nc urre nt disease 
or ot her dr u gs or c he micals a n d f oll o ws a cli nicall y reas o na ble res p o nse o n wit h dra wal; 
i nf or mati o n a b o ut rec halle n ge is n ot re q uire d. 
•  “ p ossi ble ” : A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y i n a reas o na ble ti me 
se q ue nce t o a d mi nistrati o n of t he dr u g, b ut A E c o ul d als o be e x plai ne d b y c o nc urre nt 
diseases or ot her dr u gs or c he micals; i nf or mati o n o n dr u g wit h dra wal ma y be lac ki n g or 
u nclear. 
•  “ u nli kel y ” : A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h a wea k te m p oral 
relati o ns hi p t o dr u g a d mi nistrati o n. Ot her fact ors, s uc h as t he u n derl yi n g, c o nc o mita nt 
diseases, c o nc o mita nt me dicati o n, are pla usi ble t o ha ve c o ntri b ute d t o t he e ve nt. 
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•  “ n ot rel at e d ”: N o relati o ns hi p t o a d mi nistrati o n of trial dr u g, ie, t here is a clear alter nati ve 
e x pla nati o n, a n u nreas o na ble te m p oral relati o ns hi p bet wee n t he dr u g a n d t he e ve nt, or 
relati o ns hi p is ot her wise n ot pla usi ble. 
6. 6. 4. 1. 6  
D efi niti o n of a d v er s e e v e nt o ut c o m e  
T he o u tc o me of a d verse e ve nts will be descri be d acc or di n g t o t he f oll o wi n g 6 cate g ories: 
1.  Res ol ve d  
2.  Res ol vi n g 
3.  N ot Res ol ve d 
4.  Res ol ve d wit h se q uelae 
5.  Fatal  
6.  U n k n o w n 
6. 6. 4. 1. 7  
D efi niti o n of e x p e ct e d n e s s  
A n a d verse reacti o n, t he nat ure a n d i nte nsit y of w hic h is c o nsiste nt wit h t he a p plica ble pr o d uct 
i nf or mati o n (e g, I n vesti gat or’s Br oc h ure f or a n u na p pr o ve d I M P) is c o nsi dere d as e x pecte d. T he 
I n vesti gat or’s Br oc h ure, Secti o n 6. 5, Refere nce Safet y I nf or mati o n, will ser ve as t he refere nce 
d oc u me nt f or t he assess me nt of e x pecte d ness o n priteli vir i n t his cli nical trial. T he m o xifl o xaci n 
S P C will ser ve as t he refere nce d oc u me nt f or t he assess me nt of e x pecte d ness o n m o xifl o xaci n. 
T he e x pecte d ness is deter mi ne d b y t he S p o ns or. 
6. 6. 4. 1. 8  
A d v er s e e v e nt r e c or di n g a n d r e p orti n g  
Peri o d of rec or di n g  
T he  peri o d of rec or di n g of A E or S A E will last fr o m t he ti me t hat t he s u bject si g ns t he I nf or me d 
C o nse nt F or m t o t he last trial d a y acc or di n g t o t he C li nical T rial Pr ot oc ol , re gar dless of t he 
relati o ns hi p t o I M P. T his i ncl u des e ve nts t hat occ ur at ti mes w he n I M P(s) is (are) n ot ta ke n, e g, 
d uri n g was h- o ut peri o ds or d uri n g a place b o r u n -i n. If t he In vesti gat or bec o mes a ware of a n S A E  
wit h a s us pecte d ca usal relati o ns hi p t o t he I M P t hat occ urs after t he e n d of t he cli nical trial i n a 
s u bject treate d b y hi m or her, t he In vesti gat or s hall, wit h o ut u n d ue dela y, re p ort t he S A E  t o t he 
S p o ns or. 
F oll o w- u p of s u bjects wit h a n a d verse e ve nt  
A Es a n d S A Es ha ve t o be f oll o we d u p u ntil t heir res ol uti o n, t he y ha ve bec o me sta ble, ret ur ne d t o 
B aseli ne c o n diti o n  or ca n be e x plai ne d b y ot her ca uses (e g, c o nc o mita nt s y m pt o m or disease) 
a n d cli nical j u d g me nt i n dicates t hat f urt her f oll o w - u p is n ot warra nte d. 
A d verse e ve nt rec or di n g  
Eac h A E a n d S A E occ urri n g t o a s u bject, eit her s p o nta ne o usl y re veale d b y t he s u bject or 
o bser ve d b y t he I n vesti gat or, w het her belie ve d b y t he I n vesti gat or t o be relate d or u nrelate d t o 
t he I M P, m ust be rec or de d o n t he A E i nf or mati o n pa ge of t he e C R F a n d i n t he s u bject’s s o urce 
data.  
T he f oll o wi n g as pects of A E/ S A Es will be d oc u me nte d b y t h e I n vesti gat or i n t he s o urce data as 
well as o n t he e C R F:  
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•  If p ossi ble, dia g n osis or s y n dr o me, ot her wise eac h si n gle s y m pt o m. 
•  Date a n d ti me of o nset a n d e n d of A E/ S A E. 
•  Seri o us ness  
(seri o us/ n o n-seri o us). 
•  I nte nsit y usi n g t he Gra di n g of t he Se verit y of A d verse E ve nts acc or di n g t o t he D AI D S  
( mil d/ m o derate/ se vere/ p ote ntiall y life-t hreate ni n g/ fatal, Secti o n 6. 6. 4. 1. 4 ). 
•  Ca usal relati o ns hi p wit h I M P  
( defi nite/ pr o ba ble/ p ossi ble/ u nli kel y/ n ot relate d, Secti o n 6. 6. 4. 1. 5 ). 
•  O utc o me 
(res ol ve d/ res ol vi n g/ n ot res ol ve d/ res ol ve d wit h se q uelae/ fatal/ u n k n o w n, Secti o n 6. 6. 4. 1. 6 ). 
•  Treat me nt of e ve nt, if a p plica ble  
(e g, a n y me dicati o n as well as a n y ot her me dical meas ures). 
•  Acti o ns ta ke n re gar di n g I M P  
( wit h dra w n, d ose re d uce d, d ose i ncrease d, d ose n ot c ha n ge d, u n k n o w n, n ot a p plica ble). 
C ha n ges i n i nte nsit y of a n A E s h o ul d be rec or de d as a se parate A E wit h a ne w o nset. If a n A E 
bec o mes seri o us, a ne w A E has t o be rec or de d fla g ge d as seri o us a n d a d diti o nall y a S A E f or m 
has t o be c o m plete d wit h a ne w o nset. 
A d verse e ve nt re p orti n g  
T he I n vesti gat or m ust re p ort t o t he S p o ns or all A Es, w hic h occ ur d uri n g t he cli nical trial, 
re gar dless of t heir relati o ns hi p t o t he I M P b y d oc u me ntati o n i n t he E D C. 
Seri o us a d verse e ve nt re p orti n g  
Ai C uris has c o ntracte d I Q V I A as a n e xter nal ser vice pr o vi der f or p har mac o vi gila nce. S A Es will 
be re p orte d b y t he I n vesti gat or t o I Q VI A i m me diatel y ( wit h o ut u n d ue dela y) after bec o mi n g 
a ware of occ urre nce.  I Q VI A i n t ur n m ust pr o m ptl y re p ort S A Es t o Ai C uris bei n g t he pri mar y 
res p o nsi ble b o d y f or p har mac o vi gila nce. 
S A Es m ust be re p orte d usi n g t he e C R F . It has t o be e ns ure d t hat all ot her rele va nt i nf or mati o n 
has bee n i ncl u de d (e g, rele va nt me dical hist or y, c o nc o mita nt me dicati o ns, la b orat or y tests, 
e xa mi nati o ns). A pa per S A E re p ort F or m m ust als o be c o m plete d i n case t he e C R F s yste m is n ot 
a vaila ble. T he ori gi nal c o p y of t he S A E Re p ort F or m a n d t he fa x c o nfir mati o n s heet or e mail 
m ust be ke pt at t he trial site. 
T he c o ntact details f or I Q VI A are:  
I Q VI A 
East p oi nt B us i ness par k, Fair vie w 
D u bli n 3 Irela n d 
 
P h o ne:   
  
  
E mail:   
  
 
I Q VI A Safet y Fa x:   
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T he f oll o wi n g i nf or mati o n will be a vaila ble i n t he S A E re p ort:  
•  Trial Pr ot oc ol n u m ber 
•  Stat us of re p ort: i nitial, f oll o w - u p 
•  S u b ject i de ntificati o n n u m ber 
•  S u bject de m o gra p hics 
•  I M P: 
o  Dr u g c o de, kit n u m ber, or na me (if a p plica ble) 
o  Batc h n u m ber (if a p plica ble)  
o  Start a n d e n d date, d ose – if k n o w n 
•  Nat ure of t he A E i ncl u di n g date of o nset, i nte nsit y, a n d treat me nt (i ncl u di n g h os pitalizati o n) 
•  Acti o n ta ke n wit h res pect t o I M P  
•  Ca usal relati o ns hi p t o I M P(s) i n t he o pi ni o n of t he I n vesti gat or 
•  Pre vi o us a n d c o nc o mita nt diseases  
•  Pre vi o us a n d c o nc o mita nt dr u g t hera p y 
•  O utc o me 
•  Rec o ver y date (if a vaila ble)  
•  I n t he case of deat h, t he ca use a n d p ost- m orte m fi n di n gs.  
T he I n vesti gat or will fill i n t he Seri o us A d verse E ve nt F or m i n E n glis h f or re p orti n g.  
F oll o w- u p re p orts relati n g t o t he s u bject’s s u bse q ue nt c o urse m ust be s u b mitte d t o I Q VI A 
res p o nsi ble f or S A E ma na ge me nt usi n g t he e C R F u ntil t h e e ve nt has s u bsi de d or t he c o n diti o n 
sta bilize d a n d be s ufficie ntl y me dicall y e x plai ne d. A pa per S A E re p ort F or m m ust als o be 
c o m plete d f or s u b missi o n b y fa x or e mail i n case t he e C R F s yste m is n ot a vaila ble. 
I n case of deat h t he I n vesti gat or m ust s u b mit t o I Q VI A b y fa x or e mail all rele va nt f oll o w- u p-
i nf or mati o n t hat ca n be o btai ne d (a n o n y mize d a ut o ps y fi n di n gs, clear p h ot oc o pies of h os pital 
rec or ds, c o ns ulta nt re p ort[s]) wit hi n 2 4 h of recei pt of t he i nf or mati o n. 
S us pecte d U ne x pecte d Seri o us A d verse Re acti o ns re p orti n g  
A n y a d verse reacti o n t hat is seri o us a n d u ne x pecte d ( S U S A Rs) has a d diti o nal re p orti n g 
re q uire me nts, as descri be d bel o w: 
•  If t he S U S A R is fatal or life-t hreate ni n g, Re g ulat or y A ut h orities ( R As), E C a n d I n vesti gat ors 
will be n otifie d  i m me diatel y, b ut at t he latest wit hi n 7 cale n dar da ys after t he S p o ns or lear ns 
of t he e ve nt. A d diti o nal f oll o w- u p (ca use of deat h, a ut o ps y re p ort, h os pital re p ort) 
i nf or mati o n s h o ul d be re p orte d t o t he C o m pete nt A ut h orities ( C As), a n d I n vesti gat ors wit hi n 
a n a d diti o nal 8 da ys ( 1 5 da ys t otal). 
•  If t he S U S A R is n ot fatal or life-t hreate ni n g b ut is ot her wise seri o us, R As, E C a n d 
I n vesti gat ors will be n otifie d i m me diatel y, b ut at t he latest wit hi n 1 5 cale n dar da ys after t he 
S p o ns or lear ns of t he e ve nt. 
T he S p o ns or will n otif y t he I n vesti gat or of rele va nt i nf or mati o n a b o ut S U S A Rs t hat c o ul d 
a d versel y affect t he safet y of s u bjects i n a ti mel y fas hi o n. F oll o w -u p i nf or mati o n ma y be 
s u b mitte d if necessar y. 
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I n case of occ urre nce of a n y ne w e ve nt or ot her safet y iss ue relati n g t o t he c o n d uct of t he trial or 
t he de vel o p me nt of t he I M P w here t hat ne w e ve nt is li kel y t o affect t he safet y of t he cli nical trial 
s u bjects, t he S p o ns or a n d t he I n vesti gat or m ust ta ke a p pr o priate ur ge nt safet y meas ures t o 
pr otect t he s u bjects a gai nst a n y i m me diate hazar d. T he S p o ns or has t o i nf or m t he c o ncer ne d C A 
of t h ose ne w e ve nts a n d t he meas ures ta ke n.  T hat n otificati o n s hall be ma de wit h o ut u n d ue dela y 
b ut n o later t ha n se ve n da ys fr o m t he date t he meas ures ha ve bee n ta ke n.  
6. 6. 4. 1. 9  
Ot h er s af et y i s s u e s, w hi c h mi g ht alt er t h e b e n efit -ri s k a s s e s s m e nt of t h e 
i n v e sti g ati o n al dr u g 
Ot her safet y iss ues w hic h mi g ht alter t he c urre nt be nefit -ris k assess me nt of t he i n vesti gati o nal 
dr u g or w hic h w o ul d be s ufficie nt t o c o nsi der c ha n ges i n t he i n vesti gati o nal dr u g a d mi nistrati o n 
or i n t he o verall c o n d uct of t he trial m ust be re p orte d t o t he C A a n d t he E C as s o o n as p ossi ble 
b ut n o later t ha n 1 5 cale n dar da ys after t he S p o ns or has first k n o wle d ge of t he m. F urt her rele va nt 
f oll o w- u p i nf or mati o n s h o ul d be gi ve n as s o on as p ossi ble.  
S uc h safet y iss ues ma y be:  
•  A n i ncrease i n t he rate of occ urre nce of a n e x pecte d seri o us a d verse reacti o n, w hic h is j u d ge d 
t o be cli nicall y i m p orta nt, 
•  P ost -trial S U S A Rs t hat occ ur after t he s u bject has c o m plete d a cli nical trial a n d are re p orte d 
b y t he I n vesti gat or t o t he S p o ns or, 
•  E ve nts relati n g t o t he c o n d uct of t he trial or t he de vel o p me nt of t he I n vesti gati o nal Me dici nal 
Pr o d uct li kel y t o affect t he safet y of t he s u bjects.  
I n vesti gat ors will be i nf or me d acc or di n gl y. 
6. 6. 4. 1. 1 0  
A n n u al S af et y R e p o rt 
T he S p o ns or will als o pr o vi de a n n ual safet y u p dates o nce a year t hr o u g h o ut t he cli nical trial or 
o n re q uest t o t he R As res p o nsi ble f or t he trial. T hese u p dates will i ncl u de i nf or mati o n o n S A R 
(i ncl u di n g S U S A R) w hic h occ urre d i n t he cli nical trial a n d other rele va nt safet y fi n di n gs.  
6. 6. 4. 1. 1 1  
Pr o c e d ur e s i n c a s e of pr e g n a n c y  
All pre g na ncies t hat occ ur d uri n g t he trial i n fe male s u bjects a n d fe male part ners of male 
s u bjects s h o ul d be f oll o we d u p. If s uc h a pre g na nc y occ urs, a Dr u g E x p os ure via Pare nt f or m has 
t o be c o m plete d a n d se nt t o I Q VI A: 
Fa x:   
 
T he c o ntact details f or I Q VI A are:  
I Q VI A  
East p oi nt B usi ness Par k, Fair vie w  
D u bli n 3 
Irela n d 
 
P h o ne:   
E mail:  
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6. 6. 4. 2  
S af et y l a b or at or y p ar a m et er s, al c o h ol br e at h t e st, dr u g t e st, a n d 
pr e g n a n c y t e st  (f e m al e s o nl y ) 
La b orat or y para meters are liste d i n  Ta ble 6- 2 . 
Bl o o d a n d uri ne sa m ples re mai ni n g after cli nical la b orat or y assess me nts ha ve bee n  perf or me d 
will n ot be st ore d f or f ut ure use a n d will be destr o ye d after a nal ysis as per la b orat or y pr oce d ure. 
Safet y la b orat or y para meters will be assesse d i n faste d  state at: 
•  Scree ni n g ( bet wee n Da y - 2 1 a n d - 3), 
•  Da y - 2 ( A d missi o n), 
•  Pre - d ose o n Da ys 6, 1 6, a n d 2 0, 
•  E o T . 
T a ble 6- 2  
L a b or at or y p ar a meters 
Ser u m c he mistr y  
A S T  
A L T  
G G T  
al kali ne p h os p hatase  
t otal bilir u bi n 
direct bilir u bi n  
c h olester ol  
tri gl y ceri des  
creati ne p h os p h o ki nase ( C K) 
C K- M B, if C K is ele vate d  
L D H  
a m ylase  
li pase 
creati ni ne  
uric aci d  
urea  
al b u mi n  
t otal pr otei n 
p otassi u m  
s o di u m 
calci u m 
c hl ori de 
in or g a nic p h os p hate  
ferriti n 
tra nsferri n 
t h yr o xi n 
T S H  
gl uc ose (fasti n g at E n d of Trial)  
C R P 
A L T =ala ni ne a mi n otra nsferase; A S T =as partate a mi n otra nsferase; C K =creati ne p h os p h o ki nase; C R P = C -reacti ve 
pr otei n; G G T = ga m ma -gl uta m yltra nsferase; L D H =lactate de h y dr o ge nase; T S H =t h yr oi d sti m ulati n g h or m o ne  
 
He m at ol o g y a n d c o a g ul ati o n p ar a meters 
he m o gl o bi n  
he mat ocrit  
er yt hr oc ytes  
M C H 
M C V 
M C H C  
w hite bl o o d c o u nt  
differe ntial bl o o d c o u nt  
platelets  
P T  
P T T  
I N R 
fi bri n o ge n 
I N R =i nter nati o nal n or malize d rati o; M C H = mea n cell he m o gl o bi n; M C H C = mea n cell he m o gl o bi n c o nce ntrati o n; 
M C V = mea n cell v ol u me; P T = pr ot hr o m bi n; P T T = partial t hr o m b o plasti n ti me  
 
Ser ol o g y ( o nl y at Pre- Tri al e x a mi n ati o n) 
HI V -I- a n d -II-a nti b o d y  
H bs A g  
a nti-H Bc (I g G + I g M)  
a nti-H C V  
H Bc = he patitis B c ore; H Bs A g = he patitis B a nti ge n; H C V = he patitis C vir us; I g G/ M =i m m u n o gl o b uli n (class G/ M)  
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Uri n al ysis  
p H  
gl uc ose  
pr otei ns  
ket o nes  
bilir u bi n  
ur o bili n o ge n  
nitrite  
bl o o d  
le uc oc ytes 
uri ne se di me nt  a) 
a) I n case of o ut -of -ra n ge fi n di n gs i n t he uri nal ysis 
 
N ote: All baseli ne para meters (ta ke n at Scree ni n g a n d Da y - 2) ha ve t o be a vaila ble a n d j u d ge d 
pri or t o d osi n g o n Da y 1. 
S A R S -C o V -2 testi n g  
S u bjects m ust als o c o m pl y wit h t he latest C O VI D -1 9 safet y meas ures/ testi n g a p plica ble at t he 
site at t hat ti me, f or e ntr y i nt o t he u nit a n d d uri n g i n- h o use sta ys. 
N ote:  
C O VI D -1 9 tests will be carrie d o ut at re g ular i nter vals, pri or t o e ntr y i n t he u nit a n d t hr o u g h o ut 
t he resi de ntial peri o d as per t he latest Ric h m o n d P har mac ol o g y C O VI D -1 9 I nfecti o n C o ntr ol 
G ui deli nes a n d pre- e ntr y al g orit h ms.  
Tests f or pre g n a nc y a n d p ost me n o p a us al st at us  
Pre g na nc y testi n g ( w o me n)  
A ser u m β- H C G  ( beta-h u ma n c h ori o nic g o na d otr o pi n) test will be perf or me d at: 
•  S cree ni n g ( bet wee n Da y - 2 1 a n d - 3) a n d 
•  E o T  
A uri ne β- H C G  test will be perf or me d o n: 
•  Da y - 2 ( A d missi o n). 
P ost me n o pa usal stat us ( w o me n of n o n-c hil d beari n g p ote ntial) 
A n F S H test will be perf or me d f or w o me n  of n o n-c hil d beari n g p ote ntial w h o ha ve a hist or y of 
n o me nses of at least 2 4 m o nt hs at: 
•  S cree ni n g ( bet wee n Da y - 2 1 a n d - 3). 
Tests f or dr u g a n d alc o h ol a b use  
A uri ne sa m ple will be teste d f or dr u gs ( be nz o diaze pi nes, o piates, a m p heta mi nes, met ha d o ne, 
c ocai ne, ca n na bi n oi ds, bar bit urates, c oti ni ne ) a n d a n alc o h ol breat h test will be perf or me d at: 
•  S cree ni n g ( bet wee n Da y - 2 1 a n d -3) a n d  
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•  Da y - 2 ( A d missi o n). 
6. 6. 4. 3  
E C G  
6. 6. 4. 3. 1  
H olt er -E C G  
A Scree ni n g H olter will be perf or me d at Scree ni n g.  
Fr o m 1 h o ur pri or t o d osi n g u ntil 8 h ( Da y 2 a n d Da y 1 7) or 2 4 h ( Da y - 1, 1, Da y 6 a n d Da y 1 6) 
after d osi n g, a H olter-E C G will be carrie d o ut i n all s u bjects. H olter -E C Gs will be rec or de d 
usi n g hi g h-res ol uti o n 1 2- c ha n nel H olter rec or ders  rec or de d i n parallel t o be dsi de 1 2- lea d E C Gs. 
H olter rec or di n gs will be d o w nl oa de d a n d st ore d f or f ut ure a nal yses. A nal yses ma y be 
perf or me d f or safet y assess me nt or P K/ P D m o delli n g as dee me d necessar y ( 1 0 sec o n ds 1 2 -lea d 
E C G e xtracte d t o re place p ote ntial u ne val ua ble E C G ti me p oi nts).  
6. 6. 4. 3. 2  
1 2 -l e a d E C G a s s e s s m e nt 
1 2- lea d sta n dar d E C Gs acc or di n g t o Ei nt h o ve n, G ol d ber ger a n d Wils o n will be rec or de d eac h 
ti me after 1 0 mi n utes rest i n a s u pi ne p ositi o n.  
At eac h ti me p oi nt, t he E C G will be rec or de d i n tri plicate, t o re d uce varia nce a n d i m pr o ve t he 
precisi o n of meas ure me nt. T he tri plicates will be perf or me d at a p pr o xi matel y 1 -mi n ute i nter vals. 
Eac h E C G rec or di n g (trace) will last 1 0 sec o n ds. Re peat E C Gs will be perf or me d u ntil at least 
t hree 1 0-sec o n d E C G rec or ds per sc he d ule d ti me-p oi nt meet t he q ualit y criteria  set o ut i n t he 
St u d y O perati o ns Ma n ual a n d t he a p plica ble Sta n dar d O perati n g Pr oce d ures. 
1 2-lea d E C Gs will be rec or de d ( 2 5 m m/sec) o n 8 t o 1 0- sec o n d stri ps. Heart rate, P R-, Q T- a n d 
Q Tc -i nter vals ( Fri dericia c orrecti o n) a n d Q R S d urati o n are meas ure d electr o nicall y ( wit h 
c orrecti o n b y t he I n vesti gat or, if c o nsi dere d necessar y). 
All rec or de d E C Gs will be re vie we d b y a Researc h P h ysicia n a n d t he re vie w will be d oc u me nte d 
i n t he s o urce w or k b o o k. If a s u bject s h o ws a n a b n or mal E C G, a d diti o nal safet y rec or di n gs 
(i ncl u di n g t he use of 1 2-lea d H olter e q ui p me nt) ma y be ma de a n d t he a b n or malit y be f oll o we d t o 
res ol uti o n if re q uire d. 
1 2- lea d E C Gs will be rec or de d at t he ti me p oi nts s pecifie d i n Ti mi n g of re peat meas ure sa m ples . 
1 2- lea d E C G-, vital si g n assess me nt a n d bl o o d wit h dra wals s h o ul d al wa ys occ ur after t he 
n o mi nal ti me p oi nts f or E C G.  
T o a v oi d t he nee d f or i nter p olati o ns i n t he P K/ P D m o deli n g o n Da y 6 a n d Da y 1 6, it is i m p orta nt 
t hat t he ti me bet wee n t he e n d of t he tri plicate E C G a n d t he res pecti ve P K b l o o d dra w is wit hi n 
t he wit hi n t he s pecifie d ti me wi n d o w (see Secti o n  6. 6 ).  
Bli n di n g of t he E C Gs wit h res pect t o s u bject n u m ber, treat me nt peri o d, trial da y a n d ti me will be 
perf or me d bef ore E C G a nal ysis b y t he ce ntral E C G la b orat or y. All E C Gs fr o m o ne s u bject 
s h o ul d be rea d b y t he sa me pers o n at t he ce ntral E C G la borat or y. 
Q R S a n d Q T i nter vals as well as heart rate ( R R i nter val) will be meas ure d i n s u peri m p ose d lea d 
o n a t least 5 Q R S c o m pl e xes .  
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6. 6. 4. 4  
Vit al si g n s  
Vital si g ns (s yst olic  bl o o d press ure [ S B P), diast olic bl o o d press ure [ D B P], a n d p ulse rate) will 
be meas ure d b y a n oscill o metric met h o d, eac h ti me after  at least 5 mi n utes rest i n a s u pi ne 
p ositi o n. 
Vital si g ns will be rec or de d at:  
•  S cree ni n g  ( bet wee n Da y - 2 1 a n d - 3), 
•  Da y - 2 ( A d missi o n), 
•  Da y 1 pre- d ose,  
•  Da ys 6, 1 6, a n d 2 0, a n d 
•  E o T  
B o d y te m per at ure  
B o d y te m perat ure will be meas ure d wit h a cali brate d de vice  at: 
•  S cree ni n g  ( bet wee n Da y - 2 1 a n d - 3), 
•  Da y - 2 ( A d missi o n), a n d 
•  E o T.  
6. 6. 4. 5  
P h y si c al e x a mi n ati o n  
T he I n vesti gat or or his desi g nee will perf or m a c o m plete p h ysical e xa mi nati o n i ncl u di n g 
assess me nt of at least t he s ki n, e yes, ears, n ose, nec k, l y m p h n o des, t hr oat a n d e xtre mities, pl us 
t he f oll o wi n g b o d y s yste ms: m usc ul os keletal, car di o vasc ular, res pirat or y, gastr oi ntesti nal a n d 
ne ur ol o gical. A n y ot her cli nicall y rele v a nt fi n di n gs will als o be rec or de d.  
T he p h ysical e xa mi nati o n will be perf or me d at: 
•  Scree ni n g ( bet wee n Da y - 2 1 a n d - 3), 
•  Da y - 2 ( A d missi o n), a n d 
•  E o T.  
Hei g ht a n d wei g ht will als o be meas ure d at:  
•  Scree ni n g ( bet wee n Da y - 2 1 a n d - 3), a n d 
•  Da y - 2 ( A d missi o n). 
6. 6. 5  
A p pr o pri at e n e s s of m e a s ur e m e nt s  
F or t he assess me nt of safet y para meters, sta n dar d met h o ds will be use d.  
P har mac o ki netic meas ure me nts will be ma de usi n g vali date d met h o ds a n d para meters deri ve d 
are a p pr o priate f or t he trial o bjecti ves.  
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6. 7  
D at a h a n dli n g  
6. 7. 1  
R e c or d s a n d  r e p ort s 
T he I n vesti gat or e ns ures t he acc urac y a n d le gi bilit y of t he data re p orte d t o Ai C uris i n t he s o urce 
w or k b o o k a n d electr o nic Case Re p ort F or ms (e C R Fs) a n d i n all re q uire d re p orts.  
T he I n vesti gat or s h o ul d mai ntai n t he trial d oc u me nts as re q uire d b y t he a p plica ble re g ulat or y 
re q uire me nts. T he I n vesti gat or s h o ul d ta ke meas ures t o pre ve nt acci de ntal or pre mat ure 
destr ucti o n of t hese d oc u me nts. Esse ntial d oc u me nts s h o ul d be retai ne d u ntil at least 2 5 years 
after t he last a p pr o val of a mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here will be n o 
pe n di n g or c o nte m plate d mar keti n g a p plicati o ns i n a n I C H re gi o n or at least 2 5 years ha ve 
ela pse d si nce t he f or mal disc o nti n uati o n of cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct. 
T hese d oc u me nts s h o ul d be retai ne d f or a l o n ger peri o d h o we ver, if re q uire d b y t he l ocal la w. It 
is t he res p o nsi bilit y of Ai C uris t o i nf or m t he I n vesti gat or w he n t hese d oc u me nts are n o l o n ger t o 
be retai ne d.  
U p o n re q uest of t he m o nit or, a u dit or, or Re g ulat or y A ut h orit y ( R A), t he I n vesti gat or s h o ul d 
ma ke all re q ueste d trial -relate d rec or ds a vaila ble f or direct access. 
Si g n at ure a ut h oriz ati o n f or m  
Bef ore c o m me nce me nt of t he trial t he I n vesti gat or m ust c o m plete a si g nat ure pa ge defi ni n g t he 
trial pers o n nel ta ki n g part i n cli nical acti vities. T he I n vesti gat or a n d eac h e m pl o yee s h o ul d be 
liste d o n t his f or m wit h si g nat ure, i nitials (f ore na me a n d s ur na me), s h ort-f or m si g nat ure a n d date 
t o i de ntif y c o m pre he nsi bilit y all data e ntries, es peciall y c orrecti o ns perf or me d i n t he s o urce 
w or k b o o k. 
Scree ni n g a n d e nr ol lme nt l o g  
T he Scree ni n g a n d e nr oll me nt l o g s heet m ust be file d f or all s u bjects partici pati n g i n t he trial 
w h o ha ve gi ve n t heir i nf or me d c o nse nt. A d diti o nall y, t he date of e ntr y i nt o t he trial a n d t he 
c o m pleti o n date ha ve t o be  d oc u me nte d i n t he e C R F. 
S o urce d at a  
S o urce data are t he ori gi nal rec or ds of all varia bles c ollecte d f or t he trial. T he y i ncl u de:  
•  Si g ne d i nf or me d c o nse nt 
•  I n di vi d ual s u bject cli nical n otes 
•  Rec or ds of a n y pr oce d ure perf or me d i n acc or da nce wit h t he pr ot oc ol 
•  A p pr o priate secti o ns of t he s o urce w or k b o o k , w here data will be rec or de d directl y i nt o 
s pecific f or ms (e g, P K bl o o d sa m pli n gs, d osi n g ti me, visit dates) 
•  Trial -s pecific s o urce d oc u me nts (e g, E C G pri nt-o uts, la b orat or y pri nt - o uts, vital si g ns, A Es, 
me dical h ist or y data) 
F or all ot her data ge nerate d b y calc ulati o n or via pri nt- o ut of e q ui p me nt, t hese pri nt- o uts are 
c o nsi dere d as s o urce data a n d will be file d i n t he I n vesti gat or F ol der. 
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S o urce W or k b o o k 
T he I n vesti gat or is res p o nsi ble t hat all i n vesti gati o ns a n d  fi n di n gs are d oc u me nte d c orrectl y a n d 
c o m pletel y o n t he s o urce w or k b o o k a n d t hat all e ntries are u p t o date t o e na ble a ti mel y 
e val uati o n a n d vali dati o n t o i de ntif y mista kes at a n earl y sta ge a n d t o a v oi d mis u n dersta n di n gs. 
T he c orrect ness of t he data s h o ul d be d oc u me nte d b y si g ni n g a n d dati n g o n t he res pecti ve s o urce 
w or k b o o k. A d diti o nal data ma y als o be d oc u me nte d. T he y s h o ul d be clearl y defi ne d as 
a d diti o nal fi n di n gs a n d s h o ul d be j ustifie d b y t he I n vesti gat or.  
T he I n vesti gat or a grees t o pr o vi de direct  access t o s o urce data/ d oc u me nts f or trial -relate d 
m o nit ori n g, a u dits, E C re vie w or i ns pecti o n. 
6. 7. 2  
M o nit ori n g  
A M S A d va nce d Me dical Ser vices Lt d. W ill be res p o nsi ble f or trial m o nit ori n g acc or di n g t o 
I C H-G C P  o n t he S p o ns or’s be half. T he trial site will be visite d at re g ular i nter vals b y a bli n de d 
T rial M o nit or t o e ns ure c o m plia nce wit h t he trial pr ot oc ol, G C P a n d le gal as pects. T his will 
i ncl u de o n-site c hec ki n g of t he e C R F f or c o m plete ness a n d clarit y, cr oss-c hec ki n g wit h s o urce 
d oc u me nts (s o urce data re vie w a n d verificati o n) , dr u g acc o u nta bilit y, I S F re vie w, a n d 
clarificati o n of a d mi nistrati ve matters.  
A n u n bli n de d Trial M o nit or will visit t he site p har mac y at t he trial start a n d trial e n d t o e ns ure 
c orrect ness of st u d y me dicati o n all ocati o n t o eac h patie nt.  
If t he o n-site m o nit ori n g visit is n ot p ossi ble e g, d ue t o C O VI D-1 9 li mitati o ns, t he Trial M o nit or 
will perf or m a re m ote m o nit ori n g visit as per t he a p plica ble A M S A d va nce d Me dical Ser vices 
Lt d.  Pr oce d ures a n d re g ulat or y g ui deli nes. 
T he I n vesti gat ors m ust a gree t o t he i ns pecti o n of trial- relate d rec or ds b y t he res p o nsi ble 
Re g ulat or y A ut h orit y ( R A) or b y Ai C uris. T he y m ust all o w direct access t o s o urce d oc u me nts t o 
re prese ntati ves of R A  or S p o ns or re prese ntati ves. 
6. 8  
C h a n g e s i n t h e c o n d u ct of t h e tri al  
A n y c ha n ge of t he desi g n or pr oce d ures of t he cli nical trial m ust be descri be d a n d file d as a 
a d mi nistrati ve letter  or i n a n a me n d me nt t o t his pr ot oc ol. A n y p ossi ble i m plicati o ns of t he 
c ha n ge(s) f or t he i nter pretati o n of t he trial m ust be j ustifie d briefl y. T he t i me(s) a n d reas o n(s) f or 
t he c ha n ge(s), t he pr oce d ure use d t o deci de o n t he c ha n ge(s), t he pers o n(s) or gr o u p(s) 
res p o nsi ble f or t he c ha n ge a n d t he nat ure a n d c o nte nt of t he data a vaila ble (a n d t o w h o m t he y 
were a vaila ble) w he n t he c ha n ge was ma de s h o ul d a ls o be descri be d. 
7 
D A T A M A N A G E M E N T  
T he data ma na ge me nt de part me nt of R ic h m o n d P har mac ol o g y will perf or m data ma na ge me nt. 
T he Data Ha n dli n g Pr ot oc ol ( D H P) will o utli ne t he data ma na ge me nt pr ocess i n detail.  
T he R ic h m o n d P har mac ol o g y data ma na ge me nt de part me nt will:  
•  de vel o p a n d mai ntai n t he D H P 
•  set a n d vali date t he cli nical trial data base ( Me di data Ra ve) 
•  pr o gra m vali dati o n c hec ks 
•  e nter data i nt o t he cli nical trial data base  
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•  re vie w data f or acc urac y, c o m plete ness, a n d c o nsiste nc y bet wee n t he C R F a n d t he data base  
•  verif y a d here nce t o t he cli nical p har mac ol o g y trial pr ot oc ol a n d t he D H P. 
Scree ni n g fail ure data will n ot be c ollecte d i n t he E D C.  
T he data base e ntries will be verifie d a gai nst s o urce data (s u bject’s me dical file) b y t he Trial 
M o nit or d uri n g t he m o nit ori n g visits. T he s o urce data verificati o n rate will be 1 0 0 %. 
Cli nical data q ueries will be ge nerate d a n d res ol ve d acc or di n g t o t he D H P. Ric h m o n d 
P har mac ol o g y cli nical staff, trial R P/ PI will assist t o res ol ve cli nical data q ueries.  
After all cli nical data q ueries are res ol ve d, fi nal err or rate is c o nfir me d, a n d Q C c hec ks are 
acce pta ble, t he data base will be l oc ke d. T he I n vesti gat or will certif y t hat t he data e ntere d i nt o t he 
E D C are c o m plete a n d acc urate.  
Sta n dar d Statistical A nal ysis S yste m ( S A S ® ) datasets will be ge nerate d fr o m t he fi nal trial 
data base rea d y f or a nal yses.  
Ric h m o n d P har mac ol o g y will perf or m me dical c o di n g. A Es, dia g n oses fr o m me dical hist or y, 
a n d pr oce d ures fr o m s ur gical hist or y will be classifie d acc or di n g t o Me d D R A. C o nc o mita nt 
me dic ati o n will be c o de d usi n g W H O- D R U G.  
S A Es i n t he cli nical data base will be rec o ncile d wit h t he safet y data base.  
Fi nal ra w S A S ®  datasets will be tra nsferre d t o t he statisticia n a n d t he S p o ns or (as a p plica ble).  
8 
S T A TI S TI C S  
8. 1  
D et er mi n ati o n of s a m pl e si z e  
Si m ulat i o ns b y H ua n g et al s u g gest t hat usi n g c o nce ntrati o n-res p o nse a nal ysis, assa y se nsiti vit y 
ca n be s h o w n wit h at least 2 4 s u bjects [ 5]. Si nce i n t his trial, t he ti me bet wee n t he 2 peri o ds of 
t he neste d cr oss o ver is 1 4 da ys, it see ms pr u de nt t o all o w f or a sli g htl y hi g her varia bilit y of 
Δ Q Tc a n d, t heref ore, a sa m ple size of 3 2 s u bjects has bee n pla n ne d. Ass u mi n g a tr ue effect of at 
m ost 3 ms, ie, a mar gi n of 7 ms, t he p o wer t o s h o w a bse nce of a n effect of priteli vir is hi g her 
t ha n t hat t o s h o w assay se nsiti vit y w here t he mar gi n ma y be ass u me d t o be 5 ms. T heref ore, 
3 2 s u bjects i n t he acti ve gr o u p were c h ose n. 
8. 2  
D efi niti o n of tri al p o p ul ati o n s  
8. 2. 1  
S af et y S et  
T he Safet y Set ( S S) will c o m prise all s u bjects w h o recei ve at least 1  d ose of trial me dicati o n. 
8. 2. 2  
P h ar m a c o ki n eti c s  S et  
T he P har mac o ki netic Set ( P K S) will i ncl u de  all s u bjects i n S S w h o ha d at least 1 vali d plas ma 
c o nce ntrati o n -ti me p oi nt t o be i ncl u de d i n t he P K a nal ysis. T he P K S will be  use d f or t he P K 
a nal yses. 
6 5 of 1 3 6

