Clinical trial NCT02478463
Conditions: Infection, Human Immunodeficiency Virus HIV Infections
Keywords: Cabotegravir Pharmacokinetic Healthy Adult Volunteers GSK1265744
Sponsor: ViiV Healthcare
Start date: 2017-02-27; Completion date: 2019-07-25
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Cabotegravir (CAB) long-acting (LA) is a promising candidate for human immunodeficiency virus (HIV) pre exposure prophylaxis (PrEP) due to its potent antiretroviral activity and infrequent dosing requirements. Currently, the CAB concentrations achieved in the anatomical sites associated with sexual HIV transmission following the proposed 600 milligram (mg) intramuscular (IM) PrEP dose are unknown. These data will enhance our understanding of CAB distribution to the anatomical mucosal tissue believed to be relevant to sexual HIV-1 transmission and supplement the data to support future PrEP clinical trial development. The primary objective is to determine the PK concentrations of CAB following LA administration in plasma and in vaginal tissue (VT), cervical tissue (CT), and cervicovaginal fluid (CVF) in healthy women and in rectal tissue (RT) and rectal fluid (RF) in healthy men and women following a single 600 mg IM dose. This will be a Phase 1, open label study in healthy subjects to assess the pharmacokinetics of CAB LA in the plasma and mucosal locations associated with sexual HIV-1 transmission: VT, CT, CVF, RT and RF. The study will consist of a screening period, a 28-day oral lead-in phase at a dose of 30 mg per day followed by a 14-42 day washout period, and a single dose of CAB LA 600 mg as an IM (intragluteal) injection with compartmental pharmacokinetic (PK) sampling for up to 12 weeks. Subjects will return for safety assessments and plasma PK sampling at Week 24 and Week 36 post-injection and undergo a follow-up/withdrawal visit at Week 52 post-injection.

Detailed description:

Arms: arm 1: Subject will receive CAB 30 mg tablet once daily oral dose for 28 days (4 weeks) followed by a washout period of 14 to 42 days. After the washout, subject will receive a single dose of CAB LA 600 mg IM to gluteal region.
Interventions: intervention 1: Cabotegravir tablet 30 mg once daily for 28 days. intervention 2: Cabotegravir injection 3 mL (200 mg/mL) IM given once on Day 1.
Intervention descriptions: intervention 1: GSK1265744B, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate, magnesium stearate, Aquarius film-coating, white BP18237 intervention 2: Cabotegravir will be supplied as sterile suspension for injection 200 mg/mL vial. Each vial appears as sterile white to slightly colored suspension containing 200 mg/mL of CAB for administration by intramuscular (intragluteal) injection and will be administered as 1 × 3 mL Injections (3 mL \[600 mg\] total) IM given once on Day 1 of injection phase

Protocol documents:
Prot_001.pdf: 
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C O N FI D E N TI A L
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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


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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
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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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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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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


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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


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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


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C O N FI D E N TI A L
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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


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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 


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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..


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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 


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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 


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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 


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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
2 0 1 7 6 7
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.


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 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. 


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 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. 


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 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. 


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
3 1
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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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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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.


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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 . 


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 6
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


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C O N FI D E N TI A L
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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.


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 5
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.

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
201767
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A Phase 1, 
Multicompartmental Pharmacokinetic Study of Cabotegravir 
Long-acting in Healthy Adult Volunteers
Compound Number
:
GSK1265744 
Effective Date 
:
14-AUG-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 201767

This RAP is intended to describe the safety, pharmacokinetics, and tolerability 
analyses required for the study 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Authors:
Approver
Date
Approval Method
Associate Director, Statistics (Parexel International,
Clinical Statistics)
22-JUL-2019
email
Manager, Clinical Pharmacology (GSK, CPMS)
22-JUL-2019
email
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


CONFIDENTIAL
201767
2
RAP Team Approvals:
Approver
Date
Approval Method
Clinical Program Lead (GSK, SAP)
16-JUL-2019
email
Director, Clinical Pharmacology (GSK, CPMS)
22-JUL-2019
email
Principal Data Manager (GSK, PCPC, DQL)
15-JUL-2019
email
Director (ViiV, Medical Monitor)
16-JUL-2019
email
Director, (ViiV, Clinical Pharmacology)
16-JUL-2019
email
Principal Statistical Programmer (Parexel 
International, Clinical Programming)
14-AUG-2019
email
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
Manager Statistics, (GSK, Clinical Statistics)
14-AUG-2019
email
Manager (GSK, Clinical Programming)
14-AUG-2019
email
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
201767
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................7
2.4.
Statistical Hypotheses...................................................................................8
3.
PLANNED ANALYSES ............................................................................................8
3.1.
Interim Analyses ...........................................................................................8
3.2.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS .....................................................................................9
4.1.
Protocol Deviations.....................................................................................10
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................11
5.1.
Study Treatment & Sub-group Display Descriptors.....................................11
5.2.
Baseline Definition......................................................................................11
5.3.
Reporting Conventions ...............................................................................11
5.4.
Data Management ......................................................................................12
5.5.
Premature Withdrawal and Missing Data ....................................................13
5.6.
Derived and Transformed Data...................................................................13
5.6.1.
Change from Baseline .................................................................13
5.6.2.
Plasma, Tissues, Fluid Data ........................................................13
5.6.2.1.
Evaluable Concentrations and Parameters.................13
5.6.3.
Multiple Measurements at One Timepoint....................................14
5.6.4.
QTc interval .................................................................................14
5.7.
Assessment Windows.................................................................................14
5.8.
Values of Potential Clinical Importance.......................................................15
6.
STUDY POPULATION...........................................................................................15
6.1.
Overview of Planned Study Population Analyses........................................15
6.2.
Subject Disposition .....................................................................................15
6.3.
Demographic and Baseline Characteristics.................................................16
6.4.
Concomitant Medications............................................................................16
6.5.
Treatment Compliance and Protocol Deviations .........................................16
7.
SAFETY ANALYSES .............................................................................................16
7.1.
Extent of Exposure .....................................................................................16
7.2.
Adverse Events...........................................................................................17
7.3.
Deaths and Serious Adverse Events...........................................................17
7.4.
Pregnancies (as applicable)........................................................................17
7.5.
Clinical Laboratory Evaluations...................................................................17
7.6.
Other Safety Measures...............................................................................18
8.
PHARMACOKINETIC ANALYSES.........................................................................18
8.1.
Reporting Standards for Pharmacokinetic...................................................19


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201767
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8.2.
Drug Concentration Measures ....................................................................19
8.3.
Deriving and Summarizing Pharmacokinetic Parameters............................20
8.4.
Statistical Analyses.....................................................................................22
8.5.
Relationship between Plasma CAB PK Concentration and Time 
Matched CVF, CT, VT, RT and RF CAB PK Concentration ........................23
9.
REFERECE............................................................................................................24
10. ABBREVIATIONS & TRADE MARKS.....................................................................25
10.1.
Abbreviations..............................................................................................25
10.2.
Trademarks ................................................................................................26
11. ATTACHMENTS ....................................................................................................27
11.1.
Table of Contents for Data Display Specifications.......................................27
11.1.1.
Study Population..........................................................................28
11.1.3.
Pharmacokinetic Figures and Tables...........................................33
11.1.4.
ICH Listings .................................................................................39


CONFIDENTIAL
201767
5
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
GSK Document No.: 
2014N213747_00
2015-MAY-04
Original
GSK Document No.: 
2014N213747_01
2015-NOV-10
Amendment No. 1: includes additional exclusion criteria for 
subjects with history of seizure disorder
GSK Document No.: 
2014N213747_02
2016-MAR-30
Amendment No. 2: updated the CAB LA IM dose from 800 mg 
(split 2 x 400 mg injections) to a single 600 mg IM dose.  In 
addition, tissue collection on Day 3 (48h post-injection) was 
changed from optional assessments to required assessments 
per protocol and removed vaginal tissue collection on Day 8, 
Week 4 and 12.  Lastly, MRI assessments were changed from 
optional assessments to required, updated dose rationale, and 
miscellaneous changes for clarification.
GSK Document No.: 
2014N213747_03
2017-Aug-14
Amendment No. 3: updated the wash-out period between oral 
and LA dosing to accommodate visit scheduling and removed 
the needle length specification for intramuscular injection in 
Section 6.1.3.


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201767
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol dated 04-MAY-2015, protocol amendment 1 dated 10-NOV-
2015, protocol amendment 2 dated 30-MAR-2016 and protocol amendment 3 dated 14-
AUG-2017.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To determine the pharmacokinetic 
concentrations of CAB following LA 
administration in blood plasma and in 
vaginal tissue (VT), cervical tissue (CT), 
and cervicovaginal fluid (CVF) in healthy 
women and in rectal tissue (RT) and 
rectal fluid (RF) in healthy men and 
women (as data permit) following a 
single 600 mg intramuscular dose. 

Concentrations observed at Day 3 (C48h), Day 8 (Cd8), 
Week 4 (CWk4), Week 8 (CWk8), and Week 12 
(CWk12) in blood plasma and in CT, and CVF in 
women, and in RT and RF in men and women (as data 
permit) following a single CAB 600 mg intramuscular 
dose.  

