Conditions: Healthy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 16
Healthy volunteers: yes

Brief summary:
The main purpose of this study is to evaluate the effect of LOXO-305 on single oral dose of caffeine cytochrome P450 1A2 (CYP1A2) substrate, S-warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate) when administered as multiple doses by collecting the blood samples and conducting the blood tests to measure how much LOXO-305 is in the bloodstream and how the body handles and eliminates LOXO-305 in adult healthy participants. The study will also evaluate the safety and tolerability of LOXO-305. The study will be conducted in two periods. Participants will stay in this study for up to 67 days, including screening.

Detailed description:

Arms:
arm 1: Participants received 200 milligrams (mg) caffeine tablet, 40 mg omeprazole capsule, and 10 mg warfarin tablet as a single dose of probe drug cocktail, along with 10 mg vitamin K tablet on Day 1. arm 2: Participants received oral dose of 200 mg Pirtobrutinib once daily (QD) from Day 6 to Day 19. On Day 15, Pirtobrutinib was co-administered with 200 mg caffeine tablet, 40 mg omeprazole capsule, and 10 mg warfarin tablet as a single dose of probe drug cocktail, along with 10 mg vitamin K tablet.

There was a 5-day washout period between the probe drug cocktail on Day 1 (Period 1) and the first dose of Pirtobrutinib on Day 6 (Period 2).

Interventions: intervention 1: Caffeine Tablet intervention 2: Omeprazole capsule intervention 3: Warfarin tablet intervention 4: Pirtobrutinib
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally. intervention 3: Administered orally. intervention 4: Administered orally.

Protocol document:
Prot_000.pdf: 
Protocol LOXO-BTK-20010 
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to Investigate the Effect 
of Multiple Oral Doses of LOXO-305 on CYP1A2, CYP2C9, and CYP2C19 Substrates 
Using a Probe Drug Cocktail in Healthy Subjects
NCT06215430 
Approval date: 10-Dec-2020 


TI T L E P A G E  
Pr ot oc ol  
A P h ase I, O pe n -l a bel, Fi xe d-se q ue nce, Dr u g I nter acti o n St u d y t o 
I n vesti g ate t he Effect of M ulti ple Or al D oses of L O X O-3 0 5 o n C Y P 1 A 2, 
C Y P 2 C 9, a n d C Y P 2 C 1 9 S u bstr ates usi n g a Pr o be Dr u g C oc kt ail i n 
He alt h y S u bjects  
Pr ot oc ol Stat us: Fi nal  
Pr ot oc ol Date: 9 Dece m b er 2 0 2 0 
Pr ot oc ol Versi o n: 1. 0 
I n v esti gati o nal Me dici nal Pr o d uct: L O X O- 3 0 5 
Pr ot oc ol Refere n ce N u m ber: L O X O -B T K - 2 0 0 1 0 
C o va nce St u d y N u m ber: 8 4 1 9 6 8 9 
I N D N u m ber: 1 3 9 8 7 6 
S p o ns or: 
L o x o O nc ol o g y, I nc. 
A w h oll y o w ne d s u bsi diar y of Eli Lill y a n d 
C o m pa n y 
7 0 1 Gate wa y B o ule v ar d, S uite 4 2 0 
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0 
U S A  
C o or di nati n g I n vesti gat or St u d y Site: 
C o va nce Cli nical Researc h U nit I nc.  
1 3 4 1 West M oc ki n g bir d La ne, S uite 2 0 0 E 
Dallas, Te xas 7 5 2 4 7 
U S A  
U p t o 2 a d diti o nal sites i n t he U nite d States 
ma y be utilize d.  
S p o ns or Si g nat or y: 
 
C o or di nati n g I n vesti gat or: 
 
I nf or mati o n descri be d herei n is c o nfi de ntial a n d m a y be discl ose d o nl y wit h t he e x press 
writte n  per missi o n of t he S p o ns or. 
P P D
P P D


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 of 6 8 
S P O N S O R A P P R O V A L  
I h a ve r ea d t he pr ot oc ol a n d a p pr o ve it: 
 
 
 
 
Date  
1 0 - D e c - 2 0  |  0 7 : 2 0 : 2 6  P S T
P P D


Pr ot o c ol 
C o v a n c e St u d y: 8 4 1 9 6 8 9 
C O N FI D E N TI A L 
Pr ot o c ol Refere nce: L O X O- B T K- 2 0 0 1 0 
I N V E S TI G A T O R A G R E E M E N T 
I h a v e r e a d t h e pr ot o c ol a n d a gree t o c o n d u ct t he st u d y as descri be d herei n. 
Pr ot o c ol V ersi o n 1. 0, 9 D e c e m b er 2 0 2 0 
D at e 
P a g e 3 of 6 8 
P P D


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 of 6 8 
S T U D Y I D E N TI FI C A TI O N  
S p o ns or 
L o x o O nc ol o g y, I nc. 
A w h oll y o w ne d s u bsi diar y of Eli Lill y a n d C o m pa n y 
7 0 1 Gate wa y B o ule v ar d, S uite 4 2 0 
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0 
U S A  
Tel ( mai n): 
 
S p o ns or’s St u d y C o ntact 
 
Direct or, Cli nical O perati o ns  
L o x o O nc ol o g y, I nc. 
Tel ( m o bile): 
 
Tel (alter n ati ve c o ntact): 
 
E mail:
 
S p o ns or’s Me dical C o ntact 
 
C o ns ulti n g t o L o x o O nc ol o g y, I nc. 
Tel ( m o bile): 
 
E mail: 
 
Seri o us A d verse E v e nt Re p orti n g 
E mail: S A EI nta ke @c o va nce.c o m  
St u d y Site(s) 
C o or di n ati n g I n vesti g at or St u d y Site  
C o va nce Cli nical Researc h U nit I nc.  
1 3 4 1 West M oc ki n g bir d La ne, S uite 2 0 0 E 
Dallas, Te xas 7 5 2 4 7 
U S A  
U p t o 2 a d diti o nal sites i n t he U nite d States ma y be 
utilize d.  
C o or di nati n g I n vesti gat or 
 
C o va nce Cli nical Researc h U nit I nc.  
1 3 4 1 West M oc ki n g bir d La ne, S uite 2 0 0 E 
Dallas, Te xas 7 5 2 4 7 
U S A  
Tel:  
 
Tel (cell): 
 
S u b-i n vesti gat or(s) 
O btai n i nf or mati o n fr o m F or m F D A 1 5 7 2s 
Cli nical La b orat or y(s) 
C o va nce Cli nical Researc h U nit I nc.  
1 3 4 1 West M oc ki n g bir d La ne, S uite 2 0 0 E 
Dallas, Te xas 7 5 2 4 7 
U S A  
Eac h a d diti o nal site will use t heir l ocal la b orat or y f or 
safet y a n al yses. 
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P P D
P P D
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Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 of 6 8 
Bi oa nal ytical La b orat or y  
Alt uras A nal ytics, I nc. 
1 3 2 4 Alt uras Dri ve 
M osc o w, I da h o 8 3 8 4 3 
U S A  
T el ( mai n): ( 2 0 8) 8 8 3- 3 4 0 0 
E mail: jzi m mer @alt uras a nal ytics.c o m 
Statisticia n  
 
C o va nce 
T el: 
 
E mail: 
 
Pr ot oc ol Me dical Writer  
 
C o va nce 
T el: 
 
E mail:
 
P P D
P P D
P P D
P P D
P P D
P P D


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 of 6 8 
S Y N O P SI S  
St u d y Title  
A P hase I, O pe n -la bel, Fi xe d-se q ue n ce, Dr u g I nteracti o n St u d y t o I n vesti gate t he Effect of 
M ulti ple Oral D oses of L O X O - 3 0 5 o n C Y P 1 A 2, C Y P 2 C 9, a n d C Y P 2 C 1 9 S u bstrates usi n g a 
Pr o be Dr u g C oc ktail i n Healt h y S u bjects  
O bjecti ves  
T he pri mar y o bjecti ve of t he st u d y is t o assess t he effect of m ulti ple oral d oses of L O X O- 3 0 5 
o n t he p har mac o ki n etic ( P K) of si n gle oral d oses of caffei ne (c yt oc hr o m e P 4 5 0 [ C Y P] 1 A 2 
s u bstrate), S-warfari n ( C Y P 2 C 9 s u bstrate), a n d o me praz ole ( C Y P 2 C 1 9 s u bstrate) i n healt h y 
s u bjects. 
T he sec o n d ar y o bjecti ve of t he st u d y is t o assess t he safet y a n d t olera bilit y of m ulti ple oral 
d oses of L O X O- 3 0 5 w he n a d mi nistere d al o ne, a n d c oa d mi nistere d wit h a si n gle oral d ose of 
pr o be dr u g c o c ktail. 
St u d y Desi g n   
T his is a P hase  1, o pe n-la bel, 2- peri o d, fi xe d-se q u e nce dr u g- dr u g i nteracti o n st u d y t o 
i n vesti gate t he eff ect of m ulti ple oral d oses of L O X O- 3 0 5 o n t he P K of si n gle oral d oses of 
caff ei ne ( C Y P 1 A 2 s u bstr ate) a n d its me ta b olite para xa nt hi ne, S- w arfari n ( C Y P 2 C 9 
s u bstrate), a n d o me praz ole ( C Y P 2 C 1 9 s u bstrate) i n healt h y s u bjects.  
I n Peri o d 1, Da y 1, 2 0 0 m g caff ei ne (ta blet), 4 0  m g o me praz ole (ca ps ule), a n d 1 0 m g 
warf ari n (ta blet) a d mi nistere d as a si n gle d ose of pr o be dr u g c o c ktail, al o n g wit h 1 0 m g 
vita mi n K (ta blets), will be a d mi nistere d i n t he m or ni n g f oll o wi n g a fast of at least 1 0  h o urs 
pre d ose a n d 2 h o urs p ost d ose. Bl o o d sa m ples f or c o nce ntrati o ns of t he s u bstrates 
(caffei ne/ para x a nt hi ne, o me praz ole, a n d S- warfari n) i n plas ma will be c ollecte d  
 
. Of t h e sa m ples c ollecte d f or c o nce ntrati o ns of eac h 
s u bstrate i n plas ma 
 p ost d ose o n Da y 1, sa m ples will be a nal yze d 
f or c o nce ntrati o n of caffei ne/ para xa nt hi ne fr o m 
 p ost d ose, f or 
c o nce ntr ati o n of o me praz ole fr o m 
 p ost d ose, a n d S-warfari n fr o m 
. 
T here will be a was h o ut peri o d of 5 da ys b et wee n a d mi nistrati o n of t he pr o be dr u g c oc kt ail 
o n Da y 1 a n d t he first d ose of L O X O- 3 0 5 o n Da y 6.  
I n Peri o d 2, o n Da ys 6 t hr o u g h 1 9, oral d oses of 2 0 0 m g L O X O - 3 0 5 will be a d mi nistere d 
o nce dail y ( Q D) f or 1 4 c o nsec uti ve da ys i n t he m or ni n g at t he act ual ti me of t he Da y 1 pr o b e 
dr u g c oc ktail d osi n g ( ± 1 h o ur). O n Da y 1 5, L O X O- 3 0 5 will be c oa d mi nistere d wit h 2 0 0 m g 
caff ei ne (ta bl et), 4 0  m g o me praz ole (ca ps ule), a n d 1 0 m g warfari n (ta blet) a d mi nistere d as a 
si n gle d ose of pr o be dr u g c oc ktail, al o n g wit h 1 0 m g of vita mi n K (ta blets) , at t he act ual t i me 
of t he Da y 1 pr o b e dr u g c oc ktail d osi n g ( ± 1 h o ur) f oll o wi n g a fast of at least 1 0 h o urs 
pre d ose a n d 2 h o urs p ost d ose. O n Da ys 7 t hr o u g h 1 1, a n d Da ys 1 3, 1 4, 1 6, 1 8, a n d 1 9, 
s u bjects will fast f or at least 2 h o urs pre d ose a n d 1 h o ur p ost d ose. O n Da ys 6, 1 2, a n d 1 7 
w here cli nical la b orat or y e val uati o ns are perf or me d, s u bjects will fast f or at least 8  h o urs 
pre d ose a n d 1 h o ur p ost d ose. Bl o o d sa m ples f or c o nce ntrati o ns of L O X O- 3 0 5 i n plas ma will 
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Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 7 of 6 8 
be c ollecte d a n d a nal y ze d 
 
. Sa m ples c ollecte d 
 will be 
c ollecte d pri or t o L O X O- 3 0 5 d osi n g o n Da ys 1 6 t hr o u g h 1 9. Bl o o d sa m ples f or 
c o nce ntr ati o ns of t he s u bstrates (caff ei ne / para xa nt hi ne, o me praz ol e, a n d S-warfari n) i n 
plas ma will be 
. Of t he sa m ples 
c ollecte d f or c o nce ntrati o n s of eac h s u bstrate i n plas ma 
 
 sa m ples will be a nal yze d f or c o nce ntrati o n of caffei ne/ para xa nt hi ne fr o m 
 
, f or c o n ce ntrati o n of o me praz ole fr o m 
 
, a n d f or c o n ce ntrati o n of S- warfari n fr o m 
.  
T o assess t heir eli gi bilit y t o e nter t he s t u d y, p ote ntial s u bjects will be scree ne d wit hi n 3 4 da ys 
( Da ys - 3 5 t o - 2) a n d be a d mitte d t o t he Cli nical Researc h U nit ( C R U) o n D a y -1 ( C hec k -i n). 
S u bjects will be c o nfi ne d at t he C R U fr o m t he ti me of C hec k -i n ( Da y - 1) u ntil E n d of 
Treat me nt ( E O T) o n D a y  2 3 u p o n c o m pleti o n of all P K a n d safet y assess m e nts or Earl y 
Ter mi nati o n ( E T) if t he s u bject disc o nti n ues. D osi n g of pr o be dr u g c oc ktail will occ ur o n 
Da y 1 a n d D a y 1 5 a n d d osi n g of L O X O- 3 0 5 will o cc ur o n D a ys 6 t hr o u g h 1 9. A f oll o w- u p 
p h o ne call will occ ur f or all s u bjects w h o recei ve d at least 1  d ose of st u d y dr u g (i ncl u di n g 
s u bjects w h o ar e ter mi nate d earl y) 7 d a ys ( ±  2 da ys) after E O T or E T.  
T he start of t he st u d y is d efi ne d as t he d ate t he first s u bject w h o is e nr olle d i n t he st u d y si g ns 
a n I nf or me d C o ns e nt F or m (I C F). N ote t h at e nr oll e d s u bjects are defi n e d as t h ose s u bjects 
w h o are assi g ne d t o recei ve a d ose of st u d y dr u g; t his defi niti o n e xcl u des scree n fail ure 
s u bjects. Re place me nt s u bjects ma y be e nr olle d o nl y if dee me d necessar y b y t he S p o ns or. 
I n t his st u d y, p h ysical e x a mi nati o ns, 1 2-lea d electr ocar di o gra ms ( E C Gs), vital si g n 
meas ure me nts, H o w D o Y o u Feel? ( H D Y F?) i n q uiries, cli nical c he mistr y pa nel, c oa g ul ati o n 
para meters, he mat ol o g y pa nel, uri nal ysis ( U A; A p pe n di x 2 ), a n d rec or di n g of c o nc o mita nt 
me dicati o ns will be perf or me d at s pecifi e d ti mes d uri n g t he st u d y (f or s pecific ti me p oi nts a n d 
details o n eac h st u d y varia ble, refer t o A p p e n di x 4 ).  
A d verse e ve nts ( A Es) a n d seri o us a d vers e e v e nts ( S A Es) will be c ollecte d be gi n ni n g at 
i nf or me d c o nse nt. A d v erse e ve nts will be re p orte d t hr o u g h o ut t he st u d y (ie, fr o m si g ni n g of 
t he I C F u ntil E n d of St u d y [ E O S], or u ntil E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d 
d oes n ot c o m plete a f oll o w- u p p h o ne call), eit her as s u bject me dical hist or y (if t he e ve nt is 
re p orte d as be gi n ni n g pri or t o si g ni n g of t he I C F or if t he e ve nt o cc urs pri or t o st u d y dr u g 
a d mi nistrati o n o n Da y 1 a n d is assesse d as n ot rel ate d t o st u d y pr oce d ures b y t he I n vesti gat or 
[ or desi g nee]) or as A Es (if t he e ve nt o cc urs after si g ni n g of t he I C F b ut pri or t o st u d y dr u g 
a d mi nistrati o n o n Da y 1 a n d is assesse d as relate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or 
desi g nee], or if t he e v e nt occ urs after st u d y dr u g a d mi nistrati o n o n Da y 1 t hr o u g h E O T or E T 
re gar dl ess of rel ati o ns hi p t o st u d y dr u g). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d 
as relate d t o st u d y dr u g b y t he I n v esti gat or ( or d esi g nee) are t o be re p orte d. All S A Es t hat 
de vel o p fr o m t he ti me of I C F si g ni n g u ntil E O S ( or E T, if t he s u bject disc o nti n ues fr o m t he 
st u d y a n d d oes n ot c o m plete a f oll o w- u p p h o n e call) are t o be re p ort e d. 
St u d y c o m pleti o n is defi ne d as t he ti me of t he last s u bject’s f oll o w- u p p h o ne call. 
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Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 8 of 6 8 
N u m ber of S u bjects  
U p t o 1 6 healt h y a d ult male a n d f e male s u bjects ( w o me n of n o n-c hil d beari n g p ote ntial o nl y) 
will be e nr olle d. E ver y atte m pt will be ma de t o e nr oll at least 4  s u bjects of eac h se x i n t he 
st u d y. 
M ai n Criteri a f o r I ncl usi o n  
Male s u bjects, a n d f e mal e s u bjects of n o n -c hil d beari n g p ote ntial m ust meet t he f oll o wi n g 
criteria:  
•  Bet wee n 1 8 a n d 5 5 y ears of a ge, i ncl usi ve, at Scree ni n g  
•  Wit hi n b o d y mass i n de x ( B MI) ra n g e 1 8. 0 t o 3 2. 0 k g/ m
2, i ncl usi ve, at Scree ni n g 
•  I n g o o d g e ner al healt h, b ase d o n me dical hist or y, p h ysical e xa mi nati o n fi n di n gs, vital 
si g ns, 1 2-lea d E C G, or cli nical la b orat or y e val uati o ns at Scree ni n g a n d/ or C hec k-i n 
( Da y -1), as deter mi ne d b y t he I n vesti gat or ( or d esi g nee)  
I n vesti g ati o n al Me dici n al Pr o d ucts, D ose, a n d M o de of A d mi nistr ati o n 
S u bjects will recei ve eac h of t he f oll o wi n g treat m e nts t hr o u g h o ut t he st u d y: 
•  I n Peri o d 1, Da y 1, 2 0 0 m g caffei ne (ta blet), 4 0  m g o me praz ole (ca ps ule) , a n d 1 0 m g 
warf ari n (ta blet) will be a d mi nistere d as a si n gle d ose of pr o be dr u g c oc kt ail, al o n g 
wit h 1 0 m g vita mi n K ( 2  × 5 m g ta blets), i n t he m or ni n g f oll o wi n g a fast of at least 
1 0 h o urs pre d ose a n d 2 h o urs p ost d ose. Water will be restricte d f or 1 h o ur pri or t o a n d 
1 h o ur after d osi n g wit h t he e xce pti o n of water a d mi nistere d f or d ose a d mi nistrati o n. 
•  I n Peri o d 2, o n Da ys 6 t hr o u g h 1 9, oral d oses of 2 0 0 m g ( 2  × 1 0 0 m g ta blets) 
L O X O - 3 0 5 will be a d mi nistere d Q D f or 1 4 c o nsec uti ve da ys i n t he m or ni n g at t he 
act ual ti me of t he D a y  1 pr o be dr u g c o c ktail d osi n g ( ± 1 h o ur). O n D a y 1 5, 
L O X O - 3 0 5 will be c o a d mi nistere d wit h 2 0 0 m g caffei n e (ta blet), 4 0  m g o me praz ole 
(ca ps ule), a n d 1 0 m g warfari n (ta blet) a d mi nistere d as a si n gle d ose of pr o b e dr u g 
c oc ktail, al o n g wit h 1 0 m g vita mi n K ( 2  × 5 m g ta blets), at t he act ual ti me of t he Da y 
1 pr o be dr u g c o c ktail d osi n g ( ± 1 h o ur) f oll o wi n g a fast of at least 1 0 h o urs pre d ose 
a n d 2 h o urs p ost d ose. O n Da ys 7 t hr o u g h 1 1, a n d Da ys 1 3, 1 4, 1 6, 1 8, a n d 1 9, 
s u bjects will fast f or at least 2 h o urs pre d ose a n d 1 h o ur p ost d ose. O n Da ys 6, 1 2, a n d 
1 7 w here cli nical la b or at or y e val uati o ns are perf or me d, s u bjects will fast f or at least 
8 h o urs pre d ose a n d 1 h o ur p ost d ose. Water will be restricte d f or 1 h o ur pri or t o a n d 1 
h o ur after d osi n g wit h t h e e xce pti o n of water a d mi nistere d f or d ose a d mi nistrati o n.  
All st u d y dr u gs will be a d mi nistere d orall y wit h a p pr o xi matel y 2 4 0 m L of water. A n 
a d diti o nal 1 0 0 m L of wat er ma y be a d mi nistere d if nee de d.  
D ur ati o n of S u bject P a rtici p ati o n i n t he St u d y:  
Pla n ne d E nr oll me nt/ Scree ni n g D urati o n: A p pr o xi matel y 3 4 da ys ( Da ys - 3 5 t o - 2).  
Le n gt h of C R U C o nfi ne me nt: U p t o 2 4 da ys ( Da ys - 1 t o 2 3). 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 9 of 6 8 
Pla n ne d St u d y C o n d uct D urati o n: U p t o 6 7 da ys ( Scree ni n g t hr o u g h f oll o w - u p call).  
Criteri a f or E v al u ati o n: 
P h ar m ac o ki netics:  
Serial bl o o d sa m ples f or plas ma c o nce ntrati o n a nal ysis of caffei n e/ para xa nt hi ne, o me praz ol e, 
a n d S- warfari n will be c ollecte d fr o m pre d ose t hr o u g h 
 
. Serial bl o o d sa m ples f or plas ma c o n ce ntrati o n a nal ysis of L O X O- 3 0 5 will be c ollecte d 
. Sa m ples 
c ollecte d 
 will be c ollecte d pri or t o L O X O- 3 0 5 
d osi n g o n Da ys 1 6 t hr o u g h 1 9. 
T he f oll o wi n g P K para m eters will be calc ulate d, w he ne ver p ossi ble,  base d o n t he plas ma 
c o nce ntr ati o ns of caffei n e / para x a nt hi ne, o me praz ole, S- warfari n, a n d L O X O- 3 0 5 (as 
a p pr o priate): ar ea u n der t he c o nce ntrati o n- ti me c ur ve ( A U C) fr o m h o ur 0 t o 2 4 h o urs 
p os t d ose ( A U C0- 2 4), A U C fr o m h o ur 0 t o t he last meas ura ble c o nce ntrati o n ( A U C 0-t), A U C 
fr o m h o ur 0 e xtr a p olate d t o i nfi nit y ( A U C0- i nf), perce nta ge e xtra p olati o n f or A U C0- i nf 
( % A U Ce xtra p), a p pare nt s yste mic clear a nce ( C L/ F), a p pare nt plas m a ter mi n al eli mi nati on 
half -life (t½ ), m a xi m u m o bser ve d plas ma c o nce ntrati o n ( Cma x ), ti me t o Cma x (tma x ), a p pare nt 
ter mi nal eli mi nati o n rate c o nsta nt ( λz), mea n resi d e nce ti me ( M R T), a p pare nt v ol u me of 
distri b uti o n at t he ter mi nal p hase ( V z/ F), a n d A U C0- 2 4 a n d A U C 0- 4 8 rati o of para xa nt hi ne t o 
caff ei ne ( M R A U C; caff ei ne / para xa nt hi ne o nl y). 
S afet y:  
Safet y will be m o nit ore d wit h H D Y F? i n q uiri es, cli nical la b orat or y e val uati o ns, vital si g n 
meas ure me nts, 1 2 -l ea d E C Gs, a n d p h ysical e xa mi nati o ns. 
St atistic al Met h o ds  
P h ar m ac o ki netics:  
T he pri mar y a n al ysis pla n ne d f or t his st u d y is a mi xe d effect m o del t hat i ncl u des treat me nt as 
a fi xe d effect a n d s u bject as a ra n d o m effect. T he a nal ysis will be perf or m e d o n t he nat ural 
l o g (l n)-tra nsf or me d P K para meters ( A U C0-t, A U C0- i nf, a n d Cma x ) a n d i ncl u de calc ul ati o n of 
least s q uare d ( L S) mea ns a n d t he differe nce bet w ee n treat me nt L S mea ns, as well as t heir 
c orres p o n di n g 9 0 % c o nfi de nce i nter v als ( CIs). T h e ge o metric mea n rati os a n d t heir 9 0 % CIs 
of t he P K para m eter f or eac h treat me nt c o m paris o n will be c o nstr ucte d usi n g t he 
e x p o ne ntiati o n of t he diff ere nce a n d t he CIs fr o m t he mi xe d effect m o del. T he c o m paris o ns 
of i nterest will be pr o be dr u gs al o ne (caffei ne a n d its meta b olite para xa nt hi ne, o me praz ole, 
a n d S- warfari n) v ers us pr o be dr u gs (caffei ne a n d its meta b olite para x a nt hi ne, o me praz ole, 
a n d S-warfari n) c oa d mi nistere d wit h L O X O - 3 0 5. T he rati o of para x a nt hi ne t o caffei ne will 
be s u m marize d.  
S afet y:  
All safet y assess me nts, i ncl u di n g A Es, S A Es, vital si g n meas ure me nts, cli nical la b orat or y 
res ults, p h ysical e xa mi nati o n res ults, c o nc o mita nt me dicati o ns, a n d 1 2-lea d E C Gs, will be 
ta b ulate d, a n d s u m marize d w her e p ossi ble, usi n g descri pti ve met h o d ol o g y b y treat me nt a n d, 
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 0 of 6 8 
as nee de d, b y ti me p oi nt. U nless ot her wise s pecifie d, baseli ne val ue is d efi ne d as t he last 
n o n- missi n g meas ure me nt bef ore a d mi nistrati o n of st u d y dr u g o n Da y 1, Peri o d 1. N o f or mal 
statistical a nal yses ar e pla n ne d f or t h e safet y data. All safet y data will be liste d b y s u bject. 
T he s pecific pr oce d ures will be d oc u me nte d i n t he Statistical A nal ysis Pla n.  
 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 1 of 6 8 
T A B L E O F C O N T E N T S  
TI T L E P A G E  ............................................................................................................................. 1 
S P O N S O R A P P R O V A L  ........................................................................................................... 2 
I N V E S TI G A T O R A G R E E M E N T............................................................................................. 3 
S T U D Y I D E N TI FI C A TI O N  ..................................................................................................... 4 
S Y N O P SI S  ................................................................................................................................. 6 
T A B L E O F C O N T E N T S  ......................................................................................................... 1 1 
LI S T O F T A B L E S A N D FI G U R E S ........................................................................................ 1 3 
LI S T O F A B B R E VI A TI O N S  .................................................................................................. 1 4 
1.  
I N T R O D U C TI O N ........................................................................................................... 1 7 
1. 1.  Bac k gr o u n d ................................................................................................................ 1 7  
1. 2.  N o ncli nical P har mac o ki n etics a n d T o xic ol o g y S u m mar y ........................................ 1 7  
1. 3.  P ote ntial f or Dr u g- dr u g I nteracti o ns  .......................................................................... 1 9 
1. 4.  S u m mar y of Cli nical E x perie nce ............................................................................... 2 0  
1. 4. 1.  
Safet y  ........................................................................................................... 2 1 
1. 4. 2.  
P har mac o ki netics  ......................................................................................... 2 2 
1. 5.  St u d y Rati o nale .......................................................................................................... 2 5  
1. 6.  Ris k As sess me nt ........................................................................................................ 2 6 
2.  
O BJ E C TI V E S A N D E N D P OI N T S  ................................................................................. 2 7 
2. 1.  O bjecti ves  .................................................................................................................. 2 7 
2. 1. 1.  
Pri mar y O bj ecti ve  ........................................................................................ 2 7 
2. 1. 2.  
Sec o n dar y O bj ecti ve .................................................................................... 2 7  
2. 2.  E n d p oi nts ................................................................................................................... 2 7  
2. 2. 1.  
Pri mar y E n d p oi nts ....................................................................................... 2 7  
2. 2. 2.  
Sec o n dar y E n d p oi nts ................................................................................... 2 7  
3.  
I N V E S TI G A TI O N A L P L A N .......................................................................................... 2 8 
3. 1.  O verall St u d y Desi g n a n d Pla n .................................................................................. 2 8  
3. 2.  Disc ussi o n of St u d y Desi g n ....................................................................................... 3 0  
3. 3.  Selecti o n of D oses i n t he St u d y ................................................................................. 3 0  
3. 3. 1.  
L O X O - 3 0 5 ................................................................................................... 3 0 
3. 3. 2.  
Pr o be Dr u g C oc ktail .................................................................................... 3 0  
4.  
S E L E C TI O N O F S T U D Y P O P U L A TI O N  ..................................................................... 3 2 
4. 1.  Scree ni n g Pr oce d ures ................................................................................................. 3 2  
4. 2.  C he c k-i n Pr oce d ures ( D a y - 1) ................................................................................... 3 2 
4. 3.  I n cl usi o n Criteria ....................................................................................................... 3 3 
4. 4.  E xcl usi o n Criteria  ...................................................................................................... 3 5 
4. 5.  S u bje ct N u m ber a n d I d e ntificati o n  ............................................................................ 3 9 
4. 6.  Re m o val of S u bjects fr o m St u d y Partici pati o n  ......................................................... 3 9 
5.  
S T U D Y T R E A T M E N T S  ................................................................................................. 4 1 
5. 1.  Descri pti o n, St ora ge, Pac ka gi n g, a n d La beli n g ......................................................... 4 1  


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 2 of 6 8 
5. 2.  St u d y Treat me nt A d mi nistrati o n  ............................................................................... 4 1 
5. 3.  Ra n d o mizati o n ........................................................................................................... 4 2  
5. 4.  Bli n di n g ..................................................................................................................... 4 2  
5. 5.  Treat me nt C o m plia nce  ............................................................................................... 4 2 
5. 6.  Dr u g Acc o u nta bilit y .................................................................................................. 4 3  
6.  
C O N C O MI T A N T T H E R A PI E S A N D O T H E R R E S T RI C TI O N S  ................................ 4 4 
6. 1.  C o nc o mita nt T hera pies .............................................................................................. 4 4  
6. 2.  Diet, Fl ui d, a n d Acti vit y C o ntr ol ............................................................................... 4 4  
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.  P har mac o ki netic Assess me nts  ................................................................................... 4 6 
7. 1. 1.  
P har mac o ki netic Bl o o d Sa m ple C ollecti o n a n d Pr ocessi n g ........................ 4 6  
7. 1. 2.  
A nal ytical Met h o d ol o g y .............................................................................. 4 6  
7. 2.  Ge n ot y pi n g ................................................................................................................ 4 6  
7. 3.  Safet y a n d T oler a bilit y Assess me nts  ......................................................................... 4 6 
7. 3. 1.  
A d verse E v e nts  ............................................................................................ 4 7 
7. 3. 2.  
Cli ni cal La b orat or y E val uati o ns .................................................................. 4 8  
7. 3. 3.  
Vital Si g ns  .................................................................................................... 4 8 
7. 3. 4.  
1 2-lea d Electr ocar di o gra m ........................................................................... 4 8  
7. 3. 5.  
P h ysical E xa mi nati o n ................................................................................... 4 9 
8.  
S A M P L E SI Z E A N D D A T A A N A L Y SI S  ...................................................................... 5 0 
8. 1.  Deter mi nati o n of Sa m ple Size  ................................................................................... 5 0 
8. 2.  A nal ysis P o p ulati o ns ................................................................................................. 5 0  
8. 3.  P ha r mac o ki netic A n al ysis ......................................................................................... 5 0 
8. 3. 1.  
Descri pti ve A n al ysis  .................................................................................... 5 1 
8. 3. 2.  
Statistical Met h o d ol o g y  ............................................................................... 5 1 
8. 4.  Safet y A nal ysis  .......................................................................................................... 5 2 
8. 5.  Data Ha n dli n g a n d Rec or d Kee pi n g .......................................................................... 5 2  
8. 6.  Q ualit y C o ntr ol a n d Q ualit y Ass ura nce ..................................................................... 5 3  
9.  
A D MI NI S T R A TI V E A S P E C T S  ..................................................................................... 5 4 
9. 1.  C ha n ge i n Pr ot oc ol .................................................................................................... 5 4  
9. 2.  Site I nitiati o n Visit/I n vesti gat or Meeti n g  .................................................................. 5 4 
9. 3.  Discl os ure .................................................................................................................. 5 4  
9. 4.  M o nit ori n g ................................................................................................................. 5 4  
9. 5.  I nstit uti o nal Re vie w B oar d ........................................................................................ 5 4 
9. 6.  I nf or me d C o nse nt ...................................................................................................... 5 5 
9. 7.  Rec or ds  ...................................................................................................................... 5 5 
9. 8.  Refere n ce t o D eclarati o n of Helsi n ki/ Basic Pri nci ples  ............................................. 5 5 
9. 9.  Fi na nci n g a n d I ns ura n ce ............................................................................................ 5 6  
1 0.  R E F E R E N C E S  ................................................................................................................ 5 7 
1 1.  A P P E N DI C E S  ................................................................................................................. 5 8 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 3 of 6 8 
A p pe n di x 1: A d verse E v e nt Re p orti n g ............................................................................... 5 9  
A p pe n di x 2: Cli nical La b orat or y E val uati o ns ..................................................................... 6 3  
A p pe n di x 3: T otal Bl o o d V ol u me ....................................................................................... 6 4  
A p pe n di x 4: Sc he d ule of Assess me nts  ............................................................................... 6 5 
 
