Clinical trial NCT03334214
Conditions: Hepatic Steatosis
Keywords: Hepatic Steatosis IONIS-DGAT2Rx Type 2 Diabetes
Sponsor: Ionis Pharmaceuticals, Inc.
Start date: 2017-11-03; Completion date: 2018-11-28
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose is to assess the Safety, Tolerability, and Pharmacodynamics effect of IONIS DGAT2Rx in up to 45 Adult Patients with Type 2 Diabetes.

Detailed description:
This short-term study will assess changes in hepatic steatosis over a 13-week treatment period in a patient population with higher risk for development of Nonalcoholic fatty liver disease (NAFLD) and Nonalcoholic steatohepatitis (NASH), obese type 2 diabetes mellitus (T2DM) with elevated HbA1c.

Arms: arm 1: Single Dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks arm 2: Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks
Interventions: intervention 1: IONIS DGAT2Rx intervention 2: Placebo
Intervention descriptions: intervention 1: Single Dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks intervention 2: Saline 0.9%

Protocol documents:
Prot_SAP_000.pdf: 
T his s u p ple me nt c o ntai ns t he f oll o wi n g ite ms:
1. Ori gi nal pr ot oc ol, fi nal pr ot oc ol, s u m mar y of c ha n ges.
2. Ori gi nal statistical a nal ysis pla n, fi nal statistical a nal ysis pla n, s u m mar y of c ha n ges.
Ori gi nal Pr ot oc ol … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … …. … ….. 2
Fi nal Pr ot oc ol … … … … ….. … … … … … … … … … … … … … … … … … … … … … … … … …... … …...... 7 7
S u m mar y of C ha n ges t o Pr ot oc ol … … … … … … … … … … … … … … … … … … … … … … … … …. … .. 8 5
Ori gi nal/ Fi nal Statistical A nal ysis Pla n … …. … … … … … … … … … … … … … …..... … …. … … … ….. 1 5 7


IO NI S  P H A R M A C E U TI C A L S,  IN C . 
I SI S 4 8 41 3 7 - C S 2 
A D o u ble -Bli n d, R a n d o mize d, P l ace b o-C o ntr olle d, P h ase 2 St u d y to 
E v al u ate t he S afet y, T oler a bilit y a n d P h ar m ac o d y n a mics of 
I SI S 4 8 4 1 3 7  (ISI S - D G A T 2R X , a n A ntise nse I n hi bit or of 
Di ac yl gl ycer ol Ac yltr a nsfer ase 2) A d mi nistere d O nce- Wee kl y f or  
1 3  Wee ks o n He p atic Ste at osis i n A d ult P atie nts wit h T y pe 2     
Di a betes 
Ori gi n al Pr ot oc ol - 1 A u g ust  2 0 1 7 
E u dr a C T  N o:  2 0 1 7- 0 0 3 1 9 7- 1 3 
S p o ns or: 
I o nis P har mace uticals,  Inc. 
2 8 5 5 Gazelle C o urt 
Carls ba d, C A  9 2 0 1 0 


P P D


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
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I SI S 4 8 4 1 3 7  
I o nis Pr ot oc ol N u m ber I SI S 4 8 4 1 3 7-C S 2  
Ori gi n al Pr ot oc ol – 1 A u g ust 2 0 1 7 
E u dr a C T N o:  2 0 1 7- 0 0 3 1 9 7- 1 3 
Cli nic al P h ase:   2 
A D o u ble -Bli n d, R a n d o mi ze d, Pl ace b o -C o ntr olle d, P h ase 2 St u d y t o 
E v al u ate t he S afet y, T oler a bilit y a n d P h ar m ac o d y n a mics of 
I SI S 4 8 4 1 3 7 ( I SI S- D G A T 2R X , a n A ntise nse I n hi bit or of 
Di ac yl gl ycer ol Ac yltr a nsfer ase 2) A d mi nistere d O nce -Wee kl y f or 
1 3  Wee ks o n He p atic Ste at osis i n A d ult P atie nts wit h T y pe 2 
Di a betes 
Trial S p o ns or: 
I o nis P har m ace uticals, I n c 
2 8 5 5 Gazelle C o urt 
Carls ba d, C A 9 2 0 1 0 
P h o ne + 0 1 7 6 0 9 3 1 9 2 0 0 
Fa x + 0 1 7 6 0 6 0 3 3 5 6 4  
Ke y S p o ns or C o ntact: 
 
E x ec uti ve Direct or, Cli nical De v el o p me nt  
P h o ne 
 
Date:  
1 A u g ust  2 0 1 7  
C o nfi de nti a lit y St ate 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 I o nis P har mace uticals, I n c .  t hat m ust n ot be 
discl ose d t o a n y o n e ot her t ha n t he reci pie nt st u d y staff a n d me m bers of t he i n de pe n de nt et hics 
c o m mittee, i nstit uti o nal re vie w b oar d, or a ut h orize d r e gulat or y a ge ncies.  T his i nf or mati o n 
ca n n ot be use d f or a n y p ur p ose ot her t ha n t he e val uati o n or c o n d uct of t he cli nical i n vesti gati o n 
wit h o ut t he pri or writte n c o nse nt of I o nis P har mace uticals, I nc . 
P P D
P P D


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
4
P R O T O C O L SI G N A T U R E P A G E  
Pr ot oc ol N u m ber:  
I SI S 4 8 4 1 3 7-C S 2 
Pr ot oc ol Title:  
A D o u ble- Bli n d, Ra n d o mize d, Place b o- C o ntr olle d, P hase 2 St u d y t o 
E val uate t he Safet y, T olera bilit y a n d P har mac o d y na mics of I SI S 4 8 4 1 3 7 
(I SI S-D G A T 2 R X , a n A ntise nse I n hi bit or of Diac yl gl ycer ol Ac yltra nsferase 
2)  A d mi nistere d O nce- Wee kl y f or 1 3 Wee k s o n H e patic Steat osis i n A d ult
Patie nts wit h T y pe 2 Dia betes
A me n d me nt:   
Ori gi nal Prot oc ol
D ate:  
1 A u g ust 2 0 1 7  
I h ere b y ac k n o wl e d ge t h at I h a ve rea d a n d u n dersta n d t he attac he d cli nical pr ot oc ol , e ntitle d “A 
D o u ble- Bli n d, Ra n d o mize d, Place b o- C o ntr olle d, P hase 2 St u d y t o E val uat e t he Safet y, 
T olera bilit y a n d P har mac o d y na mics of I SI S 4 8 4 1 3 7 ( I SI S-D G A T 2 R X , a n A ntise nse I n hi bit or of 
Diac yl gl ycer ol A c ylt ra nsferas e 2) A d mi nistere d O nce-Wee kl y f or 1 3 Wee ks o n He patic 
Steat osis i n A d ult  Patie nts wit h T y pe 2 Di a betes , ” dated 1 A u g ust 2 0 1 7 , a nd a gree t o c o n d uct t he 
st u d y as des cri be d h erei n.  
I a gree t o c o m pl y wit h t he I nter n ati o nal C o nfere n ce o n Har m o nizati o n  Tri partite G ui deli ne o n 
G o o d Cli nical Practice ( E 6).  
I a gree t o e ns ur e t hat t he c o nfi de ntial i nf or mati o n c o ntai ne d i n t his d oc u me nt will n ot be use d f or 
a n y p ur p ose ot her t ha n t he e val uati o n or c o n d uct of t he cli nical i n vesti gati o n wit h o ut t he pri or 
writte n c o nse nt of I o nis P har mace uticals, I nc .   
I n v esti gat or’s Si g n at ure 
I n v esti gat or’s N a me ( ple ase p ri nt) 
Date ( D D M o nt h Y Y Y Y)  


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
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T A B L E O F C O N T E N T S  
P a ge 
P R O T O C O L SI G N A T U R E P A G E  ............................................................................................. 4
P R O T O C O L S Y N O P SI S  ............................................................................................................. 9
S T U D Y D E S I G N A N D T R E A T M E N T S C H E M A .................................................................. 1 6
S T U D Y G L O S S A R Y  .................................................................................................................. 1 7
1.
O B J E C TI V E S  ................................................................................................................. 2 1
1. 1
Pri m ar y O bj ecti ve(s)  ...................................................................................................... 2 1
1. 2
Sec o n d ar y O bj ecti ve(s)  .................................................................................................. 2 1
1. 3 
E x pl orat or y O bjecti ves .................................................................................................. 2 1
2.
B A C K G R O U N D A N D R A TI O N A L E  .......................................................................... 2 1
2. 1
O ver v ie w of Diseas e ...................................................................................................... 2 1
2. 2
T hera p e utic Rati o nale  .................................................................................................... 2 2
2. 2. 1
O ver v ie w of Tar get ................................................................................................ 2 2
2. 2. 2
T hera p e utic Rati o nale  ............................................................................................. 2 3
2. 3 
I SI S 4 8 4 1 3 7 ................................................................................................................... 2 4
2. 3. 1
Mec ha ni s m of A cti o n ............................................................................................. 2 4
2. 3. 2
C he mis tr y ............................................................................................................... 2 4
2. 3. 3
Precli nical E x perie nce  ............................................................................................ 2 5
2. 3. 4
Cli n ical E x perie nce ................................................................................................ 2 6
2. 4 
Rat i o nale f or D ose a n d Sc he d ule of A d mi nistrati o n ..................................................... 2 7
2. 5
Ris k A ssess me nt ............................................................................................................ 2 7
3.
E X P E RI M E N T A L P L A N  .............................................................................................. 2 7
3. 1
St u d y Desi g n  .................................................................................................................. 2 7
3. 2  
N u m be r of St u d y C e nters .............................................................................................. 2 8
3. 3  
N u m be r of S u bjects ....................................................................................................... 2 8
3. 4  
O ver all St u d y D urati o n a n d F oll o w- u p ......................................................................... 2 8
3. 4. 1
Scree ni n g a n d R u n -I n ............................................................................................. 2 8
3. 4. 2
Treat m e nt  ................................................................................................................ 2 8
3. 4. 3 
P ost - Treat me nt ....................................................................................................... 2 8
3. 5
E n d - of-St u d y .................................................................................................................. 2 8
4.
S U B J E C T E N R O L L M E N T  ........................................................................................... 2 9
4. 1
Scree ni n g  ....................................................................................................................... 2 9
4. 2 
Ra n d o m izati o n ............................................................................................................... 2 9
4. 3
Re place m e nt of S u bjects  ................................................................................................ 2 9
4. 4  
U n bli n di n g of Tr eat me nt Assi g n me nt ........................................................................... 2 9
5.
S U B J E C T E LI GI BI LI T Y  .............................................................................................. 3 0
5. 1
I ncl usi o n Criteria  ........................................................................................................... 3 0
5. 2
E x cl u si o n Criteria .......................................................................................................... 3 1


I SI S 4 8 4 1 3 7-C S 2  
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S T U D Y P R O C E D U R E S  ................................................................................................ 3 3
6. 1 
St u d y Sc h e d ule .............................................................................................................. 3 3
6. 1. 1
Scree ni n g Peri o d ( Wee k - 6 t o Week - 5) ................................................................ 3 3
6. 1. 2 
R u n-I n Peri o d ( Wee k - 4 t hr u Wee k - 1) .................................................................. 3 4
6. 1. 2. 1
Li ve r M RI Assess me nt ( Wee k - 4 t o Wee k - 3) ................................................ 3 4
6. 1. 2. 2 
R u n- I n Wee k - 1................................................................................................ 3 4
6. 1. 3
Treat m e nt Peri o d ( Wee ks 1 - 1 3) ............................................................................. 3 5
6. 1. 4 
P ost -Treat me nt Peri o d ( P T 1 - 1 3) ........................................................................... 3 5
6. 2
La b or at or y Ass ess me nts  ................................................................................................ 3 6
6. 3
Restr icti o n o n t he Lif est yle of S u bjects ......................................................................... 3 7
6. 3. 1 
C o ntr ace pti o n Re q uire m e nts .................................................................................. 3 7
6. 3. 2
Fasti n g Re q uire me nts  ............................................................................................. 3 7
6. 3. 3
Lif es t yle restricti o ns ............................................................................................... 3 7
7.
S T U D Y D R U G  ................................................................................................................ 3 7
7. 1
St u d y  Dr u g D esc ri pti o n ................................................................................................. 3 7
7. 2
Pac ka g i n g a n d La b eli n g ................................................................................................. 3 8
7. 3 
St u d y Dr u g A cc o u nta bilit y ............................................................................................ 3 8
8.
T R E A T M E N T O F S U B J E C T S ..................................................................................... 3 8
8. 1
St u d y  Dr u g A d mi nistrati o n ............................................................................................ 3 8
8. 2  
Ot he r Pr ot oc ol-Re q uire d Dr u gs  ..................................................................................... 3 8
8. 3  
Ot he r Pr ot oc ol-Re q uir e d Treat me nt Pr oce d ures  ............................................................ 3 8
8. 4
Treat m e nt Preca uti o ns  ................................................................................................... 3 8
8. 5 
Saf et y M o nit ori n g R ules ................................................................................................ 3 8
8. 5. 1
Safet y  M o nit ori n g R ules f or Li v er C he mistr y Tests  .............................................. 3 9
8. 5. 2
Safe t y M o nit ori n g R ules f or Platelet C o u nt Res ults .............................................. 4 0
8. 5. 3
M o nit o ri n g R ules f or D eteri orati n g Gl yce mic C o ntr ol .......................................... 4 1
8. 6 
St o p pi n g R ules ............................................................................................................... 4 1
8. 6. 1 
St o p pi n g R ules f or Li ver C he mistr y Ele vati o ns ..................................................... 4 1
8. 6. 2 
Te m p orar y St o p pi n g R ul es f or Re nal F u ncti o n Test Res ults ................................. 4 2
8. 6. 3 
St o p pi n g R ule f or Platelet C o u nt Res ults ............................................................... 4 2
8. 6. 4 
St o p pi n g R ules f or D oc u me nte d Se vere H y p o gl yc e mia ........................................ 4 3
8. 7  
A dj us t me nt of oral a nti dia betic re gi me n f or s u bjects wit h persiste nt h y per gl yce mic ... 4 3
8. 8  
Dis c o nti n uati o n of St u d y Dr u g ...................................................................................... 4 3
8. 9  
Wit h dra wal of S u bjects fr o m t he St u d y ......................................................................... 4 4
8. 1 0 
C o nc o m ita nt T hera p y a n d Pr oce d ures ........................................................................... 4 5
8. 1 0. 1 
C o nc o m ita nt T hera p y ............................................................................................. 4 5
8. 1 0. 2 
C o nc o m ita nt Pr oce d ures ......................................................................................... 4 6
8. 1 1
Trea t me nt C o m plia nce ................................................................................................... 4 6
9.
S E RI O U S A N D N O N -S E RI O U S A D V E R S E E V E N T R E P O R TI N G  ...................... 4 6
9. 1 
S p o ns or  Re vie w of Safet y I nf or mati o n ......................................................................... 4 6


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9. 2
Re g ulat or y Re q uire me nts  .............................................................................................. 4 6
9. 3
Defi n iti o ns ..................................................................................................................... 4 6
9. 3. 1
A d ver se E v e nt ........................................................................................................ 4 6
9. 3. 2
A d ver se Reacti o n a n d S us pecte d A d verse Reacti o n .............................................. 4 7
9. 3. 3 
Ser i o us A d verse E v e nt ( S A E) ................................................................................ 4 7
9. 4  
M o nit ori n g a n d Rec or di n g A d v erse E v e nts ................................................................... 4 7
9. 4. 1 
Ser i o us A d verse E v e nts .......................................................................................... 4 7
9. 4. 2
N o n - Seri o us A d vers e E v e nts .................................................................................. 4 8
9. 4. 3 
E val uati o n of A d vers e E ve nts ( Seri o us a n d N o n- Seri o us) .................................... 4 8
9. 4. 3. 1 
Rel ati o ns hi p t o t he St u d y Dr u g ........................................................................ 4 8
9. 4. 3. 2
Se veri t y ............................................................................................................ 4 9
9. 4. 3. 3
Acti o n Ta ke n wit h St u d y Dr u g ........................................................................ 4 9
9. 4. 3. 4
Treat m e nt Gi ve n f or A d v erse E ve nt  ................................................................ 4 9
9. 4. 3. 5  
O utc o me of t he A d v erse E ve nt ........................................................................ 4 9
9. 5 
Pr oc e d ures f or H a n dli n g S pecial Sit uati o ns .................................................................. 5 0
9. 5. 1  
A b n or m alities of La b or at or y T ests ......................................................................... 5 0
9. 5. 2 
Pre sc he d ule d or Electi ve Pr oce d ures or R o uti nel y Sc he d ule d Treat me nts ............ 5 0
9. 5. 3  
D osi n g Err ors ......................................................................................................... 5 0
9. 5. 4 
C o ntr ace pti o n a n d Pre g n a nc y ................................................................................. 5 1
1 0.
S T A TI S TI C A L C O N SI D E R A TI O N S  .......................................................................... 5 1
1 0. 1 
St u d y E n d p oi nts, S u bsets, a n d C o variates ..................................................................... 5 1
1 0. 1. 1
Safe t y E n d p oi nts ..................................................................................................... 5 1
1 0. 1. 2 
Pri mar y P har mac o d y na mic E n d p oi nt ..................................................................... 5 2
1 0. 1. 3 
Sec o n dar y E n d p oi nts .............................................................................................. 5 2
1 0. 1. 4 
E x pl orat or y E n d p oi nts ............................................................................................ 5 2
1 0. 2 
Sa m ple Size C o nsi derati o ns ........................................................................................... 5 2
1 0. 3 
P o p ula ti o ns ..................................................................................................................... 5 2
1 0. 4
Defi n iti o n of Bas eli ne .................................................................................................... 5 3
1 0. 5
I nteri m A nal ysis ............................................................................................................. 5 3
1 0. 6 
Pla n ne d Met h o ds of A nal ysis ........................................................................................ 5 3
1 0. 6. 1
De m o g ra p hic a n d Baseli ne C haracteristics ............................................................ 5 3
1 0. 6. 2
Safet y  A nal ysis ....................................................................................................... 5 4
1 0. 6. 3
P har m ac o ki netic A n al ysis  ...................................................................................... 5 4
1 0. 6. 4
P har m ac o d y na mic/ Efficac y A nal ysis  ..................................................................... 5 4
1 0. 6. 5  
A d dit i o nal A nal yses ............................................................................................... 5 4
1 1.
I N V E S TI G A T O R’ S R E G U L A T O R Y O B LI G A TI O N S ............................................. 5 5
1 1. 1 
I nf or me d C o nse nt .......................................................................................................... 5 5
1 1. 2 
Et hi cal C o n d uct of t he St u d y ......................................................................................... 5 5
1 1. 3
I n d epe n de nt Et hics C o m mittee/I nstit uti o nal Re vie w B oar d  ......................................... 5 5
1 1. 4
S u bje ct C o nfi de ntialit y .................................................................................................. 5 6


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
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1 2.
A D MI NI S T R A TI V E A N D L E G A L O B LI G A TI O N S  ................................................ 5 6
1 2. 1 
Pr ot oc ol A me n d me nts .................................................................................................... 5 6
1 2. 2
St u d y  Ter mi nati o n ......................................................................................................... 5 6
1 2. 3 
St u d y D oc u me ntati o n a n d St ora ge ................................................................................ 5 6
1 2. 4 
St u d y M o nit ori n g ........................................................................................................... 5 7
1 2. 5
La n g u a ge  ........................................................................................................................ 5 8
1 2. 6 
C o m pe nsati o n f or I nj ur y ................................................................................................ 5 8
1 3.
R E F E R E N C E S  ................................................................................................................ 5 9
1 4.
A P P E N DI C E S  ................................................................................................................. 6 2
A p pe n di x  A 
Sc he d ule of Pr oce d ures .................................................................................... 6 3
A p pe n di x  B
List of La b orat or y A n al ytes  ............................................................................. 6 8
A p pe n di x  C 
P K Sa m pli n g Sc he d ule .................................................................................... 7 0
A p pe n di x  D  
Gra di n g Scale f or A d v erse E ve nts Relati n g t o La b orat or y A b n or m alities...... 7 2
T A B L E O F T A B L E S  
P a ge 
Ta ble 1
St u d y Dr u g C har acteristics  .................................................................................... 3 8
Ta ble 2
A d diti o nal La bs t o be Perf or me d i n t he E v e nt of a Pl atelet C ou nt 
< 7 5, 0 0 0/ m m 3 ......................................................................................................... 4 0
T A B L E O F FI G U R E S  
P a ge 
Fi g ure 1
Desi g n of C hi meric 2 ′- M O E Ph os p h or ot hi oate Oli g o n ucl e oti des  
( M O E-Ga p m er)  ...................................................................................................... 2 5


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
Ori gi nal 
Pr ot oc ol  
1 A u g us t 2 0 1 7 
9
 
P R O T O C O L S Y N O P SI S 
Pr ot o c ol Titl e 
A D o u bl e- Bli n d, R a n d o mi z e d, Pl a c e b o- C o ntr oll e d, P h a s e 2 St u d y t o 
E v al u at e t h e S af et y, T ol er a bilit y a n d P h ar m a c o d y n a mi c s of I SI S 4 8 4 1 3 7 
(I SI S- D G A T 2R X , a n A nti s e n s e I n hi bit or of Di a c yl gl y c er ol A c yltr a n sf er a s e 2) 
A d mi ni st er e d O n c e- W e e kl y f or 1 3 W e e k s o n H e p ati c St e a t o si s i n A d ult 
P ati e nt s wit h T y p e 2 Di a b et e s 
St u d y P h a s e 
2 
I n di c ati o n 
H e p ati c St e at o si s i n t y p e 2 di a b et e s ( T 2 D M) 
Pri m ar y O bj e cti v e( s) 
T o e v al u at e t h e s af et y a n d t ol er a bilit y of I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
s u b c ut a n e o u s ( S C) i nj e cti o n i n a d ult s u bj e ct s wit h T 2 D M. 
T o e v al u at e t h e p h ar m a c o d y n a mi c eff e ct s of I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
S C i nj e cti o n o n t h e a b s ol ut e r e d u cti o n of li v er f at ( a s s e s s e d b y m a g n eti c 
r e s o n a n c e i m a gi n g [ M RI] pr ot o n d e n sit y f at fr a cti o n [ P D F F]) i n a d ult s u bj e ct s 
wit h T 2 D M. 
S e c o n d ar y O bj e cti v e( s) 
T o e v al u at e t h e p h ar m a c o d y n a mi c eff e ct s of I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
S C i nj e cti o n o n li v er f at ( p er c e nt r el ati v e r e d u cti o n a n d p er c e nt of s u bj e ct s 
wit h ≥ 3 0 % r el ati v e r e d u cti o n) a s s e s s e d b y M RI- P D F F. 
T o e v al u at e t h e p h ar m a c o d y n a mi c eff e ct s of I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
S C i nj e cti o n o n li v er v ol u m e a s s e s s e d b y M RI- P D F F. 
T o e v al u at e t h e p h ar m a c o d y n a mi c eff e ct s of I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
S C i nj e cti o n o n pl a s m a li p o pr ot ei n pr ofil e (tri gl y c eri d e s [ T G], t ot al c h ol e st er ol, 
l o w d e n sit y li p o pr ot ei n c h ol e st er ol [ L D L- C], a p oli p o pr ot ei n B [ a p o B], v er y l o w 
d e n sit y li p o pr ot ei n s [ V L D L], hi g h d e n sit y li p o pr ot ei n [ H D L] a n d N o n- H D L). 
T o e v al u at e t h e p h ar m a c o d y n a mi c eff e ct s of I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
S C i nj e cti o n o n i n s uli n r e si st a n c e (I R) a n d gl u c o s e c o ntr ol (i n s uli n, gl u c o s e, 
h o m e o st ati c m o d el a s s e s s m e nt-i n s uli n r e si st a n c e [ H O M A-I R], h e m o gl o bi n 
A 1 c [ H b A 1 c]). 
E x pl or at or y O bj e cti v e( s) 
T o e v al u at e t h e p h ar m a c o d y n a mi c eff e ct s of I SI S 4 8 4 1 3 7 o n p ot e nti al 
bi o m ar k er s of D G A T 2 a cti vit y, ( e. g ., st e ar o yl- C o A d e s at ur a s e- 1 [ S C D- 1]) a n d 
bi o m ar k er s of h e p ati c i nfl a m m ati o n ( e. g ., c yt o k er ati n 1 8 ( C K 1 8), h a pt o gl o bi n) 
St u d y D e si g n 
R a n d o mi z e d, d o u bl e- bli n d, pl a c e b o c o ntr oll e d, m ulti- c e nt er 
N u m b er of S u bj e ct s 
A p pr o xi m at el y 4 5 p ati e nt s ar e pl a n n e d t o  b e r a n d o mi z e d i n a 2: 1 r ati o t o 
r e c ei v e S C tr e at m e nt wit h eit h er I SI S 4 8 4 1 3 7 or pl a c e b o 
St u d y P o p ul ati o n 
I n cl u si o n Crit eri a 
1.  M u st h a v e gi v e n writt e n i nf or m e d c o n s e nt ( si g n e d a n d d at e d) a n d a n y
a ut h ori z ati o n s r e q uir e d b y l o c al l a w a n d b e a bl e t o c o m pl y wit h all
st u d y r e q uir e m e nt s
2.  M al e s or f e m al e s.  A g e d 1 8 t o 7 5, i n cl u si v e, at t h e ti m e of i nf or m e d
c o n s e nt
3. F e m al e s m u st b e n o n- pr e g n a nt a n d n o n- l a ct ati n g, a n d eit h er s ur gi c all y
st eril e ( e. g., t u b al o c cl u si o n, h y st er e ct o m y, bil at er al s al pi n g e ct o m y,
bil at er al o o p h or e ct o m y) or p o st- m e n o p a u s al ( d efi n e d a s 1 2 m o nt h s of
s p o nt a n e o u s a m e n orr h e a wit h o ut a n alt er n ati v e m e di c al c a u s e a n d
F S H l e v el s i n t h e p o st m e n o p a u s al r a n g e f or t h e l a b or at or y i n v ol v e d
M al e s m u st b e s ur gi c all y st eril e, a b sti n e nt * or, if e n g a g e d i n s e x u al
r el ati o n s wit h a f e m al e of c hil d- b e ari n g p ot e nti al, t h e s u bj e ct m u st b e
u si n g a n a c c e pt a bl e c o ntr a c e pti v e m et h o d (r ef er t o S e cti o n 6. 3. 1 ) fr o m
t h e ti m e of si g ni n g t h e i nf or m e d c o n s e nt f or m u ntil at l e a st 1 3 w e e k s
aft er t h e l a st d o s e of St u d y Dr u g (I SI S 4 8 4 1 3 7 or pl a c e b o)


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
1 0
 
P R O T O C O L S Y N O P SI S  C o nti n ue d  
St u d y P o p ul ati o n  C o nti n u e d  
I n cl u si o n Crit eri a C o nti n u e d  
* A b sti n e n c e i s o nl y a c c e pt a bl e a s tr u e a b sti n e n c e, i. e., w h e n t hi s i s i n
li n e wit h t h e pr ef err e d a n d u s u al lif e st yl e of t h e p ati e nt.  P eri o di c
a b sti n e n c e ( e. g., c al e n d ar, o v ul ati o n, s y m pt ot h er m al, p o st -o v ul ati o n
m et h o d s), d e cl ar ati o n of a b sti n e n c e f or t h e  d ur ati o n of a tri al a n d
wit h dr a w al ar e n ot a c c e pt a bl e m et h o d s of c o ntr a c e pti o n
4.
B o d y M a s s I n d e x ( B MI) ≥ 2 7. 0 - ≤ 3 9. 0 k g/ m 2
5.
Di a g n o si s of  T 2 D M wit h a n H b A 1 c ≥ 7. 3 % a n d ≤ 9. 5 % at S cr e e ni n g
6.
S u bj e ct s m u st h a v e b e e n o n a st a bl e d o s e of t h e f oll o wi n g or al
a nti di a b eti c t h er a p y:  m etf or mi n, s ulf o n yl ur e a ( S U), di p e pti d yl
p e pti d a s e -I V ( D P PI V i n hi bit or) or s o di u m gl u c o s e li k e tr a n s p ort pr ot ei n
2 ( S G L T 2) i n hi bit or f or a mi ni m u m of 3 m o nt h s pri or t o s cr e e ni n g
e v al u ati o n a n d will b e r e q uir e d t o c o nti n u e t h eir st a bl e d o s e of or al
a nti di a b eti c t h er a p y t hr o u g h o ut t h e st u d y.  T h e u s e of
t hi a z oli di n e di o n e s ( e. g., pi o glit a z o n e, r o si glit a z o n e) a n d i nj e ct a bl e
a nti di a b eti c t h er a p y i s n ot p er mitt e d ( e. g ., i n s uli n, gl u c a g o n-li k e p e pti d e
[G L P 1 a n al o g s ])
7.
≥ 1 0 % li v er f at a s  a s s e s s e d b y M RI -P D F F pri or t o r a n d o mi z ati o n
8.
St a bl e b o d y w ei g ht  ( B W) (i. e., n ot v ar yi n g b y > 5 % f or at l e a st
3 m o nt h s) b ef or e S cr e e ni n g
9.
A gr e e t o m ai nt ai n c urr e nt di et a n d e x er ci s e r e gi m e n
1 0.
A gr e e t o a b st ai n fr o m al c o h oli c b e v er a g e s f or at l e a st 4 8 h o ur s pri or t o
cli ni c vi sit s a n d n ot i n cr e a s e al c o h ol c o n s u m pti o n d uri n g t h e st u d y
E x cl u si o n Crit eri a  
1.
Cli ni c all y -si g nifi c a nt a b n or m aliti e s i n m e di c al hi st or y ( e. g., pr e vi o u s
a c ut e c or o n ar y s y n dr o m e wit hi n 6 m o nt h s of S cr e e ni n g, m aj or s ur g er y
wit hi n 3 m o nt h s of S cr e e ni n g) or p h y si c al e x a mi n ati o n
2.
C e ntr al l a b or at or y r e s ult s pri or t o r a n d o mi z ati o n ( S cr e e ni n g a n d/ or
R u n -I n) a s f oll o w s, or a n y ot h er cli ni c all y -si g nifi c a nt  a b n or m aliti e s i n
S cr e e ni n g l a b or at or y v al u e s t h at w o ul d r e n d er a s u bj e ct u n s uit a bl e f o r
i n cl u si o n:
a.
Uri n e pr ot ei n/ cr e ati ni n e ( P/ C) r ati o > 0. 2 m g/ m g.  I n t h e e v e nt of
P/ C r ati o a b o v e t hi s t hr e s h ol d eli gi bilit y m a y b e c o nfir m e d b y a
q u a ntit ati v e t ot al uri n e pr ot ei n m e a s ur e m e nt of < 3 0 0 m g/ 2 4 -hr
b.
P er si st e ntl y p o siti v e t e st (i n cl u di n g tr a c e) f or bl o o d o n uri n al y si s.  I n
t h e e v e nt of a p o siti v e t e st eli gi bilit y m a y b e c o nfir m e d wit h uri n e
mi cr o s c o p y s h o wi n g <  5 r e d bl o o d c ell s ( R B C) p er hi g h p o w er fi el d
( P er si st e ntl y p o siti v e d efi n e d a s 2 o ut of 3)
c.
S er u m cr e ati ni n e > u p p er li mit of n or m al  ( U L N)
d.
E sti m at e d gl o m er ul ar filtr ati o n r at e  (G F R ) < 6 0 m L/ mi n ( a s
d et er mi n e d b y t h e C o c k cr oft -G a ult E q u ati o n f or cr e ati ni n e
cl e ar a n c e)
e.
Al a ni n e a mi n otr a n sf er a s e ( A L T) or a s p art at e a mi n otr a n sf er a s e
( A S T) > 1. 5 U L N
f.
T ot al bilir u bi n > U L N
g.
H a v e a c ur r e nt or pr e vi o u s di a g n o si s of Gil b ert’ s di s e a s e
h.
Pl at el et c o u nt < 1 7 0, 0 0 0/ m m 3  ( < 1 7 0 X 1 09 / L)


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
1 1
 
P R O T O C O L S Y N O P SI S  C o nti n ue d  
St u d y P o p ul ati o n  C o nti n u e d  
E x cl u si o n Crit eri a  C o nti n u e d  
3.
S h o w e vi d e n c e of u n c orr e ct e d h y p ot h yr oi di s m or h y p ert h yr oi di s m
h or m o n e r e s ult s at S cr e e ni n g .  S u bj e ct s r e c ei vi n g d o s e -st a bl e t h yr oi d
r e pl a c e m e nt t h er a p y f or at l e a st 3 m o nt h s pri or t o S cr e e ni n g will b e
all o w e d t o p arti ci p at e a s l o n g a s t h yr oi d t e st s ( T S H/ T 3/ T 4) s h o w t h at
s u bj e ct  i s e ut h yr oi d
4.
Hi st or y of s oli d or g a n tr a n s pl a nt ati o n or r e n al di al y si s
5.
Cli ni c all y -si g nifi c a nt c o m pli c ati o n s of di a b et e s ( e. g ., hi st or y of p ai nf ul
n e ur o p at h y, n e p hr o p at h y, pr olif er ati v e r eti n o p at h y a n d/ or f o ot ul c er s)
6.
S u bj e ct s o n li pi d l o w eri n g m e di c ati o n s m u st b e o n a st a bl e d o s e a n d
r e gi m e n f or ≥ 3 m o nt h s pri or t o S cr e e ni n g.  S u bj e ct s r e c ei vi n g
tr e at m e nt wit h st ati n s s h o ul d b e wit hi n t h e d o s e l e v el s li st e d b el o w.
Ot h er st ati n r e gi m e n s s h o ul d b e di s c u s s e d a n d a p pr o v e d wit h t h e
S p o n s or M e di c al M o nit or or d e si g n e e
•
Si m v a st ati n, pr a v a st ati n, at or v a st ati n a n d fl u v a st ati n at
≤ 4 0  m g/ d a y
•
L o v a st ati n or r o s u v a st ati n at ≤ 2 0 m g/ d a y
•
Pit a v a st ati n u p t o 4 m g/ d a y
7.
K n o w n hi st or y of or e vi d e n c e of li v er di s e a s e wit h a p o siti v e t e st f or
h u m a n i m m u n o d efi ci e n c y vir u s ( HI V), h e p atiti s C ( H C V) or c hr o ni c
h e p atiti s B ( H B V) or c hr o ni c li v er di s e a s e ot h er t h a n N A S H i n cl u di n g
al c o h ol i c li v er di s e a s e, W il s o n’ s di s e a s e, h e m o c hr om at o si s, or ir o n
o v erl o a d, Al p h a - 1-a ntitr y p si n ( A 1 A T) d efi ci e n c y,  pri or k n o w n dr u g -
i n d u c e d li v er i nj ur y, k n o w n or s u s p e ct e d h e p at o c ell ul ar c ar ci n o m a
(H C C ), c urr e nt pl a c e m e nt o n a li v er tr a n s pl a nt li st, or M E L D s c or e
> 1 2, e st a bli s h e d fi br o si s ≥ St a g e 3 fi br o si s ( S c al e 0-4) or a n y cirr h o si s
8.
M ali g n a n c y wit hi n 5 y e ar s, e x c e pt f or b a s al or s q u a m o u s c ell
c ar ci n o m a of t h e s ki n or c ar ci n o m a i n sit u of t h e c er vi x t h at h a s b e e n
s u c c e s sf ull y tr e at e d .  S u bj e ct s wit h a hi st or y of ot h er m ali g n a n ci e s t h at
h a v e b e e n  tr e at e d wit h c ur ati v e i nt e nt a n d w hi c h h a v e n o r e c urr e n c e
wit hi n 5 y e ar s m a y al s o b e eli gi bl e if a p pr o v e d b y t h e S p o n s or M e di c al
M o nit or
9 . Tr e at m e nt wit h a n ot h er i n v e sti g ati o n al dr u g, bi ol o gi c al a g e nt, or d e vi c e
wit hi n 1 m o nt h of S cr e e ni n g, or 5 h alf -li ve s of i n v e sti g ati o n al a g e nt,
w hi c h e v er i s l o n g er
1 0 . Tr e at m e nt wit h a n y n o n - I O N- or I SI S -oli g o n u cl e oti d e (i n cl u di n g s m all
i nt erf eri n g ri b o n u cl ei c a ci d [si R N A ]) at a n y ti m e or pri or tr e at m e nt wit h
a n I O N - or I SI S -oli g o n u cl e oti d e wit hi n 9 m o nt h s of S cr e e ni n g .
S u bj e ct s w h o h a v e pr e vi o u sl y r e c ei v e d o nl y a si n gl e -d o s e of a n
I SI S-oli g o n u cl e oti d e a s p art of a cli ni c al st u d y m a y b e i n cl u d e d a s l o n g
a s a d ur ati o n of ≥ 4 m o nt h s h a s el a p s e d si n c e d o si n g
1 1 . R e c e nt hi st or y of, or c urr e nt dr u g or al c o h ol a b u s e .  R e g ul ar a n d
e x c e s si v e u s e of al c o h ol wit hi n 6 m o nt h s pri or t o S cr e e ni n g
( > 7 dri n k s/ w e e k f or f e m al e s, > 1 4 dri n k s/ w e e k f or m al e s ( 1 dri n k =
5 o u n c e s ( 1 5 0 m L) of wi n e or 1 2  o u n c e s ( 3 6 0 m L) of b e er or
1. 5  o u n c e s ( 4 5 m L) of h ar d li q u or), or u s e of s oft dr u g s ( s u c h  a s
m arij u a n a) wit hi n 3 m o nt h s pri or t o S cr e e ni n g, or h ar d dr u g s ( s u c h a s
c o c ai n e a n d p h e n c y cli di n e [ P C P]) wit hi n 1 -y e ar pri or t o S cr e e ni n g, or
p o siti v e uri n e dr u g s cr e e n at S cr e e ni n g


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
1 2
 
P R O T O C O L S Y N O P SI S  C o nti n ue d  
St u d y P o p ul ati o n  C o nti n u e d  
E x cl u si o n Crit eri a  C o nti n u e d  
1 2.  C o n c o mit a nt m e di c ati o n r e stri cti o n s:
a.
U s e of a g e nt s (i n cl u di n g h er b al or o v er -t h e c o u nt er w ei g ht l o s s
pr e p ar ati o n s) or m e di c ati o n s k n o w n t o si g nifi c a ntl y i m p a ct B W
wit hi n 3 m o nt h s pri or ( e. g ., si b utr a mi n e, p h e n et a mi n e a n d orli st at)
b.
c hr o ni c u s e of s y st e mi c c orti c o st er oi d s
c.
ot h er a nti di a b eti c m e di c ati o n s n ot o utli n e d i n I n cl u si o n Crit eri a # 6
d.
ot h er m e di c ati o n s, p er I n v e sti g at or, k n o w n t o c a u s e li v er t o xi cit y
( e. g., c hr o ni c a c et a mi n o p h e n u s e) or st e at o si s ( e. g ., a mi o d ar o n e,
m et h otr e x at e, t a m o xif e n, c ar b a m a z e pi n e)
e.
U s e of a nti c o a g ul a nt/ a nti pl at el et a g e nt s ( e. g ., w arf ari n, h e p ari n,
d a bi g atr a n, ri v ar o x a b a n, cl o pi d o gr el) u nl e s s t h e d o s e h a s b e e n
st a bl e f or 4 w e e k s pri or t o t h e fir st d o s e of St u d y Dr u g a n d r e g ul ar
cli ni c al m o nit ori n g i s p erf or m e d, u s e of t h e n o n -st er oi d al a nti -
i nfl a m m at or y dr u g ( N S AI D) ni m e s uli d e or a n y ot h er dr u g i nfl u e n ci n g
c o a g ul ati o n ( e x c e pt l o w d o s e a s piri n <  1 6 0  m g/ d a y a n d ot h er s h ort
a cti n g N S AI D S wit h a h alf -lif e < 2 0 h o ur s)
f.
o b eti c h oli c a ci d or ur s o d e o x y c h oli c a ci d
1 3.  Bl o o d d o n ati o n of 5 0 t o 4 9 9 m L wit hi n 3 0 d a y s of S cr e e ni n g or of
> 4 9 9  m L wit hi n 6 0  d a y s of S cr e e ni n g
1 4.  A cti v e i nf e cti o n r e q uiri n g s y st e mi c a nti vir al or a nti mi cr o bi al t h er a p y t h at
will n ot b e c o m pl et e d pri or t o St u d y D a y 1
1 5 . S u bj e ct s wit h k n o w n i nt ol er a n c e t o M RI or wit h c o n diti o n s
c o ntr ai n di c at e d f or M RI Pr o c e d ur e s:
•
S u bj e ct s w h o h a v e a n y m et al i m pl a nt (i n cl u di n g a h e art
p a c e m a k er, r o d s, s cr e w s, a n e ur y s m cli p)
•
S u bj e ct s wit h cl a u str o p h o bi a
1 6 . C o nfir m e d r e d u cti o n i n f a sti n g pl a s m a gl u c o s e ( F P G) of > 4 0 m g/ d L
( > 2. 2 m m ol/ L) at t h e R u n -I n Vi sit ( W e e k -1) c o m p ar e d t o  a F P G v al u e
t a k e n at S cr e e ni n g
1 7 . C o nfir m e d r e d u cti o n i n B W  ± 2 k g ( 4. 4 l b s) at t h e R u n -I n Vi sit ( W e e k -
1) c o m p ar e d t o  B W  t a k e n at S cr e e ni n g
1 8.  H a v e a n y ot h er c o n diti o n s, w hi c h,  i n t h e o pi ni o n of t h e I n v e sti g at or or
S p o n s or w o ul d m a k e t h e s u bj e ct u n s uit a bl e f or i n cl u si o n, or c o ul d
i nt erf er e wit h t h e s u bj e ct p arti ci p ati n g i n or c o m pl eti n g t h e St u d y,
i n cl u di n g u n willi n g n e s s t o c o nti n u e wit h S C i nj e cti o n s aft er t h e S C
T ol er a bilit y a s s e s s m e nt
Tr e at m e nt Gr o u p s  
Pl a c e b o a n d I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
1 3
 
P R O T O C O L S Y N O P SI S  C o nti n ue d  
St u d y Dr u g D o s a g e a n d 
A d mi ni str ati o n  
T h e S C t ol er a bilit y a s s e s s m e nt s u si n g 0. 9 % st eril e s al i n e will b e 
a d mi ni st er e d a s a 1. 2 5 m L  i nj e cti o n o n St u d y D a y W e e k - 1 ( m a y al s o b e 
d eli v er e d a s 2 n o n -c o nti g u o u s i nj e cti o n v ol u m e s of 0. 7 5 m L a n d 0. 5 0 m L) . 
I SI S 4 8 4 1 3 7 ( 2 0 0 m g/ m L) a n d pl a c e b o will b e s u p pli e d a s 1. 0 m L of s ol uti o n 
i n a 2 m L st o p p er e d gl a s s vi al. 
St u d y Dr u g (I SI S 4 8 4 1 3 7 or pl a c e b o) S C i nj e cti o n v ol u m e will b e 1. 2 5 m L 
( m a y al s o b e d eli v er e d a s t w o n o n-c o nti g u o u s i nj e cti o n v ol u m e s of 0. 7 5 m L 
a n d 0. 5 0 m L) . 
S u bj e ct s will b e a d mi ni st er e d 1 3 w e e kl y S C i nj e cti o n s d uri n g t h e 1 3 -w e e k 
tr e at m e nt p eri o d. 
R ati o n al e f or D o s e a n d S c h e d ul e 
S el e cti o n  
T h e d o s e of 2 5 0 m g of I SI S 4 8 4 1 3 7 w a s s el e ct e d f or t hi s st u d y b a s e d o n t h e 
r e s ult s of t h e P h a s e 1 tri al I SI S 4 8 4 1 3 7-C S 1 w hi c h d e m o n str at e d a n 
a c c e pt a bl e s af et y a n d t ol er a bilit y pr ofil e f or d o s e s u p t o 3 0 0 m g aft er 6 w e e k s 
( 8 t ot al d o s e s) of tr e at m e nt.  A d diti o n all y, s e v er al A S O s of t hi s cl a s s h a v e 
d e m o n str at e d si g nifi c a nt effi c a c y a n d a c c e pt a bl e s af et y pr ofil e s at a si mil ar 
d o s e l e v el f or 1 3 w e e k s a n d l o n g er ( A c k er m a n n  et al. 2 0 1 6 ; D u ell  et al.  2 0 1 6 ; 
Di g e ni o et al.  2 0 1 6 ).  T h e 1 3 -w e e k tr e at m e nt d ur ati o n i s s u p p ort e d b y t h e 
I SI S 4 8 4 1 3 7 n o n cli ni c al 1 3-w e e k t o xi c ol o g y st u d y ( s e e I n v e sti g at or s 
Br o c h ur e) a n d b y pr e vi o u s l o n g -t er m w e e kl y cli ni c al d o si n g st u di e s wit h 
s e v er al ot h er 2 ʹ-M O E -m o difi e d A S O s .  T hirt e e n ( 1 3 ) w e e k s of st u d y 
tr e at m e nt i s a s uffi ci e nt tr e at m e nt d ur ati o n t o o b s er v e c h a n g e s i n li v er f at 
c o nt e nt a n d i m pr o v e m e nt s i n I R i n t hi s p ati e nt p o p ul ati o n.   
St u d y Vi sit S c h e d ul e a n d 
Pr o c e d ur e s  
D et ail e d i nf or m ati o n r e g ar di n g t h e st u d y pr o c e d ur e s i s o utli n e d i n S e cti o n 6  
a n d A p p e n di c e s A -C . 
T h e d ur ati o n of s u bj e ct  p arti ci p ati o n i n t h e st u d y i n cl u d e s u p t o a 2 -w e e k 
S cr e e ni n g P eri o d, u p t o a 4 -w e e k R u n -I n e v al u ati o n p eri o d, a n d a 1 3-w e e k 
Tr e at m e nt P eri o d .  S u bj e ct s will b e r e q uir e d t o c o m pl et e a P o st -Tr e at m e nt 
P eri o d f or 1 3 w e e k s f oll o wi n g t h e l a st d o s e of st u d y m e di c ati o n ( or e arl y 
t er mi n ati o n).  T h e I o ni s M e di c al M o nit or or D e si g n e e will p erf or m r o uti n e 
r e vi e w s of t h e s af et y r e s ult s t hr o u g h o ut t h e c o n d u ct of t h e st u d y. 
S cr e e ni n g P eri o d:  W e e k -6 – W e e k -5 ( u p t o 2 w e e k s)  
L a b or at or y a n d ot h er st u d y pr o c e d ur e s will b e p erf or m e d t o a s s e s s eli gi bilit y 
d uri n g t h e S cr e e ni n g P eri o d .   
R u n -I n P eri o d:  W e e k -4 – W e e k -1 ( 4 w e e k s)  
S u bj e ct s will m ai nt ai n hi s/ h er di et a n d e x er ci s e r o uti n e .  
I n or d er t o r e d u c e t h e b ur d e n of u n n e c e s s ar y pr o c e d ur e s o n s u bj e ct s w h o 
s u b s e q u e ntl y el e ct n ot t o p arti ci p at e i n t h e st u d y or c o nti n u e wit h st u d y 
pr o c e d ur e s, all s u bj e ct s will c o nfir m t ol er a n c e of S C a d mi ni str ati o n pri or t o 
r a n d o mi z ati o n d uri n g t h e R u n -I n- P eri o d.  T hi s i nj e cti o n will f oll o w t h e s a m e 
pr o c e d ur e s a s i nj e c ti o n s of t h e St u d y Dr u g (I SI S 4 8 4 1 3 7 or pl a c e b o) d uri n g 
t h e tr e at m e nt p eri o d.   
D uri n g W e e k s -4 a n d -3, s u bj e ct s will h a v e a n M RI t o a s s e s s li v er f at c o nt e nt 
a n d li v er v ol u m e .  M RI s will b e c o n d u ct e d u si n g st a n d ar di z e d pr o c e d ur e s a n d 
s etti n g s .  M RI s will b e e v al u at e d b y a n i n d e p e n d e nt c e ntr al r e a d er, bli n d e d t o 
t h e s u bj e ct’ s tr e at m e nt a s si g n m e nt, t o a s s e s s li v er f at a n d li v er si z e. 


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
1 4
 
P R O T O C O L S Y N O P SI S  C o nti n ue d  
St u d y Vi sit S c h e d ul e a n d 
Pr o c e d ur e s  C o nti n u e d  
R u n -I n P eri o d:  W e e k -4 – W e e k -1 ( 4 w e e k s)  C o nti n u e d  
S u bj e ct s wit h a q u alif yi n g M RI ( at l e a st 1 0 % li v er f at a s s e s s e d b y M RI -P D F F 
vi a c e ntr al r e vi e w er) r et ur n t o cli ni c f or St u d y Vi sit W e e k -1.  At t hi s vi sit, fi n al 
q u alifi c ati o n a s s e s s m e nt s will b e c o n d u ct e d i n cl u di n g B W  a n d F P G 
a s s e s s m e nt s a s w ell a s a S C T ol er a bilit y A s s e s s m e nt wit h 0. 9 % st eril e s ali n e 
i nj e cti o n t o d et er mi n e t ol er a bilit y t o S C i nj e cti o n s.  If it i s n ot p o s si bl e f or M RI 
r e s ult s t o b e a v ail a bl e b y t h e cli ni c W e e k -1 vi sit, t h e M RI r e s ult s m u st b e 
a v ail a bl e f or fi n al q u alifi c ati o n pri or t o r a n d o mi z ati o n.  
Eli gi bl e s u bj e ct s will b e str atifi e d b a s e d o n M RI li v er f at l e v el s ( < 2 0 % v s. 
≥ 2 0 %) a n d t h e n s u bj e ct s will b e r a n d o mi z e d pri or t o t h e fir st d o s e i n a 
2: 1  r ati o t o r e c ei v e eit h er I SI S 4 8 4 1 3 7 or pl a c e b o.   
E li gi bl e/ q u alifi e d s u bj e ct s will b e r a n d o mi z e d a n d r et ur n t o cli ni c f or t h e 
Tr e at m e nt P eri o d.  
Tr e at m e nt P eri o d:  W e e k 1 – W e e k 1 3  
S T U D Y D R U G A D MI NI S T R A TI O N:  W e e kl y i nj e cti o n s will b e a d mi ni st er e d at 
t h e st u d y c e nt er. 
S A F E T Y A S S E S S M E N T S:  W e e kl y l a b or at or y a s s e s s m e nt s will b e o bt ai n e d 
i n cl u di n g c h e mi str y, h e m at ol o g y, uri n al y si s, a d v er s e e v e nt s a n d c o n c o mit a nt 
m e di c ati o n u s a g e.  Bl o o d s a m pl e s f or p h ar m a c o ki n eti c a n al y si s will b e dr a w n 
w e e kl y.  A d diti o n al bl o o d t e st s f or e x pl or at or y p ur p o s e s will b e c oll e ct e d at 
l e s s fr e q u e nt i nt er v al s i n cl u di n g li pi d s, i nfl a m m at or y m ar k er s a n d e x pl or at or y 
bi o m ar k er s.  
S u bj e ct s w h o di s c o nti n u e tr e at m e nt e arl y will e nt er t h e P o st -Tr e at m e nt 
P eri o d u nl e s s c o n s e nt i s wit h dr a w n.  
If a s u bj e ct’ s gl y c e mi c c o ntr ol d et eri or at e s aft er W e e k 8 a c c or di n g t o t h e 
M o nit ori n g R ul e, t h e or al a nti -di a b eti c ( O A D) r e gi m e n c a n b e a dj u st e d.  
P o st- Tr e at m e nt  P eri o d:  W e e k 1 4 – W e e k 2 6  
S A F E T Y A S S E S S M E N T S:  L a b or at or y a s s e s s m e nt s will b e o bt ai n e d at 
r e g ul ar i nt er v al s t hr o u g h o ut t h e 1 3-w e e k P o st -Tr e at m e nt P er i o d. 
M RI:  Li v er f at c o nt e nt a n d v ol u m e will b e m e a s ur e d i n t h e P o st -Tr e at m e nt  
P eri o d i n all s u bj e ct s w h o c o m pl et e at l e a st 5 d o s e s d uri n g t h e Tr e at m e nt 
P eri o d.   
S af et y a n d T ol er a bilit y 
E v al u ati o n s  
T h e s af et y a n d t ol er a bilit y of I SI S 4 8 4 1 3 7 will b e a s s e s s e d b y d et er mi ni n g t h e 
i n ci d e n c e, s e v erit y, d o s e-r el ati o n s hi p of a d v er s e eff e ct s a n d c h a n g e s i n 
l a b or at or y e v al u ati o n s.  S af et y r e s ult s i n s u bj e ct s d o s e d wit h I SI S 4 8 4 1 3 7 will 
b e c o m p ar e d wit h t h o s e fr o m s u bj e ct s d o s e d wit h pl a c e b o.  T h e s af et y a n d 
t ol er a bilit y pr ofil e of t h e St u d y Dr u g will b e m o nit or e d w e e kl y d uri n g t h e 
Tr e at m e nt P eri o d a n d at e a c h s c h e d ul e d vi sit i n t h e P o st -Tr e at m e nt P eri o d.  
P h ar m a c o ki n eti c E v al u ati o n s  
S el e ct e d pl a s m a tr o u g h a n d p o st -tr e at m e nt c o n c e ntr ati o n s of I SI S  4 8 4 1 3 7 
will b e a s s e s s e d i n e v al u a bl e s u bj e ct s r e c ei vi n g I SI S  4 8 4 1 3 7 tr e at m e nt.  


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
1 5
 
P R O T O C O L S Y N O P SI S  C o nti n ue d  
P h ar m a c o d y n a mi c E v al u ati o n s  
T h e eff e ct of I SI S 4 8 4 1 3 7 o n t h e f oll o wi n g will b e a s s e s s e d  
•
h e p ati c f at a n d li v er w ei g ht c o nt e nt will b e e v al u at e d o v er ti m e u si n g
m a g n eti c r e s o n a n c e i m a gi n g t h at i s c o n d u ct e d at B a s eli n e a n d
P o st- Tr e at m e nt.  A c e ntr al r e a d er will c al c ul at e t h e p er c e nt li v er f at
b y P D F F.  M RI r e s ult s i n s u bj e ct s d o s e d wit h I SI S 4 8 4 1 3 7 will b e
c o m p ar e d wit h t h o s e s u bj e ct s d o s e d wit h pl a c e b o
•
pl a s m a li p o pr ot ei n pr ofil e (tri gl y c eri d e s, t ot al c h ol e st er ol, L D L -C,
A p o B, V L D L, H D L a n d N o n -H D L)
•
h e p ati c I R a n d gl u c o s e c o ntr ol (i n s uli n, gl u c o s e, H O M A -I R, H b A 1 c)
St ati sti c al C o n si d er ati o n s  
A p pr o xi m at el y 4 5 s u bj e ct s will b e r a n d o mi z e d ( 2: 1 all o c ati o n r ati o) t o e n s ur e 
at l e a st 3 3 s u bj e ct s will h a v e d at a o n t h e pri m ar y st u d y e n d p oi nt.  T hi s will 
r e s ult i n > 9 0 % p o w er t o d et e ct a of 5 % diff er e n c e i n m e a n a b s ol ut e c h a n g e 
i n li v er f at a s m e a s ur e d b y M RI-P D F F b et w e e n t h e a cti v e a n d pl a c e b o 
gr o u p s wit h a 2- si d e d al p h a of 0. 0 5, a s s u mi n g a c o m m o n st a n d ar d d e vi ati o n 
of 4 %.  
S p o n s or  
I o ni s P h ar m a c e uti c al s, I n c 


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
1 6
 
S T U D Y D E SI G N A N D T R E A T M E N T S C H E M A  
W e e k s  1-1 3  
C lin i c Vi sit s f or WE E K L Y D O SI N G 
D a y s 1 t o 8 5 
C lin i c vi sit s we e kl y f or St u d y Dr u g a d mi ni st r ati on .  
R o uti n e  s af et y a s s e s sm e nt s .  P D a s s e s s m e nt s 
i ncl u d e d at s p e ci fi e d ti me p oi n t s 
P o st - Tr e at m e nt Vi sit s 1 - 1 2  
P O S T -T R E A T M E N T  ( P T) E V A L U A TI O N S 
( 7 Cli ni c V i sit s) 
D a y 9 2 t o 1 6 9  
Cli ni c al vi sit s w e e kl y f or first 4 w e e k s f oll o wi n g t h e l a st d o s e 
(P T 1 - 4) t h e n cli ni c vi sit s o n P T 6, 8, a n d 1 2 f or r o uti n e s af et y 
c h e c k , P D a n d bi o m ar k er a s s e s s m e nt s at s p e ci fi e d i nter v a l s  
P T 1 3 - D a y 1 7 6  
L a st St u d y C o nt a ct vi a 
T el e p h o n e C o nt a ct
D a y 1 7 6  
E A R L Y 
T R E A T M E N T 
T E R MI N A TI O N  
F oll o w  P T 1  ( D ay 9 2 )
S C R E E N
U p t o  -4 2  t o - 29  d a y s 
b ef or e D a y  1 
W k - 6 t o W k - 5 
W e e k s -4 t hr u - 1 
R U N -I N P E RI O D D a y s - 2 8 t o  - 1 
At h o m e,  p a ti ent c o nti n u e s c urr e nt e x er ci s e a n d di et r e gi m e n  
W e e k - 4 t hr u W e e k - 2:  M RI pr o c e d ur e c o n d u ct e d 
W e e k - 1 ( D ay - 7 t hr u - 2):  R e tur n t o  clini c f or fi nal el i gib ilit y 
a s s e s s m e nt s ( B W, F P G, S C T ol er a bilit y A s s e s s m e nt)  
P O S T -
T R E A T M E N T 
E A R L Y 
T E R MI N A TI O N
F oll o w  P T 1 2 ( D ay 1 6 9 ) 


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
1 7
 
S T U D Y G L O S S A R Y  
A b bre vi ati o n 
Defi niti o n  
2′ -M O E  
2′ -O -( 2-met h o x yet h yl)  
A E  
a d verse e ve nt  
A L P  
al kali ne p h os p hatase 
A L T  
ala ni ne a mi n otra nsferas e ( S G P T)  
a p oB 
a p oli p o pr otei n B 
a P T T 
acti vate d partial t hr o m b o plasti n ti me  
A S O  
a ntise nse oli g o n u cle oti de 
A S T  
as partate a mi n otra nsferas e ( S G O T)  
B b  
c o m ple me nt fact or B b (acti vate d c o m ple me nt s plit pr o d uct) 
β h C G  
beta -s u b u nit of h u ma n c h ori o nic g o n a d otr o pi n ( pre g n a nc y test) 
B W  
b o d y w ei g ht 
B P  
bl o o d press ure 
B U N  
bl o o d urea nitr o ge n 
C 5a 
c o m ple me nt fact or C 5a (acti vate d c o m ple me nt s plit pr o d uct)  
C B C  
c o m plete bl o o d c o u nt 
C K 1 8  
c yt o k erati n 1 8 
C M V  
C yt o m e gal o vir us 
C R F  
case r e p ort f or m  
C R N M B  
cli nicall y-rele v a nt n o n-m aj or blee di n g  
C R O  
c o ntract researc h or ga nizati o n  
C T  
c o m p ute d t o m o gra p h y 
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts  
D A G  
s n- 1, 2-diac yl gl ycer ol  
D G A T  
Diac yl gl ycer ol A c yltra nsferas e  
D G A T 1 
diac yl gl ycer ol O -ac yltra nsferas e 1  
D G A T 2 
diac yl gl ycer ol O -ac yltra nsferas e 2  
D N A  
p h os p h or ot hi oate m o difie d oli g o de o x y n u cle oti des 
D P PI V i n hi bit or 
di pe pti d yl pe pti dase- I V 
E B V  
E pstei n -Barr vir us  
E C G  
electr ocar di o gra m  


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
1 8
 
e C R F 
electr o nic Cas e Re p ort F or m  
E D C  
electr o nic d ata ca pt ure  
F P G  
fasti n g plas ma gl u c ose 
E T P T  
Earl y T er mi nati o n patie nts fr o m t he P ost -Treat me nt Peri o d  
F S H  
f ollicle-sti m ulati n g h or m o ne 
G C P  
G o o d C li nical P ractice 
G F R  
gl o mer ular filtrati o n rat e  
G L P 1  
gl uca g o n -li ke pe pti de 1 
H A V  
he patitis A vir us   
H b A 1 C  
He m o gl o bi n A 1 C 
H Bs A g  
he patitis B s urface a nti ge n  
H B V  
He patitis B vir us  
H C C  
He pat ocell ular carci n o m a  
H C V  
He patitis C vir us  
H D L  
Hi g h de nsit y li p o pr otei n 
HI P A A  
Healt h I ns ura nce P orta bilit y a n d A cc o u nta bilit y A ct  
HI V  
h u ma n i m m u n o deficie nc y vir us 
H O M A -I R 
H o me ostatic m o del assess me nt - i ns uli n resista nce 
H R  
heart r ate  
hs C R P  
C R P meas ure d b y hi g h s e nsiti vit y assa y 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I E C 
I n d e pe n de nt Et hics C o m mittee 
I g A 
i m m u n o gl o b uli n A 
I g M 
i m m u n o gl o b uli n M 
I N R 
i nter nati o nal n or malize d rati o 
I L 6 
I nterle u ki n- 6 
I R 
i ns uli n resista nce 
I R B 
I nstit uti o nal Re vie w B oar d 
I SI S 4 8 4 1 3 7 
a ntise nse i n hi bit or of D G A T 2 
I V 
I ntr a ve n o us(l y) 
I X R S 
I nteracti ve v oice/i nter n et res p o nse s yste m 
L D H  
lactate de h y dr o ge nas e 


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
1 9
 
L D L - C 
L o w d e nsit y li p o pr otei n c h olester ol 
M A G  
m o n oac yl gl ycer ol 
M B  
maj or blee di n g  
M C H  
mea n c or p us c ular he m o gl o bi n 
M C H C  
mea n c or p us c ular he m o gl o bi n c o nce ntrati o n 
M C V  
mea n c or p us c ular v ol u m e 
Me d D R A
T M  
Me dical Dicti o nar y f or R e g ul at or y Acti vities 
M P V  
mea n platelet v ol u me  
M RI  
ma g n etic res o n a nce i ma gi n g  
M RI -P D F F  
Ma g n etic res o n a nce i ma gi n g -esti mate d pr ot o n de nsit y fat 
fracti o n 
m R N A  
messe n ger ri b o n u cleic aci d  
N A F L D  
N o nalc o h olic fatt y li ver disease  
N A S H  
N o nalc o h olic steat o he p atitis  
N C S  
n ot cli nicall y-si g nifica nt 
N o n -H D L  
N o n - hi g h d e nsit y li p o pr otei n 
N S AI D  
n o n- ster oi dal a nti-i nfla m mat or y dr u g 
O A D  
oral a nti -dia betic a ge nt  
P/ C 
uri ne pr otei n/creati ni ne 
P D  
p har mac o d y n a mic(s)  
P D F F  
pr ot o n de nsit y fat fracti o n 
p H 
meas ure of t h e aci dit y or basicit y of a s ol uti o n  
P K  
p har mac o ki netic(s) 
p R B C  
pac ke d r e d bl o o d cells 
P T  
pr ot hr o m bi n ti me 
R B C  
re d bl o o d cells 
R N A  
ri b o n ucleic aci d 
R Nase H 1  
a n u bi q uit o us e n d o n uclease t hat s pecificall y h y dr ol yz es t he 
R N A stra n d i n R N A/ D N A h y bri ds  
R R  
res pirat or y rate 
S A E  
seri o us a d vers e e v e nt 
S A P  
Statistical A nal ysis Pla n  


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
2 0
 
si R N A 
s mall i nterferi n g ri b o n ucl eic aci d 
S C  
s u bc uta ne o us(l y) 
S C D - 1 
Stear yl C o A d esat uras e - 1 
S G L T 2  
S o di u m gl uc ose li ke tra ns p ort pr otei n 2 
St u d y Da y 1  
defi ne d as t he first da y St u d y Dr u g pr o d uct is a d mi nistere d t o 
t he s u bject 
St u d y Dr u g  
I SI S 4 8 4 1 3 7 or place b o 
S U  
s ulf o n yl urea 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T 3  
Trii o d ot h yr o ni ne 
T 4  
T h yr o xi ne 
T 2 D M  
ty pe 2 dia b etes mellit us  
T E A E  
treat me nt-e mer ge nt a d v erse e ve nt  
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 
V L D L  
Ver y l o w de nsit y li p o pr otei ns 
W A T  
w hite a di p ose tiss ue 
W B C  
w hite bl o o d cell 
W H O  
W orl d Healt h Or ga nizati o n  
W M A  
W orl d Me dical Ass ociati o n  


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
Ori gi nal 
Pr ot oc ol  
1 A u g us t 2 0 1 7 
2 1
 
1.  
O B J E C TI V E S
1. 1
 Pri m ar y
 
O bjecti ve(s)
 
T he pri mar y o bjecti ves are: 
1. T o e val uate t he safet y a n d t olera bilit y of I SI S 4 8 4 1 3 7 2 5 0 m g per wee k s u bc uta ne o us
( S C) i njecti o n i n a d ult s u bjects wit h t y pe 2 dia betes mellit us ( T 2 D M)
2. T o e val uate t he p har mac o d y na mic effects of  I SI S 4 8 4 1 3 7 2 5 0 m g per wee k S C i njecti o n
o n t he a bs ol ute re d ucti o n of li ver fat (assesse d b y ma g netic res o na nce i ma gi n g [ M RI]
pr ot o n de nsit y fat fracti o n [ P D F F]) i n a d ult s u bjects wit h T 2 D M
1. 2
 Sec o n d ar y
 
O bjecti ve(s)
 
T he sec o n dar y o bjecti ves are: 
1. T o e val uate t he p har mac o d y na mic effects of  I SI S 4 8 4 1 3 7 2 5 0 m g per wee k S C i njecti o n
o n li ver fat ( perce nt relati ve re d uc ti o n a n d perce nt of s u bjects wit h ≥ 3 0 % relati ve
re d ucti o n) assesse d b y M RI- P D F F
2. T o e val uate t he p har mac o d y na mic effects of  I SI S 4 8 4 1 3 7 2 5 0 m g per wee k S C i njecti o n
o n li ver v ol u me assesse d b y M RI- P D F F
3. T o e val uate t he p har mac o d y na mic effects of  I SI S 4 8 4 1 3 7 2 5 0 m g per wee k S C i njecti o n
o n plas ma li p o pr otei n pr ofile (tri gl yceri des  [ T G], t otal c h olester ol, l o w de nsit y
li p o pr otei n c h olester ol [ L D L- C], a p oli p o pr otei n B [a p o B], ver y l o w de nsit y li p o pr otei ns
[ V L D L], hi g h de nsit y li p o protei n [ H D L] a n d N o n- H D L)
4. T o e val uate t he p har mac o d y na mic effects of  I SI S 4 8 4 1 3 7 2 5 0 m g per wee k S C i njecti o n
o n i ns uli n resista nce (I R) a n d gl uc ose c o nt r ol (i ns uli n, gl uc ose, h o me ostatic m o del
assess me nt-i ns uli n resista nce [ H O M A-I R], he m o gl o bi n A 1c [ H b A 1c])
1. 3
 E x pl or at or y
 
O bjecti ves
 
T he e x pl orat or y o bjecti ves are t o e val uate t he p har mac o d y na mic ( P D) effects of I SI S 4 8 4 1 3 7 o n 
p ote ntial bi o mar kers of D G A T 2 acti vit y (e . g., stear o yl- C o A desat urase- 1 [ S C D- 1] a n d 
bi o mar ker of he patic i nfla m mati o n (e. g., c yt o kerati n 1 8 [ C K 1 8], ha pt o gl o bi n). 
2. 
B A C K G R O U N D A N D R A TI O N A L E
2. 1  
O ver vie w of Dise ase
N o nalc o h olic fatt y li ver disease ( N A F L D) is c o ns i dere d t o be a he patic ma nifestati o n of t he 
meta b olic s y n dr o me ( Marc hesi ni et al. 2 0 0 3 ) a n d is c haracterize d b y t he acc u m ulati o n of 
tri gl yceri des i n t he li ver of s u bjects wit h o ut a hist or y of e xcessi ve alc o h ol c o ns u m pti o n.  
N A F L D is classifie d i nt o si m ple steat osis, i n  w hic h o nl y he patic steat osis is o bser ve d, a n d 
n o n-alc o h olic steat o he patitis ( N A S H), i n w h ic h i ntral o b ular i nflam mati o n a n d ball o o ni n g 
de ge nerati o n of he pat oc ytes is o b ser ve d al o n g wit h he patic steat osis.  T he maj orit y of patie nts 
wit h N A F L D are o bese or m or bi dl y o bese a n d ha ve acc o m pa n yi n g I R ( B yr ne a n d Tar g her 2 0 1 5 ) 
a n d t y pe 2 dia betes mellit us.  N A S H is a pr o gress i ve disease a n d ma y lea d t o li ver cirr h osis a n d 
he pat ocell ular carci n o ma ( H C C) ( Farrell a n d Larter 2 0 0 6 ; C o he n et al. 2 0 1 1 ).  T we nt y ( 2 0) 
perce nt of N A S H patie nts are re p orte d t o de vel o p cirr h osis, a n d 3 0- 4 0 % of patie nts wit h N A S H 


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cirr h osis e x perie nce li ver -relate d d eat h (M c C ull o u g h 2 0 0 6 ).  T h e i nci de n ce of N A F L D  a n d 
N A S H ha ve bee n r a pi dl y i ncreasi n g  w orl d wi de c o nsiste nt wit h t he i ncrease d pre vale n ce of 
o besit y, a n d is c urre ntl y t he m ost c o m m o n c hr o nic li ver disease.  Rece ntl y, t he i nci de nce of 
N A F L D a n d N A S H w as re p orte d t o be 4 6 % a n d 1 2 %, res pecti vel y, i n a lar gel y mi d dle- a ge d 
p o p ulati o n ( Willia ms et al. 2 0 1 1 ).  N A S H has bec o me t he t hir d m ost c o m m o n i n dicati o n f or 
li ver tra ns pla ntati o n i n t he U nite d States (C harlt o n et al. 2 0 1 1 ). 
He patic steat osis r es ults fr o m a n i m bala nce b et wee n tri gl yceri de acc u m ulati o n a n d eli mi nati o n i n 
t he li ver.  I ns uli n resista n ce, w hic h is fre q ue ntl y see n i n o bese i n di vi d uals, is cl osel y li n ke d t o 
t his pr ocess beca use it alters n utrie nt distri b uti o n a m o n g tiss ues a n d n utrie nt meta b olis m 
(T o me n o et al. 2 0 1 3 ).  Peri p heral I R lea ds t o a n i nfl u x of free fatt y aci ds i nt o t he li ver b y 
decrease d s u p pr essi o n of li p ol ysis a n d i n crease d d e n ov o  li p o ge nesis (I bra hi m et al. 2 0 1 3 ).  
Alt h o u g h t he pat h o ge nesis of N A F L D/ N A S H has n ot bee n c o m pletel y el uci date d, t he “t w o- hit” 
(Da y a n d J a mes 1 9 9 8 ) a n d “ m ulti ple parallel hit” (Til g a n d M osc h e n 2 0 1 0 ) h y p ot hes es ha ve 
bee n pr o p ose d.  I n t he t w o- hit h y p ot hesis, he patic steat osis occ urs first t hr o u g h a n i nitial 
meta b olic dist ur ba nce a n d pr o gresses t o N A S H b y s u bse q ue nt sec o n d hits d eri ve d fr o m t he g ut 
a n d/ or t he a di p ose tiss ue s uc h as i ncrease d le v els of i nfla m mat or y c yt o ki nes (e. g., t u m or necr osis 
fact or-α, i nterle u ki n - 6 [I L 6]), decrease d le vels of a nti-i nfla m mat or y c yt o ki nes (e. g., 
a di p o necti n), o xi dati ve stress, a n d e n d ot o xi ns ori gi nati n g fr o m i ntesti nal bacterial fl ora.  
T heref ore, a c o m p o u n d s uc h as a n a ntise ns e oli g o n ucle oti de ( A S O) a gai nst Diac yl gl ycer ol 
Ac yltr a nsferase 2  (D G A T 2 ) t hat re d uces he p atic steat osis c o ul d res ult i n pre ve nti o n or 
atte n uati o n of t he sec o n d ar y i nfla m mati o n a n d o xi dati ve stress t here b y b e n efiti n g N A F L D a n d 
N A S H patie nt s. 
2. 2  
T her a pe utic R ati o n ale  
2. 2. 1 
Overvie w of T ar get  
Diac yl gl ycer ol ac yltra nsf erase ( D G A T ) catal yzes t he fi nal ste p i n T G s y nt h esis b y facilitati n g 
t he li n ka ge of s n- 1, 2- di ac yl gl ycer ols (D A G ) wit h a n ac yl- C o A.  D G A T  has 2 is of or ms, 
diac yl gl ycer ol O -ac yltr a nsferas e 1  (D G A T 1 ) a n d diac yl gl ycer ol O -ac yltra nsferas e 2  (D G A T 2 ), 
a n d st u dies i n dicate t hat b ot h D G A T 1 a n d D G A T 2 pla y i m p orta nt r ol es i n T G s y nt hesis.  
D G A T 1 is m ost hi g hl y e x presse d i n s mall i ntesti ne a n d w hite a di p ose tiss u e  (W A T ), w hereas 
D G A T 2  is pri maril y e x presse d i n li ver a n d W A T (Cases et al. 1 9 9 8 ; Cases et al. 2 0 0 1 ).  T he 
e xiste nce of D G A T 2 w as pre dicte d fr o m t he fi n di n g t hat mice l ac ki n g D G A T 1 ha ve a b u n da nt 
T G i n t heir tiss ues .  T he h D G A T 2 ge n e is c o m p ose d of 8 e x o ns, a n d s pa ns 4 2. 0 3 k b o n 
C hr o m os o me 1 1.  It is l o cate d ~ 3 7. 5 k b fr o m t he m o n oac yl gl ycer ol ac yltra nsferas e 2 ( M G A T 2) 
ge n e ( Y e n et al. 2 0 0 8 ).  I n m ost s pecies, t he ge ne e nc o des a pr otei n of 3 5 0- 4 0 0 resi d ues, a n d t he 
calc ulate d m olec ular mass f or D G A T 2 e nz y mes is i n t he ra n ge of 4 0 - 4 4 k D ( Ye n et al. 2 0 0 8). 
Alt h o u g h b ot h D G A T 1 a n d D G A T 2 catal yze t he s a me reacti o ns i n T G s y nt hesis wit h D A G or 
m o n oac yl gl ycer ols ( M A G ) a n d ac yl- C o A as s u bstrates, t he y are f u n cti o nall y disti n g uis he d b y 
t heir differ e nces i n catal ytic pr o perties (Ca o et al.  2 0 0 7; C he n g et al. 2 0 0 8 ), s u bcell ular 
l ocalizati o n (St o ne et al. 2 0 0 9 ), p h ysi ol o gical re g ulati o n (Mee galla et al. 2 0 0 2 ), a n d p he n ot y pic 
c o nse q ue nces w he n re n d ere d deficie nt ( S mit h et al. 2 0 0 0 ) or o vere x presse d i n precli nical m o dels 
(Nai k et al. 2 0 1 4 ).  D G A T 1 n ull mice were f o u n d t o be resista nt t o hi g h- fat-diet -i n d uce d o b esit y 
beca use of a n i ncreas e d meta b olic rate ( p artl y d u e t o i ncreas e d p h ysical acti vit y), m o d estl y 
decrease d le v els of tiss ue T Gs, a n d i ncrease d i ns uli n a n d le pti n se nsiti vit y ( S mit h et al. 2 0 0 0).  


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D G A T 2 n ull mice ar e li p o pe nic a n d die s o o n after birt h as a res ult of pr of o u n d re d ucti o ns i n 
s u bstrates f or e n er g y met a b olis m a n d i m paire d s ki n per mea bilit y (St o ne et al. 2 0 0 4 ), w hile 
D G A T 2 heter oz y g o us mi ce ar e via ble, h ealt h y, a n d p h ysicall y i n disti n g uis ha ble fr o m n o n-
deficie nt mice ( Y u et al. 2 0 0 5 ).  T he effects of s pecific p har m ac ol o gic a nta g o nis m of he p atic 
D G A T 2 e x pressi o n wer e n ot k n o w n u ntil st u dies c o n d ucte d wit h D G A T 2 A S Os. 
D G A T 2 A S Os were de v el o pe d t o re d uce t he rate of T G s y nt hesis b y s p ecificall y re d uci n g 
he patic D G A T 2 e x pressi o n .  S u p pressi o n of D G A T 2, b ut n ot of D G A T 1, b y A S O treat me nt 
i m pr o ve d he patic steat osis a n d bl o o d li pi d le vels i n de pe n de nt of a di p osit y i n r o de nt m o dels of 
o besit y a n d d ata i n dicate d t hat t hese effects w ere rela te d t o decrease d he p atic li pi d s y nt hesis 
( Y u et al. 2 0 0 5).  I n rats wit h diet-i n d uce d he patic steat osis ( m o del of h u ma n N A F L D), treat me nt 
wit h b ot h D G A T 1 a n d D G A T 2 A S Os selecti vel y re d uce d D G A T 1 a n d D G A T 2 ri b o n ucleic aci d 
(R N A ) le vels i n li ver a n d fat.  H o we v er, o nl y D G A T 2 A S O treat me nt si g nifica ntl y re d uce d 
he patic li pi ds ( D A G a n d T G b ut n ot l o n g c hai n ac yl -C o As) a n d re v erse d di et -i n d uce d he p atic I R 
i n t his rat m o del of diet-i n d uce d N A F L D (C h oi et al. 2 0 0 7 ).  P har mac ol o gi c effects c orrelat e d 
wit h t he le v el of a ntise ns e i n hi biti o n of D G A T 2 li ver e x pressi o n a n d > 8 0 % decrease of D G A T 2 
i n li ver a n d a di p ose tiss ue di d n ot ca use a n y t ar get relate d t o xicit y.  T hese p har mac ol o gic d ata 
i n dicate differe nt f u ncti o ns of the t w o D G A T e nz y m es d uri n g T G bi os y nt hesis a nd are c o nsiste nt 
wit h t h ose fr o m o vere x pr essi o n st u dies.  I n o v ere x pressi o n st u dies i n mice, D G A T 2 has bee n 
i de ntifie d as bei n g m ore acti ve t ha n D G A T 1, yi el di n g a hi g her i ncrease i n i ntracell ular T G t h at 
acc u m ulates as lar ge, ce ntrall y l ocate d c yt os olic dr o plets ( St o ne et al. 2 0 0 4).  F urt her m ore, i n rat 
he pat o ma cells, D G A T 1 o vere x pressi o n res ulte d i n c o nsi dera bl y less T G acc u m ulati o n t ha n was 
s h o w n b y D G A T 2 o vere x pressi o n. 
T hese res ults s u g gest t hat D G A T 2 pla ys a n i m p orta nt r ole i n he patic li pi d meta b olis m , he patic 
steat osis, he patic i ns uli n si g nali n g, a n d he p atic i ns uli n se nsiti vit y a n d t hat t hera pe utic 
i nter ve nti o ns ai me d at re d uci n g D G A T 2 f u n cti o n i n li p o ge nic tiss ues ma y pr o vi de cli nical 
be nefit f or fatt y li ver disease, meta b olic s y n dr o me a n d car di o v asc ular dis eas es .   
2. 2. 2  
T her a pe utic R ati o n ale 
I SI S 4 8 4 1 3 7 is bei n g i n v esti gate d as a p ossi ble treat me nt f or N A F L Ds i ncl u di n g N A S H.  
C urre ntl y, t he pri nci pal tr eat me nt f or N A F L D/ N A S H is lifest yl e m o dificati o n b y diet a n d 
e x ercise.  T her e ar e n o a p pr o ve d me dicati o ns f or t hese c o n diti o ns.  H o we v er, p har m ac ol o gical 
t hera p y is i n dis pe nsa ble beca use o b ese p atie nts wit h N A F L D ofte n h a ve diffic ult y m ai ntai ni n g 
i m pr o ve d lifest yles.  Sel ecti ve i n hi biti o n of D G A T 2 has bee n s u g gest e d as a ne w tar get f or t he 
treat me nt of t hese o b esit y-r elate d m eta b olic diseases.  I m p orta nt a d va n ces ha ve bee n ma de 
re gar di n g p ote ntial a p plicati o ns f or D G A T i n hi bit ors, i ncl u di n g se v eral re p orts of D G A T 
i n hi bit ors wit h i m pr o ve d s ol u bilit y, cell- base d acti vit y, a n d p har mac o ki neti c ( P K) pr op erties .  
Des pite str o n g i nterest a n d eff orts of p h ar mace utical c o m pa nies a n d ma n y aca de mic researc h 
gr o u ps, v er y f e w c o m p o u n ds ha ve reac h e d cli nical trials.  He nce, t h e nee d f or t he de vel o p me nt 
of safe a n d effecti ve D G A T i n hi bit ors re mai ns hi g h. 
T here are  c urr e ntl y n o k n o w n strate gies f or a s mall m olec ule a p pr oac h t o l o wer D G A T 2 
e x pressi o n s pecificall y i n li ver a n d/ or a di p ose tiss ue.  I n c o ntrast, I SI S 4 8 4 1 3 7 has bee n s h o w n 
t o s pecificall y l o wer h e p atic D G A T 2 e x pressi o n a n d, ma y t heref ore, ha v e t he p ote ntial t o re d uce 
li ver steat osis a n d de vel o p me nt of N A S H.   


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T his s h ort- ter m st u d y will assess c ha n ges i n h e patic steat osis o ver a 1 3-wee k treat me nt peri o d  i n 
a patie nt p o p ulati o n wit h hi g her ris k f or d e vel o p me nt of N A F L D a n d N A S H, o bese T 2 D M wit h 
ele vate d H b A 1 c.  C ha n ges i n t he P D F F i n t he li ver will be esti mate d b y M RI, referre d t o as 
M RI -P D F F .  It is t he fracti o n of t he M RI visi ble pr ot o ns b o u n d t o fat di vi de d b y all pr ot o ns i n 
t he li ver ( b o u n d t o fat a n d water).  T h e li ver M RI -P D F F has b ee n utilize d as a n o ni n vasi ve 
bi o mar ker of h e patic steat osis  as it has bee n str o n gl y c orrelat ed wit h hist ol o gic gra de of he patic 
steat osis (D ulai et al . 2 0 1 6; Patel et al. 2 0 1 6 ) a n d has bee n use d i n trials as a n o bjecti ve, 
q ua ntitati ve, precise a n d re pr o d uci ble  n o ni n v asi ve i ma gi n g bi o mar ker of li ver fat c o nte nt 
(Le  et al. 2 0 1 2 ; K a n g et al. 2 0 1 1 ).  T he pri mar y e n d p oi nt is t o assess a bs ol ute c ha n ges i n t he 
li ver M RI- P D F F after t h era p y wit h I SI S 4 8 4 1 3 7 or place b o, as l o n git u di n al c ha n ges i n P D F F 
ha ve i de ntifie d s u bjects wit h re d uce d steat osis gra de wit h re d u cti o n of P D F F ( Mi d dlet o n et al. 
2 0 1 7 ).   
2. 3 
I SI S 4 8 4 1 3 7 
2. 3. 1 
Mec h a nis m of Acti o n  
I SI S 4 8 4 1 3 7 is a sec o n d-ge n erati o n 2′ -O -( 2-m et h o x yet h yl) ( 2′ -M O E) c hi meric A S O i n hi bit or of 
t he m olec ular tar get D G A T 2.  It is c o m ple me ntar y t o a re gi o n wit hi n t he n o n-c o di n g re gi o n of 
t he D G A T 2 R N A a n d bi n ds t o t he R N A b y Wats o n a n d Cric k base p airi n g .  T he h y bri dizati o n 
( bi n di n g) of I SI S  4 8 4 1 3 7 t o t he c o g n ate R N A res ults i n t he R Nase  H 1 -me d i ate d de gra dati o n of 
t he D G A T 2 R N A, t h us pre ve nti n g pr o d ucti o n of t he D G A T 2 pr ot ei n.  Ma xi mal a ntise ns e-
me diate d re d u cti o n of tar get R N A l e vels is t y picall y greater t h a n 9 0 % of c o ntr ol le vels i n 
se nsiti ve tiss ues (Cr o o ke a n d Be n n ett 1 9 9 6 ; Z h a n g et al. 2 0 1 0 ).  F u rt her m ore, re d ucti o n i n tar get 
R N A le vels usi n g t his a p pr oac h c orrel ates directl y wit h a s u bse q ue nt re d u cti o n i n tar get pr otei n 
le vels.   
2. 3. 2 
C he mistry  
I SI S 4 8 4 1 3 7 is a sec o n d ge n erati o n 2′ -M O E c hi meric a ntise nse dr u g .  C he micall y, I SI S  4 8 4 1 3 7 
is a s y nt hetic oli g o mer of 2 0 n ucle oti des (i.e., a 2 0-mer) t hat are c o n necte d se q ue ntiall y b y 
p h os p h or ot hi oate li n ka ges.  T he n ucle oti de se q u e n ce of I SI S  4 8 4 1 3 7 (Fi g ure 1 ) is f ull y 
c o m ple me ntar y t o a 2 0- n ucle oti de stretc h wit hi n t he sec o n d i ntr o nic re gi o n of t he D G A T 2 ge ne 
at p ositi o n 6 – 1 5.  Str uct urall y, t he oli g o n ucl e oti de has 3 re gi o ns.  T w o ( 2) of t he m, t he 
5 n ucle oti des at t he 5′ e n d a n d t he 5  n ucle oti des at t he 3′ e n d, are c o m p ose d of 2 -O -( 2-
met h o x yet h yl) ( M O E) - m o difie d ri b o n ucle oti des.  T hese M O E - m o difie d n u cle oti des c o nfer ( 1) 
i ncreas e d affi nit y t o t he t ar get m R N A (Alt ma n n et al. 1 9 9 6 ; Mc Ka y  et al. 1 9 9 9 ), ( 2) i ncrease d 
resista nce t o e x o n ucleas es a n d e n d o n ucleases (t here b y i ncreasi n g sta bilit y i n tiss ue) 
(Gear y  et al. 2 0 0 3), a n d ( 3) a meli orati o n of s o me of t he hi g h-d ose t o xicities, t here b y res ulti n g i n 
a n i m pr o ve d saf et y pr ofil e c o m par e d t o first ge nerati o n a ntise nse dr u gs c o ntai ni n g 
p h os p h or ot hi oate m o difie d oli g o de o x y n u cle oti des ( D N A) ( He nr y  et al. 2 0 0 0 ).  T he t hir d re gi o n, 
t he ce ntral p orti o n of t he oli g o n ucle oti de, is c o m p ose d of 1 0 oli g o d e o x y n u cle oti des.  T his 
c hi meric desi g n is calle d a M O E - G a p mer, a n d I SI S 4 8 4 1 3 7 e m pl o ys t his c hi meric str uct ure t o 
e na ble use of t he R Nase H 1 -mec ha nis m f or a ntise nse acti vit y.  T his is beca use w hile t he 2′ -M O E 
m o dificati o n c o nfers i n cr ease d sta bilit y a n d affi nit y, it d oes n ot s u p p ort R N ase H 1 catal ysis of 
R N A h y bri dize d t o 2′ -M O E - m o difie d n ucle oti des (Mc Ka y  et al. 1 9 9 9).  T his is ca use d b y 
c o nf or mati o nal c h a n ges i n d uce d i n t he heter o d u ple x b y 2′ -al k o x y: R N A h y bri ds t hat are n ot 
rec o g nize d b y R Nase H 1 e nz y me (I n o ue et al. 1 9 8 7 ; M o nia et al. 1 9 9 3 ).  B y li miti n g t he 2′ -M O E 




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P har mac o ki netics a n d Pr o d uct Meta b olis m i n A ni mals 
D ose - de p e n de nt e x p os ures t o I SI S 4 8 4 1 3 7 i n plas ma a n d li ver a n d ki d ne y tiss ues were 
esta blis he d i n t he 1 3- wee k m o use a n d m o n ke y t o xicit y st u dies at d oses bet wee n 4 a n d 
1 0 0 m g/ k g/ w k a n d bet w ee n 4 a n d 4 0 m g/ k g/ w k, res pecti vel y .  A half -life of a p pr o xi matel y 2 t o 
3 wee ks w as o bser ve d i n m o n ke ys.  P har m ac o ki netics o bser ve d i n m o n ke ys f or t his class of 
c o m p o u n ds t y picall y pr e dict t he o bser ve d plas ma e x p os ure le vels i n h u ma ns o n t he basis 
of m g/ k g e q ui val e nt d oses ( Gear y et al. 2 0 0 3 ; Y u  et al. 2 0 0 7 ). 
I SI S 4 8 4 1 3 7 was hi g hl y b o u n d t o plas ma pr otei ns, greater t ha n 9 6 % i n m o use, m o n ke y, a n d 
h u ma n plas ma st u dies.  T he hi g h pr otei n bi n di n g pre ve nts gl o mer ular filtrati o n a n d li mits uri nar y 
e x creti o n.  T he bi n di n g sites f or t hese t y pes of h y dr o p hilic dr u gs differ fr o m t he bi n di n g sites of 
l o w m olec ular wei g ht h y dr o p h o bic dr u gs; t h us, fe w D DIs o n t he le v el of pl as ma pr otei n bi n di n g 
are e x pecte d at cli nicall y-rele v a nt c o nce ntrati o ns. 
T o xic ol o g y a n d Sa fet y P har mac ol o g y 
Ge ner al t o xic ol o g y st u di es wer e c o n d uct e d wit h I SI S 4 8 4 1 3 7 i n t he m o use a n d m o n ke y f or 
1 3 wee ks of tr eat me nt .  D ose a d mi nistrati o n was b y S C  i njecti o n at wee kl y d oses of 4, 1 2, 4 0, 
a n d 1 0 0 m g/ k g/ w k I SI S  4 8 4 1 3 7 i n mice or 4, 8, 1 2, a n d 4 0 m g/ k g/ w k I SI S  4 8 4 1 3 7 i n m o n ke ys. 
T he m ost n ote w ort h y fi n di n gs o bser v e d i n mice a n d m o n ke y t o xic ol o g y st u dies f oll o wi n g 
1 3- wee ks of I SI S  4 8 4 1 3 7 treat me nt were, i n ge n eral, n o n-s pecific class effects t hat are t y pical
f or 2′-M O E A S Os ( He nr y et al. 2 0 0 8 ).  T he re was n o dr u g-relat e d m ortalit y or c ha n ges i n
cli nical si g ns u p t o t he hi g hest d oses t este d ( 1 0 0 m g / k g i n mice a n d 4 0 m g / k g i n m o n ke ys).
Re d ucti o n i n platelet c o u nt ( 3 3, 0 0 0/ m m 3) was o bser ve d i n a si n gle m o n ke y ( 1 of 1 0) i n t he
1 2 m g/ k g/ w k d ose gr o u p o n D a y 9 3, wit h n o cli nical si g ns i n t his a ni mal, a n d n o micr osc o pic
e vi de nce of he m orr h a ge .  Si nce platelet re d u cti o n bel o w 2 0 0, 0 0 0/ m m 3 was n ot o bser ve d i n a n y
ot her a ni mals i n t he st u d y, i ncl u di n g t he hi g h d os e of 4 0 m g / k g/ w k, t he rel ati o ns hi p t o t he test
article is u nclear.
I n viv o saf et y p har m ac ol o g y st u dies c o n d u cte d t o date i n dicate t hat I SI S 4 8 4 1 3 7 ha d n o effects 
o n car di o vas c ular para m eters ( bl o o d press ure [ B P ], heart rate [ H R ] a n d electr ocar di o gra m 
[E C G ]) or p ul m o nar y f u ncti o n or ne ur o be h a vi or i n m o nke ys .  G e netic t o xicit y st u dies (t he A m es 
assa y a n d i n vitr o c hr o m os o mal a berr ati o ns i n C hi nese ha mster l u n gs [ C H L cells ]) were 
ne gati ve.  
T here w ere n o t o xic ol o gi call y si g nifica nt fi n di n gs at d oses u p t o 1 2 m g/ k g/ w k f or 1 3 wee ks i n 
t he m o use a n d m o n ke y st u dies, a n d t heref ore t h ere is s ufficie nt t hera p e utic mar gi n t o s u p p ort t he 
safe cli nical use of I SI S 4 8 4 1 3 7 at t he pr o p ose d cli nical d oses a n d re gi me n.   
2. 3. 4 
Cli nic al E x perie nce  
T he safet y a n d t olera bilit y of I SI S  4 8 4 1 3 7 w as e v al uate d i n a t otal of 4 0 healt h y o ver wei g ht 
s u bjects i n a d o u ble- bli n de d, place b o-c o ntr olle d, d ose-escalati o n P hase 1 st u d y I SI S  4 8 4 1 3 7-
C S 1 .  Of t hese 4 0 s u bjects, 3 0 recei v e d I SI S 4 8 4 1 3 7 ( 1 2 i n t he si n gle- d os e c o h orts a n d 1 8 i n t he 
m ulti ple - d ose c o h orts), a n d 1 0 recei v e d place b o.  ISI S  4 8 4 1 3 7 was well-t olerate d at d oses u p t o 
3 0 0 m g/ w k f or 6 wee ks.  T here w ere n o S A Es a n d all re p orte d A Es were mil d i n se verit y .  T here 
were n o d os e- de p e n de nt cli nicall y mea ni n gf ul tre n ds i n la b orat or y assess me nts.   


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
Ori gi nal 
Pr ot oc ol  
1 A u g us t 2 0 1 7 
2 7
 
2. 4  
R ati o n ale f or D ose a n d Sc he d ule of A d mi nistr ati o n 
T he safet y data o btai ne d i n t he P hase 1 st u d y (I SI S 4 8 4 1 3 7- C S 1) as we ll as t he cli nical 
e x perie nce wit h se veral ot her 2 ′- M O E- m o difie d A S Os (Se well et al. 2 0 0 2 ; C hi et al. 2 0 0 5 ; 
Kastelei n et al. 2 0 0 6 ), s u p p orts t he d osi n g re gi me n pla n ne d f or t his P hase 2 st u d y.  T he pla n ne d 
re gi me n has bee n e m pl o ye d safel y i n pre vi o us cli nical st u dies wit h a n u m ber of ot her A S Os.  
T his class of A S Os has bee n safel y a d mi nist ere d i ntra ve n o usl y (I V) a n d s u bc uta ne o usl y i n 
m ulti ple cli nical st u dies at d oses u p t o 1 0 0 0 m g ( K w o h 2 0 0 8 ; Cr o o ke et al. 2 0 1 6 ) a n d treat me nt 
d urati o ns t hat e xce e d 2 4 m o nt hs.   
T he c urre ntl y pr o p ose d 2 5 0 m g I SI S 4 8 4 1 3 7 d ose le ve l was selecte d base d o n res ults fr o m t he 
pre vi o us I SI S 4 8 4 1 3 7- C S 1 P hase 1 cli nical st u d y ( d oses 5 0 t o 4 0 0 m g) t hat s h o we d a 
satisfact or y safet y pr ofile wit h t hese d ose le vels after 6 wee ks ( 8 t otal d oses) of treat me nt.  
A d diti o nall y, se veral A S Os of t his class ha ve de m o nstrate d si g nifica nt efficac y a n d acce pta ble 
safet y pr ofiles at a si milar d ose le vel f or 1 3 wee ks a n d l o n ger (Ac ker ma n n et al. 2 0 1 6 ; 
D uell et al. 2 0 1 6 ; Di ge ni o et al. 2 0 1 6 ) 
Wee kl y a d mi nistrati o n f or 1 3- wee ks is als o s u p p orte d b y t he I SI S 4 8 4 1 3 7 n o ncli nical 1 3- wee k 
t o xic ol o g y st u d y (see I n vesti gat ors Br oc h ure).  Ki d ne y, li ver, a n d a di p ose tiss ue c o nce ntrati o ns 
of I SI S 4 8 4 1 3 7 c ollecte d after 1 3 wee ks of d os i n g d uri n g a m o n ke y t o xic ol o g y st u d y i n dicate 
t hat tiss ue distri b uti o n f or t his c o m p o u n d is c o nsiste nt wit h pre vi o usl y a d mi nistere d a ntise nse 
oli g o n ucle oti des.  P ost- dis tri b uti o n plas ma c o nce ntrati o ns (i.e., ter mi nal eli mi nati o n p hase) of 
I SI S 4 8 4 1 3 7 are e x pecte d t o be i n e q uili bri u m wit h tiss ue c o nce ntrati o ns i n h u ma ns, as was 
o bser ve d i n m o n ke ys, mice, a n d rats f or si milar 2 ′- M O E ga p mers.  Wit h a n esti mate d tiss ue 
half-life of a p pr o xi matel y 2- 3 wee ks f or I SI S 4 8 4 1 3 7 pre dicte d f or h u ma ns base d o n pre vi o us 
e x perie nce wit h ot her sec o n d ge nerati o n A S Os ( Y u et al. 2 0 0 9 ), ac hie vi n g stea d y-state 
c o nce ntrati o ns i n t he li ver (t he tar get or ga n) will be a pr ol o n ge d pr ocess (e. g., ti me t o 
a p pr o xi matel y 9 0 % of stea d y-state i n tiss ues is esti mate d t o ta ke a b o ut 8 wee ks wit h 
o nce- wee kl y d osi n g re gi me n).  T hirtee n ( 1 3) we e ks of st u d y treat me nt is a s ufficie nt treat me nt 
d urati o n t o o bser ve c ha n ges i n li ver fat c o nt e nt a n d i m pr o ve me nts i n I R i n t his patie nt 
p o p ulati o n. 
2. 5
 Ris k
 
Assess me nt
 
T he k n o w n p ote ntial ris ks t o st u d y partici pa nts a ss ociate d wit h I SI S 4 8 4 1 3 7 are ela b orate d o n i n 
t he G ui da nce t o I n vesti gat or secti o n of t he I SI S 4 8 4 1 3 7 I n vesti gat or’s Br oc h ure.  Ris ks 
ass ociate d wit h D G A T 2 re d ucti o n are n ot a n tici pate d i n t his s h ort-ter m trial. 
3. 
E X P E RI M E N T A L
 
P L A N
3. 1
 St u d y
 
Desi g n
T his is a P hase 2 m ultice nter, d o u ble- bli n d, ra n d o mize d, stratifie d, place b o-c o ntr olle d st u d y i n 
s u bjects wit h t y pe 2 dia betes a n d e vi de nce of hepatic steat osis see n o n M RI sca n.  S u bjects will 
be stratifie d base d o n t he li ver c o nte nt b y M R I- P D F F d uri n g t he R u n-I n- Peri o d ( < 2 0 % vs. 
≥ 2 0 %).  S u bjects will be ra n d o mize d i n a 2: 1 rati o t o recei ve S C treat me nt wit h eit her 
I SI S 4 8 4 1 3 7 2 5 0 m g or place b o ( See St u d y Desi g n a n d Treat me nt Sc he ma ).   


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
2 8
 
3. 2 
N u m ber of St u d y Ce nters  
T his st u d y will be c o n d u cte d at m ulti ple ce nters w orl d wi de . 
3. 3 
N u m ber of S u bjects  
A p pr o xi matel y 4 5 s u bj ects are pla n ne d t o b e e nr olle d i n t his st u d y, ra n d o mize d 2: 1 t o 
I SI S 4 8 4 1 3 7 or place b o.   
3. 4  
O ver all St u d y D ur ati o n a n d F oll o w- u p  
T he st u d y will c o nsist of  Scree ni n g a n d R u n -i n, Treat me nt, a n d P ost- Treat me nt Peri o ds.  Please 
refer t o t he Sc he d ule of Pr oce d ur es i n A p pe n di x A .  T he e x pecte d d urati o n of t he st u d y will be 
u p t o 6 wee ks of S cr ee ni n g wit h t he R u n- I n-Peri o d , 1 3 wee ks of St u d y Dr u g d osi n g, a n d 
1 3 wee ks of p ost-tr eat me nt e val uati o ns, f or a t otal of u p t o 3 2 wee ks of p artici pati o n. 
S u bjects ma y be re q uir e d t o atte n d a d diti o nal visits f or m o nit ori n g of a d verse e ve nts ( A E) or 
a b n or mal i n vesti gati o n r es ults.  T he fre q ue n c y of a d diti o nal m o nit ori n g will be deter mi ne d b y 
t he St u d y Me dical M o nit or i n c o ns ultati o n wit h t he I n vesti gat or. 
3. 4. 1 
Scree ni n g  a n d R u n-I n 
S u bject eli gi bilit y f or t h e st u d y will be deter mi ne d wit hi n 6 wee ks  pri or t o st u d y e ntr y, c o nsisti n g 
of u p t o 2- wee k Scree ni n g ( Wee k - 6 t o Wee k - 5) a n d a 4-wee k R u n- I n-Peri o d  ( Wee k - 4 t o 
Wee k  -1).  
D uri n g t h e be gi n ni n g of t he R u n- I n-Peri o d  (a p pr o xi matel y Wee k - 4 t o Wee k - 3), s u bjects will 
ha ve a b aseli ne he p atic M RI t o assess eli gi bilit y wit h li ver fat c o nte nt.  M RIs will be c o n d u cte d 
usi n g sta n dar dize d pr oce d ures a n d setti n gs .  M RIs will be e val uate d b y a  ce ntral rea d er, bli n de d 
t o t he s u bject’s treat me nt assi g n me nt, t o assess li v er fat a n d li ver size. 
3. 4. 2 
Tre at m e nt  
Eli gi ble s u bjects will be r a n d o mize d  will re p ort t o t he St u d y Ce nter  f or st u d y treat me nt ever y 
wee k  f or 1 3 wee ks  ( Wee k 1- Wee k 1 3). 
3. 4. 3 
P ost -Tre at m e nt  
S u bjects  are t o ret ur n t o t he St u d y Ce nter  f or f oll o w-u p visits at t he f oll o wi n g ti me p oi nts after 
t he last d ose:  1 wee k ( P T 1), 2 wee ks ( P T 2), 3 wee ks ( P T 3), 4 wee ks ( P T 4), 6 wee ks ( P T 6), 
8 wee ks ( P T 8), 1 2 w ee ks ( P T 1 2).  T he fi nal st u d y visit will occ ur 1 3 wee ks after t he l ast d ose 
a n d via tele p h o ne. 
C o m plete d s u bjects will ha ve a  P ost-Treat me nt  he patic M RI t o ass ess li ver  fat c o nte nt a n d 
v ol u me 2 wee ks after t he last d ose .  T he ti mi n g of t he P ost-Treat me nt M RI  f or s u bjects w h o 
ter mi nate earl y fr o m t he Treat me nt Peri o d is o utli ne d i n Secti o n 6. 1. 4 a n d A p pe n di x A.   
3. 5 
E n d - of-St u d y  
T he E n d - of- St u d y is defi ne d as w he n t h e last s u bject has ha d t heir last visit. 


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
2 9
 
4.
S U B J E C T E N R O L L M E N T
4. 1 
Scree ni n g
Bef ore s u bjects ma y b e e nr olle d i nt o t he St u d y, t h e S p o ns or a n d desi g nate d c o ntract researc h 
or ga nizati o n ( C R O) re q uires a c o p y of t h e St u d y Ce nter’s writte n i ns tit uti o nal re vie w b o ar d 
(I R B) a p pr o val of t he pr ot oc ol, i nf or me d c o nse nt f or m, a n d all ot her s u bject i nf or mati o n a n d/ or 
recr uit me nt material. 
S u bjects  or t heir le gall y acce pta bl e re prese ntati ves m ust si g n t he c o nse nt f or m bef ore a n y 
scree ni n g tests or assess me nts are perf or me d .  At t he ti me of c o nse nt, t he s u bject will be 
c o nsi dere d e nr olle d i nt o t he St u d y a n d will be assi g ne d a u ni q ue scree ni n g n u m ber bef ore a n y 
St u d y pr oce d ures, i ncl u di n g scr ee ni n g pr o ce d ures, are perf or m e d.  I n t he e ve nt t he s u bject is 
re-c o ns e nte d or r e-scree n e d t he patie nt m ust be gi ve n a ne w s cree ni n g n u m ber.  Scree ni n g 
n u m bers, o nce assi g n e d, will n ot be re- use d. 
4. 2  
R a n d o miz ati o n 
S u bjects will be ra n d o mize d after all S cree ni n g a n d R u n-I n assess me nts  t hr o u g h Wee k - 1 ha ve 
bee n c o m plete d a n d aft er t he I n v esti gat or has v erifie d t hat t he y are eli gi ble per criteria i n 
Secti o ns 5. 1  a n d 5. 2 .  N o s u bject ma y b e gi n treat me nt pri or t o ra n d o mizati o n a n d assi g n me nt of 
a u ni q ue s u bject i de ntificati o n n u m ber. 
All s u bjects will be ra n d o mize d usi n g a n a ut o mat e d s yste m (I X R S) .  S u bjects will be stratifie d 
base d o n li ver f at c o nte nt res ults fr o m t he M RI c o n d ucte d i n t he R u n- I n Peri o d  ( < 2 0 % or 
≥ 2 0 %), a n d t he n s u bjects will be ra n d o mize d i n a 2: 1 rati o t o recei v e S C treat me nt wit h eit her 
I SI S 4 8 4 1 3 7 2 5 0 m g or place b o .  T he S p o ns or or desi g nee will pre p are t he ra n d o mizati o n list. 
4. 3 
Re pl ace me nt of S u bjects  
S u bjects w h o  wit h dra w fr o m t he st u d y will n ot be re place d . 
4. 4 
U n bli n di n g of Tre at me nt Assi g n me nt  
T he S p o ns or a n d all s u bjects, m o nit ors, a n d St u d y C e nter pers o n n el relate d t o t he st u d y will be 
bli n de d t hr o u g h o ut t he st u d y.  H o w e ver, if a s u bject has s uffere d a S eri o us A d verse E v e nt ( S A E) 
(as defi ne d i n Secti o n 9. 3. 3 ), a n d/ or w he n k n o wle d ge of t he treat me nt assi g n me nt will i m pact t he 
cli nical ma na ge me nt of t he s u bject , t he I n v esti gat or will ha ve t he a bilit y t o u n bli n d t he treat me nt 
assi g n me nt f or t hat s u bject usi n g t he a ut o mat e d I X R S.  T he S p o ns or or desi g nee will be 
i nf or me d of t he u n bli n di n g of a s u bject wit hi n 2 4 h o urs.  A n u n bli n de d ra n d o mizati o n sc he ma 
will be mai ntai ne d sec ur el y  b y t he S p o ns or’s desi g nat e d ve n d or.  I n a d diti o n, all s us pecte d 
u ne x pecte d seri o us a d verse reacti o n s (S U S A Rs ) wil l be u n bli n de d b y t he S p o ns or or desi g nee  
f or t he p ur p ose of re g ul at or y re p orti n g (s ee Secti o n 9. 2 ). 
E ver y reas o na ble atte m pt s h o ul d be ma de t o c o m plete t he earl y t er mi nati o n st u d y pr oce d ures a n d 
o bser vati o ns (see A p pe n dices A  a n d C ) pri or t o u n bli n di n g, as k n o wle d ge of t he treat me nt ar m 
c o ul d i nfl ue nce s u bject assess me nt . 
I n a d diti o n, t he safet y tea m assi g ne d t o re vie w rele va nt St u d y Dr u g safet y a n d t olera bilit y data 
d uri n g t he st u d y i n a bli n de d fas hi o n will als o ha v e t he a bilit y t o re q uest t he I o nis Dr u g Saf et y 


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
3 0
 
O versi g ht C o m mittee, c haire d b y t he C hief M e dical Officer, f o r u n bli n di n g t he treat me nt 
assi g n me nt if nee de d f or safet y a n d d ata i nter pretati o n. 
5.
S U B J E C T E LI GI BI LI T Y
T o be eli gi ble t o p artici p ate i n t his st u d y ca n di d ates m ust meet t he f oll o wi n g eli gi bilit y criteria at 
Scree ni n g a n d t hr o u g h ra n d o mizati o n or at t he ti me p oi nt s pecifie d i n t he i n di vi d ual eli gi bilit y 
criteri o n liste d.  
5. 1 
I ncl usi o n Criteri a 
1.  M ust ha ve gi v e n writte n i nf or me d c o nse nt (si g ne d a n d date d) a n d a n y a ut h orizati o ns
re q uire d b y l ocal la w a n d be a ble t o c o m pl y wit h all st u d y re q uire m e nts
2.
Males or fe m ales .  A ge d 1 8 t o 7 5, i ncl usi ve, at t he ti me of i nf or me d c o nse nt
3.
Fe males m ust be n o n - pre g na nt a n d n o n-lact ati n g, a n d eit her s ur gicall y st erile (e. g., t u bal
occl usi o n, h ysterect o m y, bilateral sal pi n gect o m y, bilateral o o p h orect o m y) or p ost-
me n o pa usal ( defi ne d as 1 2 m o nt hs of s p o nta ne o us a me n orr h ea wit h o ut a n alter nati ve
me dical ca us e a n d  F S H le vels i n t he p ost me n o pa usal ra n ge f or t he la b orat or y i n v ol ve d
Males m ust be s ur gicall y sterile, a bsti ne nt * or, if e n ga ge d i n se x ual relati o ns wit h a
fe male of c hil d- beari n g p ote ntial, t he s u bject m ust be usi n g a n acce pta ble c o ntrace pti ve
met h o d (ref er t o Secti o n 6. 3. 1 ) fr o m t he ti me of si g ni n g t he i nf or m e d c o nse nt f or m u ntil
at least 1 3 wee ks after t he last d ose of St u d y Dr u g (I SI S 4 8 4 1 3 7 or pl ace b o)
*  A bsti ne nce is o nl y acce pta ble as tr ue a bsti ne nce, i.e., w he n t his is i n li ne wit h t he
preferre d a n d us ual lifest yl e of t h e patie nt .  Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n,
s y m pt ot her mal, p ost- o v ulati o n met h o ds), declarati o n of a bsti ne nce f or t he d urati o n of a
trial a n d wit h dra w al are n ot acce pt a ble met h o ds of c o ntrace pti o n.
4.
B o d y Mass I n d e x ( B MI) ≥ 2 7. 0 - ≤ 3 9. 0 k g/ m 2
5.  Dia g n osis  of T 2 D M wit h a n H b A 1c ≥ 7. 3 % a n d ≤ 9. 5 % at Scree ni n g
6. S u bjects m ust ha ve bee n o n a sta ble d ose of t he f oll o wi n g ora l a nti dia b etic t hera p y:
metf or mi n, s ulf o n yl ur ea ( S U), di pe pti d yl pe pti das e-I V ( D P PI V i n hi bit or) or s o di u m
gl uc ose li ke tra ns p ort pr otei n 2 ( S G L T 2) i n hi bit or f or a mi ni m u m of 3 m o nt hs pri or t o
scree ni n g e val uati o n a n d will be re q uire d t o c o nti n ue t heir sta ble d ose of oral a nti dia betic
t hera p y t hr o u g h o ut t he st u d y.  T he use of t hiaz oli di ne di o nes (e. g., pi o glitaz o ne,
r osi glitaz o ne) a n d i njecta ble a nti dia betic t hera p y is n ot per mitte d (e. g., i ns uli n,
gl uca g o n -li ke pe pti de [G L P 1 a nal o gs ])
7.
≥ 1 0 % li ver fat as  assess e d b y M RI- P D F F pri or t o ra n d o mizati o n
8. Sta ble b o d y w ei g ht ( B W) (i.e., n ot var yi n g b y > 5 % f or at least 3 m o nt hs) bef ore
S cree ni n g
9.
A gree t o mai ntai n c urre nt diet a n d e x ercise re gi m e n
1 0.  A gree t o a bst ai n fr o m alc o h olic be vera ges f or at least 4 8 h o urs pri or t o cli nic visits a n d
n ot i ncrease alc o h ol c o ns u m pti o n d uri n g t he st u d y


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5. 2 
E xcl usi o n Criteri a  
1.
Cli nicall y -si g nifica nt a b n or malities i n me dical hist or y (e. g., pre vi o us ac ute c or o nar y
s y n dr o me wit hi n 6 m o nt hs of Scree ni n g, maj or s ur ger y wit hi n 3 m o nt hs of Scree ni n g) or
p h ysical e x a mi nati o n
2. Ce ntral La b or at or y res ults pri or t o ra n d o mizati o n ( Scree ni n g a n d/ or R u n-I n) as f oll o ws,
or a n y ot her cli nicall y-si g nifica nt a b n or malities i n scree ni n g la b orat or y v al ues t hat w o ul d
re n der a s u bject u ns uita ble f or i ncl usi o n:
a.
Uri ne pr otei n/cr eati ni ne ( P/ C) rati o > 0. 2 m g/ m g .  I n t he e ve nt of P/ C rati o a b o ve t his
t hres h ol d eli gi bilit y ma y be c o nfir me d b y a q ua ntitati ve t otal uri ne pr otei n
meas ure me nt of < 3 0 0 m g/ 2 4- hr
b.
Persiste ntl y p ositi ve test (i ncl u di n g trace) f or bl o o d o n uri nal ysis.  I n t he e v e nt of a
p ositi ve test eli gi bilit y m a y b e c o nfir me d wit h uri ne micr osc o p y s h o wi n g < 5 re d
bl o o d cells ( R B C) per hi g h p o w er fiel d ( Persiste ntl y p ositi ve defi ne d as 2 o ut of 3)
c. Ser u m creati ni ne > u p per li mit of n or mal ( U L N )
d.
Esti mate d gl o mer ular filtrati o n rate  (G F R ) < 6 0 m L/ mi n (as det er mi ne d b y t he
C oc kcr oft- G a ult E q uati o n f or creati ni ne cleara n ce)
e.  Ala ni ne a mi n otra nsf eras e ( A L T ) A L T or as p artat e a mi n otra nsferase  (A S T ) >
1. 5 U L N
f.
T otal bilir u bi n > U L N
g.  Ha ve a c urr e nt or pr e vi o us dia g n osis of Gil bert’s disease
h. Platelet c o u nt < 1 7 0, 0 0 0/ m m 3 ( < 1 7 0 x 1 09/ L)
3. S h o w e vi de nce of u nc orr ecte d h y p ot h yr oi dis m or h y pert h yr oi dis m h or m o ne res ults at
S cree ni n g.  S u bjects recei vi n g d ose-sta ble t h yr oi d re place me nt thera p y f or at least
3 m o nt hs pri or t o Scree ni n g will be all o w e d t o partici pate as l o n g as t h yr oi d tests
( T S H/ T 3/ T 4) s h o w t hat s u bject is e ut h yr oi d
4.  Hist or y of s oli d or ga n tra ns pla ntati o n or re nal dial ysis
5.
Cli nicall y -si g nifica nt c o m plicati o ns of dia betes (e. g., hist or y of pai nf ul ne ur o pat h y,
ne p hr o pat h y, pr oliferati v e reti n o pat h y a n d/ or f o ot ulcers)
6. S u bjects o n li pi d l o weri n g me dicati o ns m ust be o n a sta ble d ose a n d re gi me n f or
≥ 3 m o nt hs pri or t o Scree ni n g.  S u bjects recei vi n g treat me nt wit h stati ns  s h o ul d be wit hi n
t he d ose le vels liste d bel o w.  Ot her stati n re gi me ns s h o ul d be disc usse d a n d a p pr o ve d
wit h t he S p o ns or Me dical M o nit or or desi g nee:
•
Si m vastati n, pra vastati n, at or vastati n a n d fl u vast ati n at ≤ 4 0 m g/ da y
•
L o vast ati n or r os u vastati n at ≤ 2 0 m g/ da y
•
Pita vastati n u p t o 4 m g/ da y
7.  K n o w n hist or y of or e vi d e nce of li ver diseas e wit h a p ositi ve test f or h u ma n
i m m u n o deficie nc y vir us ( HI V), h e patitis C ( H C V) or c hr o nic h e patitis B ( H B V) or
c hr o nic li ver disease ot her t ha n N A S H i ncl u di n g alc o h olic li ver disease, Wils o n’s


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disease, he m oc hr o mat osis, or ir o n o verl oa d, Al p h a- 1- a ntitr y psi n ( A 1 A T) d eficie nc y, 
pri or k n o w n dr u g-i n d uce d li ver i nj ur y, k n o w n or s us pecte d he p at ocell ular carci n o ma 
( H C C), c urr e nt place m e nt o n a li ver tra ns pla nt list, or M E L D sc ore > 1 2, est a blis he d 
fi br osis ≥ S ta ge 3 fi br osis ( Scale 0-4) or a n y cirr h osis  
8.  Mali g na n c y wit hi n 5 years, e x ce pt f or basal or s q ua m o us cell carci n o ma of t he s ki n or
carci n o ma i n sit u of t he cer vix t hat has bee n s uccessf ull y treate d .  S u bjects wit h a hist or y
of ot her mali g na nci es t hat ha ve bee n treate d wit h c urati ve i nte nt a n d w hi c h ha ve n o
rec urre nce wit hi n 5 years ma y als o be eli gible if a p pr o ve d b y t he S p o ns or Me dical
M o nit or
9.
Treat me nt wit h a n ot her i n vesti gati o nal dr u g, bi ol o gical a ge nt, or d e vice wit hi n 1 m o nt h
of S cree ni n g, or 5 half -li ves of i n vesti gati o nal a ge nt, w hic he ver is l o n ger
1 0. Treat me nt wit h a n y  n o n- I O N- or I SI S - oli g o n ucl e oti de (i ncl u di n g s mall i nterferi n g
ri b o n ucleic aci d [si R NA] ) at a n y ti me or pri or treat me nt wit h a n I O N- or
I SI S- oli g o n ucle oti de wit hi n 9 m o nt hs of Scree ni n g.  S u bjects w h o h a ve pre vi o usl y
recei v e d o nl y a si n gle- d ose of a n I SI S-oli g o n ucle oti de as part of a cli nical st u d y ma y be
i ncl u de d as l o n g as a d ur ati o n of ≥ 4 m o nt hs has ela pse d si nce d osi n g
1 1. Rece nt hist or y of, or c urr e nt dr u g or alc o h ol a b use.  Re g ular a n d e x cessi ve use of alc o h ol
wit hi n 6 m o nt hs pri or t o Scree ni n g ( > 7 dri n ks/ wee k f or fe males, > 1 4 dri n ks/ wee k f or
males ( 1 dri n k = 5 o u nces ( 1 5 0 m L) of wi ne or 1 2 o u nces ( 3 6 0 m L) of beer or 1. 5 o u nces
( 4 5 m L) of har d li q u or), or use of s oft dr u gs (s u c h as marij ua na) wit hi n 3 m o nt hs pri or t o
Scree ni n g, or h ar d dr u gs (s uc h as c o cai ne a n d p he nc ycli di ne [ P C P]) wit hi n 1- year pri or
t o scree ni n g, or p ositi ve uri ne dr u g scree n at Scree ni n g
1 2. C o nc o mita nt me dicati o n restricti o ns:
a.  Use of a ge nts (i ncl u di n g her bal or o v er-t he c o u nter wei g ht l oss pre parati o ns) or
me dicati o ns k n o w n t o si g nifica ntl y i m pact B W  wit hi n 3 m o nt hs pri or (e. g.,
si b utra mi ne, p he neta mi n e a n d orlistat)
b. c hr o nic use of s yst e mic c ortic oster oi ds
c. ot her a nti dia betic me dicati o ns n ot o utli ne d i n I n cl usi o n Criteria # 6,
d. ot her me dicati o ns, per I n vesti gat or, k n o w n t o ca us e li ver t o xicit y (e. g., c hr o nic
aceta mi n o p he n us e) or st eat osis (e. g ., a mi o dar o ne, met h otre x ate, ta m o xife n,
car ba m aze pi ne)
e.
Use of a ntic o a g ula nt/a nti platelet a ge nts (e. g ., warfari n, he pari n, da bi gatra n,
ri var o x a ba n, cl o pi d o grel) u nless t he d ose has bee n sta ble f or 4 w ee ks pri or t o t he first
d ose of St u d y Dr u g a n d r e g ul ar cli nical m o nit ori n g is perf or me d, us e of t he
n o n- ster oi dal a nti-i nfla m mat or y dr u g ( N S AI D) ni mes uli de or a n y ot her dr u g
i nfl ue nci n g c oa g ulati o n ( e x ce pt l o w d ose as piri n < 1 6 0 m g/ da y a n d ot h er s h ort acti n g
N S AI D S wit h a half -life < 2 0 h o urs)
f.
o betic h olic aci d or urs o de o x yc h olic aci d
1 3. Bl o o d d o nati o n of 5 0 t o 4 9 9 m L wit hi n 3 0 da ys of Scree ni n g or of > 4 9 9 m L wit hi n
6 0 da ys of S cree ni n g


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1 4. Acti ve i nfecti o n r e q uiri n g s yste mic a nti viral or a nti micr o bial t hera p y t hat will n ot be
c o m plete d pri or t o St u d y Da y 1
1 5. S u bjects wit h k n o w n i nt olera nce t o M RI or wit h c o n diti o ns c o ntrai n dicate d f or M RI
Pr oce d ures:
•
S u bjects w h o ha ve a n y m etal i m pla nt (i ncl u di n g a heart pace ma k er, r o ds, scre ws,
a ne ur ys m cli p)
•
S u bjects wit h cla ustr o p h o bia
1 6. C o nfir me d re d ucti o n i n f asti n g plas ma gl uc os e ( F P G) of > 4 0 m g/ d L ( > 2. 2 m m ol/ L) at
t he R u n-I n Visit ( Wee k -1) c o m pare d t o a F P G v al ue ta ke n at Scree ni n g
1 7. C o nfir me d re d ucti o n i n B W  ± 2 k g ( 4. 4 l bs) at t he R u n-I n Visit ( Wee k - 1) c o m pare d t o
B W  ta ke n at Scr ee ni n g
1 8. Ha ve a n y ot h er c o n diti o ns, w hic h, i n t he o pi ni o n of t he I n vesti gat or or S p o ns or w o ul d
ma ke t he s u bject u ns uita ble f or i ncl usi o n, or c o ul d i nterfere wit h t he s u bject partici pati n g
i n or c o m pleti n g t he St u d y, i ncl u di n g u n willi n g n ess t o c o nti n ue wit h S C i njecti o ns after
t he S C T olera bilit y assess me nt
6.
S T U D Y P R O C E D U R E S
6. 1 
St u d y Sc he d ule
T he st u d y p eri o d f or a n i n di vi d ual s u bject c o nsists of a ≤ 6 -wee k Scree ni n g  a n d R u n-i n Peri o d 
f oll o we d b y a 1 3-w ee k Treat me nt Peri o d, a n d a 1 3 -wee k P ost -Treat me nt Peri o d .  A d diti o nal 
visits m a y b e sc he d ul e d if re q uire d f or f urt her e val uati o n of a n a b n or m al la b orat or y val ue or 
re p orte d A E. 
A n y A Es, c o nc o mita nt m e dicati o ns, a n d ot her s afet y a n d t olera bilit y pr ofili n g dat a will be 
pr o m ptl y re p orte d a n d re vie we d b y S p o ns or’s Me dical M o nit or ( or de si g nee). 
All re q uire d st u d y pr oce d ures ar e o utli ne d i n A p pe n dices A , B  a n d C . 
6. 1. 1 
Scree ni n g  Peri o d ( Wee k - 6 t o Wee k - 5) 
Writte n i nf or me d c o nse nt f or t he st u d y will be o btai ne d pri or t o t he perf or ma nce of a n y 
st u d y-r elate d pr o ce d ur es i ncl u di n g Scree ni n g a n d R u n- I n pr oce d ures .  A ≤ 6-wee k p eri o d is 
pr o vi de d t o c o m plete Scr ee ni n g assess me nts a n d t o deter mi ne s u bject eli gi bilit y f or t he st u d y, 
wit h S cree ni n g at Wee k - 6 t o Wee k - 5, a n d t he R u n-I n Peri o d fr o m Wee k - 4 t o Wee k - 1.  
S u bjects will be q uesti o ne d f or me dical hist or y, a n d u n der g o p h ysical e x a mi nati o n, c o nfir mati o n 
of t heir dia betes stat us a n d e x cl u de ot her ca us es of li ver disease  a n d fi br osis , 1 2-lea d 
electr ocar di o gr a m ( E C G)  c o n d ucte d i n tri plicate, vital si g ns, B W , a n d hei g ht.  S u bjects will als o 
be scree ne d f or i nfecti o ns of HI V, H e patitis B a n d C, a n d f or bl o o d c oa g ulati o n a b n or malities 
i ncl u di n g pr ol o n ge d acti vate d partial t hr o m b o plasti n ti me  (a P T T), pr ot hr o m bi n ti me ( P T), a n d 
i nter nati o nal n or malize d rati o (I N R), a n d t h yr oi d f u ncti o n tests ( T S H, free T 4 a n d free T 3) 
le vels.  F ollicle -sti m ulati n g h or m o n e ( F S H) will be meas ure d t o c o nfir m m e n o pa use i n w o me n 
w h o ha ve n ot u n der g o ne s ur gical sterilizati o n.  A d diti o nal bl o o d sa m ples will be ta ke n f or 
r o uti ne cli nical la b orat or y testi n g (A p p e n di x A). 


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I n di vi d uals ma y b e dis q ualifie d if t he res ult of a n y la b orat or y test is o utsi de of t he ra n ge 
s pecifie d i n t he eli gi bilit y criteria (Secti o ns 5. 1  a n d 5. 2 ) or, if n o ra n ge is s pecifie d, is a b n or m al 
a n d cli nicall y-si g nifica nt as j u d ge d b y t he I n vesti gat or or S p o ns or Me dical M o nit or or Desi g n ee. 
D uri n g t h e Scree ni n g Peri o d, scree ni n g res ults ma y be reteste d f or ass ess me nt b y t he S p o ns or 
Me dical M o nit or or Desi g nee f or eli gi bilit y p ur p oses.   
6. 1. 2 
R u n -I n Peri o d ( Wee k -4 t hr u We e k - 1) 
U p o n c o m pleti o n of t he Scree ni n g peri o d, eli gi bl e patie nts e nter t h e 4- wee k R u n-I n Peri o d f or 
s u bjects t o mai ntai n t heir r o uti ne diet a n d e x ercise sta bilizati o n d uri n g t his peri o d a n d f or a 
baseli ne li ver M RI Assess me nt .  S u bjects will mai ntai n t hei r r o uti ne diet a n d e x ercise r o uti ne 
a n d c o nti n ue t o ta ke t heir oral a nti -dia betic a ge nt ( O A D ) dail y d uri n g t his 4-wee k p eri o d .  
S u bsta ntial c ha n ges i n diet a n d e x ercise  acti vities c o ul d ha ve a n i m pact o n li ver fat c o nte nt a n d 
s h o ul d be a v oi de d d uri n g st u d y partici p ati o n.  
6. 1. 2. 1 
Liver  M RI Assess m e nt ( Wee k - 4 t o Wee k - 3) 
A n M RI of t h e li ver will be c o n d ucte d 2 ti mes d uri n g st u d y partici pati o n, o nce bef ore treat me nt 
a n d o nce after tr eat me nt .  T he  Baseli ne  M RI will be c o n d ucte d d uri n g t h e R u n-I n Peri o d 
( Wee k - 4 t o Wee k - 3) a n d t he P ost-Treat me nt  M RI Assess me nt will be c o n d ucte d d uri n g t he 
P ost- Treat me nt  Peri o d (Wee k  of P T 2 Visit). 
T hese M RIs will be c o n d ucte d usi n g sta n d ar dize d pr oce d ures a n d setti n gs a n d will be e val uate d 
b y a ce ntr al rea der, bli n d e d t o t he s u bject’s treat me nt assi g n me nt, t o ass ess li ver fat a n d li ver 
v ol u me. 
All s u bjects ma y b e  re q uire d t o fast f or at least 4 h o urs bef ore t he M RI assess me nt. 
S u bjects  wit h a q ualif yi n g Baseli ne M RI (at least 1 0 % li ver fat ass esse d b y M RI -P D F F via 
ce ntral r e vie w er) will ret ur n t o cli nic f or R u n-I n Wee k - 1 Visit .  If it is n ot p ossi ble f or M RI 
res ults t o be a vaila ble b y t his visit or if it nee ds t o be re peate d , t he M RI res ults m ust be a vaila ble 
f or fi nal q ualificati o n pri or t o ra n d o mizati o n.  Fail ure t o reac h el i gi bilit y criteria of li ver fat 
c o nte nt b y M RI is c o nsi d ere d a s cree n fail ure a n d will n ot be re peate d. 
6. 1. 2. 2 
R u n -I n Wee k - 1 
At t his visit, fi nal q ualificati o n assess me nts will be c o n d ucte d  acc or di n g t o A p pe n di x A  
i ncl u di n g B W  a n d F P G assess me nts as well  as a S C T olera bilit y Assess me nt .  S u bjects will 
mai ntai n t heir r o uti ne diet a n d e x ercise r o uti ne a n d c o nti n ue t o t a ke t heir O A D dail y d uri n g t his  
peri o d.  S u bsta ntial c ha n ges i n eit her o ne of t h ese acti vities c o ul d ha ve a n i m pact o n li ver fat 
c o nte nt a n d s h o ul d be a v oi de d d uri n g st u d y partici pati o n.   
6. 1. 2. 2. 1 
F P G a n d B W Eli gi bility Assess m e nts ( Wee k - 1) 
Patie nts will be re q uire d t o visit t he cli nic f or F P G  a n d B W meas ure me nts i n b ot h t he Scree ni n g 
Peri o d ( W k - 6 - W k -4) a n d  R u n-I n Peri o d ( Wee k - 1).  T he F P G ce ntral la b res ults  a n d B W cli nic 
assess me nt  fr o m t hese 2 visits (at least 3 wee ks a p art) will be c o m pare d t o assess t he patie nt’s 
eli gi bilit y f or ra n d o mizati o n .   


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•
If a > 4 0 m g/ d L ( 2. 2 m m ol/ L) F P G re d u cti o n is o bser ve d (a n d c o nfir me d wit h a retest)
fr om t he scr ee ni n g res ult t o t he R u n- I n Week- 1, t h e patie nt ca n n ot b e ra n d o mize d
(E x cl usi o n Criteria # 1 5 ).  If a patie nt is n ot ra n d o mize d d ue t o a n o bser ve d > 4 0 m g/ d L
( 2. 2 m m ol/ L) dr o p i n f asti n g gl uc ose, t he p atie nt ma y b e eli gi ble f or rescreeni n g after
6 wee ks ha v e ela ps e d
•
If a r e d ucti o n i n B W  ± 2 k g ( 4. 4 l bs) (a n d co nfir m e d wit h a retest) fr o m t he  scree ni n g
res ult t o t he R u n-I n Wee k - 1, t he patie nt ca n n ot b e ra n d o mize d (E x cl usi o n Criteria # 1 6 )
6. 1. 2. 2. 2 
S C T oler a nce Assess m e nt  
I n or der t o r e d uce t he b ur de n of u n necessar y pr oce d ures o n s u bjects w h o s u bse q ue ntl y elect n ot 
t o partici pate i n t he st u d y or c o nti n ue wit h st u d y pr oce d ures, all s u bjects will c o nfir m t olera nce 
of S C a d mi nistrati o n pri or t o ra n d o mizati o n .  T his i njecti o n will f oll o w t he sa me  pr oce d ures as 
t he i njecti o n of t he St u d y Dr u g (I SI S 4 8 4 1 3 7 or pl ace b o) d uri n g t he treat me nt peri o d .  
S pecificall y, d uri n g t he R u n- I n-Peri o d  d uri n g Wee k - 1, s u bjects will recei ve 1 S C i njecti o n of 
1. 2 5 m L sali ne ( m a y als o be deli vere d as 2 n o n-c o nti g u o us i njecti o n v ol u mes of 0. 7 5 m L a n d 
0. 5 0 m L). 
W he n t he Scree ni n g  a n d R u n-I n res ults are a vaila ble t hr u Wee k - 1, i n di vi d uals will be n otifie d of 
t heir eli gi bilit y.  Q u alifie d patie nts will be ra n d o mize d a n d will pr ocee d t o t he Treat me nt Peri o d 
wit h Wee k 1, Da y 1 Assess me nts.  
6. 1. 3 
Tre at m e nt Peri o d  ( Wee ks 1- 1 3) 
E nr olle d s u bjects w ill be a d mi nistere d I SI S 4 8 4 1 3 7 or place b o o n ce eac h w ee k f or a t otal of 
1 3 wee ks of tr eat me nt .  O nce -wee kl y S C a d mi nistrati o n  will occ ur  d uri n g t he visits .  At eac h 
visit, s u bjects will  be re mi n de d t o retai n t he sa m e diet a n d e x ercise re gi m e n as was f oll o we d 
d uri n g t he Scree ni n g a n d R u n-I n Peri o d.  S u bsta ntial c ha n ges i n eit her o ne of t hese acti vities 
c o ul d ha ve a n i m pact o n li ver fat c o nte nt a n d s h o ul d be a v oi de d d uri n g st u d y partici pat i o n.  
S u bjects will c o nti n ue t o ta ke t heir O A D dail y d uri n g t his peri o d . 
Safet y a n d cli nical  la b orat or y e v al uati o ns will be p erf or me d o n a wee kl y basis.  Vital si g ns, B P  
assess me nts, A E s a n d c o nc o mita nt usa ge will be assesse d d uri n g cli nic visits.  Ot her a ssess me nts 
will be c o n d ucte d d uri n g t he Treat me nt Peri o d i n l ess fre q u e nt i nter vals as i n dicate d i n 
A p pe n dices A , B , a n d C  i ncl u de E C G, dr u g/alc o h ol scree ni n g, H b A 1 c, F P G, li pi d pa nel, i ns uli n, 
hs C R P, T S H, e x pl orat or y mar k ers a n d P K.  A n y A E s a n d c o nc o mitant me dicati o ns will be 
rec or d e d a n d r e vie w e d b y t he S p o ns or’s M e dical M o nit or or desi g n ee.  A n y q uesti o ns o n st u d y 
pr oce d ur es a n d visit wi n d o ws ma y b e directe d t o t he S p o ns or ( or desi g nee). 
Earl y ter mi nati o n patie nts fr o m t he Treat me nt Peri o d will be re q uire d t o c o m plete t heir st u d y 
ter mi nati o n e val uati o ns f oll o wi n g t he P T 1  st u d y pr oce d ures (see A p pe n di x A).  T he ti mi n g of 
t he P ost- Treat me nt M RI f or earl y t er mi nati o n patie nts fr o m t he Treat me nt Peri o d is o utli ne d i n 
Secti o n 6. 1. 4 .  All patie nts recei vi n g at  least 1 d os e of st u d y m e dicati o n are re q uire d t o e nt er t he 
P ost- Treat me nt Peri o d f or c o nti n ui n g safet y e v al uati o ns.   
6. 1. 4 
P ost -Tre at m e nt  Peri o d  (P T 1 - 1 3) 
After c o m pleti n g t he 1 3  wee ks of t he Treat me nt Peri o d , i ncl u di n g s u bjects w h o disc o nti n ue earl y 
fr o m t he Treat me nt Peri o d, s u bjects will ret ur n f or p ost-treat me nt f oll o w- u p e val uati o n visits as 


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i n dicate d i n A p pe n di x A .  All s u bject s will be f oll o we d f or 1 3 w ee ks u ntil t he P T 1 3 visit.  
D uri n g t h e P ost- Treat me nt Peri o d  fr o m P T 1 - 4 ( wee kl y visits), a visit wi n d o w of ± 3 da ys is 
p er mitte d, w her eas f or visits P T 6 - 1 3 a visit wi n d o w of ± 7 da ys is per mitte d .  Safet y a n d cli nical 
la b orat or y e v al uati o ns as well as P D mar kers, i ncl u di n g t h ose f or P K a nal ysis, will be perf or me d 
as i n dicate d i n A p pe n dices A, B , a n d C .  A n y A E s a n d c o nc o mita nt me dicati o ns will be rec or d e d 
a n d re vie w e d b y t he S p o ns or’s Me dical M o nit or or desi g n ee.  At eac h visit, s u bjects will be 
re mi n de d t o retai n t he s a me diet a n d e x ercise re gi me n as was f oll o w e d d uri n g t he Scree ni n g a n d 
R u n-I n Peri o d.  S u bjects will c o nti n ue t o ta ke t heir O A D dail y d uri n g t his peri o d. 
A P ost- Treat me nt  M RI ( See Secti o n 6. 1. 2. 1 ) t o assess li ver fat c o nte nt a n d v ol u me will occ ur 
d uri n g P T 2 Visit  ( 2 wee ks after last d ose)  f or all s u bjects c o m pleti n g 1 3 d oses.  F or s u bjects w h o 
ter mi nate fr o m t he tr eat me nt peri o d earl y, t h e ti mi n g a n d c o n d u ct of t he M RI i n t he 
P ost- Treat me nt Peri o d will be a dj uste d as f oll o ws  ( +/- 7-da y wi n d o w)  
i.
S u bject recei v e d 4 or less d oses, t he P ost- Treat me nt M RI Assess me nt will n ot be
re q uire d
ii.
S u bject recei v e d 5 - 9 d os es, t he P ost-Treat me nt M RI Assess me nt will occ ur 2 wee ks
after last d ose at t he P T 2 Visit
iii.
S u bject recei v e d 1 0 - 1 2 d oses, t he P ost-Treat me nt M RI Assess me nt will be sc he d ule d
as f oll o ws:
•
If s u bject r ecei ve d 1 0 d oses, s u bject m o ves i nt o P ost- Treat me nt  Peri o d, t he M RI
will be c o n d ucte d 5 w ee ks after t he last d ose  ( duri n g St u d y Wee k P T 5)
•
If s u bject r ecei v e d 1 1 d oses, s u bject m o ves i nt o P ost-Treat me nt Peri o d, t he M RI
will be c o n d ucte d 4 w ee ks after t he last d ose ( d uri n g St u d y Wee k P T 4)
•
If s u bject r ecei v e d 1 2 d oses, s u bject m o ves i nt o P ost-Treat me nt Peri o d, t he M RI
will be c o n d ucte d 3 w ee ks after t he last d ose ( d uri n g St u d y Wee k P T 3)
Earl y ter mi nati o n patie nts fr o m t he P ost- Treat me nt  Peri o d ( E T P T) will be re q uire d t o c o m plet e 
t heir E n d-Of - St u d y e v al uati o ns f oll o wi n g t he E T P T 1 2 Visit st u d y pr o ce d ures (see 
A p pe n di x A).  
6. 2  
L a b or at or y Assess me nts 
La b orat or y a nal yte sa m pl es will be c ollecte d t hr o u g h o ut t he st u d y.  A list of t hese a nal ytes is 
c o ntai ne d i n A p pe n di x B .  Bl o o d c he mistr y a n d uri ne sa m ples s h o ul d be ta ke n be ta ke n after 
fasti n g f or at least 8 h o urs.  D uri n g t he fasti n g peri o d, t he s u bject ca n dri n k water a n d t h e y 
s h o ul d e ns ure t hat t he y c o ns u me s ufficie nt wat er i n or der t o n ot bec o m e de h y drate d. 
If d uri n g t he treat me nt peri o d, a platelet, creati ni ne, or A L T res ult is u ni nter preta ble (e. g., d ue t o 
cl u m pi n g, he m ol ysis, or q ua ntit y n ot s ufficie nt) t he test m ust be re peate d a n d a res ult n ot 
meeti n g st o p pi n g r ule m ust be o btai ne d pri or t o n e xt d ose. 


