A Phase I, Open Label, Fixed-sequence Drug Interaction Study to Investigate the Effect of Multiple Oral Doses of LOXO-305 on the Pharmacokinetics of a Single Dose of Intravenous and Oral Midazolam (CYP3A4 Substrate) in Healthy Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol LOXO-BTK-20008 
A Phase I, Open Label, Fixed-sequence Drug Interaction Study to Investigate the Effect 
of Multiple Oral Doses of LOXO-305 on the Pharmacokinetics of a Single Dose of 
Intravenous and Oral Midazolam (CYP3A4 Substrate) in Healthy Subjects
NCT06180967 
Approval date: 13-Sep-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 t he 
P h ar m ac o ki netics  of a Si n gle D ose of I ntr a ve n o us  a n d Or al Mi d az ol a m 
( C Y P 3 A 4 S u bstr ate) i n He alt h y S u bjects 
Pr ot oc ol Stat us:  Fi nal  
Pr ot oc ol Date: 1 1 Se pte m ber 2 0 2 0 
Pr ot oc ol Versi o n: 2. 0 
 
I n vesti gati o nal Me dici nal Pr o d uct: L O X O - 3 0 5 
 
 
Pr ot oc ol Refere nce N u m ber: L O X O -B T K - 2 0 0 0 8 
C o va nce St u d y N u m ber: 8 4 1 9 6 8 7 
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 var d, S uite 4 2 0 
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0 
St u d y Site: 
C o va nce Cli nical Researc h U nit I nc.  
1 9 0 0 Mas o n A ve n ue, S uite 1 4 0 
Da yt o na Beac h, F L 3 2 1 1 7 
U S A  
 
 
S p o ns or Si g nat or y: 
 
Pri nci pal 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 ma y be discl ose d o nl y wit h t he e x press 
writte n per mi ssi o n of t he S p o ns or. 
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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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 2 of 7 0 
S P O N S O R A P P R O V A L  
I ha ve rea d t he pr ot oc ol a n d a p pr o ve it: 
 
 
Date  
1 3 - S e p - 2 0  |  2 3 : 2 6 : 0 2  P D T
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 4 of 7 0 
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 var 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 
 
 
L o x o O nc ol o g y, I nc. 
Tel ( m o bile): 
 
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 ve nt ( S A E) 
Re p orti n g 
E mail: S A EI nta ke @c o va nce.c o m  
St u d y Site 
C o va nce Cli nical Researc h U nit I nc.  
1 9 0 0 Mas o n A ve n ue, S uite 1 4 0 
Da yt o na Beac h, F L 3 2 1 1 7 
U S A  
Pri nci pal I n vesti gat or  
 
Me dical Direct or  
C o va nce Cli nical Researc h U nit I nc.  
1 9 0 0 Mas o n A ve n ue, S uite 1 4 0 
Da yt o na Beac h, F L 3 2 1 1 7 
U S A  
Tel: 
 
Fa x: 
 
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 2 
Cli nical La b orat or y 
La b C or p – H oll y w o o d 
4 2 0 0 N ort h 2 9t h A ve n ue 
H oll y w o o d, F L 3 3 0 2 0 
U S A  
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 
Tel ( mai n): ( 2 0 8) 8 8 3- 3 4 0 0 
E mail: jzi m mer @alt urasa nal ytics.c o m  
P P D
P P D
P P D
P P D
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 5 of 7 0 
St atisticia n 
, M Sc 
C o va nce 
Tel: 
 
E mail: 
 
Pr ot oc ol Me dical Writer  
, B Sc 
C o va nce 
Tel:  
 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 6 of 7 0 
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 nce 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 t he Phar mac o ki netics  of a Si n gle D ose of I ntra ve n o us 
a n d Oral Mi daz ola m ( C Y P 3 A 4 S u bstrate) i n Healt h y S u bjects  
O bjecti ves  
T he pri mar y o bjecti ves of t he st u d y are: 
•  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 netics  (P K ) 
of a si n gle oral d ose of mi daz ola m i n healt h y s u bjects  
•  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 a si n gle 
i ntra ve n o us (I V) d ose of mi daz ola m i n healt h y s u bjects  
T he sec o n dar y o bjecti ves of t he st u d y are: 
•  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, c oa d mi nistere d wit h a si n gle oral d ose of mi daz ola m a n d 
c oa d mi nistere d wit h a si n gle I V d ose of mi daz ola m.  
•  to assess t he P K  of si n gle a n d m ulti ple d oses of L O X O- 3 0 5 w he n gi ve n al o ne or wit h 
mi daz ola m i n healt h y s u bjects.  
T he e x pl orat or y o bjecti ve of t he st u d y is: 
•  t o assess t he effect of a si n gle oral d ose of L O X O- 3 0 5 a n d stea d y state L O X O- 3 0 5 o n 
t he P K of 
 as bi o mar kers of t he h u ma n or ga nic 
a ni o n tra ns p orti n g p ol y pe pti de 1 B 1 ( O A T P 1 B 1 ) a n d 1 B 3 (O A T P 1 B 3 ) i n hi biti o n i n 
healt h y s u bjects.  
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 ue nce dr u g- 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 t he P K of a si n gle oral d ose of 
mi daz ola m a n d o n t he P K of a si n gle I V d ose of mi daz ola m i n healt h y s u bjects. T he st u d y 
will als o assess t he si n gle a n d m ulti ple oral d ose P K of L O X O- 3 0 5 a n d t he effect of a  si n gle 
oral d ose of L O X O- 3 0 5 a n d t he effect of L O X O- 3 0 5 at stea d y state (f oll o wi n g m ulti ple d ose 
a d mi nistrati o n) o n t he P K of 
III as bi o mar kers of 
O A T P 1 B 1 a n d O A T P 1 B 3 i n hi biti o n i n healt h y s u bjects.  
I n Peri o d 1, Da y 1, a si n gle 2 5 0 μ g ( 0. 2 5 m L  of 1 -m g/ m L s ol uti o n) I V b ol us d ose of 
mi daz ola m will be a d mi nistere d o ver a p pr o xi matel y 3 0 sec o n ds i n t he m or ni n g f oll o wi n g a 
1 0- h o ur fast pri or t o d osi n g a n d a 4- h o ur fast p ost d ose. O n Da y 3, a si n gle 5 0 0 μ g ( 0. 2 5 m L  
of 2- m g/ m L s yr u p) oral d ose of mi daz ola m 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 pri or t o d osi n g a n d 4 h o urs p ost d ose. O n Da y 3, t he oral mi daz ola m 
d ose will be a d mi nistere d al o ne at t he act ual ti me of t he Da y 1 I V mi daz ola m d o se 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 7 of 7 0 
( ± 1 h o ur). Bl o o d sa m ples f or c o nce ntrati o n of mi daz ola m a n d 1- h y dr o x y mi daz ola m 
( 1-O H -mi daz ola m) , a n d 
 i n plas ma will be c ollecte d  o n Da ys 1, 2, 3, 
a n d 4 (i n acc or da nce wit h t he Sc he d ule of Assess me nts  [A p pe n di x 4 ]).   
I n Peri o d 2 (starti n g o n Da y 5), 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 3 c o nsec uti ve da ys ( Da ys 5 t hr o u g h 1 7) i n t he m or ni n g. O n Da ys 5, 1 4, 1 5, 
a n d 1 7 oral d oses of 2 0 0 m g L O X O -3 0 5 will be a d mi nistere d 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 at least 4 h o urs p ost d ose. O n Da y 6 t hr o u g h 1 3, a n d Da y 1 6 oral 
d oses of 2 0 0 m g L O X O -3 0 5 will be a d mi nistere d f oll o wi n g a fast of at least 2 h o urs pri or t o 
d osi n g a n d 1- h o ur p ost d ose , wit h t he e xce pti o n of da ys w here cli nical la b orat or y e val uati o ns 
are perf or me d . O n Da ys 5 t hr o u g h 1 4, a n d Da y 1 6, 2 0 0 m g L O X O - 3 0 5 will be a d mi nistere d 
al o ne at t he act ual ti me of t he D a y 1 I V mi daz ola m d ose ( ±  1 h o ur). O n t he m or ni n g of 
Da y  1 5, a n oral d ose of 2 0 0  m g L O X O -3 0 5 will be a d mi nistere d  2 h o urs (± 1 5 mi n utes) pri or 
t o a d mi nisteri n g a si n gle 2 5 0 μ g ( 0. 2 5 m L  of 1- m g/ m L s ol uti o n) I V b ol us d ose of 
mi daz ola m . O n  t he m or ni n g of Da y  1 7, a n oral d ose of 2 0 0 m g L O X O - 3 0 5 will be 
a d mi nistere d  first bef ore  a si n gle oral 5 0 0 μ g ( 0. 2 5 m L  of 2-m g/ m L s yr u p) d ose of 
mi daz ola m  is a d mi nistere d (wit hi n 5 mi n utes)  i n acc or da nce wit h t he Sc he d ule of 
Assess me nts  [A p pe n di x 4 ]). O n Da ys 1 5 a n d 1 7, L O X O - 3 0 5 will be a d mi nistere d at t he 
act ual ti me of t he Da y 1 I V mi daz ola m d ose ( ±  1 h o ur). Bl o o d sa m ples f or c o nce ntrat i o n of 
L O X O - 3 0 5 a n d 
 i n plas ma will be c ollecte d o n Da ys 5 t hr o u g h 1 6 
(i n acc or da nce wit h t he Sc he d ule of Assess me nts [A p pe n di x 4 ]).  Bl o o d sa m ples f or 
c o nce ntrati o n of mi daz ola m , 1-O H -mi daz ola m , a n d L O X O-3 0 5 i n plas ma will be c ollecte d 
o n Da ys 1 5, 1 6, 1 7, a n d 1 8. A d diti o nall y, bl o o d sa m ples f or c o nce ntrati o n of L O X O- 3 0 5 i n 
plas ma will be c ollecte d o n Da ys 1 9, 2 0, a n d 2 1 ( u p t o 1 0 0 h o urs p ost- L O X O - 3 0 5 d ose o n 
Da y 1 7 ; i n acc or da nce wit h t he Sc he d ule of Assess me nts [A p pe n di x 4 ]). 
T here will be a was h o ut peri o d of 2 da ys bet wee n  t he I V d ose of mi daz ola m a n d t he oral d ose 
of mi daz ola m o n Da ys 1 a n d 3 ( Peri o d 1) a n d Da ys 1 5 a n d 1 7 ( Peri o d 2), res pecti vel y.  
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 2 8  da ys 
( Da ys - 2 9 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 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 n d of 
Treat me nt ( E O T) o n Da y  2 1 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 nati o n ( E T) if t he s u bject disc o nti n ues. 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 da ys ( ±  2 da ys) after E O T or E T.  
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. 
T he 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 ne d as t h ose s u bjects 
w h o are assi g ne d 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. 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. 
I n t his st u d y, p h ysical e xa mi nati o ns, 1 2-lea d electr ocar di o gra ms ( E C Gs ), vital si g n 
meas ure me nt s, o x y ge n sat urati o n meas ure d b y c o ntin u o us p ulse o xi metr y, 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 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 8 of 7 0 
perf or me d at s pecifie 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 Es) a n d seri o us A Es (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 verse 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 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), 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 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 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 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 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 assess e d as relate d t o st u d y dr u g b y t he I n vesti gat or ( or desi 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 ne call) are t o be re p orte d.  
N u m ber of S u bjects  
Si xtee n healt h y a d ult male a n d fe 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 his is a P hase  1 st u d y a n d t he sa m ple size is n ot base d u p o n a n y f or mal 
p o wer calc ulati 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. Si xtee n s u bjects 
are a ntici pate d 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 varia bilit y 
of t he i nteracti o n.  
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 Crite ri a f or I ncl usi o n  
Male s u bjects a n d fe male s u bjects 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, a n d wit hi n b o d y mass i n de x ( B MI) ra n ge 1 8. 0 t o 3 2. 0 k g/ m 2, 
i ncl usi ve. S u bjects will be i n g o o d ge neral healt h, base 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 n  meas ure me nts , o x y ge n sat urati o n meas ure d b y p ulse 
o xi metr y, 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 desi 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 
I n Peri o d 1, Da y 1, a si n gle I V b ol us d ose of 2 5 0 μ g mi daz ola m a d mi nistere d as 0. 2 5 m L  of 
1- m g/ m L s ol uti o n will be a d mi nistere d i n t he m or ni n g  o ver a p pr o xi matel y 3 0 sec o n ds 
f oll o wi n g a 1 0- h o ur fast pri or t o d osi n g a n d a 4- h o ur fast p ost d ose. O n Da y 3, a si n gle oral 
d ose of 5 0 0 μ g mi daz ola m a d mi nistere d as 0. 2 5 m L of 2 -m g/ m L s yr u p will be a d mi nistere d 
i n t he m or ni n g f oll o wi n g a 1 0-h o ur fast pri or t o d osi n g a n d a 4- h o ur fast p ost d ose.  O n Da y 3, 
t he oral mi daz ola m d ose will be a d mi nistere d al o ne at t he act ual ti me of t he Da y 1 I V 
mi daz ola m d ose ( ±  1 h o ur). 
I n Peri o d 2, 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 he m or ni n g f or 1 3 
c o nsec uti ve da ys ( Da ys 5 t hr o u g h 1 7). O n Da ys 5, 1 4, 1 5 a n d 1 7, 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 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 at least 4 h o urs p ost d ose. O n Da ys 6 t hr o u g h 1 3, a n d Da y 1 6 oral d oses 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 9 of 7 0 
2 0 0 m g L O X O -3 0 5 will be a d mi nistere d Q D i n t he m or ni n g f oll o wi n g a fast of at least 
2 h o urs pri or t o d osi n g a n d 1- h o ur p ost d ose,  wit h t he e xce pti o n of da ys w here cli nical 
la b orat or y e val uati o ns are perf or me d. O n Da ys 5 t hr o u g h 1 4, a n d Da y 1 6, 2 0 0 m g 
L O X O -3 0 5 will be a d mi nistere d al o ne at t he act ual ti me of t he Da y 1 I V mi daz ola m d ose 
( ± 1 h o ur). O n t he m or ni n g of Da y 1 5, a n oral d ose of 2 0 0 m g L O X O- 3 0 5 will be 
a d mi nistere d 2 h o urs ( ± 1 5 mi n utes) pri or t o a d mi nisteri n g a si n gle 2 5 0 μ g ( 0. 2 5  m L o f 
1- m g/ m L s ol uti o n) I V b ol us d ose of mi daz ola m.  O n t he m or ni n g of Da y 1 7, a n oral d ose of 
2 0 0 m g L O X O- 3 0 5 will be a d mi nistere d  first bef ore a si n gle oral 5 0 0 μ g ( 0. 2 5  m L of 
2- m g/ m L s yr u p) d ose of mi daz ola m is a d mi nistere d ( wit hi n 5 mi n utes ). O n Da ys 1 5 a n d 1 7, 
L O X O -3 0 5 will be a d mi nistere d at t he act ual ti me of t he Da y 1 I V mi daz ola m d ose 
( ± 1 h o ur). 
D ur ati o n of S u bject P artici p ati o n i n t he S t 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 2 8 da ys  ( Da ys - 2 9 t o - 2).  
Le n gt h of C R U C o nfi ne me nt:  U p t o 2 2 da ys ( Da ys - 1 t o 2 1). 
Pla n ne d St u d y C o n d uct D urati o n: U p t o 5 9 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:  
W he ne ver p ossi ble, t he f oll o wi n g P K para meters will be calc ulate d base d o n plas ma 
c o nce ntrati o ns of mi daz ola m ( oral a n d I V) a n d meta b olite 1 -O H -mi daz ola m , as a p pr o priate: 
area 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 t he last meas ura ble 
c o nce ntrati o n ( A U C 0-t), A U C  fr o m ti me 0 e xtra p olate d t o i nfi nit y ( A U C 0-i nf), perce nta ge 
e xtra p olati o n f or A U C 0- i nf ( % A U Ce xtra p), ma xi m u m o bser ve d plas ma  c o nce ntrati o n ( C ma x ), 
ti me t o ma xi m u m o bser ve d plas ma  c o nce ntrati o n (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 s yste mic cleara nce ( oral mi daz ola m; C L/ F), t otal clear a nce (I V 
mi daz ola m; C L), a p pare nt plas ma ter mi nal eli mi nati o n half-life (t½ ), a p pare nt v ol u me of 
distri b uti o n ( oral mi daz ola m; Vz/ F ), v ol u me of distri b uti o n (I V mi daz ola m; Vz), a n d v ol u me 
of distri b uti o n at stea d y state (I V mi daz ola m; V ss). 
W here ver p ossi ble, t he f oll o wi n g P K para meters will be calc ulate d  base d o n t he plas ma 
c o nce ntrati o ns of L O X O- 3 0 5: A U C 0-t, A U C d uri n g a d osi n g i nter val ( A U Cta u), a p pare nt 
s yste mic plas ma cle ara nce at stea d y state ( C L ,ss/ F), Cma x , c o nce ntrati o n o bser ve d at t he e n d of 
t he d osi n g i nter val ( Ctr o u g h), tma x , a n d acc u m ulati o n rati o ( RA U C ). 
T he f oll o wi n g P K para meters will be calc ulate d w he ne ver p ossi ble, base d o n t he plas ma 
c o nce ntrati o ns of 
 f oll o wi n g si n gle d ose mi daz ola m (I V 
a d mi nistrati o n), si n gle d ose L O X O- 3 0 5, a n d stea d y- state L O X O- 3 0 5 (as a p pr o priate): Cma x , 
tma x , A U C fr o m h o ur 0 t o 24 h o urs ( A U C0- 2 4), a n d stea d y state c o nce ntrati o n ( Css). 
S afet y: 
Safet y will be m o nit ore d wit h A E i n q uiries, cli nical la b orat or y e val uati o ns, vital si g n 
meas ure me nts, E C Gs, o x y ge n sat urati o n meas ure d b y p ulse o xi metr y, a n d p h ysical 
e xa mi nati o ns.  
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 1 0 of 7 0  
St atistic al Met h o ds  
T he pri mar y a nal 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 me d o n t he 
l n-tra nsf or me d mi daz ola m a n d 1- O H -mi daz ola m P K para meters ( A U C 0-t, A U C0-i nf, a n d Cma x ) 
a n d i ncl u de calc ulati o n of least s q uare d ( L S) mea ns a n d t he differe nce bet wee 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 vals ( CIs). T he ge o metric 
mea n rati os a n d t heir 9 0 % CIs 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 differe nce b et wee n L S mea ns a n d t he CIs fr o m t he mi xe d effect m o del.  
T he rati o of mi daz ola m t o 1 -O H -mi daz ola m will be s u m marize d.  
T he sa me met h o d a n d m o del as a b o ve will be use d t o a nal yze t he A U C 0- 2 4 a n d Cma x  of 
 para meters. 
A stea d y state a nal ysis will be perf or me d o n t he l n -tra nsf or me d Ctr o u g h c o nce ntrati o ns f or 
L O X O - 3 0 5 usi n g Hel mert c o ntrasts. 
 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 1 1 of 7 0  
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 netics  ................................................................................... 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  ............................................................................... 1 9 
1. 4. 1.  
Safet y  ........................................................................................................... 2 0 
1. 4. 2.  
P har mac o ki netics  ......................................................................................... 2 1 
1. 5.  St u d y Rati o nale  .......................................................................................................... 2 4 
1. 6.  Ris k Assess me nt  ........................................................................................................ 2 4 
2.  
O BJ E C TI V E S A N D E N D P OI N T S  ................................................................................. 2 6 
2. 1.  O bjecti ves  .................................................................................................................. 2 6 
2. 1. 1.  
Pri mar y O bjecti ves  ....................................................................................... 2 6 
2. 1. 2.  
Sec o n dar y O bjecti ves  ................................................................................... 2 6 
2. 1. 3.  
E x pl orat or y O bjecti ve  .................................................................................. 2 6 
2. 2.  E n d p oi nts ................................................................................................................... 2 6  
2. 2. 1.  
Pri mar y E n d p oi nts  ....................................................................................... 2 6 
2. 2. 2.  
Sec o n dar y E n d p oi nts ................................................................................... 2 7  
2. 2. 3.  
E x pl orat or y E n d p oi nts  ................................................................................. 2 7 
3.  
IN 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 ....................................................................................... 2 9  
3. 3.  Selecti o n of D oses i n t he St u d y ................................................................................. 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 1 
4. 1.  Scree ni n g Pr oce d ures ................................................................................................. 3 1  
4. 2.  C hec k -i n Pr oce d ures ( Da y - 1) ................................................................................... 3 1 
4. 3.  I ncl usi o n Criteria ....................................................................................................... 3 2 
4. 4.  E xcl usi o n Criteria  ...................................................................................................... 3 4 
4. 5.  S u bject N u m ber a n d I de ntificati o n  ............................................................................ 3 7 
4. 6.  Re m o val of S u bjects fr o m St u d y Partici pati o n  ......................................................... 3 7 
5.  
S T U D Y T R E A T M E N T S  ................................................................................................. 3 9 
5. 1.  Descri pti o n, St ora ge, Pac ka gi n g, a n d La beli n g ......................................................... 3 9  