VT concentrations observed at Day 3 (C48h), and 
Week 8 (CWk8), in women following a single CAB 600 
mg intramuscular dose.  
Secondary Objectives
Secondary Endpoints

To compare the pharmacokinetic 
concentrations following a single 
intramuscular dose of CAB LA 600 mg in 
VT, CT, and CVF relative to blood 
plasma and CVF in healthy women, and 
in RT and RF relative to blood plasma 
and RF in healthy men and women (as 
data permit). 

Concentration ratios including VT:blood plasma, 
CT:blood plasma, CVF:blood plasma, CT:CVF, VT:CVF 
in women, and RT:blood plasma, RF:blood plasma and 
RT:RF in men and women (as data permit) at matched 
timepoints evaluated. 

To describe the pharmacokinetic profile 
of CAB LA in blood plasma and CT, CVF, 
in healthy women and in RT and RF in 
healthy men and women (as data permit) 
following a single 600 mg intramuscular 
dose.

Maximum observed concentration (Cmax) and time of 
maximum observed concentration (tmax) in blood 
plasma and in CT, CVF, RT, RF matrices.

Area under the concentration time curve from time zero 
to last quantifiable time point (AUC(0-last)), area under 
the concentration time curve from time zero to infinity 
(AUC(0-)), area under the concentration time curve 
from time zero to Week 4 (AUC(0-Wk4)), area under 
the concentration time curve from time zero to Week 8 
(AUC(0-Wk8)) area under the concentration time curve 
from time zero to Week 12 (AUC(0-Wk12)) and 
apparent terminal phase half-life (t½) in blood plasma, 
CT, CVF, RT, RF, as data permit.  

Tissue:blood plasma and fluid:blood plasma ratio of 
AUCs of intervals specified above.

To determine the trough concentration 
achieved following repeat administration 
of oral CAB 30 mg once daily to steady 

CAB concentration (C24) following oral administration in 
VT, CT, CVF, RT, RF and blood plasma.


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201767
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Objectives
Endpoints
state in blood plasma and VT, CT, and 
CVF in healthy women and in RT and RF 
in healthy men and women (as data 
permit). 

To assess the safety and tolerability of 
CAB following repeat oral doses and 
single dose intramuscular administration 
in healthy subjects.

Safety and tolerability parameters, including adverse 
events, clinical laboratory tests, and vital signs 
assessments.
Exploratory Objectives
Exploratory Endpoints

To assess evolution of the injection depot 
localization following a single CAB 600 
mg intramuscular dose.

Volumetric and T1, T2 assessment of depot via non-
contrast-enhanced magnetic resonance imaging (MRI)
images of the injection site at the time of injection, Day 
3 (48 hours) and 1 week post-injection as data permit. 
2.3.
Study Design

This will be a Phase 1, open label study in healthy subjects to assess the PKs of CAB 
LA in the blood plasma and anatomic locations associated with sexual HIV-1 
transmission: VT, CT, CVF, RT, and RF.  

The study will consist of a screening period, a 28-day oral lead-in phase using a CAB 
dose of 30 mg once per day followed by a 14- 42 day washout period, and a single 
dose of CAB LA 600 mg IM with compartmental PK sampling for up to 12 weeks.   
Subjects will return for safety assessments and PK sampling of the blood plasma at 
Week 24 and Week 36 post-injection and undergo a follow-up/withdrawal visit at 
Week 52 post-injection.

Approximately 20 healthy subjects from up to two clinic sites will be enrolled such 
that approximately 16 evaluable subjects (8 males and 8 females) will receive a CAB 
LA IM dose and complete compartmental PK sampling.  Non-contrast-enhanced MRI 
will be performed in a subset of up to 4 males and 4 females. Evaluable subjects are 
defined as those who provide at least one primary PK endpoint without major 
protocol deviations.

If subjects prematurely discontinue the study, additional replacement subjects may be 
enrolled at the discretion of the Sponsor in consultation with the investigator. The 
replacement subject will have same treatment and procedures per protocol as the 
discontinued subject.

Each subject will participate in the study for approximately 66 weeks. The study 
design is defined in Table 1.


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Table 1
Study Design*
Screening
Oral 
Lead-in 
Washout
CAB Injection and 
Compartmental PK Sampling
Safety/
Blood Plasma 
Sampling
Follow-up/ 
Withdrawal 
Visit
Within 30 
days of 1st
oral CAB 
dose
Oral CAB 30 
mg tablet 
once daily 
x 4 weeks
No drug 
administered 
14 – 42 days
Single 600 mg 
CAB LA IM dose
Tissue/luminal fluid/blood plasma 
sampling up to 12 weeks 
post-injection
Safety assessments 
and blood plasma PK 
sampling will occur at 
24 and 36 Weeks 
post-dose
Follow-up 
assessments 
to be 
performed 52 
Weeks post-
injection
*Given the cervicovaginal sampling in the protocol, timing and duration of menses 
should be taken into account when scheduling screening, oral lead-in phase and injection.  
Figure 1
Study Schematic
1. In addition to compartmental PK sampling following CAB LA injection, subjects will undergo PK sampling of blood 
plasma and CT/VT/CVF (females) and/or RT/RF after Day 28 of the oral lead-in, on Day 29.   
2.4.
Statistical Hypotheses 
The primary objectives of this study are to assess the pharmacokinetics of CAB LA in 
blood plasma and vaginal, cervical, and rectal tissues and secretions following a single 
600mg intramuscular dose. No formal statistical hypotheses are to be tested. Where 
appropriate, an estimation approach will be taken, and point estimates and confidence 
intervals will be constructed. There will be no formal comparison.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
There will be no formal interim analysis; however preliminary CAB LA PK parameters 
may be generated and reviewed internally at GSK to assess the current CAB LA batch 
being used in this study (Protocol Section 6.1.2) relative to historical data.   


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3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
4.
ANALYSIS POPULATIONS

Screened Population
All subjects who have signed the consent form and enrolled in the study will be included 
in this population.

Safety Population
All subjects enrolled in the study who have received at least one dose of study drug will
be included in the Safety Population. This will be the population for the safety analyses, 
as well as for presentation and summarization of baseline/demographic characteristics.

Pharmacokinetic (PK) Plasma Populations

Pharmacokinetic Plasma 
Concentration
Population
The PK Plasma Concentration Population will include all subjects 
who undergo plasma and compartmental PK sampling following oral 
and/or IM injection and have evaluable PK assay results. This 
population will be used for the concentration listing and individual 
plotting of the concentration-time data. 

Pharmacokinetic Plasma 
Parameter Population
The PK Plasma Parameter Population will include all subjects who 
undergo plasma and compartmental PK sampling after IM injection 
and have PK parameters estimated. This population will be used for 
PK parameter listing.

Evaluable 
Pharmacokinetic Plasma 
Parameter Summary 
Population
The PK Plasma Parameter Population will include all subjects who 
undergo plasma PK sampling after IM injection and have evaluable 
PK parameters estimated (measurable) and no major protocol 
deviation (no important protocol deviation). This population will be
used for evaluable PK parameters and concentrations’ mean/median 
plots and summary tables.

Tissue and fluid Populations:
For the tissue or fluid samples, analysis populations will be derived for the following 9 
specimens:


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201767
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
Tissue_fluid PK 
Concentration 
Population
The tissue_fluid PK Concentration Population will include all subjects 
who undergo VT/CT/CVF/RT/RF sampling following oral and/or IM 
injection and have at least one evaluable PK assay result in 
VT/CT/CVF/RT/RF. This population will be used for the individual 
concentration listing and plot

Tissue_fluid PK 
Parameter Population
(IM)
The evaluable tissue_fluid Parameter Population will include all 
subjects who undergo sampling following IM injection and have at 
least one evaluable parameter estimated in VT/CT/CVF/RT/RF. This 
population will be used for the individual parameter listing

EvaluableTissue_fluid 
and PK Parameter 
Population (IM)
The evaluable PK and tissue_fluid Parameter Population will include 
all subjects who undergo sampling following IM injection and have
both evaluable PK and evaluable tissues_fluid parameters estimated 
in VT/CT/CVF/RT/RF. This population will be used for the parameter
summary and mean/median plots, and ratios calculations.
4.1.
Protocol Deviations

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, dosing, conduct of the trial, subject management or 
subject assessment) will be evaluated and determined by the team and be listed.

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are
captured and categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the listing of protocol deviations.

A separate listing of all inclusion/exclusion criteria deviations will also be provided
if any. 


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Data display treatment descriptors with actual treatment dose will be defined as follows:
RANDALL NG Randomization System
Data Displays for Reporting
Code
Description
Description 
Order in TLF
A
Oral CAB 30mg tablet once daily 
28 days lead-in
Oral CAB 30mg QD
1
B
Single 600mg CAB LA IM dose
IM CAB 600mg
2
Footnotes: Oral CAB 30mg=Cabotegravir 30mg QD 28 days lead-in; IM CAB 600mg=Cabotegravir IM 600mg SD.
5.2.
Baseline Definition
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline. If there are multiple assessments collected on the same 
scheduled time, the average of these assessments will be used.
The following table indicates the baseline day to be used in the analysis for each phase of 
the study:
Parameter 
Baseline (Predose) Days Collected
Baseline (Predose) Day Used in 
Analysis 
Screening
Day 1 of Each Phase
Laboratory
X
X*
Screening (or Day 1 predose in the lead-in 
phase if collected) for the lead-in phase; 
Day 1 predose for the injection phase
Vital Signs 
X
X
Day 1 (Predose) for each phase
ECG
X
X
Screening (or Day 1 predose in the lead-in 
phase if collected) for all subjects
* The results of the hematology with differential, and clinical chemistry tests on Day 1 are not required prior to 
administering the first oral dose of CAB 30 mg, but should be drawn prior to CAB administration.
5.3.
Reporting Conventions

Statistical data analyses will be performed by, or under the direct auspices of, 
Clinical Statistics and Programming, GlaxoSmithKline.