LI S T O F T A B L E S A N D FI G U R E S  
Ta ble 1: P har mac o ki n etic Para meters of L O X O -3 0 5 i n Ca ncer Patie nts 
( St u d y L O X O -B T K - 1 8 0 0 1) at Stea d y State ( C ycl e 1 Da y 8) ............................. 2 3 
Ta ble  2: St u d y Dr u gs ......................................................................................................... 4 1 
Fi g ure 2: D ose- E x p os ure C orrelati o n Assesse d b y A U C 0- 8 vs D ose f or Cycle 1 Da y 8  ... 2 5 
Fi g ure 3: St u d y Sc he matic ................................................................................................. 2 9  
 
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 4 of 6 8 
LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n 
Defi niti o n  
% A U C
e xtra p 
perce nt a ge e xtra p olati o n f or area u n der t he c o n ce ntrati o n -ti me c ur ve 
fr o m h o ur 0 e xtr a p olate d t o i nfi nit y 
A D L  
Acti vities of Dail y Li vi n g  
A E  
a d verse e ve nt  
A U C  
area u n d er t he c o nce ntrati o n -ti me c ur ve 
A U C 0 -2 4 
area u n d er t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 t o 2 4 h o urs p ost d ose  
A U C 0- i nf 
area u n d er t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 e xtra p olate d t o 
i nfi nit y 
A U C 0-t 
area u n d er t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 t o t he last 
meas ura ble c o nce ntrati o n  
A V  
atri o ve ntric ular  
B C R P  
breast ca ncer resista n ce pr otei n  
BI D  
t wice dail y 
B MI  
b o d y mass i n de x  
B P  
bl o o d press ure  
B S E P  
bile salt e x p orter p u m p  
B T K  
Br ut o n’s t yr osi ne ki nase  
C F R  
C o de of Fe d er al Re g ulati o ns  
CI  
c o nfi de nce i nter val(s)  
C K D -E PI  
C hr o nic Ki d ne y Diseas e E pi de mi ol o g y C olla b orati o n  
C L/ F  
a p pare nt s yste mic cleara nce  
C L L  
c hr o nic l y m p h oc ytic le u k e mia  
C ma x  
ma xi m u m o bser ve d plas ma c o nce ntrati o n  
C O VI D -1 9  
S A R S -C o V -2  
C R F  
Case Re p ort F or m  
C R U  
Cli nical Resea rc h U nit 
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts  
C V  
c oeffi cie nt of variati o n  
C Y P  
c yt oc hr o me P 4 5 0  
D DI  
dr u g -dr u g i nter acti o n  
E C G  
electr ocar di o gr a m  
e C R F 
electr o nic Cas e Re p ort F or m  
e G F R  
esti mate d gl o mer ular filtrati o n rate  
E O S  
E n d of St u d y  
E O T  
E n d of Treat me nt  
E T  
Earl y Ter mi nati o n  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S H  
f ollicle-sti m ulati n g h or m o ne 
G L P  
G o o d La b orat or y Practice  
H b A 1c  
he m o gl o bi n A 1c  


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 5 of 6 8 
H Bs A g  
he patitis B s urface a nti ge n  
H B V  
he patitis B vir us  
H C V  
he patitis C vir us  
H D Y F?  
H o w D o Y o u Feel?  
h E R G  
h u ma n et her -à-g o -g o -rel ate d ge ne 
HI V  
h u ma n i m m u n o deficie nc y vir us  
H R  
heart r ate  
H R T  
h or m o ne re place me nt t hera p y  
I B 
I n v esti gat or’s Br oc h ure 
I C5 0 
5 0 % i n hi bit or y c o nce ntrati o n  
I C9 0 
c o nce ntr ati o n re q uire d f or 9 0 % i n hi biti o n 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o u ncil f or/ C o nfere nce o n Har m o nisati o n 
I g M 
i m m u n o gl o b uli n M 
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
I U D 
i ntra uteri ne de vice 
I V 
i ntra ve n o us 
L F T  
li ver f u ncti o n test(s) 
L n  
nat ural l o g  
L S  
least s q uares 
M A T E  
m ulti dr u g a n d t o xi n e xtr usi o n  pr otei n  
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
m R N A  
messe n ger R N A  
M R T  
mea n resi de n ce ti me  
N H L  
n o n -H o d g ki n l y m p h o ma  
O A T  
or ga nic a ni o n tr a ns p orter 
O A T P  
or ga nic a ni o n tr a ns p orti n g p ol y pe pti de  
O A T P 1 B 1  
or ga nic a ni o n tr a ns p orti n g p ol y pe pti de 1 B 1  
O A T P 1 B 3  
or ga nic a ni o n tr a ns p orti n g p ol y pe pti de 1 B 3  
O C T  
or ga nic cati o n tra ns p orter  
P C R  
p ol y merase c h ai n reacti o n  
P -g p  
P -gl yc o pr otei n  
P K  
p har mac o ki netic(s)  
Q D  
o nce dail y  
Q Tc F  
Q T i nter val c orrecte d f or heart rate usi n g Fri d erici a’s met h o d  
R B C  
re d bl o o d cell(s) 
R P 2 D  
rec o m me n de d P has e 2 d ose 
S A D  
si n gle asce n di n g d ose 
S A E  
seri o us a d vers e e v e nt(s) 
S A P  
Statistical A nal ysis Pla n  
S D  
sta n dar d de viati o n 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 6 of 6 8 
S D D  
s pra y-drie d dis p ersi o n  
S L L  
s mall l y m p h oc ytic l y m p h o ma 
S O C  
s yste m or ga n class 
S O P  
Sta n dar d O per ati n g Pr oce d ure  
S U S A R  
s us pecte d u ne x p ecte d seri o us a d verse reacti o n 
t½  
a p pare nt plas m a ter mi nal eli mi nati o n half -life 
T E A E  
treat me nt-e mer ge nt a d v erse e ve nt  
T F Ls  
ta bles, fi g ures, a n d listi n gs 
tma x  
ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n 
T S H  
t h yr oi d-sti m ulati n g h or m o ne 
U A  
uri nal ysis  
V z 
v ol u me of distri b uti o n  
V z/ F 
a p pare nt v ol u me of distri b uti o n  
W B C  
w hite bl o o d cell(s)  
W H O  
W orl d Healt h Or ga nizati o n  
λ Z  
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt  


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 7 of 6 8 
1.  I N T R O D U C TI O N 
Refer t o t he I n v esti gat or’s Br oc h ure (I B) f or d etaile d i nf or mati o n c o ncer ni n g t he a vaila ble 
p har mac ol o g y, t o xic ol o g y, dr u g meta b olis m, cli nical st u dies, a n d a d v erse e ve nt ( A E) pr ofile 
of t he i n vesti gati o nal me dici nal pr o d uct, L O X O- 3 0 5. 1 
1. 1.  
B ac k gr o u n d 
L O X O - 3 0 5 ( als o k n o w n as L Y 3 5 2 7 7 2 7) is a sel ecti ve i n hi bit or of t he Br ut o n’s t yr osi ne 
ki nase ( B T K) b ei n g de vel o pe d b y L o x o O nc ol o g y. L O X O- 3 0 5 is disti nct fr o m t he a p pr o ve d 
B T K i n hi bit ors (i br uti ni b, acala br uti ni b, a n d za n u br uti ni b) i n se veral i m p orta nt wa ys 
i ncl u di n g o n t he basis of its selecti vit y, fa v ora ble a bs or pti o n, distri b uti o n, meta b olis m, a n d 
e xcreti on pr o p erties, a n d n o n-c o vale nt bi n di n g m o de. 2 T h ese feat ures e n a bl e L O X O - 3 0 5 t o 
ac hie ve p h ar mac o ki netic ( P K) e x p os ures t h at e xcee d t he B T K c o nce ntrati o n res ulti n g i n 9 0 % 
i n hi biti o n (I C9 0) at tr o u g h, a n d t h us deli ver t o nic B T K tar get i n hi biti o n t hr o u g h o ut t he d osi n g 
peri o d, re g ar dless of t he i ntri nsic rate of B T K t ur n o ver. M ore o v er, t he n o n-c o vale nt bi n di n g 
m o de of L O X O- 3 0 5 is u naffecte d b y B T K C 4 8 1 s u bstit uti o ns, a c o m m o n mec ha nis m of dr u g 
resista nce d escri be d f or all a vaila ble c o vale nt i n hi bit ors.3 ,4 ,5 ,6 ,7 Fi nall y, L O X O- 3 0 5 is als o a 
hi g hl y selecti ve m olec ule t hat is m ore t ha n 3 0 0-f ol d m ore selecti ve f or B T K vers us 3 7 0 ot her 
ki nases teste d wit h n o si g nifica nt i n hi biti o n of n o n- ki nase off- tar g ets at 1 µ M, t h us li miti n g 
t he p ote ntial f or off-tar g et me diate d t o xicities. C ollecti vel y, t hese u ni q ue pr o perties of 
L O X O - 3 0 5 are e x pect e d t o deli ver m ore p ote nt, c o nti n u o us, a n d selecti ve i n hi biti o n of B T K 
i n a variet y of setti n gs, p ote ntiall y res ulti n g i n i ncrease d effi cac y. Of n ote, t he acti vit y of 
L O X O - 3 0 5 i n di vers e pr ecli nical m o del s yste ms s u p p orts t his u n derl yi n g h y p ot hesis.2 
L O X O - 3 0 5 is a s mall m olec ule t hat was d esi g ne d t o bl oc k t he a de n osi ne tri p h os p hate ( A T P) 
bi n di n g site of t he B T K ki nase c o m petiti vel y. T here is n o e vi de n ce of irre versi ble bi n di n g. 
L O X O - 3 0 5 has a m olec ular wei g ht of a p pr o xi matel y 5 0 0 g/ m ol. L O X O- 3 0 5 will be s u p plie d 
as a n i m me diate-r eleas e ta blet c o ntai ni n g 2 5 m g or 1 0 0 m g of dr u g s u bsta n ce. 
1. 2.  
N o ncli nic al P h ar m ac o ki netics a n d T o xic ol o g y S u m m ar y 
L O X O - 3 0 5 ha d hi g h p er mea bilit y i n vitr o, b ut l o w a q ue o us s ol u bilit y. T o re d uce t h e 
varia bilit y i n oral a bs or pti o n, a s pra y- dri e d dis persi o n ( S D D) ta blet f or m ulati o n was 
de vel o pe d t hat s h o we d c o nsiste nt oral bi oa vaila bilit y of a p pr o xi matel y 5 0 % i n rats a n d 8 0 % 
i n d o gs. T he bi oa vaila bilit y of t he S D D f or m ulati o n was als o n ot de pe n d e nt o n fee di n g state 
i n d o gs. 
As is c o m m o n i n r o de nts, oral e x p os ur e of L O X O- 3 0 5 was c o nsiste ntl y m uc h hi g her i n 
fe male r ats t ha n i n males gi ve n t he sa me d ose of L O X O- 3 0 5. T h e se x differe nce was als o 
a p pare nt after i ntr a ve n o us (I V) a d mi nistrati o n of L O X O- 3 0 5. T h ere w as n o differe n ce i n t he 
P K of L O X O - 3 0 5 b et wee n se xes of d o g, a n d n o n e is e x pecte d i n ot her no n -r o de nt s peci es, 
i ncl u di n g h u ma ns.  
T he v ol u me of distri b uti o n ( V z) of L O X O- 3 0 5 ra n ge d fr o m a p pr o xi matel y 2 L/ k g i n t he d o g 
t o 5 L/ k g i n t he male rat, w hic h i n dicates t hat L O X O - 3 0 5 distri b utes i nt o tiss ues. L O X O- 3 0 5 
ha d pr otei n bi n di n g of a p pr o xi matel y 9 5 % i n h u ma n plas ma. A s o me w h at l o wer e xte nt of 
bi n di n g (a p pr o xi matel y 8 2 % t o 9 2 %) was o bs er ve d acr oss m o use, rat, ra b bit, a n d d o g. 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 8 of 6 8 
L O X O - 3 0 5 w as meta b oli ze d sl o wl y b y h u ma n micr os o mal fracti o ns a n d h e pat oc ytes. T h e 
l o w rates of meta b olis m i n b ot h t hese h u ma n i n vitr o s yste ms s u g gest t hat L O X O- 3 0 5 will 
ha ve l o w cleara n ce i n h u ma ns. I n vitr o d ata wit h cl o ne e x presse d c yt oc hr o me P 4 5 0 ( C Y P) 
e nz y mes a n d h u ma n li ver micr os o mes i n dicate t h at C Y P 3 A 4 is t he pri mar y C Y P e nz y me t hat 
meta b olizes L O X O - 3 0 5. It is als o a s u bstrate f or direct gl uc ur o ni dati o n. 
I n l o n g-t er m he pat o c yte i nc u bati o ns, L O X O- 3 0 5 was meta b olize d b y b ot h o xi dati o n a n d 
gl uc ur o ni dati o n. I n hi biti o n of o xi dati ve meta b olis m b y a d diti o n of t he P 4 5 0 i n hi bit or 
1-a mi n o be nz otriaz ole s h o we d t hat o xi dati ve meta b olis m is C Y P de pe n de nt. All meta b olites 
f or me d b y h u ma n he p at o c ytes wer e als o f or me d i n rat a n d/ or d o g he p at oc ytes s u p p orti n g t he 
use of rat a n d d o g f or n o ncli nical safet y ass ess me nt. 
Re nal cleara nce of L O X O - 3 0 5 i n male a n d fe mal e rats was n e gli gi ble. N o data o n re n al 
clear a nce are a vaila ble i n ot her s pecies; h o w e ver, t he re nal e xcreti o n pat h w a y is ofte n 
c o nser ve d acr oss s p ecies, a n d t heref ore n o re nal cleara n ce w o ul d b e e x pect e d i n h u ma ns.  
I n a G o o d La b orat or y Pr actice ( G L P) i n vitr o assa y f or h u ma n et her-à- g o-g o -relate d g e ne 
( h E R G) acti vit y, t he c o n ce ntrati o n r es ulti n g i n 5 0 % i n hi bit or y c o nce ntrati o n (I C5 0) f or t he 
i n hi bit or y effects of L O X O- 3 0 5 o n h E R G p otassi u m c urre nts was   μ M, w hic h is 
a p pr o xi matel y  -f ol d hi g her t ha n t he ma xi m u m u n b o u n d c o nce ntrati o n of L O X O - 3 0 5 i n 
patie nts treate d wit h t he d ose of 2 0 0 m g o nce d ail y ( Q D). T h ere w ere n o L O X O - 3 0 5-relate d 
c ha n ges i n a n y car di o v asc ular e n d p oi nts i ncl u di n g Q Tc at si n gle d oses u p t o 6 0 m g/ k g i n t he 
G L P car di o vas c ular st u d y i n t he c o nsci o us tele metr y- i nstr ume nte d d o g. T h e ma xi m u m 
o bser ve d plas ma c o nce ntrati o n ( C ma x ) f or t his d ose was 1 0 0 0 0 n g/ m L, w hi c h is 
a p pr o xi matel y  
 a b o ve t he pre dict e d C ma x  ( 
n g/ m L) at t he pr o p ose d cli nical 
t hera pe utic d os e of 2 0 0 m g Q D. F urt her m ore, t here were n o L O X O- 3 0 5-relate d 
a b n or malities i n r h yt h m or wa vef or m m or p h ol o g y i n t he G L P 2 8- da y re p eate d - d ose t o xicit y 
st u d y i n d o gs at t he l o w a n d mi d- d ose gr o u ps base d o n c o m paris o n of pre d ose a n d p ost d ose 
electr ocar di o gr a m ( E C G) rec or di n gs. T h e hi g h d ose ( 9 0/ 6 0 m g/ k g/ d ose t wice dail y [ BI D]) 
was n ot e val uate d as a ni mals i n t his gr o u p were m ori b u n d/ de bilitate d a n d were ter mi nate d o n 
Da y 1 3. Mea n Q Tc i nter val was statisticall y si g nifica ntl y pr ol o n ge d ( + 6 %; + 1 5 msec) o n 
Da y  2 6 of t he d osi n g p hase i n males a d mi nistere d 3 0/ 1 0 m g/ k g/ d ose BI D c o m pare d wit h 
c o ntr ols. T he pr ol o n gati o n i n Q Tc f or males was b el o w t he 1 0 % i ncrease or t he t hres h ol d 
re p orte d f or ca ni nes e x p ose d t o t hera pe utic c o nce ntrati o ns of dr u gs k n o w n t o ca use Q T 
pr ol o n gati o n i n h u ma ns. 8 T heref ore, t he Q Tc c h a n ges were c o nsi dere d p h ysi ol o gicall y 
u ni m p orta nt, a n d t h us n ot dee me d t o be a d v erse. T o get her, t hese d ata i n di cate t hat 
L O X O - 3 0 5 has a l o w ris k of i n d uci n g dela ye d v e ntric ular re p ol arizati o n, pr ol o n gati o n of t he 
Q Tc i nter val, a n d u nsta ble arr h yt h mias i n patie nts. 
T here w ere n o L O X O - 3 0 5-relate d fi n di n gs o n t he ce ntral ner v o us s yste m w he n e val uat e d i n 
rat f u ncti o nal o bser vatio nal batter y tests a n d l oc o m ot or acti vit y assess me nts after 4 wee ks of 
d osi n g or d uri n g rec o v er y at d oses of u p t o 5 0 0 m g/ k g/ d ose BI D i n male rats a n d 
1 7 5 m g/ k g/ d ose BI D i n f e male rats as part of t he G L P 2 8- da y re p eat -d os e st u d y.  
L O X O - 3 0 5 ha d n o eff ect o n res pirati o n rat e i n t he d o g at d oses u p t o 1 0 m g/ k g/ d ose BI D. 
Tar gets of t o xicit y were c haracteri ze d i n re p eate d - d ose st u dies c o n d ucte d i n 2 rele va nt 
t o xicit y s pecies. Certai n tar gets (t he h e mat o p oietic a n d l y m p h oi d s yste ms) were f o u n d i n 
b ot h t he rat a n d t he d o g. Rat- s pecific c ha n ges i n t he pa ncreas are s p ecies-s pecific a n d s ee n 
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 9 of 6 8 
wit h ot her B T K i n hi bit ors. D o g-s pecific c ha n g es i n l u n g a n d lar ge i ntesti ne were lesi o ns 
c o ntri b uti n g t o m ori b u n dit y i n hi g h- d ose a ni mals i n t he 2 8- da y st u d y. D oses e val uate d i n 
t he 2 8- da y d o g st u d y de m o nstrate d a stee p d os e-res p o nse c ur v e f or t o xicit y a n d pr o n o u nce d 
c ha n ges i n he mat ol o gic p ara meters at hi g h e x p os ures. A d diti o nall y, i n d o gs treate d f or 
3 m o nt hs, 2 male d o gs at 5 m g/ k g BI D (t he hi g hest d ose teste d) were o bser ve d t o ha ve e y e 
lesi o ns via b ot h o p ht hal mic a n d micr osc o pic e xa mi nati o n. Fi n di n gs were o bser ve d i n b ot h 
e yes of t hese a ni mals a n d c o nsiste d of ver y sli g ht t o sli g ht m ultif ocal or f ocal areas of c or neal 
o pacit y i n t he ce nter of t he c or nea al o n g wit h c o nstellati o n hist o pat h ol o gical fi n di n gs 
s u g gesti ve of mi ni mal t o mil d c or neal i nj ur y. T he ti me of o nset of t hese effects is u n k n o w n, 
as o p ht hal mic e xa ms wer e o nl y perf or m e d pri or t o t he start of d osi n g a n d d uri n g t he last 
wee k of t he st u d y; h o w e ver, n o e ye eff ects w ere o bser ve d i n t he pre vi o us 2 8- da y st u d y. N o 
oc ular fi n di n gs were o bs er ve d i n f e males. See t he I B f or a d diti o nal details. 1 
L O X O - 3 0 5 w as n ot m uta ge nic i n 2 bacterial re v erse m utati o n assa ys a n d w as ne gati ve i n a 
n o n- G L P micr o n ucle us assa y usi n g C hi nese ha mster o var y cells. L O X O- 3 0 5 was p ositi ve f or 
t he i n d ucti o n of micr o n u clei via a n a n e u ge nic mec ha nis m i n t he a bse nce a n d prese nce of t he 
e x o ge n o us meta b olic acti vati o n s yste m i n a G L P i n vitr o micr o n ucle us assa y i n h u ma n 
peri p her al bl o o d l y m p h oc ytes. H o we v er, L O X O- 3 0 5 was ne gati ve i n a G L P i n vi v o 
micr o n ucle us assa y i n r ats at d oses u p t o a n d i ncl u di n g a d ose of  
 m g/ k g. T he C ma x  at t he 
n o o bser ve d effect le vel of  
 m g/ k g was  
 n g/ m L f or males a n d  
 n g/ m L f or 
fe males. 
L O X O - 3 0 5 w as n ot f o u n d t o be p h ot ot o xic w he n e val uate d i n a n i n vitr o n e utral re d u pt a ke 
p h ot ot o xicit y assa y. 
1. 3.  
P ote nti al f or D r u g -dr u g I nter acti o ns  
L O X O - 3 0 5 s h o w e d n o d etecta ble i n hi biti o n (I C5 0 >   µ M) of C Y P 1 A 2, C Y P 2 B 6, 
C Y P 2 C 1 9, a n d C Y P 2 D 6, a n d wea k i n hi biti o n of C Y P 2 C 8, C Y P 2 C 9, a n d C Y P 3 A 4 i n h u ma n 
li ver micr os o mes. After pre-i nc u b ati o n of micr os o mes wit h L O X O- 3 0 5 a n d nic oti na mi de 
a de ni ne di n ucle oti de p h os p hate pri or t o a d diti o n of C Y P 4 5 0 pr o be s u bstrat e, t he C Y P 3 A 4 
i n hi bit or y p ote nc y of L O X O- 3 0 5 was i ncrease d, s u g gesti n g t he p ote ntial f or ti me- de pe n d e nt 
i n hi biti o n of C Y P 3 A 4. F urt her ki netic e v al uati o n c o nfir me d t hat L O X O- 3 0 5 is a 
ti me- de pe n de nt i n hi bit or of C Y P 3 A 4. 
I n a n i n vitr o he pat oc yt e assa y, L O X O- 3 0 5 i n d uce d messe n ger R N A ( m R N A) f or C Y P 3 A 4, 
C Y P 3 A 5, C Y P 2 B 6, a n d C Y P 2 C 1 9. F or b ot h C Y P 2 B 6 a n d C Y P 2 C 1 9, a n i ncreas e i n acti vit y 
was see n. F or C Y P 3 A 4, L O X O- 3 0 5 di d n ot ca us e a n i ncrease i n acti vit y, li kel y d ue t o 
c o nc urr e nt i n hi biti o n of C Y P 3 A 4 b y L O X O - 3 0 5. L O X O-3 0 5 ca use d a decrease i n m R N A f or 
C Y P 1 A 2 b ut di d n ot lea d t o a re d ucti o n of C Y P 1 A 2 acti vit y. I n t h e st u d y, C Y P 2 D 6, 
C Y P 2 C 8, a n d C Y P 2 C 9 m R N A were n ot i n d uce d. 
I n vitr o L O X O- 3 0 5 i n hi bite d P- gl yc o pr otei n ( P-g p), breast ca ncer resista nce pr otei n ( B C R P), 
m ulti dr u g a n d t o xi n e xtr usi o n pr otei n ( M A T E) 1, a n d M A T E 2 K. L O X O- 3 0 5 di d n ot i n hi bit 
or ga nic a ni o n tr a ns p orter ( O A T) 1 a n d wea kl y i n hi bite d or ga nic a ni o n tra ns p orti n g 
p ol y pe pti de ( O A T P) 1 B 1, O A T P 1 B 3, or ga nic cati o n tra ns p orter ( O C T) 1, O C T 2, O A T 3, a n d 
bile salt e x p orter p u m p ( B S E P). 
L O X O - 3 0 5 is a s u bstrat e of P- g p a n d B C R P. It is n ot a s u bstrate of t he h e p atic tra ns p orters 
O C T 1, O A T P 1 B 1, O A T P 1 B 3, or B S E P. 
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 0 of 6 8 
1. 4.  
S u m m ar y of Cli nic al E x perie nce  
L O X O - 3 0 5 is c urre ntl y b ei n g st u die d i n a n o n g oi n g gl o bal P hase 1/2 first -i n- h u ma n st u d y, 
L O X O -B T K - 1 8 0 0 1 (t he B R UI N St u d y), i n patie nts wit h pre vi o usl y treate d c hr o nic 
l y m p h oc ytic le u ke mia ( C L L)/ s mall l y m p h oc ytic l y m p h o ma ( S L L) or n o n- H o d g ki n 
l y m p h o ma ( N H L). T he st arti n g d ose of L O X O- 3 0 5 was 2 5 m g Q D.  
As of Se pte m ber 2 7, 2 0 2 0, safet y data were a vaila ble fr o m a t otal of 3 3 0 patie nts treate d i n 
t he L O X O -B T K - 1 8 0 0 1 st u d y. T his i ncl u des 3 2 4 patie nts treate d at d os es ra n gi n g fr o m 2 5 m g 
Q D t o  3 0 0 m g Q D i n P hase 1/ 2 M o n ot hera p y c o h orts, a n d 6 patie nts treat e d i n P hase 1 b 
C o m bi na ti o n Ar m A ( L O X O- 3 0 5 2 0 0 m g Q D pl us ve net ocla x 4 0 0 m g Q D [after ra m p - u p] 
Secti o n  1. 4. 1 ).  
As of Se pte m ber 3 0, 2 0 2 0, P K data were a v aila ble fr o m 1 8 1 pat ie nts e nr olle d i n t he 
L O X O -B T K - 1 8 0 0 1 st u d y (Secti o n  1. 4. 2 ). 
As of N o ve m ber 2 3, 2 0 2 0, L O X O- 3 0 5 ha d b ee n rece ntl y i n vesti gate d i n 1 st u d y i n healt h y 
v ol u nteers ( L O X O- B T K- 2 0 0 1 4), w hic h was c o m plete d. L O X O- B T K - 2 0 0 1 4 was a pil ot 
f o o d-effect cr oss o ver st u d y e val uati n g t he effects of f o o d a n d a pr ot o n p u m p i n hi bit or 
( o me praz ole) o n t he P K of L O X O- 3 0 5 w here 1 0 healt h y v ol u nteers w ere gi ve n 2 0 0 m g of 
L O X O - 3 0 5 o n 3 se p arat e da ys, eac h f oll o we d b y a was h o ut peri o d.  
As of N o ve m ber 2 3, 2 0 2 0, f o ur a d diti o nal st u dies were o n g oi n g i n healt h y v ol u nteers 
( L O X O-B T K - 2 0 0 0 6, L O X O-B T K - 2 0 0 1 7, L O X O-B T K - 2 0 0 0 7, a n d L O X O-B T K - 2 0 0 0 8).  
L O X O -B T K - 2 0 0 0 6 is a dr u g- dr u g i nteracti o n ( D DI) st u d y e val u ati n g t he effects of a str o n g 
C Y P 3 A 4 i n hi bit or (itrac o naz ole) a n d a str o n g C Y P 3 A 4 i n d ucer (rifa m pi n) o n t he P K of 
L O X O - 3 0 5 w h ere, at t he ti me of t his pr ot oc ol’s de vel o p me nt, 3 healt h y v ol u nteers were 
gi ve n 1 d ose of 2 0 0 m g of L O X O - 3 0 5, 1 2 h ealt h y v ol u nteers were gi ve n 2 0 0 m g of 
L O X O - 3 0 5 o n 2 se p arat e da ys ( 1 of w hic h was c o-a d mi nistere d wit h itrac o naz ole), eac h 
f oll o we d b y a w as h o ut peri o d, a n d 1 2 healt h y v ol u nteers were gi ve n 2 0 0 m g of L O X O - 3 0 5 
o n 3 se parat e da ys ( 2 of w hic h wer e c o -a d mi nistere d wit h rifa m pi n) , eac h f oll o we d b y a 
was h o ut peri o d.  
L O X O -B T K - 2 0 0 1 7 is a si n gle asce n di n g d ose ( S A D) st u d y e val uati n g t he s afet y a n d 
t olera bilit y of L O X O- 3 0 5 at 3 0 0 m g, 6 0 0 m g, 8 0 0 m g, a n d 9 0 0 m g d oses, w here, at t he ti me 
of t his pr ot oc ol’s de vel o p me nt, 6 healt h y v ol u nteers were gi ve n a si n gle d ose of 3 0 0 m g 
L O X O - 3 0 5, 6 healt h y v ol u nteers wer e gi ve n a si n gle d ose of 6 0 0 m g L O X O - 3 0 5, 6 healt h y 
v ol u nteers were gi ve n a si n gle d ose of 8 0 0 m g L O X O - 3 0 5, a n d 6 h ealt h y v ol u nteers were 
gi ve n a si n gle d ose of 9 0 0 m g L O X O - 3 0 5.  
L O X O -B T K - 2 0 0 0 7 is a 2- part st u d y of t he a bs or pti o n, meta b olis m, e xcreti o n, a n d t he 
a bs ol ute bi oa vaila bilit y of [ 1 4C] -L O X O - 3 0 5 w here, at t he ti me of t his pr ot oc ol’s 
de vel o p me nt, 4 s u bjects were gi ve n a si n gle oral d ose of 2 0 0 m g of [ 1 4C] -L O X O - 3 0 5 
(c o ntai ni n g ~ 2 0 0 µ Ci) as a n oral s ol uti o n a n d 5 s u bjects were gi ve n a si n gl e oral d ose of 
2 0 0 m g L O X O - 3 0 5 as 2 × 1 0 0-m g ta blets f oll o we d 2  h o urs later b y a si n gl e d ose of < 1 0 0 µ g 
of [ 1 4C] -L O X O - 3 0 5 (c o ntai ni n g ~ 1  µ Ci of ra di oacti vit y [ micr otracer]) a d mi nistere d as a n I V  
p us h o ver a p pr o xi matel y 2 mi n utes.  


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 1 of 6 8 
L O X O -B T K - 2 0 0 0 8 is a D DI st u d y e val uati n g t he effects of L O X O- 3 0 5 o n t he P K of a 
se nsiti ve C Y P 3 A 4 s u bstrate ( mi daz ola m) w here, at t he ti me of t his pr ot oc ol’s de vel o p me nt, 
1 5 healt h y v ol u nteers w ere gi ve n 2 0 0 m g Q D of L O X O- 3 0 5 o n 1 3 c o ns ec uti ve da ys ( 1 da y of 
w hic h was c o -a d mi nister e d wit h I V mi daz ola m a n d 1 da y of w hic h w as c o-a d mi nistere d wit h 
oral mi daz ola m).  
1. 4. 1.  
S afet y  
As of Se pte m ber 2 7, 2 0 2 0, 3 3 0 patie nts were treat e d i n t he L O X O- B T K - 1 8 0 0 1 st u d y a n d 
recei v e d L O X O- 3 0 5. T his i ncl u des 3 2 4 patie nts treate d at d oses ra n gi n g fr o m 2 5 m g Q D 
t o 3 0 0 m g Q D i n P hase 1/ 2 M o n ot hera p y c o h orts, a n d 6 patie nts treat e d i n P hase 1 b 
C o m bi nati o n Ar m A ( L O X O- 3 0 5 2 0 0 m g Q D pl us ve net ocla x 4 0 0 m g Q D [after v e net ocla x 
ra m p- u p]). A f ull s u m mar y of treat me nt-e mer g e nt a d verse e ve nts ( T E A Es) f or patie nts i n t he 
st u d y is pr o vi de d i n t he L O X O- 3 0 5 I B a n d t h e I n vesti gat or is directe d t o t he safet y 
i nf or mati o n descri be d i n t hat d oc u me nt.1 A s u m mar y of safet y f or L O X O - 3 0 5 gi ve n as 
m o n ot hera p y t o patie nts i n t he L O X O- B T K - 1 8 0 0 1 st u d y is pr o vi de d bel o w.  
•  I n t he 3 2 4 patie nts i n t he P hase 1/ 2 M o n ot hera p y c o h orts, T E A Es re p ort e d i n ≥ 1 0 % 
of patie nts ( n = 3 3 or m ore) w ere fati g ue ( 2 0. 1 % t otal, 8. 3 % relate d), diarr hea ( 1 7. 0 % 
t otal, 8. 6 % relate d), a n d c o nt usi o n ( 1 3. 0 % t otal, 9. 0 % relate d). Dr u g-relat e d T E A Es 
were re p orte d i n 1 5 6 of 3 2 4 patie nts ( 4 8. 1 %) i n t h e P hase 1/ 2 M o n ot hera p y c o h orts. 
T he m ost fre q ue ntl y r e p orte d dr u g- relate d T E A Es f or L O X O- 3 0 5 (t h ose i n > 5 % of 
patie nts o verall) w ere c o nt usi o n ( 9. 0 %), diarr h ea ( 8. 6 %), a n d fati g ue ( 8. 3 %). All 
ot her dr u g- r elate d T E A Es were re p orte d i n < 5 % of patie nts (ie, < 1 7 p atie nts eac h). 
Treat me nt - e mer ge nt A Es of se verit y Gra de 3 or 4 were re p orte d i n 8 7 of 3 2 4 patie nts 
( 2 6. 9 %) i n t he P hase 1/ 2 M o n ot hera p y c o h orts, wit h 4 1 ( 1 2. 7 %) of t hes e Gra de 3 or 4 
A Es re p orte d as rel ate d t o st u d y dr u g.  
•  O n -st u d y deat h ( d eat h wit hi n 2 8 da ys of t he last d ose of st u d y dr u g) d ue t o a Gra d e 5 
(fatal) A E was r e p orte d i n 4 of 3 2 4 patie nts ( 1. 2 %) i n t he P hase 1/ 2 M o n ot hera p y 
c o h orts . O ne Gra de 5 A E, E nter oc occ us f aeci u m -relate d se ptic s h oc k, was c o nsi dere d 
t o be relate d t o st u d y dr u g (f urt her d etails are pr o vi de d i n t he L O X O-3 0 5 I B 1). All 
ot her Gra d e 5 A Es w ere c o nsi dere d t o be n ot relat e d t o st u d y dr u g; t hese i ncl u de d 
p ne u m o nia f u n gal, s h oc k, a n d ple ural eff usi o n. 
Treat me nt - e mer ge nt A Es re p orte d f oll o wi n g L O X O- 3 0 5 a d mi nistrati o n i n healt h y v ol u nteers 
i n t he L O X O-B T K - 2 0 0 1 4 st u d y ( hea dac he, na us ea, a n d v o miti n g), were all Gra de 1 i n 
se verit y a n d c o nsi dere d t o be relate d t o L O X O- 3 0 5. All 3 e ve nts were re p orte d b y 1 s u bject 
a n d res ol ve d wit hi n 1 t o 1. 5 da ys.  
Treat me nt - e mer ge nt A Es re p orte d f oll o wi n g L O X O- 3 0 5 a d mi nistrati o n i n healt h y v ol u nteers 
i n t he L O X O-B T K - 2 0 0 0 6 st u d y (i nter mitte nt belc hi n g, bl oati n g, i nsect bite, a p ht h o us ulcer, 
na usea, i nter mitte nt diarr hea [ x 2], m us cle t witc h), were all Gra d e 1 i n se verit y, a n d bl oati n g, 
1 i nsta nce of i nter mitte nt diarr hea, a n d i nt er mitte nt belc hi n g were c o nsi dere d t o be relat e d t o 
L O X O - 3 0 5 a n d rifa m pi n. All 7 A Es were re p ort e d b y 3 s u bjects a n d all e v e nts res ol ve d pri or 
t o E n d of Treat me nt ( E O T; preli mi nar y data o n fil e at t he ti me of t his pr ot oc ol’s 
de vel o p me nt).  