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

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 1 3 of 7 0  
1 1.  A P P E N DI C E S  ................................................................................................................. 5 6 
A p pe n di x 1: A d verse E ve nt Re p orti n g ............................................................................... 5 7  
A p pe n di x 2: Cli nical La b orat or y E val uati o ns  ..................................................................... 6 1 
A p pe n di x 3: T otal Bl o o d V ol u me ....................................................................................... 6 2  
A p pe n di x 4: Sc he d ule of Assess me nts  ............................................................................... 6 3 
A p pe n di x 5: Pr ot oc ol A me n d me nt S u m mar y of C ha n ges .................................................. 6 9  
 
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 netic 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 ycle 1 Da y 8) ..................................................... 2 1 
Ta ble 2  P har mac o ki netic of L O X O - 3 0 5 F oll o wi n g a Si n gle 2 0 0-m g D ose 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, C ycle 1 Da y 1) 
a n d Healt h y S u bjects ( St u d y L O X O- B T K - 2 0 0 1 4) .............................................. 2 3 
Ta ble  3 St u d y Dr u gs .......................................................................................................... 3 9 
 
Fi g ure 1 Arit h metic Mea n ( ± S D) Plas ma C o nce ntrati o ns of L O X O - 3 0 5 F oll o wi n g 
Dail y Oral A d mi nistrati o ns o n Da y 1 (t o p pa nel) a n d Da y 8 ( b ott o m pa nel) of 
C ycle 1 i n Ca ncer Patie nts  ................................................................................... 2 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 1 4 of 7 0  
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 nce ntrati o n -ti me c ur ve 
fr o m ti me 0 e xtra p olate d t o i nfi nit y  
1 -O H -mi daz ola m  1 -h y dr o x y mi daz ola m  
A D L  
Acti vities of Dail y Li vi n g  
A E  
a d verse e ve nt  
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 h o ur 0 t o 2 4  h o urs p ost d ose  
A U C 0-i nf 
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 e xtra p olate d t o 
i nfi nit y 
A U C 0-t 
area u n der 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 U C ta u 
area u n der t he c o nce ntrati o n -ti me c ur ve d uri n g a d osi n g i nter val 
A V  
atri o ve ntric ular  
B C R P  
breast ca ncer resista nce 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 deral Re g ulati o ns  
CI  
c o nfi de nce i nter val(s)  
C L  
t otal cleara nce 
C L/ F  
a p pare nt s yste mic cleara nce  
C L ,ss/ F 
a p pare nt s yste mic cleara nce at stea d y state  
C L L  
c hr o nic l y m p h oc ytic le u ke 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 U  
Cli nical Researc 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 verse E ve nts  
C ss 
stea d y state c o nce ntrati o n  
C tr o u g h 
c o nce ntrati o n o bser ve d at t he e n d of t he d osi n g i nter val  
C V  
c oefficie 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 nteracti o n(s)  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic Case Re p ort F or m  
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 

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 1 5 of 7 0  
h E R G  
h u ma n et her -à-g o -g o -relate d ge ne 
H b A 1c  
he m o gl o bi n A 1c  
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?  
HI V  
h u ma n i m m u n o deficie nc y vir us  
H R T  
h or m o ne re place me nt t hera p y  
I B 
I n vesti 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 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 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 Re g ulat or y Acti vities  
m R N A  
messe n ger R N A  
M Z L  
mar gi nal z o ne l y m p h o ma  
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 tra ns p orter  
O A T P  
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  
or ga nic a ni o n  tra ns p orti n g p ol y pe pti de 1 B1  
O A T P 1 B 3  
or ga nic a ni o n  tra 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 hai n reacti o n  
P -g p  
P -gl yc o pr otei n  
P K  
p har mac o ki netic(s)  
P T  
preferre d ter m  
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 dericia’s met h o d  
R A U C  
acc u m ulati o n rati o  
R B C  
re d bl o o d cell(s) 
S A E  
seri o us a d verse e ve nt(s) 
S A P  
Statistical A nal ysis Pla n  
S D D  
s pra y-drie d dis persi 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 

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 1 6 of 7 0  
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
t½  
a p pare nt  plas ma  ter mi nal eli mi nati o n half-life 
T E A E  
treat me nt-e mer ge nt a d verse 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 ss 
v ol u me of distri b uti o n at stea d y state  
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 1 7 of 7 0  
1.  I N T R O D U C TI O N 
Re fer t o t he I n vestigat or ’s Br oc h ure (I B) f or detaile 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 verse e ve nt ( A E) pr ofile 
of t he i n vesti gati o nal  me dici nal pr o d uct (I M P). 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 selecti ve i n hi bit or of t he Br ut o n’s t yr osi ne 
ki nase ( B T K) bei 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 o n  pr o perties, a n d n o n-c o vale nt bi n di n g m o de. 2 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 descri be d f or all a vaila ble c o vale nt i n hi bit ors.3 ,4 ,5 ,6 ,7   T hese feat ures e na ble L O X O -
3 0 5 d ose d orall y at 1 0 0 m g a n d hi g her o nce dail y ( Q D) t o ac hie ve p har mac o ki netic ( P K) 
e x p os ures t hat e xcee d t he co nce ntrati o n re q uire d f or 9 0 % i n hi biti o n  (I C9 0) of B T K - wil d-t y pe 
a n d B T K C 4 8 1  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 gar dless of t he i ntri nsic rate of B T K t ur n o ver.  L O X O - 3 0 5 is als o a hi g hl y selecti ve 
m olec u le, wit h m ore t ha n 3 0 0-f ol d m ore selecti vit y f or B T K vers us 3 7 0 ot her ki nases teste d 
a n d n o si g nifica nt i n hi biti o n of n o n- ki nase off- tar gets at 1 μ M, t h us li miti n g t he p ote ntial f or 
off-tar get 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 5are 
e x pecte 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 efficac y. Of n ote, t he acti vit y of L O X O- 3 0 5 i n 
di verse precli 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 desi g ne d t o bloc k t he a de n osi ne tri p h os p hate 
bi n di n g site of t he B T K c o m petiti vel y, wit h n o e vi de nce of irre versi ble bi n di n g.  
1. 2.  
N o ncli nic al P h ar m ac o ki netics  
L O X O - 3 0 5 ha d hi g h per 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 he 
varia bilit y i n oral a bs or pti o n,  a s pra y-drie 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 de 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 ure of L O X O- 3 0 5 was c o nsiste ntl y m uc h hi g her i n 
fe male rats t ha n i n males gi ve n t he sa me d ose of L O X O-3 0 5. T he se x differe nce was als o 
a p pare nt after i ntra ve n o us (I V) a d mi nistrati o n of L O X O - 3 0 5. T here was n o differe nce i n t he 
P K of L O X O - 3 0 5 bet wee n se xes of d o g, a n d n o ne is e x pecte d i n ot her n o n-r o de nt s pecies, 
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 hat 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 bser ve d acr oss m o use, rat, ra b bit, a n d d o g. 
L O X O - 3 0 5 was meta b olize d sl o wl y b y h u ma n micr os o mal fracti o ns a n d he pat oc ytes. T he 
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 

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 1 8 of 7 0  
ha ve l o w cleara nce i n h u ma ns. I n vitr o data wit h cl o ne d 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 hat 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-ter m he pat oc 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 pat oc ytes were als o f or me d i n rat a n d/ or d o g he pat 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 assess me nt.  
Re nal cleara nce of L O X O - 3 0 5 i n male a n d fe male rats was ne gli gi ble. N o data o n re nal 
cleara nce are a vaila ble i n ot her s pecies; h o we ver, t he re nal e xcreti o n pat h wa y is ofte n 
c o nser ve d acr oss s pecies, a n d t heref ore n o re nal cleara nce w o ul d be e x pecte d i n h u ma ns.  
I n a G o o d La b orat or y Practice ( G L P) i n vitr o assa y f or h u ma n et her-à- g o- g o-relate d ge ne 
(h E R G ) acti vit y, t he c o nce ntrati o n res ulti n g i n 5 0 % i n hi biti o n 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 Μ , w hic h is a p pr o xi matel y  
 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 dail y ( Q D). T here were n o L O X O- 3 0 5- relate d c ha n ges i n a n y car di o vasc 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 vasc ular st u d y i n 
t he c o nsci o us tele metr y-i nstr u me nte d d o g. T he ma xi m u m o bser ve d plas ma  c o nce ntrati o n 
( Cma x ) f or t his d ose was  
 n g/m L , w hic h is a p pr o xi matel y  
 a b o ve t he pre dicte d 
C ma x  plas ma L O X O - 3 0 5 c o nce ntrati o n ( 
n g/m L ) at t he pr o p ose d cli nical t hera pe utic 
d ose 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 peate 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 E C G rec or di n gs. T he 
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 bel 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 ha 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 verse. T o get her, t hese data i n dicate 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 
ve ntric ular re p olarizati 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 were 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 uate d i n 
rat f u ncti o nal o bser vati o 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 ver y at d oses of u p t o 5 0 0 m g/ k g/ d ose BI D i n male ra ts a n d 
1 7 5 m g/ k g/ d ose BI D i n fe male rats as part of t he G L P 2 8 - da y re peat-d ose st u d y.  
L O X O - 3 0 5 ha d n o effect o n res pirati o n rate 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 haracterize d i n re peate 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 he 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 pecies s pecific a n d see n 
wit h ot her B T K i n hi bit ors. D o g s pecific c ha n ges 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 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 1 9 of 7 0  
t he 2 8- da y d o g st u d y de m o nstrate d a stee p d ose res p o nse c ur ve 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 para meters at hi g h e x p os ures.  
L O X O - 3 0 5 was n ot m uta ge nic i n 2 bacterial re verse m utati o n assa ys a n d was 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 h a 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 uclei via a n a ne 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 heral bl o o d l y m p h oc ytes. H o we ver, 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 rat 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 ( N O E L) 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 was 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 ne utral re d u pta ke 
p h ot ot o xicit y assa y. 
1. 3.  
P ote nti al f or Dr u g -dr u g I nter acti o ns 
L O X O - 3 0 5 s h o we d n o detecta ble i n hi biti o n ( 5 0 % i n hi bit or y c o nce ntrati o n [I C5 0]  
) 
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 bati 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 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 de nt i n hi biti o n of C Y P 3 A 4. F urt her ki netic e val 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 yte 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 ncrease 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 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 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. 
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 tra 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 1 B 1 ( O A T P 1 B 1 ), or ga nic a ni o n tra ns p orti n g p ol y pe pti de 1 B 3 (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 bstrate of P-g p a n d B C R P. It is n ot a s u bstrate of t he he patic 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.  
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 bei 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 starti n g d ose of L O X O- 3 0 5 was 2 5 m g Q D.  
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 2 0 of 7 0  
As of 0 9 A pril 2 0 2 0, safet y data were a vaila ble fr o m 1 7 2 treate d patie nts, wit h 3 0 0 m g Q D as 
t he hi g hest d ose a d mi nistere d (Secti o n  1. 4. 1 ). As of 3 0 Marc h 2 0 2 0 ( data c ut off date), P K 
data were a vaila ble fr o m 1 0 7 patie nts (Secti o n  1. 4. 2 ).  
L O X O - 3 0 5 was 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). 
L O X O -B T K -2 0 0 1 4 is 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 
were gi ve n 2 0 0 m g of L O X O- 3 0 5 o n  3 se parate da ys, eac h f oll o we d b y a was h o ut peri o d. 
T w o a d diti o nal st u dies are 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 a n d 
L O X O -B T K - 2 0 0 1 7). L O X O-B T K - 2 0 0 0 6 is a dr u g-dr u g i nteracti o n st u d y e val uati 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 here, at t he ti me of pr ot oc ol a me n d me nt de vel o p me nt, 3 healt h y 
v ol u nteers were gi ve n o ne d ose of 2 0 0  m g of L O X O - 3 0 5, 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 parate 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 was h o ut peri o d, a n d 3 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 parate da ys ( 1 of w hic h was 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 st u d y 
e val uati n g t he safet y a n d t olera bilit y of L O X O- 3 0 5 at 3 0 0 m g, u p t o 6 0 0 m g, a n d u p t o 
9 0 0 m g d oses, w here, at t he ti me of pr ot oc ol a me n d me nt 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 of L O X O- 3 0 5.  
1. 4. 1.  
S afet y  
As  of 0 9 A pril 2 0 2 0, 1 7 2 patie nts were treate d i n t he first-i n- h u ma n st u d y 
( L O X O-B T K - 1 8 0 0 1) a n d recei ve d L O X O- 3 0 5 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. A f ull s u m mar y of treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) f or patie nts i n t his 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 he 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  
O verall, T E A Es were re p orte d i n 1 2 3 of 1 7 2 treate d patie nts i n t he safet y p o p ulati o n a n d 
were mil d or m o derate se verit y ( Gra de 1 or 2) i n 8 9 of 1 2 3 ( 5 1. 7 %) patie nts a n d were 
Gra de  3 or 4 i n se verit y i n 3 3 of 1 2 3 ( 1 9. 2 %) patie nts. T he m ost fre q ue ntl y re p orte d T E A Es 
occ urri n g i n ≥1 0 % of patie nts were fati g ue ( 1 2. 8 % t otal, 7. 0 % relate d) a n d diarr hea ( 1 0. 5 % 
t otal, 6. 4 % relate d). T he m ost fre q ue ntl y re p orte d dr u g-relate d T E A Es (t h ose i n > 5 % of 
patie nts) were fati g ue ( 7. 0 %), diarr hea ( 6. 4 %), a n d c o nt usi o n ( 5. 2 %). All ot her dr u g- relate d 
T E A Es occ urre d i n < 5 % of patie nts eac h. T he m ost fre q ue ntl y re p orte d Gra de ≥ 3 T E A Es 
i ncl u de d ne utr o pe nia ( 4. 1 % t otal; 2. 9 % relate d), ne utr o p hil c o u nt decrease d ( 2. 3 % t otal; 1. 2 % 
relate d), a ne mia ( 1. 7 % t otal; 0. 6 % relate d), fati g ue a n d platelet c o u nt decrease d (eac h 1. 2 % 
t otal; eac h 0. 6 % relate d), a n d h y p o kale mia ( 1. 2 % t otal; n o ne relate d).  
Fi ve patie nts ( 2. 9 % of all 1 7 2 patie nts treate d) disc o nti n ue d L O X O- 3 0 5 beca use of T E A Es; 
2 of t he 5 patie nts ( 1. 2 % of all patie nts treate d) di sc o nti n ue d L O X O-3 0 5 beca use of a 
treat me nt-relate d e ve nt. O ne of t hese patie nts wit h ma ntle cell l y m p h o ma treate d i n t he 
1 0 0 m g Q D gr o u p disc o nti n ue d d ue t o Gra de 3 le u k oc yt osis c o nsi dere d relate d t o st u d y dr u g. 
St u d y t hera p y was hel d f or res ol uti o n of le u k oc yt osis a n d t he patie nt s u bse q ue ntl y pr o gresse d 
a n d st u d y t hera p y was n ot res u me d; t he e ve nt of le u k oc yt osis was rec or de d as 
rec o vere d/res ol ve d. T he sec o n d patie nt treate d i n t he 1 5 0 m g Q D gr o u p disc o nti n ue d d ue t o 
Gra de 2 m yal gia; t he m yal gia was o n g oi n g. T he patie nt ha d pre vi o usl y recei ve d i br uti ni b 
w hic h was disc o nti n ue d after 3 m o nt hs of treat me nt f or 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 2 1 of 7 0  
A t otal of 5 deat hs ha ve bee n re p orte d f or patie nts treate d i n t his st u d y, L O X O- B T K - 1 8 0 0 1. 
N o deat hs were c o nsi dere d relate d t o L O X O - 3 0 5. 
Fr o m A E d ata 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, all T E A Es ( hea dac he, na usea, a n d v o miti n g) were Gra de 1 i n 
se verit y a n d c o nsi dere d 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 ( data o n file at t he ti me of pr ot oc ol a me n d me nt de vel o p me nt). 
Fr o m preli mi nar y A E data 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, all T E A Es ( belc hi n g, bl oati n g, insect b ite, 
a p ht h o us ulcer, m uscle twitc h ) were Gra de 1 i n se verit y a n d bl oati n g was c o nsi dere d relate d 
t o L O X O- 3 0 5. All T E A Es  were re p orte d b y 3 s u bjects a n d res ol ve d pri or t o E n d of 
Treat me nt ( E O T; data o n file at t he ti me of pr ot oc ol a me n d me nt de vel o p me nt). T here were 
n o 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 6 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 fr o m preli mi nar y data a vaila ble ( data o n file at t he ti me of pr ot oc ol 
a me n d me nt de vel o p me nt). 
1. 4. 2.  
P h ar m ac o ki netics  
As of Marc h 3 0, 2 0 2 0, P K data were a vaila ble fr o m 1 0 7 patie nts e nr olle d i n 
L O X O -B T K - 1 8 0 0 1. Stea d y-state P K para meters of L O X O- 3 0 5 i n t hese ca ncer patie nts c o ul d 
be deri ve d fr o m data c ollecte d o n C ycle 1 Da y 8 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 ntrati 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 ue 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 t he C ycle 1, Da y 8 pre d ose sa m ple, lea di n g t o a n esti mate d plas ma half -life of 
a p pr o xi matel y 2 0 h o urs. F oll o wi n g a d mi nistrati o n of d oses of 1 0 0 m g Q D or hi g her, mea n 
tr o u g h plas ma le vels of L O X O-3 0 5 e xcee de d t he 
) of B T K i n vitr o 
(Fi g ure 1 ). 
T a ble  1 P h ar m ac o ki netic P ar a meters 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 me a n 
( % C V) 
T m a x   
( h)  
Me di a n  
( mi n, m a x) 
A U C 0- 2 4 
( n g * h/ m L)  
Ge o me a n 
( % C V) 
C L/ F  
( L/ h) 
Ge o me a n 
( % C V) 
T 1/ 2  
 ( h) 
Ge o me a n 
( % C V) 
2 5 m g Q D  
5 0 m g Q D  
 