Data will be listed and summarized according to GlaxoSmithKline reporting 
standards, where applicable. Listings will be sorted by Site, subject, phase, day, and 
time, noting treatment; summaries will be presented by treatment (for safety and 
study population) or sex (for PK data), or by Site (demog), day, and time. 


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
Unless stated otherwise, descriptive summaries will include n, mean, standard 
deviation (SD), coefficient of variation (%CV), median, minimum, and maximum, 
geometric mean with associated 95% confidence interval (CI), and the between-
subject CV (%CVb) for continuous variables, whereas n and percent will be used as 
summary statistics for categorical variables.

Baseline or pre-dose assessment is the last available assessment prior to time of dose 
administration unless it is specified otherwise.  If there are multiple assessments 
collected on the same scheduled time, the average of these assessments will be used.  
For tabulated safety summaries, only the scheduled assessments will be included in 
the summary tables. Unscheduled assessments will be presented in listings. 

Deviations from planned times will be examined for scheduled assessments. PK 
parameters will be calculated using actual assessment times. Actual assessment 
times will be used in the individual concentration-time plots. Nominal times will be 
used for the purposes of summarization and in mean and median plots. 
Concentration-time data will be listed using actual assessment times.

Any changes/deviations to the analyses specified in the RAP will be described in the 
final Clinical Pharmacology Study Report (CPSR).

Version 9.4 or higher of the SAS system will be used to analyze the CRF data as 
well as to generate tables, figures, and listings. PK parameters will be calculated 
using standard non-compartmental methods using Phoenix WinNonLin Version 7 or 
higher.

All final displays will be produced according to Clinical Data Interchange Standards 
Consortium (CDISC) reporting standards based on the final Study Data Tabulation 
Model (SDTM) and Analysis Data Model (ADaM) datasets.
5.4.
Data Management
Data 
Type
Source 
Format of Data
Planned Date of Final 
File
Responsibility
Safety
Database
SDTM
DBF
Data 
Management
PK/Tiss
ues 
samples
SMS2000 /PK HARP
DAT
Prior to SDL
DMPK
SMS2000, Randomisation 
& CRF data (merge)
CSV file
Approximately 1 week 
after SDL
Data 
Management 
using EDU
Derived PK parameters
CSV file
Approximately 4 weeks 
after DBF
CPMS
LAB
Local lab
SDTM
DBF
Data 
Management


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5.5.
Premature Withdrawal and Missing Data
All subjects who withdraw prematurely from the study/study drug will be documented 
and the reason for their withdrawal recorded in the final Clinical Pharmacology Study 
Report (CPSR).  All available data from subjects who withdraw will be listed and all 
available planned data will be included in the summaries according to the populations 
defined in Section 4.
In the event that the study is prematurely discontinued, all available data will be listed 
and a review carried out by the study team to assess which statistical analyses are still 
considered appropriate.
5.6.
Derived and Transformed Data
5.6.1.
Change from Baseline
The change from baseline will be calculated by subtracting the baseline values from the 
individual post-baseline values.  If either the baseline or post-baseline value is missing, 
the change from baseline is set to missing as well.
5.6.2.
Plasma, Tissues, Fluid Data
Plasma and a variety of compartment tissues and fluid samples are collected during the 
study, and all will be listed with actual time and calculated visit weeks. Samples with 
protocol deviation will be reviewed by the team to determine whether these samples will 
be excluded from the summary tables.
5.6.2.1.
Evaluable Concentrations and Parameters
Flags for evaluable concentrations for each type of samples will be created and are 
defined as samples collected within the specified window without major protocol 
deviations. Evaluable parameters are calculated based on evaluable concentrations. 
Flags will be created for the samples which are collected when the injections are done at 
gluteal muscle under ultrasound guidance. Concentrations data could be summarized by 
gluteal muscle flag.
For the purposes of calculating summary statistics and for statistical analysis, only
parameters with the exception of tmax will be loge transformed.
Between subject’s coefficient of variation (%CVb) will be calculated according to the 
following methods:
Untransformed Data : 100 * (SD/Mean)
Transformed Data       : 100 * (sqrt(exp(SDlog2)-1))
where SDlog indicates the standard deviation of log-transformed data.


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5.6.3.
Multiple Measurements at One Timepoint
Where multiple measurements are recorded for a particular time point, the mean of the 
measurements will be calculated and used in any derivation of summary statistics.  
However, all available data will be listed.
5.6.4.
QTc interval
QTc interval will be corrected by both Bazett’s (QTcB) and Fridericia’s (QTcF) formula 
and will be included in all relevant listings. 
QTcB interval (msec) = QT interval (msec) / square root (RR interval (msec)/1000)
QTcF interval (msec) = QT interval (msec) / cubic root (RR interval (msec)/1000)
If QTcB is provided by the Electrocardiogram (ECG) machine, then that RR value will 
be used to calculate the QTcF.
For example, if a vendor provides QTcB but not QTcF, RR will be calculated as: 
RR = [(QT/QTcB)**2 ]*1000, provided at the SDTM level.
5.7.
Assessment Windows
Scheduled visits and unscheduled visits for lab, ECG and vital sign data will be assigned 
to assessment windows by actual study day. For PK, tissues and fluid samples, actual 
days will be used to calculate the actual visit Week (round-up), and evaluable samples 
will be summarized by actual visit week. Actual days will be used for the listings, and 
scheduled windows will be used for the Summary Displays.
Phase
Study Visit and Unscheduled Visit window
Reported on Summary 
Displays
Screen
30 days prior to Day 1
Screen
Oral Lead-in
Day 1, Day 14, Day 29
Day 1, Day 14, Day 29
Injection phase
Days 1,3,5,8
Days 1,3,5,8
Week 4 3 days
Week 4
Week 8 3 days
Week 8
Week 12 3 days
Week 12
Week 24 3 days
Week 24
Week 36 3 days
Week 36
Week 52 3 days
Week 52


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5.8.
Values of Potential Clinical Importance
ECG Values of Potential Clinical Importance (Healthy Volunteers)
ECG Parameter
Potential Clinical Importance Range (PCI)
Unit
Absolute QTc interval
>450
msec
Increase from baseline QTc 
>60 
msec
PR interval
<110 and >220
msec
QRS interval
<75 and >110
msec
Vital Sign Values of Potential Clinical Importance (Healthy Volunteers)
Parameter
Potential Clinical Importance Range (PCI)
Unit
Systolic Blood Pressure
< 85 and > 160
mmHg
Diastolic Blood Pressure
< 45 and > 100
mmHg
Heart Rate
< 40 and > 110
bpm
6.
STUDY POPULATION
Study population data will be summarised by, or under the direct auspices of, Clinical 
Statistics, GlaxoSmithKline.
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the screened and safety population, unless 
otherwise specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards if 
applicable.  Details of the planned displays are presented in Section 11.1.1 and Section 
11.1.4 of the RAP.
6.2.
Subject Disposition
A summary table will be generated to provide the count of subjects included in each 
analysis population for the study (see Section 4 for definition of analysis populations) and 
this table will be displayed by treatment and overall.
The End of Study Record will be listed and summarized by Site and overall.  The listing 
will include whether subjects prematurely withdrew from the study, the reason for 
premature discontinuation, along with the start and end date of investigational product 
(IP) dosing and the date of completion or premature discontinuation from the study.


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6.3.
Demographic and Baseline Characteristics
Demographic data includes date of birth, gender, race, and ethnicity. Demographic data 
will be summarized by Site and Overall, and listed for the Safety Population.  Race will 
be summarized by Site and Overall, and listed separately from the other demographic 
characteristics.
Baseline characteristics (Height, weight, BMI, etc.) will be listed by subject and 
summarized by Site and Overall according to data display specifications given in Section 
11.1.2 and Section 11.1.4. 
6.4.
Concomitant Medications
Concurrent medication verbatim text will be coded and classified by the Anatomical 
Therapeutic Chemical Classification level 1 (ATC Level 1) code and the preferred term 
using the GSK coding system, GSK DRUG. Subjects who take concurrent medications 
during the study will be summarized and listed according to data display specifications 
given in Section 11.1 of this RAP. Coding of concurrent medications will be the 
responsibility of the GSK coding group.
Information on whether or not the subject consented to having a pharmacogenetic sample 
drawn will be listed.
6.5.
Treatment Compliance and Protocol Deviations
Information for each subject who did not receive the correct dose, the reason for not 
receiving the correct dose, and any other protocol deviations will be summarized by the 
important flag and by Site and listed by Site and subject. Subjects who did not satisfy all 
inclusion and exclusion criteria and corresponding criteria that were violated will be 
listed.
7.
SAFETY ANALYSES
Safety data will be summarised descriptively and listed by according to GSK’s Integrated 
Data Standards Library (IDSL) standards, or under the direct auspices of, Clinical 
Statistics, GlaxoSmithKline 
No formal statistical analysis of the safety data will be conducted.
The precise format and content of Safety figures, tables and listings are shown in 
Section 11.1.2 and Section 11.1.4 of the RAP.
The tables will use the “Safety” population unless otherwise specified.
7.1.
Extent of Exposure
A by-subject summary of treatments administered in each phase will be generated, with 
dose, number of doses and dosing start date and dosing end date. A by-subject listing of 


