A Single Arm, Open-Label Study to Assess the Safety, Efficacy, and Pharmacodynamic Effects of Pozelimab and Cemdisiran Combination Therapy in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Switch From Eculizumab Therapy
Phase: PHASE2
Conditions: Paroxysmal Nocturnal Hemoglobinuria
Sponsor: Regeneron Pharmaceuticals



Cli nical St u d y Pr ot oc ol  
 
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C O N FI D E N TI A L  
A M E N D M E N T HI S T O R Y  
A me n d me nt 3  
T he mai n p ur p ose f or t his a me n d me nt is t o m o dif y t he ti mi n g of t he  i nteri m a nal ysis. 
Descri pti o n of C h a n ge  
B rief R ati o n ale  
Secti o n # a n d N a me  
M o difie d t he descri pti o n of t he 
i nteri m a nal ysis t o all o w f or a n 
a nal ysis of t he data at a n earlier ti me  
p oi nt ( wee k 1 6)  
T he i nteri m a nal ysis ti mi n g a n d 
sc o pe is re vise d t o all o w f or a n 
earlier a nal ysis a n d f or t he 
preli mi nar y res ults t o be s hare d 
e xter nall y (f or e xa m ple, u p o n 
re q uest b y re g ulat or y 
a ut h orities).  
Cli nica l St u d y Pr ot oc ol S y n o psis: 
Statistical Pla n  
Secti o n  6. 2  Pla n ne d I nteri m A nal ysis  
Secti o n  1 1. 5  I nteri m A nal ysis 
Re vise d a n d clarifie d t he f oll o wi n g 
sec o n dar y e n d p oi nts: 
•  Pr o p orti o n of patie nts w h o 
mai ntai n a d e q uate c o ntr ol of 
he m ol ysis, defi ne d as lactate 
de h y dr o ge nase ( L D H) ≤1. 5  x 
u p per li mit of n or mal ( U L N) fr o m 
p ost -baseli ne ( o n da y 1) t hr o u g h 
da y 2 2 5 a n d fr o m da y  5 7 t hr o u g h 
da y 2 2 5, i ncl usi ve  
•  Pr o p orti o n of patie nts wi t h 
n or malizati o n of L D H  at eac h visit , 
defi ne d as L D H ≤1. 0  x U L N fr o m 
p ost -baseli ne ( o n da y 1) t hr o u g h 
da y 2 2 5, i ncl usi ve  
C orres p o n di n g c ha n ges were ma d e t o 
sec o n dar y e n d p oi nts f or t he o pti o nal 
o pe n -la bel e xte nsi o n peri o d ( O L E P) 
T his c ha n ge clarifies h o w t hes e 
a nal yses will be perf or me d. “ At 
all ti me p oi nts at w hic h L D H is 
meas ure d” is delete d t o better 
reflect t he a nal yses t hat will be 
perf or me d  
Cli nical St u d y Pr ot oc ol S y n o psis: 
Sec o n dar y E n d p oi nts  
Secti o n  4. 1. 2  Sec o n dar y E n d p oi nts  
Secti o n  4. 1. 2. 1  Se c o n dar y E n d p oi nts 
f or t he O pti o nal O pe n -La bel 
E x te nsi o n P eri o d 
Secti o n  1 1. 4. 3. 1  Sec o n dar y Efficac y 
A nal ysis  
A d de d ne w sec o n dar y e n d p oi nt o n t he 
pr o p orti o n of patie nts wit h a d e q uate 
c o ntr ol of he m ol ysis  at eac h visit  
T his ne w e n d p oi nt assesses 
c o ntr ol of he m ol ysis usi n g a n 
a d diti o nal met h o d ol o g y  
Cli nical St u d y Pr ot oc ol S y n o psis: 
Sec o n dar y E n d p oi nts  
Secti o n  4. 1. 2  Sec o n dar y E n d p oi nts  
Secti o n  4. 1. 2. 1  Sec o n d ar y E n d p oi nts 
f or t he O pti o nal O pe n-La bel 
E xte nsi o n  P eri o d  
Secti o n  1 1. 4. 3. 1  Sec o n dar y Efficac y 
A nal ysis  
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C O N FI D E N TI A L  
Descri pti o n of C h a n ge  
B rief R ati o n ale  
Secti o n # a n d N a me  
U p date d i nf or mati o n a b o ut p ost -trial 
treat me nt access f or patie nts w h o 
c o m plete t he o pti o nal O L E P  
T his c ha n ge pr o vi des 
i nf or mati o n o n p ost-trial access 
t o st u d y dru gs f or t h ose wit h a 
fa v ora ble be nefit-ris k pr ofile 
f or c o nti n ue d treat me nt 
Cli nical St u d y Pr ot oc ol S y n o psis: 
St u d y Desi g n , St u d y D urati o n  
Secti o n  6. 1  St u d y Descri pti o n a n d 
D urati o n  
Fi g ure  1 : St u d y Fl o w Dia gra m 
Secti o n  6. 1. 1. 3  O pti o nal O pe n -La b el 
E xte nsi o n P eri o d  
Secti o n  6. 1. 1. 4  P ost -Treat me nt 
Safet y F oll o w -U p  
Secti o n  6. 1. 1. 5  E n d of St u d y 
Defi niti o n  
Secti o n  8. 9  P ost -Trial Access t o 
St u d y Treat me nt  
Secti o n  9. 1. 1. 4  F o ot n otes f or T a ble 4 
Sc he d ule of E ve nts ( P ost -Treat me nt 
Safet y F oll o w -U p P eri o d f or All 
P atie nts), f o ot n ote # 1   
C ha n ge d baseli ne sa m ple c oll ecti o n 
f or P N H cl o nes fr o m da y 1 t o 
scree ni n g visit V 1a 
T his c ha n ge is ma de t o 
facilitate st u d y c o n d uct 
T a ble  1  Sc he d ule of E ve nts f or 
O pe n -La bel Treat me nt P eri o d  
Clarifie d t hat free he m o gl o bi n is 
c ollecte d as a se p arate sa m ple at visits 
O L E P -1 a n d O L E P -7 o nl y  
T his c ha n ge clarifies details 
re gar di n g sam ple c ollecti o n  
T a ble  3 : Sc he d ule of E ve nts 
( O pti o nal O pe n-La bel E xte nsi o n 
P eri o d)  
Secti o n  9. 1. 1. 3  F o ot n otes f or T a ble 3 
Sc he d ule of E ve nts (f or O pti o nal 
O pe n -La bel E xte nsi o n P eri o d), 
f o ot n ote #1 4   
F or patie nts re q uiri n g i nte nsifi e d 
treat me nt, clarifie d t hat sa m pl es f or 
p ozeli ma b c o nce ntrati o n a n d t otal C 5 
will b e c ollecte d o n da y 1r pre -d ose 
a n d p ost -i nf usi o n 
T his c ha n ge clarifies details 
re gar di n g sa m ple c ollecti o n 
Secti o n  9. 1. 1. 2  F o ot n otes f or T a ble 2 
Sc he d ule of E ve nts ( O pe n -La bel 
Treat me nt P eri o d f or P atie nts o n 
I nte nsifie d T hera p y), f o ot n ote #1 3   
A d de d i m m u n o ge nicit y sa m pl e (a nti -
p ozeli ma b a nti b o dies) a n d D -di mer as 
part of la b orat or y a nal yses i n t he 
e ve nt of s us pecte d brea kt hr o u g h 
he m ol ysis  
T his c ha n ge i ncl u des a d diti o nal 
sa m ple c ollecti o n i n t he e ve nt 
of s us pecte d brea kt hr o u g h 
he m ol ysis t o ai d a nal ysis  
Secti o n  9. 1. 1. 1  F o ot n otes f or T a ble 1  
Sc he d ule of E ve nts ( O pe n -La bel 
Treat me nt  P eri o d) , f o ot n ote #1 7  
Secti o n  9. 1. 1. 2  F o ot n otes f or T a ble 2 
Sc he d ule of E ve nts ( O pe n -La bel 
Treat me nt P eri o d f or P atie nts o n 
I nte nsifie d T hera p y), f o ot n ote #9   
Secti o n  9. 1. 1. 3  F o ot n otes f or T a ble 3 
Sc he d ule of E ve nts (f or O pti o nal 
O pe n -La bel E xte nsi o n P eri o d), 
f o ot n ote #1 1   
Secti o n  9. 2. 3. 5  La b orat or y T esti n g 
( Safet y a n d Ot her) 
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C O N FI D E N TI A L  
Descri pti o n of C h a n ge  
B rief R ati o n ale  
Secti o n # a n d N a me  
I ncl u de d dail y a nti bi otic pr o p h yla xis 
a n d re vie w of pat ie nt safet y car d i n 
t he safet y f oll o w-u p peri o d  
T his is a c orrecti o n. T hese 
pr oce d ures are i nte n de d t o be 
perf or me d t hr o u g h o ut t he st u d y 
f or ris k miti gati o n 
T a ble  4  Sc he d ule of E ve nts f or 
O pe n -La bel Treat me nt P eri o d  
Secti o n  9. 1. 1. 4  F o ot n otes f or T a ble 4 
Sc he d ule of E ve nts ( P ost -Treat me nt 
Safet y F oll o w -U p P eri o d f or All 
P atie nts), f o ot n otes # 2  a n d # 3  ( ne w) 
Re m o ve d fasti n g re q uire me nt f or 
bl o o d c he mistr y sa m ple  
T his c ha n ge re d uces st u d y 
c o m ple xit y as t he res ults of t he 
e n d p oi nts s h o ul d n ot be 
i m pacte d i n a mea ni n gf ul wa y 
b y fasti n g stat us  
Secti o n  9. 2. 3. 5  La b orat or y T esti n g 
( Safet y a n d Ot her), Bl o o d C he mistr y 
A d de d  la n g ua ge t o as k t hat patie nts 
refrai n fr o m stre n u o us e xercis e wit hi n 
2 4  h o urs pri or t o a bl o o d dra w  
T his c ha n ge is a d de d t o 
mi ni mize t he effect of vi g or o us 
e xercise o n bl o o d a nal yses  
Secti o n  8. 8. 1  Pr o hi bite d Me dicati o ns 
a n d Pr oce d ures  
Re vise d sa m ple size la n g ua ge t o “ u p 
t o 1 2 patie nts” 
T his c ha n ge  all o ws m ore 
fle xi bility  re gar din g 
e nr oll me nt. Beca use t he 
a nal ysis is descri pti ve o nl y  a n d 
n ot base d o n a n y f or mal sa m ple 
size calc ulati o n, t his c ha n ge has 
n o i m pact o n t he a nal ysis  
Cli nical St u d y Pr ot oc ol S y n o psis: 
St u d y Desi g n , P o p ulati o n , 
Statistical  Pla n  
Secti o n  6. 1  St u d y Descri pti o n a n d 
D urati o n  
Secti o n  7. 1  N u m ber  of  P atie nts 
Pla n ne d  
Secti o n  1 1. 2  J ustificati o n of S a m ple 
Size  
Re m o ve d ec uliz u ma b c o nce ntrati o n 
fr o m o pe n-la bel e xte nsi o n peri o d 
( O L E P) a nal ysis 
T his is a c orrecti o n: 
ec uliz u ma b c o nce ntrati o n is n ot 
meas ure d d uri n g t he o pti o n al 
o pe n -la bel e xte nsi o n peri o d 
Secti o n  4. 1. 2. 1  Sec o n dar y E n d p oi nts 
f or t he O pti o nal O pe n-La bel 
E xte nsi o n P eri o d  
Re vise d descri pti o n of F u ncti o nal 
Asse ss me nt of C hr o nic Ill ness 
T hera p y –  Fati g ue ( F A CI T -Fati g ue) 
t o a 5-p oi nt Li kert scale . A hi g her 
sc ore i n dicates a hi g her q ualit y of life 
T his is a c orrecti o n  
Secti o n  9. 2. 2. 2. 1  F u ncti o nal 
Assess me nt of C hr o nic Ill ness 
T hera p y –  Fati g ue  
Clarificati o ns a n d c orrecti o ns  
T hese are mi n or e dit orial 
c ha n ges t o i m pr o ve clarit y  
T hr o u g h o ut t he d oc u me nt  
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C O N FI D E N TI A L  
A me n d me nt 2  
T he mai n p ur p ose f or t his a me n d me nt is t o e ns ure t hat p ozeli ma b c o nce ntr ati o ns will be assesse d 
pre -d ose a n d 1 5 mi n utes p ost -d ose o n t he da y of treat me nt i nte nsificati o n ( da y 1r) i n patie nts 
re q uiri n g d ose i nte nsificati o n.  I n a d diti o n, t he n u m ber of patie nts e nr olle d w h o are ta ki n g 
ec uliz u ma b at t he la bele d d ose vs t h ose ta ki n g ec uliz u ma b at a d ose hi g her or m ore fre q ue ntl y 
t ha n la bele d, was re m o ve d, t o all o w patie nts t o e nr oll re gar dless of w het her t he y are o n t he 
la bele d d ose of ec uliz u ma b or o n a hi g her or m ore fre q ue ntl y t ha n la b ele d d ose. 
Descri pti o n of C h a n ge  
B rief R ati o n ale  
Secti o n # a n d N a me  
T he s pecific n u m ber of patie nts 
e nr olle d w h o are c urre ntl y rec ei vi n g 
ec uliz u ma b at t he la bele d d ose or 
patie nts recei vi n g ec uliz u ma b at a 
d ose hi g her t ha n la bele d or m ore 
fre q ue ntl y t ha n la bele d has be e n 
re m o ve d.   
T o all o w a n y pr o p orti o n of 
patie nts t o be e nr olle d w het her o n 
t he la bele d d ose or o n a d ose 
hi g her t ha n la bele d/ m ore 
fre q ue ntl y t he n la bele d u p t o a 
t otal of a p pr o xi matel y 1 2 pati e nts.  
T his will all o w e nr ol l me nt of t hese 
patie nt s u b gr o u ps t o facilitate 
recr uit me nt. 
Cli nical St u d y Pr ot oc ol S y n o psis, 
( St u d y Desi g n; J ustificati o n of 
Sa m ple Size)  
Secti o n  6. 1  St u d y Descri pti o n a n d 
D urati o n  
Secti o n  1 1. 2  J ustificati o n of 
Sa m ple Size  
T he criteri o n f or pr o visi o n of a n 
a d diti o nal I V p ozeli ma b d ose i n t he 
e ve nt of a n ac ute c o m ple me nt -
acti vati n g c o n diti o n was m o difie d.  
T o all o w f or patie nts t o recei ve a n 
a d diti o nal I V p ozeli ma b d ose i n 
t he e ve nt t he y ha ve a n ele vate d 
L D H ≥2 x U L N res ulti n g fr o m a n 
ac ute c o m ple me nt -acti vati n g 
c o n diti o n e ve n if n ot meeti n g t he 
pr ot oc ol defi niti o n of brea kt hr o u g h 
he m ol ysis.   
Cli nical St u d y Pr ot oc ol S y n o psis 
( Treat me nt(s) St u d y Dr u g 
D ose/ R o ute/ Sc he d ule)  
Secti o n  6. 1. 3  Treat me nt 
I nte nsificati o n 
Secti o n  8. 3. 2  Treat me nt 
I nte nsificati o n  
Ti mi n g of statistical a nal ysis u p date d 
t o i ncl u de t he ti mi n g of t he a n al ysis 
f or t he i nte nsifie d O L T P. 
T o clarif y t hat t he pri mar y a nal ysis 
will be perf or me d at t he 
c o m pleti o n of t he mai n O L T P a n d 
pri or t o t he e n d of t he i nte nsi fi e d 
o pe n la bel treat me nt peri o d.    
Cli nical St u d y Pr ot oc ol S y n o psis 
( Statistical Pla n) 
La n g ua ge o n st u d y dr u g 
a d mi nistrati o n i n patie nts w h o 
re q uire treat me nt i nte nsificati o n a n d 
t he c orres p o n di n g i nte nsifie d 
treat me nt visit sc he d ule clarifi e d  
Clarif yi n g la n g ua ge has bee n 
a d de d t o e ns ure pr o per 
u n dersta n di n g of t he ti mi n g of 
st u d y visits a n d st u d y dr u g 
a d mi nistrati o n f or patie nts w h o 
re q uire treat me nt i nte nsificati o n.   
Secti o n  6. 1. 1. 3  O pti o nal O pe n -
La bel E xte nsi o n P eri o d  
Secti o n  6. 1. 3  Treat me nt 
I nte nsificati o n 
Assess me nt of b o d y wei g ht a d de d 
pri or t o a n y a d mi nistrati o n of I V 
p ozeli ma b.  
W ei g ht a d de d i n or der t o assist i n 
t he calc ulati o n of d ose t o be 
a d mi nistere d f or I V p ozeli ma b i n 
patie nts w h o re q uire treat me nt 
i nte nsificati o n or a d diti o nal 
p ozeli ma b a d mi nistrati o n i n t he 
e ve nt of a c o m ple me nt -acti vati n g 
c o n diti o n.  
Secti o n  6. 1. 3  Treat me nt 
I nte nsificati o n 
Secti o n  8. 3. 2  Treat me nt 
I nte nsificati o n 
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C O N FI D E N TI A L  
Descri pti o n of C h a n ge  
B rief R ati o n ale  
Secti o n # a n d N a me  
Re vise d e xcl usi o n criteri o n re gar di n g 
p ositi ve i nfecti o n wit h he p atitis B or 
C.  
T o har m o nize t he criteria wit h 
ot her st u dies i n t he pr o gra m a n d t o 
m ore cl osel y ali g n wit h sta n dar d 
practice wit h re gar ds t o scree ni n g 
f or he patitis B 
Secti o n  7. 2. 2  E xcl usi o n Criteria, 
# 1 1  
Clarifie d e xcl usi o n criteri o n 
pertai ni n g t o H ae m o p hil us i nfl ue nz a  
ser ot y pe b a n d Stre pt oc o cc us 
p ne u m o ni ae vacci nati o ns  
T o ali g n t he criteri o n wit h t he 
u p date d ce m disira n i n vesti gat ors 
br oc h ure a n d t o har m o nize wit h 
t he ot her p hase 2 st u d y of 
p ozeli ma b a n d ce m disira n 
c o m bi nati o n treat me nt.  
Secti o n  7. 2. 2  E xcl usi o n Criteria, 
# 3 0  
Re m o ve d 3 0 -mi n ute o bser vati o n 
peri o d after s u bc uta ne o us i nj ecti o n 
o n t he da y of treat me nt 
i nte nsificati o n. 
C orrecte d as patie nts o nl y re q uire 
3 0 -mi n ute o n -site o bser vati o n after 
i ntra ve n o us p ozeli ma b a n d t he first 
ce m disira n a n d p ozeli ma b 
s u bc uta ne o us i nj ecti o ns 
S ecti o n 8. 3. 2  Treat me nt 
I nte nsificati o n 
Secti o n  9. 1. 1. 2 F o ot n otes f or 
T a ble 2 Sc he d ule of E ve nts ( O pe n -
La bel Treat me nt P eri o d f or 
P atie nts o n I nte nsifie d T hera p y)  –  
F o ot n ote # 2.  
Re m o val of t he re q uire me nt f or 
ma n dat or y disc o nti n uati o n of st u d y 
dr u g i n t he e ve nt of treat me nt f or a 
me ni n g oc o ccal i nfecti o n  
T o all o w i n vesti gat ors t o use 
cli nical discreti o n wit h re gar ds t o 
c o nti n ui n g c o m ple me nt i n hi biti o n 
d uri n g a seri o us me ni n g oc occal 
i nfecti o n. Wit h dra wal of 
c o m ple me nt i n hi biti o n i n t he face 
of a n o n g oi n g c o m p le me nt 
acti vati n g c o n diti o n ma y ha ve 
seri o us cli nical c o nse q ue nces 
Secti o n 8. 3. 3. 1 Reas o ns f or 
P er ma ne nt Disc o nti n uati o n of 
St u d y Dr u g  
Bl o o d sa m ples f or t he c o nce ntrati o n 
of p ozeli ma b are t o be ta ke n pri or t o 
I V p ozeli ma b a d mi nistrati o n a n d 1 5 
mi n utes p os t-d ose o n da y 1r a n d t he 
da y of i nte nsificati o n f or patie nts 
recei vi n g treat me nt i nte nsificati o n i n 
t he o pe n la bel e xte nsi o n.  A pr e-d ose 
P K sa m ple was als o i ncl u de d o n 
D 1 5r.   
C orrecte d as patie nts w h o recei ve 
i nte nsifie d treat me nt will recei ve 
a n I V l oa d i n g d ose of p ozeli ma b 
o n t he first da y of t he i nte nsifi e d 
o pe n la bel treat me nt peri o d ( da y 
1r) re q uiri n g earlier assess me nt of 
dr u g c o nce ntrati o ns i n t he 
i nte nsifie d O L T P.  A pre- a n d 
1 5 -mi n ute p ost -d ose P K 
assess me nt als o s hall be perf or me d 
i n t he o pe n label e xte nsi o n peri o d 
t he da y of i nte nsificati o n f or 
patie nts w h o recei ve a n u n pla n ne d 
treat me nt i nte nsificati o n.  A pre-
d ose P K sa m ple was a d de d at da y 
1 5r.  
T a ble  2  Sc he d ule of E ve nts f or 
Treat me nt P eri o d (f or P atie nts o n 
I nte nsifie d Treat me nt i n t he 
O L T P )  
Secti o n  9. 1. 1. 3 F o ot n otes f or 
T a ble  3 Sc he d ule of E ve nts (f or 
O pti o nal O pe n -La bel E xte nsi o n 
P eri o d) –  F o ot n ote 1 6  
Bl o o d sa m ples f or ec uliz u ma b 
c o nce ntrati o ns re m o ve d fr o m t he 
i nte nsifie d O L T P S O E. 
C orrecte d as patie nts will n ot 
recei ve ec uliz u ma b d uri n g t he 
i nte nsifie d O L T P. 
T a ble  2  Sc he d ule of E ve nts f or 
Treat me nt P eri o d (f or P atie nts o n 
I nte nsifie d Treat me nt i n t he 
O L T P ) 
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C O N FI D E N TI A L  
Descri pti o n of C h a n ge  
B rief R ati o n ale  
Secti o n # a n d N a me  
Clarificati o n t hat patie nts w h o 
disc o nti n ue st u d y treat me nt i n t he 
i nte nsifie d O L T P will als o be as ke d 
t o re mai n i n st u d y u ntil wee k 3 2r 
E O T).  
Clarifie d t hat t he re q uest t o re mai n 
i n t he st u d y off-treat me nt p ert ai ns 
t o b ot h t he mai n a n d t he 
i nte nsifie d O L T P. 
Secti o n  8. 3. 3  St u d y Dr u g 
Disc o nti n uati o n  
Secti o n  9. 1. 1. 4 F o ot n otes f or 
T a ble 4 Sc he d ule of E ve nts ( P ost -
Treat me nt Safet y F oll o w -U p 
P eri o d f or All P atie nts) –  
F o ot n ote  1  
Criteria f or uri ne c ult ure u p dat e d.  
T o all o w uri ne c ult ure t o be 
perf or me d per t he I n vesti gat or 
j u d g me nt i n t he e ve nt of cli nic al 
s us pici o n of i nfecti o n.   
Secti o n  9. 2. 3. 5 La b orat or y T esti n g 
( Safet y a n d Ot her)  
U nsc he d ule d bl o o d c ollecti o n f or 
s us pecte d brea kt hr o u g h he m ol ysis 
e ve nts was u p date d.  
A d diti o nal list of bl o o d c ollecti o ns 
f or s us pecte d brea kt hr o u g h 
he m ol ysis were i ncl u de d.  
Secti o n  9. 1. 1. 1  F o ot n otes f or 
T a ble 1 Sc he d ule of E ve nts ( O pe n -
La bel Treat me nt P eri o d)   
Secti o n  9. 1. 1. 2  F o ot n otes f or 
T a ble 2 Sc he d ule of E ve nts ( O pe n -
La bel Treat me nt P eri o d f or 
P atie nts o n I nte nsifie d T hera p y)   
Secti o n  9. 1. 1. 3  F o ot n otes f or 
T a ble  3 Sc he d ule of E ve nts (f or 
O pti o nal O pe n -La bel E xte nsi o n 
P eri o d)   
Secti o n  9. 2. 3. 5 La b orat or y T esti n g 
( Safet y a n d Ot her) 
List of assess me nts f or dr u g 
h y perse nsiti vit y e ve nts re vise d t o 
re m o ve t he a d diti o nal assess me nts i n 
t he e ve nt of s us pecte d brea kt hr o u g h 
he m ol ysis.  
C orrecti o n as a d diti o nal list of 
assess me nts was i nte n de d f or dr u g 
h y perse nsiti vit y e ve nts o nl y.  
Secti o n  9. 2. 3. 5 La b orat or y T esti n g 
( Safet y a n d Ot her)  
List of A E SIs u p date d t o re place 
‘a n y t hr o m b otic or e m b olic e v e nt’ 
wit h ‘ Maj or A d verse Vasc ular 
E ve nts’  
T o pr o vi de m ore s pecific 
i nstr ucti o ns o n t he t y pe of e ve nts 
q ualif yi n g as a n A E SI a n d 
har m o nize t he A E SI acr oss t he 
pr o gra m.  
Secti o n  1 0. 1. 3  E ve nts t hat Re q uire 
E x pe dite d Re p orti n g t o S p o ns or.  
T otal n u m ber of scree ne d pati e nts 
re vise d t o i ncl u de all patie nts w h o 
si g ne d t he I C F. 
T o c o nsi der a patie nt as scree ne d if 
si g ni n g t he mai n I C F e ve n if 
i ncl usi o n criteri o n is n ot met. 
Secti o n  1 1. 4. 1  P atie nt Dis p ositi o n  
Statistical a nal ysis f or sec o n dar y 
e n d p oi nts re vise d t o re m o ve m ulti ple 
i m p utati o n a n d s u b gr o u p a nal ysis. 
U p date d gi ve n t hat patie nt 
n u m bers i n eac h s u b gr o u p of 
patie nts ma y be t o o s mall t o all o w 
f or m ulti ple i m p utati o n.  S u b gr o u p 
a nal yses will be s pecifie d i n t he 
S A P.  
Cli nical St u d y Pr ot oc ol S y n o psis 
( Sec o n dar y E n d p oi nts,) 
Secti o n  1 1. 4. 3. 1  Sec o n dar y 
Efficac y  A nal ysis  
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C O N FI D E N TI A L  
Descri pti o n of C h a n ge  
B rief R ati o n ale  
Secti o n # a n d N a me  
La n g ua ge a d de d t o all o w f or 
u n use d/left o ver sa m ples t o be use d 
f or e x pl orat or y researc h. 
E x pl orat or y researc h ca n be 
c o n d ucte d i n all patie nts usi n g 
left o ver/ u n use d bl o o d sa m ples. 
Secti o n  9. 2. 6  P har mac o d y na mic 
a n d E x pl orat or y Bi o mar ker 
Pr oce d ur es  
E dit orial c ha n ges a n d clarificati o ns  
F or c o nsiste nc y wit hi n t he 
pr ot oc ol, clarit y, a d mi nistrati ve 
u p dates, a n d c orrecti o n of 
t y p o gra p hical err ors. 
Title P a ge  
List of A b bre viati o ns a n d 
Defi niti o ns of T er ms  
Cli nical St u d y Pr ot oc ol S y n o psis 
( Sec o n dar y E nd p oi nts,)  
Secti o n  4. 1. 2  Sec o n dar y E n d p oi nts   
Secti o n  5. 6  P har mac o d y na mic a n d 
Ot her Bi o mar ker Varia bles  
T a ble  1 : Sc he d ule of E ve nts f or 
O pe n -La bel Treat me nt P eri o d  
T a ble  2:  Sc he d ule of E ve nts f or 
Treat me nt P eri o d (f or P atie nts o n 
I nte nsifie d Treat me nt i n t he 
O L T P)  
T a ble  3:  Sc he d ule of E ve nts 
( O pti o nal O pe n -La bel E xte nsi o n 
P eri o d)  
Secti o n  9. 1. 1. 2 F o ot n otes f or 
T a ble 2 Sc he d ule of E ve nts ( O pe n -
La bel Treat me nt P eri o d f or 
P atie nts o n I nte nsifie d T hera p y)  
Secti o n  6. 1. 2  Brea kt hr o u g h 
He m ol ysis  
Secti o n  9. 2. 3. 5  La b orat or y T esti n g 
( Safet y a n d Ot her ) 
Secti o n  9. 2. 5  I m m u n o ge nicit y 
Meas ure me nts a n d Sa m ples  
Secti o n  9. 2. 6  P har mac o d y na mic 
a n d E x pl orat or y Bi o mar ker 
Pr oce d ures  
Secti o n  1 1. 4. 3. 1  Sec o n dar y 
Efficac y A nal ysis  
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C O N FI D E N TI A L  
A me n d me nt 1  
T he mai n p ur p ose f or t his a me n d me nt is t o a d dress fee d bac k fr o m a healt h a ut h orit y.  
Descri pti o n of C h a n ge  
B rief R ati o n ale  
Secti o n # a n d N a me  
A d de d e xcl usi o n criteri o n f or 
patie nts wit h se vere aller gies a n d/ or 
patie nts w h o has ha d a na p h yla ctic 
reacti o n t o prescri pti o n or 
n o n -prescri pti o n dr u gs.  
 
 
Secti o n  7. 2. 2  E xcl usi o n Criteria, 
# 2 9  (ne w)  
A d de d e xcl usi o n criteri o n f or 
patie nts w h o ca n n ot or will n ot 
recei ve vacci nati o ns a gai nst 
Stre pt oc occ us p ne u m o ni ae  a n d 
H ae m o p hil us i nfl ue nz a  t y pe B. 
 
 
Secti o n  6. 1. 1. 1  Scree ni n g P eri o d  
Secti o n  7. 2. 2  E xcl usi o n Criteria, 
# 3 0  (ne w)  
T a ble  1  Sc he d ule  of E ve nts f or 
O pe n -La bel Treat me nt P eri o d  
Secti o n  9. 2. 1  Pr o ce d ures 
P erf or me d O nl y  at t he 
Scree ni n g/ Baseli ne Visit  
Re place d “ U” wit h “ X” i n sc he d ule 
of e ve nts.  
T his is a t y p o gra p hical c orrecti o n. 
Uri ne pre g na nc y test will be 
perf or me d, as i n dicate d b y t he 
f o ot n ote. 
T a ble  3  Sc he d ule of E ve nts 
( O pti o nal O pe n-La bel E xte nsi o n 
P eri o d)  
E dit orial c ha n ge t o i ncl u de t he 
I nte grate d Researc h A p plicati o n 
S yste m (I R A S) n u m ber.  
T his c ha n ge was ma de t o a d dress a 
re q uest fr o m t he et hics c o m mittee. 
Title P a ge  
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C O N FI D E N TI A L  
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  
A D A  
A nti -dr u g a nti b o d y  
A E  
A d verse e ve nt  
A E SI  
A d verse e ve nt of s pecial i nterest  
A H 5 0  
Alter nati ve pat h wa y he m ol ytic acti vit y assa y  
A L T  
Ala ni ne a mi n otra nsferase  
A N C O V A  
A nal ysis of c o varia nce  
a P T T 
Acti vate d partial t hr o m b o plasti n ti me  
A S T  
As partate a mi n otra nsferase  
a H U S 
At y pical he m ol ytic ure mic s y n dr o me 
A U C  
Area u n der t he c ur ve  
C  
C o m ple me nt c o m p o ne nt (e g, C 3, C 5)  
C B C  
C o m plete bl o o d c o u nt  
C H 5 0  
T otal c o m ple me nt he m ol ytic acti vit y assa y  
CI  
C o nfi de nce i nter val  
C O A  
Cli nical O utc o me Assess me nt  
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  
C R F  
Case re p ort f or m (electr o nic or pa per) 
C R O  
C o ntract researc h or ga nizati o n  
C R P  
C -reacti ve pr otei n 
C S R  
Cli nical st u d y re p ort  
C T F G  
Cli nical Trial Facilitati o n Gr o u p  
d L  
Deciliter  
D T D  
Dr u g -tar get-dr u g  
E C G  
Electr ocar di o gra m  
E D C  
Electr o nic data ca pt ure  
e G F R 
Esti mate d gl o mer ular filtrati o n rate  
E O R T C -Q L Q -3 0  
E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life 
of Ca ncer Patie nts Q uesti o n naire -3 0  
E O T  
E n d of treat me nt  
E S R  
Er yt hr oc yte se di me ntati o n rate  
E T  
Earl y ter mi nati o n  
E C  
Et hics C o m mittee  
E U  
E ur o pea n U ni o n  
F A CI T -Fati g ue  
F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y -Fati g ue  
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C O N FI D E N TI A L  
F A S  
F ull a nal ysis set  
F B R  
F ut ure bi o me dical researc h  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S H  
F ollicle sti m ulati n g h or m o ne  
g  
Gra ms  
G C P  
G o o d Cli nical Practice  
G H S  
Gl o bal healt h stat us  
g M G  
Ge neralize d m yast he nia gra vis  
G PI  
Gl yc o p h os p hati d yli n osit ol  
H Bs A g  
He patitis B s urface a nti ge n  
H C V  
He patitis C  
HI V  
H u ma n i m m u n o deficie nc y vir us  
H R Q o L  
Healt h -relate d q ualit y of life 
H S C  
He mat o p oietic ste m cell  
I B 
I n vesti gat or’s Br oc h ure 
I C F 
I nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil o n Har m o nisati o n 
I N R 
I nter nati o nal n or malize d rati o 
I U D 
I ntra uteri ne de vice 
I U S 
I ntra uteri ne h or m o ne-releasi n g s yste m 
I V 
I ntra ve n o us 
I V R S 
I nteracti ve V oice Res p o nse S yste m  
I W R S 
I nteracti ve We b Res p o nse S yste m 
k g  
Kil o gra m  
L A M  
Lactati o nal a me n orr hea met h o d  
L D H  
Lactate de h y dr o ge nase  
L T BI  
Late nt t u berc ul osis i nfecti o n  
m A b  
M o n ocl o nal a nti b o d y  
M A C  
Me m bra ne attac k c o m ple x  
M A V E  
Maj or a d verse vasc ular e ve nt  
m g  
Milli gra m  
MI  
M ulti ple i m p utati o n  
m R N A  
messe n ger R N A  
µ g  
Micr o gra m  
m L  
Milliliter  
M M R M  
M ulti ple mi xe d -effect re peate d meas ures  
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C O N FI D E N TI A L  
N O A E L  
N o o bser va ble a d verse effect le vel  
O L E P  
O pe n -la bel e xte nsi o n peri o d (a n o pti o nal peri o d) 
O L T P  
O pe n -la bel treat me nt peri o d ( mai n st u d y peri o d)  
P D  
P har mac o d y na mic  
P GI C  
Patie nt Gl o bal I m pressi o n of Se verit y  
P GI S  
Patie nt Gl o bal I m pressi o n of C ha n ge  
PI G A  
P h os p hati d yli n osit ol gl yca n a nc h or bi os y nt hesis class A  
P K  
P har mac o ki netic  
P N H  
Par o x ys mal n oct ur nal he m o gl o bi n uria  
P T  
Preferre d ter m  
Q 2 W  
E ver y 2  wee ks  
Q 4 W  
E ver y 4  wee ks  
Q 8 W  
E ver y 8 wee ks  
Q W  
E ver y wee k  
R B C  
Re d bl o o d cell  
R N A  
Ri b o n ucleic aci d  
R Nase  
Ri b o n uclease   
S A E  
Seri o us a d verse e ve nt  
S A F  
Safet y a nal ysis set  
S A P  
Statistical a nal ysis pla n  
S C  
S u bc uta ne o us  
S D V  
S o urce data verificati o n  
si R N A 
s mall i nterferi n g R N A 
S O C  
S yste m or ga n class  
T B  
T u berc ul osis  
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt  
T S Q M  
Treat me nt Satisfacti o n Q uesti o n naire f or Me dicati o n  
U L N  
U p per li mit of n or mal  
U S  
U nite d States  
W B C  
W hite bl o o d cell  
W O C B P  
W o me n of c hil d beari n g p ote ntial  
W O C F  
W orst o bser vati o n carrie d f or war d  
 
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Re ge n er o n P har mace uticals, I n c.  
 
Pa ge 1 3  
 
C O N FI D E N TI A L  
T A B L E O F C O N T E N T S  
A M E N D M E N T HI S T O R Y  .............................................................................................................2  
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 0  
C LI NI C A L S T U D Y P R O T O C O L S Y N O P SI S .............................................................................2 0  
1.  
I N T R O D U C TI O N ......................................................................................................2 5  
1. 1.  
Bac k gr o u n d o n Par o x ys mal N oct ur nal He m o gl o bi n uria  ............................................2 5  
1. 2.  
Bac k gr o u n d o n P ozeli ma b  ..........................................................................................2 6  
1. 3.  
Bac k gr o u n d o n Ce m disira n  ........................................................................................2 8  
1. 4.  
P ozeli ma b + Ce m disira n: A C o m bi nati o n A p pr oac h  .................................................2 9  
2.  
S T U D Y O BJ E C TI V E S  ..............................................................................................2 9  
2. 1.  
Pri mar y O bj ecti ve  .......................................................................................................2 9  
2. 2.  
Sec o n dar y O bj ecti ves  .................................................................................................2 9  
2. 3.  
E x pl orat or y O bjecti ves  ...............................................................................................3 0  
3.  
H Y P O T H E SI S A N D R A TI O N A L E  ..........................................................................3 0  
3. 1.  
H y p ot hes es  ..................................................................................................................3 0  
3. 2.  
Rati o nale  .....................................................................................................................3 0  
3. 2. 1.  
Rati o nale f or St u d y D esi g n a n d E n d p oi nts  .................................................................3 0  
3. 2. 2.  
Rati o nale f or D ose Sel ecti o n  ......................................................................................3 2  
3. 3.  
Ris k -Be nefit  ................................................................................................................3 5  
3. 3. 1.  
I nf usi o n Reacti o ns ......................................................................................................3 5  
3. 3. 2.  
P ote ntial Ris k of Neisseria I nfecti o n  ..........................................................................3 5  
3. 3. 3.  
Li ver F u n cti o n Test A b n or malities  .............................................................................3 6  
3. 3. 4.  
St u d y C o n d u ct i n Res p o nse t o C or o na vir us Disease 2 0 1 9  .........................................3 7  
3. 3. 5.  
Ot her Ris ks  .................................................................................................................3 7  
4.  
E N D P OI N T S  ..............................................................................................................3 7  
4. 1.  
Pri mar y a n d Sec o n dar y E n d p oi nts ..............................................................................3 7  
4. 1. 1.  
Pri mar y E n d p oi nt  ........................................................................................................3 7  
4. 1. 2.  
Sec o n dar y E n d p oi nts  ..................................................................................................3 7  
4. 1. 2. 1.  
Sec o n dar y E n d p oi nts f or t he O pti o nal O pe n -La bel E xte nsi o n Peri o d  .......................3 9  
4. 1. 3.  
E x pl orat or y E n d p oi nts  ................................................................................................4 0  
5.  
S T U D Y V A RI A B L E S ................................................................................................4 1  
5. 1.  
De m o gra p hic a n d Baseli ne C haracteristics  ................................................................4 1  
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C O N FI D E N TI A L  
5. 2.  
Efficac y Varia bles  ......................................................................................................4 1  
5. 2. 1.  
La b orat or y V aria bl es f or t he Assess me nt of Effi cac y  ................................................4 1  
5. 2. 2.  
Tra nsf usi o n Rec or d  .....................................................................................................4 1  
5. 2. 3.  
C li nical O utc o me Assess me nts ...................................................................................4 1  
5. 3.  
Safet y Vari a bles  ..........................................................................................................4 2  
5. 4.  
P har mac o ki netic Varia bl es  .........................................................................................4 2  
5. 5.  
I m m u n o ge nicit y V aria bl es ..........................................................................................4 2  
5. 6.  
P har mac o d y na mic a n d Ot her Bi o mar ker Varia bles  ...................................................4 2  
6.  
S T U D Y D E SI G N  .......................................................................................................4 3  
6. 1.  
St u d y Descri pti o n a n d D urati o n  .................................................................................4 3  
6. 1. 1.  
St u d y Peri o ds  ..............................................................................................................4 4  
6. 1. 1. 1.  
Scree ni n g Peri o d  .........................................................................................................4 4  
6. 1. 1. 2.  
O pe n -La b el Treat me nt Peri o d  ....................................................................................4 5  
6. 1. 1. 3.  
O pti o nal O pe n -La b el E xte nsi o n Peri o d  ......................................................................4 7  
6. 1. 1. 4.  
P ost -Treat me nt Safet y F oll o w -U p  ..............................................................................4 7  
6. 1. 1. 5.  
E n d of St u d y Defi niti o n  ..............................................................................................4 7  
6. 1. 2.  
Brea kt hr o u g h H e m ol ysis  ............................................................................................4 8  
6. 1. 3.  
Treat me nt I nte nsifi cati o n  ............................................................................................4 8  
6. 1. 4.  
Tra nsf usi o n Al g orit h m  ................................................................................................4 9  
6. 1. 5.  
Lar ge dr u g -tar get-dr u g i m m u ne c o m ple x es  ...............................................................4 9  
6. 2.  
Pla n ne d I nteri m A nal ysis  ............................................................................................4 9  
7.  
S E L E C TI O N, WI T H D R A W A L, A N D R E P L A C E M E N T O F P A TI E N T S  ..............5 0  
7. 1.  
N u m ber of Patie nts Pla n ne d  .......................................................................................5 0  
7. 2.  
St u d y P o p ulati o n  .........................................................................................................5 0  
7. 2. 1.  
I n cl usi o n Criteria ........................................................................................................5 0  
7. 2. 2.  
E x cl usi o n Criteria  .......................................................................................................5 0  
7. 3.  
Pre mat ure Wit h dra wal fr o m t he St u d y  .......................................................................5 3  
7. 4.  
Re place me nt of Patie nts  .............................................................................................5 4  
8.  
S T U D Y T R E A T M E N T S ............................................................................................5 4  
8. 1.  
I n v esti gati o nal a n d Refere nce Treat me nts ..................................................................5 4  
8. 1. 1.  
P ozeli ma b  ...................................................................................................................5 4  
8. 1. 2.  
Ce m disira n  ..................................................................................................................5 4  
8. 2.  
Bac k gr o u n d Treat me nts a n d Ris k Miti gati o n  .............................................................5 4  
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C O N FI D E N TI A L  
8. 2. 1.  
Me ni n g o c occal Vacci nati o ns  ......................................................................................5 4  
8. 2. 2.  
M o nit ori n g f or M e ni n g o c occal I nfecti o n  ...................................................................5 5  
8. 2. 3.  
Oral A nti bi otics f or Me ni n g oc o ccal I nfecti o n  ............................................................5 5  
8. 2. 4.  
Ris k Ma na ge me nt of Neisseri a G o n orr he a  ................................................................5 5  
8. 3.  
D ose M o dificati o n a n d St u d y Treat me nt Disc o nti n uati o n R ules  ...............................5 6  
8. 3. 1.  
D ose M o dificati o n  ......................................................................................................5 6  
8. 3. 2.  
Treat me nt I nte nsifi cati o n  ............................................................................................5 6  
8. 3. 3.  
St u d y Dr u g Disc o nti n uati o n  .......................................................................................5 6  
8. 3. 3. 1.  
Reas o ns f or Per ma n e nt Disc o nti n uati o n of St u d y Dr u g  .............................................5 7  
8. 3. 3. 2.  
Reas o ns f or Te m p orar y Disc o nti n uati o n of St u d y Dr u g  ............................................5 7  
8. 4.  
Ma na ge me nt of Ac ute R eacti o ns  ................................................................................5 8  
8. 4. 1.  
Ac ute I ntr a ve n o us I nf usi o n Reacti o ns  ........................................................................5 8  
8. 4. 1. 1.  
I nterr u pti o n of t he I ntra v e n o us I nf usi o n .....................................................................5 8  
8. 4. 1. 2.  
Ter mi nati o n of t he I ntr a v e n o us I nf usi o n  ....................................................................5 9  
8. 4. 2.  
Ac ute I nje cti o n Reacti o ns  ...........................................................................................5 9  
8. 4. 2. 1.  
S yste mic I nje cti o n Reacti o ns  ......................................................................................5 9  
8. 4. 2. 2.  
L ocal I nje cti o n Site Reacti o ns  ....................................................................................5 9  
8. 5.  
Met h o d of Treat me nt Assi g n me nt  ..............................................................................5 9  
8. 6.  
Bli n di n g  ......................................................................................................................6 0  
8. 7.  
Treat me nt L o gistics a n d Acc o u nta bilit y  .....................................................................6 0  
8. 7. 1.  
Pac ka gi n g, La beli n g, a n d St ora ge  ..............................................................................6 0  
8. 7. 2.  
S u p pl y a n d Dis p ositi o n of Treat me nts  .......................................................................6 0  
8. 7. 3.  
Treat me nt A cc o u nta bilit y  ...........................................................................................6 0  
8. 7. 4.  
Treat me nt C o m plia nce  ................................................................................................6 0  
8. 8.  
C o nc o mita nt Me dicati o ns  ...........................................................................................6 0  
8. 8. 1.  
Pr o hi bite d Me dicati o ns a n d Pr oce d ures  .....................................................................6 1  
8. 8. 2.  
Per mitte d Me dicati o ns a n d Pr oce d ures  ......................................................................6 1  
8. 9.  
P ost -Trial Access t o St u d y Treat me nt  ........................................................................6 1  
9.  
S T U D Y S C H E D U L E O F E V E N T S A N D P R O C E D U R E S  ......................................6 2  
9. 1.  
Sc he d ule of E ve nts  .....................................................................................................6 2  
9. 1. 1.  
F o ot n otes f or t he Sc h e d ule of E ve nts Ta bles  .............................................................7 1  
9. 1. 1. 1.  
F o ot n otes f or T a ble 1 Sc he d ule of E ve nts ( O pe n -La b el Treat me nt Peri o d)  ..............7 1  
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C O N FI D E N TI A L  
9. 1. 1. 2.  
F o ot n otes f or T a ble 2 Sc he d ule of E ve nts ( O pe n -La b el Treat me nt Peri o d f or 
Patie nts o n I nte nsifie d T hera p y)  .................................................................................7 5  
9. 1. 1. 3.  
F o ot n otes f or T a ble  3 Sc he d ule of E ve nts (f or O pti o nal O pe n -La b el 
E xte nsi o n Peri o d)  ........................................................................................................7 7  
9. 1. 1. 4.  
F o ot n otes f or T a ble 4 Sc he d ule of E ve nts ( P ost -Treat me nt Safet y F oll o w -U p 
Peri o d f or All Patie nts)  ...............................................................................................7 9  
9. 1. 2.  
Earl y Ter mi nati o n Visit  ..............................................................................................7 9  
9. 1. 3.  
U nsc he d ule d Visits  .....................................................................................................7 9  
9. 2.  
St u d y Pr oce d ures  ........................................................................................................8 0  
9. 2. 1.  
Pr oce d ures Perf or me d O nl y at t he Scree ni n g/ Baseli ne Visit  .....................................8 0  
9. 2. 2.  
Efficac y Pr oce d ures  ....................................................................................................8 1  
9. 2. 2. 1.  
La b orat or y Ass ess me nts of Efficac y  ..........................................................................8 1  
9. 2. 2. 2.  
Cli nical O utc o me Assess me nt s ...................................................................................8 1  
9. 2. 3.  
Safet y Pr oce d ures  .......................................................................................................8 3  
9. 2. 3. 1.  
B o d y -Wei g ht  ...............................................................................................................8 3  
9. 2. 3. 2.  
Vital Si g ns  ..................................................................................................................8 3  
9. 2. 3. 3.  
P h ysical E x a mi nati o n  .................................................................................................8 3  
9. 2. 3. 4.  
Electr ocar di o gra m  .......................................................................................................8 3  
9. 2. 3. 5.  
La b orat or y T esti n g ( Safet y a n d Ot h er)  .......................................................................8 4  
9. 2. 3. 6.  
Bl o o d Tra nsf usi o n  ......................................................................................................8 6  
9. 2. 3. 7.  
A d verse E v e nts  ...........................................................................................................8 6  
9. 2. 4.  
Dr u g C o nce ntr ati o n a n d Meas ure me nts  .....................................................................8 6  
9. 2. 4. 1.  
C o nce ntrati o ns of T otal P ozeli ma b, Ec uliz u ma b, a n d T otal C 5  ................................8 6  
9. 2. 4. 2.  
C o nce ntrati o ns of Ce m disira n a n d Ce m disir a n Meta b olites  ......................................8 6  
9. 2. 5.  
I m m u n o ge nicit y Meas ur e me nts a n d Sa m ples ............................................................8 6  
9. 2. 6.  
P har mac o d y na mic a n d E x pl orat or y Bi o mar ker Pr oce d ures  .......................................8 7  
9. 2. 7.  
F ut ure Bi o me dical Res earc h ( O pti o nal)  .....................................................................8 7  
9. 2. 8.  
P har mac o ge n o mic A n al ysis ( O pti o nal)  ......................................................................8 8  
1 0.  
S A F E T Y E V A L U A TI O N A N D R E P O R TI N G  .........................................................8 8  
1 0. 1.  
Rec or di n g a n d Re p orti n g A d verse E v e nts  ..................................................................8 8  
1 0. 1. 1.  
Ge neral G ui deli nes  .....................................................................................................8 8  
1 0. 1. 2.  
Re p orti n g Pr oce d ure  ...................................................................................................8 9  
1 0. 1. 3 . 
E ve nts t hat Re q uire E x pe dite d Re p orti n g t o S p o ns or  ................................................9 0  
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C O N FI D E N TI A L  
1 0. 1. 4.  
Ot her A d verse E ve nts of S pecial I nterest t hat d o n ot Re q uire E x pe dit e d 
Re p orti n g t o S p o ns or  ..................................................................................................9 1  
1 0. 2.  
Defi niti o ns  ..................................................................................................................9 1  
1 0. 2. 1.  
A d verse E v e nt  .............................................................................................................9 1  
1 0. 2. 2.  
Seri o us A d verse E v e nt  ................................................................................................9 1  
1 0. 2. 3.  
A d verse E v e nts of S peci al I nt erest  .............................................................................9 2  
1 0. 2. 4.  
I nf usi o n Reacti o ns ......................................................................................................9 2  
1 0. 2. 5.  
Se verit y  .......................................................................................................................9 2  
1 0. 2. 6.  
Ca usalit y  .....................................................................................................................9 3  
1 0. 3.  
Safet y M o nit ori n g  .......................................................................................................9 4  
1 0. 4.  
N otif yi n g H ealt h A ut h orities, Et hics C o m mittee, a n d I n v esti gat ors  ..........................9 5  
1 1.  
S T A TI S TI C A L P L A N ................................................................................................9 5  
1 1. 1.  
Statistical H y p ot hesis  ..................................................................................................9 5  
1 1. 2.  
J ustificati o n of Sa m ple Size........................................................................................9 5  
1 1. 3.  
A nal ysis Sets  ...............................................................................................................9 5  
1 1. 3. 1.  
Efficac y A nal ysis Sets  ................................................................................................9 5  
1 1. 3. 2.  
Safet y A nal ysis Sets  ...................................................................................................9 6  
1 1. 3. 3.  
P har mac o ki netic A n al ysis Set  ....................................................................................9 6  
1 1. 3. 4.  
I m m u n o ge nicit y A n al ysis Set .....................................................................................9 6  
1 1. 4.  
Statistical Met h o ds  ......................................................................................................9 6  
1 1. 4. 1.  
Patie nt Dis p ositi o n  ......................................................................................................9 6  
1 1. 4. 2.  
De m o gra p h y a n d Baseli ne C haracteristics  .................................................................9 7  
1 1. 4. 3.  
Efficac y A nal yses  .......................................................................................................9 7  
1 1. 4. 3. 1.  
Sec o n dar y Efficac y A nal ysis  ......................................................................................9 7  
1 1. 4. 4.  
C o ntr ol of M ulti plicit y  ................................................................................................9 8  
1 1. 4. 5.  
Safet y A nal ysis  ...........................................................................................................9 9  
1 1. 4. 5. 1.  
A d verse E v e nts  ...........................................................................................................9 9  
1 1. 4. 5. 2.  
Ot her Safet y  ..............................................................................................................1 0 0  
1 1. 4. 5. 3.  
Treat me nt E x p os ure  ..................................................................................................1 0 0  
1 1. 4 . 5. 4. 
Treat me nt C o m plia nce  ..............................................................................................1 0 0  
1 1. 4. 6.  
P har mac o ki netics  ......................................................................................................1 0 1  
1 1. 4. 6. 1.  
A nal ysis of Dr u g C o nce ntrati o n Data  .......................................................................1 0 1  
1 1. 4. 7.  
A nal ysis of I m m u n o ge nicit y Data  ............................................................................1 0 1  
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C O N FI D E N TI A L  
1 1. 4. 8.  
A nal ysis of P har mac o d y na mic a n d E x pl orat or y Bi o mar ker Data  ............................1 0 1  
1 1. 5.  
I nteri m A nal ysis ........................................................................................................1 0 1  
1 1. 6.  
Statistical C o nsi derati o ns S urr o u n di n g t he Pr e mat ure Ter mi nati o n of a St u d y  .......1 0 2  
1 2.  
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  .......................................1 0 2  
1 2. 1.  
Data Ma na ge me nt a n d El ectr o nic S yste ms  ..............................................................1 0 2  
1 2. 1. 1.  
Data Ma na ge me nt  .....................................................................................................1 0 2  
1 2. 1. 2.  
Electr o nic S yst e ms  ....................................................................................................1 0 2  
1 2. 2.  
St u d y M o nit ori n g  ......................................................................................................1 0 3  
1 2. 2. 1.  
M o nit ori n g of St u d y Sites  .........................................................................................1 0 3  
1 2. 2. 2.  
S o urce D oc u m e nt Re q uire me nts  ..............................................................................1 0 3  
1 2. 2. 3.  
Case Re p ort F or m Re q uire me nts  ..............................................................................1 0 3  
1 2. 3.  
A u dits a n d I ns p ecti o ns  ..............................................................................................1 0 4  
1 2. 4.  
St u d y D oc u me ntati o n  ...............................................................................................1 0 4  
1 2. 4. 1.  
Certificati o n of Acc urac y of Data  .............................................................................1 0 4  
1 2. 4. 2.  
Rete nti o n of Rec or ds  ................................................................................................1 0 4  
1 3.  
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  ........................................1 0 5  
1 3. 1.  
G o o d Cli nical Practice State me nt  .............................................................................1 0 5  
1 3. 2.  
I nf or me d C o nse nt .....................................................................................................1 0 5  
1 3. 3.  
Patie nts C o nfi de ntialit y a n d Data Pr otecti o n  ............................................................1 0 5  
1 3. 4.  
I nstit uti o nal Re vie w B oar d .......................................................................................1 0 6  
1 3. 5.  
Cli nical St u d y D ata Tra ns pare nc y  ............................................................................1 0 6  
1 4.  
P R O T O C O L A M E N D M E N T S  ................................................................................1 0 6  
1 5.  
P R E M A T U R E T E R MI N A TI O N O F T H E S T U D Y O R C L O S E -O U T O F A 
SI T E  ..........................................................................................................................1 0 7  
1 5. 1.  
Pre mat ure Ter mi nati o n of t he St u d y  .........................................................................1 0 7  
1 5. 2.  
Cl ose -o ut of a Site  ....................................................................................................1 0 7  
1 6.  
C O N FI D E N TI A LI T Y  ..............................................................................................1 0 7  
1 7.  
FI N A N CI N G A N D I N S U R A N C E  ...........................................................................1 0 7  
1 8.  
P U B LI C A TI O N P O LI C Y  ........................................................................................1 0 7  
1 9.  
R E F E R E N C E S  .........................................................................................................1 0 8  
2 0.  
I N V E S TI G A T O R’ S A G R E E M E N T  ........................................................................1 1 1  
SI G N A T U R E O F S P O N S O R ’ S R E S P O N SI B L E O F FI CE R S  ...................................................1 1 2  
 
