A Phase 1, Multicompartmental Pharmacokinetic Study of Cabotegravir Long-acting in Healthy Adult Volunteers
Phase: PHASE1
Conditions: Infection, Human Immunodeficiency Virus, HIV Infections
Sponsor: ViiV Healthcare

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s
2 0 1 7 6 7
1
TI T L E P A G E
Di visi o n: W orl d w i de De vel o p me nt
I nf or m ati o n T y pe: Pr ot oc ol A me n d me nt
Title:
A P hase 1, M ultic o m part me nt al P har mac o ki netic St u d y  of 
Ca b ote gra vir L o n g- acti n g i n Healt h y A d ult V ol u nteers
C o m p o u n d N u m ber:
G S K 1 2 6 5 7 4 4
De vel o p me nt P h ase:
I
Effecti ve D ate:
1 4 -A U G - 2 0 1 7
Pr ot oc ol A me n d me nt N u m ber :  0 3
A ut h or (s):
P P D
Direct or , Cli nical De vel o p me nt, Vii V
Direct or, Cli nical De vel o p me nt, Vii V
Q ua ntitati ve Cli nical De vel o p me nt, P A R E X E L
Cli nical Statis tics, P A R E X E L
Cli nical P har mac ol o g y  Tea m Lea der, Vii V
Me dical C o m m u nicati o ns Ma na ger, Vii V 
Cli nical P har mac ol o g y  Scie nce a n d St u d y O perati o ns
Di visi o ns of Cli nical P har mac ol o g y  & I nfecti o us Disease, J o h ns 
H o p ki ns U ni versit y
Di visi o ns of Cli nical P har mac ol o g y  & I nfecti o us Disease, J o h ns 
H o p ki ns U ni versit y
Di visi o n of Cli nical P har mac ol o g y , J o h ns H o p ki ns U ni versit y
C o p y ri g ht 2 0 1 7 t he Vii V Healt hcare a n d t he Gla x o S mit h Kli ne gr o u p of c o m pa nies.  All 
ri g hts reser ve d.  U na ut h orise d c o pyi n g or use of t his i nf or mati o n is pr o hi bite d

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s
2 0 1 7 6 7
2
Re visi o n C hr o n ol o g y
Gl a x o S mit h Kli ne 
D oc u me nt N u m ber
D ate
Versi o n
2 0 1 4 N 2 1 3 7 4 7 _ 0 0
2 0 1 5 -M A Y - 0 4
Ori gi nal
2 0 1 4 N 2 1 3 7 4 7 _ 0 1
2 0 1 5 -N O V- 1 0
A me n d me nt N o. 1
A me n d me nt 1 i ncl u des a d diti o nal e xcl usi o n criteria f or s u bjects wit h hist or y  of seiz ure 
dis or der
2 0 1 4 N 2 1 3 7 4 7 _ 0 2
2 0 1 6 -M A R - 3 0
A me n d me nt N o. 2
A me n d me nt 2 u p date d t he C A B L A I M d ose fr o m 8 0 0 m g (s plit 2 x 4 0 0 m g i njecti o ns) 
t o a si n gle 6 0 0 m g I M d ose.  I n a d diti o n, tiss ue c ollecti o n o n Da y  3 ( 4 8 h p ost-i njecti o n) 
was c ha n ge d fr o m o pti o nal assess me nts t o re q uire d assess me nts per pr ot oc ol a n d 
re m o ve d va gi nal tiss ue c ollecti o n o n Da y 8, Wee k 4 a n d 1 2.  Lastl y, M RI assess me nts 
were c ha n ge d f r o m o pti o nal assess me nts t o re q uire d, u p date d d ose rati o nale, a n d 
miscella ne o us c ha n ges f or clarificati o n. 
2 0 1 4 N 2 1 3 7 4 7 _ 0 3
2 0 1 7 -A U G - 1 4
A me n d me nt N o. 3
A me n d me nt 3 u p date d t he was h -o ut peri o d bet wee n oral a n d L A d osi n g t o acc o m m o date 
visit sc he d uli n g , a n d re m o ve d t he nee dle le n gt h s pecificati o n f or i ntra m usc ular i njecti o n 
i n Secti o n 6. 1. 3.

P P D
P P D
P P
D
P P D

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C O N FI D E N TI A L
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4
M E DI C A L M O NI T O R/ S P O N S O R I N F O R M A T I O N P A G E
Me dic al M o nit or/ S A E C o nt act I nf or m ati o n: 
R ol e
N a m e
D ay Ti m e P h o n e 
N u m b er a n d 
e m ail a d dr ess
Aft er -h o urs 
P h o n e/ C ell/
P a g er N u m b er
F ax N u m b er
Sit e A d dr ess
Pri m ary 
M e dic al 
M o nit or
,
D O, M Sc
Vii V H e alt hc ar e
5 M o or e Driv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
S ec o n d ary 
M e dic al 
M o nit or
, M D
Vii V H e alt hc ar e
5 M o or e Driv e,
R es e arc h Tr i a n gl e, 
N C 2 7 7 0 9
T erti ary 
M e dic al 
M o nit or
, 
M D
Vii V H e alt hc ar e
5 M o or e Driv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
S p o ns or Le g al Re gistere d A d dress:
T his st u d y  is s p o ns ore d by Vii V Healt hcare.  Gla x o S mit h Kli ne is i m ple me nti n g a n d 
ma na gi n g all as pects of t his st u d y . 
Vii V Re gistere d A d dress
P P D
Vii V Healt hcare
9 8 0 Great West R oa d
Bre ntf or d
Mi d dlese x, T W 8 9 G S
U K
Re g ulat or y  A ge nc y Ide ntif y i n g N u m ber(s): 1 0 9, 6 7 8
P P D
P P D
P P D

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C O N FI D E N TI A L
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5
I N V E S TI G AT O R P R O T O C O L A G R E E M E N T P A G E
F or pr ot oc ol n u m ber 2 0 1 7 6 7, A me n d me nt 3
I c o nfir m a gree me nt t o c o n d uct t he st u d y  i n c o m plia nce wit h t he pr ot oc ol, as a me n de d b y 
t his pr ot oc ol a me n d me nt.
I ac k n o wle d ge t hat I a m res p o nsi ble f or o verall st u d y  c o n d uct. I a gree t o pers o nally 
c on d uct or s u per vise t he descri be d st u d y.
I a gree t o e ns ure t hat all ass ociates, c ollea g ues a n d e m pl o y ees assisti n g i n t he c o n d uct of 
t he st u d y are i nf or me d a b o ut t heir o bli gati o ns. Mec ha nis ms are i n place t o e ns ure t hat site 
staff recei ves t he a p pr o priate inf or mati o n t hr o u g h o ut t he st u d y . 
I n vesti gat or Na me:
I n vesti gat or A d dress:
I n vesti gat or P h o ne N u m ber:
I n vesti gat or Si g nat ure
Date

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
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6
T A B L E O F C O N T E N T S
P A G E
1.
P R O T O C O L S Y N O P SI S F O R S T U D Y 2 0 1 7 6 7 ........................................................9
2.
I N T R O D U C TI O N....................................................................................................1 2
2. 1.
St u d y R ati o n al e ..........................................................................................1 2
2. 2.
Bri ef B a c k gr o u n d ........................................................................................1 3
3.  
O B J E C TI V E( S) A N D E N D P OI N T( S) ......................................................................1 4
4.
S T U D Y D E SI G N ....................................................................................................1 5
4. 1.
O v er all D e si g n ............................................................................................1 5
4. 1. 1.
S cr e e ni n g ....................................................................................1 5
4. 1. 2.
Or al L e a d -i n P h a s e......................................................................1 6
4. 1. 3.
C A B I nj e ct i o n a n d P K S a m pli n g...................................................1 6
4. 1. 4.
F oll o w -u p/ W it h dr a w al Vi sit...........................................................1 6
4. 2.
Tr e at m e nt Ar m s a n d D ur ati o n .....................................................................1 7
4. 3.
T y p e a n d N u m b er of S u bj e ct s .....................................................................1 7
4. 4.
D e si g n J u stifi c ati o n .....................................................................................1 7
4. 5.
D o s e J u stifi c ati o n ........................................................................................1 9
4. 6.
B e n efit: Ri s k A s s e s s m e nt ............................................................................2 2
4. 6. 1.
Ri s k A s s e s s m e nt .........................................................................2 3
4. 6. 1. 1.
Ot h er Cli ni c all y R el e v a nt I nf or m ati o n ..........................3 0
4. 6. 2.
B e n efit A s s e s s m e nt .....................................................................3 0
4. 6. 3.
O v er all B e n efit: Ri s k C o n cl u si o n ...................................................3 0
5. 
S E L E C TI O N O F S T U D Y P O P U L A TI O N A N D WI T H D R A W A L C RI T E RI A .............3 1
5. 1.
I n cl u si o n Crit eri a.........................................................................................3 1
5. 2.
E x cl u si o n Crit eri a ........................................................................................3 3
5. 3.
S cr e e ni n g/ B a s eli n e/ R u n -i n F ail ur e s............................................................3 6
5. 4.
Wi t h dr a w al/ St o p pi n g Crit eri a.......................................................................3 7
5. 4. 1.
Li v er C h e mi str y St o p pi n g Crit eri a ................................................3 8
5. 4. 2.
Q T c St o p pi n g Crit eri a ..................................................................3 9
5. 5.
S u bj e ct a n d St u d y C o m pl eti o n ....................................................................4 0
6.
S T U D Y T R E A T M E N T ............................................................................................4 1
6. 1.
I n v e sti g ati o n al Pr o d u ct a n d Ot h er St u d y Tr e at m e nt....................................4 1
6. 1. 1.
C a b ot e gr a vir - T a bl et ....................................................................4 2
6. 1. 2.
C a b ot e gr a vir - I nj e ct a bl e S u s p e n si o n ...........................................4 2
6. 1. 3.
D o si n g C o n si d er ati o n s f or C A B L A ..............................................4 2
6. 2.
Tr e at m e nt A s si g n m e nt ................................................................................4 2
6. 3.
Bli n di n g .......................................................................................................4 2
6. 4.
P a c k a gi n g a n d L a b eli n g ..............................................................................4 3
6. 5.
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y ..............................................4 3
6. 6.
C o m pli a n c e wit h St u d y Tr e at m e nt A d mi ni str ati o n .......................................4 3
6. 7.
Tr e at m e nt of St u d y Tr e at m e nt O v er d o s e ....................................................4 4
6. 8.
Tr e at m e nt aft er t h e E n d of t h e St u d y ..........................................................4 4
6. 9.
Lif e st yl e a n d/ or Di et ar y R e stri cti o n s ............................................................4 4
6. 9. 1.
M e al s a n d Di et ar y R e stri cti o n s ....................................................4 4
6. 9. 2.
Al c o h ol .........................................................................................4 5
6. 9. 3.
A cti vit y .........................................................................................4 5

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
7
6. 1 0.
C o n c o mit a nt M e di c ati o n s a n d N o n -Dr u g T h er a pi e s ....................................4 5
6. 1 0. 1.
P er mitt e d M e di c ati o n s a n d N o n -Dr u g T h er a pi e s ..........................4 5
6. 1 0. 2.
Pr o hi bit e d M e di c ati o n s a n d N o n -Dr u g T h er a pi e s .........................4 5
7.
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S .....................................................4 6
7. 1.
Ti m e a n d E v e nt s T a bl e ...............................................................................4 8
7. 1. 1. 
S cr e e ni n g a n d Or al L e a d -i n P h a s e..............................................4 8
7. 1. 2.  
C A B I nj e cti o n, C o m p art m e n t al P K S a m pli n g, a n d F oll o w-
u p ................................................................................................4 9
7. 2.
S cr e e ni n g a n d Criti c al B a s eli n e A s s e s s m e nt s ............................................5 0
7. 3.
S cr e e ni n g ...................................................................................................5 0
7. 3. 1.
B a s eli n e .......................................................................................5 0
7. 4. 
S af et y .........................................................................................................5 1
7. 4. 1.
A d v er s e E v e nt s ( A E) a n d S eri o u s A d v er s e E v e nt s ( S A E s) ..........5 1
7. 4. 1. 1.
I nj e cti o n Sit e R e a cti o n s..............................................5 1
7. 4. 1. 2.
Ti m e p eri o d a n d Fr e q u e n c y f or c oll e cti n g A E 
a n d S A E i n f or m ati o n...................................................5 1
7. 4. 1. 3.
M et h o d of D et e cti n g A E s a n d S A E s ...........................5 2
7. 4. 1. 4.
F oll o w -u p of A E s a n d S A E s ........................................5 3
7. 4. 1. 5.
C ar di o v a s c ul ar a n d D e at h E v e nt s ..............................5 3
7. 4. 1. 6.
Di s e a s e -R el at e d E v e nt s a n d/ or Di s e a s e -
R el at e d O ut c o m e s N ot Q u alif yi n g a s S A E s, 
I n cl u di n g HI V S er o c o n v er si o n ....................................5 3
7. 4. 1. 7.
R e g ul at or y R e p orti n g R e q uir e m e nt s f or S A E s ............5 3
7. 4. 2.
Pr e g n a n c y ...................................................................................5 4
7. 4. 3.
P h y si c al E x a m s ...........................................................................5 5
7. 4. 4.
Vit al Si g n s ....................................................................................5 5
7. 4. 5.
El e ctr o c ar di o gr a m ( E C G) .............................................................5 5
7. 4. 6.
Cli ni c al S af et y L a b or at or y A s s e s s m e nt s ......................................5 5
7. 4. 7.
M a g n eti c R e s o n a n c e I m a gi n g ......................................................5 7
7. 5.
P h ar m a c o ki n eti c s .......................................................................................5 7
7. 5. 1.
S a m pl e A n al y si s ..........................................................................5 8
7. 6.
G e n eti c s .....................................................................................................5 8
8.
D A T A M A N A G E M E N T ...........................................................................................5 8
9.
S T A TI S TI C A L C O N SI D E R A TI O N S A N D D A T A A N A L Y S E S .................................5 9
9. 1.
H y p ot h e s e s .................................................................................................5 9
9. 2.
S a m pl e Si z e C o n si d er ati o n s .......................................................................5 9
9. 2. 1.
S a m pl e Si z e A s s u m pti o n s ...........................................................5 9
9. 2. 2.
S a m pl e Si z e R e -e sti m ati o n or A dj u st m e nt ...................................5 9
9. 3.
D at a A n al y si s C o n si d er ati o n s .....................................................................5 9
9. 3. 1.
A n al y si s P o p ul ati o n s ....................................................................5 9
9. 3. 2.
I nt eri m A n al y si s ...........................................................................6 0
9. 4.
K e y El e m e nt s of A n al y si s Pl a n ...................................................................6 0
9. 4. 1.
Pri m ar y A n al y s e s .........................................................................6 0
9. 4. 2.
S e c o n d ar y A n al y s e s ....................................................................6 0
1 0.
S T U D Y G O V E R N A N C E C O N SI D E R A TI O N S ........................................................6 1
1 0. 1.
P o sti n g of I nf or m ati o n o n P u bli cl y A v ail a bl e Cli ni c al Tri al R e gi st er s ............6 1
1 0. 2.
R e g ul at or y a n d Et hi c al C o n si d er ati o n s, I n cl u di n g t h e I nf or m e d 
C o n s e nt Pr o c e s s ........................................................................................6 1

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
8
1 0. 3.
Q u alit y C o ntr ol ( St u d y M o nit ori n g) ..............................................................6 2
1 0. 4.
Q u alit y A s s ur a n c e .......................................................................................6 2
1 0. 5.
St u d y a n d Sit e Cl o s ur e ...............................................................................6 3
1 0. 6.
R e c or d s R et e nti o n ......................................................................................6 3
1 0. 7.
Pr o vi si o n of St u d y R e s ult s t o I n v e sti g at or s, P o sti n g of I nf or m ati o n 
o n P u bli c all y A v ail a bl e Cli ni c al Tri al s R e gi st er s a n d P u bli c ati o n .................6 4
1 1.
R E F E R E N C E S .......................................................................................................6 5
1 2.
A P P E N DI C E S ........................................................................................................6 7
1 2. 1.
A p p e n di x 1: A b br e vi ati o n s a n d Tr a d e m ar k s ................................................6 7
1 2. 2.
A p p e n di x 2: Li v er S af et y R e q uir e d A cti o n s a n d F oll o w u p 
A s s e s s m e nt s ..............................................................................................6 9
1 2. 3.
A p p e n di x 3: D efi niti o n of a n d Pr o c e d ur e s f or R e c or di n g, E v al u ati n g, 
F oll o w -U p a n d R e p orti n g of A d v er s e E v e nt s ...............................................7 1
1 2. 3. 1.
D efi niti o n of A d v er s e E v e nt s ........................................................7 1
1 2. 3. 2.
D efi niti o n of S eri o u s A d v er s e E v e nt s ...........................................7 2
1 2. 3. 3.
D efi niti o n of C ar di o v a s c ul ar E v e nt s .............................................7 3
1 2. 3. 4.
A E s of S p e ci al I nt er e st: ................................................................7 4
1 2. 3. 5.
R e c or di n g of A E s a n d S A E s ........................................................7 4
1 2. 3. 6.
E v al u ati n g A E s a n d S A E s ............................................................7 5
1 2. 4.
A p p e n di x 4: Di vi si o n Of 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 atri c A v er s e E v e nt s V er si o n 2. 0, N o v e m b er 2 0 1 4 ................7 7
1 2. 5.
A p p e n di x 5: T o xi cit y M a n a g e m e nt ..............................................................9 6
1 2. 6.
A p p e n di x 6: C oll e cti o n of Pr e g n a n c y I nf or m ati o n ......................................1 0 1
1 2. 7.
A p p e n di x 7: S c h e d ul e f or A d diti o n al L a b or at or y Pr o c e d ur e s f or 
E nr oll e d P arti ci p a nt s w h o h a v e a R e a cti v e P o siti v e HI V T e st R e s ult 
( P o st-HI V C o nfir m ati o n Vi sit) ....................................................................1 0 2
1 2. 8.
A p p e n di x 8: G e n eti c R e s e ar c h .................................................................1 0 3
1 2. 9.
A p p e n di x 9:  Pr ot o c ol A m e n d m e nt C h a n g e s .............................................1 0 6

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
9
1.
P R O T O C O L S Y N O P SI S F O R S T U D Y 2 0 1 7 6 7
R ati o n al e
Ca b ote gra vir ( C A B) l o n g-acti n g ( L A) is a pr o misi n g ca n di date f or HI V pre-e x p os ure 
pr o p h y la xis ( Pr E P) d ue t o its p ote nt a ntiretr o viral acti vit y a n d i nfre q ue nt d osi n g 
re q uire me nts.  C urre ntl y, t he C A B c o nce ntrati o ns ac hie ve d i n t he a nat o mical sites 
ass ociate d wit h se x ual HI V tra ns mi ssi o n f oll o wi n g t he pr o p ose d 6 0 0 m g  i ntra m usc ular 
Pr E P d ose are u n k n o w n.  T his P hase 1 st u d y  will pr o vi de a c o m part me ntal
p har mac o ki netic ( P K ) a nal ysis of C A B f oll o wi n g a si n gle 6 0 0 m g  i ntra m usc ular d ose i n 
healt h y  v ol u nteers.  T hese data will f urt her o ur u n dersta n di n g of C A B distri b uti o n t o t he 
a nat o mical m uc osal tiss ue belie ve d t o be rele va nt t o se x ual HI V- 1 tra ns missi o n a n d 
s u p ple me nt t he data a vaila ble t o s u p p ort f ut ure Pr E P cli nical trial de vel o p me nt.  T he 
st u d y will i ncl u de a 4 wee k oral d ose lea d-i n t o assess safety a n d t olera bilit y, a 1 4 - 4 2 d a y  
was h o ut peri o d, a n d a si n gle 6 0 0 m g  d ose of C A B L A a d mi nistere d as a si n gle 3 m L  
i ntra gl uteal i njecti o n. P ost-i njecti o n P K sa m pli n g will i ncl u de bl o o d plas ma, va gi nal, 
cer vical a n d rectal tiss ue, as well as cer vic o va gi nal a n d rectal fl ui d o ver 1 2 wee ks.
O bj e cti v e( s)/ E n d p oi nt( s)
O bj e cti v e s
E n d p oi nt s
Pri m ar y

T o d et er mi n e t h e p h ar m ac oki n etic 
c o nc e ntr ati o ns of C A B f oll o wi n g L A 
a d mi nistr ati o n i n bl o o d pl as m a a n d i n v a gi n al 
tiss u e ( V T), c ervic al tiss u e ( C T), a n d 
c ervic ov a gi n al fl ui d ( C V F) i n h e alt hy w o m e n 
a n d i n r ect al tiss u e ( R T) a n d r ect al fl ui d ( R F) i n 
h e alt hy m e n a n d w o m e n ( as d at a p er mit) 
f oll o wi n g a si n gl e 6 0 0 m g i ntr a m usc ul ar d os e. 

C o nc e ntr ati o ns o bs erv e d at D ay 3 ( C 4 8 h), D ay 
8 ( C d 8), W e ek 4 ( C Wk 4), W e ek 8 ( C Wk 8), a n d 
W e ek 1 2 ( C Wk 1 2) i n bl o o d pl as m a a n d i n C T, 
a n d C V F i n w o m e n, a n d i n R T a n d R F i n m e n 
a n d w o m e n ( as d at a p er mit) f oll o wi n g a si n gl e 
C A B 6 0 0 m g i ntr a m usc ul ar d os e.  

V T c o nc e ntr ati o ns o bs erv e d at D ay 3 ( C 4 8 h), 
a n d W e ek 8 ( C Wk 8), i n w o m e n f oll o wi n g a 
si n gl e C A B 6 0 0 m g i ntr a m usc ul ar d os e.  
S e c o n d ar y

T o c o m p ar e t h e p h ar m ac oki n etic c o nc e ntr ati o ns 
f oll o wi n g a si n gl e i ntr a m usc ul ar d os e of C A B L A 
6 0 0 m g i n V T, C T, a n d C V F r el ativ e t o bl o o d 
pl as m a a n d C V F i n h e alt hy w o m e n, a n d i n R T 
a n d R F r el ativ e t o bl o o d pl as m a a n d R F i n 
h e alt hy m e n a n d w o m e n ( as d at a p er mit). 

C o nc e ntr ati o n r ati os i ncl u di n g V T: bl o o d pl as m a, 
C T: bl o o d pl as m a, C V F: bl o o d pl as m a, C T: C V F, 
V T: C V F i n w o m e n, a n d R T: bl o o d pl as m a, 
R F: bl o o d pl as m a a n d R T: R F i n m e n a n d 
w o m e n ( as d at a p er mit) at m atc h e d ti m e p oi nts 
ev al u at e d. 

T o d escri b e t h e p h ar m ac oki n etic pr ofil e of C A B 
L A i n bl o o d pl as m a a n d C T, C V F, i n h e alt hy 
w o m e n a n d i n R T a n d R F i n h e alt hy m e n a n d 
w o m e n ( as d at a p er mit) f oll o wi n g a si n gl e 6 0 0 
m g i ntr a m usc ul ar d os e.

M axi m u m o bs erv e d c o nc e n tr ati o n ( C m ax) a n d 
ti m e of m axi m u m o bs erv e d c o nc e ntr ati o n (t m ax) 
i n bl o o d pl as m a a n d i n C T, C V F, R T, R F 
m atric es.

Ar e a u n d er t h e c o nc e ntr ati o n ti m e c urv e fr o m 
ti m e z er o t o l ast q u a ntifi a bl e ti m e p oi nt ( A U C( 0-
l ast)), ar e a u n d er t h e 
c o nc e ntr ati o n ti m e c urv e fr o m ti m e z er o t o 
i nfi nity ( A U C( 0-)), ar e a u n d er t h e 
c o nc e ntr ati o n ti m e c urv e fr o m ti m e z er o t o 
W e ek 4 ( A U C( 0 -Wk 4)), ar e a u n d er t h e 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 0
O bj e cti v e s
E n d p oi nt s
c o nc e ntr ati o n ti m e c urv e fr o m ti m e z er o t o 
W e ek 8 ( A U C( 0 -Wk 8)) ar e a u n d er t h e 
c o nc e ntr ati o n ti m e c urv e fr o m ti m e z er o t o 
W e ek 1 2 ( A U C( 0 -Wk 1 2)) a n d a p p ar e nt t er mi n al 
p h as e h alf -lif e (t ½) i n bl o o d pl as m a, C T, C V F, 
R T, R F, as d at a p er mit.  

Tiss u e: bl o o d pl as m a a n d fl ui d: bl o o d pl as m a 
r ati o of A U Cs of i nt erv als s p ecifi e d a b ov e.

T o d et er mi n e t h e tr o u g h c o nc e ntr ati o n ac hi ev e d 
f oll o wi n g r e p e at a d mi nistr ati o n of or al C A B 3 0 
m g o nc e d aily t o st e a dy st at e i n bl o o d pl as m a 
a n d V T, C T, a n d C V F i n h e alt hy w o m e n a n d i n 
R T a n d R F i n h e alt hy m e n a n d w o m e n ( as d at a 
p er mit) . 

C A B c o nc e ntr ati o n ( C 24) f oll o wi n g or al 
a d mi nistr ati o n i n V T, C T, C V F, R T, R F a n d 
bl o o d pl as m a.

T o ass ess t h e s af ety a n d t ol er a bility of C A B 
f oll o wi n g r e p e at or al d os es a n d si n gl e d os e 
i ntr a m usc ul ar a d mi nistr ati o n i n h e alt hy s u bj ects.

S af ety a n d t ol er a bility p ar a m et ers, i ncl u di n g 
a dv ers e ev e nts, cli nic al l a b or at ory t ests, a n d 
vit al si g ns ass ess m e nts.
E x pl or at or y 

T o ass ess ev ol uti o n of t h e i nj ecti o n d e p ot 
l oc aliz ati o n f oll o wi n g a si n gl e C A B 6 0 0 m g 
i ntr a m usc ul ar d os e.

V ol u m etric a n d T 1, T 2 ass ess m e nt of d e p ot vi a 
n o n -c o ntr ast-e n h a nc e d M RI i m a g es of t h e 
i nj ecti o n sit e at t he ti m e of i nj ecti o n, D ay 3 ( 4 8 
h o urs), a n d 1 w e ek p ost -i nj ecti o n as d at a 
p er mit. 
O v er all D e si g n
T his will be a P hase 1, o pe n la bel st u d y i n healt h y s u bjects t o assess t he 
p har mac o ki netics of C A B L A i n t he bl o o d plas ma a n d a nat o mic l ocati o ns ass ociate d w it h 
se x ual HIV- 1 tra ns missi o n: va gi nal tiss ue ( V T), cer vical tiss ue ( C T), cer vic o va gi nal fl ui d 
( C V F), rectal tiss ue ( R T), a n d rectal fl ui d ( R F).  T he st u d y will c o nsist of a scree ni n g 
peri o d, a 2 8 -d a y  oral lea d-i n p hase usi n g a C A B d ose of 3 0 m g o nce per d a y f oll o we d b y 
a 1 4- 4 2 d a y  was h o ut peri o d, a n d a si n gle d ose of C A B L A 6 0 0 m g I M wit h 
c o m part me ntal P K sa m pli n g f or u p t o 1 2 wee ks.   S u bjects will ret ur n f or safet y 
assess me nts a n d P K sa m pli n g of t he bl o o d plas ma at Wee k 2 4 a n d Wee k 3 6 p ost -
i njecti o n a n d u n der g o a f oll o w -u p visit at Wee k 5 2 p ost -i njecti o n or wit h dra wal visit if a 
s u bject is ter mi nate d earlier. 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 1
St u d y  D e si g n*
S cr e e ni n g
Or al 
L e a d -i n 
W a s h o ut
C A B I nj e cti o n a n d 
C o m p art m e nt al P K S a m pli n g
S af et y/
Bl o o d Pl a s m a 
S a m pli n g
F oll o w -u p/ 
Wit h dr a w al 
Vi si t
Wit hi n 3 0 
d ays of 1 st
or al C A B 
d os e
Or al C A B 3 0 
m g t a bl et 
o nc e d aily 
x 4 w e eks
N o dr u g 
a d mi nist er e d 
1 4 – 4 2 d ays
Si n gl e 6 0 0 m g 
C A B L A I M d os e
Tiss u e/l u mi n al fl ui d/ bl o o d pl as m a 
s a m pli n g u p t o 1 2 w e eks 
p ost -i nj ecti o n
S af ety ass ess m e nts 
a n d bl o o d pl as m a P K 
s a m pli n g will occ ur at 
2 4 a n d 3 6 W e eks 
p ost -d os e
F oll o w -u p 
ass ess m e nts 
t o b e 
p erf or m e d 5 2 
W e eks p ost -
i nj ecti o n
* Gi ve n t he cer vic o va gi nal sa m pli n g i n t he pr ot oc ol, ti mi n g a n d d urati o n of me nses 
s h o ul d be ta ke n i nt o acc o u nt w he n sc he d uli n g scree ni n g, oral lea d-i n p hase a n d i njecti o n.  
Tr e at m e nt A r m s a n d D ur ati o n
Eac h s u bject will partici pate i n t he st u d y  f or a p pr o xi matel y u p t o 6 6 wee ks. All s u bjects 
will u n der g o scree ni n g assess me nts wit hi n 3 0 da ys of t he oral -lea d i n p hase.  If eli gi ble t o 
partici pat e, s u bjects will pr ocee d t o t he oral lea d -i n p hase d uri n g w hic h t he y will self-
a d mi nister C A B 3 0 m g  orall y o nce daily f or 2 8 da y s a n d u n der g o P K sa m pli n g o n Da y 
2 9 .  All s u bjects will ha ve a 1 4 – 4 2 d a y  was h o ut peri o d w here n o C A B will be 
a d mi nistere d.  After t he was h o ut peri o d, eac h s u bject will recei ve a si n gle ultras o u n d-
g ui de d 6 0 0 m g  ( 1 x 3 m L  i njecti o n) IM d ose of C A B
L A i nt o gl uteal m uscle a n d u n der g o 
P K sa m pli n g f or u p t o 1 2 wee ks.  After t he Wee k 1 2 assess me nts, s u bjects will ret ur n t o 
t he cli nic f or safety assess me nts a n d a d diti o nal bl o o d plas ma P K sa m pli n g at 2 4, 3 6, a n d 
5 2 wee ks p ost C A B i njecti o n. 
T y p e a n d N u m b er of S u bj e ct s
A p pr o xi matel y  2 0 healt h y s u bjects fr o m u p t o t w o cli nic sites will be e nr olle d s uc h t hat 
a p pr o xi matel y 1 6 e val ua ble s u bjects ( 8 males a n d 8 fe males) will recei ve a C A B L A I M 
d ose a n d c o m plete c o m part me ntal P K sa m pli n g.  N o n -c o ntrast-e n ha nce d ma g netic 
res o na nce i ma gi n g ( M RI) will be perf or me d i n a s u bset of u p t o 4 males a n d 4 fe males. 
A n al y si s
Sa m ples of plas ma, tiss ues, a n d secreti o ns will be assa ye d f or C A B c o nce ntrati o ns usi n g 
H P L C- M S/ M S. P har mac o ki netic para meters will be esti mate d via n o nc o m part me ntal 
a nal ys is usi n g Wi n N o nli n pr o gra m ( Versi o n 5. 2 or hi g her, P harsi g ht, I nc., Car y, N C). 
All t he deri ve d P K para meters will be liste d a n d s u m marize d b y  ge n der a n d o verall. F or 
eac h of t hese P K para meters, wit h t he e xce pti o n of t ma x a n d rati os, t he f oll o wi n g 
descri pti ve s u m mar y  statistics will be calc ulate d f or eac h treat me nt: n, arit h metic mea n 
wit h ass ociate d 9 5 % CI, sta n dar d de viati o n, me dia n, mi ni m u m, ma xi m u m, ge o metric 
mea n wit h ass ociate d 9 5 % CI , sta n dar d de viati o n of l o garit h micall y tra nsf or me d data, 
a n d bet wee n -s u bject c oefficie nt of variati o n ( C V b( %)). F or t ma x a n d rati os, n o ge o metric 
mea n, n or ass ociate d 9 5 % CI  or sta ndar d de viati o n of l o garit h micall y  tra nsf or me d data 
will be pr o vi de d. 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 2
2.
I N T R O D U C TI O N
C A B is a n i n vesti gati o nal HI V- 1 i nte grase stra n d tra nsfer i n hi bit or (I N S TI) c urre ntl y 
bei n g de vel o pe d as b ot h a n oral ta blet a n d na n os us pe nsi o n f or m ulati o n s uita ble f or a 
l o n g-acti n g ( L A) i ntra m usc ular (I M) i njecti o n.  T he de vel o p me nt of C A B is base d o n its 
p ote ntial f or a hi g h ge netic barrier t o resista nce a n d a p har mac o ki netic ( P K) pr ofile 
all o wi n g f or l o w-d ose, o nce -dail y oral a d mi nistrati o n or m o nt hl y  t o q uarterl y IM d os i n g 
usi n g a na n os us pe nsi o n f or m ulati o n.  T hese attri b utes ha ve le d t o t he de vel o p me nt of t he 
c o m p o u n d f or b ot h t he treat me nt of HI V -1 i nfecti o n, as well as pre -e x p os ure pr o p h yl a xis 
( Pr E P) i n dicati o ns.
2. 1.
St u d y R ati o n al e
T his P hase 1 st u d y  ai ms t o descri be t he P K pr ofile of C A B L A i n bl o o d plas ma, va gi nal 
tiss ue ( V T), cer vical tiss ue ( C T), cer vic o va gi nal fl ui d ( C V F), rectal tiss ue ( R T), a n d 
rectal m uc osal fl ui d ( R F) f oll o wi n g a si n gle 6 0 0 m g i ntra m usc ular d ose.  A 
c o m part me ntal P K a nal ysis of C A B will f urt her o ur u n dersta n di n g of C A B distri b uti o n t o 
t he a nat o mical sites belie ve d t o be rele va nt t o se x ual HI V-1 tra ns missi o n.  Pre vi o usl y , 
C A B c o nce ntrati o ns ha ve bee n deter mi ne d i n C T, V T, a n d R T f or u p t o 1 2 wee ks 
f oll o wi n g a si n gle 4 0 0 m g  i ntra m usc ular d ose [Ta ble 1 , Gla x o S mit h Kli ne D oc u me nt 
N u m ber 2 0 1 3 N 1 5 9 6 0 5 _ 0 0 ].  Tiss ue: plas ma rati os were l o w: 1 6-2 8 % i n cer vic o va gi nal 
tiss ue a n d 8 % i n rectal tiss ue ( Ta ble 2 ).  Ass u mi n g a tiss ue de nsit y of 1 g/ m L, me dia n 
cer vical a n d va gi nal tiss ue c o nce ntrati o ns were a p pr o xi matel y  e q ui vale nt t o t he i n vitr o
pr otei n a dj uste d ( P A) -I C9 0 ( 0. 1 6 6g/ m L) at s o me visits.  As a li near relati o ns hi p bet wee n 
tiss ue a n d plas ma c o nce ntrati o ns was o bser ve d gra p hicall y , tiss ue c o nce ntrati o ns are 
pre dicte d t o i ncrease at hi g her d oses of C A B L A w hic h pr o d uce plas ma c o nce ntrati o ns i n 
t he tar get t hera pe utic ra n ge.  T his st u dy will e xte n d o ur u n dersta n di n g of C A B L A as a 
pre ve ntati ve a ge nt a n d deter mi ne t he c o nce ntrati o ns ac hie ve d i n t he a nat o mical sites 
ass ociate d wit h se x ual HI V - 1 tra ns missi o n f oll o wi n g a si n gle 6 0 0 m g  IM L A d ose.  
T hese data ca n be utilize d t o b uil d c o m ple x p har mac o metric, m ulti -c o m part me nt m o dels 
t hat ma y si g nifica ntl y i nf or m cli nical trial si m ulati o ns a n d st u d y desi g n i n t he f ut ure.  
T a bl e 1
S u m m ar y  of C AB L A  Ti s s u e C o n c e ntr ati o n s b y Vi sit ( L AI 1 1 4 4 3 3)1
Ti s s u e T y p e
Ti s s u e C o n c e ntr ati o n ( g/ g) ( n = 4/ vi sit)
4 0 0 m g I M u n s plit ( C o h ort 8) 
4 0 0 m g I M s plit ( 2 x 2 0 0 m g I M, C o h ort 9)
W e e k 2  
W e e k 8
W e e k 4
W e e k 1 2
C er vi c al
0. 0 8 1 ( N Q - 0. 1 7)
0. 0 9 6 ( 0. 0 6 - 0. 1 9)
0. 1 7 7 ( 0. 0 7 - 0. 5 0)
0. 1 3 3 ( N Q - 0. 2 1) 3
V a gi n al 2
0. 1 2 1 ( N Q - 0. 1 8)
0. 1 8 4 ( 0. 0 9 - 0. 4 4)
0. 1 5 5 ( N Q - 0. 9 0)
0. 1 8 1 ( N Q - 0. 3 5)
R e ct al 2
N Q ( N Q - 0. 1 0)
N Q ( N Q - 0. 0 5)
0. 0 7 9 ( N Q - 0. 2 0)
0. 0 6 3 ( N Q - 0. 0 8)
D at a s o urc e: L AI 1 1 4 4 3 3 Cli nic al P h ar m ac ol o gy St u dy R e p ort
1.
m e di a n (r a n g e)
2.
n = 8 s a m pl es
3.
n = 3 s a m pl es
N Q - N o n -q u a ntifi a bl e c o nc e ntr ati o n m e as ur e d as b el o w L L Q

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 3
T a bl e 2
S u m m ar y  of O v er all C AB L A  Ti s s u e: Pl a s m a R ati o s b y Ti s s u e T y p e 
( L AI 1 1 4 4 3 3)1
4 0 0 m g I M u n s plit ( C o h ort 8)  
4 0 0 m g I M s plit ( 2 x 2 0 0 m g I M, C o h ort 9)
C er vi c al 2
0. 2 0 ( 0. 0 - 0. 4 0)
0. 1 6 ( 0. 0 - 0. 4)
V a gi n al 3
0. 2 8 ( 0. 0 - 0. 7)
0. 1 9 ( 0. 0 - 0. 7)
R e ct al 3
0. 0 0 ( 0. 0 - 0. 1)
0. 0 8 ( 0. 0 - 0. 2)
D at a s o urc e: L AI 1 1 4 4 3 3 Cli nic al P h ar m ac ol o gy St u dy R e p ort
1.
m e di a n (r a n g e) ( acr oss all visits a n d s u bj ects)
2.
n = 8 u ns plit; n = 7 s plit
3.
n = 2 4
2. 2.
Bri ef B a c k gr o u n d
C A B is a n i n vesti gati o nal HI V- 1 I N S TI t hat p ossesses attri b utes fa v ora ble f or b ot h HI V 
treat me nt a n d pre ve nti o n i n dicati o ns.  C A B has de m o nstrate d p ote nt i n vitr o acti vit y 
a gai nst a br oa d ra n ge of HI V strai ns.  D ue t o its u ni q ue p h y si oc he mical pr o perties, C A B 
has bee n f or m ulate d as b ot h a o nce dail y oral ta blet a n d a L A na n os us pe nsi o n f or 
m o nt hl y  t o q uarterly i ntra m usc ular a d mi nistrati o n.  T he C A B ta blet will ser ve as oral 
lea d-i n t hera p y t o assess safet y a n d t olera bilit y pri or t o s witc hi n g t o t he L A f or m ulati o n 
f or HI V-1 treat me nt a n d/ or pre ve nti o n .  T he L A -i njecta ble, w hic h has a plasma half -life 
of a p pr o xi matel y  2 1-5 0 da y s, is a pr o misi n g ca n di date f or Pr E P a n d has de m o nstrate d 
pr otecti ve a nti viral acti vit y  i n b ot h rectal a n d va gi nal n o n-h u ma n pri mate ( N H P) 
Si mia n/ H u ma n I m m u n o deficie nc y  Vir us ( S HI V)-c halle n ge m o dels [A n dre ws , 2 0 1 4; 
Ra dzi o , 2 0 1 5]. 
I n a precli nical st u d y, ei g ht male r hes us maca q ues were i njecte d wit h C A B L A 
( 5 0 m g/ k g I M) at t w o ti me p oi nts, 1 wee k pri or t o t he first vir us e x p os ure a n d 4 wee ks 
later [A n dre ws , 2 0 1 4].  A n a d diti o nal ei g ht male maca q ues were u ntreate d a n d ser ve d as 
place b o c o ntr ols.  After wee kl y i ntrarectal c halle n ges wit h S HI V 1 6 2 p 3 [ 5 0 tiss ue c ult ure 
i nfecti ve d ose ( T CI D)5 0] f or u p t o ei ght e x p os ures, all ei g ht place b o maca q ues beca me 
i nfecte d after a me dia n of t w o rectal e x p os ures (ra n ge 1 t o 7).  Of t he ei g ht C A B L A-
treate d maca q ues, n o ne ha d detecta ble sys te mic vire mia 1 0 wee ks after t he last vir us 
c halle n ge.  I n t hese pr otecte d a ni mals , t he plas ma c o nce ntrati o ns of C A B t hr o u g h o ut t he 
peri o d of vir us c halle n ges were c o m para ble t o cli nicall y  rele va nt e x p os ure i n h u ma ns.  In 
a si milarl y desi g ne d st u d y, t hree i ntra m usc ular d oses of C A B 5 0 m g / k g a d mi nistere d 4 
wee ks a part f ull y pr otecte d fe m ale pi gtail maca q ues ( n = 6) fr o m t wice wee kl y  l o w d ose 
( 5 0 T CI D5 0) S HIV 1 6 2 p 3 c halle n ges [ Ra dzi o , 2 0 1 5].  T hese data s u p p ort t he c o nti n ue d 
de vel o p me nt of C A B L A as a Pr E P ca n di date f or b ot h me n a n d w o me n at hi g h ris k f o r 
HI V tra ns missi o n.  
As of 0 1 Ja n uar y  2 0 1 6, a p pr o xi matel y 1 1 6 0 a d ult s u bjects ha ve bee n e x p ose d t o C A B i n 
eit her oral or i njecta ble f or m ulati o ns.  B ot h healt h y v ol u nteers a n d HI V -i nfecte d patie nts 
ha ve bee n d ose d wit h oral C A B, a n d a p pr o xi matel y 5 6 6 healt h y  v ol u nteers a n d HI V-
i nfecte d patie nts ha ve recei ve d at least 1 i njecti o n of C A B L A.  Pre vi o us P hase I a n d o n-
g oi n g P hase II st u dies ha ve de m o nstrate d t hat C A B is well t olerate d w he n a d mi nistere d 
as b ot h a o nce dail y oral ta blet a n d L A I M i njecti o n.  T he safety, t olera bilit y, a n d 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 4
acce pta bilit y of C A B L A i n HI V u ni nfecte d me n is c urre ntly bei n g e val uate d i n t he 
E C L AI R st u d y  [ Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 3 N 1 8 4 0 4 8 _ 0 1 ] a n d will be 
assesse d i n HI V u ni nfecte d me n a n d w o me n i n t he H P T N 0 7 7 P hase 2 st u d y .
3.
O B J E C TI V E( S) A N D E N D P OI N T( S)
O bj e cti v e s
E n d p oi nt s
Pri m ar y

T o d et er mi n e t h e p h ar m ac oki n etic 
c o nc e ntr ati o ns of C A B f oll o wi n g L A 
a d mi nistr ati o n i n bl o o d pl as m a a n d i n v a gi n al 
tiss u e ( V T), c ervic al tiss u e ( C T), a n d 
c ervic ov a gi n al fl ui d ( C V F) i n h e alt hy w o m e n 
a n d i n r ect al tiss u e ( R T) a n d r ect al fl ui d ( R F) i n 
h e alt hy m e n a n d w o m e n ( as d at a p er mit) 
f oll o wi n g a si n gl e 6 0 0 m g i ntr a m usc ul ar d os e. 

C o nc e ntr ati o ns o bs erv e d at D ay 3 ( C 4 8 h), D ay 
8 ( C d 8), W e ek 4 ( C Wk 4), W e ek 8 ( C Wk 8), a n d 
W e ek 1 2 ( C Wk 1 2) i n bl o o d pl as m a a n d i n C T, 
a n d C V F i n w o m e n, a n d i n R T a n d R F i n m e n 
a n d w o m e n ( as d at a p er mit) f oll o wi n g a si n gl e 
C A B 6 0 0 m g i ntr a m usc ul ar d os e. 

V T c o nc e ntr ati o ns o bs erv e d at D ay 3 ( C 4 8 h), 
a n d W e ek 8 ( C Wk 8), i n w o m e n f oll o wi n g a 
si n gl e C A B 6 0 0 m g i ntr a m usc ul ar d os e.  
S e c o n d ar y

T o c o m p ar e t h e p h ar m ac oki n etic c o nc e ntr ati o ns 
f oll o wi n g a si n gl e i ntr a m usc ul ar d os e of C A B L A 
6 0 0 m g i n V T , C T, a n d C V F r el ativ e t o bl o o d 
pl as m a a n d C V F i n h e alt hy w o m e n, a n d i n R T 
a n d R F r el ativ e t o bl o o d pl as m a a n d R F i n 
h e alt hy m e n a n d w o m e n ( as d at a p er mit)  . 

C o nc e ntr ati o n r ati os i ncl u di n g V T: bl o o d pl as m a, 
C T: bl o o d pl as m a, C V F: bl o o d pl as m a, C T: C V F, 
V T: C V F i n w o m e n, a n d R T: bl o o d pl as m a, 
R F: bl o o d pl as m a a n d R T: R F i n m e n a n d 
w o m e n ( as d at a p er mit)   at m atc h e d ti m e p oi nts 
ev al u at e d.

T o d escri b e t h e p h ar m ac oki n etic pr ofil e of C A B 
L A i n bl o o d pl as m a a n d C T, C V F, i n h e alt hy 
w o m e n a n d i n R T a n d R F i n h e alt hy m e n a n d 
w o m e n ( as d at a p er mit) f oll o wi n g a si n gl e 6 0 0 
m g i ntr a m usc ul ar d os e.

M axi m u m o bs erv e d c o nc e ntr ati o n ( C m ax) a n d 
ti m e of m axi m u m o bs erv e d c o nc e ntr ati o n (t m ax) 
i n bl o o d pl as m a a n d i n C T, C V F, R T, R F 
m atric es.

Ar e a u n d er t h e c o nc e ntr ati o n ti m e c urv e fr o m 
ti m e z er o t o l ast q u a ntifi a bl e ti m e p oi nt ( A U C( 0-
l ast)), ar e a u n d er t h e 
c o nc e ntr ati o n ti m e curv e fr o m ti m e z er o t o 
i nfi nity ( A U C( 0-)), ar e a u n d er t h e 
c o nc e ntr ati o n ti m e c urv e fr o m ti m e z er o t o 
W e ek 4 ( A U C( 0 -Wk 4)), ar e a u n d er t h e 
c o nc e ntr ati o n ti m e c urv e fr o m ti m e z er o t o 
W e ek 8 ( A U C( 0 -Wk 8)), ar e a u n d er t h e 
c o nc e ntr ati o n ti m e c urv e fr o m ti m e z er o t o 
W e ek 1 2 ( A U C( 0 -Wk 1 2)) a n d a p p ar e nt t er mi n al 
p h as e h alf -lif e (t ½) i n bl o o d pl as m a, C T, C V F, 
R T, R F, as d at a p er mit..  

Tiss u e: bl o o d pl as m a a n d fl ui d: bl o o d pl as m a 
r ati o of A U Cs of i nt erv als s p ecifi e d a b ov e..

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 5
O bj e cti v e s
E n d p oi nt s

T o d et er mi n e t h e tr o u g h c o nc e ntr ati o n ac hi e v e d 
f oll o wi n g r e p e at a d mi nistr ati o n of or al C A B 3 0 
m g o nc e d aily t o st e a dy st at e i n bl o o d pl as m a 
a n d V T, C T, a n d C V F i n h e alt hy w o m e n a n d i n 
R T a n d R F i n h e alt hy m e n a n d w o m e n ( as d at a 
p er mit) . 

C A B c o nc e ntr ati o n ( C 24) f oll o wi n g or al 
a d mi nistr ati o n i n V T, C T, C V F, R T, R F a n d 
bl o o d pl as m a

T o ass ess t h e s af ety a n d t ol er a bility of C A B 
f oll o wi n g r e p e at or al d os es a n d si n gl e d os e 
i ntr a m usc ul ar a d mi nistr ati o n i n h e alt hy s u bj ects.

S af ety a n d t ol er a bility p ar a m et ers, i ncl u di n g 
a dv ers e ev e nts, cli nic al l a b or at ory t ests, a n d 
vit al si g ns ass ess m e nts
E x pl or at or y 

T o ass ess ev ol uti o n of t h e i nj ecti o n d e p ot 
l oc aliz ati o n f oll o wi n g a si n gl e C A B 6 0 0 m g 
i ntr a m usc ul ar d os e.

V ol u m etric a n d T 1, T 2 ass ess m e nt of d e p ot vi a 
n o n -c o ntr ast-e n h a nc e d M RI i m a g es of t h e 
i nj ecti o n sit eat t h e ti m e of i nj ecti o n, D ay 3 ( 4 8 
h o urs), a n d 1 w e ek p ost -i nj ecti o n as d at a 
p er mit. 
4.
S T U D Y D E SI G N
4. 1.
O v er all D e si g n
T his will be a P hase 1, o pe n la bel st u d y i n healt h y s u bjects t o assess t he P K of C A B L A 
i n bl o o d plas ma a n d a nat o mical tiss ues a n d secreti ons ass ociate d wit h se x ual HI V - 1 
tra ns missi o n f oll o wi n g a si n gle 6 0 0 m g  IM d ose.  T he st u d y  will c o nsist of a scree ni n g 
peri o d, a 2 8 -d a y  oral lea d-i n p hase at a C A B d ose of 3 0 m g o nce per da y  f oll o we d b y a 
1 4 - 4 2 d a y  was h o ut peri o d, a n d a si n gle d ose of C A B L A 6 0 0 m g wit h c o m part me ntal P K 
sa m pli n g f or u p t o 1 2 wee ks.   S u bjects will ret ur n f or safet y assess me nts a n d P K 
sa m pli n g of t he bl o o d plas ma at Wee k 2 4 a n d Wee k 3 6 p ost-i njecti o n a n d u n der g o a 
f oll o w-u p visit at Wee k 5 2 p ost -i njecti o n or a wit h dra wal vis it if a s u bject is ter mi nate d 
earlier.
T a bl e 3
St u d y  D e si g n*
S cr e e ni n g
Or al 
L e a d -i n 
W a s h o ut
C A B I nj e cti o n a n d 
C o m p art m e nt al P K S a m pli n g
S af et y/
Bl o o d Pl a s m a 
S a m pli n g
F oll o w -u p/ 
Wit h dr a w al 
Vi sit
Wit hi n 3 0 
d ays of 1 st
or al C A B 
d os e
Or al C A B 
3 0 m g t a bl et 
o nc e d aily 
x 4 w e eks
N o dr u g 
a d mi nist er e d 
1 4 – 4 2 d ays
Si n gl e 6 0 0 m g 
C A B L A I M d os e
Tiss u e/l u mi n al fl ui d/ bl o o d pl as m a 
s a m pli n g u p t o 1 2 w e eks 
p ost -i nj ecti o n
S af ety ass ess m e nts 
a n d bl o o d pl as m a P K 
s a m pli n g will occ ur at 
2 4 a n d 3 6 W e eks 
p ost -d os e
F oll o w -u p 
ass ess m e nts 
t o b e 
p erf or m e d 5 2 
W e eks p ost -
i nj ecti o n
* Gi ve n t he cer vic o va gi nal sa m pli n g i n t he pr ot oc ol, ti mi n g a n d d urati o n of me nses 
s h o ul d be ta ke n i nt o acc o u nt w he n sc he d uli n g scree ni n g, oral lea d-i n p hase a n d i njecti o n.
4. 1. 1.
S cr e e ni n g
All s u bjects will u n der g o a scree ni n g visit wit hi n 3 0 da ys of t he first d ose of t he oral -lea d 
i n.  S u bjects ma y be rescree ne d o nce. S u bjects w h o are e nr olle d i nt o t he trial a n d 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 6
s u bse q ue ntl y wit h dra w n fr o m t he st u d y, f or a n y reas o n, ma y n ot be re-scree ne d. S u bjects 
ma y  c o nti n ue t o t he oral lea d-i n p hase as s o o n as all eli gi bilit y re q uire me nts ha ve bee n 
met.
4. 1. 2.
Or al L e a d -i n P h a s e
S u bjects t hat are eli gi ble t o partici pate will ret ur n t o t he cli nic o n Da y  1 of t he oral lea d-
i n p hase a n d recei ve t heir first oral d ose of C A B 3 0 m g after t he c o m pleti o n of all pre -
d ose assess me nts as o utli ne d i n t he Ti me a n d E ve nts Ta ble ( Sect i o n 7. 1 ).  S u bjects will 
be dis pe nse d a s ufficie nt s u p pl y  of oral C A B 3 0 m g  ta blets t o c o m plete 27 da y s of o nce 
dail y  d osi n g at h o me a n d be c o u nsele d t o ta ke t heir d ose at a b o ut t he sa me ti me eac h da y.  
O n Da y  1 4 of t he oral lea d-i n p hase, s u bjects will ret ur n t o t he cli nic t o assess safety, 
t olera bilit y, a n d s u bject a d here nce t o st u d y dr u g.  S u bjects s h o ul d bri n g t heir s u p pl y  of 
oral C A B t o t he Da y  1 4 visit t o ha ve dr u g acc o u nta bilit y perf or me d.  
S u bjects will ret ur n t o t he cli nic o n Da y  2 9 t o ha ve dr u g acc o u nta bilit y, P K a n d all
assess me nts perf or me d as descri be d i n t he Ti me a n d E ve nts Ta ble ( Sec ti o n 7. 1 ).  
S u bjects will u n der g o P K sa m pli n g of bl o o d plas ma a n d C T/ V T/ C V F  (fe males) a n d/ or 
R T/ R F. Fe male s u bjects w h o c o nse nt t o rectal tiss ue a n d rectal fl ui d sa m pli n g will ha ve 
paire d rectal a n d ge nital trac t sa m ples c ollecte d at eac h ti me p oi nt.  Fe male s u bjects w h o 
d o n ot wis h t o partici pate i n rectal P K sa m pli n g ma y  still partici pate i n t he st u d y.  E ver y 
atte m pt s h o ul d be ma de t o ac q uire P K sa m ples a p pr o xi matel y  2 4 h o urs after t he last
o ut patie nt d ose of C A B 3 0 m g.  After recei vi n g t heir last d ose of oral C A B 3 0 m g o n 
D a y  2 8, s u bjects will be gi n a 1 4- 4 2 d a y  was h-o ut peri o d, d uri n g w hic h n o C A B will be 
a d mi nistere d.
4. 1. 3.
C A B I nj e cti o n a n d P K S a m pli n g
After a mi ni m u m of a 1 4 -d a y  was h o ut peri o d, s u bjects will ret ur n t o t he cli nic a n d 
recei ve a si n gle d ose of C A B L A 6 0 0 m g  IM i nt o t he gl uteal m uscle.  T o e ns ure t hat 
i njecti o ns are gi ve n I M rat her t ha n s u bc uta ne o usl y, ultras o u n d g ui da nce d uri n g i njecti o n 
will be use d. S u bjects will re mai n i n t he researc h u nit f or at le ast 4 h o urs after t he 
i njecti o n f or P K sa m pli n g a n d safety assess me nts.  N o n -c o ntrast-e n ha nce d M RI i ma gi n g 
will be perf or me d as o utli ne d i n t he Ti me a n d E ve nts Ta ble ( Sec ti o n 7. 1 ) i n a s u bset of 
a p pr o xi matel y 8 s u bjects ( 4 fe males a n d 4 males) t o assess e v ol uti o n of t he i njecti o n 
de p ot l ocalizati o n.  S u bjects will ret ur n t o t he researc h u nit f or P K sa m pli n g a n d f or st u d y 
assess me nts as descri be d i n t he Ti me a n d E ve nts Ta ble ( Secti o n 7. 1 ).
S u bjects w h o recei ve a n i njecti o n of C A B L A will ret ur n t o t he cli nic f or safet y  
assess me nts a n d plas ma P K sa m pli n g at Wee k 2 4 a n d Wee k 3 6 p ost- i njecti o n, as well as 
t he f oll o w- u p/ wit h dra wal visit as o utli ne d i n Secti o n 4. 1. 4 .  
4. 1. 4.
F oll o w -u p/ Wit h dr a w al Vi sit
Beca use of t he l o n g acti n g p har mac o ki netic pr ofile of C A B L A, e ver y  eff ort s h o ul d be 
ma de t o bri n g s u bjects bac k i n t hr o u g h t he 5 2 wee ks f oll o wi n g t he C A B L A i njecti o n.  A 
fi nal f oll o w- u p visit will be pla n ne d f or Wee k 5 2 p ost-i njecti o n.  If a s u bject is 
wit h dra w n pri or t o recei vi n g t he C A B L A i njecti o n, t he n a f oll o w -u p/ wit h dra wal visit 
s h o ul d be sc he d ule d 1 0-1 4 da y s after t he last oral d ose of C A B. If a s u bject is wit h dra w n 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 7
or dis q ualifie d fr o m t he st u d y after recei vi n g t he C A B L A i njecti o n, b eca use of t he l o n g 
acti n g p har mac o ki netic pr ofile of C A B L A e ver y  eff ort s h o ul d be ma de t o bri n g t he 
s u bject bac k i n f or t he 5 2 wee ks of safety a n d P K asse ss me nts f oll o wi n g t he i njecti o n. 
F urt her deta il re gar di n g wit h dra wal/f oll o w-u p pr oce d ures ca n be f o u n d i n Secti o n 5. 4 .  
4. 2.
Tr e at m e nt A r m s a n d D ur ati o n
Eac h s u bject will partici pate i n t he st u d y  f or a p pr o xi matel y u p t o 6 6 wee ks.  
Fi g ur e 1
St u d y  S c h e m ati c
1. I n a d diti o n t o c o m p art m e nt al P K s a m pli n g f oll o wi n g C A B L A i nj ecti o n, s u bj ects will u n d er g o P K s a m pli n g of bl o o d 
pl as m a a n d C T/ V T/ C V F (f e m al es) a n d/ or R T/ R F aft er D ay 2 8 of t h e or al l e a d -i n, o n D ay 2 9.   
4. 3.
T y p e a n d N u m b er of S u bj e ct s
A p pr o xi matel y  2 0 healt h y s u bjects fr o m at least t w o cli nic sites will be e nr olle d s uc h t hat 
a p pr o xi matel y 1 6 e val ua ble s u bjects ( 8 males a n d 8 fe males) will recei ve a C A B L A I M 
i njecti o n a n d c o m plete 1 2 wee ks of P K sa m pli n g. N o n-c o ntrast-e n ha nce d M RI i ma gi n g 
will be perf or me d i n a s u bset of u p t o 8 s u bjects ( 4 males a n d 4 fe males).  E val ua ble 
s u bjects are defi ne d as t h ose w h o pr o vi de at least o ne pri mar y P K e n d p oi nt wit h o ut maj or 
pr ot oc ol de viati o ns.
If s u bjects pre mat urely disc o nti n ue t he st u d y or is n ot- e val ua ble, a d diti o nal re place me nt 
s u bjects ma y be e nr olle d at t he discreti o n of t he S p o ns or i n c o ns ultati o n wit h t he 
i n vesti gat or. T he re place me nt s u bject will ha ve sa me treat me nt a n d pr oce d ures per 
pr ot oc ol as t he disc o nti n ue d s u bject.
4. 4.
D e si g n J u stifi c a ti o n
T he r ectal a n d va gi nal m uc osa are li kel y rele va nt sites of C A B acti o n w he n use d t o 
pre ve nt se x ual HI V tra ns missi o n. After IM i njecti o n of 4 0 0
m g of C A B L A i n earlier P K 
st u dies, tiss ue t o plas ma rati os were l o w, at 1 6-2 8 % f or cer vic o va gi nal tiss ue a n d < 8 % 
f or c ol orectal tiss ue [S pree n , 2 0 1 4]. T he ai m of t his st u d y  is t o deter mi ne t he m ulti-site 
P K of C A B L A I M f or 1 2 wee ks f oll o wi n g a 6 0 0 m g I M d ose . 
Beca use t he c urre nt pla n ne d C A B L A i njecti o n d ose fre q ue nc y  is e ver y 8 wee ks, we pla n 
P K sa m pli n g of bl o o d plas ma, cer vic o va gi nal a n d rectal l u mi nal fl ui d, a n d bi o psies of 
cer vical, va gi nal, a n d rectal tiss ue at t he e n d of t he 4 wee k oral lea d -i n a n d at 1 wee k, 4 
wee ks, 8 wee ks, a n d 1 2 wee ks p ost -i njecti o n t o u n derstan d dr u g e x p os ure at all of t hese 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 8
sites t hr o u g h o ut a d osi n g i nter val a n d as c o nce ntrati o ns wa ne t hr o u g h Wee k 1 2 p ost -
i njecti o n.  A n a d diti o nal l u mi nal fl ui d ( C V F a n d/ or R F) a n d tiss ue ( C T/ V T a n d/ or R T) 
sa m ple will be c ollecte d o n Da y 3 (a p pr o xi matel y 4 8 h o urs p ost-i njecti o n) t o assess t he 
earl y distri b uti o n of C A B i nt o t he ge nital tract a n d rectal c o m part me nts . I n a d diti o n t o t he 
paire d bl o o d plas ma sa m ples, bl o o d plas ma will be c ollecte d at a d diti o nal ti me p oi nts 
t hr o u g h t he e xte n de d safet y visits f or a p pr o xi matel y o ne year after i njecti o n as o utli ne d 
i n Secti o n 7. 1 .  T his sa m pli n g sc he me will pr o vi de a c o m pre he nsi ve assess me nt of C A B 
L A P K f oll o wi n g a si n gle 6 0 0 m g I M d ose ( Ta ble 4 ). 
T a bl e 4
C o m p art m e nt al P K S a m pli n g
C o m p art m e nt al P K S a m pli n g Ti m e s 
S e x
Or al L e a d -I n 
P o st 6 0 0 m g I M D o s e 
F e m al e s
( B P/ V T/ C T/ C V F/ R T
1/ R F
1) 
D a y 2 9
R ect al fl ui d a n d 
r ect al tiss u e is 
o pti o n al
1
D a y 3 ( 4 8 h), D a y 8 ( 1 6 8 h), W e e k 4, W e e k 8, W e e k 1 2
R ect al fl ui d a n d R ect al tiss u e o pti o n al at e ac h ti m e p oi nt
1; 
V a gi n al tiss u e will b e c oll ect e d o nly o n D ay 3 ( 4 8h) a n d W e ek 
8.
M al e s
( B P/ R T/ R F) 
D a y 2 9
D a y 3 ( 4 8 h), D a y 8 ( 1 6 8 h), W e e k 4, W e e k 8, W e e k 1 2
1.
F e m al e s u bj ects will b e giv e n t h e c h oic e t o pr ovi d e n e ar si m ult a n e o us p air e d r ect al c o m p art m e nt s a m pl es at e ac h 
fl ui d a n d tiss u e s a m pli n g ti m e-p oi nt. T his is a n o pti o n al ass ess m e nt f or w hic h w o m e n m ust pr ovi d e c o ns e nt.  
F e m al e s u bj ects w h o d o n ot wis h t o p artici p at e i n r ect al P K s a m pli n g m ay still p artici p at e i n t h e st u dy.
Fe male s u bjects will be gi ve n t he c h oice t o pr o vi de near si m ulta ne o us paire d rectal 
c o m part me nt sa m ples at eac h fl ui d a n d tiss ue sa m pli n g ti me p oi nt.  C o nse nt m ust be 
o btai ne d pri or t o c ollecti n g rectal tiss ue or rectal fl ui d sa m ples fr o m fe male partici pa nts. 
Rectal P K sa m ples are o pti o nal f or fe male s u bjects a n d, t heref ore, fe males w h o d o n ot 
wis h t o partici pate i n rectal P K sa m pli n g ma y  still partici pate i n t he st u d y.  Tiss ue a n d 
fl ui d c o nce ntrati o ns o btai ne d fr o m paire d rectal a n d ge nital tract sa m ples will e n ha nce 
o ur u n dersta n di n g of a nat o mic variati o n i n C A B distri b uti o n a n d all o w bet wee n -ge n der 
c o m paris o ns i n rectal c o m part me nt pe netrati o n. 
T o i m pr o ve t he c o nsiste nc y of I M d osi n g, we will a d mi nister t he C A B L A i njecti o n wit h 
ultras o u n d g ui da nce. P ost -i njecti o n ma g netic res o na nce i ma gi n g ( M RI) will als o be 
perf or me d i n a s u bset of s u bjects t o assess t he c ha n ges o ver ti me i n t he i njecti o n de p ot 
v ol u me.
I n or der t o ma xi mize s u bject safety, a 4 wee k oral C A B l ea d -i n p hase will prece de t he 
i njecti o n t o i de ntif y t h ose s u bjects wit h a d verse dr u g reacti o ns pri or t o t he C A B L A 
i njecti o n.  If a Gra de 3 or a b o ve A E is o bser ve d, or a n y  A E t hat is dee me d cli nicall y 
si g nifica nt by t he i n vesti gat or a n d is j u d ge d b y t he i n vesti gat or t o be attri b ute d t o t he 
st u d y pr o d uct or pr oce d ures, t he s u bject will be wit h dra w n a n d will n ot recei ve t he C A B 
i njecti o n.  If t he s u bject is wit h dra w n pri or t o i njecti o n, a f oll o w u p visit will be 
perf or me d 1 0 -1 4 da y s after t he last oral d ose of st u d y dr u g.  

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 9
T his desi g n is well -esta blis he d f or t he e val uati o n of m ulti -c o m part me ntal 
p har mac o ki netics.  It is s u bject t o Instit uti o nal Re vie w B oar d (I R B) a p pr o val a n d t he 
a p pr o priate re g ulat or y a p pr o vals, a n d will be liste d o n t he we bsite Cli nical Trials. g o v.  N o 
bli n di n g or place b o c o ntr ol will be use d, as t hese are n ot necessar y f or t he p ur p oses of 
t his st u d y. 
4. 5.
D o s e J u stifi c ati o n
Or al D ose:
Base d u p o n t he res ults t hr o u g h Wee k 4 8 of t he P hase II b, L A I 1 1 6 4 8 2 st u d y, a n d i n 
acc or da nce wit h t he pre -s pecifie d d ose selecti o n criteria at Wee k 2 4, C A B 3 0 m g P O 
o nce dail y has bee n selecte d as part of s h ort -ter m oral lea d-i n t hera p y i n c o m bi nati o n 
wit h ril pi viri ne f or mai nte na nce of vir ol o gic s u p pressi o n i n f ut ure cli nical st u dies i n 
s u bjects wit h HI V i nfecti o n as well as f or s h ort-ter m oral lea d -i n t hera p y as C A B 
m o n ot hera p y pri or t o C A B L A i njecta ble d osi n g i n t he É C LAI R a n d H P T N 0 7 7 Pr E P 
st u dies i n healt h y u ni nfecte d s u bjects [ Gla x o S mit h Kli ne D oc u me nt N u m ber 
2 0 1 3 N 1 8 4 0 4 8 _ 0 1 ; D AI D S D oc u me nt I D 1 1 9 6 4, 2 0 1 4].  T heref ore, t he C A B 3 0 m g oral 
d ose will be a d mi nistere d d uri n g t he oral lea d -i n p hase of t his st u d y t o assess safety a n d 
t olera bilit y pri or t o t he C A B I M i njecti o n. 
L A D ose: 
In a n earl y st u d y, a s mall c o h ort of healt h y partici pa nts recei vi n g t w o q uarterl y d oses 
( Q 1 2 W) of C A B L A 8 0 0 m g I M ac hie ve d a ge o metric mea n ( C V b %) Cof 1. 1 1 m g/ m L 
( 1 3 9 %), a p pr o xi matel y 6. 7-f ol d a b o ve t he P A-I C9 0 a n d bet wee n t he 5 m g a n d 1 0 m g oral 
d oses. T hese data, as well ot her P K data f oll o wi n g C A B L A f oll o wi n g si n gle or re peat 
d oses ra n gi n g fr o m 1 0 0 m g t o 8 0 0 m g I M, were i ncl u de d i n t he i nitial p o p ulati o n P K 
m o del.  Base d o n t he i nitial p o p ulati o n P K m o del, C A B L A 8 0 0 m g I M gi ve n e ver y  1 2 
wee ks ( Q 1 2 W) was pre dicte d t o ac hie ve a mea n c o nce ntrati o n a b o ve t he 1. 3 5 g/ m L  
tar get base d o n 1 0 m g dail y oral d osi n g wit h t he l o wer b o u n d of t he 9 0 % c o nfi de nce 
i nter val ( CI) at ~ 4-f ol d P A IC 9 0.  T he o verall ra n ge of pre dicte d C A B Cval ues 
f oll o wi n g C A B L A 8 0 0 m g IM was si milar t o t hat f oll o wi n g o nce dail y d osi n g of oral 
C A B 1 0 m g. 
T he P hase 2a 2 0 1 1 2 0 ( É C L AI R) st u d y  was u n derta ke n t o e val uate P K a n d safety 
f oll o wi n g Q 1 2 W C A B L A 8 0 0 m g I M d oses i n healt h y male partici pa nts.  E val uati o n of 
P K data fr o m É C L AI R s h o we d t hat 3 0 t o 3 7 % of C A B L A C val ues were 4 -f ol d P A-
I C9 0 f oll o wi n g eac h of t he t hree q uarterly i njecti o ns w hile 1 5 t o 3 1 % were bel o w t he P A -
I C9 0.  Gra p hical e val uati o n of t he C A B plas ma c o nce ntrati o n-ti me pr ofiles s u g gests t hat 
a bs or pti o n was m ore ra pi d a m o n g partici pa nts i n t he É C L AI R st u d y  t ha n t hat o bser ve d i n 
pri or st u dies, res ulti n g i n hi g her pea k a n d l o wer tr o u g h c o nce ntrati o ns.  Of n ote, t he C A B 
L A na n os us pe nsi o n f or m ulati o n has re mai ne d esse ntiall y  u nc ha n ge d t hr o u g h o ut t he 
cli nical de vel o p me nt pr o gra m, i n dicati n g t hat ot her fact ors are c o ntri b uti n g t o t he 
o bser ve d P K differe nces. Gi ve n t his i nf or mati o n, a re gi me n of C A B L A 8 0 0 m g Q 1 2 W 
ma y  n ot mai ntai n s ufficie nt e x p os ures i n all partici pa nts, partic ularly i n males.  T he 
o n g oi n g P hase 2a st u d y  2 0 1 1 0 3 (H P T N 0 7 7), w hic h li ke É C L AI R is e val uati n g C A B L A 
8 0 0 m g I M Q 1 2 W i n healt h y  male a n d fe male partici pa nts, was a me n de d t o e nr oll a 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
2 0
sec o n d c o h ort wit h d osi n g of C A B L A 6 0 0 m g I M at t w o ti me p oi nts 4 wee ks a part a n d 
e ver y 8 wee ks ( Q 8 W) t hereafter f or 5 i njecti o n visits.  A si milar re gi me n ( C A B L A 8 0 0 
m g I M i nitial d ose f oll o we d b y  6 0 0 m g I M at t w o ti me p oi nts 4 wee ks a part a n d Q 8 W 
t hereafter) has bee n e val uate d i n HI V i nfecte d partici pa nts ( n = 1 1 5; 1 0 7 males a n d 8 
fe males) i n c o m bi nati o n wit h ril pi viri ne ( R P V) L A i n st u d y 2 0 0 0 5 6 ( L A T T E -2).  T his 
re gi me n ac hie ve d a mea n C A B Cof 1. 5 3 g/ m L ( me dia n 1. 4 5 g/ m L) at Wee k 3 2, a b o ve 
t he ge o metric mea n Cval ue f or t he 1 0 m g oral d ose i n L A T T E.  At Wee k 3 2, t he 
pr o p orti o n of partici pa nts mai ntai ni n g s u p pressi o n of HI V i n t he Q 8 W ar m was 9 5 % as 
c o m pare d t o 9 4 % i n t he Q 4 W ar m ( C A B L A 8 0 0 m g I M i nitial d ose f oll o we d b y 4 0 0 m g 
I M e ver y 4 wee ks fr o m Wee k 4, n = 1 1 5).       
T he C A B p o p ulati o n P K m o del has bee n u p date d wit h P K data fr o m É C L AI R (a n 
a d diti o nal 9 4 males) a n d L A T T E - 2 (a n a d diti o nal 2 3 0 partici pa nts; 2 1 6 males a n d 1 4 
fe males), si g nifica ntl y i ncreasi n g t he data i n t he p o p ulati o n P K dataset.  T he a bs or pti o n 
rate c o nsta nt f or t he e ntire p o p ulati o n f oll o wi n g C A B L A f or t he ne w m o del was 
i ncrease d a p pr o xi matel y 2-f ol d ( 4. 5 4 x 1 0 - 4 hr-1 t o 9. 1 9 x 1 0 - 4 hr-1; i.e., m ore ra pi d 
a bs or pti o n) as c o m pare d t o t he pre vi o us m o del a n d res ulte d i n hi g her pea k t o tr o u g h 
rati os t ha n pre vi o usly o bser ve d.  Se x re mai ns a si g nifica nt c o variate i n t he m o del 
affecti n g t he a bs or pti o n rate c o nsta nt f oll o wi n g L A a d mi nistrati o n ( K A L A), reflecti n g 
sl o wer a bs or pti o n i n fe males t ha n i n males.  A d diti o nal data fr o m H P T N 0 7 7 will i ncrease 
t he data o btai ne d fr o m fe males i n t he m o del t o i m pr o ve u n dersta n di n g of t he i m pact of 
se x o n K A LA.   
Si m ulati o ns base d o n t he u p date d p o p ulati o n P K m o del ha ve bee n c o n d ucte d t o e val uate 
se veral p ote ntial d osi n g re gi me ns.  C urre ntly, t he H P T N 0 7 7 C o h ort 2 re gi me n ( C A B L A 
6 0 0 m g I M at t w o ti me p oi nts 4 wee ks a part a n d e ver y  8 wee ks ( Q 8 W) t hereafter) is 
pla n ne d f or e val uati o n i n l o n g -ter m P hase 3 Pr E P st u dies.  C A B L A 6 0 0 m g I M is t he 
lar gest C A B L A d ose t hat ca n be a d mi nistere d by si n gle i njecti o n ( 3 m L of 2 0 0 m g/ m L 
na n os us pe nsi o n).  F or t hese reas o ns, a si n gle 6 0 0 m g I M is t he pr o p ose d d ose f or 
e val uati o n of plas ma a n d tiss u e P K i n t his st u d y. Si m ulate d pr ofiles f oll o wi n g a si n gle 
C A B L A 6 0 0 m g I M i njecti o n o ne wee k after disc o nti n uati o n of t he C A B 3 0 m g o nce 
dail y  oral lea d- i n t o e val uate safet y are s h o w n f or males a n d fe males se paratel y (Fi g ure 2 , 
Fi g ure 3 ).  T he pr ofiles s h o w t he last oral d ose, w hic h are e x pecte d t o ac hie ve mea n pea k 
a n d tr o u g h c o nce ntrati o ns of 7. 5 g/ m L a n d 4. 2 g/ m L , res pecti vely.  C o nsiste nt wit h t he 
i m pact of se x o n a bs or pti o n, males will ac hie ve a hi gher C ma x of ~ 3 g/ m L t ha n fe males, 
w h o will ac hie ve a C ma x of ~ 1. 3 5 g/ m L. Plas ma c o nce ntrati o ns are e x pecte d t o re mai n 
a b o ve 4 x P A-I C9 0 ( 0. 6 6 4g/ m L) f or a p pr o xi matel y  4 wee ks a n d a b o ve P A-I C9 0
( 0. 1 6 6g/ m L) f or a p pr o xi matel y  8 wee ks i n 9 5 % of males; greater varia bilit y  i n 
c o nce ntrati o ns bet wee n 8 a n d 1 2 wee ks p ost i njecti o n is e x pecte d i n males.  Plas ma 
c o nce ntrati o ns are e x pecte d t o re mai n a b o ve t he P A -I C9 0 ( 0. 1 6 6g/ m L) i n 9 5 % of 
fe males t hr o u g h o ut t he 1 2- wee k tiss ue sa m pli n g peri o d.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
2 1
Fi g ur e 2
Pr e di ct e d M e di a n
( 9 0 % P I) C AB C o n c e ntr ati o n -ti m e Pr ofil e i n M al e s 
f oll o wi n g a si n gl e C A B L A  6 0 0 m g I M I nj e cti o n ( aft er a 1 w e e k 
w a s h o ut fr o m 3 0 m g o n c e d ail y  or al l e a d-i n)

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
2 2
Fi g ur e 3
Pr e di ct e d M e di a n
( 9 0 % P I) C AB C o n c e n tr ati o n-ti m e Pr ofil e i n 
F e m al e s f oll owi n g a si n gl e C A B L A  6 0 0 m g I M I nj e cti o n ( aft er a 1 
w e e k w a s h o ut fr o m 3 0 m g o n c e d ail y  or al l e a d-i n)
I n a pre vi o us st u dy, a m o dest c orrelati o n bet wee n plas ma C A B c o nce ntrati o ns a n d 
cer vic o va gi nal a n d rectal tiss ue c o nce ntrati o ns was o bser ve d f oll o wi n g a si n gle d ose of 
C A B L A 4 0 0 m g  IM i n healt h y  male a n d fe male s u bjects ( Secti o n 2. 1 ).  As t he pr o p ose d 
d ose is 5 0 % hi g her a n d tiss ue sa m pli n g will be c o n d ucte d d uri n g  t he oral phase a n d 
f oll o wi n g C A B L A a d mi nistrati o n, it is e x pecte d t hat tiss ue sa m pli n g will be c o n d ucte d 
o ver a n ~ 1 0 0 -f ol d ra n ge of plas ma c o nce ntrati o ns ( ~ 0. 0 5g/ m L t o ~ 5 g/ m L ). T he 
partiti o ni n g of C A B i nt o ge nital tract a n d rectal tiss ue ac hie ve d o ver a 1 2 - wee k wi n d o w
f oll o wi n g a si n gle C A B L A 6 0 0 m g  IM d ose will e n ha nce o ur u n dersta n di n g of C A B
L A
as Pr E P. 
4. 6.
B e n efit: Ri s k A s s e s s m e nt
S u m maries of fi n di n gs fr o m b ot h cli nical a n d n o n- cli nical st u dies c o n d ucte d wit h C A B 
ca n be f o u n d i n t he I n vesti gat or’s Br oc h ure.  T he f oll o wi n g secti o n o utli nes t he ris k 
assess me nt a n d miti gati o n strate g y f or t his pr ot oc ol: 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
2 3
4. 6. 1.
Ri s k A s s e s s m e nt
P ot e nti al Ri s k of 
Cli ni c al 
Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
I n v e sti g ati o n al Pr o d u ct (I P) G S K 1 2 6 5 7 4 4/ C a b ot e gr a vir
El ev at e d liv er 
tr a ns a mi n as es
A f e w s u bj ects i n t h e C A B pr o gr a m h av e ex p eri e nc e d tr a ns a mi nitis ( el ev at e d liv er tr a ns a mi n as es c h ar act eris e d by 
pr e d o mi n a nt A L T el ev ati o n). S o m e of t h es e s u bj ects’ tr a nsi e nt tr a ns a mi nitis w er e ex pl ai n e d by ac ut e h e p atitis C
i nf ecti o n a n d ot h ers di d n ot h av e alt er n ativ e ex pl a n ati o ns, s u g g esti n g a mil d f or m of Dr u g i n d uc e d Liv er I nj urt 
(DI LI ) wit h o ut h e p atic dysf u ncti o n w hic h r es olv e d u p o n wit h dr a w al of tr e at m e nt wit h C A B. 
C u m ul ativ ely (t hr o u g h J a n u ary 1, 2 0 1 6) 1 1 6 0 s u bj ects h av e b e e n ex p os e d t o or al C A B a n d/ or I M C A B. S ev e nt e e n 
s u bj ects h av e m et pr ot oc ol-d efi n e d liv er st o p pi n g crit eri a, of w hic h fiv e ar e c o nsi d er e d t o r e pr es e nt p ossi bl e or 
pr o b a bl e c as es of DI LI.  Ei g ht of t h e 1 7 s u bj ects m et liv er st o p pi n g crit eri a aft er h av i n g r ec eiv e d C A B I M, six 
s u bj ects as a r es ult of ac ut e H e p atitis C, o n e ac ut e HI V s er oc o nv ersi o n a n d o n e p ossi bl e or pr o b a bl e DI LI 
f oll o wi n g C A B I M or Pl ac e b o I M a d mi nistr ati o n.
Of t h e fiv e s u bj ects wit h p ossi bl e or pr o b a bl e c as es of DI LI, f o ur s u bj ects w er e r ec eivi n g or al C A B a n d o n e s u bj ect 
d ev el o p e d pr o b a bl e DI LI f oll o wi n g C A B I M or Pl ac e b o I M a d mi nistr ati o n. N o n e of t h es e s u bj ects h av e d ev el o p e d 
evi d e nc e of h e p atic dysf u ncti o n a n d all h a d i m pr ov e m e nts i n A S T a n d A L T ov er ti m e u p o n wit h dr a w al o f C A B.
E xcl usi o n crit eri a as d escri b e d i n 
S ecti o n 5. 2 will pr o hi bit s u bj ects wit h 
c urr e nt or c hr o nic liv er dis e as es a n d 
si g nific a nt liv er i m p air m e nt b as e d o n 
scr e e ni n g liv er c h e mistry i ncl u di n g 
tr a ns a mi n as es ( A L T a n d A S T). 
A 4 -w e ek o r al l e a d- i n p eri o d is b ei n g 
i m pl e m e nt e d i n t his st u dy, w h er e all 
s u bj ects will r ec eiv e or al C A B pri or t o 
t h e a d mi nistr ati o n of I M C A B t o 
d et er mi n e i n divi d u al s af ety a n d 
t ol er a bility 
Liv er tr a ns a mi n as es ( A L T a n d A S T) 
will b e cl os ely m o nit or e d t hr o u g h o ut 
t his st u dy (r ef er t o Ti m e & Ev e nts 
T a bl e) a n d t h e liv er c h e mistry st o p pi n g 
crit eri a will b e a d o pt e d as d escri b e d i n 
S ecti o n 5. 4. 1 of t his pr ot oc ol. S u bj ects 
will b e wit h dr a w n fr o m C A B tr e at m e nt 
w h er e n o c o m p elli n g alt er n ativ e c a us e 
is i d e ntifi e d All i nst a nc es of liv er 
tr a ns a mi n as e el ev ati o ns will b e 
f oll o w e d t o r es ol uti o n. S u bj ects 
wit h dr a w n fr o m C A B tr e at m e nt d u e t o 
m e eti n g liv er c h e mistry st o p pi n g 
crit eri a will b e r e g ul arly m o nit or e d b ot h 
cli nic ally a n d  usi n g liv er c h e mistri es t o 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
2 4
P ot e nti al Ri s k of 
Cli ni c al 
Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
d et er mi n e pr o gr ess t o w ar ds r es ol uti o n 
of t h e liv er ev e nt
I nj ecti o n Sit e 
R e acti o ns (I S Rs)
Cli nic al, ex p eri e nc e t o d at e h as d e m o nstr at e d I S Rs occ ur i n t h e m aj ority of ex p os e d s u bj ects tr e at e d wit h I M C A B 
b ut ar e g e n er ally mil d ( Gr a d e 1 ) or m o d er at e ( Gr a d e 2) a n d i ncl u d e ev e nts of p ai n, t e n d er n ess, eryt h e m a, or 
n o d ul e f or m ati o n of s ev er al d ays d ur ati o n ( m e di a n d ur ati o n f or i n divi d u al ev e nts < 1 w e ek). I S Rs m ay occ ur m or e 
t h a n o nc e i n a n i n divi d u al s u bj ect r ec eivi n g m ulti pl e i nj ecti o ns. Alt h o u g h s o m e Gr a d e 3 I S Rs w er e r e p ort e d, ov er all 
I S Rs h av e b e e n w ell t ol er at e d a n d h av e n ot t o d at e b e e n ass oci at e d wit h a n exc ess of s u bj ects’ wit h dr a w al d u e t o 
I S Rs.
N o n e of t h e I S Rs w as s eri o us a n d n o cli nic al si g nific a nt c o m plic ati o ns w er e r e p ort e d
A d mi nistr ati o n a dvic e t o mi ni miz e risk 
of p o or a d mi nistr ati o n t ec h ni q u e givi n g 
ris e t o I S Rs. A dvic e o n c ar e, 
m o nit ori n g, n at ur al c o urs e, a n d 
tr e at m e nt of I S Rs giv e n i n st u dy 
d oc u m e nt ati o n 
A dvic e t o s u bj ects o n c ar e of i nj ecti o n 
sit e o n d ay/ d ays i m m e di at ely p ost 
a d mi nistr ati o n, us e of a n al g esi a, 
c o m pr ess es w h er e a p pr o pri at e.
S u bj ects will b e cl os ely m o nit or e d f or 
I S Rs p artic ul arly f or si g ns of p ai n, 
t e n d er n ess, i nf ecti o ns, eryt h e m a, 
s w elli n g, i n d ur ati o n, or n o d ul es 
( gr a n ul o m as or cysts) t hr o u g h o ut t h e 
st u dy. C o m plic ati o ns of I S Rs s uc h as 
i nf ecti o ns ( a bsc ess, c ell ulitis) a n d 
c oll ecti o ns of fl ui d r e q uiri n g dr ai n a g e 
will b e m o nit or e d 
Si g nific a nt I S Rs m ay b e p h ot o gr a p h e d 
a n d r ef err e d t o a d er m at ol o gist f or 
s p eci alist a dvic e.
.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
2 5
P ot e nti al Ri s k of 
Cli ni c al 
Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
Hy p ers e nsitivity 
R e acti o ns
( H S R)
Hy p ers e nsitivity r e acti o ns h av e b e e n r e p ort e d wit h i nt e gr as e i n hi bit ors, i ncl u di n g d ol ut e gr avir, a n d w er e 
c h ar act eriz e d by r as h, c o nstit uti o n al fi n di n gs, a n d s o m eti m es, or g a n dysf u ncti o n, i ncl u di n g liv er i nj ury . 
W hil e t h er e h av e b e e n n o cli nic al c as es of hy p ers e nsitivity t o C A B, t h er e is a t h e or etic al risk of syst e mic or s ev er e 
hy p ers e nsitivity r e acti o ns wit h or wit h o ut h e p atic sy m pt o ms ass oci at e d wit h us e of I M C A B. T h e l o n g ex p os ur es 
a ntici p at e d aft er I M C A B i nj ecti o n m ay c o m plic at e t h e m a n a g e m e nt of a dr u g hy p ers e nsitivity r e acti o n, w er e it t o 
occ ur.
T h e risk of d ev el o pi n g a 
hy p ers e nsitivity r e acti o n p ost 
a d mi nistr ati o n of I M C A B will b e 
mi ni miz e d by t h e us e of a 4 -w e ek or al 
l e a d-i n of C A B t o d et er mi n e i n divi d u al 
s af ety a n d t ol er a bility pri or t o t h e 
i ntr o d ucti o n of I M C A B. 
Cli nic al ass ess m e nts, l a b or at ory t ests 
(i ncl u di n g liv er tr a ns a mi n as es) a n d 
vit al si g ns will b e p erf or m e d t hr o u g h o ut 
t his st u dy (r ef er t o Ti m e & Ev e nts 
T a bl e). R es ults fr o m t h es e 
ass ess m e nts m ay ai d e arly d et ecti o n 
of H S R. 
Or al C A B will b e wit h dr a w n 
i m m e di at ely f or c as es wit h s us p ect e d 
H S R d uri n g t h e l e a d -i n p h as e. D uri n g 
or al a n d I M C A B tr e at m e nt, a ny H S R 
r e acti o ns t h at occ ur w o ul d b e 
m a n a g e d s u p p ortiv ely.
Dr u g -Dr u g I nt er acti o ns 
( D DIs)
R esi d u al c o nc e ntr ati o ns of C A B will r e m ai n i n t h e syst e mic circ ul ati o n of s u bj ects f or pr ol o n g e d p eri o ds ( m o nt hs). 
S u bj ects disc o nti n ui n g a L A r e gi m e n m ay b e at risk f or d ev el o pi n g D DIs m a ny w e eks aft er disc o nti n ui n g i nj ect a bl e 
t h er a py. Of n ot e, i n vitr o a n d cli nic al evi d e nc e t o d at e, i n dic at es t h at wit h t h e exc e pti o n of s e nsitiv e O A T s u bstr at es 
wit h n arr o w t h er a p e utic i n d ex ( e. g. m et h otr ex at e), C A B h as a  l o w risk f or c a usi n g  cli nic ally si g nific a nt dr u g 
i nt er acti o ns. 
All s u bj ects will b e i nf or m e d of 
pr o hi bit e d m e dic ati o ns t hr o u g h o ut t h e 
st u dy a n d up d at es pr ovi d e d as n e e d e d 
vi a i nf or m e d c o ns e nt.
D ev el o p m e nt of 
R esist a nc e i n
t h e s etti n g of HI V 
ac q uisiti o n
R esi d u al c o nc e ntr ati o ns of C A B L A w o ul d r e m ai n i n t h e syst e mic circ ul ati o n of p artici p a nts f or pr ol o n g e d p eri o ds 
( u p t o 5 2 w e eks i n s o m e s u bj ects). P artici p a nts m ay b e at risk f or d ev el o pi n g r esist a nc e t o C A B m a ny w e eks aft er 
disc o nti n ui n g i nj ect a bl e t h er a py w er e t h ey t o b ec o m e n e wly i nf ect e d wit h HI V.
All p artici p a nts will b e i nf or m e d of t his 
risk. P artici p a nts will b e f oll o w e d f or 5 2 
w e eks fr o m t h e ti m e of t h e l ast 
i nj ecti o n wit h C A B. T h e risk of HI V 
ac q uisiti o n s h o ul d b e mi ni miz e d by 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
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2 6
P ot e nti al Ri s k of 
Cli ni c al 
Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
o nly i ncl u di n g h e alt hy v ol u nt e ers at l o w 
risk f or ac q uiri n g HI V, a n d by 
e nc o ur a gi n g all s u bj ects t o pr actic e 
s af e s ex f or at l e ast 5 2 w e eks aft er t h e 
l ast i nj ecti o n ofC A B L A. HI V t esti n g 
will occ ur p eri o dic ally t hr o u g h o ut t h e 
st u dy. If a p artici p a nt ac q uir es HI V o n 
st u dy h e or s h e will b e r ef err e d f or 
a p pr o pri at e c ar e.
I n a d v ert e nt 
I ntr a v e n o u s I nj e cti o n 
( A c ci d e nt al 
M al a d mi ni str ati o n)
As wit h a ny i ntr a m usc ul ar i nj ecti o n , it is p ossi bl e t h at I M C A B c a n b e i n a dv ert e ntly a d mi nist er e d i ntr av e n o usly 
i nst e a d of i ntr a m usc ul arly r es ulti n g i n hi g h er t h a n ex p ect e d c o nc e ntr ati o ns of C A B.  T his c o ul d b e d u e t o 
a d mi nistr at or err or, i m pr o p er i nj ecti o n t ec h ni q u e a n d / or i m pr o p er n e e dl e l e n gt h us e d b as e d o n b o dy ty p e. T h e 
cli nic al c o ns e q u e nc es of ov er d os e wit h C A B ar e c urr e ntly u nk n o w n.
All I M i nj ecti o ns will b e d o n e u n d er 
ultr as o u n d g ui d a nc e by a tr ai n e d 
cli nici a n, w hic h will mi ni miz e t h e risk of 
i ntr av e n o us a d mi nistr ati o n.  
S h o ul d I M m al a d mi nistr ati o n b e 
s us p ect e d at a ny ti m e ( e. g. s us p ect e d 
u n d er or ov er d os e or i n a dv ert e nt I V 
d osi n g), a p ost d os e E C G , vit al si g ns 
or a ny ot h er s u p p ortiv e t esti n g m ay b e 
o bt ai n e d at t h e discr eti o n of t h e 
i nv esti g at or, a n d t h e m e dic al m o nit or 
n otifi e d. 
L a b or at ory s a m pl es f or s af ety 
p ar a m et ers will b e cl os ely m o nit or e d i n 
all s u bj ects.  A d diti o n ally, 2 h o ur p ost 
d os e P K s a m pl es will b e o bt ai n e d at a 
f e w e arly ti m e p oi nts f or d et er mi n ati o n 
of C A B c o nc e ntr ati o n a n d p ossi bl e 
p h ar m ac oki n etic c orr el ati o n wit h s af ety 
p ar a m et ers s uc h as E C G c h a n g es.

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2 7
P ot e nti al Ri s k of 
Cli ni c al 
Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
St u d y Pr o c e d ur e s
A n osc o py t o o bt ai n 
r ect al fl ui d s a m pli n g
It is p ossi bl e t h at t h e p artici p a nt m ay ex p eri e nc e mil d disc o mf ort, e m b arr ass m e nt or, r ar ely, p ai n (s h o ul d t h ey h av e 
a n ot h er c o n diti o n t h at is alr e a dy c a usi n g p ai n i n t h e ar e a) d uri n g t his pr oc e d ur e.  
If t h er e is a ny p ai n ex p eri e nc e d d uri n g 
t h e pr oc e d ur es, t h e st u dy cli nici a n will 
a d a pt or st o p t h e pr oc e d ur e.
C ervic al a n d v a gi n al 
bi o psy vi a s p ec ul u m 
ex a m
It is p ossi bl e t h at t h e p artici p a nt m ay ex p eri e nc e mil d disc o mf ort, e m b arr ass m e nt, or, r ar ely, p ai n d uri n g s p ec ul u m 
ex a m a n d bi o psi es. T h er e is als o a s m all risk of bl e e di n g a n d a n extr e m ely l o w risk of i nf ecti o n aft er bi o psy. I n r ar e 
circ u mst a nc es, t h e bl e e di n g m ay r e q uir e bl o o d tr a nsf usi o ns a n d s ur gic al r e p air.  A s m all a m o u nt of disc o mf ort 
d uri n g s ex u al i nt erc o urs e m ay f oll o w i n t h e f e w d ays aft er t h e pr oc e d ur e. 
If t h er e is a n a dv ers e ev e nt, 
p artici p a nts will b e r ef err e d 
i m m e di at ely t o t h e a p pr o pri at e c ar e. If 
t h er e is a ny p ai n ex p eri e nc e d d uri n g 
t h e pr oce d ur es, t h e st u dy cli nici a n will 
a d a pt or st o p t h e pr oc e d ur es. S u bj ects 
s h o ul d a bst ai n fr o m i ns erti n g a nyt hi n g 
i nt o t h e v a gi n a ( e. g., t a m p o ns, s ex u al 
i nt erc o urs e) wit hi n 7 2 h o urs aft er 
c ervic al or v a gi n al bi o psi es.
C ol o nic bi o psi es vi a 
fl exi bl e si g m oi d osco py
Fl exi bl e si g m oi d osc o py is a c o m m o nly pr actic e d m e dic al pr oc e d ur e a n d t h e e n d osc o pic pr oc e d ur es d o n e i n t his 
tri al will n ot i nv olv e a ny u n us u al risks or disc o mf orts. T h e risks ass oci at e d wit h t h es e pr oc e d ur es i ncl u d e mil d 
disc o mf ort a n d t h e f e eli n g of h avi n g a “ bl o at e d st o m ac h”.  E n d osc o pic bi o psi es ar e p ai nl ess a n d h e al q uickly wit hi n 
3 d ays. O n extr e m ely r ar e occ asi o ns, t h e e n d osc o pic pr oc e d ur e or bi o psi es m ay l e a d t o p ai n, i nf ecti o n (s e psis), 
bl e e di n g or p erf or ati o n of t h e g astr oi nt esti n al tr act. P erf or ati o n occ urs a p pr oxi m at ely o nc e o ut of ev ery 1 0, 0 0 0 
pr oc e d ur es. If t his extr e m ely r ar e c o m plic ati o n occ urs, a nti bi otics a n d s ur g ery t o r e p air t h e t e ar m ay b e n ec ess ary.  
I n r ar e circ u mst a nc es, t h e bl e e di n g m ay r e q uir e bl o o d tr a nsf usi o ns a n d s ur gic al r e p air. S u bj ects will s elf -a d mi nist er 
a 1 2 5 m L e n e m a s ev er al h o urs pri or t o t h e fl ex i bl e si g m oi d osc o pypr oc e d ur e. T h e m ai n risk fr o m h avi n g a n e n e m a 
is t e m p or ary disc o mf ort. S o m e air m ay b e p u m p e d i nt o t h e r ect u m as w ell, c a usi n g a bl o ati n g or g assy s e ns ati o n.
V ery r ar ely, t h e e n e m a ti p m ay c a us e a p erf or ati o n, as d escri b e d a b ov e. S u bj ects will als o b e ask e d t o h av e 
n ot hi n g t o e at f or 8 h o urs pri or t o t h e e n d osc o py pr oc e d ur e.
T his pr oc e d ur e will b e p erf or m e d 
excl usiv ely by ex p eri e nc e d 
pr actiti o n ers of e n d osc o py , w h o ar e 
f a mili ar wit h s af ety pr oc e d ur es a n d 
miti g ati o n of a ny c o m plic ati o ns t h at 
s h o ul d e ns u e. 

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2 8
P ot e nti al Ri s k of 
Cli ni c al 
Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
P hl e b ot o my f or bl o o d 
dr a ws
T h er e is a s m all risk of disc o mf ort, bl e e di n g, i n a dv ert e nt art eri al p u nct ur e, or a dv ers e r e acti o n wit h v e ni p u nct ur e 
s uc h as f ai ntin g. 
S h o ul d a ny bl e e di n g occ ur, t h e 
pr oc e d ur e will b e a b ort e d at t h at 
p u nct ur e sit e a n d pr ess ur e will b e h el d 
f or t h e a p pr o pri at e p eri o d of ti m e. 
S h o ul d a ny a dv ers e r e acti o ns t o 
v e ni p u nct ur e occ ur, t h e p artici p a nt will 
b e r ef err e d i m m e di at ely t o t h e 
a p pr o p ri at e c ar e.
Ot h er 
Ultr as o u n d g ui d a nc e 
f or I M i nj ecti o n
T h er e is n o c o nvi nci n g evi d e nc e of a dv ers e eff ects fr o m ultr as o u n d i m a gi n g, es p eci ally o n e -ti m e, s h ort-liv e d 
i m a gi n g w hic h is ex p ect e d t o l ast l ess t h a n a mi n ut e. N o or mi ni m al p ai n is ass oci at e d wit h t his pr oc e d ur e. 
Acc or di n g t o t h e W orl d F e d er ati o n of Ultr as o u n d i n M e dici n e a n d Bi ol o gy Cli nic al S af ety St at e m e nt f or Di a g n ostic 
Ultr as o u n d I m a gi n g ( htt p:// w w w. wf u m b. or g/ a b o ut/st at e m e nts. as px), “ Di a g n ostic ultr as o u n d h as b e e n wi d ely us e d 
i n cli nic al m edici n e f or m a ny y e ars wit h n o pr ov e n d el et eri o us eff ects. H o w ev er, i nv esti g ati o ns i nt o t h e p ossi bility of 
s u btl e or tr a nsi e nt eff ects ar e still at a n e arly st a g e. Bi ol o gic al eff ects (s uc h as l oc aliz e d p ul m o n ary c a pill ary 
bl e e di n g) h av e b e e n r e p ort e d i n m a m m ali a n syst e ms at di a g n ostic ally r el ev a nt ex p os ur es b ut t h e cli nic al 
si g nific a nc e of s uc h eff ects is n ot y et k n o w n. C o ns e q u e ntly, di a g n ostic ultr as o u n d c a n o nly b e c o nsi d er e d s af e if 
us e d pr u d e ntly. 
Ultr as o u n d pr o d uc es h e ati n g, pr ess ur e c h a n g es a n d m ec h a n ic al dist ur b a nc es i n tiss u e. Di a g n ostic l ev els of 
ultr as o u n d ar e c a p a bl e of pr o d uci n g t e m p er at ur e ris es t h at m ay b e h az ar d o us t o s e nsitiv e or g a ns a n d t h e 
e m bry o/f et us. Bi ol o gic al eff ects of n o n -t h er m al ori gi n h av e b e e n r e p ort e d i n a ni m als b ut, t o d at e, n o s uc h eff ects 
h av e b e e n d e m o nstr at e d i n h u m a ns, exc e pt w h e n a micr o b u b bl e c o ntr ast a g e nt is pr es e nt. 
Ultr as o u n d will b e e m pl oy e d f or t h e 
mi ni m u m ti m e n ec ess ary i n or d er t o 
o bt ai n t h e r e q uir e d vis u aliz ati o n a n d 
will b e p erf or m e d by c o m p et e nt 
p ers o n n el w h o a r e tr ai n e d a n d u p d at e d 
i n s af e pr oc e d ur al t ec h ni q u e
M RI ( n o n -e n h a nc e d) 
of i nj ecti o n sit e t o 
vis u aliz e i nj ecti o n 
d e p ot
F D A g ui d a nc e o n s af ety a n d us e of M a g n etic R es o n a nc e I m a gi n g ( htt p:// w w w.f d a. g ov/ R a di ati o n -
E mitti n g Pr o d ucts/ R a di ati o n E mitti n g Pr o d ucts a n d P r oc e d ur es/ M e dic alI m a gi n g/ uc m 2 0 0 0 8 6. ht m) st at es: “M RI d o es 
n ot us e i o nizi n g r a di ati o n ( hi g h -e n er gy r a di ati o n t h at c a n p ot e nti ally c a us e d a m a g e t o D N A, lik e t h e x -r ays us e d C T 
sc a ns). T h er e ar e n o k n o w n h ar mf ul si d e -eff ects ass oci at e d wit h t e m p or ary ex p os ur e t o t h e str o n g m a g n etic fi el d 
us e d by M RI sc a n n ers. H o w ev er, t h er e ar e i m p ort a nt s af ety c o nc er ns t o c o nsi d er b ef or e p erf or mi n g or u n d er g oi n g 
a n M RI sc a n:
All p artici p a nts will b e scr e e n e d 
acc or di n g t o l oc al h os pit al crit eri a a n d 
tri al i ncl usi o n/ excl usi o n b ef or e e nt eri n g 
t h e M RI r o o m t o e ns ur e t h ey ar e a bl e 
t o h av e t h e M RI c o n d uct e d t o 
m axi miz e t h e s af ety of t his pr oc e d ur e. 