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 2 of 6 8 
Treat me nt -e mer gent A Es re p orte d f oll o wi n g L O X O- 3 0 5 a d mi nistrati o n i n healt h y v ol u nteers 
i n t he L O X O-B T K - 2 0 0 1 7 st u d y ( hea dac he [ o bs er ve d at t he 3 0 0 m g L O X O - 3 0 5 d ose], a n d 
hea dac he [ x 2], i nter mitte nt hea dac h e, a n d p etec hi al ras h left t hi g h [ o bser ve d at t he 9 0 0 m g 
L O X O - 3 0 5 dose]), w ere all Gra de 1 i n se v erit y. O ne i nsta nce of h ea d ac he o bser ve d at t he 
3 0 0 m g L O X O - 3 0 5 d ose a n d 1 i nsta nce o bser ve d at t he 9 0 0 m g L O X O - 3 0 5 d ose, t he 
i nter mitte nt hea dac h e, a n d t he petec hial ras h left t hi g h were c o nsi d ere d t o be relate d t o 
L O X O - 3 0 5. All fi ve A Es were re p orte d b y 4 s u bjects a n d res ol ve d wit hi n 2 h o urs t o 5 da ys 
of o nset ( preli mi nar y d ata o n file at t he ti me of t his pr ot oc ol’s de vel o p me nt).  
Treat me nt - e mer ge nt A Es re p orte d f oll o wi n g L O X O- 3 0 5 a d mi nistrati o n i n healt h y v ol u nteers 
i n Part 1 of t he L O X O- B T K - 2 0 0 0 7 st u d y ( bl o o d y n ose, hea dac he, l o ose st o ol [ x 2], re d 
b u m ps o n left k nee, s mall a brasi o n t o ri g ht el b o w), were all Gra d e 1 i n se verit y a n d hea dac he 
was c o nsi der e d t o be r elate d t o L O X O- 3 0 5. All 7 A Es were re p orte d b y 4 s u bjects a n d al l 
e ve nts res ol ve d wit hi n 1 t o 2 da ys ( preli mi nar y data o n file at t he ti me of t his pr ot oc ol’s 
de vel o p me nt).  
Treat me nt - e mer ge nt A Es re p orte d f oll o wi n g L O X O- 3 0 5 a d mi nistrati o n i n healt h y v ol u nteers 
i n Part 2 of t he L O X O-B T K - 2 0 0 0 7 st u d y (te n der n ess at left ve ni p u nct ure site [ x 2], br uisi n g 
t o left a ntec u bital sec o n d ar y t o p hle b ot o m y [ x 2], br uisi n g t o ri g ht a ntec u bital sec o n dar y t o 
p hle b ot o m y, a n d aller gic reacti o n), were all Gra de 1 i n se verit y a n d n o e v e nts were 
c o nsi dere d t o be relate d t o L O X O- 3 0 5. All 6 A Es were re p orte d b y 4 s u bjects a n d all e ve nts 
res ol ve d wit hi n 1 t o 2 da ys ( preli mi nar y data o n file at t he ti me of t his pr ot oc ol’s 
de vel o p me nt).  
Treat me nt - e mer ge nt A Es re p orte d f oll o wi n g L O X O- 3 0 5 a d mi nistrati o n i n healt h y v ol u nteers 
i n t he L O X O-B T K - 2 0 0 0 8 st u d y (i njecti o n site pai n, nasal c o n gesti o n, flat ule nce, 
c o nsti pati o n, i ncrease d uri nar y fr e q ue n c y, facial ras h, a n d s ki n tear fr o m ta pe at I V site), were 
all Gra de 1 i n se v erit y, a n d flat ule nce, c o nsti pati o n, a n d i ncrease d uri nar y fre q ue nc y were 
c o nsi dere d  t o be relate d t o L O X O- 3 0 5. All 7 A Es were re p orte d b y 3 s u bjects a n d all e ve nts 
res ol ve d wit hi n 1 t o 8 da ys ( preli mi nar y data o n file at t he ti me of t his pr ot oc ol’s 
de vel o p me nt). 
As part of eac h cli nical trial c o n d ucte d i n patie nts or healt h y v ol u nteers, E C G a n d vital si g ns 
are perf or m e d at i nter vals s pecifie d b y pr ot oc ol. F or st u d y L O X O- B T K - 1 8 0 0 1 c o n d ucte d i n 
patie nts, n o cli nicall y si g nifica nt fi n di n gs of Q Tc pr ol o n gati o n ha ve bee n i de ntifie d i n 3 3 0 
patie nts as of Se pte m ber 2 7, 2 0 2 0 ( L O X O- 3 0 5 I B 1). I n a d diti o n, t here ha ve bee n n o cli nicall y 
si g nifica nt a b n or mal fi n di n gs i n vital si g ns a n d E C G data i n t he st u dies i n vesti gati n g 
L O X O - 3 0 5 c o n d u cte d i n healt h y v ol u nteers as of N o ve m ber 2 3, 2 0 2 0 ( preli mi nar y data o n 
file at t he ti me of t his pr ot oc ol’s de vel o p me nt). 
1. 4. 2.  
P h ar m ac o ki netics  
As of Se pte m ber 3 0, 2 0 2 0, P K data were a v aila ble fr o m 1 8 1 patie nts e nr olle d i n t he 
L O X O -B T K - 1 8 0 0 1 st u d y. Stea d y-state P K para meters of L O X O-3 0 5 i n t h ese ca n cer patie nts 
c o ul d be deri ve d fr o m data c ollecte d o n C ycle 1 D a y 8 ( Fi g ure 1 ), a n d are s h o w n i n Ta ble 1 . 
T hese data s h o w t hat L O X O -3 0 5 is a bs or be d after oral a d mi nistrati o n wit h a me dia n ti me t o 
ma xi m u m o bser ve d plas ma c o nce ntr ati o n (t ma x ) of a p pr o xi matel y 2 h o urs a n d l o w cleara nce 
(Ta ble 1 ). D u e t o t he li mite d sa m pli n g i nter val ( 0- 8 h o urs), i m p utati o n f or t he 2 4- h o ur sa m ple 
was ma de fr o m C ycle 1 Da y 8 pre d os e sa m ple, lea di n g t o a n esti mate d plas ma half- life of 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 3 of 6 8 
a p pr o xi matel y 2 0 h o urs. Ma xi m u m o bser ve d plas ma c o nce ntrati o n a n d area u n der t he plas m a 
c o nce ntr ati o n -ti me c ur ve ( A U C) of L O X O- 3 0 5 s h o we d i ncrease pr o p orti o nal t o d ose 
(Fi g ure 2 ). F oll o wi n g a d mi nistrati o n of t he rec o m me n de d P hase 2 d ose ( R P 2 D) 2 0 0 m g Q D, 
mea n tr o u g h plas ma le v els of L O X O- 3 0 5 e x cee de d t he c o nce ntrati o n re q uire d f or 9 6 % 
i n hi biti o n of B T K i n vitr o (I C5 0  =  
n g/ m L, I C9 6 =  
 n g/ m L). F urt h er details ma y be 
f o un d i n t he I B. 1 
P har mac o ki netic dat a f oll o wi n g oral a d mi nistrati o n of a 2 0 0- m g d ose of L O X O- 3 0 5 i n ta blet 
f or m i n healt h y v ol u nteers i n t he L O X O-B T K -2 0 0 1 4 st u d y i n dicate t hat t here was little effect 
of eit her a sta n d ar d meal or t he pr ot o n p u m p i n hi bit or o me praz ole o n t h e P K of L O X O- 3 0 5.  
T a ble 1 : P h ar m ac o ki netic P ar a m eters of L O X O- 3 0 5 i n C a ncer P atie nts 
( St u d y L O X O -B T K - 1 8 0 0 1) at Ste a d y St ate ( C ycle 1 D a y 8) 
D ose Le vel  
N  
C m a x 
( n g/ m L) 
Ge o m e a n 
( % C V) 
tm a x  ( h) 
Me di a n  
( mi n, m a x) 
A U C 0- 8 
( n g * h/ m L) 
Ge o m e a n 
( % C V) 
A U C 0- 2 4 
( n g * h/ m L) 
Ge o m e a n 
( % C V) 
C L/ F ( L/ h)  
Ge o m e a n 
( % C V) 
t1/ 2 ( h) 
Ge o m e a n 
( % C V) 
R ati o  
A U C 0- 8  
D a y 
8/ D a y 1  
Ge o 
m e a n 
( % C V) 
2 5  m g Q D  
5 
7 3 4 
( 1 1. 0 %) 
2 ( 1, 8)  
4 2 4 0 
( 1 2. 4 %) 
9 8 0 0 
( 2 5. 8 %) 
1. 5 5 a 
( 6 9. 6 %) 
1 8. 2 a 
( 6 0. 1 %) 
1. 4 4 
( 2 3. 0 %) 
5 0  m g Q D  
6 
1 4 2 0 
( 1 9. 2 %) 
1. 5 ( 1, 4)  
8 6 6 0 
( 2 4. 7 %) 
2 0 1 0 0 
( 3 4. 9 %) 
2. 6 2 b 
( 3 6. 7 %) 
1 7. 6 b 
( 3 9. 6 %) 
1. 5 1 
( 2 5. 9 %) 
1 0 0  m g Q D  
9 
3 9 1 0 
( 3 5. 6 %) 
2 ( 1, 4)  
2 2 0 0 0 
( 3 7. 2 %) 
5 2 4 0 0 
( 3 9. 7 %) 
0. 9 6 8 c 
( 6 3. 0 %) 
2 2. 2 c 
( 3 3. 9 %) 
1. 8 8 
( 4 2. 8 %) 
1 5 0  m g Q D  
2 0  
4 6 8 0 
( 2 9. 1 %) 
2 ( 1, 8)  
2 8 0 0 0 
( 2 9. 6 %) 
6 4 4 0 0 
( 3 9. 6 %) 
1. 3 6 d  
( 6 6. 7 %) 
1 8. 1 d  
( 5 1. 8 %) 
1. 7 4 
( 2 4. 9 %) 
2 0 0  m g Q D  
9 9  
5 7 7 0 
( 4 7. 7 %) 
2 ( 1, 8)  
3 6 9 0 0  
( 4 0. 8 %) 
9 1 0 0 0 
( 4 2. 0 %) 
1. 1 4 e 
( 6 1. 8 %) 
1 9. 9 e 
( 5 6. 2 %) 
1. 6 9 h 
( 2 9. 6 %) 
2 5 0  m g Q D  
2 5  
8 1 0 0 
( 2 8. 1 %) 
2 ( 1, 4)  
4 9 7 0 0 
( 3 1. 3 %) 
1 1 1 0 0 0 
( 3 8. 7 %) 
1. 2 6 f 
( 1. 0 8 %) 
1 7. 4 f 
( 5 0. 6 %) 
1. 6 8 
( 2 4. 5 %) 
3 0 0  m g Q D  
1 7  
1 0 7 0 0 
( 2 6. 6 %)  
2 ( 1, 4)  
6 5 8 0 0 
( 3 5. 9 %) 
1 5 8 0 0 0 
( 4 9. 2 %) 
1. 6 3 g  
( 4 2. 5 %) 
3 0. 1 g  
( 1 0 2 %) 
2. 1 5 
( 3 1. 2 %) 
A b bre viati o ns: A U C 0- 8 = area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 8 h o urs; A U C 0- 2 4 = area u n der 
t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 2 4 h o urs; C L/ F  = a p pare nt oral cleara nce; C ma x  = ma xi m u m dr u g 
c o nce ntrati o n; Ge o mea n = Ge o metrical mea n; N = n u m ber of s u bjec ts; Q D = o nce dail y; C V = c oefficie nt of 
variati o n; t1/ 2 = half -life; tma x  = ti me of ma xi mal plas ma c o nce ntrati o n.  
a N =  4, b N =  5, c N =  8, d N =  1 8, e N = 6 4, f N =  2 1, g N =  1 6, h N =  7 3  
S D T M Tra nsfer: Se pte m ber 3 0, 2 0 2 0  
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 4 of 6 8 
 
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 5 of 6 8 
S D T M Tra nsfer: Se pte m ber 3 0, 2 0 2 0  
Preli mi nar y a n d i nteri m plas ma c o nce ntrati o n dat a fr o m o n g oi n g st u d y L O X O- B T K - 2 0 0 0 8 
i n dicate t hat t he d ose of 2 0 0 m g Q D i n healt h y v ol u nteers pr o d uces a L O X O- 3 0 5 stea d y-stat e 
ge o metric mea n C ma x  of 
 n g/ m L a n d A U C fr o m h o ur 0 t o 2 4 h o urs p ost d ose ( A U C0- 2 4) 
of a p pr o xi matel y  
 n g * h/ m L. T hese res ults i n dicate t hat t he d ose of 2 0 0 m g Q D i n t his 
st u d y will pr o vi de e x p os ure i n t he ra n g e of t he R P 2 D of L O X O- 3 0 5 s ee n i n patie nts, w hile 
re mai ni n g well u n der t h e n o o bser ve d a d v erse effect le vel Cma x  f or ge n ot o xicit y of 
a p pr o xi matel y  
 n g/ m L.  
1. 5.  
St u d y R ati o n ale 
T he o bjecti ve of D DI st u dies is t o deter mi ne w het her p ote ntial i nteracti o ns bet wee n a n 
i n vesti gati o nal dr u g a n d ot her dr u gs e xist. Dr u g- dr u g i nteracti o n st u dies ha ve a n i m p orta nt 
r ole i n dr u g de vel o p me nt,9 a n d t his st u d y is bei n g perf or me d as part of t he de vel o p me nt 
pr o gra m f or L O X O - 3 0 5. 
L O X O - 3 0 5 s h o w e d n o d etecta ble i n hi biti o n (I C5 0  
 μ M) of C Y P 1 A 2, C Y P 2 B 6, 
C Y P 2 C 1 9, a n d C Y P 2 D 6, a n d wea k i n hi biti o n of C Y P 2 C 8, C Y P 2 C 9, a n d C Y P 3 A 4 wit h 
i n hi bit or y c o nsta nt ( Ki) val ues ra n gi n g fr o m  
 μ M i n h u ma n li ver micr os o mes. 
After pr e -i nc u b ati o n of micr os o mes wit h L O X O- 3 0 5 a n d nic oti na mi de a d e ni ne di n ucle oti de 
p h os p hate f or 3 0 mi n utes pri or t o a d diti o n of C Y P 4 5 0 pr o be s u bstrate, t he C Y P 3 A 4 
i n hi bit or y p ote nc y of L O X O- 3 0 5 was i ncrease d, s u g gesti n g t he p ote ntial f or ti me- de pe n d e nt 
i n hi biti o n of C Y P 3 A 4. F urt her ki netic e v al uati o n c o nfir me d t hat L O X O- 3 0 5 is a 
ti me- de pe n de nt i n hi bit or of C Y P 3 A 4 wit h a Ki val ue of  
 μ M a n d a ki nact ( ma xi mal 
i nacti vati o n rate c o nsta nt) val ue of  
. 1 5 h- 1 res ulti n g i n a Cli nact val ue (i nacti vati o n 
clear a nce) of 8. 6 4 mi n - 1 m M - 1. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 6 of 6 8 
I n a n i n vitr o he pat oc yt e assa y, L O X O- 3 0 5 i n d uce d m R N A f or C Y P 3 A 4, C Y P 3 A 5, 
C Y P 2 B 6, a n d C Y P 2 C 1 9. F or b ot h C Y P 2 B 6 a n d C Y P 2 C 1 9, a n i ncreas e i n acti vit y was see n. 
F or C Y P 3 A 4, L O X O - 3 0 5 di d n ot ca use a n i ncrease i n acti vit y, li kel y d ue t o c o nc urre nt 
i n hi biti o n of C Y P 3 A 4 b y L O X O- 3 0 5. L O X O-3 0 5 ca use d a d ecreas e i n m R N A  f or C Y P 1 A 2 
b ut di d n ot lea d t o a re d u cti o n of C Y P 1 A 2 acti vit y. I n t he st u d y, C Y P 2 D 6, C Y P 2 C 8, a n d 
C Y P 2 C 9 m R N A were n ot i n d uce d. 
L O X O - 3 0 5 ma y h a ve t he p ote ntial t o raise plas ma c o nce ntrati o ns of dr u gs t hat are s u bstrates 
of C Y P 2 C 8, C Y P 2 C 9, a n d C Y P 3 A 4 or l o w er plas ma c o nce ntrati o ns t hat are meta b olize d b y 
C Y P 1 A 2, C Y P 2 B 6, C Y P 2 C 1 9, or C Y P 3 A 4. T his st u d y is desi g ne d t o deter mi ne t he effect of 
L O X O - 3 0 5 o n t he P K of caff ei ne ( C Y P 1 A 2 s u bstrate), S- warfari n ( C Y P 2 C 9 s u bstrate), a n d 
o me praz ole ( C Y P 2 C 1 9 s u bstrate). T he effects of L O X O - 3 0 5 o n t he P K of ot her C Y P 4 5 0 
s u bstrates will be e x pl ore d i n se parate cli nical st u dies. Caffei ne, warfari n, a n d o me praz ole 
are c o m m o nl y use d as i n de x s u bstrates f or C Y P 4 5 0 e nz y mes i n D DI st u di es. 9 
1. 6.  
Ris k Assess m e nt  
S u bjects i n t he c urre nt st u d y will n ot recei ve a n y healt h be nefit ( b e y o n d t h at of a n assess m e nt 
of t heir me dical stat us) fr o m partici pati n g i n t he st u d y. T he ris ks of partici p ati o n are 
pri maril y t h ose ass ociate d wit h a d verse reacti o ns t o t he st u d y treat me nts, alt h o u g h t here ma y 
als o be s o me disc o mf ort fr o m c ollecti o n of bl o o d sa m ples a n d ot her st u d y pr oce d ures. T he 
d ose of L O X O- 3 0 5 a d mi nistere d i n t his st u d y is n ot a ntici pate d t o i n d uce a n y p ote ntial ris k t o 
s u bjects partici pati n g i n t his st u d y as t he d ose d oes n ot e xcee d t he hi g h est d ose safel y 
a d mi nistere d i n first -i n- h u ma n st u d y or healt h y v ol u nteer st u dies.1 M ore i nf or mati o n a b o ut 
t he k n o w n a n d e x p ecte d be nefits, ris ks, a n d reas o na bl y a ntici pate d A Es ass ociate d wit h 
L O X O - 3 0 5 ma y b e f o u n d i n t he I B. 1 
T here is a p ote ntial ris k t hat m ulti ple d oses of L O X O - 3 0 5 ma y lea d t o decreases i n w hite 
bl o o d cells i ncl u di n g ne utr o p hils, l y m p h oc ytes, m o n oc ytes, a n d e osi n o p hils. T heref ore, t o 
miti gate a n y p ote ntial i m m u n os u p pressi ve ris ks d uri n g t he o n g oi n g S A R S- C o V- 2 
( C O VI D-1 9) pa n de mic, s u bjects will re mai n i n t he Cli nical Researc h U nit ( C R U) f or 
9 6 h o urs p ost d ose ( Da y 2 3) t o all o w f or L O X O - 3 0 5 eli mi nati o n. I n a d diti o n, s u bject’s 
he mat ol o g y la b orat or y r es ults will be re vie we d pri or t o disc har ge fr o m t he C R U. M ore 
i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be n efits, ris ks, a n d reas o na bl y a ntici pate d A Es 
ass ociate d wit h L O X O - 3 0 5 ma y be f o u n d i n t he I B.1 
T he d ose of caff ei ne, o m e praz ol e, vita mi n K, a n d warfari n a d mi nistere d i n t his st u d y are n ot 
a ntici pate d t o i n d uce a n y p ote ntial ris k or be nefit t o s u bjects partici pati n g i n t his st u d y, as 
t he y are si n gle d oses a d mi nistere d acc or di n g t o t he d osi n g rec o m me n d ati o ns i n t he f ull 
prescri bi n g i nf or mati o n.  
T he safet y m o nit ori n g pr actices e m pl o ye d will i ncl u de A E re p orti n g, vital si g n 
meas ure me nts, 1 2 -l ea d E C Gs, cli nical la b orat or y e val uati ons, a n d p h ysical e xa mi nati o ns, a n d 
are c o nsi d ere d a de q uat e t o pr otect t he s u bjects’ s afet y.  
 
 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 7 of 6 8 
2.  O B J E C TI V E S A N D E N D P OI N T S  
2. 1.  
O bjecti ves  
2. 1. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve of t he st u d y is t o assess t he effect of m ulti ple oral d oses of L O X O- 3 0 5 
o n t he P K of si n gle oral d oses of caffei ne ( C Y P 1 A 2 s u bstrate), S- w arfari n ( C Y P 2 C 9 
s u bstrate), a n d o me praz ole ( C Y P 2 C 1 9 s u bstrate) i n healt h y s u bjects. 
2. 1. 2.  
Sec o n d ar y O bjecti ve  
T he sec o n d ar y o bjecti ve of t he st u d y is t o assess t he safet y a n d t olera bilit y of m ulti ple oral 
d oses of L O X O- 3 0 5 w he n a d mi nistere d al o ne, a n d c oa d mi nistere d wit h a si n gle oral d ose of 
pr o be dr u g c o c ktail. 
2. 2.  
E n d p oi nts  
2. 2. 1.  
Pri m ar y E n d p oi nts  
T he f oll o wi n g P K para m eters will be calc ulate d w he ne ver p ossi ble, b ase d o n t he plas ma 
c o nce ntr ati o ns of caffei n e/ para x a nt hi ne, o me praz ole, S- warfari n, a n d L O X O- 3 0 5 (as 
a p pr o priate): 
•   A U C 0- 2 4 
•  A U C fr o m h o ur 0 t o t he l ast meas ura ble c o nce ntrati o n ( A U C 0-t) 
•  A U C fr o m h o ur 0 e xtr a p olate d t o i nfi nit y ( A U C 0- i nf) 
•  perce nt a ge e xtra p olati o n f or A U C 0- i nf ( % A U Ce xtra p) 
•  a p pare nt s yste mic cleara nce ( C L/ F) 
•  a p pare nt plas m a ter mi nal eli mi nati o n half -life (t½ ) 
•  C ma x  
•  tma x  
•  a p pare nt ter mi nal eli mi nati o n rate c o nsta nt ( λ z) 
•  a p pare nt v ol u me of distri b uti o n at t he ter mi nal p hase ( V z/ F) 
•  mea n resi de n ce ti me ( M R T)  
•  A U C 0- 2 4 a n d A U C 0- 4 8 rati o of para x a nt hi ne t o caffei ne ( M R A U C; 
caff ei ne/ par a xa nt hi ne o nl y). 
2. 2. 2.  
Sec o n d ar y E n d p oi nts  
Safet y a n d t oler a bilit y will be assesse d b y m o nit ori n g A Es, perf or mi n g p h ysical e xa mi nati o ns 
a n d cli nical la b or at or y e v al uati o ns, meas uri n g vital si g ns, a n d rec or di n g 1 2- lea d E C Gs.  


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 8 of 6 8 
3.  I N V E S TI G A TI O N A L P L A N 
3. 1.  
O ver all St u d y Desi g n a n d Pl a n  
T his is a P hase  1, o pe n-la bel, 2- peri o d, fi xe d-se q u e nce D DI st u d y t o i n vesti gate t he effect of 
m ulti ple oral d oses of L O X O- 3 0 5 o n t he P K of si n gle oral d oses of caffei ne ( C Y P 1 A 2 
s u bstrate) a n d its meta b olite para xa nt hi ne, S- w arfari n ( C Y P 2 C 9 s u bstrate), a n d o me praz ole 
( C Y P 2 C 1 9 s u bstrate) i n healt h y s u bjects.  
I n Peri o d 1, Da y 1, 2 0 0 m g caff ei ne (ta blet), 4 0  m g o me praz ole (ca ps ule), a n d 1 0 m g 
warf ari n  (ta blet) a d mi nistere d as a si n gle d ose of pr o be dr u g c o c ktail, al o n g wit h 1 0 m g 
vita mi n K (ta blets), will be a d mi nistere d i n t he m or ni n g f oll o wi n g a fast of at least 1 0  h o urs 
pre d ose a n d 2 h o urs p ost d ose. Bl o o d sa m ples f or c o nce ntrati o ns of t he s u bstrates 
(caffei ne/ para x a nt hi ne, o me praz ole, a n d S-warfar i n) i n plas ma will be c ollecte d  
 
. Of t h e sa m ples c ollecte d f or c o nce ntrati o ns of eac h 
s u bstrate i n plas ma 
, sa m ples will be a nal yze d 
f or c o nce ntrati o n of caffei ne/ para xa nt hi ne fr o m 
, f or 
c o nce ntr ati o n of o me praz ole fr o m 
, a n d c o nce ntrati o ns of 
S- warf ari n fr o m 
. 
T here will be a was h o ut peri o d of 5 da ys b et wee n a d mi nistrati o n of t he pr o be dr u g c oc kt ail 
o n Da y 1 a n d t he first d ose of L O X O- 3 0 5 o n Da y 6.  
I n Peri o d 2, o n Da ys 6 t hr o u g h 1 9, oral d oses of 2 0 0 m g L O X O - 3 0 5 will be a d mi nistere d Q D 
f or 1 4 c o nsec uti ve da ys i n t he m or ni n g at t he act u al ti me of t he Da y 1 pr o b e dr u g c oc kt ail 
d osi n g ( ± 1 h o ur). O n Da y 1 5, L O X O- 3 0 5 will be c oa d mi nistere d wit h 2 0 0 m g caffei ne 
(ta blet), 4 0 m g o me praz ole (ca ps ule ), a n d 1 0 m g warfari n (ta blet) a d mi nistere d as a si n gle 
d ose of pr o be dr u g c oc kt ail, al o n g wit h 1 0 m g of vita mi n K (ta blets) at t he act ual ti me of t he 
Da y 1 pr o be dr u g c oc kt ail d osi n g ( ± 1 h o ur) f oll o wi n g a fast of at least 1 0 h o urs pre d ose a n d 
2 h o urs p ost d ose. O n Da ys 7 t hr o u g h 1 1, a n d Da ys 1 3, 1 4, 1 6, 1 8, a n d 1 9, s u bjects will fast 
f or at least 2 h o urs pre d ose a n d 1- h o ur p ost d ose. O n Da ys 6, 1 2, a n d 1 7 w here cli nical 
la b orat or y e v al uati o ns ar e perf or me d, s u bjects will fast f or at least 8 h o urs pre d ose a n d 1 h o ur 
p ost d ose. Bl o o d sa m ples f or c o nce ntrati o ns of L O X O- 3 0 5 i n plas ma will be c ollecte d a n d 
a nal yze d 
 
 
 Bl o o d sa m ples f or c o n ce ntrati o ns of t he s u bstrates 
(caffei ne/ para x a nt hi ne, o me praz ole, a n d S-warfari n)  i n plas ma 
 
 Of t h e sa m ples c ollecte d f or c o nce ntrati o ns of eac h 
s u bstrate i n plas ma pre d ose 
, sa m ples will be a nal yze d 
f or c o nce ntrati o n of caffei ne/ para xa nt hi ne 
, f or 
c o nce ntr ati o n of o me praz ole 
, a n d f or c o nce ntrati o n 
of S - warf ari n 
. 
T he sc he matic of t he st u d y desi g n is dis pla ye d i n Fi g ure 3 . T h e start of t he st u d y is defi ne d as 
t he date t he first s u bject w h o is e nr olle d i n t he st u d y si g ns a n I nf or me d C o nse nt F or m (I C F). 
N ote t hat e nr olle d s u bjects are defi n e d as t h ose s u bjects w h o are assi g ne d t o recei v e a d ose of 
st u d y dr u g; t his defi niti on e xcl u des scree n fail ure s u bjects. Re place me nt s u bjects ma y be 
e nr olle d o nl y if dee m e d necessar y b y t he S p o ns or. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 9 of 6 8 
S u bjects w h o are d eter mi ne d t o be scr ee n fail ures are per mitte d t o be re -s cree ne d if t he 
I n v esti gat or ( or d esi g nee), wit h a gree me nt fr o m t he S p o ns or, feels t hat t he s u bject ma y meet 
eli gi bilit y criteria u p o n re -scr ee n. Re-s cree ne d s u bjects will be pr o vi de d a ne w s u bject 
n u m ber. 
T o assess t heir eli gi bilit y t o e nter t he st u d y, p ote ntial s u bjects will be scree ne d wit hi n 3 4  da ys 
( Da ys - 3 5 t o - 2) a n d be a d mitte d t o t he C R U o n Da y -1 ( C hec k -i n). 
S u bjects will be c o nfi ne d at t he C R U fr o m t he ti me of C hec k -i n ( Da y - 1) u ntil E O T o n 
Da y  2 3 u p o n c o m pleti o n of all P K a n d safet y assess me nts or Earl y Ter mi n ati o n ( E T) if t he 
s u bject disc o nti n ues. D osi n g of pr o be dr u g c oc ktail will occ ur o n Da y 1 a n d Da y 1 5 a n d 
d osi n g of L O X O- 3 0 5 will occ ur o n Da ys 6 t hr o u g h 1 9. A f oll o w- u p p h o ne call will occ ur f or 
all s u bjects w h o recei ve d at least 1  d ose of st u d y dr u g (i ncl u di n g s u bjects w h o are ter mi nate d 
earl y) 7 d a ys ( ± 2 da ys) after E O T or E T. T he d urati o n of partici pati o n is e x pecte d t o be 
a p pr o xi matel y 6 7 da ys ( Scree ni n g t hr o u g h f oll o w- u p p h o ne call). 
Fi g ure  3: St u d y Sc he m atic 
 
