Clinical trial NCT02527343
Conditions: Familial Partial Lipodystrophy
Sponsor: Akcea Therapeutics
Start date: 2015-12-28; Completion date: 2019-11-13
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of volanesorsen given for 52 weeks in a randomized treatment (RT) period in participants with familial partial lipodystrophy (FPL). Following the randomized treatment period, participants who did not enter the open-label extension (OLE) period went straight to the 13-week post-treatment (PT) follow-up period and participants who were entered in the OLE period continued to receive volanesorsen for another 52 weeks (Weeks 53 to 104). Following the Week 104 visit of the OLE period, participants had an option of continued dosing for up to an additional 52 weeks (Week 105 to 156). Participants who did not enter the OLE period went straight to a 13-week post-treatment follow-up period. Following the Week 104 OLE period, participants were entered a 13-week post-treatment follow-up period, if they did not choose the option for continued dosing.

Detailed description:

Arms: arm 1: Randomized Period: Volanesorsen-matching placebo as SC, QW for Weeks 1-52. Participants who received volanesorsen-matching placebo in RT period and not enter in OLE period went straight to 13-week PT follow-up period. Dose adjustment based on monitoring rules were allowed.

OLE Period: Participants who received volanesorsen-matching placebo in RT period and completed RT period, were to receive 300 mg of volanesorsen as SC QW for 52 weeks (Weeks 53-104) in OLE period. Dose adjustment based on monitoring rules were allowed. After Week 104, participants had option of continuing treatment with 300 mg of volanesorsen as SC injection for up to additional 52 weeks (Weeks 105-156). Participants not entered in option for additional 52 weeks of dosing in OLE PT period went straight to 13-week PT follow-up period after completion of first 52 weeks (Weeks 53-104) of OLE. Participants entered in OLE PT period went straight to 13-week PT follow-up period after completion of Week 156 of OLE. arm 2: Randomized Period: 300 mg of volanesorsen as SC, QW for Weeks 1-52. Participants who received 300 mg of volanesorsen in RT period and did not enter in OLE period went straight to 13-week PT follow-up period. Dose adjustment based on monitoring rules were allowed.

OLE Period: Participants who received volanesorsen in RT period and completed RT period, were to receive 300 mg of volanesorsen as SC QW for 52 weeks (Weeks 53-104) in OLE period. Dose adjustment based on monitoring rules were allowed. After Week 104, participants had option of continuing treatment with 300 mg of volanesorsen as SC injection for up to additional 52 weeks (Week 105-156). Participants who were not entered in option for additional 52 weeks of dosing in OLE PT period went straight to 13-week PT follow-up period after completion of first 52 weeks (Weeks 53-104) of OLE. Participants entered in OLE PT period went straight to 13-week PT follow-up period after completion of Week 156 of OLE.
Interventions: intervention 1: volanesorsen intervention 2: Placebo
Intervention descriptions: intervention 1: 300 mg of volanesorsen administered subcutaneous (SC) injection, once-weekly (QW). intervention 2: Volanesorsen-matching placebo administered SC injection.

Protocol documents:
Prot_000.pdf: 
 
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  
 

SAP_001.pdf: 
Official Title: 
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 
NCT Number:           NCT02527343 
Document Date:       SAP Version 2 - June 19, 2019 


Clinical Study Report 
ISIS 304801-CS17 
16.1 Study Information 
Akcea Therapeutics, Inc. 
Confidential 
9. 
DOCUMENTATION OF STATISTICAL METHODS 
The following statistical analysis plan is included: 
• Statistical Analysis Plan, ISIS 304801-CS17, Version 2.0 dated 19 June 2019 


  
 
 
 
 
Sponsor:  
Akcea Therapeutics, Inc.  
22 Boston Wharf Road, 9th Floor 
Boston, MA 02210 
 
 
Statistical Analysis Plan 
 
ISIS 304801–CS17 
The BROADEN Study 
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 
 
 
 
Date:  June 19, 2019  
 
Version:  2.0 
 
Collaborator:  
Ionis Pharmaceuticals, Inc.  
2855 Gazelle Court  
Carlsbad, CA 92010  


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
ii 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
iii 
 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
iv 
PAREXEL SIGNATURE PAGE 
 
This document has been signed electronically on the final page by the following: 
 
 
Signatory 
Author 
Project Role
 
 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
v 
Table of Contents 
 
ABBREVIATIONS ...................................................................................................................... 2 
1 
INTRODUCTION ................................................................................................................ 4 
1.1 
Study Overview .............................................................................................................. 4 
1.2 
Objectives ...................................................................................................................... 5 
1.2.1 
Primary Objective ............................................................................................................. 5 
1.2.2 
Secondary Objectives ....................................................................................................... 5 
1.3 
Hypotheses .................................................................................................................... 5 
1.4 
Endpoints ...................................................................................................................... 6 
1.4.1 
Primary Endpoints ............................................................................................................ 6 
1.4.2 
Secondary Endpoints ........................................................................................................ 6 
 
 
1.4.4 
Safety Endpoints ............................................................................................................... 8 
2 
PROCEDURES .................................................................................................................... 8 
2.1 
General Overview of Procedures ................................................................................... 8 
2.1.1 
Screening and Baseline ..................................................................................................... 8 
2.1.2 
Randomized Treatment Period ......................................................................................... 8 
2.1.3 
Randomized Period Post-Treatment Follow-Up ............................................................... 9 
2.1.4 
OLE Period ....................................................................................................................... 9 
2.1.5 
OLE Post-Treatment Period ............................................................................................. 9 
2.2 
Randomization and Treatment Allocation ..................................................................... 9 
2.3 
Conduct ...................................................................................................................... 10 
2.4 
Data Monitoring ......................................................................................................... 11 
2.4.1 
Safety Data Monitoring .................................................................................................. 11 
2.4.2 
Data Monitoring Board ................................................................................................... 11 
2.5 
Data Management ....................................................................................................... 11 
2.5.1 
Case Report Form (CRF) Data ....................................................................................... 11 
2.5.2 
Laboratory Data .............................................................................................................. 12 
2.5.3 
Pharmacokinetics (PK) and Anti-drug Antibody (ADA) Data ....................................... 12 
2.5.4 
Other Data ....................................................................................................................... 12 
2.5.5 
Adverse Events Adjudication ......................................................................................... 12 
3 
ANALYSIS PLAN .............................................................................................................. 12 
3.1 
Statistical Design Summary ......................................................................................... 12 
3.2 
General Overview of Analyses ..................................................................................... 13 
3.2.1 
Statistical Methods.......................................................................................................... 13 
3.2.2 
Patient Population Analyzed ........................................................................................... 14 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
vi 
3.2.3 
Baseline and Endpoint Definition ................................................................................... 15 
3.2.4 
Patient Disposition and Demographics ........................................................................... 16 
3.3 
Primary Analyses ........................................................................................................ 17 
3.3.1 
Primary Endpoint Definition .......................................................................................... 17 
3.3.2 
Analysis of Primary Endpoint ........................................................................................ 17 
3.3.3 
Sample Size Consideration ............................................................................................. 18 
3.3.4 
Planned Interim Analysis ................................................................................................ 18 
3.3.5 
Incomplete or Missing Data ............................................................................................ 18 
3.4 
Secondary Analyses ..................................................................................................... 18 
3.4.1 
Secondary Endpoint Definitions ..................................................................................... 18 
3.4.2 
Analysis of Secondary Endpoints ................................................................................... 19 
3.4.2.1 
Secondary Endpoint 1:  Percent Change from Baseline in hepatic steatosis (as 
assessed by hepatic fat fraction using magnetic resonance imaging [MRI]) ......... 19 
3.4.2.2 
Secondary Endpoint 2:  Change from Baseline in HbA1c ..................................... 19 
3.4.2.3 
Secondary Endpoint 3:  Proportion of patients who achieve a >=40% reduction in 
fasting triglyceride from Baseline and >=30% reduction of hepatic fat fraction 
percent from baseline at Month 6 .......................................................................... 20 
3.4.2.4 
Secondary Endpoint 4:  Patient reported pain and hunger ..................................... 20 
No aggregated summary will be created. ................................................................................ 20 
3.4.2.5 
Secondary Endpoint 4:  Change from baseline in QOL (EQ-5D, SF-36) .............. 20 
 
 
3.6 
Pharmacokinetic and Anti-drug Antibody Analysis ..................................................... 20 
3.6.1 
Pharmacokinetic Analysis .............................................................................................. 20 
3.6.2 
 Anti-drug Antibody ....................................................................................................... 22 
3.7 
Safety Analyses ........................................................................................................... 22 
3.7.1 
Imputation of Missing/Partial Dates ............................................................................... 24 
3.7.1.1 
Adverse Events ...................................................................................................... 24 
3.7.1.2 
Prior/Concomitant Medications ............................................................................. 24 
3.7.2 
Adverse Events ............................................................................................................... 25 
3.7.2.1 Injection site reaction (ISR)......................................................................................... 27 
3.7.2.2 
Flu-Like Reactions ................................................................................................. 27 
3.7.2.3 
Adverse Events of Special Interest: ....................................................................... 27 
3.7.3 
Vital Signs Measurements .............................................................................................. 28 
3.7.4 
Laboratory Measurements .............................................................................................. 28 
3.7.5 
Exposure ......................................................................................................................... 31 
3.7.6 
Physical Examination ..................................................................................................... 31 
3.7.7 
12-Lead Electrocardiogram ............................................................................................ 31 
3.7.8 
Echocardiogram .............................................................................................................. 32 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
vii 
3.7.9 
Concomitant Medications ............................................................................................... 32 
3.7.10 MRIs ............................................................................................................................... 33 
3.8 Changes in the Planned Analysis ....................................................................................... 33 
4 
BIBLIOGRAPHY .............................................................................................................. 34 
5 
APPENDICES .................................................................................................................... 35 
Appendix A – Data to be reviewed by DSMB......................................................................... 35 
Appendix B – Efficacy measurement analysis visit window ................................................... 37 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
1 
SUMMARY OF CHANGES 
Version 2.0 – Added new derived FPL Group based on criteria stated in Section 2.2.  In the secondary 
endpoint, added analysis of change from baseline for hepatic fat fraction and HbA1C.  Also included 
a subgroup analysis of change from baseline for fasting triglycerides, hepatic fat fraction, and HbA1c 
by genetic mutation status LMNA + PPARG, or no mutation. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
2 
ABBREVIATIONS 
AE 
Adverse Event 
ADA 
Anti-drug Antibody 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
 
 
 
 
apoC-III 
Apolipoprotein C-III 
AST 
Aspartate Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
BMI 
BUN 
Body Mass Index 
Blood Urea Nitrogen 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
DSMB 
 
 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ET 
Early Termination 
FAS 
Full Analysis Set 
 
FPL 
 
Familial Partial Lipodystrophy 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-apoC-III 
High-Density Lipoprotein-Apolipoprotein C-III 
 