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C O N FI D E N TI A L
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2 9
P ot e nti al Ri s k of 
Cli ni c al 
Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y

T h e m a g n et m ay c a us e p ac e m ak ers, artifici al li m bs, a n d ot h er i m pl a nt e d m e dic al d evic es t h at c o nt ai n 
m e t al t o m alf u ncti o n or h e at u p d uri n g t h e ex a m.

A ny l o os e m et al o bj ect m ay c a us e d a m a g e or i nj ury if it g ets p ull e d t o w ar d t h e m a g n et.

Dy es fr o m t att o os or t att o o e d ey eli n er c a n c a us e ski n or ey e irrit ati o n.

M e dic ati o n p atc h es c a n c a us e a ski n b ur n.

T h e wir e l e a ds us e d t o m o nit or a n el ectr oc ar di o gr a m ( E C G) tr ac e or r es pir ati o n d uri n g a sc a n m ust b e 
pl ac e d c ar ef ully t o av oi d c a usi n g a ski n b ur n. Pr ol o n g e d ex p os ur e t o r a di o w av es d uri n g t h e sc a n c o ul d 
l e a d t o sli g ht w ar mi n g of t h e b o dy.”

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C O N FI D E N TI A L
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3 0
4. 6. 1. 1.
Ot h er Cli ni c all y  R el e v a nt I nf or m ati o n
A d diti o nal det ails c o ncer ni n g safet y o bser vati o ns fr o m cli nical st u dies a n d f or w hic h a 
ca usal ass ociati o n has n ot bee n esta blis he d or w hic h are of mi ni mal cli nical si g nifica nce 
ma y  be f o u n d i n t he In vesti gat or’s Br oc h ure. Please refer t o Secti o n 6: ‘ S u m mar y  of Data 
a n d G ui da nce f or t he I n vesti gat or’. 
A dverse Eve nts of S peci al I nterest
Seiz ure
T hree cases of seiz ures ha ve occ urre d i n t he ca b ote gra vir pr o gra m c u m ulati vel y  t hr o u g h 
0 1 Oct o ber 2 0 1 5. T w o of t he cases occ urre d i n HI V u ni nfecte d s u bjects wit h a pri or 
hist or y  of seiz ure a n d o ne case i n v ol ve d a s u bject i n st u d y 2 0 0 0 5 6 wit h circ u msta ntial 
a n d a nec d otal e vi de nce of illicit dr u g use. O verall, t here is n ot c o n vi nci n g e vi de nce t hat 
ca b ote gra vir e x p os ure ma y  be ca usall y ass ociate d wit h seiz ure or wit h re d ucti o n of 
seizure t hres h ol d, d ue t o t he l o w fre q ue nc y  of re p orts, t he c o nf o u n ders prese nt i n t he 
cases recei ve d t o date a n d lac k of a n y pre -cli nical si g nal or i de ntifie d pla usi ble 
mec ha nis m. H o we ver seiz ure a n d seiz ure- li ke e ve nts are c o nsi dere d as A Es of s pecial 
i nterest f or cl ose m o nit ori n g i n all st u dies. S u bjects wit h rece nt hist or y of, or rece nt 
treat me nt f or seiz ure will be e xcl u de d fr o m st u d y partici pati o n.
4. 6. 2.
B e n efit A s s e s s m e nt
S u bjects partici pati n g i n t his st u d y  ma y n ot recei ve a n y cli nical be nefit, b ut will be 
c om pe nsate d f or t heir ti me a n d partici pati o n.
Be nefit c o nsi derati o ns ma y  i ncl u de:

C o ntri b uti n g t o t he pr ocess of de vel o pi n g ne w t hera pies f or HI V treat me nt a n d 
pre ve nti o n t hat are n ot criticall y de pe n de nt u p o n a d here nce t o daily d osi n g.

Me dical e val uati o ns a n d assess me nts ass ociate d wit h st u d y pr oce d ures (e. g. 
p h y sical e xa m, E C G, la b orat or y st u dies, etc.).  
4. 6. 3.
O v er all B e n efit: Ri s k C o n cl u si o n
Re vie w of t he c u m ulati ve safet y data o n C A B oral a n d L A has n ot i de ntifie d a n y  safety 
si g nals w hic h are c o nsi dere d t o p ose a n u nacce pta ble ris k t o healt h y v ol u nteers. 
C o nsi deri n g t he m ulti ple a n d o verla p pi n g meas ures t hat will be ta ke n t o mi ni mize ris k t o 
s u bjects partici pati n g i n t his st u d y, t he p ote ntial ris ks i de ntifie d i n ass ociati o n wit h C A B 
are j ustifie d b y t he a ntici p ate d be nefits t hat ma y be aff or de d t o s u bjects i ncl u di n g cl ose 
me dical m o nit ori n g a n d satisfacti o n of c o ntri b uti n g t o t he o n g oi n g c o nti n ue d cli nical 
de vel o p me nt of C A B f or b ot h t he treat me nt a n d pre ve nti o n of HI V i nfecti o n. 

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5.
S E L E C TI O N O F S T U D Y P O P U L A TI O N A N D 
WI T H D R A W A L C RI T E RI A
De viati o ns fr o m i ncl usi o n a n d e xcl usi o n criteria are n ot all o we d beca use t he y ca n 
p ote ntiall y  je o par dize t he scie ntific i nte grit y of t he st u d y, re g ulat or y acce pta bilit y or 
s u bject safety. T heref ore, a d here nce t o t he criteria as s peci fie d i n t he pr ot oc ol is esse ntial.
5. 1.
I n cl u si o n Crit eri a
T his st u d y  d oes n ot i n v ol ve a ra n d o mizati o n pr oce d ure, as all s u bjects will recei ve t he 
sa me d ose of t he sa me pr o d uct.
S pecific i nf or mati o n re gar di n g war ni n gs, preca uti o ns, c o ntrai n dicati o ns, a d verse e v e nts, 
a n d ot her perti ne nt i nf or mati o n o n t he Vii V Healt hcare i n vesti gati o nal pr o d uct or ot her 
st u d y treat me nt t hat ma y i m pact s u bject eli gi bilit y is pr o vi de d i n t he I nvesti gat or’s 
Br oc h ure.
A s u bject will be eli gi ble f or i ncl usi o n i n t his st u d y o nl y if all of t he f oll o wi n g criteria 
a p pl y:
A G E
1.
Bet wee n 1 8 a n d 5 5 ye ars of a ge i ncl usi ve, at t he ti me of si g ni n g t he i nf or me d 
c o nse nt.
T Y P E O F S U BJ E C T A N D DI A G N O SI S I N C L U DI N G DI S E A S E S E V E RI T Y 
2.
Healt h y as deter mi ne d b y t he i n vesti gat or or me dicall y q ualifie d desi g nee base d 
o n a me dical e val uati o n i ncl u di n g me dical hist or y , p h ysical e xa mi nati o n, 
la b orat or y tests a n d car diac m o nit ori n g.
3.
A s u bject wit h a cli nical a b n or malit y  or la b orat or y para meter(s) w hic h is/are n ot 
s pecifically liste d i n t he i ncl usi o n or e xcl usi o n criteria, o utsi de t he refere nce ra n ge 
f or t he p o p ulati o n bei n g st u die d ma y be i ncl u de d o nl y if t he i n vesti gat or i n 
c o ns ultati o n wit h t he Me dical M o nit or a gree a n d d oc u me nt t hat t he fi n di n g is 
u nli kel y  t o i ntr o d uce a d diti o nal ris k fact ors a n d will n ot i nterfere wit h t he st u d y 
pr oce d ures.  A si n gle re peat of a pr oce d ure or la b para meter is all o we d t o 
deter mi ne eli gi bilit y .
W EI G H T
4.
B o d y wei g ht 4 0 k g a n d b o d y  mass i n de x ( B MI) wit hi n t he ra n ge 1 8. 5 t o 
3 5 k g/ m 2 (i ncl usi ve).
S E X
5.
Male or fe male 

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C O N FI D E N TI A L
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3 2
6.
A fe male s u bject is eli gi ble t o partici pate if s he is pre -me n o pa usal, has a n i ntact 
uter us a n d cer vi x, A N D is n ot pre g na nt (as c o nfir me d b y  a ne gati ve h u ma n 
c h ori o nic g o na d otr o p hi n ( h C G) test), n ot lactati n g, a n d at least o ne of t he 
f oll o wi n g c o n diti o ns a p plies:
a.
N o n -re pr o d ucti ve p ote ntial defi ne d as:

Pre -me n o pa usal fe males wit h o ne of t he f oll o wi n g:

D oc u me nte d t u bal li gati o n

D oc u me nte d h ys ter osc o pic t u bal occl usi o n pr oce d ure wit h f oll o w- u p 
c o nfir mati o n of bilateral t u bal occl usi o n 

D oc u me nte d Bilateral O o p h orect o m y
b.
Re pr o d ucti ve p ote ntial a n d a grees t o f oll o w o ne of t he o pti o ns liste d bel o w i n 
t he G S K M o difie d List of Hi g hly Effecti ve Met h o ds f or A v oi di n g Pre g na nc y i n 
Fe males of Re pr o d ucti ve P ote ntial ( F R P) re q uire me nts fr o m 3 0 da ys pri or t o t he 
first d ose of st u d y me dicati o n a n d u ntil at least fi ve ter mi nal half -li ves O R u ntil 
a n y c o nti n ui n g p har mac ol o gic effect has e n de d, w hic he ver is l o n ger (ca n be u p 
t o 6 6 wee ks o n st u d y ) after t he last d ose of st u d y me dicati o n a n d c o m pleti o n of 
t he f oll o w-u p visit.
G S K M o difie d L ist of Hi g hl y Effecti ve Met h o ds f or A v oi di n g Pre g na nc y i n Fe males of 
Re pr o d ucti ve P ote ntial ( F R P) T his list d oes n ot a p pl y  t o F R P wit h sa me se x part ners, 
w he n t his is t heir preferre d a n d us ual lifest yl e or f or s u bjects w h o are a n d will c o nti n ue t o 
be a bsti ne n t fr o m pe nile- va gi nal i nterc o urse o n a l o n g ter m a n d persiste nt basis.

C o ntrace pti ve s u b der mal i m pla nt t hat meets t he S O P effecti ve ness criteria 
i ncl u di n g a < 1 % rate of fail ure per ye ar, as state d i n t he pr o d uct la bel

I ntra uteri ne de vice or i ntra uteri ne syste m t hat meets t he S O P effecti ve ness criteria 
i ncl u di n g a < 1 % rate of fail ure per ye ar, as state d i n t he pr o d uct la bel [ Hatc her , 
2 0 0 7a]

Oral C o ntrace pti ve, eit her c o m bi ne d or pr o gest o ge n al o ne [ Hatc her , 2 0 0 7a] 

I njecta ble pr o gest o ge n [Hatc her , 2 0 0 7a]

Perc uta ne o us c o ntrace pti ve patc hes [ Hatc her , 2 0 0 7a]

Male part ner sterilizati o n wit h d oc u me ntati o n of az o os per mia pri or t o t he fe male 
s u bject's e ntr y i nt o t he st u d y, a n d t his male is t he s ole part ner f or t hat s u bject 
[Hatc her , 2 0 0 7a].  
T hese all o we d met h o ds of c o ntrace pti o n are o nl y  effecti ve w he n use d c o nsiste ntl y, 
c orrectl y a n d i n acc or da nce wit h t he pr o d uct la bel.  T he i n vesti gat or is res p o nsi ble f or 
e ns uri n g t hat s u bjects u n dersta n d h o w t o pr o perl y use t hese met h o ds of c o ntrace pti o n.  
Fe male s u bjects desiri n g pre g na nc y  or f oresee t hat t he y mi g ht wis h t o beco me pre g na nt 
wit hi n 5 2 wee ks of recei vi n g a C A B L A i njecti o n m ust be e xcl u de d. 
All s u bjects partici pati n g i n t he st u d y  m ust be c o u nsele d o n safe se x ual practices 
i ncl u di n g t he use of effecti ve barrier met h o ds t o mi ni mize ris k of HIV tra ns missi o n.

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I NF O R M E D C O N S E N T
7.
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as descri be d i n Secti o n 1 0. 2 , w hic h 
i ncl u des c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n t he c o nse nt 
f or m a n d i n t his pr ot oc ol.
5. 2.
E x cl u si o n Cr it eri a
A s u bject will n ot be eli gi ble f or i ncl usi o n i n t his st u d y  if a ny of t he f oll o wi n g criteria 
a p pl y:
C O N C U R R E N T C O N DI TI O N S/ M E DI C A L  HI S T O R Y (I N C L U D E S LI V E R 
F U N C TI O N A N D Q Tc I N T E R V A L) 
Li ver F u ncti o n:
1.
A L T or A S T > U L N
2.
T otal bilir u bi n > U L N (is olate d t ot al bilir u bi n > U L N is acce pta ble if t otal bilir u bi n 
is fracti o nate d a n d direct bilir u bi n < 3 5 %). 
3.
C urre nt or c hr o nic hist or y of li ver disease, or k n o w n he patic or biliar y  
a b n or malities ( wit h t he e xce pti o n of Gil bert's s y n dr o me or as y m pt o matic 
gallst o nes)
Q Tc I nter v al:
4.
Q Tc > 4 5 0 msec
N O T E S:

T he Q Tc is t he Q T i nter val c orrecte d f or heart rate acc or di n g t o Bazette’s 
f or m ula ( Q Tc( Q TcF B), mac hi ne -rea d or ma n uall y o ver-rea d.

Q Tc B will be use d t o deter mi ne eli gi bilit y  f or a n i n di vi d ual s u bject. 

F or p ur p oses of dat a a nal ysis, Q Tc B or a c o m p osite of a vaila ble val ues of 
Q Tc will be use d as s pecifie d i n t he Re p orti n g a n d A nal y sis Pla n ( R A P).

E xcl usi o n criteria f or scree ni n g E C G (a si n gle re peat is all o we d f or 
eli gi bilit y deter mi nati o n):
M al e s
F e m al e s
H e art r at e
< 4 5 a n d > 1 0 0 b p m
< 5 0 a n d > 1 0 0 b p m
Q R S d ur ati o n
> 1 2 0 ms ec
Q Tc i nt erv al 
> 4 5 0 ms ec
5.
T he s u bject’s s ys t olic bl o o d press ure is o utsi de t he ra n ge of 9 0-1 4 0 m m H g, or 
diast olic bl o o d press ure is o utsi de t he ra n ge of 4 5 – 9 0 m m H g.
6.
Hist or y  of cli nicall y si g nifica nt car dio vasc ular disease i ncl u di n g: 
E vi de nce of pre vi o us m y ocar dial i nfarcti o n ( pat h ol o gic Q wa ves, S -T se g me nt 
c ha n ges (e xce pt earl y re p olarizati o n).
Hist or y /e vi de nce of sy m pt o matic arr h yt h mia, a n gi na/isc he mia, c or o nar y  

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arter y b ypass grafti n g ( C A B G) s ur ger y  or perc uta ne o us tra nsl u mi nal c or o nar y  
a n gi o plast y ( P C T A) or a n y  cli nicall y si g nifica nt car diac disease.
A n y  c o n d ucti o n a b n or malit y (i ncl u di n g b ut n ot s pecific t o left or ri g ht 
c o m plete b u n dle bra nc h bl oc k, A V bl oc k [ 2 n d de gree (t y p e II) or hi g her], 
W olf Par ki ns o n W hite [ W P W] s y n dr o me).
Si n us pa uses > 3 sec o n ds.
7.
A n y  si g nifica nt arr hyt h mia w hic h, i n t he o pi ni o n of t he pri nci pal I n vesti gat or a n d 
G S K Me dical M o nit or, will i nterfere wit h t he safet y  f or t he i n di vi d ual s u bject. 
N o n -s ustai ne d (3 c o nsec uti ve ve ntric u lar ect o pic beats) or s ustai ne d ve ntric ular 
tac hycar dia.
8.
Hist or y  of o n g oi n g or cli nicall y rele va nt seiz ure dis or der wit hi n t he pre vi o us 
2 ye ars, i ncl u di n g s u bjects w h o ha ve re q uire d treat me nt f or seiz ures wit hi n t his 
ti me peri o d.  A pri or hist or y of seiz ure, wit h a seiz ure free peri o d of at least 
2 ye ars, off a nti-e pile ptics, ma y be c o nsi dere d f or e nr ol me nt if t he i n vesti gat or 
belie ves t he ris k of seiz ure rec urre nce is l o w.  All cases of pri or seiz ure hist or y  
s h o ul d be disc usse d wit h t he me dical m o nit or prior t o e nr ol me nt.
C O N C O MI T A N T M E DI C A TI O N S
9.
T he use of a n y c o nc urre nt pr o hi bite d me dicati o ns as o utli ne d i n Secti o n 6. 1 0. 2
R E L E V A N T H A BI T S
1 0. Hist or y  of re g ular alc o h ol c o ns u m pti o n wit hi n 6 m o nt hs of t he st u d y defi ne d as: 
A n a vera ge wee kl y i nta ke of > 1 4 dri n ks f or males or > 7 dri n ks f or fe males.  O ne 
dri n k is e q ui vale nt t o 1 2 g of alc o h ol: 1 2 o u nces ( 3 6 0 ml) of beer, 5 o u nces ( 1 5 0 
ml) of wi ne or 1. 5 o u nces ( 4 5 ml) of 8 0 pr o of distille d s pirits.
1 1. I na bilit y or u n willi n g ness t o c o m pl y wit h lifest yle a n d/ or dietar y restricti o ns 
o utli ne d i n Secti o n 6. 9 .
1 2. Hi g h -ris k be ha vi or f or HI V i nfecti o n w hic h i ncl u des, b ut is n ot li mite d t o o ne of 
t he f oll o wi n g ris k fact ors wit hi n si x m o nths bef ore e nteri n g t he st u d y ( da y 1 of 
t he oral lea d-i n): U n pr otecte d va gi nal or a nal se x wit h a k n o w n HI V-i nfecte d 
pers o n or a cas ual part ner, e n ga ge d i n se x w or k f or m o ne y or dr u gs, ac q uire d a 
se x uall y tra ns mitte d disease, hi g h ris k part ner c urre ntl y or i n t he pre vi o us si x 
m o nt hs or i ntra ve n o us dr u g use.

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3 5
C O N T R AI N DI C A TI O N S 
1 3. Hist or y  of se nsiti vit y t o a n y of t he st u dy me dicati o ns, or c o m p o ne nts t here of or a 
hist or y  of dr u g or ot her aller g y t hat, i n t he o pi ni o n of t he i n vesti gat or or Me dical 
M o nit or, c o ntr ai n dicates t heir partici pati o n.  
1 4. F or s u bjects partici pati n g i n M RI  i ma gi n g: C o ntrai n dicati o n f or M RI sca n ni n g (as 
assesse d b y l ocal M RI safet y q uesti o n naire), w hic h i ncl u des b ut is n ot li mite d t o:
a.
I ntracra nial a ne ur ys m cli ps (e xce pt S u gita) or ot her n on -M RI c o m pati ble 
metallic o bjects
b.
I ntra- or bital metal fra g me nts t hat ha ve n ot bee n re m o ve d b y  a me dical 
pr ofessi o nal
c.
Pace ma kers or ot her i m pla nte d car diac r h yt h m ma na ge me nt de vices a n d n o n -
M RI  c o m pati ble heart val ves
d.
I n ner ear i m pla nts
e.
Hist or y of cla ustr o p h o bia
DI A G N O S TI C A S S E S S M E N T S A N D O T H E R C RI T E RI A
1 5. P ositi ve he patitis B s urface a nti ge n , or a p ositi ve he patitis B c ore a nti b o d y wit h 
ne gati ve he patitis B s urface a nti b o d y) test res ult at scree ni n g or wit hi n 3 m o nt hs 
pri or t o first d ose of st u d y  treat me nt.
1 6. P ositi ve he patitis C a nti b o d y  test res ult at scree ni n g or wit hi n 3 m o nt hs pri or t o 
first d ose of st u d y treat me nt
1 7. A p ositi ve pre -st u d y dr u g/alc o h ol scree n (s pecific dr u gs are liste d i n Secti o n 
7. 4. 6 ).  A p ositi ve dr u g scree n is per mitte d if d ue t o a prescri be d me dicati o n, 
pr o vi de d t hat me dicati o n is n ot o n t he list of pr o hi bite d me dic ati o ns i n Secti o n 
6. 1 0. 2 a n d a p pr o ve d b y t he i n vesti gat or a n d me dical m o n it or. 
1 8. A p ositi ve test f or HI V a nti b o d y .
1 9. A p ositi ve pre -st u d y scree n f or se x uall y tra ns mitte d diseases i ncl u di n g Neisseri a 
g o n orr h oe a or C hl a my di a tr ac h o m atis , Tric h o m o nas, s yp hilis, or a n acti ve H S V 
ge nital lesi o n.
2 0. Prese nce of a tatt o o or ot her der mat ol o g ical c o n diti o n o verl yi n g t he b utt oc ks 
w hic h i n t he o pi ni o n of t he i n vesti gat or ma y  i nterfere wit h t he i nter pretati o n of 
i njecti o n site reacti o ns. 
2 1. T he s u bject has partici pate d i n a cli nical trial a n d has recei ve d a n i n vesti gati o nal 
pr o d uct wit hi n t he f oll o wi n g ti me peri o d pri or t o t he first d osi n g da y  i n t he 
c urre nt st u d y:  3 0 da ys, 5 half-li ves or t wice t he d urati o n of t he bi ol o gical effect of 
t he i n vesti gati o nal pr o d uct ( w hic he ver is l o n ger).
2 2. E x p os ure t o m ore t ha n f o ur ne w c he mical e ntities wit hi n 1 2 m o nt h s pri or t o t he 
first d osi n g da y. 

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DI A G N O S TI C A S S E S S M E N T S A N D O T H E R C RI T E RI A
2 3. W here partici pati o n i n t he st u d y  w o ul d res ult i n d o nati o n of bl o o d or bl o o d 
pr o d ucts i n e xcess of 5 0 0 ml wit hi n a 5 6 da y  peri o d.
2 4. U n willi n g ness or i na bilit y t o f oll o w t he pr oce d ures o utli ne d i n t he pr ot oc ol.
2 5. S u bject is me nt all y or le gall y i nca pacitate d.
A d diti o n al Criteri a f or Fe m ale S u bjects O nl y:
2 6. A n y  c urre nt me dical c o n diti o ns t hat i n t he o pi ni o n of t he i n vesti gat or ma y 
c o m pr o mise t he c o n d uct or a nal ys is of t he ge nital tract sa m pli n g (e. g., acti ve 
ge nital tract i nfecti o n o r lesi o ns).
2 7. I na bilit y t o a bstai n fr o m t he use of i ntra va gi nal pr o d ucts (e. g. ta m p o ns, 
s per mici des, l u brica nts, va gi nal h y gie ne pr o d ucts, dia p hra g ms) f or 7 2 h o urs pri or 
t o t he ge nital tract sa m ple c ollecti o n visits a n d f or u p t o 7 2 h o urs after.
2 8. I na bilit y t o a bstai n fr o m a n y se x ual acti vit y (e. g., va gi nal i nterc o urse, 
mast ur bati o n, a n d pe netrati o n of t he va gi na b y pe nises, fi n gers, ta m p o ns, se x 
t o ys) f or 7 2 h o urs pri or t o t he ge nital tract sa m ple c ollecti o n visits a n d f or u p t o 
7 2 h o urs after.
A d diti o n al Crit eri a f or M ale S u bjects a n d Fe m ale S u bjects w h o c o nse nt t o rect al 
P K s a m pli n g:
2 9. A n y  c urre nt me dical c o n diti o ns t hat i n t he o pi ni o n of t he i n vesti gat or ma y 
c o m pr o mise t he c o n d uct or a nal ys is of t he rectal c o m part me nt sa m pli n g (e. g., 
acti ve rectal c o m part me nt i nfecti o n, lesi o ns or disease).
3 0. I na bilit y t o a bstai n fr o m t he use of i ntrarectal pr o d ucts (e. g., s u p p osit ories, 
l u brica nts) f or 7 2 h o urs pri or t o t he rectal c o m part me nt sa m ple c ollecti o n visits 
a n d f or u p t o 7 2 h o urs after.
3 1. I na bilit y t o a bstai n fr o m a n y rece pti ve a nal se x ual acti vit y (e. g., a nal rece pti ve 
i nterc o urse a n d pe netrati o n of t he rect u m b y fi n gers, se x t o ys or ot her) f or 7 2 
h o urs pri or t o t he rectal c o m part me nt sa m ple c ollecti o n visit a n d f or u p t o 7 2 
h o urs after.
5. 3.
S cr e e ni n g/ B a s eli n e/ R u n -i n F ail ur e s
Scree n fail ures are defi ne d as s u bjects w h o c o nse nt t o partici pate i n t he cli nical trial, b ut 
are ne ver s u bse q ue ntl y e nr olle d. I n or der t o e ns ure tra ns pare nt re p orti n g of scree n fail ure 
s u bjects, meet t he C o ns oli date d Sta n dar ds of Re p orti n g Trials ( C ON S O R T) p u blis hi n g 
re q uire me nts, a n d res p o n d t o q ueries fr o m Re g ulat or y a ut h orities, a mi ni mal set of scree n 
fail ure i nf or mati o n is re q uire d i ncl u di n g De m o gra p h y, Scree n Fail ure details, Eli gi bilit y 
Criteria, a n d a n y Seri o us A d verse E ve nts.

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5. 4.
Wit h dr a w al/ St o p p i n g Crit eri a
S u bjects ma y  v ol u ntarily wit h dra w fr o m t he st u d y at a n y ti me a n d f or a n y reas o n. Site 
i n vesti gat ors a n d st u dy staff ma y  wit h dra w partici pa nts bef ore t heir sc he d ule d 
ter mi nati o n visit f or safet y, be ha vi oral, or a d mi nistrati ve reas o ns, or if t he partici pa nts are 
u na ble or u n willi n g t o c o m pl y  wit h st u d y pr oce d ures. T he reas o ns f or wit h dra wals will 
be rec or de d i n t he partici pa nts’ st u d y rec or ds. If a s u bject wit h dra ws fr o m t he st u d y , 
he/s he ma y  re q uest destr ucti o n of a n y sa m ples ta ke n, a n d t he i n vesti gat or m ust d oc u me nt 
t his i n t he site st u d y rec or ds. 
D uri n g t he oral lea d -i n peri o d, earl y wit h dra wal o n me dical gr o u n ds will occ ur if t he 
partici pa nt de vel o ps a gra de 3 or hi g her A E t hat is j u d ge d b y t he i n vesti gat or t o be relate d 
directl y  t o t he st u d y pr o d uct (see A p pe n di x 3 a n d A p pe n di x 4 f or defi niti o ns a n d gra di n g 
of se verit y of a d verse e ve nts), or a n y A E t hat is dee me d cli nicall y si g nifica nt b y t he 
i n vesti gat or a n d is j u d ge d b y t he i n vesti gat or t o be relate d directly t o t he st u d y  pr o d uct.
F or li ver -relate d st o p pi n g criteria, please refer t o Secti o n 5. 4. 1 .
If a s u bject recei ves t he I M i njecti o n of C A B L A, t he y will be f oll o we d 5 2- wee ks p os t 
i njecti o n per pr ot oc ol f or a p pr o priate pr oce d ures , i ncl u di n g bl o o d plas ma P K sa m pli n g,
a n d safet y e val uati o ns, a n d will n ot be re m o ve d fr o m t he st u d y  f or me dical reas o ns, 
u nless t he y  ref use t o c o nti n ue partici pati o n.
D uri n g t he oral lea d i n p hase a d diti o nal pre -s pecifie d reas o ns f or disc o nti n ui n g a 
partici pa nt fr o m t he st u d y  ( or, at mi ni m u m, disc o nti n ui n g a d mi nistrati o n of st u d y pr o d uct 
a n d c o nti n ui n g safet y e val uati o ns) i ncl u de:

Pre g na nc y  ( please see Secti o n 7. 4. 2 )

Pr ot oc ol de viati o n

N o n -c o m plia nce

S u bject wit h dra ws c o nse nt

S u bject l ost t o f oll o w - u p

I n vesti gat or discreti o n

S p o ns or disc o nti n ues st u d y

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T he f oll o wi n g acti o ns m ust be ta ke n i n relati o n t o a s u bject w h o fails t o atte n d t he cli nic 
f or a re q uire d st u dy visit:

T he site m ust atte m pt t o c o ntact t he s u bject a n d re- sc he d ule t he misse d visit as s o o n 
as p ossi ble. 

T he site m ust c o u nsel t he s u bject o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule a n d ascertai n w het her or n ot t he s u bject wis hes t o a n d/ or s h o ul d c o nti n ue i n 
t he st u d y. 

I n cases w here t he s u bject is dee me d ‘l ost t o f oll o w u p’, t he i n vesti gat or or desi g nee 
m ust ma ke e ver y  eff ort t o re gai n c o ntact wit h t he s u bject ( w here p ossi ble, 3 
tele p h o ne calls a n d if necessar y a certifie d letter t o t he s u bject’s last k n o w n maili n g 
a d dress or l ocal e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d 
i n t he s u bject’s me dical rec or d. 

S h o ul d t he s u bject c o nti n ue t o be u nreac ha ble, o nl y t he n will he/s he be c o nsi dere d t o 
ha ve wit h dra w n fr o m t he st u d y wit h a pri mar y reas o n of “ L ost t o F oll o w-u p”. 
F or partici pa nts w h o ha ve o nl y  recei ve d oral d oses of C A B a n d de vel o p a n a d verse effect 
w hic h meets criteria f or st o p pi n g t he a d mi nistrati o n of st u d y  pr o d uct, safet y visits a n d 
f oll o w- u p will be c o nti n ue d u ntil t he res ol uti o n of t he e ve nt, a n d t he n t he s u bject will be 
wit h dra w n fr o m t he st u d y a n d will n ot recei ve t he C A B L A i njecti o n. If partici pa nts are 
u na ble t o recei ve t he I M i njecti o n f or a n y reas o n, t he y will ha ve a f oll o w -u p/ wit h dra wal 
visit wit hi n 1 0 -1 4 da y s of t he last oral d ose of C A B a n d t he n be ter mi nate d fr o m t he 
st u d y. If t he reas o n is HI V ac q uisiti o n or pre g na nc y, refer t o Secti o n 7. 4. 1. 6 a n d Secti o n 
7. 4. 2 , res pecti vely. F or partici pa nts w h o de vel o p a n a d verse effect w hic h meets criteria 
f or st o p pi n g t he a d mi nistrati o n of st u d y pr o d uct, a n d ha ve recei ve d b ot h t he oral C A B 
a n d a n I M i njecti o n of C A B L A, f oll o w- u p a n d safet y  visits will be c o nti n ue d f or a t otal 
of 5 2 wee ks after t he i njecti o n of C A B L A. All f oll o w -u p visits a n d sc he d ule d safet y 
e val uati o ns (e n u merate d i n t he Ti me a n d E ve nts Ta ble i n Secti o n  7. 1 ) will re mai n t he 
sa me. 
T he me dical m o nit or s h o ul d b e i nf or me d of all st u d y wit h dra wals.
5. 4. 1.
Li v er C h e mi str y St o p pi n g Crit eri a
F or s u bjects wit h A L T ele vati o n 1. 2 5 x b ut < 3 x U L N , retest A L T wit hi n o ne wee k. If 
t he retest A L T is < 1. 2 5 x U L N , s u bjects ma y c o nti n ue t o Da y 2 8 d osi n g . If t he retest 
A L T is ≥ 1. 2 5 x U L N , d osi n g will be ter mi nate d, a n d s u bjects are pr o hi bite d fr o m 
e nteri n g t he i njecti o n p hase. Wee kl y assess me nts s h o ul d be c o n d ucte d u ntil A LT is < 
1. 2 5 x U L N . F or s u bjects wit h A L T ele vati o n 1. 2 5 x U L N at Da y 2 9, d osi n g will be 
ter mi nate d, s u bjects are pr o hi bite d fr o m e nteri n g t he i njecti o n p hase, a n d wee kl y 
assess me nts s h o ul d be c o n d ucte d u ntil A L T is < 1. 2 5 x U L N . S u bjects wit h A L T 
3 x U L N at a n y ti me p oi nt will be disc o nti n ue d fr o m st u d y  treat me nt. Please refer t o t he 
Li ver Safet y Re q uire d Acti o ns a n d F oll o w u p Assess me nts Secti o n i n A p pe n di x 2 f or 
s u bse q ue nt e val uati o ns. If a ny of t he a b o ve de vel o ps, please n otif y  t he me dical m o nit or.
S t a n d ar d li ver c he mistr y st o p pi n g a n d i ncre ase d m o nit ori n g criteri a ha ve be e n 
desi g ne d t o ass ure s u bject safet y a n d e val uate li ver e ve nt eti ol o g y (i n ali g n me nt wit h t he 

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F D A pre mar keti n g cli nical li ver safet y g ui da nce). 
htt p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui d
a nces/ U C M 1 7 4 0 9 0. p df
St u d y  treat ment will be disc o nti n ue d f or a s u bject if li ver c he mistr y st o p pi n g criteria are 
met pri or t o C A B L A i njecti o n.  If li ver st o p pi n g criteria are met after recei vi n g a C A B 
L A i njecti o n, s u bjects will n ot be wit h dra w n fr o m t he st u d y b ut c o nti n ue t o ha ve safet y 
assess me nts perf or me d as n ote d bel o w a n d wit hi n t he Ti me a n d E ve nts ta ble f or 5 2 
wee ks p ost -i njecti o n or u ntil res ol uti o n of t he li ver e ve nt, w hic he ver is l o n ger.
Li ver C he mistr y St o p pi n g Criteri a – Li ver St o p pi n g E ve nt Al g orit h m
Li ver Safet y  Re q uire d Acti o ns a n d F oll o w u p Assess me nts Secti o n ca n be f o u n d i n 
A p pe n di x 2 .
5. 4. 2.
Q T c St o p pi n g Crit eri a

T he sa me Q T c c orrecti o n f or m ula m ust be use d f or e ac h i n divi d u al s u bject t o 
deter mi ne eli gi bilit y  f or a n d disc o nti n uati o n fr o m t he st u d y.  T his f or m ula ma y 
n ot be c ha n ge d or s u bstit ute d o nce t he s u bject has bee n e nr olle d. F or t his 
pr ot oc ol, t he Q Tc B will be use d f or all Q Tc d at a bei n g c ollecte d f or d at a 
a n alysis .  Safet y E C Gs a n d ot her n o n-pr ot oc ol s pecifie d E C Gs are a n e xce pt i o n.  

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
T he Q Tc s h o ul d be base d o n si n gle or a vera ge d Q Tc val ues of tri plicate 
electr ocar d i o gra ms o btai ne d o ver a brief (e. g., 5 -1 0 mi n ute) rec or di n g peri o d . If 
t he f oll o w-u p E C G s h o ws a Q Tc t hat meets a n y  of t he st o p pi n g criteria liste d 
bel o w, t hree c o nfir mat or y  E C Gs s h o ul d be d o ne o ver a brief rec or di n g peri o d 
(e. g., 5 – 1 0 mi n utes), a n d t he n use t he a vera ge d Q Tc val ues of t he 3 E C Gs t o 
deter mi ne w het her t he s u bject s h o ul d be disc o nti n ue d fr o m t he st u d y.
A s u bject t hat meets t he b ullete d criteri o n b el o w will be wit h dra w n fr o m t he st u d y.  

Q Tc > 5 0 0 msec

Q Tc i ncrease fr o m baseli ne > 6 0 msec
5. 5.
S u bj e ct a n d St u d y  C o m pl eti o n
A s u bject t hat recei ves at least o ne d ose of oral C A B, b ut wit h dra ws earl y fr o m treat me nt 
is c o nsi dere d a n o n-c o m pleter f or treat me nt a n d st u d y .  E ver y eff ort s h o ul d be ma de t o 
bri n g t he s u bject bac k i n f or a f oll o w -u p visit wit hi n 1 0 – 1 4 da y s of t he last d ose of 
st u d y me dicati o n.
A s u bject t hat recei ves t he C A B L A i njecti o n a n d c o m pletes t he P K assess me nts f or 
1 2 wee ks b ut wit h dra ws pri or t o t he 5 2 wee k f oll o w u p visit, will be c o nsi dere d 
c o m pleti n g t he treat me nt p hase of t he st u d y, b ut n ot a st u d y  c o m pleter.  
A s u bject t hat wit h dra ws after i njecti o n a n d d oes n ot c o m plete P K assess me nts t hr o u g h 
wee k 1 2 is c o nsi dere d a n o n-c o m pleter f or treat me nt a n d st u d y.   Beca use of t he l o n g 
acti n g p har mac o ki netic pr ofile of C A B L A e ver y  eff ort s h o ul d be ma de t o bri n g t he 
s u bject bac k i n f or t he 5 2 wee ks of safety a n d P K assess me nts f oll o wi n g t he i njecti o n.
A c o m plete d s u bject is o ne w h o has c o m plete d al l p hases of t he st u dy i ncl u di n g t he 
5 2 wee k f oll o w u p peri o d.  T his s u bject will be c o nsi dere d a treat me nt a n d st u d y  
c o m pleter.
T he date of e n d of t he st u d y  is defi ne d as t he last s u bject’s last c o ntact.

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6.
S T U D Y T R E A T M E N T
6. 1.
I n v e sti g ati o n al Pr o d u ct a n d Ot h er Stu d y  Tr e at m e nt
T he ter m ‘st u d y treat me nt’ is use d t hr o u g h o ut t he pr ot oc ol t o descri be a n y c o m bi nati o n 
of pr o d ucts recei ve d b y t he s u bject as per t he pr ot oc ol desi g n. St u d y treat me nt ma y 
t heref ore refer t o t he i n di vi d ual st u d y treat me nts or t he c o m bi nati o n of t h ose st u d y 
treat me nts.
St u d y Tr e at m e nt
Pr o d u ct n a m e:
Or al C A B
C A B L A I nj ect a bl e S us p e nsi o n
F or m ul ati o n 
d e s cri pti o n:
G S K 1 2 6 5 7 4 4 B, l act os e 
m o n o hy dr at e, micr ocryst alli n e 
c ell ul os e, hy pr o m ell os e, s o di u m 
st arc h glyc ol at e, m a g n esi u m 
st e ar at e, A q u ari us film- c o ati n g, w hit e 
B P 1 8 2 3 7
St eril e S us p e nsi o n f or I nj ecti o n
D o s a g e f or m:
T a bl et
Vi al
U nit d o s e 
str e n gt h( s)/ D o s a g e 
l e v el( s):
D os e l ev el: 1 t a bl et
T a bl et str e n gt h: 3 0 m g
E ac h vi al c o nt ai ns 4 0 0 m g/ 2 m L 
s us p e nsi o n of C A B
R o ut e of 
A d mi ni str ati o n:
A d mi nist er or ally, o nc e d aily
I ntr a m usc ul ar I nj ecti o n
D o si n g i n str u cti o n s:
T ak e 1 t a bl et or ally ev ery 2 4 h o urs
G e ntly i nv ert s us p e nsi o n vi al f or 2 0 
s ec o n ds t o r e-s us p e n d s e di m e nt.  
All o w b u b bl es t o s u bsi d e, t h e n us e a 
syri n g e t o wit h dr a w t h e r e q uir e d 
v ol u m e of s us pe nsi o n f or I M 
i nj ecti o n. D et ail e d i nstr ucti o ns ar e 
pr ovi d e d i n t h e st u dy r ef er e nc e 
m a n u al ( S R M ).
P h y si c al d e s cri pti o n:
T a bl ets ar e w hit e t o al m ost w hit e 
c o at e d ov al t a bl ets
St eril e w hit e t o sli g htly pi nk 
s us p e nsi o n c o nt ai ni n g 4 0 0 m g/ 2 m L 
of C A B f or a d mi nis tr ati o n by 
i ntr a m usc ul ar i nj ecti o n
M et h o d f or 
i n di vi d u alizi n g 
d o s a g e:
O n e 3 0 m g t a bl et t ak e n o nc e a d ay 
f or 4 w e eks.
1 X 3 m L I nj ecti o ns ( 3 m L [ 6 0 0 m g] 
t ot al) I M giv e n o nc e o n D ay 1 of 
i nj ecti o n p h as e.

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6. 1. 1.
C a b ot e gr a vir - T a bl et
T he i n vesti gati o nal pr o d uct (I P) C A B is ma n ufact ure d b y  G S K a n d is f or m ulate d as 
w hite t o al m ost w hite o val s ha pe d fil m c oate d 3 0 m g ta blets f or oral a d mi nistrati o n, 
pac ka ge d i n hi g h de nsit y p ol y et h yl e ne ( H D P E) b ottles wit h c hil d -resista nt cl os ure t hat 
i ncl u de a n i n d ucti o n seal. T he C A B ta blets will be pac ka ge d i n b ottles c o ntai ni n g 3 0 
ta blets eac h. S u bjects m ust kee p all IP i n its ori gi nal pac ka ge c o ntai ner. C A B ta blets are 
t o be st ore d u p t o 3 0 ° C a n d pr otecte d fr o m m oist ure.
6. 1. 2.
C a b ot e gr a vir - I nj e ct a bl e S u s p e n si o n
T he I P C A B L A is ma n ufac t ure d b y G S K a n d is a sterile w hite t o sli g htl y pi n k 
s us pe nsi o n c o ntai ni n g 2 0 0 m g/ m L of C A B as free aci d f or a d mi nistrati o n b y 
i ntra m usc ular i njecti o n. T he pr o d uct is pac ka ge d i n a 3 m L U S P T ype I glass vial wit h a 
1 3 m m gra y  st o p per a n d al u mi ni u m seal. Eac h vial is f or si n gle use c o ntai ni n g a 
wit h dra wa ble fill of 2. 0 m L , a n d d oes n ot re q uire dil uti o n pri or t o a d mi nistrati o n. C A B 
L A i njecta ble s us pe nsi o n is t o be st ore d at u p t o 3 0° C, d o n ot freeze.  
6. 1. 3.
D o si n g C o n si d er ati o n s f or C A B L A
Vials of C A B L A are s u p plie d as a s us pe nsi o n a n d nee d n o f urt her dil uti o n or
rec o nstit uti o n. H o we ver, sites s h o ul d ge ntl y i n vert t he vials a fe w ti mes t o re-s us pe n d
se di me nts a n d all o w b u b bles t o s u bsi de, a n d t he n use a syri n ge t o wit h dra w t he re q uire d
v ol u me of s us pe nsi o n f or I M i njecti o n.
Sites ma y  use t heir discreti o n as t o w here i n t he gl ute us m uscle t he i njecti o n is gi ve n 
acc or di n g t o i n di vi d ual s u bject circ u msta nce. 
T he pr ot oc ol f or i njecti o n will be as f oll o ws: T he patie nt’s b utt oc k re gi o n will be i ma ge d 
t o i de ntif y t he gl uteal m uscle, a n d a mar k will be place d o ver a s uita ble area. After 
clea ni n g t he s ki n wit h alc o h ol s wa b, u n der direct ultras o u n d vis ualizati o n, a 2 2 -ga u ge 
s pi nal nee dle will be i ntr o d uce d i nt o t he gl uteal m uscle. T he n 6 0 0 m g  C A B LA 
(c o nce ntrati o n = 2 0 0 m g/ m L  ( 3 m L ) will be i njecte d as a si n gle I M i njecti o n sl o wl y  
u n der c o nti n u o us ultras o u n d vis ualizati o n. Pre - a n d p ost- i njecti o n i ma ges will be 
rec or de d o nt o t he ultras o u n d Pict ure Arc hi val a n d C o m m u nicati o n S yste m ( P A C S) 
s yste m. T he l ocati o n (left/ri g ht) a n d ti me of i njecti o n will be ca pt ure d i n t he e C R F.
F urt her d osi n g i nstr ucti o ns ca n be f o u n d i n t he S R M .
6. 2.
Tr e at m e nt A s si g n m e nt
All eli gi ble s u bjects will c o m plete a 4 -wee k C A B oral lea d -i n ( 3 0 m g  oral ta blet dail y) 
peri o d f oll o we d b y a 1 4 - 4 2da y  was h o ut peri o d.  O n Da y 1, all s u bjects will recei ve a 
si n gle 6 0 0 m g  IM d ose of C A B L A.
6. 3.
Bli n di n g
T his will be a n o pe n -la bel st u d y.  

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6. 4.
P a c k a gi n g a n d L a b eli n g
T he c o nte nts of t he la bel will be i n acc or da nce wit h all a p plica ble re g ulat or y  
re q uire me nts.
6. 5.
Pr e p ar ati o n/ H a n dl i n g/ St or a g e/ A c c o u nt a bilit y
A descri pti o n of t he met h o ds a n d materials re q uire d f or pre parati o n of C A B L A will be 
detaile d i n a St u d y  S pecific Tec h nical A gree me nt/ Me m o ( T T S) or P har mac y Ma n ual 
w hic h will be acc o m pa nie d b y  a Q uality A gree me nt.

O nl y  s u bjects e nr olle d i n t he st u d y ma y recei ve st u d y treat me nt a n d o nly a ut h orize d 
site staff ma y s u p pl y or a d mi nister st u d y treat me nt.  All st u d y treat me nts m ust be 
st ore d i n a sec ure e n vir o n me ntall y c o ntr olle d a n d m o nit ore d ( ma n ual or a ut o mate d) 
area i n acc or da nce wi t h t he la belle d st ora ge c o n diti o ns wit h access li mite d t o t he 
i n vesti gat or a n d a ut h orize d site staff. 

T he i n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) 
is res p o nsi ble f or st u dy treat me nt acc o u nta bilit y, rec o nciliati o n, a n d rec or d 
mai nte na nce (i.e. recei pt, rec o nciliati o n a n d fi nal dis p ositi o n rec or ds).  

F urt her g ui da nce a n d i nf or mati o n f or fi nal dis p ositi o n of u n use d st u d y  treat me nt are 
pr o vi de d i n t he Pr oce d ures Ma n ual. 

U n der n or mal c o n diti o ns of ha n dli n g a n d a d mi n istrati o n, st u d y treat me nt is n ot 
e x pecte d t o p ose si g nifica nt safet y ris ks t o site staff .  Ta ke a de q uate preca uti o ns t o 
a v oi d direct e ye or s ki n c o ntact a n d t he ge nerati o n of aer os ols or mists. I n t he case of 
u ni nte nti o nal occ u pati o nal e x p os ure n otif y  t he m o nit or, Me dical M o nit or a n d/ or 
G S K st u d y  c o ntact.

A Material Safet y  Data S heet ( M S D S)/e q ui vale nt d oc u me nt descri bi n g occ u pati o nal 
hazar ds a n d rec o m me n de d ha n dli n g preca uti o ns eit her will be pr o vi de d t o t he 
i n vesti gat or, w here t his is re q uire d by l ocal la ws, or is a vaila ble u p o n re q uest fr o m 
G S K.
6. 6.
C o m pli a n c e wit h St u d y  Tr e at m e nt Ad mi ni str ati o n
W he n t he i n di vi d ual d ose f or a s u bject is pre pare d fr o m a b ul k s u p pl y, t he pre parati o n of 
t he d ose will be c o nfir me d b y a sec o n d me m ber of t he st u d y site staff.   W h e n s u bjects 
are d ose d at t he site, t he y will recei ve st u d y treat me nt directl y fr o m t he i n vesti gat or or 
desi g nee, u n der me dical s u per visi o n.  T he date a n d ti me of eac h d ose a d mi nistere d i n t he 
cli nic will be rec or de d i n t he s o urce d oc u me nts.  T he d ose of st u d y  treat me nt a n d st u d y 
s u bject i de ntificati o n will be c o nfir me d at t he ti me of d osi n g by a me m ber of t he st u d y 
site staff ot her t ha n t he pers o n a d mi nisteri n g t he st u d y treat me nt.  
St u d y  s u bjects will be dis pe nse d C A B oral ta blets d uri n g t he lea d-i n peri o d.  W he n 
s u bjects self-a d mi nister st u d y treat me nt(s) at h o me, c o m plia nce wit h oral C A B will be 
assesse d t hr o u g h q uer yi n g t he s u bject d uri n g t he site visits a n d d oc u me nte d i n t he s o urce 
d oc u me nts a n d C R F.  A d diti o nal c hec ks o n a d here nce t o st u d y  pr ot oc ol will ta ke place 
via pill c o u nt, h o me diaries, a n d peri o dic re vie w of t he diaries d uri n g st u d y visits. A 

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rec or d of t he n u m ber of C A B ta blets dis pe nse d t o a n d ta ke n by eac h s u bject m ust be 
mai ntai ne d a n d rec o ncile d wit h st u d y  treat me nt a n d c o m plia nce rec or ds.  Treat me nt start 
a n d st o p dates, i ncl u di n g dates f or treat me nt dela ys, will als o be rec or de d i n t he C R F.
6. 7.
Tr e at m e nt of St u d y  Tr e at m e nt O v er d o s e
F or t he oral lea d i n peri o d of t his st u d y , a ny d ose of C A B > 3 0 m g wit hi n a 2 4 h o ur ti me 
peri o d [ 4 h o urs ] will be c o nsi dere d a n o ver d ose.
F or t he i njecti o n p hase of t he st u d y , a ny d ose of C A B L A > 6 0 0 m g will be c o nsi dere d a n 
o ver d ose.
G S K d oes n ot rec o m me n d s pecific treat me nt ot her t ha n s u p p orti ve care f or a n o ver d ose.  
T he i n vesti gat or will use cli nical j u d ge me nt t o treat a n y o ver d ose.
I n t he e ve nt of a n o ver d ose t he i n vesti gat or or treati n g p h y sicia n s h o ul d:
1.
c o ntact t he Me dical M o nit or i m me diatel y
2.
cl osel y m o nit or t he s u bject f or a d verse e ve nts ( A Es)/seri o us a d verse e ve nts 
( S A Es) a n d la b orat or y a b n or malities u ntil C A B ca n n o l o n ger be detecte d 
s yste mically (at least 5 2 wee ks f or C A B L A).
3.
o btai n a plas ma sa m ple f or p har mac o ki netic ( P K) a nal ys is if re q ueste d b y t he 
Me dical M o nit or ( deter mi ne d o n a case -b y -case basis)
4.
d oc u me nt t he q ua ntit y  of t he e xcess d ose as well as t he d urati o n of t he o ver d osi n g 
i n t he C R F.
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y  t he i n vesti gat or 
i n c o ns ultati o n wit h t he Me dical M o nit or base d o n t he cli nical e val uati o n of t he s u bject.
6. 8.
Tr e at m e nt aft er t h e E n d of t h e St u d y
S u bjects will n ot recei ve a n y a d diti o nal treat me nt fr o m G S K after c o m pleti o n of t he 
st u d y beca use o nly healt h y v ol u nteers are eli gi ble f or st u d y partici pati o n.
6. 9.
Lif e st yl e a n d/ or Di et ar y  R e stri cti o n s
6. 9. 1.
M e al s a n d Di et ar y  R e stri cti o n s
A n o ver ni g ht fast is pr eferre d pri or t o scree ni n g la b orat or y assess me nts; h o we ver, a 
mi ni m u m of a 6 h o ur fast is acce pta ble.  Ot her wise, f o o d a n d dri n k ca n be gi ve n a d 
li bit u m t hr o u g h o ut t he c o urse of t he trial.   At visits w here s u bjects will be i n t he cli nic 
f or m ulti ple h o urs, meals will be pr o vi de d b y t he st u d y site (i n t he f or m of a b o xe d l u nc h 
or car d f or use at t he site cafeteria).  S u bjects will be as ke d t o fast f or 8 h o urs pri or t o t he 
e n d osc o p y pr oce d ures.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
4 5
6. 9. 2.
Al c o h ol
S u bjects will a bstai n fr o m alc o h ol f or 4 8 h o urs pri or t o i nitiati n g oral d osi n g a n d pri or t o 
t he i njecti o n.  S u bjects will a bstai n fr o m alc o h ol f or 4 8 h o urs pri or t o t he c ollecti o n of t he 
p har mac o ki netic sa m pli n g a n d cli nical la b orat or y  tests d uri n g eac h sessi o n.
6. 9. 3.
A c ti vit y
S u bjects will a bstai n fr o m stre n u o us e x ercise f or 4 8 h o urs pri or t o eac h bl o o d c ollecti o n 
f or cli nical la b orat or y tests.  S u bjects ma y partici pate i n li g ht recreati o nal acti vities w hile 
i n t he researc h cli nic (e. g., watc h tele visi o n, rea d).
6. 1 0.
C o n c o mit a nt M e di c ati o n s a n d N o n -Dr u g T h er a pi e s
6. 1 0. 1.
P er mitt e d M e di c ati o n s a n d N o n- Dr u g T h er a pi e s
Aceta mi n o p he n, at d oses of 2 gra ms/ da y  is per mitte d f or use a ny ti me d uri n g t he st u d y.  
C o nc o mita nt me dicati o ns ( prescri pti o n a n d n o n- prescri pti o n) s h o ul d be ta ke n o nl y  as 
me dicall y  necessar y d uri n g t he st u d y (e xce pt f or pr o hi bite d me dicati o ns descri be d i n 
Secti o n 6. 1 0 . 2).  All c o nc o mita nt me dicati o ns, bl o o d pr o d ucts, a n d vacci nes ta ke n d uri n g 
t he st u d y will be rec or de d i n t he e C R F wit h dates of a d mi nistrati o n.
6. 1 0. 2.
Pr o hi bit e d M e di c ati o n s a n d N o n -Dr u g T h er a pi e s
E x peri me ntal a ge nts n ot ot her wise s pecifie d i n t he pr ot oc ol, a ntiretr o virals, c y t ot o xic 
c he m ot hera p y, or ra diati o n t hera p y ma y n ot be a d mi nistere d. S y ste mically a d mi nistere d 
i m m u n o m o d ulat ors are pr o hi bite d.  C hr o nic dail y n o n-ster oi dal a nti-i nfla m mat or y dr u g 
use f or m ore t ha n 1 4 da ys c o nsec uti vel y ( wit h t he e xce pti o n of as piri n use d f or 
pr o p h y la xis) is n ot per mitte d at a n y ti me d uri n g t he st u d y.
T he f oll o wi n g me dicati o ns c o ul d si g nifica ntl y decrease t he le vels of C A B d ue t o e nz yme 
i n d ucti o n a n d t heref ore m ust n ot be a d mi nistere d c o nc urre ntl y:

bar bit urates

car ba maze pi ne

o xcar baze pi ne

p he n y t oi n

rifa b uti n

rifa m pi n

rifa pe nti ne

St. J o h n’s w ort
T he f oll o wi n g me dicati o ns are a ntic oa g ula nt/a nti platelet me dicati o ns a n d c o ul d i ncreas e 
t he ris k of blee di n g d uri n g bi o psy pr oce d ures a n d i nterfere wit h t he a bilit y t o recei ve 
i ntra m usc ular i njecti o ns. T heir use is pr o hi bite d wit hi n 7 da ys bef ore a n d f or 7 da ys after 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
4 6
t he i njecti o n a n d bi o ps y pr oce d ures:

hi g h d ose as piri n

a na greli de

a pi xa ba n

ar gatr o ba n

bi valir u di n

cl o pi d o grel

da bi gatra n

dalte pari n

e n o xa pari n

f o n da pari n u x

he pari n

le pir u di n

pras u grel

ri var o xa ba n

tica grel or

ticl o pi di ne

warfari n
D uri n g t he oral lea d -i n, oral C A B 3 0 m g  s h o ul d be a d mi nistere d 2 h o urs bef ore or 6 
h o urs after ta ki n g a ntaci ds, vita mi ns, calci u m a n d ir o n s u p ple me nts c o ntai ni n g p ol y vale nt 
cati o ns (e. g., al u mi ni u m a n d ma g nesi u m).
7.
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S
Pr ot oc ol wai vers or e xe m pti o ns are n ot all o we d wit h t he e xce pti o n of i m me diate safet y  
c o ncer ns. T heref ore, a d h ere nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose 
s pecifie d i n t he Ti me a n d E ve nts Ta ble, are esse ntial a n d re q uire d f or st u dy c o n d uct.
T his secti o n lists t he pr oce d ures a n d para meters of eac h pla n ne d st u d y assess me nt.  T he 
e xact ti mi n g of eac h asse ss me nt is liste d i n t he Ti me a n d E ve nts Ta ble Secti o n 7. 1 . 
T he f oll o wi n g p oi nts m ust be n ote d: 

If assess me nts are sc he d ule d f or t he sa me n o mi nal ti me, T H E N t he assess me nts 
s h o ul d occ ur i n t he f oll o wi n g or der:
1. Vital si g ns
2. 1 2 lea d E C G

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
4 7
3. Bl o o d dra ws.  
N ote: T he ti mi n g of t he assess me nts s h o ul d all o w t he bl o o d dra w t o occ ur at t he 
e xact n o mi nal ti me.

T he ti mi n g a n d n u m ber of pla n ne d st u d y  assess me nts ma y be altere d d uri n g t he 
c o urse of t he st u d y base d o n ne wl y a vail a ble data (e. g., t o o btai n data cl oser t o 
t he ti me of pea k plas ma c o nce ntrati o ns) t o e ns ure a p pr o priate m o nit ori n g. 

T he c ha n ge i n ti mi n g or a d diti o n of ti me p oi nts f or a n y  pla n ne d st u dy 
assess me nts m ust be d oc u me nte d i n a N ote t o File w hic h is a p pr o ve d b y t he 
rele va nt G S K st u dy tea m me m ber a n d t he n arc hi ve d i n t he st u d y s p o ns or a n d 
site st u d y files, b ut t his will n ot c o nstit ute a pr ot oc ol a me n d me nt. 

T he I R B will be i nf or me d of a n y  safety iss ues t hat re q uire alterati o n of t he 
safety m o nit ori n g sc he me or a m e n d me nt of t he I nf or me d C o nse nt F or m. 

N o m ore t ha n 5 0 0 m L of bl o o d will be c ollecte d o ver t he d urati o n of t he st u d y , 
i ncl u di n g a ny e xtra assess me nts t hat ma y be re q uire d

All o wa ble ti me wi n d o ws f or st u d y assess me nts ca n be f o u n d i n t he S R M.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
4 8
7. 1.
Ti m e a n d E v e nt s T a bl e
7. 1. 1.
S cr e e ni n g a n d Or al L e a d -i n P h a s e
St u d y P eri o d
S cr e e ni n g 1
Or al L e a d- i n7
W a s h o ut 
P eri o d
D o si n g D a y s 1 -2 8
Vi sit Wi n d o w  
Wit hi n 
3 0 d a y s 
of or al 
l e a d-i n
D a y 
1
D a y 
1 4
D a y 
2 9
1 4 – 4 2
d a y s
I nf or m e d C o ns e nt
X
D e m o gr a p hics
X
M e dic al / M e di c ati o n / Dr u g / Alc o h ol Hist ory
X
Eli gi bility Ass ess m e nt - I ncl usi o n/ Excl usi o n Crit eri a
X
H ei g ht, W ei g ht, B MI
X
P hysic al Ex a m
X
Vit al Si g ns ( S ecti o n 7. 4. 4 )2
X
X
X
X
1 2 -L e a d E C G  ( Secti o n 7. 4. 5 )
X
X
X
Dr u g / Alc o h ol Scr e e n ( S ecti o n 7. 4. 6 )2
X
X
P r e g n a ncy T est ( S ecti o n 7. 4. 6)2
X
X
X
H e p atitis B, H e p a titis C Scr e e ni n g ( S ecti o n 7. 4. 6 )
X
HI V T est ( S ecti o n 7. 4. 6 )
X
X
S T D Scr e e ni n g ( S ecti o n 7. 4. 6 )
X
Uri n e Di ps tick Scr e e ni n g ( S ecti o n 7. 4. 6 )
X
H e m at ol o gy wit h diff er e nti al; Cli nic al C h e mistry T ests
( S ecti o n 7. 4. 6 )2
X 
X 
X 
X
C o a g ul ati o n T ests ( S ecti o n 7. 4. 6 )
X
X
A d mi nist er or al C A B 3
X
X
Dis p e ns e Or al l e a d -i n I P
X
Dis p e ns e M e dic ati o n D osi n g Di ary
X
Dr u g acc o u nt a bility/ pill c o u nt/r evi e w dr u g di ary
X 
X
B l o o d pl as m a P K s a m pli n g
X
T iss u e/ C V F/ R F P K s a m plin g 4
X
A E Ass ess m e nt 5
X 
X 
X
C o nc o mit a nt M e dic ati o n R evi e w
X 
X 
X
P Gx 6
X
1.
Scr e e ni n g m ay occ ur ov er m or e t h a n o n e visit b ut wit hi n 3 0 d ays of t h e first d os e of or al C A B 3 0 m g i n t h e or al 
l e a d i n p h as e.
2.
Pri or t o a d mi nist eri n g t h e first or al d os e of C A B, st u dy p ers o n n el m ust v erify t h e f oll o wi n g pr e -d os e ass ess m e nts 
t o b e wit hi n n or m al li mits pri or t o a d mi nistr ati o n: vit al si g ns, pr e g n a ncy t est ( n e g ativ e; F R P o nly). T h e r es ults of 
t h e Dr u g/ Alc o h ol scr e e n, h e m at ol o gy wit h diff er e nti al, a n d cli nic al c h e mistry t ests o n D ay 1 ar e n ot r e q uir e d pri or 
t o a d mi nist eri n g t h e first or al d os e of C A B 3 0 m g, b ut s h o ul d b e dr a w n pri or t o C A B a d mi nistr ati o n.
3.
Or al C A B d osi n g f or D ays 1 t o 2 8. D ay 2 9 ass ess m e nts t o b e p erf or m e d wit hi n 2 4 h o urs fr o m t h e l ast d os e o n 
D ay 2 8. 
4.
F e m al e s u bj ects m ay c o ns e nt t o h av e p air e d r ect al tiss u e a n d r ect al fl ui d s a m pl es c oll ect e d at e ac h ti m e -p oi nt. 
F e m al e s u bj ects w h o d o n ot wis h t o p artici p at e i n r ect al P K s a m pli n g m ay still p artici p at e i n t h e st u dy.
5.
A E ass ess m e nt will i ncl u d e a br i ef, sy m pt o m-dir ect e d p hysic al ex a m as n e e d e d.
6.
P Gx: C a n b e c oll ect e d a ny ti m e; h o w ev er, it is pr ef er a bl e t o c oll ect t h e s a m pl e at t h e e arli est c o nv e ni e nt ti m e aft er 
t h e first d os e i n t h e or al l e a d i n p h as e.
7.
If a s u bj ect is wit h dr a w n pri or t o r ec eivi n g t h e C A B L A i nj ecti o n, a f oll o w -u p/ wit h dr a w al visit s h o ul d b e sc h e d ul e d 
1 0 -1 4 d ays aft er t h e l ast or al d os e of C A B.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
4 9
7. 1. 2.
C A B I nj e cti o n, C o m p art m e nt al P K S a m pli n g, a n d F oll o w -u p
Pr o c e d ur e s
D a y 1
D a y 
3
D a y 
5
D a y 
8
W e e k 4
W e e k 8
W e e k 1 2
W e e k 2 4
W e e k 3 6
W e e k 5 2
Wit h dr a w al 1
Pr e-
d os e 2
0 h
4 h
4 8 h
9 6 h
1 6 8 h
I nt eri m M e di c al / M e di c ati o n / 
Dr u g / Al c o h ol Hi st or y
X
Bri ef P h y si c al E x a m 
( S ecti o n 7. 4. 3 )
X
X
Vit al Si g n s ( S ecti o n 7. 4. 4 ) 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Pr e g n a n c y T e st 
( S ecti o n 7. 4. 6 )
X
X 
X 
X 
X 
X 
X 
X
H e m at ol o g y wit h diff er e nti al; 
Cli ni c al C h e mi str y T e st s
( S ecti o n 7. 4. 6 )
X
X 
X 
X
X
HI V T e st ( S ecti o n 7. 4. 6 )
X 
X 
X 
X 
X
S T D t e sti n g ( S ecti o n 7. 4. 6 ) 
X
A d mi ni st er C A B L A 6 0 0 m g 
I M
X
I nj e cti o n Sit e R e a cti o n 
A s s e s s m e nt
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
A E A s s e s s m e nt 3
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
C o n c o mit a nt M e di c ati o n 
R e vi e w
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Bl o o d pl a s m a P K S a m pli n g
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
L u mi n al Fl ui d ( C V F/ R F) P K 
S a m pli n g 4
X 
X 
X 
X 
X
Ti s s u e P K S a m pli n g 4 (T a bl e 
4 )
X 5
X 
X 
X 5
X
M RI 6
X 
X 
X
1.  S u bj ects w h o t er mi n at e b ef or e w e ek 5 2 will b e ask e d t o r et ur n t o t h e sit e f or a wit h dr a w al visit .
2.  O n D ay 1, st u dy p ers o n n el m ust v erify t h e f oll o wi n g pr e-d os e ass ess m e nts t o b e wit hi n n or m al li mits pri or t o 
i nj ecti o n:  bri ef p hysic al ex a m, vit al si g ns, pr e g n a ncy t est ( n e g ativ e; F R P o nly), A E ass ess m e nt, a n d c o nc o mit a nt 
m e dic ati o n ass ess m e nt.    If a cli nic al a b n or m ality, cli nic ally si g nific a nt A E, or pr o hi bit e d m e dic ati o n t h at pr ecl u d es 
i nj ecti o n is o bs erv e d/r ec or d e d, t h e m e dic al m o nit or m ust b e c o nt act e d f or f urt h er i nstr ucti o n.  
3.  A E ass ess m e nt will i ncl u d e a bri ef, sy m pt o m -dir ect e d p hysic al ex a m as n e e d e d.
4. F e m al e s u bj ects m ay c o ns e nt t o h av e p air e d r ect al tiss u e a n d r ect al fl ui d s a m pl es c oll ect e d at e ac h ti m e -p oi nt. 
F e m al e s u bj ects w h o d o n ot wis h t o p artici p at e i n r ect al P K s a m pli n g m ay still p artici p at e i n t h e st u dy.
5 . V a gi n al tiss u e will b e c oll ect e d o nly o n D ay 3 ( 4 8 h o ur) a n d W e ek 8.
6.  N o n -c o ntr ast M R I m a gi n g will b e p erf or m e d i n a s u bs et of u p t o 8 s u bj ects ( 4 m al es a n d 4 f e m al es).  T h e M RI at 0 h 
will b e p erf or m e d i m m e di at ely aft er C A B i nj ecti o n a n d b ef or e t h e 4 h bl o o d pl as m a P K ass ess m e nt.  

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
5 0
7. 2.
S cr e e ni n g a n d Criti c al B a s eli n e A s s e s s m e nt s
Car di o vasc ular me dical hist or y /ris k fact ors (as detaile d i n t he C R F) will be assesse d at 
scree ni n g.
Writte n i nf or me d c o nse nt m ust be o btai ne d fr o m eac h p ote ntiall y eli gi ble s u bject ( or his 
or her le gal re prese ntati ve) b y st u d y site pe rs o n nel pri or t o t he i nitiati o n of a n y scree ni n g 
pr oce d ures as o utli ne d i n t his pr ot oc ol. T he c o nse nt f or m m ust ha ve bee n a p pr o ve d b y 
t he Instit uti o nal Re vie w B oar d/I nstit uti o nal Et hics C o m mittee (I R B/I E C).
After si g ni n g 
a n i nf or me d c o nse nt, s u bjects wil l c o m plete scree ni n g assess me nts t o deter mi ne s u bject 
eli gi bilit y. Eac h s u bject bei n g scree ne d f or st u d y  e nr ol me nt e val uati o n will be assi g ne d a 
s u bject n u m ber. T his n u m ber will be gi ve n se q ue ntiall y  i n c hr o n ol o gical or der of s u bject 
prese ntati o n.
S u bjec ts m ust be c o u nsele d o n t he practice of safer se x ual practices i ncl u di n g t he use of 
effecti ve barrier met h o ds (e. g. male c o n d o m) f or t he le n gt h of ti me i n w hic h t he y  are 
re q uire d f or partici pati o n i n t his st u d y as part of t he eli gi bilit y pr ocess.
T he f oll o wi n g de m o gra p hic para meters will be ca pt ure d: y ear of birt h, se x, race a n d 
et h nicit y.
Me dical/ me dicati o n/fa mil y  hist or y will be assesse d as relate d t o t he i ncl usi o n/e xcl usi o n 
criteria liste d i n Secti o n 5 .  
7. 3. 
S cr e e ni n g
All cli nical a n d la b orat or y assess me nts of eli gi bilit y  m ust be perf or me d a n d re vie we d 
wit hi n 3 0 da y s of i nitiati n g t he oral lea d-i n p hase. All Scree ni n g res ults m ust be a vaila ble 
pri or t o e nr oll me nt. 
Eli gi bilit y  criteria m ust be caref ully assesse d a t t he Scree ni n g visit a n d c o nfir me d at t he 
D a y  1 Oral lea d-i n p hase visit a n d re-c o nfir me d pri or t o i njecti o n. 
S u bjects ma y  be e nr olle d a n d be gi n t he oral lea d-i n p hase as s o o n as all Scree ni n g 
assess me nts are c o m plete a n d t he res ults are a vaila ble a n d d o c u me nte d.  
S u bjects w h o meet all e ntr y  criteria are e nr olle d a n d assi g ne d a s u bject n u m ber. S u bjects 
n ot meeti n g all i ncl usi o n a n d e xcl usi o n criteria at i nitial scree n ma y  be re-scree ne d o ne 
ti me wit h a ne w s u bject n u m ber. S u bjects w h o are e nr olle d i nt o the trial a n d s u bse q ue ntl y  
wit h dra w n fr o m t he st u d y f or a n y reas o n ma y n ot be rescree ne d.
7. 3. 1.
B a s eli n e
S u bjects will ha ve “ Baseli ne” assess me nts c o m plete d at Da y  1 of t he oral lea d-i n d osi n g 
peri o d.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
5 1
7. 4.
S af et y
Pla n ne d ti me p oi nts f or all safet y  assess me nts are liste d i n t he Ti me a n d E ve nts Ta ble 
( Secti o n 7. 1 ).  A d diti o nal ti me p oi nts f or safety tests s uc h as vital si g ns, p h ysical e xa ms 
a n d la b orat or y safety tests ma y be a d de d d uri n g t he c o urse of t he st u d y base d o n ne wl y 
a vaila ble data t o e ns ure a p pr o priate safet y m o nit ori n g. 
I n or der t o m o nit or safet y a n d t o res p o n d t o occ urre nces of t o xicit y e x pe diti o usl y, t he 
tea m will h ol d c o nfere nce calls o n a re g ular basis d uri n g st u dy i m ple me ntati o n, a n d 
a d diti o nal c o nfere nces call s will ta ke place o n a n a d h oc basis. St u d y  site i n vesti gat ors 
will be res p o nsi ble f or cl ose m o nit ori n g a n d ma na ge me nt of A Es, a n d will ha ve detaile d 
S O Ps f or t he re p orti n g of A Es a n d t he ma na ge me nt of t o xicit y . T he Safety M o nit or will 
be res p o nsi ble f or p r o vi di n g s u p p ort t o st u d y i n vesti gat ors re gar di n g t he cli nical 
ma na ge me nt of i n di vi d ual partici pa nts (i ncl u di n g decisi o n -ma ki n g s urr o u n di n g 
eli gi bilit y, disc o nti n uati o n/ h ol ds/ter mi nati o n of st u d y dr u g, a n d cli nical ma na ge me nt).
7. 4. 1.
A d v er s e E v e nt s ( A E) a n d S eri o u s A d v er s e E v e nt s ( S A E s)
T he defi niti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x 3 a n d A p pe n di x 4 .  T he 
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 Versi o n 
2. 0 ( Secti o n 1 2. 4 ) will be e m pl o ye d t o gra de t he se verit y of t he detecte d a d verse e ve nts. 
F or t his st u d y , t he S p o ns or c o nsi ders seiz ures as a n A E of s pecial i nterest (see 
I n vesti gat or’s Br oc h ure f or bac k gr o u n d i nf or mati o n). W here seiz ures occ ur, t he S p o ns or 
w o ul d li ke t o better c haracterize t hese oc c urre nces t o e na ble s ys te matic an al y ses.
I n vesti gat ors are re q ueste d t o d oc u me nt a n d re p ort seiz ure or p ossi ble seiz ure e ve nts 
pr o m ptl y  (wit hi n 2 4 h o urs of lear ni n g o f t he e ve nt) t o t he S p o ns or f or e val uati o n a n d 
o n war d re p orti n g .  Data s h o ul d be d oc u me nte d o n t he a p pr o priate A E/ S A E pa ge (see 
Secti o n 1 2. 3 ).
T he i n vesti gat or a n d t heir desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g a n d 
re p orti n g e ve nts t hat meet t he defi niti o n of a n A E or S A E. 
7. 4. 1. 1.
I nj e cti o n Sit e R e a cti o n s
I njecti o n Site Reacti o n (I S R) e xa mi nati o n will i ncl u de a n assess me nt of pai n, te n der ness, 
pr urit us, war mt h, i nfecti o ns, ras h, er y t he ma, s welli n g, i n d urati o n, a n d n o d ules 
(gra n ul o mas or c y sts). Di gital p h ot o gra p hs will be d oc u me nte d o n all s u bjects w h o ha ve 
a n IS R t hat are Gra de 2 if persiste nt be y o n d 2 wee ks, a n y  Gra de 3 or a b o ve, or are 
seri o us. Der mat ol o g y will be c o ns ulte d o n all s u bjects w h o ha ve a n i njecti o n site reacti o n 
c o nsi dere d seri o us, Gra de 3 or a b o ve, or if persiste nt be y o n d 3 0 da y s a n d ot hers if t he 
I n vesti gat or or Me dical M o nit or feels it is me dicall y necessar y.
7. 4. 1. 2.
Ti m e p eri o d a n d Fr e q u e n c y  f or c oll e cti n g AE a n d S A E i nf or m ati o n

A Es a n d S A Es will be c ollecte d fr o m t he start of St u d y  Treat me nt u ntil t he f oll o w-
u p c o ntact (see Secti o n 7. 4. 1. 4 ), at t he ti me p oi nts s pecifie d i n t he Ti me a n d E ve nts 
Ta ble ( Secti o n 7. 1 ).

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
Me dical occ u rre nces t hat be gi n pri or t o t he start of st u d y treat me nt b ut after 
o btai ni n g i nf or me d c o nse nt ma y  be rec or de d o n t he Me dical Hist or y/ C urre nt 
Me dical C o n diti o ns secti o n of t he C R F.

A n y  S A Es assesse d as relate d t o st u d y partici pati o n (e. g., pr ot oc ol-ma n date d
pr oce d ures, i n vasi ve tests, or c ha n ge i n e xisti n g t hera p y) or relate d t o a G S K pr o d uct 
will be rec or de d fr o m t he ti me a s u bject c o nse nts t o partici pate i n t he st u d y u p t o a n d 
i ncl u di n g a ny f oll o w -u p c o ntact. 

All S A Es will be rec or de d a n d re p orte d t o G S K wit hi n 2 4 h o urs, as i n dicate d i n 
A p pe n di x 3 .

I n vesti gat ors are n ot o bli gate d t o acti vely see k A Es or S A Es i n f or mer st u d y 
s u bjects. H o we ver, if t he i n vesti gat or lear ns of a ny S A E, i ncl u di n g a deat h, at a n y 
ti me after a s u bject has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he 
e ve nt reas o na bl y relate d t o t he st u d y  treat me nt or st u d y partici pati o n, t he i n vesti gat or 
m ust pr o m ptl y  n otif y G S K.
N O T E: T he met h o d of rec or di n g, e val uati n g a n d assessi n g ca usalit y  of A Es a n d S A Es 
pl us pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts t o G S K are pr o vi de d i n 
A p pe n di x 3 . T he relate d ness of a gi ve n A E t o t he st u d y pr o d uct will be assesse d b y st u d y 
i n vesti gat ors as descri be d i n A p pe n di x 3 .
7. 4. 1. 3.
M et h o d of D et e cti n g A E s a n d S A E s
St u d y  partici pa nts will be pr o vi de d wit h a 2 4-h o ur tele p h o ne a n d pa ger n u m ber t o c o ntact 
site i n vesti gat ors, a n d will be e nc o ura ge d t o c o ntact t he st u d y cli nicia n/ i n vesti gat or at t he 
first si g n of a ny a d verse e ve nt t he y ma y e x perie nce. F or life -t hreate ni n g e ve nts, t he y will 
be i nstr ucte d t o see k i m me diate e mer ge nc y  care. If feasi ble, t he y will be as ke d t o see k 
care at t he facilit y w here t he site i n vesti gat or is base d, a n d t o tell t he me dical staff t o 
c o ntact t he site i n vesti gat or u p o n t heir arri val t here. Me dical rec or ds fr o m s uc h 
e nc o u nters will be re vie we d b y st u d y i n vesti gat ors after a p pr o priate per missi o ns are 
o btai ne d fr o m t he s u bject, a n d data relati n g t o p ote ntial a d v erse e ve nts will be e ntere d 
i nt o A E C R Fs. 
All A Es Gra de I a n d hi g her will be rec or de d by st u d y  staff o n s o urce d oc u me nts a n d t he 
a p pr o priate C R F. T his will occ ur re gar dless of relate d ness t o st u d y  pr o d uct. 
Care will be ta ke n n ot t o i ntr o d uce bias w he n de tecti n g A Es a n d/ or S A Es. O pe n-e n de d 
a n d n o n -lea di n g ver bal q uesti o ni n g of t he s u bject is t he preferre d met h o d t o i n q uire a b o ut 
A E occ urre nce.  A p pr o priate q uesti o ns i ncl u de:

“ H o w are y o u feeli n g?” 

“ Ha ve y o u ha d a n y ( ot her) me dical pr o ble ms si nce yo ur last visit/c o ntact?” 

“ Ha ve y o u ta ke n a n y ne w me dici nes, ot her t ha n t h ose pr o vi de d i n t his st u d y , si nce 
y o ur last visit/c o ntact?” 

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7. 4. 1. 4.
F oll o w- u p of A E s a n d S A E s
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h 
s u bject at s u bse q ue nt visits/c o ntacts.  All S A Es, a n d n o n-seri o us A Es of s pecial i nterest 
(as defi ne d i n Secti o n 7. 4. 1 a n d Secti o n 1 2. 3. 4 ) will be f oll o we d u ntil res ol uti o n, u ntil t he 
c o n diti o n sta bilizes, u ntil t he e ve nt is ot her wise e x plai ne d, or u ntil t he s u bject is l ost t o 
f oll o w-u p (as defi ne d i n Secti o n 5. 4 ). F urt her i nf or mati o n o n f oll o w-u p pr oce d ures is 
gi ve n i n A p pe n di x 3 .
7. 4. 1. 5.
C ar di o v a s c ul ar a n d D e at h E v e nt s
A n y  car di o vasc ular or deat h e ve nt, as defi ne d i n Secti o n 1 2. 3. 3 , will be re p orte d t o t he 
S A E pr ot oc ol c o ntact a n d Me dical M o nit or. I n t he case of a car d iac e ve nt, t he partici pa nt 
will be referr e d t o t he a p pr o priate ac ute me dical care.
7. 4. 1. 6.
Di s e a s e -R el at e d E v e nt s a n d/ or Di s e a s e -R el at e d O ut c o m e s N ot 
Q u alif y i n g a s S AE s, I n cl u di n g HI V S er o c o n v er si o n
Disease -Relate d E ve nts or Disease -Relate d o utc o mes i n t his case are n ot e x pecte d, as t his 
will be a st u d y  i n healt h y v ol u nteers.  HI V scree ni n g will be perf or me d at scree ni n g a n d 
at vari o us p oi nts t hr o u g h o ut t he st u d y . I n di vi d uals wit h o ne or m ore reacti ve test will be 
i neli gi ble t o partici pate i n t he st u d y. F urt her m ore, i n di vi d uals wit h si g ns of ac ute 
retr o viral sy n dr o me at scree ni n g or e nr oll me nt (te m perat ure > 1 0 1 de grees, 
l ym p ha de n o pat h y, p har y n gitis, m y al gias/art hral gias) will n ot be e nr olle d. D uri n g 
s u bse q ue nt st u d y visits, i n di vi d uals w h o de vel o p si g ns or sy m pt o ms of ac ute retr o viral 
s yn dr o me will be re -s cree ne d wit h ser u m HI V R N A P C R. 
I n t he case of t he detecti o n of HI V b y scree ni n g test, c o nfir mat or y testi n g will be 
perf or me d. See A p pe n di x 6 .  If HI V ser oc o n versi o n occ urs d uri n g t he st u d y, t he s u bject 
will be i nf or me d of t hese res ults a n d referre d f or a p pr o priate care,  a n d t he e ve nt will be 
i m me diatel y re p orte d t o t he S p o ns or a n d t o t he rele va nt di visi o n of t he State De part me nt 
of Healt h. If HI V ser oc o n versi o n occ urs after t he C A B L A I M i njecti o n, i m me diate 
s u p pressi ve A R T will be facilitate d t o pre ve nt t he p ossi ble de vel o p me nt of resista nce o n 
m o n ot hera p y. T his will be c o nti n ue d f or a mi ni m u m of 5 2 wee ks p ost I M i njecti o n. 
I n t he case of a s u bject re p orti n g a hi g h-ris k HI V e x p os ure, t he pr o visi o n of p ost 
e x p os ure pr o p h yla xis will be e x pe dite d at t he site le vel. If i n t he oral p hase, n o f urt her 
st u d y dr u g will be gi ve n. H o we ver, if t he I M C A B LA has alrea d y  bee n recei ve d, safet y 
assess me nts a n d m o nit ori n g will be c o nti n ue d f or 5 2 wee ks after i njecti o n or u nti l t he 
st u d y pr o d uct is n o l o n ger detecta ble i n plas ma, w hic he ver is l o n ger. F urt her m ore, a n y 
p ossi ble e x p os ure t o HI V t hat occ urs d uri n g t he st u d y , as i de ntifie d b y t he st u d y 
partici pa nt, m ust be re p orte d t o t he st u d y  i n vesti gat ors, S p o ns or, a n d Safet y M o nit or. 
7. 4. 1. 7.
R e g ul at or y  R e p orti n g R e q uir e m e nt s f or S AE s
Pr o m pt n otificati o n b y  t he i n vesti gat or t o G S K of S A Es, A Es of s pecial i nterest (i.e. 
seiz ures, see Secti o n 7. 4. 1 ) a n d n o n -seri o us A Es relate d t o st u d y treat me nt is esse ntial s o
t hat le gal o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safety of s u bjects a n d t he 
safety of a pr o d uct u n der cli nical i n vesti gati o n are met. 

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G S K has a le gal res p o nsi bilit y  t o n otif y b ot h t he l ocal re g ulat or y a ut h ority a n d ot her 
re g ulat or y a ge ncies a b o ut t he safety of a pr o d uct u n der cli nical i n vesti gati o n.  G S K will 
c o m pl y wit h c o u ntr y s pecific re g ulat or y re q uire me nts relati n g t o safety re p orti n g t o t he 
re g ulat or y a ut h ority, I nstit uti o nal Re vie w B oar d (I R B)/I n de pe n de nt Et hics C o m mittee 
(I E C) a n d in vesti gat ors.
I n vesti gat or safet y re p orts are pre pare d f or s us pecte d u ne x pecte d seri o us a d verse 
reacti o ns acc or di n g t o l ocal re g ulat or y re q uire me nts a n d G S K p olic y a n d are f or war de d 
t o i n vesti gat ors as necessar y.
A n i n vesti gat or w h o recei ves a n i n vesti gat o r safet y re p ort descri bi n g a S A E(s) or ot her 
s pecific safety i nf or mati o n (e. g., s u m mar y or listi n g of S A Es) fr o m G S K will file it wit h 
t he I B a n d will n otif y t he IR B/I E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.
7. 4. 2.
Pr e g n a n c y
As o utli ne d i n t he I ncl usi o n Criteria, all fe male partici pa nts of re pr o d ucti ve p ote ntial are 
re q uire d t o use a n effecti ve c o ntrace pti ve met h o d f or t he d urati o n of t he st u d y, as well as 
c o n d o ms ( male or fe male) f or t he pre ve nti o n of S TI s. C o ntrace pti ve c o u nseli n g will be 
pr o vi de d o n a n as -nee de d basis t o partici pa nts, a n d st u d y  staff will ma ke t he a p pr o priate 
referrals t o s o urces of re pr o d ucti ve care. 
As o utli ne d i n t he Ti me a n d E ve nts Ta ble ( Secti o n 7. 1 ), fe male partici pa nts of 
re pr o d uctive p ote ntial will ha ve pre g na nc y  testi n g perf or me d; t he y will als o be 
e nc o ura ge d t o re p ort all si g ns or s y m pt o ms of pre g na nc y  t o st u d y staff. A n y pre g na nc y 
t hat occ urs d uri n g fe male s u bjects’ partici pati o n i n t he st u d y will be re p orte d t o t he 
S p o ns or a n d S afet y M o nit or i m me diatel y u p o n site a ware ness a n d c o nfir me d wit h ser u m 
pre g na nc y  testi n g. 
If a s u bject s h o ul d bec o me pre g na nt d uri n g t he oral lea d-i n phase, t he st u d y pr o d uct will 
be i m me diatel y  disc o nti n ue d  a n d t he s u bject will c o nti n ue t o be f oll o we d for safet y 
e val uati o ns e ver y 4-5 wee ks u ntil t he pre g na nc y  o utc o me is reac he d, at w hic h p oi nt t he 
s u bject will be ter mi nate d fr o m t he st u d y. If a s u bject s h o ul d bec o me pre g na nt at a n y 
ti me p oi nt after t he I M C A B L A i njecti o n has bee n recei ve d, s he will c o nti n ue o n st u d y 
a n d will recei ve t he a p pr o priate safet y f oll o w-u p e val uati o ns i ncl u di n g plas ma P K, per 
t he Ti me a n d E ve nts Ta ble. 
T he site or desi g nee will c o u nsel a n y partici pa nts w h o bec o me pre g na nt re gar di n g 
p ossi ble ris ks t o t he fet us acc or di n g t o site -s pecific S O Ps. Partici pa nts ma y n ot e nr oll if 
t he y are c urre ntl y breastfee di n g a n d st u d y pr o d uct s h o ul d be disc o nti n ue d if a n y 
partici pa nt i de ntifies t hat s he is breastfee di n g after e nr oll me nt. T he site or desi g nee als o 
will refer t he partici pa nt t o t he a p pr o priate care. 

Details of all pre g na ncies i n fe male s u bjects will be c ollecte d after t he start of d osi n g 
a n d u ntil t he last f oll o w -u p assess me nt.

If a pre g na nc y is re p orte d t he n t he i n vesti gat or s h o ul d i nf or m G S K wit hi n 2 wee ks 
of lear ni n g of t he pre g na n c y a n d s h o ul d f oll o w t he pr oce d ures o utli ne d i n A p pe n di x 
6 .

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
All pre g na nc y  o utc o mes will be re p orte d o n rele va nt Case Re p ort F or ms ( C R Fs). 
O utc o mes meeti n g criteria f or e x pe dite d a d verse e ve nt ( E A E) re p orti n g a ls o will be 
re p orte d.
7. 4. 3.
P h y si c al E x a m s

A c o m plete p h ys ical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nt of t he 
S ki n, Car di o vasc ular, Res pirat or y , Gastr oi ntesti nal, Ge nit o uri nar y, a n d Ne ur ol o gical 
s yste ms. Hei g ht a n d wei g ht will als o be meas ure d a n d recor de d. 

A brief p h ys ical e xa mi nati o n will i ncl u de assess me nts of t he s ki n, l u n gs, 
car di o vasc ular s ys te m, a n d a b d o me n (li ver a n d s plee n).
7. 4. 4.
Vit al Si g n s

Vital si g ns will be meas ure d i n se mi -s u pi ne p ositi o n after 1 0 mi n utes rest a n d will 
i ncl u de te m perat ure, sy st olic a n d diast olic bl o o d press ure a n d p ulse rate. 

Si n gle bl o o d press ure ( B P) a n d heart rate ( H R) meas ure me nts will be ta ke n o n Da y  1 
of t he oral lea d -i n a n d will be classifie d as baseli ne.  A si n gle re peat meas ure me nt is 
all o we d t o deter mi ne eli gi bilit y.  Si n gle B P a n d H R meas ure me nts will be o btai ne d 
at all ot her ti me p oi nts d uri n g t he st u d y.  
7. 4. 5.
El e ctr o c ar di o gr a m ( E C G)

1 2 -lea d E C G will be perf or me d wit h t he s u bject i n a se mi-s u pi ne p ositi o n ha vi n g 
reste d i n t his p ositi o n f or at least 1 0 mi n utes bef ore ha n d.

1 2 -lea d E C Gs will be o btai ne d usi n g a n E C G mac hi ne t hat a ut o maticall y calc ulates 
t he heart rate a n d meas ures P R, Q R S, Q T, a n d Q Tc i nter vals. A si n gle re peat 
meas ure me nt is all o we d t o deter mi ne eli gi bilit y .
7. 4. 6.
Cli ni c al S af et y  L a b or at or y As s e s s m e nt s
All pr ot o c ol re q uire d la b orat or y assess me nts, as defi ne d i n Ta ble 5 , m ust be c o n d ucte d i n 
acc or da nce wit h t he La b orat or y  Ma n ual, a n d Pr ot oc ol Ti me a n d E ve nts Sc he d ule.
La b orat or y  re q uisiti o n f or ms m ust be c o m plete d a n d sa m ples m ust be clearl y la belle d 
wit h t he s u bject n u m ber, pr ot oc ol n u m ber, site/ce ntre n u m ber, a n d visit date.
Refere nce 
ra n ges f or all safet y para meters will be pr o vi de d t o t he site b y t he la b orat or y res p o nsi ble 
f or t he assess me nts. A n o ver ni g ht fast is preferre d pri or t o scree ni n g la b orat or y 
assess me nts; h o we ver, a mi ni m u m of a 6 h o ur fast is acce pta ble.  
If a d diti o nal n o n-pr ot oc ol s pecifie d la b orat or y  assess me nts are perf or me d at t he 
i nstit uti o n’s l ocal la b orat or y a n d res ult i n a c ha n ge i n s u bject ma na ge me nt or are 
c o nsi dere d cli nicall y  si g nifica nt b y t he i n vesti gat or (e. g., S A E or A E or d ose 
m o dificati o n) t he res ults m ust be rec or de d i n t he C R F.
A si n gle re peat la b orat or y test will be all o we d f or eli gi bilit y . He mat ol o g y, cli nical 
c he mistr y, uri nal ys is a n d a d diti o nal para meters t o be teste d are liste d i n Ta ble 5 . 

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T a bl e 5
Pr ot o c ol R e q uir e d S af et y  L a b or at or y As s e s s m e nt s
L a b or at or y 
Assess me nts 1
P ar a meters
He mat ol o g y  wit h 
differe ntial
Pl at el et C o u nt
R B C I n d ic es:
W B C a bs ol ut e c o u nt wit h 
Diff er e nti al :
R B C C o u nt
M C V
N e utr o p hils
H e m o gl o bi n
M C H
Ly m p h ocyt es
H e m at ocrit
M C H C
M o n ocyt es
E osi n o p hils
B as o p hils
I m m at ur e b a n d f or ms
C oa g ulati o n Tests
P T 
P T T
I N R
Cli nical C he mistr y  
Tests 2
B U N
P ot assi u m
A S T ( S G O T)
T ot al a n d dir ect 
bilir u bi n
Cr e ati ni n e
S o di u m
A L T ( S G P T)
T ot al Pr ot ei n
Gl uc os e 
C alci u m
Alk ali n e 
p h os p h at as e
Al b u mi n
C P K
R o uti n e Uri n e di pstick 
wit h r efl ex uri n alysis if 
a b n or m al

S p ecific gr avity

p H, gl uc os e, pr ot ei n, bl o o d a n d k et o n es by di pstick

Micr osc o pic ex a mi n ati o n (if bl o o d or pr ot ei n is a b n or m al)
S T D Scr e e n 3

G o n orr h o e a 

C hl a my di a 

Sy p hilis 

Tric h o m o n as 
Ot h er Scr e e ni n g 
T ests

HI V:  HI V 1 -2 A b/ A g t esti n g

H e p atitis B scr e e n:  H e p atits B s urf ac e a nti g e n ( H Bs A g ) H e p atitis B 
s urf ac e a nti b o dy(H Bs A b ), a n d H e p atitis c or e a nti b o dy ( H Bc A b )

H e p atitis C ( H e p C a nti b o dy)

Alc o h ol scr e e n a n d dr u gs of a b us e scr e e n (t o i ncl u d e at mi ni m u m: 
a m p h et a mi n es, b ar bit ur at es, c oc ai n e, o pi at es, c a n n a bi n oi ds a n d 
b e nz o di az e pi n es)

Uri n e ( or s er u m) h C G Pr e g n a ncy t est ( as n e e d e d f or w o m e n of c hil d 
b e ari n g p ot e nti al) 4
N O T E S :
1.
A n ov er ni g ht f ast is pr ef err e d pri or t o scr e e ni n g l a b or at ory ass ess m e nts; h o w ev er, a mi ni m u m of a 6 h o ur 
f ast is acc e pt a bl e.  
2.
D et ails of Liv er C h e mistry St o p pi n g Crit eri a a n d R e q uir e d Acti o ns a n d F oll o w -U p Ass ess m e nts aft er liv er 
st o p pi n g or m o nit ori n g ev e nt ar e giv e n i n S ecti o n 5. 4. 1 a n d A p p e n dix 2 .
3.
S T D scr e e ni n g t ests will b e p erf or m e d p er l oc al sit e st a n d ar ds. Pr ef er a bly, uri n e s h o ul d b e s e nt f or n ucl eic 
aci d t esti n g ( N A A T) f or g o n orr h e a ( G C), C hl a my di a a n d tric h o m o n as, a n d a r ect al s w a b s h o ul d b e s e nt f or 
N A A T f or G C a n d C hl a my di a. F or sy p hilis scr e e ni n g, a pl as m a R P R will s uffic e.
4.
L oc al uri n e t esti n g will b e st a n d ar d f or t h e pr ot oc ol u nl ess s er u m t esti n g is r e q uir e d by l oc al r e g ul ati o n or 
et hics c o m mitt e e or sit e pr ef er e nc e.
All la b orat or y  tests wit h val ues t hat are c o nsi dere d cli nicall y si g nifica ntly a b n or mal 
d uri n g partici pati o n i n t he st u d y  or wit hi n 52 wee ks after t he last d ose of st u d y  treat me nt 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
5 7
s h o ul d be re peate d u ntil t he val ues ret ur n t o n or mal or baseli ne.  If s uc h val ues d o n ot 
ret ur n t o n or mal wit hi n a peri o d j u d ge d reas o na ble b y t he i n vesti gat or, t he eti ol o g y 
s h o ul d be i de ntifie d a n d t he s p o ns or n otifie d.
7. 4. 7.
M a g n eti c R e s o n a n c e I m a gi n g 
N o n -c o ntrast -e n ha nce d M RI i ma gi n g will be perf or me d after i njecti o n at t he ti me p oi nts 
o utli ne d i n t he Ti me a n d E ve nts Ta ble ( Secti o n 7. 1 ) i n a s u bset of u p t o 4 fe males a nd 4 
males t o assess e v ol uti o n of i njecti o n de p ot l ocalizati o n.   S u bjects will u n der g o a M RI 
sca n ni n g sessi o n i n t he pr o ne p ositi o n n ot t o e xcee d 6 0 mi n utes. T he sca n ni n g d urati o n 
will be desi g ne d t o be a p pr o xi matel y  3 0 mi n utes. N o c o ntrast a ge nts will be use d. All 
sca n ni n g sessi o ns f or a n i n di vi d ual s u bject s h o ul d occ ur o n t he sa me sca n ner. A refere nce 
p ha nt o m ma y  be place d ne xt t o t he s u bject t o all o w f or si g nal n or malizati o n bet wee n 
visits.
T he sca n ni n g pr oce d ures will c o nsist of r o uti ne l ocalizers f oll o we d b y a n e xa mi nati o n of 
t he i njecti o n de p ot i n t he gl uteal m uscle. F urt her details of t he sca n ni n g pr ot oc ol will be 
pr o vi de d i n a de dicate d I ma gi n g Ma n ual.  M RI  i ma ges a n d q ua ntitati ve assess me nts will 
be c ollecte d a n d re p orte d se paratel y  b y G S K Platf or ms Tec h n ol o g y  Scie nces. 
All M RI  sca ns will be re p orte d ( n o n-a n o n ymize d) f or cli nical a b n or malities. 
7. 5.
P h ar m a c o ki n eti c s
Bl o o d sa m ples f or plas ma p har mac o ki netic ( P K) a nal ys is of C A B will be c ollecte d at t he 
ti me p oi nts i n dicate d i n Secti o n 7. 1 , Ti me a n d E ve nts Ta ble.  T he act ual date a n d ti me of 
eac h bl o o d sa m ple c ollecti o n will be rec or de d.  Wit h t he e xce pti o n of P K sa m pli n g i n t he 
first wee k p ost-i njecti o n w hic h s h o ul d be perf or me d acc or di n g t o sc he d ule, the ti mi n g of 
P K sa m ple c ollecti o n ma y  be altere d (3 da y s) f or sc he d uli n g p ur p oses if dee me d 
a p pr o priate b y t he i n vesti gat or i n c o ns ultati o n wit h t he s p o ns or.
Bl o o d sa m ples ( 4 m L  eac h) will be c ollecte d i nt o p otassi u m E D T A t u bes f or plas ma 
C A B a nal ys is, a n d i nitial pr ocessi n g will ta ke place as f oll o ws:
I m me diatel y after c ollecti o n, ge ntly i n vert ( D O N O T S H A K E) t he e vac uate d bl o o d 
c ollecti o n t u be 8-1 0 ti mes t o mi x t he P otassi u m Et h y le ne dia mi netetraacetic aci d 
(p otassi u m E D T A) a ntic oa g ula nt wit h t he w h ole bl o o d a n d place t he sa m ple(s) o n ice. 
Wit hi n 1 h o ur of sa m ple c ollecti o n, se parate t he plas ma b y  refri gerate d ( 4C) 
ce ntrif u gati o n at 1, 5 0 0 t o 2, 0 0 0 x g f or a mi ni m u m of 1 0 mi n utes. 
I m me diatel y after sa m ple pr ocessi n g freeze t he plas ma st ora ge t u bes i n t he u pri g ht
p ositi o n i n a n o n -self- defr osti n g freezer. St ore at - 2 0C or l o wer u ntil tra nsfer t o 
bi oa nal y tical facilit y. 
Va gi nal, cer vical a n d rectal tiss ue bi o psies a n d l u mi nal (cer vic o va gi nal a n d rectal) fl ui d 
c ollecti o ns will be d o ne at t he ti me p oi nts i n dicate d i n Secti o n 7. 1 .  At eac h fe male 
ge nital tiss ue sa m pli n g ti me p oi nt, u p t o 3 va gi nal a n d 3 cer vical bi o psies will be 
c ollecte d via s pec ul u m e xa m per s u bject.  At eac h rect osi g m oi d tiss ue sa m pli n g ti me 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
5 8
p oi nt, u p t o 1 0 bi o psies will be c ollecte d at 1 5 c m fr o m t he a nal mar gi n via fle xi ble 
si g m oi d osc o py.   Details o utli ni n g t he c ollecti o n a n d pr ocessi n g of tiss ue/ C V F/ R F ca n 
be f o u n d i n t he S R M. 
7. 5. 1.
S a m pl e A n al y si s
Plas ma/tiss ue/l u mi nal fl ui d a nal y sis will be perf or me d by t he Cli nical P har mac ol o g y 
A nal y tical La b orat or y ( C P A L) at J o h ns H o p ki ns U ni versit y a n d u n der t he ma na ge me nt 
of G S K P T S/ BI B . T he details of sa m ple c ollecti o n a n d a nalys is will be i ncl u de d i n t he 
S R M a n d a d diti o nall y i n t he st u d y sa m ple a nalys is pla n. C o nce ntrati o ns of C A B will be 
deter mi ne d i n sa m ples usi n g t he c urre ntl y a p pr o ve d bi oa nal ytical met h o d ol o g y. Ra w 
data will be st ore d at t he bi oa nal y tical site.  Vali dati o n testi n g will be perf or me d i n 
acc or da nce wit h t he F D A Bi oa nal yt ical Met h o d Vali dati o n G uida nce f or I n d ustr y  a n d 
assa ys re vie we d i n acc or da nce wit h t he NI H-cr oss net w or k Cli nical P har mac ol o g y  
Q ualit y  Ass ura nce ( C P Q A) pr o gra m. 
O nce t he bl o o d plas ma/tiss ue/ C V F/ R F sa m ple has bee n a nal y ze d f or C A B a n y re mai ni n g 
sa m ple ma y be a nal yze d f or ot her c o m p o u n d- relate d meta b olites or t o f urt her u n dersta n d 
t he c o m p o u n d or t he disease bei n g st u die d a n d t he res ults re p orte d u n der a se parate 
pr ot oc ol a n d a nal ys is pla n.
7. 6.
G e n eti c s
6 m L  of bl o o d will be c ollecte d i nt o a n E D T A t u be f or f ut ure p har mac o ge n o mic a nal ys is.  
I nfor mati o n re gar di n g p har mac o ge netic ( P G x) researc h is i ncl u de d i n A p pe n di x 8 .  T he 
I RB/I E C a n d, w here re q uire d, t he a p plica ble re g ulat or y  a ge nc y m ust a p pr o ve t he P G x 
assess me nts bef ore t hese ca n be c o n d uc te d at t he site.  In s o me cases, a p pr o val of t he 
P G x assess me nts ca n occ ur after a p pr o val is o btai ne d f or t he rest of t he st u d y .  If s o, t he n 
t he writte n a p pr o val will clearly i n dicate a p pr o val of t he P G x assess me nts is bei n g 
deferre d a n d i n m ost cases, t h e st u d y, e xce pt f or P G x assess me nts, ca n be i nitiate d.  
W he n P G x assess me nts will n ot be a p pr o ve d, t he n t he a p pr o val f or t he rest of t he st u d y  
will clearl y i n dicate t his a n d t heref ore, P G x assess me nts will n ot be c o n d ucte d.
8.
D A T A  MA N A G E M E N T

F or t his st u d y , s u bject data will be e ntere d i nt o G S K defi ne d C R Fs, tra ns mitte d 
electr o nicall y t o G S K or desi g nee a n d c o m bi ne d wit h data pr o vi de d fr o m ot her 
s o urces i n a vali date d data s yste m.  

F or t his st u d y  s u bject data will be c ollecte d usi n g G S K defi ne d case re p ort for ms a n d 
c o m bi ne d wit h data pr o vi de d fr o m ot her s o urces i n a vali date d data s ys te m.

Ma na ge me nt of cli nical data will be perf or me d i n acc or da nce wit h a p plica ble G S K 
sta n dar ds a n d data clea ni n g pr oce d ures t o e ns ure t he i nte grit y of t he data, e. g., 
re m o vi n g err ors a n d i nc o nsiste ncies i n t he data.

A d verse e ve nts a n d c o nc o mita nt me dicati o ns ter ms will be c o de d usi n g Me d D R A 
( Me dical Dicti o nar y f or Re g ulat or y Acti vities) a n d a n i nter nal vali date d me dicati o n 
dicti o nar y , G S K Dr u g.  

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
5 9

Ori gi nal C R Fs will be retai ne d b y G S K, w hile t he i n vesti gat or will retai n a c o p y .  
S u bject i nitials will n ot be c ollecte d or tra ns mitte d t o G S K acc or di n g t o G S K p olic y .
9.
S T A TI S TI C A L C O N SI D E R A TI O N S A N D D A T A  
A N A L Y S E S
9. 1.
H y p ot h e s e s
T he pri mar y  o bjecti ves of t his st u d y are t o assess t he p har mac o kinetics of C A B L A i n 
bl o o d plas ma a n d va gi nal, cer vical, a n d rectal tiss ues a n d secreti o ns f oll o wi n g a si n gle 
6 0 0 m g i ntra m usc ular d ose. N o f or mal statistical h y p ot heses are t o be teste d. W here 
a p pr o priate, a n esti mati o n a p pr oac h will be ta ke n, a n d p oi nt es ti mates a n d c o nfi de nce 
i nter vals will be c o nstr ucte d. T here will be n o f or mal c o m paris o n.
9. 2.
S a m pl e Si z e C o n si d er ati o n s
9. 2. 1.
S a m pl e Si z e A s s u m pti o n s
T here was n o f or mal calc ulati o n of p o wer or sa m ple size f or t his st u d y . 
A p pr o xi matel y  2 0 healt h y s u bjects fr o m u p t o t w o cli nic sites will be e nr olle d i n oral 
lea d-i n p hase s uc h t hat a p pr o xi matel y 1 6 e val ua ble s u bjects ( 8 males a n d 8 fe males) will 
recei ve a C A B I M i njecti o n a n d c o m plete 1 2 wee ks of P K sa m pli n g.
Base d u p o n t he p har mac o ki netic data ge nerate d i n pre vi o us p har mac o ki netic tiss ue 
st u dies a n d t he c o m ple xit y a n d i nte nsity of sa m pli n g of plas ma a n d tiss ue i n t his st u d y , 
t he pr o p ose d sa m ple size of 1 6 e val ua ble s u bjects ( 8 w o me n a n d 8 me n) will all o w f or a n 
i nf or mati ve assess me nt a n d descri pti o n of p har mac o ki netic para meters. 
9. 2. 2.
S a m pl e Si z e R e -e sti m ati o n or A dj u st m e nt
N o sa m ple size re -esti mati o n will be perf or me d.
9. 3.
D at a A n al y si s C o n si d er ati o n s
9. 3. 1.
A n al y si s P o p ul ati o n s
S afet y P o p ul ati o n
All s u bjects e nr olle d i n t he st u d y  w h o ha ve recei ve d at least o ne d ose of st u d y dr u g will 
be i ncl u de d i n t he Safet y P o p ulati o n.
P h ar m ac o ki netic C o nce ntr ati o n P o p ul ati o n
T he P K C o nce ntrati o n P o p ulati o n will i ncl u de all s u bjects w h o u n der g o plas ma a n d 
c o m part me ntal P K sa m pli n g a n d ha ve e val ua ble P K assa y  res ults. T his p o p ulati o n will be 
use d f or t he c o nce ntrati o n listi n g.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
6 0
P h ar m ac o ki netic P ar a meter P o p ul ati o n
T he P K Para meter P o p ulati o n will i ncl u de all s u bjects w h o u n der g o plas ma a n d 
c o m part me ntal P K sa m pli n g a n d ha ve e val ua ble C A B P K para meters esti mate d. T his 
p o p ulati o n will be use d f or P K para meter listi n g, pl otti n g of t he c o nce ntrati o n- ti me data 
a n d P K para meter s u m mar y .
9. 3. 2.
I nt eri m An al y si s
T here will be n o f or mal i nteri m a nal ys is; h o we ver preli mi nar y C A B L A P K para meters 
ma y  be ge nerate d a n d re vie we d i nter nally at G S K t o assess t he c urre nt C A B L A batc h 
bei n g use d i n t his st u d y  ( Secti o n 6. 1. 2 ) relati ve t o hist orical data.   
9. 4.
K e y  El e m e nt s of An al y si s Pl a n
P har mac o ki netic a nal ys is will be t he res p o nsi bilit y of t he Cli nical P har mac o ki netics 
M o deli n g & Si m ulati o n De part me nt wit hi n G S K.  All P K data will be st ore d i n t he 
Arc hi ves, G S K P har mace uticals, R & D.
Statistical a nal y ses of t he P K para meter data will be t he res p o nsi bilit y of Cli nical 
Statistics, G S K. 
Data will be liste d a n d s u m marize d acc or di n g t o G S K re p orti n g sta n dar ds, w here 
a p plica ble. Listi n gs will be s orte d b y s u bject, P hase, da y, a n d ti me, n oti n g treat me nt; 
s u m maries will be prese nte d b y treat me nt, ge n der a n d o verall. 
U nless state d ot her wise, descri pti ve s u m maries will i ncl u de n, mea n, sta n dar d de viati o n 
( S D), c oefficie nt of variati o n ( % C V), me dia n, mi ni m u m, a n d ma xi m u m f or safety a n d 
P K para meters, ge o metric mea n wit h ass ociate d 9 5 % c o nfi de nce i nter val ( CI ), a n d t he 
bet wee n -s u bject C V ( % C V b) f or selecte d P K para meters, w hereas n a n d perce nt will be 
use d as s u m mar y  statistics f or cate g orical safety varia bles.
9. 4. 1.
Pri m ar y  An al y s e s
Pri mar y  e n d p oi nts i ncl u de C A B c o nce ntrati o ns i n bl o o d plas ma a n d i n V T, C T, C V F, R T 
a n d R F (as data per mit) i n w o me n a n d R T a n d R F i n me n u p t o Wee k 1 2 .  T hese 
c o nce ntr ati o ns will be deter mi ne d directl y fr o m c o nce ntrati o n -ti me data fr o m eac h 
matri x.  Descri pti ve statistics a n d gra p hics will be create d t o descri be t he pri mar y  P K 
e n d p oi nts of i nterest. 
9. 4. 2.
S e c o n d ar y  An al y s e s
Safet y  data will be prese nte d i n ta b ular a n d/ or grap hical f or mat a n d s u m marize d 
descri pti vel y acc or di n g t o G S K’s I nte grate d Data Sta n dar ds L i brar y (ID S L) sta n dar ds.
Plas ma a n d tiss ue /fl ui d c o nce ntrati o n -ti me data will be a nal yze d b y n o n-c o m part me ntal 
met h o ds wit h Wi n N o nli n 5. 2 or hi g her ( P harsi g ht, I nc., C ar y, N C ).  P har mac o ki netic 
para meters will be esti mate d via n o nc o m part me ntal a nal ys is usi n g t he li near u p/l o g d o w n 
a p plicati o n of t he tra pez oi dal r ule f or m o del 2 0 0 (e xtra vasc ular a d mi nistrati o n) of t he 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
6 1
Wi n N o nli n pr o gra m.   Calc ulati o ns will be base d o n t h e act ual sa m pli n g ti mes rec or de d 
d uri n g t he st u d y. T he f oll o wi n g P K para meters will be calc ulate d if a vaila ble:

C V F: B P, C T: B P, V T: B P, C T: C V F, V T: C V F r ati o i n w o m e n a n d, R T: B P, a n d R T: R F r ati os i n m al es a n d 
f e m al es at m atc hi n g ti m e p oi nts w h er e d at a p er mit d uri n g t h e i nj ecti o n p h as e. 

C m ax,t m ax, A U C( 0 -), A U C( 0-l ast), A U C( 0-Wk 4), A U C( 0 -Wk 8) a n d A U C( 0 -Wk 1 2) a n d t ½ i n bl o o d 
pl as m a a n d i n C T, a n d C V F i n f e m al es a n d  R T a n d R F i n m al es a n d f e m al es.  

R ati os of ti m e -m atc h e d A U Cs  tiss u e m atric es/l u mi n al fl ui d: bl o o d pl as m a w h er e d at a p er mit.  

C A B c o nc e ntr ati o n i n V T, C T, C V F, R T, R F a n d B P o n D ay 2 9 of t h e or al l e a d -i n p h as e pri or t o I M 
i nj ecti o n
Rati os will be calc ulate d f or eac h s u bject. E val ua ble P K para meters a n d calc ulate d rati os 
will be s u m marize d b y  gen der a n d/ or o verall f or eac h matri x. A se x -base d c o m paris o n 
will be ma de f or all t he e val ua ble bl o o d plas ma P K para meters a n d esti mate d rati o 
bet wee n fe males vs males a n d its ass ociate d 9 0 % CI  will be pr o vi de d. C o variates of B MI 
a n d ot her fact ors ma y als o be c o nsi dere d i n t he m o del f or t he bl o o d plas ma P K para meter 
c o m paris o n. C A B c o nce ntrati o n i n eac h matri x fr o m t he oral lea d- i n p hase ma y be 
c o m pare d wit h Wee ks 4, 8, a n d 1 2 c o nce ntrati o ns if data per mit. T he relati o ns hi p 
bet wee n t he plas ma C A B P K c o nce ntr ati o n wit h ti me matc he d C V F, C T, V T, R T a n d/ or 
R F will be assesse d wit h pl ots a n d b y  t he S A S Pr oc C orr pr oce d ure.  
1 0.
S T U D Y G O V E R N A N C E C O N SI D E R A TI O N S
1 0. 1.
P o sti n g of I nf or m ati o n o n P u bli cl y  Av ail a bl e Cli ni c al Tri al 
R e gi st er s
St u d y  i nf or mati o n fr o m t his pr ot oc ol will be p oste d o n p u blicl y a vaila ble cli nical trial 
re gisters bef ore e nr oll me nt of s u bjects be gi ns.
1 0. 2.
R e g ul at or y  a n d Et hi c al C o n si d er ati o n s, I n cl u di n g t h e 
I nf or m e d C o n s e nt Pr o c e s s
T he st u d y  will be c o n d ucte d i n acc or da nce wit h all a p plica ble re g ulat or y re q uire me nts, 
a n d wit h Vii V/ G S K p olic y .
T he st u d y  will als o be c o n d ucte d i n acc or da nce wit h IC H G o o d Cli nical Practice ( G C P), 
all a p plica ble s u bject pri vac y  re q uire me nts, a n d t he g ui di n g pri nci ples of t he c urre nt 
versi o n of t he Declarati o n of Helsi n ki.  T his i nc l u des, b ut is n ot li mite d t o, t he f oll o wi n g:

I RB/I E C re vie w a n d fa v ora ble o pi ni o n/a p pr o val of t he st u d y  pr ot oc ol a n d 
a me n d me nts as a p plica ble

Si g ne d i nf or me d c o nse nt t o be o btai ne d f or eac h s u bject bef ore partici pati o n i n t he 
st u d y (a n d f or a me n d me nts as ap plica ble)

I n vesti gat or re p orti n g re q uire me nts (e. g. re p orti n g of A Es/ S A Es/ pr ot oc ol de viati o ns 
t o IR B/I E C)

Vii V/ G S K will pr o vi de f ull details of t he a b o ve pr oce d ures, eit her ver ball y,  i n 
writi n g, or b ot h.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
6 2

T he I E C/I R B, a n d w here a p plica ble t he re g ulat or y a u t h orit y, a p pr o ve t he cli nical 
pr ot oc ol a n d all o pti o nal assess me nts, i ncl u di n g ge netic researc h.  

O pti o nal assess me nts (i ncl u di n g t h ose i n a se parate pr ot oc ol a n d/ or u n der se parate 
i nf or me d c o nse nt) a n d t he cli nical pr ot oc ol s h o ul d be c o nc urre ntly s u b mitte d f or 
a p pr o val u nless re g ulati o n re q uires se parate s u b missi o n.  

A p pr o val of t he o pti o nal assess me nts ma y  occ ur after a p pr o val is gra nte d f or t he 
cli nical pr ot oc ol w here re q uire d b y re g ulat or y  a ut h orities.  In t his sit uati o n, writte n 
a p pr o val of t he cli ni cal pr ot oc ol s h o ul d state t hat a p pr o val of o pti o nal assess me nts is 
bei n g deferre d a n d t he st u d y , wit h t he e xce pti o n of t he o pti o nal assess me nts, ca n be 
i nitiate d.
1 0. 3.
Q u alit y C o ntr ol ( St u d y  M o nit ori n g)

I n acc or da nce wit h a p plica ble re g ulati o ns i ncl u di n g G C P a nd Vii V/ G S K pr oce d ures, 
G S K m o nit ors will c o ntact t he site pri or t o t he start of t he st u d y  t o re vie w wit h t he 
site staff t he pr ot oc ol, st u d y re q uire me nts, a n d t heir res p o nsi bilities t o satisf y 
re g ulat or y, et hical, a n d G S K re q uire me nts.  

W he n re vie wi n g data
c ollecti o n pr oce d ures, t he disc ussi o n will als o i ncl u de 
i de ntificati o n, a gree me nt a n d d oc u me ntati o n of data ite ms f or w hic h t he C R F will 
ser ve as t he s o urce d oc u me nt.
G S K will m o nit or t he st u d y  a n d site acti vit y t o verif y t hat t he:

Data are a ut he ntic, acc urate, a n d c o m plete.

Safet y  a n d ri g hts of s u bjects are bei n g pr otecte d.

St u d y  is c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her 
st u d y a gree me nts, G C P, a n d all a p plica ble re g ulat or y re q uire me nts.
T he i n vesti gat or a n d t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) a grees t o 
all o w t he m o nit or direct access t o all rele va nt d oc u me nts
1 0. 4.
Q u alit y A s s ur a n c e

T o e ns ure c o m plia nce wit h G C P a n d all a p plica ble re g ulat or y  re q uire me nts, 
Vii V/ G S K ma y  c o n d uct a q ualit y ass ura nce assess me nt an d/ or a u dit of t he site 
rec or ds, a n d t he re g ulat or y a ge ncies ma y c o n d uct a re g ulat or y i ns pecti o n at a n y ti me 
d uri n g or after c o m pleti o n of t he st u d y . 

I n t he e ve nt of a n assess me nt, a u dit or i ns pecti o n, t he i n vesti gat or (a n d i nstit uti o n) 
m ust a gree t o gra n t t he a d vis or(s), a u dit or(s) a n d i ns pect or(s) direct access t o all 
rele va nt d oc u me nts a n d t o all ocate t heir ti me a n d t he ti me of t heir staff t o disc uss t he 
c o n d uct of t he st u d y, a n y fi n di n gs/rele va nt iss ues a n d t o i m ple me nt a n y  c orrecti ve 
a n d/ or pre ve ntati ve acti o ns t o a d dress a n y fi n di n gs/iss ues i de ntifie d.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
6 3
1 0. 5.
St u d y a n d Sit e Cl o s ur e

U p o n c o m pleti o n or pre mat ure disc o nti n uati o n of t he st u d y , t he G S K m o nit or will 
c o n d uct site cl os ure acti vities wit h t he i n vesti gat or or site staff, as a p pr o priate, i n 
acc or da nce wit h a p plica ble re g ulati o ns i ncl u di n g G C P, a n d Vii V/ G S K Sta n dar d 
O perati n g Pr oce d ures.

Vii V reser ves t he ri g ht t o te m p orarily s us pe n d or pre mat urel y disc o nti n ue t his st u d y  
at a n y ti me f or reas o ns i ncl u di n g, b ut n ot li mite d t o, safet y or et hical iss ues or s e vere 
n o n- c o m plia nce. F or m ultice nter st u dies, t his ca n occ ur at o ne or m ore or at all sites.  

If Vii V deter mi nes s uc h acti o n is nee de d, Vii V will disc uss t he reas o ns f or ta ki n g 
s uc h acti o n wit h t he i n vesti gat or or t he hea d of t he me dical i nstit uti o n ( w here 
a p plica ble).  W he n feasi ble, Vii V will pr o vi de a d va nce n otificati o n t o t he 
i n vesti gat or or t he hea d of t he me dical i nstit uti o n, w here a p plica ble, of t he 
i m pe n di n g acti o n.

If t he st u d y is s us pe n de d or pre mat urel y disc o nti n ue d f or safety reas o ns, Vii V wil l 
pr o m ptl y  i nf or m all i n vesti gat ors, hea ds of t he me dical i nstit uti o ns ( w here 
a p plica ble) a n d/ or i nstit uti o n(s) c o n d ucti n g t he st u d y . Vii V will als o pr o m ptl y  
i nf or m t he rele va nt re g ulat or y a ut h orities of t he s us pe nsi o n or pre mat ure 
disc o nti n uati o n of t he s t u d y a n d t he reas o n(s) f or t he acti o n.  

If re q uire d by a p plica ble re g ulati o ns, t he i n vesti gat or or t he hea d of t he me dical 
i nstit uti o n ( w here a p plica ble) m ust i nf or m t he IR B/I E C pr o m ptl y a n d pr o vi de t he 
reas o n f or t he s us pe nsi o n or pre mat ure disc o nti n uati o n.
1 0. 6.
R e c or d s R et e nti o n

F oll o wi n g cl os ure of t he st u d y, t he i n vesti gat or or t he hea d of t he me dical i nstit uti o n 
( w here a p plica ble) m ust mai ntai n all site st u d y rec or ds (e xce pt f or t h ose re q uire d b y 
l ocal re g ulati o ns t o be mai ntai ne d else w here), i n a safe a n d sec ure l ocati o n.  

T he rec or ds m ust be mai ntai ne d t o all o w eas y a n d ti mel y  retrie val, w he n nee de d 
(e. g., f or a Vii V/ G S K a u dit or re g ulat or y  i ns pecti o n) a n d m ust be a vaila ble f or 
re vie w i n c o nj u ncti o n wit h assess me nt of t he facilit y, s u p p orti n g sys te ms, a nd 
rele va nt site staff.  

W here per mitte d b y l ocal la ws/re g ulati o ns or i nstit uti o nal p olic y, s o me or all of t hese 
rec or ds ca n be mai ntai ne d i n a f or mat ot her t ha n har d c o py (e. g., micr ofic he, 
sca n ne d, electr o nic); h o we ver, ca uti o n nee ds t o be e xercise d bef ore s uc h acti o n is 
ta ke n.  

T he i n vesti gat or m ust e ns ure t hat all re pr o d ucti o ns are le gi ble a n d are a tr ue a n d 
acc urate c o p y of t he ori gi nal a n d meet accessi bilit y a n d retrie val sta n dar ds, i ncl u di n g 
re-ge nerati n g a har d c o p y, if re q uire d.  F urt her m ore, t he i n vesti gat or m ust e ns ure 
t here is a n acce pta ble bac k-u p of t hese re pr o d ucti o ns a n d t hat a n acce pta ble q ualit y  
c o ntr ol pr ocess e xists f or ma ki n g t hese re pr o d ucti o ns.

Vii V/ G S K will i nf or m t he i n vesti gat or of t he ti me peri o d f or retai ni n g t hese rec or ds 
t o c o mpl y  wit h all a p plica ble re g ulat or y re q uire me nts.  T he mi ni m u m rete nti o n ti me 
will meet t he strictest sta n dar d a p plica ble t o t hat site f or t he st u d y, as dictate d b y a n y 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
6 4
i nstit uti o nal re q uire me nts or l ocal la ws or re g ulati o ns, Vii V/ G S K 
sta n dar ds/ pr oce d ures, a n d/ or i nstit uti o nal re q uire me nts.  

T he i n vesti gat or m ust n otif y  Vii V/ G S K of a n y c ha n ges i n t he arc hi val arra n ge me nts, 
i ncl u di n g, b ut n ot li mite d t o, arc hi val at a n off-site facilit y or tra nsfer of o w ners hi p 
of t he rec or ds i n t he e ve nt t he i n vesti gat or is n o l o n ger ass ociate d wit h t he site.
1 0. 7.
Pr o vi si o n of St u d y  R e s ult s t o I n v e sti g at or s, P o sti n g of 
I nf or m ati o n o n P u bli c all y Av ail a bl e Cli ni c al Tri al s R e gi st er s 
a n d P u bli c ati o n
W here re q uire d b y a p plica ble re g ulat or y  re q uire me nts, a n i n vesti gat or si g nat or y will be 
i de ntifie d f or t he a p pr o val of t he cli nical st u d y re p ort.  T he i n vesti gat or will be pr o vi de d 
reas o na ble access t o statistical ta bles, fi g ures, a n d rele va nt re p orts a n d will ha ve t he 
o p p ort u nit y  t o re vie w t he c o m plete st u d y res ults at a G S K site or ot her m ut uall y -
a greea ble l ocati o n.
G S K will als o pr o vi de t he i n vesti gat or wit h t he f ull s u m mar y  of t he st u dy res ults.  T he 
i n vesti gat or is e nc o ura ge d t o s hare t he s u m mar y res ults wit h t he st u d y s u bjects, as 
a p pr o priate.
T he pr oce d ures a n d ti mi n g f or p u blic disc l os ure of t he res ults s u m mar y a n d f or 
de vel o p me nt of a ma n uscri pt f or p u blicati o n will be i n acc or da nce wit h G S K P olic y .

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
6 5
1 1.
R E F E R E N C E S
A n dre ws C D, S pree n W R, M o hri H, et al. L o n g -acti n g i nte grase i n hi bit or pr otects 
maca q ues fr o m i ntrarectal si mia n/ h u ma n i m m u n o deficie nc y vir us. Scie nce. 
2 0 1 4; 3 4 3: 1 1 5 1 - 4. 
D AI D S D oc u me nt I D 1 1 9 6 4 St u d y  ID H P T N 0 7 7. A P hase IIa St u d y  t o E val uate t he 
Safet y , T olera bility a n d P har mac o ki netics of t he I n vesti gati o nal I njecta ble HI V I nte grase 
I n hi bit or, G S K 1 2 6 5 7 4 4, i n HI V- u ni nfecte d Men a n d W o me n. Re p ort Date 0 1 -M A Y -
2 0 1 4. 
Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 3 N 1 5 9 6 0 5 _ 0 0 St u d y  ID L AI 1 1 4 4 3 3. A n 
O bser ver - a n d S u bject -Bli n de d, Ra n d o mize d, Place b o - C o ntr olle d, Si n gle D ose 
Escalati o n St u d y  t o I n vesti gate t he Safety, T olera bilit y  a n d P har mac o ki netics of 
I ntra m usc ular a n d S u bc uta ne o us L o n g Acti n g G S K 1 2 6 5 7 4 4 i n Healt h y S u bjects. Re p ort 
Date 2 1 -A U G - 2 0 1 3. 
Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 3 N 1 8 4 0 4 8 _ 0 1 St u d y  ID 2 0 1 1 2 0. A P hase IIa 
St u d y  t o E val uate t he Safet y, T olera bilit y a n d Acce pta bilit y of L o n g Acti n g Injecti o ns of 
t he HI V I nte grase I n hi bit or, G S K 1 2 6 5 7 4 4, i n HI V U ni nfecte d Me n ( É C L AI R). Re p ort 
Date 1 2 -M A R - 2 0 1 4. 
Hatc her R A, Tr ussell J, Nels o n A L, Cates W Jr, Ste wart F, K o wal D, e dit ors. 
C o ntrace pti ve Tec h n ol o g y . 1 9t h e diti o n. Ne w Y or k: Ar de nt Me dia, 2 0 0 7(a): 2 4. Ta ble 3 -
2.
Hatc her R A, Tr ussell J, Nels o n A L, Cates W Jr, Ste wart F, K o wal D, e dit ors. 
C o ntrace pti ve Tec h n ol o g y . 1 9t h e diti o n. Ne w Y or k: Ar de nt Me dia, 2 0 0 7( b): 2 8.
J oi nt U nite d Nati o ns Pr o gra m me o n HI V/ AI D S ( U N AI D S). Gl o bal re p ort: U N AI D S 
re p ort o n t he gl o bal AI D S e pi de mic 2 0 1 3. Accesse d: 0 1 O C T 2 0 1 4.  A vaila ble at: 
htt p:// w w w. u nai ds. or g/e n/ me dia/ u nai ds/c o nte ntassets/ d oc u me nts/e pi de mi ol o g y / 2 0 1 3/ gr 2
0 1 3/ U N AI D S _ Gl o bal _ Re p ort _ 2 0 1 3 _e n. p df .  
Mar g olis D, et al. 7 4 4 a n d Ril pi viri ne as T w o- Dr u g Oral Mai nte na nce T hera p y : 
L A I 1 1 6 4 8 2 ( L A T T E) Wee k 4 8 Res ults. C o nfere nce o n Retr ovir uses a n d O p p ort u nistic 
I nfecti o ns, Marc h 3 - 6 2 0 1 4; B ost o n, M A: Oral a bstract 9 1 L B.
Ra dzi o J, S pree n W, Y ue h Y L , et al. T he l o n g-acti n g i nte grase i n hi bit or G S K 7 4 4 pr otects 
maca q ue s fr o m re peate d i ntra va gi nal S HI V c halle n ge. Sci Tr a nsl Me d. 2 0 1 5; 7: 2 7 0ra 5. 
d oi: 1 0. 1 1 2 6/scitra nsl me d. 3 0 1 0 2 9 7. 
S pree n W, F or d S L, C he n S, Wilfret D, Mar g olis D, G o ul d E, Piscitelli S. G S K 1 2 6 5 7 4 4 
p har mac o ki netics i n plas ma a n d tiss ue after si n gle -d ose l o n g -acti n g i njecta ble 
a d mi nistrati o n i n healt h y s u bjects. J Ac q uir I m m u ne Defic Sy n dr. 2 0 1 4; 1 5: 4 8 1 - 6. 
S pree n W, Mi n S, F or d S L, et al. P har mac o ki netics, safet y, a n d m o n ot hera p y a nti viral 
acti vit y of G S K 1 2 6 5 7 4 4, a n HI V i nte grase stra n d tra nsfer i n hi bit or. HI V Cli n Tri als. 
2 0 1 3; 1 4: 1 9 2 - 2 0 3. 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
6 6
S pree n W, Willia ms P, Mar g olis D, F or d S L, Cra u wels H, L o u Y, G o ul d E, Ste ve ns M, 
Piscitelli S. P har mac o ki netics, safet y, a n d t olera bilit y wit h re peat d oses of G S K 1 2 6 5 7 4 4 
a n d ril pi viri ne ( T M C 2 7 8) l o n g-acti n g na n os us pe nsi o ns i n healt h y a d ults. J Ac q uir 
I m m u ne Defic Sy n dr. 2 0 1 4; 6 7: 4 8 7 - 4 9 2.
U. S. De part me nt of Healt h a n d H u ma n Ser vices, Nati o nal I nstit utes of Healt h, Nati o nal 
I nstit ute of Aller g y a n d I nfecti o us Diseases, Di visi o n of AI D S. Di visi o n of AI D S 
( D AI D S) Ta ble f or Gra din g t he Se verit y  of A d ult a n d Pe diatric A d verse E ve nts, Versi o n 
2. 0. [ N o ve m ber 2 0 1 4].

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
6 7
1 2.
A P P E N DI C E S
1 2. 1.
A p p e n di x 1: A b br e vi ati o n s a n d Tr a d e m ar k s
A b br e v i ati o n s
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase ( S G P T)
A S T
as partate a mi n otra nsferase ( S G O T)
A U C( 0 -last)
Area u n der t he c o nce ntrati o n ti me c ur ve fr o m ti me zer o t o 
last q ua ntifia ble ti me p oi nt 
A U C( 0 -)
Area u n der t he 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 C( 0 -W k 4)
Area u n der t he c o nce ntrati o n ti me c ur ve fr o m ti me zer o t o 
Wee k 4
A U C( 0 -W k 8)
Area u n der t he c o nce ntrati o n ti me c ur ve fr o m ti me zer o t o 
Wee k 8
A U C( 0 -W k 1 2)
Area u n der t he c o nce ntrati o n ti me c ur ve fr o m ti me zer o t o 
Wee k 1 2
C 
Stea d y -state pre- d ose C A B c o nce ntrati o n 
C M P
c o m plete meta b olic pa nel
C P A L
Cli nical P har mac ol o g y  A nal ytical La b orat or y  (J H U)
C P K
Creati ne p h os p h o ki nase
C T
cer vical tiss ue
C V F
cer vic o va gi nal fl ui d
C 4 8 h
C o nce ntrati o ns o bser ve d at Da y  3 ( 4 8 h)
C d 8
C o nce ntrati o n o bser ve d o n Da y  8
C W k 4
C o nce ntrati o n o bser ve d at Wee k 4 
C W k 8
C o nce ntrati o n o bser ve d at Wee k 8
C W k 1 2
C o nce ntrati o n o bser ve d at Wee k 1 2
D Bili
direct bilir u bi n
F R P
fe males of re pr o d ucti ve p ote ntial
G S K
Gla x o S mit h Kli ne
H D P E
hi g h de nsit y p ol yet h yl e ne
HI V
h u ma n i m m u n o deficie nc y vir us
I C9 0
9 0 % ma xi mal i n hi bit or y c o nce ntrati o n
I E C
i n de pe n de nt et hics co m mittee
I M
i ntra m usc ular(ly)
I N R
i nter nati o nal n or malize d rati o
I N S TI
I nte grase stra n d tra nsfer i n hi bit or
I P
i n vesti gati o nal pr o d uct

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
6 8
I RB
i nstit uti o nal re vie w b oar d
I S R
i njecti o n site reacti o n
J H U
J o h ns H o p ki ns U ni versit y
L A
l o n g-acti n g
M C H
mea n c or p usc ular he m o gl o bi n
M C H C
mea n c or p usc ular he m o gl o bi n c o nce ntrati o n
M C V
mea n c or p usc ular v ol u me
M RI
ma g netic res o na nce i ma gi n g
N H P
n o n -h u ma n pri mate
P K
p har mac o ki netic(s)
Pr E P
Pre -e x p os ure pr o p h yl a xis
P T
pr ot hr o m bi n ti me
P T T
partial t hr o m b o plasti n ti me
R B C
re d bl o o d cell
R F
rectal fl ui d
R N A
ri b o n ucleic aci d
R T
rectal tiss ue
S HI V
si mia n/ h u ma n i m m u n o deficie nc y vir us
S R M
S t u d y refere nce m a n ual
S O P
sta n dar d o perati n g pr oce d ure
t ½
a p pare nt ter mi nal p hase half -life 
T Bili
t otal bilir u bi n
V T
va g i nal tiss ue
W B C
w hite bl o o d cell
Tr a d e m ar k I nf or m ati o n
Tr a d e m ar k s of Vii V H e alt h c ar e
Tr a d e m ar k s n ot o w n e d b y Vii V 
H e alt h c ar e
N O N E
Pare xel
S A S
Wi n N o nli n

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
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6 9
1 2. 2.
A p p e n di x 2: Li v er S af et y  R e q uir e d Acti o n s a n d F oll o w u p 
A s s e s s m e nt s
Li v er C h e mi str y St o p pi n g Crit eri a – Li v er St o p pi n g E v e nt
A L T -a b s ol ut e
A L T ≥3x U L N
If A L T≥3 x U L N A N D bilir u bi n 1, 2 2x U L N ( > 3 5 % dir ect bilir u bi n) or  I N R > 1. 5, 
R e p ort as a n S A E.
S e e a d diti o n al Acti o ns a n d F oll o w U p Ass ess m e nts list e d b el o w
R e q uir e d A cti o n s a n d F oll o w u p A s s e s s m e nt s f oll o wi n g Li v er St o p pi n g E v e nt
A cti o n s
F oll o w U p A s s e s s m e nt s

I m m e di at el y disc o nti n u e st u dy tr e at m e nt 

R e p ort t h e ev e nt t o G S K wit hi n 2 4 h o ur s

C o m pl et e t h e liv er ev e nt C R F, a n d c o m pl et e 
a n S A E d at a c oll ecti o n t o ol if t h e ev e nt als o 
m e ets t h e crit eri a f or a n S A E2

P erf or m liv er ev e nt f oll o w u p ass ess m e nts 

M o nit or t h e s u bj ect u ntil liv er c h e mistri es 
r es olv e, st a biliz e, or r et ur n t o wit hi n b as eli n e 
(s e e M O NI T O RI N G b el o w)
M O NI T O RI N G:
If A L T≥3 x U L N A N D bilir u bi n 2 x U L N or I N R 
> 1. 5

R e p e at liv er c h e mistri es (i ncl u d e A L T, A S T, 
alk ali n e p h os p h at as e, bilir u bi n) a n d p erf or m 
liv er ev e nt f oll o w u p ass ess m e nts wit hi n 2 4 
hr s

M o nit or s u bj ects t wic e w e ekly u ntil liv er 
c h e mistri es r es olv e, st a biliz e or r et ur n t o 
wit hi n b as eli n e

A s p eci alist or h e p at ol o gy c o ns ult ati o n is 
r ec o m m e n d e d
If A L T≥3 x U L N A N D bilir u bi n < 2 x U L N a n d I N R 
≤1. 5:

R e p e at liv er c h e mistri es (i ncl u d e A L T, A S T, 
alk ali n e p h os p h at as e, bilir u bi n) a n d p erf or m 
liv er ev e nt f oll o w u p ass ess m e ntswit hi n 2 4 -
7 2 hr s

Vir al h e p atitis s er ol o gy 3

Bl o o d s a m pl e f or p h ar m ac oki n etic ( P K) 
a n alysis

S er u m cr e ati n e p h os p h oki n as e ( C P K) a n d 
l act at e d e hy dr o g e n as e ( L D H).

F r acti o n at e bilir u bi n, if t ot al 
bilir u bi n 2x U L N

O bt ai n c o m pl et e bl o o d c o u nt wit h 
diff er e nti al t o ass ess e osi n o p hili a

R ec or d t h e a p p e ar a nc e or w ors e ni n g of 
cli nic al sy m pt o ms of liv er i nj ury, or 
hy p ers e nsitivity, o n t h e A E r e p ort f or m

R ec or d us e of c o nc o mit a n t m e dic ati o ns o n 
t h e c o nc o mit a nt m e dic ati o ns r e p ort f or m 
i ncl u di n g ac et a mi n o p h e n, h er b al r e m e di es, 
ot h er ov er t h e c o u nt er m e dic ati o ns.

R ec or d alc o h ol us e o n t h e liv er ev e nt 
alc o h ol i nt ak e c as e r e p ort f or m
If A L T≥3 x U L N A N D bilir u bi n 2 x U L N or I N R 
> 1. 5 :

A nt i-n ucl e ar a nti b o dy, a nti -s m o ot h m uscl e 
a nti b o dy, Ty p e 1 a nti -liv er ki d n ey 
micr os o m al a nti b o di es, a n d q u a ntit ativ e 
t ot al i m m u n o gl o b uli n G (I g G or g a m m a 
gl o b uli ns).

S er u m ac et a mi n o p h e n a d d uct H P L C ass ay 
( q u a ntifi es p ot e nti al ac et a mi n o p h e n 
c o ntri b uti o n t o liver i nj ury i n s u bj ects wit h 

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Li v er C h e mi str y St o p pi n g Crit eri a – Li v er St o p pi n g E v e nt

M o nit or s u bj ects w e ekly u ntil liv er 
c h e mistri es r es olv e, st a biliz e or r et ur n t o 
wit hi n b as eli n e
d efi nit e or lik ely ac et a mi n o p h e n us e i n t h e 
pr ec e di n g w e ek [ J a m es, 2 0 0 9]. 

R ef err al f or t h e a p pr o pri at e c ar e, i ncl u di n g 
Liv er i m a gi n g ( ultr as o u n d, m a g n etic 
r es o n a nc e, or c o m p ut eris e d t o m o gr a phy) 
liv er bi o psy; c o m pl et e Liv er I m a gi n g 
a n d/ or Liv er Bi o psy C R F f or ms.
P hase I Li ver c he mistr y  st o p pi n g criteria ha ve bee n desi g ne d t o ass ure s u bject safet y a n d 
t o e val uate li ver e ve nt eti ol o g y (i n ali g n me nt wit h t he F D A pre mar keti n g cli nical li ver 
safet y g ui da nce).  
htt p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui d
a nces/ U C M 1 7 4 0 9 0. p df.
P h ase I li ver c he mistr y st o p pi n g criteri a a n d re q uire d f oll o w u p assess me nts
1.
S er u m bilir u bi n fr acti o n ati o n s h o ul d b e p erf or m e d if t esti n g is av ail a bl e. If s er u m bilir u bi n fr acti o n ati o n is n ot 
i m m e di at ely av ail a bl e, disc o nti n u e st u dy tr e at m e nt f or t h at s u bj ect if A L T 3x U L N a n d bilir u bi n 2x U L N. 
A d diti o n ally, if s er u m bilir u bi n fr acti o n ati o n t esti n g is u n av ail a bl e, r e c or d pr e s e n c e of d et e ct a bl e uri n ar y 
bilir u bi n o n di p sti c k , i n dic ati n g dir ect bilir u bi n el ev ati o ns a n d s u g g esti n g liv er i nj ury. 
2.
All ev e nts of A L T 3x U L N a n d bilir u bi n 2x U L N ( > 3 5 % dir ect bilir u bi n) or A L T 3x U L N a n d I N R > 1. 5, if I N R 
m e as ur e d, w hic h m ay i n dic at e s ev er e liv er i nj u ry ( p ossi bl e ‘ Hy’s L a w’), m u st b e r e p ort e d a s a n S A E ( e x cl u di n g 
st u di e s of h e p ati c i m p air m e nt or cirr h o si s) ; I N R m e as ur e m e nt is n ot r e q uir e d a n d t h e t hr es h ol d v al u e st at e d 
will n ot a p ply t o s u bj ects r ec eivi n g a ntic o a g ul a nts
3.
I ncl u d es: H e p atitis A I g M a nti b ody; H e p atitis B s urf ac e a nti g e n a n d H e p atitis B C or e A nti b o dy (I g M); H e p atitis C 
R N A; Cyt o m e g al ovir us I g M a nti b o dy; E pst ei n -B arr vir al c a psi d a nti g e n I g M a nti b o dy ( or if u n av ail a bl e, o bt ai n 
h et er o p hil e a nti b o dy or m o n os p ot t esti n g);  H e p atitis E I g M a nti b o dy 
4.
P K s a m pl e m ay n ot b e r e q uir e d f or s u bj ects k n o w n t o b e r ec eivi n g pl ac e b o or n o n -G S K c o m p ar at or tr e at m e nts.  
R ec or d t h e d at e/ti m e of t h e P K bl o o d s a m pl e dr a w a n d t h e d at e/ti m e of t h e l ast d os e of st u dy tr e at m e nt pri or t o 
bl o o d s a m pl e dr a w o n t h e C R F. If t h e d at e or ti m e of t h e l ast d os e is u ncl e ar, pr ovi d e t h e s u bj ect’s b est 
a p pr oxi m ati o n. If t h e d at e/ti m e of t h e l ast d os e c a n n ot b e a p pr oxi m at e d O R a P K s a m pl e c a n n ot b e c oll ect e d i n 
t h e ti m e p eri o d i n dic at e d a b ov e, d o n ot o bt ai n a P K s a m pl e. I nstr ucti o ns f or s a m pl e h a n dli n g a n d s hi p pi n g ar e i n 
t h e S R M
Refere nces
Ja mes LP, Letzi g L, Si m ps o n P M, Ca p parelli E, R o berts D W, Hi ns o n J A, Da ver n TJ, Lee 
W M. P har mac o ki netics of Aceta mi n o p he n - A d d uct i n A d ults wit h Aceta mi n o p he n 
O ver d ose a n d Ac ute Li ver Fail ure. Dr u g Meta b Dis p os 2 0 0 9; 3 7: 1 7 7 9 - 1 7 8 4.

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1 2. 3.
A p p e n di x 3: D efi niti o n of a n d Pr o c e d ur e s f or R e c or di n g, 
E v al u ati n g, F oll o w -U p a n d R e p orti n g of A d v er s e E v e nt s
1 2. 3. 1.
D efi niti o n of A d v er s e E v e nt s
A d verse E ve nt Defi niti o n:

A n A E is a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
s u bject, te m p orally ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot 
c o nsi dere d relate d t o t he me dici nal pr o d uct.

N O T E: 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 din g), s y m pt o m, or disease ( ne w or e xacer bate d) te m p orall y  
ass ociate d wit h t he use of a me dici nal pr o d uct.
E ve nts meeti n g A E defi niti o n i ncl u de:

A n y  a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) 
or ot her safet y assess me n ts (e. g., E C Gs, ra di ol o gical sca ns, vital si g ns 
meas ure me nts), i ncl u di n g t h ose t hat w orse n fr o m baseli ne, a n d felt t o be cli nicall y  
si g nifica nt i n t he me dical a n d scie ntific j u d ge me nt of t he i n vesti gat or.

E xacer bati o n of a c hr o nic or i nter mitte nt pre- e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncrease i n fre q ue nc y a n d/ or i nte nsit y of t he c o n diti o n.

Ne w c o n diti o ns detecte d or dia g n ose d after st u d y treat me nt a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve bee n prese nt pri or t o t he start of t he st u d y.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d i nteracti o n.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y  
treat me nt or a c o nc o mita nt me dicati o n ( o ver d ose per se will n ot be re p orte d as a n 
A E/ S A E u nless t his is a n i nte nti o nal o ver d o se ta ke n wit h p ossi ble s uici dal/self-
har mi n g i nte nt.  T his s h o ul d be re p orte d re gar dless of se q uelae).

T he si g ns a n d s y m pt o ms a n d/ or cli nical se q uelae res ulti n g fr o m lac k of efficac y  will 
be re p orte d if t he y  f ulfill t he defi niti o n of a n A E or S A E.  Als o, "lac k of efficac y" or 
"fail ure of e x pecte d p har mac ol o gical acti o n" als o c o nstit utes a n A E or S A E.
E ve nts N O T meeti n g defi niti o n of a n A E i ncl u de:

A n y  cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs or ot her a b n or mal safety 
assess me nts w hic h are ass oc iate d wit h t he u n derlyi n g disease, u nless j u d ge d b y  t he 
i n vesti gat or t o be m ore se vere t ha n e x pecte d f or t he s u bject’s c o n diti o n.

T he disease/ dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o ms of 
t he disease/ dis or der bei n g st u die d, u nless more se vere t ha n e x pecte d f or t he s u bject’s 
c o n diti o n.

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
Me dical or s ur gical pr oce d ure (e. g., e n d osc o p y, a p pe n dect o m y): t he c o n diti o n t hat 
lea ds t o t he pr oce d ure is a n A E.

Sit uati o ns w here a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nc e a d missi o n t o a h os pital).

A ntici pate d da y -t o-d a y  fl uct uati o ns of pre-e xisti n g disease(s) or c o n diti o n(s) prese nt 
or detecte d at t he start of t he st u d y t hat d o n ot w orse n.
1 2. 3. 2.
D efi niti o n of S eri o u s A d v er s e E v e nt s
If a n e ve nt is n ot a n A E per defi niti o n a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us 
c o n diti o ns are met (e. g., h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n der st u d y , 
deat h d ue t o pr o gressi o n of disease, etc).
Seri o us A d verse E ve nt ( S A E) is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, 
at a n y d ose:
a.
Res ults i n de at h
b.
Is life-t hre ate ni n g
N O T E:
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 were m ore se vere.
c.
Re q uires h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n
N O T E:

I n ge neral, h os pitalizati o n si g nifies t hat t he s u bject has bee n detai ne d ( us uall y 
i n v ol vi n g at least a n o ver ni g ht sta y) at t he h ospital or e mer ge nc y  war d f or 
o bser vati o n a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h y sicia n’s 
office or o ut -patie nt setti n g.  C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are 
A Es.  If a c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfill s a n y ot her seri o us criteria, 
t he e ve nt is seri o us.  W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was 
necessar y , t he A E s h o ul d be c o nsi dere d seri o us.

H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n 
fr o m baseli ne is n ot c o nsi dere d a n A E.
d.
Res ults i n dis a bilit y/i nc a p acit y
N O T E:

T he ter m disa bilit y mea ns a s u bsta ntial 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.

T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or m e dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, 

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a n d acci de ntal tra u ma (e. g. s prai ne d a n kle) w hic h ma y  i nterfere or pre ve nt e ver yd a y  
life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n
e.
Is a c o n ge nit al a no m al y/ birt h defect
f.
Ot her sit u ati o ns:

Me dical or 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 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 hos pitalizati o n b ut ma y  je o par dize 
t he s u bject or ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
ot her o utc o mes liste d i n t he a b o ve defi niti o n.  T hese s h o ul d als o be c o nsi dere d 
seri o us.

E xa m ples of s uc h e ve nts are i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt i n a n 
e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g de pe n de nc y  
or dr u g a b use
g.
Is ass oci ate d wit h li ver i nj ur y a n d i m p aire d li ver f u ncti o n defi ne d as:

A L T 3 x U L N a n d t otal bilir u bi n * 2 x U L N ( > 3 5 % direct), o r

A L T 3 x U L N a n d I N R * * > 1. 5.
* Ser u m bilir u bi n fracti o nati o n s h o ul d be perf or me d if testi n g is a vaila ble; if u na vaila ble, 
meas ure uri nar y  bilir u bi n via di pstic k.  If fracti o nati o n is u na vaila ble a n d A L T 3 x U L N 
a n d t otal bilir u bi n 2 x U L N, t he n t he e ve nt is still t o be re p orte d as a n S A E.
* * I N R testi n g n ot re q uire d per pr ot oc ol a n d t he t hres h ol d val ue d oes n ot a p pl y  t o 
s u bjects recei vi n g a ntic oa g ula nts.  If I N R meas ure me nt is o btai ne d, t he val ue is t o be 
rec or de d o n t he S A E f or m.
1 2. 3. 3.
D efi niti o n of C ar di o v a s c ul ar E v e nt s
C ar di o v asc ul ar E ve nts ( C V) Defi niti o n:
I n vesti gat ors will be re q uire d t o fill o ut t he s pecific C V e ve nt pa ge of t he C R F f or t he 
f oll o wi n g A Es a n d S A Es:

M y ocar dia l i nfarcti o n/ u nsta ble a n gi na

C o n gesti ve heart fail ure

Arr h yt h mias

Val v ul o pat h y

P ul m o nar y  h yperte nsi o n

Cere br o vasc ular e ve nts/str o ke a n d tra nsie nt isc he mic attac k

Peri p heral arterial t hr o m b oe m b olis m

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
Dee p ve n o us t hr o m b osis/ p ul m o nar y  e m b olis m

Re vasc ularizati o n
1 2. 3. 4.
A E s of S p e ci al I nt er e st:
Seiz ures :
T hree cases of seiz ures h a ve occ urre d i n t he C A B pr o gra m c u m ulati vel y t hr o u g h 
0 1 Oct o ber 2 0 1 5. Vii V Healt hcare has re vie we d t hese cases i n detail a n d d oes n ot 
belie ve t he y  c o nstit ute a reas o na ble li keli h o o d of ca usati o n ass ociate d wit h C A B.  T his 
assess me nt is s u p p orte d b y t he lac k of precli nical si g nal, class effect or k n o w n C N S 
mec ha nis m, t he relati vel y l o w fre q ue nc y of seiz ures relati ve t o e x pecte d rates i n b ot h 
healt h y  a n d HI V p ositi ve s u bjects a n d cli nical c o nf ou n ders i n eac h case.  
W here seiz ures occ ur, t he S p o ns or w o ul d li ke t o better c haracterize t hese occ urre nces t o 
e na ble s ys te matic a nalys es. I n vesti gat ors are re q ueste d t o d oc u me nt a n d re p ort seiz ure or 
p ossi ble seiz ure e ve nts pr o m ptl y ( wit hi n 2 4 h o urs of l ear ni n g of t he e ve nt) t o t he S p o ns or 
f or e val uati o n a n d o n war d re p orti n g.  Data s h o ul d be d oc u me nte d o n t he a p pr o priate 
A E/ S A E pa ge.
1 2. 3. 5.
R e c or di n g of A E s a n d S A E s
A Es a n d S A E Rec or di n g:

W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y  of t he i n vesti gat or t o re vie w all 
d oc u me ntati o n (e. g., h os pital pr o gress n otes, la b orat or y, a n d dia g n ostics re p orts) 
relati ve t o t he e ve nt.

T he i n vesti gat or will t he n rec or d all rele va nt i nf or mati o n re gar di n g a n A E/ S A E i n 
t he C R F

It is n ot acce pta ble f or t he i n vesti gat or t o se n d p h ot oc o pies of t he s u bject’s me dical 
rec or ds t o G S K i n lie u of c o m pleti o n of t he G S K, A E/ S A E C R F pa ge.

T here ma y  be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are 
re q ueste d by G S K.  I n t his i nsta nce, all s u bject i de ntifiers, wit h t he e xce pti o n of t he 
s u bject n u m ber, will be bli n de d o n t he c o pies of t he me dical rec or ds pri or t o 
s u b missi o n of t o G S K.

T he i n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s ym pt o ms, a n d/ or ot her cli nical i nf or mati o n.  I n s uc h cases, t he dia g n osis will be 
d oc u me nte d as t he A E/ S A E a n d n ot t he i n di vi d ual si g ns/s y m pt o ms.

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1 2. 3. 6.
E v al u ati n g A E s a n d S A E s
A s s e s s m e nt of I nt e n sit y
T he i n vesti gat or will ma ke a n assess me nt of i nte nsit y f or eac h A E a n d S A E re p orte d 
d uri n g t he st u d y a n d will assi g n i t t o o ne of t he f oll o wi n g cate g ories:

Mil d:  A n e ve nt t hat is easil y  t olerate d b y t he s u bject, ca usi n g mi ni mal disc o mf ort 
a n d n ot i nterferi n g wit h e ver y d a y  acti vities.

M o derate:  A n e ve nt t hat is s ufficie ntl y  disc o mf orti n g t o i nterfere wit h n or mal 
e ver yd a y acti vities

Se vere:  A n e ve nt t hat pre ve nts n or mal e ver y d a y  acti vities. - a n A E t hat is assesse d 
as se vere will n ot be c o nf use d wit h a n S A E. Se verit y  is a cate g or y utilize d f or rati n g 
t he i nte nsit y of a n e ve nt; a n d b ot h A Es a n d S A Es ca n be assesse d as se vere.

A n e ve nt is defi ne d as ‘seri o us’ w he n it meets at least o ne of t he pre -defi ne d 
o utc o mes as descri be d i n t he defi niti o n of a n S A E.
A s s e s s m e nt of C a u s alit y

T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y treat me nt a n d 
t he occ urre nce of eac h A E/ S A E.

A "reas o na ble p ossi bilit y " is mea nt t o c o n ve y t hat t here are facts/e vi de nce or 
ar g u me nts t o s u g gest a ca usal relati o ns hi p, rat her t ha n a relati o ns hi p ca n n ot be r ule d 
o ut.

T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he rel ati o ns hi p.

Alter nati ve ca uses, s uc h as nat ural hist or y  of t he u n derl yi n g diseases, c o nc o mita nt 
t hera py, ot her ris k fact ors, a n d t he te m p oral relati o ns hi p of t he e ve nt t o t he st u d y  
treat me nt will be c o nsi dere d a n d i n vesti gate d.

T he i n vesti gat or will als o c o ns ult t he I n vesti gat or Br oc h ure (I B) a n d/ or Pr o d uct 
I nf or mati o n, f or mar kete d pr o d ucts, i n t he deter mi nati o n of his/ her assess me nt.

F or eac h A E/ S A E t he i n vesti gat or m ust d oc u me nt i n t he me dical n otes t hat he/s he 
has re vie we d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y.

T here ma y  be sit uati o ns w he n a n S A E has occ urre d a n d t he i n vesti gat or has mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o G S K.  H o we ver, it is ver y i m p ort a nt 
t h at t he i n vesti g at or al w a ys m a ke a n assess me nt of c a us alit y f or e ver y e ve nt 
pri or t o t he i niti al tr a ns missi o n of t he S A E d at a t o G S K.

T he i n vesti gat or ma y  c ha n ge his/ her o pi ni o n of ca usalit y i n li g ht of f oll o w- u p 
i nf or mati o n, a me n di n g t he S A E data c ollecti o n t o ol acc or di n gly.

T he ca usalit y  assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y  
re p orti n g re q uire me nts.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
7 6
F oll o w -u p of A E s a n d S A E s

T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as ma y  be i n dicate d or as re q ueste d b y G S K t o 
el uci date as f ull y as p ossi ble t he nat ure a n d/ or ca usalit y of t he A E or S A E.

T he i n vesti gat or is o bli gate d t o assist.  T his ma y  i ncl u de a d diti o nal la b orat or y tests 
or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns or c o ns ultati o n wit h ot her healt h 
care pr ofessi o nals.

If a s u bject dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll o w- u p 
peri o d, t he i n vesti gat or will pr o vi de G S K wit h a c o p y  of a n y p ost-m orte m fi n di n gs, 
i ncl u di n g hist o pat h ol o g y.

Ne w or u p date d i nf or mati o n will be rec or de d i n t he or i gi nall y c o m plete d C R F.

T he i n vesti gat or will s u b mit a n y  u p date d S A E data t o G S K wit hi n t he desi g nate d 
re p orti n g ti me fra mes.
Re p orti n g of S A Es t o G S K
S A E re p orti n g t o G S K vi a electr o nic d at a c ollecti o n t o ol

Pri mar y  mec ha nis m f or re p orti n g S A Es t o G S K will be t he electr o nic data c ollecti o n 
t o ol

If t he electr o nic sys te m is u na vaila ble f or greater t ha n 2 4 h o urs, t he site will use t he 
pa per S A E data c ollecti o n t o ol a n d sca n a n d e mail it t o t he S A E c o or di nat or.

Site will e nter t he seri o us a d verse e ve nt data i nt o t he electr o nic s ys te m as s o o n as it 
bec o mes a vaila ble.

After t he st u d y is c o m plete d at a gi ve n site, t he electr o nic data c ollecti o n t o ol (e. g., 
I nF or m s ys te m) will be ta ke n off-li ne t o pre ve nt t he e ntr y of ne w data or c ha n ges t o 
e xisti n g data

If a site recei ves a re p ort of a ne w S A E fr o m a st u d y s u bject or recei ves u p date d data 
o n a pre vi o usl y re p orte d S A E after t he electr o nic data c ollecti o n t o ol has bee n ta ke n 
off -li ne, t he site ca n re p ort t his i nf or mati o n o n a pa per S A E f or m or t o t he S A E 
c o or di nat or b y  tele p h o ne.

C o ntacts f or S A E recei pt ca n be f o u n d at t he be gi n ni n g of t his pr ot oc ol o n t he 
S p o ns or/ Me dical M o nit or C o ntact I nf or mati o n pa ge.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
7 7
1 2. 4.
A p p e n di x 4: Di vi si o n Of A I 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 atri c A v er s e E v e nt s V er si o n 2. 0, 
N o v e m b er 2 0 1 4
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
E S TI M A TI N G S E V E RI T Y G R A D E
Cli nic al a dv ers e 
ev e nt N O T i d e ntifi e d 
els e w h er e i n t h e 
gr a di n g t a bl e
Mil d sy m pt o ms 
c a usi n g n o or 
mi ni m al 
i nt erf er e nc e with 
us u al s oci al & 
f u ncti o n al 
activiti es wit h 
i nt erv e nti o n n ot 
i n dic at e d
M o d er at e 
sy m pt o ms c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
wit h i nt erv e nti o n n ot 
i n dic at e d
S ev er e sy m pt o ms 
c a usi n g i n a bility t o 
p erf or m us u al s oci al 
& f u ncti o n al activiti es 
wit h i nt erv e nti o n or 
h os pit aliz ati o n 
i n dic at e d
P ot e nti ally lif e -
t hr e at e ni n g sy m pt o ms 
c a usi n g i n a bility t o 
p erf or m b asic s elf -c ar e 
f u ncti o ns O R M e dic al or 
o p er ativ e i nt erv e nti o n 
i n dic at e d t o pr ev e nt 
p er m a n e nt i m p air m e nt, 
p ersi st e nt dis a bility, or 
d e at h 
C A R DI O V A S C U L A R
Arr h yt h mi a
( by E C G or p hysic al
ex a mi n ati o n)
S p ecify ty p e, if
a p plic a bl e
N o sy m pt o ms 
A N D N o 
i nt erv e nti o n 
i n dic at e d
N o sy m pt o ms A N D
n o n -ur g e nt 
i nt erv e nti o n 
i n dic at e d
N o n -lif e-t hr e at e ni n g 
sy m pt o ms A N D N o n-
ur g e nt i n t erv e nti o n 
i n dic at e d
Lif e -t hr e at e ni n g 
arr hyt h mi a O R Ur g e nt 
i nt erv e nti o n i n dic at e d
Bl o o d Pr e s s ur e 
A b n or m aliti e s 1 
H y p ert e n si o n ( wit h 
t h e l o w est r e a di n g 
t ak e n aft er r e p e at 
t esti n g d uri n g a visit) 
≥ 1 8 y e ars of a g e 
1 4 0 t o < 1 6 0 
m m H g syst olic 
O R 9 0 t o < 1 0 0 
m m H g di ast olic 
≥ 1 6 0 t o < 1 8 0 
m m H g syst olic O R 
≥ 1 0 0 t o < 1 1 0 
m m H g di ast olic 
≥ 1 8 0 m m H g syst olic 
O R ≥ 1 1 0 m m H g 
di ast olic 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es i n a 
p artici p a nt n ot 
pr evi o usly di a g n os e d 
wit h hy p ert e nsi o n ( e. g., 
m ali g n a nt hy p ert e nsi o n) 
O R H os pi t aliz ati o n 
i n dic at e d 
< 1 8 y e ars of a g e 
> 1 2 0/ 8 0 m m H g 
≥ 9 5t h t o < 9 9t h 
p erc e ntil e + 5 
m m H g a dj ust e d f or 
a g e, h ei g ht, a n d 
g e n d er (syst olic 
a n d/ or di ast olic) 
≥ 9 9t h p erc e ntil e + 5 
m m H g a dj ust e d f or 
a g e, h ei g ht, a n d 
g e n d er (syst olic 
a n d/ or di ast olic) 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es i n a 
p artici p a nt n ot 
pr evi o usly di a g n os e d 
wit h hy p ert e nsi o n ( e. g., 
m ali g n a nt hy p ert e nsi o n) 
O R H os pit aliz ati o n 
i n dic at e d 
H y p ot e n si o n 
N o sy m pt o ms 
Sy m pt o ms 
c orr ect e d wit h or al 
fl ui d r e pl ac e m e nt 
Sy m pt o ms A N D I V 
fl ui ds i n dic at e d 
S h ock r e q uiri n g us e of 
v as o pr ess ors or 
m ec h a nic al assist a nc e 
t o m ai nt ai n bl o o d 
pr ess ur e 
C ar di a c I s c h e mi a or 
I nf ar cti o n 
R e p ort o nly o n e 
N A 
N A 
N e w sy m pt o ms wit h 
isc h e mi a (st a bl e 
a n gi n a) O R N e w 
t esti n g c o nsist e nt 
wit h isc h e mi a 
U nst a bl e a n gi n a O R 
Ac ut e my oc ar di al 
i nf arcti o n 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
7 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
H e art F ail ur e 
N o sy m pt o ms 
A N D L a b or at ory 
or c ar di ac i m a gi n g 
a b n or m aliti es 
Sy m pt o ms wit h mil d 
t o m o d er at e activity 
or ex erti o n 
Sy m pt o ms at r est or 
wit h mi ni m al activity 
or ex erti o n ( e. g., 
hy p ox e mi a) O R 
I nt erv e nti o n i n dic at e d 
( e. g., oxy g e n) 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es O R 
Ur g e nt i nt erv e nti o n 
i n dic at e d ( e. g., 
v as o activ e m e dic ati o ns, 
v e ntric ul ar assist d evic e, 
h e art tr a ns pl a nt) 
H e m orr h a g e ( wit h 
si g nific a nt ac ut e 
bl o o d l oss) 
N A 
Sy m pt o ms A N D N o 
tr a nsf usi o n 
i n dic at e d 
Sy m pt o ms A N D
Tr a nsf usi o n of ≤ 2 
u nits p ack e d R B Cs 
i n dic at e d 
Lif e -t hr e at e ni n g 
hy p ot e nsi o n O R 
Tr a nsf usi o n of > 2 u nits 
p ack e d R B Cs (f or 
c hil dr e n, p ack e d R B Cs 
> 1 0 cc/k g) i n dic at e d 
Pr ol o n g e d P R 
I nt er v al or A V Bl o c k 
R e p ort o nly o n e 
> 1 6 y e ars of a g e 
P R i nt erv al 0. 2 1
t o < 0. 2 5 s ec o n ds 
P R i nt erv al ≥ 0. 2 5 
s ec o n ds O R Ty p e I 
2 n d d e gr e e A V 
bl ock 
Ty p e II 2 n d d e gr e e 
A V bl ock O R 
V e ntric ul ar p a us e ≥ 
3. 0 s ec o n ds 
C o m pl et e A V bl ock 
≤ 1 6 y e ars of a g e 
1st d e gr e e A V 
bl ock ( P R i nt erv al 
> n or m al f or a g e 
a n d r at e) 
Ty p e I 2 n d d e g r e e 
A V bl ock 
Ty p e II 2 n d d e gr e e 
A V bl ock O R 
V e ntric ul ar p a us e ≥ 
3. 0 s ec o n ds 
C o m pl et e A V bl ock 
Pr ol o n g e d Q T c 
I nt er 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 ov e 
b as eli n e 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
T ors a d e d e p oi nt es, 
ot h er ass oci at e d s eri o us 
v e ntric ul ar dysr hyt h mi a) 
T hr o m b o si s or 
E m b oli s m 
R e p ort o nly o n e 
N A 
Sy m pt o ms A N D N o 
i nt erv e nti o n 
i n dic at e d 
Sy m pt o ms A N D 
I nt erv e nti o n i n dic at e d 
Lif e -t hr e at e ni n g e m b olic 
ev e nt ( e. g., p ul m o n ary 
e m b olis m, t hr o m b us) 
D E R M A T O L O GI C
Al o p e ci a (sc al p o nly) 
D et ect a bl e by 
st u dy p artici p a nt, 
c ar e giv er, or 
p hysici a n A N D 
C a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
O bvi o us o n vis u al 
i ns p ecti o n A N D 
C a usi n g gr e at er 
t h a n mi ni m al 
i nt erf er e nce wit h 
us u al s oci al & 
f u ncti o n al activiti es 
N A 
N A 
Br ui si n g 
L oc aliz e d t o o n e 
ar e a 
L oc aliz e d t o m or e 
t h a n o n e ar e a 
G e n er aliz e d 
N A 
C ell uliti s 
N A 
N o n -p ar e nt er al 
tr e at m e nt i n dic at e d 
( e. g., or al 
a nti bi otics, 
a ntif u n g als, 
a ntivir als) 
I V tr e at m e nt 
i n dic at e d ( e. g., I V 
a nti bi otics, 
a ntif u n g als, a ntivir als) 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
s e psis, tiss u e n ecr osis) 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
7 9
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
H y p er pi g m e nt ati o n 
Sli g ht or l oc aliz e d 
c a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
M ark e d or 
g e n er aliz e d c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
N A 
N A 
H y p o pi g m e nt ati o n 
Sli g ht or l oc aliz e d 
c a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
M ark e d or 
g e n er aliz e d c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
N A 
N A 
P et e c hi a e 
L oc aliz e d t o o n e 
ar e a 
L oc aliz e d t o m or e 
t h a n o n e ar e a 
G e n er aliz e d 
N A 
Pr urit u s 3 ( wit h o ut 
ski n l esi o ns) 
Itc hi n g c a usi n g n o 
or mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
fu ncti o n al 
activiti es 
Itc hi n g c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
Itc hi n g c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
N A 
R a s h 
S p ecify ty p e, if 
a p plic a bl e 
L oc aliz e d r as h 
Diff us e r a s h O R 
T ar g et l esi o ns 
Diff us e r as h A N D 
V esicl es or li mit e d 
n u m b er of b ull a e or 
s u p erfici al ulc er ati o ns 
of m uc o us m e m br a n e 
li mit e d t o o n e sit e 
Ext e nsiv e or g e n er aliz e d 
b ull o us l esi o ns O R 
Ulc er ati o n of m uc o us 
m e m br a n e i nv olvi n g t w o 
or m or e disti nct m uc os al 
sit es O R St ev e ns-
J o h ns o n sy n dr o m e O R 
T oxic e pi d er m al 
n ecr olysis 
E N D O C RI N E A N D M E T A B O LI C
Di a b et e s M ellit u s 
C o ntr oll e d wit h o ut 
m e dic ati o n 
C o ntr oll e d wit h 
m e dic ati o n O R 
M o dific ati o n of 
c urr e nt m e dic ati o n 
r e gi m e n 
U nc o ntr oll e d d es pit e 
tr e at m e nt 
m o dific ati o n O R 
H os pit aliz ati o n f or 
i m m e di at e gl uc os e 
c o ntr ol i n dic at e d 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
k et o aci d osis, 
hy p er os m ol ar n o n -
k et otic c o m a, e n d or g a n 
f ail ur e) 
G y n e c o m a sti a 
D et ect a bl e by 
st u dy p artici p a nt, 
c ar e giv er, or 
p hysici a n A N D 
C a usi n g n o or 
m i ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
O bvi 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 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
Disfi g uri n g c h a n g es 
A N D Sy m pt o ms 
r e q uiri n g i nt erv e nti o n 
or c a usi n g i n a bility t o 
p erf or m us u al s oci al 
& f u ncti o n al activiti es 
N A 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
8 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
H y p ert h yr oi di s m 
N o sy m pt o ms 
A N D A b n or m al 
l a b or at ory v al u e 
Sy m pt o ms c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
O R T hyr oi d 
s u p pr essi o n 
t h er a py i n dic at e d 
Sy m pt o ms c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
O R U nc o ntr oll e d 
d es pit e tr e at m e nt 
m o dific ati o n 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
t hyr oi d st or m) 
H y p ot h yr oi di s m 
N o sy m pt o ms 
A N D A b n or m al 
l a b or at ory v al u e 
Sy m pt o ms c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
O R T hyr oi d 
r e pl ac e m e nt 
t h er a py i n dic at e d 
Sy m pt o ms c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
O R U nc o ntr oll e d 
d es pit e tr e at m e nt 
m o dific ati o n 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
myx e d e m a c o m a) 
Li p o atr o p h y 4 
D et ect a bl e by 
st u dy p artici p a nt, 
c ar e giv er, or 
p hysici a n A N D 
C a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
O bvi o us o n vis u al 
i ns p ecti o n A N D 
C a usi n g gr e at er 
t h a n mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
Disfi g uri n g c h a n g es 
N A 
Li p o h y p ertr o p h y 5
D et ect a bl e by 
st u dy p artici p a nt, 
c ar e giv er, or 
p hysici a n A N D 
C a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
O bvi o us o n vis u al
i ns p ecti o n A N D 
C a usi n g gr e at er 
t h a n mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
Disfi g uri n g c h a n g es 
N A 
G A S T R OI N T E S TI N A L
A n or e xi a 
L oss of a p p etit e 
wit h o ut d ecr e as e d 
or al i nt ak e 
L oss of a p p etit e 
ass oci at e d wit h 
d ecr e as e d or al 
i nt ak e wit h o ut 
si g nific a nt w ei g ht 
l oss 
L oss of a p p etit e 
ass oci at e d wit h 
si g nific a nt w ei g ht l oss 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es O R 
A g gr essiv e i nt erv e nti o n 
i n dic at e d ( e. g., t u b e 
f e e di n g, t ot al p ar e nt er al 
n utriti o n) 
A s cit e s 
N o sy m pt o ms 
Sy m pt o ms A N D 
I nt erv e ntio n 
i n dic at e d ( e. g., 
di ur etics, 
t h er a p e utic 
p ar ac e nt esis) 
Sy m pt o ms r ec ur or 
p ersist d es pit e 
i nt erv e nti o n 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
8 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
Bl o ati n g or 
Di st e n si o n 
R e p ort o nly o n e 
Sy m pt o ms 
c a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
ac tiviti es 
Sy m pt o ms c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
Sy m pt o ms c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
N A 
C h ol e c y stiti s 
N A 
Sy m pt o ms A N D 
M e dic al i nt erv e nti o n 
i n dic at e d 
R a di ol o gic, 
e n d osc o pic, or 
o p er ativ e i nt erv e nti o n 
i n dic at e d 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
s e psis, p erf or ati o n) 
C o n sti p ati o n 
N A 
P ersist e nt 
c o nsti p ati o n 
r e q uiri n g r e g ul ar 
us e of di et ary 
m o dific ati o ns, 
l ax ativ es, or 
e n e m as 
O bsti p ati o n wit h 
m a n u al ev ac u a ti o n 
i n dic at e d 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
o bstr ucti o n) 
Di arr h e a ≥ 1 y e ar of 
a g e 
Tr a nsi e nt or 
i nt er mitt e nt 
e pis o d es of 
u nf or m e d st o ols 
O R I ncr e as e of ≤ 
3 st o ols ov er 
b as eli n e p er 2 4 -
h o ur p eri o d 
P ersist e nt e pis o d es 
of u nf or m e d t o 
w at ery st o ols O R 
I ncr e as e of 4 t o 6 
st o ols ov er b as eli n e 
p er 2 4 -h o ur p eri o d 
I ncr e as e of ≥7 st o ols 
p er 2 4 -h o ur p eri o d 
O R I V fl ui d 
r e pl ac e m e nt 
i n dic at e d 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
hy p ot e nsiv e s h ock) 
D y s p h a gi a or 
O d y n o p h a gi a 
R e p ort o nl y o n e 
a n d s p e cif y 
l o c ati o n 
Sy m pt o ms b ut 
a bl e t o e at us u al 
di et 
Sy m pt o ms c a usi n g 
alt er e d di et ary 
i nt ak e wit h n o 
i nt erv e nti o n 
i n dic at e d 
Sy m pt o ms c a usi n g 
s ev er ely alt er e d 
di et ary i nt ak e wit h 
i nt erv e nti o n i n dic at e d 
Lif e -t hr e at e ni n g 
r e d ucti o n i n or al i nt ak e 
G a str oi nt e sti n al 
Bl e e di n g 
N ot r e q uiri n g 
i nt erv e nti o n ot h er 
t h a n ir o n 
s u p pl e m e nt 
E n d osc o pic 
i nt erv e nti o n 
i n dic at e d 
Tr a nsf usi o n i n dic at e d 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
hy p ot e nsiv e s h ock) 
M u c o siti s or 
St o m atiti s 
R e p ort o nly o n e a n d 
s p ecify l oc ati o n 
M uc os al eryt h e m a 
P atc hy 
ps e u d o m e m br a n es 
or ulc er ati o ns 
C o nfl u e nt 
ps e u d o m e m br a n es 
or ulc e r ati o ns O R 
M uc os al bl e e di n g 
wit h mi n or tr a u m a 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
as pir ati o n, c h oki n g) O R 
Tiss u e n ecr osis O R 
Diff us e s p o nt a n e o us 
m uc os al bl e e di n g 
N a u s e a 
Tr a nsi e nt ( < 2 4 
h o urs) or 
i nt er mitt e nt A N D 
N o or mi ni m al 
i nt erf er e nc e wit h 
or al i nt ak e 
P ersist e nt n a us e a 
r es ulti n g i n 
d ecr e as e d or al 
i nt ak e f or 2 4 t o 4 8 
h o urs 
P ersist e nt n a us e a 
r es ulti n g i n mi ni m al 
or al i nt ak e f or > 4 8 
h o urs O R 
R e hy dr ati o n i n dic at e d 
( e. g., I V fl ui ds) 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
hy p ot e nsiv e s h ock) 
P a n cr e ati ti s 
N A 
Sy m pt o ms wit h 
h os pit aliz ati o n n ot 
i n dic at e d 
Sy m pt o ms wit h 
h os pit aliz ati o n 
i n dic at e d 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
circ ul at ory f ail ur e, 
h e m orr h a g e, s e psis) 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
8 2
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
P erf or ati o n 
(c ol o n or r ect u m) 
N A 
N A 
I nt erv e nti o n i n dic at e d 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es 
Pr o ctiti s 
R ect al disc o mf ort 
wit h n o 
i nt erv e nti o n 
i n dic at e d 
Sy m pt o ms c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
O R M e dic al 
i nt erv e nti o n 
i n dic at e d 
Sy m pt o ms c a usi n g 
i n a bility t o p erf or m 
us u al s oci al &
f u ncti o n al activiti es 
O R O p er ativ e 
i nt erv e nti o n i n dic at e d 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
p erf or ati o n) 
R e ct al Di s c h ar g e 
Visi bl e disc h ar g e 
Disc h ar g e r e q uiri n g 
t h e us e of p a ds 
N A 
N A 
V o miti n g 
Tr a nsi e nt or 
i nt er mitt e nt A N D 
N o or mi ni m al 
i nt erf er e nc e wit h 
or al i nt ak e 
Fr e q u e nt e pis o d es 
wit h n o or mil d 
d e hy dr ati o n 
P ersist e nt v o miti n g 
r es ulti n g i n 
ort h ost atic 
hy p ot e nsi o n O R 
A g gr essiv e 
r e hy dr ati o n i n dic at e d 
( e. g., I V fl ui ds) 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
hy p ot e nsiv e s h ock) 
M U S C U L O S K E L E T A L
Art hr al gi a 
J oi nt p ai n c a usi n g 
n o or mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
J oi nt p ai n c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
J oi nt p ai n c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
fu ncti o n al activiti es 
Dis a bli n g j oi nt p ai n 
c a usi n g i n a bility t o 
p erf or m b asic s elf -c ar e 
f u ncti o ns 
Art hriti s 
Stiff n ess or j oi nt 
s w elli n g c a usi n g 
n o or mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
Stiff n ess or j oi nt 
s w elli n g c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
Stiff n ess or j oi nt 
s w elli n g c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
Dis a bli n g j oi nt stiff n ess 
or s w elli n g c a usi n g 
i n a bility t o p erf or m b asic 
s elf-c ar e f u ncti o ns 
M y al gi a 
( g e n er aliz e d) 
M uscl e p ai n 
c a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
M uscl e p ai n 
c a usi n g gr e at er 
t h a n mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
M uscl e p ai n c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
Dis a bli n g m uscl e p ai n 
c a usi n g i n a bility t o 
p erf or m b asic s elf -c ar e 
f u ncti o ns 
O st e o n e cr o si s 
N A 
N o sy m pt o ms b ut 
wit h r a di o gr a p hic 
fi n di n gs A N D N o 
o p er ativ e 
i nt erv e nti o n 
i n dic at e d 
B o n e p ai n wit h 
r a di o gr a p hic fi n din gs 
O R O p er ativ e 
i nt erv e nti o n i n dic at e d 
Dis a bli n g b o n e p ai n wit h 
r a di o gr a p hic fi n di n gs 
c a usi n g i n a bility t o 
p erf or m b asic s elf -c ar e 
f u ncti o ns 
O st e o p e ni a 6
≥ 3 0 y e ars of a g e 
B M D t -sc or e -2. 5 
t o -1 
N A 
N A 
N A 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
8 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
< 3 0 y e ars of a g e 
B M D z -sc or e -2 t o 
-1 
N A 
N A 
N A 
O st e o p or o si s 6
≥ 3 0 y e ars of a g e 
N A 
B M D t -sc or e < -2. 5 
P at h ol o gic fr act ur e 
( e. g., c o m pr essi o n 
fr act ur e c a usi n g l oss 
of v ert e br al h ei g ht) 
P at h ol o gic fr act ur e 
c a usi n g lif e-t hr e at e ni n g 
c o ns e q u e nc es 
< 3 0 y e ars of a g e 
N A 
B M D z -sc or e < -2 
Pa t h ol o gic fr act ur e 
( e. g., c o m pr essi o n 
fr act ur e c a usi n g l oss 
of v ert e br al h ei g ht) 
P at h ol o gic fr act ur e 
c a usi n g lif e-t hr e at e ni n g 
c o ns e q u e nc es 
N E U R O L O GI C
A c ut e C N S 
I s c h e mi a 
N A 
N A 
Tr a nsi e nt isc h e mic 
att ack 
C er e br al v asc ul ar 
acci d e nt ( e. g., str ok e 
wit h n e ur ol o gic al d eficit) 
Alt er e d M e nt al 
St at u s (f or 
D e m e nti a, s e e 
C o g nitiv e, 
B e h avi or al, or 
Att e nti o n al 
Dist ur b a nc e b el o w) 
C h a n g es c a usi n g 
n o or mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
Mil d l et h ar gy or 
s o m n ol e nc e 
c a usi n g gr e at er 
t h a n mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
C o nf usi o n, m e m ory 
i m p air m e nt, l et h ar gy, 
or s o m n ol e nc e 
c a usi n g i n a bility t o 
p erf or m us u al s oci al 
& f u ncti o n al activiti es 
D eliri u m O R 
O bt u n d ati o n O R C o m a 
At a xi a 
Sy m pt o ms 
c a usi n g n o or 
mi ni m a l 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es O R N o 
sy m pt o ms wit h 
at axi a d et ect e d o n 
ex a mi n ati o n 
Sy m pt o ms c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
Sy m pt o ms c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
Dis a bli n g sy m pt o ms 
c a usi n g i n a bility t o 
p erf or m b asic s elf -c ar e 
f u ncti o ns 
C o g niti v e, 
B e h a vi or al, or 
Att e nti o n al 
Di st ur b a n c e 
(i ncl u d es d e m e nti a 
a n d att e nti o n d eficit 
dis or d er) 
S p ecify ty p e, if 
a p plic a bl e 
Dis a bility c a usi n g 
n o or m i ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es O R 
S p eci aliz e d 
r es o urc es n ot 
i n dic at e d 
Dis a bility c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
O R S p eci aliz e d 
r es o urc es o n p art-
ti m e b asis i n dic at e d 
Dis a bility c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
O R S p eci aliz e d 
r es o urc es o n a f ull-
ti m e b asis i n dic at e d 
Dis a bility c a usi n g 
i n a bility t o p erf or m b asic 
s elf-c ar e f u ncti o ns O R 
I nstit uti o n aliz ati o n 
i n dic at e d 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
8 4
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
D e v el o p m e nt al 
D el a y < 1 8 y e ars of 
a g e 
S p ecify ty p e, if 
a p plic a bl e 
Mil d 
d ev el o p m e nt al 
d el ay, eit h er 
m ot or or 
c o g nitiv e, as 
d et er mi n e d by 
c o m p aris o n wit h a 
d ev el o p m e nt al 
scr e e ni n g t o ol 
a p pr o pri at e f or t h e 
s etti n g 
M o d er at e 
d ev el o p m e nt al 
d el ay, eit h er m ot or 
or c o g nitiv e, as 
d et er m i n e d by 
c o m p aris o n wit h a 
d ev el o p m e nt al 
scr e e ni n g t o ol 
a p pr o pri at e f or t h e 
s etti n g 
S ev er e 
d ev el o p m e nt al d el ay, 
eit h er m ot or or 
c o g nitiv e, as 
d et er mi n e d by 
c o m p aris o n wit h a 
d ev el o p m e nt al 
scr e e ni n g t o ol 
a p pr o pri at e f or t h e 
s etti n g 
D ev el o p m e nt al 
r e gr essi o n, eit h er m ot or 
or c o g nitiv e, as 
d et er mi n e d by 
c o m p aris o n wit h a 
d ev el o p m e nt al 
scr e e ni n g t o ol 
a p pr o pri at e f or t h e 
s etti n g 
H e a d a c h e 
Sy m pt o ms 
c a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
Sy m pt o ms c a usi n g 
gr e at er t h a n 
mi ni m a l 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
Sy m pt o ms c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
Sy m pt o ms c a usi n g 
i n a bility t o p erf or m b asic 
s elf-c ar e f u ncti o ns O R 
H os pit aliz ati o n i n dic at e d 
O R H e a d ac h e wit h 
si g nific a nt i m p air m e nt of 
al ert n ess or ot h er 
n e ur ol o gic f u ncti o n 
N e ur o m u s c ul ar 
W e a k n e s s (i ncl u d es 
my o p at hy a n d 
n e ur o p at hy) 
S p ecify ty p e, if 
a p plic a bl e 
Mi ni m al m uscl e 
w e ak n ess c a usi n g 
n o or mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es O R N o 
sy m pt oms wit h 
d ecr e as e d 
str e n gt h o n 
ex a mi n ati o n 
M uscl e w e ak n ess 
c a usi n g gr e at er 
t h a n mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
M uscl e w e ak n ess 
c a usi n g i n a bility t o 
p erf or m us u al s oci al 
& f u ncti o n al activiti es 
Dis a bli n g m uscl e 
w e ak n ess c a u si n g 
i n a bility t o p erf or m b asic 
s elf-c ar e f u ncti o ns O R 
R es pir at ory m uscl e 
w e ak n ess i m p airi n g 
v e ntil ati o n 
N e ur o s e n s or y 
Alt er ati o n (i ncl u d es 
p ar est h esi a a n d 
p ai nf ul n e ur o p at hy) 
S p ecify ty p e, if 
a p plic a bl e 
Mi ni m al 
p ar est h esi a 
c a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es O R N o 
sy m pt o ms wit h 
s e ns ory alt er ati o n 
o n ex a mi n ati o n 
S e ns ory alt er ati o n 
or p ar est h esi a 
c a usi n g gr e at er 
t h a n mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
S e ns ory alt er ati o n or 
p ar est h esi a c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
Dis a bli n g s e ns ory 
alt er ati o n or p ar est h esi a 
c a usi n g i n a bility t o 
p erf or m b asic s elf -c ar e 
f u ncti o ns 
S eiz ur e s N e w O n s et 
S eiz ur e 
≥ 1 8 y e ars of a g e 
N A 
N A 
1 t o 3 s eiz ur es 
Pr ol o n g e d a n d r e p etitiv e 
s eiz ur es ( e. g., st at us 
e pil e ptic us) O R Diffic ult 
t o c o ntr ol ( e. g., 
r efr act ory e pil e psy) 
< 1 8 y e ars of a g e 
(i ncl u d es n e w or pr e-
existi n g f e bril e 
s eiz ur es) 
S eiz ur e l asti n g < 
5 mi n ut es w it h < 
2 4 h o urs p ostict al 
st at e 
S eiz ur e l asti n g 5 t o 
< 2 0 mi n ut es wit h < 
2 4 h o urs p ostict al 
st at e 
S eiz ur e l asti n g ≥ 2 0 
mi n ut es O R > 2 4 
h o urs p ostict al st at e 
Pr ol o n g e d a n d r e p etitiv e 
s eiz ur es ( e. g., st at us 
e pil e ptic us) O R Diffic ult 
t o c o ntr ol ( e. g., 
r efr act ory e pil e psy) 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
8 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
Pr e -e xi sti n g S eiz ur e 
N A 
I ncr e as e d 
fr e q u e ncy fr o m 
pr evi o us l ev el of 
c o ntr ol wit h o ut 
c h a n g e i n s eiz ur e 
c h ar act er 
C h a n g e i n s eiz ur e 
c h ar act er eit h er i n 
d ur ati o n or q u ality 
( e. g., s ev erity or 
f oc ality) 
Pr ol o n g e d a n d r e p etitiv e 
s eiz ur es ( e. g., st at us 
e pil e ptic us) O R Diffic ult 
t o c o ntr ol ( e. g., 
r efr act ory e pil e psy) 
S y n c o p e 
N e ar sy nc o p e 
wit h o ut l oss of 
c o nsci o us n ess 
( e. g., pr e-
sy nc o p e) 
L oss of 
c o nsci o us n ess wit h 
n o i nt erv e nti o n 
i n dic at e d 
L oss of 
c o nsci o us n ess A N D 
H os pit aliz ati o n or 
i nt erv e nti o n r e q uir e d 
N A 
P R E G N A N C Y, P U E R P E RI U M, A N D P E RI N A T A L
F et al D e at h or 
Still birt h (r e p ort 
usi n g m ot h er’s 
p artici p a nt I D) 
R e p ort o nly o n e 
N A 
N A 
F et al l oss occ urri n g 
at ≥ 2 0 w e eks 
g est ati o n 
N A 
Pr et er m D eli v er y 7
(r e p ort usi n g 
m ot h er’s p artici p a nt
I D) 
D eliv ery at 3 4 t o < 
3 7 w e eks 
g est ati o n al a g e 
D eliv ery at 2 8 t o < 
3 4 w e eks 
g est ati o n al a g e 
D eliv ery at 2 4 t o < 2 8 
w e eks g est ati o n al 
a g e 
D eliv ery at < 2 4 w e eks 
g est ati o n al a g e 
S p o nt a n e o u s 
A b orti o n or 
Mi s c arri a g e 8 (r e p ort 
usi n g m ot h er’s 
p artici p a nt I D) 
R e p ort o nly o n e 
C h e mic al 
pr e g n a ncy 
U nc o m plic at e d 
s p o nt a n e o us 
a b orti o n or 
misc arri a g e 
C o m plic at e d 
s p o nt a n e o us a b orti o n 
or misc arri a g e 
N A 
P S Y C HI A T RI C
I n s o m ni a 
Mil d diffic ulty 
f alli n g asl e e p, 
st ayi n g asl e e p, or 
w aki n g u p e arly 
M o d er at e diffic u lty 
f alli n g asl e e p, 
st ayi n g asl e e p, or 
w aki n g u p e arly 
S ev er e diffic ulty 
f alli n g asl e e p, st ayi n g 
asl e e p, or w aki n g u p 
e arly 
N A 
P s y c hi atri c 
Di s or d er s 
(i ncl u d es a nxi ety, 
d e pr essi o n, m a ni a, 
a n d 
psyc h osis) 
S p ecify dis or d er 
Sy m pt o ms wit h 
i nt erv e nti o n not 
i n dic at e d O R 
B e h avi or c a usi n g 
n o or mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
Sy m pt o ms wit h 
i nt erv e nti o n 
i n dic at e d O R 
B e h avi or c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
Sy m pt o ms wit h 
h os pi t aliz ati o n 
i n dic at e d O R 
B e h avi or c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
T hr e at e ns h ar m t o s elf 
or ot h ers O R Ac ut e 
psyc h osis O R B e h avi or 
c a usi n g i n a bility t o 
p erf or m b asic s elf -c ar e 
f u ncti o ns 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
8 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
S ui ci d al I d e ati o n or 
Att e m pt 
R e p ort o nly o n e 
Pr e occ u pi e d wit h 
t h o u g hts of d e at h 
A N D N o wis h t o 
kill o n es elf 
Pr e occ u pi e d wit h 
t h o u g hts of d e at h 
A N D Wis h t o kill 
o n es elf wit h n o 
s p ecific pl a n or 
i nt e nt 
T h o u g hts of killi n g 
o n es elf wit h p arti al or 
c o m pl et e pl a ns b ut 
n o att e m pt t o d o s o 
O R H os pit aliz ati o n 
i n dic at e d 
S uici d e att e m pt e d 
R E S PI R A T O R Y
A c ut e 
Br o n c h o s p a s m 
F orc e d ex pir at ory 
v ol u m e i n 1 
s ec o n d or p e ak 
fl o w r e d uc e d t o ≥ 
7 0 t o < 8 0 % O R 
Mil d sy m pt o ms 
wit h i nt erv e nti o n 
n ot i n dic at e d 
F orc e d ex pir at ory 
v ol u m e i n 1 s ec o n d 
or p e ak fl o w 5 0 t o < 
7 0 % O R Sy m pt o ms 
wit h i nt erv e nti o n 
i n dic at e d O R 
Sy m pt o ms c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
F orc e d ex pir at ory 
v ol u m e i n 1 s ec o n d 
or p e ak fl o w 2 5 t o < 
5 0 % O R Sy m pt o ms 
c a usi n g i n a bility t o 
p erf or m us u al s oci al 
& f u ncti o n al activiti es 
F orc e d ex pir at ory 
v ol u m e i n 1 s ec o n d or 
p e ak fl o w < 2 5 % O R 
Lif e -t hr e at e ni n g 
r es pir at ory or 
h e m o dy n a mic 
c o m pr o mis e O R 
I nt u b ati o n 
D y s p n e a or 
R e s pir at or y 
Di str e s s 
R e p ort o nly o n e 
Dys p n e a o n 
ex erti o n wit h n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es O R 
W h e ezi n g O R 
Mi ni m al i ncr e as e 
i n r es pir at ory r at e 
f or a g e 
Dys p n e a o n 
ex erti o n c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
O R N as al fl ari n g 
O R I nt erc ost al 
r etr acti ons O R 
P uls e oxi m etry 9 0 
t o < 9 5 % 
Dys p n e a at r est 
c a usi n g i n a bility t o 
p erf or m us u al s oci al 
& f u ncti o n al activiti es 
O R P uls e oxi m etry < 
9 0 % 
R es pir at ory f ail ur e wit h 
v e ntil at or s u p p ort 
i n dic at e d ( e. g., C P A P, 
B P A P, i nt u b ati o n) 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
8 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
S E N S O R Y
H e ari n g L o s s 
≥ 1 2 y e ars of a g e 
N A 
H e ari n g ai d or 
i nt erv e nti o n n ot 
i n dic at e d 
H e ari n g ai d or 
i nt erv e nti o n i n dic at e d 
Pr of o u n d bil at er al 
h e ari n g l oss ( > 8 0 d B at 
2 k Hz a n d a b ov e) O R 
N o n -s ervic e a bl e h e ari n g 
(i. e., > 5 0 d B a u di o gr a m 
a n d < 5 0 % s p e ec h 
discri mi n ati o n) 
< 1 2 y e 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 e ari n g 
l oss at ≤ 4 k Hz 
> 2 0 d B h e ari n g 
l oss at > 4 k Hz 
> 2 0 d B h e ari n g l oss 
at ≥ 3 k Hz i n o n e e ar 
wit h a d diti o n al 
s p e ec h l a n g u a g e 
r el at e d s ervic es 
i n dic at e d ( w h er e 
av ail a bl e) O R 
H e ari n g l oss 
s uffici e nt t o i n dic at e 
t h er a p e utic 
i nt erv e nti o n, i ncl u di n g 
h e ari n g ai ds 
A u di ol o gic i n dic ati o n f or 
c oc hl e ar i m pl a nt a n d 
a d diti o n al s p e ec h -
l a n g u a g e r el at e d 
s ervic es i n dic at e d 
( w h er e av ail a bl e) 
Ti n nit u s 
Sy m pt o ms 
c a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es wit h 
i nt erv e nti o n n ot 
i n dic at e d 
Sy m pt o ms c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
wit h i nt erv e nti o n 
i n dic at e d 
Sy m pt o ms c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti on al activiti es 
N A 
U v eiti s 
N o sy m pt o ms 
A N D D et ect a bl e 
o n ex a mi n ati o n 
A nt eri or uv eitis wit h 
sy m pt o ms O R 
M e dic a myl as al 
i nt erv e nti o n 
i n dic at e d 
P ost eri or or p a n -
uv eitis O R O p er ativ e 
i nt erv e nti o n i n dic at e d 
Dis a bli n g vis u al l oss i n 
aff ect e d ey e(s) 
V erti g o 
V erti g o c a usi n g 
n o or mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
V erti g o c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
V erti g o c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
Dis a bli n g v erti g o 
c a usi n g i n a bility t o 
p erf or m b asic s elf -c ar e 
f u ncti o ns 
Vi s u al C h a n g e s 
( ass ess e d fr o m 
b as eli n e) 
Vis u al c h a n g es 
c a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
Vis u al c h a n g es 
c a usi n g gr e at er 
t h a n mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
Vis u al c h a n g es 
c a usi n g i n a bility t o 
p erf or m us u al s oci al 
& f u ncti o n al activiti es 
Dis a bli n g vis u al l oss i n 
aff ect e d ey e(s) 
S Y S T E MI C
A c ut e All er gi c 
R e a cti o n 
L oc aliz e d urtic ari a 
( w h e als) wit h n o 
m e dic al 
i nt erv e nti o n 
i n dic at e d 
L oc aliz e d urtic ari a 
wit h i nt erv e nti o n 
i n dic at e d O R Mil d 
a n gi o e d e m a wit h 
n o i nt erv e nti o n 
i n dic at e d 
G e n er aliz e d urtic ari a 
O R A n gi o e d e m a wit h 
i nt erv e nti o n i n dic at e d 
O R Sy m pt o ms of 
mil d br o nc h os p as m 
Ac ut e a n a p hyl axis O R 
Lif e -t hr e ate ni n g 
br o nc h os p as m O R 
L ary n g e al e d e m a 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
8 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
C hill s 
Sy m pt o ms 
c a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
Sy m pt o ms c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
Sy m pt o ms c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
N A 
C yt o ki n e R el e a s e 
S y n dr o m e 9
Mil d si g ns a n d 
sy m pt o ms A N D 
T h er a py (i. e., 
a nti b o dy i nf usi o n) 
i nt err u pti o n n ot 
i n dic at e d 
T h er a py (i. e., 
a nti b o dy i nf usi o n) 
i nt err u pti o n 
i n dic at e d A N D 
R es p o n ds pr o m ptly 
t o sym pt o m atic 
tr e at m e nt O R 
Pr o p hyl actic 
m e dic ati o ns 
i n dic at e d f or ≤ 2 4 
h o urs 
Pr ol o n g e d s ev er e 
si g ns a n d sy m pt o ms 
O R R ec urr e nc e of 
sy m pt o ms f oll o wi n g 
i niti al i m pr ov e m e nt 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
r e q uiri n g pr ess or or 
v e ntil at or s u p p ort) 
F ati g u e o r M al ai s e 
R e p ort o nly o n e 
Sy m pt o ms 
c a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
Sy m pt o ms c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
Sy m pt o ms c a usi n g 
i n a bility t o p erf or m 
us u al s oc i al & 
f u ncti o n al activiti es 
I nc a p acit ati n g 
sy m pt o ms of f ati g u e or 
m al ais e c a usi n g i n a bility 
t o p erf or m b asic s elf-
c ar e f u ncti o ns 
F e v er ( n o n-axill ary 
t e m p er at ur es o nly) 
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 1 0 ( n ot 
ass oci at e d wit h st u dy 
a g e nt i nj ecti o ns a n d 
n ot s p ecifi e d 
els e w h er e) 
S p ecify l oc ati o n 
P ai n c a usi n g n o 
or mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
P ai n c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
P ai n c a usi n g i n a bility 
t o p erf or m us u al 
s oci al & f u ncti o n al 
activiti es 
Dis a bli n g p ai n c a usi n g 
i n a bility t o p erf or m b asic 
s elf-car e f u ncti o ns O R 
H os pit aliz ati o n i n dic at e d 
S er u m Si c k n e s s 1 1 
Mil d si g ns a n d 
sy m pt o ms 
M o d er at e si g ns a n d 
sy m pt o ms A N D 
I nt erv e nti o n 
i n dic at e d ( e. g., 
a nti hist a mi n es) 
S ev er e si g ns a n d 
sy m pt o ms A N D 
Hi g h er l ev el 
i nt erv e nti o n i n dic at e d 
( e. g., st er oi ds or I V 
fl ui ds) 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
r e q uiri n g pr ess or or 
v e ntil at or s u p p ort) 
U n d er w ei g ht 1 2
> 5 t o 1 9 y e ars of 
a g e 
N A 
W H O B MI z -sc or e < 
-2 t o ≤ -3 
W H O B MI z -sc or e < -
3 
W H O B MI z -sc or e < -3 
wit h lif e -t hr e at e ni n g 
c o ns e q u e nc es 
2 t o 5 y e ars of a g e 
N A 
W H O W ei g ht -f or-
h ei g ht z -sc or e 
< -2 t o ≤ -3 
W H O W ei g ht -f or-
h ei g ht z -sc or e < -3 
W H O W ei g ht -f or-h ei g ht 
z-sc or e < -3 wit h lif e -
t hr e at e ni n g 
c o ns e q u e nc es 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
8 9
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
< 2 y e ars of a g e 
N A 
W H O W ei g ht -f or-
l e n gt h z-sc or e 
< -2 t o ≤ -3 
W H O W ei g ht -f or-
l e n gt h z-scor e < -3 
W H O W ei g ht -f or-l e n gt h 
z-sc or e < -3 wit h lif e -
t hr e at e ni n g 
c o ns e q u e nc es 
W ei g ht L o s s 
( excl u d es p ost p art u m 
w ei g ht l oss) 
N A 
5 t o < 9 % l oss i n 
b o dy w ei g ht fr o m 
b as eli n e 
≥ 9 t o < 2 0 %  l oss i n 
b o dy w ei g ht fr o m 
b as eli n e 
≥ 2 0 % l oss i n b o dy 
w ei g ht fr o m b as eli n e O R 
A g gr essiv e i nt erv e nti o n 
i n dic at e d ( e. g., t u b e 
f e e di n g, t ot al p ar e nt er al 
n utriti o n) 
U RI N A R Y
Uri n ar y Tr a ct 
O b str u cti o n 
N A 
Si g ns or sy m pt o ms 
of uri n ary tr act 
o bstr ucti o n wit h o ut 
hy dr o n e p hr osis or 
r e n al dysf u ncti o n 
Si g ns or sy m pt o ms of 
uri n a ry tr act 
o bstr ucti o n wit h 
hy dr o n e p hr osis or 
r e n al dysf u ncti o n 
O bstr ucti o n c a usi n g lif e -
t hr e at e ni n g 
c o ns e q u e nc es 
SI T E R E A C TI O N S T O I NJ E C TI O N S A N D I N F U SI O N S
I nj e cti o n Sit e P ai n 
or T e n d er n e s s 
R e p ort o nly o n e 
P ai n or 
t e n d er n ess 
c a usi n g n o or 
mi ni m al li mi t ati o n 
of us e of li m b 
P ai n or t e n d er n ess 
c a usi n g gr e at er 
t h a n mi ni m al 
li mit ati o n of us e of 
li m b 
P ai n or t e n d er n ess 
c a usi n g i n a bility t o 
p erf or m us u al s oci al 
& f u ncti o n al activiti es 
P ai n or t e n d er n ess 
c a usi n g i n a bility t o 
p erf or m b asic s elf -c ar e 
f u ncti o n O R 
H os pit aliz ati o n i n dic at e d 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s 1 3 
R e p ort o nly o n e 
> 1 5 y e ars of a g e 
2. 5 t o < 5 c m i n 
di a m et er O R 6. 2 5 
t o < 2 5 c m 2 
s urf ac e ar e a A N D 
Sy m pt o ms 
c a usi n g n o or 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al 
activiti es 
≥ 5 t o < 1 0 c m i n 
di a m et er O R ≥ 2 5 
t o < 1 0 0 c m 2 
s urf ac e ar e a O R 
Sy m pt o ms c a usi n g 
gr e at er t h a n 
mi ni m al 
i nt erf er e nc e wit h 
us u al s oci al & 
f u ncti o n al activiti es 
≥ 1 0 c m i n di a m et er 
O R ≥ 1 0 0 c m 2 
s urf ac e ar e a O R 
Ulc er ati o n O R 
S ec o n d ary i nf ecti o n 
O R P hl e bitis O R
St eril e a bsc ess O R 
Dr ai n a g e O R 
Sy m pt o ms c a usi n g 
i n a bility t o p erf or m 
us u al s oci al & 
f u ncti o n al activiti es 
P ot e nti ally lif e -
t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
a bsc ess, exf oli ativ e 
d er m atitis, n ecr osis 
i nv olvi n g d er mis or 
d e e p er tiss u e) 
≤ 1 5 y e ars of a g e 
≤2. 5 c m i n 
di a m et er 
> 2. 5 c m i n 
di a m et er wit h < 
5 0 % s urf ac e ar e a 
of t h e extr e mity 
s e g m e nt i nv olv e d 
( e. g., u p p er ar m or 
t hi g h) 
≥ 5 0 % s urf ac e ar e a 
of t h e extr e mity 
s e g m e nt i nv olv e d 
( e. g., u p p er ar m or 
t hi g h) O R Ulc er ati o n 
O R S ec o n d ary 
i nf ecti o n O R P hl e bitis 
O R St eril e a bsc ess 
O R Dr ai n a g e 
P ot e nti ally lif e -
t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
a bsc ess, exf oli ativ e 
d er m atitis, n ecr osis 
i nv olvi n g d er mis or 
d e e p er tiss u e) 
I nj e cti o n Sit e 
I n d ur ati o n or 
S w elli n g 
R e p ort o nly o n e 
> 1 5 y e ars of a g e 
S a m e as f or 
I nj e ctio n Sit e 
Er yt h e m a or 
R e d n e s s, > 1 5 
y e ars of a g e 
S a m e as f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, > 1 5 
y e ars of a g e 
S a m e as f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, > 1 5 y e ars 
of a g e 
S a m e as f or I nj e cti o n 
Sit e Er yt h e m a or 
R e d n e s s, > 1 5 y e ars of 
a g e 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
9 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
≤ 1 5 y e ars of a g e 
S a m e as f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, ≤ 1 5 
y e ars of a g e 
S a m e as f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, ≤ 1 5 
y e ars of a g e 
S a m e as f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, ≤ 1 5 y e ars 
of a g e 
S a m e as f or I nj e cti o n 
Sit e Er yt h e m a or 
R e d n e s s, ≤ 1 5 y e ars of 
a g e 
I nj e cti o n Sit e 
Pr urit u s 
Itc hi n g l oc aliz e d 
t o t h e i nj ecti o n 
sit e t h at is 
r eli ev e d 
s p o nt a n e o usly or 
i n < 4 8 h o urs of 
tr e at m e nt 
Itc hi n g b ey o n d t h e 
i nj ecti o n sit e t h at is 
n ot g e n er aliz e d O R 
Itc hi n g l oc aliz e d t o 
t h e i nj ecti o n sit e 
r e q uiri n g ≥ 4 8 
h o urs tr e at m e nt 
G e n er aliz e d itc hi n g 
c a usi n g i n a bility t o 
p erf or m us u al s oci al 
& f u ncti o n al activiti es 
N A 
L A B O R A T O R Y V A L U E S C h e mistri es
A ci d o si s 
N A 
p H ≥ 7. 3 t o < L L N 
p H < 7. 3 wit h o ut lif e -
t hr e at e ni n g 
c o ns e q u e nc es 
p H < 7. 3 wit h l if e-
t hr e at e ni n g 
c o ns e q u e nc es 
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 n e 
P h o s p h at a s 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 o si s 
N A 
p H > U L N t o ≤ 7. 5 
p H > 7. 5 wit h o ut lif e -
t hr e at e ni n g 
c o ns e q u e nc es 
p H > 7. 5 wit h lif e -
t hr e at e ni n g 
c o ns e q u e nc es 
A L T or S G P T, Hi g h 
R e 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 a s e 
( P a n cr e ati c) or 
A m yl a s e ( T ot al), 
Hi g h 
R e 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 
R e 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 
Bi c 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 e ct 
Bilir u bi n 1 4, Hi g h 
> 2 8 d ays of a g e 
N A 
N A 
> U L N 
> U L N wit h lif e -
t hr e at e ni n g 
c o ns e q u e nc es ( e. g., 
si g ns a n d sy m pt o ms of 
liv er f ail ur e) 
≤ 2 8 d ays 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 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
9 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
T ot al Bilir u bi n, Hi g h 
> 2 8 d ays 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 ays of a g e 
T ot al Bilir u bi n f or 
T er m a n d Pr et er m 
N e o n at es 
T ot al Bilir u bi n f or 
T er m a n d Pr et er m 
N e o n at es 
T ot al Bilir u bi n f or 
T er m a n d Pr et er m 
N e o n at es 
T ot al Bilir u bi n f or T er m 
a n d Pr et er m N e o n at es 
C al ci u m, Hi g h 
( m g/ d L; m m ol/ L ) 
≥ 7 d ays 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 ays 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 al ci u m (I o niz e 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 al ci u m, L o w 
( m g/ d L; m m ol/ L ) 
≥ 7 d ays 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 ays 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 al ci u m (I o niz e 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 a c Tr o p o ni n I, 
Hi g h 
N A 
N A 
N A 
L ev els c o nsist e nt wit h 
my oc ar di al i nf arcti o n or 
u nst a bl e a n gi n a as 
d efi n e d by t h e l oc al 
l a b or at ory 
Cr e ati n e Ki n a s 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 
Cr e ati ni n e, Hi g h 
1. 1 t o 1. 3 x U L N 
> 1. 3 t o 1. 8 x U L N 
O R I ncr e as e of > 
0. 3 m g/ d L a b ov e 
b as eli n e 
> 1. 8 t o < 3. 5 x U L N 
O R I ncr e as e of 1. 5 t o 
< 2. 0 x a b ov e 
b as eli n e 
≥ 3. 5 x U L N O R 
I ncr e as e of ≥ 2. 0 x 
a b ov e b as eli n e 
Cr e ati ni n e 
Cl e ar a n c e 1 5 or
e G F R, L o w 
R e 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 ecr e as e fr o m 
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 ecr e as e fr o m 
b as eli n e 
< 3 0 ml/ mi n or 
ml/ mi n/ 1. 7 3 m 2 O R ≥ 
5 0 % d ecr e as e fr o m 
b as eli n e or di alys is 
n e e d e d 
Gl u c o s e 
( m g/ d L; m m ol/ L ) 
F a sti 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 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
9 2
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
N o nf a sti 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 
Gl u c o s 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 
L a ct 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 ncr e as e d l act at e wit h 
p H < 7. 3 wit h o ut lif e -
t hr e at e ni n g 
c o ns e q u e nc es 
I ncr e as e d l act at e wit h 
p H < 7. 3 wit h lif e -
t hr e at e ni n g 
c o ns e q u e nc es 
Li p a s 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 Di s or d er s 
( m g/ d L; m m o l/ L) 
C h ol e st er ol, 
F a sti n g, Hi g h 
≥ 1 8 y e 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 y e 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 a sti n g, Hi g h 
≥ 1 8 y e 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 y e 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 gl y c eri d e s, 
F a sti 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 n e si u m 16, 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 o s p h at e, L o w 
( m g/ d L; m m ol/ L ) 
> 1 4 y e ars of a g e 
2. 0 t o < L L N 
0. 8 1 t o < L L N 
1. 4 t o < 2. 0 
0. 6 5 t o < 0. 8 1 
1. 0 t o < 1. 4 
0. 3 2 t o < 0. 6 5 
< 1. 0 
< 0. 3 2 
1 t o 1 4 y e 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 y e 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 a s si 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 a s si 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 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
9 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
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 5 
1 2 1 t o < 1 2 5 
1 2 1 t o < 1 2 5 
≤ 1 2 0 
≤ 1 2 0 
Uri c A ci 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 
H e m at ol o gy
A b s ol ut e C D 4 + 
C o u nt, L o w 
(c ell/ m m3; c ells/ L) 
> 5 y e ars of a g e ( n ot 
HI V i nf ect 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 b s ol ut e 
L y m p h o c yt e C o u nt, 
L o w 
(c ell/ m m3; c ells/ L) 
> 5 y e ars of a g e 
( n ot HI V i nf ect 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 b s ol ut e N e utr o p hil 
C o u nt ( A N C), L o w 
(c ells/ m m3; c ells/ L) 
> 7 d ays 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 ays 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 ay 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, 
D e cr e a s 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 oci at e d wit h 
gr oss bl e e di n g 
H e m o gl o bi n 17, L o w 
( g/ d L; m m ol/ L )1 8 
≥ 1 3 y e ars of a g e 
( m al e 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 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
9 4
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
≥ 1 3 y e ars of a g e 
(f e m al e 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 
5 7 d ays of a g e t o < 
1 3 y e ars of a g e 
( m al e a n d f e m al e) 
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 ays of a g e 
( m al e a n d f e m al e) 
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 ays of a g e 
( m al e a n d f e m al e) 
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 ays of a g e 
( m al e a n d f e m al e) 
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 ays of a g e 
( m al e a n d f e m al e) 
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 ul ati o n 
t h er a py) 
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 h e 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 ul ati o n 
t h er a py) 
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 at el et s, 
D e cr e a s e d 
(c ells/ m m 3; c ells/ L) 
1 0 0, 0 0 0 t o < 
1 2 4, 9 9 9 1 0 0. 0 0 0 
x 1 0 9 t o < 1 2 4. 9 9 9 
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 ul ati o n 
t h er a py 
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, D e cr e a s e d 
(c ells/ m m3; c ells/ L) 
> 7 d ays 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

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
9 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
≤ 7 d ays 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. 49 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
Uri n alysis
Gl y c o s uri a ( r a n d o m 
c oll ecti o n t est e d by 
di pstick) 
Tr ac e 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 
H e m at uri a ( n ot t o b e 
r e p ort e d b as e d o n 
di pstick fi n di n gs or 
o n bl o o d b eli ev e 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 w er 
fi el d 
≥ 1 0 R B Cs p er hi g h 
p o w er fi el d 
Gr oss, wit h or wit h o ut 
cl ots O R Wit h R B C 
c asts O R I nt erv e nti o n 
i n dic at e d 
Lif e -t hr e at e ni n g 
c o ns e q u e nc es 
Pr ot ei n uri a (ra n d o m 
c oll ecti o n t est e d by 
di pstick) 
1 + 
2 + 
3 + or hi g h er 
N A 
1.
Bl o o d pr ess ur e n or ms f or c hil dr e n < 1 8 y e ars of a g e c a n b e f o u n d i n: Ex p ert P a n el o n I nt e gr at e d G ui d eli n es f or 
C ar di ov asc ul ar H e alt h a n d Risk R e d ucti o n i n C hil dr e n a n d A d ol esc e nts. P e di atrics 2 0 1 1 ; 1 2 8; S 2 1 3; ori gi n ally 
p u blis h e d o nli n e N ov e 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.  
2.
As p er B az ett’s f or m ul a.  
3.
F or pr urit us ass oci at e d wit h i nj ecti o ns or i nf usi o ns, s e e t h e Sit e R e acti o ns t o I nj ecti o ns a n d I nf usi o ns s ecti o n 
( p a g e 2 3).  
4.
D efi niti o n: A dis or d er c h ar act eriz e d by f at l oss i n t h e f ac e, extr e miti es, a n d b utt ocks. 
5.
D efi niti o n: A dis or d er c h ar act eriz e d by a b n or m al f at acc u m ul ati o n o n t h e b ack of t h e n eck, br e asts, a n d a b d o m e n.  
6.
B M D t a n d z sc or es c a n b e f o u n d i n: K a nis J A o n b e h alf of t h e W orl d H e alt h Or g a niz ati o n Sci e ntific Gr o u p ( 2 0 0 7).
Ass ess m e nt of ost e o p or osis at t h e pri m ary h e alt h -c ar e l ev el. T ec h nic al R e p ort. W orl d H e alt h Or g a niz ati o n 
C oll a b or ati n g C e ntr e f or M et a b olic B o n e Dis e as es, U niv ersity of S h effi el d, U K. 2 0 0 7: Pri nt e d by t h e U niv ersity of 
S h effi el d.  
7.
D efi niti o n: A d eliv ery of a liv e -b or n n e o n at e occ urri n g at ≥ 2 0 t o < 3 7 w e eks g est ati o n al a g e. 
8.
D efi niti o n: A cli nic ally r ec o g niz e d pr e g n a ncy occ urri n g at < 2 0 w e eks g est ati o n al a g e.  
9.
D efi niti o n: A dis or d er c h ar act eriz e d by n a us e a, h e a d ac h e, t ac hyc ar di a, hy p ot e nsi o n, r as h, a n d/ or s h ort n ess of 
br e at h. 
1 0.
F or p ai n ass oci at e d wit h i nj ecti o ns or i nf usi o ns, s e e t h e Sit e R e acti o ns t o I nj ecti o ns a n d I nf usi o ns s ecti o n ( p a g e 
2 3).
1 1.
D efi niti o n: A dis or d er c h ar act eriz e d by f ev er, art hr al gi a, my al gi a, ski n er u pti o ns, ly m p h a d e n o p at hy, m ark e d 
disc o mf ort, a n d/ or dys p n e a.
1 2.
W H O r ef er e nc e t a bl es m ay b e acc es e d by clicki n g t h e d esir e d a g e r a n g e or by acc essi 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 hr ef/ w h o 2 0 0 7 _ b mi _f or _ a g e/ e n/ f or p artici p a nts > 5 t o 1 9 y e ars of a g e a n d 
htt p:// w w w. w h o.i nt/c hil d gr o wt h/st a n d ar ds/c h art _c at al o g u e/ e n/ f or t h os e ≤ 5 y e ars of a g e.  
1 3.
I nj ecti o n Sit e Eryt h e m a or R e d n ess s h o ul d b e ev al u at e d a n d gr a d e d usi n g t h e gr e at est si n gl e di a m et er or 
m e as ur e d s urf ac e ar e a. 
1 4.
Dir ect bilir u bi n > 1. 5 m g/ d L i n a p artici p a nt < 2 8 d ays of a g e s h o ul d b e gr a d e d as gr a d e 2, if < 1 0 % of t h e t ot al 
bilir u bi n.  
1 5.
Us e t h e a p plic a bl e f or m ul a (i. e., C ockr oft -G a ult i n m L/ mi n or Sc h w atrz i n m L/ mi n/ 1. 7 3 m 2).  
1 6.
T o c o nv ert a m a g n esi u m v al u e fr o m m g/ d L t o m m ol/ L , l a b or at ori es s h o ul d m ulti ply by 0. 4 1 1 4.  
1 7.
M al e a n d f e m al e s ex ar e d efi n e d as s ex at birt h. 
1 8.
T h e c o nv ersi o n f act or us e d t o c o nv ert g/ d L t o m m ol/ L is 0. 6 2 0 6 a n d is t h e m ost c o m m o nly us e d c o nv ersi o n f act or. 
F or gr a di n g h e m o gl o bi n r es ults o bt ai n e d by a n a n al ytic m et h o d wit h a c o nv ersi o n f act or ot h er t h a n 0. 6 2 0 6, t h e 
r es ult m ust b e c o nv ert e d t o g/ d L usi n g t h e a p pr o pri at e c o nv ersi o n f act or f or t h e p artic ul ar l a b or at ory.  

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
9 6
1 2. 5.
A p p e n di x 5: T o xi cit y  M a n a g e m e nt
A N E MI A
Gr a de 1 ( mil d) he m o gl o bi n decre ase:
A n y  he m o gl o bi n decrease meeti n g t he defi niti o n of Gra de 1 m ust be re peate d wit h t he 
f oll o wi n g a d diti o nal tests:

peri p heral bl o o d s mear

i n direct bilir u bi n 
(a b n or mal if i ncrease d > 5 0 % fr o m baseli ne)

ha pt o gl o bi n
(a b n or mal if 2 5 m g/ d L)

retic ul oc yte c o u nt
(a b n or mal if 4 % ) 
If t he a d diti o nal tests are wit hi n t he n or mal ra n ge, s u bjects ma y c o nti n ue st u d y 
me dicati o n.  If o ne or m ore of t he a d diti o nal tests is a b n or mal or s u g gesti ve of he m ol y tic 
a ne mia as s pecifie d a b o ve, s u bjects will per ma ne ntl y  disc o nti n ue st u d y me dicati o n a n d 
be wit h dra w n fr o m t he trial.  S u bjects s h o ul d be f oll o we d u p u ntil res ol uti o n of a ne mia.
Gr a de 2 ( m o der ate) he m o gl o bi n decre ase:
A n y  he m o gl o bi n decrease meeti n g t he defi niti o n of Gra de 2 m ust be re peate d wit h t he 
f oll o wi n g a d diti o nal tests:

peri p heral bl o o d s mear

i n direct bilir u bi n 
(a b n or mal if i ncrease d > 5 0 % fr o m baseli ne)

ha pt o gl o bi n
(a b n or mal if 2 5 m g/ d L)

retic ul oc yte c o u nt
(a b n or mal if 4 %) 
If t he a d diti o nal tests are wit hi n t he n or mal ra n ge, s u bjects ma y c o nti n ue st u d y 
me dicati o n.  If o ne or m ore of t he a d diti o nal tests is a b n or mal or s u g gesti ve of he m ol y tic 
a ne mia as s pecifie d a b o ve, s u bjects will per ma ne ntl y  disc o nti n ue st u d y me dicati o n a n d 
be wit h dra w n fr o m t he trial.  C o ns ultati o n wit h a He mat ol o gist s h o ul d be c o nsi dere d.  
S u bjects s h o ul d be f oll o we d u p u ntil res ol uti o n of a ne mia.
Gr a de 3 (se vere) or Gr a de 4 ( p ote nti all y life t hre ate ni n g) he m o gl o bi n decre ase:
A n y  he m o gl o bi n decrease meeti n g t he defi niti o n of Gra de 3 or 4 m ust be re peate d wit h 
t he f oll o wi n g a d diti o nal tests:

peri p heral bl o o d s mear

i n direct bilir u bi n

ha pt o gl o bi n

retic ul oc yte c o u nt 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
9 7
S u bjects will per ma ne ntl y disc o nti n ue st u d y me dicati o n a n d be wit h dra w n fr o m t he trial.  
C o ns ultati o n wit h a He mat ol o gist s h o ul d be c o nsi dere d.  S u bjects s h o ul d be f oll o we d u p 
u ntil res ol uti o n of a ne mia.
T O T A L BI LI R U BI N E L E V A TI O N
Gr a de 1 ( mil d) bilir u bi n ele v ati o n ( 1. 1 - 1. 5 ti mes U L N) or Gr a de 2 ( m o der ate - 1. 6-
2. 5 ti mes U L N):
A n y  bilir u bi n val ue a b o ve t he u p per li mit of n or mal m ust be re peate d a n d fracti o nate d 
( direct a n d i n direct bilir u bi n).  S u bjects ma y c o nti n ue st u d y me dicati o n.  S u bjects s h o ul d 
be f oll o we d u p u ntil res ol uti o n (ret ur n t o baseli ne) of ele vati o n.
Gr a de 3 (se vere – 2. 6 -5. 0 ti mes U L N) or 4 (life -t hre ate ni n g - > 5. 0 ti mes U L N) 
bilir u bi n ele v ati o n:
A n y  bilir u bi n val ue a b o ve t he u p per li mit of n or mal m ust be re peate d a n d fracti o nate d 
( direct a n d i n direct bilir u bi n).  S u bjects will per ma ne ntl y disc o nti n ue st u d y me dicati o n 
a n d be wit h dra w n fr o m t he trial.  S u bjects s h o ul d be f oll o we d u p u ntil res ol uti o n (ret ur n 
t o baseli ne) of bilir u bi n ele vati o n.
A S T A N D A L T E L E V A TI O N
See A p pe n di x 2 .
R A S H
Gr a de 1 r as h ( L oc alize d m ac ul ar r as h):
S u bjects wit h Gra de 1 ras h s h o ul d be e val uate d b y  t he I n vesti gat or i m me diatel y.  A 
der mat ol o gist ma y  be c o ns ulte d a n d a bi o ps y  ma y be o btai ne d if rec o m me n de d b y t he 
der mat ol o gist.  T he st u d y dr u g s h o ul d be per ma ne ntl y  disc o nti n ue d if t he f oll o wi n g si g ns 
or s y m pt o ms are n ote d at a n y  ti me:

Te m perat ure > 3 8. 5° C

L y m p ha de n o pat h y

P har y n gitis

A n y  i n dicati o n of i nter nal or ga n i n v olve me nt ( he patitis, ne p hritis)
I n t he a bse nce of t he a b o ve si g ns or sy m pt o ms, s u bjects wit h Gra de 1 ras h ma y  c o nti n ue 
t he st u d y dr u g at t he discreti o n of t he I n vesti gat or.  T he s u bject s h o ul d be a d vise d t o 
c o ntact t he I n vesti gat or i m me diatel y if t here is a ny w orse ni n g of t he ras h, if a n y  sys te mic 
si g ns or sy m pt o ms w orse n, or if m uc osal ulcerati o n de vel o ps. If t he ras h is c o nsi dere d t o 
be m ost li kel y  d ue t o c o nc o mita nt ill ness or n o n-st u d y me dicati o n, sta n dar d ma na ge me nt, 
i ncl u di n g disc o nti n uati o n of t he li kel y ca usati ve a ge nt, s h o ul d be u n derta ke n. If n o ot her 
ca usati ve fact or is f o u n d after cli nical e val uati o n, t he s u bject ma y  be treate d 
s ym pt o maticall y u ntil t he ras h res ol ves. A nti hista mi nes, t o pical c ortic oster oi ds or 
a nti pr uritic a ge nts ma y be prescri be d.  T he s u bject s h o ul d re mai n o n t he st u d y  t o be 
f oll o we d f or safety a n d P K as o utli ne d i n t he Ti me a n d E ve nts ta ble.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
9 8
Gr a de 2 r as h ( Diff use m ac ul ar, m ac ul o p a p ul ar, or m or billif or m r as h O R T ar get 
lesi o ns):
S u bjects wit h Gra de 2 ras h s h o ul d be e val uate d b y  t he I n vesti gat or i m me diatel y.  Di gital 
p h ot o gra p hs s h o ul d be o btai ne d.  A der mat ol o gist ma y  be c o ns ulte d a n d a bi o ps y ma y be 
o btai ne d if rec o m me n de d b y  t he der mat ol o gist.  T he st u d y dr u g s h o ul d be per ma ne ntly 
disc o nti n ue d if t he f oll o wi n g si g ns or s y m pt o ms ar e n ote d at a n y ti me:

Te m perat ure > 3 8. 5° C

L y m p ha de n o pat h y

P har y n gitis

A n y  i n dicati o n of i nter nal or ga n i n v ol ve me nt ( he patitis, ne p hritis)
I n t he a bse nce of t he a b o ve si g ns or sy m pt o ms, s u bjects wit h Gra de 2 ras h ma y  c o nti n ue 
t he st u d y dr u g at t he discreti on of t he I n vesti gat or.  I t s h o ul d be n ote d t hat oral m uc osal 
er osi o ns ma y  be part of a Gra de 2 ras h.  A n y m uc osal ulcer ati o n i ncreases t he se verity 
of t he ras h t o at least Gra de 3.  T he s u bject s h o ul d be a d vise d t o c o ntact t he I n vesti gat or 
i m me diatel y if there is a n y  w orse ni n g of t he ras h, if a n y sys te mic si g ns or s ym pt o ms 
w orse n, or if m uc osal ulcerati o n de vel o ps. If t he ras h is c o nsi dere d t o be m ost li kel y  d ue 
t o c o nc o mita nt ill ness or n o n-st u d y me dicati o n, sta n dar d ma na ge me nt, i ncl u di n g 
disc o nti n uati o n o f t he li kel y ca usati ve a ge nt, s h o ul d be u n derta ke n. If n o ot her ca usati ve 
fact or is f o u n d after cli nical e val uati o n, t he s u bject ma y be treate d sy m pt o maticall y  u ntil 
t he ras h res ol ves. A nti hista mi nes, t o pical c ortic oster oi ds or a nti pr uritic a ge nts ma y be 
p rescri be d.  T he s u bject s h o ul d re mai n o n t he st u d y t o be f oll o we d f or safet y a n d P K as 
o utli ne d i n t he Ti me a n d E ve nts ta ble.
Gr a de 3 r as h ( Diff use m ac ul ar, m ac ul o p a p ul ar, or m or billif or m r as h wit h vesicles 
or li mite d n u m ber of b ull ae O R S u perfici al ulcer a ti o ns of m uc o us me m br a ne 
li mite d t o o ne site):
S u bjects wit h a Gra de 3 ras h will per ma ne ntl y disc o nti n ue t he st u d y me dicati o n.  T he 
s u bject s h o ul d be e val uate d i n t he p h ysicia n’s office i m me diatel y a n d s h o ul d be see n i n 
t he p h ysicia n’s office or c o ntacte d b y  p h o ne e ver y 2 da ys u ntil t he ras h res ol ves.  A 
der mat ol o gist s h o ul d be c o ns ulte d a n d di gital p h ot o gra p hs a n d a bi o ps y s h o ul d be 
o btai ne d.  A nti hista mi nes, t o pical c ortic oster oi ds or a nti pr uritic a ge nts ma y be prescri be d 
at t he discreti o n of t he I nvesti g at or.  T he s u bject s h o ul d be a d vise d t o c o ntact t he 
I n vesti gat or i m me diately if t here is a n y w orse ni n g of t he ras h, if a n y s ys te mic si g ns or 
s ym pt o ms a p pear, or if m uc osal i n v ol ve me nt de vel o ps.  T he s u bject s h o ul d re mai n o n t he 
st u d y t o be f oll o we d f or safet y a n d P K as o utli ne d i n t he Ti me a n d E ve nts ta ble.
Gr a de 4 r as h ( E xte nsi ve or ge ner alize d b ull o us lesi o ns O R Ste ve ns -J o h ns o n 
s y n dr o me O R Ulcer ati o n of m uc o us me m br a ne i n v ol vi n g t w o or m ore disti nct 
m uc os al sites O R T o xic e pi der m al necr ol ysis ( T E N)):
S u bj ects wit h a Gra de 4 ras h will per ma ne ntl y disc o nti n ue t he st u d y me dicati o n.  A 
der mat ol o gist s h o ul d be c o ns ulte d a n d di gital p h ot o gra p hs a n d a bi o ps y s h o ul d be 
o btai ne d.  S p o ns or a n d G S K Me dical M o nit or s h o ul d be n otifie d of t his seri o us a d verse 
e ve nt wit hi n 2 4 hr via p h o ne or fa x or e mail .  T he s u bject s h o ul d be cl osely f oll o we d 
e ver yd a y  u ntil res ol uti o n of t he reacti o n.  T he s u bject s h o ul d re mai n o n t he st u d y t o be 
f oll o we d f or safety a n d P K as o utli ne d i n Ti me a n d E ve nts ta ble.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
9 9
A L L E R GI C R E A C TI O N
Gr a de 1 a ller gic re acti o n ( Pr uitis wit h o ut r as h):
S u bjects wit h Gra de 1 aller gic reacti o n s h o ul d be e val uate d b y t he I n vesti gat or 
i m me diatel y.  T he st u dy dr u g s h o ul d be per ma ne ntl y  disc o nti n ue d if t he f oll o wi n g si g ns 
or s y m pt o ms are n ote d at a n y  ti me:

Te m perat ure > 3 8. 5° C

E osi n o p hilia

Res pirat or y  i n v ol ve me nt i ncl u di n g br o nc h os pas m, lar yn g os pas m, or a n gi oe de ma

A n y  i n dicati o n of i nter nal or ga n i n v ol ve me nt ( he patitis, ne p hritis)
I n t he a bse nce of t he a b o ve si g ns or sy m pt o ms, s u bjects wit h Gra de 1 aller gic reacti o n 
ma y  c o nti n ue t he st u d y dr u g at t he discreti o n of t he I n vesti gat or.  T he s u bject s h o ul d be 
a d vise d t o c o ntact t he I nvesti gat or i m me diatel y if t here is a n y w orse ni n g of t he aller gic 
reacti o n a n d/ or if a ny s ys te mic si g ns or sy m pt o ms w orse n.  If t he aller gic react i o n is 
c o nsi dere d t o be m ost li kel y d ue t o c o nc o mita nt ill ness or n o n-st u d y me dicati o n, sta n dar d 
ma na ge me nt, i ncl u di n g disc o nti n uati o n of t he li kel y  ca usati ve a ge nt, s h o ul d be 
u n derta ke n.  If n o ot her ca usati ve fact or is f o u n d after cli nical e val uati o n, t he s u bject ma y 
be treate d s y m pt o maticall y  u ntil t he ras h res ol ves. A nti hista mi nes, t o pical c ortic oster oi ds 
or a nti pr uritic a ge nts ma y be prescri be d.  T he s u bject s h o ul d re mai n o n t he st u d y  t o be 
f oll o we d f or safety a n d P K as o utli ne d i n t he Ti me a n d E ve nts ta ble.
Gr a de 2 aller gic re acti o n ( L oc alize d urtic ari a):
S u bjects wit h Gra de 2 aller gic reacti o n s h o ul d be e val uate d b y t he I n vesti gat or 
i m me diatel y.  T he st u dy dr u g s h o ul d be per ma ne ntl y  disc o nti n ue d if t he f oll o wi n g si g ns 
or s y m pt o ms are n ote d at a n y  ti me:

Te m perat ure > 3 8. 5° C

E osi n o p hilia

Res pirat or y  i n v ol ve me nt i ncl u di n g br o nc h os pas m, lar yn g os pas m, or a n gi oe de ma

A n y  i n dicati o n of i nter nal or ga n i n v ol ve me nt ( he patitis, ne p hritis)
I n t he a bse nce of t he a b o ve si g ns or sy m pt o ms, s u bjects wit h Gra de 2 aller gi c reacti o n 
ma y  c o nti n ue t he st u d y dr u g at t he discreti o n of t he I n vesti gat or.  T he s u bject s h o ul d be 
a d vise d t o c o ntact t he I nvesti gat or i m me diatel y if t here is a n y w orse ni n g of t he aller gic 
reacti o n a n d/ or if a ny s ys te mic si g ns or sy m pt o ms w orse n.  If t he aller gic reacti o n is 
c o nsi dere d t o be m ost li kel y d ue t o c o nc o mita nt ill ness or n o n-st u d y me dicati o n, sta n dar d 
ma na ge me nt, i ncl u di n g disc o nti n uati o n of t he li kel y  ca usati ve a ge nt, s h o ul d be 
u n derta ke n.  If n o ot her ca usati ve fact or is f o u n d after cli nical e val uati o n, t he s u bject ma y 
be treate d s y m pt o maticall y  u ntil t he ras h res ol ves. A nti hista mi nes, t o pical c ortic oster oi ds 
or a nti pr uritic a ge nts ma y be prescri be d.  T he s u bject s h o ul d re mai n o n t he st u d y  t o be 
f oll o we d f or safety a n d P K as o utli ne d i n t he Ti me a n d E ve nts ta ble.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
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1 0 0
Gr a de 3 aller gic re acti o n ( Ge ner alize d urtic ari a or a n gi oe de m a):
S u bjects will per ma ne ntl y disc o nti n ue t he st u d y me dicati o n a n d be wit h dra w n fr o m t he 
trial.  S u bjects will be treate d as cli nicall y a p pr o priate.  S u bjects s h o ul d be f ollo we d u p 
u ntil res ol uti o n of t he a d verse e ve nt a n d sta n dar d ma na ge me nt s h o ul d be u n derta ke n.
Gr a de 4 aller gic re acti o n ( A n a p h yl a xis):
S u bjects will per ma ne ntl y disc o nti n ue t he st u d y me dicati o n a n d be wit h dra w n fr o m t he 
trial.  S u bjects will be treate d as cli nically a p pr o priate.  S u bjects s h o ul d be f oll o we d u p 
u ntil res ol uti o n of t he a d verse e ve nt a n d sta n dar d ma na ge me nt s h o ul d be u n derta ke n.
R e vi s e d A C T G T o xi cit y Gr a d e
D efi niti o n s
I n v e sti g at or A cti o n
Gr a d e 1
Pr urit us wit h o ut r as h
M ay c o nti n u e t h er a py
Gr a d e 2
L oc aliz e d urtic ari a
M ay c o nti n u e t h er a py
Gr a d e 3
G e n er aliz e d urtic ari a
A n gi o e d e m a
Disc o nti n u e T h er a py
Gr a d e 4
A n a p hyl axis
Disc o nti n u e T h er a py

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 0 1
1 2. 6.
A p p e n di x 6: C oll e cti o n of Pr e g n a n c y  I nf or m ati o n

I n vesti gat or will c ollect pre g na nc y i nf or mati o n o n a n y fe male s u bject, w h o bec o mes 
pre g na nt w hile partici pati n g i n t his st u d y

I nf or mati o n will be rec or de d o n t he a p pr o priate f or m a n d s u b mitte d t o G S K wit hi n 2 
wee ks of lear ni n g of a s u bject's pre g na nc y .

S u bject will be f oll o we d t o deter mi ne t he o utc o me of t he pre g n a nc y. T he 
i n vesti gat or will c ollect f oll o w u p i nf or mati o n o n m ot her a n d i nfa nt, w hic h will be 
f or war de d t o G S K.  Ge nerally, f oll o w - u p will n ot be re q uire d f or l o n ger t ha n 6 t o 8 
wee ks be y o n d t he esti mate d deli ver y  date. 

A n y  ter mi nati o n of pre g na nc y will be re p orte d, re gar dless of fetal stat us ( prese nce or 
a bse nce of a n o malies) or i n dicati o n f or pr oce d ure.

W hile pre g na nc y  itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na nc y 
c o m plicati o n or electi ve ter mi nati o n of a pre g na nc y will be re p orte d as a n A E or 
S A E.

A s p o nta ne o us a b orti o n is al wa y s c o nsi dere d t o be a n S A E a n d will be re p orte d as 
s uc h.  

A n y  S A E occ urri n g as a res ult of a p ost-st u d y pre g na nc y w hic h is c o nsi dere d 
reas o na bly  relate d t o t he st u d y treat me nt b y t he i n vesti gat or, will be re p orte d t o G S K 
as descri be d i n A p pe n di x 3 . W hile t he i n vesti gat or is n ot o bli gate d t o acti vel y see k 
t his i nf or mati o n i n f or mer st u d y partici pa nts, he or s he ma y lear n of a n S A E t hr o u g h 
s p o nta ne o us re p orti n g.
A n y fe m ale s u bject w h o bec o mes pre g n a nt w hile p artici p ati n g 

Oral P hase:  Will cease t o ha ve a n y dr u g a d mi nistere d, b ut will c o nti n ue t o recei ve 
safety, cli nical a n d la b orat or y m o nit ori n g t o mi ni mize f urt her e x p os ure t o t he fet us.

I njecti o n P hase:  will c o nti n ue t o recei ve safety, cli nical a n d la b orat or y  m o nit ori n g 
t hr o u g h t he c o m pleti o n of t he pre g na nc y.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 0 2
1 2. 7.
A p p e n di x 7: S c h e d ul e f or A d diti o n al L a b or at or y  Pr o c e d ur e s 
f or E nr oll e d P arti ci p a nt s w h o h a v e a R e a cti v e P o siti v e HI V 
T e st R e s ult ( P o st -HI V C o nfir m ati o n Vi sit)
P o st -HI V C o nfir m ati o n Vi sit
R ef er f or c ar e
X
HI V C o u ns eli n g 
X
Off er C o n d o ms
X
Cli ni c al E v al u ati o n s a n d Pr o c e d ur e s
Bl o o d c oll ecti o ns f or pl as m a st or a g e 1
X
Sc h e d ul e F oll o w -u p Visits 2
X
C D 4 C ell C o u nt 3
X
HI V Vir al L o a d 3
X
HI V R esist a nc e T esti n g 3
X
( 1) St ore d plas ma sa m ples will be c ollecte d fr o m partici pa nts w h o ac q uire HI V i nfecti o n, 
t hese assess me nts ma y i ncl u de P K assess me nt, resista nce testi n g, HI V s u bt ypi n g, 
c haracterizati o n of t he vir us a n d/ or t he h ost res p o nse t o i nfecti o n. T hese assess me nts will 
be perf or me d retr os pecti vel y ; res ults will n ot be ret ur ne d t o st u d y sites or partici pa nts.
( 2) S u bjects will c o nti n ue t o be f oll o we d at t he sa me fre q ue nc y as re g ular st u d y visits. 
( Secti o n 7. 1 ).
( 3) Sites will c ollect s peci me ns f or testi n g at Q uest a n d ha ve t he o pti o n t o als o se n d
sa m ples t o a l ocal la b orat or y t o assist wit h cli nical ma na ge me nt.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
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1 0 3
1 2. 8.
A p p e n di x 8: G e n eti c R e s e ar c h
G e n eti c s – B a c k gr o u n d
Nat urall y occ urri n g ge netic variati o n ma y  c o ntri b ute t o i nter-i n di vi d ual varia bilit y i n 
res p o nse t o me dici nes, as well as a n i n di vi d ual's ris k of de vel o pi n g s pecific diseases. 
Ge netic fact ors ass ociate d wit h disease c haracteristics ma y  als o be ass ociate d wit h 
res p o nse t o t hera py, a n d c o ul d hel p t o e x plai n s o me cli nical st u d y o ut c o mes. F or 
e xa m ple, ge netic varia nts ass ociate d wit h a ge- relate d mac ular de ge nerati o n ( A M D) are 
re p orte d t o acc o u nt f or m uc h of t he ris k f or t he c o n diti o n [G ori n , 2 0 1 2] wit h certai n 
varia nts re p orte d t o i nfl ue nce treat me nt res p o nse [C he n , 2 0 1 2]. T h us, k n o wle d ge of t he 
ge netic eti ol o g y  of disease ma y better i nf or m u n dersta n di n g of disease a n d t he 
de vel o p me nt of me dici nes. A d diti o nall y , ge netic varia bilit y ma y i m pact t he 
p har mac o ki netics (a bs o r pti o n, distri b uti o n, meta b olis m, a n d eli mi nati o n), or 
p har mac o d y n a mics (relati o ns hi p bet wee n c o nce ntrati o n a n d p har mac ol o gic effects or t he 
ti me c o urse of p har mac ol o gic effects) of a s pecific me dici ne a n d/ or cli nical o utc o mes 
(efficac y a n d/ or safety) o bse r ve d i n a cli nical st u d y.
G e n eti c R e s e ar c h O bj e cti v e s a n d A n al y s e s
T he o bjecti ves of t he ge netic researc h are t o i n vesti gate t he relati o ns hi p bet wee n ge netic 
varia nts a n d: 

Res p o nse t o me dici ne, i ncl u di n g a n y treat me nt re gi me ns u n der i n vesti gati o n i n t his 
st u d y or a ny c o nc o mita nt me dici nes;

HI V s usce pti bilit y , se verit y, a n d pr o gressi o n a n d relate d c o n diti o ns
Ge netic data ma y  be ge nerate d w hile t he st u d y is u n der wa y or f oll o wi n g c o m pleti o n of 
t he st u d y.  Ge netic e val uati o ns ma y i ncl u de f oc use d ca n di date ge ne a p pr oac hes a n d/ or 
e xa mi nati o n of a lar ge n u m ber of ge netic varia nts t hr o u g h o ut t he ge n o me ( w h ole ge n o me 
a nal ys es).  Ge netic a nal yses will utilize data c ollecte d i n t he st u d y a n d will be li mite d t o 
u n dersta n di n g t he o bjecti ves hi g hli g hte d a b o ve.  A nal y ses m a y  be perf or me d usi n g data 
fr o m m ulti ple cli nical st u dies t o i n vesti gate t hese researc h o bjecti ves.
A p pr o priate descri pti ve a n d/ or statistical a nal y sis met h o ds will be use d.  A detaile d 
descri pti o n of a n y pla n ne d a nal ys es will be d oc u me nte d i n a Re p orti n g a n d A nal y sis Pla n 
( R A P) pri or t o i nitiati o n of t he a nalys is.  Pla n ne d a nalys es a n d res ults of ge netic 
i n vesti gati o ns will be re p orte d eit her as part of t he cli nical R A P a n d st u d y re p ort, or i n a 
se parate ge netics R A P a n d re p ort, as a p pr o priate.
St u d y P o p ul ati o n
A n y  s u bject w h o is e nr olle d i n t he st u d y ca n partici pate i n ge netic researc h.  A n y s u bject 
w h o has recei ve d a n all o ge neic b o ne marr o w tra ns pla nt m ust be e xcl u de d fr o m t he 
ge netic researc h.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
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1 0 4
St u d y A s s e s s m e nt s a n d Pr o c e d ur e s
A ke y  c o m p o ne nt of s uccessf ul ge netic researc h is t he c ollecti o n of sa m ples d uri n g 
cli nical st u dies.  C ollecti o n of sa m ples, e ve n w he n n o a pri ori h y p ot hesis has bee n 
i de ntifie d, ma y e na ble f ut ure ge netic a nalys es t o be c o n d ucte d t o hel p u n dersta n d 
varia bilit y  i n disease a n d me dicine res p o nse.

A 6 ml bl o o d sa m ple will be ta ke n f or De o x yri b o n ucleic aci d ( D N A) e xtracti o n.  A 
bl o o d sa m ple is c ollecte d at t he baseli ne visit, after t he s u bject has bee n ra n d o mize d 
a n d pr o vi de d i nf or me d c o nse nt f or ge netic researc h.  I nstr ucti o ns f or c olle cti o n a n d 
s hi p pi n g of t he ge netic sa m ple are descri be d i n t he la b orat or y ma n ual.  T he D N A 
fr o m t he bl o o d sa m ple ma y u n der g o q ualit y c o ntr ol a nal yses t o c o nfir m t he i nte grit y 
of t he sa m ple.  If t here are c o ncer ns re gar di n g t he q ualit y  of t he sa m ple, t he n t he 
sa m ple ma y be destr o ye d.  T he bl o o d sa m ple is ta ke n o n a si n gle occasi o n u nless a 
d u plicate sa m ple is re q uire d d ue t o a n i na bilit y t o utilize t he ori gi nal sa m ple.  
T he ge netic sa m ple is la belle d ( or “c o de d”) wit h t he sa me st u d y s pecific n u m ber use d t o 
la bel ot her sa m ples a n d data i n t he st u d y.  T his n u m ber ca n be trace d or li n ke d bac k t o 
t he s u bject b y t he i n vesti gat or or site staff.  C o de d sa m ples d o n ot carr y pers o nal 
i de ntifiers (s uc h as na me or s ocial sec urit y n u m ber). 
Sa m ples will be st ore d sec urel y a n d ma y be ke pt f or u p t o 1 5 years after t he last s u bject 
c o m pletes t he st u d y, or G S K ma y destr o y t he sa m ples s o o ner.  G S K or t h ose w or ki n g 
wit h G S K (f or e xa m ple, ot her researc hers) will o nl y use sa m ples c ollecte d fr o m t he st u d y  
f or t he p ur p ose state d i n t his pr ot oc ol a n d i n t he i nf or me d c o nse nt f or m.  Sa m ples ma y be 
use d as part of t he de vel o p me nt of a c o m pa ni o n dia g n ostic t o s u p p ort t he G S K me dici nal 
pr o d uct.
S u bjects ca n re q uest t heir sa m ple t o be destr o ye d at a n y  ti me.
I nf or m e d C o n s e nt
S u bjects w h o d o n ot wis h t o partici pate i n t he ge netic researc h ma y  still partici pate i n t he 
st u d y.  Ge netic i nf or me d c o nse nt m ust be o btai ne d pri or t o a n y bl o o d bei n g ta ke n.
S u bj e ct Wit h dr a w al fr o m St u d y
If a s u bject w h o has c o nse nte d t o partici pate i n ge netic researc h wit h dra ws fr o m t he 
cli nical st u d y f or a n y reas o n ot her t ha n bei n g l ost t o f oll o w- u p, t he s u bject will be gi ve n a 
c h oice of o ne of t he f oll o wi n g o pti o ns c o ncer ni n g t he ge netic sa m ple, if alrea d y  
c ollecte d:

C o nti n ue t o partici pate i n t he ge netic researc h i n w hic h case t he ge netic D N A sa m ple 
is retai ne d.

Disc o nti n ue partici pati o n i n t he ge netic researc h a n d destr o y  t he ge netic D N A 
sa m ple. 
If a s u bject wit h dra ws c o nse nt f or ge netic researc h or re q uests sa m ple destr ucti o n f or a ny 
reas o n, t he i n vesti gat or m ust co m plete t he a p pr o priate d oc u me ntati o n t o re q uest sa m ple 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 0 5
destr ucti o n wit hi n t he ti mefra me s pecifie d b y G S K a n d mai ntai n t he d oc u me ntati o n i n 
t he site st u d y rec or ds. 
Ge n ot y pe data ma y  be ge nerate d d uri n g t he st u d y or after c o m pleti o n of t he st u d y a n d 
ma y  be a nal yz e d d uri n g t he st u d y or st ore d f or f ut ure a nalys is. 

If a s u bject wit h dra ws c o nse nt f or ge netic researc h a n d ge n oty pe data has n ot bee n 
a nal yz e d, it will n ot be a nal yze d or use d f or f ut ure researc h.  

Ge netic data t hat has bee n a nal yz e d at t he ti me o f wit h dra w n c o nse nt will c o nti n ue 
t o be st ore d a n d use d, as a p pr o priate. 
S cr e e n a n d B a s eli n e F ail ur e s
If a sa m ple f or ge netic researc h has bee n c ollecte d a n d it is deter mi ne d t hat t he s u bject 
d oes n ot meet t he e ntr y  criteria f or partici pati o n i n t he st u d y, t he n t he i n vesti gat or s h o ul d 
i nstr uct t he s u bject t hat t heir ge netic sa m ple will be destr oye d.  N o f or ms are re q uire d t o 
c o m plete t his pr ocess as it will be c o m plete d as part of t he c o nse nt a n d sa m ple 
rec o nciliati o n pr ocess.  I n t his i nsta nce a sa m ple destr ucti o n f or m will n ot be a vaila ble t o 
i ncl u de i n t he site files.
Pr o vi si o n of St u d y R e s ult s a n d C o nfi d e nti alit y  of S u bj e ct’ s G e n eti c D at a
G S K ma y  s u m marize t he ge netic researc h res ults i n t he cli nical st u d y re p ort, or 
se paratel y a n d ma y p u blis h t he res ults i n scie ntific j o ur nals. 
G S K ma y  s hare ge netic researc h data wit h ot her scie ntists t o f urt her scie ntific 
u n dersta n di n g i n ali g n me nt wit h t he i nf or me d c o nse nt.  G S K d oes n ot i nf or m t he s u bject, 
fa mil y me m bers, i ns urers, or e m pl o yers of i n di vi d ual ge n ot yp i n g res ults t hat are n ot 
k n o w n t o be rele va nt t o t he s u bject’s me dical care at t he ti me of t he st u d y , u nless 
re q uire d by la w.  T his is d ue t o t he fact t hat t he i nf or mati o n ge nerate d fr o m ge netic 
st u dies is ge nerally preli mi nar y i n nat ure, a n d t heref ore t he si g nifica nce a n d scie ntific 
vali dit y  of t he res ults are u n deter mi ne d.  F urt her, data ge nerate d i n a researc h la b orat or y 
ma y  n ot meet re g ulat or y re q uire me nts f or i ncl usi o n i n cli nical care.
R ef er e n c e s
C he n H, Y u K D, X u G Z. Ass ociati o n bet wee n Varia nt Y 4 0 2 H i n A ge- Relate d Mac ular 
De ge nerati o n ( A M D) S usce pti bilit y  Ge ne C F H a n d Treat me nt Res p o nse of A M D: A 
Meta -A nal ys is. Pl o S O N E 2 0 1 2; 7: e 4 2 4 6 4
G ori n M B. Ge netic i nsi g hts i nt o a ge -relate d mac ular de ge nerati o n: C o ntr o versies 
a d dressi n g ris k, ca usalit y, a n d t her a pe utics. M ol. As p. Me d. 2 0 1 2; 3 3: 4 6 7 - 4 8 6.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 0 6
1 2. 9.
A p p e n di x 9:  Pr ot o c ol A m e n d m e nt C h a n g e s
A m e n d me nt 3 : Effecti ve Date 1 4 -A U G - 2 0 1 7
T his a me n d me nt a p plies t o all s u bjects w h o will partici pate i n t he st u d y .
S u m m ar y of A me n d me nt C h a n ges wit h R ati o n ale
I n a d diti o n to mi n or e dits, u p date d t he was h - o ut peri o d bet wee n oral a n d L A d osi n g t o 
acc o m m o date visit sc he d uli n g, a n d re m o ve d t he nee dle le n gt h a n d s pecificati o n f or 
i ntra m usc ular i njecti o n i n Secti o n 6. 1. 3.
List of A ut h ors
 was a d de d t o t he list. 
Me d ic al m o nit or/ S p o ns or I nf or m ati o n P a ge
Rati o nale : 
Me dical m o nit or/ S A E C o ntact i nf or mati o n was u p date d t o reflect t he c urre nt me dical 
m o nit or.
P R E VI O U S T E X T
R ol e
N a m e
D ay Ti m e P h o n e 
N u m b er a n d 
e m ail a d dr ess
Aft er -h o urs 
P h o n e/ C ell/
P a g er N u m b er
F ax N u m b er
S it e A d dr ess
Pri m ary 
M e dic al 
M o nit or 
, M D
Vii V H e alt hc ar e
5 M o or e Driv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
S ec o n d ary 
M e dic al 
M o nit or
, 
M D
Vii V H e alt hc ar e
5 M o or e Driv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
T erti ary 
M e dic al 
M o nit or
, 
M D, M P H
Vii V H e alt hc ar e
5 M o or e Driv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
P P D
P P D
P P D
P P D
P P D

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 0 7
R E VI S E D T E X T
R ol e
N a m e
D ay Ti m e P h o n e 
N u m b er a n d 
e m ail a d dr ess
Aft er -h o urs 
P h o n e/ C ell/
P a g er N u m b er
F ax N u m b er
Sit e A d dr ess
Pri m ary 
M e dic al 
M o nit or
,
D O, M Sc
Vii V H e alt hc ar e
5 M o or e Driv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
S ec o n d ary 
M e dic al 
M o nit or
, M D
Vii V H e alt hc ar e
5 M o or e D riv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
T erti ary 
M e dic al 
M o nit or
, 
M D
Vii V H e alt hc ar e
5 M o or e Driv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
Secti o n 4. 1 O ver all Desi g n
Rati o nale: 
Wa s h o ut peri o d is u p date d t o ai d t he sites fle xi bilit y wit h t he sc he d uli n g.
T he d urati o n of was h o ut peri o d is bei n g u p date d fr o m 1 4- 2 1 da y s t o 1 4-4 2 da y s.
T his c ha n ge is ma de c o nsiste ntl y  t hr o u g h o ut t he d oc u me nt.
Secti o n 4. 2 Tre at me nt Ar ms a n d D ur ati o n
Rati o nale: 
D ue t o t he l o n ger was h o ut peri o d, t he st u d y d urati o n is u p date d fr o m u p t o 6 2 wee ks t o 
6 6 wee ks. 
P R E VI O U S T E X T
Eac h s u bject will partici pate i n t he st u d y  f or a p pr o xi matel y u p t o 6 2 wee ks.  
R E VI S E D T E X T
Eac h s u bject will partici pate i n t he st u d y  for a p pr o xi matel y  u p t o 6 6
P P D
wee ks.  
P P D
P P D
P P D

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 0 8
Secti o n 4. 1. 4 F oll o w -u p/ Wit h dr a w al Visit
Rati o nale: 
T he f oll o wi n g te xt was a d de d t o clarif y  o n t he f oll o w u p after recei vi n g t he C A B L A 
i njecti o n. 
A D DI TI O N A L T E X T: 
If a s u bject is wit h dra w n or dis q ualifie d fr o m t he s t u d y after recei vi n g t he C A B L A 
i njecti o n, beca use of t he l o n g acti n g p har mac o ki netic pr ofile of C A B L A e ver y  eff ort 
s h o ul d be ma de t o bri n g t he s u bject bac k i n f or t he 5 2 wee ks of safety a n d P K 
assess me nts f oll o wi n g t he i njecti o n.   
Secti o n 5. 1 I ncl usi o n Criteri a
Rati o nale: 
T he list of c o ntrace pti ves was u p date d t o ma ke it c o nsiste nt wit h t he c urre nt pr o gra m list 
i n i ncl usi o n criteri o n # 6. 
R E M O V E D T E X T:

Male c o n d o m c o m bi ne d wit h a va gi nal s per mici de (f oa m, gel, fil m, crea m, or 
s u p p osit or y) [Hatc her , 20 0 7 b]:
Secti o n 5. 4 Wit h dr a w al/ St o p pi n g Criteri a
Rati o nale: 
A clarificati o n is ma de f or t he s u bjects wit h dra w i n g after t he L A i njecti o n. 
P R E VI O U S T E X T
O nce a s u bject has recei ve d t he I M i njecti o n of C A B L A, t he y  will be f oll o we d per 
pr ot oc ol f or a p pr o priate pr oce d ures a n d safet y e val uati o ns, a n d will n ot be re m o ve d fr o m 
t he st u d y f or me dical reas o ns, u nless t he y ref use t o c o nti n ue partici pati o n.
R E VI S E D T E X T
If a s u bject recei ves t he I M i njecti o n of C A B L A, t he y will be f oll o we d 5 2- wee ks p ost 
i njecti o n per pr ot oc ol f or a p pr o priate pr oce d ures , i ncl u di n g bl o o d plas ma P K sa m pli n g,
a n d safet y e val uati o ns, a n d will n ot be re m o ve d fr o m t he st u d y  f or me dical reas o ns, 
u nless t he y  ref use t o c o nti n ue partici pati o n.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 0 9
Secti o n 5. 5 S u bject a n d St u d y C o m pleti o n
Rati o nale:
T he d urati o n f or t he c o m pleter f or P K assess me nts is u p date d t o 1 2 wee ks fr o m 8 wee ks 
t o ali g n wit h t he d urati o n f or pri mar y o bjecti ve.
P R E VI O U S T E X T
A s u bject t hat recei ves t he C A B L A i njecti o n a n d c o m pletes t he P K assess me nts f or 8
wee ks b ut wit h dra ws pri or t o t he 5 2 wee k f oll o w u p visit, will be c o nsi dere d c o m pleti n g 
t he treat me nt p hase of t he st u d y, b ut n ot a st u d y c o m pleter.  
A s u bject t hat wit h dra ws after i njecti o n a n d d oes n ot c o m plete P K assess me nts t hr o u g h 
wee k 8 is c o nsi dere d a n o n-c o m pleter f or treat me nt a n d st u d y.   Beca use of t he l o n g 
acti n g p har mac o ki netic pr ofile of C A B L A e ver y  eff ort s h o ul d be ma de t o bri n g t he 
s u bject bac k i n f or t he 5 2 wee ks of safety a n d P K assess me nts f oll o wi n g t he i njecti o n.
R E VI S E D T E X T
A s u bject t hat recei ves t he C A B L A i njecti o n a n d c o m pletes t he P K assess me nts f or 1 2
wee ks b ut wit h dra ws pri or t o t he 5 2 wee k f oll o w u p visit, will be c o nsi dere d c o m pleti n g 
t he treat me nt p hase of t he st u d y, b ut n ot a st u d y c o m pleter.  
A s u bje ct t hat wit h dra ws after i njecti o n a n d d oes n ot c o m plete P K assess me nts t hr o u g h 
wee k 1 2 is c o nsi dere d a n o n-c o m pleter f or treat me nt a n d st u d y .   Beca use of t he l o n g 
acti n g p har mac o ki netic pr ofile of C A B L A e ver y  eff ort s h o ul d be ma de t o bri n g t he 
s u bject bac k i n f or t he 5 2 wee ks of safet y a n d P K assess me nts f oll o wi n g t he i njecti o n.
Secti o n 6. 1. 3 D osi n g C o nsi der ati o ns f or C A B L A
Rati o nale:
T he nee dle s pecificati o ns are re m o ve d f or t he s yri n ge , t he details of w hic h are pr o vi de d 
i n St u d y Refere nce Ma n ual ( S R M) .
P R E VI O U S T E X T
After clea ni n g t he s ki n wit h alc o h ol s wa b, u n der direct ultras o u n d vis ualizati o n, a 9 -c m 
l o n g, 2 5-ga u ge s pi nal nee dle will be i ntr o d uce d i nt o t he gl uteal m uscle. T he n 6 0 0 m g 
C A B L A (c o nce ntrati o n = 2 0 0 m g/ m L ( 3 m L) will be i njecte d as a si n g le I M i njecti o n 
sl o wl y u n der c o nti n u o us ultras o u n d vis ualizati o n
R E VI S E D T E X T
After clea ni n g t he s ki n wit h alc o h ol s wa b, u n der direct ultras o u n d vis ualizati o n , a 9-c m 
l o n g, 2 5 2 2 -ga u ge s pi nal nee dle will be i ntr o d uce d i nt o t he gl uteal m uscle. T he n 6 0 0 m g 
C A B L A (c o nce ntrati o n = 2 0 0 m g/ m L ( 3 m L ) will be i njecte d as a si n gle I M i njecti o n 
sl o wl y u n der c o nti n u o us ultras o u n d vis ualizati o n.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 1 0
Secti o n 7. 1. 1 Scree ni n g a n d Or al Le a d -i n P h ase
Rati o nale:
T he f o ot n ote was a d de d as n u m ber 7 t o clarif y  wit h dra wal visit i n oral c y cle t o ali g n wit h 
t he wit h dra wal criteria. 
A D DI TI O N A L T E X T: 
7. If a s u bject is wit h dra w n pri or t o recei vi n g t he C A B L A i njecti o n, a f oll o w -
u p/ wit h dra wal visit s h o ul d be sc he d ule d 1 0 - 1 4 da ys after t he last oral d ose of C A B.
Secti o n 1 2. 4 A p pe n di x 4
Rati o nale:
T he title was u p date d t o reflect Versi o n 2. 0, as t he re m o ve d te xt was a p plica ble t o ol d 
D AI D S Versi o n 1. 0.
P R E VI O U S T E X T
Secti o n 1 2. 4 A p pe n di x 4: Di visi o n Of AI D S T a ble F or Gr a di n g T he Se verit y Of 
A d ult A n d Pe di atric A verse E ve nts Versi o n 2. 0, N o ve m ber 2 0 1 4; Cl arific ati o n 
A u g ust 2 0 0 9
R E VI S E D T E X T
Secti o n 1 2. 4 A p pe n di x 4: Di visi o n Of AI D S T a ble F or Gr a di n g T he Se verit y Of 
A d ult A n d Pe di atric A verse E ve nts Versi o n 2. 0, N o ve m ber 2 0 1 4 ; Cl arific ati o n 
A u g ust 2 0 0 9

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 1 1
A m e n d me nt 2 : Effecti ve Date 3 0 -M A R - 2 0 1 6
T his a me n d me nt a p plies t o all s u bjects w h o will partici pate i n t he st u d y .
S u m m ar y of A me n d me nt C h a n ges wit h R ati o n ale
Secti o n 3 O bjecti ves a n d E n d p oi nts
Pri mar y e n d p oi nt:
P R E VI O U S T E X T

C o nce ntrati o ns o bser ve d at Da y  3 ( C 4 8 h), Wee k 1 ( C W k 1), Wee k 4 ( C W k 4), Wee k 8 
( C W k 8), a n d Wee k 1 2 ( C W k 1 2) i n bl o o d plas ma a n d i n V T, C T, a n d C V F i n w o me n, 
a n d i n R T a n d R F i n me n a n d w o me n (as data per mit)  f oll o wi n g a si n gle C A B 8 0 0
m g i ntra m usc ular (s plit i njecti o n) d ose.  
R E VI S E D T E X T

C o nce ntrati o ns o bser ve d at Da y  3 ( C 4 8 h), Da y 8 ( C d 8), Wee k 4 ( C W k 4), Wee k 8 
( C W k 8), a n d Wee k 1 2 ( C W k 1 2) i n bl o o d plas ma a n d i n C T, a n d C V F i n w o me n, a n d 
i n R T a n d R F i n me n a n d w o me n (as data per mit)  f oll o wi n g a si n gle C A B 6 0 0 m g 
i ntra m usc ular d ose. 

V T c o nce ntrati o ns o bser ve d at Da y  3 ( C4 8 h), a n d Wee k 8 ( C W k 8), i n w o me n 
f oll o wi n g a si n gle C A B 6 0 0 m g i ntra m usc ular d ose.  
Sec o n dar y E n d p oi nts
P R E VI O U S T E X T
C o nce ntrati o n rati os i ncl u di n g V T: bl o o d plas ma, C T: bl o o d plas ma, C V F: bl o o d plas ma, C T: C V F, 
V T: C V F i n w o me n, a n d R T: bl o o d plas ma, R F: bl o o d plas ma a n d R T: R F i n me n a n d w o me n (as 
data per mit)   at C 4 8 h, C W k 1, C W k 4, C W k 8, a n d C W k 1 2
R E VI S E D T E X T
C o nce ntrati o n rati os i ncl u di n g V T: bl o o d plas ma, C T: bl o o d plas ma, C V F: bl o o d plas ma, C T: C V F, 
V T: C V F i n w o me n, a n d R T: bl o o d plas ma, R F: bl o o d plas ma a n d R T: R F i n m e n a n d w o me n (as 
data per mit) at m atc he d ti me p oi nts e v al u ate d.
T he f oll o wi n g Sec o n dar y E n d p oi nt was a d de d. 

T iss ue: bl o o d plas ma a n d fl ui d: bl o o d plas ma r ati o of A U Cs of i nter vals s pecifie d a b o ve.
Secti o n 4. 4 Desi g n J ustific ati o n
T his secti o n was u p date d t o reflect c urre nt data a n d u p date d d osi n g of C A B L A.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 1 2
C A B L A D osi n g
Base d o n a vaila ble data pr o vi de d i n Secti o n 4. 5, C A B L A d ose of 8 0 0 m g  ( 2 x 4 0 0 m g) 
was u p date d t o si n gle d ose of 6 0 0 m g f or t he st u d y.  As a res ult, f oll o wi n g secti o ns were 
u p date d wit h t he d osi n g

Secti o n 4. 5 d ose j ustificati o n t o reflect c urre nt data. 

Secti o n 6. 1 t o i n dicate f or m ulati o n a n d d osi n g c ha n ges.

Secti o n 9, d osi n g c ha n ges were ma de.
   
Re q uire me nt f or V a gi n al Tiss ue s a m pli n g
T he re q uire me nt of va gi nal tiss ue sa m pli n g w as re d uce d t o o nl y D a y 3 ( 4 8 h) a n d Wee k 8. 
Acc or di n gl y, t he c ha n ges were ma de t o o bjecti ves a n d e n d p oi nt a n d sa m pli n g assess me nt 
ta bles.
Secti o n 4. 6 . 1 Be nefit: Ris k Assess me nt 
T his secti o n was u p date d t o reflect u p date d c urre nt C A B safet y pr ofile. 
4. 6. 1 T a ble was u p date d.
4. 6. 1. 1 Ot her Cli nical Rele va nt I nf or mati o n was a d de d. 
Secti o n 5. 2 E xcl usi o n Criteri a
E xcl usi o n criteri o n n u m ber 1 5 f or he patitis B a n d he patitis C were se parate d i nt o n u m ber 
1 5 a n d 1 6, as per bel o w. 
P R E VI O U S T E X T
1 5. Prese nce of he pat itis B s urface a nti ge n ( or p ositi ve he patitis B c ore a nti b o d y wit h 
ne gati ve he patitis B s urface a nti b o d y) or p ositi ve he patitis C a nti b o d y  test res ult at 
scree ni n g or wit hi n 3 m o nt hs pri or t o first d ose of st u d y treat me nt.
R E VI S E D T E X T
1 5. P ositi ve he patit is B s urface a nti ge n, or a p ositi ve he patitis B c ore a nti b o d y wit h 
ne gati ve he patitis B s urface a nti b o d y) test res ult at scree ni n g or wit hi n 3 m o nt hs pri or t o 
first d ose of st u d y treat me nt.
1 6. P ositi ve he patitis C a nti b o d y  test res ult at scree ni n g or wit hi n 3 m o nt hs pri or t o first 
d ose of st u d y  treat me nt
Secti o n 5. 4 Wit h dr a w al/ St o p pi n g Criteri a
Secti o n 5. 4. 2 f or Q Tc St o p pi n g Criteria was a d de d.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 1 3
Secti o n 5. 5 S u bject a n d St u d y C o m pleti o n
P R E VI O U S T E X T
A s u bject t hat recei ves t he C A B L A i njecti o n a n d c o m plete s t he P K assess me nts f or 1 2 
wee ks b ut wit h dra ws pri or t o t he 5 2 wee k f oll o w u p visit, will be c o nsi dere d c o m pleti n g 
t he treat me nt p hase of t he st u d y, b ut n ot a st u d y c o m pleter.  
R E VI S E D T E X T
A s u bject t hat recei ves t he C A B L A i njecti o n a n d c o m pletes t he P K assess me nts f or 8 
wee ks b ut wit h dra ws pri or t o t he 5 2 wee k f oll o w u p visit, will be c o nsi dere d c o m pleti n g 
t he treat me nt p hase of t he st u d y, b ut n ot a st u d y c o m pleter.  
Secti o n 7. 1 Ti me a n d E ve nts T a ble
Secti o n 7. 1. 1 Scree ni n g a n d Or al Le a d -i n P h ase
Da y 2 8 assess me nts were u p date d t o Da y 2 9, da y after t he last oral d ose of C A B. 
D a y  1 4 he mat ol o g y a n d c he mistr y tests were a d de d, a n d Da y 1 4 li ver tests were 
re m o ve d.
Secti o n 7. 1. 2 C A B i njecti o n, C o m p art me nt al P K S a m pli n g, a n d F oll o w -u p
Li ver tests were del ete d, a n d Pre-d ose Da y  1 he mat ol o g y a n d c he mistr y tests were a d de d.
Secti o n 7. 4. 1 A d verse E ve nts ( A E) a n d Seri o us A d verse E ve nts ( S A Es)
F oll o wi n g te xt w as a d de d
F or t his st u d y , t he S p o ns or c o nsi ders seiz ures as a n A E of s pecial i nterest (see Secti o n 
1 2. 3. 4 f or bac k gr o u n d  i nf or mati o n). W here seiz ures occ ur, t he S p o ns or w o ul d li ke t o 
better c haracterize t hese occ urre nces t o e na ble s ys te matic a nalys es. I n vesti gat ors are 
re q ueste d t o d oc u me nt a n d re p ort seiz ure or p ossi ble seiz ure e ve nts pr o m ptl y ( wit hi n 2 4 
h o urs of lear ni n g of t he e ve nt) t o t he S p o ns or f or e val uati o n a n d o n war d re p orti n g.  Data 
s h o ul d be d oc u me nte d o n t he a p pr o priate A E/ S A E pa ge (see Secti o n 1 2. 3.).
Secti o n 7. 4. 3 P h ysic al E x a ms
P R E VI O U S T E X T

A c o m plete p h ys ical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nt of t he 
Car di o vasc ular, Res pirat or y , Gastr oi ntesti nal, Ge nit o uri nar y, a n d Ne ur ol o gical 
s yste ms. Hei g ht a n d wei g ht will als o be meas ure d a n d rec or de d. 
R E VI S E D T E X T

A c o m plete p h ys ical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nt of t he 
S ki n, Car di o vasc ular, Res pirat or y , Gastr oi ntesti nal, Ge nit o uri nar y, a n d Ne ur ol o gical 
s yste ms. Hei g ht a n d wei g ht will als o be meas ure d a n d rec or de d. 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 1 4
Secti o n 7. 4. 4 Vit al Si g ns
Res pirat or y  rate was re m o ve d.

Vital si g ns will be meas ure d i n se mi -s u pi ne p ositi o n after 1 0 mi n utes rest a n d will 
i ncl u de te m perat ure, sys t olic a n d diast olic bl o o d press ure a n d p ulse rate a n d 
res pirat or y rate. 
Secti o n 7. 4. 6 Cli nic al S afet y L a b or at or y Assess me nts
Clarificati o n f or S T D Scree n i n Ta ble 5 was a d de d i n t he f o ot n ote.
Se cti o n 7. 4. 7 M a g netic Res o n a nce I m a gi n g
F oll o wi n g te xt was delete d:
S u bjects will be as ke d t o u n der g o M RI i ma gi n g o n a first c o me first ser ve basis u ntil 8 
s u bjects ( 4 fe males a n d 4 males) c o nse nt t o partici pate or u ntil t he pri mar y st u d y is f ull y 
e nr olle d, w hic he ver c o mes first.    
Secti o n 7. 5 P h ar m ac o ki neti cs
P R E VI O U S T E X T
Bl o o d sa m ples ( 4 m L  eac h) will be c ollecte d i nt o K 3 E D T A t u bes f or plas ma C A B 
a nal ys is, a n d i nitial pr ocessi n g will ta ke place as f oll o ws:
R E VI S E D T E X T
Bl o o d sa m ples ( 4 m L  eac h) will be c ollecte d i nt o p ot assi u m E D T A t u bes f or plas ma 
C A B a nal ys is, a n d i nitial pr ocessi n g will ta ke place as f oll o ws:
Secti o n 7. 5 P h ar m ac o ki neti cs
P R E VI O U S T E X T
Va gi nal, cer vical a n d rectal tiss ue bi o psies a n d l u mi nal (cer vic o va gi nal a n d rectal) fl ui d 
c ollecti o ns will be d o ne at t he ti me p oi nts i n dicate d i n Secti o n 7. 1.  At eac h tiss ue 
sa m pli n g ti me p oi nt, u p t o 5 va gi nal, 5 cer vical, or a c o m bi nati o n of 5 bi o psies fr o m b ot h 
sites ( 5 t otal cer vic o va gi nal bi o psies) will be c ollecte d via s pec ul u m e xa m per s u bject. 
At eac h tiss ue sa m pli n g ti me p oi nt, u p t o 3 0 bi o psies will be c ollecte d fr o m t he 
rect osi g m oi d via fle xi ble si g m oi d osc o py.   
R E VI S E D T E X T
Va gi nal, cer vical a n d rectal tiss ue bi o psies a n d l u mi nal (cer vic o va gi nal a n d rectal) fl ui d 
c ollecti o ns will be d o ne at t he ti me p oi nts i n dicate d i n Secti o n 7. 1.  At eac h fe male 
ge nital tiss ue sa m pli n g ti me p oi nt, u p t o 3 va gi nal a n d 3 cer vical bi o psies wil l be 
c ollecte d via s pec ul u m e xa m per s u bject.  At eac h rect osi g m oi d tiss ue sa m pli n g ti me 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 1 5
p oi nt, u p t o 1 0 bi o psies will be c ollecte d at 1 5 c m fr o m t he a n al m ar gi n via fle xi ble 
si g m oi d osc o py.   
Secti o n 9. 4. 2 Sec o n d ar y A n al yses
P R E VI O U S T E X T

C V F: B P, C T: B P, V T: B P, C T: C V F, V T: C V F r ati o i n w o m e n a n d, R T: B P, a n d R F: R T r ati os i n m al es 
a n d f e m al es at 4 8 hr, W e eks 1, 4, 8, a n d 1 2 d uri n g t h e i nj ecti o n p h as e. 

C m ax a n d t m ax i n all m atric es

A U C( 0 -), A U C( 0-l ast), A U C( 0-Wk 4)), A U C( 0 -Wk 8), a n d t ½ i n bl o o d pl as m a.

A U C( 0 - Wk 1 2) i n bl o o d pl as m a a n d i n V T, C T, a n d C V F i n f e m al es a n d  R T a n d R F i n m al es a n d 
f e m al es.  

R ati o of A U C( 0 -Wk 1 2) tiss u e m atric es/l u mi n al fl ui d: bl o o d pl as m a.  

St e a dy -st at e pr e-d os e C A B c o nc e ntr ati o n ( C ) i n V T, C T, C V F, R T, R F a n d B P o n D ay 2 8 of t h e o r al 
l e a d-i n p h as e pri or t o I M i nj ecti o n
R E VI S E D T E X T

C V F: B P, C T: B P, V T: B P, C T: C V F, V T: C V F r ati o i n w o m e n a n d, R T: B P, a n d R T: R F r ati os i n m al es a n d 
f e m al es at m atc hi n g ti m e p oi nts w h er e d at a p er mit d uri n g t h e i nj ecti o n p h as e. 

C m ax,t m ax, A U C( 0 -), A U C( 0-last), A U C( 0 -Wk 4), A U C( 0 -Wk 8) a n d A U C( 0 -Wk 1 2) a n d t ½ i n bl o o d 
pl as m a a n d i n C T, a n d C V F i n f e m al es a n d  R T a n d R F i n m al es a n d f e m al es.  

R ati os of ti m e -m atc h e d A U Cs  tiss u e m atric es/l u mi n al fl ui d: bl o o d pl as m a w h er e d at a p er mit.  

C A B c o nc e ntr ati o n i n V T, C T, C V F, R T, R F a n d B P o n D ay 2 9 of t h e or al l e a d -i n p h as e pri or t o I M 
i nj ecti o n
Secti o n 9. 4. 2 Sec o n d ar y A n al yses
F oll o wi n g state me nts were a d de d.
Rati os will be calc ulate d f or eac h s u bject. E val ua ble P K para meters a n d calc ulate d rati os 
will be s u m marize d b y  ge n der a n d/ or o verall f or eac h matri x.
C o variates of B MI a n d ot her fact ors ma y  als o be c o nsi dere d i n t he m o del f or t he bl o o d 
plas ma P K para meter c o m paris o n. C A B c o nce ntrati o n i n eac h matri x fr o m t he oral lea d -
i n p hase ma y be c o m pare d wit h Wee ks 4, 8, a n d 1 2 c o nce ntrati o ns if data per mit.
Secti o n 1 2. 3. 4 A Es of S peci al I nterest
F oll o wi n g i nf or mati o n w as a d de d.
Seiz ures :
T hree cases of seiz ures h a ve occ urre d i n t he C A B pr o gra m c u m ulati vel y t hr o u g h 
0 1 Oct o ber 2 0 1 5. Vii V Healt hcare has re vie we d t hese cases i n detail a n d d oes n ot 
belie ve t he y  c o nstit ute a reas o na ble li keli h o o d of ca usati o n ass ociate d wit h C A B.  T his 
assess me nt is s u p p orte d b y t he lac k of precli nical si g nal, class effect or k n o w n C N S 
mec ha nis m, t he relati vel y l o w fre q ue nc y  of seiz ures relative t o e x pecte d rates i n b ot h 

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 1 6
healt h y  a n d HI V p ositi ve s u bjects a n d cli nical c o nf o u n ders i n eac h case.  
W here seiz ures occ ur, t he S p o ns or w o ul d li ke t o better c haracterize t hese occ urre nces t o 
e na ble s ys te matic a nalys es. I n vesti gat ors are re q ueste d t o d oc u me nt a n d re p ort seiz ure or 
p ossi ble seiz ure e ve nts pr o m ptl y  ( wit hi n 2 4 h o urs of lear ni n g of t he e ve nt) t o t he S p o ns or 
f or e val uati o n a n d o n war d re p orti n g.  Data s h o ul d be d oc u me nte d o n t he a p pr o priate 
A E/ S A E pa ge.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 1 7
A m e n d me nt 1 – Effecti ve Date 1 0- N O V - 2 0 1 5
W here t he A me n d me nt A p plies
T his a me n d me nt a p plies t o all s u bjects w h o will partici pate i n t he st u d y .
S u m m ar y of A me n d me nt C h a n ges wit h R ati o n ale
A me n d me nt 1 i ncl u des a d diti o nal e xcl usi o n criteria f or s u bjects wit h hist or y  of seiz ure 
dis or der.
List of S pec ific C h a n ges
Me dic al M o nit or/ S A E C o nt act I nf or m ati o n: 
P R E VI O U S T E X T
R ol e
N a m e
D ay Ti m e P h o n e 
N u m b er a n d 
e m ail a d dr ess
Aft er -h o urs 
P h o n e/ C ell/
P a g er N u m b er
F ax N u m b er
Sit e A d dr ess
Pri m ary 
M e dic al 
M o nit or 
, M D
Gl ax o S mit h Kli n e
5 M o or e Driv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
S ec o n d ary 
M e dic al 
M o nit or
, 
M D
Gl ax o S mit h Kli n e
5 M o or e Driv e,
R es e arc h Tri a n gl e , 
N C 2 7 7 0 9
T erti ary 
M e dic al 
M o nit or
, 
M D, M P H
Gl ax o S mit h Kli n e
5 M o or e Driv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
R E VI S E D T E X T
R ol e
N a m e
D ay Ti m e P h o n e 
N u m b er a n d 
e m ail a d dr ess
Aft er -h o u rs 
P h o n e/ C ell/
P a g er N u m b er
F ax N u m b er
Sit e A d dr ess
Pri m ary 
M e dic al 
M o nit or 
, M D
Vii V H e alt hc ar e
5 M o or e Driv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
S ec o n d ary 
M e dic al 
M o nit or
, 
M D
Vii V H e alt hc ar e
5 M o or e Driv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
P P D
P P D
P P D
P P D
P P D
P P D
P P D

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 1 8
T erti ary 
M e dic al 
M o nit or
, 
M D, M P H
Vii V H e alt hc ar e
5 M o or e Driv e,
R es e arc h Tri a n gl e, 
N C 2 7 7 0 9
Secti o n 4. 6. 1 Ris k Assess me nt
P R E VI O U S T E X T
P ot e nti al 
Ri s k of 
Cli ni c al 
Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n 
Str at e g y
I n v e sti g ati o n al Pr o d u ct (I P) G S K 1 2 6 5 7 4 4/ C a b ot e gr a vir
El ev at e d liv er 
tr a ns a mi n as es
I n o n g oi n g P h as e 2 HI V tr e at m e nt st u di es wit h C A B ( L AI 1 1 6 4 8 2, 2 0 0 0 5 6) 
t hr e e s u bj ects d ev el o p e d si g nific a ntly el ev at e d liv er e nzy m es, ( o n e als o 
ex hi bit e d el ev at e d bilir u bi n) c o nsi d er e d p ossi bly / pr o b a bly r el at e d t o C A B 
ex p os ur e.  All t hr e e s u bj ects w er e r e q uir e d t o i m m e di at ely disc o nti n u e 
st u dy dr u gs p er pr ot oc ol liv er st o p pi n g crit eri a a n d t h e tr a ns a mi n as es 
s u bs e q u e ntly r et ur n e d t o pr e-tr e at m e nt l ev els.  P e ak A L T el ev ati o ns i n 
t h es e s u bj ects w as > 1 0x UL N a n d occ urr e d fr o m 4 t o 8 w e eks, aft er 
i niti ati n g d aily or al C A B.  N o n e of t h e s u bj ects h a d m e as ur a bl e c h a n g e i n 
h e p atic f u ncti o n a n d all w er e l ar g ely asy m pt o m atic.  All t hr e e s u bj ects h a d 
u n d erlyi n g h e p atic dis e as e (st e at o h e p atitis n = 2; c hr o nic H e p atiti s C wit h 
fi br osis n = 1).  T h er e h av e b e e n n o Gr a d e 3 or 4 A L T el ev ati o ns i n st u di es 
i n w hic h  C A B L A h as b e e n a d mi nist er e d t o h e alt hy v ol u nt e ers ( n = 1 3 6) or 
as Pr E P.  Tr a nsi e nt tr a ns a mi n as e el ev ati o ns ( Gr a d es 1 a n d 2) h av e b e e n 
r e p ort e d i n s u bj ects i n P h as e 2 st u di es, w hic h h av e r es olv e d o n c o nti n u e d 
tr e at m e nt.
Liv er tr a ns a mi n as es 
will b e cl os ely 
m o nit or e d t hr o u g h o ut 
t his st u dy (r ef er t o 
Ti m e & Ev e nts T a bl e 
S ecti o n 7. 1) a n d Liv er 
c h e mistry st o p pi n g 
crit eri a as o utli n e d i n 
S ecti o n 5. 4. 1 will b e 
i m pl e m e nt e d as 
n e e d e d.  All i nst a nc es 
of liv er tr a ns a mi n as e 
el ev ati o ns of Gr a d e 2 
a n d a b ov e will b e 
f oll o w e d t o r es ol uti o n.  
T his risk will als o b e 
miti g at e d by e nr olli n g 
h e alt hy v ol u nt e ers 
wit h n or m al liv er 
c h e mistri es as 
o utli n e d by t h e 
excl usi o n crit eri a 
d escri b e d i n S ecti o n 
5. 2.
I nj ecti o n Sit e 
R e acti o ns 
(I S Rs)
T h e occ urr e nc e of I S Rs w as i d e ntifi e d i n r ats a n d m o nk eys at all d os e 
l ev els of C A B L A a n d ass oci at e d wit h b ot h t h e I M a n d S C r o ut e of 
a d mi nistr ati o n. I n h u m a ns, ex p eri e nc e t o d at e h as d e m o nstr at e d t h at I S Rs 
o cc ur i n t h e m aj ority of ex p os e d s u bj ects b ut ar e g e n er ally mil d ( Gr a d e 1) 
a n d i ncl u d e t e n d er n ess, eryt h e m a, or n o d ul e f or m ati o n of s ev er al d ays 
d ur ati o n. R e acti o ns t o d at e h av e b e e n m ostly w ell t ol er at e d. T w o s u bj ects 
h av e wit h dr a w n fr o m st u dy d u e t o I S Rs. O n e s u bj ect i n 2 0 1 1 2 0 ( E C L AI R) 
d ev el o p e d i nj ecti o n sit e p ai n, f ev er a n d my al gi as aft er I M d osi n g wit h 
c a b ot e gr avir L A a n d wit h dr e w fr o m t h e st u dy. A n ot h er s u bj ect i n t h e 
m ai nt e n a nc e p h as e of 2 0 0 0 5 6 ( HI V -1 tr e at m e nt st u dy) d ev el o p e d gr a d e 2 
i nj ecti o n sit e,p ai n, eryt h e m a a n d s w elli n g wit h mil d f ev ers aft er a n I M d os e 
of c a b ot e gr avir L A, a n d als o wit h dr e w fr o m t h e st u dy.  
S u bj ects will b e 
cl os ely m o nit or e d f or 
I S Rs p artic ul arly f or 
si g ns of p ai n, 
t e n d er n ess, 
i nf ecti o ns, eryt h e m a, 
s w elli n g, i n d ur ati o n, 
or n o d ul es 
( gr a n ul o m as or cysts) 
t hr o u g h o ut t h e st u dy. 
S p eci alist 
d er m at ol o gy 
c o ns ult ati o n will b e 
s o u g ht if w arr a nt e d 
P P D
P P D

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 1 9
P ot e nti al 
Ri s k of 
Cli ni c al 
Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n 
Str at e g y
f or i n divi d u al s u bj ects.  
Cr e ati ni n e 
P h os p h oki n as e 
( C P K) 
el ev ati o ns
Occ urr e nc es of tr a nsi e nt i nst a nc es of el ev ati o ns of C P K l ev els h av e b e e n
o bs erv e d i n P h as e 1 st u di es a n d o n g oi n g P h as e 2 st u di es wit h C A B at 
d os e l ev els of 1 0, 3 0 a n d 6 0 m g ( L AI 1 1 6 4 8 2, 2 0 0 0 5 6, 2 0 1 1 2 0). T h es e 
g e n er ally a p p e ar e d t o b e r el at e d t o p hysic al activity, w er e n ot ass oci at e d 
wit h cli nic al sy m pt o ms a n d r et ur n e d t o pr e -tre at m e nt l ev els i n t h e m aj ority 
of c as es. N o s u bj ect h as r e q uir e d a disc o nti n u ati o n of or al C A B as a r es ult 
of a C P K el ev ati o n t o d at e. H o w ev er 3 s u bj ects i n t h e o n g oi n g Pr E P st u dy 
( 2 0 1 1 2 0) w er e n ot tr a nsiti o n e d t o i nj ect a bl e dr u g as a pr ec a uti o n ary 
m e as ur e h avi n g d ev el o p e d el ev ati o ns i n C P K.  N o r e p orts of 
r h a b d o my olysis h av e b e e n r ec eiv e d.  
St a n d ar d l a b or at ory 
m o nit ori n g as d et ail e d 
i n S ecti o n 7. 4. 6.
B o n e m arr o w 
d e pl eti o n
T his risk w as d e m o nstr at e d i n a hi g h d os e ( 1 0 0 0 m g/k g/ d ay) C A B m o nk ey 
st u dy b ut w as n ot a p p ar e nt fr o m st u di es c o n d uct e d i n r ats or at l o w er d os e 
l ev els i n m o nk eys. Si g n al n ot c o nfir m e d by h u m a n d at a t o d at e.  T h er e 
h av e b e e n is ol at e d r e p orts of tr a nsi e nt n e utr o p e ni a ( m axi m u m Gr a d e 3) i n 
s u bj ects p artici p ati n g i n a n o n g oi n g Pr E P st u dy b u t t his g e n er ally 
n or m alis e d o n c o nti n u e d tr e at m e nt, w as asy m pt o m atic a n d a p p e ar e d t o 
r e pr es e nt r o uti n e fl uct u ati o ns i n s u bj ect’s b ack gr o u n d bl o o d pict ur e.
T h e d os e us e d wit hi n 
t his st u dy will r es ult i n 
m a ny f ol d l o w er l ev el 
ex p os ur e c o m p ar e d 
t o t h e eff ect l ev el i n 
pri m at es. C ar ef ul 
m o nit ori n g of a dv ers e 
h e m at ol o gic al ev e nts 
(i ncl u di n g l a b or at ory 
m o nit ori n g as i n 
S ecti o n 7. 4. 6) will 
occ ur d uri n g st u dy 
c o n d uct.  
S eri o us/s ev er e 
ev e nts will b e 
m a n a g e d 
a p pr o pri at ely wit h 
s u p p ortiv e c ar e, a n d 
will b e f oll o w e d t o 
r es ol uti o n as p er 
S p o ns or’s st a n d ar d 
m e dic al m o nit ori n g 
pr actic es.
G astr oi nt esti n al 
i nt ol er a bility
T h e risk i d e ntifi e d i n a m o nk ey t oxicity st u dy at t h e hi g h est a d mi nist er e d 
d os e of C A B a n d c o nsi d er e d r el at e d t o l oc al irrit ati o n (r at h er t h a n a 
syst e mic eff ect) l e a di n g t o m or bi dity ass oci at e d wit h cli nic al si g ns of 
i nt ol er a nc e.  I n h u m a n s u bj ects t h e fr e q u e ncy of GI ev e nts ( n a us e a, 
v o miti n g, g astr o e nt eritis, dys p e psi a) h as b e e n si mil ar t o activ e 
c o m p ar at ors.  N o s u bj ects h av e wit h dr a w n d u e t o dr u g r el at e d G I ev e nts 
t o d at e.
C ar ef ul m o nit ori n g of 
a dv ers e GI ev e nts will 
occ ur t hr o u g h o ut t h e 
st u dy.  
S eri o us/s ev er e 
ev e nts will b e 
m a n a g e d 
a p pr o pri at ely wit h 
s u p p ortiv e c ar e, a n d 
will b e f oll o w e d t o 
r es ol uti o n as p er 
S p o ns or’s st a n d ar d 
m e dic al m o nit ori n g 
pr actic es.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 2 0
R E VI S E D T E X T
P ot e nti al 
Ri s k of 
Cli ni c al 
Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n 
Str at e g y
I n v e sti g ati o n al Pr o d u ct (I P) G S K 1 2 6 5 7 4 4/ C a b ot e gr a vir
El ev at e d liv er 
tr a ns a mi n as es
As of Oct o b er 1, 2 0 1 5, 1 1 5 3 s u bj ects h av e b e e n ex p os e d t o C A B ( or al 
a n d/ or l o n g -acti n g i nj ecti o n) i n p h as e 1 a n d 2 st u di es. S ev e nt e e n s u bj ects 
h av e m et pr ot oc ol -d efi n e d liv er st o p pi n g crit eri a, aft er h avi n g r ec eiv e d 
c a b ot e gr avir ov er  at l e ast f o ur w e eks,  of w hic h fiv e ar e c o nsi d er e d t o 
r e pr es e nt p ossi bl e or pr o b abl e c as es of dr u g -i n d uc e d liv er i nj ury..  N o n e of 
t h es e s u bj ects d ev el o p e d cli nic al sy m pt o ms of liv er dysf u ncti o n, a n d 
tr a ns a mi n as es r et ur n e d t o pr e-tr e at m e nt l ev els aft er st o p pi n g dr u g. 
Liv er tr a ns a mi n as es 
will b e cl os ely 
m o nit or e d t hr o u g h o ut 
t his st u dy (r ef er t o 
Ti m e & Ev e nts T a bl e 
S ecti o n 7. 1) a n d Liv er 
c h e mistry st o p pi n g 
crit eri a as o utli n e d i n 
S ecti o n 5. 4. 1 will b e 
i m pl e m e nt e d as 
n e e d e d.  All i nst a nc es 
of liv er tr a ns a mi n as e 
el ev ati o ns of Gr a d e 2 
a n d a b ov e will b e 
f oll o w e d t o r es ol uti o n.  
T his risk wil l als o b e 
miti g at e d by e nr olli n g 
h e alt hy v ol u nt e ers 
wit h n or m al liv er 
c h e mistri es as 
o utli n e d by t h e 
excl usi o n crit eri a 
d escri b e d i n S ecti o n 
5. 2.
I nj ecti o n Sit e 
R e acti o ns 
(I S Rs)
I S Rs ass oci at e d wit h C A B L A i nj ecti o n w er e v ery c o m m o n, occ urri n g i n 
7 4 % of I M-ex p os e d s u bj ects, b ut g e n er ally w er e mil d. T h e m ost fr e q u e nt 
I S Rs w er e p ai n, eryt h e m a a n d n o d ul es. M e di a n I M I S R d ur ati o n w as 7 
d ays f or p ai n a n d eryt h e m a a n d a p pr oxi m at ely 2 2 d ays f or n o d ul es. 
S u bj ects will b e 
cl os ely m o nit or e d f or 
I S Rs p artic ul arly f or 
si g ns of p ai n, 
t e n d er n ess, 
i nf ecti o ns, eryt h e m a, 
s w elli n g, i n d ur ati o n, 
or n o d ul es 
( gr a n ul o m as or cysts) 
t hr o u g h o ut t h e st u dy. 
S p eci alist 
d er m at ol o gy 
c o ns ult ati o n will b e 
s o u g ht if w arr a nt e d 
f or i n divi d u al s u bj ects.  
Cr e ati ni n e 
P h os p h oki n as e 
( C P K) 
el e v ati o ns
Occ urr e nc es of tr a nsi e nt el ev ati o ns of C P K l ev els h av e b e e n o bs erv e d i n 
P h as e 1 st u di es a n d o n g oi n g P h as e 2 st u di es wit h C A B at d os e l ev els of 
1 0, 3 0 a n d 6 0 m g ( L AI 1 1 6 4 8 2, 2 0 0 0 5 6, 2 0 1 1 2 0). T h es e g e n er ally 
a p p e ar e d t o b e r el at e d t o p hysic al activity , w er e n ot ass oci at e d wit h 
cli nic al sy m pt o ms a n d r et ur n e d t o pr e -tr e at m e nt l ev els i n t h e m aj ority of 
c as es. R h a b d o my olysis of u nc ert ai n c a us e h as b e e n i ncl u d e d i n l a b elli n g 
f or a c urr e ntly av ail a bl e i nt e gr as e i n hi bit or (r alt e gr avir) b ut h as n ot b e e n 
s e e n in a ny s u bj ect r ec eivi n g C A B t o d at e.   
St a n d ar d l a b or at ory 
m o nit ori n g as d et ail e d 
i n S ecti o n 7. 4. 6.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 2 1
P ot e nti al 
Ri s k of 
Cli ni c al 
Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n 
Str at e g y
B o n e m arr o w 
d e pl eti o n
T his risk w as d e m o nstr at e d i n a hi g h d os e ( 1 0 0 0 m g/k g/ d ay) C A B m o nk ey 
st u dy b ut w as n ot a p p ar e nt fr o m st u di es c o n d uct e d i n r ats or at l o w er d os e 
l ev els i n m o nk eys. Si g n al n ot c o nfir m e d by h u m a n d at a t o d at e.  T h er e 
h av e b e e n is ol at e d r e p orts of tr a nsi e nt n e utr o p e ni a ( m axi m u m Gr a d e 3) i n 
s u bj ects p artici p ati n g i n a n o n g oi n g Pr E P st u dy b ut t his g e n er ally 
n or m alis e d o n c o nti n u e d tr e at m e nt , w as asy m pt o m atic a n d a p p e ar e d t o 
r e pr es e nt r o uti n e fl uct u ati o ns i n s u bj ect’s b ack gr o u n d bl o o d pict ur e.
T h e d os e us e d wit hi n 
t his st u dy will r es ult i n 
m a ny f ol d l o w er l ev el 
ex p os ur e c o m p ar e d 
t o t h e eff ect l ev el i n 
pri m at es. C ar ef ul 
m o nit ori n g of a dv ers e 
h e m at ol o gic al ev e nts 
(i ncl u di n g l a b or at ory 
m o nit ori n g as i n 
S ecti o n 7. 4. 6) will 
occ ur d uri n g st u dy 
c o n d uct.  
S eri o us/s ev er e 
ev e nts will b e 
m a n a g e d 
a p pr o pri at ely wit h 
s u p p ortiv e c ar e, a n d 
will b e f oll o w e d t o 
r es ol uti o n as p er 
S p o ns or’s st a n d ar d 
m e dic al m o nit ori n g 
pr actic es.
G astr oi nt esti n al 
i nt ol er a bility
T his risk w as i d e ntifi e d i n a m o nk ey t oxicity st u dy at t h e hi g h est 
a d mi nist er e d d os e of C A B a n d c o nsi d er e d r el at e d t o l oc al irrit ati o n (r at h er 
t h a n a syst e mic eff ect) l e a di n g t o m or bi dity ass oci at e d wit h cli nic al si g ns of 
i nt ol er a nc e.  Di arr h e a, a b d o mi n al p ai n a n d v o miti n g h av e b e e n o bs erv e d 
i n cli nic al st u di es b ut ar e g e n er ally w ell t ol er at e d wit h f e w wit h dr a w als.
C ar ef ul m o nit ori n g of 
a dv ers e GI ev e nts will 
occ ur t hr o u g h o ut t h e 
st u dy.  
S eri o us/s ev er e 
ev e nt s will b e 
m a n a g e d 
a p pr o pri at ely wit h 
s u p p ortiv e c ar e, a n d 
will b e f oll o w e d t o 
r es ol uti o n as p er 
S p o ns or’s st a n d ar d 
m e dic al m o nit ori n g 
pr actic es.
Secti o n 5. 2 E xcl usi o n Criteri a
A D D E D T E X T
8.
Hist or y  of o n g oi n g or cli nicall y rele va nt seiz ure dis or der wit hi n t he pre vi o us 2 years, 
i ncl u di n g s u bjects w h o ha ve re q uire d treat me nt f or seiz ures wit hi n t his ti me peri o d.  
A pri or hist or y of seiz ure, wit h a seiz ure free peri o d of at least 2 y ears, off a nti -
e pile ptics, ma y be c o nsi dere d f or e nr ol me nt if t he i n vesti gat or belie ves t he ris k of 
seiz ure rec urre nce is l o w.  All cases of pri or seiz ure hist or y s h o ul d be disc usse d wit h 
t he me dical m o nit or pri or t o e nr ol me nt.

2 0 1 4 N 2 1 3 7 4 7 _ 0 3
C O N FI D E N TI A L
2 0 1 7 6 7
1 2 2
Secti o n 7 St u d y Assess me nts a n d Pr oce d ures
A D D E D T E X T

All o wa ble ti me wi n d o ws f or st u d y  assess me nts ca n be f o u n d i n t he SR M.
Secti o n 7. 5. 1 S a m ple A n al ysis
P R E VI O U S T E X T
Plas ma/tiss ue/l u mi nal fl ui d a nal ysis will be perf or me d u n der t he c o ntr ol of t he Cli nical 
P har mac ol o g y  A nalyt ical La b orat or y ( C P A L) at J o h ns H o p ki ns U ni versit y.  T he details 
of sa m ple c ollecti o n a n d a nal ys is will be i ncl u de d i n t he Pr oce d ures Ma n ual a n d S O Ps.  
C o nce ntrati o ns of C A B will be deter mi ne d i n sa m ples usi n g t he c urre ntl y a p pr o ve d 
bi oa nal y tical met h o d ol o g y.  Ra w data will be arc hi ve d at t he bi oa nalyt ical site.
Assa y s are vali date d f oll owi n g F D A g ui deli nes a n d a p pr o ve d b y a n NI H -cr oss net w or k 
Cli nical P har mac ol o g y  Q ualit y Ass ura nce ( C P Q A) pr o gra m bef ore use d i n cli nical 
st u dies.
R E VI S E D T E X T
Plas ma/tiss ue/l u mi nal fl ui d a nal y sis will be perf or me d b y t he Cli nical P har mac ol o g y 
A nal y tical La borat or y  ( C P A L) at J o h ns H o p ki ns U ni versit y a n d u n der t he ma na ge me nt 
of G S K D M P K. T he details of sa m ple c ollecti o n a n d a nal ys is will be i ncl u de d i n t he 
S P M a n d a d diti o nall y  i n t he st u d y sa m ple a nalys is pla n. C o nce ntrati o ns of C A B will be 
deter mi ne d i n sa m pl es usi n g t he c urre ntl y a p pr o ve d bi oa nal ytical met h o d ol o g y.  Ra w 
data will be st ore d at t he bi oa nal y tical site.  At t he e n d of t he st u d y, a c o py of t he ra w 
data will be se nt t o G S K.
Vali dati o n testi n g will be perf or me d i n acc or da nce wit h t he F D A Bi oa nal yt i cal Met h o d 
Vali dati o n G ui da nce f or I n d ustr y  a n d assa ys re vie we d i n acc or da nce wit h t he NI H-cr oss 
net w or k Cli nical P har mac ol o g y  Q ualit y Ass ura nce ( C P Q A) pr o gra m.
Secti o n 1 0. 6 Rec or ds Rete nti o n
A D D E D T E X T

A c o p y of all bi oa nal yt ical rec or ds will be ret ur ne d to G S K at t he c o ncl usi o n of 
t he st u d y.