Conditions: Bariatric Surgery Obesity Weight Gain
Keywords: Obesity Bariatric Surgery Weight Gain Anti-Obesity Agents
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate safety and efficacy of twice-daily ARD-101 in subjects at least one year after bariatric surgery (sleeve gastrectomy or gastric bypass).

Detailed description:
This is a Phase 2, open-label study to investigate the safety and efficacy of twice-daily ARD-101 in subjects at least one year after bariatric surgery (sleeve gastrectomy or gastric bypass). This study has a planned enrollment of 30 subjects (approximately 15 for each preceding surgical procedure) and will be conducted in a single center in the United States.

The study will consist of a Screening Period (up to 28 days), a Treatment Period (28 days), and a Follow-up Period (EOS Visit within 14 days after receiving the last dose of ARD-101). The screening procedures will be initiated upon completion of the informed consent process. Following completion of screening procedures and confirmation of eligibility, subjects will be enrolled to receive ARD-101.

Arms:
arm 1: Dose 200 mg of ARD-101, twice daily for 28 days

Interventions: intervention 1: ARD-101
Intervention descriptions: intervention 1: Twice daily, oral administration

Protocol document:
Prot_SAP_000.pdf: 
Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 1  of 6 7  
0 9 Ma y  2 0 2 2  
 
Cli nic al St u d y Pr ot oc ol  
A P h ase 2  O pe n L a bel St u d y t o E v al u ate t he S afet y, Toler a bilit y, 
a n d E ffic ac y of A R D-1 0 1 i n S u bjects At L e ast  O ne Y e ar A fter 
B ari atric S ur ger y  
S p o ns or:  
Aar d var k T hera pe utics  
4 7 4 7 E xec uti ve Dri ve , S uite 1 0 2 0  
Sa n Die g o, C A 9 2 1 2 1  
 
S p o ns or St u d y  N u m ber:  
A A R D -2 0 2  
I N D N u m ber:  
1 4 2 2 8 8  
I M P Na m e: 
A R D -1 0 1  
De v el o p me nt P hase:  
P hase 2  
Versi o n  ( Date) of Pr ot oc ol:  
A me n d me nt 1  
A me n d me nt 2  
A me n d me nt 3  
A me n d me nt 4  
A me n d me nt 5  
 1. 0  (Ma rc h 12 , 2 0 2 1) 
 2. 0 ( Ma y 2 6, 2 0 2 1)  
 3. 0 ( Oct o ber  2 1 , 2 0 2 1)  
4. 0 (Ja n uar y 2 5, 2 0 2 2)  
5. 0 ( Marc h 1 0, 2 0 2 2)  
6. 0 ( Ma y 0 9, 2 0 2 2)  
 
 
 
 
 
T his cli nical st u d y will be c o n d ucte d i n acc or da nce wit h t he I nter nati o nal C o u ncil f or Har m o ni zati o n Tri partite 
G ui deli ne f or G o o d Cli nical Practice ( G C P) E 6 ( R 2), t he pr ot oc ol a n d wit h ot her a p plica ble re g ulat or y re q uire me nts. 
C o nfi de ntialit y State me nt  
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n of Aar d var k T hera pe utics . D o n ot c o p y or distri b ute wit h o ut writte n 
per missi o n  fr o m t he S p o nsor.  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
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SI G N A T U R E P A G E  
Decl ar ati o n of S p o ns or  
Pr ot oc ol Title:  A P has e 2  O pe n L a bel St u d y t o E val uate t he Safet y, T olera bilit y, a n d Efficac y of 
A R D -1 0 1 i n S u bjects A t Least O ne Y ear After B ariatric S ur ger y  
T his cli nical st u d y pr ot oc ol was s u bjec te d t o critical re vie w. T h e i nf or mati o n it c o ntai ns is 
c o nsiste nt wit h c urre nt k n o wle d ge of t he ris ks a n d be nefits of t he i n vesti gati o nal me dici nal pr o d uct 
(I M P), as well as wit h t he m oral, et hical a n d s cie ntific pri nci ples g o v er ni n g cli nical researc h as set 
o ut i n t he g ui deli nes o n G C P a p plica ble t o t his cli nical st u d y.  
 
S p o ns or Si g n at or y  
 
 
Z he n h ua n Z he n g, P h D  
E V P of Researc h a n d Scie ntific Affairs  
Aar d var k T hera pe utics, I nc.  
 
Date  
 
M a y 1 2, 2 0 2 2


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
Pa ge 3  of 6 7  
0 9 Ma y  2 0 2 2  
SI G N A T U R E P A G E  
Decl ar ati o n of S p o ns or  
Pr ot oc ol Title:  A P has e 2  O pe n L a bel St u d y t o E val uate t he Safet y, T olera bilit y, a n d Efficac y of 
A R D -1 0 1 i n S u bjects A t Least O ne Y ear After B ariatric S ur ger y  
T his cli nical st u d y pr ot oc ol was s u bjecte d t o critical re vie w. T h e i nf or mati o n it c o ntai ns is 
c o nsiste nt wit h c urre nt k n o wl e d ge of t he ris ks a n d be nefits of t he i n vesti gati o nal me dici nal pr o d uct 
(I M P), as well as wit h t he m oral, et hical a n d s cie ntific pri nci ples g o v er ni n g cli nical researc h as s et 
o ut i n t he g ui deli nes o n G C P a p plica ble t o t his cli nical st u d y.  
S p o ns or Si g n at or y  
A n dreas Niet ha m mer, M D, P h D  
C hief Me dical Officer  
Aar d var k T hera pe utics, I nc.  
Date  
1 2 M A Y 2 0 2 2


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 4  of 6 7  
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SI G N A T U R E P A G E  
Decl ar ati o n of t he Pri nci p al I n vesti g at or  
Pr ot oc ol Title:  A P has e 2  O pe n L a bel St u d y t o E val uate t he Safet y, T olera bilit y, a n d Efficac y of 
A R D -1 0 1 i n S u bjects A t Least O ne Y ear After B ariatric S ur ger y  
T his cli nical st u d y pr ot oc ol was s u bjecte d t o critic al re vie w a n d h as bee n release d b y t h e S p o ns or. 
T he i nf or mati o n it c o ntai ns is c o nsiste nt wit h c urre nt ris k a n d be nefit e val uati o n of t he I M P, as 
well as wit h t he m or al, et hical a n d scie ntific pri nci ples g o ver ni n g cli nical researc h as set o ut i n t he 
g ui deli nes o n G C P a p pl ica ble t o t his cli nical st u d y. 
 
Pri nci p al I n vesti g a t or  
 
 
Pri n ci pal I n vesti gat or  
 
 
Si g nat ure  
 
Date  
 
 
Site N u m ber  
 


Aar d var k T hera pe utics, I nc.  
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T A B L E O F C O N T E N T S  
SI G N A T U R E P A G E  ...................................................................................................................... 2  
SI G N A T U R E P A G E  ...................................................................................................................... 3  
SI G N A T U R E P A G E  ...................................................................................................................... 4  
T A B L E O F C O N T E N T S  ................................................................................................................ 5  
List of Ta bles  ..................................................................................................................... 7  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  ................................................... 8  
1.  
P R O T O C O L S U M M A R Y ............................................................................................... 1 1  
1. 1.  
Pr ot oc ol S y n o psis  ............................................................................................... 1 1  
1. 2.  
Sc he ma  ............................................................................................................... 1 6  
1. 3.  
Sc he d ule of Asses s me nts, Ti me P oi nts, a n d Wi n d o w All o wa nce ..................... 1 7  
2.  
I N T R O D U C TI O N ........................................................................................................... 1 9  
2. 1.  
Bac k gr o u n d ......................................................................................................... 1 9  
2. 2.  
Ris k -be nefit Assess me nt  .................................................................................... 2 1  
2. 2. 1.  
K n o w n P ote ntial Ris ks .................................................................................... 2 1  
2. 2. 2.  
K n o w n P ote ntial Be nefits  ............................................................................... 2 1  
2. 3.  
S u m mar y of Fi n di n gs fr o m N o n -cli nical, i n vitr o St u dies wit h P ote ntial 
Cli nical Rele va nce  .............................................................................................. 2 2  
2. 3. 1.  
N o n -cli nical P har mac ol o g y  ............................................................................ 2 2  
2. 3. 2.  
N o n -cli nical P har mac o ki netics  ....................................................................... 2 2  
2. 3. 3.  
N o n -Cli nical Safet y P har mac ol o g y a n d T o xic ol o g y  ...................................... 2 4  
2. 4.  
S u m mar y of Fi n di n gs fr o m Pre vi o us Cli nical St u dies  ....................................... 2 5  
2. 4. 1.  
O ver vie w of Cli nical P har mac ol o g y  ............................................................... 2 6  
2. 4. 2.  
O ver vie w of Cli nical Efficac y  ........................................................................ 2 8  
2. 4. 3.  
O ver vie w of Cli nical Safet y  ........................................................................... 2 8  
2. 4. 4.  
Be nefits a n d Ris ks C o ncl usi o ns  ...................................................................... 3 0  
3.  
S T U D Y E N D P OI N T S  ..................................................................................................... 3 1  
3. 1.  
Pri mar y E n d p oi nt ................................................................................................ 3 1  
3. 2.  
Sec o n dar y E n d p oi nts:  ......................................................................................... 3 1  
3. 3.  
E x pl orat or y E n d p oi nts:  ....................................................................................... 3 1  
4.  
S T U D Y D E SI G N  ............................................................................................................ 3 3  
4. 1.  
O ver vie w  ............................................................................................................ 3 3  
4. 2.  
J ustificati o n f or D ose .......................................................................................... 3 3  
4. 3.  
St u d y D urati o n .................................................................................................... 3 3  
4. 4.  
St u d y C o m pleti o n  ............................................................................................... 3 4  
4. 5.  
Earl y T er mi nati o n  ............................................................................................... 3 4  
5.  
S T U D Y P O P U L A TI O N  .................................................................................................. 3 5  
5. 1.  
N u m ber of S u bjects  ............................................................................................ 3 5  
5. 2.  
I n cl usi o n Criteria ................................................................................................ 3 5  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
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0 9 Ma y  2 0 2 2  
 
5. 3.  
E xcl usi o n Criteria  ............................................................................................... 3 7  
5. 4.  
Restricti o ns  ......................................................................................................... 3 8  
5. 4. 1.  
Dietar y a n d Fl ui d Restricti o ns  ........................................................................ 3 8  
5. 4. 2.  
Lifest yle C o nsi derati o ns  ................................................................................. 3 9  
6.  
I N V E S TI G A TI O N A L M E DI CI N A L P R O D U C T .......................................................... 4 0  
6. 1.  
Pre me dicati o n  ..................................................................................................... 4 0  
6. 2.  
I d e ntit y of t he I n vesti gati o nal Me dici nal Pr o d ucts ............................................ 4 0  
6. 3.  
S u p pl y, Pac ka gi n g, La beli n g a n d St ora ge  .......................................................... 4 0  
6. 4.  
Dr u g Acc o u nta bilit y, Dis pe nsi n g a n d Destr u cti o n  ............................................. 4 0  
6. 5.  
D ose M o dificati o n  .............................................................................................. 4 1  
6. 6.  
St o p pi n g R ules .................................................................................................... 4 1  
6. 7.  
S u bject I d e ntificati o n .......................................................................................... 4 2  
6. 7. 1.  
Scree ni n g N u m bers  ......................................................................................... 4 2  
6. 7. 2.  
E nr oll me nt N u m bers  ....................................................................................... 4 2  
6. 8.  
C o m plia nce  ......................................................................................................... 4 2  
6. 9.  
S pecial Preca uti o ns a n d Ma na ge me nt of A Es  .................................................... 4 2  
6. 9. 1.  
Eati n g dis or ders  .............................................................................................. 4 2  
6. 9. 2.  
All er gic reacti o ns ............................................................................................ 4 2  
6. 9. 3.  
Ma na ge me nt of gastr oi ntesti nal dis or ders  ...................................................... 4 3  
6. 9. 4.  
E m br y o -fetal T o xicit y..................................................................................... 4 3  
6. 1 0.  
Per mitte d Me dicati o ns/ Pr oce d ures  ..................................................................... 4 3  
6. 1 0. 1.  
Per mitte d Me dicati o ns/ Pr oce d ures  ................................................................. 4 3  
7.  
DI S C O N TI N U A TI O N  .................................................................................................... 4 4  
7. 1.  
S u bject Wit h dra wal a n d Re place me nt  ................................................................ 4 4  
8.  
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 5  
8. 1.  
Eli gi bilit y Scree ni n g  ........................................................................................... 4 5  
8. 2.  
S afet y Vari a bles .................................................................................................. 4 5  
8. 2. 1.  
A d verse E ve nts  ............................................................................................... 4 5  
8. 2. 2.  
Cli nical La b orat or y Assess me nts  .................................................................... 5 0  
8. 2. 3.  
Vital Si g ns  ...................................................................................................... 5 0  
8. 2. 4.  
Sta n dar d 1 2 -lea d Electr ocar di o gra ms ............................................................. 5 0  
8. 2. 5.  
Bi oi m pe da nce  ................................................................................................. 5 0  
8. 2. 6.  
M RI P D F F a n d F ull B o d y C o m p ositi o n Sca n  ................................................ 5 1  
8. 2. 7.  
Mi xe d Meal T olera nce Test ( M M T T)  ............................................................ 5 1  
8. 2. 8.  
I n direct Cal ori metr y ........................................................................................ 5 1  
8. 2. 9.  
P h ysical E xa mi nati o ns  .................................................................................... 5 1  
8. 2. 1 0.  
C o nti n u o us Gl uc ose M o nit ori n g  ..................................................................... 5 2  
8. 2. 1 1.  
Circ ulati n g H or m o nes  ..................................................................................... 5 2  
8. 2. 1 2.  
Fecal Micr o bi o me A nal ysis  ............................................................................ 5 2  
8. 2. 1 3.  
N o n -i n vasi ve P he n ot y pic Bitter Taste Test .................................................... 5 3  
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ............................................................................ 5 4  
9. 1.  
St u d y P o p ulati o n  ................................................................................................ 5 4  
9. 1. 1.  
Pr ot oc ol De viati o ns  ........................................................................................ 5 4  


Aar d var k T hera pe utics, I nc.  
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9. 2.  
G e neral C o nsi derati o ns  ...................................................................................... 5 4  
9. 3.  
S u bject Dis p ositi o n  ............................................................................................. 5 4  
9. 4.  
De m o gra p hic a n d A nt hr o p o metric I nf or m ati o n a n d Baseli ne C haracteristics ... 5 4  
9. 5.  
Pri or a n d C o nc o mita nt Me dicati o n a n d Dr u g A d mi nistrati o n  ........................... 5 5  
9. 6.  
E x p os ure  ............................................................................................................. 5 5  
9. 7.  
Safet y A nal yses  .................................................................................................. 5 5  
9. 7. 1.  
A d verse E ve nts  ............................................................................................... 5 5  
9. 7. 2.  
Cli ni cal La b orat or y Tests ................................................................................ 5 5  
9. 7. 3.  
Vital Si g ns  ...................................................................................................... 5 6  
9. 7. 4.  
Sta n dar d 1 2 -lea d Electr ocar di o gra m .............................................................. 5 6  
9. 7. 5.  
P h ysical E xa mi nati o n  ..................................................................................... 5 6  
9. 8.  
E x pl orat or y a nal ysis  ........................................................................................... 5 6  
9. 9.  
Deter mi nati o n of Sa m ple Size  ............................................................................ 5 6  
1 0.  
E T HI C A L, L E G A L A N D A D MI NI S T R A TI V E A S P E C T S  .......................................... 5 7  
1 0. 1.  
Data Q ualit y Ass ur a nce  ...................................................................................... 5 7  
1 0. 2.  
Data C ollecti o n a n d Access t o S o urce Dat a/ D oc u me nts  .................................... 5 7  
1 0. 3.  
Arc hi vi n g St u d y D oc u me nts  .............................................................................. 5 7  
1 0. 4.  
G o o d Cli nical Practice  ........................................................................................ 5 8  
1 0. 5.  
I nf or me d C o nse nt ............................................................................................... 5 8  
1 0. 6.  
I ns ura nce a n d C o m pe nsati o n f or I nj ur y ............................................................. 5 9  
1 0. 7.  
Pr ot oc ol A p pr o val a n d A me n d me nt(s)  ............................................................... 5 9  
1 0. 8.  
C o nfi de ntialit y Data Pr otecti o n  .......................................................................... 5 9  
1 0. 9.  
P u blicati o n P olic y  ............................................................................................... 6 0  
1 1.  
R E F E R E N C E LI S T  ......................................................................................................... 6 1  
1 2.  
A P P E N DI X  ..................................................................................................................... 6 2  
 
List of T a bles  
Ta ble 1  
Sc he d ule of Assess me nts  ......................................................................................... 1 7  
Ta ble 2  
Cac o -2 cell 
M o n ola yer Per mea bilit y of A R D -1 0 1, 
Warfari n, Ra niti di ne a n d 
Tali n ol ol  ................................................................................................................... 2 0  
Ta ble 3  
T he P har mac o ki netic P ara meters of A R D -1 0 1 After Si n gle I ntr a ve n o us or 
I ntr a gastric A d mi nistrati o n t o C y n o m ol g us M o n ke ys ............................................. 2 3  
Ta ble 4  
 Ge o metric Mea n ( % C V) P K Para meters of A R D -1 0 1 F oll o wi n g Si n gle Oral 
D ose A d mi nistrati o n of A R D -1 0 1  ........................................................................... 2 6  
Ta ble 5  
 Ge o metric 
mea n ( % C V) P K para meters of 
A R D -1 0 1 
BI D oral d ose 
a d mi nistrati o n of A R D -1 0 1 f or 1 4 da ys ................................................................... 2 8  
Ta ble 6  
S u m mar y of Treat me nt -e mer ge nt A d verse E ve nts - M A D Part  .............................. 2 9  
Ta ble 7  
S u m mar y of Treat me nt -relate d Treat me nt-e m er ge nt A d verse E v e ns b y S yste m 
Or ga n Class a n d Preferre d Ter m - M A D Part  .......................................................... 3 0  
 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
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LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  
A b bre vi ati o n  
Defi niti o n  
A E  
A d verse e ve nt  
A L T  
A la ni ne a mi n otra nsferase 
A S T  
As partate tra nsa mi nase  
A U C  
Area u n der t he c ur ve   
A U C 0 -τ 
Area u n der t he plas ma  c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o 
ti me τ  
b.i. d.  
T wice a da y  
B L Q  
B el o w t he q ua ntitati o n li mi t 
B MI  
B o d y mass i n de x  
b p m  
Beats per mi n ute  
C B C  
C o m plete bl o o d c o u nt  
C C K  
C h olec yst o ki ni n  
C F R  
C o de of Fe deral Re g ulati o ns  
C G M  
C o nti n u o us g l uc ose m o nit ori n g  
C H O  
Car b o h y drate  
C L  
S yste mic cleara nce  
C ma x  
Ma xi m u m o bser ve d c o nce ntrati o n  
C N S  
Ce ntral ner v o us s yste m  
C o E Q  
C o ntr ol of Eati n g Q uesti o n naire  
C R O  
C o ntract researc h or ga ni zati o n 
C R P  
C -reacti ve pr otei n 
C S R  
Cli nical st u d y re p ort  
C -S S R S  
C ol u m bia -S uici de Se verit y Rati n g Scale  
C Y P 4 5 0  
C yt oc hr o me P 4 5 0  
E C G  
Electr ocar di o gra m  
e G F R  
E sti mate d gl o mer ular filtrati o n rate 
E O S  
E n d  of St u d y  
F I H 
F irst-i n-H u ma n  
F %  
O ral bi oa vaila bilit y 
F S H  
F ollicle sti m ulati n g h or m o ne  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 9  of 6 7  
0 9 Ma y  2 0 2 2  
 
A b bre vi ati o n  
Defi niti o n  
G C P  
G o o d Cli nical Practice  
G I 
Gastr oi ntesti nal  
GI P  
Gastric i n hi bit or y p ol y pe pti de  
G L P  
G o o d La b orat or y Practice  
G L P -1  
Gl uca g o n -li ke pe pti de-1  
H b A 1c  
G l ycate d he m o gl o bi n  
h E R G  
H u ma n et her -a-g o -g o -relate d ge ne 
H O M A -I R 
H o me ostatic m o del assess me nt f or i ns uli n resista nce  
H P B L  
H u ma n peri p heral bl o o d l y m p h oc ytes  
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 o n Har m o nizati o n  
IC 5 0 
H alf ma xi mal I n hi bit or y C o nce ntrati o n  
IE C  
I n de p e n de nt et hic c o m mittee  
i. g. 
I ntra gastric 
I gE  
I m m u n o gl o b uli n E  
IM P  
In vesti gati o nal me dici nal pr o d uct  
IL  
I nterle u ki n 
I P 
I ntra perit o neal 
I N D 
I n vesti gati o nal n e w d r u g 
I R B 
I nstit uti o nal re vie w b oar d  
i.v. 
Intra v e n o us  
M A T E  
M ulti dr u g a n d t o xic c o m p o u n d e xtr usi o n  
M D RI  
M ulti -dr u g resista nce -1  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M M T T  
Mi x e d Meal T olera nce Test  
M RI -P D F F  
M a g netic res o na nce i ma gi n g -deri ve d pr ot o n de nsit y fat fracti o n  
N A S H  
N o nalc o h olic steat o he patitis  
N O A E L  
N o o bser va ble a d verse effect le vel  
O A T 3  
O r ga nic a ni o n tra ns p orter 3  
O C T 2  
O r ga nic cati o n tra ns p orter 2 
O G T T  
O ral gl uc ose t olera nce test 


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A b bre vi ati o n  
Defi niti o n  
O T C  
O ver -t he-c o u nter 
P K  
P har mac o ki netics  
p. o.  
per. os  ( orall y) 
P Y Y  
Pe pti de Y Y  
Q Tc B  
Q T i nter val c orrecte d f or heart rate usi n g Bazett’s c orrecti o n  
Q Tc F  
Q T i nter val c orrecte d f or heart rate usi n g Fri dericia’s c orrecti o n  
S A E  
Seri o us a d verse e ve nt  
S D  
S ta n dar d de viati o n 
S M C  
Safet y M o nit ori n g C o m mittee  
S O C  
S yste m or ga n class  
S O P  
Sta n dar d o perati n g pr oce d ure  
S U S A R  
S us pecte d u ne x pecte d seri o us a d verse reacti o n  
t1/ 2 
Ter mi nal eli mi nati o n half -life calc ulate d as: l n 2/ λz  
tma x  
Ti me of t he ma xi m u m o bser ve d c o nce ntrati o n  
T E A Es  
Treat me nt -e mer ge nt a d verse e ve nts  
T N F  
T u m or necr osis fact or  
T S H  
T h yr oi d -sti m ulati n g h or m o ne 
U L N  
U p per li mit of n or mal  
U S  
U nite d States  
V d 
V ol u me of distri b uti o n  
V ss 
V ol u me of distri b uti o n at stea d y state  
W H O  
W orl d Healt h Or ga nizati o n  
W H O -D D  
W H O Dr u g Dicti o nar y  
 


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1.  
P R O T O C O L S U M M A R Y  
1. 1.  
Pr ot oc ol S y n o psis  
Pr ot oc ol Title  
A P hase 2 O pe n La bel St u d y t o E val uate t he Safet y, T olera bilit y, a n d Efficac y 
of A R D -1 0 1 i n S u bjects At L east O ne Year After Bariatric S ur ger y  
St u d y N u m ber  
A A R D -2 0 2  
De v el o p me nt P hase  
P hase 2  
S p o ns or  
Aar d var k T hera pe utics , I nc. 
St u d y Ce nter  
T he st u d y will be c o n d ucte d at a si n gle ce nter  i n t he U nite d States ( U S) 
St u d y E n d p oi nts  
Pri m ar y E n d p oi nt : 
•  
T he perce nt t otal wei g ht c ha n ge at t he e n d of treat me nt fr o m baseli ne  
 
Sec o n d ar y E n d p oi nts : 
•  
Safet y of A R D -1 0 1 b y assess me nt of t he inci de nce of T reat me nt-
E mer ge nt A d verse E ve nts ( T E A E)  
•  
T he c ha n ge i n bl o o d li pi d c o nce ntrati o ns (t otal c h olester ol, tri gl yceri de, 
hi g h de nsit y li p o pr otei n c h olester ol, a n d l o w -de nsit y li p o pr otei n c h olester ol) 
at t he e n d of treat me nt fr o m t he baseli ne  
•  
T he c ha n ge i n waist circ u mfere nce at t he e n d of treat me nt fr o m t he 
baseli ne  as well as 1 4  da ys after e n d of treat me nt  
•  
T he  c ha n ge i n gl ycate d he m o gl o bi n ( H b A 1c) at t he e n d of treat me nt fr o m 
t he baseli ne 
 
E x pl or at or y E n d p oi nts : 
•  
Cate g orical wei g ht l oss. Pr o p orti o n of s u bjects w h o l os e < 5 % a n d ≥ 5 % 
of i nitial wei g ht 
•  
Fasti n g c irc ulati n g le vels of gl uca g o n-li ke pe pti de ( G L P)-1  (t otal a n d 
acti ve) , c h olec yst o ki ni n ( C C K), pe pti de 
Y Y ( P Y Y), a m yli n, gl uc ose-
de p e n de nt i ns uli n otr o pic p ol y pe pti de ( GI P)  (t otal a n d acti ve), g hreli n, le pti n, 
a n d a di p o necti n  bef ore t he first d osi n g, a n d at 1 h a n d 2 h after t he first d osi n g 
o n da y 1  
•  
C ha n ges i n res p o nse t o mi xe d -meal t olera nce test ( M M T T), i ncl u di n g:  
▪ 
Ser u m le vels of gl uc ose, i ns uli n, a n d C -pe pti de pri or t o 
( ne gati ve ti me p oi nts) a n d p ost ( p ositi ve ti me p oi nts) t he E ns ure 
meal gi ve n f or M M T T  at baseli ne (r u n -i n visit) a n d o n da y 2 8  
▪ 
Ser u m le vel of f ree fatt y aci ds ( F F A) pri or t o ( ne g ati ve 
ti me p oi nts) a n d p ost ( p ositi ve ti me p oi nts) t he E ns ure meal gi ve n 
f or M M T T  at baseli ne (r u n -i n visit) a n d o n da y 2 8 
▪ 
Circ ulati n g le vel s of G L P -1 (t otal a n d acti ve) , C C K, P Y Y, 
a m yli n, GI P (t otal a n d acti ve), gl uca g o n, a n d g hreli n pri or t o 
( ne gati ve ti me p oi nts) a n d p ost ( p ositi ve ti me p oi nts) t he E ns ure 
meal gi ve n f or M M T T at baseli ne (r u n -i n visit) a n d o n da y 2 8 
▪ 
Circ ulati n g c yt o ki nes a n d i nfla m mat or y mar kers s uc h as C -
reacti ve pr otei n ( C R P) at r u n-i n visit a n d e n d of treat me nt ( da y 
2 8) perf or me d d uri n g t he M M T T  


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▪ 
Circ ulati n g le vels of bile aci ds, ferriti n, le pti n, a n d a di p o necti n 
at r u n -i n visit a n d e n d of treat me nt ( da y 2 8) perf or me d d uri n g 
t he M M T T 
•  
B o d y c o m p ositi o n as meas ure d b y bi oelectrical i m pe da nce scale  
•  
B o d y c o m p ositi o n a n d he patic steat osis b y ma g netic res o na nce i ma gi n g -
deri ve d pr ot o n de nsit y fat fracti o n  (M RI -P D F F ) + f ull b o d y c o m p ositi o n sca n  
pretreat me nt a n d e n d of treat me nt  
•  
T he c ha n ge i n h o me os tatic m o del assess me nt f or i ns uli n resista nce 
(H O M A -I R) at t he e n d of treat me nt fr o m t he baseli ne   
•  
T he c ha n ge i n fasti n g bl o o d gl uc ose at t he e n d of treat me nt fr o m t he 
baseli ne  
•  
H u n ger a n d c o ntr ol of eati n g as meas ure d b y Li kert a n d vis ual a nal o g ue 
scales, res pecti vel y 
•  
C ha n ge i n i n direct cal ori metr y  
•  
T he fecal sa m ples will be  c ollecte d d uri n g t he r u n -i n visit a n d o n da y 2 8 
f or micr o bi o me a nal ysis t o e val uate p ote ntial effects of t he st u d y me dicati o n  
o n fecal micr o bi o me pr ofile ( o pti o nal f or s u bjects)  
•  
P he n ot y pic  bitter  taste test ( usi n g c o m merciall y a vaila ble test stri ps/ kis) 
d uri n g t he r u n -i n visit of t he st u d y ( o pti o nal f or s u bjects) 
St u d y Desi g n  
T his is a  P hase 2 , o pe n la bel  st u d y of A R D -1 0 1 i n su bjects wit h rele v a nt 
w ei g ht re gai n at least o ne y ear after bariatric  s urger y  c o m pari n g i ntra patie nt 
meta b olic d y na mics . 
 