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C O N FI D E N TI A L  
LI S T O F T A B L E S  
Ta ble  1:  
Sc he d ule of E ve nts f or O pe n -La b el Treat me nt Peri o d  ...............................................6 3  
Ta ble  2:  
Sc he d ule of E ve nts f or Treat me nt Peri o d (f or Patie nts o n I nt e nsifie d 
Treat me nt i n t he O L T P)  ..............................................................................................6 6  
Ta ble  3:  
Sc he d ule of E ve nts ( O pti o nal O pe n -La bel E xte nsi o n Peri o d)  ...................................6 8  
Ta ble  4:  
Sc he d ule of E ve nts f or P ost -Treat me nt Safet y F oll o w -U p Peri o d ( All 
Patie nts)  ......................................................................................................................7 0  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
St u d y Fl o w Dia gra m  ...................................................................................................4 4  
 
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C O N FI D E N TI A L  
C LI NI C A L S T U D Y P R O T O C O L S Y N O P SI S  
Title  
A 
Si n gle 
Ar m, 
O pe n -La bel 
St u d y t o 
Assess t he 
S afet y, 
Efficac y, a n d 
P har mac o d y na mic Effects of P ozeli ma b a n d Ce m disira n C o m bi nati o n T hera p y i n 
P atie nts 
wit h 
P ar o x ys mal 
N oct ur nal 
He m o gl o bi n uria 
W h o 
S witc h 
Fr o m 
Ec uliz u ma b T hera p y  
Site L oc ati o n(s)  
 
Pri nci p al I n vesti g at or  
U nite d Ki n g d o m  
Ric har d Kell y, M B C h B, P h D  
O bjecti ve(s)  
T he pri mar y o bj ecti ve of t he st u d y is t o e val uate t he safet y a n d t olera bilit y of 
p ozeli ma b  a n d  ce m disira n c o m bi nati o n  t hera p y i n patie nts wit h par o x ys mal 
n oct ur nal he m o gl o bi n uria ( P N H) w h o s witc h fr o m ec uliz u ma b t hera p y.  
T he sec o n dar y o bj ecti ves of t he st u d y are:  
•  T o e val uate t he effect of t he c o m bi nati o n treat me nt o n t he f oll o wi n g 
para meters of i ntra vasc ular he m ol ysis: l actate de h y dr o ge nas e 
( L D H) c o ntr ol, brea kt hr o u g h he m ol ysis, a n d i n hi biti o n of c o m ple me nt 
he m ol ysis acti vit y ( C H 5 0)     
•  T o e val uate t he sta bilit y of L D H d uri n g t he tra nsiti o n peri o d fr o m 
ec uliz u ma b m o n ot hera p y t o c o m bi nati o n wit h p ozeli ma b a n d ce m disira n  
•  T o e val uate t he effect o n re d bl o o d cell ( R B C) tra nsf usi o n re q uire me nts  
•  T o e val uate t he effect of t he c o m bi nati o n treat me nt o n he m o gl o bi n le vels  
•  T o e val uate t he effect of t he c o m bi nati o n treat me nt o n cli ni cal o utc o me 
assess me nts ( C O As) meas uri n g fati g ue a n d healt h -relate d q ualit y of life 
( H R Q o L) 
•  T o assess t he c o nce ntrati o ns of t otal p ozeli ma b a n d ec uliz u ma b i n ser u m; 
a n d t otal ce m disira n a n d C 5 pr otei n i n plas ma  
•  T o assess t he i m m u n o ge nicit y of p ozeli ma b a n d ce m disira n  
•  T o assess safet y after d ose i nt e nsificati o n  
•  T o e val uate t he l o n g -ter m safet y a n d efficac y of t he c o m bi nati o n treat me nt 
i n a n o pti o nal o pe n-la bel e xte nsi o n peri o d ( O L E P)  
St u d y Desi g n  
T he st u d y is a si n gle -ar m, o pe n -la bel st u d y w here b y u p t o  1 2  patie nts wit h  P N H 
w h o are c urre ntl y recei vi n g ec uliz u ma b will be s witc he d t o p ozeli ma b a n d 
ce m disira n c o m bi nati o n t hera p y. T he st u d y will i ncl u de patie nts w h o are c urre ntl y 
recei vi n g ec uliz u ma b at t he l a bele d d osi n g re gi me n ( 9 0 0 m g i ntra ve n o usl y [I V] 
e ver y 2 wee ks [ Q 2 W ]) or patie nts w h o are c urre ntl y recei vi n g ec uliz u ma b at a d ose 
hi g her t ha n t he la bele d d ose ( > 9 0 0 m g I V) or m ore fre q ue ntl y t ha n la bele d. T he 
st u d y c o nsists of 4 peri o ds: a scree ni n g peri o d of u p t o 4 2 da ys, a 3 2 -wee k o pe n -
la bel treat me nt peri o d ( O L T P, l on ger f or patie nts w h o are s witc he d t o treat me nt 
i nte nsificati o n), a n o pti o nal 5 2-wee k O L E P, a n d a 5 2 -wee k p ost -treat me nt safet y 
f oll o w-u p peri o d. T he f o urt h peri o d be gi ns 
w he n a patie nt c o m pletes or 
per ma ne ntl y disc o nti n ues st u d y treat me nt ( e g, at t he ti me of pre mat ure st u d y dr u g 
disc o nti n uati o n, at t he c o m pleti o n of st u d y treat me nt i n t he O L T P f or patie nts w h o 
decli ne t he o pti o nal O L E P, or at t he c o m pleti o n of st u d y tre at me nt i n t he o pti o nal 
O L E P).  
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C O N FI D E N TI A L  
P atie nts w h o f ulfill all t he eli gi bilit y criteria will be e nr olle d i n t he st u d y a n d recei ve 
t heir first d ose  of st u d y treat me nt o n da y 1 of t he O L T P, w hi c h s h o ul d occ ur o n t he 
da y of t he patie nt’s sc he d ule d treat me nt wit h ec uliz u ma b. P atie nts will be c o -
a d mi nistere d ce m disira n wit h ec uliz u ma b o n da y 1, a n d t he n r ecei ve ec uliz u ma b 
al o ne o n t he da y of t he patie nt’s ne xt pla n ne d d ose ( da y 1 5 or earlier de pe n di n g o n 
t he patie nt’s us ual d ose fre q ue nc y). T he first d ose of c o m bi nati o n s u bc uta ne o us 
( S C) t hera p y wit h p ozeli ma b a n d ce m disira n wit h o ut bac k gr o u n d ec uliz u ma b will 
be a d mi nistere d o n da y 2 9 a n d e ver y 4 wee ks ( Q 4 W) t hereafter f or 2 8 wee ks. T he 
first d ose of c o m bi nati o n S C t hera p y o n da y 2 9 will be prece de d b y a n I V l oa di n g 
d ose of p ozeli ma b t o ac hie ve hi g h c o nce ntrati o ns of p ozeli ma b ra pi dl y i n or der t o 
pr o vi de c o m plete i n hi biti o n of C 5 as s o o n as p ossi ble d uri n g t he s witc h fr o m 
ec uliz u ma b t o p ozeli ma b. T he S C d oses will be a d mi nist ere d after at least 3 0 
mi n utes f oll o wi n g c o m pleti o n of t he I V  a d mi nistrati o n, a n d t he patie nt s h o ul d be 
o bser ve d d uri n g t he i nter val. P atie nts will c o nti n ue t o be m o nit ore d f or at least 
3 0  mi n utes after c o m pleti n g t he first S C i nj ecti o ns f or t he p ozeli ma b a n d 
ce m disira n c o m bi nati o n.  
After t he first S C d ose of t he p ozeli ma b a n d ce m disira n c o m bi nati o n o n da y  2 9, 
s u bse q ue nt st u d y treat me nt a d mi nistrati o ns ma y be c o nti n ue d b y t he site pers o n nel, 
healt h care pr ofessi o nal (if a vaila ble) or a d mi nistere d b y t he patie nt or desi g nate d  
pers o n at t he patie nt’s preferre d l ocati o n. T hese o pti o ns f or st u d y treat me nt 
a d mi nistrati o n will de pe n d o n prefere nce of t he i n vesti gat or a n d patie nt, l ocal 
re g ulati o ns as well as a vaila bilit y of healt hcare pr ofessi o nals.   
D uri n g t he st u d y, a patie nt me eti n g brea kt hr o u g h he m ol ysis criteria a n d i na de q uate 
L D H res p o nse will q ualif y f or i nte nsifie d treat me nt w hic h c o nsi sts of a n i nitial I V 
l oa di n g d ose of p ozeli ma b a n d i nte nsifie d p ozeli ma b re gi me n t o be  a d mi nistere d 
Q 2 W al o n g wit h ce m disira n at Q 4 W, f or a peri o d of 3 2 wee ks. T his re gi me n is 
pr o p ose d t o pr o vi de e xtra  C 5 s u p pressi o n t hat s o me patie nts ma y nee d a n d w hic h 
ca n n ot be ma na ge d a de q uatel y b y t he sta n dar d d ose re gi me n (see I nte nsifie d 
Treat me nt secti o n of t his s y n o psis).  
T he l o n g -ter m safet y a n d effic ac y of t he c o m bi nati o n treat me nt will be assesse d b y 
pr o vi di n g t he patie nts 
w h o c o m plete t he st u d y treat me nt i n t he  O L T P o n 
c o m bi nati o n treat me nt a n o pti o n t o partici pate i n a l o n g-t er m O L E P, i n w hic h 
patie nts s hall c o nti n ue t o recei ve st u d y treat me nt f or a n a d diti o nal 5 2 wee ks. F or 
patie nts w h o c o m plete t he o pti o nal O L E P, p ost -trial access t o treat me nt ma y be 
a vaila ble.  
All patie nts w h o per ma ne ntl y st o p st u d y treat me nt will be as ke d t o c o m plete a 5 2 -
wee k safet y f oll o w -u p peri o d after t he last d ose of t he st u d y treat me nt. T he safet y 
f oll o w-u p peri o d will be gi n w he n a patie nt c o m pletes or per ma ne ntl y disc o nti n ues  
st u d y treat me nt (e g, at t he ti me of pre mat ure st u d y dr u g disc o nti n uati o n, at t he 
c o m pleti o n of st u d y treat me nt i n t he O L T P f or patie nts w h o decli ne t he o pti o nal 
O L E P, or at t he c o m pleti o n of t he o pti o nal O L E P f or patie nts w h o d o n ot c o nti n ue 
treat me nt i n a p ost-trial access setti n g). 
St u d y D ur ati o n  
T he scree ni n g peri o d is u p t o 4 2 da ys i n d urati o n. T he d urati o n of t he treat me nt 
peri o d f or i n di vi d ual patie nts is 3 2 wee ks b ut will be l o n ger f or patie nts w h o are 
s witc he d t o i nte nsifie d treat me nt. All patie nts w h o d o  n ot e nter i nt o t he o pti o nal 
O L E P will be f oll o we d f or a n a d diti o nal 5 2 wee ks after t he last d ose of c o m bi nati o n 
treat me nt. P atie nts o pti n g t o partici pate i n t he o pti o nal O L E P will c o nti n ue o pe n-
la bel treat me nt f or a 5 2-wee k peri o d, t o be f oll o we d b y a 5 2 -wee k safet y f oll o w -u p 
peri o d after t he last d ose of st u d y treat me nt (t he safet y f oll o w -u p peri o d is wai ve d 
f or patie nts w h o c o nti n ue treat me nt i n t he p ost-trial access pr o gra m). 
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C O N FI D E N TI A L  
E n d of St u d y Defi niti o n  
T he e n d of t he mai n st u d y is defi ne d as t he date of t he last visit of t he last patie nt 
i n t he O L T P, i ncl u di n g patie nts w h o disc o nti n ue d treat me nt d uri n g t he O L T P a n d 
are bei n g f oll o we d i n t he p ost -treat me nt safet y f oll o w-u p peri o d.  
T he e n d of t he o pti o nal O L E P is defi ne d as t he date of t he last visit of t he last patie nt 
i n t he o pti o nal O L E P, i ncl u di n g patie nts w h o disc o nti n ue d treat me nt d uri n g t he 
o pti o nal O L E P a n d are bei n g f oll o we d i n t he p ost -treat me nt safet y f oll o w-u p 
peri o d.  
P o p ul ati o n  
 
 
S a m ple Size:  
U p t o 1 2 patie nts  
 
T ar g et P o p ul ati o n:  
P atie nts will be me n a n d w o me n ≥1 8 years of a ge wit h a dia g n osis of P N H, a n d 
c urre ntl y o n treat me nt wit h sta ble ec uliz u ma b t hera p y f or at least 1 2  wee ks pri or t o 
scree ni n g.  
Tre at me nts  
All patie nts  will  recei ve p ozeli ma b + ce m disira n c o m bi nati o n treat me nt.  
 
St u d y Dr u g  
 
D ose/ R o ute/ Sc he d ule:  
P ozeli ma b  
I nitial d ose ( o n da y 2 9): 6 0 m g/ k g I V l oa di n g d ose ( o nce) f oll o we d after 3 0 mi n utes  
b y 4 0 0 m g S C.   
After i nitial d ose of I V a n d S C p ozeli ma b o n da y 2 9, patie nts will recei ve 4 0 0  m g 
S C  Q 4 W.  
3 0 m g/ k g I V b ol us as nee de d ma y be c o nsi dere d f or patie nts w h o e x perie nce a n 
L D H i ncrease ≥2 x U L N d ue t o a n ac ute c o m ple me nt -acti vati n g c o n diti o ns (see 
pr ot oc ol f or details)  
 
St u d y Dr u g  
 
D ose/ R o ute/ Sc he d ule:  
Ce m disira n  
2 0 0 m g S C Q 4 W  
F or t he first a p pr o xi matel y 2 wee ks, patie nts will re mai n o n e c uliz u ma b bac k gr o u n d 
treat me nt at t heir us ual d ose, a n d ce m disira n will be i ntr o d uce d: 
Lea d -i n ce m disira n treat me nt a n d bac k gr o u n d c o nc o mita nt treat me nt wit h 
ec uliz u ma b:  
− 
Da y 1 (t he da y of t he s c he d ule d ec uliz u ma b a d mi nistrati o n): 
ce m disira n 2 0 0 m g S C a n d ec uliz u ma b ≥9 0 0 m g I V (at t he patie nt’s 
us ual d ose)  
− 
Da y 1 5 ( or earlier): ec uliz u ma b ≥9 0 0 m g I V ( patie nt’s us ual d ose a n d 
fre q ue nc y)   
T he f oll o wi n g d osa ge re gi me n of p ozeli ma b/ce m disira n c o m bi nati o n t hera p y will 
be a d mi nistere d d uri n g t he s witc h fr o m ec uliz u ma b treat me nt:  
P ozeli ma b/ce m disira n c o m bi nati o n treat me nt:  
− 
Da y 2 9 ( wee k 4): p ozeli ma b 6 0 m g/ k g I V l oa di n g d ose, f oll o we d b y 
p ozeli ma b 4 0 0 m g S C a n d ce m disira n 2 0 0  m g  S C  
− 
Da y 5 7 ( wee k 8) t o da y 1 9 7 ( wee k 2 8): p ozeli ma b 4 0 0  m g  S C a n d 
ce m disira n 2 0 0 m g S C Q 4 W ( ± 7  da ys) mai nte na nce re gi me n  
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C O N FI D E N TI A L  
I nte nsifie d 
Tre at me nt/ R o ute/ Sc he d ule:  
(f or p atie nts w h o meet 
pre -s pecifie d criteri a o n 
L D H a n d bre a kt hr o u g h 
he m ol ysis)  
Si n gle a d mi nistrati o n of p ozeli ma b 3 0 m g/ k g I V o n t he da y of i nitiati o n of t he ne w  
re gi me n, f oll o we d after 3 0 mi n utes b y p ozeli ma b 4 0 0 m g S C a n d ce m disira n 2 0 0 
m g S C. T hereafter, p ozeli ma b 4 0 0 m g will be a d mi nister e d S C  Q 2 W ( ± 3 da ys ) 
al o n g wit h ce m disira n 2 0 0 m g S C Q 4 W ( ± 3 da ys).  
E n d p oi nt(s)  
 
 
Pri m ar y:  
T he pri mar y st u d y e n d p oi nt is t he i nci de nce a n d se verit y of treat me nt-e mer ge nt 
a d verse e ve nts ( T E A Es) t hr o u g h da y 2 2 5 of t he O L T P.  
 
Sec o n d ar y:  
T he mai n sec o n dar y e n d p oi nts are:  
•  
T he  perce nt c ha n ge i n L D H fr o m pre -treat me nt (as defi ne d b y t he mea n of 
t he L D H val ues at t he scree ni n g visit a n d baseli ne ( da y 1 visit pri or t o dr u g 
a d mi nistrati o n) t o e n d -of -treat me nt peri o d (as defi ne d b y t he mea n of t he 
L D H val ues at da ys 1 9 7 a n d 2 2 5 of t he O L T P).  
•  
T he pr o p orti o n of patie nts w h o are tra nsf usi o n -free ( defi ne d as n ot 
re q uiri n g a n R B C tra nsf usi o n as per pr ot oc ol al g orit h m, ie, tra nsf usi o n 
a v oi da nce) fr o m baseli ne t hr o u g h da y 2 2 5, a n d fr o m da y  2 9 t hr o u g h da y 
2 2 5, i ncl usi ve  
•  
T he pr o p orti o n of pa tie nts wit h brea kt hr o u g h he m ol ysis fr o m baseli ne 
t hr o u g h da y 2 2 5, a n d fr o m da y 2 9 t hr o u g h da y 2 2 5, i ncl usi ve  
•  
T he pr o p orti o n of patie nts  w h o mai ntai n  a de q uate c o ntr ol of he m ol ysis, 
defi ne d as L D H ≤1. 5 x u p per li mit of n or mal ( U L N) fr o m p ost -baseli ne ( o n 
d a y 1) t hr o u g h da y 2 2 5, a n d fr o m da y 5 7 t hr o u g h da y 2 2 5, i ncl usi ve  
•  
T he pr o p orti o n of patie nts wit h a de q uate c o ntr ol of he m ol ysis at eac h visit 
fr o m p ost-baseli ne ( o n da y 1) t hr o u g h da y 2 2 5, i ncl usi ve  
•  
T he pr o p orti o n of patie nts wit h n or malizati o n of t heir L D H  at eac h visit , 
defi ne d as L D H ≤1. 0 x U L N fr o m p ost -baseli ne ( o n da y 1) t hr o u g h da y 
2 2 5, i ncl usi ve  
•  
T he pr o p orti o n of patie nts wit h he m o gl o bi n sta bilizati o n  ( defi ne d as 
patie nts w h o d o n ot recei ve a n R B C tra nsf usi o n a n d ha ve n o decrease i n 
he m o gl o bi n le v el of ≥2 g/ d L) fr o m baseli ne t hr o u g h da y  2 2 5, a n d fr o m da y 
2 9 t hr o u g h da y 2 2 5, i ncl usi ve  
•  
C ha n ge i n fati g ue as meas ure d b y t he F u ncti o nal Assess me nt of C hr o nic 
Ill ness T hera p y-Fati g ue ( F A CI T -Fati g ue) Scale fr o m baseli ne t o da y 2 2 5  
•  
C ha n ge fr o m baseli ne t o da y 2 2 5 i n gl o bal healt h stat us/ Q O L scale ( G H S) 
a n d p h ysical f u ncti o n ( P F) sc ores o n t he E ur o pea n Or ga nizati o n f or 
Researc h a n d Treat me nt of Ca ncer: Q ualit y -of -Life Q uesti o n naire c ore 
3 0  ite ms ( E O R T C Q L Q-C 3 0)   
•  
C o nce ntrati o ns of t otal p ozeli ma b a n d ec uliz u ma b i n ser u m, a n d t otal 
ce m disira n i n plas ma assesse d t hr o u g h o ut t he st u d y  
•  
C ha n ge i n t otal c o m ple me nt he m ol ytic acti vit y assa y ( C H 5 0) fr o m baseli ne 
t o da y 2 2 5, i ncl usi ve 
•  
C ha n ge fr o m baseli ne i n c o nc e ntrati o n of t otal C 5 assesse d t hr o u g h o ut t he 
st u d y 
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Pa ge 2 4  
 
C O N FI D E N TI A L  
•  
Assess me nt of i m m u n o ge nicit y t o p ozeli ma b a n d ce m disira n as deter mi ne d 
b y t he i nci de nce, titer, a n d cli nical i m pact of treat me nt -e mer ge nt a nti -dr u g 
a nti b o d y ( A D A) res p o nses o ver ti me  
Pr o ce d ures a n d Assess me nts  
Safet y pr oce d ures i ncl u de 
meas ure me nt of b o d y 
wei g ht a n d r o uti ne safet y 
assess me nts ( vital si g ns, p h ysical e xa mi nati o n, electr ocar di o gra m). La b orat or y  
assess me nts  of safet y i ncl u de c oa g ulati o n pa nel, c he mistr y, he mat ol o g y, uri nal ysis, 
a n d pre g na nc y (if a p p lica ble). A d verse e ve nts a n d c o nc o mita nt me dicati o ns a n d 
pr oce d ures will be m o nit ore d t hr o u g h o ut t he st u d y.  
Efficac y pr oce d ures i ncl u de la b orat or y assess me nts of effica c y ( L D H, he m o gl o bi n , 
a n d C H 5 0), tra nsf usi o n rec or d u p date, a n d cli nical o utc o me assess me nts ( F A CI T -
Fati g ue, E O R T C Q L Q -C 3 0, Treat me nt Satisfacti o n Q uesti o n naire f or Me dicati o n 
[ T S Q M], P atie nt Gl o bal I m pr essi o n of Se verit y [ P GI S], P atie nt Gl o bal I m pressi o n 
of C ha n ge [ P GI C], a n d P N H  s y m pt o m-s pecific q uesti o n nair e). 
Ot her pr oce d ures  i ncl u de t he collecti o n of bl o o d sa m ples f or bi o mar kers, dr u g 
c o nce ntrati o ns , i m m u n o ge nicit y, a n d e x pl orat or y assess me nts. 
St atistic al Pl a n  
J ustific ati o n of S a m ple Size  
U p t o 1 2 patie nts wit h P N H w h o are c urre ntl y recei vi n g ec uliz u ma b will s witc h t o 
p ozeli ma b a n d ce m disira n c o m bi nati o n t hera p y. P atie nts will be s witc he d fr o m 
ec uliz u ma b a d mi nistrati o n at t he la bele d d osi n g re gi me n or fr o m ec uliz u ma b at a 
d ose hi g her t ha n la bele d a n d/ or a d mi nistere d m ore fre q ue ntl y t ha n la bele d.  
U p t o 1 2 patie nts wit h  P N H will be e nr olle d t o descri be a n d e x pl ore t he i nci de nce 
a n d se verit y of T E A Es t hr o u g h da y 2 2 5 of t he O L T P.  
Pri m ar y A n al ysis  
T he pri mar y  e n d p oi nt is t he i nci de nce a n d se verit y of T E A Es t hr o u g h da y  2 2 5 of 
t he O L T P. Descri pti ve s u m maries will be pr o vi de d b y treat me nt gr ou p.  
Sec o n d ar y A n al ysis  
Sec o n dar y e n d p oi nts o n effica c y will be descri pti vel y s u m marize d.  
Ti mi n g of St atistic al A n al ysis  
T he pri mar y a nal ysis will be c o n d ucte d w he n all patie nts ha ve c o m plete d t he 
3 2 -wee k treat me nt peri o d or ha ve recei ve d i nte nsifie d treat me nt or ha ve 
pre mat urel y disc o nti n ue d t he st u d y d uri n g t he O L T P.  
T he a nal ysis of t he i nte nsifie d O L T P will be c o n d ucte d w he n all i nte nsifie d patie nts 
ha ve c o m plete d t he 3 2 -wee k i nte nsifie d o pe n la bel treat me nt peri o d or ha ve 
pre mat urel y disc o nti n ue d t he st u d y d uri n g t he i nte nsifie d O L T P.   
T he O L E P a nal ysis will be c o n d ucte d w he n all patie nts ha ve c o m plete d t he  
5 2 -wee k  O L E P or ha ve pre mat urel y disc o nti n ue d t he st u d y . 
A d diti o nal safet y data fr o m t he p ost -treat me nt safet y f oll o w-u p peri o d will be 
i ncl u de d i n a s u bse q ue nt a nal ysis.   
A n i nteri m a nal ysis ma y be c o n d ucte d af ter 6 patie nts ha ve c o m plete d at least 
1 6  wee ks of t he o pe n -la bel tre at me nt peri o d.  A d diti o nal/ ot her i nteri m  a nal yses 
ma y be perf or me d t o s u p p ort re g ulat or y i nteracti o ns.  
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Pa ge 2 5  
 