 
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8. 2. 3  
E C G S et  
T he E C G set will i ncl u de all s u bjects i n t he S S w h o ha ve a vali d B aseli ne a n d at least o ne vali d 
p ost- B aseli ne E C G. E C Gs are c o nsi dere d vali d if t he y are base d o n at least 2 re plicates. 
8. 2. 4  
A n al y si s s et f or c o n c e ntr ati o n -Q T a n al y si s  
T his a nal ysis set i ncl u des t he s u bjects w hic h ha ve a vali d  baseli ne a n d at least o ne vali d p ost-
baseli ne E C G wit h f or w hic h P K sa m ples were ta ke n a n d w here b ot h t he E C G a n d P K sa m ples 
were ta ke n wit hi n t he res pecti ve wi n d o ws. O nl y t h ose pairs of E C G a n d P K data w here sa m ples 
were ta ke n wit hi n t hese ti me wi n d o ws w ill be i ncl u de d i n t his a nal ysis set. N ote t hat a d ose 
re d ucti o n is n ot a reas o n t o e xcl u de a s u bject fr o m t his a nal ysis set. 
8. 3  
E n d p oi nt s  
E C G v ari a bles 
T he f oll o wi n g E C G para meters will be a nal yze d:  
Pri mar y varia ble (relate d t o t he pri mar y e n d p oi nt)  
•  Q Tc usi n g Fri dericia c orrecti o n met h o d ( Q Tc F) 
Sec o n dar y varia bles  
•  Heart rate  
•  P R i nter val  
•  Q R S i nter val  
•  U nc orrecte d Q T  i nter val 
•  C ha n ge i n E C G m or p h ol o gical patter ns 
S afet y a n d toler a bilit y  
•  O verall t olera bilit y  
•  Nat ure, fre q ue nc y, d urati o n, i nte nsit y, seri o us ness, a n d ca usalit y of a d verse e ve nts  
•  P h ysical e xa mi nati o n, vital si g ns, a n d b o d y te m perat ure 
•  Cli nical la b orat or y para meters: ser u m c he mistr y, he mat ol o g y a n d c oa g ulati o n para meters, 
uri nal ysis  
•  Sta n dar d 1 2- lea d E C G 
P h ar m ac o ki netics  
T he f oll o wi n g para meters of pritel i vir a n d its meta b olites AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 will be 
deter mi ne d:  
•  
C 0 h (tr o u g h le vels) of priteli vir, AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 o n t he Da ys 1 t o 5 a n d 1 3 t o 1 5, 
•  
A U C τ, Cma x , tma x , tla g, C L/ F, Vd/ F, M R T of priteli vir i n plas ma o n Da y 1, 
•  
A U C τ,ss, Css, ma x, Cmi n, Css,a v, tma x , C Lss/ F, Vd,ss/ F, M R T of priteli vir i n plas ma o n Da ys 6 a n d 1 6, 
•  
A U C τ, Cma x , tma x , tla g, M R T of meta b olites AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 i n plas ma o n Da y 1. 
•  
A U C τ,ss, Cma x,ss , Cmi n , Css,a v, tma x , M R T of meta b olites AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 i n plas ma o n 
Da ys  6 a n d 1 6.  
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M o xifl o xaci n plas ma c o nce ntrati o ns will be deter mi ne d f or t he p ur p ose of t he c o nce ntrati o n-
effect a nal ysis t o de m o nstrate assa y se nsiti vit y . T he c o nce ntrati o ns will be re p orte d, b ut n o 
p har mac o ki netic para meters will be deter mi ne d.  
P h ar m ac o ge n o mics/ ge ne e x pressi o n  
P ost -h oc a nal ysis of alleles ass ociate d wit h altere d dr u g meta b olis m/ dis p ositi o n ma y be 
deter mi ne d. 
8. 4   
An al y s e s  
Details of t he statistical a nal ysis will be defi ne d i n a Statistical A nal ysis Pla n ( S A P). S h o ul d 
t here be a need t o a da pt t he trial desi g n f oll o wi n g t he a da pti ve feat ures (see A p pe n di x 4 ), t he 
a nal ysis pla n ma y nee d t o be u p date d w hile t he pri nci ples of t he a nal ysis as s pecifi e d bel o w are 
mai ntai ne d. T hese a da ptati o ns will be reflecte d i n t he S A P.  
8. 4. 1  
E C G v ari a bl e s  
Statistical a nal yses of E C G varia bles will be perf or me d acc or di n g t o t he rec o m me n dati o ns 
pr o vi de d b y t he g ui deli ne I C H- E 1 4 a n d its Q & A d oc u me nts. Q Tc a n d H R data will be  a nal yze d 
usi n g a c o nce ntrati o n- effect m o del . All q ua ntitati ve E C G para meters will be a nal yse d wit h 
res pect t o t heir ti me c o urse usi n g a mi xe d effects li near m o del.  
I n a d diti o n, E C G data will be prese nte d as a nal yses of ce ntral te n de nc y ( mea n, me dia n, sta n dar d 
de viati o n, mi ni m u m a n d ma xi m u m) a n d cate g orical e val uati o ns.  
Baseli ne f or q ua ntitati ve E C G varia bles will be t he a vera ge of t he 3 pre- d ose val ues meas ure d o n 
Da y 1. 
T he pri mar y e n d p oi nt is defi ne d as t he m o del base d Q Tc F differe nces fr o m baseli ne ( Δ Q Tc F), 
w here baseli ne is t he a vera ge of t he 3 pre- d ose meas ure me nts of Da y 1. E C Gs fr o m Da y 1, Da y 
6 a n d Da y 1 6 will be use d f or c o m paris o n a gai nst baseli ne. M ore s pecificall y, a series of li near 
mi xe d effect m o dels relati n g t he c ha n ge fr o m baseli ne t o t he  c o nce ntrati o ns of priteli vir a n d t he 
meta b olites AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5, t o get her or se paratel y, will be fitte d. A part fr o m t hese 
c o nce ntrati o ns, t he m o dels will i ncl u de fi xe d effects f or ti me a n d treat me nt ( Acti ve or place b o) 
a n d baseli ne as a c o variate . Ra n d o m effects per s u bject f or t he i nterce pt a n d, if feasi ble, f or t he 
c o nce ntrati o ns i ncl u de d i n t he res pecti ve m o dels will be gi ve n. Selecti o n of t he pri mar y m o del 
will be base d o n m o del fit a n d t he A kai ke I nf or mati o n Criteri o n. Pre dicti o ns of t he effect of 
priteli vir a n d meta b olites at t he c o nce ntrati o ns see n at tma x  of eac h of t he m oieties i n v ol ve d will 
be use d t o e xcl u de a n effect of re g ulat or y c o ncer n (ie, a o ne-si de d 9 5 % c o nfi de nce i nter val f or 
Δ Q Tc F c o m pletel y bel o w 1 0 ms). 
T he gr o u ps 2a a n d 2 b w ill be p o ole d f or a nal ysis. 
A c o m paris o n bet wee n m o xifl o xaci n a n d matc hi n g place b o will be d o ne i n gr o u ps 2a a n d 2 b t o 
de m o nstrate assa y se nsiti vit y usi n g a si milar m o del t o t he o nes descri be d a b o ve. Assa y 
se nsiti vit y will be c o ncl u de d if t he l o wer li mit of t he o ne-si de d 9 5 % CI f or t he pre dicte d effect 
will be > 5 ms.  
If t here are i n dicati o ns t hat priteli vir has a n effect o n H R e xcee di n g 1 0 b p m, H R will als o be 
s u b mitte d t o a si milar a nal ysis. If t his c o nfir ms a n effect e xcee di n g 1 0 b p m , t he n a n i n di vi d ual 
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correcti o n will be deter mi ne d base d o n t he E C G data fr o m  Da y - 1, a n d Q T val ues c orrecte d 
acc or di n g t o t his met h o d ( Q TcI) will re place Q Tc F i n t he pri mar y a nal yses. 
T he a p pr o priate ness of t he m o dels use d will be i n vesti gate d. I n partic ular, t his i ncl u des t he  
a bse nce of a dela ye d effect (res pecti ve t o all 3 m oieties) a n d a n y rele va nt de viati o ns fr o m 
li nearit y. 
All q ua ntitati ve E C G varia bles a n d t heir c ha n ge fr o m baseli ne will be s u m marize d b y ti me p oi nt 
a n d treat me nt gr o u p. T he differe nce bet wee n t he 2 treat me nt gr o u ps will als o be prese nte d. 
M or p h ol o gical a b n or malities will be descri be d a n d t he data will be prese nte d i n ter ms of t he 
n u m ber a n d perce nta ges of s u bjects u n der eac h treat me nt ha vi n g c ha n ges fr o m baseli ne t hat 
re prese nt t he a p peara nce or w orse ni n g of t he m or p h ol o gical a b n or malit y. 
T he fre q ue nc y of o utl yi n g val ues, ie, val ues satisf yi n g t he criteria bel o w, will be ta b ulate d b y 
ti me p oi nt a n d treat me nt a n d acr oss all ti me p oi nts b y treat me nt: 
•  A bs ol ute Q Tc F val ues > 4 5 0 ms , > 4 8 0 ms , a n d > 5 0 0 ms  
•  C ha n ge fr o m baseli ne i n Q Tc F val ue ( Δ Q Tc F) of > 3 0 ms  a n d > 6 0 ms ; 
•  F ulfilli n g b ot h, a bs ol ute Q Tc F val ues > 5 0 0 ms  a n d Δ Q Tc F > 6 0 ms ; 
•  A bs ol ute P R val ues > 2 0 0 ms , > 2 2 0 ms , wit h a pre-d ose val ue bel o w t he res pecti ve t hres h ol d  
•  Δ P R ≥2 5 %, ie, p ost- d ose P R o utsi de t he ra n ge of ( 0. 7 5, 1. 2 5) of t he baseli ne val ue 
•  A bs ol ute Q R S d urati o n > 1 1 0 ms a n d > 1 2 0 ms 
•  Δ Q R S ≥2 5 %, ie, p ost- d ose Q R S o utsi de t he ra n ge of ( 0. 7 5, 1. 2 5) of t he baseli ne val ue 
•  A bs ol ute H R of < 5 0 b p m or ≥1 0 0 b p m 
•  Heart rate decrease ≥2 5 % fr o m baseli ne t o a H R of < 5 0 b p m a n d/ or i ncrease ≥2 5 % fr o m 
baseli ne t o a H R of ≥1 0 0 b p m. 
8. 4. 2  
P h ar m a c o ki n eti c a n al y s e s  
Priteli vir a n d t he met a b olites AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 
All meas ure d P K varia bles a n d deri ve d P K para meters will be liste d a n d s u m marize d b y 
descri pti ve statistics. Descri pti ve  statistics will be calc ulate d f or plas ma c o nce ntrati o ns of 
priteli vir a n d t he meta b olites AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 i n Gr o u p 1 o nl y . Statistics will i ncl u de 
sa m ple size ( n), mea n, sta n dar d de viati o n, c oefficie nt of variati o n ( % C V), ge o metric mea n, 
me dia n, mi ni m u m, a n d ma xi m u m. D ose pr o p orti o nalit y of priteli vir will be assesse d gra p hicall y, 
b y c o m pari n g i n di vi d ual d ose n or malize d C ss, ma x, A U C τ,ss, a n d Cmi n  val ues bet wee n t he 
t hera pe utic a n d s u pra-t hera pe utic d ose le vels. I n Gr o u p 2 ( m o xifl o xaci n/ place b o), 
p har mac o ki netic sa m ples will be dra w n t o mai ntai n bli n di n g, b ut will n ot be a nal yze d. 
M o xifl o x aci n 
M o xifl o xaci n plas ma c o nce ntrati o ns will be deter mi ne d f or t he p ur p ose of t he c o nce ntrati o n-
effect a nal ysis t o de m o nstrate assa y se nsiti vit y. T he c o nce ntrati o n s will be re p orte d, b ut n o 
p har mac o ki netic para meters will be deter mi ne d.  
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8. 4. 3  
S af et y a n al y s e s  
I n di vi d ual partici pa nt de m o gra p hics (a ge, ge n der a n d race) a n d b o d y meas ure me nt data ( hei g ht, 
wei g ht, a n d B MI) at scree ni n g will be liste d. T hese de m o gra p hic c haracte ristics a n d b o d y 
meas ure me nts will be s u m marize d b y treat me nt gr o u p a n d o verall, usi n g t he safet y a nal ysis set. 
Ot her baseli ne c haracteristics will be liste d o nl y.  
A E data will be liste d a n d s u m marise d usi n g descri pti ve statistics: t he n u m ber (a n d perce nta ge) 
of partici pa nts w h o e x perie nce d a n y A Es a n d t he n u m ber of A E e pis o des will be s u m marize d f or 
eac h treat me nt gr o u p. All A Es will be s u m marize d a n d liste d b y usi n g t he S yste m Or ga n Class 
( S O C) a n d Preferre d Ter m ( P T) assi g ne d t o t he e ve nt usi n g t he Me d D R A. F urt her m ore, t hese 
e ve nts will be s u m marize d b y t heir ma xi m u m i nte nsit y. T he n u m ber of partici pa nts w h o 
e x perie nce d dr u g -relate d A Es will als o be s u m marize d. A n y S A Es a n d/ or A Es t hat le d t o trial 
wit h dra wal will be s u m marize d a n d liste d.  
Vital si g ns dat a ( S B P, D B P, p ulse rate , te m perat ure) will be liste d a n d s u m marize d, al o n g wit h 
c ha n ges fr o m baseli ne, usi n g descri pti ve statistics ( mea n, me dia n, sta n dar d de viati o n, mi ni m u m, 
ma xi m u m). O ut - of-refere nce-ra n ge val ues will be fla g ge d as hi g h or l o w a n d as bei n g cli nicall y 
rele va nt or n ot. T he n u m ber of partici pa nts prese nti n g o ut- of-ra n ge a n d cli nicall y rele va nt val ues 
will be s u m marize d.  
All safet y cli nical la b orat or y data will be liste d. La b orat or y test res ults will als o be c o m pare d t o 
la b orat or y refere nce ra n ges. T h ose val ues o utsi de of t he a p plica ble ra n ge will be fla g ge d as hi g h 
or l o w, a n d as cli nicall y rele va nt or n ot. T he n u m ber of partici pa nts t hat prese nt o ut- of-ra n ge, 
a n d cli nicall y rele va nt val ues, will be s u m marize d. T he q ua ntitati ve la b orat or y data a n d c ha n ges 
fr o m baseli ne will be s u m marize d usi n g descri pti ve statistics ( mea n, me dia n, sta n dar d de viati o n, 
mi ni m u m, ma xi m u m). C ha n ge fr o m baseli ne val ues at eac h assess me nt will be calc ulate d as t he 
assess me nt val ue mi n us t he baseli ne val ue. T he q uali tati ve uri nal ysis data will be liste d o nl y. 
E C G a nal yses will be perf or me d o n t w o sets of E C Gs: all E C Gs pri or t o a dj u dicati o n a n d 
selecte d tri plicates fr o m eac h ti me- p oi nt after a dj u dicati o n (see Secti o n 8. 4. 1 ). 
All u n -a dj u dicate d E C G data ( P R, Q R S, Q T, Q Tc B, Q Tc F a n d H R) a n d o verall E C G e val uati o n 
will be liste d. E C G data a n d c ha n ges fr o m baseli ne will be s u m marize d usi n g descri pti ve 
statistics ( mea n, me dia n, sta n dar d de viati o n, mi ni m u m, ma xi m u m). 
9 
A D MI NI S T R A TI V E P R O C E D U R E S  
9. 1  
Et hi c s C o m mitt e e a n d R e g ul at or y A g e n c y a p pr o v al  
It is t he res p o nsi bilit y of t he PI t o s u b mit t his C T P , t he i nf or me d c o nse nt d oc u me nt (a p pr o ve d b y 
Ai C uris), rele va nt s u p p orti n g i nf or mati o n, a n d all t y pes of partici pa nt recr uit me nt i nf or mati o n t o 
t he E C a n d R A f or c o m bi ne d re vie w, a n d all m ust be a p pr o ve d pri or t o t he start of partici pa nt 
scree ni n g. I n a d diti o n, a d vertise me nts m ust be a p pr o ve d b y t he E C a n d R A pri or t o use at t he 
site. Pri or t o i m ple me nti n g cha n ges i n t he trial, Ai C uris a n d t he E C a n d R A m ust als o a p pr o ve 
a n y s u bsta ntial a me n d me nts t o t he C T P  a n d c orres p o n di n g u p dates t o i nf or me d c o nse nt 
d oc u me nts. F or n o n-s u bsta ntial pr ot oc ol a me n d me nts (t hat d o n ot re q uire E C re g ulat or y 
a p pr o val) a n d s u bse q ue nt u p dates of t he I C F all c ha n ges will be d o ne i n a gree me nt wit h Ai C uris 
a n d Ric h m o n d P har mac ol o g y. 
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9. 2  
G C P c o m pli a n c e  
Ai C uris a n d a n y t hir d part y t o w h o m as pects of t he trial ma na ge me nt or m o nit ori n g ha ve bee n 
dele gate d will u n derta ke t heir r oles f or t his trial i n c o m plia nce wit h all a p plica ble re g ulati o ns a n d 
I C H G C P G ui deli nes. 
Visits t o I n vesti gat or sites will be c o n d ucte d b y re prese ntati ves of Ai C uris t o i ns pect trial data, 
partici pa nts’ me dical rec or ds, a n d C R Fs i n acc or da nce wit h c urre nt I C H G o o d Cli nical Practice 
G ui deli ne E 6 ( R 2) ( 2 0 1 6) a n d t he res pecti ve l ocal a n d nati o nal g o ver n me nt re g ulati o ns a n d 
g ui deli nes. Rec or ds a n d data ma y a d diti o nall y be re vie we d b y a u dit ors or b y c o m pete nt 
a ut h orities. 
T he I n vesti gat or m ust u n derta ke t o perf or m t he trial i n acc or da nce wit h I C H G C P G ui deli nes, 
E U Directi ve 2 0 0 1/ 2 0/ E C, a n d t he a p plica ble re g ulat or y re q uire me nts.  
It is t he I n vesti gat or’s res p o nsi bilit y t o e ns ure t hat a de q uate ti me a n d a p pr o priate res o urces are 
a vaila ble at t he trial site pri or t o c o m mit me nt t o partici pate i n t his trial. T he I n vesti gat or s h o ul d 
als o be a ble t o esti mate or de m o nstrate a p ote ntial f or recr uiti n g t he re q uire d n u m ber of s uita ble 
p artici pa nts wit hi n t he a gree d recr uit me nt peri o d.  
T he I n vesti gat or will mai ntai n a rec or d of a p pr o priatel y q ualifie d pers o ns t o w h o m t he 
I n vesti gat or has dele gate d si g nifica nt trial -relate d tas ks. A n u p-t o- date c o p y of t he c urric ul u m 
vitae f or t he I n vesti gat or, s u b-I n vesti gat or(s), a n d esse ntial trial staff will be pr o vi de d t o Ai C uris 
( or desi g nee) bef ore starti n g t he trial. 
A gree me nt wit h t he fi nal Cli nical Trial Re p ort will be d oc u me nte d b y t he date d si g nat ure of t he 
PI, i n c o m plia nce wit h Directi ve 7 5/ 3 1 8/ E E C, Directi ve 2 0 0 1/ 8 3/ E C, a n d I C H E 3. 
9. 3  
R e g ul at or y a p pr o v al  
Ai C uris ( or dele gate) will e ns ure t hat L ocal C o m pete nt A ut h orit y re q uire me nts are met bef ore 
t he start of t he trial.  
9. 4  
Et hi c al c o n d u ct of t h e tri al  
T he cli nical trial will be c o n d ucte d i n acc or da nce wit h t he et hical pri nci ples t hat ha ve t heir 
ori gi ns i n t he Declarati o n of Helsi n ki a n d i n acc or da nce wit h t he pri nci ples of G C P as well as 
relate d l ocal le gislati o n. 
P ossi ble ris ks of t he pla n ne d cli nical trial see m t o be j ustifia ble fr o m a me di cal p oi nt of vie w 
wit h re gar d t o a p ossi ble safer a n d m ore effecti ve treat me nt of f ut ure patie nts.  
9. 5  
S u bj e ct i nf or m ati o n a n d i nf or m e d c o n s e nt  
T he I n vesti gat or ( or desi g nee) will i nf or m all s u bjects ver ball y a n d i n writi n g a b o ut t he nat ure, 
si g nifica nce a n d sc o pe of t he cli nical trial. Writte n i nf or me d c o nse nt will be o btai ne d fr o m eac h 
s u bject pri or t o Scree ni n g acti vities. A sa m ple I nf or me d C o nse nt For m will be pr o vi de d i n t he 
I n vesti gat or's trial file as a se parate d oc u me nt. 
All c o nse nt d oc u me ntati o n m ust be i n acc or da nce wit h a p plica ble re g ulati o ns a n d t he I C H G o o d 
Cli nical Practice G ui deli ne E 6 ( R 2) ( 2 0 1 6). Eac h partici pa nt is re q ueste d t o si g n t he I C F after 
t he y ha ve recei ve d a n d rea d t he writte n partici pa nt i nf or mati o n a n d recei ve d a n e x pla nati o n of 
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w hat  t he trial i n v ol ves, i ncl u di n g b ut n ot li mite d t o: t he o bjecti ves, p ote ntial be nefits a n d ris k, 
i nc o n ve nie nces, a n d t he partici pa nt’s ri g hts a n d res p o nsi bilities. 
It m ust be ma de c o m pletel y a n d u na m bi g u o usl y clear t o eac h s u bject t hat he is free t o ref use t o 
partici pate i n t he trial or ca n wit h dra w c o nse nt at a n y ti me a n d f or a n y reas o n, wit h o ut e n d uri n g 
a n y pe nalt y or wit h h ol di n g of treat me nt o n t he part of t he I n vesti gat or. 
T he ori gi nal si g ne d I nf or me d C o nse nt F or m m ust be ke pt i n t he ce nter’s file b y t he I n vesti gat or 
a n d d oc u me nte d i n t he e C R F a n d t he s u bject’s me dical rec or ds. Si g ne d I C Fs m ust re mai n o n file 
a n d m ust be a vaila ble f or verificati o n b y Trial M o nit ors at a n y ti me. A n ot her si g ne d ori gi nal of 
t he I C F m ust be gi ve n t o t he partici pa nt or t he partici pa nt’s le gall y a ut h orize d re prese ntati ve. 
T he PI or dele gate will pr o vi de t he S p o ns or wit h a c o p y of t he E C a p pr o ve d c o nse nt f or ms, a n d a 
c o p y of t he E C writte n a p pr o val, pri or t o t he start of t he trial. 
9. 6  
Pr e m at ur e t er mi n ati o n or di s c o nti n u ati o n of t h e tri al 
T he cli nical part of t he trial is c o ncl u de d after t he last visit of t he last s u bject has bee n 
perf or me d. T he S p o ns or has t he ri g ht t o cl ose t his trial a n d t he Pri nci pal I n vesti gat or is 
a ut h orize d t o set t he trial at a n y p oi nt of ti me o n h ol d, alt h o u g h t his s h o ul d occ ur o nl y after 
c o ns ulti n g i n v ol ve d parties. T he E C a n d R A m ust be i nf or me d a b o ut t his. If t he trial/ce nter will 
be cl ose d pre mat urel y, all trial i nf or mati o n, e xce pt t h ose t hat ha ve t o re mai n at t he trial ce nter, 
m ust be ret ur ne d t o t he S p o ns or. Destr ucti o n of d oc u me nts/trial me dicati o n will be d o ne o n 
n otificati o n of t he S p o ns or. 
T he trial/ce nter will be ter mi nate d pre mat urel y if:  
•  Ne w t o xic ol o gical or p har mac ol o gical fi n di n gs or S A Es i n vali date t he earlier p ositi ve 
be nefit- ris k-assess me nt.  
•  A d verse e ve nts occ ur i n s uc h pr o mi ne nce (ie, i nte nsit y a n d fre q ue nc y) t hat a c o nti n uati o n of 
t he trial is n o l o n ger j ustifie d. 
•  T he S p o ns or deci des t o disc o nti n ue t he cli nical trial. 
T he I n vesti gat or m ust i nf or m his/ her l ocal E C  a b o ut t he ter mi nati o n of t he trial at t his site a n d 
t he partic ular reas o ns f or it. He/s he s h o ul d als o i nf or m s u bjects c urre ntl y i ncl u de d. 
9. 7  
C o nfi d e nti alit y  
F or t he p ur p oses of t his Secti o n, “ A p plica ble Data Pr otecti o n La w” s hall mea n (a) t he Data 
Pr otecti o n Act 2 0 1 8; ( b), t he U K G D P R (a s defi ne d i n Secti o n 3( 1 0) of t he Data Pr otecti o n Act 
2 0 1 8) a n d (c) t he Ge neral Data Pr otecti o n Re g ulati o n (( E U) 2 0 1 6/ 6 7 9) as a p plica ble, a n d a n y 
a p plica ble le gislati o n i ntr o d uce d i n t he U K. 
Data c ollecte d d uri n g t his trial ma y be use d t o s u p p ort t he de vel o p me nt, re gistrati o n, or 
mar keti n g of me dici nal pr o d uct. Ai C uris will c o ntr ol all data c ollecte d d uri n g t he trial a n d will 
a bi de b y t he A p plica ble Data Pr otecti o n La w. F or t he p ur p ose of t he A p plica ble Data Pr otecti o n 
La w, Ai C uris will be t he data c o ntr oller. T o t he e xte nt t hat R ic h m o n d P har mac ol o g y pr ocesses 
pers o nal data o n be half of Ai C uris, i n relati o n t o s uc h data Ric h m o n d P har mac ol o g y s hall o nl y 
act i n acc or da nce wit h t he ter ms of t his pr ot oc ol a n d Ai C uris’s reas o na ble writte n i nstr ucti o ns 
a n d Ric h m o nd P har mac ol o g y s hall ta ke a p pr o priate tec h nical a n d or ga nisati o nal meas ures 
a gai nst t he u na ut h orise d or u nla wf ul pr ocessi n g of s uc h pers o nal data. 
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After partici pa nts ha ve c o nse nte d t o ta ke part i n t he trial, t heir me dical rec or ds a n d t he data 
c ollecte d d ur i n g t he trial will be re vie we d b y Ai C uris a n d/ or its re prese ntati ves. T hese rec or ds 
a n d data ma y, i n a d diti o n, be re vie we d b y t he f oll o wi n g: i n de pe n de nt a u dit ors w h o vali date t he 
data o n be half of Ai C uris; nati o nal or l ocal re g ulat or y a ut h orities, a n d t he E C w hic h ga ve its 
a p pr o val f or t his trial t o pr ocee d.  
Alt h o u g h partici pa nts will be k n o w n b y a u ni q ue n u m ber, t heir date of birt h will als o be 
c ollecte d b y R ic h m o n d P har mac ol o g y a n d use d t o assist Ai C uris t o verif y t he acc urac y of t he 
data, f or e xa m ple, t hat t he res ults of trial assess me nts are assi g ne d t o t he c orrect partici pa nt. T he 
res ults of t his trial c o ntai ni n g t he u ni q ue n u m ber, date of birt h, a n d rele va nt me dical i nf or mati o n 
i ncl u di n g et h nicit y ma y be rec or de d a n d tra nsferre d t o a n d use d i n ot her c o u ntries t hr o u g h o ut t he 
w orl d. If pers o nal data is tra nsferre d o utsi de t he U K, R ic h m o n d P har mac ol o g y will e ns ure 
a p plica ble data tra nsfer mec ha nis ms are i n place t o e ns ure t he data recei ves esse ntiall y 
e q ui vale nt pr otecti o n as are a p plica ble i n t he U K. T he p ur p ose of a n y s uc h tra nsfer w o ul d be t o 
s u p p ort re g ulat or y s u b missi o ns ma de b y Ai C uris i n s uc h c o u ntries. T he Parties a gree t o c o m pl y 
wit h t he rele va nt pr o visi o ns of t he A p plica ble Data Pr otecti o n La w a n d a n y directi o ns iss ue d b y 
t he U K I nf or mati o n C o m missi o ner’s Office i n its pr ocessi n g of s uc h pers o nal Data. All 
n o mi nati ve i nf or mati o n i n t he partici pa nt’s me dical rec or d will be ke pt strictl y c o nfi de ntial. 
N o mi nati ve i nf or mati o n s hall mea n t he na me, t he a d dress a n d all ot her pers o nall y i de ntifia ble 
i nf ormati o n ass ociate d wit h a partici pa nt’s na me. Ai C uris access t o partici pa nt’s data s hall be 
perf or me d i n s uc h a wa y t hat n o partici pa nt c o ul d be i de ntifie d b y s uc h data. 
If t here are a n y c o ntra dicti o ns i n ter ms of c o nfi de ntialit y re q uire me nts, t he re q uire ments of 
A p plica ble Data Pr otecti o n La w will pre vail.  
T o t he e xte nt t hat R ic h m o n d P har mac ol o g y pr ocesses pers o nal data o n be half of Ai C uris, t he 
ter ms of A p pe n di x 6  s hall als o a p pl y. 
1 0  
A D MI NI S T R A TI V E R E S P O N SI BI LI TI E S  
1 0. 1  
Pr ot o c ol a d h er e n c e a n d I n v e sti g at or a gr e e m e nt  
T he PI a n d dele gates m ust a d here t o t he C T P  as detaile d i n t his d oc u me nt. T he PI will be 
res p o nsi ble f or i ncl u di n g o nl y t h ose partici pa nts w h o ha ve met C T P  eli gi bilit y criteria. T he PI 
will be re q uire d t o si g n a n I n vesti gat or A gree me nt t o c o nfir m acce pta nce a n d willi n g ness f or 
t he msel ves a n d dele gates t o c o m pl y wit h t he C T P . 
1 0. 2  
Et hi c s  
It is t he I n vesti gat or’s res p o nsi bilit y: 
•  T o e ns ure c o m plia nce wit h t he pri nci ples of t he c urre nt versi o n of t he Declarati o n of 
Helsi n ki, G C P sta n dar ds a n d l ocal la ws a n d re g ulati o ns c o ncer ni n g cli nical trials.  
•  T o o btai n a p ositi ve v ote f or t he trial fr o m t he a p pr o priate i n de pe n de nt E C bef ore t he trial 
starts. 
•  T o i nf or m at least o nce a year t he E C o n t he cli nical trial stat us.  
•  T o o btai n a n d d oc u me nt i nf or me d c o nse nt fr o m eac h s u bject partici pati n g i n t he trial, bef ore 
a n y trial-s pecific pr oce d ure is perf or me d. T he c o nse nt m ust be o btai ne d after t he e x pla nati o n 
of t he ai ms, met h o ds, be nefits,  a n d p ote ntial ris ks of t he trial.  
7 2 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
7 3  of 7 6  
 