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6. 3 
Restricti o n o n t he Lif est yle of S u bjects  
6. 3. 1 
C o ntr ace pti o n Re q uire me nts  
Male s u bjects m ust refr ai n fr o m s per m d o nati o n a n d eit her be a bsti ne nt† or, if e n ga ge d i n se x ual 
relati o ns wit h a fe mal e of c hil d-beari n g p ote ntial , t he y m ust use effecti ve barrier c o ntrace pti o n 
wit h t heir part ner fr o m t he ti me of si g ni n g t he i nf or me d c o nse nt f or m u ntil at least 1 3 wee ks 
after t heir l ast d ose  of St u d y Dr u g .  Effecti ve c o ntrace pti o n i ncl u des a vasect o m y wit h ne gati ve 
se me n a nal ysis at F oll o w- u p, or t he use of c o n d o ms t o get her wit h s per mici dal 
f oa m/ gel/fil m/crea m/s u p p osit or y.  Male s u bjects e n ga ge d i n se x ual relati o ns wit h a fe male of 
c hil d-beari n g p ote ntial  m ust als o e nc o ura ge t heir fe male part n er t o use effecti ve c o ntrace pti o n 
fr o m t he ti me of si g ni n g t he i nf or me d c o nse nt u ntil 1 3 wee ks after t he s u bj ect ’s last d ose of 
st u d y treat me nt.  Eff ecti ve c o ntrace pti o n f or t he fe male part ner i ncl u des: s ur gical sterilizati o n 
(e. g., bilater al t u bal li gati o n), h or m o nal c o ntrace pti o n, i ntra uteri ne c o ntrace pti o n/ de vice, or 
barrie r m et h o ds (fe m ale c o n d o m*, dia p hra g m, s p o n ge, cer vi cal ca p ) t o get her wit h s per mici dal 
f oa m/ gel/fil m/crea m/s u p p osit or y.  Male s u bjects wit h part ners t hat are pre g na nt m ust use 
c o n d o ms t o e ns ure t hat t he fet us is n ot e x p ose d t o t he St u d y Dr u g . 
† N ote: A bsti ne nce is o nl y acce pta ble as tr ue a bsti ne nce, i.e., w he n t his is i n li ne wit h t he 
preferre d a n d us ual lifest yl e of t h e s u bject .  Peri o dic a bsti ne nce (e. g., cale n dar, 
o v ulati o n, s y m pt ot her mal, p ost- o v ulati o n met h o ds), declarati o n of a bsti ne n ce f or t h e 
d urati o n of a trial a n d wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n.  
* N ote: A f e m ale c o n d o m a n d a m ale c o n d o m s h o ul d n ot be use d t o get her as fricti o n
bet w ee n t he t w o c a n res ult i n eit her or b ot h pr o d uct s f aili n g. 
6. 3. 2 
F asti n g  Re q uire m e nts  
All s u bjects will be re q uire d t o fast f or at least 8 h o urs bef ore eac h st u d y visit. 
6. 3. 3 
Lifestyle restricti o ns  
S u bjects are i nstr ucte d t o refr ai n fr o m alc o h ol c o ntai ni n g be v era ges at least 4 8 h o urs pri or t o a 
cli nic visit  a n d s h o ul d n ot i ncrease alc o h ol c o ns u m pti o n d uri n g t he st u d y.  A d diti o nall y, s u bjects 
are r e q ueste d t o mai ntai n a sta ble  diet a n d e x ercis e re gi me n  t hr o u g h o ut t he st u d y. 
7. 
S T U D Y D R U G
7. 1 
St u d y Dr u g Descri pti o n
St u d y Dr u g ( I SI S 4 8 4 1 3 7 or Place b o) c haracteristics are liste d i n Ta ble 1 .  
T he St u d y Dr u g ( I SI S 4 8 4 1 3 7 or Place b o) is c o ntai ne d i n 2 m L st o p pere d glass vials.  T he St u d y 
Dr u g ( I SI S 4 8 4 1 3 7 or Place b o) a n d its st ora ge a n d pre parati o n i nstr ucti o ns will be pr o vi de d b y 
t he S p o ns or or desi g n ee.  T he St u d y Dr u g ( I SI S 4 8 4 1 3 7 or place b o) m ust be st ore d sec urel y at 
2- 8 ° Celsi us a n d be pr otecte d fr o m li g ht.


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T a ble 1 
St u d y Dr u g C h ar acteristics  
St u d y Dr u g  
I SI S 4 8 4 1 3 7  
Pl a c e b o  
Str e n gt h 
2 0 0 m g/ m L 
N ot A p pli c a bl e  
V ol u m e/ F or m ul ati o n  
1 m L s ol uti o n p er vi al 
1 m L s ol uti o n p er vi al  
R o ut e of A d mi ni str ati o n  
S C 
S C 
* S C = s u b c ut a n e o u s
7. 2  
P ac k a gi n g a n d L a beli n g  
T he S p o ns or will pr o vi de t he I n v esti gat or wit h pac ka ge d St u d y Dr u g ( I SI S 4 8 4 1 3 7 or place b o) 
la bele d i n acc or da n ce wit h s pecific c o u ntr y re g ulat or y re q uire m e nts.   
7. 3 
St u d y Dr u g Acc o u nt a bilit y  
T he st u d y staff is re q uir e d t o d oc u me nt t he recei pt, dis pe nsi n g, a n d ret ur n of St u d y Dr u g 
(I SI S 4 8 4 1 3 7 or pl ace b o) s u p plies pr o vi de d b y t he S p o ns or.   
8. 
T R E A T M E N T O F S U B J E C T S
8. 1 
St u d y  Dr u g A d mi nistr ati o n
St u d y Dr u g  a d mi nistrati o n will occ ur at wee kl y st u d y visits fr o m Wee k 1 t hr o u g h Wee k 1 3 b y 
t he trai ne d pers o n nel at t he st u d y site.  I SI S 4 8 4 1 3 7 or place b o will be a d mi nistere d 
s u bc uta ne o usl y.  St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) S C i njecti o n v ol u me will be 1. 2 5 m L at 
eac h w ee k l y visit ( ma y als o be deli vere d as 2 n o n-c o nti g u o us i njecti o n v ol u mes of 0. 7 5 m L a n d 
0. 5 0 m L).  Vi als are f or si n gle use o nl y.  
Please ref er t o t he St u d y Dr u g Ma n ual pr o vi d e d b y t he S p o ns or f or m ore d etaile d i nstr ucti o ns f or 
St u d y Dr u g ( I SI S 4 8 4 1 3 7 or place b o) pre p arati o n a n d a d mi nistrati o n. 
8. 2 
Ot her Pr ot o c ol -Re q uire d Dr u gs  
0. 9 % sterile sali ne will b e use d f or a S C  t olera bilit y i njecti o n.  D uri n g t he R u n-I n Peri o d 
Wee k  - 1, s u bjects will recei ve a 1. 2 5 m L S C i njecti o n ( ma y als o b e deli vere d as 2 n o n-
c o nti g u o us i njecti o n v ol u mes of 0. 7 5 m L a n d 0. 5 0 m L). 
8. 3 
Ot her Pr ot o c ol -Re q uire d Tre at me nt Pr oce d ures  
T here are n o ot her pr ot oc ol- re q uire d treat me nt pr o ce d ures. 
8. 4 
Tre at me nt Prec a uti o ns  
T here are n o s p ecific tr eat me nt preca uti o ns re q uire d . 
8. 5  
S af et y M o nit ori n g R ules  
Please ref er als o t o t he ‘ G ui da nce f or I n vesti gat or’ secti o n of t he I n vesti gat or’s Br o c h ure  
Baseli ne is defi ne d as t he  a vera ge of w ee k -1 visit ( Da y - 7) a n d D a y 1 pre-d ose val ues . 


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I n a d diti o n t o t he sta n dar d m o nit ori n g of cli nical s afet y para meters, t he f oll o wi n g g ui deli nes are 
pr o vi de d f or t he m o nit ori n g of s electe d p ara m eters c h ose n base d o n precli nical a n d cli nical 
o bser vati o ns. 
C o nfir mati o n G ui da nce :  At a n y ti me d uri n g t he st u d y ( Treat me nt or P ost-Treat me nt Peri o ds), 
t he i nitial cli nical la b orat or y res ults meeti n g t he safet y m o nit ori n g criteria prese nte d b el o w m ust 
be c o nfir me d b y perf or mi n g meas ur e me nts (i deall y i n t he sa me l a b orat or y t hat perf or me d t h e 
i nitial meas ure me nt) o n ne w s peci me ns.  All ne w s peci me n c ollecti o ns s h o ul d ta ke place as s o o n 
as p ossi ble (i deall y wit hi n 3 da ys of t he i nitial c ollecti o n) .  F or st o p pi n g r ul es, if t he i nitial 
la b orat or y r es ult is o bser ve d d uri n g t he Treat me nt Peri o d, t he res ults fr o m t he retest m ust be 
a v ail a ble pri or t o a d mi nisteri n g t he n e xt d ose of St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o).  
Re - d osi n g G ui d a nce:  S u bjects wit h i nitial la b orat or y test v al ues t hat reac h a st o p pi n g r ule m ust 
n ot be re- d ose d u ntil t he re- test r es ults are a v aila ble.  I n ge neral, s u bjects w h o d o n ot meet t he 
st o p pi n g r ules bas e d u p o n retest ma y c o nti n ue d osi n g.  H o w e ver, t h e I n vesti gat or a n d t he 
S p o ns or Me dical M o nit or ( or a p pr o priatel y q ualifi e d desi g n ee) s h o ul d c o nfer as t o w het h er 
a d diti o nal cl ose m o nit ori n g of t he s u bj ect is a p pr o priate.  If a n y of t he st o p pi n g criteria des cri be d 
i n A p pe n di x E are met, t he s u bject will be per m a ne ntl y disc o nti n ue d fr o m f urt her treat me nt wit h 
St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o), e val u ate d f ull y as o utli ne d bel o w a n d i n c o ns ultati o n wit h 
t he S p o ns or Me dical M o nit or or a p pr o priat el y q u alifie d desi g nee, a n d will be f oll o we d u p i n 
acc or d a nce wit h Secti o n 8. 8  of t he Pr ot oc ol.   
8. 5. 1 
S afety M o nit ori n g R ules f or Liver C he mistry Tests  
T he f oll o wi n g r ules ar e a da pte d fr o m t he draft g ui da nce f or i n d ustr y, “ Dr u g- I n d uce d Li v er 
I nj ur y: Pr e mar keti n g Cli nical E val uati o n,” iss ue d b y t he U. S.  D e part me nt of Healt h a n d H u ma n 
Ser vices, F o o d a n d Dr u g A d mi nistrati o n, J ul y 2 0 0 9.  F or a d efi niti o n of Baseli ne please refer t o 
g ui da n ce i n Secti o n 8. 5 a b o ve. 
I n t he e ve nt of a n A L T or A S T meas ure m e nt t hat is > 3 x U L N : ( or t he greater of 2 x baseli ne 
val ue or 3 x U L N if t he b aseli ne val ue w as > U L N) at a n y ti me d uri n g t he st u d y ( Treat me nt or 
P ost- Treat me nt Peri o d), t he i nitial meas ure me nt(s) s h o ul d be c o nfir me d as descri be d a b o ve.  
A d diti o nal, c o nfir mat or y meas ure me nts s h o u l d als o be perf or me d if A L T or A S T le vels i ncrease 
t o 5 x U L N. 
Fre q u e nc y of R e peat Meas ure me nts :  S u bjects wit h c o nfir me d A L T or A S T le vels > 3 x U L N ( or 
t he gr eater of 2 x baseli ne val ue or 3 x U L N if t he baseli ne val ue w as > U L N) s h o ul d ha ve t heir 
li ver c he mistr y tests ( A L T, A S T, al kali ne p h os p hatase [ A L P ], I N R, a n d t otal bilir u bi n) reteste d 
at least o nce -wee kl y u ntil A L T a n d A S T le vels bec o me ≤ 1. 2 x U L N or 1. 2 x baseli ne val ue if 
t he baseli ne val ue was > U L N. 
F urt her I n vesti gati o n i nt o Li ver C he mistr y El e vati o ns:  F or s u bjects wit h c o nfir me d A L T or A S T 
le vels > 3 x U L N ( or t he gr eater of 2 x baseli ne val ue or 3 x U L N if t he b as eli ne val ue w as 
>  U L N), t he f oll o wi n g e val uati o ns s h o ul d be perf or me d:
1.  O btai n a m ore det aile d hist or y of s y m pt o ms a n d pri or a n d c o nc urre nt diseases


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2.  O btai n f urt her hist or y f or c o nc o mita nt dr u g use (i n cl u di n g n o n prescri pti o n me dicati o ns,
her bal a n d diet ar y s u p ple me nt pre parati o ns), alc o h ol use, recreati o nal dr u g use, a n d
s pecial diets
3.  O btai n a hist or y f or e x p os ure t o e n vir o n m e ntal c h e mical a ge nts a n d tra vel
4.
Ser ol o g y f or viral he p atitis ( he patitis A vir us  [H A V ] i m m u n o gl o b uli n M [I g M], he patitis
B s urf ace a nti ge n  [H Bs A g ], H C V a nti b o d y, c yt o me gal o vir us [C M V ] I g M, a n d
E pstei n -Barr vir us  [ E B V a nti b o d y pa n el])
5.
Ser ol o g y f or a ut oi m m u ne he patitis (e. g., a nti n ucl ear a nti b o d y [ A N A])
A d diti o nal li ver e val uati o ns, i ncl u di n g gastr oe nt er ol o g y/ he p at ol o g y c o ns ultati o ns, he patic C T or 
M RI sca ns, ma y be p erf or me d at t he discreti o n of t he I n v esti gat or, i n c o ns ultati o n wit h t he 
S p o ns or Me d ical M o nit or.  Re petiti o n of t he a b o v e e val uati o ns s h o ul d be c o nsi dere d if a 
s u bject’s A L T a n d/ or A S T le vels reac h 5 x U L N. 
8. 5. 2 
S afety M o nit ori n g R ules f or Pl atelet C o u nt Res ults  
If a s u bject ’s platelet c o u nt falls b y 3 0 % or greater fr o m Bas eli ne or t he a bs ol ute platelet c o u nt is 
1 0 0, 0 0 0/ m m 3 or less, t he n t he s u bject’s platelet c o u nts s h o ul d be m o nit ore d at least wee kl y.  I n 
t he e ve nt of a pl atelet c o u nt < 7 5, 0 0 0/ m m 3, a d diti o nal la b orat or y i n vesti gati o ns will be 
c o n d ucte d ( T a ble 2).  T h e fre q u e nc y of  m o nit ori n g a n d a d diti o nal la b tests will be deter mi ne d b y 
t he I n v esti gat or i n c o ns ultati o n wit h t he S p o ns or Me dical M o nit or or desi g nee. 
T a ble 2 
A d diti o n al L a bs t o be Perf or me d i n t he E ve nt of a Pl atelet C o u nt 
< 7 5, 0 0 0/ m m 3 
T o B e P erf or m e d at L o c al L a b  
P eri p h er al s m e ar ( s h o ul d b e p erf or m e d l o c all y, fi x e d a n d s e nt t o c e ntr al l a b f or r e vi e w)  
Fi bri n o g e n s plit pr o d u ct s or  D-di m er o n fr e s h bl o o d  
T o B e P erf or m e d at C e ntr al L a b  
Citr at e d s a m pl e f or pl at el et s  
C o a g ul ati o n p a n el ( P T/I N R, a P T T)  
C o m pl et e bl o o d c o u nt ( C B C ) wit h r eti c ul o c yt e s  a n d m e a n pl at el et v ol u m e ( M P V)  
Fi bri n o g e n  
v o n Will e br a n d f a ct or  
T ot al gl o b uli n s, t ot al i m m u n o gl o b uli n A  (I g A), I g G a n d I g M 
C o m pl e m e nt:  t ot al C 3, t ot al C 4, B b, C 5 a 
C R P m e a s ur e d b y hi g h s e n siti vit y a s s a y ( h s C R P ) 
S er ol o g y f or:  
H B V, H C V, HI V (if n ot d o n e f or s cr e e ni n g)  
R u b ell a  
C M V  
E B V 
P ar v o B 1 9  
H eli c o b a ct er p yl ori (I g G s er u m t e st)  


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T a ble 2  
A d diti o n al L a bs t o be Perf or me d i n t he E ve nt of a Pl atelet C o u nt 
< 7 5, 0 0 0/ m m 3 C o nti n ue d  
T o B e P erf or m e d at C e ntr al L a b  
A ut o- a nti b o d y s cr e e n:  
A nti p h o s p h oli pi d  
R h e u m at oi d f a ct or  
A nti- d s D N A  
A nti- t h yr oi d 
T o B e P erf or m e d at S p e ci alt y L a b( s)  
A nti pl at el et a nti b o di e s a n d A nti -P F 4 a s s a y  
A nti- A S O a nti b o d y  (if a v ail a bl e) 
N ot e:  T h e f oll o wi n g l a b s m a y c h a n g e a s a d diti o n al d at a i s a s s e s s e d, a n d sit e s will b e u p d at e d r e g ar di n g a n y 
c h a n g e s.  
8. 5. 3 
M o nit ori n g  R ules f or Deteri or ati n g Glyce mic C o ntr ol 
If after 8 wee ks of treat me nt wit h St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o), F P G le vels 
> 2 7 0 m g/ d L ( or >  1 5 m m ol/ L) c o nfir me d o n 2 c o nsec uti ve wee kl y st u d y visits wit h n o ot her
e x pla nati o n(s) f or t he ele vati o n, a d diti o nal oral gl uc ose- l o weri n g t hera p y ma y b e starte d or
pre vi o us t hera pies m a y b e titrate d u p b y t he I n v esti gat or  i n c o ns ultati o n wit h t he S p o ns or
Me dical M o nit or or desi g nee.  T he us e of t hiaz oli di ne di o nes (e. g., pi o glitaz o ne, r osi glitaz o ne)
a n d i njecta ble a nti dia b etic t hera p y (e. g ., i ns uli n, G L P 1 a nal o gs) is n ot per mitte d.  See D ose
A dj ust me nt G ui da nce i n Secti o n 8 . 7.
8. 6 
St o p pi n g R ules 
F or t he p ur p os es of t he st o p pi n g r ules b aseli ne is d efi ne d as t he a vera ge of Da y - 7 a n d Da y 1 
val ues.  
8. 6. 1 
St o p pi n g R ules f or Liver C he mistry Elev ati o ns  
I n t he e ve nt of l a b orat or y res ults meeti n g t he f oll o wi n g criteria, a n d t he e v e nt is wit h o ut a n 
alter n ati ve e x pl a n ati o n as disc usse d wit h t he S p o ns or Me dic al M o nit or,  d osi n g of a s u bj ect 
wit h St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) will be st o p pe d per ma n e ntl y; v al ues t hat are n ot 
c o nfir me d d ue fail ure t o retest or missi n g la b v al ues w ill be pres u me d c o nfir me d: 
1.
A L T or A S T >  8 x U L N, w hic h is c o nfir me d
2.
A L T or A S T >  5 x U L N, w hic h is c o nfir me d a n d persists f or ≥ 2 wee ks
3.
A L T or A S T >  3 x U L N  ( or t he greater of 2 x baseli ne val ue or 3 x U L N if t he baseli ne
val ue was > U L N), w hic h is c o nfir me d a n d t otal bilir u bi n > 2 x U L N or I N R >  1. 5
4.
A L T or A S T >  3 x U L N ( or t he greater of 2 x baseli ne val ue or 3 x U L N if t he baseli ne
val ue was > U L N) wit h t he ne w a p p eara nce (i.e ., o nset c oi nci des wit h t he c ha n ges i n
he patic e nz y m es) of fati g ue,  na usea, v o miti n g, ri g ht u p per q ua dra nt pai n or te n der ness,
fe ver, ras h, a n d/ or c o nc o mita nt e osi n o p hilia ( > U L N)


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8. 6. 2  
Te m p or ary St o p pi n g R ules f or Re n al F u ncti o n Test Res ults 
I n t he e ve nt of a persiste nt ele vati o n t hat is o bser ve d o ver 2 c o nsec uti ve w ee ks, f or eit her of t he 
2 criteria b el o w, d osi n g of a s u bject  wit h St u d y Dr u g (I SI S 4 8 4 1 3 7 or pl ace b o) ma y be st o p pe d 
te m p oraril y: 
1. S er u m creati ni ne i ncreas e t hat f ulfills all of t he f oll o wi n g criteria:  ≥ 0. 3 m g/ d L
( 2 6. 5 μ m ol/ L) i ncr ease a n d ≥ 4 0 % a b o ve ba s eli ne creati ni ne v al ues  a n d > U L N (refer t o
defi niti o n of Bas eli ne  i n Secti o n 8. 6 )
2. Pr otei n uria, di pstic k 2 + (c o nfir me d b y di pstic k retest a n d t he n f urt her c o nfir me d b y a
q ua ntitati ve t otal uri ne pr otei n meas ure me nt of > 1. 0 g/ 2 4 h o ur)
T he p ossi ble d osi n g r e- i nitiati o n or f oll o w- u p sc he d ule f or a n y e ve nts meeti n g eit her of t hese 
criteria will be det er mi ne d b y t he I n vesti gat or i n c o ns ult ati o n wit h t he S p o ns or Me dical 
M o nit or or desi g n ee. 
8. 6. 3 
St o p pi n g R ule f or Pl atelet C o u nt Res ults  
I n the e ve nt of a c o nfir me d  platelet c o u nt less t ha n 7 5, 0 0 0/ m m3, a n d i n t he prese nce of maj or 
blee di n g ( M B)  or cli nicall y-r ele va nt n o n- m aj or blee di n g ( C R N M B) ( d efi ne d bel o w; Sc h ul ma n  
et al. 2 0 0 5 ), d osi n g of a s u bject wit h St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) will be st o p pe d 
per ma ne ntl y .  F urt her m ore, a d diti o nal la b orat or y i n vesti gati o ns will be c o n d ucte d as o utli ne d i n 
Ta ble 2 .  T he f oll o w-u p sc he d ule f or a n y e v e nts meeti n g  t his st o p pi n g criteri o n will be 
deter mi ne d b y t he I n v esti gat or i n c o ns ultati o n wit h t he S p o ns or Me dical M o nit or. 
I n t he e ve nt of a c o nfir me d platelet c o u nt less t ha n 5 0, 0 0 0/ m m3, d osi n g of a s u bject wit h St u d y 
Dr u g (I SI S 4 8 4 1 3 7 or place b o) will be st o p pe d p er ma ne ntl y .  T h e f oll o w- u p sc he d ule f or a n y 
e ve nts meeti n g t his st o p pi n g criteri o n will be deter mi ne d b y t he I n v esti gat or i n c o ns ultati o n wit h 
t he S p o ns or Me dical M o nit or or desi g n ee. 
Defi niti o ns:  
Maj or blee di n g ( M B) is defi ne d as o n e of t he f oll o wi n g: 
1.
Fatal blee di n g
2.
S y m pt o matic bl ee di n g i n a critical area or or ga n, s uc h as i ntracra nial, i ntras pi nal,
i ntra oc ular, r etr o perit o neal, i ntraartic ular if i n a m aj or j oi nt, or pericar dial, or
i ntra m usc ular wit h c o m p art me nt s y n dr o me
3.
Cli nicall y o v ert blee di n g lea di n g t o tra nsf usi o n of ≥ 2 u nits of pac ke d re d bl o o d cells
(p R B C ) or w h ole bl o o d or a fall i n he m o gl o bi n of 2 0 g/ L ( 1. 2 4 m m ol/ L) or m ore wit hi n
2 4 h o urs
Cli nicall y -rel e va nt n o n-maj or blee di n g ( C R N M B)  is defi ne d as o v ert blee di n g n ot meeti n g t he 
criteria f or M B  b ut t hat r es ulte d, f or e x a m ple, i n me dical e x a mi nati o n, i nter ve nti o n, or ha d 
cli nical c o nse q ue n ces f or a s u bject ( B üller et al. 2 0 0 7 ). 


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8. 6. 4 
St o p pi n g R ules f or D oc u m e nte d Severe Hy p o glyce mi a  
I n t he e ve nt of a d oc u me nte d se ver e h y p o gl yce mi c e ve nt as d efi ne d b el o w, d osi n g of t he s u bject 
wit h St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) will be st o p pe d per ma n e ntl y.  Als o, if t he I n vesti gat or 
c o nsi ders a h y p o gl yce mic e ve nt as cli nicall y -si g nifica nt, he/s he ma y st o p d osi n g at a n y ti me .  
A n y s u bject wit h a cli nicall y -si g nifica nt e ve nt of h y p o gl yce mia s h o ul d be disc usse d wit h t he 
S p o ns or Me dical M o nit or or Desi g nee. 
A d oc u me nte d se v ere h y p o gl yce mic e ve nt is defi ne d as o ne i n w hic h t he s u bject re q uires 
assista nce of a n ot her pers o n t o o btai n treat me nt f or t he e ve nt a n d h as a plas ma gl uc os e le vel 
< 6 0 m g/ d L ( 3. 3 m m ol/ L) .  T his ma y i ncl u d e treat me nt wit h I V gl uc os e or b uccal or 
i ntra m usc ular gl uca g o n.   
All s u bjects partici pati n g i n t he trial m ust be i nstr ucte d t o rec o g nize t he c h aract eristic s y m pt o ms 
of h y p o gl yce mia a n d recei ve detaile d i nstr ucti o ns fr o m t he I n vesti gat or o n t he treat me nt a n d 
re p orti n g of h y p o gl yce mi c e ve nts. 
T he s y m pt o ms of h y p o gl yce mia ca n be di vi de d i nt o 2 cate g ories, n e ur o gl yc o pe nic a n d 
ne ur o ge n ic ( or a ut o n o mi c) res p o ns es. 
•
Ne ur o gl yc o pe nic s y m pt o ms are t he direct res ult of ce ntral ner v o us s yste m ne ur o nal
gl uc ose d e pri vati o n a n d i ncl u de be ha vi oral c ha n ges ( dizzi ness, hea dac hes, cl o u d y visi o n,
c o nf usi o n, a b n or mal be h a vi or, l oss of c o nsci o us n ess, a n d seiz ures)
•
H y p o gl yce mia -i n d uce d n e ur o ge nic (a ut o n o mic) res p o nses are t h ose relate d t o i ncrease d
a dre ner gic acti vit y (s w eati n g, tre m or, tac h ycar dia, a n xiet y, a n d h u n ger)
If a s u bject prese nts wit h s y m pt o ms of h y p o gl yce mia, t he I n v esti gat or will nee d t o ta ke  
i m me diate acti o n t o c o nfir m t he s u bject’s gl uc ose le vel a n d treat t he s u bject acc or di n gl y 
8. 7 
A dj ust me nt of or al a nti di a betic re gi me n  f or s u bjects wit h persiste nt 
h y per gl yce mic  
If after 8 wee ks of treat me nt wit h St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o), F P G le vels 
> 2 7 0 m g/ d L ( or >  1 5 m m ol/ L) c o nfir me d o n 2 c o nsec uti ve wee kl y st u d y visits wit h n o ot her
e x pla nati o n(s) f or t he ele vati o n, a d diti o nal oral gl uc ose- l o weri n g t hera p y ma y b e starte d or
e xisti n g t hera pies ma y be titrate d  i n d ose b y t h e I n vesti gat or  i n c ons ultati o n wit h t he S p o ns or
Me dical M o nit or or desi g nee.  T he us e of t hiaz oli di ne di o nes (e. g., pi o glitaz o ne, r osi glitaz o ne)
a n d i njecta ble a nti dia b etic t hera p y is n ot per m itte d (e. g., i ns uli n, G L P 1 a n al ogs) .
8. 8 
Disc o nti n u ati o n of St u d y Dr u g  
A s u bject  m ust per ma ne ntl y disc o nti n ue st u d y treat me nt f or a n y of t he f oll o wi n g: 
•
T he s u bject  bec o mes pre g na nt.  Re p ort t he pre g n a nc y acc or di n g t o i nstr ucti o ns i n
Secti o n  9. 5. 4
•
T he s u bject  wit h dra ws c o nse nt
•
T he s u bject  e x perie nces a n A E  t hat necessitates p er ma ne nt disc o nti n uati o n of St u d y Dr u g


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•
T he s u bject  de v el o ps la b orat or y test a b n or m alities t hat meet a n y of  t he st o p pi n g r ules
liste d i n Secti o ns  8. 6. 1 t o 8. 6. 4
•
T he s u bject  e x perie nces a n A E t hat necessitates u n bli n di n g of t he I n v esti gat or or S p o ns or
t o t he s u bject’s treat me nt assi g n me nt
•
I nitiati o n of c hr o nic disall o we d t hera pies w hic h i n cl u de t he use of t hiaz oli di ne di o nes
(e. g., pi o gitaz o ne, r osi glitaz o ne) a n d i njecta ble a nti dia betic t hera p y (e. g ., i ns uli n, G L P 1
a nal o g s), use of a ge nts (i ncl u di n g her bal or o v er- t he co u nter w ei g ht l oss pre parati o ns)
a n d me dicati o ns k n o w n t o si g nifica ntl y i m pact B W  (e. g., si b utra mi ne, p h e neta mi ne a n d
orlistat )
T he reas o n f or disc o nti n uati o n of S t u d y Dr u g m ust be rec or d e d i n t he electr o nic Case Re p ort 
F or m (e C R F ) a n d s o ur ce d oc u me ntati o n. 
S u bjects w h o disc o nti n ue St u d y D r u g s h o ul d be e n c o ura ge d t o re mai n i n t he st u d y a n d c o m plete 
t he P ost- Treat me nt E val u ati o n P eri o d a n d c o nti n ue pr ot oc ol re q uire d tests a n d assess me nts.  
E ver y eff ort s h o ul d be m a de t o c o m plete t he earl y ter mi n ati o n st u d y pr oce d ures a n d o bser vati o ns 
at t he ti me of wit h dra w al (see A p p e n di x A ). 
8. 9 
Wit h dr a w al of S u bjects f r o m t he S t u d y 
S u bjects  m ust be wit h dra w n fr o m t he st u d y f or a n y of t he f oll o wi n g: 
•
Wit h dra wal of c o nse nt
•
T he s u bject  is u n willi n g or u na ble t o c o m pl y wit h t he pr ot oc ol
Ot her r eas o ns f or wit h dr a wal of s u bjects fr o m t he st u d y mi g ht i ncl u de:  
•
At t he discreti o n of t he I n vesti gat or f or me dical reas o ns
•
At t he discreti o n of t he I n vesti gat or or S p o ns or f or n o nc o m plia nce
•
S i g nifica nt pr ot oc ol d e viati o n
All eff orts will be ma de t o c o m plete a n d re p ort t he o bser vati o ns as t h or o u g hl y as p ossi ble u p t o 
t he date of wit h dr a wal.  All i nf or mati o n, i ncl u di n g t he reas o n f or wit h dra wal fr o m st u d y, m ust be 
rec or d e d i n t he e C R F as a p pr o priate. 
A n y s u bject w h o wit h dra ws c o nse nt t o partici pate i n t he st u d y will be re m o ve d fr o m f urt h er 
treat me nt a n d st u d y o bser vati o n i m me diatel y u p o n t he date of re q uest.  T h ese s u bjects  s h o ul d be 
e nc o ura ge d t o c o m plete t he earl y ter mi nati o n st u d y pr o ce d ures a n d o bser vati o ns at t he ti me of 
wit h dra wal  ( A p p e n di x A). 
F or s u bjects wit h dr a w n f or reas o ns ot her t ha n wit h dra wal of c o nse nt e v er y eff o rt s h o ul d be ma d e 
t o c o m plete t he earl y t er mi nati o n st u d y pr oce d ures a n d o bser vati o ns at t he ti me of wit h dra wal  
(see A p p e n di x A). 


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8. 1 0 
C o nc o mit a nt T her a p y  a n d Pr oce d ures  
T he use of c o nc o mita nt t hera pies or pr oce d ures d efi ne d bel o w m ust be rec or de d o n t he s u bject’s 
e C R F.  Ad vers e e ve nts r elate d t o a d mi nistrati o n of t hese t hera pies or pr o ce d ures m ust als o b e 
d oc u me nte d o n t he a p pr o priate e C R F as a p pr o pri ate. 
8. 1 0. 1  
C o nc o mit a nt T her a py 
A c o nc o mita nt t hera p y is a n y n o n- pr ot oc ol s pecifi e d dr u g or s u bsta nce (i ncl u di n g o ver-t he-
c o u nter me dicati o ns, her bal me dicati o ns a n d vita mi n s u p ple me nts) a d mi nistere d bet w ee n t he 
si g ni n g of t he i nf or m e d c o nse nt a n d t he last pr ot oc ol s pecifie d P ost- Treat me nt E val uati o n Peri o d 
(A p pe n di x A ). 
All o w e d C o nc o mit a nt T her a p y 
A n y me di cati o ns dee me d necessar y b y t he I n v esti gat or are all o we d e x ce pt t h ose liste d i n t he 
disall o we d c o nc o mita n t t hera p y.   
Dis all o w e d C o nc o mit a nt T her a p y 
T he use of t hiaz oli di ne di o nes (e. g., pi o gitaz o ne, r osi glitaz o ne) a n d i njecta ble a nti dia betic t hera p y 
is n ot per mitte d (e. g., i ns uli n, G L P 1 a nal o gs) w hile o n St u d y Dr u g.  I n cas e a s h ort-ter m i ns uli n 
t hera p y is gi ve n w he n a patie nt is h os pitalize d d uri n g t he st u d y, t he I n v esti gat or n ee ds t o c o ns ult 
wit h t he S p o ns or Me dical M o nit or or desi g nee t o e val uate w h et her t he p atie nt will be all o we d t o 
c o nti n ue t he st u d y.  Us e of a ge nts (i ncl u di n g her b al or o ver-t h e c o u nter wei g ht l oss pre parati o ns) 
or me dicati o ns k n o w n t o  si g nifica ntl y i m pact B W  wit hi n 3 m o nt hs pri or (e. g., si b utra mi ne, 
p he neta mi ne a n d orlistat ) is n ot per mitte d w hile on St u d y D r u g.   
Hi g h - d os e stati n t hera p y is n ot per mitte d, n or is i nitiati n g a ne w statin or i n creasi n g t hera p y 
a b o ve t he t hres h ol ds liste d.  Si m vastati n, at or vastati n, fl u vastati n, pra vastati n m ust be mai ntai ne d 
≤ 4 0 m g/ da y.  R os u vastati n a n d l o vastati n d oses s h o ul d be ≤ 2 0 m g/ da y, a n d pita vastati n m ust be 
≤ 4 m g/ da y.  Fis h oils or prescri pt i o n li pi d-re g ulati n g dr u gs (e. g., bile aci d a nal o g u es [e. g., 
o betic h olic aci d or urs o de o x yc h olic aci d], bile -aci d se q uesteri n g resi ns, fi brates  a n d d eri vati ves) 
are n ot per mitte d .  If stati n t hera p y is necessar y a b o ve t hese n ote d d ose l e vels or ot her li pi d 
l o weri n g t h era pi es ar e re q uire d, t he I n vesti gat or s h o ul d disc uss wit h t he Me dical M o nit or 
w het her t he s u bject m ust disc o nti n ue St u d y D r u g.   
C hr o nic use of s yste mic c ortic oster oi ds a n d ot her me dicati o ns, per I n v esti gat or, k n o w n t o ca us e 
li ver t o xicit y ( e. g., c hr o ni c aceta mi n o p he n use) or ca use steat osis (e. g., a mi o dar o ne, 
met h otre x ate) are n ot p er mitte d w hile o n St u d y Dr u g. 
Use of a ntic o a g ula nts/a nti platelet a ge nts (e. g., warfari n, he p ari n, da bi gatra n, ri var o x a ba n, 
cl o pi d o gr el) t he n o n- ster oi dal a nti-i nfla m mat or y dr u g ( N S AI D) ni mes uli de or a n y ot her dr u g 
i nfl ue nci n g c oa g ulati o n ( e x ce pt l o w d ose as piri n < 1 6 0 m g/ da y a n d ot h er s h ort acti n g N S AI D S 
wit h a half -life < 2 0 h o urs) are n ot per mitte d w hile o n St u d y Dr u g. 
A nti ne o plastic a ge nts ar e n ot p er mitte d w hile o n St u d y Dr u g.  


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8. 1 0. 2  
C o nc o mit a nt Pr oce d ures 
A c o nc o mita nt pr oce d ure is a n y t hera pe utic i nter v e nti o n (e. g., s ur ger y/ bi o ps y, p h ysical t hera p y) 
or dia g n ostic assess me nt (e. g., bl o o d gas meas ure me nt, bacterial c ult ures) perf or me d b et wee n  
si g ni n g of t he i nf or m e d c o nse nt a n d t he last pr ot oc ol-s pecifie d P ost-Treat me nt E val uati o n  visit 
(A p pe n di x A ) 
8. 1 1 
Tre at me nt C o m pli a nce  
C o m plia nce wit h St u d y Dr u g  d osi n g is t o be m o nit ore d a n d rec or de d i n t h e e C R F b y St u d y 
Ce nter staff . 
9.
S E RI O U S A N D N O N - SE RI O U S A D V E R S E E V E N T  R E P O R TI N G
9. 1  
S p o ns or Re vie w of S af et y I nf or m ati o n
Safet y i nf or mati o n will be c ollecte d, re vie w e d, a n d e val uate d  b y  t he S p o ns or or desi g nee i n 
acc or d a nce wit h t he Safet y Ma na ge me nt Pla n a n d t he Me dical M o nit ori n g Pla n t hr o u g h o ut t he 
c o n d uct of t he cli nical trial.  
9. 2 
Re g ul at or y Re q uire me nts  
T he S p o ns or or desi g nee is res p o nsi ble f or re g ulat or y s u b missi o ns a n d re p orti n g t o t he 
I n v esti gat ors of S A Es i n cl u di n g S U S A Rs per t he I nter nati o nal C o nfere nce o n Har m o nizati o n 
(I C H) g ui deli nes E 2 A a n d I C H E 6 .  C o u ntr y-s p ecific re g ulat or y re q uire m e nts will be f oll o we d i n 
acc or d a nce wit h l ocal c o u ntr y r e g ulati o ns a n d g ui deli nes. 
I nstit uti o nal Re vie w B oar ds (I R B)/I n de pe n d e nt Et hics C o m mittees (I E C) will be n otifie d of a n y 
S A E acc or di n g t o a p plica ble re g ulati o ns.   
I n a d diti o n t o t he I n v esti gat or’s assess me nt of rel ate d ness, t he S p o ns or or desi g nee  will e val uat e 
t he a vaila ble i nf or m ati o n a n d perf or m a n i n de pe n de nt assess me nt of relate d ness.  W h ile t he 
S p o ns or ma y u p gr a de a n I n v esti gat or’s decisi o n it is n ot per missi ble t o d o w n gra de t he 
I n v esti gat or’s o pi ni o n f or t he p ur p oses of det er mi ni n g w het h er t he S A E meets t he defi niti o n of a 
S U S A R.  
A p pr o priate p ers o n nel at t he S p o ns or or desi g n ee  will u n bli n d S U S A Rs f or t he p ur p ose of 
re g ulat or y r e p orti n g.  Th e S p o ns or or desi g nee will s u b mit S U S A Rs t o Re g ulat or y A ge ncies i n 
bli n de d or u n bli n de d fas hi o n acc or di n g t o l ocal la w.  T he S p o ns or or desi g nee will s u b mit 
S U S A Rs t o I n v esti gat ors i n a bli n de d fas hi o n. 
9. 3 
Defi niti o ns  
9. 3. 1 
A dverse Eve nt  
A n a d vers e e ve nt  is a n y u nfa v ora bl e a n d u ni nte n d e d si g n (i n cl u di n g a cli nicall y-si g nifi ca nt 
a b n or mal la b or at or y fi n di n g, f or e x a m p le), s y m pt o m, or disease te m p orall y ass o ciate d wit h t he 
st u d y or use of i n vesti gati o nal dr u g pr o d uct, w het her or n ot t he A E is c o nsi dere d relate d t o t he 
i n vesti gati o nal dr u g pr o d uct. 


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9. 3. 2 
A dverse Re acti o n a n d S us pecte d A dverse Re a cti o n  
A n a d vers e reacti o n  is a n y A E  ca use d b y t h e St u d y Dr u g . 
A s us pecte d a d v erse reacti o n is a n y A E  f or w hic h t here is a reas o na bl e p ossi bilit y t hat t he dr u g 
ca use d t he A E .  A s us pecte d a d vers e reacti o n i m plies a lesser d e gree of cert ai nt y a b o ut ca usalit y 
t ha n a n a d verse r eacti o n. 
9. 3. 3 
Seri o us A dverse Eve nt ( S A E)  
A seri o us a d verse e v e nt is a n y a d vers e e ve nt t hat i n t he vie w of eit her t he I n vesti gat or or 
S p o ns or, meets a n y of t h e f oll o wi n g criteria:  
•
Res ults i n deat h
•
Is life t hreat e ni n g: t hat is, p oses a n i m me diate ris k of deat h at t he ti me of t h e e ve nt
A n A E  or s us pect e d a d verse reacti o n is c o nsi dere d “life -t hreate ni n g” if, i n t he vie w of
eit her t he I n v esti gat or or S p o ns or , its occ urre n ce places t he s u bject at i m me diate ris k of
deat h .  It d oes n ot i ncl u d e a n A E  or s us p ecte d a d v erse reacti o n t hat , ha d it occ urre d i n a
m ore se ver e f or m, mi g ht ha ve ca use d deat h
•
Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n
H os pitalizati o n is defi ne d as a n a d missi o n of greater t ha n 2 4 h o urs t o a me dical facilit y
a n d d oes n ot al wa ys q u alif y as a n A E
•
Res ults i n a persiste nt or si g nifica nt 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 n cti o ns
•
Res ults i n a c o n ge nital a n o mal y or birt h d efect i n t he offs pri n g of t he s u bject ( w het her
t he s u bject is male or f e male)
•
I m p ort a nt me dical e v e nts t hat ma y n ot res ult i n deat h, are n ot life-t hreat e ni n g, or d o n ot
re q uire h os pitalizati o n ma y als o be c o nsi dere d seri o us w he n, base d u p o n a p pr o priate
me dical j u d g m e nt, t he y ma y je o p ar 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 ve nt o ne of t he o utc o mes liste d i n t his defi niti o n.  E x a m ples of s uc h
me dical e ve nt s i ncl u de aller gi c br o nc h os p as 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 at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n
i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g de p e n de n c y or dr u g a b use
9. 4 
M o nit ori n g a n d Rec or di n g  A d verse E ve nts  
A n y pre - e xisti n g c o n diti o ns or si g ns a n d/ or s y m pt o ms prese nt i n a s u bject pri or t o t he start of t he 
st u d y (i.e., b ef or e i nf or m e d c o nse nt) s h o ul d be rec or de d as Me di cal Hist or y a n d n ot rec or de d as 
A Es  u nless t he pre- e xisti n g c o n diti o n w ors e ne d.  T he I n vesti gat or s h o ul d al wa ys gr o u p si g ns a n d 
s y m pt o ms i nt o a si n gle ter m t hat c o nstit utes a si n gle u nif yi n g di a g n osis if p ossi ble. 
9. 4. 1 
Seri o us A dverse Eve nts  
I n t he i nterest of s u bject safet y, a n d i n or d er t o f ulfill re g ul at or y re q uire me nts, all S A Es 
(re gar dless of t heir relati o ns hi p t o St u d y Dr u g ) s h o ul d be re p orte d t o t he S p o ns or or desi g nee  
wit hi n 2 4 h o urs of t he St u d y Ce nter’s first k n o wle d ge of t he  e v e nt.  T he c ollecti o n of S A Es will 


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be gi n after t h e s u bject  si g ns t he i nf or me d c o nse nt f or m a n d st o p at t he e n d of t he s u bject’s 
f oll o w- u p peri o d w hic h is defi ne d as St u d y Wee k P T 1 3  (Secti o n 3. 4. 3 ).  W he n  t he I n vesti gat or is 
re p orti n g b y tele p h o ne, it is i m p orta nt t o s pea k t o s o me o ne i n pers o n vs. lea vi n g a messa ge.  T h e 
S A E s h o ul d be re p orte d usi n g electr o nic S A E re p orti n g f or m b y s ca n ni n g a n d e maili n g t h e f or m 
t o I N C Dr u g Safet y @i ncr esear c h.c o m.  If t he electr o nic s u b missi o n is u na vaila ble, a n I nitial 
Seri o us A d verse E v e nt F or m s h o ul d be c o m plete d a n d a c o p y s h o ul d be fa x e d t o t he S p o ns or or 
des i g nee.  T he fa x n u m ber f or re p orti n g S A Es ca n be f o u n d i n t he St u d y Refere nce M a n ual .   
Detaile d i nf or mati o n s h o ul d be acti vel y s o u g ht a n d i ncl u de d o n F oll o w- U p Seri o us A d verse 
E ve nt F or ms as s o o n as a d diti o nal i nf or mati o n bec o mes a vaila ble.  All S A Es will  be f oll o we d 
u ntil res ol uti o n.  S A Es t hat re mai n o n g oi n g past t h e s u bject’s last pr ot oc ol-s pecifie d f oll o w- u p 
visit will be e val uate d b y t he  I n v esti gat or a n d S p o ns or.  If t he I n v esti gat or a n d S p o ns or a gree t he 
s u bject’s c o n diti o n is u nli kel y t o res ol v e, t he I n vesti gat or a n d S p o ns or will determi ne t he 
f oll o w- u p re q uir e me nt. 
9. 4. 2 
N o n -Seri o us A dverse Eve nts  
T he rec or di n g of n o n-s eri o us A Es will be gi n aft er t he s u bject si g ns t he i nf or me d c o nse nt f or m 
a n d will st o p at t he e n d of t he s u bject’s f oll o w- u p peri o d , w hic h is defi ne d as 1 3 wee ks after t h e  
last d ose ( St u d y Visit P T 1 3), see Secti o n 3. 4. 3.  T he I n vesti gat or will m o nit or eac h  s u bject 
cl osel y a n d rec or d all o bs er ve d or v ol u nteere d A Es o n t he A d verse E v e nt Case Re p ort F or m. 
9. 4. 3 
Ev al u ati o n of A dverse Eve nts  ( Seri o us a n d N o n-Seri o us)  
T he I n vesti gat or’s o pi ni o n of t he f oll o wi n g s h o ul d be d oc u me nte d o n t he A d verse E ve nt Cas e 
Re p ort F or m: 
9. 4. 3. 1 
Rel ati o ns hi p t o t he St u dy Dr u g  
T he e ve nt’s relati o ns hi p t o t he St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) is c haracterize d b y o ne of 
t he f oll o wi n g: 
•
Rel ate d:   T here is clear e vi de nce t h at t he e ve nt is relate d t o t he use of St u d y Dr u g , e. g.,
c o nfir mati o n b y p ositi ve re- c h alle n ge test
•
P ossi ble:   T he e ve nt ca n n ot be e x plai ne d b y t he s u bject’s me dical c o n diti o n, c o nc o mita nt
t hera p y, or ot her ca us es, a n d t here is a pl a usi ble te m p oral relati o ns hi p bet w ee n t he e v e nt
a n d St u d y Dr u g ( I SI S 4 8 4 1 3 7 or place b o) a d mi nistrati o n
•
U nli kel y/ Re m ot e:  A n e ve nt f or w hic h a n alter n ati ve e x pla nati o n is m ore li kel y (e. g.,
c o nc o mita nt medicati o ns or o n g oi n g me dical c o n diti o ns) or t he te m p oral rel ati o ns hi p t o
St u d y Dr u g ( I SI S 4 8 4 1 3 7 or place b o) a d mi nistrati o n a n d/ or e x p os ure s u g gests t hat a
ca usal r elati o ns hi p  is u nli kel y ( F or re p orti n g p ur p oses, U nli kel y/ Re m ote will be gr o u pe d
t o get her wit h N ot Relate d)
•
N ot Rel at e d:   T he e v e nt ca n be rea dil y e x plai ne d b y t he  s u bject’s u n derl yi n g me dical
c o n diti o n, c o nc o mita nt t hera p y, or ot h er ca uses, a n d t heref ore, t he I n v esti gat or belie ves
n o relati o ns hi p e xists bet wee n t he e ve nt a n d St u d y Dr u g


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9. 4. 3. 2 
Severity  
T he se verit y of A Es a n d S A Es will be gra de d bas e d o n criteri a fr o m t he C o m m o n Ter mi n ol o g y 
Criteria f or A d v erse E v e nts ( C T C A E) Versi o n 4. 0 3, J u ne 2 0 1 0 (refer t o A p pe n di x D ).  A n y A E 
n ot liste d i n A p pe n di x D will be gr a de d as f oll o ws: 
•
Mil d:   T he e ve nt is easil y t oler ate d b y t he s u bject a n d d oes n ot affect t he s u bject’s us ual
dail y acti vities
•
M o der ate:   T he e ve nt ca uses t he s u bject m ore dis c o mf ort a n d i nterr u pts t he s u bject’s
us ual dail y acti vities
•
Se vere:  T he e v e nt is i nca pacitati n g a n d ca uses c o nsi dera ble i nterfere nce wit h t he
s u bject’s us ual dail y acti vities
If t he e v e nt is a n S A E, t he n all a p plica ble s eri o us n ess criteria m ust be i n dicate d (criteria liste d i n 
Secti o n 9. 3. 3 ). 
9. 4. 3. 3 
Acti o n T a ke n wit h St u dy Dr u g  
Acti o n ta ke n wit h St u d y Dr u g ( I SI S  4 8 4 1 3 7 or pl ace b o) d u e t o t he e v e nt is c haracterize d b y o ne 
of t he f oll o wi n g. 
•
N o ne:  N o c h a n ges were ma de t o St u d y Dr u g ( I SI S  4 8 4 1 3 7 or place b o) a d mi nistrati o n
a n d d ose
•
Per m a ne ntl y Disc o nti n ue d:   St u d y D r u g was disc o nti n ue d a n d n ot restarte d
•
Te m p or a ril y I nterr u pte d, R est arte d :  D osi n g w as te m p oraril y i nterr u pt e d or dela ye d
d ue t o t he A E  a n d r estart e d
9. 4. 3. 4 
Tre at m e nt G ive n f or A dverse Eve nt 
A n y  tr eat me nt (e. g., me dicati o ns or pr oce d ures) gi ve n f or t he A E  s h o ul d be rec or d e d o n t he 
A d verse E v e nt Case Re p ort  F or m .  Tr eat me nt s h o ul d als o be rec or de d o n t he c o nc o mita nt 
treat me nt or a n cillar y pr o ce d ures  e C R F, as a p pr o priate. 
9. 4. 3. 5 
O utc o m e of t he A dverse Eve nt  
If t he e v e nt is a n o n-seri o us A E, t he n the e ve nt’s o utc o me is c haracterize d b y o ne of t he 
f oll o wi n g: 
•
A E Persists:   S u bject  ter mi nates fr o m t he trial a n d t he A E c o nti n ues
•
Rec o vere d:   S u bject  rec o vere d c o m plet el y fr o m t he A E
•
Bec a me Seri o us:   T he e ve nt beca m e seri o us (t he date t hat t he e ve nt b eca m e seri o us
s h o ul d be rec or de d as t he Res ol uti o n Date of t hat A E a n d t he O nset D ate of t he
c orres p o n di n g S A E)
•
C h a n ge i n Se verit y (if a p plic a ble):   A E se verit y c ha n ge d
If t he e v e nt is an S A E , t he n t he e ve nt’s o ut c o me is c haracterize d b y o ne of t he f oll o wi n g: 


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•
O n g oi n g:   S A E c o nti n ui n g
•
Persists ( as n o n -seri o us A E):  S u bject  has n ot f ull y rec o vere d b ut t he e v e nt n o l o n ger
meets seri o us criteria a n d s h o ul d be ca pt ure d as a n A E o n t he n o n-seri o us A E e C R F (t he
S A E res ol uti o n date s h o ul d be e ntere d as t he dat e of o nset of t hat A E)
•
Rec o vere d:   S u bject  r ec o vere d c o m plet el y fr o m t he S A E (t he date of rec o ver y s h o ul d be
e ntere d as t he S A E res ol uti o n da te)
•
F at al:   S u bject die d (t he date of deat h s h o ul d be e ntere d as t he S A E res ol uti o n date)
9. 5 
Pr o ce d ures f or H a n dli n g S peci al Sit u ati o ns
9. 5. 1  
A b n or m alities of L a b or at ory Tests 
Cli nicall y -si g nifica nt a b n or mal la b orat or y test res ults ma y, i n t he o pi ni o n of t he I n vesti gat or, 
c o nstit ute or be ass ociat e d wit h a n A E .  E x a m ples of t hese i ncl u de a b n or m al la b orat or y res ults 
t hat are ass o ciate d wit h s y m pt o ms, or re q uire treat me nt, e. g., bl ee di n g d ue t o t hr o m b oc yt o pe ni a, 
teta n y d u e t o h y p ocal ce mia, or car di ac arr h yt h mias d ue t o h y per k ale mia.  W he ne ver p ossi ble, t he 
u n derl yi n g dia g n osis s h o ul d be liste d i n prefere nce t o  a b n or mal la b orat or y val ues as A Es.  
Cli nicall y -si g nifica nt a b n or malities will be m o nit ore d b y t he I n v esti gat or u ntil t he para meter 
ret ur ns t o its baseli ne val ue  or u ntil a gree me nt is reac h e d bet wee n t he I n v esti gat or a n d S p o ns or 
Me dical M o nit or.  La b or at or y a b n or malities dee me d n ot cli nicall y -si g nifi ca nt ( N C S) b y t he 
I n v esti gat or s h o ul d n ot be re p ort e d as A Es.  Si milarl y, l a b orat or y a b n or malities re p orte d as A Es 
b y t he I n vesti gat or s h o ul d n ot be dee me d N C S o n t he la b orat or y s heet. 
T he I n vesti gat or is r es p o nsi ble f or re vie wi n g a n d si g ni n g all la b orat or y re p orts.  T he si g n e d 
cli nical la b orat or y re p orts will ser ve as s o urce d oc u me nts a n d s h o ul d i ncl u de t he I n vesti gat or’s 
assess me nt of cli nical si g nifica nce of o ut of ra n ge/ a b n or mal la b orat or y val u es . 
9. 5. 2 
Presc he d ule d or Elective Pr oce d ures or R o uti nely Sc he d ule d Tre at m e nts  
A presc h e d ul e d or electi ve pr oce d ure or a r o uti nel y sc he d ul e d treat me nt will n ot be c o nsi dere d 
a n S A E, e ve n if t he s u bject is h os pitalize d; t he St u d y Ce nter m ust d oc u me nt all of t he f oll o wi n g:  
•
T he presc h e d ule d or electi ve pr oce d ure or r o uti nel y sc h e d ule d treat me nt was sc he d ule d
( or was o n a waiti n g list t o be sc he d ule d) pri or t o o btai ni n g t he s u bject’s c o nse nt t o
partici pate i n t he st u d y
•
T he c o n diti o n t hat re q uir e d t he pres c he d ule d or el ecti ve pr oce d ure or r o uti nel y sc h e d ule d
treat me nt was pr ese nt bef ore a n d di d n ot w orse n or pr o gress i n t he o pi ni o n of t he
I n v esti gat or bet wee n t he s u bject’s c o nse nt t o parti ci pate i n t he st u d y a n d t h e ti mi ng of t he
pr oce d ur e or tr eat me nt
•
T he presc h e d ule d or electi ve pr oce d ure or r o uti nel y sc h e d ule d treat me nt is t he s ole
reas o n f or t he i nter ve nti o n or h os pital a d missi o n
9. 5. 3 
D osi n g Err ors  
St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) err ors s h o ul d be d oc u me nte d as Pr ot oc ol De viati o ns.  A 
brief descri pti o n s h o ul d be pr o vi de d i n t he de viati o n, i ncl u di n g w het h er t he s u bject was 
s y m pt o matic (list s y m pt o ms) or as y m pt o matic, a n d t he e ve nt acci de ntal or i nte nti o nal. 