C O N FI D E N TI A L  
1.  
I N T R O D U C TI O N  
1. 1.  
B ac k gr o u n d o n P ar o x ys m al N oct ur n al He m o gl o bi n uri a  
Par o x ys mal n o ct ur n al h e m o gl o bi n uria ( P N H) is a c hr o nic, pr o gressi ve, life -t hreate ni n g a n d rare 
m ultis yste m disease. It is c haracterize d b y u nc o ntr olle d c o m ple me nt acti vati o n o n re d bl o o d cells 
( R B Cs), res ulti n g i n i ntra vasc ular he m ol ysis (Sa hi n, 2 0 1 6 ), a n d o n w hite bl o o d cells ( W B Cs) a n d 
platelets, res ulti n g i n a n i ncreas e d ris k of t hr o m b osis. T he esti mate d i nci de nce of P N H is 1. 3  cas es 
per milli o n i n di vi d uals p er year, a n d t he esti mate d pre vale nce is 1 5. 9 cases per milli o n i n di vi d uals 
per year (Preis, 2 0 1 4 ).  
Par o x ys mal n o ct ur nal h e m o gl o bi n uria ori gi nates fr o m a m ulti p ote nt, he mat o p oietic ste m cel l 
( H S C) t hat ac q uir es a m utati o n of t he p h os p hati d yli n osit ol gl yca n a n c h or bi os y nt hesis class A 
( PI G A) 
ge n e. 
T he 
PI G A 
ge n e 
pr o d uct is re q uire d f or t he 
bi os y nt hesis 
of t he 
gl yc o p h os p h ati d yli n osit ol ( G PI) a n c h or, a gl yc oli pi d m oiet y t hat attac hes d o ze ns of p r otei ns t o t he 
plas ma me m bra ne of cells. C o nse q ue ntl y, t he P N H ste m cell a n d all of its pr o ge n y ha v e a re d ucti o n 
or a bse n ce of G PI -a n c h ore d pr otei ns. T he mat ure bl o o d cells deri ve d fr o m t h e he mat o p oietic cl o ne 
ca n ha v e a c o m plete deficie nc y (t y p e III) or a  partial deficie nc y (t y pe II) of G PI -li n ke d pr otei ns 
(Hill me n, 2 0 0 4 ). T w o of t he pr otei ns t hat are affecte d b y t he a bs e nce of G PI a nc h ors are C D 5 5 
a n d C D 5 9, c o m ple me nt re g ulat or y pr ot ei ns. T he C D 5 5 pr otei n re g ul ates c o m ple me nt acti vati o n 
b y i n hi biti n g c o m ple me nt c o m p o ne nt 3 ( C 3) c o n v ertases, w hereas C D 5 9 i n hi bits t he asse m bl y of 
t he me m bra n e-attac k c o m ple x ( M A C) C 5 b -C 9 b y i nteracti n g wit h C 8 a n d C 9  (Br o ds k y, 2 0 0 9 ). 
T heir a bse nce re n d ers P N H er yt hr oc ytes s usce pti ble t o c o m ple me nt -me diate d i ntra vasc ul ar 
he m ol ysis. T his i ntra vasc ular he m ol ysis i n patie nts wit h P N H ca uses a n e mia (fre q u e ntl y re q uiri n g 
bl o o d tra nsf usi o n) a n d he m o gl o bi n uria. C o m plicati o ns of P N H i ncl u de t hr o m b osis, a b d o mi nal 
pai n, 
d ys p ha gi a, 
erectile 
d ysf u ncti o n, 
a n d 
p ul m o nar y 
h y p erte nsi o n 
(Hill me n, 
2 0 0 6 ). 
T hr o m b oe m b olis m is t he m ost c o m m o n ca use of m ortalit y i n patie nts wit h P N H a n d acc o u nts f or 
a p pr o xi matel y 4 0 % t o 6 7 % of attri b uta ble deat hs . P ote ntial mec ha nis ms f or t hr o m b oe m b olis m 
i ncl u de platelet acti vati o n, t o xicit y of free he m o gl o bi n, nitric o xi de de pleti o n, a bse nce of ot her 
G PI -li n ke d 
pr ot ei ns, 
a n d 
e n d ot helial 
d ysf u ncti o n (Hill, 
2 0 1 3 ). 
Par o x ys mal 
n oct ur nal 
he m o gl o bi n uria fre q ue ntl y o cc urs wit h a ut oi m m u ne a plastic a ne mia (L uzzatt o, 2 0 1 8 ). E vi de nce 
s u g gests t hat l oss of PI G A pr o vi des pr otecti o n f or the P N H cl o ne a gai nst H S C l oss b y re m o vi n g 
a p utati ve G PI-a n c h ore d a ut oa nti ge n ser vi n g as a tar get f or a n a ut oi m m u ne res p o nse a gai nst t he 
H S C.  
T he dia g n osis of P N H is esta blis he d usi n g t h e i nt er nati o nall y acce pte d d efi niti o n of prese n ce of 
i ncreas e d P N H gra n ul oc yt e cl o ne siz e meas ure d i n peri p heral bl o o d b y fl o w c yt o metr y. A n 
acce pte d defi niti o n of acti ve disease is t he pres e n ce of 1  or m or e of t h e f oll o wi n g P N H -relate d 
si g ns or s y m pt o ms wit hi n 3 m o nt hs: fati g ue, he m o gl o bi n uria, a b d o mi nal p ai n, s h ort ness of breat h 
( d ys p n ea), a n e mia ( he m o gl o bi n < 1 0 g/ d L), hist or y of a maj or a d v erse vasc ular e ve nt ( M A V E; 
i ncl u di n g t hr o m b osis), d ys p ha gi a, or erectile d ysf u ncti o n. 
Alter nati vel y, acti vit y ca n be 
esta blis he d b y a hist or y of R B C tra nsf usi o n d ue t o P N H wit hi n 3 m o nt h s.  
Ec uliz u ma b ( S oliris ® ) a n d ra v uliz u ma b ( Ult o miris® ), a p pr o ve d f or t he treat me nt of P N H i n ma n y 
c o u ntries w orl d wi de, i ncl u di n g t he U nite d States ( U S) a n d E ur o pea n U ni o n ( E U) me m ber stat es, 
are h u ma nize d m o n ocl o nal a nti b o dies directe d a gai nst t he ter mi nal  c o m ple me nt pr otei n C 5. T he y 
bl oc k t he f or mati o n of t he M A C  C 5 b -C 9, t h us pr otecti n g P N H R B Cs fr o m c o m ple me nt -me diate d 
i ntra vasc ular h e m ol ysis. T heir effecti ve n ess has b ee n de m o nstrat e d b y t h e re d ucti o n of t he lactate 
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de h y dr o ge nas e ( L D H) le vel a n d a re d uce d  n ee d f or R B C tra nsf usi o ns. Ec uliz u ma b has 
de m o nstrate d effecti ve n ess o ver t he l o n g ter m b y a re d uce d nee d f or bl o o d tra nsf usi o n, re d uce d 
i nci de nce of t hr o m b osis, a n d a n i m pr o ve me nt i n a ne mia, q ualit y of life, a n d s ur vi val 
(Griffi n,  2 0 1 7 ). Ec uliz u ma b is a p pr o ve d f or use i n c o m ple me nt -me di ate d seri o us ultra-rare 
c o n diti o ns ( pre val e nce of 1 t o 5 per milli o n), i ncl u di n g P N H, at y pical h e m ol ytic ure mic s y n dr o m e 
(a H U S), n e ur o m yelitis o ptica s pectr u m dis or der ( N M O S D), a n d ge n erali ze d m yast he ni a gra vis 
( g M G). Ra v uliz u ma b is a p pr o ve d i n P N H a n d a H U S. 
W hile  ec uliz u ma b has de m o nstrate d t o be a n effecti ve t hera p y f or t hese p atie nts,  n ot all patie nts 
recei v e o pti mal t hera p e utic be nefit. F or e x a m ple, a p pr o xi matel y 2 5 % of patie nts still nee d 
rec urre nt, al beit less fre q ue nt, bl o o d tra nsf usi o ns a n d half of p atie nts ac hie ve L D H n or malizati o n 
(Lee, 2 0 1 9 ). U p t o 2 7 % of ec uliz u ma b-treate d patie nts ma y e x perie nce brea kt hr o u g h he m ol ysis, 
w hic h is a rec urre nce of t he patie nt’s i ntra vasc ul ar he m ol ysis a n d ass ociate d si g ns a n d s y m pt o ms. 
Ma n y 
patie nts 
e x perie nce 
brea kt hr o u g h 
he m ol ysis 
d ue t o i na de q uate 
C 5 i n hi biti o n 
(Br o ds k y,  2 0 1 7 ). U p t o 2 0 % of patie nts o n ec uli z u ma b t hera p y re q uir e si g nifica nt i ncreas es i n 
d ose or d ose fre q ue n c y d ue t o brea kt hr o u g h he m ol ysis se c o n dar y t o i nc o m plete i n hi biti o n of C 5 
(Hill, 2 0 1 3 )(Na k a ya ma, 2 0 1 6 )(Peffa ult de 
Lat o ur, 2 0 1 5 ). 
A d diti o n all y, ec uliz u ma b is 
a d mi nistere d b y i ntra ve n o us (I V) i nf usi o n e ver y 2 wee ks ( Q 2 W) a n d h as b ee n d escri be d as bei n g 
b ur de ns o me f or patie nts a n d ma y ne gati vel y i m pact q ualit y of life  (Gr ot h, 2 0 1 7 ). 
W hile t he 
re g ulat or y a p pr o val of ra v uliz u ma b has i m pr o ve d c o n ve nie nce wit h a d osi n g fre q ue n c y of e ver y 
8  wee ks, it is n ot a vaila ble i n m ost of t he w orl d a n d patie nts still e x perie nce s o me he m ol ytic 
brea kt hr o u g h. 
M or e o ver, i n rare i nsta nces, ec uliz u ma b, a n d pres u ma bl y ra v uliz u ma b, is 
i neffecti ve d ue t o p ol y m or p hic variati o n i n t he ge ne e nc o di n g C 5 s uc h t hat t he pr otei n is n ot 
rec o g niz e d b y t h e 2 m o n ocl o nal a nti b o dies ( m A bs)  (Nis hi m ura, 2 0 1 4 ) (S heri da n, 2 0 1 8 ). T h e 
heter o ge n eit y i n t hese h e ma t ol o gic al res p o nses ma y be relate d t o u n derl yi n g a plastic a ne mia, 
C 3 b -me diate d e xtra vasc ular he m ol ysis, or i nc o m plete p har mac ol o gi c bl oc ka de of C 5, a n d rare 
p ol y m or p his ms i n t he ge ne c o di n g f or C 5 (Al -A ni, 2 0 1 6 ). T h us, t here re mai ns a n u n met me di cal 
nee d f or p atie nts wit h P N H.  
Re ge n er o n has de vel o p e d a c o m bi nati o n 
m A b/si R N A t hera p y, p ozeli ma b -ce m disira n, t hat 
pr o vi des effi cac y i n pati e nts wit h P N H, i ncl u di n g t h ose wit h p ol y m or p hic varia nt C 5  pr otei n 
w hic h re n ders 
e xisti n g t hera pies i neffecti ve, 
a n d 
offers t he 
a d de d 
c o n ve nie nce 
of 
s u bc uta ne o us/self-a d mi nistrati o n w hic h ma y a d dress t he re mai ni n g u n m et nee d.  
1. 2.  
B ac k gr o u n d o n P ozeli m a b  
P ozeli m a b is a h u ma n m o n ocl o nal i m m u n o gl o b uli n G 4 P  (I g G 4P ) a nti b o d y dir ecte d a gai nst t he 
ter mi nal c o m ple me nt pr otei n C 5, w hic h i n hi bits ter mi nal c o m ple m e nt acti vati o n b y pre ve nti n g 
C 5  clea va ge b y C 5 c o n v ertase i nt o C 5a (a na p h ylat o xi n) a n d C 5 b, t here b y bl oc ki n g t h e f or mati o n 
of t he M A C  C 5 b -C 9, a str uct ure me diati n g cell l ysis. P ozeli ma b is bei n g de vel o pe d f or t he 
treat me nt of P N H a n d ot her diseas es i n w hic h tiss ue da ma ge is me diate d b y ter mi nal c o m ple me nt 
pat h wa y acti vit y. P ozeli ma b ca n be a d mi nistere d b y I V or s u b c uta ne o us ( S C) a d mi nistrati o n. 
A d diti o nall y, p ozeli ma b bi n ds t o p ol y m or p hi c variati o ns i n C 5 t hat are n ot rec o g nize d b y 
ec uliz u ma b or ra v uliz u ma b.  
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P ozeli ma b was well -t olerate d i n a t o xic ol o g y st u d y i n c y n o m ol g us m o n ke ys at d oses u p t o 
1 0 0  m g/ k g/ wee k f oll o w i n g I V a d mi nistrati o n f or 2 6 wee ks, wit h a 1 3-wee k rec o v er y p eri o d. T h e 
n o o bser va bl e a d v erse effect le v el ( N O A E L) bas e d o n t he res ults of t his t o xic ol o g y st u d y was 
deter mi ne d t o be 1 0 0 m g/ k g, t he hi g hest d ose teste d. P ozeli ma b was de m o nstrate d t o ha ve l o w  
p ote ntial f or c yt o ki ne rel ease i n cell -bas e d, i n -vitr o e x peri me nts. C o m ple x es of p ozeli ma b a n d C 5 
di d n ot res ult i n t he f or mati o n of i m m u ne c o m ple x es ca pa ble of bi n di n g t o c o m ple me nt C 1 q.  
P ozeli ma b has bee n e val uate d i n a P hase 1 ra n d o mize d, place b o -c o ntrolle d, d o u ble -bli n d st u d y 
( R 3 9 1 8-H V -1 6 5 9) i n 
5 6 
healt h y 
s u bj ects i n 
7 
d ose 
c o h orts 
( N = 8, 
ra n d o mize d 
6: 2  p ozeli ma b: place b o f or eac h c o h ort). P ozeli ma b was f o u n d t o b e ge n erall y well t olerate d i n 
asce n di n g si n gle d os es of 1, 3, 1 0, 3 0 m g/ k g I V, a n d 3 0 0 m g a n d 6 0 0 m g S C. T he se ve nt h c o h ort, 
a re peat -d ose c o h ort of 4  wee kl y ( Q W) S C d oses of 4 0 0 m g f oll o wi n g a 1 5 m g/ k g I V l oa di n g d ose, 
res ulte d i n 1 res ol ve d seri o us a d v erse e ve nt ( S A E) i n t he st u d y, a n e pis o de of Sal pi n gitis of 
u n deter mi ne d micr o bi al eti ol o g y. D os e -de p e n de nt i n hi biti o n of C 5 was de m o nstrate d f or t he 
si n gle-d os e c o h orts usi n g t he t otal c o m ple me nt he m ol ysis acti vit y ass a y ( C H 5 0), a n e x -vi v o 
meas ure of c o m ple me nt l ytic acti vit y. T he re peat -d ose c o h ort de m o nstrate d c o m plete c o m ple me nt 
i n hi biti o n t hr ou g h o ut t he d osi n g peri o d.  A t hres h ol d ser u m c o nce ntr ati o n of a p pr o xi matel y 
1 0 0  µ g/ m L of p ozeli ma b was deter mi ne d s ufficie nt t o ac hie ve c o m plete i n hi biti o n of C H 5 0. T o 
acc o u nt f or p o p ul ati o n -b ase d v aria bilit y i n C 5 le vels a n d f or tr a nsie nt i ncreases i n c o m p le me nt 
acti vit y sec o n d ar y t o i nterc urre nt ill ness, a desire d mi ni m u m ser u m c o nce ntrati o n of p ozeli ma b 
greater t ha n t he t hr es h ol d was use d t o esta blis h a d osi n g re gi me n f or p ozeli ma b i n patie nts wit h 
P N H:  3 0 m g/ k g I V l oa di n g d ose f oll o we d b y 8 0 0 m g S C Q W.  
P ozeli ma b is c urre ntl y b ei n g e v al uate d i n a n o n g oi n g p hase 2 st u d y i n P N H patie nts wit h acti ve 
si g ns a n d s y m pt o ms w h o are n aï ve t o c o m ple me nt i n hi bit or t hera p y or ha v e n ot rece ntl y recei ve d 
c o m ple me nt i n hi bit or t hera p y i n t he past 6 m o nt hs ( R 3 9 1 8 -P N H -1 8 5 2) . I n t his o pe n-la bel, 
si n gle-ar m tr eat me nt st u d y, p atie nts recei ve d p o zeli ma b as a n I V l oa di n g d os e of 3 0  m g/ k g 
f oll o we d b y 8 0 0 m g S C Q W f or a peri o d of 2 6 wee ks. A n i nteri m a nal ysis was perf or me d wit h a 
t otal of 1 7 patie nts e nr olle d, a m o n g w h o m 1 0 patie nt s c o m plete d 2 6 wee ks ( 1 8 2 d a ys) of 
treat me nt/st u d y a n d 7 patie nts recei ve d at least 1 0 wee ks ( 7 0 d a ys) of p o zeli ma b treat me nt. T h e 
mea n baseli ne L D H w as 6. 1 × u p per li mit of n or mal ( U L N), he m o gl o bi n was 9 7. 0 g/ L a n d 
nearl y  6 0 % of patie nts ha d a n R B C tra nsf usi o n d uri n g t he pre vi o us year. Treat me nt wit h 
p ozeli ma b le d t o a ra pi d a n d s ustai ne d re d ucti o n i n L D H t hr o u g h st u d y wee k 2 6. N or malizati o n 
of L D H le vels w as o bser ve d at da y 2 9 i n all 1 7  patie nts, i ncl u di n g a p atie nt wit h a C 5 varia nt 
k n o w n t o be resista nt  t o bl oc ka de b y ec uliz u ma b/ra v uliz u ma b. Re d ucti o n i n L D H was s ustai ne d 
bel o w 1. 5 × U L N u ntil da y 1 8 3. He m o gl o bi n le vels were als o i ncrease d wit h mea n (sta n dar d 
de viati o n [ S D]) i ncrease of 8. 6  ( 1 4. 1 g/ L) fr o m b aseli ne t o wee k 2 6 ( N = 9, data fr o m 9 patie nts 
w ere a vaila ble a n d use d f or t he cal c ulati o n). F oll o wi n g t he p ozeli ma b treat me nt, a n i m pr o ve me nt 
i n t he F u ncti o nal Ass ess me nt of C hr o nic Ill ness T hera p y -Fati g ue sc ore (F A CI T -Fati g ue,  a 
1 3 -ite m, patie nt-re p ort e d o utc o me meas ure assessi n g a n i n di vi d ual’s le vel of fati g ue o ver t he past 
wee k) was o bser ve d wit h mea n c h a n ge ( S D) of 1 3. 1 ( 1 3. 7) fr o m b aseli n e t o wee k 2 6 ( N = 9). 
C o m ple me nt i n hi biti o n as meas ur e d b y a C H 5 0 was 1 0 0 % a n d s ustai n e d p ost -p ozeli ma b I V 
i nf usi o n o n da y 1 t hr o u g h o ut da y 1 8 3 ( N = 9). T h ere was a t otal of 1 3 treat me nt -e mer ge nt a d verse 
e ve nts ( T E A Es) a n d n o  S A Es; 2  T E A Es were assesse d as se vere a n d 6 were c o nsi dere d treat me nt -
relate d; t he m ost fre q ue nt T E A Es are h ea dac he a n d na usea.  
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It is n ote d t hat t he re gi me n re pres e nts relati vel y hi g h d oses f or a bi ol o gic a ge nt. T he c urre ntl y 
a p pr o ve d a nti -C 5 
m A bs, ec uliz u ma b a n d ra v uliz u ma b, are si milarl y d ose d at hi g h le vels 
( mai nte na nce d ose of 9 0 0 m g I V Q 2 W a n d 3 0 0 0 m g t o 3 5 0 0 m g I V e ver y 8 wee ks [ Q 8 W] f or 
ec uliz u ma b a n d ra v uliz u ma b, res pecti vel y). F or P N H, d os es hi g her t ha n 9 0 0 m g of ec uliz u ma b 
are s o meti mes use d i n practice. T he re q uire me nt f or s uc h hi g h a nti -C 5 m A b d oses is dri ve n b y 
2  fact ors. First, t here is a nee d f or 1 0 0 % i n hi biti o n w hic h ca n o nl y b e ac hie ve d wit h c o m plete 
tar get e n ga ge me nt (Peffa ult de Lat o ur, 2 0 1 5 ) a n d C 5 le vels are hi g h; sec o n d, i n or der t o ac hi e ve 
1 0 0 % i n hi bi ti o n o n a p o p ulati o n basis, i nter- a n d i ntra-patie nt varia bilit y of C 5 c o nce ntrati o ns a n d 
i nsta nces of e n ha nce d c o m ple me nt acti vati o n ( w hic h ma y occ ur wit h i nterc urre nt ill ness) m ust be 
c o nsi dere d.  
A d diti o nal bac k gr o u n d i nf or mati o n o n p ozeli ma b a n d t he de v el o p me nt pr o gra m ca n be f o u n d i n 
t he I n v esti gat or’s Br oc h ure (I B) f or p ozeli ma b. 
1. 3.  
B ac k gr o u n d o n Ce m disir a n  
Ce m disira n is a s y nt hetic si R N A tar geti n g C 5 messe n ger R N A ( m R N A) t hat is c o vale ntl y li n ke d 
t o a tria nte n nar y N-acet yl gal act osa mi ne ( Gal N Ac) li ga n d. C e m disira n is desi g ne d t o s u p press li ver 
pr o d ucti o n of C 5 pr otei n, w he n a d mi nistere d via S C i njecti o n. T he C 5 is e nc o de d b y a si n gle ge n e 
a n d is e x presse d a n d secrete d pre d o mi na ntl y b y he pat oc ytes. T hr o u g h t he R N A i nterfere nce 
pat h wa y, t he ce m disira n si R N A lea ds t o t he d e gra dati o n of C 5 m R N A b y ri b o n ucleases ( R Nases), 
t here b y re d uci n g C 5 pr ot ei n pr o d ucti o n, lea di n g t o re d uce d l e vels of circ ul ati n g C 5 pr otei n.  
Ce m disira n has bee n e v al uate d i n a p h ase 1/ 2 st u d y i n healt h y s u bjects a n d p atie nts wit h P N H w h o 
are n aï ve t o a nti -C 5 treat me nt or o n a b ac k gr o u n d t hera p y of ec uliz u ma b ( A L N -C C 5 -0 0 1). 
Ce m disira n ha d a n acce pta ble safet y pr ofile i n 3 2 healt h y s u bjects f oll o wi n g si n gle i njecti o n at 
d oses u p t o 9 0 0 m g S C or f oll o wi n g re peat e d i njecti o ns at d oses u p t o 4 0 0  m g  Q W or 
6 0 0  m g  Q 2 W. I n t he 6 patie nts wit h P N H i ncl u de d i n t he st u d y, safet y of ce m disira n was 
acce pta ble at 2 0 0 m g a n d 4 0 0 m g Q W, eit her al o ne or o n a bac k gr o u n d of ec uliz u ma b at sta n dar d 
d oses. D ose -de p e n de nt a n d d ura ble re d ucti o n i n C 5 pr otei n a n d c o m pl e me nt acti vit y were 
o bser ve d a n d t he ma xi m u m re d ucti o n i n C 5 was bet wee n 9 0 % t o 9 9 %. H o we ver, t he  ma xi m u m 
re d ucti o n i n C 5 le vels ac hie ve d b y ce m disir a n  m o n ot hera p y di d n ot c o m pletel y i n hi bit 
c o m ple me nt acti vit y a n d was n ot s ufficie nt i n ac hie vi n g a d e q uate L D H re d ucti o n. I m p orta ntl y, 
alt h o u g h ce m disira n m o n ot hera p y was i ns uffici e nt i n ac hie vi n g a de q uate re d ucti o n i n L D H, 
patie nts wit h P N H w h o were tr eate d wit h ce m disira n c o -a d mi nistere d wit h ec uliz u ma b were a ble 
t o re d uce t heir ec uliz u ma b d ose a n d/ or i ncrease t he i nter val bet wee n ec uliz u ma b d oses w hile 
mai ntai ni n g cli nicall y me a ni n gf ul i n hi biti o n of c o m ple me nt acti vit y.  
A d diti o nal bac k gr o u n d i nf or mati o n o n ce m disira n a n d t he de vel o p me nt pr o gra m ca n be f o u n d i n 
t he I B f or ce m disira n. 
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1. 4.  
P ozeli m a b + Ce m disir a n: A  C o m bi n ati o n A p pr o ac h  
T he c o m bi nati o n tr eat me nt of ce m disira n a n d p ozeli ma b is bei n g d e vel o pe d i n patie nts wit h P N H 
d ue t o u n met nee ds i de ntifie d wit h c urre nt a v aila ble treat me nts a n d a p ote ntial f or a d de d 
c o n ve nie nce i n t he d osi n g re gi me n. T his st u d y is d esi g n e d t o e val uate t h e safet y, efficac y, a n d 
p har mac o d y n a mic ( P D) effects of t he p ozeli ma b a n d ce m disira n c o m bi nati o n i n patie nts wit h P N H 
w h o are c urre ntl y o n sta ble ec uliz u ma b t hera p y. P har mac o ki netic ( P K)/ P D m o deli n g of o bser ve d 
data fr o m b ot h p ozeli ma b a n d ce m disira n first -i n-h u ma n st u dies i n healt h y s u bjects a n d patie nts 
wit h P N H ( naï v e t o a nti -C 5 treat me nt or o n a b ac k gr o u n d t hera p y of ec uliz u ma b) s u g gests t hat, 
b y c o m bi ni n g ce m disira n a n d p ozeli ma b, t he d esire d C 5 s u p pressi o n ma y b e d ura ble wit h 
si gnifica ntl y l o w er d os es of b ot h a ge nts a n d a l o n ger d osi n g i nter val. A n assess me nt of t he 
ris k-be nefit of t he p ozeli ma b a n d ce m disira n c o m bi nati o n f or t his st u d y is pr o vi de d i n Secti o n  3. 3 .  
2.  
S T U D Y O B J E C TI V E S   
2. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve of t he st u d y is t o e v al uat e t he safet y a n d t olera bilit y of p ozeli ma b a n d 
ce m disira n c o m bi nati o n t hera p y i n patie nts wit h P N H w h o s witc h fr o m ec uliz u ma b t hera p y. 
2. 2.  
Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ves of t he st u d y are:  
•  T o e val uate t he effect of t he c o m bi nati o n treat me nt o n t he f oll o wi n g para meters of 
i ntra vasc ular h e m ol ysis: L D H c o ntr ol, brea kt hr o u g h he m ol ysis, a n d i n hi biti o n of 
C H 5 0     
•  T o e val u ate t he effect of t he c o m bi nati o n tr eat me nt o n t he st a bilit y of L D H d uri n g t he 
tra nsiti o n peri o d fr o m ec uliz u ma b m o n ot hera p y t o c o m bi nati o n wit h p ozeli ma b a n d 
ce m disira n  
•  T o e val uate t he effect of t he c o m bi nati o n treat me nt o n re d bl o o d cell ( R B C) tra nsf usi o n 
req uire me nts  
•  T o e val uate t he effect of t he c o m bi nati o n treat me nt o n he m o gl o bi n le vels  
•  T o e val uate t he effect of t he c o m bi nati o n treat me nt o n cli nical o utc o me assess me nts 
( C O As) meas uri n g fati g u e a n d healt h relate d q u alit y of life ( H R Q o L) 
•  T o assess t he c o nce ntrati o ns of t otal p ozeli ma b a n d ec uliz u ma b i n ser u m; a n d t otal 
ce m disira n a n d C 5 pr otei n i n plas ma  
•  T o assess t he i m m u n o ge nicit y of p ozeli ma b a n d ce m disira n  
•  T o assess safet y after d ose i nte nsificati o n  
•  T o e val uate t h e l o n g -ter m safet y a n d efficac y of t he c o m bi nati o n treat me nt i n a n 
o pti o nal o pe n -la bel e xte nsi o n peri o d ( O L E P) 
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2. 3.  
E x pl or at or y O bjecti ves  
T he e x pl orat or y o bj ecti v es of t he st u d y are:  
•  T o e x pl ore t he nee d f or i nte nsifie d treat me nt  
•  T o e x pl ore t he effect o n cli nical t hr o m b osis e ve nts  
•  T o e x pl ore t he ef fect o n r e nal f u ncti o n a n d re nal i nj ur y bi o mar kers  
•  T o e x pl ore t he effect o n c o m ple me nt acti vati o n a n d i ntra vasc ular he m ol ysis rele va nt 
t o P N H a n d ot her rel ate d diseases  
•  T o e x pl ore t he effect o n P N H cl o ne size  
•  T o e val uate t he effect o n a C O A meas uri n g tr eat m e nt satisfacti o n ( T S Q M)  
•  T o e x pl ore t he effect o n a n o vel C O A meas uri n g P N H -s pecific s y m pt o ms 
•  T o e x pl ore t he effect o n P N H s y m pt o ms  
•  T o e x pl ore p ote ntial differe nces i n ge n ot y pe a n d ge n e e x pressi o n t hat ma y i nfl ue nce 
effic ac y a n d safet y of t he c o m bi nati o n treat me nt f or f urt her u n d ersta n di n g of C 5, P N H, 
or ot her c o n diti o ns ass o ciate d wit h c o m ple me nt -me diate d i nj ur y (f or patie nts w h o 
c o nse nt t o partici pate i n a ge n o mics s u b -st u d y) 
•  T o e x pl ore p ozeli ma b a n d ce m disira n mec h a nis m of acti o n (rel ate d t o effi cac y a n d/ or 
safet y), c o m ple me nt pat h wa y bi ol o g y, P N H, a n d relate d c o m ple m e nt -me diate d 
diseases  
•  T o e x pl ore effic ac y after d ose i nte nsificati o n wit h p ozeli ma b a n d ce m disira n  
•  T o e x pl ore t he l o n g -ter m effects of t he c o m bi nati o n treat me nt o n cli nical a n d 
P D  assess ments i n a n o pti o nal O L E P  
3.  
H Y P O T H E SI S A N D R A TI O N A L E  
3. 1.  
H y p ot heses  
T he cli nical h y p ot h esis is t hat p ozeli ma b a n d ce m disira n c o m bi nati o n treat me nt has a n acce pta ble 
safet y a n d t olera bilit y pr ofile i n patie nts wit h P N H w h o were pre vi o usl y tr eate d wit h ec uliz u ma b.  
3. 2.  
R ati o n ale  
3. 2. 1.  
R ati o n ale f or St u d y Desi g n a n d E n d p oi nts  
T he c urre nt cli nical st u d y is a si n gle -ar m st u d y of patie nts wit h P N H w h o are c urre ntl y o n 
ec uliz u ma b, a n d w h o will s witc h t o p ozeli ma b a n d ce m disira n c o m bi nati o n t hera p y. As a 
si n gle-ar m, o pe n -la bel st u d y, p atie nts a n d i n vesti gat ors will be a ware of treat me nt all ocati o n. T h e 
st u d y d oes n ot i ncl u de a place b o c o ntr ol, as it is c o nsi dere d u nacce pt a ble w he n t here is a pr o ve n 
i nter ve nti o n (ie, ec uliz u ma b or ra v uliz u ma b) a n d patie nts wit h P N H w h o are n ot o n C 5 in hi biti o n 
face ris ks of seri o us or irre versi ble har m fr o m se q uelae of t he dise ase. T h e pri mar y o bjecti ve of 
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t his st u d y is t o e val uate t he safet y a n d t olera bilit y of p ozeli ma b a n d ce m disira n c o m bi nati o n 
t hera p y after 3 2 wee ks of treat me nt i n patie nts wit h PN H w h o s witc h fr o m ec uliz u ma b t hera p y.  
T he pri mar y e n d p oi nt f or t his st u d y is a n assess me nt of t he i nci de nce a n d se verit y of 
treat me nt-e mer ge nt a d verse e v e nts, i ncl u di n g a d v erse e v e nts of s p ecial i nterest ( A E SIs) a n d S A Es, 
t hr o u g h o ut a 3 2-w ee k tr eat me nt pe ri o d. B ot h p o zeli ma b a n d ce m disira n ha ve bee n e val uate d i n 
healt h y v ol u nteers a n d p atie nts wit h P N H as m o n ot hera p y. A d diti o nall y, ce m disira n has bee n 
st u die d i n c o m bi nati o n wit h ec uliz u ma b. T he safet y of eac h i n di vi d ual c o m p o ne nt has bee n 
dee me d fa v ora ble t o all o w f or c o nti n ue d de vel o p me nt. T his will be t he first st u d y i n w hic h t he 
c o m bi nati o n of p ozeli ma b a n d ce m disira n is a d mi nistere d t o patie nts wit h  P N H w h o are ta ki n g 
ec uliz u ma b a n d will s witc h t o t he c o m bi nati o n t hera p y.   
A d diti o nal safet y meas ures t h at will be e v al uat e d i ncl u de c h a n ges t o vital si g ns, la b orat or y 
para meters, ele ctr ocar di o gra m para meters, a n d brea kt hr o u g h he m ol ysis.  
I n a d diti o n t o e val uati o n of safet y, t he st u d y i ncl u des sec o n dar y efficac y e n d p oi nts t o assess t he 
effect of t he c o m bi nati o n treat me nt o n c o ntr ol of i ntra vasc ular he m ol ysis, as meas ure d b y L D H, 
w hic h is ce ntral t o t he cli nical m o nit ori n g of P N H (R ot her, 2 0 0 5 ), i ncl u di n g d uri n g ec uliz u ma b 
t hera p y. Lactat e de h y dr o ge n ase is a n o bjecti ve la b orat or y-bas e d p ara m eter t hat is u nli kel y t o be 
biase d b y k n o wle d ge of treat me nt assi g n me nt. A n L D H of at least 1. 5  ×  U L N al o n g wit h relate d 
cli nical s y m pt o ms is c o nsi dere d a n i n dicati o n of acti ve P N H, a n d f or treat me nt wit h ec uliz u ma b 
(Sa hi n, 2 0 1 6 )(S oliris ® , 2 0 2 1). F urt h er m ore, re d u cti o ns i n L D H bel o w t h e 1. 5 ×  U L N t hres h ol d 
wit h ec uliz u ma b t hera p y ha ve bee n s h o w n t o c orrelate wit h i m pr o ve me nt i n a patie nt’s s y m pt o ms, 
Q o L me as ures, a n d tra nsf usi o n re q uire me nts (Br o ds k y, 2 0 0 8 ).  
T he use of L D H as a meas ur e of i ntra vas c ular h e m ol ysis all o ws f or a n o bjecti ve a n d precise mea ns 
t o ga u ge w h et her t he c o ntr ol i n i ntra vasc ul ar h e m ol ysis wit h ec uliz u ma b is s ustai ne d w he n patie nts 
s witc h t o p ozeli ma b a n d ce m disira n treat me nt. T h us, t he a bse nce of a cli nicall y si g nif ica nt rise i n 
L D H i n patie nts s witc hi n g fr o m ec uliz u ma b t o p ozeli ma b a n d ce m disira n treat me nt s u p p orts t he 
effic ac y of t he c o m bi nati o n a p pr oac h.  
T he bi ol o gic mec ha nis m t hat dri ves cli nical efficac y of a n a nti -C 5 t hera p y is t he a bilit y t o 
c o m pletel y a n d d ur a bl y s u p press t he cell l ytic acti vit y of ter mi nal p orti o n of t he c o m ple me nt 
pat h wa y, t he M A C. T his bi ol o g y is meas ure d usi n g t h e C H 5 0 assa y a n d ot her ass a ys meas uri n g 
c o m ple me nt pat h w a y acti vit y. T he rel ati o ns hi p of C H 5 0, as a P D meas ure of acti ve C 5  f u ncti o n, 
wit h cli nical effic ac y h as bee n de m o nstr ate d f or p ozeli ma b a n d f or ce m disira n i n patie nts 
wit h  P N H. I n se p arat e st u dies of p ozeli ma b a n d ce m disira n i n acti ve patie nts wit h P N H, cli nical 
effic ac y, as m eas ur e d b y re d ucti o n i n L D H, a mar ker of i ntra vasc u l ar he m ol ysis, c orrelate d wit h 
re d ucti o n i n C H 5 0 or ot her c o m ple me nt acti vit y assa ys. I n t he ce m disira n st u d y, i nc o m plete 
C H 5 0  i n hi biti o n was ass ociate d wit h s u b o pti mal L D H re d u cti o n. I n t h e p ozeli ma b st u d y, c o m plete 
C H 5 0  i n hi biti o n was ass ociate d wit h o pti mal L D H re d ucti o n. T heref ore, C H 5 0 ca n be relia bl y 
use d t o f oll o w t he de gree of i n hi biti o n of t he c o m ple me nt pat h wa y acti vit y a n d is cl osel y c orrelat e d 
wit h t he le vel of L D H w hic h is a mar ker of i ntra v asc ular h e m ol ysis.  
T he st u d y p o p ulati o n i ncl u des patie nts wit h P N H c urre ntl y b ei n g treate d wit h ec uliz u ma b f or at 
least t he pri or 1 2 wee ks wit h a n y l e vel of L D H. Ec uliz u ma b is a d mi nistere d as a n I V i nf usi o n. 
I ntr a ve n o us a d mi nistrati o n places a b ur de n o n t he healt h care s yste m as it re q uires a d mi nistrati on 
i n a n i nf usi o n ce nter or b y a h ealt hcare pr ofessi o nal at t he p atie nt’s h o me. P ozeli ma b a n d 
ce m disira n c o m bi nati o n t hera p y is e x pecte d t o re m o ve t he re q uire m e nt f or res o urce -c o ns u mi n g 
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visits t o i nf usi o n ce nters or h o me n urs e visits, a n d ti me off f or t he p atie nt fr o m t heir w or k/s c h o ol 
a n d ti me a wa y fr o m t heir fa milies. I n a d diti o n, t he i nc o n ve nie nce a n d i nterr u pti o ns ass ociate d wit h 
I V i nf usi o ns 
ma y i m pact 
c o m plia nce, 
w hi c h is 
e x pecte d t o 
be 
a d dresse d 
wit h 
e ver y-4 -wee k  ( Q 4 W) s elf-a d mi nistere d 
p ozeli ma b a n d 
ce m disira n c o m bi nati o n t hera p y. 
Disr u pti o ns d ue t o t he C O VI D -1 9 pa n de mic a n d re q uire me nts fr o m g o ver n me nts o n tra vel 
restricti o ns, sta y-at-h o m e or ders, a n d mai ntai ni n g s o cial dista nci n g ca n i m pact I V -a d mi nistere d 
dr u gs s uc h as ec uliz u ma b, w hereas t his i m pa ct w o ul d be mi ni mize d wit h self -a d mi nistere d 
p ozeli ma b a n d ce m disira n c o m bi nati o n t hera p y. A d diti o nall y, a del a ye d d ose is e x pecte d t o h a ve 
less i m pact c o m pare d t o patie nts treate d wit h ec uliz u ma b base d o n a n a d va nta ge o us P K/ P D pr ofile 
wit h t he c o m bi nati o n . Fi nall y, I V access iss ues ma y be e nc o u ntere d wit h i nf usi o ns, ma ki n g it 
diffic ult t o c o m plete t he a d mi nistrati o n.  
T he st u d y treat me nt d urati o n of 3 2 w ee ks i n t h e o p e n -la bel tr eat me nt p eri o d ( O L T P) is c o nsi dere d 
s ufficie nt t o pr o vi de a n a de q uate u n d ersta ndi n g of t he safet y, efficac y, a n d P D effects of p ozeli ma b 
a n d ce m disira n f or c o nti n ue d de vel o p me nt. It is e x pecte d t hat b y wee ks 2 8 t o 3 2, t here will be n o 
c o ntri b uti o n of ec uliz u ma b t o war ds efficac y as assesse d b y L D H b ase d o n t he k n o w n d osi n g 
i nter val a nd half -life of ec uliz u ma b. B y t he e n d-of -treat me nt peri o d at wee k 3 2, t he effect o n L D H 
will be d ue t o t he s ole c o ntri b uti o n of t he p ozeli ma b a n d ce m disira n c o m bi nati o n wit h o ut a n y 
i m pact fr o m t he l oa di n g d ose of p ozeli ma b.  
T he l o n g -t er m safet y a n d efficac y of t he c o m bi nati o n treat me nt will be assesse d b y pr o vi di n g t he 
patie nts w h o c o m plete t he mai n O L T P o n c o m bi n ati o n treat me nt a n o p p ort u nit y t o partici pate i n 
a n o pti o nal l o n g-ter m O L E P, i n w hic h patie nts s hall c o nti n ue t o recei ve st u d y tr eat me nt f or a n 
ad diti o nal 5 2 wee ks. Patie nts w h o o pt n ot t o p artici pate i n t he o pti o nal O L E P ( or t h ose w h o st o p 
treat me nt f or a n y reas o n) will be f oll o we d f or 5 2 wee ks after t he last d ose of st u d y tr eat me nt, t o 
m o nit or f or safet y as t he st u d y dr u gs are gra d uall y 
eli mi nate d fr o m t he b o d y. A d diti o nal 
c o nsi derati o ns o n p ost -st u d y treat me nt access are descri be d i n Secti o n 8. 9 . 
3. 2. 2.  
R ati o n ale f or D ose Sele cti o n  
T he pr o p os e d d osa ge re gi me n of p ozeli ma b/ce m disira n c o m bi nati o n t h era p y ( Secti o n  6. 1 ) f or 
patie nts wit h P N H, w h o s witc h fr o m ec uliz u ma b tr eat me nt, was select e d bas e d o n s afet y, efficac y, 
a n d P K/ P D data fr o m c o m plete d a n d o n g oi n g st u dies f or eac h i n di vi d ual a ge nt i n healt h y s u bjects 
a n d i n patie nts wit h P N H. T he rati o nal e f or t h e c h ose n re gi me n is 1) t o pr o vi de ra pi d a n d s ustai ne d 
c o m plete C 5 i n hi biti o n after t he i nitiati o n of t he c o m bi nati o n treat me nt a n d t hr o u g h o ut t he d osi n g 
i nter vals, a n d 2) t o miti gat e t he p ote ntial f or t h e f or m ati o n of hi g h m ol ec ular wei g ht ( H M W) 
c o m ple x es of ec uliz u ma b -C 5 -p ozeli ma b d uri n g t h e treat me nt s witc h.  
P ozeli m a b  
I n t he c o m plete d ph ase 1 st u d y i n h ealt h y s u bjects ( R 3 9 1 8 -H V -1 6 5 9), p ozeli ma b was f o u n d t o b e 
ge n erall y w ell t olerate d at si n gle d oses u p t o 3 0 m g/ k g I V a n d 6 0 0 m g S C, or 4 wee kl y S C d oses 
of 4 0 0  m g S C prece de d b y a 1 5 m g/ k g I V l oa di n g d ose. M a xi m u m C 5 i n hi biti o n wit h c o m pl ete 
s u p pressi o n of c o m ple m e nt acti vit y, as meas ure d b y a C H 5 0 ass a y, was o bser ve d at hi g h er d os es 
( ≥3 m g/ k g I V d osi n g). T he P K of t otal p ozeli ma b a p pears n o n-li near at l o wer c o nce ntr ati o ns, 
bec o mi n g li near as c o n ce ntrati o ns i ncreas e. T his is t h o u g ht t o be d ue t o sat ura ble, tar get -me diat e d 
eli mi nati o n. I n t h e o n g oi n g P hase 2 st u d y i n patie nts wit h P N H naï v e t o a nti -C 5 treat me nt 
( R 3 9 1 8-P N H -1 8 5 2), n o safet y si g n al has e mer ge d f oll o wi n g a l oa di n g d ose of 3 0 m g/ k g I V of 
p ozeli ma b ( da y 1) f oll o w e d b y 8 0 0 m g S C Q W  (starti n g o n da y 8). I nteri m a nal ysis s h o we d t hat 
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effic ac y, as me as ure d b y re d uci n g L D H t o bel o w 1. 5 U L N, was ac hi e ve d i n all 6 patie nts at da y  5 7. 
M ore i nf or m ati o n re gar di n g t he res ults of t he P hase 1 a n d 2 st u dies is pr o vi de d i n t he 
P ozeli ma b  I B. 
Ce m dis ir a n 
Ce m disira n has bee n e v al uate d i n a p h ase 1/ 2 st u d y i n healt h y s u bjects a n d p atie nts wit h P N H w h o 
are n aï ve t o a nti -C 5 treat me nt or o n a b ac k gr o u n d t hera p y of ec uliz u ma b ( A L N -C C 5 -0 0 1). 
Ce m disira n ha d a n acce pta ble safet y pr ofile i n healt h y s u bjects f ol l o wi n g si n gle i njecti o n at d oses 
u p t o 9 0 0 m g S C or f oll o wi n g re peat e d i njecti o ns at d oses u p t o 4 0 0 m g Q W or 6 0 0 m g Q 2 W. I n 
t he 6 patie nts wit h P N H i ncl u de d i n t he st u d y, s afet y of ce m disira n was acce pta ble at 2 0 0 m g a n d 
4 0 0 m g Q W, eit her al o ne or o n a b a c k gr o u n d of ec uliz u ma b at sta n dar d d oses. D ose -d e pe n de nt 
a n d d ura ble re d ucti o n i n C 5 pr otei n a n d c o m ple me nt acti vit y were o bs er ve d a n d t he ma xi m u m 
re d ucti o n i n C 5 w as bet w ee n 9 0 % t o 9 9 %. H o we v er, t he ma xi m u m re d ucti o n i n C 5 le vels ac hie ve d 
b y c e m disira n  m o n ot hera p y di d n ot c o m pletel y i n hi bit c o m ple me nt acti vit y a n d was n ot s ufficie nt 
i n ac hie vi n g a d e q uate L D H re d ucti o n. M ore i nf or mati o n re gar di n g t he res ults of t he p hase 1/ 2 
st u d y is pr o vi de d i n t he Ce m disira n I B. 
P ozeli m a b/ Ce m disir a n C o m bi n ati o n  
T o i nf or m t he c h oice of t he d osi n g re gi me n f or t he c o m bi nati o n t hera p y i n patie nts wit h P N H, a 
tar get-me diate d dr u g dis p ositi o n ( T M D D) p o p ulati o n P K m o del f or p ozeli ma b a n d a p o p ulati o n 
P K/ P D m o del f or ce m disira n were de vel o p e d base d o n res pecti ve data o n healt h y s u bjects. T he 
m o dels f or p ozeli ma b a n d ce m disira n were c o m bi ne d b y i ntr o d uci n g C 5 pr o d ucti o n s u p pressi o n 
effect of ce m disira n t o t he s y nt hesis rat e of C 5 i n t he T M D D m o del f or p ozeli ma b. T he u nifie d 
m o del was use d t o perf or m si m ulati o ns t o i nf or m d ose select i o ns of p ozeli ma b i n c o m bi nati o n 
wit h ce m disira n.  
Miti g ati o n of p ote nti al l ar ge dr u g -t ar get-dr u g i m m u ne c o m ple x f or m ati o ns d uri n g 
tre at me nt s witc h  
W hile t he o verall g oal of t he pr o p ose d d osi n g re gi me n is t o pre ve nt h e m ol ysis, t he tra nsiti o n peri o d 
of t he  c o m bi nati o n treat me nt i nitiati o n is als o desi g ne d t o miti gate t he p ot e ntial f or t he f or mati o n 
of lar ge dr u g -tar get-dr u g ( D T D) i m m u ne c o m ple x es of ec uliz u ma b -C 5 -p ozeli ma b d uri n g t he 
treat me nt s witc h. As e x plai ne d bel o w, a lea d-i n ce m disira n d ose pl us a l o adi n g d os e of p ozeli ma b 
is pr o p ose d i n or der t o mi ni mize lar ge D T D i m m u ne c o m ple x f or mati o n. 
A pre vi o us cli nical st u d y re p orte d a d verse reacti o ns (e g, ser u m si c k ness -li ke reacti o ns, s ki n ras h), 
u p o n s witc hi n g fr o m ec uliz u ma b t o a n ot her a nti -C 5 m A b, cr o vali m a b, attri b ute d t o t he f or mati o n 
of i m m u ne c o m ple x es bet wee n C 5 a n d t he 2 n o n -c o m peti n g C 5 m A bs (R öt h, 2 0 1 8 ). Si milarl y, 
p ozeli ma b has bee n s h o w n t o bi n d C 5 n o n -c o m petiti vel y wit h ec uliz u ma b ( R 3 9 1 8 -P H -1 9 0 7 4), 
a n d t h us has t he p ote ntial t o f or m hi g her -or der i m m u ne c o m ple x es i n t he prese nce of ec uliz u ma b 
a n d C 5.  
I n vitr o st u dies w ere c o n d ucte d t o si m ulate c o n ditio ns t hat ma y occ ur w he n p ozeli ma b is 
a d mi nistere d t o a patie nt pre vi o usl y d os e d wit h ec uliz u ma b. T he s p o ns or ge n erat e d a n ‘i n -h o use 
ec uliz u ma b’ t o c o n d uct i n vitr o st u dies, w hic h has t he sa me a mi n o aci d se q ue nce a n d bi n ds t o t he 
sa me e pit o pe o n C 5 as ec uliz u ma b. Neit her p oz eli ma b n or ‘i n -h o us e ec uliz u ma b’ i n di vi d uall y 
f or me d hi g h er or der m ulti mers lar ger t ha n a 1: 2 m A b: C 5 c o m ple x. P ozeli ma b was a d de d t o 
pre -f or me d i n-h o us e ec uliz u ma b: C 5 c o m ple xes u n der c o n diti o ns of e x cess p ozeli ma b 
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( 5: 1: 1 p ozeli ma b: i n -h o u se ec uliz u ma b: C 5) a n d e q ui m olar a m o u nts of t otal 
m A b t o C 5 
( 1: 1: 2 p ozeli ma b: i n -h o use ec uliz u ma b: C 5). T he latter c o n diti o ns were e x pecte d t o pr o m ote 
f or mati o n of lar ge D T D i m m u ne c o m ple x es. U n der c o n diti o ns of p ozeli ma b e x cess, t he maj orit y 
of c o m ple x es o b ser ve d ( ~ 8 6 %) were eit her tri meric or pe nta meric ( 2: 1 or 3: 2 m A b: C 5  m olar 
rati os, res p ecti vel y), wit h t he re mai n der c o m prisi n g lar ge D T D i m m u n e c o m ple x es. At a n 
e q ui m olar rati o of t otal 
m A b a n d C 5, t he 
maj orit y of t he s a m ples ( ~ 8 6 %) c o nsiste d of 
heter o ge n e o us lar ge D T D i m m u ne c o m ple x es lar ger t ha n pe nta mers. I n s u m mar y, w hile ‘i n -h o use 
ec uliz u ma b’ a n d p ozeli ma b i n c o m bi nati o n were a ble t o f or m heter o meric c o m ple x es wit h C 5, t he 
prese nce of e x cess p ozeli ma b re d uce d t he f or mati o n of hi g her -or der i m m u ne c o m ple x es relati ve 
t o c o n diti o ns w here t otal m A b a n d C 5 were prese nt at e q ui m olar c o nce ntrati o ns. 
I n t he c urre nt st u d y, a 4-wee k lea d -i n peri o d wit h a d ose of ce m disira n 2 0 0 m g S C is pr o vi de d. 
 re d u ce C 5 pr o d ucti o n a n d c o nse q ue ntl y l o wer t he tot al C 5 (ec uliz u ma b -C 5 
c o m ple x es pl us free C 5) le vel (a b o ut 8 6 % re d ucti o n of t otal C 5 o n da y 2 9 c o m pare d t o da y 1), 
bef ore t he i nitiati o n of t he p ozeli ma b/ce m disira n c o m bi nati o n treat me nt. C o nse q ue ntl y, t he 
p ote ntial f or t he f or mati o n of t he lar ge D T D i m m u ne c o m ple x es s h o ul d be si g nifica ntl y re d u ce d. 
T o f urt her mi ni miz e t he ris k of f or mati o n of lar ge D T D i m m u ne c o m ple xes u p o n i nitiati n g 
p ozeli ma b/ce m disira n c o m bi nati o n treat me nt, a l oa di n g d ose of p ozeli ma b 6 0 m g/ k g I V is 
pr o vi de d. 
Base d o n re p orte d 
me a n tr o u g h c o nce ntr ati o ns of ec uli z u ma b of 9 7 
m g/ L 
(S oliris ® , 2 0 2 1 ) a n d pre dicte d p ozeli ma b c o nce ntrati o n o ver ti me, t he m olar c o nce ntrati o ns of 
p ozeli ma b are e x pecte d t o be i n e x cess of ec uliz u ma b f oll o wi n g t he I V l oa di n g d ose wit h a n 
esti mate d rati o of a p pr o xi matel y 1 7: 1. I n dee d, cr o vali ma b was n ote d t o ha ve tra nsie nt re d u cti o ns 
of c o nce ntr ati o ns i n ser u m d uri n g t he s witc h peri o d i n patie nts recei vi n g ec uliz u ma b, a n d t his iss ue 
was a d dress e d wit h a n o pti mize d d osi n g re gi me n (a l oa di n g d ose seri es bef ore t he mai nte na nce 
d oses). A le a d -i n ce m disira n d ose pl us a l oa di n g d ose of p ozeli ma b is c o nsi dere d t he best s ol uti o n 
t o a d dress t his c o ncer n. 
Pr o vi de r a pi d a n d s ust ai ne d m a xi m u m C 5 i n hi biti o n after t he i niti ati o n of t he c o m bi n ati o n 
tre at me nt a n d t hr o u g h o ut t he d osi n g i nter v als  
I n a d diti o n t o bei n g part of t he a p pr oac h t o miti gate t he p ote ntial f or t he f or mati o n of lar ge 
D T D  i m m u ne c o m ple x es, t he I V l oa di n g d ose of p ozeli ma b 6 0 m g/ k g is pr o p ose d t o e ns ure ra pi d 
a n d c o m plete i n hi biti o n o f C 5 t o a v oi d a n y brea kt hr o u g h he m ol ysis t hat c o ul d occ ur d uri n g t he 
treat me nt tra nsiti o n. Base d o n si m ulati o ns, t he d osa ge re gi me n of t he I V l oa di n g d ose f oll o we d b y 
t he S C mai nte na nce d os e of p ozeli ma b/ce m disira n 4 0 0 m g/ 2 0 0 m g Q 4 W starti n g o n da y 2 9 is 
ex pecte d t o res ult i n ra pi d a n d s ustai ne d s u p pressi o n of C 5 t o bi ol o gicall y i nacti ve le vels.  
 
 
 T he 
C H 5 0  assa y will be use d t o c o nfir m c o m plete i n hi biti o n of c o m ple me nt acti vit y h as bee n ac hi e ve d 
t hr o u g h o ut t he d osi n g i nter val i n patie nts wit h P N H.  
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Tre at me nt I nt e nsific ati o n  
A m o difie d re gi me n c o nsisti n g of a n i nte nsifie d re gi me n of p ozeli ma b is i n cl u de d t o pr o vi de e xtra 
C 5  s u p pressi o n t hat s o me patie nts ma y nee d t o ac hi e ve a de q u ate c o ntr ol of i ntra vasc ular he m ol ysis 
a n d is i nte n de d t o b e use d as a n i nte nsifie d re gi me n i n t he pla n ne d p hase 3 st u dies. See 
Secti o n  6. 1. 3 . 
3. 3.  
Ris k -Be nefit  
A ris k -be n efit state me nt wit h res pect t o t he o verall de vel o p me nt pr o gra m is pr o vi de d i n t he I B f or 
p ozeli ma b a n d t he I B f or ce m disira n. T h e c o m bi n ati o n treat me nt of ce m disira n a n d p ozeli ma b is 
bei n g de v el o pe d i n patie nts wit h P N H f or t he f oll o wi n g reas o ns: ( 1) b ot h dr u gs w or k via a 
c o m ple me ntar y a p pr oac h o n a vali date d pat h wa y wit h t he p ossi bilit y of c o m plete i n hi biti o n of t he 
pat h wa y, w hic h ma y tra nslate i nt o o pti mal efficac y i n nearl y all patie nts a n d a ntici pate d better 
c o ntr ol of brea kt hr o u g h he m ol ysis; ( 2) ce m disira n is i ns ufficie nt t o treat P N H as m o n ot hera p y; 
( 3) p ozeli ma b was effecti ve as m o n ot hera p y i n treat me nt of P N H i n a p hase 2 st u d y, b ut t he 
re gi me n was c o nsi dere d p otentiall y b ur de ns o me; ( 4) p ozeli ma b a n d ce m disira n c o m bi nati o n 
t hera p y will a d dress si g nifica nt u n met nee ds f or patie nts a n d pr o vi de f or re d uce d tr eat me nt b ur de n 
wit h self -a d mi nistrati o n Q 4 W w hic h s h o ul d tra nslate i nt o be n efit f or patie nts w h o ha v e t o ta ke 
thera p y f or l o n g -ter m d urati o n; ( 5) p ozeli ma b a n d ce m disira n c o m bi nati o n t hera p y is n ot e x pecte d 
t o be ass ociate d wit h a n y i n crease d ris k be y o n d t hat of t he i n di vi d ual a ge nts, w here b y t h e 
i n di vi d ual a ge nts ha ve si milar ris k pr ofiles a n d m a y be ass ociate d wit h a d ecrease i n t h e n u m ber 
of i njecti o n site reacti o ns d ue t o re d uce d fre q u e nc y of a d mi nistrati o n; a n d ( 6) efficac y is  
 
i n patie nts wit h C 5 varia nt pr otei n, w hic h re n d ers ec uliz u ma b or ra v uliz u ma b i neffecti ve. 
T he f oll o wi n g s ecti o ns d escri be p ote n tial ris ks a n d strate gies f or miti gati o n. 
3. 3. 1.  
I nf usi o n Re acti o ns 
T he l oa di n g d ose of 6 0 m g/ k g I V is e x pecte d t o be well t olerate d. T here were n o i nf usi o n reacti o ns, 
a n d p ozeli ma b was well t olerate d i n healt h y s u bjects w h o recei ve d I V d oses of u p t o 3 0 m g/ k g a n d 
i n patie nts wit h P N H naï ve t o c o m ple me nt i n hi bit or t hera p y, w h o recei ve d a n I V l oa di n g d ose of 
3 0 m g/ k g. I n t he 1 3 - a n d 2 6 -wee k t o xic ol o g y st u di es d ose d u p t o 1 0 0  m g/ k g/ wee k i n c y n o m ol g us 
m o n ke ys, n o a d vers e effects were re p ort e d ( See P o zeli ma b  I B). 
3. 3. 2.  
P ote nti al Ris k of Neisseri a I nfecti o n  
A n esta blis he d ris k of bl oc ki n g C 5 c o m ple me nt acti vit y is i ncreas e d s usce pti bilit y t o i nf ecti o ns, 
s pecificall y t o e n ca ps ulate d or ga nis ms, t he m ost p ote ntiall y se v ere of w hic h is i nfecti o n wit h 
Neisseri a  me ni n giti dis  (Fi g uer oa, 1 9 9 1 ). T he ris k f or me ni n g oc o ccal i nfecti o n is lar gel y dri ve n b y 
t he de gree of i n hi biti o n of C 5. T w o differe nt a ge nts acti n g o n C 5 t hr o u g h i n de pe n de nt pat h w a ys 
are n ot e x pecte d t o i ncrease t h e ris k f or me ni n g oc o ccal i nfecti o n a b o v e t hat of eac h of t he 
i n di vi d ual a ge nts. T his e x pectati o n is base d o n t he g oal of c o m ple me nt i n hi biti o n t hera p y a n d 
h u ma n ge n etic data. T he o bjecti ve of p ozeli ma b a n d ce m disira n c o m bi nati o n t hera p y is c o m plete 
i n hi biti o n of C 5 acti vit y. O nce t his is ac hie ve d, t he n f urt her i n hi biti o n is n ot p ossi ble a n d t he 
a ntici pate d ris k is n ot e x pecte d t o i ncreas e f ur t her. H u ma n ge n etic data re veal t hat t he i ncrease d 
ris k of i nfecti o ns wit h Neisseri a  s p p. occ urs w he n t here is h o m oz y g o us l oss of c o m ple me nt fact or 
5 ( C 5). I m p ort a ntl y, i n di vi d uals w h o are C 5 heter oz y g o us l oss of f u ncti o n d o n ot ha ve i ncreas e d 
ris k of i nfecti o ns wit h Neisseri a  s p p. (Plat o n o v, 1 9 9 7 ).  
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E x perie nce wit h ec uliz u ma b s u g gests t hat pretr eat me nt wit h a p pr o pri ate vacci nati o ns c o v eri n g 
m ulti ple ser ot y pes a n d c o n c urre nt t hera p y wit h oral a nti bi otics is effecti ve at s u bsta ntiall y 
miti gati n g t his ris k (Hill me n, 2 0 1 3 )(Mc Na mara, 2 0 1 7 )(N H S E n gla n d, 2 0 1 3 )(S oliris ® , 2 0 2 1). 
C urre nt treat me nt g ui d eli nes f or P N H a n d t he ec uliz u ma b pac ka ge i nsert rec o m me n d s uc h 
vacci nati o ns pri or t o d osi n g. Beca use v acci nati o n d oes n ot pr o vi de 1 0 0 % c o vera ge t o all str ai ns 
a n d t here are n o pr o ve n titer le vels ass ociate d wit h 1 0 0 % pr otecti o n, pr o p h ylactic oral a nti bi otics 
are als o c o m m o nl y gi ve n t o patie nts wit h ge n etic or p har mac o l o gic deficie nc y i n ter mi nal 
c o m ple me nt acti vit y. I n vari o us disease setti n gs s uc h as as ple nia i n sic kle cell disease, a n d wit h 
ter mi nal c o m ple me nt d eficie nc y, use of l o n g-t er m pr o p h ylactic a nti bi otics has bee n safel y 
i m ple me nte d f or t he 
pre ve nti o n 
of e ncaps ulate d 
or ga nis ms, i ncl u di n g 
N.  me ni n giti dis 
(Gast o n,  1 9 8 6 )(We dzic h a, 2 0 0 8 ).  
I n t his st u d y, vacci nati o n pri or t o st u d y treat me nt i nitiati o n ( or at t he ti me of a d mi nistrati o n, base d 
o n l ocal practice, see Secti o n  8. 2. 1 ) will be re q uire d t o miti gate t he ris k of i nfecti o n b y 
e nca ps ulate d or ga nis ms t o a le vel t hat has bee n c o nsi dere d acce pt a ble i n ot her a nti -C 5 cli nical 
de vel o p me nt pr o gra ms. I n a d diti o n t o vacci nati o n, m o nit ori n g f or earl y si g ns a n d s y m pt o ms of 
i nfecti o n ( Secti o n 8. 2. 2 ), pr o vi di n g a patie nt safet y car d t hat descri bes t he si g ns a n d s y m pt o ms of 
i nfecti o n a n d ste ps t o f oll o w i n case of s us p ecte d i nfecti o n, as well as c o nc urre nt t hera p y wit h 
rec o m me n de d oral a nti bi otics ( Secti o n 8. 2. 3 ), will furt her miti gate t his ris k. T hese ris k miti gati o n 
strate gies ha v e bee n acce pta ble a n d well t olerate d i n t he prece de nt h ealt h y v ol u nteer a n d 
P N H  patie nt st u dies f or p ozeli ma b a n d ce m disira n i n di vi d uall y, as well as i n ot her a nti -C 5 cli nical 
de vel o p me nt pr o gr a ms.   
Rece ntl y, seri o us i nfecti o ns wit h Neisseri a  s p ecies ( ot her t ha n N. me ni n giti dis ), i ncl u di n g 
disse mi nate d 
g o n oc o ccal i nfecti o ns, 
ha ve 
bee n re p ort e d 
d uri n g ec uliz u ma b treat me nt 
(S oliris ® , 2 0 2 1 ). T heref ore, patie nts will u n der g o a ris k ass ess me nt a n d c o u nseli n g re gar di n g t he 
p ote ntial ris k of Neisseri a g o n orr he a  as per t h e i n vesti gat or’s l ocal g ui deli nes. Patie nts will be 
c o u nsele d a b o ut N. g o n orr he a  pre v e nti o n, a n d re g ular testi n g will be a d vise d f or at -ris k patie nts. 
A r is k-fact or assess me nt will be base d o n l ocal practice or nati o nal g ui deli nes t o deter mi ne if t he 
patie nt is at ris k, w hic h w o ul d lea d t o f urt her ma na ge m e nt of pre v e nti o n, testi n g, a n d treat me nt of 
N.  g o n orr he a  ( Secti o n 8. 2. 4 ). 
3. 3. 3.  
Li ver F u ncti o n Test A b n or m alities  
Li ver f u ncti o n test a b n or malities are n ot e d as a p ote ntial ris k d ue t o t h e tar get e d deli ver y of 
ce m disira n t o he p at oc yt es a n d  were caref ull y f oll o we d i n t he ce m disira n pr o gra m. N o si g nal h as 
e mer ge d fr o m t he p hase 1 a n d 2 cli nical st u dies t o date. I n t he h ealt h y v ol u nteer st u d y wit h 
ce m disira n, a b o ut 3 0  t o 4 0 % of h ealt h y s u bjects ha d as y m pt o matic, tra nsi e nt, mil d ele vati o ns i n 
ala ni ne a mi n otra nsferase ( A L T) a n d as p artate a mi n otra nsferase ( A S T) t hat were < 3  ×  U L N i n t h e 
ce m disira n d osi n g ar ms. I n patie nts wit h P N H ( n = 6), 1 patie nt ha d a relate d A E of i ncrease d 
tra nsa mi nases wit h A L T a n d A S T ≥ 3 × U L N. T he patie nt ha d s e veral u n derl yi n g c o ntri b uti n g 
fact ors, a n d t he A E res ol ve d wit hi n 1 2 0 da ys of o nset i n t he setti n g of o n g oi n g ce m disira n 
p har mac ol o g y. T he patie nt was rec halle n ge d i n a c o m passi o nate use setti n g, a n d n o i ncrease A L T 
or A S T ≥3 X U L N has b ee n re p orte d.  A d diti o nal de tails ma y b e f o u n d i n t he Ce m disira n I B . 
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I n t his st u d y, patie nts will be cl osel y m o nit ore d f or A L T a n d A S T a b n or malities. T h ose wit h 
si g nifica nt A L T or A S T a b n or malities or k n o w n li ver f u ncti o n i m pair m e nt will be e x cl u de d fr o m 
partici pati n g i n t he st u d y. L e vels of A L T a n d A S T will be cl osel y f oll o we d t hr o u g h o ut t he trial. 
I n di vi d ual p atie nt st o p pi n g r ules will i ncl u d e a ma n dat or y disc o nti n uati o n of st u d y tr eat me nt if 
s pecific t hr es h ol ds f or A L T or A S T are m et as p er pr ot oc ol. T hes e miti gati o n ste ps are c o ns i dere d 
s ufficie nt t o a d dress t his p ote ntial ris k. 
3. 3. 4.  
St u d y C o n d uct i n Res p o nse t o C or o n a vir us Dise ase 2 0 1 9  
Rec o g nizi n g t h at t he “ C or o na vir us Diseas e 2 0 1 9” ( C O VI D -1 9) pa n de mic will ha ve a n i m pact o n 
t he c o n d uct of cli nical trials, t he s p o ns or d oes n ot i nte n d to scree n a n y p atie nts i n t his st u d y u ntil 
t he i m pact of t he C O VI D-1 9 pa n d e mic is d ee me d ma na gea ble a n d n o l o n ger i nterferi n g wit h t he 
c o n d uct of trials at i n di vi d ual sites, a n d patie nts ca n safel y partici p ate i n t his st u d y. U ntil t he n, t h e 
s p o ns or pla ns t o o btai n a p pr o vals fr o m Healt h A ut h orities/ Et hics C o m mittees t o e na ble i nitiati o n 
of st u d y sites f or t his st u d y, as all o we d b y l ocal la ws a n d re g ulati o ns.  
3. 3. 5.  
Ot her Ris ks  
Ot her ris ks are descri be d u n der S afety C o nsi der ati o ns  i n Secti o n 6. 1. 1. 2 .   
4.  
E N D P OI N T S   
4. 1.  
Pri m ar y a n d Sec o n d ar y E n d p oi nts  
4. 1. 1.  
Pri m ar y E n d p oi nt  
T he pri mar y st u d y e n d p oi nt is t he i nci de nce a n d se verit y of T E A Es t hr o u g h da y 2 2 5 of t he O L T P. 
4. 1. 2.  
Sec o n d ar y E n d p oi nts  
T he sec o n d ar y e n d p oi nts f or t he O L T P are:  
•  T he perce nt c ha n ge i n L D H fr o m pre -treat me nt (as defi ne d b y t he m ea n of t he 
L D H  val ues at t he scree ni n g visit [ o btai ne d n o m ore t ha n o ne da y b ef ore a d mi nistrati o n 
wit h ec uliz u ma b] a n d baseli ne ( da y 1 visi t, pri or t o a d mi nistrati o n of ce m disira n a n d 
ec uliz u ma b) t o e n d -of -tr eat me nt peri o d (as defi ne d b y t h e mea n of t he L D H val ues at 
da ys  1 9 7 a n d 2 2 5 i n t he O L T P)  
•  T he perce nt c h a n ge i n L D H fr o m pre -treat me nt t o da y 2 9 
•  T he pr o p orti o n of patie nts w h o are tra nsf u si o n-free ( defi ne d as n ot re q uiri n g a n 
R B C  tra nsf usi o n as per pr ot oc ol al g orit h m, ie, tra nsf usi o n a v oi da nce) fr o m baseli ne 
t hr o u g h d a y 2 2 5, a n d fr o m da y 2 9 t hr o u g h d a y 2 2 5, i ncl usi ve 
•  T he rate a n d n u m ber of u nits of R B Cs tra nsf use d fr o m baseli ne t hr o u g h d a y  2 2 5, a n d 
fr o m da y 2 9 t hr o u g h da y 2 2 5, i ncl usi ve. 
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•  T he pr o p orti o n of patie nts wit h brea kt hr o u g h he m ol ysis fr o m baseli ne t hr o u g h 
da y  2 2 5, a n d fr o m d a y 2 9 t hr o u g h d a y 2 2 5, i ncl usi ve  
•  T he pr o p orti o n of patie nts w h o mai ntai n a de q u ate c o ntr ol of he m ol ysis, defi n e d as 
L D H  ≤1. 5  x U L N fr o m p ost -baseli ne ( o n da y  1) t hr o u g h da y 2 2 5, a n d fr o m da y 5 7 
t hr o u g h d a y 2 2 5, i ncl usi ve 
•  T he pr o p orti o n of patie nts wit h a de q uate c o ntr ol of he m ol ysis at eac h visit fr o m p ost -
baseli ne ( o n da y  1) t hr o u g h da y 2 2 5, i n cl usi ve  
•  T he pr o p orti o n of patie nts wit h n or malizati o n of t heir L D H at eac h visit, defi ne d as 
L D H  ≤1. 0  x  U L N, fr o m p ost -baseli ne ( o n da y  1) t hr o u g h d a y 2 2 5, i ncl usi ve  
•  T he area u n der t he c ur ve ( A U C) of L D H o ver ti me bet wee n  bas eli ne t hr o u g h da y  2 2 5, 
a n d fr o m da y 5 7 t hr o u g h da y 2 2 5, i n cl usi ve  
•  T he pr o p orti o n of patie nts wit h he m o gl o bi n sta bilizati o n ( defi ne d as patie nts w h o d o 
n ot recei ve a n R B C tra nsf usi o n a n d ha ve n o decrease i n he m o gl o bi n le vel of ≥2  g/ d L) 
fr o m baseli ne t hr o u g h d a y 2 2 5, a n d fr o m da y 2 9 t hr o u g h d a y 2 2 5, i ncl usi ve  
•  T he c ha n ge i n he m o gl o bi n le vels fr o m baseli ne t o da y 2 2 5, i n cl usi ve  
•  C ha n ge i n fati g u e as me as ure d b y t h e F A CI T -Fati g ue Scale fr o m baseli ne t o da y  2 2 5, 
i ncl usi ve 
•  C ha n ge fr o m baseli ne t o da y 2 2 5 i n gl o b al healt h stat us/ Q o L scal e ( G H S) a n d p h ysical 
f u ncti o n ( P F) sc ores o n t he E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of 
Ca ncer: Q u alit y -of -Life Q uesti o n naire c ore -3 0 ite ms ( E O R T C  Q L Q -C 3 0)   
•  C ha n ge i n t otal C H 5 0 fr o m baseli ne t o da y 2 2 5, i ncl usi ve   
•  C o nce ntrati o ns of t otal p ozeli ma b a n d ec uliz u ma b i n ser u m, a n d t otal ce m disira n i n 
plas ma assesse d t hr o u g h o ut t he st u d y  
•  C ha n ge fr o m bas eli ne i n c o nce ntr ati o n of t otal C 5 assesse d t hr o u g h o ut t he st u d y  
•  Assess me nt of i m m u n o ge nicit y t o p ozeli ma b a n d ce m disira n as deter mi ne d b y t he 
i nci de nce, titer, a n d cli nical i m pact of tr eat me nt-e mer ge nt a nti -dr u g a nti b o d y ( A D A) 
res p o nses o ver ti me 
•  I n ci de nce a n d se verit y of T E A Es f or patie nts w h o recei v e d ose i nte nsificati o n t hr o u g h 
da y 2 2 5r  
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4. 1. 2. 1.  
Sec o n d ar y E n d p oi nts f or t he O pti o n al O pe n -L a bel E xte nsi o n Peri o d  
T he sec o n d ar y e n d p oi nts f or t he o pti o nal O L E P are:  
•  I n ci de nce a n d se v erit y of T E A Es d uri n g t he 5 2-wee k O L E P i n patie nts treate d wit h 
p ozeli ma b a n d ce m disira n c o m bi nati o n t hera p y  
•  C ha n ge a n d p erce nt c h a n ge of L D H fr o m da y  1 e ( baseli ne of t he O L E P) t o wee k  2 4 e 
a n d wee k 5 2 e  
•  T he pr o p orti o n of p atie nts w h o are tra nsf usi o n -free ( defi ne d as n ot re q uiri n g a n R B C 
tra nsf usi o n as p er pr ot oc ol al g orit h m) fr o m d a y 1e t hr o u g h wee k  2 4e a n d wee k  5 2e (ie, 
tra nsf usi o n a v oi da nce) 
•  T he rate a n d n u m ber of u nits of R B Cs tra nsf use d fr o m d a y 1e t hr o u g h wee k  2 4e a n d 
wee k  5 2e.  
•  T he pr o p orti o n of patie nts wit h brea kt hr o u g h h e m ol ysis fr o m d a y  1e t hr o u g h wee k  2 4 e 
a n d wee k  5 2 e  
•  T he pr o p orti o n of p atie nts w h o mai ntai n a de q u ate c o ntr ol of t heir h e m ol ysis, defi ne d 
as L D H ≤1. 5  x  U L N b et wee n da y  1 e t hr o u g h wee k  2 4e a n d wee k  5 2e, i ncl usi ve  
•  T he pr o p orti o n of patie nts wit h a de q uat e c o ntr ol of he m ol ysis at eac h visit fr o m da y 1e 
t hr o u g h w ee k 2 4 e a n d w ee k  5 2e, i ncl usi ve  
•  T he 
pr o p orti o n 
of 
p atie nts 
wit h 
n or malizati o n 
of t heir 
L D H, 
d efi ne d as 
L D H  ≤1. 0  x  U L N  at eac h visit fr o m da y 1 e t hr o u g h wee k  2 4 e a n d wee k  5 2e, i ncl usi ve  
•  T he A U C of L D H o v er ti me bet wee n d a y  1e t hr o u g h wee k  2 4e a n d wee k  5 2 e, i ncl usi ve  
•  T he pr o p orti o n of patie nts wit h he m o gl o bi n sta bilizati o n ( defi ne d as patie nts w h o d o 
n ot recei ve a n R B C tra ns f usi o n a n d ha ve n o decrease i n he m o gl o bi n le vel of ≥2 g/ d L) 
fr o m da y 1e t hr o u g h wee k  2 4e a n d wee k  5 2e  
•  T he c ha n ge i n he m o gl o bi n le vels fr o m da y 1e t o w ee k  2 4e a n d wee k  5 2e of t he O L E P  
•  C ha n ge i n fati g u e as me as ure d b y t he F A CI T -Fati g ue Scal e fr o m da y 1e t o wee k  5 2e 
of t he O L E P  
•  C ha n ge fr o m da y 1e t o wee k  5 2e of t he O L E P  i n G H S/ Q o L scal e P F sc ores o n t he 
E O R T C Q L Q -C 3 0   
•  C ha n ge i n C H 5 0 fr o m da y  1e t o w ee k  1 6 e, wee k  2 4e, a n d wee k  5 2e of t he O L E P   
•  C o nce ntrati o ns of t otal p ozeli ma b i n ser u m, a n d t otal C 5 a n d ce m disira n i n plas ma, 
assesse d o ver ti me d uri n g t he O L E P  
•  Assess me nt of i m m u n o ge nicit y t o p ozeli ma b a n d ce m disira n as deter mi ne d b y t he 
i nci de nce, titer, a n d cli ni cal i m pact of treat me nt-e mer ge nt A D A res p o nses o ver ti me 
d uri n g t he O L E P  
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4. 1. 3.  
E x pl or at or y E n d p oi nts  
T he e x pl orat or y e n d p oi nts f or t he O L T P are:  
•  Pr o p orti o n of patie nts w h o re q uire tr eat me nt i nte nsificati o n t hr o u g h o ut t he st u d y  
•  I n ci de nce of 
M A V E, d efi ne d as a d v erse e ve nts of s pecial i nterest t h at i ncl u de 
t hr o m b o p hle bitis/ dee p vei n t hr o m b osis, p ul m o nar y e mb ol us, m y ocar dial i nfarcti o n, 
u nsta ble a n gi na, re n al vei n or arter y t hr o m b osis, ac ute peri p heral v asc ular occl usi o n, 
he patic vei n t hr o m b osis, p ortal vei n t hr o m b osis, mese nteric/ visceral vei n t hr o m b osis 
or i nfarcti o n, mese nteric/ visceral arterial t hr o m b osis  or i nfarcti o n, tra nsi e nt isc he mic 
attac k, cere bral arterial o ccl usi o n/cere br o vas c ular acci de nt, cere bral ve n o us occl usi o n, 
ga n gre ne ( n o ntra u matic; n o n -dia betic), a m p utati o n ( n o ntra u matic; n o n -dia betic) fr o m 
baseli ne t hr o u g h da y 2 2 5  
•  C ha n ge i n re nal f u ncti o n as meas ure d b y esti mate d gl o mer ular filtrati o n rate (e G F R) 
fr o m baseli ne t o da y 2 2 5 
•  Perce nt c h a n ge i n free h e m o gl o bi n fr o m baseli ne t o da y 2 2 5  
•  C ha n ge i n bilir u bi n fr o m baseli ne t o da y 2 2 5  
•  C ha n ge i n retic ul oc yte c o u nt fr o m baseli ne t o da y 2 2 5  
•  C ha n ge a n d p erce nt c ha n ge i n A H 5 0 fr o m bas eli ne t o da y 2 2 5  
•  Pr o p orti o n of P N H er yt hr oc yt es a n d gra n ul oc ytes fr o m baseli ne t o da y 2 2 5  
•  C ha n ge fr o m baseli ne t o da y 2 2 5 i n f u ncti o nal scale s c ores ( R ole F u ncti o ni n g, 
E m oti o nal F u ncti o ni n g, C o g niti ve F u n cti o ni n g, a n d S ocial F u n cti o ni n g) a n d s y m pt o m 
scale s c ores ( Fati g ue, Na usea a n d v o miti n g, Pai n, D ys p n o ea, I ns o m nia, A p petite L oss, 
C o nsti pati o n, Diarr h oea) of t he E O R T C Q L Q -C 3 0  
•  Pr o p orti o n of patie nts wit h sta bilit y i n gl o b al healt h stat us, f u ncti o ni n g, a n d s y m pt o ms 
as meas ure d  b y t h e E O R T C Q L Q -C 3 0 fr o m baseli ne t o da y 2 2 5  
•  C o m paris o n of tr eat me nt satisfacti o n (as assesse d b y t he T S Q M) at bas eli ne ( wit h 
ec uliz u ma b) vers us  treat me nt at da y 2 2 5 ( wit h p o zeli ma b/ce m disira n) 
•  C ha n ge i n P N H s y m pt o ms as meas ure d b y t he de n o v o P N H S y m pt o m -S pecific 
Q uesti o n naire fr o m baseli ne t o da y 2 2 5  
•  C ha n ge i n Patie nt Gl o bal I m pressi o n of Se verit y ( P GI S) fr o m baseli ne  t o da y 2 2 5, 
i ncl u di n g q uesti o ns o n P N H s y m pt o ms, i m pacts, a n d fati g ue 
•  Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI C) at da y 2 2 5, i ncl u di n g q u esti o ns o n 
P N H  s y m pt o ms, i m pacts, a n d fati g ue 
•  I d e ntif y a n y p ote ntial differe n ces t hat i nfl ue nce efficac y a n d safet y via ge n ot y pi n g a n d 
ge n e e x pressi o n a nal ysis ( b y R N A s e q ue n ci n g)  
E x pl orat or y e n d p oi nts relate d t o t he a nal yses f or t h ose patie nts recei vi n g d ose i nte nsificati o n a n d 
patie nts partici pati n g i n t he o pti o nal O L E P will be pr o vi de d i n t he statistical a nal ysis pla n ( S A P).  
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5.  
S T U D Y V A RI A B L E S   
5. 1.  
De m o gr a p hic a n d B aseli ne C h ar acteristics  
I n acc or da n ce wit h l oc al re g ulati o ns, baseli ne c h aract eristics will be coll ecte d a n d will i ncl u de 
sta n dar d de m o gra p hi c i nf or mati o n (e g, a ge, ge n d er, race, et h nicit y, etc), disease c haract eristics, 
me dical hist or y, a n d me dicati o n hist or y f or eac h patie nt. T he d ata will b e use d t o d escri be t he 
patie nt p o p ulati o n u n der st u d y a n d ma y i nf or m w het her t here are differe nces i n t he safet y or 
effic ac y pr ofile bas e d o n t he defi ne d patie nt c haracteristics. I n a d diti o n, c ollecti o n of data o n race 
a n d et h nicit y is r e q uire d b y certai n r e g ulat or y a ge ncies, s uc h as t he F D A.  
5. 2.  
Effic ac y V ari a bles  
5. 2. 1.  
L a b or at or y V ari a bles f or t he Assess me nt of Effic ac y  
Efficac y i n t his st u d y is e val uate d b y t he f oll o wi n g la b orat or y ass ess me nts:  
•  L D H (ser u m)  
•  He m o gl o bi n  
•  C H 5 0  
T hese la b orat or y vari a bles are rele v a nt t o t he c h aract erizati o n a n d diseas e mec ha nis ms of P N H 
(Br o ds k y, 2 0 1 4 ). Lactat e de h y dr o ge n ase as a meas ure of i ntra v asc ular he m ol ysis all o ws f or a n 
o bjecti ve a n d precise mea ns t o ga u ge w het her t he c o ntr ol of i ntra v asc ular he m ol ysis wit h 
ec uliz u ma b is s ustai ne d w he n t he p atie nts are s witc he d t o p ozeli ma b a n d ce m disira n c o m bi nati o n 
treat me nt. T he C H 5 0 ass a y will be use d t o c o nfir m c o m plete i n hi biti o n of c o m ple me nt acti vit y 
has bee n ac hie ve d t hr o u g h o ut t he d osi n g i nter val i n patie nts wit h P N H.  
5. 2. 2.  
Tr a nsf usi o n Rec or d  
He m ol ytic a n e mia is a cli nical ma nifestati o n of P N H, a n d patie nts ofte n re q uire bl o o d tra nsf usi o n 
f or s y m pt o matic ma na ge me nt. T he fre q ue n c y of bl o o d tra nsf usi o n has b ee n use d i n ot her st u dies 
of P N H t o assess efficac y (Hil l me n, 2 0 0 6) (R öt h, 2 0 1 8 ). 
5. 2. 3.  
Cli nic al O utc o me Ass ess me nts  
T he f oll o wi n g cli nical o utc o me assess me nts ( des cri be d i n Secti o n  9. 2. 2. 2 ) will be c o m plete d b y 
t he patie nt: 
•  F A CI T -Fati g ue  
•  E O R T C Q L Q -C 3 0  
•  T S Q M  
•  P N H S y m pt o m -S pecific Q uesti o n naire  
•  P GI S  
•  P GI C  
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C O N FI D E N TI A L  
5. 3.  
S afet y V ari a bles  
T he safet y v aria bles i n t his st u d y i n cl u de:  
•  T E A Es  
•  B o d y wei g ht  
•  Vital si g ns  
•  Electr ocar di o gra m ( E C G)  
•  P h ysical e x a mi nati o n  
•  R o uti ne safet y  la b orat or y t ests ( he mat ol o g y, c h e mistr y, uri nal ysis, a n d pre g n a nc y 
testi n g [f or w o me n of c hil d beari n g p ote ntial or W O C B P]) 
•  C o nc o mita nt me dicati o ns a n d treat me nts  
5. 4.  
P h ar m ac o ki netic V ari a bles  
T he P K vari a bles are t h e c o nce ntrati o n of t otal p ozeli ma b, ce m disir a n, ce m disira n meta b olites, 
t otal ec uliz u ma b, t otal C 5, a n d ti me.  
5. 5.  
I m m u n o ge nicit y V ari a bles 
T he i m m u n o ge nicit y varia bles are A D A stat us, titer, a n d ti me p oi nt/ visit .  
5. 6.  
P h ar m ac o d y n a mic a n d Ot her Bi o m ar ker V ari a bles  
P har mac o d y na mic a n d ot her bi o mar ker vari a bl es i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  Ser u m C H 5 0, a n assa y assessi n g t he acti vit y of t he classical pat h w a y of c o m ple me nt,  
will be use d t o m eas ur e C 5 acti vit y. It is t he pri n ci pal  P D mar k er f or t he st u d y a n d is 
als o a n effi cac y v aria ble i n t hi s st u d y 
•  Free he m o gl o bi n  
•  Para meters of i ntra v asc ular he m ol ysis: ie, ha pt o gl o bi n, retic ul oc yte c o u nt, a n d 
bilir u bi n  
•  A H 5 0, ser u m   
•  C o m ple me nt acti vati o n mar kers: ie, s C 5 b -9  
•  P N H cl o ne size: ie, P N H er yt hr oc ytes a n d gra n ul o c yt es  
T he list ma y be altere d or e x pa n de d, as it is rec o g nize d t hat m ore rel e va nt or n o vel bi o mar kers 
ma y b e disc o vere d d uri n g t he c o urse of t his st u d y. T he bi o mar kers st u die d will be o nes belie ve d 
t o be rele va nt t o t he u n dersta n di n g of effi cac y, p at h o p h ysi ol o g y of i n dicati o n tar get e n ga ge me nt, 
mec ha nis m of acti o n, a n d p ossi ble t o xicities of p ozeli ma b a n d ce m disira n.  
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6.  
S T U D Y D E SI G N   
6. 1.  
St u d y Descri pti o n a n d D ur ati o n  
T he st u d y is a si n gle -ar m, o pe n -la b el st u d y w here b y u p t o 1 2 patie nts wit h P N H  w h o are c urre ntl y 
recei vi n g ec uliz u ma b will be s witc he d t o p ozeli ma b a n d ce m disira n c o m bi nati o n t hera p y. T he 
st u d y is pla n ne d t o be c o n d ucte d i n a si n gl e ce nt er i n t he U nite d Ki n g d o m, b ut if nee de d, a d diti o nal 
sites/c o u ntries ma y be i n cl u de d. Patie nts w h o are c urre ntl y recei vi n g ec uliz u ma b at t he la bele d 
d osi n g re gi me n ( 9 0 0 m g I V Q 2 W) or w h o are c urre ntl y recei vi n g ec uliz u ma b at a d ose hi g h er t ha n 
t he la bele d d ose ( > 9 0 0 m g I V) or m ore fre q ue ntl y t ha n la bele d will be e nr olle d. A st u d y s c he matic 
is pr o vi de d i n Fi g ure  1 . 
T he st u d y c o nsists of 4 peri o ds: a scree ni n g peri o d of u p t o 4 2 da ys, a 3 2 -wee k O L T P (t his mai n 
st u d y peri o d will be l o n ger f or p atie nts w h o re q uire i nte nsifie d treat me nt), a n o pti o nal 5 2-wee k 
O L E P, a n d a 5 2 -wee k p ost -treat me nt safet y f oll o w-u p peri o d. T he f o urt h peri o d be gi ns w he n a 
patie nt c o m pletes or per ma ne ntl y disc o nti n ues st u d y tr eat me nt (e g, at t h e ti me of pre mat ure st u d y 
dr u g disc o nti n uati o n, at t he c o m pleti o n of st u d y treat me nt i n t he O L T P f or patie nts w h o decli ne 
t he o pti o nal O L E P, or at t he c o m pleti o n of st u d y treat me nt i n t he o pti o nal O L E P f or patie nts w h o 
d o n ot c o nti n ue st u d y treat me nt i n a p ost -trial access pr o gra m i m me diatel y f oll o wi n g t he st u d y). 
T he treat me nt peri o d be gi ns fr o m t he first d ose of st u d y dr u g a n d e n ds after t he c o m pleti o n of t he 
d osi n g i nter val of t h e last d ose t o acc o u nt f or t he tr eat me nt effect of t h e fi nal d ose of st u d y dr u g.  
F or t he first a p pr o xi matel y 2 wee k s, p atie nts will re mai n o n ec uliz u ma b bac k gr o u n d treat me nt at 
t heir us ual d ose/fre q u e nc y, a n d ce m disira n al o ne will be i ntr o d uce d: 
•  Lea d -i n ce m disira n treat me nt a n d bac k gr o u n d c o nc o mita nt treat me nt wit h ec uliz u ma b: 
− D a y 1  (t he da y of patie nt’s sc he d ule d ec uliz u ma b a d mi nistrati o n): ce m disira n 
2 0 0  m g S C a n d ec uliz u ma b ≥9 0 0 m g I V ( patie nt’s us ual d ose). N ote: ec uliz u ma b 
ma y b e a d mi nistere d u p t o 2 da ys after ce m disira n if n ot a d mi nistere d wit h 
ce m disira n o n da y 1.  
− D a y 1 5 :  
o  F or patie nts o n ec uliz u ma b Q 1 4 da ys (la bel e d d ose re gi me n): da y 1 5 ( ± 2 d a ys), 
ie, da y 1 3 t o da y 1 7 
o  F or patie nts o n ec uliz u ma b m ore fre q ue ntl y t h a n Q 1 4 da ys: patie nts s h o ul d be 
d ose d wit hi n 2 da ys of t heir us ual pla n ne d d ose  
T he f oll o wi n g d osa ge re gi me n of p ozeli ma b/ce m disira n c o m bi nati o n t h era p y will be a d mi nistere d 
d uri n g t he s witc h fr o m e c uliz u ma b treat me nt:  
•  P ozeli ma b/ce m disira n c o m bi nati o n treat me nt:  
− D a y 2 9  ( wee k 4): p ozeli ma b 6 0 m g/ k g I V l oa di n g d os e, f oll o we d (after a dela y of 
at least 3 0 mi n utes) b y p ozeli ma b 4 0 0 m g S C a n d ce m disira n 2 0 0 m g S C  
− D a y 5 7  ( wee k 8) t o d a y 1 9 7 ( wee k 2 8): p ozeli ma b 4 0 0 m g S C a n d ce m disira n 
2 0 0  m g S C Q 4 W mai nte na nce re gi me n ( ± 7 da ys)  
Details of all d ose a d mi nistrati o n wi n d o ws are pr o vi de d i n Ta ble  1  (f o ot n otes #9 , 1 0 , 1 1 , a n d 1 2 ). 
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D uri n g scree ni n g, patie nts w h o ha ve n ot bee n vacci nate d a gai nst Stre pt oc o cc us p ne u m o ni ae  a n d 
H ae m o p hil us i nfl ue nz a  t y p e B acc or di n g t o c urre nt nati o nal/l ocal vacci nati o n g ui deli nes will be 
re q uire d t o be v acci nate d t o be eli gi ble f or t he st u d y ( Secti o n 7. 2. 2 ). 
I n a d diti o n t o N. m e ni n giti dis , fatal or seri o us i nf ecti o ns wit h N. g o n orr he a  ha ve bee n re p orte d i n 
pati e nts ta ki n g ec uliz u ma b. T heref ore, a ris k ass ess me nt a n d c o u nseli n g re gar di n g t he p ote ntial 
ris k of N. g o n orr he a  i nfecti o n will be c o n d ucte d per l ocal pr actice ( Secti o n 8. 2. 4 ).  
Patie nts will be assesse d f or acti ve or late nt t u berc ul osis i nfecti o n bas e d o n l ocal practice or 
a p plica ble g ui deli nes. Base d o n t he ris k assess me nt, t he nee d f or scree ni n g wit h eit her t u berc uli n 
s ki n test or T cell i nterfer o n-ga m ma release assa y will be ma de. T he i nter pretati o n of t hese res ults, 
as a p plica bl e, will be m a de b y t h e i n vesti gat or. F urt her ma na ge me nt a n d treat me nt will be t he 
res p o nsi bilit y of t he i n vesti gat or.  
I n a d diti o n t o scree ni n g pr oce d ures, patie nts will be as ke d t o c o m plete a P N H S y m pt o m -S pecific 
Q uesti o n naire dail y f or at least 1 4 c o nsec uti ve d a ys pri or t o t he d a y  1 visit.  
Patie nts ma y c h o os e t o partici pate i n t he o pti o nal O L E P, o pti o nal f ut ure bi o me dical researc h, 
a n d/ or o pti o nal p h ar mac o ge n o mics c o m p o ne nt of t he st u d y b y si g ni n g t he res pecti ve o pti o nal 
i nf or me d c o nse nt f or ms (I C Fs). 
6. 1. 1. 2.  
O pe n -L a bel Tre at me nt Peri o d  
Patie nts w h o f ulfill all t he eli gi bilit y criteria will be e nr olle d i n t he st u d y a n d recei ve t heir first 
d ose of st u d y dr u g o n da y 1, w hic h s h o ul d occ ur o n t he da y of t he patie nt’s sc he d ule d treat me nt 
wit h ec uliz u ma b. As descri be d i n Secti o n  6. 1 , patie nts will be a d mi nistere d ce m disira n wit h 
ec uli z u ma b o n da y 1 ( n ote: ec uliz u ma b ma y be a d mi nistere d u p t o 2 da ys after da y 1 ce m disira n 
i n or der t o acc o m m o date t he l o gistical c o m ple xities ass ociate d 
wit h its a d mi nistrati o n). 
Ec uliz u ma b will be a d mi nistere d al o ne o n d a y 1 5 ( + 2 d a ys or earlier, acc or di n g  t o t he patie nt’s 
us ual d osi n g fre q ue nc y (refer t o Secti o n  6. 1 ). T he first d ose of c o m bi n ati o n S C t hera p y wit h 
p ozeli ma b a n d ce m disira n wit h o ut bac k gr o u n d ec uliz u ma b will be a d mi nistere d o n da y 2 9 a n d 
c o nti n ue Q 4 W t hereafter. T he first d ose of c o m bi n ati o n S C t hera p y o n da y 2 9 will be prece de d b y 
a n I V l o a di n g d ose of p o zeli ma b t o ac hie ve hi g h c o nce ntr ati o ns of p ozeli ma b ra pi dl y i n or der t o 
pr o vi de c o m plete i n hi biti o n of C 5, as s o o n as p ossi ble, d uri n g t he s witc h fr o m ec uliz u ma b t o 
p ozeli ma b. T he S C d oses s h o ul d n ot be gi ve n u ntil at least 3 0  mi n utes after c o m pleti o n of t he 
I V a d mi nistrati o n, a n d t he patie nt s h o ul d be o bser ve d d uri n g t he i nter val. Patie nts will als o be 
m o nit ore d f or at least 3 0  mi n utes after c o m pleti n g t he first S C i njecti o ns f or t he p ozeli ma b a n d 
ce m disira n c o m bi nati o n.  
After t he first S C d ose of t he p o zeli ma b a n d ce m disira n c o m bi nati o n o n da y 2 9, s u bse q ue nt st u d y 
treat me nt a d mi nistrati o ns ma y be c o nti n ue d b y t he site pers o n nel, a healt hcare pr ofessi o nal if 
a vaila ble, or a d mi nistere d b y t he p atie nt or desi g nate d pers o n at t he patie nt’s preferre d l o cati o n . 
T hese o pti o ns f or st u d y tr eat me nt a d mi nistrati o n will de pe n d o n prefere n ce of t he i n vesti gat or a n d 
patie nt, l ocal re g ulati o ns, a n d a vaila bilit y of healt hcare pr ofessi o nal. If s elf -a d mi nistrati o n ( or 
a d mi nistrati o n b y a d esi g nat e d pers o n) is u n dert a ke n, t he n s uffi cie nt i nj ecti o n trai ni n g at t he 
sc he d ule d a d mi nistrati o n(s) wit h a p ozeli ma b a n d ce m disira n mai nte na nce re gi me n will be 
pr o vi de d b y t he i n vesti gat or or q u alifie d st u d y st aff d esi g n ee. After trai ni n g, o bs er vati o n of self -
a d mi nistrati o n ( or a d mi nist rati o n b y desi g n ate d pers o n) will be c o n d u cte d b y cli nical site 
pers o n nel a n d ma y be c o n d ucte d i n p ers o n at t h e patie nt’s h o me or via t ele me dici ne. O nce t his 
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o bser vati o n is c o nsi dere d satisfact or y, t he p ozeli ma b a n d ce m disira n mai nte na nce re gi me n ca n be 
s ubse q ue ntl y a d mi nistere d i n de pe n de ntl y b y p atie nt/ desi g nat e d pers o n f or t he re m ai n der of t he 
st u d y. A patie nt diar y will be pr o vi de d pri or t o i nitiati o n of self-a d mi nistrati o n f or rec or di n g data 
o n st u d y tr eat me nt a d mi nistrati o n. T he diar y s h o ul d be c o m plet e d u p o n eac h st u d y dr u g 
a d mi nistrati o n.  
S afet y C o nsi der ati o ns  
Brea kt hr o u g h he m ol ysis is assesse d b y t he i n vesti gat or t hr o u g h o ut t he st u d y a n d is defi ne d i n 
Secti o n  6. 1. 2 . D uri n g t he st u d y, a patie nt 
meeti n g criteri a f or brea kt hr o u g h he m ol ysis or 
i na de q uate L D H res p o ns e ma y q ualif y f or treat me nt i nte nsificati o n as descri be d i n Secti o n 6. 1. 3 . 
T he decisi o n t o tra nsf us e wit h R B Cs d uri n g t he st u d y s h o ul d pr ocee d acc or di n g t o t he pre defi ne d 
criteria i n Secti o n  6. 1. 4 .  
Patie nts s h o ul d be cl osel y m o nit ore d f or t he e ntire st u d y f or earl y si g ns a n d s y m pt o ms of 
me ni n g oc o ccal i nfecti o n a n d e val uate d i m me diatel y if a n i nfecti o n is s us pecte d (see 
Secti o n  8. 2. 2 ). Patie nts will be pr o vi de d a patie nt safet y car d d escri bi n g si g ns a n d s y m pt o ms of 
s us pecte d me ni n g o c occal i nfecti o n al o n g wit h i nstr ucti o ns t o f oll o w i n cas e of a p ote ntial 
me ni n g oc o ccal i nfecti o n as w ell as i nf or mati o n f or t he n o n -i n vesti gat or h ealt hcare pr o vi der f or 
a ware ness. D ail y oral a nti bi otic pr o p h yla xis is rec o m me n de d (see Secti o n  8. 2. 3 ).   
D uri n g i ntra ve n o us i nf usi o n of p ozeli ma b, d ue t o c o ncer n of p ote ntial I V i nf usi o n reacti o ns, 
patie nts s h o ul d be o bser ve d f or at le ast 3 0 mi n utes after t he i nf usi o n. I n a d diti o n, e mer ge nc y 
e q ui p me nt a n d me dicati o n f or t he treat me nt of i nf usi o n reacti o ns m ust be a vaila ble at t he cli nical 
site f or i m me diate use. All i nf usi o n reacti o ns m ust be re p orte d as a d verse e v e nts ( A Es) a n d gra d e d 
usi n g t he gra di n g scal es pr o vi de d i n Secti o n  1 0. 2. 5 . Patie nts s h o ul d als o b e o bser ve d f or at least 
3 0 mi n utes after c o m pleti n g t he first S C i njecti o ns of t he p ozeli ma b a n d ce m disira n c o m bi nati o n.   
D uri n g t he tr a nsiti o n of t hera p y fr o m ec uliz u ma b t o p ozeli ma b, i n vesti gat ors s h o ul d ha v e 
hei g hte n e d a w are n ess f or p ossi ble A Es as a res ult of t he ris k of f or mati o n of lar ge m ulti mers of 
c o m ple x es of ec uliz u ma b -C 5 -p ozeli ma b (ie, lar ge D T D i m m u ne c o m ple x es) ( See Secti o n  6. 1. 5 ).  
St u d y Pr oce d ures  
St u d y pr oce d ures i n t he treat me nt peri o d i ncl u de la b orat or y ass ess me nts of efficac y ( L D H, 
he m o gl o bi n, a n d C H 5 0), tra nsf usi o n rec or d u p dat e, cli nical o utc o me  assess me nts, b o d y wei g ht, 
a n d r o uti ne s afet y assess me nts ( vital si g ns, p h ysi cal e x a mi nati o n, E C G, safet y l a b orat or y testi n g). 
Treat me nt -e mer ge nt a d v erse e ve nts a n d c o nc o mita nt me dicati o ns will b e m o nit ore d t hr o u g h o ut 
t he st u d y. Patie nts will pr o vi de bl o o d sa m ples f or bi o mar kers, dr u g c o nce ntrati o n f or p ote ntial P K 
a n d P D assess me nt, i m m u n o ge ni cit y, a n d e x pl orat or y assess me nts. St u d y pr oce d ures are liste d b y 
visit i n Ta ble  1  a n d des cri be d i n Secti o n  9. 2 . St u d y pr oce d ures, i ncl u di n g sa m ple c ollecti o n f or 
la b orat or y a nal ysis, ma y be perf or me d at t he st u d y cli nic or at a n ot her l ocati o n t hat is m ore 
c o n ve nie nt f or t he patie nt (i ncl u di n g h o me visits), if t his o pti o n is a vaila ble a n d wit h s p o ns or 
a p pr o val.  T h e l ast d oses of st u d y treat me nt f or p atie nts w h o d o n ot recei v e d ose i nte nsificati o n are 
a d mi nistere d o n  d a y 1 9 7 ( wee k  2 8 ). Patie nts will ret ur n f or safet y, efficac y, a n d ot her assess me nts 
at t he e n d of treat me nt ( E O T) visit at wee k  3 2. F or patie nts w h o restarte d o n i nte nsifie d treat me nt 
d uri n g t h e st u d y, t he last d ose of st u d y treat me nt is a d mi nistere d at w ee k 3 0. Patie nts will ret ur n 
f or safet y, effi cac y, a n d ot her assess me nts at t he E O T visit at wee k 3 2 ( T a ble  2 ). 
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6. 1. 1. 3.  
O pti o n al O pe n -L a bel E xte nsi o n Peri o d  
All patie nts w h o c o m plete t he O L T P st u d y treat me nt, i ncl u di n g patie nts w h o recei ve d t he 
i nte nsifie d re gi me n, will be offere d t h e o p p ort u nit y t o c o nti n ue i n a n o pti o nal 5 2-wee k O L E P, 
w here b y t he treat me nt wit h p ozeli ma b a n d ce m disira n fr o m t he O L T P t o t he O L E P is pla n ne d t o 
be u ni nterr u pte d (ie, d a y 1e visit of t he O L E P will c orres p o n d t o t he E O T visit i n t he O L T P, a n d 
a n y c o m m o n assess me nts will be perf or m e d o nce f or b ot h visits). St u d y ass ess me nts a n d c o n d uct 
f or t he o pti o nal O L E P are as d escri be d pre vi o usl y f or t he O L T P a n d are det aile d i n T a ble  3  
( Sc he d ule of E v e nts f or t he o pti o nal O L E P). 
D uri n g  t h e o pti o nal O L E P, patie nts w h o are n ot o n i nte nsifie d trea t me nt w h o meet t he pre-defi ne d 
criteria f or treat me nt i nte nsificati o n will f oll o w t he d osi n g re gi me n as d escri be d i n Secti o n  8. 3. 2  
wit h t he ne w re gi me n  starti n g o n t h e da y of i nte nsificati o n, a n d will c o nti n ue t heir visit sc he d ule 
at t he ne xt O L E P visit.   
T his mea ns t hat starti n g t he da y of i nte nsificati o n ( da y pre -d efi ne d criteria ha ve b ee n met), t he 
patie nt will recei ve a si n gle a d mi nistrati o n of p ozel i ma b 3 0 
m g/ k g I V f oll o we d b y S C 
a d mi nistrati o n of p ozeli ma b a n d ce m disira n t he sa me da y.  T hereafter, t he patie nts will recei ve 
p ozeli ma b 4 0 0 m g Q 2 W a n d ce m disira n 2 0 0 m g Q 4 W starti n g fr o m t he da y of i nte nsificati o n ( ± 3 
da ys).  T he visit sc he d ule f or t he O L E P will re mai n u nc ha n ge d.   
F or p atie nts w h o c o m pl ete t he o pti o nal O L E P, p ost -trial access t o treat me nt ma y b e a v aila ble 
( Secti o n 8. 9 ). 
6. 1. 1. 4.  
P ost -Tre at me nt  S afet y F oll o w -U p  
Patie nts w h o per ma ne ntl y disc o nti n ue st u d y treat me nt f or a n y reas o n (i n cl u di n g patie nts w h o 
decli ne c o nti n uati o n i n t he o pti o nal O L E P a n d patie nts w h o c o m plete t he O L E P  b ut d o n ot 
c o nti n ue treat me nt i n a p ost -trial access setti n g) will u n der g o a n off -treat me nt f oll o w-u p peri o d 
u ntil 5 2 wee ks aft er t he l ast d ose of st u d y tr eat me nt  as des cri be d i n Ta bl e  4 . T he p ost-tr eat me nt 
f oll o w-u p m o ni t ors t he safet y of t he patie nt as t he st u d y dr u gs are eli mi nate d gra d u all y fr o m t he 
b o d y.  
Patie nts w h o per ma ne ntl y disc o nti n ue st u d y treat me nt s h o ul d be treate d i n acc or da nce wit h l ocal 
sta n dar ds of care. 
6. 1. 1. 5.  
E n d of St u d y Defi niti o n  
T he e n d of t h e mai n st u d y i s defi ne d as t he d ate of t he last visit of t he last patie nt i n t he O L T P, 
i ncl u di n g p atie nts w h o disc o nti n ue d treat me nt d uri n g t h e O L T P a n d are bei n g f oll o we d i n t he 
p ost -treat me nt safet y f oll o w-u p peri o d of t h e O L T P.  
T he e n d of t he o pti o nal O L E P is defi ne d  as t he d ate of t he last visit of t he last patie nt i n t he o pti o nal 
O L E P, i ncl u di n g patie nts w h o disc o nti n ue d treat me nt d uri n g t he O L E P a n d are bei n g f oll o we d i n 
t he p ost-treat me nt safet y f oll o w-u p peri o d of t he O L E P.  
T he safet y f oll o w -u p p eri o d is wai ve d f or patie nts w h o c o nti n ue treat me nt i n t he p ost -trial access 
pr o gra m.  
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6. 1. 2.  
Bre a kt hr o u g h He m ol ysis  
Brea kt hr o u g h he m ol ysis is defi ne d as a n i ncrease i n L D H wit h c o nc o mita nt si g ns or s y m pt o ms 
ass ociate d wit h he m ol ysis:  
•  A n i ncreas e i n L D H o cc urs w he n:  
− L D H ≥2 x U L N i f pre-tr eat me nt L D H is ≤1. 5 x U L N or 
− L D H ≥2 x U L N s u bse q ue nt t o i nitial ac hie ve me nt of L D H ≤1. 5 x U L N if 
pre -treat me nt L D H is > 1. 5 x U L N  
N ote: pre -tr eat me nt L D H is defi ne d b y t he mea n of t he L D H v al ues at t he scree ni n g 
visit a n d da y 1 visit  
•  T he si g ns or s y m pt o ms s h o ul d c orres p o n d t o t h ose k n o w n t o be ass ociate d wit h 
i ntra vasc ular he m ol ysis d ue t o P N H, li mite d t o t he f oll o wi n g: n e w o nset or w orse ni n g 
fati g u e, hea dac h e, d ys p n ea, he m o gl o bi n uria, a b d o mi nal pai n, scleral icter us, erectile 
d ysf u n ct i o n, c hest pai n, c o nf usi o n, d ys p ha gia, ne w t hr o m b otic e ve nt, a ne mia i ncl u di n g 
he m o gl o bi n val ue si g nifica ntl y l o wer (ie, ≥2 g/ d L decrease) as c o m pare d t o patie nt’s 
k n o w n baseli ne he m o gl o bi n val ues.  
6. 1. 3.  
Tre at me nt I nt e nsific ati o n  
A n  i nte nsifie d re gi me n is pr o p ose d t o pr o vi de e xtra C 5 s u p pressi o n t hat s o me patie nts ma y n ee d 
a n d w hic h ca n n ot be ma n a ge d a d e q uatel y b y t he st a n dar d d ose re gi me n.  Patie nts will recei ve 
i nte nsificati o n of t heir p o zeli ma b treat me nt fr o m d a y 5 7 o n war d as descri be d i n Secti o n 8. 3. 2  if 
t he y me et b ot h criteria b el o w:  
•  Brea kt hr o u g h he m ol ysis t hat is n ot d ue t o a c o m ple me nt -acti vati n g c o n diti o n 
(ie i nterc urre nt i nfecti o n) a n d   
•  I n a de q uat e L D H res p o ns e (ie, L D H > 1. 5 x U L N) t hat is s ustai ne d (ie, o n 2 c o nsec uti ve 
meas ure me nts s pa n ni n g at least 2 wee ks).  
D uri n g t he O L T P, patie nts w h o u n der g o treat me nt i nte nsificati o n ma y re q uire u nsc he d ule d visit(s) 
bef ore i nitiati o n. T he da y of i ni tiati o n of t he i nte nsifie d re gi me n s h o ul d be re-a nc h ore d t o baseli ne 
of t he I nte nsifi e d Treat me nt Peri o d i n t he O L T P ( da y 1r) a n d t hereafter f oll o wi n g a si milar 
sc he d ule of s u bse q ue nt visits a n d assess me nts as ne wl y e nr olle d patie nts (see  Ta ble  2 ). Patie nts 
w h o are o n i nte nsifie d treat me nt will be c o nsi dere d t o ha ve c o m plete d t he O L T P o n ce t h e y fi nis h 
t he 3 2-wee k treat me nt p eri o d o n t he i nte nsifie d re gi me n . 
D uri n g t he o pti o nal O L E P, patie nts w h o are n ot o n i nte nsifie d treat me nt w h o meet criteria f or 
treat me nt i nte nsific ati o n will f oll o w t he d osi n g re gi me n d escri b e d i n Secti o n 8. 3. 2  wit h t he n e w 
re gi me n starti n g o n t he da y of i nte nsificati o n a n d f or t he re m ai n der of t he O L E P. Patie nts will 
c o nti n ue t heir visit sc he d ule at t he ne xt O L E P visit ( Ta ble  3 ). 
Patie nts are eli gi ble t o recei ve i nte nsificati o n of p ozeli ma b o nl y o nce ( w h et her d uri n g t he mai n 
treat me nt peri o d or t he o pti o nal O L E P), be y o n d w hic h n o f urt her i nte nsificati o n will be per mitte d. 
N ote: After d a y 2 9,  pati e nts w h o ha ve a n L D H i ncreas e ≥2 x U L N d ue t o a n ac ut e c o m ple me nt -
acti vati n g c o n diti o n d uri n g t he O L T P, i nte nsifie d O L T P or o pti o nal O L E P ma y recei ve a n I V 
p ozeli ma b d ose of 3 0 m g/ k g I V at t he discreti o n of t he i n vesti gat or a n d i n c o ns ult ati o n wit h t he 
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s p o ns or (see Secti o n 8. 3. 2 ).  A n assess me nt of t he patie nt’s wei g ht s h o ul d be perf or me d o n t he 
da y of t he I V p ozeli ma b l oa d i n or der t o  calc ul ate t he a p pr o pri ate d ose.  T his is n ot c o nsi dere d 
treat me nt i nte nsificati o n as t here will be n o c ha n ge i n re gi me n a n d n o re q uire me nt t o reset t heir 
sc he d ule t o da y 1.  
6. 1. 4.  
Tr a nsf usi o n Al g orit h m  
Tra nsf usi o ns wit h R B Cs d uri n g t he scree ni n g peri o d a n d w hil e t he patie nt is recei vi n g st u d y 
treat me nt ma y pr ocee d acc or di n g t o t he f oll o wi n g pre defi n e d criteria t hat will tri g ger a tra nsf usi o n 
as cli nicall y i n dicate d, h o we ver t he act ual n u m ber of u nits t o be tra nsf use d is at t he discreti o n of 
t he i n vesti gat or: 
•  Tra nsf use wit h R B C(s) if t he he m o gl o bi n le vel is ≤9 g/ d L wit h ne w o nset or w orse ni n g 
si g ns or s y m pt o ms res ulti n g fr o m a ne mia t hat are of s uffici e nt se verit y t o warra nt 
tra nsf usi o n or 
•  Tra nsf use wit h R B C(s) if t he he m o gl o bi n le vel is ≤7 g/ d L wit h or wit h o ut si g ns or 
s y m pt o ms of a ne mia.   
6. 1. 5.  
L ar ge dr u g -t ar g et-dr u g i m m u ne c o m pl e xes  
D uri n g t he tr a nsiti o n of t hera p y fr o m ec uliz u ma b t o p ozeli ma b, i n vesti gat ors s h o ul d ha v e 
hei g hte n e d a w are n ess f or p ossi ble A Es as a res ult of t he ris k of f or mati o n of lar ge m ulti mers of 
c om ple x es of ec uliz u ma b -C 5 -p ozeli ma b (ie, lar ge D T D i m m u ne c o m ple x es). Patie nts ma y pres e nt 
wit h a variet y of si g ns a n d s y m pt o ms s uc h as fe v er, malaise, ras h, a n d p ol yart hral gia. I n vesti gat ors 
s h o ul d als o c o nsi der me ni n g oc o ccal i nf ecti o n as t he ca us e of t he af ore me nti o ne d s y m pt o ms. If a 
ras h d oes de vel o p, t he site ma y c o nsi der ta ki n g pict ures of t he s ki n lesi o ns as all o we d base d o n 
l ocal re q uire m e nts a n d/ or perf or m a s ki n bi o ps y if cli nicall y i n dicat e d. If p h ot os are o btai ne d, t he n 
c o pies s h o ul d be ke pt as s o urce d o c u me nts, w hic h ma y l ater b e c ollecte d b y t he s p o ns or. If t here 
is a s us pici o n of a n A E p ote ntiall y d ue t o lar ge D T D i m m u ne c o m ple x es, a n u nsc he d ule d 
la b orat or y test s h o ul d b e o btai ne d a n d at mi ni m u m will i ncl u de a c o m plet e bl o o d c o u nt ( C B C), 
er yt hr oc yte s e di me ntati o n rate ( E S R), C -reacti ve pr otei n ( C R P), c he mistr y, C 3, C 4, a n d uri nal ysis 
(i ncl u di n g micr osc o pic e val uati o n). It is rec o m me n de d t hat t he i n vesti gat or c o ns ult wit h a 
r he u mat ol o gist or ne p hr ol o gist if nee de d a n d  i nf or m t he s p o ns or. H o we ver, f urt her i n vesti gati o ns 
are at t he discreti o n of t h e i n vesti gat or. I n v esti gat ors s h o ul d c o nsi der treat me nt wit h a n a d diti o nal 
d ose of p ozeli ma b 3 0 m g/ k g I V. T his a d diti o nal d ose will esta blis h c o n diti o ns of p ozeli ma b e x cess 
i n t he circ ulati o n a n d mi ni mize the ris k of f urt her f or mati o n of i m m u ne c o m ple x es. F urt her 
ma na ge me nt s h o ul d be base d o n cli nical e x perie n ce wit h t y pe III h y perse nsiti vit y reacti o ns (ie, 
ser u m sic k ness) w hic h i ncl u des a nti hista mi nes, n o n-ster oi dal a nti-i nfla m mat or y dr u gs, t o pical 
c ortic oster oi ds f or l ocali ze d s ki n ras h, a n d s yste mic c ortic oster oi ds f or ge neralize d s ki n ras h or 
s yste mic ma nif estati o ns. 
6. 2.  
Pl a n ne d I nteri m A n al ysis  
A n i nteri m a nal ysis ma y be c o n d ucte d after 6 patie nts ha ve c o m plete d at least 1 6  wee ks of t he 
O L T P  ( Secti o n 1 1. 5 ). A d diti o nal/ ot her i nteri m a nal yses ma y b e perf or m e d t o s u p p ort re g ulat or y 
i nteracti o ns. 
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7.  
S E L E C TI O N, WI T H D R A W A L, A N D R E P L A C E M E N T O F 
P A TI E N T S  
7. 1.  
N u m ber of P atie nts Pl a n ne d  
U p t o 1 2 patie nts .  
7. 2.  
St u d y P o p ul ati o n  
7. 2. 1.  
I ncl usi o n Criteri a  
A patie nt m ust meet t he f oll o wi n g criteria t o be eli gi ble f or i ncl usi o n i n t he st u d y:  
1.  Male or fe m ale ≥1 8 years of a ge at t he ti me of c o nse nt  
2.  Dia g n osis of par o x ys mal n oct ur nal 
h e m o gl o bi n uria c o nfir m e d b y a hist or y of 
hi g h -se nsiti vit y fl o w c yt o metr y fr o m pri or testi n g 
3.  Treate d wit h sta ble (i e, n o c ha n ge i n d ose or fre q u e nc y) ec uliz u ma b t hera p y at t he la bele d 
d osi n g re gi me n or a hi g h er d ose a n d/ or m or e fre q ue ntl y a d mi nistere d t ha n la bele d f or at 
least 1 2 wee ks pri or t o scree ni n g visit 
4.  Pr o vi de i nf or me d c o nse nt si g ne d b y st u d y patie nt  
5.  Willi n g a n d a ble t o c o m pl y wit h cli nic/re m ote visits a n d st u d y -relate d pr oce d ures 
6.  A ble t o u n dersta n d a n d c o m plete st u d y -relate d q u esti o n naires 
7. 2. 2.  
E xcl usi o n  Criteri a  
A patie nt w h o meets a n y of t he f oll o wi n g criteri a will be e x cl u de d fr o m t he st u d y:  
1.  Hist or y of b o n e marr o w tra ns pla ntati o n or recei pt of a n or ga n tr a ns pla nt  
2.  B o d y wei g ht < 4 0 k g at scree ni n g  
3.  C urre nt pla ns f or m o dificati o n (i nitiati o n, disc o nti n uati o n, or d ose/ d osi n g i nter val c ha n ge) 
of t he f oll o wi n g b ac k gr o u n d c o nc o mita nt me dicati o ns, as a p plica bl e, d uri n g s cree ni n g a n d 
treat me nt peri o d: er yt hr o p oieti n, i m m u n os u p pressi ve dr u gs, c ortic oster oi ds, a nti-
t hr o m b otic a ge nts, a ntic o a g ul a nts, ir o n s u p ple me nts, a n d f olic aci d 
4.  A n y use of c o m ple me nt i n hi bit or t hera p y ot her t h a n ec uliz u ma b i n t he 1 2 wee ks pri or t o 
t he scree ni n g visit or pla n ne d use d uri n g t he st u d y 
5.  A n y 2 of t he f oll o wi n g 3 a b n or malities  at t he scree ni n g visit ( o ne re p eat m eas ure m e nt is 
all o we d d u ri n g scree ni n g peri o d): 
a. Peri p heral bl o o d a bs ol ute ne utr o p hil c o u nt ( A N C) < 5 0 0/ μ L [ < 0. 5 x 1 0 9/ L] or 
b.  Peri p heral bl o o d platelet c o u nt < 2 0, 0 0 0/ μ L or  
c. Peri p heral bl o o d retic ul o c yt e c o u nt a b n or m alit y d efi ne d as < 2 0, 0 0 0/ μ L or < 1 %  
6.  K n o w n h y p o cell ular b o n e marr o w b ase d o n a hist or y of re d u ce d a ge -a dj uste d b o ne marr o w 
cell ularit y a n d/ or b o ne m arr o w cell ularit y ≤2 5 %.  
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7.  N o d oc u me nte d me ni n g o c occal vacci nati o n wit hi n 5 years pri or t o scree ni n g visit u nless it 
is d oc u me nte d t hat vacci nati o n has bee n a d mi nistere d d uri n g t he scree ni n g peri o d a n d pri or 
t o i nitiati o n of st u d y treat me nt 
8.  U na ble t o ta ke a nti bi otics f or me ni n g oc o ccal pr o p h yla xis, if re q uire d b y l ocal sta n dar d of 
care  
9.  A n y acti ve, o n g oi n g i nf ecti o n or a rece nt i nfecti o n re q uiri n g o n g oi n g s yste mic treat me nt 
wit h a nti bi otics, a nti virals, or a ntif u n gals wit hi n 2 wee ks of s cree ni n g or d uri n g t he 
scree ni n g p eri o d 
1 0.  D oc u me nte d hist or y of s yst e mic f u n gal diseas e or u nres ol ve d t u berc ul osis ( T B), or 
e vi de nce of acti ve or l ate nt t u berc ul osis i nfecti o n ( L T BI) d uri n g scree ni n g per i o d. 
Assess me nt f or acti ve T B a n d L T BI s h o ul d be acc or di n g wit h l ocal practice or g ui deli nes, 
i ncl u di n g t h ose pertai ni n g t o ris k ass ess me nt, a n d t he use of t u berc uli n s ki n test or T-cell 
i nterfer o n ga m ma rele ase assa y 
1 1.  P ositi ve he patitis B s urface a nti ge n o r he p atitis C vir us R N A d uri n g s cree ni n g. 
 
N O T E: Cases wit h u nclear i nter pretati o n s h o ul d be disc usse d wit h t he me dical m o nit or.   
1 2.  Hist or y of h u m a n i m m u n o deficie nc y vir us ( HI V) i nfecti o n.  
1 3.  D oc u me nte d * p ositi ve p ol y merase c h ai n reacti o n ( P C R) or e q ui vale nt t est base d o n 
re gi o nal rec o m me n dati o ns f or C O VI D-1 9 or s us p ecte d  S A R S -C o V -2 i nfecti o n, a n d:  
a. Ha ve n ot rec o vere d fr o m C O VI D -1 9 (ie, all C O VI D -1 9 -relate d s y m pt o ms a n d maj or 
cli nical fi n di n gs w hic h ca n p ote ntiall y affect t he safet y of t he p atie nt ha v e n ot bee n  
res ol ve d), a n d  
b.  Di d n ot ha ve 2 ne gati ve res ults fr o m n ucleic aci d a m plificati o n ( P C R) test or e q ui vale nt 
test base d o n re gi o nal rec o m me n dati o ns f or C O VI D-1 9 t o c o nfir m t hat t he patie nt is 
ne gati ve f or S A R S -C o V -2 or, if C O VI D -1 9 P C R ( or e q ui vale nt) testi n g  is n ot feasi ble, 
at least 3 m o nt hs ha ve tra ns pire d si nce t he i nitial dia g n osis.  
* N ote : Scree ni n g f or C O VI D-1 9 will n ot b e perf or me d as p art of eli gi bilit y 
assess me nts f or t his st u d y  
1 4.  K n o w n here ditar y c o m pl e me nt deficie nc y  
1 5.  D oc u me nte d hist or y of acti ve, u n c o ntr olle d, o n g oi n g s yste mic a ut oi m m u ne diseases  
1 6.  D oc u me nte d hist or y of li ver cirr h osis or patie nts wit h li ver disease wit h e vi de nce of 
c urre nt, i m paire d li ver f u ncti o n, or patie nts wit h A L T or A S T ( u nrelat e d t o P N H) greater 
t ha n 3 × U L N at t he scree ni n g visit ( o ne re peat assess me nt all o we d d uri n g scree ni n g)  
1 7.  Patie nts wit h a n e G F R of < 3 0 m L/ mi n/ 1. 7 3 m 2 (acc or di n g t o C hr o nic Ki d ne y Diseas e - 
E pi de mi ol o g y C olla b orati o n e q uati o n 2 0 0 9 [ C K D -E PI]) at scree ni n g visit ( o ne re peat 
assess me nt all o we d d uri n g scree ni n g)  
1 8.  Rece nt, u nsta ble me dical c o n diti o ns, e x cl u di n g P N H a n d P N H -rel ate d c o m plicati o ns, 
wit hi n t he past 3 m o nt hs pri or t o scree ni n g visit (e g, m y ocar dial i nfarcti o n, c o n gesti ve 
heart fail ure wit h Ne w Y or k Heart Ass o ciati o n Class III or I V, seri o us u n c o ntr olle d c ar diac 
arr h yt h mia, cere br o vasc ular acci de nt, acti ve gastr oi ntesti nal blee d)  
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1 9.  A ntici pate d nee d f or maj or s ur ger y d uri n g t h e st u d y.  
2 0.  Hist or y of ca ncer wit hi n t he past 5 years, e x ce pt f or a de q u atel y treate d basal cell s ki n 
ca ncer, s q ua m o us cell s ki n ca ncer, or i n sit u cer vical ca ncer 
2 1.  K n o w n h y p erse nsiti vit y t o p ozeli ma b, ce m disira n, or t o a n y c o m p o ne nts of t he res pecti ve 
f or m ulati o ns 
2 2.  K n o w n or d oc u me nt e d f u ncti o nal or a nat o mic as ple nia  
2 3.  A n y cli nicall y si g nifica nt a b n or malit y i d e ntifie d at t he ti me of scree ni n g t hat  i n t he 
j u d g me nt of t he i n vesti gat or or a n y s u b-i n vesti gat or w o ul d precl u de safe c o m pleti o n of t he 
st u d y or c o nstrai n e n d p oi nts assess me nt s uc h as m aj or s yst e mic diseas es, or patie nts wit h 
s h ort life e x pecta nc y 
2 4.  C o nsi dere d b y t he i n vesti gat or or a n y s u b -i n vesti gat or as i na p pr o priate f or t his st u d y f or 
a n y reas o n, i n cl u di n g b ut n ot li mite d t o t he f oll o wi n g:  
•  Dee me d u n a ble t o meet s pecific pr ot o c ol re q uir e me nts, s uc h as sc he d ul e d visits  
•  Dee me d u n a ble t o a d mi nister or t olerate l o n g -t er m i njecti o ns 
•  Prese nce of a n y ot h er c o n diti o ns (e g, ge o gra p hic, s ocial), act ual or a ntici p ate d, t hat t he 
i n vesti gat or feels w o ul d restrict or li mit t he patie nt’s partici pati o n f or t he d urati o n of 
t he st u d y 
•  Part of a v ul nera ble p o p ulati o n s uc h as t he i nstit uti o nalize d  
2 5.  Me m bers of t he c li nical site st u d y tea m a n d/ or his/ her i m me diate fa mil y, u nless pri or 
a p pr o val gra nte d b y t he s p o ns or  
2 6.  Pre g n a nt or breastfee di n g w o me n  
2 7.  W o me n of c hil d beari n g p ote ntial ( W O C B P) * w h o are u n willi n g t o practice hi g hl y 
effecti ve c o ntr ace pti o n pri or t o t he i nitial  d ose/start of t he first tr eat me nt, d uri n g t he st u d y, 
a n d f or at least 5 2 wee ks after t he last d ose. Hi g hl y effecti ve c o ntr ace pti ve meas ures 
i ncl u de:  
a. sta ble use of c o m bi ne d (estr o ge n- a n d pr o gest o ge n -c o ntai ni n g) h or m o nal c o ntrace pti o n 
( oral, i ntra v a gi nal, tr a ns der mal) or pr o gest o ge n-o nl y h or m o nal c o ntr ace pti o n ( oral, 
i njecta ble, i m pla nta ble) ass ociate d wit h i n hi biti o n of o v ulati o n i nitiate d 2 or m ore 
me nstr ual c ycles pri or t o scree ni n g;  
b.  i ntra uteri ne de vic e (I U D); i ntra uteri ne h or m o ne-releasi n g s yste m (I U S); 
c. bilateral t u bal li gati o n;  
d.  vasect o miz e d part n er ( pr o vi de d t hat t he male v as ect o mize d part ner is t he s ole se x ual 
part ner of t h e W O C B P st u d y partici pa nt a n d t hat t he vasect o mize d part ner has o btai ne d 
me dical assess me nt of s ur gical s uccess f or t he pr oce d ure) ; a n d/ or 
e. se x ual a bsti ne nce†, ‡ . 
*   W O C B P are d efi ne d as w o me n w h o are fertile f oll o wi n g m e narc he u ntil bec o mi n g 
p ost me n o pa usal, u nless per ma n e ntl y sterile. Per ma ne nt sterilizati o n 
met h o ds 
i ncl u de h ysterect o m y, bil ateral sal pi n gect o m y, a n d bilateral o o p h orect o m y. 
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A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca use. A hi g h f ollicle -sti m ulati n g h or m o ne ( F S H) le vel i n t he p ost me n o pa usal 
ra n ge ma y be us e d t o c o nfir m a p ost me n o pa us al state i n w o me n n ot usi n g h or m o n al 
c o ntrac e pti o n or h or m o nal re place m e nt t hera p y. H o we ver, i n t he a bse nce of 1 2 m o nt hs of 
a me n orr hea, a si n gle F S H meas ure me nt is i ns ufficie nt t o deter mi ne t he occ urre nce of a 
p ost me n o pa usal state. T h e a b o ve d efi niti o ns are acc or di n g t o t he Cli nical Trial Facilitati o n 
Gr o u p ( C T F G) g ui da n ce (C T F G, 2 0 2 0 ). Pre g n a nc y testi n g a n d c o ntrace pti o n are n ot 
re q uire d f or w o me n wit h d oc u me nte d h ysterect o m y or t u bal li gati o n. 
† Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if defi ne d as refrai ni n g 
fr o m heter os e x ual i nterc o urse d uri n g t he e ntire p eri o d of ris k ass o ciate d wit h t he st u d y 
dr u gs. T h e relia bilit y of s e x ual a bsti ne nce nee ds t o be e val uate d i n rel ati o n t o t he d urati o n 
of t he cli nical trial a n d t h e preferre d a n d us ual lif est yl e of t he p atie nt.  
‡ 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 o nl y, c o n d o m use a n d lactati o nal a me n orr hea met h o d 
( L A M) are n ot acce pta bl e met h o ds of c o ntrace pti o n. Fe male c o n d o m a n d male c o n d o m 
s h o ul d n ot be use d t o get h er.  
2 8.  Partici pati o n i n a n ot her i nte r ve nti o nal cli nical st u d y or us e of a n y e x peri me ntal t hera p y 
wit hi n 3 0 da ys b ef ore s cree ni n g visit or wit hi n 5 h alf -li ves of t hat i n v esti gati o nal pr o d uct, 
w hic he ver is greater.  
2 9.  Patie nts wit h a hist or y of si g nifica nt 
m ulti ple i nt olera bilit y a n d/ or s e vere a ller gies 
(i ncl u di n g lat e x gl o ves) or patie nts w h o ha v e ha d a n a na p h yl actic reacti o n or si g nifi ca nt 
m ulti ple i nt olera bilit y t o prescri pti o n or n o n -prescri pti o n dr u gs.  
3 0.  Patie nts 
w h o ha ve n ot bee n vacci nate d a gai nst 
Stre pt oc occ us p ne u m o ni ae  a n d 
H ae m o p hil us i nf l ue nz a t y pe B if rec o m me n de d b y c urre nt nati o nal/l ocal vacci nati o n 
g ui deli nes.  ( N ot e t hat p atie nts w h o were n ot pre vi o usl y v acci n ate d s hall recei ve t hes e 
vacci nati o ns d uri n g scree ni n g, if rec o m me n de d b y c urre nt nati o nal/l ocal vacci nati o n 
g ui deli nes.)  
7. 3.  
Pre m at ure Wit h dr a w al fr o m t he St u d y  
A patie nt has 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, f or a n y reas o n, a n d wit h o ut 
re perc ussi o n. 
T he i n vesti gat or a n d/ or s p o ns or has t he ri g ht t o wit h dra w a p atie nt fr o m t h e st u d y if it is n o l o n ger 
i n t he i nterest of t he patie nt t o c o nti n ue i n t he st u d y, or if t he patie nt’s c o nti n uati o n i n t he st u d y 
places t he sci e ntific o utc o me of t he st u d y at ris k (e g, if a patie nt d oes n ot or ca n n ot f oll o w st u d y 
pr oce d ures). A n e x cessi v e rate of wit h dra wals w o ul d re n der t he st u d y u ni nter preta bl e; t heref ore, 
u n necessar y wit h dra w al of patie nts s h o ul d be a v oi de d.  
R ules f or disc o nti n uati o n of st u d y treat me nt ( per ma n e nt or t e m p or ar y) are disc usse d i n 
Secti o n  8. 3. 3 . 
Patie nts w h o are wit h dr a w n pre mat urel y fr o m t he st u d y will be as k e d t o c o m plete t he earl y 
ter mi nati o n visit, as descri be d i n Secti o n 9. 1. 2 . 
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7. 4.  
Re pl ace me nt of P atie nts  
Patie nts pre mat urel y wit h dra w n fr o m t he st u d y dr u g ca n be re place d, if nee de d, t o e ns ure t hat at 
least 6 patie nts c o m plete 3 2 wee ks of treat me nt. T he me dical/st u d y direct or, i n c o o perati o n wit h 
t he st u d y bi ostatisticia n, will deci de w het her or n ot t o re place a wit h dra w n patie nt.  
8.  
S T U D Y T R E A T M E N T S   
See Secti o n  6. 1  f or det ails o n treat me nt re gi me n. 
8. 1.  
I n vesti g ati o n al a n d Refere nce Tre at me nts 
8. 1. 1.  
P ozeli m a b  
P ozeli ma b dr u g pr o d uct will be pr o vi de d i n a sterile, si n gl e -use gl ass vial f or S C a n d 
I V a d mi nistrati o n a n d will be s u p plie d b y t he s p o ns or.  
Detaile d i nf or mati o n a b o ut t he dr u g pr o d uct a n d d ose pre parati o n are pr o vi de d i n t he p har mac y 
ma n ual.  
8. 1. 2.  
Ce m disir a n  
Ce m disira n dr u g pr o d uct will be pr o vi de d i n a sterile, si n gl e -use glass vial f or S C  a d mi nistrati o n 
a n d will be s u p plie d b y t he s p o ns or . 
Detaile d i nf or mati o n a b o ut t he dr u g pr o d uct a n d d ose pre parati o n are p r o vi de d i n t he p har mac y 
ma n ual.  
8. 2.  
B ac k gr o u n d Tre at me nts a n d Ris k Miti g ati o n  
E nr olle d patie nts will be o n bac k gr o u n d c o nc o mita nt treat me nt wit h ec uliz u ma b at t he patie nt’s 
us ual d ose a n d i nter val u ntil t he y are s witc he d t o t he st u d y dr u g c o m bi nati o n.  
8. 2. 1.  
Me ni n g oc occ al V acci n ati o ns  
Patie nts will ha ve h a d pre vi o us d oc u me nte d vacci nati o n f or m e ni n g o c occ us (ser ot y pes A, C, Y, 
W, a n d ser ot y pe B if a vaila ble) a n d s h o ul d be re -vacci nat e d if pri or i m m u nizati o n was m ore t ha n 
5  years pri or t o scree ni n g, or less t ha n  5 years pri or t o scree ni n g if re q uire d acc or di n g t o c urre nt 
nati o nal vacci nati o n g ui d eli nes f or vacci nati o n use wit h c o m ple me nt i n hi bit ors or l ocal pr actice.  
D uri n g t he c o urse of t he st u d y, t he i n vesti gat or s h o ul d e ns ure t he patie nt c o nti n ues t o meet t he  
re q uire me nt f or vacci nati o n as state d a b o ve. Patie nts w h o re q uire re-vacci nati o n d uri n g t he c o urse 
of t he st u d y s h o ul d c o nti n ue st u d y treat me nt. Vacci nati o ns will be s o urce d l ocall y b y t he 
i n vesti gat or or d esi g nee a n d rei m b urse d b y t he s p o ns or. 
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8. 2. 2.  
M o nit ori n g  f or Me ni n g oc occ al I nfecti o n 
Patie nts s h o ul d be cl osel y m o nit ore d f or earl y si g ns a n d s y m pt o ms of me ni n g o c occal i nfecti o n 
a n d e val uat e d i m me diatel y if a n i nf ecti o n is s us pecte d.  
Patie nts will be pr o vi d e d wit h a patie nt safet y car d descri bi n g si g ns a n d s y m pt o ms of 
me ni n g oc o ccal i nfecti o n, al o n g wit h i nstr ucti o ns i n cas e of a p ot e ntial me ni n g oc o ccal i nfecti o n, 
as well as i nf or mati o n f or t he n o n -i n vesti gat or healt hcare pr o vi der. 
8. 2. 3.  
Or al A nti bi otics f or Me ni n g oc occ al I nfecti o n  
It is rec o m me n de d t hat dail y oral a nti micr o bial pr o p h yla xis f or me ni n g o c occal i nfecti o n wit h 
eit her pe nicilli n or a m acr oli de class a nti bi otic c o m me nce o n t he da y of first d osi n g of st u d y dr u g 
( or per ti mi n g of me ni n g oc occal vacci nati o n, Secti o n  8. 2. 1 ) a n d c o nti n ue f or t he d urati o n of t he 
st u d y, u nless t he ris ks o ut wei g h t he be n efits or it is i nc o nsiste nt wit h l ocal practice. It is 
rec o m me n de d t hat pr o p h yl a xis be c o nti n ue d f or at least 5 2 wee ks after l ast d ose of p ozeli ma b a n d 
ce m disira n c o m bi nati o n treat me nt, i ncl u di n g f or p a tie nts w h o pre m at urel y disc o nti n ue st u d y dr u g. 
If t he i n vesti gat or prescri bes a nti bi otic pr o p h yl a xis, t he n t he i n vesti gat or s h o ul d f oll o w t he l ocal 
prescri bi n g i nf or m ati o n, partic ularl y as it relates t o war ni n gs, preca uti o ns, m o nit ori n g, etc, w hic h 
ma y n ecessitate a d diti o nal 
m o nit ori n g, atte nti o n t o dr u g -dr u g i nt eracti o ns, a n d ot h er 
c o nsi derati o ns.  
Ulti matel y, t he d ecisi o n t o a d mi nister pr o p h yla xis wit h oral a nti bi oti cs, t he start d a y of 
a d mi nistrati o n, t he d urati o n of pr o p h yla xis, a n d t he c h oice a n d d osi n g re gi me n of a nti bi otics will 
be at t he dis creti o n of t he i n vesti gat or a n d s h o ul d be c o nsiste nt wit h l ocal g ui deli nes , u nless t he 
patie nt recei ves v acci n ati o n wit hi n 2 wee ks fr o m da y 1, i n w hi c h case t h e patie nt m ust recei ve 
a nti bi otic pr o p h yla xis f or a mi ni m u m of 2 wee ks fr o m t he date of vacci nati o n . Oral a nti bi otics will 
be s o urce d l o call y b y t he i n vesti gat or or d esi g nee a n d rei m b urse d b y t he s p o ns or.  
8. 2. 4.  
Ris k M a n a ge me nt  of Neisseri a G o n orr he a   
Patie nts s h o ul d be c o u nsele d a b o ut N. g o n orr he a  pre ve nti o n a n d re g ular testi n g s h o ul d be a d vise d 
f or at-ris k patie nts.  
A ris k -fact or assess me nt s h o ul d be base d o n l ocal practice or nati o nal g ui deli nes. T he i n vesti gat or 
s h o ul d ma ke his/ her o w n assess me nt of ris k (a n d if nee de d, c o ns ultati o n wit h ot her healt hcare 
pr o vi der) t o det er mi ne if t he patie nt is at ris k, w hic h w o ul d lea d t o f urt her ma na ge me nt of 
pre ve nti o n, testi n g, a n d treat me nt of N. g o n orr he a .  
Testi n g a n d tr eat me nt s h o ul d  be i n acc or da nce wit h l ocal practice or nati o n al g ui deli nes.  
Ge neral pre ve nti ve me as ures i ncl u de a bsti ne nce a n d use of a c o n d o m. A d diti o nal pre ve nti ve 
meas ures s h o ul d be c o nsi dere d bas e d o n l ocal pr actice or nati o nal g ui deli nes.  
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8. 3.  
D ose M o dific ati o n a n d St u d y Tre at me nt Disc o nti n u ati o n R ules  
8. 3. 1.  
D ose M o dific ati o n  
D ose m o dificati o n f or a n i n di vi d ual patie nt is n ot all o we d, u nless t he patie nt meets t he criteria f or 
i nte nsifie d treat me nt as d escri be d i n Secti o n  6. 1. 3 .  
8. 3. 2.  
Tre at me nt I nt e nsific ati o n  
Patie nts w h o meet criteria f or treat me nt i nte nsificati o n ( Secti o n  6. 1. 3 ) will recei ve a si n gle 
a d mi nistrati o n of p ozeli ma b 3 0 m g/ k g I V o n t he da y of i nitiati o n (ca n be i nitiate d fr o m da y  5 7 
o n war d) i n a d diti o n t o a 
mai nte na nce re gi me n wit h a s h orte ne d fre q ue nc y of p ozeli ma b 
a d mi nistrati o n 4 0 0 m g S C Q 2 W al o n g wit h ce m disi ra n 2 0 0 m g S C Q 4 W ( ± 3 da ys) f or a peri o d of 
3 2  wee ks starti n g o n t he da y of i nitiati o n.   
A n assess me nt of t he pati e nt’s wei g ht s h o ul d be perf or me d o n t he da y of t he I V p ozeli ma b l oa d i n 
or der t o calc ul ate t he a p pr o priate d ose. T he I V d ose s h o ul d be a d mi ni stere d first. T he S C d oses 
s h o ul d be gi ve n at least 3 0 mi n utes after c o m pleti o n of t he I V a d mi nistrati o n.   
N ote: Patie nts w h o e x perie nce brea kt hr o u g h he m ol ysis t hat is n ot d ue t o a c o m ple me nt -acti vati n g 
c o n diti o n, a n d meet criteria f or treat me nt i nte nsifi cati o n, are eli gi ble t o recei ve i nte nsificati o n of 
p ozeli ma b o nl y o n ce ( w het her d uri n g t he mai n tr eat me nt peri o d or t he o pti o nal O L E P), be y o n d 
w hic h n o f urt her i nte nsificati o n will be per mitte d . 
I n t h e e ve nt of a n L D H i ncreas e ≥2 x U L N d ue t o a n ac ut e c o m ple me nt -acti vati n g c o n diti o n (ie, 
i nterc urre nt i nfecti o n) after da y 2 9 i n t he O L T P, i nte nsifie d O L T P or at a n y ti me i n t he o pti o nal 
O L E P, a n I V l oa di n g d ose of p ozeli ma b 3 0  m g/ k g  I V ma y be gi ve n at t he discreti o n of t he 
i n vesti gat or a n d i n c o ns ultati o n wit h t he s p o ns or. A n assess me nt of t he patie nt’s wei g ht s h o ul d be 
perf or me d o n t h e d a y of t he I V p ozeli ma b l oa d i n or der t o calc ulate t he a p pr o priate d os e .  T his is 
n ot c o nsi dere d treat me nt i nte nsificati o n. N o ot her c ha n ges will be ma de t o t he st u d y treat me nt 
re gi me n (ie, t he re g ular d ose a n d fre q u e nc y of p ozeli ma b a n d ce m disira n will pr ocee d u n c ha n ge d). 
Patie nts will c o nti n ue o nt o t he ne xt visit of t heir c urre nt visit sc he d ule.  
8. 3. 3.  
St u d y Dr u g Disc o nti n u ati o n  
Patie nts w h o per m a ne ntl y dis c o nti n ue fr o m st u d y tre at me nt eit her i n t he O L T P or t he i nte nsifie d 
O L T P s h o ul d b e e nc o ura ge d t o re mai n i n t he st u d y. T h os e w h o a gree a n d d o n ot wit h dra w fr o m 
t he st u d y will be as ke d t o ret ur n t o t he cli nic f or all re mai ni n g st u d y visits per t he visit sc he d ule , 
i ncl u di n g safet y f oll o w-u p u ntil 5 2 wee ks after t h eir last d ose of st u d y tr eat me nt ( Ta ble  4 ). 
Patie nts w h o per ma n e ntl y disc o nti n ue fr o m st u d y tr eat me nt a n d w h o o pt t o wit h dra w fr o m t he 
st u d y s h o ul d ret ur n f or a n earl y t er mi nati o n ( E T) visit c o nsisti n g of a p plica ble assess me nts at t he 
E O T  visit f or t he c orres p o n di n g st u d y peri o d , per Secti o n  9. 1 . 2. 
Patie nts w h o per ma ne ntl y disc o nti n ue st u d y treat me nt s h o ul d be treate d i n acc or da nce wit h l ocal 
sta n dar ds of care. 
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8. 3. 3. 1.  
Re as o ns f or Per m a ne nt Disc o nti n u ati o n of St u d y Dr u g  
St u d y dr u g d osi n g of a n i n di vi d ual patie nt will be per ma ne ntl y st o p pe d i n t he e ve nt of:  
•  E vi de nce of pre g na n c y  
•  Seri o us or se vere aller gi c reacti o ns c o nsi dere d relate d t o p ozeli ma b or ce m disira n  
− Please n ote t hat A Es p ote ntiall y d ue t o lar ge D T D i m m u ne c o m ple x es are n ot 
c o nsi dere d as a n a ut o matic reas o n f or per ma n e nt treat me nt disc o nti n uati o n. T he 
i n vesti gat or s h o ul d re vie w t he partic ular cas e a n d c o ns ult wit h t he me dical m o nit or 
pri or t o deci di n g o n per m a ne nt treat me nt disc o nti n uati o n.   
•  Li ver i m pair me nt as e vi de nce b y 1 or m or e of t he f oll o wi n g criteria a n d n o ot her reas o n 
ca n be f o u n d t o e x plai n t he f oll o wi n g la b a b n or m alities, s uc h as vir al he patitis A, B, or 
C; pre -e xisti n g or ac ute li ver disea se; P N H-relate d c o m plicati o n; or a n ot her dr u g 
ca pa ble of ca usi n g t he o bser ve d i nj ur y:  
− A L T or A S T > 8 × U L N, or  
− A L T or A S T > 5 × U L N f or m ore t ha n 2 wee ks, or  
− A L T or A S T > 3 × U L N a n d t otal bilir u bi n > 2 × U L N ( or i nter nati o nal n or malize d 
rati o [I N R] > 1. 5)  
•  Pat ie nt wit h dra wal of c o nse nt 
•  Patie nt n o nc o m plia nce as deter mi ne d b y t he i n v esti gat or (e g, n ot c o m pl yi n g wit h 
pr ot oc ol -re q uir e d visits, assess me nts, a n d/ or d osi n g i nstr ucti o ns) 
•  I n v esti gat or’s cli nical j u d g me nt t hat it is i n t he best i nterest of t he patie nt 
N o te: A d oc u me nte d, p ositi ve P C R or e q ui vale nt test per l ocal rec o m me n d ati o ns f or C O VI D-1 9 
is n ot c o nsi dere d a n a ut o matic reas o n f or p er ma ne nt disc o nti n uati o n a n d s h o ul d be disc usse d wit h 
t he me dical m o nit or. It ma y be a reas o n f or per ma ne nt disc o nti n uati o n if t he be nefit-ris k 
assess me nt of c o nti n ui n g treat me nt wit h p ozeli ma b a n d ce m disira n is dee me d u nfa v ora ble.  
8. 3. 3. 2.  
Re as o ns f or Te m p or a r y Disc o nti n u ati o n of St u d y Dr u g  
Te m p orar y disc o nti n uati o n ma y be c o nsi d ere d b y t he i n vesti gat or b eca us e of s us pecte d A Es. St u d y 
dr u g d osi n g ma y res u me after t he c o n diti o n lea di n g t o te m p orar y disc o nti n uati o n of st u d y dr u g 
res ol ves. Alter n ati vel y, t he i n vesti gat or ca n rei nitiate treat me nt wit h st u d y dr u g u n der cl ose a n d 
a p pr o priate cli nical a n d/ or la b orat or y m o nit ori n g o nce t he i n ve sti gat or h as c o nsi dere d, acc or di n g 
t o his/ her best me dical j u d g me nt, t hat t h ere is a n u nli kel y relati o ns hi p bet w ee n t he occ urre n ce of 
t he A E a n d t he st u d y dr u g. 
After re -i nitiati o n of treat me nt, t he patie nt s h o ul d recei ve a n y misse d d ose as s o o n as p ossi ble. T he 
patie nt s h o ul d t he n ret ur n t o t he ori gi nal d osi n g s c he d ule.  
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N ote re gar di n g i nf ecti o n wit h S A R S -C o V -2: If, i n t he i n vesti gat or’s me di cal j u d ge me nt, it is i n 
t he patie nt’s best i nterest t o i nterr u pt treat me nt wit h p ozeli ma b a n d ce m disira n u ntil t he patie nt 
rec o vers fr o m S A R S-C o V -2, t he n it is a d visa bl e t hat 2 re peat C O VI D -1 9 P C R tests, or e q ui val e nt 
tests de pe n di n g o n re gi o nal rec o m me n d ati o ns, be c o n d ucte d t o c o nfir m t he patie nt is ne gati ve f or 
S A R S -C o V -2.  If C O VI D-1 9 P C R testi n g is n ot feasi ble, it is  a d vise d t hat at least 3  m o nt hs ha ve 
tra ns pire d si nce t he i nitial dia g n osis. T he i n vesti gat or ma y res u me tr eat me nt wit h p ozeli ma b a n d 
ce m disira n u n der cl ose cli nical m o nit ori n g if t he i n vesti gat or feels t hat t he be nefit of res u mi n g 
t hera p y o ut wei g hs t he ris ks a n d t he patie nt h as n o ne w c o ntr ai n dicati o ns t o treat me nt.  I n p ut fr o m 
t he s p o ns or re gar di n g t h e per missi ble d urati o n of i nterr u pti o n t o all o w res u m pti o n of treat me nt 
ma y b e s o u g ht.  
8. 4.  
M a n a ge me nt of Ac ute Re acti o ns   
8. 4. 1.  
Ac ute I ntr a v e n o us I nf usi o n Re acti o ns  
D u ri n g i ntra ve n o us i nf usi o n of p ozeli ma b, d ue t o c o ncer n of p ote ntial reacti o ns, patie nts s h o ul d 
be o bser ve d f or at least 3 0 mi n utes after t he i nf usi o n.   
E mer ge nc y e q ui p me nt a n d me dicati o n f or t he treat me nt of i nf usi o n reacti o ns m ust be a vaila ble at 
t he clinical site  f or i m me diate use. All i nf usi o n reacti o ns m ust be re p orte d as A Es (as defi ne d i n 
Secti o n  1 0. 2. 4 ) a n d gra d e d usi n g t he gra di n g scal es as instr ucte d i n Secti o n  1 0. 2. 5 .  
8. 4. 1. 1.  
I nterr u pti o n of t he I ntr a ve n o us I nf usi o n 
T he i nf usi o n s h o ul d be i nterr u pte d if a n y of t he f oll o wi n g A Es are o bser ve d:  
•  S ustai ne d/se vere c o u g h  
•  Ri g ors/c hills  
•  Ras h, pr urit us (itc hi n g)  
•  Urticaria ( hi ves, welts, w heals)  
•  Dia p h oresis (s weati n g)  
•  H y p ote nsi o n  
•  D ys p n ea (s h ort n ess of breat h)  
•  V o miti n g  
•  Fl us hi n g  
T he reacti o n(s) s h o ul d be treate d s y m pt o maticall y, a n d t he i nf usi o n ma y b e restarte d at 5 0 % of t h e 
ori gi nal rate pr o vi de d t h at t he s y m pt o ms are a de q u atel y m a na ge d.  
If t h e i n vesti gat or feels t here is a me dical nee d f or treat me nt or disc o nti n uati o n of t he i nf usi o n 
ot her t ha n descri be d a b o ve, he/s he s h o ul d use cli nical j u d g me nt t o p r o vi de t he a p pr o priat e 
res p o nse acc or di n g t o t y pical cli nical practice. 
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8. 4. 1. 2.  
Ter mi n ati o n of t he I ntr a ve n o us I nf usi o n  
T he i nf usi o n s h o ul d be ter mi nate d a n d N O T restarte d if a n y of t he f oll o wi n g A Es o cc ur:  
•  A na p h yl a xis *  
•  Lar y n geal/ p har y n geal e d e ma  
•  Se vere br o nc h os pa s m 
•  C hest pai n  
•  Seiz ure  
•  Se vere h y p ote nsi o n  
•  Ot her ne ur ol o gic al s y m pt o ms (c o nf usi o n, l oss of c o nsci o us ness, parest hesi a, 
paral ysis, etc)  
•  A n y ot her s y m pt o m or si g n t hat, i n t he o pi ni o n of t he i n vesti gat or, warra nts 
ter mi nati o n of t he I V i nf usi o n 
* C o nsi der a na p h yla xis if t he f oll o wi n g is o bser ve d (Sa m ps o n, 2 0 0 6 ): ac ute o nset of a n ill ness 
( mi n utes t o se veral h o urs) wit h i n v ol ve me nt of t h e s ki n, m uc osal tiss ue, or b ot h (e g, ge n eralize d 
hi ves, pr urit us or ﬂus hi n g, s w olle n li ps -t o n g u e-u v ula) 
A N D A T L E A S T O N E O F T H E 
F O L L O WI N G:  
•  Res pirat or y c o m pr o mise (e g, d ys p nea, w heeze -br o nc h os pas m, stri d or, re d uce d pea k 
e x pirat or y fl o w, h y p o x e mia)  
•  Re d uce d bl o o d press ur e or ass ociate d s y m pt o m s of e n d-or ga n d ysf u ncti o n (e g, 
h y p ot o nia [c olla pse], s y n c o pe, i nc o nti ne nce)  
8. 4. 2.  
Ac ute I njecti o n Re acti o ns  
8. 4. 2. 1.  
S yste mic I njecti o n Re acti o ns  
Patie nts s h o ul d be o bser ve d f or at le ast 3 0 mi n utes after t he first S C i njecti o n. A d diti o nall y, 
e mer ge n c y e q ui p me nt a n d me di cati o n f or t h e treat me nt of s yste mic reacti o ns m ust be a vaila ble at 
t he cli nical site f or i m me diate use. All i njecti o n reacti o ns m ust be re p orte d as A Es (as d efi ne d i n 
Secti o n  1 0. 2. 1 ) a n d gra d e d usi n g t he gra di n g scal es as i nstr ucte d i n Secti o n 1 0. 2. 5 . 
Ac ute s yste mic  reacti o ns f oll o wi n g S C i njecti o n of st u d y dr u g s h o ul d be treate d usi n g cli nical 
j u d g me nt t o d eter mi ne t he a p pr o priate res p o nse acc or di n g t o t y pi cal cli nical practice a n d l ocal 
sta n dar ds of care.  
8. 4. 2. 2.  
L oc al I njecti o n Site Re acti o ns  
L ocal  i njecti o n site reacti o ns m ust be re p orte d as A Es a n d gra d e d acc or di n g t o Secti o n  1 0. 2. 5 . 
8. 5.  
Met h o d of Tre at me nt Assi g n me nt  
N ot a p plica ble as t his is a si n gle-ar m st u d y.  
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8. 6.  
Bli n di n g  
N ot a p plica ble as t his is a n o pe n -la b el st u d y. 
8. 7.  
Tre at me nt L o gistics a n d Acc o u nt a bilit y  
8. 7. 1.  
P ac k a gi n g, L a beli n g, a n d St or a ge  
O pe n -la bel st u d y dr u g will be pac ka ge d i n cart o ns a n d will dis pla y t he pr o d uct l ot n u m ber o n t he 
cart o n a n d vial la b el.  
St u d y dr u g will be st ore d at t he site at a te m perat ure of 2º C t o 8º C; st ora ge i nstr ucti o ns will be 
pr o vi de d i n t he p har mac y ma n u al.  
8. 7. 2.  
S u p pl y a n d Dis p ositi o n of Tre at me nts  
St u d y dr u g will be s hi p pe d at a te m perat ur e of 2º C t o 8º C t o t he i n vesti ga t or or desi g n ee at re g ular 
i nter vals or as n ee de d d uri n g t he st u d y. At s p ecifi e d ti me p oi nts d uri n g t he st u d y (e g, i nteri m site 
m o nit ori n g visits), at t he site cl ose -o ut visit, a n d f oll o wi n g dr u g rec o n ciliati o n a n d d oc u me ntati o n 
b y t h e site m o nit or, all o p e ne d a n d u n o pe n e d st u d y dr u g will be destr o ye d/ret ur ne d t o t he s p o ns or 
or desi g n ee.  
8. 7. 3.  
Tre at me nt Acc o u nt a bilit y  
All dr u g acc o u nta bilit y rec or ds m ust be ke pt c urre nt.  
T he i n vesti gat or m ust be a ble t o acc o u nt f or all o pe ne d a n d u n o pe n e d st u d y dr u g. T hes e rec or d s 
s h o ul d c o ntai n t he dates, q ua ntit y, a n d st u d y me di cati o n 
•  Dis pe nse d t o eac h patie nt  
•  Ret ur ne d fr o m e ac h p atie nt (if a p plica ble), a n d  
•  Dis p ose d of at t he site or ret ur ne d t o t he s p o ns or or desi g n ee.  
All acc o u nta bilit y rec or ds m ust be ma de a vaila bl e f or i ns pecti o n b y t he s p o ns or a n d re g ulat or y 
a ge nc y i ns pe ct ors; p h ot oc o pies m ust be pr o vi de d t o t he s p o ns or at t he c o ncl usi o n of t he st u d y.  
8. 7. 4.  
Tre at me nt C o m pli a nce  
All dr u g c o m plia n ce rec or ds m ust be k e pt c urr e nt a n d ma de a vaila ble f or i ns pecti o n b y t he s p o ns or 
a n d re g ulat or y a ge n c y i ns pect ors.  
8. 8.  
C o nc o mit a nt Me dic ati o ns  
A n y treat me nt a d mi nistere d fr o m t he ti me of i nf or me d c o nse nt t o t he e n d of t he safet y f oll o w-u p 
peri o d will be c o nsi dere d c o nc o mita nt me dicati o n. T his i ncl u des me dicati o ns t hat were starte d 
bef ore t h e st u d y a n d are o n g oi n g d uri n g t he st u d y.  
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8. 8. 1.  
Pr o hi bite d Me dic ati o ns a n d Pr oce d ures  
T he f oll o wi n g m e dicati o ns are pr o hi bite d, wit h t he e x ce pti o n of t h ose liste d i n Secti o n  8. 8. 2 , as 
descri be d b el o w:  
•  T he use of a n y ot her c o m ple me nt i n hi bit or is pr o hi bite d w hile t he patie nt is ta ki n g 
st u d y tr eat me nts, wit h t he e x ce pti o n of ec uliz u ma b as o n g oi n g bac k gr o u n d t hera p y 
d uri n g tr a nsiti o n of s witc h t o c o m bi nati o n treat me nt  
•  Ot her i n vesti gati o nal treat me nts d uri n g t he c o urse of t he st u d y  
•   I n a d diti o n, t he patie nt s h o ul d n ot c o ns u me a n y alc o h ol a n d, if p ossi ble, refrai n fr o m 
stre n u o us e x ercise wit hi n 2 4  h o urs pri or t o eac h cli nic visit w he n bl o o d is dra w n 
8. 8. 2.  
Per mitte d Me dic ati o ns a n d Pr oce d ures  
T he f oll o wi n g m e dicati o ns a n d pr oce d ures will be per mitte d, u n der t he f oll o wi n g c o n diti o ns:  
•  A n y me dicati o n re q uir e d t o treat a n A E, i ncl u di n g s yste mic c ortic ost er oi ds, at t he 
dis creti o n of t he i n vesti gat or  
•  Me ni n g o c occal vacci nati o n, as descri b e d i n Secti o n  8. 2. 1   
•  Oral a nti bi otic pr o p h yla xis as rec o m me n de d, as descri be d i n Sec ti o n 8. 2. 3    
•  Oral c o ntrace pti ves a n d h or m o ne -re pl ace m e nt t hera p y ma y c o nti n ue  
•  Aceta mi n o p he n/ paraceta m ol, as piri n, or i b u pr ofe n at t he rec o m me n de d d ose  per t he 
l ocal prescri bi n g i nf or mati o n 
•  C o nc o mita nt 
a d mi nistrati o n 
of 
er yt hr o p oieti n, 
i m m u n os u p pressi ve 
dr u gs, 
c ortic oster oi ds, a nti -t hr o m b otic a ge nts, a ntic o a g ul a nts, ir o n s u p ple me nts, a n d f olic aci d 
are per mitte d a n d if p ossi ble, s h o ul d be k e pt c o nsta nt t hr o u g h o ut t he st u d y. A n y 
c ha n ges t o t h ese c o nc o mita nt me dicati o ns will be at t he discreti o n of t he i n vesti gat or 
a n d c o nsiste nt wit h practice i n t he pri or 2 6 wee ks fr o m e nr oll me nt i nt o t his st u d y, w he n 
p ossi ble. A n y ot her me dicati o ns ma y u n der g o d ose a dj ust me nt or disc o nti n uati o n at 
t he discreti o n of t he i n vesti gat or.  
•  A n y ot her me dicati o n re q uire d f or t he tr eat me nt of t he patie nt’s bac k gr o u n d me dical 
c o n diti o ns  
8. 9.  
P ost -Tri al Access t o St u d y Tre at me nt  
P ost -trial access t o p ozeli ma b a n d ce m disira n will be pr o vide d u ntil re g ulat or y a p pr o val has b ee n 
gra nte d i n t he re gi o n t he patie nt resi des a n d c o nsiste nt wit h s p o ns or g ui deli nes. S uc h access t o 
p ozeli ma b a n d ce m disira n will be base d o n t he re q uest of t he patie nt a n d i n vesti gat or i n li ne wit h 
l ocal re g ulati o ns, pro vi de d t hat t he patie nt meets all p ost -trial access s p o ns or re q uire m e nts. 
 
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9.  
S T U D Y S C H E D U L E O F E V E N T S A N D P R O C E D U R E S  
9. 1.  
Sc he d ule of E ve nts  
I n li g ht of t h e p u blic healt h e mer ge n c y relate d t o C O VI D-1 9, t he c o nti n uit y of cli nical st u d y 
c o n d uct a n d o versi g ht ma y re q uir e i m ple me ntati o n of te m p orar y or alter nati ve mec h a nis ms. 
E x a m ples of s uc h mec ha nis ms ma y i n cl u de, b ut are n ot li mite d t o, a n y of t he f oll o wi n g: p h o ne 
c o ntact, virt ual visits, tele me dici ne visits, o nli ne meeti n gs, n o n -i n vasi ve re m ote m o nit ori n g 
de vices,  us e of l ocal cli nic or la b orat or y l ocati o ns, a n d h o me visits b y s kille d staff. A d diti o nall y, 
n o wai vers t o de viat e fr o m pr ot oc ol e nr oll me nt criteria d u e t o C O VI D -1 9 will be gra nte d. All 
te m p orar y me c ha nis ms utilize d, a n d de viati o ns fr o m pla n ne d st u d y pr oce d ures i n res p o ns e t o 
C O VI D -1 9, are t o b e d o c u me nte d as bei n g relate d t o C O VI D -1 9 a n d will re mai n i n effect o nl y f or 
t he d urati o n of t he p u blic healt h e mer ge nc y. 
St u d y assess me nts a n d pr oce d ures are prese nt e d b y visit i n Ta bl e  1  ( O L T P), Ta ble  2  (treat me nt 
peri o d f or patie nts w h o re q uire i nte nsifie d t hera p y  i n t he O L T P), Ta bl e  3  ( o pti o nal O L E P), a n d 
Ta ble  4  ( p ost-treat me nt safet y f oll o w-u p p eri o d). S t u d y pr oce d ures, i ncl u di n g sa m ple c ollecti o n 
f or la b orat or y a nal ysis, ma y be p erf or me d at t he st u d y cli nic or at a n ot her l ocati o n t hat is m ore 
c o n ve nie nt f or t he patie nt (i ncl u di n g h o me visits), if t his o pti o n i s a vaila ble a n d wit h s p o ns or 
a p pr o val.  
 
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9. 1. 1.  
F o ot n ot es f or t he Sc he d ule of E ve nts T a bles  
9. 1. 1. 1.  
F o ot n ot es f or T a ble 1 Sc he d ule of E ve nts ( O pe n -L a bel Tre at me nt Peri o d)  
1.  St u d y pr oce d ures: w he n m ulti ple pr oce d ures are p erf or me d o n t h e sa me da y, t he se q u e nce 
of pr oce d ures is as f oll o ws: C O A assess me nts, E C G a n d/ or vital si g ns, bl o o d c ollecti o n, 
st u d y treat me nt a d mi nistrati o n, a n d a n y pre-s pecifie d p ost-d ose sa m ple c oll ecti o n.  
2.  Scree ni n g visit 1 b ca n be c o m bi ne d wit h visit 1a, if  L D H ca n be o btai ne d o ne da y b ef ore 
or o n t he da y of ec uliz u ma b a d mi nistrati o n. Visit 1 b a n d a d diti o nal i nteri m visits ma y als o 
be nee d e d f or re peat bl o o d c ollecti o n, vacci n ati o n , etc.  
3.  Me dical hist or y: tra nsf usi o ns, brea kt hr o u g h he m ol ysis hist or y, a n d la b orat or y p ara met ers 
f or meas ur e me nt of he m ol ysis (s uc h as L D H, bilir u bi n, ha pt o gl o bi n, retic ul oc yte c o u nt, 
a n d he m o gl o bi n) s h o ul d be o btai ne d f or t he past 1 year, if p ossi ble. Pri or hist or y at a n y 
ti me of t hr o m b osis a n d Neisseri a  i nfecti o ns will be c ollected if feasi ble. O n g oi n g 
P N H  s y m pt o ms a n d si g ns will als o be c ollecte d. 
4.  Pri or me dicati o ns: i ncl u di n g d etaile d ec uliz u ma b a d mi nistrati o n hist or y ( past 2 6 w ee ks) 
a n d N. me ni n giti dis  vacci nati o n ( past 5 years); all ot her pri or me dicati o ns 1 2 wee ks pri or 
t o scree ni n g 
5.  Patie nts will re q uire a d mi nistrati o n wit h me ni n g o c occal v acci n ati o n u nless d oc u me ntati o n 
is pr o vi de d of pri or i m m u niz ati o n i n t he past 5 years pri or t o scree ni n g, or less t ha n 5 years 
if re q uire d acc or di n g t o nati o nal vacci nati o n g ui deli nes f or vaccin ati o n use 
wit h 
c o m ple me nt i n hi bit ors or l ocal practice. F or patie nts w h o re q uir e a d mi nistrati o n wit h 
me ni n g oc o ccal vacci nati o n(s) d uri n g t h e scree ni n g p eri o d, a d mi nistrati o n s h o ul d occ ur 
prefera bl y at least 2 wee ks pri or t o da y 1, or at a n ot her ti me p oi nt  acc or di n g t o l ocal practice 
or nati o nal g ui d eli nes.   
6.  T u berc ul osis hist or y a n d assess me nt. Scree ni n g b y t u berc uli n s ki n test or T -cell i nterfer o n -
ga m ma rele ase assa y ma y b e perf or me d acc or di n g t o l ocal practice or g ui deli nes at t he 
discreti o n of t he i n ves ti gat or. 
7.  A ris k fact or assess me nt f or N. g o n orr he a  is rec o m me n de d, a n d c o u nseli n g is a d vise d f or 
at-ris k patie nts.  
8.  Patie nt safet y car d: pr o vi de t he patie nt safet y car d f or N. me ni n giti dis  i nfecti o n t o t he 
patie nt o n da y 1 or a n y ot her visit w he n nee de d. S ite s h o ul d re vie w t he i nstr ucti o ns o n t he 
safet y car d wit h t he patie nt at eac h visit.   
9.  Ce m disira n a d mi nistrati o n: t he first da y of d osi n g of ce m disira n will ta ke place at t he 
patie nt’s us ual sc he d ule of a d mi nistrati o n f or ec uliz u ma b.   
1 0.  P ozeli ma b I V a d mi nistrati o n: a d mi nistrati o n at da y 2 9 s h o ul d prece de S C  a d mi nistrati o n. 
After c o m pleti o n of I V a d mi nistrati o n, t he patie nt s h o ul d be o bser ve d f or at least 
3 0  mi n utes a n d if n o cli nical c o ncer n, t he n S C a d mi nistrati o n of t he c o m bi nati o n s h o ul d 
pr ocee d. P atie nts s h o ul d be m o nit ore d f or at least a n ot her 3 0  mi n utes after t h e first 
S C  d osi n g.  
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1 1.  T he S C d oses of p ozeli ma b a n d ce m disira n s h o ul d be gi ve n Q 4 W (e ver y  2 8  da ys) starti n g 
at da y 2 9 ( wee k 4). Fr o m da y 5 7 ( wee k 8) o n war d, ce m disira n a n d p ozeli ma b 
S C  a d mi ni strati o n ma y eit her be c o nti n ue d b y t h e site pers o n nel or a n ot her healt hcare 
pr ofessi o nal at t he patie nt’s h o me, or a d mi nistrati o n b y t he patie nt or desi g nate d pers o n at 
t he patie nt’s preferre d l ocati o n after a d e q uate trai ni n g. T h e fi nal S C d osi n g of t he 
co m bi nati o n d uri n g t he O L T P is at w ee k 2 8.  
D uri n g t he Q 4 W d ose a d mi nistrati o n i nter val starti n g at da y 5 7, t he d ose of ce m disira n a n d 
p ozeli ma b S C s h o ul d be gi ve n o n t he da y of t he c orres p o n di n g st u d y visit w he ne ver 
p ossi ble.  St u d y treat me nt a d mi nistrati o n s h o ul d al wa ys be t h e last pr oce d ure aft er all bl o o d 
sa m ple c ollecti o n a n d st u d y assess me nts ha ve bee n c o m plete d u nless ot her wise 
s pecifie d.  If p ozeli ma b or ce m disira n ca n n ot be a d mi nistere d o n t he da y of t he 
c orres p o n di n g st u d y visit, t he c o m bi nati o n ma y be a d mi nistere d u p t o 7 da ys bef ore or u p 
t o 7 da ys aft er t he pla n ne d d osi n g date, pr o vi de d t hat t he d osi n g ta kes place after t he 
c orres p o n di n g st u d y visit has bee n c o m plete d.  F or e x a m ple, t he da y 5 7 ( wee k 8) visit ca n 
ta ke place fr o m da y 5 4 t o da y 6 0 gi ven t he visit wi n d o w.  T he c orres p o n di n g d ose of 
p ozeli ma b a n d ce m disira n ca n be gi ve n fr o m da y 5 4 t o da y 6 4, b ut o nl y after t he wee k  8 
visit assess me nts ha ve bee n perf or me d.  Si milarl y, t he da y 1 1 3 ( wee k 1 6) visit ca n ta ke 
place fr o m da y 1 0 6 t o da y 1 2 0 gi ve n t he visit wi n d o w. T he c orres p o n di n g d ose of 
p ozeli ma b a n d ce m disira n ca n b e gi ve n fr o m d a y 1 0 6 t o da y 1 2 0, b ut o nl y after t h e wee k 
1 6 visit assess me nts h a ve b ee n p erf or me d.  P ozeli ma b a n d ce m disira n s h o ul d be 
a d mi nistere d o n t he sa me da y w he ne ver p ossi ble. Care m ust be ta ke n t o c o or di nate d osi n g 
f or visits w here a p ost-d ose sa m ple is c ollecte d t o meas ure t h e c o n ce ntr ati o n of ce m disira n 
a n d its meta b olites.   
1 2.  Ec uliz u ma b a d mi nistrati o n: c o nti n ue patie nt’s ec uliz u ma b a d mi nistrati o n at t he us ual d os e 
a n d d osi n g i nter val. A d mi nistrati o n of ec uliz u ma b at da y 1 ( w h e n first d ose of ce m disira n 
is a d mi nistere d) ma y occ ur u p t o 2 da ys l ater.  
N O T E: t he wee k 2 visit s h o ul d be sc he d ule d relati ve t o t he patie nt’s t y pical d osi n g 
fre q ue n c y. F or patie nts ta ki n g ec uliz u ma b wit h a fre q ue nc y of:  
•  E ver y 1 2 da ys  
− T he visit s h o ul d be sc he d ule d o n da y 1 3 ( ± 2 da ys).  
•  E ver y 1 3 da ys  
− T he visit s h o ul d be sc he d ule d o n da y 1 4 ( ± 2 da ys).  
•  E ver y 1 4 da ys  
− T he visit s h o ul d be sc he d ule d o n da y 1 5 ( ± 2 da ys).  
T he d ose of ec uliz u ma b s h o ul d be a d mi nistere d acc or di n g t o t he us ual d ose fre q ue n c y a n d 
m ust be d ose d o n or after t he visit a n d c orres p o n di n g ass ess me nts ha ve b ee n perf or me d.  
1 3.  I nje cti o n trai ni n g will be pr o vi de d t o patie nts w h o desire self-i njecti o n or i njecti o n b y a 
desi g nat e d pers o n. Sit e staff s h o ul d o bser ve p atie nt’s self -i njecti o n or i njecti o n b y a 
desi g nat e d pers o n a n d c o nfir m a de q uac y. Patie nt i nstr ucti o n materials will be pr o vi de d.  
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1 4.  If n ee d e d, base d o n patie nt self-a d mi nistrati o n/a d mi nistrati o n b y a desi g n ate d pers o n, t he 
patie nt wil l c o m plete a diar y f or rec or di n g data o n st u d y treat me nt a d mi nistrati o n starti n g 
at t he da y 5 7 visit or a s u bse q ue nt visit. If p atie nt diar y is pr o vi d e d t o t he patie nt, t he n it 
s h o ul d be re vi e we d at eac h cli nic visit a n d d ata c oll ecte d i nt o t he cas e re p ort  f or ms ( C R Fs). 
O n t he fi nal visit, t he diar y s h o ul d be c ollecte d b y t he site.  
1 5.  Dail y oral a nti bi otic pr o p h yla xis a gai nst N. me ni n giti dis  is rec o m me n de d starti n g o n t he 
first da y of d osi n g wit h st u d y tr eat me nt a n d c o nti n ui n g u ntil 5 2 wee ks aft er disc o nti n uat i o n 
of p ozeli ma b/ce m disira n. If vacci nati o n f or N. me ni n giti dis  occ urs less t ha n 2 wee ks pri or 
t o da y 1, t he n a nti bi otic pr o p h yla xis m ust be a d mi nistere d f or at least 2 wee ks fr o m t he 
ti me of vacci nati o n.    
1 6.  Patie nts will c o m plete t he P N H S y m pt o m -S pecifi c Q uesti o n naire o n a dail y basis f or at 
least 1 4 da ys pri or t o t he da y 1 visit. 
Patie nts s h o ul d tr y t o c o m plete t he 
P N H  S y m pt o m -S pecific  Q uesti o n naire at t he s a me ti me eac h d a y w he n e ver p ossi ble.  
1 7.  Brea kt hr o u g h he m ol ysis assess me nt: if a patie nt is s us pecte d o f ha vi n g a brea kt hr o u g h 
he m ol ysis e v e nt, t he n i n a d diti o n t o t he re q uire d l a b orat or y c ollecti o n, a d diti o nal sa m ples 
f or c oa g ul ati o n para m eters, c he mistr y, he mat ol o g y, retic ul oc yte c o u nt, D-di mer, t otal C 5, 
C H 5 0, A D A (a gai nst p o zeli ma b), a n d dr u g c o nce ntrat i o ns of p ozeli ma b a n d ec uliz u ma b 
will be c ollecte d u nless alrea d y n ote d i n t he S c he d ule of E ve nts f or t hat visit. If t he 
s us pecte d e ve nt d o es n ot occ ur at a s c he d ule d visit, t he n a n u nsc he d ule d visit s h o ul d occ ur 
wit h a n e val uati o n of t h e patie nt a n d c olle cti o n of c oa g ulati o n para meters, c he mistr y, 
he mat ol o g y, retic ul o c yt e c o u nt, t otal C 5, C H 5 0 a n d dr u g c o nce ntrati o ns of p ozeli ma b a n d 
ec uliz u ma b .  
1 8.  D uri n g la b c ollecti o n, ha n dli n g, a n d pr ocessi n g, t he sa me met h o d ol o g y will be a p plie d 
acr oss st u d y visits, as b est as p ossi ble, t o preser ve t he q ualit y of sa m ple a n d a v oi d 
he m ol ysis. T he c o a g ulati o n bl o o d sa m ple (t u be) m ust al wa ys be c ollecte d first, f oll o we d 
b y t h e bl o o d c he mistr y s a m ple (t u be). If t he i n vesti gat or or s p o ns or s us pects t hat t he l a b 
res ult is n ot a n acc urate reflecti o n of t he patie nt’s c o n diti o n, t he la b sa m ple s h o ul d be 
re peat e d. 
1 9.  Ser u m L D H, C R P, a n d bilir u bi n will be assesse d as part of t he bl o o d c he mistr y a nal ysis. 
T he c oa g ulati o n bl o o d sa m ple (t u be) m ust al wa ys be c ollecte d first, f oll o we d b y t he bl o o d 
c he mistr y sa m ple (t u b e).  D uri n g scree ni n g, o bt ai n c he mistr y i ncl u di n g L D H pri or t o 
ec uliz u ma b a d mi nistrati o n o n t he da y of ( or if n ot p ossi ble, o ne da y bef ore) ec uliz u ma b 
a d mi nistrati o n. O n da y 1 a n d all s u bse q ue nt visits, o btai n c he mistr y i ncl u di n g L D H pri or 
t o a n y st u d y treat me nt a d mi nistrati o n.   
2 0.  Pre g n a nc y test f or W O C B P : a ser u m test will be d o ne at t he scree ni n g visit a n d a uri ne test 
will be d o ne at all ot her visits i n dicate d. A n y p ositi ve uri ne test s h o ul d be c o nfir me d wit h 
a ser u m pre g n a nc y te st. 
2 1.  Bl o o d sa m ple c ollecti o n f or c o nce ntrati o ns of p ozeli ma b, ec uliz u ma b, t otal C 5, C H 5 0 
(effic ac y e n d p oi nt), a n d A H 5 0: o btai n sa m ples pri or t o a n y st u d y dr u g a d mi nistrati o n 
( pre-d os e). O n da y 2 9, o btai n bl o o d sa m ples pri or t o I V a d mi nistrati o n of p ozeli ma b  a n d 
als o wit hi n 1 5  mi n utes after t he e n d of t h e I V i nf usi o n.  
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2 2.  Bl o o d sa m ples f or c o nce ntrati o ns of ce m disira n a n d its meta b olites will be c ollecte d pri or 
t o a n y st u d y treat me nt a d mi nistrati o n ( pre-d ose) a n d at 2 t o 6 h o urs p ost -ce m disira n 
a d mi nistrati o n . The p ost -d ose sa m ple s h o ul d be caref ull y c o or di nat e d wit h t he d osi n g of 
ce m disira n a n d ma y b e c ollecte d at t he cli nic or b y a visiti n g h ealt hcare pr ofessi o nal.  
2 3.  Bl o o d sa m ples f or i m m u n o ge ni cit y will be c ollecte d bef ore t he a d mi nistrati o n of a n y st u d y 
dr u g ( pre -d ose). At t he visits w here i m m u n o ge nicit y sa m ples are t o be ta ke n, t he sa m ple 
s h o ul d be c ollecte d wit h t he dr u g c o nce ntrati o n s a m ple. I n t he e v e nt of s us pecte d S A Es, 
s uc h as a na p h yla xis or h y perse nsiti vit y, a d diti o nal sa m ples f or dr u g c o nce ntrati o n a n d  
i m m u n o ge nicit y ma y be c ollecte d at or n ear t h e e ve nt. 
2 4.  F ut ure researc h s er u m a n d plas ma ( o pti o nal): sa m ples s h o ul d be c ollecte d, as per mitte d b y 
patie nt c o nse nt a n d l oc al re g ulat or y p olicies. T h e y ma y b e st ore d f or u p t o 1 5 years or as 
per mitte d b y l o cal r e g ulat or y p olici es, w hic he v er is s h orter, f or f ut ure bi o me dical researc h.  
2 5.  W h ole bl o o d sa m ples ( o pti o nal) f or D N A e xtracti o n s h o ul d be c ollecte d o n da y  1 
( pre-d os e) b ut ca n be c oll ecte d at a later st u d y visit.   
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9. 1. 1. 2.  
F o ot n ot es f or T a ble 2 Sc he d ule of E ve nts ( O pe n-L a bel Tre at me nt Peri o d f or 
P ati e nts o n I nte nsifie d T her a p y)  
1.  St u d y pr oce d ures: W he n m ulti ple pr oce d ures are p erf or me d o n t he sa me da y, t he s e q ue nce 
of pr oce d ures is as f oll o ws: C O A assess me nts, E C G a n d/ or vital si g ns, bl o o d c ollecti o n, 
st u d y treat me nt a d mi nistrati o n, a n d a n y pre -s pecifie d p ost-d ose sa m ple c oll ecti o n.  
2.  Patie nts s h o ul d be m o nit ore d f or at least 3 0  mi n utes after c o m pleti o n of p ozeli ma b 
3 0  m g/ k g  I V. S u bse q u e nt S C d oses will be a d mi nistere d Q 2 W ( p ozeli ma b) a n d Q 4 W 
(ce m disira n) a n d m a y eit her be perf or me d b y t h e site pers o n nel or a n ot her healt hcare 
pr ofessi o nal at t he patie nt’s h o me, or a d mi nistere d b y t he patie nt or b y a desi g n ate d 
pers o n.  F or patie nts o n i nte nsifie d treat me nt i n t he O L T P, t he fi nal S C d ose of ce m disira n 
is at da y 1 9 7r, wee k  2 8r, a n d t he fi nal S C d ose of p ozeli ma b is at da y  2 1 1r ( wee k  3 0r).   
3.  P ozeli ma b a n d ce m disira n S C a d mi nistrati o n: t he d ose of p ozeli ma b S C s h o ul d be gi ve n 
Q 2 W  (e ver y 1 4 da ys) a n d ce m disira n s h o ul d be gi v e n Q 4 W (e v er y 2 8 da ys) a n d o n t he da y 
of t he c orres p o n di n g st u d y visit w he ne ver p ossi ble a n d as a p plica ble.  St u d y treat me nt 
a d mi nistrati o n s h o ul d al wa ys be t he last pr oce d ure after all bl o o d sa m ple c ollecti o n a n d 
st u d y assess me nts ha ve bee n c o m plete d u nless ot her wise s pecifie d. If a d mi nistrati o n of 
p ozeli ma b or ce m disira n ca n n ot b e a d mi nistere d o n t he da y of t he c orres p o n di n g st u d y 
visit, t he d ose ma y b e a d mi nistere d u p t o 3 da ys bef ore or u p t o 3  da ys after t he  pla n ne d 
d osi n g date as l o n g as t he d osi n g ta kes place after t he c orres p o n di n g st u d y visit has bee n 
c o m plete d. F or e x a m ple, t he da y 2 9r ( wee k 4r) visit ca n ta ke place fr o m d a y 2 6r t o da y 3 2r 
gi ve n t he visit wi n d o w.  T he d ose of p ozeli ma b a n d ce m disira n t heref ore ca n be gi ve n fr o m 
da y 2 6r t o da y 3 2r, b ut o nl y o n or after t he wee k  4r visit assess me nts ha ve bee n 
perf or me d.  Si milarl y, t he da y 1 1 3r ( wee k 1 6r) visit ca n ta ke place fr o m da y 1 0 6r t o da y 
1 1 6r gi ve n t he visit wi n d o w.  T he d ose of p ozeli ma b a n d ce m disira n ca n be gi ve n fr o m d a y 
1 1 0r t o da y 1 1 6r, b ut o nl y o n or after t he wee k 1 6r visit assess me nts ha ve b ee n 
perf or me d.  W he n e ver p ossi ble, t he d ose of ce m disira n s h o ul d be a d mi nistere d o n t he sa me 
da y as t he Q 4 W d ose of p ozeli ma b.  T he fi nal d ose of ce m disira n is at wee k  2 8r a n d t he 
fi nal d ose of p ozeli ma b is at wee k 3 0r.  
4.  I nje cti o n trai ni n g will be pr o vi de d to patie nts w h o desire self -i njecti o n or i njecti o n b y a 
desi g nat e d pers o n. T h e site s h o ul d o bser ve p atie nt self -i njecti o n or i njecti o n b y a 
desi g nat e d pers o n a n d c o nfir m a de q uac y. Patie nt i nstr ucti o n materials will be pr o vi de d.  
5.  If n ee d e d, base d o n patie nt self-a d mi nistrati o n/a d mi nistrati o n b y a desi g n ate d pers o n, t he 
patie nt will c o m plete a diar y f or rec or di n g d ata o n st u d y treat me nt a d mi nistrati o n. If t he 
patie nt diar y is pr o vi de d t o t he patie nt, t he n it s h o ul d be re vie we d at eac h cli nic visit a n d 
data c oll ecte d i nt o t he C R Fs. O n t he fi nal visit, t he diar y s h o ul d be c ollecte d b y t he site.  
6.  Dail y oral a nti bi otic pr o p h yla xis a gai nst N. me ni n giti dis  is rec o m me n de d u ntil 5 2 wee ks 
after disc o nti n uati o n of p ozeli ma b/ce m disira n.  
7.  Patie nts s h o ul d tr y t o c o m plete t he P N H S y m pt o m -S pecific Q uesti o n nair e at t he sa me ti me 
eac h d a y w he n e ver p ossi ble.  
8.  Patie nt safet y car d: t h e site s h o ul d re vi e w t he i nstr ucti o ns o n t he safet y car d wit h t he patie nt 
at eac h visit.   
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9.  Brea kt hr o u g h he m ol ysis assess me nt: if a patie nt is s us pecte d o f ha vi n g a brea kt hr o u g h 
he m ol ysis e v e nt, t he n i n a d diti o n t o t he re q uire d l a b orat or y c ollecti o n, a d diti o nal sa m ples 
f or c oa g ul ati o n para m eters, c he mistr y, he mat ol o g y, retic ul oc yte c o u nt, D-di mer, t otal C 5, 
C H 5 0 , A D A (a gai nst p o zeli ma b), a n d dr u g c o nce ntrat i o ns of p ozeli ma b will be c ollecte d 
u nless alrea d y n ote d i n t he Sc he d ule of E v e nts f or t hat visit. If t he s us pecte d e v e nt d oes 
n ot occ ur at a sc he d ule d visit, t he n a n u nsc he d ule d visit s h o ul d occ ur wit h a n e val uati o n 
of t he patie nt a n d c ollecti o n of c oa g ul ati o n para meters, c h e mistr y, he mat ol o g y, 
retic ul oc yte c o u nt, t otal C 5, C H 5 0 a n d dr u g c o nce ntrati o ns of p ozeli ma b.  
1 0.  D uri n g la b c ollecti o n, ha n dli n g, a n d pr ocessi n g, t he sa me met h o d ol o g y will be a p plie d 
acr oss st u d y visits, as b est as p ossi ble, t o preser ve t he q u alit y of t he sa m ple a n d a v oi d 
he m ol ysis. T he c o a g ulati o n bl o o d sa m ple (t u be) m ust al wa ys be c ollecte d first, f oll o we d 
b y t he bl o o d c h e mistr y s a m ple (t u be).  
1 1.  Ser u m L D H, C R P, a n d bilir u bi n will be assesse d as part of t he bl o o d c h e mistr y a n al ysis.     
1 2.  Pre g n a nc y test f or W O C B P : a uri ne test will be d o ne at all visits i n dicate d.   
1 3.  Bl o o d sa m ple c ollecti o n f or c o nce ntrati o ns of p ozeli ma b, t otal C 5, C H 5 0 (efficac y 
e n d p oi nt), a n d A H 5 0: o btai n sa m ples pri or t o a n y st u d y dr u g a d mi nistrati o n ( pre -d os e). O n 
da y 1, o btai n bl o o d sa m ple f or p ozeli ma b c o nce ntrati o n a n d t otal C 5 pri or t o I V 
a d mi nistrati o n of p ozeli ma b a n d als o wit hi n 1 5  mi n utes after t he e n d of t he I V i nf usi o n.  
1 4.  Bl o o d sa m ples f or c o nce ntrati o ns of ce m disira n a n d its meta b olites will be c ollecte d pri or 
t o a n y st u d y tr eat me nt a d mi nistrati o n ( pre -d ose) a n d at 2 t o 6 h o urs p ost -ce m disira n d osi n g. 
T he p ost -d ose sa m ple s h o ul d be caref ull y c o or di n ate d wit h t he d osi n g of ce m disira n a n d 
ma y b e c ollecte d at t he cli nic or b y a visiti n g healt hcare pr ofessi o nal.  
1 5.  Bl o o d  sa m ples f or i m m u n o ge ni cit y will be c ollecte d bef ore t he a d mi nistrati o n of a n y st u d y 
dr u g ( pre -d ose). At t he visits w here i m m u n o ge nicit y sa m ples are t o be ta ke n, t he sa m ple 
s h o ul d be c ollecte d wit h t he dr u g c o nce ntrati o n s a m ple. I n t he e v e nt of s us pecte d S A Es, 
s uc h as a na p h yla xis or h y perse nsiti vit y, a d diti o nal sa m ples f or dr u g c o nce ntrati o n a n d 
i m m u n o ge nicit y ma y be c ollecte d at or n ear t h e e ve nt. 
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9. 1. 1. 3.  
F o ot n ot es f or T a ble  3 Sc he d ule of E ve nts (f or O pti o n al O pe n -L a bel E xte nsi o n 
Peri o d)  
1.  Visits ma y b e at t he cli ni cal site or a n ot her preferre d l ocati o n, s u c h as t he p atie nt’s h o me. 
T he l ocati o n will de pe n d o n t he a vaila bilit y of a h o me healt hcare visiti n g pr ofessi o nal as 
well as t he prefere nces of t he i n vesti gat or a n d p atie nt. I n t he e ve nt of tr a vel restricti o ns d ue 
t o a gl o bal pa n de mic, alter nati ve mec ha nis ms s uc h as b ut n ot li mite d t o tele me dici ne visits 
ma y b e i m ple me nte d t o mai ntai n c o nti n uit y of st u d y c o n d u ct.  
2.  St u d y pr oce d ures ( visits): w he n m ulti ple pr oce d ures are p erf or me d o n t he sa me d a y, t he 
se q ue nce of pr oced ures is as f oll o ws: C O A assess me nts, E C G a n d/ or vital si g ns, bl o o d 
c ollecti o n, st u d y treat me nt a d mi nistrati o n, a n d a n y pre -s pecifie d p ost-d ose sa m ple 
c ollecti o n .  
3.  Da y  1e of O L E P s h o ul d be sc he d ule d o n t he s a me da y as wee k  3 2 ( or wee k  3 2r f or patie nts 
o n i nte nsifie d treat me nt) of t he O L T P, a n d a n y c o m m o n assess me nts will be perf or me d 
o nce f or b ot h t he O L T P a n d O L E P visits.  
4.  D uri n g t he O L E P, t he d ose of ce m disira n a n d p ozeli ma b S C s h o ul d be gi ve n o n t he da y of 
t he c orres p o n di n g st u d y visit w he ne ver p ossi ble. St u d y tr eat me nt a d mi nistrati o n s h o ul d 
al wa ys be t he last pr oce d ure after all bl o o d sa m ple c ollecti o n a n d st u d y assess me nts ha ve 
bee n c o m plete d u nless ot her wise s p ecifie d.  If p ozeli ma b or ce m disira n ca n n ot be 
a d mi nistere d o n t he da y of t h e c orres p o n di n g st u d y visit, t he c o m bi nati o n ma y b e 
a d mi nistere d u p t o 3 da ys bef ore or u p t o 3 da ys after t he  pla n ne d d osi n g d ate f or patie nts 
i n a n i nte nsifie d treat me nt re gi me n ( p ozeli ma b Q 2 W d osi n g) or u p t o 7 da ys bef ore or 
7  da ys after t he pla n ne d d osi n g date f or patie nts o n a mai nte na nce treat me nt re gi me n 
( p ozeli ma b Q 4 W d osi n g), pr o vi de d t hat t h e d osi n g ta kes place after t he c orres p o n di n g 
st u d y visit has bee n c o m plete d. Care m ust be ta ke n t o c o or di nate d osi n g f or visits w here a 
p ost -d ose sa m ple is c ollecte d t o meas ure c o nce ntr ati o n of ce m disira n a n d its meta b olites.  
5.  F or p atie nts w h o di d n ot receiv e i nte nsifie d tre at m e nt d uri n g O L T P:  at a n y ti me d uri n g t h e 
O L E P, p atie nts w h o me et pre -s p ecifie d criteria will recei ve i nte nsifie d treat me nt c o nsisti n g 
of a p ozeli ma b 3 0  m g/ k g I V l oa di n g d os e f oll o we d 3 0  mi n utes later b y t he i nitiati o n of 
p ozeli ma b 4 0 0  m g S C Q 2 W a n d ce m disira n 2 0 0  m g S C Q 4 W.  Patie nts will c o nti n ue t heir 
visit sc he d ule at t he ne xt O L E P visit.  
6.  St u d y treat me nt a d mi nistrati o n s h o ul d al w a ys b e t he last pr oce d ure after all bl o o d sa m ple 
c ollecti o n a n d st u d y ass ess me nts ha ve bee n c o m plete d u nless ot her wise s pecifie d. F or 
patie nts w h ose treat me nt is n ot i nte nsifie d d uri n g t he O L E P, t he last d oses of ce m disira n 
a n d p ozeli ma b are a d mi nistere d at wee k  5 2 e. F or patie nts w h ose treat me nt was i nte nsifie d 
d uri n g t he O L E P, t he last d oses of st u d y treat me nt will be deter mi ne d b ase d o n t he ti me of 
treat me nt i nte nsificati o n. 
7.  I nje cti o n trai ni n g will be pr o vi de d t o patie nts w h o desire self -i njecti o n or i njecti o n b y a 
desi g nat e d pers o n. T h e site s h o ul d o bser ve p atie nt self -i njecti o n or i njecti o n b y a 
desi g nat e d pers o n a n d c o nfir m a de q uac y. Patie nt i nstr ucti o n materials will be pr o vi de d.  
8.  If st u d y tr eat me nt is gi ve n b y the p atie nt or b y a d esi g n ate d pers o n, t he patie nt will 
c o m plete a diar y f or rec or di n g c o m plia nce wit h st u d y tr eat me nt a d mi nistrati o n. If t h e 
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C O N FI D E N TI A L  
patie nt diar y is pr o vi de d t o t he patie nt, t he n it s h o ul d be re vie we d at eac h cli nic visit a n d 
data c ollecte d i nt o t he C R Fs. O n t he fi nal visit, t he diar y s h o ul d be c ollecte d b y t he site.  
9.  Dail y oral a nti bi otic pr o p h yla xis a gai nst N. me ni n giti dis  is rec o m me n de d u ntil 5 2 wee ks 
after disc o nti n uati o n of st u d y treat me nt.  
1 0.  Patie nt safet y car d: t h e site s h o ul d re vi e w t he i nstr u cti o ns o n t he safet y car d wit h t he patie nt 
at eac h visit.  
1 1.  Brea kt hr o u g h he m ol ysis assess me nt: if a patie nt is s us pecte d of ha vi n g a brea kt hr o u g h 
he m ol ysis e v e nt, t he n i n a d diti o n t o t he re q uire d l a b orat or y c ollecti o n, a d diti o nal sa m ples 
f or c oa g ul ati o n param eters, c he mistr y, he mat ol o g y, retic ul oc yte c o u nt, D -di mer, t otal C 5, 
C H 5 0, A D A (a gai nst p o zeli ma b), a n d dr u g c o nce ntrati o ns of p ozeli ma b will be c ollecte d 
u nless alrea d y n ote d i n t he Sc he d ule of E v e nts f or t hat visit. If t he s us pecte d e v e nt d oes 
n ot occ ur  at a sc he d ule d visit, t he n a n u nsc he d ule d visit s h o ul d occ ur wit h a n e val uati o n 
of t he patie nt a n d c ollecti o n of c oa g ul ati o n para meters, c h e mistr y, he mat ol o g y, 
retic ul oc yte c o u nt, t otal C 5, C H 5 0 a n d dr u g c o nce ntrati o ns of p ozeli ma b. 
1 2.  Cli nical la b sa m ples w ill be c ollecte d pri or t o a n y st u d y dr u g a d mi nistrati o n ( pre-d os e) 
u nless ot her wise s pecifie d. T he c oa g ul ati o n bl o o d sa m ple (t u be) m ust al wa ys be c ollecte d 
first, f oll o we d b y t h e bl o o d c he mistr y s a m ple (t u b e). D uri n g la b c ollecti o n, ha n dli n g, a n d 
pr ocessi n g, t he sa me m et h o d ol o g y will be a p plie d acr oss st u d y visits, as best as p ossi ble, 
t o preser ve t h e q ualit y of t he sa m ple a n d a v oi d he m ol ysis. 
1 3.  Ser u m L D H, C R P, a n d bilir u bi n will be assesse d as part of t he bl o o d c he mistr y a nal ysis. 
T he bl o o d c he mistr y sa m ple s h o ul d be c ollecte d bef ore st u d y tr eat me nt a d mi nistrati o n 
( pre-d os e). If t he i n vesti gat or or s p o ns or s us pects t hat t he la b res ult is n ot a n acc urat e 
reflecti o n of t he patie nt’s c o n diti o n, t he la b sa m ple s h o ul d be re p eate d. 
1 4.  T he he mat ol o g y sa m ple s h o ul d be c ollecte d bef ore st u d y treat me nt a d mi nistrati o n ( pre -
d ose).  
1 5.  Pre g n a nc y t est f or W O C B P: a uri ne t est will be d o ne at all visits i n dicate d. A n y p ositi ve 
uri ne pre g n a nc y test s h o ul d be c o nfir me d wit h a s er u m pre g n a nc y test.  
1 6.  Bl o o d sa m ples f or p ozeli ma b c o nce ntrati o n a n al ysis a n d t otal C 5 a nal ysis will be o btai ne d 
o n t he s pecifie d da ys pri or t o a n y st u d y treat me nt a d mi nistrati o n ( pre -d ose).  If t he patie nt 
recei v es treat me nt i nte nsificati o n d uri n g t he o pe n-la bel e xte nsi o n peri o d, a P K sa m ple 
s h o ul d be o btai ne d pri or t o I V p ozeli ma b a d mi nistrati o n a n d 1 5 mi n utes p ost -d ose.  
1 7.  Bl o o d sa m ples f or ce m disira n c o nce ntr ati o n a nal ysis  a n d c o nce ntrati o ns of its meta b olites 
will be c ollecte d o n t he s pecifie d da ys pri or t o a n y st u d y treat me nt a d mi nistrati o n ( pre -
d ose)  a nd 2 t o 6 h o urs p ost -ce m disira n a d mi nistrati o n.  T he p ost -d ose sa m ple s h o ul d be 
caref ull y c o or di nate d wit h t he d osi n g of ce m disira n a n d ma y b e c ollecte d at t he cli nic or 
b y a visiti n g h ealt hcare pr ofessi o nal.  
1 8.  Bl o o d sa m ples f or i m m u n o ge ni cit y will be c oll ect e d o n t he s pecifie d d a ys pri or t o a n y 
st u d y tr eat me nt a d mi nistrati o n ( pre-d ose). At t h e visits w here i m m u n o ge ni cit y s a m ples are 
t o be ta ke n, t he s a m ple s h o ul d be c ollecte d wit h t he dr u g c o nce ntrati o n sa m ple. I n t he e v e nt 
of s us pect e d treat me nt -relate d S A Es, s u c h as a n a p h yl a xis or h y p erse nsiti vit y, a d diti o nal 
dr u g c o n ce ntrati o n a n d i m m u n o ge nicit y sa m ples ma y be c ollecte d at or n ear t he o nset a n d 
t he res ol uti o n of t he e ve nt. 
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Cli nical St u d y Pr ot oc ol  
 
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C O N FI D E N TI A L  
1 9.  Bl o o d sa m ples f or C H 5 0 (effic ac y e n d p oi nt) a n d A H 5 0 will be o btai ne d pri or t o a n y 
st ud y treat me nt a d mi nistrati o n ( pre -d os e).  
9. 1. 1. 4.  
F o ot n ot es f or T a ble 4 Sc he d ule of E ve nts ( P ost -Tre at me nt S afet y F oll o w -U p 
Peri o d f or All P atie nts)  
1.  Patie nts w h o disc o nti n ue st u d y treat me nt i n eit her t he O L T P or t he i nte nsifie d O L T P will 
be as ke d t o re mai n i n t he st u d y u ntil wee k  3 2  E O T ( or wee k 3 2r E O T) a n d f oll o w t he 
ori gi nal Sc he d ule of E v e nts as a p plica ble. After t he wee k  3 2  or wee k 3 2r E O T visit, t he 
e ntr y p oi nt i nt o t he safet y f oll o w -u p sc h e d ule will de pe n d o n t he n u m ber of wee ks t hat 
ha ve el a pse d si nc e patie nt ’s last d ose (e g, a patie nt w h o is 2 0 wee ks after his/ her fi nal d os e 
of st u d y treat me nt at E O T will e nter i nt o t he safet y f oll o w -u p p eri o d at Visit F U -4 [ 2 6 
wee ks after last d ose]). Patie nts w h o c o m plete d wee k 3 2r i n t he O L T P w h o c h o ose n ot t o 
c o nti n ue tre at me nt i n t he O L E P, patie nts w h o c o m plete t he o pti o nal O L E P b ut d o n ot 
c o nti n ue st u d y treat me nt i n a p ost -trial access pr o gra m, a n d p atie nts w h o per ma n e ntl y 
disc o nti n ue treat me nt d uri n g t he O L E P will e nter i nt o t he safet y f oll o w -u p peri o d at F U -1.  
2.  Patie nt safet y car d: Site s h o ul d re vie w t he i nstr ucti o ns o n t he safet y car d wit h t he patie nt 
at eac h visit. Re place me nt car ds ma y be gi v e n t o t he patie nt as nee de d.  
3.  Dail y oral a nti bi otic pr o p h yla xis a gai nst N . me ni n giti dis  is rec o m me n de d u ntil 5 2 wee ks 
after disc o nti n uati o n of st u d y treat me nt . 
9. 1. 2.  
E arl y Ter mi n ati o n Visit  
D uri n g t he O L T P, patie nts w h o per ma ne ntl y dis c o nti n ue fr o m st u d y treat me nt a n d w h o o pt t o 
wit h dra w fr o m t he st u d y s h o ul d ret ur n f or a n E T visit c o nsisti n g of t he assess me nts as descri be d 
i n t he wee k 3 2 ( E O T) visit i n Ta ble  1  a n d Ta ble  2  (f or patie nts o n i nte nsifie d t hera p y). 
D uri n g t he o pti o nal O L E P, patie nts w h o pre mat urel y disc o nti n ue fr o m st u d y treat me nt w h o als o 
wit h dra w fr o m t he st u d y will be as ke d t o ret ur n t o t he cli ni c o nce f or a n earl y ter mi nati o n visit 
c o nsisti n g of wee k  5 2e assess me nts descri be d i n Ta ble  3 . 
9. 1. 3.  
U nsc he d ule d Visits  
All atte m pts s h o ul d be ma de t o kee p patie nts o n t he st u d y sc h e d ule. U ns c he d ule d visits ma y b e 
necessar y t o re peat testi n g f oll o wi n g a b n or mal/ u ni nter preta bl e la b orat or y res ults, f or f oll o w -u p of 
A Es, t o e val uate e ve nts of brea kt hr o u g h he m ol ysis ( Secti o n  6. 1. 2 ), t o pr o vi de i nte nsifie d treat me nt 
( Secti o n 6. 1. 3 ), or f or a n y ot her reas o n, as warra nte d. I n t he e ve nt of s us pecte d treat me nt-relate d 
S A Es, s uc h as a na p h yla xis or h y pers e nsiti vit y, a d diti o nal dr u g c o nce ntrati o n a n d i m m u n o ge nicit y 
sa m ples ma y b e c ollecte d at or near t he o nset a n d t he res ol uti o n of t he e ve nt.  
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9. 2.  
St u d y Pr oce d ures  
9. 2. 1.  
Pr o ce d u res Perf or me d O nl y at t he Scree ni n g/ B aseli ne Visit  
T he f oll o wi n g pr oce d ures will be perf or me d f or t he s ole p ur p ose of deter mi ni n g st u d y eli gi bilit y 
or c haracterizi n g t he bas eli ne p o p ulati o n:   
•  O btai n i nf or me d c o nse nt (i ncl u di n g o pti o nal s u b -st u dies) 
•  Re vie w  i ncl usi o n/e x cl usi o n criteria 
•  Me dical hist or y: tra nsf usi o ns, brea kt hr o u g h h e m ol ysis hist or y, a n d la b orat or y 
para meters f or meas ure me nt of he m ol ysis (s uc h as L D H, bilir u bi n, ha pt o gl o bi n, 
retic ul oc yte c o u nt, a n d h e m o gl o bi n) s h o ul d be o btai ne d f or t he past 1 year, if p ossi ble. 
Pri or hist or y at a n y ti m e of t hr o m b osis a n d Neisseri a  i nfecti o ns will b e c ollecte d. 
O n g oi n g P N H s y m pt o ms a n d si g ns will als o be c ollecte d.  
•  Rec or d pri or me di cati o ns ( wit hi n 1 2 wee ks pri or t o scree ni n g), a n d  det aile d ec uliz u ma b 
a d mi nistrat i o n hist or y ( past 2 6 wee ks) 
•  Rec or d de m o gra p hics  
•  Meas ure h ei g ht  
•  A d mi nistrati o n of vacci nati o n f or N. me ni n giti dis  or d oc u me ntati o n of me ni n g oc o ccal 
vacci nati o n wit hi n t he past 5 years ( or less t ha n 5 years if re q uire d acc or di n g t o nati o nal 
vacci nati o n g ui deli nes f or vacci nati o n us e wit h c o m ple me nt i n hi bit ors or l ocal 
practice)  
•  Vacci n ati o n a gai nst Stre pt oc occ us p n e u m o ni ae  a n d H ae m o p hil us i nfl ue nz a  t y p e B (if 
nee de d f or eli gi bilit y re q uire me nt). Vacci nati o ns s h o ul d be gi ve n acc or di n g t o t he 
c urre nt n ati o n al/l ocal g ui deli nes a n d ma y be rei m b urse d b y t he s p o ns or.  
•  Titers t o meas ure N. m e ni n giti dis  ( o nl y if re q uire d per l ocal pr actice/re g ulati o ns) 
•  T u berc ul osis hist or y a n d assess me nt: scree ni n g b y t u b erc uli n s ki n t est or T-cell 
i nterfer o n-ga m ma rele as e assa y ma y be perf or me d acc or di n g t o l ocal practice or 
g ui deli nes at t he dis creti o n of t he i n vesti gat or.  
•  Ris k fact or assess me nt f or N. g o n orr he a  is rec o m me n de d, a n d c o u nseli n g is a d vise d 
f or at-ris k patie nts  
•  Pr o vi de patie nt safet y car d f or m e ni n g o c occal i nf ecti o n a n d re vie w i nstr ucti o ns. T his 
car d will be pr o vi d e d t o t he patie nt at baseli ne or a n y ot her visit w he n nee d e d.  
•  Sa m ple t o assess F S H (t o deter mi ne p ost me n o pa us al stat us, if a p plica ble)  
•  Sa m ple f or he patitis B a n d C  
At t he discreti o n of t he i n vesti gat or, a d diti o nal visits d uri n g t he s cree ni n g peri o d ma y be sc h e d ule d 
as nee d e d t o c o m plete s cree ni n g pr oce d ures. Patie nts ma y b e rescree ne d u p t o 2 ti mes after 
disc ussi o n bet wee n t he i n vesti gat or a n d t he s p o ns or.  
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9. 2. 2.  
Effic ac y Pr o ce d ures  
9. 2. 2. 1.  
L a b or at or y Assess me nts of Effi c ac y 
La b orat or y assess me nts of effic ac y will be p erf or me d at sc he d ule d visits a cc or di n g t o Ta ble  1  
( O L T P),Ta ble  2  (f or patie nts o n i nte nsifie d treat m e nt), a n d Ta bl e  3  ( o pti o nal O L E P).   
9. 2. 2. 1. 1.  L act ate D e h y dr o ge n ase  
Sa m ples f or L D H testi n g are c ollect e d as p art of t he bl o o d c he mistr y p a nel ( Secti o n  9. 2. 3. 5 ) a n d 
will be c ollecte d pri or t o st u d y dr u g a d mi nistrati o n at sc he d ule d visits . Le vels of L D H  i n ser u m 
will be a nal yze d b y a ce ntral la b orat or y.  
Care m ust be ta ke n wit h t he c ollecti o n of L D H as it is t he pri mar y e n d p oi nt i n t he st u d y. D uri n g 
bl o o d c ollecti o n, ha n dli n g, a n d pr ocessi n g, t he sa me met h o d ol o g y will be a p plie d acr oss st u d y 
visits, as best as p ossi ble. E ver y prec a uti o n m ust be t a ke n t o a v oi d he m ol ysis.  Detaile d 
i nstr ucti o ns f or c ollecti n g sa m ples f or L D H are pr o vi de d i n t he st u d y-rel ate d d oc u me nts pr o vi de d 
t o t he st u d y site a n d s h o ul d be revie we d pri or t o eac h c ollecti o n.  
9. 2. 2. 1. 2.  He m o gl o bi n  
Sa m ples f or he m o gl o bi n testi n g are c ollecte d as part of t he he mat ol o g y pa n el ( Secti o n  9. 2. 3. 5 ) a n d 
will be  c ollecte d pri or t o st u d y dr u g a d mi nistrati o n  at sc he d ule d visits.  
9. 2. 2. 1. 3.  T ot al C o m ple me nt He m ol yti c Acti vit y  
Sa m ples f or C H 5 0 testi n g will be c ollecte d pri or t o st u d y dr u g a d mi nistrati o n  at sc he d ule d visits.  
9. 2. 2. 2.  
Cli nic al O utc o me Ass ess me nts  
T he f oll o wi n g cli nical o utc o me assess me nts are self -re p ort e d a n d will be c o m plete d b y t he patie nt 
at ti me p oi nts acc or di n g t o Ta ble  1  a n d  Ta ble  2  (f or patie nts o n i nte nsifie d treat me nt) a n d Ta ble  3  
( o pti o nal O L E P). 
9. 2. 2. 2. 1.  F u ncti o n al Assess me nt of C hr o nic Ill ness T her a p y -F ati g ue  
T he F A CI T -Fati g u e is a 1 3 -ite m, self-a d mi nistere d C O A meas ure assessi n g a n i n di vi d ual’s le vel 
of fati g ue d uri n g t h eir us ual dail y acti vities o ver t he past wee k. T his q uesti o n naire is part of t he 
F A CI T  me as ure me nt s yste m, a c o m pilati o n of q uesti o ns meas uri n g H R Q o L i n p atie nts wit h 
ca ncer a n d ot her c hr o nic ill nesses. T he F A CI T -Fati g ue assesses t he le vel of fati g ue usi n g a 5 -p oi nt 
Li kert scale ra n gi n g fr o m 0 ( n ot at all) t o 4  ( ver y m uc h). Sc ores ra n ge fr o m 0 t o 5 2, wit h hi g h er 
sc ores i n dicati n g a hi g h er q ualit y of life . Alt h o u g h t he F A CI T -Fati g ue was ori gi n all y de v el o pe d 
t o assess fati g ue i n patie nts wit h ca ncer, it has bee n use d i n trials e val uati n g t he efficac y of 
ec uliz u ma b (Br o ds k y, 2 0 0 8 ) (Hill me n, 2 0 0 6 ). T he F A CI T-Fati g ue has de m o nstrate d c o nte nt 
vali dit y a m o n g patie nts wit h P N H (Weitz, 2 0 1 3 ). 
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9. 2. 2. 2. 2.  E ur o pe a n Or g a niz ati o n f or t he Rese arc h a n d Tre at me nt of C a ncer: Q u alit y of 
Lif e of C a ncer P atie nts Q uesti o n n aire -3 0  
T he E O R T C -Q L Q -C 3 0  is a 3 0-ite m, self-a d mi nistere d, ge neri c q uesti o n naire c o m m o nl y use d t o 
assess 
H R Q o L 
i n 
patie nts 
wit h 
ca n cer 
(Stea d, 
1 9 9 9 ) 
(C oc ks, 
2 0 0 7 ). 
T he 
E O R T C -Q L Q -C 3 0  assesses H R Q o L acr oss m ulti ple d o mai ns, i ncl u di n g gl o b al healt h stat us, 
gl o bal q u alit y of life, f u ncti o ni n g ( p h ysi cal, r ole, e m oti o nal, c o g niti ve, a n d s ocial f u ncti o ni n g), 
s y m pt o m scal es (fati g u e, na usea a n d v o miti n g, p ai n, a p petite l oss), a n d si n gle ite ms ( d ys p nea, 
i ns o m nia, c o nsti pati o n, diarr hea, slee p, fi na nci al i m pact). Alt h o u g h t he E O R T C -Q L Q -3 0 w as 
ori gi nall y de v el o pe d t o assess H R Q o L  i n patie nts wit h ca ncer, it has b ee n use d i n trials e val u ati n g 
t he effi cac y of ec uliz u ma b (Br o ds k y, 2 0 0 8 ) (Hill me n, 2 0 0 6 ). T he E O R T C-Q L Q -C 3 0 als o has 
de m o nstrate d c o nte nt v ali dit y a m o n g patie nts wit h P N H (Weitz, 2 0 1 3 ). 
9. 2. 2. 2. 3.  Tre at me nt S atisf acti o n Q uesti o n n aire f or Me dic ati o n  
T he  T S Q M is a ge neric meas ure t hat ass esses patie nts’ satisfacti o n wit h t heir me dicati o n 
(At ki ns o n, 2 0 0 4 ) (At ki ns o n, 2 0 0 5 ). T he T S Q M is a 9-q uesti o n, self -a d mi nistere d C O A meas ure 
w hic h assesses 3  d o mai ns of satisfacti o n: effecti ve ness  ( 3 ite ms), c o n ve nie nce ( 3 ite ms), a n d 
gl o bal satisf acti o n ( 3  ite ms). F or eac h q u esti o n, t he patie nt rates his/ her satisfacti o n eit her o n a 
7 -p oi nt Li k ert scale (ra n gi n g fr o m e xtre mel y dissatisfie d t o e xtre mel y s atisfie d) or a 5 -p oi nt Li kert 
scale (ra n gi n g fr o m e xtre mel y dissatisfie d t o n ot dissatisfie d at all), wit h hi g her sc ores re prese nti n g 
greater satisf acti o n. T he i nstr u me nt was de v el o pe d usi n g patie nt i n p ut a n d h as e vi de nce of 
ps yc h o m etric vali dit y.  
9. 2. 2. 2. 4.  P N H S y m pt o m -S pecific Q uesti o n n aire  
T he P N H s y m pt o m -specific q uesti o n naire is self -a d mi nistere d a n d will c ollect dail y i nf or m ati o n 
o n P N H s y m pt o ms i ncl u di n g: fati g ue, s h ort ness of breat h, m uscle wea k ness, hea dac h e, a b d o mi nal 
pai n, pai n i n bac k/le gs, c hest disc o mf ort, diffic ult y slee pi n g, diffic ult y t hi n ki n g cl earl y, a n d 
diffic ult y s wall o wi n g. T h e i nstr u me nt was de vel o p e d b y c o n d u cti n g a literat ure re vie w, c o ns ulti n g 
wit h cli nical e x pert i n p ut, a n d t hr o u g h p atie nt i nter vie ws assessi n g c o m pre he nsi ve ness of 
s y m pt o ms c ollecte d a n d t he patie nt’s a bilit y t o rea d, un dersta n d, a n d res p o n d t o t he q uesti o n naire. 
T he q uesti o n nair e was de vel o pe d i n acc or da n ce wit h re g ul at or y g ui deli nes (F D A, 2 0 0 9 ) an d 
scie ntific best practices (Patric k, 2 0 1 1 ). 
Patie nts s h o ul d tr y t o c o m plete t he  q uesti o n naire at t he sa me ti me eac h da y w he ne ver p ossi ble.  
9. 2. 2. 2. 5.  P ati e nt Gl o b al I m pressi o n of Se verit y/ P atie nt Gl o b al I m pressi o n of C h a n ge  
T he P GI S c o nsists of 3 s elf -a d mi nistere d C O A q u esti o ns assessi n g t he pati e nt’s perce pti o n of t he 
o verall se verit y of t he s y m pt o ms of his/ her disease a n d/ or of a s pecific s y m pt o m of his/ her disease. 
At st u d y visits, patie nts will be as ke d t o rate t he se verit y of t h eir P N H s y m pt o ms o n a 6 -p oi nt 
Li kert scale ra n gi n g fr o m “I a m n ot e x perie nci n g P N H s y m pt o ms” t o “ v er y se vere;” t h e i m pact 
t heir P N H s y m pt o ms ha v e o n t heir a bilit y t o p erf or m us ual dail y acti vities o n a 5-p oi nt Li kert scale 
ra n gi n g fr o m “ n ot at all i m pacte d” t o “e xtre mel y i m pacte d;” a n d t heir o verall fati g ue o n a 5-p oi nt 
Li kert scale ra n gi n g fr o m “ n ot fati g u e d” t o “e x tre mel y fati g u e d.” 
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T he P GI C c o nsists of 3 s elf -a d mi nistere d C O A q u esti o ns assessi n g t he p atie nt’s perce pti o n of t h e 
c ha n ge i n o verall se v erit y of t he s y m pt o ms of t heir disease a n d/ or of a s pecific s y m pt o m of t heir 
disease c o m pare d t o t he start of t he st u d y . At ke y ti me p oi nts d uri n g t he st u d y, patie nts will be 
as ke d t o rate t he c ha n ge i n P N H s y m pt o ms, i n t heir a bilit y t o perf or m us ual dail y acti vities, a n d i n 
o verall fati g ue c o m pare d t o bef ore t he start of t he st u d y o n a 7 -p oi nt Li k ert scale ra n gi n g fr o m 
“ muc h better” t o “ n o c h a n ge” t o “ m uc h w orse.”  
T he P GI S a n d P GI C q uesti o ns are de vel o pe d f or t his trial a n d all o w f or t he i nter pretati o n of 
C O A  fi n di n gs a n d t he i n vesti gati o n of a res p o n der defi niti o n. T he a ns wers o n t he P GI S a n d 
P GI C  ite ms ser ve as “a nc h ors ” t o hel p i nter pret t he 
mea n c h a n ge i n disease-s p ecific 
C O A  meas ures o ver ti me a n d t o esti mate res p o n der defi niti o ns. T his e m pirical a nc h or -b ase d 
a p pr oac h is t he pri mar y F D A -rec o m me n d e d a p pr oac h f or defi ni n g a res p o n der a n d a n al yzi n g 
res p o n der-base d C O A  results.  
9. 2. 3.  
S afet y Pr oce d ures  
T he f oll o wi n g s afet y pr oce d ures  will be meas ure d at visits a n d ti me p oi nts acc or di n g Ta ble  1 , 
Ta ble  2  (f or p atie nts o n i nte nsifie d treat me nt), Ta ble  3  ( o pti o nal O L E P), a n d T a ble  4  (safet y 
f oll o w-u p peri o d).    
9. 2. 3. 1.  
B o d y -Wei g ht  
B o d y w ei g ht will be rec or de d at sc he d ul e d visits. B o d y wei g ht s h o ul d be o btai ne d wit h t he patie nt 
weari n g u n der gar me nts or ver y li g ht cl ot hi n g a n d n o s h oes. If p ossi ble, t he sa me t y p e/ m o del of 
scale s h o ul d be use d t hr o u g h o ut t he st u d y. 
9. 2. 3. 2.  
Vit al Si g ns  
Vital si g ns ( te m p erat ur e, sitti n g bl o o d press ure, a n d p ulse) will be c ollecte d pre d ose at sc he d ul e d 
visits.  
Vital si g ns will be o btai ne d after t h e patie nt has bee n sitti n g q uietl y f or at least a p pr o xi matel y 
5  mi n utes.  
9. 2. 3. 3.  
P h ysic al E x a mi n ati o n  
A p h ysic al e x a mi nati o n will be perf or me d at sc h e d ule d visits. Eac h p h ysical e x a mi nati o n will 
i ncl u de a n e v al uati o n of t he hea d a n d n ec k, l u n gs, heart, a b d o me n, e xtre mities, a n d s ki n. Care 
s h o ul d be ta ke n t o e x a mi ne a n d assess a n y a b n or malities t hat ma y be pres e nt, as i n dicate d b y t he 
patie nt’s me dical hist or y.  
9. 2. 3. 4.  
Electr oc a r di o gr a m  
A sta n dar d 1 2 -le a d E C G will be perf or me d l ocall y at sc h e d ule d visits. Electr ocar di o gra ms s h o ul d 
be perf or me d bef ore bl o o d is dra w n d uri n g visits re q uiri n g bl o o d dr a ws.   
T wel ve -le a d E C Gs will be s yste m aticall y rec or de d after t he p atie nt has been i n t he se mi -rec u m be nt 
p ositi o n f or at least 1 0 mi n utes.  
T he E C G will be i nter prete d l ocall y b y t he i n vesti gat or. A n y n e w a n d/ or cli nicall y si g nifica nt 
c ha n ges i n E C G para met ers s h o ul d be i m me diatel y rec hec ke d f or c o nfir mati o n bef ore ma ki n g a n y 
decisi o n f or t he c o n cer ne d patie nt.  
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Heart rate will be rec or de d fr o m t he ve ntric ular rat e, a n d t he P R, Q R S, Q T i nter vals, a n d Q T c F 
will be rec or de d. T he E C G stri ps or re p orts will b e retai ne d wit h t he s o urce.  
9. 2. 3. 5.  
L a b or at or y Testi n g ( S af et y a n d Ot her)  
Sa m ples f or la b o rat or y testi n g will be c ollecte d at sc he d ule d visits. T he c oa g ulati o n bl o o d sa m ple 
m ust al wa ys b e c ollect e d first, f oll o we d b y t he bl o o d c he mistr y s a m ple.   
D uri n g bl o o d c ollecti o n, ha n dli n g, a n d pr ocessi n g, t he sa me met h o d ol o g y will be a p plie d acr oss 
st u dy visits, as best as p ossi ble, t o preser ve t h e q ualit y of t h e sa m ple a n d a v oi d he m ol ysis 
( Secti o n 9. 2. 2. 1. 1 ). Detaile d i nstr ucti o ns f or bl o o d sa m ple collecti o n, i ncl u di n g t he se q ue nce i n 
w hic h bl o o d dra ws m ust be perf or me d, are i n t he l a b orat or y ma n ual pr o vi d e d t o st u d y sites.  
U nsc he d ule d visits ma y be sc h e d ule d t o c ollect bl o o d sa m ples as p art of safet y m o nit ori n g 
( Secti o n 9. 1. 3 ). 
He mat ol o g y, c he mistr y, a n d uri nal ysis sa m ples are pla n ne d t o be a nal yz e d b y a ce ntr al la b orat or y 
w he ne ver p ossi ble. A l ocal la b orat or y m a y be acce pta ble i n s pecial circ u mst a nces (e g,  f or 
eli gi bilit y) after disc ussi o n a n d a gree me nt fr o m t h e s p o ns or. Pre g na nc y testi n g ma y be perf or me d 
at a ce ntr al or a l oc al la b orat or y.  
Ot her testi n g (e g, t otal C 5, C H 5 0, A H 5 0) will be d o ne b y a s pecialize d la b orat or y as o utli ne d i n 
st u d y-relate d d oc u m e nts pr o vi de d t o t he site.  
Bl o o d C he mistry  
S o di u m  
T otal pr otei n, ser u m  
T otal bilir u bi n *  
P otassi u m  
Creati ni ne * *  
Uric aci d  
C hl ori de  
Bl o o d urea nitr o ge n ( B U N)/ bl o o d urea  
C -reacti ve pr otei n ( C R P) 
Car b o n di o xi de/ bicar b o nate  
As partate a mi n otra nsferase ( A S T)  
 
Calci u m  
Ala ni ne a mi n otra nsferase ( A L T)  
 
Gl uc ose  
Al kali ne p h os p hatase  
 
Al b u mi n  
Lactate de h y dr o ge nase ( L D H)  
 
*  O btai n t otal, direct,  a n d i n direct bilir u bi n  
* *   I n a d diti o n, t he esti mate d gl o mer ular filtrati o n rate will be calc ulate d  wit h t he C K D -E PI e q uati o n 
(Le ve y,  2 0 0 9 ) 
He m at ol o gy  
He m o gl o bi n  
Differe ntial:  
He mat ocrit  
 
Ne utr o p hils  
Re d bl o o d cells ( R B C)  
 
L y m p h oc ytes  
W hite bl o o d cells ( W B C)  
 
M o n oc ytes  
Re d cell i n dices  
 
Bas o p hils  
Platelet c o u nt  
 
E osi n o p hils  
Retic ul oc ytes  
 
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Uri n alysis *  
p H  
Pr otei n  
Ur o bili n o ge n  
S pecific gra vit y  
Gl uc ose  
Bl o o d  
Ket o nes  
Bilir u bi n  
Le u k oc yte esterase   
 