1 0. 3  
I n d e m nit y/li a bilit y a n d i n s ur a n c e 
Ai C uris will a d here t o t he rec o m me n dati o ns of t he Ass ociati o n of Britis h P har mace utical 
I n d ustr y ( A B PI) G ui deli nes. A c o p y of t he I n de m nit y d oc u me nt will be s u p plie d t o t he 
I n vesti gat or bef ore trial i nitiati o n.  
Ai C uris will e ns ure t hat s uita ble i ns ura nce c o ver is i n place pri or t o t he start of t he trial. A n 
i ns ura nce certificate a n d a state me nt of i ns ura nce will be s u p plie d t o Ric h m o n d P har mac ol o g y. 
1 0. 4  
Pr ot o c ol m a n a g e m e nt  
All pr ot oc ols a n d a me n d me nts will be pre pare d b y Ai C uris. If it bec o mes necessar y t o iss ue a 
pr ot oc ol a me n d me nt d uri n g t he trial, Ai C uris will n otif y t he I n vesti gat or a n d c ollect d oc u me nte d 
I n vesti gat or A gree me nt t o t he a me n d me nt.  
1 0. 5  
E n d of tri al n otifi c ati o n  
Ric h m o n d P har mac ol o g y o n be half of Ai C uris will s u b mit a n e n d of trial n otificati o n t o t he 
c o m pete nt a ut h orit y of t he Me m ber State wit hi n 9 0 da ys of t he e n d of t he trial i n acc or da nce 
wit h E U Directi ve 2 0 0 1/ 2 0/ E C as f o u n d o n t he le gislati o n. g o v. u k we bsite . T he PI will be 
res p o nsi ble f or s u b mitti n g t hese t o t he E C a n d R A t hr o u g h c o m bi ne d re vie w wit hi n 9 0 da ys of 
t he e n d of t he trial. 
F or t he p ur p oses of t his n otificati o n, t he e n d of t he trial will be d efi ne d as data base l oc k.  
1 0. 6  
D o c u m e nt ati o n a n d r et e nti o n of r e c or d s  
After c o m pl eti o n of t he trial, all d oc u me nts a n d data relati n g t o t he trial will be ke pt i n a n or derl y 
ma n ner a n d sec urel y b y t he PI i n a sec ure file a n d/ or electr o nicall y. T he data will be a v aila ble f or 
i ns pecti o n b y Ai C uris or t heir re prese ntati ves. Esse ntial d oc u me nts m ust be retai ne d f or 2 5 years 
after t he fi nal mar keti n g a p pr o val i n a n I C H re gi o n or at least 2 5 years ha ve ela pse d si nce t he 
f or mal disc o nti n uati o n of cli nical de vel o p me nt of priteli vir. T he PI or dele gate m ust c o ntact 
Ai C uris bef ore destr o yi n g a n y trial- relate d d oc u me ntati o n a n d it is t he res p o nsi bilit y of Ai C uris 
t o i nf or m t he i n vesti gati ve site of w he n t hese d oc u me nts ca n be destr o ye d. I n a d diti o n, all 
partici pa nt rec or ds a n d ot her s o urce d oc u me ntati o n will be ke pt f or a l o n ger peri o d if re q uire d b y 
t he a p plica ble re g ulat or y re q uire me nts.  
1 0. 7  
M o nit ori n g  
A M S A d va nce d Me dical Ser vices Lt d. will be res p o nsi ble f or trial m o nit ori n g acc or di n g t o I C H -
G C P.  
1 0. 8  
D at a m a n a g e m e nt  
Ric h m o n d P har mac ol o g y will be res p o nsi ble f or data ma na ge me nt. 
1 0. 9  
St ati sti c s  
Statistical a nal ysis a n d re p orti n g will be perf or me d b y Ric h m o n d P har mac ol o g y f or safet y a n d 
de m o gra p hics a n d b y Ve n n Life Scie nces f or p har mac o ki netics.  
1 0. 1 0  
R e p ort w riti n g 
Ai C uris will be res p o nsi ble f or t he Cli nical Trial Re p ort acc or di n g t o I C H - E 3 g ui deli ne. 
7 3 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
7 4  of 7 6  
 
1 0. 1 1  
P o sti n g or s u b mi s si o n of s u m m ar y of cli ni c al tri al r e p ort t o 
c o m p et e nt a ut h oriti e s of m e m b er st at e s c o n c er n e d a n d E C s  
Ai C uris or dele gate will p ost res ult -relate d i nf or mati o n o n t his cli nical trial t o t he E ur o pea n 
Data base ( w hic h is c o nsi dere d as t he s u b missi o n of a s u m mar y of t he cli nical trial re p ort) wit hi n 
o ne year of t he e n d of t he c o m plete trial t o t he c o m pete nt a ut h orit y of t he Me m ber State 
c o ncer ne d as re q uire d b y t he re g ulat or y re q uire me nt a n d t o c o m pl y wit h t he C o m m u nit y 
g ui deli ne o n G o o d Cli nical Practice. Ric h m o n d P har mac ol o g y o n be half of Ai C uris will s u b mit 
a s u m mar y of t he cli nical trial re p ort t o t he c o ncer ne d E C via c o m bi ne d re vie w.  
1 0. 1 2  
Q u alit y a s s ur a n c e  
T he trial res ults a n d t he c orres p o n di n g s o urce data/ d oc u me nts m ust be ma de a vaila ble b y t he 
I n vesti gat or f or trial-relate d m o nit ori n g, a u dits, E C re vie w or i ns pecti o n b y t he C A. 
1 0. 1 3  
Fi n a n ci n g a n d i n s ur a n c e  
Fi na nci n g of t his trial is t he res p o nsi bilit y of Ai C uris a n d is detaile d i n a se parate d oc u me nt. 
Ai C uris pr o vi des a certificate of i ns ura nce f or trial s u bjects. D uri n g t he trial, s u bjects will be 
i ns ure d as a s u bject of t he trial acc or di n g t o t he nati o nal re g ulati o ns.  
1 0. 1 4  
P u bli c ati o n of r e s ult s  
B y si g ni n g t he trial pr ot oc ol, t he I n vest i gat or a grees t hat Ai C uris reser ves t he ri g ht t o p u blis h or 
n ot p u blis h t he data fr o m t his trial. F or a n y p u blicati o n a ma n uscri pt will be pre pare d b y Ai C uris 
a n d Ai C uris reser ves t he ri g ht t o select t he I n vesti gat or(s) w h o will be a ut h ors a n d u n derta ke 
re vie w of t he ma n uscri pt bef ore p u blicati o n. Ai C uris will all o w t he selecte d I n vesti gat ors 
4 5 da ys f or f ull re vie w of t he ma n uscri pt bef ore p u blicati o n. 
F or t he a v oi da nce of d o u bt, t he I n vesti gat or m ust n ot p u blis h t he data fr o m t his trial wit h o ut 
S p o ns or’s pri or writte n c o nse nt. I n t he e ve nt t hat Ai C uris gi ves its c o nse nt, t he n t he I n vesti gat or 
a grees t o pr o vi de Ai C uris wit h t he pla n ne d p u blicati o n i n d ue ti me, at least 4 5 da ys pri or t o its 
s u b missi o n. If Ai C uris disa grees wit h a n y w or di n gs, i nter pretati o ns, or c o ncl usi o ns, t he n Ai C uris 
has t he ri g ht t o re q uest re visi o n(s), mea ni n g t hat s u bject t o t he re q uire me nt f or scie ntific 
o bjecti vit y a n d ne utralit y Ai C uris retai ns t he ri g ht t o re q uest re visi o n a n d t o ha ve e dit orial 
c o ntr ol of s uc h data a n d trial fi n di n g s pri or t o p u blicati o n. 
If a n y C R O w o ul d li ke t o p u blis h or prese nt partial or c o m plete data fr o m t his trial, it m ust 
o btai n pri or writte n per missi o n fr o m Ai C uris. I n t he e ve nt of Ai C uris gi vi n g its c o nse nt, C R O 
a grees t o pr o vi de Ai C uris wit h t he pla n ne d p u blicati o n f or its re vie w at least 4 5  da ys pri or t o its 
s u b missi o n. State me nts o n t he pr o p ose d p u blicati o n, fr o m Ai C uris, m ust be ta ke n i nt o acc o u nt 
pri or t o p u blicati o n. T he fi nal pr o p ose d p u blicati o n m ust be f or mall y cleare d b y Ai C uris pri or t o 
p u blicati o n i n a n y j o ur nal or ot her f or mat. 
 
 
 
7 4 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
7 5  of 7 6  
 
R E F E R E N C E S  
1.  
Bl o o mfiel d, D. M., et al., T he effect of m oxifl ox aci n o n Q Tc a n d i m plic ati o ns f or t he 
desi g n of t h or o u g h Q T st u dies.  Cli n P har mac ol T her, 2 0 0 8. 8 4 ( 4): p. 4 7 5- 8 0. 
2.  
C ulle y, C. M., et al., M oxifl ox aci n: cli nic al effic acy a n d s afety.  A m J Healt h S yst P har m, 
2 0 0 1. 5 8 ( 5): p. 3 7 9- 8 8. 
3.  
E 1 4 I m ple me ntati o n W or ki n g Gr o u p, I C H G ui deli ne E 1 4/ S 7 B: cli nic al a n d N o ncli nic al 
Ev al u ati o n of Q T/ Q Tc I nterv al Pr ol o n g ati o n a n d Pr o arr hyt h mic P ote nti al - q uesti o ns 
a n d a ns wers - Ste p 5 . 2 0 2 2: Ge ne va, S witzerla n d. 
4.  
F o o d a n d Dr u g A d mi nistrati o n, G ui d a nce f or I n d ustry - E 1 4 Cli nic al Ev al u ati o n of 
Q T/ Q Tc I nterv al Pr ol o n g ati o n a n d Pr o arr hyt h mic P ote nti al f or N o n- A nti arr hyt h mic 
Dr u gs . 2 0 0 5: R oc k ville, M D, U S A. 
5.  
H ua n g, D. P., et al., Ass ay se nsitivity i n " Hy bri d t h or o u g h Q T/ Q Tc ( T Q T)" st u dy.  J 
Bi o p har m St at, 2 0 1 9. 2 9 ( 2): p. 3 7 8- 3 8 4. 
 
 
 
 
 
7 5 of 1 3 6

Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
C O N FI D E N TI A L  
7 6  of 7 6  
1 1  
S U M M A R Y O F C H A N G E S  
1 1. 1  
Pr ot o c ol V er si o n 2  
T he pr ot oc ol V 2. 0 was pri maril y iss ue d t o a d dress c o m me nts fr o m t he M H R A. At t he A ge nc y’ s 
re q uest, t he f oll o wi n g c ha n ges were ma de t o t he pr ot oc ol: 
T he s electi o n criteria f or t he trial p o p ulati o n were m o difie d wit h re gar d t o c ore la b orat or y 
para meters a n d c o nc o mita nt me dicati o ns . 
T he r ules f or s us pe nsi o n of d osi n g i n case of a d verse reacti o ns  were m o difie d f or se vere a d verse 
reacti o ns, he mat ol o gical reacti o ns, li ver reacti o ns, a n d der mat ol o gical reacti o ns. 
I n a d diti o n, mi n or t y p o gra p hical c orrecti o ns were ma de. 
7 6 of 1 3 6

Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
C O N FI D E N TI A L  
A P P E N DI X 1  
DI VI SI O N O F AI D S ( D AI D S) T A B L E F O R G R A DI N G 
T H E S E V E RI T Y O F A D U L T A N D P E DI A T RI C A D V E R S E 
E V E N T S ( C O R R E C T E D V E R SI O N 2. 1 , J U L Y 2 0 1 7)  
7 7 of 1 3 6

 
 
Di visi o n of AI D S ( D AI D S) T a bl e f or 
Gr a di n g t h e S e v erit y of A d ult a n d 
P e di atric A d v ers e E v e nts  
 
C or r e ct e d Ve rsi o n 2. 1  
J u l y 2 0 1 7 
Di visi o n of AI D S  
N ati o n al I nstit ute of Aller g y a n d I nfecti o us Dise ases  
N ati o n al I nstit utes of He alt h  
U S De p art me nt of H e alt h a n d H u m a n S er vices  
 
 
7 8 of 1 3 6

 
 
 
7 9 of 1 3 6

 
T a ble of C o nte nts 
Gl ossar y a n d Acr o n y ms  ....................................................................................................................... 1  
I ntr o d u cti o n ........................................................................................................................................... 3  
I nstr u cti o ns f or Use .............................................................................................................................. 4  
Maj o r Cli ni cal C o n diti o ns .................................................................................................................... 7  
Car di o vasc ular  ................................................................................................................................ 7  
Der mat ol o gi c  .................................................................................................................................. 9  
E n d o cri n e a n d M eta b oli c  ............................................................................................................. 1 0  
Gastr oi nt esti nal  ............................................................................................................................. 1 2  
M usc ul os k el e tal ............................................................................................................................ 1 4  
Ne ur ol o gi c ..................................................................................................................................... 1 5  
Pre g na n c y, P u er p eri u m, a n d P eri natal  ........................................................................................ 1 7  
Ps y c hiatri c  ..................................................................................................................................... 1 8  
Res pirat or y .................................................................................................................................... 1 9  
Se ns or y  .......................................................................................................................................... 2 0  
S yst e mi c  ........................................................................................................................................ 2 1  
Uri nar y  .......................................................................................................................................... 2 3  
Sit e R ea cti o ns t o I nj e cti o ns a n d I nf usi o ns  ........................................................................................ 2 4  
La b orat or y Val u es  .............................................................................................................................. 2 5  
C h e mistri es  ................................................................................................................................... 2 5  
He mat ol o g y  ................................................................................................................................... 2 9  
Uri nal ysis  ...................................................................................................................................... 3 1  
A p p e n di x A.  T otal Bilir u bi n T a bl e f or T er m a n d Pr et er m N e o nates  ............................................. 3 2  
 
8 0 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 1 
Gl ossar y a n d Acr o n y ms  
A E  
A d vers e e ve nt; A n y u nfa v or a bl e a n d u ni nt e n de d si g n (i ncl u di n g a n 
a b n or mal l a b orat or y fi n di n g), s y mpt o m, or diseas e t e mp or all y 
ass oci at e d wit h t he use of a me di cal treat me nt or pr oce d ure re gar dl ess 
of w het her it is c o nsi dere d rel at e d t o t he me di c al treat me nt or 
pr oce d ure. 
A L T ( S G P T)  
Al a ni ne a mi n otra nsferas e ( ser u m gl ut a mi c pyr uvi c tr a ns a mi n ase) 
A N C  
A bs ol ut e ne utr o p hil c o u nt 
A S T ( S G O T)  
As part at e a mi n otra nsferase ( ser u m gl ut a mi c- ox al o aceti c tr a ns a mi n ase) 
A V  
Atri o ve ntri c ul ar  
B asi c S elf -care F u ncti o ns 
A d ult 
Acti viti es s uc h as bat hi n g, dr essi n g, t oil eti n g, tra nsfer or mo ve me nt, 
c o nti ne nce, a n d fee di n g. 
 
Y o u n g C hil dre n 
Acti v iti es t hat are a ge a n d c ult urall y a p pr o pri at e, s uc h as fee di n g o ne’s 
self wit h c ult urall y a p pr o pri at e e ati n g i mpl e me nts. 
B MI z -sc or e 
B o d y mass i n de x z- sc ore; A b o d y ref ere nc e n or m. S pecifi c all y, t he 
n u mb er of st a n dar d de vi ati o ns a parti ci pa nt's B MI diff er s fr o m t he 
a vera ge B MI f or t heir a ge, se x, a n d et h ni cit y. 
B M D t -sc ore 
B o ne mi ner al de nsit y t- sc ore; The n u mber of st a n dar d de vi ati o ns a b o ve 
or bel o w t he mea n b o ne mi neral de nsit y of a he alt h y 3 0 year ol d a d ult 
of t he sa me se x a n d et h ni cit y as t he parti ci pa nt. 
B M D z -sc ore 
B o ne mi ner al de nsit y z-sc or e; T h e n u mber of st a n dar d de vi ati o ns a 
parti ci pa nt's B M D differs fr o m t he a vera ge B M D f or t heir a ge, se x, a n d 
et h ni cit y. 
B P A P  
Bil e vel p ositi ve air wa y press ure; A mo de use d d uri n g n o ni n vasi ve 
p ositi ve press ure ve nt il ati o n. 
C he mi c al Pre g na n c y  
A pre g n a nc y i n w hi c h a p ositi ve pr e g n a nc y t est is f oll o we d b y a 
ne gati ve pre g n a nc y t est wit h o ut e vi de nc e of a cli ni cal pre g na nc y l oss. 
C N S  
C e ntral ner vo us s yst e m 
C P A P  
C o nti n u o us p ositi ve air wa y press ure 
D A E R S  
D AI D S A d verse E x per i e nce R e p orti n g S yst e m; A n i nt er net-base d 
s yst e m de vel o pe d f or cli ni cal resear c h sit es t o re p ort E x pe dit e d 
A d vers e E ve nts ( E A Es) t o D AI D S.  It facilit at es ti mel y E A E r e p ort 
s u b missi o n a n d ser ves as a ce ntr ali ze d l ocati o n f or accessi n g a n d 
pr ocessi n g E A E i nf or mati o n f or re p orti n g p ur p oses. 
Disa bilit y  
A s u bst a nti al disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life 
f u ncti o ns. 
E C G  
El ectr ocar di o gra m  
e G F R  
Esti mat e d gl o mer ul ar filtrati o n rat e  
H os pit ali zati o n  
D oes n ot i ncl u de t he f oll o wi n g h os pit al a d missi o ns: u n der 2 4 h o urs, 
u nrel at e d t o a n a d verse e ve nt (e. g., f or l a b or a n d deli ver y, c os meti c 
s ur ger y, s oci al or a d mi nistrati ve f or t e m p orar y pl ac e me nt [f or l ac k of a 
pl ace t o sl ee p]), pr ot oc ol-s pecifi e d, a n d f or di a g n osis or t hera p y of a 
c o n diti o n t hat e xist e d bef ore t he recei pt of a st u d y a ge nt a n d w hi c h has 
n ot i ncrease d i n se verit y or fr e q ue nc y.  
I N R 
I nt er n ati o nal n or mali ze d rati o  
8 1 of 1 3 6

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I nt er ve nti o n 
Me di cal, s ur gi cal, or ot her pr oce d ur es rec o m me n de d or pr o vi de d b y a 
healt hcare pr of essi o nal f or t he treat me nt of a n a d verse e ve nt.  
I V 
I ntra ve n o us 
I VI G 
I ntra ve n o us i m m u ne gl o b uli n 
L D L  
L o w de nsit y li p o pr ot ei n 
L L N  
L o wer li mit of n or mal 
Life -t hreat e ni n g A E 
A n y a d vers e e ve nt t hat pl aces t he parti ci pa nt, i n t he vi e w of t he 
i n vesti gat or, at i m me di at e ris k of deat h fr o m t he re acti o n w he n it 
occ urre d (i.e., it d oes n ot i ncl u de a reacti o n t hat w o ul d ha ve ca use d 
deat h if it ha d occ urre d i n a more se vere f or m).  
N A  
N ot a p pli ca bl e 
P arti ci pa nt I D  
T he i de ntifi cati o n n u mber assi g n e d t o a st u d y parti ci pa nt w hi c h is use d 
t o trac k st u d y-rel at e d d oc u me nt ati o n, i ncl u di n g a n y re p ort e d A Es. 
P R I nt er val  
T he i nt er val bet we e n t he be gi n ni n g of t he P wa ve a n d t he be gi n ni n g of 
t he Q R S c o mpl e x of a n el ectr o car di o gra m t hat re prese nts t he ti me 
bet we e n t h e be gi n ni n g of t he c o ntracti o n of t he atri a a n d t he be gi n ni n g 
of t he c o ntracti o n of t he ve ntri cl es. 
P T  
Pr ot hr o mbi n ti me 
P T T  
P arti al t hr o mb o pl asti n ti me  
Q Tc I nt er val  
T he meas ur e of ti me bet we e n t he o nset of ve ntri c ul ar de p ol ari zati o n 
a n d c o mpl eti o n of ve ntri c ul ar r e p ol ari zati o n c orre ct e d f or ve ntri c ul ar 
rat e. 
R B C  
R e d bl o o d cell 
SI  
St a n dar d i nt er nati o nal u nit 
U L N  
U p per li mit of n or mal 
Us ual S oci al & F u ncti o nal Acti viti es   
Acti viti es w hi c h a d ults a n d c hil dre n perf or m o n a r o uti ne basis a n d 
t h ose w hi c h are part of re g ul ar a cti viti es of dail y li vi n g, f or e xa m pl e:  
 
A d ults 
A da pti ve t as ks a n d desira bl e acti viti es, s uc h as g oi n g t o w or k, 
s h o p pi n g, c o o ki n g, use of tra ns p ort ati o n, or p urs ui n g a h o b b y. 
 
Y o u n g C hil dre n 
Acti viti es t hat are a ge a n d c ult urall y a p pr o pri at e, s uc h as s oci al 
i nt eracti o ns, pl a y acti viti es, or l ear ni n g t as ks. 
W B C  
W hit e bl o o d cell 
W H O  
W orl d He alt h Or ga ni z ati o n  
W N L  
Wit hi n n or mal li mits  
 
 
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I ntr o d u cti o n 
T he Di visi o n of AI D S ( D AI D S) o v erse es m ore t ha n 3 0 0 cli ni cal trials d o m esti call y a n d 
i nt er nati o nall y, w hi c h e val u at e t h e safet y a n d effi ca c y of t h era pe utic pr o d u cts, va c ci nes, a n d 
ot her pre v e nti ve m o daliti es.  A d v erse e v e nt ( A E) data c oll e ct e d d uri n g t h ese  cli nical trials f or m 
t h e basis f or s u bse q u e nt safet y a n d effi ca c y a nal yses of p har ma c e utical pr o d u cts a n d m e di cal 
de vi c es.  I nc orr e ct a n d i n c o nsist e nt A E se v erit y gra di n g ca n l ea d t o i na c c urate data a nal yses a n d 
i nt er pr etati o n, w hi c h i n t ur n ca n i m pa ct t he safet y a n d well -b ei n g of cli ni cal trial parti ci pa nts a n d 
f ut ur e pati e nts usi n g p har ma c e uti cal pr o d u cts.  
 
O v er t h e years, D AI D S sci e ntific k n o wl e d g e a n d e x p eri e n c e ha v e e x pa n d e d , n e cessitati n g 
re visi o ns of t he D AI D S gra di n g ta bl e w hi c h ser ves as a g ui d e f or assessi n g t he se v erit y of A Es 
(i n cl u di n g cli nical a n d la b orat or y a b n or maliti es) i n partici pa nts e nr oll e d i n D AI D S-s p o ns ore d 
a n d -s u p p orte d cli nical trials.  T h e Divisi o n of AI D S ( D AI D S) T a ble f or Gr a di n g t h e S e v erity of 
A d ult a n d Pe di atric A d v erse Ev e n ts, C orre cte d Versi o n 2. 1 (J uly 2 0 1 7) u p d ates a n d  re pla c es 
versi o n 2. 1 ( Mar c h 2 0 1 7) .  
 