I n t his st u d y, p h ysical e x a mi nati o ns, 1 2-lea d E C Gs, vital si g n meas ure me nts, H o w D o Y o u 
Feel ? ( H D Y F?) i n q uiries, cli nical c he mistr y pa nel, c oa g ulati o n para meters, he mat ol o g y 
pa nel, uri nal ysis ( U A; A p pe n di x 2 ), a n d rec or di n g of c o nc o mita nt me dicati o ns will be 
perf or me d at s pecifi e d ti mes d uri n g t he st u d y (f or s pecific ti me p oi nts a n d details o n eac h 
st u d y varia ble, refer t o A p pe n di x 4 ).  
A d verse e ve nts a n d seri o us a d verse e ve nts ( S A Es) will be c ollecte d be gi n ni n g at i nf or me d 
c o nse nt. A d vers e e v e nts will be re p orte d t hr o u g h o ut t he st u d y (ie, fr o m si g ni n g of t he I C F 
u ntil E n d of St u d y [ E O S], or u ntil E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot 
c o m plete a f oll o w - u p p h o ne call), eit her as s u bject me dical hist or y (if t he e ve nt is re p orte d as 
be gi n ni n g pri or t o si g ni n g of t he I C F or if t he e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n 
o n Da y 1 a n d is assess e d as n ot relate d t o st u d y pr oce d ures b y t h e I n vesti gat or [ or desi g nee]) 
or as A Es (if t he e ve nt occ urs after si g ni n g of t he I C F b ut pri or t o st u d y dr u g a d mi nistrati o n 
o n Da y 1 a n d is assess e d as relate d t o st u d y pr o ce d ures b y t he I n v esti gat or [ or desi g nee], or if 
t he e ve nt occ urs aft er st u d y dr u g a d mi nistrati o n o n Da y 1 t hr o u g h E O T or E T re gar dless of 
relati o ns hi p t o st u d y dr u g). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d as relat e d t o 
st u d y dr u g b y t he I n vesti gat or ( or desi g n ee) are t o be re p ort e d. All S A Es t hat de vel o p fr o m 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 0 of 6 8 
t he ti me of I C F si g ni n g u ntil E O S ( or E T, if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes 
n ot c o m plete a f oll o w- u p p h o ne call) are t o be re p orte d. 
A Sc he d ule of Ass ess me nts is prese nte d i n A p pe n di x 4 . St u d y c o m pleti o n is defi ne d as t he 
ti me of t he last s u bject’s f oll o w- u p p h o ne call. 
3. 2.  
Disc ussi o n of St u d y Desi g n  
Meta b olic r o utes of eli mi nati o n, i ncl u di n g m ost of t h ose occ urri n g t hr o u g h t he C Y P fa mil y of 
e nz y mes, ca n be i n hi bite d or i n d uce d b y c o n c o mita nt dr u g treat me nt. C ha n ges arisi n g fr o m 
meta b olic D DI ca n be si g nifica nt a n d c o ntri b ute t o i ncreas es or decreases i n t he bl o o d a n d 
tiss ue c o nce ntrati o ns of t he pare nt dr u g or acti ve meta b olite. I n crease d or decrease d 
c o nce ntr ati o ns of a pare nt dr u g or its meta b olites ca n alter t he s afet y a n d efficac y pr ofile of a 
dr u g.  
T he pr o be dr u gs c h ose n i n t his st u d y all o w i n vesti gati o n of D DIs me diate d t hr o u g h C Y P 4 5 0 
e nz y mes. L O X O - 3 0 5 s h o we d n o detecta ble i n hi biti o n (I C 5 0  
 μ M) of C Y P 1 A 2, 
C Y P 2 B 6, a n d C Y P 2 D 6 a n d s h o we d wea k i n hi biti o n of C Y P 2 C 8, C Y P 2 C 9, C Y P 2 C 1 9, a n d 
C Y P 3 A 4.  I n vitr o L O X O- 3 0 5 i n d uce d C Y P 3 A 4, C Y P 2 C 1 9, a n d C Y P 2 B 6 a n d d o w n 
re g ulate d C Y P 1 A 2. T h e pr o be dr u gs w ere c h ose n as t he y are k n o w n t o be s e nsiti ve s u bstrates 
of C Y P 1 A 2 (caffei ne), a n d C Y P 2 C 9 ( warfari n), a n d C Y P 2 C 1 9 ( o me praz ol e). Vita mi n K will 
be a d mi nistere d wit h warfari n t o c o u nteract its a ntic oa g ula nt effect.  
T he fi xe d si n gle-se q u e nce desi g n use d i n t his st u d y is t y pical f or dr u g i nteracti o n st u dies, 
beca use it all o ws i ntra -s u bject c o m paris o ns. A si n gle se q ue nce will be use d t o a v oi d carr y 
o ver effects. T his st u d y will be o pe n-la bel beca us e t he pri mar y e n d p oi nts are n ot c o nsi dere d 
s u bjecti ve. 
C o n d ucti n g t he st u d y i n healt h y a d ult s u bjects miti gates t he p ote ntial c o nf o u n di n g effects of 
t he disease state a n d c o n c o mita nt me dicati o ns. 
3. 3.  
Selecti o n of D oses i n t he St u d y  
3. 3. 1.  
L O X O - 3 0 5 
M ulti ple oral d oses of 2 0 0 m g L O X O - 3 0 5 Q D will be a d mi nistere d o n Da ys 6 t hr o u g h 
Da y  1 5 t o ac hie v e L O X O - 3 0 5 stea d y state, e ns uri n g t he ma xi mal effect of L O X O- 3 0 5 w h e n 
c oa d mi nistere d wit h t he pr o be dr u g c o c ktail o n D a y 1 5. L O X O- 3 0 5 2 0 0 m g Q D will 
c o nti n ue o n Da y 1 6 t hr o u g h Da y 1 9 t o mai ntai n stea d y state of L O X O- 3 0 5. W hile d oses of 
2 5 m g Q D t o 3 0 0 m g Q D ha ve bee n e val u ate d, L O X O - 3 0 5 2 0 0 m g gi ve n Q D has bee n 
c h ose n as t he R P 2 D f or t he o n g oi n g gl o bal P hase 1/ 2 first -i n- h u ma n st u d y, 
L O X O -B T K - 1 8 0 0 1 i n p atie nts wit h pre vi o usl y treate d C L L/ S L L or N H L. T he a vaila ble d ata 
de m o nstrate t hat L O X O -3 0 5 a p pears s afe a n d well t olerate d at t hese d os es. At all e val uate d 
d oses, n o d ose- li miti n g t o xicities ha ve bee n i d e ntifie d i n h u ma ns.1  
3. 3. 2.  
Pr o be Dr u g C oc kt ail  
T he select e d d oses of t he pr o be dr u gs caffei ne, o me praz ole,  an d warfari n  were b ase d o n 
t y pical d oses f or t hese dr u gs w he n t he y are use d as i n de x s u bstrates i n D DI st u dies, a n d are 
c o nsi dere d t o be hi g h e n o u g h t o pr o vi de s ufficie nt plas ma c o nce ntrati o ns t o ac hie ve t h e 
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 1 of 6 8 
o bjecti ves of t he st u d y.  T he reas o n f or t he a d mi nistrati o n of t he d ose of vita mi n K selecte d is 
t o o verc o me t he a nti-c oa g ula nt effects of warfari n base d o n t y pical d oses use d f or D DI 
st u dies. 
 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 2 of 6 8 
4.  S E L E C TI O N O F S T U D Y P O P U L A TI O N  
4. 1.  
Scree ni n g Pr oce d ures  
T he f oll o wi n g scree ni n g pr oce d ur es will be perf or me d f or all p ote ntial s u bjects at a visit 
c o n d ucte d wit hi n 3 5 da ys of st u d y e ntr y (ie, pri or t o C hec k- i n [ Da y -1]):  
1.  I n cl usi o n/ E xcl usi o n criteria 
2.  I nf or me d c o ns e nt 
3.  De m o gra p hic d ata  
4.  Me dical hist or y (i ncl u di n g re vie w of m e dicati o n[s]) 
5.  Hei g ht, wei g ht, a n d b o d y mass i n d e x ( B MI)  
6.  1 2-lea d E C G meas ure d after t he s u bject h as bee n resti n g i n t he s u pi ne p ositi o n f or at 
least 1 0 mi n utes ( Secti o n  7. 3. 4 ) 
7.  Vital si g n meas ure me nts (i ncl u di n g b o d y te m perat ure, res pirat or y rate, o x y ge n 
sat urati o n, a n d s u pi ne bl o o d press ure [ B P] a n d p ulse rate [ meas ure d after t he s u bject 
has bee n s u pi ne f or at lea st 5 mi n utes]; Secti o n  7. 3. 3 ) 
8.  H D Y F? i n q uir y, A E, S A E, a n d c o nc o mita nt me di cati o n e val uati o ns ( Secti o n  7. 3. 1 ) 
9.  Cli nical la b orat or y e val u ati o ns ( Secti o n  7. 3. 2 ; cli nical c he mistr y pa n el [faste d at least 
8 h o urs], c oa g ul ati o n par a meters, he m at ol o g y pa n el, a n d U A;  A p pe n di x 2 ) 
1 0.  Scree ns f or he patitis C vir us ( H C V) a nti b o d y, he p atitis B s urface a nti ge n ( H Bs A g), 
he patitis B vir us ( H B V) i m m u n o gl o b uli n M (I g M) c ore a nti b o d y, h u ma n 
i m m u n o deficie nc y vir us ( HI V) a nti b o d y, a n d C O VI D - 1 9 via p ol y merase c hai n 
reacti o n ( P C R) testi n g or e q ui vale nt (A p pe n di x 2 ) 
1 1.  He m o gl o bi n A 1c ( H b A 1 c) test ( A p pe n di x 2 ) 
1 2.  Uri ne dr u g scree n f or sel ecte d dr u gs of a b use (i ncl u di n g c oti ni ne) a n d alc o h ol scree n 
( breat h or uri ne; A p pe n di x 2 ) 
1 3.  Esti mate d gl o mer ular filtr ati o n rate (e G F R) cal c ulate d usi n g t he  C hr o nic Ki d ne y 
Disease E pi de mi ol o g y C olla b orati o n ( C K D- E PI)  e q uati o n (A p pe n di x 2 ) 
1 4.  Ser u m pre g na n c y test (f or fe male  s u bjects o nl y; A p pe n di x 2 ) 
1 5.  F ollicle -sti m ulati n g h or m o ne ( F S H) test (f or p ost-me n o pa usal fe m ale s u bjects o nl y; 
A p pe n di x 2 ) 
1 6.  T h yr oi d- sti m ulati n g h or m o ne ( T S H) test (A p p e n di x 2 ) 
1 7.  Bl o o d sa m ple f or ge n ot y pi n g ( A p pe n di x 2 ) 
4. 2.  
C hec k -i n Pr oce d ures ( D a y - 1) 
At C hec k -i n ( D a y -1), s u bjects will re p ort t o t he C R U  a n d t he f oll o wi n g pr oce d ures will be 
perf or me d:  
1.  Re vie w of i ncl usi o n/e xcl usi o n criteria 
2.  I nteri m me dical hist or y, i ncl u di n g c o nc o mita nt me dicati o n(s) 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 3 of 6 8 
3.  Wei g ht a n d B MI 
4.  C o m plete p h ysical e xa mi nati o n ( Secti o n  7. 3. 5 ) 
5.  1 2-lea d E C G meas ure d after t he s u bject h as bee n resti n g i n t he s u pi ne p ositi o n f or at 
least 1 0 mi n utes ( Secti o n  7. 3. 4 ) 
6.  Vital si g n m eas ure me nts (i ncl u di n g b o d y te m perat ure, res pirat or y rate, o x y ge n 
sat urati o n, a n d s u pi ne B P a n d p ulse rate [ meas ure d after t he s u bject has bee n s u pi ne 
f or at least 5 mi n utes]; Secti o n  7. 3. 3 ) 
7.  H D Y F? i n q uir y, A E, S A E, a n d c o nc o mita nt me di cati o n e val uati o ns ( Secti o n  7. 3. 1 ) 
8.  Cli nical la b orat or y e val u ati o ns (Secti o n  7. 3. 2 ; cli nical c he mistr y pa n el [faste d at least 
8 h o urs], c oa g ul ati o n par a meters, he m at ol o g y pa n el, a n d U A; A p pe n di x 2 ) 
9.  Scree n f or C O VI D - 1 9 via P C R test ( or e q ui vale nt; A p pe n di x 2 ) 
1 0.  Uri ne dr u g scree n f or sel ecte d dr u gs of a b use (i ncl u di n g c oti ni ne) a n d alc o h ol scree n 
( breat h or uri ne; A p pe n di x 2 ) 
1 1.  e G F R calc ulate d usi n g t h e C K D - E PI e q u ati o n (A p pe n di x 2 ) 
1 2.  Ser u m pre g na n c y test (f or fe male s u bjects o nl y; A p pe n di x 2 ) 
1 3.  C o m plia nce wit h c o nc o mita nt me dicati o ns a n d e xcl usi o nar y restricti o ns ( Secti o n  6 ) 
F or s u bjects t o c o nti n ue t heir partici pati o n i n t he st u d y, t he i ncl usi o n/e xcl usi o n criteria m ust 
c o nti n ue t o be met at C hec k -i n ( D a y -1 [as a p pr o priate; # 1 , Secti o n  4. 2 ]). I n a d diti o n, 
c o nti n ue d c o m pli a nce wit h c o nc o mita nt me dicati o n a n d ot her restricti o ns will be verifie d.  
T he S p o ns or will re vie w me dical hist or y a n d all scree ni n g e v al uati o ns f or p ote ntial s u bjects 
pri or t o C hec k-i n ( D a y - 1). Pri or t o d osi n g, t he S p o ns or will pr o vi de a p pr o val of s u bject s 
selecte d f or e nr oll me nt b y t he I n v esti gat or ( or d esi g nee). 
S u bjects w h o meet all t he i ncl usi o n criteria a n d f or w h o m n o ne of t he e xcl usi o n criteria a p pl y 
will be eli gi ble t o be e nr olle d i nt o t he st u d y. Safet y e val uati o ns ma y be re peate d at t he 
discreti o n  of t he I n v esti gat or ( or desi g n ee) or S p o ns or. 
4. 3.  
I ncl usi o n Criteri a 
S u bjects w h o meet t he f oll o wi n g criteria at Scree ni n g a n d C hec k -i n ( D a y - 1), u nless 
ot her wise s pecifie d, ma y be i ncl u de d i n t he st u d y: 
1.  Males, a n d fe m ales of n o n -c hil d beari n g p ote ntial, bet wee n 1 8 a n d 5 5 years of a ge, 
i ncl usi ve, at Scree ni n g. 
2.  Wit hi n B MI ra n g e 1 8. 0 t o 3 2. 0 k g/ m
2, i ncl usi ve. 
3.  I n g o o d h ealt h, deter mi ne d b y n o cli nicall y si g nifica nt fi n di n gs fr o m me dical hist or y, 
p h ysical e xa mi nati o n, 1 2- lea d E C G, vital si g n meas ure me nts, or cli nical la b orat or y 
e val uati o ns (A p pe n di x 4 ) at Scree ni n g a n d/ or C hec k-i n ( Da y - 1) as assesse d b y t he 
I n v esti gat or ( or d esi g nee). 
4.  Fe male s u bjects of n o n- c hil dbeari n g p ote ntial, defi ne d as bei n g per m a ne ntl y sterile 
(ie, d ue t o h ysterect o m y, bilateral t u bal li gati o n, bilateral sal pi n gect o m y, bil ateral 
o o p h orect o m y, or c o nfir me d t u bal occl usi o n m ore t ha n 6 m o nt hs pri or t o Da y 1) or 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 4 of 6 8 
p ost- me n o pa usal ( defi ne d as at l east 1 2 m o nt hs p ost-cessati o n of me nses wit h o ut a n 
alter nati ve me dical ca us e). P ost - me n o pa usal stat us will be c o nfir me d wit h a scree ni n g 
ser u m F S H le vel c o nsiste nt wit h p ost- me n o pa usal stat us per t he la b orat or y’s refere nce 
ra n ges. All fe m ale s u bjects m ust ha ve a ne gati ve q ualitati ve ser u m pre g n a n c y test 
(ser u m h u ma n c h ori o nic g o na d otr o pi n; ser u m q ua ntitati ve h u ma n c h ori o nic 
g o na d otr o pi n tests ma y be use d f or c o nfir mati o n as nee de d) at Scree ni n g a n d 
C hec k -i n ( Da y -1). Fe male s u bjects are re q uire d t o refrai n fr o m d o nati o n of o va fr o m 
C hec k -i n ( Da y - 1) u ntil 6 m o nt hs after Da y 1 9 ( or last a d mi nistrati o n of st u d y dr u g if 
s u bject ter mi nates fr o m t he st u d y earl y).  
5.  Male s u bjects w h o are ca pa ble of fat heri n g a c hil d m ust a gree t o use 1 of t h e 
f oll o wi n g met h o ds of c o ntrace pti o n: 
a. Male sterilizati o n, wit h d oc u me nte d c o nfir mati o n of s ur gical s uccess. Male 
s u bjects will be s ur gicall y sterile f or at least 9 0 da ys pri or t o C hec k-i n 
( Da y - 1), or 
b.  If d oc u me ntati o n of s ur gi cal sterilizati o n is n ot a vaila ble, male s u bjects m ust 
f oll o w 1 of t he c o ntrace pti o n met h o ds bel o w fr o m Da y 1 t hr o u g h 6 m o nt hs 
after D a y 1 9 ( or l ast a d mi nistrati o n of st u d y dr u g if s u bject ter mi nates fr o m 
t he st u d y earl y): 
i. Male c o n d o m wit h s per mici de, or 
ii. A male s u bject m ust e ns ure t hat t heir fe male part ner me ets 1 of t he 
f oll o wi n g criteria: 
1.  i ntra uteri ne de vice (I U D) ( h or m o nal I U D; e g, Mire na® ). 
C o p per I U Ds are acce pta ble (e g, Para Gar d ® ); or 
2.  esta blis he d use of oral, i m pla nte d, i njecte d, tra ns der mal, 
i ntra va gi nal, or h or m o nal met h o d of c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n; or 
3.  n o n-c hil d beari n g p ote nti al, defi ne d as b ei n g per m a ne ntl y sterile 
(ie, d ue t o h ysterect o m y, bilateral t u bal li gati o n, bilateral 
sal pi n gect o m y, bilateral o o p h orect o m y, or c o nfir me d t u bal 
occl usi o n m ore t ha n 6 m o nt hs pri or t o Da y 1 f or male part ner); 
or 
4.  be p ost- me n o pa usal wit h a me n orr h ea f or at least 1  year pri or t o 
Da y 1 a n d F S H ser u m le vels c o nsiste nt wit h p ost- me n o pa usal 
stat us. 
Male s u bjects w h o pr acti ce tr ue a bsti ne nce b eca us e of a lifest yle c h oice (i e, d o n ot 
bec o me a bsti ne nt j ust f or t he p ur p ose of st u d y partici pati o n) are e xe m pt fr o m 
c o ntrace pti ve re q uir e me nts. Peri o dic a bsti ne nce b y a fe male p art ner (e g, cal e n dar, 
o v ulati o n, s y m pt ot her mal, p ost- o v ulati o n met h o ds) a n d wit h dra w al are n ot acce pta ble 
met h o ds of c o ntrace pti o n. If a male s u bject is a bsti ne nt at t he ti me of si g ni n g t he I C F 
b ut bec o mes se x uall y acti ve fr o m C hec k-i n ( Da y - 1) t hr o u g h 6 m o nt hs after Da y 1 9 
( or last a d mi nistrati o n of st u d y dr u g if s u bject ter mi nates fr o m t he st u d y earl y), he 
m ust a gree t o  use c o ntrace pti o n as descri be d a b o v e. 
F or male s u bjects, se x ual i nterc o urse wit h fe male part ners w h o are pre g n a nt, or 
breastfee di n g s h o ul d be a v oi de d fr o m C hec k-i n ( D a y - 1) t hr o u g h 6 m o nt hs after 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 5 of 6 8 
Da y  1 9 ( or last a d mi nistrati o n of st u d y dr u g if s u bject ter mi nates fr o m t he st u d y 
earl y), u nless t he m ale s u bject uses a c o n d o m wit h s per mici de. Male s u bjects are 
re q uire d t o r efr ai n fr o m d o nati o n of s per m fr o m C hec k-i n ( D a y - 1) u ntil 6 m o nt hs 
after D a y 1 9 ( or l ast a d mi nistrati o n of st u d y dr u g if s u bject ter mi nates fr o m t he st u d y 
earl y).  
F or s u bjects w h o are e xcl usi vel y i n sa me-se x rel ati o ns hi ps, c o ntrace pti ve 
re q uire me nts d o n ot a p pl y. 
6.  A ble t o u n dersta n d a n d pr o vi de writte n i nf or me d c o nse nt. 
7.  A ble t o c o m pl y wit h all st u d y pr oce d ures, i ncl u di n g t he 2 3- ni g ht sta y at t he C R U a n d 
f oll o w- u p p h o ne call. 
4. 4.  
E xcl usi o n Criteri a  
T he f oll o wi n g will e xcl u de p ote ntial s u bjects fr o m t he st u d y: 
1.  Hist or y or prese n ce of a n y of t he f oll o wi n g, dee m e d cli nicall y si g nifica nt b y t he 
I n v esti gat or ( or d esi g nee), a n d/ or S p o ns or: 
a. li ver disease 
b.  pa ncreatitis  
c. pe ptic ulcer disease  
d.  i ntesti nal mala bs or pti o n 
e. c h olec ystect o m y  
f. gastric re d u cti o n s ur ger y 
g.  hist or y or pres e n ce of cli nicall y si g nifica nt car di o vasc ular disease:  
i. m y ocar dial i nfarcti o n or cere br o vasc ul ar t hr o m b o e m b olis m wit hi n 
6 m o nt hs pri or t o Da y 1  
ii. s y m pt o matic a n gi na pect oris wit hi n 6 m o nt hs pri or t o Da y 1 
iii. c o n gesti ve heart fail ure ≥ sta ge 2 per N e w Y or k H eart Ass ociati o n 
Classificati o n wit hi n 6  m o nt hs pri or t o Da y 1 
i v. c o n ge nital pr ol o n ge d Q T s y n dr o me  
v.  ve ntric ular pr e- e xcitati o n s y n dr o me ( W olff- Par ki ns o n W hite 
s y n dr o me) 
vi.  arr h yt h mia (e x cl u di n g be ni g n si n us arr h yt h mia) or hist or y of 
arr h yt h mia re q uiri n g me dical i nter ve nti o n wit hi n 6 m o nt hs pri or t o 
Da y 1  
vii.  ve ntric ular d ysf u n cti o n or ris k fact ors f or T ors a des de P oi ntes (e g, 
heart f ail ure, car di o m y o p at h y, fa mil y hist or y of L o n g Q T S y n dr o me)  
viii.  E C G a b n or malities t hat are cli nicall y si g nifica nt at Scree ni n g, 
C hec k -i n ( Da y -1),  or pre d ose o n Da y 1, i ncl u di n g, b ut n ot li mite d t o: 
1.  c o m plete left b u n dle- bra nc h bl oc k  


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 6 of 6 8 
2.  sec o n d- de gree atri o ve ntri c ular ( A V) bl oc k, t y pe 2, or 
t hir d- de gree A V bl oc k 
3.  Q T i nter val c orrecte d f or heart rate ( H R) usi n g Fri dericia’s 
met h o d ( Q Tc F) > 4 5 0 ms ec  
S u bjects wit h o ut- of-ra n g e E C G val ues or a b n or m al E C G 
fi n di n gs t hat are n ot cli nicall y si g nifica nt will be per mitte d t o 
ha ve E C Gs re p eate d u p t o 2 ti mes d uri n g Scree ni n g, C hec k-i n 
( Da y - 1), a n d pre d ose o n Da y 1 t o c o nfir m eli gi bilit y f or st u d y 
partici pati o n,  if t he re p eat val ue(s) are n or mal/fall o utsi de of 
t he ra n ges state d a b o ve. 
2.  S u bjects wit h o ut- of- ra n g e, at-rest (ie, s u pi ne f or at least 5 mi n utes) vital si g n 
meas ure me nts at Scree ni n g, C hec k -i n ( D a y - 1), or pri or t o d osi n g o n Da y 1. 
O ut - of-r a n ge vital si g n meas ure m e nts are d efi ne d as:  
a. b o d y te m perat ur e > 3 7. 5° C; 
b.  p ulse rate <  5 0 or > 9 9 b eats per mi n ute ( b p m); 
c. s yst olic B P < 8 9 or > 1 3 9 m m H g;  
d.  diast olic B P <  5 0 or > 8 9 m m H g;  
e. o x y ge n sat urati o n < 9 5 % (r o o m air).  
S u bjects wit h o ut- of- ra n g e val ues f or t h ese para meters t hat are n ot cli nicall y 
si g nifica nt will be per mitte d t o ha ve vital si g n meas ure me nts re peat e d u p t o 2 ti mes 
d uri n g Scree ni n g, C hec k-i n ( Da y - 1), a n d pre d ose o n Da y 1 t o c o nfir m eli gi bilit y f or 
st u d y partici pati o n if t he re peat v al ue(s) are n or mal/fall o utsi de of t he ra n ges state d 
a b o ve.  
3.  Hist or y or prese n ce of cli nicall y si g nifica nt me dical or ps yc hiatric c o n diti o n or 
disease i n t he o pi ni o n of t he I n v esti gat or ( or d esi g nee), or m e ntall y or le gall y 
i nca pacitate d or has si g nifica nt e m oti o nal pr o ble ms at t he ti me of t he Scree ni n g visit 
or e x pect e d d uri n g t he c o n d uct of t he st u d y. 
4.  Cli nicall y si g nifica nt a b n or malit y, as deter mi ne d b y t he I n v esti gat or ( or d esi g nee), 
fr o m p h ysical e xa mi nati o n at C hec k-i n ( D a y -1).  
5.  A b n or mal la b orat or y v al ues ( he mat ol o g y pa n el, U A, cli nical c h e mistr y pa nel [faste d 
at least 8 h o urs]) t hat are cli nicall y si g nifica nt e xcl u di n g t h ose f urt her defi ne d i n 
e xcl usi o n criteria # 6 , # 7 , a n d # 8  at Scree ni n g a n d/ or C hec k-i n ( D a y - 1). S u bjects wit h 
o ut- of- ra n g e cli nical la b orat or y res ults t hat are n ot cli nicall y si g nifica nt (e x cl u di n g 
t h ose f urt her d efi ne d i n e xcl usi o n criteria #6 , # 7 , a n d # 8 ) ma y ha ve la b orat or y 
assess me nts re peate d at t he I n vesti gat or ( or desi g nee)’s discreti o n u p t o 2 ti mes 
d uri n g Scree ni n g a n d C h ec k-i n ( D a y - 1) t o c o nfir m eli gi bilit y f or st u d y partici pati o n 
if t he re peat val ue(s) fall wit hi n n or mal ra n ges or are sta bilizi n g. 
6.  A b n or mal li ver f u ncti o n tests ( L F Ts ) as defi ne d b y as partate a mi n otra nsferase , 
ala ni ne a mi n otra nsf eras e, a n d ser u m (t otal a n d direct) bilir u bi n, as well as a m ylase, or 
li pase a b o ve t he u p p er li mit of t he n or mal ra n ge p er t he la b orat or y’s refere nce ra n g es 
at Scree ni n g or C hec k -i n ( Da y - 1). S u bjects wit h o ut- of-ra n g e L F Ts, a m ylase, a n d 
li pase val ues a b o v e t he u p per li mit of n or mal t hat are n ot cli nicall y si g nifica nt will be 
per mitte d t o ha ve L F Ts, a m ylase, or li pase assess me nts re peat e d u p t o 2 ti mes d uri n g 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 7 of 6 8 
Scree ni n g a n d C hec k-i n ( Da y - 1) t o c o nfir m eli gi bilit y f or st u d y partici pati o n if t he 
re peat v al ue(s) fall wit hi n n or mal ra n ges.  
7.  Creati ne ki nase v al ues a b o ve t he u p per li mit of t he n or mal ra n ge p er t he la b orat or y’s 
refere nce r a n ges t hat are cli nicall y si g nifica nt at Scree ni n g or C hec k-i n ( Da y - 1). 
S u bjects wit h o ut- of- ra n g e creati ne ki nase v al ues t hat are n ot cli nicall y si g nifica nt 
will be per mitte d t o ha ve t he creati ne ki nase ass ess me nts re peate d u p t o 2  ti mes 
d uri n g Scree ni n g a n d C h ec k-i n ( D a y - 1) t o c o nfir m eli gi bilit y f or st u d y partici pati o n 
if t he re peat val ue(s) ar e sta ble or n or malizi n g. 
8.  Esti mate d gl o mer ular filtrati o n rate (e G F R) ≤ 8 0 m L/ mi n ute/ 1. 7 3 m2 calc ulate d usi n g 
t he C K D-E PI e q uati o n at Scree ni n g  or C hec k-i n ( Da y - 1). S u bjects wit h o ut- of- ra n g e 
e G F R val u es t hat are n ot cli nicall y si g nifica nt will be per mitte d t o ha ve e G F R 
assess me nts re peate d u p t o 2 ti mes d uri n g Scree ni n g a n d C hec k-i n ( Da y - 1) t o 
c o nfir m eli gi bilit y f or st u d y partici pati o n if t he re p eat val ue(s) fall a b o v e t h e ra n ge 
state d a b o ve.  
9.  H b A 1c ≥ 6. 5 % at Scree ni n g. S u bjects wit h o ut- of- ra n ge H b A 1c val u es t hat are n ot 
cli nicall y si g nifica nt will be per mitte d t o ha ve H b A 1c assess me nts re peat e d u p t o 2 
ti mes d uri n g Scree ni n g t o c o nfir m eli gi bilit y f or st u d y partici pati o n if t he re peat 
val ue(s) f all bel o w t he r a n ge state d a b o ve. 
1 0.  P ositi ve ser ol o gic test f or H Bs A g, H B V I g M c ore a nti b o d y, H C V a nti b o d y, or HI V 
a nti b o d y at Scree ni n g. S u bjects w h o are p ositi ve f or H B V I g M c ore a nti b o d y or H C V 
a nti b o d y re q uire c o nfir m ati o n b y P C R bef ore e nr o ll me nt t o detect prese nce of acti ve 
vir us. S u bjects w h o are H B V c ore a nti b o d y or H C V a nti b o d y p ositi ve or f or w h o m a 
P C R is u na ble t o be o btai ne d will n ot be eli gi ble. 
1 1.  P ositi ve P C R test ( or e q ui vale nt) f or C O VI D- 1 9 at Scree ni n g or C hec k-i n ( Da y - 1). 
F urt he r d etails re g ar di n g C O VI D- 1 9 testi n g (i ncl u di n g pr oce d ures f or s u bjects w h o 
test p ositi ve at a n y ti me t hr o u g h o ut C R U c o nfi ne me nt) are s p ecifie d i n a se parat e 
d oc u me nt.   
1 2.  Hist or y of c o n ge nital n o n- he m ol ytic h y per bilir u bi ne mia (e g, Gil bert’s s y n dr o me). 
1 3.  Si g nif ica nt hist or y or cli nical ma nifestati o n of a n y aller gic, der mat ol o gical, biliar y, 
he patic, gastr oi ntesti nal, re nal, meta b olic, h e mat ol o gical , p ul m o nar y, car di o vasc ular 
(i ncl u di n g a n y pri or hist or y of car di o m y o pat h y or heart fail ure), n e ur ol o gical, or 
ps yc hiatric dis or der (as d eter mi ne d b y t he I n v esti gat or [ or desi g n ee]), or ca ncer 
wit hi n t he past 5  years ( e xce pt l ocalize d b asal cell, s q ua m o us, or i n sit u ca ncer of t h e 
s ki n). N ote: s u bjects wit h a hist or y of a p pe n d ect o m y a n d/ or her nia re pairs will be 
acce pta ble.  
1 4.  Hist or y or prese n ce, u p o n cli nical e val uati o n, of a n y ill ness t hat, i n t he o pi ni o n of t he 
I n v esti gat or ( or d esi g nee), w o ul d i nterfere wit h t h e a bilit y t o pr o vi de i nf or me d 
c o nse nt or c o m pl y wit h st u d y i nstr ucti o ns, or t hat mi g ht c o nf o u n d t he i nter pretati o n 
of t he st u d y res ults, or p ut t he s u bject at u n d ue ris k. 
1 5.  Hist or y of a maj or s ur gical pr oce d ure wit hi n 3 0 da ys pri or t o Scree ni n g. 
1 6.  K n o w n o n g oi n g alc o h ol a n d/ or dr u g a b us e wit hi n 2 years pri or t o Scree ni n g, or 
e vi de nce of s uc h a b us e as i n dicate d b y t he la b orat or y assa ys f or dr u gs of a b use 
(i ncl u di n g c oti ni ne a n d alc o h ol) c o n d ucte d d uri n g Scree ni n g a n d/ or at C hec k-i n 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 8 of 6 8 
( Da y - 1). Tests f or dr u gs of a b use m ust be ne g ati ve at b ot h Scree ni n g a n d C hec k-i n 
( Da y -1).  
1 7.  Use of t o bacc o, s m o ki n g-cessati o n pr o d u cts, or pr o d ucts c o ntai ni n g nic oti ne a n d 
e-ci garettes ( nic oti ne a n d n o n- nic oti ne), wit hi n 3 m o nt hs pri or t o Scree ni n g a n d 
t hr o u g h E O T or E T. 
1 8.  Use or i nte nti o n t o use a n y prescri pti o n or o ver-t he-c o u nter me dicati o ns (i ncl u di n g 
b ut n ot li mite d t o a n y m o derate or str o n g C Y P 3 A 4 a n d/ or C Y P 3 A 5 i n hi bit ors or 
i n d ucers [i ncl u di n g her bal pr o d ucts s uc h as St. J o h n’s w ort], C Y P 2 C 8 s u bstrates, 
str o n g P- g p i n hi bit ors, pr ot o n p u m p i n hi bit ors, a ntaci ds, H 2-rece pt or a nta g o nists, a n d 
dr u gs t hat pr ol o n g Q T/ Q Tc i nter val, vita mi n s u p ple m e nts, caffei ne [ wit h t he 
e xce pti o n of caff ei ne a d mi nistere d f or t he p ur p os es of t his st u d y/i n acc or d a nce wit h 
t he pr ot oc ol], her b al pr o d ucts, nat ural or her bal s u p ple me nts, a n d 
h or m o ne- re pl ace m e nt t hera p y [ H R T]) fr o m 1 4 da ys pri or t o Da y 1 or 5 half-li ves (if 
k n o w n, w hic he ver is l o n ger [e x ce pt f or paracet a m ol/aceta mi n o p he n ma xi m u m of 
2 g/ da y f or u p t o 3 c o nsec uti ve da ys d uri n g t he st u d y]) t hr o u g h E O T or E T, u nless 
dee me d acce pta ble b y t h e I n vesti gat or ( or desi g nee) a n d S p o ns or. 
1 9.  C o ns u m pti o n of gra pefr uit/ gra pefr uit j uice or Se ville ora n ges or its j uice wit hi n 
7 da ys pri or t o C hec k- i n ( Da y - 1) a n d t hr o u g h E O T or E T. 
2 0.  C o ns u m pti o n of alc o h ol-c o ntai ni n g f o o ds or be vera ges or caffei ne-c o ntai ni n g f o o ds 
or be ver a ges (i n cl u di n g b ut n ot li mite d t o teas [i ncl u di n g decaf fei nate d teas], c offees 
[i ncl u di n g decaffei nat e d c offees], c ol as [i ncl u di n g decaffei nat e d c olas], e ner g y 
dri n ks, g u m c o ntai ni n g caffei n e, c h oc ol ate, a n d f o o ds a n d be vera ges c o ntai ni n g 
c h oc olate) wit hi n 7 2 h o urs pri or t o C hec k- i n ( Da y - 1) a n d t hr o u g h E O T or E T.  
2 1.  Hist or y of si g nifica nt h y perse nsiti vit y, i nt olera nce, or aller g y t o a n y dr u g c o m p o u n d, 
f o o d, or ot her s u bsta n ce, u nless a p pr o ve d b y t he I n vesti gat or ( or desi g nee). 
2 2.  Has bee n o n a diet i nc o m pati ble wit h t he o n-st u d y diet, i n t he o pi ni o n of t he 
I n v esti gat or ( or d esi g nee), wit hi n t he 3 0 da ys pri or t o Da y 1 a n d t hr o u g h E O T or E T. 
2 3.  Partici pati o n i n a n y ot her i n vesti gati o nal st u d y dr u g trial i n v ol vi n g a d mi nistrati o n of 
a n y i n vesti gati o nal dr u g i n t he past 3 0 da ys or 5 half-li ves (if k n o w n), w hi c he ver is 
l o n ger, pri or t o Da y 1. 
2 4.  Has pre vi o usl y recei ve d L O X O- 3 0 5 i n a n y ot her st u d y i n vesti gati n g L O X O- 3 0 5, 
wit hi n 3 0 da ys pri or t o Da y 1. 
2 5.  Stre n u o us e xer cise wit hi n 5 da ys pri or t o C hec k- i n ( Da y - 1) a n d t hr o u g h E O T or E T. 
2 6.  P o or peri p her al ve n o us access. 
2 7.  D o nati o n of bl o o d fr o m 5 6 da ys pri or t o Scree ni n g, plas ma or platelets fr o m 4 wee ks 
pri or t o Scree ni n g. 
2 8.  Recei pt of bl o o d pr o d ucts wit hi n 2 m o nt hs pri or t o C hec k- i n ( D a y -1).  
2 9.  S u bjects w h o, i n t he o pi ni o n of t he I n vesti gat or ( or desi g nee), s h o ul d n ot p artici pate 
i n t his st u d y. 
3 0.  S u bject w h o are n o n- a n d sl o w C Y P 2 C 9 ( C Y P 2 C 9 * 2/ * 3 or C Y P 2 C 9 * 3/ * 3 
ge n ot y pes) a n d C Y P 2 C 1 9 ( C Y P 2 C 1 9 * 2/ * 2, C Y P 2 C 1 9 * 2/ * 3, or C Y P 2 C 1 9 * 3/ * 3 
ge n ot y pes) meta b olizers as deter mi ne d b y g e n ot y pi n g at Scree ni n g.  


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 9 of 6 8 
4. 5.  
S u bject N u m ber a n d I de nt ific ati o n 
S u bject n u m bers will c o nsist of 6 di gits i n w hic h t he first set of 3 di gits will i de ntif y t he site 
a n d t he sec o n d s et of 3 di gits will i de ntif y t he s u bject (e g, 0 0 1- 1 0 1).  
F or s u bjects w h o are wit h dra w n b y t he I n v esti gat or ( or desi g nee) or v ol u nt aril y wit h dra w 
pre mat urel y fr o m t he st u d y, re place me nt s u bjects will be e nr olle d o nl y if d ee me d necessar y 
b y t he S p o ns or.  
If necessar y, as deter mi n e d b y t he S p o ns or, s u bjects w h o fail t o c o m plete t he treat me nt or 
ha ve i ns ufficie nt P K dat a ma y be re place d.  Re pl ace me nt s u bjects will be assi g ne d a s u bject 
n u m ber b y a d di n g 2 0 0 t o t he last 3 di gits of t he s u bject n u m ber f or t h e s u bject t he y are 
re placi n g ( e g, S u bject N u m ber 0 0 1- 3 0 1 re places S u bject N u m ber 0 0 1- 1 0 1). 
S u bjects w h o are d eter mi ne d t o be scr ee n fail ures are per mitte d t o be re -s cree ne d if t he 
I n v esti gat or ( or d esi g nee), wit h a gree me nt fr o m t he S p o ns or, feels t hat t he s u bject ma y meet 
eli gi bilit y criteria u p o n re -scr ee n. Re-s cree ne d s u bjects will be pr o vi de d a ne w s u bject 
n u m ber as defi n e d a b o ve. 
4. 6.  
Re m o v a l of S u bjects fr o m St u d y P artici p ati o n 
S u bjects will be i nf or me d t hat t he y are free t o 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. T he I n v esti gat or ( or desi g n ee) ma y re m o ve a s u bject fr o m t he st u d y if, i n t he 
I n v esti gat or’s ( or desi g nee’s) o pi ni o n, it is n ot i n t he best i nterest of t he s u bject t o c o nti n ue 
t he st u d y. S u bjects ma y be wit h dra w n b eca us e of t he f oll o wi n g:  
•  c ha n ge i n c o m plia n ce wit h i ncl usi o n/e xcl usi o n criteri o n t hat is cli nicall y rele va nt a n d 
affects s u bject saf et y  
•  occ urr e nce of A Es  
•  occ urr e nce of pr e g na nc y 
•  n o n- c o m plia nce wit h st u d y restricti o ns  
•  i nta ke of n o n-per mitte d c o nc o mita nt me dicati o n t hat mi g ht affect s u bject safet y or 
st u d y assess me nts/ o bjecti ves, etc. 
N otificati o n of wit h dra w al will i m me diatel y be ma de t o t he S p o ns or. I n cas e of wit h dra w al, 
eff orts will be ma d e t o perf or m all E T assess me nts ( A p pe n di x 4 ). T he d ate t he s u bject is 
wit h dra w n fr o m t he st u d y a n d t he reas o n f or wi t h dra wal will be rec or d e d o n t he s u bject’s 
electr o nic Cas e Re p ort F or m (e C R F). All wit h dra w n s u bjects wit h A Es t hat are assess e d as 
relate d t o st u d y dr u g a n d w hic h are o n g oi n g at E T ma y c o nti n ue t o be f oll o we d u ntil t he 
s y m pt o ms or val ue(s) ret ur n t o n or mal, or acce pta ble le vels, as j u d ge d b y t he I n vesti gat or ( or 
desi g nee) a n d c o nfir m e d b y t he S p o ns or. 
T he e ntire st u d y ma y be disc o nti n ue d at t he discreti o n of t he I n v esti gat or ( or desi g nee) or 
S p o ns or, base d o n t he occ urre n ce of t h e f oll o wi n g: 
•  A Es u n k n o w n t o date wit h res pect t o t heir n at ure, se verit y, a n d/ or d urati o n 
•  i ncreas e d fr e q ue nc y a n d/ or se verit y a n d/ or d urati o n of k n o w n A Es 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 0 of 6 8 
•  me dical or et hical reas o ns affecti n g t he c o nti n ue d perf or ma n ce of t he st u d y  
•  diffic ulties i n t he recr uit me nt of s u bjects  
•  ca ncellati o n of dr u g de v el o p me nt. 
I n t he e ve nt t hat t he st u d y is ter mi nate d earl y, t he S p o ns or or its desi g nee will pr o vi de 
s pecific g ui da n ce t o t he C R U re gar di n g t he E O S pr oce d ures. 
 
 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 1 of 6 8 
5.  S T U D Y T R E A T M E N T S  
5. 1.  
Descri pti o n, St or a ge, P ac k a gi n g, a n d L a beli n g 
T he S p o ns or ( or desi g nee) will pr o vi de t he I n v esti gat or ( or desi g nee) wit h a de q uate 
q ua ntities of L O X O - 3 0 5. C o va nce will pr oc ure a d e q uate q ua ntities of caffei ne, o me praz ol e, 
warf ari n , a n d vita mi n K (Ta ble  2). 
T a ble 2: St u d y Dr u gs  
St u d y Dr u g  
F or m a 
Stre n gt h  
S u p plier  
M a n uf act urer
b 
L O X O - 3 0 5 
Ta blet  
2 × 1 0 0 m g  
L o x o 
O nc ol o g y, I nc.  
Catale nt Sa n Die g o or L o nza 
P har ma & Bi otec h  
C affei ne  
Ta blet  
2 0 0 m g  
Mc Kess o n  
Me da C o ns u mer Healt h  
O me pr az ole 
Ca ps ule 
4 0 m g  
Mc Kess o n  
Sa n d oz 
W arf ari n 
Ta blet  
1 0 m g  
Mc Kess o n  
Tar o  
Vit a mi n K  
Ta blets  
2 × 5 m g  
Mc Kess o n  
Valea nt P har mace uticals  
 a S pecific i n gre die nts/ p urit y will be i de ntifie d i n t he Certificate of A nal ysis ( or e q ui vale nt) t hat is s u p plie d wit h 
t he st u d y dr u g(s). 
b T he ma n ufact urer will be c o nfir me d b y t he site at t he ti me of dr u g pr oc ure me nt.  
T he ta blets c o ntai ni n g 1 0 0 m g L O X O - 3 0 5 will be s u p plie d b y t he S p o ns or ( or desi g nee), 
al o n g wit h t he batc h/l ot n u m bers a n d Certificate of A nal ysis. It will be pr o vi de d i n 
hi g h- de nsit y p ol yet h yle ne b ottles a n d will be st ore d acc or di n g t o t he i nstr ucti o ns o n t he la bel. 
T he pr o be dr u g c oc ktail st u d y dr u gs will be s u p plie d b y C o va nce, al o n g wit h t he l ot n u m bers. 
T he pr o be dr u g c oc ktail st u d y dr u gs will be pr o vi de d i n hi g h- de nsit y p ol yet h yle ne b ottles 
( o me praz ole a n d w arf ari n) a n d blister pac ks (caffei ne) a n d will be st ore d acc or di n g t o t he 
i nstr ucti o ns o n t he pac ka ge i nsert.  
Vita mi n K ta blets will be s u p plie d b y C o va nce, al o n g wit h t he l ot n u m bers. T he vita mi n K 
ta blets will be pr o vi de d i n hi g h- de nsit y p ol yet h yle ne b ottles a n d will be st ore d acc or di n g t o 
t he i nstr ucti o ns o n t he pac ka ge i nsert.  
St u d y dr u gs will be st ore d at t he C R U i n a l ocati o n t hat is l oc ke d wit h restricte d access. 
T he b ul k dr u g c o ntai ner a n d u nit d ose c o ntai ners will be la bele d i n acc or d a nce wit h nati o nal 
la ws a n d re g ul ati o ns. T he st u d y dr u gs will be st ore d i n acc or da nce wit h t he la beli n g. T he 
st u d y dr u gs will be tra nsf erre d fr o m b ul k s u p plies i nt o t he s u bject’s d ose c o ntai ner b y 
q ualifie d C R U e m pl o yees. Eac h u nit d ose c o ntai n er will be a p pr o priatel y l a bele d. 
5. 2.  
St u d y Tre at m e nt A d mi nistr ati o n  
S u bjects will r ecei ve eac h of t he f oll o wi n g treat m e nts t hr o u g h o ut t he st u d y: 
•  I n Peri o d 1, Da y 1, 2 0 0 m g caffei ne (ta blet), 4 0  m g o me praz ole (ca ps ule), a n d 1 0 m g 
warf ari n (ta blet)  will be a d mi nistere d as a si n gle d ose of pr o be dr u g c oc kt ail, al o n g 
wit h 1 0 m g vita mi n K ( 2  × 5 m g ta blets), i n t he m or ni n g f oll o wi n g a fast of at least 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 2 of 6 8 
1 0 h o urs pre d ose a n d 2 h o urs p ost d ose. Water will be restricte d f or 1 h o ur pri or t o a n d 
1 h o ur after d osi n g wit h t he e xce pti o n of water a d mi nistere d f or d ose a d mi nistrati o n. 
•  I n Peri od 2, o n Da ys 6 t hr o u g h 1 9, oral d oses of 2 0 0 m g ( 2  × 1 0 0 m g ta blets) 
L O X O - 3 0 5 will be a d mi nistere d Q D f or 1 4 c o nsec uti ve da ys i n t he m or ni n g at t he 
act ual ti me of t he D a y  1 pr o be dr u g c o c ktail d osi n g ( ± 1 h o ur). O n D a y 1 5, 
L O X O -3 0 5 will be c o a d mi nistere d w it h 2 0 0 m g caffei n e (ta blet), 4 0  m g o me praz ole 
(ca ps ule), a n d 1 0 m g warfari n (ta blet) a d mi nistere d as a si n gle d ose of pr o b e dr u g 
c oc ktail, al o n g wit h 1 0 m g vita mi n K ( 2  × 5 m g ta blets), at t he act ual ti me of t he Da y 
1 pr o be dr u g c o c ktail d osi n g ( ± 1 h o ur) f oll o wi n g a fast of at least 1 0 h o urs pre d ose 
a n d 2 h o urs p ost d ose. O n Da ys 7 t hr o u g h 1 1, a n d Da ys 1 3, 1 4, 1 6, 1 8, a n d 1 9, 
s u bjects will fast f or at least 2 h o urs pre d ose a n d 1 h o ur p ost d ose. O n Da ys 6, 1 2, a n d 
1 7 w here cli nical la b or at or y e val uati o ns are perf or me d, s u bjects will fast f or at least 
8 h o urs pre d ose a n d 1 h o ur p ost d ose. Water will be restricte d f or 1 h o ur pri or t o a n d 1 
h o ur after d osi n g wit h t h e e xce pti o n of water a d mi nistere d f or d ose a d mi nistrati o n. 
All st u d y dr u gs will be a d mi nistere d orall y wit h a p pr o xi matel y 2 4 0 m L of water . A n 
a d diti o nal 1 0 0 m L of wat er ma y be a d mi nistere d if nee de d. Water will be restricte d f or 
1- h o ur pre d os e a n d 1- h o ur p ost d ose, wit h t he e xce pti o n of water a d mi nistere d f or d os e 
a d mi nistrati o n.  
Eac h u nit d ose will be pr e pare d b y q u alifie d C R U staff.  
A p pr o priate u nit d ose(s), as descri be d a b o ve, will be a d mi nistere d t o s u bjects. Alt h o u g h t he 
ti mi n g of e ve nts re q uires t hat eac h s u bject will be a d mi nistere d t he a p pr o priate d ose at a 
s pecific ti me, t he e x act d ose ti me of su bjects ma y be sta g gere d t o o b viate t he nee d t o ha v e all 
s u bjects o n precisel y t he sa me st u d y sc he d ule. F or eac h d ose, t h e s u bject’s act ual d ose ti me 
will be rec or d e d i n t he s o urce d oc u m e nts a n d tra ns cri be d i nt o t he e C R F. 
S u bjects will be i nstr ucte d n ot t o  cr us h, s plit, or c he w t he st u d y dr u gs. 
S u bjects will n ot la y s u pi ne f or 4 h o urs f oll o wi n g L O X O- 3 0 5 d ose a d mi nistrati o n, e xce pt as 
necessitate d b y t he o cc urre nce of a n A E(s) a n d/ or st u d y pr oce d ure(s). 
5. 3.  
R a n d o miz ati o n 
T his is a n o n-ra n d o mize d st u d y. T he st u d y has a fi xe d treat me nt se q u e nce.  
5. 4.  
Bli n di n g  
T his is a n o pe n-la bel st u d y. 
5. 5.  
Tre at m e nt C o m pli a nce  
T he f oll o wi n g meas ur es will be e m pl o ye d t o e ns ure treat me nt c o m plia nce: 
•  All d oses will be a d mi nistere d u n der t he s u per visi o n of s uita bl y q ualifie d C R U staff. 
•  I m me diat el y after oral d ose a d mi nistrati o n, a vis ual i ns pecti o n of t he m o ut h a n d 
ha n ds will be perf or me d f or eac h s u bject. 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 3 of 6 8 
•  At eac h d ose pre p arati o n occasi o n, a pre d ose a n d p ost d ose i n ve nt or y of L O X O- 3 0 5 , 
caff ei ne, w arf ari n, vita mi n K, a n d o me praz ole  will be per f or me d. 
5. 6.  
Dr u g Acc o u nt a bilit y  
T he I n vesti gat or ( or desi g nee) will mai ntai n a n acc urate rec or d of t he recei pt of L O X O - 3 0 5, 
caff ei ne, w arf ari n, a n d vita mi n K ta blets, a n d t he o me praz ole ca ps ules recei ve d . I n a d diti o n, 
a n acc urate dr u g dis p ositi o n rec or d will be k e pt, s pecif yi n g t he a m o u nt dis pe nse d t o eac h 
s u bject a n d t he date of dis pe nsi n g. T his dr u g acc o u nta bilit y rec or d will be a vaila ble f or 
i ns pecti o n at a n y ti me. At t he c o m pleti o n of t he st u d y, t he ori gi nal dr u g acc o u nta bilit y rec or d 
will be a vaila ble f or re vi e w b y t he S p o ns or u p o n re q uest. 
F or eac h bat c h of u nit d oses, t he e m pt y use d u nit d ose c o ntai ners will be discar de d u p o n 
satisfact or y c o m pleti o n of t he c o m plia nce a n d acc o u nta bilit y pr oce d ures. A n y u n use d 
asse m ble d u nit d oses will be retai ne d u ntil c o m pleti o n of t he st u d y. 
At t he c o m pleti o n of t he st u d y, all u n use d L O X O- 3 0 5 ta blets will be dis p ose d of b y t he C R U, 
i n acc or d a nce wit h t he C R U’s Sta n dar d O perati n g Pr oce d ures ( S O Ps) a n d l ocal/state/fe deral 
g ui deli nes g o ver ni n g waste dis p osal of i n vesti gati o nal dr u gs, f oll o wi n g t he S p o ns or’s writte n 
a ut h orizati o n. T he caff ei ne,  warfari n, a n d vita mi n K ta blets a n d o me praz ol e ca ps ules will be 
dis p ose d of b y t he C R U i n acc or d a nce wit h t he C R U’s S O Ps.  
 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 4 of 6 8 
6.  C O N C O MI T A N T T H E R A PI E S A N D O T H E R R E S T RI C TI O N S  
6. 1.  
C o nc o mi t a nt T her a pies 
Paracet a m ol/aceta mi n o p he n ( ma xi m u m of 2  g/ da y f or u p t o 3 c o nsec uti ve da ys) is a n 
acce pta ble c o n c o mita nt me dicati o n.  
S u bjects will refrai n fr o m partici pati o n i n a n y ot her i n vesti gati o nal st u d y dr u g trial i n w hic h 
recei pt of a n y i n vesti gati o nal dr u g occ urs wit hi n 5 half -li ves (if k n o w n) or 3 0 da ys, 
w hic he ver is l o n ger, pri or t o Da y 1. 
All prescri pti o n me dicati o ns a n d o ver- t h e-c o u nter me dicati o ns i ncl u di n g b ut n ot li mite d t o: 
m o derate or str o n g C Y P 3 A 4 a n d/ or C Y P 3 A 5 i n hi bit ors or i n d ucers (i ncl u di n g her bal 
pr o d ucts s uc h as St. J o h n’s w ort), C Y P 2 C 8 s u bstrates, str o n g P- g p i n hi bit ors, pr ot o n p u m p 
i n hi bit ors, a ntaci ds, H2-rece pt or a nta g o nists, a n d dr u gs t hat pr ol o n g Q T/ Q Tc i nter val, her bal 
pr o d ucts, vita mi n s u p ple me nts,  nat ural or her bal s u p ple me nts, caffei ne ( wit h t he e xce pti o n of 
caff ei ne a d mi nistere d f or t he p ur p oses of t his st u d y/i n acc or da n ce wit h t he pr ot oc ol), a n d 
H R T are pr o hi bite d f or 1 4 da ys or 5 half-li ves (if k n o w n; e xce pt f or 
paraceta m ol/aceta mi n o p he n as refer e nce d a b o ve), w hic he ver is l o n ger, pri or t o Da y 1 a n d 
t hr o u g h E O T or E T, u nless dee me d acce pt a ble b y t he, I n v esti gat or ( or d esi g nee), a n d 
S p o ns or. A n y me dicati o n ta ke n b y a s u bject d uri n g t he c o urse of t he st u d y, i ncl u di n g details 
of its d osa ge, a d mi nistrati o n, a n d t he reas o n f or its use, will be d oc u me nte d i n t he e C R F. 
T he a d mi nistrati o n of a n y c o nc o mita nt me dicati o n d uri n g t he st u d y is pr o hi bite d wit h o ut 
pri or a p pr o val of t he I n v esti gat or ( or desi g nee) a n d S p o ns or, u nless its use is dee me d 
necessar y i n a me dical e mer ge nc y. I n t his c ase, t h e use of t he c o nc o mita nt me dicati o n will be 
re p orte d as s o o n as is practical. 
6. 2.  
Diet, Fl ui d, a n d Acti vit y C o ntr ol 
S u bjects are r e q uire d t o r efrai n fr o m use of t o bacc o, s m o ki n g-cessati o n pr o d ucts, a n d 
nic oti ne-c o ntai ni n g pr o d ucts a n d e- ci garettes ( nic oti ne a n d n o n- nic oti ne) wit hi n 3  m o nt hs 
pri or t o Scree ni n g t hr o u g h E O T or E T. 
C o ns u m pti o n of f o o ds or be vera g es c o ntai ni n g gra pefr uit/ gra p efr uit j uice or Se ville ora n ges 
or its j uice wit hi n 7  da ys pri or t o C hec k-i n ( D a y - 1) a n d t hr o u g h E O T or E T will n ot be 
all o we d.  
C o ns u m pti o n of alc o h ol-c o ntai ni n g f o o ds or be vera ges or caffei ne-c o ntai ni n g f o o ds or 
be vera g es (i ncl u di n g b ut n ot li mite d t o teas [i ncl u di n g decaffei nate d teas], c offees [i ncl u di n g 
decaffei nat e d c offees], c olas [i ncl u di n g decaffei n ate d c olas], e ner g y dri n ks, g u m c o ntai ni n g 
caff ei ne, c h o c olate, a n d f o o ds a n d be vera ges c o ntai ni n g c h oc olate) wit hi n 7 2 h o urs pri or t o 
C hec k -i n ( Da y - 1) a n d t hr o u g h E O T or E T will n ot be all o we d. 
S u bjects will refrai n fr o m stre n u o us e xercise fr o m 5  da ys pri or t o C hec k-i n ( Da y -1) a n d 
d uri n g t he peri o d of c o nfi ne me nt at t he C R U a n d will ot her wise mai ntai n t heir n or mal le vel 
of p h ysical acti vit y t hr o u g h E O T or E T (ie, s h o ul d n ot be gi n a ne w e x ercis e pr o gra m or 
partici pate i n a n y u n us u all y stre n u o us p h ysical e x erti o n).  


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 5 of 6 8 
W hile c o nfi ne d at t he C R U, s u bjects will recei v e a sta n dar d diet at sc h e d ule d ti mes t hat d o 
n ot c o nflict wit h ot her st u d y- relate d acti vities. All st u d y dr u gs will be a d mi nistere d orall y 
wit h a p pr o xi matel y 2 4 0 m L of water . A n a d diti o nal 1 0 0 m L of  water m a y be a d mi nistere d if 
nee de d.  
Fasti n g re q uir e me nts a n d water r estricti o ns i n relati o n t o d osi n g are descri b e d i n Secti o n  3. 1  
a n d Secti o n  5. 2 .  
 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 6 of 6 8 
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  
7. 1.  
P h ar m ac o ki netic Assess m e nts  
7. 1. 1.  
P h ar m ac o ki netic Bl o o d S a m ple C ollecti o n a n d Pr ocessi n g  
Bl o o d sa m ples f or P K a n al ysis of eac h s u bstrate (caffei ne / para xa nt hi ne, o me praz ole, a n d 
S- warf ari n) a n d L O X O -3 0 5 plas ma le vels will be c ollecte d at t he ti me p oi nts s pecifie d i n 
A p pe n di x 4 . T he e x act ti me of t he st u d y dr u g a d mi nistrati o n a n d t he act ual ti me of bl o o d 
sa m pli n g f or P K a nal ysis will be rec or d e d o n t he e C R F. 
Pr ocessi n g, st ora ge, a n d s hi p pi n g i nstr ucti o ns f or t hese P K bl o o d sa m ples will be pr o vi de d i n 
a se par ate La b orat or y M a n ual. T he n u m ber of bl o o d sa m ples a n d t otal bl o o d v ol u me re q uire d 
f or P K testi n g is prese nte d i n A p pe n di x 3 . 
7. 1. 2.  
A n al y tic al Met h o d ol o g y 
Plas ma c o nce ntr ati o ns of eac h s u bstrat e (caffei ne / para xa nt hi ne, o m e praz ol e, a n d S-warfari n) 
a n d L O X O- 3 0 5 will be deter mi ne d usi n g vali date d bi oa nal ytical met h o ds. S pecifics of t he 
bi oa nal ytical met h o ds will be pr o vi de d i n a se parate d oc u m e nt.  
7. 2.  
Ge n ot y pi n g  
A bl o o d sa m ple f or ge n ot y pi n g t o e xcl u de s u bjects w h o are n o n- a n d sl o w C Y P 2 C 9  
( C Y P 2 C 9 * 2/ * 3 or C Y P 2 C 9 * 3/ * 3 ge n ot y pes) a n d C Y P 2 C 1 9 (C Y P 2 C 1 9 * 2/ * 2, C Y P 2 C 1 9 
* 2/ * 3, or C Y P 2 C 1 9 * 3/ * 3 ge n ot y pes) meta b olizers  will be c ollecte d at t he Scree ni n g.  
Bl o o d v ol u me re q uire d f or ge n ot y pi n g is prese nte d i n A p pe n di x 3 .  
7. 3.  
S afet y a n d T oler a bilit y Assess me nts 
Safet y e val uati o ns ma y b e re peate d at t he discreti o n of t he I n vesti gat or ( or desi g nee) or 
S p o ns or. 
E ver y eff ort will be ma d e t o sc he d ule a n d p erf or m t he pr oce d ures i n acc or da nce wit h t he 
n o mi nal ti me, gi vi n g c o nsi derati o ns t o a p pr o priate p ost ure c o n diti o ns, practical restricti o ns, 
a n d a n y ot her pr oce d ures t o be perf or m e d at t he sa me ti me p oi nt. T he or der of pri orit y f or 
sc he d uli n g pr oce d ures ar o u n d a ti me p oi nt is (i n or der of pri orit y): 
•  d osi n g 
•  P K bl o o d sa m pli n g 
•  vital si g n meas ure me nts *  
•  1 2- lea d E C Gs * 
•  bl o o d a n d uri ne sa m ples f or cli nical la b orat or y e v al uati o ns 
•  p h ysical e xa mi nati o n. 
* W he n vital si g n meas ur e me nts a n d 1 2- lea d E C Gs are sc h e d ule d at t he s a me ti me as P K 
bl o o d sa m pli n g, t he P K bl o o d sa m pli n g will be o btai ne d at t he sc h e d ule d ti me p oi nt, a n d t he 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 7 of 6 8 
vital si g n meas ure me nts f oll o we d b y 1 2- lea d E C Gs will be o btai ne d pri or t o a n d as cl ose as 
p ossi ble t o t he sc he d ule d P K bl o o d sa m pli n g. 
7. 3. 1.  
A d verse E ve nts  
A d verse e ve nt defi niti o ns; assi g n me nt of se verit y, ca usalit y, acti o n ta ke n, a n d o utc o me; a n d 
pr oce d ur es f or re p orti n g S A Es are detaile d i n A p p e n di x 1 . 
S u bjects will be as ke d a n o n-lea di n g H D Y F? q u esti o n s uc h as “ Ha v e t here bee n a n y c ha n ges 
i n y o ur healt h stat us si nce Scree ni n g/si nce y o u were last as ke d ?” at t he ti m e p oi nts s pecifie d 
i n A p pe n di x 4  (ie, at Scr ee ni n g [after t he I C F is si g ne d], at C hec k-i n [ Da y -1], at eac h 
p ost d ose vital si g n meas ure me nt, a n d at a n a p pr o priate ti me f or all ot her d a ys). S u bjects will 
als o be e nc o ura ge d t o v ol u ntaril y re p ort A Es occ urri n g at a n y ot her ti me t hr o u g h t he E O S. 
A d verse e ve nts, w het h er v ol u nteere d, i de ntifie d b y t he s u bject’s res p o ns es t o H D Y F? 
i n q uiries, or n ote d o n p h ysical e xa mi nati o n, E C G, vital si g n meas ure me nts, or cli nical 
la b orat or y e v al uati o ns, will be rec or d e d t hr o u g h o ut t he st u d y (ie, fr o m si g ni n g of t he I C F 
u ntil E O S [ or E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a 
f oll o w- u p p h o ne call]), eit her as s u bject me dical hist or y (if t he e ve nt is re p orte d as be gi n ni n g 
pri or t o si g ni n g of t he I C F or if t he e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 
a n d is assesse d as n ot r el ate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or d esi g nee]) or as A Es 
(if t he e ve nt o cc urs after si g ni n g of t he I C F b ut pri or t o st u d y dr u g a d mi nistrati o n on Da y  1 
a n d is assesse d as relate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or desi g nee], or if t h e e ve nt 
occ urs after st u d y dr u g a d mi nistrati o n o n Da y 1 t hr o u g h E O T or E T re gar dless of relati o ns hi p 
t o st u d y dr u g). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d as relate d t o st u d y dr u g b y 
t he I n v esti gat or ( or d esi g nee) are t o be re p ort e d. All S A Es t hat de vel o p fr o m t he ti me of I C F 
si g ni n g u ntil E O S ( or E T, if t he s u bject disc o nti n ues fr o m t he st u d y a n d d o es n ot c o m plete a 
f oll o w- u p p h o ne call) ar e t o be re p orte d. 
U nless a s u bject wit h dra ws c o nse nt or is wit h dra w n fr o m t he st u d y a n d d oes n ot c o m plete t he 
f oll o w- u p p h o ne call, all s u bjects m ust be f oll o we d u ntil E O S. S u bjects wit h A Es t hat are 
assesse d as r elate d t o st u d y dr u g b y t he I n vesti gat or ( or desi g nee) w hi c h are o n g oi n g at E O S 
ma y c o nti n ue t o be f oll o we d u ntil t he s y m pt o ms or val ue(s) ret ur n t o n or mal, or acce pta ble 
le vels, as j u d ge d b y t he I n vesti gat or ( or desi g nee) a n d c o nfir me d b y t h e S p o ns or. T he 
I n v esti gat or ( or d esi g nee) s h o ul d use a p pr o pri ate j u d g me nt i n or deri n g a d diti o nal tests as 
necessar y t o m o nit or t he res ol uti o n of e ve nts. T he S p o ns or ma y re q uest t hat a d diti o nal safet y 
tests be perf or m e d. 
S u bjects will recei ve a f oll o w- u p p h o ne call 7 da ys ( ±  2 da ys) aft er E O T or E T t o deter mi ne 
if a n y S A E or dr u g-relate d A E has occ urre d si n ce t he E O T or E T visit. 
At all ti mes, a s u bject ma y be re q uir e d t o re mai n at t he C R U f or l o n ger at t he discreti o n of 
t he I n v esti gat or ( or d esi g nee). 
A n y e ve nt t hat meets t he criteria of a s us pect e d u n e x pecte d s eri o us a d vers e reacti o n 
( S U S A R) will be re p orte d t o t he I nstit uti o nal Re vie w B oar d (I R B) acc or di n g t o C R U p olic y 
b y t he I n vesti gat or ( or d esi g nee) a n d t o re g ulat or y a ut h orities b y t he S p o ns or ( or S p o ns or 
desi g nee) acc or di n g t o re g ulat or y a ut h orit y re q uire me nts. Refer t o Refere n ce Safet y 
I nf or mati o n i n t he c urre nt I B1 f or L O X O- 3 0 5 f or a d diti o nal safet y i nf or mati o n. 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 8 of 6 8 
7. 3. 2.  
Cli nic al L a b or at or y E v al u ati o ns 
Cli nical la b orat or y e val u ati o ns (cli nical c he mistr y pa nel [faste d at least 8  h o urs; at E T or t he 
da y bef or e E O T, s u bjects are n ot r e q uire d t o be faste d pri or t o cli nical la b orat or y 
e val uati o ns], c o a g ulati o n para meters, he mat ol o g y pa nel, T S H [ Scree ni n g o nl y], H b A 1c 
[ Scree ni n g o nl y], e G F R [ Scree ni n g a n d C hec k -i n ( Da y -1)],  a n d U A) will be c ollecte d at t he 
ti me p oi nts s pecifie d i n A p pe n di x 4 . 
Scree ns f or H C V a nti b o d y, H Bs A g, H B V I g M c ore a nti b o d y, a n d HI V a nti b o d y will be 
perf or me d at Scree ni n g .  
Testi n g f or C O VI D- 1 9 via P C R ( or e q ui vale nt) will be perf or me d at t he ti me p oi nts s pecifie d 
i n A p pe n di x 4 . Testi n g f or C O VI D- 1 9 ma y als o b e c o n d ucte d p eri o dicall y d uri n g t he 
s u bject’s C R U c o nfi ne m e nt, at t he discreti o n of t h e I n vesti gat or ( or desi g nee). F urt her det ails 
re gar di n g C O VI D- 1 9 testi n g (i ncl u di n g pr oce d ures f or s u bjects w h o test p ositi ve at a n y ti me 
t hr o u g h o ut C R U c o nfi ne me nt) are s p ecifie d i n a se parat e d oc u me nt.  
A uri ne dr u g scree n f or s electe d dr u gs of a b use (i ncl u di n g c oti ni ne) a n d a n alc o h ol scree n 
( uri ne or br eat h) will be perf or me d at Scree ni n g a n d re peat e d at C hec k-i n ( Da y -1) f or all 
s u bjects. A ser u m q ualitati ve pre g na nc y t est (fe m ale s u bjects o nl y [ser u m q ua ntitati ve ma y 
be use d f or c o nfir mati o n, if nee de d]) a n d a n F S H t est ( p ost- me n o pa usal fe male s u bjects o nl y) 
will be perf or me d at t he ti me p oi nts s pecifie d i n  A p pe n di x 4 . 
T he n u m ber of bl o o d sa m ples a n d t otal bl o o d v ol u me re q uire d f or cli nical la b orat or y 
e val uati o ns ar e pres e nte d i n A p pe n di x 3 . A list of t he s pecific e val uati o ns is i n A p pe n di x 2 . 
7. 3. 3.  
Vit al Si g ns  
Vital si g n meas ure me nts (i ncl u di n g b o d y te m perat ure, res pirat or y rate, o x y ge n sat urati o n, 
a n d s u pi ne B P a n d p ulse rate) will be o btai n e d at t he ti me p oi nts s pecifie d i n  A p pe n di x 4 . 
Bl o o d press ure a n d p ulse rate meas ure me nts s h o ul d be perf or me d usi n g t he sa me ar m f or 
eac h r ea di n g a n d m eas ur e me nts s h o ul d be ta ke n after t he s u bject h as bee n resti n g i n t he 
s u pi ne p ositi o n for at least 5  mi n utes.  
W he n vital si g n meas ure me nts are sc h e d ule d at t h e sa me ti me as P K bl o o d dra ws, t he P K 
bl o o d dra ws will be o btai ne d at t he sc he d ul e d ti me p oi nt, a n d t he vital si g n meas ure me nts will 
be o btai ne d pri or t o a n d as cl ose as p ossi ble t o t he sc he d ule d P K bl o o d dra w. 
7. 3. 4.  
1 2- le a d Electr oc a r di o gr a m 
A 1 2 -lea d E C G (i n cl u di n g H R, P R, R R, Q R S, a n d Q T i nter val para meters) will be o btai ne d 
after t he s u bject has bee n resti n g f or at least 1 0  mi n utes i n t he s u pi ne p ositi o n at t he 
ti me p oi nts s pecifie d i n A p pe n di x 4 . T he Q T i nter v al will be c orrecte d f or H R b y Fri dericia’s 
( Q Tc F = Q T/[ R R] 1/ 3) f or m ula. 
W he n 1 2- lea d E C Gs ar e sc he d ule d at t he s a me ti me as P K bl o od dra ws, t he P K bl o o d dra ws 
will be o btai ne d at t he sc he d ule d ti me p oi nt, a n d t he 1 2-lea d E C Gs will be o btai ne d pri or t o 
a n d as cl ose as p ossi ble t o t he sc he d ule d P K bl o o d dra w. 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 9 of 6 8 
7. 3. 5.  
P h ysic al E x a mi n ati o n 
A c o m plete or a b bre viat e d p h ysical e xa mi nati o n will be per f or me d at t he ti me p oi nts s pecifie d 
i n A p pe n di x 4 . C o m plete p h ysical e xa mi nati o ns will e val uate ge neral a p p eara nce a n d t he 
f oll o wi n g b o d y s yste ms/ or ga ns: der mat ol o gical; h ea d a n d e yes; ears, n ose, m o ut h, a n d t hr oat; 
p ul m o nar y; car di o vas c ular; a b d o mi nal; l y m p hatic; m usc ul os keletal/e xtre mities; a n d 
ne ur ol o gical. Wei g ht a n d hei g ht will be re p orte d ( hei g ht o nl y re p orte d d uri n g Scree ni n g). 
A b bre viate d p h ysical e xa mi nati o ns will e val uate ge neral a p peara n ce a n d t h e f oll o wi n g b o d y 
s yste ms/ or ga ns: der mat ol o gical; p ul m o nar y; car di o vasc ular; a b d o mi nal; a n d ne ur ol o gical. 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 0 of 6 8 
8.  S A M P L E SI Z E A N D D A T A A N A L Y SI S  
8. 1.  
Deter mi n ati o n of S a m ple Size  
U p t o 1 6 healt h y a d ult male a n d f e male s u bjects ( w o me n of n o n-c hil d beari n g p ote ntial o nl y) 
will be e nr olle d. T he sa m ple size c h ose n f or t his st u d y was select e d wit h o ut statistical 
c o nsi derati o ns b ut is c o nsiste nt wit h pre vi o us st u dies of a si milar desi g n. U p t o 1 6 s u bjects 
are a ntici p ated t o be s ufficie nt t o pr o vi de a relia ble esti mate of t he ma g nit u de a n d vari a bilit y 
of t he i nteracti o n. Re place me nt s u bjects ma y be e nr olle d o nl y if dee me d n ecessar y b y t he 
S p o ns or. E ver y atte m pt will be ma de t o e nr oll at least 4  s u bjects of eac h s e x i n t he st u d y.  
8. 2.  
A n al ysis P o p ul ati o ns 
T he  P K P o p ul ati o n will c o nsist of all s u bjects w h o ha ve recei ve d a d ose of L O X O- 3 0 5 or 
t he pr o be c o c ktail dr u gs, ha ve at least 1 q ua ntifia ble plas ma c o nce ntrati o n, a n d f or w h o m at 
least 1 P K para met er ca n be c o m p ute d. A s u bjec t ma y be e xcl u d e d fr o m t h e P K s u m mar y 
statistics a n d statistical a nal ysis if t he s u bject has a n A E of v o miti n g t hat occ urs at or b ef ore 
tma x . T he i m pact of pr ot oc ol de viati o ns o n t he P K p o p ulati o n will be e val uate d o n a 
case- b y-cas e basis.  
T he  S afet y P o p ul ati o n will c o nsist of all s u bjects w h o ha ve recei v e d at least 1  d ose of st u d y 
dr u g ( pr o be c oc ktail dr u gs a n d/ or L O X O- 3 0 5). S u bjects will be classifie d i nt o gr o u ps base d 
o n act ual treat me nt recei ve d.  
8. 3.  
P h ar m ac o ki netic A n al ysis  
Serial bl o o d sa m ples f or plas ma c o nce ntrati o n a nal ysis will be a nal yze d usi n g sa m ples 
c ollecte d at t he f oll o wi n g ti me p oi nts:  
•  Caffei ne / para x a nt hi ne: 
o  
 f oll o wi n g a d mi nistrati o n al o ne o n 
 