 
HIV 
Human Immunodeficiency Virus 
 
 
ICH 
International Council on Harmonisation 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
3 
IM  
Immunogenicity  
INR 
International Normalized Ratio 
ISR 
Injection Site Reaction 
IxRS 
Interactive Voice/Web-Response System 
LCR 
Local Cutaneous Reaction 
LCRIS 
Local Cutaneous Reaction at the Injection Site 
LDL-C 
Low-Density Lipoprotein Cholesterol 
MACE 
Major Acute Cardiovascular Event 
MCMC 
Markov Chain Monte Carlo 
MMRM 
MRI 
OLE 
Mixed Model for Repeated Measures 
Magnetic Resonance Imaging 
Open-Label Extension 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PPSR 
PPSO 
PRO 
Per Protocol Set in the Randomized Treatment Period 
Per Protocol Set in the Open-Label Extension 
Patient-Reported Outcomes  
PT 
QOL 
Prothrombin Time 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
 
SMBG 
SSR 
SSO 
Statistical Analysis Plan 
 
Self-Monitoring of Blood Glucose 
Safety Set in Randomized treatment period 
Safety Set in Open-label extension period 
T2DM 
Type 2 Diabetes Mellitus 
TEAE 
Treatment-Emergent Adverse Event 
TG 
Triglyceride(s) 
ULN 
Upper Limit of Normal 
 
VLDL-apoC-III 
 
Very Low-Density Lipoprotein-Apolipoprotein C-III 
 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
4 
1 
INTRODUCTION 
This document provides a description of the statistical methods and procedures to be implemented for 
the analyses of data from the Ionis Pharmaceuticals, Inc. study with Protocol Number ISIS 304801-
CS17 (Amendment 4 – 22 August 2017).  Section 1 discusses study design, objectives, and endpoints; 
Section 2 provides the study procedures; and, Section 3 provides the detailed plan for the statistical 
analyses. 
Any deviations from the final version of this Statistical Analysis Plan will be substantiated by sound 
statistical rationale and will be documented in the final clinical study report. 
1.1 
Study Overview 
Volanesorsen (ISIS 304801) has been evaluated in one Phase 1 study and two Phase 2 studies, all 
double-blinded and placebo-controlled.  The total exposures in completed studies comprise 99 patients 
and healthy volunteers administered volanesorsen at doses ranging from 50 to 400 mg, administered 
subcutaneously for up to 3 months (compared to 37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in fasting 
plasma apolipoprotein C-III (apoC-III) and triglyceride (TG) (~80% and 70%, respectively, mean 
reduction from Baseline with 300 mg dose once weekly) with a very high degree of consistency of 
response between the different patient groups.  This includes healthy volunteers, patients with moderate 
to severe hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to 
severe hypertriglyceridemia on a background of stable fibrate therapy, patients with Familial 
Chylomicronemia Syndrome (FCS), and patients with type 2 diabetes mellitus (T2DM). 
There has been no clinical or laboratory evidence of drug-drug interactions. 
This is a multi-center, randomized, double blind, placebo-controlled study with an open-label 
extension.  
The study will comprise the following periods: 
•
Screening. An up to 6-week Screening Period, including at least a 4-week diet stabilization
phase. 
•
Randomized Treatment Period. Following the diet-stabilization, up to 70 eligible patients will
be randomized 1:1 to receive volanesorsen or placebo once-weekly for 52 weeks.
o
Patients will be stratified by assignment into 1 of 3 groups based on Familial Partial
Lipodystrophy (FPL) phenotype, genetic variants and family history of PL. (Minor
criteria refers to protocol section 5.1 inclusion criteria)
1. Group 1 will consist of patients with the FPL phenotype and genetic variants of FPL
2. Group 2 will consist of patients with the FPL phenotype, but lacking a genetic variant,
and having a confirmed family history of FPL or abnormal and similar fat distribution,
plus 1 minor criterion


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
5 
3. Group 3 will consist of those with the FPL phenotype, but without either a genetic 
variant or family history, plus 2 minor criteria and a BMI < 35 kg/m2 
• 
Randomized Treatment Post-Treatment Follow-up. Patients who do not enter the OLE period 
will go straight to the 13-week post-treatment follow-up period. 
• 
An Open-Label Extension (OLE) Year 1 Period. After completion of the 52-week randomized 
treatment period patients will enter the OLE period and will receive volanesorsen for 52 weeks. 
Assessments and study visits will be generally similar to the randomized treatment period. 
• 
OLE Year 2 Period.  Following the Week 52 visit of the OLE period, patients will have the 
option of continuing dosing for up to an additional 52 weeks, for a total of up to 2 years (104 
weeks) of open label dosing following the 1 year (52 weeks) randomized phase. The schedule 
of procedures will follow the same schedule as the first year of the OLE.   
• 
A 13-week Post-treatment Evaluation Period. Patients who do not enter the option for 
additional dosing in the OLE post-treatment period will go straight to a 13-week post-treatment 
follow-up period after completion of the first 52 weeks or after discontinuing treatment during 
the first 52 weeks of the OLE. Patients who enter the OLE post-treatment period will go straight 
to a 13-week post-treatment follow-up period after completion of the Week 104 OLE or after 
discontinuing treatment prior to Week 104 of the OLE. 
The primary endpoint for the study will be evaluated after the last patient has completed the Week 
52/ET (Early Termination) visit of the Randomized Treatment Period and will be based on the percent 
change from Baseline in fasting triglyceride at the primary analysis time point (Month 3). 
1.2 
Objectives 
1.2.1 
Primary Objective 
To evaluate the efficacy of volanesorsen for reduction in severity of metabolic derangement in patients 
with Familial Partial Lipodystrophy (FPL) with hypertriglyceridemia and uncontrolled diabetes. 
 
1.2.2 
Secondary Objectives 
To evaluate the safety and tolerability of volanesorsen in patients with FPL. 
To further evaluate the role of serum triglyceride in modulating insulin resistance in FPL patients and 
the impact of triglyceride reduction on adipose tissue distribution. 
 
1.3 
Hypotheses 
The study hypothesis is that volanesorsen can significantly reduce the severity of metabolic 
derangement and is well-tolerated for patients with FPL with hypertriglyceridemia and uncontrolled 
diabetes. 
The hypotheses for primary endpoint at the primary analysis time point are: 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
6 
• 
Null hypothesis:  volanesorsen and placebo have the same percent change from Baseline in 
fasting triglyceride  to Month 3 
• 
Alternative hypothesis:  volanesorsen and placebo have significantly different percent changes 
from Baseline in fasting triglyceride  to Month 3 
1.4 
Endpoints 
The primary analysis time point is at the end of Month 3 where the value is defined as the average of 
Week 12 (Day 78) and Week 13 (Day 85) fasting lipid assessments  
The Month 6 analysis time point is at the end of Month 6 where the values defined as the average of 
Week 25 (Day 169) and Week 26 (Day 176) fasting lipid assessments 
The Month 12 analysis time point is at the end of Month 12 where the values defined as the average 
of Week 50 (Day 344) and Week 52 (Day 358) fasting lipid assessments.  
 
1.4.1 
Primary Endpoints 
The primary efficacy analysis will be the comparison of percent changes from Baseline to the primary 
analysis time point in fasting triglyceride between volanesorsen group and placebo group in the Full 
Analysis Set (FAS). 
1.4.2 
Secondary Endpoints 
The secondary endpoints include: 
• 
Percent change from Baseline in hepatic steatosis (as assessed by hepatic fat fraction using 
magnetic resonance imaging [MRI])  
• 
The comparison of percent changes from Baseline to the analysis time point in hepatic steatosis 
(as assessed by hepatic fat fraction using magnetic resonance imaging [MRI]) between 
treatment groups 
• 
Change from Baseline in hemoglobin A1c (HbA1c) 
• 
The comparison of changes from Baseline to the analysis time point in hemoglobin A1c 
(HbA1c) between treatment groups  
• 
A composite endpoint at Month 6 for percent of patients who achieve 
a. ≥ 40% reduction in fasting triglyceride , and 
b. ≥ 30% reduction of hepatic fat fraction percent 
• 
Change in patient-reported outcomes (PRO)  
o Patient-reported pain 
o Patient-reported hunger 
o Quality of life (QOL) questionnaires (EQ-5D, SF-36) 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
7 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
8 
1.4.4 
Safety Endpoints  
• 
AEs including adjudicated events of pancreatitis and MACE  
• 
Vital signs and weight  
• 
Physical examinations  
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis)  
• 
Echocardiography  
• 
Electrocardiogram (ECG)  
• 
Use of concomitant medications  
• 
Magnetic Resonance Imaging (MRI)  
The details on the safety analyses are discussed in the section 3.7. 
 
2 
PROCEDURES 
2.1 
General Overview of Procedures 
2.1.1 
Screening and Baseline  
Before any study-specific procedures or evaluations are initiated, patients must sign and date the 
informed consent form.  A 6-week period, including a diet stabilization period of at least 4 weeks, is 
given to perform the screening evaluations.  The baseline assessments will be performed at Week -2 
to -1, and on Study Day 1.  Abnormal screening results may be retested for review by the Study Medical 
Monitor for eligibility purposes. 
 
2.1.2 
Randomized Treatment Period 
During the randomized treatment period, patients will report to the study center for clinic visits a 
minimum of 6 times during Weeks 1-52 (see Schedule of Procedures in Protocol Appendix A).  Study 
Drug will be administered once-weekly (Protocol Section 8.1).  Collection and measurement of vital 
signs, physical examination results, 
 
, ECGs, liver MRIs, echocardiograms, clinical laboratory parameters (including 
hematology; serum chemistry; lipid panel; 
, and CRP measured by 
high sensitivity assay [hsCRP]; urinalysis, and other analytes listed in Protocol Appendix B), 
volanesorsen plasma trough concentrations, anti-drug antibody (ADA) testing, 
, 
collection of SMBG and insulin diary, hunger diary, pain diary, and AEs, concomitant 
medication/procedure information, and QOL assessments will be performed according to the schedule 
of procedures in Protocol Appendix A.  AEs at the injection site should be collected as AEs.  
Dietary/alcohol counseling will commence at the start of the diet stabilization period and will be 
reinforced at intervals throughout the treatment and follow-up period. 
Patients must be fasted prior to drawing all lipid samples and samples drawn locally should also be sent 
to the central laboratory for analysis whenever possible.  Blood sampling at Weeks 2, 3, 4, 5, 6, 7, 8, 9, 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
9 
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 
37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51 may be conducted by a home healthcare 
service.  While allowed, it is preferable that visits at Week 8 and 12 are conducted at the clinic if 
possible.  Dosing instructions and training will be provided to the patient where applicable. 
All visits have a visit window of at least ± 2 days.  All reasonable attempts should be made to ensure 
compliance with the visit schedule as outlined in Appendix A of the protocol.  However, in the event 
that a visit does not occur or is delayed, all subsequent visits should be calculated based on the time 
elapsed since Day 1 rather than from the date of the previous visit. 
 
2.1.3 
Randomized Period Post-Treatment Follow-Up 
Patients who do not enter the OLE period will go straight to the 13-week post-treatment follow-up 
period.  This period consists of 7 visits, as outlined in the Schedule of Procedures in Appendix A of 
the protocol. 
2.1.4 
OLE Period 
After completion of the 52-week randomized treatment period patients will enter the OLE period and 
will receive volanesorsen for an additional 52 weeks.  Assessments and study visits will be generally 
similar to the randomized treatment period as outlined in the Schedule of Procedures in Protocol 
Appendix A, with the inclusion of weekly platelet monitoring. 
Following 52 weeks of treatment in the Open-Label Extension Period, patients will have the option of 
continuing dosing for up to an additional 52 weeks. The schedule of procedures will follow the same 
schedule as the first year of OLE. 
 
2.1.5 
OLE Post-Treatment Period 
Following the Week 52 visit of the Open-Label Extension Period, patients will have the option of 
continuing dosing for up to an additional 52 weeks (second OLE period). Patients who do not enter this 
option for additional dosing in the OLE period will go straight to the 13-week OLE post-treatment 
period after completion of the first 52 weeks or after discontinuing treatment during the first 52 weeks 
of OLE. This period consists of 7 visits, as outlined in the Schedule of Procedures in Protocol Appendix 
A.  
For patients who continue to receive investigational treatment for the second OLE period, the 13-week 
OLE post-treatment period will follow completion of the Week 156 visit or after early treatment 
discontinuation. 
2.2 
Randomization and Treatment Allocation 
Patients will be randomized after all screening and qualification assessments have been completed and 
after the Investigator has verified that they are eligible per criteria in the protocol sections 5.1 and 5.2.  
No patient may begin treatment prior to randomization and assignment of a unique patient identification 
number. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
10 
Using an Interactive Voice/Web-Response System (IxRS), eligible patients will be randomized 1:1 to 
receive volanesorsen or placebo.   
Patients will be stratified by assignment into 1 of 3 groups based on FPL phenotype, genetic variants 
and family history of PL. (Minor criteria refers to protocol section 5.1 inclusion criteria) 
FPL Groups for Stratification 
1. Group 1 will consist of patients with the FPL phenotype and genetic variants of FPL. 
2. Group 2 will consist of patients with the FPL phenotype, but lacking a genetic variant, and 
having a confirmed family history of FPL or abnormal and similar fat distribution, plus 1 minor 
criterion. 
3. Group 3 will consist of those with the FPL phenotype, but without either a genetic variant or 
family history, plus 2 minor criteria and a BMI < 35 kg/m2. 
Genetic analysis reports include characterization of variants into 5 classifications:  benign, likely 
benign, variant of unknown significance, likely pathogenic or pathogenic. 
For stratification purposes: 
Positive on genetic testing:  Documentation of pathogenic or likely pathogenic genes associated with 
familial partial lipodystrophy will be considered positive for genetic analysis if these changes are likely 
to represent the underlying cause of the subject’s phenotype.  This should be documented in a written 
report. 
Negative on genetic testing:  When sequencing analysis of the partial lipodystrophy panel for variants 
determines that no pathogenic or likely pathogenic variant were identified or is a variant of unknown 
significance, this will be considered as evidence for negative for genetics.  Negative on genetics will 
also be considered for those subjects for whom the genetic analysis results are unlikely, unknown, or 
untested. 
Positive family history of FPL or family history of abnormal and similar fat distribution includes 
immediate family / first degree relatives (father, mother, brother, sister, daughter, son), as well as 
second degree relatives (grandparents, aunts and uncles, nieces and nephews, and grandchildren). 
A permuted block schedule will be used.  The Sponsor Quality Assurance department or designee will 
hold a copy of the randomization lists generated by the IxRS vendor. 
Patients who withdraw from the study will not be replaced. 
 
2.3 
Conduct 
The study will be conducted in accordance with current Good Clinical Practice (GCP) and 
International Conference on Harmonization (ICH) guidelines, the World Medical Association 
Declaration of Helsinki guidelines, the Food and Drug Agency (FDA) Code of Federal Regulations, 
and all other local regulatory requirements. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
11 
2.4 
Data Monitoring 
2.4.1 
Safety Data Monitoring 
The Sponsor (or designee) is responsible for processing all reported adverse events (AEs).  Processing 
of serious adverse events (SAEs) is delegated to a CRO although the Sponsor remains accountable for 
this activity and process. AEs and SAEs are reviewed according to standard operating procedures.  The 
Sponsor medical monitor will review all AEs and SAEs on an ongoing basis throughout the study.  The 
Sponsor (or designee) will prepare and submit safety reports to the health authorities worldwide in 
accordance with local requirements.  If it becomes necessary to communicate new safety information, 
the Sponsor (or designee) will also prepare a safety notification letter and transmit it to all applicable 
study sites. 
2.4.2 
Data Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be assembled to review safety, 
tolerability and efficacy (as needed) data collected on volanesorsen during this study.  Based on its 
ongoing assessment of the safety and tolerability of volanesorsen, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  Details 
on the safety assessments, frequency of review, meeting schedules and controlled access to unblinded 
data are outlined in the DSMB Charter. 
In order to ensure maintenance of the study blind, lipid panel results, including apoC-III, will not be 
available to the Sponsor, monitors, Investigators, Study Center personnel, or the patients, except for the 
procedure related to safety monitoring for LDL-C elevations as specified in protocol section 8.5.6. 
For the purpose of pre-programming and data cleaning, Parexel unblinded programming team (the CRO 
performing the statistical analysis) and an independent data manager at 
 Laboratories will 
receive post-baseline lipid panel results. 
Appendix A lists what data will be included in the DSMB. 
 
2.5 
Data Management 
2.5.1 
Case Report Form (CRF) Data 
Bioclinica® is responsible for creating the Electronic Data Capture (EDC) data entry screens, database 
and edit checks using definitions developed by the Sponsor (or designee).  The Sponsor (or designee) 
is responsible for the review, data management querying, and locking of the database. 
Data are single-entered into the EDC system by the Investigator site staff.  Programmed edit checks 
(computer logic that checks the validity of the data entered and also prompts for missing data that is 
expected to be entered) are run and automatic queries are generated.  The Sponsor performs blinded 
review of all data for accuracy and validity; generating additional queries in the EDC system, when 
necessary.  The data is corrected or an explanation concerning the query is provided in the EDC system.  
After all data is entered, reviewed, source data verified, and after all queries are resolved, the database 
will be locked. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
12 
2.5.2 
Laboratory Data 
The Sponsor is responsible for the format of the laboratory electronic data transfers and the transfer 
schedule.  The Sponsor (or designee) is responsible for the review of the clinical laboratory data.  
Central lab data is not stored in the EDC system.  Investigator sites have access to this data via printed 
lab reports sent directly from the laboratory.  MRL manages the Central lab data. 
2.5.3 
Pharmacokinetics (PK) and Anti-drug Antibody (ADA) Data 
The Sponsor is responsible for the management and review of the PK and IM data.  This process 
involves reviewing the patient and visit identifiers with the clinical data collected in the EDC system.  
The PK and IM data are not stored in the EDC system. 
2.5.4 
Other Data 
 Central Lab manages MRI/ECHO/
.  Both data will also not be stored in the 
EDC system but will be transferred to Ionis Pharmaceuticals, Inc. as external data. 
2.5.5 
Adverse Events Adjudication 
SOCAR is the vendor that manages the adjudication process.  All SAEs that occur during the study 
that are consistent with MACE will be adjudicated by a blinded, independent committee as outlined 
in the MACE Adjudication Charter.  In addition, this committee will also adjudicate the data for 
episodes of MACE over the last 3 years prior to randomization, collected by review of each patient’s 
medical chart.  All AEs and SAEs that occur during the study that are consistent with an event of 
acute pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis Adjudication 
Charter.   
The adjudication data will be transferred electronically using EXCEL file from SOCAR to Ionis 
Pharmaceuticals, Inc.  
3 
ANALYSIS PLAN 
3.1 
Statistical Design Summary 
This is a multi-center, randomized, double blind, placebo-controlled study with an open-label extension 
comprised of study periods outlined in Section 1.1.  
The primary efficacy measurement is fasting triglyceride which will be collected at baseline and all 
post-baseline visits.  The primary analysis model will be a parametric analysis model for percent change 
in triglyceride from Baseline to Randomized Treatment Period Month 3 by treatment group.  As study 
treatment is discontinued before completing the protocol specified treatment period, missing data 
imputation and various sensitivity analyses defined by protocol will not be conducted. 
The primary endpoint for the study will be evaluated after the last patient has completed the 
Week 52/early termination (ET) visit and will be based on the percent change from Baseline in fasting 
TG at the primary analysis time point (Month 3).  The Study Team will be unblinded after the last 
patient’s Week 52/ET visit is completed and database is locked.   


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
13 
3.2 
General Overview of Analyses 
3.2.1 
Statistical Methods 
All eCRF(Electronic Case Report Form) data, lab data transfers, as well as any outcomes derived from 
the data, will be provided in the patient data listings.  Patient data listings will be presented for all 
patients randomized into the study.  Descriptive summary statistics including n, mean, median, standard 
error, standard deviation, interquartile range (25th percentile, 75th percentile), range (minimum, 
maximum) for continuous variables, and counts and percentages for categorical variables will be used 
to summarize most data.  Where appropriate, p-values will be reported.  All statistical tests will be 
conducted using 2-sided tests with 5% Type 1 error rates unless otherwise stated. 
Summary of primary efficacy endpoint will only include the on-treatment assessment. On-treatment 
assessment is defined as assessment since first dose date, up to 28 days after last dose of study 
medication. Assessment beyond last dose of study medication + 28 days will be excluded from efficacy 
summary. Lipid, hepatic fat fraction, and HbA1c assessments will be summarized by analysis visit 
according to the visit window defined in Appendix B. Other assessments will be summarized by 
nominal visit as collected in CRF. 
Lipid (triglyceride and non-triglyceride), hepatic fat fraction, and HbA1c data will be mapped to 
analysis visit as specified in Appendix B. Assessments collected during randomized treatment period, 
will have analysis visit assigned according to the days relative to first dose date of randomized treatment 
period.  Assessments collected during OLE period will have analysis visit assigned according to the 
days relative to first dose date of OLE period.  The intent of these analysis visit windows is not to align 
with those prescribed for visit scheduling in the clinical study protocol but, rather, based on the 
protocol-defined target study day, to delineate mutually exclusive windows so that all efficacy 
assessments proximal to a particular study week can be integrated to best represent the patient’s status 
during that period of the study.  If a patient discontinued early from the treatment period but attended 
applicable landmark visits at Weeks 12, 13, 25, and etc. to collect lipid assessments, then those 
assessments collected at ET visit and during post-treatment follow-up period should be mapped to 
analysis visits as well, excluding assessment beyond 28 days after last dose of study medication.  For 
the hepatic fat fraction and HbA1c data, data collected within the analysis visit window defined in 
Appendix B will be used.  If there are multiple assessments within a visit window, only scheduled visit 
will be used, and the average will be used if there are multiple scheduled assessments, or the worst will 
be used if categorical result is collected in multiple scheduled assessments.  If the assessments are all 
unscheduled, the visit nearest the scheduled date will be used, unless 2 visits are equally near, in which 
case the average will be used, or the worst will be used if categorical result is collected.   
For efficacy data, local lab data will not be used unless central lab assessments are not available at 
certain visit.  When calculating the baseline and analysis endpoints, only if the data from central lab is 
missing, then the local lab data will be utilized. 
Safety assessments will be summarized by the nominal visit as collected in CRF.  Multiple results with 
the same nominal visit will be averaged.   
For safety lab, unscheduled assessment (both central lab and local lab) will not be included in the by-
visit summaries, except for platelet analysis. Unscheduled results from the central lab will be used in 
the determination of baseline, laboratory abnormality summaries, shift from Baseline to worst post-
baseline, and platelets reduction analyses. Local lab will be used in the determination of laboratory 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
14 
abnormality summaries, shift from Baseline to worst post-baseline, and platelets reduction analyses, 
but not in baseline determination. For platelet, when central lab is not available at baseline, local lab 
result will be used in baseline determination.  
3.2.2 
Patient Population Analyzed 
The following analysis sets will be used for the analysis of data as described within each analysis set. 
Full Analysis Set (FAS):  All patients who are randomized and received at least 1 dose of Study Drug 
in the randomized treatment period, and who have a baseline fasting triglyceride assessment (see 
definition in Section 3.2.3 for fasting lipid measurements).  The FAS represents the practically-feasible 
intent-to-treat population as delineated in ICH Guideline E9.   
Patients for whom the blind is broken during the trial will not be excluded from the FAS population.  
Patients will be analyzed in the treatment group to which they were randomized.  Efficacy endpoint 
collected in both Randomized Treatment Period and OLE Period will be analyzed in FAS by the 
treatment group to which they were randomized. Although all patients receive volanesorsen during 
OLE period, assessment during OLE period will be analyzed according to the treatment assigned at 
previous Randomized Treatment Period. For example, if patient is assigned to the Placebo treatment at 
the Randomized Treatment Period, this patient will be analyzed in Placebo treatment group for both 
Randomized Treatment Period and OLE period.  
Safety Set 1 (SAF1):  All patients who are randomized and receive at least 1 dose of Study Drug 
(volanesorsen or Placebo) in the Randomized Treatment Period.     
Patients will be analyzed in the actual treatment group patients received during the Randomized 
Treatment Period.  Patients randomized to receive placebo, but incorrectly treated with volanesorsen 
will be counted in the volanesorsen group for the whole study period. 
Safety Set 2 (SAF2):  All patients who enter the OLE Period and receive at least 1 dose of Study Drug 
(volanesorsen) in the OLE Period.     
As patients all receive volanesorsen in OLE period. In SAF 2, patients will be analyzed by the actual 
treatment received in the Randomized Treatment Period.   
PK Population:  All patients who are randomized, receive at least 1 dose of volanesorsen, and have at 
least one evaluable PK data, in either Randomized Treatment Period or OLE Period.   
Patients will be analyzed in the actual treatment group patients received. Patients randomized to receive 
placebo, but incorrectly treated with volanesorsen will be counted in the volanesorsen group for the 
whole study period. 
All primary, secondary 
 efficacy endpoints will be assessed in the FAS.  Safety 
measures at Randomized Treatment Period and Randomized Treatment Period Post-Treatment Follow-
up will be analyzed in SAF1. Safety assessment at OLE Period and OLE Post-Treatment Period will 
be analyzed in SAF2.   PK endpoints will be assessed in the PK Population as applicable.  Anti-drug 
antibody endpoints will be assessed in the SAF1. 
Analysis populations will be summarized with counts and percentages by treatment group to which 
they were randomized, and overall.  


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
15 
3.2.3 
Baseline and Endpoint Definition 
The baseline for fasting lipid measurements is defined as the average of Day 1 pre-dose assessment 
and the last non-missing measurement prior to Day 1 pre-dose assessment.  If 1 of the 2 measurements 
is missing, then the other measurement will be assigned as the baseline value.  If both are missing, then 
the baseline will be set as missing and the patient will be excluded from the FAS.  Note that if on Day 
1, there are multiple pre-dose assessments, then the last assessment with non-missing value will be used 
as the Day 1 pre-dose assessment.  
The baseline for other measurements is defined as the last non-missing assessment prior to the first 
dose of Study Drug with the exception that platelet baseline is defined as the average of all assessments 
prior to the first dose of Study Drug. 
Randomized Treatment Period and Open-Label Extension Period refer to one baseline, which is based 
on the pre-dose assessment of Day 1 in Randomized Treatment Period. 
Efficacy by visit summary will include following time point, when data available. Both visit week and 
month will be presented. 
 Randomized Treatment Period Month 3 analysis time point is at the end of Randomized Treatment 
Period Month 3.  For fasting lipid measurements, value at Month 3 is defined as the average of Week 
12 (Day 78) and Week 13 (Day 85) fasting lipid measurements.  If one visit is missing, then the other 
visit will be used.  If both visits are missing, then the value will be set as missing 
 Randomized Treatment Period Month 6 analysis time point is at the end of Randomized Treatment 
Period Month 6. For fasting lipid assessments, value at Month 6 is defined as the average of Week 25 
(Day 169) and Week 26 (Day 176) fasting assessments.  If one visit is missing, then the other visit will 
be used.  If both visits are missing, then value will be set as missing.  .   
 Randomized Treatment Period Month 12 analysis time point is at the end of Randomized 
Treatment Period Month 12.  For fasting lipid assessments, value at Month 12 is defined as the average 
of Week 50 (Day 344) and Week 52 (Day 358) fasting assessments.  If one visit is missing, then the 
other visit will be used.  If both visits are missing, then the value will be set as missing.  .   
OLE Month 3 analysis time point is at the end of OLE Month 3. For fasting lipid measurements, 
value at OLE Month 3 is defined as the average of OLE Week 12 (OLE Day 78) and OLE Week 13 ( 
OLE Day 85) fasting lipid measurements.  If one visit is missing, then the other visit will be used.  If 
both visits are missing, then the value will be set as missing.  . 
OLE Month 6 analysis time point is at the end of OLE Month 6. For fasting lipid assessments, value 
at OLE Month 6 is defined as the average of OLE Week 25 (OLE Day 169) and OLE Week 26 (OLE 
Day 176) fasting assessments.  If one visit is missing, then the other visit will be used.  If both visits 
are missing, then value will be set as missing.  .   
OLE Month 12 analysis time point is at the end of OLE Month 12.  For fasting lipid assessments, 
value at OLE Month 12 is defined as the average of OLE Week 50 (OLE Day 344) and OLE Week 52 
(OLE Day 358) fasting assessments.  If one visit is missing, then the other visit will be used.  If both 
visits are missing, then the value will be set as missing.  .   


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
16 
OLE Month 15 analysis time point is at the end of OLE Month 15.  For fasting lipid assessments, 
value at OLE Month 15 is defined as the average of OLE Week 64 (OLE Day 442) and OLE Week 65 
(OLE Day 449) fasting assessments.  If one visit is missing, then the other visit will be used.  If both 
visits are missing, then the value will be set as missing.  .   
OLE Month 18 analysis time point is at the end of OLE Month 18.  For fasting lipid assessments, 
value at OLE Month 18 is defined as the average of OLE Week 77 (OLE Day 533) and OLE Week 78 
(OLE Day 540) fasting assessments.  If one visit is missing, then the other visit will be used.  If both 
visits are missing, then the value will be set as missing.  .   
OLE Month 24 analysis time point is at the end of OLE Month 24.  For fasting lipid assessments, 
value at OLE Month 24 is defined as the average of OLE Week 102 (OLE Day 708) and OLE Week 
104 (OLE Day 722) fasting assessments.  If one visit is missing, then the other visit will be used.  If 
both visits are missing, then the value will be set as missing.  .   
3.2.4 
Patient Disposition and Demographics 
Demographic, baseline characteristics will be summarized in FAS. Demographic including age, gender, 
ethnicity, race, region, Familial Partial Lipodystrophy (FPL) Group as entered on the Randomization 
CRF will be summarized using descriptive statistics. In addition, FPL Group derived based on the data 
entered on the Disease History CRF and the genetic testing results as below will be summarized. 
• 
Patients with a pathogenic mutation in known FPL genes according to the University of 
Chicago data (for patients who consented to genetic testing) or historical genetic testing results 
(for patients who did not consent) will be assigned to Group 1. 
• 
Patients who do not belong in Group 1 and have a family history of FPL or a similar fat 
distribution and/or history of fat loss in a first degree relative, plus at least 1 minor criterion as 
entered in the Disease History CRF will be assigned to Group 2. Minor criteria refers to 
protocol section 5.1 inclusion criteria. 
• 
Patients who do not belong in Group 1 or Group 2 and have at least 2 minor criteria as entered 
in the Disease History CRF and a Screening BMI < 35 kg/m2 will be assigned to Group 3. 
• 
Patients who do not fall into one of the categories above will be assigned to None. 
Baseline characteristics includes: body weight, height at screening, BMI, fasting lipids results including 
 
 
  Baseline data will be listed for all randomized patients.   
All screened patients will be included in the summary of patient disposition.  The number of patients 
screened, randomized, dosed, number of patients included in each analysis set, completed treatment, 
discontinued treatment along with reasons for discontinuing treatment, entered post-treatment follow-
up, completed post-treatment follow-up, and discontinued post-treatment follow-up along with reasons 
for early terminating post-treatment follow-up, will be presented for both randomized treatment period 
and OLE period by treatment group to which they were randomized, and overall.   
Listing of patient disposition will also be provided for all randomized patients. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
17 
Medical history will be coded by Medical Dictionary for Regulatory Activities (MedDRA) dictionary 
Version 19.1 and will be summarized by system organ class and preferred term by treatment and overall 
for the SAF1 .  Medical history will also be provided in the data listings.  
3.3 
Primary Analyses  
Fasting triglyceride and change from baseline (absolute value and percentage of change) will be 
summarized by analysis visit using descriptive statistics in FAS. Descriptive summary statistics refers 
to section 3.2.1. Analysis visit includes baseline, endpoint as defined in section 3.2.3, and analysis week 
as specified in Appendix B. 
3.3.1 
Primary Endpoint Definition 
The primary endpoint is the percent change in fasting triglyceride from Baseline to the primary analysis 
time point.  The primary analysis time point is at the end of Month 3 where the value is defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments.  
3.3.2 
Analysis of Primary Endpoint 
The primary efficacy analysis will be the comparison of the percent change from Baseline to 
Randomized Treatment Period Month 3 in fasting triglyceride between volanesorsen group and placebo 
group in the FAS.  The data will be analyzed using an analysis of covariance (ANCOVA) model with 
the randomization stratification factor (diagnosis of disease with or without genetics and family history) 
derived based on the Disease History CRF and genetic testing results and treatment group as factors 
and baseline fasting triglyceride as a covariate.  In the ANCOVA model, triglyceride will be log-
transformed. Patients with a missing primary endpoint will be excluded from primary efficacy analysis.     
The primary efficacy analysis model (ANCOVA) will be repeated for the percent change from 
baseline in fasting triglyceride at Randomized Treatment Period endpoint month 6 and month 12. 
A subgroup analysis of the primary efficacy analysis model (ANCOVA) will also be conducted in the 
group of genetically confirmed patients according to the University of Chicago data for patients who 
consented to genetic testing or historical data for patients who did not consent, and for patients with 
no mutation at month 3, month 6 and month 12. An interaction term of treatment group by derived 
FPL group will be included as a factor in the ANCOVA model. 
The sample SAS code for the ANCOVA model can be found below: 
********************************************************************* 
* Note: Base = Baseline fasting triglyceride                                                                 * 
*       LOGBASE = Log-transformed baseline fasting triglyceride                               * 
*       PCHG = Percent change from Baseline at Month 3                                             * 
*       TRTP = Treatment group: Placebo, volanesorsen                                                * 
*       FPLGRPD = Derived FPL groups: 1 = FPL1, 2 = FPL2, 3=FPL3                       * 
*          FPL1 - Phenotype + Genetic Variants                                                                * 
*         FPL2 - Phenotype + No Genetic Variant + Family Hist or Abnormal and          *  


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
18 
*                      Similar Fat  + 1 Minor Criterion                                                            *                   
*        FPL3 - Phenotype + No Genetic Variant + No Family Hist or Abnormal and    * 
*  Similar Fat + 2 Minor Criteria + BMI<35kg/m2                                                       * 
*                                                                                                                                      * 
********************************************************************* 
ods output lsmeans=lsm diffs=diff; 
proc mixed data = M3TG; 
     class TRTP (ref=’Placebo’) FPLGRPD; 
     model PCHG = TRTP FPLGRPD LOGBASE /solution cl residual outp=predresid; 
     lsmeans TRTP/e diff cl;    
run; 
 
3.3.3 
Sample Size Consideration 
Based upon prior clinical trial experience with volanesorsen, it is estimated that the standard deviation 
of the percent change in total fasting triglyceride is approximately 40%.  With 20 volanesorsen patients 
and 20 placebo patients there would be approximately 80% power to detect a 40% difference in fasting 
triglyceride levels between treatment groups at an alpha level of 0.05, assuming 50% reduction in the 
volanesorsen treatment patients and 10% reduction in the placebo patients.   
A sample size of 35 patients (20 active and 15 control) provides 92% power to detect a liver fat 
treatment difference of 4.7% based on a between patient standard deviation of 4% and a two-sided 
alpha of 0.05. 
3.3.4 
Planned Interim Analysis 
There is no interim analysis planned for the study. 
3.3.5 
Incomplete or Missing Data 
Patients with a missing primary endpoint will be excluded from primary efficacy analysis.     
3.4 
Secondary Analyses  
Secondary efficacy endpoints will be summarized by visit using descriptive statistics in FAS.  
Descriptive summary statistics refers to section 3.2.1. Visit includes baseline, and nominal visit as 
collected in CRF, or according to the visit window defined in Appendix B for MRI, HbA1c, and lipid 
endpoints 
3.4.1 
Secondary Endpoint Definitions 
The secondary endpoints include: 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
19 
1. Percent Change from Baseline in hepatic steatosis (as assessed by hepatic fat fraction using 
magnetic resonance imaging [MRI]) 
2. Change from Baseline in hemoglobin A1c (HbA1c)  
3. A composite endpoint at Month 6 for percent of patients who achieve 
a. ≥ 40% reduction in fasting triglyceride, and 
b. ≥ 30% reduction of hepatic fat fraction percent 
4. Change in patient-reported outcomes (PRO): 
o Patient-reported pain 
o Patient-reported hunger 
o QOL (EQ-5D, SF-36) 
3.4.2 
Analysis of Secondary Endpoints 
3.4.2.1 Secondary Endpoint 1:  Percent Change from Baseline in hepatic steatosis (as assessed by 
hepatic fat fraction using magnetic resonance imaging [MRI]) 
Hepatic fat fraction (%), change from baseline, and percent change from baseline will be summarized 
by analysis visit using descriptive statistics in FAS. They will also be summarized separately by genetic 
mutation category: LMNA+PPARG, or neither. Descriptive summary statistics refers to section 3.2.1. 
Visit includes baseline and analysis visits according to the visit window defined in Appendix B. 
The percent change in Hepatic Fat Fraction (%) from Baseline to month 6 and month 12 at 
Randomized Treatment Period will be analyzed using the similar ANCOVA model as for the primary 
efficacy analysis model (ANCOVA) . 
A subgroup analysis of the ANCOVA will also be run for percent change in hepatic fat fraction in the 
group of genetically confirmed patients according to the University of Chicago data for patients who 
consented to genetic testing or historical data for patients who did not consent, and in patients with no 
mutation at month 6 and month 12 respectively. 
3.4.2.2 Secondary Endpoint 2:  Change from Baseline in HbA1c 
HbA1c (%), change from baseline, and percent change from baseline will be summarized by analysis 
visit using descriptive statistics in FAS. They will also be summarized separately by genetic mutation 
category: LMNA, PPARG, or neither. Descriptive summary statistics refers to section 3.2.1. Visit 
includes baseline and analysis visits according to the visit window defined in Appendix B. 
The change in HbA1c from Baseline to Randomized Treatment Period month 3,  month 6, month 9 
and month 12 will be analyzed using this similar ANCOVA model as for the primary efficacy 
analysis  
A subgroup analysis of the ANCOVA will also be run for change in HbA1c from baseline in the 
group of genetically confirmed patients according to the University of Chicago data for patients who 
consented to genetic testing or historical data for patients who did not consent, and in patients with no 
mutation at month 3, month 6, month 9 and month 12 respectively. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
20 
3.4.2.3 Secondary Endpoint 3:  Proportion of patients who achieve a >=40% reduction in fasting 
triglyceride from Baseline and >=30% reduction of hepatic fat fraction percent from baseline at 
Month 6 
Frequency and proportion of patients who achieve a >=40% reduction in fasting triglyceride from 
baseline and >=30% reduction of hepatic fat fraction from baseline at Month 6 will be displayed. 
3.4.2.4 Secondary Endpoint 4:  Patient reported pain and hunger 
No aggregated summary will be created.  
3.4.2.5 Secondary Endpoint 4:  Change from baseline in QOL (EQ-5D, SF-36) 
No aggregated summary will be created. 
 
  
 
 
 
3.6 
Pharmacokinetic and Anti-drug Antibody Analysis 
3.6.1 
Pharmacokinetic Analysis 
During the treatment period, blood samples for the determination of plasma volanesorsen 
concentrations will be collected from all patients prior to dosing, and at various times throughout the 
dosing and post-treatment follow-up period.   
The sampling schedule is noted in the Plasma PK Sampling Schedule table below.   
Plasma PK Sampling Schedule 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
19 
Wk 
26 
Wk 
32 
Wk 
38 
Wk 
44 
Wk 
52 
Study 
Day 
1 
22 
50 
85 
127 
176 
218 
260 
302 
358 
Visit 
Window 
+/- Days 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
Dose 
Pre-
Dose 
 
Patients continuing to first year of OLE period 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
21 
Week 
Wk 
56 
Wk 
60 
Wk 
65 
Wk 
71 
Wk 
78 
Wk 
84 
Wk 
90 
Wk 
96 
Wk 
104 
Wk 
110 
Wk 
117 
Study 
Day 
386 
414 
449 
491 
540 
582 
624 
666 
722 
764 
813 
Visit 
Window 
+/- Days 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
Dose 
Anyti
me 
Anyti
me 
 
Patients continuing to second year of OLE period 
Week 
Wk 
108 
Wk 
112 
Wk 
117 
Wk 
123 
Wk 
130 
Wk 
136 
Wk 
142 
Wk 
148 
Wk 
156 
Wk 
 162 
Wk 
 169 
Study 
Day 
750 
778 
813 
855 
904 
946 
988 
1030 
1086 
1128 
1177 
Visit 
Window 
+/- Days 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
 
Pre-
dose 
Pre-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anyti
me 
Anyti
me 
 
Plasma concentrations of volanesorsen, along with the scheduled (nominal) and actual sampling times 
(i.e., time from SC dosing) will be listed (when applicable) for each patient, by treatment, patient ID, 
patient anti-drug antibody (ADA) status, and IM onset (if applicable) as defined in Section 3.6.2, and 
day.  Plasma concentrations below the lower limit of quantification (LLOQ) will be presented as “0.00”. 
For all patients who receive volanesorsen treatment, trough (pre-dose) and post-treatment volanesorsen 
plasma concentrations will be summarized by study day, with and without stratification by IM status 
(positive/negative or unknown), using descriptive statistics (n, mean, SD, SEM, %CV, geometric mean, 
geometric %CV, median, minimum, and maximum).  For the purpose of calculating typical descriptive 
statistics for plasma concentrations, all below the lower limit of quantification (BLQ) values will be set 
to zero.  Mean plasma concentrations that are BLQ will be presented as BLQ, and the SD and %CV 
will be reported as “NA” (not applicable).  At the discretion of the pharmacokineticist and/or 
biostatistician, samples may be excluded from descriptive statistics if there are large deviations between 
scheduled and actual sampling times, or large deviations between actual dose and nominal dose. 
Mean (±SD) plasma volanesorsen concentration-time plots with stratification by anti-drug antibody  
status will be generated on  semi logarithmic scales. 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
22 
3.6.2 
 Anti-drug Antibody 
Samples collected for  anti-drug antibody (ADA) assessment at selected time points will be analyzed 
for anti-volanesorsen antibodies (i.e., anti-drug antibodies; ADA).  Samples will be designated ‘ADA 
positive’ based on both positive screening and confirmation assay results (i.e., confirmed positive 
result), and otherwise be deemed ‘ADA negative’.  Patients will be given ‘positive’ subject ADA status 
if they have at least one confirmed positive sample at any time before or during the treatment or post-
treatment evaluation periods.  Patients will be given ‘negative’ subject ADA status if all evaluated ADA 
sample results during the treatment and post-treatment evaluation periods are negative and they have 
at least one evaluable ADA result post-dose.  Otherwise, patients will be given ‘unknown’ subject ADA 
status. 
Sample ADA status (screen positive/negative, confirmed positive/negative or unevaluable, and when 
applicable, titer of anti-volanesorsen antibodies) before, during, and after treatment with Study Drug 
(volanesorsen or placebo) will be listed by treatment.   
Patient ADA status (positive/negative or unknown) for all evaluable patients, along with the study day 
associated with the first positive ADA status emerged (Tfirst, i.e., onset of ADA development), the last 
positive ADA status observed (Tlast), the time of last evaluable ADA sample collected (Tlast sampling), and 
max titer, will be listed by treatment. 
Additionally, the ADA incidence (number) and incidence rate (percent) at each evaluated time point 
will be summarized by treatment, as the total number and percent of evaluated patients with antibody 
negative, positive, and unknown status.  Similarly, the ADA incidence and incidence rate at patient 
level will be summarized by treatment.  Furthermore, onset, and max titer of the ADA response, if 
applicable, will be summarized as median, quartiles (25% and 75%), range by treatment for patients 
with positive ADA status.  
Potential relationships between anti-drug antibody results (e.g., ADA status) and AE incidence will be 
evaluated in an exploratory manner.   
3.7 
Safety Analyses 
Safety measures include:  treatment exposure, adverse events, clinical safety lab, vital signs, physical 
examination, 12-Lead ECG, ECHO, concomitant medication use, and MRIs.  Safety measures at 
Randomized Treatment Period and Randomized Treatment Period Post-Treatment Follow-up will be 
summarized in SAF1. Safety measures at OLE Period and OLE Post-Treatment Period will be 
summarized in SAF2.    
Adverse events, lab shift table, and concomitant medication will be summarized by three analysis 
periods, including the Randomized Treatment Period using SAF1, Randomized Treatment Period Post-
Treatment Follow-up among patients who do not continue to OLE using SAF1, and the combined OLE 
and OLE Period Post-Treatment Follow-up using SAF2. Start and end date of each analysis period is 
specified in the table below.  
The rest safety measures will be summarized by nominal visit as collected in CRF, including vital 
sign, physical examination, clinical lab, Echocardiograph, ECG, and MRIs, etc. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
23 
If an AE starts in the Randomized Treatment Period and get worse in the combined OLE and OLE 
Period Post-Treatment Follow-up, the AE will be included in the summary of both period.  If an AE 
starts in the Randomized Treatment Period and continues to the combined OLE and OLE Period Post-
Treatment Follow-up in same or reduced severity, the AE will be included in the summary of first 
period only. If a concomitant medication starts in the Randomized Treatment Period and continues to 
Safety analysis period 
Period Start Date (inclusive) 
Period End Date (inclusive) 
Randomized Treatment 
Period (SAF1)  
First dose date in Randomized 
Treatment Period 
Volanesorsen group: Last dose date 
in the Randomized Treatment 
Period + one dose interval (7 days 
for weekly dosing schedule/ 14 days 
for bi-weekly dosing schedule)  or 
first dose date in the OLE period -1 
day, whichever is earlier.  
Placebo group: if patient continue to 
OLE, end date will be first dose date 
of volanesorsen in the OLE period -
1 day. Otherwise, last dose date in 
the Randomized Treatment Period + 
one dose interval (7 days for weekly 
dosing schedule/ 14 days for bi-
weekly dosing schedule)   
Randomized Treatment 
Period Post-Treatment 
Follow-up (SAF1,  
patients who do not 
continue to OLE)  
Last dose date in the  
Randomized Treatment Period 
+ one dose interval (7 days for 
weekly dosing schedule/ 14 
days for bi-weekly dosing 
schedule) + 1 day 
End date of Post-Treatment Follow-
up Period 
Combined OLE and OLE 
Period Post-Treatment 
Follow-up (SAF2)  
Volanesorsen group: Last dose 
date in the Randomized 
Treatment Period + one dosing 
interval (7 day for weekly 
dosing schedule/ 14 day for bi-
weekly dosing schedule) + 1 
day or first dose date in the 
OLE period, whichever is 
earlier 
Placebo group: First dose date 
of volanesorsen in the OLE 
period  
End date of Post-Treatment Period 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
24 
the combined OLE and OLE Period Post-Treatment Follow-up, the medication will be included in the 
summary of both periods  
3.7.1 
Imputation of Missing/Partial Dates 
3.7.1.1 Adverse Events 
For AEs, the following imputation rules will be applied to impute start dates under conservative 
principles: 
• 
If year, month and day are all missing then assign the date of first dose of Study Drug 
• 
If month and day are missing and year is: 
o the same as the year of the first dose of Study Drug then assign the month-day of first Study 
Drug 
o earlier than the year of the first dose of Study Drug then assign December 31 
o after the year of the first dose of Study Drug then assign January 1 
• 
If only day is missing and month-year is: 
o the same as the month-year of the first dose of Study Drug then assign the day of first Study 
Drug 
o earlier than the month-year of the first dose of Study Drug then assign the last day of the 
month 
o after the month-year of the first dose of Study Drug then assign the first day of the month 
Imputation will be performed only for the end date only if the day or month is missing (i.e., year is 
present) for a resolved AE as follows: 
• 
If month and day are missing and year is 
o the same as the year of the last dose of Study Drug then assign the month-day of the last 
dose of Study Drug 
o otherwise, assign December 31 
• 
If only day is missing then assign the last day of the month 
If the imputed start date is later than the imputed end date then set the imputed start date to the imputed 
end date. 
Analysis period will be assigned by comparing the imputed AE start date with the period start/end date. 
3.7.1.2 Prior/Concomitant Medications 
For prior/concomitant medications, the following imputation rules will be applied to impute start dates 
under conservative principles: 
• 
If year, month and day are all missing then assign the date of first dose of Study Drug 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
25 
• 
If month and day are missing and year is: 
o earlier than the year of the first dose of Study Drug then assign December 31 
o otherwise, assign January 1 
• 
If only day is missing and month-year is: 
o earlier than the month-year of the first dose of Study Drug then assign the first day of the 
month 
o otherwise, assign the last day of the month 
Imputation will be performed only for the end date only if the day or month is missing (i.e., year is 
present) for a stopped prior/concomitant medication as follows: 
• 
If month and day are missing then assign December 31 
• 
If only day is missing then assign the last day of the month 
If the imputed start date is later than the imputed end date then set the imputed start date to the imputed 
end date. 
Analysis period will be assigned by comparing the imputed medication start/end date with the period 
start/end date. 
3.7.2 
Adverse Events 
All adverse events will be coded by the MedDRA dictionary version 19.1.  Missing or partial dates will 
be imputed as outlined in Section 3.7.1.  A treatment-emergent adverse event (TEAE) is defined as any 
event starting or getting worse on or after the first dose of Study Drug.   
TEAE will be identified as follows based on the (imputed) AE start dates: 
Case 1:  If there is no “Formlink” link, and the AE (start date/time) occurs on or after the patient’s first 
dosing date/time, then the AE is treatment-emergent.  Otherwise, if the AE (start date/time) occurs prior 
to the patient’s first dosing date/time, then the AE is not treatment-emergent.  
Case 2:  If there is a “Formlink” link between 2 AE records, then the 2 AE records will be 
chronologically ordered by AE start date/time and will be referred to as the “first” and the “second” AE 
respectively.  AE severity (mild/moderate/severe) will then be compared pairwise.   
Case 2a:  The first AE record in the pair occurs before first dosing, and the second record occurs 
on/after dosing.   
If the AE severity on the second record is worse than the severity on the first record or the severity 
on the second record becomes Serious AE, then only count the second AE as treatment-emergent.  
But, if the severity doesn’t worsen (i.e., the second record severity is the same or less severe than 
the first record severity) or doesn’t become SAE, then neither record is counted as treatment-
emergent. 
Case 2b:  Both AE records in the pair occur on/after first dosing.   


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
26 
If the AE severity on the second record is worse than the severity on the first record or the severity 
on the second record becomes SAE, then count both records as treatment-emergent.  But, if the 
severity doesn’t worsen or doesn’t become SAE, then only count the first record as treatment-
emergent. 
Case 2c:  Both AE records in the pair occur before first dosing. 
Neither AE is counted as treatment-emergent. 
When counting the total number of treatment-emergent events, events linked together through 
change in severity will still be counted as separate events. 
For AEs occurred during the Randomized Treatment Period, and the Combined OLE and OLE Post-
Treatment Period , the frequency of patients with any incidence of AEs and the number of events will 
be summarized by analysis period, MedDRA preferred term and system organ class for: 
• 
Any TEAE 
• 
TEAEs potentially related to Study Drug.  Related is defined as “Related”, “Possible”, or 
missing relationship to Study Drug 
• 
Any treatment-emergent adverse event by severity.  At each level of patient summarization, a 
patient with multiple events is counted only once according to the worst reported severity.  
Adverse events with missing severity will be categorized as “Missing” for this summary. 
• 
TEAEs potentially related to Study Drug by severity  
• 
Serious TEAEs 
• 
Serious TEAEs potentially related to Study Drug 
• 
TEAEs leading to permanent treatment discontinuation 
• 
TEAEs leading to death. 
Adverse event summaries will be presented by descending frequency of the percentage of patients in 
the Total column.  An overview of AEs will be provided for all TEAEs.  Treatment-emergent AEs, 
treatment-emergent SAEs, TEAEs that lead to treatment discontinuation, and TEAEs leading to death 
will be listed.  Note that imputed dates will be used for defining TEAEs and classification of TEAEs 
into  analysis periods.  Originally reported dates will be used for listings.  
For AEs occurred during Randomized Treatment Post-Treatment Period, the frequency of patients and 
number of events  of any TEAEs, Serious TEAE will be summarized by MedDRA preferred term and 
system organ class.  
In addition, an overview of adjudicated AEs will be provided for pancreatitis and MACE separately.  
Adjudicated events will also be listed. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
27 
3.7.2.1 Injection site reaction (ISR) 
 Injection site reaction (ISR) at injection site will also be summarized by treatment group and overall 
using the MedDRA coding system, by analysis period, system organ class and preferred term.  Number 
and percent of patients reporting at least one ISR will be summarized also. 
ISR is defined as any AE with MedDRA preferred term or verbatim that contains “INJECTION SITE”, 
that starts on the day of injection and persist for at least 2 days, or start any time and persist for at least 
2 days, AE resolution date – AE start date + 1 day should be great than two days. AE with preferred 
term or verbatim that contains “INJECTION SITE” and missing resolution date will also be included. 
Percentage of injections leading to Injection Site Reaction will be summarized by treatment group and 
overall using descriptive statistics. 
Percentage of injections leading to Injection  Site Reaction will be calculated as follows for each patient: 
(A/B)*100, where A = number of injections leading to  Injection site reaction (ISR), and B = total 
number of injections. 
3.7.2.2 Flu-Like Reactions 
Flu-like reactions (FLRs) will also be summarized by analysis period, treatment group and overall using 
the MedDRA coding system, by system organ class and preferred term.  Number and percent of patients 
reporting at least one FLR will be summarized also. 
Flu-like reactions are defined as AEs with following preferred term or verbatim: flu-like illness,  chills, 
myalgia, arthralgia, pyrexia, feeling hot, or body temperature increased,  starting on the day of injection 
or the next day.  
Percentage of injections leading to flu-like reactions will be summarized by analysis period, treatment 
group, and overall using descriptive statistics. 
Percentage of the injections leading to flu-like reactions will be calculated as follows for each patient: 
(A/B)*100, where A = number of injections leading to flu-like reactions, and B = total number of 
injections. 
3.7.2.3 Adverse Events of Special Interest:  
Treatment-emergent Bleeding, Hypersensitivity/Immunogenicity, Hepatotoxicity, Nephro-toxicity 
adverse events will be summarized using MedDRA preferred term and system organ class.  
Relationship between Treatment-emergent Bleeding event and presence of Concomitant Anti-
Coagulant or Anti-Platelet Medication will be explored. Concomitant anti-coagulant or anti-platelet 
medications include medications that were taken before or on bleeding event onset date/time and 
stopped on or after bleeding onset date/time or ongoing at the end of study. 
The Bleeding TEAE will be defined based on the Haemorrhages (SMQ) Export from MedDRA.  
The Hypersensitivity/Immunogenicity TEAE is defined as AEs with either of two condition 1) meet 
Hypersensitivity (SMQ) Export from MedDRA, or 2) preferred term “Drug specific antibody” or “Drug 
specific antibody present” within system organ class “Investigations”.  
The Hepatotoxicity TEAE will be defined based on the Drug-related hepatic disorders – comprehensive 
search (SMQ) Export from MedDRA, excluding neoplasms.  


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
28 
The Nephrotoxicity TEAE will be defined based on, either the Acute Renal Failure (SMQ) Export from 
MedDRA, or Proteinuria  (SMQ) Export from MedDRA. 
Treatment-emergent bleeding adverse events will be listed as well. 
3.7.3 
Vital Signs Measurements 
Vital signs will include weight, BMI, body temperature, heart rate, respiratory rate, and systolic, 
diastolic blood pressure, and 
.  Summary tables will be created by treatment group 
and overall to present the descriptive statistics (n, mean, standard error, standard deviation, median, 
P25, P75, minimum, and maximum) for vital sign values as well as the change from Baseline at each 
nominal study visit.  
3.7.4 
Laboratory Measurements 
The following is the list of lab analytes that will be collected throughout the study: 
• 
Chemistry:  sodium, potassium, chloride, bicarbonate, total protein, albumin, calcium, 
magnesium, phosphorus, BUN (blood urea nitrogen), creatinine, creatinine clearance, 
estimated glomerular filtration rate, uric acid, total bilirubin, direct bilirubin, indirect bilirubin, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase,  
• 
Hematology:  red blood cells, hemoglobin, hematocrit, MCV, MCH, MCHC, Platelets, white 
blood cells (WBCs), and WBC differential in both percentage and absolute count (Neutrophils, 
eosinophils, basophils, lymphocytes, and monocytes) 
• 
Coagulation:  aPTT, PT, international normalized ratio (INR) 
• 
Complement:  C5a, Bb 
• 
Other assessments:  Troponin I, hsCRP, Sedimentation Rate, 
 
 
• 
Screening Tests:  Hepatitis B surface antigen, Hepatitis C antibody, HIV antibody, FSH 
(women), serum βhCG (women), and HbA1c, TSH, T3, T4.  The screening test data will only 
be displayed in patient listings. 
• 
Urinalysis:  color, appearance, specific gravity, pH, protein, blood, ketones, urobilinogen, 
glucose, bilirubin, leukocytes esterase, nitrate, and microscopic examination.  For expanded 
urinalysis at certain visits, additional measurements will be performed including:  total protein 
(quantitative), microalbumin, and β2-microglobulin.  The expanded urinalysis data will be only 
displayed in patient listings. 
Missing WBC differential absolute counts and percentages will be derived:  
If WBC differential absolute counts are missing, and percentages are available, then absolute 
counts will be calculated by multiplying the percentage by total WBC count.  Conversely, if 
absolute count is available, and percentage is missing, then percentage will be calculated by 
dividing absolute count by the total WBC count.  If neutrophil counts and percentages are 
missing, and segmented neutrophil and band neutrophil results are available, then neutrophils 
will be calculated by adding segmented neutrophils and band neutrophils. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
29 
Quantitative laboratory measurements reported as ‘< X’, i.e. below the lower limit of quantification 
(BLQ), or ‘> X’, i.e. above the upper limit of quantification (ULQ),  or ‘Cannot calc’, i.e. outside the 
limit of quantification, will be converted to X (or limit of quantification) for the purpose of 
quantitative summaries. 
The MDRD equation will be used to calculate estimated Glomerular Filtration Rate (GFR) base on 
central lab serum creatinine (µmol/l) as: 
eGFR (mL/min/1.73m2) = 32788 × Serum Creatinine (µmol/l) ^ (-1.154) × Age ^ (-0.203) × (1.210 if 
Black or African American) × (0.742 if female). 
  Chemistry, hematology, coagulation, complement, other assessments and quantitative urinalysis 
(result, change from Baseline) will be summarized using descriptive statistics (n, mean, standard error, 
standard deviation, median, P25, P75, minimum, and maximum) and urinalysis dipstick protein will be 
summarized by frequency counts by treatment group,  overall, and by nominal study visit.    
The number and percent of patients falling in each of the following category after first dose will be 
tabulated by treatment group and overall, for each analysis period: 
• 
The higher of ALT > 3 x upper limit of normality (ULN) or ALT > 2 x Baseline 
• 
ALT/AST > 3 x ULN 
• 
ALT/AST > 5 x ULN 
• 
ALT/AST > 8 x ULN 
• 
ALT/AST > 10 x ULN 
• 
ALT/AST > 20 x ULN 
• 
ALT > 3 x ULN - ≤ 5 x ULN 
• 
ALT > 5 x ULN - ≤ 10 x ULN 
• 
ALT > 10 x ULN - ≤ 20 x ULN 
• 
Total bilirubin > 2 x ULN 
• 
ALP > 2 x ULN and (baseline ALP < 2 x ULN or baseline ALP missing) 
The number and percent of patients falling in each of the following categories based on confirmed 
results after first dose will be tabulated by treatment group, and overall for each analysis period (a 
confirmed value is based on a consecutive lab value performed on a different day to, but within 7 
days of, the initial value. If that value is in the same or worse category then the initial value is 
confirmed. If the consecutive value is in a better category then the initial value is confirmed using the 
consecutive value category. If there is no retest within 7 days then the initial value is presumed 
confirmed. If there are multiple results on the same day, then the worst value will be utilized in the 
analysis): 
• 
The higher of ALT/AST > 3 x ULN or ALT/AST > 2 x Baseline, which is confirmed 
• 
ALT/AST > 3 x ULN, which is confirmed   
• 
ALT/AST > 5 x ULN, which is confirmed   
• 
ALT/AST > 10 x ULN, which is confirmed   
• 
ALT/AST > 20 x ULN, which is confirmed   
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
30 
For patients having confirmed 3-fold or greater elevations above the ULN for ALT or AST, a listing of 
all of the ALT, AST, total bilirubin, INR, and alkaline phosphatase records will be provided.  Other 
liver abnormalities including elevation of ALT (> 3 x ULN) accompanied by elevated total bilirubin (> 
2 x ULN), elevation of ALT (> 3 x ULN) accompanied by INR > 1.5 x ULN, elevation of ALT (> 3 x 
ULN) accompanied by elevated total bilirubin > 2 x ULN and ALP < 2 x ULN, and elevation of 
ALT/AST in temporal association with nausea, vomiting, anorexia, abdominal pain, or fatigue will be 
reviewed by the study team and summarized if needed. 
The following hematology and hepatic enzymes lab results will be graded based on Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
(September 2007), and the incidence of shift from Baseline to worst post-baseline value will be 
summarized for each analysis period.  Post-baseline lab results are defined as any assessment taken 
after the first dose.  If a patient is missing a baseline value but has a post-baseline value, then the 
baseline assessment will be labeled as “unknown”.  Likewise, if a patient has a baseline value but has 
no post-baseline values, then the worst value will be labeled as “unknown”. Number and proportion of 
patients with shift from baseline to worst post-baseline values based on the confirmed results by toxicity 
grade for GFR, ALT, AST, and platelets will also be tabulated. 
• 
Hemoglobin:  shift from Baseline to minimum post-baseline value 
• 
WBCs:  shift from Baseline to minimum post-baseline value  
• 
Platelets:  shift from Baseline to minimum post-baseline value  
• 
Creatinine:  shift from Baseline to maximum post-baseline value   
• 
BUN: shift from Baseline to maximum post-baseline value   
• 
eGFR:  shift from Baseline to minimum post-baseline value 
• 
Proteinuria:  shift from Baseline to worst post-baseline value 
• 
ALT:  shift from Baseline to maximum post-baseline value   
• 
AST:  shift from Baseline to maximum post-baseline value   
• 
Alkaline phosphatase:  shift from Baseline to maximum post-baseline value   
• 
Total bilirubin:  shift from Baseline to maximum post-baseline value   
eGFR will be graded using the following criteria: 
• 
≥ 90 mL/min/1.73m2 
• 
≥ 60 mL/min/1.73m2 to < 90 mL/min/1.73m2 
• 
≥ 30 mL/min/1.73m2 to < 60 mL/min/1.73m2 
• 
≥ 15 mL/min/1.73m2 to < 30 mL/min/1.73m2 
• 
< 15 mL/min/1.73m2 
 
The incidence of platelet reduction from Baseline ≥ 30% and ≥ 50% and each of the following 
categories will be summarized for the worst post-baseline value for patients in SAF 1 and SAF2, by 
analysis period:  any 2 occurrences of platelet count < 140,000/mm3, any single occurrence of platelet 
count < 100,000/mm3, , 100,000/mm3 to < 140,000/mm3, 75,000 to < 100,000/mm3, 50,000 to < 
75,000/mm3, 25,000 to < 50,000/mm3, 0 to < 25,000/mm3.  These categories will be summarized based 
confirmed values as well. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
31 
A listing will be provided for patients who terminated treatment due to a protocol-defined stopping 
rule (see Protocol Section 8.6 for details) with categories (liver chemistry elevation, renal function 
test results, platelet count results) and narratives. 
3.7.5 
Exposure  
Treatment duration and amount of Study Drug received will be summarized by Randomized 
Treatment Period and OLE period, and by treatment group and overall for the SAF1 and SAF2.  
Treatment duration is defined as the last day on Study Drug in a specific period minus the first day on 
Study Drug in the analysis period plus one day.  
Compliance to Study Drug will be summarized by descriptive statistics by treatment, and in total, for 
each period. 
Compliance will be calculated as follows:  
100 x (number of injections of Study Drug) / (number of injections scheduled during the 
treatment period).  
Note that number of injections scheduled during the treatment period will be calculated as the Study 
Week of the last dose for patients did not get dose adjustment to biweekly.  For patients who got dose 
adjustment to biweekly, if the dose adjustment started at Week x, then number of injections scheduled 
during the treatment period will be calculated as x plus the largest integer that is less than or equal to 
(study week of the last dose minus x) divided by 2, [number of weeks on weekly dose + integer of 
(number of weeks on bi-weekly dose)/2 ] 
For early withdrawals/terminations, the number of injections will be calculated for the period up to 
their withdrawal/termination. 
3.7.6 
Physical Examination 
Abnormal changes in physical examinations that are deemed clinically-significant by the Investigator 
will be classified as adverse events.  Physical examination results will be listed by labeled visit. 
3.7.7 
12-Lead Electrocardiogram 
ECGs will be performed in triplicate at the visits indicated in the protocol Schedule of Procedures.  The 
ECG data will include ventricular rate, PR interval, QRS duration, QT and corrected QT intervals, and 
overall interpretation.  For the continuous variables, the average of measurements at a given visit will 
be used for analysis.  For overall interpretation, the worst categorical results of triplicate results and the 
associated findings will be used for analysis.  For the continuous variables above, descriptive statistics 
(n, mean, standard error, standard deviation, median, P25, P75, minimum, and maximum) of the results, 
as well as the change from Baseline to each study visit, will be presented by treatment group, and 
overall in summary tables; for the categorical responses to overall interpretation, counts and 
percentages will be provided. 
All the data collected in triplicate will be listed. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
32 
 
3.7.8 
Echocardiogram 
Echocardiogram results will be listed. 
3.7.9 
Concomitant Medications 
All medications will be coded by WHODrug (Version Mar2014).  Medications start and stop dates that 
are recorded on the Prior and Concomitant Medications CRF will be used to determine whether the 
medications are prior or concomitant to the treatment period.  Missing or partial dates will be imputed 
as outlined in Section 3.7.1.  Prior medications include medications started prior to the first dose of 
Study Drug regardless whether continued while on treatment or not.  Concomitant medications include 
medications that patients exposed to on or after the first dose of Study Drug.  A prior medication with 
an imputed stop date that is missing or on or after date of first dose of Study Drug will also be considered 
as a concomitant medication.  Medications will be classified based on (imputed) start and (imputed) 
stop dates as follows: 
1) Prior Medication 
Start Date 
End Date 
< FDD 
Any non-missing stop date  
Missing 
FDD = Date of First Dose of Study Drug 
2) Concomitant Medication  
Start Date 
End Date 
< FDD 
≥ FDD 
Missing 
≥ FDD  
Any non-missing stop date 
Missing 
FDD = Date of First Dose of Study Drug 
Medication verbatim terms will be coded to Anatomical Therapeutic Chemical (ATC) classification 
and preferred name using the World Health Organization Drug Dictionary (Version Dec 2014).   
Prior and concomitant medications will be summarized separately for each analysis period by ATC 
class, preferred name, treatment group and overall with counts and percentages, sorting by decreasing 
frequency in the overall column.  
Additionally, antidiabetic medication changes during  each analysis period, which include those 
medications that are started, stopped, or changed dose during the analysis period, will be summarized 
by ATC class, preferred name, analysis period, treatment group and overall with counts and percentages 
for the SAF1 and SAF2 , sorting by decreasing frequency in the overall column. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
33 
Prior and concomitant medications will be displayed in patient listings for all randomized patients.  
Note that imputed dates will be used for prior and concomitant medications classification.  Originally 
reported dates will be used for listings. 
3.7.10 MRIs 
The hepatic volume and splenic volume as assessed by MRI will be summarized using descriptive 
statistics by analysis windows outlined in Appendix B.  Liver (hepatic fat fraction, 
) and 
spleen MRIs will also be displayed in patient listings for all randomized patients.  
3.8 Changes in the Planned Analysis 
Study treatment is discontinued before completing the protocol specified treatment period. The 
following protocol specified analysis will not be conducted at the final analysis. 
1. Protocol section 10.3 “Per Protocol Set (PPS)”, in final analysis, Per Protocol Set will not be 
classified. All analysis endpoint will not be assessed in PPS. 
2. Protocol section 10.6.3 primary efficacy analysis, patient with missing primary endpoint will 
be excluded from primary efficacy analysis (ANCOVA). Protocol specified imputation method 
and sensitivity analysis to assess the robustness of the primary analysis results will not be 
conducted. For secondary efficacy analysis (patients who achieve a ≥ 40% reduction in fasting 
triglyceride from Baseline and ≥ 30% reduction of hepatic fat fraction percent from baseline at 
Month 6), protocol specified statistical comparison will not be conducted, only descriptive 
summary will be provided. The change from baseline in fasting triglycerides, hepatic fat 
fraction, and HbA1c will be assessed using ANCOVA model with derived FPL based off of 
genetic confirmation as a stratification factor.  A subset analysis will look at the change from 
baseline in fasting triglycerides, hepatic fat fraction, and HbA1c by gene mutation of LMNA 
+ PPARG and no mutation. The ANOCOVA model used for this analysis will include an 
interaction term between treatment and FPL group 
3. Protocol section 10.1.2 states that Disease burden score is one of secondary efficacy endpoint. 
However this patient-reported outcome is not collected in the study. Disease burden score will 
not be summarized. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
34 
4 
BIBLIOGRAPHY 
Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatic-2012: revision of the 
Atlanta classification and definitions by internation concensus. Gut 2013; 62: 102-111. 
Carpenter J, Roger J, and Kenward M. Analysis of longitudinal trials with protocol deviations: a 
framework for relevant, accessible assumptions, and inference via multiple imputation. Journal of 
Biopharmaceutical Statistics 2013; 23: 1352-1371. 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, Final, July 
2009. 
Little RJA and Rubin DB. Statistical analysis with missing data. Second Edition, New York: John 
Wiley & Sons 2002. 
Schafer JL. Analysis of incomplete multivariate data. New York: Chapman and Hall 1997. 
Schafer JL. Multiple imputation: A Primer. Statistical Methods in Medical Research 1999;8: 3-15. 
Wei LJ and Johnson WE. Combining dependent tests with incomplete repeated measurements. 
Biometrika 1985; 72: 359-364. 
 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
35 
5 
APPENDICES 
Appendix A – Data to be reviewed by DSMB 
The data to be reviewd by DSMB is referenced to the CS17 DSMB Charter v1.0-Aug 6, 2015.  
 
1. Additional data may be requested by DSMB and will be provided in agreed upon format 
2. Summary tables will be produced as number of patients enrolled allow 
3. Protocol Deviations will be listed by the following types: 
• 
Eligibility criteria not met 
• 
Study drug administration errors 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
36 
• 
Patient not withdrawn according to protocol requirements 
• 
Missed laboratory sample collection for safety and/or primary endpoint 
• 
Safety end/or primary endpoint procedures that are missed or improperly 
conducted 
• 
Disallowed/restricted concomitant medications 
• 
Non-compliance to stopping rules 
• 
Improper informed consent procedures 
4. The following key parameters will be presented graphically: 
• 
Alanine aminotransferase (ALT) 
• 
Aspartate aminotransferase (AST) 
• 
Alkaline phosphatase (ALP) 
• 
BUN 
• 
Total, direct and indirect bilirubin 
• 
Creatinine 
• 
Hemoglobin 
• 
Lymphocyte, absolute 
• 
Neutrophil, absolute 
• 
Platelet count 
• 
White blood cell count 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
37 
Appendix B – Efficacy measurement analysis visit window 
Efficacy Measure 
Study Period 
Period week 
Target Day 
Study Day Window 
Lipid 
Screening 
  
-56 to -15 
≤ -15 
Qual Visit 
  
-14 to -7 
-14 to < 1 
Randomized Treatment Period 
1 
1 
1 
4 
22 
2 to 36 
8 
50 
37 to 64 
12 
78 
65 to 82 
13 
85 
83 to 106 
19 
127 
107 to 148 
25 
169 
149 to 173 
26 
176 
174 to 197 
32 
218 
198 to 239 
38 
260 
240 to 281 
44 
302 
282 to 323 
50 
344 
324 to 351 
52 
358 
≥ 352 
Lipid 
Open Label Extension (OLE) 
4 
22 
1 to 36 
8 
50 
37 to 64 
12 
78 
65 to 82 
13 
85 
83 to 106  
19 
127 
107 to 148  
25 
169 
149  to 173 
26 
176 
174 to 197 
32 
218 
198 to 239 
38 
260 
240 to 281 
44 
302 
282 to 323 
50 
344 
324 to 351 
52 
358 
352 to 372 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
 
38 
Efficacy Measure 
Study Period 
Period week 
Target Day 
Study Day Window 
56 
386 
373 to 400 
60 
414 
401 to 428 
64 
442 
429 to 446 
65 
449 
447 to 470 
71 
491 
471 to 512 
77 
533 
513 to 537 
78 
540 
538 to 561 
84 
582 
562 to 603 
90 
624 
604 to 645 
96 
666 
646 to 687 
102 
708 
688 to 715 
104 
722 
≥ 716 
Post-Treatment  Follow-up 
7 
43 
1 to 64 
13 
85 
≥ 65 
 
Efficacy Measure 
Study Period 
Period week 
Target Day 
Study Day Window 
MRI liver (hepatic 
fat fraction) 
Screening 
  
-42 to 1 
≤ 14 
Randomized Treatment Period 
Month 6 
(25, 26) 
169-176 
109 to 236 
Month 12 
(50, 52) 
344-358 
284 to 418 
Extension Open Label 
Month 6 
(25, 26) 
169-176 
109 to 236 
Month 12 
(50, 52) 
344-358 
284 to 418 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
June 19, 2019 
Statistical Analysis Plan V2.0 
ISIS 304801-CS17 
39 
Efficacy Measure 
Study Period 
Period week 
Target Day 
Study Day Window 
 
, 
HbA1c 
Screening 
-56 to -15 
≤ -15 
Randomized Treatment Period 
or Open Label Extension Period 
1 
1 
1 
Month 3 
(13) 
85 
55 to 115 
Month 6 
(26) 
176 
146 to 206 
Month 9 
(38) 
260 
230 to 290 
Month 12 
(52) 
358 
328 to 388 


Docwuan ID: 516903650 4 N':une at 
_ \•2.0.pdf 
This documem contains 3 total of 47 p3ges including any signature pagefs. 
PAREXEL International Electronic Signature Page 
This page. is the manifestation of the electronic. signanire(s) used in compliance \\lib PAREXEL 
International' s electronic. signature. policies and procedures and in compliance \\lib applicable regulations. 
UserName:
Title: 
Date: Monday, 01 July 2019, 11 :43 AM GMT Standard Time 
Meaning: Docwnent contents approved.