D AI D S is gratef ul t o t h e D AI D S Gra di n g T a bl e W or ki n g Gr o u p, n u m er o us g o v er n m e nt a n d 
n o n -g o v er n me nt affiliat e d m e di cal s u bje ct matt er e x p erts a n d r e vi e wers w h o wer e i nstr u m e ntal 
i n t h e r e visi o n of t h e D AI D S gra di n g ta bl e. 
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I nstr ucti o ns f or Use 
Ge ne r al C o nsi de r ati o ns  
T he Divisi o n of AI D S  (D AI D S) T a ble f or Gr a di n g t h e S e v erity of A d ult a n d Pe di atric A d v erse 
Ev e nts, Versi o n 2. 1 c o nsists of para m et ers, or A Es, wit h se v erit y gra di n g g ui da n c e t hat are t o be 
use d i n D AI D S cli ni cal trials f or safet y data r e p orti n g t o mai ntai n a c c ura c y a n d c o nsist e n c y i n 
t h e e val u ati o n of A Es.  T he t er m “se v er e” is n ot t he sa m e as t he t er m “seri o us” i n classif yi n g 
A Es.  T h e se v erit y of a s p e cifi c e v e nt d escri b es its i nt e nsit y, a n d it is t h e i nt e nsit y w hi c h is 
gra d e d.  S eri o us n ess, w hi c h is n ot gra d e d, r elates t o a n o ut c o me of a n A E a n d is a r e g ulat or y 
defi niti o n.  
 
Cli nical sit es ar e e n c o ura ge d t o r e p ort para m et ers i n t h e D AI D S gra di n g  ta bl e as t h e y ar e writt e n 
t o mai ntai n data c o nsiste n c y a cr oss cli ni cal trials.  H o we v er, si n c e s o m e para m et ers ca n b e 
re p orte d wit h m ore s p e cificit y, cli ni cal sit es ar e e nc o ura g e d t o re p ort para m et ers t hat c o n v e y 
a d diti o nal cli ni cal i nf or mati o n.  F or e xa m pl e, diarr h ea c o ul d b e r e p ort e d as ne o natal diarr h ea; 
sei z ures, as fe bril e sei z ur es; a n d pai n, as ja w pai n. 
 
T he D AI D S gra di n g ta bl e pr o vi des a n A E se verit y gra di n g scal e ra n gi n g fr o m gra d es 1 t o 5 wit h 
descri pti o ns f or ea c h A E base d o n t he f oll o wi n g g e neral g ui d eli n es:  
•  Gra de 1 i n dicat es a mil d e ve nt  
•  Gra de 2 i n dicat es a m o d erat e e v e nt  
•  Gra de 3 i n dicat es a se v er e e ve nt  
•  Gra de 4 i n dicat es a p ot e ntiall y life -t hr eat e ni n g e v e nt 
•  Gra de 5 i n dicat es d eat h ( N ote : T his gra d e is n ot s p ecifi call y list e d o n ea c h p a ge of t he 
gra di n g ta bl e).  
 
Ot h er p oi nts t o c o nsi d er i n cl u d e:  
•  Use  a ge a n d se x val u es as a p pli ca ble.  
•  U nl ess n ote d, la b orat or y val u es are f or t er m n e o nat es.  Pr et er m n e o nat es s h o ul d be assesse d 
usi n g l o cal la b orat or y n or mal ra n g es.  
•  W h er e a p pli ca bl e, Sta n dar d I nter nati o nal ( SI) u nits ar e i n cl u d e d i n italics.  
 
Sele cti n g a n d Re p o rti n g a Pri m ar y A E Te r m  
W h e n sel e cti n g a pri mar y A E ter m t o r e p ort, sit es s h o ul d sel e ct t h e ter m t hat b est d escri bes w hat 
oc c urr e d t o t h e parti ci pa nt.   F or e xa m pl e, a parti ci pa nt ma y pr ese nt wit h it c hi n g, urticaria, 
fl us hi n g, a n gi o e d e ma of t h e fa c e, a n d d ys p nea.  If t he u n d erl yi n g dia g n osis is d et er mi n e d t o b e 
a n a c ut e all er gic r ea cti o n, sit es s h o ul d re p ort “ Ac ut e Aller gi c R ea cti o n” as t he pri mar y A E ter m.  
 
Pri mar y A E t er ms s h o ul d b e r e p ort e d usi n g t he D AI D S A d v erse E x p eri e nc e Re p orti n g S yst e m 
( D A E R S) o nl y if t h e y me et e x p e dit e d r e p orti n g criteria.  H o we v er, all pri mar y A E t er ms s h o ul d 
be r e p ort e d usi n g pr ot o c ol -s pe cifi c case re p ort f or ms ( C R Fs).  B eca use t h e r e p ort e d i nf or mati o n 
is st ore d i n differe nt data bases (i. e., safet y a n d cli ni cal), sit es s h o ul d r e p ort pri mar y A E t er ms 
usi n g t h e sa m e ter mi n ol o g y f or data c o nsist e n c y.  
 
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W h e n r e p orti n g usi n g D A E R S, ot h er cli ni call y si g nifi ca nt e ve nts ass o ciat e d wit h a pri mar y A E 
ter m t hat m or e f ull y d escri b e t h e nat ure, se verit y, or c o m pli cati o ns of t h e pri mar y A E t er m 
s h o ul d b e e nt ere d i n t he “ Ot h er E v e nts” se cti o n.  H o we v er, t he se v erit y gra d e f or t h ese e ve nts 
m ust b e l o wer t ha n or e q u al t o t he se v erit y gra d e of t h e pri mar y A E t er m.   I n t h e e xa m pl e a b o v e, 
d ys p nea a n d a n gi o e d e ma of t h e fa c e ma y be e nter e d i n t h e “ Ot h er E ve nts” se cti o n, b eca use t h e y 
are m ore d escri pt i v e a n d pr o vi d e a d diti o nal i nf or mati o n o n t h e se v erit y of t h e a c ute all er gi c 
rea cti o n.  H o we ver, t h eir se v erit y gra des m ust b e l o wer t ha n or e q u al t o t h e se v erit y gra d e of t h e 
pri mar y A E t er m of “ Ac ute All er gi c Rea cti o n”.  
 
Differ e n ces e xist i n t h e r e p orti n g a n d r e c or di n g of i nf or mati o n ( e. g., si g ns a n d s y m pt o ms, 
cli ni call y si g nifica nt e v e nts) i n D A E R S a n d C R Fs.  T h er ef or e, sites s h o ul d r efer t o t h eir 
pr ot o c ols a n d C R F r e q uir e m e nts f or f urt h er i nstr u cti o ns.  
 
Gr a di n g A d ult a n d Pe di atric A Es  
W h e n a si n gl e para m et er is n ot a p pr o priat e f or gra di n g a n A E i n b ot h a d ult a n d p e diatri c 
p o p ulati o ns, se parate para m et ers wit h s p e cifie d a g e ra n g es ar e pr o vi d e d.  If n o disti n cti o n  
bet wee n a d ult a n d p e diatric p o p ulati o ns has b e e n ma d e, t h e list e d para m et er s h o ul d b e use d f or 
gra di n g a n A E i n b ot h p o p ulati o ns.  
 
Re p o rti n g Pr e g n a nc y O utc o mes  
I n t h e Pre g n a n c y, P u er p eri u m, a n d Peri n at al  se cti o n, all para meters are pre g na n c y o ut c o mes 
a n d s h o ul d b e re p ort e d usi n g t h e m ot h er's parti ci pa nt I D.  If a n i nfa nt is n ot e nr oll e d i n t he s a me 
st u d y as t he m ot h er, a n y i d e ntifi e d birt h d efe cts s h o ul d b e r e p ort e d usi n g t h e m ot h er's parti ci pa nt 
I D.  H o we v er, if a n i nfa nt is e nr oll e d i n t h e sa me st u d y as t h e m ot h er or i n a n ot h er st u d y, a n y 
i d e ntifi e d birt h d efects s h o ul d b e r e p orte d usi n g t h e i nfa nt's parti ci pa nt I D.  Sit es s h o ul d r efer t o 
t h e a p plica bl e n et w or k sta n dar ds f or r e p orti n g a b n or mal pr e g na n c y o utc o m es o n t h e C R Fs. 
 
Dete r mi ni n g Se v e rit y Gr a de f o r P ar a mete rs bet we e n Gr a des  
If t h e se v erit y of a n A E c o ul d fall i n eit h er o n e of t w o gra d es (i.e., t h e se v erit y of a n A E c o ul d b e 
eit h er gra d e 2 or gra d e 3), sit es s h o ul d sel e ct t h e hi g her of t h e t w o gra des.  
 
L a b o r at o r y V al ues  
Ge n er al. A n as y m pt o mati c, a b n or mal la b orat or y fi n di n g wit h o ut a n a c c o m p a n yi n g A E s h o ul d 
n ot be r e p ort e d t o D AI D S i n a n e x pe dite d ti m efra me u nl ess it m e ets pr ot oc ol -s p e cifi c r e p orti n g 
re q uire m e nts.  Sit es s h o ul d r efer t o t h e a p plica bl e n et w or k sta n dar ds f or r e p orti n g a b n or mal 
la b orat or y fi n di n gs o n t h e cli ni cal case r e p ort f or ms .  
 
V al u es b el o w Gr a d e 1.  A n y la b orat or y val u e  t hat is b et we e n t h e U L N a n d gra de 1 (f or hi g h 
val u es) or t he L L N a n d gra de 1 (f or l o w val u es) s h o ul d n ot be gra d e d or r e p ort e d as a n A E.  
Sit es s h o ul d c o ns ult t h e M a n u al f or Ex p e dite d Re p orti n g of A d v erse Ev e nts t o D AI D S, Versi o n 
2. 0  a n d t h eir pr ot o c ol w h e n ma ki n g a n assess m e nt of t h e n e e d t o r e p ort a n A E.  
 
Ov erl a p of L o c al L a b or at ory N or m al V al u es wit h Gr a di n g T a ble R a n g es .  W h e n l o cal la b orat or y 
n or mal val u es fall wit hi n gra di n g ta ble la b orat or y ra n g es, t he se v erit y gra di n g is base d o n t h e 
ra n g es i n t h e gra di n g ta bl e u nl ess t h er e is a pr ot o c ol -s p e cifi c gra di n g crit eri o n f or t h e la b orat or y 
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val u e.  F or e xa m pl e, “ Ma g n esi u m, L o w" has a gra d e 1 ra n ge of 1. 2 t o < 1. 4 m E q/ L, w hil e a 
parti c ular la b orat or y’s n or mal ra n g e f or ma g nesi u m ma y b e 1. 3 t o 2. 8 m E q/ L.  If a st u d y 
parti ci pa nt’s ma g n esi u m la b orat or y val u e is 1. 3 m E q/ L, t h e la b orat or y val u e s h o ul d b e gra de d as 
gra d e 1.  
 
A p pe n di x Us a g e  
A p p e n di x A ta k es pri orit y o ver t h e mai n gra di n g ta bl e i n all assess m e nts of t otal bilir u bi n f or 
ter m a n d preter m n e o nates. 
 
Usi n g A d de n d a 1 -3: Gr a di n g T a bles Use d i n Mic r o bici de St u dies  
I n pr ot o c ols i n v ol vi n g t o pi cal a p pli cati o n of pr o d u cts t o t h e fe mal e a n d mal e g e nital tra cts or 
re ct u m, str o n g c o nsi d erati o n s h o ul d be gi v e n t o usi n g A d d e n da 1 -3 (se e b el o w) as t h e pri mar y 
gra di n g ta bl es f or t h ese ar eas.  Alt h o u g h t h ese gra di n g ta bl es ar e use d s p e cificall y i n mi cr o bi ci d e 
st u di es, t h e y ma y b e use d i n ot h er pr ot o c ols as a dj u n cts t o t h e mai n gra di n g ta bl e (i. e., t he 
Divi si o n of AI D S ( AI D S) T a ble f or Gr a di n g t h e S e v erity of A d ult a n d Pe di atric A d v erse Ev e nts, 
Versi o n 2. 0 ).  It s h o ul d b e clearl y stat e d i n a pr ot o c ol w hi c h a d d e n d u m is b ei n g use d as t h e 
pri mar y gra di n g ta bl e (a n d t h us ta k es pr e ce d e nc e o v er t h e mai n gra di n g ta bl e) a n d w hic h 
a d d e nd u m is b ei n g use d i n a c o m pl e m e ntar y fas hi o n.  
•  A d d e n d u m 1 – F e mal e G e nital Gra di n g T a bl e f or Use i n Micr o bi ci d e St u di es - 
htt p://rsc.te c h -res.c o m/cli nic al-rese arc h-sites/s afety-re p orti n g/ d ai ds-gr a di n g -t a bles 
•  A d d e n d u m 2 – Mal e G e nital Gra di n g T a bl e f or Use i n Mi cr o bi ci d e St u dies – 
htt p://rsc.te c h -res.c o m/cli nic al-rese arc h-sites/s afety-re p orti n g/ d ai ds-gr a di n g -t a bles 
•  A d d e n d u m 3 – Re ctal Gra di n g T a ble f or Use i n Mi cr o bici d e St u di es – 
htt p://rsc.te c h -res.c o m/cli nic al-rese arc h-sites/s afety-re p orti n g/ d ai ds-gr a di n g -t a bles 
 
Esti m ati n g Se v e rit y Gr a de f o r P ar a mete rs N ot I de ntifie d i n t he Gr a di n g T a ble  
T he f u ncti o nal ta ble b el o w s h o ul d b e use d t o gra d e t h e se v erit y of a n A E t hat is n ot s pe cifi call y 
i d e ntifi e d i n t h e gra di n g ta bl e.  I n a d diti o n, all deat hs r elate d t o a n A E ar e t o b e classifie d as 
gra d e 5.   
 
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -T H R E A T E NI N G  
C li nic al a d vers e 
e ve nt N O T  
i d e ntifie d 
els e w h ere i n t h e 
gra di n g ta ble  
Mil d s y m pt o ms 
ca usi n g n o or 
mi ni m al  
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
wit h i nter ve nti o n 
n ot i n dicate d  
M o d erate s y m pt o ms 
ca usi n g gr eater t h a n 
mi ni m al i nterfere n ce 
wit h us u al s o cial & 
f u n cti o n al acti vities 
wit h i nter ve nti o n 
i n dicate d 
Se vere s y m pt o ms 
ca usi n g i n a bilit y t o 
p erf or m us u al s o cial & 
f u n cti o n al acti vities 
wit h i nter ve nti o n or 
h os pitalizati o n 
i n dicate d 
P ote ntiall y life -t hreate ni n g 
s y m pt o ms ca usi n g i n a bilit y 
t o p erf or m b asic s elf-care 
f u n cti o ns wit h i nter ve nti o n 
i n dicate d t o pre ve nt 
p er m a n e nt i m p air m e nt, 
p ersiste nt dis a bilit y, or d eat h  
 
 
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M aj or Cli ni c al C o n diti o ns  
C ar di o vas c ular  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Arr h yt h mi a    
(b y E C G or p h ysical 
e x a mi n ati o n) 
S p ecify t y p e, if 
a p pli c a ble  
N o s y m pt o ms A N D  
N o i nter ve nti o n 
i n dicate d 
N o s y m pt o ms A N D  
N o n -ur ge nt 
i nter ve nti o n 
i n dicate d 
N o n -life-t hreate ni n g 
s y m pt o ms A N D 
N o n -ur ge nt 
i nter ve nti o n i n dicate d  
Life -t hreate ni n g 
arr h yt h mia O R  Ur ge nt 
i nter ve nti o n i n dicate d 
Bl o o d P ress ure 
A b n or m alities 1  
Hy p erte nsi o n ( wit h 
t h e l o west r e a di n g 
t a ke n aft er r e p e at 
t esti n g d uri n g a visit) 
≥ 1 8 ye ars of a g e  
1 4 0 t o < 1 6 0 m m H g 
s yst olic 
O R  
9 0 t o < 1 0 0 m m H g 
diast olic  
≥ 1 6 0 t o < 1 8 0 
m m H g s yst olic  
O R  
≥ 1 0 0 t o < 1 1 0 
m m H g diast olic  
≥ 1 8 0 m m H g s yst olic  
O R  
≥ 1 1 0 m m H g 
diast olic  
Life -t hreate ni n g 
c o ns e q u e n ces i n a 
p artici p a nt n ot 
pre vi o usl y dia g n os e d 
wit h h y p erte nsi o n (e. g., 
m ali g n a nt h y p erte nsi o n) 
O R  H os pitalizati o n 
i n dicate d 
< 1 8 ye ars of a g e  
> 1 2 0/ 8 0 m m H g  
≥ 9 5 t h t o < 9 9t h 
p erce ntile  + 5 m m H g 
a dj uste d f or a ge, 
h ei g ht, a n d ge n d er 
(s yst olic a n d/ or 
diast olic)  
≥ 9 9 t h p erce ntile  
+ 5 m m H g a dj uste d 
f or a ge, h ei g ht, a n d 
ge n d er (s yst olic 
a n d/ or diast olic)  
Life -t hreate ni n g 
c o ns e q u e n ces i n a 
p artici p a nt n ot 
pre vi o usl y dia g n os e d 
wit h h y p erte nsi o n  (e. g., 
m ali g n a nt h y p erte nsi o n) 
O R  H os pitalizati o n 
i n dicate d 
Hy p ote nsi o n  
N o s y m pt o ms  
S y m pt o ms c orrecte d 
wit h oral fl ui d 
re place m e nt 
S y m pt o ms A N D I V 
fl ui ds i n dicate d 
S h o c k re q uiri n g us e of 
vas o press ors or 
m ec h a nical assista n ce t o 
m ai ntai n bl o o d  press ure  
C ar di ac Is c he mi a or 
I nf arcti o n 
Re p ort o nly o n e  
N A  
N A  
Ne w s y m pt o ms wit h 
is c h e mia (sta ble 
a n gi n a) O R  Ne w 
testi n g c o nsiste nt 
wit h is c h e mia  
U nsta ble a n gi n a O R 
Ac ute m y o car dial 
i nfarcti o n 
He art F ail ure  
N o s y m pt o ms A N D  
La b orat or y or 
car diac i m a gi n g 
a b n or m alities  
S y m pt o ms wit h mil d 
t o m o d erate acti vit y 
or e x erti o n  
S y m pt o ms at rest or 
wit h mi ni m al acti vit y 
or e x erti o n (e. g., 
h y p o x e mia) O R  
I nter ve nti o n 
i n dicate d (e. g., 
o x y ge n)  
Life -t hreate ni n g 
c o ns e q u e n ces O R  
Ur ge nt i nter v e nti o n 
i n dicate d (e. g., 
vas o acti ve m e dicati o ns, 
ve ntric ular assist d e vice, 
h eart tra ns pla nt)  
                                                          
1  Bl o o d press ure n or ms f or c hil dre n < 1 8 y ears of a ge ca n b e f o u n d i n: E x p ert Pa n el o n I nte grate d G ui d eli n es f or C ar di o vas c ular  
Healt h a n d Ris k R e d u cti o n i n C hil dre n a n d A d oles ce nts. Pe di atri cs  2 0 1 1; 1 2 8; S 2 1 3; ori gi n all y p u blis h e d o nli n e N o ve m b er 1 4, 
2 0 1 1; D OI: 1 0. 1 5 4 2/ p e ds. 2 0 0 9 -2 1 0 7 C.  
8 7 of 1 3 6

Car di o vasc ular  
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 - J ul y 2 0 1 7 
Pa ge 8 
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
He m orr h a g e  
( wit h si g nifica nt ac ute 
bl o o d l oss)  
N A  
S y m pt o ms A N D N o 
tra nsf usi o n i n dicate d 
S y m pt o ms A N D  
Tra nsf usi o n of  ≤ 2 
u nits p ac ke d R B Cs 
i n dicate d  
Life -t hreate ni n g 
h y p ote nsi o n O R 
Tra nsf usi o n of >  2 u nits 
p ac ke d R B Cs (f or 
c hil dre n , p ac ke d R B Cs  
> 1 0 cc/ k g) i n dicate d  
P r ol o n g e d P R I nter v al   
or A V Bl oc k  
Re p ort o nly o n e  
> 1 6 ye ars of  a g e  
P R i nter val 0. 2 1 t o 
< 0. 2 5 s ec o n ds  
P R i nter val ≥ 0. 2 5 
s ec o n ds O R  Ty p e I 
2 n d d e gree A V bl o c k  
Ty p e II 2 n d d e gre e 
A V bl o c k O R  
Ve ntric ular p a us e ≥ 
3. 0 s ec o n ds  
C o m plete A V bl o c k  
≤ 1 6 ye ars of a g e  
1 st d e gree A V bl o c k 
( P R i nter v al  
> n or m al f or a ge 
a n d rate) 
Ty p e I 2 n d  d e gree 
A V bl o c k  
Ty p e II 2 n d d e gre e 
A V bl o c k O R  
Ve ntric ular p a us e ≥ 
3. 0 s ec o n ds  
C o m plete A V bl o c k  
P r ol o n g e d Q T c 
I nter v al2  
0. 4 5 t o 0. 4 7 s ec o n ds  
> 0. 4 7 t o 0. 5 0 
s ec o n ds 
> 0. 5 0 s ec o n ds O R  
≥ 0. 0 6 s ec o n ds a b o ve 
b as eli n e  
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
Tors a d e d e p oi ntes, 
ot h er ass o ciate d s eri o us 
ve ntric ular 
d ysr h yt h mia)  
T hr o m b osis or  
E m b olis m  
Re p ort o nly o n e  
N A  
S y m pt o ms A N D  N o 
i nter ve nti o n 
i n dicate d  
S y m pt o ms A N D 
I nter ve nti o n 
i n dicate d  
Life -t hreate ni n g 
em b olic e ve nt ( e. g., 
p ul m o n ar y e m b olis m, 
t hr o m b us)  
 
 
                                                          
2  As p er Bazett’s f or m ula.  
8 8 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 9 
D er mat ol o gic  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Al o peci a  (s cal p o nl y)  
Detecta ble b y st u d y 
p artici p a nt, 
care gi ver, or 
p h ysicia n A N D  
C a usi n g n o or 
mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O b vi o us o n vis u al 
i ns p ecti o n A N D  
C a usi n g greater t h a n 
mi ni m al i nterfere n ce 
wit h us u al s o cial & 
f u n cti o n al acti vities 
N A  
N A  
B r uisi n g  
L o calize d t o o n e 
area  
L o calize d t o m ore 
t h a n o n e area  
Ge n eralize d  
N A  
Cell ulitis  
N A  
N o n -p are nteral 
treat m e nt i n dicate d 
(e. g., oral a nti bi otics, 
a ntif u n gals, 
a nti virals)  
I V treat m e nt 
i n dicate d (e. g., I V 
a nti bi otics, 
a ntif u n gals, 
a nti virals)  
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
s e psis, tiss u e n ecr osis) 
H y per pi g me nt ati o n  
Sli g ht or l o calize d 
ca usi n g n o or 
mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
Mar ke d or 
ge n eralize d ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
N A  
N A  
H y p o pi g me nt ati o n  
Sli g ht or  l o calize d 
ca usi n g n o or 
mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
Mar ke d or 
ge n eralize d ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
N A  
N A  
P etec hi ae  
L o calize d t o o n e 
area  
L o calize d t o m ore 
t h a n o n e area  
Ge n eralize d  
N A  
P r urit us 3  
( wit h o ut s ki n lesi o ns) 
Itc hi n g ca usi n g n o 
or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
Itc hi n g ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
Itc hi n g ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities  
N A  
R as h  
S p ecify t y p e, if 
a p pli c a ble  
L o calize d ras h  
Diff us e ras h O R 
Tar get lesi o ns  
Diff us e ras h A N D  
Vesicles or li mite d 
n u m b er of b ullae or 
s u p erficial 
ulcerati o ns of 
m u c o us m e m bra n e 
li mite d t o o n e site 
E xte nsi ve or ge n eraliz e d 
b ull o us lesi o ns O R 
Ulcerati o n of m u c o us 
m e m bra n e i n v ol vi n g 
t w o or m ore disti n ct 
m u c os al sites O R  
Ste ve ns -J o h ns o n 
s y n dr o m e O R To xic 
e pi d er m al n ecr ol ysis  
 
                                                          
3  F or pr urit us ass o ciate d wit h i njecti o ns or i nf usi o ns, s ee t h e Sit e Re a cti o ns t o I njecti o ns a n d I nf usi o ns  s ecti o n ( p a ge 2 3). 
8 9 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 1 0 
E n d o cri ne a n d M et a b olic  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Di a betes M ellit us  
C o ntrolle d wit h o ut 
m e dicati o n  
C o ntrolle d wit h 
m e dicati o n O R  
M o dificati o n of 
c urre nt m e dicati o n 
re gi m e n 
U n c o ntr olle d d es pite 
treat m e nt 
m o dificati o n O R 
H os pitalizati o n f or 
i m m e diate gl u c os e 
c o ntr ol i n dicate d  
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
ket o aci d osis, 
h y p er os m olar n o n -
ket otic c o m a, e n d or ga n 
fail ure)  
G y nec o m asti a  
Detecta ble b y st u d y 
p artici p a nt, 
care gi ver, or 
p h ysicia n A N D 
C a usi n g n o or 
mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O b vi o us o n vis u al 
i ns p ecti o n A N D  
C a usi n g p ai n wit h 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
Disfi g uri n g c h a n ges 
A N D  S y m pt o ms 
re q uiri n g i nter ve nti o n 
or ca usi n g i n a bilit y t o 
p erf or m us u al s o cial 
& f u n cti o n al 
acti vities  
N A  
H y pert h yr oi dis m  
N o s y m pt o ms A N D  
A b n or m al 
la b orat or y val u e 
S y m pt o ms ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O R  Th yr oi d 
s u p pressi o n t h era p y 
i n dicate d 
S y m pt o ms ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
O R  U n c o ntr olle d 
d es pite treat m e nt 
m o dificati o n  
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
t h yr oi d st or m) 
H y p ot h yr oi dis m  
N o s y m pt o ms A N D  
A b n or m al 
la b orat or y val u e 
S y m pt o ms ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O R Th yr oi d 
re place m e nt t h era p y 
i n dicate d 
S y m pt o ms ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
O R  U n c o ntr olle d 
d es pite treat m e nt 
m o dificati o n  
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
m y x e d e m a c o m a)  
Li p o atr o p h y 4  
Detecta ble b y st u d y 
p artici p a nt, 
care gi ver, or 
p h ysicia n A N D 
C a usi n g n o or 
mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O b vi o us o n vis u al 
i ns p ecti o n A N D  
C a usi n g greater t h a n 
mi ni m al i nterfere n ce 
wit h us u al s o cial & 
f u n cti o n al acti vities 
Disfi g uri n g c h a n ges  
N A  
                                                          
4  Defi niti o n: A dis or d er c h aracterize d b y fat l oss i n t h e fac e, e xtre mities, a n d b utt o c ks.  
9 0 of 1 3 6

E n d ocri ne a n d Meta b olic 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 - J ul y 2 0 1 7 
Pa ge 1 1 
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Li p o h y pertr o p h y 5  
Detecta ble b y st u d y 
p artici p a nt, 
care gi ver, or 
p h ysicia n A N D 
C a usi n g n o or 
mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O b vi o us o n vis u al 
i ns p ecti o n A N D 
C a usi n g greater t h a n 
mi ni m al i nterfere n ce 
wit h us u al s o cial & 
f u n cti o n al acti vities 
D isfi g uri n g c h a n ges  
N A  
                                                          
5  Defi niti o n: A dis or d er c h aracterize d b y a b n or m al fat acc u m ulati o n o n t h e b ac k of t h e n ec k, breasts, a n d a b d o m e n.  
9 1 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 1 2 
G astr oi nt esti nal  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
A n ore xi a  
L oss of a p p etite 
wit h o ut d ecreas e d 
oral i nta ke  
L oss of a p p etite 
ass o ciate d wit h 
d ecreas e d oral i nta ke 
wit h o ut si g nifica nt 
wei g ht l oss  
L oss of a p p etite 
ass o ciate d wit h 
si g nifica nt wei g ht 
l oss 
Life -t hreate ni n g 
c o ns e q u e n ces O R 
A g gressi ve i nter ve nti o n 
i n dicate d (e. g., t u b e 
fee di n g, t otal p are nteral 
n utriti o n)  
As cites  
N o s y m pt o ms  
S y m pt o ms A N D  
I nter ve nti o n 
i n dicate d (e. g., 
di uretics, t h era p e utic 
p arace ntesis)  
S y m pt o ms rec ur or 
p ersist d es pite 
i nter ve nti o n 
Life -t hreate ni n g 
c o ns e q u e n ces 
Bl o ati n g or Diste nsi o n  
Re p ort o nly o n e  
S y m pt o ms ca usi n g 
n o or mi ni m al 
i nterfere n ce wit h 
us u al s o ci al & 
f u n cti o n al acti vities 
S y m pt o ms ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
S y m pt o ms ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
N A  
C h ole c ystitis  
N A  
S y m pt o ms A N D  
Me dical i nter v e nti o n 
i n dicate d 
R a di ol o gic, 
e n d os c o pic, or 
o p erati ve 
i nter ve nti o n i n dicate d 
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
s e psis, p erf orati o n)  
C o nsti p ati o n  
N A  
Persiste nt 
c o nsti p ati o n 
re q uiri n g re g ular us e 
of dietar y 
m o dificati o ns, 
la x ati ves, or e n e m as  
O bsti p ati o n wit h 
m a n u al e vac u ati o n 
i n dicate d 
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
o bstru cti o n)  
Di arr he a  
≥ 1 ye ar of a g e  
Tra nsie nt or 
i nter mitte nt 
e pis o d es of 
u nf or m e d st o ols O R  
I n creas e of ≤ 3 
st o ols o ver b as eli n e 
p er 2 4 -h o ur p eri o d  
Persiste nt e pis o d es 
of u nf or m e d t o 
water y st o ols O R  
I n creas e of 4 t o  6 
st o ols o ver b as eli n e 
p er 2 4 -h o ur p eri o d  
I n creas e of  ≥ 7 
st o ols p er 2 4-h o ur 
p eri o d O R  I V fl ui d 
re place m e nt 
i n dicate d 
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
h y p ote nsi ve s h o c k)  
< 1 ye ar of a g e  
Li q ui d st o ols ( m ore 
u nf or m e d t h a n 
us u al) b ut us u al 
n u m b er of st o ols  
Li q ui d st o ols wit h 
i n creas e d n u m b er of 
st o ols O R  Mil d 
d e h y drati o n  
Li q ui d st o ols wit h 
m o d erate d e h y drati o n  
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
li q ui d st o ols res ulti n g i n 
s e vere d e h y drati o n, 
h y p ote nsi ve s h o c k)  
D ys p h a gi a or  
O d y n o p h a gi a  
Re p ort o nly o n e a n d 
s p ecify l o c ati o n 
S y m pt o ms b ut a ble 
t o eat us u al diet 
S y m pt o ms ca usi n g 
altere d dietar y i nta ke 
wit h  n o  i nter ve nti o n 
i n dicate d 
S y m pt o ms ca usi n g 
s e verel y altere d 
dietar y i nta ke wit h 
i nter ve nti o n i n dicate d 
Life -t hreate ni n g 
re d u cti o n i n oral i nta k e 
G astr oi ntesti n al 
Blee di n g  
N ot re q uiri n g 
i nter ve nti o n ot h er 
t h a n ir o n 
s u p ple m e nt 
E n d os c o pic  
i nter ve nti o n 
i n dicate d 
Tra nsf usi o n i n dicate d  
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
h y p ote nsi ve s h o c k)  
9 2 of 1 3 6