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data on subject exposure will be generated including dose date and time, unit, 
formulation, route, frequency and location. 
7.2.
Adverse Events
Adverse event verbatim text will be coded and classified by system organ class (body
system) and preferred term using a standardized GSK coding system: Medical Dictionary 
for Regulatory Activities (MedDRA, v22 or higher). Treatment emergent AEs data and 
drug-related AEs for lead-in phase and for LA dosing phase will be summarized by Site 
and treatment and overall. The relationship of AE system organ class, preferred term, and 
verbatim text will be listed. All AEs will be listed by Site, subject and treatment. Serious 
adverse events (SAEs) will be listed. A listing of grade 3 or 4 non-ISR AEs will be 
provided if any grade 3 or 4 AE occur.
Injection site reaction (ISR) symptoms, size, severity grade and duration for the LA 
dosing phase will be summarized overall and will be listed by Site and subject.
For subjects who have an ISR that is serious, Grade 2 if persistent beyond 2 weeks, any 
Grade 3 or if any ISR persistent beyond 30 days and others if the Investigator or Medical 
Monitor feels it is medically necessary, a listing will be provided in table listing. All ISR
data including treatment received and medical intervention as well as reaction outcome 
will be listed by subject. Plots of top 3 injection site reaction duration will be provided.
7.3.
Deaths and Serious Adverse Events
Deaths and other serious adverse events will be listed if any of these events occur.
Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal 
from the Study and Other Significant Adverse Events
A by-subject listing of AEs leading to withdrawal will be provided.
Patient profile for deep venous thrombosis/pulmonary embolus will be generated for 
cardiovascular event.
7.4.
Pregnancies (as applicable)
If any female subjects become pregnant during the study, a narrative of such subjects will 
be provided.
7.5.
Clinical Laboratory Evaluations
A listing of reference ranges for clinical laboratory tests performed during the study will 
be generated.  Hematology, clinical chemistry and urinalysis (listing only) data will be 
listed by subject, phase, visit, and actual date and time and summarized by treatment and 
visit.  Summary of change from baseline in hematology and clinical chemistry by 
treatment and visit will be created for each site. If any laboratory test results are outside 
of the reference range, they will be flagged with high/low and/or toxicity grade in the 
listing. Only the tests which have specified in the protocol will be included on the 
displays.


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Laboratory abnormalities that are recorded as adverse events will be listed separately and 
corresponding lab values will be provided.
Modified Division of AIDS (DAIDS) AE grades will be derived in analysis dataset by 
using Division Of AIDS Table For Grading The Severity Of Adult And Pediatric 
Adverse Events Version 2.0, November 2014. Grades 2, 3, and 4 of lab abnormalities 
will be listed by Site, subject, phase, visit, treatment and actual date and time.
7.6.
Other Safety Measures
Vital sign data (temperature, systolic and diastolic blood pressure, and pulse rate) will be 
summarized by treatment, visit, and planned time and listed by site, subject, phase, visit, 
planned time, and actual date and time. In addition, a listing of vital signs for subjects 
with abnormalities of potential clinical importance will be provided.
ECG data will be listed by site, subject, visit, and actual date and time. Clinically
significant ECG abnormalities will be flagged. 
Any surgical procedures will be listed.
Medical and medication history, physical examination, pregnancy and drug screen 
(including alcohol) results will be captured in the source document supporting the 
enrolment criteria and summary will not be provided.
MRI images and quantitative assessments will be collected and reported separately by 
GSK Platforms Technology Sciences. Only MRI collection dates will be provided in the 
listing package.
8.
PHARMACOKINETIC ANALYSES
The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be 
performed by, or under the direct auspices of, Clinical Pharmacology Sciences and Study 
Operations (CPSSO), GlaxoSmithKline.
The merge of PK concentration data, randomisation and CRF data will be performed by, 
or under the direct auspices of, Clinical Statistics (Programmer), GlaxoSmithKline.
Derivation of pharmacokinetic parameters will be performed by, or under the direct 
auspices of, Clinical Pharmacokinetic Modelling Simulation (CPMS), GlaxoSmithKline.
Statistical analysis of pharmacokinetic parameters will be performed by, or under the 
direct auspices of, Clinical Statistics (Statistician), GlaxoSmithKline.


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8.1.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to GSK 
PK guidance
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
The following PK parameters will be derived or extracted from SDTM PC file or 
SDTM PP by the Programmer: 
From SDTM PC Concentrations:
Ctau on Day 29, C48h, C8d, CWk4, CWk8, CWk12, CWk24, CWk36, and CWk52
from concentration data (as data permit) & the ratios: VT:blood plasma, CT:blood 
plasma, CVF:blood plasma, CT:CVF, VT:CVF in women, and RT:blood plasma, 
RF:blood plasma and RT:RF in men and women (as data permit) at matched 
timepoints evaluated. 
From SDTM PP file: 
VT:blood plasma, CT:blood plasma, CVF:blood plasma, CT:CVF, VT:CVF in 
women, and RT:blood plasma, RF:blood plasma and RT:RF in men and women 
ratios for Cmax, AUC(0-), AUC(0-last), AUC(0-Wk4), AUC(0-Wk8) and AUC(0-
Wk12)
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to Standards for the Transfer and Reporting of PK Data using HARP.
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards & refer to Standards for the Transfer and 
Reporting of PK Data using HARP.
8.2.
Drug Concentration Measures
CAB concentrations will be collected at following time points after a single CAB 600 mg 
IM dose:

Blood plasma (BP) of CAB concentrations: Day 1 (pre-dose, 4hr), Day 3 (C48h), Day 
5 (C96h), Day 8 (C168h), Weeks 4, 8, 12, 24, 36, and 52 (CWk4, CWk8, CWk12, 
CWk24, CWk36 and CWk52)

Cervical tissue (CV) and cervicovaginal fluid (CVF) of CAB concentrations in 
women: Day 3 (C48h), Day 8 (Cd8), Weeks 4, 8, and 12 (CWk4, CWk8, and 
CWk12)

Rectal tissue (RT) and rectal fluid (RF) in men and women (as data permit): Day 3 
(C48h), Day 8 (Cd8), Weeks 4, 8, and 12 (CWk4, CWk8, and CWk12)


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
Vaginal tissue (VT) of CAB concentrations in women: Day 3 (C48h), and Week 8 
(CWk8)  
These concentrations will be determined directly from concentration-time data from each 
matrix (BP, CV, CVF, RT, RF, VT). Descriptive statistics (i.e. mean, standard deviation, 
median, minimum and maximum) and graphics will be created to describe the primary 
PK endpoints of interest.
Refer to the standard operating procedure, SOP-CPK-0001, for more information 
regarding the treatment of plasma concentrations below the assay’s lower limit of 
quantification (BQL).
Individual concentration-time profiles and median/mean profiles from each matrix will be 
plotted.  Each of the figures will contain one plot on the untransformed scale (i.e. a linear 
plot) and one plot on the log transformed scale (i.e. semi-log plot). See Section 11.1.3
Pharmacokinetic Figures and Tables for details.
8.3.
Deriving and Summarizing Pharmacokinetic Parameters
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacokinetics 
Modeling & Simulation department within GlaxoSmithKline. 
Plasma and tissue/fluid concentration-time data will be analyzed by non-compartmental 
methods with Phoenix WinNonlin 7 or higher (New Jersey).  Pharmacokinetic parameters 
will be estimated via noncompartmental analysis using the linear up/log down application 
of the trapezoidal rule for model 200 (extravascular administration) of the WinNonlin 
program.   Calculations will be based on the actual sampling times recorded during the 
study.  The following CAB PK parameters will be calculated for each matrix if available:

Cmax, tmax, AUC(0-), AUC(0-last), AUC(0-Wk4), AUC(0-Wk8) and AUC(0-
Wk12) and t½ in blood plasma and in CT, and CVF in females and  RT and RF in 
males and females.  
1. CAB concentrations at Day 3 (C48h), Day 8 (Cd8), Weeks 4, 8, and 12 (CWk4, 
CWk8, and CWk12) in blood plasma and in CT, CVF in women, and in RT and RF in 
men and women (as data permit) will be considered as evaluable data if they are 
collected within 4 hours of schedule time for C48h and Cd8, and collected within 3
days of scheduled time for CWk4, CWk8 and CWk12. Actual weeks (rounding to the 
integer weeks) will be used for CWk24, CWk36 and CWk52.
2. VT samples will be considered as evaluable C48h and CWk8 concentration if 
samples are collected at Day 3 (C48h with 4hrs of window of scheduled collection), 
and Week 8 (CWk8 with 3 days of scheduled visit), in women following a single 
CAB 600 mg IM dose.  
3. CAB concentration in VT, CT, CVF, RT, RF and BP on Day 29 will be considered as 
evaluable data if these samples are collected within 4hr of scheduled window. 