1 0 0 m g Q D  
 
1 5 0 m g Q D  
 
2 0 0 m g Q D  
 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 2 2 of 7 0  
2 5 0 m g Q D  
 
3 0 0 m g Q D  
 
A b bre viati o ns: 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 bjects; 
P K  = p har mac o ki netic; Q D = o nce dail y; % C V = c oefficie nt of variati o n i n perce nt; T 1/ 2 = half -life; Tma x  = ti me 
of ma xi mal plas ma c o nce ntrati o n.  
a N = 5; b N = 8; c N = 1 8; d N = 1 6; e N = 2 0; f N = 1 6; g N = 1 5  
Data c ut off date: Marc h 3 0, 2 0 2 0.  
 
 
Ti m e ( h)
0
2
4
6
8
M e a n C o n c e ntr ati o n ( n g/ m L)
2 5 m g ( N = 5)
5 0 m g ( N = 6)
1 0 0 m g ( N = 1 0)
1 5 0 m g ( N = 2 0)
2 0 0 m g ( N = 2 9)
2 5 0 m g ( N = 2 4)
3 0 0 m g ( N = 1 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 2 3 of 7 0  
 
Data c ut off date: Marc h 3 0, 2 0 2 0  
Si n gle d oses of 2 0 0 m g  L O X O -3 0 5 were i n vesti gate d i n a 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, Pil ot F o o d Effect st u d y) i n w hic h t he P K was deter mi ne d. F oll o wi n g a 
si n gle d ose of 2 0 0 m g L O X O- 3 0 5 t o patie nts or healt h y s u bjects, A U C 0- 8 was si milar 
bet wee n t he t w o gr o u ps a n d C ma x  was a p pr o xi matel y 3 5 % hi g her i n healt h y s u bjects, as 
s h o w n i n t he ta ble bel o w ( data o n file at t he ti me of pr ot oc ol a me n d me nt de vel o p me nt). 
T a ble  2 P h ar m ac o ki netic of L O X O - 3 0 5 F oll o wi n g a Si n gle 2 0 0-m g D ose 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, C ycle 1 D a y 1) a n d He alt h y 
S u bjects ( St u d y L O X O -B T K - 2 0 0 1 4)  
P ar a meter 
He alt h y V ol u nteers a 
C a ncer P atie nts b  
Ge o metric Me a n  
C V  
n 
Ge o metric Me a n  
C V  
n 
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 0 t o 8 h o urs ; C V =c oefficie nt of variati o n; 
C ma x = ma xi m u m c o nce ntrati o n ; n = n u m ber of s u bjects. 
a L O X O -B T X -2 0 0 1 4, 2 0 0  m g  si n gle d ose, faste d  
b L O X O -B T K -1 8 0 0 1, 2 0 0  m g  si n gle d ose, faste d 
I n healt h y v ol u nteers, t he ge o metric mea n  si n gle- d ose Cma x  of a p pr o xi matel y 5 4 5 0 n g/ m L 
f oll o wi n g a 2 0 0-m g si n gle d ose is 
 bel o w t he N O E L (i n rat, 
 n g/ m L) f or 
mic r o n uclei i n d ucti o n. Ass u mi n g t hat healt h y v ol u nteers ha ve a si milar acc u m ulati o n rati o as 
Ti m e ( h)
0
2
4
6
8
M e a n C o n c e nt ati o n ( n g/ m L)
2 5 m g ( N = 5)
5 0 m g ( N = 6)
1 0 0 m g ( N = 9)
1 5 0 m g ( N = 2 0)
2 0 0 m g ( N = 2 4)
2 5 0 m g ( N = 2 5)
3 0 0 m g ( N = 1 6)
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 2 4 of 7 0  
o bser ve d i n patie nts, t he t y pical C ma x  at stea d y state after re peate d dail y d oses of 2 0 0 m g 
w o ul d be e x pecte d t o be  
 n g/ m L, well bel o w t he N O E L t hres h ol d. 
1. 5.  
St u d y R ati o n ale  
T he o bjecti ve of dr u g- dr u g i nteracti o n ( 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. 
After pre -i nc u bati o n of micr os o mes or he pat oc ytes wit h L O X O- 3 0 5, t he i n hi bit or y p ote nc y 
of L O X O - 3 0 5 f or C Y P3 A 4 was i ncrease d  a n d it als o i n d uce d t he m R N A of C Y P 3 A 4. Gi ve n 
t he t he oretical p ote ntial f or L O X O- 3 0 5 t o alter t he P K of C Y P 3 A 4 s u bstrates, a cli nical dr u g 
i nteracti o n st u d y is warra nte d t o deter mi ne t he e xte nt of a n y i nteracti o n. 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 a C Y P 3 A 4 s u bstrate, mi daz ola m 
w he n a d mi nistere d as a si n gle oral d ose a n d a si n gle I V d ose . 
C Y P 3 A 4 is a b u n da nt i n t he i ntesti nes a n d orall y a d mi nistere d mi daz ola m is s u bject t o b ot h 
i ntesti nal a n d he patic C Y P 3 A meta b olis m. I ntra ve n o us mi daz ola m is meta b olize d b y he patic 
C Y P 3 A a n d n ot i ntesti nal C Y P 3 A. Oral a n d I V mi daz ola m has bee n c h ose n as a wa y t o 
e xa mi ne t he i n hi bit or y effect of L O X O - 3 0 5 o n b ot h i ntesti nal a n d he patic C Y P 3 A acti vit y.1 0 
I n n o n-cli nical st u dies, L O X O - 3 0 5 was meta b olize d sl o wl y b y h u ma n micr os o mal fracti o ns 
a n d he pat oc ytes. L O X O - 3 0 5 als o wea kl y i n hi bite d t he hu ma n O A T P 1 B 1 a n d O A T P1 B 3, 
w hic h  are u pta ke tra ns p orters e x presse d o n he pat oc ytes, res p o nsi ble f or t he he patic u pta ke of 
n u mer o us dr u gs a n d e n d o ge n o us c o m p o u n ds. I n or der t o deter mi ne t he p ote ntial f or 
O A T P 1 B 1 a n d O A T P 1 B 3 i n hi biti o n f oll o wi n g L O X O -3 0 5 a d mi nistrati o n , t his st u d y will 
als o assess t he effect of  si n gle d ose a n d stea d y state c o nce ntrati o ns of L O X O - 3 0 5 o n t he 
plas ma P K of e n d o ge n o us 
, w hic h are de m o nstrate d e n d o ge n o us 
bi o mar kers of O A T P 1 B 1 a nd O A T P 1 B 3 f u ncti o nal acti vit y.1 1  
1. 6.  
R is k Assess me 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 ( be y o n d t hat of a n assess me 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 pati 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 hest d ose safel y 
a d mi nistere d i n first i n h u ma n st u dies. 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 1 0 0 h o urs p ost d ose (a p pr o xi matel y 5 half- li ves) o n Da y 2 1 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 res 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 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 be f o u n d i n 
t he I B.1 Mi daz ola m is a well -esta blis he d, se nsiti ve, a n d selecti ve pr o be f or t he C Y P 3 A 
meta b olic pat h wa y. Mi daz ola m is s u bject t o e xte nsi ve first - pass meta b olis m b y C Y P 3 A 
l ocate d i n b ot h t he i ntesti ne a n d t he li ver.1 2 ,1 0 Its maj or meta b olite, 1’- h y dr o x y mi daz ola m 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 2 5 of 7 0  
( 1-O H -mi daz ola m ), is f or me d al m ost e xcl usi vel y b y C Y P 3 A a n d is f urt her gl uc ur o ni date d 
a n d e xcrete d i n t he uri ne. It f oll o ws t hat i n hi biti o n or i n d ucti o n of C Y P 3 A i n t he s mall 
i ntesti ne a n d/ or t he li ver will affect t he oral bi oa vaila bilit y of mi daz ola m. Precli nicall y 
L O X O - 3 0 5 i n hi bits a n d i n d uces C Y P 3 A i n t he i ntesti ne a n d/ or i n t he li ver, t he c urre nt st u d y 
will e val uate mi daz ola m e x p os ure after b ot h I V a n d oral a d mi nistrati o n.  
T he d osi n g re gi me n of b ot h t he oral a n d I V d ose of mi daz ola m i n t he c urre nt st u d y is 
c o nsiste nt wit h  use i n D DI st u dies. B ot h t he oral a n d I V d ose are well bel o w t he t hera pe utic 
d ose of mi daz ola m use d f or se dati o n 1 3 ,1 4; h o we ver, se dati o n is a p ossi ble si de effect. T he 
p ote ntial ris k of partici pati n g i n t his st u d y a n d recei vi n g t his dr u g is well ma na ge d b y t he 
st u d y set- u p a n d c o nsi dere d ne gli gi ble.  
T he safet y m o nit ori n g practices 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,  o x y ge n sat urati o n meas ure d b y c o nti n u o us p ulse o xi metr y, 1 2-lea d 
electr ocar di o gra m ( E C G ), cli nical la b orat or y e val uati o n s, a n d p h ysical e xa mi nati o ns, a n d are 
c o nsi dere d a de q uate t o pr otect t he s u bjects’ safet 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 2 6 of 7 0  
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 ves  
T he pri mar y o bjecti ves of t h e st u d y are: 
•  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 a si n gle oral 
d ose of mi daz ola m i n healt h y s u bjects 
•  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 a si n gle I V d ose 
of mi daz ola m i n healt h y s u bjects  
2. 1. 2.  
Sec o n d ar y O bjecti ve s 
T he sec o n dar y o bjecti ves of t h e st u d y are: 
•  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, c oa d mi nistere d wit h a si n gle oral d ose of mi d az ola m a n d 
c oa d mi nistere d wit h a si n gle I V d ose of mi daz ola m . 
•  to assess t he P K  of si n gle a n d m ulti ple d oses of L O X O- 3 0 5 w he n gi ve n al o ne or wit h 
mi daz ola m i n healt h y s u bjects.  
2. 1. 3.  
E x pl or at or y O bjecti ve 
T he e x pl orat or y o bjecti ve of t he st u d y is: 
•  t o assess t he effect of a si n gle oral d ose of L O X O- 3 0 5 a n d stea d y state L O X O- 3 0 5 o n 
t he P K of e n d o ge n o us 
 as bi o mar kers of O A T P 1 B 1 a n d 
O A T P 1 B 3 i n hi biti o n i n healt h y s u bjects.  
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 meters will be calc ulate d w he ne ver p ossi ble, base d o n t he plas ma 
c o nce ntrati o ns of mi daz ola m  a n d its meta b olite 1-O H -mi daz ola m  f oll o wi n g oral a n d I V 
si n gle d ose a d mi nistrati o n  (as a p pr o priate):  
•  area u n der 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 U C 0-t) 
•  area u n der t he c o nce ntrati o n- ti me fr o m ti me 0 e xtra 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 C e xtra p) 
•  C ma x  
•  tma x  
•  a p pare nt ter mi nal eli mi nati o n rate c o nsta nt ( λZ ) 
•  a p pare nt s yste mic  cleara nce ( C L/ F ; oral mi daz ola 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 2 7 of 7 0  
•  t otal cleara nce ( C L; I V mi daz ola m) 
•  a p pare nt  plas ma  ter mi nal eli mi nati o n half-life (t½ ) 
•  a p pare nt v ol u me of distri b uti o n ( V z/ F; oral mi daz ola m) 
•  V z (I V mi daz ola m ) 
•  v ol u me of distri b uti o n  at stea d y state ( V ss; I V mi daz ola m). 
2. 2. 2.  
Sec o n d ar y E n d p oi nts  
Safet y a n d t olera 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 orat or y e val uati o ns, meas uri n g vital si g ns, o x y ge n sat urati o n meas ure d b y 
c o nti n u o us p ulse o xi metr y,  a n d 1 2-lea d E C Gs.  
T he f oll o wi n g P K para meters will be calc ulate d w he ne ver p ossi ble, base d o n t he plas ma 
c o nce ntrati o ns of L O X O- 3 0 5 f oll o wi n g si n gle a n d m ulti ple d ose a d mi nistrati o n (as 
a p pr o priate): 
•  A U C 0-t 
•  A U C d uri n g a d osi n g i nter val ( A U C t a u) 
•  C ma x  
•  c o nce ntrati o n o bser ve d at t he e n d of t he d osi n g i nter val ( C tr o u g h) 
•  tma x    
•  C L/ F at stea d y state ( C L ,ss/ F) 
•  acc u m ulati o n rati o ( R A U C ). 
2. 2. 3.  
E x pl or at or y E n d p oi nts 
T he f oll o wi n g P K para meters will be calc ulate d w he ne ver p ossi bl e, base d o n t he plas ma 
c o nce ntrati o ns of 
 f oll o wi n g si n gle d ose a n d stea d y-state 
L O X O - 3 0 5 (as a p pr o priate): Cma x , tma x , A U C fr o m h o ur 0 t o 24 h o urs ( A U C0- 2 4), a n d stea d y 
state c o nce ntrati o n ( Css). 
 
 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 2 8 of 7 0  
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 ue 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 a si n gle oral d ose of mi daz ola m a n d o n t he 
P K of  a si n gle I V d ose of mi daz ola m i n healt h y s u bjects. T he st u d y will als o assess t he  si n gle 
a n d m ulti ple oral d ose P K of L O X O- 3 0 5 a n d t he effect of a si n gle oral d ose of L O X O - 3 0 5 
a n d t he effect of L O X O - 3 0 5 at stea d y state (f oll o wi n g m ulti ple d ose a d mi nistrati o n) o n t he 
P K of e n d o ge n o us 
 as bi o mar kers of O A T P 1 B1 a n d O A T P1 B 3 
i n hi biti o n i n healt h y s u bjects.  
I n Peri o d 1, Da y 1, a si n gle 2 5 0 μ g ( 0. 2 5 m L  of 1 -m g/ m L s ol uti o n) I V b ol us d ose of 
mi daz ola m will be a d mi nistere d o ver a p pr o xi matel y 3 0 sec o n ds i n t he m or ni n g f oll o wi n g a 
1 0- h o ur fast pri or t o d osi n g a n d a 4- h o ur fast p ost d ose. O n Da y 3, a si n gle 5 0 0 μ g ( 0. 2 5 m L  
of 2- m g/ m L s yr u p) oral d ose of mi daz ola m 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 pri or t o d osi n g a n d 4 h o urs p ost d ose. O n Da y 3, t he oral mi daz ola m 
d ose will be a d mi nistere d al o ne at t he act ual ti me of t he Da y 1 I V mi daz ola m d ose 
( ± 1 h o ur). Bl o o d sa m ples f or c o nce ntrati o n of mi daz ola m, 1- h y dr o x y mi daz ola m 
( 1-O H -mi daz ola m) , a n d 
 i n plas ma
 
 i n acc or da nce wit h t he 
Sc he d ule of Assess me nts [ A p pe n di x 4 ]).  
I n Peri o d 2 (starti n g o n Da y 5), 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 3 c o nsec uti ve da ys ( Da ys 5 t hr o u g h 1 7) i n t he m or ni n g. O n Da ys 5, 1 4, 1 5, 
a n d 1 7 oral d oses of 2 0 0 m g L O X O - 3 0 5 will be a d mi nistere d 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 at least 4 h o urs p ost d ose. O n Da y 6 t hr o u g h 1 3, a n d Da y 1 6 oral 
d oses of 2 0 0 m g L O X O -3 0 5 will be a d mi nistere d f oll o wi n g a fast of at least 2 h o urs pri or t o 
d osi n g a n d 1- h o ur p ost d ose, wit h t he e xce pti o n of da ys w here cli nical la b orat or y e val uati o ns 
are perf or me d. O n Da ys 5 t hr o u g h 1 4, a n d Da y 1 6, 2 0 0 m g L O X O - 3 0 5 will be a d mi nistere d 
al o ne at t he act ual ti me of t he Da y 1 I V mi daz ola m d ose ( ±  1 h o ur). O n t he m or ni n g of Da y 
1 5, a n oral d ose of 2 0 0 m g L O X O - 3 0 5 will be a d mi nistere d 2 h o urs (± 1 5 mi n utes) pri or t o 
a d mi nisteri n g a si n gle 2 5 0  μ g ( 0. 2 5  m L of 1 - m g/ m L s ol uti o n) I V b ol us d ose of mi daz ola m. 
O n t he m or ni n g of Da y 1 7, a n oral d ose of 2 0 0 m g L O X O -3 0 5 will be a d mi nistere d  first 
bef ore a si n gle oral 5 0 0 μ g ( 0. 2 5  m L of 2 -m g/ m L s yr u p) d ose of mi daz ola m is a d mi nistere d 
( wit hi n 5 mi nutes). O n Da ys 1 5 a n d 1 7, L O X O- 3 0 5 will be a d mi nistere d at t he act ual ti me of 
t he Da y 1 I V mi daz ola m d ose ( ± 1 h o ur). Bl o o d sa m ples f or c o nce ntrati o n of L O X O- 3 0 5 a n d 
 i n plas ma will be c ollecte d o n Da ys 5 t hr o u g h 1 6 ( o n Da y 6, 2 4 
h o ur p ost d ose sa m ple; i n acc or da nce wit h t he Sc he d ule of Assess me nts  [A p pe n di x 4 ]). Bl o o d 
sa m ples f or c o nce ntrati o n of mi daz ola m, 1-O H -mi daz ola m , a n d L O X O-3 0 5 i n plas ma will be 
c ollecte d o n Da ys 1 5, 1 6  ( 2 4- h o ur p ost d ose sa m ple), 1 7, a n d 1 8 ( 2 4-h o ur p ost d ose sa m ple ). 
A d diti o nall y, bl o o d sa m ples f or c o nce ntrati o n of L O X O- 3 0 5 i n plas ma will be c ollecte d o n 
Da ys 1 9, 2 0, a n d 2 1 ( u p t o 1 0 0 h o urs p ost- L O X O - 3 0 5 d ose o n Da y 1 7; i n acc or da nce wit h 
t he Sc he d ule of Assess me nts [ A p pe n di x 4 ]). 
T her e will be a was h o ut peri o d of 2 da ys bet wee n t he I V d ose of mi daz ola m a n d t he oral d ose 
of mi daz ola m o n Da ys 1 a n d 3 ( Peri o d 1) a n d Da ys 1 5 a n d 1 7 ( Peri o d 2), res pecti vel y.  
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 2 8  da ys 
( Da ys - 2 9 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). 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 2 9 of 7 0  
S u bjects will be c o nf i 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 Da y  2 1 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 nati o n ( E T) if t he s u bject disc o nti n ues. 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 ved 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 da 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 5 9 da ys ( Scree ni n g t hr o u g h f oll o w- u p p h o ne call). 
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. 
T he 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 ne d as t h ose s u bjects 
w h o are assi g ne d 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. 
I n t his st u d y, p h ysical e xa mi nati o ns, 1 2-lea d E C Gs, vital si g n meas ure me nts,  o x y ge n 
sat urati o n meas ure d b y c o nti n u o us p ulse o xi metr y, 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 pecifie 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 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 verse 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 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 oce d ures b y t he I n vesti gat or [ or desi g nee]) or as A Es (i f 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 s t 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 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 vesti gat or ( or desi 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 disco 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 Assess 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 th e last s u bject’s f oll o w - u p. 
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 o f 
e nz y mes, ca n be i n hi bite d or i n d uce d b y c o nc 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 ncreases 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 ncrease d co nce ntrati o ns of a 
pare nt dr u g or its acti ve meta b olite ca n alter t he safet y a n d efficac y pr ofile of a dr u g.  
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 a C Y P 3 A 4 
s u bstrate, mi daz ola m. C Y P 3 A 4 is a b u n da nt i n t he i ntesti nes a n d or all y a d mi nistere d 
mi daz ola m is s u bject t o b ot h i ntesti nal a n d he patic C Y P 3 A meta b olis m. I ntra ve n o us 
mi daz ola m is meta b olize d b y he patic C Y P 3 A a n d n ot i ntesti nal C Y P 3 A. Oral a n d I V 
mi daz ola m has bee n c h ose n as a wa y t o e xa mi ne t he i n hi bit or y effect of L O X O - 3 0 5 o n b ot h 

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 3 0 of 7 0  
i ntesti nal a n d he patic C Y P 3 A acti vit y.1 0 Mi daz ola m selecti o n as a s u bstrate is base d o n 
pre vi o us wi des prea d use as a s uita ble esta blis he d mar ker of C Y P 3 A acti vit y a n d it is 
rec o m me n de d t o be use d as a C Y P 3 A se nsiti ve pr o be b y t he F D A; t heref ore, assessi n g t he 
p ote ntial i n hi bit or y effect of L O X O - 3 0 5 o n C Y P 3 A 4 acti vit y.1 5 M ulti ple d oses of L O X O - 3 0 5 
will all o w  t he D DI effect(s) of L O X O-3 0 5 o n mi daz ola m t o be assesse d at stea d y -state, 
t heref ore t he ma xi mal effect o n C Y P 3 A 4 will be ac hie ve d. 
T his st u d y is als o desi g ne d t o deter mi ne t he effect of a si n gle d ose of L O X O- 3 0 5 a n d stea d y 
state ( m ulti ple d ose a d mi nistrati o n) L O X O- 3 0 5 o n e n d o ge n o us 
 
 ha ve bee n de m o nstrate d as e n d o ge n o us bi o mar kers of he patic 
O A T P f u ncti o nal acti vit y i n vitr o a n d i n vi v o. 1 1 T here f ore, t he P K of 
 
 will be deter mi ne d f oll o wi n g si n gle a n d m ulti ple d oses of L O X O- 3 0 5. 
T he fi xe d si n gle- se q ue 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 
w here a relati vel y s mall n u m ber of s u bjects are re q uire d, beca use it all o ws i ntra -s u bject 
c o m paris o ns. T his st u d y will be o pe n- la bel beca use 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 nc o mita nt me dicati o ns. 
3. 3.  
Selecti o n of D oses i n t he St u d y  
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 5 t hr o u g h 
Da y  1 4 t o ac hie ve 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 he n 
c oa d mi nistere d wit h mi daz ola m . Dail y 2 0 0 m g L O X O - 3 0 5 d osi n g will c o nti n ue o n Da y 1 5 
t hr o u g h Da y 1 7 t o mai ntai n stea d y state of L O X O- 3 0 5 w he n c oa d mi nistere d wit h a si n gle I V 
d ose a n d a si n gle oral d ose of mi daz ola m , res pecti vel y. D oses of L O X O - 3 0 5 fr o m 2 5 m g Q D  
t o 3 0 0 m g Q D  ha ve bee n e val uate d i n 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 ( B R UI N St u d y) i n patie nts wit h pre vi o usl y treate d C L L/ S L L or N H L 
wit h d ose escalati o n u p t o 3 0 0 m g Q D a p pr o ve d b y t he st u d y’s Safet y Re vie w C o m mittee. 
T he a vaila ble data de m o nstrate t hat L O X O - 3 0 5 a p pears safe a n d well t olerate d at t hese 
d os es. At all e val uate d d oses, i ncl u di n g d oses of u p t o  3 0 0 m g Q D , 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 
Mi d az ol a m 
T he selecte d d oses f or t he I V a n d oral d ose of t he pr o be dr u g mi daz ola m was base d o n 
t y pical d oses f or t his dr u g 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 he o bjecti ves of t he st u d y.   
 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 3 1 of 7 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  
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 ures 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 2 8 da ys of st u d y e ntr y (ie, pri or t o C he c k-i n [ Da y -1]):  
1.  I ncl usi o n/ Excl usi o n criteria  
2.  I nf or me d c o nse nt 
3.  De m o gra p hic data 
4.  Me dical hist or y (i ncl u di n g re vie w of me dicati o n[s])  
5.  Hei g ht, wei g ht, a n d b o d y mass i n de x ( B MI) 
6.  1 2- lea d E C G meas ure d after t he s u bject has 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. 2. 4 ) 
7.  Vital si g n  meas ure me nts  (i ncl u di n g oral te m perat ure, res pirat or y rate, 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 
least 5 mi n utes]; Secti o n  7. 2. 3 ) 
8.  O x y ge n sat urati o n meas ure d b y p ulse o xi metr y ( See Secti o n  7. 2. 5 ) 
9.  H D Y F? i n q uir y, A E, S A E, a n d c o nc o mita nt me dicati o n e val uati o ns ( Secti o n  7. 2. 1 ) 
1 0.  Cli nical la b orat or y e val uati o ns ( Secti o n  7. 2. 2 ; cli nical c he mistr y pa nel [faste d at least 
8 h o urs], c oa g ulati o n para meters,  he mat ol o g y pa nel, a n d U A;  A p pe n di x 2 ) 
1 1.  Scree ns f or he patitis C vir us ( H C V) a nti b o d y, he patitis B s urface a nti ge n ( H Bs A g), 
he patitis B vir us ( H B V) 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 testi n g ([ P C R] or e q ui vale nt 
(A p pe n di x 2 ) 
1 2.  He m o gl o bi n A 1c ( H b A 1c) test ( A p pe n di x 2 ) 
1 3.  Scree n f or selecte 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 ( A p pe n di x 2 ) 
1 4.  Esti mate d gl o mer ular filtrati o n rate ( A p pe n di x 2 ) 
1 5.  Ser u m pre g na nc y test (f or fe male s u bjects o nl y; A p pe n di x 2 ) 
1 6.  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 male s u bjects o nl y; 
A p pe n di x 2 ) 
1 7.  T h yr oi d- sti m ulati n g h or m o ne ( T S H) test (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 ( Da 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) 
3.  Wei g ht a n d B MI  

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 3 2 of 7 0  
4.  C o m plete  p h ysical e xa mi nati o n  (Secti o n  7. 2. 6 ) 
5.  1 2- lea d E C G meas ure d after t he s u bject has 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. 2. 4 ) 
6.  Vital si g n  meas ure me nt s (i ncl u di n g oral te m perat ure, res pirat or y rate, 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. 2 . 3) 
7.  O x y ge n sat urati o n meas ure d b y p ulse o xi metr y ( See Secti o n  7. 2. 5 ) 
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 dicati o n e val uati o ns (Secti o n  7. 2. 1 ) 
9.  Cli nica l la b orat or y e val uati o ns (Secti o n  7. 2. 2 ; cli nical c he mistr y pa nel [faste d at least 
8 h o urs], c oa g ulati o n para meters,  he mat ol o g y pa nel, a n d U A; A p pe n di x 2 ) 
1 0.  Scree n f or C O VI D - 1 9 via P C R or e q ui vale nt  (A p pe n di x 2 ) 
1 1.  Scree n f or selecte 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 ( A p pe n di x 2 ) 
1 2.  Esti mate d gl o mer ular filtrati o n rate ( A p pe n di x 2 ) 
1 3.  Ser u m pre g na nc y test (f or fe male s u bjects o nl y; A p pe n di x 2 ) 
1 4.  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 (Da 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 plia 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 val uati o ns f or p ote ntial s u bjects 
pri or t o e nr oll me nt. 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 bjects selecte d f or 
e nr oll me nt b y t he I n vesti gat or ( or desi 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 vesti gat or ( or desi g nee) 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 ( Da 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 males 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 ge 1 8. 0 t o 32. 0 k g/ m 2, i ncl usi ve. 
3.  I n g o o d healt 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 vesti gat or ( or desi g nee). 
4.  Fe male  s u bjects of n o n-c hil d beari n g p ote ntial, defi ne d as bei n g per ma 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 st u d y dr u g 
a d mi nistrati o n) or p ost- me n o pa usal ( defi ne d as at least 1 2  m o nt hs p ost-cessati 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 3 3 of 7 0  
me nses wit h o ut a n alter nati ve me dical ca use). P ost- me n o pa usal stat us will be 
c o nfir me d wit h a scree ni n g se r u m F S H le vel ≥ 4 0 mI U /m L . All fe male s u bjects m ust 
ha ve a ne gati ve q ualitati ve ser u m pre g na nc 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 
a d mi nistrati o n of st u d y dr u g. 
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 he 
f oll o wi n g met h o ds of c o ntrace pti o n fr o m t he ti me of t he d ose a d mi nistrati o n t hr o u g h 
6 m o nt hs after t he last d ose of L O X O - 3 0 5 a d mi nistrati 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 urgicall y sterile f or at least 9 0  da ys pri or t o C hec k-i n 
( Da y - 1). If d oc u me ntati o n is n ot a vailable, 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: 
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 mal e part ner meets 1 of t he 
f oll o wi n g criteria: 
1.  intra 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 ® ); 
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 ntial, defi ne d as bei n g per ma ne ntl y sterile 
(ie, d ue t o h ysterect o m y, b ilateral 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 male part ner’s st u d y 
dr u g a d mi nistrati o n); or 
4.  be p ost- me n o pa usal wit h a me n orr hea f or at least 1  year pri or t o 
d osi n g 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  su bjects  w h o practice tr ue a bsti ne nce beca use of a lifest yle c h oice (ie, 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 uire me nts. Peri o dic a bsti ne nce b y a fe male part ner (e g, cale 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 wal 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 t hr o u g h 6 m o nt hs after st u d y dr u g a d mi nistrati o n , he 
m ust a gree t o use c o ntrace pti o n as descri be d a b o ve.  
F or male s u bjec ts, se x ual i nterc o urse wit h fe male part ners w h o are pre g na nt, or 
breastfee di n g s h o ul d be a v oi de d. Male s u bjects are re q uire d t o refrai n fr o m d o nati o n 
of s per m fr o m C hec k -i n ( Da y - 1) u ntil 6 m o nt hs after a d mi nistrati o n of st u d y dr u g. 
F or s u bjects w h o are e x cl usi vel y i n sa me -se x relati 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. 