Gastr oi nt esti nal  
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 - J ul y 2 0 1 7 
Pa ge 1 3 
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
M uc ositis or St o m atitis  
Re p ort o nly o n e a n d 
s p ecify l o c ati o n 
M u c os al er yt h e m a  
Patc h y 
ps e u d o m e m bra n es or 
ulcerati o ns  
C o nfl u e nt 
ps e u d o m e m bra n es  or 
ulcerati o ns O R 
M u c os al blee di n g 
wit h mi n or tra u m a  
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
as pirati o n, c h o ki n g) O R 
Tiss u e n ecr osis O R 
Diff us e s p o nta n e o us 
m u c os al blee di n g  
N a us e a  
Tra nsie nt ( < 2 4 
h o urs) or 
i nter mitte nt A N D  
N o or mi ni m al 
i nterfere n ce wit h 
oral i nta ke  
Persiste nt n a us ea 
res ulti n g i n 
d ecreas e d oral i nta ke 
f or 2 4 t o 4 8 h o urs 
Persiste nt n a us ea 
res ulti n g i n mi ni m al 
oral i nta ke f or > 4 8 
h o urs O R  
R e h y drati o n 
i n dicate d (e. g., I V 
fl ui ds) 
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
h y p ote nsi ve s h o c k)  
P a ncre atitis  
N A  
S y m pt o ms wit h 
h os pitalizati o n n ot 
i n dicate d 
S y mpt o ms wit h 
h os pit ali zati o n 
i n di cat e d  
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
circ ulat or y fail ure, 
h e m orr h a ge, s e psis)  
P erf or ati o n  
(c ol o n or rect u m) 
N A  
N A  
I nter ve nti o n 
i n dicate d 
Life -t hreate ni n g 
c o ns e q u e n ces 
P r octitis  
R ectal dis c o mf ort 
wit h n o i nter ve nti o n 
i n dicate d 
S y m pt o ms ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O R  Me dical 
i nter ve nti o n 
i n dicate d  
S y m pt o ms ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
O R  O p erati v e 
i nter ve nti o n i n dicate d  
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
p erf orati o n)  
Rect al Dis c h ar g e  
Visi ble dis c h ar ge  
Dis c h ar ge re q uiri n g 
t h e us e of p a ds 
N A  
N A  
V o miti n g  
Tra nsie nt or  
i nter mitte nt A N D  
N o or mi ni m al 
i nterfere n ce wit h 
oral i nta ke  
Fre q u e nt e pis o d es 
wit h n o or mil d 
d e h y drati o n  
Persiste nt v o miti n g 
res ulti n g i n 
ort h ostatic 
h y p ote nsi o n O R  
A g gressi ve 
re h y drati o n i n dicate d 
(e. g., I V fl ui ds) 
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
h y p ote nsi ve s h o c k)  
 
9 3 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 1 4 
M us c ul os k elet al  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Art hr al gi a  
J oi nt p ai n ca usi n g 
n o or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
J oi nt p ai n ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
J oi nt p ai n ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
Dis a bli n g j oi nt p ai n 
ca usi n g i n a bilit y t o 
p erf or m b asic s elf -care 
f u n cti o ns 
Art hritis  
Stiff n ess or j oi nt 
s welli n g ca usi n g n o 
or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
Stiff n ess or j oi nt 
s welli n g ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
Stiff n ess or j oi nt 
s welli n g ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
Dis a bli n g j oi nt stiff n ess 
or s welli n g ca usi n g 
i n a bilit y t o p erf or m 
b asic s elf -care f u n cti o ns  
M y al gi a  ( ge n eralize d) 
M us cle p ai n 
ca usi n g n o or 
mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
M us cle p ai n ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
M us cle p ai n ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
Dis a bli n g m us cle p ai n 
ca usi n g i n a bilit y t o 
p erf or m b asic s elf -care 
f u n cti o ns 
Oste o necr osis  
N A  
N o s y m pt o ms b ut 
wit h ra di o gra p hic 
fi n di n gs A N D  N o 
o p erati ve 
i nter ve nti o n 
i n dicate d 
B o n e p ai n wit h 
ra di o gra p hic fi n di n gs 
O R  O p erati v e 
i nter ve nti o n i n dicate d 
Dis a bli n g b o n e p ai n 
wit h ra di o gra p hic 
fi n di n gs ca usi n g 
i n a bilit y t o p erf or m 
b asic s elf -care f u n cti o ns  
Oste o pe ni a
6  
≥ 3 0 ye ars of a g e  
B M D t -s c ore  
-2. 5 t o - 1 
N A  
N A  
N A  
   < 3 0 ye ars of a g e  
B M D z -s c ore  
-2 t o - 1 
N A  
N A  
N A  
Oste o p or osis 6 
≥ 3 0 ye ars of a g e  
N A  
B M D t -s c ore < -2. 5  
Pat h ol o gic fract ure 
(e. g., c o m pressi o n 
fract ure ca usi n g l oss 
of verte bral h ei g ht)  
Pat h ol o gic fract ure 
ca usi n g life-t hreate ni n g 
c o ns e q u e n ces  
< 3 0 ye ars of a g e  
N A  
B M D z -s c ore < - 2 
Pat h ol o gic fract ure 
(e. g., c o m pressi o n 
fract ure ca usi n g l oss 
of verte bral h ei g ht)  
Pat h ol o gic fract ure 
ca usi n g life-t hreate ni n g 
c o ns e q u e n ces  
 
                                                          
6  B M D t a n d z s c ores ca n b e f o u n d i n: Ka nis  J A o n b e h alf of t h e W orl d Healt h Or ga nizati o n Scie ntific Gr o u p ( 2 0 0 7). Ass ess m e nt 
of oste o p or osis at t h e pri m ar y h ealt h -care le vel. Te c h nical R e p ort. W orl d Healt h Or ga nizati o n C olla b orati n g C e ntre f or 
Meta b olic B o n e Dis eas es, U ni versit y of S h effiel d, U K. 2 0 0 7: Pri nte d b y t h e U ni versit y of S h effiel d.  
9 4 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 1 5 
N e ur ol o gic  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Ac ute C N S Is c he mi a  
N A  
N A  
Tra nsie nt is c h e mic 
attac k  
C ere bral vas c ular  
acci d e nt (e. g., str o k e 
wit h n e ur ol o gical 
d eficit)  
Altere d M e nt al St at us  
(f or De m e ntia, s ee 
C o g niti ve, Be h a vi or al, or 
Att e nti o n al Dist ur b a n ce  
b el o w)  
C h a n ges ca usi n g n o 
or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
Mil d let h ar g y or 
s o m n ole n ce ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
C o nfusi o n, m e m or y 
i m p air m e nt, let h ar g y, 
or  s o m n ole n ce 
ca usi n g i n a bilit y t o 
p erf or m us u al s o cial 
& f u n cti o n al 
acti vities  
Deliri u m O R  
O bt u n d ati o n O R  
C o m a  
At a xi a  
S y m pt o ms ca usi n g 
n o or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O R  N o s y m pt o ms 
wit h ata xia d etecte d 
o n e x a mi n ati o n  
S y m pt o ms ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
S y m pt o ms ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities  
Dis a bli n g s y m pt o ms 
ca usi n g i n a bilit y t o 
p erf or m b asic s elf -care 
f u n cti o ns 
C o g niti v e, B e h a vi or al, 
or Atte nti o n al 
Dist ur b a nce  (i n cl u d es 
d e m e ntia a n d atte nti o n 
d eficit dis or d er)  
S p ecify t y p e, if a p pli c a ble  
Dis a bilit y ca usi n g 
n o or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O R  S p ecialize d 
res o urces n ot 
i n dicate d 
Dis a bilit y ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O R  S p ecialize d 
res o urces o n p art-
ti m e b asis i n dicate d 
Dis a bilit y ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
O R  S p ecialize d 
res o urces o n a f ull-
ti m e b asis i n dicate d 
Dis a bilit y ca usi n g 
i n a bilit y t o p erf or m 
b asic s elf -care f u n cti o ns 
O R  I nstit uti o n alizati o n 
i n dicate d 
D e v el o p me nt al Del a y  
< 1 8 ye ars of a g e  
 
S p ecify t y p e, if a p pli c a ble  
Mil d d e vel o p m e ntal 
d ela y, eit h er m ot or 
or c o g niti ve, as 
d eter mi n e d b y 
c o m p aris o n wit h a 
d e vel o p m e ntal 
s cree ni n g t o ol 
a p pr o priate f or t h e 
s etti n g  
M o d erate 
d e vel o p m e ntal d ela y, 
eit h er m ot or or 
c o g niti ve, as 
d eter mi n e d b y 
c o m p aris o n wit h a 
d e vel o p m e ntal 
s cree ni n g t o ol 
a p pr o priate f or t h e 
s etti n g  
Se vere 
d e vel o p m e ntal d ela y, 
eit h er m ot or or 
c o g niti ve, as 
d eter mi n e d b y 
c o m p aris o n wit h a 
d e vel o p m e ntal 
s cree ni n g t o ol 
a p pr o priate f or t h e 
s etti n g  
De vel o p m e ntal 
re gressi o n, eit h er m ot or 
or c o g niti ve, as 
d eter mi n e d b y 
c o m p aris o n wit h a 
d e vel o p m e ntal 
s cree ni n g t o ol 
a p pr o priate f or t h e 
s etti n g 
He a d a c he  
S y m pt o ms ca usi n g 
n o or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
S y m pt o ms ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities  
S y m pt o ms ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities  
S y m pt o ms ca usi n g 
i n a bilit y t o p erf or m 
b asic s elf -care fu n cti o ns 
O R  H os pitalizati o n 
i n dicate d  O R  Hea d ac h e 
wit h si g nifica nt 
i m p air m e nt of alert n ess 
or ot h er n e ur ol o gic 
f u n cti o n  
9 5 of 1 3 6

Ne ur ol o gic  
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 - J ul y 2 0 1 7 
Pa ge 1 6 
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Ne ur o m us c ul ar 
We a k ness  (i n cl u d es 
m y o p at h y a n d 
n e ur o p at h y)  
S p ecify t y p e, if a p pli c a ble  
Mi ni m al m us cle 
wea k n ess ca usi n g 
n o or mi ni m al 
interfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O R  N o s y m pt o ms 
wit h d ecreas e d 
stre n gt h o n 
e x a mi n ati o n  
M us cle wea k n ess 
ca usi n g gr eater t h a n 
mi ni m al i nterfere n ce 
wit h us u al s o cial & 
f u n cti o n al acti vities 
M us cle wea k n ess 
ca usi n g i n a bilit y t o 
p erf or m us u al s o cial 
& f u n cti o n al 
acti vities  
Dis a bli n g m us cle 
wea k n ess ca usi n g 
i n a bilit y t o p erf or m 
b asic s elf -care f u n cti o ns 
O R R es pirat or y m us cle 
wea k n ess i m p airi n g 
ve ntilati o n  
Ne ur os e ns or y 
Alter ati o n  (i n cl u d es 
p arest h esia a n d p ai nf ul 
n e ur o p at h y)  
S p ecify t y p e, if  a p pli c a ble  
Mi ni m al p arest h esia 
ca usi n g n o or 
mi ni m al  
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O R  N o s y m pt o ms 
wit h s e ns or y 
alterati o n o n 
e x a mi n ati o n  
Se ns or y alterati o n or 
p arest h esia ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities  
Se ns or y alterati o n or 
p arest h esia ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
Dis a bli n g s e ns or y 
alterati o n or  p are st h esia 
ca usi n g i n a bilit y t o 
p erf or m b asic s elf -care 
f u n cti o ns 
Seiz ures  
Ne w O ns et Seiz ur e  
≥ 1 8 ye ars of a g e  
N A  
N A  
1 t o  3 s eiz ures  
Pr ol o n ge d a n d re p etiti ve 
s eiz ures (e. g., stat us 
e pile ptic us) O R  
Diffic ult t o c o ntr ol (e. g., 
refract or y e pile ps y) 
< 1 8 ye ars of a g e 
(i n cl u d es n e w or pr e-
existi n g fe brile 
s eiz ur es) 
Seiz ure lasti n g < 5 
mi n utes wit h < 2 4 
h o urs p ostictal state  
Seiz ure lasti n g 5 t o < 
2 0 mi n utes wit h  
< 2 4 h o urs p ostictal 
state 
Seiz ure lasti n g ≥ 2 0 
mi n utes O R  > 2 4 
h o urs p ostictal state  
Pr ol o n ge d a n d re p etiti ve 
s eiz ures (e. g., stat us 
e pile ptic us) O R  
Diffic ult t o c o ntr ol (e. g., 
refract or y e pile ps y) 
Pr e -e xisti n g Seiz ur e 
N A  
I n creas e d fre q u e n c y 
fr o m pre vi o us le vel 
of c o ntr ol wit h o ut 
c h a n ge i n s eiz ure 
c h aracter  
C h a n ge i n s eiz ure 
c h aracter eit h er i n 
d urati o n or q u alit y  
(e. g., s e verit y or  
f o calit y) 
Pr ol o n ge d a n d re p etiti ve 
s eiz ures (e. g., stat us 
e pile ptic us) O R  
Diffic ult t o c o ntr ol (e. g., 
refract or y e pile ps y) 
S y nc o pe  
Near s y n c o p e 
wit h o ut l oss of 
c o ns ci o us n ess (e. g., 
pre -s y n c o p e) 
L oss of 
c o ns ci o us n ess wit h 
n o i nter ve nti o n 
i n dicate d 
L oss of 
c o ns ci o us n ess A N D  
H os pitalizati o n or 
i nter ve nti o n re q uire d 
N A  
 
9 6 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 1 7 
Pr e g na nc y, P uer p eri u m, a n d P eri nat al  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Still birt h (re p ort usi n g 
m ot h er’s p artici p a nt I D)  
Re p ort o nly o n e  
N A  
N A  
Fetal d eat h o cc urri n g 
at ≥ 2 0 wee ks 
gestati o n  
N A  
P reter m  Birt h  (re p ort 
usi n g m ot h er’s 
p artici p a nt I D)  
Li ve birt h  at 3 4 t o  
< 3 7 wee ks  
gestati o n al  a ge  
Li ve birt h  at 2 8 t o  
< 3 4 wee ks 
gestati o n al  a ge  
Li ve birt h  at 2 4 t o  
< 2 8 wee ks 
gestati o n al  a ge  
Li ve birt h at < 2 4 w ee ks 
gestati o n al a ge  
S p o nt a ne o us A b orti o n 
or Mis c arri a g e 7  (re p ort 
usi n g m ot h er’s 
p artici p a nt I D)  
Re p ort o nly o n e  
C h e mical 
pre g n a n c y  
U n c o m plicate d 
s p o nta n e o us a b orti o n 
or mis carria ge  
C o m plicate d 
s p o nta n e o us a b orti o n 
or mis carria ge  
N A  
 
                                                          
7  Defi niti o n:  A  pre g n a n c y l oss o cc urri n g at < 2 0 wee ks gestati o n al a ge.  
9 7 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 1 8 
Ps yc hiatric  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
I ns o m ni a  
Mil d diffic ult y 
falli n g aslee p, 
sta yi n g aslee p, or 
wa ki n g u p earl y  
ca usi n g n o or 
mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities  
M o d erate diffic ult y 
falli n g aslee p, 
sta yi n g aslee p, or 
wa ki n g u p earl y  
ca usi n g m ore t h a n 
mi ni m al i nterfere n ce 
w it h us u al s o cial & 
f u n cti o n al acti vities 
Se vere diffic ult y 
falli n g aslee p, sta yi n g 
aslee p, or wa ki n g u p 
earl y  ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
re q uiri n g i nter ve nti o n 
or h os pitalizati o n  
N A  
Ps yc hi atric Dis or ders  
(i n cl u d es a n xiet y, 
d e pressi o n, m a nia, a n d  
ps y c h osis)  
S p ecify dis or d er  
S y m pt o ms wit h 
i nter ve nti o n n ot 
i n dicate d O R  
Be h a vi or ca usi n g 
n o or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
S y m pt o ms wit h 
i nter ve nti o n 
i n dicate d O R  
Be h a vi or ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
S y m pt o ms wit h 
h os pitalizati o n 
i n dicate d O R  
Be h a vi or ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
Threate ns h ar m t o s elf 
or ot h ers O R  Ac ute 
ps y c h osis O R  Be h a vi or 
ca usi n g i n a bilit y t o 
p erf or m b asic s elf -care 
f u n cti o ns 
S uici d al I de ati o n or 
Atte m pt  
Re p ort o nly o n e  
Pre o cc u pie d wit h 
t h o u g hts of d eat h 
A N D  N o wis h t o 
kill o n es elf  
Pre o cc u pie d wit h 
t h o u g hts of d eat h 
A N D  Wis h t o kill 
o n es elf wit h n o 
s p ecific pla n or 
i nte nt 
Th o u g hts of killi n g 
o n es elf wit h p artial 
or c o m plete pla ns b ut 
n o atte m pt t o d o s o 
O R H os pitalizati o n 
i n dicate d 
S uici d e atte m pte d  
 
9 8 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 1 9 
R es pir at or y  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Ac ute B r o nc h os p as m  
F orce d e x pirat or y 
v ol u m e i n 1 s ec o n d 
or p ea k fl o w 
re d u ce d t o  
≥ 7 0 t o < 8 0 % O R 
Mil d s y m pt o ms 
wit h i nter ve nti o n 
n ot i n dicate d  
F orce d e x pirat or y 
v ol u m e i n 1 s ec o n d 
or p ea k fl o w 5 0 t o  
< 7 0 % O R  S y m pt o ms 
wit h i nter ve nti o n 
i n dicate d O R  
S y m pt o ms ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
F orce d e x pirat or y 
v ol u m e i n 1 s ec o n d 
or p ea k fl o w 2 5 t o  
<  5 0 % O R  
S y m pt o ms ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
F orce d e x pirat or y 
v ol u m e i n 1 s ec o n d or 
p ea k fl o w < 2 5 % O R  
Life -t hreate ni n g 
res pirat or y or 
h e m o d y n a mic 
c o m pro mis e O R  
I nt u b ati o n  
D ys p ne a or Res pir at or y 
Distress  
Re p ort o nly o n e  
D ys p n ea o n 
e x erti o n wit h n o or 
mi ni m al  
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
O R  W h eezi n g O R 
Mi ni m al i n creas e i n 
res pirat or y rate f or 
a ge  
D ys p n ea o n e x erti o n 
ca usi n g gr eater t h a n 
mi ni m al i nterfere n ce 
wit h us u al s o cial & 
f u n cti o n al acti vities 
O R  Nas al flari n g O R 
I nterc ostal retr acti o ns 
O R  P uls e o xi m etr y 
9 0 t o < 9 5 %  
D ys p n ea at rest 
ca usi n g i n a bilit y t o 
p erf or m us u al s o cial 
& f u n cti o n al 
acti vities O R  P uls e 
o xi m etr y < 9 0 %  
R es pirat or y fail ure wit h 
ve ntilat or s u p p ort 
i n dicate d (e. g., C P A P, 
B P A P, i nt u b ati o n)  
 
9 9 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 2 0 
S e ns or y 
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4 
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
He ari n g L oss  
≥ 1 2 ye ars of a g e  
 
N A  
 
Heari n g ai d or 
i nter ve nti o n n ot 
i n dicate d 
 
Heari n g ai d or 
i nter ve nti o n i n dicate d 
 
Pr of o u n d bilateral 
h eari n g l oss ( > 8 0 d B at 
2 k Hz a n d a b o ve) O R  
N o n -s er vicea ble h eari n g 
(i.e., > 5 0 d B a u di o gr a m 
a n d < 5 0 % s p eec h 
dis cri mi n ati o n)  
< 1 2 ye ars of a g e 
( b as e d o n a 1, 2, 3, 4, 
6 a n d 8 k Hz 
a u di o gr a m)  
> 2 0 d B h eari n g 
l oss at  ≤ 4 k Hz 
> 2 0 d B h eari n g l oss 
at > 4 k Hz  
> 2 0 d B h eari n g l oss 
at  ≥ 3 k Hz i n o n e ear 
wit h a d diti o n al 
s p eec h la n g u a ge 
relate d s er vices 
i n dicate d ( w h ere 
a vaila ble) O R  
Heari n g l oss 
s ufficie nt t o i n dicate 
t h era p e utic 
i nter ve nti o n, 
i n cl u di n g h eari n g 
ai ds  
A u di ol o gic i n dica ti o n 
f or c o c hlear i m pla nt a n d 
a d diti o n al s p eec h -
la n g u a ge relate d 
s er vices i n dicate d 
( w h ere a vaila ble) 
Ti n nit us  
S y m pt o ms ca usi n g 
n o or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
wit h i nter ve nti o n 
n ot i n dicate d  
S y m pt o ms ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
wit h i nter ve nti o n 
i n dicate d 
S y m pt o ms ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
N A  
U v eitis  
N o s y m pt o ms A N D  
Detecta ble o n 
e x a mi n ati o n  
A nteri or u veitis wit h 
s y m pt o ms O R  
Me dical  i nter v e nti o n 
i n dicate d 
P osteri or or p a n -
u veitis O R  O p erati ve 
i nter ve nti o n i n dicate d 
Dis a bli n g vis u al l oss i n 
affecte d e y e(s)  
Verti g o  
Verti g o ca usi n g n o 
or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
Verti g o ca usi n g 
greater t h a n mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
Verti g o ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
Dis a bli n g verti g o 
ca usi n g i n a bilit y t o 
p erf or m b asic s elf -care 
f u n cti o ns 
Vis u al C h a n g es  
(ass ess e d fr o m b as eli n e) 
Vis u al c h a n ges 
ca usi n g n o or 
mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
Vis u al c h a n ges 
ca usi n g gr eater t h a n 
mi ni m al i nterfere n ce 
wit h us u al s o cial & 
f u n cti o n al acti vities 
Vis u al c h a n ges 
ca usi n g i n a bilit y t o 
p erf or m us u al s o cial 
& f u n cti o n al 
acti vities  
Dis a bli n g vis u al l oss i n 
affecte d e y e(s)  
 
1 0 0 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 2 1 
S yst e mic  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Ac ute Aller gic 
Re acti o n  
L o calize d urticaria 
( w h eals) wit h n o 
m e dical i nter ve nti o n 
i n dicate d 
L o calize d urticaria 
wit h i nter ve nti o n 
i n dicate d O R  Mil d 
a n gi o e d e m a wit h 
n o i nter ve nti o n 
i n dicate d 
Ge n eralize d urticaria 
O R  A n gi o e d e m a wit h 
i nter ve nti o n i n dicate d 
O R  Sy m pt o ms of 
mil d br o n c h os p as m  
Ac ute a n a p h yla xis O R  
Life -t hreate ni n g 
br o n c h os p as m O R 
Lar y n geal e d e m a  
C hills  
S y m pt o ms ca usi n g n o 
or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
S y m pt o ms ca usi n g 
greater t h a n 
mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities  
S y m pt o ms ca usi n g 
i n a bilit y t o p erf orm 
us u al s o cial & 
f u n cti o n al acti vities 
N A  
C yt o ki ne Rele as e 
S y n dr o me 8  
Mil d si g ns a n d 
s y m pt o ms A N D  
Th era p y (i.e., 
a nti b o d y i nf usi o n)  
i nterr u pti o n n ot 
i n dicate d 
Th era p y (i.e., 
a nti b o d y i nf usi o n) 
i nterr u pti o n 
i n dicate d A N D  
R es p o n ds pr o m ptl y 
t o s y m pt o m atic 
treat m e nt O R  
Pr o p h ylactic 
m e dicati o ns 
i n dicate d f or ≤ 2 4 
h o urs  
Pr ol o n ge d s e vere 
si g ns a n d s y m pt o ms 
O R  R ec urre n ce of 
s y m pt o ms f oll o wi n g 
i nitial i m pr o ve m e nt 
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
re q uiri n g press or or 
ve ntilat o r s u p p ort) 
F ati g ue or M al ais e  
Re p ort o nly o n e  
S y m pt o ms ca usi n g n o 
or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
S y m pt o ms ca usi n g 
greater t h a n 
mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
S y m pt o ms ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
I n ca p acitati n g s y m pt o ms 
of fati g u e or m alais e 
ca usi n g i n a bilit y t o 
p erf or m b asic s elf -care 
f u n cti o ns 
F e v er  ( n o n-a xillar y 
te m p erat ures o nl y) 
3 8. 0 t o < 3 8. 6° C or  
1 0 0. 4 t o < 1 0 1. 5° F  
≥ 3 8. 6  t o < 3 9. 3° C  
or ≥ 1 0 1. 5 t o  
< 1 0 2. 7° F  
≥ 3 9. 3 t o < 4 0. 0° C or  
≥ 1 0 2. 7 t o < 1 0 4. 0° F  
≥ 4 0. 0° C or ≥ 1 0 4. 0° F  
P ai n 9  ( n ot ass o ciate d 
wit h st u d y a ge nt 
i njecti o ns a n d n ot 
s p ecifie d els e w h ere) 
S p ecify l o c ati o n  
Pai n ca usi n g n o or 
mi ni m al i nterfere n ce 
wit h us u al s o cial & 
f u n cti o n al acti vities 
Pai n ca usi n g 
greater t h a n 
mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities  
Pai n ca usi n g i n a bilit y 
t o p erf or m us u al 
s o cial & f u n cti o n al 
acti vities  
Dis a bli n g p ai n ca usi n g 
i n a bilit y t o p erf or m b asic 
s elf-care f u n cti o ns O R  
H os pitalizati o n i n dicate d  
                                                          
8  Defi niti o n: A dis or d er c h aracterize d b y n a us ea, h ea d ac h e, tac h y car dia, h y p ote nsi o n, ras h, a n d/ or s h ort n ess of breat h.  
9  F or p ai n ass o ciate d wit h i njecti o ns or i nf usi o ns, s ee t h e Sit e Re a cti o ns t o I njecti o ns a n d I nf usi o ns  s ecti o n ( p a ge 2 3).   
1 0 1 of 1 3 6

S yst e mic  
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 - J ul y 2 0 1 7 
Pa ge 2 2 
Ser u m Sic k ness 1 0  
Mil d si g ns a n d 
s y m pt o ms 
M o d erate si g ns a n d 
s y m pt o ms A N D 
I nter ve nti o n 
i n dicate d (e. g., 
a nti hista mi n es)  
Se vere si g ns a n d 
s y m pt o ms A N D  
Hi g h er le vel 
i nter ve nti o n i n dicate d 
(e. g., ster oi ds or I V 
fl ui ds) 
Life -t hreate ni n g 
c o ns e q u e n ces (e. g., 
re q uiri n g press or or 
ve ntilat or s u p p ort)  
U n der wei g ht 1 1  
> 5 t o 1 9 ye ars of 
a g e  
W H O B M I z-s c ore 
< -1 t o - 2 
W H O B MI z -s c ore 
< -2 t o  - 3 
W H O B MI z -s c ore  
< - 3 
W H O B MI z -s c ore  
< -3 wit h life -t hreate ni n g 
c o ns e q u e n ces 
2 t o 5 ye ars of a g e  
W H O W ei g ht -f or-
h ei g h t z-s c ore  
< -1 t o - 2 
W H O W ei g ht -f or-
h ei g ht z-s c ore  
< -2 t o - 3 
W H O W ei g ht -f or-
h ei g ht z -s c ore < - 3 
W H O W ei g ht -f or-h ei g ht 
z-s c ore < -3 wit h life -
t hreate ni n g c o ns e q u e n ces 
< 2 ye ars of a g e  
W H O W ei g ht -f or-
le n gt h z-s c ore  
< -1 t o - 2 
W H O W ei g ht -f or-
le n gt h z-s c ore  
< -2 t o  - 3 
W H O W ei g ht -f or-
le n gt h z-s c ore < - 3 
W H O W ei g ht -f or-le n gt h 
z-s c ore < -3 wit h life -
t hreate ni n g c o ns e q u e n ces 
U ni nte nti o n al 
Wei g ht L oss  
(e x cl u d es p ost p art u m 
wei g ht l oss)  
N A  
5 t o < 9 % l oss  i n 
b o d y wei g ht fr o m 
b as eli n e  
≥ 9 t o < 2 0 % l oss i n 
b o d y wei g ht fr o m 
b as eli n e  
≥ 2 0 % l oss i n b o d y 
wei g ht fr o m b as eli n e O R   
A g gressi ve i nter ve nti o n 
i n dicate d (e. g., t u b e 
fee di n g, t otal p are nteral 
n utriti o n)  
 
                                                          
1 0  Defi niti o n: A dis or d er c h aracterize d b y fe ver, art hral gia, m y al gia, s ki n er u pti o ns, l y m p h a d e n o p at h y, m ar ke d dis c o mf ort, a n d/ o r 
d ys p n ea.  
1 1  W H O refere n ce ta bles m a y b e access e d b y clic ki n g t h e d esire d a ge ra n ge or b y accessi n g t h e f oll o wi n g U R Ls:  
htt p:// w w w. w h o.i nt/ gr o wt href/ w h o 2 0 0 7 _ b mi _f or _ a ge/e n/ f or p artici p a nts > 5 t o 1 9 y ears of a ge a n d  
htt p:// w w w. w h o.i nt/c hil d gr o wt h/sta n d ar ds/c h art _ catal o g u e/e n/ f or t h os e ≤ 5 y ears of a ge.  
1 0 2 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 2 3 
Uri nar y  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Uri n ar y Tr act 
O bstr ucti o n  
N A  
Si g ns or s y m pt o ms 
of uri n ar y tract 
o bstru cti o n wit h o ut  
h y dr o n e p hr osis or 
re n al d ysf u n cti o n 
Si g ns or s y m pt o ms of 
uri n ar y tract 
o bstru cti o n wit h 
h y dr o n e p hr osis or 
re n al d ysf u n cti o n 
O bstr u cti o n ca usi n g 
life-t hreate ni n g 
c o ns e q u e n ces 
 
1 0 3 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 2 4 
Sit e Rea cti o ns t o I nj ecti o ns a n d I nf usi o ns 
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
I njecti o n Site P ai n or  
Te n der ness  
Re p ort o nly o n e  
Pai n or te n d er n ess 
ca usi n g n o or 
mi ni m al li mitati o n 
of us e of li m b  
Pai n or te n d er n ess 
ca usi n g gr eater t h a n 
mi ni m al li mitati o n of 
us e of li m b  
Pai n or te n d er n ess 
ca usi n g i n a bilit y t o 
p erf or m us u al s o cial 
& f u n cti o n al 
acti vities  
Pai n or te n d er n ess 
ca usi n g i n a bilit y t o 
p erf or m b asic s elf -care 
f u n cti o n O R 
H os pitalizati o n 
i n dicate d 
I njecti o n Site E r yt he m a 
or Re d ness 1 2  
Re p ort o nly o n e  
> 1 5 ye ars of a g e  
 