 
Nitrite  
*  N ote : If macr osc o p y ( uri ne di pstic k) is a b n or mal, uri ne micr osc o p y will be perf or me d. A uri ne c ult ure s h o ul d 
be perf or me d  if t here is a cli ni cal s us pici o n of i nfecti o n, per t he I n vesti gat or j u d g me nt.  
Ot her L a b or at ory Tests  
Ot her la b orat or y tests i ncl u de:  
•  C oa g ulati o n pa n el: pr ot hr o m bi n ti me a n d acti vate d partial t hr o m b o plasti n ti me (a P T T)  
•  He patitis B a n d C testi n g  
•  Pre g n a nc y testi n g ( W O C B P o nl y): ser u m h u ma n c h ori o nic g o na d otr o p hi n pre g na nc y 
testi n g at scree ni n g, a n d uri ne pre g na n c y testi n g at all s u bse q ue nt sc he d ule d visits. 
P ost me n o pa usal w o me n m ust be a me n orr heic f or at least 1 2  m o nt hs i n or der n ot t o be 
c o nsi dere d of c hi l d beari n g p ote ntial. Pre g n a nc y testi n g a n d c o ntr ace pti o n are n ot 
re q uire d f or w o me n wit h d oc u me nte d h ysterect o m y or t u bal li gati o n. 
•  U nsc he d ule d bl o o d c ollecti o n f or dr u g h y perse nsiti vit y e ve nts i ncl u di n g s us pici o n of 
a n A E p ote ntiall y d u e t o lar ge D T D  i m m u ne c o m pl e x es. At mi ni m u m t o i ncl u de: C B C, 
E S R, C R P, c he mistr y, C 3, C 4, a n d uri nal ysis (i ncl u di n g micr osc o pic e val u ati o n).  
•  U nsc he d ule d bl o o d c oll ecti o n f or s us pect e d brea kt hr o u g h he m ol ysis e v e nts s h o ul d 
i ncl u de, at a mi ni m u m, C B C, retic ul oc yte c o u nt, c he mistr y, c oa g ulati o n para meters, 
D -di mer, t otal C 5, C H 5 0, A D A (a gai nst p ozeli ma b), a n d dr u g c o nce ntrati o ns of 
p ozeli ma b a n d ec uliz u ma b, as a p plica ble .   
•  Titers t o meas ure N. m e ni n giti dis  ( o nl y if re q uire d per l ocal pr actice/re g ulati o ns) 
•  Dr u g c o nce ntrat i o n meas ure me nts ( Secti o n 9. 2. 4 )  
•  I m m u n o ge nicit y me as ure me nts ( Secti o n 9. 2. 5 ) 
•  P har mac o d y na mic a n d e x pl orat or y bi o mar kers ( Secti o n  9. 2. 6 ) 
•  O pti o nal: p har mac o ge n o mic a n d f ut ure bi o m ar ker researc h ( Secti o n  9. 2. 7  a n d 
Secti o n  9. 2. 8 ) 
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A b n or m al L a b or at ory V al ues a n d L a b or at ory A dverse Eve nts  
All la b orat or y val ues m ust be re vie we d b y t he i n v esti gat or or a ut h orize d desi g nee.  
Si g nifica ntl y a b n or mal t est res ults or u ni nter pret a ble sa m ples t hat occ ur after start of tr eat me nt 
s h o ul d be re peate d t o c o nfir m t he nat ure a n d de gree of t he a b n or m alit y. 
W he n necessar y, 
a p pr o priate a n cillar y i n vesti gati o ns s h o ul d be i nitiate d. If t he a b n or malit y fails t o res ol ve or ca n n ot 
be e x plai ne d b y e ve nts or c o n diti o ns u nrelate d t o t he st u d y me dicati o n or its a d mi nistrati o n, t he 
me dical/st u d y dir ect or m ust be c o ns ulte d.    
T he cli nical si g nifi ca nce of a n a b n or mal test val ue, wit hi n t he c o nte xt of t h e diseas e u n der st u d y, 
m ust be deter mi ne d b y t h e i n vesti gat or.  
Criteria f or re p orti n g la b o rat or y val ues as a n A E are pr o vi d e d i n Secti o n 1 0. 1. 1 . 
9. 2. 3. 6.  
Bl o o d Tr a nsf usi o n  
Tra nsf usi o ns wit h R B Cs d uri n g t he st u d y s h o ul d pr ocee d acc or di n g t o t he pre defi ne d criteria i n 
Secti o n  6. 1. 4 . A n y bl o o d tra nsf usi o n will be ca pt ure d i n t he tra nsf usi o n rec or d C R F.  
9. 2. 3. 7.  
A d verse E ve nts  
At e ver y visit, A Es will be c o llecte d a n d assess e d as descri be d i n Secti o n 1 0 .  
9. 2. 4.  
Dr u g C o nce ntr ati o n a n d Me as ure me nts  
Detaile d i nstr ucti o ns f or bl o o d sa m ple c ollecti o n are i ncl u de d i n t he la b orat or y ma n ual pr o vi de d 
t o t he st u d y site. T he e x act sa m pli n g ti me m ust be rec or de d, as all o we d per l ocal re g ulati o n.  
A n y u n use d s a m ples m a y be use d f or f ut ure e x pl orat or y researc h if t h e patie nt h as pr o vi de d 
c o nse nt f or o pti o nal r esearc h, a n d as  all o we d p er l ocal re g ulati o n .  
9. 2. 4. 1.  
C o nce ntr ati o ns of T ot al P ozeli m a b, Ec uliz u m a b, a n d T ot al C 5  
Sa m ples t o meas ure t he c o nce ntrati o n of t otal p ozeli ma b, ec uliz u ma b, a n d t otal C 5 will be 
c ollecte d at ti me p oi nts s pecifie d i n Ta ble  1  ( O L T P), Ta bl e  2  (f or p atie nts o n i nte nsifie d 
treat me nt), a n d T a ble  3  ( o pti o nal O L E P).  
O n da y 2 9, o btai n bl o o d sa m ples pri or t o I V a d mi nistrati o n of p ozeli ma b a n d wit hi n 1 5  mi n utes 
after t he e n d of t he I V i nf usi o n. At ot her visits, o btai n bl o o d sa m ples pri or t o a n y S C st u d y dr u g 
a d mi nistrati o n.  
9. 2. 4. 2.  
C o nce ntr ati o ns of Ce m disir a n a n d Ce m disir a n Met a b olites  
Sa m ples t o meas ure t he c o nce ntrati o n of ce m disira n a n d ce m disira n meta b olites will be c ollecte d 
at ti me p oi nts s pecifie d i n Ta ble  1  ( O L T P), Ta bl e  2  (f or patie nts o n i nte nsifie d treat me nt), a n d 
Ta ble  3  ( o pti o nal O LE P ). At eac h ti me p oi nt, bl o o d sa m ples will be c ollecte d pri or t o a n y S C  st u d y 
dr u g a d mi nistrati o n a n d 2 t o 6  h o urs after st u d y dr u g a d mi nistrati o n.  
9. 2. 5.  
I m m u n o ge nicit y Me as ure me nts a n d S a m ples 
Bl o o d sa m ples f or i m m u n o ge ni cit y ass ess me nt will be c ollecte d f or p ozeli ma b a n d f or ce m disira n 
pri or t o a n y st u d y dr u g a d mi nistrati o n at ti me p oi nts liste d i n Ta ble  1  ( O L T P), Ta ble  2  (f or patie nts 
o n i nte nsifie d treat me nt), a n d Ta ble  3  ( o pti o nal O L E P).  
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9. 2. 6.  
P h ar m a c o d y n a mi c a n d E x pl or at or y Bi o m ar ker Pr o ce d ures  
Sa m ples f or bi o mar kers will be c ollecte d  at ti me p oi nts s pecifie d i n T a ble  1  ( O L T P), T a ble  2  (f or 
patie nts o n i nte nsifie d treat me nt), a n d Ta bl e  3  ( o pti o nal O L E P). B i o mar ker varia bles are d escri be d 
i n Secti o n 5. 6  a n d i ncl u de:   
•  C H 5 0 (ser u m) is t he pri nci pal  P D mar ker f or t he st u d y a n d is als o a n efficac y meas ure 
i n t his st u d y. 
•  Para m eters of i ntra v asc ular he m ol ysis: ie, ha pt o gl o bi n, retic ul oc yte c o u nt, a n d 
bilir u bi n  
•  Free he m o gl o bi n  
•  A H 5 0 (ser u m)  
•  C o m ple me nt acti vati o n mar kers: ie, s C 5 b -9  
•  P N H cl o ne size: ie, P N H er yt hr oc ytes a n d gra n ul o c yt es  
Bi o mar ker meas ure me nts will be perf or me d i n t he s pecifi e d matrices t o deter mi ne effects of 
p ozeli ma b a n d ce m disira n o n rele va nt p h ysi ol o gical a n d pat h o ge nic pr ocesses. T he list ma y be 
altere d or e x pa n de d, as it is rec o g niz e d t hat m ore rele va nt or n o vel bi o mar k ers ma y be disc o v ere d 
d uri n g t he pr ocess of t his st u d y. T h e bi o mar kers st u die d will be o nes belie ve d t o be rele va nt t o t he 
pat h o p h ysi ol o g y of P N H, tar get e n ga ge me nt, p ozeli ma b a n d ce m disira n mec ha nis m of acti o n, a n d 
p ossi ble t o xicities.  A n y u n use d or left o ver s a m ples, c ollecte d f or a n y p ur p ose fr o m t his st u d y, 
ma y b e use d f or e x pl orat or y researc h.  
Bi o mar ker res ults will be re p orte d se p aratel y fr o m t he cli nical st u d y re p ort ( C S R), u nless 
bi o mar ker meas ure me nts are i ncl u de d i n pri mar y or sec o n dar y o bject i ves. 
9. 2. 7.  
F ut ure Bi o me dic al Rese arc h ( O pti o n al)  
Patie nts w h o a gree t o p artici pate i n t he f ut ure bi o me dical researc h ( F B R) s u b -st u d y will be 
re q uire d t o c o nse nt t o t his o pti o nal s u b-st u d y b ef ore sa m ples are ba n ke d f or F B R. A d diti o nal 
sa m ples will be c ollect e d for F B R. Resi d ual bi o mar ker sa m ples f or st u d y-relate d res earc h, as well 
as u n use d dr u g c o nce ntr ati o n a n d i m m u n o ge nicit y sa m ples, will be st ore d f or u p t o 1 5  years after 
t he fi nal date of t h e data base l oc k ( or f or a s h orter ti me peri o d if re q uire d per re gi o n al la ws a n d 
re g ulati o ns). T he sa m ples ma y b e utilize d f or F B R t hat ma y or ma y n ot be directl y relate d t o t he 
st u d y, i ncl u di n g bei n g us e d as refere n ce sa m ples a n d assa y de v el o p me nt or vali dati o n. T he res ults 
of t hese F B R a n al ys es will n ot  be prese nte d i n t he C S R.  
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9. 2. 8.  
P h ar m a c o ge n o mic A n al ysis ( O pti o n al)  
Patie nts w h o a gree t o partici pate i n t he ge n o mics s u b -st u d y will be re q uir e d t o c o nse nt t o t his 
o pti o nal s u b -st u d y bef ore c ollecti o n of t he sa m ples. W h ole bl o o d sa m ples f or D N A e xtracti o n 
s h o ul d be c ollecte d o n da y 1/ bas eli ne ( pre d os e), b ut ca n be c ollecte d at a later st u d y visit. W h ole 
bl o o d sa m ples f or R N A e xtracti o n will be c ollect e d at ti me p oi nts acc or di n g t o  Ta ble  1  ( O L T P) 
a n d Ta ble  3  ( o pti o nal O L E P). D N A a n d R N A s a m ples will be c ollecte d f or p har mac o ge n o mics 
a nal ys es t o u n dersta n d t he ge n etic deter mi na nts of efficac y a n d safet y ass ociate d wit h t he 
treat me nts i n t his st u d y a n d t he m olec ular basis of P N H a n d relate d diseases. T hese s a m ples will 
be si n gle -c o de d as defi n e d 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 ne E 1 5. 
Sa m p les will be st or e d f or u p t o 1 5 years after t he fi nal date of t he d ata base l oc k ( or f or a s h orter 
ti me peri o d if re q uire d per re gi o nal la ws a n d re g ulati o ns). If t here are s pecific site or c o u ntr y 
re q uire me nts i n v ol vi n g t he p har mac o ge n o mic a n al yses, w hic h the s p o ns or is u na ble t o c o m pl y 
wit h, sa m ples will n ot be c ollecte d at t h ose sites.   
T he p ur p ose of t he p har mac o ge n o mic a nal yses is t o i de ntif y ge n o mic ass o ciati o ns wit h cli nical or 
bi o mar ker res p o nse t o p ozeli ma b a n d/ or ce m disira n, ot her P N H cli nical o utc o me meas ures, a n d 
p ossi ble A Es.  I n a d diti o n, ass ociati o ns bet wee n ge n o mic varia nts a n d pr o g n osis or pr o gressi o n of 
P N H, as well as relate d c o m ple me nt -me diate d  diseases, ma y als o be st u die d.  T hese data ma y b e 
use d or c o m bi ne d wit h d ata c ollecte d fr o m ot her st u dies t o i de ntif y a n d v ali date ge n o mic mar kers 
relate d t o t he st u d y dr u g, tar get pat h wa y, or P N H a n d relate d dise ases.   
A nal ys es ma y i ncl u d e s e q ue nce deter mi nati o n or si n gle n ucle oti de p ol y m or p his m st u dies of 
ca n di date ge n es a n d s urr o u n di n g ge n o mic re gi o ns. Ot her met h o ds, i ncl u di n g w h ole -e x o me 
se q ue nci n g, 
w h ole-ge n o me se q ue nci n g, 
D N A c o p y n u m ber vari ati o n, a n d tra nscri pt o me 
se q ue nci n g ( or ot her met h o ds f or q ua ntitati n g R N A e x pressi o n) ma y als o be perf or me d.  T h e list 
of met h o ds ma y be e x pa n de d t o i ncl u de n o vel m et h o d ol o g y t h at ma y b e de vel o pe d d uri n g t he 
c o urse of t his st u d y or s a m ple st ora ge p eri o d. R es ults fr o m t he ge n o mic a nal yses will n ot be 
re p orte d i n t he C S R. 
1 0.  
S A F E T Y E V A L U A TI O N A N D R E P O R TI N G  
1 0. 1.  
Rec or di n g a n d Re p orti n g A d verse E ve nts  
1 0. 1. 1.  
Ge ner al G ui deli nes  
T he i n vesti gat or ( or d esi g nee) m ust pr o m ptl y rec or d all a d verse e v e nts occ urri n g d uri n g t he st u d y 
data c ollecti o n , fr o m t he ti me of si g ni n g t he I C F t o t he e n d of t h e st u d y. M edical c o n diti o ns t hat 
e xiste d or were dia g n ose d pri or t o t he si g ni n g of t he I nf or m e d C o nse nt will be rec or de d as part of 
me dical hist or y. A b n or mal la b orat or y val ues a n d vital si g ns o bser ve d at t he ti me of I nf or me d 
C o nse nt s h o ul d als o be rec or de d as me dical hist or y. A n y s u bse q ue nt w ors e ni n g (ie, a n y cli nicall y 
si g nifica nt c h a n ge i n fre q ue nc y a n d/ or i nte nsit y) of a pre -e xisti n g c o n diti o n t hat is te m p orall y 
ass ociate d wit h t he use of t he st u d y dr u g s h o ul d als o be rec or de d as a n A E.  
At eac h visit, t he i n v esti gat or will deter mi ne w het her a n y A Es ha v e occ urre d b y e v al uati n g t he 
patie nt. A d vers e e ve nts ma y be directl y o bs er ve d, re p ort e d s p o nta n e o usl y b y t he patie nt, or b y 
q uesti o ni n g t he patie nt at eac h st u d y visit. Patie nts s h o ul d be q uesti o ne d i n a ge neral wa y, wit h o ut 
as ki n g a b o ut t he occ urre nce of a n y s pecific s y m pt o ms. T he i n vesti gat or m ust  assess all A Es t o 
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deter mi ne seri o us ness, se verit y, a n d ca usalit y, i n acc or da n ce wit h t he defi niti o ns i n Secti o n  1 0. 2 . 
T he i n vesti gat or’s assess me nt m ust be clearl y d o c u me nte d i n t he site’s s o urce d oc u me ntati o n wit h 
t he i n vesti gat or’s si g nat ure. T he i n vesti gat or s h o ul d f oll o w u p o n S A Es (a n d A E SIs) u ntil t he y 
ha ve res ol ve d or are c o nsi dere d cli nic all y st a ble; A Es s h o ul d be f oll o w e d u ntil t he y are res ol ve d 
or u ntil last st u d y visit, w hic he ver c o mes first.  
Al wa ys re p ort t he dia g n osis as t he A E or S A E ter m. W he n a dia g n osis is u na vaila ble, re p ort t he 
pri mar y si g n or s y m pt o m as t he A E or S A E ter m wit h a d diti o nal details i ncl u de d i n t he narrati ve 
u ntil t he dia g n osis bec o mes a vaila ble. If t he si g ns a n d s y m pt o ms are disti nct a n d d o n ot s u g gest a 
c o m m o n dia g n osis, re p ort t he m as i n di vi d ual e ntries of A E or S A E.   
La b orat or y res ults, vital si g ns, a n d ot her dia g n ostic res ults or fi n di n gs s h o ul d be a p praise d b y t h e 
i n vesti gat or t o deter mi ne t heir cli nical si g nifica nce. Is olate d a b n or mal la b orat or y res ults, vital si g n 
fi n di n gs, or ot her dia g n ostic fi n di n gs (ie, n ot part of a re p orte d dia g n osis) s h o ul d be re p ort e d as 
A Es if t he y are s y m pt o m atic, lea d t o st u d y dr u g di sc o nti n uati o n, re q uire c orrecti ve tr eat me nt, or 
c o nstit ute a n A E i n t he i n vesti gat or’s cli nical j u d g me nt.  
F or e v e nts t hat are seri o us d ue t o res ulti n g i n h os pitalizati o n, t he reas o n f or h os pitalizati o n m ust 
be re p orte d as t he seri o us a d vers e e ve nt ( dia g n os is or s y m pt o m re q uiri n g h os pitalizati o n). A 
pr oce d ure is n ot a n A E or S A E, b ut t h e reas o n f or t he pr oce d ure ma y b e a n A E or S A E. Pre -
pla n ne d ( pri or t o si g ni n g t h e I nf or me d C o nse nt F or m) pr oce d ure s, treat me nts re q uiri n g 
h os pitaliz ati o n f or pre -e xisti n g c o n d iti o ns t hat d o n ot w orse n i n se verit y, a n d a d missi o n f or 
palliati ve or s ocial care s h o ul d n ot be re p orte d as S A Es (see Secti o n  1 0. 2  f or Defi niti o ns).   
F or deat hs, t he u n derl yi n g or i m me diate ca us e of deat h s h o ul d al wa ys be re p orte d as a n S A E.   
A n y S A E t hat ma y occ ur s u bse q ue nt t o t he re p orti n g peri o d (e n d of t he st u d y) t hat t he i n vesti gat or 
assesses as r elate d t o st u d y dr u g s h o ul d als o b e re p orte d.  
A ll A Es, seri o us a d vers e e ve nts ( S A Es), A E SIs, a n d pre g na nc y re p orts are t o be re p orte d acc or di n g 
t o t he pr oce d ures i n Secti o n 1 0. 1. 3 .   
1 0. 1. 2.  
Re p orti n g Pr oce d ure  
All e ve nts (seri o us a n d n o n -seri o us) m ust be re p orte d wit h i n vesti gat or’s assess me nt of t he e ve nt’s 
seri o us ness, se v erit y, a n d ca us alit y t o t h e st u d y dr u g. F or S A Es a n d A E SIs, a det aile d narrati v e 
s u m marizi n g t he c o urse of t he e ve nt, i ncl u di n g its e val uati o n, tr eat me nt, a n d o utc o me s h o ul d b e 
pr o vi de d o n t he A E C R F. S pecific or esti mate d dates of e ve nt o nset, tr eat me nt, a n d res ol uti o n 
s h o ul d be i ncl u de d, w he n a vaila ble. Me dical hist or y, c o nc o mita nt me dicati o ns, a n d la b orat or y d ata 
t hat are rele v a nt t o t he e ve nt s h o ul d als o be s u m marize d i n t he narrati ve. F or fatal e ve nts, t he 
narrati ve s h o ul d state w het her a n a ut o ps y was or will be perf or me d a n d  i ncl u de t he res ults if 
a vaila ble. I nf or mati o n n ot a vaila ble at t he ti me of t he i nitial re p ort m ust be d oc u me nte d i n a 
f oll o w-u p re p ort. S o urce d oc u me nts  (i ncl u di n g h os pital or me dical re c or ds, dia g n ostic re p orts, etc ) 
will be s u m marize d i n t he narrati ve o n t he A E C R F, a n d retai ne d at t he st u d y ce nter a n d a v aila ble 
u p o n re q uest.   
Ur ge nt safet y q ueries m ust be f oll o we d u p a n d a d dresse d pr o m ptl y. F oll o w-u p i nf or mati o n a n d 
res p o nse t o n o n-ur ge nt safet y q u eries s h o ul d be c o m bi ne d f or re p orti n g t o pr o vi de t he m ost 
c o m plete data p ossi ble wit hi n eac h f oll o w -u p.  
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1 0. 1. 3.  
E ve nts t h at Re q uire E x pe dite d Re p orti n g t o S p o ns or  
T he f oll o wi n g e ve nts re q uire re p orti n g t o t he s p o ns or ( or desi g nee) wit hi n 2 4 h o urs of lear ni n g of 
t he e ve nt: 
•  S A Es (see defi niti o n i n Secti o n 1 0. 2. 2 ). 
•  Selecte d A d ve rse E ve nts of S peci al I nterest ( A E SI [see defi niti o n i n Secti o n 1 0. 2. 3 ]; 
seri o us a n d n o nseri o us: a d verse e ve nts of s pecial i nterest f or t his st u d y i ncl u de t he 
f oll o wi n g:   
− S us pecte d Neisseri a i nfecti o n  
− M o derate or s e vere i nf usi o n reacti o ns  
− A n y 
M A V E: I ncl u des t hr o m b o p hle bitis/ dee p vei n t hr o m b osis, p ul m o nar y 
e m b ol us, m y ocar dial i nf arcti o n, u nsta ble a n gi na, re nal v ei n or arter y t hr o m b osis, 
acute peri p h eral vas c ular occl usi o n, he patic vei n t hr o m b osis, p ortal vei n 
t hr o m b osis mese nteric/ visceral v ei n t hr o m b osis or i nfarcti o n, mese nteric/ visceral 
arterial t hr o m b osis or i nfarcti o n, tr a nsie nt isc he mic attac k, cere bral arterial 
occl usi o n/cere br o vas c u lar  
acci de nt,  
cere bral  
ve n o us  
occl usi o n, 
ga n gre ne( n o ntra u matic; n o n -dia betic), a m p utati o n ( n o ntra u matic; n o n -dia betic)  
− M o derate or s e vere h y perse nsiti vit y reacti o ns p ote ntiall y relat e d t o st u d y treat me nt  
− A d verse e ve nts p ote ntiall y d ue t o s us pecte d lar ge D T D i m m u ne c o m ple x es  
−  Li ver tra nsa mi nas e ele vati o ns as e vi de nce d b y o ne or m ore of t h e f oll o wi n g:  
o  
A L T or A S T > 8 × U L N, or  
o  
A L T or A S T > 5 × U L N f or m ore t ha n 2 wee ks, or  
o  
A L T or A S T > 3 × U L N a n d t otal bilir u bi n > 2 × U L N ( or i nter nati o nal 
n or malize d rati o [I N R] > 1. 5) n ot relate d t o P N H  
N ote : T his A E SI m ust be re p ort e d t o t he s p o ns or wit hi n 2 4 h o urs o nce t he 
i n vesti gat or c o nfir ms t he a b n or mal la b orat or y val ue.  
•  Pre g n a nc y:  alt h o u g h pre g na n c y is n ot c o nsi dere d a n A E, it is t he res p o nsi bilit y of t he 
i n vesti gat or t o re p ort t o t he s p o ns or ( or desi g nee), wit hi n 2 4  h o urs of i de ntificati o n, 
a n y pre g n a nc y occ urri n g i n a fe male  p atie nt d uri n g t he st u d y or wit hi n 5 2 wee ks of t he 
last d ose of st u d y dr u g. A n y c o m plicati o n of pre g n a nc y affecti n g a fe m ale st u d y p atie nt 
a n d/ or fet us a n d/ or ne w b or n t hat meets t he S A E criteria m ust be re p orte d as a n S A E. 
O utc o me f or all pre g na n cies s h o ul d be re p orte d t o t he s p o ns or . 
•   S y m pt o m ati c  o ver d ose of st u d y dr u g : acci de ntal or i nte nti o nal o ver d ose of a t least 
2  ti mes t he i nte n de d d ose of st u d y dr u g wit hi n t he i nte n de d t hera pe utic wi n d o w, if 
ass ociate d wit h a n A E.  
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1 0. 1. 4.  
Ot her A d verse E v e nts of S peci al I nterest t h at d o n ot Re q uire E x pe dite d 
Re p orti n g t o S p o ns or  
Alt h o u g h t hese A E SIs d o n ot re q uire e x pe dite d re p o rti n g t o t he s p o ns or, t h e f oll o wi n g e ve nts are 
of i nterest a n d will i n v ol ve s pecific d ata c ollecti o n t o c haracterize better:  
•  Mil d i nf usi o n reacti o ns d ue t o st u d y treat me nt  
•  Mil d h y pers e nsiti vit y reacti o ns d ue t o st u d y treat me nt  
•  I nje cti o n site reacti o ns d ue t o st u d y treat me nt 
1 0. 2.  
Defi niti o ns  
1 0. 2. 1.  
A d verse E ve nt  
A n A E is a n y u nt o war d me dical occ urre n ce i n a patie nt a d mi nistere d a st u d y dr u g w hic h ma y or 
ma y n ot ha ve a ca usal relati o ns hi p wit h t he st u d y dr u g. T heref ore, a n A E is 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 b n or m al la b orat or y fi n di n g), s y m pt o m, or disease w hic h is te m p orall y 
ass ociate d wit h t he use of a st u d y dr u g, w het her or n ot c o nsi dere d relate d t o t he st u d y dr u g 
(I C H E 2 A  G ui deli ne. Cli nical Safet y Dat a Ma n a ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe d ite d 
Re p orti n g, O ct 1 9 9 4).  
1 0. 2. 2.  
Seri o us A d verse E ve nt  
A n S A E is a n y u nt o w ar d me dical occ urre n ce t hat at a n y d ose:  
•  Res ults i n de at h  –  i ncl u des all deat hs, e ve n t h ose t hat a p pear t o b e c o m plet el y u nrelate d 
t o st u d y dr u g (e g, a car acci de nt i n w hic h a p atie nt is a passe n ger) 
•  Is life-t hre ate ni n g –  i n t he vie w of t h e i n vesti gat or, t he p atie nt is at i m me diate ris k of 
deat h at t h e ti me of t he e ve nt. T his d oes n ot i ncl u de a n A E t hat h a d it occ urre d i n a 
m ore se vere f or m, mi g ht ha ve ca use d deat h.  
•  Re q uires i n -patie nt h os pit aliz ati o n  or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n . 
I n-patie nt h os pitaliz ati o n is defi ne d as a h os pital a d missi o n (a n y d urati o n) or a n 
e mer ge n c y r o o m visit f or l o n ger t ha n 2 4 h o urs. Pr ol o n gati o n of e xisti n g h os pitalizati o n 
is defi ne d as a h os pital sta y t hat is l o n ger t ha n was ori gi nall y a ntici pate d f or t he e ve nt, 
or is pr ol o n ge d d u e t o t h e de vel o p me nt of a ne w A E as d eter mi ne d b y t h e i n vesti gat or 
or treati n g p h ysicia n.  
•  Res ults i n persiste nt or si g nifica nt dis a bilit y/i nc a p acit y  (s u bsta ntial disr u pti o n of 
o ne’s a bilit y t o c o n d u ct n or mal life f u ncti o ns)   
•  Is a c o n ge nit al a n o m al y/ birt h defect  
•  Is a n i m p ort a nt me dic al e ve nt. I m p orta nt me dical e ve nts ma y n ot be i m me diatel y life-
t hreate ni n g or res ult i n deat h or h os pitalizati o n, b ut ma y je o par dize t he patie nt or ma y 
re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her seri o us o utc o mes liste d a b o ve (e g, 
i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me f or aller gic br o nc h os p as m; bl o o d 
d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n; or de vel o p me nt of dr u g 
de pe n de n c y or dr u g a b us e).  
Criteria f or re p orti n g S A Es m ust be f oll o we d f or t hese e ve nts.  
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1 0. 2. 3.  
A d verse E ve nts of S peci al I nterest  
A n a d vers e e ve nt of s p eci al i nterest ( A E SI; seri o us or n o n -seri o us) is o ne of scie ntific a n d me dical 
i nterest s pecific t o t he s p o ns or’s pr o d uct or pr o gra m, f or w hic h o n g oi n g m o nit ori n g a n d ra pi d 
c o m m u nicati o n b y t h e i n vesti gat or t o t h e s p o ns or ca n be a p pr o pri ate. S uc h a n e ve nt mi g ht warra nt 
f urt her i n v esti gati o n i n or der t o c haracterize a n d u n dersta n d it. A d verse e ve nts of s pecial i nterest 
f or t his st u d y are liste d i n Secti o n 1 0. 1. 3  a n d Secti o n  1 0. 1. 4 . 
1 0. 2. 4.  
I nf usi o n Re acti o ns 
I nf usi o n reacti o ns are defi ne d as a n y rele va nt A E t hat occ urs d uri n g t he i nf usi o n or wit hi n 2 h o urs 
after t he i nf usi o n is c o m plete d.  
1 0. 2. 5.  
Se verit y  
T he se verit y of A Es will be g ra de d acc or di n g t o t he f oll o wi n g s cale: 
Mil d: D oes n ot i nterfere i n a si g nifica nt ma n ner wit h t he patie nt’s n or mal f u ncti o ni n g le vel. It 
ma y be a n a n n o ya n ce. Prescri pti o n dr u gs are n ot or di naril y nee de d f or relief of s y m pt o ms, b ut ma y 
be gi v e n beca use of p ers o nalit y of t he p atie nt.  
M o der ate:  Pr o d uces s o me i m pair me nt of f u ncti o ni n g b ut is n ot hazar d o us t o healt h. It is 
u nc o mf orta ble or a n e m b arrass me nt. Treat me nt f or s y m pt o ms ma y be nee d e d.  
Se vere:  Pr o d uces si g nifi ca nt i m pair me nt of f u ncti o ni n g or i nca pacita ti o n a n d is a defi nite hazar d 
t o t he patie nt’s healt h. Treat me nt f or s y m pt o ms ma y b e gi ve n a n d/ or p atie nt h os pitalize d. 
If a la b orat or y val u e is c o nsi dere d a n A E, its se verit y s h o ul d b e bas e d o n t he de gree of 
p h ysi ol o gical i m pair me nt t he val ue i n dicates.  
Inf usi o n Re acti o ns  
T he se v erit y of i nf usi o n reacti o ns will be gra d e d acc or di n g t o t he f oll o wi n g s cale (se mi -c ol o n 
i n dicates “ or” wit hi n descri pti o n of t he gra d e): 
Mil d : Mil d tra nsie nt reacti o n; i nf usi o n i nterr u pti o n n ot i n dicate d; i nter ve nti o n n ot i n dicate d 
M o der ate : T h era p y or i nf usi o n i nterr u pti o n i n dicate d b ut res p o n ds pr o m ptl y t o s y m pt o matic 
treat me nt (e g, a nti hista mi nes, N S AI Ds, n arc otics, I V fl ui ds); pr o p h ylactic me dicati o ns i n dicate d 
f or ≤2 4 h o urs 
Se vere : Pr ol o n ge d (e g, n ot ra pi dl y res p o nsi ve t o s y m pto matic me dicati o n a n d/ or brief i nterr u pti o n 
of i nf usi o n); rec urre nce of s y m pt o ms f oll o wi n g i nitial i m pr o ve me nt; h os pitalizati o n i n dicate d f or 
cli nical se q uela e; life -t hr eate ni n g c o nse q u e nces; ur ge nt i nter ve nti o n i n dicat e d; deat h 
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I njecti o n Site Re acti o ns 
T h e se verit y of i njecti o n site reacti o ns will be gra d e d acc or di n g t o t h e f oll o wi n g s cale (se mi -c ol o n 
i n dicates “ or” wit hi n descri pti o n of gra de: 
Mil d : Pai n t hat d oes n ot i nterfere wit h acti vit y; mil d disc o mf ort t o t o uc h; < 5 c m of er yt he ma or 
i n d urati o n t hat d oes n ot i nterfere wit h acti vit y  
M o der ate : Pai n t hat re q uires re peate d use of n o n-narc otic p ai n relie v er > 2 4 h o urs or i nterferes 
wit h acti vit y; disc o mf ort wit h m o ve me nt; 5. 1 c m t o 1 0 c m er yt h e ma or i n d urati o n or i n d urati o n 
t hat i nterferes wit h acti vit y 
Se vere : Pai n t hat re q uires a n y use of narc otic pai n relie ver or t hat pre ve nts dail y acti vit y; 
si g nifica nt disc o mf ort at rest; > 1 0 c m er yt he ma or i n d urati o n; pre ve nts dail y acti vit y; re q uires 
E R  visit or h os pitalizati o n; necr osis or e xf oliati ve der matitis  
1 0. 2. 6.  
C a us alit y  
T he i n vesti gat or m ust pr o vi de ca usalit y assess me nt as t o w het her or n ot t here is a reas o na ble 
p ossi bilit y t hat t he dr u g ca use d t he a d verse e v e nt, base d o n e vi de nce or facts, his/ her cli nical 
j u d g me nt, a n d t he f oll o wi n g defi niti o ns. T he ca usalit y assess me nt m ust  be ma de base d o n t he 
a vaila ble i nf or mati o n a n d ca n be u p d ate d as ne w i nf or mati o n bec o mes a v aila ble.  
T he f oll o wi n g fact ors s h o ul d be c o nsi dere d w he n assessi n g ca usalit y:  
•  Te m p oral rel ati o ns hi p: ti me t o o nset vers us ti me dr u g was a d mi nistere d  
•  Nat ure of t h e reacti o ns: i m me diate vers us l o n g ter m  
•  Cli nical a n d pat h ol o gic al feat ur es of t he e v e nts  
•  E xisti n g i nf or mati o n a b o ut t he dr u g a n d sa me class of dr u gs  
•  C o nc o mita nt me dicati o ns  
•  U n derl yi n g a n d c o n c urre nt ill nesses  
•  Res p o nse t o dec halle n ge ( dr u g d isc o nti n uati o n) or d ose re d ucti o n  
•  Res p o nse t o rec h alle n ge (re -i ntr o d ucti o n of t he dr u g) or d ose i ncreas e, w he n 
a p plica ble  
•  Patie nt’s me dical a n d s ocial hist or y  
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Ca usalit y t o t he st u d y dr u g (i ncl u di n g st u d y dr u g a d mi nistrati o n):  
•  Relate d:  
− T he A E f oll o ws a r eas o n a ble te m p oral se q u e nce fr o m st u d y dr u g a d mi nistrati o n, 
a n d ca n n ot be reas o na bl y e x plai ne d b y t he n at ure of t he reacti o n, patie nt’s cli nical 
state (e g, dise ase u n der st u d y, c o n c urre nt diseas es, c o nc o mita nt me dicati o ns), or 
ot her e xter nal fact ors.  
or  
− T h e A E f oll o ws a reas o n a ble te m p oral se q u e nce fr o m st u d y dr u g a d mi nistrati o n, 
a n d is a k n o w n reacti o n t o t he dr u g u n der st u d y or its class of dr u gs, or is pre dicte d 
b y k n o w n p h ar mac ol o g y.  
•  N ot Relate d:  
− T he A E d oes n ot f oll o w a reas o na bl e se q ue nce fr o m st u d y d r u g a d mi nistrati o n, or 
ca n be reas o na bl y e x plai ne d b y t he n at ure of t he reacti o n, p atie nt’s cli nical state 
(e g, diseas e u n der st u d y, c o nc urre nt diseas es, a n d c o nc o mita nt me dicati o ns) or 
ot her e xter nal fact ors.  
Ca usalit y t o t he st u d y c o n d uct ( pr ot oc ol-s pecifie d pr oce d ure): 
•  Relate d:  
− T he A E f oll o ws a reas o na ble te m p oral s e q ue nce fr o m a pr ot oc ol -s p ecifie d 
pr oce d ure, a n d ca n n ot be reas o na bl y e x plai ne d b y t he nat ur e of t he reacti o n, 
patie nt’s cli nical state (e g, disease u n der st u d y, c o nc urre nt dise as es, c o nc o mita nt 
me dicati o ns), or ot her e xter nal fact ors.  
•  N ot Relate d:  
− T he A E d oes n ot f oll o w a reas o na bl e se q ue n ce fr o m a pr ot oc ol -s pecifie d pr oce d ure, 
or ca n be reas o n a bl y e x plai ne d b y t he nat ure of t he reacti o n, patie nt’s cli nical state 
(e g, diseas e u nder st u d y, c o nc urre nt diseas es, a n d c o nc o mita nt me dicati o ns) or 
ot her e xter nal fact ors.  
1 0. 3.  
S afet y M o nit ori n g  
T he i n vesti gat or will m o nit or t he safet y of t he st u d y patie nt at his/ her site(s) as per t he re q uire m e nts 
of t his pr ot oc ol a n d c o nsiste nt wit h c urre nt G o o d Cli nical Practice ( G C P). A n y q u esti o ns or 
c o ncer ns s h o ul d be disc usse d wit h t he s p o ns or i n a ti mel y fas hi o n. T he s p o ns or will m o nit or t he 
safet y data fr o m acr oss all st u d y sites. T h e me dical/st u d y direct or will ha ve pri mar y res p o nsi bilit y 
f or t he e mergi n g s afet y pr ofile of t he c o m p o u n d, b ut will be s u p p orte d b y ot her d e part me nts 
(e g, G P S; Bi ostatistics a n d Data 
Ma na ge me nt). Safet y m o nit ori n g will be perf or me d o n a n 
o n g oi n g basis (e g, i n di vi d ual re vie w of S A Es) a n d o n a peri o dic, c u m ulati ve a g gre gate ba sis. 
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1 0. 4.  
N otif yi n g He alt h A ut h orities, Et hics C o m mittee, a n d I n vesti g at ors  
D uri n g t he st u d y, t he s p o ns or a n d/ or t h e c o ntr act researc h or ga nizati o n ( C R O) will i nf or m h ealt h 
a ut h orities, t he Et hics C o m mittee ( E C) , a n d t he partici pati n g i n vesti gat ors of a n y S U S A Rs 
( S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns) occ urri n g i n ot her st u d y ce nters or ot her 
st u dies of t he acti ve st u d y dr u g (p ozeli ma b a n d ce m disira n ), as a p pr o pri ate per l ocal re p orti n g 
re q uire me nts. I n a d diti o n, t he s p o ns or a n d/ or C R O will c o m pl y wit h a n y a d diti o nal l ocal safet y 
re p orti n g re q uir e me nts.  
U p o n recei pt of t h e s p o ns or’s n otificati o n of a S U S A R t hat occ urre d wit h t he st u d y dr u g, t he 
i n vesti gat or will i nf or m t he E C u nless dele gate d t o t he s p o ns or. 
E ve nt e x pecte d ness f or st u d y dr u g ( p ozeli ma b a n d ce m disira n ) is assess e d a gai nst t he Refere nce 
Safet y I nf or m ati o n secti o n of t he I B t hat is effecti ve f or e x pe dite d safet y re p orti n g.   
At t he c o m pleti o n of t he st u d y, t he s p o ns or will re p ort all safet y o bs er vati o ns ma de d uri n g t h e 
c o n d uct of t he trial i n t he C S R t o healt h a ut h orities a n d E C as a p pr o pri ate. 
1 1.  
S T A TI S TI C A L P L A N  
T his secti o n pr o vi des a hi g h -le v el descri pti o n of t he pla n ne d a nal yses a n d will ser ve as t he basis 
f or t he S A P f or t he st u d y.  
E n d p oi nts are liste d i n Secti o n  4 . A nal ysis varia bles are liste d i n Secti o n 5 .  
1 1. 1.  
St atistic al H y p ot hesis  
N o f or mal statistical h y p ot hesis is t o be teste d. 
1 1. 2.  
J ustific ati o n of S a m ple Size  
U p t o  1 2 patie nts wit h P N H w h o are c urre ntl y recei vi n g ec uliz u ma b will s witc h t o p ozeli ma b a n d 
ce m disira n c o m bi nati o n t hera p y. Patie nts will be s witc he d fr o m ec uliz u ma b a d mi nistrati o n at t he 
la bele d d osi n g re gi me n or at a d os e hi g her t ha n la bele d a n d/ or a d mi nistere d m ore fre q u e ntl y t ha n 
la bele d.  
U p t o  1 2 patie nts wit h P N H  will be e nr olle d t o descri be a n d e x pl ore t he i n ci de nce a n d s e verit y of 
T E A Es t hr o u g h da y 2 2 5 of t he O L T P.  
1 1. 3.  
A n al ysis Sets  
1 1. 3. 1.  
Effic ac y A n al ysis Sets  
T he f ull a nal ysis set ( F A S) i ncl u des all e nr olle d patie nts  w h o recei ve d a n y a m o u nt of st u d y dr u gs 
a n d ha ve at least 1  p ost -b aseli ne assess me nt. Efficac y e n d p oi nts will be a nal yz e d usi n g t he F A S.  
T he O L E P F A S i ncl u des all patie nts w h o partici pate d i n t he O L E P w h o recei ve d a n y a m o u nt of 
st u d y dr u g i n t he O L E P a n d ha ve at least 1 p ost-baseli ne assess me nt i n t he O L E P . 
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C O N FI D E N TI A L  
1 1. 3. 2.  
S afet y  A n al ysis Sets  
T he safet y a n al ysis set ( S A F) i ncl u d es all e nr olle d patie nts w h o recei ve d a n y a m o u nt of st u d y 
dr u g. Treat me nt c o m plia nce/a d mi nistrati o n a n d all cli nical safet y v aria bles will be a nal yz e d usi n g 
t he S A F. 
T he O L E P S A F i ncl u des all patie nts w h o partici pate d i n t he O L E P w h o recei ve d a n y a m o u nt of 
st u d y dr u g i n t he O L E P. 
1 1. 3. 3.  
P h ar m a c o ki netic A n al ysis Set  
T he P K a nal ysis p o p ulati o n i ncl u des all patie nts w h o recei ve d a n y a m o u nt of st u d y dr u g a n d w h o 
ha d at least 1 n o n -missi n g res ult f oll o wi n g t he first d o se of st u d y dr u g. 
T he O L E P P K a nal ysis s et i ncl u des all p atie nts w h o partici pate d i n t he O L E P w h o recei ve d a n y 
a m o u nt of st u d y dr u g i n t he O L E P a n d w h o h a d at least 1 n o n -missi n g res ult f oll o wi n g t he first 
d ose of st u d y dr u g i n t he O L E P.  
1 1. 3. 4.  
I m m u n o ge nicit y A n al ysis Set 
T he A D A a n al ysis set i ncl u des all patie nts w h o recei ve d st u d y dr u g a n d ha d at least 1 n o n -missi n g 
A D A  res ult f oll o wi n g t h e first st u d y d os e.  
T he O L E P A D A a nal ysis set i ncl u des all patie nts w h o partici pate d i n t he O L E P w h o recei ve d 
st u d y dr u g i n t he O L E P a n d ha d at least 1 n o n-missi n g A D A res ult f oll o wi n g t he first O L E P d ose.  
1 1. 4.  
St atistic al Met h o ds  
F or c o nti n u o us varia bles, descri pti ve statistics will i ncl u de t he f oll o wi n g i nf or mati o n: t he n u m ber 
of patie nts reflecte d i n t he calc ulati o n ( n), mea n, s ta n dar d de viati o n, Q 1, me dia n, Q 3, mi ni m u m, 
a n d ma xi m u m.  
F or cate g orical or or di nal data, fre q ue nci es a n d perce nta ges will be dis pla ye d f or eac h cate g or y.  
1 1. 4. 1.  
P ati e nt Dis p ositi o n  
T he f oll o wi n g will be pr o vi de d:  
•  T he t otal n u m ber of scree ne d patie nts: si g n e d t h e mai n I C F  
•  T he t otal n u m ber of e nr olle d patie nts  
•  T he t otal n u m ber of p atie nts w h o disc o nti n ue d t he st u d y, a n d t he reas o ns f or 
disc o nti n uati o n  
•  T he t otal n u m ber of pati e nts w h o disc o nti n ue d fr o m st u d y treat me nt, a n d t he reas o ns 
f or disc o nti n uati o n 
•  A listi n g of patie nts pre mat urel y disc o nti n ue d fr o m treat me nt, al o n g wit h reas o ns f or 
disc o nti n uati o n  
•  T otal n u m ber of patie nts w h o recei ve d treat me nt i nte nsificati o n  
•  T otal n u m ber of patie nts w h o c o nti n ue d i nt o t he O L E P  
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1 1. 4. 2.  
De m o gr a p h y a n d B aseli ne C h ar acteristics  
De m o gra p hic a n d bas eli ne c haract eristics will be s u m marize d descri pti vel y b y tr eat me nt gr o u p, 
a n d b y all patie nts c o m bi ne d .   
Baseli ne is d efi ne d as t h e last a vaila ble v al ue pri or t o st u d y dr u g a d mi nistrati o n u nless ot her wise 
s pecifie d. 
1 1. 4. 3.  
Effic ac y A n al yses  
1 1. 4. 3. 1.  Sec o n d ar y Effic ac y A n al ysis  
T here are n o pri mar y effi cac y e n d p oi nts i n t his st u d y.  
F or sec o n d ar y efficac y e n d p oi nts t hat are defi ne d b y t he c ha n ge fr o m baseli ne t o a ti me p oi nt i n a 
varia ble, t he a nal ysis set will c o nsist of all treate d patie nts w h o ha ve a n o n -missi n g baseli ne 
meas ure me nt of t h e vari a ble. Sec o n dar y e n d p oi nts i ncl u de:  
•  Pe rce nt c ha n ge i n L D H fr o m pre-treat me nt (as defi ne d b y t he mea n of t he L D H val ues 
at t he s cree ni n g visit [ o btai ne d n o m or e t ha n o ne da y bef ore a d mi nistrati o n wit h 
ec uliz u ma b] a n d baseli n e ( da y 1 visit, pri or t o a d mi nistrati o n of ce m disira n a n d 
ec uliz u ma b) t o E O T p eri o d (as d efi ne d b y t h e mea n of t he L D H v al ues at d a ys 1 9 7 a n d 
2 2 5 i n t he O L T P)  
•  Perce nt c h a n ge i n L D H fr o m pre -tr eat me nt t o da y 2 9  
•  C ha n ge i n C H 5 0 le v els fr o m baseli ne t o da y 2 2 5, i ncl usi ve  
•  C ha n ge i n h e m o gl o bi n le vels fr o m baseli ne t o da y 2 2 5, i ncl u si ve 
•  C ha n ge fr o m bas eli ne i n c o nce ntr ati o n of t otal C 5 assesse d t hr o u g h o ut t he st u d y  
•  C ha n ge i n fati g u e as me as ure d b y t h e F A CI T -Fati g ue Scale fr o m baseli ne t o da y  2 2 5, 
i ncl usi ve 
•  C ha n ge fr o m bas eli ne t o da y 2 2 5 i n G H S a n d P F s c ores o n t he E O R T C  Q L Q -C 3 0  
T o assess t he a b o ve s ec o n dar y e n d p oi nts, s u m mar y statistics will be prese nte d b y visit f or t he 
perce nt c ha n ge fr o m bas eli ne (f or L D H) a n d c ha n ge fr o m bas eli ne (f or t he re mai ni n g varia bles) 
as descri be d a b o ve, al o n g wit h 9 5 % c o nfi d e nce i nter vals.  I n a d diti o n,  s u m mar y statistics will be 
prese nte d f or val ues at all visits u p t o da y 2 2 5.  
T hese s u m mari es will be re peat e d f or a n y of t h e f oll o wi n g s u b gr o u ps t hat h a ve at least 3 patie nts:  
•  Patie nts w h o s witc he d fr o m ec uliz u ma b a d mi nistrati o n at t he la bele d d osi n g re gi me n  
•  Patie nts w h o s witc he d fr o m ec uliz u ma b at a d ose hi g her t h a n la bele d a n d/ or m ore 
fre q ue ntl y t ha n la b ele d 
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F or bi n ar y s ec o n dar y e n d p oi nts, all treate d patie nts will be a n al yze d. T he bi nar y sec o n d ar y 
e n d p oi nts are as f oll o ws:  
•  Pr o p orti o n of patie nts w h o mai ntai n a de q uat e c o ntr ol of he m ol ysis , defi ne d as 
L D H  ≤1. 5  x  U L N fr o m p ost -baseli ne ( o n da y  1) t hr o u g h da y 2 2 5, a n d fr o m da y  5 7 
t hr o u g h da y 2 2 5, i n cl usi ve (a patie nt will be treat e d as n ot ac hie vi n g a d e q uate c o ntr ol  
if he/s he is missi n g > 2 5 % of sc he d ule d L D H meas ure me nts, missi n g a n y 2 c o nsec uti ve 
L D H 
meas ure me nts,  h as recei ve d i nte nsifie d treat me nt, or has p er ma ne ntl y 
disc o nti n ue d treat me nt . F or ot her patie nts, L D H meas ure me nts will be assesse d b y 
n o n -missi n g L D H me as ure me nts).  
•  Pr o p orti o n of patie nts wit h a d e q uate c o ntr ol of he m ol ysis at eac h visit fr o m p ost -
baseli ne ( o n da y  1) t hr o u g h da y 2 2 5, i n cl usi ve  
•  Pr o p orti o n of patie nts wit h n or malizati o n of t heir L D H at eac h visit, defi n e d as L D H 
≤1. 0  x  U L N fr o m p ost -b aseli ne ( o n da y  1) t hr o u g h da y 2 2 5, i n cl usi ve   
•  Pr o p orti o n of patie nts wit h brea kt hr o u g h he m ol ysis fr o m b aseli ne t hr o u g h d a y  2 2 5 a n d 
fr o m da y 2 9 t hr o u g h d a y  2 2 5, i ncl usi ve ( n o n -res p o n der i m p utati o n will be a p plie d f or 
patie nts w h o recei ve i nte nsifie d treat me nt).  
•  Pr o p orti o n of patie nts wit h he m o gl o bi n sta bi lizati o n ( defi n e d as patie nts w h o d o n ot 
recei v e a n R B C tra nsf usi o n a n d ha ve n o decreas e i n he m o gl o bi n le vel ≥ 2 g/ d L) fr o m 
baseli ne t hr o u g h da y 2 2 5, a n d fr o m da y  2 9 t hr o u g h da y  2 2 5, i n cl usi ve.  
•  Pr o p orti o n of patie nts 
w h o are tra nsf usi o n -free ( defi ne d as not re q uiri n g a n 
R B C  tra nsf usi o n as per pr ot oc ol al g orit h m) fr o m baseli ne t hr o u g h da y 2 2 5, a n d fr o m 
da y  2 9 t hr o u g h da y  2 2 5, i ncl usi ve (ie, tra nsf usi o n a v oi da nce).  
F or t hese e n d p oi nts, o bser ve d pr o p orti o ns a n d 9 5 % c o nfi de nce i nter vals usi n g t he Cl o p per -
Pears o n e x act met h o d will be re p orte d.  
F or t he rate a n d n u m ber of u nits of R B Cs tra nsf use d fr o m baseli ne t hr o u g h da y 2 2 5, a n d fr o m 
da y  2 9 t hr o u g h d a y  2 2 5, i ncl usi ve, t he a n al ysis set will c o nsist of all treat e d patie nts w h o ne v er 
recei v e d t he i nte nsifie d re gi men d uri n g treat me nt. T he rate of u nits of tra nsf usi o n f or a patie nt will 
be calc ulat e d base d o n t he d urati o n of treat me nt e x p os ure of t he patie nt. 
Mea ns a n d 
9 5 %  c o nfi de n ce i nter vals will be re p orte d f or all patie nts a n d f or t he 2  p atie nt s u b gr o u ps n a me d 
a b ove, if a p plica ble.  
F or t he A U C of L D H o ver ti me fr o m baseli ne t hr o u g h da y 2 2 5, a n d fr o m da y  5 7 t hr o u g h da y  2 2 5, 
i ncl usi ve, t he a nal ysis set will i ncl u de all treate d patie nts. T he A U C will be c o m p ute d usi n g 
a vaila ble L D H v al ues. M ea n A U C, 9 5 % CI, a n d ot her s u m mar y statistics will be pr o vi de d. 
Sec o n dar y efficac y a n al ysis f or t he o pti o nal O L E P will be perf or m e d usi n g t h e sa m e a p pr oac h as 
descri be d f or c orres p o n di n g a n al ys es i n t he O L T P.  
1 1. 4. 4.  
C o ntr ol of M ulti plicit y  
N ot a p plica ble.  
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Cli nical St u d y Pr ot oc ol  
 
R 3 9 1 8 -P N H -2 0 1 0 5 A me n d me nt 3  
Re ge n er o n P har mace uticals, I n c.  
 
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C O N FI D E N TI A L  
1 1. 4. 5.  
S afet y A n al ysis  
T he pri mar y e n d p oi nt i n t his st u d y is t he i nci de nce a n d se verit y of T E A Es t hr o u g h da y 2 2 5 of t he 
O L T P. Safet y a n al ysis will be c o n d ucte d w he n all patie nts (i ncl u di n g patie nts o n treat me nt 
i nte nsificati o n) c o m plet e t he 3 2-w ee k tr eat me nt peri o d or pre mat urel y disc o nti n u e st u d y. 
A d diti o nal safet y a nal ysis will be pr o vi de d as a s u p ple me nt o nce all treat me nt -disc o nti n ue d 
patie nts c o m plete t heir safet y f oll o w -u p .  
1 1. 4. 5. 1.  A d verse E ve nts  
Defi niti o ns  
F or safet y vari a bles, 3 o bser vati o n peri o ds are defi ne d:  
•  T he pretreat me nt peri o d is defi ne d as t he ti me fr o m si g ni n g t he I C F t o bef ore t he first 
d ose of st u d y dr u g.  
•  T he o n -treat me nt peri o d is defi ne d as t he da y fr o m first d ose of st u d y dr u g t o eit her: 
− t he last d ose of st u d y dr u g i n t he O L T P f or t h ose n ot c o nti n ui n g i n t he O L E P pl us 
5 2  wee ks,  or   
− t he last d ose of st u d y dr u g i n t he O L E P f or t h os e c o nti n ui n g i n t he O L E P pl us 
5 2  wee ks.  
•  T he p ost -treat me nt peri o d is defi ne d as t he ti me aft er t he e n d of t h e o n-treat me nt peri o d.  
Treat me nt -e mer ge nt a d v erse e ve nts are d efi ne d as t h ose t hat are n ot  pres e nt at baseli ne or re prese nt 
t he e x acer bati o n of a pre-e xisti n g c o n diti o n d uri n g t he o n -treat me nt p eri o d. 
A n alysis  
All A Es re p ort e d i n t his st u d y will be c o de d usi n g t he c urre ntl y a vaila bl e versi o n of t he M e dical 
Dicti o nar y f or Re g ulat or y A cti vities ( Me d D R A
® ). C o di n g will be t o l o west-le vel ter ms. T h e 
preferre d t er m ( P T), a n d t he pri mar y s yste m or ga n class ( S O C) will be liste d.  
S u m maries of all T E A Es will i ncl u de:  
•  T he n u m ber ( n) a n d perce nta ge ( %) of p atie nts wit h at least 1 T E A E b y S O C a n d P T  
•  T E A Es b y  se v erit y (acc or di n g t o t he gra di n g scale o utli ne d i n Secti o n  1 0. 2. 5 ), 
prese nte d b y S O C a n d P T  
•  T E A Es b y relati o ns hi p t o treat me nt (relate d, n ot rela te d), pres e nte d b y S O C a n d P T 
•  Treat me nt -e mer ge nt A E SIs ( defi ne d wit h a P T or a pres pecifie d gr o u pi n g)  
Deat hs a n d ot her S A Es will be liste d a n d s u m marize d.  
Treat me nt -e mer ge nt a d v erse e v e nts lea di n g t o per ma ne nt treat me nt disc o nti n uati o n will be liste d 
a n d su m marize d.  
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C O N FI D E N TI A L  
1 1. 4. 5. 2.  Ot her S afet y  
Vit al Si g ns  
Vital si g ns (te m p erat ur e, p ulse, bl o o d press ure) will be s u m marize d b y b aseli ne a n d c ha n ge fr o m 
baseli ne t o eac h sc he d ul e d assess me nt ti me p oi nt wit h descri pti ve statistics.  
L a b or at ory Tests  
La b orat or y test res ults will be s u m marize d b y b aseli ne a n d c ha n ge fr o m bas eli ne t o eac h sc h e d ule d 
assess me nt ti me p oi nt wit h descri pti ve statistics.  
N u m ber a n d perce nta ge of patie nts wit h a p ote ntiall y cli nicall y si g nifi ca nt val ue ( P C S V) at a n y 
p ost -treat me nt ti me p oi nt will be s u m marize d f or eac h cli nical l a b orat or y t est f or all patie nts a n d 
se parat el y f or patie nts i n w h o m t he P C S V criteri o n was n or mal or missi n g at baseli ne.  
S hift ta bles base d o n bas eli ne n or mal/a b n or mal a n d ot her ta b ular a n d gra p hical met h o ds ma y be 
use d t o prese nt  t he res ults f or la b orat or y t ests of i nterest.  
Listi n gs will be pr o vi de d wit h fla gs i n dicati n g t he o ut -of -la b orat or y ra n ge v al ues. 
E C G  
E C G para meters ( P R i nter val, Q T i nter val, Q Tc F i nter val, Q R S i nter val, a n d heart rate [fr o m 
ve ntric ular rat e]) will be s u m marize d b y visit a n d c ha n ge fr o m baseli ne t o eac h sc he d ule d a n d 
c ollecte d ass ess me nt ti me p oi nt.  
Listi n gs will be pr o vi de d wit h fla gs i n dicati n g P C S Vs.  
1 1. 4. 5. 3.  Tre at me nt E x p os ure  
Treat me nt e x p os ure will be prese nt e d se paratel y f or p ozeli ma b a n d ce m disira n.  
T he d urati o n of st u d y dr u g e x p os ure f or a st u d y peri o d is calc ulate d as:  
•  ( Date of last a d mi nistrati o n of st u d y dr u g - d ate of t he first a d mi nistrati o n of st u d y dr u g 
f or t he st u d y peri o d) + 2 8 da ys (f or Q 4 W) 
•  ( Date of last a d mi nistrati o n of st u d y dr u g - d ate of t he first a d mi nistrati o n of st u d y dr u g 
f or t he st u d y peri o d) + 1 4 da ys (f or Q 2 W) 
S u m maries (i ncl u di n g t he n u m ber of patie nts e x p ose d, t he d urati o n of e x p os ure, a n d t he d ose 
re gi me n t o w hic h patie nts were e x p ose d) will be pr o vi de d f or p ozeli ma b a n d f or ce m disira n. 
1 1. 4. 5. 4.  Tre at me nt C o m pli a nce  
C o m plia nce wit h pr ot oc ol -defi ne d st u d y dr u g d osi n g will be calc ulate d as f oll o ws:  
Treat me nt c o m plia n ce = ( N u m ber of st u d y dr u g d oses ta ke n d uri n g treat me nt peri o d) / 
( N u m ber of st u d y dr u g d oses pla n ne d f or t h e treat me nt peri o d) × 1 0 0 %  
Te m p orar y d os e disc o nti n uati o n is i g n ore d. Se parate s u m maries will be pr o vi de d f or p ozeli ma b 
a n d ce m disira n.  
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Cli nical St u d y Pr ot oc ol  
 
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C O N FI D E N TI A L  
1 1. 4. 6.  
P h ar m a c o ki netics  
1 1. 4. 6. 1.  A n al ysis of Dr u g C o nce ntr ati o n D at a  
T he c o nce ntrati o ns of t ot al p ozeli ma b, t otal C 5, ce m disira n, a n d ce m disira n meta b olites  o ver ti me 
a n d selecte d p h ar mac o ki netic para m eters will be s u m marize d b y des cri pti ve statistics.  
N o f or mal statistical h y p ot hesis testi n g will be perf or me d.  
1 1. 4. 7.  
A n al ysis of I m m u n o ge nicit y D at a  
I m m u n o ge nicit y will be c haracteriz e d b y t he A D A res p o nse a n d titer o bser ve d:  
•  Pre -e xisti n g i m m u n oreacti vit y, defi ne d as a p ositi ve A D A assa y res p o nse at baseli ne, 
wit h all p ost -d ose A D A res ults ne gati ve, or a p ositi ve assa y res p o nse at bas eli ne, wit h 
all p ost -d ose A D A assa y res p o nses less t ha n 9 -f ol d f or p ozeli ma b A D A assa y, or 4-f ol d 
f or ce m disira n A D A ass a y o ver baseli ne titer l e vels 
•  Treat me nt -e mer ge nt A D A res p o nse, defi ne d as a n y p ost -d ose p ositi ve A D A  assa y 
res p o nse w h e n t he baseli ne res ults are ne gati ve 
•  Treat me nt -b o oste d A D A res p o nse, defi ne d as a n y p ost -d ose p ositi v e A D A assa y 
res p o nse t hat is greater t h a n or e q u al t o 9-f ol d f or p ozeli ma b A D A assa y, or 4-f ol d f or 
ce m disira n A D A  assa y o ver baseli ne titer le vels w he n baseli ne is p ositi ve i n t he 
A D A  assa y  
•  Ma xi m u m A D A Titer val ues  
− L o w (titer < 1, 0 0 0)  
− M o derate ( 1, 0 0 0 ≤titer ≤1 0, 0 0 0)  
− Hi g h (titer > 1 0, 0 0 0)  
Listi n gs of pre -e xisti n g, treat me nt -b o oste d, a n d tr eat me nt -e mer ge nt A D A res p o nses, A D A  titers, 
p ositi vit y prese nte d b y p atie nt, a n d ti me p oi nt will be pr o vi d e d. I n ci de nce of treat me nt -e mer ge nt 
A D A will be assesse d as a bs ol ute occ urre nce ( N) a n d perce nt of patie nts ( %), gr o u pe d b y st u d y 
c o h orts a n d A D A titer le vel.  
Pl ots of dr u g c o nce ntrati o ns will be e x a mi ne d a n d t he i nfl ue nce of A D As o n i n di vi d ual P K  pr ofiles 
e val uate d. Ass ess me nt of i m pact of A D A o n safet y a n d effi cacy m a y be pr o vi de d.  
1 1. 4. 8.  
A n al ysis of P h ar m ac o d y n a mic a n d E x pl or at or y Bi o m ar ker D at a  
A nal ysis of C H 5 0 is d escri be d i n Secti o n  1 1. 4. 3. 1 . A nal ysis of ot h er bi o mar ker dat a is defi ne d i n 
t he S A P. T he res ults of e x pl orat or y bi o mar kers mi g ht n ot be prese nte d i n t h e C S R.  
1 1. 5.  
I nteri m A n al ysis 
A n i nteri m a nal ysis ma y be c o n d ucte d after 6 patie nts ha ve c o m plete d at least 1 6 wee ks of t he 
O L T P. A d diti o nal/ ot her i nteri m  a nal ys es ma y b e perf or me d t o s u p p ort re g ul at or y i nteracti o ns.  
Data will be s u m marize d descri pti vel y.  
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C O N FI D E N TI A L  
1 1. 6.  
St atistic al C o nsi der ati o ns S urr o u n di n g t he Pre m at ure Ter mi n ati o n 
of a St u d y   
If t he st u d y is ter mi nat e d pre mat urel y, o nl y t h ose para m eters re q uire d f or t he de v el o p me nt 
pr o gra m a n d/ or re p orti n g t o re g ulat or y a ut h orities will be s u m marize d. I n v esti gat or a n d s p o ns or 
res p o nsi bilities s urr o u n di n g t he pre mat ure ter mi nati o n of a st u d y are prese nte d i n Secti o n 1 5. 1 . 
1 2.  
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  
I n acc or da nce wit h I C H E 6, t he s p o ns or is res p o nsi ble f or q u alit y ass ur a nce t o ens ure t hat t he 
st u d y is c o n d uct e d a n d t h e data ge nerate d, rec or de d, a n d re p orte d i n c o m pli a nce wit h t he pr ot oc ol, 
G C P, a n d a n y a p plica bl e re g ulat or y re q uire m e nt(s). T he pla n ne d q ualit y ass ura nce a n d q ualit y 
c o ntr ol pr oce d ures f or t he st u d y are d escri be d i n  t his secti o n.   
1 2. 1.  
D at a M a n a ge me nt a n d Electr o nic S yste ms  
1 2. 1. 1.  
D at a M a n a ge me nt  
A data ma na ge me nt pla n s pecif yi n g all rele va nt as pects of data pr ocessi n g f or t he st u d y (i ncl u di n g 
data vali dati o n [ q ualit y -c hec ki n g], clea ni n g, c orrecti n g, releasi n g) will be mai ntai ne d a n d st ore d 
at Re ge ner o n (s p o ns or).  
A me dical c o di n g pla n will s pecif y t he pr ocess es a n d t he dicti o nar y use d f or c o di n g. All data 
c o di n g (e g, A Es, baseli ne fi n di n gs, me di cati o n, me dical hist or y/s ur gical hist or y) will b e d o ne 
usi n g i nter nati o nall y  rec o g niz e d a n d acce pte d dicti o naries. 
T he C R F data f or t his st u d y will be c ollecte d wit h a n electr o ni c data ca pt ur e ( E D C) t o ol.  
1 2. 1. 2.  
Electr o nic S yste ms  
Electr o nic s yste ms t hat ma y b e use d t o pr ocess a n d/ or c ollect dat a i n t his st u d y will i ncl u de t he 
f oll o wi n g: 
•  I V R S/I W R S s yst e m –  e nr oll me nt, st u d y dr u g s u p pl y  
•  E D C s yste m –  data ca pt ure  –  Me di data Ra v e  
•  Statistical A nal ysis S yste m ( S A S) –  statistical re vie w a n d a n al ysis 
•  P har mac o vi gila nce s afet y dat a base  
•  e C O A s yst e m –  ca pt ur e C O A  
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1 2. 2.  
St u d y M o nit ori n g  
1 2. 2. 1.  
M o nit ori n g of St u d y Sites  
Re ge n er o n uses a st u d y -s pecific ris k-bas e d a p pr oac h t o st u d y m o nit ori n g a n d o versi g ht, ali g ne d 
wit h ris k -base d q ualit y pri nci ples, o utli ne d i n I C H E 6 ( R 2) G ui deli ne f or G o o d Cli nical Practice. 
Ris k -base d q ualit y m o nit ori n g ( R B Q M) met h o d ol o g y f o c uses o n e m pl o yi n g a fit -f or-p ur p ose 
m o nit ori n g strate g y, s u p p orte d eit her directl y b y Re ge n er o n as t he s p o ns or, or via o ur 
C R O  part ners. Ris k -base d q ualit y m o nit ori n g strate gies i ncl u d e: re d uce d s o urce dat a verificati o n 
( S D V), tar gete d s o ur ce data re vi e w ( S D R), t h e use of off-site/re m ote a n d tri g gere d o n-site 
m o nit ori n g visits, a n d ce ntralize d m o nit ori n g t o i de ntif y site -le vel ris ks a n d st u d y-l e vel tr e n ds. 
T he i n vesti gat or m ust all o w st u d y -relate d m o nit ori n g acti vities t o occ ur. 
T he st u d y m o nit ors will per f or m o n g oi n g s o urce data re vie w t o v erif y t h at data rec or de d i n t he 
C R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifi a ble fr o m s o urce d oc u me nts, 
t hat t he safet y a n d ri g hts of patie nts are bei n g pr otecte d, a n d t hat t he st u d y is bei n g c o n d ucte d i n 
acc or da nce wit h t he c urre nt a p pr o ve d pr ot oc ol versi o n a n d a n y ot her st u d y a gree me nts, I C H G C P, 
a n d all a p plica ble re g ulat or y re q uire m e nts.  
1 2. 2. 2.  
S o urce D oc u me nt Re q uire me nts  
I n v esti gat ors are re q uire d t o pre pare a n d mai ntai n a de q uat e a n d acc urat e patie nt rec or ds (s o urce 
d oc u me nts). T he site is res p o nsi ble t o e ns ure q ualit y wit hi n t heir rec or ds a n d s yste ms a n d is 
acc o u nta bl e f or e ns uri n g t hat all s o urce dat a a n d C R F data are ti mel y, acc urate, a n d c o m plete.  
T he i n vesti gat or m ust k ee p all s o ur ce d oc u me nts o n  file wit h t h e C R F (t hr o u g h o ut t his pr ot o c ol, 
C R F refers t o eit her a p a per C R F or a n electr o ni c C R F [e C R F]). Case re p ort f or ms a n d s o urce 
d oc u me nts m ust be a vaila ble at all ti mes f or i ns pecti o n b y a ut h orize d re prese nt ati ves of t he 
s p o ns or a n d re g ulat or y a ut h orities. 
1 2. 2. 3.  
C ase Re p ort F or m R e q uire me nts  
St u d y data o btai ne d i n t he c o urs e of t he cli nical st u d y will be rec or de d o n e C R Fs wit hi n t he 
E D C  s yste m b y trai n e d site pers o n nel. All re q uir e d C R Fs m ust be c o m plete d f or eac h a n d e ver y 
patie nt e nr olle d i n t he st u d y . T he i n v esti gat or m ust e ns ure t he acc urac y, c o m plete ness, a n d 
ti meli ness of t he data re p orte d t o t he s p o ns or i n t he C R Fs. After re vie w of t he cli nical data f or 
eac h p atie nt, t he i n vesti gat or m ust pr o vi de a n electr o nic si g n at ure. A c o p y of eac h patie nt 
C R F  case b o o k is t o be retai ne d b y t h e i n vesti gat or as part of t he st u d y rec or d a n d m ust b e a vaila ble 
at all ti mes f or i ns pecti o n b y a ut h orize d re pres e ntati ves of t he s p o ns or a n d re g ul at or y a ut h orities.  
C orrecti o ns t o t he C R F  will be e ntere d i n t he C R F b y t he i n vesti gat or or a n a ut h orize d desi g nee. 
All c ha n ges, i ncl u di n g date a n d pers o n perf or mi n g c orrecti o ns, will be a vail a ble via t he a u dit trail, 
w hic h is part of t he E D C s yste m. F or c orrecti o ns ma de via d ata q u eries, a reas o n f or a n y alterati o n 
m ust be pr o vi d e d. 
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Cli nical St u d y Pr ot oc ol  
 
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1 2. 3.  
A u dits a n d I ns pecti o ns  
T his st u d y ma y b e s u bject t o a q ualit y ass ura n ce a u dit or i ns pecti o n b y t he s p o ns or or re g ulat or y 
a ut h orities. S h o ul d t his occ ur, t he i n vesti gat or is r es p o nsi ble f or:  
•  I nf or mi n g t he s p o ns or of a pla n ne d i ns pecti o n b y t he a ut h orities as s o o n as 
n otificati o n is recei ve d, a n d a ut h orizi n g t he s p o ns or’s partici pati o n i n t he i ns pecti o n  
•  Pr o vi di n g access t o all necessar y facilities, st u d y d ata, a n d d oc u m e nts f or t h e 
i ns pecti o n or a u dit 
•  C o m m u nicati n g a n y i nf or mati o n arisi n g fr o m i ns pecti o n  b y t h e re g ulat or y a ut h orities 
t o t he s p o ns or i m me diatel y 
•  Ta ki n g all a p pr o priat e meas ures re q ueste d b y t he s p o ns or t o res ol ve t he pr o ble ms 
f o u n d d uri n g t h e a u dit or i ns pecti o n 
D oc u me nts s u bject t o a u dit or i ns pecti o n i ncl u de b ut are n ot li mite d t o all s o ur ce d oc u m e nts, C R Fs, 
me dical rec or ds, c orres p o n de nce, I C Fs, E C fil es, d oc u me nt ati o n of certificati o n a n d q ualit y 
c o ntr ol of s u p p orti n g la b orat ories, a n d rec or ds rel e va nt t o t he st u d y mai ntai ne d i n a n y s u p p orti n g 
p har mac y facilities. C o n diti o ns of st u d y m ate rial st ora ge are als o s u bject t o i ns pecti o n. I n a d diti o n, 
re pres e ntati ves of t he s p o ns or ma y o bser ve t he c o n d uct of a n y as pect of t he cli nical st u d y or its 
s u p p orti n g acti vities b ot h wit hi n a n d o utsi de of t he i n vesti gat or’s i nstit uti o n. 
I n all i nsta nces, the c o nfi de ntialit y of t he d ata m ust be res pecte d.  
1 2. 4.  
St u d y D oc u me nt ati o n  
1 2. 4. 1.  
Certific ati o n of Acc ur a c y of D at a  
A declarati o n ass uri n g t h e acc urac y a n d c o nte nt of t he data rec or de d o n t h e C R F/e C R F m ust be 
si g ne d electr o ni call y b y t he i n vesti gat or. T his si g n e d decl arati o n acc o m pa nies eac h set of p atie nt 
fi nal C R Fs/e C R Fs t hat will be pr o vi de d t o t he s p o ns or. 
1 2. 4. 2.  
Rete nti o n of Rec or ds  
T he i n vesti gat or m ust retai n all esse ntial st u d y d oc u me nts, i ncl u di n g I C Fs, s o urce d oc u me nts, 
i n vesti gat or c o pies of C R Fs, a n d dr u g acc o u ntabilit y rec or ds f or at least 1 5  years f oll o wi n g t he 
c o m pleti o n or disc o nti n u ati o n of t he st u d y, or l o n ger, if a l o n ger p eri o d is re q uire d b y rele va nt 
re g ulat or y a ut h orities. T he i n vesti gat or m ust o bt ai n writte n a p pr o val fr o m t he s p o ns or bef ore 
discar di n g or  destr o yi n g a n y esse ntial st u d y d o c u me nts d uri n g t he rete nti o n peri o d f oll o wi n g st u d y 
c o m pleti o n or disc o nti n uati o n. Rec or ds m ust be destr o ye d i n a ma n ner t h at e ns ures c o nfi de ntialit y.  
If t he i n vesti gat or’s p ers o nal sit uati o n is s uc h t hat arc hi vi n g ca n n o l o n ger be e ns ure d, t h e 
i n vesti gat or m ust i nf or m t he s p o ns or ( writte n n otificati o n) a n d t he rele va nt rec or ds will be 
tra nsferre d t o a m ut uall y a gree d-u p o n desti nati o n.  
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1 3.  
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S   
1 3. 1.  
G o o d Cli nic al Pr actice St ate me nt  
It is t he res p onsi bilit y of b ot h t he s p o ns or a n d t he i n vesti gat or(s) t o e ns ure t hat t his cli nical st u d y 
will be c o n d ucte d i n acc or da nce wit h t he 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 t hat are c o nsiste nt wit h t he I C H g ui deli nes f or G C P a n d a p plica ble re g ulat or y 
re q uire me nts. 
1 3. 2.  
I nf or me d C o nse nt 
T he pri nci ples of i nf or me d c o nse nt are des cri be d i n I C H g ui deli nes f or G C P.  
T he I C F use d b y t he i n vesti gat or m ust be re vie we d a n d a p pr o ve d b y t he s p o ns or pri or t o 
s u b missi o n t o t he a p pr o priate E C. A c o p y of t he E C -a p pr o ve d I C F a n d d o c u me ntati o n of a p pr o val 
m ust be pr o vi de d t o t he s p o ns or bef ore st u d y dr u g will be s hi p pe d t o t he st u d y site.  
It is t he res p o nsi bilit y of t he i n vesti gat or or d esi g n ee (if acce pta bl e b y l ocal re g ulati o ns) t o o btai n 
wri tte n i nf or me d c o nse nt fr o m e ac h p atie nt pri or t o his/ her partici p ati o n i n t he st u d y a n d after t he 
ai ms, met h o ds, o bjecti ves, a n d p ote ntial hazar ds of t he st u d y ha v e bee n e x plai ne d t o t he patie nt i n 
la n g u a ge t hat h e/s he ca n u n dersta n d. T he I C F s h o ul d be si gn e d a n d d ate d b y t he p atie nt a n d b y t h e 
i n vesti gat or or a ut h orize d desi g nee w h o re vie we d t he I C F wit h t he patie nt.   
•  Patie nts w h o ca n write b ut ca n n ot rea d will ha ve t he I C F rea d t o t he m bef ore si g ni n g 
a n d dati n g t h e I C F.  
•  Patie nts w h o ca n u n derst a n d b ut w h o ca n n eit her write n or rea d will ha ve t he I C F 
rea d t o t he m i n t he prese nce of a n i m partial wit ness, w h o will si g n a n d dat e t he I C F t o 
c o nfir m t hat i nf or me d c o nse nt was gi ve n.  
T he ori gi nal I C F m ust b e ret ai ne d b y t h e i n vesti gat or as p art of t he p atie nt’s s t u d y rec or d, a n d a 
c o p y of t he si g ne d I C F m ust be gi ve n t o t he patie nt.  
If n e w safet y i nf or mati o n res ults i n si g nifica nt c h a n ges i n t he ris k/ be nefit assess me nt, or if t here 
are si g nifica nt c h a n ges t o t he st u d y pr oce d ures, t he I C F 
m ust b e re vie we d a n d u p d at e d 
a p pr o priatel y. All st u d y p atie nts m ust be i nf or me d of t he n e w i nf or m ati o n a n d pr o vi de t heir writte n 
c o nse nt if t he y wis h t o c o nti n ue i n t he st u d y. T he ori gi nal, si g n e d re vise d I C F m ust be mai ntai ne d 
i n t he patie nt’s st u d y rec or d a n d a c o p y m ust be gi ve n t o t he patie nt. 
1 3. 3.  
P atie nts C o nfi de nti alit y a n d D at a Pr otecti o n  
T he i n vesti gat or m ust ta ke all a p pr o pri ate meas ures t o e ns ure t h at t he a n o n y mit y of eac h st u d y 
patie nt will be mai ntai ne d. Patie nts s h o ul d be i de ntifie d b y a p atie nt i de ntificati o n n u m ber o nl y, 
o n C R Fs or ot her d oc u m e nts s u b mitte d t o t he s p o ns or. D oc u me nts t hat will n ot be s u b mitte d t o 
t he s p o ns or (e g, si g ne d I C F) m ust be ke pt i n strict c o nfi de nce. 
T he patie nt’s a n d i n vesti gat or’s pers o nal data, w hi c h ma y be i ncl u de d i n t he s p o ns or data base, will  
be treate d i n c o m plia n ce wit h all a p plica ble la ws a n d re g ulati o ns. T he s p o ns or s hall ta ke all 
a p pr o priate me as ures t o safe g uar d a n d pre v e nt access t o t his data b y a n y u n a ut h orize d t hir d part y.  
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Re ge n er o n P har mace uticals, I n c.  
 
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C O N FI D E N TI A L  
1 3. 4.  
I nstit uti o n al Re vie w B o ar d 
A n a p pr o priatel y c o nstit ute d E C, as  descri be d i n I C H g ui deli nes f or G C P, m ust re vie w a n d 
a p pr o ve:  
•  T he pr ot oc ol, I C F, a n d a n y ot her 
materials t o be pr o vi de d t o t he patie nts 
(e g, a d vertisi n g) bef ore a n y patie nt ma y b e e nr olle d i n t he st u d y  
•  A n y a me n d me nt or m o dificati o n t o t he st u d y pr ot oc ol o r I C F b ef ore i m ple me ntati o n, 
u nless t he c ha n ge is necessar y t o eli mi nate a n i m me diate hazar d t o t he patie nt, i n w hic h 
case t he E C s h o ul d be i nf or me d as s o o n as p ossi ble  
•  O n g oi n g st u dies o n a n a n n ual basis or at i nter vals a p pr o priate t o t he de gree of ris k  
I n a d diti o n, t he E C s h o ul d be i nf or me d of a n y e v e nt li kel y t o affect t he safet y of patie nts or t he 
c o nti n ue d c o n d uct of t he cli nical st u d y.  
A c o p y of t he E C a p pr o val letter wit h a c urre nt list of t he E C me m bers a n d t heir f u ncti o ns m ust 
be recei ve d b y t h e s p o ns or pri or t o s hi p me nt of dr u g s u p plies t o t he i n vesti gat or. T h e a p pr o val 
letter s h o ul d i ncl u de t he st u d y n u m ber a n d title, t he d oc u me nts re vie we d, a n d t he date of t he 
re vie w. 
Rec or ds of t he E C re vie w a n d a p pr o val of all st u d y d o c u me nts (i n cl u di n g a p pr o v al of o n g oi n g 
st u dies) m ust be ke pt o n file b y t he i n v esti gat or. 
1 3. 5.  
Cli nic al St u d y D at a Tr a ns p are nc y  
Fi nal st u d y res ults will be p u blis he d o n a p u blic cli nical trial we bsite acc or di n g t o a p plica bl e l ocal 
g ui deli nes a n d re g ulati o ns. Treat me nt c o des will be dis se mi nate d t o eac h i n vesti gati o n site 
t hereafter. 
1 4.  
P R O T O C O L A M E N D M E N T S  
T he s p o ns or ma y n ot i m ple me nt a c h a n ge i n t he desi g n of t h e pr ot oc ol or I C F wit h o ut a n 
E C -a p pr o ve d a me n d me nt. W here re q uir e d per l ocal le gislati o n, re g ulat or y a ut h orit y a p pr o val will 
als o be s o u g ht.  
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C O N FI D E N TI A L  
1 5.  
P R E M A T U R E T E R MI N A TI O N O F T H E S T U D Y O R 
C L O S E -O U T O F A SI T E  
1 5. 1.  
Pre m at ure Ter mi n ati o n of t he St u d y  
T he s p o ns or has t he ri g ht t o ter mi nate t he st u d y pre mat urel y. Reas o ns ma y i n cl u de efficac y, safet y, 
or f utilit y, a m o n g ot hers. S h o ul d t he s p o ns or deci d e t o ter mi nate t he st u d y, t he i n vesti gat or(s) will 
be n otifie d i n writi n g.  
1 5. 2.  
Cl ose -o ut of a Site  
T he s p o ns or a n d t he i n vesti gat or ha v e t he ri g ht t o cl ose -o ut a site pre mat urel y.  
I nvesti g at or’s Decisi o n 
T he i n vesti gat or m ust n otif y t he s p o ns or of a desire t o  cl ose-o ut a site i n writi n g, pr o vi di n g at least 
3 0 da ys’ n otice. T he fi nal decisi o n s h o ul d be ma de t hr o u g h m ut ual a gree m e nt wit h t he s p o ns or. 
B ot h parties will arra n ge t he cl ose -o ut pr oce d ures after re vie w a n d c o ns ultati o n.  
S p o ns or’s Decisi o n  
T he s p o ns or will n otif y t h e i n vesti gat or(s) of a decisi o n t o cl ose -o ut a st u d y site i n writi n g. Reas o ns 
ma y i ncl u d e t he f oll o wi n g, a m o n g ot hers:  
•  T he i n vesti gat or has recei ve d all ite ms a n d i nf or mati o n necessar y t o p erf or m t he st u d y, 
b ut has n ot e nr olle d a n y patie nt w it hi n a reas o n a ble peri o d of ti me 
•  T he i n vesti gat or has vi olate d a n y f u n da me nt al o bli gati o n i n t he st u d y a gree m e nt, 
i ncl u di n g b ut n ot li mite d t o, breac h of t his pr ot oc ol (a n d a n y a p plica ble a m e n d me nts), 
breac h of t he a p plica ble la ws a n d re g ulati o ns, or brea c h of a n y a p plica ble 
I C H g ui deli nes  
•  T he t otal n u m ber of patie nts re q uire d f or t he st u d y are e nr olle d earlier t ha n e x pecte d  
I n all cases, t he a p pr o pri ate E C a n d Healt h A ut h orities m ust be i nf or me d acc or di n g t o a p plica ble 
re g ulat or y re q uir e me nts, a n d a de q u ate c o nsi derati o n m ust be gi ve n t o t he pr ot ecti o n of t he 
patie nts’ i nterests.  
1 6.  
C O N FI D E N TI A LI T Y  
C o nfi de ntialit y of i nf or m ati o n is pr o vi de d as a se p arate a gree me nt.  
1 7.  
FI N A N CI N G A N D I N S U R A N C E   
Fi na nci n g a n d i ns ura nce i nf or mati o n is pr o vi de d as a se parate a gree m e n t. 
1 8.  
P U B LI C A TI O N P O LI C Y   
P u blicati o n ri g hts a n d pr oce d ures will be o utli ne d i n a se parate cli nical st u d y a gree m e nt.  
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Re ge n er o n P har mace uticals, I n c.  
 
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C O N FI D E N TI A L  
1 9.  
R E F E R E N C E S   
Al -A ni F, C hi n -Yee I, La z o -La n g n er A. Ec uliz u ma b i n t he ma na ge me nt of par o x ys mal n oct ur nal 
he m o gl o bi n uria: patie nt selecti o n a n d s pecial c o nsi derati o ns. T her Cli n Ris k 
Ma na g 2 0 1 6; 
1 2: 1 1 6 1 -7 0.  
At ki ns o n MJ, K u mar R, Ca p pelleri J C, Hass S L. Hierarc hical c o nstr uct vali dit y of t he treat me nt 
satisfacti o n q uesti o n nair e f or 
me dicati o n ( T S Q M versi o n II) a m o n g o ut patie nt  p har mac y 
c o ns u mers. Val u e Healt h 2 0 0 5; 8 S u p pl 1: S 9 -S 2 4.  
At ki ns o n MJ, Si n ha A, Hass S L, C ol ma n S S, K u mar R N, Br o d M, et al. Vali dati o n of a ge n eral 
meas ure of treat me nt s atisfacti o n, t he Treat me nt Satisfacti o n Q uesti o n naire f or 
Me dicati o n 
( T S Q M), usi n g a nati o nal pa nel st u d y of c hr o nic disease. Healt h Q ual Life O utc o mes 2 0 0 4; 2: 1 2.  
Br o ds k y R A. Ec uliz u ma b: a n ot her brea kt hr o u g h. Bl o o d 2 0 1 7; 1 2 9( 8): 9 2 2 -3.  
Br o ds k y R A. H o w I treat par o x ys mal n oct ur nal h e m o gl o bi n uria. Bl o o d 2 0 0 9; 1 1 3( 2 6): 6 5 2 2 -7.  
Br o ds k y R A. Par o x ys mal n oct ur nal he m o gl o bi n uria. Bl o o d 2 0 1 4; 1 2 4( 1 8): 2 8 0 4 -1 1.  
Br o ds k y R A, Y o u n g N S, A nt o ni oli E, Risita n o A M, Sc hreze n meier H, Sc h u bert J, et al. 
M ultice nter p hase 3 st u d y of t he c o m ple me nt i n hi bit or ec uliz u ma b f or t he treat me nt of patie nts 
wit h par o x ys m al  n oct ur n al he m o gl o bi n uria. Bl o o d 2 0 0 8; 1 1 1( 4): 1 8 4 0 -7.  
C oc ks K, C o he n D, Wisl off F, Sezer O, Lee S, Hi p pe E, et al. A n i nter nati o nal fiel d st u d y of t he 
relia bilit y a n d vali dit y of a dise ase-s p ecific q uesti o n naire m o d ule (t he Q L Q-M Y 2 0) i n assessi n g 
t he q ualit y of lif e of patie nts wit h m ulti ple m yel o ma. E ur J Ca ncer 2 0 0 7; 4 3( 1 1): 1 6 7 0-8.  
C T F G. 2 0 2 0.  Rec o m me n dati o ns relate d t o c o ntrace pti o n a n d pre g na n c y testi n g i n cli nical trials. 
V ol. v 1. 1. Cli nical Trials Facilitati o n a n d C o or di n ati o n Gr o u p.  
F D A. 2 0 0 9.  G ui d a nce f or I n d ustr y: Patie nt -Re p orte d O utc o me Meas ures: Use i n Me dical Pr o d uct 
De vel o p me nt t o S u p p ort La b eli n g Clai ms.  
Fi g u er oa J E, De nse n P. I nfecti o us diseases ass ociate d wit h c o m ple me nt defici e ncies. Cli n 
Micr o bi ol Re v 1 9 9 1; 4( 3): 3 5 9 -9 5.  
Gast o n M H, V erter  JI, W o o ds G, Pe gel o w C, Kelle her J, Pres b ur y G, et al. Pr o p h yla xis wit h oral 
pe nicilli n i n c hil dre n wit h sic kle cell a ne mia. A ra n d o mize d trial. N E n gl J 
Me d 1 9 8 6; 
3 1 4( 2 5): 1 5 9 3 -9.  
Griffi n M, M u nir T. M a na ge me nt of t hr o m b osis i n par o x ys m al n oct ur nal he m o gl o bi n uria: a 
cli nicia n's g ui de. T her A d v He mat ol 2 0 1 7; 8( 3): 1 1 9 -2 6.  
Gr ot h 
M, Si n ger S, Ni e de g ge n C, Peter m a n n -Me yer A, R ot h A, Sc hreze n meier H, et al. 
De vel o p me nt of a diseas e -s pecifi c q ualit y of life q uesti o n naire f or patie nts wit h a plastic a ne mia 
a n d/ or par o x ys mal n oct ur nal he m o gl o bi n uria ( Q L Q -A A/ P N H) -re p ort o n p hases I a n d II. A n n 
He mat ol 2 0 1 7; 9 6( 2): 1 7 1 -8 1.  
Hill A, Kell y RJ, Hill me n P. T hr o m b osis i n par o x ys mal n oct ur nal he m o gl o bi n uria. Bl o o d 2 0 1 3; 
1 2 1( 2 5): 4 9 8 5 -9 6; q uiz 5 1 0 5.  
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R 3 9 1 8 -P N H -2 0 1 0 5 A me n d me nt 3  
Re ge n er o n P har mace uticals, I n c.  
 
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C O N FI D E N TI A L  
Hill me n P, Hall C, Mars h J C, Ele b ute M, B o m bara M P, Petr o B E, et al. Effect of ec uliz u ma b o n 
he m ol ysis a n d tra nsf usi o n re q uire m e nts i n patie nts wit h par o x ys mal n oct ur nal he m o gl o bi n uria. N 
E n gl J Me d 2 0 0 4; 3 5 0( 6): 5 5 2 -9.  
Hill me n P, M u us P, R ot h A, Ele b ute M O, Risita n o A M, Sc hreze n meier H, et al. L o n g -t er m safet y 
a n d effic ac y of s ustai ne d ec uliz u ma b treat m e nt i n patie nts 
wit h par o x ys mal n oct ur nal 
hae m o gl o bi n uria. Br J Hae mat ol 2 0 1 3; 1 6 2( 1): 6 2 -7 3.  
Hill me n P, Y o u n g N S, Sc h u bert J, Br o ds k y R A, S ocie G, M u us P, et al. T he c o m ple me nt i n hi bit or  
ec uliz u ma b i n par o x ys m al n oct ur nal he m o gl o bi n uria. N E n gl J Me d 2 0 0 6; 3 5 5( 1 2): 1 2 3 3 -4 3.  
Lee J W, Sicre de F o nt br u ne F, 
W o n g Lee Lee L, Pess oa V, G ual a n dr o S, F ure der W, et al. 
Ra v uliz u ma b ( A L X N 1 2 1 0) vs ec uliz u ma b i n a d ult patie nts wit h P N H nai ve t o c o m ple me nt 
i n hi bit ors: t he 3 0 1 st u d y. Bl o o d 2 0 1 9; 1 3 3( 6): 5 3 0-9.  
Le v e y A S, Ste ve ns L A, S c h mi d C H, Z ha n g Y L, Castr o A F, 3r d, Fel d ma n HI, et al. A ne w e q u ati o n 
t o esti mate gl o mer ular filtrati o n rate. A n n I nt er n Me d 2 0 0 9; 1 5 0( 9): 6 0 4-1 2.  
L uzzatt o L, Risita n o A M. A d va nc es i n u n dersta n di n g t he pat h o ge nesis of ac q uire d a plastic 
a nae mia. Br J Hae mat ol 2 0 1 8; 1 8 2( 6): 7 5 8 -7 6.  
Mc Na mara L A, T o paz N, 
Wa n g X, Hariri S, F o x L, 
Mac Neil J R. Hi g h Ris k f or I n vasi v e 
Me ni n g o c occal Diseas e A m o n g Patie nts Recei vi n g Ec uliz u ma b ( S oliris) Des p ite Recei pt of 
Me ni n g o c occal Vacci ne. M M W R M or b M ortal W kl y Re p 2 0 1 7; 6 6( 2 7): 7 3 4 -7.  
Na ka ya m a H, Us u ki K, Ec hiz e n H, O ga wa R, Orii T. Ec uliz u ma b D osi n g I nt er vals L o n ger t ha n 
1 7 Da ys Ma y Be Ass ociate d wit h Greater Ris k of Brea kt hr o u g h He m ol ysis i n Patie nts w it h 
Par o x ys mal N o ct ur nal H e m o gl o bi n uria. Bi ol P har m B ull 2 0 1 6; 3 9( 2): 2 8 5 -8.  
N H S E n gla n d. 2 0 1 3.  B 0 5/ S( H S S)/a. 2 0 1 3/ 1 4 N H S Sta n dar d C o ntract f or Par o x ys mal N oct ur n al 
Hae m o gl o bi n uria Ser vice ( A d ults a n d A d oles ce nts).  
Nis hi m ura J, Ya ma m ot o M, Ha yas hi S, O h yas hi ki K, A n d o K, Br o ds k y A L, et al. Ge netic varia nts 
i n C 5 a n d p o or res p o nse t o ec uliz u ma b. N E n gl J Me d 2 0 1 4; 3 7 0( 7): 6 3 2-9.  
Patric k D L, B ur ke L B, G walt ne y CJ, Lei d y N K, Marti n M L, M olse n E, et al. C o nte nt vali dit y --
esta blis hi n g a n d re p orti n g t he e vi de n ce i n ne wl y de vel o pe d patie nt -re p orte d o utc o mes ( P R O) 
i nstr u me nts f or me di cal pr o d uct e v al uati o n: I S P O R P R O G o o d Researc h Practices Tas k F orce 
re p ort: part 2--assessi n g res p o n de nt u n dersta n di n g. Val ue Healt h 2 0 1 1; 1 4( 8): 9 7 8 -8 8.  
Peffa ult de Lat o ur R, Fre mea u x -B acc hi V, P orc her R, X haar d A, R osai n J, Casta ne da D C, et al. 
Assessi n g c o m ple me nt bl oc ka de i n patie nts wit h p ar o x ys mal n oct ur n al he m o gl o bi n uria recei vi n g 
ec uliz u ma b. Bl o o d 2 0 1 5; 1 2 5( 5): 7 7 5 -8 3.  
Plat o n o v A E, S hi p uli n G A, S hi p uli na OJ, Vers hi ni na I V, De nse n P . Heter oz y g o us C 8 bet a 
c o m ple me nt deficie nc y d oes n ot pre dis p ose t o me ni n g oc o ccal diseas e. Cli n E x p I m m u n ol 1 9 9 7; 
1 0 8( 3): 4 9 7 -9.  
Preis M, L o wre y C H. La b orat or y tests f or p ar o x ys mal n oct ur nal he m o gl o bi n uria. A m J He mat ol 
2 0 1 4; 8 9( 3): 3 3 9 -4 1.  
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Cli nical St u d y Pr ot oc ol  
 
R 3 9 1 8 -P N H -2 0 1 0 5 A me n d me nt 3  
Re ge n er o n P har mace uticals, I n c.  
 
Pa ge 1 1 0  
 
C O N FI D E N TI A L  
R öt h A, R otti n g ha u s S T, Hill A, Bac h ma n E S, Ki m J S, Sc hreze n meier H, et al. Ra v uliz u ma b 
( A L X N 1 2 1 0) i n p atie nts wit h par o x ys m al n oct ur nal he m o gl o bi n uria: res ults of 2 p hase 1 b/ 2 
st u dies. Bl o o d A d v 2 0 1 8; 2( 1 7): 2 1 7 6-8 5.  
R ot her R P, Bell L, Hill me n P, Gla d wi n M T. T h e cli nical se q uelae of i ntra v asc ular he m ol ysis a n d 
e xtracell ular plas ma he m o gl o bi n: a n o vel 
mec ha nis m of h u ma n dis ease. J A M A 2 0 0 5; 
2 9 3( 1 3): 1 6 5 3 -6 2.  
Sa hi n F, A ka y O M, A yer M, Dal M S, Ert o p S, Il h a n O, et al. Pes g P N H di a g n osis, f oll o w -u p a n d 
treat me nt g ui deli nes. A m J Bl o o d Res 2 0 1 6; 6( 2): 1 9-2 7.  
Sa m ps o n H A, M u n oz -F url o n g A, Ca m p bell R L, A d ki ns o n N F, Jr., B oc k S A, Bra n u m A, et al. 
Sec o n d s y m p osi u m o n t he defi niti o n a n d ma na ge me nt of a na p h yla xis: s u m mar y re p ort --Sec o n d 
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Disease/ F o o d Aller g y a n d A na p h yl a xis Net w or k 
s y m p osi u m. J Aller g y Cli n I m m u n ol 2 0 0 6; 1 1 7( 2): 3 9 1-7.  
S heri da n D, Y u Z X, Z ha n g Y, Patel R, S u n F, Lasar o 
M A, et al. Desi g n a n d precli nical 
c haracteriz ati o n of A L X N 1 2 1 0: A n o v el a nti -C 5 a nti b o d y wit h e xte n de d d urati o n of acti o n. P L o S 
O ne 2 0 1 8; 1 3( 4):e 0 1 9 5 9 0 9.  
S oliris ® . 2 0 2 1.  Prescri bi n g i nf or m ati o n f or ec uliz u ma b. Ale xi o n P har mace uticals, I n c. 
Stea d M L, Br o w n J M, Veli k o va G, K aasa S, Wisl off F, C hil d J A, et al. De v el o p me nt of a n E O R T C 
q uesti o n naire m o d ule t o be use d i n healt h -relate d q ualit y-of -life assess me nt f or patie nts wit h 
m ulti ple m yel o ma. E ur o p ea n Or ga niz ati o n f or Researc h a n d Treat me nt of Ca ncer St u d y Gr o u p o n 
Q ualit y of Lif e. Br J Hae mat ol 1 9 9 9; 1 0 4( 3): 6 0 5 -1 1.  
We dzic ha J A. A nti bi otics at C O P D e x acer bati o ns: t he de bate c o nti n ues. T h ora x 2 0 0 8; 6 3( 1 1): 9 4 0 -
2.  
Weitz I, M e yers G, La m y T, Ca h n J Y, Ura n ga M T, Garcia Vela J A, et al. Cr oss -secti o nal 
vali dati o n st u d y of p atie nt -re p ort e d o utc o mes i n 
patie nts 
wit h 
p ar o x ys mal n oct ur n al 
hae m o gl o bi n uria. I nter n Me d J 2 0 1 3; 4 3( 3) : 2 9 8-3 0 7.  
 
 
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C O N FI D E N TI A L  
2 0.  
I N V E S TI G A T O R’ S A G R E EM E N T  
I ha v e rea d t he attac h e d pr ot oc ol: ‘ A Si n gle Ar m, O pe n-La b el St u d y t o Assess t he Safet y, Efficac y, 
a n d P har mac o d y na mic Effects of P ozeli ma b a n d Ce m disira n C o m bi nati o n T hera p y i n Patie nts 
wit h Par o x ys mal N o ct ur nal He m o gl o bi n uria W h o S witc h Fr o m Ec uliz u ma b T hera p y’ a n d a gree 
t o a bi de b y all pr o visi o ns set f ort h t herei n. 
I a gree t o c o m pl y wit h t he c urre nt I nter nati o nal C o u ncil f or Har m o nisati o n G ui deli ne f or G o o d 
Cli nical Practice a n d t h e la ws, r ules, re g ulati o ns, a n d  g ui d eli nes of t he c o m m u nit y, c o u ntr y, state, 
or l ocalit y relati n g t o t he c o n d uct of t he cli nical st u d y.  
I als o a gree t hat pers o ns de barre d fr o m c o n d ucti n g or w or ki n g o n cli nical st u dies b y a n y c o urt or 
re g ulat or y a ge nc y will n ot be all o we d t o c o n d uct or wor k o n st u dies f or t he s p o ns or or a part ners hi p 
i n w hic h t he s p o ns or is i n v ol ve d. I will i m me diatel y discl ose it i n writi n g t o t he s p o ns or if a n y 
pers o n w h o is i n v ol ve d i n t he st u d y is de b arre d, or if a n y pr ocee di n g f or d e bar me nt is pe n di n g, or, 
t o t he best of m y k n o wl e d ge, t hr eate n e d. 
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n of t he s p o ns or, w hi c h m ust n ot be discl ose d t o 
a n y o n e ot her t ha n t he reci pie nt st u d y staff a n d me m bers of t he E C. I a gree t o e ns ure t h at t his 
i nf or mati o n will n ot be use d f or a ny p ur p os e ot her t ha n t he e val uati o n or c o n d uct of t he cli nical 
i n vesti gati o n wit h o ut t he pri or writte n c o nse nt of t he s p o ns or. 
 
 
 
( Si g nat ur e of I n v esti gat or) 
 
( Date) 
 
 
 
( Pri nte d Na me) 
 
 
 
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C O N FI D E N TI A L  
SI G N A T U R E O F S P O N S O R ’ S R E S P O N SI B L E O F FI CE R S  
 ( Me dic al/ St u d y 
Direct or, 
Re g ul at or y 
Re prese nt ati ve, 
Cli nic al 
St u d y 
Le a d, 
a n d 
Bi ost atistici a n)  
T o t he best of my k n o wle d ge, t his re p ort acc ur atel y descri bes t he pl a n ne d c o n d uct of t he st u dy.  
St u d y Title:  
 A 
Si n gle ar m, 
O pe n -la bel 
St u d y t o 
Assess t he 
Safet y, 
Efficac y, a n d 
P har mac o d y na mic Effects of P ozeli ma b a n d C e m disira n C o m bi nati o n T hera p y i n Patie nts wit h 
Par o x ys mal N o ct ur nal H e m o gl o bi n uria W h o S witc h Fr o m Ec uliz u ma b T hera p y   
Pr ot oc ol N u m ber:   R 3 9 1 8 -P N H -2 0 1 0 5  
Pr ot oc ol Versi o n:  R 3 9 1 8 -P N H -2 0 1 0 5 A me n d me nt  3  
See a p pe n d e d ele ctr o nic si g n at ure p a ge  
S p o ns or’s Res p o nsi ble Me dical/ St u d y Direct or  
See a p pe n d e d ele ctr o nic si g n at ure p a ge  
S p o ns or’s Res p o nsi ble Re g ul at or y Liais o n  
See a p pe n d e d ele ctr o nic si g n at ure p a ge  
S p o ns or’s Res p o nsi ble Cli nical St u d y Lea d  
See a p pe n d e d ele ctr o nic si g n at ure p a ge  
S p o ns or’s Res p o nsi ble Bi ostatisticia n  
                                        V V- RI M- 0 0 1 7 2 3 7 7- 1. 0 A p pr o ve d - 0 6 Dec 2 0 2 1 G M T- 5: 0 0

Si g nat ure Pa ge f or V V- RI M- 0 0 1 7 2 3 7 7 v 1. 0
Si g nat ure Pa ge f or V V- RI M- 0 0 1 7 2 3 7 7 v 1. 0 A p pr o ve d
A p pr o val/e Si g nat ure
0 3- Dec- 2 0 2 1 2 1: 3 9: 0 3 G M T + 0 0 0 0
A p pr o val/e Si g nat ure
0 6- Dec- 2 0 2 1 1 5: 4 1: 1 0 G M T + 0 0 0 0
A p pr o val/e Si g nat ure
0 6- Dec- 2 0 2 1 1 7: 4 4: 0 7 G M T + 0 0 0 0
A p pr o val/e Si g nat ure
0 6- Dec- 2 0 2 1 2 1: 3 0: 1 0 G M T + 0 0 0 0
                                        V V- RI M- 0 0 1 7 2 3 7 7- 1. 0 A p pr o ve d - 0 6 Dec 2 0 2 1 G M T- 5: 0 0