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 3 4 of 7 0  
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 1- 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 Crit eri 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 nce of a n y of t he f oll o wi n g, dee me d cli nicall y si g nifica nt b y t he 
I n vesti gat or ( or desi 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 ucti o n s ur ger y  
g.  hist or y or prese nce 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 ular t hr o m b oe m b olis m wit hi n 
6 m o nt hs pri or t o t he first d ose a d mi nistrati o n ( 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 t he first d ose 
a d mi nistr ati o n ( Da y 1)  
iii. Ne w Y or k Heart Ass ociati o n Class ≥ 2 c o n gesti ve heart fail ure wit hi n 
6 m o nt hs pri or t o t he first d ose a d mi nistrati o n ( 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 pre -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 xc l 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  
vii.  Ve ntric ular d ysf u ncti o n or ris k fact ors f or T orsa des de P oi ntes (e g, 
heart fail ure, car di o m y o pat h y, fa mil y hist or y of L o n g Q T S y n dr o me)  
viii.  Si g nifica n t scree ni n g E C G a b n or malities:  
1.  left b u n dle- bra nc h bl oc k 
2.  sec o n d- de gree atri o ve ntric 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 usi n g Fri dericia’s met h o d 
( Q Tc F) is > 4 5 0 msec   
4.  E C G fi n di n gs dee me d a b n or mal wit h cli nical si g nifica nce b y 
t he I n vesti gat or ( or desi g nee), at Scree ni n g, C hec k-i n ( Da y - 1), 
or pri or t o d osi n g o n Da y 1. 
F or t hese E C G para meters, o ut - of-ra n ge para meters t hat are n ot 
cli nicall y si g nifica nt (as deter mi ne d b y t he I n vesti gat or [ or desi g nee]) 

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 3 5 of 7 0  
ma y be re peate d t wice 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. N ote: Re peat E C Gs will be per mitte d u p t o 2  ti mes 
t o c o nfir m eli gi bilit y f or st u d y. 
2. S u bjects wit h o ut- of- ra n ge, 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 ( Da y - 1), or pri or t o d osi n g o n Da y 1,
i ncl u di n g:
a.
o ral b o d y te m perat ure > 3 7. 5° C;
b. p ulse rate < 5 0 or > 9 9 beats per mi n ute ( b p m );
c.
s yst olic B P < 8 9 or > 1 3 9 m m H g ;
d. d iast olic B P < 5 0 or > 89 m m H g ;
e.
o x y ge n sat urati o n < 9 5 % (r o o m air)
F or  t hese para meters, o ut- of-ra n ge val ues t hat are n ot cli nicall y si g nifica nt (as 
deter mi ne d b y t he I n vesti gat or [ or desi g nee ]) ma y be re peate d t wice 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. N ote: Rec hec ks of  p ulse rate , 
B P val ues, a n d o x y ge n sat urati o n will be per mitte d u p t o 2 ti mes t o c o nfir m eli gi bilit y 
f or st u d y partici pati o n. S u bjects ma y be eli gi ble f or partici pati o n i n t he st u d y base d o n 
rec hec ke d p ulse rate  a n d/ or B P val ues a n d/ or o x y ge n sat urati o n if t he val ues fall 
wit hi n t he ra n ges state d a b o ve. 
3.
A b n or mal la b orat or y val ues ( he mat ol o g y pa nel, U A,  cli nical c he mistr y pa nel [faste d 
at least 8 h o urs], e xcl u di n g t h ose f urt her defi ne d i n e xcl usi o n criteria # 5 , # 6 , # 7 , a n d 
# 8  bel o w) deter mi ne d  t o be cli nicall y si g nifica nt by  t he I nvesti gat o r ( or desi g nee),  
a n d S p o ns or at Scree ni n g a n d/ or C hec k-i n ( Da y - 1) as c o nfir me d b y re peat 
assess me nt .
4.
Cli nicall y  si g nifica nt a b n or malit y, as deter mi ne d  by  t he I nvesti gat o r ( or desi g nee),  
fr o m p h ysical e xa mi nati o n at Chec k -i n ( Da y - 1).
5.
A b n or mal li ver fu ncti o n  tests (L F Ts ), as defi ne d  by  as partate a mi n otra nsferase , 
ala ni ne a mi n otra nsferase , an d  seru m  (t otal a nd  direct) bilir u bi n, as well as a mylase  
a n d li pase a b o ve t he u p per li mit of t he n or mal ra n ge at Scree ni n g or C hec k-i n
( Da y - 1). Rec hec ks of L F Ts, a m ylase, a n d li pase will be per mitte d u p t o 2 t i mes t o 
c o nfir m eli gi bilit y  f or st u d y partici pati o n  if t he val ues fall wit hi n nor ma l ra n ges.
6.
A n y  cli nicall y si g nifica nt de viati o ns fr o m n or mal ran ges  i n creati ne ki nase  unless  
a p pr o ve d b y t he I n vesti gat or ( or desi g nee) a n d S p o ns or. Rec hec ks of creati ne ki nase  
will be  per mitte d  up  t o 2 ti mes t o co nfir m eli gi bilit y  f or st u d y partici pati o n  if t he o ut-
of-ra n ge val ues are sta ble or tre n di n g d o w n a n d the  I nvesti gat or ( or desi g nee) a n d t he 
S p o ns o r dee m t hat t he  res ults are n ot cli nicall y  si g nifica nt an d  will n ot i m pact st u d y 
c o n d uct.
7.
Esti mate d  gl o mer ular filtrati o n  rate ≤ 9 0 mL/ mi n ute / 1. 7 3 m2 at Scree ni n g  or  Chec k -i n 
( Da y - 1) 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- EPI)  e q uati o n. Out  of ra n ge  esti mate d gl o mer ular filtrati o n rates that are  not  
cli nicall y  si g nifica nt (as deter mi ne d  b y  t he I nvesti gat or [ or desi g nee ]) ma y  be 
re peate d t wice d uri n g Scree ni n g a n d C hec k i n ( Da y - 1). Note:  Re peat esti mate d 
gl o mer ular filtrati o n  rate will be per mitte d up  t o 2 t i mes t o co nfir m eli gi bilit y  f or 
st u d y partici pati o n. S u bjects ma y be eli gi ble f or partici pati o n i n t he st u d y base d 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 3 6 of 7 0  
rec hec ke d esti mate d gl o mer ular filtrati o n rate if t he val ues fall wit hi n t he ra n ge state d 
a b o ve. 
8.  He m o gl o bi n, w hite bl o o d cell c o u nt , a n d platelet c o u nts bel o w t he l o wer li mit of 
n or mal ra n ge at Scree ni n g or C hec k -i n ( Da y -1). Rec hec ks of he m o gl o bi n, w hite 
bl o o d cell c o u nt, a n d platelet c o u nts will be per mitte d u p t o 2 ti mes t o c o nfir m 
eli gi bilit y f or st u d y partici pati o n if t he val ues fall wit hi n n or mal ra n ges.  
9.  P ositi ve ser ol o gic test f or  H bs A g, H B V c ore a nti b o d y, H C V , 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 C V b y a nti b o d y will re q uire c o nfir mati o n 
b y P C R bef ore e nr oll me nt t o detect prese nce of acti ve vir us. S u bjects w h o are H C V 
P C R 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 0.  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 her details re gar di n g C O VI D - 1 9 testi n g (i ncl u di n g pr oce d ures 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 pecifie d i n a se parate d oc u me nt.  
1 1.  S u bjects wit h k n o w n o n g oi n g alc o h ol a n d/ or dr u g a b use wit hi n 2 years pri or t o 
Scree ni n g, or e vi de nce of s uc h a b use 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 ( Da y - 1). Tests f or dr u gs of a b use m ust be ne gati ve at b ot h Scree ni n g a n d 
C hec k -i n ( Da y - 1). 
1 2.  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. 
1 3.  C o ns u m pti o n of alc o h ol- or caffei ne -c o ntai ni n g f o o ds or be vera ges 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, u nless dee me d acce pta ble b y t he 
I n vesti gat or ( or desi g nee) a n d S p o ns or. 
1 4.  Stre n u o us e xercise 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. 
1 5.  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 nce, u nless a p pr o ve d b y t he I n vesti gat or ( or desi g nee). 
1 6.  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 hic he ver is 
l o n ger, pri or t o t he first d ose a d mi nistrati o n ( Da y 1). 
1 7.  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; wit h t he e xce pti o n of 
mi daz ola m 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 nce wit h t he 
pr ot oc ol), 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, her bal pr o d ucts, nat ural or 
her bal s u p ple me nts , a n d h or m o ne-re place me nt t hera p y [ H R T]) wit hi n 1 4  da ys pri or t o 
t he first d ose a d mi nistrati o n ( Da y 1) a n d t hr o u g h E O T or E T, u nless dee me d 
acce pta ble b y t he I n vesti gat or ( or desi g nee) a n d S p o ns or. 
1 8.  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 9.  Hist or y or prese nce, 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 vesti gat or ( or desi g nee), w o ul d i nterfere wit h t he a bilit y t o pr o vi de i nf or me d 
c o nse nt or co 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. 

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 3 7 of 7 0  
2 0.  P o or peri p heral ve n o us access . 
2 1.  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 Scr ee ni n g. 
2 2.  Rec ei 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 ( Da y - 1). 
2 3.  Use of t o bacc o, s m o ki n g cessati o n pr o d ucts, or pr o d ucts c o ntai ni n g 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. 
2 4.  Si g nifica 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, he 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 car diac fail ure), ne ur ol o gical, or 
ps yc hiatric dis or der (as deter mi ne d b y t h e I n vesti gat or [ or desi g nee]), or ca ncer 
wit hi n t he past 5 years  (e xce pt l ocalize d basal cell, s q ua m o us, or i n sit u ca ncer of t he 
s ki n). N ote: s u bjects wit h a hist or y of a p pe n dect o m y a n d/ or her nia re pairs will be 
acce pta ble. 
2 5.  Hist or y of dia betes mellit us; H b A 1c ≥ 6. 5 % . 
2 6.  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) . 
2 7.  Ha s pre vi o usl y c o m plete d or wit h dra w n fr o m a n y ot her st u d y i n vesti gati n g 
L O X O - 3 0 5, a n d ha ve pre vi o usl y recei ve d t he i n vesti gati o nal pr o d uct. 
2 8.  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 vesti gat or ( or desi g nee), a n d as c o nfir me d b y t he S p o ns or, wit hi n t he 3 0 da ys pri or 
t o t he first d osi n g a n d t hr o u g h E O T or E T. 
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 partici pate 
i n t his st u d y. 
4. 5.  
S u bject N u m ber a n d I de ntific 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 set of 3 di gits will i de ntif y t he s u bject (e g , 0 0 1- 1 0 1). If s u bjects are 
wit h dra w n b y t he I n vesti gat or ( or desi g nee) or v ol u ntaril 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 dee me d necessar y b y t he S p o ns or. If 
necessar y, as deter mi ne 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 data ma y be re place d. Re place 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 he 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 replaces S u bject N u m ber  0 0 1- 1 0 1). 
4. 6.  
Re m o v al 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 vesti gat or ( or desi g nee) 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 vesti 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 beca use of t he f oll o wi n g:  
•  c ha n ge i n c o m plia nce 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 safet y  
•  occ urre nce of 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 3 8 of 7 0  
•  occ urre nce of pre g na nc y  
•  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 wal will i m me diatel y be ma de t o t he  S p o ns or. I n case of wit h dra wal, 
eff orts will be ma de t o perf or m all fi nal st u d y da y assess me nt s (A p pe n di x 4 ). T he date 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 wit h dra wal will be rec or de d o n t he 
s u bject’s electr o nic Case 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 
assesse 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 me 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 vesti gat or ( or desi g nee) or 
S p o ns or, base d o n t he occ urre nce of t he f oll o wi n g: 
•  a d verse e ve nts u n k n o w n t o date wit h res pect t o t heir nat ure, se verit y, a n d/ or d urati o n; 
•  i ncrease d fre 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 ; 
•  m e dical or et hical reas o ns affecti n g t he c o nti n ue d perf or ma nce of t he st u d y;  
•  d iffic ulties i n t he recr uit me nt of s u bjects; 
•  ca ncellati o n of dr u g de vel 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 nce 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 3 9 of 7 0  
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 bel i n g 
T he S p o ns or ( or desi g nee) will pr o vi de t he I n vesti gat or ( or desi g nee) wit h a de q uate 
q ua ntities of t he st u d y dr u g ( Ta ble  3). C o va nce will s u p pl y mi daz ola m s ol uti o n (I V) a n d 
s yr u p ( oral).   
T a ble  3 St u d y Dr u gs  
St u d y Dr u g  
L O X O -3 0 5  
Mi daz ola m (i ntra ve n o us)  
Mi daz ola m ( oral)  
F or m a 
Ta blet  
S ol uti o n  
S yr u p  
Stre n gt h  
1 0 0  m g  
1 -m g/ m L  
2 -m g/ m L  
S u p plier  
L o x o O nc ol o g y, I nc.  
C o va nce  
C o va nce  
M a n uf act urer  
Be n d Researc h , I nc. 
West -War d  
P har mace uticals C or p. b 
West -War d 
P har mace uticals C or p. b 
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 st ore d acc or di n g t o t he i nstr ucti o ns o n t he la bel. 
M i daz ola m ( oral a n d I V) 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 da nce wit h nati o nal 
la ws a n d re g ulati 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 nsferre d fr o m b ul k s u p plies i nto 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 ner will be a p pr o priatel y la bele d. 
5. 2.  
St u d y Tre at me nt A d mi nistr ati o n  
I n Peri o d 1, Da y 1, a si n gle I V b ol us d ose of 2 5 0 μ g mi daz ola m a d mi nistere d as 0. 2 5 m L  of 
1- m g/ m L  s ol uti o n wil l be a d mi nistere d i n t he m or ni n g f oll o wi n g a 1 0-h o ur fast pri or t o 
d osi n g a n d a 4- h o ur fast p ost d ose . O n Da y 3, a si n gle oral d ose of 5 0 0 μ g mi daz ola m 
a d mi nistere d as 0. 2 5 m L  of 2-m g/ m L  s yr u p will be a d mi nistere d i n t he m or ni n g  f oll o wi n g a 
1 0- h o ur fast pri or t o d osi n g a n d a 4- h o ur fast p ost d ose. O n Da y 3, t he oral mi daz ola m d ose 
will be a d mi nistere d al o ne at t he act ual ti me of t he Da y 1 I V mi daz ola m d ose ( ±  1 h o ur). 
I n Peri o d 2, 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  
i n t he m or ni n g f or 13 c o nsec uti ve da ys ( Da ys 5 t hr o u g h 1 7). O n Da ys 5, 1 4, 1 5 a n d 1 7, 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 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 at least 4 h o urs p ost d ose. O n Da ys 6 t hr o u g h 1 3, a n d Da y 
1 6 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 he m or ni n g f oll o wi n g a fast 
of at least 2 h o urs pri or t o d osi n g a n d 1- h o ur p ost d ose,  wit h t he e xce pti o n of da ys w here 
cli nical la b orat or y e val uati o ns are perf or me d . O n Da ys 5 t hr o u g h 1 4, a n d Da y 1 6, L O X O - 3 0 5 
will be a d mi nistere d al o ne at t he act ual ti me of t he Da y 1 I V mi daz ola m d ose ( ±  1 h o ur). 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 4 0 of 7 0  
t he m or ni n g of Da y 1 5, a n oral d ose of 2 0 0 m g  L O X O - 3 0 5 will be a d mi nistere d 2 h o urs ( ± 
1 5 mi n utes) pri or t o a d mi nisteri n g a si n gle 2 5 0 μ g ( 0. 2 5  m L of 1 -m g/ m L s ol uti o n) I V b ol us 
d ose of mi daz ola m. O n t he m or ni n g of Da y 1 7, a n oral d ose of 2 0 0 m g  L O X O - 3 0 5 will be 
a d mi nistere d first bef ore a si n gle oral 5 0 0  μ g ( 0. 2 5  m L of 2 -m g/ m L s yr u p) d ose of 
mi daz ola m is a d mi nistere d ( wit hi n 5 mi n utes ). O n Da ys 1 5 a n d 1 7, L O X O- 3 0 5 will be 
a d mi nistere d at t he act ual ti me of t he Da y 1 I V mi daz ola m d ose ( ±  1 h o ur). 
All oral 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 ma y be a d mi nistere d if nee de d.  
Eac h u nit d ose will be pre pare d b y q ualifie d C R U staff. Eac h u nit d ose c o ntai ner will be 
a p pr o priatel y la bele d. 
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 c o nsiste ntl y a d mi nistere d t he a p pr o priate 
d ose at a s pecific ti me, t he e xact d ose ti me of s u bjects ma y be sta g gere d t o o b viate t he nee d 
t o ha ve 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 he s u bject’s act ual 
d ose ti me will be rec or de d i n t he s o urce d oc u me nts a n d tra nscri 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 occ 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 ue 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 me nt C o m pli a nce  
T he f oll o wi n g meas ures 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. 
•  Im me diatel 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 . 
•  At eac h d ose pre parati 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 
a n d mi daz ola m will be perf 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 
ta blets a n d mi daz ola m oral s yr u p a n d mi daz ola m I V s ol uti o n 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 ke 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 vie w b y t he S p o ns or u p o n re q uest. 

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 4 1 of 7 0  
F or eac h batc 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 om 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, 
f oll o wi n g t he S p o ns or’s writte n/e maile d i nstr ucti o ns. Mi daz ola m  oral  s yr u p a n d mi daz ola m 
I V s ol uti o n will be dis p ose d of b y t he C R U i n acc or da nce wit h t he C R U’s sta n dar d o perati n g 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 4 2 of 7 0  
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 mit a nt T her a pies  
Paraceta 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 nc 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 d ose a d mi nistrati o n ( Da y  1). 
All prescri pti o n / n o n prescri pti o n me dicati o ns a n d o ver -t he-c o u nter me dicati o ns (i ncl u di n g 
H R T, her bal pr o d ucts, nat ural or her bal s u p ple me nts, e xce pt f or p araceta m ol/aceta mi n o p he n 
as refere nce d a b o ve) are pr o hi bite d f or 1 4 da ys pri or t o d ose a d mi nistrati o n ( Da y 1) a n d 
t hr o u g h E O T or E T, u nless dee me d acce pta ble b y t he I n vesti gat or ( or desi g nee) a n d S p o ns or. 
T his i ncl u des b ut is 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; wit h t he e xce pti o n of mi daz ola m 
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 nce wit h t he pr ot oc ol), str o n g P- g p 
i n hi bit ors, pr ot o n p u m p i n hi bit or s, 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.  
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 vesti 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 case, t he 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 re q uire d t o refrai 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 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 ges c o ntai ni n g 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 will n ot be 
all o we d u nless dee me d acce pta ble b y t he I n vesti gat or ( or desi g nee) a n d S p o ns or. 
C o ns u m pti o n of alc o h ol- or caffei ne -c o ntai ni n g f o o ds or be vera ges 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 u nless dee me d acce pta ble b y 
t he I n vesti gat or ( or desi g nee) a n d S p o ns or. 
S u bjects will refrai n fr o m st re 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 xercise pr o gra m or 
partici pate i n a n y  u n us uall y stre n u o us p h ysical e xerti o n). 
W hile c o nfi ne d at t he C R U, s u bjects will recei ve a sta n dar d diet at sc he 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. Fasti n g re q uire me nt i n relati o n t o d osi n g are 
descri be 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 4 3 of 7 0  
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 me 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 nal ysis of mi daz ola m, 1- O H - mi daz ola m, L O X O - 3 0 5, a n d 
 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 xact 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 de 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 parate La b orat or y Ma 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 ytic al Met h o d ol o g y  
C o nce ntrati o ns of mi daz ola m, 1 -O H -mi daz ola m, L O X O - 3 0 5, a n d 
 
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 p r o vi de d i n a se parate d oc u me nt. 
7. 2.  
S afet y a n d T oler a bilit y Assess me nts  
Safet y e val uati o ns ma y be 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 de t o sc he d ule a n d perf or m t he pr oce d ures i n acc or da nce w it 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 me 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 desce n di n g or der of pri orit y): 
•  d osi n g 
•  P K bl o o d sa m pli n g 
•  v ital si g n meas ure me nts  
•  1 2- lea d E C G s 
•  bl o o d a n d uri ne sa m ples f or cli nical la b orat or y e val uati o ns 
•  p h ysical e xa mi nati o n. 
7. 2. 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 ures f or re p orti n g S A Es are detaile d i n A p pe 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 uesti o n s uc h as “ Ha ve 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 me p oi nts s pecifie d 
i n A p pe n di x 4  (ie, at Scree 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 nts , a n d at a n a p pr o priate ti me f or all ot her da ys). S u bjects will 
als o be e nc o ura ge d t o v ol u ntaril y re p or t 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. 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 4 4 of 7 0  
A d verse e ve nts, w het her v ol u nteere d, i de ntifie d b y t he s u bject’s res p o nses 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,  o x y ge n 
sat urati o n meas ure d b y c o nti n u o us p ulse o xi metr y,  or cli nical la b orat or y e val uati o ns, will be 
rec or de 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 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 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 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 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 vesti gat or ( or 
desi 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 ne 
call) are 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 relate d t o st u d y dr u g b y t he I n vesti gat or ( or desi g nee) w hic 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 he S p o ns or. T he 
I n vesti gat or ( or desi g nee) s h o ul d use a p pr o priate 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 me 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) after E O T or E T t o deter mi ne 
if a n y SA E or dr u g- relate d A E has occ urre d si nce t he E O T or E T visit. 
At all ti mes, a s u bject ma y be re q uire 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 vesti gat or ( or desi g nee). 
A n y e v e nt t hat meets t he criteria of a s us pecte d u ne x pecte d seri o us a d verse 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 desi 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 nce 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 . 
7. 2. 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 uati o ns (cli nical c he mistr y pa nel [faste d at least 8  h o urs; at E T or 
E O T , s u bjects are n ot  re 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 oa 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], 
esti mate d gl o mer ular filtrati o n rate  [ 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 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 be c o n d ucte d peri o dicall y d uri n g t he s u bject’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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 4 5 of 7 0  
C R U c o nfi ne me nt, at t he discreti o n of t he I n vesti gat or ( or desi g nee). F urt her details 
re gar di n g C O VI D- 1 9 testi n g (i ncl u di n g pr oce d ures 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 pecifie d i n a se parate d oc u me nt.  
A uri ne dr u g scree n f or selecte 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) will be 
perf or me d at Scree ni n g a n d re peate d at C hec k -i n ( Da y - 1) f or all s u bjects. A seru m 
q ualitati ve pre g na nc y test (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 test ( 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 is prese 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. 2. 3.  
Vit al Si g n s 
Vital si g n  meas ure me nts  (i ncl u di n g oral te m perat ure, res pirat or y rate, o x y ge n sat urati o n 
meas ure d b y p ulse o xi metr y a n d s u pi ne B P , a n d p ulse rate) will be o btai ne 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 rea di n g a n d meas ure me nts s h o ul d be ta ke n after t he  s u bject has bee n resti n g i n t he 
s u pi ne p ositi o n f or at least 5 mi n utes.  
W he n vital si g n meas ure me nt s are sc he d ule d at t he sa me ti me as bl o o d dra ws, t he 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 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 bl o o d dra w. 
7. 2. 4.  
1 2-l e a d Electr oc ar di o gr a m  
A 1 2 -lea d E C G (i ncl 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 val will be c orrecte d f or heart rate 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 are sc he d ule d at t he sa me ti me as bl o o d dra ws, t he 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 bl o o d dra w. 
7. 2. 5.  
O x y ge n S at ur ati o n Me as ure d b y C o nti n u o us P ulse O xi metr y  
Eac h s u bject will ha ve a baseli ne p ulse o xi metr y rea di n g d o ne pri or t o mi daz ola m 
a d mi nistrati o n a n d will be m o nit ore d c o nti n u o usl y f or a p pr o xi matel y 6 h o urs wit h a p ulse 
o xi meter ( o x y ge n le vels as sat urati o n  [ %]) wit h rea di n gs ta ke n at sc he d ule d ti me p oi nts 
(A p pe n di x 4 ). 
W here t he ti me of m o nit ori n g c oi nci des wit h a bl o o d sa m pli n g ti me p oi nt, t he rea di n g will be 
ta ke n a p pr o xi matel y 1 5 mi n utes pri or t o t he sc he d ule d ti me p oi nt. Rea di n gs ma y be ta ke n at 
ot her ti mes, if dee me d necessar y b y t he I n vesti gat or ( or desi g nee). 

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 4 6 of 7 0  
O utsi de of t he sc he d ule d ti me p oi nts, a n y o x y ge n sat urati o n rea di n g dee me d cli nicall y 
si g nifica nt b y t he I n vesti gat or ( or desi g nee) will be d oc u me nte d. 
7. 2. 6.  
P h ysic al E x a mi n ati o n  
A c o m plete or a b bre viate d p h ysical e xa mi nati o n 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 . C o m plete p h ysical e xa mi nati o ns will e val uate ge neral a p peara 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; hea 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 vasc 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 n s will e val uate ge neral a p peara 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; 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 4 7 of 7 0  
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  
Si xtee n  healt h y a d ult male a n d fe 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 his is a p hase  1 st u d y a n d t he sa m ple size is n ot base d u p o n a n y f or mal 
p o wer calc ulati 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 . Si xtee n s u bjects 
are a ntici pate d 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 varia bilit y 
of t he i nteracti o n.  
E ver y atte m pt w ill 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. 
8. 2.  
A n al ysis P o p ul ati o ns  
8. 2. 1.  
St u d y P o p ul ati o ns  
T h e 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  st u d y dr u g, 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 meter ca n be 
c o m p ute d. A s u bject  ma y  be e xcl u de d fr o m t he 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 bef ore 2 ti mes me dia n ti me t o 
ma xi m u m c o nce ntrati o n. T he i m pact of pr ot oc ol de viati o ns o n P K p o p ulati o n will be 
e val uate d o n a case - b y-case 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 ve d at least 1  d ose of st u d y 
dr u g. 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  
Bl o o d sa m ples f or plas ma c o nce ntrati o n a nal ysis  will be c ollecte d f or t he f oll o wi n g : 
•  Mi daz ola m a n d 1- O H -mi daz ola m :  
o  Serial P K bl o o d sa m ples 
 
a n d wit h L O X O- 3 0 5  
  
o  Serial P K bl o o d sa m ples 
 
a n d wit h L O X O- 3 0 5  
. 
•  L O X O - 3 0 5:  
o  Serial P K bl o o d sa m ples 
 p ost d ose al o ne   
 
. A d diti o nall y, bl o o d sa m ples will be c ollecte d o n  
 
. 
o  
 
•  
:  
o  Serial b l o o d sa m ples
 
 
o  Bl o o d sa m ples 
 
 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 4 8 of 7 0  
W he ne ver p ossi ble, t he f oll o wi n g P K para meters will be calc ulate d f or eac h s u bject, base d o n 
t he plas ma c o nce ntrati o ns of mi daz ola m a n d its meta b olite  1-O H -mi daz ola m  f oll o wi n g oral 
a n d I V si n gle d ose a d mi nistrati o n  (as a p pr o priate): 
A U C 0-t 
A U C fr o m h o ur 0 t o t he last meas ura ble c o nce ntrati o n, calc ulate d usi n g 
t he li near tra pez oi dal r ule f or i ncreasi n g a n d decreasi n g c o nce ntrati o ns 
A U C 0-i nf 
A U C fr o m ti me 0 e xtra p olate d t o i nfi nit y, calc ulate d usi n g t he f or m ula:  
  
 
A U C 0-i nf = A U C 0-t + 
z
t
λ
C
 
w here C t is t he last meas ura ble c o nce ntrati o n a n d λZ  is t he a p pare nt 
ter mi nal eli mi nati o n rate c o nsta nt. 
% A U C
e xtra p perce nt a ge e xtra p olati o n f or A U C 0-i nf 
C ma x  
ma xi m u m o bser ve d plas ma c o nce ntrati o n  
tma x  
ti me t o ma xi m u m o bser ve d plasma  c o nce ntrati o n 
λ Z  
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt, w here λ Z  is t he ma g nit u de 
of t he sl o pe of t he li near re gressi o n of t he l o g c o nce ntrati o n vers us ti me 
pr ofile d uri n g t he ter mi nal p hase  
C L/ F  
a p pare nt s yste mic  cleara nce  ( oral mi daz ola m) 
C L  
t otal cleara nce (I V mi daz ola m) 
t½  
a p pare nt plas ma ter mi nal eli mi nati o n half-life ( w he ne ver p ossi ble), 
w here t ½  = l n( 2)/ λZ  
Vz / F 
a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase ( oral 
mi daz ola m)  
V z 
v ol u me of distri b uti o n  (I V mi daz ola m) 
V ss 
v ol u me of distri b uti o n at stea d y state (I V mi daz ola m)  
W here ver p ossi ble, t he f oll o wi n g P K para meters will be calc ulate d f or eac h s u bject, base d o n 
t he plas ma c o nce ntrati o ns of L O X O- 3 0 5 f oll o wi n g si n gle a n d m ulti ple d ose a d mi nistrati o n:  
A U C 0-t 
A U C fr o m h o ur 0 t o t he last meas ura ble c o nce ntrati o n, calc ulate d usi n g 
t he li near tra pez oi dal r ule f or i ncreasi n g a n d decreasi n g c o nce ntrati o ns 
A U C ta u: 
area u n der t he c o nce ntrati o n-ti me c ur ve d uri n g a d osi n g i nter val 
C L ,ss/ F: 
ap pare nt s yste mic plas ma cleara nce after oral (e xtra vasc ular) 
a d mi nistrati o n, calc ulate d as D ose/ A U C ta u (Da y 1 4 ) 
C ma x : 
m a xi m u m o bser ve d plas ma c o nce ntrati o n at stea d y -state 
C tr o u g h: 
co nce ntrati o n o bser ve d at t he e n d of t he d osi n g i nter val  
tma x : 
ti me t o reac h Cma x . If t he ma xi m u m val ue occ urs at m ore t ha n o ne 
ti me p oi nt, tma x is defi ne d as t he first ti me p oi nt wit h t his val ue 
R A U C  
acc u m ulati o n rati o 
T he f oll o wi n g P K para meters will be calc ulate d w he ne ver p ossi ble, base d o n t he plas ma 
c o nce ntrati o ns of 
 f oll o wi n g si n gle d ose mi daz ola m (I V 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 4 9 of 7 0  
a d mi nistrati o n), si n gle d ose L O X O- 3 0 5, a n d stea d y- state L O X O- 3 0 5 (as a p pr o priate): Cma x , 
tma x , A U C fr o m h o ur 0 t o 24 h o urs ( A U C0- 2 4), a n d Css. 
P har mac o ki netic calc ulati o ns will be perf 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 ( Certara U S A I nc.).   
Ot her para meters ma 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 nal ysis will use act ual ti mes as rec or de d o n t he e C R F. All statistical 
a nal ysis will be perf or me d usi n g S A S  Versi o n  9. 4 or greater. 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 ntrati o ns a n d P K para meters will be 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 oefficie nt of variati 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 mea n plas ma c o nce ntrati 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 nal 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 me d o n t he 
l n-tra nsfor me d mi daz ola m  a n d 1-O H -mi daz ola m  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 ulati o n of least s q uare d ( L S) mea ns a n d t he differe nce bet wee 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 vals ( CIs). T he ge o metric 
mea n rati os a n d t heir 9 0 % C Is 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 differe nce bet wee n L S mea ns  a n d the C Is fr o m t he mi xe d effect m o del . 
T he rati o of mi daz ola m t o 1 -O H -mi daz ola m will be s u m marize d.  
T he sa me met h o d a n d m o del as a b o ve will be use d t o a nal yze t he A U C 0- 2 4 a n d Cma x  of 
 para meters. 
A stea d y state a nal ysis will be perf or me d o n t he  l n-tra nsf or me d Ctr o u g h c o nce ntrati o ns f or 
L O X O - 3 0 5 usi n g Hel mert c o ntrasts.1 6 Hel mert  c o ntrasts are c o nstr ucte d s uc h t hat eac h 
ti me p oi nt is c o m pare d t o t he mea n of t he s u bse q ue nt ti me p oi nts.   
8. 4.  
S afet y A n al ysis 
All safet y assess me nts, i ncl u di n g A Es  a n d 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 descri pti ve met h o d ol o g y, as nee de d, b y 
treat me nt a n d ti me p oi nt. U nless ot her wise s pecifie d, baseli ne val ue is defi ne d as t he last 
n o n- missi n g meas ure me n t bef ore a d mi nistrati o n of st u d y dr u g i n eac h peri o d. N o f or mal 
statistical a nal yses are pla n ne d f or t he safet y data. All safet y data will be liste d b y s u bject. 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 5 0 of 7 0  
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 verse e ve nts will be c o de d usi n g 
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 se 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 vesti gat or or desi g nee ( A p pe 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 O C a n d P T . 
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 ha n ge 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 ges will be ma de b y stri ki n g a si n gle li ne t hr o u g h err o ne o us data a n d clearl y 
e nteri n g t he c orrect data (e g, wr o n g data ri g ht data). 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 ge will be writte n a djace nt t o t he c ha n ge b y t he 
cli nicia n. 
T he Data Ma na ge me 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 verifie d b y t he St u d y M o nit or. Data 
will t he n be re vie we d b y t he data ma na ge 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 data base is clea ne d b y data  ma na ge me nt a n d will be 
re vie we d b y t he C o va nce scie ntific tea m. T he e C R F a n d a ncillar y data will be c o n verte 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 clie nt- pr o vi de d s pecificati o ns. 
T he fi nal datasets str uct ure will be verifie d u si n g We b S u b missi o n Data Ma na ger ® , w hile t he 
dataset c o nte nt will be peer  re vie we d b y a n i n de pe n de nt pr o gra m mer. 
T he ta bles, fi g ures, a n d listi n gs ( T F Ls) will be pr o gra m me d per t he 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 scie 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 de 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.  
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 sta n dar d 
o perati n g pr oce d ures or per clie nt 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 5 1 of 7 0  
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 bet wee n t he S p o ns or a n d t he 
I n vesti gat or ( or desi 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 he S p o ns or, I n vesti gat or ( or desi 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 prese ntati ve(s) of t he 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 vesti gat or ( or 
desi 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 wit 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 ne ws pa pers, oral 
prese ntati o ns, a bstracts) b y t he I n vesti gat or ( or desi g nee) or t heir re prese ntati 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 de i n vi olati o n of t he S p o ns or’s c o nfi de n tialit 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 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 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 oc 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 will visit t he C R U at s uita ble i nter vals a n d be i n 
fre q ue nt c o ntact t hr o u g h ver bal a n d writte n c o m m u nicatio n. It is esse ntial t hat t he S p o ns or’s 
St u d y M o nit or has access t o all d oc u me nts (relate 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 are re q ueste d. I n t ur n, t he S p o ns or’s St u d y M o nit or 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 vesti gat or ( or 
desi g nee) a n d I n vesti gat or’s staff will be e x pecte d t o c o o perate wit h t he S p o ns or’s St u d y 
M o nit or, 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 nce wit h U S Title 2 1 C o de of Fe deral Re 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 de d t o s u bjects will be re vie we d a n d 
a p pr o ve d b y t he I R B. T he S p o ns or will s u p pl y r ele va nt material f or t he I n vesti 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. Verificati o n of 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 5 2 of 7 0  
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 he writte n I C F state me nt will be tra ns mitte d 
t o t he I n vesti gat or ( or desi 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 bse 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 ueste 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 ulat or y i ns pecti o ns b y pr o vi di n g direct access 
t o s o urce data/ d oc 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 pr iate 
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) partici pati o n i n t he st u d y. 
9. 6.  
I nf or me d C o nse nt 
Writte n i nf or me d c o nse nt f or t he st u d y will be o btai ne d fr o m all s u bjects bef ore 
pr ot oc ol-s pecific pr oce d ures are carrie d o ut. T he I C F will be a p pr o ve 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 nat 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 oc 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 oc ol-s pecific pr oce d ures bei n g perf or me d. 
T he s u bject will si g n 2 c o pies of t he I C F. O ne 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 rec or ds.  
9. 7.  
Rec or ds  
T he res ults fr o m data c ollecte d at Scree 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 pies of eac h e C R F 
will be retai ne d b y t h e 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 da 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 heets, 
c orres p o n de nce, p h ot o gra 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 re p ort, will be retai ne 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 ncial Discl os ure b y Cli nical 
I n vesti gat ors ( 2 1 C F R 5 4), I R Bs ( 2 1 C F R 5 6), I n vesti gati o nal Ne w Dr u g A p plicati o n 
( 2 1 C F R  3 1 2), A p plicati o ns f or F D A A p pr o val t o Mar ket a Ne w Dr u g ( 2 1 C F R 3 1 4), a n d 
Ra di oacti ve Dr u gs f or Certai n Researc h Uses ( 2 1 C F R 3 6 1. 1), as a p pr o priate. As s uc h, t hese 
secti o ns of U S Title 2 1 C F R, al o n g wit h t he a p plica ble I nter nati o nal C o uncil f 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 5 3 of 7 0  
Har m o nisati o n (I C H) G ui deli 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 ura nce will be a d dresse d i n a se 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 5 4 of 7 0  
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 vesti gat or’s Br oc h ure ( Versi o n 3. 1). 2 4 J u ne 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 re 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.
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, Blac 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 ua n g Y, R o g ers K, B hat S A, Gre ver 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. 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 gra m mi n g f or PI 3 K in hi biti o n o verri des a rela pse -s pecific C 4 8 1 S B T K m utati o n
re veale 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, De m os M, et al. Ac q uire d m utati o ns
ass oci ate d wit h i br uti ni b resista nce i n Wal de 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, Na 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 har 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: Dr u g I nteracti o n St u dies - St u d y
desi g n, data a nal ysis, a n d i m plicati o ns f or d osi n g a n d la beli n g. Draft G ui da nce [I nter net].
F o o d a n d Dr u g A d mi nistrati o n; 2 0 0 6. A vaila ble fr o m:
htt p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui d
a nces/ uc m 2 9 2 3 6 2. p df
1 0.  G ors ki J C, J o nes D R, Hae h ner- Da niels B D, Ha m ma n M A, O’ Mara E M, Hall S D. T he
c o ntri b uti o n of i ntesti nal a n d he patic C Y P 3 A t o t he i nteracti o n bet wee n mi daz ola m a n d
clarit hr o m yci n. Cli n P har mac ol T her. 1 9 9 8 A u g; 6 4( 2): 1 3 3 – 4 3.
1 1.  S he n H, Dai J, Li u T, C he n g Y, C he n W, Free de n C, et al. 
 as
F u ncti o nal Mar kers of O A T P 1 B Acti vit y: I n Vitr o a n d I n Vi v o E val uati o n i n Precli nical
S pecies. J P har mac ol E x p T her. 2 0 1 6 Ma y; 3 5 7( 2): 3 8 2 – 9 3.
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 5 5 of 7 0  
1 2.  T h u m mel K E, O’ S hea D, Pai ne M F, S he n D D, K u n ze K L, Per ki ns J D, et al. Oral first -
pass eli mi nati o n of mi daz ola m i n v ol ves b ot h gastr oi ntesti nal a n d he patic C Y P 3 A-
me diate d meta b olis m. Cli n P har mac ol T her. 1 9 9 6 Ma y; 5 9( 5): 4 9 1 – 5 0 2.  
1 3.  West - War d P har mace uticals C or p. Mi daz ola m H y dr oc hl ori de S yr u p CI V (for oral use) - 
Pac ka ge I nsert. 2 0 1 7.  
1 4.  West -War d P har mace uticals C or p. Mi daz ola m I njecti o n, U S P CI V ( mi daz ola m i njecti o n) 
- Pac ka ge I nsert.  
1 5.  Researc h C f or D E a n d. Cli nical Dr u g I nteracti o n St u dies — C yt oc hr o me P 4 5 0 E nz y me- 
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 net]. 2 0 2 0 [cite d 
2 0 2 0 Fe b 4]. A vaila ble fr o m: htt p:// w w w.f da. g o v/re g ulat or y- i nf or mati o n/searc h-f da-
g ui da nce- d oc u me nts/cli nical - dr u g-i nteracti o n-st u dies-c yt oc hr o me - p 4 5 0-e nz y me-a n d-
tra ns p orter-me diate d -dr u g -i nteracti o ns 
1 6.  C h o w S C, Li u J P. Desi g n a n d a nal ysis of bi oa vaila bilit y a n d bi oe q ui vale nce st u dies. Ne w 
Y or k: Marcel De k ker; 1 9 9 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 5 6 of 7 0  
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 5 7 of 7 0  
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 o f A d verse E ve nts 
A n a d verse e ve nt ( A E; or a d verse e x perie nce) is defi ne d as a n y u nt o war d me dical occ urre nce 
e x perie nce d b y a patie 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-relate d b y 
t he I n vesti gat or ( or desi g nee). A treat me nt-e mer ge nt a d verse e ve nt ( T E A E) is a n A E t hat 
starts o n or after t he first a d mi 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 ble c ha n ges i n ge neral c o n diti o n; 
•  
su bjecti ve or o bjecti ve si g ns/s y m pt o ms;  
•  
co nc o mita nt diseases or acci de nts;  
•  
cli nically rele va nt a d verse c ha n ges i n la b orat or y para meters o bser ve 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 ge 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 malities t hat are dee me d cli nicall y si g nifica nt 
b y t he I n vesti gat or [ or desi g nee ]), a n d acci de nts o bser ve d i n t he c o nte xt of a cli nical trial, 
irres pecti ve of a p ossi ble ca usal relati 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 verse E ve nts 
T he se verit y o f A Es will be cate g orize d base 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 ve 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 ate: 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 Se vere or me 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 ve 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 des are a p pr o priate f or al l A Es. T heref ore, s o m e A Es are liste d wit hi n t he C T C A E wit h fe wer t ha n 
5 o pti o ns f or gra de selecti o n. Gra de 5 ( deat h) is n ot a p pr o priate f or s o m e A Es a n d t heref ore is n ot a n  o pti 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 oceries or cl ot hes, usi n g t he tele p h o ne, ma na gi n g m o ne y, etc. 
* * Self- care A D L refer t o bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 5 8 of 7 0  
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 wee 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 urre nce or w orse ni n g of t he A E r ules o ut a ca usal 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 nce or w orse ni n g of t he A E is c o nsiste nt wit h a ca usal relati 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 us e of t he dr u g if the re is a reas o na ble p os si bility t hat t he 
e x perie nc e ma y  have bee n  ca use d by  the dr u g. 
Pr e g na nc y 
A s inf or mati o n is availa ble, a pr e g na nc y (i ncl u di n g pre g na nc y i n fe male part ners of male 
s u bjects) d ia g n ose d t hr o u g h E n d of S t u d y (E O S ) or E arl y Ter mi nati o n ( E T ; if t he su bject 
disc o nti n ues fr o m t he st u d y a n d d oes n ot co m plete a foll 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 dru g a d mi nistrati o n s h o ul d be rep orte d b y t he In vesti gat or (or de si g nee) 
via email t o C o va nce or the S p o ns or’s C li nical Safet y Re prese ntati ve w it hi n 2 4 h o urs o f 
bei n g n otifie d. C o va nce or the S p o ns or’s Cli nical  Safet y Re prese 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  su bject bec o mi n g  pre g na nt w hile on  st u d y dru g  will im me diatel y  be wit h dra w n fr om t he  
st u d y a n d ET  st u d y pr oce d ures w ill be pe rf or me d. T he su bject or pa rt ner sh o ul d be foll o we d 
b y t he In vesti gat or ( or desi g nee)  u ntil co m pleti o n of the pr e g na nc y. If t he pr e g na nc y e n ds for 
a n y reas o n bef ore t he antici pate d date, t he In vesti gat or (or de si g nee) sh o ul d n otif y C o va nce 
or the S p o ns or’s C li nical S afet y Re prese ntati ve . At the co m pleti o n of the pre g na nc y, t he 
I n vesti gat or ( or de si g nee) will d oc u me nt t he  o utc o me of the p re g na ncy. If t he o ut co me of the 
pre g na nc y  meets t he criteria f or  im me diate 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 ab orti o n, still birt h, ne o natal d eat h, or co n ge nital 
a n o mal y), t he In vesti gat or ( or desi g nee) s h o uld f oll o w the p roce d ures f or re p orti n g a n S A E. 
Male  su bjects  will be i nstr ucte d t o n otif y t he I n vesti gat or ( or de si g nee) i m me diatel y if the y  
disc o ver t heir se x ual pa rt ner is pr e g na nt. I n t his i nsta nce, t he part ner m us t pr o vi de w ritte n 
c o nse nt be f ore pre g na nc y inf or mati o n  ca n be c ollecte d. W he n a Cli nical Researc h  Unit  
(C R U ) bec o mes a ware t hat  the  fe male part ner of a male s u bject  is pre g na nt, the y  are t o 
c o ntact t he In vesti gat or ( or de si g nee) i m me diatel y ( wit hi n 2 4 h o urs of the C R U  staff 
bec o mi n g a w are of the e ve nt) i n a d diti o n t o n otif yi n g C o va nce or the S p o ns or’s Cli nical  
S afet y R e prese ntati ve via e mail.  
All pr e g na ncies sh o ul d be rec or ded o n t he A E electr o nic Case Re p ort For m (eC R F ; as 
a p pro priate), i n a d diti o n t o c o m pleti o n of the req uire d pre g na nc y f or ms. If t he In vesti gat or 
( or de si g nee) s us pects t hat a pre g na nc y  was t he res ult  of a n interacti o n  bet wee n the  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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 5 9 of 7 0  
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 he dr u g i nteracti o n 
s h o ul d als o be ca pt ure d as a se parate A E.  
Defi niti o n of Seri o us A d verse E ve nts  
A n S A E ( b y 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 verse dr u g e x perie nce 
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 verse dr u g e x perie nce (ie, o ne t hat places t he s u bject, i n t he
vie w of t he I n vesti gat or [ or desi g nee], at i m me diate ris k of deat h);
•
I n patie 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 defe ct;
•
A n i m p orta nt me dical e ve 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 o ne of t he a b o ve o utc o mes.
I m p orta nt me dical e ve nts  t hat ma y  not res u lt i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y be co nsi dere d S A Es w he n, base d o n a p pr o priate m edical ju d g me nt , the y 
ma y  jeo par dize  t he patie nt or s u bject an d  may  re q uire me dical or s ur gical i nter ve nti o n  t o 
pre ve nt o ne  of t he  o utc o mes liste d i n t his defi niti o n. 
U ne x pecte d  A d verse Dr u g  Reacti o n 
A n  AE  or s uspecte d  a d verse dr u g  reacti on  is co nsi dere d  ‘ u ne x pecte d’ if t he eve nt  is not liste d  
i n the Refere nce Safet y  I nf or mati o n sectio n  of th e In vesti gat or’s B r oc h ure (I B) or if it is  n ot 
liste d at t he s pecificit y or se verity t hat ha s be en o bser ve d f or an 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  
F o o d a n d Dr u g A d mi nistrati o n-re p orta ble A Es ar e A Es t hat  are ass ociate d  wit h  the us e of  the  
dr u g a n d re prese nt e ve nts that are assesse d as seri o us, relate d, a n d u ne x pecte d. F o o d a n d 
D r u g Ad m i nistrati o n-re p orta ble A Es w ill be re p orte d b y t he C R U to t he S p o ns or an d t he 
res p o nsi ble I nstit uti o nal Re vie w B o ard  (IR B).  Final deter mi nati o n  of w het her a n e ve nt 
re prese nts a s us pecte d une x pecte d  seri o us a d verse reacti o n (S U S A R ) will be  t he 
resp o nsi bilit y of the S p o ns or. 
Wit hi n  2 4 ho urs of w he n a n A E that is p ot e ntiall y F D A- re p orta 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 SA E  (re gar dless of whet her  t he e ve nt is assesse d as 
relate d or u n relate d to st u d y dr u g) be in g first rec o g nize d or re p orte d, C o va nce or t he 
S p o ns or’s C li nical Safet y Re prese ntati ve w ill be n ot ifie d b y t he In ves ti gat or (or  desi g nee) in 
writi n g  usi n g t he f oll o wi n g email 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 co m plete d re p ort for m sh o ul d be se nt b y e mail to C o va nce or the 
S p o ns or’s C li nical Safet y R e prese ntat i ve wit hi n 2 4 h o urs of aware ness. 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 6 0 of 7 0  
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 are 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- re 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 pecte 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 6 1 of 7 0  
A p pe n di x  2: Cli nic 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  
Plate let 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  
H u ma n i m m u n o deficie nc y vir us 
( HI V) a nti b o d y 
He patitis B s urface a nti ge n  
( H BsA g)  
He patitis B vir us ( H B V) c ore 
a nti b o d y 
He patitis C vir us ( H C 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 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)  
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 0/ / 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.  

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 6 2 of 7 0  
A p pe n di x  3: T ot al Bl o o d V ol u me 
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 bject: 
a At P K sa m pli n g ti me p oi nts w here m ulti ple a nal ytes  (ie, mi daz ola m, O H- 1-mi daz ola m, L O X O -3 0 5, or 
 
) are assesse d, a si n gle bl o o d sa m ple will be ta ke n  f or a nal ysis (see A p pe n di x 4 ).  
b T h yr oi d sti m ulati n g h or m o ne a n d esti mate d gl o mer ular filtrati o n rate will be assesse d as part of t he cli nical c he mistr y 
sa m ple. 
If e xtra bl o o d sa m ples are re q uire 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 5 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 pl e 
( 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 m e 
( 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  
Mi daz ola m p har mac o ki netic ( P K) 
sa m pli n g 
4. 0   
 
1 0 0 a 
4 0 0 . 0 
L O X O -3 0 5 P K sa m pli n g  
 P K sa m pli n g 
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 p ara meters  
 
4 . 0 
4 . 0 
3 . 0 
7 
7 7 . 0 
Ser u m creati ni ne al o ne 
2. 0  
6  
1 2 . 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 ( F S H; 
p ost -me n o pa usal fe male s u bjects o nl y)  
4 . 0 
1 
4. 0  
T ot al:  
5 1 7 . 0 m L  
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 6 3 of 7 0  
A p pe n di x  4: Sc he d ule of Assess me nt 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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 6 4 of 7 0  
St u d y Pr oce d ures a 
Scree ni n g  
( D a ys -2 9 
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 y 
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  
7 ( ± 2) d a ys p ost 
E O T/ E T a a 
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 
 
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 c 
X c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical 
E xa mi nati 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 ns f 
X g 
X g 
X  
 
X  
 
X  
 
 
 
X  
 
 
 
X  
 
X  
 
X  
 
 
 
X g 
 
O x y ge n Sat urati o n 
Meas ure d b y P ulse 
O xi metr y h 
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  
Mi daz ola m I V 
D osi n g k 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Mi daz ola m Oral 
D osi n g l 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
L O X O -3 0 5 
D osi n g m  
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 6 5 of 7 0  
St u d y Pr oce d ures a 
Scree ni n g  
( D a ys -2 9 
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 y 
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  
7 ( ± 2) d a ys p ost 
E O T/ E T a a 
Cli nical La b orat or y 
E val uati o ns r 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X z 
X z 
 
Esti mate d 
G l o mer ular 
F iltrati o n R ate 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ser u m Creati ni ne s 
 
 
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 t 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H b A 1c Test  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr u g Scree n u 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri or a n d 
C o nc o mita nt 
Me dicati o ns
v 
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 w  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X z 
X z 
 
F S H Test x 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T S H Test  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A b bre viati o ns: A E  = a d verse e ve nt; B MI  = b o d y mass i n de 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 U = Cli nical Researc h U nit; E C G  = electr ocar di o gra m; 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 mo 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 Feel?; HI V  = h u ma n i m m u n o deficie nc y vir us; 
I C F = I nf or me d C o nse nt F or m; I V = i ntra ve n o us; P K = p har mac o ki netic; Q D = o nce dail y; 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 ne; U A = uri nal ysis. 
a. F or details o n st u d y pr oce 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 o d y mass i n de x  base d o n Scree ni n g hei g ht.  
d.  A c o m plete p h ysical e xa mi nati o n will be perf or me d at  C hec k -i n ( Da y - 1). A n a b bre viate d p h ysical e xa mi nati o n will be perf or me d at E n d of Treat me nt ( E O T ; Da y  2 1) or Earl y Ter mi nati o n 
( E T). 
e. 1 2- lea d electr ocar di o gra ms ( E C Gs ) will be c ollecte d after t he s u bject has reste d i n t he s u pi ne p ositi o n f or at least 1 0 mi n utes , a n d 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 bl o o d dra ws at Scree ni n g a n d C hec k -i n (Da y  - 1), Da y 1 ( pre d ose, 2 h o urs after i ntra ve n o us [I V] mi daz ola m d osi n g), Da y  3 ( pre d ose, 2  h o urs after oral mi daz ola m d osi n g), Da y  5 
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 6 6 of 7 0  
( pre d ose a n d 2 h o urs a fter L O X O-3 0 5 d osi n g), pre d ose  o n Da y  9 a n d Da y 1 3 , Da y 1 5 ( pre d ose, a n d 2 h o urs after I V mi daz ola m d osi n g), Da y  1 7 ( pre d ose, a n d 2 h o urs after oral mi daz ola m 
d osi n g), a n d at E O T ( Da y 2 1) or E T . 
f. Vital si g n meas ure me nts (s u pi ne bl o o d press ure [ B P], p ulse rate, a n d res pirat or y rate) will be o btai ne d at Scree ni n g a n d C hec k -i n (Da y  - 1), Da y 1 ( pre d ose, 2 h o urs after I V mi daz ola m 
d osi n g), Da y  3 ( pre d ose, 2 h o urs after oral mi daz ola m d osi n g), Da y  5 ( pre d ose a n d 2 h o urs after L O X O-3 0 5 d osi n g), pre d ose Da y  9 a n d Da y 1 3, Da y 1 5 ( pre d ose, a n d 2 h o urs after I V 
mi daz ola m d osi n g), Da y  1 7 ( pre d ose, a n d 2 h o urs after oral mi daz ola m d osi n g), a n d at E O T ( Da y 2 1) or E T. Vital si g n meas ure me nts s h o ul d be carrie d o ut 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. BP a n d p ulse rate will be meas ure d usi n g t he sa me ar m f or eac h rea di n g after t he s u bject has bee n s u pi ne f or at least 5  mi n utes.  
g.  Oral te m perat ure  will be o btai ne d at Scree ni n g , Da y - 1, a n d at E O T (Da y 2 1 ) or E T . 
h.  O x y ge n sat urati o n meas ure d b y p ulse o xi metr y will be meas ure d  at Scree ni n g, Da y - 1, a n d at E O T ( Da y 2 1) or E T . O n Da ys 1, 3, a n d 1 7, o x y ge n sat urati o n  will be meas ure d  b y p ulse 
o xi metr y pre d ose a n d will be m o nit ore d o ver a 6 -h o ur c o nti n u o us peri o d p ost d ose, wit h data c ollecte d pre d ose a n d at 15 mi n utes , 30 mi n utes , 1 h o ur, 2 h o urs , 3 h o urs a n d 6 h o urs p ost d ose.  
O n Da y 1 5, o x y ge n sat urati o n will be meas ure d b y p ulse o xi metr y pre -I V mi daz ola m d ose a n d will be m o nit ore d o ver a 6-h o ur c o nti n u o us peri o d p ost -I V mi daz ola m d ose, wit h data 
c ollecte d pre I V mi daz ola m d ose a n d at 1 5 mi n utes, 3 0 mi n utes, 1 h o ur, 2 h o urs, 3 h o urs a n d 6 h o urs p ost I V mi daz ola m d ose . 
i. A H o w D o Y o u Feel?  i n q uir y will be perf or me d at Scree 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 u re me nts, 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 Es) a n d seri o us A Es  ( 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 verse e ve nts will be rec or de 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 h e I nf or me d 
C o nse nt F or m [ 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 assesse d as n ot 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 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 he I n vesti gat or [ or desi g nee]) 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 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 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 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.  
k.  O n Da y  1, mi daz ola m will be a d mi nistere d i n t he m or ni n g as a n  I V d ose f oll o wi n g a fast of at least 10 h o urs pri or t o a n d 4 h o urs p ost d ose. O n Da y 1 5, L O X O -3 0 5 will be c oa d mi nistere d 
wit h a n I V d ose of mi daz ola m i n t he m or ni n g f oll o wi n g a fast of at least 8 h o urs pri or t o a n d 4 h o urs p ost- d osi n g of I V mi daz ola m. O n D a y 1 5, L O X O - 3 0 5 will be a d mi nistere d 2 h o urs  (± 
1 5 mi n utes)  pri or t o a d mi nisteri n g a n I V d ose of mi daz ola m . O n Da y 1 5, L O X O - 3 0 5 s h o ul d be a d mi nistere d  at t he act ual ti me of t he Da y 1 I V mi daz ola m d ose ( ±  1 h o ur). 
l. O n Da y 3, mi daz ola m will be a d mi nistere d i n t he m or ni n g as a n oral d ose f oll o wi n g a fast of at least 1 0 h o urs pri or t o a n d 4 h o urs p ost d ose. O n Da y 1 7 , L O X O-3 0 5 will be c oa d mi nistere d 
wit h a n o ral d ose of mi daz ola m 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 a n d 4  h o urs p ost - d osi n g of oral mi daz ola m . O n Da y 1 7 , L O X O - 3 0 5 will be a d mi nistere d wit hi n 5 
mi n utes  pri or t o a d mi nisteri n g a n oral d ose of mi daz ola m . O n Da y 3 oral mi daz ol a m s h o ul d be a d mi nistere d  at t he act ual ti me of t he Da y 1 I V mi daz ola m d ose ( ±  1 h o ur) a n d o n Da y 1 7 , 
L O X O -3 0 5 s h o ul d be a d mi nistere d  at t he act ual ti me of t he Da y 1 I V mi daz ola m d ose ( ±  1 h o ur). 
m.  O n Da y 5 t hr o u g h Da y 1 7, L O X O -3 0 5 will be d ose d Q D i n t he m or ni n g. O n Da y 1 5, L O X O -3 0 5 will be a d mi nistere d 2 h o urs  ( ± 1 5 mi n utes ) pri or t o a d mi nisteri n g a n I V d ose  of 
mi daz ola m . O n Da y 1 7, L O X O-3 0 5 will be a d mi nistere d wit hi n 5 mi n utes  pri or t o a d mi nisteri n g a n  oral d ose of mi daz ola m . O n Da ys 5, 1 4, 1 5, a n d 1 7, L O X O -3 0 5 will be a d mi nistere d 
f oll o wi n g a fast of at least 10 h o urs pri or t o a n d at least 4 h o urs p ost d ose ( of L O X O -3 0 5 a n d I V mi daz ola m [ o n Da y 1 5] a n d L O X O -3 0 5 a n d oral mi daz ola m [ o n Da y 1 7]). O n Da y 6 , a n d 
Da y 8  t o 1 3, L O X O -3 0 5 will be a d mi nistere d f oll o wi n g a fast of at least 2 h o urs pri or t o d osi n g a n d 1 -h o ur p ost d ose.  O n Da ys 7  a n d 1 6 w he n cli nical la bs will be c ollecte d, L O X O - 3 0 5 will 
be a d mi nistere d f oll o wi n g a fast of at least 8 h o urs pri or t o a n d 1 h o ur p ost d ose . O n Da ys 5 t hr o u g h Da y 1 7,  L O X O - 3 0 5 s h o ul d be a d mi nistere d al o ne at t he act ual ti me of t he Da y 1 I V 
mi daz ola m d ose ( ±  1 h o ur). 
n.
o.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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 6 7 of 7 0  
p.  
q.  
r. Cli ni cal c he mistr y pa nel (faste d f or at least 8 h o urs ), c oa g ulati o n para meters, he mat ol o g y pa nel , a n d uri nal ysis ( U A)  will be perf or me d . At E T  or E O T , su bjects are n ot re q uire d t o be fasted 
pri or t o cli nical la b orat or y e val uati o ns.  
s. Ser u m creati ni ne will be c ollecte d pre d ose . On da ys w he n cli nical la b orat or y  e val uati o ns a n d ser u m creati ni ne are c ollecte d (ie D a ys 3, 7, a n d 1 4), ser u m creati ni ne will be assesse d as part of 
t he sa me sa m ple use d f or cli nical la b orat or y e val uati o ns. 
t. Testi n g f or C O VI D -1 9 will be c o n d ucte d at a mi ni m u m of  Scree ni n g  a n d C hec 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 Cli nical 
Researc h U nit ( C R U) c o nfi ne me nt , at t he discreti o n of t he I n vesti gat or ( or desi g nee). Tests will be perf or me d b y ra pi d p ol y merase c hai n reacti o n or e q ui vale nt . 
u.  Dr u gs of a b use uri ne test, i ncl u di n g c oti ni ne  a n d alc o h ol . Res ults fr o m t he dr u gs of a b use  tests will be use d t o deter mi ne s u bject eli gi bilit y per t he i ncl usi o n/e xcl usi o n criteria. 
v.  Pri or a n d c o nc o mita nt me dicati o n a d mi nistrati o n will be rec or de 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 vesti gat or -a p pr o ve d me dicati o ns ta ke n b y a s u bject wit hi n 1 4  da ys pri or t o 
st u d y dr u g a d mi nistrati o n f or prescri pti o n me dicati o ns a n d n o n-prescri pti o n me dicati o n,  will be rec or de d o n t he s u bject’s electr o nic Case Re p ort F or m.  
w.  Fe male s u bjects o nl y.  
x.  P ost -me n o pa usal fe male s u bjects o nl y.  
y.  E O T is defi ne d as w he n t he s u bject is release d fr o m t he C R U f oll o wi n g c o m pleti o n of all assess me nts t hr o u g h Da y  2 1 . E T is defi ne d as w he n t he s u bject is release d fr o m t he C R U if t he 
s u bject ter mi nates t he 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 he C R U at t he E O T visit ( Da y 2 1) or E T. Cli nical la b orat or y res ults (f or cli nical c he 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 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 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 vaila ble. 
z. Cli nical la b orat or y e val uati o ns a n d ser u m pre g na nc y test ( fe male s u bjects o nl y) will be perf or me d o n t he da y pri or t o s u bject release fr o m t he C R U ( Da y 2 0) if t he s u bject c o m pletes t he 
st u d y ( E O T). Cli nical la b orat or y e val uati o ns a n d ser u m pre g na nc y test (fe male s u bjects o nl y) will be perf or me d o n t he da y of s u bject release fr o m t he C R U if t he s u bject ter mi nat es earl y 
( E T).   
aa.  T o be c o n d ucte d 7 da ys ( ± 2 da ys ) f oll o wi n g E O T or E T. E O S is defi ne d as w he n t he s u bject atte n ds t he C R U f or 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 
deter mi ne if a n y S A E or st u d y dr u g -relate d A E has occ urre d si nce t he E O T or E T visit. All s u bjects w h o recei ve d L O X O-3 0 5 (i ncl u di n g s u bjects w h o are ter mi nate d earl y) will recei ve a 
f oll o w-u p p h o ne call.  
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 6 8 of 7 0  
b b
cc.
d d.  De n otes pre d ose sa m ple c ollecti o n o nl y.
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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 6 9 of 7 0  
A p pe n di x  5: Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges  
Pr ot oc ol Versi o n 2. 0 ( date d 1 1 Se pte m ber 2 0 2 0) i nc or p orate d t he f oll o wi n g c ha n ges i n 
Pr ot oc ol Versi o n 1. 0 ( date d 3 r d A u g ust 2 0 2 0): 
•  A d diti o nal preli mi nar y data fr o m o n g oi n g st u dies wit h L O X O - 3 0 5 has bee n a d de d t o 
Secti o n 1. 4, S u m m ary of Cli nic al Ex perie nce . 
•  E xcl usi o n criteri o n # 1, s u bsecti o n g , viii, a n d 4 , has bee n u p date d t o all o w o ut- of-
ra n ge val ues f or electr ocar di o gra m para meters t hat are n ot cli nicall y si g nifica nt t o be 
re peate d t wice 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 a n d re peat 
E C Gs will be per mitte d u p t o 2  ti mes t o c o nfir m eli gi bilit y f or st u d y. 
•  E xcl usi o n criteri o n # 2 has bee n u p date d t o all o w o ut- of- ra n ge val ues f or o x y ge n 
sat urati o n t hat are n ot cli nicall y si g nifica nt t o be re peate d t wice 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 a n d re peat o x y ge n sat urati o n meas ure me nts  
will be per mitte d u p t o 2  ti mes t o c o nfir m eli gi bilit y f or st u d y. 
•  E xcl usi o n criteri o n # 7 has bee n u p date d t o all o w o ut- of- ra n ge val ues f or esti mate d 
gl o mer ular filtrati o n rate t hat are n ot cli nicall y si g nifica nt t o be re peate d t wice d uri n g 
Scree ni n g  a n d C hec k -i n ( Da y - 1) a n d re peat f or esti mate d gl o mer ular filtrati o n rate 
meas ure me nts  will be per mitte d u p t o 2  ti mes t o c o nfir m eli gi bilit y f or st u d y. 
•  A n a d diti o nal p har mac o ki netic ( P K) bl o o d s a m ple will be c ollecte d at 5 mi n utes p ost -
mi daz ola m i ntra ve n o us (I V) d osi n g o n Da y 1 a n d Da y 1 5. 
•  T he pr ot oc ol state d t hat o n t he m or ni n g of Da y 1 5, a n oral d ose of 2 0 0 m g L O X O-
3 0 5 w o ul d be a d mi nistere d 2 h o urs pri or t o a d mi nisteri n g a si n gle 2 5 0 μ g ( 0. 2 5 m L of 
1 m g/ m L s ol uti o n) I V b ol us d ose of mi daz ola m . T his has bee n u p date d t o state t hat 
w he n  I V mi daz ola m is a d mi nistere d 2 h o urs after L O X O - 3 0 5 a d mi nistrati o n o n 
Da y  1 5, t his ca n be wit hi n a wi n d o w of ± 1 5 mi n utes. 
•  T he s pecifie d ser u m creati ni ne assess me nt ti me p oi nts i n A p pe n di x 4, Sc he d ule of 
Assess me nts  o n Da y 2 0 ( pri or t o s u bject release fr o m t he cli nical researc h u nit if t he 
s u bject c o m pletes t he st u d y) a n d Da y 2 1 (earl y ter mi nati o n) were err o ne o usl y 
i ncl u de d a n d ha ve bee n re m o ve d  fr o m t he ta ble a n d fr o m f o ot n ote ‘s’. 
•  F o ot n ote ‘ h’ of A p pe n di x 4, Sc he d ule of Assess me nts  has bee n clarifie d t o  state t hat o n 
Da y 1 5, o x y ge n sat urati o n meas ure d b y p ulse o xi metr y s h o ul d be meas ure d relati ve t o 
t he n o mi nal I V mi daz ola m d ose ti me p oi nt.  
•  F o ot n ote ‘ k’ of A p pe n di x 4, Sc he d ule of Assess me nts  i nc orrectl y state d t hat s u bjects 
s h o ul d fast f or 1 0 h o urs pri or t o d osi n g of I V mi daz ola m; t his has bee n u p date d t o 8 
h o urs pri or t o d osi n g of I V mi daz ola m.  
•  F o ot n ote ‘ m ’ of A p pe n di x 4, Sc he d ule of Assess me nts i nc orrectl y state d t hat s u bjects 
s h o ul d fast f or 2 h o urs p ost d ose o n Da y 7 a n d Da y 1 6; t his has bee n u p date d t o 1- h o ur 
p ost d ose o n Da y 7 a n d Da y 1 6. 
•  F o ot n ote ‘ b b’ of A p pe n di x 4, Sc he d ule of Assess me nts  stated t hat P K bl o o d sa m ples 
f or I V mi daz ola m, oral mi daz ola m, a n d L O X O - 3 0 5 c o ul d be c ollecte d wit hi n 1 5 
mi n utes pri or t o d osi n g f or t he pre d ose sa m pli n g ti me p oi nt; t his has b ee n u p date d t o 
3 0 mi n utes t o be c o nsiste nt wit h t he P K sa m pli n g ti me p oi nts i n f o ot n otes ‘ n’, ‘o’, ‘p’, 
a n d ‘ q’.  

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 7 
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 0 8 
Pr ot oc ol Versi o n  2. 0, 1 1 Se pte m ber 2 0 2 0 
Pa ge 7 0 of 7 0  
Mi n or u p dates:  
•  T he a me n d me nt/ versi o n n u m ber a n d date were u p date d t hr o u g h o ut t he pr ot oc ol. 
•  T y p o gra p hical err ors a n d f or matti n g err ors were c orrecte d, a n d mi n or clarificati o ns 
were ma de , as necessar y. 
•  T he s y n o psis was u p date d t o be c o nsiste nt wit h t he c ha n ges ma de t o t he b o d y te xt.