Clinical trial NCT05671029
Conditions: Healthy Subjects
Keywords: Pritelivir, QT, QTc, thorough QT study
Sponsor: AiCuris Anti-infective Cures AG
Start date: 2022-12-04; Completion date: 2023-05-18
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 1 clinical trial was a double-blind, single-center, randomized and placebo-controlled trial in which healthy male and female subjects received in 2 parallel-groups daily oral doses of pritelivir (Group 1) or matching placebo (Group 2). Within Group 2, a single oral administration of moxifloxacin (positive control) and corresponding matching placebo was administered in a 2-sequence crossover design (nested crossover).

Detailed description:
Subjects were in-house from Day -2 to Day 20 and were randomized to one of the 2 parallel treatment groups (as part of the blind, both groups received the same number of tablets and capsules at the same timepoints, though some were verum and some were placebo depending on the randomized regimen). Group 1 received a therapeutic and a supra-therapeutic dose of pritelivir plus moxifloxacin placebo. Group 2 received pritelivir placebo as well as one dose of moxifloxacin and one dose of matching placebo in a 2-sequence crossover design (nested crossover). 12-lead electrocardiogram (ECG) triplicates were recorded from the bedside 12-lead ECG on the Days -1, 1, 2, 6, 16, and 17 and were analyzed afterwards in each group for these 6 days of documentation by a blinded reader.

It is of note that Holter ECG data was collected in parallel at Screening to exclude anyone with pre-existing cardiac abnormalities as well as on Days -1, 1, 2, 6, 16, and 17 as a back-up for the bedside 12-lead ECGs.

In Group 1, 32 male and female subjects (at least 12 subjects per sex) received a loading dose of 400 mg pritelivir on Day 1. Afterwards they received 100 mg pritelivir qd from Day 2 to 6 and 400 mg pritelivir qd from Day 7 to 16. Furthermore, these subjects received matching moxifloxacin placebo on the Days 2 and 17.

In Group 2, 32 male and female subjects (at least 12 subjects per sex) receive the respective amounts of tablets of matching pritelivir placebo from Day 1 to Day 16 in Group 2 as verum tablets in Group 1. Furthermore, subjects in Group 2a (16 male and female subjects) received 400 mg moxifloxacin on Day 2 and matching moxifloxacin placebo on Day 17 and subjects in Group 2b (16 male and female subjects) received 400 mg moxifloxacin on Day 17 and matching moxifloxacin placebo on Day 2.

To maintain double-blinding the following measures were needed, and data evaluations generated for Group 1 and Group 2:

* 12-lead ten second ECG triplicates were digitally recorded and analyzed (from the bedside 12-lead-ECG devices) in subjects of both groups on the Days -1, 1, 2, 6, 16 and 17.
* PK samples were collected from subjects of both groups on the Days 1, 6, and 16 for pritelivir and the metabolites AIC090015 and AIC090105 as well as for moxifloxacin on the Days 2 and 17.
* Over-encapsulated moxifloxacin- and matching placebo were used.

Arms: arm 1: Subjects (32 male and female subjects) received 400 mg pritelivir on Day 1, 100 mg pritelivir from Day 2 to 6 and 400 mg pritelivir from Day 7 to 16.

Furthermore, these subjects received moxifloxacin matching placebo on the Days 2 and 17. arm 2: Subjects (16 male and female subjects) received the respective amounts of tablets of matching pritelivir matching placebo on Day 1 to Day 16 in Group 2a as verum tablets in Group1.

Furthermore, these subjects received 400 mg moxifloxacin on Day 2 and moxifloxacin matching placebo on Day 17. arm 3: Subjects (16 male and female subjects) received the respective amounts of tablets of matching pritelivir matching placebo on Day 1 to Day 16 in Group 2b as verum tablets in Group1.

Furthermore, these subjects received moxifloxacin matching placebo on Day 2 and 400 mg moxifloxacin on Day 17.
Interventions: intervention 1: Pritelivir and moxifloxacin placebo intervention 2: Pritelivir placebo, moxifloxacin and moxifloxacin placebo intervention 3: Pritelivir placebo, moxifloxacin placebo and moxifloxacin
Intervention descriptions: intervention 1: oral administration intervention 2: oral administration intervention 3: oral administration

Protocol documents:
Prot_000.pdf: 
 
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  
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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


 
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  
5 of 7 6  
 
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


 
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 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


 
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  
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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 
7 of 1 3 6


 
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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  
 
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  
1 0  of 7 6  
 
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  
 
 
1 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  
1 1  of 7 6  
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
1 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  
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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V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
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  
1 3 of 1 3 6


 
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2 5 N o v 2 0 2 2 
 
 
 
C O N FI D E N TI A L  
1 4  of 7 6  
 
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 
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  
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 
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  
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 
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  
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 
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  
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 
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  
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 
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 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 
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 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 
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 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 
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 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 
2 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  
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 
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 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 
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 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


 
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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 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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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 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


 
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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).  
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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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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.  
4 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  
4 9  of 7 6  
 
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.  
4 9 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  
5 0  of 7 6  
 
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. 
5 0 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  
5 1  of 7 6  
 
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  
5 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  
5 2  of 7 6  
 
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. 
5 2 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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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  
5 3 of 1 3 6


 
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V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
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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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V 2. 0 
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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. 
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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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V 2. 0 
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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 
6 7 of 1 3 6


 
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V 2. 0 
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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.  
6 8 of 1 3 6


 
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AI C 3 1 6 - 0 3-I- 0 7 
V 2. 0 
2 5 N o v 2 0 2 2 
 
 
 
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6 9  of 7 6  
 
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. 
6 9 of 1 3 6


 
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V 2. 0 
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7 0  of 7 6  
 
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 
7 0 of 1 3 6


 
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V 2. 0 
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7 1  of 7 6  
 
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. 
7 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  
7 2  of 7 6  
 
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  
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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  
 
 
8 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 7 
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  
 
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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)  
 
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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).   
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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.  
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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 
 
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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  
 
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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.  
1 1 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 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  
 
1 1 3 of 1 3 6


 
A p pe n di x 2: R ules i n t he e ve nt of A R  
AI C 3 1 6- 0 3 -I-0 7 Cli nical Trial Pr ot oc ol  
V 2 . 0 
2 5 N o v 2 0 2 0  
 
 
 
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  
 
 
 
1 1 4 of 1 3 6


 
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V 2 . 0 
2 5 N o v 2 0 2 0  
 
 
 
C O N FI D E N TI A L  
2 of 6 
 
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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2 5 N o v 2 0 2 0  
 
 
 
C O N FI D E N TI A L  
3 of 6 
 
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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AI C 3 1 6- 0 3 -I-0 7 Cli nical Trial Pr ot oc ol  
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2 5 N o v 2 0 2 0  
 
 
 
C O N FI D E N TI A L  
4 of 6 
 
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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5 of 6 
 
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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C O N FI D E N TI A L  
1  of 4  
 
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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A p pe n di x 4: A da pti ve Trial Desi g n  
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C O N FI D E N TI A L  
1  of 3  
 
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.  
1 2 6 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  
2  of 3  
 
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

SAP_001.pdf: 
S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x             P a g e 1 of 1 5  
 
S P O N S O R’ S R E F E R E N C E N U M B E R: A I C 3 1 6 - 0 3 - I - 0 7  
E U D R A C T N U M B E R: 2 0 2 2 - 0 0 0 2 0 3 - 1 2  
R P L S T U D Y C O D E: C 2 1 0 4 2  
S T A T I S T I C A L A N A L Y S I S P L A N  
 
A d o u bl e - bli n d, si n gl e - c e n t e r, r a n d o mi z e d, pl a c e b o - a n d p o si ti v e -
c o n t r oll e d, p a r all el - g r o u p t ri al wit h a n e s t e d c r o s s o v e r p a rt o n t h e 
el e c t r o c a r di o g r a p hi c eff e c t s of 1 0 0 a n d 4 0 0 m g p ri t eli vi r p e r d a y 
i n h e al t h y s u bj e c t s: a t h r o u g h Q T / Q T c t ri al 
F I N A L V E R S I O N 1. 0 , 1 6 D E C 2
 
 
 
I s s u e d b y: 
  
  
Si g n at ur e...................... 
Ri c h m o n d P h ar m a c ol o g y   
  
  
  
 
S e ni or Bi o st ati sti ci a n   
  
  
  
D at e..........
 
 
R e vi e w e d b y: 
 
       
Si g n at ur e..
Ri c h m o n d P h ar m a c ol o g y   
 
A s s o ci at e m e di c al dir e ct or  
  
          D at e........
 
 
R e vi e w e d b y: 
       
  
Si g n at ur e
Ri c h m o n d P h ar m a c ol o g y   
 
P h y si ci a n S ci e nti st   
  
            
D at e......
 