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4. The area under the plasma concentration-time curve from time zero to the last 
quantifiable concentration (AUC(0-last)) will be determined using the linear 
trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for 
decreasing concentrations in blood plasma and in CT, and CVF in females and RT 
and RF in males and females.  
5. The AUC extrapolated to infinity (AUC(0-)) will be calculated, where data permit, 
as the sum of AUC(0-t) and Ct/λz, where Ct is the observed plasma concentration 
obtained from the log-linear regression analysis of the last quantifiable time-point in 
blood plasma and in CT, and CVF in females and RT and RF in males and females.  
6. AUC(0-Wk4), AUC(0-Wk8) and AUC(0-Wk12) are the area under the concentration 
time curve from time zero to week 4, week 8 and week 12 respectively, determined 
using the linear trapezoidal rule for increasing concentrations and the logarithmic 
trapezoidal rule for decreasing concentrations in blood plasma and in CT, and CVF in 
females and RT and RF in males and females.  
7. The first occurrence of the maximum observed plasma concentration (Cmax) will be 
determined directly from the raw concentration-time data in blood plasma and in CT, 
and CVF in females and RT and RF in males and females.  
8. The time at which Cmax is observed (tmax), determined directly from the raw 
concentration-time data in blood plasma and in CT, and CVF in females and RT and 
RF in males and females.  
9. The apparent terminal elimination half-life (t1/2) obtained as the ratio of ln2/ λz, 
where z is the terminal phase rate constant estimated by linear regression analysis of 
the log transformed concentration-time data in blood plasma and in CT, and CVF in 
females and RT and RF in males and females.  
10. Ratios of time-matched AUC(0-), AUC(0-last), AUC(0-Wk4), AUC(0-Wk8) and 
AUC(0-Wk12) tissue matrices/luminal fluid: blood plasma (CVF:BP, CT:BP, RT:BP, 
and RF:BP), where data permit.
11. CVF:BP, CT:BP, VT:BP, CT:CVF, VT:CVF ratio in women and, RT:BP, and RT:RF 
ratios in males and females at matching time points (48h, 8d, 4w, 8w, 12w) where 
data permit during the injection phase, are calculated by CAB concentration in one of 
the matrices divided by another specified matrix. For example, the ratio of CVF, CT, 
VT, and RT concentration to blood plasma will be calculated as R_CVF (CT, VT, 
RT) = CVF (CT, VT, RT) concentration (ng/g) / Plasma Concentration (ng/mL).  
Assuming tissue density of 1g/mL, the tissue concentration to plasma ratio will be 
unitless.   For CVF, CT, VT, and RT concentration below lower level of qualification 
(LLQ), it will be imputed as half of LLOQ.
Plasma PK parameters should be reported in g/mL and gh/mLfor Cmax and AUC and 
in hours for tmax.  Tissue concentrations in ng/g will be converted to ug/mL assuming a 
1g/mL density and 1000ng/ug.


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Clinical statistics and programming will extract the Ctau on Day 29, Day 3 (C48h), Day 8 
(C8d), Weeks 4, 8, and 12 (CWk4, CWk8, and CWk12) from concentration data to 
calculate the ratios: CVF:BP, CT:BP, VT:BP, CT:CVF, VT:CVF ratio in women and, RT:BP, 
RF:BP and RT:RF ratios in males and females at matching time points where data permit during 
the injection phase.
8.4.
Statistical Analyses
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of the 
statistics and programming, PAREXEL, under the direct auspices of statistics and 
programming, GlaxoSmithKline.    
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively by sex, by flag for evaluable data, by flag for injection 
location, by Site and overall. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D.
All the derived PK parameters will be listed and summarized by sex and overall. For
each of these PK parameters, with the exception of tmax and ratios, the following
descriptive summary statistics will be calculated for each treatment: n, arithmetic mean
with associated 95% CI, standard deviation, median, minimum, maximum, geometric
mean with associated 95% CI, standard deviation of logarithmically transformed data,
and between-subject coefficient of variation (CVb(%)). 
For tmax and all concentration ratios, no geometric mean, nor associated 95% CI or 
standard deviation of logarithmically transformed data will be provided.
A sex-based comparison will be made for all the evaluable blood plasma PK parameters 
and estimated ratio between female vs male and its associated 90% CI will be provided. 
Log-transformed PK parameters (AUC(0-), AUC(0-last), AUC(0-Wk4)), AUC(0-
Wk8), AUC(0-Wk12), Cmax and t½ in blood plasma) will be analyzed by analysis of 
covariance (ANCOVA). The analysis will consider sex as fixed effect with BMI as 
continuous covariate using the mixed linear models procedure within the SAS/STAT 
module of the SAS system (Version 9.4 or higher). For each log-transformed PK 
parameter, point estimate and its associated 90% CI will be constructed for the sex
difference (females vs males), and the difference and its 90%CI will be exponentiated to 
obtain the ratio of geometric least-squares (GLS) means and its 90% CI on the original 
scale. 
Examples of SAS codes: 
Proc Mixed;
     class subjid sex;
     model logPKpar = sex bmi/ddfm=kr; 
   
lsmeans sex; 
     estimate 'Females vs Males' Sex 1 -1 /cl alpha=0.1;
run;


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Ratios will be calculated for each subject. Evaluable PK parameters and calculated ratios 
will be summarized by gender and/or overall for each matrix.
CAB concentration in each matrix from the oral lead-in phase may be compared with 
Weeks 4, 8, and 12 concentrations if data permit using the exploratory model below.
Descriptive summary will be provided by sex, by flag for evaluable PK, by flag for 
injection location and/or overall.
Examples of SAS codes: if model converges
Proc Mixed; (only include Ctau from Day 29, Weeks 4, 8 and 12)
    class subjid sex visit;
     model log(Ctau) = sex bmi visit/ddfm=kr; 
     random subjid;
     lsmeans sex; 
     lsmeans visit;
     estimate 'Females vs Males' Sex 1 -1 /cl alpha=0.1;
     estimate ‘IM vs oral’ visit -1 0.3333 0.3333 0.3333/cl
alpha=0.1;
     estimate ‘Week 4 vs week 12’ visit 0 1 0 -1/cl alpha=0.1;
     estimate ‘Week 8 vs week 12’ visit 0 0 1 -1/cl alpha=0.1;
run;
Data display specifications for derived PK parameter summaries and listings are given in 
Section 11.1.3 of this RAP.        
8.5.
Relationship between Plasma CAB PK Concentration and
Time Matched CVF, CT, VT, RT and RF CAB PK 
Concentration
The relationship between the plasma CAB PK concentration and the time matched CVF, 
CT, VT, RT and/or RF CAB PK concentration will be assessed with plots and by the 
SAS Proc Corr procedure.


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9.
REFERECE
GlaxoSmithKline Document Number 2014N213747_00: A Phase 1, Multicompartment 
Pharmacokinetic Study of Cabotegravir Long-acting in Healthy Adult Volunteers. 
Effective Date: 04-MAY-2015
GlaxoSmithKline Document Number 2014N213747_01: A Phase 1, Multicompartment 
Pharmacokinetic Study of Cabotegravir Long-acting in Healthy Adult Volunteers. 
Effective Date: 10-NOV-2015
GlaxoSmithKline Document Number 2014N213747_02: A Phase 1, Multicompartmental 
Pharmacokinetic Study of Cabotegravir Long-acting in Healthy Adult Volunteers. 
Effective Date: 30-MAR-2016
GlaxoSmithKline Document Number 2014N213747_03: A Phase 1, Multicompartmental 
Pharmacokinetic Study of Cabotegravir Long-acting in Healthy Adult Volunteers. 
Effective Date: 14-AUG-2017


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10.
ABBREVIATIONS & TRADE MARKS
10.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
ALT
alanine aminotransferase (SGPT)
ANCOVA
Analysis of Covariance
AST
Aspartate aminotransferase (SGOT)
ATC
Anatomical Therapeutic Chemical Classification level
AUC(0-last)
Area under the concentration time curve from time zero to last quantifiable time 
point 
AUC(0-)
Area under the concentration time curve from time zero to infinity
AUC(0-Wk4)
Area under the concentration time curve from time zero to Week 4
AUC(0-Wk8)
Area under the concentration time curve from time zero to Week 8
AUC(0-Wk12)
Area under the concentration time curve from time zero to Week 12
BMI
Body mass index
BP
Blood pressure
BPM
Beats per minute
BQL
Below the quantification limit
CAB
Cabotegravir
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence interval
Cmax
Maximum observed concentration
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacokinetic Modelling Simulation
CPSSO
Clinical Pharmacology Sciences and Study Operations
C
Steady-state pre-dose CAB concentration 
CT
Cervical tissue
CV
Coefficient of variance
CVb
Coefficient of variation between subjects
CVF
Cervicovaginal fluid
C48h
Concentrations observed at Day 3 (48h)
Cd8
Concentration observed at Day 8
CWk4
Concentration observed at Week 4 
CWk8
Concentration observed at Week 8
CWk12
Concentration observed at Week 12
ECG
Electrocardiogram
GLS
Geometric least-squares
GSK
GlaxoSmithKline
HIV
Human immunodeficiency virus
IDSL
GSK’s Integrated Data Standards Library
IM
Intramuscular(ly)
IP
Investigational product
ISR
Injection site reaction


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Abbreviation
Description
LA
Long-acting
MRI
Magnetic resonance imaging
PK
Pharmacokinetic(s)
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RF
Rectal fluid
RT
Rectal tissue
SAE
Serious adverse event(s)
SAS
Statistical Analysis Software
SD
Standard deviation
SDTM
Study Data Tabulation Model
SOP
Standard operating procedure
t½
Apparent terminal phase half-life 
VT
Vaginal tissue
10.2.
Trademarks
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
None
PAREXEL
SAS
Winonlin


CONFIDENTIAL
201767
27
11.
ATTACHMENTS
11.1.
Table of Contents for Data Display Specifications
Listed below are the planned figures, tables and listings to be produced for inclusion in the clinical study report. Example shells from 
GSK1265744 studies LAI116815\final_cdisc, LAI114433\final, mid201741\final and GSK2881078\mid200030\final are located under 
the same compound (GSK1265744) in HARP. Example shells for some of the PK figures are also under the GSK2881078/mid200030
study reporting effort final.
Reporting Area
HARP Server
: US1SALX00259
HARP Area
: \ARPROD\GSK1265744\MID201767\Final_01
QC Spreadsheet
: \ARWORK\ GSK1265744\MID201767\Final\Documents


CONFIDENTIAL
201767
28
11.1.1.
Study Population
Table 
No.
Population
IDSL No. / 
Example Shell
Title
Additional Programming Notes
QC Level
Deliverable 
Priority
1.1
Safety
LAI116815, 
Table 1.1
Summary of Analysis Populations
By Site and Treatment and Overall
3
SAC
1.2
Safety
LAI116815, 
Table 1.2
Summary of End of Study Record by Site and 
Overall
By Site and overall
2
SAC
1.3
Safety
LAI116815, 
Table 1.3
Listing of End of Study Record
Include the sub-reason where it has.
1
SAC
1.4
Safety
IDSL, IE4
Listing of Subjects with Inclusion/Exclusion 
Criteria Deviations
1
SAC
1.5
Safety
LAI116815, 
Table 1.4
Summary of Demographic Characteristics for 
Safety Population by Site
By Site and overall
2
SAC
1.6
Safety
IDSL, DM6
Summary of Race for Safety Population
By Site and overall
2
SAC
1.7
Safety
IDSL, CP_CM4
Summary of Concomitant Medications
Replace this listing with summary table by 
treatment if it has more than 4 pages of 
conmed data
1
SAC
1.8
Safety
IDSL, GN9
Listing of Genetics Subject Accountability
With Site information
1
SAC
1.9
Safety
LAI116815, 
Table 1.8
Listing of Treatment Non-Compliance by Site
Only list subjects with treatment non-
compliance
1
SAC
1.10
Safety
LAI116815, 
Table 1.9
Summary of Protocol Deviations
Sorted by Site
1
SAC
1.11
All Screened
mid201741, 
Table 1.11
Summary of Screen Failure by Site
By Site
2
SAC


CONFIDENTIAL
201767
29
11.1.2.
Safety 
Figures
Figure 
No.
2.X
Population
IDSL No. / Example 
Shell
Title
Additional Programming 
Notes
QC Level
Deliverable 
Priority
1
Safety
LAI116815, 
Figure 2.3
Individual Subject ISR Duration for the Top 3 ISRs
Select the top 3 ISRs, like 
Pain, nodule, and 
induration
1
SAC
Tables
Table 
No.
Population
IDSL No. / Example 
Shell
Title
Programming Notes
QC Level
Deliverable 
Priority
2.1
Safety
LAI116815/Table 2.1
Summary of Exposure Data
Include number of dose(s), 
formulation/route, and 
injection site, needle 
length, fat depth, injection 
length, etc
Sorted by Site
1
SAC
2.2
Safety
IDSL, AE2
Relationship of Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
2
SAC
2.3
Safety
IDSL, CP_AE1x
Summary of All Adverse Events
By Site and Overall
2
SAC
2.4
Safety
IDSL, CP_AE1x
Summary of Drug-Related Adverse Events
Include all study treatment 
related, not procedure 
related AEs
By Site and Overall
2
SAC


CONFIDENTIAL
201767
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Table 
No.
Population
IDSL No. / Example 
Shell
Title
Programming Notes
QC Level
Deliverable 
Priority
2.5
Safety
IDSL, CP_AE9a
Listing of Subjects with Serious Adverse Events
1
SAC
2.6
Safety
IDSL, CP_AE9
Listing of Adverse Events Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from 
Study
1
SAC
2.7
Safety
LAI116815, Table 2.7
Listing of Grade 3 and 4 Adverse Events
1
SAC
2.8
Safety
LAI116815, Table 2.8
Summary of Injection Site Reaction by Site and 
Overall
This table summarizes the 
data at Subject level; ‘LM 
CAB 600mg SD’ only, by 
site and overall
2
SAC
2.9
Safety
LAI116815, Table 2.9
Summary of ISR Event by Toxicity Grade
for Each Site and Overall
This table summarizes the 
data at event level for ‘IM 
CAB 600mg SD’ only; by 
site and overall
2
SAC
2.10
Safety
LAI116815, Table 2.10
Summary of Injection Site Reaction
Symptoms Maximum Size Measured in
Diameter(cm) by Site and Overall
Average the max of each 
event size for each subject 
with ISR by treatment; ‘IM 
CAB 600mg SD’ only
2
SAC
2.11
Safety
LAI116815, Table 2.11
Summary of Duration of Injection Site
Reaction by Site and Overall
This table summarizes the 
data at ISR event level; IM 
CAB 600mg SD’ only
2
SAC
2.12
Safety
LAI116815, Table 2.12
Listing of Grade 2 or Higher Injection Site
Reaction Symptoms or ISR persist beyond
30 days
For ISR
2
SAC
2.13
Safety
LAI116815, Table 2.13
IDSL, LB13
Listing of Reference Ranges for Clinical 
Laboratory Tests
1
SAC
2.14
Safety
LAI116815, Table 2.14
Summary of Hematology Data by Treatment and 
Time by Site and Overall
Include oral CAB 30mg and 
600mg LA in one table 
2
SAC
2.15
Safety
LAI116815, Table 2.15
Summary of Change from Baseline in Hematology 
Data by Treatment and Time by Site and Overall
2
SAC


CONFIDENTIAL
201767
31
Table 
No.
Population
IDSL No. / Example 
Shell
Title
Programming Notes
QC Level
Deliverable 
Priority
2.16
Safety
LAI116815, Table 2.16
Summary of Clinical Chemistry Data by Treatment
and Time for Each Site and Overall
2
SAC
2.17
Safety
LAI116815, Table 2.17
Summary of Change from Baseline in Clinical 
Chemistry Data by Treatment and Time for Each 
Site and Overall
2
2.18
Safety
LAI116815, Table 2.19
Summary of Treatment Emergent Grade 2 or 
Higher Lab Abnormalities for Each Site and 
Overall
Include all tests in which 
we have DAIDS criteria.
1
SAC
2.19
Safety
LAI116815, Table 2.20
Listing of Treatment Emergent Grade 2 or Higher 
Lab Abnormalities
Include all tests in which 
we have DAIDS criteria.
1
SAC
2.20
Safety
LAI116815, Table 2.21
Summary of Vital Signs by Treatment and Time
Include BP, HR, and 
Temperature
2
SAC
2.21
Safety
LAI116815, Table 2.22
Summary of Change from baseline in Vital Signs 
by Treatment and Time
Include BP, HR, and 
Temperature
2
SAC
2.22
Safety
LAI116815, Table 2.23
Listing of All Vital Signs for Subjects with Any 
Values of Potential Clinical Importance
1
SAC
2.23
Safety
LAI116815, Table 2.24
Summary of ECG Findings
2
SAC
2.24
Safety
LAI116815, Table 2.25
Summary of ECG Values
2
SAC
2.25
Safety
LAI116815, Table 2.26
Summary of Change from baseline for ECG 
Values
2
SAC
2.26
Safety
LAI116815, Table 2.27
Summary of Category of QTc Data by Treatment
and Time
2
SAC
2.27
Safety
LAI116815, Table 2.28
Summary of Category of QTc Change from 
Baseline by Treatment and Time
2
SAC
2.28
Safety
IDSL, CP_EG6
Listing of Clinically Significant ECG Abnormalities
List all data for a subject 
with clinically significant 
abnormalities
1
SAC
2.29
Safety
IDSL, CP_EG4,
LAI116815, Table 2.29
Listing of All ECG Values for Subjects with Any 
Value of Potential Clinical Importance
1
SAC


CONFIDENTIAL
201767
32
Table 
No.
Population
IDSL No. / Example 
Shell
Title
Programming Notes
QC Level
Deliverable 
Priority
2.30
Safety
IDSL, SP1
Listing of Surgical Procedures
See format
1
SAC
2.31
Safety
IDSL, MH2
Listing of Medical Conditions
See format
1
SAC


CONFIDENTIAL
201767
33
11.1.3.
Pharmacokinetic Figures and Tables
Flag for injection location indicates whether the injection gets to the gluteal muscle, it is not necessary to be considered as not evaluable 
samples/parameters. Flag for evaluable sample/parameter indicates the samples are collected at specified window and injection location, 
and no major deviation of process.  When specified by evaluable flag, by flag for injection location, it means the plots or tables should be 
generated for each flag levels only, and plus overall. When specified by evaluable flag and injection location, it means the plots or tables 
should be generated for each combination levels of evaluable and injection location, and plus overall. Footnote the treatments (oral CAB, 
or IM CAB) based on the sample collection days should be added when time (Days/Weeks) are presented in plots. Tissue/fluid data may 
contain up to 5 different matrices: vaginal tissue (VT), cervical tissue (CT), and cervicovaginal fluid (CVF) in healthy women and in rectal tissue 
(RT) and rectal fluid (RF) in healthy men and women (as data permit).
Figures: 
Figure
No.
Population
IDSL No. / Example Shell
Title
Programming Notes
QC 
Level
Deliverable 
Priority
3.1
PK Concentration
GSK1265744/LAI114433,
Figure 11.1
Individual Plasma Cabotegravir
Concentration-Time Plots (Linear 
and Semi-Log) by Gender and 
Flag for Injection Location
Plot all data using actual schedule 
Days/Weeks, one symbol per 
gender and location 
(combinations), with multiple 
subjects on the same page, 
Footnote the treatment based on 
the sample collection days/Weeks
1
SAC
3.2
Evaluable 
Pharmacokinetic 
Plasma Parameter 
Summary Population
GSK1265744/LAI114433,
Figure 11.2
Mean Plasma Cabotegravir
Concentration-Time Plots (Linear 
and Semi-Log) by Gender and 
Evaluable Flag and Overall
Four curves for gender by 
evaluable flag, all are on one 
page, one Overall, Footnote the 
treatment based on the sample 
collection days/Weeks
1
SAC
3.3
Evaluable 
Pharmacokinetic 
Plasma Parameter 
Summary Population
GSK1265744/LAI114433,
Figure 11.3
Median Plasma Cabotegravir
Concentration-Time Plots (Linear 
and Semi-Log) by Gender and 
Evaluable Flag and Overall
Four curves for gender by 
evaluable flag, all are on one 
page, one Overall, Footnote the 
treatment based on the sample 
collection days/Weeks
1
SAC


CONFIDENTIAL
201767
34
Figure
No.
Population
IDSL No. / Example Shell
Title
Programming Notes
QC 
Level
Deliverable 
Priority
3.4
Evaluable Tissue_fluid 
and PK Parameter(IM)
GSK1265744/LAI114433,
Figure 11.5
Individual Tissue_fluid 
Cabotegravir Concentration-Time 
Plots (Linear and Semi-Log) by 
Evaluable Flag for Each Matrix
Include all subjects on the same 
page per matrix 
(VT/CT/CVF/RT/RF) with different 
symbol by Evaluable Flag, 
Footnote the treatment based on 
the sample collection days/Weeks 
Oral CAB: C24, IM CAB: Day 3 
(C48h), Day 8 (Cd8), Week 4 
(CWk4), Week 8 (CWk8), and 
Week 12 (CWk12) if available
1
SAC
3.5
Evaluable Tissue_fluid 
and PK Parameter(IM)
GSK1265744/LAI114433,
Figure 11.6
Mean Tissue_fluid Cabotegravir
Concentration-Time Plots (Linear 
and Semi-Log) by Evaluable Flag 
and Overall for Each Matrix
Each matrix with a page and 
different symbol, by Evaluable 
Flag and Overall, Footnote the 
treatment based on the sample 
collection days/Weeks
1
SAC
3.6
Evaluable Tissue_fluid 
and PK Parameter(IM)
GSK1265744/LAI114433,
Figure 11.7
Median Tissue_fluid Cabotegravir
Concentration-Time Plots (Linear 
and Semi-Log) by Evaluable Flag 
and Overall for Each Matrix
Each matrix with a page and 
different symbol by Evaluable
Flag and Overall, Footnote the 
treatment based on the sample 
collection days/Weeks
1
SAC
3.7
Evaluable Tissue_fluid 
and PK Parameter(IM)
GSK2881078/mid200030
Figure 3.10
Scatter Plot of Plasma 
Cabotegravir PK Concentration vs 
Time Matched Cabotegravir 
Concentration in Vaginal Tissue 
by Evaluable Flag
All Time-matched Concentrations,
with a regression line and R from 
SAS Proc Corr procedure, for 
evaluable of Oral CAB: C24, and 
IM CAB data: Day 3 (C48h), Day 
8 (Cd8), Week 4 (CWk4), Week 8 
(CWk8), and Week 12 (CWk12) if 
available
1
SAC


CONFIDENTIAL
201767
35
Figure
No.
Population
IDSL No. / Example Shell
Title
Programming Notes
QC 
Level
Deliverable 
Priority
3.8
Evaluable Tissue_fluid 
and PK Parameter(IM)
GSK2881078/mid200030
Figure 3.10
Scatter Plot of Plasma 
Cabotegravir PK Concentration vs 
Time Matched Cabotegravir 
Concentration in Cervical Tissue
by Evaluable Flag
All Time-matched Concentrations,
with a regression line and R from 
SAS Proc Corr procedure for 
evaluable of Oral CAB: C24, and 
IM CAB data: Day 3 (C48h), Day 
8 (Cd8), Week 4 (CWk4), Week 8 
(CWk8), and Week 12 (CWk12) if 
available
1
SAC
3.9
Evaluable Tissue_fluid 
and PK Parameter (IM)
GSK2881078/mid200030
Figure 3.10
Scatter Plot of Plasma 
Cabotegravir PK Concentration vs 
Time Matched Cabotegravir 
Concentration in Cervicovaginal 
Fluid by Evaluable Flag 
All Time-matched Concentrations,
with a regression line and R from 
SAS Proc Corr procedure for 
evaluable of Oral CAB: C24, and 
IM CAB data: Day 3 (C48h), Day 
8 (Cd8), Week 4 (CWk4), Week 8 
(CWk8), and Week 12 (CWk12) if 
available
1
SAC
3.10
Evaluable Tissue_fluid 
and PK Parameter (IM)
GSK2881078/mid200030
Figure 3.10
Scatter Plot of Plasma 
Cabotegravir PK Concentration vs 
Time Matched Cabotegravir 
Concentration in Rectal Tissue by 
Evaluable Flag 
All Time-matched
Concentrations, with a regression 
line and R from SAS Proc Corr 
procedure for evaluable of Oral 
CAB: C24, and IM CAB data: Day 
3 (C48h), Day 8 (Cd8), Week 4 
(CWk4), Week 8 (CWk8), and 
Week 12 (CWk12) if available
1
SAC


CONFIDENTIAL
201767
36
Figure
No.
Population
IDSL No. / Example Shell
Title
Programming Notes
QC 
Level
Deliverable 
Priority
3.11
Evaluable Tissue_fluid 
and PK Parameter (IM)
GSK2881078/mid200030
Figure 3.10
Scatter Plot of Plasma 
Cabotegravir PK Concentration vs 
Time Matched Cabotegravir 
Concentration in Rectal Fluid, by 
Evaluable Flag 
All Time-matched
Concentrations, with a regression 
line and R from SAS Proc Corr 
procedure for evaluable of Oral 
CAB: C24, and IM CAB data: Day 
3 (C48h), Day 8 (Cd8), Week 4 
(CWk4), Week 8 (CWk8), and 
Week 12 (CWk12) if available
1
SAC


CONFIDENTIAL
201767
37
Tables
Table 
No.
Population
IDSL No. / Example 
Shell
Title
Programming Notes
QC 
Level
Deliverable 
Priority
3.1
Evaluable PK
Plasma 
Parameter 
Summary
PKCT1
Summary of Plasma Cabotegravir PK 
Concentration (unit)-Time Data by Gender, 
by Site, by Evaluable Flag and by Injection 
Location
Include the plasma CAB Concentration 
on Day 29 of oral lead-in and IM CAB
Samples, do summary by Gender, by 
Evaluable Flag and by Injection location 
and overall
2
SAC
3.2
PK Parameter
GSK1265744/LAI114433 
Table 11.3
Listing of Derived Plasma Cabotegravir PK 
Parameters 
Sort by clinical site, sex and subject ID
with flags evaluable and injection 
location
1
SAC
3.3
Evaluable PK
Plasma 
Parameter 
Summary
GSK1265744/LAI114433 
Table 11.4
Summary of Derived Plasma Cabotegravir
PK Parameters by Gender by Site, by 
Evaluable Flag and by Injection Location
For each parameter, summarized the 
data by Gender, by Evaluable Flag, by 
Injection location and overall
2
SAC
3.4
Evaluable PK
Plasma 
Parameter 
Summary
GSK1265744/LAI114433,
Table 11.7
Summary of Result of Plasma 
Cabotegravir PK Parameter Comparisons 
Between Gender for Evaluable PK
Limited to evaluable PK data, and 
include sex and BMI in model, evaluate 
the difference between gender for 
AUC(0-t), AUC(0-∞), Cmax, AUC(0-
Wk4), AUC(0-Wk8), AUC(0-Wk12) and 
t1/2, 
3
SAC
3.5
Evaluable PK
Plasma 
Parameter 
Summary
GSK1265744/LAI114433,
Table 11.7
Summary of Result of Plasma 
Cabotegravir PK Parameter Ctau 
Comparisons Between Oral and IM for 
Evaluable PK
Limited to evaluable PK data, and 
include sex, BMI and Visits in model, 
evaluate the difference between IM vs 
oral CAB Ctau
3
SAC
3.6
Evaluable
Tissue_fluid 
and PK 
Parameter(IM)
GSK1265744/LAI114433 
Table 11.10
Summary of Tissue and Fluid Cabotegravir 
Parameters for each Treatment and Matrix 
by Site, by Evaluable Flag and by Gender 
Include the CAB Parameters from 
tissue/fluid on Day 29 of oral lead-in, put 
each by variable on different page or 
sub-category
2
SAC
3.7
Tissue fluid 
Parameter
GSK1265744/LAI114433 
Table 11.8
Listing of Derived Tissue and Fluid 
Cabotegravir Parameters
Sort by clinical site, sex and subject ID 
and flags for evaluable and injection 
locations
1
SAC