  
•  O me praz ol e:  
o  
 f oll o wi n g a d mi nistrati o n al o ne o n 
 
 
•  S- War f ari n: 
o  
 f oll o wi n g a d mi nistrati o n al o ne o n 
 
 
•  L O X O - 3 0 5:  
o  
 f oll o wi n g a d mi nistrati o n al o ne o n 
 
o  
 f oll o wi n g a d mi nistrati o n wit h  
 
  
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 1 of 6 8 
W he ne v er p ossi ble, t he f oll o wi n g P K para meters f or eac h s u bstrate (caffei ne/ para x a nt hi ne, 
o me praz ole , a n d S-warfari n) a n d L O X O -3 0 5 will be calc ul ate d f or eac h s u bject base d o n t he 
plas ma c o nce nt rati o ns (as a p pr o priate): 
•  area u n d er t he c o nce ntrati o n ti me c ur ve ( A U C ) fr o m h o ur 0 t o 2 4 h o urs p ost d ose 
( A U C0- 2 4) 
•  A U C fr o m h o ur 0 t o t he l ast meas ura ble c o nce ntrati o n ( A U C 0-t) 
•  A U C fr o m h o ur 0 e xtr a p olate d t o i nfi nit y ( A U C 0- i nf) 
•  perce nt a ge e xtra p olati o n f or A U C 0- i nf ( % A U Ce xtra p) 
•  a p pare nt s yste mic cleara nce ( C L/ F)  
•  C ma x  
•  mea n resi de n ce ti me ( M R T)  
•  a p pare nt plas m a ter mi nal eli mi nati o n half -life (t½ ) w here v er p ossi ble, w here t 1/ 2  = 
nat ural l o g ( 2)/ λ Z  
•  ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n (t ma x ) 
•  a p pare nt ter mi nal eli mi nati o n rate c o nsta nt ( λ Z ) 
•  a p pare nt v ol u me of distri b uti o n at ter mi nal p hase ( V z/F)  
•  A U C 0- 2 4 a n d A U C 0- 4 8 rati o of para x a nt hi ne t o caffei ne ( M R A U C; 
caff ei ne/ par a xa nt hi ne o nl y) 
P har mac o ki netic calc ulati o ns will be pe rf or me d usi n g c o m mercial s oft ware s uc h as P h oe ni x™ 
Wi n N o nli n
®  Versi o n  8. 1 or hi g her ( Cert ara U S A I nc.).  
Ot her par a meters m a y be a d de d as a p pr o priate. Fi nal P K para meters re p orte d will be detaile d 
i n t he Statistical A nal ysis Pla n ( S A P). 
P har mac o ki netic a n a l ysis will use act ual ti mes as rec or de d o n t h e e C R F. All statistical 
a nal yses will be perf or m e d usi n g S A S  Versi o n  9. 4 or great er. M ore details o n t he a nal yses 
will be i ncl u de d i n t he S A P. 
8. 3. 1.  
Descri pti ve A n al ysis  
Plas ma c o nce ntr ati o ns a n d P K para meters will b e s u m marize d wit h descri pti ve statistics 
( n u m ber, arit h metic mea n, sta n dar d de viati o n, c o efficie nt of v ariati o n [ C V %], ge o metric 
mea n, ge o metric C V %, me dia n, mi ni m u m, a n d ma xi m u m). 
I n di vi d ual a n d m ea n plas ma c o nce ntr ati o n-ti me c ur ves ( b ot h li near a n d l o g li near) will be 
i ncl u de d i n t he fi nal re p ort. 
8. 3. 2.  
St atistic al Met h o d ol o g y 
T he pri mar y a n al ysis pla n ne d f or t his st u d y is a mi xe d effect m o del t hat i ncl u des treat me nt as 
a fi xe d effect a n d s u bject as a ra n d o m effect. T he a nal ysis will be perf or m e d o n t he nat ural 
l o g (l n)-tra nsf or me d P K para meters ( A U C0-t, A U C0- i nf, a n d Cma x ) a n d i ncl u de calc ul ati o n of 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 2 of 6 8 
least s q uare d ( L S) mea ns a n d t he differe nce bet w ee n treat me nt L S mea ns, as well as t heir 
c orres p o n di n g 9 0 % c o nfi de nce i nter v als ( CIs). T h e ge o metric mea n  rati os a n d t heir 9 0 % CIs 
of t he P K para m eter f or eac h treat me nt c o m paris o n will be c o nstr ucte d usi n g t he 
e x p o ne ntiati o n of t he diff ere nce a n d t he CIs fr o m t he mi xe d effect m o del. T he c o m paris o ns 
of i nterest will be pr o be dr u gs al o ne (caffei ne a n d its meta b olite para xa nt hi ne, o me praz ole, 
a n d S- warfari n) v ers us pr o be dr u gs (caffei ne a n d its meta b olite para x a nt hi ne, o me praz ole, 
a n d S-warfari n) c oa d mi nistere d wit h L O X O - 3 0 5. T he rati o of para x a nt hi ne t o caffei ne will 
be s u m marize d.  
8. 4.  
S afet y A n al ysis 
All safet y assess me nts, i ncl u di n g A Es, S A Es, vital si g n meas ure me nts, cli nical la b orat or y 
res ults, p h ysical e xa mi nati o n res ults, c o nc o mita nt me dicati o ns, a n d 1 2-lea d E C Gs, will be 
ta b ulate d a n d s u m marize d w here p ossi ble, usi n g d escri pti ve met h o d ol o g y, as nee de d, b y 
ti me p oi nt. U nless ot her wise s pecifie d, bas eli ne val ue is defi ne d as t he l ast n o n-missi n g 
meas ure me nt b ef or e a d mi nistrati o n of st u d y dr u g o n Da y 1, Peri o d 1. N o f or mal statistical 
a nal yses ar e pla n ne d f or t he safet y d ata. All safet y data will be  liste d b y s u bject. 
C o nc o mita nt me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n ( W H O) Dr u g 
Dicti o nar y ( W H O Dr u g Gl o bal B 3, Se pte m ber 2 0 1 9). A d vers e e ve nts will be c o de d usi n g 
Me dical Dicti o nar y f or R e g ulat or y Acti vities ( Me d D R A) Versi o n 2 2. 1 ( or hi g her). T he 
i nci de nce of A Es will be prese nte d b y s e verit y a n d b y relati o ns hi p t o st u d y dr u g as 
deter mi ne d b y t he I n v esti gat or or desi g nee ( A p p e n di x 1  f or A E re p orti n g). All T E A Es will be 
s u m marize d b y s yste m or ga n class a n d preferre d t er m. 
8. 5.  
D at a H a n dli n g a n d Rec or d Kee pi n g  
A n y c ha n ges t o i nf or mati o n i n t he trial pr o gress n otes a n d ot her s o urce d oc u me nts will be 
i nitiale d a n d date d o n t he da y t he c han g e is ma de b y a C R U staff me m ber a ut h orize d t o ma ke 
t he c ha n ge. C ha n g es will be ma de b y stri ki n g a si n gle li ne t hr o u g h err o n e o us data a n d clearl y 
e nteri n g t he c orrect data (e g, wr o n g d ata ri g ht dat a). If t he reas o n f or t he c ha n ge is n ot 
a p pare nt, a brief e x pla nati o n f or t he c ha n g e will be writte n a djace nt t o t he c ha n ge b y t he 
C R U staff me m ber.  
T he Data M a na ge m e nt Pla n will be a p pr o ve d b y t he S p o ns or. 
Data will be vali date d d uri n g data e ntr y b y t he C R U a n d verifi e d b y t he St u d y M o nit or. Data 
will t he n be re vie w e d b y t he data ma na g e me nt gr o u p t o res ol ve a n y o utsta n di n g iss ues. 
Listi n gs will be ge nerate d after t he d ata bas e is clea ne d b y data m a na ge m e nt a n d will be 
re vie we d b y t h e C o va nce scie ntific tea m. T he e C R F a n d a n cillar y data will be c o n vert e d i nt o 
fi nal S A S ®  datasets f oll o wi n g St u d y Data Ta b ulati o n M o del or S p o ns or- pr o vi de d 
s pecificati o ns. T he fi nal datasets str uct ure will be verifie d usi n g We b S u b missi o n Data 
Ma na ger
® , w hile t he d ataset c o nte nt will be peer re vie we d b y a n i n de pe n d e nt pr o gra m mer. 
T he ta b les, fi g ur es, a n d listi n gs ( T F Ls) will be pr o gra m me d per t h e fi nal S A P. All T F Ls will 
be peer re vie we d b y a n i n de pe n de nt pr o gra m mer. I n a d diti o n, draft T F Ls will be re vie we d b y 
t he C o va nce sci e ntific tea m d uri n g t he dr y r u n a n d data re vie w meeti n gs. 
T he peer re vie w will be perf or me d b y i n d e pe n de nt pr o gra m mers f oll o wi n g t he q ualit y c o ntr ol 
pr ocess a n d pr o gra m mi n g c hec klists. 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 3 of 6 8 
8. 6.  
Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce 
Q ualit y c o ntr ol a n d q ualit y ass ura nce will be perf or me d acc or di n g t o C o va nce S O Ps or per 
S p o ns or re q uest, a n d as a p plica ble, acc or di n g t o t he c o ntract bet wee n C o va nce a n d t he 
S p o ns or. 
 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 4 of 6 8 
9.  A D MI NI S T R A TI V E A S P E C T S  
9. 1.  
C h a n ge i n Pr ot oc ol 
T here will be n o alterati o ns i n t he pr ot oc ol wit h o ut a gree me nt b et wee n t h e S p o ns or a n d t he 
I n v esti gat or ( or d esi g nee).  
T here will be n o alterati o ns i n t he pr ot oc ol affecti n g s u bject safet y wit h o ut t he e x press 
writte n a p pr o val of t h e S p o ns or, I n vesti gat or ( or d esi g nee), a n d t he I R B (see F or m 
F D A  1 5 7 2). 
9. 2.  
Site I niti ati o n Visit/I n vesti g at or Meeti n g  
Pri or t o t he start  of t he cli nical st u d y, t he re pres e ntati ve(s) of t he S p o ns or a n d/ or S p o ns or will 
meet wit h t he I n vesti gat or ( or desi g nee) a n d a p pr o priate C R U staff t o fa miliarize t he 
I n v esti gat or ( or d esi g nee) a n d C R U staff wit h t he materials necessar y f or c o n d ucti n g t he 
cli nical st u d y.  
9. 3.  
Discl os ure  
All i nf or mati o n pr o vi de d re gar di n g t he st u d y, as well as all i nf or mati o n 
c ollecte d/ d oc u me nte d d uri n g t he st u d y, will be re gar de d as c o nfi de ntial. T he I n vesti gat or ( or 
desi g nee) a grees n ot t o discl ose s uc h i nf or mati o n i n a n y wa y w it h o ut pri or writte n per missi o n 
fr o m t he S p o ns or. 
A n y p u blicati o n of t he res ults, i n part or i n t otal (e g, articles i n j o ur nals or n e ws pa pers, oral 
prese ntati o ns, a bstracts) b y t he I n vesti gat or ( or d esi g nee) or t heir re prese nt ati ve(s), s hall 
re q uire pri or n otificati o n a n d re vie w, wit hi n a reas o na ble ti mefra me, b y t he S p o ns or, a n d 
ca n n ot be ma d e i n vi olati o n of t he S p o ns or’s c o nfi de ntialit y restricti o ns or t o t he detri me nt of 
t he S p o ns or’s i ntellect ual pr o pert y ri g hts. 
9. 4.  
M o nit ori n g  
T he S p o ns or will desi g nate a St u d y M o nit or(s) w h o will be res p o nsi ble f or m o nit ori n g t his 
cli nical trial. T he S p o ns or’s St u d y M o nit or(s) will m o nit or t he st u d y c o n d uct, pr o per e C R F 
a n d s o urce d o c u me ntati o n c o m pleti o n a n d rete nti o n, a n d acc urate st u d y dr u g acc o u nta bilit y. 
T o t his e n d, t he S p o ns or’s St u d y M o nit or(s) will visit t he C R Us at s uita ble i nter vals ( or ma y 
perf or m acti vities re m otel y as per t he M o nit ori n g Pla n f or t his st u d y) a n d be i n fre q u e nt 
c o ntact t hr o u g h ver bal a n d writte n c o m m u nicati o n. It is esse ntial t hat t he S p o ns or’s St u d y 
M o nit or(s) has access t o all d oc u me nts (relat e d t o t he st u d y a n d t he i n di vi d ual partici pa nts) at 
a n y ti me t hese ar e re q u este d. I n t ur n, t he S p o ns or’s St u d y M o nit or(s) will a d here t o all 
re q uire me nts f or s u bject c o nfi de ntialit y as o utli ne d i n t he I C F. T he I n v esti gat or ( or desi g n ee) 
a n d I n vesti gat or’s staff will be e x pecte d t o c o o p erate wit h t he S p o ns or’s St u d y M o nit or(s), t o 
be a vaila ble d uri n g a p orti o n of t he m o nit ori n g visit t o a ns wer q uesti o ns, a n d t o pr o vi de a n y 
missi n g i nf or mati o n.  
9. 5.  
I nstit uti o n al Re vie w B o ar d  
I n acc or da n ce wit h U S Title 2 1 C o de of Fe d eral R e g ulati o ns ( C F R) 5 6, t he pr ot oc ol, 
a d vertise me nt, I C F, a n d ot her i nf or mati o n pr o vi d e d t o s u bjects will be re vie we d a n d 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 5 of 6 8 
a p pr o ve d b y t he I R B. T h e S p o ns or will s u p pl y rele va nt material f or t he I n v e sti gat or ( or 
desi g nee) t o s u b mit t o t he  I R B f or t he pr ot oc ol’s re vie w a n d a p pr o val. V erificati o n of t he 
I R B u nc o n diti o nal a p pr o val of t he pr ot oc ol a n d t h e writte n I C F stat e me nt will be tra ns mitte d 
t o t he I n v esti gat or ( or d esi g nee). 
T he I R B will be i nf or me d  b y t he I n vesti gat or ( or desi g nee) of s u bs e q ue nt pr ot oc ol 
a me n d me nts a n d of seri o us a n d u ne x pecte d A Es. A p pr o val f or pr ot oc ol a me n d me nts will be 
tra ns mitte d i n writi n g t o t he I n vesti gat or ( or desi g nee). If re q u este d, t he I n vesti gat or ( or 
desi g nee) will per mit a u dits b y t he I R B a n d re g ul at or y i ns pecti o ns b y pr o vi di n g direct access 
t o s o urce data/ d o c u me nts. 
T he I n vesti gat or ( or desi g nee) will pr o vi de t he I R B wit h pr o gress re p orts at a p pr o priate 
i nter vals ( n ot t o e xcee d 1 year) a n d a St u d y Pr o gress Re p ort f oll o wi n g t he c o m pleti o n, 
ter mi nati o n, or disc o nti n uati o n of t he I n vesti gat or’s ( or desi g nee’s) p artici pati o n i n t he st u d y. 
9. 6.  
I nf or m e d C o nse nt 
Writte n i nf or me d c o ns e nt f or t he st u d y will be o btai ne d fr o m all s u bjects b ef ore 
pr ot oc ol- s pecifi c pr oce d ures ar e carrie d o ut. T h e I C F will be a p pr o v e d (al o n g wit h t he 
pr ot oc ol) b y t he I R B a n d will be acce pta ble t o t he S p o ns or. 
T he I n vesti gat or ( or desi g nee) will e x plai n t he n at ure of t he st u d y a n d t he acti o n of t he test 
pr o d uct. T he s u bjects will be i nf or me d t hat partici pati o n is v ol u ntar y a n d t hat t he y ca n 
wit h dra w fr o m t he st u d y at a n y ti me. I n acc or da nce wit h 2 1 C F R 5 0, t he i nf or me d c o nse nt 
pr ocess s hall be d o c u me nte d b y t he use of a writte n I C F a p pr o ve d b y t he I R B a n d si g ne d b y 
t he s u bject pri or t o pr ot o c ol-s pecific proce d ures b ei n g perf or m e d. 
T he s u bject will si g n 2 c o pies of t he I C F. O n e c o p y will be gi ve n t o t he s u bject, a n d t he ot her 
will be mai ntai ne d wit h t he s u bject’s r ec or ds.  
9. 7.  
Rec or ds  
T he res ults fr o m dat a c ollecte d at Scr ee ni n g a n d d uri n g t he st u d y will be rec or de d i n t he 
s u bject’s e C R F. T o mai ntai n c o nfi de ntialit y, t he s u bjects will be i de ntifie d o nl y b y n u m bers. 
T he c o m plete d e C R Fs will be tra nsferre d t o t he S p o ns or ( or desi g nee). C o pi es of eac h e C R F 
will be retai ne d b y t he I n vesti gat or ( or desi g nee). All s o urce d oc u me nts, rec or ds, a n d re p orts 
will be retai ne d b y t he C R U i n acc or d a nce wit h 2 1 C F R 3 1 2. 6 2(c). 
All pri mar y data, or c o pies t here of (e g, la b orat or y rec or ds, e C R Fs, data s h eets, 
c orres p o n d e nce, p h ot o gr a p hs, a n d c o m p uter rec or ds), w hic h are a res ult of t he ori gi nal 
o bser vati o ns a n d acti vities of t he st u d y a n d are necessar y f or t he rec o nstr ucti o n a n d 
e val uati o n of a n y st u d y r e p ort, will be retai n e d i n t he C R U arc hi ves. 
9. 8.  
Refere nce t o Decl ar ati o n of Helsi n ki/ B asic Pri nci ples  
T he st u d y pr oce d ures o utli ne d i n t his pr ot oc ol will be c o n d ucte d i n acc or da nce wit h t he U S 
C F R g o ver ni n g Pr otecti o n of H u ma n S u bjects ( 2 1 C F R 5 0), Fi na n cial Discl os ure b y Cli nical 
I n v esti gat ors ( 2 1 C F R 5 4), I R Bs ( 2 1 C F R 5 6), a n d I n v esti gati o nal Ne w Dr u g A p plicati o n 
( 2 1 C F R  3 1 2), as a p pr o priate. As s uc h, t hes e secti o ns of U S Title 2 1 C F R, al o n g wit h t he 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 6 of 6 8 
a p plica ble I C H G ui d eli nes, are c o m m o nl y k n o w n as G o o d Cli nical Practices, w hic h are 
c o nsiste nt wit h t he Declarati o n of Helsi n ki.  
9. 9.  
Fi n a nci n g a n d I ns ur a nce  
Fi na nci n g a n d i ns ur a nce will be a d dress e d i n a s e parate a gree me nt.  
 
 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 7 of 6 8 
1 0.  R E F E R E N C E S  
1.   L o x o O nc ol o g y, I nc. L O X O- 3 0 5 - I n v esti gat or’s Br oc h ure ( Versi o n 4. 0). 2 9 Oct o ber 
2 0 2 0.  
2.   Bra n d h u ber B, G o mez E, S mit h S, Ear y T, S pe ncer S, R ot he n ber g S M, et al. A ne xt 
ge nerati o n r e versi ble B T K I n hi bit or, f or o verc o mi n g ac q uire d resista nce t o irre versi ble 
B T K i n hi bit ors. Cli n L y m p h o ma M yel o ma Le u k. 2 0 1 8; 1 8; S 2 1 6.  
3.   B yr d J C, F ur ma n R R, C o utre S E, Fli n n I W, B ur ger J A, Bl u m K A, et al. Tar geti n g B T K 
wit h i br uti ni b i n rela pse d c hr o nic l y m p h oc ytic le u ke mia. N E n gl J Me d. 2 0 1 3 J ul 
4; 3 6 9( 1): 3 2 – 4 2.  
4.  W o yac h J A, R u p pert A S, G ui n n D, Le h ma n A, Bl ac hl y J S, L oza ns ki A, et al. 
B T K C 4 8 1 S- Me diate d Resista nce t o I br uti ni b i n C hr o nic L y m p h oc ytic Le u ke mia. J Cli n 
O nc ol. 2 0 1 7 Ma y 1; 3 5( 1 3): 1 4 3 7 – 4 3.  
5.   W o yac h J, H u a n g Y, R o gers K, B hat S A, Gre v er M R, L oza ns ki A, et al. Resista nce t o 
acala br uti ni b i n C L L is me diate d pri maril y b y B T K m utati o ns. Bl o o d. 
2 0 1 9; 1 3 4( S u p ple me nt _ 1).  
6.   C hir o n D, Di Li bert o M, Marti n P, H ua n g X, S har ma n J, Blec ua P, et al. Cell- c ycle 
re pr o gr a m mi n g f or PI 3 K i n hi biti o n o verri des a rel a pse-s pecific C 4 8 1 S B T K m utati o n 
re veal e d b y l o n git u di nal f u ncti o nal ge n o mics i n ma ntle cell l y m p h o ma. Ca ncer Disc o v. 
2 0 1 4 Se p; 4( 9): 1 0 2 2 – 3 5.  
7.   X u L, Tsa k ma klis N, Ya n g G, C he n J G, Li u X, D e m os M, et al. Ac q uire d m utati o ns 
ass ociate d wit h i br uti ni b resista nce i n Wal d e nstr ö m macr o gl o b uli ne mia. Bl o o d. 2 0 1 7 
0 4; 1 2 9( 1 8): 2 5 1 9 – 2 5.  
8.   T o y os hi ma S, Ka n n o A, Kita ya ma T, Se ki ya K, N a kai K, Har u na M, et al. Q T 
P R O D A C T: I n Vi v o Q T Assa y i n t he C o nsci o us D o g f or Assessi n g t he P ote ntial f or Q T 
I nter val Pr ol o n gati o n b y H u ma n P har mace uticals [I nter net]. J o ur nal of p h ar mac ol o gical 
scie nces. 2 0 0 5 [cite d 2 0 2 0 J u n 1 0]. A vaila ble fr o m: 
htt ps:// p u b me d. nc bi. nl m. ni h. g o v/ 1 6 4 9 3 1 8 7/ 
9.   F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or I n d ustr y: Cli nical Dr u g I nteracti o n St u dies 
- C yt oc hr o me P 4 5 0 E nz yme - a n d Tra ns p orter- Me diate d Dr u g I nteracti o ns G ui da nce f or 
I n d ustr y [I nter n et]. F o o d a n d Dr u g A d mi nistrati o n; 2 0 2 0 [cite d 2 0 2 0 Se p 2 5]. A vaila ble 
fr o m: htt ps:// w w w.f da. g o v/ me dia/ 1 3 4 5 8 1/ d o w nl oa d 
 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 8 of 6 8 
1 1.  A P P E N DI C E S  