2. 5 t o < 5 c m i n 
dia m eter O R  6. 2 5 t o 
< 2 5 c m 2  s urface 
area A N D  
S y m pt o ms ca usi n g 
n o or mi ni m al 
i nterfere n ce wit h 
us u al s o cial & 
f u n cti o n al acti vities 
≥ 5 t o < 1 0 c m i n 
dia m eter O R  ≥ 2 5  t o 
< 1 0 0 c m 2  s urface 
area O R S y m pt o ms 
ca usi n g gr eater t h a n 
mi ni m al i nterfere n ce 
wit h us u al s o cial & 
f u n cti o n al acti vities 
≥ 1 0 c m i n dia m eter 
O R  ≥ 1 0 0 c m 2  
s urface area O R  
Ulcerati o n O R  
Sec o n d ar y i nfecti o n 
O R  P hle bitis O R  
Sterile a bs cess O R  
Drai n a ge O R  
S y m pt o ms ca usi n g 
i n a bilit y t o p erf or m 
us u al s o cial & 
f u n cti o n al acti vities 
P ote ntiall y life -
t hreate ni n g 
c o ns e q u e n ces (e. g., 
a b s cess, e xf oliati ve 
d er m atitis, n ecr osis 
i n v ol vi n g d er mis or 
d ee p er tiss u e)  
≤ 1 5 ye ars of a g e  
≤ 2. 5 c m i n 
dia m eter  
> 2. 5 c m i n dia m eter 
wit h < 5 0 % s urface 
area of t h e e xtre mit y 
s e g m e nt i n v ol v e d 
(e. g., u p p er ar m or 
t hi g h) 
≥ 5 0 % s urface area 
of t h e e xtre mit y 
s e g m e nt i n v ol v e d 
(e. g., u p p er ar m or 
t hi g h) O R Ulcer ati o n 
O R Sec o n d ary 
i nfecti o n O R  
P hle bitis O R Sterile 
a bs cess O R  Drai n a ge  
P ote ntiall y life -
t hreate ni n g 
c o ns e q u e n ces (e. g., 
a bs cess, e xf oliati ve 
d er m atitis, n ecr osis 
i n v olvi n g d er mis or 
d ee p er tiss u e)  
I njecti o n Site 
I n d ur ati o n o r S welli n g 
Re p ort o nly o n e  
> 1 5 ye ars of a g e  
Sa m e as f or 
I njecti o n Site 
E r yt he m a or 
Re d ness,  > 1 5 
ye ars of a g e 
Sa m e as f or 
I njecti o n Site 
E r yt he m a or 
Re d ness,  > 1 5 ye ars 
of a g e  
Sa m e as f or 
I njecti o n Site  
E r yt he m a or 
Re d ness,  > 1 5 ye ars 
of a g e  
Sa m e as f or I njecti o n 
Site  E r yt he m a or 
Re d ness,  > 1 5 ye ars of 
a g e  
≤ 1 5 ye ars of a g e  
Sa m e as f or 
I njecti o n Site 
E r yt he m a or 
Re d ness,  ≤ 1 5 ye ars 
of a g e  
Sa m e as f or 
I njecti o n Site 
E r yt he m a or 
Re d ness,  ≤ 1 5 ye ars 
of a g e  
Sa m e as f or 
I njecti o n Site 
E r yt he m a or 
Re d ness,  ≤ 1 5 ye ars 
of a g e  
Sa m e as f or I njecti o n 
Site  E r yt he m a or 
Re d ness,  ≤ 1 5 ye ars of 
a g e  
I njecti o n Site P r urit us   
 
Itc hi n g l o calize d t o 
t h e i njecti o n site 
t h at is relie ve d 
s p o nta n e o usl y or i n 
< 4 8 h o urs of 
treat m e nt  
Itc hi n g b e y o n d t h e 
i njecti o n site t h at is 
n ot ge n eralize d O R 
Itc hi n g l o calize d t o 
t h e i njecti o n site 
re q uiri n g ≥ 4 8 h o urs 
treat m e nt  
Ge n eralize d itc hi n g 
ca usi n g i n a bilit y t o 
p erf or m us u al s o cial 
& f u n cti o n al 
acti vities  
N A  
                                                          
1 2 I njecti o n Site Er yt h e m a or R e d n ess s h o ul d b e e val u ate d a n d gra d e d usi n g t h e greatest si n gle dia m eter or m eas ure d s urface area. 
1 0 4 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 2 5 
L a b or at ory Val ues *  
C he mistries  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Aci d osis  
N A  
p H ≥ 7. 3  t o < L L N 
p H < 7. 3 wit h o ut lif e -
t hreate ni n g 
c o ns e q u e n ces 
p H < 7. 3 wit h life -
t hreate ni n g 
c o ns e q u e n ces 
Al b u mi n, L o w  
( g/ d L; g/ L ) 
3. 0 t o < L L N  
3 0  t o < L L N  
≥ 2. 0 t o < 3. 0  
≥ 2 0  t o < 3 0  
< 2. 0  
< 2 0  
N A  
Al k ali ne P h os p h at as e,  
Hi g h  
1. 2 5  t o < 2. 5  
x U L N  
2. 5  t o < 5. 0 x U L N  
5. 0 t o < 1 0. 0 x U L N  
≥ 1 0. 0 x U L N  
Al k al osis  
N A  
p H > U L N t o ≤ 7. 5  
p H > 7. 5 wit h o ut lif e -
t hreate ni n g 
c o ns e q u e n ces 
p H > 7. 5 wit h life -
t hreate ni n g 
c o ns e q u e n ces  
A L T  or  S G P T, Hi g h  
Re p ort o nly o n e  
1. 2 5  t o < 2. 5  
x U L N  
2. 5 t o  < 5. 0 x U L N  
5. 0  t o < 1 0. 0 x U L N  
≥ 1 0. 0 x U L N  
A m yl as e ( P a ncre atic) or 
A m yl as e ( T ot al), Hi g h  
Re p ort o nly o n e  
1. 1  t o < 1. 5 x U L N  
1. 5  t o < 3. 0 x U L N  
3. 0  t o < 5. 0 x U L N  
≥ 5. 0 x U L N  
A S T or S G O T, Hi g h  
Re p ort o nly o n e  
1. 2 5  t o < 2. 5  
x U L N  
2. 5  t o  < 5. 0 x U L N  
5. 0  t o < 1 0. 0 x U L N  
≥ 1 0. 0 x U L N  
Bic ar b o n at e, L o w  
(m E q/ L ; m m ol/ L ) 
1 6. 0 t o <  L L N  
1 6. 0 t o <  L L N  
1 1. 0   t o < 1 6. 0  
1 1. 0  t o < 1 6. 0  
8. 0  t o < 1 1. 0  
8. 0  t o < 1 1.0  
< 8. 0  
< 8. 0  
Bilir u bi n  
Dir ect Bilir u bi n 1 3 , 
Hi g h  
> 2 8 d a ys of a g e  
 
 
N A  
 
N A  
 
> U L N  wit h ot h er 
si g ns a n d s y m pt o ms 
of h e p at ot o xicit y.  
 
> U L N wit h life -
t hreate ni n g 
c o ns e q u e n ces (e. g., 
si g ns a n d s y m pt o ms of 
li ver fail ure) 
≤ 2 8 d a ys of a g e  
U L N t o ≤ 1 m g/ d L  
> 1 t o ≤ 1. 5 m g/ d L  
> 1. 5 t o ≤ 2 m g/ d L  
> 2 m g/ d L  
T ot al Bilir u bi n, Hi g h  
> 2 8 d a ys  of a g e  
 
1. 1 t o < 1. 6 x U L N  
 
1. 6 t o < 2. 6 x U L N  
 
2. 6 t o < 5. 0 x U L N  
 
≥ 5. 0 x U L N   
≤ 2 8 d a ys of a g e  
See A p p e n di x A. 
Total Bilir u bi n f or 
Ter m a n d Preter m 
Ne o n ates  
See A p p e n di x A. 
Total Bilir u bi n f or 
Ter m a n d Preter m 
Ne o n ates  
See A p p e n di x A. 
Total Bilir u bi n  f or 
Ter m a n d Preter m 
Ne o n ates  
See A p p e n di x A. Total 
Bilir u bi n f or Ter m a n d 
Preter m Ne o n ates  
                                                          
* R e mi n d er: A n as y m pt o m atic a b n or m al la b orat or y fi n di n g wit h o ut a n acc o m p a n yi n g A E  s h o ul d n ot be re p orte d t o D AI D S i n a n 
e x p e dite d ti m e fra m e u nless it m eets pr ot o c ol-s p ecific re p orti n g re q uire m e nts. 
 
1 3  Direct bilir u bi n > 1. 5 m g/ d L i n a p artici p a nt < 2 8 d a ys of a ge s h o ul d b e gra d e d as gra d e 2, if < 1 0 % of t h e t otal bilir u bi n.  
1 0 5 of 1 3 6

C he mistries  
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 - J ul y 2 0 1 7 
Pa ge 2 6 
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
C alci u m, Hi g h  
( m g/ d L; m m ol/ L ) 
≥ 7 d a ys of a g e  
1 0. 6   t o < 1 1. 5  
2. 6 5  t o < 2. 8 8  
1 1. 5  t o < 1 2. 5  
2. 8 8  t o < 3. 1 3  
1 2. 5   t o < 1 3. 5  
3. 1 3  t o < 3. 3 8  
≥  1 3. 5  
≥  3. 3 8  
< 7 d a ys of a g e  
1 1. 5  t o < 1 2. 4  
2. 8 8  t o < 3. 1 0  
1 2. 4  t o < 1 2. 9  
3. 1 0  t o < 3. 2 3  
1 2. 9   t o < 1 3. 5  
3. 2 3  t o < 3. 3 8  
≥  1 3. 5  
≥  3. 3 8  
C alci u m (I o nize d), Hi g h  
( m g/ d L; m m ol/ L ) 
> U L N t o < 6. 0  
> U L N  t o < 1.5  
6. 0 t o < 6. 4  
1. 5 t o < 1. 6  
6. 4 t o < 7. 2  
1. 6 t o < 1. 8  
≥ 7. 2  
≥ 1. 8   
C alci u m, L o w  
( m g/ d L; m m ol/ L ) 
≥ 7 d a ys of a g e  
7. 8  t o < 8. 4  
1. 9 5  t o < 2. 1 0  
7. 0   t o < 7. 8  
1. 7 5  t o < 1. 9 5  
6. 1  t o < 7. 0  
1. 5 3  t o < 1. 7 5  
< 6. 1  
< 1. 5 3  
< 7 d a ys of a g e  
6. 5  t o < 7. 5  
1. 6 3  t o < 1. 8 8  
6. 0 t o < 6. 5  
1. 5 0  t o < 1. 6 3  
5. 5 0  t o < 6. 0  
1. 3 8  t o < 1. 5 0  
< 5. 5 0  
< 1. 3 8  
C alci u m  (I o nize d),  L o w  
( m g/ d L; m m ol/ L ) 
< L L N  t o 4. 0  
< L L N  t o 1. 0  
3. 6 t o < 4. 0  
0. 9 t o < 1. 0  
3. 2 t o < 3. 6  
0. 8 t o < 0. 9  
< 3. 2  
< 0. 8   
C ar di ac Tr o p o ni n I, 
Hi g h  
N A  
N A  
N A  
Le vels c o nsiste nt wit h 
m y o car dial i nfarcti o n 
or u nsta ble a n gi n a as 
d efi n e d b y t h e l o cal 
la b orat or y 
Cre ati ne Ki n as e,  Hi g h  
3 t o < 6 x U L N  
6 t o < 1 0 x U L N  
1 0  t o < 2 0 x U L N  
≥ 2 0  x U L N  
Cre ati ni ne, Hi g h  
* Re p ort o nly o n e  
1. 1 t o 1. 3 x U L N  
> 1. 3 t o 1. 8 x U L N 
O R  I n creas e t o 1. 3 t o 
< 1. 5 x p artici p a nt’s 
b as eli n e  
> 1. 8  t o < 3. 5  
x U L N O R  I n creas e 
t o 1. 5 t o < 2. 0 x 
p artici p a nt’s b as eli n e  
≥ 3. 5 x U L N O R  
I n creas e of  ≥ 2. 0 x 
p artici p a nt’s b as eli n e  
Cre ati ni ne Cle ar a nce
1 4  
or e G F R, L o w  
* Re p ort o nly o n e  
N A  
< 9 0 t o 6 0 ml/ mi n or 
ml/ mi n/ 1. 7 3 m 2   
O R  
1 0 t o < 3 0 % d ecre as e  
fr o m p artici p a nt’s  
b as eli n e  
< 6 0 t o 3 0 ml/ mi n or 
ml/ mi n/ 1. 7 3 m 2 
O R  
 3 0 t o < 5 0 % 
d ecreas e fr o m  
p artici p a nt’s  b as eli n e  
< 3 0 ml/ mi n or 
ml/ mi n/ 1. 7 3 m 2 
O R  
≥ 5 0 % d ecreas e fr o m 
p artici p a nt’s b as eli n e or 
dial ysis n ee d e d  
Gl uc os e  
( m g/ d L; m m ol/ L ) 
F asti n g, Hi g h  
 
 
1 1 0 t o 1 2 5 
6. 1 1 t o < 6. 9 5  
 
 
> 1 2 5 t o 2 5 0  
6. 9 5 t o < 1 3. 8 9  
 
 
 > 2 5 0 t o 5 0 0  
1 3. 8 9 t o < 2 7. 7 5  
 
 
≥  5 0 0  
≥ 2 7. 7 5  
N o n f asti n g, Hi g h 
1 1 6 t o 1 6 0 
6. 4 4 t o < 8. 8 9  
> 1 6 0 t o 2 5 0 
8. 8 9 t o < 1 3. 8 9  
> 2 5 0  t o 5 0 0  
1 3. 8 9  t o < 2 7.7 5  
≥  5 0 0  
≥ 2 7. 7 5  
                                                          
1 4  Us e t h e a p plica ble f or m ula (i.e., C o c kcr oft -Ga ult i n m L/ mi n or Sc h wartz, M D R D, C K D -E pi i n m L/ mi n/ 1. 7 3 m 2). Sites s h o ul d 
c h o os e t h e m et h o d d efi n e d i n t h eir st u d y a n d w h e n n ot s p ecifie d, us e t h e m et h o d m ost rele va nt t o t h e st u d y p o p ulati o n.  
  
* R e mi n d er: C h o os e t h e m e t h o d t h at s elects f or t h e hi g h er gra d e. 
1 0 6 of 1 3 6

C he mistries  
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 - J ul y 2 0 1 7 
Pa ge 2 7 
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Gl uc os e,  L o w  
( m g/ d L; m m ol/ L ) 
≥ 1 m o nt h of a g e  
5 5  t o 6 4  
3. 0 5  t o < 3. 5 5  
4 0  t o < 5 5  
2. 2 2  t o < 3.0 5  
3 0  t o < 4 0  
1. 6 7 t o < 2. 2 2  
< 3 0  
< 1. 6 7  
< 1 m o nt h of a g e  
5 0 t o 5 4  
2. 7 8  t o < 3.0 0  
4 0 t o < 5 0  
2. 2 2 t o < 2. 7 8  
3 0 t o  < 4 0  
1. 6 7 t o < 2. 2 2  
< 3 0  
< 1. 6 7  
L act at e, Hi g h  
U L N t o  < 2. 0  
x U L N wit h o ut 
aci d osis  
≥ 2. 0 x U L N wit h o ut 
aci d osis  
I n creas e d lactate wit h 
p H < 7. 3 wit h o ut lif e -
t hreate ni n g 
c o ns e q u e n ces  
I n creas e d lactate wit h 
p H < 7. 3 wit h life -
t hreate ni n g 
c o ns e q u e n ces  
Li p as e, Hi g h  
1. 1  t o < 1. 5 x U L N  
1. 5  t o < 3. 0 x U L N  
3. 0  t o < 5. 0 x U L N  
≥ 5. 0 x U L N  
Li pi d Dis or ders  
( m g/ d L; m m ol/ L ) 
C h olester ol , F asti n g, 
Hi g h  
≥ 1 8 ye ars of a g e  
 
2 0 0  t o < 2 4 0  
5. 1 8  t o < 6.1 9  
 
2 4 0   t o < 3 0 0  
6. 1 9  t o < 7.7 7  
 
≥  3 0 0  
≥  7. 7 7  
 
N A  
< 1 8 ye ars of a g e 
1 7 0  t o < 2 0 0  
4. 4 0  t o < 5.1 5  
2 0 0  t o < 3 0 0 
5. 1 5  t o < 7.7 7  
≥  3 0 0  
≥  7. 7 7  
N A  
L D L , F asti n g, Hi g h 
≥ 1 8 ye ars of a g e  
 
1 3 0  t o < 1 6 0   
3. 3 7  t o < 4.1 2  
 
1 6 0  t o < 1 9 0  
4. 1 2  t o < 4.9 0  
 
≥ 1 9 0  
≥ 4. 9 0  
 
N A  
> 2 t o < 1 8 ye ars of 
a g e  
1 1 0  t o < 1 3 0   
2. 8 5  t o < 3.3 4  
1 3 0  t o < 1 9 0  
3. 3 4  t o < 4.9 0  
≥ 1 9 0  
≥ 4. 9 0  
N A  
Tri glyceri d es, F asti n g, 
Hi g h  
1 5 0 t o 3 0 0  
1. 7 1 t o 3. 4 2  
> 3 0 0  t o 5 0 0  
> 3. 4 2 t o 5. 7  
> 5 0 0 t o < 1, 0 0 0  
> 5. 7 t o 1 1. 4  
> 1, 0 0 0  
> 1 1. 4  
M a g nesi u m
1 5 , L o w 
( m E q/ L; m m ol/ L ) 
1. 2   t o < 1. 4  
0. 6 0  t o  < 0.7 0  
0. 9  t o < 1. 2  
0. 4 5  t o < 0.6 0  
0. 6  t o < 0. 9  
0. 3 0  t o < 0.4 5  
< 0. 6  
< 0. 3 0  
P h os p h ate, L o w  
( m g/ d L; m m ol/ L ) 
> 1 4 ye ars of a g e  
2. 0 t o < L L N  
0. 6 5  t o < L L N 
1. 4 t o < 2. 0  
0. 4 5 t o < 0. 6 5   
1. 0 t o < 1. 4  
0. 3 2 t o < 0. 4 5  
< 1. 0  
< 0. 3 2  
1 t o 1 4 ye ars of a g e  
3. 0  t o < 3. 5  
0. 9 7  t o < 1.1 3  
2. 5  t o < 3. 0  
0. 8 1  t o < 0.9 7  
1. 5  t o < 2. 5  
0. 4 8  t o < 0.8 1  
< 1. 5  
< 0. 4 8  
< 1 ye ar of a g e  
3. 5  t o < 4. 5  
1. 1 3  t o < 1.4 5  
2. 5  t o < 3. 5  
0. 8 1  t o < 1.1 3  
1. 5  t o < 2. 5  
0. 4 8  t o < 0.8 1  
< 1. 5  
< 0. 4 8  
P ot assi u m,  Hi g h  
( m E q/ L; m m ol/ L ) 
5. 6  t o < 6. 0  
5. 6  t o < 6. 0  
6. 0  t o < 6. 5  
6. 0  t o < 6. 5  
6. 5  t o < 7. 0  
6. 5  t o < 7. 0  
≥ 7. 0  
≥ 7. 0  
P ot assi u m,  L o w  
( m E q/ L; m m ol/ L ) 
3. 0  t o < 3. 4  
3. 0  t o < 3. 4  
2. 5  t o < 3. 0  
2. 5  t o < 3. 0  
2. 0  t o < 2. 5  
2. 0  t o < 2. 5  
< 2. 0  
< 2. 0  
                                                          
1 5  To c o n vert a m a g n esi u m val u e fr o m m g/ d L t o m m ol/ L, la b orat ories s h o ul d m ulti pl y b y 0. 4 1 1 4 . 
1 0 7 of 1 3 6

C he mistries  
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 - J ul y 2 0 1 7 
Pa ge 2 8 
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
S o di u m, Hi g h  
( m E q/ L; m m ol/ L ) 
1 4 6  t o < 1 5 0  
1 4 6  t o < 1 5 0  
1 5 0  t o < 1 5 4  
1 5 0  t o < 1 5 4  
1 5 4  t o < 1 6 0  
1 5 4  t o < 1 6 0  
≥ 1 6 0  
≥ 1 6 0  
S o di u m, L o w  
( m E q/ L; m m ol/ L ) 
1 3 0  t o < 1 3 5  
1 3 0  t o < 1 3 5  
1 2 5  t o < 1 3 0  
1 2 5  t o < 1 3 0 
1 2 1  t o < 1 2 5  
1 2 1  t o < 1 2 5  
≤ 1 2 0  
≤ 1 2 0  
Uric Aci d,  Hi g h  
( m g/ d L; m m ol/ L ) 
7. 5  t o < 1 0. 0  
0. 4 5  t o < 0.5 9  
1 0. 0  t o < 1 2. 0  
0. 5 9  t o < 0.7 1  
1 2. 0  t o < 1 5. 0  
0. 7 1  t o < 0.8 9  
≥ 1 5. 0  
≥ 0. 8 9  
1 0 8 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 2 9 
H e mat ol o g y  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
A bs ol ute C D 4 + C o u nt, 
L o w  
(cell/ m m3 ; cells/ L ) 
> 5 ye ars of a g e  
( n ot HI V i nfect e d) 
 
 
 
3 0 0 t o < 4 0 0  
3 0 0 t o < 4 0 0  
 
 
 
2 0 0 t o < 3 0 0  
2 0 0 t o < 3 0 0  
 
 
 
1 0 0 t o < 2 0 0  
1 0 0 t o  < 2 0 0  
 
 
 
< 1 0 0  
< 1 0 0  
A bs ol ute L y m p h oc yte 
C o u nt, L o w   
(cell/ m m3 ; cells/ L ) 
> 5 ye ars of a g e  
( n ot HI V i nfect e d) 
 
 
 
6 0 0 t o  < 6 5 0  
0. 6 0 0 x 1 0 9  t o 
< 0. 6 5 0 x 1 0 9 
 
 
 
5 0 0 t o  < 6 0 0  
0. 5 0 0 x 1 0 9  t o 
< 0. 6 0 0 x 1 0 9 
 
 
 
3 5 0 t o < 5 0 0  
0. 3 5 0 x 1 0 9  t o 
< 0. 5 0 0 x 1 0 9 
 
 
 
< 3 5 0  
<  0. 3 5 0 x 1 0 9 
A bs ol ute Ne utr o p hil 
C o u nt  ( A N C), L o w 
(cells/ m m3 ; cells/ L ) 
> 7 d a ys of a g e  
 
 
 
8 0 0 t o 1, 0 0 0  
0. 8 0 0 x 1 0 9  t o 1.0 0 0 
x 1 0 9 
 
 
 
6 0 0 t o 7 9 9  
0. 6 0 0 x 1 0 9 t o 0.7 9 9 
x 1 0 9 
 
 
 
4 0 0 t o 5 9 9  
0. 4 0 0 x 1 0 9  t o 0.5 9 9 
x 1 0 9 
 
 
 
< 4 0 0  
< 0. 4 0 0 x 1 0 9 
2 t o 7 d a ys of a g e  
1, 2 5 0 t o 1, 5 0 0  
1. 2 5 0 x 1 0 9 t o 1.5 0 0 
x 1 0 9 
1, 0 0 0 t o 1, 2 4 9  
1. 0 0 0 x 1 0 9 t o 1.2 4 9 
x 1 0 9 
7 5 0 t o 9 9 9  
0. 7 5 0 x 1 0 9  t o 0.9 9 9 
x 1 0 9 
< 7 5 0  
< 0. 7 5 0 x 1 0 9 
≤ 1 d a y of a g e  
4, 0 0 0 t o 5, 0 0 0  
4. 0 0 0 x 1 0 9 t o 
5. 0 0 0 x 1 0 9 
3, 0 0 0 t o 3, 9 9 9  
3. 0 0 0 x 1 0 9  t o 3.9 9 9 
x 1 0 9 
1, 5 0 0 t o 2, 9 9 9  
1. 5 0 0 x 1 0 9  t o 2.9 9 9 
x 1 0 9 
< 1, 5 0 0  
< 1. 5 0 0 x 1 0 9 
Fi bri n o g e n, Decre as e d  
( m g/ d L; g/ L ) 
1 0 0 t o  < 2 0 0  
1. 0 0 t o < 2. 0 0  
O R  
0. 7 5 t o < 1. 0 0  
x L L N  
7 5 t o  < 1 0 0  
0. 7 5  t o < 1.0 0  
O R  
≥ 0. 5 0 t o < 0. 7 5  
x L L N  
5 0 t o  < 7 5  
0. 5 0  t o < 0.7 5  
O R  
0. 2 5 t o < 0. 5 0  
x L L N  
< 5 0  
< 0. 5 0  
O R  
< 0. 2 5 x L L N  
O R  Ass o ciate d wit h 
gr oss blee di n g  
He m o gl o bi n
1 6 , L o w 
( g/ d L; m m ol/ L ) 1 7  
≥ 1 3 ye ars of a g e  
( m ale o nly) 
 
 
1 0. 0 t o 1 0. 9  
6. 1 9 t o 6. 7 6  
 
 
 
9. 0 t o < 1 0. 0  
5. 5 7 t o < 6. 1 9  
 
 
7. 0 t o < 9. 0  
4. 3 4 t o < 5. 5 7  
 
 
< 7. 0  
< 4. 3 4  
≥ 1 3 ye ars of a g e  
(fe m ale o nly) 
9. 5 t o 1 0. 4  
5. 8 8 t o 6. 4 8  
8. 5 t o < 9. 5  
5. 2 5 t o < 5. 8 8  
6. 5 t o < 8. 5  
4. 0 3 t o < 5. 2 5  
< 6. 5  
< 4. 0 3  
                                                          
1 6  Male a n d fe m ale s e x ar e d efi n e d as s e x at birt h.  F or tra ns ge n d er p artici p a nts ≥1 3 y ears of a ge w h o h a ve b ee n o n h or m o n e 
t h era p y f or m ore t h a n 6 c o ns ec uti ve m o nt hs, gra d e h e m o gl o bi n b as e d o n t h e ge n d er wit h w hic h t h e y i d e ntif y (i.e., a tra ns ge n d er 
fe m ale s h o ul d b e gra d e d usi n g t h e fe m ale s e x at birt h h e m o gl o bi n la b orat or y val u es). 
 
1 7  Th e m ost c o m m o nl y us e d c o n versi o n fact or t o c o n vert g/ d L t o m m ol/ L is 0. 6 2 0 6. F or gra di n g h e m o gl o bi n res ults o btai n e d b y 
a n a n al ytic m et h o d wit h a c o n versi o n fact or ot h er t h a n 0. 6 2 0 6, t h e res ult m ust b e c o n verte d t o g/ d L usi n g a p pr o priate c o n vers i o n 
fact or f or t h e p artic ular la b orat or y.  
 