CONFIDENTIAL
201767
38
Table 
No.
Population
IDSL No. / Example 
Shell
Title
Programming Notes
QC 
Level
Deliverable 
Priority
3.8
Evaluable
Tissue_fluid 
and PK 
Parameter 
(IM)
GSK1265744/LAI114433 
Table 11.10
Summary of Tissue and Fluid to Blood 
Plasma Cabotegravir PK Parameter Ratio
for each Matrix by Site and by Gender  
Ratios of Tissue or fluid vs plasma for 
AUC(0-t), AUC(0-∞), Cmax, AUC(0-
Wk4), AUC(0-Wk8), AUC(0-Wk12), for 
VT:blood plasma, CT:blood plasma, 
CVF:blood plasma, by site, by gender 
and overall
2
SAC
3.9
Evaluable
Tissue_fluid 
and PK 
Parameter 
(IM)
GSK1265744/LAI114433 
Table 11.10
Summary of Tissue and Fluid to Blood 
Plasma Cabotegravir PK Concentration 
Ratios of Each Visit by Site and by Gender
Ratios of Tissue fluid vs plasma for oral 
C29d, and IM C3d, C8d, CWk4, CWk8, 
CWk12 of VT:blood plasma, CT:blood 
plasma, CVF:blood plasma, by site, by 
gender and overall 
2
SAC
3.10
Evaluable
Tissue_fluid 
and PK 
Parameter(IM)
GSK1265744/LAI114433 
Table 11.10
Summary of Tissue to Fluid Cabotegravir
Parameter Ratios by Site and by Gender
Ratios of tissue vs fluid for AUC(0-t), 
AUC(0-∞), Cmax, AUC(0-Wk4), AUC(0-
Wk8), AUC(0-Wk12), by site and by 
gender plus overall for ratios: CT:CVF, 
VT:CVF in women, and RT:RF in men 
and women (as data permit)   
2
SAC
3.11
Evaluable
Tissue_fluid 
and PK 
Parameter 
Population 
(IM)
GSK1265744/LAI114433 
Table 11.10
Summary of Tissue to Fluid Cabotegravir
PK Concentration Ratios of Each Visit by 
Site, by Gender
Ratios of Tissue vs fluid for oral C29d, 
and IM C3d, C8d, CWk4, CWk8, CWk12 
of for ratios: CT:CVF, VT:CVF in 
women, and RT:RF in men and women 
(as data permit)   
2
SAC
3.12
Tissue fluid 
Parameter 
GSK1265744/LAI114433 
Table 11.8
Listing of Individual Tissue and Fluid to 
Blood Plasma or Tissue vs Fluid
Cabotegravir PK Concentration Ratios 
Ratios of tissue fluid vs plasma or tissue 
vs fluid for oral C29d, and IM C3d, C8d, 
CWk4, CWk8, CWk12, include flags for 
evaluable data and injection location 
variables
2
SAC


CONFIDENTIAL
201767
39
Table 
No.
Population
IDSL No. / Example 
Shell
Title
Programming Notes
QC 
Level
Deliverable 
Priority
3.13
Tissue fluid 
Parameter 
GSK1265744/LAI114433 
Table 11.8
Listing of Individual Tissue and Fluid to 
Blood Plasma or Tissue vs Fluid
Cabotegravir PK Parameter Ratios 
Ratios of tissue fluid vs plasma or tissue 
vs fluid for AUC(0-t), AUC(0-∞), Cmax,
AUC(0-Wk4), AUC(0-Wk8), AUC(0-
Wk12), include flags for evaluable data 
and injection location variables
2
SAC
11.1.4.
ICH Listings
Listing
No.
Population
IDSL No. / Example 
Shell
Title
Programming Notes
QC Level
Deliverable 
Priority
1
Safety
IDSL, DM4
Listing of Demographic Characteristics
1
SAC
2
Safety
IDSL, DM10
Listing of Race
1
SAC
3
Safety
IDSL, CP_AE9
Listing of All Non-Injection Reaction Site
Adverse Events
1
SAC
4
Safety
IDSL, CP_AE9
Listing of Injection Site Reactions 
AE dataset
1
SAC
5
Safety
LAI116815, Listing 5
Listing of All Injection Site Reaction 
Symptoms
ISR dataset
1
SAC
6
Safety
IDSL, CP_CM4
Listing of Concomitant Medications
Provide listing if summary of 
Concomitant Medication table 
provided. 
1
SAC
7
Safety
IDSL, CP_AE9
Listing of All Adverse Events
AE severity is captured as 
“Maximum grade or intensity of 
event
1
SAC


CONFIDENTIAL
201767
40
Listing
No.
Population
IDSL No. / Example 
Shell
Title
Programming Notes
QC Level
Deliverable 
Priority
8
Safety
LAI116815, Listing 6
Listing of Female Subjects or Female 
Partners of Male Subjects Who Became 
Pregnant During the Study
1
SAC
9
Safety
LAI116815, Listing 7
Listing of Hematology Data
1
SAC
10
Safety
LAI116815, Listing 8
Listing of Clinical Chemistry Data
1
SAC
11
Safety
LAI116815, Listing 9
Listing of Urinalysis Data
1
12
Safety
IDSL, CP_VS5
Listing of Vital Signs
Include BP, HR, RR, 
Temperature
1
SAC
13
Safety
IDSL, CP_EG4
Listing of ECG Values
1
SAC
14
Safety
IDSL, CP_EG6
Listing of Abnormal ECG Findings
1
SAC
15
Safety
IDSL,
CP_RA1x
Listing of Planned and Actual Treatments
1
SAC
16
Safety
LAI114433, Table 10.1
Listing of Exposure Data
Location of dose is applicable 
for LA only 
1
SAC
17
Safety
LAI116815, Table 1.9
Listing of Subject with Protocol Deviations
Sorted by Site
1
SAC
18
Safety
IDSL, CP_CM4
Listing of Concomitant Medications
Replace this listing with 
summary table by treatment if 
it has more than 4 pages of 
conmed data
1
SAC
19
All Subjects 
Who Failed 
Screening
LAI117011, Listing 18
Listing of Screen Failure
1
SAC
20
PK 
Concentration
PKCL1x
Listing of Plasma Cabotegravir PK 
Concentration-Time Data 
Include the flags for evaluable 
sample and injection location 
variables
1
SAC
21
Tissue_fluid 
Concentration
PKCL1x
Listing of Vaginal Tissue Cabotegravir PK 
Concentration-Time Data 
Include the flags for evaluable 
sample and injection location 
variables
1
SAC
22
Tissue_fluid 
Concentration
PKCL1x
Listing of Cervical Tissue Cabotegravir PK 
Concentration-Time Data 
Include the flags for evaluable 
sample and injection location 
variables
1
SAC


CONFIDENTIAL
201767
41
Listing
No.
Population
IDSL No. / Example 
Shell
Title
Programming Notes
QC Level
Deliverable 
Priority
23
Tissue_fluid 
Concentration
PKCL1x
Listing of Cervicovaginal Fluid Cabotegravir 
PK Concentration-Time Data 
Include the flags for evaluable 
sample and injection location 
variables
1
SAC
24
Tissue_fluid 
Concentration
PKCL1x
Listing of Rectal Tissue Cabotegravir PK 
Concentration-Time Data 
Include the flags for evaluable 
sample and injection location 
variables
1
SAC
25
Tissue_fluid 
Concentration
PKCL1x
Listing of Rectal Fluid Cabotegravir PK 
Concentration-Time Data 
Include the flags for evaluable 
sample and injection location 
variables
1
SAC
26
PK 
Parameter
SAS output
SAS Output of Summary of Result of Plasma 
Cabotegravir PK Parameter Comparisons by 
Gender
2
SAC
27
PK 
Parameter
SAS output
SAS Output of Summary of Result of Plasma 
Cabotegravir PK Parameter Ctau 
Comparisons between IM and Oral CAB
2
SAC


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Example SP1
Protocol: ABC123456                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Listing X
Listing of Medical/Surgical Procedures
Treat-
ment
Inv.
Sub-
Ject
Date of
Procedure
Time of
Procedure
Study
Day
Classification
Condition
Trt A
13:00
-46
Vascular Therapeutic 
Procedures
VARICOSE VEINS LIGATION
-15
Head and Neck Therapeutic 
Procedures
OSSICULOPLASTY
-39
Head and Neck Therapeutic 
Procedures
EAR TUBE INSERTION
Trt B
18:45
-14
Aortic Therapeutic 
Procedures
AORTIC BYPASS
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Example MH2
Protocol: ABC123456                                                           Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Listing X
Listing of Medical Conditions
Treatment
Inv.
Subject
Classification
Condition
Status
Treatment A
Hepatobiliary
HEPATITIS A
Current
Psychiatric
PARANOIA COMBINED WITH MANIA.
Past
Eye
ASTIGMATISM
Current
Treatment B
Metabolism and 
nutrition
RICKETS
Current
PPD
PPD
PPD
PPD
PPD