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D osi n g det ails s h o ul d be ca pt ure d o n t he D osi n g C ase Re p ort F or m .  If t he s u bject ta kes a d os e 
of St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) t hat e x cee ds pr ot oc ol s pecifi cati o ns a n d t he s u bject is 
s y m pt o matic, t he n t he s y m pt o m(s) s h o ul d be d oc u me nte d as a n A E  a n d be re p orte d p er 
Secti o n  9. 4. 
T here h as bee n n o o cc urr e nce of a n A S O o ver d ose i n ma n fr o m c o m plete d or o n g oi n g cli nical 
st u dies wit h A S Os .   
9. 5. 4  
C o ntr ace pti o n a n d Pre g n a ncy 
Fe male s u bje cts of c hil d beari n g p ote ntial are e x cl u de d fr o m t his st u d y.  
Male s u bjects m ust c o nti n ue t o use a p pr o priate c o ntrace pti o n wit h t heir part ners of c hil d beari n g 
p ote ntial, or refrai n fr o m se x ual acti vit y, as descri be d i n Secti o n 6. 3. 1 . 
If a s u bject ma k es or beli e ves t hat he has m a de s o me o ne pre g n a nt d uri n g t he st u d y, t he n t he 
St u d y C e nter staff m ust be i nf or me d i m me diatel y.  A n I nitial Pre g n a nc y F or m s h o ul d be 
s u b mitte d t o t he S p o ns or or desi g n ee  wit hi n 2 4 h o urs  of first lear ni n g of t h e occ urre n ce of  
pre g na nc y.  F oll o w- u p i nf or mati o n i ncl u di n g d eli ver y or ter mi nati o n is re p orte d b y d esi g nati n g 
as ‘ F oll o w- u p’ o n t he Pre g na n c y F or ms a n d re p ort e d wit hi n 2 4 h o urs. 
Pa y me nt f or all as pects of o bstetrical care, c hil d or relate d care will be t he s u bject’s 
res p o nsi bilit y.   
T he pr o gress of t he pr e g na nc y of a m ale s u bject’s  part ner  s h o ul d be f oll o we d u ntil t he o utc o me 
of t he pre g n a nc y is k n o w n (i.e., deli ver y, electi ve t er mi nati o n, or s p o nta ne o us a b orti o n).  If t he 
pre g na nc y res ults i n t he birt h of a c hil d, the St u d y Ce nter a n d S p o ns or m a y re q uest  access t o 
t he m ot her a n d i nf a nt’s me dic al rec o r ds t o o bt ai n a d diti o n al i nf or m ati o n.  F oll o w- u p will 
be perf or me d  t o t he e xte nt per mitte d b y t he a p plica ble re g ulati o ns a n d pri vac y c o nsi derati o ns. 
1 0.
S T A TI S TI C A L C O N SI D E R A TI O N S
1 0. 1 
St u d y E n d p oi nts, S u bsets, a n d C o v ari ates  
1 0. 1. 1 
S afety  E n d p oi nts 
T he safet y a n d t olera bilit y of I SI S  4 8 4 1 3 7 will be accesse d b y deter mi ni n g t he i nci de nce a n d 
se verit y of A Es a n d will be e val uat e d b y re vie wi n g:  
•
A E s (i ncl u di n g blee di n g e ve nts)
•
Vital si g ns a n d w ei g ht
•
P h ysical e x a mi nati o n
•
Cli nical la b orat or y tests
•
C oa g ulati o n para meters
•
Use of c o n c o mita nt me dicati o ns


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
Ori gi nal 
Pr ot oc ol  
1 A u g us t 2 0 1 7 
5 2
 
1 0. 1. 2  
Pri m ary P h ar m ac o dy n a mic E n d p oi nt  
T he pri mar y P D e n d p oi nt is t he a bs ol ute c ha n ge  i n li ver fat perce nta ge as q ua ntifie d b y 
M RI- P D F F fr o m Baseli ne M RI t o P ost- Treat me nt M RI. 
1 0. 1. 3
 Sec o n d ary
 
E n d p oi nts
 
Sec o n dar y e n d p oi nts i ncl u de:  
•
Relati ve perce nt c ha n ge i n li ver fat perce nta ge fr o m Baseli ne M RI t o P ost- Treat me nt
M RI
•
Pr o p orti o n of s u bjects wit h ≥ 3 0 % relati ve re d ucti o n i n li ver fat perce nta ge fr o m Baseli ne
M RI t o P ost- Treat me nt M RI
•
Perce nt c ha n ge i n li ver v ol u me fr o m Baseli ne M RI t o P ost- Treat me nt M RI
•
Perce nt c ha n ge i n plas ma li p o pr otei n pr ofile (tri gl yceri des, t otal c h olester ol, L D L- C,
a p o B, V L D L, H D L, a n d N o n- H D L) fr o m Baseli ne t o t he a vera ge of t he P ost- Treat me nt
val ues assesse d 1 a n d 2 wee ks after t he last d ose ( P T 1 a n d P T 2 Visits)
•
Perce nt c ha n ge i n para meters of he patic I R ( F P G, i ns uli n, a n d H O M A-I R) fr o m Baseli ne
t o t he first P ost- Treat me nt val ue assesse d 1 wee k after t he last  d ose ( P T 1 Visit)
•
A bs ol ute c ha n ge i n H b A 1c fr o m Baseli ne t o t he first P ost- Treat me nt val ue assesse d
1 wee k after t he last d ose ( P T 1 Visit)
1 0. 1. 4
 E x pl or at ory
 
E n d p oi nts
 
 
 
1 0. 2  
S a m ple Size C o nsi der ati o ns  
A p pr o xi matel y 4 5 s u bjects will be ra n d o mize d ( 2: 1 all ocati o n rati o).  Wit h 4 5 s u bjects t here will 
be > 9 0 % p o wer t o detect a of 5 % differe nce i n m ea n a bs ol ute c ha n ge i n li ver fat as meas ure d b y 
P D F F bet wee n t he acti ve a n d place b o gr o u ps wit h  a 2-si de d al p ha of 0. 0 5, ass u mi n g a c o m m o n 
sta n dar d de viati o n of 4 % a n d 2 5 % n o n-c o m pleters.   
T he 5 % effect size was selecte d base d o n cli n ical rele va nce wit h e vi de nce t hat 5 % P D F F 
re d ucti o n i de ntifie d s u bjects wit h re d uce d steat osis gra de i n N A S H s u bjects (Mi d dlet o n et al.  
2 0 1 7 ). 
1 0. 3
 P o p ul ati o ns
 
Ra n d o mize d:  All s u bjects w h o are ra n d o mize d i nt o t he st u d y re gar dless of w het her t he y 
recei ve d St u d y Dr u g. 
Per- Pr ot oc ol P o p ulati o n:  Will i ncl u de t he s u bset of t he Ra n d o mize d P o p ulati o n w h o ha ve 
recei ve d at least 1 0 of t he prescri be d d oses a n d m ust recei ve t he first 4 d oses i n t he first 5 wee ks, 
ca n n ot miss 3 c o nsec uti ve wee kl y d oses a n d n o si g nifica nt pr ot oc ol de viati o ns t hat w o ul d be 
e x pecte d t o i m pact efficac y.  
C CI


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
Ori gi nal 
Pr ot oc ol  
1 A u g us t 2 0 1 7 
5 3
 
Safet y P o p ulati o n:  All s u bject s w h o are ra n d o mize d a n d recei ve at least 1 d ose of St u d y Dr u g. 
P K P o p ulati o n:  All s u bjects w h o ha ve rece i ve d at least 1 d ose of acti ve St u d y Dr u g 
(I SI S 4 8 4 1 3 7), a n d ha ve at least 1 P K sa m ple c ollecte d a n d a nal yze d wit h e val ua ble res ults. 
1 0. 4  
Defi niti o n of B aseli ne  
•
Baseli ne M RI he patic fat c o nte nt a n d v ol u me will be fr o m t he M RI pri or t o a n d cl osest t o
ra n d o mizati o n
•
Baseli ne f or plas ma li p o pr otei n pr ofile (tri gl yceri des, t otal c h olester ol, L D L- C, a p o B,
V L D L, H D L, a n d N o n- H D L), e x pl orat or y bi o mar kers of D G A T 2 acti vit y ( S C D- 1), a n d
bi o mar kers of i nfla m mati o n (e. g., C K 1 8, ha pt o gl o bi n) a n d assess me nts f or I R ( F P G,
i ns uli n, H O M A I R) will be t he a vera ge of wee k - 1 visit ( Da y - 7) a n d Da y 1 pre- d ose
assess me nts
•
Baseli ne f or platelets, creati ni ne, A L T a n d A S T will be t he a vera ge of wee k - 1 visit
( Da y - 7) a n d Da y 1 pre- d ose assess me nts
•
Baseli ne f or H b A 1c a n d f or ot her r o uti ne cli nical assess me nts of c he mistr y a n d
he mat ol o g y, P K assess me nts, vital si g ns a n d E C G f or t he st u d y will be t he last n o n-
missi n g val ue pri or t o t he first a d mi nistra ti o n of St u d y Dr u g will be t he last n o n- missi n g
val ue pri or t o t he first a d mi nistrati o n of St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o;
A p pe n di x A ).
1 0. 5
 I nteri m
 
A n al ysis
 
N o i nteri m a nal ysis is pla n ne d.  H o we ver, d ur i n g t he st u d y, a n u n bli n de d i nteri m a nal ysis ma y 
be c o n d ucte d t o assess t he safet y, P K/ P D, a n d e x pl orat or y efficac y of t he res ults.  T he a nal ysis 
will be e xec ute d wit h c o ntr olle d disse mi nati o n t o e ns ure t he i nte grit y of o n g oi n g data c ollecti o n 
w hile mai ntai ni n g s ufficie nt bli n di n g i n t he st u d y.  Details of t hese c o ntr ols will be descri be d i n 
t he Statistical A nal ysis Pla n ( S A P). 
1 0. 6  
Pl a n ne d Met h o ds of A n al ysis 
All e C R F data, la b data tra nsfers, as well as  a n y o utc o mes deri ve d fr o m t he data, will be 
pr o vi de d i n t he s u bject data list i n gs.  S u bject data listi n gs will be prese nte d f or all s u bjects 
e nr olle d i nt o t he st u d y.  Descri pti ve s u m mar y statistics i ncl u d i n g n, mea n, me dia n, sta n dar d 
de viati o n, i nter q uartile ra n ge ( 2 5 t h perce ntile, 7 5t h perce ntile), a n d ra n ge ( mi ni m u m, ma xi m u m) 
f or c o nti n u o us varia bles, a n d co u nts a n d perce nta ges f or cate g orical  varia bles will be use d t o 
s u m marize m ost data.  W here a p pr o priate, p- val ues will be re p orte d.  All statistical tests will be 
c o n d ucte d usi n g 2-si de d tests wit h 5 % t y pe I err or rate s u nless ot her wise state d. 
T he efficac y a n d P D e n d p oi nts will be assesse d o n t he Ra n d o mize d P o p ulati o n a n d Per- Pr ot oc ol 
P o p ulati o n.  T he safet y a nal yses will be perf or me d o n t he Safet y P o p ulati o n. 
1 0. 6. 1  
De m o gr a p hic a n d B aseli ne C h ar acteristics 
De m o gra p hic a n d Baseli ne c harac teristics will be s u m marize d usi n g descri pti ve statistics b y 
treat me nt gr o u p.  S u bject ra n d o mizati o n will be s u m marize d b y c o h ort a n d treat me nt gr o u p.  T he 
s u bject dis p ositi o n will be s u m marize d.  All s u bjects e nr olle d will be i ncl u de d i n a s u m mar y of 
s u bject dis p ositi o n. 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
Ori gi nal 
Pr ot oc ol  
1 A u g us t 2 0 1 7 
5 4
 
1 0. 6. 2
 S afety
 
A n alysis
 
Treat me nt d urati o n a n d a m o u nt of St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) recei ve d will be 
s u m marize d b y treat me nt gr o u p.  S ubject i nci de nce rates of all A Es will be ta b ulate d b y t he 
Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A ™) s yste m or ga n class, a n d b y 
Me d D R A
™ ter m.  Ta bles a n d/ or narrati ves of treat me nt-e mer ge nt deat hs, se ri o us a n d si g nifica nt 
A Es, i ncl u di n g earl y wit h dra wals d ue t o A Es, will als o be pr o vi de d. 
All treat me nt-e mer ge nt A Es, a ll treat me nt-e mer ge nt A Es p ote ntiall y relate d t o St u d y Dr u g, all 
treat me nt-e mer ge nt seri o us A Es, a n d all treat me nt-e mer ge nt seri o us A Es p ote ntiall y relate d t o 
St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) will be s u m marize d. 
La b orat or y tests t o e ns ure s u bject safet y i ncl u di n g c he mistr y pa nel, c o m plete bl o o d c o u nt wit h 
differe ntial, c oa g ulati o n pa nel, c o m ple me nt etc., will be s u m marize d b y st u d y visits f or eac h 
treat me nt gr o u p.  T hese safet y varia bles will als o be prese nte d as c ha n ge a n d perce nt c ha n ge 
fr o m Baseli ne o ver ti me after St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) a d mi nistrati o n, as 
a p pr o priate. 
Vital si g n a n d E C G meas ures will  be ta b ulate d b y treat me nt gro u p.  I n a d diti o n, t he n u m ber of 
s u bjects w h o e x perie nce a b n or malities i n cli nical la b orat or y e val uati o ns will be s u m marize d b y 
treat me nt gr o u p. 
I nci de nce of blee di n g e ve nts i ncl u di n g t he f oll owi n g will be ta b ulate d b y treat me nt f or M B, 
C R N M B, mi n or blee di n g, a n d c o m bi n ati o n of maj or a n d cli nicall y-rele va nt n o n maj or blee di n g. 
P h ysical e xa mi nati o n data will be pr o vi de d i n t h e data listi n g.  C o nc o mita nt me dicati o ns will be 
c o de d usi n g W orl d Healt h Or ga nizati o n ( W H O) Dr u g dicti o nar y a n d s u m marize d b y treat me nt, 
A T C class a n d ge neric na me. 
1 0. 6. 3
 P h ar m ac o ki netic
 
A n alysis
 
F or all e val ua ble s u bjects recei vi n g I SI S 4 8 4 1 3 7, plas ma I SI S 4 8 4 1 3 7 c o nce ntrati o ns at tr o u g h 
d uri n g t he Treat me nt Peri o d a n d c o nce ntrati o ns o bser ve d d uri n g t he P ost- Treat me nt E val uati o n 
Peri o d will be liste d b y d ose, st u d y da y, ti me p oi nt, a n d s u m marize d us i n g descri pti ve statistics.  
A d diti o nal details re gar di n g t he P K a nal ys is will be descri be d i n t he S A P.   
P ote ntial relati o ns hi ps bet wee n selecte d P D  a n d plas ma e x p os ure meas ures (e. g., tr o u g h 
c o nce ntrati o ns) ma y als o be e x pl ore d, w here dee me d a p pr o priate. 
1 0. 6. 4
 P h ar m ac o dy n a mic/ E ffic acy A n alysis 
M RI res ults will be s u m marize d a n d ta b ulate d base d o n P D F F re d ucti o ns fr o m Baseli ne a bs ol ute 
a n d relati ve re d ucti o ns a n d li ver v ol u me.  Details  of pla n ne d a nal ysis of efficac y e n d p oi nts 
i ncl u de d P D e n d p oi nts will be pr o vi de d i n t he S A P. 
1 0. 6. 5
 A d diti o n al
 
A n alyses
 
 
 
C CI


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
5 5
 
1 1.
I N V E S TI G A T O R’ S R E G U L A T O R Y O B LI G A TI O N S
1 1. 1 
I nf or me d C o nse nt 
T he writte n i nf or me d c o nse nt d oc u me nt s h o ul d be pre pare d i n t he la n g u a ge(s) of t he p ot e ntial 
patie nt p o p ulati o n, base d o n a n E n glis h versi o n pr o vi de d b y t he S p o ns or or desi g nee. 
Bef ore a s u bj ect’s partici pati o n i n t he trial, t he  I n v esti gat or is res p o nsi ble f or o btai ni n g writte n 
i nf or me d c o nse nt fr o m t he s u bject or le gall y acce pta ble re prese ntati ve  after a de q uate e x pla nati o n 
of t he ai ms, met h o ds, a ntici pate d be nefits, a n d p ote ntial hazar ds of t he st ud y  a n d b ef ore a n y 
pr ot oc ol- s pecifi c scr ee ni n g pr o ce d ur es or a n y St u d y Dr u g ( I SI S 4 8 4 1 3 7 or place b o) are 
a d mi nistere d .  T he s u bject or le gall y acce pta bl e re prese nt ati ve m ust be gi v e n s ufficie nt ti me t o 
c o nsi der w het h er t o parti ci pate i n t he st u d y.   
T he ac q uisiti o n of i nf or me d c o nse nt a n d t he s u bj ect’s a gree me nt or ref usal t o n otif y his/ her 
pri mar y care p h ysicia n  s h o ul d be d oc u me nte d i n t he s u bject’s me dical rec or ds a n d t he i nf or me d 
c o nse nt f or m s h o ul d be si g ne d a n d pers o n all y d ate d b y t h e s u bject or a le gall y acce pta ble 
re pres e ntati ve a n d b y t he pers o n w h o c o n d u cte d t he i nf or me d c o ns e nt disc ussi o n ( n ot necessaril y 
a n I n vesti gat or).  T h e ori gi nal si g ne d i nf or m e d c o nse nt f or m s h o ul d be retai ne d i n t he St u d y 
Master File a n d i n a n y ot her l ocati o ns re q uire d b y i nstit uti o nal p olic y, a n d a c o p y of t he si g ne d 
c o nse nt f or m s h o ul d be pr o vi de d t o t he s u bject or le gall y acce pta ble re pres e ntati ve . 
If a p ote ntial s u bject is illiterate or vis uall y i m paire d a n d d oes n ot ha v e a le gall y acce pta ble 
re pres e ntati ve, t he In v est i gat or m ust pr o vi de a n i m partial wit ness t o rea d t he i nf or me d c o ns e nt 
f or m t o t he s u bject a n d m ust all o w f or q uesti o ns.  T hereafter, b ot h t he s u bject or le gall y 
acce pta ble r e pres e ntati ve a n d t he wit ness m ust si g n t he i nf or me d c o nse nt f or m t o attest t hat 
i nf or me d c o nse nt w as fr eel y gi ve n a n d u n derst o o d. 
1 1. 2 
Et hic al C o n d uct of t he St u d y  
T he G ui deli nes of t he W orl d Me dical Ass ociati o n ( W M A) Declarati o n of Helsi n ki date d 
Oct o ber  2 0 0 2 t he a p plica ble re g ulati o ns a n d g ui deli nes of c urre nt G o o d Cli nical Practice (G C P) 
as well as t he de m a n ds of nati o nal dr u g a n d d ata pr otecti o n la ws a n d ot her a p plica ble re g ulat or y 
re q uire me nts will be strictl y f oll o we d.   
1 1. 3 
I n de pe n de nt Et hics C o m mittee/I nstit uti o n al Re vie w B o ar d 
A c o p y of t he pr ot o c ol, pr o p ose d i nf or me d c o nse nt /asse nt f or ms, ot her writte n s u bject 
i nf or mati o n, a n d a n y pr o p ose d a d vertisi n g materi al m ust be s u b mitte d t o t he I E C/I R B f or writte n 
a p pr o val.  A c o p y of t he writte n a p pr o val of t h e pr ot oc ol a n d i nf or me d c o ns e nt f or m m ust be 
recei v e d by t he S p o ns or or desi g n ee  b ef ore recr uit me nt of s u bjects i nt o t he st u d y a n d s hi p me nt 
of St u d y Dr u g .  A c o p y of t he writte n a p pr o v al of a n y ot h er ite ms/ materials t hat m ust be 
a p pr o ve d b y t he St u d y Ce nter  or I E C/I R B  m ust als o be recei ve d b y t he S p o ns or or desi g nee 
bef ore rec r uit me nt of s u bjects i nt o t he st u d y a n d s hi p me nt of St u d y Dr u g .  T he I n vesti gat or’s 
Br oc h ure m ust be s u b mitte d t o t he I E C/I R B  f or ac k n o wle d ge me nt. 
T he In vesti gat or m ust s u b mit t o a n d, w here necessar y, o btai n a p pr o v al fr o m t he I E C/I R B, f or all 
s u bse q ue nt pr ot oc ol a me n d me nts a n d c ha n ges t o t he i nf or me d c o ns e nt d oc u me nt.  T he 
I n v esti gat or s h o ul d n otif y t he I E C/I R B of de vi ati o ns fr o m t he pr ot oc ol i n acc or d a nce wit h I C H 
G C P  Secti o n  4. 5. 2.  T he I n v esti gat or s h o ul d als o n otif y t he I E C/I R B of S A Es  occ urri n g at t he 


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
5 6
 
St u d y C e nter  a n d ot h er A E  re p orts recei ve d fr o m t he S p o ns or or desi g nee, i n acc or d a nce wit h 
l ocal pr oce d ures. 
T he I n vesti gat or will be r es p o nsi ble f or o btai ni n g a n n ual I E C/I R B a p pr o val/re ne wal t hr o u g h o ut 
t he d urati o n of t he st u d y.  C o pies of t he I n vesti gat or’s re p orts , all I E C/I R B s u b missi o ns a n d t he 
I E C/I R B c o nti n ua nce of a p pr o val m ust be se nt t o t he S p o ns or or desi g n ee. 
1 1. 4 
S u bject C o nfi de nti alit y  
T he In vesti gat or m ust e ns ure t hat t he s u bject’s c o nfi de ntialit y is mai ntai ne d .  O n t he cas e re p ort 
f or ms ( C R F) or ot her d oc u me nts s u b mitte d t o t he S p o ns or or desi g n ee, s u bjects s h o ul d be 
i de ntifie d b y i nitials (if p er mitte d b y l ocal la w) a n d a s u bject  i de ntificati o n n u m ber o nl y.  
D oc u me nts t hat ar e n ot f or s u b missi o n t o t he S p o ns or or desi g nee ( e. g., si g ne d i nf or me d c o ns e nt 
f or ms) s h o ul d be ke pt i n strict c o nfi de nce b y t he I n vesti gat or. 
I n c o m plia nce wit h Fe deral a n d l ocal re gulati o ns/I C H G C P G ui deli nes, it is re q uire d t hat t he 
I n v esti gat or a n d i nstit uti o n per mit a ut h orize d re prese ntati ves of t he c o m pa n y, of t he re gulat or y 
a ge nc y(s), a n d t he I E C/I R B direct access t o re vie w t he s u bject’s ori gi nal me dical rec or ds f or 
verificati o n of st u d y- relat e d pr oce d ures a n d data.  Direct access i ncl u d es e x a mi ni n g, a n al yzi n g, 
verif yi n g, a n d r e pr o d uci n g a n y rec or ds a n d re p orts t hat are i m p orta nt t o t he e val uati o n of t he 
st u d y.  T he I n vesti gat or is o bli gate d t o i nf or m a n d o btai n t he c o nse nt of t he s u bject t o per mit 
na me d re prese ntati ves t o ha ve access t o his/ her st u d y -relate d rec or ds wit h o ut vi olati n g t he 
c o nfi de ntialit y of t he s u bject. 
1 2.
A D MI NI S T R A TI V E A N D L E G A L O B LI G A TI O N S
1 2. 1 
Pr ot oc ol A me n d me nts  
Pr ot oc ol a me n d me nts m ust be ma de o nl y wit h t he pri or a p pr o val of t he S p o ns or or desi g nee.  
A gree me nt fr o m t he I n v esti gat or m ust be o btai ne d f or all pr ot oc ol a me n d m e nts a n d a me n d me nts 
t o t he i nf or me d c o nse nt d oc u me nt.  T he re g ulat or y a ut h orit y a n d I E C/I R B m ust be i nf or me d of 
all a me n d me nts a n d gi ve a p pr o val f or a n y a me n d me nts li kel y t o affect t he safet y of t he s u bjects 
or t he c o n d uct of t h e trial.  T he I n vesti gat or m ust  se n d a c o p y of t h e a p pr o val letter fr o m t he 
I E C/I R B t o t he S p o ns or or desi g n ee. 
1 2. 2 
St u d y Ter mi n ati o n  
T he S p o ns or or desi g nee  reser v es t he ri g ht t o ter mi nate t he st u d y.  T h e I n vesti gat or reser v es t he 
ri g ht t o ter mi nate t heir partici pati o n i n t he st u d y, acc or di n g t o t he ter ms of t he site c o ntract .  T he 
I n v esti gat or/ S p o ns or or d esi g nee s h o ul d n otif y t h e I E C/I R B i n writi n g of t he trial’s c o m pleti o n 
or earl y ter mi nati o n a n d se n d a c o p y of t h e n otificati o n t o t he S p o ns or or desi g nee. 
1 2. 3 
St u d y D oc u me nt ati o n a n d St or a ge 
A n e C R F utilizi n g a n Electr o nic Data C a pt ure ( E D C) a p plicati o n will be use d f or t his st u d y. 
T he I n vesti gat or s h o ul d e ns ure t hat all  a p pr o priatel y q ualifie d p ers o ns t o w h o m he/s he has 
del e gate d trial d uties  are rec or d e d o n a S p o ns or-a p pr o ve d Dele gati o n of Site Res p o nsi bilities 
F or m . 


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S o urce d oc u me nts are ori gi nal d oc u m e nts, data, a n d rec or ds fr o m w hic h t he s u bject’s C R F  data 
are o btai ne d .  T hese i ncl u de b ut are n ot li mite d t o h os pital rec or ds, cli nical a n d office c harts, 
la b orat or y a n d p h ar mac y recor ds, i ma gi n g, a n d c orres p o n de n ce.  I n t his st u d y, e C R F m a y n ot be 
use d as s o urce d oc u me nts. 
T he I n vesti gat or a n d S t u d y Ce nter staff are res p o nsi ble f or mai ntai ni n g a c o m pre he nsi ve a n d 
ce ntralize d fili n g s yste m of all st u d y-relate d (esse ntial) d oc u me ntati o n i n acc or da n ce wit h 
Secti o n 8  of t he I C H G ui deli nes ( E 6), s uita ble f or i ns pecti o n at a n y ti me b y re pres e ntati ves fr o m 
t he S p o ns or or desi g n ee a n d/ or a p plica ble r e gulat or y a ut h orities .  Ele me nts s h o ul d i ncl u de: 
•
S u bject files c o ntai ni n g c o m pleted C R F s, i nf or me d c o nse nts, a n d s u p p orti n g c o pi es of
s o urce d oc u m e ntati o n
•
St u d y files c o ntai ni n g t h e pr ot oc ol wit h all a me n d me nts, I n v esti gat or’s Br o c h ure, c o pi es
of pre -st u d y d oc u m e ntati o n a n d all c orres p o n de nce t o a n d fr o m t he I E C/I R B a n d t he
S p o ns or or d esi g n ee
•
If dr u g s u p plies ar e mai ntai ne d at t he St u d y Ce nter, pr o of of recei pt, St u d y Dr u g Pr o d uct
Acc o u nta bilit y Rec or d, Ret ur n of St u d y Dr u g Pr o d uct f or Destr u cti o n, fi nal St u d y Dr u g
pr o d uct rec o nciliati o n, a n d all dr u g- relat e d c orres p o n de nce
I n a d diti o n, all ori gi nal s o urce d oc u m e nts s u p p orti n g e ntries i n t he C R F s m ust be mai ntai ne d a n d 
be rea dil y a v aila ble.  
N o st u d y d oc u m e nt s h o ul d be destr o ye d wit h o ut pri or writte n a gree me nt b et wee n t he S p o ns or or 
desi g nee  a n d t he I n vesti gat or.  S h o ul d t he I n v esti gat or wis h t o assi g n t he st u d y rec or ds t o 
a n ot her part y or m o ve t h e m t o a n ot her l ocati o n, h e/s he m ust n otif y t he S p o ns or or desi g nee. 
1 2. 4 
St u d y M o nit ori n g  
T he S p o ns or re pr ese ntati ve a n d re g ul at or y a ut h orit y i ns pect ors are res p o nsi ble f or c o ntacti n g a n d 
visiti n g t he I n vesti gat or f or t he p ur p ose of i ns p ecti n g t he facilities a n d, u p o n re q uest, i ns pecti n g 
t he vari o us rec or ds of t he trial (e. g., C R F s a n d ot h er perti ne nt d ata) pr o vi d e d t hat s u bject 
c o nfi de ntialit y is r es pect e d.  
T he S p o ns or m o nit or or desi g nee is res p o nsi ble f or i ns pecti n g t h e C R F s at re g ular i nter v als 
t hr o u g h o ut t he st u d y t o v erif y a d h ere n ce t o t he pr ot oc ol; c o m plete ness, acc urac y, a n d 
c o nsiste nc y of t he dat a; a n d a d here n ce t o l ocal re g ulati o ns o n t he c o n d uct of cli nical res earc h.  
T he m o nit or s h o ul d ha ve access t o s u bject me dical rec or ds a n d ot her st u d y-relate d rec or ds 
nee de d t o verif y t he e ntri es o n t he C R F s. 
T he I n vesti gat or a grees t o c o o perat e wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms detecte d i n t he 
c o urse of t hes e m o nit ori n g visits, i ncl u di n g del a ys i n c o m pleti n g C R F s, are res ol ve d. 
I n acc or da n ce wit h I C H G C P a n d t he S p o ns or’s a u dit pla ns, t his st u d y ma y be s electe d f or a u dit 
b y r e pres e ntati ves fr o m t he S p o ns or’s Cli nical Q ualit y Ass ura nce De part me nt ( or desi g nees) .  
I ns p ecti o n of St u d y Ce nt er facilities (e. g., p har m ac y, dr u g st ora ge areas, la b orat ories) a n d re vie w 
of st u d y- relate d rec or ds will occ ur t o e val uat e t he trial c o n d uct a n d c o m pli a nce wit h t he 
pr ot oc ol, I C H G C P, a n d a p plica ble r e g ulat or y re q uire me nts.  


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T o e ns ure t he q u alit y of cli nical data a cli nical dat a ma na ge m e nt re vie w will be perf or me d o n 
s u bject data r ecei ve d b y  t he S p o ns or or desi g n ee.  D uri n g t his re vie w, s u bject data will be 
c hec k e d f or c o nsiste nc y, o missi o ns, a n d a n y a p p are nt discre pa n cies.  I n a d diti o n, t he data will be 
re vie we d f or a d h er e nce t o t he pr ot oc ol a n d G C P.  T o res ol ve a n y q u esti o ns arisi n g fr o m t he 
cli nical data ma na ge me n t re vie w pr o cess, dat a q ueries a n d/ or St u d y Ce nt er  n otificati o ns will be 
se nt t o t he St u d y C e nter  f or c o m pleti o n a n d ret ur n t o S p o ns or or desi g nee. 
T he Pri nci pal I n vesti gat or will si g n a n d dat e t he i n dicate d places o n t he C R F .  T hese si g n at ures 
will i n dicate t hat t he Pri nci pal I n vesti gat or i ns pecte d or re vi e we d t he d ata o n t he C R F , t he data 
q ueries, a n d t he St u d y Ce nter  n otificati o ns, a n d a grees wit h t he c o nt e nt. 
1 2. 5  
L a n g u a ge 
Case re p ort f or ms m ust be c o m plete d i n E n glis h .  Ge neric a n d Tra de na m es are acce pta ble .  
C o m bi nati o n me dicati o ns s h o ul d be rec or d e d usi n g t heir tra de n a me i n E n glis h if p ossi ble. 
All writte n i nf or mati o n a n d ot her material t o be us e d b y s u bj ects a n d i n vesti gati ve staff m ust use 
v oca b ular y a n d la n g ua ge t hat are cl earl y u n derst o o d. 
1 2. 6 
C o m pe ns ati o n f or I nj ur y  
T he S p o ns or mai ntai ns a p pr o priate i ns ura n ce c o v era ge f or cli nical trials a n d will f oll o w 
a p plica ble l ocal c o m pe ns ati o n la ws .  S u bjects  will be treate d a n d/ or c o m p e nsate d f or a n y st u d y-
relate d ill ness/i nj ur y i n acc or da n ce wit h t he i nf or mati o n pr o vi de d i n t he C o m pe nsati o n f or I nj ur y 
secti o n of t he I nf or me d C o nse nt d oc u me nt. 


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1 3.
R E F E R E N C E S
Ac ker ma n n  EJ , G u o S, B e ns o n M D , et al. S u p pressi n g tra nst h yre ti n pr o d ucti o n i n mice, m o n ke ys a n d h u ma ns usi n g 
2 n d -Ge nerati o n a ntise nse oli g o n ucle oti des . A m yl oi d  2 0 1 6; 2 3( 3), 1 -1 0 .  
Alt ma n n K H, Dea n N M, Fa b br o D, et al. Sec o n d ge nerati o n of a ntise nse oli g o n ucle oti des: fr o m n uclease resista nce 
t o bi ol o gical efficac y i n a ni mals. C hi mia 1 9 9 6; 5 0: 1 6 8 -1 7 6.  
B ü ller H R, C o he n A T, Da vi ds o n B, et al. I dra pari n u x vers us sta n dar d t hera p y f or ve n o us t hr o m b oe m b olic disease.  
N EJ M  2 0 0 7; 3 5 7: 1 0 9 4 -1 1 0 4.  
B yr ne C D a n d T ar g her G . N A F L D: A m ultis yste m disease . J He pat ol 2 0 1 5; 6 2( S 1): S4 7 -S 6 4.  
Ca o J, C he n g L, S hi Y . Catal ytic pr o perties of M G A T 3, a p utati ve triac yl g ycer ol s y net hase . J Li pi d Res 2 0 0 7; 4 8: 
5 8 3 – 5 9 1.  
Cases S, S mit h SJ, Z he n g Y W, et al. I de ntificati o n of a ge ne e nc o di n g a n ac yl C o A: diac yl gl ycer ol ac yltra nsferase, a 
ke y e nz y me i n triac yl gl ycer ol s y nt hesis . Pr oc Natl Aca d Sci U S A 1 9 9 8; 9 5 : 1 3 0 1 8 -1 3 0 2 3.  
Cases S, St o ne SJ, Z h o u P, et al. Cl o ni n g of D G A T 2, a sec o n d ma m malia n diac yl gl ycer ol ac yltra nsferase, a n d 
relate d fa mil y me m bers. J Bi ol C he m 2 0 0 1; 2 7 6 : 3 8 8 7 0 -3 8 8 7 6.  
C harlt o n M R, B ur ns J M, P e derse n R A, et al. Fre q ue nc y a n d o utc o mes of li ver tra ns pla ntati o n f or n o nalc o h olic 
steat o he patitis i n t he U nite d St ates. Gastr oe nter ol 2 0 1 1; 1 4 1: 1 2 4 9 -1 2 5 3.  
C he n g D, I q bal J, De ve n n y J, et al. Ac ylati o n of ac yl gl ycer ols b y ac yl c oe nz y me A:  di ac yl gl ycer ol ac yltra nsferase 1 
( D G A T 1). F u ncti o nal i m p orta nce of D G A T 1 i n t he i ntesti nal fat a bs or pti o n . J Bi ol C he m 2 0 0 8; 2 8 3: 2 9 8 0 2 -2 9 8 1 1.  
C hi K N, Eise n ha uer E, Fazli L, et al. A P hase I p har mac o ki netic a n d p har mac o d y na mic st u d y of O G X -0 1 1, a 
2′ -met h o x yet h yl a ntise nse oli g o n ucle oti de t o cl usteri n, i n patie nts wit h l ocalize d pr ostate ca ncer . J Natl Ca ncer I nst 
2 0 0 5; 9 7: 1 2 8 7 -1 2 9 6.  
C h oi C S, Sa va ge D B, K ul kar ni A, et al. S u p pressi o n of diac yl gl ycer ol ac yltra nsferase -2 ( D G A T 2), b ut n ot D G A T 1, 
wit h a nt ise nse oli g o n ucle oti des re verses diet-i n d uce d he pati c steat osis a n d i ns uli n resista nce. J Bi ol C he m 2 0 0 7; 
2 8 2: 2 2 6 7 8 -2 2 6 8 8.  
C o he n J C, H ort o n J D, H o b bs H H . H u ma n fatt y li ver disease: ol d q uesti o ns a n d ne w i nsi g hts . Sci 2 0 1 1; 3 3 2: 
1 5 1 9 -1 5 2 3.  
Cr o o ke S T a n d B e n nett C F . Pr o gress i n a ntise nse oli g o n ucle oti de t hera pe utics . A n n Re v P har mac ol T o xic ol 1 9 9 6; 
3 6: 1 0 7 -1 2 9.  
Cr o o ke S T, B a ker B F, K w o h J T, et al. I nte grate d safet y ass ess me nt of 2ʹ-O -met h o x yet h yl c hi meric a ntise nse 
oli g o n ucle oti des i n n o n h u ma n pri mates a n d h ealt h y h u ma n v ol u nteers . M ol T her 2 0 1 6; 2 4: 1 7 7 1 -1 7 8 2.  
Da y C P a n d J a mes O F . Steat o he patitis: a tale of t w o “ hits”? Gastr oe nter ol 1 9 9 8; 1 1 4: 8 4 2 -8 4 5.  
Di ge ni o A , D u n bar R L, Ale xa n der  VJ, et al. A nt ise nse- me di ate d lo weri n g of p las ma ap oli p o pr otei n C -III b y 
V ola nes orse n im pr o ves d ysli pi de mia a n d ins uli n se nsiti vit y i n ty pe 2 d ia betes. Dia betes Care  2 0 1 6;  3 9( 8 ): 
1 4 0 8 -1 4 1 5 .   
D uell  P B, Sa nt os R D , Kir wa n B A, et al. L o n g -ter m mi p o merse n treat me nt is ass ociate d wit h a re d ucti o n i n 
car di o vasc ular e ve nts i n patie nts wit h fa milial h y perc h olest er ole mi a. J Cli n  Li pi d  2 0 1 6 , 1 0( 4): 1 0 1 1 -1 0 2 1 . 
D ulai P S, Sirli n C B, L o o m ba R . M RI a n d M R E f or n o n -i n vasi ve q ua ntitati ve assess me nt of he patic steat osis a n d 
fi br osis i n N A F L D a n d N A S H: Cli nical trials t o cli nical practice. J He pat ol 2 0 1 6; 6 5: 1 0 0 6-1 0 1 6.  
Farrell G C  a n d Larter C Z. N o nalc o h olic fatt y li ver disease: fr o m steat osis t o cirr h osis . He pat ol 2 0 0 6; 4 3: S 9 9 -S 1 1 2 . 
Gear y R S, Y u R Z, W ata na be T, et al. P har mac o ki netics of a t u m or necr osis fact or -α p h os p h or ot hi oate 2ʹ -O -( 2-
met h o x yet h yl) m o difie d a ntise nse oli g o n ucl e oti de: c o m paris o n acr oss s pecies . Dr u g Meta b Dis p os 2 0 0 3; 3 1: 
1 4 1 9 -1 4 2 8.  


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He nr y S P, Stec ker K, Br o o ks D, et al. C he micall y m o difie d oli g o n ucle oti des e x hi bit decrease d i m m u ne sti m ulati o n 
i n mice. J P har mac ol E x p T her 2 0 0 0; 2 9 2: 4 6 8-4 7 9.  
He nr y S P, Ki m T W, Kra mer -Stic kla n d K, et al. T o xic ol o gic pr o perties of 2ʹ -O -met h o x yet h yl c hi meric a ntise nse 
i n hi bit ors i n a ni mals a n d ma n. I n: Cr o o ke S, e dit or, A ntise ns e Dr u g T ec h n ol o g y, 2n d e d . C R C Press, B oca Rat o n, F L 
2 0 0 8; 1 0: 3 2 7 -3 6 4.  
I bra hi m M A, Kelle ni M, Ge d da w y A. N o nalc o h olic fatt y li ver disease: c urre nt a n d p ote nti al t hera pies . Life Sci 
2 0 1 3; 9 2: 1 1 4 -1 1 8.  
I n o ue H, Ha yase Y, I wai S, et al. Se q ue nce -de pe n de nt h y dr ol ysis of R N A usi n g m o difie d oli g o n ucle oti de s pli nts 
a n d R Nase H .  F E B S Letters 1 9 8 7; 2 1 5:  3 2 7 -3 3 0 . 
Ka n g G H, Cr uite I, S hie h m ort eza M,  et al. Re pr o d uci bilit y of M RI -deter mi ne d pr ot o n de nsit y fat fracti o n acr oss t w o 
differe nt M R sca n ner platf or ms . J Ma g n Res o n I ma gi n g 2 0 1 1; 3 4:  9 2 8 -9 3 4 . 
Kastelei n JJ P, W e del M K; B a ker B F, et al. P ote nt re d ucti o n of a p oli p o pr o tei n B a n d l o w-d e nsit y li p o pr otei n 
c h olester ol b y s h ort -ter m a d mi nistrati o n of a n a ntise nse i n hi bit or of a p oli p o pr otei n B. Circ 2 0 0 6; 1 1 4: 1 7 2 9 -1 7 3 5.  
K w o h TJ . A n o ver vie w of t he cli nical safet y e x perie nce of first a n d sec o n d ge nerati o n a ntise nse oli g o n ucle oti des .  
I n: Cr o o ke S T, e dit or. A ntise nse Dr u g T ec h n ol o g y: Pri nci ples, Strate gies a n d A p plicati o ns, 2 n d E diti o n . B oca Rat o n, 
F L . T a yl or & Fra ncis Gr o u p  2 0 0 8; 3 6 5 -4 0 0.  
Le T A, C he n J, C ha n gc hie n C, et al. Effect of c olese vela m o n li ver fat q ua ntifi e d b y ma g netic res o na nce i n 
n o nalc o h olic steat o he patitis: a ra n d o mize d c o ntr olle d trial . H e pat ol 2 0 1 2; 5 6:  9 2 2 -9 3 2 . 
Marc hesi ni G, B u gia nesi E, F orla ni G, et al. N o nalc o h olic fatt y li ver, steat o he patitis, a n d t he meta b olic s y n dr o me . 
He pat ol 2 0 0 3; 3 7: 9 1 7 -9 2 3.  
Mc C ull o u g h AJ . P at h o p h ysi ol o g y of n o nalc o h olic steat o he p atitis . J Cli n Gastr oe nter ol 2 0 0 6; 4 0 S u p pl 1: S 1 7-S 2 9.  
Mc Ka y R A, Mira glia LJ, C u m mi ns L L, et al. C haracterizati o n of a p ote nt a n d s pecific class of a ntise nse 
oli g o n ucle oti de i n hi bit or of h u ma n pr o tei n ki nase C-α e x pressi o n . J Bi ol C he m 1 9 9 9 ; 2 7 4: 1 7 1 5 -1 7 2 2.  
Mee galla R L, Bill hei mer J T, C he n g D . C o ncerte d ele vati o n of ac yl -c oe nz y me A: diac yl gl ycer ol ac yltra nsferase 
( D G A T) acti vit y t hr o u g h i n de pe n de nt sti m ulati o n of m R N A e x pressi o n of D G A T 1 a n d D G A T 2 b y car b o h y drate 
a n d i ns uli n. Bi oc he m Bi o p h ys Res C o m m u n 2 0 0 2, 2 9 8 : 3 1 7 -3 2 3.  
Mi d dl et o n M F, He ba E R, H o o ker C A, et al. A gree me nt b et wee n ma g netic r es o na nce ima gi n g p r ot o n d e nsit y fat 
fracti o n m eas ure me nts a n d p at h ol o gist-assi g ne d steat osis g ra des of li ver bi o psies fr o m ad ults wit h n o nalc o h olics 
steat o he patitis. Gastr oe nter ol  2 0 1 7 ; I n Press: 1- 9. 
M o nia B P, Les ni k E A, G o nzal ez C, et al. E val uati o n of 2 ′-m o difie d oli g o n ucle oti des c o ntai ni n g 2 ′-de o x y ga ps as 
a ntise nse i n hi bit ors of ge ne e x pressi o n. J Bi ol C he m  1 9 9 3; 2 6 8:  1 4 5 1 4 -1 4 5 2 2.  
Nai k R, O bia n g -O b o u n o u B W, Ki m M, et al. T hera pe utic strate gies f or meta b olic diseases: s mall -m olec ule 
diac yl gl ycer ol ac yltra nsferase ( D G A T) I n hi bit ors . C he m  Me d  C he m 2 0 1 4; 9( 1 1): 2 4 1 0 -2 4 2 4.  
P atel J, B etter nc o urt R, C ui J, et al. A ss ociati o n of n o ni n vasi ve q ua ntitati ve decli ne i n li ver fat c o nte nt o n M RI wit h 
hist ol o gic res p o nse i n n o nalc o h olic steat o he patitis . T her A d v Gastr oe nter ol 2 0 1 6; 9: 6 9 2 -7 0 1.  
Sc h ul ma n S, Kear o n C, S u bc o m mittee o n C o ntr ol of A ntic o a g ulati o n of t he Scie ntific  a n d Sta n dar dizati o n 
C o m mittee of t he I nter nati o nal S ociet y o n T hr o m b osis a n d Hae m ostasis . Defi niti o n of maj or blee di n g i n cli nical 
i n vesti gati o ns of a nti he m ostati c me dical pr o d ucts i n n o n-s ur gical patie nts. J T hr o m b Hae m ost 2 0 0 5; 3( 4): 6 9 2-6 9 4  
Se well K L , Gear y R S, B a ker B F, et al. P hase I trial of I SI S 1 0 4 8 3 8, a 2ʹ -met h o x yet h yl m o difie d a ntise nse 
oli g o n ucle oti de tar geti n g t u m or necr osis fact or . J P har m E x p T her 2 0 0 2; 3 0 3: 1 3 3 4 -1 3 4 3.  
S mit h SJ, Cases S, J e nse n D R, et al. O besit y resista nce a n d m ulti ple mec ha nis ms of tri gl yceri de s y nt hesis i n mice 
lac ki n g D gat. Nat Ge net 2 0 0 0; 2 5: 8 7 -9 0.  
St o ne SJ, M yers H M, W at ki ns S M, et al. Li p o pe nia a n d s ki n barrier a b n or malities i n D G A T 2 -deficie nt mice . J Bi ol 
C he m 2 0 0 4; 2 7 9: 1 1 7 6 7 -1 1 7 7 6.  


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6 1
 
St o ne SJ, Le vi n M C, Z h o u P, et al. T he e n d o plas mic retic ul u m e nz y me D G A T 2 is f o u n d i n mit oc h o n dria -ass ociate d 
me m bra nes a n d has a mit oc h o n drial tar geti n g si g nal t hat pr o m otes its ass ociati o n wit h mit oc h o n dria. J Bi ol C he m 
2 0 0 9, 2 8 4 : 5 3 5 2 -5 3 6 1.  
Til g H a n d M osc he n A R . E v ol uti o n of i nfla m mati o n i n n o nal c o h olic fatt y li ver disease: t he m ulti ple parallel hits 
h y p ot hesis . He pat ol 2 0 1 0; 5 2: 1 8 3 6 -1 8 4 6.  
T o me n o W, Y o ne da M, I maj o K, et al. E mer gi n g dr u gs f or n o n -alc o h olic steat o he patitis . E x pert O pi n E mer g Dr u gs 
2 0 1 3; 1 8: 2 7 9 -2 9 0.  
Willia ms C D, Ste n gel J, Asi ke MI, et al. Pre vale nce of n o nal c o h olic fatt y li ver disease a n d n o nalc o h olic 
steat o he patitis a m o n g a lar gel y mi d dle a ge d p o p ulati o n utili zi n g ultras o u n d a n d li ver bi o ps y: a pr os pecti ve st u d y. 
Gastr oe nter ol 2 0 1 1; 1 4 0: 1 2 4 -1 3 1.  
Ye n C L, St o ne SJ, K oli wa d S, et al. T he matic re vie w series: gl ycer oli pi ds . D G A T e nz y mes a n d triac yl gl ycer ol 
bi os y nt hesis . J Li pi d Res 2 0 0 8; 4 9: 2 2 8 3-2 3 0 1.  
Y u X X, M urra y S F, P a n de y S K, et al. A ntise nse oli g o n ucle oti de re d ucti o n of D G A T 2 e x pressi o n i m pr o ves he patic 
steat osis a n d h y perli pi de mia i n o bese mice . He pat ol 2 0 0 5; 4 2: 3 6 2 -3 7 1.  
Y u R Z, Ki m T W, H o n g A, et al. Cr oss -s pecies p har mac o ki netic c o m paris o n fr o m m o use t o ma n of a sec o n d-
ge nerati o n a ntise nse oli g o n ucl e oti de, I SI S 3 0 1 0 1 2, t ar geti n g h u ma n a p oli p o pr otei n B -1 0 0 . Dr u g Meta b Dis p os 
2 0 0 7 ; 3 5:  4 6 0 -4 6 8.  
Y u R Z, Le m o ni dis K M, Gra ha m MJ, et al. Cr oss -s pecies c o m paris o n of i n viv o P K/ P D relati o ns hi ps f or sec o n d 
ge nerati o n a ntise nse oli g o n ucl e oti des tar geti n g a p oli p o pr otei n B -1 0 0. Bi oc he m P har mac ol 2 0 0 9; 7 7: 9 1 0 -9 1 9.  
Z ha n g H, L ö we n ber g E C, Cr os b y J R, et al. I n hi biti o n of t he i ntri nsic c oa g ulati o n pat h wa y Fact or XI b y a ntise nse 
oli g o n ucle oti des: a n o vel a ntit hr o m b otic strate g y wit h l o wer e d blee di n g ris k .  Bl o o d 2 0 1 0; 1 1 6: 4 6 8 4 -4 6 9 2.  


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
6 2
 
1 4.
A P P E N DI C E S


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
6 3
 
A p pe n di x A  
Sc he d ule of Pr oce d ures 


I SI S 4 8 4 1 3 7 -C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust 2 0 1 7  
6 4
 
A p pe n di x A  Sc he d ule of Pr oce d ure s 
St u d y P eri o d  
S cr e e n  
R u n -I n 
Tr e at m e nt  
St u d y W e e k  
W k -6 t hr u  
W k - 5 
W k -4 
t hr u 
W k - 3 
W k - 1 
W 1  
W 2  
W 3  
W 4  W 5  
W 6  
W 7  W 8  
W 9  
W 1 0  W 1 1  W 1 2  W 1 3  
St u d y D a y  
S- 4 2 t hr u
S- 2 9
D- 2 8
t hr u
D- 1 5
D- 7
t o
D- 1
D 1  
D 8  D 1 5  D 2 2  D 2 9  D 3 6  D 4 3  D 5 0  D 5 7  
D 6 4  D 7 1  D 7 8  
D 8 5  
Vi sit Wi n d o w ( +/ - d a y s)  
A 
3 
2 
I nf or m e d C o n s e nt 
X 
I n cl u si o n/ E x cl u si o n 
X 
X 
X 
M e di c al Hi st or y  
X 
P h y si c al E x a m 1  
X 
X 
X 
H ei g ht, B o d y W ei g ht a n d B MI 2  
X 
X 7
X 
X 
X 
W ai st/ Hi p Cir c u mf er e n c e  
X 
X 
X 
X 
Vit al Si g n s 3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bl o o d Pr e s s ur e  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
E C G ( 1 2 – l e a d) i n tri pli c at e1 5  
X 
3 X 6  
X 
F S H 4 / S er u m Pr e g n a n c y 5  
X 
X 7  
X 
HI V, H e p atiti s B & C  
X 
Dr u g/ Al c o h ol S cr e e n  
X 
X 7  
X 
C h e mi str y P a n el ( F a sti n g) 8  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
H e m at ol o g y 8  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Uri n al y si s (i n cl u di n g P/ C) 9  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
P T/ a P T T/I N R  
X 
H b A 1 c  
X 
X 
X 
F a sti n g Pl a s m a Gl u c o s e ( F P G) 1 0  
X 
X 7  
X 
X 
X 
X 
X 


I SI S 4 8 4 1 3 7 -C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust 2 0 1 7  
6 5
 
A p pe n di x A  Sc he d ule of Pr oce d ures C o nti n ue d  
St u d y P eri o d  
S cr e e n  
R u n -I n 
Tr e at m e nt  
St u d y W e e k  
W k -6 t hr u  
W k - 5 
W k -4 
t hr u 
W k - 3 
W k - 1 
W 1  
W 2  
W 3  
W 4  
W 5  
W 6  
W 7  
W 8  
W 9  
W 1 0  W 1 1  W 1 2  W 1 3  
St u d y D a y  
S- 4 2 t hr u
S- 2 9
D- 2 8
t hr u
D- 1 5
D- 7
t o
D- 1
D 1  
D 8  
D 1 5  D 2 2  D 2 9  
D 3 6  D 4 3  D 5 0  
D 5 7  
D 6 4  
D 7 1  
D 7 8  
D 8 5  
Vi sit Wi n d o w ( +/ - d a y s)  
A 
3 
2 
Li pi d P a n el ( s er u m, f a sti n g) 1 0  
X 
X 
X 
X 
I n s uli n (f a sti n g)1 0  
X 
X 
X 
X 
h s C R P  
X 
X 
T S H  
X 
X 
X 
Tri o dt h yr o ni n e ( T 3)  
X 
T h yr o xi n e ( T 4) ( s er u m)  
X 
E x pl or at or y M ar k er s  
X 
X 
X 
X 
Ar c hi v e d S a m pl e s 1 1  
X 
X 
X 
P K S a m pli n g 1 2  
X 
X 
X 
X 
X 
X 
X 
X 
X 
H e p ati c F at C o nt e nt ( M RI ) 
X 
S C T ol er a bilit y A s s e s s m e nt  
X 
St u d y Dr u g A d mi ni str ati o n  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
O A D  A d mi ni str ati o n 1 3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Di et ar y a n d E x er ci s e 
C o u n s eli n g  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
A d v er s e E v e nt s  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C o n c o mit a nt M e di c ati o n s  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
P h o n e C o nt a ct 1 4  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
6 6
 
A p pe n di x A  Sc he d ule of Pr oce d ures C o nti n ue d  
St u d y P eri o d  
P o st- Tr e at m e nt  P eri o d ( 1 3 W e e k s)  
St u d y W e e k  
E T/ P T 1 
P T 2 
P T 3 
P T 4 
P T 6 
P T 8 
E T 
P T 1 2 
P T 1 3 
St u d y D a y  
D 9 2  
D 9 9  
D 1 0 6  
D 1 1 3  
D 1 2 7  
D 1 4 1  
D 1 6 9  
D 1 7 6  
Vi sit Wi n d o w ( +/ - d a y s)  
3
7 
P h y si c al E x a m 1
X 
X 
X 
X 
B o d y W ei g ht a n d B MI 2
X 
X 
X 
X 
W ai st/ Hi p Cir c u mf er e n c e  
X 
X 
X 
X 
Vit al Si g n s 3  
X 
X 
X 
X 
X 
X 
X 
Bl o o d Pr e s s ur e ( B P)  
X 
X 
X 
X 
X 
X 
X 
E C G ( 1 2 – l e a d) i n tri pli c at e1 5  
X 
X 
P K S a m pli n g  
X 
X 
X 
X 
X 
Ar c hi v e d S a m pl e  
X 
X 
X 
X 
C h e mi str y P a n el ( s er u m, f a sti n g)  
X 
X 
X 
X 
X 
X 
X 
H e m at ol o g y  
X 
X 
X 
X 
X 
X 
X 
Uri n al y si s (i n cl u di n g P/ C r ati o) 9  
X 
X 
X 
X 
X 
X 
X 
H b A 1 c ( s er u m)  
X 
X 
X 
X 
Li pi d P a n el ( s er u m, f a sti n g) 1 0  
X 
X 
X 
I n s uli n ( pl a s m a, f a sti n g)1 0  
X 
X 
X 
F a sti n g Pl a s m a Gl u c o s e  ( F P G)1 0
X 
X 
X 
X 
X 
X 
X 
h s C R P ( s er u m)  
X 
X 
T S H ( s er u m)  
X 
X 
S er u m Pr e g n a n c y 5  
X 
X 
E x pl or at or y M ar k er s  
X 
X 
X 
X 
H e p ati c F at  C o nt e nt  ( M RI) 
X B  
O A D A d mi ni str ati o n 1 3  
X 
X 
X 
X 
X 
X 
X 
X 
Di et ar y & E x er ci s e M ai nt e n a n c e  
X 
X 
X 
X 
X 
X 
X 
X 
A d v er s e E v e nt s  
X 
X 
X 
X 
X 
X 
X 
X 
C o n c o mit a nt M e di c ati o n s  
X 
X 
X 
X 
X 
X 
X 
X 
P h o n e C o nt a ct 1 4  
X 
X 
X 
X 
X 
X 
X 
X 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
Ori gi nal 
Pr ot oc ol  
1 A u g us t 2 0 1 7 
6 7
 
A p pe n di x A  Sc he d ule of Pr oce d ures C o nti n ue d 
L e g e n d T e xt 
1. 
F ull p h y si c al e x a m t o b e gi v e n at S cr e e ni n g a n d a b br e vi at e d p h y si c al e x a m t o b e gi v e n d uri n g tr e at m e nt a n d
f oll o w- u p p eri o d a s i n di c at e d t o a s s e s s c h a n g e s fr o m S cr e e ni n g
2.  
H ei g ht a s s e s s e d at S cr e e ni n g vi sit o nl y
3.  
H R, r e s pir at or y r at e ( R R), t e m p
4. 
F S H:  R e q uir e d t o c o nfir m m e n o p a u s e f or w o m e n ≤ 5 5 y e ar s w h o h a v e 1 2 m o nt h s of s p o nt a n e o u s a m e n orr h e a
wit h n o alt er n ati v e m e di c al c a u s e, a n d w h o ar e n ot s ur gi c all y st eril e
5.  
W o m e n w h o ar e n ot s ur gi c all y st eril e.  S er u m t e st at  s cr e e n, D 5 0, D 9 2 a n d D 1 6 9; di p sti c k a c c e pt a bl e at D a y 1
o nl y
6. 
A s s e s s m e nt s c o n d u ct e d at pr e- d o s e, 1 hr a n d 2 hr s p o st- d o s e
7.  
R e s ult s r e q uir e d pri or t o r a n d o mi z ati o n
8. 
If d uri n g t h e tr e at m e nt p eri o d, a pl at el et, cr e ati ni n e, or A L T r e s ult i s u ni nt er pr et a bl e ( e. g., d u e t o cl u m pi n g,
h e m ol y si s, or q u a ntit y n ot s uffi ci e nt) t h e t e st m u st b e r e p e at e d a n d a r e s ult  n ot m e eti n g st o p pi n g r ul e m u st b e
o bt ai n e d pri or t o n e xt d o s e
9. 
Pr ef er a bl y c oll e ct s p e ci m e n f or a n al y si s fr o m t h e s u bj e ct’ s s e c o n d v oi d of t h e d a y
1 0. F a st e d s a m pl e s s h o ul d b e t a k e n aft er f a sti n g f or at l e a st 8- 1 0 h o ur s.  D uri n g t hi s ti m e t h e s u bj e ct c a n dri n k w at er
a n d t h e y s h o ul d e n s ur e t h at t h e y c o n s u m e s uffi ci e nt w at er i n or d er t o n ot b e c o m e d e h y dr at e d
1 1. St or e d at - 7 0 ( ± 1 0) ° C f or f oll o w- u p e x pl or ati o n
1 2.  
D uri n g t h e tr e at m e nt p eri o d, P K s a m pl e s ar e c oll e ct e d pr e- d o s e.  D uri n g t h e P o st- Tr e at m e nt P eri o d, P K
s a m pl e s ar e c oll e ct e d a n y ti m e.  S e e  A p p e n di x C
1 3.  O A D d o s e s ar e t o b e s elf- a d mi ni st er e d d ail y b y t h e s u bj e ct t hr o u g h o ut t h e st u d y
1 4. If s u bj e ct mi s s e s cli ni c vi sit, a p h o n e c o nt a ct will b e att e m pt e d t o a s s e s s A E a n d c o n m e d s
1 5. Tri pli c at e E C G st u d y pr o c e d ur e will c o n si st of 3 E C G s wit h 2 mi n ut e s b et w e e n e a c h E C G (- 1/ + 2 mi n s wi n d o w
b et w e e n e a c h a s s e s s m e nt)
N ot e s: 
All a s s e s s m e nt s s h o ul d b e c oll e ct e d pr e- d o s e u nl e s s i n di c at e d ot h er wi s e. 
N ot e s R e g ar di n g Ti mi n g of M RI A s s e s s m e nt s: 
A  
M a g n eti c R e s o n a n c e I m a gi n g ( M RI) A s s e s s m e nt Wi n d o w s  
B a s eli n e M RI A s s e s s m e nt:  W e e k - 4 or - 3 ( D a y - 2 8 t o D a y - 1 4) + 7 d a y s 
P o st- Tr e at m e nt M RI A s s e s s m e nt:  W e e k of P T 2 Vi sit ( D a y s 9 9 t o D a y 1 0 5) +/- 7 d a y s 
B  
A P o st- Tr e at m e nt M RI t o a s s e s s li v er f at c o nt e nt a n d v o l u m e will o c c ur d uri n g t h e w e e k of P T 2 Vi sit f or all 
s u bj e ct s c o m pl eti n g 1 3 d o s e s.  F or s u bj e ct s w h o t er mi n at e fr o m t h e tr e at m e nt p eri o d e arl y, t h e ti mi n g a n d 
c o n d u ct of t h e M RI i n t h e P o st- Tr e at m e nt P eri o d will b e a dj u st e d a s f oll o w s 
i. 
S u bj e ct r e c ei v e d 4 or l e s s d o s e s, t h e P o st- Tr e at m e nt M RI A s s e s s m e nt will n ot b e r e q uir e d
ii. 
S u bj e ct r e c ei v e d 5- 9 d o s e s, t h e P o st- Tr e at m e nt M RI A s s e s s m e nt will o c c ur 2 w e e k s aft er t h e l a st d o s e
d uri n g t h e w e e k of t h e P T 2 Vi sit.  ( +/- 7 d a y s)
iii. 
S u bj e ct r e c ei v e d 1 0 - 1 2 d o s e s, t h e P o st- Tr e at me nt M RI A s s e s s m e nt will b e s c h e d ul e d a s f oll o w s:
N u m b er of D o s e s R e c ei v e d  
P o st- Tr e at m e nt M RI A s s e s s m e nt 
1 0 
5 w e e k s aft er l a st d o s e ( +/- 7 d a y s) 
1 1 
4 w e e k s aft er l a st d o s e ( +/- 7 d a y s) 
1 2 
3 w e e k s aft er l a st d o s e ( +/- 7 d a y s) 


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
6 8
 
A p pe n di x B  
List of L a b or at or y A n al ytes  


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
Ori gi nal 
Pr ot oc ol  
1 A u g us t 2 0 1 7 
6 9
 
A p pe n di x B  List of L a b or at or y A n al ytes 
Base d o n e mer gi n g data fr o m t his or f ut ure st u dies, a d diti o nal tests n ot liste d bel o w ma y be 
perf or me d o n st ore d sa m ples t o better c haract erize t he pr ofile of I S I S 4 8 4 1 3 7 or ot her si milar 
oli g o n ucle oti des 
F asti n g Cli nic al 
C he mistr y P a nel 
• S o di u m
• P otassi u m
• C hl ori de
• Bicar b o nate
• T otal pr otei n
• Al b u mi n
• Calci u m
• Ma g nesi u m
• P h os p h or us
• Gl uc ose
• B U N
• Creati ni ne
• C h olester ol
• Uric Aci d
• T otal bilir u bi n
• Direct (c o nj u gate d)
bilir u bi n
• I n direct ( u nc o nj u gate d)
bilir u bi n 
• A L T
• A S T
• Al kali ne p h os p hatase
• Creati ni ne ki nase
• G G T
Scree ni n g Tests 
• He patitis B s urface
a nti ge n
• He patitis C a nti b o d y
• HI V a nti b o d y
• F S H ( w o me n o nl y)
• Ser u m β h C G
• Dr u g/ Alc o h ol scree n
C o a g ul ati o n 
• a P T T (sec)
• P T (sec)
• I N R
P D P a nel 
• Fasti n g Gl uc ose
• I ns uli n
• H b A 1c
F asti n g Li pi d P a nel 
• Tri gl y ceri des
• T otal C h olester ol
• A p o B
• V L D L c h olester ol
• L D L c h olester ol
• H D L c h olester ol
• N o n- H D L c h olester ol
He m at ol o g y 
• Re d bl o o d cells
• He m o gl o bi n
• He mat ocrit
• M C V, M C H, M C H C
• Platelets
• W hite bl o o d cells
• W B C Differe ntial
( % a n d a bs ol ute)
• Ne utr o p hils
• E osi n o p hils
• Bas o p hils
• L y m p h oc ytes
• M o n oc ytes
T h y r oi d P a nel 
• T S H
• Free T 4
• Free T 3
P h ar m ac o ki netics 1 
• I SI S 4 8 4 1 3 7 le vels i n
plas ma
E x pl or at or y 3 
a di p o necti n 
S C D- 1  
C K 1 8  
ha pt o gl o bi n 
le pti n 
I nfl a m m at or y 
• hs- C R P 3
Uri n al ysis 
• C ol or
• A p peara nce
• S pecific gra vit y
• p H
• uri ne Pr otei n/ Creati ni ne
Rati o
• Pr otei n
• Bl o o d
• Ket o nes
• Ur o bili n o ge n
• Gl uc ose
• Bilir u bi n
• Le u k oc yte esterase
• Nitrate
• Micr osc o pic
e xa mi nati o n 2
Ot her 1 
• Arc hi ve d ser u m sa m ples
1  
S er u m a n d pl a s m a P K s a m pl e s m a y al s o b e u s e d f or m et a b ol o mi c s/li pi d o mi c s a s s e s s m e nt s, pr ofili n g of dr u g 
bi n di n g pr ot ei n s, bi o a n al yti c al m et h o d v ali d ati o n p ur p o s e s, st a bilit y a s s e s s m e nt s,  m et a b olit e a s s e s s m e nt s, 
i m m u n o g e ni cit y a s s a y d e v el o p m e nt/t e stin g, or t o a s s e s s ot h er a cti o n s of I SI S 4 8 4 1 3 7 wit h pl a s m a c o n stit u e nt s 
2  
Will b e p erf or m e d o n a b n or m al fi n di n g s u nl e s s ot h er wi s e s p e cifi e d 
3  
S a m pl e s will b e c oll e ct e d h o w e v er m a y n ot b e a n al y z e d   


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
7 0
 
A p pe n di x C  
P K S a m pli n g Sc h e d ule  


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
7 1
 
A p pe n di x C  P K S a m pli n g Sc he d ule 
Tr e at m e nt P eri o d  
W 1  
W 2  
W 4  
W 6  
W 8  
W 9  
W 1 0  
W 1 2  
W 1 3  
D 1  
D 8  
D 2 2  
D 3 6  
D 5 0  
D 5 7  
D 6 4  
D 7 8  
D 8 5  
Pr e- d o s e  
Pr e- d o s e  
Pr e- d o s e  
Pr e- d o s e  
Pr e- d o s e  
Pr e- d o s e  
Pr e- d o s e  
Pr e- d o s e  
Pr e- d o s e  
P o st- Tr e at m e nt P eri o d ( 1 3 W e e k s)  
E T/ P T 1  
P T 2  
P T 3  
P T 6 
P T 1 2  
D 9 2  
D 9 9  
D 1 1 3  
D 1 2 7  
D 1 6 9  
Bl o o d s a m pl e c a n b e dr a w n a n yti m e d uri n g t h e vi sit  


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
7 2
 
A p pe n di x D  
Gr a di n g Sc ale f or A d verse E ve nts Rel ati n g t o 
L a b or at or y A b n or m aliti es  


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
7 3
 
A p pe n di x D   Gr a di n g Sc ale f or A d verse E ve nts Rel ati n g t o L a b or at or y A b n or m alities 
T he f oll o wi n g gra di n g r ec o m me n dati o ns f or a d v erse e ve nts rel ati n g t o la b t est a b n or malities are 
base d u p o n t he C o m m o n Ter mi n ol o g y Criteri a f or A d verse E v e nts ( C T C A E) Versi o n 4. 0 3, 
J u ne 2 0 1 0 


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
7 4
 
A p pe n di x D   Gr a di n g Sc ale f or A d verse E ve nts Rel ati n g t o L a b or at or y A b n or m alities 
C o nti n ue d  


I SI S 4 8 4 1 3 7-C S 2  
C O N FI D E N TI A L  
Ori gi nal  
Pr ot oc ol  
1 A u g ust  2 0 1 7  
7 5
 
A p pe n di x D   Gr a di n g Sc ale f or A d verse E ve nts Rel ati n g t o L a b or at or y A b n or m alities 
C o nti n ue d  


I O NI S P H A R M A C E U TI C A L S, I N C. 
I SI S 4 8 4 1 3 7- C S 2 
A D o u ble- Bli n d, R a n d o mize d, Pl ace b o- C o ntr olle d, P h ase 2 St u d y t o 
E v al u ate t he S afet y, T oler a b ilit y a n d P h ar m ac o d y n a mics of 
I SI S 4 8 4 1 3 7 (I SI S- D G A T 2 R X , a n A ntise nse I n hi bit or of 
Di ac yl gl ycer ol Ac yltr a nsfer ase 2)  A d mi nistere d O nce- Wee kl y f or 
1 3 Wee ks o n He p atic Ste at osis i n  A d ult P atie nts wit h T y pe 2 
Di a betes 
Pr ot oc ol A me n d me nt 1 – 2 3 M arc h 2 0 1 8 
E u dr a C T N o:  2 0 1 7- 0 0 3 1 9 7- 1 3 
S p o ns or: 
I o nis P har mace uticals, I nc. 
2 8 5 5 Gazelle C o urt 
Carls ba d, C A  9 2 0 1 0 


P P D


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
3
 
I SI S 4 8 4 1 3 7 
I o nis Pr ot oc ol N u m ber I SI S 4 8 4 1 3 7- C S 2 
Pr ot oc ol A me n d me nt 1 – 2 3 M arc h 2 0 1 8 
E u dr a C T N o:  2 0 1 7- 0 0 3 1 9 7- 1 3 
Cli nic al P h ase:  2 
A D o u ble- Bli n d, R a n d o mize d, Pl ace b o- C o ntr olle d, P h ase 2 St u d y t o 
E v al u ate t he S afet y, T oler a b ilit y a n d P h ar m ac o d y n a mics of 
I SI S 4 8 4 1 3 7 (I SI S- D G A T 2 R X , a n A ntise nse I n hi bit or of 
Di ac yl gl ycer ol Ac yltr a nsfer ase 2)  A d mi nistere d O nce- Wee kl y f or 
1 3 Wee ks o n He p atic Ste at osis i n  A d ult P atie nts wit h T y pe 2 
Di a betes 
Trial S p o ns or: 
I o nis P har mace uticals, I nc 
2 8 5 5 Gazelle C o urt 
Carls ba d, C A 9 2 0 1 0 
P h o ne + 0 1 7 6 0 9 3 1 9 2 0 0 
Fa x + 0 1 7 6 0 6 0 3 3 5 6 4 
Ke y S p o ns or C o ntact: 
 
E xec uti ve Direct or, Cli nical De vel o p me nt  
P h o ne 
 
Date: 
2 3 Marc h 2 0 1 8 
C o nfi de nti alit y St ate me nt 
T his d oc u me nt c o ntai ns c o nfi de ntia l i nf or mati o n of I o nis P har mace uticals, I nc. t hat m ust n ot be 
discl ose d t o a n y o ne ot her t ha n t h e reci pie nt st u d y staff a n d me m b ers of t he i n de pe n de nt et hics 
c o m mittee, i nstit uti o nal re vie w b oar d, or a ut h orize d re g ulat or y a ge ncies .  T his i nf or mati o n 
ca n n ot be use d f or a n y p ur p ose ot her t ha n t he e val uati o n or c o n d uct of t he cli nical i n vesti gati o n 
wit h o ut t he pri or writte n c o nse nt of I o nis P har mace uticals, I nc. 
P P D
P P D


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
4
 
P R O T O C O L SI G N A T U R E P A G E 
Pr ot oc ol N u m ber:  I SI S
 
4 8 4 1 3 7- C S 2
 
Pr ot oc ol Title: 
A D o u ble- Bli n d, Ra n d o mize d, Place b o- C o ntr olle d, P hase 2 St u d y t o 
E val uate t he Safet y, T olera bilit y a n d P har mac o d y na mics of I SI S 4 8 4 1 3 7 
(I SI S- D G A T 2R X , a n A ntise nse I n hi bit or of Diac yl gl ycer ol Ac yltra nsferase 
2)  A d mi nistere d O nce- Wee kl y f or 1 3 Wee ks o n He patic Steat osis i n A d ult
Patie nts wit h T y pe 2 Dia betes
A me n d me nt:  A me n d me nt
 
1
 
D ate: 
2 3 Marc h 2 0 1 8  
I here b y ac k n o wle d ge t hat I ha ve rea d a n d u n dersta n d t he attac he d cli nical pr ot oc ol, e ntitle d “ A 
D o u ble- Bli n d, Ra n d o mize d, Place b o- C o ntr olle d, P hase 2 St u d y t o E val uate t he Safet y, 
T olera bilit y a n d P har mac o d y na mics of I SI S 4 8 4 1 3 7 (I SI S- D G A T 2 R X , a n A ntise nse I n hi bit or of 
Diac yl gl ycer ol Ac yltra nsferase 2) A d mi nist ere d O nce- Wee kl y f or 1 3 Wee ks o n He patic 
Steat osis i n A d ult Patie nts wit h T y pe 2 Dia betes , ” date d 2 3 Marc h 2 0 1 8, a n d a gree t o c o n d uct 
t he st u d y as descri be d herei n. 
I a gree t o c o m pl y wit h t he I nter nati o nal Co nfere nce o n Har m o nizati o n Tri partite G ui deli ne o n 
G o o d Cli nical Practice ( E 6). 
I a gree t o e ns ure t hat t he c o nfi de ntial i nf or mati o n c o ntai ne d i n t his d oc u me nt will n ot be use d f or 
a n y p ur p ose ot her t ha n t he e val ua ti o n or c o n d uct of t he cli nical i n vesti gati o n wit h o ut t he pri or 
writte n c o nse nt of I o nis P har mace uticals, I nc.   
I n vesti gat or’s Si g nat ure 
I n vesti gat or’s Na me ( ple ase pri nt) 
Date ( D D M o nt h Y Y Y Y) 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
5
 
T A B L E O F C O N T E N T S 
P a ge 
P R O T O C O L SI G N A T U R E P A G E ............................................................................................. 4  
P R O T O C O L A M E N D M E N T...................................................................................................... 9  
P R O T O C O L S Y N O P SI S ........................................................................................................... 1 4  
S T U D Y D E SI G N A N D T R E A T M E N T S C H E M A .................................................................. 2 1  
S T U D Y G L O S S A R Y ................................................................................................................ .. 2 2 
1.
O B J E C TI V E S ................................................................................................................. 2 6  
1. 1
 Pri mar y
 
O bjecti ve(s)
 
...................................................................................................... 2 6 
1. 2
 Sec o n dar y
 
O bjecti ve(s)
 
.................................................................................................. 2 6  
1. 3
 E x pl orat or y
 
O bjecti ves
 
.................................................................................................. 2 6  
2. 
B A C K G R O U N D A N D R A TI O N A L E .......................................................................... 2 6  
2. 1  
O ver vie w of Disease ...................................................................................................... 2 6 
2. 2
 T hera pe utic
 
Rati o nale
 
.................................................................................................... 2 7 
2. 2. 1  
O ver vie w of Tar get ................................................................................................ 2 7 
2. 2. 2
 T hera pe utic
 
Rati o nale
 
............................................................................................. 2 8  
2. 3
 I SI S
 
4 8 4 1 3 7
 
............................................................................................................... .... 2 9 
2. 3. 1  
Mec ha nis m of Acti o n ............................................................................................. 2 9 
2. 3. 2
 C he mistr y
 
............................................................................................................... 2 9 
2. 3. 3
 Precli nical
 
E x perie nce
 
............................................................................................ 3 0  
2. 3. 4
 Cli nical
 
E x perie nce
 
................................................................................................ 3 1  
2. 4  
Rati o nale f or D ose a n d Sc he d ule of A d mi nistrati o n ..................................................... 3 2 
2. 5
 Ris k
 
Assess me nt
 
........................................................................................................... . 3 2 
3. 
E X P E RI M E N T A L P L A N .............................................................................................. 3 2  
3. 1
 St u d y
 
Desi g n
 
.............................................................................................................. .... 3 2 
3. 2  
N u m ber of St u d y Ce nters .............................................................................................. 3 3 
3. 3
 N u m ber
 
of
 
S u bjects
 
....................................................................................................... 3 3 
3. 4  
O verall St u d y D urati o n a n d F oll o w- u p ......................................................................... 3 3 
3. 4. 1
 Scree ni n g
 
a n d
 
R u n-I n
 
............................................................................................. 3 3  
3. 4. 2
 Treat me nt
 
............................................................................................................... . 3 3 
3. 4. 3
 P ost- Treat me nt
 
....................................................................................................... 3 3  
3. 5
 E n d- of- St u d y
 
.............................................................................................................. .... 3 3 
4.
S U B J E C T E N R O L L M E N T ........................................................................................... 3 4  
4. 1
 Scree ni n g
 
................................................................................................................. ...... 3 4 
4. 2
 Ra n d o mizati o n
 