 
A p pr o v e d b y: Dir k Kr o p eit, M D, P h D 
  
Si g n at ur
Ai C uri s A nti -i nf e cti v e C ur e s A G  
H e a d of E arl y Cli ni c al D e v el o p m e nt  
  
D at e......
 
 
A p pr o v e d b y: 
    
Si g n at
Ai C uri s A nti -i nf e cti v e C ur e s A G   
 
R ol e P h ar m a c o vi gil a n c e M a n a g er            
D at e..
1 2/ 1 6/ 2 0 2 2
1 2/ 1 6
1 2/
0 1/ 2 3/


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x             P a g e 2 of 1 5  
 
C o n
o n t et ents
nts  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S ................................... 3 
1.  
I N T R O D U C T I O N  .............................................................................. 4 
2.  
T R I A L O B J E C T I V E S A N D E N D P O I N T S  ............................................... 4 
2. 1  
Tri al o bj e cti v e s ............................................................................... 4 
2. 2  
E n d p oi nt s ...................................................................................... 4 
3.  
T R I A L D E S I G N  ................................................................................ 5 
3. 1 O v er all Tri al D e si g n ........................................................................... 5 
3. 2  
S a m pl e Si z e ................................................................................... 6 
3. 3  
R a n d o mi s ati o n a n d Bli n di n g .............................................................. 7 
4. S T A T I S T I C A L A N A L Y S E S  ..................................................................... 7 
4. 1 G e n er al N ot e s f or St ati sti c al A n al y s e s ................................................... 7 
4. 2  
I nt eri m A n al y si s ............................................................................. 8 
4. 3  
A n al y si s S et s ................................................................................. 8 
4. 4  
S u bj e ct Di s p o siti o n ......................................................................... 9 
4. 5  
D e m o gr a p hi c C h ar a ct eri sti c s ............................................................. 9 
4. 6  
I n cl u si o n a n d E x cl u si o n Crit eri a ....................................................... 1 0  
4. 7  
Pr ot o c ol D e vi ati o n s ....................................................................... 1 0  
4. 8  
M e di c al a n d S ur gi c al Hi st or y ........................................................... 1 0  
4. 9  
Tri al Dr u g A d mi ni str ati o n ............................................................... 1 0  
4. 1 0  
Pri or a n d C o n c o mit a nt M e di c ati o n s ................................................ 1 0  
4. 1 1  
S af et y A n al y si s .......................................................................... 1 0  
4. 1 1. 1 A d v er s e E v e nt s ........................................................................ 1 1  
4. 1 1. 2 L a b or at or y D at a ....................................................................... 1 1  
4. 1 1. 3 Vit al Si g n s ............................................................................... 1 1  
4. 1 1. 4 H olt er ..................................................................................... 1 2  
4. 1 1. 5 P h y si c al E x a mi n ati o n ................................................................ 1 2  
4. 1 1. 6 El e ctr o c ar di o gr a m s ................................................................... 1 2  
4. 1 2 E C G s a n al y s e s ( a dj u di c at e d ) ............................................................ 1 3  
4. 1 2. 1 C o n c e ntr ati o n - Q T c a n al y si s ........................................................ 1 3  
4. 1 3 P h ar m a c o ki n eti c D at a ..................................................................... 1 5  
5.  
R E F E R E N C E S  ................................................................................. 1 5  
 
 
 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x             P a g e 3 of 1 5  
 
L I S T O F A B B R E V I A T I O N S A N D D E F I N I T I O N S O F T E R M S 
A b b r e vi ati o n 
o r S p e ci ali s t 
T e r m  
E x pl a n a ti o n  
A E  
A d v er s e E v e nt  
C T R 
Cli ni c al Tri al R e p ort 
D R M  
D at a R e vi e w M e eti n g 
E C G  
El e ctr o c ar di o gr a m  
H 
Hi g h 
H R  
H e art r at e 
I M P 
I n v e sti g ati o n al M e di ci n al Pr o d u ct 
L 
L o w 
M e d D R A 
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s 
P K  
P h ar m a c o ki n eti c ( s)  
P K S 
P h ar m a c o ki n eti c S et 
P R  
E C G P R I nt er v al 
P R O C 
Pr o c e d ur e i n S A S 
Q R S 
E C G V e ntri c ul ar C o n d u ct a n c e Ti m e 
Q T  
E C G Q T i nt er v al u n c orr e ct e d 
Q T c 
E C G Q T i nt er v al c orr e ct e d  
Q T c F  
E C G Q T i nt er v al c orr e ct e d u si n g Fri d eri ci a’ s f or m ul a  
Q T cI 
E C G Q T i nt er v al c orr e ct e d u si n g a s u bj e ct s p e cifi c 
( "i n di vi d u al " ) c orr e cti o n 
Q T c S 
E C G Q T i nt er v al c orr e ct e d u si n g a tri al s p e cifi c c orr e cti o n 
R P L 
Ri c h m o n d P h ar m a c ol o g y Lt d 
S A P  
St ati sti c al A n al y si s Pl a n 
S A S  
St ati sti c al A n al y si s S oft w ar e 
S D  
St a n d ar d D e vi ati o n 
S O C 
S y st e m Or g a n Cl a s s 
T O M  
Tri al O p er ati o n M a n u al 
S S  
S af et y S et 
T E A E 
Tr e at m e nt - E m er g e nt A d v er s e E v e nt 
tm a x   
Ti m e t o M a xi m u m O b s er v e d Pl a s m a C o n c e ntr ati o n  
 
 
 
 
 
 
 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x             P a g e 4 of 1 5  
 
1.  
I N T R O D U C T I O N 
T h e p ur p o s e of t hi s St ati sti c al A n al y si s Pl a n ( S A P ) i s t o d efi n e t h e v ari a bl e s a n d  
pr o vi d e d et ail s of t h e pl a n n e d a n al y si s f or a d dr e s si n g t h e o bj e cti v e s of t hi s tri al. 
T h e pr ot o c ol d at e d 2 5  N o v e m b er 2 0 2 2, v er si o n 2. 0 w a s u s e d t o pr e p ar e t hi s S A P. 
St ati sti c al a n al y si s a n d r e p orti n g will b e p erf or m e d b y Ri c h m o n d P h ar m a c ol o g y 
( R P L) f or s af et y , d e m o gr a p hi c s a n d E C G a n al y si s a s  d e s cri b e d wit hi n t hi s S A P. 
P h ar m a c o ki n eti c ( P K) p ar a m et er s c al c ul ati o n s a n d st ati sti c al a n al y s e s ar e o ut of 
s c o p e of t hi s S A P a n d d et ail s will b e pr o vi d e d b y V e n n Lif e S ci e n c e s. 
2.  
T ri al O B J E C T I V E S A N D E N D P O I N T S 
2. 1 
T r i al o bj e c ti v e s 
P ri m a r y 
•  
T o d efi n e t h e eff e ct s of prit eli vir o n t h e Q T c F i nt er v al d eri v e d fr o m 1 2 -l e a d 
E C G s i n c o m p ari s o n wit h pl a c e b o i n m al e a n d f e m al e s u bj e ct s 
S e c o n d a r y 
•  
T o  a s s e s s p h ar m a c o ki n eti c pr o p erti e s of m ulti pl e d o s e s of prit eli vir a n d t o 
e x a mi n e t h e c orr el ati o n s b et w e e n prit eli vir pl a s m a c o n c e ntr ati o n a n d it s 
eff e ct s, if a n y, o n t h e Q T c F i nt er v al 
•  
T o e v al u at e a d diti o n al el e ctr o c ar di o gr a p hi c eff e ct s of prit eli vir 
•  
T o s h o w t h e tri al’ s a s s a y s e n siti vit y b y a s s e s si n g t h e eff e ct s of m o xifl o x a ci n  
( p o siti v e c o ntr ol v s. pl a c e b o ) o n t h e Q T c F i nt er v al 
•  
T o i n v e sti g at e t h e s af et y a n d t ol er a bilit y of prit eli vir 
 
2. 2  
E n d p oi n t s 
P ri m a r y 
•  
Q T c u si n g Fri d eri ci a c orr e cti o n m et h o d ( Q T c F ) . T h e pri m ar y e n d p oi nt i s 
d efi n e d a s t h e m o d el b a s e d Q T c F c h a n g e fr o m b a s eli n e ( Δ Q T c F ), w h er e 
b a s eli n e i s t h e a v er a g e of t h e 3 pr e - d o s e m e a s ur e m e nt s of D a y 1. E C G s 
fr o m D a y 1, D a y 6 a n d D a y 1 6 will b e u s e d f or c o m p ari s o n a g ai n st b a s eli n e. 
S e c o n d a r y  
• 
H e art r at e 
• 
P R i nt er v al 
• 
Q R S i nt er v al 
• 
U n c orr e ct e d Q T i nt er v al 
• 
C h a n g e i n E C G m or p h ol o gi c al p att er n s 
 
