A Randomized, Double-Blind, Placebo-Controlled, With an Open Label Extension, Phase 2/3 Study of ISIS 304801 Administered Subcutaneously to Patients With Familial Partial Lipodystrophy
Phase: PHASE2
Conditions: Familial Partial Lipodystrophy
Sponsor: Akcea Therapeutics

 
Offici al Titl e:         A R a n d o miz e d, D o u bl e -Bli n d, Pl ac e b o -c o ntr oll e d, wit h a n O p e n    
                                 L a b el E xt e nsi o n, P h as e 2/ 3 St u d y of I SI S 3 0 4 8 0 1 A d mi nist er e d  
                                 S u bc ut a n e o usl y t o P ati e nts wit h F a mili al P arti al Li p o d ystr o p h y 
 
N C T N u m b er:        N C T 0 2 5 2 7 3 4 3  
 
D oc u m e nt D at es: Pr ot oc ol A m e n d m e nt 4 - 2 2  A u g ust  2 0 1 7 

 
 
 
 
 
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 
C oll a b or at or: 
A kcea T h era pe utics  
5 5 Ca m bri d ge Par k wa y, S uite 1 0 0 
Ca m bri d ge, M A  0 2 1 4 2 
 
 
I O NI S PH A R M A C E U TI C A L S,  IN C . 
 
 
I SI S 3 0 4 8 0 1 - C S 1 7 
 
T he B R O A D E N St u d y  
A R a n d o mi ze d, D o u ble -Bli n d, Pl ac e b o - C o ntr olle d, wit h a n O pe n 
L a bel E xte nsi o n, P h ase 2/ 3 St u d y of I SI S 3 0 4 8 0 1  A d mi nistere d 
S u bc ut a ne o usl y t o P atie nts wit h F a mili al P arti al Li p o d ystr o p h y   
 
Pr ot oc ol  A me n d me nt 4 – 2 2  A u g ust  2 0 1 7  
 
E u dr a C T N o:   2 0 1 5- 0 0 0 4 9 3- 3 5 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
4
 
Pr ot oc ol Si g n at ur e P a ge  
 
Pr ot oc ol N u m ber:  
I SI S 3 0 4 8 0 1-C S 1 7 
Pr ot oc ol Title:  
A Ra n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d, wit h a n O pe n La b el  
E xte nsi o n , P hase 2/ 3 St u d y of I SI S 3 0 4 8 0 1 A d mi nistere d S u bc uta ne o usl y 
t o Patie nts wit h Fa milial Partial Li p o d ystr o p h y  
A me n d me nt:   
A me n d me nt 4 
D ate:     
 
2 2 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, “ A 
Ra n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d, wit h a n O pe n La b el E xte nsi o n, P hase 2/ 3 St u d y 
of I SI S 3 0 4 8 0 1 A d mi nistere d S u bc uta n e o usl y t o P atie nts wit h Fa milial Partial Li p o d ystr o p h y ” 
date d 2 2 A u g ust 2 0 1 7 a n d a gree t o c o n d uct t he St u d y as d escri b e d herei n.  
I a gree t o c o m pl y wit h t he I nter n ati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts 
f or P har mace uticals f or H u ma n Use (I C H) 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 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
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 A M E N D M E N T .................................................................................................... 1 0 
P R O T O C O L S Y N O P SI S  ........................................................................................................... 1 7 
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 5 
S T U D Y G L O S S A R Y  .................................................................................................................. 2 6 
1.  
O B J E C TI V E S A N D E N D P OI N T S  ............................................................................... 2 9 
1. 1  
O bjecti ves  ...................................................................................................................... 2 9 
1. 1. 1  
Pri mar y O bj ecti ve  .................................................................................................... 2 9 
1. 1. 2  
Sec o n dar y O bj ecti ves  .............................................................................................. 2 9 
1. 2  
E n d p oi nts ....................................................................................................................... 2 9  
1. 2. 1  
Pri mar y E n d p oi nt ..................................................................................................... 2 9  
1. 2. 2  
Sec o n dar y E n d p oi nts ............................................................................................... 2 9  
 
2 9  
2.  
B A C K G R O U N D A N D R A TI O N A L E  .......................................................................... 3 0 
2. 1  
O ver vie w of Diseas e  ...................................................................................................... 3 0 
2. 2  
T hera p e utic Rati o nale  .................................................................................................... 3 3 
2. 3  
I SI S 3 0 4 8 0 1 ................................................................................................................... 3 5 
2. 3. 1  
Mec ha n is m of A cti o n .............................................................................................. 3 5 
2. 3. 2  
C he mistr y ................................................................................................................. 3 6 
2. 3. 3  
Precli nical E x perie nce  ............................................................................................. 3 7 
2. 3. 4  
Cli nical E x perie nce  .................................................................................................. 3 8 
2. 4  
Rati o nale f or D ose a n d Sc he d ule of A d mi nistrati o n ..................................................... 3 9  
3.  
E X P E RI M E N T A L P L A N  .............................................................................................. 4 0 
3. 1  
St u d y Desi g n  .................................................................................................................. 4 0 
3. 2  
N u m ber o f St u d y C e nters .............................................................................................. 4 0 
3. 3  
N u m ber of Patie nts ........................................................................................................ 4 0  
3. 4  
O verall St u d y D urati o n a n d F oll o w- u p ......................................................................... 4 0  
3. 4. 1  
Scree ni n g  ................................................................................................................. 4 1 
3. 4. 2  
Ra n d o m ize d Treat me nt Peri o d ................................................................................ 4 1 
3. 4. 3  
O L E Peri o d  .............................................................................................................. 4 1 
3. 4. 4  
P ost- Treat me nt Peri o d  ............................................................................................. 4 1 
3. 5  
E n d - of- St u d y .................................................................................................................. 4 1 
3. 6  
Data a n d Saf et y M o nit ori n g B oar d ................................................................................ 4 1  
4.  
P A TI E N T E N R O L L M E N T  ........................................................................................... 4 2 
4. 1  
Scree ni n g  ....................................................................................................................... 4 2 
4. 2  
Ra n d o mizati o n ............................................................................................................... 4 2  
4. 3  
Re plac e me nt of Patie nts  ................................................................................................. 4 3 
4. 4  
U n bli n di n g of Tr eat me nt Assi g n me nt ........................................................................... 4 3  

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
7
 
8. 5. 8  
M o nit ori n g R ule f or D oc u me nte d H y per gl yce mia .................................................. 6 0  
8. 5. 9  
Ac ute Pa ncreatitis .................................................................................................... 6 1  
8. 6  
St o p pi n g R ules ............................................................................................................... 6 1  
8. 6. 1  
St o p pi n g R ules f or Li ver C he mistr y Ele vati o ns ...................................................... 6 1  
8. 6. 2  
St o p pi n g R ules f or Re nal F u ncti o n Test Res ults ..................................................... 6 2  
8. 6. 3  
St o p pi n g R ules f or Platelet C o u nt Res ults .............................................................. 6 2  
8. 6. 4  
St o p pi n g R ule f or D oc u me nte d Se vere H y p o gl yce mia ........................................... 6 4  
8. 7  
A dj ust me nt of D ose a n d/ or Treat me nt Sc he d ule ........................................................... 6 4  
8. 8  
Disc o nti n uati o n of St u d y Treat me nt .............................................................................. 6 5  
8. 8. 1  
F oll o w- u p Visits f or Earl y Ter mi nati o n fr o m Treat me nt a n d O L E Peri o ds ........... 6 5  
8. 8. 2  
F oll o w- u p Visits f or Earl y Ter mi nati o n fr o m P ost- Treat me nt F oll o w- u p  
Peri o d ....................................................................................................................... 6 5  
8. 9  
Wit h dra wal of Patie nts fr o m t he St u d y .......................................................................... 6 6  
8. 1 0  
C o nc o mita nt T hera p y a n d Pr oce d ures ........................................................................... 6 6  
8. 1 0. 1  
C o nc o mita nt T hera p y .............................................................................................. 6 7  
8. 1 0. 2  
C o nc o mita nt Pr oce d ures .......................................................................................... 6 7  
8. 1 1  
Treat me nt C o m plia nce ................................................................................................... 6 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 ...................... 6 8  
9. 1  
S p o ns or Re vie w of Safet y I nf or mati o n ......................................................................... 6 8  
9. 2  
Re g ulat or y Re q uire me nts .............................................................................................. 6 8  
9. 3  
Defi niti o ns ................................................................................................................... .. 6 8 
9. 3. 1  
A d verse E ve nt .......................................................................................................... 6 8  
9. 3. 2  
A d verse Reacti o n a n d S us p ecte d A d verse Reacti o n ............................................... 6 8  
9. 3. 3  
Seri o us A d verse E ve nt ( S A E) ................................................................................. 6 9  
9. 4  
M o nit ori n g a n d Rec or di n g A d verse E ve nts ................................................................... 6 9  
9. 4. 1  
Seri o us A d verse E ve nts ........................................................................................... 6 9  
9. 4. 2  
N o n- Seri o us A d verse E ve nts ................................................................................... 7 0  
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) ...................................... 7 0  
9. 4. 3. 1  
Relati o ns hi p t o t he St u d y Dr u g ........................................................................ 7 0  
9. 4. 3. 2  
Se verit y ............................................................................................................ 7 0  
9. 4. 3. 3  
Acti o n Ta ke n wit h St u d y Dr u g ........................................................................ 7 1  
9. 4. 3. 4  
Treat me nt Gi ve n f or A d verse E ve nt ................................................................ 7 1  
9. 4. 3. 5  
O utc o me of t he A d verse E ve nt ........................................................................ 7 1  
9. 4. 4  
A dj u dicati o n C o m mittees ........................................................................................ 7 1  
9. 5  
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns .................................................................. 7 2  
9. 5. 1  
A b n or malities of La b orat or y Tests .......................................................................... 7 2  
9. 5. 2  
Presc 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 ............. 7 2  
9. 5. 3  
D osi n g Err ors ........................................................................................................... 7 2  
9. 5. 4  
C o ntrace pti o n a n d Pre g na nc y .................................................................................. 7 3  
1 0.  
S T A TI S TI C A L C O N SI D E R A TI O N S .......................................................................... 7 3  
1 0. 1  
St u d y E n d p oi nts ............................................................................................................. 7 3  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
8
 
1 0. 1. 1  
Pri mar y E n d p oi nt ..................................................................................................... 7 4  
1 0. 1. 2  
Sec o n dar y E n d p oi nts ............................................................................................... 7 4  
 
 
1 0. 1. 4  
Safet y E n d p oi nts  ...................................................................................................... 7 5 
1 0. 2  
Sa m ple Size C o nsi derati o ns ........................................................................................... 7 5  
1 0. 3  
P o p ulati o ns ..................................................................................................................... 7 6  
1 0. 4  
Defi niti o n of Bas eli ne  .................................................................................................... 7 6 
1 0. 5  
I nteri m A nal ysis a n d Earl y St o p pi n g G ui deli nes .......................................................... 7 6 
1 0. 6  
Pla n ne d Met h o ds of A nal ysis ........................................................................................ 7 6  
1 0. 6. 1  
De m o gra p hic a n d Baseli ne C haracteristics  ............................................................. 7 7 
1 0. 6. 2  
Safet y A nal ysis  ........................................................................................................ 7 7 
1 0. 6. 3  
Efficac y A nal ysis ( Pri mar y a n d Sec o n d ar y)  ........................................................... 7 7 
1 0. 6. 4  
P har mac o ki netic a n d I m m u n o ge nicit y A n al ysis ..................................................... 7 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 ............................................. 8 0 
1 1. 1  
I nf or me d C o nse nt .......................................................................................................... 8 0 
1 1. 2  
Et hical C o n d uct of t he St u d y ......................................................................................... 8 0  
1 1. 3  
I n d e pe n de nt Et hics C o m mittee/I nstit uti o nal Re vie w B oar d ......................................... 8 0 
1 1. 4  
Patie nt C o nfi de ntialit y  ................................................................................................... 8 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  ................................................ 8 1 
1 2. 1  
Pr ot oc ol A me n d me nts .................................................................................................... 8 1  
1 2. 2  
St u d y Ter mi nati o n  ......................................................................................................... 8 1 
1 2. 3  
St u d y D oc u me ntati o n a n d St ora ge ................................................................................ 8 1  
1 2. 4  
St u d y M o nit ori n g ........................................................................................................... 8 2  
1 2. 5  
L a n g u a ge  ........................................................................................................................ 8 3 
1 2. 6  
C o m pe nsati o n f or I nj ur y ................................................................................................ 8 3  
1 3.  
R E F E R E N C E S  ................................................................................................................ 8 4 
1 4.  
A P P E N DI C E S  ................................................................................................................. 8 7 
A p pe n di x A  
Sc h e d ule of Pr oce d ures .................................................................................... 8 8  
A p pe n di x B  
List of La b orat or y A n al ytes  ............................................................................. 9 8 
A p pe n di x C  
P K Sa m pli n g Sc he d ule .................................................................................. 1 0 0  
 
 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
9
 
 
T A B L E O F T A B L E S  
P a ge 
Ta ble 1  
Mea n Perce nt C ha n ge fr o m Baseli ne of Li pi d Para meters i n 
H y p ertri gl yceri de mia Patie nts Treate d wit h I SI S 3 0 4 8 0 1 ( 3 0 0 m g/ w k f or 
3 m o nt hs) i n P hase 2 St u dies ................................................................................. 3 8  
Ta ble 2  
St u d y Dr u g C har acteristics  .................................................................................... 5 3 
Ta ble 3  
La bs t o Be Perf or me d i n t he E ve nt of a Platelet C o u nt Less t ha n t he 
L o w er Li mit of N or mal ( x 2) or < 1 0 0, 0 0 0/ m m 3 ( x 1) ............................................ 5 7 
Ta ble 4  
Acti o ns i n Patie nts wit h L o w Platelet C o u nt or Dr o p i n Platelet C o u nt  ................ 6 3 
 
T A B L E O F FI G U R E S  
P a ge 
Fi g ure 1  
A p o C- III Re g ulat es Li p o pr otei n Meta b olis m b y M ulti ple Mec ha nis ms ............... 3 4 
Fi g ure 2  
Desi g n of C hi meric 2ʹ - M O E P h os p h or ot hi oate Oli g o n ucl e oti des 
( M O E-Ga p m er).  T h e se q ue nce of I SI S  3 0 4 8 0 1 is s h o w n .................................... 3 6 
 
 
 

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
1 0
 
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 3 0 4 8 0 1- C S 1 7 
Pr ot oc ol Title: 
A Ra n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d, wit h a n O pe n  
La bel E xte nsi o n,  P hase 2/ 3 St u d y of I SI S 3 0 4 8 0 1 A d mi nistere d 
S u bc uta ne o usl y t o Patie nts w it h Fa milial Partial Li p o d ystr o p h y 
A me n d me nt N u m ber:  4
 
A me n d me nt D ate: 
2 2 A u g ust 2 0 1 7 
 
T he p ur p ose of t his pr ot oc ol a me n d me nt is t o i m p le me nt t he f oll o wi n g m o dificati o ns t o Pr ot oc ol 
I SI S 3 0 4 8 0 1- C S 1 7 A me n d me nt 3 date d 1 7 A pril 2 0 1 7: 
 T o u p date i ncl usi o n criteri o n, re vise sec o n dar y a n d tertiar y e n d p oi nts, a d d a n o pti o n f or 
a n a d diti o nal 5 2 wee ks of o pe n-la bel d osi n g, a d d sc ori n g of disease b ur de n, clarif y 
acti o ns t o be ta ke n i n re gar ds t o e ve nts  of d oc u me nte d h y p o gl yce mia a n d h y per gl yce mia, 
a n d a d d all o wa nce f or u n bli n di n g of tri gl yceri de  val ues t o b ot h I n vesti gat or a n d patie nt 
after 1 3 wee ks o n t he o pe n-la bel treat me nt p hase of t he st u d y. 
Mi n or c ha n ges ( n ot i ncl u de d i n t he list of c ha n ges bel o w) ha ve bee n ma de t hr o u g h o ut t he 
pr ot oc ol t o c orrect err ors a n d/ or  t o i m pr o ve t he o verall clarit y of t he ori gi nal pr ot oc ol b ut 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 ta ble pr o vi des a s u m mar y list of maj or c ha n ges t o t he pr ot oc ol, a d diti o ns are 
i n dicate d as b ol d a n d deleti o ns are i n dicate d as  stri ket hr o u g h: 
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 D e si g n a n d 
Tr e at m e nt S c h e m a  
W A S:  
N ot a p pli c a bl e 
 
I S: 
F oll o wi n g t h e W e e k 1 0 4 vi sit of t h e O p e n- L a b el E xt e n si o n P eri o d, 
p ati e nt s will h a v e t h e o pti o n of c o nti n u e d d o si n g f or u p t o a n 
a d diti o n al 5 2 w e e k s.  T h e s c h e d ul e of pr o c e d ur e s will f oll o w t h e 
s a m e s c h e d ul e a s t h e fir st y e ar of O L E. 
All o w a n c e f or 
a d diti o n al d o si n g f or 
p ati e nt s c o m pl eti n g 
t h e fir st y e ar of o p e n-
l a b el d o si n g 
  
 

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
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 
I n cl u si o n Crit eri o n  
S e cti o n 5. 1  
W A S: 
4.  Di a g n o si s of t y p e 2 di a b et e s m ellit u s a s d efi n e d b y 2 0 0 6 W H O 
crit eri a (f a sti n g pl a s m a gl u c o s e c o n c e ntr ati o n ≥ 7. 0 m m ol/ L 
( 1 2 6 m g/ d L) or 2- h p o st- gl u c o s e l o a d pl a s m a gl u c o s e 
≥ 1 1. 1 m m ol/ L ( 2 0 0 m g/ d L), m a d e at l e a st 6 m o nt h s pri or t o 
t h e S cr e e ni n g vi sit, a n d 2 of t h e f oll o wi n g: 
•  
o n st a n d ar d- of- c ar e a nti-di a b eti c t h er a p y, a n d 
•
 H b A 1 c
 
≥ 7 % t o ≤ 1 0 % at S cr e e ni n g 
 
I S: 
4.  A di a g n o si s of t y p e 2 di a b et e s m ellit u s, a s d efi n e d b y t h e 
I nt er n ati o n al Di a b et e s F e d er ati o n g ui d eli n e s of 2 0 1 2, m a d e at 
l e a st 6 m o nt h s pri or t o t h e S cr e e ni n g, a n d: 
 A
 
H b A 1 c
 ≥ 7 % t o ≤ 1 2 % at S cr e e ni n g 
  
O n a nti- di a b eti c t h er a p y c o n si sti n g of: 
a.
 M etf or mi n
 ≥ 1 5 0 0 m g/ d a y, or 
b.  If t h e d o s e of m etf or mi n i s < 1 5 0 0 m g/ d a y, or 
m etf or mi n i s n ot t ol er at e d, t h e n t h e p ati e nt s h o ul d b e 
o n ot h er or al a nti- di a b eti c dr u g s ( O A D) or a n 
i nj e ct a bl e gl u c a g o n-li k e p e pti d e- 1 ( G L P- 1) r e c e pt or 
a g o ni st, or 
c.  I n s uli n t h er a p y al o n e or i n c o m bi n ati o n wit h ot h er 
a nti- di a b eti c dr u g s 
R e vi s e d t h e di a b eti c 
crit eri a c o n si st e nt 
wit h m or e c urr e nt 
g ui d eli n e s a n d a n 
i n cr e a s e d H b A 1 c 
t hr e s h ol d of 1 2 %.  
R e q uir e t h at all 
p ati e nt s e nt eri n g t h e 
st u d y ar e o n 
a nti di a b eti c a g e nt s, 
w h et h er or al or 
i nj e ct a bl e. 
S y n o p si s 
I n cl u si o n Crit eri o n 
S e cti o n 5. 1  
W A S: 
5.  H y p ertri gl y c eri d e mi a i s d efi n e d a s F a sti n g T G l e v el s 
≥ 5 0 0 m g/ d L (≥ 5. 7 m m ol/ L) at S cr e e ni n g a n d Q u alifi c ati o n vi sit. 
  
If t h e f a sti n g T G v al u e at S cr e e ni n g a n d/ or Q u alifi c ati o n 
vi sit i s < 5 0 0 m g/ d L ( < 5. 7 m m ol/ L) b ut ≥ 3 5 0 m g/ d L 
(≥ 4. 0 m m ol/ L) u p t o 2 a d diti o n al t e st s m a y b e p erf or m e d i n 
or d er t o q u alif y 
 
I S: 
5.  H y p ertri gl y c eri d e mi a a s d efi n e d b y F a sti n g T G l e v el s 
≥ 5 0 0 m g/ d L (≥ 5. 7 m m ol/ L) at b ot h S cr e e ni n g a n d Q u alifi c ati o n 
vi sit s.  P ati e nt s wit h t h e cli ni c al di a g n o si s of F P L a n d wit h 
F a sti n g T G l e v el s ≥ 2 0 0 (≥ 2. 2 6 m m ol/ L) t o < 5 0 0 m g/ d L 
(≥ 5. 7 m m ol/ L) at b ot h S cr e e ni n g a n d Q u alifi c ati o n Vi sit s w h o 
m e et t h e g e n eti c or f a mil y hi st or y crit eri a f or st u d y i n cl u si o n m a y 
b e f urt h er s cr e e n e d a n d e nr oll e d i n t h e st u d y 
6.  Pr e s e n c e of h e p at o st e at o si s (f att y li v er), a s e vi d e n c e d b y a 
S cr e e ni n g M RI i n di c ati n g a h e p ati c f at fr a cti o n ( H F F) ≥ 6. 4 % 
R e vi s e d i n cl u si o n 
crit eri a t o all o w 
Gr o u p 1 a n d Gr o u p 2 
p ati e nt s wit h T G s of 
2 0 0 m g/ d L or gr e at er 
t o p arti ci p at e. All 
gr o u p s will n o w 
r e q uir e e vi d e n c e of 
f att y li v er. 
S y n o p si s 
Str atifi c ati o n  
Gr o u p s 
W A S:   
N ot a p pli c a bl e 
 
I S: 
1.  Gr o u p 1 will c o n si st of p ati e nt s wit h t h e F P L p h e n ot y p e a n d 
g e n eti c v ari a nt s of F P L  
2.  Gr o u p 2 will c o n si st of p ati e nt s wit h t h e F P L p h e n ot y p e, b ut 
l a c ki n g a g e n eti c v ari a nt, a n d h a vi n g a c o nfir m e d f a mil y hi st or y 
of F P L or a b n or m al a n d si mil ar f at di stri b uti o n, pl u s 1 mi n or 
crit eri o n  
3.  Gr o u p 3 will c o n si st of t h o s e wit h  t h e F P L p h e n ot y p e, b ut wit h o ut 
eit h er a g e n eti c v ari a nt or f a mil y hi st or y, pl u s 2 mi n or crit eri a a n d 
a B MI < 3 5 k g/ m 2  
F or cl arit y, a d d e d 
Str atifi c ati o n Gr o u p s 
t o S y n o p si s a s st at e d 
i n S e cti o n 4. 2  – 
R a n d o mi z ati o n  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
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 y n o p si s  
St ati sti c al 
C o n si d er ati o n s  
S e cti o n 1 0. 5  
I nt eri m A n al y si s 
a n d E arl y St o p pi n g  
G ui d eli n e s  
W A S:  
A n i nt eri m a n al y si s of T G i s pl a n n e d aft er a p pr o xi m at el y t h e fir st 
2 0  p ati e nt s (t ot al I SI S 3 0 4 8 0 1 a n d pl a c e b o tr e at e d) h a v e 
c o m pl et e d t h e W e e k 1 3 vi sit.  T h e p ur p o s e of t hi s a n al y si s i s f utilit y 
a s m e a s ur e d b y eff e ct o n T G l e v el s, s o t h er e will b e n o st ati sti c al 
p e n alt y.  
 
I S: 
A n i nt eri m a n al y si s of t h e st u d y i s n ot pl a n n e d.  
A n i nt eri m a n al y si s i s 
n o l o n g er pl a n n e d f or 
f utilit y a s t h e 
e x p e ct ati o n i s t h at 
b a s e d u p o n t h e 
r e s ult s of t h e C S 6 
a n d C S 1 6 tri al s t h er e 
s h o ul d b e si g nifi c a nt 
r e d u cti o n i n 
tri gl y c eri d e s. 
S y n o p si s  
St ati sti c al 
C o n si d er ati o n s  
S e cti o n 1 0. 2  
S a m pl e Si z e 
C o n si d er ati o n s  
W A S:  
N ot a p pli c a bl e  
 
I S: 
A s a m pl e si z e of 3 5 p ati e nt s ( 2 0 a cti v e a n d 1 5 c o ntr ol) pr o vi d e s 
9 2 % p o w er t o d et e ct a li v er f at tr e at m e nt diff er e n c e  of 4. 7 % b a s e d 
o n a b et w e e n p ati e nt st a n d ar d d e vi ati o n of 4 % a n d a t w o -si d e d 
al p h a of 0. 0 5.  
A d d e d a d diti o n al 
s a m pl e si z e 
i nf or m ati o n b a s e d o n 
t h e fir st s e c o n d ar y 
e n d p oi nt  
S e cti o n 2. 1  
O v er vi e w of  
Di s e a s e  
W A S:  
N ot a p pli c a bl e  
 
I S: 
A d d e d 3 a d diti o n al p ar a gr a p h s d e s cri bi n g t h e m et a b oli c 
m a nif e st ati o n s of f a mili al p arti al li p o d y str o p h y  
A d d e d f urt h er 
i nf or m ati o n o n t h e 
m et a b oli c 
c o m pli c ati o n s of F P L  
S e cti o n 3. 4. 3   
O L E P eri o d  
W A S:  
N ot a p pli c a bl e  
 
I S: 
Aft er a p ati e nt h a s b e e n i n t h e O L E p eri o d f or a p eri o d of 3 m o nt h s, 
a n I n v e sti g at or m a y c o n s ult wit h t h e st u d y M e di c al M o nit or a n d 
r e q u e st t h at tri gl y c eri d e v al u e s b e c o m e u n bli n d e d t o t h e 
I n v e sti g at or a n d p ati e nt aft er W e e k 1 3 f or t h e d ur ati o n of t h e st u d y. 
F ol l o wi n g t h e W e e k 1 0 4 of t h e O p e n-L a b el E xt e n si o n P eri o d,  
p ati e nt s will h a v e t h e o pti o n of c o nti n ui n g d o si n g f or u p t o a n 
a d diti o n al 5 2 w e e k s.   T h e s c h e d ul e of pr o c e d ur e s will f oll o w t h e 
s a m e s c h e d ul e a s t h e fir st y e ar of O L E.  
A d d e d t h at p ati e nt s 
a n d I n v e sti g at or s 
m a y b e c o m e 
u n bli n d e d t o 
tri gl y c eri d e v al u e s 
aft e r W e e k 1 3 of 
o p e n -l a b el d o si n g s o 
t h at p ati e nt s ar e 
a w ar e of p ot e nti al 
b e n efit s of c o nti n u e d 
st u d y p arti ci p ati o n . 
P ati e nt s m a y al s o 
el e ct t o c o nti n u e 
st u d y p arti ci p ati o n 
aft er 1 y e ar of 
o p e n -l a b el d o si n g 
S e cti o n 3. 6  
D at a a n d S af et y 
M o nit ori n g B o ar d  
W A S:  
A d diti o n all y, t h e D S M B will r e vi e w d at a d uri n g t h e i nt eri m a n al y si s 
of T G aft er a p pr o xi m at el y t h e fir st 2 0 p ati e nt s h a v e c o m pl et e d t h e 
W e e k 1 3 vi sit.  M or e d et ail s r e g ar di n g t hi s i nt eri m a n al y si s ar e 
pr e s e nt e d i n S e cti o n 1 0. 5.  
 
I S: 
D el et e d  
R e m o v e d i nt eri m 
a n al y si s f or f utilit y  
 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
1 4
 
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  
W A S:  
6. 1. 2  
R a n d o mi z e d Tr e at m e nt P eri o d  
6. 1. 3  
O L E P eri o d  
6. 1. 4   
P o st-Tr e at m e nt P eri o d  
 
I S: 
6. 1. 2  
R a n d o mi z e d Tr e at m e nt P eri o d  
6. 1. 3  
R a n d o mi z e d P eri o d P o st -Tr e at m e nt F oll o w -U p  
6. 1. 4  
O L E P eri o d  
6. 1. 5  
O L E P o st -Tr e at m e nt P eri o d  
R e vi s e d S e cti o n 
H e a di n g s f or 
cl arifi c ati o n  i n 
r e g ar d s t o f oll o w-u p 
of p ati e nt s  
S e cti o n 6. 1. 5  
O L E P o st -
Tr e at m e nt P eri o d  
W A S:  
N ot a p pli c a bl e  
 
I S: 
F or p ati e nt s w h o c o nti n u e t o r e c ei v e i n v e sti g ati o n al tr e at m e nt f or 
t h e a d diti o n al 5 2 w e e k s, t h e 1 3-w e e k p o st -tr e at m e nt f oll o w-u p 
p eri o d will  f oll o w t h e s e c o n d y e ar of o p e n-l a b el d o si n g. 
A d d e d a n o pti o n f or 
p ati e nt s t o c o nti n u e 
f or a n a d diti o n al 
5 2  w e e k s i n O L E  
S e cti o n 6. 2. 9  
Q u alit y of Lif e  
A s s e s s m e nt s  
W A S:  
6. 2. 9  
Q u alit y of Lif e A s s e s s m e nt s  
All p ati e nt s will c o m pl et e Q u alit y of Lif e Q u e sti o n n air e s ( E Q -5 D 
a n d S F -3 6) at t h e ti m e s i n di c at e d i n A p p e n di x A.   
 
I S: 
6. 2. 9  
Q u alit y of Lif e A s s e s s m e nt s  
All p ati e nt s will c o m pl et e Q u alit y of Lif e Q u e sti o n n air e s ( E Q -5 D 
a n d S F -3 6) at t h e ti m e s i n di c at e d i n A p p e n di x A.  P ati e nt s will 
c o m pl et e a s ur v e y t h at will e v al u at e c h a n g e s i n a di s e a s e 
b ur d e n s c or e b ef or e a n d aft er t h er a p y. T h e di s e a s e b ur d e n 
s c or e will b e c al c ul at e d t hr o u g h a n al y si s of a n at ur al hi st or y 
s ur v e y of p ati e nt s wit h F P L.  I n a d diti o n, p ati e nt s will 
c o m pl et e t h e Di a b et e s H e alt h Pr ofil e ( D H P 1 8) at t h e ti m e s 
i n di c at e d i n A p p e n di x A. 
A d d e d s c ori n g of 
di s e a s e b ur d e n, i n 
a d diti o n t o t h e 
st a n d ar d q u alit y of 
lif e a s s e s s m e nt s 
( S F-3 6 a n d E Q -5 D) .  
T h e s c ori n g will b e 
d eri v e d fr o m a 
n at ur al hi st or y s ur v e y 
of F P L p ati e nt s a n d 
i n cl u d e d i n t h e st u d y 
w h e n  a v ail a bl e.  
I n a d diti o n, t h e 
Di a b et e s H e alt h 
Pr ofil e – 1 8 i s a d d e d 
a s a di s e a s e -s p e cifi c 
i n str u m e nt t o c a pt ur e 
t h e i m p a ct of li vi n g 
wit h di a b et e s o n t h e 
p ati e nt’ s 
p s y c h ol o gi c al a n d 
b e h a vi or al 
f u n cti o ni n g. 
S e cti o n 8. 5. 7  
S af et y M o nit ori n g  
f or H y p o gl y c e mi a  
W A S:  
N ot a p pli c a bl e  
 
I S: 
I n t h e e v e nt of a n e pi s o d e of s y m pt o m ati c d o c u m e nt e d 
h y p o gl y c e mi a  ( F P G < 7 0 m g/ d L) , if t h e p ati e nt i s o n i n s uli n, t he 
In v e sti g at or s h all  r e d u c e t h e t ot al d ail y d o s e b y 5-1 5 %.  If t h e 
p ati e nt i s o n or al a nt -di a b eti c dr u g s, t h e I n v e sti g at or s h o ul d u s e hi s 
or h er di s cr eti o n r e g ar di n g c h a n g e s t o t h e dr u g r e gi m e n t o h el p 
pr e v e nt f ut ur e i n ci d e n c e s of h y p o gl y c e mi c e v e nt s.  I n all  c a s e s, t h e 
a dj u st m e nt s m a d e t o m e di c ati o n s h o ul d b e c ar ef ull y d o c u m e nt e d 
vi a el e ctr o ni c di ar y (i n s uli n) a n d/ or c o n c o mit a nt m e di c ati o n C R F.  
Pr o vi d e d g ui d a n c e t o 
t h e In v e sti g at or o n 
m e di c ati o n 
a dj u st m e nt s i n t h e 
pr e s e n c e of 
s y m pt o m ati c 
d o c u m e nt e d 
h y p o gl y c e mi a  
 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
1 5
 
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. 5. 8  
M o nit ori n g R ul e f or  
D o c u m e nt e d 
H y p er gl y c e mi a  
 
W A S:  
T h e t hr e s h ol d v al u e s ar e d efi n e d a s f oll o w s, d e p e n di n g o n st u d y 
p eri o d:  
 
Fr o m B a s eli n e vi sit t o W e e k 1 2 (i n cl u di n g v al u e at 
W e e k  1 2) of R a n d o mi z e d Tr e at m e nt p eri o d or O L E 
p eri o d:  
o  
F P G > 2 7 0 m g/ d L ( 1 5. 0 m m ol/ L)  
 
Fr o m W e e k 1 2 t o W e e k 2 4 (i n cl u di n g v al u e at W e e k 2 4) 
of R a n d o mi z e d Tr e at m e nt p eri o d or O L E p eri o d:  
o  
F P G > 2 4 0 m g/ d L ( 1 3. 3 m m ol/ L) or  
o  
H b A 1 c > 9 % (f or p ati e nt s wit h B a s eli n e H b A 1 c < 8 %) 
a n d H b A 1 c i n cr e a s e of m or e t h a n 1 % fr o m B a s eli n e 
(f or p ati e nt s wit h B a s eli n e H b A 1 c ≥ 8 %) 
 
Fr o m W e e k 2 4 u p t o W e e k 5 2 of R a n d o mi z e d Tr e at m e nt 
p eri o d or O L E p eri o d:  
o  
H b A 1 c > 9 % (f or p ati e nt s wit h B a s eli n e H b A 1 c < 8 %) 
a n d H b A 1 c i n cr e a s e of m or e t h a n  1 % fr o m B a s eli n e 
(f or p ati e nt s wit h B a s eli n e H b A 1 c ≥ 8 %) 
 
I S: 
T h e t hr e s h ol d v al u e s ar e d efi n e d a s f oll o w s, d e p e n di n g o n st u d y 
p eri o d:  
 
Fr o m B a s eli n e vi sit t o W e e k 1 2 (i n cl u di n g v al u e at 
W e e k  1 2) of R a n d o mi z e d Tr e at m e nt p eri o d or O L E 
p eri o d:  
o  
F P G > 3 0 0 m g/ d L  ( 1 6. 6 m m ol/ L) 
 
Fr o m W e e k 1 2 t o W e e k 2 4 (i n cl u di n g v al u e at W e e k 2 4) 
of R a n d o mi z e d Tr e at m e nt p eri o d or O L E p eri o d:  
o  
F P G > 2 7 0 m g/ d L ( 1 5. 0 m m ol/ L)  or  
o  
H b A 1 c > 9. 5 %  (f or p ati e nt s wit h B a s eli n e H b A 1 c 
< 8 %) a n d H b A 1 c i n cr e a s e of m or e t h a n 1. 5 % fr o m 
B a s eli n e (f or p ati e nt s wit h B a s eli n e H b A 1 c ≥ 8 %)  
 
Fr o m W e e k 2 4 u p t o W e e k 5 2 of R a n d o mi z e d Tr e at m e nt 
p eri o d or O L E p eri o d:  
o  
F P G > 2 4 0 m g/ d L ( 1 3. 3 m m ol/ L)  or  
o  
H b A 1 c > 9. 5 %  (f or p ati e nt s wit h B a s eli n e H b A 1 c 
< 8 %) a n d H b A 1 c i n cr e a s e of m or e t h a n 1. 5 % fr o m 
B a s eli n e (f or p ati e n t s wit h B a s eli n e H b A 1 c ≥ 8 %) 
T hr e s h ol d v al u e s f or 
h y p er gl y c e mi a ar e 
a dj u st e d t o r efl e ct t h e 
i n cl u si o n of p ati e nt s 
wit h a n H b A 1 c of u p 
t o 1 2 %. 
S e cti o n 8. 5. 8  
M o nit ori n g R ul e f or  
D o c u m e nt e d 
H y p er gl y c e mi a  
W A S:  
If n o n e fr o m t h e a b o v e  m e nti o n e d r e a s o n c a n b e f o u n d, or if 
a p pr o pri at e a cti o n f ail s t o d e cr e a s e F P G/ H b A 1 c u n d er t h e 
t hr e s h ol d v al u e s, r e s c u e m e di c ati o n m a y b e i ntr o d u c e d at t h e 
I n v e sti g at or di s cr eti o n a n d a c c or di n g t o l o c al g ui d eli n e s. 
 
I S: 
If n o n e fr o m t h e a b o v e-m e nti o n e d r e a s o n s c a n b e f o u n d, or if 
a p pr o pri at e a cti o n f ail s t o d e cr e a s e F P G/ H b A 1 c u n d er t h e 
t hr e s h ol d v al u e s, a n i n cr e a s e i n c urr e nt m e di c ati o n or t h e 
a d diti o n of n e w a nti -di a b eti c  r e s c u e m e di c ati o n m a y b e 
i ntr o d u c e d at I n v e sti g at or di s cr eti o n a n d a c c or di n g t o l o c al 
g ui d eli n e s.  I n v e sti g at or s s h o ul d mi ni mi z e c h a n g e s pri or t o t h e 
pri m ar y e n d p oi nt, w h e n p o s si bl e.  All a dj u st m e nt s t o 
m e di c ati o n s h o ul d b e c a pt ur e d o n t h e c o n c o mit a nt 
m e di c ati o n C R F a n d/ or el e ctr o ni c di ar y.  
Cl arifi e d a cti o n s t o b e 
t a k e n i n t h e i n st a n c e 
of d o c u m e nt e d 
h y p er gl y c e mi a  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
1 6
 
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 1 0. 6. 3  
Effi c a c y A n al y si s  
( Pri m ar y a n d 
S e c o n d ar y)  
U p d at e d t o r efl e ct c h a n g e s i n s e c o n d ar y  
 e n d p oi nt s 
n ot e d a b o v e , i n cl u di n g: 
 
Pr o p orti o n of p ati e nt s w h o a c hi e v e a ≥ 4 0 % r e d u cti o n 
i n f a sti n g T G fr o m B a s eli n e a n d a ≥ 3 0 % r e d u cti o n of 
h e p ati c f at fr a cti o n p er c e nt fr o m b a s eli n e at M o nt h 6 
b et w e e n I SI S 3 0 4 8 0 1 3 0 0 m g o n c e -w e e kl y a n d 
pl a c e b o gr o u p will b e a n al y z e d u si n g a l o gi sti c 
r e gr es si o n m o d el wit h t h e r a n d o mi z ati o n str atifi c ati o n 
f a ct or s, l o g tr a n sf or m e d B a s eli n e T G, a n d B a s eli n e 
h e p ati c f at fr a cti o n a s c o v ari at e s.   
U p d at e d st ati sti c al 
a n al y s e s  
A p p e n di x A  
S c h e d ul e of  
Pr o c e d ur e s  
W A S:  
Q u alit y of Lif e A s s e s s m e nt s  
 
I S: 
Q u alit y of Lif e  / Di s e a s e B ur d e n A s s e s s m e nt s / D H P 1 8 
A s s e s s m e nt( s)  
A d d e d a n 
a s s e s s m e nt of 
di s e a s e b ur d e n, 
w h e n a v ail a bl e, fr o m 
a n at ur al hi st or y 
s ur v e y of F P L 
p ati e nt s  
 
 
 

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
1 7
 
P R O T O C O L S Y N O P SI S 
Pr ot o c ol Titl e 
A 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 nt r oll e d, wit h a n O p e n L a b el E xt e n si o n, 
P h a s e 2/ 3 St u d y of I SI S 3 0 4 8 0 1 A d mi ni st er e d S u b c ut a n e o u sl y t o P ati e nt s wit h F a mili al 
P arti al Li p o d y str o p h y 
St u d y P h a s e 
P h a s e 2/ 3 
I n di c ati o n 
F a mili al P arti al Li p o d y str o p h y ( F P L) 
I n v e sti g ati o n al Dr u g 
I SI S 3 0 4 8 0 1 i s a s e c o n d- g e n er ati o n 2-O -( 2- m et h o x y et h yl) c hi m eri c a nti s e n s e 
oli g o n u cl e oti d e i n hi bit or of t h e a p oli p o pr ot ei n C-III ( a p o C-III) 
Pri m ar y O bj e cti v e 
T o e v al u at e t h e effi c a c y of I SI S 3 0 4 8 0 1 f or r e d u cti o n i n s e v erit y of m et a b oli c 
d er a n g e m e nt i n p ati e nt s wit h F P L wit h h y p er tri gl y c eri d e mi a a n d u n c o ntr oll e d di a b et e s. 
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 s af et y a n d t ol er a bilit y of I SI S 3 0 4 8 0 1 i n p ati e nt s wit h F P L. 
T o f urt h er e v al u at e t h e r ol e of s er u m T G s i n m o d ul ati n g i n s uli n r e si st a n c e i n F P L 
p ati e nt s a n d t h e i m p a ct of T G r e d u cti o n o n a di p o s e ti s s u e di stri b uti o n. 
St u d y D e si g n 
T hi s i s a m ulti- c e nt er, r a n d o mi z e d, d o u b l e- bli n d, pl a c e b o- c o ntr oll e d st u d y wit h a n 
o p e n-l a b el e xt e n si o n. 
T h e st u d y will c o m pri s e t h e f oll o wi n g p eri o d s: 
 
S cr e e ni n g.   A n u p t o 6- w e e k S cr e e ni n g P eri o d, i n cl u di n g at l e a st a 4- w e e k di et 
st a bili z ati o n p h a s e 
 
R a n d o mi z e d Tr e at m e nt P eri o d.   F oll o wi n g st a bili z ati o n, u p t o 6 0 eli gi bl e 
p ati e nt s will b e r a n d o mi z e d 1: 1 t o r e c ei v e I SI S 3 0 4 8 0 1 3 0 0 m g or pl a c e b o 
o n c e- w e e kl y f or 5 2 w e e k s 
 
A n O p e n- L a b el E xt e n si o n P eri o d 
F oll o wi n g t h e W e e k 5 2 vi sit, p ati e nt s m a y e nt er a n O p e n- L a b el E xt e n si o n 
( O L E) P eri o d f or a n ot h er 5 2 w e e k s d uri n g w hi c h t h e y will all r e c ei v e 
I SI S 3 0 4 8 0 1 
F oll o wi n g t h e W e e k 1 0 4 vi sit of t h e O p e n- L a b el E xt e n si o n P eri o d, p ati e nt s will 
h a v e t h e o pti o n of c o nti n u e d d o si n g f or u p t o a n a d diti o n al 5 2 w e e k s. T h e 
s c h e d ul e of pr o c e d ur e s will f oll o w t h e s a m e  s c h e d ul e a s t h e fir st y e ar of O L E. 
 
A 1 3- w e e k P o st-tr e at m e nt E v al u ati o n P eri o d 
P ati e nt s w h o d o n ot e nt er t h e O L E p er i o d will g o str ai g ht t o a 1 3- w e e k 
p o st-tr e at m e nt f oll o w- u p p eri o d.   
F oll o wi n g t h e W e e k 1 0 4 O L E p eri o d, p ati e nt s will e nt er a 1 3- w e e k 
p o st-tr e at m e nt f oll o w- u p p eri o d, if t h e y d o n ot o pti o n f or c o nti n u e d d o si n g. 
T h e pri m ar y e n d p oi nt f or t h e st u d y will b e e v al u at e d aft er t h e l a st p ati e nt h a s c o m pl et e d 
t h e W e e k 5 2/ E arl y T er mi n ati o n ( E T) vi sit of t h e r a n d o mi z e d tr e at m e nt p eri o d a n d will b e 
b a s e d o n t h e p er c e nt c h a n g e fr o m B a s eli n e i n f a sti n g T G at t h e pri m ar y a n al y si s ti m e 
p oi nt ( M o nt h 3). 
N u m b er of P ati e nt s 
U p t o 6 0 p ati e nt s wit h F P L will b e r a n d o mi z e d. 
 
 

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
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 P o p ul ati o n 
I n cl u si o n Crit eri a: 
1.  M u st gi v e writt e n i nf or m e d c o n s e nt t o p ar ti ci p at e i n t h e st u d y ( 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 a w 
2.  A g e  ≥ 1 8 y e ar s at t h e ti m e of i nf or m e d c o n s e nt 
3.  Cli ni c al di a g n o si s of f a mili al p arti al li p o d y str o p h y pl u s di a g n o si s of t y p e 2 di a b et e s 
m ellit u s a n d h y p ertri gl y c eri d e mi a. 
Di a g n o si s of li p o d y str o p h y i s b a s e d o n d efi ci e n c y of s u b c ut a n e o u s b o d y f at i n a 
p arti al f a s hi o n a s s e s s e d b y p h y si c al e x a mi n ati o n a n d l o w s ki nf ol d t hi c k n e s s i n 
a nt eri or t hi g h b y c ali p er m e a s ur e m e nt: m e n ( ≤ 1 0 m m) a n d w o m e n (≤ 2 2 m m), a n d 
at l e a st 1 of t h e f oll o wi n g: 
-  
G e n eti c di a g n o si s of f a mili al P L ( e. g., m ut ati o n s i n L M N A, P P A R-γ , A K T 2, 
CI D E C, P LI N 1 g e n e s) 
O R 
-  F a mil y hi st or y of F P L or f a mil y hi st ory of a b n or m al a n d si mil ar f at di stri b uti o n 
pl u s 1 Mi n or Crit eri a 
O R 
-  2 Mi n or Crit eri a (I n t h e a b s e n c e of F P L- a s s o ci at e d g e n eti c v ari a nt or f a mil y 
hi st or y) a n d B MI < 3 5 k g/ m 2  
MI N O R Crit eri a 
a.  R e q uir e m e nt f or hi g h d o s e s of i n s uli n, e. g., r e q uiri n g ≥ 2 0 0 U/ d a y, ≥ 2 U/ k g/ d a y, 
or c urr e ntl y t a ki n g U- 5 0 0 i n s uli n 
b.  Pr e s e n c e of a c a nt h o si s ni gr i c a n s o n p h y si c al e x a mi n ati o n 
c.  E vi d e n c e/ hi st or y of p ol y c y sti c o v ar y s y n dr o m e ( P C O S) or P C O S-li k e s y m pt o m s 
( hir s uti s m, oli g o m e n orr h e a, a n d/ or p ol y c y sti c o v ari e s) 
d.  Hi st or y of p a n cr e atiti s a s s o ci at e d wit h h y p ertri gl y c eri d e mi a 
e.  E vi d e n c e of n o n- al c o h oli c f att y li v er di s e a s e 
-  H e p at o m e g al y a n d/ or el e v at e d tr a n s a mi n a s e s i n t h e a b s e n c e of a k n o w n 
c a u s e of li v er di s e a s e or r a di o gr a p hi c e vi d e n c e of h e p ati c st e at o si s ( e. g., o n 
ultr a s o u n d or C T) 
4.  A di a g n o si s of t y p e 2 di a b et e s m ellit u s , a s d efi n e d b y t h e I nt er n ati o n al Di a b et e s 
F e d er ati o n g ui d eli n e s of 2 0 1 2, m a d e at l e a st 6 m o nt h s pri or t o t h e S cr e e ni n g, a n d: 
 A
 
H b A 1 c
 ≥ 7 % t o ≤ 1 2 % at S cr e e ni n g, 
  
O n a nti- di a b eti c t h er a p y c o n si sti n g of: 
a.  M etf or mi n  ≥ 1 5 0 0 m g/ d a y, or 
b.  If t h e d o s e of m etf or mi n i s < 1 5 0 0 m g / d a y, or m etf or mi n i s n ot t ol er at e d, 
t h e n t h e p ati e nt s h o ul d b e o n ot h er oral a nti- di a b eti c dr u g s ( O A D) or a n 
i nj e ct a bl e gl u c a g o n-li k e p e pti d e- 1 ( G L P- 1) r e c e pt or a g o ni st, or 
c.  I n s uli n t h er a p y al o n e or i n c o m bi n ati o n wit h ot h er a nti- di a b eti c dr u g s 
5.  H y p ertri gl y c eri d e mi a a s d efi n e d b y F a sti n g T G l e v el s ≥ 5 0 0 m g/ d L (≥ 5. 7 m m ol/ L) at 
b ot h S cr e e ni n g a n d Q u alifi c ati o n vi sit s.  P ati e nt s wit h t h e cli ni c al di a g n o si s of F P L 
a n d wit h F a sti n g T G l e v el s ≥ 2 0 0 (≥ 2. 2 6 m m ol/ L) t o < 5 0 0 m g/ d L (≥ 5. 7 m m ol/ L) at 
b ot h S cr e e ni n g a n d Q u alifi c ati o n Vi sit s w h o m e et t h e g e n eti c or f a mil y hi st or y crit eri a 
f or st u d y i n cl u si o n m a y b e f urt h er s cr e e n e d a n d e nr oll e d i n t h e st u d y. 
6.  Pr e s e n c e of h e p at o st e at o si s (f att y li v er), a s e vi d e n c e d b y a S cr e e ni n g M RI i n di c ati n g 
a h e p ati c f at fr a cti o n ( H F F) ≥ 6. 4 % 
7.  Willi n g t o m ai nt ai n t h eir c u st o m ar y p h y si c al a cti vit y l e v el a n d t o f oll o w a di et 
m o d er at e i n c ar b o h y dr at e s a n d f at s wit h a f o c u s o n c o m pl e x c ar b o h y dr at e s a n d 
r e pl a ci n g s at ur at e d f or u n s at ur at e d f at s 
 
 

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
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 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 
8.  S ati sf y 1 of t h e f oll o wi n g: 
a.  F e m al e s:  N o n- pr e g n a nt a n d n o n-l a ct at i n g; 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), 
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 olli cl e- sti m ul ati n g 
h or m o n e ( 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), 
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 of c hil d- b e ari n g p ot e nti al, p ati e nt i s 
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 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 a d mi ni str ati o n. 
b.  M al e s:  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, p ati e nt i s utili zi 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 ast d o s e of St u d y Dr u g a d mi ni str ati o n. 
* 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 ce, 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. 
E x cl u si o n Crit eri a: 
1.  
A di a g n o si s of g e n er ali z e d li p o d y str o p h y 
2.  
A di a g n o si s of a c q uir e d p arti al li p o d y str o p h y ( A P L) 
3.
 A c ut e
 p a n cr e atiti s
 wit h i n 4 w e e k s of S cr e e ni n g 
4.  
Hi st or y wit hi n 6 m o nt h s of S cr e e ni n g of a c ut e or u n st a bl e c ar di a c i s c h e mi a 
( m y o c ar di al i nf ar cti o n, a c ut e c or o n ar y s y n dr o m e, n e w o n s et a n gi n a), str o k e, 
tr a n si e nt i s c h e mi c att a c k or u n st a bl e c o ng e sti v e h e art f ail ur e r e q uiri n g a c h a n g e i n 
m e di c ati o n 
5.  
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 
6.  
Hi st or y of h e art f ail ur e wit h N e w Y or k H e art A s s o ci ati o n f u n cti o n al cl a s sifi c ati o n 
( N Y H A) gr e at er t h a n Cl a s s II or u n st a bl e c o n g e sti v e c ar di a c f ail ur e r e q uiri n g a 
c h a n g e i n m e di c ati o n 
7.  
U n c o ntr oll e d h y p ert e n si o n ( bl o o d pr e s s u r e [ B P] > 1 6 0 m m H g s y st oli c a n d/ or 
1 0 0 m m H g di a st oli c) 
8.  
A n y of t h e f oll o wi n g l a b or at or y v al u e s at S cr e e ni n g: 
a.  
C ar di a c tr o p o ni n I > u p p er li mit of n or m al ( U L N) 
b.  L D L- C > 1 3 0 m g/ d L o n m a xi m a l t ol er at e d st ati n t h er a p y 
c.
 H e p ati c:
  
i.  
T ot al bilir u bi n > U L N 
ii.  
Al a ni n e a mi n otr a n sf er a s e ( A L T) > 3. 0 x U L N 
iii.  
A s p art at e a mi n otr a n sf er a s e ( A S T) > 3. 0 x U L N 
 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
2 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  
E x cl u si o n Crit eri a:   C o nti n u e d  
d. 
R e n al:  
i. 
P er si st e ntl y p o siti v e ( 2 o ut of 3 t e st s ≥ tr a c e p o siti v e) f or bl o o d o n uri n e 
di p sti c k .  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 p er hi g h p o w er fi el d  
ii. 
T w o ( 2) o ut of 3 c o n s e c uti v e t e st s ≥ 1+ f or pr ot ei n o n uri n e di p sti c k.  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 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 < 1. 0 g/ 2 4 hr s  
iii. 
E sti m at e d cr e ati ni n e cl e ar a n c e c al c ul at e d a c c or di n g t o t h e f or m ul a of 
C o c k cr oft a n d G a ult < 6 0 m L/ mi n  
e.  
Pl at el et c o u nt < l o w er li mit of n or m al ( L L N)  
f. 
Cli ni c all y -si g nifi c a nt ( a s d et er mi n e d b y t h e  I n v e sti g at or or S p o n s or) 
a b n or m aliti e s o n l a b or at or y e x a mi n ati o n t h at will i n cr e a s e ri s k t o t h e p ati e nt or 
i nt erf er e wit h d at a i nt e grit y 
9.  
U n c o ntr oll e d h y p ot h yr oi di s m ( a b n or m al t h yr oi d f u n cti o n t e st s s h o ul d b e a p pr o v e d 
b y St u d y m e di c al m o nit or)  
1 0.  Hi st o r y wit hi n 6 m o nt h s of S cr e e ni n g  of dr u g or al c o h ol a b u s e  
1 1.  Hi st or y of bl e e di n g di at h e si s or c o a g ul o p at h y or cli ni c all y -si g nifi c a nt  a b n or m alit y i n 
c o a g ul ati o n p ar a m et er s at S cr e e ni n g  
1 2.  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 3.  K n o w n hi st or y of or 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 or c hr o ni c h e p atiti s B  
1 4.  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 a r 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  
1 5.  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 6.  U n willi n g t o c o m pl y  wit h lif e st yl e r e q uir e m e nt s ( s e e S e cti o n 6. 3 ) 
1 7.  U s e of a n y of t h e f oll o wi n g:  
a.   
Metr el e pti n wit hi n t h e l a st 3 m o nt h s pri or t o S cr e e ni n g  
b.  
A nti di a b eti c , li pi d l o w eri n g, or at y pi c al a nti p s y c h oti c m e di c ati o n, u nl e s s o n a 
st a bl e d o s e f or at l e a st 3 m o nt h s pri or t o s cr e e ni n g.  F or li pi d l o w eri n g 
m e di c ati o n s ( e. g., o m e g a -3 f att y a ci d s) d o s e, br a n d a n d r e gi m e n ar e 
e x p e ct e d t o r e m ai n t h e s a m e fr o m D a y 1 t hr o u g h o ut W e e k 1 3.  P ati e nt s n ot 
r e c ei vi n g t h e s e dr u g s wit hi n 4 w e e k s pri or t o s cr e e ni n g ar e al s o eli gi bl e. 
c.  
I n s uli n u nl e s s o n a st a bl e d ail y i n s uli n d o s e r e gi m e n ( ± 2 0 %) f or at l e a st 
4 w e e k s pri or t o d o si n g  
d.  
G L P -1 a g o ni st s wit hi n  4 w e e k s pri or t o d o si n g , if p ati e nt h a s a hi st or y of 
p a n cr e atiti s  
e.   
Ni c oti ni c a ci d or d eri v ati v e s of ni c oti ni c a ci d wit hi n 4 w e e k s pri or t o s cr e e ni n g  
f. 
S y st e mi c c orti c o st er oi d s or a n a b oli c st er oi d s wit hi n 6 w e e k s pri or t o s cr e e ni n g 
u nl e s s 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  
 
 

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
2 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 
g.  
A nti h y p ert e n si v e m e di c ati o n u nl e s s o n a st a bl e d o s e f or at l e a st 4 w e e k s pri or 
t o d o si n g 
h.  T a m o xif e n, e str o g e n s or pr o g e sti n s u nl e s s o n a st a bl e d o s e f or at l e a st 
4 m o nt h s pri or t o s cr e e ni n g a n d d o s e a n d r e gi m e n e x p e ct e d t o r e m ai n 
c o n st a nt t hr o u g h o ut t h e st u d y 
i.  
Or al a nti c o a g ul a nt s u nl e s s o n a st a bl e d o s e f or at l e a st 4 w e e k s pri or t o 
d o si n 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 
j.  
A nti- o b e sit y dr u g s [ e. g., t h e c o m bi n ati o n of p h e nt er mi n e a n d e xt e n d e d-
r el e a s e t o pir a m at e ( Q s y mi a), orli st at ( X e ni c al), lir a gl uti d e [r D N A ori gi n] 
i nj e cti o n ( S a x e n d a) a n d l or c a s eri n ( B el vi q), p h e nt er mi n e, a m p h et a mi n e s, 
h er b al pr e p ar ati o n s] wit hi n 1 2 w e e k s pri or t o s cr e e ni n g 
k.  
Pri or e x p o s ur e t o I SI S 3 0 4 8 0 1 
l.  
A n y ot h er m e di c ati o n u nl e s s st a bl e at l e a st 4 w e e k s pri or t o d o si n g 
( o c c a si o n al or i nt er mitt e nt u s e of o v er-th e- c o u nt er m e di c ati o n s will b e all o w e d 
at I n v e sti g at or’ s di s cr eti o n) 
1 8.  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 9.  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 t h e S p o n s or 
w o ul d m a k e t h e p ati e nt u n s uit a bl e f or i n cl u s i o n, or c o ul d i nt erfer e wit h t h e p ati e nt 
p arti ci p ati n g i n or c o m pl eti n g t h e st u d y 
Tr e at m e nt Gr o u p s 
Pl a c e b o- c o ntr oll e d p eri o d:  3 0 0 m g I SI S 3 0 4 8 0 1 o n c e p er w e e k, or pl a c e b o o n c e p er 
w e e k 
O p e n- L a b el E xt e n si o n p eri o d:  3 0 0 m g I SI S 3 0 4 8 0 1 o n c e p er w e e k 
Str atifi c ati o n Gr o u p s 
1.  Gr o u p 1 will c o n si st of p ati e nt s wit h t h e F P L p h e n ot y p e a n d g e n eti c v ari a nt s of F P L  
2.  Gr o u p 2 will c o n si st of p ati e nt s wit h t h e F P L p h e n ot y p e, b ut l a c ki n g a g e n eti c 
v ari a nt, a n d h a vi n g a c o nfir m e d f a mil y hi st or y of F P L or a b n or m al a n d si mil ar f at 
di stri b uti o n, pl u s 1 mi n or crit eri o n  
3.  Gr o u p 3 will c o n si st of t h o s e wit h t h e F P L p h e n ot y p e, b ut wit h o ut eit h er a g e n eti c 
v ari a nt or f a mil y hi st or y, pl u s 2 mi n or crit eri a a n d a B MI < 3 5 k g/ m 2  
St u d y Dr u g D o s a g e 
a n d A d mi ni str ati o n 
I SI S 3 0 4 8 0 1 ( 3 0 0 m g) a n d pl a c e b o will b e a d mi ni st er e d a s S C i nj e cti o n s.  S elf-
a d mi ni str ati o n will b e all o w e d aft er a p pr o pri at e tr ai ni n g of p ati e nt a n d/ or c ar e gi v er 
D o s e A dj u st m e nt s 
D o s e a dj u st m e nt s, i n cl u di n g d o s e i nt err u pti o n s, a n d/ or d e cr e a si n g t h e d o s e fr e q u e n c y 
will b e all o w e d f or s af et y or t ol er a bilit y aft er c o n s ult ati o n wit h t h e S p o n s or M e di c al 
M o nit or.  D o s e a dj u st m e nt s s h o ul d n ot o c c u r u nl e s s a b s ol ut el y n e c e s s ar y pri or t o t h e 
pri m ar y a n al y si s ti m e p oi nt ( M o nt h 3) 
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 
D o s e of 3 0 0 m g o n c e- w e e kl y w a s c h o s e n b a s e d o n t h e p h ar m a c o d y n a mi c a n d s af et y 
a n al y si s of t h e P h a s e 2 st u di e s i n p ati e nt s wit h T G l e v el s ≥ 2 0 0 m g/ d L i n cl u di n g p ati e nt s 
wit h t y p e 2 di a b et e 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 
T h e st u d y f or a n i n di vi d u al p ati e nt will g e n er all y c o n si st of t h e f oll o wi n g p eri o d s: 
  
A n u p t o 6- w e e k S cr e e ni n g P eri o d, i n cl u di n g at l e a st a 4- w e e k di et st a bili z ati o n 
p h a s e 
  
A 5 2- w e e k R a n d o mi z e d Tr e at m e nt P eri o d d uri n g w hi c h St u d y Dr u g will b e 
a d mi ni st er e d a s a o n c e- w e e kl y S C i nj e cti o n f oll o w e d b y eit h er: 
o   
A 1 3- w e e k p o st-tr e at m e nt e v al u ati o n p eri o d (f or p ati e nt s n ot e nt eri n g t h e 
O L E p eri o d) 
o   
A 5 2- w e e k O L E p eri o d d uri n g w hi c h I SI S 3 0 4 8 0 1 will b e a d mi ni st er e d a s a 
o n c e- w e e kl y S C i nj e cti o n, wit h a s u b s e q u e nt 1 3- w e e k p o st-tr e at m e nt 
e v al u ati o n p eri o d, or a n o pti o n f o r c o nti n u e d tr e at m e nt f or 5 2 w e e k s 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
2 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 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  
C oll e cti o n a n d m e a s ur e m e nt of vit al si g n s, p h y si c al e x a mi n ati o n r e s ult s,  
 
, el e ctr o c ar di o gr a m s ( E C G s), li v er 
M RI s, e c h o c ar di o gr a m s, cli ni c al l a b or at or y p ar a m et er s (i n cl u di n g h e m at ol o g y; s er u m 
c h e mi str y; li pi d p a n el; 
,  
,  
, a n d 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); uri n al y si s, a n d ot h er a n al yt e s li st e d i n A p p e n di x B ), 
I SI S 3 0 4 8 0 1 pl a s m a tr o u g h c o n c e ntr ati o n s, i m m u n o g e ni cit y (I M) t e sti n g
, 
c oll e cti o n of S M B G a n d h u n g er di ar y r e s ult s, a d v er s e e v e nt s ( A E s), c o n c o mit a nt 
m e di c ati o n/ pr o c e d ur e i nf or m ati o n, a n d q u alit y of lif e a s s e s s m e nt s will b e p erf or m e d 
a c c or di n g t o t h e s c h e d ul e of pr o c e d ur e s i n A p p e n di x A . 
S af et y a n d T ol er a bilit y 
E v al u ati o n s  
S af et y a n d t ol er a bilit y a s s e s s m e nt s i n cl u d e: A E s, vit al si g n s a n d w ei g ht, p h y si c al 
e x a mi n ati o n s, cli ni c al l a b or at or y t e st s, E C G s, e c h o c ar di o gr a m s, u s e of c o n c o mit a nt 
m e di c ati o n s, a n d i n d e p e n d e ntl y a dj u di c at e d e v e nt s of p a n cr e atiti s a n d M A C E f or 
I SI S 3 0 4 8 0 1  a s c o m p ar e d t o p l a c e b o 
Effi c a c y E v al u ati o n s  
Pri m ar y E n d p oi nt:  
T h e eff e ct  of I SI S  3 0 4 8 0 1  a s c o m p ar e d t o pl a c e b o o n t h e p er c e nt c h a n g e fr o m B a s eli n e  
i n f a sti n g tri gl y c eri d e s ( T G) at  M o nt h 3  
S e c o n d ar y E n d p oi nt s:  
 
C h a n g e fr o m B a s eli n e i n h e p ati c st e at o si s ( a s a s s e s s e d b y h e p ati c f at fr a cti o n 
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 [ M RI ]) 
 
C h a n g e fr o m B a s eli n e i n h e m o gl o bi n A 1 c ( H b A 1 c )  
 
A c o m p o sit e e n d p oi nt at M o nt h 6 f or p er c e nt of p ati e nt s w h o  a c hi e v e  
a.  ≥ 4 0 % r e d u cti o n i n f a sti n g T G, a n d  
b.  ≥ 3 0 % r e d u cti o n of h e p ati c f at fr a cti o n p er c e nt  
 
C h a n g e i n p ati e nt -r e p ort e d o ut c o m e s ( P R O): 
o  
Di s e a s e b ur d e n s c or e  
o  
P ati e nt -r e p ort e d p ai n 
o  
P ati e nt -r e p ort e d h u n g er 
 
Q u alit y of lif e  
 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
2 3
 
P R O T O C O L S Y N O P SI S C o nti n ue d  
Effi c a c y E v al u ati o n s  
C o nti n u e d  
P h ar m a c o ki n eti c 
E v al u ati o n s  
Pl a s m a s a m pl e s will b e t a k e n fr o m all p ati e nt s f or t h e m e a s ur e m e nt of I SI S  3 0 4 8 0 1 
tr o u g h a n d p o st-tr e at m e nt l e v el s t hr o u g h o ut tr e at m e nt a n d d uri n g t h e p o st-tr e at m e nt 
F oll o w -u p p eri o d.  Pl a s m a s a m pl e c oll e cti o n ti m e p oi nt s ar e d et ail e d i n A p p e n di x A  a n d 
A p p e n di x C . 
St ati sti c al 
C o n si d er ati o n s  
F or all li pi d p ar a m et er s t h e b a s eli n e i s d efi n e d a s t h e a v er a g e of D a y 1 pr e -d o s e 
a s s e s s m e nt a n d t h e l a st f a sti n g m e a s ur e m e nt pri or t o D a y 1 .  T h e pri m ar y a n al y si s ti m e 
p oi nt i s at t h e e n d of M o nt h 3 w h er e t h e v al u e at pri m ar y a n al y si s ti m e p oi nt i s d efi n e d 
a s t h e a v er a g e of W e e k 1 2 a n d W e e k 1 3 f a sti n g a s s e s s m e nt s, t h e v al u e at M o nt h 6 i s 
d efi n e d a s t h e a v er a g e of W e e k 2 5 a n d W e e k 2 6 a n d t h e v al u e at M o nt h 1 2 i s d efi n e d 
a s t h e a v er a g e of W e e k 5 1 a n d W e e k 5 2 f a sti n g a s s e s s m e nt s.  
T h e pri m ar y effi c a c y a n al y si s will b e t h e c o m p ari s o n of p er c e nt c h a n g e s fr o m B a s eli n e  
t o t h e pri m ar y a n al y si s ti m e p oi nt i n f a sti n g T G b et w e e n t h e I SI S 3 0 4 8 0 1  3 0 0 m g q w 
gr o u p a n d t h e pl a c e b o gr o u p i n t h e F ull A n al y si s S et . 
A n al y s e s will al s o b e p erf or m e d i n w hi c h t h e a b o v e pri m ar y a n d s e c o n d ar y e n d p oi nt s 
ar e e v al u at e d at t h e M o nt h 6 , M o nt h 9 a n d M o nt h 1 2 a n al y si s ti m e p oi nt s, w h er e 
a p pli c a bl e.  
A n i nt eri m a n al y si s of t h e st u d y i s n ot pl a n n e d .  
S a m pl e Si z e C o n si d er ati o n s:  B a s e d u p o n pri or cli ni c al tri al e x p eri e n c e wit h 
I SI S 3 0 4 8 0 1 , it i s e sti m at e d t h at t h e st a n d ar d d e vi ati o n ( S D) of t h e p er c e nt c h a n g e i n 
t ot al T G i s a p pr o xi m at el y 40 % .  Wit h 2 0 I SI S 3 0 4 8 0 1  3 0 0 m g o n c e -w e e kl y p ati e nt s a n d 
2 0  pl a c e b o p ati e nt s t h er e w o ul d b e a p pr o xi m at el y 8 0 % p o w er t o d et e ct a 4 0 % diff er e n c e 
i n T G l e v el s b et w e e n tr e at m e nt gr o u p s at a n al p h a l e v el of 0. 0 5, a s s u mi n g 5 0 % 
r e d u cti o n i n t h e I SI S 3 0 4 8 0 1  tr e at e d p ati e nt s a n d 1 0 % r e d u cti o n i n t h e pl a c e b o p ati e nt s. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
2 4
 
P R O T O C O L S Y N O P SI S C o nti n ue d  
St ati sti c al 
C o n si d er ati o n s  
C o nti n u e d  
A s a m pl e si z e of 3 5 p ati e nt s ( 2 0 a cti v e a n d 1 5 c o ntr ol) pr o vi d e s 9 2 % p o w er t o d et e ct a 
li v er f at tr e at m e nt diff er e n c e of 4. 7 % b a s e d o n a b et w e e n p ati e nt st a n d ar d d e vi ati o n of 
4 % a n d a t w o -si d e d al p h a o f 0. 0 5. 
Eli gi bl e p ati e nt s will b e r a n d o mi z e d 1: 1 (I SI S  3 0 4 8 0 1: pl a c e b o) a n d str atifi e d b y F P L 
Gr o u p a s si g n m e nt.  
 
Gr o u p 1 will c o n si st of p ati e nt s wit h t h e F P L p h e n ot y p e a n d g e n eti c v ari a nt s of 
F P L 
 
Gr o u p 2 will c o n si st of p ati e nt s wit h t h e F P L p h e n ot y p e, b ut  l a c ki n g a g e n eti c 
v ari a nt, a n d h a vi n g a c o nfir m e d f a mil y hi st or y of F P L or a b n or m al a n d si mil ar 
f at di stri b uti o n, pl u s 1 mi n or crit eri o n 
 
Gr o u p 3 will c o n si st of t h o s e wit h t h e F P L p h e n ot y p e, b ut wit h o ut eit h er a 
g e n eti c v ari a nt or f a mil y hi st or y, pl u s 2 mi n or crit eri a a n d a B MI  < 3 5 k g/ m 2  
S p o n s or  
I o ni s P h ar m a c e uti c al s, I n c. 
C oll a b or at or  
A k c e a T h er a p e uti c s  
 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
2 5
 
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  
 
 
S C R E E NI N G A N D  
DI E T S T A BI LI Z A TI O N 
P E RI O D  
W e e k s -6 t o - 1 
E A R L Y 
T E R MI N A TI O N 
( E T) 
F oll o w W e e k 5 2 
S c h e d ul e of 
Pr o c e d ur e s at E T; 
P ati e nt str o n gl y 
e n c o ur a g e d t o vi sit 
cli ni c f or p o st -tr e at m e nt 
a s s e s s m e nt s  
T R E A T M E N T P E RI O D  
W e e k s 1 t o 5 2  
W e e kl y a d mi ni str ati o n of S C 3 0 0 m g q w 
I SI S 3 0 4 8 0 1 or pl a c e b o.  
R o uti n e s af et y a s s e s s m e nt s.  P K a n d 
P D/ effi c a c y a s s e s s m e nt s at s p e ci fi e d 
ti m e p oi nt s 
O P E N L A B E L E X T E N SI O N 
P E RI O D  
U p t o 1 -y e ar tr e at m e nt p eri o d  
3 0 0 m g I SI S 3 0 4 8 0 1 o n c e p er w e e k, wit h 
a n o pti o n f or a n a d diti o n al 1 y e ar of 
tr e at m e nt 
P O S T -T R E A T M E N T 
E V A L U A TI O N P E RI O D  
W e e k s 1 0 5 t o 1 1 7  
or W e e k s 5 3 t o 6 5 f or p ati e nt s n ot 
e nt eri n g t h e O L E  
S af et y, effi c a c y, P K a n d P D 
a s s e s s m e nt s  
E A R L Y 
T E R MI N A TI O N 
( E T) 
F oll o w W e e k 1 0 4 
S c h e d ul e of 
Pr o c e d ur e s at E T; 
P ati e nt str o n gl y 
e n c o ur a g e d t o vi sit 
cli ni c f or p o st -tr e at m e nt 
a s s e s s m e nt s  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
2 6
 
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 G L  
ac q uire d ge neralize d li p o d ystr o p h y 
A L T  
ala ni ne a mi n otra nsferas e ( S G P T)  
A N A  
a nti n uclear a nti b o d y 
A N C O V A  
a nal ysis of c o varia nce  
A P L  
ac q uire d p artial  li p o d ystr o p h y 
 
 
 
 
a p o C- III 
a p oli p o pr otei n C- III 
a p o E 
a p oli p o pr otei n E 
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 MI  
b o d y mass i n de x 
B P  
bl o o d press ure 
B U N  
bl o o d urea nitr o ge n 
C B C  
c o m plete bl o o d c o u nt 
C G L  
c o n ge nital ge neralize d li p o d ystr o p h y  
C T  
c o m p ute d t o m o gra p h y 
 
 
D S M B  
Data a n d Safet y M o nit ori n g B oar d 
E C G  
electr ocar di o gra m  
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  
E T  
earl y ter mi nati o n  
F A S  
f ull a nal ysis set 
F P G  
fasti n g plas ma gl u c ose 
F P L  
fa milial partial li p o d ystr o p h y 
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 L P - 1 
gl uca g o n-li ke pe pti de 1 
H A V  
he patitis A vir us  
 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
2 7
 
S T U D Y G L O S S A R Y  C o nti n ue d  
A b bre vi ati o n  
Defi niti o n  
H Bs A g  
he patitis B s urface a nti ge n  
H b A 1 C  
he m o gl o bi n A 1 C 
H C V  
he patitis C vir us  
H D L -C  
hi g h -de nsit y li p o pr otei n c h olester ol  
h E R G  
h u ma n et her-a- g o -g o  
HI V  
h u ma n i m m u n o deficie nc y vir us 
 
 
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 nisati o n 
I D L 
i nter me diate- de nsit y li p o pr otei n 
I E C 
I n d e pe n de nt Et hics C o m mittee 
I M 
i m m u n o ge nicit y 
I N R 
inter nati o nal n or malize d rati o  
I R B 
I nstit uti o nal Re vie w B oar d 
I SI S 3 0 4 8 0 1 
a ntise nse i n hi bit or of a p oli p o pr otei n C 3 
I T T 
i nte nt-t o-treat 
I X R S 
interacti ve v oice/i nter net res p o nse s yste m  
L C RI S  
l ocal c uta ne o us reacti o ns at t he i njecti o n site 
L D L -C  
l o w-de nsit y li p o pr otei n c h olester ol  
L P L  
li p o pr otei n li pase 
M A C E  
m aj or a d vers e car di o vasc ular e ve nt  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M RI  
ma g n etic res o n a nce i ma gi n g  
N C S  
n ot cli nicall y-si g nifica nt 
N O A E L  
n o o bser va ble a d vers e effect le vel  
N Y H A  
Ne w Y or k Heart Ass ociati o n  
O L E  
o pe n- la bel e xte nsi o n 
o n st u d y 
T he patie nt is ‘ o n st u d y’ fr o m si g ni n g of t he i nf or me d 
c o nse nt u ntil t heir last st u d y visit  
P C O S  
P ol yc ystic o var y s y n dr o me  
P F S  
pre -fille d s yri n ges 
P K  
p har mac o ki netic(s) 
P L  
partial li p o d ystr o p h y  
P T  
pr ot hr o m bi n ti me  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
2 8
 
S T U D Y G L O S S A R Y  C o nti n ue d  
A b bre vi ati o n  
Defi niti o n  
R E M S  
Ris k E val uati o n a n d Miti gati o n Strate g y  
S A E  
seri o us a d vers e e v e nt 
S A P  
Statistical A nal ysis Pla n  
 
 
S C  
s u bc uta ne o us(l y) 
S M B G  
self- m o nit ori n g bl o o d gl uc ose 
S D  
sta n dar d de viati o n 
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 patie nt 
S t u d y D r u g 
I SI S 3 0 4 8 0 1 or place b o 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T C h ol 
t otal c h olester ol 
T G  
tri gl yceri de(s) 
U L N  
u p per li mit of n or mal  
 
 
V L D L - C 
ver y l o w- de nsit y li p o pr ot ei n c h olester ol 
W B C  
w hite bl o o d cell 
W M A  
W orl d Me dical Ass ociati o n  
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
2 9
 
1. 
O B J E C TI V E S  A N D E N D P OI N T S  
1. 1 
O bjecti ves  
1. 1. 1 
Pri m ary O bjective  
T o e val uate t he effi cac y of I SI S 3 0 4 8 0 1 f or re d u cti o n i n se verit y of met a b olic dera n ge m e nt i n 
patie nts wit h F P L  wit h  h y p ertri gl yceri d e mia a n d u nc o ntr olle d dia betes. 
1. 1. 2 
Sec o n d ary O bjectives  
T o e val uate t he s afet y a n d t olera bilit y of I SI S 3 0 4 8 0 1 i n patie nts wit h F P L. 
T o f urt her e val uate t he r ole of ser u m T Gs i n m o d ulati n g i ns uli n resista nce i n F P L p atie nts a n d 
t he i m pact of T Gs r e d ucti o n o n a di p ose tiss ue distri b uti o n i n F P L patie nts. 
1. 2 
E n d p oi nts  
1. 2. 1  
Pri m ary E n d p oi nt 
T he pri mar y efficac y a n al ysis will be t he c o m paris o n of perce nt c ha n ges fr o m Baseli ne  t o t he 
pri mar y a nal ysis ti me p oi nt i n fasti n g T G bet w ee n I SI S  3 0 4 8 0 1 3 0 0 m g o nce-wee kl y  gr o u p a n d 
place b o gr o u p i n t he F ull A nal ysis Set ( F A S). 
1. 2. 2  
Sec o n d ary E n d p oi nts 
 C ha n ge fr o m Baseli ne i n h e patic steat osis (as assesse d b y h e patic fat fracti o n usi n g 
ma g n etic res o n a nce i ma gi n g [ M RI])  
 C ha n ge fr o m Baseli ne i n he m o gl o bi n A 1c ( H b A 1 c)  
 A c o m p osite e n d p oi nt at M o nt h 6 f or perce nt of p atie nts w h o ac hie v e  
a. ≥ 4 0 % re d ucti o n i n fasti n g T G, a n d  
b. ≥ 3 0 %  re d ucti o n of h e patic fat fracti o n perce nt 
 C ha n ge i n p atie nt -re p orte d o utc o mes ( P R O): 
o  Disease b ur d e n sc or e  
o  Patie nt -re p orte d p ai n 
o  Patie nt -re p orte d h u n ger 
o  Q ualit y of lif e  

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
3 0
 
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 
Li p o d ystr o p h y s y n dr o mes are a gr o u p of rare meta b olic diseases c haracterize d b y selecti ve l oss 
of a di p ose tiss ue t hat lea ds t o ect o pic fat de p osi ti o n i n li ver a n d m uscle a n d t he de vel o p me nt of 
i ns uli n resista nce, dia betes, d ysli pi de mia a n d fatt y li ver disease (Gar g 2 0 0 4 ; C ha n a n d Oral  
2 0 1 0 ; Gar g 2 0 1 1 ; S h ul ma n 2 0 1 4 ). 
T hese s y n dr o mes are cate g orize d acc or di n g t o t he distri b uti o n of fat l oss i nt o ge neralize d or 
partial a n d acc or di n g t o t he u n derl yi n g e ti ol o g y as i n herite d or ac q uire d ( Gar g 2 0 0 4; 
C ha n a n d Oral 2 0 1 0; Gar g 2 0 1 1).  

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
3 1
 
T hese s y n dr o mes c o nstit ute a si g nifica nt me dical u n met nee d as t hese patie nts are refract or y t o 
c urre nt t hera pies, mai nl y use d t o treat dia betes a n d ele vate d T G le vels, i n a n atte m pt t o re d uce 
t he ris k of seri o us ass ociate d c o m plicati o ns (c or o nar y arter y disease, dia betic ne p hr o pat h y, 
cirr h osis a n d pa ncreatitis). 
As s uc h, i n Fe br uar y 2 0 1 4, t he F D A a p pr o ve d M y ale pt ( metrele pti n) as re place me nt t hera p y t o 
treat t he c o m plicati o ns of le pti n deficie nc y i n a d diti o n t o diet i n patie nts wit h c o n ge nital or 
ac q uire d ge neralize d li p o d ystr o p h y.  T he safet y a n d effecti ve ness of M yale pt was e val uate d i n 
2 o pe n-la bel st u dies c o n d ucte d at  t he NI H, w hic h i ncl u de d 7 2 patie nts ( 4 8 wit h ge neralize d 
li p o d ystr o p h y a n d 2 4 wit h partial li p o d ystr o p h y [ PL]) wit h dia betes, hi g h T G, a n d ele vate d 
le vels of fasti n g i ns uli n.  T he best res ults were ac hie ve d i n patie nts wit h ge neralize d 
li p o d ystr o p h y w h o ha d l o w le pti n le vels ( mea n [ S D]: 1. 3 [ 1. 1] n g/ m L), w hile patie nts wit h 
partial li p o d ystr o p h y w h o ha d a wi der ra n ge of baseli ne le pti n val ues ( mea n [ S D]: 
4. 9 [ 3. 1] n g/ m L) ha d a m ore varie d a n d atte n uate d res p o nse.  Beca use of t he ris ks ass ociate d 
wit h t he de vel o p me nt of ne ut ralizi n g a nti b o dies a n d l y m p h o ma, M yale pt is a vaila ble o nl y 
t hr o u g h a ris k e val uati o n a n d miti gati o n strateg y ( R E M S) pr o gra m, w hic h re q uires prescri ber 
a n d p har mac y certificati o n a n d s pecial d oc u me ntati o n ( C ha n et al. 2 0 1 1 ; M yale pt, F D A Briefi n g  
D oc u me nt 2 0 1 3 ). 
At t he prese nt ti me, t he S p o ns or d oes n ot i nte n d t o st u d y t he ge neralize d f or ms f or w hic h a 
s pecific t hera p y e xists ( metrele pti n) n or t he ac q uire d f or ms of t he partial li p o d ystr o p h y dis or ders 
beca use of t he heter o ge neit y of eti ol o gies, s o me iatr o ge nic, a n d t he hi g h i nci de nce of ass ociate d 
i m m u ne dis or ders i n t hese p o p ulati o ns.  T heref ore, t his st u d y will f oc us o nl y o n patie nts wit h t he 
c o n ge nital f or m of t he partial li p o d ystr o p h y dis or ders a n d, a m o n g t h ose, o n t he m ost se vere 
s u bt y pe, patie nts wit h fa milial partial li p o d ystr o p h y, or F P L.  
Fa milial Partial Li p o d ystr o p h y ( F P L) is a n or p ha n disease f or w hic h n o s pecific p har mac ol o gic 
treat me nt c urre ntl y e xists.  F P L was descri bed i n t he 1 9 7 0s i n de pe n de ntl y b y K ö b berli n g a n d 
D u n ni ga n ( D u n ni ga n et al. 1 9 7 4 ; K ö b berli n g et al. 1 9 7 5 ), a n d is t he m ost c o m m o n s u bt y pe of 
i n herite d P L (Nati o nal Or ga nizati o n f or Rare Dis or ders [ N O R D] 2 0 1 2 ).  It has bee n esti mate d 
t hat F P L affects a p pr o xi matel y 0. 2 i n 1 0, 0 0 0 pe o ple i n t he E ur o pea n U ni o n, w hic h is e q ui vale nt 
t o a t otal of ar o u n d 1 0, 0 0 0 pe o ple (C o m mittee f or Or p ha n Me dici nal Pr o d ucts 2 0 1 2 ).  F P L 
e nc o m passes se veral s u bt y pes differe ntiate d b y t h e u n derl yi n g ge netic m utati o n ( 6 F P L s u bt y pes 
a n d m utati o ns i n 5 ge nes ha ve bee n i de ntifie d ).  F P L t y pe 1, K ö b berli n g variet y has bee n 
re p orte d i n a ha n df ul of i n di vi d uals a n d its m olec ular basis is u n k n o w n.  F P L t y pe 2, D u n ni ga n 
variet y is t he m ost c o m m o n f or m a n d t he m ost we ll c haracterize d dis or der a n d is d ue t o misse nse 
m utati o ns i n t he A a n d C L M N A ge ne.  F P L t y pe 3 has bee n re p orte d i n 3 0 patie nts a n d is d ue t o 
m utati o ns i n t he P P A R  ge ne.  F P L t y pe 4 has bee n re p orte d i n 5 patie nts a n d is d ue t o m utati o ns 
i n t he P LI N 1 ge ne.  F P L t y pe 5 has bee n re p orte d i n 4 me m bers of a fa mil y w h o prese nte d wit h 
i ns uli n resista nce a n d dia betes a n d is d ue t o m utati o ns i n t he A K T 2 ge ne.  T he last s u bt y pe, 
A ut os o mal Recessi ve F P L has bee n i de ntifie d re ce ntl y i n 1 patie nt wit h h o m oz y g o us m utati o ns 
i n CI D E C.  S o me i n di vi d uals wit h F P L d o n ot have m utati o ns i n a n y of t hese ge nes, s u g gesti n g 
t hat a d diti o nal, as yet u ni de ntified ge nes ca n ca use t he dis or der ( He gele et al. 2 0 0 7 ; Gar g 2 0 1 1 ; 
Nati o nal Or ga nizati o n f or Rare Dis or ders [ N O R D] 2 0 1 2). 
T he dia g n osis of F P L is mai nl y cli nical a n d nee d s t o be c o nsi dere d i n patie nts prese nti n g wit h 
t he tria d of i ns uli n resista nce ( wit h or wit h o ut o vert dia betes), si g nifi ca nt d ysli pi de mia i n t he 

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
3 2
 
f or m of h y pertri gl yceri de mia, a n d fatt y li ver (H ua n g- D ora n et al. 2 0 1 0 ).  Patie nts ofte n prese nt 
wit h dia betes a n d se vere i ns uli n resista nce re q uiri n g hi g h d oses of i ns u li n.  Ot her e vi de nce of 
se vere i ns uli n resista nce is pr o vi de d b y t he prese nce of aca nt h osis ni grica ns a n d p ol yc ystic o var y 
s y n dr o me ( P C O S) ( wit h s y m pt o ms li ke h y pera n dr o genis m a n d oli g o me n orr hea).  S o me patie nts 
de vel o p se vere h y pertri gl yceri de mia res ulti n g i n e pis o des of pa ncreatitis.  I n ma n y patie nts, t he 
T G le vels re mai n persiste ntl y ele vate d des pite f ull y o pti mize d t hera p y or diet m o dificati o ns.  
Ra di o gra p hic e vi de nce of he patic steat osis or steat o he patitis wit h he pat o me gal y a n d/ or ele vate d 
tra nsa mi nases is c o m m o n (Ha n dels ma n et al. 2 0 1 3 ).  Patie nts wit h t he D u n ni ga n variet y ha ve a 
hi g her ris k of c or o nar y arter y disease ( He gele 2 0 0 1 ).  Alt h o u g h ver y rare, patie nts wit h a s pecific 
m utati o n i n t he L M N A ge ne are at a n i ncrease d ris k of car di o m y o pat h y a n d its ass ociate d 
c o m plicati o ns, c o n gesti ve heart fa il ure a n d c o n d ucti o n defects. 
T here is li mite d nat ural hist or y data, m ostl y cr oss-secti o nal a n d deri ve d fr o m p u blicati o n of 
baseli ne c haracteristics of patie nts e nteri n g a cli nical trial ( A h me d et al. 2 0 1 3 ; Bi da ult et al.  
2 0 1 3 ; Di ker- C o he n et al. 2 0 1 5 ; Ajl u ni al. 2 0 1 6 ; A ki nci et al. 2 0 1 7 ).  T he e vi de nce t hat F P L 
pr o gresses o ver ti me c o mes fr o m a pr os pecti v e, o pe n-la bel NI H st u d y w it h o n g oi n g e nr oll me nt 
si nce 2 0 0 0 ( N = 8 7).  Data a nal yze d i n 2 0 1 4 s h o we d t hat meta b olic ma nifestati o ns of t he c o h ort 
of 3 2 partial li p o d ystr o p h y patie nts (i ncl u di n g 2 5 F P L) were as se vere as t h ose of t he c o h ort of 
ge neralize d li p o d ystr o p h y ( N = 5 5) , w hic h is rec o g nize d as a m ore se vere f or m of li p o d ystr o p h y 
( Di ker- C o he n et al. 2 0 1 5).  
Patie nts wit h F P L ha ve b ot h a partial l oss a n d mal d istri b uti o n of a di p ose tiss ue lea di n g t o t heir 
disti nct p he n ot y pe.  I n ma n y of t hese patie nts m utati o ns i n pr otei ns i n v ol ve d i n a di p oc yte 
differe ntiati o n, fatt y aci d u pta ke b y a di p oc ytes, tri g l yceri de s y nt hesis, or li pi d dr o plet f or mati o n 
ha ve bee n i de ntifie d ( Gar g 2 0 1 1 ; Ha n dels ma n et al. 2 0 1 3).  D ue t o t his se vere d ysf u ncti o n of 
a di p ose tiss ue F P L patie nts ha ve m uc h l o we r T G st ora ge ca pacit y t ha n patie nts wit h 
h y pertri gl yceri de mia wit h o ut F P L, hi g hli g hti n g t he i m p orta nce of T Gs i n t he pat h o p h ysi ol o g y of 
F P L.  Plas ma T G le vels i n F P L patie nts varie d  acr oss st u dies fr o m mea n ( 2 5- 7 5 perce ntile) 
4 8 3 m g/ d L ( 2 3 2, 8 5 6) ( Di ker- C o he n et al. 2 0 1 5),  me dia n ( 2 5- 7 5 perce ntile) 3 4 2 m g/ d L ( 2 7 9, 
8 0 1) ( A ki nci et al. 2 0 1 7), mea n 3 8 3 m g/ d L ( Bi d a ult et al. 2 0 1 3), me dia n 3 8 9 m g/ d L ( 1 5 5- 3 4 5 5) 
( A h me d et al. 2 0 1 3) a n d mea n 1 0 5 8 m g/ d L ( Ajl u ni et al. 2 0 1 6).  It is esti mated t hat 1/ 4 t o 1/ 5 of 
patie nts wit h F P L ma y ha ve T G le vels > 5 0 0 m g/ d L. 
D ue t o i na bilit y of a di p ose tiss ue t o acc o m m o date e xcess T Gs, T Gs are de p osite d i n hi g her 
a m o u nts i n or ga ns ot her t ha n a di p ose tiss ue t hat  are less well a da pte d t o e xcess li pi d st ora ge 
(“ect o pic fat”) ( H ua n g- D ora m et al. 2 0 1 0; Gar g 2 0 1 1; Ha n dels ma n et al. 2 0 1 3; N olis 2 0 1 4 ; 
R o b bi ns a n d Sa va ge 2 0 1 5 ).  T his ect o pic fat acc u m ulati o n has bee n f o u n d i n a n d ar o u n d ma n y 
or ga ns a n d is m ost clearl y ass ociate d wit h me ta b olic a b n or malities i n t he li ver, pa ncreas a n d 
s keletal m uscle c o ntri b uti n g t o se vere i ns uli n resista nce, he patic steat osis, dia betes a n d 
h y pertri gl yceri de mia a n d i ncrease d ris k of pa ncreatitis, n o n-alc o h olic  steat o he patitis a n d 
cirr h osis ( H ua n g- D ora m et al. 2 0 1 0; Slei g h et al. 2 0 1 2 ; Vatier et al. 2 0 1 3 ; R o b bi ns a n d Sa va ge 
2 0 1 5). 
Caref ul cli nical assess me nt of fat distri b uti o n t hr o u g h vis ual a n d p h ys ical e xa mi nati o n ca n 
c o nfir m t he dia g n osis.  Patie nts wit h F P L ha ve re d uce d s u bc uta ne o us fat i n t he li m bs a n d tr u ncal 
re gi o ns a n d ma y ha ve e xcess s u bc uta ne o us fat de p ositi o n i n nec k, face a n d i ntra-a b d o mi nal 
re gi o ns.  Patie nts wit h t he D u n ni ga n variet y ha ve n or mal b o d y fat dist ri b uti o n i n c hil d h o o d a n d 

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
3 3
 
gra d uall y l ose s u bc uta ne o us fat fr o m t he e xtr e mities a n d tr u n k ar o u n d t he ti me of p u bert y.  I n 
w o me n, t he l oss of fat ma y be m ost stri ki n g i n t he b utt oc ks a n d hi ps.  At t he sa me ti me t hese 
patie nts acc u m ulate fat o n t he face (“ d o u ble c hi n”), nec k a n d u p per bac k (“ C us hi n g oi d 
a p peara nce wit h b uffal o h u m p”).  T he e xte nt of a di p ose tiss ue l oss us uall y deter mi nes t he 
se verit y of t he meta b olic a b n or malities.  Patie nts dis pla y pr o mi ne nt m usc ularit y a n d 
p hle b o me gal y (e nlar ge d vei ns) i n t he e xtre mities a n d c o m plai n of dis pr o p orti o nate h y per p ha gia.  
T he c o n diti o n i n fe males is m ore easil y rec o g nize d  t ha n i n me n, a n d s o is re p orte d m ore ofte n.  
Patie nts ma y als o ha ve a fa mil y hist or y of si milar p h ysical a p peara nce a n d/ or fat l oss. 
Ge netic testi n g, w he n a vaila ble, is c o nfir mat or y. ( He gele et al. 2 0 0 7 ; H ua n g- D ora n et al. 2 0 1 0 ; 
Gar g 2 0 1 1 ). 
C urre nt treat me nt i ncl u des lifest yle m o dificati o n s uc h as re d uci n g cal oric i nta ke a n d i ncreasi n g 
e ner g y e x pe n dit ure via e xercise.  C o n ve nti o nal t her a pies use d t o treat se vere i ns uli n resista nce 
( metf or mi n, t hiaz oli di ne di o nes, Gl uca g o n-li ke pe pti de 1s [ G L P- 1], i ns uli n), a n d/ or hi g h T Gs 
( dietar y fat restricti o n, fi brates, fis h oils) are n ot ver y efficaci o us i n t hese patie nts (C ha n a n d  
Oral 2 0 1 0 ). 
Fa milial Partial Li p o d ystr o p h y is a n ultra- or p ha n i n dicati o n f or w hic h t here is a si g nifica nt 
u n met me dical nee d.  Dia betes, he patic steat osis, a n d h y pertri gl yceri de mia ass ociate d wit h t his 
c o n diti o n ca n lea d t o seri o us c o m plicati o ns ( Ha n dels ma n et al. 2 0 1 3 ) s uc h as: 
 Ac ute pa ncreatitis, es peciall y w he n tri gl yceri de le vels are > 1, 0 0 0 m g/ d L 
 Accelerate d micr o vasc ular c o m plicat i o ns fr o m u nc o ntr olle d dia betes 
 Accelerate d car di o vasc ular disease fr o m li pi d a b n or malities a n d i ns uli n resista nce 
 Steat o he patitis t hat ca n pr o gre ss t o cirr h osis a n d a n i ncrease d ris k of he pat ocell ular 
carci n o ma 
 Pr otei n uric ne p hr o pat hies w hic h ca n pr o gress t o e n d sta ge re nal disease 
I n patie nts wit h Ge neralize d Li p o d ystr o p h y t he meta b olic c o m plicat i o ns are partiall y relate d t o 
le pti n deficie nc y, a n d ca n be a meli orate d i n part b y le pti n re place me nt.  H o we ver, le pti n 
deficie nc y al o ne ca n n ot e x plai n t h e se verit y of meta b olic disease i n patie nts wit h P L w h o ha ve 
varia ble le pti n le vels.  A rece nt st u d y s h o we d  t hat ele vate d a p o C-III pla ys a r ole i n t he 
h y pertri gl yceri de mia see n i n b ot h ge neralize d  a n d partial li p o d ystro p h y a n d mi g ht t heref ore 
re prese nt a t hera pe utic tar get i n t hese patie nts (Kassai et al. 2 0 1 5 ). 
B y re d uci n g a p o C-III a n d T G le vels, I SI S 3 0 4 8 0 1 ma y i m pr o ve t he meta b olic pr ofile of patie nts 
wit h F P L a n d re d uce t heir ris k of  ac ute pa ncreatitis.  I n a d ditio n, re d ucti o ns i n T G c o ul d i m pr o ve 
he patic steat osis a n d re d uce cirr h osis ris k. F u rt her m ore, t his mec ha nis m ma y als o i m pr o ve 
i ns uli n se nsiti vit y i n t hese patie nts a n d p ote ntiall y lea d t o a re d ucti o n i n t he c o m plicati o ns 
ass ociate d wit h dia betes.   
2. 2
 T her a pe utic
 
R ati o n ale
 
A p o C-III is a 7 9 a mi n o aci d gl yc o pr otei n s y nt hesize d pri nci pall y i n t he li ver ( O oi et al. 2 0 0 8 ; 
Fi g ure 1 ).  A p o C-III is a maj or re g ulator of li p o pr otei n meta b olis m a n d pla ys a pi v otal r ole i n 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
3 4
 
re g ulati n g pl as ma T G le v els ( C ha n et al. 2 0 0 8 ).  It is a c o m p o ne nt of T G -ric h li p o pr otei ns 
( T R Ls) a n d a p ote nt i n hi bit or of li p o pr otei n li pase ( L P L; Le mie u x et al. 2 0 0 3 ).  At hi g h er 
c o nce ntr ati o ns, a p o C- III als o i n hi bits t he acti vit y of he patic li pase ( Ki n n u n e n a n d E h n ol m 1 9 7 6 ), 
a n e nz y me w hic h pla ys a n i m p orta nt r ole i n t he c o n versi o n of de nse V L D L t o i nter me diate-
de nsit y li p o pr otei n ( I D L) a n d t o L D L (Me n di vil et al. 2 0 1 0 ), as well as i n t he re m o deli n g of 
H D L ( Br o w n et al. 2 0 1 0 ).  I n a d diti o n, i ncreas e d a p o C-III c o nte nt a d vers el y affects 
a p oli p o pr otei n E (a p o E)- me diate d he patic u pta k e of T G -ric h re m na nts (M a n n et al. 1 9 9 7 ).  T h us, 
ele vate d plas ma a p o C- III le vels are ass ociate d wit h i m paire d h y dr ol ysis a n d retar d e d cleara n ce 
of T G -ric h p articles, r es ulti n g i n t he acc u m ulati o n of V L D L- T G a n d c h yl o micr o ns i n plas ma a n d 
t he de vel o p me nt of h y pertri gl yceri de mia (It o et al. 1 9 9 0 ). 
 
Fi g ure 1 
A p o C -III Re g ul ates Li p o pr otei n Met a b olis m b y M ulti ple Mec h a nis ms  
Fr o m O oi et al. 2 0 0 8; A B C A 1  = A T P -bi n di n g c assette A 1, a p o  = a p oli p o pr otei n, C E  = c h olester ol ester, 
C E T P  = c h olester ol ester tr a nsfer pr otei n, F C  = free c h olester ol, H D L = hi g h -de nsit y li p o pr otei n, 
H L  = he p atic li p ase, I D L  = i nter me di ate-de nsit y li p o pr ot ei n, L C A T  = lecit hi n c h olest er ol ac yltr a nsfer ase, 
L D L  = l o w-de nsit y li p o pr otei n, L D Lr  = L D L rece pt or, L P L  = li p o pr otei n li p ase, L S R = li p ol ysis-sti m ul ate d 
rece pt or, S R -B 1  = sc a ve n ger rece pt or B-1, T G  = tri gl yceri de, V L D L = ver y l o w -de nsit y li p o pr otei n.  
 
Alt h o u g h n ot t he pri mar y ai m of treat me nt, a gr o wi n g b o d y of h u ma n ge netic data ha v e 
de m o nstrate d ass oci ati o ns wit h f u ncti o nal m utati o ns affecti n g a p o C-III ge n e e x pressi o n a n d 
C V D ris k (Atz m o n  et al. 2 0 0 6 ; P olli n et al. 2 0 0 8 ; Peterse n et al. 2 0 1 0 ; Cr os b y et al. 2 0 1 4 ; 
J ørge nse n et al. 2 0 1 4 ).  H u ma n ge netic d ata ha v e de m o nstrate d p ositi ve p he n ot y pic 
c haracteristics wit h l oss of f u ncti o n m utati o ns i n a p o C-III e x pressi o n, a n d n o deleteri o us effects 
ha ve be e n re p orte d .  A n o vel n ull m utati o n i n t he a p o C-III ge ne ( R 1 9 X) w as i de ntifie d i n t he 
Herita bilit y a n d P he n ot y pe I nter v e nti o n ( H A PI ) h eart st u d y i n Ol d Or der A mis h i n di vi d uals w h o 
were  h eter oz y g o us carriers .  M utati o n carriers i n t his p o p ulati o n ha d a life-l o n g a p o C-III 
deficie nc y ( ~ 5 0 % of n or mal) t hat res ulte d i n l o wer plas ma T G le vels (fasti n g a n d p ost - pra n dial), 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
3 5
 
a car di o pr otecti ve li pi d pr ofile (i.e., hi g her H D L- C a n d l o wer L D L- C) a n d re d uce d 
at her oscler osis (as meas ure d b y c or o n ar y arter y calcificati o n)  c o m pare d wit h n o ncarri ers 
(P olli n  et al. 2 0 0 8 ).  A d diti o nall y, h o m oz y g osit y i n t he a p o C-III pr o m oter (A P O C 3 - 6 4 1 C C 
ge n ot y p e), i de ntifie d i n a gr o u p of As h ke n azi J e ws of a d va nce d a ge ( near or a b o ve 1 0 0 years of 
a ge), w as ass ociat e d wit h si g nifica ntl y l o wer le vels of a p o C-III, fa v ora ble li p o pr otei n pr ofile 
(i ncrease d H D L, re d uce d T G/ H D L, i ncrease d L D L particle size), l o wer i n ci de nce of 
h y perte nsi o n, greater i ns uli n se nsiti vit y, car di o vasc ular healt h, a n d l o n ge vit y c o m pare d t o 
c o ntr ols ( heter oz y g o us C A or h o m oz y g o us A A ge n ot y pes) ( Atz m o n  et al. 2 0 0 6 ). 
M ost rece ntl y, 2 st u dies usi n g a Me n d elia n ra n d o mizati o n a p pr oac h pr o vi de d c o m pelli n g 
e vi de nce t h at re d uci n g a p o C -III e x pressi o n ma y re d uce c or o nar y h eart d isease ris k (Cr os b y et al. 
2 0 1 4 ; J ør ge nse n et al. 2 0 1 4 ).  O ne ( 1)  st u d y i de ntifie d 4 rare varia nts i n a p o C-III t hat were 
ass ociate d wit h a 3 9 % re d ucti o n i n plas ma T G le v els (Cr os b y et al. 2 0 1 4).  T he varia nts w ere 
t he n teste d f or ass o ciati o n wit h C H D i n 1 1 0, 0 9 7 i n di vi d uals fr o m 1 5 differe nt st u dies.  M utati o n 
carri ers ha d a 4 0 % r e d ucti o n i n C H D c o m pare d t o n o n -carriers .  T h e ot her st u d y, usi n g a si milar 
strate g y (J ør ge nse n et al. 2 0 1 4 ) fo u n d 3 a p oC- III v aria nts  t hat were ass oci ate d wit h a 4 4 % 
re d ucti o n i n plas ma T G l e vels a n d i n a c o h ort of 7 5, 7 2 5 Da nes; carrie rs of t hese vari a nts ha d a 
4 1 % re d ucti o n i n C H D.  
I n c o ntrast t o t he a b o v e, a p o C-III p ol y m or p his ms ass ociate d wit h hi g her pl as ma T G ha v e als o 
bee n rece ntl y des cri be d ( Peterse n  et al. 2 0 1 0 ).  I n a c o h ort of lea n ( mea n b o d y mass i n de x 
[ B MI] = 2 4. 7 ± 3. 6 k g/ m 2) Asia n I n dia ns, carriers of a p o C-III varia nt alleles ( C- 4 8 2 T, T- 4 5 5 C, 
or b ot h) wer e n ote d t o ha ve si g nifica ntl y hi g h er pl as ma a p o C-III a n d T G le vels, a n d decreas e d 
a bilit y t o clear p ost -pra n dial plas ma T G fr o m t he circ ulati o n .  Ta ke n t o get her, t he a v aila ble data 
str o n gl y s u p p ort t he de v el o p me nt of a t hera p y t h at re d uces pl as ma a p o C-III le vels i n or der t o 
re d uce t h e ver y hi g h circ ulati n g T G  a n d c h yl o micr o n le vels t hat are acc o m pa nie d b y i ncreasi n g 
ris k f or ac ut e pa ncreatitis. 
P ote ntial mec ha nis ms t hat e x pla i n h o w a p o C-III i n hi biti o n res ults i n T G  re d ucti o n i n i ncl u de:  
(1) b y e n ha n ci n g t he acti vit y of L P L , ( 2) t hr o u g h p ote ntiall y e n h a nce d acti vit y of ot her li pas es 
als o i n v ol ve d i n t he meta b olis m a n d brea k d o w n of tri gl yceri des, s uc h as he patic li pase or 
e n d othelial li pase ( Ki n n u ne n a n d E h n ol m 1 9 7 6 ), a n d ( 3) it is k n o w n t hat a p o C-III i nteracts wit h 
a p o E, a n i m p orta nt fact or i n li ver re u pta ke of li pi d particles b y bl oc ki n g a p o E- me diate d u pta k e 
of li pi d particles i n t he li ver ( Bre yer et al. 1 9 9 9 ), a n d t heref ore, re d uci n g a p o C-III mi g ht e n ha nce 
a p o E- me diate d u pt a ke of li pi d particles.  I SI S 3 0 4 8 0 1- me diate d re d ucti o n of a p o C-III c o ul d be 
c o ntri b uti n g t o 1 or all of t hese mec ha nis ms res ulti n g i n t he o bser v e d p ote nt a n d s ustai ne d 
re d ucti o ns i n T G. 
T hr o u g h a n o vel, a p o C-III l o w eri n g mec h a nis m of acti o n, I SI S 3 0 4 8 0 1 ma y pr o vi de t he p ote ntial 
t o ma na ge T G  le v els a n d ass ociate d meta b olic d era n ge me nts  i n patie nts wit h F P L . 
2. 3 
I SI S 3 0 4 8 0 1 
2. 3. 1 
Mec h a nis m of Acti o n  
I SI S 3 0 4 8 0 1 is a sec o n d- ge n erati o n a ntise ns e oli g o n ucle oti de ( A S O) dr u g tar gete d t o h u ma n 
a p o C- III.  It is c o m ple me ntar y t o a re gi o n wit hi n t he 3ʹ u ntra nslate d re gi o n of t he a p o C- III 
m R N A a n d bi n ds t o t he m 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) 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
3 7
 
2. 3. 3 
Precli nic al E x perie nce  
I n hi biti o n of a p o C-III usi n g I SI S 3 0 4 8 0 1 has b ee n s h o w n t o p ote ntl y re d u ce he patic a p o C-III 
m R N A as well as plas ma a p o C- III pr otei n a n d T G i n a d ose- a n d ti me- d e pe n de nt fas hi o n i n 
se veral s pecies, i ncl u di n g h u ma n a p o C-III tra ns ge nic mice, a n d ot h er r o d e nt a n d m o n ke y 
m o dels.  Treat me nt wit h I SI S 3 0 4 8 0 1 als o res ulte d i n re d uce d V L D L a n d c h yl o micr o n T G a n d 
re d uce d p ost- pra n dial TG i n h y pertri gl yceri d e mic m o n ke ys ( Gra ha m et al. 2 0 1 3 ). 
T he p har mac o ki netics ( P K) a n d t o xicit y of I SI S 3 0 4 8 0 1 ha ve bee n assesse d i n mice, rats, a n d 
c y n o m ol g us m o n ke ys.  G e neral t o xicit y st u dies wit h I SI S 3 0 4 8 0 1 f or u p t o 3 9 wee ks of 
treat me nt f oll o we d b y a 2 0-wee k rec o v er y peri o d are c o m plet e .  T he precli nical t o xic ol o g y 
pr o gra m f or I SI S 3 0 4 8 0 1 c o nsists of si n gle- d os e safet y p har mac ol o g y st u dies i n t he m o n ke y 
(car di o v asc ular) a n d m o use ( ne ur o b e ha vi oral a n d p ul m o nar y assess me nt st u dies), i n vitr o a n d 
i n viv o ge netic t o xicit y assess me nt, re peat - d ose fertilit y a n d/ or d e vel o p me nt al re pr o d u cti ve 
t o xic ol o g y st u dies i n t he m o use a n d ra b bit a n d e val uati o n i n t he i n vitr o h u ma n Et her-á-g o -g o -
relate d ge n e ( h E R G) assa y. 
I SI S 3 0 4 8 0 1 treat me nt-relate d fi n di n gs i n mice a nd m o n ke ys w ere ge nerall y c o nsiste nt wit h 
t h ose e x pecte d f or t he 2′ -O -( 2-met h o x yet h yl)  (2′ -M O E )-class of A S Os .  Treat me nt -relate d 
fi n di n gs i ncl u de d eff ects c o nsiste nt wit h dr u g acc u m ulati o n i n tiss ues i n r o de nts a n d m o n ke ys, 
s pecies- de p e n de nt pr oi nfla m mat or y res p o nse i n r o de nts a n d m o n ke ys a n d c o m ple me nt acti vati o n 
a n d re d ucti o ns i n platelet c o u nts i n t he m o n ke y.  I n t he m o use a n d m o n ke y ge n eral t o xicit y 
st u dies, re d ucti o n of he p atic a p o C-III m R N A ( > 7 5 %) was n ot ass o ciate d wit h a n y fi n di n gs t hat 
c o ul d be c o nsi der e d rel ate d t o t he p har mac ol o gi c i n hi biti o n of a p o C- III f or u p t o 3 9 wee ks of 
treat me nt. 
T he l o n g-ter m, c hr o nic t o xic ol o g y st u dies i n r o de nts wit h I SI S 3 0 4 8 0 1 pr o d uce d a si g nifica nt 
pr oi nfla m mat or y res p o ns e t hat le d t o s u bse q ue nt effects o n t he h eart at hi g h d oses.  T he r o de nt 
s pecies ar e m ost se nsiti ve t o t he pr oi nfla m mat or y effects of a ntise nse m olec ules.  I m p orta ntl y, 
t hese eff ects o n t he h eart were n ot o bser ve d i n t he m o n ke y c hr o nic t o xicit y st u dies e ve n at t he 
hi g hest d oses teste d w her e dr u g e x p os ure was hi g h er t ha n t hat i n r o de nts. 
Beca use t hes e c ha n ges w ere n ot o bser v e d i n m o n ke ys, t he fi n di n gs i n t he h eart are c o nsi dere d t o 
be r o de nt-s pecific a n d n ot rele va nt t o h u ma ns.  Ne vert heless, s uc h effects are m o nit ora ble b y 
meas ure me nt of ec h o car di o gra m s a n d car diac tr o p o ni n I t hat will be i ncl u de d i n t his cli nical 
st u d y. 
I SI S 3 0 4 8 0 1 ca use d n o u nt o war d effects i n safet y p har mac ol o g y st u dies (i n vitr o a n d i n viv o) 
a n d was n o n- ge n ot o xic ( i n vitr o a n d i n viv o).  I SI S 3 0 4 8 0 1 ha d n o effects o n fertilit y or 
e mbr y o/fetal de v el o p me nt i n t he m o use or ra b bit re pr o d ucti ve t o xicit y st u dies.  I n t h ese st u dies, 
I SI S 3 0 4 8 0 1 was d etect e d i n place ntal tiss ue b ut n ot i n fetal tiss ue i n dicati n g t hat little, if a n y, 
dr u g was a ble t o cr oss t h e place nt a t o reac h t he fet us .  Re d ucti o n of a p o C- III m R N A ( 6 4 % i n 
males a n d 4 7 % i n fe m ales) als o di d n ot affect fertilit y or ca us e u nt o war d effects o n e m br y o/f etal 
de vel o p me nt i n mice. 
Detaile d i nf or mati o n c o n cer ni n g t he pr ecli nical st u dies c o n d ucte d wit h I SI S 3 0 4 8 0 1 ca n be 
f o u n d i n t he ISI S  3 0 4 8 0 1 I n v esti gat or’s Br oc h ure. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
3 8
 
2. 3. 4 
Cli nic al E x perie nce  
Detaile d i nf or mati o n c o n cer ni n g t he cli nical st u dies c o n d ucte d wit h I SI S 3 0 4 8 0 1 ca n be f o u n d i n 
t he I SI S 3 0 4 8 0 1 I n v esti gat or’s Br oc h ure.  A s u m mar y is i ncl u d e d bel o w. 
I SI S 3 0 4 8 0 1 has b ee n e v al uate d i n o ne P hase 1 st u d y a n d t w o P has e 2 st u dies, all d o u ble bli n de d 
a n d place b o c o ntr olle d.  T he t otal e x p os ures c o m prise 9 9 patie nts a n d healt h y v ol u nteers 
a d mi nistere d I SI S 3 0 4 8 0 1 fr o m 5 0 t o 4 0 0 m g s u b c uta ne o usl y u p t o 3 m o nt hs (c o m pare d t o 
3 7 a d mi nistere d place b o). 
All cli nical trials of I SI S  3 0 4 8 0 1 ha ve s h o w n ver y lar ge a n d cli nicall y m ea ni n gf ul re d ucti o ns i n 
fasti n g a p o C-III a n d T G ( ~ 8 0 % a n d 7 0 %, res pecti vel y, mea n re d u cti o n fr o m Baseli ne  wit h 
3 0 0 m g d ose) wit h a ver y hi g h d e gree of c o nsiste n c y of res p o ns e bet wee n t he differe nt patie nt 
gr o u ps.  T his i ncl u des h ealt h y v ol u nteers, patie nts wit h m o derate t o se vere h y pertri gl yceri d e mia 
n ot o n bac k gr o u n d T G- l o weri n g t her a p y, patie nts wit h m o derate t o se vere h y pertri gl yceri d e mia 
o n a bac k gr o u n d of sta bl e fi brate t h era p y, p atie nts wit h Fa milial C h yl o micr o ne mia S y n dr o me 
( F C S), a n d patie nts wit h h y pertri gl yceri d e mia a n d T 2 D M.  C o m paris o n of t he effects of 
I SI S 3 0 4 8 0 1 at t he 3 0 0 m g/ w k  d ose acr oss se v eral patie nt p o p ulati o ns is s h o w n i n Ta ble 1. 
T a ble 1 
Me a n Perce nt C h a n ge fr o m B aseli ne of Li pi d P ar a meters i n 
H y pertri gl yceri de mi a P atie nts Tre ate d wit h I SI S 3 0 4 8 0 1 ( 3 0 0 m g/ w k f or 
3 m o nt hs) i n P h ase 2 St u dies  
M e a n % ( S D) 
C h a n g e fr o m 
B a s eli n e  
M o n ot h er a p y i n 
H y p ertri gl y c eri d e mi a a n d 
T 2 D M ( N = 7)  
M e a n B a s eli n e T G  
2 5 9 m g/ d L  
M o n ot h er a p y i n 
H y p ertri gl y c eri d e mi a ( N = 1 1)  
M e a n B a s eli n e T G  
5 5 9 m g/ d L  
A d d -o n t o Fi br at e i n 
H y p ertri gl y c eri d e mi a ( N = 1 0)  
M e a n B a s eli n e T G  
3 9 4 m g/ d L  
A p o C -III 
- 8 8 % ( 6. 0)*  
- 8 0 % ( 9. 3)***  
- 7 1 % ( 1 3. 0)**  
Tri gl y c eri d e s  
- 7 2 % ( 8. 3)*  
- 7 1 % ( 1 4. 1)***  
- 6 4 % ( 8. 9)**  
H D L - C 
+ 4 0 % ( 1 9. 8)*  
+ 4 6 % ( 2 4. 0)***  
+ 5 2 % ( 2 3. 7)**  
* 
p ≤ 0. 0 5 v s . pl a c e b o ;    **p ≤ 0. 0 1 v s . pl a c e b o ;    *** p ≤ 0. 0 0 1 v s . pl a c e b o  
 
I n a d diti o n t o t he li pi d a nal ysis, t he effect of l o weri n g a p o C-III o n gl yce mic  c o ntr ol a n d i ns uli n 
se nsiti vit y w as e val u ate d i n t he s u b gr o u p of patie nts wit h h y pertri gl yceri d e mia a n d t y pe 2 
dia betes,  b y meas uri n g fr uct osa mi ne, gl ycate d al b u mi n, a n d H b A 1c a n d b y perf or mi n g a 
h y peri ns uli ne mic e u gl yce mic cla m p at Baseli ne  a n d at t he e n d of t he ra n d o mize d treat me nt 
peri o d. 
Treat me nt wit h I SI S 3 0 4 8 0 1 si g nifica ntl y re d uce d T G le vels ( 6 9 %, P = 0. 0 2) a n d i n d uce d a 5 7 % 
i m pr o ve me nt i n w h ole-b o d y i ns uli n se nsiti vit y ( P < 0. 0 0 1).  T he st u d y als o f o u n d a str o n g 
relati o ns hi p bet wee n e n h a nce d i ns uli n se nsiti vit y a n d b ot h plas ma a p o C-III (r = 2 0. 6 1, P = 0. 0 3) 
a n d T G re d u cti o n (r = 2 0. 6 8, P = 0. 0 1) ( Di ge ni o et al . 2 0 1 6). 
Statisticall y si g nifica nt decreases w ere o bs er ve d i n t he mea n c h a n ge fr o m Baseli ne i n % gl ycate d 
al b u mi n a n d i n fr uct osa mi ne 1 wee k  after t he l ast d ose a n d i n H b A 1c a n d fr uct osa mi ne at t he 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
3 9
 
e n d of t he F oll o w- u p Peri o d ( 3 m o nt hs after t he last d ose).  T hese si g nifica nt effects later i n t he 
F oll o w- u p Peri o d were li kel y a res ult of t he l o n g d urati o n of res p o ns e of I SI S 3 0 4 8 0 1. 
I n cli nical st u dies c o n d ucte d t o date, I SI S 3 0 4 8 0 1 has bee n w ell -t olerate d a n d has s h o w n a 
fa v ora bl e saf et y pr ofile.  T here h as bee n n o cli nical or la b orat or y e vi d e nce of dr u g-dr u g 
i nteracti o ns. 
I n t he c o m plete d st u dies, t here ha v e bee n n o v ol a nes orse n ass o ciate d la b orat or y a b n or malities 
s u g gesti ve of a n effect o n t he re nal (s er u m creati ni ne, pr otei n uria) or he pati c s yste ms (ala ni ne 
a mi n otra nsfer ase ( A L T), as partate a mi n otra nsferas e ( A S T), b ilir u bi n).  I n P hase 2 st u dies, t here 
was a mil d decr ease of pl atelet c o u nt ass oci ate d wit h v ola nes orse n a d mi nistrati o n t hat rec o v ere d 
i n t he p ost-treat me nt peri o d a n d was n ot ass oci ate d wit h platelet-relate d a d verse e v e nts ( A Es).  
I n t he bli n de d o n g oi n g cli nical trials of v ola nes ors e n, 6 patie nts o ut of 1 8 2 d ose d (a p pr o xi matel y 
1 1 0 recei vi n g v ola n es ors e n a n d 7 2 recei vi n g place b o) as of 2 7 Ma y 2 0 1 6 h a ve e x perie nce d m ore 
pr o n o u nce d f alls i n platelet c o u nt a n d ha v e ha d St u d y Dr u g  i nterr u pte d or st o p pe d as a 
c o nse q ue nce.  Of t h ese 6 patie nts, 2 of t he m ha d t o be h os pitalize d wit h platelet c o u nts less t ha n 
2 5, 0 0 0 / m m3 f or cl oser m o nit ori n g a n d treat me nt wit h c ortic oster oi ds.  I n 1 case t he p atie nt was 
als o a d mi nistere d i ntra ve n o us i m m u n o gl o b uli n (I VI G).  N o p atie nts ha d cli nicall y-rele va nt 
blee di n g, a n d platelet c o u nts rec o ver e d f oll o wi n g disc o nti n uati o n of d osi n g , wit h a d mi nistrati o n 
of c ortic oster oi ds ( +/- I VI G) i n t he 2 cases of p atie nts wit h platelet c o u nts  less t ha n 2 5, 0 0 0/ m m3. 
T he m ost fre q ue ntl y o bser ve d A Es  wit h I SI S 3 0 4 8 0 1 were l ocal reacti o ns at t he i njecti o n site .  
L ocal c uta n e o us reacti o ns at t he i njecti o n site ( L C RI S) defi ne d as t h ose e ve nts prese nti n g as 
eit her pai n, te n der ness, er yt he m a, pr urit us or s w elli n g occ urri n g o n t he da y of i njecti o n a n d 
persisti n g f or at least 2 d a ys wer e i nfre q u e nt ( ~ 1 5 % of i njecti o ns), were al m ost al wa ys mil d, 
res ol ve d s p o nta ne o usl y, were n o n-pr o gressi ve, a n d were n ot ass o ciate d wit h s yste mic se q u elae.  
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 d ose a n d s c he d ule selecte d f or t his st u d y is 3 0 0 m g per wee k f or 5 2 w ee ks.  T he d ose of 
3 0 0 m g per wee k is s u p p orte d b y b ot h t he c u m ulati ve n o ncli nical data a v aila ble t o date a n d t he 
P hase 2 cli nical data .  I n n o ncli nical st u dies, I SI S 3 0 4 8 0 1 treat me nt-relate d effects i n r o de nts a n d 
m o n ke ys w ere c o nsiste nt wit h dr u g acc u m ulati o n i n tiss ues a n d als o i ncl u de s pecies- s p ecific 
pr oi nfla m mat or y res p o ns es.  I n t he m o n ke y, t he n o o bser va ble a d vers e effect le vel  ( N O A E L) 
was defi ne d b y t h e c u m ulati ve cli nical pat h ol o g y res ults a n d hist o pat h ol o g y dat a pr o vi de a n 
a de q uate cli nical saf et y mar gi n .  N o ncli nical fi n di n gs were n ot c o nsi dere d t o be relate d t o t he 
p har mac ol o gic i n hi biti o n of a p o C- III. 
T he safet y d ata t o date s u g gest t hat I SI S 3 0 4 8 0 1 h as bee n w ell -t olerate d at d ose le vels u p t o 
3 0 0 m g i n patie nts wit h hi g h T G  (i n cl u di n g t y pe 2 dia betes patie nts a n d a d mi nistrati o n i n 
c o m bi nati o n wit h fi brates a n d stati ns) wit h t he m ost c o m m o n A Es  bei n g l ocal t o t he i njecti o n 
site a n d pre d o mi na ntl y mil d.  A p o ole d a nal ysis of safet y f or t h e P hase 2 st u dies di d n ot 
de m o nstrate a n y clear differe n ce i n safet y or t olera bilit y b et wee n t h e differe nt d oses teste d 
( 1 0 0 m g, 2 0 0 m g, a n d 3 0 0 m g per wee k f or 1 3 w ee ks).  A nal ysis of t he c o h orts i n w hic h 
I SI S 3 0 4 8 0 1 was st u die d at differ e nt d oses de m o nstrates d ose- d e pe n de nt p har mac ol o g y wit h 
res pect t o p har mac o d y n a mic effect o n t he tar get, a p o C- III, wit h a clear differe nce i n t he 
T G -l o weri n g effect bet w ee n t he diff ere nt d os es i n t he 1 0 0 m g t o 3 0 0 m g d ose ra n ge as c o m pare d 
t o place b o. 

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
4 0
 
I n a d diti o n t o t he n o ncli nical a n d cli nical e x perie nce of I SI S 3 0 4 8 0 1, t he d ose a n d sc he d ule of 
a d mi nistrati o n is s u p p orte d b y t he precli nical a n d cli nical safet y e x perie nce of se veral ot her 
2 ′- M O E- m o difie d A S Os t hat ha ve bee n a d mi nistere d i ntra ve n o usl y a n d S C i n m ulti ple cli nical 
st u dies at d oses u p t o 1 2 0 0 m g a n d f or treat me nt d urati o ns t hat e xcee d 2 4 m o nt hs ( Sa nt os et al.  
2 0 1 5 ). 
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 m ulti-ce nter, ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d st u d y wit h a n o pe n-la bel 
e xte nsi o n.  A p pr o xi matel y 4 0 t o  7 0 eli gi ble patie nts will be ra n d o mize d 1: 1 (I SI S 3 0 4 8 0 1: 
place b o) a n d stratifie d b y F P L Gr o u p assi g n me nt (see Secti o n 4. 2  Ra n d o mizati o n).  
T he st u d y will c o m prise t he f oll o wi n g peri o ds: 
 Scree ni n g.  A n u p t o 6- wee k Scree ni n g Peri o d, i ncl u di n g at least a 4- wee k diet 
sta bilizati o n p hase d uri n g w hic h patie nts will be e nc o ura ge d t o c o nti n ue o n t heir c urre nt 
diet. 
 Ra n d o mize d Treat me nt Peri o d.  F oll o wi n g sta bilizati o n, u p t o 7 0 eli gi ble patie nts will be 
ra n d o mize d 1: 1 t o recei ve I SI S 3 0 4 8 0 1 3 0 0 m g or place b o o nce- wee kl y f or 5 2 wee ks 
f oll o we d b y eit her: 
o  O pe n-la bel E xte nsi o n ( O L E) Peri o d w he n  patie nts will recei ve I SI S 3 0 4 8 0 1 3 0 0 m g 
o nce- wee kl y f or 5 2 wee ks.  F oll o wi n g t he Wee k 1 0 4 visit of t he O pe n- La bel 
E xte nsi o n Peri o d, patie nts will ha ve t he o pt i o n of c o nti n ui n g d osi n g f or u p t o a n 
a d diti o nal 5 2 wee ks. 
o  A 1 3- wee k P ost- Treat me nt E val uati o n Peri o d. 
T he pri mar y e n d p oi nt f or t he st u d y will be e val ua te d after t he last patie nt has c o m plete d t he 
Wee k 5 2/earl y ter mi nati o n ( E T) visit a n d will be base d o n t he perce nt c ha n ge fr o m Baseli ne i n 
fasti n g T G at t he pri mar y a nal ysis ti me p oi nt ( M o nt h 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 P atie nts 
U p t o 6 0 patie nts wit h F P L will be ra n d o mize d.  Sa m ple size c o nsi derati o ns are disc usse d i n 
Secti o n 1 0. 2 . 
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 a n u p t o 6- wee k Scree ni n g Peri o d a n d a 5 2- wee k Ra n d o mize d 
Treat me nt Peri o d.  F oll o wi n g t he Wee k 5 2 visi t, patie nts ma y e nter a 5 2- wee k O L E Peri o d 
f oll o we d b y a 1 3- wee k P ost-treat me nt E val uati o n Peri o d.  A n o pti o n f or patie nts c o m pleti n g t he 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
4 1
 
5 2- wee k O L E peri o d will be a n a d diti o nal 1 year of treat me nt.  Patie nts ma y p artici pate u p t o a 
t otal of 3 years o n st u d y. 
Please ref er t o t he Sc h e d ule of Pr oce d ures i n A p p e n di x A . 
3. 4. 1 
Scree ni n g  
A peri o d of 6 w ee ks is gi ve n t o c o m plete t he scree ni n g a n d b aseli ne assess me nts o utli ne d i n t he 
Sc he d ule of Pr oce d ures i n A p pe n di x A. 
3. 4. 2  
R a n d o mize d Tre at m e nt  Peri o d  
T he ra n d o mize d treat me nt peri o d is 5 2 wee ks.  Eli gi ble patie nts will re p ort t o t he St u d y Ce nt er 
f or assess me nts at s pecifi e d i nter vals t hr o u g h o ut t he 5 2-wee k treat me nt peri o d as detaile d i n t he 
Sc he d ule of Pr oce d ures i n A p pe n di x A.  D uri n g t he ra n d o mize d treat me nt peri o d, St u d y Dr u g 
will be a d mi nistere d b y S C i njecti o n o nce -wee kl y.  
3. 4. 3 
O L E Peri o d  
F oll o wi n g t he 5 2- wee k r a n d o mize d treat me nt peri o d, patie nts will  c o nti n ue treat me n t i n t he O L E  
treat me nt peri o d.  T h e O L E p eri o d is 5 2 wee ks as detaile d i n t he Sc he d ule of Pr oce d ures i n 
A p pe n di x A. 
After a p atie nt has bee n i n t he O L E peri o d f or a p eri o d of 3 m o nt hs, a n I n v esti gat or m a y c o ns ult 
wit h t he st u d y Me dical M o nit or a n d re q uest t hat tri gl yceri de val ues b ec o me u n bli n de d t o t he 
I n v esti gat or a n d patie nt after Wee k 1 3 f or t he d urati o n of t he st u d y. 
F oll o wi n g t he Wee k 1 0 4 of t he O pe n- La bel E xte nsi o n Peri o d, patie nts will ha ve t he o pti o n of 
c o nti n ui n g d osi n g f or u p t o a n a d diti o nal 5 2 wee ks.   T he sc he d ule of pr oce d ures will f oll o w t he 
sa me sc he d ule as t he first year of O L E. 
3. 4. 4 
P ost -Tre at m e nt Peri o d  
F oll o wi n g t he O L E peri o d, patie nts will e nter a 1 3 - wee k p ost-treat me nt f oll o w- u p peri o d.  
Patie nts w h o d o n ot e nter t he O L E peri o d will g o strai g ht t o t he 1 3- wee k p ost -treat me nt 
f oll o w- u p peri o d. 
3. 5 
E n d - of-St u d y  
T he E n d - of- St u d y is last patie nt , last visit. 
3. 6  
D at a a n d S af et y M o nit ori n g B o ar d 
A n i n de pe n de nt D ata a n d Safet y M o nit ori n g B oar d ( D S M B) will be ass e m ble d t o re vie w safet y, 
t olerabilit y a n d efficac y ( as nee de d) data c ollecte d o n I SI S 3 0 4 8 0 1 d uri n g t his st u d y.  Base d o n 
its o n g oi n g assess me nt of t he safet y a n d t olera bilit y of I SI S 3 0 4 8 0 1, t he D S M B will pr o vi de 
rec o m me n dati o ns t o t he S p o ns or f or m o dif yi n g, st o p pi n g or c o nti n ui n g t he st u d y as pla n n e d.  
Details o n t he safet y assess me nts, fre q ue n c y of re vie w, meeti n g sc he d ules a n d c o ntr olle d access 
t o u n bli n de d data are o utli ne d i n t he D S M B C harter a n d/ or t he statistical a n al ysis pla n ( S A P). 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
4 2
 