............................................................................................................. .. 3 4 
4. 3  
Re place me nt of S u bjects ................................................................................................ 3 4 
4. 4  
U n bli n di n g of Treat me nt Assi g n me nt ........................................................................... 3 4 
5.
S U B J E C T E LI GI BI LI T Y .............................................................................................. 3 5  
5. 1
 I ncl usi o n
 
Criteria
 
........................................................................................................ ... 3 5 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
6
 
5. 2
 E xcl usi o n
 
Criteria
 
........................................................................................................ .. 3 6 
6.
S T U D Y P R O C E D U R E S ................................................................................................ 3 8  
6. 1
 St u d y
 
Sc he d ule
 
............................................................................................................ .. 3 8 
6. 1. 1  
Scree ni n g Peri o d ( Wee k - 6 t o Wee k - 5) ................................................................ 3 8 
6. 1. 2  
R u n-I n Peri o d ( Wee k - 4 t hr u Wee k - 1) .................................................................. 3 9 
6. 1. 2. 1  
Li ver M RI Assess me nt ( Wee k - 4 t o Wee k - 3) ................................................ 3 9 
6. 1. 2. 2  
R u n-I n Wee k - 1................................................................................................ 3 9 
6. 1. 3  
Treat me nt Peri o d ( Wee ks 1- 1 3) ............................................................................. 4 0 
6. 1. 4  
P ost- Treat me nt Peri o d ( P T 1- 1 3) ........................................................................... 4 1 
6. 2
 La b orat or y
 
Assess me nts
 
................................................................................................ 4 1  
6. 3  
Restricti o n o n t he Lifest yle of S u bjects ......................................................................... 4 2 
6. 3. 1
 C o ntrace pti o n
 
Re q uire me nts
 
.................................................................................. 4 2  
6. 3. 2
 Fasti n g
 
Re q uire me nts
 
............................................................................................. 4 2  
6. 3. 3
 Lifest yle
 
Restricti o ns
 
.............................................................................................. 4 2  
7. 
S T U D Y D R U G ................................................................................................................ 4 2  
7. 1  
St u d y Dr u g Descri pti o n ................................................................................................. 4 2 
7. 2  
Pac ka gi n g a n d La beli n g ................................................................................................. 4 3 
7. 3  
St u d y Dr u g Acc o u nta bilit y ............................................................................................ 4 3 
8. 
T R E A T M E N T O F S U B J E C T S ..................................................................................... 4 3  
8. 1  
St u d y Dr u g A d mi nistrati o n ............................................................................................ 4 3 
8. 2  
Ot her Pr ot oc ol- Re q uire d Dr u gs ..................................................................................... 4 3 
8. 3
 Ot her
 
Pr ot oc ol- Re q uire d
 
Treat me nt Pr oce d ures ............................................................ 4 3 
8. 4
 Treat me nt
 
Preca uti o ns
 
................................................................................................... 4 3  
8. 5  
Safet y M o nit ori n g R ules ................................................................................................ 4 3 
8. 5. 1  
Safet y M o nit ori n g R ules f or Li ver C he mistr y Tests .............................................. 4 4 
8. 5. 2  
Safet y M o nit ori n g R ules f o r Platelet C o u nt Res ults .............................................. 4 5 
8. 5. 3  
M o nit ori n g R ules f or Deteri orati n g Gl yce mic C o ntr ol .......................................... 4 6 
8. 6
 St o p pi n g
 
R ules
 
............................................................................................................ ... 4 6 
8. 6. 1  
St o p pi n g R ules f or Li ver C he mistr y Ele vati o ns ..................................................... 4 6 
8. 6. 2  
Te m p orar y St o p pi n g R ules f or Re nal F u ncti o n Test Res ults ................................. 4 7 
8. 6. 3  
St o p pi n g R ule f or Platelet C o u nt Res ults ............................................................... 4 7 
8. 6. 4  
St o p pi n g R ules f or D oc u me nte d Se vere H y p o gl yce mia ........................................ 4 8 
8. 7  
A dj ust me nt of Oral A nti dia betic Re gi me n f or S u bjects w it h Persiste nt  
H y per gl yce mic ............................................................................................................... 4 8  
8. 8  
Disc o nti n uati o n of St u d y Dr u g ...................................................................................... 4 8 
8. 9  
Wit h dra wal of S u bjects fr o m t he St u d y ......................................................................... 4 9 
8. 1 0  
C o nc o mita nt T hera p y a n d Pr oce d ures ........................................................................... 5 0 
8. 1 0. 1
 C o nc o mita nt
 
T hera p y
 
............................................................................................. 5 0  
8. 1 0. 2
 C o nc o mita nt
 
Pr oce d ures
 
......................................................................................... 5 1  
8. 1 1
 Treat me nt
 C o m plia nce
 
................................................................................................... 5 1  


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
7
 
9.
S E RI O U S A N D N O N- S E RI O U S A D V E R S E E V E N T R E P O R TI N G ...................... 5 1  
9. 1  
S p o ns or Re vie w of Safet y I nf or mati o n ......................................................................... 5 1 
9. 2
 Re g ulat or y
 
Re q uire me nts
 
.............................................................................................. 5 1  
9. 3
 Defi niti o ns
 
............................................................................................................... ...... 5 1 
9. 3. 1
 A d verse
 
E ve nt
 
........................................................................................................ 5 1  
9. 3. 2  
A d verse Reacti o n a n d S us pecte d A d verse Reacti o n .............................................. 5 2 
9. 3. 3  
Seri o us A d verse E ve nt ( S A E) ................................................................................ 5 2 
9. 4  
M o nit ori n g a n d Rec or di n g A d verse E ve nts ................................................................... 5 2 
9. 4. 1  
Seri o us A d verse E ve nts .......................................................................................... 5 2 
9. 4. 2  
N o n- Seri o us A d verse E ve nts .................................................................................. 5 3 
9. 4. 3  
E val uati o n of A d verse E ve nts ( Seri o us a n d N o n- Seri o us) .................................... 5 3 
9. 4. 3. 1  
Relati o ns hi p t o t he St u d y Dr u g ........................................................................ 5 3 
9. 4. 3. 2
 Se verit y
 
............................................................................................................ 5 4  
9. 4. 3. 3  
Acti o n Ta ke n wit h St u d y Dr u g ........................................................................ 5 4 
9. 4. 3. 4  
Treat me nt Gi ve n f or A d verse E ve nt ................................................................ 5 4 
9. 4. 3. 5  
O utc o me of t he A d verse E ve nt ........................................................................ 5 4 
9. 5  
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns .................................................................. 5 5 
9. 5. 1  
A b n or malities of La b orat or y Tests ......................................................................... 5 5 
9. 5. 2  
Presc he d ule d or Electi ve Pr oce d ures  or R o uti nel y Sc hed ule d Treat me nts ............ 5 5 
9. 5. 3
 D osi n g
 
Err ors
 
......................................................................................................... 5 5  
9. 5. 4  
C o ntrace pti o n a n d Pre g na nc y ................................................................................. 5 6 
1 0.
S T A TI S TI C A L C O N SI D E R A TI O N S .......................................................................... 5 6  
1 0. 1  
St u d y E n d p oi nts, S u bsets, a n d C o variates ..................................................................... 5 6 
1 0. 1. 1
 Safet y
 
E n d p oi nts
 
..................................................................................................... 5 6  
1 0. 1. 2  
Pri mar y P har mac o d y na mic E n d p oi nt ..................................................................... 5 7 
1 0. 1. 3
 Sec o n dar y
 
E n d p oi nts
 
.............................................................................................. 5 7  
1 0. 1. 4
 E x pl orat or y
 
E n d p oi nts
 
............................................................................................ 5 7  
1 0. 2  
Sa m ple Size C o nsi derati o ns ........................................................................................... 5 7 
1 0. 3
 P o p ulati o ns
 
.............................................................................................................. ....... 5 7 
1 0. 4  
Defi niti o n of Baseli ne .................................................................................................... 5 8 
1 0. 5
 I nteri m
 A nal ysis
 
......................................................................................................... .... 5 8 
1 0. 6  
Pla n ne d Met h o ds of A nal ysis ........................................................................................ 5 8 
1 0. 6. 1  
De m o gra p hic a n d Baseli ne C haracteristics ............................................................ 5 8 
1 0. 6. 2
 Safet y
 A nal ysis
 
....................................................................................................... 5 9 
1 0. 6. 3
 P har mac o ki netic
 A nal ysis
 
...................................................................................... 5 9  
1 0. 6. 4
 P har mac o d y na mic/ Efficac y
 A nal ysis
 
..................................................................... 5 9  
1 0. 6. 5
 A d diti o nal
 A nal yses
 
............................................................................................... 5 9  
1 1. 
I N V E S TI G A T O R’ S R E G U L A T O R Y O B LI G A TI O N S ............................................. 6 0  
1 1. 1
 I nf or me d
 C o nse nt
 
......................................................................................................... . 6 0 
1 1. 2  
Et hical C o n d uct of t he St u d y ......................................................................................... 6 0 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
8
 
1 1. 3  I n de pe n de nt Et hics C o m mittee/I nstit uti o nal Re vie w B oar d ......................................... 6 0 
1 1. 4
 S u bject
 C o nfi de ntialit y
 
.................................................................................................. 6 1 
1 2.
A D MI NI S T R A TI V E A N D L E G A L O B LI G A TI O N S ................................................ 6 1  
1 2. 1
 Pr ot oc ol
 A me n d me nts
 
.................................................................................................... 6 1  
1 2. 2
 St u d y
 Ter mi nati o n
 
........................................................................................................ . 6 1 
1 2. 3  
St u d y D oc u me ntati o n a n d St ora ge ................................................................................ 6 1 
1 2. 4
 St u d y
 M o nit ori n g
 
......................................................................................................... .. 6 2 
1 2. 5
 La n g ua ge
 
................................................................................................................. ....... 6 3 
1 2. 6  
C o m pe nsati o n f or I nj ur y ................................................................................................ 6 3  
1 3.
R E F E R E N C E S ................................................................................................................  6 4  
1 4.
A P P E N DI C E S ................................................................................................................. 6 7  
A p pe n di x A  
Sc he d ule of Pr oce d ures .................................................................................... 6 8 
A p pe n di x B  
List of La b orat or y A nal ytes ............................................................................. 7 3 
A p pe n di x C  
P K Sa m pli n g Sc he d ule .................................................................................... 7 5 
A p pe n di x D  
Gra di n g Scale f or A d verse E ve n ts Relati n g t o La b orat or y A b n or malities ...... 7 7 
T A B L E O F T A B L E S 
P a ge 
Ta ble 1  
St u d y Dr u g C haracteristics .................................................................................... 4 3 
Ta ble 2  
A d diti o nal La bs t o be Perf or me d i n t he E ve nt of a Platelet C o u nt 
< 7 5, 0 0 0/ m m 3 ......................................................................................................... 4 5 
T A B L E O F FI G U R E S 
P a ge 
Fi g ure 1  
Desi g n of C hi meric 2 ′- M O E P h os p h or ot hi oate Oli g o n ucle oti des 
( M O E- Ga p mer) ...................................................................................................... 3 0 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
9
 
P R O T O C O L A M E N D M E N T 
Pr ot oc ol N u m ber:  I SI S
 
4 8 4 1 3 7- C S 2
 
Pr ot oc ol Title:   
A D o u ble- Bli n d, Ra n d o mize d, Place b o- C o ntr olle d, P hase 2 St u d y t o 
E val uate t he Safet y, T olera bilit y a n d P har mac o d y na mics of I SI S 4 8 4 1 3 7 
(I SI S- D G A T 2R X , a n A ntise nse I n hi bit or of Diac yl gl ycer ol 
Ac yltra nsferase 2) A d mi nistere d O nce- Wee kl y f or 1 3 Wee ks o n He patic 
Steat osis i n A d ult Patie nts wit h T y pe 2 Dia betes  
A me n d me nt N u m ber:  1 
A me n d me nt D ate:   
2 3 Marc h 2 0 1 8 
T he p ur p ose of t his a me n d me nt is t o clarif y i n c o nsiste ncies wit hi n t h e pr ot oc ol a n d i ncl u de 
fle xi bilit y wit h pr ot oc ol pr oce d ures t o i m pr o ve o perati o nal l o gistics at t he st u d y ce nters.  T he 
o bjecti ves of t he st u d y re mai n u nc ha n ge d a n d t he u p dates d o n ot i m pact t he assess me nt of safet y, 
e x p os ure, o verall st u d y desi g n or efficac y asse ss me nts of I SI S 4 8 4 1 3 7 i n T 2 D patie nts wit h 
he patic steat osis. 
Als o, a d mi nistrati ve clarificat i o ns a n d c orrecti o ns f or t y p o grap hical err ors ha ve bee n ma de 
t hr o u g h o ut t he pr ot oc ol t o i m pr o ve t he o verall clarit y of t he ori gi nal pr ot oc ol, h o we ver, t hese 
c ha n ges d o n ot i m pact s u bject safet y, e x p os ure, or t he o verall st u d y desi g n. 
T he f oll o wi n g m o dificati o ns t o Pr ot oc ol I SI S  4 8 4 1 3 7- C S 2 ha ve bee n ma de. T he ta ble bel o w 
pr o vi des a list of c ha n ges t o t he pr ot oc ol: 
Pr ot o c ol S e cti o n 
D e s cri pti o n of C h a n g e 
R ati o n al e 
S y n o p si s: St u d y P o p ul ati o n ; 
S e cti o n 5. 1 
I n cl u si o n Crit eri a # 3; 
A p p e n di x A L e g e n d F o ot  
n ot e # 4 
F e m al e s m u st b e n o n- pr e g n a nt a n d n o n-
l a ct ati n g, a n d eit h er s ur gi c all y st eril e ( e. g., 
t u b al o c cl u si o n, h y st er e ct o m y, bil at er al 
s al pi n g e ct o m y, bil at er al o o p h or e ct o m y) or 
p o st- m e n o p a u s al ( d efi n e d a s 1 2 m o nt h s of 
s p o nt a n e o u s a m e n orr h e a i n f e m al e s > 
5 5 y e ar s of a g e or, i n f e m al e s ≤ 5 5 y e ar s, 
1 2 m o nt h s of s p o nt a n e o u s a m e n orr h e a  
wit h o ut a n alt er n ati v e m e di c al c a u s e a n d 
F S H l e v el s i n t h e p o st m e n o p a u s al r a n g e 
f or t h e l a b or at or y i n v ol v e d). 
D efi niti o n of p o st- m e n o p a u s al 
cl arifi e d f or c o n si st e n c y t hr o u g h o ut 
t h e pr ot o c ol. 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
1 0
 
Pr ot o c ol S e cti o n 
D e s cri pti o n of C h a n g e 
R ati o n al e 
S y n o p si s:  St u d y P o p ul ati o n ; 
S e cti o n 5. 1 
I n cl u si o n Crit eri a # 6 
S u bj e ct s m u st h a v e b e e n o n st a bl e m o n o 
t h er a p y or st a bl e c o m bi n ati o n t h er a p y of 
t h e f oll o wi n g or al a nti di a b eti c t h er a p y:  
m etf or mi n, s ulf o n yl ur e a ( S U), di p e pti d yl 
p e pti d a s e-I V ( D P PI V i n hi bit or) or s o di u m 
gl u c o s e li k e tr a n s p ort pr ot ei n 2 ( S G L T 2) 
i n hi bit or f or a mi ni m u m of 3 m o nt h s pri or t o 
s cr e e ni n g e v al u ati o n a n d will b e r e q uir e d t o 
c o nti n u e t h eir st a bl e d o s e of or al 
a nti di a b eti c t h er a p y t hr o u g h o ut t h e st u d y. 
T h e u s e of t hi a z oli di n e di o n e s ( e. g., 
pi o glit a z o n e, r o si glit a z o n e) a n d i nj e ct a bl e 
a nti di a b eti c t h er a p y i s n ot p er mitt e d ( e. g., 
i n s uli n, gl u c a g o n-li k e p e pti d e [ G L P 1 
a n al o g s] 
Cl arifi c ati o n of I n cl u si o n Crit eri a t h at 
c o m bi n ati o n di a b eti c t h er a p y i s 
a c c e pt a bl e. 
S y n o p si s: St u d y P o p ul ati o n ; 
S e cti o n 5. 2 
E x cl u si o n Crit eri a # 2  
All c e ntr al l a b or at or y  r e s ult s pri or t o D a y 1  
a s f oll o w s, or a n y ot h er cli ni c all y- si g nifi c a nt 
a b n or m aliti e s i n S cr e e ni n g l a b or at or y v al u e s 
t h at  w o ul d  r e n d er  a  s u bj e ct  u n s uit a bl e  f or  
i n cl u si o n: 
a.  Uri n e pr ot ei n/ cr e ati ni n e ( P/ C) r ati o 
> 0. 2 m g/ m g.  I n t h e e v e nt of P/ C r ati o 
a b o v e t hi s t hr e s h ol d eli gi bilit y m a y b e 
c o nfir m e d b y a q u a ntit ati v e t ot al uri n e 
pr ot ei n m e a s ur e m e nt of < 3 0 0 m g/ 
2 4- hr at S cr e e ni n g  
b.  P er si st e ntl y p o siti v e t e st (i n cl u di n g 
tr a c e) f or bl o o d o n uri n al y si s.  I n t h e 
e v e nt of a p o siti v e t e st eli gi bilit y m a y 
b e c o nfir m e d wit h uri n e mi cr o s c o p y 
s h o wi n g < 5 r e d bl o o d c ell s ( R B C) p er 
hi g h p o w er fi el d ( P er si st e ntl y p o siti v e 
d efi n e d a s 2 o ut of 3 t h at c a n b e 
c o nfir m e d d uri n g t h e R u n-I n P eri o d 
c.  S er u m cr e ati ni n e > u p p er li mit of 
n or m al ( U L N) 
d.  E sti m at e d gl o m er ul ar filtr ati o n r at e 
( G F R) < 6 0 m L/ mi n ( a s d et er mi n e d b y 
t h e C o c k cr oft- G a ult E q u ati o n f or 
cr e ati ni n e cl e ar a n c e) 
e.  Al a ni n e a mi n otr a n sf er a s e ( A L T) or 
a s p art at e a mi n otr a n sf er a s e ( A S T) 
> 1. 5 U L N 
f.  T ot al bilir u bi n > U L N 
g.  H a v e a c urr e nt or pr e vi o u s di a g n o si s 
of Gil b ert’ s di s e a s e at S cr e e ni n g   
h.  Pl at el et  c o u nt < 1 7 0, 0 0 0/ m m 3   
( < 1 7 0 X 1 09 / L) 
Cl arifi c ati o n t h at a ll r e s ult s pri or t o 
D a y 1 m u st m e et eli gi bilit y crit eri a. 
 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
1 1
 
Pr ot o c ol S e cti o n 
D e s cri pti o n of C h a n g e 
R ati o n al e 
S y n o p si s: St u d y P o p ul ati o n ; 
S e cti o n 5. 2 
E x cl u si o n Crit eri a # 6  
W a s: 
S u bj e ct s o n li pi d l o w eri n g m e di c ati o n s m u st 
b e o n a st a bl e d o s e a n d r e gi m e n f or ≥ 
3 m o nt h s pri or t o S cr e e ni n g.  S u bj e ct s 
r e c ei vi n g tr e at m e nt wit h st ati n s s h o ul d b e 
wit hi n t h e d o s e l e v el s li st e d b el o w.  Ot h er 
st ati n r e gi m e n s s h o ul d b e di s c u s s e d a n d 
a p pr o v e d wit h t h e S p o n s or M e di c al M o nit or 
or d e si g n e e: 
•   Si m v a st ati n, pr a v a st ati n, at or v a st ati n 
a n d fl u v a st ati n at ≤ 4 0 m g/ d a y 
•   L o v a st ati n or r o s u v a st ati n at ≤ 
2 0 m g/ d a y 
•  Pit a v a st ati n  u p t o 4 m g/ d a y 
I S: 
S u bj e ct s o n H M G- C o A r e d u ct a s e 
i n hi bit or s m e di c ati o n s (‘ st ati n s’) m u st 
b e o n a st a bl e d o s e a n d r e gi m e n f or ≥ 
3 m o nt h s pri or t o S cr e e ni n g.  Ot h er li pi d 
l o w eri n g t h er a pi e s i n cl u di n g fi s h oil s or 
pr e s cri pti o n li pi d-r e g ul ati n g dr u g s ( e. g., 
bil e- a ci d s e q u e st eri n g r e si n s, fi br at e s 
a n d t h eir d eri v ati v e s a n d e z eti mi b e) ar e 
n ot p er mitt e d.  Alt er n at e li pi d l o w eri n g 
r e gi m e n s s h o ul d b e di s c u s s e d a n d 
a p pr o v e d wit h t h e S p o n s or M e di c al 
M o nit or or d e si g n e e.  
I n cl u si o n Crit eri a u p d at e d t o e n s ur e 
st ati n t h er a p y r e q uir e m e nt s ar e 
c o n si st e nt wit h c urr e nt st a n d ar d of 
c ar e ( T h e mi ni m u m d o s e s c a n b e 
hi g h er t o r e a c h g o al s fr o m n e w 
g ui d eli n e s) a n d crit eri a e x p a n d e d t o 
i n cl u d e r e stri cti o n s alr e a d y o utli n e d 
i n t h e Di s all o w e d C o n c o mit a nt 
T h er a p y s e cti o n.  
S y n o p si s: St u d y P o p ul ati o n ; 
S e cti o n 5. 2  
E x cl u si o n Crit eri a # 1 7  
C o nfir m e d r e d u cti o n i n b o d y w ei g ht of 2  k g 
( 4. 4 l b s) at t h e R u n-I n Vi sit ( W e e k- 1) 
c o m p ar e d t o b o d y w ei g ht t a k e n at 
S cr e e ni n g  
T h e " ±" si g n w a s a n err or, h a s b e e n 
r e m o v e d. 
S y n o p si s: St u d y Vi sit 
S c h e d ul e a n d Pr o c e d ur e s ;  
S e cti o n 6. 1. 2. 2. 2  
S C T ol er a bilit y 
T o r e d u c e t h e b ur d e n of u n n e c e s s ar y 
pr o c e d ur e s o n s u bj e ct s w h o s u b s e q u e ntl y 
el e ct n ot t o p arti ci p at e i n t h e st u d y or 
c o nti n u e wit h st u d y pr o c e d ur e s, all s u bj e ct s 
will c o nfir m t ol er a n c e of S C a d mi ni str ati o n 
of 0. 9 % s ali n e pri or t o r a n d o mi z ati o n d uri n g 
t h e S cr e e ni n g or t h e R u n-I n- P eri o d .  T hi s 
i nj e cti o n will f oll o w t h e s a m e pr o c e d ur e s a s 
i nj e cti o n s of t h e St u d y Dr u g (I SI S 4 8 4 1 3 7 
or pl a c e b o) d uri n g t h e tr e at m e nt p eri o d. 
Cl arifi e d t h at t hi s pr o c e d ur e c a n 
t a k e pl a c e n ot o nl y at S cr e e ni n g, 
b ut at a n y ti m e d uri n g S cr e e ni n g or 
R u n-I n t o i m pr o v e o p er ati o n al 
l o gi sti c s at t h e st u d y c e nt er. 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
1 2
 
Pr ot o c ol S e cti o n 
D e s cri pti o n of C h a n g e 
R ati o n al e 
S e cti o n 6. 1. 4 P o st -
Tr e at m e nt P eri o d ( P T 1- 1 3 );  
A p p e n di x A 
N ot e s R e g ar di n g Ti mi n g of  
M RI A s s e s s m e nt s 
A P o st- Tr e at m e nt M RI ( S e e S e cti o n 6. 1. 2. 1 ) 
t o a s s e s s li v er f at c o nt e nt a n d v ol u m e will 
o c c ur d uri n g P T 2 Vi sit ( 2 w e e k s aft er l a st 
d o s e) f or all s u bj e ct s c o m pl eti n g 1 3 d o s e s.  
F or s u bj e ct s w h o t er mi n at e fr o m t h e 
tr e at m e nt p eri o d e arl y, t h e ti mi n g a n d 
c o n d u ct of t h e M RI i n  t h e P o st- Tr e at m e nt 
P eri o d will b e a dj u st e d a s f oll o w s ( +/- 7- d a y 
wi n d o w).  T h e ti mi n g of t h e P o st-
Tr e at m e nt M RI s h o ul d b e di s c u s s e d wit h 
t h e I o ni s St u d y T e a m b ut m a y b e 
s c h e d ul e d a s f oll o w s :  
i.  
S u bj e ct r e c ei v e d 4 or l e s s d o s e s, t h e 
P o st- Tr e at m e nt M RI A s s e s s m e nt will 
n ot b e r e q uir e d 
ii.  
S u bj e ct r e c ei v e d 5- 9 d o s e s, t h e P o st-
Tr e at m e nt M RI A s s e s s m e nt will o c c ur 
2 w e e k s aft er l a st d o s e at t h e P T 2 Vi sit 
iii.  
S u bj e ct r e c ei v e d 1 0- 1 2 d o s e s, t h e 
P o st- Tr e at m e nt M RI A s s e s s m e nt will 
b e s c h e d ul e d a s f oll o w s:  
•   If s u bj e ct r e c ei v e d 1 0 d o s e s, s u bj e ct 
m o v e s i nt o P o st- Tr e at m e nt P eri o d, 
t h e M RI will b e c o n d u ct e d 5 w e e k s 
aft er t h e l a st d o s e  
•   If s u bj e ct r e c ei v e d 1 1 d o s e s, s u bj e ct 
m o v e s i nt o P o st- Tr e at m e nt P eri o d, 
t h e M RI will b e c o n d u ct e d 4 w e e k s 
aft er t h e l a st d o s e  
If s u bj e ct r e c ei v e d 1 2 d o s e s, s u bj e ct m o v e s 
i nt o P o st- Tr e at m e nt P eri o d, t h e M RI will b e 
c o n d u ct e d 3 w e e k s aft er t h e l a st d o s e 
T h e ti mi n g of t h e P o st Tr e at m e nt 
M RI s h o ul d b e di s c u s s e d wit h I o ni s 
if t h e p ati e nt di s c o nti n u e s tr e at m e nt 
aft er 1 0, 1 1 or 1 2 d o s e s.  L a n g u a g e 
w a s a d d e d t o i m pr o v e o p er ati o n al 
l o gi sti c s at t h e st u d y c e nt er. 
S e cti o n 8. 1 0. 1 
All o w e d C o n c o mit a nt  
T h er a p y 
A n y m e di c ati o n s d e e m e d n e c e s s ar y b y t h e 
I n v e sti g at or ar e all o w e d e x c e pt t h o s e li st e d 
i n t h e di s all o w e d c o n c o mit a nt t h er a p y.  I n 
t h e P o st- Tr e at m e nt P eri o d, a nti- di a b eti c 
a g e nt s m a y b e a d d e d or alt er e d f or 
d et eri or ati n g gl y c e mi c c o ntr ol i n 
c o n s ult ati o n wit h t h e I n v e sti g at or a n d 
S p o n s or M e di c al M o nit or.  
A d diti o n al l a n g u a g e i n c or p or at e d t o 
s p e cif y t h at c h a n g e s i n a nti di a b eti c 
t h er a p y ar e p er mitt e d i n t h e p o st 
tr e at m e nt p eri o d i n pr e s e n c e of 
d et eri or ati n g gl u c o s e c o ntr ol. 
 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
1 3
 
Pr ot o c ol S e cti o n 
D e s cri pti o n of C h a n g e 
R ati o n al e 
S e cti o n 8. 1 0. 1 
Di s all o w e d C o n c o mit a nt  
T h er a p y 
W A S: 
U s e of a nti c o a g ul a nt s/ a nti pl at el et a g e nt s 
( e. g., w arf ari n, h e p ari n, d a bi g atr a n, 
ri v ar o x a b a n, cl o pi d o gr el) t h e n o n- st er oi d al 
a nti-i nfl a m m at or y dr u g ( N S AI D) ni m e s uli d e 
or a n y ot h er dr u g i nfl u e n ci n g c o a g ul ati o n 
( e x c e pt l o w d o s e a s piri n < 1 6 0 m g/ d a y a n d 
ot h er s h ort a cti n g N S AI D S wit h a h alf-lif e 
< 2 0 h o ur s).  T h e s e a g e nt s w er e t o b e 
st a bl e pri or t o t h e fir st d o e s of St u d y Dr u g. 
I S: 
N e w or i n cr e a s e d  u s e of 
a nti c o a g ul a nt s/ a nti pl at el et a g e nt s ( e. g., 
w arf ari n, h e p ari n, d a bi g atr a n, ri v ar o x a b a n, 
cl o pi d o gr el  u nl e s s t h e d o s e h a s b e e n 
st a bl e f or 4 w e e k s pri or t o t h e fir st d o s e 
of St u d y Dr u g a n d r e g ul ar cli ni c al 
m o nit ori n g i s p erf or m e d; u s e of t h e n o n-
st er oi d al a nti-i nfl a m m at or y dr u g ( N S AI D) 
ni m e s uli d e or a n y ot h er dr u g i nfl u e n ci n g 
c o a g ul ati o n ( e x c e pt l o w d o s e a s piri n 
< 1 6 0 ◦m g/ d a y a n d ot h er s h ort a cti n g 
N S AI D S wit h a h alf-lif e < 2 0 h o ur s) ar e n ot 
p er mitt e d w hil e o n St u d y Dr u g.  
L a n g u a g e u p d at e d f or c o n si st e n c y 
b et w e e n eli gi bilit y crit eri a a n d 
Di s all o w e d C o n c o mit a nt 
M e di c ati o n s. 
S e cti o n 1 0. 6. 2 
S af et y A n al y si s  
R E M O V E D: 
I n ci d e n c e of bl e e di n g e v e nt s i n cl u di n g t h e 
f oll o wi n g will b e t a b ul at e d b y tr e at m e nt f or 
M B, C R N M B, mi n or bl e e di n g, a n d 
c o m bi n ati o n of m aj or a n d cli ni c all y-r el e v a nt 
n o n m aj or bl e e di n g.  
R e m o v e d fr o m S af et y A n al y si s 
s e cti o n a n d will b e a d dr e s s e d 
f urt h er i n t h e St ati sti c al A n al y si s 
Pl a n, if a p pli c a bl e. 
A p p e n di x A  
S c h e d ul e of Pr o c e d ur e s  
Uri n al y si s (i n cl u di n g P/ C) r e m o v e d at 
W e e k- 1  
R e m o v e d t o d e cr e a s e st u d y b ur d e n 
o n s u bj e ct a n d st u d y c e nt er.  F or 
m o st s u bj e ct s o nl y 1 uri n al y si s 
pr o c e d ur e will b e r e q uir e d d uri n g 
S cr e e ni n g. 
A p p e n di x A 
L e g e n d F o ot n ot e # 5  
W o m e n w h o ar e n ot s ur gi c all y st eril e.   
Pr e g n a n c y t e st s aft er s cr e e ni n g ar e 
n ot r e q uir e d f or p o st- m e n o p a u s al or 
s ur gi c all y st eril e s u bj e ct s d uri n g t h e 
st u d y a n d h a v e b e e n r e m o v e d. 
A p p e n di x A  
L e g e n d F o ot n ot e # 1 5 
Tri pli c at e E C G st u d y pr o c e d ur e will c o n si st 
of 3 E C G s wit h 2 mi n ut e s b et w e e n e a c h 
E C G (- 1/ + 2 mi n s wi n d o w b et w e e n e a c h 
a s s e s s m e nt), e x c e pt a s n ot e d f or 
f o ot n ot e # 6 w h er e pr e- d o s e, 1 hr s a n d 
2 hr s p o st- E C G s ar e t o b e p erf or m e d  
W or di n g a d d e d t o cl arif y t h e 
n u m b er of E C G s t o b e p erf or m e d 
d uri n g t h e st u d y. 
 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
1 4
 
P R O T O C O L S Y N O P SI S 
Pr ot o c ol Titl e 
A D o u bl e- Bli n d, R a n d o mi z e d, Pl a c e b o- C o ntr oll e d, P h a s e 2 St u d y t o 
E v al u at e t h e S af et y, T ol er a bilit y a n d P h ar m a c o d y n a mi c s of I SI S 4 8 4 1 3 7 
(I SI S- D G A T 2R X , a n A nti s e n s e I n hi bit or of Di a c yl gl y c er ol A c yltr a n sf er a s e 2) 
A d mi ni st er e d O n c e- W e e kl y f or 1 3 W e e k s o n H e p ati c St e a t o si s i n A d ult 
P ati e nt s wit h T y p e 2 Di a b et e s 
St u d y P h a s e 
2 
I n di c ati o n 
H e p ati c St e at o si s i n t y p e 2 di a b et e s ( T 2 D M) 
Pri m ar y O bj e cti v e( s) 
T o e v al u at e t h e s af et y a n d t ol er a bilit y of I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
s u b c ut a n e o u s ( S C) i nj e cti o n i n a d ult s u bj e ct s wit h T 2 D M. 
T o e v al u at e t h e p h ar m a c o d y n a mi c eff e ct s of I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
S C i nj e cti o n o n t h e a b s ol ut e r e d u cti o n of li v er f at ( a s s e s s e d b y m a g n eti c 
r e s o n a n c e i m a gi n g [ M RI] pr ot o n d e n sit y f at fr a cti o n [ P D F F]) i n a d ult s u bj e ct s 
wit h T 2 D M. 
S e c o n d ar y O bj e cti v e( s) 
T o e v al u at e t h e p h ar m a c o d y n a mi c eff e ct s of I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
S C i nj e cti o n o n li v er f at ( p er c e nt r el ati v e r e d u cti o n a n d p er c e nt of s u bj e ct s 
wit h ≥ 3 0 % r el ati v e r e d u cti o n) a s s e s s e d b y M RI- P D F F. 
T o e v al u at e t h e p h ar m a c o d y n a mi c eff e ct s of I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
S C i nj e cti o n o n li v er v ol u m e a s s e s s e d b y M RI- P D F F. 
T o e v al u at e t h e p h ar m a c o d y n a mi c eff e ct s of I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
S C i nj e cti o n o n pl a s m a li p o pr ot ei n pr ofil e (tri gl y c eri d e s [ T G], t ot al c h ol e st er ol, 
l o w d e n sit y li p o pr ot ei n c h ol e st er ol [ L D L- C], a p oli p o pr ot ei n B [ a p o B], v er y l o w-
d e n sit y li p o pr ot ei n s [ V L D L], hi g h d e n sit y li p o pr ot ei n [ H D L] a n d N o n- H D L). 
T o e v al u at e t h e p h ar m a c o d y n a mi c eff e ct s of I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
S C i nj e cti o n o n i n s uli n r e si st a n c e (I R) a n d gl u c o s e c o ntr ol (i n s uli n, gl u c o s e, 
h o m e o st ati c m o d el a s s e s s m e nt-i n s uli n r e si st a n c e [ H O M A-I R], h e m o gl o bi n 
A 1 c [ H b A 1 c]). 
E x pl or at or y O bj e cti v e( s) 
T o e v al u at e t h e p h ar m a c o d y n a mi c eff e ct s of I SI S 4 8 4 1 3 7 o n p ot e nti al 
bi o m ar k er s of D G A T 2 a cti vit y, ( e. g ., st e ar o yl- C o A d e s at ur a s e- 1 [ S C D- 1]) a n d 
bi o m ar k er s of h e p ati c i nfl a m m ati o n ( e. g ., c yt o k er ati n 1 8 ( C K 1 8), h a pt o gl o bi n) 
St u d y D e si g n 
R a n d o mi z e d, d o u bl e- bli n d, pl a c e b o c o ntr oll e d, m ulti- c e nt er 
N u m b er of S u bj e ct s 
A p pr o xi m at el y 4 5 p ati e nt s ar e pl a n n e d t o  b e r a n d o mi z e d i n a 2: 1 r ati o t o 
r e c ei v e S C tr e at m e nt wit h eit h er I SI S 4 8 4 1 3 7 or pl a c e b o 
St u d y P o p ul ati o n 
I n cl u si o n Crit eri a 
1.  M u st h a v e gi v e n writt e n i nf or m e d c o n s e nt ( si g n e d a n d d at e d) a n d a n y 
a ut h ori z ati o n s r e q uir e d b y l o c al l a w a n d b e a bl e t o c o m pl y wit h all st u d y 
r e q uir e m e nt s 
2.  M al e s or f e m al e s.  A g e d 1 8 t o 7 5, i n cl u si v e, at t h e ti m e of i nf or m e d 
c o n s e nt 
3.  F e m al e s m u st b e n o n- pr e g n a nt a n d n o n- l a ct ati n g, a n d eit h er s ur gi c all y 
st eril e ( e. g., t u b al o c cl u si o n, h y st er e ct o m y, bil at er al s al pi n g e ct o m y, 
bil at er al o o p h or e ct o m y) or p o st- m e n o p a u s al ( d efi n e d a s 1 2 m o nt h s of 
s p o nt a n e o u s a m e n orr h e a i n f e m al e s > 5 5 y e ar s of a g e or, i n f e m al e s 
≤ 5 5 y e ar s, 1 2 m o nt h s of s p o nt a n e o u s a m e n orr h e a wit h o ut a n 
alt er n ati v e m e di c al c a u s e a n d F S H l e v el s i n t h e p o st m e n o p a u s al r a n g e 
f or t h e l a b or at or y i n v ol v e d). 
M al e s m u st b e s ur gi c all y st eril e, a b sti n e nt * or, if e n g a g e d i n s e x u al 
r el ati o n s wit h a f e m al e of c hil d- b e ari n g p ot e nti al, t h e s u bj e ct m u st b e 
u si n g a n a c c e pt a bl e c o ntr a c e pti v e m et h o d (r ef er t o S e cti o n 6. 3. 1 ) fr o m 
t h e ti m e of si g ni n g t h e i nf or m e d c o n s e nt f or m u ntil at l e a st 1 3 w e e k s 
aft er t h e l a st d o s e of St u d y Dr u g (I SI S 4 8 4 1 3 7 or pl a c e b o) 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
1 5
 
P R O T O C O L S Y N O P SI S C o nti n ue d 
St u d y P o p ul ati o n C o nti n u e d  I n cl u si o n
 
Crit eri a
 C o nti n u e d 
* A b sti n e n c e i s o nl y a c c e pt a bl e a s tr u e a b sti n e n c e, i. e., w h e n t hi s i s i n 
li n e wit h t h e pr ef err e d a n d u s u al life st yl e of t h e p ati e nt.  P eri o di c 
a b sti n e n c e ( e. g., c al e n d ar, o v ul ati o n, s y m pt ot h er m al, p o st- o v ul ati o n 
m et h o d s), d e cl ar ati o n of a b sti n e n c e f or t h e d ur ati o n of a tri al a n d 
wit h dr a w al ar e n ot a c c e pt a bl e m et h o d s of c o ntr a c e pti o n 
4.  B o d y M a s s I n d e x ( B MI) ≥ 2 7. 0 - ≤ 3 9. 0 k g/ m2 at S cr e e ni n g 
5.  Di a g n o si s of T 2 D M wit h a n H b A 1 c ≥ 7. 3 % a n d ≤ 9. 5 % at S cr e e ni n g 
6.  S u bj e ct s m u st h a v e b e e n o n st a bl e m o n o t h er a p y or st a bl e 
c o m bi n ati o n t h er a p y of t h e f oll o wi n g or al a nti di a b eti c t h er a p y:  
m etf or mi n, s ulf o n yl ur e a ( S U), di p e pti d yl p e pti d a s e-I V ( D P PI V i n hi bit or) 
or s o di u m gl u c o s e li k e tr a n s p ort pr ot ei n 2 ( S G L T 2) i n hi bit or f or a 
mi ni m u m of 3 m o nt h s pri or t o S cr e e ni n g e v al u ati o n a n d will b e r e q uir e d 
t o c o nti n u e t h eir st a bl e d o s e of or al a nti di a b eti c t h er a p y t hr o u g h o ut t h e 
st u d y.  T h e u s e of t hi a z oli di n e di o n e s  ( e. g., pi o glit a z o n e, r o si glit a z o n e) 
a n d i nj e ct a bl e a nti di a b eti c t h er a p y i s n ot p er mitt e d ( e. g., i n s uli n, 
gl u c a g o n-li k e p e pti d e [ G L P 1 a n al o g s]) 
7. ≥ 1 0 % li v er f at a s a s s e s s e d b y M RI- P D F F pri or t o r a n d o mi z ati o n 
8.  St a bl e b o d y w ei g ht (i. e., n ot v ar yi n g b y > 5 % f or at l e a st 3 m o nt h s) 
b ef or e S cr e e ni n g 
9.  A gr e e t o m ai nt ai n c urr e nt di et a n d e x er ci s e r e gi m e n 
1 0.  A gr e e t o a b st ai n fr o m al c o h oli c b e v er a g e s f or at l e a st 4 8 h o ur s pri or t o 
cli ni c vi sit s a n d n ot i n cr e a s e al c o h ol c o n s u m pti o n d uri n g t h e st u d y 
E x cl u si o n Crit eri a 
1.  Cli ni c all y- si g nifi c a nt a b n or m aliti e s i n m e di c al hi st or y ( e. g., pr e vi o u s 
a c ut e c or o n ar y s y n dr o m e wit hi n 6 m o nt h s of S cr e e ni n g, m aj or s ur g er y 
wit hi n 3 m o nt h s of S cr e e ni n g) or p h y si c al e x a mi n ati o n 
2.  All c e ntr al l a b or at or y r e s ult s pri o r t o D a y 1 a s f oll o w s, or a n y ot h er 
cli ni c all y- si g nifi c a nt a b n or m aliti e s i n S cr e e ni n g l a b or at or y v al u e s t h at 
w o ul d r e n d er a s u bj e ct u n s uit a bl e f or i n cl u si o n: 
a.  Uri n e pr ot ei n/ cr e ati ni n e ( P/ C) r ati o > 0. 2 m g/ m g.  I n t h e e v e nt of 
P/ C r ati o a b o v e t hi s t hr e s h ol d eli gi bilit y m a y b e c o nfir m e d b y a 
q u a ntit ati v e t ot al uri n e pr ot ei n m e a s ur e m e nt of < 3 0 0 m g/ 2 4- hr at 
S cr e e ni n g 
b.  P er si st e ntl y p o siti v e t e st (i n cl u di n g tr a c e) f or bl o o d o n uri n al y si s.  I n 
t h e e v e nt of a p o siti v e t e st eli gi bilit y m a y b e c o nfir m e d wit h uri n e 
mi cr o s c o p y s h o wi n g < 5 r e d bl o o d c ell s ( R B C) p er hi g h p o w er fi el d 
( P er si st e ntl y p o siti v e d efi n e d a s 2 o ut of 3 c a n b e c o nfir m e d d uri n g 
t h e R u n-I n P eri o d 
c.  S er u m cr e ati ni n e > u p p er li mit of n or m al ( U L N) 
d.  E sti m at e d gl o m er ul ar filtr ati o n r at e ( G F R) < 6 0 m L/ mi n ( a s 
d et er mi n e d b y t h e C o c k cr oft- G a ult E q u ati o n f or cr e ati ni n e 
cl e ar a n c e) 
e.  Al a ni n e a mi n otr a n sf er a s e ( A L T ) or a s p art at e a mi n otr a n sf er a s e 
( A S T) > 1. 5 U L N 
f.  T ot al bilir u bi n > U L N 
g.  H a v e a c urr e nt or pr e vi o u s di a g n o si s of Gil b ert’ s di s e a s e at 
S cr e e ni n g  
h.  Pl at el et  c o u nt < 1 7 0, 0 0 0/ m m 3  ( < 1 7 0 X 1 09 / L) 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
1 6
 
P R O T O C O L S Y N O P SI S C o nti n ue d  
St u d y P o p ul ati o n C o nti n u e d 
E x cl u si o n Crit eri a C o nti n u e d 
3.  S h o w e vi d e n c e of u n c orr e ct e d h y p ot h yr oi di s m or h y p ert h yr oi di s m 
h or m o n e r e s ult s at S cr e e ni n g.  S u bj e ct s r e c ei vi n g d o s e- st a bl e t h yr oi d 
r e pl a c e m e nt t h er a p y f or at l e a st 3 m o nt h s pri or t o S cr e e ni n g will b e 
all o w e d t o p arti ci p at e a s l o n g a s t h yr oi d t e st s ( T S H/ T 3/ T 4) s h o w t h at 
s u bj e ct i s e ut h yr oi d 
4.  Hi st or y of s oli d or g a n tr a n s pl a nt ati o n or r e n al di al y si s 
5.  Cli ni c all y- si g nifi c a nt  c o m pli c ati o n s  of di a b et e s ( e. g., hi st or y of p ai nf ul 
n e ur o p at h y, n e p hr o p at h y, pr olif er ati v e r eti n o p at h y a n d/ or f o ot ul c er s) 
6.  S u bj e ct s o n H M G- C o A r e d u ct a s e i n hi bit or s m e di c ati o n s (‘ st ati n s’) m u st 
b e o n a st a bl e d o s e a n d r e gi m e n f or ≥ 3 m o nt h s pri or t o S cr e e ni n g. 
Ot h er li pi d l o w eri n g t h er a pi e s i n cl u di n g fi s h oil s or pr e s cri pti o n li pi d-
r e g ul ati n g dr u g s ( e. g., bil e- a ci d s e q u e st eri n g r e si n s, fi br at e s a n d t h eir 
d eri v ati v e s a n d e z eti mi b e) ar e n ot p er mitt e d. Alt er n at e li pi d l o w eri n g 
r e gi m e n s s h o ul d b e di s c u s s e d a n d a p pr o v e d wit h t h e S p o n s or M e di c al 
M o nit or or d e si g n e e  
7.  K n o w n hi st or y of or e vi d e n c e of li v er di s e a s e wit h a p o siti v e t e st f or 
h u m a n i m m u n o d efi ci e n c y vir u s ( HI V), h e p atiti s C ( H C V) or c hr o ni c 
h e p atiti s B ( H B V) or c hr o ni c li v er di s e a s e ot h er t h a n N A S H i n cl u di n g 
al c o h oli c li v er di s e a s e, Wil s o n’ s di s e a s e, h e m o c hr o m at o si s, or ir o n 
o v erl o a d, Al p h a- 1- a ntitr y p si n ( A 1 A T) d efi ci e n c y, pri or k n o w n dr u g-
i n d u c e d li v er i nj ur y, k n o w n or s u s p e ct e d h e p at o c ell ul ar c ar ci n o m a 
( H C C), c urr e nt pl a c e m e nt o n a li v er tr a n s pl a nt li st, or M E L D s c or e 
> 1 2, e st a bli s h e d fi br o si s ≥ St a g e 3 fi br o si s ( S c al e 0- 4) or a n y cirr h o si s 
8.  M ali g n a n c y wit hi n 5 y e ar s, e x c e pt f or b a s al or s q u a m o u s c ell 
c ar ci n o m a of t h e s ki n or c ar ci n o m a i n sit u of t h e c er vi x t h at h a s b e e n 
s u c c e s sf ull y tr e at e d.  S u bj e ct s wit h a hi st or y of ot h er m ali g n a n ci e s t h at 
h a v e b e e n tr e at e d wit h c ur ati v e i nt e nt a n d w hi c h h a v e n o r e c urr e n c e 
wit hi n 5 y e ar s m a y al s o b e eli gi bl e if a p pr o v e d b y t h e S p o n s or M e di c al 
M o nit or 
9.  Tr e at m e nt wit h a n ot h er i n v e sti g ati o n al dr u g, bi ol o gi c al a g e nt, or d e vi c e 
wit hi n 1 m o nt h of S cr e e ni n g, or 5 h alf-li v e s of i n v e sti g ati o n al a g e nt, 
w hi c h e v er i s l o n g er 
1 0. Tr e at m e nt wit h a n y n o n- I O N- or I SI S- oli g o n u cl e oti d e (i n cl u di n g s m all 
i nt erf eri n g ri b o n u cl ei c a ci d [ si R N A]) at a n y ti m e or pri or tr e at m e nt wit h 
a n I O N- or I SI S- oli g o n u cl e oti d e wit hi n 9 m o nt h s of S cr e e ni n g.  
S u bj e ct s w h o h a v e pr e vi o u sl y r e c ei v e d o nl y a si n gl e- d o s e of a n 
I SI S- oli g o n u cl e oti d e a s p art of a cli ni c al st u d y m a y b e i n cl u d e d a s l o n g 
a s a d ur ati o n of ≥ 4 m o nt h s h a s el a p s e d si n c e d o si n g 
1 1. R e c e nt hi st or y of, or c urr e nt dr u g or al c o h ol a b u s e.  R e g ul ar a n d 
e x c e s si v e u s e of al c o h ol wit hi n 6 m o nt h s pri or t o S cr e e ni n g 
( > 7 dri n k s/ w e e k f or f e m al e s, > 1 4 dri n k s/ w e e k f or m al e s ( 1 dri n k = 
5 o u n c e s ( 1 5 0 m L) of wi n e or 1 2 o u n c e s ( 3 6 0 m L) of b e er or 
1. 5 o u n c e s ( 4 5 m L) of h ar d li q u or), or u s e of s oft dr u g s ( s u c h a s 
m arij u a n a) wit hi n 3 m o nt h s pri or t o S cr e e ni n g, or h ar d dr u g s ( s u c h a s 
c o c ai n e a n d p h e n c y cli di n e [ P C P]) wit hi n 1- y e ar pri or t o S cr e e ni n g, or 
p o siti v e uri n e dr u g s cr e e n f or t h e s e dr u g s at S cr e e ni n g 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
1 7
 
P R O T O C O L S Y N O P SI S C o nti n ue d 
St u d y P o p ul ati o n C o nti n u e d  E x cl u si o n
 
Crit eri a
 C o nti n u e d 
1 2. C o n c o mit a nt m e di c ati o n r e stri cti o n s: 
a.  U s e of a g e nt s (i n cl u di n g h er b al  or o v er-t h e c o u nt er w ei g ht l o s s 
pr e p ar ati o n s) or m e di c ati o n s k n o w n t o si g nifi c a ntl y i m p a ct b o d y 
w ei g ht wit hi n 3 m o nt h s pri or ( e. g., si b utr a mi n e, p h e n et a mi n e a n d 
orli st at) 
b.  c hr o ni c u s e of s y st e mi c c orti c o st er oi d s 
c.  ot h er a nti di a b eti c m e di c ati o n s n ot o utli n e d i n I n cl u si o n Crit eri a # 6 
d.  ot h er m e di c ati o n s, p er I n v e sti g at or, k n o w n t o c a u s e li v er t o xi cit y 
( e. g., c hr o ni c a c et a mi n o p h e n u s e) or st e at o si s ( e. g., a mi o d ar o n e, 
m et h otr e x at e, t a m o xif e n, c ar b a m a z e pi n e) 
e.  U s e of a nti c o a g ul a nt/ a nti pl at el e t a g e nt s ( e. g., w arf ari n, h e p ari n, 
d a bi g atr a n, ri v ar o x a b a n, cl o pi d o gr el) u nl e s s t h e d o s e h a s b e e n 
st a bl e f or 4 w e e k s pri or t o t h e fir st d o s e of St u d y Dr u g a n d r e g ul ar 
cli ni c al m o nit ori n g i s p erf or m e d, u s e of t h e n o n- st er oi d al 
a nti-i nfl a m m at or y dr u g ( N S AI D) ni m e s uli d e or a n y ot h er dr u g 
i nfl u e n ci n g c o a g ul ati o n ( e x c e pt l o w d o s e a s piri n < 1 6 0 m g/ d a y a n d 
ot h er s h ort a cti n g N S AI D S wit h a h alf-lif e < 2 0 h o ur s) 
f.  o b eti c h oli c a ci d or ur s o d e o x y c h oli c a ci d 
1 3. Bl o o d d o n ati o n of 5 0 t o 4 9 9 m L wit hi n 3 0 d a y s of S cr e e ni n g or of 
> 4 9 9 m L wit hi n 6 0 d a y s of S cr e e ni n g  
1 4. A cti v e i nf e cti o n r e q uiri n g s y st e mi c a nt i vir al or a nti mi cr o bi al t h er a p y t h at 
will n ot b e c o m pl et e d pri or t o St u d y D a y 1 
1 5. S u bj e ct s wit h k n o w n i nt ol er a n c e t o M RI or wit h c o n diti o n s 
c o ntr ai n di c at e d f or M RI Pr o c e d ur e s: 
•   
S u bj e ct s w h o h a v e a n y m et al i m pl a nt (i n cl u di n g a h e art 
p a c e m a k er, r o d s, s cr e w s, a n e ur y s m cli p) 
•  S u bj e ct s
 
wit h
 
cl a u str o p h o bi a
 
1 6. C o nfir m e d r e d u cti o n i n f a sti n g pl a s m a gl u c o s e ( F P G) of > 4 0 m g/ d L 
( > 2. 2 m m ol/ L) at t h e R u n-I n Vi sit ( W e e k - 1) c o m p ar e d t o a F P G v al u e 
t a k e n at S cr e e ni n g 
1 7. C o nfir m e d r e d u cti o n i n b o d y w ei g ht of  2 k g ( 4. 4 l b s) at t h e R u n-I n Vi sit  
( W e e k - 1) c o m p ar e d t o b o d y w ei g ht t a k e n at S cr e e ni n g 
1 8. H a v e a n y ot h er c o n diti o n s, w hi c h, i n  t h e o pi ni o n of t h e I n v e sti g at or or 
S p o n s or w o ul d m a k e t h e s u bj e ct u n s uit a bl e f or i n cl u si o n, or c o ul d 
i nt erf er e wit h t h e s u bj e ct p arti ci p ati n g i n or c o m pl eti n g t h e St u d y, 
i n cl u di n g u n willi n g n e s s t o c o nti n u e wit h S C i nj e cti o n s aft er t h e S C 
T ol er a bilit y a s s e s s m e nt  
Tr e at m e nt Gr o u p s 
Pl a c e b o a n d I SI S 4 8 4 1 3 7 2 5 0 m g p er w e e k 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
1 8
 
P R O T O C O L S Y N O P SI S C o nti n ue d 
St u d y Dr u g D o s a g e a n d 
A d mi ni str ati o n 
T h e S C t ol er a bilit y a s s e s s m e nt s u si n g 0. 9 % st eril e s ali n e will b e 
a d mi ni st er e d a s a 1. 2 5 m L i nj e cti o n at a n y vi sit d uri n g t h e S cr e e ni n g or 
R u n-I n P eri o d s ( m a y al s o b e d eli v er e d a s 2 n o n- c o nti g u o u s i nj e cti o n v ol u m e s 
of 0. 7 5 m L a n d 0. 5 0 m L). 
I SI S 4 8 4 1 3 7 ( 2 0 0 m g/ m L) a n d pl a c e b o will b e s u p pli e d a s 1. 0 m L of s ol uti o n 
i n a 2 m L st o p p er e d gl a s s vi al. 
St u d y Dr u g (I SI S 4 8 4 1 3 7 or pl a c e b o) S C  i nj e cti o n v ol u m e will b e 1. 2 5 m L 
( m a y al s o b e d eli v er e d a s t w o n o n- c o nti g u o u s i nj e cti o n v ol u m e s of 0. 7 5 m L 
a n d 0. 5 0 m L). 
S u bj e ct s will b e a d mi ni st er e d 1 3 w e e kl y S C i nj e cti o n s d uri n g t h e 1 3- w e e k 
tr e at m e nt p eri o d. 
R ati o n al e f or D o s e a n d S c h e d ul e 
S el e cti o n 
T h e d o s e of 2 5 0 m g of I SI S 4 8 4 1 3 7 w a s s el e ct e d f or t hi s st u d y b a s e d o n t h e 
r e s ult s of t h e P h a s e 1 tri al I SI S 4 8 4 1 3 7- C S 1 w hi c h d e m o n str at e d a n 
a c c e pt a bl e s af et y a n d t ol er a bilit y pr ofil e f or d o s e s u p t o 3 0 0 m g aft er 6 w e e k s 
( 8 t ot al d o s e s) of tr e at m e nt.  A d diti o n all y, s e v er al A S O s of t hi s cl a s s h a v e 
d e m o n str at e d si g nifi c a nt effi c a c y a n d a c c e pt a bl e s af et y pr ofil e s at a si mil ar 
d o s e l e v el f or 1 3 w e e k s a n d l o n g er ( A c k er m a n n et al. 2 0 1 6 ; Di g e ni o et al.  
2 0 1 6 ; D u ell et al. 2 0 1 6 ).  T h e 1 3- w e e k tr e at m e nt d ur ati o n i s s u p p ort e d b y t h e 
I SI S 4 8 4 1 3 7 n o n cli ni c al 1 3- w e e k t o xi c ol o g y st u d y ( s e e I n v e sti g at or s 
Br o c h ur e) a n d b y pr e vi o u s l o n g-t er m w e e kl y cli ni c al d o si n g st u di e s wit h 
s e v er al ot h er 2 ʹ- M O E- m o difi e d A S O s.  T hirte e n ( 1 3) w e e k s of st u d y 
tr e at m e nt i s a s uffi ci e nt tr e at m e nt d ur ati o n t o o b s er v e c h a n g e s i n li v er f at 
c o nt e nt a n d i m pr o v e m e nt s i n I R i n t hi s p ati e nt p o p ul ati o n.   
St u d y Vi sit S c h e d ul e a n d 
Pr o c e d ur e s 
D et ail e d i nf or m ati o n r e g ar di n g t h e st u d y pr o c e d ur e s i s o utli n e d i n S e cti o n 6  
a n d A p p e n di c e s A -C . 
T h e d ur ati o n of s u bj e ct p arti ci p ati o n i n t h e st u d y i n cl u d e s u p t o a 2- w e e k 
S cr e e ni n g P eri o d, u p t o a 4- w e e k R u n-I n E v al u ati o n P eri o d, a n d a 1 3- w e e k 
Tr e at m e nt P eri o d.  S u bj e ct s will b e r e q uir e d t o c o m pl et e a P o st- Tr e at m e nt 
P eri o d f or 1 3 w e e k s f oll o wi n g t h e l a st d o s e of st u d y m e di c ati o n ( or e arl y 
t er mi n ati o n).  T h e I o ni s M e di c al M o nit or or D e si g n e e will p erf or m r o uti n e 
r e vi e w s of t h e s af et y r e s ult s t hr ou g h o ut t h e c o n d u ct of t h e st u d y. 
T o r e d u c e t h e b ur d e n of u n n e c e s s ar y pr o c e d ur e s o n s u bj e ct s w h o 
s u b s e q u e ntl y el e ct n ot t o p arti ci p at e i n  t h e st u d y or c o nti n u e wit h st u d y 
pr o c e d ur e s, all s u bj e ct s will c o nfir m t o l er a n c e of S C a d mi ni str ati o n of 0. 9 % 
s ali n e pri or t o r a n d o mi z ati o n d uri n g t h e S cr e e ni n g or t h e R u n-I n P eri o d.  T hi s 
i nj e cti o n will f oll o w t h e s a m e pr o c e d ure s a s i nj e cti o n s of t h e St u d y Dr u g 
(I SI S 4 8 4 1 3 7 or pl a c e b o) d urin g t h e tr e at m e nt p eri o d.   
S cr e e ni n g P eri o d:  W e e k - 6 – W e e k - 5 ( u p t o 2 w e e k s) 
L a b or at or y a n d ot h er st u d y pr o c e d ur e s will b e p erf or m e d t o a s s e s s eli gi bilit y 
d uri n g t h e S cr e e ni n g P eri o d.   
R u n-I n P eri o d:  W e e k - 4 – W e e k - 1 ( 4 w e e k s) 
S u bj e ct s will m ai nt ai n hi s/ h er di et a n d e x er ci s e r o uti n e.   
D uri n g W e e k s - 4 a n d - 3, s u bj e ct s will h a v e a n M RI t o a s s e s s li v er f at c o nt e nt 
a n d li v er v ol u m e.  M RI s will b e c o n d u ct e d u si n g st a n d ar di z e d pr o c e d ur e s a n d 
s etti n g s.  M RI s will b e e v al u at e d b y a n i n d e p e n d e nt c e ntr al r e a d er, bli n d e d t o 
t h e s u bj e ct’ s tr e at m e nt a s si g n m e nt, t o a s s e s s li v er f at a n d li v er si z e. 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
1 9
 
P R O T O C O L S Y N O P SI S C o nti n ue d 
St u d y Vi sit S c h e d ul e a n d 
Pr o c e d ur e s C o nti n u e d 
R u n-I n P eri o d:  W e e k - 4 – W e e k - 1 ( 4 w e e k s)  C o nti n u e d 
S u bj e ct s wit h a q u alif yi n g M RI ( at l e a st 1 0 % li v er f at a s s e s s e d b y M RI- P D F F 
vi a c e ntr al r e vi e w er) r et ur n t o cli ni c f or St u d y Vi sit W e e k - 1.  At t hi s vi sit, fi n al 
q u alifi c ati o n a s s e s s m e nt s will b e c o n d u ct e d i n cl u di n g b o d y w ei g ht a n d F P G 
a s s e s s m e nt s.  If it i s n ot p o s si bl e f or M RI r e s ult s t o b e a v ail a bl e b y t h e cli ni c 
W e e k - 1 vi sit, t h e M RI r e s ult s m u st b e a v ail a bl e f or fi n al q u alifi c ati o n pri or t o 
r a n d o mi z ati o n. 
Eli gi bl e s u bj e ct s will b e str atifi e d b a s e d o n M RI li v er f at l e v el s ( < 2 0 % v s. 
≥ 2 0 %) a n d t h e n s u bj e ct s will b e r a n d o mi z e d pri or t o t h e fir st d o s e i n a 
2: 1 r ati o t o r e c ei v e eit h er I SI S 4 8 4 1 3 7 or pl a c e b o.   
Eli gi bl e/ q u alifi e d s u bj e ct s will b e r a n d o mi z e d a n d r et ur n t o cli ni c f or t h e 
Tr e at m e nt P eri o d. 
Tr e at m e nt P eri o d:  W e e k 1 – W e e k 1 3 
S T U D Y D R U G A D MI NI S T R A TI O N:  W e e kl y i nj e cti o n s will b e a d mi ni st er e d at 
t h e st u d y c e nt er. 
S A F E T Y A S S E S S M E N T S:  W e e kl y l a b or at or y a s s e s s m e nt s will b e o bt ai n e d 
i n cl u di n g c h e mi str y, h e m at ol o g y, uri n al y si s, a d v er s e e v e nt s a n d c o n c o mit a nt 
m e di c ati o n u s a g e.  Bl o o d s a m pl e s f or p h ar m a c o ki n eti c a n al y si s will b e dr a w n 
w e e kl y.  A d diti o n al bl o o d t e st s f or e x pl or at or y p ur p o s e s will b e c oll e ct e d at 
l e s s fr e q u e nt i nt er v al s i n cl u di n g li pi d s, i nfl a m m at or y m ar k er s a n d e x pl or at or y 
bi o m ar k er s. 
S u bj e ct s w h o di s c o nti n u e tr e at m e nt e ar l y will e nt er t h e P o st- Tr e at m e nt 
P eri o d u nl e s s c o n s e nt i s wit h dr a w n. 
If a s u bj e ct’ s gl y c e mi c c o ntr ol d et eri or at e s aft er W e e k 8 a c c or di n g t o t h e 
M o nit ori n g R ul e, t h e or al a nti- di a b eti c ( O A D) r e gi m e n c a n b e a dj u st e d. 
P o st- Tr e at m e nt P eri o d:  W e e k 1 4 – W e e k 2 6 
S A F E T Y A S S E S S M E N T S:  L a b or at or y a s s e s s m e nt s will b e o bt ai n e d at 
r e g ul ar i nt er v al s t hr o u g h o ut t h e 1 3- w e e k P o st- Tr e at m e nt P eri o d. 
M RI:  Li v er f at c o nt e nt a n d v ol u m e will  b e m e a s ur e d i n t h e P o st- Tr e at m e nt 
P eri o d i n all s u bj e ct s w h o c o m pl et e at l e a st 5 d o s e s d uri n g t h e Tr e at m e nt 
P eri o d.   
S af et y a n d T ol er a bilit y 
E v al u ati o n s 
T h e s af et y a n d t ol er a bilit y of I SI S 4 8 4 1 3 7 will b e a s s e s s e d b y d et er mi ni n g t h e 
i n ci d e n c e, s e v erit y, d o s e-r el ati o n s hi p of a d v er s e eff e ct s a n d c h a n g e s i n 
l a b or at or y e v al u ati o n s.  S af et y r e s ult s i n s u bj e ct s d o s e d wit h I SI S 4 8 4 1 3 7 will 
b e c o m p ar e d wit h t h o s e fr o m s u bj e ct s d o s e d wit h pl a c e b o.  T h e s af et y a n d 
t ol er a bilit y pr ofil e of t h e St u d y Dr u g will b e m o nit or e d w e e kl y d uri n g t h e 
Tr e at m e nt P eri o d a n d at e a c h s c h e d ul e d vi sit i n t h e P o st- Tr e at m e nt P eri o d. 
P h ar m a c o ki n eti c E v al u ati o n s 
S el e ct e d pl a s m a tr o u g h a n d p o st-tr e at m e nt c o n c e ntr ati o n s of I SI S 4 8 4 1 3 7 
will b e a s s e s s e d i n e v al u a bl e s u bj e ct s r e c ei vi n g I SI S 4 8 4 1 3 7 tr e at m e nt. 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
2 0
 
P R O T O C O L S Y N O P SI S C o nti n ue d 
P h ar m a c o d y n a mi c E v al u ati o n s 
T h e eff e ct of I SI S 4 8 4 1 3 7 o n t h e f oll o wi n g will b e a s s e s s e d 
•   
h e p ati c f at a n d li v er w ei g ht c o nt e nt will b e e v al u at e d o v er ti m e u si n g 
m a g n eti c r e s o n a n c e i m a gi n g t h at i s c o n d u ct e d at B a s eli n e a n d 
P o st- Tr e at m e nt.  A c e ntr al r e a d er will c al c ul at e t h e p er c e nt li v er f at 
b y P D F F.  M RI r e s ult s i n s u bj e ct s d o s e d wit h I SI S 4 8 4 1 3 7 will b e 
c o m p ar e d wit h t h o s e s u bj e ct s d o s e d wit h pl a c e b o 
•   
pl a s m a li p o pr ot ei n pr ofil e (tri gl y ceri d e s, t ot al c h ol e st er ol, L D L- C, 
A p o B, V L D L, H D L a n d N o n- H D L) 
•   
h e p ati c I R a n d gl u c o s e c o ntr ol (i n suli n, gl u c o s e, H O M A-I R, H b A 1 c) 
St ati sti c al C o n si d er ati o n s 
A p pr o xi m at el y 4 5 s u bj e ct s will b e r a n d o mi z e d ( 2: 1 all o c ati o n r ati o) t o e n s ur e 
at l e a st 3 3 s u bj e ct s will h a v e d at a o n t h e pri m ar y st u d y e n d p oi nt.  T hi s will 
r e s ult i n > 9 0 % p o w er t o d et e ct a of 5 % diff er e n c e i n m e a n a b s ol ut e c h a n g e 
i n li v er f at a s m e a s ur e d b y M RI- P D F F b et w e e n t h e a cti v e a n d pl a c e b o 
gr o u p s wit h a 2- si d e d al p h a of 0. 0 5, a s s u mi n g a c o m m o n st a n d ar d d e vi ati o n 
of 4 %. 
S p o n s or 
I o ni s P h ar m a c e uti c al s, I n c 
 
 




I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
2 2
 
S T U D Y G L O S S A R Y 
A b bre vi ati o n 
Defi niti o n 
2 ′- M O E
 2′-O -( 2- met h o x yet h yl) 
A E
 a d verse
 
e ve nt
 
A L P
 al kali ne
 
p h os p hatase
 
A L T 
ala ni ne a mi n otra nsferase ( S G P T) 
a p o B
 a p oli p o pr otei n
 
B
 
a P T T 
acti vate d partial t hr o m b o plasti n ti me 
A S O
 a ntise nse
 
oli g o n ucle oti de
 
A S T
 as partate
 
a mi n otra nsferase
 
( S G O T)
 
B b 
c o m ple me nt fact or B b (acti vate d c o m ple me nt s plit pr o d uct) 
β h C G 
beta-s u b u nit of h u ma n c h ori o nic g o na d otr o pi n ( pre g na nc y test) 
B P
 bl o o d
 
press ure
 
B U N 
bl o o d urea nitr o ge n 
C 5a 
c o m ple me nt fact or C 5a (acti vate d c o m ple me nt s plit pr o d uct) 
C B C 
c o m plete bl o o d c o u nt 
C K 1 8
 c yt o kerati n
 