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 9 of 6 8 
A p pe n di x  1: A d verse E ve nt Re p orti n g  
A d verse E ve nts  
Defi niti o n of A d vers e E v e nts 
A n a d vers e e ve nt ( A E; or a d verse e x peri e nce) is  defi ne d as a n y u nt o war d me dical occ urre n ce 
e x perie n ce d b y a p atie nt or healt h y a d ult s u bject, w het her or n ot c o nsi dere d dr u g- relat e d b y 
t he I n v esti gat or ( or d esi g nee). A tr eat me nt-e mer g e nt a d vers e e ve nt ( T E A E) is a n A E t hat 
starts o n or after t he first a dmi nistrati o n of st u d y dr u g. 
T he f oll o wi n g are all A Es: 
•  
u nfa v ora bl e c ha n g es i n ge neral c o n diti o n 
•  
s u bjecti ve or o bjecti ve si g ns/s y m pt o ms 
•  
c o nc o mita nt diseases or acci de nts  
•  
cli nicall y si g nifica nt a d v erse c h a n ges i n la b orat or y para meters o bser v e d i n a s u bject 
d uri n g a cli nical st u d y 
A d verse e ve nts c o m prise all dist ur ba nces of g e neral healt h stat us, s u bjecti ve a n d o bjecti ve 
disease s y m pt o ms (i ncl u di n g la b orat or y a b n or m alities t hat are dee m e d cli nicall y si g nifica nt 
b y t he I n vesti gat or [ or d esi g nee]), a n d acci de nts o bser ve d i n t he c o nt e xt of a cli nical trial, 
irres pecti ve of a p ossi ble ca usal r elati o ns hi p wit h t he a d mi nistrati o n of t he trial s u bsta nce. 
Cate g orizati o n of A d v ers e E ve nts 
T he se verit y of A Es will be cate g orize d b ase d o n t he Nati o nal Ca ncer I nstit ute C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E v e nts ( C T C A E) Versi o n 5. 0 as f oll o ws: 
•  
Gr a de  1 Mil d:  As y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic 
o bser vati o ns o nl y; i nter ve nti o n n ot i n dicate d 
•  
Gr a de  2 M o der at e:  Mi ni mal, l ocal, or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g 
a ge-a p pr o priate i nstr u me ntal Acti vities of Dail y Li vi n g ( A D L) *  
•  
Gr a de  3 Severe o r m e dic all y si g nific a nt b ut n ot i m me di atel y life -t hre ate ni n g: 
H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g 
self-care A D L * *  
•  
Gr a de  4 Life -t hre ate ni n g c o nse q ue nces: A n e v e nt t hat p uts t he s u bject at 
i m me diate ris k of deat h  
•  
Gr a de  5: Deat h relate d t o A E  
N ote: N ot all gra d es are a p pr o priate f or all A Es. T h eref ore, s o me A Es are liste d wit hi n t h e C T C A E wit h fe wer t h a n 
5 o pti o ns f or gra d e selecti o n. Gra d e 5 ( d eat h) is n ot a p pr o priate f or s o me A Es a n d t h eref ore is n ot a n o pt i o n. 
* I nstr u me ntal A D L refer t o pre pari n g meals, s h o p pi n g f or gr o ceries, or cl ot h es, usi n g t h e tele p h o n e, ma n a gi n g m o n e y, etc. 
* * Self -car e A D L refer t o b at hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t h e t oilet, ta ki n g me dicati o ns, a n d n ot 
be dri d de n . 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 0 of 6 8 
T he I n vesti gat or ( or desi g nee) will ma ke a deter mi nati o n of t he relati o ns hi p of t he A E t o t he 
st u d y dr u g usi n g a 2-cate g or y s yste m acc or di n g t o t he f oll o wi n g g ui deli nes: 
•  
N O T R E L A T E D  = T he ti me c o urse bet w ee n t he a d mi nistrati o n of i n vesti gati o nal 
pr o d uct a n d t he occ urr e n ce or w orse ni n g of t he A E r ules o ut a ca us al relati o ns hi p 
a n d a n ot her ca use (e g, c o nc o mita nt dr u gs, t hera pies, c o m plicati o ns, c o m or bi dities) 
is s us pecte d 
•  
R E L A T E D  = T he ti me c o urse bet wee n a d mi nistrati o n of i n vesti gati o nal pr o d uct 
a n d t he occ urre n ce or w orse ni n g of t he A E is c o nsiste nt wit h a ca usal rel ati o ns hi p 
a n d n o ot her ca use ( e g, c o nc o mita nt dr u gs, t hera pies, c o m plicati o ns, c o m or bi dities) 
ca n be i de ntifie d  
A n A E is ass ociate d wit h t he use of t he dr u g if t h ere is a reas o na ble p ossi bilit y t hat t he 
e x perie n ce ma y h a ve bee n ca use d b y t he dr u g. 
Pre g na nc y  
As i nf or mati o n is a vaila ble, a pre g n a nc y (i n cl u di n g pre g na nc y i n fe male p art ners of male 
s u bjects) dia g n ose d t hr o u g h E n d of St u d y ( E O S) or Earl y Ter mi nati o n ( E T; if t he s u bject 
disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a f oll o w- u p p h o ne call)  a n d f or u p t o 
9 0 da ys after st u d y dr u g a d mi nistrati o n o n Da y 1 9 ( or last a d mi nistrati o n of st u d y dr u g if 
s u bject ter mi nates fr o m t he st u d y earl y) s h o ul d be re p orte d b y t he I n vesti gat or ( or desi g nee) 
via e mail t o C o va nce or t he S p o ns or’s Cli nical Safet y Re prese ntati ve wit hi n 2 4 h o urs of 
bei n g n otifie d. C o va nce or t he S p o ns or’s Cli nical Safet y Re pres e ntati ve will t he n f or war d t he 
Pre g na nc y F or m t o t he I n vesti gat or ( or desi g nee) f or c o m pleti o n. 
e m ail: S A EI nt a ke @ C o v a nce.c o m 
A s u bject bec o mi n g pr e g na nt w hile o n st u d y dr u g will i m me diatel y be wit h dra w n fr o m t he 
st u d y a n d E T st u d y pr oce d ures will be perf or me d. T he s u bject or part ner s h o ul d be f oll o we d 
b y t he I n vesti gat or ( or d esi g nee) u ntil c o m pleti o n of t he pre g n a nc y. If t he pre g na nc y e n ds f or 
a n y reas o n b ef or e t he a ntici pate d date, t he I n vesti gat or ( or desi g n ee) s h o ul d n otif y C o va nce 
or t he S p o ns or’s Cli nical Safet y Re pres e ntati ve. At t he c o m pleti o n of t he pre g na nc y, t he 
I n v esti gator ( or d esi g nee) will d oc u me nt t he o utc o me of t he pre g n a nc y. If t he o utc o me of t he 
pre g na nc y m eets t he criteria f or i m me diat e classificati o n as a seri o us a d verse e ve nt ( S A E; ie, 
p ost part u m c o m plicati o n, s p o nta ne o us a b orti o n, still birt h, ne o natal deat h, or c o n ge nital 
a n o mal y), t he I n v esti gat or ( or desi g nee) s h o ul d f oll o w t he pr oce d ures f or re p orti n g a n S A E. 
Male s u bjects will be i nstr ucte d t o n otif y t he I n vesti gat or ( or desi g nee) i m me diatel y if t he y 
disc o ver t heir se x u al part ner is pre g na nt. I n t his i nsta nce, t he part ner m ust pr o vi de writte n 
c o nse nt bef or e pr e g na nc y i nf or mati o n ca n be c ollecte d. W h e n a Cli nical Researc h U nit 
( C R U) bec o mes a war e t h at t he fe male p art ner of a male s u bject is pre g na nt, t he y are t o 
c o ntact t he I n v esti gat or ( or desi g nee) i m me diat el y ( wit hi n 2 4 h o urs of t he C R U staff 
bec o mi n g a ware of t h e e ve nt) i n a d diti o n t o n otif yi n g C o va nce or t he S p o ns or’s Cli nical 
Safet y Re pres e ntati ve via e mail.  
All pre g na ncies s h o ul d b e rec or de d o n t he A E electr o nic Case Re p ort F or m (e C R F; as 
a p pr o priate), i n a d diti o n t o c o m pleti o n of t he re q uire d pre g n a nc y f or ms. If t he I n vesti gat or 
( or desi g nee) s us pects t h at a pre g n a nc y w as t he res ult of a n i nteracti o n bet wee n t he st u d y 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 1 of 6 8 
treat me nt a n d t he c o ntrace pti ve met h o d, i n a d diti o n t o t he pre g na nc y t h e dr u g i nteracti o n 
s h o ul d als o be ca pt ure d as a se par ate A E. 
Defi niti o n of Seri o us A d verse E ve nts 
A n S A E b y t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) defi niti o n is a n y a d v erse dr u g 
e x perie n ce occ urri n g at a n y d ose t hat res ults i n a n y of t he f oll o wi n g o utc o mes: 
•  
Deat h  
•  
A life -t hreate ni n g a d vers e dr u g e x perie nce (ie, o n e t hat places t he s u bj ect, i n t he 
vie w of t he I n v esti gat or [ or desi g nee], at i m me diate ris k of deat h) 
•  
I n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
•  
A persiste nt or si g nifica nt disa bilit y/i nca pacit y  
•  
A c o n ge nital a n o mal y/ birt h defect 
•  
A n i m p orta nt me dical e v e nt t hat ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt 1 of t he a b o ve o utc o mes 
I m p ort a nt me dical e v e nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d S A Es w he n, b ase d o n a p pr o priate me di cal j u d g me nt, t he y 
ma y je o par dize t he patie nt or s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt 1 of t he o ut c o mes liste d i n t his defi niti o n. 
U ne x pect e d A d verse Dr u g Reacti o n  
A n A E or s us pect e d a d verse dr u g r eacti o n is c o nsi dere d ‘ u n e x pecte d’ if t he e ve nt is n ot liste d 
i n t he Refere n ce Safet y I nf or mati o n secti o n of t he I n v esti gat or’s Br oc h ure (I B) or if it is n ot 
liste d at t he s pecificit y or se verit y t hat has bee n o bser ve d f or a n u na p pr o ve d i n vesti gati o nal 
me dici nal pr o d uct (I M P). 
Re p orti n g 
T he F D A -r e p orta ble A Es are A Es t hat are ass ociat e d wit h t he use of t he dr u g a n d re prese nt 
e ve nts t hat ar e assesse d as seri o us, relate d, a n d u n e x pecte d. T h e F D A -re p orta ble A Es will be 
re p orte d b y t he C R U t o t he S p o ns or a n d t he res p o nsi ble I nstit uti o nal Re vie w B oar d (I R B). 
Fi nal deter mi nati o n of w het her a n e ve nt re pres e nts a s us pecte d u n e x pecte d seri o us a d vers e 
reacti o n ( S U S A R) will b e t he res p o nsi bilit y of t he S p o ns or. 
Wit hi n 2 4 h o urs of w he n a n A E t hat is p ote ntiall y F D A-re p ort a ble is first rec o g nize d or 
re p orte d, a n d wit hi n 2 4 h o urs of a n y S A E (re gar dless of w het her t he e v e nt is assesse d as 
relate d or u nrelate d t o st u d y dr u g) bei n g first rec o g nize d or re p orte d, C o va n ce or t he 
S p o ns or’ s Cli nical Safet y Re prese ntati ve will be n otifie d b y t he I n vesti gat or ( or desi g nee) i n 
writi n g usi n g t he f oll o wi n g e mail a d dress: 
e m ail: S A EI nt a ke @ C o v a nce.c o m 
T o re p ort t he S A E, t he c o m plete d re p ort f or m s h o ul d be se nt b y e mail t o C o va nce or t h e 
S p o ns or’s Cli nical Safet y Re prese ntati ve wit hi n 2 4  h o urs of a w are n ess. I nc o mi n g re p orts are 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 2 of 6 8 
re vie we d d uri n g n or mal b usi ness h o urs. A d diti o nal re p orti n g i nstr ucti o ns a n d t he S A E Re p ort 
F or m ar e pr o vi de d i n t he St u d y Ma n ual. 
T he I R B will be n otifie d of a n y F D A-r e p orta ble A E wit hi n t he ti mefra me re q uire d b y t he 
I R B. T he I R B Seri o us a n d U ne x pect e d A d verse E x perie nce S u b missi o n F or m will be 
c o m plete d a n d s u b mitte d wit h t he c o p y of t he writte n c o nfir mati o n or s u m mar y of t he A E. 
 
 


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 3 of 6 8 
A p pe n di x  2: Cli n ic al L a b or at or y E v al u ati o ns 
Cli nic al C he mistr y P a nel 
( F aste d): 
He m at ol o g y P a nel: 
Ot her Tests:  
Ala ni ne a mi n otra nsferase ( A L T)  
Al b u mi n 
Al kali ne p h os p hatase ( A L P)  
A m ylase  
As partate a mi n otra nsferase 
( A S T) 
Bilir u bi n ( direct a n d t otal)  
Bl o o d urea nitr o ge n  
Calci u m  
C hl ori de 
C h olester ol 
Creati ne ki nase  
Creati ni ne  
Gl uc ose 
Ir o n 
Li pase  
Ma g nesi u m  
P h os p h or us 
P otassi u m  
S o di u m 
T otal pr otei n  
Tri gl yceri des 
Uric aci d  
He mat ocrit  
He m o gl o bi n  
Mea n c or p usc ular he m o gl o bi n  
Mea n c or p usc ular he m o gl o bi n 
c o nce ntrati o n 
Mea n c or p usc ular v ol u me  
Platelet c o u nt 
Re d bl o o d cell ( R B C) c o u nt 
R B C distri b uti o n wi dt h  
W hite bl o o d cell ( W B C) c o u nt  
W B C differe ntial ( perce nt a n d 
a bs ol ute): 
    Bas o p hils 
    E osi n o p hils 
    L y m p h oc ytes 
    M o n oc ytes 
    Ne utr o p hils 
He m o gl o bi n A 1c ( H b A 1c) b 
T h yr oi d- sti m ulati n g h or m o ne 
( T S H)b 
Esti mate d gl o mer ular filtrati o n 
ratea, d 
S A R S -C o V -2 ( C O VI D -1 9) test  
C o a g ul ati o n P ar a meters: 
Partial t hr o m b o plasti n ti me  
Pr ot hr o m bi n ti me  
I nter nati o nal n or malize d rati o 
Ser ol o g y: b 
He patitis B s urface a nti ge n 
( H Bs A g) 
He patitis B vir us ( H B V) 
i m m u n o gl o b uli n M (I g M) c ore 
a nti b o d y 
He patitis C vir us ( H C V) 
a nti b o d y 
H u ma n i m m u n o deficie nc y vir us 
( HI V) a nti b o d y 
F or Fe m ale S u bjects O nl y:  
Pre g na nc y test (ser u m 
q ualitati ve, ser u m q ua ntitati ve 
ma y be use d f or c o nfir mati o n if 
nee de d) c 
F ollicle -sti m ulati n g h or m o ne 
( p ost-me n o pa usal fe male 
s u bjects o nl y) b 
 
Uri n al ysis:  
Bilir u bi n  
C ol or a n d a p peara nce  
Gl uc ose 
Ket o nes 
Le u k oc yte esterase  
Nitrite  
Occ ult bl o o d 
p H a n d s pecific gra vit y  
Pr otei n  
Ur o bili n o ge n 
Micr osc o pic e xa mi nati o n 
i ncl u di n g bacteria, casts, 
cr ystals, e pit helial cells, R B Cs, 
a n d W B Cs (if pr otei n, le u k oc yte 
esterase, nitrite, or occ ult bl o o d 
is p ositi ve) 
Uri ne Dr u g Scree n: a 
I ncl u di n g b ut n ot li mite d t o t he 
f oll o wi n g: 
Alc o h ol (et ha n ol) e 
A m p heta mi nes  
Bar bit urates  
Be nz o diaze pi nes  
Ca n na bi n oi ds 
C ocai ne ( meta b olite)  
Met ha d o ne  
O piates  
P he nc ycli di ne 
C oti ni ne  
a. Perf or me d at Scree ni n g a n d C hec k -i n ( Da y -1) o nl y.  
b.  Perf or me d at Scree ni n g o nl y.  
c. Perf or me d at Scree ni n g, C hec k -i n ( Da y -1), a n d Da y 2 2 f or E n d of Treat me nt ( E O T) or Earl y Ter mi nati o n 
( E T) o nl y. 
d.  Calc ulate d usi n g t he C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n ( C K D -E PI) e q uati o n.  
e. Uri ne or breat h test.  


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 4 of 6 8 
A p pe n di x  3: T ot al Bl o o d V ol u m e 
T he f oll o wi n g bl o o d v ol u mes will be wit h dra w n f or eac h s u bj ect: 
a F or P K sa m ples f or a n al ysis of eac h s u bstrate ( caffei n e/ p ara x a nt hi n e , o me praz ole, a n d S-warfari n) a  si n gle bl o o d sa m ple will 
be c ollecte d . 
b T h yr oi d -sti m ulati n g h or m o n e ( T S H) a n d esti mate d gl o mer ular filtrati o n rate (e G F R) will b e assesse d as p art of t h e cli nical 
c he mistr y sa m ple.  
If e xtra bl o o d s a m ples ar e re q uir e d, t he ma xi m u m bl o o d v ol u me t o be wit h dra w n per s u bject 
will n ot e xcee d 5 0 0 m L.  
Assess me nt  
A p pr o xi m ate 
Bl o o d V ol u me per 
S a m ple ( m L)  
M a xi m u m N u m ber of 
Bl o o d S a m ples  
A p pr o xi m ate 
T ot al 
V ol u me 
( m L) 
Ser ol o g y  
8. 0  
1  
8. 0  
He m o gl o bi n A 1c ( H b A 1c)  
4. 0  
1  
4. 0  
Pr o be d r u g coc ktail  p har mac o ki netic  
(P K ) sa m pli n ga 
4. 0  
3 6 
1 4 4. 0 
L O X O -3 0 5 P K sa m pli n g  
4. 0  
3 0  
1 2 0 . 0 
Cli nical la b orat or y e val uati o ns:  
    He mat ol o g y  
    Cli nical c he mistr y b 
    C oa g ulati o n  
4. 0 
4. 0 
3. 0  
9 
9 
9  
9 9. 0 
Ser u m pre g na nc y test (fe male s u bjects 
o nl y)  
4. 0 
3 
1 2. 0 
Ser u m f ollicle -sti m ulati n g h or m o ne 
( p ost- me n o pa usal fe male s u bjects o nl y)  
4. 0 
1 
4. 0 
Ge n ot y pi n g  
1 4. 0  
1  
1 4. 0  
T ot al:  4 0 5 . 0 m L  


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 5 of 6 8 
A p pe n di x  4: Sc he d ule of Assess m e nts


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9  
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 6 of 6 8 
 
 
St u d y Pr o ce d ures a 
Scree ni n g  
( D a ys -3 5 
t o -2)  
C hec k -i n 
( D a y -1)  
Peri o d  1 
Peri o d 2  
Cli nic 
Disc h ar ge 
E O T/ E T u  
F oll o w -u p 
p h o ne c all  
( E O S) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0  1 1  1 2  1 3  1 4  1 5  1 6  1 7  1 8  1 9  2 0  2 1  2 2  
2 3  
7 ( ± 2) d a ys 
p ost E O T/ E T v  
C o nfi ne d t o t he C R U  
 
X  
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  
X  
 
I ncl usi o n/ E xcl usi o n Criteria 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y  
X  
X b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hei g ht/ Wei g ht/ B MI  
X  
X c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
e G F R  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ge n ot y pi n g  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical E xa mi n ati o n d 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
1 2 -lea d E C Ge 
X  
X  
X   
 
 
X  X  
 
 
 
 
 
X  
 
 
X  
 
X  
 
 
X  
 
 
X  
 
Vital Si g n Meas ure me nts f, g, h 
X  
X  
X   
 
 
X  X  
 
 
 
 
 
X  
 
 
X  
 
X  
 
 
X  
 
 
X  
 
H D Y F? I n q uir y i 
X  
X  
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  
 
 
X  
X  
A Es/ S A Es j 
X  
X  
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  
 
 
X  
X  
Pr o be Dr u g C oc ktail D osi n g k 
 
 
X   
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
L O X O -3 0 5 D osi n g l 
 
 
 
 
 
 
 
X  X  X  X  X  X  X  X  X  X  X  X  X  X  
 
 
 
 
 
Cli nical La b orat or y 
E val uati o ns o 
X 
X 
 X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
He patitis a n d HI V Scree n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C O VI D -1 9 Test p 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H b A 1c Test  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr u g Scree n q 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri or a n d C o nc o mita nt 
Me dicati o ns
r 
X 
X 
X  X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ser u m Pre g na nc y Test s 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
 
F S H Test t 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T S H Test  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9  
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 7 of 6 8 
A b bre viati o ns: A E  = a d v erse e v e nt; B MI = b o d y mass i n d e x; B P  = bl o o d press ure; C O VI D -1 9  = S A R S - C o V-2; C R F = Case Re p ort F or m; C R U  = Cli nical Researc h U nit; 
E C G = ele ctr ocar di o gra m; e G F R = esti mate d gl o mer ular filtrati o n rate; E O S  = E n d of St u d y; E O T  = E n d of Treat me nt; E T  = Earl y Ter mi nati o n; F S H  = f ollicle-sti m ulati n g h or m o ne; H b A 1c = 
he m o gl o bi n A 1c; H D Y F?  = H o w D o Y o u Fee l?; HI V = h u ma n i m m u n o d eficie n c y vir us; I C F  = I nf or me d C o nse nt F or m; P K = p har mac o ki netic; S A E  = seri o us a d verse e ve nt; 
T S H  = t h yr oi d-sti m ulati n g h or m o n e; U A = uri n al ysis.  
a. F or details o n st u d y pr o ce d ures, see Secti o n  7 . 
b.  I nteri m me dical hist or y o nl y. 
c. Hei g ht c ollecte d at Scree ni n g o nl y; B MI calc ulate d b ase d o n Scree ni n g h ei g ht . 
d.  A c o m plete p h ysical e x a mi n ati o n will b e p erf or me d at C h ec k -i n ( Da y -1). A n a b bre viate d p h ysical e x a mi n ati o n will b e perf or me d at Da y 2 3 ( E O T) or at E T.  
e. 1 2 -lea d E C Gs will b e o btai n e d at Scree ni n g a n d C h ec k-i n ( Da y -1), Da y  1 ( pre d ose), Da y 5 ( 9 6  h o urs p ost d ose o n Da y 1), Da y  6 ( pre d ose a n d 2  h o urs  p ost d ose), Da y 1 2 ( pre d ose), Da y 1 5 
( pre d ose a n d 2 h o urs p ost d ose), Da y 1 7 ( pre d ose), a n d Da y 2 0 ( 2 4  h o urs p ost d ose o n Da y 1 9), a n d Da y 2 3 ( 9 6  h o urs p ost d ose o n Da y 1 9 [ E O T]) or E T. 1 2 -lea d E C Gs will be c ollecte d after 
t he s u bject h as reste d i n t h e s u pi ne p ositi o n f or at least 1 0  mi n utes. W h e n sc h e d ule d at t h e sa me ti me as P K bl o o d dra ws, 1 2 -lea d E C Gs will be o btai ne d pri or t o a n d as cl ose as p ossi ble t o 
ha vi n g bl o o d dra w n. T h e all o we d sa m pli n g wi n d o w f or 1 2 -lea d E C Gs is ± 3 0  mi n utes fr o m t h e n o mi n al ti me p oi nt f or all p ost d ose 1 2 -lea d E C Gs a n d n o less t ha n 1 0 mi n utes pri or t o d osi n g 
f or pre d ose 1 2-lea d E C Gs. 
f. Vital si g n meas ure me nts (s u pi n e B P a n d p ulse rate) will b e o btai n e d at Scree ni n g, C h ec k -i n ( Da y -1), Da y  1 ( pre d ose), Da y 5 ( 9 6  h o urs p ost d ose o n Da y 1 ), Da y 6 ( pre d ose a n d 2  h o urs 
p ost d ose), Da y 1 2 ( pre d ose), Da y 1 5 ( pre d ose a n d 2  h o urs p ost d ose), Da y 1 7 ( pre d ose), a n d Da y 2 0 ( 2 4  h o urs p ost d ose o n Da y 1 9), a n d Da y 2 3 ( 9 6  h o urs p ost d ose o n Da y 1 9 [ E O T]) or E T. 
Bl o o d press ure a n d p ulse rate will b e meas ure d usi n g t h e sa me ar m f or eac h rea di n g after t h e s u bject h as b ee n s u pi n e f or at least 5  mi n utes. W he n sc he d ule d at t he sa me ti me as P K bl o o d 
dra ws, vital si g n meas ure me nts s h o ul d b e carrie d o ut pri or t o a n d as cl ose as p ossi ble t o h a vi n g bl o o d dra w n. T h e all o we d sa m pli n g wi n d o w f or vital si g n meas ure me nts is ±  3 0  mi n utes fr o m 
t he n o mi nal ti me p oi nt f or all p ost d ose vital si g n meas ure me nts a n d n o less t h a n 1 0 mi n utes pri or t o d osi n g f or pre d ose vital si g n meas ure me nts.  
g.  Res pirat or y rate a n d b o d y te m p erat ure will b e o btai n e d at Scree ni n g, C h ec k -i n ( Da y -1), a n d Da y 2 3 ( 9 6  h o urs p ost d ose o n Da y 1 9 [ E O T]) or E T.  
h.  O x y ge n sat urati o n will b e meas ure d via p ulse o xi metr y at Scree ni n g, C h ec k -i n ( Da y -1), pre d ose o n Da y 1, a n d Da y 2 3 ( 9 6  h o urs p ost d ose o n Da y 1 9 [ E O T]) o r E T. T he all o we d sa m pli n g 
wi n d o w f or o x y g e n sat urati o n meas ure me nts is ±  3 0  mi n utes fr o m t h e n o mi n al ti me p oi nt f or all p ost d ose o x y g e n sat urati o n meas ure me nts a n d n o less t ha n 1 0  mi n utes pri or t o d osi n g f or 
pre d ose o x y g e n sat urati o n meas ure me nts.  
i. A H D Y F? i n q uir y will b e p erf or me d at Scree ni n g (after t h e I C F is si g n e d), at C h ec k-i n ( Da y -1), at eac h p ost d ose vital si g n meas ure me nt, a n d at a n a p pr o priate ti me f or all ot her da ys.  
j. A d verse e ve nts a n d S A Es will b e c ollecte d b e gi n ni n g at i nf or me d c o nse nt. A d v erse  e v e nts will b e rec or d e d t hr o u g h o ut t he st u d y (ie, fr o m si g ni n g of t he I C F u ntil E O S, or u ntil E T if t he 
s u bject disc o nti n u es fr o m t h e st u d y a n d d o es n ot c o m plete a f oll o w-u p p h o n e call), eit h er as s u bject me dical hist or y (if t he e ve nt is re p orte d as be gi n ni n g pri or t o si g ni n g of t he I C F or if t he 
e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 a n d is assesse d as n ot relate d t o st u d y pr o ce d ures b y t h e I n v esti gat or [ or desi g nee]) or as A Es (if t he e ve nt occ urs after si g ni n g of t he 
I C F b ut pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 a n d is assesse d b y t h e I n v esti g at or [ or d esi g n ee]) as relate d t o st u d y pr oce d ures, or if t he e ve nt occ urs after st u d y dr u g a d mi nistrati o n o n 
Da y  1 t hr o u g h E O T or E T re g ar dless of relati o ns hi p t o st u d y dr u g). Fr o m E O T or E T  t hr o u g h E O S, o nl y A Es assesse d as relate d t o st u d y dr u g are t o be rec or de d. All S A Es t hat de vel o p fr o m 
t he ti me of I C F si g ni n g u ntil E O S ( or E T if t h e s u bject disc o nti n u es fr o m t h e st u d y a n d d o es n ot c o m plete a f oll o w-u p p h o ne call) are t o be re p orte d.  
k.  O n  Da y  1 a n d Da y 1 5, t h e pr o b e dr u g c o c ktail ( 2 0 0  m g caffei n e [ta blet], 4 0  m g o me praz ole [ca ps ule], a n d 1 0 m g warfari n [ta blet]) a n d  1 0  m g vita mi n K (ta blets) will be a d mi nistere d orall y 
i n t he m or ni n g f oll o wi n g a fast of at least 1 0 h o urs pri or t o d osi n g a n d 2  h o urs p ost d ose ( wit h water restricte d f or 1 h o ur pri or t o a n d 1 h o ur p ost d ose a d mi nistrati o n). 
l. O n Da y 6 t hr o u g h Da y 1 9, oral d oses of 2 0 0  m g L O X O -3 0 5 will be a d mi nistere d Q D i n t h e m or ni n g at t h e act u al ti me of t he Da y 1 pr o be dr u g c oc ktail d osi n g ( ±  1 h o ur). O n Da ys 7 t hr o u g h 
1 1, a n d Da ys 1 3, 1 4, 1 6, 1 8, a n d 1 9, s u bjects will b e faste d f or at least 2  h o urs pre d ose a n d 1 h o ur p ost d ose. O n d a ys w here cli nical la b orat or y e val uati o ns are perf or me d ( Da y 2, Da y 6, Da y 
1 2, a n d Da y 1 7) s u bjects will b e faste d f or 8  h o urs pre d ose a n d 1 h o ur p ost d ose. O n Da y 1 5, 2 0 0  m g L O X O -3 0 5 will b e c oa d mi nistere d wit h pr o be dr u g c oc ktail ( 2 0 0  m g caffei ne [ta blet], 
4 0  m g o me pra z ole [ca ps ule], a n d 1 0  m g warfari n [ta blet]) a n d 1 0  m g vita mi n K (ta blets) i n t h e m or ni n g at t h e act u al ti me of t he Da y 1 pr o be dr u g c oc ktail d osi n g ( ± 1 h o ur), f oll o wi n g a fast 
of 1 0  h o urs pri or t o d osi n g  a n d 2  h o urs p ost d ose ( wit h water restricte d f or 1 h o ur pri or  t o a n d 1 h o ur p ost d ose).  
m.  C CI


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9  
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 8 of 6 8 
n.  
o.  Cli n ical c he mistr y p a n el (faste d f or at least 8 h o urs), c o a g ulati o n par a meters, h e mat ol o g y p a n el, a n d U A will b e p erf or me d at Scree ni n g, C hec k -i n (Da y -1), Da y 2 ( 2 4  h o urs p ost d ose 
o n  Da y  1), Da y  6 ( pre d ose), Da y 1 2 ( pre d ose), Da y  1 5 ( pre d ose), Da y 1 7 ( pre d ose), Da y 2 0 ( 2 4 h o urs p ost d ose o n Da y 1 9), a n d Da y 2 2 ( 7 2  h o urs p ost d ose o n Da y 1 9, if t he s u bject 
c o m pletes t he st u d y [ E O T]), or o n t h e d a y of E T. At E T or t h e d a y b ef ore E O T ( Da y 2 2), s u bjects are n ot re q uire d t o b e faste d  pri or t o cli nical la b orat or y e val uati o ns.  
p.  Testi n g f or C O VI D -1 9 will b e c o n d u cte d at a mi ni m u m at Scree ni n g a n d C h ec k -i n ( Da y -1). Testi n g f or C O VI D -1 9 ma y als o be c o n d ucte d peri o dicall y d uri n g t he s u bject’s C R U 
c o nfi ne me nt, at t h e discreti o n of t h e I n v esti g at or ( or d esi g n ee). Tests will b e p erf or me d b y ra pi d p ol y merase c h ai n reacti o n or e q ui vale nt.  
q.  Uri n e dr u g scree n f or dr u gs of a b use (i n cl u di n g c oti ni n e) a n d alc o h ol scree n ( uri n e or breat h).  
r. Pri or a n d c o n c o mita nt me dicati o n a d mi nistrati o n will b e rec or d e d be gi n ni n g at i nf or me d c o nse nt. I n a d diti o n, all I n v esti gat or -a p pr o ve d prescri pti o n a n d o ver -t he-c ou nter me dicati o ns ta ke n 
b y a s u bject wit hi n 1 4  d a ys or 5 half -li v es (if k n o w n), w hic h e v er is l o n g er, pri or t o Da y 1 will b e rec or d e d o n t h e s u bject’s electr o nic C R F. 
s. Fe male s u bjects o nl y. Perf or me d at Scree ni n g, C h ec k -i n ( Da y -1), a n d Da y 2 2 ( 7 2  h o urs p ost d ose o n Da y 1 9), if t h e s u bject c o m pletes t he st u d y ( E O T) or o n t he da y of E T.  
t. P ost -me n o pa usal fe male s u bjects o nl y.  
u.  E n d of Treat me nt is d efi n e d as w h e n t h e s u bject is release d fr o m t h e C R U f oll o wi n g c o m pleti o n of all assess m e nts t hr o u g h Da y  2 3. Earl y Ter mi nati o n is defi ne d as w he n t he s u bject is 
release d fr o m t h e C R U if t h e s u bject ter mi n ates t h e st u d y earl y. Vital si g n meas ure me nts, E C G, a n d a b bre viate d p h ysical e xa mi nati o n res ults are t o be a vaila ble f or re vie w b y t he I n vesti gat or  
( or desi g nee) pri or t o s u bject release fr o m t h e C R U o n Da y 2 3 ( E O T) or E T. Cli nical la b orat or y res ults (f or cli nical c h e mistr y, he mat ol o g y, c oa g ulati o n, a n d U A) a n d ser u m pre g na nc y test 
res ults (fe male s u bjects o nl y) are t o b e a v aila ble f or re vie w b y t h e I n v esti g at or ( or d esi g n ee) pri or t o s u bject release fr o m t he C R U at t he E O T visit a n d pri or t o s u bject release fr o m t he C R U 
at t he E T visit if a v aila ble. 
v.  T o be c o n d ucte d 7  d a ys ( ±  2 d a ys) f oll o wi n g E O T or E T. E n d of St u d y is d efi n e d as w h e n t h e s u bject is c o ntacte d b y t he C R U f o r a f oll o w-u p p h o ne call 7  da ys ( ±  2 da ys) after t he E O T visit 
or E T visit t o d eter mi n e if a n y S A E or st u d y dr u g -relate d A E h as o cc urre d si n ce t h e E O T or E T visit. All s u bjects w h o recei ve d L O X O-3 0 5 or pr o be dr u g c oc ktail (i ncl u di n g s u bjects w h o 
are ter mi nate d earl y) will recei v e a f oll o w -u p p h o n e call.  
w.  De n otes pre d ose sa m ple c ollecti o n o nl y.  
C CI

SAP_001.pdf: 
Statistical Analysis Plan LOXO-BTK-20010 
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to Investigate the Effect of 
Multiple Oral Doses of LOXO-305 on CYP1A2, CYP2C9, and CYP2Cl9 Substrates Using a Probe 
Drug Cocktail in Healthy Subjects 
NCT06215430 
Approval date: 26-Mar-2021 


Statistical Analysis Plan 
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to 
Investigate the Effect of Multiple Oral Doses of LOXO-305 on CYP1A2, 
CYP2C9, and CYP2C19 Substrates using a Probe Drug Cocktail in 
Healthy Subjects 
SAP Status: Sponsor Final 
SAP Version: 1.0 
SAP Date: 26MAR2021 
Investigational Product: LOXO-305 
Protocol Reference: LOXO-BTK-20010 
Covance Stttdy: 8419689 
Sponsor: 
Loxo Oncology, Inc. 
A wholly owned subsidia1y of Eli Lilly and 
Company 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
Coordinating Principal Investigator: 
PD 
Coordinating Investigator Study Site: 
Covance Clinical Research Unit Inc. 
1341 West Mockingbird Lane, Suite 200E 
Dallas, Texas 75247 
USA 
Info1111ation described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 


SAP 
Covance Study: 8419689 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20010 
TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................. 1 
TABLE OF CONTENTS ............................................................................................................ 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ........................................ ......................................................................... 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
2 .1. Prima1y Objective ........................................................................................................... 6 
2.2. Secondaiy Objective ........................................................................................................ 6 
3. STUDY ENDPOINTS ........................................................................................................... 6 
3 .1. Prima1y Endpoints ............................................................................................................ 6 
3.2. Secondaiy Endpoints .............................. ......................................................................... 7 
4. STUDY DESIGN .................................................................................................................... 7 
5. SAMPLE SIZE WSTIFICATION ............... ......................................................................... 9 
6. STUDY TREATMENTS ........................................................................................................ 9 
7. DEFINITIONS OF POPULATIONS .................................................................................. 10 
7.1. All Subjects Population .................................................................................................. 10 
7 .2. Safety Population ........................................................................................................... 11 
7 .3. Pharmacokinetic Population .......................................................................................... 11 
8. STATISTICAL METHODOLOGY ..................................................................................... 11 
8.1. General ................................................... ....................................................................... 11 
8.1.1. Calculation of the Summa1y Statistics ................................................................... 11 
8.1.2. Repeat and Unscheduled Readings ........................................................................ 12 
8.1.3. Definitions of Baseline and Change from Baseline ............................................... 12 
8.2. Subject Disposition and Population Assignment .......................................................... 13 
8.3. Screening Demographics and Baseline Characteristics ................................................ 13 
8.4. Prior and Concomitant Medication ................................................................................ 13 
8.5. Pharmacokinetic Assessments ............... ....................................................................... 13 
8.5.1. Phannacokinetic Analysis ...................................................................................... 13 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 16 
8.5.3. Phannacokinetic Statistical Methodology .............................................................. 16 
8.6. Safety and Tolerability Assessments ..... ....................................................................... 17 
8.6.1. Adverse Events ........................................................................................................ 17 
8.6.2. Clinical Laboratory Parameters ....... ....................................................................... 19 
Sponsor Final, Version 1.0, 26MAR2021 
Page 2 of 21 
ST-AD-031 Version 01 


SAP 
Covance Study: 8419689 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20010 
8.6.3. Vital Signs Parameters .................... ....................................................................... 19 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 19 
8.6.5. Other Assessments .................................................................................................. 20 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 20 
9. INTERIM ANALYSES ........................................................................................................ 20 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 20 
11. REFERENCES ................................................................................................................... 20 
12. APPENDICES .................................................................................................................... 21 
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LIST OF ABBREVIATIONS 
Abbreviations pe1tain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs ]). 
%AUCextrap 
AUCo-24 
AUCo-t 
AUCo-inf 
ADaM 
AE 
BLQ 
CDISC 
CI 
CL/F 
Cnax 
CRU 
CSR 
CTCAE 
CV 
CYP 
ECG 
EOS 
EOT 
ET 
Geom CV 
Geom Mean 
ICF 
ICH 
Az 
"A,z Lower 
"A,z N 
Az Span Ratio 
"A,z Upper 
LSM 
Az 
percentage extrapolation for AUCo-inf 
area under the concentration-time cmve from hour Oto 24 hours 
postdose 
area under the concentration-time cmve from hour Oto the last 
measurable concentration 
area under the concentration-time cmve from hour 0 extrapolated to 
infinity 
analysis data model 
adverse event 
below the limit of quantification 
Clinical Data Interchange Standards Consortium 
confidence inte1val 
apparent systemic clearance 
maximum obse1ved plasma concentration 
Clinical Research Unit 
clinical study repo1t 
Common Tenninology Criteria for Adverse Events 
coefficient of variation 
cytochrome P450 
electrocardiogram 
End of Study 
End of Treatment 
Early Tennination 
geometric CV 
geometric mean 
Infonned Consent Fann 
International Council for/Conference on Hannonisation of Technical 
Requirements for Registration of Phannaceuticals for Human Use 
apparent tenninal elimination rate constant 
sta1t of exponential fit 
number of data points included in the log-linear regression 
time period over which Az was determined as a ratio oftv2 
end of exponential fit 
least squares mean 
apparent terminal elimination rate constant 
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MedDRA 
MRAUCo-24 
MRLnt 
NC 
NR 
PK 
QD 
QTcF 
R2-adj 
SAE 
SAP 
SD 
ti,2 
TEAE 
TFL 
tmax 
VzlF 
WHODmg 
Medical Dictiona1y for Regulatory Activities 
ratio of paraxanthine AUCo-24 to caffeine AUCo-24 
mean residence time extrapolated to infinity 
not calculated 
notrep01ted 
phannacokinetic( s) 
once daily 
QT interval conected for l1ea1t rate using Fridericia 's f 01mula 
adjusted coefficient for dete1mination of exponential fit 
serious adverse event 
statistical analysis plan 
standard deviation 
apparent plasma tenninal elimination half-life 
treatment-emergent adverse event 
table, figure, and listing 
time to maximum observed plasma concentration 
apparent volume of distrib11tion at the te1minal phase 
World Health Organization Drng Dictiona1y 
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1. INTRODUCTION 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20010 
This SAP has been developed after review of the clinical study protocol (Final Version 1. 0 
dated 09 December 2020) and electronic case report forn1. 
This SAP describes the planned analysis of the pha1macokinetic (PK), and safety and 
tolerability data from this study. A detailed description of the planned TFLs to be presented 
in the clinical study repo1t (CSR) is provided in the accompanying TFL shells document. 
In general, the analyses are based on info1mation from the protocol, unless they have been 
modified by agreement with Loxo Oncology, Inc. A limited amount of inf01mation about this 
study (eg, objectives, study design) is given to :help the reader's interpretation. Th.is SAP 
must be finalized prior to the lock of the clinical database for this study. When the SAP and 
TFL shells are approved, they will serve as the template for this study's CSR. 
This SAP supersedes any statistical considerati-ons identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be perfo1med 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Loxo Oncology, Inc. and identified in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Ha1monisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content o.fClinical Study Reports.1,2 
The document history is presented in Appendix 1. 
2. STUDY OBJECTIVES 
2.1. Primuy Objective 
The p1imary objective of the study is to assess the effect of multiple oral doses ofLOXO-305 
on the PK of single oral doses of caffeine (cytochrome P450 [CYP]1A2 substrate), 
S-warfarin (CYP2C9 substrnte), and omeprazole (CYP2C19 substrate) in healthy subjects. 
2.2. Secondary Objective 
The secondary objective of the study is to assess the safety and tolerability of multiple oral 
doses ofLOXO-305 when administered alone, and coadministered with a single oral dose of 
probe drng cocktail. 
3. STUDY ENDPOINTS 
3.1. Primary Endpoints 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of caffeine/paraxanthine, omeprazole, S-warfarin, and LOXO-305 (as 
appropriate): 
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• area under the concentration-time curve from hour Oto 24 hours postdose (AUCo-24) 
• area under the concentration-time cmve from ham 0 to the last measurable 
concentration (AUCo-t) 
• area under the concentration-time cmve from ham 0 extrapolated to infinity (AUCo-inf) 
• percentage extrapolation for AUCo-inf (%AUCext:rap) 
• apparent systemic clearance (CL/F) 
• apparent plasma tenninal elimination half-life (tin) 
• maximum obse1ved plasma concentration (Cnax) 
• time to maximum obse1ved plasma concentration (tmax) 
• apparent te1minal elimination rate constant (Az) 
• apparent volume of distribution at the terminal phase 01 zlF)) 
• mean residence time extrapolated to infinity (MRTinf) 
• AUCratio ofparaxanthine to caffeine ([MRAUC]; paraxanthine only). 
3.2. Secondary Endpoints 
Safety and tolerability will be assessed by monitoring adverse events (AEs), perfonning 
physical examinations and clinical laborato1y evaluations, measuring vital signs, and 
recording 12-lead electrocardiograms (ECGs). 
4. STUDY DESIGN 
This is a Phase 1, open-label, 2-period, fixed-sequence drng-drug interaction study to 
investigate the effect of multiple oral doses oflLOXO-305 on the PK of single oral doses of 
caffeine (CYP1A2 substrate) and its metabolite paraxanthine, S-warfarin (CYP2C9 
substrate), and omeprazole (CYP2C19 substrate) in healthy subjects. 
fu Period 1, Day 1, 200 mg caffeine (tablet), 40 mg omeprazole (capsule), and 
10 mg warfarin (tablet) administered as a single dose of probe dmg cocktail, along with 
10 mg vitamin K (tablets), will be administered in the morning following a fast of at least 
10 hours predose and 2 hours postdose. Blood samples for concentrations of the substrates 
( ca.ffeine/paraxanthine, omeprazole, and S-warfarin) in plasma will be collected predose 
through 120 hours postdose on Day 1. Of these samples, samples will be analyzed for 
concentrations of caffeine/paraxanthine from pTedose through 24 hours postdose, for 
concentrations of omeprazole 
, and for 
concentrations of 
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There will be a washout period of 5 days between administration of the probe drng cocktail 
on Day 1 and the fust dose of LOXO-305 on Day 6. 
fu Period 2, on Days 6 through 19, oral doses of200 mg LOXO-305 will be administered 
once daily (QD) for 14 consecutive days in the morning at the actual time of the Day 1 probe 
drng cocktail dosing (± 1 hour). On Day 15, LOXO-305 will be coadministered with 200 mg 
caffeine (tablet), 40 mg omeprazole (capsule), and 10 mg warfarin (tablet) administered as a 
single dose of probe drng cocktail, along with 10 mg of vitamin K (tablets) at the actual time 
of the Day 1 probe chug cocktail dosing ( ± 1 hour) following a fast of at least 10 hours 
predose and 2 hours postdose. On Days 7 throllgh 11, and Days 13, 14, 16, 18, and 19, 
subjects will fast for at least 2 hours predose and 1-hour postdose. On Days 6, 12, and 17 
where clinical laboratory evaluations are performed, subjects will fast for at least 8 hours 
predose and 1 hour postdose. Blood samples for concentrations ofLOXO-305 in plasma will 
. Samples collected 
LOXO-305 dosing 
. Blood samples for 
concentrations of the substrates (caffeine/parax:anthine, omeprazole, and S-warfarin) in 
plasma will be 
; of these samples, 
samples will be analyzed for concentrations of caffeine/paraxanthine fro 
, for concentrations of omeprazole 
and for concentrations of 
A schematic of the study design is presented in. Figure 1. 
Figure 1: 
Study Design 
.____,___.I ....__
I
____. .___ _ 
__.I ,____I ___ 
__.I ....__I____. 
Days -35 to -2 
11 
Day -1 
Days 1 to 5 
11 
Oays 6 to 23 
I 
7 (± 2) days 
_ ....
. ----~ ~-----
-~ 
afterOlscharge 
j 
Days 6to 19 
i j Oay 23 I 
I 
1 
LOXO-305 
f 
C llnlc ·Ofsch1roe 
EOTIET 
I 
Pro be Drug Coe II.tall 
I 
PK sampling: 
I 
Day 1: )20 hours postdos,e 
LOXO-305 • Probe Drug 
CockraH 
PK Sampling: 
Days 6 to 14~ Predose 
Oay 15: 19:Z hour$ po$tdose 
Salery As!lessments: From signing the ICF to loUow-up pho~ call 
EOT= end of treatment; ET = early tennination; ICF = informed consent form. 
The sta1t of the study is defined as the date the first subject who is enrolled in the study 
signed an fufo1med Consent F01m (ICF). Note that enrolled subjects are defined as those 
subjects who are assigned to receive a dose of study chug; this definition excludes screen 
failure subjects. Replacement subjects may be enrolled only if deemed necessary by the 
Sponsor. 
Subjects who are dete1mined to be screen faihll"es are pennitted to be re-screened if the 
fuvestigator (or designee), with agreement from the Sponsor, feels that the subject may meet 
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eligibility criteria upon re-screen. Re-screened subjects will be provided a new subject 
number. 
To assess their eligibility to enter the study, potential subjects will be screened within 34 days 
(Days -35 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day-1) until End of 
Treatment (EOT) on Day 23 upon completion of all PK and safety assessments or Early 
Tennination (ET) if the subject discontinues. Dosing of probe drng cocktail will occur on 
Day 1 and Day 15 and dosing ofLOXO-305 will occur on Days 6 through 19. A follow-up 
phone call will occur for all subjects who received at least 1 dose of study dmg (including 
subjects who are tenninated early) 7 days(± 2 days) after EOT or ET. The duration of 
pa1ticipation is expected to be approximately 67 days (Screening through follow-up phone 
call). 
fu this study, physical examinations, 12-lead ECGs, vital sign measurements, How Do You 
Feel? inquiries, clinical chemistiy panel, coagulation parameters, hematology panel, 
urinalysis, and recording of concomitant medications will be perfmmed at specified times 
during the study. 
AEs and serious AEs (SAEs) will be collected 1beginning at inf01med consent AEs will be 
rep01ted throughout the study (ie, from signing of the ICF until End of Study [EOS], or until 
ET if the subject discontinues from the study amd does not complete a follow-up phone call), 
either as subject medical history (if the event is reported as beginning prior to signing of the 
ICF or if the event occurs p1ior to study drng administration on Day 1 and is assessed as not 
related to study procedures by the fuvestigator [ or designee]) or as AEs (if the event occurs 
after signing of the ICF but prior to study drng adminisu·ation on Day 1 and is assessed as 
related to study procedures by the fuvestigator [ or designee], or if the event occurs after study 
drug administration on Day 1 through EOT or ET regardless of relationship to study drug). 
From EOT or ET through EOS, only AEs assessed as related to study drng by the 
fuvestigator (or designee) are to be repo1ted. All SAEs that develop from the time ofICF 
signing until EOS ( or ET, if the subject discontinues from the study and does not complete a 
follow-up phone call) are to be repmted. Study completion is defined as the time of the last 
subject's follow-up. 
5. SAMPLE SIZE JUSTIFICATION 
Up 
healthy adult male and female subjects (women of non-childbearing potential only) 
will be enrolled. The sample size chosen for this study was selected without statistical 
considerations but is consistent with previous studies of a similar design. Up 
subjects 
are anticipated to be sufficient to provide a reliable estimate of the magnitude and va1iability 
of the interaction. Replacement subjects may be enrolled only if deemed necessa1y by the 
Sponsor. Every attempt will be made to enroll at least 4 subjects of each sex in the study. 
6. STUDY TREATMENTS 
The study treatment sequence name and ordering to be used in the TFLs are presented in 
Table 1. 
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Table 1: 
Presentation of Study Treatment Sequence in TFLs 
Study Treatment Sequence Label 
Probe Dmg Cocktail (Dl-5)/ 200 mg LOXO-305 QD (D6-14)/ 200 mg LOXO-305 QD + Probe 
Drug Cocktail (DlS-19)/ 200 mg LOXO-305 QD (D20) 
QD = once daily; TFL = table, figure, and listing. 
Error! Reference source not found. shows a list of the PK treatment labels and ordering 
that will be used in the TFLs. 
Table 2: 
Pharmacokinetic Treatment Labels 
Study Treatment Labels 
Orde1· in TFLs 
200 mg caffeine 
1 
200 mg LOXO-305 QD + 200 mg caffeine 
2 
40 mg omeprazole 
3 
200 mg LOXO-305 QD + 40 mg omeprazole 
4 
10 mg wa.rfarin 
5 
200 mg LOXO-305 QD + 10 mg wa.rfa1in 
6 
200 mg LOXO-305 QD 
7 
QD = once daily; TFL = table, figure, and listing. 
The study treatment names and ordering to be used in the TFLs are presented in Table 3. 
Table 3: 
Presentation of Study Treatment Labels in TFLs (Safety) 
Study Treatment Labels 
Probe Dmg Cocktail* 
200 mg LOXO-305 QD 
200 mg LOXO-305 QD + Probe Dmg Cocktail* 
QD = once daily; TFL = table, figure, and listing. 
*200 mg caffeine + 40 mg omeprazole + 10 mg warfarin + 10 :mg Vitamin K 
Order in TFLs 
1 
2 
3 
All treatments described above are the planned treatments. The TFLs will reflect the actual 
t1eatments received. 
7. DEFINITIONS OF POPULATIONS 
Any protocol deviations will be considered prior to database lock for their importance and 
taken into consideration when assigning subjects to populations. 
7.1. All Subjects Population 
The all subjects population will consist of all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol. 
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7 .2. Safety Population 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20010 
The safety population will consist of all subjects who have received at least 1 dose of study 
drng (probe cocktail chugs and/or LOXO-305). Subjects will be classified into groups based 
on actual treatment received. 
7 .3. Pharmacokinetic Population 
The PK population will consist of all subjects who have received a dose ofLOXO-305 or the 
probe cocktail chugs, have at least 1 quantifiable plasma concentrntion, and for whom at least 
1 PK parameter can be computed. A subject may be excluded from the PK summa1y statistics 
and statistical analysis if the subject has an AE of vomiting that occms at or before 2 times 
the median tmax- The impact of protocol deviations on the PK population will be evaluated on 
a case-by-case basis. 
8. STATISTICAL METHODOLOGY 
8.1. General 
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all subjects population and include data up to the point of study 
completion or discontinuation. Subjects are generally considered to have completed the study 
if they completed all protocol-specified procedures and assessments for the EOS visit. Any 
subject who discontinued the study will be identified accordingly in the listings. Summa1ies 
and statistical analyses will include the subjects assigned to the relevant population based on 
data type. 
Data analysis will be performed using the SAS® statistical software package Version 9 .4 ( or 
higher if upversioned during the study). 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data futerchange 
Standards Conso1tium (CDISC) ADaM Versio112.1 (or higher ifupversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.2 (or higher ifupversioned 
dming the study). Pinnacle 21 Community Validator Version 3.1.0 (or higher ifupversioned 
dming the study) will be utilized to ensme compliance with CDISC standards. 
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations. 
Where reference is made to 'all calculations', this includes, but is not limited to, smnma1y 
statistics, statistical analyses, baseline derivation, changes from baseline and any parameter 
derivations. 
8.1.1. Calculation of the Summary Statistics 
For continuous data the following rnles will be applied: 
• 
Missing values will not be imputed, unless specifically stated otherwise. 
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• 
Unrounded data will be used in the calculation of sumnuny statistics. 
• If the number of subjects with valid obse1vations (n) <3, summa1y statistics will not 
be calculated, with the exception of n, minimum, and maximum. 
• 
As ET data is not associated with any scheduled timepoint, it will be excluded from 
all calculations of summa1y statistics. 
• 
Postdose repeats and unscheduled assessments will not be included in calculations of 
summa1y statistics. 
For categorical data the following rnles will be applied: 
• If the categories of a parameter are ordered ( eg, AE seve1ity), all categories between 
the possible minimum and maximum categolies will be included, even if n = 0 for a 
given catego1y. If the categories are not ordered ( eg, race), only those categories for 
which there is at least 1 subject represented will be included. 
• 
Missing values will not be imputed, with the exception of AEs where the 'worst-case' 
approach will be taken (see Section 8.6_ 1), or unless specifically stated othe1wise. A 
'missing' catego1y will be included for any parameter for which info1mation is 
missing. This will ensure that the population size totals are consistent across different 
parameters. 
All protocol deviations and data issues (eg missing data, out of protocol window) that occur 
during the study, including those related to COVID-19, will be considered prior to database 
lock for their seve1ity/impact on how the data will be displayed. 
8.1.2. Repeat and Unscheduled Readings 
For vital signs measurements and ECG data only, any predose value recorded in addition to 
the 01iginal value or a postdose value recorded within 15 minutes of the original value will be 
defined as a repeat value; any postdose value recorded more than 15 minutes after the 
original value will be defined as an unscheduled value. For all other data types (eg, laboratory 
parameters), any value recorded in addition to the original value will be defined as an 
unscheduled value. 
The original scheduled value will be used in all calculations post dose. In the event of any 
repeats or unscheduled measurements taken pre-dose the values will be considered when 
determining the baseline value. 
Post dose repeats, unscheduled assessments, and ET measurements will be excluded from all 
calculations, with the exception of the baseline derivation (see Section 8.1.3). 
8.1.3. Definitions of Baseline and Change from Baseline 
The baseline will be defined as the last non-missing measurement before administration of 
study mug on Day 1, Period 1. 
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If the date/time of the value is incomplete or missing, it will be excluded from the baseline 
calculation, unless the incomplete date/time indicates the value was recorded prior to dosing. 
fudividual changes from baseline will be calculated by subtracting the individual subject's 
baseline value from the value at the tin1epoint. The mean change from baseline will be 
defmed as the mean of the individual changes from baseline for all subjects. 
See Section 8.1.2 for more detail on handling repeat and unscheduled readings in the 
calculations. 
8.2. Subject Disposition and Population Assignment 
Subject disposition and population assignment will be listed. 
A summa1y table by treatment sequence will be provided, based on the all subjects 
population. 
8.3. Screening Demographics and Baseline Characteristics 
The screening demographics and baseline characteristics including age, sex, race, ethnicity, 
height, body weight, and body mass index will be listed. 
A summaiy table will be provided, based on the safety population. 
8,4, Prior and Concomitant Medication 
Prior medication will be defmed as medication that ends prior to the first dose. Concomitant 
medication will be defined as medication that s tarts during or after the first dose or sta1ts but 
does not end prior to the first dose. 
Prior and concomitant medications will be coded using the World Health Organization Dmg 
Dictionary (WHODmg) Global, Fmmat B3, Version March 2020. Prior and concomitant 
medications will be listed. 
8.5. Pharmacokinetic Assessments 
8.5.1. Pharmacokinetic Analysis 
The following PK parameters will be dete1mined where possible from the plasma 
concentrations of caffeine, paraxanthine, omep:rnzole, S-warfarin, and LOXO-305 (unless 
othe1wise indicated) using noncompa1tmental methods in validated software program 
Phoenix WinNonlin (Ce1tara, Version 8.1 or higher): 
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Parameter 
Units
3 
AUCo-24 
h*ng/mL 
AUCo-t 
h*ng/mL 
AUCo-inf 
h*ng/mL 
¾AUCextrap 
% 
Cxnax 
ng/mL 
tmax 
h 
Az 
1/h 
t112 
h 
CL/F 
L/h 
Vz/F 
L 
MRTinf 
h 
MRAUC 
NA 
NA Not applicable 
Definition 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20010 
area under the concentration-time curve from hour O to 24 hours 
postdoseb 
area under the concentrntion-time cmve from hour O to the last 
measurable concentration (t1as1? 
ai-ea under the concentration-time cmve from hour O extrapolated 
to infinity" ( except LOXO-305) 
percentage extrapolation for AUC0-inf ( except LOXO-305) 
maximum observed plasma concentration 
time to maximum obse1ved plasma concentration 
apparent terminal elimination rate constant ( except LOXO-305) 
apparent tenninal elimination half-life 
apparent systemic clearance ( except paraxanthine) 
apparent volume -of distiibution at the terminal phase ( except 
LOXO-305 and paraxanthine) 
mean residence time (based on AUCo-inf; except for LOXO-305) 
ratio ofparaxanthine AUC to caffeine AUC (based on AUC0-24 
and AUC0-48 if possible) 
• Units are based on concentration units (provided by the bioanalytical lab or prefe1Ted units for presentation of PK 
parameters) and dose units used in the study. 
b .Al"ea m1der the concentration-time curve will be calculated using the Ii.near trapezoidal mle for increasing and decreasing 
concentrations 
c Based on the last observed quantifiable concentration 
Additional PK parameters may be dete1mined where appropriate. 
The PK analysis will be cani.ed out where possible using actual blood sampling times 
postdose. If an actual time is missing, the sample concentration result will be treated as 
missing unless there is scientific justification to include the result using the nominal time. 
The parameters Cmax and tmax will be obtained directly from the concentration-time profiles. If 
Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occmTence of Cmax. 
8.5.1.1. Criteria for the Calculation of Appat·ent Terminal Elimination Rate Constant 
and Half-life 
The start of the te1minal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations. 
The apparent te1minal elimination rate constant (Az) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for dete1mination of exponential fit (R2-adj) of the regression line is 2:0.7. 
Parameters requiring Az for their calculation (eg, AUCo-inf, t112, CL/F, V.JF, and MRTinf) will 
only be calculated if the R2-adj value of the regression line is 2:0.7. 
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The following regression-related diagnostic PK parameters will be determined, when 
possible: 
Parameter 
Az Upper 
Az Lower 
Az N 
Az Span Ratio 
R2-adj 
Units 
h 
h 
NA 
NA 
NA 
Definition 
end of exponential fit 
sta1t of exponential fit 
number of data points included in the log-linear regression 
time period over which Az was determined as a ratio of 1112 
adjusted coefficient for determination of exponential fit 
Where possible, the span of time used in the detem1ination of 11.z (ie, the difference between Az 
Upper and Az Lower) should be 22 half-lives. If the Az Span Ratio is <2, the robustness of the 
ti12 values will be discussed in the CSR. 
8.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive concentrations above the lower limit of quantification. If there are only 3 
consecutive concentrations, at least 1 should fo-llow Cmax. 
AUCo-infvalues where the percentage extrapolation is less than 30% will be reported. 
AUCo-infvalues where the percentage extrapolation is greater than 30% will be listed but 
excluded from descriptive statistics. 
If AUCo-inf cannot be determined reliably for all subjects, an alternative AUC measure, such 
as AUC to a fixed time point or AUCo-t, may be used in the statistical analysis. 
8.5.1.3. Criteria for Handling Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQs will be treated as missing. The 
following rnles apply with special situations defined below: 
• If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
• 
Where 2 or more consecutive concentrations are BLQ at the end of a profile, the 
profile will be deemed to have terminated and any fmiher quantifiable concentrations 
will be set to missing for the calculation of the PK parameters, unless they are 
considered to be a trne characteristic of the profile of the dtug. 
• If a predose plasma concentration is missing, it may be set to O by default, with the 
exception ofLOXO-305 on Day 15. If the Day 15 predose plasma concentration of 
LOXO-305 is missing, the Day 15 24-h.our concentration may be used as the predose 
concentration. 
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8.5.1.4. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in the CSR. 
Any quantifiable predose concentration value will be considered anomalous and set to 
missing for the PK analysis. 
8.5.2. Presentation of Pharmacokinetic Data 
fudividual concentrations deemed to be anomalous will be flagged in the listings and 
excluded from the summary statistics. 
For PK concentration data the following rnles w ill apply: 
• 
Values that are BLQ will be set to O for the calculation of sllIIllnaiy statistics. 
• 
Arithmetic mean or median values that are BLQ will be presented as 0. 
• If any BLQ results (treated as 0) are in a series of smnmai·ized data, geometric mean 
and coefficient of vai·iation (CV) of geometric mean will be reported as not calculated 
(NC). 
For PK parameters the following mle will apply; 
• For the calculation of summa1y statistics of PK parameters, all not rep011ed (NR) and 
not calculated (NC) values in a data se1ies will be set to missing. 
• The A.UC values will be set to NC if they have been calculated using fewer than 3 
concentrations, and/or 3 concentrations if the last is Cmax. 
• 
Geometric mean and CV will not be calculated for tmax. 
8.5.3. Pharmacokinetic Statistical Metbodolmgy 
All PK concentrations and parameters will be listed. 
Smnmary tables, mean(+ standard deviation [SD]) figures, overlaying individual figures, and 
individual figures by analyte and time postdose will be provided for plasma PK 
concentrations. All PK concentration figures will be produced on both linear and semi-
logarithmic scales, with the exception of figures across all days, which will be produced on 
the linear scale only. The +SD bai·s will only be displayed on the linear scale. 
Smnmruy tables by treatment will be provided for all PK pai·ameters, with the exception of 
diagnostic regression-related PK parameters. Surnma1y statistics (n, Mean, SD, CV, 
minimum, median, maximum, geometric mean [ Geom Mean] and geometric CV [ Geom CV]) 
will be calculated for plasma LOXO-305, caffeine, paraxanthine, omeprazole ai1d S-warfarin 
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PK parameters. Excluded subjects will be listed in the PK parameter tables, but will be 
excluded from the statistical analysis and summary statistics and noted as such in the tables. 
A statistical analysis will be conducted to investigate the chug-chug interaction on the PK of 
the following comparisons: 
• 
LOXO-305 plus caffeine (test) versus c.affeine alone (reference) To test the ch1.1g-drug 
interaction on the PK of caffeine and paraxanthine 
• 
LOXO-305 plus omeprazole (test) versus omeprazole alone (reference) 
• 
LOXO-305 plus wa1farin (test) versus warfarin alone (reference) 
The natural log-transfonned3 PK parameters (AUCo-t, AUCo-inf, Cmax, and:MRAUC for 
paraxanthine only) will be analyzed using a mixed model.4 The model will include actual 
treatment as a fixed effect, and subject as a random effect. 
For each PK parameter separately, the least squares mean (LSM) for each treatment, 
difference in LSMs between the test and reference treatments, and conesponding 90% 
confidence inte1val (Cl) will be calculated; these values will then be exponentiated to give the 
geomet1ic least squares mean, geometric mean ratios, and conesponding 90% CI. 
Additionally, the pooled estimate (across all treatments) of the within-subject CV will be 
calculated, and residual plots will be produced to assess the adequacy of the model(s) fitted. 
Examples of the SAS code that will be used are as follows: 
Mixed Model Analysis 
proc mixed data = <da ta in>; 
by parcat ln par catl par amn param; 
cla ss t rtan us ub jid ; 
model l pk = t r t an / cl res idual ddfm = kr2 ; 
l smeans t r t an / cl pdiff = reference ('l' ) a lpha 
0 .1; 
r andom intercept / s ub jec t
= u s ubjid(t r t s eqp); 
ods output lsmeans = <da t a out>; 
ods output diffs = <da t a out >; 
ods output covparms = <da t a out>; 
r un; 
8.6. Safety and Tolerability Assessments 
8.6.1. Adverse Events 
All AEs will be coded using the Medical Dictiona1y for Regulatmy Activities (MedDRA) 
Version 23.0. All AEs will be assigned severity grade using National Cancer Common 
Te1minology Critelia for Adverse Events (CTCAE) Version 5.0. 
A treatment-emergent adverse event (TEAE) will be defined as an AE that sta1ts during or 
after the first dose, or staits prior to the first dose and increases in severity after the first dose. 
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A trnatment-related TEAE will be defined as a TEAE with a relationship of related to the 
study t:reatmentLOXO-305 and probe drngs and vitamin K, as detennined by the 
investigator. 
The assignment ofTEAEs to the treatments will be as follows: 
• 
A TEAE occm:ring during or after Day 1 dosing and prior to Day 6 dosing will be 
assigned to Probe Drug Cocktail/or 101mg vitamin K 
• 
A TEAE occuning during or after Day 6 dosing and prior to Day 15 dosing will be 
assigned to 200 mg LOXO-305 
• 
A TEAE occuning during or after Day 15 dosing will be assigned to 200 mg LOXO-
305 + Probe Drng Cocktail/or 10 mg viltamin K 
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include de1ived onset time and duration. Onset time will be calculated from the time of the 
last dose for TEAEs only. 
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories: 
• 
TEAEs ( overall, serious, leading to discontinuation, and leading to death) by 
treatment 
• 
TEAEs by severity and treatment 
• 
Treatment-related TEAEs ( overall, serious, leading to discontinuation, and leading to 
death) by treatment 
• 
Treatment-related TEAEs by severity aud treatment 
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following: 
• 
System organ class, prefened tenn, and treatment 
• 
Pref ened te1m and treatment 
For the AE data the following rnles will apply: 
• 
For the derivation of TEAE status: If the sta1t date/time of an AE is incomplete or 
missing, an AE will be assumed to be a TEAE, unless the incomplete sta1t date/time 
or the end date/time indicates an AE sta11ted prior to the first dose. 
• 
For the derivation of treatment-related 1I'EAE status: If the study treatment 
relationship for a TEAE is missing, a T!EAE will be assumed to be a treatment-related 
TEAE. 
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• 
For the derivation of onset time: If the sta1t date/time of an AE is missing, onset time 
will not be calculated. If the start date/time of an AE is incomplete, where possible, 
the minimum possible onset time will be calculated and presented in '2'.DD:HH:MM' 
fonnat (eg, if the date/time of the last dose is 0lMA Y2019/08:00 and recorded start 
date/time of an AE is 03MAY2019, then the minimum possible onset time will be 
calculated by assuming the AE sta1ted at the first hour and minute of03MAY2019 
[03MAY2019/00:00], thus will be presented as onset time ~01:16:00 in the listing). 
• 
For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the strut or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in 'g)D:HH:MM' 
fo1mat (eg, if the strut of an AE date/time is 0lMA Y2019/08:00 and its recorded end 
date/time is 03MA Y2019, then the max:imum possible duration will be calculated by 
assuming the AE ended at the last hour and minute of 03MA Y2019 
[03MAY2019/23:59], thus will be presented as duration ~02:15:59 in the listing). 
• 
For the calculation of summaiy statistics: If a subject experienced multiple TEAEs 
with the same prefen-ed te1m for the same treatment, this will be counted as 1 TEAE 
for that treatment under the maximum severity recorded. 
8.6.2. Clinical Laboratory Parameters 
All clinical laborat01y parameters, with changes from baseline, will be listed; any value 
outside the clinical reference range will be flag_ged, and whether the out of range value was 
deemed clinically significant or not clinically significant will be indicated. 
Tue obse1ved results and change from baseline for clinical chemisfly, hematology, and 
coagulation parameters will be summaiized descriptively by timepoint. Values recorded as 
<x, ~x, >x, or ~x will be displayed in the listings as recorded. For the derivation of listing 
flags, calculation of summaiy statistics, <x and ~x values will be set to 0, whereas >x and ~x 
values will be set to x. 
8.6.3. Vital Signs Parameters 
All vital signs paraineters, with changes from baseline, will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated. 
The obse1ved results and change from baseline for all vital signs results will be summarized 
descriptively by treatment and timepoint. 
8.6.4. 12-lead Electrocardiogram Parameters 
All 12-lead ECG parameters, with changes from baseline, will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated. 
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The observed results and change from baseline for all 12-lead ECG parameters will be 
summarized descriptively by treatment and timepoint. QTcF values that are > 450 msec and 
increase from baseline > 30 msec will be flagged in the data listing. 
8.6.5. Other Assessments 
Medical hist01y and physical examination will be listed. Any physical examination 
abnormalities rep01ted will also be flagged as clinically significant or not clinically 
significant as indicated. 
All other safety and tolerability assessments not detailed in the above sections will be listed 
only. 
8.6.6. Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned. 
9. INTERIM ANALYSES 
No interim analyses are planned. 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES 
There were no significant changes from the protocol-specified analyses. 
11.REFERENCES 
1. ICH. ICH Harmonised Tripaitite Guideline: Statistical p1inciples for clinical trials (E9). 
5 February 1998. 
2. ICH. ICH Hannonised Tripa1tite Guideline: Strncture and content of clinical study repo1ts 
(E3). 30 November 1995. 
3. Keene ON. The log transfonnation is special. Stat Med. 1995;14(8):811-819. 
4. Brown H, Prescott R. Applied Mfred Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
5. Schuinnann DJ. A compai·ison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet 
Biopharm. 1987;15(6):657-680. 
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12. APPENDICES 
Appendix 1: 
Document History 
CONFIDENTIAL 
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Status, Version 
Date of Change 
Summary/Reason for Changes 
Final, Version 1.0 
NA 
NA; the first version. 
NA= not applicable 
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