S af e t y a n d t ol e r a bili t y 
•  
O v er all t ol er a bilit y 
•  
N at ur e, fr e q u e n c y, d ur ati o n, i nt e n sit y, s eri o u s n e s s, a n d c a u s alit y of a d v er s e 
e v e nt s 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x             P a g e 5 of 1 5  
 
•  
P h y si c al e x a mi n ati o n, vit al si g n s, a n d b o d y t e m p er at ur e 
•  
Cli ni c al l a b or at or y p ar a m et er s : s er u m c h e mi str y, h e m at ol o g y a n d 
c o a g ul ati o n p ar a m et er s, uri n al y si s 
•  
St a n d ar d 1 2 -l e a d E C G c oll e ct e d u si n g a 1 2 -l e a d E C G d e vi c e 
P h a r m a c o ki n e ti c s 
Pl a s m a c o n c e ntr ati o n s of prit eli vir a n d it s m et a b olit e s AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5 
will b e d et er mi n e d  f or t h e p ur p o s e of t h e c o n c e ntr ati o n - eff e ct a n al y si s ( d e s cri b e d 
i n t hi s d o c u m e nt ) a s w ell a s f or st a n d ar d p h ar m a c o ki n eti c e v al u ati o n ( d e s cri b e d i n 
t h e s e p ar at e P K S A P ). 
M o xifl o x a ci n pl a s m a c o n c e ntr ati o n s 
will b e d et er mi n e d f or t h e p ur p o s e of t h e 
c o n c e ntr ati o n- eff e ct a n al y si s t o d e m o n str at e a s s a y s e n siti vit y. T h e c o n c e ntr ati o n s 
will b e r e p ort e d, b ut n o p h ar m a c o ki n eti c p ar a m et er s will b e d et er mi n e d. 
P h a r m a c o g e n o mi c s / g e n e e x p r e s si o n 
• 
P o st- h o c a n al y si s of all el e s a s s o ci at e d wit h alt er e d dr u g m et a b oli s m / 
di s p o siti o n m a y b e d et er mi n e d. 
 
3.   
T R I A L D E S I G N 
3. 1 O v e r all T ri al D e si g n 
 
T hi s P h a s e 1 cli ni c al tri al i s a d o u bl e - bli n d, si n gl e - c e nt er, r a n d o mi z e d, p l a c e b o - 
a n d p o siti v e - c o ntr oll e d, p ar all el - gr o u p, ‘ n e st e d cr o s s o v er’ tri al wit h m ulti pl e or al  
d o s e a d mi ni str ati o n of prit eli vir or m at c hi n g pl a c e b o a s w ell a s a si n gl e or al  
a d mi ni str ati o n of m o xifl o x a ci n ( p o siti v e - c o ntr ol ) a n d c orr e s p o n di n g m at c hi n g 
pl a c e b o i n h e alt h y m al e a n d f e m al e s u bj e ct s. 
 
S u bj e ct s will b e i n- h o u s e fr o m D a y - 2 t o D a y 2 0 a n d will b e r a n d o mi z e d t o o n e of 
t h e 2 p ar all el tr e at m e nt gr o u p s : Gr o u p 1 will r e c ei v e a t h er a p e uti c a n d a s u pr a -
t h er a p e uti c d o s e of prit eli vir pl u s m o xifl o x a ci n pl a c e b o. Gr o u p 2 will r e c ei v e 
prit eli vir pl a c e b o a s w ell a s m o xifl o x a ci n a n d m at c hi n g pl a c e b o ( n e st e d cr o s s o v er : 
Gr o u p 2 a a n d Gr o u p 2 b ). 1 2 -l e a d E C G tri pli c at e s will b e r e c or d e d fr o m t h e b e d si d e 
1 2 -l e a d- E C G o n t h e D a y s - 1, 1, 2, 6, 1 6, a n d 1 7 a n d will b e a n al y s e d a ft er w ar d s 
i n e a c h gr o u p f or t h e s e 6 d a y s of d o c u m e nt ati o n b y a bli n d e d r e a d er. 
 
It i s of n ot e t h at H olt er E C G d at a will b e c oll e ct e d i n p ar all el at s cr e e ni n g t o 
e x cl u d e a n y o n e wit h pr e - e xi sti n g c ar di a c pr o bl e m s a s w ell a s o n D a y s - 1, 1, 2, 6,  
1 6, a n d 1 7 a s a b a c k - u p f or t h e b e d si d e 1 2 -l e a d- E C G s. 
 
I n Gr o u p 1, 3 2 m al e a n d f e m al e s u bj e ct s ( at l e a st 1 2 s u bj e ct s p er s e x ) will r e c ei v e 
a l o a di n g d o s e of 4 0 0 m g prit eli vir o n D a y 1. Aft er w ar d s t h e y will r e c ei v e 1 0 0 m g 
prit eli vir q d fr o m D a y 2 t o 6 a n d 4 0 0 m g prit eli vir q d fr o m D a y 7 t o 1 6. 
F urt h er m or e, t h e s e s u bj e ct s will r e c ei v e m at c hi n g m o xifl o x a ci n pl a c e b o o n t h e 
D a y s 2 a n d 1 7. 
 
I n Gr o u p 2, 3 2 m al e a n d f e m al e s u bj e ct s ( at l e a st 1 2 s u bj e ct s p er s e x ) will r e c ei v e 
t h e r e s p e cti v e a m o u nt s of t a bl et s of m at c hi n g prit eli vir pl a c e b o fr o m D a y 1 t o D a y 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x             P a g e 6 of 1 5  
 
1 6 i n Gr o u p 2 a s v er u m t a bl et s i n Gr o u p 1. F urt h er m or e, s u bj e ct s i n Gr o u p 2 a ( 1 6 
m al e a n d f e m al e s u bj e ct s ) will r e c ei v e 4 0 0 m g m o xifl o x a ci n o n D a y 2 a n d 
m at c hi n g m o xifl o x a ci n pl a c e b o o n D a y 1 7 a n d s u bj e ct s i n Gr o u p 2 b ( 1 6 m al e a n d 
f e m al e s u bj e ct s) will r e c ei v e 4 0 0 m g m o xifl o x a ci n o n D a y 1 7 a n d m at c hi n g 
m o xifl o x a ci n pl a c e b o o n D a y 2. 
 
Diff er e nt m e a s ur e s will b e n e e d e d, a n d d at a e v al u ati o n s g e n er at e d f or Gr o u p 1 
a n d Gr o u p 2, h o w e v er, t o m ai nt ai n d o u bl e bli n di n g b et w e e n Gr o u p 1 a n d Gr o u p  2 ; 
• 1 2 -l e a d E C G tri pli c at e s will b e r e c or d e d a n d a n al y s e d fr o m t h e b e d si d e 
1 2 -l e a d- E C G d e vi c e s i n s u bj e ct s of b ot h gr o u p s o n t h e D a y s - 1, 1, 2, 6, 1 6 
a n d 1 7. 
• P K s a m pl e s will b e c oll e ct e d fr o m s u bj e ct s of b ot h gr o u p s o n t h e D a y s 1, 
6, a n d 1 6 f or prit eli vir a n d t h e m et a b olit e s AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5  a s 
w ell a s f or m o xifl o x a ci n o n t h e D a y s 2 a n d 1 7. 
• O v er - e n c a p s ul at e d m o xifl o x a ci n - a n d m at c hi n g pl a c e b o will b e u s e d. 
 
If A E s i nt erf er e wit h a d e q u at e E C G r e c or di n g, a Ri s k B e n efit C o m mitt e e 
( p arti ci p a nt s fr o m Ai C uri s a s w ell a s t h e Pri n ci p al I n v e sti g at or) mi g ht d e ci d e t o 
l o w er t h e ( s u pr a-t h er a p e uti c ) d o s e i n i n di vi d u al s u bj e ct s. 
 