1 0 9 of 1 3 6

H e mat ol o g y  
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 - J ul y 2 0 1 7 
Pa ge 3 0 
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
5 7 d a ys of a g e t o < 1 3 
ye ars of a g e  
( m ale a n d fe m ale) 
9. 5 t o 1 0. 4  
5. 8 8 t o 6. 4 8  
8. 5 t o < 9. 5  
5. 2 5 t o < 5. 8 8  
6. 5 t o < 8. 5  
4. 0 3 t o < 5. 2 5  
< 6. 5  
< 4. 0 3  
3 6 t o 5 6 d a ys of a g e 
( m ale a n d fe m ale) 
8. 5 t o 9. 6  
5. 2 6 t o 5. 9 9  
7. 0 t o < 8. 5  
4. 3 2 t o < 5. 2 6  
6. 0 t o < 7. 0 
3. 7 2 t o < 4. 3 2 
< 6. 0  
< 3. 7 2  
2 2 t o 3 5 d a ys of a g e 
( m ale a n d fe m ale) 
9. 5 t o 1 1. 0  
5. 8 8 t o 6. 8 6  
8. 0 t o < 9. 5  
4. 9 4 t o < 5. 8 8  
6. 7 t o < 8. 0  
4. 1 5 t o < 4. 9 4  
< 6. 7  
< 4. 1 5  
8 t o ≤ 2 1 d a ys of a g e 
( m ale a n d fe m ale) 
1 1. 0 t o 1 3. 0  
6. 8 1 t o 8. 1 0  
9. 0 t o < 1 1. 0  
5. 5 7 t o < 6. 8 1  
8. 0 t o < 9. 0  
4. 9 6 t o < 5. 5 7  
< 8. 0  
< 4. 9 6  
≤ 7 d a ys of a g e  
( m ale a n d fe m ale) 
1 3. 0 t o 1 4. 0  
8. 0 5 t o 8. 7 2  
1 0. 0 t o < 1 3. 0  
6. 1 9 t o < 8. 0 5  
9. 0 t o < 1 0. 0  
5. 5 9 t o < 6. 1 9  
< 9. 0  
< 5. 5 9  
I N R, Hi g h  
( n ot o n a ntic o a g ulati o n 
t h era p y) 
1. 1  t o < 1. 5 x U L N  
1. 5  t o < 2. 0 x U L N  
2. 0  t o < 3. 0 x U L N  
≥  3. 0 x U L N  
M et he m o gl o bi n  
( % h e m o gl o bi n) 
5. 0  t o < 1 0. 0 %  
1 0. 0  t o < 1 5. 0 %  
1 5. 0  t o < 2 0. 0 %  
≥  2 0. 0 %  
P T T, Hi g h   
( n ot o n a ntic o a g ulati o n 
t h era p y) 
1. 1  t o < 1. 6 6  
x U L N  
1. 6 6 t o < 2. 3 3  
x U L N  
2. 3 3 t o < 3. 0 0  
x U L N  
≥  3. 0 0 x U L N  
Pl atelets, Decre as e d  
(cells/ m m3 ; cells/ L ) 
1 0 0, 0 0 0  t o  
< 1 2 5 ,0 0 0   
1 0 0. 0 0 0 x 1 0 9   t o 
< 1 2 5. 0 0 0  x 1 0 9 
5 0, 0 0 0  t o  
< 1 0 0, 0 0 0  
5 0. 0 0 0 x 1 0 9   t o 
< 1 0 0.0 0 0 x 1 0 9 
2 5, 0 0 0  t o  
< 5 0, 0 0 0   
2 5. 0 0 0 x 1 0 9   t o  
< 5 0. 0 0 0 x 1 0 9 
< 2 5, 0 0 0   
< 2 5. 0 0 0 x 1 0 9 
P T, Hi g h   
( n ot o n a ntic o a g ulati o n 
t h era p y 
1. 1  t o < 1. 2 5  
x U L N  
1. 2 5  t o < 1. 5 0  
x U L N  
1. 5 0  t o < 3. 0 0  
x U L N  
≥  3. 0 0 x U L N  
W B C, Dec re as e d  
(cells/ m m3 ; cells/ L ) 
> 7 d a ys of a g e  
 
 
2, 0 0 0 t o 2, 4 9 9  
2. 0 0 0 x 1 0 9  t o 2.4 9 9 
x 1 0 9 
 
 
1, 5 0 0 t o 1, 9 9 9  
1. 5 0 0 x 1 0 9  t o 1.9 9 9 
x 1 0 9 
 
 
1, 0 0 0 t o 1, 4 9 9  
1. 0 0 0 x 1 0 9  t o 1.4 9 9 
x 1 0 9 
 
 
< 1, 0 0 0  
< 1. 0 0 0 x 1 0 9 
≤ 7 d a ys of a g e  
5, 5 0 0 t o 6, 9 9 9  
5. 5 0 0 x 1 0 9  t o 6.9 9 9 
x 1 0 9 
4, 0 0 0 t o 5, 4 9 9  
4. 0 0 0 x 1 0 9  t o 5.4 9 9 
x 1 0 9 
2, 5 0 0 t o 3, 9 9 9  
2. 5 0 0 x 1 0 9  t o 3.9 9 9 
x 1 0 9 
< 2, 5 0 0  
< 2. 5 0 0 x 1 0 9 
1 1 0 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 3 1 
Uri nal ysis  
P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
Gl yc os uri a ( ra n d o m 
c ollecti o n teste d b y 
di pstic k)  
Trace t o 1 + or  
≤ 2 5 0 m g  
2 + or ˃ 2 5 0 t o   
≤ 5 0 0 m g  
> 2 + or > 5 0 0 m g  
N A  
He m at uri a  ( n ot t o b e 
re p orte d b as e d o n 
di pstic k fi n di n gs or o n 
bl o o d b elie ve d t o b e of 
m e nstr u al ori gi n)  
6  t o < 1 0 R B Cs p er 
hi g h p o wer fiel d  
≥ 1 0 R B Cs p er hi g h 
p o wer fiel d  
Gr oss, wit h or 
wit h o ut cl ots O R 
Wit h R B C casts O R 
I nter ve nti o n 
i n dicate d 
Life -t hreate ni n g 
c o ns e q u e n ces 
P r otei n uri a (r a n d o m 
c ollecti o n teste d b y 
di pstic k)  
1 +  
2 +  
3 +  or hi g h er  
N A  
 
1 1 1 of 1 3 6

 
D AI D S A E Gra di n g T a ble C orre cte d Versi o n 2. 1 -J ul y 2 0 1 7 
Pa ge 3 2 
A p p e n di x A.  
Tot al Bilir u bi n Ta bl e f or Ter m a n d Pret er m N e o nat es  
   P A R A M E T E R  
G R A D E 1  
MI L D  
G R A D E 2  
M O D E R A T E  
G R A D E 3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y  
LI F E -
T H R E A T E NI N G  
T ot al Bilir u bi n 1 8 , Hi g h 
( m g/ d L; µ m ol/ L ) 1 9  
 
Ter m Ne o n ate 2 0  
 < 2 4 h o urs of a g e  
 
4 t o < 7  
6 8. 4 t o < 1 1 9. 7   
7 t o < 1 0  
1 1 9. 7 t o < 1 7 1   
1 0 t o  < 1 7  
1 7 1 t o < 2 9 0. 7   
≥ 1 7  
≥ 2 9 0. 7   
2 4 t o < 4 8 h o urs of 
a g e  
5 t o < 8  
8 5. 5 t o < 1 3 6. 8   
8 t o < 1 2  
1 3 6. 8 t o < 2 0 5. 2   
1 2 t o  < 1 9  
2 0 5. 2 t o <  3 2 4. 9   
≥ 1 9  
≥ 3 2 4. 9  
4 8 t o  < 7 2 h o urs of 
a g e  
8. 5 t o < 1 3  
1 4 5. 3 5 t o < 2 2 2. 3   
1 3 t o < 1 5  
2 2 2. 3 t o < 2 5 6. 5   
1 5 t o  < 2 2  
2 5 6. 5 t o < 3 7 6. 2   
≥ 2 2  
≥ 3 7 6. 2  
7 2 h o urs t o < 7 d a ys 
of a g e  
1 1 t o < 1 6  
1 8 8. 1 t o < 2 7 3. 6  
1 6 t o < 1 8  
2 7 3. 6 t o < 3 0 7. 8  
1 8 t o  < 2 4  
3 0 7. 8 t o < 4 1 0. 4  
≥ 2 4  
≥ 4 1 0. 4  
7 t o 2 8 d a ys of a g e 
( br e ast fee di n g) 
5 t o < 1 0  
8 5. 5 t o < 1 7 1   
1 0 t o < 2 0  
1 7 1 t o < 3 4 2   
2 0 t o < 2 5  
3 4 2 t o < 4 2 7. 5   
≥ 2 5  
≥ 4 2 7. 5  
7 t o 2 8 d a ys of a g e 
( n ot br e ast fee di n g) 
1. 1 t o < 1. 6 x U L N  
1. 6 t o < 2. 6 x U L N  
2. 6 t o < 5. 0 x U L N  
≥ 5. 0  x U L N  
Pr eter m Ne o n ate 2 0   
3 5 t o < 3 7 weeks 
g est ati o n al a g e  
Sa m e as f or T ot al 
Bilir u bi n, Hi g h, 
Ter m Ne o n ate  ( b as e d 
o n d a ys of a ge) . 
Sa m e as f or T ot al 
Bilir u bi n, Hi g h, 
Ter m Ne o n ate  ( b as e d 
o n d a ys of a ge) . 
Sa m e as f or T ot al 
Bilir u bi n, Hi g h, 
Ter m Ne o n ate  ( b as e d 
o n d a ys of a ge) . 
Sa m e as f or T ot al 
Bilir u bi n, Hi g h, 
Ter m Ne o n ate  ( b as e d 
o n d a ys of a ge) . 
3 2 t o  < 3 5 weeks 
g est ati o n al a g e  a n d  
< 7 d a ys of a g e  
N A  
N A  
1 0 t o < 1 4  
1 7 1 t o < 2 3 9. 4  
≥ 1 4  
≥ 2 3 9. 4  
2 8 t o < 3 2 weeks 
g est ati o n al  a g e  a n d  
< 7 d a ys of a g e  
N A  
N A  
6 t o < 1 0  
1 0 2. 6 t o < 1 7 1   
≥ 1 0  
≥ 1 7 1  
< 2 8 weeks 
g est ati o n al a g e  a n d  
< 7 d a ys of a g e  
N A  
N A  
 5 t o < 8  
8 5. 5 t o < 1 3 6. 8   
≥ 8  
≥ 1 3 6. 8  
7 t o  2 8 d a ys of a g e 
( br e ast fee di n g) 
5 t o < 1 0  
8 5. 5 t o < 1 7 1   
1 0 t o < 2 0  
1 7 1 t o < 3 4 2   
2 0 t o < 2 5  
3 4 2 t o < 4 2 7. 5   
≥ 2 5  
≥ 4 2 7. 5  
7 t o 2 8 d a ys of a g e 
( n ot br e ast fee di n g) 
1. 1 t o < 1. 6 x U L N  
1. 6 t o < 2. 6 x U L N  
2. 6 t o < 5. 0 x U L N  
≥  5. 0 x U L N  
 
 
                                                          
1 8  Se ver it y gra di n g f or t otal bilir u bi n i n n e o n ates is c o m ple x b eca us e of ra pi dl y c h a n gi n g t otal bilir u bi n n or m al ra n ges i n t h e first 
wee k of life f oll o we d b y t h e b e ni g n p h e n o m e n o n of breast mil k j a u n dice after t h e first wee k of life.  S e verit y gr a di n g i n t hi s 
a p p e n di x c orres p o n ds a p pr o xi m atel y t o c ut -offs f or i n dicati o ns f or p h ot ot h era p y at gra d e 3 a n d f or e x c h a n ge tra nsf usi o n at gra d e 
4.  
1 9  A la b orat or y val u e of 1 m g/ d L is e q ui vale nt t o 1 7. 1 µ m ol/ L.  
2 0  Defi niti o ns: Ter m is d efi n e d as ≥ 3 7 wee ks  gestati o n al  a ge; n ear-ter m, as ≥ 3 5 wee ks gestati o n al a ge; preter m, as < 3 5 wee ks 
gestati o n al a ge; a n d n e o n ate, as 0 t o 2 8 d a ys of a ge.  
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C O N FI D E N TI A L  
 
 
A P P E N DI X 2   
RU L E S I N T H E E V E N T O F  A D R U G -R E L A T E D A E  
 
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C O N FI D E N TI A L  
1 of 6 
 
R U L E S I N T H E E V E N T O F A N A D V E R S E R E A C TI O N 
 
T A B L E O F C O N T E N T S  
Ta ble of c o nte nts ............................................................................................................................. 1  
List of ta bles   ................................................................................................................................. 1 
I ntr o d ucti o n  ................................................................................................................................. 2 
Gl o bal acti o n r ules i n t he e ve nt of a n a d verse reacti o n  .................................................................. 2 
Acti o n r ules i n t he e ve nt of a he mat ol o gical a d verse reacti o n ....................................................... 2  
Acti o n r ules i n t he e ve nt of a li ver a d verse reacti o n  ....................................................................... 3 
Acti o n r ules i n t he e ve nt of a der mat ol o gical a d verse reacti o n  ...................................................... 4 
Acti o n r ules i n t he e ve nt of a car diac a d verse reacti o n  .................................................................. 4 
D ose re d ucti o n sc he d ule ................................................................................................................. 6  
 
LI S T O F T A B L E S  
Ta ble 1  
Acti o n r ules i n t he e ve nt of li ver A Rs  ................................................................ 3 
Ta ble 2  
Acti o n r ules i n t he e ve nt of der mat ol o gical A Rs ............................................... 4  
Ta ble 3  
Sc he d ule f or d ose re d ucti o ns fr o m 4 0 0 t o 2 0 0 m g/ da y priteli vir ...................... 6  
 
 
 
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I N T R O D U C TI O N 
T he f oll o wi n g ta bles s h o w t he i n di vi d ual s u bject r ules a n d t he trial pr o gressi o n r ules, w hic h will 
o nl y a p pl y t o A Es/ S A Es w here t here is a reas o na ble p ossi bilit y of relati o ns hi p t o t he I M P (ie, 
a d verse reacti o ns [A Rs ] a n d seri o us a d verse reacti o ns [S A Rs ]). Gra di n g of A Es will be 
perf or me d as descri be d i n Secti o n  6. 6. 4. 1. 4 of t he C T P.  
R B C has t he o pti o n t o u n bli n d a partici pa nt if dee me d necessar y. If m o xifl o xaci n or eit her of t he 
t w o place b os are f o u n d t o be t he ca use of t he u n bli n di n g e ve nt i n q uesti o n, t he n t he trial ma y 
pr ocee d wit h o ut a s u bsta ntial a me n d me nt bei n g s u b mitte d t o E C/ R A.  
Res pecti ve A Rs res ulti n g fr o m safet y la b orat or y a b n or malities m ust be c o nfir me d b y a c o ntr ol 
meas ure me nt bef ore a n acti o n is ta ke n.  
Gl o b al a cti o n r ul e s i n t h e e v e nt of a n a d v er s e r e a cti o n  
S eri o us a d verse re acti o n 
If an S A R i n a n y s u bject, f urt her d osi n g of all s u bjects will be s us pe n de d. 
Re -c o m me nce me nt of d osi n g will re q uire re g ulat or y a p pr o val via a s u bsta ntial a me n d me nt a). 
M o der ate A R ( D AI D S Gr a de 2)  
I n t he e ve nt of m o derate A Rs, trial me dicati o n ma y be c o nti n ue d as pla n ne d, c o nti n ue d at a 
re d uce d d ose b), or disc o nti n ue d i n acc or da nce wit h I n vesti gat or’s cli nical j u d g me nt. 
Se vere A R ( D AI D S Gr a de 3) 
I n t he e ve nt of a se vere A R i n a si n gle s u bject, trial me dicati o n will be disc o nti n ue d .  
If ≥2 s u bjects e x perie nce se vere A Rs, f urt her d osi n g of all s u bjects will be s us pe n de d.  
Re -c o m me nce me nt of d osi n g will re q uire re g ulat or y a p pr o val via a s u bsta ntial a me n d me nt a). 
P ote nti all y life -t hre ate ni n g or f at al A R ( D AI D S Gr a de ≥4) 
If a p ote ntiall y life -t hreate ni n g or fatal A R i n a n y s u bject, f urt her d osi n g of all s u bjects will be 
s us pe n de d. 
Re -c o m me nce me nt of d osi n g will re q uire re g ulat or y a p pr o val via a s u bsta ntial a me n d me nt a). 
A cti o n r ul e s i n t h e e v e nt of a h e m at ol o gi c al a d v er s e r e a cti o n  
I n vesti gat or’s j u d ge me nt will be use d t o deter mi ne w hic h of t he pre-d ose meas ure me nts are 
c o nsi dere d t he baseli ne. W here p ossi ble, t he baseli ne val ue s h o ul d be t he o ne t hat was ta ke n at 
t he cl osest ti me of da y t o t he sa m ples bei n g assesse d f or c ha n ge, t o acc o u nt f or di ur nal variati o n.  
If t he he mat ol o gical A Rs descri be d bel o w occ urri n g i n a si n gle s u bject, trial me dicati o n will be 
disc o nti n ue d. 
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If ≥2 s u bjects eac h ha ve t he sa me he mat ol o gical A Rs descri be d bel o w (ie, b ot h s u bjects ha vi n g 
t he sa me P T), f urt her d osi n g of all s u bjects will be s us pe n de d. Re-c o m me nce me nt of d osi n g will 
re q uire re g ulat or y a p pr o val via a s u bsta ntial a me n d me nt a). 
•  He m o gl o bi n dr o p of > 2 5 % fr o m t he baseli ne  val ue ( w hic h is a b o ve t he l o wer li mit of 
n or mal) t o a val ue bel o w t he la b orat or y refere nce ra n ge, or t o a n a bs ol ute val ue of < 1 0 0 g/ L 
•  Platelet c o u nt dr o p of > 2 5 % fr o m t he baseli ne val ue (w hic h is a b o ve t he l o wer li mit of 
n or mal), t o a val ue bel o w t he la b orat or y refere nce ra n ge, or t o a n a bs ol ute val ue of < 1 2 0 x 
1 0 9/ L 
•  Cli nica ll y si g nifica nt ne utr o p hil dr o p, defi ne d as re q uiri n g of a d diti o nal i n vesti gati o n or 
treat me nt t o pr o perl y ma na ge t he fi n di n g 
•  A n y ot her he mat ol o gical t o xicit y w hic h i n t he o pi ni o n of t he I n vesti gat or w o ul d precl u de 
f urt her d osi n g i n a partici pa nt 
a) A s u bsta n tial a me n d me nt ma y i ncl u de a n a me n d me nt t o t he pr ot oc ol, t he I C F, or ot her trial relate d d oc u me nts 
as a p pr o priate.  
 
A cti o n r ul e s i n t h e e v e nt of a li v er a d v er s e r e a cti o n  
Acti o n r ules i n t he e ve nt of li ver A Rs are descri be d i n Ta ble 1 . 
T a ble 1 
Acti o n r ules i n t he e ve nt of li ver A R s 
T hres h ol d  
Acti o n r ules f or i n di vi d u al 
s u bjects 
Acti o n r ules f or tri al pr o gressi o n  
A L T or A S T val ue > 3 x a n d 
< 5 x U L N  
Trial me dicati o n ma y be 
c o nti n ue d as pla n ne d, c o nti n ue d 
at a re d uce d d ose  b), or 
disc o nti n ue d i n acc or da nce wit h 
I n vesti gat or’s cli nical j u d g me nt 
If ≥4 s u bjects: 
F urt her d osi n g of all s u bjects will 
be s us pe n de d.  
Re- c o m me nce me nt of d osi n g  will 
re q uire re g ulat or y a p pr o val via a 
s u bsta ntial a me n d me nt  a). 
A L T or A S T > 3 t o < 5 × U L N, 
a n d s y m pt o matic  c),  
A L T or A S T val ue > 5 × U L N  
± s y m pt o ms c) 
Trial me dicati o n will be 
disc o nti n ue d  
If ≥2 s u bjects: 
F urt her d osi n g of all s u bjects will 
be s us pe n de d.  
Re- c o m me nce me nt of d osi n g will 
re q uire re g ulat or y a p pr o val via a 
s u bsta ntial a me n d me nt  a). 
A L T or A S T val ue > 3 × U L N 
a n d bilir u bi n > 1. 5 x U L N, 
wit h o ut ot her e vi de nce of 
c h olestasis  
F urt her d osi n g of all s u bjects will be s us pe n de d.  
Re- c o m me nce me nt of d osi n g will re q uire re g ulat or y a p pr o val via a 
s u bsta ntial a me n d me nt a). 
A L T =ala ni ne a mi n otra nsferase; A R =a d verse reacti o n; A S T =as partate a mi n otra nsferase; U L N = u p per li mit of 
n or mal  
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a) A s u bsta ntial a me n d me nt ma y i ncl u de a n a me n d me nt t o t he pr ot oc ol, t he I C F, or o t her trial relate d d oc u me nts 
as a p pr o priate.  
b)  See Secti o n: D ose re d ucti o n sc he d ule, bel o w.  
c) S y m pt o ms i ncl u de fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt pai n or te n der ness, fe ver, ras h a n d/ or 
e osi n o p hilia (e osi n o p hil perce nt or c o u nt a b o ve t he U L N).  
 
A cti o n r ul e s i n t h e e v e nt of a d er m at ol o gi c al a d v er s e r e a cti o n  
Acti o n r ules i n t he e ve nt of der mat ol o gical A Rs are descri be d i n Ta ble 2 . 
T a ble 2 
Acti o n r ules i n t he e ve nt of der m at ol o gic al A R s 
T hres h ol d  
Acti o n r ules f or i n di vi d u al 
s u bjects 
Acti o n r ules f or tri al pr o gressi o n  
M o derate  
( D AI D S Gra de 2) 
T rial me dicati o n ma y be c o nti n ue d 
as pla n ne d, c o nti n ue d at a re d uce d 
d ose  b), or disc o nti n ue d i n 
acc or da nce wit h I n vesti gat or’s 
cli nical j u d g me nt . 
Cl ose m o nit ori n g of A E a n d 
der mat ol o g y c o ns ultati o n t o be 
s o u g ht. 
If ≥4 s u bjects: 
F urt her d osi n g of all s u bjects will 
be s us pe n de d.  
Re- c o m me nce me nt of d osi n g will 
re q uire re g ulat or y a p pr o val via a 
s u bsta ntial a me n d me nt  a). 
Se vere  
( D AI D S Gra de 3) 
Trial me dicati o n will be 
disc o nti n ue d.  
Cl ose m o nit ori n g of A E a n d 
der mat ol o g y c o ns ultati o n t o be 
s o u g ht. 
If ≥2 s u bjects:  
F urt her d osi n g of all s u bjects will 
be s us pe n de d.  
Re- c o m me nce me nt of d osi n g will 
re q uire re g ulat or y a p pr o val via a 
s u bsta ntial a me n d me nt  a). 
P ote ntiall y life -t hreate ni n g 
( D AI D S Gra de 4) 
F urt her d osi n g of all s u bjects will be s us pe n de d.  
Re- c o m me nce me nt of d osi n g will re q uire re g ulat or y a p pr o val via a 
s u bsta ntial a me n d me nt  a). 
A E =a d verse e ve nt; A R =a d verse reacti o n  
a) A s u bsta ntial a me n d me nt ma y i ncl u de a n a me n d me nt t o t he pr ot oc ol, t he I C F, or ot her trial relate d d oc u me nts 
as a p pr o priate.  
b)  See Secti o n: D ose re d ucti o n sc he d ule, bel o w.  
 
A cti o n r ul e s i n t h e e v e nt of a c ar di a c a d v er s e r e a cti o n  
If a s u bject has a s ustai ne d pr ol o n gati o n of t he u nc orrecte d Q T i nter val ≥5 0 0 ms, t he s u bject ma y 
be m o nit ore d f or o ne a d diti o nal d osi n g a n d if s h o w n t o be c o nsiste nt wit h a d ose res p o nse, t he n 
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trial dr u g a d mi nistrati o n will be re d uce d i n d ose  or s us pe n de d, usi n g c o nsiste nt, tec h nicall y vali d 
tri plicate E C G.  
T he f oll o wi n g r ules will a p pl y: 
If Q T pr ol o n g ati o n first occ urs o n D a y 1 
•  Partici pa nt ma y c o nti n ue t o D 2 1 0 0 m g priteli vir or place b o d osi n g. If Q T pr ol o n gati o n is 
s ustai ne d f oll o wi n g d osi n g o n D 2 t he n i n di vi d ual partici pa nt t o st o p t he trial.  
•  If Q T pr ol o n gati o n is n ot s ustai ne d, t he n t he partici pa nt ca n c o nti n ue t o d ose at 1 0 0 m g u p t o 
D 6 a n d t o 4 0 0 m g fr o m D 7 o n war ds.  
•  If Q T pr ol o n gati o n rec urs o n D 2-D 6 : i n di vi d ual partici pa nt t o st o p t he trial.  
•  If Q T pr ol o n gati o n rec urs o n D 7- D 1 6: i n di vi d ual partici pa nt’s d ose will be re d uce d b). If Q T 
pr ol o n gati o n is s ustai ne d or rec urs at a n y ti me f oll o wi n g d ose re d ucti o n, partici pa nt t o st o p 
t he trial. 
If i niti al Q T pr ol o n g ati o n prese nts o n D 2-D 6  
•  Partici pa nt ma y c o nti n ue a n d be m o nit ore d f or o ne a d diti o nal d ose. If Q T pr ol o n gati o n is n ot 
s ustai ne d, partici pa nt ca n c o nti n ue; if Q T pr ol o n gati o n is s ustai ne d, t he n i n di vi d ual 
partici pa nt t o st o p t he trial.   
•  If Q T pr ol o n gati o n rec urs u ntil D 6: i n di vi d ual partici pa nt t o st o p t he trial. 
•  If Q T pr ol o n gati o n rec urs o n D 7- D 1 6: i n di vi d ual partici pa nt’s d ose will be re d uce d b. If Q T 
pr ol o n gati o n is s ustai ne d or rec urs at a n y ti me f oll o wi n g d ose re d ucti o n, partici pa nt t o st o p 
t he trial.  
If i niti al Q T pr ol o n g ati o n prese nts o n D 7- 1 6 
•  Partici pa nt ma y c o nti n ue a n d be m o nit ore d f or o ne a d diti o nal d ose. If Q T pr ol o n gati o n is n ot 
s ustai ne d, partici pa nt ca n c o nti n ue. 
•  If Q T pr ol o n gati o n rec urs o n D 7- D 1 6: i n di vi d ual partici pa nt’s d ose will be re d uce d b). If Q T 
pr ol o n gati o n is s ustai ne d or rec urs at a n y ti me f oll o wi n g d ose re d ucti o n, partici pa nt t o st o p 
t he trial. 
If ≥2 s u bjects disc o nti n ue d ue t o s ust ai ne d pr olo n g ati o n of t he u nc orrecte d Q T ≥5 0 0 ms  
•  F urt her d osi n g of all s u bjects will be s us pe n de d.  
•  Re -c o m me nce me nt of d osi n g will re q uire re g ulat or y a p pr o val via a s u bsta ntial a me n d me nt a). 
a) A s u bsta ntial a me n d me nt ma y i ncl u de a n a me n d me nt t o t he pr ot oc ol, t he I C F, o r ot her trial relate d d oc u me nts 
as a p pr o priate.  
b)  See Secti o n: D ose re d ucti o n sc he d ule, bel o w.  
 
 
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D o s e r e d u cti o n s c h e d ul e  
D ose re d ucti o n is n ot p ossi ble if t he a d verse reacti o n occ urs d uri n g D 1 t o D 6 d osi n g.  
F or a d verse reacti o ns t hat occ ur d uri n g t he 4 0 0 m g / da y s u prat hera pe utic d osi n g peri o d ( D 7 t o 
D 1 6), t he f oll o wi n g r ules a p pl y re gar di n g re d ucti o n t o 2 0 0 m g/ da y d osi n g.  
T a ble 3 
Sc he d ule f or d ose re d ucti o ns fr o m 4 0 0  t o 2 0 0 m g/ d a y priteli vir  
D a y of A R  
D ose re d u cti o n  
Da y 7  
•  
D osi n g will  eit her c o nti n ue at t he 4 0 0  m g d ose (if a b o ve r ules per mit), 
or will be disc o nti n ue d a n d s u bject wit h dra w n fr o m t he trial.  
•  
D ose re d ucti o n is n ot p ossi ble as plas ma c o nce ntrati o ns (e x p os ure) 
after t he first 4 0 0 m g priteli vir d ose are at t he pre dicte d 2 0 0 m g / da y 
c o nce ntrati o n i n stea d y state.  
Da y 8  
•  
N o d ose Da y 9  
•  
2 0 0 m g/ da y Da ys 1 0 t o 1 6  
Da y 9  
•  
N o d ose Da y 1 0  
•  
2 0 0 m g/ da y Da ys 1 1 t o 1 6  
Da y 1 0  
•  
n o d ose Da ys 1 1 a n d 1 2  
•  
2 0 0 m g/ da y Da y 1 3 t o 1 6  
Da y 1 1  
•  
n o d ose Da y 1 2 a n d 1 3  
•  
2 0 0 m g/ da y. Da y 1 4 t o 1 6  
Da y 1 2  
•  
n o d ose Da y 1 3 a n d 1 4  
•  
2 0 0 m g/ da y Da y 1 5 t o 1 6  
Da y 1 3  
•  
n o d ose Da y 1 4 a n d 1 5  
•  
2 0 0 m g/ da y Da y 1 6  
Da y 1 4  
•  
n o d ose Da y 1 5 a n d 1 6  
Da y 1 5  
•  
n o d ose Da y 1 6  
A R =a d verse reacti o n  
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RI S K MI TI G A TI O N T A B L E  
 
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P ote nti al ris ks  
Priteli vir  
T here is pr e vi o us P hase 1 a n d P hase 2 cli nical e x perie nce wit h Priteli vir. P ote ntial ris ks will be 
cl osel y m o nit ore d as part of t he safet y e val uati o ns bei n g perf or m e d i n t his trial. T he ris k 
miti gati o n meas ures are s u m marize d bel o w:  
T a ble 1  
S u m m ar y of p ote nti al ris ks a n d res pecti ve ris k miti g ati o n 
T ar get S yste m  
Effect  
Ris k Miti g ati o n  
Re nal a n d 
Ur ol o gical 
S yste m  
N o effect o n re nal f u ncti o n was 
o bser ve d i n safet y p har mac ol o gical 
st u dies. 
 
Priteli vir is re nall y e xcrete d b ut n o 
effect o n re nal f u ncti o n has bee n see n 
s o far i n a n y cli nical or n o n-cli nical 
st u dies. 
1)  Sta n dar d m o nit ori n g as wit h all earl y 
p hase trials.  
2)  Safet y bl o o ds i ncl u di n g urea a n d 
creati ni ne as well as gl o mer ular 
filtrati o n rate will be ta ke n at re g ular 
i nter vals hi g hli g hte d i n t he sc he d ule 
of assess me nts.  
3)  A d diti o nal assess me nts ma y be 
c o m plete d if m ore t ha n trace pr otei n 
is f o u n d i n t he uri ne (i ncl u di n g re nal 
ultras o u n d, u nsc he d ule d micr osc o p y 
or 2 4- h o ur uri ne c ollecti o n).  
He patic S yste m  
N o n -s pecific i ncreases i n A L T a n d 
A S T seei n g i n P hase 1 a n d 2 trials. 
T hese were n ot directl y relate d t o 
priteli vir.  
1)  I ncrease d m o nit ori n g of s u bjects.  
2)  E xte nsi ve li ver f u ncti o n testi n g will 
be c o m plete d i ncl u di n g A L P, A S T, 
A L T, G G T, t otal pr otei n as well as 
al b u mi n a n d gl o b uli n, a n d 
c oa g ulati o n will be meas ure d as per 
t he cli nical sc he d ule of assess me nts.  
3)  S pecific i ncl usi o n a n d e xcl usi o n 
criteria will be use d t o select p ote ntial 
s u bjects. 
4)  Pre vi o us e x p os ure t o he patitis B ( +/ - 
D) a n d C will be assesse d (e xcl u di n g 
s u bjects w h o ha ve pre vi o us 
e x p os ure).  
5)  S pecific A R r ules will be 
i m ple me nte d. 
6)  A d diti o nal assess me nts c o ul d be 
a d de d de pe n di n g o n cli nical 
re q uireme nts, i ncl u di n g a fi br o sca n 
of t he li ver.  
7)  A n y s u bject w h o ma y ha ve bee n 
pre vi o usl y e x p ose d t o a bi ol o gic 
dr u g, will n ot be i ncl u de d.  
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T ar get S yste m  
Effect  
Ris k Miti g ati o n  
8)  A d diti o nal i n vesti gati o n of C Y P 
is of or ms ca n be perf or me d if a n y 
c o ncer ni n g data e mer ges fr o m E C G, 
P K or A E a nal ysis.  
Car di o vasc ular 
s yste m  
N o effect n ote d i n n o ncli nical st u dies.  
 
N o effect see n i n h u ma n P hase 1 a n d 2 
trials  
1)  Sta n dar d m o nit ori n g as wit h all earl y 
p hase trials   
2)  T h or o u g h Q T trial, s o e xte nsi ve 
car diac m o nit ori n g will be c o n d ucte d  
3)  E C G i nte nsi ve da ys a n d t h or o u g h 
H olter a nal ysis  
Res pirat or y 
S yste m   
N o effect n ote d i n n o ncli nical st u dies. 
 
N o effect see n i n h u ma n P hase 1 a n d 2 
trials. 
1)  Sta n dar d m o nit ori n g as wit h all earl y 
p hase trials.   
Ce ntral ner v o us 
s yste m  
N o effect n ote d i n n o ncli nical trials.  
N o n -s pecific C N S effects see n. 
Hea dac he, fati g ue, dizzi ness, i ns o m nia 
c o m m o nl y see n i n P hase 1 a n d 2 trials 
after priteli vir a n d place b o treat me nt.  
1)  Sta n dar d m o nit ori n g as wit h all earl y 
p hase trials   
Hae mat ol o gical 
s yste m  
A nae mia i n d o gs a n d m o n ke ys after 
re peate d oral d osi n g.  
 
Decrease d he mat ocrit; decrease d 
he m o gl o bi n see n i n h u ma n P hase 1 
a n d 2 trials (after ver u m a n d place b o 
treat me nt). 
1)  Sta n dar d m o nit ori n g as wit h all earl y 
p hase trials   
2)  S u bjects will be e xcl u de d fr o m t his 
trial if t he y s uffer wit h a ne mia or 
ot her he m o gl o bi n o pat h y  
3)  S pecific A d verse Reacti o n r ules 
re gar di n g re d ucti o n i n he m o gl o bi n, 
platelets a n d ne utr o p hils  
Gastr oi ntesti nal 
s yste m 
(i ncl u di n g taste)  
C o m p o u n d de p ositi o ns (cr ystall oi d 
s paces) a n d ass ociate d f orei g n b o d y 
reacti o ns were o bser ve d 
hist o pat h ol o gicall y at hi g h d ose le vels 
i n mice, rats a n d m o n ke ys mai nl y i n 
t he di gesti ve tract. 
 
N o n -s pecific GI dist ur ba nce ( na usea, 
diarr hea, a b d o mi nal pai n a n d 
c o nsti pati o n) c o m m o nl y see n i n P hase 
1 a n d 2 trials after priteli vir a n d 
place b o treat me nt.  
1)  Sta n dar d m o nit ori n g as wit h all earl y 
p hase trials  
2)  A n y self-re p orte d GI dist ur ba nce will 
be i n vesti gate d f urt her wit h 
a p pr o priate i n vesti gati o n 
3)  S u bjects will be e xcl u de d fr o m t his 
trial if t he y ha ve a n y pre vi o us hist or y 
of Irrita ble B o wel 
S y n dr o me/I nfla m mat or y B o wel 
Disease or k n o w n c o n diti o ns t hat 
ma y affect a bs or pti o n i n t he GI tract.  
4)  S u bjects will n ot be d ose d wit h 
priteli vir a n d m o xifl o xaci n 
c o nc o mita ntl y  
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T ar get S yste m  
Effect  
Ris k Miti g ati o n  
S ki n  
Ras h, pr urit us, er yt he ma a n d dr y s ki n 
see n i n a P hase 1 trial wit h re peate d 
d oses of 4 0 0  m g/ da y.  
 
Diff use hair t hi n ni n g, disc ol ore d 
areas, cr usts o n t he hea d, a n d sca b b y 
s ki n c orrelati n g hist o pat h ol o gicall y 
wit h a c yt ot o xic i nterface der matitis 
a n d perif ollic ular i nfla m mati o n i n a 
c hr o nic m o n ke y t o xicit y st u d y.  
1)  Sta n dar d m o nit ori n g a n d re g ular A E 
c hec ks as wit h all earl y p hase trials  
2)  Dail y s ki n e xa mi nati o n d uri n g i n-
h o use peri o d a n d f oll o w u p.  
3)  S u bjects will be e xcl u de d if t he y ha ve 
a n y pre vi o us hist or y of 
der mat ol o gical c o n diti o ns  
4)  If der mat ol o gical A E of D AI D S 
Gra de 2 occ urs, t he n der mat ol o g y 
c o ns ultati o n t o be s o u g ht. If dee me d 
treat me nt relate d d ose re d ucti o n or 
d ose s us pe nsi o n t o be c o nsi dere d.  
5)  If der mat ol o gical A E of D AI D S 
Gra de 3 trial me dicati o n t o be 
st o p pe d f or t hat partici pa nt. See A R 
r ules f or f urt her details.  
6)  S u prat hera pe utic d ose ma y be 
re d uce d w he n s ki n effects occ ur 
d uri n g s u prat hera pe utic d osi n g p hase. 
Re pr o d ucti ve 
s yste m 
N o n terat o ge nic i n rats a n d ra b bit 
st u dies.  
 
Re versi ble treat me nt relate d effects o n 
male rat fertilit y c o nsisti n g of a 
decrease i n e pi di d y mal s per m 
c o nce ntrati o ns a n d m otilit y a n d 
prese nce of a b n or mal s per m 
m or p h ol o g y. 
 
N o effects were see n e ve n at t he 
hi g hest d ose le vel ( 1, 0 0 0 m g/ k g/ da y) 
i n se x uall y mat ure m o n ke ys o ver a 
treat me nt peri o d of 3 9 wee ks. 
T heref ore, t hese fi n di n gs i n rats are 
c o nsi dere d u nli kel y t o be rele va nt t o 
h u ma ns. 
1)  S pecific c o ntrace pti ve re q uire me nts 
will be i n place f or s u bjects.  
2)  C o ntrace pti ve g ui da nce will be use d 
i n i ncl usi o n criteria. 
3)  Fe male s u bjects will nee d e vi de nce of 
ne gati ve pre g na nc y tests pri or t o 
d osi n g. 
L y m p hatic 
S yste m  
Mil d l y m p ha de n o pat h y n ote d i n 
priteli vir treate d s u bjects all of w hic h 
res ol ve d b y f oll o w u p.  
1)  Sta n dar d m o nit ori n g as wit h all earl y 
p hase trials  
2)  A n y self- re p orte d l y m p ha de n o pat h y 
will be i n vesti gate d f urt her wit h 
a p pr o priate e xa mi nati o n a n d 
i n vesti gati o n.  
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T ar get S yste m  
Effect  
Ris k Miti g ati o n  
O p ht hal m ol o g y  
Le ntic ular o pacities (cataracts) a n d 
le ntic ular s welli n g see n i n n o ncli nical 
st u dies i n rats a n d mice.  
T hese fi n di n gs were n ot o bser ve d i n 
n o n- r o de nt s pecies.  
C o nsi dere d as hi g hl y u nli kel y t o be 
rele va nt t o h u ma ns. 
 
N o  vis ual dist ur ba nce see n i n h u ma n 
P hase 1 a n d 2 trials  
1)  Sta n dar d m o nit ori n g as wit h all earl y 
p hase trials  
2)  A n y self-re p orte d vis ual dist ur ba nce 
will be i n vesti gate d f urt her wit h 
t h or o u g h e xa mi nati o n  
3)  S u bjects will be e xcl u de d fr o m t his 
trial if t he y ha ve a ny pre vi o us hist or y 
of i m paire d visi o n  
 
 
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A D A P TI V E F E A T U R E S O F T RI A L D E SI G N  
 
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T his trial i nc or p or ates t h e use of a n a da pti ve d esi g n. Trial  s pe cifi c a da pti ve fe at ures a n d t heir 
li mits are descri be d i n Ta ble 1  b el o w . 
A da pti ve fe at ures ma y b e i m ple m e nte d o nl y wit h t h e a p pr o val of t h e S p o ns or.  I m ple m e ntati o n of 
a da pti v e feat ures affecti n g  all f oll o wi n g s u bjects will be d oc u me nte d i n a n o n -s u bsta ntial 
a me n d m e nt.  
T he e xc e pti o ns t o t his are t he Ge neri c A da pti v e Feat ures, w hic h relate t o  v ol u nteer saf et y (see 
Ta ble 2 ). T hese m a y be i m ple m e nte d at t h e discreti o n of t he I n vesti g at or a n d re c or de d i n t hat 
v ol u nteer’s s o urce d ata.  
T a ble 1  
A d a pti ve pr ot oc ol fe at ures - tri al s pecific 
A d a pti ve Tri al Desi g n Are as 
(t ri al-s pe cific) 
Fe at ur es  
Li mits  
D ose  
D osi n g  
Hi g her d ose ma y be d o w n titrate d t o 
2 0 0  m g per da y f or i n di vi d ual  s u bje cts 
( ple ase refer t o A R r ules ta ble)  
A R = a d verse reacti o n  
 
T a ble 2  
A d a pti ve pr ot oc ol fe at ures - ge neri c  
A d a pti ve Tri al 
Desi g n Ar e as 
( ge ne ric) 
Fe at ur es  
Li mits  
S a m ples a n d 
Assess me nts (safet y)  
1)  A d diti o nal safet y assess me nts 
ma y be perf or me d o n a n 
i n di vi d ual s u bje ct if it is 
c o nsi dere d cli nic all y nec essar y b y 
t he PI f or i n di vi d uals o n a c ase-
b y -c ase basis. 
2)  A d diti o nal safet y assess me nts 
(i ncl u di n g b ut n ot li mite d t o 
la b orat or y safet y sa m ples, vital 
si g ns a n d E C Gs) ma y be a d de d t o 
t he sc he d ule of assess me nts at 
a d diti o nal ti me p oi nts f or 
f oll o wi n g s u bje cts if t he PI 
c o nsi ders it ne cessar y fr o m a 
safet y/t olera bilit y pers pecti ve, o n 
t he basis of e v ol vi n g data a n d 
d osi n g re gi me ns.  
3)  A d diti o nal safet y assess me nts 
ma y refer t o eit her:  
1)  F or i n di vi d uals, a ma xi m u m 
n u m ber of safet y bl o o d sa m ples 
will be deter mi ne d o n a case -b y -
c ase basis a n d ca n n ot be pre -
defi ne d as i n vesti gati o ns will be 
perf or me d as ne cessar y t o e ns ur e 
t he safet y of t he i n di vi d ual 
s u bje ct.  
2)  Trial s pecific ma xi m u m bl o o d 
v o l u me will n ot be e xc ee de d 
(3 0 0  m L , se e S ecti o n  6. 6. 3  of t he 
C T P ). 
3)  If a d diti o nal ti me p oi nts f or saf et y 
assess me nts are re q uire d f or 
f oll o wi n g s u bje cts, t his will be 
d oc u me nte d i n a n o n -s u bsta ntial 
a me n d me nt, pr o vi di n g t he o ver all 
ris k pr ofile of [I M P] has n ot 
c ha n ge d.  
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A d a pti ve Tri al 
Desi g n Ar e as 
( ge ne ric) 
Fe at ur es  
Li mits  
a) A n i ncrease d n u m ber of t he 
sa me safet y assess me nts 
pla n ne d i n t he e xisti n g 
sc he d ules of assess me nts.  
b)  A d diti o nal para meters 
(s pecific tests) o n assess me nts 
alrea d y sc he d ule d, e g, 
tr o p o ni n tests o n safet y blo o d 
sa m ples. 
c) A d diti o nal safet y tests 
re q uiri n g a d diti o nal 
bl o o d/ uri ne sa m ple 
c olle cti o ns or ot her cli nic al 
pr oc e d ures ( e g, ultras o u n d 
sca ns).  
4)  T he ti mi n g of safet y assess me nts 
i ncl u di n g b ut n ot li mite d t o 
la b orat or y safet y sa m ples, vital 
si g ns a n d E C Gs ma y be a dj uste d 
i n a c c or da nce wit h e v ol vi n g data 
a n d d osi n g sc he d ule. 
4)  If a d diti o nal safet y assess me nts or 
para meters are re q uire d f or 
f oll o wi n g s u bje cts a n d ha ve a 
si milar ris k pr ofile t o t h ose 
pla n ne d i n t his trial pr ot oc ol, t he y 
will be d oc u me nte d i n a n o n -
s u bsta ntial a me n d me nt. 
A d diti o nal safet y assess me nts 
re q uire d f or u pc o mi n g gr o u p t hat 
are m ore i n vasi ve or ha ve a 
differe nt ris k pr ofile t o t h ose i n 
t his c urre nt pr ot oc ol m ust be 
detaile d i n a s u bsta ntial 
a me n d me nt. 
5)  Alterati o ns i n ti mi n g of t he saf et y 
assess me nts nee d t o be a 
reflecti o n of t he esta blis he d 
safet y/t olera bilit y a n d P K pr ofile 
u p t o t he de cisi o n -ma ki n g ti me -
p oi nt.  
6)  If t here are n o cli nic all y 
si g nific a nt fi n di n gs i n safet y 
assess me nts a n y m ore , f urt her 
f oll o w-u p ma y  be disc o nti n ue d.  
 
5)  S pe cialist referrals ( e g, t o a 
c ar di ol o gist) ma y be ma de (a n d 
ma y i ncl u de all rele va nt 
assess me nts a n d i n vesti gati o ns) if 
it is c o nsi dere d cli nic all y 
ne c essar y b y t he PI , Sp o ns or , or 
R B C  f or i n di vi d uals o n a c ase-b y -
c ase basis  
7)  A ma xi m u m  n u m ber of s pecialist 
referrals f or i n di vi d uals will be 
deter mi ne d o n a c ase -b y -c ase  
basis a n d c a n n ot be pre -defi ne d as 
i n vesti gati o ns will be perf or me d 
as necessar y t o e ns ure t he safet y 
of t he i n di vi d ual partici pa nts.  
S a m ples a n d 
Assess me nts ( P K)  
1)  A d diti o nal or less bl o o d P K 
a n d/ or e x pl orat or y assess me nts 
ma y be ta ke n i n a cc or da nc e wit h 
e v ol vi n g data a n d d osi n g 
sc he d ule. T his i ncl u des t h ose f or 
t he a nal ysis of meta b olites. 
2)  T he ti mi n g of bl o o d P K, a n d/ or 
a n y p ote ntial e x pl orat or y 
assess me nts  ma y be a dj uste d i n 
a c c or da nc e wit h e v ol vi n g data 
a n d d osi n g sc he d ule. T his 
1)  Mi ni m u m: s ufficie nt P K sa m ples 
t o esta blis h f ull pr ot oc ol s pecific 
plas ma P K pr ofile.  
2)  Trial s pecific ma xi m u m bl o o d 
v ol u me will n ot be e xc ee de d 
(3 0 0  m L , se e S ecti o n  6. 6. 3  of t he 
C T P ). 
1 2 7 of 1 3 6

 
A p pe n di x 4: A da pti ve Trial Desi g n  
AI C 3 1 6 -0 3 -I-0 7 Cli nic al Trial Pr ot oc ol  
V 1. 0  
2 4 Ma y 2 0 2 2  
 
 
 
C O N FI D E N TI A L  
3  of 3  
 
A d a pti ve Tri al 
Desi g n Ar e as 
( ge ne ric) 
Fe at ur es  
Li mits  
i ncl u des t h ose f or t he a nal ysis of 
meta b olites.  
C T P = Cli nical Trial Pr ot oc ol ; E C G = electr ocar di o gra m; I M P =I n vesti gati o nal M e dici nal Pr o d uct; PI = Pri nci pal 
I n vesti gat or; P K = p har mac o ki netics; R B C = R is k B e nefit C o m mittee  
 
1 2 8 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
C O N FI D E N TI A L  
 
 
A P P E N DI X 5  
F D A R E S P O N S E T O T Q T T RI A L D E SI G N  
 
1 2 9 of 1 3 6

U. S. F o o d a n d Dr u g A d mi ni str ati o n
Sil v er S pri n g, M D 2 0 9 9 3
w w w.f d a. g o v
E L E C T R O NI C M AI L C O R R E S P O N D E N C E:
I N F O R M A TI O N R E Q U E S T/ A D VI C E
D at e: 
J a n u ar y 1 3, 2 0 2 2
T o:
Iri s h a J o h n s o n, R A C, R e g ul at or y Aff air s C o n s ult a nt
S p o n s or:
Ai C uri s A nti-i nf e cti v e C ur e s A G
Fr o m:
C hri sti n e Ki m, P h ar m D, R A C- U S, S e ni or R e g ul at or y Pr oj e ct M a n a g er
I N D: 
1 0 4 3 4 6
Dr u g: 
Prit eli vir 1 0 0 m g or al t a bl et s
S u bj e ct:  
 St u d y AI C 3 1 6- 0 3-I- 0 7
R ef er e n c e i s m a d e t o y o ur s u b mi s si o n d at e d D e c e m b er 8, 2 0 2 1, w h er ei n y o u pr o vi d e d 
a c o m pr e h e n si v e s y n o p si s f or t h e T Q T tri al AI C 3 1 6- 0 3-I- 0 7 f or r e vi e w.  Y o ur 
s u b mi s si o n h a s b e e n r e vi e w e d b y t h e m ulti di s ci pli n ar y t e a m, i n cl u di n g c o n s ult ati o n b y 
t h e I nt er di s ci pli n ar y R e vi e w T e a m f or C ar di a c S af et y St u di e s. W e h a v e t h e f oll o wi n g 
c o m m e nt s: 
O v er all, t h e pr o p o s e d st u d y d e si g n a n d a n al y si s pl a n a p p e ar a c c e pt a bl e t o
c h ar a ct eri z e t h e eff e ct s of prit eli vir o n t h e Q T c i nt er v al.
W e h a v e t h e f oll o wi n g a d diti o n al c o m m e nt s:
1.
T h e a d e q u a c y of t h e d o s e s el e cti o n i s still a r e vi e w i s s u e a n d will d e p e n d o n t h e 
hi g h e st t h er a p e uti c d o s e a n d w h et h er t h e s el e ct e d s u pr at h er a p e uti c d o s e c o v er s t h e 
hi g h cli ni c al e x p o s ur e s c e n ari o (i. e., i n cr e a s e s i n e x p o s ur e d u e t o dr u g i nt er a cti o n or 
or g a n i m p air m e nt) of p ar e nt a n d a n y r el e v a nt m et a b olit e s f or t h e t h er a p e uti c d o s e.
2.
F or e x p o s ur e-r e s p o n s e a n al y si s, w e r e c o m m e n d t h e a n al y si s a n d r e p orti n g of 
r e s ult s f oll o w t h e r e c o m m e n d ati o n s d e s cri b e d i n “S ci e ntifi c w hit e p a p er o n 
c o n c e ntr ati o n- Q T c m o d eli n g”  ( G ar n ett, C. et al., J P h ar m a c o ki n et P h ar m a c o d y n 
2 0 1 7; d oi 1 0. 1 0 0 7/ s 1 0 9 2 8- 0 1 7- 9 5 5 8- 5) a n d “ C orr e cti o n t o: S ci e ntifi c w hit e p a p er o n 
c o n c e ntr ati o n- Q T c m o d eli n g ” ( G ar n ett, C. et al., J P h ar m a c o ki n et P h ar m a c o d y n 
2 0 1 8; d oi 1 0. 1 0 0 7/ s 1 0 9 2 8- 0 1 7- 9 5 6 5- 6).
3. I n a d diti o n t o pri m ar y a n al y si s, w e r e c o m m e n d t h at y o u c o n d u ct t h e b y-ti m e a n al y si s 
u si n g a li n e ar mi x e d m o d el a n d p erf or m c at e g ori c al a n al y si s f or all E C G bi o m ar k er s 
( Q T c, Δ Q T c,  H R, P R, Q R S, a n d T- w a v e m or p h ol o g y).
4. If y o ur pr o d u ct i s li k el y t o i n cr e a s e or d e cr e a s e t h e h e art r at e si g nifi c a ntl y ( e. g., > 1 0 
b p m) i n t h e st u d y, y o u will n e e d t o c o n si d er t h e u s e of alt er n ati v e m et h o d s f or 
a s s e s si n g c h a n g e s i n t h e Q T i nt er v al, s u c h a s Q T cI (i n di vi d u ali z e d Q T c orr e cti o n). 
T o s u p p ort alt er n ati v e m et h o d s, it i s i m p ort a nt t h at dr u g-fr e e b a s eli n e s ar e a v ail a bl e 
fr o m a wi d e e n o u g h s p a n of h e art r at e s t o c o v er o n tr e at m e nt c h a n g e s i n h e art r at e, 
R ef er e n c e I D: 4 9 2 0 2 6 3
1 3 0 of 1 3 6

wit hi n e a c h i n di vi d u al. O n e w a y t o a c hi e v e t hi s c o ul d b e t o h a v e t h e s u bj e ct s 
u n d er g o p o st ur al m a n e u v er s ( e. g., u n s u p p ort e d sitti n g a n d st a n di n g) o n dr u g-fr e e 
vi sit s. I n a d diti o n, it i s al s o i m p ort a nt t o a c c o u nt f or Q T/ R R h y st er e si s pri or t o 
d eri vi n g t h e i n di vi d u al Q T/ R R r el ati o n s hi p t o a v oi d bi a s w h e n e sti m ati n g t h e 
i n di vi d u al Q T/ R R r el ati o n s hi p. F or a d diti o n al i nf or m ati o n, pl e a s e s e e “ M et h o d ol o gi e s 
t o c h ar a ct eri z e t h e Q T/ c orr e ct e d Q T i nt er v al i n t h e pr e s e n c e of dr u g-i n d u c e d h e art 
r at e c h a n g e s or ot h er a ut o n o mi c eff e ct s” ( G ar n ett, C. et al., A m H e art J 
2 0 1 2; 1 6 3( 3): 9 1 2- 3 0). I n t h e a b s e n c e of si g nifi c a nt h e art r at e eff e ct s, w e r e c o m m e n d 
t h e u s e of Q T c F f or t h e pri m ar y a n al y si s.
5.
W h e n y o u s u b mit y o ur Q T e v al u ati o n r e p ort, pl e a s e i n cl u d e a c o m pl et e d v er si o n of 
t h e m o st r e c e nt “ Q T E v al u ati o n R e p ort S u b mi s si o n C h e c kli st” l o c at e d at t h e I R T 
w e b sit e ( htt p s:// w w w.f d a. g o v/ a b o ut-f d a/ c e nt er- dr u g- e v al u ati o n- a n d-r e s e ar c h-
c d er/i nt er di s ci pli n ar yr e vi e w-t e a m- c ar di a c- s af et y- st u di e s-f or m erl y- qt-irt  ).
P L E A S E R E P L Y B Y E M AI L t o c o nfir m r e c ei pt at C hri sti n e. Ki m @f d a. h h s. g o v.  If y o u 
h a v e a n y q u e sti o n s r e g ar di n g t h e c o nt e nt s of t hi s c orr e s p o n d e n c e, pl e a s e c o nt a ct m e 
b y e m ail or p h o n e ( 3 0 1- 7 9 6- 5 9 6 4).
{ S e e a p p e n d e d el e ctr o ni c si g n at ur e p a g e}
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
C hri sti n e Ki m, P h ar m D, R A C- U S
S e ni or R e g ul at or y Pr oj e ct M a n a g er
A nti vir al s Gr o u p
Di vi si o n of R e g ul at or y O p er ati o n s f or I nf e cti o u s 
Di s e a s e s
Offi c e of R e g ul at or y O p er ati o n s
C e nt er f or Dr u g E v al u ati o n a n d R e s e ar c h                                       
R ef er e n c e I D: 4 9 2 0 2 6 3
1 3 1 of 1 3 6

--------------------------------------------------------------------------------------------
T hi s i s a r e pr e s e nt ati o n of a n el e ctr o ni c r e c or d t h at w a s si g n e d
el e ctr o ni c all y. F oll o wi n g t hi s ar e m a nif e st ati o n s of a n y a n d all
el e ctr o ni c si g n at ur e s f or t hi s el e ctr o ni c r e c or d.
--------------------------------------------------------------------------------------------
/ s/
------------------------------------------------------------
C H RI S TI N E KI M
0 1/ 1 3/ 2 0 2 2 0 2: 3 1: 2 2 P M
Si g n at ur e P a g e 1 of 1
R ef er e n c e I D: 4 9 2 0 2 6 3
1 3 2 of 1 3 6

 
Cli nical Trial Pr ot oc ol 
AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
C O N FI D E N TI A L  
 
 
A P P E N DI X 6  
D A T A P R O C E S SI N G S C H E D U L E T O T H E P R O T O C O L  
 
1 3 3 of 1 3 6

 
A p pe n di x 6: Data pr oc essi n g sc he d ule  
AI C 3 1 6 -0 3 -I-0 7 Cli nic al Trial Pr ot oc ol  
V 1. 0  
2 4 Ma y 2 0 2 2  
 
 
 
C O N FI D E N TI A L  
1  of 3  
 
1.  W here R P L pr oc esses pers o nal data o n b e half of Ai C uris, R P L s hall act  
as a data pr o cess or a n d t he Ai C uris s hall be a d ata c o ntr oller. T o t he e xte nt  
R P L is t he dat a pr ocess or o n be half of Ai C uris, R P L s hall:  
 
1. 1  
pr ocess t he pers o nal d ata o nl y i n ac c or da nc e wit h t h e d oc u me nte d i nstr u cti o ns of 
Ai C uris;  
 
1. 2  
i m ple me nt a p pr o priate te c h nic al a n d or g a nisati o nal meas ures t o pr ot ect t he 
pers o nal dat a a gai nst u na ut h orise d or u nla wf ul pr oc essi n g a n d a gai nst a cci d e ntal 
l oss, destr ucti o n, da ma ge, alt erati o n or discl os ure. T hese meas ures s hall be 
a p pr o priat e t o t h e har m a n d ris k w hic h mi g ht res ult fr o m a n y u na ut h orise d or 
u nla wf ul pr ocessi n g, a cci de ntal l oss, destr ucti o n or d a ma ge t o t he p ers o nal dat a 
a n d ha vi n g re g ar d t o t h e n at ure of t he pers o nal dat a w hic h is t o be pr ot ect e d a n d 
s hall i ncl u de i nter alia as a p pr o priat e: 
 
1. 2. 1  t he pse u d o n y misati o n a n d e ncr y pti o n of pers o nal dat a. 
 
1. 2. 2  t he a bilit y t o e ns ure t h e o n-g oi n g c o nfi d e nti alit y, i nt e grit y, a v ail a bilit y a n d 
resilie n ce of s yste ms a n d ser vices pr ocessi n g pers o n al dat a. 
 
1. 2. 3  t he a bilit y t o rest ore t he a vaila bilit y a n d a ccess t o pers o nal data i n a ti mel y 
ma n ner i n t he e v e nt of a p h ysic al or t ec h ni cal i nci d e nt; a n d  
 
1. 2. 4  a pr ocess f or re g ular t esti n g, assessi n g  a n d e v al uati n g t he effe cti v e ness of 
tec h ni cal a n d or ga nisati o n me as ures f or e ns uri n g t he sec urit y of pr oc essi n g. 
 
I n or der t o e na ble R P L t o i m pl e me nt a p pr o priate t ec h nical a n d or ga nisati o nal 
meas ures, Ai C uris s hall pr o vi de t o R P L a n y i nf or m ati o n reas o na bl y re q uir e d b y 
R P L t o e na bl e it t o assess t he a p pr o pri ate ness of s uc h meas ures.  
 
1. 3  
o nl y e m pl o y or a p p oi nt p ers o n nel t o pr o cess t he pers o nal dat a w h o ha ve gi v e n 
bi n di n g u n dert a ki n gs of c o nfi d e nti alit y or are u n der a stat ut or y o bli gati o n of 
c o nfi de ntialit y;  
 
1 3 4 of 1 3 6

 
A p pe n di x 6: Data pr oc essi n g sc he d ule  
AI C 3 1 6 -0 3 -I-0 7 Cli nic al Trial Pr ot oc ol  
V 1. 0  
2 4 Ma y 2 0 2 2  
 
 
 
C O N FI D E N TI A L  
2  of 3  
 
1. 4  
re mai n e ntitle d t o a p p oi nt t hir d part y s u b-pr ocess ors. W here R P L a p p oi nts a 
t hir d-part y s u b -pr oc ess or, it s hall:  
 
1. 4. 1  e ns ure t hat t he t hir d part y is s u bject t o, a n d c o ntr act u all y b o u n d b y, at 
least t h e sa me o bli gati o ns as R P L; 
  
1. 4. 2  pr o vi de t o Ai C uris c o pies of a n y d oc u me ntati o n t o d e m o nstrat e 
c o m pli a nce wit h t he o bli gati o ns u n der t his Secti o n 1. 4; a n d  
 
1. 4. 3  re mai n f ull y lia bl e t o Ai C uris f or all acts a n d o missi o ns of t he t hir d part y; 
 
1. 5  
n otif y Ai C uris wit h o ut u n d u e del a y aft er bec o mi n g a ware t hat it has s uffere d a 
data bre ac h;  
 
1. 6  
at Ai C uris’s c ost, per mit Ai C uris (s u bje ct t o r eas o na ble a n d a p pr o priat e 
c o nfi de ntialit y u n derta ki n gs), t o i ns pect a n d a u dit R P L’s data pr ocessi n g 
acti viti es t o e na ble Ai C uris t o v erif y a n d/ or pr o c ure t hat R P L is i n f ull c o m plia n ce 
wit h its o bli g ati o ns u n der t he pr ot o c ol;  
 
1. 7  
ta ki n g i nt o ac c o u nt t h e nat ure of t he pr oc essi n g, assist Ai C uris b y a p pr o priat e 
tec h ni cal a n d or ga nisati o nal meas ures, i ns ofar as t his is p ossi ble, wit h t he 
f ulfil m e nt of Ai C uris’s o bli g ati o n t o res p o n d t o re q u ests fr o m data p arti ci pa nts i n 
c o n necti o n t o t his pr ot oc ol e xercisi n g t heir ri g hts u n der A p plica ble Data 
Pr otecti o n La w;  
 
1. 8  
u nless a p plic a ble la w re q uires ot h er wise, u p o n ter mi nati o n of t h e pr ot oc ol:  
 
1. 8. 1  at t he o pti o n of Ai C uris c o m pl y or pr oc ure t he c o m plia nc e wit h t h e 
f oll o wi n g: 
 
(a) 
ret ur n t o Ai C uris all pers o nal data a n d a n y ot h er i nf or mati o n 
pr o vi de d b y Ai C uris t o R P L;  a n d/ or  
 
( b) 
per ma ne ntl y delete all p ers o nal data pr o vi d e d b y Ai C uris t o R P L; 
a n d 
1 3 5 of 1 3 6

 
A p pe n di x 6: Data pr oc essi n g sc he d ule  
AI C 3 1 6 -0 3 -I-0 7 Cli nic al Trial Pr ot oc ol  
V 1. 0  
2 4 Ma y 2 0 2 2  
 
 
 
C O N FI D E N TI A L  
3  of 3  
 
 
1. 8. 2  cease t o pr o cess t he pers o nal d ata.  
 
N ot wit hsta n di n g t h e f ore g oi n g, R P L s hall be e ntitle d t o retai n pers o nal d ata t o t he 
e xte nt t hat it is re q uire d t o d o s o p urs ua nt t o t he l a w of t he U nite d Ki n g d o m;  
1. 9  
w here t he l a ws of t he c o u ntr y w here R P L is esta blis he d re q uire R P L t o tra nsfer 
t he pers o nal d ata t o a t hir d c o u ntr y or a n i nter n ati o n al or ga nisati o n, i nf or m 
Ai C uris as s o o n as reas o na bl y p ossi ble of t h at l e gal r e q uire m e nt u nl ess t hat l a w 
pr o hi bits s uc h c o m m u nic ati o n o n i m p ort a nt gr o u n ds of p u blic i nterest.  
 
1. 1 0  
R P L s hall o nl y tr a nsfer pers o nal d ata o utsi de t he U nite d Ki n g d o m t o c o u ntr y or 
territ or y t hat is s u bject t o a U K or E ur o pea n C o m missi o n a de q uac y d ecisi o n, 
w here a p pr o priate safe g uar ds ar e i n pl ace, a n d o n t he c o n diti o n t hat t he l e vel of 
pr otecti o n offere d t o t he data s u bje ct i n t he t hir d c o u ntr y are esse ntiall y e q ui vale nt 
t o t h ose offere d b y t he A p pli ca ble Data Pr ote cti o n L a w. 
 
1 3 6 of 1 3 6