4. 
P A TI E N T E N R O L L M E N T  
4. 1 
Scree ni n g  
Bef ore patie nts  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 re q uires a c o p y of t he St u d y Ce nter’s 
writte n I E C/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 patie nt 
i nf or mati o n a n d/ or recr uit me nt material. 
Patie nts  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 patie nt 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 ur es, i ncl u di n g scree ni n g pr oce d ures, are perf or m e d .  At t he ti me of ra n d o mizati o n , 
patie nt s will be assi g ne d a u ni q ue patie nt  i de ntificati o n n u m ber.  T his n u m ber will be use d t o 
i de ntif y t he p atie nt t hr o u g h o ut t he trial a n d m ust be use d o n all st u d y d o c u m e ntati o n relate d t o 
t hat patie nt.  T he scr ee ni n g n u m ber a n d patie nt i d e ntificati o n n u m ber m ust re mai n c o nsta nt 
t hr o u g h o ut t he e ntir e trial.  I n t he e ve nt t he patie nt is re-c o nse nt e d or re-scree ne d t he p atie nt 
m ust be gi ve n a n e w scree ni n g n u m ber.  Scree ni n g n u m bers a n d patie nt i d e ntificati o n n u m bers, 
o nce assi g ne d, will n ot b e re- us e d. 
4. 2  
R a n d o miz ati o n 
Patie nts will be ra n d o mize d after all  scree ni n g a n d q ualificati o n assess me nts ha ve bee n 
c o m plete d a n d after t he I n vesti gat or h as verifi e d t hat t he y are eli gi ble p er criteria i n Secti o ns 5. 1  
a n d 5. 2 .  N o patie nt ma y be gi n tr eat 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 
patie nt  i de ntificati o n n u m ber. 
Usi n g a n I nter acti ve V oi ce/ We b -Res p o nse S yste m (I X R S), eli gi ble p atie nts will be ra n d o mize d 
1: 1 t o recei ve I SI S 3 0 4 8 0 1 or place b o .   
Patie nts will be stratifie d b y assi g n me nt i nt o 1 of 3 gr o u ps b ase d o n F P L p h e n ot y p e, ge netic 
varia nts  a n d f a mil y hist or y of P L.  
F P L  Gr o u ps f or Str atific ati o n 
1.  Gr o u p 1 will c o nsist of patie nts wit h t he F P L p h e n ot y pe a n d ge netic v aria nts  of F P L  
2.  Gr o u p 2 will c o nsist of patie nts wit h t he F P L p h e n ot y pe, b ut lac ki n g a ge n etic varia nt, 
a n d ha vi n g a c o nfir me d f a mil y hist or y of F P L or a b n or mal a n d si milar fat distri b uti o n, 
pl us 1 mi n or criteri o n 
3.  Gr o u p 3 will c o nsist of t h ose wit h t he F P L p he n ot y pe, b ut wit h o ut eit her a ge n etic vari a nt 
or fa mil y hist or y, pl us 2 mi n or criteria a n d a B MI < 3 5 k g/ m 2 
Ge netic a n al ysis r e p orts i ncl u de c hara ct erizati o n of varia nts i nt o 5 classificati o ns:  be ni g n, li kel y 
be ni g n, v aria nt of u n k n o w n si g nifica nce, li kel y p at h o ge nic or pat h o ge nic. 
F or stratificati o n p ur p oses: 
P ositi ve o n ge netic testi n g:  D oc u m e ntati o n of pat h o ge ni c or li kel y pat h o ge nic ge nes ass o ciate d 
wit h fa milial partial li p o d ystr o p h y will be c o nsi d ere d p ositi ve f or ge netic a nal ysis if t hes e 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
4 3
 
c ha n ges are li kel y t o re pr ese nt t he u n derl yi n g ca us e of t he s u bject’s p h e n ot y p e.  T his s h o ul d be 
d oc u me nte d i n a writte n re p ort. 
Ne gati ve o n ge n etic testi n g:  W he n se q ue n ci n g a n al ysis of t he p artial li p o d ystr o p h y pa n el f or 
varia nts deter mi nes t h at n o pat h o ge nic or li kel y p at h o ge nic vari a nt were i d e ntifie d or is a varia nt 
of u n k n o w n si g nifi ca nce, t his will be c o nsi dere d as e vi de nce f or ne gati ve f or ge netics.  N e gati ve 
o n ge n etics will als o be c o nsi dere d f or t h os e s u bjects f or w h o m t he ge n etic a nal ysis res ults are 
u nli kel y, u n k n o w n, or u nteste d. 
P ositi ve fa mil y hist or y of F P L or fa mil y hist or y of a b n or mal a n d si milar fat distri b uti o n i ncl u des 
i m me diate fa mil y / first d e gree relati ves (fat her, m ot her, br ot her, sister, d a u g hter, s o n), as w ell as 
sec o n d de gr ee r elati ves ( gr a n d par e nts, a u nts a n d u ncles, nieces a n d ne p h e ws, a n d gra n dc hil dre n). 
A per m ute d bl oc k sc h e d ule will be use d.  T he S p o ns or Q ualit y Ass ura nce de part me nt or 
desi g nee will h ol d a c o p y of t he ra n d o mizati o n lists ge n erat e d b y t he I X R S ve n d or. 
4. 3 
Re pl ace me nt of P atie nt s 
Patie nt s w h o  wit h dra w fr o m t he st u d y will n ot be re place d .  T he st u d y will c o nti n ue e nr olli n g 
u ntil u p t o 6 0 patie nts ha ve bee n d ose 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 patie nts , m o nit ors, a n d St u d y C e nter pers o n n el will be bli n de d t o treat me nt 
assi g n me nt t hr o u g h o ut t h e st u d y u ntil all patie nts ha ve c o m plete d t h e ra n d o mize d treat me nt 
peri o d a n d t he Wee k 5 2 assess me nts a n d t he data base has bee n l oc ke d .  All patie nts, m o nit ors 
a n d St u d y Ce nter p ers o n nel will mai ntai n bli n de d t o treat me nt assi g n m e nt u ntil all patie nts ha ve 
c o m plete d t he St u d y Wee k 6 5 as sess me nts i n t he O L E  p eri o d  ( Wee k 1 3 of t he O L E).  T he 
D S M B  ma y be u n bli n de d u p o n re q uest as d escri b e d i n t he D S M B C harter.  I n or der t o e ns ure 
mai nte na nce of t he st u d y bli n d, li pi d pa nel res ults, i ncl u di n g a p o C- III, will n ot be a vaila ble t o 
t he S p o ns or, m o nit ors, I n vesti gat ors, St u d y Ce nter pers o n nel, or t he p atie nts u ntil data base l oc k .  
H o we ver, if a patie nt h as s uffer e d a Seri o us A d v erse E ve nt ( S A E, as d efi ne d i n Secti o n 9. 3. 3 ), 
a n d/ or w he n k n o wl e d ge of t he treat me nt assi g n m e nt will i m pact t he cli nical ma na ge me nt of t h e 
patie nt , 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 patie nt 
usi n g t he 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 patie nt wit hi n 
2 4 h o urs b ut will re mai n bli n de d t o t he patie nt’s treat me nt all ocati o n .  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 ns ( S U S A Rs ) wil l be u n bli n de d b y t he S p o ns or’s Dr u g Safet y 
a n d Q ualit y Ass ura n ce p ers o n nel f or t h e p ur p ose of re g ulat or y re p or ti n g (s ee Secti o n 9. 2 ).  Strict 
fire walls will be i n place bet wee n t he u n bli n de d Dr u g Safet y a n d Q u alit y Ass ura nce staff a n d 
ot her S p o ns or e m pl o yees t o pre ve nt i na d verte nt u n bli n di n g of i n di vi d uals i n v ol ve d i n st u d y 
c o n d uct or a n al ysis. 
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 di x A ) pri or t o u n bli n di n g, as k n o wle d ge of t h e treat me nt ar m c o ul d 
i nfl ue nce patie nt assess me nt . 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
4 4
 
5. 
P A TI E N 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 
wit hi n 6 wee ks of St u d y Da y 1, o r 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 gi ve writte n i nf or m e d c o nse nt t o partici p ate i n t he st u d y (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 la w 
2. A ge ≥ 1 8 years at t he ti me of i nf or me d c o nse nt 
3.  Cli nical dia g n osis of fa milial partial li p o d ystr o p h y pl us dia g n osis of t y pe 2 dia betes 
mellit us a n d h y pertri gl yceri de mia.  
Dia g n osis of li p o d ystr o p h y is base d o n d eficie n c y of s u bc uta ne o us b o d y fat i n a partial 
fas hi o n assesse d b y p h ysical e x a mi nati o n a n d l o w s ki nf ol d t hic k ness i n a nteri or t hi g h b y 
cali per meas ure me nt: me n ( ≤ 1 0 m m) a n d w o me n ( ≤ 2 2 m m), a n d at least 1 of t he 
f oll o wi n g: 
- 
Ge netic dia g n osis of f a milial P L (e. g., m utati o ns i n L M N A, P P A R -γ, A K T 2, CI D E C, 
P LI N 1 ge nes)  
O R  
-  Fa mil y hist or y of F P L or fa mil y hist or y of a b n or mal a n d si milar fat distri b uti o n pl us 
1 Mi n or Criteria  
O R  
-  2 Mi n or Criteria (I n t he a bse nce of F P L-ass o ciate d ge n etic vari a nt or fa mil y hist or y) 
a n d B MI < 3 5 k g/ m 2 
MI N O R Criteria  
a.  Re q uire me nt f or hi g h d oses of i ns uli n, e. g., re q uiri n g ≥ 2 0 0 U/ da y, ≥ 2 U/ k g/ da y, or 
c urre ntl y ta ki n g U - 5 0 0 i ns uli n 
b. Prese nce of aca nt h osis ni grica ns o n p h ysical e x a mi nati o n  
c.  E vi de nce/ hist or y of p ol yc ystic o v ar y s y n dr o me ( P C O S) or P C O S-li ke s y m pt o ms 
( hirs utis m, oli g o me n orr h ea, a n d/ or p ol yc ystic o v aries) 
d. Hist or y of p a ncr eatitis ass ociate d wit h h y p ertri gl yceri de mia  
e.  E vi de nce of n o n-alc o h oli c fatt y li ver diseas e  
-  
He pat o me gal y a n d/ or ele vate d tra nsa mi nas es i n t he a bse nce of a k n o w n ca use of 
li ver disease or ra di o gra p hic e vi de nce of he p atic steat osis (e. g., o n ultras o u n d or 
C T)  
4.  A dia g n osis of t y p e 2 dia betes mellit us, as defi ne d b y t he I nt er nati o nal Di a betes 
Fe derati o n g ui deli nes of 2 0 1 2, ma de at least 6 m o nt hs pri or t o t he Scree ni n g, a n d: 
 A H b A 1c ≥ 7 % t o ≤ 1 2 % at Scree ni n g,  

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
4 5
 
 O n a nti- dia betic t hera p y c o nsisti n g of: 
a.  Metf or mi n  ≥ 1 5 0 0 m g/ da y, or 
b.  If t he d ose of metf or mi n is < 1 5 0 0 m g/ da y, or metf or mi n is n ot t olerate d, t he n t he 
patie nt s h o ul d be o n ot her oral a nti- d ia betic dr u gs ( O A D) or a n i njecta ble 
gl uca g o n-li ke pe pti de- 1 ( G L P- 1 ) rece pt or a g o nist, or 
c.  I ns uli n t hera p y al o ne or i n c o m bi n ati o n wit h ot her a nti- dia betic dr u gs 
5.  H y pertri gl yceri de mia  as  de fi ne d b y Fasti n g T G le vels ≥ 5 0 0 m g/ d L (≥ 5. 7 m m ol/ L) at 
b ot h Scree ni n g a n d Q ualificati o n visits.  Patie n ts wit h t he cli nical dia g n osis of F P L a n d 
wit h Fasti n g T G le vels ≥ 2 0 0 (≥ 2. 2 6 m m ol/ L) t o < 5 0 0 m g/ d L (≥ 5. 7 m m ol/ L) at b ot h 
Scree ni n g a n d Q ualificati o n Visi ts w h o meet t he ge netic or fa mil y hist or y criteria f or 
st u d y i ncl usi o n ma y be f urt her scree ne d a n d e nr olle d i n t he st u d y 
6.  Prese nce of he pat osteat osis (fatt y li ver), as e vi de nce d b y a Scree ni n g M RI i n dicati n g a 
he patic fat fracti o n ( H F F) ≥ 6. 4 % 
7.  Willi n g t o mai ntai n t heir c ust o mar y p h ysical acti vit y le vel a n d t o f oll o w a diet m o derate 
i n car b o h y drates a n d fats wit h a f oc us o n c o m ple x car b o h y drates a n d re placi n g sat urate d 
f or u nsat urate d fats 
8.  Satisf y 1 of t he f oll o wi n g: 
a.  Fe males:  N o n- pre g na nt a n d n o n-lactati n g; s ur gicall y sterile  (e. g., t u bal occl usi o n, 
h ysterect o m y, bilateral sa l pi n gect o m y, bilateral oo p h orect o m y), 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 men 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 ollicle-sti m ulati n g h or m o ne ( 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), a bsti ne nt*, or if e n ga ge d i n se x ual relati o ns of 
c hil d- beari n g p ote ntial, patie nt is 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 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 a d mi nistrati o n. 
b.  Males:  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, patie nt is utilizi 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 a d mi nistrati o n. 
* 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 yle of t he patie nt.  Peri o dic a bsti n e 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. 
5. 2
 E xcl usi o n
 
Criteri a
 
1.  A dia g n osis of ge neralize d li p o d ystr o p h y 
2.  A dia g n osis of ac q uire d partial li p o d ystr o p h y ( A P L) 
3.  Ac ute pa ncreatitis wit hi n 4 wee ks of Scree ni n g 

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
4 6
 
4.  Hist or y wit hi n 6 m o nt hs of Scree ni n g of ac ute or u nsta ble car diac isc he mia ( m y ocar dial 
i nfarcti o n, ac ute c or o nar y s y n dr o me, ne w o nset a n gi na), str o ke , tra nsie nt isc he mic attac k, 
or u nsta ble c o n gesti ve heart fail ur e re q uiri n g a c ha n ge i n me dicati o n 
5.  Maj or s ur ger y wit hi n 3 m o nt hs of Scree ni n g  
6.  Hist or y of heart fail ure wit h Ne w Y or k Heart Ass ociati o n f u ncti o nal classificati o n 
( N Y H A) greater t ha n Class II or u nsta ble c o n gesti ve car diac fail ure re q uiri n g a c ha n ge i n 
me dicati o n 
7.  U nc o ntr olle d h y perte nsi o n ( bl o o d press ure  [ B P] > 1 6 0 m m H g s yst olic a n d/ or 1 0 0 m m 
H g diast olic) 
8.  A n y of t he f oll o wi n g la b orat or y val ues at Scree ni n g: 
a.  Car diac tr o p o ni n I > U L N 
b.  L D L- C > 1 3 0 m g/ d L o n ma xi mal t olerate d stati n t hera p y 
c.  He patic:   
i. 
T otal bilir u bi n > U L N 
ii. 
A L T > 3. 0 x U L N 
iii. 
A S T > 3. 0 x U L N 
d.  Re nal:   
i. 
Persiste ntl y p ositi ve ( 2 o ut of 3 tests ≥ trace p ositi ve) f or bl o o d o n uri ne 
di pstic k.  I n t he e ve nt of a p ositi ve te st 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 per hi g h p o wer fiel d 
ii. 
T w o ( 2) o ut of 3 c o nsec uti ve tests ≥ 1 + f or pr otei n o n uri ne di pstic k.  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 b y a q ua ntitati ve t otal 
uri ne pr otei n meas ure me nt of < 1 g/ 2 4 hrs 
iii. 
Esti mate d creati ni ne cleara nce calc ul ate d acc or di n g t o t he f or m ula of 
C oc kcr oft a n d Ga ult < 6 0 m L/ mi n 
e.  Platelet c o u nt < l o wer li mit of n or mal ( L L N) 
f.  Cli nicall y-si g nifica nt (as deter mi ne d b y t he I n vesti gat or or S p o ns or) a b n or malities o n 
la b orat or y e xa mi nati o n t hat will i ncrease ris k t o t he patie nt or i nterfere wit h data 
i nte grit y 
9.  U nc o ntr olle d h y p ot h yr oi dis m (a b n or mal t h yr oi d f u ncti o n tests s h o ul d be a p pr o ve d b y 
St u d y me dical m o nit or) 
1 0. Hist or y wit hi n 6 m o nt hs of Sc ree ni n g of dr u g or alc o h ol a b use 
1 1. Hist or y of blee di n g diat hesis or c oa g ul o pa t h y or cli nicall y-si g nifica nt a b n or malit y i n 
c oa g ulati o n para meters at Scree ni n g 
1 2. 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 3. K n o w n hist or y of or p ositi ve test f or h u ma n  i m m u n o deficie nc y vir us ( HI V), he patitis C 
or c hr o nic he patitis B 

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
4 7
 
1 4. 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 
1 5. 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 6. U n willi n g t o c o m pl y wit h lifest yle re q uire me nts (see Secti o n 6. 3 ) 
1 7. Use of a n y of t he f oll o wi n g: 
a.  Metrele pti n wit hi n t he last 3 m o nt hs pri or t o scree ni n g 
b.  A nti dia betic, li pi d l o weri n g, or at y pical a n ti ps yc h otic me dicati o n, u nless o n a sta ble 
d ose f or at least 3 m o nt hs pri or t o scr ee ni n g.  F or li pi d l o weri n g me dicati o ns (e. g., 
o me ga- 3 fatt y aci ds) d ose, bra n d a n d re gi me n are e x pecte d t o re mai n t he sa me fr o m 
Da y 1 t hr o u g h o ut Wee k 1 3.  Patie nts n ot rece i vi n g t hese dr u gs wit hi n 4 wee ks pri or 
t o scree ni n g are als o eli gi ble 
c.  I ns uli n u nless o n a sta ble dail y i ns uli n d ose re gi me n ( ± 2 0 %) f or at least 4 wee ks 
pri or t o d osi n g 
d.  G L P- 1 a g o nists wit hi n 4 wee ks pri or t o d osi n g, if patie nt has a hist or y of pa ncreatitis 
e.  Nic oti nic aci d or deri vati ves of nic oti nic aci d wit hi n 4 wee ks pri or t o scree ni n g 
f.  S yste mic c ortic oster oi ds or a na b olic steroi ds wit hi n 6 wee ks pr i or t o scree ni n g u nless 
a p pr o ve d b y t he S p o ns or Me dical M o nit or 
g.  A nti h y perte nsi ve me dicati o n u nless o n a sta b le d ose f or at least 4 wee ks pri or t o 
d osi n g 
h.  Ta m o xife n, estr o ge ns or pr o gesti ns u nless o n a sta ble d ose f or at least 4 m o nt hs pri or 
t o scree ni n g a n d d ose a n d re gi me n e x pecte d t o re mai n c o nsta nt t hr o u g h o ut t he st u d y 
i.  Oral a ntic oa g ula nts u nless o n a sta ble d ose f or at least 4 wee ks pri or t o d osi n g a n d 
re g ular cli nical m o nit ori n g is perf or me d 
j.  A nti- o besit y dr u gs [e. g., t he c o m bi natio n of p he nter mi ne a n d e xte n de d-release 
t o pira mate ( Qs y mia), orlistat ( Xe nical), lira gl uti de [r D N A ori gi n] i njecti o n ( Sa xe n da) 
a n d l orcaseri n ( Bel vi q), p he nter mi ne, a m p he ta mi nes, her bal pre parati o ns] wit hi n 
1 2 wee ks pri or t o scree ni n g 
k.  Pri or e x p os ure t o I SI S 3 0 4 8 0 1 
l.  A n y ot her me dicati o n u nless sta ble at least 4 wee ks pri or t o d osi n g ( occasi o nal or 
i nter mitte nt use of o ver-t he-co u nter me dicati o ns will be all o we d at I n vesti gat or’s 
discreti o n) 
1 8. 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 9. 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 t he S p o ns or w o ul d 
ma ke t he patie nt u ns uita ble f or i ncl usi o n, or c o ul d i nterfere wit h t he patie nt partici pati n g 
i n or c o m pleti n g t he st u d y 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
4 8
 
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  
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  a n d B aseli ne 
Bef ore a n y st u d y-s p ecifi c pr oce d ures or e val uati o ns are i nitiate d, patie nts m ust si g n a n d date t he 
i nf or me d c o nse nt f or m.  A 6- wee k peri o d, i ncl u di n g a di et sta bilizati o n peri o d of at least 
4 wee ks , is gi ve n t o perf or m t he scree ni n g e val uati o ns.  T he baseli ne assess m e nts will be 
perf or me d at Wee k - 2 t o - 1, a n d o n St u d y D a y 1.  A b n or mal scree ni n g res ults ma y be reteste d 
f or re vie w b y t he St u d y Me dical M o nit or f or eli gi bilit y p ur p os es. 
6. 1. 2  
R a n d o mize d Tre at m e nt Peri o d  
D uri n g t h e ra n d o mize d tr eat me nt peri o d, patie nts will re p ort t o t he st u d y ce nter f or cli nic visits a 
mi ni m u m of 6 ti mes d uri n g Wee ks 1- 5 2 (see Sc h e d ule of Pr oce d ures i n A p pe n di x A).  St u d y 
Dr u g will be a d mi nistere d o nce -w ee kl y ( Secti o n 8. 1 ).  C ollecti o n a n d meas ure me nt of vital 
si g ns, p h ysical e x a mi nati o n res ults, 
, 
 
, 
, electr ocar di o gr a ms ( E C Gs ), li ver M RIs, ec h o car di o gra ms, cli nical la b orat or y 
p ara meters  (i ncl u di n g he mat ol o g y; ser u m c h e mistr y; li pi d pa nel; 
,  
, 
, a n d C R P meas ure d b y hi g h s e nsiti vit y assa y [hs C R P ]; uri nal ysis , a n d ot her a n al yt es 
liste d i n A p pe n di x B), I SI S 3 0 4 8 0 1 plas ma tr o u g h c o nce ntrati o ns, i m m u n o ge ni cit y (I M) testi n g, 
, c ollecti o n of S M B G a n d i ns uli n diar y, h u n ger diar y, pai n diar y, a n d  A Es , 
c o nc o mita nt me dicati o n/ pr oce d ur e i nf or mati o n, a n d q ualit y of life assess m e nts will be 
perf or me d acc or di n g t o t he sc he d ule of pr oce d ures i n A p pe n di x A.  A Es  at t he i njecti o n site 
s h o ul d be c ollecte d as A Es .  Dietar y /alc o h ol c o u nseli n g will c o m me nce at t he start of t he diet 
sta bilizati o n peri o d a n d will be rei nf orce d at i nter vals t hr o u g h o ut t he treat me nt a n d f oll o w- u p 
peri o d. 
Patie nts m ust be faste d pri or t o dra wi n g all li pi d sa m ples a n d sa m ples dra w n l ocall y s h o ul d als o 
be se nt t o t he ce ntr al la b orat or y f or a nal ysis  w he n e ver p ossi ble.  Bl o o d sa m pli n g at Wee ks 2, 3, 4, 
5, 6, 7, 8, 9, 1 0, 1 1, 1 2, 1 3, 1 4, 1 5, 1 6, 1 7, 1 8, 1 9, 2 0, 2 1, 2 2, 2 3, 2 4, 2 5, 2 6, 2 7, 2 8, 2 9, 3 0, 3 1, 
3 2, 3 3, 3 4, 3 5, 3 6, 3 7, 3 8, 3 9, 4 0, 4 1, 4 2, 4 3, 4 4, 4 5, 4 6, 4 7, 4 8, 4 9, 5 0 a n d 5 1 ma y b e c o n d uct e d 
b y a h o m e healt hcare  s er vice.  W hile all o we d, it is prefera ble t hat visits at Wee k 8 a n d 1 2 are 
c o n d ucte d at t he cli nic if p ossi ble.  D osi n g i nstr ucti o ns a n d trai ni n g will be pr o vi de d t o t he 
patie nt w here a p plica ble . 
All visits ha ve a visit wi n d o w of at least ± 2 da ys .  All reas o na ble atte m pts s h o ul d be ma de t o 
e ns ure c o m plia n ce wit h t he visit sc he d ule as o utli ne d i n A p pe n di x A.  H o we ver, i n t he e ve nt t hat 
a visit d oes n ot occ ur or is dela ye d, all s u bse q ue nt visits s h o ul d be calc ulate d base d o n t he ti me 
ela pse d si nce Da y 1 r at her t ha n fr o m t he dat e of t h e pre vi o us visit. 
6. 1. 3  
R a n d o mize d Peri o d  P ost - Tre at m e nt F oll o w-U p  
Patie nts w h o d o n ot e nter t he O L E peri o d will g o strai g ht t o t he 1 3- wee k p ost -treat me nt 
f oll o w- u p peri o d.  T his p eri o d c o nsists of 7 visits, as o utli ne d i n t he Sc he d ule of Pr oce d ures i n 
A p pe n di x A. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
5 2
 
F or t he p ur p os es of t he st u d y, effecti ve c o ntrace pti o n is defi ne d as f oll o ws: 
F or male p atie n ts: 
 Effecti ve m ale c o ntr ace pti o n i ncl u des a vasect o m y wit h ne gati ve se me n a n al 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 patie nts m ust als o e nc o ura ge t heir fe male p art ner t o use 
effecti ve c o ntr ac e 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 ns e nt u ntil 3 m o nt hs after 
t he patie nt’s last d ose of st u d y treat me nt.  Effecti ve c o ntrace pti ve f or t he fe male 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 c o ntr ace pti o n/ de vice, or barrier met h o ds (fe male 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 o a m/ gel/fil m/crea m/s u p p osit or y.  Male 
patie n ts 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 . 
F or f e male patie nts : 
 Usi n g 1 or m or e of t he f oll o wi n g acce pta bl e met h o ds of c o ntrace pti o n:  s ur gical 
sterilizati o n (e. g., bilater al t u bal li gati o n), h or m o n al c o ntrace pti o n, i ntra uteri ne 
c o ntrace pti o n/ de vice, or a n y 2 b arri er met h o ds (a c o m bi nati o n of male or fe male 
c o n d o m * wit h  dia p hra g m, s p o n ge, or cer vical ca p) t o get h er wit h s per mici dal 
f oa m/ gel/fil m/crea m/s u p p osit or y. 
* N ote:  A f e m al e 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 pr o d uct f aili n g.  
* 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 pr eferre d a n d 
us ual lifest yle of t he pati e nt.  Peri o dic a bsti ne nce (e. g., cal e n dar, o v ul ati o n, s y m pt ot her mal, p ost-
o v ulati o n met h o ds), decl arati o n of a bsti ne n ce 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 . 
6. 3. 2 
Ot h er Re q uire m e nts 
All patie nt s will be re q uire d t o fast f or at least 1 0 h o urs, b ut prefera bl y n ot m ore t ha n 1 2 h o urs, 
bef ore visits re q uiri n g f aste d bl o o d sa m pli n g. 
All patie nts will be c o u nsele d t o f oll o w a m o derate diet c o m p ose d of ~ 5 0 % kcal fr o m 
car b o h y dr ates (f o c us i n g o n c o m ple x car b o h y drate s a n d a v oi da nce of c o n ce ntrate d s u gars  li ke 
j uice a n d ca n d y) a n d 3 0 % or less kcal fr o m fat  (f oc usi n g o n d ecreasi n g i nta ke of tra ns a n d 
sat urate d f ats a n d i ncr easi n g i nta ke of m o n o- u nsat urate d fats ), wit h a n em p has is o n mi x e d meals 
(c o m bi nati o n of pr otei n, car b o h y dr ate a n d fat).  P atie nts s h o ul d mai ntai n t heir c ust o mar y 
p h ysical acti vit y le v el t hr o u g h o ut t he st u d y . 
Alc o h ol c o ns u m pti o n s h o ul d be li mite d t o n ot m ore t ha n 3 dri n ks/ wee k a n d n ot m ore t ha n 
1 dri n k/ da y f or  f e males a n d n ot m ore t ha n 5 dri n ks/ wee k a n d n ot m ore t h a n 2 dri n ks/ da y 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).  I n a d diti o n, p atie nts s h o ul d refr ai n fr o m dri n ki n g alc o h ol f or at 
le ast 4 8 h o urs pri or t o a cli nic visit.  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
5 3
 
All patie nts will be gi ve n a n i nstr ucti o n car d t hat m ust be prese nte d t o t he treati n g p h ysi cia n if a 
s us pecte d case of p a ncr eatitis occ urs, or t he patie nt e x perie nces s y m pt o ms of decrease d pl atelets 
or h y p o gl yce mia/ h y per gl yce mia .  T he car d will e x plai n t hat t he patie nt is i n a cli nical trial a n d 
t hat ser u m li pase a n d/ or a m ylas e meas ures s h o ul d be d o ne i n or der t o a dj u dicate t he e v e nt, base d 
o n Atla nta Classificati o n ( Ba n ks et al. 2 0 1 3 ).  If ser u m or a m yl ase acti vit y is less t ha n 3 x U L N, 
i ma gi n g, prefer a bl y c o ntr ast-e n ha n ce d c o m p ute d t o m o gra p h y ( C T), s h o ul d be c o nsi dere d t o 
c o nfir m t he dia g n osis of ac ute pa n creatitis per t he Atla nta Criteria.  
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 ( d efi ne d as I SI S 3 0 4 8 0 1 or p lace b o) c haract eristics are liste d i n Ta ble 2. 
T he St u d y Dr u g is c o ntai ne d i n glass pre- fille d s yri n ges ( P F S).  T he St u d y Dr u g st ora ge a n d 
pre par ati o n i nstr ucti o ns will be pr o vi de d b y t h e S p o ns or or desi g nee.  T he St u d y Dr u g m ust be 
st ore d sec ur el y at 2° t o 8° Celsi us a n d be pr otecte d fr o m li g ht. 
T a ble 2 
St u d y Dr u g C h ar acteristics  
St u d y Dr u g  
I SI S 3 0 4 8 0 1  
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. 5 m L s ol uti o n p er P F S  
1 . 5 m L s ol uti o n p er P F S 
D o s e  
3 0 0 m g o n c e -w e e kl y  
N ot a p pli c a bl e  
R o ut e of A d mi ni str ati o n  
S C 
S C 
 
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 la bele d i n acc or d a nce 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/ d estr ucti o n of St u d y 
Dr u g s u p plies pr o vi de d b y t he S p o ns or.  T h e St u d y Ce nter m ust ret ur n all u n use d St u d y Dr u g t o 
t he S p o ns or or desi g n ee.  All use d s yri n ges m ust be dis p ose d of as per t he site’s hazar d o us waste 
destr ucti o n p olic y. 
8.  
T R E A T M E N T O F P A TI E N T S 
8. 1 
St u d y  Dr u g A d mi nistr ati o n 
F or eac h i n di vi d ual patie nt, St u d y Dr u g will be a d mi nistere d S C  as a si n gle 1. 5 m L i njecti o n 
o nce- w ee kl y f or Wee ks 1 - 5 2 of t he Ra n d o mize d Treat me nt peri o d of t he st u d y, a n d 
Wee ks  5 3- 1 0 4 of t he O L E peri o d of t he st u d y.  Self -a d mi nistrati o n will be all o we d after 
a p pr o priate tr ai ni n g of patie nt a n d/ or care gi ver. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
5 4
 
Patie nts s h o ul d recei ve 1  d ose per w ee k, wit h wee ks al wa ys defi n e d relati v e t o St u d y Da y 1.  F o r 
e x a m ple, if a patie nt recei ves t he first d ose o n a M o n da y, s u bs e q ue nt d oses s h o ul d be gi ve n o n 
M o n da ys, if p ossi ble.  If a patie nt misses a n i njecti o n, or if d osi n g o n t he us ual da y is n ot 
p ossi ble, t he patie nt ca n r esc he d ule t he i njecti o n pr o vi de d t hat 2 d oses are a d mi nistere d at least 
2 da ys a part.  
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 pr e par ati 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  
T here are n o ot her pr ot oc ol-re q uir e d dr u gs. 
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 tr eat me nt pr o ce d ures f or t his st u d y. 
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 f or t his st u d y. 
8. 5  
S af et y M o nit ori n g R ules 
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 n ical a n d cli nical 
o bser vati o ns. 
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. 
F or t he p ur p os es of safet y m o nit ori n g b aseli ne is defi ne d as t he a vera ge of Da y 1 pre- d ose 
assess me nt a n d t he last meas ure me nt pri or t o Da y 1 . 
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 ( Ra n d o mize d Treat me nt , O L E, or 
P ost- Tr eat me nt P eri o ds), t he i nitial cli nical la b orat or y res ults meeti n g t h e safet y m o nit ori n g 
criteria pr ese nte d b el o w m ust be c o nfir me d b y p erf or mi n g meas ure me nts (i deall y i n t he s a 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 nitial 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 ret est m u st 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 . 
Re - d osi n g G ui d a nce:  Patie nt s 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, patie nt s 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 patie nt  is a p pr o priate.  Re d ucti o n i n d ose or d ose fre q ue n c y 
ma y als o be i nitiate d as n ote d i n Secti o n 8. 7 .  If a n y of t he st o p pi n g criteria descri be d b el o w are 
met bel o w (refer t o Secti o ns 8. 6. 1  t o 8. 6. 3 ) a n d are c o nfir me d, t h e patie nt  will be  d ose pa use d or 
per ma ne ntl y disc o nti n ue d (as descri be d i n t he a p pr o priate st o p pi n g criteri o n) fr o m f urt her 
treat me nt wit h St u d y Dr u g, a n d e val uat e 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 ualifi e d desi g n ee, a n d will be e ntere d i nt o t he 
p ost- treatme nt e val u ati o n p orti o n of t he st u d y (s ee Secti o n 8. 8 ). 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
5 5
 
8. 5. 1 
S afety M o nit ori n g 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 bas eli ne please refer t o 
g ui da n ce i n Secti o n 8. 5  a b o ve. 
F or patie nts wit h Baseli n e A L T or A S T bel o w 2 x U L N 
I n t he e ve nt of a n AL 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 Baseli ne v al ue  w as > U L N ) at a n y ti me d uri n g t he St u d y ( Ra n d o mize d 
Treat me nt , O L E, or P ost -Treat me nt Peri o d ), t h e 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 ncreas e t o 5 x U L N.  
F or patie nts wit h Baseli n e  A L T or A S T bet w ee n ≥ 2 a n d < 3 x U L N  
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 2 x t he Baseli ne  le vel a n y ti me d uri n g t he 
st u d y (Ra n d o mize d Treat me nt , O L E, 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 d escri be d a b o ve.  Si milarl y, 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 u e nc y of R e peat Meas ure me nts:   Patie nts wit h c o nfir me d A L T or A S T le vels t hat are 
c o nti n ui n g t o rise s h o ul d ha ve t heir li ver c he mistr y tests ( A L T, A S T, A L P, i nter nati o nal 
n or malize d rati o  [I N R] a n d t otal bilir u bi n) reteste d at least bi - m o nt hl y u ntil le vels sta bilize a n d 
be gi n t o r ec o ver ( 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).  
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 patie nts 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  v al ue o r 3 x U L N if t he Baseli 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 
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 me 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 g M, he p atitis B s urface a nti ge n 
[H Bs A g ], he patitis C vir us  [H C V ] a nti b o d y, C M V I g M, a n d 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 o m p ute d t o m o gr a p h y ( C T ) or M RI s ca ns, ma y b e perf 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 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 p atie nt’s A L T a n d/ or A S T le vels reac h 5 x U L N. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
5 6
 
8. 5. 2 
S afety M o nit ori n g f or Re n al F u ncti o n  
Patie nts wit h c o nfir me d persiste nt c ha n ges  t h at are o bser ve d o v er 2 c o nsec uti ve visits, at least 
7 da ys a part, f or t he criterio n bel o w s h o ul d be reteste d e ver y 2 w ee ks wit h ser u m creati ni ne a n d 
uri ne c he mistries  u ntil cr eati ni ne a n d P/ C rati o sta bilize : 
 P/ C rati o c ha n ge fr o m baseli ne > 5 0 % a n d ≥ 1. 5 U L N  
8. 5. 3 
S afety M o nit ori n g f or Pl atelet C o u nt Res ults  
M o nit or e ver y 1 w ee k u nless ot her wise s pecifie d. 
St u d y Dr u g  a d mi nistrati o n is c o nti n ge nt o n t he a v aila bilit y of t he i m me diat el y prece di n g t est 
res ult.  A n i nter pret a ble platelet val ue m ust be a v aila ble wit hi n 7 da ys pri or t o d osi n g.  O nl y t he 
st u d y d oct or or q ualifie d desi g nee ca n a ut h orize c o nti n ue d St u d y Dr u g  a d mi nistrati o n base d o n 
a n acce pta ble plat elet val ue.  Patie nts s h o ul d n ot a d mi nister a d ose u ntil t he y ha v e bee n 
c o ntacte d b y t heir st u d y d oct or or desi g nee a n d t ol d t hat it is acce pta ble t o d ose.  A ut h orizati o n 
t o d ose m ust be d oc u me nte d i n t he patie nt’s me dical rec or ds.  
D ue t o t he 1 t o 2- year st u d y d ur ati o n it is a ntici pate d t hat patie nts ma y u n derta ke tra v el i ncl u di n g 
vacati o ns, w hic h ma y i m pe de wee kl y platelet m o nit ori n g.  I n s o me sit uati o ns, it ma y be p ossi ble 
t o arra n ge f or l ocal la b or at or y t esti n g or us e of t he h o me healt hcare ser vice at t heir te m p orar y 
l ocati o n.  T he i nte nt is t o mai ntai n wee kl y platelet m o nit ori n g a n d d osi n g w here p ossi ble, as well 
as I n vesti gat or site c o ntact wit h t he st u d y patie nts.  H o we ver, if t he a b o v e o pti o ns are n ot 
p ossi ble, a te m p orar y i nt err u pti o n of st u d y treat m e nt will be pla n ne d wit h a pr o m pt bl o o d dra w 
u p o n t he patie nt’s ret ur n w hic h m ust be re p orte d a n d re vie we d b y t h e I n vesti gat or pri or t o t he 
patie nt res u mi n g d osi n g. 
Acti o ns t o be ta ke n i n t he e ve nt of re d uce d platel et c o u nt are s h o w n i n Ta ble 4  i n Secti o n 8. 6. 3 . 
T he tests o utli ne d i n  Ta ble 3  s h o ul d als o be perf or me d as s o o n as p ossi ble.  A d diti o nal la b tests 
will be deter mi ne d b y t he S p o ns or Me dical M o nit or or desi g nee i n c o ns ultati o n wit h t he 
I n v esti gat or.  
A n y case of a platel et c o u nt ≤ 5 0, 0 0 0/ m m3 s h o ul d be re p ort e d i n a n e x pe dite d fas hi o n t o t he 
S p o ns or ( See als o St o p pi n g R ules Secti o n 8. 6. 3). 
 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
5 7
 
T a ble 3 
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 Less t h a n t he L o w er 
Li mit of N or m al ( x 2) or < 1 0 0, 0 0 0/ m m 3 ( x 1) * 
*I n p atie nts w h o ha ve a n y 2 occ urr e nces ( n o n-c o nsec uti ve or c o ns ec uti ve) of platelet c o u nt less 
t ha n t he l o wer li mit of n or mal or w h o ha v e a n y 1 o cc urre nce of platelets < 1 0 0, 0 0 0/ m m3.  La bs 
o nl y nee d t o be perf or me d o nce.  La bs ma y b e c ollecte d o ver m ulti ple visits, if bl o o d 
re q uire me nts are a c o ncer n, as per I n vesti gat or dis creti o n. 
N ote:  T he f oll o wi n g la bs ma y c h a n ge as a d diti o nal data is assesse d, a n d sites will be u p date d 
re gar di n g a n y c ha n ges. 
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 B C wit h r eti c ul o c yt e s  
F ol at e (f oli c a ci d)  
Vit a mi n B 1 2  
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 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, C5 a 
h s C R P  
H eli c o b a ct er p yl ori ( br e at h t e st)  
S er ol o g y f or:  
H B V, H C V, HI V (if n ot d o n e r e c e ntl y 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  
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  
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
5 8
 
8. 5. 4  
S afety M o nit ori n g f or Mi n or Blee di n g Eve nts 
Mi n or blee di n g e ve nts ar e t h ose t hat d o n ot f ulfill t he criteria f or maj or blee di n g or cli nicall y-
rele va nt, n o n- m aj or blee di n g e v e nts ( w hic h are d efi ne d i n Secti o n 8. 6. 3 ), f or e x a m ple e x cess 
br uisi n g, petec hiae, gi n gi val blee di n g o n br us hi n g teet h.  If a mi n or blee di n g e v e nt occ urs, t he 
I n v esti gat or m ust n otif y t he S p o ns or Me dical M o nit or a n d a d diti o nal testi n g of c oa g ulati o n 
para meters ( 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 ], I N R) a n d 
platelet c o u nt s h o ul d be perf or me d. 
8. 5. 5 
S afety M o nit ori n g f or C o nstit uti o n al Sy m pt o ms  
Patie nts will be i nstr ucte d t o pr o m ptl y re p ort a n y si g ns of s y m pt o ms of fe v er or c o nstit uti o nal 
s y m pt o ms t hat ma y arise d uri n g t he st u d y a n d t h e I n v esti gat or s h o ul d cl osel y e v al uate all 
p ote ntial ca uses, i ncl u di n g c o n c o mita nt ill ness .  Patie nts w h o  e x perie nce p ersiste nt c o nstit uti o nal 
s y m pt o ms 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 t o deter mi ne 
w het her a d diti o nal m o nit ori n g or l a b orat or y t ests are re q uire d. 
8. 5. 6  
S afety M o nit ori n g f or L D L- C Elev ati o ns  
Be gi n ni n g at Wee k 1 3 , la b orat or y alerts will be i n place t o n otif y t he I n v esti gat or if a patie nt h as 
a n L D L-C > 1 6 0 m g/ d L o n 2 c o nsec uti ve visits.  If t his occ urs, L D L- C v al ue s f or t his patie nt 
will be u n bli n de d f or t he re mai n der of t he st u d y a n d t he I n v esti gat or will be e nc o ura ge d t o 
i nitiate/a dj ust treat me nt t o l o wer L D L-C acc or di n g t o c o u ntr y- s pecifi c g ui deli nes (e. g., i nitiate 
stati n t hera p y, i ncrease t h e stati n d ose f or patie nts w h o are alrea d y o n treat me nt , a d d ezeti mi be if 
o n ma xi mal stati n t hera p y ). 
8. 5. 7  
S afety M o nit ori n g f or Hy p o glyce mi a 
Cl assific ati o n of Hy p o glyce mi a 
Alert val ue  f or h y p o gl yc e mia  
≤ 7 0 m g/ d L ( ≤ 3. 9 m m ol/ L) pl as ma c o nce ntrati o n 
Se vere H y p o gl yce mia  
Re q uires assista nce of a n ot her pers o n t o acti vel y a d mi nister car b o h y drates, gl uca g o n, or ta ke 
ot her c orr ecti ve acti o ns .  Plas ma gl uc ose c o nce ntrati o ns ma y n ot be a vaila bl e d uri n g a n e ve nt.  
Ne ur ol o gical r ec o v er y f oll o wi n g plas ma gl uc ose l e vels ret ur ni n g t o n or mal c o nsi dere d s ufficie nt 
e vi de nce t h at e ve nt was i n d uce d b y l o w plas ma gl uc ose c o nce ntrati o n  
D oc u me nte d S y m pt o matic H y p o gl yce mia  
T y pical h y p o gl yce mia s y m pt o ms acc o m pa nie d b y meas ure d plas ma gl u c os e ≤ 7 0 m g/ d L 
(≤ 3. 9 m m ol/ L)  
As y m pt o matic  H y p o gl yce mia  
N ot acc o m pa ni e d b y t y pi cal h y p o gl yce mia s y m pt o ms b ut wit h meas ure d plas ma gl uc os e 
≤ 7 0 m g/ d L ( ≤ 3. 9 m m ol/ L) 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
5 9
 
Pr o ba ble S y m pt o matic H y p o gl yce mia  
T y pical h y p o gl yce mia s y m pt o ms n ot acc o m pa nie d b y plas ma gl uc os e deter mi nati o n b ut li kel y 
ca use d b y plas ma gl u c ose ≤ 7 0 m g/ d L ( ≤ 3. 9 m m ol/ L) 
I n t he e ve nt of a n e pis o d e of s y m pt o matic d o c u m e nte d h y p o gl yce mia ( F P G < 7 0 m g/ d L), if t he 
patie nt is o n i ns uli n, t he In vesti ga t or s h all re d uce t he t otal dail y d ose b y 5-1 5 %.  If t he patie nt is 
o n oral a nt- dia b etic dr u gs, t he I n v esti gat or s h o ul d use his or her  discreti o n re gar di n g c ha n ges t o 
t he dr u g re gi me n t o hel p pre ve nt f ut ur e i nci de nces of h y p o gl yce mic e v e nts.  In all cases, t he 
a dj ust me nts ma de t o me dicati o n s h o ul d be caref ull y d oc u m e nte d via el ectr o nic diar y (i ns uli n) 
a n d/ or c o nc o mita nt me di cati o n C R F.  
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 h e patie nt re q uires 
assista nce of a n ot her p ers o n t o o btai n treat me nt f or t he e ve nt a n d h as a plas m a gl uc os e le vel 
≤ 7 0 m g/ d L ( ≤ 3. 9  m m ol/ L) .  T h e r esc ue treat me nt of h y p o gl yce mia ma y i n cl u de I V gl uc os e or 
b uccal or i ntr a m usc ular gl uca g o n. 
T he defi niti o n of se vere s y m pt o matic h y p o gl yce mia i ncl u des all e pis o des i n w hic h ne ur ol o gical 
i m pair me nt was se vere e n o u g h t o pr e ve nt self-treat me nt a n d w hic h w ere t h us t h o u g ht t o place 
patie nts at ris k f or i nj ur y t o t he msel ves or ot hers.  N ote t hat “re q uires assist a nce” mea ns t hat t he 
patie nt c o ul d n ot hel p hi msel f or herself.  S o me o ne bei n g ki n d t hat assists s p o nta ne o usl y t he 
patie nt w he n n ot necessar y d o es n ot q ualif y as “re q uires assista nce. ” 
Se vere h y p o gl yce mia will be q ualifie d as a S A E o nl y if it f ulfills S A E criteria . 
If a patie nt pr ese 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 patie nt’s gl u c ose le vel a n d treat t he patie nt acc or di n gl y. 
Patie nts m ust be i nstr ucte d o n t he m o nit ori n g a n d ma na ge me nt of h y p o gl yce mic e pis o des at t he 
Baseli ne Visit . 
T he e x perie nce of h y p o gl yce mia ma y var y greatl y fr o m patie nt t o patie nt .  H o we ver, t here are 
certai n cl assical si g ns a n d s y m pt o ms, of w hic h patie nts s h o ul d be a ware as a cl ue t hat t heir bl o o d 
gl uc ose m a y be l o w.  C o m m o n s y m pt o ms i ncl u de hea dac he, heart p o u n di n g, c o nf usi o n, 
dis orie ntati o n, n u m b ness or ti n gli n g, p ale s ki n, s h a ki ness or tre m ul o us ness, i ncreas e d a p petite, 
a n xi o us ness or ner v o us ness, li g ht hea d e d ness or di zzi ness, s weati n g, a n d w ea k ness.  C o ma c o ul d 
occ ur if bl o o d s u gar c orr ecti o n is n ot perf or me d. 
If patie nts s us pect t he y mi g ht be ha vi n g a h y p o gl yce mia reacti o n, t he y s h o ul d c hec k t heir bl o o d 
gl uc ose usi n g t heir m eters as s o o n as p ossi ble, bef ore treat me nt if p ossi ble, pr o vi de d t he y feel it 
is safe t o d o s o.  If t here is d o u bt a b o ut safet y t he y s h o ul d treat t he e ve nt first, usi n g s o me s u gar, 
mil k, or j uice f or e x a m ple, t he n o btai n a n d rec or d a bl o o d gl uc os e val ue as s o o n as p ossi ble 
t hereafter.  T h e ti me a n d nat ure of tr eat me nt s h o ul d be n ote d, a n d es p eciall y if a n y bl o o d gl uc os e 
res ult was bef ore or after treat me nt.  It w o ul d be h el pf ul f or t he patie nt t o n ote if a c o ntri b ut or y 
fact or ( e. g., misse d or r e d uce d meals, u nacc ust o me d p h ysical acti vit y) occ urre d earlier i n t he da y 
of t he e ve nt. 
I nstr u cti o ns s h o ul d be pr o vi de d t o all patie nts o n t he a p pr o pri ate use of a gl uc ose meter. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
6 0
 
8. 5. 8  
M o nit ori n g R ule f or D oc u m e nte d Hy per glyce mi a  
R o uti ne fasti n g S M B G a n d ce ntral la b alerts o n F P G (a n d H b A 1c after Wee k 1 2) are set u p t o 
e ns ure t hat gl yce mic par a meters r e mai n u n der pre defi ne d t hres h ol ds val u es .  If o ne fasti n g 
S M B G val ue e x cee ds t he s pecific gl yce mic li mit o n 1 da y, t h e patie nt c h ec ks it a gai n d uri n g t he 
2 f oll o wi n g da ys.  If all t he val ues i n 3 c o nsec uti ve da ys e x cee d t he s p ecifi c li mit, t he patie nt 
s h o ul d c o ntact t he I n vesti gat or a n d a ce ntral la b orat or y F P G meas ure me nt (a n d H b A 1 c af ter 
Wee k 1 2) is perf or me d. 
T he t hres h ol d val ues are defi ne d as f oll o ws, d e pe n di n g o n st u d y peri o d: 
 Fr o m Baseli ne  visit t o Wee k 1 2 (i ncl u di n g val ue at Wee k 1 2) of Ra n d o mize d Treat me nt 
peri o d or O L E p eri o d: 
o  F P G > 3 0 0 m g/ d L ( 1 6. 6 m m ol/ L)  
 Fr o m W ee k 1 2 t o Wee k 2 4 (i ncl u di n g val u e at Wee k 2 4) of Ra n d o mize d Treat me nt 
peri o d or O L E p eri o d: 
o  F P G > 2 7 0 m g/ d L ( 1 5. 0 m m ol/ L) or  
o  H b A 1c > 9. 5 % (f or p atie nts wit h Baseli ne  H b A 1 c  < 8 %) a n d H b A 1c i ncrease of 
m ore t ha n 1. 5 % fr o m Baseli ne  (f or p atie nts wit h Baseli ne  H b A 1c ≥ 8 %)  
 Fr o m W ee k 2 4 u p t o Wee k 5 2  of Ra n d o mize d Treat me nt peri o d or O L E p eri o d: 
o  F P G > 2 4 0 m g/ d L ( 1 3. 3 m m ol/ L) or 
o  H b A 1c > 9. 5 % (f or p atie nts wit h Baseli ne  H b A 1 c  < 8 %) a n d H b A 1c i ncrease of 
m ore t ha n 1. 5 % fr o m Baseli ne  (f or p atie nts wit h Baseli ne  H b A 1c ≥ 8 %)  
I n case of F P G/ H b A 1 c a b o ve t he t hres h ol d val ues, t he I n v esti gat or s h o ul d e ns ure t hat n o 
reas o na bl e e x pla nati o n e xists f or i ns ufficie nt gl u c ose c o ntr ol a n d i n partic ular t hat:  
 Plas ma gl uc ose was act uall y meas ure d i n t he fasti n g c o n diti o n  
 A bse nce of i nterc urre nt disease w hic h ma y j e o par dize gl yce mic c o ntr ol .  I n case of a n 
e mer ge n c y (e . g., s ur ger y, i nfecti o n), t he I n v esti gat or ca n ta k e a p pr o priate m eas ures f or 
gl yce mic c o ntr ol .  If t h e meas ure d o es n ot e x cee d 7 da ys, t h e n it will n ot be c o nsi dere d a 
resc ue.  If t he meas ure l asts be y o n d 7 da ys t h e n it will be treate d as a res c u e 
 C o m plia nce t o treat me nt is a p pr o priate  
 C o m plia nce t o diet a n d lifest yl e is a p pr o priat e 
If a n y of t he a bo ve ca n r eas o na bl y e x plai n t he i ns ufficie nt gl yce mic c o ntr ol, t he I n v esti gat or 
s h o ul d u n derta ke a p pr o priate acti o n, i.e.: 
 I n v esti gati o n a n d treat me nt of i nterc urre nt disease (t o be re p ort e d i n A E/c o n c o mita nt 
me dicati o n pa rts of t he eC R F)  
 Stress o n t he a bs ol ute ne e d t o be c o m plia nt t o treat me nt  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
6 1
 
 Or ga nize a s pecific i nter vie w wit h a Re gistere d Dieticia n or ot her q u alifie d n utriti o n 
pr ofessi o nal a n d str ess o n t he a bs ol ute nee d t o be c o m plia nt t o diet a n d lifest yl e 
rec o m me n dati o ns 
 Sc he d ule a F P G/ H b A 1c assess me nt  at t he ne xt visit 
If n o ne fr o m t he a b o ve- me nti o ne d reas o ns ca n b e f o u n d, or if a p pr o priate acti o n fails t o decreas e 
F P G/ H b A 1c u n der t he t hres h ol d val ues, a n i ncrease i n c urre nt me di cati o n or t he a d diti o n of ne w 
a nti-dia betic res c ue me di cati o n ma y be i ntr o d uce d at I n v esti gat or discreti o n a n d acc or di n g t o 
l ocal g ui d eli nes.  I n vesti gat ors s h o ul d mi ni mize c ha n ges pri or t o t he pri mar y e n d p oi nt, w he n 
p ossi ble. All a dj ust me nts t o me dicati o n s h o ul d be ca pt ure d o n t he c o nc o mit a nt me dicati o n C R F 
a n d/ or electr o nic di ar y.   
All assess me nts f or pri m ar y a n d sec o n dar y effi cac y a n d safet y para meters pla n ne d i n fi nal 
pri mar y e n d p oi nt assess me nt visit s h o ul d be perf or me d bef ore a d di n g t he resc ue m e dicati o n.  
T he n t he patie nt c o nti n ues t he st u d y treat me nt a n d sta ys i n t he st u d y i n or der t o c ollect safet y 
i nf or mati o n.  T he pla n ne d visits a n d assess me nts s h o ul d occ ur u ntil t he last sc he d ule d visit. 
( See m ore d etails i n A p pe n di x A ). 
N ote:  After St u d y Dr u g  disc o nti n uati o n a n y treat me nts are per mitte d, as d ee me d necessar y b y 
t he I n v esti gat or. 
8. 5. 9 
Ac ute P a ncre atitis  
If a patie nt h as a n e pis o d e of ac ut e pa ncreatitis, d osi n g wit h St u d y Dr u g  s h o ul d be s us pe n de d 
te m p oraril y u ntil t he patie nt is cli nicall y sta ble.  T he s uita bilit y of t he patie nt f or c o nti n ue d 
d osi n g a n d t he n ee d f or a n y m o dificati o n t o t he treat me nt sc he d ule (refer t o Secti o n 8. 7 ) 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 St u d y Me dical M o nit or . 
8. 6 
St o p pi n g R ules  
F or t he p ur p os es of st o p pi n g r ules, b aseli ne is defi ne d as t he a v era ge of D a y 1 pre- d ose 
assess me nt a n d t he last meas ure me nt pri or t o Da y 1. 
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 c o nfir me d la b orat or y r es 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 patie nt wit h St u d y Dr u g will be st o p pe d per m a ne ntl y: 
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 Bas eli ne  val ue or 3 x U L N if t he Bas eli 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 Bas eli ne  val ue or 3 x U L N if t he Bas eli ne  
val ue was >  U L N), w hic h is c o nfir me d, a n d t he n e w a p peara n ce (i.e., o nset c oi ncides 
wit h t he c ha n ges i n he p atic e nz y mes) of  fati g ue, n a usea, v o miti n g, ri g ht u p per q ua dra nt 
pai n or te n der n ess, fe v er, ras h, or e osi n o p hi lia (> U L N ) felt b y t he I n vesti gat or t o be 
p ote ntiall y rel ate d t o he p atic i nfla m mati o n  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
6 2
 
8. 6. 2 
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 p ersiste nt c ha n ges  t hat are o bser ve d o ver 2 c o nsec uti ve wee ks, f or a n y of t he 
criteria b el o w, d osi n g of a patie nt wit h St u d y Dr u g ma y b e st o p pe d te m p oraril y: 
1.  Q ua ntitati ve t otal uri ne pr otei n meas ure m e nt of > 3. 5 g/ 2 4 h o urs 
2. Esti mate d creati ni ne cleara nce calc ul ate d acc or di n g t o t he f or m ula of C oc k cr oft a n d 
Ga ult ≤ 4 0 m L/ mi n t hat is c o nfir me d b y a 2 4- h o ur uri ne c ollecti o n  
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 ules f or Pl atelet C o u nt Res ults 
Acti o ns t o be ta ke n i n t he e ve nt of a l o w platelet c o u nt are s u m marize d i n Ta ble 4  bel o w. 
I n t he e ve nt of a platelet c o u nt less t ha n 7 5, 0 0 0/ m m3 t hat is ass ociate d wit h maj or blee di n g or 
cli nicall y-rele v a nt n o n-m aj or blee di n g ( d e fi ne d bel o w; Sc h ul ma n et al. 2 0 0 5 ), d osi n g of a patie nt 
wit h St u d y Dr u g  will be st o p pe d per ma ne ntl y.  T h e f oll o w-u p sc h e 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 ni t or. 
I n t he e ve nt of a n y platel et c o u nt less t ha n 5 0, 0 0 0/ m m 3, or a platelet c o u nt less t ha n 7 5, 0 0 0/ m m3 
t hat occ urs w hile t he p atie nt is o n d osi n g at 3 0 0 m g e v er y 2 w ee ks t he n d osi n g of a p atie nt wit h 
v ola nes orse n will be st o p pe d per ma n e ntl y.  Platelet c o u n t will be m o nit ore d as o utli ne d i n 
Ta ble  4. 
A d mi nistrati o n of c ortic o ster oi ds is rec o m me n de d f or patie nts w h ose plat elet c o u nt is less t ha n 
5 0, 0 0 0/ m m 3.  Rec o ver y i n platelet c o u nt ma y be accelerate d b y a d mi nistrati o n of hi g h d ose 
c ortic oster oi ds.  Tr eat me nt g ui deli nes f or i m m u ne t hr o m b oc yt o pe ni a (Pr o v a n et al. 2 0 1 0 ) 
rec o m me n d d e x a met has o ne 4 0 m g d ail y f or 4 da ys e ver y 2 - 4 w k f or 1-4 c ycles; pre d nis( ol) o ne 
0. 5- 2 m g/ k g/ d a y f or 2-4 wee ks t he n ta p er; or met h yl pre d nis ol o ne 3 0 m g/ k g/ da y f or 7 da ys  
(n ote:   ma y r e q uire c o nti n uati o n wit h oral c ortic o ster oi ds after met h ylpre d nis ol o ne). 
Tri gl yceri de le v els will be m o nit ore d wee kl y, a n d A E m o nit ori n g will c o nti n ue d uri n g 
c ortic oster oi d treat me nt a n d t he la b orat or y alert will be c ha n ge d fr o m a n i ncrease of 2, 0 0 0 t o 
5 0 0 m g/ d L d uri n g t hat peri o d. 
I n t he e ve nt of a platelet c o u nt less t ha n 7 5, 0 0 0/ m m3, a n d i n t he a bse nce of maj or blee di n g or 
cli nicall y-rele v a nt n o n- m aj or blee di n g ( d efi ne d bel o w; Sc h ul ma n et al. 2 0 0 5), d osi n g of a patie nt 
wit h St u d y Dr u g  will be s us pe n de d te m p oraril y u ntil t he platelet c o u nt has rec o vere d t o 
≥ 1 0 0, 0 0 0/ m m3.  If d osi n g is rei nitiate d it s h o ul d be at a re d uce d d os e fre q u e nc y of 3 0 0 m g e v er y 
2 wee ks (ref er t o Secti o n 8. 7 ).  T he s uita bilit y of t he patie nt f or rei nitiati o n of dosi n g 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 St u d y Me dical M o nit or a n d will be base d 
o n fact ors s uc h as t he ori gi nal r ate of d ecli ne i n t he patie nt’s platelet c o u nt, w het her a n y blee di n g 
e ve nts wer e e x perie nce d b y t he p atie nt, a n d t he s p ee d of rec o v er y of plat elet c o u nt u p o n h ol di n g 
of d osi n g. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
6 3
 
If after t he first d osi n g rec halle n ge t he plat elet c o u nt a gai n falls bel o w 7 5, 0 0 0/ m m 3, t he n d osi n g 
of t he patie nt wit h St u d y Dr u g will be s t o p pe d per ma ne ntl y. 
Defi niti o n of M aj or Blee di n g E ve n ts (Sc h ul ma n et al . 2 0 0 5): 
1.  Fatal blee di n g, a n d/ or 
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 ntra-art erial or p ericar dial, or i ntra m usc ular wit h 
c o m part me nt s y n dr o me, a n d/ or 
3. Blee di n g ca usi n g a f all i n he m o gl o bi n le vel of 2 0. 0 g/ L ( 1. 2 4 m m ol/ L) or m ore wit hi n 
2 4 h o urs, or lea di n g t o tr a nsf usi o n of 2 or m ore u nits of w h ole or re d cells 
Defi niti o n of Cli nic all y - Rele v a nt, N o n-M aj or Blee di n g E ve nts  ( Sc h ul ma n et al. 2 0 0 5): 
1. M ulti ple -s o urce blee di n g 
2.  S p o nta ne o us he mat o ma > 2 5 c m 2 
3.  E x cessi ve w o u n d he mat o ma ( n ot i njecti o n site relate d) 
4.  Macr osc o pic he mat uria (s p o nta ne o us or lasti n g > 2 4 h o urs if ass ociate d wit h a n 
i nter ve nti o n) 
5.  S p o nta ne o us rectal blee di n g; e pis tax is, gin gi v al blee di n g, he m o pt ysis, h e mate mesis  
6.  Blee di n g after v e ni p u nct ure f or > 5 mi n utes 
T a ble 4 
Acti o ns i n P atie nts wit h L o w Pl atelet C o u nt  or Dr o p i n Pl atelet C o u nt 
Pl at el et 
C o u nt o n R x  
Dr u g D o s e  
M o nit ori n g  
 
St u d y Dr u g  a d mi ni str ati o n i s c o nti n g e nt 
o n t h e a v ail a bilit y of t h e i m m e di at el y 
pr e c e di n g t e st r e s ult.   A n i nt er pr et a bl e 
pl at el et v al u e m u st b e a v ail a bl e wit hi n 
7  d a y s pri or t o d o si n g.  O nl y t h e st u d y 
d o ct or or q u alifi e d d e si g n e e c a n 
a ut h ori z e c o nti n u e d St u d y Dr u g  
a d mi ni str ati o n b a s e d o n a n a c c e pt a bl e 
pl at el et v al u e.  P ati e nt s s h o ul d n ot 
a d mi ni st er a d o s e u ntil t h e y h a v e b e e n 
c o nt a ct e d b y t h eir st u d y d o ct or or 
d e si g n e e a n d t ol d t h at it i s a c c e pt a bl e t o 
d o s e.  A ut h ori z ati o n t o d o s e m u st b e 
d o c u m e nt e d i n t h e p ati e nt’ s m e di c al 
r e c or d s. 
M o nit or e v er y 1 w e e k u nl e s s ot h er wi s e 
s p e cifi e d  
O bt ai n a d diti o n al l a b t e st s ( T a bl e  3) if 
2 o c c urr e n c e s ( c o n s e c uti v e or n o n-
c o n s e c uti v e) of pl at el et c o u nt  
1 4 0 K - > 1 0 0 K/ m m 3 or 1 o c c urr e n c e of 
pl at el et c o u nt ≤ 1 0 0 K/ m m 3 .  L a b s o nl y 
n e e d t o b e  p erf or m e d o n c e.  L a b s m a y 
b e c oll e ct e d o v er m ulti pl e vi sit s, if bl o o d 
r e q uir e m e nt s ar e a c o n c er n, a s p er 
I n v e sti g at or di s cr eti o n.  
>  1 0 0 K/ m m 3  
W e e kl y 3 0 0 m g St u d y Dr u g  
a d mi ni str ati o n  
 
 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
6 4
 
T a ble 4  
Acti o ns i n P atie nts wit h L o w Pl atelet C o u nt or Dr o p i n Pl atelet C o u nt  
C o nti n ue d  
Pl at el et 
C o u nt o n R x  
Dr u g D o s e  
M o nit ori n g  
1 0 0 K/ m m 3  - 
> 7 5 K/ m m 3  
P er m a n e ntl y r e d u c e d o s e fr e q u e n c y t o 
3 0 0  m g e v er y 2  w e e k s  
 
7 5 K/ m m 3  
- > 5 0 K/ m m 3  
If o c c ur s w hil e o n d o s e of 3 0 0 m g e v er y 
2 w e e k s t h e n p er m a n e ntl y di s c o nti n u e 
St u d y Dr u g, ot h er wi s e d o s e p a u s e  
W h e n pl at el et c o u nt r et ur n s t o 
> 1 0 0 K/ m m 3  r e st art d o si n g at d o s e 
fr e q u e n c y of 3 0 0 m g e v er y 2 w e e k s o nl y 
if a p pr o v e d b y S p o n s or M e di c al M o nit or 
M o nit or e v er y 2 -3 d a y s u ntil 
2 s u c c e s si v e v al u e s ar e > 7 5 K/ m m 3  t h e n 
m o nit or e v er y 1 w e e k  
C o n si d er di s c o nti n u ati o n of a nti pl at el et 
a g e nt s/ N S AI D S/ a nti c o a g ul a nt 
m e di c ati o n  
≤ 5 0 K/ m m 3  
 P er m a n e ntl y di s c o nti n u e St u d y Dr u g  
 M o nit or d ail y u ntil 2 s u c c e s si v e v al u e s 
s h o w i m pr o v e m e nt t h e n m o nit or e v er y  
2- 3 d a y s u ntil 2  s u c c e s si v e v al u e s ar e 
> 7 5 K/ m m 3 t h e n m o nit or e v er y 1 w e e k 
 P ati e nt s h o ul d b e e v al u at e d b y a 
h e m at ol o gi st t o pr o vi d e di a g n o sti c a n d 
t h er a p e uti c m a n a g e m e nt 
 St er oi d s r e c o m m e n d e d*.  It i s str o n gl y 
r e c o m m e n d e d t h at, u nl e s s t h e p ati e nt 
h a s a m e di c al c o ntr ai n di c ati o n t o 
re c ei vi n g gl u c o c orti c oi d s, t h e p ati e nt 
r e c ei v e s gl u c o c orti c oi d t h er a p y t o 
r e v er s e t h e pl at el et d e cli n e.   
 M o nit or tri gl y c eri d e l e v el s w e e kl y a n d 
c o nti n u e A E m o nit ori n g d uri n g st er oi d 
t h er a p y 
 Di s c o nti n u e a nti pl at el et a g e nt s/ 
N S AI D S/ a nti c o a g ul a nt m e di c ati o n 
w hil e pl at el et c o u nt i s  < 5 0 K/ m m 3  if 
p o s si bl e  
**  
Re c o v er y i n pl at el et c o u nt m a y b e a c c el er at e d b y a d mi ni str ati o n of hi g h d o s e  c orti c o st er oi d s.  Tr e at m e nt 
g ui d eli n e s f or i m m u n e t hr o m b o c yt o p e ni a ( Pr o v a n et al. 2 0 1 0 ) r e c o m m e n d d e x a m et h a s o n e 4 0 m g d ail y f or 
4 d a y s e v er y 2 -4 w k f or 1 -4 c y cl e s; p r e d ni s( ol) o n e 0. 5-2 m g/ k g/ d a y  f or 2-4 w e e k s t h e n t a p er; or 
m et h yl pr e d ni s ol o n e 3 0 m g/ k g/ d a y f or 7 d a y s ( n ot e:   m a y r e q uir e c o nti n u ati o n wit h or al c orti c o st er oi d s aft er 
m et h yl pr e d ni s ol o n e)  
 
8. 6. 4  
St o p pi n g R ule f or D oc u m e n te d Severe Hy p o glyce mi a 
I n t he e ve nt of a first i nsta nce of d o c u me nte d s e vere h y p o gl yce mia , d osi n g of a patie nt wit h 
St u d y Dr u g  will be s us pe n de d te m p oraril y.  T he n ee d t o a dj ust t he bac k gr o u n d me dicati o n a n d 
t he s uita bilit y of t he patie nt f or c o nti n ue d d osi n g 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 St u d y Me dical M o nit or .  I n t he e ve nt of a sec o n d i nst a nce of d o c u me nte d 
se vere h y p o gl yce mia, after a r ec h alle n ge, d osi n g of a patie nt wit h St u d y Dr u g will be st o p pe d 
per ma ne ntl y.  
8. 7 
A dj u st me nt of D ose a n d/ or Tre at me nt Sc he d ule 
D ose a dj ust me nts f or platelet c o u nt re d ucti o n m ust be ma de i n acc or da n ce wit h Secti o n 8. 6. 3  a n d 
Ta ble 4  a b o ve. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
6 5
 
Ot her d ose a dj ust me nts, i ncl u di n g d ose i nterr u pti o ns, a n d/ or decreasi n g t he d ose or d ose 
fre q ue n c y will be all o we d f or saf et y a n d t olera bilit y.  A n y pr o p os e d a dj ust me nt t o treat me nt 
sc he d ule m ust be disc uss e d wit h, a n d a p pr o v e d b y, t he St u d y Me dical M o nit or pri or t o i nitiati o n.  
D ose a dj ust me nts s h o ul d n ot occ ur u nless a bs ol ut el y n ecess ar y pri or t o t he pri ma r y a nal ysis ti me 
p oi nt ( M o nt h 3). 
Patie nts ma y be d os e pa use d i n res p o nse t o A Es after c o ns ultati o n wit h St u d y Me dical M o nit or. 
8. 8 
Disc o nti n u ati o n of St u d y Tre at me nt  
A patie nt  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 patie nt  bec o m es 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 patie nt  wit h dra ws c o nse nt  
 T he patie nt  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 
treat me nt 
 T he patie nt  de vel o ps la b orat or y test a b n orm alities t hat meet a n y of  t he st o p pi n g r ules 
liste d i n Secti o n  8. 6 
 T he patie nt  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 t o t he 
patie nt’s treat me nt assi g n me nt  
T he reas o n f or disc o nti n uati o n of s t u d y treat me nt m ust be rec or d e d i n t he electr o nic Cas e Re p ort 
F or m  (e C R F ) a n d s o ur ce d oc u me ntati o n. 
8. 8. 1  
F oll o w- u p Visits f or E arly Ter mi n ati o n fr o m Tre at m e nt a n d O L E Peri o d s 
P atie nts s h o ul d be str o n gl y e n c o ura ge d t o atte n d a p plica ble la n d mar k visits at Wee ks 1 2, 1 3, 2 5, 
2 6 a n d 5 0, 5 2 of Ra n d o mize d Treat me nt peri o d (calc ulate d bas ed o n t he ti me ela pse d si nce 
Da y  1) a n d at Wee ks  6 4, 6 5, 7 7, 7 8 a n d 1 0 2, 1 0 4 of O L E peri o d t o c ollect fasti n g li pi d pa nels 
a n d c o n d uct safet y assess me nts i n acc or d a nce wit h t he sc he d ule of pr oce d ures i n A p pe n di x A . 
A n y p atie nt w h o disc o nti n ues earl y fr o m treat me nt i n t he Ra n d o mize d Treat me nt Peri o d or O L E 
wit h platelet c o u nts < L L N s h o ul d be f oll o we d as per Secti o n 8. 5. 3  ( Safet y M o nit ori n g f or 
Platelet C o u nt Res ults ) a n d Secti o n 8. 6. 3  ( St o p pi n g R ules f or Platel et C o u nt Res ults) f or t he first 
6 wee ks after disc o nti n ui n g St u d y Dr u g.  F oll o wi n g t his peri o d, if t he plat elet c o u nt is sta ble (at 
least 3 c o nsec uti ve v al ues t hat are sta ble as deter mi ne d b y t he S p o ns or M e dical M o nit or a n d 
> 1 0 0, 0 0 0/ m m 3), t he ne xt platelet co u nt s h o ul d be ta ke n wit hi n at least 6 w ee ks s o t hat patie nts 
are m o nit ore d f or at least 1 2 wee ks after disc o nti n ui n g St u d y Dr u g.   
If t he patie nt decli nes or is u na ble t o partici pate i n t he a b o ve , a n earl y ter mi nati o n visit 
(Wee k  5 2 or Wee k 1 0 4 visit assess me nts ) s h o ul d be perf or me d at t he ti me of wit h dra wal, at a 
mi ni m u m, a n d i deall y wit hi n 2 wee ks fr o m t he last d ose of St u d y Dr u g. 
8. 8. 2  
F oll o w- u p Visits f or E arly Ter mi n ati o n fr o m P ost- Tre at m e nt F oll o w -u p Peri o d  
Patie nts s h o ul d be e nc o ura ge d t o u n der g o a fi nal f oll o w- u p visit ( Wee k 1 1 7 f or O L E f or 
p ost- treat me nt f oll o w-u p, see A p pe n di x A ) pri or t o lea vi n g t h e st u d y. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
6 6
 
T he patie nt w h o r e q uests t o wit h dra w fr o m t he st u d y d uri n g t he P ost- Treat me nt F oll o w - u p 
Peri o d wit h platelet c o u nts < L L N s h o ul d als o be e nc o ura ge d t o f oll o w t he platelet m o nit ori n g 
r ules as per Secti o n 8. 5. 3  ( Safet y M o nit ori n g f or Platelet C o u nt Res ults) a n d Secti o n  8. 6. 3 
( St o p pi n g R ules f or Platelet C o u nt Res ults) f or t he first 6 wee ks after disc o nti n ui n g St u d y Dr u g.  
F oll o wi n g t his peri o d, if t he platelet c o u nt is sta ble (at least 3 c o nsec uti ve val ues t hat are sta ble 
as deter mi ne d b y t he S p o ns or M e dical M o nit or a n d > 1 0 0, 0 0 0/ m m
3), t he ne xt platelet c o u nt 
s h o ul d be ta ke n wit hi n at least 6 wee ks s o t hat pati e nts are m o nit ore d f or at least 1 2 wee ks after 
disc o nti n ui n g St u d y Dr u g. 
If a patie nt wit h dr a ws d u e t o a n A E at a n y ti me d uri n g t he st u d y, t he I n v esti gat or s h o ul d arra n ge 
f or t he patie nt t o ha v e a p pr o priate f oll o w- u p u ntil t he A E has res ol v e d or st a bilize d. 
8. 9  
Wit h dr a w al of P atie nt s fr o m the S t u d y 
Patie nt s 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 patie nt  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 patie nt s 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. 
A n y p atie nt  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 patie nt s 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  (s ee pr o ce d ur es a n d assess me nts f or E arl y Ter mi nati o n/ Wee k 5 2/ 1 0 4; see Secti o n 8. 8  
a n d A p pe n di x A ). 
F or patie nt s wit h dra 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 de t o c o m plete t he  earl y termi nati o n st u d y pr oce d ures a n d o bs er vati o ns at t he ti me of 
wit h dra wal  (s ee pr o ce d ur es a n d assess me nts f or E arl y Ter mi nati o n/ Wee k 5 2/ 1 0 4; see Secti o n 8. 8 
a n d A p pe n di x A). 
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 patie nt ’s 
eC R F .  A Es  rel ate 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 priat e e C R F. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
6 7
 
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 si g ni n g 
i nf or me d c o nse nt a n d c o m pleti o n of t he p ost- treat me nt f oll o w- u p peri o d.  All c o nc o mita nt 
me dicati o ns/treat me nts a n d si g nifica nt n o n - dr u g t hera pies (i n cl u di n g s u p pl e me nts a n d assisti ve 
de vices) r ecei ve d b y a p atie nt, i ncl u di n g c ha n ges i n t he patie nt’s c urre nt me dicati o ns, m ust be 
rec or d e d i n t he patie nt’s s o urce d oc u m e nts a n d C R F.  Patie nts ta ki n g o ver-t he-c o u nter o me ga - 3 
fatt y aci ds s h o ul d ma ke e ver y eff ort t o re mai n o n t he sa me bra n d t hr o u g h o ut t he st u d y. 
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 nt t hera p y. 
Dis all o w e d C o nc o mit a nt T her a p y 
N o li pi d l o weri n g t hera pi es (e. g., fi br ates, niaci n, fis h oil or ot her pr o d ucts c o ntai ni n g o me ga- 3 
fatt y aci ds [i ncl u di n g O T C pre parati o ns], plas ma a p heresis), G L P-1 a g o nists or s yste mic 
c ortic oster oi ds ma y be st arte d or a dj uste d after scree ni n g (e x ce pt as d escri b e d i n Secti o n 8. 5. 6 ) 
a n d d oses of e xisti n g oral a nti- dia betic me dicati o n, oral c o ntrace pti ves, h or m o ne re place me nt 
thera p y, a ntic o a g ula nts, or dr u gs or dietar y s u p ple me nts wit h p ote ntial li pi d- alteri n g effects 
s h o ul d n ot be a dj uste d (e x ce pt as descri be d i n Secti o n s 8. 5. 7 a n d 8. 5. 8 ). 
St u d y p atie nts ar e pr o hi bite d fr o m recei vi n g ot h er e x peri me ntal a ge nts d uri n g t he st u d y.  T his 
i ncl u des mar kete d a ge nts at e x peri me ntal d osa ges t hat are bei n g test e d f or t he treat me nt of 
h y pertri gl yceri d e mia.  
Patie nts s h o ul d c o ns ult wit h t he Site I n vesti gat or or desi g n ee pri or t o i nitiati n g a n y n e w 
me dicati o n, i ncl u di n g n o n- prescri pti o n or her bal c o m p o u n ds or a n y ot h er n o n- dr u g t hera p y.  
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 i nf or me d c o ns e nt a n d Wee k 6 5 visit. 
Dis all o w e d C o nc o mit a nt Pr oce d ure 
Plas ma a p heresis is n ot all o we d d uri n g t he st u d y. 
8. 1 1 
Tre at me nt C o m pli a nce  
C o m plia nce wit h treat me nt d osi n g is t o be m o nit ore d a n d rec or d e d b y St u d y Ce nter staff.  T h e 
St u d y C e nter staff is re q uire d t o d oc u me nt t he recei pt, dis pe nsi n g, a n d ret ur n / destr ucti o n of 
St u d y Dr u g s u p plies.  Patie nts w h o  are s elf-a d mi nisteri n g St u d y Dr u g at h o me m ust rec or d 
treat me nt i n a d osi n g diar y t hat will be re vie we d p eri o dicall y b y St ud y Ce nter staff a n d t he 
Cli nical M o nit or.  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
6 8
 
9. 
S E RI O U S A N D N O N -S E R I O U S A D V E R S E E V E N T RE 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 in acc or da nce wit h 
t he Safet y Ma na ge me nt 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 is res p o nsi ble f or re g ul at 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 
seri o us a d vers e e v e nts ( S A Es) i ncl u di n g s us p ecte d u ne x pecte d seri o us a d verse reacti o ns 
( SU S A Rs) per t he I nter n ati o nal C o nfere n ce o n H ar m o nizati o n (I C H) g ui d eli nes E 2 A a n d I C H 
E 6 .  C o u ntr y-s p ecific r e g ulat or y re q uire m e nts will be f oll o we d i n acc or d a n ce 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 (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.  T he i n d e pe n de nt D S M B will be n otifie d of a n y S A E 
as s pecifie d i n t he D S M B c harter.  
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 hile 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 whet 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  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 will s u b mit S U S A Rs t o Re g ulat or y A ge nci es 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 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 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 v esti 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. 
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. 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
6 9
 
9. 3. 3 
Seri o us A dverse Eve nt ( S A E)  
A S A E  is a n y A E  t hat i n t he vie w of eit her t he I n v esti 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 patie nt  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 p atie nt  ( w het her t he 
patie nt  is male or fe mal e) 
 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 patie nt a n d ma y re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt 1 of t he o 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 nts 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 patie nt  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 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 p atie nt  safet y, a n d i n or d er 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 v e nt.  T he c ollecti o n of S A Es will 
be gi n after t h e patie nt  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 patie nt’s 
f oll o w- u p peri o d w hic h is defi ne d as t he Wee k 6 5 visit f or patie nts n ot c o nti n ui n g wit h t he O L E 
a n d g oi n g str ai g ht t o  t he P ost-Treat me nt F oll o w - u p peri o d or t he Wee k 1 1 7 visit f or patie nts w h o  
c o nti n ue wit h t he O L E.  W he n  t he I n v esti 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 vers us lea vi n g a messa ge.  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 x e d t o t he S p o ns or. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
7 0
 
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 patie nt ’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 
patie nt ’s c o n diti o n is u nli kel y t o r es ol ve, t he I n v esti 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 patie nt  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 patie nt ’s f oll o w-u p peri o d , w hic h is defi ne d as t he Wee k 6 5 visit 
f or patie nts n ot c o nti n ui n g wit h t he O L E a n d g oi n g strai g ht t o t he P ost-Treat me nt F oll o w - u p 
peri o d or t he Wee k 1 1 7 visit f or patie nts w h o  c o nti n ue wit h t he O L E.  T he I n vesti gat or will 
m o nit or eac h  patie nt cl os el y a n d rec or d all o bser v e 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 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 is c h aracterize d b y 1 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 p atie nt ’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 a d mi nistrat i 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 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 rel ati o ns hi p t o 
St u d y Dr u g 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 p e 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  p atie nt ’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  
9. 4. 3. 2 
Severity  
T he e ve nt’s s e verit y is c h aract erize d b y 1 of t he f oll o wi n g: 
 Mil d:   T he e ve nt is easil y t oler ate d b y t he patie nt a n d d oes n ot affect t he p atie nt’s us ual 
dail y acti vities  
 M o der ate:   T he e ve nt ca uses t he patie nt m ore dis c o mf ort a n d i nterr u pts t he patie nt’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 
patie nt’s us ual dail y acti vities  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
7 1
 
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 d ue t o t he e v e nt is c haracterize d b y 1 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 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 a ril y I nterr u pte d, Rest arte d – S a me D ose :  D osi n g was te m p oraril y 
i nterr u pte d or del a ye d d u e t o t he A E  a n d restarte d at t he sa me d ose  
 Re d uce d Sc he d ule :  D osi n g fre q ue n c y was re d uce 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 1 of t he f oll o wi n g: 
 A E Persists:   Patie nt 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:   Patie nt r ec o vere d c o m plet el y fr o m t h e 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 1 of t he f oll o wi n g: 
 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):  Patie nt has n ot f ull y rec o 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 dat e of o nset of t hat A E) 
 Rec o vere d:   Patie nt  r ec o vere d c o m plet el y fr o m t h e S A E (t he date of rec o v er 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:   P atie nt 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. 4. 4 
A dj u dic ati o n C o m mittees  
All S A Es t hat occ ur d uri n g t he st u d y t hat are c o nsiste nt wit h a maj or a d verse car di o v asc ular 
e ve nt ( M A C E) will be a dj u dicate d b y a bli n de d, i n de pe n de nt c o m mittee as o utli ne d i n t he 
M A C E A dj u dicati o n C harter.  I n a d diti o n, t his c o m mittee will als o a dj u dicate t he data f or 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
7 2
 
e pis o des of M A C E o ver t he last 3 years pri or t o ra n d o mizati o n, c ollecte d b y re vie w of eac h 
patie nt’s me dical c h art.  
All A Es a n d S A Es t hat occ ur d uri n g t he st u d y t hat are c o nsiste nt wit h a n e v e nt of ac ute 
pa ncreatitis will be a dj u dicate d b y a bli n de d, i n de pe n de nt c o m mittee acc or di n g t o t he Atla nta 
classificati o n of ac ute pa ncreatitis ( Ba n ks et al. 2 0 1 3 ) a n d as o utli ne d i n t he Pa ncreatitis 
A dj u dicati o n C harter. 
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. 
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 ule 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 p atie nt  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 patie nt ’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 patie nt ’s c o nse nt t o parti ci pate i n t he St u d y a n d t he 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 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 d escri 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 p atie nt  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 h e e v e nt acci d e ntal or i nte nti o nal.  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
7 3
 
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 patie nt  ta kes a d ose 
of St u d y Dr u g t hat e x cee ds pr ot oc ol s pecificati o ns a n d t he patie nt  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 o c u me nte d as a n A E  a n d b e re p ort e d per Secti o n  9. 4. 
S h o ul d a n o ver d ose occ ur , t he I n vesti gat or or d esi g nee s h o ul d refer t o t he G ui da nce t o 
I n v esti gat or’s secti o n of t he I n vesti gat or’s Br o c h ure a n d c o ntact t he S p o ns or or desi g nee wit hi n 
2 4 h o urs. 
9. 5. 4  
C o ntr ace pti o n a n d Pre g n a ncy 
Male patie nts a n d f e male patie nts of c hil d beari n g p ote ntial  m ust c o nti n ue t o use a p pr o pri ate 
c o ntrace pti o n wit h t heir part ners, 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 patie nt b ec o mes pr e g na nt or a pr e g na nc y is s us pecte d, or if a male pati e nt ma kes or belie v es 
t hat he has ma de s o me o n e pre g na nt d uri n g t h e st u d y, t he n t he St u d y Ce 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 nee wit hi n 2 4 h o urs  of first lear ni n g of t he o cc 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 nati o n is re p orte d o n F oll o w- u p Pre g na n c 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 bstetrical care, c hil d or relate d care will be t he patie n t’s 
res p o nsi bilit y. 
Fe male p atie nts:  If a s us pecte d pr e g na nc y o cc urs  w hile  o n t he st u d y (i n cl u di n g F oll o w- u p), a 
pre g na nc y t est will be perf or me d.  T h e patie nt  wit h a c o nfir me d pre g na n c y will be i m me diatel y 
wit h dra w n fr o m tr eat me nt wit h St u d y Dr u g .  H o w e ver, t he p atie nt  will be e nc o ura ge d t o 
c o m plete t he p ost- treat me nt f oll o w- u p p orti o n of t he st u d y t o t he e xte nt t hat st u d y pr oce d ures d o 
n ot i nterfere wit h t he pre g na n c y.  Re gar dless of c o nti n ue d st u d y partici p ati o n, t he st u d y 
p h ysicia n will assist t he patie nt  i n getti n g o bstetri cal care a n d t h e pr o gress of t he pre g n a nc y will 
be f oll o we d u ntil t he o utc o me of t he pre g na n c 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 n a 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 ma y r e q uire access t o t he m ot her a n d i nfa nt’s me dical rec or ds f or a n a d diti o nal 8 wee ks 
after birt h.  
Male patie nts:  T he pr o gr ess of t he pre g n a nc y i n a male patie nt ’s part n er 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 n ati o n, or s p o nta ne o us 
a b orti o n).  If t he pre gna n c y res ults i n t he birt h of a c hil d, a d diti o nal f oll o w- u p i nf or mati o n ma y 
be re q uest e d f or t he m ot h er a n d i nf a nt.  F oll o w- u p will be perf or me d t o t he e xte nt per mitte d b y 
a p plica ble r e 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  
F or all li pi d para m eters , t he baseli ne is defi n e d as t he a vera ge of Da y 1 pre-d ose assess me nt a n d 
t he last fasti n g meas ure m e nt pri or t o Da y 1. 
T he pri mar y a n al ysis ti me p oi nt is at t he e n d of M o nt h 3 w here t he v al ue at pri mar y a nal ysis 
ti me p oi nt is defi ne d as t he a ver a ge of Wee k 1 2 an d Wee k  1 3 fasti n g assess me nts .  T he val ue at 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
7 6
 
t o detect a 4 0 % differ e nce i n T G le vels bet w ee n treat me nt gr o u ps at a n al p ha le vel of 0. 0 5, 
ass u mi n g 5 0 % r e d ucti o n i n t he I SI S 3 0 4 8 0 1 treate d patie nts a n d 1 0 % re d u cti o n i n t he place b o 
patie nts . 
A sa m ple size of 3 5 patie nts ( 2 0 acti ve a n d 1 5 c o ntr ol) pr o vi des 9 2 % p o w er t o detect a li ver fat 
treat me nt differe nce of 4. 7 % base d o n a b et wee n p atie nt sta n dar d de vi ati o n of 4 % a n d a 
t w o-si de d al p ha of 0. 0 5. 
1 0. 3  
P o p ul ati o ns 
F ull A nal ysis Set ( F A S) :  All patie nts w h o are ra n d o mize d a n d recei ve d at least 1 d ose of St u d y 
Dr u g a n d ha v e a Bas eli ne  T G assess me nt .  T h e F A S re pres e nts t he practicall y -feasi ble i nte nt-t o-
treat (I T T) p op ulati o n as deli neate d i n I C H G ui deli ne E 9. 
Per Pr ot oc ol Set ( P P S) :  S u bset of t he F A S w h o recei ve d 9 of 1 3 d oses a n d wit h 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 affect efficac y a n d P D assess me nts.  T he detaile d 
criteria will be s peci fie d a n d fi nalize d pri or t o t he fi nal data bas e l oc k. 
Safet y Set :  All patie nts w h o are ra n d o mize d a nd recei v e at least 1 d ose of St u d y Dr u g . 
P K P o p ulati o n :  All patie nts w h o are r a n d o mize d, recei v e at least 1 d ose of acti ve St u d y Dr u g  
(I SI S 3 0 4 8 0 1), a n d ha v e at least 1 P K sa m ple c oll ecte d a n d a nal yz e d.  
1 0. 4 
Defi niti o n of B aseli ne  
T he baseli ne f or fasti n g li pi d meas ure me nts is defi ne d as t he a vera ge of Da y 1 pre- d ose 
assess me nt a n d t he last meas ure me nt pri or t o Da y 1 .  T he baseli ne f or ot h er meas ure me n ts is 
defi ne d as t he l ast n o n- missi n g assess me nt pri or t o t he first d ose of St u d y Dr u g. 
1 0. 5 
I nteri m A n al ysis a n d E arl y St o p pi n g G ui deli nes 
A n i nteri m a nal ysis of t he st u d y is n ot pla n ne d. 
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 dat a 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 patie nt data listi n gs.  Patie nt data listi n gs will be prese nt e d f or all patie nts 
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 di n g n, mea n, me dia n, sta n dar d 
de viati o n, sta n dar d err or, i nter q uartile ra n ge ( 2 5t h perce ntile, 7 5t h perce ntil e), 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 c o 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 b y treat me nt gr o u p .  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 p e I err or 
rates u nless ot her wise state d. 
All pri mar y, s ec o n dar y 
 e n d p oi nts will be assesse d i n t he F A S  a n d P P S , 
wit h t he f or mer bei n g t he basis f or t he pri mar y effi cac y a nal ysis .  All safet y assess me nts will be 
perf or me d o n t h e Safet y Set .  P K e n d p oi nts will be assesse d i n t he P K Set as a p plica ble.  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
7 7
 
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 n e c har acteristics  will be s u m marize d usi n g descri pti ve statistics b y 
treat me nt gr o u p.  T he p atie nt dis p ositi o n will be s u m marize d  b y treat me nt gr o u p .  All patie nts 
e nr olle d will be i ncl u de d i n a s u m mar y of patie nt dis p ositi o n. 
1 0. 6. 2 
S afety A n alysis  
Treat me nt d ur ati o n a n d a m o u nt of St u d y Dr u g  recei ve d will be s u m marize d b y treat me nt gr o u p. 
Patie nt i nci de nce r ates of A Es  will be ta b ulate d b y 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, Me d D R A preferre d  ter m, a n d treat me nt gr o u p.  Narrati ves of 
treat me nt-e mer ge nt  deat hs, seri o us a n d si g nifi ca 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, all 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 rel ate d t o 
St u d y Dr u g will be s u m marize d.  
Injecti o n Site a d verse e v e nts  will be s u m marize d b y treat me nt gr o u p, Me d D R A preferre d ter m 
a n d se verit y. 
La b orat or y tests t o e ns ur e patie nt saf et y i n cl u di n g c he mistr y p a nel, c o m plete bl o o d c o u nt ( C B C) 
wit h differe ntial, c o a g ulati o n pa nel, i m m u n o ge nicit y, 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 h ese 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 v er ti me after St u d y Dr u g  a d mi nistrati o n, as a p pr o pri ate. 
Vital si g n s a n d E C G meas ures  will be ta b ulate d b y treat me nt gr o u p . 
1 0. 6. 3 
Effic acy A n alysis ( Pri m ary a n d Sec o n d ary)  
T he pri mar y efficac y a n al ysis will be t he c o m paris o n of perce nt c ha n ge fr o m Baseli ne  t o t he 
pri mar y a nal ysis ti me p oi nt i n fasti n g T G bet w ee n I SI S  3 0 4 8 0 1 3 0 0 m g o nce- wee kl y gr o u p a n d 
place b o gr o u p i n t he F A S.  T he data will be a nal yze d usi n g a n a n al ysis of  c o varia n ce 
( A N C O V A) m o d el wit h t he ra n d o mizati o n stratificati o n fact or (dia g n osis of disease wit h or 
wit h o ut ge netics  a n d fa mil y hist or y) a n d Baseli ne  T G as c o variates .  I n t he A N C O V A m o del, 
T G will be l o g -tr a nsf or m e d.  Patie nts wit h a missi n g pri mar y e n d p oi nt will ha ve T G val u e 
m ulti pl y i m p ute d usi n g a n i m p utati o n m o del t hat c o ntai ns t he f oll o wi n g v aria bles:  baseli ne T G, 
T G val ues at p ost- bas eli ne visits a n d t he stratificati o n fact or, a n d t h e m ulti ple i m p utati o n will be 
stratifie d b y treat me nt (S c hafer 1 9 9 7 ; Sc hafer 1 9 9 9 ).  A n y patie nt w h o disc o nti n ues earl y fr o m 
t he Treat me nt Peri o d will be str o n gl y e n c o ura ge d t o atte n d a p plica ble la n d mar k visits i ncl u di n g 
Wee ks 1 2 a n d 1 3 d uri n g w hic h T G val ues will be c ollecte d a n d us e d i n t he pri mar y a nal ysis. 
T he pri m ar y efficac y a n al ysis will ta ke place after t he last patie nt has c o m plete d t he Wee k 5 2/ E T 
visit a n d t he data base h as bee n l oc ke d, a n d will be base d o n t he perce nt c ha n ge fr o m Baseli ne  i n 
fasti n g T G at t he pri mar y a nal ysis ti me p oi nt (e n d of M o nt h 3). 
A fe w  se nsiti vit y a nal yses usi n g c o ntr olle d i m p utati o ns ( patter n mi xt ure m o dels ( P M M) wit h 
A N C O V A) will be c o n d ucte d t o assess t he r o b ust ness of t he pri mar y a nal ysis res ults o n b ot h t he 
F A S a n d P P S .  Wit h t his a p pr oac h, missi n g n ot at ra n d o m ( M N A R) is ass u me d a n d t he mea n 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
7 8
 
f u ncti o n f or t he missi n g data fr o m patie nts w h o disc o nti n ue t he st u d y is pre-s pecifie d i n w a ys 
t hat assess t he r o b ust ness of t he M A R ass u m pti o n.  T he mea n f u n cti o n para meterizati o n will be 
c o m plete d usi n g t he f oll o wi n g a p pr oac hes: 
 Patie nts treate d wit h v ola nes orse n w h o disc o nti n u e t he st u d y d u e t o lac k of efficac y or 
A d verse E v e nts  or ot her t y p es of treat me nt fail ure will ha ve missi n g p ost -treat me nt 
disc o nti n uati o n T G  val ues m ulti pl y i m p ute d usi n g esti mates fr o m t he place b o patie nts.  
S pecificall y, t he c o p y i ncre me nt fr o m refere n ce ( CI R) a p pr oac hes will be us e d.  
Ot her wise, n o n- i nf or mati ve missi n g data will be i m p ute d usi n g MI met h o d as t he sa me as 
t he pri mar y a n al ysis 
 All patie nts treate d wit h v ol a nes orse n  w h o disc o nti n ue t he st u d y will ha ve missi n g p ost-
treat me nt disc o nti n uati o n T G  val ues m ulti pl y i m p ute d usi n g esti mates fr o m t he place b o 
patie nts.  S pecificall y, t he c o p y i ncre me nt fr o m refere n ce ( CI R) a p pr o ac hes will be use d  
 Patie nts treate d wit h v ola nes orse n w h o disc o nti n u e t he st u d y will ha ve missi n g p ost-
disc o nti n uati o n T G val ues m ulti pl y i m p ute d base d o n baseli ne T G a n d t h e i m p utati o n 
m o del f or t he place b o 
T he a d diti o nal se nsiti vit y a nal ys es will be c o n d u cte d f or t he pri mar y efficac y a n al ysis, a n d 
details of t he a nal ys es will be s pecifie d i n t he S A P: 
 T he pri mar y a n al ysis will be re peate d i n t he P P S  
 T he pri mar y a n al ysis will be re peate d i n t he s u bset of F A S w h o ha v e a n o n- missi n g 
pri mar y e n d p oi nt 
 T he f oll o wi n g a nal yses will be c o n d ucte d o n b ot h t he F A S a n d P P S:  
o  T he pri mar y a n al ysis will be re peate d t o c o m pare t he perce nt c ha n ge fr o m Baseli ne  t o 
a vera ge of Wee ks 8 ( Da y 5 0), 1 2 ( Da y 7 8) a n d 1 3 ( Da y 8 5) b et wee n treat m e nt 
gr o u ps.  Missi n g data will n ot be i m p ute d 
o  T he pri mar y efficac y e n d p oi nt will be a nal yze d usi n g Wilc o x o n ra n k- s u m test f or 
se nsiti vit y a nal ysis, a n d t he treat me nt effect will be esti mate d usi n g H o d ges- Le h ma n n 
esti mat or 
o  F or t he r es p o n der a nal ysis descri be d a b o ve, all patie nts wit h a missi n g pri mar y 
e n d p oi nt will be c o nsi der e d as n o n- resp o n ders 
o  T he pri mar y efficac y e n d p oi nt will als o be a nal yze d usi n g t he n o n para metri c 
Wei -J o h ns o n me t h o d 
Sec o n dar y  
 efficac y a nal yses will be c o n d ucte d i n b ot h t he F A S a n d P P S, a n d 
descri be d f ull y i n t he S A P: 
 C ha n ge fr o m Baseli ne i n he patic fat fracti o n ( %) as assesse d b y M RI will be c o m pare d 
bet wee n I SI S  3 0 4 8 0 1 3 0 0 m g q w a n d pl ace b o gr o u ps usi n g a n A N C O V A m o del wit h 
baseli ne a n d t he str atificati o n fact or as c o v ariates  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
7 9
 
 C ha n ge fr o m Baseli ne i n H b A 1c will be c o m pare d bet wee n  I SI S 3 0 4 8 0 1 3 0 0 m g 
o nce- w ee kl y  a n d place b o gr o u p usi n g a n A N C O V A m o del wit h baseli ne a n d t he 
stratificati o n fact or as c o variates 
 Pr o p orti o n of patie nts w h o ac hie ve a ≥ 4 0 % re d ucti o n i n fasti n g T G fr o m Baseli ne a n d 
≥ 3 0 % re d ucti o n of h e patic fat f racti o n perce nt fr o m baseli ne at M o nt h 6 bet wee n 
I SI S 3 0 4 8 0 1 3 0 0 m g o nce- wee kl y a n d place b o gr o u p will be a nal yze d usi n g a l o gistic 
re gressi o n m o del wit h t h e ra n d o mizati o n stratificati o n fact ors, l o g tra nsf or me d Bas eli ne 
T G, a n d Baseli ne he p atic fat fracti o n as c o v ariates.  Missi n g data w ill be c o nsi dere d as 
i nf or mati ve missi n g f or p atie nts w h o disc o nti n ue t he st u d y pri or t o t he pri mar y a nal ysis 
ti me p oi nt d ue t o lac k of efficac y or A d v erse E ve nts or ot her t y p es of treat me nt fail ure; 
ot her wise, missi n g dat a will be c o nsi dere d as n o n- i nf or mati ve missi n g.  I n t he res p o n der 
a nal ysis, p atie nts wit h i nf or mati ve missi n g data will be treate d as n o n -res p o n ders.  
N o n -i nf or mati ve missi n g data will be ha n dle d usi n g t he sa m e m ulti ple i m p utati o n 
met h o d as t he pri mar y a n al ysis.  A nal ys es will als o be per f or me d i n w hic h t he a b o ve 
pri mar y a n d sec o n dar y efficac y e n d p oi nts are e val uate d at t he M o nt h 3, M o nt h 6, a n d 
M o nt h 1 2 a nal ysis ti me p oi nt s, w here a p plica ble.  T he effi cac y e n d p oi nts will als o be 
e val uate d at M o nt h 1 5, M o nt h 1 8, a n d M o nt h 2 4 i n t he O L E p eri o d as a p pr o priate.  
1 0. 6. 4  
P h ar m ac o ki netic a n d I m m u n o ge ni city A n alysis  
P K  a nal ysis will i ncl u de t he f oll o wi n g:  
 T o deter mi ne tr o u g h ( pre- d ose) a n d p ost- treat me nt I SI S 3 0 4 8 0 1 plas ma c o n ce ntrati o ns i n 
all patie nts w h o recei ve St u d y Dr u g.  F or all patie nts  w h o recei v e  I SI S 3 0 4 8 0 1 treat me nt, 
tr o u g h ( pre- d os e) a n d p ost-treat me nt I SI S 3 0 4 8 0 1 plas ma c o nce ntrati o ns will be 
s u m marize d b y treat me nt peri o d, d ose a n d St u d y Da y , wit h a n d wit h o ut stratificati o n b y 
i m m u n o ge nicit y stat us, usi n g descri pti ve statistics  
I mm u n o ge nicit y (I M) a n al ys es will i ncl u de t he f oll o wi n g: 
 T o e val uate I M (c o nfir me d p ositi ve/ ne gati ve a n d, w he n a p plica bl e, titer of a nti-
I SI S 3 0 4 8 0 1 a nti b o dies) bef ore, d uri n g, a n d after treat me nt wit h St u d y Dr u g  i n all 
e val ua ble p atie nts a n d a p pr o priatel y s u m marize  b y treat me nt peri o d, treat me nt a n d d ose 
o ver ti me  
 T o deter mi ne t he I M i n ci de nce ( n u m b er) a n d i nci de nce rate ( p erce nt) at eac h e val uat e d 
st u d y ti me p oi nt, a n d f or t he o verall treat me nt a n d p ost-treat me nt e val u ati o n peri o d a n d 
s u m marize b y treat me nt peri o d, treat me nt a n d d ose, as t he t otal n u m ber of a n d perce nt of 
e val uate d p atie nts wit h a nti b o d y ne gati ve, p ositi v e, a n d u n k n o w n stat us 
 St u d y p atie nts wit h p ositi ve a nti -I SI S 3 0 4 8 0 1 a nti b o d y stat us ma y be f urt h er classifie d 
( w he n a p plica ble) as bei n g eit her ‘ persiste nt’, ‘tra nsie nt’, or n ot deter mi na ble 
 T o e val uate p ote ntial r elati o ns hi ps of i m m u n o ge nicit y wit h selecte d efficac y, safet y, a n d 
P K  meas ures  
A d diti o nal details re gar di n g t he P K a n d i m m u n o ge nicit y a n al ysis will be descri be d i n t he S A P. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
8 0
 
P o p ulati o n P K  a n d c o variate a nal ysis ma y be p erf or me d if dee m e d a p pr o priate, a n d res ults will 
be re p ort e d se paratel y.  
A d diti o nal details re gar di n g t he P K  a n al ysis will be descri b e d i n t he S A P. 
 
 
 
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. 
Bef ore a p atie nt ’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 patie nt  after a de q u ate 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 u d y a n d b ef ore a n y pr ot oc ol- s pecifi c scree ni n g 
pr oce d ur es or a n y St u d y Dr u g ar e a d mi nistere d .  T he patie nt m ust be gi ve 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  p atie nt’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 patie nt’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 patie nt  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 n e 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 M aster File a n d i n a n y ot h er 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 h e 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 
patie nt . 
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 
1 9 Oct o ber  2 0 1 3 t he a p plica ble re g ul ati 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 d e ma n ds of nati o nal dr u g a n d data 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 patie nt  
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 bef ore recr uit me nt of patie nt s 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 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 p atie nts 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 h e I n v esti 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 RB 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 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
8 1
 
E 6  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 
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, i n acc or da nce wit h l ocal 
pr oce d ur es. 
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 on 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 su 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. 
1 1. 4 
P ati e nt  C o nfi de nti alit y  
T he I n vesti gat or m ust e ns ure t hat t he patie nt ’s c o nfi de ntialit y is mai ntai ne d .  O n t he cas e re p ort 
f or ms or ot her d o c u me nts s u b mitte d t o t he S p o ns or, patie nts 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 patie nt  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 (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 In v esti 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 E 6  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 patie nt ’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 v esti 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 patie nt  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 pati e nt . 
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.  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 m e n d me nts t o t he 
i nf or me d c o nse nt d oc u m e nt.  T he re g ul at 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 h e patie nt s or 
t he c o n d uct of t he tri al.  T he I n vesti gat or m ust  s e 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. 
1 2. 2 
St u d y Ter mi n ati o n  
T he S p o ns or  reser ves t he ri g ht t o ter mi nate t he St u d y.  T he I n 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 he ter ms of t h e site c o ntract.  T h e 
I n v esti gat or/ S p o ns or s h o ul d n otif y t he I E C/I R B i n writi n g of t he tri al’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. 
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 . 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
8 2
 
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 patie nt ’s case re p ort 
f or m 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 or at or y a n d p h ar mac y rec or ds, diaries, i ma gi n g, a nd 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 m e 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 I C H E 6, s uita ble f or i ns pecti o n at a n y ti me b y re prese nt ati ves fr o m t he S p o ns or 
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: 
 Patie nt  files c o ntai ni n g c o m plete d case re p ort f or ms, i nf 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 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  
 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 ng e ntries i n t he case re p ort f or ms m ust be 
mai ntai ne d a n d be r ea 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 
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 o t 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 . 
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., case re p ort f or ms a n d ot her perti ne nt data) pr o vi de d t hat 
patie nt  c o nfi de ntialit y is res pect e d.  
T he S p o ns or m o nit or is res p o nsi ble f or i ns pecti n g t he case re p ort f or ms at re g ul ar 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 patie nt  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 cas e re p ort f or ms. 
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 case re p ort f or ms, are res ol ve d. 
I n acc or da n ce wit h I C H E 6  a n d t he S p o ns or’s a u dit pla ns, t his St u d y ma y b e selecte 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 nic al Q ualit y Ass ura nce De part me nt .  I ns p ecti o n of 
St u d y C e nter  f acilities (e. g., p har mac 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 r ec or ds will occ 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 
E 6 , a n d a p plica ble re g ulat or y r e q uire me nts. 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
8 3
 
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 
patie nt  data recei ve d b y  t he S p o ns or.  D uri n g t his re vie w, patie nt  d ata 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 par e nt discre p a ncies.  I n a d diti o n, t he data will be re vie w e 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 v e a n y q uesti o ns arisi n g fr o m t he cli nical data 
ma na ge me nt r e vie w pr o cess, data q ueri es 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 C e nter  f or c o m pleti o n a n d ret ur n t o S p o ns or. 
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 cas e re p ort f or m .  T hese 
si g nat ur es will i n dicate t hat t he Pri nci pal I n vesti gat or i ns pecte d or re vie we d t he data o n t he case 
re p ort f or m, t he d ata q ueries, a n d t he St u d y Ce nt er 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 n a mes f or c o nc o mita nt me dicati o ns 
s h o ul d be rec or de d i n E n glis h if p ossi ble, u nless it is a c o m binati o n dr u g, t h e n rec or d t he t ra d e 
na me i n E n glis h. 
All writte n i nf or mati o n a n d ot her material t o be us e d b y p atie nt s 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 .  Patie nt s 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 ormati 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 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
8 4
 
1 3. 
R E F E R E N C E S  
A h me d Z , S u bra ma n ya m L, S zcze pa nia k L, et al. C h olic aci d f or he patic steat osis i n patie nts wit h li p o d ystr o p h y: a 
ra n d o mize d, c o ntr olle d trial. E urJ E n d ocri n ol 2 0 1 3. 
Ajl u ni N , Meral R, Nei dert A H, et al. S pectr u m of disease ass ociate d wit h partial li p o d ystr o p h y: less o ns fr o m a trial 
c o h ort. Clin E n d ocri n ol 2 0 1 7 . 
A ki nci B , O na y H, De mir T et al. Cli nical prese ntati o ns, met a b olic a b n or malities a n d e n d -or ga n c o m plicati o ns i n 
patie nts wit h fa milial partial li p o d ystr o p h y. Meta b olis m 2 0 1 7; 7 2: 1 0 9 -1 1 9.  
Alt ma n n K H, Fa b br ot D, Dea n N M, et al. Sec o n d ge n erati 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.  
Atz m o n G, Ri nc o n M, Sc hec hter C B, et al . Li p o pr otei n ge n ot y pe a n d c o nser ve pat h wa y f or e xce pti o nal l o n ge vit y i n 
h u ma ns . P L o S Bi ol 2 0 0 6; 4: 0 5 6 2 -0 5 6 9. e 1 1 3.  
B a n ks P A , B olle n TL , Der ve nis C, et al. Ac ute P a ncreatitis Classificati o n W or ki n g Gr o u p . Classificati o n of ac ute 
pa ncreatitis - 2 0 1 2: re visi o n of t he Atla nta classificati o n a n d defi niti o ns b y i nter nati o nal c o nse ns us . G ut 2 0 1 3; 6 2:  
1 0 2 -1 1 1.  
Bi da ult G , Garcia M, Va nt y g he m M C, et al. Li p o d ystr o p h y -li n ke d L M N A p. R 4 8 2 W m utati o n i n d uces cli nical earl y 
at her oscler osis a n d i n vitr o e n d ot helial d ysf u ncti o n. Arteri os cler T hr o m b Vasc Bi ol 2 0 1 3.  
Bre yer E D, Le N -A, Li X, et al. A p oli p o pr otei n C -III dis place me nt of a p oli p o pr otei n E fr o m V L D A L: e ffect of 
particle size . J Li pi d Res 1 9 9 9; 4 0: 1 8 7 5-1 8 8 2.  
Br o w n RJ, La g or W R, Sa n kar a nara va na n S, et al. I m pact of c o m bi ne d deficie nc y of he pati c li pase a n d e n d ot helial 
li pase o n t he meta b olis m of b ot h hi g h-de nsit y li p o pr otei ns a n d a p oli p o pr otei n B -c o ntai ni n g li p o pr otei ns . Circ Res 
2 0 1 0; 1 0 7: 3 5 7 -3 6 4.  
C ha n D C, C he n M M, O oi E M M, W atts G F. A n A B C of a p oli p o pr otei n C -III: a cli nicall y usef ul ne w car di o vasc ular 
ris k fact or? I nt J Cli n Pract 2 0 0 8; 6 2 : 6 7 4 -6 7 6 . 
C ha n J L  a n d  Oral E A . Cli nical classificati o n a n d treat me nt of c o n ge nital a n d ac q uire d li p o d ystr o p h y . E n d ocr Pract  
2 0 1 0;  1 6:  3 1 0 -3 2 3.  
C ha n, J L, L utz K, C oc hra n E, et al. Cli nical effects of l o n g -t er m metrele pti n treat me nt i n p atie nts wit h 
li p o d ystr o p h y. E n d ocr  Pract  2 0 1 1; 1 7( 6): 9 2 2 – 9 3 2.  
C o m mittee f or Or p ha n Me dici nal Pr o d ucts . P u blic S u m mar y of O pi ni o n o n Or p ha n Desi g nati o n . Metrele pti n f or t he 
treat me nt of fa milial partial li p o d ystr o p h y 2 0 1 2. 
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 he ra 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 os b y J, P el os o G, A uer P L, et al. T he T G a n d H D L W or ki n g Gr o u p of t he E x o me Se q ue nci n g Pr oj ect,  Nati o nal 
Hea rt, L u n g, a n d Bl o o d I nstit ute. L oss -of -fu ncti o n m utati o ns i n A P O C 3,  tri gl yceri des, a n d cor o nar y d isease. N E n gl 
J Me d 2 0 1 4; 3 7 1: 2 2 -3 1 . 
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.  
Di ker -C o he n C oc hra n E, G or de n T P, Br o w n RJ. P artial a n d ge neralize d li p o d ystr o p h y: C o m paris o n of baseli ne 
c haracteristics a n d res p o nse t o metrele pti n. J Cli n E n d ocri n ol Meta b 2 0 1 5 . 
D u n ni ga n M G, C oc hra ne M A, Kell y A, Sc ott J W. Fa milial li p oatr o p hic dia betes wit h d o mi na nt tra ns missi o n. A ne w 
s y n dr o me. Q J Me d 1 9 7 4; 4 3: 3 3-4 8.  
Gar g A. Ac q uire d a n d i n herite d li p o d ystr o p hies. N E n gl J Me d 2 0 0 4; 3 5 0: 1 2 2 0 -1 2 3 4.  

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
8 5
 
Gar g A . Cli nical re vie w #: Li p o d ystr o p hies: ge netic a n d ac q uire d b o d y fat dis or ders . J Cli n E n d ocri n ol Meta b  2 0 1 1; 
9 6: 3 3 1 3 -3 3 2 5.  
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 -al p ha p h os p h or ot hiate 2′ -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 olis m a n d Dis p ositi o n  
2 0 0 3; 3 1: 1 4 1 9 -1 4 2 8.  
Gra ha m MJ, Lee R G, B ell T A, et al . A ntise nse oli g o n ucle oti de i n hi biti o n of a p oli p o pr otei n C -III re d uces plas ma 
tri gl yceri des i n r o de nts, n o n h u ma n pri mates, a n d h u ma ns. Circ Res 2 0 1 3; 1 1 2: 1 4 7 9 -1 4 9 0 . 
Ha n dels ma n Y, Oral E A, Bl o o m gar de n Z T, et al. A merica n Ass ociati o n of Cli nical E n d ocri n ol o gists . T he cli nical 
a p pr oac h t o t he detecti o n of li p o d ystr o p h y - A n A A C E C o nse ns us State me nt . E n d ocr Pract  2 0 1 3; 1 9: 1 0 7 -1 1 6.  
He gele R A. Pre mat ure at her os cler osis ass ociate d wit h m o n o ge nic  i ns uli n resista nce. Circ  2 0 0 1; 1 0 3:  2 2 2 5 -2 2 2 9.  
He gele R A, J o y T R, Al -Attar S A, R utt B K . T he matic re vie w series: A di p oc yte Bi ol o g y. Li p o d ystr o p hies: Wi n d o ws 
o n a di p ose bi ol o g y a n d meta b olis m . J Li pi d  Res  2 0 0 7; 4 8: 1 4 3 3 -1 4 4 4 . 
He nr y S, 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 decreas e 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.  
H ua n g- D ora n I, Slei g h A, R oc hf or d JJ, et al. Li p o d ystr o p h y: meta b olic i nsi g hts fr o m a rare dis or der . J E n d ocri n ol 
2 0 1 0; 2 0 7: 2 4 5 -2 5 5 . 
I n o ue H, Ha yase Y, I wai S, O hts u ka E. 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 Lett 1 9 8 7; 2 1 5: 3 2 7 -3 3 0.  
It o Y, Azr ola n N, O' C o n nell A, et al. H y pertri gl yceri de mia as a res ult of h u ma n a p o CIII ge ne e x p ressi o n i n 
tra ns ge nic mice. Scie nce 1 9 9 0 A u g 1 7; 2 4 9: 7 9 0 -7 9 3.  
J ør ge nse n A B, Fri k ke-Sc h mi dt R, N or dest gaar d B G, T y bj aer g -Ha nse n A . L oss -of -f u ncti o n m utati o ns i n A P O C 3 
a n d ris k of isc he mic vasc ular disease . N E n gl J Me d 2 0 1 4; 3 7 1: 3 2 -4 1.  
Kassai  A, W alter M, A bel  B S , et al. A p oli p o pr otei n C III le vels are ele vate d i n li p o d ystr o p h y p atie nts. Acce pte d as a 
Late -Brea ki n g A bstract at t he E n d ocri ne S ociet y A n n ual Me eti n g, Marc h 5 - 8, 2 0 1 5, Sa n Die g o, C A. 
Ki n n u ne n P K a n d E h n ol m C . Effect of ser u m a n d C -a p o pr otei ns fr o m ver y l o w de nsit y li p o pr otei ns o n h u ma n 
p ost he pari n plas ma he patic li p ase . F E B S Lett  1 9 7 6; 6 5: 3 5 4 – 3 5 7.  
K ö b berli n g J, Will ms B, Katter ma n n R, Cre utzfel dt W. Li p o d ystr o p h y of t he e xtre mities. A d o mi na ntl y i n herite d 
s y n dr o me ass ociate d wit h li patr o p hic dia betes. H u ma n ge neti k 1 9 7 5; 2 9: 1 1 1-1 2 0.  
Le mie u x I, Sal o m o n H, Des pr és J P . C o ntri b uti o n of a p o CIII re d ucti o n t o t he greater effect of 1 2 -wee k micr o nize d 
fe n ofi brate t ha n at or vastati n t hera p y o n tri gl yceri de le vels a n d L D L size i n d ysli pi de mic patie nts. A n n Me d 2 0 0 3; 
3 5: 4 4 2 -4 4 8.  
Ma n n CJ, Tr o ussar d A A, Ye n F T, et al. I n hi bit or y effects of s pecific a p oli p o pr otei n C-III is of or ms o n t he bi n di n g of 
tri gl yceri de-ric h li p o pr otei ns t o t he li p ol ysis-sti m ulate d rece pt or. J Bi ol C he m 1 9 9 7; 2 7 2: 3 1 3 4 8 -3 1 3 5 4.  
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 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.  
Me n di vil C O, Z he n g C, F urta d o J, et al. Meta b olis m of ver y -l o w-de nsit y li p o pr otei n a n d l o w -de nsit y li p o pr otei n 
c o ntai ni n g a p oli p o pr otei n C -III a n d n ot ot her s mall a p oli p o pr otei ns. Arteri oscler T hr o m b Vasc Bi ol 2 0 1 0; 3 0: 
2 3 9 -2 4 5.  
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.  
M yale pt, F D A Briefi n g D oc u me nt, B L A 1 2 5 3 9 0, A m yli n P har mace uticals, Dece m ber 1 1, 2 0 1 3 . 
Nati o nal Or ga nizati o n f or Rar e Dis or ders [ N O R D] . T he P h ysicia n’s G ui de  t o Li p o d ystr o p h y Dis or ders 2 0 1 2.  

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol 
 
2 2 A u g ust 2 0 1 7 
 
8 6
 
N olis T. E x pl ori n g t he pat h o p h ysi ol o g y be hi n d t he m ore c o m m o n ge netic a n d ac q uire d li p o d ystr o p hies. J of H u ma n 
Ge n 2 0 1 4; 5 9: 1 6- 2 3.  
O oi E M M, Barrett P H R, C ha n D C, Watts G F. A p oli p o pr otei n C-III: U n dersta n di n g a n e mer gi n g car di o vasc ular ris k 
fact or. Cli n Scie nce 2 0 0 8; 1 1 4: 6 1 1- 6 2 4. 
Peterse n K F, D uf o ur S, Hariri A, et al . A p oli p o pr otei n C 3 ge ne varia nts i n n onalc o h olic fatt y li ver disease. N E n gl J 
Me d 2 0 1 0; 3 6 2: 1 0 8 2- 1 0 8 9. 
P olli n TI, Da mc ott C M, S he n H, et al. A n ull m utati o n i n  h u ma n A P O C 3 c o nfers a fa v ora ble plas ma li pi d pr ofile 
a n d a p pare nt car di o pr otecti o n. Scie nce 2 0 0 8; 3 2 2: 1 7 0 2- 1 7 0 5. 
Pr o va n D, Stasi R, Ne wla n d A C. et al. I nter nati o nal c o nse ns us re p ort o n t he i n vesti gati o n a n d ma na ge me nt of 
pri mar y i m m u ne t hr o m b oc yt o pe nia. Bl o o d 2 0 1 0; 1 1 5: 1 6 8- 1 8 6. 
R o b bi ns A L a n d Sa va ge D B. T he ge netics of li pi d st ora ge a n d h u ma n li p o d ystr o p hies. Tre n ds M ol Me d 2 0 1 5; 2 1: 
4 3 3- 4 3 8.  
Sa nt os R D, D uell P B, East C, et al . L o n g-ter m efficac y a n d safet y of mip o merse n i n patie nts wit h fa milial 
h y perc h olester olae mia: 2- year i nteri m res ults of a n o pe n-la bel e xte nsi o n. E ur Heart J 2 0 1 5; 3 6: 5 6 6- 5 7 5. 
Sc hafer J L. A nal ysis of I nc o m plete M ulti variate Data, Ne w Y or k: C ha p ma n a n d Hall 1 9 9 7. 
Sc hafer J L. M ulti ple i m p utati o n: a pri mer, Statistic al Met h o ds i n Me dical Researc h 1 9 9 9; 8: 3 – 1 5. 
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. 
S h ul ma n GI. Ect o pic fat i n i ns uli n resista nce, d ysli pi de mia, a n d car di o meta b olic disease. N E n gl J Me d 2 0 1 4; 3 7 1: 
1 1 3 1- 1 1 4 1. 
Slei g h A, Stears A, T hac kra y K et al. Mit oc h o n drail o xi dati ve p h os p h or ylati o n is i m paire d i n patie nts wit h 
c o n ge nital li p o d ystr o p h y. J Cli n E n d ocri n ol Me d 2 0 1 2; 9 7: E 4 3 8- 4 4 2. 
Vatier C, Bi da ult G, Bria n d N, et al. W hat t he ge netics of li p o d ystr o p h y ca n teac h us  a b o ut i ns uli n resista nce a n d 
dia betes. C urr Dia b Re p 2 0 1 3; 1 3 Se p ( o nli ne). 
W orl d Healt h Or ga nizati o n: Defi niti o n, dia g n osis a n d classificati o n of dia betes mellit us a n d i nter me diate 
h y per gl yce mia. Re p ort of a W H O/I D F C o ns ultati o n. Ge ne va, W orl d Healt h Or g. 2 0 0 6. 
Z ha n g H, L o 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 d ris k. Bl o o d 2 0 1 0; 1 1 6: 4 6 8 4- 4 6 9 2. 
 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
8 7
 
 
 
 
 
 
 
 
1 4. 
A P P E N DI C E S  
 
 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
8 8
 
 
 
 
 
 
 
 
A p pe n di x A  
Sc he d ule of Pr oce d ures 
 
Pl ace b o -C o ntr olle d  Peri o d  
F oll o w e d b y 
O pe n -L a bel  E xte nsi o n Peri o d  
 

I SI S 3 0 4 8 0 1- C S 1 7 
C O N FI D E N TI A L  
A me n d me nt 4 
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7 
 
9 3
 
A p pe n di x A  Sc he d ule of Pr oce d ures – Pl ace b o- C o ntr olle d C o nti n ue d 
F o ot n ot e s:  
a  
S cr e e ni n g pr o c e d ur e s p erf or m e d a n d t h e p ati e nt st art s t h e di et, lif e st yl e a n d m e di c ati o n st a bili z ati o n p eri o d.  U p t o 4 vi sit s m a y b e r e q uir e d d uri n g t h e di et 
st a bili z ati o n p eri o d i n or d er t o s c h e d ul e a n d c oll e ct M RI  
 a s s e s s m e nt s 
b  
H ei g ht o nl y r e q uir e d at S cr e e ni n g.  B o d y w ei g ht i s t o b e m e a s ur e d at S cr e e ni n g, W e e k 1, W e e k 1 3, W e e k 2 6, W e e k 5 2, a n d W e e k 6 5 
c  
E x p a n d e d uri n al y si s ( s e e A p p e n di x B ) 
d  
T o b e c oll e ct e d d uri n g s cr e e ni n g/r u n i n b ef or e W e e k - 2, if n e e d e d f or eli gi bilit y, ot h er wi s e t o b e c oll e ct e d b ef or e W e e k 1 2.  G e n eti c t e sti n g will o nl y b e 
c o n d u ct e d if all o w e d i n t h e g e o gr a p hi c r e gi o n a n d o nl y aft er t h e p ati e nt h a s gi v e n s p e cifi c wr itt e n i nf or m e d c o n s e nt f or g e n etic t e sti n g. If t h e p ati e nt d o e s n ot 
c o n s e nt t o t h e bl o o d s a m pl e a n d g e n eti c t e sti n g, b ut h a s d o c u m e nt ati o n of  pr e vi o u s g e n eti c t e sti n g f or p arti al li p o d y str o p h y, an d i s willi n g, a n d h a s c o n s e nt e d, 
t o pr o vi d e t h at d o c u m e nt ati o n t o t h e sit e, t hi s s h o ul d i d e all y b e pr o vi d e d b y t h e ti m e of t h e q u alifi c ati o n vi sit.  R e s ult s fr om pr e vi o u s g e n eti c t e sti n g s h o ul d b e 
d o c u m e nt e d pri or t o r a n d o mi z ati o n/ str atifi c ati o n 
e  
Bl o o d s a m pl e s t o b e c oll e ct e d aft er a n o v er ni g ht f a st of at l e a s t 1 0 h o ur s, a n d pr ef er a bl y n o l o n g er t h a n 1 2 h o ur s.  D uri n g tr e at m e nt p eri o d, uri n e a n d bl o o d 
s a m pl e s will b e c oll e ct e d pri or t o St u d y Dr u g a d mi ni str ati o n 
f  
E a c h ti m e a h e m at ol o g y l a b i s dr a w n a n d s e nt t o t h e c e ntr al l a b or at or y f or a n al y si s a n a d diti o n al s a m pl e s h o ul d b e c oll e ct e d i n p ar all el a n d a n al y z e d l o c all y. 
I n t h e e v e nt t h at b ot h t h e c e ntr al a n d l o c al s a m pl e ar e u nr e p ort a bl e or u ni nt er pr et a bl e ( e. g., d u e t o h e m ol y z e d or cl u m p e d bl o od s a m pl e s) a n ot h er s a m pl e 
m u st b e r e p e at e d wit hi n 1 w e e k a n d t h e r e s ult m u st b e r e vi e w e d b y  t h e I n v e sti g at or a n d c o nfir m e d t o b e a c c e pt a bl e b ef or e d o si n g c a n c o nti n u e.  All pl at el et 
c o u nt r e s ult s will b e pr o m ptl y r e vi e w e d b y t h e I n v e sti g at or t o d et er mi n e if t h e c o u nt h a s m et a st o p pi n g r ul e, or t h e d o s e r e d u cti o n r ul e of 1 0 0, 0 0 0/ m m 3 , or t h e 
d o s e p a u s e r ul e of 7 5, 0 0 0/ m m 3 .  A n y c a s e of a pl at el et c o u nt < 5 0, 0 0 0/ m m3  s h o ul d b e r e p ort e d i n a n e x p e dit e d f a s hi o n t o t h e S p o n s or 
g  
F e m al e s of c hil d b e ari n g p ot e nti al o nl y 
h  
S er u m a n d pl a s m a s a m pl e s will b e c oll e ct e d a n d st or e d f or f oll o w- u p e x pl or ati o n of l a b or at or y fi n di n g s a n d/ or A E s ( e. g., m e a s ur e m e nt of c yt o ki n e a n d/ or 
c h e m o ki n e l e v el s, m e a s ur e m e nt of a d diti o n al m ar k er s of ki d n e y f u n cti o n, m e a s ur e m e nt of a nti b o di e s, et c. ) i n t hi s or s u b s e q u e nt cli ni c al st u di e s of 
I SI S 3 0 4 8 0 1 
i  
P ati e nt s o n i n s uli n will e nt er S M B G v al u e s pr ef er a bl y d ail y a n d i n s uli n d o s e at l e a st o n c e a w e e k.  P ati e nt s n ot o n i n s uli n will e nt er S M B G v al u e s pr ef er a bl y at 
l e a st o n c e a w e e k.  S u bj e ct s w h o u s e a gl u c o m et er s ho ul d bri n g t h eir gl u c o m et er t o e v er y cli ni c vi sit 
j  
T o r ei nf or c e c o m pli a n c e t o t h e lif e st yl e r e c o m m e n d ati o n s 
k  
Q u alifi c ati o n r e q uir e s a f a sti n g T G ≥ 2 0 0 m g/ d L at S cr e e ni n g a n d aft er at l e a st 4 w e e k s of di et st a bili z ati o n 
l  
A s s e s s m e nt s a n d pr o c e d ur e s t o b e c o n d u ct e d b y eit h er a h o m e h e alt h c ar e s er vi c e, or t h e St u d y Ce nt er a s arr a n g e d b y t h e St u d y C e nt er p er s o n n el 
 
 
 
 
 
 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
9 7
 
A p pe n di x A  Sc he d ule of Pr oce d ures  – O pe n -L a bel C o nti n ue d  
F o ot n ot e s : 
a 
E x p a n d e d uri n al y si s ( s e e A p p e n di x B ) 
b 
Bl o o d s a m pl e s t o b e c oll e ct e d aft er a n o v er ni g ht f a st of at l e a st 1 0 h o ur s, a n d pr ef er a bl y n o l o n g er t h a n 1 2 h o ur s.  D uri n g t r e at m e nt p eri o d, uri n e a n d bl o o d 
s a m pl e s will b e c oll e ct e d pri or t o St u d y Dr u g a d mi ni str ati o n  
c 
E a c h ti m e a h e m at ol o g y l a b i s dr a w n a n d s e nt t o t h e c e ntr al l a b or at or y f or a n al y si s a n a d diti o n al s a m pl e s h o ul d b e c oll e ct e d i n p ar all el a n d a n al y z e d l o c all y. 
I n t h e e v e nt t h at b ot h t h e c e ntr al a n d l o c al s a m pl e ar e u nr e p ort a bl e or u ni nt er pr et a bl e ( e. g., d u e t o h e m ol y z e d or cl u m p e d bl o o d s a m pl e s) a n ot h er s a m pl e 
m u st b e r e p e at e d wit hi n 1 w e e k a n d t h e r e s ult m u st b e r e vi e w e d b y t h e I n v e sti g at or a n d c o nfir m e d t o b e a c c e pt a bl e b ef or e d o si n g c a n c o nti n u e.  All pl at el et 
c o u nt r e s ult s will b e pr o m ptl y r e vi e w e d b y t h e I n v e sti g at or t o d et er mi n e if t h e c o u nt h a s m et a st o p pi n g r ul e, or t h e d o s e r e d u cti o n r ul e of 1 0 0, 0 0 0/ m m 3 , or t h e 
d o s e p a u s e r ul e of 7 5, 0 0 0/ m m 3 .  A n y c a s e of a pl at el et c o u nt < 5 0, 0 0 0/ m m3  s h o ul d b e r e p ort e d i n a n e x p e dit e d f a s hi o n t o t h e S p o n s or  
d 
F e m al e s of c hil d b e ari n g p o t e nti al o nl y 
e 
S er u m a n d pl a s m a s a m pl e s will b e c oll e ct e d a n d st or e d f or f oll o w -u p e x pl or ati o n of l a b or at or y fi n di n g s a n d/ or A E s ( e. g., m e a s ur e m e nt of c yt o ki n e a n d/ or 
c h e m o ki n e l e v el s, m e a s ur e m e nt of a d diti o n al m ar k er s of ki d n e y f u n cti o n, m e a s ur e m e nt of a nti b o di e s, et c.) i n t hi s or s u b s e q u e nt cli ni c al st u di e s of 
I SI S 3 0 4 8 0 1  
f 
P ati e nt s o n i n s uli n will e nt er S M B G v al u e s pr ef er a bl y d ail y a n d i n s uli n d o s e  at l e a st o n c e -w e e kl y .  P ati e nt s n ot o n i n s uli n will e nt er S M B G v al u e s at l e a st 
w e e kl y.  S u bj e ct s w h o u s e a gl u c o m et er s h o ul d bri n g t h eir gl u c o m et er t o e v er y cli ni c vi sit  
g 
T o r ei nf or c e c o m pli a n c e t o t h e lif e st yl e r e c o m m e n d ati o n s  
h 
A s s e s s m e nt s a n d pr o c e d ur e s t o b e c o n d u ct e d b y eit h er a h o m e h e alt h c ar e s er vi c e, or t h e St u d y C e nt er a s arr a n g e d b y t h e St u d y C e nt er p er s o n n el  
i 
Di s e a s e b ur d e n s ur v e y t o b e c o n d u ct e d aft er h a vi n g c o m pl et e d at l e a st 6 m o nt h s of t h e o p e n -l a b el p eri o d 

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
9 8
 
 
 
 
 
 
 
 
A p pe n di x B   
List of La b or at or y A n al ytes 
 
 

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

I SI S 3 0 4 8 0 1 -C S 1 7  
C O N FI D E N TI A L  
A me n d me nt 4  
Pr ot oc ol  
 
2 2 A u g ust 2 0 1 7  
 
1 0 1
 
A p pe n di x C  P h ar m a c o ki netic S a m pli n g Sc he d ule  
Bl o o d sa m ples f or t he d eter mi nati o n of plas ma I SI S 3 0 4 8 0 1 c o n ce ntrati o ns will be c ollecte d 
pri or t o d osi n g, a n d at vari o us ti mes t hr o u g h o ut t he d osi n g a n d p ost- treat m e nt f oll o w- u p peri o d 
as n ote d i n t he ta bles bel o w.  Plas ma P K sa m ples ma y als o be use d f or  pr ofili n g of dr u g bi n di n g 
pr otei ns, bi oa nal yti cal met h o d vali dati o n p ur p oses, sta bilit y a n d meta b olite assess me nts, 
i m m u n o ge nicit y testi n g ( or p ossi bl y f or p ur p oses of i m m u n o ge nicit y assa y de vel o p me nt a n d/ or 
vali dati o n), or t o assess ot her acti o ns of I SI S 3 0 4 8 0 1 wit h plas ma c o nstit ue nts.  
Pl as m a Tr o u g h S a m pli n g Sc he d ule f or all P ati e nts  d uri n g R a n d o mize d Tre at me nt Peri o d  
W e e k  
W k 1  
W k 4  
W k 8  
W k 1 3  
W k 1 9  
W k 2 6  
W k 3 2  
W k 3 8  
W k 4 4  
W k 5 2  
St u d y D a y  
D 1  
D 2 2  
D 5 0  
D 8 5  
D 1 2 7  
D 1 7 6  
D 2 1 8  
D 2 6 0  
D 3 0 2  
D 3 5 8  
Vi sit 
Wi n d o w  
+/ - D a y s  
0 
2 
2 
2 
3 
2 
3 
3 
3 
2 
 
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  
Pr e-
d o s e  
 
Pl as m a Tr o u g h a n d P ost- Tre at me nt S a m pli n g Sc he d ule f or all P atie nts  d uri n g O pe n -L a bel 
a n d P ost- Tre at me nt Peri o d s 
W e e k  
W k 5 3  
W k 5 6  
W k 6 0  
W k 6 5  
W k 7 1  
W k 7 8  
W k 8 4  
W k 9 0  
W k 9 6  W k 1 0 4  W k 1 1 0  W k 1 1 7  
St u d y D a y  D 3 6 5  
D 3 8 6  
D 4 1 4  
D 4 4 9  
D 4 9 1  
D 5 4 0  
D 5 8 2  
D 6 2 4  
D 6 6 6  
D 7 2 2  
D 7 6 4  
D 8 1 3  
Vi sit 
Wi n d o w  
+/ - D a y s  
0 
2 
2 
2 
3 
2 
3 
3 
3 
2 
7 
7 
 
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  
Pr e-
d o s e  
A n yti m e  A n yti m e