1 8
 
C M V
 C yt o me gal o vir us
 
C R F 
case re p ort f or m 
C R N M B
 cli nicall y-rele v a nt n o n- maj or blee di n g 
C R O 
c o ntract researc h or ga nizati o n 
C T
 c o m p ute d
 
t o m o gra p h y
 
C T C A E 
C o m m o n Ter mi n ol o g y Criter ia f or A d verse E ve nts  
D A G 
s n- 1, 2- diac yl gl ycer ol 
D G A T
 Diac yl gl ycer ol
 
Ac yltra nsferase
 
 
D G A T 1
 diac yl gl ycer ol
 
O -ac yltra nsferase 1 
D G A T 2
 diac yl gl ycer ol
 
O -ac yltra nsferase 2 
D N A
 p h os p h or ot hi oate
 
m o difi e d oli g o de o x y n ucle oti des 
D P PI V i n hi bit or  
di pe pti d yl pe pti dase-I V 
E B V 
E pstei n- Barr vir us 
E C G
 electr ocar di o gra m
 
e C R F 
electr o nic Case Re p ort F or m 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
2 3
 
E D C 
electr o nic data ca pt ure 
F P G 
fasti n g plas ma gl uc ose 
E T P T 
Earl y Ter mi nati o n patie nts fr o m t he P ost- Treat me nt Peri o d 
F S H
 f ollicle-sti m ulati n g
 
h or m o ne
 
G C P 
G o o d Cli nical Practice 
G F R 
gl o mer ular filtrati o n rate 
G L P 1 
gl uca g o n-li ke pe pti de 1 
H A V 
he patitis A vir us  
H b A 1 C
 He m o gl o bi n
 
A 1 C
 
H Bs A g 
he patitis B s urface a nti ge n 
H B V
 He patitis
 
B
 
vir us
 
H C C
 He pat ocell ular
 
carci n o ma
 
H C V
 He patitis
 
C
 
vir us
 
H D L 
Hi g h de nsit y li p o pr otei n 
HI P A A 
Healt h I ns ura nce P orta b ilit y a n d Acc o u nta bilit y Act 
HI V 
h u ma n i m m u n o deficie nc y vir us 
H O M A-I R
 H o me ostatic
 
m o del
 
assess me nt- i ns uli n resista nce 
H R
 heart
 
rate
 
hs C R P 
C R P meas ure d b y hi g h se nsiti vit y assa y 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I E C 
I n de pe n de nt Et hics C o m mittee 
I g A
 i m m u n o gl o b uli n
 
A
 
I g M
 i m m u n o gl o b uli n
 
M
 
I N R 
i nter nati o nal n or malize d rati o 
I L 6
 I nterle u ki n- 6
 
I R
 i ns uli n
 
resista nce
 
I R B
 I nstit uti o nal
 
Re vie w
 
B oar d
 
I SI S 4 8 4 1 3 7 
a ntise nse i n hi bit or of D G A T 2 
I V
 I ntra ve n o us(l y)
 
I X R S
 I nteracti ve
 
v oice/i n ter net res p o nse s yste m 
L D H
 lactate
 
de h y dr o ge nase
 
L D L- C 
L o w de nsit y li p o pr otei n c h olester ol 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
2 4
 
M A G
 m o n oac yl gl ycer ol
 
M B
 maj or
 
blee di n g
 
M C H  
mea n c or p usc ular he m o gl o bi n 
M C H C  
mea n c or p usc ular he m o gl o bi n c o nce ntrati o n 
M C V  
mea n c or p usc ular v ol u me 
Me d D R A
T M  
Me dical Dicti o nar y f o r Re g ulat or y Acti vities  
M P V 
mea n platelet v ol u me 
M RI 
ma g netic res o na nce i ma gi n g 
M RI- P D F F 
Ma g netic res o na nce i ma gi n g-esti mate d pr ot o n de nsit y fat 
fracti o n 
m R N A 
messe n ger ri b o n ucleic aci d 
N A F L D 
N o nalc o h olic fatt y li ver disease 
N A S H
 N o nalc o h olic
 
steat o he patitis
 
N C S
 n ot
 
cli nicall y-si g nifica nt
 
N o n- H D L 
N o n- hi g h- de nsit y li p o pr otei n 
N S AI D 
n o n-ster oi dal a nti-i nfla m mat or y dr u g 
O A D
 oral
 
a nti- dia betic
 
a ge nt
 
P/ C
 uri ne
 
pr otei n/creati ni ne
 
P D
 p har mac o d y na mic(s)
 
P D F F 
pr ot o n de nsit y fat fracti o n 
p H 
meas ure of t he aci dit y or  basicit y of a s ol uti o n 
P K
 p har mac o ki netic(s)
 
p R B C 
pac ke d re d bl o o d cells 
P T
 pr ot hr o m bi n
 
ti me
 
R B C 
re d bl o o d cells 
R N A
 ri b o n ucleic
 
aci d
 
R Nase H 1 
a n u bi q uit o us e n d o n uclease t hat s pecificall y h y dr ol yzes t he 
R N A stra n d i n R N A/ D N A h y bri ds 
R R
 res pirat or y
 
rate
 
S A E
 seri o us
 
a d verse
 
e ve nt
 
S A P 
Statistical A nal ysis Pla n 
si R N A 
s mall i nterferi n g ri b o n ucleic aci d 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
2 5
 
S C
 s u bc uta ne o us(l y)
 
S C D- 1  
Stear yl C o A desat urase- 1 
S G L T 2  
S o di u m gl uc ose li ke tra ns p ort pr otei n 2 
St u d y Da y 1  
defi ne d as t he first da y St u d y Dr u g pr o d uct is a d mi nistere d t o 
t he s u bject 
St u d y Dr u g 
I SI S 4 8 4 1 3 7 or place b o 
S U
 s ulf o n yl urea
 
S U S A R 
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T 3
 Trii o d ot h yr o ni ne
 
T 4
 T h yr o xi ne
 
T 2 D M 
t y pe 2 dia betes mellit us 
T E A E 
treat me nt-e mer ge nt a d verse e ve nt 
T S H 
t h yr oi d sti m ulati n g h or m o ne 
U L N 
u p per li mit of n or mal 
V L D L 
Ver y l o w- de nsit y li p o pr otei ns 
W A T 
w hite a di p ose tiss ue 
W B C
 w hite
 
bl o o d
 
cell
 
W H O 
W orl d Healt h Or ga nizati o n 
W M A 
W orl d Me dical Ass ociati o n 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
2 6
 
1.
 O B J E C TI V E S
 
1. 1
 Pri m ar y
 
O bjecti ve(s)
 
T he pri mar y o bjecti ves are: 
1.  T o e val uate t he safet y a n d t olera bilit y of I SI S 4 8 4 1 3 7 2 5 0 m g per wee k s u bc uta ne o us 
( S C) i njecti o n i n a d ult s u bjects wit h t y pe 2 dia betes mellit us ( T 2 D M) 
2.  T o e val uate t he p har mac o d y na mic effects of  I SI S 4 8 4 1 3 7 2 5 0 m g per wee k S C i njecti o n 
o n t he a bs ol ute re d ucti o n of li ver fat (assesse d b y ma g netic res o na nce i ma gi n g [ M RI] 
pr ot o n de nsit y fat fracti o n [ P D F F]) i n a d ult s u bjects wit h T 2 D M 
1. 2
 Sec o n d ar y
 
O bjecti ve(s)
 
T he sec o n dar y o bjecti ves are: 
1.  T o e val uate t he p har mac o d y na mic effects of  I SI S 4 8 4 1 3 7 2 5 0 m g per wee k S C i njecti o n 
o n li ver fat ( perce nt relati ve re d uc ti o n a n d perce nt of s u bjects wit h ≥ 3 0 % relati ve 
re d ucti o n) assesse d b y M RI- P D F F 
2.  T o e val uate t he p har mac o d y na mic effects of  I SI S 4 8 4 1 3 7 2 5 0 m g per wee k S C i njecti o n 
o n li ver v ol u me assesse d b y M RI- P D F F 
3.  T o e val uate t he p har mac o d y na mic effects of  I SI S 4 8 4 1 3 7 2 5 0 m g per wee k S C i njecti o n 
o n plas ma li p o pr otei n pr ofile (tri gl yceri des  [ T G], t otal c h olester ol, l o w de nsit y 
li p o pr otei n c h olester ol [ L D L- C], a p oli p o pr otei n B [a p o B], ver y l o w- de nsit y li p o pr otei ns 
[ V L D L], hi g h de nsit y li p o protei n [ H D L] a n d N o n- H D L) 
4.  T o e val uate t he p har mac o d y na mic effects of  I SI S 4 8 4 1 3 7 2 5 0 m g per wee k S C i njecti o n 
o n i ns uli n resista nce (I R) a n d gl uc ose c o nt r ol (i ns uli n, gl uc ose, h o me ostatic m o del 
assess me nt-i ns uli n resista nce [ H O M A-I R], he m o gl o bi n A 1c [ H b A 1c]) 
1. 3
 E x pl or at or y
 
O bjecti ves
 
T he e x pl orat or y o bjecti ves are t o e val uate t he p har mac o d y na mic ( P D) effects of I SI S 4 8 4 1 3 7 o n 
p ote ntial bi o mar kers of D G A T 2 acti vit y (e . g., stear o yl- C o A desat urase- 1 [ S C D- 1] a n d 
bi o mar ker of he patic i nfla m mati o n (e. g., c yt o kerati n 1 8 [ C K 1 8], ha pt o gl o bi n). 
2.  
B A C K G R O U N D A N D R A TI O N A L E 
2. 1  
O ver vie w of Dise ase 
N o nalc o h olic fatt y li ver disease ( N A F L D) is a he patic ma nifestati o n of t he meta b olic s y n dr o me 
(Marc hesi ni et al. 2 0 0 3 ) a n d is c haracterize d b y t he acc u m ulatio n of tri gl yceri des i n t he li ver of 
s u bjects wit h o ut a hist or y of e xcessi ve alc o h ol c o ns u m pti o n.  N A F L D is classifie d i nt o si m ple 
steat osis, i n w hic h o nl y he patic steat osis is o bser ve d, a n d n o n-alc o h olic steat o he patitis ( N A S H), 
i n w hic h i ntral o b ular i nfla m mati o n a n d ball o o ni ng de ge nerati o n of he pat oc ytes is o bser ve d al o n g 
wit h he patic steat osis.  M ost patie nts wit h  N A F L D are o bese or m or bi dl y o bese a n d ha ve 
acc o m pa n yi n g I R ( B yr ne a n d Tar g her 2 0 1 5 ) a n d t y pe 2 dia betes mellit us.  N A S H is a 
pr o gressi ve disease a n d ma y lea d t o li ver cirr h osis a n d he pat oce ll ular carci n o ma ( H C C) (Farrell  
a n d Larter 2 0 0 6 ; C o he n et al. 2 0 1 1 ).  T we nt y ( 2 0) perce nt of N A S H patie nts are re p orte d t o 
de vel o p cirr h osis, a n d 3 0- 4 0 % of patie nts wit h  N A S H cirr h osis e x perie nce li ver-relate d deat h 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
2 7
 
(Mc C ull o u g h 2 0 0 6 ).  T he i nci de nce of N A F L D a n d N A S H ha ve bee n ra pi dl y i ncreasi n g 
w orl d wi de c o nsiste nt wit h t he i ncrease d pre vale n ce of o besit y, a n d is c urre ntl y t he m ost c o m m o n 
c hr o nic li ver disease.  Rece ntl y, t he i nci de n ce of N A F L D a n d N A S H wa s re p orte d t o be 4 6 % 
a n d 1 2 %, res pecti vel y, i n a la r gel y mi d dle-a ge d p o p ulati o n (Willia ms et al. 2 0 1 1 ).  N A S H has 
bec o me t he t hir d m ost c o m m o n i n dicati o n f or li ver tra ns pla ntati o n i n t he U nite d States 
(C harlt o n et al. 2 0 1 1 ). 
He patic steat osis res ults fr o m a n i m bala nce bet w ee n tri gl yceri de acc u m ulati o n a n d eli mi nati o n i n 
t he li ver.  I ns uli n resista nce, w hic h is fre q ue ntl y see n i n o bese i n di vi d uals, is cl osel y li n ke d t o 
t his pr ocess beca use it alters n utrie nt distri b uti o n a m o n g tiss ues a n d n utrie nt meta b olis m 
(T o me n o et al. 2 0 1 3 ).  Peri p heral I R lea ds t o a n i nfl u x of free fatt y aci ds i nt o t he li ver b y 
decrease d s u p pressi o n of li p ol ysis a n d i ncrease d de n ov o  li p o ge nesis (I bra hi m et al. 2 0 1 3).  
Alt h o u g h t he pat h o ge nesis of N A F L D/ N A S H has n ot bee n c o m pletel y el uci date d, t he “t w o- hit” 
(Da y a n d Ja mes 1 9 9 8 ) a n d “ m ulti ple parallel hit” (Til g a n d M osc he n 2 0 1 0 ) h y p ot heses ha ve 
bee n pr o p ose d.  I n t he t w o- hit h y p ot hesis, he pa tic steat osis occ urs first t hr o u g h a n i nitial 
meta b olic dist ur ba nce a n d pr o gresses t o N A S H b y s u bse q ue nt sec o n d hits deri ve d fr o m t he g ut 
a n d/ or t he a di p ose tiss ue s uc h as  i ncrease d le vels of i nfla m mat or y c yt o ki nes (e. g., t u m or necr osis 
fact or-α , i nterle u ki n- 6 [I L 6]), decrease d le vels of a nti-i nfla m mat or y c yt o ki nes (e. g., 
a di p o necti n), o xi dati ve stress, a n d e n d ot o xi ns ori gi nati n g fr o m i ntesti nal bacterial fl ora.  
T heref ore, a c o m p o u n d s uc h as a n a ntise nse oli g o n ucle oti de ( A S O) a gai nst Diac yl gl ycer ol 
Ac yltra nsferase 2 ( D G A T 2) t hat re d uces he pa tic steat osis c o ul d res ult i n pre ve nti o n or 
atte n uati o n of t he sec o n dar y i nfla m mati o n a n d o xi dati ve stress t here b y be nefiti n g N A F L D a n d 
N A S H patie nts. 
2. 2
 T her a pe utic
 
R ati o n ale
 
2. 2. 1  
Overvie w of T ar get 
Diac yl gl ycer ol ac yltra nsfe rase ( D G A T) catal yzes t he fi nal ste p i n T G s y nt hesis b y facilitati n g 
t he li n ka ge of s n- 1, 2- diac yl gl ycer ols ( D A G) wit h a n ac yl- C o A.  D G A T has 2 is of or ms, 
diac yl gl ycer ol O -ac yltra nsferase 1 ( D G A T 1) a n d diac yl gl ycer ol O -ac yltra nsferase 2 ( D G A T 2), 
a n d st u dies i n dicate t hat b ot h D G A T 1 a n d D G A T 2 pla y i m p orta nt r oles i n T G s y nt hesis.  
D G A T 1 is m ost hi g hl y e x presse d i n s mall i ntes ti ne a n d w hite a di p ose tiss ue ( W A T), w hereas 
D G A T 2 is pri maril y e x presse d i n li ver a n d W A T ( Cases et al. 1 9 9 8 ; Cases et al. 2 0 0 1 ).  T he 
e xiste nce of D G A T 2 was pre dicte d fr o m t he fi n di n g t hat mice lac ki n g D G A T 1 ha ve a b u n da nt 
T G i n t heir tiss ues.  T he h D G A T 2 ge ne is  c o m p ose d of 8 E x o ns, a n d s pa ns 4 2. 0 3 k b o n 
C hr o m os o me 1 1.  It is l ocate d  ~ 3 7. 5 k b fr o m t he m o n oac yl gl ycerol ac yltra nsferase 2 ( M G A T 2) 
ge ne ( Ye n et al. 2 0 0 8 ).  I n m ost s pecies, t he ge ne e nc o des a pr otei n of 3 5 0- 4 0 0 resi d ues, a n d t he 
calc ulate d m olec ular mass f or D G A T 2 e nz y mes is i n t he ra n ge of 4 0- 4 4 K D ( Ye n et al. 2 0 0 8). 
Alt h o u g h b ot h D G A T 1 a n d D G A T 2 catal yze t he sa me reacti o ns i n T G s y nt hesis wit h D A G or 
m o n oac yl gl ycer ols ( M A G) a n d ac yl- C o A as s u bstr ates, t he y are f u ncti o nall y disti n g uis he d b y 
t heir differe nces i n catal ytic pr o perties (Ca o et al. 2 0 0 7 ; C he n g et al. 2 0 0 8 ), s u bcell ular 
l ocalizati o n (St o ne et al. 2 0 0 9 ), p h ysi ol o gical re g ulati o n (Mee galla et al. 2 0 0 2 ), a n d p he n ot y pic 
c o nse q ue nces w he n re n dere d deficie nt ( S mit h et al. 2 0 0 0 ) or o vere x presse d i n precli nical m o dels 
(Nai k et al. 2 0 1 4 ).  D G A T 1 n ull mi ce were f o u n d t o be resista nt t o hi g h-fat- diet-i n d uce d o besit y 
beca use of a n i ncrease d meta b olic rate ( partl y d ue t o i ncrease d p h ysical acti vit y), m o destl y 
decrease d le vels of tiss ue T Gs, a n d i ncrease d i ns uli n a n d le pti n se nsiti vit y ( S mit h et al. 2 0 0 0).  


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
2 8
 
D G A T 2 n ull mice are li p o pe nic a n d die s o o n after birt h beca use of pr of o u n d re d ucti o ns i n 
s u bstrates f or e ner g y meta b olis m a n d i m paire d s ki n per mea bilit y (St o ne et al. 2 0 0 4 ), w hile 
D G A T 2 het er oz y g o us mice are via ble, healt h y, a n d p h ysicall y i n disti n g uis ha ble fr o m n o n-
deficie nt mice ( Y u et al. 2 0 0 5 ).  T he effects of s pecific p har mac ol o gic a nta g o nis m of he patic 
D G A T 2 e x pressi o n were n ot k n o w n u ntil st u dies c o n d ucte d wit h D G A T 2 A S Os. 
D G A T 2 A S Os were de vel o pe d t o re d uce t he rate  of T G s y nt hesis b y s pecificall y re d uci n g 
he patic D G A T 2 e x pressi o n.  S u p pressi o n of D G A T 2, b ut n ot of D G A T 1, b y A S O treat me nt 
i m pr o ve d he patic steat osis a n d bl o o d li pi d le vels i n de pe n de nt of a di p osit y i n r o de nt m o dels of 
o besit y a n d data i n dicate d t hat t hese effects we re relate d t o decrease d he patic li pi d s y nt hesis 
( Y u et al. 2 0 0 5).  I n rats wit h diet-i n d uce d he patic steat osis ( m o del of h u ma n N A F L D), treat me nt 
wit h b ot h D G A T 1 a n d D G A T 2 A S Os  selecti vel y re d uce d D G A T 1 a n d D G A T 2 ri b o n ucleic aci d 
( R N A) le vels i n li ver a n d fat.  H o we ver, o nl y D G A T 2 A S O treat me nt si g nifica ntl y re d uce d 
he patic li pi ds ( D A G a n d T G b ut n ot  l o n g c hai n ac yl- C o As) a n d re verse d diet-i n d uce d he patic I R 
i n t his rat m o del of diet-i n d uce d N A F L D (C h oi et al. 2 0 0 7 ).  P har mac ol o gic effects c orrelate d 
wit h t he le vel of a ntise nse i n hi biti o n of D G A T 2 li v er e x pressi o n a n d > 8 0 % decrease of D G A T 2 
i n li ver a n d a di p ose tiss ue di d n ot ca use a n y tar get relate d t o xicit y.  T hese p har mac ol o gic data 
i n dicate differe nt f u ncti o ns of t he t w o D G A T e nz y mes d uri n g T G bi os y nt hesis a n d are c o nsiste nt 
wit h t h ose fr o m o vere x pressi o n st u dies.  I n o ve re x pressi o n st u dies i n mice, D G A T 2 has bee n 
i de ntifie d as bei n g m ore acti ve t ha n D G A T 1, yieldi n g a hi g her i ncrease i n i ntracell ular T G t hat 
acc u m ulates as lar ge, ce ntrall y l ocat e d c yt os olic dr o plets ( St o ne et al. 2 0 0 4).  F urt her m ore, i n rat 
he pat o ma cells, D G A T 1 o vere x pressi o n res ulte d i n c o nsi dera bl y less T G acc u m ulati o n t ha n was 
s h o w n b y D G A T 2 o vere x pressi o n. 
T hese res ults s u g gest t hat D G A T 2 pl a ys a n i m p orta nt r ole i n he patic li p i d meta b olis m, he patic 
steat osis, he patic i ns uli n sig nali n g, a n d he patic i ns uli n se ns iti vit y a n d t hat t hera pe utic 
i nter ve nti o ns ai me d at re d uci n g D G A T 2 f u ncti o n i n li p o ge nic tiss ues ma y pr o vi de cli nical 
be nefit f or fatt y li ver disease, meta b olic s y n dr o me a n d car di o vascular diseases.   
2. 2. 2
 T her a pe utic
 
R ati o n ale
 
I SI S 4 8 4 1 3 7 is bei n g i n vesti gate d as a p ossible treat me nt f or N A F L Ds i ncl u di n g N A S H.  
C urre ntl y, t he pri nci pal treat me nt f or N A F L D/ N A S H is lifest y le m o dificati o n b y diet a n d 
e xercise.  T here are n o a p pr o ve d me dicati o ns f o r t hese c o n diti o ns.  H o we ver, p har mac ol o gical 
t hera p y is i n dis pe nsa ble beca use o bese patie nts wit h N A F L D ofte n ha ve diffic ult y mai ntai ni n g 
i m pr o ve d lifest yles.  Selecti ve i n hi biti o n of D G A T 2 has bee n s u g geste d as a ne w tar get f or t he 
treat me nt of t hese o besit y-relate d meta b olic diseases.  I m p orta nt a d va nces ha ve bee n ma de 
re gar di n g p ote ntial a p plicati o ns f or D G A T in hi bit ors, i ncl u di n g se veral re p orts of D G A T 
i n hi bit ors wit h i m pr o ve d s ol u bilit y, cell- base d acti vit y, a n d p har mac o ki ne tic ( P K) pr o perties.  
Des pite str o n g i nterest a n d eff orts of p har m ace utical c o m pa nies a n d ma n y aca de mic researc h 
gr o u ps, ver y fe w c o m p o u n ds ha ve reac he d cli nical trials.  He nce, t he nee d f or t he de vel o p me nt 
of safe a n d effecti ve D G A T i n hi bit ors re mai ns hi g h. 
T here are c urre ntl y n o k n o w n st rate gies f or a s mall m olec ule a p pr oac h t o l o wer D G A T 2 
e x pressi o n s pecificall y i n li ver a n d/ or a di p ose tiss ue.  I n c o nt rast, I SI S 4 8 4 1 3 7 has bee n s h o w n 
t o s pecificall y l o wer he patic D G A T 2 e x pressi o n an d, ma y t heref ore, ha ve t he p ote ntial t o re d uce 
li ver steat osis a n d de vel o p me nt of N A S H.   


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
2 9
 
T his s h ort-ter m st u d y will assess c ha n ges i n he pa tic steat osis o ver a 1 3- wee k treat me nt peri o d i n 
a patie nt p o p ulati o n wit h hi g her ris k f or de ve l o p me nt of N A F L D a n d N A S H, o bese T 2 D M wit h 
ele vate d H b A 1c.  C ha n ges i n t he P D F F i n t he li ver will be esti mate d b y M RI, referre d t o as 
M RI- P D F F.  It is t he fracti o n of  t he M RI visi ble pr ot o ns b o u n d t o fat di vi de d b y all pr ot o ns i n 
t he li ver ( b o u n d t o fat a n d water).  T he li ver M RI- P D F F has bee n utilize d as a n o ni n vasi ve 
bi o mar ker of he patic steat osis as it has bee n st r o n gl y c orrelate d wit h hist ol o gic gra de of he patic 
steat osis (D ulai et al. 2 0 1 6 ; Patel et al. 2 0 1 6 ) a n d has bee n use d i n trials as a n o bjecti ve, 
q ua ntitati ve, precise a n d re pr o d uci ble n o ni n vasi ve i ma gi n g bi o mar ker of li ver fat c o nte nt 
(Le et al. 2 0 1 2 ; Ka n g et al. 2 0 1 1 ).  T he pri mar y e n d p oi nt is t o assess a bs ol ute c ha n ges i n t he 
li ver M RI- P D F F after t hera p y wit h I SI S 4 8 4 1 3 7 or place b o, as l o n git u dinal c ha n ges i n P D F F 
ha ve i de ntifie d s u bjects wit h re d uce d steat osis gra de wit h re d ucti o n of P D F F (Mi d dlet o n et al.  
2 0 1 7 ).   
2. 3
 I SI S
 
4 8 4 1 3 7
 
2. 3. 1
 Mec h a nis m
 
of
 
Acti o n
 
I SI S 4 8 4 1 3 7 is a sec o n d- ge nerati o n 2′-O -( 2- met h o x yet h yl) ( 2′- M O E) c hi meric A S O i n hi bit or of 
t he m olec ular tar get D G A T 2.  It is c o m ple me ntar y t o a re gi o n wit hi n t he n o n-c o di n g re gi o n of 
t he D G A T 2 R N A a n d bi n ds t o t he R N A b y Wats o n a n d Cric k base pairi n g.  T he h y bri dizati o n 
( bi n di n g) of I SI S 4 8 4 1 3 7 t o t he c o g nate R N A res ults i n t he R Nase H 1- me diate d de gra dati o n of 
t he D G A T 2 R N A, t h us pre ve nti n g pr o d ucti o n of t he D G A T 2 pr otei n.  Ma xi mal a ntise nse-
me diate d re d ucti o n of tar get R N A le vels is t y pi call y greater t ha n 9 0 % of c o ntr ol le vels i n 
se nsiti ve tiss ues (Cr o o ke a n d Be n nett 1 9 9 6 ; Z ha n g et al. 2 0 1 0 ).  F urt her m ore, re d ucti o n i n tar get 
R N A le vels usi n g t his a p pr oac h c o rrelates directl y wit h a s u bse q uent re d ucti o n i n tar get pr otei n 
le vels.   
2. 3. 2
 C he mistry
 
I SI S 4 8 4 1 3 7 is a sec o n d ge nerati o n 2′- M O E c hi meric a ntise nse dr u g.  C he micall y, I SI S 4 8 4 1 3 7 
is a s y nt hetic oli g o mer of 2 0 n ucle oti des (i.e., a 2 0- mer) t hat are c o n necte d se q ue ntiall y b y 
p h os p h or ot hi oate li n ka ges.  T he n ucle oti de se q ue nce of I SI S 4 8 4 1 3 7 ( Fi g ure 1 ) is f ull y 
c o m ple me nt ar y t o a 2 0- n ucle oti d e stretc h wit hi n t he sec o n d i ntr o nic re gi o n of t he D G A T 2 ge ne 
at p ositi o n 6 – 1 5.  Str uct urall y, t he oli g o n ucle o ti de has 3 re gi o ns.  T w o ( 2) of t he m, t he 
5 n ucle oti des at t he 5 ′ e n d a n d t he 5 n ucle oti des at t he 3′ e n d, are c o m p ose d of 2-O -( 2-
met h o x yet h yl) ( M O E)- m o difie d ri b o n ucle oti des.  T hese M O E- m o difie d n ucle oti des c o nfer ( 1) 
i ncrease d affi nit y t o t he tar get m R N A (Alt ma n n et al. 1 9 9 6 ; Mc Ka y et al. 1 9 9 9 ), ( 2) i ncrease d 
resista nce t o e x o n ucleases a n d e n d o n ucleases (t here b y i ncreasi n g sta bilit y i n tiss ue) 
(Gear y et al. 2 0 0 3 ), a n d ( 3) a meli orati o n of s o me of t he hi g h- d ose t o xicities, t here b y res ulti n g i n 
a n i m pr o ve d safet y pr ofile c o m pare d t o first ge nerati o n a ntise nse dr u gs c o ntai ni n g 
p h os p h or ot hi oate m o difie d o li g o de o x y n ucle oti des ( D N A) (He nr y et al. 2 0 0 0 ).  T he t hir d re gi o n, 
t he ce ntral p orti o n of t he olig o n ucle oti de, is c o m p ose d of 1 0 oli g o de o x y n ucle oti des.  T his 
c hi meric desi g n is calle d a M O E- Ga p mer, a n d I SI S 4 8 4 1 3 7 e m pl o ys t his c hi meric str uct ure t o 
e na ble use of t he R Nase H 1- mec ha nis m f or a ntise nse acti vit y.  T his is beca use w hile t he 2 ′- M O E 
m o dificati o n c o nfers i ncrease d sta bilit y a n d affi nit y, it d oes n ot s u p p ort R Nase H 1 catal ysis of 
R N A h y bri dize d t o 2 ′- M O E- m o difie d n ucle oti des ( Mc Ka y et al. 1 9 9 9).  T his is ca use d b y 
c o nf or mati o nal c ha n ges i n d uce d  i n t he heter o d u ple x b y 2′-al k o x y: R N A h y bri ds t hat are n ot 
rec o g nize d b y R Nase H 1 e nz y me (I n o ue et al. 1 9 8 7; M o nia et al. 1 9 9 3 ).  B y li miti n g t he 2′- M O E 




I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
3 1
 
P har mac o ki netics a n d Pr o d uct Meta b olis m i n A ni mals 
D ose- de pe n de nt e x p os ures t o I SI S 4 8 4 1 3 7 i n plas ma a n d li ver a n d ki d ne y tiss ues were 
esta blis he d i n t he 1 3- wee k m o use a n d m o n ke y t o xicit y st u dies at d oses bet wee n 4 a n d 
1 0 0 m g/ k g/ w k a n d bet wee n 4 a n d 4 0 m g/ k g/ w k, res p ecti vel y.  A half-life of a p pr o xi matel y 2 t o 
3 wee ks was o bser ve d i n m o n ke ys.  P har mac o ki ne tics o bser ve d i n m o n ke ys f or t his class of 
c o m p o u n ds t y picall y pre dict t he o bser ve d plas ma e x p os ure le vels i n h u ma ns o n t he basis 
of m g/ k g e q ui vale nt d oses ( Gear y et al. 2 0 0 3 ; Y u et al. 2 0 0 7 ). 
I SI S 4 8 4 1 3 7 was hi g hl y b o u n d t o plas ma pr otei ns, greater t ha n 9 6 % i n m o use, m o n ke y, a n d 
h u ma n plas ma st u dies.  T he hi g h pr otei n bi n di n g pre ve nts gl o mer ular  filtrati o n a n d li mits uri nar y 
e xcreti o n.  T he bi n di n g sites f or t hese t y pes of h y dr o p hilic dr u gs differ fr o m t he bi n di n g sites of 
l o w m olec ular wei g ht h y dr o p h o bic dr u gs; t h us, fe w D DIs o n t he le ve l of plas ma pr otei n bi n di n g 
are e x pecte d at cli nicall y -rele va nt c o nce ntrati o ns. 
T o xic ol o g y a n d Safet y P har mac ol o g y 
Ge neral t o xic ol o g y st u dies were c o n d ucte d wit h I SI S 4 8 4 1 3 7 i n t he m o use a n d m o n ke y f or 
1 3 wee ks of treat me nt.  D ose a d mi nistrati o n wa s b y S C i njecti o n at wee kl y d oses of 4, 1 2, 4 0, 
a n d 1 0 0 m g/ k g/ w k I SI S 4 8 4 1 3 7 i n mice or 4, 8, 1 2, a n d 4 0 m g/ k g/ w k I SI S 4 8 4 1 3 7 i n m o n ke ys. 
T he m ost n ote w ort h y fi n di n gs o bser ve d i n mice a n d m o n ke y t o xic ol o g y st u dies f oll o wi n g 
1 3- wee ks of I SI S 4 8 4 1 3 7 treat me nt were, i n ge neral,  n o n-s pecific class effects t hat are t y pical 
f or 2′- M O E A S Os (He nr y et al. 2 0 0 8 ).  T here was n o dr u g-relate d m ortalit y or c ha n ges i n 
cli nical si g ns u p t o t he hi g hest  d oses teste d ( 1 0 0 m g/ k g i n mice a n d 4 0 m g/ k g i n m o n ke ys).  
Re d ucti o n i n platel et c o u nt ( 3 3, 0 0 0/ m m 3) was o bser ve d i n a si n gle m o n ke y ( 1 of 1 0) i n t he 
1 2 m g/ k g/ w k d ose gr o u p o n Da y 9 3, wit h n o cli nical  si g ns i n t his a ni mal, a n d n o micr osc o pic 
e vi de nce of he m orr ha ge.  Si nce platelet re d ucti o n bel o w 2 0 0, 0 0 0/ m m 3 was n ot o bser ve d i n a n y 
ot her a ni mals i n t he st u d y, i ncl u di n g t he hi g h d ose of 4 0 m g/ k g/ w k, t he relati o ns hi p t o t he test 
article is u nclear. 
I n viv o safet y p har mac ol o g y st u dies c o n d ucte d t o date i n dicate t hat I SI S 4 8 4 1 3 7 ha d n o effects 
o n car di o vasc ular para meters ( b l o o d press ure [ B P], heart rate [ H R] a n d electr ocar di o gra m 
[ E C G]) or p ul m o nar y f u ncti o n or ne ur o be ha vi or i n m o n ke ys.  Ge netic  t o xicit y st u dies (t he A mes 
assa y a n d i n vitr o c hr o m os o mal a berrati o ns i n C hi nese ha mster l u n gs [ C H L cells]) were 
ne gati ve. 
T here were n o t o xic ol o gicall y si g nifica nt fi n di n gs at d oses u p t o 1 2 m g/ k g/ w k f or 1 3 wee ks i n 
t he m o use a n d m o n ke y st u dies, a n d t heref ore t here is s ufficie nt t hera pe utic mar gi n t o s u p p ort t he 
safe cli nical use of I SI S 4 8 4 1 3 7 at t he pr o p ose d cli nical d oses a n d re gi me n.   
2. 3. 4
 Cli nic al
 
E x perie nce
 
T he safet y a n d t olera bilit y of I SI S 4 8 4 1 3 7 was e val uate d i n a t otal of 4 0 healt h y o ver wei g ht 
s u bjects i n a d o u ble- bli n de d, place b o-c o ntr olle d, d ose-escalati o n P hase 1 st u d y I SI S 4 8 4 1 3 7-
C S 1.  Of t hese 4 0 s u bjects, 3 0 recei ve d I SI S 4 8 4 1 3 7 ( 1 2 i n t he si n gle- d ose c o h orts a n d 1 8 i n t he 
m ulti ple- d ose c o h orts), a n d 1 0 recei ve d place b o.  I SI S 4 8 4 1 3 7 was well-t olerate d at d oses u p t o 
3 0 0 m g/ w k f or 6 wee ks.  T here were n o S A Es a n d a ll re p orte d A Es were mil d i n se verit y.  T here 
were n o d ose- de pe n de nt cli nical l y mea ni n gf ul tre n ds i n lab orat or y assess me nts.   


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
3 2
 
2. 4  
R ati o n ale f or D ose a n d Sc he d ule of A d mi nistr ati o n 
T he safet y data o btai ne d i n t he P hase 1 st u d y (I SI S 4 8 4 1 3 7- C S 1) as we ll as t he cli nical 
e x perie nce wit h se veral ot her 2 ′- M O E- m o difie d A S Os (Se well et al. 2 0 0 2 ; C hi et al. 2 0 0 5 ; 
Kastelei n et al. 2 0 0 6 ), s u p p orts t he d osi n g re gi me n pla n ne d f or t his P hase 2 st u d y.  T he pla n ne d 
re gi me n has bee n e m pl o ye d safel y i n pre vi o us cli nical st u dies wit h a n u m ber of ot her A S Os.  
T his class of A S Os has bee n safel y a d mi nist ere d i ntra ve n o usl y (I V) a n d s u bc uta ne o usl y i n 
m ulti ple cli nical st u dies at d oses u p t o 1 0 0 0 m g ( K w o h 2 0 0 8 ; Cr o o ke et al. 2 0 1 6 ) a n d treat me nt 
d urati o ns t hat e xce e d 2 4 m o nt hs.   
T he c urre ntl y pr o p ose d 2 5 0 m g I SI S 4 8 4 1 3 7 d ose le ve l was selecte d base d o n res ults fr o m t he 
pre vi o us I SI S 4 8 4 1 3 7- C S 1 P hase 1 cli nical st u d y ( d oses 5 0 t o 4 0 0 m g) t hat s h o we d a 
satisfact or y safet y pr ofile wit h t hese d ose le vels after 6 wee ks ( 8 t otal d oses) of treat me nt.  
A d diti o nall y, se veral A S Os of t his class ha ve de m o nstrate d si g nifica nt efficac y a n d acce pta ble 
safet y pr ofiles at a si milar d ose le vel f or 1 3 wee ks a n d l o n ger (Ac ker ma n n et al. 2 0 1 6 ; Di ge ni o  
et al. 2 0 1 6; D uell et al. 2 0 1 6 ) 
Wee kl y a d mi nistrati o n f or 1 3- wee ks is als o s u p p orte d b y t he I SI S 4 8 4 1 3 7 n o ncli nical 1 3- wee k 
t o xic ol o g y st u d y (see I n vesti gat ors Br oc h ure).  Ki d ne y, li ver, a n d a di p ose tiss ue c o nce ntrati o ns 
of I SI S 4 8 4 1 3 7 c ollecte d after 1 3 wee ks of d os i n g d uri n g a m o n ke y t o xic ol o g y st u d y i n dicate 
t hat tiss ue distri b uti o n f or t his c o m p o u n d is c o nsiste nt wit h pre vi o usl y a d mi nistere d a ntise nse 
oli g o n ucle oti des.  P ost- dis tri b uti o n plas ma c o nce ntrati o ns (i.e., ter mi nal eli mi nati o n p hase) of 
I SI S 4 8 4 1 3 7 are e x pecte d t o be i n e q uili bri u m wit h tiss ue c o nce ntrati o ns i n h u ma ns, as was 
o bser ve d i n m o n ke ys, mice, a n d rats f or si milar 2 ′- M O E ga p mers.  Wit h a n esti mate d tiss ue 
half-life of a p pr o xi matel y 2- 3 wee ks f or I SI S 4 8 4 1 3 7 pre dicte d f or h u ma ns base d o n pre vi o us 
e x perie nce wit h ot her sec o n d ge nerati o n A S Os ( Y u et al. 2 0 0 9 ), ac hie vi n g stea d y-state 
c o nce ntrati o ns i n t he li ver (t he tar get or ga n) will be a pr ol o n ge d pr ocess (e. g., ti me t o 
a p pr o xi matel y 9 0 % of stea d y-state i n tiss ues is esti mate d t o ta ke a b o ut 8 wee ks wit h 
o nce- wee kl y d osi n g re gi me n).  T hirtee n ( 1 3) we e ks of st u d y treat me nt is a s ufficie nt treat me nt 
d urati o n t o o bser ve c ha n ges i n li ver fat c o nt e nt a n d i m pr o ve me nts i n I R i n t his patie nt 
p o p ulati o n. 
2. 5
 Ris k
 
Assess me nt
 
T he k n o w n p ote ntial ris ks t o st u d y partici pa nts a ss ociate d wit h I SI S 4 8 4 1 3 7 are ela b orate d o n i n 
t he G ui da nce t o I n vesti gat or secti o n of t he I SI S 4 8 4 1 3 7 I n vesti gat or’s Br oc h ure.  Ris ks 
ass ociate d wit h D G A T 2 re d ucti o n are n ot a n tici pate d i n t his s h ort-ter m trial. 
3.
 E X P E RI M E N T A L
 
P L A N
 
3. 1
 St u d y
 
Desi g n
 
T his is a P hase 2 m ultice nter, d o u ble- bli n d, ra n d o mize d, stratifie d, place b o-c o ntr olle d st u d y i n 
s u bjects wit h t y pe 2 dia betes a n d e vi de nce of he patic steat osis see n o n M RI sca n.  S u bjects will 
be stratifie d base d o n t he li ver c o nte nt b y M R I- P D F F d uri n g t he R u n-I n Peri o d ( < 2 0 % vs. 
≥ 2 0 %).  S u bjects will be ra n d o mize d i n a 2: 1 rati o t o recei ve S C treat me nt wit h eit her 
I SI S 4 8 4 1 3 7 2 5 0 m g or place b o ( See St u d y Desi g n a n d Treat me nt Sc he ma ).   


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
3 3
 
3. 2  
N u m ber of St u d y Ce nters 
T his st u d y will be c o n d ucte d at m ulti ple ce nters w orl d wi de. 
3. 3  
N u m ber of S u bjects 
A p pr o xi matel y 4 5 s u bjects are pla n ne d t o be  e nr olle d i n t his st u d y, ra n d o mize d 2: 1 t o 
I SI S 4 8 4 1 3 7 or place b o.   
3. 4  
O ver all St u d y D ur ati o n a n d F oll o w- u p 
T he st u d y will c o nsist of Scree ni n g a n d R u n-I n, Treat me nt, a n d P ost- Treat me nt  Peri o ds.  Please 
refer t o t he Sc he d ule of Pr oce d ures i n A p pe n di x A .  T he e x pecte d d urati o n of t he st u d y will be 
u p t o 6 wee ks of Scree ni n g wit h t he R u n-I n Peri o d, 1 3 w ee ks of St u d y Dr u g d osi n g, a n d 
1 3 wee ks of p ost-treat me nt e val uati o ns, f or a t otal of u p t o 3 2 wee k s of partici pati o n. 
S u bjects ma y be re q uire d t o atte n d a d diti o nal vis its f or m o nit ori n g of a d verse e ve nts ( A E) or 
a b n or mal i n vesti gati o n res ults.  T he fre q ue nc y of a d diti o nal m o nit ori n g will be deter mi ne d b y 
t he St u d y Me dical M o nit or i n c o ns ultati o n wit h t he I n vesti gat or. 
3. 4. 1  
Scree ni n g a n d R u n-I n 
S u bject eli gi bilit y f or t he st u d y will  be deter mi ne d wit hi n 6 wee ks pri or t o st u d y e ntr y, c o nsisti n g 
of u p t o 2- wee k Scree ni n g ( Wee k - 6 t o Wee k - 5) a n d a 4- wee k R u n-I n Peri o d ( Wee k - 4 t o 
Wee k - 1). 
D uri n g t he be gi n ni n g of t he R u n-I n Peri o d (a p pr o xi m atel y Wee k - 4 t o Wee k - 3), s u bjects will 
ha ve a baseli ne he patic M RI t o assess eli gi bilit y wit h li ver fat c o nte nt.  M RIs will be c o n d ucte d 
usi n g sta n dar dize d pr oce d ures a n d setti n gs.  M RIs  will be e val uate d b y a ce ntral rea der, bli n de d 
t o t he s u bject’s treat me nt assi g n me nt, t o assess li ver fat a n d li ver size.  Patie nt will als o be 
re q uire d t o c o m plete a S C T olera bilit y Assess me nt at a n y visit d uri n g t he Scree ni n g or R u n-I n 
Peri o d.   
3. 4. 2
 Tre at me nt
 
Eli gi ble s u bjects will be ra n d o mize d will re p ort t o t he St u d y Ce nter f or st u d y treat me nt e ver y 
wee k f or 1 3 wee ks ( Wee k 1- Wee k 1 3).  
3. 4. 3
 P ost- Tre at me nt
 
S u bjects are t o ret ur n t o t he St u d y Ce nter f or f oll o w- u p visits at t he f oll o wi n g ti me p oi nts after 
t he last d ose:  1 wee k ( P T 1), 2 wee ks ( P T 2), 3 wee ks ( P T 3), 4 wee ks ( P T 4), 6 wee ks ( P T 6), 
8 wee ks ( P T 8), 1 2 wee ks ( P T 1 2).  T he fi nal st u d y  visit will occ ur 1 3 wee ks after t he last d ose 
a n d via tele p h o ne. 
C o m plete d s u bjects will ha ve a P ost- Treat me nt he patic M RI t o assess li ver fat c o nte nt a n d 
v ol u me 2 wee ks after t he last d ose.  T he ti mi n g of t he P ost- Treat me nt M RI f or s u bjects w h o 
ter mi nate earl y fr o m t he Treat me nt Peri o d is o utli ne d i n Secti o n 6. 1. 4  a n d A p pe n di x A.   
3. 5
 E n d- of- St u d y
 
T he E n d- of- St u d y is defi ne d as w he n t he last s u bject has ha d t heir last visit. 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
3 4
 
4.
 S U B J E C T
 
E N R O L L M E N T
 
4. 1
 Scree ni n g
 
Bef ore s u bjects ma y be e nr olle d i nt o t he St u d y, t he S p o ns or a n d desi g nate d c o ntract researc h 
or ga nizati o n ( C R O) re q uires a c o p y of t he St u d y Ce nter’s writte n i nst it uti o nal re vie w b oar d 
(I R B) a p pr o val of t he pr ot oc ol, i nf or me d c o nse nt f or m, a n d all ot her s u bject i nf or mati o n a n d/ or 
recr uit me nt material. 
S u bjects or t heir le gall y acce pta ble re prese ntati ves m ust si g n t he c o nse nt f or m bef ore a n y 
scree ni n g tests or assess me nts are perf or me d.  At t he ti me of c o nse nt, t he s u bject will be 
c o nsi dere d e nr olle d i nt o t he St u d y a n d will be assi g ne d a u ni q ue scree ni n g n u m ber bef ore a n y 
St u d y pr oce d ures, i ncl u di n g scree ni n g pr oce d ures, are perf or me d.  I n t he e ve nt t he s u bject is 
re-c o nse nte d or re-scree ne d t he patie nt m ust be gi ve n a ne w scree ni n g n u m ber.  Scree ni n g 
n u m bers, o nce assi g ne d, will n ot be re- use d. 
4. 2
 R a n d o mi z ati o n
  
S u bjects will be ra n d o mize d after all Scree ni n g a n d R u n-I n assess me nts t hr o u g h Wee k - 1 ha ve 
bee n c o m plete d a n d after t he I n vesti gat or has verifie d t hat t he y are eli gi ble per criteria i n 
Secti o ns 5. 1  a n d 5. 2 .  N o s u bject ma y be gi n treat me nt pri or t o ra n d o mizati o n a n d assi g n me nt of 
a u ni q ue s u bject i de ntificati o n n u m ber. 
All s u bjects will be ra n d o mize d usi n g a n a ut o ma te d s yste m (I X R S).  Su bjects will be stratifie d 
base d o n li ver fat c o nte nt res ults fr o m t he M R I c o n d ucte d i n t he R u n-I n Peri o d ( < 2 0 % or 
≥ 2 0 %), a n d t he n s u bjects will be ra n d o mize d i n a 2: 1 rati o t o recei ve S C treat me nt wit h eit her 
I SI S 4 8 4 1 3 7 2 5 0 m g or place b o.  T he S p o ns or or desi g nee will pre pare t he ra n d o mizati o n list. 
4. 3  
Re pl ace me nt of S u bjects 
S u bjects w h o wit h dra w fr o m t he st u d y will n ot be re place d. 
4. 4  
U n bli n di n g of Tre at me nt Assi g n me nt 
T he S p o ns or a n d all s u bjects, m o nit ors, a n d St u d y Ce nter pers o n nel relate d t o t he st u d y will be 
bli n de d t hr o u g h o ut t he st u d y.  H o we ver, if a s u bj ect has s uffere d a Seri o us A d verse E ve nt ( S A E) 
(as defi ne d i n Secti o n 9. 3. 3 ), a n d/ or w he n k n o wle d ge of t he treat me nt assi g n me nt will i m pact t he 
cli nical ma na ge me nt of t he s u bject, t he I n vesti gat or will ha ve t he a bilit y t o u n bli n d t he treat me nt 
assi g n me nt f or t hat s u bject  usi n g t he a ut o mate d I X R S.  T h e S p o ns or or desi g nee will be 
i nf or me d of t he u n bli n di n g of a s u bject wit hi n 2 4 h o urs.  A n u n bli n de d ra n d o mizati o n sc he ma 
will be mai ntai ne d sec urel y b y t he S p o ns or’s desi g nate d ve n d or.  I n a d diti o n, all s us pecte d 
u ne x pecte d seri o us a d verse react i o ns ( S U S A Rs) will be u n bli n de d b y t he S p o ns or or desi g nee 
f or re g ulat or y re p orti n g (see Secti o n 9. 2 ). 
E ver y reas o na ble atte m pt s h o ul d be ma de t o c o m p lete t he earl y ter mi natio n st u d y pr oce d ures a n d 
o bser vati o ns (see A p pe n dices A  a n d C ) pri or t o u n bli n di n g, as k n o wle d ge of t he treat me nt ar m 
c o ul d i nfl ue nce s u bject assess me nt. 
I n a d diti o n, t he safet y tea m assi g ne d t o re vie w rele va nt St u d y Dr u g safet y a n d t olera bilit y data 
d uri n g t he st u d y i n a bli n de d fas hi o n will als o ha ve  t he a bilit y t o re q uest t he I o nis Dr u g Safet y 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
3 5
 
O versi g ht C o m mittee, c haire d b y t he C hief Me dical Officer, f or u n bli n di n g t he treat me nt 
assi g n me nt if nee de d f or safet y a n d data i nter pretati o n. 
5.
 S U B J E C T
 
E LI GI BI LI T Y
 
T o be eli gi ble t o partici pate i n t his st u d y ca n di dates m ust meet t he f oll o wi n g eli gi bilit y criteria at 
Scree ni n g a n d t hr o u g h ra n d o mizati o n or at t he ti me p oi nt s pecifie d i n t he i n di vi d ual eli gi bilit y 
criteri o n liste d. 
5. 1
 I ncl usi o n
 
Criteri a
 
1.  M ust ha ve gi ve n writte n i nf or me d c o nse nt (si g ne d a n d date d) a n d a n y a ut h orizati o ns 
re q uire d b y l ocal la w a n d be a ble t o c o m pl y wit h all st u d y re q uire me nts 
2.  Males or fe males.  A ge d 1 8 t o 7 5, i ncl usi ve, at t he ti me of i nf or me d c o nse nt 
3.  Fe males m ust be n o n- pre g na nt a n d n o n-lactati n g, a n d eit her s ur gica ll y sterile (e. g., t u bal 
occl usi o n, h ysterect o m y, bilateral sal pi n gect o m y, bilateral o o p h orect o m y) or p ost-
me n o pa usal ( defi ne d as 1 2 m o nt hs of s p o nta n e o us a me n orr hea i n fe males > 5 5 years of 
a ge or, i n fe males ≤ 5 5 years, 1 2 m o nt hs of s p o nta ne o us a me n orr hea wit h o ut a n 
alter nati ve me dical ca use a n d F S H le vels i n  t he p ost me n o pa usal ra n ge f or t he la b orat or y 
i n v ol ve d) 
Males m ust be s ur gicall y sterile, a bsti ne nt * or, if e n ga ge d i n se x ual relati o ns wit h a 
fe male of c hil d- beari n g p ote ntial, t he s u bject m ust be usi n g a n acce pta ble c o ntrace pti ve 
met h o d (refer t o Secti o n 6. 3. 1 ) fr o m t he ti me of si g ni n g t he i nf or me d c o nse nt f or m u ntil 
at least 1 3 wee ks after t he last d ose of St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) 
* A bsti ne nce is o nl y acce pta ble as tr ue a bsti n e nce, i.e., w he n t his is i n li ne wit h t he 
preferre d a n d us ual lifest yle of t he patie nt.  Peri o dic a b sti ne nce (e. g., cale n dar, o v ulati o n, 
s y m pt ot her mal, p ost- o v ulati o n met h o ds), declarati o n of a bsti ne nce f or t he d urati o n of a 
trial a n d wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n. 
4.  B o d y Mass I n de x ( B MI) ≥ 2 7. 0 - ≤ 3 9. 0 k g/ m2 at Scree ni n g 
5.  Dia g n osis of T 2 D M wit h a n H b A 1c ≥ 7. 3 % a n d ≤ 9. 5 % at Scree ni n g 
6.  S u bjects m ust ha ve bee n o n sta ble m o n o t her a p y or sta ble c o m bi n ati o n t hera p y of t he 
f oll o wi n g oral a nti dia betic a ge nts:  metf or mi n, s ulf o n yl urea ( S U), di pe pti d yl pe pti dase-
I V ( D P PI V i n hi bit or) or s o di u m gl uc ose li ke tra ns p ort pr otei n 2 ( S G L T 2) i n hi bit or f or a 
mi ni m u m of 3 m o nt hs pri or t o scree ni n g e val uati o n a n d will be re q uire d t o c o nti n ue t heir 
sta ble d ose of oral a nti dia betic t hera p y t hr o u g h o ut t he st u d y.  T he use of 
t hiaz oli di ne di o nes (e. g., pi o glitaz o ne, r osi glitazo ne) a n d i njecta ble a nti dia betic t hera p y is 
n ot per mitte d (e. g., i ns uli n, gl uca g o n-li ke pe pti de [ G L P 1 a nal o gs])   
7. ≥ 1 0 % li ver fat as assesse d b y M RI- P D F F pri or t o ra n d o mizati o n 
8.  Sta ble b o d y wei g ht (i.e., n ot var yi n g b y > 5 % f or at least 3 m o nt hs) bef ore Scree ni n g 
9.  A gree t o mai ntai n c urre nt diet a n d e xercise re gi me n 
1 0. A gree t o a bstai n fr o m alc o h olic be vera ges f o r at least 4 8 h o urs pri or t o cli nic visits a n d 
n ot i ncrease alc o h ol c o ns u m pti o n d uri n g t he st u d y 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
3 6
 
5. 2
 E xcl usi o n
 
Criteri a
 
1.  Cli nicall y-si g nifica nt  a b n or malities  i n  me di cal hist or y (e. g., pre vi o us ac ute c or o nar y 
s y n dr o me wit hi n 6 m o nt hs of Scree ni n g, maj or s ur ger y wit hi n 3 m o nt hs of Scree ni n g) or 
p h ysical e xa mi nati o n 
2.  All ce ntral la b orat or y res ults pr i or t o Da y 1 as f oll o ws, or a ny ot her cli nicall y-si g nifica nt 
a b n or malities i n scree ni n g la b orat or y val ues t hat w o ul d re n der a s u bject u ns uita ble f or 
i ncl usi o n: 
a.  Uri ne  pr otei n/creati ni ne  ( P/ C ) rati o > 0. 2 m g/ m g.  I n t he e ve nt of P/ C rati o a b o ve t his 
t hres h ol d eli gi bilit y ma y be c o nfir med b y a q ua ntitati ve t o tal uri ne pr otei n 
meas ure me nt of < 3 0 0 m g/ 2 4- hr at Scree ni n g 
b.  Persiste ntl y p ositi ve test (i ncl u di n g trace) f o r bl o o d o n uri nal ysis.  I n t he e ve nt of a 
p ositi ve test eli gi bilit y ma y be c o nfir me d wit h uri ne micr osc o p y s h o wi n g < 5 re d 
bl o o d cells ( R B C) per hi g h p o wer fiel d ( Persist e ntl y p ositi ve defi ne d as 2 o ut of 3 ca n 
be c o nfir me d d uri n g t he R u n-I n Peri o d) 
c.  Ser u m creati ni ne > u p per li mit of n or mal ( U L N) 
d.  Esti mate d gl o mer ular filtrati o n rate ( G F R) < 6 0 m L/ mi n (as deter mi ne d b y t he 
C oc kcr oft- Ga ult E q uati o n f or creati ni ne cleara nce) 
e.  Ala ni ne a mi n otra nsferase ( A L T) or as partate a mi n otra nsferase ( A S T) > 1. 5 U L N 
f.  T otal bilir u bi n > U L N 
g.  Ha ve a c urre nt or pre vi o us dia g n osis  of Gil bert’s disease at Scree ni n g 
h.  Platelet c o u nt < 1 7 0, 0 0 0/ m m 3 ( < 1 7 0 x 1 09/ L)  
3.  S h o w e vi de nce of u nc orrecte d h y p ot h yr oi dis m  or h y pert h yr oi dis m h or m o ne res ults at 
Scree ni n g.  S u bjects recei vi n g d ose-sta ble t h yr oi d re pla ce me nt t hera p y f or at least 
3 m o nt hs pri or t o Scree ni n g will be all o we d t o partici pate as l o n g as t h yr oi d tests 
( T S H/ T 3/ T 4) s h o w t hat s u bject is e ut h yr oi d 
4.  Hist or y of s oli d or ga n tra ns pla ntati o n or re nal dial ysis 
5.  Cli nicall y-si g nifica n t c o m plicati o ns of dia betes (e. g., hist or y of pai nf ul ne ur o pat h y, 
ne p hr o pat h y, pr oliferati ve reti n o pat h y a n d/ or f o ot ulcers) 
6.  S u bjects o n H M G- C o A re d uctase i n hi bit ors me dicati o ns (‘stati ns’) m ust be o n a sta ble 
d ose a n d re gi me n f or ≥ 3 m o nt hs pri or t o Scree ni n g.  Ot her li pi d l o weri n g t hera pies 
i ncl u di n g fis h oils or prescri pti o n li pi d-re g ulati n g dr u gs (e. g., bile-aci d se q uesteri n g 
resi ns, fi brates a n d t heir deri vati ves a n d ezeti mi be) are n ot per mitte d.  Alter nate li pi d 
l o weri n g re gi me ns s h o ul d be disc usse d a n d a p pr o ve d wit h t he S p o ns or Me dical M o nit or 
or desi g nee 
 
 


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7.  K n o w n hist or y of or e vi de nce of li ver disease wit h a p ositi ve test f or h u ma n 
i m m u n o defi cie nc y vir us ( HI V), he patitis C ( H C V) or c hr o nic he patitis B ( H B V) or 
c hr o nic li ver disease ot her t ha n N A S H i n cl u di n g alc o h olic li ver disease, Wils o n’s 
disease, he m oc hr o mat osis, or ir o n o verl oa d, Al p ha- 1-a ntitr y psi n ( A 1 A T) deficie nc y, 
pri or k n o w n dr u g-i n d uce d li ver i nj ur y, k n o w n or s us pecte d he pat ocell ular carci n o ma 
( H C C), c urre nt place me nt o n a li ver tra ns pla nt list, or M E L D sc ore > 1 2, esta blis he d 
fi br osis ≥ Sta ge 3 fi br osis ( Scale 0- 4) or a n y cirr h osis 
8.  Mali g na nc y wit hi n 5 years, e xce pt f or basal or s q ua m o us cell carci n o ma of t he s ki n or 
carci n o ma i n sit u of t he cer vi x t hat has bee n s uccessf ull y treate d.  S u bjects wit h a hist or y 
of ot her mali g na ncies t hat ha ve bee n treate d wit h c urati ve i nte nt a n d w hic h ha ve n o 
rec urre nce wit hi n 5 years ma y als o be eli gi ble if a p pr o ve d b y t he S p o ns or Me dical 
M o nit or 
9.  Treat me nt wit h a n ot her i n vesti gati o nal dr u g, bi ol o gical a ge nt, or de vice wit hi n 1 m o nt h 
of Scree ni n g, or 5 half-li ves of i n ve sti gati o nal a ge nt, w hic he ver is l o n ger 
1 0. Treat me nt wit h a n y n o n- I O N- or I SI S- o li g o n ucle oti de (i ncl u din g s mall i nterferi n g 
ri b o n ucleic aci d [si R N A]) at a n y ti me or pri or treat me nt wit h a n I O N- or 
I SI S- oli g o n ucle oti de wit hi n 9 m o nt hs of Scree ni n g.  S u bjects w h o ha ve pre vi o usl y 
recei ve d o nl y a si n gle- d ose of a n I SI S- oli g o n ucle oti de as part of a cli nical st u d y ma y be 
i ncl u de d as l o n g as a d urati o n of ≥ 4 m o nt hs has ela pse d si nce d osi n g 
1 1. Rece nt hist or y of, or c urre nt dr u g or alc o h ol a b use.  Re g ular a n d e xcessi ve use of alc o h ol 
wit hi n 6 m o nt hs pri or t o Scree ni n g ( > 7 dr i n ks/ wee k f or fe males, > 1 4 dri n ks/ wee k f or 
males ( 1 dri n k = 5 o u nces ( 1 5 0 m L) of wi ne or 1 2 o u nces ( 3 6 0 m L) of beer or 1. 5 o u nces 
( 4 5 m L) of har d li q u or), or use of s oft dr u gs (s uc h as marij ua na) wit hi n 3 m o nt hs pri or t o 
Scree ni n g, or har d dr u gs (s uc h as c ocai ne a n d p he nc ycli di ne [ P C P]) wit hi n 1- year pri or 
t o Scree ni n g, or p ositi ve uri ne dr u g scree n f or t hese dr u gs at Scree ni n g 
1 2. C o nc o mita nt me dicati o n restricti o ns: 
a.  Use of a ge nts (i ncl u di n g her bal or o ve r-t he c o u nter wei g ht l oss pre parati o ns) or 
me dicati o ns k n o w n t o si g nifica ntl y i m pact b o d y wei g ht wit hi n 3 m o nt hs pri or (e. g., 
si b utra mi ne, p he neta mi ne a n d orlistat) 
b.  c hr o nic use of s yste mic c ortic oster oi ds 
c.  ot her a nti dia betic me di cati o ns n ot o utli ne d i n I ncl usi o n Criteria # 6, 
d.  ot her me dicati o ns, per I n vesti gat or, k n o w n t o ca use li ver t o xicit y (e. g., c hr o nic 
aceta mi n o p he n use) or steat osis (e. g., a mi o dar o ne, met h otre xate, ta m o xife n, 
car ba maze pi ne) 
e.  Use of a ntic oa g ula nt/a nti platelet a g e nts (e. g., warfari n, he pari n, da bi gatra n, 
ri var o xa ba n, cl o pi d o grel) u nless t he d ose has bee n sta ble f or 4 wee ks pri or t o t he first 
d ose of St u d y Dr u g a n d re g ular cli nical m o nit ori n g is perf or me d, use of t he 
n o n-ster oi dal a nti-i nfla m mat or y dr u g ( N S AI D) ni mes uli de or a n y ot her dr u g 
i nfl ue nci n g c oa g ulati o n (e xce pt l o w d ose aspiri n < 1 6 0 m g/ da y a n d ot her s h ort acti n g 
N S AI D S wit h a half-life < 2 0 h o urs) 
f.  o betic h olic  aci d  or urs o de o x yc h olic aci d 


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1 3. Bl o o d d o nati o n of 5 0 t o 4 9 9 m L wit hi n 3 0 da ys of Scree ni n g or of > 4 9 9 m L wit hi n 
6 0 da ys of Scree ni n g  
1 4. Acti ve i nfecti o n re q uiri n g s yste mic a nti viral  or a nti micr o bial t hera p y t hat will n ot be 
c o m plete d pri or t o St u d y Da y 1 
1 5. S u bjects wit h k n o w n i nt olera nce t o M RI or  wit h c o n diti o ns c o ntrai n dicate d f or M RI 
Pr oce d ures: 
•  S u bjects w h o ha ve a n y metal i m pla nt (i ncl u di n g a heart pace ma ker, r o ds, scre ws, 
a ne ur ys m cli p) 
•  S u bjects wit h cla ustr o p h o bia 
1 6. C o nfir me d re d ucti o n i n fasti n g plas ma gl uc ose ( F P G) of > 4 0 m g/ d L ( > 2. 2 m m ol/ L) at 
t he R u n-I n Visit ( Wee k - 1) c o m pare d t o a F P G val ue ta ke n at Scree ni n g 
1 7. C o nfir me d re d ucti o n i n b o d y wei g ht of 2 k g ( 4. 4 l bs) at t he R u n-I n Visit ( Wee k - 1) 
c o m pare d t o b o d y wei g ht ta ke n at Scree ni n g 
1 8. Ha ve a n y ot her c o n diti o ns, w hic h, i n t he o pi ni o n of t he I n vesti gat or or S p o ns or w o ul d 
ma ke t he s u bject u ns uita ble f or i ncl usi o n, or c o ul d i nterfere wit h t he s u bject partici pati n g 
i n or c o m pleti n g t he St u d y, i ncl u di n g u n willi n g ness t o c o nti n ue wit h S C i njecti o ns after 
t he S C T olera bilit y assess me nt 
6.
 S T U D Y
 
P R O C E D U R E S
 
6. 1
 St u d y
 
Sc he d ule
 
T he st u d y peri o d f or a n i n di vi d u al s u bject c o nsists of a ≤ 6- wee k Scree ni n g a n d R u n-I n Peri o d 
f oll o we d b y a 1 3- wee k Treat me nt Peri o d, a n d a 1 3- wee k P ost- Treat me nt Peri o d.  A d diti o nal 
visits ma y be sc he d ule d if re q uire d f or f urt her e val uati o n of a n a b n or mal la b orat or y val ue or 
re p orte d A E. 
A n y A Es, c o nc o mita nt me dicati o ns, a n d ot her safet y a n d t olera bilit y pr ofili n g data will be 
pr o m ptl y re p orte d a n d re vie we d b y S p o ns or’s Me dical M o nit or ( or desi g nee). 
All re q uire d st u d y pr oce d ures are o utli ne d i n A p pe n dices A , B  a n d C . 
6. 1. 1  
Scree ni n g Peri o d ( Wee k  - 6 t o Wee k - 5)  
Writte n i nf or me d c o nse nt f or t he st u d y will be o btai ne d pri or t o t he perf or ma nce of a n y 
st u d y-relate d pr oce d ures i ncl u di n g Scree ni n g a n d R u n-I n pr oce d ures.  A ≤ 6- wee k peri o d is 
pr o vi de d t o c o m plete Scree ni n g assess me nts a n d t o deter mi ne s u bject eli gi bilit y f or t he st u d y, 
wit h Scree ni n g at Wee k - 6 t o Wee k - 5, a n d t h e R u n-I n Peri o d fr o m Wee k - 4 t o Wee k - 1.  
S u bjects will be q uesti o ne d f o r me dical hist or y, a n d u n der g o p h ysical e xa mi nati o n, c o nfir mati o n 
of t heir dia betes stat us a n d e xcl u de ot her ca uses of li ver disease a n d fi br osis, 1 2-lea d 
electr ocar di o gra m ( E C G) c o n d ucte d i n tri plicate, vital si g ns, b o d y wei g ht, a n d hei g ht.  S u bjects 
will als o be scree ne d f or i nfecti o ns of HI V,  He patitis B a n d C, a n d f or bl o o d c oa g ulati o n 
a b n or malities i ncl u di n g pr ol o n ge d acti vate d partia l t hr o m b o plasti n ti me (a P T T), pr ot hr o m bi n 
ti me ( P T), a n d i nter nati o nal n or malize d rati o (I N R), a n d t h yr oi d f u ncti o n tests ( T S H, free T 4 a n d 
free T 3) le vels.  F ollicle-sti m ulati n g h or m o ne ( FS H) will be meas ure d t o c o nfir m me n o pa use i n 


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w o me n w h o ha ve n ot u n der g o ne s u r gical sterilizati o n (fe males ≤ 5 5 years, 1 2 m o nt hs of 
s p o nta ne o us a me n orr hea wit h o ut a n alter nati ve me dical ca use).  A d diti o nal bl o o d sa m ples will 
be ta ke n f or r o uti ne cli n ical la b orat or y testi n g (A p pe n di x A ). 
I n di vi d uals ma y be dis q ualifie d if t he res ult of a n y la b orat or y test is o utsi de of t he ra n ge 
s pecifie d i n t he eli gi bilit y criteria (Secti o ns 5. 1  a n d 5. 2 ) or, if n o ra n ge is s pecifie d, is a b n or mal 
a n d cli nicall y-si g nifica nt as j u d ge d b y t he I n vest i gat or or S p o ns or Me dical M o nit or or Desi g nee. 
D uri n g t he Scree ni n g Peri o d, scree ni n g res ults ma y be reteste d f or assess me nt b y t he S p o ns or 
Me dical M o nit or or Desi g nee f or eli gi bilit y p ur p oses.   
6. 1. 2  
R u n-I n Peri o d ( Wee k - 4 t hr u Wee k - 1) 
U p o n c o m pleti o n of t he Scree ni n g Peri o d, eli gi ble patie nts e nter t he 4- wee k R u n-I n Peri o d f or 
s u bjects t o mai ntai n t heir r o uti ne diet a n d e xercise sta bilizati o n d uri n g t his peri o d a n d f or a 
baseli ne li ver M RI Assess me nt.  S u bjects will mai n tai n t heir r o uti ne diet a n d e xercise r o uti ne 
a n d c o nti n ue t o ta ke t heir oral a nti- dia betic  a ge nt ( O A D) dail y d uri n g t his 4- wee k peri o d.  
S u bsta ntial c ha n ges i n diet a n d e xercise acti vities c o uld ha ve a n i m pact o n li ver fat c o nte nt a n d 
s h o ul d be a v oi de d d uri ng st u d y partici pati o n. 
6. 1. 2. 1  
Liver M RI Assess me nt ( Wee k - 4 t o Wee k - 3) 
A n M RI of t he li ver will be c o n d ucte d 2 ti mes d uri n g st u d y partici pati o n, o nce bef ore treat me nt 
a n d o nce after treat me nt.  T he Baseli ne M RI will be c o n d ucte d d uri n g t he R u n-I n Peri o d 
( Wee k - 4 t o Wee k - 3) a n d t he P ost- Treat me nt M RI Assess me nt will be c o n d ucte d d uri n g t he 
P ost- Treat me nt Peri o d ( Wee k of P T 2 Visit). 
T hese M RIs will be c o n d ucte d usi n g sta n dar dize d pr oce d ures a n d setti n gs a n d will be e val uate d 
b y a ce ntral rea der, bli n de d t o t he s u bject’s trea t me nt assi g n me nt, t o assess li ver fat a n d li ver 
v ol u me. 
All s u bjects ma y be re q uire d t o fast f or at least 4 h o urs bef ore t he M RI assess me nt. 
S u bjects wit h a q ualif yi n g Baseli ne M RI (at l east 1 0 % li ver fat assesse d b y M RI- P D F F via 
ce ntral re vie wer) will ret ur n t o cli nic f or R u n-I n Wee k - 1 Visit.  If it is n ot p ossi ble f or M RI 
res ults t o be a vaila ble b y t his visit or if it nee ds t o be re peate d, t he M RI res ults m ust be a vaila ble 
f or fi nal q ualificati o n pri or t o ran d o mizati o n.  Fail ure t o reac h eli g i bilit y criteria of li ver fat 
c o nte nt b y M RI is c o nsi dere d a scree n  fail ure a n d will n ot be re peate d. 
6. 1. 2. 2  
R u n-I n Wee k - 1 
At t his visit, fi nal q ualificati o n assess me nt s will be c o n d ucte d a n d c o nfir me d acc or di n g t o 
A p pe n di x A i ncl u di n g b o d y wei g ht a n d F P G asse ss me nts. S u bjects will mai ntai n t heir r o uti ne 
diet a n d e xercise r o uti ne a n d c o nti n ue t o ta ke t heir O A D dail y d uri n g t his peri o d.  S u bsta ntial 
c ha n ges i n eit her o ne of t hese acti vities c o ul d ha ve a n i m pact o n li ver fat c o nte nt a n d s h o ul d be 
a v oi de d d uri n g st u d y partici pati o n.   
6. 1. 2. 2. 1  
F P G a n d B o dy Wei g ht Eli gi bility Assess me nts ( Wee k - 1) 
Patie nts will be re q uire d t o visit t he cli nic f o r F P G a n d b o d y wei g ht meas ure me nts i n b ot h t he 
Scree ni n g Peri o d ( W k- 6 - W k- 4) a n d R u n-I n Peri o d ( Wee k - 1).  T he F P G ce ntral la b res ults a n d 


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b o d y wei g ht cli nic assess me nt fr o m t hese 2 visits  (at least 3 wee ks a part) will be c o m pare d t o 
assess t he patie nt’s  eli gi bilit y f or ra n d o mizati o n.   
•  If a > 4 0 m g/ d L ( 2. 2 m m ol/ L) F P G re d ucti o n is o bser ve d (a n d c o nfir me d wit h a retest) 
fr o m t he scree ni n g res ult t o t he R u n-I n Wee k- 1, t he patie nt ca n n ot be ra n d o mize d 
(E xcl usi o n Criteria # 1 6 ).  If a patie nt is n ot ra n d o mize d d ue t o a n o bser ve d > 4 0 m g/ d L 
( 2. 2 m m ol/ L) dr o p i n fasti n g gl uc ose, t he patie nt ma y be eli gi ble f or rescree ni n g after 
6 wee ks ha ve ela pse d 
•  If a re d ucti o n i n b o d y wei g ht of 2 k g ( 4. 4 l bs) (a n d c o nfir me d wit h a retest) fr o m 
t he scree ni n g res ult t o t he R u n-I n Wee k - 1, t he patie nt ca n n ot be ra n d o mize d 
(E xcl usi o n Criteria # 1 7 ) 
6. 1. 2. 2. 2  
S C T oler a nce Assess me nt 
T o re d uce t he b ur de n of u n necessa r y pr oce d ures o n s u bjects wh o s u bse q ue ntl y elect n ot t o 
partici pate i n t he st u d y or c o nti n ue wit h st u d y pr oce d ures, all s u bj ects will c o nfir m t olera nce of 
S C a d mi nistrati o n of 0. 9 % sali ne pri or t o ra n d o mizati o n.  T his i njecti o n will f oll o w t he sa me 
pr oce d ures as t he i njecti o n of t he St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) d uri n g t he treat me nt 
peri o d.  S pecificall y, at a n y vi sit d uri n g t he Scree ni n g or R u n-I n Peri o d s u bjects will recei ve 
1 S C i njecti o n of 1. 2 5 m L of 0. 9 % sali ne ( ma y al s o be deli vere d as 2 n o n-c o nti g u o us i njecti o n 
v ol u mes s uc h as 0. 7 5 m L a n d 0. 5 0 m L). 
W he n t he Scree ni n g a n d R u n-I n res u lts are a vaila ble t hr u Wee k - 1, i n di vi d uals will be n otifie d of 
t heir eli gi bilit y.  Q ualifie d patients will be ra n d o mize d a n d will pr ocee d t o t he Treat me nt Peri o d 
wit h Wee k 1, Da y 1 Assess me nts. 
6. 1. 3  
Tre at me nt Peri o d ( Wee ks 1- 1 3) 
E nr olle d s u bjects will be a d mi nistere d I SI S 4 8 4 1 3 7 or place b o o nce eac h wee k f or a t otal of 
1 3 wee ks of treat me nt.  O nce- wee kl y S C a d mi ni strati o n will occ ur d uri n g t he visits.  At eac h 
visit, s u bjects will be re mi n de d t o retai n t he sa me diet a n d e xercise re gi me n as was f oll o we d 
d uri n g t he Scree ni n g a n d R u n-I n Peri o d.  S u bsta ntial c ha n ges i n eit her o ne of t hese acti vities 
c o ul d ha ve a n i m pact o n li ver fat c o nte nt a n d s h o ul d be a v oi de d d uri n g st u d y partici pati o n.  
S u bjects will c o nti n ue t o ta ke t heir O A D dail y d uri n g t his peri o d. 
Safet y a n d cli nical la b orat or y e v al uati o ns will be perf or me d o n a wee kl y basis.  Vital si g ns, B P 
assess me nts, A Es a n d c o nc o mita nt usa ge will be a ssesse d d uri n g cli nic visits.  Ot her assess me nts 
will be c o n d ucte d d uri n g t he Treat me nt Peri o d i n  less fre q ue nt i nter vals as i n dicate d i n 
A p pe n dices  A, B , a n d C  i ncl u de E C G, dr u g/alc o h ol scree ni n g, H b A 1c, F P G, li pi d pa nel, i ns uli n, 
hs C R P, T S H, e x pl orat or y mar kers a n d P K.  A n y A Es a n d c o nc o mita nt me dicati o ns will be 
rec or de d a n d re vie we d b y t he S p o ns or’s Me dical M o nit or or desi g nee.  A n y q uesti o ns o n st u d y 
pr oce d ures a n d visit wi n d o ws ma y be di recte d t o t he S p o ns or ( or desi g nee). 
Earl y ter mi nati o n patie nts fr o m t he Treat me nt Peri o d will be re q uire d t o c o m plete t heir st u d y 
ter mi nati o n e val uati o ns f oll o wi n g t he P T 1 st u d y pr oce d ures (see A p pe n di x A).  T he ti mi n g of 
t he P ost- Treat me nt M RI f or earl y ter mi nati o n patie nts fr o m t he Treat me nt Peri o d is o utli ne d i n 
Secti o n 6. 1. 4 .  All patie nts recei vi n g at least 1 d ose of st u d y me dicati o n are re q uire d t o e nter t he 
P ost- Treat me nt Peri o d f or c o nti n ui n g safet y e val uati o ns.   


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6. 1. 4  
P ost- Tre at me nt Peri o d ( P T 1- 1 3) 
After c o m pl eti n g t he 1 3 wee ks of t he Treat me nt Pe ri o d, i ncl u di n g s u bjects w h o disc o nti n ue earl y 
fr o m t he Treat me nt Peri o d, s u bjects will ret ur n f or p ost-treat me nt f oll o w- u p e val uati o n visits as 
i n dicate d i n A p pe n di x A .  All s u bjects will be f oll o we d f or 1 3 wee ks u ntil t he P T 1 3 visit.  
D uri n g t he P ost- Treat me nt Peri o d fr o m P T 1- 4 ( w ee kl y visits), a visit wi n d o w of ± 3 da ys is 
per mitte d, w hereas f or visits P T 6- 1 3 a visit wi n d o w of ± 7 da ys is per mitte d.  Safet y a n d cli nical 
la b orat or y e val uati o ns as well as P D mar kers, i ncl u di n g t h ose f or P K a nal ysis, will be perf or me d 
as i n dicate d i n A p pe n dices A, B , a n d C .  A n y A Es a n d c o nc o mita nt me dicati o ns will be rec or de d 
a n d re vie we d b y t he S p o ns or’s Me dical M o nit or or  desi g nee.  At eac h visit, s u bjects will be 
re mi n de d t o retai n t he sa me diet a n d e xercise re gi me n as was f oll o we d d uri n g t he Scree ni n g a n d 
R u n-I n Peri o d.  S u bjects will c o nti n ue t o ta ke t heir O A D dail y d uri n g t his peri o d. 
A P ost- Treat me nt M RI ( See Secti o n 6. 1. 2. 1 ) t o assess li ver fat c o nte nt a n d v ol u me will occ ur 
d uri n g P T 2 Visit ( 2 wee ks after last d ose) f or al l s u bjects c o m pleti n g 1 3 d oses.  F or s u bjects w h o 
ter mi nate fr o m t he treat me nt peri o d earl y, t he ti mi n g a n d c o n d uct of t he M RI i n t he 
P ost- Treat me nt Peri o d will be a dj uste d as f oll o ws ( +/- 7- da y wi n d o w).  T he ti mi n g of t he 
P ost- Treat me nt M RI s h o ul d be disc usse d wit h t he I o nis St u d y Tea m b ut ma y be sc he d ule d as 
f oll o ws:  
i. 
S u bject recei ve d 4 or less d oses, t he P o st- Treat me nt M RI Assess me nt will n ot be 
re q uire d 
ii. 
S u bject recei ve d 5- 9 d oses, t he P ost- Treat me nt M RI Assess me nt will occ ur 2 wee ks 
after last d ose at t he P T 2 Visit 
iii. 
S u bject recei ve d 1 0- 1 2 d oses, t he P ost- Tre at me nt M RI Assess me nt will be sc he d ule d 
as f oll o ws:  
•  If s u bject recei ve d 1 0 d oses, s u bject mo ves i nt o P ost- Treat me nt Peri o d, t he M RI 
will be c o n d ucte d 5 wee ks after t he last d ose  
•  If s u bject recei ve d 1 1 d oses, s u bject mo ves i nt o P ost- Treat me nt Peri o d, t he M RI 
will be c o n d ucte d 4 wee ks after t he last d ose  
•  If s u bject recei ve d 1 2 d oses, s u bject mo ves i nt o P ost- Treat me nt Peri o d, t he M RI 
will be c o n d ucte d 3 wee ks after t he last d ose  
Earl y ter mi nati o n patie nts fr o m t he P ost- Treat me nt Peri o d ( E T P T) will be re q uire d t o  
c o m plete t heir E n d- Of- St u d y e val uati o ns f oll o wi n g t he E T P T 1 2 Visit st u d y pr oce d ures  
(see A p pe n di x A). 
6. 2
 L a b or at or y
 
Assess me nts
 
La b orat or y a nal yte sa m ples will be c ollecte d t hr o u g h o ut t he st u d y.  A list of t hese a nal ytes is 
c o ntai ne d i n A p pe n di x B.  Bl o o d c he mistr y a n d uri n e sa m ples s h o ul d be ta ke n after fasti n g f or at 
least 8 h o urs.  D uri n g t he fasti n g peri o d, t he s u bject ca n dri n k water a n d t he y s h o ul d e ns ure t hat 
t he y c o ns u me s ufficie nt water t o n ot bec o me de h y drate d. 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
4 2
 
If d uri n g t he treat me nt peri o d, a platelet, creati ni ne, or A L T res ult is u ni nter preta ble (e. g., d ue t o 
cl u m pi n g, he m ol ysis, or q ua ntit y n ot s ufficie nt) t he test m ust be re peate d a n d a res ult n ot 
meeti n g st o p pi n g r ule m ust be o btai ne d pri or t o ne xt d ose. 
6. 3
 Restricti o n
 
o n
 
t he
 
Lifest yle of S u bjects 
6. 3. 1
 C o ntr ace pti o n
 
Re q uire me nts
 
Male s u bjects m ust refrai n fr o m s p er m d o nati o n a n d eit her be a bsti ne nt † or, if e n ga ge d i n se x ual 
relati o ns wit h a fe male of c hil d- beari n g p ote ntial, t he y m ust use effecti ve barrier c o ntrace pti o n 
wit h t heir part ner fr o m t he ti me of si g ni n g t he i nf or me d c o nse nt f or m u ntil at least 1 3 wee ks 
after t heir last d ose of St u d y Dr u g.  Effecti ve c o ntrace pti o n i ncl u des a vasect o m y wit h ne gati ve 
se me n a nal ysis at F oll o w- u p, or t he use of c o n d o ms t o get her wit h s per mici dal 
f oa m/ gel/fil m/crea m/s u p p osit or y.  Male s u bjects e n ga ge d i n se x ual relati o ns wit h a fe male of 
c hil d- beari n g p ote ntial m ust als o e nc o ura ge t hei r fe male part ner t o use effecti ve c o ntrace pti o n 
fr o m t he ti me of si g ni n g t he i nf or me d c o nse nt u ntil 1 3 wee ks after t he s u bject’s last d ose of 
st u d y treat me nt.  Effecti ve c o ntrace pti o n f or t he female part ner i ncl u des:  s ur gical sterilizati o n 
(e. g., bilateral t u bal li gati o n), h or m o nal c o ntrace pti o n, i ntra uteri ne co ntrace pti o n/ de vice, or 
barrier met h o ds (fe male c o n d o m *, di a p hra g m, s p o n ge, cer vical ca p) t o get her wit h s per mici dal 
f oa m/ gel/fil m/crea m/s u p p osit or y.  Male s u bjects wit h part ners t hat are pre g na nt m ust use 
c o n d o ms t o e ns ure t hat t he fet us is n ot e x p ose d t o t he St u d y Dr u g. 
† N ote: A bsti ne nce is o nl y acce pta ble as tr ue a bsti ne n ce, i.e., w he n t his is i n li ne wit h t he 
preferre d a n d us ual lifest yl e of t he s u bject.  Peri o dic  a bsti ne nce (e. g., cale n dar, 
o v ulati o n, s y m pt ot her mal, p ost- o v ulati o n met h o ds ), declarati o n of a bsti ne nce f or t he 
d urati o n of a trial a n d wit h dra wal ar e n ot acce pta ble met h o ds of c o ntrace pti o n.  
* N ote:  A fe m ale c o n d o m a n d a m ale c o n d o m s h o ul d n ot be use d t o get her as fricti o n 
bet wee n t he t w o c a n res ult i n eit her or b ot h pr o d ucts f aili n g. 
6. 3. 2
 F asti n g
 
Re q uire me nts
 
All s u bjects will be re q uire d t o fast f or at least 8 h o urs bef ore eac h st u d y visit. 
6. 3. 3
 Lifestyle
 
Restricti o ns
 
S u bjects are i nstr ucte d t o refrai n fr o m alc o h ol c o ntai ni n g be vera ges at least 4 8 h o urs pri or t o a 
cli nic visit a n d s h o ul d n ot i ncrease alc o h ol c o ns u m pti o n d uri n g t he st u d y.  A d diti o nall y, s u bjects 
are re q ueste d t o mai ntai n a sta ble diet  a n d e xercise re gi me n t hr o u g h o ut t he st u d y. 
7.
 S T U D Y
 
D R U G
 
7. 1  
St u d y Dr u g Descri pti o n 
St u d y Dr u g (I SI S 4 8 4 1 3 7 or Place b o) c haract eristics are liste d i n Ta ble 1.   
T he St u d y Dr u g (I SI S 4 8 4 1 3 7 or Place b o) is c o ntai ne d i n 2 m L st o p pere d glass vials.  T he St u d y 
Dr u g (I SI S 4 8 4 1 3 7 or Place b o) a n d its st ora ge a n d pre parati o n i nstr ucti o ns will be pr o vi de d b y 
t he S p o ns or or desi g nee.  T he St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) m ust be st ore d sec urel y at 
2- 8 ° Celsi us a n d be pr otecte d fr o m li g ht. 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
4 3
 
T a ble 1  
St u d y Dr u g C h ar acteristics 
St u d y Dr u g 
I SI S 4 8 4 1 3 7 
Pl a c e b o 
Str e n gt h 
2 0 0 m g/ m L   
N ot A p pli c a bl e 
V ol u m e/ F or m ul ati o n 
1 m L s ol uti o n p er vi al   
1 m L s ol uti o n p er vi al 
R o ut e of A d mi ni str ati o n 
S C  
S C  
* S C = s u b c ut a n e o u s 
 
7. 2
 P ac k a gi n g
 
a n d
 
L a beli n g
 
T he S p o ns or will pr o vi de t he I n vesti gat or wit h pac ka ge d St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) 
la bele d i n acc or da nce wit h s pecific c o u ntr y re g ulat or y re q uire me nts.   
7. 3  
St u d y Dr u g Acc o u nt a bilit y 
T he st u d y staff is re q uire d t o d oc u me nt t he r ecei pt, dis pe nsi n g, a n d ret ur n of St u d y Dr u g 
(I SI S 4 8 4 1 3 7 or place b o) s u p plies pr o vi de d b y t he S p o ns or.   
8.  
T R E A T M E N T O F S U B J E C T S 
8. 1  
St u d y Dr u g A d mi nistr ati o n 
St u d y Dr u g a d mi nistrati o n will occ ur at wee kl y  st u d y visits fr o m Wee k 1 t hr o u g h Wee k 1 3 b y 
t he trai ne d pers o n nel at t he st u d y site.  I SI S 4 8 4 1 3 7 or place b o will be a d mi nistere d 
s u bc uta ne o usl y.  St u d y Dr u g (I SI S 4 8 4 1 3 7 or placeb o) S C i njecti o n v ol u me will be 1. 2 5 m L at 
eac h wee kl y visit ( ma y als o be deli vere d as 2 n o n-c o nti g u o us i njecti o n v ol u mes s uc h 
as - 0. 7 5 m L a n d 0. 5 0 m L).  Vials are f or si n gle use o nl y. 
Please refer t o t he St u d y Dr u g Ma n ua l pr o vi de d b y t he S p o ns or f or m ore detaile d i nstr ucti o ns f or 
St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) pre parati o n a n d a d mi nistrati o n. 
8. 2  
Ot her Pr ot oc ol- Re q uire d Dr u gs 
0. 9 % sterile sali ne will be use d f or a S C t olera bili t y i njecti o n.  At a n y visit d uri n g t he Scree ni n g 
or R u n-I n Peri o d, s u bjects will recei ve a 1. 2 5 m L S C i njecti o n ( ma y als o be deli vere d as 2 n o n-
c o nti g u o us i njecti o n v ol u mes s uc h as 0. 7 5 m L a n d 0. 5 0 m L). 
8. 3  
Ot her Pr ot oc ol- Re q uire d Tre at me nt Pr oce d ures 
T here are n o ot her pr ot oc ol-re q uire d treat me nt pr oce d ures. 
8. 4
 Tre at me nt
 
Prec a uti o ns
 
T here are n o s pecific trea t me nt preca uti o ns re q uire d. 
8. 5  
S afet y M o nit ori n g R ules 
Please refer als o t o t he ‘ G ui da nce f or I n vesti g at or’ secti o n of t he I n vesti gat or’s Br oc h ure 
Baseli ne is defi ne d as t he a vera ge of wee k - 1 visit ( Da y - 7) a n d Da y 1 pre- d ose val ues. 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
4 4
 
I n a d diti o n t o t he sta n dar d m o nit ori n g of cli nical safet y para meters, t he f oll o wi n g g ui deli nes are 
pr o vi de d f or t he m o nit ori n g of selecte d para mete rs c h ose n base d o n precli nical a n d cli nical 
o bser vati o ns. 
C o nfir mati o n G ui da nce:  At a n y ti me d uri n g t he st u d y ( Treat me nt or P ost- Treat me nt Peri o ds), 
t he i nitial cli nical la b orat or y res ults meeti n g t he safet y m o nit ori n g criteria prese nte d bel o w m ust 
be c o nfir me d b y perf or mi n g meas ure me nts (i deall y i n t he sa me la b orat or y t hat perf or me d t he 
i nitial meas ure me nt) o n ne w s peci me ns.  All ne w s peci me n c ollecti o ns s h o ul d ta ke place as s o o n 
as p ossi ble (i deall y wit hi n 3 da ys of t he i nitia l c ollecti o n).  F or st o p pi n g r ules, if t he i nitial 
la b orat or y res ult is o bser ve d d uri n g t he Treat me nt Peri o d, t he res ults fr o m t he retest m ust be 
a v ail a ble pri or t o a d mi nisteri n g t he ne xt d ose of St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o). 
Re- d osi n g G ui da nce:  S u bjects wit h i nitial la b orat or y test val ues t hat re ac h a st o p pi n g r ule m ust 
n ot be re- d ose d u ntil t he re-test res ults are a vaila ble.  I n ge neral, s u bjects w h o d o n ot meet t he 
st o p pi n g r ules base d u p o n retest ma y c o nti n ue d osi n g.  H o we ver, t he I n vesti gat or a n d t he 
S p o ns or Me dical M o nit or ( or a p pr o priatel y q ualifie d desi g nee) s h o ul d c o nfer as t o w het her 
a d diti o nal cl ose m o nit ori n g of t he s u bject is a p pr o pr iate.  If a n y of t he st o p pi n g criteria descri be d 
i n A p pe n di x D  are met, t he s u bject will be per ma ne ntl y disc o nti n ue d fr o m f urt her treat me nt wit h 
St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o), e val uate d f ull y  as o utli ne d bel o w a n d i n c o ns ultati o n wit h 
t he S p o ns or Me dical M o nit or or a p pr o priatel y q ualifie d desi g nee,  a n d will be f oll o we d u p i n 
acc or da nce wit h Secti o n 8. 8  of t he Pr ot oc ol.   
8. 5. 1  
S afety M o nit ori n g R ules f or Liver C he mistry Tests 
T he f oll o wi n g r ules are a da pte d fr o m t he draf t g ui da nce f or i n d ustr y, “ Dr u g-I n d uce d Li ver 
I nj ur y: Pre mar keti n g Cli nical E valuati o n,” iss ue d b y t he U. S.  De part me nt of Healt h a n d H u ma n 
Ser vices, F o o d a n d Dr u g A d mi nistrati o n, J ul y 2 0 0 9.  F or a defi niti o n of Baseli ne please refer t o 
g ui da nce i n Secti o n 8. 5  a b o ve. 
I n t he e ve nt of a n A L T or A S T meas ure me nt t hat is > 3 x U L N : ( or t he greater of 2 x baseli ne 
val ue or 3 x U L N if t he baseli ne val ue was > U L N) at a n y ti me d uri n g t he st u d y ( Treat me nt or 
P ost- Treat me nt Peri o d), t he i nitial meas ure me nt( s) s h o ul d be c o nfir me d as descri be d a b o ve.  
A d diti o nal, c o nfir mat or y meas ure me nts s h o ul d als o  be perf or me d if A L T or A S T le vels i ncrease 
t o 5 x U L N. 
Fre q ue nc y of Re peat Meas ure me nts:  S u bjects wi t h c o nfir me d A L T or A S T le vels > 3 x U L N ( or 
t he greater of 2 x baseli ne val ue or 3 x U L N if t he baseli ne val u e was > U L N) s h o ul d ha ve t heir 
li ver c he mistr y tests ( A L T, A S T, al kali ne p h os p hatase [ A L P], I N R, a n d t otal bilir u bi n) reteste d 
at least o nce- wee kl y u ntil A L T a n d A S T le vels bec o me ≤ 1. 2 x U L N or 1. 2 x baseli ne val ue if 
t he baseli ne val ue was > U L N. 
F urt her I n vesti gati o n i nt o Li ver C he mistr y Ele va ti o ns:  F or s u bjects wit h c o nfir me d A L T or A S T 
le vels > 3 x U L N ( or t he greater of 2 x baseli ne val ue or 3 x U L N if t he baseli ne val ue was 
> U L N), t he f oll o wi n g e val uati o ns s h o ul d be perf or me d: 
1.  O btai n a m ore detaile d hist or y of s y m p t o ms a n d pri or a n d c o nc urre nt diseases 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
4 5
 
2.  O btai n f urt her hist or y f or c o nc o mita nt dr u g use (i ncl u di n g n o n prescri pti o n me dicati o ns, 
her bal a n d dietar y s u p ple me nt pre parati o ns),  alc o h ol use, recreati o nal dr u g use, a n d 
s pecial diets 
3.  O btai n a hist or y f or e x p os ure t o e n vi r o n me ntal c he mical a ge nts a n d tra vel 
4.  Ser ol o g y f or viral he patitis ( he patitis A vir us [ H A V] i m mu n o gl o b uli n M [I g M], he patitis 
B s urface a nti ge n [ H Bs A g], H C V a nti b o d y, c yt o me gal o vir us [ C M V] I g M, a n d 
E pstei n- Barr vir us [ E B V a nti b o d y pa nel]) 
5.  Ser ol o g y f or a ut oi m m u ne he patiti s (e. g., a nti n uclear a nti b o d y [ A N A]) 
A d diti o nal li ver e val uati o ns, i ncl u di n g gastr oe nter ol o g y / he pat ol o g y c o ns ultati o ns, he patic C T or 
M RI sca ns, ma y be perf or me d at t he discreti o n of t he I n vesti gat or, i n c o ns ultati o n wit h t he 
S p o ns or Me dical M o nit or.  Re petiti o n of t he a b o ve e val uati o ns s h o ul d be c o nsi dere d if a 
s u bject’s A L T a n d/ or A S T le vels reac h 5 x U L N. 
8. 5. 2  
S afety M o nit ori n g R ules f or Pl atelet C o u nt Res ults 
If a s u bject’s platelet c o u nt falls b y 3 0 % or greater fr o m Baseli ne or t he a bs ol ute platelet c o u nt is 
1 0 0, 0 0 0/ m m 3 or less, t he n t he s u bject’s platelet c o u nts s h o ul d be m o nit ore d at least wee kl y.  I n 
t he e ve nt of a platelet c o u nt < 7 5, 0 0 0/ m m 3, a d diti o nal la b orat or y i n vesti gati o ns ma y be 
c o n d ucte d ( Ta ble 2).  T he fre q ue nc y of m o nit ori n g a n d a d diti o nal la b test s will be deter mi ne d b y 
t he I n vesti gat or i n c o ns ultati o n wit h t he S p o ns or Me dical M o nit or or desi g nee. 
T a ble 2  
A d diti o n al L a bs t o be Perf or me d i n t he E ve nt of a Pl atelet C o u nt 
< 7 5, 0 0 0/ m m 3 
T o B e P erf or m e d at L o c al L a b 
P eri p h er al s m e ar ( s h o ul d b e p erf or m e d l o c all y, fi x e d a n d s e nt t o c e ntr al l a b f or r e vi e w) 
Fi bri n o g e n s plit pr o d u ct s or D- di m er o n fr e s h bl o o d 
T o B e P erf or m e d at C e ntr al L a b 
Citr at e d s a m pl e f or pl at el et s 
C o a g ul ati o n p a n el ( P T/I N R, a P T T) 
C o m pl et e bl o o d c o u nt ( C B C) wit h r eti c ul o c yt e s a n d m e a n pl at el et v ol u m e ( M P V) 
Fi bri n o g e n 
v o n Will e br a n d f a ct or 
T ot al gl o b uli n s, t ot al i m m u n o gl o b uli n A (I g A), I g G a n d I g M 
C o m pl e m e nt:  t ot al C 3 , t ot al C 4, B b, C 5 a 
C R P m e a s ur e d b y hi g h s e n siti vit y a s s a y ( h s C R P) 
S er ol o g y f or: 
H B V, H C V, HI V (if n ot d o n e f or s cr e e ni n g) 
R u b ell a 
C M V 
E B V 
P ar v o B 1 9 
H eli c o b a ct er p yl ori (I g G s er u m t e st) 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
4 6
 
T a ble 2  
A d diti o n al L a bs t o be Perf or me d i n t he E ve nt of a Pl atelet C o u nt 
< 7 5, 0 0 0/ m m 3 C o nti n ue d  
T o B e P erf or m e d at C e ntr al L a b 
A ut o- a nti b o d y s cr e e n: 
A nti p h o s p h oli pi d 
R h e u m at oi d f a ct or 
A nti- d s D N A 
A nti-t h yr oi d 
T o B e P erf or m e d at S p e ci alt y L a b( s) 
A nti pl at el et a nti b o di e s a n d A nti- P F 4 a s s a y 
A nti- A S O a nti b o d y (if a v ail a bl e) 
N ot e:  T h e f oll o wi n g l a b s m a y c h a n g e a s a d diti o n al d at a i s a s s e s s e d, a n d sit e s will b e u p d at e d r e g ar di n g a n y 
c h a n g e s. 
 
8. 5. 3  
M o nit ori n g R ules f or Deteri or ati n g Glyce mic C o ntr ol 
If after 8 wee ks of treat me nt wit h Stu d y Dr u g (I SI S 4 8 4 1 3 7 or place b o), F P G le vels 
> 2 7 0 m g/ d L ( or > 1 5 m m ol/ L) c o nfir me d o n 2 c o nsec u ti ve wee kl y st u d y visits wit h n o ot her 
e x pla nati o n(s) f or t he ele vati o n, a d diti o nal oral  gl uc ose-l o weri n g t herap y ma y be starte d or 
pre vi o us t hera pies ma y be titrate d u p b y t he I n vesti gat or i n c o ns ulta ti o n wit h t he S p o ns or 
Me dical M o nit or or desi g nee.  T he use of t h iaz oli di ne di o nes (e. g., pi o glitaz o ne, r osi glitaz o ne) 
a n d i njecta ble a nti dia betic t hera p y (e. g., i ns u li n, G L P 1 a nal o gs) is n ot per mitte d.  See D ose 
A dj ust me nt G ui da nce i n Secti o n 8. 7 . 
8. 6
 St o p pi n g
 
R ules
  
F or t he p ur p oses of t he st o p pi n g r ules baseli ne is  defi ne d as t he a vera ge of Da y - 7 a n d Da y 1 
val ues. 
8. 6. 1  
St o p pi n g R ules f or Liver C he mistry Elev ati o ns 
I n t he e ve nt of la b orat or y res ults meeti n g t he f oll o wi n g criteria, a n d t he e ve nt is wit h o ut a n 
alter n ati ve e x pl a n ati o n as disc usse d wit h t he S p o ns or Me dic al M o nit or,  d osi n g of a s u bject 
wit h St u d y Dr u g (I SI S 4 8 4 1 3 7 or pl ace b o) will be st o p pe d per ma ne ntl y; val ues t hat are n ot 
c o nfir me d d ue fail ure t o retest or missi n g la b val ues will be pres u me d c o nfir me d: 
1.  A L T or A S T > 8 x U L N, w hic h is c o nfir me d 
2.  A L T or A S T > 5 x U L N, w hic h is c o nfir me d a n d persists f or ≥ 2 wee ks 
3.  A L T or A S T > 3 x U L N  ( or t he greater of 2 x baseli ne val ue or 3 x U L N if t he baseli ne 
val ue was > U L N), w hic h is c o nfir me d a n d t otal bilir u bi n > 2 x U L N or I N R > 1. 5 
4.  A L T or A S T > 3 x U L N ( or t he greater of 2 x baseli ne val ue or 3 x U L N if t he baseli ne 
val ue was > U L N) wit h t he ne w a p peara nce (i .e., o nset c oi nci des wit h t he c ha n ges i n 
he patic e nz y mes) of fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt pai n or te n der ness, 
fe ver, ras h, a n d/ or c o nc o mita nt e osi n o p hilia ( > U L N)  


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8. 6. 2  
Te m p or ary St o p pi n g R ules f or Re n al F u ncti o n Test Res ults 
I n t he e ve nt of a persiste nt ele vati o n t hat is o bser ve d o ver 2 c o nsec u ti ve wee ks, f or eit her of t he 
2 criteria bel o w, d osi n g of a s u bject wit h  St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) ma y be st o p pe d 
te m p oraril y: 
1.  Ser u m creati ni ne i ncrease t hat f ulfills all of t he f oll o wi n g criteria:  ≥ 0. 3 m g/ d L 
( 2 6. 5 μ m ol/ L) i ncrease a n d ≥ 4 0 % a b o ve baseli ne creati ni ne val ues a n d > U L N (refer t o 
defi niti o n of Baseli ne i n Secti o n 8. 6 ) 
2.  Pr otei n uria, di pstic k 2 + (c o nfir me d b y di pstic k retest a n d t he n f urt her c o nfir me d b y a 
q ua ntitati ve t otal uri ne pr otei n meas ure me nt of > 1. 0 g/ 2 4 h o ur) 
T he p ossi ble d osi n g re-i nitiati o n or f oll o w- u p sc he d ule f or a n y e ve nts meeti n g eit her of t hese 
criteria will be deter m i ne d b y t he I n vesti gat or i n c o ns ult ati o n wit h t he S p o ns or Me dical 
M o nit or or desi g nee. 
8. 6. 3  
St o p pi n g R ule f or Pl atelet C o u nt Res ults 
I n t he e ve nt of a c o nfir me d platelet c o u nt less t ha n 7 5, 0 0 0/ m m 3, a n d i n t he prese nce of maj or 
blee di n g ( M B) or cli nicall y -rele va nt n o n- maj or blee di n g ( C R N M B) ( defi ne d bel o w; Sc h ul ma n  
et al. 2 0 0 5), d osi n g of a s u bject wit h St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) will be st o p pe d 
per ma ne ntl y.  F urt her m ore, a d diti o nal la b orat or y i n vesti gati o ns will be c o n d ucte d as o utli ne d i n 
Ta ble 2 .  T he f oll o w- u p sc he d ule f or a n y e ve nts meeti n g t his st o p pi n g criteri o n will be 
deter mi ne d b y t he I n vesti gat or i n c o ns u ltati o n wit h t he S p o ns or Me dical M o nit or. 
I n t he e ve nt of a c o nfir me d platelet c o u nt less t ha n 5 0, 0 0 0/ m m 3, d osi n g of a s u bject wit h St u d y 
Dr u g (I SI S 4 8 4 1 3 7 or place b o) will be st o p pe d pe r ma ne ntl y.  T he f oll o w- u p sc he d ule f or a n y 
e ve nts meeti n g t his st o p pi n g criteri o n will be deter mi ne d b y t he I n vesti gat or i n c o ns ultati o n wit h 
t he S p o ns or Me dical M o nit or or desi g nee. 
Defi niti o ns: 
Maj or blee di n g ( M B) is defi ne d as o ne of t he f oll o wi n g: 
1.  Fatal  blee di n g  
2.  S y m pt o matic blee di n g i n a critical area or or ga n, s uc h as i ntracra nial, i ntras pi nal, 
i ntra oc ular, retr o perit o neal, i ntraartic ular if i n a maj or j oi nt, or pericar dial, or 
i ntra m usc ular wit h c o m part me nt s y n dr o me 
3.  Cli nicall y o vert blee di n g lea di n g t o tra nsf usi o n of ≥ 2 u nits of pac ke d re d bl o o d cells 
( p R B C) or w h ole bl o o d or a fall i n he m o gl o bi n of 2 0 g/ L ( 1. 2 4 m m ol/ L) or m ore wit hi n 
2 4 h o urs 
Cli nicall y-rele va nt n o n- m aj or blee di n g ( C R N M B) is defi ne d as o vert blee di n g n ot meeti n g t he 
criteria f or M B b ut t hat res ulte d, f or e xa m pl e, i n me dical e xa mi nati o n, i nter ve nti o n, or ha d 
cli nical c o nse q ue nces f or a s u bject ( B üller et al. 2 0 0 7 ). 


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8. 6. 4  
St o p pi n g R ules f or D oc u me nte d Severe Hy p o glyce mi a 
I n t he e ve nt of a d oc u me nte d severe h y p o gl yce mic e ve nt as defi ne d bel o w, d osi n g of t he s u bject 
wit h St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) will be st o p pe d per ma ne ntl y.  Als o, if t he I n vesti gat or 
c o nsi ders a h y p o gl yce mic e ve nt as cli nicall y-si g nifica nt,  he/s he ma y st o p d osi n g at a n y ti me.  
A n y s u bject wit h a cli n icall y-si g nifica nt e ve nt of h y p o gl yce mia s h o ul d be disc usse d wit h t he 
S p o ns or Me dical M o nit or or Desi g nee. 
A d oc u me nte d se vere h y p o gl yce mic e ve nt is defi ne d as o ne i n w hic h t he s u bject re q uires 
assista nce of a n ot her pers o n t o o btai n treat me nt f or t he e ve nt a n d has a plas ma gl uc ose le vel 
< 6 0 m g/ d L ( 3. 3 m m ol/ L).  T his ma y i ncl u de treat me nt wit h I V gl uc ose or b uccal or 
i ntra m usc ular gl uca g o n.   
All s u bjects partici pati n g i n t he trial m ust be i nstr ucte d t o reco g nize t he c haracteristic s y m pt o ms 
of h y p o gl yce mia a n d recei ve detaile d i nstr ucti o ns  fr o m t he I n vesti gat or o n t he treat me nt a n d 
re p orti n g of h y p o gl yce mic e ve nts. 
T he s y m pt o ms of h y p o gl yce mia ca n be di vi de d i nt o 2 cate g ories, ne ur o gl yc o pe nic a n d 
ne ur o ge nic ( or a ut o n o mic) res p o nses. 
•  Ne ur o gl yc o pe nic s y m pt o ms are t he direct res ult of ce ntral nerv o us s yste m ne ur o nal 
gl uc ose de pri vati o n a n d i ncl u de be ha vi oral c ha n ges ( dizzi ness, h ea dac hes, cl o u d y visi o n, 
c o nf usi o n, a b n or mal be ha vi or, l oss of c o nsci o us ness, a n d seiz ures) 
•  H y p o gl yce mia-i n d uce d ne ur o ge nic (a ut o n o mic) re s p o nses are t h ose relate d t o i ncrease d 
a dre ner gic acti vit y (s weati n g, tre m or , tac h ycar dia, a n xiet y, a n d h u n ger) 
If a s u bject prese nts wit h s y m pt o ms of h y p o glyce mia, t he I n vesti gat or will nee d t o ta ke 
i m me diate acti o n t o c o nfir m t he s u bject’s gl ucose le vel a n d treat t he s u bject acc or di n gl y 
8. 7  
A dj ust me nt of Or al A nti di a betic Re gi me n f or S u bjects wit h Persiste nt 
H y per gl yce mic 
If after 8 wee ks of treat me nt wit h Stu d y Dr u g (I SI S 4 8 4 1 3 7 or place b o), F P G le vels 
> 2 7 0 m g/ d L ( or > 1 5 m m ol/ L) c o nfir me d o n 2 c o nsec u ti ve wee kl y st u d y visits wit h n o ot her 
e x pla nati o n(s) f or t he ele vati o n, a d diti o nal oral  gl uc ose-l o weri n g t herap y ma y be starte d or 
e xisti n g t hera pies ma y be titrate d i n d ose b y t he I n vesti gat or i n c o ns ultati o n wit h t he S p o ns or 
Me dical M o nit or or desi g nee.  T he use of t h iaz oli di ne di o nes (e. g., pi o glitaz o ne, r osi glitaz o ne) 
a n d i njecta ble a nti dia betic t hera p y is n ot  per mitte d (e. g., i ns uli n, G L P 1 a nal o gs).   
8. 8  
Disc o nti n u ati o n of St u d y Dr u g 
A s u bject m ust per ma ne ntl y disc o nti n ue st u d y treat me nt f or a n y of t he f oll o wi n g: 
•  T he s u bject bec o mes pre g na nt.  Re p ort t h e pre g na nc y acc or di n g t o i nstr ucti o ns i n 
Secti o n 9. 5. 4  
•  T he s u bject wit h dra ws c o nse nt 
•  T he s u bject e x perie nces a n A E  t hat necessitates per ma ne nt disc o nti n uati o n of St u d y Dr u g 


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•  T he s u bject de vel o ps la b orat or y test a b n or malities t hat meet a n y of t he st o p pi n g r ules 
liste d i n Secti o ns 8. 6. 1  t o 8. 6. 4  
•  T he s u bject e x perie nces a n A E t hat necessitates u n bli n di n g of t he I n vesti gat or or S p o ns or 
t o t he s u bject’s treat me nt assi g n me nt 
•  I nitiati o n of c hr o nic disall o we d t hera pies w hic h i ncl u de t he use of t hiaz oli di ne di o nes 
(e. g., pi o gitaz o ne, r osi glitaz o ne) a n d i njecta ble a nti dia betic t hera p y (e. g., i ns uli n, G L P 1 
a nal o gs), use of a ge nts (i ncl u di n g her bal or o ve r-t he c o u nter wei g ht l oss pre parati o ns) 
a n d me dicati o ns k n o w n t o si g nifica ntl y i m pact b o d y wei g ht (e. g., si b utra mi ne, 
p he neta mi ne a n d orlistat) 
T he reas o n f or disc o nti n uati o n of  St u d y Dr u g m ust be rec or de d i n t he electr o nic Case Re p ort 
F or m (e C R F) a n d s o urce d oc u me ntati o n. 
S u bjects w h o disc o nti n ue St u d y Dr u g s h o ul d be e nc o ura ge d t o re mai n i n t he st u d y a n d c o m plete 
t he P ost- Treat me nt E val uati o n Peri o d a n d c o nti nue pr ot oc ol re q uire d te sts a n d assess me nts.  
E ver y eff ort s h o ul d be ma de t o c o m plete t he ea rl y ter mi nati o n st u d y pr oce d ures a n d o bser vati o ns 
at t he ti me of wit h dra wal (see A p pe n di x A ). 
8. 9  
Wit h dr a w al of S u bjects fr o m t he St u d y 
S u bjects  m ust be wit h dra w n fr o m t he st u d y f or a n y of t he f oll o wi n g: 
•  Wit h dra wal of c o nse nt 
•  T he s u bject is u n willi n g or u na ble t o c o m pl y wit h t he pr ot oc ol 
Ot her reas o ns f or wit h dra wal of s u bjects fr o m t he st u d y mi g ht i ncl u de: 
•  At t he discreti o n of t he I n ve sti gat or f or me dical reas o ns 
•  At t he discreti o n of t he I n vesti g at or or S p o ns or f or n o nc o m plia nce 
•  Si g nifica nt pr ot oc ol de viati o n 
All eff orts will be ma de t o c o m plete a n d re p ort t he o bser vati o ns as t h or o u g hl y as p ossi ble u p t o 
t he date of wit h dra wal.  All i nf or mati o n, i ncl u di n g t he reas o n f or wit h dra wal fr o m st u d y, m ust be 
rec or de d i n t he e C R F as a p pr o priate. 
A n y s u bject w h o wit h dra ws c o nse nt t o partici pat e i n t he st u d y will be re m o ve d fr o m f urt her 
treat me nt a n d st u d y o bser vati o n i m me diatel y u p o n t he date of re q uest.  T hese s u bjects s h o ul d be 
e nc o ura ge d t o c o m plete t he earl y ter mi nati o n st u d y pr oce d ures a n d o bser vati o ns at t he ti me of 
wit h dra wal ( A p pe n di x A). 
F or s u bjects wit h dra w n f or reas o n s ot her t ha n wit h dra wal of c o nse nt e ver y eff ort s h o ul d be ma de 
t o c o m plete t he earl y ter mi nati o n st u d y pr oce d ures a n d o bser vati o ns at t he ti me of wit h dra wal 
(see A p pe n di x A). 


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8. 1 0  
C o nc o mit a nt T her a p y a n d Pr oce d ures 
T he use of c o nc o mita nt t hera pies or pr oce d ures defi ne d bel o w m ust be rec or de d o n t he s u bject’s 
e C R F.  A d verse e ve nts relate d t o  a d mi nistrati o n of t hese t hera pies or pr oce d ures m ust als o be 
d oc u me nte d o n t he a p pr o priate e C R F as a p pr o priate. 
8. 1 0. 1
 C o nc o mit a nt
 
T her a py
 
A c o nc o mita nt t hera p y is a n y n o n- pr ot oc ol s peci fie d dr u g or s u bsta nce (i ncl u di n g o ver-t he-
c o u nter me dicati o ns, her bal me dicati o ns a n d vita mi n s u p ple me nts) a d mi nistere d bet wee n t he 
si g ni n g of t he i nf or me d c o nse nt a n d t he last pr otoc ol s pecifie d P ost- Treat me nt E val uati o n Peri o d 
(A p pe n di x A ). 
All o we d C o nc o mit a nt T her a p y 
A n y me dicati o ns dee me d necessar y b y t he I n ves ti gat or are all o we d e xce pt t h ose liste d i n t he 
disall o we d c o nc o mita nt t hera p y.  I n t he P ost- T reat me nt Peri o d, a nti- dia betic a ge nts ma y be 
a d de d or altere d f or deteri orati n g gl yce mic c o nt r ol i n c o ns ultati o n wit h t he I n vesti gat or a n d 
S p o ns or Me dical M o nit or. 
Dis all o we d C o nc o mit a nt T her a p y 
T he use of t hiaz oli di ne di o nes (e . g., pi o gitaz o ne, r osi glitaz o ne) a n d i njecta ble a nti dia betic t hera p y 
is n ot per mitte d (e. g., i ns uli n, G L P 1 a nal o gs) w hile o n St u d y Dr u g.  I n case a s h ort-ter m i ns uli n 
t hera p y is gi ve n w he n a patie nt is h os pitalize d d uri n g t he st u d y, t he I n vesti gat or nee ds t o c o ns ult 
wit h t he S p o ns or Me dical M o nit or or desi g nee t o e val uate w het her t he patie nt will be all o we d t o 
c o nti n ue t he st u d y.  Use of a ge nts  (i ncl u di n g her bal or o ver-t he c o u nter wei g ht l oss pre parati o ns) 
or me dicati o ns k n o w n t o  si g nifica ntl y i m pact b o d y wei g ht wit hi n 3 m o nt hs pri or (e. g., 
si b utra mi ne, p he neta mi ne a n d orlistat) is n ot per mitte d w hile o n St u d y Dr u g.   
I nitiati n g a ne w stati n or i ncreasi n g t hera p y is n ot per mitte d.  Fis h oils or prescri pti o n li pi d-
re g ulati n g dr u gs (e. g., bile aci d a nal o g ues [e. g., o betic h olic aci d or urs o deo x yc h olic aci d], bile-
aci d se q uesteri n g resi ns, fi brates a n d deri vati ves) are n ot per mitte d.  If a d diti o nal stati n t hera p y 
or ot her li pi d l o weri n g t hera pie s are re q uire d, t he I n vesti gat or s h o ul d disc uss wit h t he Me dical 
M o nit or w het her t he s u bject m ust disc o nti n ue St u d y Dr u g.   
C hr o nic use of s yste mic c ortic oster oi ds a n d ot her me dicati o ns, per I n vesti gat or, k n o w n t o ca use 
li ver t o xicit y (e. g., c hr o nic aceta mi n o p he n use) or ca use steat o sis (e. g., a mi o dar o ne, 
met h otre xate) are n ot per mitte d w hile o n St u d y Dr u g. 
Ne w or i ncrease d use of a ntic oa g ula nts/a nti plate let a ge nts (e. g., warfari n, he pari n, da bi gatra n, 
ri var o xa ba n, cl o pi d o grel) u nless t he d ose has bee n sta ble f or 4 w ee ks pri or t o t he first d ose of 
St u d y Dr u g a n d re g ular cli nical m o nit ori n g is  perf or me d; use of t he n o n-ster oi dal a nti-
i nfla m mat or y dr u g ( N S AI D) ni mes uli de or a n y other dr u g i nfl ue nci n g c o a g ulati o n (e xce pt l o w 
d ose as piri n < ◦1 6 0 ◦m g/ da y a n d ot her s h ort acti n g N S AI D S wit h a half-life < 2 0 h o urs) are n ot 
per mitte d w hile o n St u d y Dr u g.  
A nti ne o plastic a ge nts are n ot per mitte d w hile o n St u d y Dr u g. 


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8. 1 0. 2
 C o nc o mit a nt
 
Pr oce d ures
 
A c o nc o mita nt pr oce d ure is a n y t hera pe utic i nte r ve nti o n (e. g., s ur ger y/ bio ps y, p h ysical t hera p y) 
or dia g n ostic assess me nt (e. g., bl o o d gas meas ur e me nt, bacterial c ult ures) perf or me d bet wee n  
si g ni n g of t he i nf or me d c o nse nt a n d t he last pr otoc ol-s pecifie d P ost- Treat me nt E val uati o n visit 
(A p pe n di x A ) 
8. 1 1
 Tre at me nt
 
C o m pli a nce
 
C o m plia nce wit h St u d y Dr u g d osi n g is t o be m o nit ore d a n d rec or de d i n t he e C R F b y St u d y 
Ce nter staff. 
9.  
S E RI O U S A N D N O N- S E RI O U S A D V E R S E E V E N T R E P O R TI N G  
9. 1  
S p o ns or Re vie w of S afet y I nf or m ati o n 
Safet y i nf or mati o n will be c ollecte d, re vie we d, a n d e val uate d b y t he S p o ns or or desi g nee i n 
acc or da nce wit h t he Safet y Ma na ge me nt Pla n a n d t he Me dical M o nit ori n g Pla n t hr o u g h o ut t he 
c o n d uct of t he cli nical trial. 
9. 2
 Re g ul at or y
 
Re q uire me nts
 
T he S p o ns or or desi g nee is res p o nsi ble f or re g ulat or y s u b missi o ns a n d re p orti n g t o t he 
I n vesti gat ors of S A Es i ncl u di n g S U S A Rs per t he I nter nati o nal C o nfere nce o n Har m o nizati o n 
(I C H) g ui deli nes E 2 A a n d I C H E 6.  C o u ntr y-s pecific re g ulat or y req uire me nts will be f oll o we d i n 
acc or da nce wit h l ocal c o u ntr y re g ulati o ns a n d g ui deli nes. 
I nstit uti o nal Re vie w B oar ds (IR B)/I n de pe n de nt Et hics C o m mittees (I E C) will be n otifie d of a n y 
S A E acc or di n g t o a p plica ble re g ulati o ns.   
I n a d diti o n t o t he I n vesti gat or’s assess me nt of relate d ness, t he S p o ns or or desi g nee will e val uate 
t he a vaila ble i nf or mati o n a n d perf or m a n i n de pen de nt assess me nt of relate d ness.  W hile t he 
S p o ns or ma y u p gra de a n I n vesti gat or’s decisi o n it is n ot per missi ble t o d o w n gra de t he 
I n vesti gat or’s o pi ni o n f or t he p ur p oses of deter mi ni n g w het her t he S A E meets t he defi niti o n of a 
S U S A R. 
A p pr o priate pers o n nel at t he S p o ns or or de si g nee will u n bli n d S U S A Rs f or t he p ur p ose of 
re g ulat or y re p orti n g.  T he S p o ns or or desi g nee will s u b mit S U S A Rs t o Re g ulat or y A ge ncies i n 
bli n de d or u n bli n de d fas hi o n acc or di n g t o l ocal la w.  T he S p o ns or or desi g nee will s u b mit 
S U S A Rs t o I n vesti gat ors i n a bli n de d fas hi o n. 
9. 3
 Defi niti o ns
 
9. 3. 1
 A dverse
 
Eve nt
 
A n a d verse e ve nt is a n y u nfa v ora ble a n d u ni nt e n de d si g n (i ncl u di n g a cli nicall y-si g nifica nt 
a b n or mal la b orat or y fi n di n g, f or e xa m ple), s y m pt o m,  or disease te m p orall y ass ociate d wit h t he 
st u d y or use of i n vesti gati o nal dr u g pr o d uct, w het her or n ot t he A E is c o nsi dere d relate d t o t he 
i n vesti gati o nal dr u g pr o d uct. 


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9. 3. 2  
A dverse Re acti o n a n d S us pecte d A dverse Re acti o n 
A n a d verse reacti o n is a n y A E ca use d b y t he St u d y Dr u g. 
A s us pecte d a d verse reacti o n is a n y A E f or w hic h t here is a reas o na ble p ossi bilit y t hat t he dr u g 
ca use d t he A E.  A s us pecte d a d verse reacti o n i m plie s a lesser de gree of certai nt y a b o ut ca usalit y 
t ha n a n a d verse reacti o n. 
9. 3. 3  
Seri o us A dverse Eve nt ( S A E) 
A seri o us a d verse e ve nt is a n y a d verse e ve nt t hat  i n t he vie w of eit her t he I n vesti gat or or 
S p o ns or, meets a n y of t he f oll o wi n g criteria: 
•  Res ults i n deat h 
•  Is life t hreate ni n g: t hat is, p oses a n i m me diate ris k of d eat h at t he ti me of t he e ve nt 
A n A E or s us pecte d a d verse reacti o n is c o nsi d ere d “life-t hreate ni n g”  if, i n t he vie w of 
eit her t he I n vesti gat or or S p o ns or, its occ urr e nce places t he s u bject at i m me diate ris k of 
deat h.  It d oes n ot i ncl u de a n A E or s us pecte d  a d verse reacti o n t hat, ha d it occ urre d i n a 
m ore se vere f or m, mi g ht ha ve ca use d deat h 
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xis ti n g h os pitalizati o n 
H os pitalizati o n is defi ne d as a n a d missi o n of greater t ha n 2 4 h o urs t o  a me dical facilit y 
a n d d oes n ot al wa ys q ualif y as a n A E 
•  Res ults i n a persiste nt or si g nifica nt 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 
•  Res ults i n a c o n ge nital a n o mal y or birt h defect  i n t he offs pri n g of t he s u bject ( w het her 
t he s u bject is male or fe male) 
•  I m p orta nt me dical e ve nts t hat ma y 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 als o be c o nsi dere d seri o us w he n, base d u p o n a p pr o priate 
me dical 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 ve nt o ne of t he o utc o mes liste d i n t his defi niti o n.  E xa m ples of s uc h 
me dical 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 nc y r o o m or at h o me, bl o o d d yscrasi as or c o n v ulsi o ns t hat d o n ot res ult i n 
i n patie nt h os pitalizati o n, or t he de velo p me nt of dr u g de pe n de nc y or dr u g a b use 
9. 4  
M o nit ori n g a n d Rec or di n g A d verse E ve nts 
A n y pre-e xisti n g c o n diti o ns or si g ns  a n d/ or s y m pt o ms prese nt i n a su bject pri or t o t he start of t he 
st u d y (i.e., bef ore i nf or me d c o nse nt) s h o ul d be rec or de d as Me dical Hist or y a n d n ot rec or de d as 
A Es u nless t he pre-e xisti n g c o n diti o n w orse ne d.  T h e I n vesti gat or s h o ul d al wa ys gr o u p si g ns a n d 
s y m pt o ms i nt o a si n gle ter m t hat c o nstit utes a si n gle u nif yi n g di a g n osis if p ossi ble. 
9. 4. 1  
Seri o us A dverse Eve nts 
I n t he i nterest of s u bject safet y, a n d t o f ulfill re g ulat or y re q uire me nts, all S A Es (re gar dless of 
t heir relati o ns hi p t o St u d y Dr u g) s h o ul d be re p orte d t o t he S p o ns or or desi g nee wit hi n 2 4 h o urs 
of t he St u d y Ce nter’s first k n o wle d ge of t he  e ve nt.  T he c ollecti o n of S A Es will be gi n after t he 


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s u bject si g ns t he i nf or me d c o nse nt f or m a n d sto p at t he e n d of t he s u bject’s f oll o w- u p peri o d 
w hic h is defi ne d as St u d y Wee k P T 1 3 ( Secti o n 3. 4. 3 ).  W he n t he I n vesti gat or is re p orti n g b y 
tele p h o ne, it is i m p orta nt t o s pea k t o s o me o ne i n pers o n vs. lea vi n g a messa ge.  T he S A E s h o ul d 
be re p orte d usi n g electr o nic S A E re p orti n g f o r m b y sca n ni n g a n d e maili n g t he f or m t o 
I N C Dr u g Safet y @i ncresearc h.c o m.  If t he electr o nic s u b missi o n is u na vaila ble, a n  I nitial Seri o us 
A d verse E ve nt F or m s h o ul d be c o m plete d a n d a c o p y s h o ul d be fa xe d t o t he S p o ns or or 
desi g nee.  T he fa x n u m ber f or re p orti n g S A Es ca n be f o u n d i n t he St u d y Refere nce Ma n ual.   
Detaile d i nf or mati o n s h o ul d be acti vel y s o u g ht  a n d i ncl u de d o n F oll o w- U p Seri o us A d verse 
E ve nt F or ms as s o o n as a d diti o nal i nf or mati o n b ec o mes a vaila ble.  All S A Es will be f oll o we d 
u ntil res ol uti o n.  S A Es t hat re mai n o n g oi n g past t he s u bject’s last pr ot oc ol-s pecifie d f oll o w- u p 
visit will be e val uate d b y t he I n ve sti gat or a n d S p o ns or.  If t he In vesti gat or a n d S p o ns or a gree t he 
s u bject’s c o n diti o n is u nli kel y t o res ol ve, t he I n vesti gat or a n d S p o ns or will deter mi ne t he 
f oll o w- u p re q uire me nt. 
9. 4. 2  
N o n- Seri o us A dverse Eve nts 
T he rec or di n g of n o n-seri o us A Es will be gi n after t he s u bject si g ns t he i nf or me d c o nse nt f or m 
a n d will st o p at t he e n d of t he s u bject’s f oll o w- u p peri o d, w hic h is defi ne d as 1 3 wee ks after t he 
last d ose ( St u d y Visit P T 1 3), see Secti o n 3. 4. 3.  T he I n vesti gat or will m o nit or eac h s u bject 
cl osel y a n d rec or d all o bser ve d or v ol u nteere d A Es o n t he A d verse E ve nt Case Re p ort F or m. 
9. 4. 3  
Ev al u ati o n of A dverse Eve nts  ( Seri o us a n d N o n- Seri o us) 
T he I n vesti gat or’s o pi ni o n of t he f oll o wi n g s h o ul d be d oc u me nte d o n t he A d verse E ve nt Case 
Re p ort F or m: 
9. 4. 3. 1  
Rel ati o ns hi p t o t he St u dy Dr u g 
T he e ve nt’s relati o ns hi p t o t h e St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o)  is c haracterize d b y o ne of 
t he f oll o wi n g: 
•  Rel ate d:   T here is clear e vi de nce t hat t he e ve nt is relate d t o t he use of St u d y Dr u g, e. g., 
c o nfir mati o n b y p ositi ve re-c halle n ge test 
•  P ossi ble:   T he e ve nt ca n n ot be e x plai ne d b y t he s u bject’s me dical c o n diti o n, c o nc o mita nt 
t hera p y, or ot her ca uses, a n d t here is a pla usi ble te m p oral relati o ns hi p bet wee n t he e ve nt 
a n d St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) a d mi nistrati o n 
•  U nli kel y/ Re m ote:   A n e ve nt f or w hic h a n alter nati ve e x pla nati o n is m ore li kel y (e. g., 
c o nc o mita nt me dicati o ns or o n g oi n g me dical c o n diti o ns) or t he te m p oral relati o ns hi p t o 
St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) a d mi nistrati o n a n d/ or e x p os ure s u g gests t hat a 
ca usal relati o ns hi p is u nli kel y ( F or re p orti n g p ur p oses, U nli kel y/ Re m ote will be gr o u pe d 
t o get her wit h N ot Relate d) 
•  N ot Rel ate d:   T he e ve nt ca n be rea dil y e x plai ne d b y t he s u bject’s u n derl yi n g me dical 
c o n diti o n, c o nc o mita nt t hera p y, or ot her ca uses,  a n d t heref ore, t he I n vesti gat or belie ves 
n o relati o ns hi p e xists bet wee n  t he e ve nt a n d St u d y Dr u g 


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9. 4. 3. 2
 Severity
 
T he se verit y of A Es a n d S A Es will be gra de d  base d o n criteria fr o m t he C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E ve nts ( C T C A E ) Versi o n 4. 0 3, J u ne 2 0 1 0 (refer t o A p pe n di x D ).  A n y A E 
n ot liste d i n A p pe n di x D will be gra de d as f oll o ws: 
•  Mil d:   T he e ve nt is easil y t olerate d b y t he s u bject a n d d oes n ot affect t he s u bject’s us ual 
dail y acti vities 
•  M o der ate:   T he e ve nt ca uses t he s u bject m ore disc o mf ort a n d i nterr u pts t he s u bject’s 
us ual dail y acti vities  
•  Se vere:  T he e ve nt is i nca pacitati n g a n d ca uses c o nsi dera ble i nterfere nce wit h t he 
s u bject’s us ual dail y acti vities 
If t he e ve nt is a n S A E, t he n all a p plica ble seri o us ness criteria m ust be i n dicate d (criteria liste d i n 
Secti o n 9. 3. 3 ). 
9. 4. 3. 3  
Acti o n T a ke n wit h St u dy Dr u g 
Acti o n ta ke n wit h St u d y Dr u g (I SI S  4 8 4 1 3 7 or place b o) d ue t o t he e ve nt is c haracterize d b y o ne 
of t he f oll o wi n g. 
•  N o ne:   N o c ha n ges were ma de t o St u d y Dru g (I SI S  4 8 4 1 3 7 or place b o) a d mi nistrati o n 
a n d d ose 
•  Per m a ne ntl y Disc o nti n ue d:   St u d y Dr u g was disc o nti n ue d a n d n ot restarte d 
•  Te m p or aril y I nterr u pte d, Rest arte d:   D osi n g was te m p oraril y i nterr u pte d or dela ye d 
d ue t o t he A E a n d restarte d 
9. 4. 3. 4  
Tre at me nt Give n f or A dverse Eve nt 
A n y  treat me nt (e. g., me dicati o ns or pr oce d ures) give n f or t he A E s h o ul d be rec or de d o n t he 
A d verse E ve nt Case Re p ort F or m.  Treat me nt s h o ul d als o be rec or de d o n t he c o nc o mita nt 
treat me nt or a ncillar y pr oce d ures e C R F, as a p pr o priate. 
9. 4. 3. 5  
O utc o me of t he A dverse Eve nt 
If t he e ve nt is a n o n-seri o us A E, t he n t he e ve nt’s o utc o me is c haracterize d b y o ne of t he 
f oll o wi n g: 
•  A E Persists:   S u bject ter mi nates fr o m t he trial a n d t he A E c o nti n ues 
•  Rec o vere d:   S u bject rec o vere d c om pletel y fr o m t he A E 
•  Bec a me Seri o us:   T he e ve nt beca me seri o us (t he date t hat t he e ve nt beca me seri o us 
s h o ul d be rec or de d as t he Res ol uti o n Date of t hat A E a n d t he O nset Date of t he 
c orres p o n di n g S A E) 
•  C h a n ge i n Se verit y (if a p plic a ble):   A E se verit y c ha n ge d 
If t he e ve nt is a n S A E, t he n t he e ve nt’s o utc o me is c haracterize d b y o ne of t he f oll o wi n g: 


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•  O n g oi n g:   S A E c o nti n ui n g 
•  Persists ( as n o n-seri o us A E):   S u bject has n ot f ull y reco vere d b ut t he e ve nt n o l o n ger 
meets seri o us criteria a n d s h o ul d be ca pt ure d as a n A E o n t he n o n-seri o us A E e C R F (t he 
S A E res ol uti o n date s h o ul d be e ntere d as t he date of o nset of t hat A E) 
•  Rec o vere d:   S u bject rec o vere d c o m pletel y fr o m t he S A E (t he date of rec o ver y s h o ul d be 
e ntere d as t he S A E res ol uti o n date) 
•  F at al:   S u bject die d (t he date of deat h s h o uld be e ntere d as t he S A E res ol uti o n date) 
9. 5  
Pr oce d ures f or H a n dli n g S peci al Sit u ati o ns 
9. 5. 1  
A b n or m alities of L a b or at ory Tests 
Cli nicall y-si g nifica nt a b n or mal la b orat or y test re s ults ma y, i n t he o pi ni o n of t he I n vesti gat or, 
c o nstit ute or be ass ociate d wit h a n A E.  E xa m ples of t hese i ncl u de a b n or mal la b orat or y res ults 
t hat are ass ociate d wit h s y m pt o ms, or re q uire treat me nt, e. g., blee di n g d ue t o t hr o m b oc yt o pe nia, 
teta n y d ue t o h y p ocalce mia, or car diac arr h yt h mias d ue t o h y per kale mia.  W he ne ver p ossi ble, t he 
u n derl yi n g dia g n osis s h o ul d be list e d i n prefere nce t o a b n or mal la b orat or y val ues as A Es.  
Cli nicall y-si g nifica nt a b n or malities will be m o n it ore d b y t he I n vesti gat or u ntil t he para meter 
ret ur ns t o its baseli ne val ue or u ntil a gree me nt is reac he d bet wee n t he I n vesti gat or a n d S p o ns or 
Me dical M o nit or.  La b orat or y a b n or malities de e me d n ot cli nicall y-si g nifica nt ( N C S) b y t he 
I n vesti gat or s h o ul d n ot be re p orte d as A Es.  Si milarl y, la b orator y a b n or malities re p orte d as A Es 
b y t he I n vesti gat or s h o ul d n ot be de e me d N C S o n t he la b orat or y s heet. 
T he I n vesti gat or is res p o nsi ble f or re vie wi n g a n d si g ni n g all la b orat or y re p orts.  T he si g ne d 
cli nical la b orat or y re p orts will ser ve as s o urce d oc u me nts a n d s h o ul d i ncl u de t he I n vesti gat or’s 
assess me nt of cli nical si g nifica nce of o ut of ra n ge/a b n or mal la b orat or y val ues. 
9. 5. 2  
Presc he d ule d or Elective Pr oce d ures or R o uti nely Sc he d ule d Tre at me nts 
A presc he d ule d or electi ve pr oce d ure or a r o uti nel y sc he d ule d treat me nt will n ot be c o nsi dere d 
a n S A E, e ve n if t he s u bject is h os pitalize d; t he St u d y Ce nter m ust d ocu me nt all t he f oll o wi n g: 
•  T he presc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d treat me nt was sc he d ule d 
( or was o n a waiti n g list t o be sc he d ule d) pri or t o o btai ni n g t he su bject’s c o nse nt t o 
partici pate i n t he st u d y 
•  T he c o n diti o n t hat re q uire d t he presc he d ule d or electi ve pr oce d ure or  r o uti nel y sc he d ule d 
treat me nt was prese nt bef ore a n d di d n ot w orse n or pr o gress i n t he o pi ni o n of t he 
I n vesti gat or bet wee n t he s u bject’s c o nse nt t o partici pate i n t he st u d y a n d t he ti mi n g of t he 
pr oce d ure or treat me nt 
•  T he presc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d treat me nt is t he s ole 
reas o n f or t he i nter ve nti o n or h os pital a d missi o n 
9. 5. 3
 D osi n g
 
Err ors
 
St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) err ors s h o ul d be d oc u me nte d as Pr ot oc ol De viati o ns.  A 
brief descri pti o n s h o ul d be pr o vi de d i n t he de viati o n, i ncl u di n g w het her t he s u bject was 
s y m pt o matic (list s y m pt o ms) or as y m pt o matic, a n d t he e ve nt acci de ntal or i nte nti o nal. 