A t otal of a p pr o xi matel y 3 0  s u bjects ( 1 5 p ost slee v e gastrect o m y a n d 1 5 p ost 
gastric b y pass s ur ger y) will be e nr olle d i n t he cli nical st u d y.  
 
A scree ni n g pr ocess will be i nitiated  u p o n c o m pleti o n of t he i nf or me d c o nse nt 
pr ocess. S u bjects will be assesse d f or eli gi bilit y t hr o u g h scree ni n g tests 
c o n d ucte d wit hi n 2 8 da ys  pri or t o e nr oll me nt . F oll o wi n g c o m pleti o n of 
scree ni n g tests a n d c o nfir mati o n of eli gi bilit y, s u bjects will be e nr olle d t o 
recei ve A R D-1 0 1 .  
 
All a v aila ble safet y  a n d t olera bilit y data will be e val uate d t hr o u g h o ut st u d y 
c o n d uct. P har mac o d y na mic  data will be a nal yze d after st u d y c o m pleti o n.  
 
S u bjects will be recei vi n g treat me nt i n a n o ut patie nt setti n g  a n d will be  
i nstr ucte d t o visit t he cli nical ce nter peri o dicall y as sc he d ule d i n Ta ble 1  f or 
safet y a n d efficac y assess me nts. T he treat me nt ma y be disc o nti n ue d d ue t o 
i nt olera ble t o xicit y, wit h dra wal of i nf or me d c o nse nt, discreti o n of pri nci pal 
i n vesti gat or or e n d of t he st u d y.  
 
All s u bjects will be f oll o we d u p f or a p pr o xi matel y 1 4 da ys  after t he last d ose 
of st u d y dr u g.  
Test Pr o d uct, D ose, a n d M o de of 
A d mi nistrati o n  
A R D -1 0 1  at 2 0 0 m g BI D a d mi nistere d orall y f or 2 8 da ys  
I ncl usi o n Criteria 
S u bjects m ust meet all t he f oll o wi n g criteria t o be eli gi ble f or partici pati o n i n 
t his st u d y: 
 
1.  M ale a n d fe male s u bjects, 1 8 -7 5 years of a ge  


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2.  Willi n g a n d a ble t o pr o vi de si g ne d a n d date d i nf or me d c o nse nt pri or 
t o a n y st u d y-relate d pr oce d ures a n d willi n g a n d a ble t o c o m pl y wit h 
all st u d y pr oce d ures  
3.  B o d y Mass I n de x ( B MI) of ≥ 3 5 - 6 0 k g/ m 2 d uri n g t he Scree ni n g 
Peri o d  
4.  Stat us of at least 1 -year p ost slee v e gastrect o m y or gastric b y pass 
s ur ger y 
5.  O ne of t he f oll o wi n g:  
a. 
Wei g ht  l oss of at least 5 0 % of t heir e xcess wei g ht at t heir 
na dir, a n d wei g ht re gai n at least 2 0 % of t heir na dir wei g ht 
l oss. E xcess wei g ht is defi ne d as ma xi m u m pre o perati ve 
wei g ht –  wei g ht c orres p o n di n g t o B MI 2 5 k g/ m 2. 
b.  E xcess wei g ht l oss less t ha n 5 0 % at t he s u bject’s na dir 
wei g ht  
6.  S u bjects wit h resc ue s ur ger y (e. g. gastric ba n d t o slee v e gastrect o m y 
or gastric b y pass; slee v e gastrect o m y t o gastric b y pass) will be 
all o we d, wit h ti me si nce sec o n d s ur ger y of at least 1 2 m o nt hs.  
7.  S u bjects wit h a hist or y of re visi o n  pr oce d ures will be all o we d if at 
least 6 m o nt hs ha ve passe d si nce t he pr oce d ure a n d wei g ht has n ot 
de viate d m ore t ha n 5 % i n t he 3 m o nt hs pri or t o e nr oll me nt  
8.  N o a b n or mal fi n di n gs or a b n or malities of cli nical si g nifica n ce i n vital 
si g ns, p h ysical e xa mi nati on, cli nical la b orat or y tests ( c o m plete bl o o d 
c o u nt ( C B C ), uri nal ysis, bl o o d bi oc he mistr y, c oa g ulati o n, pre g na n c y 
test (fe males), uri ne dr u g test, nic oti ne test, etc.), 1 2-lea d 
electr ocar di o gra m ( E C G ) d uri n g t he S cree ni n g P eri o d   
9.  S er u m creati ni ne, al kali ne p h os p hatase, he patic e nz y mes  (as partate 
a mi n otra nsferase, ala ni ne a mi n otra nsferase) a n d t otal bilir u bi n  
( u nless t he s u bject has d oc u me nte d Gil bert s y n dr o me) n ot 
e xcee d i n g 1. 5 -f ol d t he u p per la b orat or y n or m a n d e G F R > 3 0  
m L / mi n 
1 0.  Sta n dar d 1 2 -lea d electr ocar di o gra m ( E C G) para meters after  
1 0 mi n utes resti n g i n s u pi ne p ositi o n i n t he f oll o wi n g ra n ges; 1 2 0 
ms < P R < 2 2 0 ms, Q R S < 1 2 0 ms, Q Tc < = 4 3 0 ms if male, < =  4 5 0 
ms if fe male a n d  n or mal E C G traci n g u nless t he I n vesti gat or 
c o nsi ders a n E C G a b n or malit y  w it hi n descri be d li mits t o be n ot 
cli nicall y rele v a nt 
1 1.  Sta ble or well c o ntr olle d bl o o d press ure per I n vesti gat or’ s j u d ge me nt 
d uri n g t he Scree ni n g Peri o d.  S pecificall y: Vital si g ns after 1 0 
mi n utes sitti n g i n a c hair (feet o n fl o or, bac k s u p p orte d):  
i. 9 5 m m H g <s yst olic bl o o d press ure ( S B P) < 1 6 0 m m H g,  
       ii. 4 5 m m H g < diast olic bl o o d press ure ( D B P) < 1 0 0 m m H g, 
              iii. 4 0 b p m < heart rate ( H R) < 1 0 0 b p m. 
1 2.  H b A 1c < 9. 0 % at scree ni n g  
1 3.  Patie nts wit h t y pe 2 dia betes treate d wit h metf or mi n ma y be e nr oll e d.  
H o we v er, patie nts wit h t y pe 2 dia betes o n a n y ot her t hera p y will be 
e xcl u de d.   
1 4.  Fe male s u bjects m ust ha ve ne gati ve pre g na nc y test a n d m ust n ot be 
lactati n g. F or fe males a ble t o bear c hil dre n, a h or m o nal (i.e., oral, 
i m pla nta ble, or i njecta ble) a n d si ngle barrier met h o d (i.e., s p o n ge), or 
a d o u ble -barrier 
met h o d of birt h c o ntr ol (i.e., c o n d o m 
wit h 
s per mici de) or a bsti ne nce m ust be use d/ practice d t hr o u g h o ut t he 


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st u d y a n d f or 9 0 da ys f oll o wi n g last d ose of st u d y me dicati o n; f or 
effecti ve f or m of birt h c o n tr ol. 
1 5.  Fe males of n o n -c hil d beari n g p ote ntial, defi ne d as s ur gicall y sterile 
(stat us p ost h ysterect o m y, bilateral o o p h orect o m y, bilateral t u bal 
li gati o n, bilateral sal pi n gect o m y, or bilateral t u bal occl usi o n) or p ost-
me n o pa usal f or at least 1 2 m o nt hs ( ma y be  c o nfir me d wit h a 
scree ni n g follicle sti m ulati n g h or m o ne (F S H ) le vel i n t he p ost-
me n o pa usal la b ra n ge), d o n ot re q uire c o ntrace pti o n d uri n g t he st u d y.  
1 6.  Males wit h fe male part ners of c hil d beari n g p ote ntial m ust a gree t o a 
d o u ble -barrier met h o d if t he y bec o me  se x uall y acti ve d uri n g t he 
st u d y a n d f or 9 0 da ys f oll o wi n g t he last d ose of t he st u d y me dicati o n. 
Male s u bjects m ust n ot d o nate s per m f or 9 0 da ys f oll o wi n g t heir 
partici pati o n i n t he st u d y.  
E xcl usi o n Criteria  
S u bjects w h o meet a n y  of t he f oll o wi n g criteria will be e xcl u de d fr o m st u d y 
partici pati o n:  
1.  A n y rele v a nt gastr oi ntesti nal ( GI) s ur ger y  (e xcl u di n g t he gastric 
b y pass or slee v e gastrect o m y)  per In vesti gat or j u d ge me nt  
2.  Hist or y of si g nifica nt dr u g h y perse nsiti vit y or a na p h yla xis  
3.  Pa rtici pati o n i n a wei g ht l oss pr o gra m or cli nical trial f or wei g ht 
l oss wit hi n t he 3 m o nt hs pri or t o e nr oll me nt 
4.  Recei ve d a n y e x peri me ntal dr u gs or de vices or ha ve partici pate d i n 
a cli nical st u d y wit hi n 3 0 da ys pri or t o e nr oll me nt  
5.  Dia betes treat me nt ( u nless  metf or mi n as o utli ne d), or c hr o nic oral 
ster oi ds, or treat me nt wit h i m m u ne m o d ulat ors, a nti-o besit y dr u gs, 
c hr o nic o piate t hera p y, or a nti ps yc h otic me dicati o ns  
6.  C urre ntl y recei vi n g a n y dr u g -base d t hera p y f or wei g ht ma na ge me nt    
7.  T h yr oi d -sti m ulati n g h or m o ne (T S H ) le vel is o utsi de of n or mal li mit 
d uri n g t he Scree ni n g Peri o d  
8.  T he prese nce of diseases wit h a b n or mal cli nical ma nifestati o ns t hat 
nee d t o be e xcl u de d base d o n t heir p ossi ble c o ntri b uti o n t o wei g ht 
l oss or wei g ht gai n, i ncl u di n g b ut n ot li mite d t o nerv o us, 
car di o vasc ular, bl o o d a n d l y m p hatic s yste m, i m m u ne, re nal, 
he patic, gastr oi ntesti nal, res pirat or y, meta b olic a n d s keletal diseases  
d uri n g t he Scree ni n g Peri o d  
9.  Hist or y of m y ocar dial i nfarcti o n, u nsta ble a n gi na, arterial 
re vasc ularizati o n, str o ke, Ne w Y or k Heart Ass ociati o n F u ncti o nal 
Class II -I V heart fail ure, or tra nsie nt isc he mic attac k wit hi n 6 
m o nt hs pri or t o Visit 1  
1 0.  A n y mali g na nc y n ot c o nsi dere d c ure d (e xce pt f ocal, treate d basal 
cell carci n o ma a n d s q ua m o us cell carci n o ma of t he s ki n); a 
partici pa nt is  c o nsi dere d c ure d if t here has bee n n o e vi de nce of 
ca ncer rec urre nce i n  t he pre vi o us 5 years 
1 1.  Hist or y of maj or de pressi ve dis or der or hist or y of ot her se vere 
ps yc hiatric  dis or ders (e. g., sc hiz o p hre nia or bi p olar dis or der) wit hi n 
t he last 2 years. 
1 2.  D o nate d ≥2 0 0 m L of bl o o d ( bl o o d c o m p o ne nts) or ha d massi ve 
bl o o d l oss, recei ve d bl o o d tra nsf usi o n or bl o o d pr o d ucts wit hi n 3 
m o nt hs pri or t o e nr o ll me nt 
1 3.  Pla n ne d s per m/e g g d o nati o n wit hi n 6 m o nt hs p ost e nr oll me nt  
1 4.  P ositi ve uri ne dr u g test ( m or p hi ne, met ha m p heta mi ne, k eta mi ne, 
ecstas y, a n d ca n na bis)  d uri n g t he Scree ni n g Peri o d  
1 5.  Hist or y of c o ns u mi n g m ore t ha n 1 4 u nits of alc o h olic be vera ges per 
wee k or of alc o h olis m or dr u g/c he mical/s u bsta nce a b u se wit hi n past 


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2 years pri or t o e nr oll me nt ( N ote: o ne u nit = 1 2 o u nces of bee r, 4 
o u nces of wi ne or 1 o u nce of s pirits)  
1 6.  S m o ki n g a n y a m o u nt wit hi n 3 m o nt hs pri or t o e nr oll me nt   
1 7.  E xcessi ve c o ns u m pti o n of tea, c offee, a n d/ or caffei nate d be vera g es 
( m ore t ha n 8 c u ps, 2 5 0 mL  f or eac h c u p) e ver y da y wit hi n 3 m o nt hs 
pri or t o e nr oll me nt  
1 8.  S y m p t o matic viral, bacterial (i ncl u di n g u p per res pirat or y i nfecti o n), 
or f u n gal ( n o n -c uta ne o us) i nfecti o n wit hi n 1 wee k pri or t o 
e nr oll me nt 
1 9.  Hist or y of h u ma n i m m u n o deficie n c y vir us a nti b o d y, he patitis C 
a nti b o d y or he patitis B vir us s urface a nti ge n  
2 0.  A hist or y of  ps yc hiatric a n d ps yc h ol o gical c o n diti o n t hat, i n t he 
j u d g me nt of t he i n vesti gat or, ma y i nterfere wit h t he pla n ne d 
treat me nt a n d f oll o w-u p, affect s u bject c o m plia nce or place t he 
s u bject at hi g h ris k fr o m treat me nt-relate d c o m plicati o ns 
2 1.  P o or ve n o us access or i na bilit y t o t olerate ve ni p u nct ure  
2 2.  A n y c o n diti o n or acti ve dr u g treat me nt t hat t he i n vesti gat or or 
pri mar y p h ysicia n belie ves ma y n ot be a p pr o priate f or partici pati n g 
i n t he st u d y 
D urati o n of St u d y  
T he d urati o n of partici pati o n f or eac h s u bject will be a p pr o xi matel y  8 4  da ys 
( 12  wee ks)  
•  
Scree ni n g Peri o d: U p t o 2 8 da ys ( 4 wee ks)  
•  
R u n -i n Visit: U p t o 1 4 da ys ( 2 wee ks) 
•  
Treat me nt Peri o d: 2 8 da ys o n A R D -1 0 1  ( 4 wee ks) 
•  
F oll o w -u p Peri o d: 1 4 da ys ( 2 wee ks). T he E n d of St u d y  ( E O S) Visit 
will occ ur wit hi n 1 4 da ys after recei vi n g t he d ose of A R D -1 0 1  
P har mac o d y na mic E val uati o n  
All s u bjects will be re q uire d t o pr o vi de bl o o d sa m ples at defi ne d ti me p oi nts 
a n d at t he e n d of treat me nt visit. T hese bl o o d sa m ples will be use d t o e x pl ore 
t he para meters descri be d i n t he e n d p oi nt setti n g.  T he C o ntr ol of Eati n g 
Q uesti o n naire ( C o E Q) will be a d mi nistere d at t he ti me p oi nts i n dicate d i n 
Ta ble 1.  
Safet y E val uati o ns  
A d verse e ve nts ( A E) will be c ollecte d fr o m t he ti me of  i nf or me d c o nse nt u ntil 
1 4 da ys after t he last a d mi nistrati o n of st u d y dr u g. Safet y la b orat or y 
assess me nts, i ncl u di n g C B C, c he mistries, c oa g ulati o n tests, uri nal ysis, a n d 
t h yr oi d f u ncti o n, al o n g wit h E C Gs, , a n d vital si g ns will be o btai ne d. All 
c o nc o mita n t me dicati o ns will be rec or de d. All a d verse e ve nts will be f oll o we d 
t o res ol uti o n or sta bilizati o n. O nl y T E A E will be s u m marize d . 
Efficac y E val uati o ns  
T he  efficac y assess me nts i ncl u de c ha n ges fr o m baseli ne i n b o d y wei g ht, B MI, 
waist circ u mfere nce, i ns uli n  resista nce, b o d y fat perce nta ge, H b A 1c, ser u m 
gl uc ose, li pi ds, 
a m b ulat or y 
bl o o d 
press ure 
a n d 
defi ne d 
h or m o ne 
c o nce ntrati o ns.  
Statistical A nal ysis  
All safet y, a n d efficac y data will be s u m marize d a n d prese nte d o verall f or t he 
st u d y, usi n g descri pti ve statistics. 
Mea n, 
me dia n, sta n dar d de viati o n, 
mi ni m u m, a n d ma xi m u m will be prese nte d f or c o nti n u o us varia bles a n d   
fre q ue ncies a n d perce nta ges f or discrete varia bles. 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 1 6  of 6 7  
0 9 Ma y  2 0 2 2  
 
1. 2.  
Sc he m a  
 
Scree ni n g ( u p t o 2 8 da ys)  
Eli gi ble Patie nts  
( N = 3 0) 
A R D -1 0 1  
2 0 0 m g, BI D f or 2 8 da ys 
F oll o w -u p f or 1 4 da ys  
A nal yze d  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 4 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 1 7  of 6 7  
2 5  Ja n uar y 2 0 2 2  
 
 
1. 3.  
Sc he d ule of Assess m e nts, Ti me P oi nts , a n d Wi n d o w All o w a nce  
Details o n pr oce d ures a n d ti mi n g of assess me nts are pres e nte d i n  Ta ble 1 . 
T a ble 1  
Sc he d ule of Assess m e nts  
Peri o d  
Scree ni n g  
R u n -i n Visit 
Tre at m e nt Peri o d  
( ± 3 d a ys) 
F oll o w U p/ E n d of 
St u d y  
St u d y D a ys  
-4 2  t o -1 5  
1 4 d a ys pri or t o D a y 1  
1  (pre d ose)  
1 5  
2 8  
1 4  
I nf or me d C o nse nt  
X  
 
 
 
 
 
I ncl usi o n/E xcl usi o n C riteria 
X  
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
Me dical H ist or y 
X  
 
 
 
 
 
P h ysical E xa mi nati o n a 
X  
 
X  
X  
X  
X  
Vital Si g ns  
X  
 
X  
X  
X  
X  
1 2 -lea d E C G 
X  
 
X  
 
X  
 
He m at ol o g y  
X  
 
X b 
 
 
X  
C o m pre h e nsi ve Ser u m C he mistr y  
X  
 
X b 
X  
X  
X  
Uri nal ysis  
X  
 
X b 
X  
X  
X  
Uri ne T o xic ol o g y  
X  
 
 
 
 
 
C oa g ulati o n Para meters  
X  
 
 
 
 
 
Pre g na n c y Test c 
X  
 
X b 
 
 
X  
T S H  
X  
 
 
 
 
 
Wei g ht/ B MI  
X  
X  
X  
X  
X  
X  
Hei g ht  
X  
 
 
 
 
 
Fasti n g Gl uc ose  
 
X  
 
 
 
X  
H b A 1c  
X  
 
 
 
X  
 
Waist Circ u mfere n ce  
 
 
X  
X  
X  
X  
Fasti n g Bl o o d Li pi ds  
 
X  
 
 
X  
 
Fasti n g Circ ulati n g  H or m o nes d 
 
 
X  
 
 
 
Bi oi m pe d a n ce  
 
 
X  
X  
X  
 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 4 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 1 8  of 6 7  
2 5  Ja n uar y 2 0 2 2  
 
Peri o d  
Scree ni n g  
R u n -i n Visit 
Tre at m e nt Peri o d  
( ± 3 d a ys) 
F oll o w U p/ E n d of 
St u d y  
St u d y D a ys  
-4 2  t o -1 5  
1 4 d a ys pri or t o D a y 1  
1  (pre d ose)  
1 5  
2 8  
1 4  
M RI P D F F + F ull B o d y C o m p ositi o n S ca n 
 
X  
 
 
X  
 
Mi x e d Meal T olera n ce Test ( M M T T)  
 
X  
 
 
X  
 
St u d y Dr u g Dis pe nsati o n  
 
 
X e 
 
 
 
C o nc o mita nt Me dicati o n  
X  
 
X  
X  
X  
 
I n direct C al ori metr y 
 
X  
 
 
X  
 
A d verse E ve nt  M o nit ori n g  
X  
 
X  
X  
X  
X  
C G M Place m e nt  
 
X  
 
X  
 
 
C G M Re m o val a n d D o w nl oa d  
 
 
X  
 
X  
X  
Fecal S a m ple C ollecti o n f  
 
X  
 
 
X  
 
P he n ot y pic Bitter Taste Test g 
 
X  
 
 
 
 
C o ntr ol of Eati n g Q uesti o n naire ( C o E Q)  
X  
 
X  
X  
X  
X  
a. 
C o m plete p h ysical e x a m i nati o n at scree ni n g, a n d brief p h ysical e xa mi nati o n f or all f oll o w -u p  visits  
b.  T his pr oce d ure is n ot nee de d if perf or me d wit hi n 3 da ys  
c. 
F or w o me n of c hil d -beari n g p ote ntial o nl y  
d.  G L P -1 (t otal a n d acti ve), C C K, P Y Y, a m yli n, GI P (t otal a n d acti ve), g hreli n, le pti n, a n d a di p o necti n i n all s u bjects at 3 ti me p o i nts ( bef ore t he first d osi n g 
a n d 1 h as well as 2 h after  t he first d osi n g)  
e. 
A si n gle oral d ose of oral A R D -1 0 1 will be a d mi niste re d t o s u bjects i n t he m or ni n g  of d a y 1  
f. 
Fecal sa m ple t o be c ollecte d d uri n g r u n -i n visit a n d o n d a y 2 8 . O pti o nal f or s u bjects 
g.  P he n ot y pic bitter taste test is o pti o nal f or s u bjects  
 
 
 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 1 9  of 6 7  
0 9  Ma y  2 0 2 2  
 
