Clinical trial NCT06180967
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2020-09-03; Completion date: 2020-10-20
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main purpose of this study is to assess the effect of Pirtobrutinib (LOXO-305) on how fast different formulations of midazolam gets into the blood stream and how long it takes the body to remove it when administered in healthy participants. The study will also access how much endogenous coproporphyrins I and III as biomarkers of OATP1B1 and OATP1B3 is in the bloodstream and how the body handles and eliminates them following single and multiple oral doses of Pirtobrutinib. Safety and tolerability of Pirtobrutinib will also be evaluated. For each participant, the total duration of the study will be 59 days, including screening.

Detailed description:

Arms: arm 1: A single IV bolus dose of midazolam will be administered in the morning following a 10-hour fast prior to dosing and a 4-hour fast postdose on Day 1 and Day 15. arm 2: A single oral dose of midazolam will be administered in the morning following a 10-hour fast prior to dosing and a 4-hour fast postdose on Day 3 and Day 17. arm 3: Multiple oral doses of Pirtobrutinib once a day (QD) will be administered on Days 5 through Day 17.
Interventions: intervention 1: Midazolam Syrup intervention 2: Midazolam Solution intervention 3: Pirtobrutinib
Intervention descriptions: intervention 1: Administered Orally. intervention 2: Administered IV bolus. intervention 3: Administered Orally.

Protocol documents:
Prot_000.pdf: 
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
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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 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.  
 

SAP_001.pdf: 
Statistical Analysis Plan 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: 16-Oct-2020


St ati sti c al  A n al y si s  Pl a n 
A  P h a s e I, O p e n L a b el,  Fi x e d- s e q u e n c e D r u g I nt e r a cti o n  St u d y t o 
I n v e sti g at e t h e Eff e ct of M ulti pl e O r al D o s e s of L O X O- 3 0 5 o n t h e 
P h a r m a c o ki n eti c s of a  Si n gl e D o s e of I nt r a v e n o u s a n d O r al Mi d a z ol a m 
( C Y P 3 A 4 S u b st r at e) i n H e alt h y  S u bj e ct s 
S p o ns or: 
L o x o O n c ol o g y , I n c. 
S A P St at us:  S p o n s or  Fi n al 
S A P  V er si o n: 1. 0 
S A P  D at e:  1 6 O C T 2 0 2 0 
I n v e sti g ati o n al Pr o d u ct:  L O X O- 3 0 5 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
C o v a n c e  St u d y : 8 4 1 9 6 8 7 
St u d y  Sit e: 
A  w h o lly  o w n e d  su b si dia 1 y of Eli  Lill y  a n d 
C o m p a n y 
C o v a n c e  Cli ni c al  R e s e ar c h  U nit f uc. 
1 9 0 0  M a s o n  A v e n u e , S uit e  1 4 0 
D a yt o n a  B e a ch, F L 3 2 1 1 7 
7 0 1  G at e w a y  B o ul e v ar d, S u it e 4 2 0 
S o ut h S a n Fr a n ci s c o , C a lif or ni a 9 4 0 8 0 
U S A 
Pri n c i p al I n v esti g at or: 
P D 
U S A 
I nf o n n ati o n d e s cri b e d  h er ei n i s c o nfi d e nti al a nd  m a y b e di s cl o s e d  o nl y  wit h  t h e e x pr e s s 
writt e n  p e n ni s si o n of t h e s p o ns or. 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e : L O X O- B T K- 2 0 0 0 8 
T A B L E O F C O N T E N T S 
TI T L E  P A G E  ................ .............. .. .......... .. .... .......... .. ...................... .. .........................................  1 
T A B L E O F C O N T E N T S . ....................... .. .... ........................................ ...... .. ................ ............. 2 
LI S T  O F  A B B R E VI A T I O NS ...... ..................... .................................... ..................................... 4 
1.  I N T R O D U C TI O N .............................. ...................... ...... ...... ................................................. 6 
2. S T U D Y O B J E C TI V E S  ..................................................................... ...... ............................... 6 
2 . 1.  Pri mr u y O b je ct iv e s ..................................................................... ........................ ............. 6 
2. 2.  S e c o n d ar y  O bj e cti v e s ............................. ......................................................................... 6 
2. 3.  E x pl or at or y  O bj e ct iv e ........................ ........ .. ......................................... .......................... 7 
3. S T U D Y E N D P OI N T S  ........................ .. ................................................................................. 7 
3. 1.  Pri m ar y  E n d p oi nt s ........................ .. .... ............................ ........ .......... .. .......... ................... 7 
3. 2.  S e c o n d aiy  E n d p oi nt s .......................... ................... .......................................................... 7 
3 . 3.  E x pl or at 0 1 y  e n d p oi nt s .................. .. .... .... ........................ ...... ........................................... 8 
4. S T U D Y D E SI G N  ...................... .... ........................ .... ........................ ...... ............................... 8 
5. S A M P L E SI Z E m s TI FI C A TI O N ................................................... .... ............................... 1 0 
6. S T U D Y T R E A T M E N T S  ................................................ ........................ .. ........................... 1 0 
7.  D E FI NI TI O N S  O F P O P U L A TI O N S  ....... ........................................................................... 1 1 
7 . 1.  All  S u bj e ct s  P o p u l ati o n ...................... ........................................ ................................... 1 1 
7 . 2. S af et y  P o p u lati o n .. ..................................................................... ...... ............................. 1 1 
7 . 3.  P h ai m a c o ki n eti c  P o p u latio n .................. ....................................................................... 1 1 
8.  S T A TI S T I CA L M E T H O D O L O G Y ............. ............ .................. .. ....................................... 1 1 
8 . 1.  G e n e r al ......................................... .. .................... .............................. .. ........................... 1 1 
8. 1. 1.  C al c u lati o n of t h e S u m m a 1 y  St ati sti c s .................... ........ .......................................  1 2 
8. 1. 2.  R e p e at  a n d  U n s c h e d u le d A s s e s s me nts ................................................................... 1 3 
8. 1. 3 . D efi nit io n s of B a s eli n e  an d C h a n g e  fr o m B a s e li ne ............ ...... .. ........................... 1 3 
8. 2 .  S ubj e ct Di s p o siti on  a n d  P o p u l ati o n A s si g n m e nt  ....................... ...... .. ........................... 1 3 
8. 3.  D e m o gr a p h ic s a n d  B a s eli n e  C h ar a ct eli sti c s  .................. ............ ...................................  1 4 
8. 4 . Pri or  a n d C o n c omit a nt  M e di c ati o n  ...................................... ............ .. .... .......................  1 4 
8. 5.  P h a n n a c o ki n et i c A s s e s s m e nt s ..................... .............................. ...... .............................  1 4 
8. 5. 1.  P hr u m a c o ki n eti c A n a l y sis ..... .. .... .......... .. ................ ...... .. .......... .. .... .......................  1 4 
8. 5. 2.  Pr e s e nt ati o n of P h a 1 m a c o ki n eti c D at a .................... ...... .........................................  1 7 
8. 5 . 3.  P h a1 m a c o k i n eti c St at istic al M et h o d ol o g y  ..............................................................  1 8 
8. 6.  S af e t y a n d T o ler a bilit y  A s s e s s m e nt s  ........... .. ........................ ...................... ................. 2 0 
S p o n s or  Fi n al , V er si o n 1. 0,  1 6 O C T 2 0 2 0 
2 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c o l R ef er e n c e : L O X O- B T K- 2 0 0 0 8 
8. 6 . 1. A d v er s e  E v e nt s .................................................................... ........................ ........... 2 0 
8. 6. 2.  Cli ni c a l L a b or at o 1 y  E v al u ati o n s .. .......... .. .......... ............ ............ .. .... ....................... 2 2 
8. 6. 3.  Vit al  Si g n s R e sult s .............................................................. ................................... 2 2 
8. 6. 4.  P ul s e  O xi m eti y ............................ ............................ ...... .............. ........................... 2 2 
8. 6 . 5.  1 2-l e a d El e ctr o c ar di o gr a m P ar a m et er s  ................... ............................................... 2 2 
8. 6. 6.  Ot h er A s s e s sm e nt s  .............................................................. ................................... 2 3 
8. 6. 7.  S af et y  a n d  T o ler a bilit y S t ati sti c al M et h o d o lo g y .................................................... 2 3 
9.  I N T E RI M A N A L Y S E S ...................... .. .... .................................... .......... ............ ................. 2 3 
1 0 . C H A N G E S  F R O M T H E P R O T O C O L- S P E CI FI E D  A N A L Y S E S  .................................. 2 3 
1 1 . R E F E R E N C E S  ... .................... .... ............ ............ ................ ...... ............ ...... ....................... 2 3 
1 2.  A P P E N DI C E S  ........ .... ................ ............................ ........................ ................................... 2 4 
S p o n s or  Fi n al , V er s io n 1. 0,  1 6 O C T 2 0 2 0 
3 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
L I S T O F A B B R E V I A T I O N S 
A b br e vi ati o n s  p ert ai n  t o t h e st atisti c a l a n al y si s  pl a n  ( S A P) o nl y  ( n ot t h e t a bl e s, fi g ur es,  a n d 
listi n g s  [ T F Ls ]). 
A D a M 
A E 
A U C o- 2 4 
A U C o-i nf 
A U C o-t 
A U Ct a u 
% A U C e xtr a p 
B L Q 
C DI S C 
CI 
C L 
C L/ F 
C L s J F 
C m a x 
Ctr o u g h 
C P 1 
C P 3 
Css 
C R U 
C S R 
C T C A E 
C V 
C Y P 
E C G 
E O S 
E O T 
E T 
G e o m C V 
G L S M 
G e o m  M e a n 
G M R 
H D Y F 
a n al y si s  d at a  m o d el 
a d v er s e  e v e nt 
ar e a u n d er  t h e c o n c e ntr ati o n-ti m e  c ur v e fr o m h o ur O t o 2 4 h o ur s 
p o st d o s e 
ar e a u n d er  t h e c o n c e ntr ati o n-ti m e  c ur v e fr o m ti m e O e xtr a p ol at e d  t o 
i nfi nit y 
ar e a  u n d er  t h e c o n c e ntr ati o n-ti m e  c ur v e fr o m h o ur O t o t h e l ast 
m e a s ur a bl e  c o n c e ntr ati o n 
ar e a u n d er  t h e c o n c e ntr ati o n-ti m e  c ur v e d uri n g  a  d o si n g  i nt er v al 
p er c e nt a g e  e xtr a p ol ati o n f or ar e a  u n d er  t h e c o n c e ntr ati o n-ti m e c m v e 
e xtr a p ol at e d  t o i nfi nit y 
b el o w  t h e li mit of q u a ntifi c ati o n 
Cli ni c al D at a I nt er c h a n g e St a n d ar d s  C o n s orti u m 
c o nfi d e n c e  i nt er v al 
a p p ar e nt t ot al cl e ar a n c e 
a p p ar e nt  s y st e mi c cl e ar a n c e 
a p p ar e nt s y st e mi c pl a s m a cl e ar a n c e  at st e a d y st at e 
m a xi m u m  o b s er v e d pl a s m a c o n c e ntr ati o n 
c o n c e ntr at i o n o b s er v e d at t h e e n d of a  d o si n g  i nt er v al 
e n d o g e n o u s  c o pr o p or p h yri n  I 
e n d o g e n o u s  c o pr o p or p h yri n  III 
st e a d y st at e c on c e ntr ati o n 
Cli ni c al  R e s e ar c h  U nit 
cli ni c al  st u d y r e p 0 1t 
C o m m o n  T er mi n ol o g y  Crit eri a  f or A d v er s e  E v e nt s 
c o effi ci e nt of v ari ati o n 
c yt o c hr o m e  P 4 5 0 
el e ctr o c ar di o gr a m 
e n d of st u d y 
e n d of tr e at m e nt 
e arl y t er mi n ati o n 
g e o m etri c C V 
g e o m etri c  l e ast s qu ar e s m e a n 
g e o m etri c m e a n 
g e o m etri c m e a n r ati os 
H o w D o Y o u  F e el ? 
S p o n s or  Fi n al,  V er si o n 1. 0,  1 6 O C T 2 0 2 0 
4 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
I C F 
I C H 
I V 
A z 
l n 
L S M 
M e d D R A 
M R A U C 
N C 
N R 
O A T P 1 B 1 
O A T P 1 B 3 
P K 
Q D 
R A u c 
S A E 
S A P 
S D 
t1 1 2 
T E A E 
T F L 
t m a x 
U A 
V z 
V.) F 
Vss 
W H O Dr n g 
I nf m m e d C o n s e nt F m m 
I nt er n ati o n al C o u n cil f or/C o nf er e n c e o n H ai m o ni s ati o n of T e c h ni c al 
R e q uir e m e nt s f or R e gi str ati o n of P h a 1 m a c e uti c al s  f or H u m a n U s e 
i ntr a v e n o u s 
a p p ar e nt t e 1 mi n al eli mi n ati o n r at e c o n st a nt 
n at ur al l o g 
l e a st s q u ar e s m e a n 
M e di c al  Di cti o n ar y  f or R e g ul at or y  A cti viti e s 
M et a b olit e-t o -p ar e nt A U C r ati o 
n ot c al c ul at e d 
n o r e s ult 
or g a ni c  a ni o n tr a n s p mti n g p ol y p e pti d e  1 B 1 
or g a ni c  a ni o n  tr a n s p o 1ti n g p ol y p e pti d e  1 B 3 
p h a 1 m a c o ki n eti c( s) 
o n c e  d ail y 
a c c u m ul ati o n  r ati o 
s eri o u s a d v er s e  e v e nt 
st ati sti c al a n al y si s pl a n 
st a n d ar d d e vi ati o n 
a p p ar e nt t er mi n al eli mi n ati o n h alf -lif e 
tr e at m e nt-e m er g e nt a d v er s e e v e nt 
t a bl e, fi g ur e, a n d li sti n g 
ti m e t o m a xi m u m o b s er v e d c o n c e ntr ati o n 
mi n al y si s 
v ol u m e of di stii b uti o n 
a p p ar e nt v ol u m e of di stri b uti o n 
v ol u m e of di stii b uti o n at st e a d y st at e 
W orl d H e alt h  Or g a ni z ati o n Dr n g Di cti o n ar y 
S p o n s or  Fi n al,  V er si o n 1. 0,  1 6 O C T 2 0 2 0 
5 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e : L O X O- B T K- 2 0 0 0 8 
1.  I N T R O D U C T I O N 
T hi s  S A P h a s b e e n  d e v el o p e d  aft er r e vi e w of t h e cli ni c al  st ud y  pr ot o c ol  (Fi n al  V er si o n  2. 0 
d at e d 1 1 S e pt e m b er  2 0 2 0)  a n d  el e ctr o ni c  c a s e  r e p o 1t f or m. 
T hi s  S A P  d e s cri b es t h e pl a n n e d  a n al y si s of t h e p h a n n a c o ki n eti c  (P K ), a n d s af et y a n d 
t ol er a bilit y d at a  fr o m t his  st u d y.  A  d et ail e d  d e s cri pti on of th e  pl a n n e d T F L s t o b e pr e s e nt e d 
i n t h e cli ni c al s t u dy  r e p mt ( C SR)  is pr o vi d e d i n t h e a c c o m p a n yi n g  T F L  s h e lls  d o c u m e nt. 
I n g e n er al,  t h e a n al y s e s  ar e  b a s e d o n i nf o 1 m ati o n fr o m t h e pr ot o c o l, u nl e ss  t h e y h a v e  b e e n 
m o difi e d b y a gr e e m e nt wit h  L o x o  O n c ol o g y, I nc. A  li mit e d a m o u nt of  i nf m m atio n a b out t hi s 
st u dy  ( e g, o bj e cti v e s,  s t u dy d e s i g n) i s gi v e n  t o h el p t he  r e a der' s i nt er pr et ati o n. T hi s  S A P 
m u st b e fi n ali z e d pri or  t o t h e lo c k of t h e cli ni c al d at a b a s e  f or t hi s st u dy. W h e n  t h e S A P  a n d 
T F L s h e lls ar e  a p pr o v e d,  t h ey  will  serv e a s t h e t e m pl at e f or t his  st u dy' s C S R. 
T hi s  S A P  s up er s e d e s  a n y st atisti cal  c o n si d er ati o n s  i de ntifi e d  i n t h e pr ot o c ol ; w h er e 
c o n si d er ati o n s ar e s u b st a nti ally  diff er e nt,  t h ey will b e s o i d e ntifi e d. If a d diti o n al  a n al ys es  ar e 
r e q uir e d t o s u ppl e m e nt  t h e pl a n n e d  a n al y s e s d e s cri b e d i n t his  S A P , t h ey m a y b e p erf o 1 m e d 
a nd  w ill b e i de ntifi e d  a c c or di n gl y i n t h e C S R.  .l\ n y s u b st a nti al d e vi ati o ns  fr o m t hi s S A P  w ill 
b e  a gr e e d  wit h  L o x o O n c o l og y , I nc.  a n d  i d e ntifi e d i n t h e C S R. 
T hi s  S A P  is  writt e n w it h c o n s i d er ati o n of t h e r e c o m m e n d ati o ns  o utli n e d i n t h e I nt er n ati o n al 
C o nf er e n c e o n H a n n o ni s atio n (I C H) E 9 g ui d eli n e St ati sti c al  P ri n ci pl e s f o r Cli ni c al  T ri al s 
a n d  I C H E 3  g ui d eli n e St r u ct u r e a n d C o nt e nt of Cli ni c al  St u d y  R e p o rt s. 1 ,2 
T h e  d o c u m e nt hi st or y is pr e s e nt e d i n A p p e n di x  1. 
2.  S T U D Y  O B J E C T I V E S 
2. 1. P ri m u y O bj e cti v e s 
T h e  p 1i m ar y  o bj e cti v e s of t hi s st u d y ar e: 
•  t o ass ess  t h e eff e ct  of  m ulti pl e or al d o s e s of L O X O- 3 0 5 o n t he P K of a s i n gl e or al 
d o s e of I ni d a z ol a m i n h e alt h y  s u bj e cts 
•  t o ass ess  t h e eff e ct of m ulti pl e  or al  d o s e s of L O X O- 3 0 5 o n t h e P K of a s i n gl e 
i ntr av e n o u s (I V) d o s e of I ni d a z ol a m i n h e alt h y  s u bj e c ts 
2. 2.  S e c o n d a r y  O bj e cti v e s 
T h e  s e c o nd a 1y  o bj e cti v e s of t hi s st u d y ar e: 
•  t o ass ess  t h e s af et y a n d t ol er a bilit y of m ulti pl e  or al  d o s e s of L O X O- 3 0 5  w h e n 
a d mi ni st er e d  a l o n e, c o a di ni ni st er e d w it h a  si n gl e or al  d o s e of I ni d a z ol a m a n d 
c o a di ni ni st er e d wit h  a si ng l e I V d o s e of I ni d a z ola m. 
•  t o a s s e s s  t h e P K of s i n gl e a n d  m ulti pl e  d o s e s of L O X O- 3 0 5  w h e n  gi v e n  al o n e or w it h 
1 ni d a z ol a m i n h e alt h y  s u bj e cts. 
S p o n s or Fi n al , V er si o n 1. 0,  1 6 O C T 2 0 2 0 
6  o f 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
2. 3.  E x pl o r at o r y  O bj e cti v e 
T h e  e x pl or at o 1 y o bj e cti v e of t hi s st u d y is: 
•  t o a s s e s s  t h e eff e ct of a  si n gl e or al  d o s e of L O X O- 3 0 5  a n d st e a d y st at e L O X O -3 0 5 o n 
t h e P K of e n d o g e n o u s  c o pr o p or p h yri n s  I a n d ill ( C P 1  a n d 3)  a s  bi o m ar k er s of t h e 
or g a ni c  a ni o n tr a n s p mti ng  p ol y p e pti d e  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 h e alt h y  s u bj e ct s. 
3.  S T U D Y  E N D P O I N T S 
3. 1.  P ri m a r y  E n d p oi nt s 
T h e  f oll o wi n g P K p ar a m et er s  will b e c al c ul at e d w h e n e v er  p o s s i bl e, b a s e d o n t h e pl a s m a 
c o n c e ntr at io n s of mi d a z ol a m a n d it s m et a b olit e  1- O H- mi d a z ol a m  f oll o wi n g or al a n d I V 
si n gl e d o s e  a d mi ni str ati o n  ( as a p pr o pti at e): 
•  ar e a u n d er  t h e c o n c e ntr ati o n-ti m e c m v e fr o m h o ur O t o t h e la st m e a s ur a bl e 
c o n c e ntr ati o n ( A U C o-t) 
•  ar e a u n d er  t h e c o n c e ntr ati o n-ti m e  fr o m ti m e O e xtr a p ol at e d t o i nfi nit y ( A U C o-i nf) 
• 
p e rc e nt e xtr a p o lati o n  f or A U C o-i nf( % A U C e xtr a p) 
•  m a xi m u m  o b s e 1v e d c o n c e ntr ati o n ( C m a x) 
•  ti m e t o m a xi m u m  c o n c e ntr ati o n (t m a x) 
•  a p p ar e nt  t e 1 mi n al eli mi n ati o n r at e c o n st a nt (l z) 
•  a p p ar e nt s y st e mi c  cl e ar a n c e  ( C L/ F; or al mi d a z ol a m) 
•  t ot al cl e ar a n c e  ( C L; I V mi d a z ol a m) 
•  a p p ar e nt pl a s m a t e1 mi n al  eli mi n ati o n h alf-lif e (t 1 1 2) 
•  a p p ar e nt v ol u m e of di stri b uti o n 0 1 J F ; or al  mi d a z ol a m) 
•  v ol u m e of di str i b uti o n 0 1 z) (I V mi d a z ol a m) 
•  v ol u m e of di stri b uti o n at st e a d y st at e ( Vss; I V mi d a z ol a m). 
3. 2.  S e c o n d a r y  E n d p oi nt s 
T h e  f oll o wi n g P K p ar a m et er s  will b e c al cul at e d w h e n e v er  p o s si bl e , b a s e d o n t h e pl a s m a 
c o n c e ntr at io n s of L O X O- 3 0 5  f oll o wi ng  si n gl e .a n d  m ulti pl e  d o s e  a d mi ni str ati o n  ( a s 
a p pr o pr iat e): 
• 
A U C o-t 
• 
A U C d mi n g a  d o si n g  i nt e 1 v al ( A U Ct a u) 
• 
C m a x 
•  c o n c e ntr ati o n o b s er v e d  at  t h e e n d of t h e d o s i n g i nt e 1 v al ( Ctr o u g h) 
S p o n s or  Fi n al , V er s io n 1. 0,  1 6 O C T 2 0 2 0 
7 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
•  
t m a x 
• 
C L/ F at st e a d y st at e ( CL, ss/ F) 
•  a c c u m ul atio n r ati o ( R A u c). 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e : L O X O- B T K- 2 0 0 0 8 
S af et y  a n d  t ol er a bilit y will b e a s s e s s e d b y m o nit ori n g  a d v er s e  e v e nt s  ( A E s ), p eif or mi n g 
p h y s i c al e x a mi n ati o n s  a n d  cli ni c al  l a b or at 0 1 y e v a l u ati o ns,  m e a suri n g  v it al s i g ns a n d o x y g e n 
s atur ati o n b y c o nti n u o u s  p ul s e  o xi m etr y , a n d  p erf or mi n g  1 2-l e a d  el e ctr o c a r di o gr a ms  ( E C G s) 
a n d  c o n c o mit a nt m e di c ati o n s. 
3. 3.  E x pl o r at o r y  e n d p oi nt s 
T h e  f oll o wi n g P K p a r a met er s  w ill b e c al c u lat ed  w h e n e v er  p o s s ibl e,  b a s e d o n t h e pl asm a 
c o n c e ntr at io n s of c o pr o p or p h yri ns  I a n d  III f oll o wi n g si ng l e d o s e a n d st e ad y- st at e 
L O X O- 3 0 5  ( as a p pr o pri at e): C m a x , t m a x, A U C  fr o m ti m e Ot o 2 4 h o ur s  ( AU C o-2 4), a n d  st ea d y 
st at e c o n c e ntr ati o n ( Css). 
4. S T U D Y D E S I G N 
T hi s is  a  P h a s e 1,  o p e n-l a b el,  2 - peri o d,  fi x e d-s e q u e n c e  dr u g -c h u g  i nt er a cti o n st ud y  t o 
i n v esti g at e t h e eff e ct of m ulti pl e  or al  d o s e s of L O X O- 3 0 5 o n t h e P K of a s i n gl e or a l  do s e of 
mi d a z ol a m  a n d o n t h e P K of a s i n gl e I V d o s e of mi d a z ol a m i n h e alt h y  s u bj e c ts. T h e  st u d y 
w ill al s o  ass ess  t h e si n gl e a n d  m ulti pl e or al d o s e P K of L O X O- 3 0 5  a n d  t h e eff e ct of a s i n gl e 
or al  d o s e of L O X O- 3 0 5  a n d  t h e eff e ct of L O X 0 -3 0 5  at st e a d y st at e (f oll owi n g  m ulti pl e  d o s e 
a d mi ni str ati o n) o n t h e P K of e n d o g e n o u s  c o pr o p or p h yii n s  I a n d III as  bi o m ar k er s 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 h e alt h y  s u bj e c ts. 
I n P eri o d  1, D a y  1,  a  s i n gl e 2 5 0  µ g  ( 0. 2 5 m L of 1- m g /m L s o l uti o n) I V b ol u s  d o s e of 
mi d a z ol a m  w ill b e a d mi ni st er e d  o v er  a p pr o xi m at el y  3 0  s e c on ds i n t h e m or ni n g  f oll o wi n g a 
1 0- h o ur  fa st pri or  t o d o si n g  a n d  a  4- h o ur  f ast p o std o s e . O n D a y  3,  a s i ngl e  5 0 0  µ g  ( 0.2 5 m L 
of 2- m g /m L s yiu p )  or al  d o s e of mi d a z ol a m  will b e a d mi ni st er e d i n t h e m or ni n g  f oll o wi n g a 
f a st of at l e ast  1 0  h o ur s pri or  t o d o si n g  a n d  4  h o ur s  p o st d o s e. O n D a y  3,  t h e or al  mi d a z ol a m 
d o s e  will  b e  a d mi ni st er e d al o n e at t h e a ct u al  ti m e of t h e D a y 1 I V mi d a z o l am  d o s e ( ± 
1  h o ur ). Bl o o d  s am pl e s  f or c o n c e ntr ati o n of mi d a z ol a m,  1- h y dr o x y mi d a z ol a m  ( 1- O H-
mi d a z o l a m), a n d  c o pr o p or p h yi·i ns  I a n d  III i n pl a s m a  w ill b e c oll e ct e d o n 
I n P eri o d  2  ( st a1ti n g o n D a y  5) , or al  d os es of 2 0 0 m g L O X O- 3 0 5  w ill b e a d m ini st er e d  o n c e 
d ail y  f or 1 3 c o n s e c uti v e  d a y s  (D a y s  5  t hro u g h 1 7) i n t h e m or ni n g. O n D a y s  5,  1 4 , 1 5,  a n d  1 7 
or al  d o s es of 2 0 0 m g L O X O- 3 0 5  w ill b e a d mi ni st er e d  f oll o wi n g a  f ast of at l ea st  1 0  h o ur s 
pri or  t o d o si n g a n d  at l e ast 4  h o ur s  p o st d o s e. O n D a y  6  t hr o u g h 1 3 , a n d D a y  1 6  or al  d o s es of 
2 0 0  m g  L O X O- 3 0 5  will b e a d mi ni st er e d f oll ow i n g a  f ast of at l e a st 2  h o ur s pri or  t o d o si n g 
a n d  1- h o ur  p o st d o s e ,  wit h t h e e x c e pti o n of d a y s w h er e  cli ni c al l a b or at or y e v al u ati o n s  ar e 
p erf o 1 m e d. O n D a y s  5  t hr o u g h 1 4 , a n d D a y 1 6, 2 0 0 m g L O X O- 3 0 5  w ill b e a d mi ni st er e d 
al o n e at t h e a ct u al  ti m e of t h e D a y  1  I V mi d a z ol a m d o s e( ± 1  h o ur ). O n t h e m or ni n g of 
D a y  1 5, a n or al  d o s e of 2 0 0  m g  L O X O -3 0 5  will b e a c h ni ni st er ed  2  h o ur s(±  1 5  mi n ut e s) pli or 
t o a d mi nisteri n g  a  s i n gl e 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 u s  d o s e of 
mi d a z ol a m . O n t h e m or ni n g of D a y  1 7, a n or al  d o s e of 2 0 0 m g L O X O- 3 0 5  w ill b e 
S p o n s or  Fi n al , V er si o n 1. 0,  1 6 O C T 2 0 2 0 
8 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
a d mi ni st er e d  first b ef or e  a  si n gl e or al  5 0 0  µ g  ( 0. 2 5 m L of 2- m g/ m L  s yr n p) d o s e of 
mi d a z ol a m  is a d mi ni st er e d  ( wit hi n 5  mi n ut es). O n D a y s  1 5  a n d  1 7,  L O X O -3 0 5  will b e 
a d mi ni st er e d at t h e a ct u al  ti m e of t h e D a y  1 I V mi d a z ol a m d o s e( ± 1  h o ur).  Bl o o d  s a m pl e s 
f or c o n c e ntr ati o n of L O X O -3 0 5  a n d  c o pr o p or p, h yri ns  I a n d  III i n pl a s m a  will b e c oll e ct e d o n 
. Bl o o d  s a m pl e s f or c o n c e ntr ati o n of 
mi d a z ol a m,  1- O H- mi d a z ol a m , a n d L O X O- 3 0 5 i n pl a s m a 
. A d diti o n a lly,  bl o o d 
s a m pl e s f or c o n c e ntr at io n of L O X O -3 0 5 i n pl a s m a will b e c oll e ct e d o n 
T h er e  will b e a  w a s h o ut  p eri o d of 2  d a y s b et w e e n t h e I V d o s e of mi d a z ol a m  a n d  t h e or al  d o s e 
of mi d a z ol a m o n D a y s  1  a n d  3  ( P eri o d  1)  a n d D a y s 1 5  a n d  1 7  ( P eri o d 2),  r e s p e cti v ely. 
T o  a s s e s s  t h eir eli gi bi lit y t o e nt er t h e st u d y, p ot e nt i al s u bj e ct s will b e s cr e e n e d wi thi n 2 8 d a y s 
( D a y s -2 9  t o - 2) a n d b e a d mitt e d t o t h e Cl i ni c al R e s e ar c h  U nit  ( C R U) o n D a y  - 1 ( C h e c k-i n). 
S u bj e ct s  will b e c o nfi n e d  at t h e C R U  fr o m t h e ti m e of C h e c k-i n ( D a y- 1) u ntil  E n d of 
Tr e at m e nt  ( E O T) o n D a y 2 1 u p o n  c o m pl eti o n of all P K a n d  s af et y a s s e s s m e nt s or E arl y 
T e 1 mi n ati o n  ( E T) if t h e s u bj e ct dis c o nti n u es.  A  f oll o w-u p  p h o n e  c all  will  o c c ur  f or all 
s u bj e ct s w h o  r e c ei v e d at l e a st 1  d o s e of st u d y dr n g (i n cl u di n g s u bj e ct s w h o  ar e  t e1mi n at e d 
e arl y)  7 d a y s( ± 2  d a ys)  aft er E O T or E T.  T h e  d ur ati o n of p a 1ii ci p ati o n  is e x p e ct e d t o b e 
a p pr o xi m at el y  5 9  d a y s  ( S cr e e ni n g t hr o u g h f oll o w- u p p h o n e  c all). 
R e pl a c e m e nt  s u bj e ct s m a y b e e nr oll e d  o nl y if d e e m e d n e c e s s ai y b y t h e S p o ns or. 
T h e  st art of t h e st u d y is d efi n e d  as  t h e d at e  t h e fir st s u bj e ct w h o  is e nr oll e d i n t h e st u d y si g ns 
a n I nf m m e d C o n s e nt F m m (I C F). N ot e  t h at e nr nll e d s u bj e ct s ar e  d efi n e d  as  t h o s e s u bj e ct s 
w h o  ar e  a s si g n e d  a  d o s e of st u d y dr n g ; t hi s d efi niti o n  e x cl u d e s  s cr e e n f ail ur e s u bj e cts.  St u d y 
c o m pl eti o n i s d efi n e d  as  t h e ti m e of t h e l a st s u bj e ct ' s f oll o w- u p c all. 
I n t hi s st u d y,  p h y si c a l e x ai ni n ati o n s , 1 2-l e a d  E C G s,  vit al  si g n m e a s ur e m e nt s , o x y g e n 
s at ur ati o n m e a s ur e d b y c o nti n u o u s  p ul s e  o xi m etl y , H o w D o Y o u  F e el ?  ( H D Y F ?) in q uir ie s , 
cli ni c al  c h e 1 nisti y p a n el,  c o a g ul ati o n p ar a m et er s,  h e m at ol o g y p a n el , mi n al y si s  ( U A) a n d 
r e c or di n g of c o n c o m it a nt m e di c ati o n s  will b e p erf m m e d  at s p e cifi e d ti m e s d uri n g  t h e st u d y. 
T h e  A Es  a n d  s eri o u s a d v er s e  e v e nt s  ( S A E s) will b e c oll e ct e d  b e gi n ni n g  at i nf or m e d c o ns e nt. 
T h e A E s will b e r e p o 1t e d t hr o u g h o ut t h e st u d y  (i e, fr o m si g ni n g of t h e I C F u ntil  E n d of St u d y 
[ E O S], or u ntil E T if t h e s u bj e ct di s c o nti n u e s  fr o m t h e st u d y a n d  d o e s  n ot  c o m p let e  a 
f oll o w- u p p h o n e  c all) ,  eit h er as  s u bj e ct m e di c al  hi st or y (if t h e e v e nt is r e p o 1t e d as  b e gi n ni n g 
pri or t o si g nin g of t h e I C F or if t h e e v e nt o c c ur s  pri or  t o st u d y m u g a d mi ni str ati o n o n D a y  1 
a n d  is a s s e s s e d  as  n ot  r el at e d t o st u d y pr o c e d m -e s b y t h e I n v e sti g at or [ or d e si g n e e]) or as  A E s 
(if t h e e v e nt  o c c ur s  aft er  si g ni n g of t h e I C F b ut pri or  t o st u d y m 1 1 g a d mi ni str at io n  o n D a y 1 
a n d  is a s s e s s e d  as  r el at e d t o st u d y pr o c e d ur e s b y t h e I n v e sti g at or [ or d e si g n e e ], or if t h e e v e nt 
o c c ur s  aft er  st u d y dr n g  a d mi ni str ati o n o n D a y 1  t hr o u g h E O T or E T r e g ar dl e s s of r el ati o n s 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 E s  a s s e s s e d  as  r el at e d t o st u d y m u g b y 
t h e I n v e sti g at or ( or d e si g n e e) ai· e t o b e r e p mi e d. All  S A E s  t h at d e v el o p  fr o m t h e ti m e of I C F 
si g ni n g u nt il E O S  ( or E T,  if t h e s u bj e ct di s c o nti n u e s fr o m t h e st u d y a n d  d o e s  n ot  c o m pl et e  a 
f oll o w- u p p h o n e  c all)  ar e t o b e  r e p mt e d. 
S p o n s or  Fi n al , V er si o n 1. 0,  1 6 O C T 2 0 2 0 
9 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
5.  S A M P L E  S I Z E  J U S T I F I C A T I O N 
U p t o 
a d ult  m al e  a n d  f e m al e s u bj e ct s ( w o m e n of n o n- c hil d b e ari n g  p ot e nti al 
o nl y)  will b e e m oll e d.  T hi s  is  a P h a s e  1  st u d y a n d t h e s a m pl e si z e i s n ot b a s e d  u p o n  a n y 
f o 1 m al p o w er  c al c ul ati o ns  b ut  i s c o n si st e nt wit h pr e vi o u s  st u di e s of a  si mil ar d esi g n. U p t o 
ar e  a nti c ip at e d  t o b e s uffi ci e nt  t o pr o vi d e  a  r eli a bl e e sti m at e of t h e m a g nit u d e 
a n d  v ari a bilit y of t h e i nt er a cti o n. 
E v e 1 y  att e m pt wil l b e m a d e  t o e m oll  at le a st  4  s u bj e ct s of e a c h s e x i n t h e st u d y. 
6.  S T U D Y  T R E A T M E N T S 
T h e  st u d y tr e at m e nt s e q u e n c e n a m e  a n d  or d eri n g  t o b e  u s e d  i n t h e T F L s  ar e  pr e s e nt e d i n 
T a b l e  1. 
T a bl e 1: 
P r e s e nt ati o n of St u d y  T r e at m e nt  S e q u e n c e i n T F L s 
St u d y  T r e at m e nt  S e q u e n c e 
2 5 0 µ g I V mi d a z ol a m ( D a y 1)  / 5 0 0  µ g  or al mi d a z ol a m ( D a y 3) / 2 0 0 m g L O X O- 3 0 5 
( D a y 5- D a y 1 4)  / 2 0 0 m g L O X O- 3 0 5 + 2 5 0 µ g I V mi d a z ol a m ( D a y 1 5)  / 2 0 0 m g 
L O X O- 3 0 5 ( D a y 1 6)  / 2 0 0 m g L O X O- 3 0 5 + 5 0 0 µ. g or al mi d a z ol a m ( D a y 1 7 ) 
O r d e r i n 
T F L s 
T h e  st u d y tr e at m e nt n a m e s , a n d or d eri n g  t o b e  u s e d i n t h e T F L s  ar e pr e s e nt e d  i n T a ble  2, 
T a b l e  3 a n d  T a bl e  4. 
T a bl e  2:  
P 1· es e nt ati o n of St u d y  T r e at m e nt s  i n S af et y  s u m m a r y T F L s 
P e ri o d 
1 
1 
2 
2 
2 
St u d y T n at m e nt 
2 5 0 µ g I V mi d a z ol a m 
5 0 0 ~t g or al mi d a z ol a m 
2 0 0 m g L O X O- 3 0 5 
2 0 0 m g L O X O- 3 0 5 + 2 5 0 µ g I V mi d a z ol a m 
2 0 0 m g L O X O- 3 0 5 + 5 0 0 µ g  or al  mi d a z ol a m 
T a bl e  3:  P r e s e nt ati o n of St u d y  T r e at m e nt s i n P K s u m m a r y T F L s 
P e ri o d 
1 
1 
2 
2 
2 
2 
St u d y T n at m e nt 
2 5 0 µ g I V mi d a z ol a m 
5 0 0 µ g or al mi d a z ol a m 
2 0 0 m g L O X O- 3 0 5 Q D D a y ( D a y 5) 
2 0 0 m g L O X O- 3 0 5 Q D ( D a y s 6  t hr o u g h 1 4 , D a y 1 6) 
2 0 0 m g L O X O- 3 0 5 + 2 5 0 ~t g I V mi d a z ol a m 
2 0 0 m g L O X O- 3 0 5 + 5 0 0 ~t g or al  mi d a z ol a m 
S p o n s or  Fi n al,  V er s io n 1. 0,  1 6 O C T 2 0 2 0 
O r d e r i n 
T F L s 
1 
2 
3 
4 
5 
O r d e r i n 
T F L s 
1 
2 
3 
4 
5 
6 
1 0 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e : L O X O- B T K- 2 0 0 0 8 
T a bl e  4:  P r e s e nt ati o n of St u d y  T 1· e at m e nts i n P K C P 1 a n d  3  s u m m a r y T F L s 
P e ri o d 
1 
2 
2 
St u d y T n at m e nt 
Pri or  t o A d mi ni str ati o n of L O X O- 3 0 5 (D a y s  1  a n d  1 5) * 
2 0 0  m g L O X O- 3 0 5 Q D ( D a y 5) 
2 0 0 m g L O X O- 3 0 5 Q D ( D a y s 6  t hr o u gh  1 4 , D a y 1 6) 
O r d e r i n 
T F L s 
1 
2 
3 
* O n  D a y 1 a n d D a y 1 5  w h e r e  C P  1 a n d 3 P K i s a s s e s s e d, s u bj e ct s w e r e  al s o  d o s e d  wit h  2 5 0 
u g I V mi d az ol ar n;  h o w e v e r , t h e st u d y t r e at m e nt h a s  b e e n  l a b ell e d i n r el ati o n  t o t h e d o si n g of 
L O X O- 3 0 5  a s  t h e c o m p a ri s o n of i nt e r e st i s C P 1 a n d 3  i n t h e a b s e n c e of L O X O- 3 0 5 v e r s u s 
C P 1 a n d 3  i n t h e p r e s e n c e of si n gl e a n d m ulti pl e  d os es of L O X O- 3 0 5 
All  tr e at m e nts  d e s cri b e d  a b o v e ar e t h e pl a n n e d  tr e at m e nts.  T h e T F L s will  r efl e ct t h e a ct u al 
tr eat m e nt s r e c eiv e d. 
7. D E F I N I T I O N S O F P O P U L A T I O N S 
A n y pr ot o c ol  d e vi ati o n s , i n cl u di n g t h o s e r elat e d t o C O VI D- 1 9,  will b e c o n si d er e d pri or  t o 
d at a b a s e l oc k  f or t h eir i mp 0 1t a n c e  a n d  t a k e n i nto  c o n si d er at io n w h e n a s si g ni n g  su bj e ct s  t o 
p o p ul ati o n s. 
7. 1. All S u bj e ct s  P o p ul ati o n 
T h e  a ll su bj e ct s p o p ul ati o n  will  i n cl u d e all  su bj e cts  w h o  s i g n e d t h e I C F a n d h a d  a n y s t u dy 
a s s e s s m e nt r e c or d e d i n t h e d at a b a s e p er t h e pr ot o c ol. 
7. 2. S af et y  P o p ul ati o n 
T h e  s af et y p o p ul ati o n  will  i n cl u d e a ll su bj e ct s w h o r ec e i v e d at l e ast  1 d o s e of stu d y  dt u g s 
(L O X O- 3 0 5 , I V mi d a z ol a m , or or al  mi d a z ol a m).  S u bj e cts  will b e cl a ssifi e d i nt o gr o u p s b a s e d 
o n a ct u al  tr e atm e nt  r e c ei v e d. 
7. 3. P h a r m a c o ki n eti c  P o p ul ati o n 
T h e P K p o p ul ati o n  w ill i n cl u d e all  su bj e ct s w h o r ec e iv e d at l e ast 1  d o s e of a n y  st u d y dr n g 
(L O X O- 3 0 5 , I V mi d a z ol a m , or or al mi d a z ol a m), h a v e at le a st  1  q u a ntifi a b l e P K 
c o n c e ntr ati o n , a n d f or w h o m at  l e a st 1 P K p ar a m et er  c a n b e c o m p ut e d.  A  s u bj e ct  m a y b e 
e x cl u d e d  fr o m th e P K su m m a 1 y  s t atistic s  a n d stati sti c al a n al ysis if t h e s u bj e ct h a s a n A E of 
v o miti n g  t h at o c c ur s  at or b ef or e  2  ti m e s t h e m e d ia n t m a x. 
8.  S T A T I S T I C A L  M E T H O D O L O G Y 
8. 1.  G e n e r al 
Li stin gs  will b e pr o vi d e d  f or all  d at a  c apt ur e d i n t h e d at a b as e.  Li sti n gs will  i n cl u d e all 
su bj e ct s  a s si g n e d t o t h e all  su bj e ct s p o p ul ati o n a n d i n cl u d e d at a  u p  t o t h e p oi nt of s t u dy 
c o m pl eti o n or di s c onti n u ati o n.  S u bj e cts  ar e  g e n er all y  c o n si d er e d  t o h a v e c o m pl et e d  t h e st ud y 
if t h e y c o m pl et e d a ll pr ot o c o l-sp e c ifi e d pr o c e d ur e s  a n d a s s e s s m e nt s  f or t h e E O T  vis it. A n y 
S p o n s or  Fi n al , V er s io n 1. 0,  1 6 O C T 2 0 2 0 
1 1 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
s u bj e ct w h o  di s c o nti n u e d  t h e st u d y will b e i d e ntifi e d a c c or di n gl y  i n t h e listi n gs. S u m m ari e s 
a n d st atisti c al a n al y s e s  will  i n cl u d e t h e s u bj e ct s a s s ig n e d  t o t h e r el e v a nt p o p ul ati o n  b a s e d o n 
d at a  t y p e. 
D at a  a n al y si s  will b e p erf o 1 m e d  u si n g  t h e S A S ®  st ati stic al s oft w ar e p a c k a g e  V er si o n  9 . 4 ( or 
hi g h er  if u p v er si o n e d d uri n g  t h e st u d y). 
A n al y si s D at a M o d el  ( A D a M) d at a s et s wi ll b e  pr e p ar e d  u si n g  Cli ni c al D at a f ut er c h a n g e 
St a n d ar d s  C o ns 0 1ti u m  ( C DI S C) A D a M V er si o n  2. 1  ( or hi g h er if u p v er si o n e d d uri n g  t h e 
st u d y) a n d C DI S C A D a M I m pl e m e nt ati o n G ui d e V er si o n  1. 2  ( or hi g h er if u p v er si o n e d 
d uri n g  t h e st u d y).  Pi n n a cl e  2 1  C o m m u nit y  V ali d at o r V er si o n  2. 2. 0 ( or hi g h er  if u p v er si o n e d 
d uri n g  t h e st u d y) w ill b e utili z e d  t o e n s ur e c o m pli a n c e wit h C DI S C  st a n d ar d s. 
C a uti o n  s h o ul d b e u s e d  w h e n  i nt e 1 pr eti n g r e s ult s fr o m t h e st ati sti c al a n al y s e s  c o n d u ct e d  i n 
t hi s st u d y b e c a u s e  t h e s a m pl e si z e i s n ot b a s e d o n p o w er c al c ul ati o n s. 
W h er e  r ef er e n c e i s m a d e t o ' all c al c ul ati o n s', t hi s i n cl u d e s, b ut i s n ot li mite d t o, s u m m a 1 y 
st ati sti c s, st ati sti c al a n al y s e s , b a s eli n e  d eri v ati o n , a n d c h a n g e s  fr o m b a s eli n e. 
8. 1. 1.  C al c ul ati o n of t h e S u m m a r y  St ati sti c s 
F or c o nti n u o u s  d at a  t h e f oll o wi n g ml e s  will b e a p pli e d: 
•  Mi s si n g  v al u e s  will n ot b e  i m p ut e d, u nl e s s  s p e cifi c al l y st at e d ot h e 1wi s e. 
•  U nr o u n d e d  d at a  will b e u s e d i n t h e c a lc ul ati o n of s u m m ai y st ati sti c s. 
• If t h e n u m b er of s u bj e ct s wit h  v ali d  o b s e 1 v ati o n s  ( n) < 3,  s u m m ar y st ati sti c s will  n ot 
b e  c al c ul at e d,  wit h  t h e e x c e pti o n of n, mi ni m u m , a n d  m a xi m u m. 
•  A s E T d at a  i s n ot a s s o ci at e d  wit h  a n y  s c h e d ule d ti m e p oi nt, it w ill b e e x cl u d e d fr o m 
all  c al c ul ati o n s of s u m m ai·y st ati sti c s. 
•  P o st  d o s e  r e p e at s a n d u n s c h e d ul e d  a s s e s s m e nt s  will n ot b e i n cl u d e d i n c al c ul ati o n of 
s u m m ar y st ati sti c s. 
F or c at e g 0 1i c al  d at a  t h e f oll o wi n g mi e s wi ll b e a p pli e d: 
• If t h e c at e g ori e s of a  p ai· a m et er  ar e or d er e d ( e g, A E s e v erit y),  all  c at e g ori e s b et w e e n 
t h e p o s si bl e  mi ni m u m  a n d m a xi m u m  c at e g oli e s  will b e i n cl u d e d, e v e n if n  =  0  f or a 
gi v e n  c at e g or y. If t h e c at e g ori e s ar e n ot or d er e d  ( e g, r a c e), o nl y t h o s e c at e g ori e s f or 
w hi c h  t h er e i s at l e a st 1  s u bj e ct r e pr e s e nt e d will b e i n cl u d e d. 
•  Mi s si n g  v al u e s  will n ot b e  i m p ut e d, wit h t h e e x c e pt io n of A E s  w h er e  t h e ' w or st-c a s e' 
a p pr o a c h  will b e t a k e n ( s e e S e cti o n  8. 6. 1 ), or u nl e s s  s p e cifi c all y st at e d ot h er wi s e.  A 
' mi s si n g' c at e g 0 1 y will b e i n cl u d e d f or a n y p ai· a m et er f or w hi c h  i nf o 1 m ati o n i s 
mi s si n g.  T hi s  will  e n s ur e  t h at t h e p o p ul ati o n  si z e t ot al s ar e  c o n s ist e nt a cr o s s  diff er e nt 
p ar a m et er s. 
S p o n s or  Fi n al,  V er si o n 1. 0,  1 6 O C T 2 0 2 0 
1 2 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
All  pr ot o c ol  d e vi ati o n s a n d d at a  i s s u e s (e g m i s si n g d at a, o ut of pr ot o c o l wi n d o w)  t h at 
o c c ur  d uri n g  t h e st u d y, i n cl u di n g t h o s e r e bt e d t o C O VI D- 1 9 , will b e c o n si d er e d pri or  t o 
d at a b a s e  l o c k f or t h eir s e v erit y/i m p a ct o n h o w t h e d at a  will b e di s pl a y e d. 
8. 1. 2.  R e p e at  a n d  U n s c h e d ul e d  A s s e s s m e nt s 
F or vit al  si g n m e a s ur e m e nt s  a n d  1 2-l e a d E C G d at a o nl y , a n y pr e d o s e v a lu e r e c or d e d i n 
a d diti o n  t o t h e ori gi n al  v al u e or a  p o st d o s e v al u e r e c or d e d wit hi n  1 5  mi n ut e s of t h e ori gi n a l 
v al u e  will b e d efi n e d  a s  a  r e p e at v al u e ; a n y p o st d o s e v a lu e r e c or d e d m or e  t h a n 1 5  mi n ut e s 
aft er  t h e ori gi n al  v al u e  will b e d efi n e d  a s a n u n s c h e d u le d v al u e. F or all  ot h er  d at a  t y p e s ( e g, 
cli ni c al  la b or at o 1y  v al u e s), a n y v a l ue  r e c or d e d i n a d diti o n t o t h e ori gi n al  v al u e  will b e 
d efi n e d  a s a n u n s c h e d ul e d v a l ue. 
T h e  ori gi n al  s c h e d ul e d v al u e  will b e u s e d i n all c al c u lati o n s p o st d os e. I n t h e e v e nt of a n y 
r e p e at s or u n s c h e d ul e d  m e a s ur e m e nt s  t a k e n pr e- d o s e t h e v al u e s  will b e c o n si d er e d w h e n 
d et e 1 mi ni n g  t h e b a s eli n e  v al u e  f or e a c h p eri o d. 
P o st  d o s e  r e p e at s, u n s c h e d ul e d  a s s e s s m e nt s , a n d E T m e a s ur e m e nt s  will b e e x cl u d e d fr o m all 
c al c ul ati o n s , wit h  t h e e x c e pti o n of t h e b a s eli n e  d eri v ati o n  ( s e e S e cti o n  8. 1. 3 ). 
8. 1. 3.  D efi niti o n s of B a s eli n e  a n d  C h a n g e f r o m B a s eli n e 
B a s eli n e  v al u e i s d efi n e d  a s  t h e l a st n o n mi s si n g  m e a s ur e m e nt  b ef or e  a d mi ni str ati o n of st u d y 
dr n g i n e a c h p eri o d. 
P eri o d  1 
I n g e n er al , b a s eli n e  f or p eri o d  1  r ef er s t o t h e pr e- d o s e  v al u e  c oll e ct e d o n D a y 1  p eri o d  1. F or 
cli ni c al  la b or at m y e v al u ati o n s , b a s eli n e  i s t h e v al u e c oll e ct e d o n D a y - 1 p eri o d 1. 
P eri o d  2 
I n g e n er al , b a s eli n e  f or p eri o d  2  r ef er s t o t h e pr e- d o s e  v al u e  c oll e ct e d o n D a y 5 p er io d 2. F or 
cli ni c al  l a b or at m y e v al uati o n s , b a s eli n e  is t h e v al u e c oll e ct e d pr e- d o s e o n D a y 3  p eri o d 1. 
If t h e d at e /ti m e of t h e v al u e i s i n c o m pl et e or mi s si n g , it will  b e  e x cl u d e d fr o m t h e b a s eli n e 
c al c u lati o n , u nl e s s  t h e i n c o m pl et e d at e /ti m e i n di c at e s t h e v a l ue w a s r e c or d e d pri or t o d o si n g 
wit h st u d y dr n g i n P eri o d  1 or P eri o d  2. 
I n di vi d u al c h a n g e s  fr o m b a s eli n e  will b e c al c ul at e d b y s u btr a cti n g t h e i n di vi d u al s u bj e ct' s 
b a s eli n e  v al u e  fr o m t h e v al u e at t h e ti m e p oi nt. T h e m e a n c h a n g e  fr o m b a s eli n e will b e 
d efi n e d  a s  t h e m e a n of t h e i n di vi d u al c h a n g e s fr o m b a s eli n e  f or all  s u bj e ct s. 
S e e  S e cti o n  8. 1. 2  f or m or e  d et ail o n h a n dli n g r e p e at a n d u n s c h e d ul e d  r e a di n g s i n t h e 
c al c ul ati o n s. 
8. 2.  S u bj e ct  Di s p o siti o n  a n d  P o p ul ati o n  A s si g n m e nt 
S u bj e ct  di s p o siti o n a n d p o p ul ati o n  a s si g n m e nt  will b e li st e d. 
S p o n s or  Fi n al,  V er si o n 1. 0,  1 6 O C T 2 0 2 0 
1 3 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
A  s u m m ar y t a bl e b y st u d y tr e at m e nt s e q u e n c e will b e pr o vi d e d,  b a s e d o n t h e a ll s u bj e ct s 
p o p ul ati o n. 
8. 3.  D e m o g r a p hi c s  a n d  B a s eli n e  C h a r a ct e ri sti c s 
T h e  d e m o gr a p hi c s  a n d b a s eli n e  c h ar a ct eri st ic s  i n cl u di n g a g e,  s e x , r a c e, et h n i cit y, h ei g ht , 
b o d y  w ei g ht , a n d b o d y m a s s  i n d e x will b e li st e d. 
A  s u m m a1y  t a bl e b y st u d y tr e at m e nt s e q u e n c e will b e pr o vi d e d , b a s e d o n t h e s af et y 
p o p ul ati o n. 
8. 4.  P ri o r  a n d  C o n c o mit a nt  M e di c ati o n 
Pri or  m e di c ati o n  will b e d efi n e d  a s m e di c ati o n  t h at e n d s  pri or  t o t h e fir st d o s e of Mi d a z ol a m 
N  . C o n c o mit a nt  m e di c ati o n  will b e d efi n e d  as  m e di c ati o n  t h at str uts  d uri n g or aft er  t h e fir st 
d o s e  of Mi d a z ol a m N or st a 1 1s b ut  d o e s  n ot e n d pri or  t o t h e first d o s e of Mi d a z o la m N. 
Pri or  a n d c o n c o mit a nt  m e di c ati o n s  will b e c o d e d u si n g  t h e W orl d  H e alt h Or g a ni z ati o n  Dr n g 
Di cti o n a 1 y  ( W H O Dr n g) Gl o b al, F m m at B 3,  V er si o n  M ar c h  2 0 2 0.  Pri or  a n d c o n c o mit a nt 
m e di c ati o n s  will b e list e d. 
8. 5.  P h a r m a c o ki n eti c  A s s e s s m e nt s 
8. 5. 1.  P h a r m a c o ki n eti c  A n al y si s 
T h e  f oll o wi n g P K p ar a m et er s  will b e d et e 1 mi n e d  w h er e  p o s si bl e  fr o m t h e pl a s m a 
c o n c e ntr ati o n  d at a  f or t h e f oll o wi n g a n al yt e s  u si n g  n o n c o m p ai 1 m e nt al  m et h o d s i n v ali d at e d 
s oft w ar e pr o gr a m  P h o e ni x  Wi n N o nli n  (C ert ar a , V er si o n  8. 1 or hi g h er): 
Mi d a z o la m a n d  m et a b olit e 1- 0 H- mi d a z ol a m  (f oll o wi n g N a n d  or al  d o s e s , u nl e s s 
ot h e 1 wis e  s p e cifi e d) 
P a r a m et e r 
A U C o- 1 
A U C o-i nf 
% A U C e x 1r a p 
C m a x 
t m a x 
/ 1.z 
t1 1 2 
C L/ F 
C L 
V,/ F 
v, 
U nits• 
h * n g/ m L 
h * n g/ m L 
% 
n g/ m L 
h 
1/ h 
h 
L/ h 
L/ h 
L 
L 
D efi nit io n 
ar e a  u n d er t h e c o n c e ntr ati o n-ti m e c m v e fr o m h o m O  t o t h e ti m e of 
l a st m e a s ur a bl e  c o n c e ntr ati o n (t 1 as 1l 
ar e a  u n d er  t h e c o n c e ntr ati o n-ti m e  c ur v e :fr o m h o ur O e xtr a p ol at e d 
t o i nf mit y " 
p er c e nt a g e  e xtr a p ol ati o n f or A U C o-i nf 
m a xi m u m o b s e 1 v e d  c o n c e ntr ati o n 
ti m e t o m a xi m u m o b s e 1 v e d  c o n c e ntr ati o n 
a p p ar e nt t e n ni n al eli mi n ati o n r at e c o n st a nt 
t er mi n al eli mi n ati o n h alf-lif e 
a p p ar e nt s y st el ni c cl e ar a n c e  (l ni d a z ol a m o nl y , f oll o wi n g or al  d o s e ) 
t ot al cl e ar a n c e (mi d a z ol a m o nl y , f oll o wi n g I V d o s e ) 
a p p ar e nt v ol u m e of di stii b uti o n d mi n g t h e t e n ni n al p h a s e 
(l ni d a z ol a m o nl y , f oll o wi n g or al  d o s e) 
v ol u m e of di sti·i b uti o n (l ni d a z ol a m o nl y, f oll o wi n g I V d o s e ) 
S p o n s or  Fi n al,  V er s io n 1. 0,  1 6 O C T 2 0 2 0 
1 4 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
v •• 
L 
M R A U C 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
v ol u m e of di stri b uti o n  at  st e a d y st at e ( mi d a z ol a m o nl y , f oll o wi n g 
I V d o s e) 
A U C o-i nfr ati o of 1 - O H- mi d a z ol a m  t o mi d a z ol a m d 
• U nit s ar e b a s e d o n c o n c e ntr ati o n u nit s  ( pr o vi d e d b y t h e bi o a n al yti c al  l a b or pr ef eJ T e d  u nit s  f or pr e se nt ati o n of P K 
p ar a m et er s )  a n d  d o s e  u nit s u s e d i n th e st u d y. 
b Ar e a  u n d er  th e c o n c e ntr ati o n-ti m e c urv e  will b e c al c ul at e d u si n g t h e li n e ar tr a p e z oi d al ml e f or i n cr e a si n g a n d d e cr e a si n g 
c o n c e ntr ati o n s. 
c B a se d o n t h e l a st o b s er v e d  m e a s ur a bl e  c o n c e ntr ati o n 
d If A U C o-i nf c a n n o t b e d et e n ni n e d  r eli a bl y f or all  s u bj e ct s or a n al yt e s , a n alt er n ati v e A U C m e a s ur e , s u c h as A U C t o  a fi x e d 
ti m e p oi nt or A U C o -1, m a y b e u s e d 
L O X O -3 0 5 (f oll o wi n g si n gl e a n d  m ulti pl e d o s e a d mi ni str ati o n,  u nl e s s  ot h er wi s e  s p e cifi e d) 
P a r a m et e r 
A U C o -t 
A D C. a u 
C m a x 
t m a x 
C L s JF 
Ctr o u g h 
R A u c 
U nits a 
h * n g/ m L 
h * n g/ m L 
n g/ m L 
h 
L/ h 
n g/ m L 
N A 
D efi niti o n 
ar e a  u n d er  t h e c o n c e ntr ati o n-ti m e  c ur v e fr o m h o ur Ot o t 1 as 1 b 
ar e a  u n d er  t h e c o n c e ntr ati o n-ti m e c m v e d uri n g  a  d o si n g  i nt e 1 v al b 
m a xi m u m o b s e 1 v e d  c o n c e ntr ati o n 
ti m e t o m a xi m u m o b s e 1 v e d  c o n c e ntr ati o n 
a p p ar e nt s y st e mi c cl e ar a n c e at st e a d y st at e ( aft er m ulti pl e  d o s e s ; 
d a y s 1 4 , 1 5 , a n d 1l 7) 
C o n c e ntr ati o n  o b s e 1 v e d at t h e e n d of a  d o si n g  i nt e 1 v al ( pr e d o s e 
c o n c e ntr ati o n s o n D a y s 6  t hr o u g h 1 7 a n d at 2 4 h o ur s  aft er D a y 1 7 
d o s e) 
A c c u m ul ati o n r atiio  (r ati o of D a y 1 4 A U C, a u t o D a y 5 A U C, a u) 
• U nit s ar e b a s e d o n c o n c e ntr ati o n u nit s  ( pr o vi d e d b y t h e bi o a n al yti c al  l a b or pr ef eJ T e d  u nit s  f or pr e s e nt ati o n of P K 
p ar a m et er s )  a n d  d o s e  u nit s u s e d i n t h e st u d y. 
b Ar e a  u n d er t h e c o n c e n u· ati o n-ti m e c ur v e will b e c al c ul at e d u si n g t h e li n e ar tr a p e z oi d al ml e f or i n cr e a si n g a n d d e cr e a si n g 
c o n c e ntr ati o n s. 
N A = n ot a p pli c a bl e 
C o p r o p o r p h y r in s  I  a n d  I I I (f oll o wi n g si n gl e d o s e  mi d a z ol a m  (I V a d mi ni str ati o n),  si n gl e 
d o s e  L O X O- 3 0 5,  a n d st e a d y-st at e L O X O -3 0 5 , a s  a p pr o pri at e , u nl e s s  ot h er wi s e  s p e cifi e d) 
P a r a m et e r  
U nit s
3 
A U C o- 2 4 
C m a x 
h * n g/ m L 
n g/ m L 
D efi niti o n 
ar e a u n d er t h e c o n c e ntr ati o n-ti m e  c ur v e  fr o m h o ur 0 t o 2 4 
h o urs b 
m a xi m u m  o b s e 1 v e d  c o n c e ntr ati o n 
• U ni ts ar e b a s e d o n c o n c e ntr ati o n u nit s  ( pr o vi d e d b y t h e bi o a n al yti c al  l a b or pr ef e 1 T e d  u nit s  f or pr e se nt ati o n of P K 
p ar a m et er s )  a n d  d o s e u nit s  u s e d i n th e st u d y. 
b Ar e a  u n d er  t h e c o n c e ntr ati o n-ti m e  c ur v e  will b e c al c ul at e d u si n g t h e li n e ar tr a p e z oi d al ml e f or i n cr e a si n g a n d d e cr e a si n g 
c o n c e ntr ati o n s. 
A d diti o n al P K p ar a m et er s m a y b e d et e 1 mi n e d w h er e a p pr o pri at e. 
P K a n al y si s  will b e c a 1ri e d  o ut  w h er e  p o s si bl e 1 1si n g a ct u a l bl o o d  s a m pli n g ti m e s p o st d o s e. If 
a n a ct u al  ti m e i s mi s si n g,  t h e s a m pl e c o n c e ntr ati o n r e s ult will b e tr e at e d a s  mi s si n g  u nl e s s 
t h er e is s ci e ntifi c j u stifi c ati o n t o i n cl u d e t h e r e s ult u si n g  t h e n o mi n al  ti m e. 
T h e  p ar a m et er s C m a x, a n d t m a x will b e o bt ai n e d  dir e ctl y  fr o m t h e c o n c e ntr ati o n -ti n 1 e pr ofil es. 
If C m a x o c c ur s  at m or e  t h a n 1 ti m e p oi nt , t m a x will b e a s si g n e d t o t h e fir st o c c u n e n c e of C m a x. 
S p o n s or  Fi n al,  V er si o n 1. 0,  1 6 O C T 2 0 2 0 
1 5 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e : L O X O- B T K- 2 0 0 0 8 
8. 5. 1. 1.  C rit e ri a  f o r t h e C al c ul ati o n of A p p a 1· e nt  T e r mi n al  Eli mi n ati o n  R at e  C o n st a nt 
a n d  H alf-lif e 
T h e  st art of t h e t e 1 mi n al eli mi n ati o n p h a s e f or e a c h su bj e ct  w ill b e d efi n e d  b y  vi s u al 
i ns p e cti o n a n d  g e n er all y  w ill b e t h e first p oi nt at w hi c h  t h er e is n o  s y st e m ati c d e vi ati o n  fr o m 
t h e l o g-li n e ar d e cli n e i n c o n c e ntr ati o n s. 
T h e  a p p ar e nt t e1 mi n al  eli mi n ati o n r at e c on st a nt ( A z) will  o nl y b e c al c ul at e d w h e n  a  r eli a bl e 
e sti m at e c a n b e  o bt ai n e d  u s i n g at l e ast 3  d at a p oi nt s,  pr ef er a bl y  n ot  i n cl u di n g C m a x , a n d  t h e 
a dj u st e d  c o effi ci e nt f or d et er mi n a ti o n of e x p o n e nti al  fit ( R2 - a dj) of t h e r e gr es s i o n li n e is ?.0. 7. 
P ar am e t er s r e q uiri n g A z f or t h eir  c al c ul ati o n ( e g, A U C o-i nf, t1 1 2, C L,  C L/ F, Vss, V z, a n d V J F) 
w ill o nl y b e c al c ul at e d if t h e R 2 - a dj v al u e of t h e r e gr e s si o n li n e i s ?. 0 . 7. 
T h e  f oll ow i n g r e gr e s si o n-r el at e d di a g n o sti c P K p ar a m e t er s will b e d et e 1 mi n e d , w h e n 
p o s si b l e: 
P a r a m et e r 
A, z. U p p er 
A, z. L o w er 
A, z. N 
A, z. S p a n  R ati o 
R 2 - a dj 
U nit s 
h 
h 
N A 
N A 
N A 
D efi niti o n 
e n d of e x p o n e nti al  fit 
str ut of e x p o n e nti al  fit 
n u m b er of d at a  p oi nt s  i n cl u d e d i n t h e l o g-li n e ar r e gr e s si o n 
ti m e p e 1i o d o v er w hi c h A z w a s  d et er mi n e d  a s  a  r ati o oft 1 1 2 
a dj u st e d c o effi ci e nt f or d et er mi n ati o n  of  e x p o n e nti al  fit 
W h er e p o ss i bl e, th e s p a n of ti m e u s e d i n t h e d e t e1 mi n ati o n  of A z  (i e, t h e diff er e n c e  b et w e e n A z 
U p p er a n d A z L o w er)  s h oul d b e ?. 2  h alf-li v e s. If t h e A z S p a n R a ti o is  <2,  t h e r o b u st n e s s of t h e 
tin v al u e s  will b e di s cu s s e d i n t h e C S R. 
8. 5. 1. 2.  C rit e ri a  f o r C al c ul ati o n  a n d  R e p o rti n g of A r e a  U n d e r t h e C o n c e nt r ati o n-ti m e 
C u r v e 
T h e  mi ni m u m  r e q uir e m e nt f or t h e c al c ul ati o n of ar e a  u n d er  t h e c o n c e ntr ati o n-ti m e  c ur v e 
( A U C) will b e t h e i n cl us i o n of at  le a st 3  c o n s e c uti v e  c o n c e ntr ati o n s  a b o v e  t h e l o w er li mit of 
q u a ntifi c ati o n. If t h er e ar e  o nl y  3  c o n s e c ut iv e c on c e n tr ati o ns, at l e ast 1  s h o ul d f oll o w C m a x. 
A n e x c e pt i o n m a y b e m a d e  f or m et a b olit e s,  w h er e C m a x m a y b e t h e la st ti m e p oi nt. 
If t h e e xtr a p ol at e d  ar e a  is  >3 0 %, A U C o-i nf (a n d  d eri v e d p ar a m et er s) m a y b e e x cl u d e d  fr o m 
t h e S lll 1ll 1l aIY st atisti cs a n d st atisti c al a n al y si s at t h e di s cr eti o n of t h e sp o n s or or 
p h ai m a c o ki n eti ci st. 
If A U C o-i nf c a m 1 ot  b e  d et e 1 mi n e d  r eli a bly  f or all su bj e ct s  or  tr e at n 1 e nts, a n alt er n ati v e  A U C 
m e a sur e , s u c h a s A U C t o a  fix e d ti m e p oi nt or A U C o-t , m a y b e u s e d i n t h e st ati stic al a n al y si s 
of dr n g  i nt er a cti o n. 
S p o n s or  Fi n al , V er si o n 1. 0,  1 6 O C T 2 0 2 0 
1 6  o f 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
8. 5. 1. 3.  C rit e ri a  f o r H a n dli n g  B el o w  t h e Li mit of Q u a ntifi c ati o n  o r  Mi s si n g 
C o n c e nt r ati o n s  f o r P h a r m a c o ki n eti c  A n al y si s 
Pl a s m a  c o n c e ntr ati o n s  b el o w  t h e li mit of q u a ntifi c ati o n  ( B L Q) will b e a s si g n e d a  v al u e of 0 
b ef or e  t h e first m e a s ur a bl e  c o n c e ntr ati o n  a n d t h er e aft er B L Q s  will b e tr e at e d a s  mi s si n g.  T h e 
f oll o wi n g r nl e s a p pl y wit h  s p e ci al sit u ati o n s d efi n e d  b el o w: 
• If a n  e ntir e  c o n c e ntr ati o n-ti m e pr ofil e  i s B L Q , it will b e e x cl u d e d fr o m P K a n al ysis. 
•  W h er e  2 or m or e  c o n s e c uti v e  c o n c e ntr ati o n s  ar e B L Q at t h e e n d of a  pr ofil e , t h e pr ofil e 
will  b e  d e e m e d t o h a v e  t e 1 mi n at e d a n d a n y f u 1t h er q u a ntifi a bl e  c o n c e ntr ati o n s will b e 
s et t o mi s si n g  f or t h e c al c ul ati o n of t h e P K p ar a m et er s,  u nl e s s  t h e y ar e  c o n si d er e d t o b e 
a  tr n e c h ar a ct eri sti c of t h e pr ofil e of t h e dr n g. 
• If a  pr e d o s e  pl a s m a  c o n c e ntr ati o n  i s mi s si n g  pri or  t o a n i niti al m u g tr e at m e nt, it m a y b e 
s et t o z er o b y d ef a ult  wit hi n  P h o e ni x  Wi n N o nli n , ot h er  t h a n f or C P 1  a n d C P 3,  w hi c h 
will b e s et t o mi s si n g. 
8. 5. 1. 4.  T r e at m e nt of O utli e r s i n P h a r m a c o ki n eti c  A n al y si s 
If a  v al u e  i s c o n si d er e d t o b e a n o m al o u s  d u e  t o b ei n g  i n c o n si st e nt wit h  t h e e x p e ct e d P K 
pr ofil e, it m a y b e a p pr o pri at e  t o e x cl u d e  t h e v al u e  fr o m t h e P K a n al ysis.  H o w e v er , t h e 
e x cl u si o n of a n y  d at a  m u st  h a v e  str o n g j u stifi c ati o n a n d will b e d o c u m e nt e d i n t h e C S R. 
A n y q u a ntifi a bl e pr e d os e c o n c e ntr ati o n v al u e f or t h e first d os e of a s p e cifi c st u d y dr u g wit hi n 
t h e tr e at m e nt p eri o d  will b e c o n si d er e d a n o m al o u s  a n d s et t o mi s si n g  f or t h e P K a n al ysis. 
If t h e pr e d o s e  c o n c e ntr ati o n of mi d a z ol a m or 1- O H- mi d a z ol a m  i s > 5 % of C m a x i n t h e s e c o n d , 
all P K c o n c e ntr ati o n a n d p ar a m et er  d at a  will b e e x cl u d e d fr o m t h e s u m m ar y st ati sti c s a n d 
st ati sti c al a n al y si s  f or t h at p eri o d . 
8. 5. 2.  P r es e nt ati o n of P h a r m a c o ki n eti c  D at a 
If t h e a ct u al  ti m e of s a m pl e c oll e cti o n  d e vi at e s  fr o m t h e n o mi n al  ti m e b y m or e  t h a n ± 1 0 % , 
t h e c o n c e ntr ati o n will b e fl a g g e d a n d e x cl u d e d  fr o m t h e s u m m a 1 y st ati sti c s.  I n di vi d u al 
c o n c e ntr ati o n s  d e e m e d  t o b e a n o m al o u s  will b e fl a g g e d i n t h e li sti n g s a n d e x cl u d e d fr o m t h e 
s u m m ar y st atisti cs. 
F or P K c o n c e ntr ati o n  d at a  t h e f oll o wi n g r nl e s will a p pl y: 
•  V al u e s  t h at ar e B L Q will  b e  s et t o O f or t h e c al c ul ati o n of s u m m ar y st atisti cs. 
•  Arit h m eti c  m e a n or m e di a n  v al u e s  t h at ar e B L Q will b e pr e s e nt e d  a s 0. 
• If a n y  B L Q  r e s ult s (tr e at e d a s  0)  ar e i n a  s eri e s of s u m m ari z e d d at a , g e o m etri c  m e a n 
a n d  c o effi ci e nt of v ari ati o n  ( C V) of g e o m etri c  m e a n  will b e r e p ort e d a s n ot c al c ul at e d 
( N C). 
F or P K p ar· ar n et ers  t h e f oll o wi n g r nl e will  a p pl y: 
S p o n s or  Fi n al , V er si o n 1. 0, l  6 O C T 2 0 2 0 
1 7 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e : L O X O- B T K- 2 0 0 0 8 
•  G e o m etri c  m e a n  a n d  c o effi ci e nt of v ari ati o n  will  n ot b e c al c ul at e d  f or t m a x. 
P K a n al y si s  will  u s e  a ct u al  ti m e s as  r e c or d e d o n t h e el e ctr o ni c  c a s e  r e p ort f 0 1 m. 
8. 5. 2. 1.  P r es e nt ati o n  P h a r m a c o ki n eti c  P a r a m et e r s 
F or  t h e c al c ul ati o n of s u m m ai y st atisti cs of P K p ar a m et er s , all  n ot  r e p ort e d ( N R) a n d N ot 
C al c ul at e d  ( N C) v al u e s  i n a  d at a  s eri e s will b e s et t o mi s si n g . 
T h e  A U C  v al u e s  will b e s et t o N C if t h e y h a v e  b e e n  c al c ul at e d  u si n g  f e w er t h a n 3 
c o n c e ntr ati o n s , a n d /or 3  c o n c e ntr ati o n s if t h e l a st is C m a x. 
8. 5. 3.  P h a r m a c o ki n eti c  St atisti c al  M et h o d ol o g y 
All P K c o n c e ntr ati o ns  a n d p ar a m et er s  will b e li st e d. 
S u m m ai y  t a bl es, m e a n  ( + st a n d ar d d e vi ati o n  [ S D]) fi g ur es, o v erl a yi n g  i n di vi d u al fi g ur es , a n d 
i n di vi d u al fi g ur es b y tr e at m e nt a n d  ti m e p o st d o s e  will b e pr o vi d e d  f or pl a s m a P K 
c o n c e ntr ati o ns.  All P K c o n c e ntr ati o n  fi g ur es  will b e pr o d u c e d o n b ot h  li n e ar a n d  s e mi-
l o g arit h mi c s c al es,  wit h  t h e e x c e pti o n of fi g ur e s a cr o s s  all  d a y s , w hi c h  will b e pr o d u c e d o n 
t h e li n e ar s c al e o nl y.  T h e  + S D  b ar s  will  o nl y b e di s pl a y e d o n t h e li n e ar s c al e. 
S u m m ar y  t a bl e s b y tr e at m e nt will b e pr o vi d e d  f or all P K p ar a m et er s,  wit h  t h e e x c e pti o n of 
di a g n o sti c  r e gr e s si o n-r el at e d P K p ar a m et er s. S u m m ai y st atisti cs (n,  M e a n,  S D,  C V, 
mi ni m u m , m e di a n , m a xi m u m, g e o m etri c m e a n [ G e o m M e a n] a n d g e o m etri c C V [ G e o m C V]) 
will  b e  c al c ul at e d  f or pl a s m a  L O X O- 3 0 5 , Mi d a z ol a m , 1- O H- Mi d a z ol a m  a n d C P  1  a n d  C P 
3 P K  p ar a m et er s.  E x cl u d e d  su bj e ct s  will  b e  li st e d i n t he P K p ar a m et er  t a bl es, b ut  will b e 
e x cl u d e d  fr o m t h e s u m m ai y st ati sti c s a n d n ot e d as  s u c h i n t h e t a bl es. 
8. 5. 3. 1.  St ati sti c al  A n al y s e s 
8. 5. 3. 1. 1.  P ri m a r y P K e n d p oi nt 
A  st atisti c al a n al ysis  will b e c o n d u ct e d  t o i n v e sti g at e t h e d m g- d m g  i nt er a cti o n o n t h e P K of 
mi d a z ol a m  a n d  1- O H mi d a z ol a m  f or A U C o-t , A U C o-i nf , a n d C m a x. T h e  c o m p ali s o n s of i nt er e st 
ar e: 
T o a s s e s s  t h e i m p a ct of m ulti pl e  or al  d o s e s  of L O X O- 3 0 5 o n t h e si n gl e I V d o s e P K of 
mi d a z ol a m ( A U C o-t, A U C o-i nf, a n d C m a x) 
•  
2 0 0 m g L O X O- 3 0 5  c o- a d mi ni st er e d wit h 2 5 0  µ g I V mi d a z ol a m  (D a y 1 5)  (t e st 
tr e at m e nt) v s 2 5 0 ~ L g I V mi d a z ol a m  ( D a y 1)  (r ef er e n c e tr e at m e nt). 
T o  ass ess  t h e i m p a ct of m ulti pl e  or al  d o s es of L O X O- 3 0 5 o n t h e s i n gl e or al  d o s e P K of 
mi d a z ol a m  a n d  1- O H  mi d a z ol a m ( A U C o-t, A U C o-i nf, a n d C m a x) 
•  2 0 0 m g L O X O- 3 0 5  c o- a d mi ni st er e d wit h 5 0 0  µ g  Or al  mi d a z ol a m  ( D a y 1 7)  (t e st 
tr e at m e nt) v s  5 0 0 ~ L g Or al  mi d a z ol a m ( D ay  3)  (r ef er e n c e tr e at m e nt). 
S p o n s or  Fi n al , V er si o n 1. 0,  1 6 O C T 2 0 2 0 
1 8 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e : L O X O- B T K- 2 0 0 0 8 
T h e  n at ur al l o g (l n)-tra n sf on n e d 3 mi d a z ol a m an d 1- O H- mi d a z ol a m P K p ar a m et er s  ( A U C o-t, 
A U C o-i nf , a n d C m a x) wi ll b e a n al y z e d u s i n g a mi x e d m o d el.
4 T h e  m o d el  will  i n cl u d e a ct u al 
tr e at m e nt a s fi x e d eff e ct,  a n d su bj e ct  as  a r a n d o m eff e ct. 
F or  e a c h P K p ar a m et er  s e p ar a t el y, t h e l ea s t s q u ar e s m e a n  ( L S M) f or e a c h tr e at m e nt, 
diff er e n c e i n L S M s  b et w e e n  t h e t e st a n d  r ef er e n c e tr e at m e nt s, a n d  c o n e s p o n di n g 9 0 % 
c o n fi d e n c e i nt e1v a l ( CI)  will b e c al c u lat e d;  t h es e v al u e s  w ill t h e n b e e x p o n e nti at e d t o gi v e  t h e 
g e o m etr i c le a st sq u ar e s  m e a n  ( GL S M),  g e o m etri c  m e a n  r ati o s ( G M R), a n d  c o n e s p o n di n g 
9 0 %  C I. 
A d d iti on a lly,  t h e p o ol e d  e sti ma t e ( a cr os s a ll tr e at m e nt s) of t h e w it hi n- s u bj e ct C V will b e 
c al cul at e d , a n d r es i d u al pl ot s  w ill b e pr o d u c e d t o a s s e s s  t h e a d e q u a c y of  t h e m o d el (s) fitt e d. 
E x a m pl e s of t h e S A S  c o d e t h at wi ll b e u s ed ar e a s  f oll o ws: 
Mi x e d  M o d el  A n al y si s 
pr o c mi x e d d at a
= < d at a i n >; 
cl a s s tr e at m e nt u s u bji d ; 
m o d e l   l p k = tr e at m e nt/ c l r e s i d u al d df m =   k r ; 
l s m e a n s tr e at m e nt/ cl p d iff = c o ntr ol( ' l  '  ) al p h a 
0 . 1; 
r a n d o m i nter c e p t  / s u bj e ct = u s u b j i d; 
o d s o ut p ut l s m e a ns   = < d at a o u t >; 
o d s o ut p u t   diffs   = < d at a o u t  > ; 
o d s o ut p ut c o v p ar m s = < d at a o ut > ; 
r u n ; 
8. 5. 3. 1. 2.  S e c o n d a r y P K e n d p oi nt s 
A  s t e a dy st a t e a n al y si s  w ill b e p erf o n n e d o n t h e I n-tr a nsf or m e d C 1r o u g h c on c e ntr atio n s  f or 
L O X O- 3 0 5  u s i n g H e h n e 1 t  c o ntr a st s 5 . C 1r o u g h c o n c e ntr ati o ns  f or L O X O- 3 0 5  w ill b e c al c ul at e d 
at t h e e n d of a  d o si n g i nt e 1v a l ( pr e d o s e c o n c entr a ti o ns  o n  D a y s  6  t hr o u g h 1 7 a n d at 2 4  h o ur s 
aft er D a y  1 7  d os e), D a y s  6  t hr o u g h t o D a y  1 4  w ill b e i nv e sti ga t e d f or st e a d y st at e .  T h e 
m o d el  will  i n cl u d e pr ofil e d a y a n d  su bj e ct w ill b e fitt e d a s  a  r e p e at e d m e a s ur e. 
H e h n e 1t  c o ntr a sts  ar e  c o n s tr u ct e d s u c h  t h at e a c h ti n 1 e p oi nt is c om p a r e d t o t h e m e a n of t h e 
s u b s eq u e nt  ti m e p oi nts, i. e t h e pr e- d o s e d a y  6 C 1r o u g h c o n c e ntr ati o n  is c o m p ar e d  t o t h e m e a n 
C 1r o u g h c o n c entr· ati o ns of D a y s  7  t hr o u g h t o D a y  1 4 ,  a n o n- s i g nifi c a nt p- v al u e  i n dic at e s  t h at 
st e ad y  st at e h a s  b e e n  a c hi e v e d. 
St e a d y  St at e  A n al y si s 
pr o c mi x e d d a t  a  = < d a t  a i n> ; 
cl a s s u s u bj i  d pr of ile d a y ; 
m o d e l   l p k = pr ofil e d a y ; 
r e p e at e d pr o f il e d a y / s u bj e ct = u s u b j i d; 
e sti m at e ' Pr e d o s e D a y 6 v s m e a n 
o f pr e d o s e d a y s 7 - 1 4' 
1   - 1/ 8 - 1/ 8 - 1/ 8 - 1/ 8   - 1/ 8 - 1/ 8 - 1/ 8 - 1 / 8; 
e sti m at e ' Pr e d o s e D a y 7 v s m e a n of pr e d o s e d a y s 8 - 1 4' 
0   1   - 1/ 7 - 1/ 7 - 1/ 7 - 1/ 7 - 1/ 7 - 1/ 7 - 1/ 7 ; 
e sti m at e 'Pr e d o s e D a y 8 v s m e a n of pr e d o s e d a y s 9 - 1 4' 
0   0   -  1   - 1/ 6 - 1/ 6 - 1/ 6 - 1/ 6 - 1/ 6  - 1/ 6 ; 
r u n ; 
S p o n s or  Fi n al , V er si o n 1. 0, l  6 O C T 2 0 2 0 
1 9 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
8. 5 . 3. 1. 3. E x pl o r at o r y P K e n d p oi nt 
A  st atisti c al a n al ysis  will b e c o n d u ct e d  t o i n v e sti g at e t h e eff e ct of L O X O- 3 0 5 o n t h e P K of 
e n d o g e n o u s  c o pr o p or p h yr i ns I  a n d III A U C o- 2 4 a n d C m a x. T h e  c o m p ari s o n s of i nt er e st ar e: 
T o  a s s e s s  t h e i m p a ct of si n gl e or a l d o s e s of L O X O- 3 0 5 o n t h e P K of e n d o g e n o u s 
c o pr o p or p h yri n s  I a n d  III ( A U C o- 2 4 a n d C m a x). 
•  2 0 0 m g L O X O- 3 0 5  ( D a y 5)  (t e st tr e at m e nt) v s Pri or t o A d mi n istr ati o n of L O X O -3 0 5 
( D a y 1)  (r ef er e n c e tr e at m e nt). 
T o  a s s e s s  t h e i m p a ct of m ulti pl e  or a l d o s e s of L O X O- 3 0 5  ( st e a d y st at e) o n t h e P K of 
e n d o g e n o u s  c o pr o p or p h yri n s  I a n d ill ( A U C o- 2 4 a n d C m a x). 
•  2 0 0 m g L O X O- 3 0 5  St e a d y  St at e  ( D a y 1 5)  (t e st tr e at m e nt) v s  P 1i or  t o A d mi ni str ati o n 
of L O X O- 3 0 5  ( D a y 1)  (r ef er e n c e tr e at m e nt). 
T h e  s a m e mi x e d  m o d e l a p pr o a c h o utli n e d i n s e cti o n 8. 5. 3. 1. 1  will b e us e d. 
8. 6.  S af et y  a n d T ol e r a bilit y  A s s e s s m e nt s 
8. 6. 1.  A d v e r s e  E v e nt s 
All  A E s  will b e c o d e d  u si n g  t h e M e di c al  Di cti o n a 1 y  f or R e g ul at or y  A cti viti e s  ( M e d D R A) 
V ersi o n 2 3. 0. All A Es will b e assi g n e d s e v erit y gr a d e usi n g N ati o n al C a n c e r I nstit ut e 
C o m m o n  T e n ni n ol o g y  Crit e 1i a  f or A d v er s e  E v e nt s  ( C T C A E) V er si o n  5. 0. 
A  tr e at m e nt- e m er g e nt a d v er s e  e v e nt ( T E A E) will b e d efi n e d  as a n A E t h at st a 1ts  d uri n g or 
aft er  t h e first d o s e of mi d a z ol a m  I V, or st a 1ts pi-i or  t o t h e fir st d o s e  a n d i n cr e as es i n s e v erit y 
aft er  t h e first d os e. 
A  tr e at m e nt-r el at e d T E A E  will b e d efi n e d  as  a T E A E wit h  a  r el ati o n s hi p of r el at e d t o t h e 
st u d y tr e at m e nt ( L O X O-3 0 5 or mi d a z ol a m  [ Or al or I V]), as  d et e n ni n e d b y t h e i n v esti g at or. 
•    A T E A E  o c c u ni n g  d uri n g or aft er D a y 1  d o si n g  a n d pri or  t o D a y 3  d o si n g  will b e 
a s si g n e d  t o 2 5 0 u g I V M D Z 
•    A  T E A E  o c c u ni n g  d uri n g or aft er D a y 3  d o s in g a n d pri or  t o D a y 5  d o si n g  will b e 
a s si g n e d  t o 5 0 0  u g  or al M D Z 
•    A T E A E  o c c u ni n g  d uri n g or aft er D a y 5  d o si n g  a n d pri or  t o D a y 1 5 d o si n g  w ill b e 
a s si g n e d  t o 2 0 0 m g L O X O- 3 0 5 
•    A T E A E  o c c m Ti n g  d uri n g or aft er D a y 1 5 d o si n g  a n d pri or  t o D a y 1 7  d o si n g  will b e 
a s si g n e d  t o 2 0 0 m g L O X O- 3 0 5 + 2 5 0 µ g I V mi d a z ol a m 
•    A T E A E  o c c m Ti n g  d uri n g or aft er D a y 1 7 d o si n g  will b e a s si g n e d  t o 2 0 0 m g L O X O-
3 0 5 + 5 0 0  µ g  or al  mi d a z ol a m 
S p o n s or  Fi n al,  V er s io n 1. 0,  1 6 O C T 2 0 2 0 
2 0 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
All  A E s  will b e li st e d. I n a d d iti o n t o t h e d at a  r e c or d e d i n t h e d at a b a s e , t h e li sti n g s wi ll 
i n cl u d e d eri v e d  o n s et  ti m e a n d d ur ati o n.  O n s et  ti m e will  b e  c al c ul at e d  fr o m t h e ti m e of t h e 
l a st d o s e  f or T E A E s  o nl y. 
T h e  fr e q u e n c y of s u bj e ct s wit h T E A E s  a n d t h e n u m b er of T E A E s  will b e s u m m a 1i z e d f or t h e 
f oll o wi n g c at e g ori e s: 
•  T E A E s  ( o v er all , s eri o u s , l e a di n g t o di s c o nti n u ati o n, a n d l e a di n g t o d e at h) b y 
tr e at m e nt 
•  T E A E s b y s e v erit y a n d  tr e at m e nt 
•  Tr e at m e nt-r el at e d  T E A E s  ( o v er all, s e 1i o us,  l e a di n g t o di s c o nti n u ati o n,  a n d  l e a di n g t o 
d e at h) b y tr e at m e nt 
•  Tr e at m e nt-r el at e d  T E A E s b y s e v erit y a n d tr e at m e nt 
T h e  fr e q u e n c y of s u bj e ct s will  b e  s u m m aii z e d  s e p ar at el y f or T E A E s  a n d  tr e at m e nt-r el at e d 
T E A E s b y t h e f oll o wi n g: 
•  S y st e m  or g a n  cl a s s, pr ef e n e d t e n n, a n d tr e at m e nt 
• 
Pr ef e n e d t e 1 m a n d  tr e at m e nt 
• S yst e m or g a n cl ass, pr ef e n e d t e n n, d a y  of o ns et, a n d tr e at m e nt 
F or t h e A E d at a  t h e f oll o wi n g r nle s  will  a p pl y: 
• 
F or t h e d eri v ati o n of T E A E st at u s: If t h e st a 1t d at e /ti m e of a n A E i s i n c o m pl et e or 
mi s si n g , a n A E will b e a s s u m e d t o b e a  T E A E,  u nl e s s  t h e i n c o m pl et e st ait d at e /ti m e 
or t h e e n d d at e /ti m e i n di c at e s a n A E st art e d pri or t o t h e fir st d os e. 
• 
F or t h e d eri v ati o n of tr e at m e nt-r el at e d T E A E st at us: If t h e st u d y tr e at m e nt 
r el ati o n s hi p f or a T E A E i s mi s si n g ,  a T E A E will b e a s s u m e d t o b e a  tr e at m e nt-r el at e d 
T E A E. 
• 
F or t h e d eri v ati o n of o n s et  ti m e: If t h e st ait d at e /ti m e of a n A E i s mi s si n g , o n s et  ti m e 
will n ot b e c al c ul at e d. If t h e st art d at e /ti m e of a n A E i s i n c o m pl et e, w h er e  p o s si bl e , 
t h e mi ni m u m  p o s si bl e  o n s et  ti m e will b e c al c ul at e d a n d pr e s e nt e d i n ' 2': D D: H H: M M' 
f or m at ( e g, if t h e d at e /ti m e of t h e l a st d o s e i s 0 1 M A Y 2 0 1 9 /0 8: 0 0  a n d  r e c or d e d st art 
d at e /ti m e of a n A E i s 0 3 M A Y 2 0 1 9, t h e n t h e mi ni m u m  p o s si bl e  o n s et  ti m e will b e 
c al c ul at e d b y a s s u mi n g  t h e A E st art e d at t h e fir st h o ur  a n d  mi n ut e of 0 3 M A Y 2 0 1 9 
[ 0 3 M A Y 2 0 1 9/0 0: 0 0],  t h u s will  b e  pr e s e nt e d  a s  o n s et  ti m e 2': 0 1: 1 6: 0 0 i n t h e listi n g). 
• 
F or t h e d eri v ati o n of d ur ati o n: If t h e e n d d at e /ti m e of a n A E i s mi s si n g , d ur ati o n  will 
n ot b e c al c ul at e d. If t h e s t art or e n d d at e /ti m e of a n A E i s i n c o m pl et e, w h er e  p o s si bl e, 
t h e m a xi m u m  p o s si bl e  d ur ati o n  will  b e  c al c ul at e d  a n d pr e s e nt e d i n ' g) D: H H: M M' 
f or m at ( e g, if t h e st art of a n A E d at e /tim e i s 0 1 M A Y 2 0 1 9 /0 8: 0 0  a n d it s r e c or d e d e n d 
d at e /ti m e i s 0 3 M A Y 2 0 1 9 , t h e n t h e m a xi m u m p o s si bl e  d ur ati o n  will b e c al c ul at e d b y 
S p o n s or  Fi n al , V er si o n 1. 0,  1 6 O C T 2 0 2 0 
2 1 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
a s s u mi n g  t h e A E  e n d e d at t h e l a st h o ur  a n d  mi n ut e  of  0 3 M A Y 2 0 1 9 
[ 0 3 M A Y 2 0 1 9/2 3: 5 9],  t h us w ill b e  pr e s e nt e d  as  d ur ati o n :: =; 0 2: 1 5: 5 9 i n t h e listi n g). 
•  F or  t h e c al c ul ati o n of suIIll n a 1 y  st ati sti cs: If t h e s e v erit y of a T E A E is mi s sin g ,  a 
T E A E  will b e c o u nt e d  u n d er  t h e m a xi m u m  s e v erit y p o s si bl e,  u p t o Gr a d e  4 i n t h e 
a b s e n c e of a  f at al o ut c o m e. 
•  F or  t h e c al c ul ati o n of su m m ai y  st ati stic s: If a  s u bj e ct e x p eri e n c e d  m ulti pl e  T E A E s 
wit h  th e s a m e pr ef e 1 T e d  t er m f or t h e s a m e tr e at m e nt, t hi s w ill b e c o u nt e d  as  1  T E A E 
f or t h at tr e at m e nt u n d er  t h e m a xi m m n  s e v erit y r e c or d e d. 
8. 6. 2.  Cli ni c al  L a b o r at o r y  E v al u ati o n s 
All  cli ni c al la b or at or y  e v al u ati o n s , wit h  c h a n g e s fr o m b a s eli n e,  will b e list e d; a n y  v al u e 
o ut si d e  t h e cli ni c al  r ef er e n c e r a n g e will b e fl a g g e d, a n d w h et h e r t h e o ut of r a n g e v al u e  w as 
d e e m e d  c li ni c ally  si g nifi c a nt or  n ot  cli ni c all y si g nifi c a nt wi ll b e i n di c at e d. S e p ar at e  li sti n g s 
w ill b e  pr o vi d e d  f or a n y p ar a m et er  f or w hi c h  t h er e is a n y i n di vi d ual s u bj e ct v a lu e o ut si d e  t h e 
r e s p e cti v e cli ni c al  r ef er e n c e r a n g e. 
T h e  o b s er v e d  r es ults  a n d  c h a n g e fr o m b a s eli n e  f or cli ni c al  c h e mi str y,  h e m at ol o g y , a n d 
c o a g ul ati o n p ar a m et er s  will b e s u m m ari z e d d e s cri pti v el y b y st u d y p art  a n d  ti m e p oi nt. 
V al u e s  r e c or d e d as  < x, :: =; x, > x, or ~ x w ill b e di s pl ay e d i n t h e listi n gs as  r e c or d e d. F or  t h e 
d eri v ati o n of li sti n g fla g s,  c al c ul ati o n of s u m m a 1 y st atisti cs, a n d pr e s e nt ati o n  i n t h e fig ur e s, 
< x  a n d :::; x v a l u es  w ill b e s et t o O w h er e a s > x a n d ~ x v al u es  will b e s et t o x. 
8. 6. 3.  Vit al  Si g n s  R e s ult s 
All  v ital  si g n r esult s  wit h  c h a n g es  fr o m b a s eli n e  wi ll b e li st e d; a n y  v al u e o ut si d e  t h e cli ni c al 
r ef er e n c e r a n g e will b e fl a g g e d, a n d  w h et h er t h e o ut of r a n g e v al u e w as  d e e m e d  cli ni c all y 
si g nifi c a nt or n ot  cli ni c all y si g nifi c a nt will b e i n di c at e d. 
T h e  o b s er v e d  r es ults  a n d  c h a n g e fr o m b a s eli n e  f or all  vit al  si g ns p ar a m et er s  w ill b e 
s u m m ari z e d d e s cri pti v el y b y tr e at m e nt a n d  ti m e p oi nt. 
8. 6. 4.  P ul s e  O xi m et r y 
P ul s e  o x i m etiy  wit h  c h a n g e s  fr o m t h e pr e- mi d a z ol a m  d o s e  v al u e  will b e list e d. 
T h e  o bs e 1 v e d  r e s ults  a n d  c h a n g e fr o m t h e pr e- mi d a z ol a m  d o s e v al u e of p ul s e  o xi m e h y will 
b e  s m n m ari z e d d e s cri pti v el y o n D a ys  1,  3,  1 5, a n d 1 7. 
8. 6 .5.  1 2-l e a d  El e ct r o c a r di o g r a m  P a r a m et e r s 
All  1 2-l e a d E C G p ar a m et er s  wit h  c h a n g e s  fr o m b a s eli n e will  b e  list e d; a n y v a l u e o ut si d e  t h e 
cli ni c al  r ef er e n c e r a n g e will b e fl a g g e d,  a n d w h et h er  t h e o ut of r a n g e v a l u e w a s  d e e m e d 
cli ni c all y s i g nifi c a nt or n ot  cli ni c all y si g nifi c a nt will b e i n di c at e d. 
S p o n s or  Fi n al,  V er si o n 1. 0,  1 6 O C T 2 0 2 0 
2 2 of 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e : L O X O- B T K- 2 0 0 0 8 
T h e  o bs e 1 v e d  r e s ults  a n d c h a n g e fr o m b a s eli n e  f or all 1 2 -l e a d E C G p ar a m et er s  w ill b e 
s um m ari z e d d e s cri pti v ely b y tr e at m e nt gr o u p a n d ti m e p oi nt. Q T c F v a l u es t h at ar e  >  4 5 0 
m s e c a n d i n cr e a s e fr o m b a s eli n e >  3 0  m s e c w ill b e fl a g g e d i n t h e d a t a listi n g . 
8. 6. 6.  Ot h e r  A s s e s s m e nt s 
M e di c al hi st 0 1 y a n d p h ys i c al e x a mi n ati o n  w ill b e lis t e d. A n y p h y si c al  e x a mi n ati o n 
a b n 0 1 m aliti es  r e p 0 1t e d w ill al s o b e fl ag g e d a s cli ni c all y si g nific a nt or n ot c li ni c ally 
si g nific a nt a s  i n di c at e d. 
All  ot h er  s af et y a n d t ol er a bilit y a s s e s s m e nt s n ot d et ail e d i n t h e a b o v e  s e cti o ns  w ill b e liste d 
o nl y. 
8. 6. 7.  S af et y  a n d  T ol e r a bilit y  St ati sti c al  M et h o d ol o g y 
N o i nf er e nti al st atisti c a l a n a ly s e s  ar e pl a n n e d . 
9.  I N T E R I M A N A L Y S E S 
N o i nt eri m a n al y s e s  ar e pl a n n e d. 
1 0.  C H A N G E S F R O M T H E P R O T O C O L- S P E C I F I E D  A N A L Y S E S 
T h er e w e r e n o c h a n g e s  fr o m t h e pr ot o c o l-s p e ci fi e d a n al y s e s. 
1 1. R E F E R E N C E S 
1. I C H.  I C H  H ar m o ni s e d  Tri p aitit e  G ui d eli n e:  St ati sti c al  p ri n ci pl es  f or  c li ni c al trials  ( E 9). 
5  F e br n ar y  1 9 9 8. 
2. I C H. I C H H a n n o ni s e d  Tri p aitit e  G ui d eli n e:  Str n ct ur e  an d c o nt e nt of cli ni c al st u d y r e p o 1ts 
( E 3).  3 0 N o v e m b er  1 9 9 5 . 
3. K e e n e O N . T h e  l og  tr a n sf o1 m at i o n is s p e ci al. St at  M e d. 1 9 9 5; 1 4 ( 8): 81 1- 8 1 9. 
4. Br o w n H, Pr e s cott R. A p pli e d Mi .x e d M o d el s  i n M e di ci n e. C hi c h e st er:  J o h n Wil e y  & 
S o n s,  1 9 9 9 . 
5. 
1 6.  C h o w  S C,  Li u J P.  De s i g n a n d a n al y si s  of  bi o a v ail a bi lit y a n d  bi o e q ui v a l e n c e s t u di es. 
N e w Y or k:  M ar c el  D e k k er ;  19 9 2 . 
S p o n s or Fi n al , V er si o n 1. 0,  1 6 O C T 2 0 2 0 
2 3  o f 2 4 


S A P 
C o v a n c e  St u d y:  8 4 1 9 6 8 7 
1 2.  A P P E N DI C E S 
A p p e n di x 1: 
D o c u m e nt  Hi st o r y 
C O N FI D E N TI A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 0 8 
St at us,  V e rsi o n  
D at e of C h a n g e  
S u m m a r y/ R e a s o n  f o r C h a n g es 
Fi n al , V er si o n  1. 0 
N A 
N A; t h e fir st v ersi o n. 
N A = n ot a p pli c a bl e 
S p o n s or  Fi n al , V er s io n 1. 0,  1 6 O C T 2 0 2 0 
2 4 of 2 4