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D osi n g details s h o ul d be ca pt ure d o n t he D o si n g Case Re p ort F or m.  If t he s u bject ta kes a d ose 
of St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) t hat e xc ee ds pr ot oc ol s pecificati o ns a n d t he s u bject  is 
s y m pt o matic, t he n t he s y m pt o m(s) s h o ul d be d oc u me nte d as a n A E a n d be re p orte d per 
Secti o n 9. 4 . 
T here has bee n n o occ urre nce of a n A S O o ver d os e i n ma n fr o m c o m plete d or o n g oi n g cli nical 
st u dies wit h A S Os.    
9. 5. 4  
C o ntr ace pti o n a n d Pre g n a ncy 
Fe male s u bjects of c hil d beari n g p ote n tial are e xcl u de d fr o m t his st u d y.   
Male s u bjects m ust c o nti n ue t o use a p pr o priate c o ntrace pti o n wit h t heir part ners of c hil d beari n g 
p ote ntial, or refrai n fr o m se x ual acti vit y, as descri be d i n Secti o n 6. 3. 1 . 
If a s u bject ma kes or belie ves t hat he has ma de s o me o ne pre g na nt d uri n g t he st u d y, t he n t he 
St u d y Ce nter staff m ust be i n f or me d i m me diatel y.  A n I nitial Pre g na nc y F or m s h o ul d be 
s u b mitte d t o t he S p o ns or or desi g nee wit hi n 2 4 h o urs  of first lear ni n g of t he occ urre nce of 
pre g na nc y.  F oll o w- u p i nf or mati o n i ncl u di n g deli ver y or ter mi n ati o n is re p orte d b y desi g nati n g 
as ‘ F oll o w- u p’ o n t he Pre g na nc y F or ms a n d re p orte d wit hi n 2 4 h o urs. 
Pa y me nt f or all as pects of o bste trical care, c hil d or relate d care will be t he s u bject’s 
res p o nsi bilit y.   
T he pr o gress of t he pre g na nc y of a male s u bject’s part ner s h o ul d be f oll o we d u ntil t he o utc o me 
of t he pre g na nc y is k n o w n (i.e., deli ver y, electi ve ter mi nati o n, or s p o nta ne o us a b orti o n).  If t he 
pre g na nc y res ults i n t he birt h of a c hil d, t he St u d y Ce nter a n d S p o ns or m a y re q uest access t o 
t he m ot her a n d i nf a nt’s me dic al rec or ds t o o bt ai n a d diti o n al i nf or m ati o n.  F oll o w- u p will 
be perf or me d t o t he e xte nt per mitte d b y t he a p p lica ble re g ulati o ns a n d pri vac y c o nsi derati o ns. 
1 0.
 S T A TI S TI C A L
 
C O N SI D E R A TI O N S
 
1 0. 1  
St u d y E n d p oi nts, S u bsets, a n d C o v ari ates 
1 0. 1. 1
 S afety
 
E n d p oi nts
 
T he safet y a n d t olera bilit y of I SI S 4 8 4 1 3 7 will be accesse d b y deter mi ni n g t he i nci de nce a n d 
se verit y of A Es a n d will be e val uate d b y re vie wi n g: 
•  A Es (i ncl u di n g blee di n g e ve nts) 
•  Vital si g ns a n d wei g ht  
•  P h ysical e xa mi nati o n  
•  Cli nical la b orat or y tests   
•  C oa g ulati o n para meters 
•  Use of c o nc o mita nt me dicati o ns 


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1 0. 1. 2  
Pri m ary P h ar m ac o dy n a mic E n d p oi nt  
T he pri mar y P D e n d p oi nt is t he a bs ol ute c ha n ge  i n li ver fat perce nta ge as q ua ntifie d b y 
M RI- P D F F fr o m Baseli ne M RI t o P ost- Treat me nt M RI. 
1 0. 1. 3
 Sec o n d ary
 
E n d p oi nts
 
Sec o n dar y e n d p oi nts i ncl u de:  
•
Relati ve perce nt c ha n ge i n li ver fat perce nta ge fr o m Baseli ne M RI t o P ost- Treat me nt
M RI
•
Pr o p orti o n of s u bjects wit h ≥ 3 0 % relati ve re d ucti o n i n li ver fat perce nta ge fr o m Baseli ne
M RI t o P ost- Treat me nt M RI
•
Perce nt c ha n ge i n li ver v ol u me fr o m Baseli ne M RI t o P ost- Treat me nt M RI
•
Perce nt c ha n ge i n plas ma li p o pr otei n pr ofile (tri gl yceri des, t otal c h olester ol, L D L- C,
a p o B, V L D L, H D L, a n d N o n- H D L) fr o m Baseli ne t o t he a vera ge of t he P ost- Treat me nt
val ues assesse d 1 a n d 2 wee ks after t he last d ose ( P T 1 a n d P T 2 Visits)
•
Perce nt c ha n ge i n para meters of he patic I R ( F P G, i ns uli n, a n d H O M A-I R) fr o m Baseli ne
t o t he first P ost- Treat me nt val ue assesse d 1 wee k after t he last  d ose ( P T 1 Visit)
•
A bs ol ute c ha n ge i n H b A 1c fr o m Baseli ne t o t he first P ost- Treat me nt val ue assesse d
1 wee k after t he last d ose ( P T 1 Visit)
1 0. 1. 4
 E x pl or at ory
 
E n d p oi nts
 
 
 
1 0. 2  
S a m ple Size C o nsi der ati o ns  
A p pr o xi matel y 4 5 s u bjects will be ra n d o mize d ( 2: 1 all ocati o n rati o).  Wit h 4 5 s u bjects t here will 
be > 9 0 % p o wer t o detect a of 5 % differe nce i n m ea n a bs ol ute c ha n ge i n li ver fat as meas ure d b y 
P D F F bet wee n t he acti ve a n d place b o gr o u ps wit h  a 2-si de d al p ha of 0. 0 5, ass u mi n g a c o m m o n 
sta n dar d de viati o n of 4 % a n d 2 5 % n o n-c o m pleters.   
T he 5 % effect size was selecte d base d o n cli n ical rele va nce wit h e vi de nce t hat 5 % P D F F 
re d ucti o n i de ntifie d s u bjects wit h re d uce d steat osis gra de i n N A S H s u bjects (Mi d dlet o n et al.  
2 0 1 7 ). 
1 0. 3
 P o p ul ati o ns
 
Ra n d o mize d:  All s u bjects w h o are ra n d o mize d i nt o t he st u d y re gar dless of w het her t he y 
recei ve d St u d y Dr u g. 
Per- Pr ot oc ol P o p ulati o n:  Will i ncl u de t he s u bset of t he Ra n d o mize d P o p ulati o n w h o ha ve 
recei ve d at least 1 0 of t he prescri be d d oses a n d m ust recei ve t he first 4 d oses i n t he first 5 wee ks, 
ca n n ot miss 3 c o nsec uti ve wee kl y d oses a n d n o si g nifica nt pr ot oc ol de viati o ns t hat w o ul d be 
e x pecte d t o i m pact efficac y.  
C CI


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
5 8
 
Safet y P o p ulati o n:  All s u bject s w h o are ra n d o mize d a n d recei ve at least 1 d ose of St u d y Dr u g. 
P K P o p ulati o n:  All s u bjects w h o ha ve rece i ve d at least 1 d ose of acti ve St u d y Dr u g 
(I SI S 4 8 4 1 3 7), a n d ha ve at least 1 P K sa m ple c ollecte d a n d a nal yze d wit h e val ua ble res ults. 
1 0. 4  
Defi niti o n of B aseli ne  
•
Baseli ne M RI he patic fat c o nte nt a n d v ol u me will be fr o m t he M RI pri or t o a n d cl osest t o
ra n d o mizati o n
•
Baseli ne f or plas ma li p o pr otei n pr ofile (tri gl yceri des, t otal c h olester ol, L D L- C, a p o B,
V L D L, H D L, a n d N o n- H D L), e x pl orat or y bi o mar kers of D G A T 2 acti vit y ( S C D- 1), a n d
bi o mar kers of i nfla m mati o n (e. g., C K 1 8, ha pt o gl o bi n) a n d assess me nts f or I R ( F P G,
i ns uli n, H O M A I R) will be t he a vera ge of wee k - 1 visit ( Da y - 7) a n d Da y 1 pre- d ose
assess me nts
•
Baseli ne f or platelets, creati ni ne, A L T a n d A S T will be t he a vera ge of wee k - 1 visit
( Da y - 7) a n d Da y 1 pre- d ose assess me nts
•
Baseli ne f or H b A 1c a n d f or ot her r o uti ne cli nical assess me nts of c he mistr y a n d
he mat ol o g y, P K assess me nts, vital si g ns a n d E C G f or t he st u d y will be t he last n o n-
missi n g val ue pri or t o t he first a d mi nistra ti o n of St u d y Dr u g will be t he last n o n- missi n g
val ue pri or t o t he first a d mi nistrati o n of St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o;
A p pe n di x A ).
1 0. 5
 I nteri m
 
A n al ysis
 
N o i nteri m a nal ysis is pla n ne d.  H o we ver, d ur i n g t he st u d y, a n u n bli n de d i nteri m a nal ysis ma y 
be c o n d ucte d t o assess t he safet y, P K/ P D, a n d e x pl orat or y efficac y of t he res ults.  T he a nal ysis 
will be e xec ute d wit h c o ntr olle d disse mi nati o n t o e ns ure t he i nte grit y of o n g oi n g data c ollecti o n 
w hile mai ntai ni n g s ufficie nt bli n di n g i n t he st u d y.  Details of t hese c o ntr ols will be descri be d i n 
t he Statistical A nal ysis Pla n ( S A P). 
1 0. 6  
Pl a n ne d Met h o ds of A n al ysis 
All e C R F data, la b data tra nsfers, as well as  a n y o utc o mes deri ve d fr o m t he data, will be 
pr o vi de d i n t he s u bject data list i n gs.  S u bject data listi n gs will be prese nte d f or all s u bjects 
e nr olle d i nt o t he st u d y.  Descri pti ve s u m mar y statistics i ncl u d i n g n, mea n, me dia n, sta n dar d 
de viati o n, i nter q uartile ra n ge ( 2 5 t h perce ntile, 7 5t h perce ntile), a n d ra n ge ( mi ni m u m, ma xi m u m) 
f or c o nti n u o us varia bles, a n d co u nts a n d perce nta ges f or cate g orical  varia bles will be use d t o 
s u m marize m ost data.  W here a p pr o priate, p- val ues will be re p orte d.  All statistical tests will be 
c o n d ucte d usi n g 2-si de d tests wit h 5 % t y pe I err or rate s u nless ot her wise state d. 
T he efficac y a n d P D e n d p oi nts will be assesse d o n t he Ra n d o mize d P o p ulati o n a n d Per- Pr ot oc ol 
P o p ulati o n.  T he safet y a nal yses will be perf or me d o n t he Safet y P o p ulati o n. 
1 0. 6. 1  
De m o gr a p hic a n d B aseli ne C h ar acteristics 
De m o gra p hic a n d Baseli ne c harac teristics will be s u m marize d usi n g descri pti ve statistics b y 
treat me nt gr o u p.  S u bject ra n d o mizati o n will be s u m marize d b y c o h ort a n d treat me nt gr o u p.  T he 
s u bject dis p ositi o n will be s u m marize d.  All s u bjects e nr olle d will be i ncl u de d i n a s u m mar y of 
s u bject dis p ositi o n. 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
5 9
 
1 0. 6. 2
 S afety
 
A n alysis
 
Treat me nt d urati o n a n d a m o u nt of St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) recei ve d will be 
s u m marize d b y treat me nt gr o u p.  S ubject i nci de nce rates of all A Es will be ta b ulate d b y t he 
Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A ™) s yste m or ga n class, a n d b y 
Me d D R A
™ ter m.  Ta bles a n d/ or narrati ves of treat me nt-e mer ge nt deat hs, se ri o us a n d si g nifica nt 
A Es, i ncl u di n g earl y wit h dra wals d ue t o A Es, will als o be pr o vi de d. 
All treat me nt-e mer ge nt A Es, a ll treat me nt-e mer ge nt A Es p ote ntiall y relate d t o St u d y Dr u g, all 
treat me nt-e mer ge nt seri o us A Es, a n d all treat me nt-e mer ge nt seri o us A Es p ote ntiall y relate d t o 
St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) will be s u m marize d. 
La b orat or y tests t o e ns ure s u bject safet y i ncl u di n g c he mistr y pa nel, c o m plete bl o o d c o u nt wit h 
differe ntial, c oa g ulati o n pa nel, c o m ple me nt etc., will be s u m marize d b y st u d y visits f or eac h 
treat me nt gr o u p.  T hese safet y varia bles will als o be prese nte d as c ha n ge a n d perce nt c ha n ge 
fr o m Baseli ne o ver ti me after St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) a d mi nistrati o n, as 
a p pr o priate. 
Vital si g n a n d E C G meas ures will  be ta b ulate d b y treat me nt gro u p.  I n a d diti o n, t he n u m ber of 
s u bjects w h o e x perie nce a b n or malities i n cli nical la b orat or y e val uati o ns will be s u m marize d b y 
treat me nt gr o u p. 
P h ysical e xa mi nati o n data will be pr o vi de d i n t h e data listi n g.  C o nc o mita nt me dicati o ns will be 
c o de d usi n g W orl d Healt h Or ga nizati o n ( W H O) Dr u g dicti o nar y a n d s u m marize d b y treat me nt, 
A T C class a n d ge neric na me. 
1 0. 6. 3
 P h ar m ac o ki netic
 
A n alysis
 
F or all e val ua ble s u bjects recei vi n g I SI S 4 8 4 1 3 7, plas ma I SI S 4 8 4 1 3 7 c o nce ntrati o ns at tr o u g h 
d uri n g t he Treat me nt Peri o d a n d c o nce ntrati o ns o bser ve d d uri n g t he P ost- Treat me nt E val uati o n 
Peri o d will be liste d b y d ose, st u d y da y, ti me p oi nt, a n d s u m marize d us i n g descri pti ve statistics.  
A d diti o nal details re gar di n g t he P K a nal ys is will be descri be d i n t he S A P.   
P ote ntial relati o ns hi ps bet wee n selecte d P D  a n d plas ma e x p os ure meas ures (e. g., tr o u g h 
c o nce ntrati o ns) ma y als o be e x pl ore d, w here dee me d a p pr o priate. 
1 0. 6. 4
 P h ar m ac o dy n a mic/ E ffic acy A n alysis 
M RI res ults will be s u m marize d a n d ta b ulate d base d o n P D F F re d ucti o ns fr o m Baseli ne a bs ol ute 
a n d relati ve re d ucti o ns a n d li ver v ol u me.  Details  of pla n ne d a nal ysis of efficac y e n d p oi nts 
i ncl u de d P D e n d p oi nts will be pr o vi de d i n t he S A P. 
1 0. 6. 5
 A d diti o n al
 
A n alyses
 
 
 
C CI


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
6 0
 
1 1.  
I N V E S TI G A T O R’ S R E G U L A T O R Y O B LI G A TI O N S 
1 1. 1
 I nf or me d
 
C o nse nt
 
T he writte n i nf or me d c o nse nt d oc u me nt s h o ul d be pre pare d i n t he la n g ua ge(s) of t he p ote ntial 
patie nt p o p ulati o n, base d o n a n E n glis h vers i o n pr o vi de d b y t he Sp o ns or or desi g nee. 
Bef ore a s u bject’s partici pati o n i n t he trial, t he I n vesti gat or is res p o nsi ble f or o btai ni n g writte n 
i nf or me d c o nse nt fr o m t he s u bject or le gall y acce pta ble re prese ntati ve afte r a de q uate e x pla nati o n 
of t he ai ms, met h o ds, a ntici pate d be nefits, a n d p ote ntial hazar ds of t h e st u d y a n d bef ore a n y 
pr ot oc ol-s pecific scree ni n g pr oce d ures or  a n y St u d y Dr u g (I SI S 4 8 4 1 3 7 or place b o) are 
a d mi nistere d.  T he s u bject or le gall y acce pta ble re prese ntati ve m ust be gi ve n s ufficie nt ti me t o 
c o nsi der w het her t o part ici pate i n t he st u d y.   
T he ac q uisiti o n of i nf or me d c o nse nt a n d t he s u bj ect’s a gree me nt or ref u sal t o n otif y his/ her 
pri mar y care p h ysicia n  s h o ul d be d oc u me nte d i n t he s u bject’s me dical rec or ds a n d t he i nf or me d 
c o nse nt f or m s h o ul d be si g ne d a n d pers o nall y date d b y t he s u bject or a le gall y acce pta ble 
re prese ntati ve a n d b y t he pers o n w h o c o n d ucte d t he i nf or me d c o nse nt disc ussi o n ( n ot necessaril y 
a n I n vesti gat or).  T he ori gi nal si g ne d i nf or me d  c o nse nt f or m s h o ul d be retai ne d i n t he St u d y 
Master File a n d i n a n y ot her l o cati o ns re q uire d b y i nstit uti o na l p olic y, a n d a c o p y of t he si g ne d 
c o nse nt f or m s h o ul d be pr o vi de d t o t he s u bj ect or le gall y acce pta ble re prese ntati ve. 
If a p ote ntial s u bject is illiterate or vis uall y i m paire d an d d oes n ot ha ve a le gall y acce pta ble 
re prese ntati ve, t he I n vesti gat or m ust pr o vi de a n i m partial wit ness t o rea d t he i nf or me d c o nse nt 
f or m t o t he s u bject a n d m ust all o w f or q uestio ns.  T hereafter, b ot h t he s u bject or le gall y 
acce pta ble re prese ntati ve a n d t he wit ness m ust si g n t he i nf or me d c o nse nt f or m t o attest t hat 
i nf or me d c o nse nt was freel y gi ve n a n d u n derst o o d. 
1 1. 2  
Et hic al C o n d uct of t he St u d y 
T he G ui deli nes of t he W orl d Me dical Ass oci ati o n ( W M A) Declarati o n of Helsi n ki date d 
Oct o ber 2 0 0 2 t he a p plica ble re g ulati o ns a n d g ui de li nes of c urre nt G o o d Cli nical Practice ( G C P) 
as well as t he de ma n ds of nati o nal dr u g a n d data pr otecti o n la ws a n d ot he r a p plica ble re g ulat or y 
re q uire me nts will be strictl y f oll o we d.   
1 1. 3  
I n de pe n de nt Et hics C o m mittee/I nstit uti o n al Re vie w B o ar d 
A c o p y of t he pr ot oc ol, pr o p ose d i nf or me d c o nse nt/asse nt f or ms, ot her writte n s u bject 
i nf or mati o n, a n d a n y pr o p ose d a d vertisi n g material m ust be s u b mitte d t o t he I E C/I R B f or writte n 
a p pr o val.  A c o p y of t he writte n a p pr o val of t he pr ot oc ol a n d i nf or me d c o nse nt f or m m ust be 
recei ve d b y t he S p o ns or or desig nee bef ore recr uit me nt of s u bj ects i nt o t he st u d y a n d s hi p me nt 
of St u d y Dr u g.  A c o p y of t he writte n a p pr o val of  a n y ot her ite ms/ materials t hat m ust be 
a p pr o ve d b y t he St u d y Ce nter or I E C/I R B  m ust als o be recei ve d b y t he S p o ns or or desi g nee 
bef ore recr uit me nt of s u bjects i nt o t he st u d y a n d s hi p me nt of St u d y Dr u g.  T he I n vesti gat or’s 
Br oc h ure m ust be s u b mitte d t o t he I E C/I R B  f or ac k n o wle d ge me nt. 
T he I n vesti gat or m ust s u b mit t o a n d, w here necessar y, o btai n a p pr o val fr o m t he I E C/I R B , f or all 
s u bse q ue nt pr ot oc ol a me n d me nts a n d c ha n ges t o t he i nf or me d c o nse nt d oc u me nt.  T he 
I n vesti gat or s h o ul d n otif y t he I E C/I R B of de viati o ns fr o m t he prot oc ol i n acc or da nce wit h I C H 
G C P Secti o n 4. 5. 2.  T he I n vesti gat or s h o ul d als o n otif y t he I E C/I R B of S A Es occ urri n g at t he 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
6 1
 
St u d y Ce nter a n d ot her A E re p orts  recei ve d fr o m t he S p o ns or or desi g nee, i n acc or da nce wit h 
l ocal pr oce d ures. 
T he I n vesti gat or will be res p o nsi ble f or o btai ni n g a n n ual I E C/I R B a p pr o val/re ne wal t hr o u g h o ut 
t he d urati o n of t he st u d y.  C o pies of t he I n vesti gat or’s re p orts, all I E C/I R B  s u b missi o ns a n d t he 
I E C/I R B c o nti n ua nce of a p pr o val m ust be se nt t o t he S p o ns or or desi g nee. 
1 1. 4
 S u bject
 
C o nfi de nti alit y
 
T he I n vesti gat or m ust e ns ure t hat t he s u bject’s c o nfi de ntialit y is mai ntai ne d.  O n t he case re p ort 
f or ms ( C R F) or ot her d oc u me nts s u b mitte d t o t he S p o ns or or desi g nee, s u bjects s h o ul d be 
i de ntifie d b y i nitials (if per mitte d b y l ocal la w) a n d a s u bject i de ntificati o n n u m ber o nl y.  
D oc u me nts t hat are n ot f or s u b missi o n t o t he S p o ns or or desi g nee (e. g., si g ne d i nf or me d c o nse nt 
f or ms) s h o ul d be ke pt i n strict c o nfi de nce b y t he I n vesti gat or. 
I n c o m plia nce wit h Fe deral a n d l ocal re g ulati o ns/I C H G C P G ui deli nes, it is re q uire d t hat t he 
I n vesti gat or a n d i nstit uti o n per mit a ut h orize d re prese ntati ves of t he c o m pa n y, of t he re g ulat or y 
a ge nc y(s), a n d t he I E C/I R B direct access t o re vi e w t he s u bject’s ori gi nal me dical rec or ds f or 
verificati o n of st u d y-relate d pr oc e d ures a n d data.  Direct access i ncl u des e xa mi ni n g, a nal yzi n g, 
verif yi n g, a n d re pr o d uci n g a n y rec o r ds a n d re p orts t hat are i m p ortant t o t he e val uati o n of t he 
st u d y.  T he I n vesti gat or is o bli gate d t o i nf or m a n d o btai n t he c o nse nt of  t he s u bject t o per mit 
na me d re prese ntati ves t o ha ve access t o his/ her st u d y-relate d rec or ds wit h o ut vi olati n g t he 
c o nfi de ntialit y of t he s u bject. 
1 2.  
A D MI NI S T R A TI V E A N D L E G A L O B LI G A TI O N S 
1 2. 1
 Pr ot oc ol
 
A me n d me nts
 
Pr ot oc ol a me n d me nts m ust be ma de o nl y wit h t h e pri or a p pr o val of t he S p o ns or or desi g nee.  
A gree me nt fr o m t he I n vesti gat or m ust be o btai ne d f or all pr ot oc ol a me n d me nts a n d a me n d me nts 
t o t he i nf or me d c o nse nt d oc u me nt.  T he re g ulat ory a ut h orit y a n d I E C/I R B m ust be i nf or me d of 
all a me n d me nts a n d gi ve a p pr o val f or a n y a me n d me nts  li kel y t o affect t he safet y of t he s u bjects 
or t he c o n d uct of t he trial.  T he I n vesti gat or m ust  se n d a c o p y of t he a p pr o val letter fr o m t he 
I E C/I R B t o t he S p o ns or or desi g nee. 
1 2. 2
 St u d y
 
Ter mi n ati o n
 
T he S p o ns or or desi g nee  reser ves t he ri g ht t o ter mi nate t he st u d y.  T he In vesti gat or reser ves t he 
ri g ht t o ter mi nate t heir partici pati o n i n t he st u d y, acc or di n g t o t h e ter ms of t he site c o ntract.  T he 
I n vesti gat or/ S p o ns or or desi g nee s h o ul d n otif y t he I E C/I R B i n writi n g of t he trial’s c o m pleti o n 
or earl y ter mi nati o n a n d se n d a c o p y of t h e n otificati o n t o t he S p o ns or or desi g nee. 
1 2. 3  
St u d y D oc u me nt ati o n a n d St or a ge 
A n e C R F utilizi n g a n Electr o nic Data Ca pt ure ( E D C) a p plicati o n will be use d f or t his st u d y. 
T he I n vesti gat or s h o ul d e ns ure t hat all a p pr o priatel y q ualifie d pers o ns t o w h o m he/s he has 
dele gate d trial d uties are rec o r de d o n a S p o ns or-a p pr o ve d Dele gati o n of Site Res p o nsi bilities 
F or m. 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
6 2
 
S o urce d oc u me nts are ori gi nal d oc u me nts, data, a n d rec or ds fr o m w hic h t h e s u bject’s C R F data 
are o btai ne d.  T hese i ncl u de b ut are n ot li mite d t o  h os pital rec or ds, cli nical a n d office c harts, 
la b orat or y a n d p har mac y rec or ds, i ma gi n g, a n d c orres p o n de nce.  I n t his st u d y, e C R F ma y n ot be 
use d as s o urce d oc u me nts. 
T he I n vesti gat or a n d St u d y Ce nter staff are re s p o nsi ble f or mai ntai ni n g a c o m pre he nsi ve a n d 
ce ntralize d fili n g s yste m of all st u d y-relate d (esse ntial) d oc u me ntati o n i n acc or da nce wit h 
Secti o n 8 of t he I C H G ui deli nes ( E 6), s uita ble f o r i ns pecti o n at a n y ti me b y re prese ntati ves fr o m 
t he S p o ns or or desi g nee a n d/ or a p plica ble re g ulat or y a ut h orities.  Ele me nts s h o ul d i ncl u de: 
•  S u bject files c o ntai ni n g c o m plete d C R Fs, i n f or me d c o nse nts, a n d s u p p orti n g c o pies of 
s o urce d oc u me ntati o n 
•  St u d y files c o ntai ni n g t he pr ot oc ol wit h all a m e n d me nts, I n vesti gat or’s Br oc h ure, c o pies 
of pre-st u d y d oc u me ntati o n a n d all c orre s p o n de nce t o a n d fr o m t he I E C/I R B a n d t he 
S p o ns or or desi g nee 
•  If dr u g s u p plies are mai ntai ne d at t he St u d y Ce nter, pr o of of recei pt, St u d y Dr u g Pr o d uct 
Acc o u nta bilit y Rec or d, Ret ur n of St u d y Dr u g Pr o d uct f or Destr ucti o n, fi nal St u d y Dr u g 
pr o d uct rec o nciliati o n, a n d a ll dr u g-relate d c orres p o n de nce 
I n a d diti o n, all ori gi nal s o urce d ocu me nts s u p p orti n g e ntries i n t h e C R Fs m ust be mai ntai ne d a n d 
be rea dil y a vaila ble. 
N o st u d y d oc u me nt s h o ul d be destr o ye d wit h o ut pr i or writte n a gree me nt bet wee n t he S p o ns or or 
desi g nee  a n d t he I n vesti gat or.  S h o ul d  t he I n vesti gat or wis h t o assi g n t he stu d y rec or ds t o 
a n ot her part y or m o ve t he m t o a n ot her l ocati o n, he/s he m ust n otif y t he S p o ns or or desi g nee. 
1 2. 4
 St u d y
 
M o nit ori n g
 
T he S p o ns or re prese ntati ve a n d re g ulat or y a ut h orit y i ns pect ors are res p o nsi ble f or c o ntacti n g a n d 
visiti n g t he I n vesti gat or f or t h e p ur p ose of i ns pecti n g t he faci lities a n d, u p o n re q uest, i ns pecti n g 
t he vari o us rec or ds of t he trial (e. g., C R Fs a n d ot her perti ne nt data) pr o vi de d t hat s u bject 
c o nfi de ntialit y is res pecte d. 
T he S p o ns or m o nit or or desi g nee is res p o nsi ble  f or i ns pecti n g t he C R Fs at re g ular i nter vals 
t hr o u g h o ut t he st u d y t o verif y a d here nce t o t he pr ot oc ol; c o m plete ness, acc urac y, a n d 
c o nsiste nc y of t he data; a n d a d he re nce t o l ocal re g ulati o ns o n t he c o n d uct of cli nical researc h.  
T he m o nit or s h o ul d ha ve access t o s u bject me di cal rec or ds a n d ot her st u d y-relate d rec or ds 
nee de d t o verif y t he e ntries o n t he C R Fs. 
T he I n vesti gat or a grees t o c o o pera te wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms detecte d i n t he 
c o urse of t hese m o nit ori n g visits, i ncl u di n g dela ys i n c o m pleti n g C R Fs, are res ol ve d. 
I n acc or da nce wit h I C H G C P a n d t he S p o ns or’s a u dit pla ns, t his st u d y ma y be selecte d f or a u dit 
b y re prese ntati ves fr o m t he S p o ns or’s Cli nical Q ualit y Ass ura nce De part me nt ( or desi g nees).  
I ns pecti o n of St u d y Ce nter facilities (e. g., p har macy, dr u g st ora ge areas, la b orat ories) a n d re vie w 
of st u d y-relate d rec or ds will o cc ur t o e val uate t he trial c o n d uct a n d c o m plia nce wit h t he 
pr ot oc ol, I C H G C P, a n d a p plic a ble re g ulat or y re q uire me nts. 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
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T o e ns ure t he q ualit y of cli nical data a cli nical data ma na ge me nt re vie w will be perf or me d o n 
s u bject data recei ve d b y t he Sp o ns or or desi g nee.  D uri n g t his  re vie w, s u bject data will be 
c hec ke d f or c o nsiste nc y, o missi o ns, a n d a n y a p pare nt  discre pa ncies.  I n ad diti o n, t he data will be 
re vie we d f or a d here nce t o t he pr ot oc ol a n d G C P.  T o res ol ve a n y q uesti o ns arisi n g fr o m t he 
cli nical data ma na ge me nt re vie w pr ocess, data q ueries a n d/ or St u d y Ce nter n otificati o ns will be 
se nt t o t he St u d y Ce nter f or c o m pleti o n a n d ret ur n t o S p o ns or or desi g nee. 
T he Pri nci pal I n vesti gat or will si g n a n d date t h e i n dicate d places o n t he C R F.  T hese si g nat ures 
will i n dicate t hat t he Pri nci pal I n vesti gat or i ns p ecte d or re vie we d t he data o n t he C R F, t he data 
q ueries, a n d t he St u d y Ce nter n otificati o ns, a n d a grees wit h t he c o nte nt. 
1 2. 5
 L a n g u a ge
 
Case re p ort f or ms m ust be c o m plete d i n E n glis h.  Ge neric a n d Tra de na mes are acce pta ble.  
C o m bi nati o n me dicati o ns s h o ul d be  rec or de d usi n g t heir tra de na me i n E n glis h if p ossi ble. 
All writte n i nf or mati o n a n d ot her material t o be use d b y s u bjects a n d i n ves ti gati ve staff m ust use 
v oca b ular y a n d la n g ua ge t h at are clearl y u n derst o o d. 
1 2. 6  
C o m pe ns ati o n f or I nj ur y 
T he S p o ns or mai ntai ns a p pr o priate i ns ura nce c o vera ge f or cli nical trials a n d will f oll o w 
a p plica ble l ocal c o m pe nsati o n la ws.  S u bjects wi ll be treate d a n d/ or c o m pe nsate d f or a n y st u d y-
relate d ill ness/i nj ur y i n acc or da nce wit h t he i nf or mati o n pr o vi de d i n t he C o m pe nsati o n f or I nj ur y 
secti o n of t he I nf or me d C o nse nt d oc u me nt. 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
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2 3 Marc h 2 0 1 8 
6 4
 
1 3.  
R E F E R E N C E S
Ac ker ma n n EJ, G u o S, Be ns o n M D, et al. S u p pressi n g tra nst h yreti n pr o d ucti o n i n mice, m o n ke ys a n d h u ma ns usi n g 
2 n d- Ge nerati o n a ntise nse oli g o n ucle oti des. A m yl oi d 2 0 1 6; 2 3( 3): 1- 1 0.  
Alt ma n n K H, Dea n N M, Fa b br o D, et al. Sec o n d ge nerati o n of a ntise nse oli g o n ucle oti des : fr o m n uclease resista nce 
t o bi ol o gical efficac y i n a ni mals. C hi mia 1 9 9 6; 5 0: 1 6 8- 1 7 6. 
B üller H R, C o he n A T, Da vi ds o n B, et al. I dra pari n u x vers us sta n dar d t hera p y f or ve n o us t hr o m b oe m b olic disease.  
N EJ M 2 0 0 7; 3 5 7: 1 0 9 4- 1 1 0 4. 
B yr ne C D a n d Tar g her G. N A F L D: A m ultis yste m disease. J He pat ol 2 0 1 5; 6 2( S 1): S 4 7- S 6 4. 
Ca o J, C he n g L, S hi Y. Catal ytic pr o perties of M G A T 3, a p utati ve triac yl g ycer ol s y net h ase. J Li pi d Res 2 0 0 7; 4 8: 
5 8 3 – 5 9 1. 
Cases S, S mit h SJ, Z he n g Y W, et al. I de ntificati o n of a ge ne  e nc o di n g a n ac yl C o A: diacyl gl ycer ol ac yltra nsferase, a 
ke y e nz y me i n triac yl gl ycer ol s y nt hesis. Pr oc Natl Aca d Sci U S A 1 9 9 8; 9 5: 1 3 0 1 8- 1 3 0 2 3. 
Cases S, St o ne SJ, Z h o u P, et al. Cl o ni n g of D G A T 2,  a sec o n d ma m malia n diac yl gl ycer ol ac yltra nsferase, a n d 
relate d fa mil y me m bers. J Bi ol C he m 2 0 0 1; 2 7 6: 3 8 8 7 0- 3 8 8 7 6. 
C harlt o n M R, B ur ns J M, Pe derse n R A, et al. Fre q ue nc y a n d o utc o mes of li ver tra ns pla ntati o n f or n o nalc o h olic 
steat o he patitis i n t he U nite d States. Gastr oe nter ol 2 0 1 1; 1 4 1: 1 2 4 9- 1 2 5 3. 
C he n g D, I q bal J, De ve n n y J, et al. Ac ylati o n of ac yl gl y cer ols b y ac yl c oe nz y me A: di ac yl gl ycer ol ac yltra nsferase 1 
( D G A T 1). F u ncti o nal i m p orta nce of D G A T 1 i n t he i ntesti nal fat a bs or pti o n. J Bi ol C he m 2 0 0 8; 2 8 3: 2 9 8 0 2- 2 9 8 1 1. 
C hi K N, Eise n ha uer E, Fazli L, et al. A P hase I p h ar mac o ki netic a n d p har mac o d y na mic st u d y of O G X- 0 1 1, a 
2 ′- met h o x yet h yl a ntise nse oli g o n ucle oti de t o cl usteri n, i n patie nts wit h l ocalize d pr ostate ca ncer. J Natl Ca ncer I nst 
2 0 0 5; 9 7: 1 2 8 7- 1 2 9 6. 
C h oi C S, Sa va ge D B, K ul kar ni A, et al. S u p pressi o n of diac yl gl ycer ol ac yltra nsferase- 2 ( D G A T 2), b ut n ot D G A T 1, 
wit h a ntise nse oli g o n ucle oti des re verses diet-i n d uce d he patic steat osis a n d i ns uli n resista nce. J Bi ol C he m 2 0 0 7; 
2 8 2: 2 2 6 7 8- 2 2 6 8 8. 
C o he n J C, H ort o n J D, H o b bs H H. H u ma n fatt y li ver disease: ol d q uesti o ns a n d ne w i nsi g hts. Sci 2 0 1 1; 3 3 2: 
1 5 1 9- 1 5 2 3. 
Cr o o ke S T a n d Be n nett C F. Pr o gress i n a ntise nse oli g o n ucle oti de t hera pe utics. A n n Re v P har mac ol T o xic ol 1 9 9 6; 
3 6: 1 0 7- 1 2 9. 
Cr o o ke S T, Ba ker B F, K w o h J T, et al. I nte grate d safet y assess me nt of 2 ʹ- O- met h o x yet h yl c hi meric a ntise nse 
oli g o n ucle oti des i n n o n h u ma n pri mates a n d healt h y h u ma n v ol u nteers. M ol T her 2 0 1 6; 2 4: 1 7 7 1- 1 7 8 2. 
Da y C P a n d Ja mes O F. Steat o he patitis: a tale of  t w o “ hits”? Gastr oe nter ol 1 9 9 8; 1 1 4: 8 4 2- 8 4 5. 
Di ge ni o A, D u n bar R L, Ale xa n der VJ, et al. A ntise nse- me diate d l o weri n g of plas ma a p oli p o pr otei n C-III b y 
V ola nes orse n i m pr o ves d ysli pi de mia a n d i ns uli n se nsiti vit y i n t y pe 2 dia betes. Dia betes Care 2 0 1 6; 3 9( 8): 
1 4 0 8- 1 4 1 5.   
D uell P B, Sa nt os R D, Kir wa n B A, et al. L o n g-ter m mi p o merse n treat me nt is ass oci ate d wit h a re d ucti o n i n 
car di o vasc ular e ve nts i n patie nts wit h fa milial h y perc h olester ole mia. J Cli n Li pi d 2 0 1 6, 1 0( 4): 1 0 1 1- 1 0 2 1. 
D ulai P S, Sirli n C B, L o o m ba R. M RI a n d M R E f or n o n-i n vasi ve q ua ntitati ve assess me nt of he patic steat osis a n d 
fi br osis i n N A F L D a n d N A S H: Cli nical trials t o cli nical practice. J He pat ol 2 0 1 6; 6 5: 1 0 0 6- 1 0 1 6. 
Farrell G C a n d Larter C Z. N o nalc o h olic fatt y li ver disease: fr o m steat osis t o cirr h osis. He pat ol 2 0 0 6; 4 3: S 9 9- S 1 1 2. 
Gear y R S, Y u R Z, W ata na be T, et al. P har mac o ki netics of a t u m or necr osis fact or- α  p h os p h or ot hi oate 2ʹ-O -( 2-
met h o x yet h yl) m o difie d a ntise nse oli g o n ucle oti de: c o m paris o n acr oss s pecies. Dr u g Meta b Dis p os 2 0 0 3; 3 1: 
1 4 1 9- 1 4 2 8. 


I SI S 4 8 4 1 3 7- C S 2 
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2 3 Marc h 2 0 1 8 
 
6 5
 
He nr y S P, Stec ker K, Br o o ks D, et al. C he micall y m o difie d o li g o n ucle oti des e x hi bit decrease d i m m u ne sti m ulati o n 
i n mice. J P har mac ol E x p T her 2 0 0 0; 2 9 2: 4 6 8- 4 7 9. 
He nr y S P, Ki m T W, Kra mer- Stic kla n d K, et al. T o xic ol o gic pr o perties of 2 ʹ-O - met h o x yet h yl c hi meric a ntise nse 
i n hi bit ors i n a ni mals a n d ma n. I n: Cr o o ke S, e dit or, A ntise nse Dr u g Tec h n ol o g y, 2 n d e d. C R C Press, B oca Rat o n, 
F L 2 0 0 8; 1 0: 3 2 7- 3 6 4. 
I bra hi m M A, Kelle ni M, Ge d da w y A. N o nalc o h olic fatt y li ver disease: c urre nt a n d p ot e ntial t hera pies. Life Sci 
2 0 1 3; 9 2: 1 1 4- 1 1 8. 
I n o ue H, Ha yase Y, I wai S, et al. Se q ue nce- de pe n de nt h y dr ol ysis of R N A usi n g m o difie d oli g o n ucle oti de s pli nts 
a n d R Nase H.  F E B S Letters 1 9 8 7; 2 1 5: 3 2 7- 3 3 0. 
Ka n g G H, Cr uite I, S hie h m orteza M, et al. Re pr o d uci bilit y of M RI- deter mi ne d pr ot o n de nsit y fat fracti o n acr oss t w o 
differe nt M R sca n ner platf or ms. J Ma g n Res o n I ma gi n g 2 0 1 1; 3 4: 9 2 8- 9 3 4. 
Kastelei n JJ P, We del M K; Ba ker B F, et al. P ote nt re d u cti o n of a p oli p o pr otei n B a n d l o w- de nsit y li p o pr otei n 
c h olester ol b y s h ort-ter m a d mi nistrati o n of a n a ntise nse i n hi bit or of a p oli p o pr otei n B. Circ 2 0 0 6; 1 1 4: 1 7 2 9- 1 7 3 5. 
K w o h TJ. A n o ver vie w of t he cli nical sa fet y e x perie nce of first a n d sec o n d ge nerati o n a ntise nse oli g o n ucle oti des.  
I n: Cr o o ke S T, e dit or. A ntise nse Dr u g Tec h n ol o g y: Pri nci ples, Strate gies a n d A p plicati o ns, 2n d E diti o n. B oca Rat o n, 
F L. Ta yl or & Fra ncis Gr o u p 2 0 0 8; 3 6 5- 4 0 0. 
Le T A, C he n J, C ha n gc hie n C, et al. Effect of c olese vela m o n li ver fat q ua ntifie d b y ma g netic res o na nce i n 
n o nalc o h olic steat o he patitis: a ra n d o mize d c o ntr olle d trial. He pat ol 2 0 1 2; 5 6: 9 2 2- 9 3 2. 
Marc hesi ni G, B u gia nesi E, F orla ni G, et al. N o nalc o h olic fatt y li ver, steat o he patitis, a n d t he meta b olic s y n dr o me. 
He pat ol 2 0 0 3; 3 7: 9 1 7- 9 2 3. 
Mc C ull o u g h AJ. Pat h o p h ysi ol o g y of n o nalc o h olic steat o he patitis. J Cli n Gastr oe nter ol 2 0 0 6; 4 0 S u p pl 1: S 1 7- S 2 9. 
Mc Ka y R A, Mira glia LJ, C u m mi ns L L, et al. C haracteri zati o n of a p ote nt a n d s pecific class of a ntise nse 
oli g o n ucle oti de i n hi bit or of h u ma n pr otei n ki nase C- α  e x pressi o n. J Bi ol C he m 1 9 9 9; 2 7 4: 1 7 1 5- 1 7 2 2. 
Mee galla R L, Bill hei mer J T, C he n g D. C o ncerte d ele vati o n of ac yl-c oe nz y me A: diac yl gl ycer ol ac yltra nsferase 
( D G A T) acti vit y t hr o u g h i n de pe n de nt sti m ulati o n of m R N A e x pressi o n of D G A T 1 a n d D G A T 2 b y car b o h y drate 
a n d i ns uli n. Bi oc he m Bi o p h ys Res C o m m u n 2 0 0 2, 2 9 8: 3 1 7- 3 2 3. 
Mi d dlet o n M F, He ba E R, H o o ker C A, et al. A gree me nt bet wee n ma g netic res o na nce i ma gi n g pr ot o n de nsit y fat 
fracti o n meas ure me nts a n d pat h ol o gist-assi g ne d steat osis gra des of li ver bi o psies fr o m a d ults wit h n o nalc o h olics 
steat o he patitis. Gastr oe nter ol 2 0 1 7; I n Press: 1- 9. 
M o nia B P, Les ni k E A, G o nzalez C, et al. E val uati o n of 2 ′- m o difie d oli g o n ucle oti des c o ntai ni n g 2′- de o x y ga ps as 
a ntise nse i n hi bit ors of ge ne e x pressi o n. J Bi ol C he m 1 9 9 3; 2 6 8: 1 4 5 1 4- 1 4 5 2 2. 
Nai k R, O bia n g- O b o u n o u B W, Ki m M, et al. T hera pe utic  strate gies f or meta b olic diseases: s mall- m olec ule 
diac yl gl ycer ol ac yltra nsferase ( D G A T) I n hi bit ors. C he m Me d C he m 2 0 1 4; 9( 1 1): 2 4 1 0- 2 4 2 4. 
Patel J, Better nc o urt R, C ui J, et al. Ass ociati o n of n o ni n vasi ve q ua ntitati ve decli ne i n li ver fat c o nte nt o n M RI wit h 
hist ol o gic res p o nse i n n o nalc o h olic steat o he patitis. T her A d v Gastr oe nter ol 2 0 1 6; 9: 6 9 2- 7 0 1. 
Sc h ul ma n S, Kear o n C, S u bc o m mitt ee o n C o ntr ol of A ntic oa g ulati o n of t he Scie ntific a n d Sta n dar dizati o n 
C o m mittee of t he I nter nati o nal S ociet y o n T hr o m b osis a n d Hae m ostasis. Defi niti o n of maj or blee di n g i n cli nical 
i n vesti gati o ns of a nti he m ostatic me dical pr o d ucts i n n o n-s ur gical patie nts. J T hr o m b Hae m ost 2 0 0 5; 3( 4): 6 9 2- 6 9 4. 
Se well K L, Gear y R S, Ba ker B F, et al. P hase I trial of I SI S 1 0 4 8 3 8, a 2 ʹ- met h o x yet h yl m o difie d a ntise nse 
oli g o n ucle oti de tar geti n g t u m or necr osis fact or. J P har m E x p T her 2 0 0 2; 3 0 3: 1 3 3 4- 1 3 4 3. 
S mit h SJ, Cases S, Je nse n D R, et al. O besit y resista nce a n d m ulti ple mec ha nis ms of tri gl yceri de s y nt hesis i n mice 
lac ki n g D gat. Nat Ge net 2 0 0 0; 2 5: 8 7- 9 0. 
St o ne SJ, M yers H M, W at ki ns S M, et al. Li p o pe nia a n d s ki n barrier a b n or malities i n D G A T 2- deficie nt mice. J Bi ol 
C he m 2 0 0 4; 2 7 9: 1 1 7 6 7- 1 1 7 7 6. 


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St o ne SJ, Le vi n M C, Z h o u P, et al. T he e n d o plas mic retic ul u m e nz y me D G A T 2 is f o u n d i n mit oc h o n dria-ass ociate d 
me m bra nes a n d has a mit oc h o n drial tar geti n g si g nal t hat pr o m otes its ass ociati o n wit h mit oc h o n dria. J Bi ol C he m 
2 0 0 9, 2 8 4: 5 3 5 2- 5 3 6 1. 
Til g H a n d M osc he n A R. E v ol uti o n of i nfla m mati o n i n n o nal c o h olic fatt y li ver disease: t he m ulti ple parallel hits 
h y p ot hesis. He pat ol 2 0 1 0; 5 2: 1 8 3 6- 1 8 4 6. 
T o me n o W, Y o ne da M, I maj o K, et al. E mer gi n g dr u gs f or n o n-alc o h olic steat o he patitis. E x pert O pi n E mer g Dr u gs 
2 0 1 3; 1 8: 2 7 9- 2 9 0. 
Willia ms C D, Ste n gel J, Asi ke MI, et al. Pre vale nce of  n o nalc o h olic fatt y li ver disease a n d n o nalc o h olic 
steat o he patitis a m o n g a lar gel y mi d dle a ge d p o p ulati o n utilizi n g ultras o u n d a n d li ver bi o ps y: a pr os pecti ve st u d y. 
Gastr oe nter ol 2 0 1 1; 1 4 0: 1 2 4- 1 3 1. 
Ye n C L, St o ne SJ, K oli wa d S, et al. T he matic re vie w se ries: gl ycer oli pi ds. D G A T e nz y mes a n d triac yl gl ycer ol 
bi os y nt hesis. J Li pi d Res 2 0 0 8; 4 9: 2 2 8 3- 2 3 0 1. 
Y u X X, M urra y S F, Pa n de y S K, et al. A ntise nse oli g o n ucle oti de re d ucti o n of D G A T 2 e x pressi o n i m pr o ves he patic 
steat osis a n d h y perli pi de mia i n o bese mice. He pat ol 2 0 0 5; 4 2: 3 6 2- 3 7 1. 
Y u R Z, Ki m T W, H o n g A, et al. Cr oss-s pecies p har m ac o ki netic c o m paris o n fr o m m o use t o ma n of a sec o n d-
ge nerati o n a ntise nse oli g o n ucle oti de, I SI S 3 0 1 0 1 2, tar geti n g h u ma n a p oli p o pr otei n B- 1 0 0. Dr u g Meta b Dis p os 
2 0 0 7; 3 5: 4 6 0- 4 6 8. 
Y u R Z, Le m o ni dis K M, Gra ha m MJ, et al. Cr oss-s pecies c o m paris o n of i n vi v o P K/ P D relati o ns hi ps f or sec o n d 
ge nerati o n a ntise nse oli g o n ucle oti des tar geti n g a p oli p o pr otei n B- 1 0 0. Bi oc he m P har mac ol 2 0 0 9; 7 7: 9 1 0- 9 1 9. 
Z ha n g H, L ö we n ber g E C, Cr os b y J R, et al. I n hi biti o n of t he i ntri nsic c oa g ulati o n pat h wa y Fact or XI b y a ntise nse 
oli g o n ucle oti des: a n o vel a ntit hr o m b otic strate g y wit h l o were d blee di n g ris k.  Bl o o d 2 0 1 0; 1 1 6: 4 6 8 4- 4 6 9 2. 
 
 
 


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A p pe n di x A  
Sc he d ule of Pr oce d ures 


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A p pe n di x A  Sc he d ule of Pr oce d ures  
St u d y P eri o d 
S cr e e n  
R u n-I n 
Tr e at m e nt 
St u d y W e e k 
W k - 6 t hr u 
W k - 5 
W k - 4 
t hr u 
W k - 3 
W k - 1  
W 1  
W 2  
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W 4  W 5  
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W 1 0  W 1 1  W 1 2  W 1 3 
St u d y D a y 
S- 4 2 t hr u 
S- 2 9 
D- 2 8 
t hr u 
D- 1 5 
D- 7  
t o  
D- 1  
D 1   D 8   D 1 5  D 2 2  D 2 9  D 3 6  D 4 3  D 5 0  D 5 7   D 6 4  D 7 1  D 7 8   D 8 5  
Vi sit Wi n d o w ( +/- d a y s) 
  
A  
3 
2 
I nf or m e d
 
C o n s e nt
 
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I n cl u si o n/ E x cl u si o n
 
X
 
 
  
X
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M e di c al
 
Hi st or y
 
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P h y si c al E x a m 1  
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H ei g ht, B o d y W ei g ht a n d B MI 2  X
 
 
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7 
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W ai st/ Hi p
 
Cir c u mf er e n c e
 
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Vit al Si g n s 3  
X
 
 
  
X
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Bl o o d Pr e s s ur e 
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E C G ( 1 2 –l e a d) i n tri pli c at e 1 5  X
 
 
 
X 6  
 
 
 
 X
 
 
 
 
 
 
 
 
 
 
F S H 4 / S er u m Pr e g n a n c y5  
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HI V, H e p atiti s B & C 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Dr u g/ Al c o h ol S cr e e n 
X  
  
X 7  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
C h e mi str y P a n el ( F a sti n g) 8  
X
 
 
  
X
  X
 X
 X
 X
 X
 X
 X
 X
 X
  X
 X
 X
  X
 
H e m at ol o g y 8  
X
 
 
  
X
  X
 X
 X
 X
 X
 X
 X
 X
 X
  X
 X
 X
  X
 
Uri n al y si s (i n cl u di n g P/ C) 9  
X
 
 
 
 
  X
 X
 X
 X
 X
 X
 X
 X
 X
  X
 X
 X
  X
 
P T/ a P T T/I N R
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H b A 1 c
 
X
 
 
 
 
  X
 
 
 
 
 X
 
 
 
 
 
 
 
 
 
 
F a sti n g Pl a s m a Gl u c o s e ( F P G) 1 0  X
 
 
X
7  X
 
 X
 
 
 X
 
 
 X
 
 
 
 
 X
 
 
 
 




I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
7 1
 
A p pe n di x A  Sc he d ule of Pr oce d ures C o nti n ue d  
St u d y P eri o d 
P o st- Tr e at m e nt P eri o d ( 1 3 W e e k s) 
St u d y W e e k 
E T/ P T 1
 P T 2
  P T 3
  P T 4
  P T 6
  P T 8
 
E T 
P T 1 2 
P T 1 3 
St u d y D a y 
D 9 2  
D 9 9  
D 1 0 6  
D 1 1 3  
D 1 2 7  
D 1 4 1  
D 1 6 9  
D 1 7 6 
Vi sit Wi n d o w ( +/- d a y s) 
3  
7 
P h y si c al E x a m 1 
X
 X
 
 X
 
 
 
 X
 
 
B o d y W ei g ht a n d B MI 2 
X
 X
 
 X
 
 
 
 X
 
 
W ai st/ Hi p Cir c u mf er e n c e 
X  
X  
  
X  
  
  
X  
 
Vit al Si g n s 3  X
 
X
 
X
 
X
 
X
 
X
 
X
 
 
Bl o o d Pr e s s ur e ( B P) 
X
 X
 X
 X
 X
 X
 X
  
E C G ( 1 2 –l e a d) i n tri pli c at e 1 5 
X
 
 X
 
 
 
 
 
 
P K S a m pli n g 
X  
X  
  
X  
X  
  
X  
 
Ar c hi v e d S a m pl e 
X  
X  
  
X  
  
  
X  
 
C h e mi str y P a n el ( s er u m, f a sti n g)  
X  
X  
X  
X  
X  
X  
X  
 
H e m at ol o g y
 X
 
X
 
X
 
X
 
X
 
X
 
X
 
 
Uri n al y si s (i n cl u di n g P/ C r ati o) 9  X
 
X
 
X
 
X
 
X
 
X
 
X
 
 
H b A 1 c ( s er u m) 
X  
X  
  
X  
  
X  
  
 
Li pi d P a n el ( s er u m, f a sti n g) 1 0 
X
 X
 
 X
 
 
 
 
 
 
 
 
I n s uli n ( pl a s m a, f a sti n g)1 0 
X
 X
 
 X
 
 
 
 
 
 
 
 
F a sti n g Pl a s m a Gl u c o s e ( F P G) 1 0 
X
 X
 X
 X
 X
 X
 X
 
 
h s C R P ( s er u m) 
X  
  
  
X  
  
  
  
 
T S H ( s er u m) 
X  
  
  
  
  
  
X  
 
S er u m Pr e g n a n c y 5  
 
 
 
 
 
 
 
 
E x pl or at or y M ar k er s  
X
 X
 
 X
 
 
 
 X
 
 
H e p ati c F at C o nt e nt ( M RI) 
  
XB  
 
 
 
 
 
 
 
 
 
 
 
O A D A d mi ni str ati o n 1 3  X
 
X
 
X
 
X
 
X
 
X
 
X
 
X
 
Di et ar y & E x er ci s e M ai nt e n a n c e  
X  
X  
X  
X  
X  
X  
X  
X 
A d v er s e E v e nt s 
X  
X  
X  
X  
X  
X  
X  
X 
C o n c o mit a nt M e di c ati o n s 
X  
X  
X  
X  
X  
X  
X  
X 
P h o n e C o nt a ct 1 4  X
 
X
 
X
 
X
 
X
 
X
 
X
 
X
 
 
 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
7 2
 
A p pe n di x A  Sc he d ule of Pr oce d ures C o nti n ue d 
L e g e n d T e xt 
1.  F ull p h y si c al e x a m t o b e gi v e n at S cr e e ni n g a n d a b br e vi at e d p h y si c al e x a m t o b e gi v e n d uri n g tr e at m e nt a n d 
f oll o w- u p p eri o d a s i n di c at e d t o a s s e s s c h a n g e s fr o m S cr e e ni n g 
2.  
H ei g ht a s s e s s e d at S cr e e ni n g vi sit o nl y 
3.  
H R, r e s pir at or y r at e ( R R), t e m p 
4.  F S H:  R e q uir e d a s c o nfir m ati o n of p o st- m e n o p a u s al st at u s f or all w o m e n ≤ 5 5 y e ar s w h o h a v e 1 2 m o nt h s of 
s p o nt a n e o u s a m e n orr h e a wit h n o alt er n ati v e m e di c a l c a u s e, a n d w h o ar e n ot s ur gi c all y st eril e 
5.  
W o m e n w h o ar e n ot s ur gi c all y st eril e 
6.  
A s s e s s m e nt s c o n d u ct e d at pr e- d o s e, 1 hr. a n d 2 hr s. p o st- d o s e  
7.  
R e s ult s r e q uir e d pri or t o r a n d o mi z ati o n 
8.  If d uri n g t h e tr e at m e nt p eri o d, a pl at el et, cr e ati ni n e, or A L T r e s ult i s u ni nt er pr et a bl e ( e. g., d u e t o cl u m pi n g, 
h e m ol y si s, or q u a ntit y n ot s uffi ci e nt) t h e t e st m u st b e r e p e at e d a n d a r e s ult  n ot m e eti n g st o p pi n g r ul e m u st b e 
o bt ai n e d pri or t o n e xt d o s e 
9.  
Pr ef er a bl y c oll e ct s p e ci m e n f or a n al y si s fr o m t h e s u bj e ct’ s s e c o n d v oi d of t h e d a y 
1 0.  F a st e d s a m pl e s s h o ul d b e t a k e n aft er f a sti n g f or at l e a st 8- 1 0 h o ur s.  D uri n g t hi s ti m e t h e s u bj e ct c a n dri n k w at er 
a n d t h e y s h o ul d e n s ur e t h at t h e y c o n s u m e s uffi ci e nt w at er i n or d er t o n ot b e c o m e d e h y dr at e d 
1 1.  St or e d at - 7 0 ( ± 1 0) ° C f or f oll o w- u p e x pl or ati o n  
1 2.   D uri n g t h e tr e at m e nt p eri o d, P K s a m pl e s ar e c oll e ct e d pr e- d o s e.  D uri n g t h e P o st- Tr e at m e nt P eri o d, P K 
s a m pl e s ar e c oll e ct e d a n y ti m e.  S e e A p p e n di x C  
1 3.  O A D d o s e s ar e t o b e s elf- a d mi ni st er e d d ail y b y t h e s u bj e ct t hr o u g h o ut t h e st u d y 
1 4.  If s u bj e ct i s a b s e nt fr o m a cli ni c vi sit, a p h o n e c o nt a ct will b e att e m pt e d t o a s s e s s A E a n d c o n m e d s 
1 5.  Tri pli c at e E C G st u d y pr o c e d ur e will c o n si st of 3 E C G s wit h 2 mi n ut e s b et w e e n e a c h E C G (- 1/ + 2 mi n s wi n d o w 
b et w e e n e a c h a s s e s s m e nt), e x c e pt a s n ot e d f or f o ot n ot e # 6 w h er e pr e- d o s e, 1 hr s a n d 2 hr s p o st- E C G s ar e t o 
b e p erf or m e d 
1 6.  S C T ol er a bilit y A s s e s s m e nt s c a n b e c o n d u ct e d at  a n y vi sit d uri n g t h e S cr e e ni n g or R u n-I n P eri o d s 
 
N ot e s: 
All a s s e s s m e nt s s h o ul d b e c oll e ct e d pr e- d o s e u nl e s s i n di c at e d ot h er wi s e. 
 
N ot e s R e g ar di n g Ti mi n g of M RI A s s e s s m e nt s: 
A  
M a g n eti c R e s o n a n c e I m a gi n g ( M RI) A s s e s s m e nt Wi n d o w s  
B a s eli n e M RI A s s e s s m e nt:  W e e k - 4 or - 3 ( D a y - 2 8 t o D a y - 1 4) + 7 d a y s 
P o st- Tr e at m e nt M RI A s s e s s m e nt:  W e e k of P T 2 Vi sit ( D a y s 9 9 t o D a y 1 0 5) +/- 7 d a y s 
B  
A P o st- Tr e at m e nt M RI t o a s s e s s li v er f at c o nt e nt a n d v o l u m e will o c c ur d uri n g t h e w e e k of P T 2 Vi sit f or all 
s u bj e ct s c o m pl eti n g 1 3 d o s e s.  T h e ti mi n g of t h e P o st- Tr e at m e nt M RI s h o ul d b e di s c u s s e d wit h t h e I o ni s M e di c al 
M o nit or.  F or s u bj e ct s w h o t er mi n at e fr o m t h e tr e at m e nt  p eri o d e arl y, t h e ti mi n g a n d c o n d u ct of t h e M RI i n t h e 
P o st- Tr e at m e nt P eri o d will b e a dj u st e d a s f oll o w s:   
i.  
S u bj e ct r e c ei v e d 4 or l e s s d o s e s, t h e P o st- Tr e at m e nt M RI A s s e s s m e nt will n ot b e r e q uir e d 
ii.  
S u bj e ct r e c ei v e d 5- 9 d o s e s, t h e P o st- Tr e at m e nt M RI A s s e s s m e nt will o c c ur 2 w e e k s aft er t h e l a st d o s e 
d uri n g t h e w e e k of t h e P T 2 Vi sit.  ( +/- 7 d a y s) 
iii.  
S u bj e ct r e c ei v e d 1 0 - 1 2 d o s e s, t h e P o st- Tr e at me nt M RI A s s e s s m e nt will b e s c h e d ul e d a s f oll o w s: 
N u m b er of D o s e s R e c ei v e d  
P o st- Tr e at m e nt M RI A s s e s s m e nt 
1 0 
5 w e e k s aft er l a st d o s e ( +/- 7 d a y s)  
1 1 
4 w e e k s aft er l a st d o s e ( +/- 7 d a y s)  
1 2 
3 w e e k s aft er l a st d o s e ( +/- 7 d a y s)  
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
7 3
 
 
 
 
 
 
 
 
A p pe n di x B  
List of L a b or at or y A n al ytes 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
7 4
 
A p pe n di x B  List of L a b or at or y A n al ytes 
Base d o n e mer gi n g data fr o m t his or f ut ure st u dies, a d diti o nal tests n ot liste d bel o w ma y be 
perf or me d o n st ore d sa m ples t o better c haract erize t he pr ofile of I S I S 4 8 4 1 3 7 or ot her si milar 
oli g o n ucle oti des 
F asti n g Cli nic al 
C he mistr y P a nel 
•  S o di u m 
•  P otassi u m 
•  C hl ori de 
•  Bicar b o nate 
•  T otal pr otei n 
•  Al b u mi n 
•  Calci u m 
•  Ma g nesi u m 
•  P h os p h or us 
•  Gl uc ose 
•  B U N 
•  Creati ni ne 
•  C h olester ol 
•  Uric Aci d 
•  T otal bilir u bi n 
•  Direct (c o nj u gate d) 
bilir u bi n 
•  I n direct ( u nc o nj u gate d) 
bilir u bi n 
•  A L T 
•  A S T 
•  Al kali ne p h os p hatase 
•  Creati ni ne ki nase 
•  G G T 
Scree ni n g Tests 
•  He patitis B s urface 
a nti ge n 
•  He patitis C a nti b o d y 
•  HI V a nti b o d y 
•  F S H ( w o me n o nl y) 
•  Ser u m β h C G 
•  Dr u g/ Alc o h ol scree n 
 
C o a g ul ati o n 
•  a P T T (sec) 
•  P T (sec) 
•  I N R 
 
P D P a nel 
•  Fasti n g Gl uc ose 
•  I ns uli n 
•  H b A 1c 
 
F asti n g Li pi d P a nel 
•  Tri gl y ceri des 
•  T otal C h olester ol 
•  A p o B 
•  V L D L c h olester ol 
•  L D L c h olester ol 
•  H D L c h olester ol 
•  N o n- H D L c h olester ol 
He m at ol o g y 
•  Re d bl o o d cells 
•  He m o gl o bi n 
•  He mat ocrit 
•  M C V, M C H, M C H C 
•  Platelets 
•  W hite bl o o d cells 
•  W B C Differe ntial 
( % a n d a bs ol ute) 
•  Ne utr o p hils 
•  E osi n o p hils 
•  Bas o p hils 
•  L y m p h oc ytes 
•  M o n oc ytes 
 
T h y r oi d P a nel 
•  T S H 
•  Free T 4 
•  Free T 3 
 
P h ar m ac o ki netics 1 
•  I SI S 4 8 4 1 3 7 le vels i n 
plas ma 
 
E x pl or at or y 3 
a di p o necti n 
S C D- 1  
C K 1 8  
ha pt o gl o bi n 
le pti n 
I nfl a m m at or y 
•  hs- C R P 3 
 
Uri n al ysis 
•  C ol or 
•  A p peara nce 
•  S pecific gra vit y 
•  p H 
•  uri ne Pr otei n/ Creati ni ne 
Rati o 
•  Pr otei n 
•  Bl o o d 
•  Ket o nes 
•  Ur o bili n o ge n 
•  Gl uc ose 
•  Bilir u bi n 
•  Le u k oc yte esterase 
•  Nitrate 
•  Micr osc o pic 
e xa mi nati o n 2 
 
Ot her 1 
•  Arc hi ve d ser u m sa m ples  
 
1  
S er u m a n d pl a s m a P K s a m pl e s m a y al s o b e u s e d f or m et a b ol o mi c s/li pi d o mi c s a s s e s s m e nt s, pr ofili n g of dr u g 
bi n di n g pr ot ei n s, bi o a n al yti c al m et h o d v ali d ati o n p ur p o s e s, st a bilit y a s s e s s m e nt s,  m et a b olit e a s s e s s m e nt s, 
i m m u n o g e ni cit y a s s a y d e v el o p m e nt/t e stin g, or t o a s s e s s ot h er a cti o n s of I SI S 4 8 4 1 3 7 wit h pl a s m a c o n stit u e nt s 
2  
Will b e p erf or m e d o n a b n or m al fi n di n g s u nl e s s ot h er wi s e s p e cifi e d 
3  
S a m pl e s will b e c oll e ct e d h o w e v er m a y n ot b e a n al y z e d   
 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
7 5
 
A p pe n di x C  
P K S a m pli n g Sc he d ule 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
7 6
 
A p pe n di x C  P K S a m pli n g Sc he d ule  
 
Tr e at m e nt P eri o d 
W 1 
W 2 
W 4 
W 6 
W 8 
W 9 
W 1 0 
W 1 2 
W 1 3 
D 1 
D 8 
D 2 2 
D 3 6 
D 5 0 
D 5 7 
D 6 4 
D 7 8 
D 8 5 
Pr e- d o s e 
Pr e- d o s e 
Pr e- d o s e 
Pr e- d o s e 
Pr e- d o s e 
Pr e- d o s e 
Pr e- d o s e 
Pr e- d o s e 
Pr e- d o s e 
 
P o st- Tr e at m e nt P eri o d ( 1 3 W e e k s) 
E T/ P T 1
 P T 2
  P T 3
  P T 6
  P T 1 2
 
D 9 2
 D 9 9
 D 1 1 3
 D 1 2 7
 D 1 6 9
 
Bl o o d s a m pl e c a n b e dr a w n a n yti m e d uri n g t h e vi sit 
 
 
 
 
 
 
 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
7 7
 
A p pe n di x D  
Gr a di n g Sc ale f or A d verse E ve nts Rel ati n g t o 
L a b or at or y A b n or m alities  


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
 
2 3 Marc h 2 0 1 8 
 
7 8
 
A p pe n di x D  Gr a di n g Sc ale f or A d verse E ve nts  Rel ati n g t o L a b or at or y A b n or m alities 
T he f oll o wi n g gra di n g rec o m me n dati o ns f or a d vers e e ve nts relati n g t o la b test a b n or malities are 
base d u p o n t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) Versi o n 4. 0 3, 
J u ne 2 0 1 0 
 
 
 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
7 9
 
A p pe n di x D  Gr a di n g Sc ale f or A d verse E ve nts  Rel ati n g t o L a b or at or y A b n or m alities 
C o nti n ue d 


I SI S 4 8 4 1 3 7- C S 2 
C O N FI D E N TI A L 
A me n d me nt 1 
Pr ot oc ol  
2 3 Marc h 2 0 1 8 
8 0
 
A p pe n di x D  Gr a di n g Sc ale f or A d verse E ve nts  Rel ati n g t o L a b or at or y A b n or m alities 
C o nti n ue d 




P P D
P P D
P P D








C CI


C CI
C CI


C CI




















C CI