2.  
I N T R O D U C TI O N 
2. 1.  
B ac k gr o u n d  
O besit y  
O besit y is a c hr o nic dise ase wit h a m ultifact ori al eti ol o g y i ncl u di n g be h a vi oral , e n vir o n me nt al, 
s oci oc ult ural, p h ysi ol o gical a n d ge n etic fact ors. o besit y a n d its c o nse q ue nces  are a n i ncreasi n g 
b ur de n gl o ball y . O b es e, defi ne d as a B MI > 3 0 k g/ m 2, is a n esta blis he d ris k fact or f or a n u m ber of 
diseases s uc h as h y perte nsi o n, car di o vasc ular disease, ca ncer s, dia betes t y pe 2, a n d ma n y ot hers 
(G u h D P et al. 2 0 0 9 ). C urre ntl y, t here are a n esti mate d 6 0 0 milli o n o bese pe o ple w o rl d wi de 
(C olla b orat ors G B D O et al. 2 0 1 7 ). B MI data s h o ws t hat a b o ut 4 0 % of A merica n a d ults are o bes e  
(Hr u b y A a n d H u F B 2 0 1 5 ), w hile w orl d wi de, a b o ut 3. 4 milli o n a n n ual deat hs are dir ectl y 
attri b ute d t o o besit y  (C olla b orat ors G B D O et al.  2 0 1 7 ).  
T he treat me nt of o besit y i n v ol ves lifest yle c ha n g es, bariatric s ur ger y a n d p har mac ot hera p y (Bra y 
G A et al. 2 0 1 6 ). Lif est yle c ha n ge, i n cl u di n g diet a n d e xercise, re q uires c o nsi dera ble p atie nt 
c o m mit me nt, a n d has p o or c o m plia nce. S ur ger y is e x pe nsi ve a n d i n vasi ve. P har mac ot h era p y, 
t heref ore, is t he pri mar y o pti o n f or t he maj orit y of patie nts. A variet y of dr u gs are de si g ne d t o 
pre ve nt f o o d a bs or pti o n, decreas e a p p etite, or i ncrease meta b olis m. C o m pare d t o c o ntr ols, m ost 
dr u gs ca use wei g ht l oss of < 4 k g wit h s u bsta ntial se vere a d verse e ve nts (R osa -G o ncal v es P a n d 
Majer o wicz D 2 0 1 9 ). S o me of t he a d verse e ve nts ha ve ca us e d wit h dra wal of a n u m ber of dr u gs 
fr o m t he mar ket i n se veral c o u ntries (R o d gers RJ 2 0 1 7 ). As a res ult, a si g nifica nt p orti o n of o bese 
patie nts ha ve n o treat me nt o pti o ns d ue t o a d verse e ve nts a n d li mite d wei g ht l oss. Ta ke n t o get her, 
o besit y re mai ns a n u n m et me dical nee d a n d de v el o p me nt of n e w c o m p o u n ds t hat are s afe a n d 
effecti ve is para m o u nt.  T here are c urre ntl y n o dr u g -base d tr eat me nts a v aila ble s pecificall y f or 
s u bjects re gai ni n g wei g ht after bariatric s ur ger y. 
De n at o ni u m  
De nat o ni u m is o ne of t he bitterest tasta nts a m o n g te ns of t h o usa n ds of nat ur al or s y nt hesize d bitter 
c o m p o u n ds, wit h a bi tter ness detecti o n t hres h ol d of 0. 0 5 p p m. T o date, o ne of t he de nat o ni u m 
salts, de nat o ni u m be n z oate has b ee n a p pr o ve d as a n a d diti ve t o h o us e h ol d pr o d ucts  t o pre ve nt t he 
i n gesti o n of p ote ntiall y har mf ul s u bsta nces t hr o u g h taste a versi o n (Si bert J R  a n d Fr u de N 1 9 9 1 ). 
I m p ort a ntl y, t he U S C o ns u mer Pr o d uct Safet y C o m missi o n has j u d ge d de nat o ni u m be nz oat e as 
ge nerall y s afe.  Li k e ot her bitter c o m p o u n ds, de n at o ni u m ca n str o n gl y acti v ate  u p t o 2 5 G -pr otei n 
c o u ple d rece pt ors e x press e d i n a variet y of tiss ues a n d or ga ns i ncl u di n g GI tract, pa ncreas, fat, 
trac hea, a n d ce ntral n er v o us s yste m. B itter taste rece pt ors are t h o u g ht t o be e v ol uti o naril y 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 2 0  of 6 7  
0 9  Ma y  2 0 2 2  
 
c o nser ve d f or t he det ecti o n  of p ote ntiall y t o xic c o m p o u n ds.  Acti vati o n of b itter rece pt ors i n t h e 
m o ut h elicits a fa milia r a versi ve se nsati o n, w hil e  acti vati o n of b itter rece pt ors i n t he g ut a n d 
c he m orece pt or tri g ger z o ne l ocate d i n t he me d ulla lea ds t o re d ucti o n of a p petite a n d dela ye d  
gastric e m pt yi n g as well as ot her a da ptati o ns. I n a n u m ber of a ni mal st u dies, de nat o ni u m be n z oate 
has bee n s h o w n t o i n hi bit o n g oi n g i n gesti ve be h a vi or , s u p press f o o d i nta ke, a n d i n hi bit gastric 
e m pt yi n g (Ja nsse n S et al. 2 0 1 1; Sc hier L A et al. 2 0 1 1). M ore o ver, de n at o ni u m be nz oate ca n 
sti m ulate t he rel ease of G L P-1 a n d C C K t hat are k n o w n t o ca us e satiet y a n d satiati o n (C he n M C 
et al. 2 0 0 6; Ki m K S et al. 2 0 1 4 ). I n h u ma n st u dies, t he i ntra gastric a d mi nistrati o n of de nat o ni u m 
be nz oate after a li q ui d meal has bee n re p orte d t o i n hi bit rela xati o n of t he pr o xi mal st o mac h. W hile 
i n a n oral n utrie nt t olera nce test, de nat o ni u m be nz oate was s h o w n t o i ncrease satiatio n (A va u B et 
al. 2 0 1 5). I n a cli nical tri al c o n d ucte d i n healt h y fe male v ol u nteers, i ntra gastric a d mi nistrati o n of 
de nat o ni u m be nz o ate is s h o w n t o decreas e b ot h a ntral m otilit y a n d h u n g er rati n gs d uri n g t he 
fasti n g state, pr o ba bl y via i n hi biti n g m otili n release. M ore i m p orta ntl y, n o a d verse reacti o ns ha ve 
bee n re p orte d i n all t hese h u ma n st u dies (Del o ose E et al. 2 0 1 7 ). Ta ken t o get her, i ntra gastric 
a d mi nistrati o n of de nat o ni u m salts is safe a n d ca n l ea d t o wei g ht l oss b y c h a n gi n g t he a p petite a n d 
eati n g be ha vi ors  a n d t heref ore, are pr o misi n g a ge nts f or t he treat me nt of o b esit y.  
R ati o n ale of t he St u d y  
A R D -1 0 1  is a n e nca ps ul ate d oral f or m ulati o n of de nat o ni u m  acetate salt t hat  is desi g ne d t o by pass 
t he oral taste rece pt ors w he n a d mi nistere d orall y . Aar d var k T h era p e utics has de m o nstrate d t he 
effic ac y  a n d safet y of A R D -1 0 1  i n m ulti ple precli nical a ni mal m o dels of meta b olic dis or ders a n d 
wei g ht ma na ge m e nt . T he safet y as w ell as p h ar mac o ki netics ha v e bee n c o nfir me d i n a h u m a n trial.   
I n a d diti o n, A R D-1 0 1 is mi ni mall y a bs or be d i nt o t he circ ulati o n t hr o u g h t he GI e pit heli u m cel ls 
pr o vi de d t he ver y l o w cell ular pe netrati o n rat e as de m o nstrate d b y t he Cac o -2 cell m o n ola yer 
per mea bilit y assa y ( T a bl e 2 ). 
T a ble 2  
C ac o -2 cell M o n ol a yer Per me a bilit y of A R D -1 0 1, 
W arf ari n, R a niti di ne a n d 
T ali n ol ol   
 
 
C o m p o u n ds  
Pa p p ( 1 0 -6 c m/s)  
Effl u x rati o  
A →B  
B →A  
A R D -1 0 1 ( 1 0 µ M)  
0. 3 7 8  
4. 6 5  
1 2. 3  
Ra niti di ne  
0. 3 5 5  
0. 8 1 2  
2. 2 9  
Warfari n  
3 4  
3 1  
0. 9 1 3  
Tali n ol ol  
0. 3 3 7  
5. 0 3  
1 4. 9  
Tali n ol ol + Vera p a mil  
0. 7 3 7  
1. 5 1  
2. 0 5  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 2 1  of 6 7  
0 9  Ma y  2 0 2 2  
 
Ta ke n t o get her, A R D -1 0 1 has de m o nstrate d pr o misi n g acti vit y a n d a ma na gea ble t o xicit y pr ofile. 
S u bjects wit h wei g ht re gai n or ot her wise u nsatisfact or y wei g ht ma na ge me nt after bariatric s ur ger y 
prese nt a n i ncreasi n g p o p ulati o n wit h n o s pecificall y a p pr o ve d treat me nt.  
F or details of t he precli nical res ults, pleas e refer t o t he I n v esti gat or Br oc h ure.  
2. 2.  
Ris k -b e nefit Assess m e nt  
2. 2. 1.  
K n o w n P ote nti al Ris ks  
A R D -1 0 1 has s h o w n a w ell -t olerate d safet y pr ofil e wit h n o si g nifica nt or ga n t o xicities u p t o 2 0 0 
m g/ k g/ da y i n a G L P -c o m plia nt pi v otal t o xic ol o g y st u d y wit h c y n o m ol g us m o n ke ys.   As wit h a n y 
ne w dr u g, rare or u ne x p ecte d si de effects c o ul d occ ur. T h e A R D -1 0 1  rel ate d t o xicities ma y be 
mil d t o se vere, i ncl u di n g a d verse h y p erse nsiti vities, or a d verse reacti o n i n GI s yste m.  
A d diti o nall y, c o m pre he nsi ve n o n -cli nical t o xic ol o g y st u dies ha ve bee n perf or me d t o esta blis h t he 
t o xicit y pr ofile of A R D-1 0 1. T he C y n o m ol g us m o n ke y was i de ntifie d as t he p har mac ol o gicall y 
rele va nt s pecies f or assessi n g h u ma n ris k of 
A R D-1 0 1. A R D -1 0 1 
was t olerat e d i n a 
G L P -c o m plia nt, 2 8 -da y re peat -d ose t o xic ol o g y st u d y i n C y n o m ol g us m o n ke y w here s yste mic 
e x p os ure w as c o nfir m e d i n all a ni mals.  
N o  de nat o ni u m salt has bee n a p pr o ve d f or treat me nt i n s u bjects f or a n y i n dicati o n. De nat o ni u m 
be nz oate is c urre ntl y t he o nl y de nat o ni u m salt t hat has bee n teste d i n h u ma ns. T he p ote ntial ris ks 
t hat ma y be ass ociate d wit h A R D-1 0 1 are c o nsi d ere d t o be si milar t o de nat o ni u m be nz oate, w hic h 
ha ve b ee n s h o w n t o b e well -t olerate d w he n a d mi nistere d p. o. ( orall y) wit h n o re p orte d a d verse 
reacti o n (Del o ose E et al. 2 0 1 7 ). T a ke n t o g et her, d e nat o ni u m salt is safe a n d well -t olerat e d w he n 
a d mi nistere d p. o.  i n h u ma ns. 
A R D -1 0 1  has bee n st u die d f or its safet y a n d p har mac o ki netics i n h u ma ns wit h t he res ults i n detail 
s u m marize d bel o w. I n s h ort, A R D-1 0 1 has bee n f o u n d t o be safe at a d os e le vel of u p t o 2 4 0  m g 
BI D f or 1 4 da ys a n d t he P K has c o nfir me d mi ni mal s yste mic u pta ke a n d n o  acc u m ulati o n after 1 1 
da ys.  
2. 2. 2.  
K n o w n P ote nti al Be nefits  
Precli nicall y, A R D -1 0 1 was s h o w n t o re d uce f o o d a n d water c o ns u m pti o n wit hi n 2 h o urs after 
d osi n g i n S D rats. A R D -1 0 1 e x hi bite d si g nifica nt atte n uati o n of wei g ht gai n (c o m pare d t o 
c o ntr ol mice) i n hi g h fat diet-i n d uce d o b ese mice m o del after 56  d a ys of tr eat me nt.  A R D -1 0 1 
als o e x hi bite d n o mi nal atte n uati o n of wei g ht gai n i n o b/ o b mice m o dels.  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 2 2  of 6 7  
0 9  Ma y  2 0 2 2  
 
F urt her, pre vi o us st u dies, i. g. (i ntra gastric) a d mi nistrati o n of de nat o ni u m hel pe d i n miti gati o n  of  
c hr o nic a n d ac ute i nfla m mati o n i n m ulti ple  precli nical  m o dels,  c haracterize d  b y  i m pr o ve d 
pat h ol o g y,  d o w nre g ulati o n  of  i nfla m mat or y c yt o ki nes (s uc h as I L-6,  T N F,  I L-1 β,  etc.). Be nefits  
were  als o o bser ve d  wit h  re gar ds t o c h ol ester ol  le vels, H b A 1c  a n d ot h er  meta b olic  mar kers.  
I n a 4 8 -wee k  st u d y of  diet -i n d uce d N A S H  i n mice , d osi n g  wit h  A R D -1 0 1  lar gel y a br o gat e d  
de vel o p me nt  of  li ver fi br osis o ver  c o ntr ol base d  o n  bli n de d  hist o pat h ol o gic  re vie w. 
2. 3.  
S u m m ar y of Fi n di n gs fr o m N o n -cli nic al, i n vitr o St u dies wit h P ote nti al Cli nic al 
Rele v a nce  
A n i n vitr o sec o n dar y p h ar mac ol o g y st u d y was p erf or me d t o e v al uate t he bi n di n g, e nz y me, a n d 
u pta ke acti vit y of 1 0  µ M A R D -1 0 1 a n d ass ess t he s pecificit y of A R D -1 0 1 acti vit y. T he st u d y 
teste d A R D-1 0 1 bi n di n g t o 2 7 r ece pt ors (i n cl u di n g s u bt y pes of m o n oa mi ner gic, ca n na bi n oi d, 
hista mi nic, nic oti nic, o pi oi d, a n d gl uc oc ortic oi d rece pt ors), 3 tra ns p orters, 8  i o n c ha n nels, a n d 
6  e nz y mes. Res ults fr o m 2  assa ys, α 1 A a dre ner gic rece pt or a n d h E R G p otassi u m i o n c ha n nel 
assa ys, re veale d a n i n hi biti o n or sti m ulati o n hi g her t ha n 5 0 %, de n oti n g a si g nifica nt effect of 
A R D -1 0 1 i n t hese t w o tar gets. T he re mai ni n g assa ys di d n ot s h o w si g nifica nt A R D -1 0 1 acti vit y.  
2. 3. 1.  
N o n -cli nic al P h ar m ac ol o g y  
Effect of A R D -1 0 1 t o S u p p ort Pr o p ose d I n dic ati o n  
T he ke y d ata t o s u p p ort A R D -1 0 1 f or t he treat me nt of o besit y a n d meta b olic s y n dr o me ste ms fr o m 
precli nical e x peri me nts i n m ulti ple r o de nt m o dels de m o nstrati n g be nefit of oral d osi n g wit h A R D -
1 0 1 wit h re gar ds t o miti gati o n of wei g ht gai n as well as i m pr o ve m e nt i n pat h ol o gies s uc h as 
h y perc h olester ole mia, pre dia betes a n d c hr o nic i nfla m mati o n.  
2. 3. 2.  
N o n -cli nic al P h ar m ac o ki netics  
T he P K pr ofile of A R D -1 0 1 was c haracterize d i n a pa nel of i n vitr o a n d i n viv o st u dies, i ncl u di n g 
plas ma pr otei n bi n di n g assa ys, p er mea bili t y assa ys, 
meta b olic sta bilit y a n d 
meta b olite 
i de ntificati o n assess me nts, C yt oc hr o me 4 5 0 ( C Y P 4 5 0) p he n ot y pe assa ys, i n vitr o dr u g -dr u g 
i nteracti o n st u dies o n C Y P 4 5 0s, a n d ser u m/ plas ma t o xic o ki netic st u dies i n C y n o m ol g us m o n ke ys.  
I n t he Cac o-2 cell m o n ol a y er p er mea bilit y assa y, A R D -1 0 1 s h o we d a l o w per mea bilit y t hr o u g h 
i ntesti nal e pit helia cell, t he Pa p p val ue of A R D -1 0 1 i n t he a pical t o bas olateral directi o n was 
0. 3 7 8 × 1 0 -6 c m/s. I n a d diti o n, A R D -1 0 1 e x hi bite d effl u x effect wit h a n effl u x rati o of a b o ut 1 2. 3, 
i n dicati n g A R D-1 0 1 is a s u bstrate of certai n effl u x tra ns p orters.  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 2 3  of 6 7  
0 9  Ma y  2 0 2 2  
 
T o i n vesti gate t he P K of A R D -1 0 1 i n cl u di n g s yste mic e x p os ure, oral bi oa vaila bilit y, a n d P K 
li nearit y, a n o n-G L P P K st u d y was c o n d ucte d i n C y n o m ol g us m o n ke ys. T hree male C y n o m ol g us 
m o n ke y s were assi g ne d t o 3 d ose gr o u ps a n d a si n gle d ose of A R D -1 0 1 was a d mi nistrate d p. o.  at 
0. 4 9, 1. 6 2, or 4. 8 5 m g/ k g ( de nat o ni u m base wei g ht). After a 1 4 -da y was h o ut peri o d, a n i ntra ve n o us 
(i.v.) a d mi nistrati o n of A R D-1 0 1 was gi ve n t o t he sa me a ni mal at t he s a me d ose le vel. Bl o o d 
sa m ples were c ollecte d fr o m all a ni mals o n Da y 1 a n d Da y 1 5 at 0. 2 5, 0. 5, 1, 2, 4, 8, 2 4, 3 2, a n d 
4 8  h p ost -d ose.  
F oll o wi n g a si n gle i.v. d ose of A R D -1 0 1 at 0. 4 9, 1. 6 2, a n d 4. 8 5 m g/ k g t o C y n o m ol g us m o n ke ys, 
t he Cma x  a n d A U C 0 -4 8 h were  1 2 9, 8 0 3, 2 2 7 0 n g/ m L a n d 2 7 0, 1 4 6 0, 4 7 2 0 n g * h/ m L, res pecti vel y. 
T he val ues of C L a n d V d were 2 1 5 0, 1 3 2 0, 1 2 4 0 m L/ h/ k g a n d 3 2 5 0 0, 2 5 8 0 0, 1 7 5 0 0 m L/ k g, 
res pecti vel y. T h e eli mi nati o n of A R D-1 0 1 i n m o n ke ys was sl o w, as i n dicat e d b y t he mea n t 1/ 2 of 
1 1. 2 5  h. Wi t hi n t he d ose ra n ge of 0. 4 9-4. 8 5 m g/ k g, A U C i ncrease d hi g her t h a n d ose pr o p orti o nall y 
(Ta ble 3 ).  
F oll o wi n g a si n gle oral d ose of A R D -1 0 1 at 0. 4 9, 1. 6 2, a n d 4. 8 5 m g/ k g, t he A U C 0 -4 8 h was 
i nsi g nifica nt a n d Cma x  were 0, 1. 9 8, 4. 5 5 n g/ m L, res pecti vel y, i n dicati n g a n e xtre mel y l o w 
s yste mic e x p os ure of A R D-1 0 1. T he oral bi oa vail a bilit y ( F %) i n m o n ke ys was esti mate d t o be 0 % 
at 0. 4 9, 1. 6 2, a n d 4. 8 5 m g/ k g, res pecti vel y. N o cli nical a b n or mal si g ns were n otice d gi ve n ve r y 
l o w a bs or pti o n a n d ne gli gi ble s yste mic e x p os ure (Ta ble 3 ).  
I n s u m mar y, t h e bi oa vaila bilit y of A R D-1 0 1 i n m o n ke y is ne gli gi ble, n o s yste mic e x p os ure 
reac h e d after 4.8 5 m g/ k g p. o. a d mi nistrati o n.  
T a ble 3  
T he P h ar m ac o ki netic P ar a meters of A R D -1 0 1 After Si n gle I ntr a ve n o us or 
I ntr a g astric A d mi nistr ati o n t o C y n o m ol g us M o n ke ys 
R o ute  
D ose  
( m g/ k g) 
C m a x  
n g/ m L  
A U C 0 -t 
n g * h/ m L  
t1/ 2  
h o urs  
T m a x  
h o urs  
C L m L/ mi n/ k g  
V S S  L/ k g  
F %  
i. v. 
0. 4 9  
1 2 9  
2 7 0  
1 0 5  
0. 2 5  
2 1 5 0  
3 2. 5  
 
1. 6 2  
8 0 3  
1 4 6 0  
1 3. 5  
0. 2 5  
1 3 2 0  
2 5. 8  
 
4. 8 5  
2 2 7 0  
4 7 2 0  
9. 7 4  
0. 2 5  
1 2 4 0  
1 7. 5  
 
p. o.  
0. 4 9  
B L Q  
N A  
N A  
N A  
N A  
N A  
0  
1. 6 2  
1. 9 8  
N C  
N C  
2  
N A  
N A  
0  
4. 8 5  
4. 5 5  
N C  
N C  
1  
N A  
N A  
0  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 2 4  of 6 7  
0 9  Ma y  2 0 2 2  
 
A b bre viati o ns: B L Q: bel o w t he q ua ntitati o n li mit; F: fracti o n ( %) of a n a d mi nistere d dr u g t hat reac hes t he s yste mic 
circ ulati o n [ oral bi oa v aila bilit y] ; i.v.: i ntra ve n o us a d mi nistrati o n; p. o. : orall y a d mi nistrati o n; N A: n ot a p plica ble; 
N C: n ot calc ula ble.  
P har mac o ki netic para met ers after re p eate d oral d oses were o bt ai ne d fr o m t he t o xic o ki netic st u d y 
f oll o wi n g b.i. d.  i. g. a d mi nistrati o n of 1 5, 3 0, or 1 0 0 m g/ k g/ d ose of A R D -1 0 1 ( de n at o ni u m base 
wei g ht) t o C y n o m ol g us m o n ke ys f or 2 8 da ys. Aft er t he first d ose, t he m ea n plas ma  A U C a n d C ma x  
val ues were si milar b et w ee n male a n d fe male a ni mals, i n dicati n g a lac k of se x -relate d differe nces 
i n s yste mic e x p os ure. T h ere w as a tr e n d t o war d a greater t ha n d ose-pr o p orti o nal i ncreas e i n C ma x  
a n d A U C 0 -2 4 h. At Da y 2 8, stea d y state mea n A U C 0 -2 4 h val ues w ere 2 6. 3, 4 0. 6, a n d 1 2 1 0 n g * h/ m L 
f or fe male m o n k e ys a n d 4 0. 1, 4 8. 0, a n d 1 4 0 0 n g * h/ m L f or male m o n ke ys at 1 5, 3 0, a n d 
1 0 0  m g/ k g/ d oses, res pecti vel y.  N o acc u m ulati o n of A R D -1 0 1 i n m o n ke ys was o bser ve d after 
4  wee ks of b.i. d.  a d mi nistrati o n.  
A R D -1 0 1 e x hi bite d l o w bi n di n g ( <  5 0 %) t o h u ma n a n d rat plas ma pr otei ns, a n d a relati vel y hi g h 
bi n di n g t o m o n ke y plas ma pr otei ns ( 5 0 % t o 9 0 %). A n i n vitr o li ver micr os o me sta bilit y st u d y 
s h o we d t hat A R D-1 0 1 w as q uic kl y meta b olize d b y rat li ver micr os o mes, m o deratel y b y m o n ke y 
micr os o mes, a n d al m ost n o meta b olis m i n h u ma n li ver micr os o mes. C yt oc hr o me P 4 5 0s ( C Y Ps) 
were n ot t he 
maj or e n z y mes i n v ol ve d i n A R D -1 0 1 
meta b olis m. A n  i n vitr o meta b olite 
i de ntificati o n st u d y s h o w e d t hat the N -deal k ylate d meta b olite ( M 1, li d ocai n e) was o nl y see n i n t he 
h u ma n S 9 sa m ples at trace le v els, acc o u nti n g f or o nl y 0. 0 5 % of t otal pea k areas. T h e o xi dati o n 
pr o d uct  M 2 was t he maj or meta b olite, acc o u nti n g f or 1 8. 8 8 %, 5. 8 2 %, a n d 0. 3 1 % of t otal pea k 
areas i n r at, m o n ke y a n d h u ma ns, res pecti vel y.  
A pr o be s u bstrate -base d i n hi biti o n st u d y i n h u ma n li ver micr os o mes s h o we d t hat A R D -1 0 1 was a 
m o derate i n hi bit or of C Y P 2 D 6 wit h a n I C 5 0 val ue of 0. 2 3 3 µ M. T he C Y Ps i n d ucti o n st u d y i n 
h u ma n he pat oc ytes s h o w e d t hat A R D -1 0 1 was n ot a p ote ntial i n d ucer of C Y P 1 A 2,  C Y P 2 B 6, a n d 
C Y P 3 A 4. A n i n vitr o tra ns p orter i nteracti o n assa y s h o we d t h at A R D-1 0 1 is a s u bstrate of M D RI, 
M A T E 1, M A T E 2 -K, O A T 3, a n d O C T 2 tra ns p orters. A R D -1 0 1 is a n  i n vitr o i n hi bit or of t he 
M A T E 1, M A T E 2 -K, a n d O C T -2 tra ns p ort ers, wit h I C 5 0 val ues of 2 1. 0 7, 5 7. 1 1, a n d 9. 4 7  μ M, 
res pecti vel y.  
2. 3. 3.  
N o n -Cli nic al S afet y P h ar m ac ol o g y a n d T o xic ol o g y  
T he t o xic ol o g y pr o gra m was desi g ne d t o s u p p ort cli nical st u dies i n acc or da nce wit h I C H G ui da n ce 
M 3( R 2). A n o n -G L P si n gle d ose ac ute t o xic ol o g y st u d y ( i.v. a n d p. o. ) a n d a pi v otal G L P c o m plia nt 
ge neral t o xic ol o g y st u d y wit h a 2 8 -da y treat me nt ( i. g.) a n d a 1 4-d a y rec o ver y p eri o d ha v e b ee n 
c o n d ucte d i n C y n o m ol g us m o n ke ys. I n vitr o st u dies i ncl u di n g bacterial re verse m utati o n assa y 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 2 5  of 6 7  
0 9  Ma y  2 0 2 2  
 
a n d ma m malia n cell c hr o m os o me a berrati o n  test ha ve bee n c o n d u cte d t o e val uate ge n ot o xicit y of 
A R D -1 0 1.  
A R D -1 0 1 s h o we d i n hi biti o n of h E R G c urre nt wit h a n I C 5 0 of 9 9. 2 µ M ( 3 8 1 4 3 n g/ m L) i n vitr o. 
Car di o vasc ular t o xicit y was o bser ve d i n a si n gle C y n o m ol g us m o n ke y after i.v. a d mi nistrati o n of 
A R D -1 0 1 at 4. 8 5 m g/ k g (i n t he si n gle d ose t o xic ol o g y/ P K st u d y). T he a ni mal s h o we d re p etiti ve 
arr h yt h mia i m me diatel y f oll o wi n g i njecti o n, t he ser u m c o nce ntrati o n was 2 2 7 0 n g/ m L at t he first 
sa m pli n g ti me p oi nt ( 1 5 mi ns p ost-d ose), a n d t his a d verse effect rec o vere d b y 8 h o urs p ost - d ose. 
T he t olerate d d os e f or a n i.v. r o ut e is 1. 6 2 m g/ k g wit h a s yste mic e x p os ure of 1 4 6 0 n g * h/ m L  a n d 
a pea k ser u m c o nce ntrati o n ( C ma x ) of 8 0 3 n g/ m L.  
I n t h e 2 8-d a y t o xicit y st u d y i n C y n o m ol g us m o n ke ys, 1 0 0 m g/ k g b.i. d.  i. g. a d mi nistrati o n of 
A R D -1 0 1 ( h u ma n e q ui v ale nt d ose is 6 4. 5 m g/ k g, b.i. d. ) was well-t olerate d i n all a ni mals, w hic h 
is 3 7. 3 3-f ol d of t he pr o p ose d starti n g d ose i n a first-i n-h u ma n  ( FI H) cli nical st u d y ( 4 0 m g b.i. d  f or 
a 7 0 k g a d ult). T here w as n o m ortalit y or m ori b u n dit y  f o u n d i n A R D-1 0 1 -treate d a ni mals. A R D-
1 0 1 s h o we d n o l ocal t o xi cit y i n t he GI or ga ns (st o mac h, d u o de n u m, ile u m, jej u n u m, cec u m, c ol o n, 
a n d rect u m) base d o n gr oss pat h ol o g y a n d hist ol o gical micr osc o pic e xa mi nati o ns. O nl y tra nsie nt 
decreases i n b o d y wei g hts i n a ni mals a d mi nistere d wit h 1 0 0 m g/ k g d ose were o bser ve d, w hic h 
ma y be relate d t o t he p h ar mac ol o gical effect of A R D -1 0 1. T he n o -o bser ve d -a d verse-effect le vel 
( N O A E L) w as c o nsi dere d t o be 1 0 0 m g/ k g/ d ose ( 2 0 0 m g/ k g/ da y) wit h a s yste mic e x p os ure 
A U C 0 -2 4 h of 1 2 1 0  n g * m L/ h a n d 1 4 0 0 n g * m L/ h f or fe male a n d m ale m o n ke ys, res pecti vel y.  
A R D -1 0 1 di d n ot s h o w m uta ge nic acti vit y i n t he bacterial re v erse m utati o n assa y. T he i n vitr o 
c hr o m os o mal a berrati o n assa y s h o we d t hat A R D -1 0 1 was c o nsi d ere d ne gati ve f or i n d u ci n g 
struct ural a berrati o ns of h u ma n peri p heral bl o o d l y m p h oc ytes ( H P B L) i n t he 3 -h treat me nt wit h 
meta b olic acti vati o n a n d t he 2 2 -h o ur treat me nt wit h o ut acti vati o n. A R D -1 0 1 was p ositi ve f or 
i n d uci n g str uct ural a berrati o ns of H P B L i n t he 3-h o ur treat me nt wit h o ut m eta b olic acti vati o n. N o 
preci pitate, p H c ha n ges or c yt ot o xicit y was o bser v e d at a n y d ose le vel d uri n g t he st u d y.  
F urt her details ca n b e f o u n d i n t he I n v esti gat or’s Br oc h ure.  
2. 4.  
S u m m ar y of Fi n di n gs fr o m Pre vi o us Cli nic al St u dies  
A FI H cli nic al st u d y wit h t he st u d y dr u g has bee n perf or me d i n healt h y v ol u nteers t o i nterr o gate 
safet y a n d p h ar mac o ki n etics of m ulti ple d ose le vels.  
T he st u d y c o nsiste d of 2 parts: A si n gle asce n di n g d ose part ( S A D) a n d a m ulti ple asce n di n g d ose 
part ( M A D), d osi n g s u bj ects f or 1 4  d a ys BI D. E ac h part teste d t hr ee d os e le vels ( 4 0  m g, 1 0 0  m g 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 2 6  of 6 7  
0 9  Ma y  2 0 2 2  
 
a n d 2 4 0 m g) c o nsec uti vel y  i n a ra n d o mize d, d o u ble-bli n de d ma n ner.  A t ot al of 4 3 s u bjects were 
d ose d i n t otal, 2 3 fe males a n d 2 0 males of w hic h 3 1 recei v e d A R D -1 0 1.  
T he res ults are s u m mariz e d bel o w:  
2. 4. 1.  
O ver vie w of Cli nic al P h ar m ac ol o g y  
2. 4. 1. 1.  
Si n gle Asce n di n g D ose  
T he S A D st u d y e val uat e d P K para meters f oll o wi n g a d mi nistrati o n of a si n gle oral d ose of A R D -
1 0 1 at 4 0 m g, 1 0 0 m g, or 2 4 0 m g i n healt h y a d ult s u bjects. Eli gi ble s u bjects were 1 8 -5 5 years of 
a ge, wit h a b o d y mass i n de x bet wee n 1 8-3 0 k g/ m 2 a n d a mi ni m u m wei g ht of 5 0 k g. S u bjects were 
orall y d ose d i n 3 es calati n g c o h orts of 4 0, 1 0 0, a n d 2 4 0 m g of A R D -1 0 1 or matc hi n g place b o 
ca ps ules. F or eac h d ose c o h ort, 6 s u bjects recei ve d A R D -1 0 1 a n d 2 s u bjects rece i v e d place b o. T h e 
st u d y me dicati o n was a d mi nistere d t o eli gi ble s u bjects after a mi ni m u m of 8 h of fasti n g.  
Gr o u p P K a nal yses h a ve bee n c o n d u cte d f or all d ose c o h orts i n Part 1 of t he st u d y. P K para meters 
f or all d os es are prese nt e d i n Ta ble 4 . Base d o n t h e area u n der t he c ur ves ( A U Cs) a n d ma xi m u m 
ser u m c o n ce ntrati o n ( C ma x ) bet wee n-s u bj ect v aria bilit y ( Ge o metric C V %) was hi g h, ra n gi n g fr o m 
4 5. 8  t o 5 3. 7 %. C V % f or t1/ 2 val ues i ncrease d wit h i ncreas es i n A R D -1 0 1 d ose le vel.  
T a ble 4  
 Ge o metric Me a n ( % C V) P K P ar a meters of A R D -1 0 1 F oll o wi n g Si n gle Or al 
D ose A d mi nistr ati o n of A R D -1 0 1  
Para meter  
( U nits) 
4 0 m g  
1 0 0 m g  
2 4 0 m g  
A U C last ( h * n g/ m L) 
4. 8 1  ( 2 81. 4 ) 
1 5. 9 ( 6 1. 1 ) 
5 3. 1 ( 4 5 .8 ) 
A U C i nf ( h * n g/ m L) 
1 2. 4 ( 1 0 6. 8)  
1 7. 5 ( 5 7. 6 ) 
5 5. 8  ( 4 5.2 ) 
C ma x ( n g/ m L) 
0. 9 9 9 ( 2 5 9 . 4) 
3. 0 4 ( 7 6. 2)  
1 2. 4 ( 5 3. 7)  
tma x a ( h) 
1. 3 3 ( 0. 6 6 7 –  4. 0 0)  
1. 2 1  ( 0. 6 6 7 –  2. 0 0)  
1. 0 8  ( 0. 6 6 7 –  1. 3 3)  
t1/ 2 ( h) 
8. 2 7  ( 1 4. 4) 
1 1. 1 ( 3 9 . 0) 
1 8. 4 ( 3 9. 0 )b 
C L/ F ( L/ h)  
3 2 2 0 ( 1 0 6. 8)  
5 7 1 0 ( 5 7. 6 ) 
4 3 0 0 ( 4 5. 2 ) 
Vz/ F ( L)  
3 8 4 0 0 ( 1 1 4 . 0) 
9 1 7 0 0 ( 3 0. 1)  
1 1 4 0 0 0 ( 5 6 .9 ) 
a Me dia n ( mi n -ma x) prese nte d; b Half -life esti mates were calc ulate d o ver a peri o d of less t ha n 2 half-li ves f or 3 
s u bjects i n t he 2 4 0 m g d ose gr o u p.  
F oll o wi n g a d mi nistrati o n of a si n gle 2 4 0 m g A R D -1 0 1 d ose, q u a ntifia ble c o nce ntrati o ns f or all 
s u bjects were o bser ve d at 4 8 h o urs p ost d ose, wit h 3 of 6 s u bjects ha vi n g q ua ntifia ble 
c o nce ntr ati o ns at 7 2 h o urs p ost d ose. T here was a 2. 4 -f ol d i ncrease i n d ose le vel fr o m 1 0 0 t o 2 4 0 
m g A R D -1 0 1. T his res ulte d i n i ncreases i n C ma x , A U Clast, a n d A U Ci nf ( 4. 0 8-, 3. 3 4-, a n d 3. 1 8-f ol d, 
res pecti vel y).  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 2 7  of 6 7  
0 9  Ma y  2 0 2 2  
 
T he ge o metri c me a n a n d hi g hest pea k plas m a c o nce ntrati o ns ( C ma x ) f oll o wi n g si n gle oral 
a d mi nistrati o n at t hese d oses were 0. 9 9 9 a n d 9. 5 9 n g/ m L ( 4 0 m g), 3. 0 4 a n d 1 0. 4 n g/ m L ( 1 0 0 m g), 
a n d 1 2. 4 a n d 2 9. 7 n g/ m L ( 2 4 0 m g) res pecti vel y, w hic h re prese nte d 0. 1 2 % a n d  1. 2 0 %, 0. 3 8 0 % a n d 
1. 3 0 %, a n d 1. 5 5 % a n d 3. 7 1 % of t he P K st o p pi n g criteria ( 8 0 0 n g/ m L) f or t his P hase I st u d y.  
2. 4. 1. 2.  
M ulti ple Asce n di n g D ose  
T he M A D st u d y e val uate d  P K para meters f oll o wi n g re peate d a d mi nistrati o n t o date of oral d oses 
of A R D -1 0 1 at 4 0 m g, 1 0 0  m g a n d 2 4 0  m g BI D, i n healt h y a d ult s u bjects. Eli gi ble s u bjects were 
1 8 -5 5 years of a ge, wit h a b o d y mass i n de x bet wee n 1 8 -3 0 k g/ m 2 a n d a mi ni m u m wei g ht of 5 0 k g. 
S u bjects were orall y d os e d BI D, f or 1 4 d a ys, or matc hi n g place b o ca ps ul es. 4 s u bjects recei ve d 
A R D -1 0 1 a n d 2 s u bjects recei ve d pla ce b o i n eac h d ose le vel.  Fr o m Da y 1 t o Da y 1 4, t he st u d y 
me dicati o n was a d mi nistere d t wic e dail y (e v er y 1 2 h) wit h a p pr o xi matel y 1 2 h bet wee n d os es.  
P K res ults are liste d i n T a ble 5 . 
T he ge o metri c mea n ( o n Da y 1 4) a n d hi g hest i n di vi d ual s yste mic e x p os ure ( o n Da y 1), b ase d o n 
C ma x , re prese nte d 1. 1 4 % a n d 2. 5 5 % of P K st o p pi n g criteria, res p ecti vel y, at t he 2 4 0 m g BI D d ose 
le vel.  
Acc u m ulati o n after BI D d osi n g f or 1 4 da ys was 1. 2 0 -f ol d f or Cma x  a n d 1. 6 8 -f ol d f or A U Cta u at 2 4 0 
m g BI D. Stea d y state a p pears t o ha v e bee n reac h e d b y Da y 1 1 at all te ste d d ose le vels. 
 
 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 2 8  of 6 7  
0 9  Ma y  2 0 2 2  
 
T a ble 5  
 Ge o metric 
me a n ( % C V) P K p ar a meters of 
A R D -1 0 1 
BI D o r al d ose 
a d mi nistr ati o n of A R D -1 0 1 f or 1 4 d a ys  
Para meter ( U nits)  
4 0 m g BI D  
1 0 0 m g BI D  
2 4 0 m g BI D  
Da y 1  
Da y 1 4  
Da y 1  
Da y 1 4  
Da y 1  
Da y 1 4  
A U C ta u ( h * n g/ m L) 
2. 3 1 ( 1 8 7. 9)  
5. 5 1 ( 8 3. 5)  
8. 4 8 ( 6 3. 0)  
1 6. 4 ( 5 5. 3)  
2 7. 6 ( 8 0. 3)  
4 6. 3 ( 4 6. 7)  
D A U C ta u ( h * n g/ m L/ m g) 
0. 0 5 7 7  
( 1 8 7. 9) 
0. 1 3 8  
( 8 3. 5) 
0. 0 8 4 8  
( 6 3. 0) 
0. 1 6 4  
( 5 5. 3) 
0. 1 1 5  
( 8 0. 3) 
0. 1 9 3  
( 4 6. 7) 
C ma x  ( n g/ m L) 
0. 5 8 4 ( 2 3 5. 9)  
1. 2 7 ( 1 4 1. 3)  
1. 8 5 ( 8 5. 9)  
3. 0 2 ( 8 6. 1) 
7. 6 4 ( 1 3 5. 9)  
9. 1 3 ( 5 9. 6)  
D C ma x  ( n g/ m L/ m g) 
0. 0 1 4 6 
( 2 3 5. 9) 
0. 0 3 1 7  
( 1 4 1. 3) 
0. 0 1 8 5  
( 8 5. 9) 
0. 0 3 0 2  
( 8 6. 1) 
0. 0 3 1 8  
( 1 3 5. 9) 
0. 0 3 8 0  
( 5 9. 6) 
tma x a ( h) 
1. 5 0  
( 0. 5 0 –  4. 0 0)  
1. 7 5  
( 1. 0 8 –  4. 0 0)  
1. 5 0  
( 1. 0 8 –  2. 0 0)  
1. 0 8  
( 0. 5 0 –  4. 0 0)  
1. 7 5  
( 1. 1 5 –  3. 0 0)  
1. 0 8  
( 0. 5 0 –  2. 0 0)  
C tr o u g h ( n g/ m L) 
N C  
0. 1 4 7 ( 5 1. 5)  
0. 1 8 3 ( 6 9. 3)  
0. 4 8 1 ( 3 7. 9)  
0. 4 1 5 ( 7 6. 0)  
1. 2 1 ( 2 5. 8)  
C mi n  ( n g/ m L) 
N A  
0. 1 1 9 ( 3 3. 9)  
N A  
0. 4 1 9 ( 2 5. 1)  
N A  
1. 2 1 ( 2 6. 1)  
C a v g ( n g/ m L) 
N A  
0. 4 5 9 ( 8 3. 5)  
N A  
1. 3 7 ( 5 5. 3)  
N A  
3. 8 6 ( 4 6. 7)  
C L ss/ F ( L/ h) 
N A  
7 2 6 0 ( 8 3. 5)  
N A  
6 0 9 0 ( 5 5. 3)  
N A  
5 1 8 0 ( 4 6. 7)  
R acc, Cma x  
N A  
2. 1 7 ( 4 9 5. 5)  
N A  
1. 6 6 ( 1 2 9. 3)  
N A  
1. 2 0 ( 5 0. 1)  
R acc, A U Cta u 
N A  
2. 3 9 ( 6 9. 2)  
N A  
2. 0 2 ( 6 1. 5)  
N A  
1. 6 8 ( 2 6. 9)  
R acc, Ctr o u g h 
N A  
2. 0 4 ( 2 1. 5)  
N A  
2. 8 9 ( 5 1. 9)  
N A  
2. 9 1 ( 4 5. 9)  
a Me dia n ( mi n -ma x) prese nte d ; N C, n ot calc ulate d 
 
2. 4. 2.  
O ver vie w of Cli nic al Effic ac y  
A t t he ti me of t he s u b missi o n of t his I N D, n o cli nical st u d y has bee n c o n d u cte d t o i n vesti gate t he 
effic ac y of A R D -1 0 1.  
2. 4. 3.  
O ver vie w of Cli nic al S afet y  
Cli nical safet y is base d o n , t hree d ose c o h orts of t he S A D part a n d t hr ee d ose c o h ort s of t he 
M A D part .  
I n t he S A D part of t h e st u d y, A R D-1 0 1 was w ell -t olerate d b y s u bjects after si n gle a d mi nistrati o n 
of t he t hree assi g ne d d os es ( 4 0, 1 0 0, a n d 2 4 0 m g). N o a d verse effects ( A Es) were re p orte d f or 
a n y s u bject i n t he t hree d osi n g c o h orts.  
A R D -1 0 1 was als o w ell -t olerate d b y s u bjects f or 1 4-da y re peat e d a d mi nistrati o n at 4 0 m g, 1 0 0 m g 
a n d 2 4 0 m g BI D. Treat me nt -e mer g e nt A Es t hat were j u d g e d as treat me nt relat e d b y t he 
i n vesti gat or were restrict e d t o Gra de 1 or 2, a n d were e x peri e nce d b y a t otal of 6 s u bjects o ut of 
1 3 d ose d wit h A R D -1 0 1 ( 4 6. 2 %) ( Ta ble 6 ). T hes e c o nsiste d of gastr oi ntesti nal dis or ders ( 3 cases), 
ner v o us s yste m dis or ders ( 3 cases), s ki n a n d s u bc uta ne o us dis or ders ( 2 cases), a n d car diac 
dis or ders ( 1 case) ( Ta ble 7 ). T w o  cases of s ki n restricte d h y perse nsiti vit y ( urticaria) occ urre d  at 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 2 9  of 6 7  
0 9  Ma y  2 0 2 2  
 
1 0 0 m g BI D a n d 2 4 0 m g BI D, res pecti vel y. T h e latter h y perse nsiti vit y was s uccessf ull y a d dresse d 
wit h pre me dicati o n of oral a nti hista mi ne d osi n g as per pr ot oc ol; w hile t he s u bject e x peri e nci n g 
Gra de 1 h y pers e nsiti vit y at t he i nter me diate 1 0 0 m g BI D d ose was disc o nti n ue d base d o n 
i n vesti gat or’s decisi o n a n d re place d. Gastr oi ntesti nal  s y m pt o ms us uall y occ urre d, if s o, earl y o n 
a n d were self -li miti n g. O ne case of p al pitati o ns was re p orte d lasti n g f or a b o ut 3 h. A n E C G 
perf or me d d uri n g t hat e pis o de s h o we d n or mal si n us rh yt h m at 8 3 b p m wit h n o c ha n ges fr o m 
baseli ne . 
T a ble 6  
S u m m ar y of Tre at me nt -e mer ge nt A d verse E ve nts - M A D P art  
 
 
 
 
Place b o ( BI D)  
( N = 6) 
n S ( %) [ n E]  
4 0 m g A R D -1 0 1 
( BI D) 
( N = 4) 
n S ( %) [ n E]  
1 0 0 m g A R D -1 0 1 
( BI D) 
( N = 5) 
n S ( %) [ n E]  
2 4 0 m g A R D -1 0 1 
( BI D) 
( N = 4) 
n S ( %) [ n E]  
O verall  
( N = 1 9) 
n S ( %) [ n E]  
 
T E A Es  
O verall  
3 ( 5 0. 0 %) [ 5]  
1 ( 2 5. 0 %) [ 5]  
3 ( 6 0. 0 %) [ 5]  
3 ( 7 5. 0 %) [ 6]  
1 0 ( 5 2. 6 %) [ 2 1]  
Seri o us  
--- 
--- 
--- 
--- 
--- 
Lea di n g t o Disc o nti n uati o n  
--- 
--- 
1 ( 2 0. 0 %) [ 1]  
--- 
1 ( 5. 3 %) [ 1]  
Lea di n g t o Deat h  
--- 
--- 
--- 
--- 
--- 
Se verit y  
--- 
--- 
--- 
--- 
--- 
Gra de 1  
3 ( 5 0. 0 %) [ 5] 
1 ( 2 5. 0 %) [ 5]  
2 ( 4 0. 0 %) [ 3]  
2 ( 5 0. 0 %) [ 5]  
8 ( 4 2. 1 %) [ 1 8]  
Gra de 2  
--- 
--- 
2 ( 4 0. 0 %) [ 2]  
1 ( 2 5. 0 %) [ 1]  
3 ( 1 5. 8 %) [ 3]  
Gra de 3  
--- 
--- 
--- 
--- 
--- 
Gra de 4  
--- 
--- 
--- 
--- 
--- 
 
Treat me nt -relate d T E A Es  
O verall  
1 ( 1 6. 7 %) [ 2]  
1 ( 2 5. 0 %) [ 4]  
2 ( 4 0. 0 %) [ 4] 
3 ( 7 5. 0 %) [ 6]  
7 ( 3 6. 8 %) [ 1 6]  
Seri o us  
--- 
--- 
--- 
--- 
--- 
Lea di n g t o Disc o nti n uati o n  
--- 
--- 
1 ( 2 0. 0 %) [ 1]  
--- 
1 ( 5. 3 %) [ 1]  
Lea di n g t o Deat h  
--- 
--- 
--- 
--- 
--- 
Se verit y  
--- 
--- 
--- 
--- 
--- 
Gra de 1  
1 ( 1 6. 7 %) [ 2]  
1 ( 2 5. 0 %) [ 4]  
1 ( 2 0. 0 %) [ 2] 
2 ( 5 0. 0 %) [ 5]  
5 ( 2 6. 3 %) [ 1 3]  
Gra de 2  
--- 
--- 
2 ( 4 0. 0 %) [ 2]  
1 ( 2 5. 0 %) [ 1]  
3 ( 1 5. 8 %) [ 3]  
Gra de 3  
--- 
--- 
--- 
--- 
--- 
Gra de 4  
--- 
--- 
--- 
--- 
--- 
 
BI D  =  t wice dail y;  n E  =  n u m ber  of  a d verse e ve nts;  n S  =  n u m ber  of  s u bjects wit h  a n a d verse  e ve nt; N  =  n u m ber  of  s u bjects; %  =  perce nta ge  of  s u
bjects  wit h  a n  a d verse e ve nt ( n S/ N × 1 0 0) 
Se verit y  gra des:  1  =  mil d;  2  =  m o derate;  3  =  se vere; 4  =  p ote ntiall y  life-threate ni n g  
A d verse  e ve nts were  assi g ne d se verit y gra de  usi n g  t he T o xicit y  Gra di n g  Scale  f or Healt h y  A d ult  a n d  A d olesce nt  V ol u nteers  E nr olle d  i n Pre ve nti
v e  Vacci ne  Cli nical  Trials  Versi o n  Se pte m ber  2 0 0 7.  
A  treat me nt-
e mer ge nt  a d verse  e ve nt  ( T E A E) was  defi ne d  as a n a d verse  e ve nt  t hat starte d d uri n g  or  after t he first d ose,  or  starte d pri or  t o t he first d ose  a n d i ncr
ease d  i n se verit y after t he first d ose.  
A  treat me nt-relate d T E A E  was  defi ne d  as a T E A E  wit h  a relati o ns hi p of  relate d t o t he st u d y treat me nt, as de ter mi ne d b y  t he i n vesti gat or. 
W here  a s u bject e x perie nce d  m ulti ple  T E A Es  wit h  t he sa me preferre d  ter m f or t he sa me treat me nt, t his was  c o u nte d  as 1  T E A E  f or t hat treat me nt
 u n der  t he ma xi m u m  se verit y rec or de d. 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 3 0  of 6 7  
0 9  Ma y  2 0 2 2  
 
T a ble 7  
S u m m ar y of Tre at me nt -rel ate d 
Tre at me nt -e mer ge nt 
A d verse 
E v e ns b y 
S yste m Or g a n Cl ass a n d Preferre d Ter m - M A D P art  
 
2. 4. 4.  
Be nefits a n d Ris ks C o ncl usi o ns  
Acc or di n g t o o ur n o n cli nical st u dies, cli nical data, a n d re p ort e d cli nical st u dies o n de nat o ni u m 
be nz oate, A R D -1 0 1 has de m o nstrate d a well -t olerate d safet y pr ofile a n d p ote ntial cli nical be nefit 
i n t he treat me nt of o besit y. T his safet y pr ofile s u p p orts t he use of t he d ose a n d d osi n g re gi me n t o 
be use d i n t he P hase 2 tri al i n o ver wei g ht patie nts wit h wei g ht re gai n  or ot h er wise u nsatisfact or y 
wei g ht ma na ge me nt  after slee ve-g astrect o m y  or b y pass s ur ger y . 
 
S yste m Or ga n Class  
  Preferre d Ter m  
Place b o ( BI D)  
( N = 6) 
n S ( %)  
4 0 m g A R D -1 0 1 
( BI D) 
( N = 4) 
n S ( %)  
1 0 0 m g A R D -1 0 1 
( BI D) 
( N = 5) 
n S ( %)  
2 4 0 m g A R D -1 0 1 
( BI D) 
( N = 4) 
n S ( %)  
O verall  
( N = 1 9) 
n S ( %)  
 
O verall  
1 ( 1 6. 7 %)  
1 ( 2 5. 0 %)  
2 ( 4 0. 0 %)  
3 ( 7 5. 0 %)  
7 ( 3 6. 8 %)  
 
Gastr oi ntesti nal dis or ders  
1 ( 1 6. 7 %)  
1 ( 2 5. 0 %)  
1 ( 2 0. 0 %)  
1 ( 2 5. 0 %)  
4 ( 2 1. 1 %)  
  Diarr h oea  
--- 
--- 
1 ( 2 0. 0 %)  
1 ( 2 5. 0 %)  
2 ( 1 0. 5 %)  
  D ys pe psia  
--- 
1 ( 2 5. 0 %)  
--- 
1 ( 2 5. 0 %)  
2 ( 1 0. 5 %)  
  Na usea  
--- 
1 ( 2 5. 0 %)  
1 ( 2 0. 0 %)  
--- 
2 ( 1 0. 5 %)  
  A b d o mi nal diste nsi o n  
--- 
1 ( 2 5. 0 %)  
--- 
--- 
1 ( 5. 3 %)  
  A b d o mi nal pai n  
--- 
--- 
1 ( 2 0. 0 %)  
--- 
1 ( 5. 3 %)  
  Flat ule nce  
1 ( 1 6. 7 %)  
--- 
--- 
--- 
1 ( 5. 3 %)  
 
Ner v o us s yste m dis or ders  
1 ( 1 6. 7 %)  
1 ( 2 5. 0 %)  
--- 
2 ( 5 0. 0 %)  
4 ( 2 1. 1 %)  
  Hea dac he  
1 ( 1 6. 7 %)  
1 ( 2 5. 0 %)  
--- 
--- 
2 ( 1 0. 5 %)  
  Dizzi ness  
--- 
--- 
--- 
1 ( 2 5. 0 %)  
1 ( 5. 3 %)  
  D ys ge usia  
--- 
--- 
--- 
1 ( 2 5. 0 %)  
1 ( 5. 3 %)  
 
S ki n a n d s u bc uta ne o us tiss ue 
dis or ders  
--- 
--- 
1 ( 2 0. 0 %)  
1 ( 2 5. 0 %)  
2 ( 1 0. 5 %)  
  Urticaria  
--- 
--- 
1 ( 2 0. 0 %)  
1 ( 2 5. 0 %)  
2 ( 1 0. 5 %)  
 
Car diac dis or ders  
--- 
--- 
--- 
1 ( 2 5. 0 %)  
1 ( 5. 3 %)  
  Pal pitati o ns  
--- 
--- 
--- 
1 ( 2 5. 0 %)  
1 ( 5. 3 %)  
 
BI D  =  t wice dail y;  n S  =  n u m ber  of  s u bjects wit h  a n  a d verse e ve nt;  N  =  n u m ber  of  s u bjects; %  =  perce nta ge  of  s u bjects wit h  a n a d verse  e ve nt  ( n S/
N × 1 0 0)  
A d verse  e ve nts were  c o de d  usi n g  t he Me dical  Dicti o nar y  f or Re g ulat or y  Acti vities  ( Me d D R A) Versi o n  2 3. 0.  
A  treat me nt-
e mer ge nt  a d verse  e ve nt  ( T E A E) was  defi ne d  as a n a d verse  e ve nt  t hat starte d d uri n g  or  after t he first d ose,  or  starte d pri or  t o t he first d ose  a n d i ncr
ease d  i n se verit y after t he first d ose.  
A  treat me nt-relate d T E A E  was  defi ne d  as a T E A E  wit h  a relati o ns hi p of  relate d t o t he st u d y treat me nt, as deter mi ne d  b y  t he i n vesti gat or. 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 3 1  of 6 7  
0 9  Ma y  2 0 2 2  
 
3.  
S T U D Y E N D P OI N T S  
Pri m ar y E n d p oi nt : 
3. 1.  
Pri m ar y E n d p oi nt  
•  T he perce nt t otal wei g ht c ha n ge at t he e n d of tr eat me nt fr o m baseli ne  
3. 2.  
Sec o n d ar y E n d p oi nts:  
•  Safet y of A R D -1 0 1 b y assess me nt of t he i nci de nce of T E A E 
•  T he c ha n g e i n bl o o d li pi d c o nce ntr ati o ns (t otal c h olester ol, tri gl yceri d e, hi g h de nsit y 
li p o pr otei n c h olester ol, a n d l o w-de nsit y li p o pr otei n c h olester ol) at t he e n d of treat me nt 
fr o m t he baseli ne 
•  T he c ha n ge i n waist circ u mfere n ce at t he e n d of treat me nt fr o m t he baseli ne as well as 
1 4  da ys after e n d of tr eat me nt  
•  T he c ha n g e i n H b A 1c at t he e n d of treat me nt fr o m t he baseli ne  
3. 3.  
E x pl or at or y E n d p oi nts:  
•  Cate g orical wei g ht l oss. Pr o p orti o n of s u bjects w h o l ose < 5 % a n d ≥ 5 % of i nitial 
wei g ht  
•  Fasti n g circ ulati n g le vels of G L P -1 (t otal a n d acti ve), C C K, P Y Y, a m yli n, GI P (t otal 
a n d acti ve), g hreli n, le pti n, a n d a di p o necti n bef ore t he first d osi n g, a n d at 1 h a n d 2 h 
after t he first d osi n g o n da y  1  
•  C ha n ges i n res p o nse t o t he M M T T, i ncl u di n g : 
▪ Ser u m le vels of gl uc ose, i ns uli n, a n d C -pe pti de pri or t o ( ne gati ve ti me p oi nts) 
a n d p ost ( p ositi ve ti me p oi nts) t he E ns ure meal gi v e n f or M M T T at b aseli ne 
(r u n-i n visit) a n d o n da y 28  
▪ Ser u m le vel of F F A pri or t o ( ne gati ve ti me p oi nts) a n d p ost ( p ositi ve ti me p oi nts) 
t he E ns ure meal gi ve n f or M M T T at baseli ne (r u n-i n visit) a n d o n da y 2 8  
▪ Circ ulati n g le vels of G L P -1 (t otal a n d acti ve), C C K, P Y Y, a m yli n, GI P (t otal 
a n d acti ve), gl u ca g o n, a n d g hreli n pri or t o ( ne g ati ve ti me p oi nts) a n d p ost 
( p ositi ve ti me p oi nts) t he E ns ure meal gi ve n f or M M T T at baseli ne (r u n -i n visit) 
a n d o n da y  2 8  
▪ Circ ulati n g  c yt o ki nes a n d i nfla m mat or y mar kers s uc h as C R P at r u n -i n visit a n d 
e n d of treat me nt ( da y 2 8) perf or me d d uri n g t he M M T T  
▪ Circ ulati n g le vels of bile aci ds, ferriti n, le pti n, a n d a di p o necti n at r u n -i n visit 
a n d e n d of tr eat me nt ( da y 2 8) perf or me d d uri n g t he M M T T  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 3 2  of 6 7  
0 9  Ma y  2 0 2 2  
 
•  B o d y c o m p ositi o n as meas ure d b y bi oelectrical i m pe da nce s cale  
•  B o d y c o m p ositi o n a n d he patic steat osis b y M RI-P D F F + f ull b o d y c o m p ositi o n sca n 
pretreat me nt a n d e n d of treat me nt  
•  T he c ha n g e i n H O M A -I R at t he e n d of treat me nt fr o m t he baseli ne   
•  T he c ha n g e i n fasti n g bl o o d gl uc ose at t he e n d of treat me nt fr o m t he b aseli ne  
•  H u n ger a n d c o ntr ol of eati n g as meas ure d b y Li kert a n d vis ual a nal o g ue scales, 
res pecti vel y 
•  C ha n ge i n i n direct c al ori metr y 
•  T he fecal sa m ples will be c ollecte d d uri n g t h e r u n -i n visit a n d o n da y 2 8 f or 
micr o bi o me a nal ysis t o e val uate p ote ntial effects of t he st u d y me dicati o n o n fecal 
micr o bi o me pr ofile ( o pti o nal f or s u bjects ) 
•  P he n ot y pic bitter taste test ( u si n g c o m merci all y a v aila ble test stri ps/ kis) d uri n g t he r u n-
i n visit of t he st u d y ( o pti o nal f or s u bjects) 
Alrea d y c ollecte d bl o o d a n d fecal s a m ples ma y als o be st ore d a n d us e d f or p ossi ble retr os pecti ve 
e x pl orat or y a nal ysis w hic h ma y i ncl u de, b ut will n ot be li mite d t o, u n dersta n di n g mec ha nis ms of 
res p o nse t o treat me nt ( w here res p o nse is defi ne d br oa dl y t o i ncl u de bi o mar ker c h a n ge, t olera bilit y 
or safet y) a n d i de ntificati o n of ot her mec h a nis ms of t hera p y.  
 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 3 3  of 6 7  
0 9  Ma y  2 0 2 2  
 
4.  
S T U D Y D E SI G N  
4. 1.  
O ver vie w  
T his is a P hase 2, o pe n la bel st u d y of A R D -1 0 1 i n s u bjects wit h u nsatisfact or y wei g ht ma na ge me nt 
at least o ne year after bariatric s ur ger y (slee v e gastrect o m y or gastric b y pass).  
T his st u d y has a pla n ne d e nr oll me nt of 3 0  s u bjects (a p pr o xi matel y 1 5 f or each prece di n g  s ur gical 
pr oce d ure)  a n d will be c o n d ucte d i n a si n gle ce nt er i n t he U nite d States . 
T he s t u d y will c o nsist of a Scree ni n g Peri o d ( u p t o 2 8  da ys),  a R u n-i n Visit Peri o d ( u p t o 1 4 da ys), 
a Treat me nt Peri o d  ( 2 8 d a ys), a n d a F oll o w-u p Peri o d ( E O S  Vi sit wit hi n 1 4 da ys  after recei vi n g 
t he last d ose of A R D -1 0 1) . T he  scree ni n g pr oce d ures will be i nitiate d  u p o n c o m pleti o n of t h e 
i nf or me d c o ns e nt pr ocess. F oll o wi n g c o m pleti o n of scree ni n g pr oce d ures  a n d c o nfir mati o n of 
eli gi bilit y, s u bjects will be e nr olle d t o r ecei ve A R D -1 0 1.  
A R D -1 0 1 will be a d mi nistere d orall y u n der fasti n g c o n diti o ns (a p pr o xi mat el y 6 0 mi n utes bef ore  
brea kfast a n d a p pr o xi mat el y 6 0 mi n utes bef ore  di n ner)  at 2 0 0  m g BI D f or 2 8 da ys. S u bjects will 
recei v e treat me nt i n a n o ut patie nt setti n g a n d will be i nstr ucte d t o visit t he cli nical ce nter 
peri o dicall y as sc h e d ule d i n Ta ble  1  f or s afet y a n d effi cac y assess me nts. T he tr eat me nt m a y be 
disc o nti n ue d d ue t o i nt ol era ble t o xicit y, wit h dra wal of i nf or me d c o nse nt, discreti o n of pri nci pal 
i n vesti gat or or e n d of t he st u d y.  
All a vaila ble safet y a n d t olera bilit y data 
will be e val uate d t hr o u g h o ut st u d y c o n d uct. 
P har mac o d y na mic d ata will be a nal yze d after st u d y c o m pleti o n.  
4. 2.  
J ustific ati o n f or D ose  
T he d ose of 2 0 0  m g BI D was c h ose n b ase d o n t he a vai la ble n o ncli nical st u dies a n d cli nical data. 
As descri be d a b o v e, t his d ose has bee n f o u n d safe i n t he first -i n-h u ma n trial a n d t he 
p har mac o ki netics s u p p ort t he prescri be d d os e le vel a n d d urati o n.  
4. 3.  
St u d y D ur ati o n  
T he d urati o n of partici pati o n f or eac h s u bject will be u p t o a p pr o xi matel y 8 4  da ys  (1 2  wee ks ). 
•  S cree ni n g P eri o d: U p t o 2 8  da ys  (4  wee ks)  
•  R u n -i n Visit: U p t o 1 4 da ys ( 2 wee ks) 
•  Treat me nt P eri o d: 2 8  da ys  o n A R D -1 0 1  


Aar d var k T hera pe utics, I nc.  
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•  F oll o w -u p Peri o d : 1 4 da ys ( 2 wee ks). T h e E O S Visit  will occ ur  wit hi n  1 4  da ys after 
recei vi n g t he d os e of A R D -1 0 1  
4. 4.  
St u d y C o m pleti o n  
F or t he e ntire st u d y, st u d y c o m pleti o n is defi ne d as t he last visit of t he last s u bject f or a n y pr ot oc ol 
relate d acti vit y (last s u bject, last visit). F or i n di vi d ual 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 s u bject’s last data c ollecti o n. 
4. 5.  
E arl y Ter mi n ati o n  
If a s u bject wit h dra ws pre mat urel y aft er d osi n g, all data n or mall y c ollecte d s h o ul d be c ollecte d at 
t he ti me of pre mat ure disc o nti n uati o n. If dee me d necess ar y b y t he Pri n ci pal I n vesti gat or, t he 
s u bject will be as ke d t o r et ur n at t he re g ularl y sc h e d ule d E O S Visit.  


Aar d var k T hera pe utics, I nc.  
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C O N FI D E N TI A L  
 
 
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5.  
S T U D Y P O P U L A TI O N  
T he st u d y p o p ulati o n will c o nsist of male a n d fe male s u bjects at least o ne year after slee v e 
gastrect o m y  or gastri c b y pass sur ger y ). S u bjects m ust be a ble t o pr o vi de writte n i nf or me d c o nse nt 
a n d meet all t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria.  
5. 1.  
N u m ber of S u bjects  
A t otal of a p pr o xi matel y 3 0  s u bjects will be e nr olle d i n t he cli nical st u d y.  
If a n y assess me nts f or i ncl usi o n or e xcl usi o n criteria are o ut of p er missi ble ra n ges d uri n g t he 
Scree ni n g Peri o d , re peat assess me nts ma y be all o we d f or t h ose s u bjects at Pri nci pal I n vesti gat or ’s 
discreti o n.  
5. 2.  
I ncl usi o n Criteri a 
S u bjects m ust meet all  t he f oll o wi n g criteria t o b e eli gi ble f or partici pati o n i n t his st u d y: 
1.  Male a n d fe male s u bjects, 1 8 -7 5  years of a ge  
2.  Willi n g a n d a ble t o pr o vi de si g ne d a n d date d i nf or me d c o nse nt pri or t o a n y st u d y -relate d 
pr oce d ures a n d willi n g a n d a ble t o c o m pl y wit h al l st u d y pr oce d ures 
3.  B o d y Mass I n d e x ( B MI) of ≥ 3 5 - 6 0 k g/ m 2 d uri n g t he Scree ni n g Peri o d  
4.  Stat us of at least 1 -year p ost slee ve gastrect o m y or gastric b y pass s ur ger y  
5.  O ne of t he f oll o wi n g:  
o  Wei g ht l oss of at least 5 0 % of t heir e x cess w ei g ht at t heir na dir, a n d wei g ht re gai n 
at least 2 0 % of t heir na dir wei g ht l oss. E xcess wei g ht is defi ne d as ma xi m u m 
pre o perati ve wei g ht –  wei g ht c orres p o n di n g t o B MI 2 5 k g/ m 2  
o  E xcess wei g ht l oss less t ha n 5 0 % at t he s u bject’s na dir wei g ht  
6.  S u bjects wit h resc ue s ur g er y (e. g. g astric ba n d t o slee ve gastr ect o m y or gastric b y pass; slee ve 
gastrect o m y t o gastric b y pass) will be all o we d, wit h ti me si nce sec o n d s ur ger y of at least 1 2 
m o nt hs  
7.  S u bjects wit h a hist or y of re visi o n pr oce d ures will be all o we d if at least 6 m o nt hs ha ve pa sse d 
si nce t he pr oce d ure a n d wei g ht h as n ot de viate d m ore t ha n 5 % i n t he 3 m o nt hs pri or t o 
e nr oll me nt  
8.  N o a b n or mal fi n di n gs or a b n or malities of cli nical si g nifica nce i n vital si g ns, p h ysical 
e xa mi nati o n, cli nical la b orat or y tests ( C B C, uri nal ysis, bl o o d bi o c he mistr y, c oa g ulati o n, 


Aar d var k T hera pe utics, I nc.  
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pre g na nc y test (fe males), uri ne dr u g test, nic oti ne test, etc.), 1 2 -lea d el ectr ocar di o gra m ( E C G) 
d uri n g t he Scree ni n g Peri o d  
9.  Ser u m creati ni ne, al kali n e p h os p hatase, h e patic e n z y mes (as p artate a mi n otra nsferase, al a ni ne 
a mi n otra nsfer ase) a n d t otal bilir u bi n ( u nless t he s u bject has d oc u me nte d Gil bert s y n dr o me) 
n ot e xcee di n g 1. 5 -f ol d t he u p per la b orat or y n or m a n d e G F R > 3 0 m L/ mi n 
1 0.  Sta n dar d 1 2 -lea d E C G p ara meters after 1 0 mi n utes resti n g i n s u pi ne p ositi o n i n t he f oll o wi n g 
ra n ges; 1 2 0 ms < PR < 2 2 0 ms, Q R S < 1 2 0 ms, Q Tc  < = 4 3 0 ms if male, < = 4 5 0 ms if fe male 
a n d n or mal E C G tr aci n g u nless t he I n v esti gat or c o nsi ders a n E C G a b n or malit y wit hi n 
descri be d li mits t o be n ot cli nicall y rele va nt  
1 1.  Sta ble or well c o ntr olle d bl o o d press ure p er I n v esti gat or’s  j u d ge me nt d uri n g t he Scree ni n g 
Peri o d. S pecificall y: Vital si g ns after 1 0 mi n ut es sitti n g i n a c h air (feet o n fl o or, bac k 
s u p p orte d): 
i. 9 5 m m H g < S B P < 1 6 0 m m H g,  
ii. 4 5 m m H g < D B P < 1 0 0 m m H g,  
iii. 4 0 b p m < H R < 1 0 0 b p m.  
1 2.  H b A 1c <  9. 0 % at scree ni n g.   
1 3.  Patie n ts wit h t y pe 2 dia betes treate d wit h metf or mi n ma y be e nr olle d.  H o we ver, patie nts wit h 
t y pe 2 dia betes o n a n y ot her t hera p y will be e xcl u de d.   
1 4.  Fe male s u bjects m ust ha v e ne gati ve pre g n a nc y test a n d m ust n ot be lactati n g. F or fe males a ble 
t o bear c hil dre n, a h or m o nal (i.e., oral, i m pla nta ble, or i njecta ble) a n d si n gle barrier m et h o d 
(i.e., s p o n ge), or a d o u bl e-barrier met h o d of birt h c o ntr ol (i.e., c o n d o m wit h s per mici de) or 
a bsti ne nce m ust be use d/ practice d t hr o u g h o ut t he st u d y a n d f or 9 0 da ys f oll o wi n g la st d ose of 
st u d y me dicati o n; f or effecti ve f or m of birt h c o ntr ol. 
1 5.  Fe males of n o n -c hil d beari n g p ote ntial, defi n e d as s ur gicall y sterile (stat us p ost h ysterect o m y, 
bilateral o o p h orect o m y, bilateral t u bal li gati o n, bilateral sal pi n gect o m y, or bilateral t u bal 
occl usi o n) or p ost -me n o p a usal f or at least 1 2 m o nt hs ( ma y be c o nfir me d wit h a scree ni n g F S H 
le vel i n t he p ost-me n o pa usal la b ra n ge), d o n ot re q uire c o ntrace pti o n d uri n g t he st u d y.  
1 6.  Males wit h fe male part n ers of c hil d beari n g p ote nti al m ust a gree t o a d o u ble -barrier met h o d if 
t he y bec o me s e x uall y acti ve d uri n g t he st u d y a n d f or 9 0 da ys f oll o wi n g t he last d ose of t he 
st u d y 
me dicati o n. 
Male s u bjects 
m ust n ot d o nate s per m f or 9 0 da ys f oll o wi n g t heir 
partici pati o n i n t he st u d y.  


Aar d var k T hera pe utics, I nc.  
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5. 3.  
E xcl usi o n Criteri a  
S u bjects w h o meet  a n y of t he f oll o wi n g criteri a will be e xcl u de d fr o m st u d y partici pati o n:  
1.  A n y rele va nt g astr oi ntesti nal ( GI) s ur ger y (e xcl u di n g t he gastric b y pass or sl ee ve gastrect o m y) 
per I n vesti gat or j u d g e me nt  
2.  Hist or y of si g nifica nt dr u g h y perse nsiti vit y or a na p h yla xi s 
3.  Partici pati o n i n a wei g ht l oss pr o gra m or cli nical tri al f or wei g ht l oss wit hi n t he 3 m o nt hs pri or 
t o e nr oll me nt 
4.  Recei ve d a n y e x p eri me nt al dr u gs or de vices or ha ve partici pate d i n a cli nical st u d y wit hi n 3 0 
da ys pri or t o e nr oll me nt  
5.  Dia betes treat me nt ( u nless metf or mi n as o utli ne d), or c hr o nic oral ster oi ds, or treat me nt wit h 
i m m u ne m o d ulat ors, a nti-o besit y dr u gs, c hr o nic o piate t hera p y, or a nti ps yc h otic me dicati o ns  
6.  C urre ntl y recei vi n g a n y dr u g -base d t h era p y f or wei g ht ma na ge me nt    
7.  T h yr oi d -sti m ulati n g h or m o ne ( T S H) le vel is o utsi de of n or mal li mit d uri n g t he Scree ni n g 
Peri o d  
8.  T he pres e nce of dis eases wit h a b n or mal cli nical ma nifestati o ns t hat nee d t o be e xcl u d e d bas e d 
o n t heir p ossi ble c o ntri b uti o n t o wei g ht l oss or wei g ht gai n, i ncl u di n g b ut n ot li mite d t o 
ner v o us, car di o vasc ul ar, bl o o d a n d l y m p hatic s yste m, i m m u ne, re nal, h e patic, gastr oi ntesti nal, 
res pirat or y, met a b olic a n d s keletal diseases d uri n g t he Scree ni n g Peri o d 
9.  Hist or y of m y oc ar dial i nf arcti o n, u nsta ble a n gi na, arterial re v asc ulari zat i o n, str o ke, Ne w Y or k 
Heart Ass oci ati o n F u ncti o nal Class II -I V heart fail ure, or tra nsie nt isc he mic attac k wit hi n 6 
m o nt hs pri or t o Visit 1  
1 0.  A n y mali g na nc y n ot c o nsi dere d c ure d (e xce pt f ocal, treate d bas al cell carci n o ma a n d s q ua m o us 
cell carci n o ma of t he s ki n); a partici pa nt is c o nsi dere d c ure d if t here has bee n n o e vi de nce of 
ca ncer rec urre nce i n t he pre vi o us 5 years  
1 1.  Hist or y of maj or de pressi ve dis or der or hist or y of ot her s e vere ps yc hi atric dis or ders (e. g., 
sc hiz o p hre nia or bi p olar dis or der) wit hi n t he last 2 years. 
1 2.  D o nate d ≥2 0 0 m L of bl o o d ( bl o o d c o m p o ne nts) or ha d massi ve bl o o d l oss, recei v e d bl o o d 
tra nsf usi o n or bl o o d pr o d ucts wit hi n 3 m o nt hs pri or t o e nr oll me nt 
1 3.  Pla n ne d s per m/e g g d o nati o n wit hi n 6 m o nt hs p ost e nr oll me nt  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 3 8  of 6 7  
0 9  Ma y  2 0 2 2  
 
1 4.  P ositi ve uri ne dr u g test ( m or p hi n e, met ha m p heta mi ne, keta mi ne, ecstas y, a n d ca n n a bis) d uri n g 
t he Scree ni n g Peri o d 
1 5.  Hist or y of c o ns u mi n g m ore t ha n 1 4 u nits of alc o h olic be vera ges p er wee k or of alc o h olis m or 
dr u g/c he mical/s u bsta nce a b use wit hi n past 2 years pri or t o e nr oll me nt ( N ote: o ne u n it = 1 2 
o u nces of beer, 4 o u n ces of wi ne or 1 o u nce of s pirits)  
1 6.  S m o ki n g a n y a m o u nt wit hi n 3 m o nt hs pri or t o e nr oll me nt  
1 7.  E xcessi ve c o ns u m pti o n of tea, c offee , a n d/ or caffei nate d be v era g es ( m ore t h a n 8 c u ps, 2 5 0 m L 
f or eac h c u p) e ver y da y wit hi n 3 m o nt hs prior t o e nr oll me nt  
1 8.  S y m pt o matic viral, bacterial (i ncl u di n g u p per res pirat or y i nfecti o n), or f u n gal ( n o n -c ut a ne o us) 
i nfecti o n wit hi n 1 wee k pri or t o e nr oll me nt 
1 9.  Hist or y of h u ma n i m m u n o deficie nc y vir us a nti b o d y, he patitis C a nti b o d y or he patitis B vir us 
s urface a nti ge n  
2 0.  A hist or y of ps yc hiatric a n d ps yc h ol o gical c o n diti o n t hat, i n t he j u d g me nt of t he i n vesti gat or, 
ma y i nterfere wit h t he pla n ne d treat me nt a n d f oll o w -u p, affect s u bject c o m plia nce or place t he 
s u bject at hi g h ris k fr o m treat me nt-relate d c o m pli cati o ns 
2 1.  P o or ve n o us access or i n a bilit y t o t olerate ve ni p u nct ure  
2 2.  A n y c o n diti o n or acti ve dr u g treat me nt t hat t he i n vesti gat or or pri mar y p h ysicia n belie v es ma y 
n ot be a p pr o priat e f or p artici pati n g i n t he st u d y  
5. 4.  
Restricti o ns  
5. 4. 1.  
Diet ar y a n d Fl ui d Restricti o ns  
C affei ne  
S u bjects s h o ul d n ot c o ns u me caffei ne c o ntai ni n g be vera g es e x cee di n g 5 0 0  m g caffei ne p er da y 
( 5 c u ps of c offee) d uri n g t he st u d y.  
Alc o h ol  
S u bjects s h o ul d n ot c o ns u me m ore t ha n 3  u nits ( males) or 2  u nits (fe mal es) per da y d uri n g t he 
st u d y ( 1 u nit is e q ual t o a p pr o xi matel y ½ pi nt [ 2 8 4 m L] of beer, o n e s mall glass [ 1 2 5  m L] of wi ne, 
or o ne meas ur e [ 2 5 m L] of s pirits).  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
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5. 4. 2.  
Lifest yle C o nsi der ati o ns  
Dr u gs of a b use  
S u bjects m ust refrai n fr o m use of recreati o nal dr u gs  i ncl u di n g T H C c o ntai ni n g pr o d ucts f or t he 
d urati o n of t he st u d y.  
Nic oti ne  
N o s m o ki n g or use of ot her nic oti ne -c o nt ai ni n g pr o d ucts (s n uff, c he wi n g t o bacc o, ci g ars, pi pes or 
nic oti ne -re pla ce me nt pr o d ucts s uc h as nic oti ne c he wi n g g u m a n d nic oti ne plasters) will be all o we d 
d uri n g t he st u d y . 
 


Aar d var k T hera pe utics, I nc.  
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A A R D -2 0 2  
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6.  
I N V E S TI G A TI O N A L M E DI CI N A L P R O D U C T 
6. 1.  
Pre me dic ati o n  
N o pre -me dicati o n is re q uire d pri or t o a d mi nistrati o n of st u d y m e dicati o n . F or s u bjects w h o 
e x perie n ce 
Gra d e  2 ac ute aller gic reacti o ns a n d are a ble t o  c o nti n ue o n t he treat me nt, 
pre me dicati o n wit h a n H 1 a nti hista mi ne s h o ul d be gi ve n.  
6. 2.  
I de ntit y of t he I n vesti g ati o n al Me dici n al Pr o d ucts 
A R D -1 0 1 dr u g pr o d uct is a n e nca ps ulate d oral f or m ulati o n of de nat o ni u m acetate m o n o h y drat e. 
T he A R D -1 0 1 dr u g pr o d uct will  be s u p plie d as w hite o pa q ue b o d y a n d w hite o pa q ue ca p har d 
gelati n ca ps ules. T he A R D -1 0 1 dr u g pr o d uct c o ntai ns 2 3. 6 1 m g  or 5 9. 0 3 m g  of de nat o ni u m acetat e 
m o n o h y drate (e q ui vale nt as 2 0 m g  or 5 0 m g  of de nat o ni u m base) t o get her wit h p o vi d o ne, s u gar 
s p heres, h y pr o mell ose, a n d talc as i nacti ve i n gr e die nts.  
6. 3.  
S u p pl y, P ac k a gi n g, L a beli n g a n d St or a ge  
St u d y dr u g will be s u p plie d b y S p o ns or . T he st u d y me dicati o n  will be pac ka g e d a n d la bele d 
acc or di n g t o a p plica ble l ocal a n d re g ulat or y re q uire me nts.  
All s u p plies of st u d y me dicati o n  m ust be st ore d i n acc or da nce wit h t he 
ma n ufact urer’s 
i nstr ucti o ns. T he A R D -1 0 1 will be st ore d at r o o m te m perat ur e i n a sec urel y l oc ke d area, accessi ble 
t o a ut h orize d pers o ns o nl y, u ntil dis pe nsati o n. 
F urt her details will be  pr o vi de d i n t he P h ar mac y Ma n ual.  
6. 4.  
Dr u g Acc o u nt a bilit y, Dis pe nsi n g a n d Destr ucti o n  
T he Pri nci pal I n v esti gat or  or desi g nee is res p o nsi ble f or mai ntai ni n g acc urat e acc o u nta bilit y 
rec or ds of t he st u d y dr u g  t hr o u g h o ut t he cli nical st u d y. Pr o d ucts ret ur ne d will be st ore d u n der t he 
sa me c o n diti o ns as pr o d u cts n ot yet dis pe nse d.  
All dis pe nsi n g a n d acc o u nta bilit y rec or ds will be a vaila ble f or S p o ns or re vie w. T he St u d y M o nit or 
will perf or m dr u g acc o u nta bilit y at re g ular i nter vals.  
S t u d y me dicati o n  will be dis pe nse d f or eac h s u bject acc or di n g t o t he pr ot oc ol a n d P har m ac y 
M a n ual. 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
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C O N FI D E N TI A L  
 
 
Pa ge 4 1  of 6 7  
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After recei vi n g S p o ns or a p pr o val i n writi n g, all u n use d or partiall y use d st u d y me dicati o n  will be 
ret ur ne d t o t he S p o ns or or desi g nate d t hir d part y or f or pre pari n g t he st u d y me dicati o n  f or 
destr ucti o n via i nci nerati o n.  
6. 5.  
D ose M o dific ati o n  
T he d ose le vel ma y n ot b e re d uce d. If a n y ≥ Gra d e 3 t o xicities or a n y i nt olera ble Gra de 2 t o xicit y 
occ urs, treat me nt s h o ul d be disc o nti n ue d per ma ne ntl y. I nt olera bl e t o xicit y is defi ne d as, i n t he 
o pi ni o n of Pri nci pal I n vesti gat or a n d M e dical M o nit or, a n y t o xicit y t hat p oses a si g nifica nt h ealt h 
ris k t o t he s u bject. Treat me nt ma y c o nti n ue o n a n y Gra de 1 t o xic reacti o ns or Gra d e 2 a n ore xia or 
Gra de 2 wei g ht l oss. F or a n y ot her Gra d e 2 t o xicities, d osi n g ma y be i nterr u pte d f or u p t o 3 da ys 
a n d ma y be res u me d at t he me dical j u d g me nt  of In vesti gat or o nce t he t o xicit y has res ol ve d t o 
Gra de 0 -1. A misse d d ose s h o ul d n ot be ma de u p. I n t he e v e nt of m ulti ple t o xicit ies, d osi n g 
ma na ge me nt s h o ul d be b ase d o n t he w orst t o xicit y o bser ve d. S u bjects will be i nstr ucte d t o n otif y 
In v esti gat ors at t he first o cc urre nce of a n y a d verse s y m pt o m.  
6. 6.  
St o p pi n g R ules  
At a n y ti me d uri n g t he st u d y, t he s u bject m ust disc o nti n ue st u d y dr u g treat me nt, if o ne of t he 
f oll o wi n g e ve nts occ ur:  
 
•  A n i ncreas e of A S T a n d/ or A L T ( > 3 x U L N) are o bser ve d i n t he prese nce of 
i ncreas e d ( > 2 x U L N) al kali ne p h os p hatase a n d/ or t otal bilir u bi n.  
•  A s ustai ne d A S T or A L T i ncreas e, defi ne d as t hree c o nsec uti ve v al ues of A S T 
a n d/ or A L T greater t h a n 5 x U L N wit hi n a peri o d of 1 4 da ys.  
•  A treat me nt -relate d Gra d e 3 or greater a d verse e v e nt ( ot her t ha n A S T or A L T 
i ncreas e as des cri be d a b o ve) is n ote d by t he I n vesti gat or.  
•  A rele va nt d ecrease of e G F R as per i n vesti gat or  
  
If a n y of t he a b o ve st o p pi n g r ules are met t he f oll o wi n g acti o n(s) s h o ul d b e ta ke n:  
 
1. St o p d osi n g a n d c o n ve ne a Safet y Re vi e w C o m mittee meeti n g;  
2. Re vie w A E f or e vi de n ce of relati o ns hi p t o treat me nt;   
3 . Ma y res u me e nr oll me nt a n d c o nti n ue t he st u d y if rec o m me n d e d b y t he Safet y Re vie w 
C o m mittee.  
 


Aar d var k T hera pe utics, I nc.  
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6. 7.  
S u bject I de ntific ati o n  
6. 7. 1.  
Scree ni n g N u m bers  
All scree ne d s u bjects are assi g ne d a u ni q ue scree ni n g n u m ber. T he scree ni n g n u m bers are n u m bers  
t hat i de ntif y s u bjects fr o m ti me of scree ni n g u ntil ti me of e nr oll me nt .  
6. 7. 2.  
E nr oll me nt  N u m bers  
Eli gi ble s u bjects will be assi g ne d a n e nr oll me nt  n u m ber. T he e nr oll me nt n u m ber  will i ncl u de 6 -
di git site n u m ber a n d s u bject n u m bers starti n g wit h 2 0 1  as bel o w.  
•  S u bject 1 0 0 -2 0 1  
O nce a n e nr oll me nt  n u m ber h as bee n all ocate d t o o ne  s u bject, it ma y n ot be assi g ne d t o a n ot her 
s u bject.  
6. 8.  
C o m pli a nce  
D osi n g will be perf or me d b y trai ne d,  q ualifie d pers o n nel desi g nate d b y t he Pri nci pal I n vesti gat or .  
6. 9.  
S peci al Prec a uti o ns a n d M a n a ge me nt of A Es  
6. 9. 1.  
E ati n g dis or ders  
A R D -1 0 1 ma y decrease a p petite a n d s u bse q ue ntl y c ha n ge a s u bject’s eati n g be ha vi or b y dela yi n g 
gastric e m pt y i n g a n d i n d uci n g t he g l ucag o n -li ke pe pti de-1  a n d ch olec yst o ki ni n  secreti o n i nt o t he 
circ ulati o n t hat tar gets t he ce ntral n er v o us s yst e m ( C N S ) t o ca use satiet y/ h u n ger se ns ati o n. 
S u bjects w h o de vel o p a n y eati n g dis or ders d uri n g st u d y treat me nt s h o ul d be per ma ne ntl y 
disc o nti n ue d fr o m st u d y dr u g. 
6. 9. 2.  
Aller gic re acti o ns  
O ne case of aller gic reacti o n has bee n re p orte d i n a fe male s u bject recei vi n g d e nat o ni u m be nz o ate , 
a c o m p o u n d i n t he sa me class as A R D -1 0 1 (Del o ose E et al. 2 0 1 7 ). Dr u g aller gic reacti o ns ca n b e 
eit her ac ute or del a ye d. T he ac ute aller gic reacti o ns t hat us uall y occ ur wit hi n 1  h aft er dr u g 
e x p os ure are t y picall y I g E me diate d w hile t h ose t hat us uall y occ ur 2  t o 6  h after dr u g e x p os ure 
ha ve m ore c o m plicate d p at h o p h ysi ol o gical mec ha nis ms. S u bjects wit h a l ocalize d Gra d e 2 ac ute 
aller gic reacti o n mi g ht c o nti n ue o n t he treat me nt wit h pre me dicati o n of H 1 a nti hista mi ne. S u bjects 
wit h rec urre nt Gra de  2 ac ute aller gic reacti o ns wit h pre me dicati o n, Gra de 2 dela ye d aller gic 
reacti o ns, or Gra d e 3 t o 4 ac ute aller gic reacti o ns s h o ul d per ma ne ntl y disc o nti n ue t he st u d y dr u g.  


Aar d var k T hera pe utics, I nc.  
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6. 9. 3.  
M a n a ge me nt of g astr oi ntesti n al dis or ders  
Earl y rec o g niti o n a n d ma na ge me nt of p ote ntial GI dis or ders ma y miti gate m ore se vere a n d 
s u bse q ue nt t o xicities.  
6. 9. 4.  
E m br y o -fet al T o xicit y 
T he effect of A R D -1 0 1 o n e m br y o -fetal de vel o p m e nt has n ot bee n teste d. T h us, a hi g hl y effecti ve 
f or m of c o ntrace pti o n m ust be use d, a n d e nr olle d s u bjects s h o ul d recei ve i nstr ucti o ns re gar di n g 
t his d uri n g t he e ntire st u d y fr o m e nr oll me nt  t o 9 0  da ys after l ast d ose a d mi nistrati o n.  
6. 1 0.  Per mitte d Me dic ati o ns/ Pr oce d ures  
A n y me dici nal pr o d uct, prescri be d or O T C,  i ncl u di n g vita mi ns, nat ural, a n d her bal re me dies, t a ke n 
b y a s u bject ot her t ha n t h e st u d y me dicati o n, is c o nsi dere d c o n c o mita nt me dicati o n. 
A n y c o nc o mita nt treat m e nt will be gi ve n o nl y if dee me d strictl y n ecessar y b y t he Pri nci pal 
I n v esti gat or or d esi g ne e. Use of c o n c o mita nt 
me dicati o n will be rec or de d a n d re p orte d. 
Partic ularl y, as des cri be d i n  Secti o n 2. 3. 2 , A R D -1 0 1 is a s u bstrate of t he 
M D R 1, 
M A T E 1, 
M A T E 2 -K, O A T 3 a n d O C T 2  tra ns p orters. C oa d mi nistrati o n of t hese tra ns p orter i n hi bit ors ha ve 
t he p ote ntial t o alter t he p har mac o ki netics of A R D -1 0 1.  T heref ore, bef ore placi n g a  s u bject o n a 
s pecific me dicati o n/t herap y, it is t he res p o nsi bilit y of t he i n vesti gat or t o c hec k  o n p ote ntial dr u g -
dr u g i nteracti o ns bet wee n t hat me dicati o n/t hera p y a n d  A R D -1 0 1 base d o n t he Dr u g De v el o p me nt 
a n d  
Dr u g  
I nteracti o ns:  
Ta ble  
of  
S u bstrates,  
I n hi bit ors  
a n d  
I n d ucers  
(htt ps:// w w w.f da. g o v/ dr u gs/ dr u g -i nteracti o ns-la beli n g/ dr u g-de vel o p me nt -a n d-dr u g -i nteracti o ns-
ta ble-s u bstrates-i n hi bit ors-a n d-i nd ucers ),  
a n d 
Dr u g -Dr u g  
I nt eracti o n 
D ata bas e 
(htt ps:// w w w.f da. g o v/ dr u gs/ dr u g -i nteracti o ns-la beli n g/ data bases) of  F D A.  
6. 1 0. 1.  
Per mitte d Me dic ati o ns/ Pr oce d ures  
S u bjects are per mitte d t o u se me di cati o ns c o nsiste nt wit h t h ose p er mitte d, i ncl u di n g t he us e of 
c o ntrace pti ve me dicati o ns a n d h y dr oc ortis o ne  crea m.  All c o nc o mita nt me dicati o ns are s u bject t o 
a p pr o val b y t he pri n ci pal i n vesti gat or.  
N o c o nc o mit a nt use  of a p pr o ve d o besit y dr u gs or dia b etes treat me nt (e xcl u di n g metf or mi n), 
M D R 1, M A T E 1, M A T E 2 -K, O A T 3, or O C T 2 i n hi bit ors, or a n y dr u g dee me d i nc o m pati ble wit h 
trial partici pati o n as per i n vesti gat or j u d ge me nt. 
 


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7.  
DI S C O N TI N U A TI O N  
7. 1.  
S u bject Wit h dr a w al a n d Re pl ace me nt  
S u bject partici pati o n ma y be ter mi nate d pri or t o c o m pleti n g t he st u d y a n d t he reas o n rec or de d as 
f oll o ws: 
1.  
A d verse e ve nt  
2.  
Pr ot oc ol vi olati o n  
3.  
L os t t o f oll o w-u p  
4.  
S u bject wit h dre w c o nse nt at o w n re q uest  
5.  
Ot her  
A ge n ui ne eff ort m ust be ma de t o deter mi ne t he reas o n(s) w h y a s u bject fails t o ret ur n f or t he 
necessar y visits or is disc o nti n ue d fr o m t he st u d y. If t h e s u bject is u nreac ha ble b y tele p h o n e, a 
re gistere d letter, at t he mi ni m u m, s h o ul d be se nt t o t he s u bject re q uesti n g hi m/ her t o c o ntact t he 
cli nic. 
Wit h dra w n s u bjects ma y be re pla ce d  u ntil t he f ull c o h ort has c o m plete d t h e st u d y . 


Aar d var k T hera pe utics, I nc.  
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8.  
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  
F or ti mi n g of assess me nts, refer t o t he Sc he d ule of Assess me nts Ta ble  1 .  
8. 1.  
Eli gi bilit y Scree ni n g  
All s u bjects m ust si g n a n inf or me d c o nse nt f or m (I C F) pri or t o t he c o n d uct of a n y scree ni n g 
pr oce d ures. Scree ni n g assess me nts will occ ur wit hi n 2 8  da ys pri or t o t he first d ose of st u d y 
me dicati o n . T he s u bject’s rele v a nt me dical hist or y a n d de m o gr a p hic d ata will be o btai ne d. 
Retesti n g of a b n or mal scree ni n g va l ues t hat lea d t o e xcl usi o n are all o we d d uri n g t he Scree ni n g 
Peri o d (t o reassess eli gi bilit y). T he last res ult o btai ne d pri or t o t he first d ose of st u d y me dicati o n 
will be use d t o deter mi ne eli gi bilit y . 
8. 2.  
S afet y V ari a bles  
8. 2. 1.  
A d verse E ve nts  
A d verse e v e nt re p orti n g will be gi n f or eac h s u bject fr o m t he date t he I C F is si g ne d a n d will 
c o nti n ue u ntil t he E O S  Visit . 
8. 2. 1. 1.  
Defi niti o ns  
8. 2. 1. 1. 1.  
Defi niti o n of A d verse E ve nt  
A n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n s u bject a d mi nistere d a 
p har mace utical pr o d u ct a n d w hic h d oes n ot necessaril y ha v e a ca us al relati o ns hi p wit h t his 
treat me nt. A n A E ca n t h eref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal 
(i n vesti gati o nal) pr o d uct, w het her or n ot relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct. 
Ot her u nt o war d e ve nts o cc urri n g i n t he fra me w or k of a cli nical st u d y will be rec or de d as A Es, e. g. 
t h ose occ urri n g d uri n g treat me nt-free peri o ds (i ncl u di n g scree ni n g or p ost -treat me nt foll o w -u p 
peri o ds), i n ass o ciati o n wit h st u d y -relate d pr oce d ures a n d assess me nts, or u n der place b o. F or st u d y 
me dicati o n , lac k of effic ac y ma y be a n e x pecte d p ote ntial o utc o me a n d s h o ul d n ot be re p orte d as 
a n A E u nless t he e v e nt is u n u s ual i n s o me wa y, e. g., greater i n se verit y.  
C o nc o mita nt ill nesses, w hic h e xiste d pri or t o e ntr y i nt o t he cli nical st u d y, will n ot be c o nsi dere d 
A Es u nless t he y w orse n d uri n g t he T reat me nt P eri o d. Pre -e xisti n g  c o n diti o ns will be rec or de d as 
part of t he s u bject’s me dical hist or y.  


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8. 2. 1. 1. 2.  
Defi niti o n of Seri o us A d verse E ve nt  
A n S A E is defi ne d as a n y u nt o war d me dical o cc urre nce t hat at a n y d os e:  
•  Res ults i n deat h  
•  Is life-t hreate ni n g; t his mea ns t hat t he s u bject was at ris k of d eat h at t h e ti me of t he e ve nt; it 
d oes n ot mea n t hat t he e v e nt h y p ot heticall y mi g ht ha ve ca use d deat h if it were m or e se vere  
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n i n e xisti n g h os pitalizati o n  
•  Res ults i n persiste nt or si g nifica nt disa bilit y/ i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y 
t o c o n d uct n or mal life f u ncti o ns 
•  Is a c o n ge nital a n o mal y/birt h defect, or  
•  Is a n ot her i m p orta nt me dical e ve nt (s ee bel o w) 
I m p ort a nt me dical e v e nts t hat d o n ot res ult i n deat h, are n ot life-t hreate ni n g or d o n ot re q uire 
h os pitalizati o n ma y be c o nsi dere d S A Es w he n, base d o n a p pr o priate me di cal j u d g me nt, t he y ma y 
je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre v e nt o ne of t he 
o utc o me s liste d a b o ve. E xa m ples of s uc h me di cal e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g 
i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or i n a p h ysicia n’s office, bl o o d d yscrasias or sei z ures 
t hat d o n ot res ult i n i n-patie nt h os pitalizati o n, a n d t he de vel o p me nt of dr u g de pe n de nc y or dr u g 
a b use.  
A disti ncti o n s h o ul d be dra w n bet w ee n s eri o us a n d se vere A Es. Se verit y is a meas ure of i nte nsit y 
w hereas seri o us ness is defi ne d b y t he criteria a b o v e. F or e x a m ple, a mil d de gree of gastr oi ntesti nal 
blee di n g re q uiri n g a n o v er ni g ht h os pitalizati o n f or m o nit ori n g p ur p oses w o ul d be c o nsi dere d a n 
S A E b ut  is n ot necess aril y se vere. Si milarl y, a n A E t hat is se vere i n i nte nsit y is n ot necessaril y a n 
S A E. F or e x a m ple, al o pe cia ma y be assesse d as s e vere i n i nte nsit y b ut w o ul d n ot be c o nsi dere d 
a n S A E. 
Me dical a n d scie ntific j u d g me nt s h o ul d be e x ercise d i n deci di n g if a n A E is seri o us a n d if 
e x pe dite d re p orti n g is a p pr o priate.  
8. 2. 1. 2.  
Rec or di n g of A d vers e E ve nts  
A d verse e ve nts s h o ul d b e c ollecte d a n d rec or de d f or eac h s u bject fr o m t h e date t he  I CF  is si g n e d 
u ntil t he e n d of t heir partici pati o n i n t he st u d y, i.e., t he s u bject has disc o nti n ue d or c o m plete d t he 
st u d y. 


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A d verse e ve nts m a y be v ol u nteere d s p o nta ne o usl y b y t he s u bject, or dis c o vere d b y st u d y staff 
d uri n g p h ysical e xa mi nati o ns or b y as k i n g a n o pe n, n o n-lea di n g q uesti o n s uc h as ‘ H o w ha ve y o u 
bee n feeli n g si nce y o u were last as k e d?’ All A Es a n d a n y re q uir e d re me dial acti o n will be 
rec or de d. T he nat ure of A E, date (a n d ti me, if k n o w n) of A E o nset, date (a n d ti me, if k n o w n) of 
A E o utc o me t o date, se v erit y a n d acti o n ta ke n of t he A E will be d oc u me nte d t o get her wit h t he 
Pri nci pal I n vesti gat or ’s assess me nt of t he seri o us ness of t he A E a n d ca usal relati o ns hi p  t o st u d y 
dr u g a n d/ or st u d y pr oce d ure.  
All A Es s h o ul d be rec or de d i n di vi d uall y i n t he s u b ject’s o w n w or ds ( ver bati m) u nless, i n t he 
o pi ni o n of t he Pri nci pal I n v esti gat or , t he A Es c o nstit ute c o m p o ne nts of a rec o g nize d c o n diti o n, 
disease or s y n dr o me. I n t he latter case, t he c o n diti o n, disease or s y n dr o me s h o ul d be na me d rat her 
t ha n eac h i n di vi d ual s y m pt o m. T he A Es will s u bse q ue ntl y be c o de d usi n g t he Me dical Dicti o nar y 
f or Re g ulat or y Acti vities ( Me d D R A). Se verit y of A Es will be gra de d usi n g t he T o xicit y Gra di n g 
Scale f or H ealt h y A d ult a n d A d olesce nt V ol u nteers  E nr olle d i n Pre ve nti ve Vacci n e Cli ni cal Trials  
( Se pte m ber, 2 0 0 7). 
8. 2. 1. 3.  
Assess m e nt of A d verse E ve nts  
Eac h A E will be assesse d b y t he Pri nci pal I n vesti gat or  as per t he cate g ories disc usse d i n t he 
f oll o wi n g secti o ns. 
8. 2. 1. 3. 1.  
I nte nsit y 
T he Pri nci pal I n vesti gat or  will assess all A Es f or se verit y i n acc or da n ce  wit h t he f oll o wi n g 
sta n dar d rati n gs. 
•  Mil d  ( Gra de 1): Or di naril y tra nsie nt s y m pt o ms, d oes n ot i nfl ue nce perf or ma nce of s u bject’s 
dail y acti vities. Treat me nt is n ot or di naril y i n dicate d.  
•  M o derate  ( Gra de 2): 
Mar ke d s y m pt o ms, s ufficie nt t o ma ke t he s u bject u nc o mf orta ble. 
M o derate i nfl ue n ce o n p erf or ma n ce of s u bject’s d ail y acti vities. Treat me nt ma y be necessar y.  
•  Se vere  ( Gra de 3): S y m pt o ms ca use c o nsi dera ble disc o mf ort. S u bsta ntial i nfl ue nce o n s u bject’s 
dail y acti vities. Ma y be u na ble t o c o nti n ue i n t he st u d y a n d treat me nt ma y b e necessar y.  
•  P ote ntiall y Life T hreate ni n g ( Gra de 4): S y m pt o ms re q uire e mer ge n c y r o o m ( E R) visit or 
h os pitalizati o n.  
W he n c h a n ges i n t he i nte nsit y of a n A E occ ur m ore fre q ue ntl y t ha n o nce a da y, t he ma xi m u m 
i nte nsit y f or t he e ve nt s h o ul d be n ote d f or t hat da y. A n y c ha n ge i n se verit y of si g ns a n d s y m pt o ms 


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o ver a n u m ber of da ys will be ca pt ure d b y rec or di n g a ne w A E, wit h t he a me n de d se verit y gra de, 
a n d t he date (a n d ti me, if k n o w n) of t he c h a n ge.  
8. 2. 1. 3. 2.  
C a us alit y  
T he Pri nci pal I n vesti gat or  will assess t h e ca usalit y/relati o ns hi p bet wee n t he st u d y me dicati o n  a n d 
t he A E. T he  Pri nci pal  I n v esti gat or is res p o nsi ble f or assessi n g t he relati o ns hi p t o st u d y me dicati o n  
usi n g cli nical j u d g me nt a n d t he f oll o wi n g c o nsi derati o ns : 
•  N o: E vi de nce e xists t hat t he A E has a n eti ol o g y ot her t ha n t he st u d y dr u g. F or S A Es, a n 
alter nati ve ca usalit y 
m ust be pr o vi de d (e. g., pre -e xisti n g c o n diti o n, c o nc o mita nt 
me dicati o n)  
•  Yes : T here is reas o n a ble p ossi bilit y t hat t he e ve nt ma y ha v e bee n ca use d b y t he st u d y 
me dicati o n . 
8. 2. 1. 4.  
Re p orti n g of Seri o us A d verse E ve nts  
T he Pri nci pal I n v esti gat or  will re vie w eac h S A E a n d e val uate t he i nte nsit y a n d t he ca usal 
relati o ns hi p of t he e ve nt t o st u d y dr u g. All S A Es will be rec or de d fr o m si g ni n g of t he I CF  u ntil 
t he E O S  V isit. Seri o us A Es occ urri n g after t he E O S  Visit  a n d c o mi n g t o t he atte nti o n of t he 
Pri nci pal I n vesti gat or  m ust be re p ort e d o nl y if t here is (i n t he o pi ni o n of t he Pri nci pal I n vesti gat or ) 
reas o na bl e ca us al relati o ns hi p wit h t he st u d y dr u g. 
T he Pri nci pal I n vesti gat or  is res p o nsi ble f or pr o vi di n g n otificati o n t o S p o ns or of a n y S A E, w het her 
dee me d st u d y me dicati o n-relate d or n ot, t hat a s u bject e x perie nces d uri n g t heir partici pati o n i n 
st u d y wit hi n 2 4 h  o f bec o mi n g a ware of t he e v e nt. 
I nitial re p orts of S A Es m ust be f oll o we d later wit h detaile d descri pti o ns, i ncl u di n g clear 
p h ot oc o pies of ot her d oc u me nts as necessar y ( e. g., h os pital re p orts, c o ns ulta nt re p orts, a ut o ps y 
re p orts), wit h t he s u bject’s pers o nal i de ntifiers re m o ve d.  
I nf or mati o n o n S U S A Rs will be c ollecte d a n d re p orte d t o t he re g ulat or y a ut h orit y a n d t he I E C as 
re q uire d p er g ui deli nes . 
If t he S U S A R is fatal or life-t hreat e ni n g, ass ociate d wit h t he use of t he st u d y me dicati o n, a n d 
u ne x pecte d, t he re g ulat or y a ut h orit y a n d t he I E C will be n otifie d per g ui deli nes after bei n g ma de 
a ware of t he case. A d diti o nal f oll o w -u p (ca use of deat h, a ut o ps y re p ort, h os pital re p ort) 
i nf or mati o n s h o ul d be re p orte d per g ui d eli nes. S U S A Rs w hic h are n ot fatal a n d n ot life -t hreat e ni n g 
are t o be re p orte d p er g ui deli nes.  


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T he S p o ns or will n otif y t he I n v esti gat ors of rel e va nt i nf or mati o n a b o ut S U S A Rs t hat c o ul d 
a d versel y affect t he safet y of s u bjects i n a ti mel y fas hi o n. F oll o w -u p i nf or mati o n ma y be s u b mitte d 
if necessar y. T h e S p o ns or will als o pr o vi de a n n ual safet y re p orts f or s u b missi o n t o t he re g ulat or y 
a ut h orit y a n d t h e I E C res p o nsi ble f o r t h e cli nical st u d y. T hese u p dates will i ncl u de i nf or m ati o n o n 
S U S A Rs a n d ot her rele v a nt safet y fi n di n gs.  
8. 2. 1. 5.  
F oll o w -u p of A d verse E ve nts  
All A Es e x perie n ce d b y a s u bject, irres pecti ve of t he s us pecte d ca usalit y, will be m o nit ore d u ntil 
t he e ve nt h as res ol ve d, u ntil a n y a b n or mal l a b orat or y val ues h a ve ret ur n e d t o baseli ne or sta bilize d 
at a le v el acce pta bl e t o t h e Pri nci pal I n v esti gat or  a n d Me dical M o nit or, u ntil t here is a satisfact or y 
e x pla nati o n f or t he c ha n g es o bser ve d or u ntil t he s u bject is l ost t o foll o w -u p.  
8. 2. 1. 6.  
Pre g n a nc y  
T he S p o ns or has a res p o nsi bilit y t o m o nit or t he o utc o me of all pre g na nci es re p orte d d uri n g t he 
cli nical st u d y.  
Pre g na nc y al o ne is n ot re gar de d as a n A E u nless t here is a s us pici o n t hat t he st u d y dr u g ma y h a ve 
i nterfere d wit h t he effecti ve ness of a c o ntr ace pti ve me dicati o n. Electi ve a b orti o ns wit h o ut 
c o m plicati o ns s h o ul d n ot be re gar de d as A Es, u nless t he y were t hera pe utic a b orti o ns (see bel o w). 
H os pitalizati o n f or n or m al deli ver y of a healt h y n e w b or n s h o ul d n ot be c o nsi dere d a n S A E.  
Eac h pre g na nc y m ust be re p orte d b y t he Pri nci pal I n v esti gat or  t o t he S p o ns or wit hi n 2  d a ys  after 
bec o mi n g a w are of t h e pre g na nc y. T he Pri nci pal I n v esti gat or  m ust f oll o w -u p a n d d o c u me nt t he 
c o urse a n d t he o utc o me of all pre g na ncies e ve n if t he s u bject was wit h dra w n  fr o m t he cli nical 
st u d y or if t he cli nical st u d y has fi nis he d. 
All o utc o mes of pre g n a n c y m ust be re p orte d b y t he Pri nci pal I n vesti gat or  t o t he S p o ns or o n t he 
pre g na nc y o ut c o me re p ort f or m wit hi n 2  d a ys  after he/s he has g ai ne d k n o wle d ge of t he n or m al 
deli v er y or el ecti ve a b orti o n.  
A n y S A E t hat occ urs d uri n g pre g na nc y m ust be rec or de d o n t he S A E R e p ort F or m (e. g., mater nal 
seri o us c o m plicati o ns, t hera pe utic a b orti o n, ect o pic pre g n a nc y, still birt h, ne o natal d eat h, 
c o n ge nital a n o m al y, birt h defect) a n d re p ort e d wit hi n 2 4  h i n acc or da n ce wit h t he pr oce d ure f or 
re p orti n g S A Es. 


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8. 2. 2.  
Cli nic al L a b or at or y Assess m e nts  
Sa m ples f or cli nical la b orat or y assess me nts will be c ollecte d at t he ti me p oi nts detaile d i n t he 
Sc he d ule of Assess me nts ( Ta ble 1 ). Sa m ples will be c ollecte d i n a p pr o priate t u bes a n d ha n dle d 
acc or di n g t o sta n d ar d pr o ce d ures of t he a p plica ble la b orat or y . 
A n y val ue o utsi de t he n or mal ra n g e will be fla g ge d f or t he atte nti o n of t h e Pri nci pal I n vesti gat or  
or desi g nee at t he site. T he Pri nci pal I n vesti gat or  or desi g nee will i n dicate w het her  t he val u e is of 
cli nical si g nifica n ce. A d diti o nal testi n g d uri n g t h e st u d y ma y be d o ne if me dicall y i n dicate d. If a 
cli nicall y si g nifica nt a b n or malit y is f o u n d i n t he sa m ples ta ke n after d osi n g, d uri n g t he st u d y, 
a n d/ or at t he E O S  V isit, it s h o ul d be rec or de d as a n A E a n d t he s u bject will be f oll o we d u ntil t he 
test(s) has (ha v e) n or m alize d or s ta bilize d, at t he discreti o n of t he Pri nci pal I n v esti gat or. 
8. 2. 3.  
Vit al Si g ns  
Vital si g ns will be assesse d at t he ti me p oi nts detaile d i n t he Sc he d ule of Assess me nts Ta ble  1 . 
T he f oll o wi n g vital si g ns will be meas ur e d:  
•  Bl o o d press ure (s yst olic a n d diast olic [ m m H g])  
•  P ulse  ( b p m) 
•  B o d y te m perat ure (° C)  
•  Res pirat or y rate ( breat hs per mi n ute)  
8. 2. 4.  
St a n d ar d 1 2 -le a d Electr oc ar di o gr a ms 
Sta n dar d safet y 1 2 -lea d E C Gs will be perf or me d at t he ti me p oi nts detaile d i n t he Sc he d ule of 
Assess me nts ( Ta ble 1 ). 
T he E C G will i ncl u de all 1 2 sta n dar d lea ds.  
All E C Gs m ust be e val uate d  b y a q ualifie d p h ysicia n f or t he prese n ce of a b n or malities. If a 
cli nicall y si g nifica nt a b n or malit y is f o u n d, it s h o ul d be rec or de d as a n A E a n d t he s u bject will be 
f oll o we d u ntil t he test(s) has ( ha ve) n or malize d or sta bilize d, at t he dis creti o n of t h e P ri nci pal 
I n v esti gat or. 
8. 2. 5.  
Bi oi m pe d a nce  
B o d y c o m p ositi o n will be assess e d via s cale m eas uri n g bi oi m pe da nce at t he ti me p oi nts detaile d 
i n t he Sc he d ule of Assess me nts (Ta ble 1 ). 


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8. 2. 6.  
M RI P D F F a n d F ull B o d y C o m p ositi o n Sc a n  
I n or der t o better assess o verall b o d y c o m p ositi o n i ncl u di n g q ua ntificati o n of lea n b o d y mass, li ver 
fat c o nte nt a n d ot her relate d para meters, M RI sca n will be perf or me d at t he ti me p oi nts detaile d at 
t he ti me p oi nts detaile d i n t he Sc he d ule of Ass ess me nts (Ta ble 1 ). 
8. 2. 7.  
Mi xe d Me al T oler a nce Test ( M M T T)  
T he M M T T per mits me as ure me nt of i ntesti nal (i ncreti n secreti o n), β -cell (i ns uli n secreti o n), 
he patic (i ns uli n e xtrac ti o n), m uscle, a n d a di p ose tiss ue res p o nses t o i n gesti n g cal ories. T he mi xe d 
meal, c o ntai ni n g gl uc os e, fat a n d pr ot ei n ( 2 x E ns ure 8 o z. f or a t otal of 1 6 o z., 6 6 gra ms 
car b o h y drate ( C H O), 4 4 0 cal ori es), is m ore p h ysi ol o gic t ha n t he gl uc ose o nl y c halle n g e i n a n oral 
gl uc ose t olera nce test ( O G T T). T he M M T T will be perf or m e d at t he ti me p oi nts detaile d i n t he 
Sc he d ule of Assess me nts ( Ta ble 1) a n d as des cri b e d i n t he A p pe n di x. (T a ble 1 ). 
8. 2. 8.  
I n direct C al ori metr y 
C o nti n u o us i n direct cal ori metr y usi n g a c o m mercial i nstr u me nt ( V ma x E nc ore 
V S 2 9 N, 
Care F usi o n, Y or ba Li n da, C A, U S A) will be perf or me d d uri n g b asal a n d p ost pra n dial peri o ds o n 
t he da ys w he n t he M M T T are perf or m e d.   
At -8 0 a n d 1 9 5 mi n utes d uri n g t he M M T T, t he ca n o p y will be place d o ver t he s u bject’s hea d t o 
c ollect data fr o m 1 0 c o nti n u o us mi n utes at stea d y -state ( n o l o n ger t ha n 3 0 mi n utes) d uri n g eac h 
i nter val f or deter mi nati o n of t he s u bstrate o xi dati o n rates at basal c o n diti o n, a n d d uri n g t he M M T T 
ass o utli ne d i n t he  Sc he d ule of Assess me nts ( Ta bl e 1 ). 
8. 2. 9.  
P h ysic al E x a mi n ati o ns  
P h ysical e xa mi nati o ns will be perf or m e d at t he ti m e p oi nts detaile d i n t he Sc he d ule of Ass ess me nts 
(Ta ble 1 ). 
F ull  p hysic al ex a mi n ati o n:  
A n assess me nt of g e neral a p peara nce a n d a re vie w of s yste ms ( der mat ol o gic, hea d, e yes, ears, 
n ose, 
m o ut h/t hr oat/ nec k, t h yr oi d, l y m p h n o des, res pirat or y, car di o vas c ular, gastr oi ntesti nal, 
e xtre mities, m usc ul os keletal, ne ur ol o gic a n d ps y c hiatric s yste ms).  
Brief p hysic al e x a mi n ati o n:  
A n assess me nt of t he ge neral a p peara n ce, s ki n, car di o vas c ular s yste m, res pirat or y s yste m a n d 
a b d o me n.  


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T he brief p h ysical e x a mi nati o n ma y be e xte n de d t o a f ull p h ysical e xa mi nati o n if c o nsi dere d 
necessar y b y t he Pri nci pal I n v esti gat or. Ot her e va l uati o ns ma y be perf or me d as dee me d n ecessar y 
b y t he Pri nci pal I n vesti gat or.  
8. 2. 1 0.  
C o nti n u o us Gl uc ose M o nit ori n g  
Assess me nts  will be perf or me d at t he ti me p oi nts detaile d i n t he Sc h e d ule of Assess me nts (T a ble 
1 ). 
Gl uc ose le vels will be m o nit ore d usi n g t he C o nti n u o us Gl uc ose M o nit ori n g  (C G M ) de vice. T h e 
C G M de vice will be use d t o trac k bl o o d s u gar le vels da y a n d ni g ht, a n d it will c ollect rea di n gs 
a ut o maticall y e ver y 5 mi n utes. T he C G M se ns or is a r o u n d dis k wit h t he circ u mfere nce e q u al t o 
t hat of a q uarter, wit h t he t hic k ness of 2 q u arters. It h as a s mall fila me nt t hat is i nserte d 
s u bc uta ne o usl y via a s m all nee dle t hat is t he n retracte d a n d re m o v e d, lea vi n g j ust t he fila me nt.  
T he C G M se ns or a d h eres t o t he s ki n lea vi n g t h e fila me nt i n place f or 1 4 da ys a n d st ores t he 
rec or de d gl uc ose rea di n gs u ntil d o w nl oa de d b y a st u d y tea m me m ber.   
D uri n g t he R u n -i n Peri o d, t he C G M s e ns or will b e a p plie d t o t he s u bject a n d t he y will be re q uire d 
t o wear it f or a mi ni m u m d urati o n of t w o wee ks pri or t o Treat me nt Peri o d Da y 1. Data fr o m t he 
C G M will be d o w nl oa d e d a n d a re p ort will be ge n erate d usi n g t he s oft ware  pr o vi de d b y t he de vice . 
T he re p ort o utli nes t y pical meas ures of gl y ce mic c o ntr ol: mea n gl uc ose, st a n dar d de vi ati o n, ti me 
i n ra n ge a n d dail y patter ns. I n a d diti o n, a ra w data file is a vaila ble wit h eac h ti me p oi nt of 
c ollecti o n a n d gl uc ose rea di n g.”   
8. 2. 1 1.  
Circ ul ati n g H or m o nes  
T o i n vesti gate t he effect of t he st u d y me di cati o n o n circ ulati n g g ut h or m o n e le vels, all s u bjects of 
t he st u d y will u n der g o a fasti n g bl o o d dra w bef ore t he first d ose, a n d 1 h a n d 2 h after t he first d ose 
o n da y 1 f or meas uri n g fasti n g circ ulati n g le vels of t he f oll o wi n g g ut h or m n o nes: G L P-1 (t otal a n d 
acti ve), C C K, P Y Y, a m yli n, GI P (t otal a n d acti ve), g hreli n, le pti n, a n d a di p o necti n ( Ta ble 1 ). 
8. 2. 1 2.  
Fec al Mic r o bi o m e A n al ysis  
All s u bjects of t he st u d y will o pti o nall y pr o vi de t heir fecal sa m ples d uri n g t he r u n -i n visit a n d o n 
da y 2 8 f or micr o bi o me a nal ysis t o e val uate p ote ntial effects of t h e st u d y me dicati o n o n fecal 
micr o bi o me pr ofile ( T a ble 1 ). 


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8. 2. 1 3.  
N o n -i n v asi ve P he n ot y pic Bitter T aste Test 
All s u bjects of t he st u d y will o pti o nall y u n der g o a n o n -i n vasi ve p h e n ot y pic bitter taste test usi n g 
c o m mercializ e d p he n ylt h i ocar ba mi de ( P T C) a n d 6-n -pr o p ylt hi o uracil ( P R O P) taste stri ps, a n d a 
c o m mercializ e d Alle gr o Bitre x ®  Fit Test Kit d uri n g t he r u n -i n visit of t he st u d y (Ta ble 1 ). T his 
data ca n be use d t o retr o acti vel y assess a c orrelati o n of bitter taste se nsiti vit y of s u bjects wit h t he 
effic ac y of t he st u d y me dicati o n.  
 
 


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9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
9. 1.  
St u d y P o p ul ati o n  
9. 1. 1.  
Pr ot oc ol D e vi ati o ns  
I m p ort a nt pr ot oc ol de viatio ns will be liste d b y s u bject.  
9. 2.  
Ge ner al C o nsi der ati o ns  
C o nti n u o us data will be s u m marize d usi n g descri pti ve statistics ( n u m ber, mea n, sta n dar d de viati o n 
[ S D], mi ni m u m, me dia n a n d ma xi m u m). Cate g orical data will be s u m marize d usi n g fre q ue n c y 
ta bles ( n u m ber a n d perce nta ge).  
9. 3.  
S u bject Dis p ositi o n  
S u bjects e xcl u de d fr o m t he safet y  a nal ysis sets  will be liste d i ncl u di n g t he reas o n f or e xcl usi o n. 
S u bject dis p ositi o n will be s u m marize d a n d will i ncl u de t he f oll o wi n g i nf or mati o n: n u m ber of 
s u bjects d ose d , n u m b er a n d percent a ge of s u bjects c o m pleti n g t he st u d y a n d t h e n u m ber a n d 
perce nt a ge of s u bjects w h o were wit h dra w n (i ncl u di n g reas o ns f or wit h dra wal). Dis p ositi o n data 
will be prese nte d b ase d o n all.  
S u bject disc o nti n uati o ns will be liste d i ncl u di n g t he date of st u d y e xi t, d urati o n of tr eat me nt a n d 
reas o n f or disc o nti n uati o n. A listi n g of i nf or me d c o nse nt res p o nse will als o be prese nt e d. 
9. 4.  
De m o gr a p hic a n d A nt hr o p o metric I nf or m ati o n a n d B aseli ne C h ar acteristics  
De m o gra p hic a n d a nt hr o p o metric varia bles (a ge, se x, et h nicit y, r ace, hei g ht, b o d y wei g ht a n d 
B MI) will be liste d b y s u bject. De m o gra p hi c c h aract eristics (a g e, se x, et h nicit y a n d race) a n d 
a nt hr o p o metric c haracteristics ( hei g ht, b o d y wei g ht , a n d B MI) will be s u m marize d f or all s u bjects 
i n t he safet y a n al ysis set. T he d en o mi nat or f or p erce nta ges will be t h e n u m ber of s u bjects i n t he 
safet y a n al ysis set f or eac h treat me nt or f or all s u bjects as a p plica ble.  
Me dical hist or y data will be liste d b y s u bject i ncl u di n g visit, descri pti o n of t he disease/ pr oce d ure, 
Me d D R A s yste m orga n class (S O C ), Me d D R A preferre d ter m (P T ), start date, a n d st o p d ate ( or 
o n g oi n g if a p plica ble).  


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9. 5.  
Pri or a n d C o nc o mit a nt Me dic ati o n a n d Dr u g A d mi nistr ati o n  
Pri or me dicati o ns are t h ose t hat starte d a n d st o p pe d pri or t o t he first d ose of st u d y me dicati o n . 
C o nc o mita nt me dicati o ns are t h ose ta ke n after first d osi n g (i ncl u di n g me dicati o ns t hat starte d pri or 
t o d osi n g a n d c o nti n ue d after). 
Pri or a n d c o nc o mita nt me d icati o n will be liste d b y s u bject a n d will i ncl u de t he f oll o wi n g 
i nf or mati o n: re p orte d na me, P T , t he r o ute of a d mi nistrati o n, d ose, fre q ue nc y, start date/ti me, 
d urati o n a n d i n dicati o n.  
Pri or a n d c o nc o mita nt me dicati o n will be c o de d acc or di n g t o t he W orl d Healt h Or ga nizati o n Dr u g 
Dicti o nar y ( W H O -D D) l atest versi o n.  
Dr u g a d mi nistrati o n dates a n d ti mes will be liste d f or eac h s u bject.  
9. 6.  
E x p os ure  
A listi n g of dr u g a d mi nistrati o n will be create d a n d will i ncl u de t he date a n d ti me of a d mi nistrati o n.  
9. 7.  
S afet y A n al yses  
W here a p plica bl e, pre -d ose meas ur e me nts o n Da y 1 are c o nsi dere d bas eli ne val ues f or s afet y 
varia bles.  
9. 7. 1.  
A d verse E ve nts  
All A Es will be liste d. T h e n u m ber a n d perce nt of s u bjects e x p erie nci n g a n e ve nt will be ta b ulate d 
f or eac h S O C  a n d P T . T h e A Es wil l als o be ta b ul ate d acc or di n g t o i nte nsit y a n d ca us alit y. A T E A E 
is defi ne d as a n A E wit h a start d ate o n or after t he first d ose of st u d y dr u g, or t hat w orse ne d 
f oll o wi n g first a d mi nistrati o n of st u d y dr u g. F or p ur p oses of data a nal ysis, t he e n d of t he T EA E 
peri o d will be t he last ti me p oi nt w he n a s u bject was e val uat e d f or A Es.  
T he A Es ( T E A Es) will be ta b ulate d acc or di n g t o i nte nsit y a n d ca usalit y, as a p plica ble.  
N o n -T E A Es will be liste d, as a p plica ble.  
Seri o us A Es will be liste d se parat el y.  
9. 7. 2.  
Cli nic al L a b o r at or y Tests  
I n di vi d ual data listi n gs of la b orat or y res ults will be prese nte d f or eac h s u bject. Fla gs will be 
attac he d t o val ues o utsi de of t he la b orat or y’s refere n ce li mits al o n g 
wit h t he Pri nci p al 


Aar d var k T hera pe utics, I nc.  
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C O N FI D E N TI A L  
 
 
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I n v esti gat or’s assess me nt or desi g ne e . Cli nicall y si g nifica nt la b orat or y test a b n or malities t hat were 
c o nsi dere d A Es b y t he Pri nci pal I n v esti gat or  will be  prese nt e d i n t he A E listi n gs.  
Cli nical la b orat or y tests ( o bser ve d val ues) will be s u m marize d descri pti vel y i n ta b ular f or mat. 
S hift ta bles will be prese nte d f or  sele ct la b orat or y para meters. 
9. 7. 3.  
Vit al Si g ns  
I n di vi d ual d ata listi n gs of vital si g ns ( o bser ve d a n d c ha n g e fr o m bas eli ne) will be pres e nte d f or 
eac h s u bject. I n di vi d ual cli nicall y si g nifica nt vital si g n s fi n di n gs t hat were c o nsi dere d A Es b y t he 
Pri nci pal I n v esti gat or  will be prese nte d i n t he A E listi n gs.  
O bser ve d val ues as w ell as c ha n g e fr o m baseli ne data will be s u m marize d d escri pti vel y i n ta b ular 
f or mat. 
9. 7. 4.  
St a n d ar d 1 2 -le a d Electr oc ar di o gr a m 
Sta n dar d 1 2 -le a d E C G d ata ( o bser ve d a n d c h a n g e fr o m b aseli ne) will be liste d f or eac h s u bject 
a n d ti me p oi nt. O bser ve d val ues will be s u m marize d descri pti vel y i n ta b ular f or mat. C ha n ge fr o m 
baseli ne will be s u m marize d des cri pti vel y f or Q Tc data. A cate g orical Q Tc a nal ysis will als o  b e 
perf or me d.  
9. 7. 5.  
P h ysic al E x a mi n ati o n  
A b n or mal p h ysical e x a mi n ati o n fi n di n gs will be liste d.  
9. 8.  
E x pl or at or y a n al ysis  
E x pl orat or y a nal ysis ma y be prese nte d se paratel y fr o m t he mai n cli nical st u d y re p ort ( C S R ). 
F urt her details o n e x pl or at or y a nal yses will be pr o vi de d i n t he S A P . 
9. 9.  
Deter mi n ati o n of S a m ple Size  
T he deter mi nati o n of sa m ple size is n ot bas e d o n st atistical c o nsi derati o ns of p o wer b ut 2 5  s u bj ects 
is c o nsi dere d s uffi cie nt t o meet t he st u d y o bjecti ves. 


Aar d var k T hera pe utics, I nc.  
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1 0.  
E T HI C A L, L E G A L A N D A D MI NI S T R A TI V E A S P E C T S  
1 0. 1.  D at a Q u alit y Ass ur a nce  
T he S p o ns or or d esi g nee will c o n d uct a st u d y i nitiati o n visit t o verif y t he q ualificati o ns of t h e 
Pri nci pal I n v esti gat or , i ns pect t he facilities a n d i nf or m t he Pri nci pal I n vesti gat or  of res p o nsi bilities 
a n d pr oce d ures f or e ns uri n g a de q uate a n d c orrect d oc u me ntat i o n. 
T he Pri nci pal I n vesti gat or  m ust pre pare a n d mai ntai n a de q uate a n d acc urate rec or ds of all 
o bser vati o ns a n d ot her d ata perti ne nt t o t he cli ni cal st u d y f or eac h st u d y partici pa nt. Fre q ue nt 
c o m m u nicati o n bet wee n t he cli nical site a n d t he S p o ns or is esse n tial t o e ns ure t hat t he safet y of 
t he st u d y is m o nit ore d a de q uatel y. T he Pri nci pal I n vesti gat or  will ma ke all a p pr o priate safet y 
assess me nts o n a n o n g oi n g basis. T he Me dical M o nit or ma y re vie w s afet y i nf or mati o n as it 
bec o mes a v aila ble t hr o u g h o ut t he st u d y . 
All as pects of t he st u d y will be caref ull y m o nit ore d wit h res pect t o G o o d Cli nical Practice (G C P ) 
a n d S O Ps f or c o m plia nce wit h a p plica ble g o ver n me nt re g ulati o ns. T he St u d y M o nit or will be a n 
a ut h orize d i n di vi d ual desi g nate d b y t he S p o ns or. T he St u d y M o ni t or will ha ve access t o all rec or ds 
necessar y t o e ns ure i nte grit y of t he data a n d will p eri o dicall y re vie w t he pr o g ress of t he st u d y wit h 
t he Pri nci pal I n vesti gat or . 
1 0. 2.  D at a C ollecti o n a n d Access t o S o urce D at a/ D oc u me nts  
T he Pri nci pal  I n vesti gat or will e ns ure t he acc urac y, c o m plete ness a n d ti meli ness of t he data 
re p orte d t o t he S p o ns or. T he I n v esti gat or or desi g nee will c o o perate wit h t he S p o ns or’s 
re pres e ntati ve(s) f or t he peri o dic re vie w of st u d y d oc u me nts t o e ns ure t he acc urac y a n d 
c o m plete ness of t he d ata at eac h sc he d ule d m o nit ori n g visit.  Data clarificati o n re q uests will be 
pr o vi de d t o t he st u d y tea m b y mea ns of electr o nic or ma n ual q ueri es.  
T he I n vesti gat or will all o w S p o ns or re pres e ntati ves, c o ntract d esi g nees, a ut h orize d re g ulat or y 
a ut h orit y i ns pect ors a n d t he I E C t o ha v e dir ect access t o all electr o nic rec or ds pertai ni n g t o t he 
st u d y. 
All data s h o ul d be rec or de d, ha n dle d a n d st ore d i n a wa y t hat all o ws its acc urat e re p orti n g, 
i nter pretati o n a n d v erific ati o n. 
1 0. 3.  Arc hi vi n g St u d y D oc u me nts  
All s o ur ce d oc u me nts g e nerate d i n c o n necti o n wit h t he st u d y will be retai n e d i n t he li mite d access 
file st ora ge area, res pecti n g t he pri vac y a n d c o nfi de ntialit y of all rec or ds t hat c o ul d i de ntif y t he 


Aar d var k T hera pe utics, I nc.  
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C O N FI D E N TI A L  
 
 
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0 9  Ma y  2 0 2 2  
 
s u bjects. Direct access is all o we d o nl y f or a ut h orize d pe o ple f or m o nit ori n g a n d a u diti n g p ur p oses. 
S o urce d oc u me nts will b e ha n dle d, st ore d a n d arc hi ve d acc or di n g t o i n -h o use pr oce d ures.  
T he I n v esti gat or's Site File will be arc hi v e d b y t he C R O f or at least 2  y ears after c o m pleti o n of t he 
st u d y or l o n ger if a gree d u p o n  b y t he S p o ns or . 
1 0. 4.  G o o d Cli nic al Pr actice  
T he pr oce d ures set o ut i n t his cli nical st u d y pr ot oc ol are desi g ne d t o e ns ure t hat t he S p o ns or a n d 
t he Pri nci pal I n vesti gat or  a bi de b y t he pri n ci ples of t he I C H g ui deli nes o n G C P. T he cli nical st u d y 
als o will be carr ie d o ut i n kee pi n g wit h nati o nal a n d l ocal le gal re q uire me nts (i n acc or da n ce wit h 
U nite d States i n vesti gati o nal ne w dr u g [I N D] re g ulati o ns [ 2 1  C F R  5 6]).  
1 0. 5.  I nf or me d C o nse nt 
Eli gi ble s u bjects ma y o nl y be i ncl u de d i n t he st u d y after pr o vi di n g I R B/I E C a p pr o ve d inf or me d 
c o nse nt.  
I nf or me d c o nse nt m ust be o btai ne d fr o m t he s u bject bef ore c o n d u cti n g a n y st u d y-s pecifi c 
pr oce d ure.  
As part of t h e i nf or m e d c o nse nt pr oce d ure, t he Pri nci pal I n v esti gat or or d esi g nee m ust e x plai n 
orall y a n d i n writi n g t he nat ure, d urati o n a n d p ur p ose of t h e st u d y a n d t h e acti o n of t he dr u g i n 
s uc h a ma n n er t h at t he s u bject is a w are of t he p ote ntial ris ks, i nc o n ve nie nces or A Es t hat ma y 
occ ur. T he s u bject s h o ul d be i nf or me d t hat he/s he is free t o wit h dra w fr o m t he st u d y at a n y ti me. 
S u bjects w ill recei ve all i nf or mati o n t hat is re q uire d b y fe deral re g ulati o ns a n d I C H g ui deli nes. 
T he I C F m ust be si g ne d a n d d ate d; o n e c o p y will be ha n d e d t o t h e s u bj ect, a n d t he Pri nci pal 
I n v esti gat or will retai n a c o p y as part of t he cli nical st u d y rec or ds. T he Pri nci pal I n vesti gat or will 
n ot u n derta ke a n y i n vesti gati o n s pecificall y re q uire d f or t he cli nical st u d y u ntil writte n c o ns e nt 
has bee n o btai n e d. T he ter ms of t he c o nse nt a n d w he n it was o btai ne d m ust be d oc u me nte d i n t he 
s u bject s o urce d o c u me nts. 
T he S p o ns or will re vie w t he In v esti gat or -pr o p os e d I C F t o e ns ure it c o m plies wit h t he I C H G C P 
g ui deli ne (i ncl u di n g t he et hical pri nci ples t hat ha ve t heir ori gi ns i n t he Declarati o n of Helsi n ki) 
a n d re g ulat or y re q uire me nts a n d is c o nsi dere d a p pr o priate f or t his st u d y . T he Pri nci pal I n vesti gat or 
or desi g ne e will pr o vi de t he S p o ns or wit h a c o p y of t he I R B/I E C a p pr o ve d I C F pri or t o t he start 
of t he st u d y.  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
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C O N FI D E N TI A L  
 
 
Pa ge 5 9  of 6 7  
0 9  Ma y  2 0 2 2  
 
If a pr ot oc ol a me n d me nt is re q uire d, t h e n t he I C F ma y nee d t o be re vise d t o reflect t he c ha n g es t o 
t he pr ot oc ol. If th e I C F is re vise d, it m ust be re vie we d a n d a p pr o ve d b y t h e res p o nsi ble I R B/I E C 
a n d si g ne d b y all s u bjects s u bse q ue ntl y e nr olle d i n t he cli nical st u d y, as well as t h ose c urre ntl y 
e nr olle d i n t he cli nical st u d y as a p plica ble.  
1 0. 6.  I ns ur a nce a n d C o m pe ns ati o n f or Inj ur y  
T he S p o ns or has c o vere d t his cli nical st u d y b y mea ns of a n i ns ur a nce of t he cli nical st u d y 
acc or di n g t o nati o nal re q uire me nts. T he na me a n d a d dress of t he rele va nt i ns ura nce c o m pa n y, t he 
certificate of i ns ura n ce, t he p olic y n u m ber a n d t h e s u m i ns ure d  are pr o vi d e d i n t he I n v esti gat or’s 
Site File.  
1 0. 7.  Pr ot oc ol A p pr o v al a n d A me n d me nt(s)  
Bef ore t h e start of t he cli nical st u d y, t he cli nical st u d y pr ot oc ol a n d ot her rele va nt d oc u me nts will 
be a p pr o ve d b y t he I R B /I E C, i n acc or da n ce wit h l ocal le gal re q uire me nts. T he S p o ns or m ust 
e ns ure t hat all et hical a n d le gal re q uire me nts ha ve bee n met bef ore t he first s u bject is e nr olle d i n 
t he cli nical st u d y. 
T his pr ot oc ol is t o be f oll o we d e x actl y. T o alter t h e pr ot oc ol, a me n d me nts m ust be writte n, w hi c h 
m ust be release d b y t h e res p o nsi ble staff a n d recei ve I R B/I E C a p pr o val pri or t o i m ple me ntati o n 
(as a p pr o priate). 
A d mi nistrati ve c ha n ges ma y be ma de wit h o ut t he nee d f or a f or mal a me n d me nt b ut  will als o be 
me nti o ne d i n t he i nte grate d C S R . All a me n d me nts will be distri b ute d t o all st u d y pr ot oc ol 
reci pie nts, wit h a p pr o priate i nstr ucti o ns. 
1 0. 8.  C o nfi de nti alit y D at a Pr otecti o n  
All cli nical st u d y fi n di n gs a n d d oc u me nts will be re gar de d as c o nfi de ntial.  St u d y d oc u me nts 
( pr ot oc ols, I Bs a n d ot her material) will be st ore d a p pro priatel y t o e ns ure t heir c o nfi de ntialit y. T he 
Pri nci pal I n vesti gat or  a n d me m bers of his/ her researc h tea m (i ncl u di n g t he I R B /I E C) m ust n ot 
discl ose s uc h i nf or mati o n wit h o ut pri or writte n a p pr o val fr o m t he S p o ns or, e xce pt t o t he e xte nt 
necessar y t o o btai n i nf or me d c o nse nt fr o m s u bjects w h o wis h t o partici p ate i n t he st u d y or t o 
c o m pl y wit h re g ulat or y re q uire me nts.  
T he a n o n y mit y of partici pati n g s u bjects m ust be mai ntai ne d. S u bjects will be s pecifie d o n st u d y 
d oc u me nts b y t heir s u bject n u m ber, i nitial or bir t h date, n ot b y na me. D oc u me nts t hat i de ntif y t he 
s u bject (e. g., t he si g ne d I CF ) m ust be mai ntai ne d i n c o nfi de nce b y t he Pri nci pal I n v esti gat or . 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 6 0  of 6 7  
0 9  Ma y  2 0 2 2  
 
1 0. 9.  P u blic ati o n P olic y  
B y si g ni n g t he cli nical st u d y pr ot oc ol, t he Pri nci pal I n vesti gat or  a grees wit h t he use of re s ults of 
t he cli nical st u d y f or t h e p ur p oses of nati o nal a n d i nter nati o nal re gistrati o n, p u blicati o n a n d 
i nf or mati o n f or me dical a n d p har mace utical pr ofessi o nals. If necessar y, t h e re g ulat or y a ut h orities 
will be n otifie d of t he Pri nci pal I n vesti gat or ’s na me, a d dress, q u alifi cati o ns a n d e xte nt of 
i n v ol ve me nt. 
A Pri nci pal I n vesti gat or s hall n ot p u blis h a n y data ( p oster, a bstr act, pa p er, etc.) wit h o ut ha vi n g 
c o ns ulte d wit h t he S p o ns or i n a d va nce.  


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 6 1  of 6 7  
0 9  Ma y  2 0 2 2  
 
1 1.  
R E F E R E N C E LI S T  
A va u, B., A. R ot o n d o, T. T hijs,  et al. 2 0 1 5. ' Tar geti n g e xtra -oral bitter tast e rece pt ors 
m o d ulates gastr oi ntesti nal m otilit y wit h effects o n satiati o n', Sci Re p , 5: 1 5 9 8 5. 
Bra y, G. A., G. Fr u h bec k, D. H. R ya n, et al. 2 0 1 6. ' Ma na ge me nt of o b esit y', L a ncet , 3 8 7: 
1 9 4 7 -5 6.  
C he n, M. C., S. V. W u, J. R. Ree ve, Jr., et al. 2 0 0 6. ' Bitter sti m uli i n d uce Ca 2 + si g nali n g a n d 
C C K release i n e nt er oe n d ocri ne S T C -1 cells: r ole of L -t y pe v olta ge-se nsiti ve Ca 2 + 
c ha n nels', A m J P hysi ol Cell P hysi ol , 2 9 1: C 7 2 6-3 9.  
C olla b orat ors, G. B. D. O besit y, A. Afs hi n , M. H. F or o uza nfar, et al. 2 0 1 7. ' Healt h Effects of 
O ver wei g ht a n d O besit y i n 1 9 5 C o u ntries o ver 2 5 Years', N E n gl J Me d , 3 7 7: 1 3-2 7.  
Del o ose, E., P. Ja nsse n, M. C orsetti, et al. 2 0 1 7. 'I ntr a gastric i nf usi o n of de nat o ni u m 
be nz oate atte n uates i nter di gesti v e gastric m otilit y a n d h u n ger sc ores i n healt h y fe male 
v ol u nteers', A m J Cli n N utr , 1 0 5: 5 8 0-8 8.  
G u h, D. P., W. Z ha n g, N. Ba ns bac k, et al. 2 0 0 9. ' T he i nci de nce of c o -m or bi dities relate d t o 
o besit y a n d o ver wei g ht: a s yste matic re vie w a n d meta -a nal ysis', B M C  P u blic He alt h , 
9: 8 8.  
Hr u b y, A., a n d F. B. H u. 2 0 1 5. ' T he E pi de mi ol o g y of O besit y: A Bi g Pict ure', 
P h ar m ac oec o n o mics , 3 3: 6 7 3-8 9.  
Ja nsse n, S., J. Laer ma ns, P. J. Ver h ulst, et al. 2 0 1 1. ' Bitter taste rece pt ors a n d al p ha -g ust d uci n 
re g ulate t he s ecreti o n of g hreli n wit h f u ncti o nal effects o n f o o d i nta ke a n d gastric 
e m pt yi n g', Pr oc N atl Ac a d Sci U S A , 1 0 8: 2 0 9 4-9.  
Ki m, K. S., J. M. E ga n, a n d H. J. Ja n g. 2 0 1 4. ' De n at o ni u m i n d uces secreti o n of gl uca g o n -li ke 
pe pti de -1 t hr o u g h acti vati o n of bitter taste rece pt or pat h wa ys', Di a bet ol o gi a , 5 7: 
2 1 1 7 -2 5.  
R o d gers, R. J. 2 0 1 7. ' Be nc h t o be dsi de i n a p petite researc h: L ost i n tra nslati o n?', Ne ur osci 
Bi o be h av Rev , 7 6: 1 6 3-7 3.  
R osa -G o ncal v es, P., a n d D. Majer o wicz. 2 0 1 9. ' P har mac ot hera p y of O besit y: Li mits a n d 
Pers pecti ves',  A m J C ar di ov asc Dr u gs , 1 9: 3 4 9-6 4.  
Sc hier, L. A., T. L. Da vi ds o n, a n d T. L. P o wle y. 2 0 1 1. ' O n g oi n g i n gesti ve be ha vi or is ra pi dl y 
s u p presse d b y a prea bs or pti ve, i ntesti nal " bitter taste" c ue', A m J P hysi ol Re g ul I nte gr 
C o m p P hysi ol , 3 0 1: R 1 5 5 7-6 8.  
Si bert, J. R., a n d N. Fr u de. 1 9 9 1. ' Bitteri n g a ge nts i n t he pre ve nti o n of acci d e ntal p ois o ni n g: 
c hil dre n's reacti o ns t o de nat o ni u m be nz oate ( Bitre x)', Arc h E mer g Me d , 8: 1-7.  
 
 
 


Aar d var k T hera pe utics, I nc.  
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A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
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1 2.  
A P P E N DI X  
Pr ot oc ol: A A R D -2 0 1  
M M T T
 
S u bject #: _ _ _ _ _ _ _ _ _ _ _ _ _  
I R B # 2 1 0 2 1 0 
 
PI: Jere m y Pett us, M D 
Date: _ _ _ _ / _ _ _ _ _ _ / _ _ _ _ _ _ _ _  
S u bject I niti als:    _ _ _   _ _ _   _ _ _  
 
B o d y C o m p ositi o n  
Ti me: _ _ _ _ _ _ _ _ _ _ _ _  
Hei g ht: _ _ _ _ _ _ _ _ c m                 Wei g ht: _ _ _ _ _ _ _ _ _ _ k g                B MI: _ _ _ _ _ _ _ _  
 
 
B o d y Fat Perce nta ge: _ _ _ _ _ _ _ %  
St u d y Staff  I nitials a n d Date: _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Vit al Si g ns  
B P a n d He art R ate will be me as ure d i n t he sitti n g p ositi o n. T he s u bject M U S T be reste d f or at le ast 5 mi n.  
 
Ti me S u bject Starts Resti n g: _ _ _ _ _ _ _ _ _ _: _ _ _ _ _ _ _ _ _ _ _  
 
Ar m (circle):      L E F T           RI G H T          
 
Ti me: _ _ _ _ _ _ _ _ _ _ _        Bl o o d Press ure: _ _ _ _ _ _ _ _ _ / _ _ _ _ _ _ _ _ _ _ _ m m H g         Heart Rate: _ _ _ _ _ _ _ b p m  
 
A n y re pe at me as ure me nts of b ot h t he B P a n d he art r ate m ust be t a ke n at le ast 2 mi n . a p art a n d rec or de d. 
 
Ti m e: _ _ _ _ _ _ _ _ _ _ _        Bl o o d Press ure:  _ _ _ _ _ _ _ _ _ / _ _ _ _ _ _ _ _ _ _ _ m m H g         Heart Rate: _ _ _ _ _ _ _ b p m  
Res pir at or y R ate :  _ _ _ _ _ _ _ _ _ breat hs/ mi n ute                                    B o d y Te m per at ure : _ _ _ _ _ _ _ _ _ _ _ _ ○C  
St u d y Staff I nitials a n d Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
A E/ S A Es & C o nc o mit a nt Me dic ati o ns  
Di d s u bject ha v e a n y c h a n ges t o t heir c urre nt me dicati o ns?  
*If yes, n ote c h a n ges o n t he c o nc o mit a nt me dic ati o n l o g.  
 Y E S *    N O  
Di d s u bject re p ort a n y a d verse e v e nts or st u d y relate d pr o ble ms? 
*If yes, n ote c h a n ges o n t he A E/ S A E  l o g. 
 Y E S *    N O  
St u d y Staff  I nitials a n d Date: _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 6 3  of 6 7  
0 9  Ma y  2 0 2 2  
 
 
B aseli ne  
Di d s u bject f ast 1 0 h o urs as i nstr ucte d ?  
                                                                                                                             
Date of last meal:      _ _ _ _ _/ _ _ _ _ _ _ _ _/ _ _ _ _ _ _ Ti me of last meal:   _ _ _ _ : _ _ _ _                 Y E S      N O  
I nsert I V dr a w li ne i nt o a peri p her al ar m vei n a p pr o xi m atel y o ne h o ur bef ore first 
dr a w.  
St u d y Staff  I nitials a n d Date: _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Mi xe d Me al T oler a nce Test ( M M T T)  
S C H E D U L E D 
Ti m e p oi nt  
T ar g et 
ti m e  
( h h: m m) 
A C T U A L 
TI M E  
( h h: m m) 
S a m ple(s) c ollecte d / 
T as ks  
Y SI Gl uc ose 
re a di n g  
( at e ac h ti me p oi nt)  
 
Y SI # _ _ _ _ _  
N urse 
i niti als 
-1 2 0 mi n  
 
 
I nstr uct s u bject t o e m pt y bl a d der. 
 
 
-8 0 mi n  
 
 
St art I D C # 1:  
 
_ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
-5 0 mi n  
 
 
St o p I D C # 1:  
 
_ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
-3 0 mi n  
 
 
St u d y Dr u g Gi ve n I F S E C O N D M M T T  
 
Ti m e: _ _ _ _ _ _ _ _ _ _ _  
 
 
-1 5 mi n  
 
 
⃝ Gl uc os e  
⃝ F F A  
⃝ C C K  
⃝ GI P  
 
 
⃝ I ns uli n 
⃝ Gl uc a g o n  
⃝ P Y Y  
⃝ G L P -1  
⃝ C -Pe pti de  
⃝ G hreli n  
⃝ A m yli n  
 
 
-5 mi n  
 
 
⃝ Gl uc ose  
⃝ I ns uli n 
⃝ C -Pe pti de  
 
 
⃝ C yt o ki ne p a nel  
⃝
 Bile Aci ds/ Ferriti n/ C R P  
⃝ Le pti n/ A di p o necti n  
⃝  6 ml Ser u m st or a ge          
⃝  6 ml Pl as m a  st or a ge          
0 mi n  
 
 
Gi v e E ns ure li q ui d me al  
( 2 x E ns ure) 
C o ns u m e wit hi n 5 mi n utes  
 
St art Ti m e: _ _ _ _ _ _ _ _ _ _  
 
St o p Ti me: _ _ _ _ _ _ _ _ _ _ _  
 
 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 6 4  of 6 7  
0 9  Ma y  2 0 2 2  
 
1 5 mi n  
 
 
⃝ Gl uc ose  
⃝ I ns uli n 
⃝ C -Pe pti de  
 
 
⃝  4  ml Ser u m st or a ge          ⃝  4  ml Pl as m a  st or a ge          
3 0 mi n  
 
 
⃝ Gl uc ose  
⃝ I ns uli n 
⃝ C -Pe pti de  
 
 
 
⃝  4  ml Ser u m st or a ge          ⃝  4  ml Pl as m a  st or a ge          
6 0 mi n  
 
 
⃝ Gl uc ose  
⃝ I ns uli n 
 
 
⃝ C -Pe pti de  
⃝ F F A  
⃝  4  ml Ser u m st or a ge          ⃝  4  ml Pl as m a  st or a ge          
S C H E D U L E D 
Ti m e p oi nt  
T ar get 
ti m e  
( h h: m m) 
A C T U A L 
TI M E  
( h h: m m) 
S a m ple(s) c ollecte d/  
T as ks  
Y SI Gl uc ose 
re a di n g 
( at e ac h ti me 
p oi nt)  
 
Y SI # _ _ _ _ _  
N urse 
i niti als 
9 0 mi n  
 
 
⃝ Gl uc ose  
⃝ I ns uli n 
⃝ C -Pe pti de  
 
 
 
⃝  4  ml Ser u m st or a ge          ⃝  4  ml Pl as m a  st or a ge          
1 2 0 mi n  
 
 
 
⃝ Gl uc os e  
⃝ F F A  
⃝ C C K  
⃝ GI P  
 
 
 
⃝ I ns uli n 
⃝ Gl uc a g o n  
⃝ P Y Y  
⃝ G L P -1  
⃝ C -Pe pti de  
⃝ G hreli n  
⃝ A m yli n  
⃝  6  ml Ser u m st or a ge          ⃝  6 ml Pl as m a  st or a ge          
1 5 0 mi n  
 
 
⃝ Gl uc ose  
⃝ I ns uli n 
⃝ C -Pe pti de  
 
 
 
⃝  4  ml Ser u m st or a ge          
⃝  4  ml Pl as m a  st or a ge          
1 8 0 mi n  
 
 
⃝ Gl uc ose  
⃝ F F A  
 
 
⃝ I ns uli n 
⃝ C -Pe pti de  
⃝  4  ml Ser u m st or a ge          
⃝  4  ml Pl as m a  st or a ge          
1 9 5 mi n  
 
 
St a rt I D C  # 2 : 
 
_ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
2 1 0 mi n  
 
 
⃝ Gl uc ose  
⃝ I ns uli n 
⃝ C -Pe pti de  
 
 
 
⃝  4  ml Ser u m st or a ge          ⃝  4  ml Pl as m a  st or a ge          
2 2 5 mi n  
 
 
S t o p I D C # 2 : 
 
_ _ _ _ _ _ _ _ _ _ _ _ _  
 
 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 6 5  of 6 7  
0 9  Ma y  2 0 2 2  
 
2 4 0 mi n  
 
 
⃝ Gl uc os e  
⃝ F F A  
⃝ C C K  
⃝ GI P  
 
 
 
 
⃝ I ns uli n 
⃝ Gl uc a g o n  
⃝ P Y Y  
⃝ G L P -1  
⃝ C -Pe pti de  
⃝ G hreli n  
⃝ A m yli n  
⃝  4  ml Ser u m st or a ge          
⃝  4  ml Pl as m a  st or a ge          
A F T E R  fi n al bl o o d dr a w, re m o ve I V. 
N urse c o m pleti n g pr oce d ure Si g nat ure a n d Date: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Atte n di n g P h ysicia n ( PI/ S u b -I) Si g nat ure a n d Date: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
P ost -Pr oce d ure  
P ost pr oce d ure m e al e ate n ?                      Y E S      N O          Ti m e: _ _ _ _ _ _ _ _ _ _ _  
P ost -Pr o ce d ure Gl uc ose  C hec k ?                Y E S      N O          Ti m e: _ _ _ _ _ _ _ _ _ _ _           B G: _ _ _ _ _ _ _ _ _  
m g/ d L  
 
                                                                                                            Ti m e: _ _ _ _ _ _ _ _ _ _ _           B G: 
_ _ _ _ _ _ _ _ _  m g/ d L  
A n y A d verse E ve nts t o re p ort d uri n g o r after st u d y pr oce d ure ?  Y E S *    N O  
*If yes, ple ase descri be bel o w:  
 
 
St u d y Staff  I nitials a n d Date: _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 6 6  of 6 7  
0 9  Ma y  2 0 2 2  
 
P ost -pr oce d ure Vit al Si g ns  
B P a n d He art R ate will be me as ure d i n t he sitti n g p ositi o n. T he s u bject M U S T be reste d f or at le ast 5 mi n.  
 
Ti me S u bject Starts Resti n g: _ _ _ _ _ _ _ _ _ _: _ _ _ _ _ _ _ _ _ _ _  
 
Ar m (circle):       L E F T           RI G H T          
 
Ti me: _ _ _ _ _ _ _ _ _ _ _        Bl o o d Press ure: _ _ _ _ _ _ _ _ _ / _ _ _ _ _ _ _ _ _ _ _ m m H g         Heart Rate: _ _ _ _ _ _ _ b p m  
 
A n y re pe at me as ure me nts of b ot h t he B P a n d he art r ate m ust be t a ke n at le ast 2 mi n . a p art a n d rec or de d. 
 
Ti me: _ _ _ _ _ _ _ _ _ _ _        Bl o o d Press ure:  _ _ _ _ _ _ _ _ _ / _ _ _ _ _ _ _ _ _ _ _ m m H g         Heart Rate: _ _ _ _ _ _ _ b p m  
Res pir at or y R ate :  _ _ _ _ _ _ _ _ _ breat hs/ mi n ute                                    B o d y Te m per at ure : _ _ _ _ _ _ _ _ _ _ _ _ ○C  
St u d y Staff I nitials a n d Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Ne xt Visit  
 
N E X T VI SI T :  _ _ _ _ _/ _ _ _ _ _ _ _ _ _/ _ _ _ _ _ _ _ _ _ @ _ _ _ _ _ _: _ _ _ _ _ _ _ _  
W as s u bject gi ve n i nstr ucti o ns f or ne xt visit ?  
 Y E S   N O  
St u d y Staff I nitials a n d Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
N otes  
 
 
 
 
 
 
 
 


Aar d var k T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol Versi o n 6 . 0 
A A R D -2 0 2  
C O N FI D E N TI A L  
 
 
Pa ge 6 7  of 6 7  
0 9  Ma y  2 0 2 2  
 
 
 
 
 
 
 
 
 
 
 
 
St u d y Staff I nitials a n d Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _