Conditions: Hereditary Hemochromatosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 70
Healthy volunteers: no

Brief summary:
This study is a Phase 2 multicenter, randomized, placebo controlled, single-blind study. The primary objective of the study is to compare the effect of weekly dosing of LJPC-401 (synthetic human hepcidin) versus placebo on transferrin saturation (TSAT) in an adult hereditary hemochromatosis patient population.

Detailed description:

Arms:
arm 1: LJPC-401 solution for subcutaneous injection only, 5mg/1 mL (5mg/mL) or 10mg/1mL (10mg/mL) single use vial arm 2: 0.9% Sodium Chloride Injection, USP, or equivalent

Interventions: intervention 1: LJPC-401 intervention 2: Placebo
Intervention descriptions: intervention 1: LJPC-401 subcutaneous injection, up to 20 mg weekly for 16 weeks. The minimum weekly dose will be 5 mg and the maximum weekly dose of LJPC-401 will be 20 mg. intervention 2: 0.9% Sodium Chloride Injection, USP, or equivalent

Protocol document:
Prot_000.pdf: 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
2 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
P RI N CI P A L I N V E S TI G A T O R S T A T E M E N T O F A G R E E M E N T  
I, t he u n dersi g ne d Pri nci pal I n vesti gat or, ha ve rea d a n d u n derst o o d t he f oll o wi n g pr ot oc ol 
LJ 4 0 1- H H 0 1 versi o n 6. 0, 1 4 Dece m ber 2 0 1 8 a n d its a p pe n dices.  
I pr o mise t o a bi de b y t he I nter nati o nal C o u ncil o n Har m o nisati o n (I C H) G ui deli nes f or G o o d 
Cli nical Practice s ( G C P), t he Declarati o n of Helsi n ki, a n d all a p plica ble la ws a n d re g ulati o ns, a n d 
a gree t hat, i n all cases, t he m ost restricti ve re g ulati o n relate d t o a gi ve n as pect of researc h i n v ol vi n g 
pr otecti o n of h u ma n s u bjects will be f oll o we d.  I n t he e ve nt t hat I ha ve a q uesti o n re gar di n g m y 
o bli gati o ns d uri n g t he c o n d uct of t his pr ot oc ol, I ha ve rea d y access t o t hese af ore me nti o ne d 
re g ulati o ns, as eit her m y pers o nal c o p y, or a vaila ble o n file fr o m t he C hair pers o n of t he I nstit uti o nal 
Re vie w B oar d (I R B) / Et hics C o m mittee ( E C) or t he S p o ns or, via l ocal a u t h orities a n d,  
I a m a ut h orize d t o e nter i nt o t his c o m mit me nt t o c o n d uct t he st u d y o utli ne d i n t his pr ot oc ol, a n d m y 
si g nat ure bel o w si g nifies t hat I a gree t o c o n d uct t he st u d y as o utli ne d herei n. 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
Pri nte d Na me of I n vesti gat or  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
Si g nat ure of I n vesti gat or 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
Date  




Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
4 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1.  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
La  J olla P har mace utical C o m pa n y ( La  J olla)  
N a me of I n vesti g ati o n al Pr o d uct:  
LJ P C -4 0 1  (s ol uti o n f or s u bc uta ne o us [ S C] i njecti o n) 
N a me of Dr u g S u bst a nce : 
S y nt hetic h u ma n he pci di n  ( he pci di n-2 5  acetate) 
Title of St u d y:  
A P hase 2, M ultice nter, Ra n d o mize d, Place b o -c o ntr olle d, Si n gle -bli n d St u d y wit h LJ P C -4 0 1  f or t he 
Treat me nt of Ir o n O verl oa d i n A d ult Patie nts wit h Here ditar y He m o c hr o mat osis  
St u d y Site(s):   A p pr o xi matel y 3 0  
P h ase of De vel o p me nt:  2  
O bjecti ves:    
Pri m ar y:  
•  
T o c o m pare  t he effect of LJ P C -4 0 1 vers us place b o o n tra nsferri n sat urati o n ( T S A T) i n 
a d ult patie nts wit h here ditar y he m oc hr o mat osis . 
Sec o n d ar y:  
•  
T o c o m pare  t he effect of LJ P C -4 0 1 vers us place b o o n p hle b ot o m y re q uire me nts . 
•  
T o esta blis h t he s afet y a n d t olera bilit y  of LJ P C -4 0 1 vers us place b o  i n a d ult patie nts wit h 
here ditar y he m o c hr o mat osis . 
•  
T o c o m pare  t he effect of LJ P C -4 0 1  vers us place b o  o n s er u m ferriti n . 
E x pl or at or y:  
•  
T o c o m pare t he effect of LJ P C -4 0 1 vers us place b o o n ser u m ir o n para meters . 
•  
T o c o m pare t he effect of LJ P C -4 0 1 vers us place b o o n t h yr oi d f u ncti o n. 
•  
T o c o m pare t he effect of LJ P C -4 0 1 vers us place b o o n li ver f u ncti o n.  
•  
T o c o m pare t he effect of LJ P C -4 0 1 vers us place b o o n gl y ce mic c o ntr ol.  
•  
T o c o m pare t he effect of LJ P C -4 0 1 vers us place b o o n re d bl o o d cell ( R B C) para meters 
i ncl u di n g he m o gl o bi n c o nce ntrati o n, R B C c o u nt, a n d re d cell distri b uti o n wi dt h ( R D W) . 
•  
T o c o m pare t he effect of LJ P C -4 0 1 vers us place b o o n q ualit y of life as meas ure d b y 
Q ualit y of Life Q uesti o n naire s, S h ort F or m ( 3 6) Healt h S ur ve y, Versi o n 2 (S F - 36 v 2 ), 
Wester n O ntari o a n d Mc Master U ni versities Oste oart hritis I n de x ( W O M A C) , a n d 
m o difie d Dreisler i n dices f or art hritis. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
5 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
E n d p oi nts:  
Pri m ar y effic ac y e n d p oi nt :  
•  
C ha n ge i n T S A T , defi ne d as f oll o ws: 
− F or patie nts wit h 1 p hle b ot o m y (t he sta n dar d of care t hera pe utic p hle b ot o m y o n 
Da y  1 [ pre d ose]), c ha n ge i n T S A T fr o m baseli ne t o Wee k 1 6 ( 2 4 [ ± 4] h o urs 
p ost d ose).  
− F or patie nts u n der g oi n g 2 or m ore  p hle b ot o m ies, c ha n ge i n T S A T fr o m baseli ne t o 
t he m ost rece nt p ost d ose fasti n g T S A T o bser ve d pri or t o t he sec o nd p hle b ot o m y.  
Sec o n d ar y effic ac y e n d p oi nts:  
•  
N u m ber of p hle b ot o mies fr o m Da y 2 t o E n d of St u d y ( E O S )/ 3 0 (+ 3) da ys after t he last 
d ose of st u d y dr u g . 
•  
C ha n ge i n ser u m ferriti n, defi ne d as f oll o ws:  
− F or patie nts wit h 1 p hle b ot o m y (t he sta n dar d of care t hera pe utic p hle b ot o m y o n 
Da y  1 [ pre d ose]), c ha n ge i n ser u m ferriti n fr o m baseli ne t o Wee k 1 6 ( 2 4 [ ± 4] h o urs 
p ost d ose).  
− F or patie nts u n der g oi n g 2 or m ore  p hle b ot o m ies, c ha n ge i n ser u m ferriti n fr o m 
baseli ne t o t he m ost rece nt p ost d ose ser u m ferriti n  o bser ve d pri or t o  t he sec o n d 
p hle b ot o m y.  
S afet y a n d t oler a bilit y e n d p oi nts:  
•  
A d verse e ve nts ( A Es)  fr o m c o nse nt to E O S . 
•  
C ha n ges i n cli nical la b orat or y e val uati o ns i ncl u di n g ser u m ir o n para meters  fr o m baseli ne  
t o E O S . 
•  
C ha n ges i n vital si g ns, electr ocar di o gra ms ( E C Gs), use of c o nc o mita nt me dicati o ns, a n d 
p h ysical e xa mi nati o ns fr o m baseli ne  t o E O S . 
•  
I m m u n o ge nicit y (a nti-dr u g a nti b o d y) / p har mac o ki netics ( P K) fr o m baseli ne  to E O S . 
E x pl or at or y e n d p oi nts:  
•  
C ha n ge i n ser u m ir o n para meters , defi ne d as f oll o ws: 
− F or patie nts wit h 1 p hle b ot o m y (t he sta n dar d of care t hera pe utic p hle b ot o m y o n 
Da y  1 [ pre d ose]) , c ha n ge i n ser u m ir o n para meters fr o m baseli ne t o Wee k 1 6 
( 2 4 [ ± 4] h o urs p ost d ose).  
− F or patie nts u n der g oi n g 2 or m ore  p hle b ot o m ies, c ha n ge i n ser u m ir o n para meters 
fr o m baseli ne t o t he m ost rece nt p ost d ose ser u m ir o n para meters o bser ve d pri or t o  t he 
sec o n d p hle b ot o m y.  
− F or patie nts wit h 1 p hle b ot o m y (t he sta n dar d of care t hera pe utic p hle b ot o m y o n 
Da y  1 [ pre d ose]) , c ha n ge i n ser u m ir o n para meters fr o m baseli ne t o Wee k 1 7  
(a p pr o xi matel y 7 da ys after t he last d ose of st u d y dr u g). 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
6 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
− F or patie nts u n der g oi n g 2 or m ore  p hle b ot o m ies, c ha n ge i n ser u m ir o n para meters 
fr o m baseli ne t o t he m ost rece nt pre d ose ser u m ir o n para meters o bser ve d pri or t o  t he 
sec o n d p hle b ot o m y.  
•  
C ha n ge i n t h yr oi d f u ncti o n fr o m baseli ne t o Wee k 1 6 . 
•  
C ha n ge i n li ver f u ncti o n fr o m baseli ne t o Wee k 1 6 . 
•  
C ha n ge i n he m o gl o bi n A 1 c fr o m baseli ne t o Wee k 1 6 . 
•  
C ha n ge i n R B C para meters i ncl u di n g he m o gl o bi n c o nce ntrati o n, R B C c o u nt, a n d R D W  
as defi ne d as  f oll o ws: 
− F or patie nts wit h 1 p hle b ot o m y (t he sta n dar d of care t hera pe utic p hle b ot o m y o n 
Da y  1 [ pre d ose]), c ha n ge i n R B C para meters fr o m baseli ne t o 
Wee k  1 6  ( 2 4 [ ± 4]  h o urs p ost d ose) . 
− F or patie nts u n der g oi n g 2 or m ore p hle b ot o mies, c ha n ge i n R B C para meters fr o m 
baseli ne t o t he m ost rece nt p ost d ose R B C para meters o bser ve d pri or t o t he sec o n d 
p hle b ot o m y.  
•  
C ha n ge i n Q ualit y of Life Q uesti o n naire s, S F -3 6 v 2 , W O M A C, a n d m o difie d Dreisler 
i n dices f or art hritis, fr o m baseli ne  t o Wee k 1 6 . 
St u d y Desi g n:   T his st u d y is a m ultice nter, ra n d o mize d, place b o -c o ntr olle d, si n gle-bli n d st u d y.  T he 
pri mar y o bjecti ve of t he st u d y is t o e val uate t he effect of LJ P C -4 0 1  o n T S A T i n  a d ults wit h 
here ditar y he m o c hr o mat osis.  
Eli gi b le patie nts will be ra n d o mize d 1: 1 t o LJ P C -4 0 1  or place b o .  Ra n d o mizati o n will be stratifie d b y 
baseli ne T S A T ( > 4 5 % t o 7 0 % vers us  > 7 0 %) a n d p hle b ot o m y fre q ue nc y o ver t he last 1 2  m o nt hs 
( 0 t o 3 vers us >  3). 
All ra n d o mize d patie nts will recei ve a sta n dar d of care t hera pe utic p hle b ot o m y ( 5 00 cc  or a p pr o priate 
f or wei g ht) o n Da y 1  ( pre d ose).  T hereafter, p hle b ot o m y decisi o ns b y t he I n vesti gat or will be base d 
o n t he patie nt’s fasti n g T S A T res ults c ollecte d 2 4  ( ± 4) h o urs p ost d ose at Wee k 4  (Da y 2 3 ); Wee k  8 
(Da y 5 1 ); Wee k 1 2  (Da y  7 9 ); a n d Wee k  1 6  (Da y 1 0 7 ); a n d base d o n t he 2 0 1 1 Ir o n Dis or ders I nstit ute 
(I DI) p hle b ot o m y g ui deli nes f or patie nts wit h here ditar y he m oc hr o mat osis .  If a p hle b ot o m y is 
i n dicate d base d o n t he T S A T criteria of t he I DI p hle b ot o m y g ui deli ne s, t he patie nt s h o ul d recei ve 
p hl e b ot o m y treat me nt pre d ose , o n or bef ore t he f oll o wi n g visit . 
T he pri mar y efficac y a nal ysis will ta ke place after all patie nts ha ve c o m plete d t he We ek 1 6 
assess me nts  ( or ha ve wit h dra w n fr o m t he st u d y earl y).    
N u m ber of p atie nts ( pl a n ne d):   A p pr o xi matel y 6 8 t o 7 6 patie nts   


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
7 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
I ncl usi o n Criteri a: 
1.  Patie nts wit h a c li nical dia g n osis of here ditar y he m o c hr o mat osis. 
2.  Patie nts w h o are prescri be d  t hera pe utic p hle b ot o m y f or t he treat me nt of here ditar y 
he m oc hr o mat osis.  
3.  Patie nts ≥ 1 8 y ears of a ge.   
4.  Patie nts wit h a ser u m  ferriti n le vel ≥ 1 0 0 n g/ m L.  
5.  Patie nts wit h a T S A T le vel > 4 5 %.  
6.  Fe male patie nts m ust be of n o nc hil d beari n g p ote ntial or usi n g a hi g hl y effecti ve met h o d of 
c o ntrace pti o n d uri n g partici pati o n i n t he st u d y  a n d f or 3 0 da ys after t he last d ose of st u d y 
dr u g .  Hi g hl y effecti ve met h o ds of c o ntrace pti o n are defi ne d as t h ose, al o ne or i n 
c o m bi nati o n, t hat res ult i n a l o w fail ure rate w he n use d c o nsiste ntl y a n d c orrectl y.   Refer t o 
Secti o n  1 0. 1. 6. 5. 1  f or t he list of hi g hl y effecti ve met h o ds of c o ntrace pti o n t hat ca n be use d i n 
t his st u d y. 
7.  Fe male patie nts of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g na nc y test at 
Scree ni n g  ( wit hi n 3 0 da ys pri or t o t he first d ose of st u d y dr u g), a n d a ne gati ve uri ne 
pre g na nc y test o n Da y 1  (ie, pri or t o  i nitial d osi n g  of st u d y dr u g). 
8.  Male patie nts m ust be s ur gicall y sterile  ( vasect o m y) or usi n g a hi g hl y effecti ve met h o d of 
c o ntrace pti o n d uri n g partici pati o n i n t he st u d y  a n d f or 3 0 da ys after t he last d ose of st u d y 
dr u g .  Hi g hl y effecti ve met h o ds of c o ntrace pti o n are defi ne d as t h ose, al o ne or i n 
c o m bi nati o n, t hat res ult i n a l o w fail ure rate w he n use d c o nsiste ntl y a n d c orrectl y .  Refer t o 
Secti o n  1 0. 1. 6. 5. 1  f or t he list of hi g hl y effecti ve met h o ds of c o ntrace pti o n t hat ca n be use d i n 
t his st u d y. 
9.  Patie nt m ust  be willi n g a n d a ble t o pr o vi de writte n i nf or me d c o nse nt.  
 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
8 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
E xcl usi o n Criteri a:  
1.  Patie nts  recei vi n g ir o n c helati o n t hera p y wit hi n 7 da ys pri or t o t he first d ose of st u d y dr u g .  
2.  Patie nts rece ntl y dia g n ose d, w h o ha ve i nitiate d p hle b ot o m y treat me nts less t ha n 3 m o nt hs 
pri or t o t he first d ose of st u d y dr u g . 
3.  Patie nts wit h a c o nc o mita nt disease, disa bilit y or c o n diti o n, i ncl u di n g la b orat or y a b n or malit y  
a n d E C G fi n di n gs, w hic h ma y i nterfere wit h t he c o n d uct of t he st u d y, or w hic h w o ul d, i n t he 
o pi ni o n of t he In vesti gat or, p ose a n u nacce pta ble ris k t o t he patie nt i n t his st u d y, i ncl u di n g, 
b ut n ot li mite d t o, cli nicall y si g nifica nt arr h yt h mias, alc o h ol de pe n de nc y or a b use, dr u g 
de pe n de nc y or a b use, or ps y c hiatric disease.   Patie nts wit h de pressi o n are eli gi ble if recei vi n g 
a sta ble d ose of me dicati o n f or at least 9 0 da ys pri or t o t he first d ose of st u d y dr u g.  
4.  Pre g na nt or lactati n g w o me n.  
5.  Patie nts ta ki n g a n i m m u n os u p pressi ve a ge nt t hat has n ot bee n a p pr o ve d b y La J olla f or use 
(e xcl u di n g t o pical o ver-t he-c o u nter ster oi ds, i n hale d ster oi d me dicati o ns,  a n d n o nster oi dal 
a nti-i nfla m mat or y dr u gs).  Refer t o Secti o n  7. 1  f or t he list of pr o hi bite d  me dicati o ns a n d 
pr oce d ures.  
6.  Patie nts partici pati n g i n a n u na p pr o ve d i n vesti gati o nal dr u g or i n vesti gati o nal t hera pe utic 
de vice st u d y wit hi n 3 0 da ys pri or t o st u d y dr u g d osi n g, ie, t here m ust be at least 3 0 da ys i n 
bet wee n t he last d ose o n a pri or st u d y a n d t he first d ose a d mi nistrati o n o n t his trial.  
7.  Patie nts w h o are u n willi n g or u na ble t o c o m pl y wit h t he st u d y pr ot oc ol re q uire me nts.  
8.  Patie nts wit h t y pe 1 dia betes  or t y pe 2 dia betes wit h he m o gl o b i n Alc greater t ha n 8 % wit hi n 
2 m o nt hs pri or t o ra n d o mizati o n . 
9.  Patie nts wit h u nc o ntr olle d a cti ve he patitis B, he patitis C, or h u ma n i m m u n o deficie nc y vir us 
( HI V) i nfecti o n. 
1 0.  Patie nts wit h C hil d P u g h class C  cirr h osis or li ver fail ure . 
1 1.  Patie nts wit h se vere c o n gesti ve heart fail ure ( Ne w Y or k Heart Ass ociati o n [ N Y H A]  = 
Class  4). 
1 2.  Patie nts w h o ha ve a d va nce d re nal fail ure wit h a n esti mate d gl o mer ular filtrati o n rate (e G F R) 
< 1 5 m L/ mi n/ 1. 7 3 m 2. 
1 3.  Patie nts wit h a h ist or y of aller gic reacti o n t o he pci di n or e xci pie nts. 
1 4.  Patie nts w h o ha ve pla n ne d s ur ger y  (e xcl u di n g de ntal s ur ger y or si m ple der mat ol o gic 
pr oce d ures)  d uri n g partici pati o n i n t his  st u d y. 
I n vesti g ati o n al Pr o d uct/ D os a ge F or m ul ati o n: 
LJ P C -4 0 1  (s y nt hetic h u ma n he pci di n) sol uti o n f or S C injecti o n  


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
9 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
D ose Re gi me n a n d R o ute of A d mi nistr ati o n:  
Patie nts  will be d ose d  o nce -wee kl y wit h LJ P C -4 0 1  or place b o ( 0. 9 % s o di u m c hl ori de) a d mi nistere d 
S C f or 1 6  wee ks.   LJ P C -4 0 1 d ose will start at 5 m g at Wee k 1 , a n d t he d ose will i ncrease t o 1 0 m g at 
Wee k s 2 a n d 3.  T he patie nt’s fasti n g T S A T at Wee k 3 (Da y 1 6 ), c ollecte d 2 4  ( ± 4) h o urs p ost d ose,  
will deter mi n e t he Wee k  4 d ose .  At Wee k  4, i f t he patie nt’s fasti n g T S A T is  > 4 5 % , t he n t he 
LJ P C -4 0 1 d ose will i ncrease t o 2 0 m g.  If t he fasti n g T S A T re mai ns ≤ 4 5 % t he n t he d ose will re mai n 
at 1 0 m g .  T he patie nt’s fasti n g T S A T res ult s at Wee k  8 ( Da y 5 1) a n d Wee k 1 2 ( Da y 7 9) , c ollecte d 
2 4  ( ± 4) h o urs p ost d ose,  will be use d t o deter mi ne if a d ose a dj ust me nt is nee de d at Wee ks  9 a n d 1 3.  
Refer t o Secti o n 5. 4  f or d ose a dj ust me nts i nf or mati o n.  
F or t h ose patie nts ra n d o mize d t o place b o, a s yri n ge of 0. 9 % s o di u m c hl ori de i njecti o n will be 
pre pare d b y t he st u d y p har macist or desi g nee.  T o mai ntai n t he st u d y si n gle-bli n d, s yri n ge s wit h st u d y 
dr u g ( place b o a n d acti ve dr u g) will be i de ntical.      
D ur ati o n of tre at me nt: 1 6 Wee ks    
St atistic al Met h o ds:  
A sa m ple size of 4 8  patie nts has 8 0 % p o wer t o detect a 1 5 % differe nce i n t he c ha n ge i n T S A T  
bet wee n t he place b o ar m a n d t he LJ P C -4 0 1  ar m, ass u mi n g a c o m m o n sta n dar d de viati o n of 1 8 % a n d 
a 2- si de d t y pe I err or of 0. 0 5.   
Patie nts w h o d o n ot e nr oll u n der gl o bal pr ot oc ol versi o n 4. 0/ U nite d Ki n g d o m ( U K ) pr ot oc ol versi o n 
4. 1 or later or disc o nti n ue t h e st u d y earl y pri or t o d osi n g will be re place d.  Patie nts w h o recei ve st u d y 
dr u g a n d disc o nti n ue pri or t o Wee k 1 6 ma y be re place d.  A p pr o xi matel y 2 0 t o 2 8 patie nts are 
e x pecte d t o be re place d.  T he pla n is t o e nr oll a n d ra n d o mize a p pr o xi matel y 6 8 t o 7 6 pat ie nts ( 1: 1 t o 
LJ P C -4 0 1 or place b o) t o e ns ure t hat at least 4 8 patie nts are i ncl u de d i n t he pri mar y efficac y a nal ysis.  
T he pri mar y efficac y a nal ysis a n d sec o n dar y efficac y a nal yses will i ncl u de t he Efficac y Patie nt 
P o p ulati o n  w hic h is defi ne d as all patie nts e nr olle d u n der gl o bal p r ot oc ol versi o n 4. 0/ U K pr ot oc ol 
versi o n 4. 1  or later w h o recei ve d st u d y dr u g, a n d w h o  c o m pleted t he Wee k 1 6 assess me nts or ha d a n 
o n -st u d y p hle b ot o m y after t he sta n dar d of care t hera p e utic p hle b ot o m y o n Da y  1 ( pre d ose) a n d b ef ore 
Wee k  1 6 . 
All e nr olle d p atie nts, re gar dless of pr ot oc ol versi o n, w h o recei ve at least 1 d ose  of st u d y dr u g will be 
incl u de d i n t he safet y a nal yses.  
Ce ntral ra n d o mizati o n will be use d wit h stratificati o n b y baseli ne T S A T ( > 4 5 % t o 7 0 % vers us  
> 7 0 %) a n d p hle b ot o m y fre q ue nc y o ver t he last 1 2 m o nt hs (0 t o 3 vers us >  3). 
D ata will be s u m marize d b y treat me nt gr o u p, st u d y visit, a n d, if a p pr o priate, st u d y i nter val usi n g 
s u m mar y statistics f or c o nti n u o us varia bles a n d n u m b er a n d perce nta ge f or cate g orical val ues.  
Statistical c o m p aris o ns of differe nces b et wee n treat me nt ar ms will be ma de usi n g Wilc o x o n ra n k -s u m 
tests, mi xe d effects re peate d meas ures, a n d/or a nal ysis of varia nce ( A N O V A ) f or c o nti n u o us or 
or di nal varia bles, C hi -S q uare or C oc hra n -Ma ntel -Hae nszel tests f or cate g orical varia bles, Fis h er’s 
e xact tests f or bi nar y varia bles, a n d P oiss o n re gressi o n m o del f or c o u nt data (e g, n u m ber of 
p hle b ot o mies) .  


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
1 0 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
S u b gr o u ps t hat are c o nsi dere d of i nterest i ncl u de a ge, se x, race, et h nicit y, co u ntr y, ge o gra p hic re gi o n, 
b o d y mass i n de x, baseli ne T S A T, p hle b ot o m y fre q ue nc y o ver t he last 1 2 m o nt hs , baseli ne he pci di n 
le vel, baseli ne ser u m ir o n le vel, a n d baseli ne ser u m ferriti n le vel. 
T he c ha n ge i n T S A T , ser u m ir o n pa nel, t h yr oi d f u ncti o n, li ver f uncti o n, gl y ce mic c o ntr ol, R B C 
para meters , a n d q ualit y of life q uesti o n naire sc ore s fr o m baseli ne t o Wee k 1 6 (a n d Wee k 1 6 
2 4  ( ± 4) h o urs  p ost d ose  f or ser u m ir o n para meters), a n d t he c ha n ge i n ser u m ir o n para meters  fr o m 
baseli ne t o Wee k 1 7,  will be e val uate d, w here a p pr o priate, usi n g t he a p pr o priate statistical met h o ds 
liste d a b o ve wit h a dj ust me nt f or baseli ne T S A T a n d p hle b ot o m y fre q ue nc y  o ver t he last 1 2  m o nt hs . 
N u m ber of  p hle b ot o mies a n d t he n u m ber of ti mes a patie nt met criteria f or a p hle b ot o m y will be 
a nal y ze d.  W het her a patie nt meets t he criteria f or a p hle b ot o m y ( yes or n o) will be assesse d after t he 
res ults of eac h fasti n g T S A T rec or de d at p ost d ose 2 4 ( ± 4) h o urs o n  Wee k 4  (Da y 2 3 ); Wee k 8 
(Da y  5 1 ); Wee k 1 2 (Da y 7 9 ); a n d Wee k 1 6 (Da y 1 0 7 ) are k n o w n .  T he patie nt s h o ul d recei ve 
p hle b ot o m y treat me nt pre d ose, o n or bef ore t he f oll o wi n g visit .  T he prese nce of a n y p hle b ot o m y  will 
be a nal y ze d b y  a C oc hra n - Ma ntel- Hae nszel test wit h a dj ust me nt f or baseli ne T S A T a n d p hle b ot o m y 
fre q ue nc y o ver t he last 1 2 m o nt hs .  T he fre q ue nc y of a p hle b ot o m y will be a nal yze d b y P oiss o n 
re gressi o n m o del wit h baseli ne T S A T a n d p hle b ot o m y fre q ue nc y  o ver t he last 1 2 m o nt hs  i ncl u de d i n 
t he m o del. 
Se nsiti vit y a nal yses of T S A T , ser u m ferriti n, a n d n u m b er of p hle b ot o m ies will be c o n d ucte d.  Details 
will be pr o vi de d i n t he statistical a nal ysis pla n.  
Safet y data i ncl u di n g a nal yses of A Es , cli nical la b orat or y data, E C G, vital si g ns, a n d i m m u n o ge nicit y  
fi n di n gs will be s u m marize d b y descri pti ve statistics wit hi n a n d acr oss treat me nt ar ms.  Se verit y, 
relate d ness, a n d seri o us ness of A Es will be s u m marize d.  P h ysical e xa mi nati o n  data  will be pr o vi de d 
i n t he listi n gs. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
1 1 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
2.  
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F 
FI G U R E S  
P RI N CI P A L I N V E S TI G A T O R S T A T E M E N T O F A G R E E M E N T  .............................................. 2 
1.  
S Y N O P SI S  ................................................................................................................... 4 
2.  
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F FI G U R E S ............... 1 1 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  ................................................ 1 6 
3.  
I N T R O D U C TI O N ...................................................................................................... 1 9 
3. 1.  
S u m mar y of LJ P C - 4 0 1 N o ncli nical P har mac ol o g y I nf or mati o n ............................... 2 0 
3. 2.  
S u m mar y of LJ P C -4 0 1 T o xic ol o g y I nf or mati o n  ........................................................ 2 2 
3. 3.  
S u m mar y of LJ P C -4 0 1 Cli nical St u dies  ..................................................................... 2 4 
3. 3. 1.  
LJ 4 0 1- T P P 0 1  .............................................................................................................. 2 4 
3. 3. 2.  
LJ 4 0 1- N H V 0 1  ............................................................................................................ 2 5 
3. 3. 3.  
LJ 4 0 1- N H V 0 2  ............................................................................................................ 2 6 
3. 4.  
Cli nical Rati o nale f or t he LJ 4 0 1- H H 0 1 St u d y ........................................................... 2 6  
3. 4. 1.  
Rati o nale f or t he St u d y Desi g n f or St u d y LJ 4 0 1- H H 0 1  ............................................. 2 6 
3. 4. 2.  
Rati o nale f or Usi n g Ir o n Dis or ders I nstit ute P hle b ot o m y G ui deli nes ........................ 2 7  
4.  
T RI A L O BJ E C TI V E S A N D  P U R P O S E  .................................................................... 2 9 
4. 1.  
Pri mar y O bjecti ve  ....................................................................................................... 2 9 
4. 2.  
Sec o n dar y O bjecti ves  ................................................................................................. 2 9 
4. 3.  
E x pl orat or y O bjecti ves  ............................................................................................... 2 9 
5.  
I N V E S TI G A TI O N A L P L A N ..................................................................................... 3 0 
5. 1.  
O verall St u d y Desi g n  .................................................................................................. 3 0 
5. 2.  
N u m ber of Patie nts  ..................................................................................................... 3 0 
5. 3.  
Treat me nt Assi g n me nt  ................................................................................................ 3 0 
5. 4.  
D ose A dj ust me nt Criteria  ........................................................................................... 3 1 
5. 4. 1.  
Safet y Criteria f or A dj ust me nt or St o p pi n g D oses  ..................................................... 3 1 
5. 5.  
Criteria f or St u d y Ter mi nati o n  ................................................................................... 3 2 
5. 6.  
Sc he d ule of Assess me nts  ............................................................................................ 3 2 
6.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  .............................................. 3 7 
6. 1.  
Patie nt I ncl usi o n Criteria  ............................................................................................ 3 7 
6. 2.  
Patie nt E xcl usi o n Criteria  ........................................................................................... 3 7 
6. 3.  
Patie nt Wit h dra wal Criteria  ........................................................................................ 3 8 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
1 2 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
7.  
T R E A T M E N T O F P A TI E N T S .................................................................................. 4 0  
7. 1.  
C o nc o mita nt Me dicati o ns a n d Pr oce d ures  ................................................................. 4 0 
7. 2.  
Treat me nt C o m plia nce  ................................................................................................ 4 0 
7. 3.  
Ra n d o mizati o n a n d Si n gle- Bli n d  ................................................................................ 4 1 
7. 4.  
St u d y Pr oce d ures ........................................................................................................ 4 1  
7. 4. 1.  
Scree ni n g ( Wit hi n 9 0 da ys of Wee k 1/ Da y 1) ............................................................ 4 2  
7. 4. 2.  
Wee k 1 ( Da y 1) ........................................................................................................... 4 3  
7. 4. 3.  
Wee k 2 ( Da y 8) ........................................................................................................... 4 3  
7. 4. 4.  
Wee k 3 ( Da y 1 5 a n d Da y 1 6) ..................................................................................... 4 4  
7. 4. 5.  
Wee k 4 ( Da y 2 2) ......................................................................................................... 4 4  
7. 4. 6.  
Wee ks 5, 6, a n d 7 ( Da ys 2 9, 3 6, a n d 4 3) .................................................................... 4 5  
7. 4. 7.  
Wee k 8 ( Da y 5 0 a n d Da y 5 1) ..................................................................................... 4 5  
7. 4. 8.  
Wee ks 9, 1 0, a n d 1 1 ( Da ys 5 7, 6 4, a n d 7 1) ................................................................ 4 6  
7. 4. 9.  
Wee k 1 2 ( Da y 7 8 a n d Da y 7 9) ................................................................................... 4 6  
7. 4. 1 0.  
Wee ks 1 3, 1 4, a n d 1 5 ( Da ys 8 5, 9 2, a n d 9 9) .............................................................. 4 7  
7. 4. 1 1.  
Wee k 1 6 ( Da y 1 0 6 a n d Da y 1 0 7) ............................................................................... 4 7  
7. 4. 1 2.  
Wee k 1 7 ( Da y 1 1 3) ..................................................................................................... 4 8  
7. 4. 1 3.  
F oll o w- u p ( 3 0 da ys [ + 3 da ys] fr o m last d ose of st u d y dr u g) .................................... 4 8  
7. 4. 1 4.  
Earl y Wit h dra wal  ........................................................................................................ 4 9 
8.  
S T U D Y D R U G M A T E RI A L S  A N D M A N A G E M E N T  ........................................... 5 0 
8. 1.  
St u d y Dr u g .................................................................................................................. 5 0  
8. 2.  
St u d y Dr u g Pac ka gi n g a n d La beli n g .......................................................................... 5 0  
8. 3.  
St u d y Dr u g St ora ge ..................................................................................................... 5 0  
8. 4.  
St u d y Dr u g Pre parati o n .............................................................................................. 5 0  
8. 5.  
St u d y Dr u g A d mi nistrati o n ......................................................................................... 5 0  
8. 6.  
St u d y Dr u g Acc o u nta bilit y ......................................................................................... 5 1  
8. 7.  
St u d y Dr u g Ha n dli n g a n d Dis p osal ............................................................................ 5 1  
9.  
A S S E S S M E N T O F E F FI C A C Y  ................................................................................ 5 2 
9. 1.  
C o m plete Ir o n St u dies ................................................................................................ 5 2  
9. 2.  
P hle b ot o m y ................................................................................................................. 5 2  
1 0.  
A S S E S S M E N T O F S A F E T Y  ..................................................................................... 5 3 
1 0. 1.  
Safet y Para meters  ....................................................................................................... 5 3 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
1 3 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 0. 1. 1.  
De m o gra p hics ............................................................................................................. 5 3  
1 0. 1. 2.  
Me dical Hist or y  .......................................................................................................... 5 3 
1 0. 1. 3.  
Vital Si g ns  .................................................................................................................. 5 3 
1 0. 1. 4.  
P h ysical E xa mi nati o n  ................................................................................................. 5 3 
1 0. 1. 5.  
Electr ocar di o gra m  ....................................................................................................... 5 3 
1 0. 1. 6.  
La b orat or y Assess me nts  ............................................................................................. 5 4 
1 0. 1. 6. 1.  
He mat ol o g y ................................................................................................................. 5 4  
1 0. 1. 6. 2.  
Cli nical C he mistries  .................................................................................................... 5 4 
1 0. 1. 6. 3.  
T h yr oi d F u ncti o n ........................................................................................................ 5 5  
1 0. 1. 6. 4.  
Gl yce mic C o ntr ol ........................................................................................................ 5 5  
1 0. 1. 6. 5.  
Pre g na nc y Scree n  ........................................................................................................ 5 5 
1 0. 1. 6. 6.  
Uri nal ysis  .................................................................................................................... 5 6 
1 0. 1. 6. 7.  
I m m u n o ge nicit y .......................................................................................................... 5 6 
1 0. 2.  
Q ualit y of Life Q uesti o n naires  ................................................................................... 5 6 
1 1.  
A D V E R S E A N D S E RI O U S A D V E R S E E V E N T S  ................................................... 5 7 
1 1. 1.  
Defi niti o n of A d verse E ve nts ..................................................................................... 5 7  
1 1. 1. 1.  
A d verse E ve nt ............................................................................................................. 5 7  
1 1. 1. 2.  
Seri o us A d verse E ve nt  ................................................................................................ 5 7 
1 1. 2.  
Relati o ns hi p t o I n vesti gati o nal Pr o d uct a n d Se verit y  ................................................. 5 8 
1 1. 3.  
Re p orti n g of A d verse E ve nts a n d Seri o us A d verse E ve nts ........................................ 5 9  
1 1. 3. 1.  
Re p orti n g of A d verse E ve nts ...................................................................................... 5 9  
1 1. 3. 2.  
Re p orti n g of Seri o us A d verse E ve nts ......................................................................... 5 9  
1 1. 4.  
F oll o w- u p of A Es a n d S A Es ....................................................................................... 6 0  
1 1. 5.  
Pre g na nc y a n d F oll o w- u p  ........................................................................................... 6 0 
1 2.  
S T A TI S TI C S  .............................................................................................................. 6 2 
1 2. 1.  
Statistical H y p ot hesis  .................................................................................................. 6 2 
1 2. 2.  
Sa m ple Size a n d P o wer C o nsi derati o ns ..................................................................... 6 2  
1 2. 3.  
Stratificati o n a n d Ra n d o mizati o n  ............................................................................... 6 2 
1 2. 4.  
Re place me nt of Patie nts  ............................................................................................. 6 2 
1 2. 5.  
Pla n ne d A nal yses ........................................................................................................ 6 3  
1 2. 6.  
A nal ysis Para meters  .................................................................................................... 6 3 
1 2. 6. 1.  
E n d p oi nts .................................................................................................................... 6 3  


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
1 4 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 2. 6. 1. 1.  
Pri mar y Efficac y E n d p oi nt ......................................................................................... 6 3  
1 2. 6. 1. 2.  
Sec o n dar y Efficac y E n d p oi nts .................................................................................... 6 3  
1 2. 6. 1. 3.  
Safet y a n d T olera bilit y E n d p oi nts .............................................................................. 6 4  
1 2. 6. 1. 4.  
E x pl orat or y E n d p oi nts  ................................................................................................ 6 4 
1 2. 6. 2.  
Defi niti o n of S u b gr o u ps ............................................................................................. 6 5  
1 2. 7.  
A nal ysis P o p ulati o n .................................................................................................... 6 5  
1 2. 8.  
Statistical Met h o ds  ...................................................................................................... 6 6 
1 2. 8. 1.  
Patie nt Dis p ositi o n, De m o gra p hic, a n d Bac k gr o u n d C haracteristics ......................... 6 6  
1 2. 8. 2.  
Me dical Hist or y  .......................................................................................................... 6 7 
1 2. 8. 3.  
Pri or a n d C o nc o mita nt Me dicati o ns a n d Pr oce d ures .................................................. 6 7  
1 2. 8. 4.  
Efficac y A nal yses  ....................................................................................................... 6 8 
1 2. 8. 4. 1.  
Pri mar y E n d p oi nt A nal yses ( P ost d ose T S A T) ........................................................... 6 8  
1 2. 8. 4. 2.  
Sec o n dar y Efficac y E n d p oi nt A nal yses ...................................................................... 6 8  
1 2. 8. 4. 3.  
E x pl orat or y E n d p oi nt A nal yses  .................................................................................. 6 9 
1 2. 8. 5.  
Safet y A nal ysis  ........................................................................................................... 7 0 
1 2. 8. 5. 1.  
A d verse E ve nts ........................................................................................................... 7 0  
1 2. 8. 5. 2.  
St u d y Dr u g E x p os ure .................................................................................................. 7 1  
1 2. 8. 5. 3.  
Cli nical La b orat or y Data  ............................................................................................ 7 1 
1 2. 8. 5. 4.  
I m m u n o ge nicit y/ P har mac o ki netics ............................................................................ 7 1 
1 2. 8. 5. 5.  
P h ysical E xa m  ............................................................................................................ 7 1 
1 2. 8. 5. 6.  
Vital Si g ns  .................................................................................................................. 7 1 
1 2. 8. 5. 7.  
Electr ocar di o gra m  ....................................................................................................... 7 1 
1 2. 8. 6.  
Missi n g Val ues a n d Criteria f or Data E xcl usi o ns  ....................................................... 7 2 
1 2. 8. 7.  
Q ualit y of Life A nal ysis  ............................................................................................. 7 2 
1 3.  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  ......................................... 7 3 
1 3. 1.  
St u d y M o nit ori n g, A u dits, a n d I ns pecti o ns ................................................................ 7 3  
1 4.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  ......................................... 7 4 
1 5.  
I R B (I N S TI T U TI O N A L RE VI E W B O A R D) / E T HI C S  ........................................... 7 5 
1 5. 1.  
I R B / Et hics Re vie w ................................................................................................... 7 5 
1 5. 2.  
Pr ot oc ol C o m plia nce .................................................................................................. 7 5  
1 5. 3.  
Et hical C o n d uct of t he St u d y ...................................................................................... 7 5  
1 5. 4.  
Writte n I nf or me d C o nse nt .......................................................................................... 7 6  


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
1 5 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 5. 5.  
Patie nt C o nfi de ntialit y  ................................................................................................ 7 6 
1 5. 5. 1.  
Ge neral Data Pr otecti o n Re g ulati o n f or Cli nical St u die s C o n d ucte d i n t he 
E ur o pea n Ec o n o mic Ar ea ........................................................................................... 7 6  
1 6.  
R E C O R D K E E PI N G  ................................................................................................... 7 8 
1 6. 1.  
I ns pecti o n of Rec or ds ................................................................................................. 7 8 
1 6. 2.  
Rete nti o n of Rec or ds .................................................................................................. 7 8  
1 7.  
P U B LI C A TI O N P O LI C Y  .......................................................................................... 7 9 
1 8.  
R E F E R E N C E S  ........................................................................................................... 8 0 
1 8. 1.  
P u blicati o ns ................................................................................................................. 8 0  
1 8. 2.  
St u d y Re p orts .............................................................................................................. 8 1  
1 8. 2. 1.  
Cli nical  ........................................................................................................................ 8 1 
1 8. 2. 2.  
N o ncli nical .................................................................................................................. 8 1  
A P P E N DI X  1. S U M M A R Y O F L A B O R A T O R Y P A R A M E T E R S  ......................................... 8 3 
 
LI S T O F T A B L E S  
Ta ble  1: 
A b bre viati o ns a n d S pecialist Ter ms  ........................................................................... 1 6 
Ta ble  2: 
S u m mar y of LJ P C -4 0 1 N o ncli nical T o xic ol o g y St u dies  ........................................... 2 3 
Ta ble  3: 
Sc he d ule of Assess me nts  ............................................................................................ 3 3 
Ta ble  4: 
Relati o ns hi p of A d verse E ve nts t o I n vesti gati o nal Pr o d uct ....................................... 5 8  
Ta ble  5: 
Se verit y of A d verse E ve nts ........................................................................................ 5 9  
 
LI S T O F FI G U R E S  
Fi g ure 1:  
Perce nt C ha n ge i n Ser u m Ir o n i n Rats a n d D o gs at Si milar H u ma n E q ui vale nt 
D oses  ........................................................................................................................... 2 1 
 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
1 6 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  
T he f oll o wi n g a b bre viati o ns a n d s pecialist ter ms are use d i n t his st u d y pr ot oc ol. 
T a ble  1: 
A b bre vi ati o ns a n d S peci alist T er ms 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
A D A  
a nti-dr u g a nti b o d y 
A E  
a d verse e ve nt 
A L T 
ala ni ne a mi n o tra nsferase 
A N O V A  
a nal ysis of varia nce  
A S T  
as partate a mi n otra nsferase  
A T C 
A nat o mical T hera pe utic C he mical  
B MI  
b o d y mass i n de x  
C R A  
Cli nical Researc h Ass ociate  
C V  
c oefficie nt of variati o n  
E C G  
electr ocar di o gra m  
e C R F 
electr o nic case re p ort f or m  
e G F R 
esti mate d gl o mer ular filtrati o n rate  
E O S 
E n d of St u d y  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
G D P R  
Ge neral Data Pr otecti o n Re g ulati o n  
H A M P  
he pci di n a nti micr o bial pe pti de  
H E D 
h u ma n e q ui vale nt d ose  
H E E N T  
hea d , e yes, ears, n ose , t hr oat 
H F E  
h u ma n fact ors e n gi neeri n g  
H F E 2  
h u ma n fact ors e n gi neeri n g t y pe 2  
HI V  
h u ma n i m m u n o deficie nc y vir us  
I C H 
I nter nati o nal C o u ncil o n Har m o nisati o n  
I C MJ E 
I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors 
I DI 
Ir o n Dis or ders I nstit ute 
I E C / E C 
I nter nati o nal Et hics C o m mittee / Et hics C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d  
I T T 
I nte nt t o Treat 
I X R S 
I nteracti ve V oice/ W e b Res p o nse S yste m 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
1 7 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
T a ble  1: 
A b bre vi ati o ns a n d S peci alist Ter ms ( C o nti n ue d)  
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
I U D 
i ntra uteri ne de vice 
I U S 
i ntra uteri ne s yste m 
La J olla 
La J olla P har mace utical C o m pa n y 
L D H 
lactate de h y dr o ge nase 
L O C F  
last o bser vati o n carrie d f or war d 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
mI T T  
M o difie d I nte nt t o Treat  
M O E  
Mar gi ns of e x p os ure  
NI H  
Nati o nal I nstit utes of Healt h  
N T BI  
n o ntra nsferri n b o u n d ir o n  
N Y H A  
Ne w Y or k Heart Ass ociati o n  
P D  
p har mac o d y na mic  
P K  
p har mac o ki netic  
P P  
Per Pr ot oc ol P o p ulati o n  
P T  
preferre d ter m  
R B C  
re d bl o o d cell 
R D W  
re d cell distri b uti o n wi dt h 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S C  
s u bc uta ne o us(l y) 
S D  
sta n dar d de viati o n 
S F -3 6 v 2  
S h ort F or m ( 3 6) Healt h S ur ve y, Versi o n 2  
SI  
S ysté me I nter nati o nal  
S L C 4 0 A 1  
s ol ute carrier fa mil y 4 0 me m ber 1 
S O C  
s yste m or ga n class 
T 3 
T rii o d ot h yr o ni ne 
T 4 
t h yr o xi ne 
T E A E 
treat me nt-e mer ge nt a d verse e ve nt 
T F R 
tra nsferri n rece pt or 2 ( T F R 2) 
TI B C  
t otal ir o n bi n di n g ca pacit y 
T S A T 
tra nsferri n sat urati o n 
T S H 
t h yr oi d-sti m ulati n g h or m o ne 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
1 8 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
T a ble  1: 
A b bre vi ati o ns a n d S peci alist Ter ms ( C o nti n ue d)  
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
UI B C  
u nsat urate d ir o n bi n di n g ca pacit y  
U K  
U nite d Ki n g d o m  
U S P  
U nite d States P har mac o peia  
U S PI  
U nite d States Prescri bi n g I nf or mati o n  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
W O M A C  
Wester n O ntari o a n d Mc Master U ni versities Oste oart hritis I n de x  


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
1 9 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
3.  
I N T R O D U C TI O N 
Here ditar y he m oc hr o mat osis is a n a ut os o mal recessi ve dis or der t hat ca uses e xcessi ve a m o u nts of 
ir o n t o be a bs or be d a n d st ore d i n t he b o d y.  It is t he m ost c o m m o n here ditar y dis or der o bser ve d i n 
Ca ucasia ns ( Bac o n  2 0 1 1) a n d occ urs m ost ofte n i n pe o ple of n ort her n E ur o pea n desce nt, partic ularl y 
t h ose wit h N or dic or Celtic a ncestr y.  
M utati o ns i n se veral ge nes, i ncl u di n g hi g h ir o n (als o k n o w n as h u ma n fact ors e n gi neeri n g [ H F E ] 
pr otei n ), H F E 2, he pci di n a nti micr o bial pe pti de ( H A M P), s ol ute carrier fa mil y 4 0 me m ber 
1 ( S L C 4 0 A 1), a n d tra nsferri n rece pt or 2 ( T F R 2), ca n ca use here ditar y  he m oc hr o mat osis  
(Nati o nal I nstit utes  of Healt h [NI H ] 2 0 1 7).  A p pr o xi matel y 8 0 % of here ditar y  he m oc hr o mat osis  
cases are ca use d b y H F E m utati o ns, a n d t he re mai ni n g 2 0 % of cases are desi g nate d as n o n -H F E 
he m oc hr o mat osis ( de Li ma Sa nt os 2 0 1 0 ).   Classical here ditar y  he m oc hr o mat osis  prese nts wit h 
fasti n g tra nsferri n sat urati o n ( T S A T) > 4 5 % a n d ele vate d ser u m ferriti n > 3 0 0 n g/ m L i n males or 
> 2 0 0 n g/ m L i n fe males, wit h p ositi ve H F E ge netic testi n g of t he C 2 8 2 Y h o m oz y g ote or 
C 2 8 2 Y/ H 6 3 D c o m p o u n d heter oz y g ote ( Ir o n Dis or ders I nstit ute 2 0 1 1).  Alt h o u g h h o m oz y g osit y f or 
t he C 2 8 2 Y m utati o n is prese nt i n a p pr o xi matel y 1 per 2 2 0 t o 2 5 0 pe o ple wit h n ort her n E ur o pea n 
a ncestr y, less t ha n 1 0 % of t hese i n di vi d uals will de vel o p se vere ir o n o verl oa d acc o m pa nie d b y 
or ga n da ma ge a n d cli nical ma nifestati o ns of he m oc hr o mat osis.  
He pci di n c o ntr ols ir o n h o me ostasis b y dictati n g h o w ir o n is a bs or be d, use d, a n d st ore d i n t he b o d y.  
He pci di n re g ulates e ntr y of ir o n i nt o circ ulati o n t hr o u g h i n hi biti o n of ferr o p orti n, w hic h c o ntr ols 
ir o n e x p ort o ut of cells i n t he g ut a n d li ver as well as circ ulati n g er yt hr o p ha g oc ytic macr o p ha ges.  
I n patie nts wit h here ditar y  he m oc hr o mat osis , l o w plas ma he pci di n le vels ca use ferr o p orti n t o direct 
ir o n i nt o circ ulati o n (ie, a re d ucti o n i n he pci di n c orrelates wit h a n i ncrease i n circ ulati n g ir o n).  
Si nce h u ma ns lac k t he a bilit y t o e xcrete e xcess ir o n, it pr o gressi vel y acc u m ulates i n t he plas ma a n d 
or ga ns.  I n healt h y h u ma ns, t otal b o d y ir o n c o nte nt is a p pr o xi matel y 4 0 t o 5 0 m g/ k g b o d y wei g ht, 
wit h m ost of t he ir o n ( 3 0 m g/ k g) c o ntai ne d i n circ ulati n g re d bl o o d cells ( R B Cs) s uc h as 
he m o gl o bi n; 5 t o 6 m g/ k g is prese nt i n tiss ues i n a variet y of he me c o m p o u n ds, e nz y mes wit h 
ir o n-s ulf ur c o m ple xes, a n d ot her ir o n -de pe n de nt e nz y mes; 5  t o 1 2 m g/ k g is st ore d as ferriti n a n d 
he m osi deri n i n t he li ver, b o ne marr o w, s plee n, a n d m uscle; a n d a s mall fracti o n ( 3 m g/ k g) circ ulates 
i n t he plas ma.  I ncreases i n tiss ue le vels of ir o n ≥ 2 0 m g/ k g are ass ociate d wit h s y mpt o matic ir o n 
o verl oa d ( G or de u k  1 9 8 7, M u n oz  2 0 0 9), wit h p ote ntial da ma ge t o t he li ver, heart, a n d e n d ocri ne 
gla n ds, a n d e ve n deat h ( H off bra n d  2 0 1 2). 
T he pri mar y treat me nt f or here ditar y  he m oc hr o mat osis  is p hle b ot o m y (Bac o n 2 0 1 1 ).  
A p pr o xi matel y 9 0 % t o 1 0 0 % of patie nts will ac hie ve ir o n de pleti o n wit h t his treat me nt 
(Hic ke n  2 0 0 3), alt h o u g h 2 t o 3 years of wee kl y or bi wee kl y p hle b ot o m y ma y be re q uire d t o 
a de q uatel y re d uce ir o n st ores i n patie nts wit h t otal b o d y ir o n > 3 0 g ( Bac o n 2 0 1 1).   T hereafter, 
p hle b ot o m y ca n be st o p pe d a n d t he patie nt assesse d f or mai nte na nce t hera p y.  T he fre q ue nc y of 
mai nte na nce t he ra p y varies b y i n di vi d ual patie nts, wit h s o me re q uiri n g m o nt hl y p hle b ot o m y a n d 
ot hers re q uiri n g p hle b ot o m y o nl y o nce or t wice a year.  S o me patie nts de vel o p i nt olera nce t o 
p hle b ot o m y, a n d patie nt c o m plia nce wit h mai nte na nce p hle b ot o m y has bee n s h o w n t o dec li ne o ver 
ti me. 
Ot her  treat me nts t hat ma y  be use d i n cases of se vere ir o n o verl oa d or i n patie nts  i nt olera nt of 
p hle b ot o m y  i ncl u de er yt hr oc yta p heresis,  defer o xa mi ne  c helati o n, or deferasir o x  c helati o n 
(A da ms  2 0 1 0).  T hese treat me nts are ass ociate d wit h t he ris k of si g nifica nt si de effects, s uc h as 












Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
2 5 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
Acr oss all d ose gr o u ps, t he m ost fre q ue ntl y occ urri n g A Es b y preferre d ter m ( P T) were i njecti o n site 
reacti o ns ( 1 2 patie nts [ 6 6. 7 %]), na usea ( 2 patie nts [ 1 1. 1 %]), A L T  i ncrease d ( 2 patie nts [ 1 1. 1 %]), 
decrease d a p petite ( 2 patie nts [ 1 1. 1 %]) a n d h y p oest hesia ( 2 patie nts [ 1 1. 1 %]).  T he fre q ue nc y of 
i njecti o n site reacti o ns i n eac h d ose gr o u p was 0 i n 3 ( 0 %) i n  t he 1- m g gr o u p, 3 o ut of 3 ( 1 0 0 %) i n 
t he 5- m g gr o u p, 0 i n 3 ( 0%) i n  t he 1 0- m g gr o u p, 6 o ut of 6 ( 1 0 0 %) i n t he 2 0- m g gr o u p, a n d 3 o ut of 
3 ( 1 0 0 %) i n t he 3 0 - m g gr o u p.  All i njecti o n site reacti o ns were mil d i n se verit y a n d res ol ve d b y t he 
e n d of t he st u d y ( Da y 2 2).  T he mea n a n d me dia n d urati o n of i njecti o n site reacti o ns were as 
f oll o ws:  5 m g ( 1. 0 a n d 1. 0 da ys), 2 0 m g ( 2. 0 a n d 1. 0 da ys), a n d 3 0 m g ( 1 4. 8 a n d 4. 0 da ys). 
All sa m ples were c o nfir me d ne gati ve f or a nti - dr u g a nti b o dies t o LJ P C- 4 0 1. 
3. 3. 2.  
L J 4 0 1- N H V 0 1  
T he P hase 1 cli nical trial LJ 4 0 1- N H V 0 1  was a ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d, 
si n gle-ce nter st u d y t o deter mi ne t he safet y, t olera bilit y, P K, ser u m ir o n ki netics, a n d 
i m m u n o ge nicit y of escalati n g si n gle d oses of LJ P C - 4 0 1 i n 3 2 healt h y a d ult s u bjects.  T he st u d y 
e nr olle d s u bjects i n 4 d ose gr o u ps of 8 s u bjects per c o h ort, wit h 6 s u bjects assi g ne d t o LJ P C - 4 0 1 
a n d 2 s u bjects assi g ne d t o place b o i n eac h c o h ort.  T he starti n g d ose was 5 m g of LJ P C - 4 0 1 or 
place b o; s u bse q ue nt d ose gr o u ps recei ve d 1 0 m g, 2 0 m g, a n d 3 0 m g, res pecti vel y.  S u bjects 
recei ve d bet wee n o ne a n d t hree 1- m L S C i njecti o ns t o deli ver t he desire d d ose le vel.  LJ P C - 4 0 1 
c o nce ntrati o n was eit her 5 m g/ m L or 1 0 m g/ m L.  F or data a nal ysis p ur p oses, place b o s u bjects f or all 
c o h ort gr o u ps were p o ole d. 
A decrease i n ser u m ir o n le vels c o m pare d t o baseli ne was o bser ve d i n all 4 d ose gr o u ps, wit h mea n 
ma xi m u m re d ucti o n of 3 3 % t o 6 5 % at 8- h o urs p ost d ose.  Ser u m ir o n le vels ret ur ne d t o baseli ne 
bef ore 4 8 h o urs.  A si g nifica nt d ose res p o nse was o bser ve d, wit h lar ger re d ucti o ns i n ser u m ir o n 
ge nerall y ass ociate d wit h i ncreases i n d ose u p t o 2 0 m g.  T here was n o a p pare nt differe nce i n t he 
ma xi m u m re d ucti o n bet wee n t he 2 0 a n d 3 0 m g d ose le vels.  Ferriti n, TI B C, tra nsferri n, a n d T S A T 
were i ncrease d fr o m baseli ne at Da y 8 f or all treat me nt  gr o u ps.  T here was n o tre n d ass ociate d wit h 
a n i ncrease i n LJ P C - 4 0 1 d ose a n d t he a m o u nt of i ncrease i n a n y of t hese ir o n para meters.  
U nsat urate d ir o n bi n di n g ca pacit y ( U I B C) le vels s h o we d n o tre n ds i n c ha n ges fr o m baseli ne at 
Da y  8. 
T E A Es wer e re p orte d b y all 2 4 s u bjects ( 1 0 0 %) i n t he LJ P C - 4 0 1 d ose gr o u ps a n d 2 of 8 s u bjects 
( 2 5 %) i n t he place b o gr o u p.  All T E A Es were c o nsi dere d mil d ( Gra de 1) i n se verit y, a n d n o ne were 
dee me d seri o us or le d t o earl y disc o nti n uati o n or deat h.  T he n u m ber of T E A Es was si mi lar a m o n g 
all d ose gr o u ps.  Acr oss all d ose gr o u ps, t he m ost fre q ue ntl y re p orte d A Es were i njecti o n site 
reacti o ns ( 2 4 s u bjects [ 1 0 0 %] LJ P C - 4 0 1 a n d 1 s u bject [ 1 2. 5 %] place b o), cat heter site p hle bitis 
( 3 s u bjects [ 1 2. 5 %] LJ P C - 4 0 1), hea dac he ( 2 s u bjects [ 8. 3%] LJ P C - 4 0 1), pres y nc o pe ( 1 s u bject 
[ 1 2. 5 %] place b o), a n d a n xiet y, na usea, a n d ha n d der matitis ( 1 s u bject [ 4. 2 %] LJ P C - 4 0 1 eac h).  All 
i njecti o n site reacti o ns were mil d i n se verit y, a n d all b ut 1 res ol ve d bef ore t he e n d of t he st u d y.  T he 
mea n a n d me dia n d urati o n of i njecti o n site reacti o ns i n t he 5 d ose gr o u ps were as f oll o ws:  place b o 
( 1. 0, 1. 0 da ys), 5 m g ( 1. 0, 1. 0 da ys), 1 0 m g ( 5. 6, 8. 0 da ys), 2 0 m g ( 1 3. 3, 1 5. 5 da ys), a n d 3 0 m g 
( 1 1. 7, 8. 0 da ys). 
All sa m ples were c o nfir me d ne gati ve f or a nti - dr u g a nti b o dies t o LJ P C- 4 0 1. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
2 6 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
3. 3. 3.  
L J 4 0 1- N H V 0 2  
T he P hase 1 cli nical trial LJ 4 0 1- N H V 0 2  is a ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d, si n gle 
a n d m ulti ple d ose escalati o n st u d y t o assess t he safet y a n d t olera bilit y of LJ P C - 4 0 1 i n healt h y a d ult 
s u bjects. 
T he st u d y e nr olle d 2 1 s u bjects t otal.  I n t he si n gle d ose ar m of t he st u d y, 1 0 s u bjects recei ve d 
LJ P C - 4 0 1 a n d 3 s u bjects recei ve d place b o.  I n t he m ulti ple d ose ar m of t he st u d y, 6 s u bjects 
recei ve d LJ P C - 4 0 1 a n d 2 s u bjects recei ve d place b o 4 ti mes o ver a 2- wee k peri o d.  Res ults 
de m o nstrate d t hat LJ P C - 4 0 1 was well t olerate d at all a d mi nistere d d oses ( 4 m g, 1 0 m g a n d 2 0 m g).  
T here were n o d ose- li miti n g t o xicities at a n y d ose.  C o nsiste nt wit h b ot h c o m plete d P hase 1 st u dies, 
t he m ost c o m m o n a d verse e ve nt ( A E) was i njecti o n site reacti o n.  B ot h se verit y a n d d urati o n of 
t hese s ki n reacti o ns were si milar i n t his st u d y i n b ot h t he si n gle a n d m ulti ple d osi n g c o h orts 
c o m pare d t o t he pre vi o us f or m ulati o n use d i n st u dies LJ 4 0 1- T P P 0 1  a n d LJ 4 0 1- N H V 0 1 . 
3. 4.  
Cli nic al R ati o n ale f or t he L J 4 0 1 -H H 0 1 St u d y  
Patie nts wit h here ditar y  he m oc hr o mat osis  a bs or b t o o m uc h ir o n fr o m t heir diet (NI H  2 0 1 7).  H u ma n 
ir o n eli mi nati o n is li mite d a n d u na ble t o c o m pe nsate f or a n a b n or mal state of ir o n a bs or pti o n.  T his 
e xcess ir o n ca n e ve nt uall y da ma ge tiss ues a n d or ga ns, partic ularl y t he s ki n, heart, li ver, pa ncreas, 
a n d j oi nts.  T he pri mar y treat me nt f or here ditar y  he m oc hr o mat osis  is p hle b ot o m y.  T y picall y, 
p hle b ot o m y is i nitiall y perf or me d at wee kl y or t wice-wee kl y i nter vals u ntil desire d ir o n le vels are 
attai ne d, a n d t he n perf or me d less ofte n ( 2 t o 4 ti mes per year) o n a n i n defi nite basis ( C o u ns yl  2 0 1 7).  
P hle b ot o m y is i nc o n ve nie nt a n d te di o us, a n d patie nt c o m plia nce decreases o ver ti me ( Hic ke n  2 0 0 3).  
Hic ke n et al ( 2 0 0 3) re p orte d t hat 5 3 % ( 7 5/ 1 4 2 patie nts) of patie nts beca me n o nc o m plia nt at s o me 
ti me d uri n g mai nte na nce t hera p y, less t ha n 5 0 % of patie nts c o m plie d wit h mai nte na nce t hera p y b y 
t he e n d of t heir si xt h year after ac hie vi n g ir o n de pleti o n, a n d t hat a vera ge c o m plia nce wit h 
mai nte na nce t hera p y decrease d 6. 8 % a n n uall y.  Ot her treat me nts f or ir o n o verl oa d, i ncl u di n g 
er yt hr oc yta p heresis a n d c helati o n t hera p y ha ve si g nifica n t a n d un desira ble si de effects.  
T he ir o n-re g ulati n g effects of he pci di n, w hic h is re d uce d i n patie nts wit h here ditar y  
he m oc hr o mat osis , ma ke it a p ote ntiall y be neficial t hera pe utic f or t he treat me nt of here ditar y  
he m oc hr o mat osis .  LJ P C - 4 0 1, a s y nt hetic e q ui vale nt of t he e n d o ge n o us circ ulati n g pe pti de 
he pci di n- 2 5, is e x pecte d t o re d uce ir o n o verl oa d i n t his patie nt p o p ulati o n.  T he safet y pr ofile t o date 
i n dicates t hat t he pr o d uct is well t olerate d, wit h i njecti o n site reacti o n bei n g t he m ost fre q ue ntl y 
re p orte d A E .  I n a d diti o n, t he o nce- wee kl y si n gle- d ose a d mi nistrati o n, is e x pecte d t o be less 
b ur de ns o me t ha n sta n dar d p hle b ot o m y wit h a lar ge b ore nee dle. 
3. 4. 1.  
R ati o n ale f or t he St u d y Desi g n f or St u d y L J 4 0 1- H H 0 1  
T his st u d y was desi g ne d t o e val uate t he efficac y of LJ P C - 4 0 1 f or t he treat me nt of here ditar y  
he m oc hr o mat osis  b y s h o wi n g a si g nifica nt a n d cli nicall y mea ni n gf ul c ha n ge i n T S A T le vels.  T S A T 
was c h ose n as a n a p pr o priate e n d p oi nt f or assessi n g t he cli nical efficac y of LJ P C - 4 0 1 si nce it 
c o nsi ders b ot h t he ir o n le vel a n d t he TI B C  (A A C C  2 0 1 5).  N o ntra nsferri n b o u n d ir o n ( N T BI), t he 
t o xic f or m of ir o n, has bee n c orrelate d wit h car diac disease (Pi ga  2 0 1 3), a n d T S A T c orrelates wit h 
b ot h car di ac disease a n d le vels of N T BI.  
T he st u d y will e m pl o y a ra n d o mize d, place b o-c o ntr olle d, si n gle- bli n d desi g n.  Ra n d o mizati o n will 
be use d t o mi ni mize bias i n t he assi g n me nt of patie nts t o treat me nt gr o u ps b y i ncreasi n g t he 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
2 7 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
li keli h o o d t hat k n o w n a n d u n k n o w n patie nt attri b utes (e g, de m o gra p hic a n d baseli ne c haracteristics) 
are e ve nl y bala nce d, t here b y e n ha nci n g t he vali dit y of statistical c o m paris o ns a cr oss treat me nt 
gr o u ps ( LJ P C - 4 0 1 vers us place b o).  I n vesti gat ors will n ot be bli n de d t o treat me nt ar m or T S A T 
res ults s o t he y ca n a dj ust st u d y dr u g per t he d ose a dj ust me nt criteria if nee de d. 
Ra n d o mizati o n will occ ur i n a 1: 1 rati o a n d will be stratifie d b y baseli ne T S A T ( > 4 5 % t o 7 0 % 
vers us > 7 0 %) a n d p hle b ot o m y fre q ue nc y o ver t he last 1 2 m o nt hs ( 0 t o 3 vers us >  3), si nce 
a de q uatel y treate d patie nts ha ve a better pr o g n osis t ha n t h ose treate d i na de q uatel y ( D uc hi ni  2 0 1 7). 
A treat me nt peri o d of 1 6 wee ks was c o nsi dere d a de q uate t o e val uate t he efficac y of LJ P C - 4 0 1 a n d 
ser ve as t he basis f or t he desi g n of a P hase 3 st u d y.  T he decisi o n t o i ncl u de 1 p hle b ot om y at Da y  1 
( pre d ose) was ma de i n c o nsi derati o n of t he li kel y ele vati o ns i n T S A T a n d ferriti n i n t he st u d y 
p o p ulati o n at baseli ne. 
T he d ose ra n ge t hat will be use d i n t his st u d y ( Secti o n 5. 3 ) has bee n e val uate d i n 3 P hase 1 cli nical 
trials.  T he 5- m g starti n g d ose was selecte d f or t his st u d y base d o n data fr o m pre vi o us st u dies i n 
patie nts a n d healt h y v ol u nteers ( Secti o n  3. 3 ) a n d has bee n pre vi o usl y teste d i n patie nts wit h ir o n 
o verl oa d ( Secti o n  3. 3. 1 ).  T he re d ucti o n i n T S A T i n t hese patie nts at 5 m g was a p pr o xi matel y 2 7 %, 
w hic h occ urre d at 8 t o 1 2 h o urs a n d ret ur ne d t o baseli ne b y 7 2 t o 9 6 h o urs.  LJ P C- 4 0 1 5 m g was 
well t olerate d a n d pr o vi de d a mi ni mal efficac y of re d ucti o n i n T S A T.  As s uc h, t he first d ose is 
li kel y t o be b ot h safe a n d s u b-t hera pe utic wit h a n all o wa nce f or a dj ust me nt.  T he ma xi m u m d ose of 
2 0 m g was c h ose n f or t his st u d y base d o n t he res ults of patie nt St u d y LJ 4 0 1- T T P 0 1 t hat s h o we d a 
lar ger d ose-resp o nse/re d ucti o n i n ser u m ir o n was ge nerall y ass ociate d wit h i ncreasi n g d ose u p t o 
2 0 m g.  LJ P C- 4 0 1 has bee n e val uate d at d oses as hi g h as 3 0 m g ( healt h y v ol u nteer LJ 4 0 1- N H V 0 1); 
h o we ver, i n St u d y LJ 4 0 1- T T P 0 1, it was o bser ve d t hat patie nts wit h he m oc hr o mat osis ha d a l o wer 
mea n ser u m ir o n le vel at baseli ne c o m pare d wit h patie nts wit h he m o gl o bi n o pat hies.  T his is 
c o nsiste nt wit h t he hi g her mea n e n d o ge n o us he pci di n c o nce ntrati o n o bser ve d i n patie nts wit h 
he m oc hr o mat osis.  As s uc h, LJ P C- 4 0 1 2 0 m g is c o nsi dere d t he a p pr o priate ma xi m u m d ose f or t he 
patie nt p o p ulati o n i n t his st u d y.  B ot h t he ma xi m u m d ose ( 2 0 m g) a n d d ose- escalati o n pla n w ere 
well -t olerate d a n d efficaci o us i n b ot h P hase 1 st u dies.  
A 3 0- da y f oll o w- u p visit was c h ose n base d o n re g ulat or y g ui da nce f or a ssessi n g a n d m o nit ori n g 
safet y, i ncl u di n g p ote ntial i m m u n o ge nic effect, i n patie nts w h o ha ve disc o nti n ue d or c o m plete d 
cli nical st u dies of i n vesti gati o nal a ge nts wit h pr o m pt acti o n a n d relati vel y s h ort eli mi nati o n 
half- li ves (F o o d a n d Dr u g A d mi nistrati o n [ F D A ], 2 0 1 0). 
3. 4. 2.  
R ati o n ale f or Usi n g Ir o n Dis or ders I nstit ute P hle b ot o m y G ui deli nes  
T his st u d y will use t he 2 0 1 1 Ir o n Dis or ders I nstit ute (I DI) p hle b ot o m y g ui deli nes as t he basis f or 
defi n i n g t he criteria f or p hle b ot o m y.  T he I DI is part nere d wit h t he U nite d States Ce nters f or 
Disease C o ntr ol a n d Pre ve nti o n, t he Nati o nal I nstit utes of Healt h, a n d m ulti ple patie nt a d v ocac y 
gr o u ps f or pe o ple wit h ir o n dis or ders.  Ir o n Dis or ders I nstit ute pr o vi des cli nical s u p p ort, ser vices, 
a n d e d uca ti o nal i nf or mati o n.  T he I DI Me dical a n d Scie ntific A d vis or y B oar d is c o m prise d of 
e x perts i n ir o n meta b olis m a n d ir o n bala nce.  T he materials p u blis he d b y I DI c o ntai n refere nce 
ra n ges, dia g n osis al g orit h ms, dia g n ostic ai ds, t hera pe utic a p pr oac hes, a n d ge n etic a n d diet 
i nf or mati o n.  T his c o nte nt has bee n peer-re vie we d a n d a p pr o ve d b y me m bers of t he I DI Me dical a n d 
Scie ntific A d vis or y B oar d. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
2 8 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
I n a d diti o n, use of t he T S A T criteria of t he I DI p hle b ot o m y g ui deli nes will e ns ure t hat patie nts are 
prescri be d p hle b ot o m y i n a c o nsiste nt ma n ner acr oss b ot h gr o u ps a n d i m pr o ves patie nt safet y as t he 
rec o m me n dati o ns are e n d orse d b y me dical a n d scie ntific e x perts. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
2 9 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
4.  
T RI A L O B J E C TI V E S A N D  P U R P O S E  
T o e val uate t he effect of o nce- wee kl y d osi n g of LJ P C - 4 0 1 f or 1 6 wee ks  o n t he f oll o wi n g para meters 
i n a d ult patie nts wit h here ditar y he m oc hr o mat osis.  
4. 1.  
Pri m ar y O bjecti ve  
T o c o m pare t he effect of LJ P C - 4 0 1 vers us place b o  o n tra nsferri n sat urati o n ( T S A T) i n a d ult patie nts 
wit h here dit ary he m oc hr o mat osis. 
4. 2.  
Sec o n d ar y O bjecti ves  
•  T o c o m pare t he effect of LJ P C - 4 0 1 vers us place b o  o n p hle b ot o m y re q uire me nts. 
•  T o esta blis h t he s afet y a n d t olera bilit y of LJ P C - 4 0 1 vers us place b o  i n a d ult patie nts wit h 
here dit ary he m oc hr o mat osis. 
•  T o c o m pare t he effect of LJ P C - 4 0 1 vers us place b o o n s er u m ferriti n . 
4. 3.  
E x pl or at or y O bjecti ves  
•  T o c o m pare t he effect of LJ P C - 4 0 1 vers us place b o o n ser u m ir o n para meters . 
•  T o c o m pare t he effect of LJ P C - 4 0 1 vers us place b o o n t h yr oi d f u ncti o n. 
•  T o c o m pare t he effect of LJ P C - 4 0 1 vers us place b o o n li ver f u ncti o n. 
•  T o c o m pare t he effect of LJ P C - 4 0 1 vers us place b o o n gl yce mic c o ntr ol. 
•  T o c o m pare t he effect of LJ P C - 4 0 1 vers us place b o o n re d bl o o d cell ( R B C) para meters 
i ncl u di n g he m o gl o bi n c o nce ntrati o n, R B C  c o u nt, a n d re d cell distri b uti o n wi dt h ( R D W). 
•  T o c o m pare t he effect of LJ P C - 4 0 1 vers us place b o o n q ualit y of life as meas ure d b y  
Q ualit y of Life Q uesti o n naire s:  3 6-Ite m S h ort F or m (S F - 3 6 v 2), t he Wester n O ntari o a n d 
Mc Master U ni versities Oste oart hritis I n de x  (W O M A C) , a n d t he m o difie d Dreisler 
i n dices f or art hritis. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
3 0 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
5.  
I N V E S TI G ATI O N A L P L A N  
5. 1.  
O ver all St u d y Desi g n  
T his st u d y is a m ultice nter, ra n d o mize d, place b o-c o ntr olle d, si n gle- bli n d st u d y.  T he pri mar y 
o bjecti ve of t he st u d y is t o e val uate t he effect of LJ P C - 4 0 1 o n T S A T i n a d ults wit h here ditar y 
he m oc hr o mat osis. 
Eli gi ble patie nts will be ra n d o mize d o n a 1 : 1 sc he d ule a n d bli n de d t o st u d y treatme nt , LJ P C - 4 0 1 or 
place b o .  Ra n d o mizati o n will be stratifie d b y baseli ne T S A T ( > 4 5 % t o 7 0 % vers us > 7 0 %) a n d 
p hle b ot o m y fre q ue nc y o ver t he last 1 2 m o nt hs ( 0 t o 3 vers us > 3). 
All ra n d o mize d patie nts will recei ve sta n dar d of care t hera pe utic p hle b ot o m y  ( 5 0 0 cc or a p pr o priate 
f or wei g ht) o n Da y 1  ( pre d ose).  T hereafter, p hle b ot o m y decisi o ns b y t he I n vesti gat or  will be base d 
o n t he patie nt’s fasti n g T S A T res ults c ollecte d at Wee k  4 ( Da y 2 3); Wee k 8 ( Da y 5 1); Wee k 1 2 
( Da y 7 9); a n d Wee k 1 6 ( Da y 1 0 7); a n d base d o n t he T S A T criteria of t he I DI p hle b ot o m y g ui deli nes 
f or patie nts wit h here ditar y he m oc hr o mat osis.  If a p hle b ot o m y is i n dicate d, base d o n t he T S A T 
criteria of t he I DI g ui deli nes, t he patie nt s h o ul d recei ve p hle b ot o m y treat me nt pre d ose, o n or bef ore 
t he f oll o wi n g visit. 
I n vesti gat ors are n ot bli n de d t o treat me nt ar m or T S A T res ults  s o t he y ca n a dj ust st u d y dr u g per t he 
d ose a dj ust me nt criteria if nee de d . 
T he pri mar y efficac y a nal ysis will ta ke place after all o n-st u d y patie nts ha ve c o m plete d t he Wee k  1 6 
assess me nts  ( or ha ve wit h dra w n fr o m t he st u d y earl y). 
5. 2.  
N u m ber of P atie nts  
A p pr o xi matel y 6 8 t o 7 6 patie nts  are pla n ne d t o be e nr olle d  a n d ra n d o mize d acr oss a p pr o xi matel y 
3 0 sites t o e ns ure t hat at least 4 8 patie nts c o m plete t he Wee k 1 6 assess me nts a n d are i ncl u de d i n t he 
pri mar y effi cac y a nal ysis ( Secti o n  1 2. 2 ).  All pa tie nts m ust meet t he eli gi bilit y criteria o utli ne d i n 
Secti o n  6 .  O ne rescree ni n g f or eli gi bilit y will be all o we d f or eac h patie nt.  As i ncl usi o n criteria are 
la b orat or y para meters t hat are d y na mic i n t his p o p ulati o n, ad diti o nal rescree ns ma y be all o we d u p o n 
a p pr o val fr o m t he Me dical M o nit or.  If rescree ne d, t he patie nt will kee p t he pre vi o usl y assi g ne d 
scree ni n g n u m ber. 
5. 3.  
Tre at me nt Assi g n me nt  
Patie nts will be  d ose d o nce - wee kl y wit h  LJ P C -4 0 1  or place b o a d mi nistere d S C f or 1 6 wee k s.  
LJ P C - 4 0 1 d ose will start at 5 m g at Wee k 1 a n d i ncrease t o 1 0 m g at Wee k 2.  Refer t o Secti o n  5. 4  
f or d ose a dj ust me nts o utsi de of t hese fi xe d d oses.  F or  t h ose patie nts ra n d o mize d t o place b o, a 
s yri n ge of 0. 9 % s o di u m c hl ori de i njecti o n, U nite d States P har mac o p oeia ( U S P; or e q ui vale nt) will 
be pre pare d b y t he st u d y p har macist or desi g nee.  T o mai ntai n t he st u d y si n gle- bli n d, s yri n ges wit h 
st u d y dr u g ( place bo a n d acti ve dr u g) will be i de ntical .  Refer t o t he st u d y s pecific P har mac y Ma n ual 
f or detaile d g ui da nce.  


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
3 1 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
5. 4.  
D ose A dj ust me nt Criteri a  
D osi n g A dj ust me nts:  
•  Wee k 1:  5 m g LJ P C - 4 0 1 or place b o 
•  Wee k 2:  1 0 m g LJ P C - 4 0 1 or place b o 
•  Wee k 3 :  1 0 m g LJ P C- 4 0 1 or place b o 
Wee k 3:  Fasti n g T S A T ( p ost d ose 2 4 [ ± 4] h o urs), ie, 2 0 t o 2 8 h o urs, deter mi nes t he Wee k 4 d ose:  
− If t he T S A T  is > 4 5 %, d ose i ncreased t o 2 0 m g LJ P C - 4 0 1 or place b o 
− If t he T S A T is ≤ 4 5 %, d ose re mai ns at 1 0 m g LJ P C- 4 0 1 or place b o 
•  Wee k 4 :  LJ P C - 4 0 1 ( or place b o ) d ose as i n dicate d b y Wee k 3 fasti n g T S A T ( 1 0 t o 2 0 m g 
LJ P C - 4 0 1 or place b o) 
•  At Wee ks 9 a n d 1 3 (after Wee ks 8 a n d 1 2 fasti n g T S A T res ults are a vaila ble ): 
− Mai ntai n or i ncrease d ose t o 2 0 m g if T S A T is > 4 5 % 
− Mai ntai n d ose ( 1 0 or 2 0 m g ) if T S A T re mai ns ≤ 4 5 %, a n d n o d ose re d ucti o n is 
re q uire d f or t o xicit y (refer t o Secti o n 5. 4. 1 ) 
•  F or d o w n titrati o n, f oll o w t he safet y criteria o utli ne d i n Secti o n  5. 4. 1 . 
I m p ort a nt G ui deli nes: 
1.  T he last ce ntral la b orat or y fasti n g T S A T res ult at Wee k  3 ( Da y 1 6), Wee k 8 ( Da y 5 1) , a n d 
Wee k 1 2 ( Da y 7 9) will be use d t o deter mi ne if a d ose a dj ust me nt is nee de d at Wee ks  4, 9, 
a n d 1 3.  T S A T  f or d ose a dj ust me nts m ust  be c ollecte d 2 4 ( ± 4) h o urs p ost d ose. 
2.  If fasti n g T S A T le vel is greater t ha n 4 5 %  c ollecte d at p ost d ose 2 4 ( ± 4) h o urs o n Wee k 4 
( Da y 2 3); Wee k 8 ( Da y 5 1); Wee k 1 2 ( Da y 7 9); a n d Wee k 1 6 ( Da y 1 0 7), a p hle b ot o m y 
( 5 0 0 cc or a p pr o priate f or wei g ht) is i n dicate d pre d ose, o n or bef ore t he f oll o wi n g visit.     
3.  R o u n d T S A T wit h deci mal val ues usi n g t he sta n dar d r o u n di n g r ule. 
T he p har macist, or desi g nee, will pre pare t he st u d y dr u g ( LJ P C - 4 0 1 or place b o) t o e ns ure t he patie nt  
will re mai n bli n de d.  Refer t o t he st u d y s pecific P har mac y Ma n ual  f or detaile d g ui da nce. 
5. 4. 1.  
S afet y Criteri a f or A dj ust me nt or St o p pi n g D oses  
F or eac h i n di vi d ual patie nt, t he safet y criteria use d t o a dj ust (re d uce) d osi n g i ncl u de 1 or m ore of t he 
f oll o wi n g: 
1.  i njecti o n site reacti o n(s) se verit y gra de of se vere 
2.  patie nt ca n n ot or will n ot t olerate assi g ne d i njecti o ns (refer t o Secti o n  5. 4  f or d ose 
a dj ust me nt directi o ns)  
F or eac h i n di vi d ual patie nt, t he safet y criteria use d t o st o p d oses i ncl u de 1 or m ore of t he f oll o wi n g: 
1.  T E A Es, i ncl u di n g i njecti o n site reacti o n(s) se verit y gr a de of se vere or hi g her  
2.  patie nt ca n n ot or will n ot t olerate S C i njecti o n(s)  


Pr ot oc ol LJ 4 0 1- H H 0 1  
LJ P C - 4 0 1 
3 2 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
3.  cli nicall y si g nifica nt la b orat or y para meters, i ncl u di n g if T S A T is less t ha n 1 0 %  (if t his 
occ urs, c o ns ult t he Me dical M o nit or)  
5. 5.  
Criteri a f or St u d y Ter mi n ati o n  
T his st u d y ma y be pre mat urel y ter mi nate d if i n t he o pi ni o n of La  J olla, t here is s ufficie nt reas o na ble 
ca use.  Writte n n otificati o n d oc u me nti n g t he reas o n f or st u d y ter mi nati o n w o ul d be pr o vi de d t o t he 
I n vesti gat ors b y La  J olla.  Circ u msta nces t hat ma y warra nt ter mi nati o n i ncl ude, b ut are n ot li mite d 
t o: 
•  Deter mi nati o n of u ne x pecte d, si g nifica nt, or u nacce pta ble ris k t o patie nts 
•  Fail ure t o e nr oll st u d y  patie nts at a n acce pta ble rate  
•  I ns ufficie nt a d here nce t o pr ot oc ol re q uire me nts 
•  I ns ufficie nt a n d/ or u ne val ua ble data 
•  Pla ns t o m o dif y, s us pe n d, or disc o nti n ue de vel o p me nt of t he st u d y dr u g 
5. 6.  
Sc he d ule of Assess me nts  
T he pr oce d ures a n d ti mi n g of t he assess me nts sc he d ule d f or t his st u d y are dis pla ye d i n Ta ble  3.  
Efficac y a n d safet y assess me nts are descri be d i n Secti o n  9  a n d Secti o n  1 0 , res pecti vel y.  Refer t o 
Secti o n  1 0. 1. 6  lists of pr ot oc ol- s pecifie d la b orat or y a nal ytes. 
 






Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1  
 
3 5 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
Ge ner al I nstr ucti o ns:  
All assess me nts m ust be perf or me d pri or t o d osi n g u nless ot her wise s pecifie d.  
Patie nts are n ot t o eat a n y f o o d or dri n k a n y be vera ges, e xce pt water, f or at least 6 h o urs pri or t o 
c ollecti n g bl o o d f or la b orat or y tests i ncl u di n g ir o n st u dies (I m m u n o ge nicit y/ P K a n d pre g na nc y test  
sa m ples are n ot re q uire d t o be fasti n g). 
Fr o m Wee ks 2 t hr o u g h 1 7 t here is a ± 2- da y wi n d o w f or visits; o nce t he visit occ urs, t he patie nt 
s h o ul d ret ur n t o t he re g ular i nter val sc he d ule. 
Assess me nts:  
1.  F or patie nts w h o wit h dra w earl y, all Wee k 1 6 pr oce d ures pl us a 1 2-lea d E C G a n d uri ne 
pre g na nc y test (fe males of c hil d - beari n g p ote ntial o nl y) will be perf or me d, t o t he e xte nt 
p ossi ble, f or t he Earl y Wit h dra wal Visit. 
2.  T he E O S f oll o w-u p visit will occ ur 3 0 da ys ( + 3 da ys; a p pr o xi matel y Wee k 2 0 ) after t he last 
d ose of st u d y dr u g. 
3.  C o nfir m i ncl usi o n/e xcl usi o n criteria at Scree ni n g a n d o n Wee k 1/ Da y  1 ( pre d ose).  
Scree ni n g l a b orat or y res ults m ust be recei ve d a n d re vie we d f or eli gi bilit y pri or t o d osi n g.  
4.  Ra n d o mizati o n m ust occ ur after i ncl usi o n/e xcl usi o n criteria are c o nfir me d. 
5.  Hei g ht will be perf or me d at S cree ni n g o nl y; wei g ht will be perf or me d at Scree n i n g a n d 
Wee k  1 6. 
6.  Vitals will i ncl u de bl o o d press ure, heart rate, res pirati o n rate , a n d b o d y te m perat ure.  Bl o o d 
press ure will be assesse d after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes. 
7.  Rec or d all me dicati o ns ta ke n a n d a n y pr oce d ures perf or me d, be gi n ni n g 1 4  da ys pri or t o 
Scree ni n g .  Starti n g Wee k 2, rec or d all ne w or c ha n ges t o c o nc o mita nt me dicati o ns t hr o u g h 
t he f oll o w-u p visit t hat will  occ ur 3 0 da ys ( + 3 da ys) after t he last d ose of st u d y dr u g. 
8.  Rec or d a n y A Es  a n d S A Es  starti n g at c o nse nt.  Re p ort a n y S A Es per Secti o n  1 1. 3. 2 . 
9.  Patie nts will be d ose d o nce - wee kl y.  Refer t o  Secti o n  5. 4  f or d ose a dj ust me nt criteria. 
1 0.  1 2- lea d E C Gs will be c ollecte d i n tri plicate ( ≥ 1 mi n ute a part).  T he  Scree ni n g E C G m ust be 
perf or me d wit hi n 3 0 da ys pri or t o t he first d ose of st u d y dr u g.  A b n or malities n ote d at 
Scree ni n g s h o ul d be i ncl u de d i n t he me dical hist or y.  A d diti o nal E C Gs will be c ollecte d if 
cli nicall y i n dicate d ( ie, pal pitati o ns, li g ht hea de d ness).  If a patie nt wit h dra ws  fr o m t he st u d y 
earl y, a 1 2 -lea d E C G will be perf or me d as part of t he Earl y Wit h dra wal pr oce d ures (if 
p ossi ble). 
1 1.  All ra n d o mize d patie nts will recei ve a sta n dar d of care t hera pe utic p hle b ot o m y ( 5 0 0 cc or 
a p pr o priate f or wei g ht ) o n Da y  1 ( pre d ose).  T hereafter, p hle b ot o m y decisi o ns b y t he 
I n vesti gat or will be base d o n t he patie nt’s fasti n g T S A T res ults c ollecte d p ost d ose at 
Wee ks  4 ( Da y 2 3); Wee k 8 ( Da y 5 1); Wee k 1 2 ( Da y 7 9); a n d Wee k 1 6 ( Da y 1 0 7);  a n d base d 
o n t he T S A T criteria of t he I DI g ui deli nes f or patie nts wit h here ditar y he m oc hr o mat osis.  If a 
p hle b ot o m y is i n dicate d, base d o n t he T S A T criteria of t he I DI g ui deli nes , t he patie nt s h o ul d 
recei ve p hle b ot o m y treat me nt pre d ose, o n or bef ore t he f oll o wi n g visit.  If t hera pe utic 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1  
 
3 6 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
p hle b ot o m y is perf or me d t he sa me da y as d osi n g, t he or der s h o ul d be:  la b orat or y sa m ples; 
p hle b o t o m y; LJ P C- 4 0 1 or place b o d ose. 
1 2.  If t he fasti n g Scree ni n g ferriti n a n d T S A T le vels d o n ot meet e ntr y criteria, t he patie nt’s 
re g ularl y sc he d ule d p hle b ot o m y ma y be deferre d, a n d fasti n g  a n d c o m plete ir o n st u dies 
re peate d e ver y 3 0 da ys f or u p t o 9 0 da ys u ntil e ntr y criteria are met. 
1 3.  Bl o o d f or fasti n g c o m plete ir o n st u dies m ust be c ollecte d pre d ose a n d a gai n 2 4 ( ± 4) h o urs 
after d osi n g at t he sa me ti me of da y eac h visit w he ne ver p ossi ble.  T S A T at Wee ks 3, 8, a n d 
1 2 ( 2 4 [ ± 4] h o urs p ost d ose) will deter mi ne t he LJ P C- 4 0 1 d ose f or s u bse q ue nt st u d y visits 
( Wee ks 4, 9, a n d 1 3).  Refer t o Secti o n  5. 4  f or d ose i nf or mati o n a n d d ose a dj ust me nts.  
A d diti o nal bl o o d sa m ples will be c ollecte d f or scie ntific researc h, i ncl u di n g P K a nal yses a n d 
a nal yses o f a p oferriti n a n d h ol oferriti n. 
1 4.  C ollect bl o o d f or c o m plete ir o n st u dies. 
1 5.  Ser u m pre g na nc y test (fe male patie nts of c hil d beari n g p ote ntial o nl y – Scree ni n g) m ust be 
perf or me d wit hi n 3 0 da ys pri or t o t he first d ose of st u d y dr u g (fasti n g is n ot re q uire d). 
1 6.  Uri ne pre g na nc y test (ie, di pstic k) will  be perf or me d f or fe males of c hil d beari n g p ote ntial o n 
Wee k 1 / Da y 1 pre d ose a n d Wee k 2 0 or Earl y Wit h dra wal (if p ossi ble). 
1 7.  Bl o o d f or i m m u n o ge nicit y / P K testi n g t o be c ollecte d (fasti n g is n ot re q uire d) at Scree ni n g 
a n d pre d ose at :  Wee k  1 ( wit h a wi n d o w of −3 0 mi n utes  bef ore d osi n g), Wee k 2, Wee k 4, 
Wee k 8, Wee k  1 2, Wee k 1 6; a n d E O S/ 3 0  da ys ( + 3 da ys) after t he last d ose of st u d y dr u g 
(a p pr o xi matel y Wee k 2 0).  A d diti o nal i m m u n o ge nicit y testi n g ma y be perf or me d as 
descri be d i n  Secti o n  1 0. 1. 6. 7 . 
1 8.  T w o bl o o d sa m ples ( 2 t u bes) nee d t o be c ollecte d  f or t he i m m u n o ge nicit y/P K  a nal ysis at 
Scree ni n g; t hese sa m ples ma y be c ollecte d at t he sa me visit . 
1 9.  C ollect a d diti o nal bl o o d sa m ples  (fasti n g is n ot re q uire d) f or i m m u n o ge nicit y/P K a nal ysis  
p ost d ose 1 h o ur or later  at Wee ks 1 a n d 1 6. 
2 0.  Q ualit y of Life Q uesti o n naires, ( S F - 3 6 v 2), Wester n O ntari o a n d Mc Master U ni versities 
Oste oart hritis I n de x ( W O M A C), a n d m o difie d Dreisler i n dices f or art hritis, s h o ul d be 
c o m plete d pri or t o p hle b ot o m y. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
3 7 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
6.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  
Eac h patie nt m ust meet all t he f oll o wi n g i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria i n 
or der t o be e nr olle d i n t he st u d y. 
6. 1.  
P atie nt  I ncl usi o n Criteri a 
1.  Patie nts wit h a cli nical dia g n osis  of here ditar y he m oc hr o mat osis.  
2.  Patie nts w h o are prescri be d t hera pe utic p hle b ot o m y f or t he treat me nt of here ditar y 
he m oc hr o mat osis.  
3.  Patie nts  ≥ 1 8 years of a ge.  
4.  Patie nts wit h a ser u m ferriti n le vel ≥ 1 0 0 n g/ m L. 
5.  Patie nts wit h a T S A T le vel > 4 5 %.  
6.  Fe male patie nts m ust be of n o nc hil d beari n g p ote ntial or usi n g a hi g hl y effecti ve met h o d 
of c o ntrace pti o n d uri n g partici pati o n i n t he st u d y a n d f or 3 0 da ys after t he last d ose of 
st u d y dr u g.  Hi g hl y effecti ve met h o ds of c o ntrace pti o n are defi ne d as t h ose, al o ne or i n 
c o m bi nati o n, t hat res ult i n a l o w fail ure rate w he n use d c o nsiste ntl y a n d c orrectl y.  Refer 
t o Secti o n 1 0. 1. 6. 5. 1  f or t he list of hi g hl y effecti ve met h o ds of c o ntrace pti o n t hat ca n be 
use d i n t his st u d y. 
7.  Fe male patie nts  of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g na nc y test 
d uri n g S cree ni n g  ( wit hi n 3 0 da ys pri or t o t he first d ose of st u d y dr u g), a n d a ne gati ve 
uri ne pre g na nc y test at Da y 1  (ie, pri or t o i nitial d osi n g of st u d y dr u g). 
8.  Male patie nts m ust be s ur gicall y sterile  ( vasect o m y) or usi n g a hi g hl y effecti ve met h o d of 
c o ntrace pti o n d uri n g partici pati o n i n t he st u d y a n d f or 3 0 da ys after t he last d ose of st u d y 
dr u g.  Hi g hl y effecti ve met h o ds of c o ntrace pti o n are defi ne d as t h ose, al o ne or i n 
c o m bi nati o n, t hat res ult i n a l o w fail ure rate w he n use d c o nsiste ntl y a n d c orrectl y.  Refer 
t o Secti o n 1 0. 1. 6. 5. 1  f or t he list of hi g hl y effecti ve met h o ds of c o ntrace pti o n t hat ca n be 
use d i n t his st u d y. 
9.  Patie nt m ust be willi n g a n d a ble t o pr o vi de writte n i nf or me d c o nse nt. 
6. 2.  
P atie nt  E xcl usi o n Criteri a  
1.  Patie nts recei vi n g ir o n c helati o n t hera p y  wit hi n 7 da ys pri or t o t he first d ose of st u d y 
dr u g. 
2.  Patie nts i nitiati n g p hle b ot o m y treat me nts less t ha n 3 m o nt hs pri or t o t he first d ose of 
st u d y dr u g. 
3.  Patie nts wit h a c o nc o mita nt disease, disa bilit y or c o n diti o n, i ncl u di n g la b orat or y 
a b n or malit y  a n d E C G fi n di n gs, w hic h ma y i nterfere wit h t he c o n d uct of t he st u d y, or 
w hic h w o ul d, i n t he o pi ni o n of t he I n vesti gat or, p ose a n u nacce pta ble ris k t o t he patie nt 
i n t his st u d y, i ncl u di n g, b ut n ot li mite d t o, cli nicall y si g nifica nt arr h yt h mias, alc o h ol 
de pe n de nc y or a b use, dr u g de pe n de nc y or a b use, or ps yc hiatric disease.  Patie nts wit h 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
3 8 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
de pressi o n are eli gi ble if recei vi n g a sta ble d ose of me dicati o n f or at least 9 0 da ys pri or t o 
t he first d ose of st u d y dr u g. 
4.  Pre g na nt or lactati n g w o me n. 
5.  Patie nts ta ki n g a n i m m u n os u p pressi ve a ge nt t hat has n ot bee n a p pr o ve d f or use b y 
La  J olla (e xcl u di n g t o pical o ver-t he-c o u nter ster oi ds, i n hale d ster oi d me dicati o ns, a n d 
n o nster oi dal a nti-i nfla m mat or y dr u gs ).  Refer t o Secti o n  7. 1  f or t he list of pr o hi bite d 
me dicati o ns a n d pr oce d ures.  
6.  Patie nts partici pati n g i n a n u na p pr o ve d i n vest i gati o nal dr u g or i n vesti gati o nal t hera pe utic 
de vice st u d y wit hi n 3 0 da ys pri or t o st u d y dr u g d osi n g, ie, t here m ust be at least 3 0 da ys 
i n bet wee n t he last d ose o n a pri or st u d y a n d t he first d ose a d mi nistrati o n o n t his trial. 
7.  Patie nts w h o are u n willi n g or u na ble t o c o m pl y wit h t he st u d y pr ot oc ol re q uire me nts. 
8.  Patie nts wit h t y pe 1 dia betes  or t y pe 2 dia betes wit h he m o gl o bi n Alc greater t ha n 8 % 
wit hi n 2 m o nt hs pri or t o ra n d o mizati o n . 
9.  Patie nts wit h u nc o ntr olle d acti ve he patitis B, he patitis C, or h u ma n i m m u n o deficie nc y 
vir us ( HI V) i nfecti o n.  
1 0.  Patie nts wit h C hil d P u g h class C cirr h osis or li ver fail ure.  
1 1.  Patie nts wit h se vere c o n gesti ve heart fail ure ( N Y H A = Class 4).  
1 2.  Patie nts w h o ha ve a d va nce d re nal fail ure wit h a n esti mate d gl o mer ular filtrati o n rate 
(e G F R) < 1 5 m L/ mi n/ 1. 7 3 m 2. 
1 3.  Patie nts wit h a h ist or y of aller gic reacti o n t o he pci di n or e xci pie nts. 
1 4.  Patie nts  w h o ha ve pla n ne d s ur ger y (e xcl u di n g de ntal s ur ger y or si m ple der mat ol o gic 
pr oce d ures) d uri n g partici pati o n i n t his st u d y. 
6. 3.  
P atie nt  Wit h dr a w al Criteri a  
Pat ie nts will be i nf or me d t hat t he y ha ve t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me a n d f or 
a n y reas o n, wit h o ut prej u dice t o t heir me dical care.  T he I n vesti gat or als o has t he ri g ht t o 
wit h dra w patie nts fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns: 
1.  C li nicall y si g nifica nt i nterc urre nt ill ness 
2.  Occ urre nce of a n u nacce pta ble A E.  A Es of c o ncer n m ust  be disc usse d wit h La  J olla’s 
Me dical M o nit or f or p ossi ble a dj ust me nts i n d osi n g sc he d ule ( dela y, s ki p, or 
rec halle n ge). 
3.  At patie nt’s re q uest  
4.  I m p orta nt pr ot oc ol de viati o n / vi olati o n 
5.  N o n -c o m plia nce 
6.  A d mi nistrati ve reas o n  
7.  Fail ure t o ret ur n f or f oll o w- u p 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
3 9 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
8.  Ge neral or s pecific c ha n ges i n t he patie nt’s c o n diti o n u nacce pta ble f or f urt her 
partici pati o n base d u p o n t he j u d g me nt of t he I n vesti gat or 
Patie nts t hat ma y wit h dra w pri or t o Wee k 1 6 s h o ul d be disc usse d wit h t he Me dical M o nit or.  At 
t he ti me of wit h dra wal, all eff orts s h o ul d be ma de t o perf or m pr oce d ures e q ui vale nt t o Wee k 1 6 
pl us a 1 2- lea d E C G  a n d uri ne pre g na nc y test (Ta ble  3), t o t he e xte nt p ossi ble.  Patie nts s h o ul d be 
e nc o ura ge d t o c o m plete E O S  f oll o w- u p pr oce d ures 3 0 da ys ( + 3 da ys) after t he last d ose of 
LJ P C - 4 0 1.  T he reas o n(s) f or a patie n t’s wit h dra wal fr o m t he st u d y m ust  be rec or de d o n t he 
a p pr o priate electr o nic  Case Re p ort F or m ( eC R F ). 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
4 0 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
7.  
T R E A T M E N T O F P A TI E N T S  
F or d escri pti o n of st u d y dr u g, see Secti o n  8 . 
 
I n vesti g ati o n al Pr o d uct 
Pr o d uct N a me:  
LJ P C - 4 0 1 (s y nt hetic h u ma n he pci di n) 
D os a ge F or m: 
S ol uti o n f or I njecti o n  
U nit D ose : 
5 or 1 0 m g/ m L  
R o ute of A d mi nistr ati o n : 
S u bc uta ne o us 
P h ysic al Descri pti o n : 
LJ P C - 4 0 1 f or S C a d mi nistrati o n is a clear c ol orless s ol uti o n , 
wit h  esse ntiall y n o visi ble partic les, s u p plie d i n clear glass 
vials, wit h a r u b ber st o p per, al u mi n u m o ver- seal, a n d plastic 
fli p-off ca p . 
7. 1.  
C o nc o mit a nt Me dic ati o ns  a n d Pr oce d ures  
All me dicati o ns a n d ot her t hera pies t hat are a d mi nistere d  starti n g fr o m 1 4 da ys pri or t o 
Scree ni n g a n d d uri n g t he st u d y, i ncl u di n g t he start a n d st o p date(s), d ose a n d a m o u nt 
a d mi nistere d, a n d i n dicati o n, m ust be rec or de d i n t he e C R Fs a n d i n t he s o urce d oc u me nts.  N o 
ot her e x peri me ntal t hera p y is per mitte d.  C o nc o mita nt me dicati o ns f or ot her me dical c o n diti o ns 
are per mitte d as cli nicall y i n dicate d, s u bject t o s pecific re q uire me nts o utli ne d i n t his pr ot oc ol.  
Pr o hi bite d me dicati o ns a n d t hera pies:  
•  A n y i n vesti gati o nal a ge nt ot her t ha n LJ P C - 4 0 1 
•  A n y i m m u n os u p pressi ve a ge nt t hat has n ot bee n a p pr o ve d f or use b y La J olla 
(e xcl u di n g t o pical o ver-t he-c o u nter ster oi ds, i n hale d ster oi d me dicati o ns, a n d 
n o nster oi dal a nti-i nfla m mat or y dr u gs) 
•  V ita mi n C s u p ple me nts 
•  S ur ger y f or a n y reas o n (e xcl u di n g de ntal s ur ger y or si m ple der mat ol o gic pr oce d ures) 
W he n a n i m me diate de viati o n fr o m t he pr ot oc ol is re q uire d t o eli mi nate a n i m me diate hazar d(s) 
t o a patie nt, t he I n vesti gat or will c o ntact t he st u d y Me dical M o nit or, if circ u msta nces per mit, t o 
disc uss t he pla n ne d c o urse of acti o n.  A n y i m p orta nt de viati o ns fr o m t he pr ot oc ol m ust be f ull y 
d oc u me nte d o n t he a p pr o priate e C R F a n d i n t he s o urce d oc u me ntati o n. 
7. 2.  
Tre at me nt C o m pli a nce  
St u d y dr u g will be a d mi nistere d t o eli gi ble pa tie nts u n der t he s u per visi o n of t he I n vesti gat or or 
i de ntifie d S u b-I n vesti gat or(s).  U p o n c o m pleti o n of a p pr o priate trai ni n g, t he I n vesti gat or ma y 
dele gate st u d y dr u g a d mi nistrati o n t o a trai ne d h o me care n urse/researc h staff .  T he p har macist 
or desi g nee will mai ntai n rec or ds of st u d y dr u g recei pt, pre parati o n, a n d dis pe nsi n g, i ncl u di n g 
t he t otal dr u g a d mi nistere d.  T he place b o l ot n u m ber (fr o m vial of s o di u m c hl ori de f or i njecti o n) 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
4 1 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
a n d t he q ua ntit y of place b o s ol uti o n a d mi nistere d t o t he place b o patie nt w ill be mai ntai ne d i n t he 
p har mac y rec or ds.  A n y discre pa nc y bet wee n t he assi g ne d d ose a n d d ose a d mi nistere d, as well 
as t he reas o n f or t he discre pa nc y, m ust  be rec or de d i n t he s o urce d oc u me nts. 
7. 3.  
R a n d o miz ati o n a n d Si n gle -Bli n d  
T his is a ra n d o mize d, place b o -c o ntr olle d, si n gle- bli n d st u d y.  I n vesti gat ors are n ot bli n de d t o 
treat me nt ar m or T S A T res ults  s o t he y ca n a dj ust st u d y dr u g per t he d ose a dj ust me nt criteria if 
nee de d .  T he st u d y patie nts will n ot be i nf or me d of t he treat me nt bei n g a d mi nistere d  (t o mai ntai n 
t he si n gle- bli n d).  A st u d y p har macist or desi g nee at t he cli nical site will o btai n t he a p pr o priate 
ra n d o mizati o n c o de fr o m t he I nteracti ve V oice/ We b Res p o nse S yste m (I X R S) s yste m  i n or der t o 
dis pe nse st u d y dr u g t o eac h patie nt.  T he l ot n u m ber will be rec or de d wit hi n t he I X R S s yste m.  
Refer t o t he st u d y s pecific P har mac y Ma n ual f or detaile d g ui da nce.  
LJ P C - 4 0 1 will be s u p plie d i n vials as o pe n-la bel st oc k.  La beli n g will f ulfill all re q uire me nts 
s pecifie d b y g o ver ni n g re g ulati o ns. 
7. 4.  
St u d y Pr oce d ures  
T he ti mi n g a n d fre q ue nc y of assess me nts a n d t he details pr o vi de d i n  Ta ble  3 s h o ul d be t he 
pri mar y s o urce.  Fr o m Wee ks 2 t hr o u g h 1 7 t here is a ± 2- da y wi n d o w f or visits; o nce t he visit 
occ urs, t he patie nt s h o ul d ret ur n t o t he re g ular i nter val sc he d ule.  All assess me nts m ust be 
perf or me d pri or t o d osi n g, u nless ot her wise s pecifie d.  If t hera pe utic p hle b ot o m y is perf or me d 
t he sa me da y as d osi n g, t he pr oce d ure or der s h o ul d be:  la b orat or y sa m ples, t he n p hle b ot o m y, 
t he n st u d y dr u g ( LJ P C- 4 0 1 or place b o) d ose. 
Patie nts are n ot t o eat a n y f o o d or dri n k a n y be vera ges, e xce pt water, f or at least 6 h o urs pri or t o 
c ollecti n g bl o o d f or la b orat or y tests i ncl u di n g ir o n st u dies (I m m u n o ge nicit y/ P K a n d pre g na nc y 
test sa m ples are n ot re q uire d t o be fasti n g). 
Bl o o d f or c o m plete ir o n st u dies m ust be c ollecte d pre d ose a n d a gai n 2 4 ( ± 4) h o urs after d osi n g.  
Refer t o Secti o n  5. 4  f or s pecifics o n d osi n g a n d d ose a dj ust me nts.  Bl o o d f or i m m u n o ge nicit y 
m ust f oll o w t he s pecifie d c ollecti o n ti mes o utli ne d i n  Ta ble  3 is per t he f oll o wi n g secti o ns. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
4 2 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
7. 4. 1.  
Scree ni n g  (Wit hi n 9 0 d a ys of Wee k 1/ D a y 1) 
T he f oll o wi n g assess me nts will be perf or me d as reflecte d i n  Ta ble  3:  Scree ni n g ( wit hi n 9 0 da ys 
of Wee k  1/Da y  1) 
•  O btai n i nf or me d c o nse nt 
•  O btai n t he patie nt’s c o m plete me dical hist or y, i ncl u di n g t he de m o gra p hic 
i nf or mati o n, here ditar y he m oc hr o mat osis dia g n osis a n d ge n ot y pe (if a vaila ble), 
s ur gical hist or y a n d t hera pe utic p hle b ot o m y hist or y 
•  Rec or d me dicati o ns  a n d pr oce d ures, be gi n ni n g 1 4  da ys pri or t o Scree ni n g  
•  Perf or m a p h ysical e xa mi nati o n a n d meas ure me nt of hei g ht a n d wei g ht 
•  O btai n vital si g ns after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes 
•  Perf or m 1 2- lea d E C G (i n tri plicate a n d ≥ 1 mi n a part) wit hi n 3 0 da ys pri or t o t he first 
d ose of st u d y dr u g 
•  C ollect bl o o d pre d ose f or: 
− c o m plete ir o n st u dies (i ncl u di n g a n a d diti o nal sa m ple f or a p oferriti n a n d 
h ol oferriti n) ; if ferriti n a n d T S A T le vels d o n ot meet e ntr y criteria, t he patie nt’s 
re g ularl y sc he d ule d p hle b ot o m y ma y  be deferre d , a n d fasti n g a n d c o m plete ir o n 
st u dies re peate d e ver y 3 0 da ys f or u p t o 9 0 da ys u ntil e ntr y criteria are met 
− he mat ol o g y  
− ser u m c he mistr y  
− ser u m pre g na nc y test wit hi n 3 0 da ys pri or t o t he first d ose of st u d y dr u g f or 
fe males of c hil d beari n g p ote ntial o nl y (fasti n g is n ot re q uire d) 
− i m m u n o ge nicit y/ P K testi n g (c ollect 2 bl o o d sa m ples [ 2 t u bes], fasti n g is n ot 
re q uire d) 
•  C ollect uri ne f or uri nal ysis  
•  Assess  i ncl usi o n/e xcl usi o n criteria a n d patie nt eli gi bilit y 
•  Assess a n d rec or d A Es a n d S A Es , starti n g at c o nse nt 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
4 3 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
7. 4. 2.  
Wee k 1  ( D a y 1) 
T he f oll o wi n g assess me nts will be perf or me d as reflecte d i n  Ta ble  3:  Wee k 1/ Da y 1 
•  C o nfir m i ncl usi o n/e xcl usi o n criteria a n d patie nt eli gi bilit y pri or t o ra n d o mizati o n  
•  Assess a n d rec or d A Es a n d S A Es  
•  Rec or d ne w or c ha n ges t o c o nc o mita nt me dicati o ns/ pr oce d ures 
•  O btai n vital si g ns after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes 
•  C ollect bl o o d  pre d ose f or: 
− c o m plete ir o n st u dies, i ncl u di n g a n a d diti o nal sa m ple f or a p oferriti n a n d 
h ol ofer riti n 
− he mat ol o g y 
− ser u m c he mistr y 
− t h yr oi d f u ncti o n testi n g 
− he m o gl o bi n A 1 c testi n g 
− i m m u n o ge nicit y/ P K testi n g ( wit h a wi n d o w of - 3 0 mi n utes bef ore d osi n g, fasti n g 
is n ot re q uire d) 
•  C ollect uri ne fr o m fe males of c hil d beari n g p ote ntial  o nl y (ie, di pstic k) pri or t o st u d y 
dr u g a d mi nistrati o n  
•  A d mi nister Q ualit y of Life Q uesti o n naire s (S F -3 6 v 2) , W O M A C, a n d m o difie d 
Dreisler i n dices f or art hritis ) pri or t o p hle b ot o m y  
•  Sta n dar d of care t hera pe utic p hle b ot o m y ( 5 0 0 cc or a p pr o priate f or wei g ht).  
P hle b ot o m y s h o ul d be perf or me d after la b orat or y sa m ples are c ollecte d a n d bef ore 
st u d y dr u g d ose (ie, or der is la b orat or y sa m ples, p hle b ot o m y, LJ P C- 4 0 1 or place b o 
d ose). 
•  C o m plete ra n d o mizati o n pr oce d ures 
•  A d mi nister si n gle- bli n de d st u d y dr u g  (LJ P C - 4 0 1 or place b o) 
− Patie nts will n ot be i nf or me d of t he treat me nt bei n g a d mi nistere d ( t o mai ntai n t he 
si n gle- bli n d). 
•  C ollect p ost d ose bl o o d f or i m m u n o ge nicit y/ P K  ( 1 h o ur or later, fasti n g is n ot 
re q uire d) 
7. 4. 3.  
Wee k 2 ( D a y 8)  
T he f oll o wi n g assess me nts will be perf or me d as reflecte d i n  Ta ble  3:  Wee k 2/ Da y 8 
•  Assess a n d rec or d A Es a n d S A Es  
•  Rec or d ne w or c ha n ges t o c o nc o mita nt me dicati o ns/ pr oce d ures 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
4 4 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
•  O btai n vital si g ns after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes 
•  C ollect bl o o d f or i m m u n o ge nicit y / P K testi n g (fasti n g is n ot re q uire d)  
•  A d mi nister si n gle- bli n de d st u d y dr u g (LJ P C - 4 0 1 or place b o) 
− Patie nts will n ot be i nf or me d of t he treat me nt bei n g a d mi nistere d (t o mai ntai n t he 
si n gle- bli n d).   
7. 4. 4.  
Wee k 3  ( D a y 1 5 a n d D a y 1 6) 
T he f oll o wi n g assess me nts will be perf or me d as reflecte d i n  Ta ble  3:  Wee k 3/ Day 1 5  a n d 
Da y  1 6 
•  Assess a n d rec or d A Es a n d S A Es  
•  Rec or d ne w or c ha n ges t o c o nc o mita nt me dicati o ns/ pr oce d ures 
•  O btai n vital si g ns after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes  
•  C ollect bl o o d f or c o m plete ir o n st u dies , i ncl u di n g a n a d diti o nal sa m ple f or a p oferriti n 
a n d h ol oferriti n 
•  A d mi nister si n gle- bli n de d st u d y dr u g (LJ P C - 4 0 1 or place b o) 
− Patie nts will n ot be i nf or me d of t he treat me nt bei n g a d mi nistere d (t o mai ntai n t he 
si n gle- bli n d).   
•  Wee k 3 ( D a y 1 6) :  C ollect bl o o d 2 4 ( ±  4) h o urs p ost d ose f or c o m plete ir o n st u dies 
f or T S A T t o deter mi ne t he LJ P C - 4 0 1 d ose f or Wee k 4.  R efer t o d ose a dj ust me nt 
criteria a n d g ui deli nes i n Secti o n  5. 4 .) 
7. 4. 5.  
Wee k 4  ( D a y 2 2) 
T he f oll o wi n g assess me nts will be perf or me d as reflecte d i n  Ta ble  3:  Wee k 4/ Da y 2 2 
•  Assess a n d rec or d A Es a n d S A Es  
•  Rec or d ne w or c ha n ges t o c o nc o mita nt me dicati o ns/ pr oce d ures 
•  O btai n vital si g ns after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes  
•  C ollect bl o o d pre d ose f or: 
− c o m plete ir o n st u dies, i ncl u di n g a n a d diti o nal sa m ple f or a p oferriti n a n d 
h ol oferriti n  
− he mat ol o g y 
− ser u m c he mistr y 
− i m m u n o ge nicit y/ P K testi n g (fasti n g is n ot re q uire d) 
•  A d mi nister si n gle- bli n de d st u d y dr u g ( LJ P C- 4 0 1 or place b o) 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
4 5 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
− Patie nts will n ot be i nf or me d of t he treat me nt bei n g a d mi nistere d (t o mai ntai n t he 
si n gle- bli n d). 
•  Wee k 4 ( D a y  2 3):  C ollect bl o o d 2 4 ( ± 4) h o urs p ost d ose f or c o m plete ir o n st u dies 
f or T S A T t o deter mi ne t he if t he patie nt re q uires a p hle b ot o m y.  If t he T S A T res ult 
fr o m Wee k 4, Da y 2 3 is > 4 5 %, t he patie nt m ust be c o ntacte d s o he/s he ca n recei ve a 
p hle b ot o m y ( base d o n t he T S A T criteria of t he I DI g ui deli nes). 
− If i n dicate d, phle b ot o m y m ust be c o m plete d o n or bef ore Wee k 5.  If t hera pe utic 
p hle b ot o m y is perf or me d t he sa me da y as d osi n g, t he or der s h o ul d be:  la b orat or y 
sa m ples; p hle b ot o m y; LJ P C- 4 0 1 or place b o d ose. 
7. 4. 6.  
Wee ks 5, 6, a n d 7  ( D a ys 2 9, 3 6, a n d 4 3) 
T he f oll o wi n g assess me nts will be perf or me d as reflecte d i n  Ta ble  3:  Wee ks 5, 6, a n d 
7/ Da ys 2 9, 3 6, a n d 4 3  
•  Assess a n d rec or d A Es a n d S A Es  
•  Rec or d ne w or c ha n ges t o c o nc o mita nt me dicati o ns/ pr oce d ures 
•  O btai n vital si g ns after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes  
•  A d mi nister si n gle- bli n de d st u d y dr u g (LJ P C - 4 0 1 or place b o)  
− Patie nts will n ot be i nf or me d of t he treat me nt bei n g a d mi nistere d (t o mai ntai n t he 
si n gle- bli n d).   
7. 4. 7.  
Wee k 8  ( D a y 5 0 a n d D a y 5 1) 
T he f oll o wi n g assess me nts will be perf or me d as reflecte d i n  Ta ble  3:  Wee k 8/ Da y 5 0 a n d 
Da y  5 1 
•  Assess a n d rec or d A Es a n d S A Es  
•  Rec or d ne w or c ha n ges t o c o nc o mita nt me dicati o ns/ pr oce d ures  
•  O btai n vital si g ns after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes 
•  C ollect bl o o d  pre d ose f or: 
− c o m plete ir o n st u dies, i ncl u di n g a n a d diti o nal sa m ple f or a p oferriti n a n d 
h ol oferriti n  
− he mat ol o g y 
− ser u m c he mistr y 
− i m m u n o ge nicit y/ P K testi n g (fasti n g is n ot re q uire d) 
•  A d mi nister si n gle- bli n de d st u d y dr u g (LJ P C - 4 0 1 or place b o) 
− Patie nts will n ot be i nf or me d of t he treat me nt bei n g a d mi nistere d (t o mai ntai n t h e 
si n gle- bli n d). 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
4 6 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
•  Wee k 8 ( D a y 5 1) :  C ollect bl o o d 2 4 ( ± 4) h o urs p ost d ose f or c o m plete ir o n st u dies 
f or T S A T t o deter mi ne if t he patie nt re q uires a p hle b ot o m y.  If t he T S A T res ult fr o m 
Wee k 8, Da y 5 1 is > 4 5 %, t he patie nt m ust be c o ntacte d s o he/s he ca n recei ve a 
p hle b ot o m y ( base d o n t he T S A T criteria of t he I DI g ui deli nes).  
•  If i n dicate d, phle b ot o m y m ust be c o m plete d o n or bef ore Wee k 9.  If t hera pe utic 
p hle b ot o m y is perf or me d t he sa me da y as d osi n g, t he or der s h o ul d be:  la b orat or y 
sa m ples; p hle b ot o m y; LJ P C- 4 0 1 or place b o d ose. 
7. 4. 8.  
Wee ks 9, 1 0, a n d  1 1 ( D a ys 5 7, 6 4, a n d 7 1) 
T he f oll o wi n g assess me nts will be perf or me d as reflecte d i n  Ta ble  3:  Wee ks 9, 1 0, a n d 
1 1/ Da ys 5 7, 6 4, a n d 7 1 
•  Assess a n d rec or d A Es a n d S A Es  
•  Rec or d ne w or c ha n ges t o c o nc o mita nt me dicati o ns/ pr oce d ures 
•  O btai n vital si g ns after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes 
•  A d mi nister si n gle- bli n de d st u d y dr u g (LJ P C - 4 0 1 or place b o refer t o d ose a dj ust me nt 
Secti o n  5. 4 .) 
− Patie nts will n ot be i nf or me d of t he treat me nt bei n g a d mi nistere d ( t o mai ntai n t he 
si n gle- bli n d). 
7. 4. 9.  
Wee k 1 2 ( D a y 7 8 a n d D a y 7 9) 
T he f oll o wi n g ass ess me nts will be perf or me d as reflecte d i n  Ta ble  3:  Wee k 1 2/ Da y 7 8  a n d 
Da y  7 9 
•  Assess a n d rec or d A Es a n d S A Es  
•  Rec or d ne w or c ha n ges t o c o nc o mita nt me dicati o ns / pr oce d ures 
•  O btai n vital si g ns after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes 
•  C ollect bl o o d pre d ose f or: 
− c o m plete ir o n st u dies, i ncl u di n g a n a d diti o nal sa m ple f or a p oferriti n a n d 
h ol oferriti n  
− he mat ol o g y 
− ser u m c he mistr y 
− i m m u n o ge nicit y/ P K testi n g (fasti n g is n ot re q uire d) 
•  A d mi nister si n gle- bli n de d st u d y dr u g ( LJ P C- 4 0 1 or place b o) 
− Patie nts will n ot be i nf or me d of t he treat me nt bei n g a d mi nistere d ( t o mai ntai n t he 
si n gle- bli n d). 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
4 7 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
•  Wee k 1 2 ( D a y 7 9) :  C ollect bl o o d 2 4 ( ± 4) h o urs p ost d ose f or c o m plete ir o n st u dies 
f or T S A T t o deter mi ne if t he patie nt re q uires a p hle b ot o m y.  If t he T S A T res ult fr o m 
Wee k 1 2, Da y 7 9 is > 4 5 %, t he patie nt m ust be c o ntacte d s o he/s he ca n recei ve a 
p hle b ot o m y ( base d o n t he T S A T criteria of t he  I DI g ui deli nes). 
•   If i n dicate d, phle b ot o m y m ust be c o m plete d o n or bef ore Wee k 1 3.  If t hera pe utic 
p hle b ot o m y is perf or me d t he sa me da y as d osi n g, t he or der s h o ul d be:  la b orat or y 
sa m ples; p hle b ot o m y; LJ P C- 4 0 1 or place b o d ose. 
7. 4. 1 0.  
Wee ks 1 3, 1 4, a n d 1 5 ( D a ys 8 5, 9 2, a n d 9 9) 
T he f oll o wi n g assess me nts will be perf or me d as reflecte d i n  Ta ble  3:  Wee ks 1 3, 1 4, a n d 
1 5/ Da ys 8 5, 9 2, a n d 9 9 
•  Assess a n d rec or d A Es a n d S A Es  
•  Rec or d ne w or c ha n ges t o c o nc o mita nt me dicati o ns/ pr oce d ures 
•  O btai n vital si g ns after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes  
•  A d mi nister si n gle- bli n de d st u d y dr u g ( LJ P C- 4 0 1 or place b o; refer t o d ose a dj ust me nt 
Sec ti o n 5. 4 .) 
− Patie nts will n ot be i nf or me d of t he treat me nt bei n g a d mi nistere d ( t o mai ntai n t he 
si n gle- bli n d). 
7. 4. 1 1.  
Wee k 1 6 ( D a y 1 0 6 a n d D a y 1 0 7) 
T he f oll o wi n g assess me nts will be perf or me d as reflecte d i n Ta ble  3:  Wee k 1 6/ Da y 1 0 6 a n d 
Da y  1 0 7 
•  Assess a n d rec or d A Es a n d S A Es  
•  Rec or d ne w or c ha n ges t o c o nc o mita nt me dicati o ns/ pr oce d ures 
•  O btai n vital si g ns after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes 
•  Perf or m a p h ysical e xa mi nati o n (i ncl u di n g wei g ht) 
•  C ollect bl o o d pre d ose f or: 
− c o m plete ir o n st u dies, i ncl u di n g a n a d diti o n al sa m ple f or a p oferriti n a n d 
h ol oferriti n  
− he mat ol o g y 
− ser u m c he mistr y 
− t h yr oi d f u ncti o n testi n g 
− he m o gl o bi n A 1 c testi n g 
− i m m u n o ge nicit y/ P K testi n g (fasti n g is n ot re q uire d) 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
4 8 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
•  C ollect uri ne f or  uri nal ysis  
•  A d mi nister Q ualit y of Life Q uesti o n naire s ( S F- 3 6 v 2), W O M A C, a n d m o difie d 
Dreisler i n dices f or art hritis ) pri or t o p hle b ot o m y  
•  A d mi nister si n gle- bli n de d st u d y dr u g ( LJ P C- 4 0 1 or place b o) 
− Patie nts will n ot be i nf or me d of t he treat me nt bei n g a d mi nistere d ( t o mai ntai n t he 
si n gle- bli n d). 
− C ollect p ost d ose bl o o d f or i m m u n o ge nicit y/ P K ( 1 h o ur or later, fasti n g is n ot 
re q uire d) 
•  Wee k 1 6 ( D a y 1 0 7) :  C ollect bl o o d 2 4 ( ± 4) h o urs p ost d ose f or he mat ol o g y a n d 
c o m plete ir o n st u dies f or T S A T t o deter mi ne if t he patie nt re q uires a p hle b ot o m y.  If 
t he T S A T res ult fr o m Wee k 1 6, Da y 1 0 7 is > 4 5 %, t he patie nt m ust be c o ntacte d s o 
he/s he ca n recei ve a p hle b ot o m y ( base d o n t he T S A T criteria of t he  I DI g ui deli nes). 
•  If i n dicate d, phle b ot o m y m ust be c o m plete d o n or bef ore Wee k 1 7 ( Da y 1 1 3).  If 
t hera pe utic p hle b ot o m y is perf or me d t he sa me da y as t he Wee k 1 7, fasti n g ir o n 
st u dies s h o ul d be c ollecte d bef ore p hle b ot o m y. 
7. 4. 1 2.  
Wee k 1 7 ( D a y 1 1 3) 
•  C ollect bl o o d f or fasti n g ir o n st u dies  (tr o u g h sa m ple, a p pr o xi matel y 7 da ys after last 
d ose). 
7. 4. 1 3.  
F oll o w- u p ( 3 0 d a ys [ + 3 d a ys] fr o m l ast d ose of st u d y dr u g) 
T he  f oll o wi n g assess me nts will be perf or me d as reflecte d i n Ta ble  3:  A p pr o xi matel y Wee k  2 0 
( 3 0 da ys [ + 3 da ys] after t he last d ose of st u d y dr u g) 
•  Assess a n d rec or d A Es a n d S A Es 
•  Rec or d ne w or c ha n ges t o c o nc o mita nt me dicati o ns/ pr oce d ures 
•  O btai n vital si g ns after t he patie nt has bee n resti n g i n t he sitti n g p ositi o n f or at least 
5 mi n utes 
•  Perf or m a p h ysical e xa mi nati o n  
•  Perf or m 1 2-lea d E C G (i n tri plicate a n d ≥ 1 mi n a part) 
•  C ollect bl o o d f or:   
− c o m plete ir o n st u dies, i ncl u di n g a n a d diti o nal sa m ple f or a p oferriti n a n d 
h ol oferriti n  
− he mat ol o g y 
− ser u m c he mistr y 
− i m m u n o ge nicit y/ P K testi n g (fasti n g is n ot re q uire d) 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
4 9 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
•  C ollect uri ne f or : 
− uri nal ysis  
− pre g na nc y test, f or  fe males of c hil d beari n g p ote ntial o nl y (ie, di pstic k test) 
7. 4. 1 4.  
E arl y Wit h dr a w al 
T he f oll o wi n g pr oce d ures are t o be c ollecte d, t o t he e xte nt p ossi ble, f or patie nts w h o wit h dra w 
earl y.  Pr oce d ures i ncl u de all Wee k 1 6 pr oce d ures pl us a 1 2-lea d E C G a n d uri ne pre g na nc y 
testi n g (fe males of c hil d- beari n g p ote ntial o nl y). 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
5 0 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
8.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T  
8. 1.  
St u d y Dr u g  
LJ P C - 4 0 1 f or S C a d mi nistrati o n is a clear c ol orless s ol uti o n , wit h esse ntiall y n o visi ble particles,  
s u p plie d i n clear glass vials, wit h a r u b ber st o p per a n d al u mi n u m o ver-seal wit h a plastic fli p -off 
ca p.  Pr o d uct c o nce ntrati o n is 5 or 1 0 m g/ m L.  T he e xtracta ble fill v ol u me  is 1. 0 m L.  Refer t o 
t he pr o d uct la bel a n d/ or t he P har mac y Ma n ual f or d ose pre parati o n i nstr ucti o ns. 
8. 2.  
St u d y Dr u g P ac k a gi n g a n d L a beli n g  
LJ P C - 4 0 1 will be s u p plie d i n vials as o pe n-la bel st oc k.  La beli n g will f ulfill all re q uire me nts 
s pecifie d b y partici pati n g g o ver ni n g re g ulati o ns. 
A v ol u me- matc he d place b o  ( 0. 9 % s o di u m c hl ori de i njecti o n, U S P [or e q ui vale nt]) will be 
pr o vi de d b y t h e st u d y sites fr o m t heir o w n st oc k. 
Refer t o t he st u d y s pecific P har mac y Ma n ual f or detaile d g ui da nce.  
8. 3.  
St u d y Dr u g St or a ge  
Vials c o ntai ni n g LJ P C - 4 0 1 s h o ul d be st ore d refri gerate d at 5° C ± 3° ( 2° C t o 8° C) i n a sec ure 
area wit h li mite d access.  La  J olla has t este d pr o d uct sta bilit y a n d s h o w n t he pr o d uct t o be sta ble 
wit hi n t hat te m perat ure ra n ge f or t he a ntici pate d d urati o n of use. 
Refer t o t he st u d y s pecific P har mac y Ma n ual f or detaile d g ui da nce.  
8. 4.  
St u d y Dr u g Pre p ar ati o n  
Pri or t o a d mi nistrati o n, vials of LJ P C - 4 0 1 s h o ul d be st ore d at r o o m te m perat ure f or a mi ni m u m 
of 3 0 mi n utes f oll o wi n g re m o val fr o m t he refri gerat or.  St u d y dr u g ca n be st ore d at r o o m 
te m perat ure f or u p t o 2 4 h o urs pri or t o d osi n g. 
A p har macist or desi g nee will pre pare t he st u d y dr u g usi n g safe practices f or me dical i njecti o ns.  
F or t h ose patie nts ra n d o mize d t o place b o, a v ol u me- matc he d s yri n ge of 0. 9 % s o di u m c hl ori de 
i njecti o n, U S P ( or e q ui vale nt) will be pre pare d b y t he p har macist or desi g nee a n d la bele d as s uc h 
t hat t h ose s yri n ges c o ntai ni n g dr u g pr o d uct a n d t h ose c o ntai ni n g place b o a p pear i de ntical (t o 
mai ntai n t he st u d y si n gle- bli n d).  
Refer t o t he st u d y s pecific P har mac y Ma n ual f or detaile d g ui da nce.  
8. 5.  
St u d y Dr u g A d mi nistr ati o n  
Vials are f or si n gle -use a d mi nistrati o n a n d will be gi ve n via S C i njecti o n.  St u d y dr u g will o nl y 
be a d mi nistere d t o eli gi ble patie nts u n der t he s u per visi o n of t he I n vesti gat or or i de ntifie d 
S u b -I n vesti gat or(s).  U p o n c o m pleti o n of a p pr o priate trai ni n g, t he I n vesti gat or ma y dele gate 
st u d y dr u g a d mi nistrati o n t o a trai ne d h o me care n urse/researc h staff .  
Refer t o t he st u d y s pecific P har mac y Ma n ual f or detaile d g ui da nce.  


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
5 1 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
8. 6.  
St u d y Dr u g  Acc o u nt a bilit y  
All use d (e m pt y or partiall y e m pt y) a n d u n use d st u d y dr u g vials m ust be sa ve d f or t he St u d y 
M o nit or f or rec o nciliati o n pri or t o destr ucti o n or i nitiati n g a ret ur n of st u d y dr u g.  Destr ucti o n of 
st u d y dr u g ma y o nl y be perf or me d if La  J olla has a gree d t o o n-site destr ucti o n of use d vials. 
Refer t o t he st u d y s pecific P har mac y Ma n ual f or detaile d g ui da nce.  
8. 7.  
St u d y Dr u g  H a n dli n g a n d Dis p o s al 
All u n use d st u d y dr u g a n d ot her st u d y materials m ust  be ret ur ne d t o La  J olla or its desi g nee 
a n d/ or destr o ye d at t he st u d y site (if a p pr o ve d b y La  J olla) after rec o nciliati o n has bee n 
c o m plete d b y t he St u d y M o nit or, or u nless ot her wise directe d b y La  Jolla .  All u n use d material 
c o ntai ni n g LJ P C - 4 0 1 will be treate d a n d dis p ose d of as hazar d o us waste i n acc or da nce wit h 
g o ver ni n g re g ulati o ns. 
Refer t o t he st u d y s pecific P har mac y Ma n ual f or detaile d g ui da nce.  


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
5 2 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
9.  
A S S E S S M E N T  O F E F FI C A C Y  
9. 1.  
C o m plete Ir o n S t u dies  
Bl o o d sa m pl es f or a nal ysis of ir o n st u d y para meters i ncl u de: 
•  T otal Ser u m Ir o n  
•  Ferriti n  
•  Tra nsferri n  
•  TI B C  
•  UI B C  
•  T S A T   
C o m plete ir o n st u dies will be assesse d at ti mes s pecifie d i n  Ta ble  3.  Patie nts are n ot t o eat  a n y 
f o o d or dri n k a n y be vera ges, e xce pt water, f or at least 6 h o urs pri or t o c ollecti n g bl o o d f or 
c o m plete ir o n st u dies.  A d diti o nal bl o o d sa m ples will be c ollecte d f or scie ntific researc h, 
i ncl u di n g P K a nal yses a n d a nal yses of a p oferriti n a n d h ol oferriti n.  
9. 2.  
P hle b ot o m y  
All ra n d o mize d patie nts will recei ve a sta n dar d of care t hera pe utic p hle b ot o m y ( 5 0 0 cc or 
a p pr o priate f or wei g ht ) o n Da y 1  ( pre d ose).  T hereafter, p hle b ot o m y decisi o ns b y t he 
I n vesti gat or will be base d o n t he patie nt’s fasti n g T S A T res ults c ollecte d p ost d ose 2 4 ( ± 4) h o urs 
at Wee k 4 ( Da y 2 3); Wee k 8 ( Da y 5 1); Wee k 1 2 ( Da y 7 9); a n d Wee k 1 6 ( Da y 1 0 7).  If t he 
res ulti n g T S A T is > 4 5 % a p hle b ot o m y is i n dicate d.  If a p hle b ot o m y is i n dicate d, t he patie nt 
s h o ul d recei ve p hle b ot o m y treat me nt pre d ose, o n or bef ore t he f oll o wi n g visit. 
If t hera pe utic p hle b ot o m y is perf or me d t he sa me da y as d osi n g, t he or der s h o ul d be:  la b orat or y 
sa m ples; phle b ot o m y; LJ P C - 4 0 1 or place b o d ose. 
N u m ber of p hle b ot o mies a n d t he n u m ber of ti mes a patie nt met criteria f or a p hle b ot o m y will be 
e val uate d ( Secti o n  1 2. 8. 4. 2 ). 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
5 3 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 0.  
A S S E S S M E N T O F S A F E T Y  
Assess me nts will be perf or me d at ti mes s pecifie d i n  Ta ble  3. 
1 0. 1.  
S afet y P ar a meters  
Safet y assess me nts will i ncl u de m o nit ori n g of all A Es, re g ular m o nit ori n g of la b orat or y 
para meters i ncl u di n g he mat ol o g y, ser u m c he mistr y a n d ir o n pa nel, E C Gs, c o nc o mita nt 
m e dicati o ns, p h ysical e xa mi nati o ns, vital si g ns, a n d testi n g f or i m m u n o ge nicit y.   
1 0. 1. 1.  
De m o gr a p hics 
De m o gra p hic i nf or mati o n will be c ollecte d at Scree ni n g, t o i ncl u de a ge, se x, c hil d beari n g 
p ote ntial, race, et h nicit y,  a n d ge o gra p hic re gi o n ( w here all o we d, per l ocal re g ulati o ns).  Refer t o 
Secti o n  1 2. 8. 1  f or t he f ull list of c haracteristics t hat will be c ollecte d. 
1 0. 1. 2.  
Me dic al Hist or y  
A c o m plete re vie w of t he patie nt’s me dical hist or y s h o ul d i ncl u de t he patie nt’ s here ditar y 
he m oc hr o mat osis dia g n osis a n d ge n ot y pe (if a vaila ble), c o nc urre nt me dical c o n diti o ns, s ur gical 
a n d me dical pr oce d ures, a n d t hera pe utic p hle b ot o m y hist or y.   
Pri or a n d c o nc o mita nt me dicati o ns will be rec or de d t hr o u g h t he f oll o w- u p visit.  T his rec or di n g 
s h o ul d i ncl u de a n y me dicati o n ta ke n, i ncl u di n g oral c o ntrace pti ves, a n d me dical pr oce d ure(s) 
perf or me d fr o m 1 4 da ys pri or t o Scree ni n g t o t he f oll o w- u p visit ( 3 0 da ys [ + 3 da ys] after t he last 
d ose of st u d y dr u g). 
1 0. 1. 3.  
Vit al Si g ns  
Vital si g ns, i ncl u di n g heart rate, res pirat or y rate, b o d y te m perat ure, a n d bl o o d press ure , as 
o utli ne d i n  Ta ble  3, will  be meas ure d after t he patie nt has bee n resti n g i n a sitti n g p ositi o n f or at 
least 5 mi n utes . 
Vital si g ns ma y be perf or me d b y a n I n vesti gat or, S u b- I n vesti gat or, or I n vesti gat or- desi g nate d 
n urse, p h ysicia n’s assista nt, or a n y staff me m ber a p pr o priatel y trai ne d a n d i ncl u de d o n t he 
dele gati o n of a ut h orit y l o g as a ble t o c o n d uct t hese assess me nts.  
1 0. 1. 4.  
P h ysic al E x a mi n ati o n  
A c o m plete p h ysical e xa mi nati o n (i ncl u di n g e val uati o n of ge neral a p peara nce/ me ntal stat us, 
H E E N T [ hea d, e yes, ears, n ose, t hr oat] a n d t he f oll o wi n g b o d y s yste ms:  der mat ol o gic, 
car di o vasc ular, res pirat or y, gastr oi ntesti nal , a n d ne ur ol o gic) will be perf or me d  at s pecifie d ti mes, 
o utli ne d i n  Ta ble  3. 
T hese p h ysical e xa ms will i ncl u de disease relate d s y m pt o ms assess me nt a n d meas ure me nt of 
wei g ht at Scree ni n g a n d Wee k 1 6.  Hei g ht will be meas ure d at Scree ni n g o nl y. 
1 0. 1. 5.  
Electr oc ar di o gr a m  
1 2- lead E C Gs will be meas ure d i n tri plicate (≥ 1 mi n ute a part) after t he patie nt has bee n resti n g 
f or at least 5 mi n utes i n a s u pi ne p ositi o n.  A d diti o nal E C Gs will be c ollecte d if cli nicall y 
i n dicate d (e g, patie nts wit h pal pitati o ns, li g ht hea de d ness).  


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
5 4 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
A b n or malities n ote d at Scree ni n g s h o ul d be i ncl u de d i n t he me dical hist or y.  If o bser ve d as 
a b n or mal a n d cli nicall y si g nifica nt t hereafter it s h o ul d be n ote d  as a n A E. 
1 0. 1. 6.  
L a b or at or y Assess me nts  
Sa m ples will be c ollecte d  at ti mes s pecifie d i n  Ta ble  3.  A p pe n di x 1  pr o vi des a s u m mar y list of 
t he la b orat or y para meters  i n t his st u d y.  All sa m ples will be se nt t o t he ce ntral la b orat or y u nless 
i n t he case of a safet y or e mer ge nt e ve nt, or ot her wise i nstr ucte d b y t he S p o ns or.  U nsc he d ule d 
la borat or y  kits s h o ul d be use d f or all re peat la b orat or y test s w he ne ver p ossi ble. 
Patie nts are n ot t o eat a n y f o o d or dri n k a n y be vera ges, e xce pt water, f or at least 6 h o urs pri or t o 
c ollecti n g bl o o d f or la b orat or y tests (i m m u n o ge nicit y / P K a n d pre g na nc y test  sa m ples are n ot 
re q uire d t o be fasti n g). 
If t hera pe utic p hle b ot o m y is perf or me d t he sa me da y as d osi n g, t he or der s h o ul d be:  la b orat or y 
sa m ples; p hle b ot om y; LJ P C - 4 0 1 or place b o d ose. 
1 0. 1. 6. 1.  He m at ol o g y  
Bl o o d sa m pl es f or a nal ysis of t he he mat ol o gic para meters i ncl u de:  
•  He mat ocrit  
 
•  He m o gl o bi n 
•  Platelet c o u nt  
•  R B C c o u nt, i ncl u di n g retic ul oc yte 
c o u nt, R D W, mea n c or p usc ular 
he m o gl o bi n, mea n c or p usc ular 
he m o gl o bi n c o nce ntrati o n, a n d 
mea n c or p usc ular v ol u me 
•  W hite bl o o d cell c o u nt a n d 
differe ntial i ncl u di n g perce nt a n d 
a bs ol ute:  ne utr o p hils, 
l y m p h oc ytes, m o n oc ytes, 
e osi n o p hils, a n d bas o p hils  
1 0. 1. 6. 2.  Cli nic al  C he mistr ies 
Bl o o d sa m pl es f or a nal ysis of cli nical c he mistr y para meters i ncl u de: 
•  Ser u m creati ni ne 
•  Uric aci d 
•  Calci u m  
•  Ma g nesi u m  
•  Al kali ne 
p h os p hatase 
•  Lactate 
de h y dr o ge nase 
( L D H) 
 
•  Bl o o d u rea n itr o ge n 
•  P h os p hate 
•  C hl ori de 
•  Bicar b o nate 
•  A L T  
(ser u m gl uta mic-
p yr u vic 
tra nsa mi nase) 
•  Al b u mi n  
•  S o di u m 
•  P otassi u m  
•  Gl uc ose 
•  As partate a mi n otra nsferase 
(A S T ) 
(ser u m gl uta mic- 
o xal oacetic tra nsa mi nase)  
•  Bilir u bi n (t otal, direct , 
a n d i n direct) 
•  T otal pr otei n  


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
5 5 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 0. 1. 6. 3.  T h yr oi d F u ncti o n  
Bl o o d sa m pl es f or a nal ysis of t h yr oi d f u ncti o n para meters i ncl u de: 
•  T h yr oi d- sti m ulati n g 
h or m o ne ( T S H ) 
•  T h yr o xi ne ( T 4) 
•  Trii o d ot h yr o ni ne ( T 3 ) 
•  Free T 4  
1 0. 1. 6. 4.  Gl yce mic C o ntr ol  
Bl o o d sa m pl es f or a nal ysis of he m o gl o bi n A 1 c will be c ollecte d t o assess gl yce mic c o ntr ol.  
1 0. 1. 6. 5.  Pre g n a nc y Scree n  
A ser u m pre g na nc y test will be perf or me d f or w o me n of c hil d beari n g p ote ntial d uri n g Scree ni n g 
wit hi n 3 0 da ys pri or t o t he first d ose of st u d y dr u g.  Fasti n g is n ot re q uire d.  
A uri ne pre g na nc y test (ie, di pstic k) will  be perf or me d f or w o me n of c hil d beari n g p ote ntial at 
Wee k  1/ Da y 1 pre d ose a n d Wee k 2 0 or Earl y Wit h dra wal (if p ossi ble). 
Refer t o Secti o n  1 1. 5  f or pre g na nc y re p orti n g a n d f oll o w- u p pr oce d ures. 
1 0. 1. 6. 5. 1.  C o ntr ace pti o n 
T he effects of t he st u d y dr u g, LJ P C- 4 0 1, or pr oce d ures perf or me d d uri n g t his st u d y ma y p ose 
s o me u n k n o w n ris ks t o t he re pr o d ucti ve s yste m, de vel o pi n g fet us or d uri n g breastfee di n g.  Si nce 
t he effects of t he i n vesti gati o nal dr u g o n t he fe male a n d male re pr o d ucti ve s yste ms are still 
u n k n o w n, it is ver y i m p orta nt t hat patie nts i n t his st u d y use a hi g hl y effecti ve met h o d of 
c o ntrace pti o n d uri n g partici pati o n i n t his st u d y a n d f or 3 0 da ys after t he last d ose of st u d y dr u g, 
a n d n ot bec o me pre g na nt or fat her a c hil d d uri n g t his st u d y a n d f or 3 0 da ys after t he last d ose of 
st u d y dr u g.   
W o me n w h o are pre g na nt or breastfee di n g ma y n ot partici pate i n t his st u d y.  Hi g hl y effecti ve 
met h o ds of c o ntrace pti o n are re q uire d d uri n g partici pati o n i n t his st u d y, a n d f or 3 0 da ys after t he 
last d ose of st u d y dr u g, f or b ot h male a n d fe male patie nts a n d/ or f or t heir part ners, u nless he or 
s he is s ur gicall y sterile or of n o nc hil d beari n g p ote ntial (ie, p ost me n o pa usal, defi ne d as 
1 2 c o nsec uti ve m o nt hs wit h n o me nses wit h o ut a n alter nate me dical ca use).  Hi g hl y effecti ve 
met h o ds of c o ntrace pti o n are defi ne d as t h ose t hat res ult i n a l o w fail ure rate w he n use d 
c o nsiste ntl y a n d c orrectl y, al o ne or i n c o m bi nati o n.  N ote, t he effects of LJ P C - 4 0 1 o n t he 
effecti ve ness of h or m o nal c o ntrace pti o n are c urre ntl y u n k n o w n. 
T he f oll o wi n g are c o nsi dere d hi g hl y effecti ve met h o ds of c o ntrace pti o n: 
•  S ur gical sterilit y ( vasect o m y, bilateral t u bal li gati o n, or h ysterect o m y)  
•  I ntra uteri ne de vice (I U D) 
•  H or m o na l i ntra uteri ne s yste m (I U S), i m pla nts, or i njecti o ns  
•  C o nsiste nt use of a n a p pr o ve d oral c o ntrace pti ve pill (c o m bi ne d pr o gesti n/estr o ge n 
pill or pr o gesti n - o nl y pill) 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
5 6 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
•  C o m bi ne d i ntra va gi nal or tra ns der mal met h o d  
A bsti ne nce ca n be use d as a met h o d of c o ntrace pti o n.  Peri o dic a bsti ne nce (cale n dar, 
s y m pt ot her mal, p ost o v ulati o n met h o ds), wit h dra wal (c oit us i nterr u pt us), s per mici des or 
c o n d o ms o nl y, a n d lactati o nal a me n orr hea met h o d are n ot acce pta ble met h o ds of c o ntrace pti o n. 
Oral, i m pla nta ble, or i njecta ble c o nt race pti ves are o nl y c o nsi dere d effecti ve if use d pr o perl y a n d 
be g u n at least 3 0 da ys pri or t o t he Scree ni n g visit. 
1 0. 1. 6. 6.  Uri n al ysis  
Uri ne sa m ples f or r o uti ne uri nal ysis para meters i ncl u de: 
•  S pecific gra vit y  
•  p H 
•  Bl o o d 
•  Bilir u bi n  
•  Pr otei n  
•  Ket o nes 
•  Gl uc ose 
•  Nitrite  
 
A n y para meter wit h a b n or mal uri nal ysis res ults will be f urt her c haracterize d t hr o u g h uri ne 
micr osc o p y. 
1 0. 1. 6. 7.  I m m u n o ge nicit y 
Bl o o d s a m pl es will be c ollecte d t o assess i m m u n o ge nic effect .  P har mac o ki netics will be 
assesse d c o nc o mita ntl y t o deter mi ne if t here is a relati o ns hi p bet wee n dr u g c o nce ntrati o n a n d 
i m m u n o ge nicit y (if a nti- dr u g a nti b o dies or ne utralizi n g a nti b o dies de vel o p).  I n a d diti o n, t he 
s parse c o nce ntrati o n data of LJ P C- 4 0 1 t hat will be c ollecte d ma y be use d i n c o m bi nati o n wit h 
data c ollecte d fr o m ot he r st u dies t o s u p p ort f ut ure c o m p osite P K/ P D m o deli n g a n d a nal ysis t hat 
will be n ot be re p orte d i n t his st u d y . 
If a patie nt de vel o ps a nti b o dies t o LJ P C - 4 0 1, treat me nt will be disc o nti n ue d, a n d t he patie nt will 
be m o nit ore d u ntil a nti b o d y le vels ret ur n t o ba seli ne.  I n patie nts t hat ser oc o n vert, a nti b o d y 
le vels will be m o nit ore d u ntil t he y ret ur n t o baseli ne a n d c haracterize d f or titer, bi n di n g t o 
e n d o ge n o us c o u nter parts, a n d ne utralizi n g ca pacit y.  F or safet y, p atie nts ma y be as ke d t o ret ur n 
t o t he cli nic f or c ollecti o n of a d diti o nal i m m u n o ge nicit y sa m ples t o c o nfir m w het her a nti b o d y 
le vels ha ve ret ur ne d t o baseli ne .  
1 0. 2.  
Q u alit y of Life Q uesti o n n aire s 
Q ualit y - of-Life Q uesti o n na ires ( S F-3 6 v 2) , W O M A C, a n d t he m o difie d  Dreisler i n dices f or  
art hritis will be a d mi nistere d  t o patie nt s (i n l ocal la n g ua ge) t o c o m plete d uri n g st u d y visits.  
E val uati o ns will be perf or me d at ti mes s pecifie d i n Ta ble  3. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
5 7 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 1.  
A D V E R S E A N D S E RI O U S A D V E R S E E V E N T S  
1 1. 1.  
Defi niti o n of A d verse E ve nts  
1 1. 1. 1.  
A d verse E ve nt  
A n A E is defi ne d as a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
s u bject a d mi nistere d a p har mace utical pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal 
relati o ns hi p wit h t his treat me nt.  
A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y 
fi n di n g, f or e xa m ple), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal 
pr o d uct, w het her or n ot c o nsi dere d re late d t o t he me dici nal pr o d uct. 
A Es i ncl u de, b ut are n ot li mite d t o: ( 1) a w orse ni n g or c ha n ge i n nat ure, se verit y, or fre q ue nc y of 
c o n diti o n(s) prese nt at t he start of t he st u d y; ( 2) s u bject deteri orati o n d ue t o pri mar y  ill ness; 
( 3) i nterc urre nt ill ness; a n d ( 4) dr u g i nteracti o n.  F or rec or di n g p ur p oses, pre g na nc y is a me dical 
c o n diti o n a n d is n ot c o nsi dere d a n A E (see t he Pre g na nc y a n d F oll o w- u p Secti o n  1 1. 5  bel o w). 
Patie nts  s h o ul d be q uesti o ne d i n a ge neral wa y, wit h o ut lea di n g t he s u bject or as ki n g a b o ut t he 
occ ur re nce of a n y s pecific s y m pt o m. 
T he I n vesti gat or s h o ul d atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, s y m pt o ms, 
a n d/ or ot her cli nical i nf or mati o n.  T he dia g n osis a n d n ot t he i n di vi d ual si g ns/s y m pt o ms s h o ul d 
be d oc u me nte d as t he A E.  F or e xa m ple, if t he u n derl yi n g disease pr ocess is a gastric ulcer, it 
w o ul d n ot be a p pr o priate t o rec or d t he A E b y descri bi n g t he s y m pt o ms “st o mac h pai n, or 
i n di gesti o n, or a p petite l oss, etc.”  T he A E me dical ter m of “ gastric ulcer” s h o ul d be rec or de d as 
t he A E. 
1 1. 1. 2.  
Seri o us A d verse E ve nt  
A n S A E  (e x perie nce or reacti o n) is a n A E  t hat res ults i n 1 or m ore of t he f oll o wi n g: 
•  Res ults i n deat h - A n A E  t hat ca use d or c o ntri b ute d t o a fatal o utc o me. 
•  Is life-t hreate ni n g - Refers t o a n e ve nt/reacti o n i n w hic h t he patie nt was at ris k of 
deat h at t he ti me of t he e ve nt/reacti o n.  It d oes n ot refer t o a n e ve nt/reacti o n w hic h 
h y p ot heticall y mi g ht ha ve ca use d deat h if it were m ore se vere. 
•  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. 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y.  
•  Res ults i n a c o n ge nital a n o mal y/ birt h defect.  
•  I m p ortant me dical e ve nts w he n base d u p o n a p pr o priate me dical j u d g me nt, ma y 
je o par dize t he patie nt or s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt 1 of t he o utc o mes liste d i n t his defi niti o n. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
5 8 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 1. 2.  
Rel ati o ns hi p t o I n vesti g ati o n al Pr o d uct  a n d Se veri t y 
T he I n vesti gat or will d oc u me nt her/ his o pi ni o n of t he relati o ns hi p of t he A E t o treat me nt wit h 
t he i n vesti gati o nal pr o d uct usi n g t he criteria o utli ne d i n Ta ble 4 .  A n A E f or w hic h t here is a 
“reas o na ble p ossi bilit y” t hat t he i n vesti gati o nal pr o d uct ca us e d t he A E mea ns t here is e vi de nce 
t o s u g gest a ca usal relati o ns hi p bet wee n t he i n vesti gati o nal pr o d uct a n d t he A E. 
If t he relati o ns hi p bet wee n t he A E/ S A E a n d t he i n vesti gati o nal pr o d uct is deter mi ne d t o be 
“ p ossi ble” or “ pr o ba ble,” t he e ve nt will be c o nsi d ere d t o be relate d t o t he i n vesti gati o nal pr o d uct. 
T a ble  4: 
Rel ati o ns hi p of A d verse E ve nts t o I n vesti g ati o n al Pr o d uct  
Rel ati o ns hi p  
Descri pti o n  
Relate d  
A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h a reas o na ble ti me 
se q ue nce t o a d mi nistrati o n of t he i n vesti gati o nal pr o d uct, u nli kel y t o be attri b ute d 
t o c o nc urre nt disease or ot her dr u gs or c he micals, a n d w hic h f oll o ws a cli nicall y 
reas o na ble res p o nse o n wit h dra wal ( de -c halle n ge); or  
a n e ve nt t hat c o ul d als o be e x plai ne d b y c o nc urre nt disease or ot her dr u gs or 
c he micals w h ere i nf or mati o n o n i n vesti gati o nal pr o d uct wit h dra wal ma y be lac ki n g 
or u nclear.  
Re- c halle n ge or de -c halle n ge i nf or mati o n  is n ot re q uire d t o f ulfill t his defi niti o n. 
N ot Relate d  
A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h s ufficie nt e vi de nce t o 
acce pt t hat t here is n o ca usal relati o ns hi p t o i n vesti gati o nal pr o d uct a d mi nistrati o n 
(e g, n o te m p oral relati o ns hi p t o i n vesti gati o nal pr o d uct a d mi nistrati o n, beca use t he 
i n vesti gati o nal pr o d uct was a d mi nistere d after o nset of e ve nt; i n vesti gati o n s h o ws 
t hat t he dr u g was n ot a d mi nistere d; pr o of of ot her ca use; etc.); or 
a n e ve nt wit h a te m p oral relati o ns hi p t o i n vest i gati o nal pr o d uct a d mi nistrati o n, 
w hic h ma kes a ca usal relati o ns hi p i m pr o ba ble, a n d ot her dr u gs, c he micals or 
u n derl yi n g disease pr o vi de pla usi ble e x pla nati o ns.  
 
A Es m ust be gra de d f or se verit y ( mil d, m o derate, se vere , life-t hreate ni n g, a n d fatal) as define d i n 
Ta ble  5, a n d m ust be e ntere d o n t he A E pa ge of t he e C R F.  It s h o ul d be n ote d t hat t he ter m 
“se vere” use d t o gra de i nte nsit y is n ot s y n o n y m o us wit h t he ter m “seri o us.”  T he assess me nt of 
se verit y is ma de re gar dless of i n vesti gati o nal pr o d uct relati o ns hi p or of t he seri o us ness of t he 
A E .   


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
5 9 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
T a ble  5: 
Se verit y of A d verse E ve nts  
Gr a de  
Cli nic al Descri pti o n of Se verit y  
Mil d  
A n e x perie nce t hat is tra nsie nt  or mil d  a n d re q uires n o me dical  treat me nt 
or i nter ve nti o n.  T he e x perie nce d oes n ot ge nerall y i nterfere wit h us ual 
dail y acti vities.  T his i ncl u des tra nsie nt la b orat or y test alterati o ns.  
M o derate  
N o or mi ni mal me dical i nter ve nti o n/t hera p y re q uire d.  Mil d t o m o de rate 
li mitati o n i n acti vit y – s o me assista nce ma y be nee de d.  I ncl u des 
la b orat or y test alterati o ns i n dicati n g i nj ur y, b ut wit h o ut l o n g-ter m ris k. 
Se vere  
A n e x perie nce t hat re q uires me dical i nter ve nti o n/t hera p y, h os pitalizati o n 
p ossi ble.  Mar ke d li mitati o n  i n acti vit y, s o me assista n ce us uall y re q uire d.  
Life -t hreate ni n g 
Life -t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d. 
Fatal  
Deat h relate d t o A E  
1 1. 3.  
Re p orti n g of A d verse E ve nts a n d Seri o us A d verse E ve nts  
1 1. 3. 1.  
Re p orti n g of A d verse E ve nts  
A E data will be c ollecte d at c o nse nt  u ntil t he patie nt f ull y c o m pletes her/ his st u d y partici pati o n. 
All A Es, w het her belie ve d b y t he I n vesti gat or t o be relate d or u nrelate d t o t he i n vesti gati o nal 
pr o d uct, m ust be d oc u me nte d i n t he patie nt’s me dical rec or ds, i n acc or da nce wit h t he 
I n vesti gat or’s n or mal cli nical practice a n d o n t he A E e C R F.  Eac h A E is t o be e val uate d f or 
d urati o n, i nte nsit y, fre q ue nc y, seri o us ness, o utc o me, ot her acti o ns ta ke n, a n d relati o ns hi p t o t he 
i n vesti gati o nal pr o d uct.     
1 1. 3. 2.  
Re p orti n g of Seri o us A d verse E ve nts  
I n a greei n g t o t he pr o visi o ns of t his pr ot oc ol, t he I n vesti gat or acce pts all le gal res p o nsi bilities f or 
i m me diate re p orti n g of S A Es t o La  J olla.  I m me diate re p orti n g i m plies wit hi n 2 4 h o urs of 
bec o mi n g a ware of t h e occ urre nce of a n S A E.  
S A E data will be c ollecte d starti n g at c o nse nt u ntil t he patie nt f ull y c o m pletes her/ his st u d y 
partici pati o n.  
All S A Es t hat occ ur wit hi n 3 0 da ys f oll o wi n g t he cessati o n of i n vesti gati o nal pr o d uct, re gar dless 
of t he ca usal relati o ns hi p t o t he i n vesti gati o nal pr o d uct, m ust be re p orte d t o La  J olla b y 
f oll o wi n g t he i nstr ucti o ns pr o vi de d i n t his secti o n.  Re dacte d me dical rec or d s o urce 
d oc u me ntati o n will be re q ueste d f or all S A Es a n d e mer ge nc y r o o m visits. 
T he met h o d f or re p orti n g a S A E is b y c o m pleti n g t he A E/ S A E e C R F a n d se n di n g a Seri o us 
A d verse E ve nt Re p ort F or m.  T he Seri o us A d verse E ve nt Re p ort F or m, a n d if a p plica ble, a c o p y 
of re dacte d s o urc e d oc u me nts (s uc h as h os pital disc har ge s u m mar y, me dical rec or ds, etc.) relate d 
t o t he S A E will  be se nt t o:  
•  E- mail t o:   safet y @lj pc.c o m 
•  Or fa x t o:  + 1- 8 5 8- 2 6 3- 1 5 9 3 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
6 0 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
T he I n vesti gat or will assess w het her t he e ve nt is ca usall y relate d t o t he i n vesti gati o nal pr o d uct.  
La  J olla will als o assess w het her t he e ve nt is ca usall y relate d t o t he i n vesti gati o nal pr o d uct, i n 
a d diti o n t o assessi n g t he o verall safet y pr ofile of t he i n vesti gati o nal pr o d uct. 
La  J olla will n otif y t he a p pr o priate re g ulat or y a ut h orities i n acc or da nce wit h c o u ntr y re g ulati o ns. 
F oll o wi n g t he i nitial re p ort, a n y a d diti o nal i nf or mati o n o btai ne d b y t he I n vesti gat or a b o ut t he 
S A E m ust be re p orte d pr o m ptl y t o La  J olla i n t he sa me ma n ner as descri be d a bo ve f or t he i nitial 
S A E re p ort.  
If a n I n vesti gat or bec o mes a ware of a n S A E t hat ma y be attri b uta ble t o t he i n vesti gati o nal 
pr o d uct after t he st u d y is c o m plete d, La  J olla s h o ul d be n otifie d as s o o n as p ossi ble via e mail, 
p h o ne, or fa x at: 
•  E- mail t o:  safet y @lj pc.c o m 
•  P h o ne (see title pa ge f or p h o ne n u m bers)   
•  Or fa x t o:  + 1 - 8 5 8- 2 6 3- 1 5 9 3 
1 1. 4.  
F oll o w -u p of A Es a n d S A Es  
All A Es m ust be f oll o we d d uri n g t he c o urse of t he st u d y u ntil t he A E res ol ves, is n o l o n ger of 
cli nical c o ncer n, has sta bilize d or is ot her wise e x plai ne d, or t he patie nt is l ost t o f oll o w- u p. 
A Es o n g oi n g at t he fi nal f oll o w- u p visit t hat are dee me d t o be “relate d” t o t he i n vesti gati o nal 
pr o d uct or of ot her cli nical si g nifica nce, m ust be f oll o we d f or as l o n g as necessar y t o a de q uatel y 
e val uate t he safet y of t he patie nt or u ntil t he e ve nt sta bilizes, res ol ves, or is n o l o n ger of cli nical 
c o ncer n.  If res ol ve d, a res ol uti o n date f or t he A E s h o ul d be d oc u me nte d i n t he e C R F.  T he 
I n vesti gat or m ust e ns ure t hat f oll o w-u p i ncl u des a n y  s u p ple me ntal i n vesti gati o ns i n dicate d t o 
el uci date t he nat ure a n d/ or ca usalit y of t he A E.  T his ma y i ncl u de a d diti o nal la b orat or y tests or 
i n vesti gati o ns, or c o ns ultati o n wit h ot her healt hcare pr ofessi o nals, as c o nsi dere d cli nicall y 
a p pr o priate b y t he I n v esti gat or. 
1 1. 5.  
Pre g n a nc y a n d F oll o w -u p  
Pre g na ncies are n ot c o nsi dere d A Es i n a n d of t he msel ves; h o we ver, if a fe male st u d y partici pa nt 
bec o mes pre g na nt w hile s he is e nr olle d i n t he cli nical st u d y, or if a male patie nt ma kes his 
part ner pre g na nt w hile he is e nr olle d i n t he cli nical st u d y, t he n t he I n vesti gat or m ust be i nf or me d 
i m me diatel y.  La  J olla m ust be n otifie d wit hi n 2 4 h o urs of t he I n vesti gat or’s lear ni n g of t he 
pre g na nc y b y c o m pleti n g a n d se n di n g t he Pre g na nc y Re p ort F or m t o safet y @lj pc.c o m ( or 
alter nati vel y, fa x t o + 1 ( 8 5 8) 2 6 3- 1 5 9 3). 
C o m pleti n g t he Pre g na nc y Re p ort F or m is n ot a s u bstit ute f or re p orti n g a n A E/ S A E w he n a n 
A E/ S A E has occ urre d.  I n t he sit uati o n w he n a n A E/ S A E has occ urre d, t he A E/ S A E re p orti n g 
pr oce d ures descri be d i n Secti o ns  1 1. 3. 1  a n d 1 1. 3. 2   m ust als o be f oll o we d. 
Fe male patie nts :  T he fe male patie nt m ust disc o nti n ue treat me nt wit h i n vesti gati o nal pr o d uct if 
s he bec o mes pre g na nt.  T he pr o gress of t he pre g na nc y will be f oll o we d b y t he I n vesti gat or u ntil 
t he o utc o me of t he pre g na nc y is k n o w n.  If t he pre g na nc y res ults i n t he birt h of a c hil d, t he 
patie nt a n d ne o nate m ust be f oll o we d f or o utc o me i nf or mati o n a n d/ or as c o nsi dere d a p pr o priate 
b y t he I n vesti gat or a n d La J olla. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
6 1 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
Male patie nts :  T he pr o gress of t he pre g na nc y i n a male patie nt’s part ner s h o ul d be f oll o we d 
u ntil t he o utc o me of t he pre g na nc y is k n o w n.  If t he pre g na nc 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 o utc o me i nf or mati o n ma y be re q ueste d f or t he m ot her a n d ne o nate.  
F oll o w- u p will o nl y be perf or me d t o t he e xte nt per mitte d b y a p plica ble re g ulati o ns a n d pri vac y 
c o nsi derati o ns.  
Refer t o Secti o n  1 0. 1. 6. 5. 1  f or c o ntrace pti o n g ui da nce a n d i nf or mati o n. 
 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
6 2 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 2.  
S T A TI S TI C S  
1 2. 1.  
St atistic al H y p ot hesi s 
It is h y p ot hesize d t hat t h ose treate d wit h LJ P C - 4 0 1 will ha ve a differe nt c ha n ge i n T S A T fr o m 
baseli ne t o Wee k 1 6 p ost d ose 2 4 ( ± 4) h o urs t ha n t h ose treate d wit h place b o. 
N ull H y p ot hesis:    
  
  
µ acti ve = µ place b o 
Alter nati ve H y p ot hesis:     
µacti ve ≠ µplace b o 
w here µ is t he mea n c ha n ge i n T S A T fr o m baseli ne t o Wee k 1 6 p ost d ose 2 4 ( ± 4) h o urs. 
1 2. 2.  
S a m ple Size a n d P o wer C o nsi der ati o ns  
A sa m ple size of 4 8 patie nts has 8 0 % p o wer t o detect a 1 5 % differe nce i n t he c ha n ge i n T S A T 
bet wee n t he place b o ar m a n d t he LJ P C - 4 0 1 ar m, ass u mi n g a c o m m o n sta n dar d de viati o n ( S D) of 
1 8 % a n d a 2-si de d t y pe I err or of 0. 0 5.  T he pri mar y efficac y a nal ysis a n d sec o n dar y efficac y 
a nal yses will i ncl u de t he Efficac y Patie nt P o p ulati o n defi ne d i n Secti o n  1 2. 7  (ie, all patie nts 
e nr olle d u n der gl o bal p r ot oc ol versi o n 4. 0/ U nite d Ki n g d o m ( U K ) pr ot oc ol versi o n 4. 1 or later 
w h o recei ve d st u d y dr u g, a n d w h o  c o m plete d t he Wee k  1 6 assess me nt s or ha d a n o n-st u d y 
p hle b ot o m y after t he sta n dar d of care t hera pe utic p hle b ot o m y o n Da y 1 [ pre d ose ] a n d bef ore 
Wee k 1 6).  Patie nts w h o d o n ot e nr oll u n der gl o bal p r ot oc ol versi o n 4. 0/ U K pr ot oc ol versi o n 4. 1 
or later or disc o nti n ue t he st u d y earl y pri or t o d osi n g will be re place d ( patie nts ma y be re place d 
f or a d diti o nal reas o ns as descri be d i n Secti o n 1 2. 4 ).  T he pla n is t o e nr oll a n d ra n d o mize 
a p pr o xi matel y 6 8 t o 7 6 patie nts ( 1: 1 t o LJ P C- 4 0 1 or place b o) t o e ns ure t hat at least 4 8  patie nts 
are i ncl u de d i n t he pri mar y efficac y a nal ysis . 
Refer t o Secti o n  1 2. 5  f or pla n ne d a nal yses. 
1 2. 3.  
Str atific ati o n a n d R a n d o miz ati o n  
Ce ntral ra n d o mizati o n will be perf or me d  usi n g I X R S.  Eli gi ble patie nts will be ra n d o mize d o n a 
1: 1 sc he d ule t o LJ P C - 4 0 1 or place b o.  Ra n d o mizati o n will be stratifie d b y baseli ne T S A T 
( > 4 5% t o 7 0 % vers us > 7 0 %) a n d p hle b ot o m y fre q ue nc y o ver t he last 1 2 m o nt hs ( 0 t o 3 vers us 
> 3). 
1 2. 4.  
Re pl ace me nt of P atie nts  
Patie nts w h o are ra n d o mize d b ut ter mi nate pri or t o d osi n g will be re place d a n d e xcl u de d fr o m 
t he safet y a n d efficac y a nal yses.  Patie nts w h o ha ve recei ve d st u d y dr u g a n d ter mi nate t he st u d y 
earl y ma y be re place d b y decisi o n of t he I n vesti gat or a n d La J olla.  Patie nts w h o d o n o t e nr oll 
u n der pr ot oc ol versi o n 4. 0/ U K pr ot oc ol versi o n 4. 1 or later will be re place d a n d e xcl u de d fr o m 
efficac y a nal yses.  A p pr o xi matel y 2 0 t o 2 8 patie nts are e x pecte d t o be re place d.  Patie nts w h o 
c o nse nt a n d e nr oll u n der pr ot oc ol versi o n 4. 0/ U K pr ot oc ol versi o n 4. 1 or later will be i ncl u de d i n 
efficac y a nal yses.  All e nr olle d patie nts, re gar dless of pr ot oc ol versi o n, w h o recei ve at least 
1 d ose of st u d y dr u g will be i ncl u de d i n safet y a nal yses.   
Patie nt e nr oll me nt n u m bers are u ni q ue  a n d will n ot be re-assi g ne d.  Patie nts will n ot be 
per mitte d re -ra n d o mizati o n after t he i nitial ra n d o mizati o n f or a n y reas o n.  Patie nts will n ot be 
per mitte d t o re -e nr oll after wit h dra wi n g fr o m t he st u d y f or a n y reas o n. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
6 3 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 2. 5.  
Pl a n ne d A n al yses  
A n i nteri m a nal ysis of efficac y data will be c o n d ucte d after t he first 1 6 patie nts  fr o m t he Efficac y 
Patie nt P o p ulati o n  ( defi ne d i n Secti o n 1 2. 7 ) c o m plete t he Wee k  1 6 assess me nts  or ha ve a n 
o n-st u d y p hle b ot o m y aft er t he sta n dar d of care t hera pe utic p hle b ot o m y o n Da y 1 ( pre d ose) a n d 
bef ore Wee k 1 6.  T he La n  De mets a p pr oac h t o t he O’ Brie n- Fle mi n g met h o d f or se q ue ntial 
desi g ns w ill be a p plie d t o preser ve t he o verall t y pe I err or rate res ulti n g i n t y pe I rates of val ues 
of 0. 0 0 0 2 1 at t he i nteri m a nal ysis ( n = 1 6) a n d 0. 0 4 9 9 at t he fi nal a nal ysis ( n = 4 8).  A n y 
s u bse q ue nt i nteri m a nal yses will si milarl y i ncl u de a dj ust me nt usi n g t he La n Dem ets a p pr oac h t o 
t he O’ Brie n- Fle mi n g met h o d f or se q ue ntial desi g ns.   
T he fi nal a nal yses will be perf or me d after t he statistical a nal ysis pla n (S A P ) is fi nalize d a n d t he 
data base is l oc ke d.  T he details of data q ualit y ass ura nce a n d data base l oc k are pr o vi de d i n S A P . 
I n a d diti o n t o t he i nteri m a nal ysis of efficac y data, a n i nter nal Safet y M o nit ori n g C o m mittee will 
c o n d uct a n i nitial safet y re vie w si m u lta ne o usl y wit h t he i nteri m efficac y a nal ysis; a d diti o nal 
safet y re vie ws will be c o n d ucte d t hereafter.  Details, s uc h as me m bers hi p of t he c o m mittee, will 
be disc usse d i n t he Safet y M o nit ori n g C o m mittee  C harter.  
M o dificati o ns t o t he pla n ne d statistical a na l yses s h o ul d be mi ni mize d.  H o we ver, t he data 
o btai ne d fr o m t he st u d y ma y i n dicate t hat t he pla n ne d a nal yses are i na p pr o priate or t hat 
a d diti o nal a nal yses nee d t o be perf or me d d ue t o fact ors s uc h as t he distri b uti o n of t he data or t he 
prese nce of i m p orta nt c o variates.  A n y de viati o ns fr o m t he pla n ne d statistical a nal yses will be 
re p orte d i n t he cli nical st u d y re p ort. 
1 2. 6.  
A n al ysis P ar a meters  
1 2. 6. 1.  
E n d p oi nts  
1 2. 6. 1. 1.  Pri m ar y Effic ac y E n d p oi nt  
T he pri mar y efficac y e n d p oi nt is c ha n ge i n T S A T, defi ne d as f oll o ws: 
•  F or patie nts wit h  1 p hle b ot o m y (t he sta n dar d of care t hera pe utic p hle b ot o m y o n 
Da y  1 [ pre d ose]), c ha n ge i n T S A T fr o m baseli ne t o Wee k 1 6 ( 2 4 [ ± 4] h o urs 
p ost d ose). 
•  F or patie nts u n der g oi n g 2 or m ore p hle b ot o mies, c ha n ge i n T S A T fr o m baseli ne t o 
t he m ost rece nt p ost d ose fasti n g T S A T o bser ve d pri or t o t he sec o n d p hle b ot o m y. 
1 2. 6. 1. 2.  Sec o n d ar y Effic ac y E n d p oi nts  
T he sec o n dar y e n d p oi nts t o be e val uate d i ncl u de: 
•  N u m ber of p hle b ot o m ies fr o m Da y 2 t o E O S . 
•  C ha n ge i n ser u m ferriti n, defi ne d as f oll o ws: 
− F or patie nts wit h 1 p hle b ot o m y (t he sta n dar d of care t hera pe utic p hle b ot o m y o n 
Da y 1 [ pre d ose]) , c ha n ge i n ser u m ferriti n fr o m baseli ne t o Wee k 1 6 
( 2 4 ± 4] h o urs p ost d ose). 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
6 4 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
− F or patie nts u n der g oi n g 2 or m ore p hle b ot o m ies, c ha n ge i n ser u m ferriti n fr o m 
basel i ne t o t he m ost rece nt p ost d ose ser u m ferriti n o bser ve d pri or t o t he sec o n d 
p hle b ot o m y. 
1 2. 6. 1. 3.  S afet y a n d T oler a bilit y E n d p oi nts  
T he safet y a n d t olera bilit y e n d p oi nts t o be e val uate d i ncl u de: 
•  A d verse E ve nts fr o m c o nse nt t o E O S. 
•  C ha n ges i n cli nical la b orat or y e val uati o ns i ncl u di n g ser u m ir o n para meters fr o m 
baseli ne t o E O S . 
•  C ha n ges i n vital si g ns, electr ocar di o gra ms ( E C Gs), use of c o nc o mita nt me dicati o ns, 
a n d p h ysical e xa mi nati o ns fr o m baseli ne t o E O S. 
•  I m m u n o ge nicit y (a nti- dr u g a nti b o d y)/ P K baseli ne t o E O S. 
1 2. 6. 1. 4.  E x pl or a t or y E n d p oi nts 
T he e x pl orat or y e n d p oi nts t o be e val uate d i ncl u de: 
•  C ha n ge i n ser u m ir o n para meters , defi ne d as f oll o ws: 
− F or patie nts wit h 1 p hle b ot o m y (t he sta n dar d of care t hera pe utic p hle b ot o m y o n 
Da y 1 [ pre d ose]), c ha n ge i n ser u m ir o n para meters fr o m baseli ne t o Wee k 1 6 
( 2 4 [ ± 4] h o urs p ost d ose). 
− F or patie nts u n der g oi n g 2 or m ore p hle b ot o m ies, c ha n ge i n ser u m ir o n para meters 
fr o m baseli ne t o t he m ost rece nt p ost d ose ser u m ir o n para meters o bser ve d pri or t o 
t he sec o n d p hle b ot o m y. 
− F or patie nts wit h 1 p hle b ot o m y (t he sta n dar d of care t hera pe utic p hle b ot o m y o n 
Da y  1 [ pre d ose]), c ha n ge i n ser u m ir o n para meters fr o m baseli ne t o Wee k 1 7 
(a p pr o xi matel y 7 da ys after t he last d ose of st u d y dr u g). 
− F or patie nts u n der g oi n g 2 or m ore p hle b ot o m ies, c ha n ge i n ser u m ir o n para meters 
fr o m baseli ne t o t he m ost rece nt pre d ose ser u m ir o n para meters o bser ve d pri or t o 
t he sec o n d p hle b ot o m y. 
•  C ha n g e i n t h yr oi d f u ncti o n fr o m baseli ne t o Wee k 1 6. 
•  C ha n ge i n li ver f u ncti o n fr om baseli ne t o Wee k 1 6 . 
•  C ha n ge i n he m o gl o bi n A 1 c fr o m baseli ne t o Wee k 1 6 . 
•  C ha n ge i n R B C para met ers i ncl u di n g he m o gl o bi n c o nce ntrati o n , R B C c o u nt, a n d 
R D W  defi ne d as f oll o ws: 
− F or patie nts wit h 1 p hle b ot o m y (t he sta n dar d of care t hera pe utic p hle b ot o m y o n 
Da y  1 [ pre d ose]), c ha n ge i n R B C para meters fr o m baseli ne t o 
Wee k  1 6 ( 2 4 [ ± 4] h o urs p ost d ose). 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
6 5 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
− F or patie nts u n der g oi n g 2 or m ore p hle b ot o mies, c ha n ge i n R B C para meters fr o m 
baseli ne t o t he m ost rece nt p ost d ose R B C para meters o bser ve d pri or t o t he sec o n d 
p hle b ot o m y. 
•  C ha n ge i n Q ualit y of Life Q uesti o n naire s, (S F -3 6 v 2) , W O M A C, a n d m o difie d 
Dreisler i n dices f or art hritis,  fr o m baseli ne  t o Wee k 1 6. 
1 2. 6. 2.  
Defi niti o n of S u b gr o u ps  
T he f oll o wi n g s u b gr o u ps are c o nsi dere d of i nterest t o c o m parati vel y e x pl ore t he treat me nt effect: 
•  A ge  cate g or y :  < 6 5 years vers us ≥ 6 5 years 
•  Se x :  male vers us fe male 
•  Et h nic it y:  His pa nic or Lati n o, N ot His pa nic or Lati n o  
•  C o u ntr y:  U nite d States of A merica, A ustralia, U nite d Ki n g d o m, a n d Fra nce ( ma y be 
c olla pse d pri or t o data freeze)  
•  Ge o gra p hic re gi o ns : (t o be deter mi ne d base d o n e nr olli n g c o u ntries) 
•  Race:  W hite  vers us n o n-W hite  
•  B o d y mass i n de x ( B MI):  < 3 0 k g/ m 2; ≥ 3 0 k g/ m2 (B MI = wei g ht( k g)/ hei g ht( m) 2) 
•  P hle b ot o m y fre q ue nc y o ver t he last 1 2 m o nt hs:  0 t o 3 vers us > 3 
•  Baseli ne T S A T:   > 4 5 % t o 7 0 % vers us > 7 0 % 
•  Basel i ne he pci di n le vels:  < me dia n vers us ≥ me dia n 
•  Baseli ne ser u m ir o n le vels:  < me dia n vers us ≥ me dia n 
•  Baseli ne ser u m ferriti n le vels:  < me dia n vers us ≥ me dia n  
Baseli ne is c o nsi dere d t he last bl o o d sa m ple c ollecti o n pri or t o t he re q uire d p hle b ot o m y of 
Da y  1. 
1 2. 7.  
A n al ysis P o p ul ati o n  
A nal ysis p o p ulati o ns are as f oll o ws:  
•  I nte nt t o Treat (I T T) P o p ulati o n:  all ra n d o mize d patie nts, as ra n d o mize d. 
•  M o difie d I nte nt t o Treat ( mI T T) P o p ulati o n:  e nr olle d patie nts , as ra n d o mize d, w h o 
recei ve d at least 1 d ose of st u d y dr u g. 
•  Efficac y P o p ulati o n :  e nr olle d patie nts  u n der gl o bal p r ot oc ol versi o n 4. 0/U K pr ot oc ol 
versi o n 4. 1 or later , as ra n d o mize d, w h o recei ve d st u d y dr u g, a n d w h o c o m plete d 
4 m o nt hs ( Wee k 1 6) o n st u d y or w h o ha d at least 1 p hle b ot o m y after t he sta n dar d of 
care t hera pe utic p hle b ot o m y o n Da y 1 ( pre d ose) a n d bef ore Wee k 1 6. 
•  Per Pr ot oc ol P o p ulati o n ( P P):  Efficac y patie nts, wit h o ut a n y i m p orta nt pr ot oc ol 
de viati o ns. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
6 6 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
•  Safet y P o p ulati o n:  e nr olle d patie nts, as treate d, w h o recei ve d at least 1 d ose of st u d y 
dr u g. 
•  P K P o p ulati o n:  e nr olle d patie nts , as treate d, w h o recei ve at least 1 d ose of st u d y dr u g 
a n d f or w h o m at least 1 P K para meter ca n be esti mate d . 
1 2. 8.  
St atistic al Met h o ds  
C o nti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics, i ncl u di n g t he n u m ber of 
o bser vati o ns, mea n, S D , mi ni m u m, me dia n, a n d ma xi m u m val ues.  Ot her descri pti ve statistics 
s uc h as l o wer q uartile, u p per q uartile, ge o metric mea n, a n d ge o metric S D ma y be calc ulate d if 
a p pr o priate .  Cate g orical ( q ualitati ve) varia bles will be s u m marize d b y t he  n u m ber of 
o bser vati o ns a n d perce nta ges.   U nless ot her wise state d, t he calc ulati o n of pr o p orti o ns will be 
base d o n t he sa m ple size of t he p o p ulati o n of i ntere st. 
Data will be s u m marize d b y treat me nt gr o u p, st u d y visit, a n d if a p pr o priate, st u d y i nter val.  
Statistical c o m paris o ns of differe nces bet wee n treat me nt ar ms will be ma de usi n g Wilc o x o n 
ra n k-s u m tests, mi xe d effects re peate d meas ures, a n d/or a nal ysis of varia nce ( A N O V A ) f or 
c o nti n u o us or or di nal varia bles, C hi- S q uare or C oc hra n- Ma ntel -Hae nszel tests f or cate g orical  
varia bles, Fis her’s e xact tests f or bi nar y varia bles , a n d P oiss o n re gressi o n m o del f or c o u nt data 
(e g, n u m ber of p hle b ot o mies). 
All statistical tests will be d o ne at t he 2- si de d, 5 % si g nifica nce le vel, u nless ot her wise s pecifie d.  
T he ass u m pti o ns u n derl yi n g t he statistical tests a p plie d will be e val uate d f or a p pr o priate ness (ie, 
sa m ple distri b uti o n, paire d or c orrelate d data, e q ualit y of varia nces).  C o nfi de nce i nter vals will 
be d o ne at 9 5 %, u nless ot her wise s pecifie d.  
All a nal yses will be perf or me d usi n g S A S, Versi o n 9. 4 or later ( S A S I nstit ute, Car y, N C).  
Gra p hic dis pla ys ma y be pr o d uce d usi n g S A S, S- Pl us or R, Versi o n 3. 1. 1  or later ( R F o u n dati o n 
f or Statistical C o m p uti n g, Vie n na, A ustria). 
A c o m plete descri pti o n of statistical c o nsi derati o ns will be pr o vi de d i n a se parate S A P . 
1 2. 8. 1.  
P atie nt  Dis p ositi o n, De m o gr a p hic, a n d B ac k gr o u n d C h ar acteristics  
Patie nt  dis p ositi o n will be s u m mari ze d b y treat me nt gr o u p as f oll o ws: 
•  N u m ber of patie nt s e nr olle d i n t he st u d y 
•  N u m ber of patie nt s i n eac h a nal ysis p o p ulati o n  
•  Treat me nt i nitiate d? ( yes or n o)  
•  Last visit c o m plete d  
•  Last st u d y da y c o m plete d  
•  Di d t he patie nt c o m plete treat me nt? ( yes or n o) 
− If n o, pri mar y reas o n f or disc o nti n uati o n of treat me nt 
•  Patie nt ali ve at E n d of Treat me nt? ( yes or n o) 
•  Was Da y 3 0 f oll o w- u p c o n d ucte d? ( yes or n o) 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
6 7 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
•  Di d t he patie nt c o m plete t he st u d y? ( yes or n o) 
− If n o, pri mar y reas o n f or st u d y disc o nti n uati o n 
•  Patie nt ali ve at E O S visit? ( yes or n o)  
De m o gra p hics a n d baseli ne c haracteristics will be s u m marize d descri pti ve l y b y treat me nt gr o u p 
as f oll o ws: 
•  A ge cate g or y ( < 6 5 years, ≥ 6 5 years) a n d a ge ( years) 
•  Se x  ( male, fe male) 
•  C hil d beari n g p ote ntial ( yes , n o) 
•  Et h nicit y ( His pa nic or Lati n o, N ot His pa nic or Lati n o) 
•  Race ( A merica n I n dia n or Alas ka Nati ve, Asia n, Blac k or Africa n A merica n, Nati ve 
Ha waiia n or Ot her Pacific Isla n der, W hite, Ot her ; a n d W hite or N o n-W hite ) 
•  Ge o gra p hic re gi o n of ori gi n (t o be deter mi ne d base d o n e nr olli n g c o u ntries) 
•  Ge n ot y pe (if a vaila ble) 
•  Baseli ne hei g ht (c m)  
•  Baseli ne wei g ht ( k g)  
•  Baseli ne B MI  cate g or y ( < 3 0 k g/ m2, ≥ 3 0 k g/ m2) a n d B MI  ( k g/ m2) 
•  Baseli ne T S A T  
•  Baseli ne p hle b ot o m y fre q ue nc y o ver t he last 1 2 m o nt hs 
Refer t o t he S A P f or de m o gra p hic s u m mar y statistical met h o ds.  
1 2. 8. 2.  
Me dic al Hist or y  
Me dical hist or y will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Affairs ( Me d D R A) 
m ost rece nt versi o n a n d gr o u pe d b y s yste m or ga n class ( S O C) a n d P T.  T he c o de d ter ms will be 
s u m marize d b y treat me nt gr o u p, S O C, a n d P T i n al p ha betical or der as t he n u m ber of 
c o n diti o ns/e ve nts a n d t he n u m ber a n d perce nta ge of patie nt s wit h a c o n diti o n or e x perie nci n g a n 
e ve nt 1 or m ore ti mes.  
I n a d diti o n, s u m maries of me dical hist or y ma y be re peate d f or m ost freq ue nt me dical hist or y 
w here “ m ost fre q ue nt” is defi ne d as a me dical e ve nt occ urri n g i n > X % of t he sa m ple i n eit her 
treat me nt ar m, w here X % will be deter mi ne d fr o m t he data. 
1 2. 8. 3.  
Pri or a n d C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures  
Pri or a n d c o nc o mita nt me dicati o ns will be s u m marize d se paratel y.  Pri or me dicati o ns are t h ose 
wit h a start date be gi n ni n g 1 4 da ys pri or t o Scree ni n g .  C o nc o mita nt me dicati o ns are me dicati o ns 
t hat are ta ke n a n y ti me w hile o n st u d y ( o n or after first st u d y dr u g a d mi nistrati o n). 
Pri or a n d c o nc o mita nt me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n Dr u g 
Dicti o nar y ( W H O -D D) m ost rece nt versi o n a n d gr o u pe d b y A nat o mical T hera pe utic C he mical 
( A T C) a n d P T.  T he c o de d me dicati o ns will be s u m marize d b y treat me nt gr o u p, A T C, a n d P T i n 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
6 8 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
al p ha betical or der as t he n u m ber of me dicati o ns a n d t he n u m ber a n d perce nta ge of patie nt s 
recei vi n g me dicati o n 1 or m ore ti mes.  
Pri or p hle b ot o m y pr oce d ures ( n u m ber recei ve d d uri n g t he 1 2 m o nt hs pri or t o ra n d o mizati o n) a n d 
c o nc o mita nt p hle b ot o m y pr oce d ures ( n u m ber recei ve d o n st u d y) will be s u m marize d b y 
treat me nt gr o u p usi n g descri pti ve statistics . 
1 2. 8. 4.  
Effic ac y A n al yses 
1 2. 8. 4. 1.  Pri m ar y E n d p oi nt A n al yses ( P ost d ose T S A T)  
T he pri mar y e n d p oi nt will be a nal yze d usi n g a ge neral li near m o del wit h a dj ust me nt f or baseli ne 
T S A T ( > 4 5 % t o 7 0 % vers us > 7 0 %) a n d p hle b ot o m y fre q ue nc y o ver t he last 1 2 m o nt hs ( 0 t o 3 
vers us >  3) .  A 2-taile d al p ha of 0. 0 5 ( 1-si de d al p ha of 0. 0 2 5) will be use d i n testi n g t he 
h y p ot hesis of treat me nt differe nce  wit h a dj ust me nts, as a p pr o priate, f or i nteri m a nal yses . 
I n a d diti o n, T S A T will be s u m marize d b y treat me nt gr o u p a n d visit, a n d b y l o west p ost baseli ne 
val ue, hi g hest p ost baseli ne val ue, a n d last p ost baseli ne visit.  T he c ha n ge fr o m baseli ne a n d 
perce nt c ha n ge fr o m baseli ne will be s u m marize d i n a si milar ma n ner.  
T S A T a n d c ha n ge fr o m baseli ne i n T S A T will be pl otte d b y treat me nt a n d visit o n a li near scale. 
1 2. 8. 4. 1. 1.  Se nsiti vit y A n al ysis of Pri m ar y Effic ac y A n al ysis  
T he prese nce of a site effect a n d site b y treat me nt i nteracti o n will be e xa mi ne d usi n g a ge neral 
li near m o del wit h a dj ust me nt f or site a n d site b y treat me nt i nteracti o n.  Al p ha of 0. 1 5 will be 
use d f or testi n g of site effects.  Selecti o n of sites f or t he m o delli n g will be c o n d ucte d after 
e nr oll me nt has bee n  c o m plete d.  
S u b gr o u p a nal yses will be c o n d ucte d usi n g a ge neral li near m o del wit h a dj ust me nts f or 
treat me nt, s u b gr o u p, a n d s u b gr o u ps b y treat me nt i nteracti o n.   
M ulti variate a nal ysis ma y be perf or me d utilizi n g t he s u b gr o u ps of i nterest defi ne d i n 
Secti o n  1 2. 6. 2 .  Detail will be pr o vi de d i n t he statistical a nal ysis pla n.  
A se nsiti vit y a nal ysis of T S A T will be c o n d ucte d o n t he mI T T P o p ulati o n.  Detail will be 
pr o vi de d i n t he statistical a nal ysis pla n . 
E x pl orat or y  a nal yses of pre d ose T S A T will be perf or me d usi n g t he para meters descri be d a b o ve. 
1 2. 8. 4. 2.  Sec o n d ar y Effic ac y E n d p oi nt A n al yses 
C ha n ge i n ser u m ferriti n fr o m baseli ne t o eac h wee kl y p ost d ose visit a n d eac h wee kl y pre d ose 
visit  will be a nal yze d usi n g a ge neral li near m o del wit h a dj ust me nt f or baseli ne T S A T ( > 4 5 % t o 
7 0 % vers us > 7 0 %) a n d fre q ue nc y of p hle b ot o m y pr oce d ure o ver t he last 1 2 m o nt hs ( 0 t o 3 
vers us > 3) .  A se nsiti vit y a nal ysis of c ha n ge ser u m ferriti n fro m baseli ne t o eac h wee kl y 
p ost d ose visit a n d eac h wee kl y pre d ose visit  will be c o n d ucte d o n t he mI T T P o p ulati o n.  Patie nts 
n ot c o m pleti n g Wee k 1 6 or Wee k 1 7 f or t he p ost d ose a n d pre d ose a nal yses will be i ncl u de d i n 
t he a nal ysis mi xe d effects re peate d meas ures a nal ysis wit h a dj ust me nt s f or baseli ne T S A T 
( > 4 5 % t o 7 0 % vers us > 7 0 %) a n d fre q ue nc y of p hle b ot o m y pr oce d ure (0 t o 3 vers us > 3). 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
6 9 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
P hle b ot o m y criteria will be base d o n T S A T criteria of t he I DI g ui deli nes.  Criteria f or recei vi n g a 
p hle b ot o m y will be assesse d after t he res ults of eac h fasti n g T S A T assess me nt at p ost d ose 
( 2 4 [ ± 4] h o urs) o n Wee ks 4 ( Da y 2 3), 8 ( Da y 5 1), 1 2 ( Da y 7 9), a n d 1 6 ( Da y 1 0 7) are k n o w n. 
N u m ber of p hle b ot o mies  is defi ne d as: 
a. n u m ber of p hle b ot o mies fr o m Da y 2 t o E O S, or 
b.  n u m ber of p hle b ot o mies fr o m Da y 2 t o E O S + 1  (if, t hr o u g h t he Wee k 1 6 assess me nt, 
n o p hle b ot o m y has bee n a d mi nistere d si nce t he last o bser ve d fasti n g T S A T a n d t he 
last o bser ve d fasti n g T S A T is > 4 5 %). 
N u m ber of ti mes a p atie nt met criteri a f or a p hle b ot o m y  is defi ne d as n u m ber of ti mes fr o m 
Da y  2 t o E O S t hat 1 of t he f oll o wi n g c o n diti o ns is met: 
a. Patie nt recei ve d a p hle b ot o m y. 
b.  Patie nt ha d a fasti n g T S A T >  4 5 %, b ut t he patie nt ref use d/ misse d a p hle b ot o m y, or 
t he treati n g p h ysicia n deci de d a gai nst a p hle b ot o m y.  W het her a patie nt meets t he 
criteria f or a p hle b ot o m y ( yes or n o) will be assesse d after t he res ults of eac h fasti n g 
T S A T rec or de d at p ost d ose 2 4 ( ± 4) h o urs o n Wee ks ( Da y 2 3), 8 ( Da y 5 1), 1 2 ( 7 9), 
a n d 1 6 ( Da y 1 0 7) are k n o w n. 
T he prese nce of a n y  p hle b ot o m y will be a nal yze d b y a C oc hra n- Ma ntel- Hae nszel test wit h 
a dj ust me nt f or baseli ne T S A T a n d p hle b ot o m y fre q ue nc y o ver t he last 1 2 m o nt hs.  T he 
fre q ue nc y of p hle b ot o mies will be a nal yze d b y P oiss o n re gressi o n m o del wit h baseli ne T S A T 
a n d p hle b ot o m y fre q ue nc y o ver t he last 1 2 m o nt hs a n d will offset t o acc o u nt f or ti me at ris k . 
Se nsiti vit y a nal yses of t he n u m ber of p hle b ot o m ies will be c o n d ucte d as f oll o ws: 
•  Usi n g t he mI T T P o p ulati o n, a n a nal ysis i ncl u di n g patie nts n ot c o m pleti n g Wee k 1 6 
will be c o n d uct e d o n t he fre q ue nc y of ti mes a patie nt met criteria f or a p hle b ot o m y .  
F or t hese data , t he P oiss o n re gressi o n m o del a n d C oc hra n-Ma ntel -Hae nszel test as 
defi ne d a b o ve will be re peate d.  T o acc o u nt f or ti me at ris k, t he offset para meter will 
be use d i n t he P oiss o n re gressi o n m o del.  F or t he C oc hra n- Ma ntel -Hae nszel test, 
patie nt s w h o d o n ot c o m plete Wee k 1 6 will be cate g orize d as e x perie nci n g a 
p hle b ot o m y ( yes or n o) base d o n t heir a vaila ble data.  
•  I m pact of s u b gr o u ps of i nterest (i ncl u di n g site) will be a nal yze d b y P oiss o n 
re gressi o n wit h ter ms f or treat me nt s u b gr o u p a n d treat me nt b y s u b gr o u p i nteracti o n. 
•  A m ulti variate l o gistic re gressi o n will be perf or me d o n patie nts recei vi n g at least 
1 p hle b ot o m y ( yes or n o) utilizi n g t he s u b gr o u ps of i nterest defi ne d i n Secti o n  1 2. 6. 2 .  
Detail will be pr o vi de d i n t he S A P.  
T he n u m ber of ti mes a patie nt met c riteria f or p hle b ot o m y will be a nal yze d is a si milar ma n ner 
as descri be d a b o ve.  
1 2. 8. 4. 3.  E x pl or at or y E n d p oi nt A n al yses 
S er u m ir o n  para meters (ser u m ir o n, tra nsferri n, ferritin, a p oferriti n, h ol oferriti n,  UI B C, TI B C)  
will be a nal yze d b y eac h p ost d ose visit a n d eac h pre d ose visit  usi n g a ge neral li near  m o del wit h 
a dj ust me nt f or baseli ne T S A T  ( > 4 5 % t o 7 0 % vers us > 7 0 %) a n d fre q ue nc y of p hle b ot o m y 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
7 0 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
pr oce d ure o ver t he last 1 2 m o nt hs  ( 0 t o 3 vers us > 3).  Se nsiti vit y a nal ysis will be c o n d ucte d o n 
t he mI T T p o p ulati o n. 
T h yr oi d f u ncti o n ( T 3, T 4, T S H, a n d free T 4), li ver f u ncti o n (al b u mi n, al kali ne p h os p hatase, 
A L T, A S T, bilir u bi n [t otal, direct , a n d i n direct], L D H, a n d t otal pr otei n) , gl yce mic c o ntr ol, a n d 
R B C para meters ( he m o gl o bi n c o nce ntrati o n, R B C c o u nt, a n d R D W) will be  a nal yze d usi n g a 
ge neral li near m o del wit h a dj ust me nt f or baseli ne T S A T ( %) ( > 4 5 % t o 7 0 % vers us > 7 0 %) a n d 
fre q ue nc y of p hle b ot o m y pr oce d ure o ver t he last 1 2 m o nt hs  ( 0 t o 3 vers us > 3).  If warra nte d , a 
l og tra nsf or mati o n ma y be a p plie d t o data. 
T otal S F - 3 6 v 2, W O M A C, a n d m o difie d Dreisler i n dices f or art hritis  sc ores will be calc ulate d 
acc or di n g t o t he a ut h ors’ i nstr ucti o ns.  T he t otal sc ore as well as t he 8 s u bscales will be a nal yze d 
as e x pl orat or y varia bl es.  F or t he t otal sc ore of eac h s u bscale, c ha n ge fr o m baseli ne t o Wee k 1 6 
will be calc ulate d a n d t he n a nal yze d usi n g a ge neral li near m o del wit h a dj ust me nt f or baseli ne 
T S A T ( %) ( >  4 5 % t o 7 0 % vers us > 7 0 %) a n d fre q ue nc y of p hle b ot o m y pr oce d ure (0 t o 3 vers us 
> 3). 
1 2. 8. 5.  
S afet y A n al ysis 
1 2. 8. 5. 1.  A d verse E ve nts  
T E A Es are t h ose A Es t hat occ ur or w orse n o n or after t he first st u d y dr u g a d mi nistrati o n t hr o u g h 
E O S, 3 0 ( + 3 da ys) da ys after last d ose of st u d y dr u g. 
T E A Es will be c o de d usi n g t he m ost rece nt versi o n of Me d D R A a n d gr o u pe d b y s yste m or ga n 
class ( S O C ) a n d preferre d ter m ( P T ).  T he c o de d ter ms will be s u m marize d b y treat me nt gr o u p, 
S O C, a n d P T i n al p ha betical or der as t he n u m ber of e ve nts a n d t he n u m ber a n d perce nta ge of 
patie nts e x perie nci n g a n e ve nt 1 or m ore ti m es. 
T E A Es will be gra de d f or se verit y usi n g mil d, m o derate , se vere, life-t hreate ni n g, a n d fatal 
(Ta ble  5).  Se verit y, relate d ness, a n d seri o us ness of A Es will be s u m marize d.  A Es lea di n g t o 
disc o nti n uati o n of st u d y dr u g a n d A Es lea di n g t o deat h will be s u m marize d if a p plica ble.  If t he 
relati o ns hi p t o st u d y dr u g is missi n g, t he T E A E will be classifie d as relate d.  I n t he case of m ore 
t ha n 1 occ urre nce o f a T E A E f or a gi ve n patie nt, b y-patie nt a nal yses will i ncl u de t he ma xi m u m 
relati o ns hi p t o st u d y dr u g a n d t he ma xi m u m se verit y of t h ose T E A Es.  
A d verse e ve nts of s pecial i nterest ma y be defi ne d b y La J olla t o s u p p ort t he c haracterizati o n of 
t he safet y pr ofile of LJ P C- 4 0 1 acr oss S O Cs a n d/ or P Ts.  T hese e ve nts ma y be defi ne d d uri n g t he 
o n g oi n g cli nical de vel o p me nt of LJ P C- 4 0 1. 
1 2. 8. 5. 1. 1.  De at hs  
Deat hs will be s u m mari ze d b y treat me nt ar m a n d ca use of deat h.  A listi n g of fatal A Es will be 
pr o vi de d a n d s u m marize d b y S O C a n d P T.  Deat hs d ue t o A E c o nsi dere d relate d t o st u d y dr u g 
will be disc usse d.  
1 2. 8. 5. 1. 2.  I njecti o n Site Re acti o n 
I njecti o n site reacti o n will be s u m marize d b y treat me nt gr o u p a n d visit.  S u m maries will c o ntai n 
t he n u m ber a n d perce nta ge of patie nts e x perie nci n g a reacti o n 1 or m ore ti mes. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
7 1 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 2. 8. 5. 2.  St u d y Dr u g E x p os ure  
T he t otal d ose a d mi nistere d , t he t otal n u m ber of i njecti o ns per wee k, a n d t he a vera ge n u m ber of 
i njectio ns per wee k  will be s u m mari ze d b y treat me nt gr o u p. 
1 2. 8. 5. 3.  Cli nic al L a b or at or y D at a 
Cli nical la b orat or y data ( he mat ol o g y, ser u m c he mistr y, ot her cli nical tests, a n d uri nal ysis) 
o btai ne d fr o m l ocal la b orat ories will be c o n verte d t o S ysté me I nter nati o nal ( SI) u nits  a n d/ or 
U nite d States c o n ve nti o nal u nits.  La b orat or y res ults will be classifie d as l o w, n or mal, a n d hi g h 
de pe n de nt o n t he refere nce ra n ges of t he l ocal la b orat or y.  Cli nicall y si g nifica nt la b orat or y 
a b n or malities t hat res ult i n treat me nt m o dificati o n a n d/ or re q uire i nter ve nti o n will be rec or de d as 
A Es per Secti o n  1 1. 1 . 
La b orat or y res ults will be s u m marize d b y treat me nt gr o u p a n d visit, l o west p ost baseli ne gra de, 
hi g hest p ost baseli ne gra de, a n d last p ost baseli ne visit.  T he c ha n ge fr o m baseli ne a n d perce nt 
c ha n ge fr o m baseli ne will als o be s u m marize d.  S hifts fr o m t he baseli ne val ue t o eac h visit, 
l o west p ost baseli ne gra de, hi g hest p ost baseli ne gra de, a n d last p ost baseli ne visit ma y be 
dis pla ye d. 
1 2. 8. 5. 4.  I m m u n o ge nicit y/ P h ar m ac o ki netics 
I m m u n o ge nicit y/ P K will be s u m mari ze d b y visit a n d ti me p oi nt (e g, Wee k 1 a n d Wee k 1 6 
re q uire pre d ose bl o o d sa m ple c ollecti o n a n d a n a d diti o nal bl o o d sa m ple c ollecti o n p ost dose 
1 h o ur or later).  Fasti n g is n ot re q uire d f or i m m u n o ge nicit y/ P K bl o o d c ollecti o ns. 
I m m u n o ge nicit y (a nti b o d y titer, base d o n scree ni n g c ut p oi nt) will be s u m marize d b y treat me nt 
gr o u p a n d visit.  At eac h assess me nt, p ote ntiall y p ositi ve res ults ( base d o n t he scree ni n g assa y ) 
will be f oll o we d b y s u bse q ue nt c o nfir mat or y assa ys, w h ere t he titer will be assi g ne d.  
T he relati o ns hi p bet wee n dr u g c o nce ntrati o n a n d i m m u n o ge nicit y (if a nti- dr u g a nti b o dies or 
ne utralizi n g a nti b o d ies de vel o p) will be assesse d. 
A va l ue of zer o will be s u bstit ute d f or all dr u g c o nce ntrati o ns bel o w t he l o wer li mit of 
q ua ntificati o n.  
1 2. 8. 5. 5.  P h ysic al E x a m 
P h ysical e xa m fi n di n gs will be re p orte d i n patie nt listi n gs. 
1 2. 8. 5. 6.  Vit al Si g ns  
Vital si g ns (s yst olic bl o o d press ure, diast olic bl o o d press ure, heart rate, res pirati o n rate, a n d 
b o d y te m perat ure) will be s u m marize d b y treat me nt gr o u p a n d visit.  T he c ha n ge fr o m baseli ne 
will als o be s u m marize d.  
1 2. 8. 5. 7.  Electr oc ar di o gr a m  
C orrecte d Q T i nter vals  will be calc ulate d usi n g t he Q T i nter val a n d heart rate.  Q Tc B will be 
deri ve d b y Bazett’s f or m ula a n d Q Tc F will be deri ve d b y Fri dericia’s f or m ula as f oll o ws: 
Q Tc B = Q T / ( 6 0/ H R) 1/ 2 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
7 2 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
Q Tc F = Q T / ( 6 0/ H R) 1/ 3 
Q Tc B a n d Q Tc F val ues will be classifie d as f oll o ws:  
•  ≤ 4 5 0 msec 
•  > 4 5 0 msec t o ≤ 4 8 0 msec 
•  > 4 8 0 msec t o ≤ 5 0 0 msec 
•  > 5 0 0 msec 
Q Tc B a n d Q Tc F c ha n ge fr o m baseli ne will be classifie d as f oll o ws:  
•  ≤ 3 0 msec 
•  > 3 0 msec t o ≤ 6 0 msec 
•  > 6 0 msec  
Electr ocar di o gra m ( heart rate, P R i nter val, Q R S i nter val, Q T i nter val, Q Tc B i nter val, a n d Q Tc F 
i nter val) will be s u m marize d b y treat me nt gr o u p a n d visit.  T he c ha n ge fr o m baseli ne will als o 
be s u m mari ze d.  
1 2. 8. 6.  
Missi n g V al ues a n d Criteri a f or D at a E xcl usi o ns  
Missi n g val ues will n ot be esti mate d u nless s pecifie d i n t he S A P .  All data will be i ncl u de d i n 
safet y a nal ysis. 
I nc o m plete dates fr o m me dical hist or y, A E , a n d c o nc o mita nt me dicati o n l o gs will be i m p ute d t o 
calc ulate t he st u d y da y a n d d urati o ns as f oll o ws: 
•  Start/ O nset Date:  If missi n g da y a n d/ or m o nt h, t he da y will be re place d wit h  t he 1st 
of t he m o nt h a n d t he m o nt h will be re place d wit h  Ja n uar y.  F or A Es, if t he i m p ute d 
date res ults i n a date bef ore t he date of first st u d y dr u g a d mi nistrati o n, t he n t he date 
of first st u d y dr u g a d mi nistrati o n will be use d , u nless m o nt h is k n o w n a n d is pri or t o 
t he d osi n g m o nt h, i n w hic h case t he i m p ute d date will be use d. 
•  E n d/ Res ol uti o n Date:  If missi n g da y a n d/ or m o nt h, t he da y will be re place d b y t he 
last da y of t he m o nt h a n d t he m o nt h will be re place d wit h  Dece m ber .  If t he i m p ute d 
date res ul ts i n a date later t ha n t he date of deat h, t he n t he date of deat h will be use d. 
I n patie nt data listi n gs, i nc o m plete dates will be dis pla ye d as e ntere d o n t he e C R F wit h o ut a n y 
i m p utati o ns.  St u d y da ys will be deri ve d wit h i m p utati o n a n d dis pla ye d i n t he data listi n gs. 
1 2. 8. 7.  
Q u alit y of Life A n al ysis  
Sta n dar dize d S F- 3 6 v 2 sc ores will be calc ulate d acc or di n g t o t he a ut h ors’ i nstr ucti o ns. 
Eac h of t he 8 scales is directl y tra nsf or me d i nt o a 0  t o 1 0 0 scale o n t he ass u m pti o n t hat eac h 
q uesti o n carries e q ual wei g ht.  T he l o wer t he sc ore t he m ore disa bilit y.  T he hi g her t he sc ore t he 
less disa bilit y.  A nal yses will be descri be d i n a se parate S A P . 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
7 3 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 3.  
DI R E C T A C C E S S T O S O U R C E D A T A / DO C U M E N T S  
1 3. 1.  
St u d y M o nit ori n g , A u dits, a n d I ns pecti o ns  
Site visits will be c o n d ucte d b y a n a ut h orize d La  J olla re prese ntati ve, w h o will i ns pect st u d y 
data, patie nt’s me dical rec or ds, a n d e C R Fs acc or di n g t o G o o d Cli nical Practice ( G C P) a n d F D A 
a n d I nter nati o nal C o u ncil o n Har m o nisati o n ( I C H) g ui deli nes.  I n a d diti o n t o m o nit ori n g b y 
La  J olla or its desi g nee s, t he st u d y ma y be a u dite d b y re prese ntati ves of t he F D A or ot her 
re g ulat or y a ut h orities, w h o will als o be all o we d access t o st u d y d oc u me nts.  T he I n vesti gat or 
s h o ul d i m me diatel y n otif y La  J olla’s Cli nical O perati o ns de part me nt of a n y pr o p ose d or 
sc he d ule d a u dits b y re g ulat or y a ut h orities. 
T he I n vesti gat or will per mit a ut h orize d re prese ntati ves of La  J olla a n d nati o nal or l ocal healt h 
a ut h orities t o i ns pect facilities a n d rec or ds rele va nt t o t his st u d y.  
T he I n vesti gat or m ust o btai n I nstit uti o nal Re vie w B oar d (I R B) / I nter nati o nal Et hics C o m mittee 
(I E C) a p pr o val f or t he i n vesti gati o n.  I nitial I R B or I E C a p pr o val, a n d all materials a p pr o ve d b y 
t he I R B or I E C f or t his st u d y i ncl u di n g t he patie nt c o nse nt f or m a n d recr uit me nt materials m ust 
be mai ntai ne d b y t he I n vesti gat or a n d ma de a vaila ble f or i ns pecti o n. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
7 4 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 4.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
La  J olla or its desi g nee will i nstr uct t he st u d y site re gar di n g t he c o n d uct of t he st u d y a n d data 
ca pt ure pr oce d ures o n e C R Fs.  L o gi c a n d c o nsiste nc y c hec ks will be perf or me d o n all data 
e ntere d i nt o t he eC R F or ulti matel y tra nsferre d i nt o a data base t o e ns ure acc urac y a n d 
c o m plete ness.  
Trai ni n g sessi o ns, re g ular m o nit ori n g of t he st u d y at t he st u d y site b y t he La  J olla or desi g nate d 
pers o n nel (e g,  Cli nical Researc h Ass ociate  [C R A ]), i nstr ucti o n ma n uals, data verificati o n, cr oss 
c hec ki n g, a n d data a u dits will be perf or me d t o e ns ure q ualit y of all st u d y data.  I n vesti gat ors’ 
meeti n gs a n d/ or o nsite st u d y i nitiati o ns will be perf or me d t o pre pare I n vesti gat ors a n d ot her 
st u d y site pers o n nel f or a p pr o priate c o n d uct of t he st u d y a n d c ollecti o n of st u d y data. 
It is t he I n vesti gat or’s res p o nsi bilit y t o e ns ure t he acc urac y, c o m plete ness, a n d ti meli ness of t he 
data re p orte d f or eac h patie nt.  S o urce d oc u me ntati o n s u p p orti n g t he data s h o ul d i n dicate t he 
patie nt’s partici pati o n i n t he st u d y a n d s h o ul d d oc u me nt t he dates a n d details of st u d y 
pr oce d ures, A Es, a n d patie nt stat us. 
T he I n vesti gat or, or desi g nate d re prese ntati ve, s h o ul d c o m pl ete data e ntr y as s o o n as p ossi ble 
after i nf or mati o n is c ollecte d, prefera bl y o n t he sa me da y t hat a st u d y patie nt is see n f or a n 
e xa mi nati o n, treat me nt, or a n y ot her st u d y pr oce d ure.  A n y o utsta n di n g e ntries s h o ul d be 
c o m plete d i m me diatel y after t he fi nal  e xa mi nati o n.  A n e x pla nati o n s h o ul d be gi ve n f or all 
missi n g data.  T he I n vesti gat or m ust si g n a n d date t he I n vesti gat or’s State me nt t hat will be 
s u p plie d t o e n d orse t he rec or de d data. 
All re q uests t o u nl oc k t he data base after data base l oc k will be assesse d b y La J olla a n d will 
f oll o w La J olla  data base u nl oc ki n g sta n dar d o perati n g pr oce d ures. 
T o e ns ure c o m plia nce wit h G C P a n d all a p plica ble re g ulat or y re q uire me nts, La  J olla ma y 
c o n d uct a q ualit y ass ura nce a u dit.  


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
7 5 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 5.  
I R B (I N S TI T U TI O N A L R E VI E W B O A R D ) / E T HI C S  
1 5. 1.  
I RB / Et hics Re vie w  
T he fi nal st u d y pr ot oc ol, i ncl u di n g t he fi nal versi o n of t he i nf or me d c o nse nt f or m, m ust be 
a p pr o ve d or gi ve n a fa v ora ble o pi ni o n i n writi n g b y a n I R B or I E C as a p pr o priate.  T he 
I n vesti gat or m ust s u b mit writte n a p pr o val t o La  J olla bef ore he or s he ca n prese nt i nf or me d 
c o nse nt a n d be gi n scree ni n g acti vities f or a n y patie nt o n t he st u d y. 
T he I n vesti gat or is res p o nsi ble f or i nf or mi n g t he I R B or I E C of a n y a me n d me nt t o t he pr ot oc ol 
i n acc or da nce wit h l ocal re q uire me nts.  I n a d diti o n, t he I R B or I E C  m ust a p pr o ve all a d vertisi n g 
use d t o recr uit patie nts f or t he st u d y, if a p plica ble.  T he pr ot oc ol m ust be re- a p pr o ve d b y t he I R B 
or I E C  u p o n recei pt of a me n d me nts a n d a n n uall y, as l ocal re g ulati o ns re q uire. 
T he I n vesti gat or is als o res p o nsi ble f or pr o vi di n g t he I R B or I E C wit h re p orts of a n y re p orta ble 
seri o us a d verse dr u g reacti o ns fr o m a n y ot her st u d y c o n d ucte d wit h t he i n vesti gati o nal pr o d uct.  
La  J olla will pr o vi de t his i nf or mati o n t o t he I n vesti gat or.  
Pr o gress re p orts a n d n otificati o ns of seri o us a d verse dr u g reacti o ns will be pr o vi de d t o t he I R B 
or I E C  acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes. 
1 5. 2.  
Pr ot oc ol C o m pli a nce  
T he I n vesti gat or will c o n d uct t he trial i n c o m plia nce wit h t he pr ot oc ol pr o vi de d b y La  J olla.  
M o dificati o ns t o t he pr ot oc ol ma y  n ot be ma de wit h o ut a gree me nt of b ot h t he I n vesti gat or a n d 
La  J olla.  C ha n ges t o t he pr ot oc ol will re q uire a writte n I R B or I E C a p pr o val/fa v ora ble o pi ni o n 
pri or t o i m ple me ntati o n, e xce pt w he n t he m o dificati o n is nee de d t o eli mi nate a n i m me diate 
hazar d(s) t o patie nts.  T he I R B or I E C ma y pr o vi de, if a p plica ble re g ulat or y a ut h orit y(ies) 
per mit, e x pe dite d re vie w a n d a p pr o val/fa v ora ble o pi ni o n f or mi n or c ha n ge(s) i n o n g oi n g trials 
t hat ha ve t he a p pr o val/fa v ora ble o pi ni o n of t he I R B or I E C. 
W he n i m me diate de via ti o n fr o m t he pr ot oc ol is re q uire d t o eli mi nate a n i m me diate hazar d(s) t o 
patie nts, t he I n vesti gat or will c o ntact La  J olla a n d/ or t he Me dical M o nit or, if circ u msta nces 
per mit, t o disc uss t he pla n ne d c o urse of acti o n.  A n y i m p orta nt de part ures fr o m t he pr ot oc ol 
m ust be f ull y d oc u me nt e d o n t he a p pr o priate e C R F a n d i n t he s o urce d oc u me ntati o n a n d 
re p orte d t o t he I R B or I E C per i nstit uti o nal a n d/ or l ocal re q uire me nts. 
T he pr ot oc ol de viati o ns l o g will be c o m plete d b y t he st u d y m o nit ors a n d peri o dicall y re vie we d 
b y t he S p o ns or, a n d cate g ories will be assi g ne d t o t he pr ot oc ol de viati o ns.  T he l o g a n d 
assi g n me nts will be fi nalize d pri or t o t he data base freeze/l oc k.  All i m p orta nt de viati o ns will be 
i ncl u de d i n t he fi nal data base. 
1 5. 3.  
Et hic al C o n d uct of t he St u d y  
T he st u d y will be perf or me d i n acc or da nce wit h et hical pri nci ples t hat ha ve t heir ori gi n i n t he 
Declarati o n of Helsi n ki a n d are c o nsiste nt wit h I C H/ G C P, a p plica ble re g ulat or y re q uire me nts, 
a n d La  J olla ( or its desi g nees) a p plica ble p olicies a n d sta n dar d o perati n g pr oce d ures. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
7 6 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 5. 4.  
Writte n I nf or me d C o nse nt  
T he I n vesti gat or(s) at eac h ce nter will e ns ure t hat t he patie nt is gi ve n f ull a n d a de q uate oral a n d 
writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p ossi ble ris k, a n d be nefit of t he st u d y.  Patie nts 
m ust als o be n otifie d t hat t he y are free t o disc o nti n ue fr o m t he st u d y at a n y ti me.  T he patie nt 
s h o ul d be gi ve n t he o p p ort u nit y t o as k q uesti o ns a n d all o we d ti me t o c o nsi der t he i nf or mati o n 
pr o vi de d. 
T he patie nt’s si g ne d a n d date d i nf or me d c o nse nt f or m m ust be o btai ne d bef or e c on d ucti n g a n y 
st u d y pr oce d ures. 
T he I n vesti gat or(s) m ust mai ntai n t he ori gi nal, si g ne d i nf or me d c o nse nt f or m.  A c o p y of t he 
si g ne d i nf or me d c o nse nt f or m m ust be gi ve n t o t he patie nt. 
1 5. 5.  
P atie nt  C o nfi de nti alit y  
I n or der t o mai ntai n patie nt pri vac y, data ca pt ure t o ols, i n vesti gati o nal pr o d uct acc o u nta bilit y 
rec or ds, st u d y re p orts, a n d c o m m u nicati o ns will i de ntif y t he patie nt o nl y b y i nitials a n d t he 
assi g ne d patie nt n u m ber.  T he I n vesti gat or will gra nt m o nit or(s) a n d a u dit or(s) fr o m La  J olla or 
its desi g nee a n d re g ulat or y a ut h orit y(ies) access t o t he patie nt’s ori gi nal me dical rec or ds, 
i ncl u di n g me dical hist or y, la b orat or y st u dies, a n d me dicati o n a d mi nistrati o ns, f or verificati o n of 
data gat here d a n d t o a u dit t he data c ollecti o n pr ocess.  T hi s i nf or mati o n will be accesse d f or t he 
d urati o n of t he researc h st u d y, i ncl u di n g t he f oll o w- u p peri o d, f or t he p ur p ose of data 
rec o nciliati o n.  T he patie nt’s c o nfi de ntialit y will be mai ntai ne d a n d will n ot be ma de p u blicl y 
a vaila ble t o t he e xte nt per mitte d  b y t he a p plica ble la ws a n d re g ulati o ns. 
1 5. 5. 1.  
Ge ner al D at a Pr otecti o n Re g ul ati o n f or Cli nic al St u dies C o n d ucte d i n t he 
E ur o pe a n Ec o n o mic Are a  
T he pr ocessi n g of pers o nal data i n t his st u d y is s u bject t o t he Ge neral Data Pr otecti o n Re g ulati o n 
( G D P R) a n d o nl y a p plies t o st u dies c o n d ucte d i n t he E ur o pea n Ec o n o mic Area.  T he G D P R 
re q uires t hat certai n i nf or mati o n be pr o vi de d t o t he st u d y s u bject/ patie nt i n t he I C F. 
F or p ur p oses of t his st u d y, S p o ns or will be t he “ data c o ntr oller” u n der t he G D P R.  T he c o ntract 
research or ga nizati o n t hat is assisti n g wit h t he st u d y is S p o ns or’s “ data pr ocess or”.  Ot her 
or ga nizati o ns i n v ol ve d i n pr ocessi n g pers o nal data o n S p o ns or’s be half f or p ur p oses of t he st u d y, 
s uc h as c o ntract la b orat ories t hat a nal yse bl o o d sa m ples, are als o S p o ns or’s data pr ocess ors.  
Eac h st u d y s u bject’s/ patie nt’s pers o nal data will be ha n dle d f or p ur p oses of t he st u d y a n d 
s u bse q ue nt researc h uses b y S p o ns or a n d t hir d parties as descri be d i n t he I C F. 
S p o ns or is res p o nsi ble f or c o m plia nce wit h data c o ntr oller o bli gati o ns u n der t he G D P R a n d ot her 
a p plica ble la ws i n c o n necti o n wit h t he data c ollecte d b y or o n be half of S p o ns or f or p ur p oses of 
t he st u d y.  S p o ns or ca n be c o ntacte d re gar di n g data pr otecti o n matters at La J olla P har mace utical 
C o m pa n y, Att n: Hea d of Pri vac y, 4 5 5 0 T o w ne Ce ntre C o urt, Sa n Die g o, Calif or nia, 9 2 1 2 1, or b y 
e-mail at pri vac y @lj pc.c o m.  
S u bject t o certai n li mitati o ns of t he G D P R a n d ot her a p plica ble data pr otecti o n la ws, st u d y 
s u bjects/ patie nts will ha ve t he ri g ht t o access a n d c orrect t heir pers o nal data, a n d t o re q uest its 
deleti o n or restricti o n or o bject t o its pr ocessi n g, b ut t hese ri g hts ma y be li mite d u n der t he 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
7 7 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
G D P R’s pr o visi o ns relati n g t o scie ntific researc h a n d data pr ocessi n g  t hat is c o n d ucte d i n t he 
p u bl ic i nterest, or ot her gr o u n ds. 
T he la ws g o ver ni n g cli nical st u dies re q uire c o nse nt fr o m st u d y partici pa nts (a n d f or mi n ors, t o 
o btai n a pare nt or g uar dia n’s c o nse nt t o t he c hil d’s partici pati o n i n t he st u d y).  H o we ver, t he 
la ws g o ver ni n g data pr otecti o n, i ncl u di n g t he G D P R, pr o vi de le gal bases besi des c o nse nt f or t he 
pr ocessi n g of certai n pers o nal data.  F or p ur p oses of a p plica ble data pr otecti o n la ws, S p o ns or’s 
la wf ul basis f or pr ocessi n g t he pers o nal data of its st u d y s u bjects/ patie nts is t hat t he pr ocessi n g is 
necessar y f or scie ntific researc h p ur p oses, s u bject t o Article 8 9 of t he G D P R.  Pr ocessi n g t hat is 
directl y re q uire d f or carr yi n g o ut t he st u d y is d o ne o n t he basis of necessit y of e ns uri n g hi g h 
sta n dar ds of q ualit y a n d safet y of healt h care a n d of me dici nal pr o d ucts. 
A m o n g its ot her o bli gati o ns, S p o ns or i nte n ds t o tra nsfer pers o nal data o utsi de of t he E ur o pea n 
Ec o n o mic Area a n d will e ns ure t here is a la wf ul basis f or tra nsfer of data o utsi de of t he 
E ur o pea n Ec o n o mic Ar e a. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
7 8 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 6.  
R E C O R D K E E PI N G  
1 6. 1.  
I ns pecti o n of Rec or ds 
La  J olla a n d desi g nees of La  J olla will be all o we d t o c o n d uct site visits t o t he i n vesti gati o nal 
facilities f or t he p ur p ose of m o nit ori n g a n y as pect of t he st u d y.  T he I n vesti gat or a grees t o all o w 
La  J olla re prese ntati ves t o i ns pect t he dr u g st ora ge area, LJ P C - 4 0 1 i n ve nt or y, dr u g 
acc o u nta bilit y rec or ds, patie nt c harts a n d st u d y s o urce d oc u me nts, a n d ot her rec or ds relati ve t o 
t he st u d y c o n d uct. 
1 6. 2.  
Rete nti o n of Rec or ds  
T he I n vesti gat or will c o or di nate wit h t he s t u d y site t o e ns ure rete nti o n of all d oc u me ntati o ns 
relati n g t o t he st u d y f or a peri o d of 2 years after mar keti n g a p plicati o n a p pr o val, or if n ot 
a p pr o ve d, 2 years f oll o wi n g t he n otificati o n t o F D A of t he disc o nti n ua nce of t he test article f or 
i n vesti gati on.  If it bec o mes necessar y f or La  J olla or t he Re g ulat or y A ut h orit y t o re vie w a n y 
d oc u me ntati o n relati n g t o t he st u d y, t he I n vesti gat or m ust per mit access t o s uc h rec or ds. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
7 9 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 7.  
P U B LI C A TI O N P O LI C Y  
All i nf or mati o n re gar di n g LJ P C - 4 0 1 s u p plie d b y La  J olla t o t he I n vesti gat or is pri vile ge d a n d 
c o nfi de ntial i nf or mati o n.  T he I n vesti gat or a grees t o use t his i nf or mati o n t o acc o m plis h t he st u d y 
a n d will n ot use it f or a n y ot her p ur p oses wit h o ut writte n c o nse nt fr o m La  J olla.  It is u n derst o o d 
t hat t here is a n o bli gati o n t o pr o vi de La  J olla wit h c o m plete data o btai ne d d uri n g t he st u d y.  T he 
i nf or mati o n o btai ne d fr o m t he cli nical st u d y will be use d t o war d t he de vel o p me nt of La  J olla’s 
LJ P C - 4 0 1 pr o gra m a n d ma y be discl ose d t o re g ulat or y a ut h orit y(ies), ot her I n vesti gat ors, 
c or p orate part ners, s hare h ol ders, or c o ns ulta nts as re q uire d. 
It is a ntici pate d t hat t he res ults of t his st u d y will be prese nte d at scie ntific meeti n gs a n d/ or 
p u blis he d i n a peer- re vie we d scie ntific or me dical j o ur nal. 
La J olla is c o m mitte d t o t he hi g hest scie ntific a n d et hical sta n dar ds f or p u blicati o ns.  T he data 
f or all p u blicati o ns will be re p orte d i n a n o bjecti ve, acc urate, scie ntificall y-bala nce d, a n d 
c o m plete ma n ner (e g, ma n uscri pts, re vie w articles, a bstracts, p osters, a n d/ or oral prese ntati o ns 
t hat c o ntai n data fr o m La J olla s p o ns ore d st u dies, ha ve La J olla a ut h ors, or f or w hic h La J olla 
pr o vi des writi n g a n d/ or e dit orial ass ista nce). 
La J olla’s pri nci ples f or a ut h ors hi p of p u blicati o ns are c o nsiste nt wit h criteria de vel o pe d b y t he 
I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors (I C MJ E; w w w.ic mje. or g). 
T he I C MJ E rec o m me n ds t hat a ut h ors hi p be base d o n t he f oll o wi n g 4 criteria: 
1.  S u bsta ntial c o ntri b uti o ns t o t he c o nce pti o n or desi g n of t he w or k; or t he ac q uisiti o n, 
a nal ysis, or i nter pretati o n of data f or t he w or k; A N D 
2.  Drafti n g t he w or k or re visi n g it criticall y f or i m p orta nt i ntellect ual c o nte nt; A N D  
3.  Fi nal a p pr o val of t he versi o n t o be s u b mitte d/ prese nte d; A N D  
4.  A gree me nt t o be acc o u nta ble f or all as pects of t he w or k i n e ns uri n g t hat q uesti o ns relate d 
t o t he acc urac y or i nte grit y of a n y part of t he w or k are a p pr o priatel y i n vesti gate d a n d 
res ol ve d. 
La J olla pr o hi bits t he practices of g uest a ut h ors hi p, g h ost writi n g, or pla giaris m o n p u blicati o ns.  
G uest a ut h ori n g is t he practice i n w hic h t he na mes of i n di vi d uals w h o c o ntri b ute d little t o n o 
c o nte nt o n t he p u blicati o n a p pear o n t he b yli ne.  G h ost writi n g is t he practice i n w hic h 
i n di vi d uals w h o wr ote t he p u blicati o n are neit her ac k n o wled ge d n or liste d o n t he b yli ne. 


Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1 
8 0 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
1 8.  
R E F E R E N C E S  
1 8. 1.  
P u blic ati o ns  
A da ms P C , Bart o n J C. H o w I treat he m oc hr o mat osis.   Bl o o d. 2 0 1 0; 1 1 6( 3): 3 1 7- 3 2 5. 
A merica n Ass ociati o n f or Cli nical C he mistr y ( A A C C; 2 0 1 5 ). La b Tests O nli ne. TI B C, UI B C, 
a n d Tra nsferri n. htt ps://la btests o nli ne. or g/ u n dersta n di n g/a nal ytes/ti bc/ta b/test/. Accesse d 2 3 A u g 
2 0 1 7. 
Bac o n B R, A da ms P C, K o w dle y K V, P o well L W, Ta vill A S. Dia g n osis a n d Ma na ge me nt of 
He m oc hr o mat osis: 2 0 1 1 Practice G ui deli ne b y t he A merica n Ass ociati o n f or t he St u d y of Li ver 
Diseases. He pat ol o g y. 2 0 1 1; 5 4( 1) : 3 2 8- 3 4 3. 
C o u ns yl 2 0 1 7 , H F E-ass ociate d Here d itar y He m oc hr o mat osis, 
htt ps:// w w w.c o u ns yl.c o m/ser vices/f oresi g ht/ diseases/ hfe -ass ociate d -here ditar y -
he m oc hr o mat osis/, Accesse d  2 3 A u g 2 0 1 7 
Deferasir o x U S Prescri bi n g I nf or mati o n ( 2 0 1 5). 
htt ps:// w w w. p har ma. us. n o vartis.c o m/sites/ w w w. p har ma. us. n o vartis.c o m/f iles/jade n u. p df. 
Accesse d 2 3 A u g 2 0 1 7. 
Deferi pr o ne U S Prescri bi n g I nf or mati o n ( 2 0 1 1). 
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 1/ 0 2 1 8 2 5l bl. p df. Accesse d 2 3 A u g 
2 0 1 7. 
Defer o xa mi ne mes ylate U S Prescri bi n g I nf or mati o n ( 2 0 1 1). 
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 0/ 0 1 6 2 6 7s 0 4 7l bl. p df. Accesse d 2 3 
A u g 2 0 1 7. 
de Li ma Sa nt os P, Pereira A C, Ca nça d o R D, Sc hettert I T, Hirata R D, Hirata M H. He m oj u veli n 
a n d he pci di n ge nes se q ue nci n g i n Brazilia n patie nts wit h pri mar y ir o n  o verl oa d. Ge net Test M ol 
Bi o mar kers . 2 0 1 0; 1 4( 6):8 0 3- 8 0 6. 
D uc hi ni A. He m oc hr o mat osis. I n: Me dsca pe Dr u gs a n d Diseases.  U p date d 2 0 1 7 
htt p://e me dici ne. me dsca pe.c o m/article/ 1 7 7 2 1 6- o ver vie w #a 7. Accesse d 2 3 A u g 2 0 1 7. 
F D A. Ma n ual of P olicies a n d Pr oce d ures. G o o d Re vie w Practice: Cli nical Re vie w Te m plate. 
U. S. De part me nt of Healt h a n d H u ma n Ser vices F o o d a n d Dr u g A d mi nistrati o n   Ce nter f or 
Dr u g E val uati o n a n d Researc h ( C D E R). Dec 1 0, 2 0 1 0. 
G or de u k V R, Britte n ha m G M, H u g hes M, Keati n g LJ, O p plt JJ. Hi g h - d ose car b o n yl ir o n for ir o n 
deficie nc y a ne mia: A ra n d o mize d d o u ble- bli n d trial. A m J Cli n N utr . 1 9 8 7; 4 6( 6):1 0 2 9- 1 0 3 4. 
Hic ke n, B, T uc ker, D, Bart o n, J. Patie nt c o m plia nce wit h p hle b ot o m y t hera p y f or ir o n o verl oa d 
ass ociate d wit h he m oc hr o mat osis. A m Gastr oe nter ol . 2 0 0 3;9 8 : 2 0 7 2- 2 0 7 7. 
H off bra n d A V, Ta her A, D o me nica Ca p pelli ni M. H o w I treat tra nsf usi o nal ir o n o verl oa d. 
Bl o o d. 2 0 1 2; 1 2 0( 1 8 ):3 6 5 7- 3 6 6 9. 
Ir o n Dis or ders I nstit ute, Classic He m oc hr o mat osis, 2 0 1 1. htt p:// w w w.ir o n dis or ders. or g/classic -
he m oc hr o mat osis, Accesse d 2 3 A u g 2 0 1 7. 






Pr ot oc ol LJ 4 0 1- H H 0 1  
 
LJ P C - 4 0 1  
 
8 3 
La J olla P har mace utical - C o nfi de ntial  
Date :  1 4  Dece m ber  2 0 1 8  ( Versi o n 6. 0) 
A P P E N DI X  1.  S U M M A R Y O F L A B O R A T O R Y P A R A M E T E R S  
S u m m ar y of L a b or at or y P ar a meters 
Dise ase -s pecific 
He m at ol o g y 
C he mistr y  
Uri n al ysis  
S u bset/ S peci al  
•  
T otal ser u m 
ir o nb 
•  
Ser u m 
tra nsferri n 
•  
Ser u m ferriti n b 
•  
UI B C b 
•  
TI B C b 
•  
Tra nsferri n 
sat urati o nb 
•  
A p oferriti n 
•  
H ol oferriti n 
 
•  
He mat ocrit b 
•  
He m o gl o bi n b 
•  
Platelet c o u nt b 
•  
W hite bl o o d cell 
c o u nt b, c 
•  
Re d bl o o d cell 
c o u nt b, d 
•  
Ser u m creati ni ne b 
•  
Uric aci d b  
•  
Al kali ne p h os p hatase b 
•  
Bl o o d urea nitr o ge n b 
•  
Al b u mi n 
•  
Bilir u bi n (t otal , direct, 
a n d i n direct )b 
•  
P h os p hate b 
•  
Bicar b o nate b 
•  
Lactate de h y dr o ge nase  
•  
Gl uc ose b 
•  
Calci u m b 
•  
Ma g nesi u m
b 
•  
C hl ori de b 
•  
S o di u m b 
•  
P otassi u m b 
•  
Ala ni ne 
a mi n otra nsferase 
( S G P T)b 
•  
As partate  
a mi n otra nsferase 
( S G O T)b 
•  
T otal pr otei n  
•  
S pecific 
gra vit y 
•  
Bilir u bi n 
•  
Gl uc ose  
•  
p H 
•  
Pr otei n 
•  
Nitrite  
•  
Bl o o d 
•  
Ket o nes 
•  
Pre g na nc y a 
•  
P har mac o ki netics 
•  
T h yr oi d -sti m ulati n g 
h or m o ne 
•  
He m o gl o bi n Alc  
•  
T h yr o xi ne ( T 4 a n d free 
T 4) 
•  
Trii o d ot h yr o ni ne 
(free T 3) 
•  
I m m u no ge nicit y b, e 
S G O T =ser u m gl uta mic - o xal oacetic tra nsa mi nase; S G P T =ser u m gl uta mic -p yr u vic tra nsa mi nase; TI B C =t otal ir o n 
bi n di n g ca pacit y; UI B C = u nsat urate d ir o n bi n di n g ca pacit y.  
a Ser u m a n d uri ne.  
b La b orat or y para meters t hat m ust be c ollecte d t o m o nit or patie nt safet y.  
c W hite bl o o d cell c o u nt a n d differe ntial i ncl u di n g perce nt a n d a bs ol ute:  ne utr o p hils, l y m p h oc ytes, m o n oc ytes, 
e osi n o p hils, a n d bas o p hils    
d Re d bl o o d cell c o u nt, i ncl u di n g retic ul oc yte c o u nt, re d cell distri b uti o n wi dt h, mea n c or p usc ular he m o gl o bi n, mea n 
c or p usc ular v ol u me, mea n c or p usc ular he m o gl o bi n c o nce ntrati o n.  
e LJ P C-4 0 1 a nti-dr u g  a nti b o d y.   

SAP_001.pdf: 
 
 
Statistical Analysis Plan:  LJ401-HH01 
 
A Phase 2, Multicenter, Randomized, Placebo-controlled, 
Single-blind Study with LJPC-401 for the Treatment of Iron 
Overload in Adult Patients with Hereditary Hemochromatosis 
 
 
Sponsor: 
 
 
La Jolla Pharmaceutical Company 
 
 
 
4550 Towne Centre Court 
 
 
 
San Diego, CA 92121 USA 
 
 
 
Sponsor Contact:     
Stew Kroll, Senior Vice President Biometrics 
 
 
 
skroll@ljpc.com - Email 
 
Amendment:  Version 3.0 based on Protocol Version 6.0 and 6.1 (UK), 14 December 2018 
Amendment:  Version 2.0 based on Protocol Version 6.0 and 6.1 (UK), 14 December 2018 
Original SAP:  Version 1.0 based on Protocol Version 5.0 and 5.1 (UK), 02 October 2018 
Issue Date:  22 March 2019 
 
Confidentiality Statement 
 
The information contained in this document is confidential and proprietary information of 
La Jolla Pharmaceutical Company (herein, La Jolla or Sponsor).  Any distribution, copying, or 
disclosure is strictly prohibited unless local, regional, state, or federal regulations or laws require 
such disclosure.  Prior written authorization from La Jolla is required for any disclosure or use of 
the information contained herein.  Persons to whom the information is disclosed must know that 
it is confidential and that it may not be further disclosed by them. 
 
 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
2 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND SPECIALIST TERMS...........................................................5 
1. 
INTRODUCTION ........................................................................................................7 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................10 
2.1. 
Study Objectives .........................................................................................................10 
2.1.1. 
Primary Objectives .....................................................................................................10 
2.1.2. 
Secondary Objectives .................................................................................................10 
2.1.3. 
Exploratory Objectives ...............................................................................................10 
2.2. 
Study Endpoints ..........................................................................................................10 
2.2.1. 
Primary Efficacy Endpoint .........................................................................................10 
2.2.2. 
Secondary Efficacy Endpoints ....................................................................................11 
2.2.3. 
Safety and Tolerability Endpoints ..............................................................................11 
2.2.4. 
Exploratory Endpoints ................................................................................................11 
3. 
STUDY DESIGN .......................................................................................................13 
3.1. 
Summary of Study Design ..........................................................................................13 
3.2. 
Treatment Assignment ................................................................................................13 
3.2.1. 
Dose Adjustment Criteria ...........................................................................................13 
3.2.2. 
Safety Criteria for Adjustment of Stopping Doses .....................................................14 
3.3. 
Criteria for Study Termination ...................................................................................14 
3.4. 
Sample Size Considerations .......................................................................................15 
3.5. 
Randomization, Stratification, and Blinding ..............................................................15 
3.6. 
Replacement of Patients .............................................................................................16 
4. 
PLANNED ANALYSES ............................................................................................17 
4.1. 
Interim Analyses .........................................................................................................17 
4.1.1. 
Safety Monitoring Committee ....................................................................................17 
4.2. 
Final Analysis .............................................................................................................17 
4.3. 
Changes from Planned Analyses ................................................................................17 
5. 
GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSES .....................18 
5.1. 
Data Quality Assurance ..............................................................................................18 
5.2. 
Data Standardization ...................................................................................................19 
5.3. 
General Considerations ...............................................................................................19 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
3 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
5.4. 
Analysis Populations ..................................................................................................20 
5.5. 
Definitions and Derived Data .....................................................................................20 
5.6. 
Definition of Subgroups .............................................................................................23 
5.7. 
Handling of Missing Data ...........................................................................................23 
6. 
POPULATION, ENROLLMENT, AND DEMOGRAPHICS ...................................25 
6.1. 
Informed Consent .......................................................................................................25 
6.2. 
Patient Disposition ......................................................................................................25 
6.3. 
Enrollment ..................................................................................................................25 
6.4. 
Protocol Deviations ....................................................................................................25 
6.5. 
Randomization Stratification ......................................................................................26 
6.6. 
Demographics and Baseline Characteristics ...............................................................26 
6.7. 
Medical History ..........................................................................................................27 
6.8. 
Prior and Concomitant Medications ...........................................................................27 
6.9. 
Prior and Concomitant Phlebotomy Procedures .........................................................27 
6.10. 
On Study Non-medication Therapy / Procedures .......................................................27 
7. 
EFFICACY .................................................................................................................28 
7.1. 
Test of Hypothesis ......................................................................................................28 
7.2. 
Primary Efficacy Analysis:  Postdose TSAT ..............................................................28 
7.2.1. 
Expanded Efficacy Population:  Primary Efficacy Variable ......................................28 
7.2.2. 
Univariate Subgroup Analyses:  Primary Efficacy Variable ......................................29 
7.2.3. 
By-site Analyses:  Primary Efficacy Variable ............................................................29 
7.2.4. 
Multivariate Analyses:  Primary Efficacy Variable ....................................................29 
7.2.5. 
Exploratory Analysis of Week 17 TSAT ....................................................................29 
7.2.6. 
Additional Summaries of TSAT .................................................................................29 
7.3. 
Secondary Efficacy Analyses .....................................................................................30 
7.3.1. 
Number of Phlebotomies ............................................................................................30 
7.3.2. 
Secondary Efficacy Analyses:  Serum Ferritin ...........................................................31 
7.4. 
Exploratory Efficacy Analyses ...................................................................................32 
7.4.1. 
Exploratory Efficacy Analyses:  Other Iron Parameters ............................................32 
7.4.2. 
Exploratory Efficacy Analyses:  Change in Thyroid Function ..................................33 
7.4.3. 
Exploratory Efficacy Analyses:  Change in Liver Function .......................................33 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
4 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
7.4.4. 
Exploratory Efficacy Analyses:  Change in Glycemic Control ..................................33 
7.4.5. 
Exploratory Efficacy Analyses:  Change in RBC Parameters ....................................33 
7.4.6. 
Exploratory Efficacy Analyses:  Change in Quality of Life .......................................33 
7.5. 
Multiplicity Adjustment..............................................................................................34 
8. 
SAFETY AND TOLERABILITY ..............................................................................35 
8.1. 
Adverse Events ...........................................................................................................35 
8.2. 
Deaths .........................................................................................................................35 
8.3. 
Injection Site Reaction ................................................................................................36 
8.4. 
Study Drug Exposure ..................................................................................................36 
8.5. 
Clinical Laboratory Evaluations .................................................................................36 
8.6. 
Immunogenicity/Pharmacokinetics ............................................................................36 
8.7. 
Physical Exam ............................................................................................................36 
8.8. 
Vital Signs ..................................................................................................................37 
8.9. 
Electrocardiogram .......................................................................................................37 
9. 
REFERENCES ...........................................................................................................38 
10. 
PLANNED TABLES, LISTINGS, AND FIGURES .................................................39 
10.1. 
Patient Data Tables .....................................................................................................39 
10.2. 
Tables ..........................................................................................................................39 
10.3. 
Patient Data Listings ...................................................................................................44 
10.4. 
Figures ........................................................................................................................45 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms .............................................................................5 
Table 2: 
Severity of Adverse Events ........................................................................................35 
 
 
 
 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
5 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
LIST OF ABBREVIATIONS AND SPECIALIST TERMS 
The following abbreviations and specialist terms are used in this statistical analysis plan. 
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
ADaM 
Analysis Data Model 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical classification 
system 
BMI 
body mass index 
CDISC 
Clinical Data Interchange Standards Consortium 
CMH 
Cochran-Mantel-Haenszel 
CRO 
contract research organization 
CSR 
clinical study report 
DM 
data management 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EOS 
End of Study 
EOT  
End of Treatment 
ICH 
International Council on Harmonisation 
IDI 
Iron Disorders Institute 
ITT 
Intent to Treat 
IXRS  
Interactive Voice/Web Response System 
La Jolla 
La Jolla Pharmaceutical Company 
LDH 
lactate dehydrogenase 
LLQ 
lower limit of quantification 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities  
mITT 
Modified Intent to Treat 
PK 
pharmacokinetic 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
6 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
Abbreviation or Specialist Term 
Explanation 
PP 
Per Protocol 
PT 
preferred term 
RBC 
red blood cell 
RDW 
red cell distribution width 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SF-36v2 
Short Form (36) Health Survey, Version 2 
SI 
Systéme International 
SMC 
Safety Monitoring Committee 
SOC 
system organ class 
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse events 
TIBC  
total iron-binding capacity 
TLFs 
tables, listings, and figures  
TSAT 
transferrin saturation 
TSH 
thyroid-stimulating hormone 
UIBC 
unsaturated iron-binding capacity 
UK 
United Kingdom 
USA 
United States of America  
USP 
United States Pharmacopoeia 
WHO-DD 
World Health Organization Drug Dictionary 
WOMAC 
Western Ontario and McMaster Universities 
Osteoarthritis Index 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
7 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
1. 
INTRODUCTION  
This statistical analysis plan (SAP) outlines the statistical methods that will be used to generate 
the clinical study report (CSR) for Study LJ401-HH01, “A Phase 2, Multicenter, Randomized, 
Placebo-controlled, Single-blind Study with LJPC-401 for the Treatment of Iron Overload in 
Adult Patients with Hereditary Hemochromatosis”.    
The second amendment to the SAP (version 3.0) was undertaken to incorporate hierarchical 
testing of primary and secondary endpoints as well as a clarification of the phlebotomy 
definition.  A summary of changes incorporated in version 3.0 of the SAP is provided in the 
overview below.  
Overview of Changes in Statistical Methods in LJ401-HH01 SAP Version 2.0 to 3.0 
 
Hierarchical Testing 
of Secondary 
Endpoints 
Hierarchical testing will be used to preserve the overall type I error across 
the testing of secondary endpoints (Section 7.5).  Hierarchical testing will 
proceed as follows: 
1. Given a significant treatment effect for the primary efficacy 
endpoint, an analysis of the first secondary endpoint (number of 
phlebotomies from Day 2 to End of Study) will proceed and will 
be tested for statistical significance. 
2. Given a significant treatment effect for the primary efficacy 
endpoint and the first secondary efficacy endpoint, an analysis of 
the second secondary endpoint (change in serum ferritin) will 
proceed and will be tested for statistical significance. 
The Lan DeMets approach to the O’Brien-Fleming method for sequential 
designs will be applied to preserve the overall type I error rate.  It is 
expected that a type I rate of 0.00021 will be applied for the initial interim 
analysis (n = 16) and adjustment for all interim analyses will be applied 
for the final analysis (n = 48).  At the interim analysis, if hierarchical 
testing results in a statistically significant Lan DeMets p-value for each of 
the 3 endpoints, then enrollment may be halted due to overwhelming 
efficacy. 
Number of 
Phlebotomies 
Clarified that the number of times a patient met criteria for a phlebotomy 
will include the actual number of phlebotomies from Day 2 to EOS plus 
the number of observations of a fasting postdose TSAT >45%, but the 
patient refused/missed a phlebotomy, or the treating physician decided 
against a phlebotomy within the next 7 days.   
An additional sensitivity analysis of the time to first phlebotomy 
(following the standard of care phlebotomy on Day 1 [predose]) analyzed 
by logrank test was added. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
8 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
Change in Ferritin 
Clarified that the key secondary analyses for the change in ferritin will 
follow those that are specified for the primary analysis of TSAT. 
Subgroup Analyses 
Added HH genotype (HFE versus non-HFE) and Screening TSAT (>45% 
to 70% versus >70%) to univariate and multivariate analyses. 
 
The first amendment to the SAP (version 2.0) was undertaken to incorporate the changes to the 
statistical analyses required following the amendment to global protocol version 6.0 and United 
Kingdom (UK) version 6.1 (dated 14 December 2018).  A summary of changes incorporated in 
version 2.0 of the SAP is provided in the overview below. 
Overview of Changes in Statistical Methods in LJ401-HH01 SAP Version 1.0 to 2.0   
Item 
Description and Rationale for Change 
Efficacy Analysis 
Population 
The Efficacy Patient Population was amended to include those patients 
enrolled under global protocol version 4.0/UK protocol version 4.1 or 
later only (Section 3.4 and Section 5.4). 
Prior to global protocol version 4.0/UK protocol version 4.1, a patient’s 
need for phlebotomy was based on a TSAT assessment performed predose 
on the day of study drug administration and approximately 7 days after 
the most recent study drug administration.  The amended study design 
(effective as of global protocol version 4.0/UK protocol version 4.1) 
determines a patient’s need for phlebotomy based on a TSAT assessment 
performed 24 (± 4) hours postdose to reflect the TSAT status during 
treatment and not prior to study drug administration.  As such, patients 
who enrolled prior to global protocol version 4.0/UK protocol version 4.1 
will be replaced to maintain study power for the efficacy analysis 
(patients may be replaced for additional reasons as described in 
Section 3.6).  Patients enrolled prior to global protocol version 4.0/UK 
protocol version 4.1 continue to participate in the study and will be 
included in other analyses including safety analyses (Section 8).   
Sample Size 
Considerations 
The revised study design will require the number of patients enrolled to be 
approximately 68 to 76 patients across approximately 30 sites 
(Section 3.4).  
Interim Analysis 
Clarified that the interim analysis will take place after the first 16 patients 
in the Efficacy Patient Population complete Week 16 or have an on-study 
phlebotomy prior to Week 16 after having received their initial on-study 
SOC phlebotomy at Week 1 (predose) (Section 4.1).  Any subsequent 
interim analysis (eg, the first 32 patients) will similarly use this population 
selection definition.   
 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
9 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
It is not intended that every table, listing, or figure will be included in the CSR.  It is also 
possible that additional analyses will be conducted after review of the data.  Any analyses or 
summaries not specified in the SAP, but performed after review of the data, will be identified in 
the CSR as unplanned analyses. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
10 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
The primary objective of this study is to compare the effect of LJPC-401 versus placebo on 
transferrin saturation (TSAT) in adult patients with hereditary hemochromatosis.   
2.1.2. 
Secondary Objectives 
The secondary objectives of this study are to: 
 compare the effect of LJPC-401 versus placebo on phlebotomy requirements,   
 establish the safety and tolerability of LJPC-401 versus placebo in adult patients with 
hereditary hemochromatosis, and  
 compare the effect of LJPC-401 versus placebo on serum ferritin.  
2.1.3. 
Exploratory Objectives 
The exploratory objectives of this study are to: 
 compare the effect of LJPC-401 versus placebo on serum iron parameters, 
 compare the effect of LJPC-401 versus placebo on thyroid function, 
 compare the effect of LJPC-401 versus placebo on liver function, 
 compare the effect of LJPC-401 versus placebo on glycemic control, 
 compare the effect of LJPC-401 versus placebo on red blood cell (RBC) parameters 
including hemoglobin concentration, RBC count, and red cell distribution width 
(RDW), and 
 compare the effect of LJPC-401 versus placebo on quality of life as measured by a 
Quality of Life Questionnaire:  Short Form (36) Health Survey, Version 2 (SF-36v2), 
the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and 
the modified Dreisler indices for arthritis. 
2.2. 
Study Endpoints 
2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as follows: 
 For patients with 1 phlebotomy (the standard of care therapeutic phlebotomy on 
Day 1 [predose]), change in TSAT from baseline to Week 16 (24 [± 4] hours 
postdose). 
 For patients undergoing 2 or more phlebotomies, change in TSAT from baseline to 
the most recent postdose fasting TSAT observed prior to the second phlebotomy 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
11 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
(eg, the initial phlebotomy following the standard of care phlebotomy on Day 1 
[predose]). 
2.2.2. 
Secondary Efficacy Endpoints 
The secondary endpoints to be evaluated include: 
 Number of phlebotomies, from Day 2 to End of Study (EOS). 
 Change in serum ferritin, defined as follows: 
 For patients with 1 phlebotomy (the standard of care therapeutic phlebotomy on 
Day 1 [predose]), change in serum ferritin from baseline to Week 16 
(24 [± 4] hours postdose). 
 For patients undergoing 2 or more phlebotomies, change in serum ferritin from 
baseline to the most recent postdose serum ferritin observed prior to the second 
phlebotomy. 
2.2.3. 
Safety and Tolerability Endpoints 
The safety and tolerability endpoints to be evaluated include: 
 Adverse events (AEs) from consent to EOS. 
 Changes in clinical laboratory evaluations including serum iron parameters from 
baseline to EOS. 
 Changes in vital signs, electrocardiograms (ECGs), use of concomitant medications, 
and physical examinations from baseline to EOS. 
 Immunogenicity (anti-drug antibody)/pharmacokinetics (PK) from baseline to EOS. 
2.2.4. 
Exploratory Endpoints 
The exploratory endpoints to be evaluated include: 
 Change in serum iron parameters, defined as follows:  
 For patients with 1 phlebotomy (the standard of care therapeutic phlebotomy on 
Day 1 [predose]), change in serum iron parameters from baseline to Week 16 
(24 [± 4] hours postdose). 
 For patients undergoing 2 or more phlebotomies, change in serum iron parameters 
from baseline to the most recent postdose iron parameters observed prior to the 
second phlebotomy. 
 Change in thyroid function from baseline to Week 16. 
 Change in liver function from baseline to Week 16. 
 Change in hemoglobin A1c from baseline to Week 16. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
12 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
 Change in RBC parameters (hemoglobin concentration, RBC count, and RDW 
defined as follows: 
 For patients with 1 phlebotomy (the standard of care therapeutic phlebotomy on 
Day 1 [predose]), change in RBC parameter from baseline to Week 16 
(24 [± 4] hours postdose). 
 For patients undergoing 2 or more phlebotomies, change in RBC parameters from 
baseline to the most recent postdose RBC parameters observed prior to the second 
phlebotomy. 
 Change in Quality of Life Questionnaires, SF-36v2, WOMAC, and modified Dreisler 
indices for arthritis, from baseline to Week 16. 
 Change in serum iron parameters, defined as follows: 
 For patients with 1 phlebotomy (the standard of care therapeutic phlebotomy on 
Day 1 [predose]), change in serum iron parameters from baseline to Week 17 
(approximately 7 days after the last dose of study drug). 
 For patients undergoing 2 or more phlebotomies, change in serum iron parameters 
from baseline to the most recent predose serum iron parameters observed prior to 
the second phlebotomy. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
13 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This study is a multicenter, randomized, placebo controlled, single-blind study.  The primary 
objective of the study is to evaluate the effect of LJPC-401 versus placebo on TSAT in adults 
with hereditary hemochromatosis.  
Eligible patients will be randomized on a 1:1 schedule and blinded to study treatment, LJPC-401 
or placebo.  Randomization will be stratified by screening TSAT (> 45% to 70% versus > 70%) 
and phlebotomy frequency over the last 12 months (0 to 3 versus > 3). 
All randomized patients will receive standard of care therapeutic phlebotomy (500 cc or 
appropriate for weight) on Day 1 (predose).  Thereafter, phlebotomy decisions by the 
Investigator will be based on the patient’s fasting TSAT results collected at postdose 
24 (± 4) hours on Week 4 (Day 23); Week 8 (Day 51); Week 12 (Day 79); and Week 16 
(Day 107); and based on the TSAT criteria of the Iron Disorders Institute (IDI 2011) phlebotomy 
guidelines for patients with hereditary hemochromatosis.  If a phlebotomy is indicated, based on 
the TSAT criteria of the IDI guidelines, the patient should receive phlebotomy treatment, 
predose, on or before the following visit. 
The procedures to be performed throughout the study are outlined in the Schedule of Events in 
the study protocol (Table 3, Section 5.6). 
3.2. 
Treatment Assignment 
Patients will be dosed once-weekly with study drug of LJPC-401 or placebo administered 
subcutaneously for 16 weeks.   
For those patients randomized to placebo, a syringe of 0.9% sodium chloride injection, United 
States Pharmacopoeia (USP, or equivalent) will be prepared by the study pharmacist of designee.  
To maintain the study single-blind, syringes with study drug (placebo and active drug) will be 
identical. 
3.2.1. 
Dose Adjustment Criteria 
Dosing Adjustments: 
 Week 1:  5 mg LJPC-401 or placebo 
 Week 2:  10 mg LJPC-401 or placebo 
 Week 3:  10 mg LJPC-401 or placebo 
 Week 3:  fasting TSAT (postdose 24 [± 4] hours), ie, 20 to 28 hours, determines the 
Week 4 dose:  
 If the TSAT is > 45%, dose increased to 20 mg LJPC-401 or placebo 
 If the TSAT is ≤ 45%, dose remains at 10 mg LJPC-401 or placebo 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
14 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
 Week 4:  LJPC-401 (or placebo) dose as indicated by Week 3 fasting TSAT (10 to 
20 mg LJPC-401 or placebo) 
 At Weeks 9 and 13 (after Weeks 8 and 12 fasting TSAT results are available): 
 Maintain or increase dose to 20 mg if TSAT is > 45% 
 Maintain dose (10 or 20 mg) if TSAT remains ≤ 45%, and no dose reduction is 
required for toxicity.  
 For down titration, follow the safety criteria outlined in Section 3.2.2. 
Important Guidelines: 
1. The last central laboratory fasting TSAT result at Week 3 (Day 16), Week 8 (Day 51), 
and Week 12 (Day 79) will be used to determine if a dose adjustment is needed at 
Weeks 4, 9, and 13.  TSAT for dose adjustments must be collected 24 [± 4] hours 
postdose. 
2. If fasting TSAT level is greater than 45% collected at postdose 24 (± 4) hours on Week 4 
(Day 23); Week 8 (Day 51); Week 12 (Day 79); and Week 16 (Day 107), a phlebotomy 
(500 cc or appropriate for weight) is indicated, predose, on or before the following visit.     
3. Round TSAT with decimal values using the standard rounding rule. 
The pharmacist, or designee, will prepare the study drug (LJPC-401 or placebo) to ensure the 
patient will remain blinded.  Refer to the study specific Pharmacy Manual for detailed guidance. 
3.2.2. 
Safety Criteria for Adjustment of Stopping Doses 
For each individual patient, the safety criteria used to adjust (reduce) dosing include 1 or more of 
the following: 
1. injection site reaction(s) severity grade of severe 
2. patient cannot or will not tolerate the assigned number of injections 
For each individual patient, the safety criteria used to stop doses include 1 or more of the 
following: 
1. treatment-emergent adverse events (TEAEs), including injection site reaction(s) severity 
grade of severe or higher 
2. patient cannot or will not tolerate subcutaneous injection(s) 
3. clinically significant laboratory parameters, including if TSAT is less than 10% (if this 
occurs, consult the Medical Monitor) 
3.3. 
Criteria for Study Termination 
This study may be prematurely terminated if in the opinion of La Jolla, there is sufficient 
reasonable cause.  Written notification documenting the reason for study termination would be 
provided to the Investigators by La Jolla.  Circumstances that may warrant termination include, 
but are not limited to: 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
15 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
 Determination of unexpected, significant, or unacceptable risk to patients 
 Failure to enroll study patients at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Insufficient and/or unevaluable data 
 Plans to modify, suspend, or discontinue development of the study drug 
3.4. 
Sample Size Considerations 
A sample size of 48 patients has over 80% power to detect a 15% difference in the change in 
TSAT between the placebo arm and the LJPC-401 arm, assuming a common standard deviation 
(SD) of 18% and a 2-sided type I error of 0.05.   
The primary efficacy analysis and secondary efficacy analyses will include the Efficacy Patient 
Population defined as all patients enrolled under global protocol version 4.0/UK protocol 
version 4.1 or later who received study drug, and who completed the Week 16 assessments or 
had an on-study phlebotomy after the standard of care therapeutic phlebotomy on Day 1 
(predose) and before Week 16.   
Patients who do not enroll under global protocol version 4.0/UK protocol version 4.1 or later or 
discontinue the study early prior to dosing will be replaced (patients may be replaced for 
additional reasons as described in Section 3.6).  The plan is to enroll and randomize 
approximately 68 to 76 patients (1:1 to LJPC-401 or placebo) to ensure that at least 48 patients 
are included in the primary efficacy analysis.  
An interim analysis of efficacy data will be conducted after the first 16 patients from the Efficacy 
Patient Population (defined in Section 5.4) complete the Week 16 assessments or have an 
on-study phlebotomy after the standard of care therapeutic phlebotomy on Day 1 (predose) and 
before Week 16.  The Lan DeMets approach to the O’Brien-Fleming method for sequential 
designs will be applied to preserve the overall type I error rate resulting in type I rates of values 
of 0.00021 at the interim analysis (n = 16) and adjusted for all interim analyses at the final 
analysis (n = 48).  Any subsequent interim analyses will similarly include adjustment using the 
Lan DeMets approach to the O’Brien-Fleming method for sequential designs.   
3.5. 
Randomization, Stratification, and Blinding 
This is a randomized, placebo-controlled, single-blind study.  Central randomization will be 
performed using Interactive Voice/Web Response System (IXRS).  Eligible patients will be 
randomized on a 1:1 schedule to LJPC-401 or placebo.  Randomization will be stratified by 
screening TSAT (> 45% to 70% versus > 70%) and phlebotomy frequency over the last 
12 months (0 to 3 versus > 3). 
To maintain the study single-blind, syringes with study drug (placebo and active drug) will be 
identical.  


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
16 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
3.6. 
Replacement of Patients 
Patients who are randomized but terminate prior to dosing will be replaced and excluded from 
the safety and efficacy analyses.  Patients who have received study drug and terminate the study 
early may be replaced by decision of the Investigator and La Jolla.  Patients who do not enroll 
under global protocol version 4.0/UK protocol version 4.1 or later will be replaced and excluded 
from the primary efficacy analyses.  Approximately 20 to 28 patients are expected to be 
replaced.  Patients who consent and enroll under global protocol version 4.0/UK protocol version 
4.1 or later will be included in efficacy analyses.  All enrolled patients, regardless of protocol 
version, who receive at least 1 dose of study drug will be included in safety analyses (refer to 
Section 5.4 for definitions of analysis populations).   
Patient enrollment numbers are unique and will not be reassigned.  Patients cannot be 
re-randomized after the initial randomization for any reason.  Patients cannot re-enroll after 
withdrawing from the study for any reason. 
Note:  Prior to global protocol version 4.0/UK protocol version 4.1, a patient’s need for 
phlebotomy was based on a TSAT assessment performed predose on the day of study drug 
administration and approximately 7 days after the most recent study drug administration.  The 
amended study design (effective as of global protocol version 4.0/UK protocol version 4.1) 
determines a patient’s need for phlebotomy based on a TSAT assessment performed 
24 (± 4) hours postdose to reflect the TSAT status during treatment and not prior to study drug 
administration.  As such, patients who enrolled prior to global protocol version 4.0/UK protocol 
version 4.1 will be replaced to maintain study power for the efficacy analysis.  Patients enrolled 
prior to global protocol version 4.0/UK protocol version 4.1 continue to participate in the study 
and will be included in other analyses including safety analyses. 
 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
17 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
4. 
PLANNED ANALYSES 
4.1. 
Interim Analyses 
An interim analysis of efficacy will be conducted after the first 16 patients from the Efficacy 
Patient Population (defined in Section 5.4) complete the Week 16 assessments or have an 
on-study phlebotomy after the SOC phlebotomy on Day 1 (predose) and before Week 16.  The 
analysis will be based on hierarchical testing of the primary and secondary efficacy objectives 
comparing the effect of LJPC-401 versus placebo on TSAT, phlebotomy requirements, and 
serum ferritin in adult patients with hereditary hemochromatosis. 
The Lan DeMets approach to the O’Brien-Fleming method for sequential designs will be applied 
to preserve the overall type I error rate resulting in type I rates of values of 0.00021 at the interim 
analysis (n = 16) and adjusted for all interim analyses at the final analysis (n = 48).  Any 
subsequent interim analyses will similarly include adjustment using the Lan DeMets approach to 
the O’Brien-Fleming method for sequential designs.  At the interim analysis, if hierarchical 
testing results in a statistically significant Lan DeMets p-value for each of the 3 endpoints, then 
enrollment may be halted due to overwhelming efficacy. 
4.1.1. 
Safety Monitoring Committee 
In addition to the interim analysis of efficacy data, an internal Safety Monitoring Committee 
(SMC) will conduct an initial safety review during the same time period of the interim efficacy 
analysis.  Details, such as membership of the committee and timing of additional periodic safety 
review will be discussed in the SMC Charter. 
4.2. 
Final Analysis 
The final analyses will be performed after the SAP is finalized and the database is locked.  The 
details of data quality assurance and database lock are provided in Section 5.1. 
4.3. 
Changes from Planned Analyses 
Modifications to the planned statistical analyses should be minimized.  However, the data 
obtained from the study may indicate that the planned analyses are inappropriate or that 
additional analyses need to be performed due to factors such as the distribution of the data or the 
presence of important covariates.  Any deviations from the planned statistical analyses will be 
reported in the CSR. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
18 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
5. 
GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSES 
5.1. 
Data Quality Assurance 
During the conduct of the study, monitor(s) representing the Sponsor will visit the investigative 
sites at regular intervals.  During these visits, the monitor will verify adherence to the protocol 
and the completeness, consistency, and accuracy of the data being entered on the electronic 
Case Report Form (eCRF) (source data validation) and resolve outstanding data discrepancies 
(queries).  It is the Investigator’s responsibility to ensure the accuracy, completeness, and 
timeliness of the data reported for each patient.  The monitor will have access to laboratory test 
reports and other patient records needed to verify entries on the eCRF.  After site initiation, the 
monitor will have access to the pharmacy inventory and dispensing records for study treatments. 
Data management (DM) is planned to be performed by a contract research organization (CRO).  
Data entry to the eCRF and resolution of queries will be performed by the study site personnel.  
Queries will be generated either automatically or manually within the data management system.  
Each query will be attached to the corresponding data item and contain the discrepancy message.  
The investigator or study coordinator will resolve the queries as soon as possible by editing data 
on the eCRF and/or providing clarification for the discrepancy. 
Sponsor personnel, including the study biostatistician, statistical programmer, medical monitor, 
clinical and data management team will also perform manual reviews of data on a periodic basis 
for data consistency across forms, logic across visits, patient completeness, and reconciliations 
using the most current Statistical Analysis System (SAS) programmed data listings.  A Data 
Review Plan will formally outline and specify the review to be performed.  A Data Access Plan 
will identify sponsor personnel or functional group access to specific data.  Discrepancies 
identified during the manual review process will be generated by DM to be subsequently 
addressed by the site. 
All queries generated during the course of the study, as well as any resulting data changes due to 
responses to queries, will be tracked within an audit trail.  Resolved queries that do not result in a 
data change will be reviewed by DM, or the person who created the query, to accept the data as 
is, or generate another query for subsequent resolution.  The process will be repeated until all 
data are deemed complete, clean, reconciled, and, if appropriate, monitored through a Database 
Freeze/Lock Checklist and signed-off prior to database freeze/lock. 
Safety laboratory samples (complete iron studies, hematology, serum chemistry) and 
immunogenicity samples will be collected at the sites and analyzed at the central laboratories.  If 
emergency or safety samples are analyzed by local labs, each laboratory’s units and reference 
ranges will be forwarded to DM. 
The protocol deviations log will be completed by the study monitors and periodically reviewed 
by the Sponsor.  Categories (important/minor) will be assigned to the protocol deviations by the 
medical monitor.  The monitor will enter deviations regarding study drug onto the deviation log.  
The log and assignments will be finalized prior to the database freeze/lock.  All important 
deviations will be included in the final database. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
19 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
All requests to unlock the database after database lock will be assessed by La Jolla and will 
follow relevant standard operating procedures. 
5.2. 
Data Standardization 
The Clinical Data Interchange Standards Consortium (CDISC) encompasses a suite of standards 
across the clinical space widely accepted by regulatory authorities.  CDISC standards enables the 
drug development process to become more efficient by improving data flow and allowing a 
common understanding of data across the industry.  The CDISC datasets, Study Data Tabulation 
Model (SDTM) and Analysis Data Model (ADaM) datasets, are generated to support statistical 
programming of the tables, listings, and figures (TLFs).  An implementation guide for both 
CDISC models provides guidance on how to map collected data into SDTM and ADaM datasets.  
Where SDTM contains all the clinical data collected from the study and ADaM reconfigures the 
data as needed for analyses. 
Datasets received from the eCRF will be converted to the most recent version of CDISC SDTM 
and ADaM datasets.  If updates to CDISC SDTM and/or ADaM datasets are initiated mid-study, 
La Jolla will determine which version will be implemented.  
Supplemental documents to support CDISC datasets, such as the define document (.pdf or .xml 
format) to describe the metadata and the reviewer’s guide to give additional context of the 
datasets, will be generated.  To ensure that SDTM and ADaM datasets meet expectations, the 
datasets are validated for: 
 output quality through double programming per internal standard operating 
procedures, and  
 compliance against CDISC standards per leading industry utilities such as 
Pinnacle21’s CDISC validator. 
5.3. 
General Considerations 
Continuous (quantitative) variables will be summarized using descriptive statistics, including the 
number of observations, mean, SD, minimum, median, and maximum values.  Other descriptive 
statistics such as lower quartile, upper quartile, geometric mean, and geometric SD may be 
calculated if appropriate. 
Categorical (qualitative) variables will be summarized by the number of observations and 
percentages.  Unless otherwise stated, the calculation of proportions will be based on the sample 
size of the population of interest.  
Data will be summarized by treatment group, study visit, and if appropriate, study interval.  If 
warranted, a log transformation may be applied to laboratory data. 
Statistical comparisons of differences between treatment groups may include: 
 Analysis of variance (ANOVA), mixed effects repeated measures, and/or Wilcoxon 
rank-sum test for continuous variables  


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
20 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
 Chi-Square, Cochran-Mantel-Haenszel (CMH), or Fisher’s exact test for categorical 
variables 
 Poisson regression model for count variables (ie, number of phlebotomies)  
All statistical tests will be performed using 2-sided, 5% significance levels, unless otherwise 
specified.  The assumptions underlying the statistical tests applied will be evaluated for 
appropriateness (ie, sample distribution, paired or correlated data, equality of variances).  
Confidence intervals will be done at 95%, unless otherwise specified. 
All analyses will be performed using SAS, Version 9.4 or later (SAS Institute, Cary, NC).  
Graphic displays may be produced using SAS, S-Plus or R, Version 3.1.1 or later (R Foundation 
for Statistical Computing, Vienna, Austria).  A list of the TLFs that will be generated for this 
study can be found in Section 9.  
5.4. 
Analysis Populations 
Analysis populations will be defined as follows: 
 Intent to Treat (ITT) Population:  all randomized patients, as randomized   
 Modified Intent to Treat (mITT) Population:  enrolled patients, as randomized, who 
received at least 1 dose of study drug  
 Efficacy Population:  enrolled patients under global protocol version 4.0/UK 
version 4.1 or later, as randomized, who received study drug, and who completed 
4 months (Week 16) on study or who had at least 1 phlebotomy after the SOC 
therapeutic phlebotomy on Day 1 (predose) and before Week 16 
 Per Protocol Population (PP):  Efficacy patients, without any important protocol 
deviations 
 Safety Population:  enrolled patients, as treated, who received at least 1 dose of study 
drug 
 PK Population:  enrolled patients, as treated, who received at least 1 dose of study 
drug and for whom at least 1 PK parameter can be estimated 
Summaries will not be reproduced for identical patient populations (eg, if all patients are treated 
as randomized, resulting in identical mITT Population and Safety Population analysis will not be 
produced for each analysis populations). 
5.5. 
Definitions and Derived Data  
An adverse event is defined as any untoward medical occurrence in a patient, or clinical 
investigation subject, administered a pharmaceutical product and which does not necessarily 
have a causal relationship with the treatment.   
An AE can be any unfavorable or unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not it is considered to be related to the medicinal product.   


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
21 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
AEs include, but are not limited to: (1) a worsening or change in nature, severity, or frequency of 
condition(s) present at the start of the study; (2) subject deterioration due to primary illness; 
(3) intercurrent illness; and 4) drug interaction.  For recording purposes, pregnancy is a medical 
condition and is not considered an AE. 
Age will be calculated as the integer floor value in years of the difference between the date of 
enrollment and the date of birth. 
Age = integer floor [(Date of Enrollment – Date of Birth + 1) / 365.25] 
If the day of birth is missing, the first day (01) of the month will be imputed.  If both the day and 
month of birth are missing, the first day of the year will be imputed.  For more details on 
handling of missing data see Section 5.7. 
For patients randomized, but did not receive study drug, the difference between the date of visit 
and date of enrollment Study Day will be calculated as follows: 
If Date of Visit is before the Date of Enrollment, then: 
Day = Date of Visit – Date of Enrollment 
If the Date of Visit is on or after the Date of Enrollment, then: 
Day = (Date of Visit – Date of Enrollment) + 1 
For patients who received any amount of study drug, the difference between the date of visit and 
the date of first study drug administration in days.  
If Date of Visit is before the Date of First Study Drug Administration, then: 
Day = Date of Visit – Date of First Study Drug Administration 
If the Date of Visit is on or after the Date of First Study Drug Administration, then: 
Day = (Date of Visit – Date of First Study Drug Administration) + 1 
Day 1 is the first day of study drug administration.  Day −1 is the day immediately preceding the 
first day of study drug administration.  There is no Day 0. 
Study Time will be calculated as the difference between the date/time of visit and the date/time 
of first study drug administration or enrollment data for patients without study drug.  Time will 
be displayed in hours and minutes in the format HH:MM.  If the time of visit or the time of first 
study drug administration is not available, then the study time will not be calculated.  There will 
be no imputation of collection times. 
Time = Date/Time of Visit – Date/Time of First Study Drug Administration 
Baseline measurement will generally be defined as: 
 For patients randomized who did not receive study drug, the last measurement prior 
to randomization, or   
 For patients who received any amount of study drug, the last measurement prior to 
the first study drug administration date/time (either LJPC-401 or placebo).  If only the 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
22 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
date is available and not a time, the baseline measurement will be defined as the last 
measurement on or prior to the day of study drug administration. 
Visit Windows:  Visit date/times will be compared to nominal visits for consistency.  
Discrepancies may be queried to update the visits to a more appropriate visit category or to an 
unscheduled visit. 
Change from baseline will be calculated as the difference between the value being analyzed and 
the value at baseline.  If the value being analyzed or the value at baseline is not available, then 
the change from baseline value will not be calculated. 
Change from Baseline = Value Being Analyzed – Value at Baseline 
End of Study (EOS) is the date/time of the last study visit (per the protocol scheduled as 
30 [+ 3] days after the last dose of study drug). 
End of Treatment (EOT) is the date/time of the last study drug administration.  The EOT visit is 
scheduled for Week 16. 
Study drug is placebo (0.9% sodium chloride injection, USP [or equivalent]) or LJPC-401. 
Treatment-emergent adverse event (TEAE) are those AEs that occur or worsen on or after the 
first study drug administration through EOS (30 [+3] days after last dose of study drug).  
Note:  if onset date is unknown, the AE is assumed to be treatment emergent. 
Serious adverse event (SAE) is defined as an AE with at least 1 of the following events: 
 Results in death - An AE that caused or contributed to a fatal outcome. 
 Is life-threatening - Refers to an event/reaction in which the patient was at risk of 
death at the time of the event/reaction.  It does not refer to an event/reaction which 
hypothetically might have caused death if it were more severe.    
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity.   
 Results in a congenital anomaly/birth defect. 
 Important medical events when based upon appropriate medical judgment, may 
jeopardize the patient may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition. 
Number of phlebotomies is defined as the number of phlebotomies from Day 2 to EOS. 
Number of times a patient met criteria for a phlebotomy is defined as number of times from 
Day 2 to EOS that 1 of the following conditions is met: 
a. Patient received a phlebotomy. 
b. Patient had a fasting TSAT > 45%, but the patient refused/missed a phlebotomy, or 
the treating physician decided against a phlebotomy within the next 7 days.  Whether 
a patient meets the criteria for a phlebotomy (yes or no) will be assessed after the 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
23 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
results of each fasting TSAT recorded at postdose 24 (±4) hours on Weeks 4 (Day 
23), 8 (Day 51), 12 (Day 79), and 16 (Day 107) are known.  
5.6. 
Definition of Subgroups 
The following subgroups are considered of interest to comparatively explore the treatment effect:   
 Age:  < 65 years versus ≥ 65 years  
 Sex:  male versus female 
 Race:  White versus non-White 
 Ethnicity:  Hispanic or Latino versus Not Hispanic or Latino 
 Country:  United States of America, Australia, United Kingdom, and France (may be 
collapsed prior to data freeze) 
 Geographic regions:  (to be determined based on enrolling countries) 
 Body mass index (BMI):  < 30 kg/m2; ≥ 30 kg/m2 (BMI = weight(kg)/height(m)2) 
 HH Genotype:  HFE versus non-HFE 
 Screening TSAT:  > 45% to 70% versus > 70% 
 Phlebotomy frequency over the last 12 months:  0 to 3 versus > 3 
Note:  For the following items, baseline is considered the last blood sample collection 
prior to the required phlebotomy of Day 1. 
 Baseline TSAT (last draw prior to required phlebotomy on Day 1):  > 45% to 70% 
versus > 70%  
 Baseline hepcidin levels (last draw prior to required phlebotomy on Day 1):  
< median versus ≥ median 
 Baseline serum iron levels (last draw prior to required phlebotomy on Day 1):  
< median versus ≥ median 
 Baseline serum ferritin levels (last draw prior to required phlebotomy on Day 1):  
< median versus ≥ median 
5.7. 
Handling of Missing Data 
Missing values will not be estimated or imputed unless otherwise specified below.  All data will 
be included in safety analysis.  
Incomplete dates from medical history, AE, and concomitant medication logs will be imputed to 
calculate the study day and durations as follows: 
 Start/Onset Date: 
 If missing month, month will be imputed to January 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
24 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
 If missing day, day will be imputed with the first of the month 
For AEs, if the imputed date results in a date before the date of first study drug 
administration, then the of first study drug administration will be used, unless month 
is known and is prior to the dosing month, in which case the imputed date will be 
used. 
 End/Resolution Date:  If missing day and/or month, the day will be replaced with the 
last day of the month and the month will be replaced with December.  If the imputed 
date results in a date later than the date of death, then the date of death will be used. 
In patient data listings, incomplete dates will be displayed as entered on the eCRF without any 
imputations.  Study days will be derived with imputation and displayed in the data listings.  


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
25 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
6. 
POPULATION, ENROLLMENT, AND DEMOGRAPHICS 
6.1. 
Informed Consent 
A summary of the number of patients consenting under each version will be provided by analysis 
population.  A listing will also be provided.  Select analyses, excluding patients who consented 
prior to global protocol version 4.0/UK protocol version 4.1 and/or who did not agree to consent 
to later versions, may be provided.  
6.2. 
Patient Disposition 
Patient disposition will be summarized for all randomized patients by treatment group and total 
as follows: 
 Number of patients randomized in the study 
 Number of patients in each analysis population 
 Treatment initiated? (yes or no) 
 Last visit completed 
 Did the patient complete treatment? (yes or no) 
 If no, primary reason for discontinuation of treatment 
 Patient alive at EOT? (yes or no) 
 Was Day 30 follow-up conducted? (yes or no) 
 Did the patient complete the study? (yes or no) 
 If no, primary reason for study discontinuation 
 Patient alive at EOS visit? (yes or no) 
6.3. 
Enrollment 
For the ITT, Efficacy, mITT, and Safety Populations, patient enrollment (n and %) will be 
summarized by treatment group and total for country (Australia, France, United Kingdom, and 
United States of America,) and site. 
6.4. 
Protocol Deviations 
For the ITT, Efficacy, mITT, and Safety Populations, important protocol deviations will be 
summarized (n and %) by treatment group and total for any important protocol deviation and by 
deviation category (eg, Inclusion/Exclusion, Treatment Assignment or Dose Deviation, Protocol 
Procedure Deviation, etc.). 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
26 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
6.5. 
Randomization Stratification 
For the ITT, Efficacy, mITT, and Safety Populations, summaries (n and %) of patients will be 
provided by treatment group and total for randomization strata (screening TSAT [> 45% to 70% 
versus > 70%] and phlebotomy frequency over the last 12 months [0 to 3 versus > 3]). 
In addition, for the ITT, Efficacy, mITT, and Safety Populations, summaries (n and %) of 
patients will be provided by treatment group and total for randomization versus clinical database 
(screening TSAT [> 45% to 70% versus > 70%] and phlebotomy frequency over the last 
12 months [0 to 3 versus > 3]). 
6.6. 
Demographics and Baseline Characteristics 
For the ITT, Efficacy, mITT, and Safety Populations, demographics and baseline characteristics 
will be summarized descriptively (categorical variables [n and %] and continuous variables 
[n, mean, SD, median, and range]) by treatment group for the following: 
 Age category (< 65 years,  65 years) and age (years) 
 Sex (male, female) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 Race 
 American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, Other 
 White or non-White 
 Baseline weight (kg) 
 Baseline height (cm) 
 Baseline BMI category (< 30 kg/m2,  30 kg/m2) and BMI (kg/m2) 
 Baseline TSAT, where baseline is considered the last blood sample collection prior to 
the required phlebotomy of Day 1. 
 Baseline phlebotomy frequency over the last 12 months 
 Geographic region (to be determined based on enrolling countries) 
 Childbearing potential (yes, no) 
 Genotype (if available) 
Depending on study results, demographic summaries may be repeated by another characteristic 
(eg, by geographic region, by total LJPC-401 dose, by mean overall LJPC-401 dose).  
In addition, statistical comparisons of differences between treatment arms will be made using 
Wilcoxon rank-sum tests for continuous or ordinal variables, Chi-Square tests for discrete 
variables, and Fisher’s exact tests for binary variables. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
27 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
6.7. 
Medical History 
For the Efficacy, ITT, mITT, Safety Populations, medical history will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) most recent version and grouped by 
system organ class (SOC) and preferred term (PT).  The coded terms will be summarized by 
treatment group, SOC, and PT in alphabetical order as the number of conditions/events and the 
number and percentage of patients with a condition or experiencing an event 1 or more times. 
In addition, summaries for most frequent medical history may be repeated where “most frequent” 
is defined as a medical event occurring in > X% of the sample in either treatment arm, where 
X% will be determined from the data. 
6.8. 
Prior and Concomitant Medications 
For the Efficacy and Safety Population, prior and concomitant medications will be summarized 
separately.  Prior medications are those with a start date within 14 days prior to Screening.  
Concomitant medications are medications that are taken any time while on study (on or after first 
study drug administration).  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD) most recent version and grouped by Anatomical Therapeutic Chemical 
(ATC) classification system and PT.  The coded medications will be summarized as the number 
of medications and the number and percentage of patients receiving medication 1 or more times.  
Summaries will be by treatment group, ATC, and PT in alphabetical order. 
6.9. 
Prior and Concomitant Phlebotomy Procedures 
For the ITT, Efficacy, mITT, and Safety Population, prior phlebotomy frequency (number 
received during the 12 months prior to randomization) and concomitant phlebotomy procedures 
(number received on study) will be summarized categorically ([0, 1, 2, 3, 4, etc.], n, and percent) 
and continuously (n, mean, SD, median, and range) by treatment group. 
6.10. 
On Study Non-medication Therapy / Procedures 
On study non-medication therapy/procedures will be reported in patient listings. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
28 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
7. 
EFFICACY 
Analysis of efficacy will be conducted on the Efficacy Population and using the randomization 
strata (see Section 3.5).  In addition, summaries including the mITT Population will be done for 
efficacy endpoints besides the serum iron parameters. 
If discrepancies exist in the Efficacy Population, between as treated and as randomized patients, 
efficacy analyses may be reproduced using data from patients as treated; however, these analyses 
will be considered secondary. 
7.1. 
Test of Hypothesis 
It is hypothesized that patients treated with LJPC-401 will have a different change in TSAT from 
baseline to the earlier of Week 16 (24 [± 4] hours postdose) or the most recent postdose fasting 
TSAT observed prior to the second phlebotomy (eg, the initial phlebotomy following the 
standard of care phlebotomy on Day 1 [predose]) than those treated with placebo. 
Null Hypothesis: 
 
 
µactive = µplacebo 
Alternative Hypothesis: 
 
µactive ≠ µplacebo 
where µ is the change in TSAT.  
7.2. 
Primary Efficacy Analysis:  Postdose TSAT 
The primary efficacy endpoint will be analyzed using a general linear model with adjustment for 
screening TSAT (> 45% to 70% versus > 70%) and phlebotomy frequency over the last 
12 months (0 to 3 versus > 3).  A 2-tailed alpha of 0.05 will be used in testing the hypothesis of 
treatment difference with alpha adjustments, as appropriate, for interim analyses.   
The primary analysis will utilize the randomization stratification.  Sensitivity analyses utilizing 
the clinical database stratification and an unstratified analysis will be conducted as appropriate. 
7.2.1. 
Expanded Efficacy Population:  Primary Efficacy Variable 
If five or more patients enrolled after global protocol version 4.0/UK protocol version 4.1 
discontinue prior to Week 16 without a second prior phlebotomy and were excluded from the 
Efficacy Population, two additional analyses of change in TSAT from baseline to Week 16 
(24 [± 4] hours postdose) will be conducted.   
 Patients discontinuing early without prior phlebotomy will be included in the analysis by 
use of last observation carried forward (LOCF), with the most recent TSAT observed at 
postdose on Weeks 3, 4, 8, and 12 used as the observation carried forward.  LOCF data 
will be analyzed using a general linear model with adjustment for screening TSAT 
(> 45% to 70% and > 70%) and frequency of phlebotomy procedure over the last 
12 months (0 to 3 and > 3). 
 Patients will be analyzed via a mixed effects repeated measures analysis on TSAT 
observations at 24 [± 4] hours postdose on Weeks 3, 4, 8, 12, and 16 with patient as a 
random factor. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
29 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
7.2.2. 
Univariate Subgroup Analyses:  Primary Efficacy Variable 
Univariate subgroup analyses utilizing the subgroups of interest defined in Section 5.6 may be 
analyzed for the primary efficacy endpoint as follows:  
 Treatment effect analyzed within subgroup 
 Subgroup effect analyzed within treatment group 
 Treatment effect in the general linear model stratified by subgroup covariate 
 Subgroup by treatment interaction in the general linear model 
7.2.3. 
By-site Analyses:  Primary Efficacy Variable 
The presence of a site effect and site by treatment interaction will be examined using a general 
linear model with adjustment for site and site by treatment interaction.  Alpha of 0.15 will be 
used for testing of site effects.  Selection of sites for the modeling will be conducted after 
enrollment has been completed.  
7.2.4. 
Multivariate Analyses:  Primary Efficacy Variable 
In addition, multivariate analysis may be performed utilizing the subgroups of interest defined in 
Section 5.6.  Treatment, screening TSAT randomization strata (> 45% to 70% versus > 70%), 
baseline phlebotomy randomization strata over the last 12 months (0 to 3 versus > 3), age 
category, and sex are considered as fixed factors in the model.  A stepwise general linear model 
with covariates defined by the subgroups cutoffs will be evaluated.  The values used for 
classification are generally designed based on a prior classification of interest or to split the 
population in half; if a subgroup classification results in less than 10% of the population in 
1 category, the subgroup factor will be dropped from the model.  A stepwise selection process 
will be used to determine the inclusion of each covariate in the analysis model.  For the 
covariates, the significant level to enter the model is 0.15 and the level to stay is 0.05.  Only 
significant parameters will be presented in the final model.  Treatment by variable interaction 
terms may also be explored. 
7.2.5. 
Exploratory Analysis of Week 17 TSAT 
Change from baseline to Week 17 (approximately 7 days after the last dose of study drug) or the 
most recent postdose fasting TSAT observed prior to the second phlebotomy (eg, the initial 
phlebotomy following the standard of care phlebotomy on Day 1 [predose]) will be analyzed 
using a general linear model with adjustment for screening TSAT (> 45% to 70% versus > 70%) 
and phlebotomy frequency over the last 12 months (0 to 3 versus > 3).  Additional analyses as 
proposed for the primary endpoint at Week 16 may be conducted for Week 17. 
7.2.6. 
Additional Summaries of TSAT 
TSAT will be summarized (n, mean, SD, median, range) and plotted (mean) by treatment group 
for all visits (Screening, predose, and 24 [± 4] hours postdose at Weeks 3, 4, 8, 12, 16, and a 
single value collected at Week 17 and at EOS. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
30 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
In addition, TSAT summaries (n, mean, SD, median, range) of lowest postbaseline value, highest 
postbaseline value, and value at last postbaseline visit will be provided separately by treatment 
group.   
TSAT change from baseline and percent change from baseline will be summarized in a similar 
manner. 
7.3. 
Secondary Efficacy Analyses 
7.3.1. 
Number of Phlebotomies 
The key secondary analysis included number of times a patient had a phlebotomy or met criteria 
for a phlebotomy.   
Number of phlebotomies and number of times a patient met criteria for a phlebotomy (as defined 
in Section 5.5) will be analyzed for the Efficacy Population as follows: 
 The frequency of a phlebotomy will be analyzed using Poisson regression stratified 
by screening TSAT (> 45% to 70% versus > 70%) and phlebotomy frequency over 
the last 12 months (0 to 3 versus > 3) and with offset to account for time at risk.  
Time at risk is defined as the last date of postdose TSAT collection, phlebotomy, or 
study drug exposure.  
 The time to the first phlebotomy (following the standard of care phlebotomy on Day 1 
[predose]) will be analyzed using a logrank test stratified by screening TSAT (> 45% 
to 70% versus > 70%) and phlebotomy frequency over the last 12 months (0 to 3 
versus > 3).  Patients who do not have a phlebotomy will be censored at their last on-
study assessment. 
 The presence of any phlebotomy will be analyzed using CMH test stratified by 
screening TSAT (> 45% to 70% versus > 70%) and phlebotomy frequency over the 
last 12 months (0 to 3 versus > 3).  Patients who do not complete Week 16 will be 
categorized as experiencing a phlebotomy (yes or no) based on their available data.  
 If data warrant, similar analyses may be conducted on alternative categorizations 
(ie, number of patients who experience at least 2 phlebotomies). 
The primary analysis will utilize the randomization stratification.  Sensitivity analyses utilizing 
the clinical database stratification and an unstratified analysis will be conducted as appropriate. 
7.3.1.1. 
Sensitivity Analysis:  Patients Not Completing Week 16 
If five or more patients enrolled after global protocol version 4.0/UK protocol version 4.1 
discontinue prior to Week 16 without a second prior phlebotomy and were excluded from the 
Efficacy Population, analyses will be conducted on the number of phlebotomies and number of 
times a patient met criteria for a phlebotomy as follows: 
 Frequency of phlebotomy will be analyzed by Poisson regression model stratified by 
screening TSAT (> 45% to 70% versus > 70%) and phlebotomy frequency over the 
last 12 months (0 to 3 versus > 3).  Offset will account for time at risk. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
31 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
 The time to the first phlebotomy (following the standard of care phlebotomy on Day 1 
[predose]) will be analyzed using a logrank test stratified by screening TSAT (> 45% 
to 70% versus > 70%) and phlebotomy frequency over the last 12 months (0 to 3 
versus > 3).  Patients who do not have a phlebotomy will be censored at their last on-
study assessment. 
 The presence of any phlebotomy will be analyzed using CMH test stratified by 
screening TSAT (> 45% to 70% versus > 70%) and phlebotomy frequency over the 
last 12 months (0 to 3 versus > 3).   
 If data warrant, similar analyses may be conducted on alternative categorizations 
(ie, number of patients who experience at least 2 phlebotomies). 
7.3.1.2. 
Univariate Subgroup Analyses 
Univariate subgroup analyses utilizing the subgroups of interest defined in Section 5.6 may be 
analyzed for the frequency of phlebotomy as follows:  
 Treatment effect analyzed within subgroup 
 Subgroup effect analyzed within treatment group 
 Treatment effect in the general linear model stratified by subgroup covariate 
 Subgroup by treatment interaction in the general linear model 
7.3.1.3. 
Multivariate Analyses 
A multivariate logistic regression will be performed on patients receiving at least 1 phlebotomy 
(yes or no) utilizing the subgroups of interest defined in Section 5.6.  Treatment, screening TSAT 
(> 45% to 70% versus > 70%), phlebotomy frequency over the last 12 months (0 to 3 versus 
> 3), age category, and sex are considered as fixed factors in the model.  A stepwise logistic 
regression model with covariates defined by the subgroups cutoffs will be evaluated.  The values 
used for classification are generally designed based on a prior classification of interest or to split 
the population in half; if a subgroup classification results in less than 10% of the population in 
1 category, the subgroup factor will be dropped from the model.  A stepwise selection process 
using the likelihood ratio test will be used to determine the inclusion of each covariate in the 
logistic regression model.  For the covariates, the significant level to enter the model is 0.15 and 
the level to stay is 0.05.  Only significant parameters will be presented in the final model.  The 
odds ratio for the treatment effect adjusting for other prognostic factors will be reported along 
with 95% confidence interval.  Treatment by variable interaction terms may also be explored. 
7.3.2. 
Secondary Efficacy Analyses:  Serum Ferritin 
7.3.2.1. 
Serum Ferritin 
The secondary efficacy endpoint of change from baseline in serum ferritin will be analyzed using 
a general linear model with adjustment for screening TSAT (> 45% to 70% versus > 70%) and 
phlebotomy frequency over the last 12 months (0 to 3 versus > 3).  To account for the large 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
32 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
variation in baseline serum ferritin concentrations, the primary analysis will be based on the 
percent change from baseline.     
Change in serum ferritin, defined as follows: 
 
For patients with 1 phlebotomy (the standard of care therapeutic phlebotomy on 
Day 1 [predose]), change in serum ferritin from baseline to Week 16 (24 [± 4] hours 
postdose). 
 
For patients undergoing 2 or more phlebotomies, change in serum ferritin from 
baseline to the most recent postdose serum ferritin observed prior to the second 
phlebotomy. 
7.3.2.2. 
Sensitivity Analysis:  Serum Ferritin 
Sensitivity analyses will also be conducted for the Efficacy Population with separate analyses for 
predose and postdose measure and for the mITT Population for the predose measure:  
 Postdose Analysis:  Change from baseline to 24 (± 4) hours postdose at Weeks 3, 4, 
8, 12, and 16. 
 Predose Analysis:  Change from baseline to predose at Weeks 3, 4, 8, 12, and 16, and 
at Week 17. 
A mixed effects repeated measures analysis with adjustments for screening TSAT (> 45% to 
70% versus > 70%), frequency of phlebotomy procedure over the last 12 months (0 to 3 versus > 
3), and patient (as a random factor) will be conducted in addition to the by visit analyses. 
Additional sensitivity analyses may be conducted on serum ferritin similarly to the primary 
analysis on serum TSAT. 
7.4. 
Exploratory Efficacy Analyses 
7.4.1. 
Exploratory Efficacy Analyses:  Other Iron Parameters 
The serum iron parameters of total serum iron, transferrin, ferritin, apoferritin, holoferritin, 
unsaturated iron-binding capacity (UIBC), total iron-binding capacity (TIBC), will be analyzed 
using a general linear model with adjustment for screening TSAT (> 45% to 70% versus > 70%) 
and phlebotomy frequency over the last 12 months (0 to 3 versus > 3).  For each serum iron 
parameter, separate analyses will be conducted for predose and postdose measures. 
7.4.1.1. 
Sensitivity Analyses:  Other Iron Parameters 
Sensitivity analyses will also be conducted for the Efficacy Population with separate analyses for 
predose and postdose measure and for the mITT Population for the predose measure:  
 Postdose Analysis:  Change from baseline to 24 (± 4) hours postdose at Weeks 3, 4, 
8, 12, and 16. 
 Predose Analysis:  Change from baseline to predose at Weeks 3, 4, 8, 12, and 16, and 
at Week 17. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
33 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
A mixed effects repeated measures analysis with adjustments for screening TSAT (> 45% to 
70% versus > 70%), frequency of phlebotomy procedure over the last 12 months (0 to 3 versus > 
3), and patient (as a random factor) will be conducted in addition to the by visit analyses. 
Additional sensitivity analyses may be conducted on the other iron parameters similarly to the 
primary analysis on serum TSAT. 
7.4.2. 
Exploratory Efficacy Analyses:  Change in Thyroid Function 
Thyroid function (triiodothyronine [T3], thyroxine [T4], thyroid-stimulating hormone [TSH], 
and free T4) will be analyzed as exploratory variables.  For each thyroid function test, change 
from baseline will be calculated and the change from baseline to Week 16 will be analyzed using 
a general linear model with adjustment for screening TSAT (> 45% to 70% versus > 70%) and 
frequency of phlebotomy procedure over the last 12 months (0 to 3 versus > 3).  
7.4.3. 
Exploratory Efficacy Analyses:  Change in Liver Function 
Liver function (albumin, alkaline phosphatase, alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], bilirubin [total, indirect, and direct], lactate dehydrogenase [LDH], and 
total protein) will be analyzed as exploratory variables.  For each liver function test, change from 
baseline to each postbaseline visit (Weeks 1, 4, 8, 12, 16 and 20 [follow-up]) will be calculated 
and the change from baseline to Week 16 will be analyzed using a general linear model with 
adjustment for screening TSAT (> 45% to 70% versus > 70%) and frequency of phlebotomy 
procedure over the last 12 months (0 to 3 versus > 3).   
7.4.4. 
Exploratory Efficacy Analyses:  Change in Glycemic Control 
Hemoglobin A1c will be analyzed as exploratory variables.  Change from baseline will be 
calculated and the change from baseline to Week 16 will be analyzed using a general linear 
model with adjustment for screening TSAT (> 45% to 70% versus > 70%) and frequency of 
phlebotomy procedure over the last 12 months (0 to 3 versus > 3).  
7.4.5. 
Exploratory Efficacy Analyses:  Change in RBC Parameters 
RBC parameters (hemoglobin concentration, RBC count, and RDW) will be analyzed as 
exploratory variables.  For each RBC test, change from baseline to each to each postbaseline 
visit (Weeks 1, 4, 8, 12, 16 and 20 [follow-up]) will be calculated and the change from baseline 
to Week 16 will be analyzed using a general linear model with adjustment for screening TSAT 
(> 45% to 70% versus > 70%) and phlebotomy frequency over the last 12 months (0 to 3 versus 
> 3). 
7.4.6. 
Exploratory Efficacy Analyses:  Change in Quality of Life 
Total SF-36v2, WOMAC, and modified Dreisler indices for arthritis scores will be calculated 
according to the authors’ instructions.  The total score as well as the 8 subscales will be analyzed 
as exploratory variables.  For the total score of each subscale, change from baseline to Week 16 
will be calculated and then analyzed using a general linear model with adjustment for screening 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
34 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
TSAT (> 45% to 70% versus > 70%) and frequency of phlebotomy procedure over the last 
12 months (0 to 3 versus > 3).   
7.5. 
Multiplicity Adjustment 
The hypothesis test of patients treated with LJPC-401 versus placebo for the primary efficacy 
endpoint is not affected by multiplicity.  Hierarchical testing will be used to preserve the overall 
type I error across the testing of secondary endpoints.  Hierarchical testing will proceed as 
follows: 
1. Given a significant treatment effect for the primary efficacy endpoint, an analysis of the 
first secondary endpoint (number of phlebotomies from Day 2 to End of Study) will 
proceed and will be tested for statistical significance. 
2. Given a significant treatment effect for the primary efficacy endpoint and the first 
secondary efficacy endpoint, an analysis of the second secondary endpoint (change in 
serum ferritin) will proceed and will be tested for statistical significance. 
The Lan DeMets approach to the O’Brien-Fleming method for sequential designs will be applied 
to preserve the overall type I error rate.  It is expected that a type I rate of 0.00021 will be 
applied for the interim analysis (n = 16) and adjustment for all interim analyses will be applied 
for the final analysis (n = 48).  At the interim analysis, if hierarchical testing results in a 
statistically significant Lan DeMets p-value for each of the 3 endpoints, then enrollment may be 
halted due to overwhelming efficacy.  


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
35 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
8. 
SAFETY AND TOLERABILITY 
8.1. 
Adverse Events 
Adverse events will be coded using the most recent version at time of database lock of MedDRA 
and grouped by SOC and PT.  The coded terms will be summarized by treatment group, SOC, 
and PT in alphabetical order as the number of events, and the number and percentage of patients 
experiencing an event 1 or more times.  
Adverse events (AEs) of special interest may be defined by La Jolla to support the 
characterization of the safety profile of LJPC-401 across SOCs and/or PTs.   
Adverse events will be graded for severity using mild, moderate, severe, life-threatening, and 
fatal (Table 2).  Relatedness, and seriousness of AEs will be summarized (see Table 4 in 
Section 11.2 of the protocol).   
TEAEs are those AEs that occur or worsen on or after the first study drug administration through 
EOS, 30 days after last dose of study drug.  
AEs leading to discontinuation of study drug and AEs leading to death will be summarized if 
applicable.  If the relationship to study drug is missing, the TEAE will be classified as related.  In 
the case of more than 1 occurrence of a TEAE for a given patient, by patient analyses will 
include maximum relationship to study drug and maximum severity of those TEAEs. 
Table 2: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
Mild 
An experience that is transient or mild, and requires no medical treatment 
or intervention.  The experience does not generally interfere with usual 
daily activities.  This includes transient laboratory test alterations. 
Moderate 
No or minimal medical intervention/therapy required.  Mild to moderate 
limitation in activity – some assistance may be needed.  Includes 
laboratory test alterations indicating injury, but without long-term risk. 
Severe 
An experience that requires medical intervention/therapy, hospitalization 
possible.  Marked limitation in activity, some assistance usually required.  
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
Fatal 
Death related to AE. 
8.2. 
Deaths 
Deaths will be summarized by treatment arm and cause of death.  A table of fatal AEs will be 
provided and summarized by SOC and PT.  Deaths due to AE considered related to study drug 
will be discussed. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
36 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
8.3. 
Injection Site Reaction 
Injection site reaction will be summarized by treatment group.  Summaries will contain the 
number and percentage of patients experiencing a reaction 1 or more times, and descriptive 
statistics on the duration (mean, SD, median, minimum, and maximum). 
8.4. 
Study Drug Exposure 
For the Efficacy, mITT, and Safety Populations, study drug administration will be summarized 
by duration of exposure in weeks (n, categorized [0 to < 4, 4 to < 8, 8 to < 12, 12 to 16, 16], 
mean, SD, median, and range), average number of injections per week (n, mean, SD, median, 
and range), and total dose administered (n, mean, SD, median, and range). 
In addition, mean, minimum, and maximum titrations levels (n, mean, SD, median, and range) 
will be summarized by week. 
8.5. 
Clinical Laboratory Evaluations 
Clinical laboratory data (serum iron parameters, hematology, serum chemistry, other clinical 
tests, and urinalysis) obtained from local and central laboratories will be converted to Systéme 
International (SI) units and/or United States conventional units.  Laboratory results will be 
classified as low, normal, and high dependent on the reference ranges of the local laboratory.  
Clinically significant laboratory abnormalities that result in treatment modification and/or require 
intervention will be recorded on the appropriate eCRF as AEs per Section 8.1.  
Laboratory results will be summarized by treatment group and visit, lowest postbaseline grade, 
highest postbaseline grade, and last postbaseline visit.  The change from baseline and percent 
change from baseline will also be summarized.  Shifts from the baseline value to each visit, 
lowest postbaseline grade, highest postbaseline grade, and last postbaseline visit may be 
displayed. 
8.6. 
Immunogenicity/Pharmacokinetics 
Immunogenicity/PK will be summarized by visit and timepoint (eg, Week 1 and Week 16 
require predose blood sample collection and an additional blood sample collection postdose 
1 hour or later).   
Immunogenicity (antibody titer, based on screening cut point) will be summarized by treatment 
group and visit.  At each assessment, potentially positive results (based on the screening assay) 
will be followed by subsequent confirmatory assays, where the titer will be assigned.  
The relationship between drug concentration and immunogenicity (if anti-drug antibodies or 
neutralizing antibodies develop) will be assessed.   
A value of zero will be substituted for all drug concentrations below the lower limit of 
quantification (LLQ). 
8.7. 
Physical Exam 
Physical exam findings will be reported in patient listings. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
37 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
8.8. 
Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, weight 
and body temperature) will be summarized by treatment group and visit.  The change from 
baseline will also be summarized. 
8.9. 
Electrocardiogram 
Corrected QT intervals will be calculated using the QT interval and heart rate.  The QTcB value 
will be derived by Bazett’s formula and QTcF will be derived by Frederica’s formula as follows: 
QTcB = QT / (60/HR)1/2 
QTcF = QT / (60/HR)1/3 
QTcB and QTcF values will be classified as follows: 
≤ 450 msec 
> 450 msec to ≤ 480 msec 
> 480 msec to ≤ 500 msec 
> 500 msec 
QTcB and QTcF change from baseline will be classified as follows: 
≤ 30 msec 
> 30 msec to ≤ 60 msec 
> 60 msec 
Electrocardiogram (heart rate, PR interval, QRS interval, QT interval, QTcB interval, and QTcF 
interval) will be summarized by treatment group and visit.  The change from baseline will also 
be summarized. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
38 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
9. 
REFERENCES 
Iron Disorders Institute, Phlebotomy Guidelines for Patients with Hereditary Hemochromatosis, 
2011, 
http://www.irondisorders.org/Websites/idi/files/Content/856494/Physician%20Chart%20phlebot
omy%20detail2011.pdf. Accessed 21 Nov 2017. 
 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
39 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
10. 
PLANNED TABLES, LISTINGS, AND FIGURES 
Tables, listings, and figures (TLFs) are categorized and numbered in accordance with 
International Council on Harmonisation (ICH) E3 guidelines.  TLFs will be generated using 
SAS, Version 9.4 or later (SAS Institute, Cary, NC).  Graphic displays may be produced using 
SAS, S-Plus or R, Version 3.1.1 or later (R Foundation for Statistical Computing, Vienna, 
Austria).  
It is not intended that every TLF will be included in the CSR.  It is also possible that additional 
analyses will be conducted after review of the data.  Any analyses or summaries not specified in 
the SAP, but performed after review of the data, will be identified in the CSR as posthoc. 
10.1. 
Patient Data Tables 
Tables will be summarized overall and by treatment group.  In general, population, enrollment, 
demographic, and efficacy tables will use the Efficacy Population, safety tables will use the 
Safety Population, and PK tables will use the PK Population.  
10.2. 
Tables 
Population, Enrollment, and Demographic Tables  
Tables summarizing population, enrollment and demographics will be indexed by analysis 
populations, for example 14.3.1.1.3.x: 14.1.1.3.1. Enrollment (Efficacy Population), 14.1.1.3.2. 
Enrollment (mITT Population), 14.1.1.3.3. Enrollment (ITT Population), 14.1.1.3.4. 
(Per Protocol Population), 14.1.1.3.5. Enrollment (Safety Population), and 14.1.1.3.6. Enrollment 
(PK Population).  Tables may not be produced for all analysis populations listed above.  If 
populations are identical, duplicate summaries will not be produced. 
14.1.1.1 
Patient Informed Consent by Protocol Version and Analysis Population 
14.1.1.2 
Disposition (Randomize Patients) 
14.1.1.3.x 
Enrollment  
14.1.1.4.x 
Important Protocol Deviations 
14.1.2.1.x 
Randomization versus Treated Stratification  
14.1.2.2.x 
Randomization Stratification 
14.1.2.3.x 
Demographics and Baseline Characteristics  
14.1.3.1.x 
Medical/Surgical History  
14.1.3.2.x 
Most Frequent Medical/Surgical History 
Efficacy Tables 
The following efficacy tables will be provided both for Efficacy Population with select tables 
reproduced for the mITT Population.   
In addition tables summarizing efficacy using other analysis populations may be produced, if so, 
indexing will based on analysis population, for example 14.2.1.1.1.x:  14.2.1.1.1.1 Postdose 
TSAT, Change from Baseline to Week 16:  Primary Efficacy Analysis (Efficacy Population), for 
the mITT Population (14.2.1.1.1.2), for the ITT Population (14.2.1.1.1.3), for the Per Protocol 
Population (14.2.1.1.1.4), for the Safety Population (14.2.1.1.1.5) and for the PK Population 
(14.2.1.1.3.6).  If populations are identical, duplicate summaries will not be produced. 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
40 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
  
14.2.1.1.x 
TSAT, Change from Baseline to Week 16:  Primary Efficacy Analysis  
14.2.1.2.x 
Predose TSAT, Change from Baseline to Week 16 
14.2.1.3.x 
Predose TSAT, Change from Baseline to Week 17 
14.2.2.1.x 
Frequency of Phlebotomy:  Secondary Efficacy Analysis, Poisson Regression  
14.2.2.2.x 
Time to First Post-dose Phlebotomy:  Secondary Efficacy Analysis, Kaplan-Meier  
14.2.2.3.x 
At Least One Post-dose Phlebotomy:  Secondary Efficacy Analysis, CMH  
14.2.2.4.x 
Number of Times a Patient Met Criteria for a Phlebotomy:  Secondary Efficacy Analysis, 
Poisson Regression  
14.2.2.5.x 
Time until Patient First Met Criteria for a Phlebotomy:  Secondary Efficacy Analysis, Kaplan-
Meier 
14.2.2.6.x 
Patient Met Criteria for a Phlebotomy on at Least One Visit:  Secondary Efficacy Analysis, 
CMH 
14.2.3.1.x 
Complete Iron Studies, Postdose:  Serum Ferritin (ng/mL), Change from Baseline to Week 16:  
Secondary Efficacy Analysis  
14.2.3.2.x 
Complete Iron Studies, Predose:  Serum Ferritin (ng/mL), Change from Baseline to Each 
Weekly Visit:  Secondary Efficacy Analysis 
14.2.3.3.x 
Complete Iron Studies, Postdose:  Total Serum Iron (μg/dL), Change from Baseline to Each 
Weekly Visit:  Exploratory Efficacy Analysis 
14.2.3.4.x 
Complete Iron Studies, Predose:  Total Serum Iron (μg/dL), Change from Baseline to Each 
Weekly Visit:  Exploratory Efficacy Analysis  
14.2.3.5.x 
Complete Iron Studies Postdose:  Serum Transferrin (mg/dL), Change from Baseline to Each 
Weekly Visit:  Exploratory Efficacy Analysis 
14.2.3.6.x 
Complete Iron Studies, Predose:  Serum Transferrin (mg/dL), Change from Baseline to Each 
Weekly Visit:  Exploratory Efficacy Analysis 
14.2.3.7.x 
Complete Iron Studies Postdose:  Apoferritin (mg/dL), Change from Baseline to Each Weekly 
Visit:  Exploratory Efficacy Analysis 
14.2.3.8.x 
Complete Iron Studies, Predose:  Apoferritin (mg/dL), Change from Baseline to Each Weekly 
Visit:  Exploratory Efficacy Analysis (Efficacy Population) 
14.2.3.9.x 
Complete Iron Studies Postdose:  Holoferritin (mg/dL), Change from Baseline to Each Weekly 
Visit:  Exploratory Efficacy Analysis 
14.2.3.10.x 
Complete Iron Studies, Predose:  Holoferritin (mg/dL), Change from Baseline to Each Weekly 
Visit:  Exploratory Efficacy Analysis (Efficacy Population) 
14.2.3.11.x 
Complete Iron Studies, Postdose:  Serum UIBC (μg/dL), Change from Baseline to Each Weekly 
Visit:  Exploratory Efficacy Analysis  
14.2.3.12.x 
Complete Iron Studies, Predose:  Serum UIBC (μg/dL), Change from Baseline to Each Weekly 
Visit:  Exploratory Efficacy Analysis 
14.2.3.13.x 
Complete Iron Studies, Postdose:  Serum TIBC (μg/dL), Change from Baseline to Each Weekly 
Visit:  Exploratory Efficacy Analysis  
14.2.3.14.x 
Complete Iron Studies, Predose:  Serum TIBC (μg/dL), Change from Baseline to Each Weekly 
Visit:  Exploratory Efficacy Analysis 
14.2.4.1.x 
Thyroid Function:  T3, Change from Baseline to Each Weekly Visit:  Exploratory Efficacy 
Analysis  
14.2.4.2.x 
Thyroid Function:  T4, Change from Baseline to Each Weekly Visit:  Exploratory Efficacy 
Analysis 
14.2.4.3.x 
Thyroid Function:  TSH, Change from Baseline to Each Weekly Visit:  Exploratory Efficacy 
Analysis 
14.2.4.4.x 
Thyroid Function:  Free T4, Change from Baseline to Each Weekly Visit:  Exploratory Efficacy 
Analysis 
14.2.5 
Hemoglobin A1C, Change from Baseline to Each Weekly Visit:  Exploratory Efficacy Analysis  
14.2.6.1.x 
Liver Function:  Albumin, Change from Baseline to Each Weekly Visit:  Exploratory Efficacy 
Analysis 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
41 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
14.2.6.2.x 
Liver Function:  Alkaline Phosphatase, Change from Baseline to Each Weekly Visit:  
Exploratory Efficacy Analysis 
14.2.6.3.x 
Liver Function:  ALT, Change from Baseline to Each Weekly Visit:  Exploratory Efficacy 
Analysis 
14.2.6.4.x 
Liver Function:  AST, Change from Baseline to Each Weekly Visit:  Exploratory Efficacy 
Analysis 
14.2.6.5.x 
Liver Function:  Bilirubin, Change from Baseline to Each Weekly Visit:  Exploratory Efficacy 
Analysis 
14.2.6.6.x 
Liver Function:  LDH, Change from Baseline to Each Weekly Visit:  Exploratory Efficacy 
Analysis 
14.2.6.7.x 
Liver Function:  Total Protein, Change from Baseline to Each Weekly Visit:  Exploratory 
Efficacy Analysis 
14.2.7.1.x 
RBC Parameters:  Hemoglobin Concentration, Change from Baseline to Each Weekly Visit:  
Exploratory Efficacy Analysis 
14.2.7.2.x 
RBC Parameters:  RBC Count, Change from Baseline to Each Weekly Visit:  Exploratory 
Efficacy Analysis 
14.2.7.3.x 
RBC Parameters:  RDW, Change from Baseline to Each Weekly Visit:  Exploratory Efficacy 
Analysis 
14.2.8.1.x 
Quality of Life:  SF-36v2 Total Score, Change from Baseline to Week 16:  Exploratory Efficacy 
Analysis  
14.2.8.2.x 
Quality of Life:  SF-36v2 Subscales, Change from Baseline to Week 16:  Exploratory Efficacy 
Analysis 
14.2.8.3.x 
Quality of Life:  WOMAC Total Score, Change from Baseline to Week 16:  Exploratory 
Efficacy Analysis 
14.2.8.4.x 
Quality of Life:  WOMAC Subscales, Change from Baseline to Week 16:  Exploratory Efficacy 
Analysis 
14.2.8.5.x 
Quality of Life:  Modified Dreisler Indices for Arthritis, Change from Baseline to Week 16:  
Exploratory Efficacy Analysis 
14.2.9.1.1.x 
TSAT, Change from Baseline to Week 16:  Univariate Analyses 
14.2.9.1.2.x 
TSAT, Change from Baseline to Week 16:  Multivariate Analyses  
14.2.9.1.3.x 
Serum Ferritin, Change from Baseline to Week 16:  Univariate Analyses 
14.2.9.1.4.x 
Serum Ferritin, Change from Baseline to Week 16:  Multivariate Analyses  
14.2.9.2.1.x 
Frequency of Phlebotomy: Univariate Analyses 
14.2.9.2.2.x 
Time to First Post-dose Phlebotomy: Univariate Analyses 
14.2.9.2.3.x 
At Least One Post-dose Phlebotomy: Univariate Analyses 
14.2.9.2.4.x 
Number of Times a Patient Met Criteria for a Phlebotomy: Univariate Analyses 
14.2.9.2.5.x 
Time until Patient First Met Criteria for a Phlebotomy: Univariate Analyses 
14.2.9.2.6.x 
Patient Met Criteria for a Phlebotomy on at Least One Visit: Univariate Analyses 
14.2.9.3.1.x 
Frequency of Phlebotomy: Multivariate Analyses 
14.2.9.3.2.x 
Time to First Post-dose Phlebotomy: Multivariate Analyses 
14.2.9.3.3.x 
At Least One Post-dose Phlebotomy: Multivariate Analyses 
14.2.9.3.4.x 
Number of Times a Patient Met Criteria for a Phlebotomy: Multivariate Analyses 
14.2.9.3.5.x 
Time until Patient First Met Criteria for a Phlebotomy: Multivariate Analyses 
14.2.9.3.6.x 
Patient Met Criteria for a Phlebotomy on at Least One Visit: Multivariate Analyses 
14.2.10.1 
Pharmacokinetics:  Hepcidin Concentration (PK Population) 
14.2.10.2 
Pharmacokinetics: Hepcidin Parameter Estimates (PK Population) 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
42 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
 
Safety Tables 
The following safety tables will be provided both for Safety Population.   
In addition, tables summarizing safety using other analysis populations may be produced, if so, 
indexing will based on analysis population, for example 14.3.1.1.x:  14.3.1.1.1. Study Drug 
Administration (Safety Population), and (14.3.1.1.2), for the Per Protocol Population. If 
populations are identical, duplicate summaries will not be produced. 
 
14.3.1.1 
Study Drug Administration 
14.3.2.2.1.x 
Summary of Treatment-Emergent Adverse Events 
14.3.2.2.2.x 
Treatment-Emergent Adverse Events Regardless of Relationship to Study Drug 
14.3.2.2.3.x 
Treatment-Emergent Adverse Events Regardless of Relationship to Study Drug by Maximum 
Severity:  LJPC-401 Arm 
14.3.2.2.4.x 
Treatment-Emergent Adverse Events Regardless of Relationship to Study Drug by Maximum 
Severity:  Placebo Arm 
14.3.2.2.5.x 
Treatment-Emergent Adverse Events Related to Study Drug 
14.3.2.2.6.x 
Treatment-Emergent Adverse Events Related to Study Drug by Maximum Severity:  LJPC-401 
Arm 
14.3.2.2.7.x 
Treatment-Emergent Adverse Events Related to Study Drug by Maximum Severity:  Placebo 
Arm 
14.3.2.2.8.x 
Most Frequent Treatment-Emergent Adverse Events Regardless of Relationship to Study Drug  
14.3.2.2.9.x 
Most Frequent Treatment-Emergent Adverse Events Related to Study Drug 
14.3.2.3.1.x 
Most Frequent Treatment-Emergent Non-Serious Adverse Events Regardless of Relationship to 
Study Drug 
14.3.2.3.2.x 
Most Frequent Treatment-Emergent Non-Serious Adverse Events Related to Study Drug 
14.3.2.4.1.x 
Grade 3, 4 or 5 Treatment-Emergent Adverse Events Regardless of Relationship to Study Drug  
14.3.2.4.2.x 
Grade 3, 4 or 5 Treatment-Emergent Adverse Events Related to Study Drug 
14.3.2.5.1.x 
Treatment-Emergent Serious Adverse Events Regardless of Relationship to Study Drug  
14.3.2.5.2.x 
Treatment-Emergent Serious Adverse Events Related to Study Drug  
14.3.2.5.3.x 
Treatment-Emergent Adverse Events Regardless of Relationship to Study Drug Resulting in 
Discontinuation of Study Drug 
14.3.2.5.4.x 
Treatment-Emergent Adverse Events Related to Study Drug Resulting in Discontinuation of 
Study Drug 
14.3.2.6.1.x 
Fatal Treatment-Emergent Adverse Events Regardless of Relationship to Study Drug  
14.3.2.6.2.x 
Fatal Treatment-Emergent Adverse Events Related to Study Drug 
14.3.2.7.1.x 
Treatment-Emergent Adverse Events of Special Interest 
14.3.2.7.2.x 
Treatment-Emergent Adverse Events of Special Interest - Cardiac 
14.3.2.8.1.x 
Grade 3, 4 or 5 Treatment-Emergent Adverse Events of Special Interest 
14.3.2.8.2.x 
Grade 3, 4 or 5 Treatment-Emergent Adverse Events of Special Interest - Cardiac 
14.3.2.9.1.x 
Injection Site Reactions 
14.3.2.10.1 
Deaths 
14.3.3.1.x 
Summary of Hematology Value and Change from Baseline over Time for Laboratory Test (Unit)  
14.3.3.2.x 
Summary of Chemistry Value and Change from Baseline over Time for Laboratory Test (Unit)  
14.3.3.3.x 
Summary of Urinalysis Value and Change from Baseline over Time for Laboratory Test (Unit)  
14.3.4 
Immunogenicity (PK Population) 
14.3.5.1.x 
Vital Signs:  Summary of Systolic Blood Pressure (mmHg) by Visit 
14.3.5.2.x 
Vital Signs:  Summary of Diastolic Blood Pressure (mmHg) by Visit 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
43 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
14.3.5.3.x 
Vital Signs:  Summary of Respiration Rate (breaths/minute) by Visit 
14.3.5.4.x 
Vital Signs:  Summary of Temperature (0C) by Visit 
14.3.5.5.x 
Vital Signs:  Summary of Heart Rate (beats/minute) by Visit 
14.3.6.1.x 
12-Lead Electrocardiogram:  Summary QT Interval (msec) by Visit 
14.3.6.2.x 
12-Lead Electrocardiogram:  Summary QTcF Interval (msec) by Visit 
14.3.6.3.x 
12-Lead Electrocardiogram:  Summary QTcB Interval (msec) by Visit 
14.3.6.4.x 
12-Lead Electrocardiogram:  Summary of PR Interval (msec) by Visit 
14.3.6.5.x 
12-Lead Electrocardiogram:  Summary of QRS Interval (msec) 
14.3.6.6.x 
12-Lead Electrocardiogram:  Summary of Heart Rate (beats/minute) by Visit 
14.3.7.1.x 
Prior Medications  
14.3.7.2.x 
Concomitant Medications 
14.3.7.3.x 
Prior Phlebotomies 
14.3.7.4.x 
Concomitant Phlebotomies 
14.3.7.5.x 
On-Study Procedures and Surgeries 
 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
44 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
10.3. 
Patient Data Listings 
In general, patient data listings will be sorted by patient identification (ID) number, visit, and 
study day.  Log data (ie, prior and concomitant medications, adverse events) will be sorted by 
patient ID, date, and term. 
Patient IDs, displayed in the first column of all listings, will include the patient’s age, sex, and 
treatment group.  
Number 
Title 
16.1.6 
Lot Numbers 
16.1.7 
IXRS Randomization 
16.1.8 
Patient Informed Consent 
16.2.1.1 
Patient Disposition  
16.2.1.2 
Treatment Termination 
16.2.1.3 
Study Termination 
16.2.1.4 
Unblinding of Patients 
16.2.1.5 
Patient Populations 
16.2.2 
Important Protocol Deviations  
16.2.3 
Enrollment and Eligibility  
16.2.4.1 
Demographics and Baseline Characteristics  
16.2.4.2 
Medical/Surgical History  
16.2.4.3 
Baseline Pregnancy  
16.2.4.4 
Prior and Concomitant Medications  
16.2.4.5 
Non-medication Therapy / Procedures 
16.2.5.1 
Study Drug Exposure: LJPC401 or Placebo Weekly Totals 
16.2.5.2 
Study Drug Exposure: LJPC401 or Placebo Subcutaneous Injections 
16.2.6.1.1 
Complete Iron Studies 
16.2.6.1.2 
Phlebotomy Events and Procedures  
16.2.6.2 
Quality of Life (SF-36vs2) 
16.2.6.3 
Pharmacokinetic Concentrations 
16.2.7.1 
Adverse Events  
16.2.7.2 
Serious Adverse Events 
16.2.7.3 
Death 
16.2.7.4 
Injection Site Assessment 
16.2.8.1.1 
Hematology  
16.2.8.1.2 
Hematology:  Differentials  
16.2.8.2.1 
Serum Chemistry:  Liver and Kidney Function  
16.2.8.2.2 
Serum Chemistry:  Electrolytes  
16.2.8.2.3 
Serum Chemistry:  Other  
16.2.8.3 
Screening Urinalysis  
16.2.8.4 
Microscopic Urinalysis 
16.2.8.5 
Thyroid Function 
16.2.8.6 
Immunogenicity  
16.2.8.7 
Physical Examination  
16.2.8.8 
Vital Signs  
16.2.8.9 
Pregnancy 
16.2.8.10 
12-Lead Electrocardiogram  
 
 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
45 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
10.4. 
Figures 
Figures will be summarized by treatment group. 
Number 
Title 
14.2.6.1.1 
Mean (SE) of TSAT by Treatment and Visit (Efficacy Population) 
14.2.6.1.2 
Mean (SE) of Change from Baseline in TSAT by Treatment and Visit (Efficacy 
Population) 
14.2.6.1.3 
Mean (SE) of Percent Change from Baseline in TSAT by Treatment and Visit (Efficacy 
Population) 
14.2.6.1.4 
Forest Plot of Treatment Difference in TSAT, at Week 16, by Subgroups (Efficacy 
Population) 
14.2.6.1.5 
Forest Plot of Treatment Difference in Change from Baseline in TSAT, at Week 16, by 
Subgroups (Efficacy Population) 
14.2.6.2.1 
Mean (SE) of Serum Ferritin by Treatment and Visit (Efficacy Population) 
14.2.6.2.2 
Mean (SE) of Change from Baseline in Serum Ferritin by Treatment and Visit (Efficacy 
Population) 
14.2.6.2.3 
Mean (SE) of Percent Change from Baseline in Serum Ferritin by Treatment and Visit 
(Efficacy Population) 
14.2.6.2.4 
Forest Plot of Treatment Difference in Serum Ferritin, at Week 16, by Subgroups (Efficacy 
Population) 
14.2.6.2.5 
Forest Plot of Treatment Difference in Change from Baseline Serum Ferritin, at Week 16, 
by Subgroups (Efficacy Population) 
14.2.6.3.1 
Mean (SE) of Total Serum Iron by Treatment and Visit (Efficacy Population) 
14.2.6.3.2 
Mean (SE) of Change from Baseline in Total Serum Iron by Treatment and Visit (Efficacy 
Population) 
14.2.6.3.3 
Mean (SE) of Percent Change from Baseline in Total Serum Iron by Treatment and Visit 
(Efficacy Population) 
14.2.6.4.1 
Mean (SE) of Transferrin by Treatment and Visit (Efficacy Population) 
14.2.6.4.2 
Mean (SE) of Change from Baseline in Transferrin by Treatment and Visit (Efficacy 
Population) 
14.2.6.4.3 
Mean (SE) of Percent Change from Baseline in Transferrin by Treatment and Visit 
(Efficacy Population) 
14.2.6.5.1 
Mean (SE) of Apoferritin by Treatment and Visit (Efficacy Population) 
14.2.6.5.2 
Mean (SE) of Change from Baseline in Apoferritin by Treatment and Visit (Efficacy 
Population) 
14.2.6.5.3 
Mean (SE) of Percent Change from Baseline in Apoferritin by Treatment and Visit 
(Efficacy Population) 
14.2.6.6.1 
Mean (SE) of Holoferritin by Treatment and Visit (Efficacy Population) 
14.2.6.6.2 
Mean (SE) of Change from Baseline in Holoferritin by Treatment and Visit (Efficacy 
Population) 
14.2.6.6.3 
Mean (SE) of Percent Change from Baseline in Holoferritin by Treatment and Visit 
(Efficacy Population) 
14.2.6.7.1 
Mean (SE) of UIBC by Treatment and Visit (Efficacy Population) 
14.2.6.7.2 
Mean (SE) of Change from Baseline in UIBC by Treatment and Visit (Efficacy 
Population) 
14.2.6.7.3 
Mean (SE) of Percent Change from Baseline in UIBC by Treatment and Visit (Efficacy 
Population) 
14.2.6.8.1 
Mean (SE) of TIBC by Treatment and Visit (Efficacy Population) 
14.2.6.8.2 
Mean (SE) of Change from Baseline in TIBC by Treatment and Visit (Efficacy Population) 
14.2.6.8.3 
Mean (SE) of Percent Change from Baseline in TIBC by Treatment and Visit (Efficacy 
Population) 
14.2.6.9.1 
Forest Plot of Frequency of Phlebotomy Rate Ratio 


 
Statistical Analysis Plan, Study LJ401-HH01  
LJPC-401 
 
46 
La Jolla Pharmaceutical - Confidential 
22 March 2019 (Version 3.0) 
 
14.2.6.9.2 
Forest Plot of Time to First Post-dose Phlebotomy Hazard Ratio 
14.2.6.9.3 
Forest Plot of At Least One Post-dose Phlebotomy Odds Ratio 
14.2.6.9.4 
Forest Plot of Number of Times a Patient Met Criteria for a Phlebotomy Rate Ratio 
14.2.6.9.5 
Forest Plot of Time until Patient First Met Criteria for a Phlebotomy Hazard Ratio 
14.2.6.9.6 
Forest Plot of Patient Met Criteria for a Phlebotomy on at Least One Visit Odds Ratio 
14.2.6.10.1 
Mean Hepcidin Concentration by Visit and Treatment (No Baseline Correction, PK 
Population) 
14.2.6.10.2 
Mean Hepcidin Concentration by Visit and Treatment (Baseline Correction, PK 
Population)