Fi g u r e 1: T ri al fl o w c h a r t 
 
  
 
 
3. 2  
S a m pl e Si z e 
Si m ul ati o n s b y H u a n g et al s u g g e st t h at u si n g c o n c e ntr ati o n -r e s p o n s e a n al y si s, 
a s s a y s e n siti vit y c a n b e s h o w n wit h at l e a st 2 4 s u bj e ct s [ 1 ]. Si n c e i n t hi s tri al, t h e 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x             P a g e 7 of 1 5  
 
ti m e b et w e e n t h e 2 p eri o d s of t h e n e st e d cr o s s o v er i s 1 4 d a y s, it s e e m s pr u d e nt t o 
all o w f or a sli g htl y hi g h er v ari a bilit y of Δ Q T c a n d, t h er ef or e, a s a m pl e si z e of 3 2 
s u bj e ct s h a s b e e n pl a n n e d. A s s u mi n g a tr u e eff e ct of at m o st 3 m s, i. e., a m ar gi n 
of 7 m s, t h e p o w er t o s h o w a b s e n c e of a n eff e ct of prit eli vir i s hi g h er t h a n t h at t o 
s h o w a s s a y s e n siti vit y w h er e t h e m ar gi n m a y b e a s s u m e d t o b e 5 m s. T h er ef or e, 
3 2 s u bj e ct s i n t h e a cti v e gr o u p w er e c h o s e n. 
 
3. 3  
R a n d o mi s a ti o n a n d Bli n di n g 
S u bj e ct R a n d o mi s ati o n 
S u bj e ct s will b e r a n d o ml y a s si g n e d t o Gr o u p 1, Gr o u p 2 a, or Gr o u p 2 b at a 2 : 1 : 1 
r ati o. All s u bj e ct s i n t hi s tri al will b e a s si g n e d t o a tr e at m e nt r e gi m e n a c c or di n g t o 
a r a n d o mi z ati o n s c h e d ul e g e n er at e d b y a st ati sti ci a n u si n g P R O C Pl a n. D et ail s 
r e g ar di n g t h e u ni q u e s cr e e ni n g a n d s u bj e ct n u m b er will b e i n cl u d e d i n t h e T O M. 
M ai nt e n a n c e a n d m et h o d s f or e n s uri n g bli n di n g 
T h e p h ar m a c y st aff pr e p ari n g t h e I M P will n ot b e bli n d e d t o tri al dr u g a s si g n m e nt. 
D uri n g t h e tri al, t h e i n di vi d u al r a n d o mi z ati o n c o d e s will b e k e pt i n t h e sit e’ s cli ni c al 
tri al s p h ar m a c y, a c c e s si bl e t o t h e p h ar m a c y p er s o n n el o nl y. U p o n c o m pl eti o n of t h e 
tri al, aft er t h e d at a b a s e l o c k a n d aft er t h e bli n d i s r e v e al e d, t h e r a n d o mi z ati o n li st 
will b e fil e d i n t h e Tri al M a st er Fil e. A d mi ni str ati v e a n d o p er ati o n al st aff of t h e tri al 
sit e, i n cl u di n g Pri n ci p al I n v e sti g at or a n d tri al m a n a g er a s w ell a s m o nit or s, Ai C uri s 
st aff a n d d at a 
m a n a g er s will r e m ai n bli n d e d d uri n g t h e c o ur s e of t h e tri al u nti l 
D at a b a s e L o c k a n d fi n ali z ati o n of t h e St ati sti c al A n al y si s Pl a n.  
U n bli n di n g Pr o c e d ur e 
I n t h e e v e nt of a n e m er g e n c y, a n e n v el o p e f or e a c h s u bj e ct c o nt ai ni n g hi s / h er tri al 
dr u g a s si g n m e nt will b e a v ail a bl e i n t h e p h ar m a c y at t h e cli ni c al tri al sit e. U n bli n di n g 
s h o ul d o nl y b e c o n si d er e d f or t h e s af et y of t h e s u bj e ct. If u n bli n di n g i s d e e m e d 
n e c e s s ar y b y t h e I n v e sti g at or, t h e I n v e sti g at or or d e si g n e e c a n u n bli n d t h e s u bj e ct’ s 
tr e at m e nt all o c ati o n 
u si n g t h e e n v el o p e a v ail a bl e fr o m t h e 
p h ar m a c y. T h e 
I n v e sti g at or or d e si g n e e m u st n ot e t h e d at e, ti m e, a n d r e a s o n f or u n bli n di n g a n d 
i nf or m t h e S p o n s or of u n bli n di n g a s s o o n a s pr a cti c a bl y p o s si bl e. 
 
4. S T A T I S T I C A L A N A L Y S E S 
4. 1 G e n e r al N o t e s f o r S t a ti s ti c al A n al y s e s  
St ati sti c al a n al y si s a n d r e p orti n g will b e p erf or m e d b y R P L f or s af et y, d e m o gr a p hi c s 
a n d E C G a n al y si s a n d b y V e n n Lif e S ci e n c e s f or p h ar m a c o ki n eti c s. 
I n g e n er al, d e s cri pti v e st ati sti c s f or c o nti n u o u s v ari a bl e s will i n cl u d e n u m b er of n o n -
mi s si n g v al u e s ( n ), arit h m eti c m e a n, st a n d ar d d e vi ati o n ( S D ), m e di a n, mi ni m u m , 
a n d m a xi m u m.  
C at e g ori c al v ari a bl e s will b e s u m m ari z e d u si n g fr e q u e n c y c o u nt s a n d p er c e nt a g e s.  
F or all t a bl e s, d e s cri pti v e st ati sti c s f or mi ni m u m a n d m a xi m u m will b e pr e s e nt e d 
wit h t h e s a m e d e ci m al di git s a s t h e ori gi n al d at a, a n d wit h 1 m or e d e ci m al pl a c e 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x             P a g e 8 of 1 5  
 
t h a n t h e ori gi n al d at a f or m e a n a n d m e di a n ; S D a n d S E will b e r e p ort e d wit h 2 m or e 
d e ci m al pl a c e s t h a n t h e ori gi n al d at a. D e gr e e s of fr e e d o m b a s e d o n t h e K e n w ar d  
R o g er a p pr o xi m ati o n will b e pr e s e nt e d wit h o n e d e ci m al. 
T h e a n al y s e s will b e pr e s e nt e d o v er all ( w h er e a p pr o pri at e ) a n d b y t h e tr e at m e nt 
gr o u p s. 
All c oll e ct e d d at a will b e pr e s e nt e d i n b y - s u bj e ct li sti n g s. Li sti n g s will b e or d er e d b y 
tr e at m e nt gr o u p a n d s u bj e ct n u m b er a n d will i n cl u d e all r a n d o mi z e d s u bj e ct s. 
U nl e s s ot h er wi s e st at e d, b a s eli n e will b e d efi n e d a s t h e l a st n o n- mi s si n g v al u e pri or 
t o fir st a d mi ni str ati o n of tri al dr u g. C h a n g e s fr o m b a s eli n e v al u e s will b e c al c ul a t e d 
a s t h e p o st - b a s eli n e a s s e s s m e nt v al u e 
mi n u s t h e b a s eli n e v al u e. O nl y o b s er v e d 
v al u e s fr o m s c h e d ul e d ti m e p oi nt s will b e u s e d t o cr e at e s u m m ar y t a bl e s. 
If r e p e at e d m e a s ur e m e nt s ar e m a d e at a ti m e p oi nt, t h e fir st s c h e d ul e d v al u e will 
b e u s e d f or s u m m ar y a n al y si s, u nl e s s ot h er wi s e st at e d i n r el e v a nt s e cti o n of t hi s 
S A P. 
D e vi ati o n s fr o m t h e pl a n n e d a n al y s e s will b e d e s cri b e d i n t h e fi n al cli ni c al tri al r e p ort 
( C T R ). 
  
4. 2  
I n t e ri m A n al y si s 
N o i nt eri m a n al y si s i s pl a n n e d f or t hi s tri al. 
 
4. 3  
A n al y si s S e t s  
T h e a n al y si s of d at a will b e b a s e d diff er e nt a n al y si s s et s a c c or di n g t o t h e p ur p o s e 
of a n al y si s. S u bj e ct eli gi bilit y f or e a c h a n al y si s s et will b e fi n ali s e d b ef or e t h e 
d at a b a s e h ar d l o c k. A s u bj e ct w h o wit h dr a w s pri or t o t h e l a st pl a n n e d o b s er v ati o n 
i n a trial  p eri o d will b e i n cl u d e d i n a n al y s e s u p t o t h e ti m e of di s c o nti n u ati o n.  
T h e f oll o wi n g d at a s et s will b e u s e d f or a n al y si s a n d pr e s e nt ati o n of t h e tri al d at a :  
S af et y S et  
T h e s af et y s et ( S S ) will c o n si st of all r a n d o mi s e d s u bj e ct s w h o r e c ei v e d at l e a st o n e 
d o s e of t h e tri al m e di c ati o n. 
P K S et 
T h e P h ar m a c o ki n eti c S et ( P K S ) will i n cl u d e all s u bj e ct s i n S S w h o h a d at l e a st 1 
v ali d pl a s m a c o n c e ntr ati o n -ti m e p oi nt t o b e i n cl u d e d i n t h e P K a n al y si s. T h e P K S 
will b e u s e d f or t h e P K a n al y s e s ( o ut of s c o p e f or t hi s S A P ). 
E C G s et f or c o n c e ntr ati o n - Q T c a n al y si s 
T h e E C G s et will i n cl u d e all s u bj e ct s i n t h e S S t h at h a v e at l e a st o n e v ali d pr e - d o s e 
E C G a s s e s s m e nt a n d o n e v ali d p o st - d o s e a s s e s s m e nt E C G s ar e c o n si d er e d v ali d if 
t h e y ar e b a s e d o n at l e a st 2 r e pli c at e s wit h m e a s ur a bl e Q T c a n d R R. 
T h e a n al y si s s et f or c o n c e ntr ati o n - Q T c a n al y si s will b e a s u b s et of t h e i nt er s e cti o n 
of t h e P K s et a n d t h e E C G s et. It c o nt ai n s all m e a s ur e m e nt s wit h a v ali d pl a s m a 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x             P a g e 9 of 1 5  
 
c o n c e ntr ati o n a n d v ali d Q T c r e s ult s. P o st d o s e v al u e s w h er e t h e ti m e of bl o o d 
s a m pli n g a n d t h at of t h e E C G m e a s ur e m e nt (l a st tri pli c at e ) d e vi at e b y m or e t h a n  
-  
1 1 mi n f or ti m e p oi nt s 1 5 mi n t o 1 h p o st d o s e 
-  
1 6 mi n f or ti m e p oi nt s 2 h t o 4 h p o st d o s e 
-  
1 8 mi n f or ti m e p oi nt 5 h p o st d o s e 
-  
3 3 mi n f or ti m e p oi nt s 6 h t o 1 2 h p o st d o s e. 
will b e e x cl u d e d. If t hi s r ul e l e a d s t o m or e t h a n 3 e x cl u si o n s i n a s u bj e ct p er E C G 
d a y , it will b e r e pl a c e d b y t h e f oll o wi n g pr o c e d ur e : pl a s m a c o n c e ntr ati o n s at t h e 
ti m e of t h e E C G (l a st tri pli c at e ) 
will b e i nt er p ol at e d, b a s e d o n t h e pl a s m a 
c o n c e ntr ati o n s pr e c e di n g a n d f oll o wi n g t h e ti m e of E C G. M or e s p e cifi c all y, t hi s will 
b e d o n e b y a li n e ar i nt er p ol ati o n f or E C G ti m e s b ef or e t h e i n di vi d u al T m a x  of t h e 
r e s p e cti v e s u bj e ct, a n d b y a l o g -li n e ar i nt er p ol ati o n f or ti m e s t h er e aft er. F or t h e 
fir st p o st - d o s e E C G o n D a y 1, a pl a s m a c o n c e ntr ati o n of n o u g ht at t h e ti m e of dru g 
a d mi ni str ati o n 
will b e i m p ut e d f or t hi s i nt er p ol ati o n. 
Wit h t hi s pr o c e d ur e, n o 
e x cl u si o n s d u e t o ti m e b et w e e n E C G a n d P K ar e e x p e ct e d. 
F or c o n c e ntr ati o n Q T c  a n al y s e s, t h e pr e - d o s e v al u e s of D a y 1 will o nl y b e u s e d f or 
b a s eli n e c al c ul ati o n. F or l at er d a y s, v al u e s of o n e pr e - d o s e ti m e p oi nt o nl y will b e 
i n cl u d e d. T hi s will b e t h e –  2 0 mi n ti m e p oi nt if it i s v ali d, ot h er wi s e t h e - 4 0 mi n 
ti m e p oi nt m a y b e u s e d if t h e ti m e b et w e e n t h e r e s p e cti v e E C G (l a st tri pli c at e ) a n d 
bl o o d dr a w d o e s n ot e x c e e d 4 0 mi n. 
 
4. 4  
S u bj e c t Di s p o si ti o n  
All s u bj e ct s will b e i n cl u d e d i n t h e s u m m ar y of s u bj e ct di s p o siti o n. T hi s will pr e s e nt 
t h e o v er all 
n u m b er of s u bj e ct s, t h e fr e q u e n c y a n d p er c e nt a g e of s u bj e ct s 
r a n d o mi z e d a n d tr e at e d, a n d w h o c o m pl et e d or di s c o nti n u e d fr o m t h e tri al, al o n g 
wit h r e a s o n f or di s c o nti n u ati o n.  
F urt h er m or e, t h e n u m b er a n d p er c e nt a g e of s u bj e ct s i n e a c h a n al y si s s et will b e 
t a b ul at e d. Di s c o nti n u e d s u bj e ct s will b e li st e d. S u bj e ct a s si g n m e nt t o a n al y si s s et s 
will b e li st e d. F or t h e s et of c o n c e ntr ati o n - Q T c a n al y si s, m e a s ur e m e nt s e x cl u d e d 
a n d t h e r e a s o n f or e x cl u si o n will b e li st e d. S cr e e n F ail ur e s will n ot b e li st e d or 
i n cl u d e d i n s u m m ar y t a bl e s. 
 
4. 5  
D e m o g r a p hi c C h a r a c t e ri s ti c s 
I n di vi d u al p arti ci p a nt d e m o gr a p hi c s ( a g e, s e x, et h ni cit y a n d r a c e ) a n d b o d y 
m e a s ur e m e nt d at a ( h ei g ht, w ei g ht, a n d B MI) at s cr e e ni n g will b e li st e d. T h e s e 
d e m o gr a p hi c c h ar a ct eri sti c s a n d b o d y 
m e a s ur e m e nt s 
will b e s u m m ari z e d b y 
tr e at m e nt gr o u p a n d o v er all, u si n g t h e s af et y a n al y si s s et. 
Ot h er b a s eli n e 
c h ar a ct eri sti c s will b e li st e d o nl y. 
 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x            P a g e 1 0  of 1 5  
 
4. 6  
I n cl u si o n a n d E x cl u si o n C ri t e ri a 
T h e i n cl u si o n a n d e x cl u si o n crit eri a t e xt will b e li st e d, a s w ell a s f ail e d eli gi bil it y 
crit eri a f or e a c h r a n d o mi s e d s u bj e ct, if a n y. 
 
4. 7  
P r o t o c ol D e vi a ti o n s 
T h e fi n al r e vi e w of pr ot o c ol d e vi ati o n s will b e p erf or m e d at t h e D R M pri or t o 
d at a b a s e l o c k. T h e pr ot o c ol d e vi ati o n s will b e li st e d. 
 
4. 8  
M e di c al a n d S u r gi c al Hi s t o r y 
M e di c al a n d S ur gi c al hi st or y d at a will b e c o d e d u si n g t h e M e di c al Di cti o n ar y f or 
R e g ul at or y A cti viti e s ( M e d D R A ) di cti o n ar y V er si o n 2 4. 0 ( or hi g h er) a n d li st e d 
i n di vi d u all y. S ur gi c al hi st or y d at a will b e li st e d s e p ar at el y. M e di c al a n d S urgi c al 
hi st or y d at a will b e s u m m ari s e d u si n g fr e q u e n c y a n d p er c e nt a g e b y S O C a n d 
pr ef err e d t er m. 
 
4. 9  
T ri al D r u g A d mi ni s t r a ti o n 
Tri al dr u g a d mi ni str ati o n d at a i n cl u di n g tr e at m e nt r e c ei v e d, d o s e ( u nit), d at e a n d 
ti m e of a d mi ni str ati o n will b e li st e d b y s u bj e ct. 
 
4. 1 0 
P ri o r a n d C o n c o mi t a n t M e di c ati o n s 
All pri or a n d c o n c o mit a nt 
m e di c ati o n s 
will b e c o d e d u si n g t h e 
W orl d 
H e alt h 
Or g a ni z ati o n Dr u g Di cti o n ar y v er si o n 2 0 2 2 ( or hi g h er) a n d will b e li st e d i n d i vi d u all y. 
T h e fr e q u e n c y a n d p er c e nt a g e of pri or a n d c o n c o mit a nt 
m e di c ati o n s 
will b e 
s u m m ari z e d b y A n at o mi c al T h er a p e uti c C h e mi c al a n d Pr ef err e d N a m e. S e p ar at e 
t a bl e s will b e gi v e n f or pri or a n d c o n c o mit a nt m e di c ati o n s. Pri or m e di c ati o n s ar e 
d efi n e d a s t h o s e f or w hi c h t h e e n d d at e a n d ti m e i s pri or t o t h e d at e, a n d ti m e of 
fir st tri al dr u g a d mi ni str ati o n. C o n c o mit a nt m e di c ati o n s ar e d efi n e d a s t h o s e wit h 
st art d at e a n d ti m e o n or aft er t h e d at e a n d ti m e of fir st tri al dr u g a d mi ni str a ti o n 
a n d t h o s e wit h st art d at e a n d ti m e pri or t o t h e fir st tri al dr u g a d mi ni str ati o n  b ut 
wit h e n d d at e a n d ti m e o n or aft er t h e d at e a n d ti m e of fir st tri al dr u g a d mi ni str ati o n. 
If m e di c ati o n d at e s ar e i n c o m pl et e a n d it i s n ot cl e ar w h et h er t h e m e di c ati o n w a s 
c o n c o mit a nt, it will b e a s s u m e d t o b e c o n c o mit a nt. 
 
4. 1 1 
S af e t y A n al y si s 
S af et y a n al y s e s will b e p erf or m e d o n t h e s af et y s et, u nl e s s ot h er wi s e st at e d .  
S af et y a n al y s e s will i n cl u d e a n a n al y si s of all A E s, E C G s, cli ni c al l a b or at or y d at a, 
vit al si g n 
m e a s ur e m e nt s a n d p h y si c al e x a mi n ati o n r e s ult s a n d will b e pr e s e nt e d 
u si n g d e s cri pti v e st ati sti c s. N o f or m al st ati sti c al a n al y si s will b e p erf or m e d. 
 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x            P a g e 1 1  of 1 5  
 
4. 1 1. 1 A d v er s e E v e nt s  
A Tr e at m e nt E m er g e nt A d v er s e E v e nt ( T E A E ) i s d efi n e d a s a n y a d v er s e e v e nt w hi c h 
c o m m e n c e s 
or 
a n y 
w or s e ni n g 
of 
pr e - e xi sti n g c o n diti o n s aft er t h e st art 
of 
a d mi ni str ati o n of tri al dr u g.  A E s wit h u n k n o w n st art d at e /ti m e will b e a s s u m e d t o 
b e tr e at m e nt - e m er g e nt u nl e s s t h e e n d d at e /ti m e i s k n o w n t o b e b ef or e t h e fir st 
a d mi ni str ati o n of tri al dr u g.  
A E d at a will b e li st e d a n d T E A E s s u m m ari s e d u si n g d e s cri pti v e st ati sti c s : t h e n u m b er  
( a n d p er c e nt a g e ) of p arti ci p a nt s w h o e x p eri e n c e d a n y A E s a n d t h e n u m b er of A E 
e pi s o d e s will b e s u m m ari z e d f or e a c h tr e at m e nt gr o u p. All A E s will b e s u m m ari z e d 
a n d li st e d b y u si n g t h e S y st e m Or g a n Cl a s s ( S O C ) a n d Pr ef err e d T er m ( P T) a s si g n e d 
t o t h e e v e nt u si n g t h e M e d D R A. C h a n g e s i n i nt e n sit y of a n A E s h o ul d b e r e c or d e d 
a s a s e p ar at e A E wit h a n e w o n s et. T h e n u m b er of p arti ci p a nt s w h o e x p eri e n c e d 
dr u g -r el at e d A E s will al s o b e s u m m ari z e d. A n y S A E s a n d/ or A E s t h at l e d t o tri al 
wit h dr a w al will b e s u m m ari z e d a n d li st e d. 
 
4. 1 1 . 2 L a b or at or y D at a 
All s af et y cli ni c al l a b or at or y d at a will b e li st e d. L a b or at or y t e st r e s ult s will al s o b e 
c o m p ar e d t o l a b or at or y r ef er e n c e r a n g e s. T h o s e v al u e s o ut si d e of t h e a p pli c a bl e 
r a n g e will b e fl a g g e d a s hi g h or l o w, a n d a s cli ni c all y si g nifi c a nt or n ot ( C S / N C S ) . 
T h e n u m b er of p arti ci p a nt s t h at pr e s e nt o ut - of -r a n g e, a n d cli ni c all y r el e v a nt v al u e s, 
will b e s u m m ari z e d. T h e q u a ntit ati v e l a b or at or y d at a a n d c h a n g e s fr o m b a s eli n e will 
b e s u m m ari z e d u si n g d e s cri pti v e st ati sti c s ( m e a n, 
m e di a n, st a n d ar d d e vi ati o n, 
mi ni m u m, 
m a xi m u m). C h a n g e fr o m b a s eli n e v al u e s at e a c h a s s e s s m e nt will b e  
c al c ul at e d a s t h e a s s e s s m e nt v al u e 
mi n u s t h e b a s eli n e v al u e. T h e q u alit ati v e 
uri n al y si s d at a will b e li st e d o nl y. 
T h e 
s c h e d ul e d l a b 
v al u e 
will 
b e 
u s e d f or 
s u m m ar y 
a n al y si s if r e p e at e d 
m e a s ur e m e nt s ar e m a d e at a n y ti m e p oi nt.  
F or s u m m ar y st ati sti c s, a l a b v al u e wit h “ < ” will b e r e pl a c e d wit h a n u m eri c v al u e 
b y r e m o vi n g t h e “ < ” si g n. I n t h e li sti n g s, t h e v al u e s will b e di s p l a y e d a s ori gi n all y 
r e p ort e d b y t h e l a b or at or y. 
 
4. 1 1. 3 Vit al Si g n s 
Vit al si g n s d at a ( S B P, D B P, p ul s e r at e, t e m p er at ur e ) will b e li st e d a n d s u m m ari z e d, 
al o n g 
wit h c h a n g e s fr o m b a s eli n e, u si n g d e s cri pti v e st ati sti c s ( m e a n, 
m e di a n, 
st a n d ar d d e vi ati o n, 
mi ni m u m, 
m a xi m u m ). O ut - of -r ef er e n c e -r a n g e v al u e s will b e 
fl a g g e d a s hi g h or l o w a n d a s b ei n g cli ni c all y r el e v a nt or n ot. T h e n u m b er of 
p arti ci p a nt s 
pr e s e nti n g 
o ut - of -r a n g e 
a n d 
cli ni c all y r el e v a nt 
v al u e s 
will 
b e 
s u m m ari z e d. 
 
N or m al r a n g e s f or t h e r el e v a nt p ar a m et er s ar e pr e s e nt e d b el o w : 
 
 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x            P a g e 1 2  of 1 5  
 
P ar a m et er 
N or m al R a n g e 
T e m p er at ur e (t y m p a ni c )  
3 5 - 3 8 ° C  
S y st oli c Bl o o d Pr e s s ur e ( S u pi n e )  
9 0 – 1 3 0 m m H g  
Di a st oli c Bl o o d Pr e s s ur e ( S u pi n e )  
4 0 – 9 0 m m H g  
H e art R at e ( s u pi n e )  
4 0 – 1 0 0 b p m  
 
4. 1 1. 4 H olt er  
H olt er d at a ( St art / E n d D at e ti m e a n d e v al u ati o n ) will b e li st e d b y s u bj e ct. 
 
4. 1 1. 5 P h y si c al E x a mi n ati o n  
T h e p h y si c al e x a mi n ati o n p erf or m e d at s cr e e ni n g a n d at t h e e n d of -tri al vi sit will b e 
li st e d o nl y a n d i n cl u d e a n a s s e s s m e nt of t h e f oll o wi n g: g e n er al a p p e ar a n c e, s ki n, 
e y e s / e ar s / n o s e, n e c k, l y m p h n o d e s, t hr o at, h e art, l u n g s, a b d o m e n, m u s c ul o s k el et al 
s y st e m a n d e xtr e miti e s. 
 
4. 1 1. 6 El e ctr o c ar di o gr a m s 
 
All a dj u di c at e d a n d u n - a dj u di c at e d E C G d at a ( P R, Q R S, Q T, Q T c F a n d H R ) a n d 
o v er all E C G e v al u ati o n will b e li st e d, i n cl u di n g a H / L fl a g f or o ut - of -r ef er e n c e -r a n g e 
v al u e s.  R ef er e n c e r a n g e s f or E C G s ar e a s f oll o w s : 
 
P ar a m et er 
N or m al R a n g e 
H e art R at e ( S u pi n e )  
4 0 - 1 0 0 b p m  
P R I nt er v al  
1 2 0 – 2 1 0 m s  
Q R S d ur ati o n  
≤1 2 0 m s  
Q T c F  
≤4 5 0 m s ( M al e s) ; ≤4 7 0 m s ( F e m al e s )  
 
B el o w a n al y s e s will b e p erf or m e d o n t h e a dj u di c at e d E C G s –  
m e a n v al u e s fr o m 
s el e ct e d tri pli c at e s fr o m e a c h ti m e - p oi nt aft er a dj u di c ati o n. 
 
E C G d at a a n d c h a n g e s fr o m b a s eli n e will b e s u m m ari s e d u si n g d e s cri pti v e 
st ati sti c s. 
 
F or s u m m ar y st ati sti c s, t h e ( arit h m eti c ) m e a n of t h e l a st 3 e v al u a bl e E C G s at  e a c h 
ti m e p oi nt will b e u s e d f or e a c h ti m e p oi nt.  
 
T h e c h a n g e fr o m b a s eli n e will b e d eri v e d u si n g t h e arit h m eti c m e a n v al u e of e a c h 
ti m e p oi nt tri pli c at e mi n u s b a s eli n e v al u e, w h er e b a s eli n e i s t h e arit h m eti c m e a n of 
t h e pr e - d o s e v al u e s of D a y 1 ( s e e b el o w f or b a s eli n e d efi niti o n ). 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x            P a g e 1 3  of 1 5  
 
F urt h er m or e, c at e g ori c al a n al y si s of Q T c F d at a will b e pr e s e nt e d a s f oll o w s : 
•  
A b s ol ut e Q T c F i nt er v al pr ol o n g ati o n  
o  Q T c F i nt er v al > 4 5 0 m s t o ≤ 4 8 0 m s  
o  Q T c F i nt er v al > 4 8 0 m s t o ≤ 5 0 0 m s  
o  Q T c F i nt er v al > 5 0 0 m s 
•  
C h a n g e fr o m b a s eli n e i n Q T c F i nt er v al 
o  Q T c F i nt er v al i n cr e a s e s fr o m b a s eli n e > 3 0 m s e c t o ≤ 6 0 m s e c  
o  Q T c F i nt er v al i n cr e a s e s fr o m b a s eli n e > 6 0 m s 
•  
F ulfilli n g b ot h, a b s ol ut e Q T c F v al u e s > 5 0 0 m s a n d Δ Q T c F > 6 0 m s ; 
 
A d diti o n al c at e g ori c al a n al y si s will b e pr e s e nt e d a s f oll o w s : 
• 
A b s ol ut e P R v al u e s > 2 0 0 m s, > 2 2 0 m s, wit h a pr e - d o s e v al u e b el o w t h e 
r e s p e cti v e t hr e s h ol d 
• 
Δ P R ≥2 5 %, i. e., p o st - d o s e P R o ut si d e t h e r a n g e of ( 0. 7 5, 1. 2 5) of t h e 
b a s eli n e v al u e 
• 
A b s ol ut e Q R S d ur ati o n > 1 1 0 m s a n d > 1 2 0 m s 
• 
Δ Q R S ≥2 5 %, i. e., p o st - d o s e Q R S o ut si d e t h e r a n g e of ( 0. 7 5, 1. 2 5) of t h e 
b a s eli n e v al u e 
• 
A b s ol ut e H R of < 5 0 b p m or ≥1 0 0 b p m  
• 
H e art r at e d e cr e a s e ≥2 5 % fr o m b a s eli n e t o a H R of < 5 0 b p m a n d / or 
i n cr e a s e ≥2 5 % fr o m b a s eli n e t o a H R of ≥1 0 0 b p m.  
 
T h e m e a n c h a n g e fr o m b a s eli n e v al u e of Q T cF will b e pl ott e d b y tr e at m e nt gr o u p 
a n d b y ti m e - p oi nt. T h e n u m b er of s u bj e ct s pr e s e nti n g o ut - of -r a n g e a n d cli ni c all y 
r el e v a nt v al u e s will b e s u m m ari s e d b y ti m e p oi nt a n d a cr o s s all ti m e p oi nt s. A 
s u bj e ct will b e c o u nt e d o n c e if t h e y h a v e m ulti pl e o ut of r a n g e v al u e s f or a gi v e n 
ti m e p oi nt. 
 
4. 1 2 E C G s a n al y s e s ( a dj u di c at e d ) 
 
St ati sti c al 
a n al y s e s 
of 
E C G 
v ari a bl e s 
will 
b e 
p erf or m e d 
a c c or di n g t o t h e 
r e c o m m e n d ati o n s pr o vi d e d b y t h e g ui d eli n e I C H - E 1 4 a n d it s Q & A d o c u m e nt s. Q T c  
a n d H R d at a will b e a n al y s e d u si n g a c o n c e ntr ati o n - eff e ct m o d el ( s e e b el o w ). T h e 
c o n c e ntr ati o n- E C G a n al y s e s will b e p erf or m e d o n t h e s et f or c o n c e ntr ati o n- Q T c  
a n al y si s, all ot h er a n al y s e s n ot r e q uiri n g P K d at a will b e p erf or m e d o n t h e E C G - S et. 
 
B a s eli n e f or q u a ntit ati v e E C G v ari a bl e s will b e t h e a v er a g e of t h e 3 pr e - d o s e v al u e s 
m e a s ur e d o n D a y 1 ( w hi c h i n t ur n ar e t h e a v er a g e o v er t h e i n di vi d u al tri pli c at e s ). 
 
4. 1 2. 1 C o n c e ntr ati o n - Q T c a n al y si s 
T h e pri m ar y e n d p oi nt i s d efi n e d a s t h e c o n c e ntr ati o n- Q T c - m o d el b a s e d 
Q T c F 
diff er e n c e s fr o m b a s eli n e ( Δ Q T c F), w h er e b a s eli n e i s t h e a v er a g e of t h e 3 pr e - d o s e 
m e a s ur e m e nt s of D a y 1. E C G s fr o m D a y 1, D a y 6 a n d D a y 1 6 will b e u s e d f or 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x            P a g e 1 4  of 1 5  
 
c o m p ari s o n a g ai n st b a s eli n e. M or e s p e cifi c all y, a s eri e s of 7 li n e ar 
mi x e d eff e ct 
m o d el s r el ati n g t h e c h a n g e fr o m b a s eli n e t o t h e c o n c e ntr ati o n s of prit eli vir a n d t h e 
m et a b olit e s AI C 0 9 0 0 1 5 a n d AI C 0 9 0 1 0 5, t o g et h er or s e p ar at el y, will b e fitt e d ( M 1: 
prit eli vir o nl y, M 1 2 : Prit eli vir a n d AI C 0 9 0 0 1 5, M 1 3 : prit eli vir a n d AI C 0 9 0 1 0 5, M 1 2 3 : 
all m oi eti e s, M 2 AI C 0 9 0 0 1 5 o nl y, M 2 3 : b ot h m et a b olit e s, n o p ar e nt, M 3: AI C 0 9 0 1 0 5 
o nl y). A p art fr o m t h e s e c o n c e ntr ati o n s, t h e m o d el s will i n cl u d e fi x e d eff e ct s f or ti m e 
a n d tr e at m e nt ( "tr e at m e nt i nt er c e pt " wit h l e v el s a cti v e a n d pl a c e b o ) a n d b a s eli n e 
a s a c o v ari at e. R a n d o m eff e ct s p er s u bj e ct f or t h e i nt er c e pt a n d, if f e a si bl e, f or t h e 
c o n c e ntr ati o n s i n cl u d e d i n t h e r e s p e cti v e m o d el s will b e gi v e n. M or e s p e cifi c all y, if 
a m o d el d o e s n ot c o n v er g e e v e n aft er r e s c ali n g of t h e c o v ari at e s, t h e r a n d o m eff e ct s 
f or c o n c e ntr ati o n s will b e r e m o v e d. If c o n v er g e n c e i s still n ot gi v e n, t h e c o v ari a n c e 
str u ct ur e m a y b e si m plifi e d. S el e cti o n of t h e pri m ar y m o d el will b e b a s e d o n m o d el 
fit a n d t h e A k ai k e I nf or m ati o n Crit eri o n. M or e s p e cifi c all y, a m o n g t h e m o d el s wit h 
n o si g nifi c a nt ( at t h e t w o si d e d 5 % l e v el ) tr e at m e nt i nt er c e pt, t h e o n e wit h l o w e st 
AI C will b e s el e ct e d a s pri m ar y. If t h e tr e at m e nt i nt er c e pt f or all 
m o d el s diff er s 
si g nifi c a ntl y fr o m n o u g ht, n o nli n e ar e - m a x m o d el s m a y b e i n v e sti g at e d. Pr e di cti o n s 
of t h e eff e ct of prit eli vir a n d m et a b olit e s at t h e c o n c e ntr ati o n s s e e n at t m a x  of e a c h 
of t h e m oi eti e s i n v ol v e d will b e u s e d t o e x cl u d e a n eff e ct of r e g ul at or y c o n c er n (i e, 
a o n e - si d e d 9 5 % c o nfi d e n c e i nt er v al f or Δ Q T c F c o m pl et el y b el o w 1 0 m s). 
 
Di a g n o sti c pl ot s will b e gi v e n f or all 
m o d el s. T h e s e i n cl u d e t h e pr e s e nt ati o n of 
o b s er v e d v s. pr e di ct e d v al u e s a n d t h e pl ot of t h e r e si d u al s a g ai n st t h e v ari a bl e s i n  
t h e m o d el a s w ell a s a g ai n st d a y. 
 
If t h e pri m ar y 
m o d el i s b a s e d o n o n e 
m oi et y o nl y, o b s er v e d Δ Q T c v er s u s 
c o n c e ntr ati o n will b e pr e s e nt e d. I n a d diti o n, a d e cil e pl ot a s d e s cri b e d i n t h e W hit e 
P a p er [ 2 ] will b e pr e s e nt e d wit h t h e p arti al r e si d u al wit h r e s p e ct t o c o n c e ntr ati o n  
a s d e p e n d e nt a n d c o n c e ntr ati o n a s i n d e p e n d e nt v ari a bl e. 
 
T h e gr o u p s 2 a a n d 2 b will b e p o ol e d f or a n al y si s. 
 
T h e a p pr o pri at e n e s s of t h e 
m o d el s u s e d will b e i n v e sti g at e d. I n p arti c ul ar, t hi s 
i n cl u d e s t h e a b s e n c e of a d el a y e d eff e ct (r e s p e cti v e t o all 3 
m oi eti e s ) a n d a n y 
r el e v a nt d e vi ati o n s fr o m li n e arit y. A b s e n c e of a d el a y e d eff e ct will b e i n v e sti g at e d  
b y a si m ult a n e o u s pl ot of Δ Δ Q T c F a n d t h e m e a n c o n c e ntr ati o n of t h e t hr e e m oi eti e s, 
w h er e Δ Δ Q T c F will b e o bt ai n e d fr o m t h e c o ntr a st s of t h e li n e ar mi x e d eff e ct s m o d el 
t o d e s cri b e t h e ti m e c o ur s e –  s e e b el o w. N ot e t h at a d el a y e d eff e ct will b e a pr o bl e m 
o nl y if t h e m a xi m u m of Δ Δ Q T c ( U m a x ) i s l at er t h a n t h e T m a x  of all t hr e e m oi eti e s. 
D e vi ati o n s fr o m li n e arit y will b e j u d g e d fr o m t h e tr e at m e nt i nt er c e pt a n d t h e 
di a g n o sti c pl ot s. A si g nifi c a nt tr e at m e nt i nt er c e pt will b e t a k e n a s a n i n di c at or f or 
i n a p pr o pri at e n e s s of t h e m o d el. 
 
4. 1 2. 2 A s s a y s e n siti vit y 
A c o m p ari s o n b et w e e n m o xifl o x a ci n a n d m at c hi n g pl a c e b o will b e d o n e i n gr o u p s 
2 a a n d 2 b t o d e m o n str at e a s s a y s e n siti vit y u si n g a si mil ar m o d el t o t h e m o d el M 1 
d e s cri b e d a b o v e. A s s a y s e n siti vit y will b e c o n cl u d e d if t h e l o w er li mit of t h e o n e -
si d e d 9 5 % CI f or t h e pr e di ct e d eff e ct will b e > 5 m s. 
 
4. 1 2. 3 Eff e ct o n H e art r at e a n d alt er n ati v e c orr e cti o n 


S t a ti s ti c al A n al y si s Pl a n  
 
 
 
C 2 1 0 4 2 Ai C uri s S A P Dr aft v 0. 1 1 9 A u g 2 0 2 2 C 2 1 0 4 2 Ai C uri s S A P F i n al 1. 0 1 6 D E C 2 0 2 2. d o c x            P a g e 1 5  of 1 5  
 
If t h er e ar e i n di c ati o n s t h at prit eli vir h a s a n eff e ct o n H R e x c e e di n g 1 0 b p m, H R wil l 
al s o b e s u b mitt e d t o a si mil ar a n al y si s a s Q T c F. If t hi s c o nfir m s a n eff e ct e x c e e di n g  
1 0 b p m, t h e n a n i n di vi d u al c orr e cti o n will b e d et er mi n e d b a s e d o n t h e E C G d at a 
fr o m D a y - 1, a n d Q T v al u e s c orr e ct e d a c c or di n g t o t hi s m et h o d ( Q T cI ) will r e pl a c e 
Q T c F i n t h e pri m ar y a n al y s e s. M or e s p e cifi c all y, a li n e ar m o d el r el ati n g l o g  Q T t o 
l o g R R (i n cl u di n g a n i nt er c e pt) will b e fitt e d t o t h e d at a of e a c h s u bj e ct s e p ar at el y 
a n d t h e c o effi ci e nt f or l o g R R ( β  s a y) will b e u s e d t o d efi n e Q T cI = Q T / R R [ s e c ]β f or 
e a c h s u bj e ct. T h e a p pr o pri at e n e s s of t h e c orr e cti o n s 
will al s o b e di s pl a y e d 
gr a p hi c all y u si n g Δ Q T c a n d Δ R R.  
 
4. 1 2. 4 Ot h er a n al y s e s 
All q u a ntit ati v e E C G v ari a bl e s a n d t h eir c h a n g e fr o m b a s eli n e will b e s u m m ari z e d 
b y ti m e p oi nt a n d tr e at m e nt gr o u p. T h e diff er e n c e b et w e e n t h e 2 tr e at m e nt gr o u p s 
will al s o b e pr e s e nt e d. I n a d diti o n, t h e y will b e a n al y s e d wit h r e s p e ct t o t h eir ti m e 
c o ur s e u si n g a mi x e d eff e ct s li n e ar m o d el. T hi s m o d el will h a v e tr e at m e nt ( prit eli vir,  
pl a c e b o ) a n d ti m e a s w ell a s t h eir i nt er a cti o n a s fi x e d eff e ct s a n d a r a n d o m i nt er c e pt  
p er s u bj e ct. T h e ti m e c o ur s e of t h e dr u g eff e ct will b e e sti m at e d fr o m t h e c o ntr a st 
u si n g tr e at m e nt a n d ti m e b y tr e at m e nt i nt er a cti o n. 
 
4. 1 3 P h a r m a c o ki n eti c D a t a 
 
P K p ar a m et er a n al y si s a n d r e p ort ar e o ut of s c o p e f or t hi s S A P a n d d et ail s o n t hi s 
a n al y si s will b e pr o vi d e d b y V e n n Lif e S ci e n c e s. 
 
5.   R E F E R E N C E S 
1.  D al o n g P atri c k H u a n g, J a n ell C h e n, Qi a n y u D a n g & Yi T s o n g ( 2 0 1 9 ) 
A s s a y s e n siti vit y i n “ H y bri d t h or o u g h Q T / Q T c ( T Q T ) ” st u d y, J o ur n al of 
Bi o p h ar m a c e uti c al St ati sti c s, 2 9 : 2, 3 7 8 - 3 8 4, D OI : 
1 0. 1 0 8 0 / 1 0 5 4 3 4 0 6. 2 0 1 8. 1 5 3 5 4 9 8 
2.  G ar n ett C, B o n at e P, D a n g Q, F er b er G, H u a n g D, Li u J, M e h ortr a D, 
Ril e y P, S a g er P, T or n o e C, W a n g Y. 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 elli n g. J o ur n al of P h ar m a c o ki n eti c s a n d 
P h ar m a c o d y n a mi c s. 2 0 1 8 ; 4 5, 3 8 3 - 3 9 7. 
htt p s :/ /li n k. s pri n g er. c o m / arti cl e / 1 0. 1 0 0 7 % 2 F s 1 0 9 2 8 - 0 1 7 - 9 5 5 8 - 5 . 
A c c e s s e d o n 1 5 O ct o b er 2 0 2 1. 


D o c u m e nt Hi st or y
Si g n N o w E- Si g n at ur e A u dit L o g
All d at e s e x pr e s s e d i n M M/ D D/ Y Y Y Y
( U S)
D o c u m e nt n a m e:
C 2 1 0 4 2 Ai C uri s S A P Fi n al 1. 0 1 6 D E C 2 0 2 2
D o c u m e nt cr e at e d:
1 2/ 1 6/ 2 0 2 2 1 6: 5 8: 0 8
D o c u m e nt p a g e s:
1 5
D o c u m e nt I D:
b 2 8 8 c e a 7 c 7 6 7 4 3 df 9 8 5f b 1 c 0 7 2 5f 4 e e d e e 6 1 7 9 1 8
D o c u m e nt S e nt:
1 2/ 1 6/ 2 0 2 2 1 7: 0 5: 4 6 U T C
D o c u m e nt St at u s:
Si g n e d
1 2/ 1 6/ 2 0 2 2 1 7: 0 6: 1 8 U T C
S e n d er:
Si g n er s: