Clinical trial NCT04888507
Conditions: Paroxysmal Nocturnal Hemoglobinuria
Keywords: PNH
Sponsor: Regeneron Pharmaceuticals
Start date: 2021-07-08; Completion date: 2023-05-04
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to evaluate the safety and tolerability of pozelimab and cemdisiran combination therapy in participants with PNH who switch from eculizumab therapy

The secondary objectives of the study are:

* To evaluate the effect of the combination treatment on the following parameters of intravascular hemolysis: lactate dehydrogenase (LDH) control, breakthrough hemolysis, and inhibition of CH50
* To evaluate the effect of the combination treatment on the stability of LDH during the transition period from eculizumab monotherapy to combination with pozelimab and cemdisiran
* To evaluate the effect of the combination treatment on red blood cell (RBC) transfusion requirements
* To evaluate the effect of the combination treatment on hemoglobin levels
* To evaluate the effect of the combination treatment on clinical outcome assessments (COAs) measuring fatigue and health related quality of life (HRQoL)
* To assess the concentrations of total pozelimab and eculizumab in serum; and total cemdisiran and C5 protein in plasma
* To assess the immunogenicity of pozelimab and cemdisiran
* To assess safety after dose intensification
* To evaluate the long-term safety and efficacy of the combination treatment in an optional open-label extension period (OLEP)

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Pozelimab intervention 2: Cemdisiran
Intervention descriptions: intervention 1: Intravenous (IV) loading dose (once) followed after 30 minutes by sub-cutaneous (SC) administration intervention 2: SC administration

Protocol documents:
Prot_000.pdf: 


Cli nical St u d y Pr ot oc ol  
 
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Pa ge 2  
 
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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Pa ge 3  
 
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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Pa ge 4  
 
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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Pa ge 5  
 
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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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 6  
 
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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Pa ge 2 1  
 
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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Cli nical St u d y Pr ot oc ol  
 
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Pa ge 2 2  
 
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  
                                        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


Cli nical St u d y Pr ot oc ol  
 
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Pa ge 2 3  
 
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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Cli nical St u d y Pr ot oc ol  
 
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Re ge n er o n P har mace uticals, I n c.  
 
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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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 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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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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C O N FI D E N TI A L  
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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C O N FI D E N TI A L  
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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C O N FI D E N TI A L  
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.  
                                        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


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C O N FI D E N TI A L  
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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C O N FI D E N TI A L  
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. 
                                        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


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C O N FI D E N TI A L  
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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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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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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C O N FI D E N TI A L  
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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C O N FI D E N TI A L  
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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C O N FI D E N TI A L  
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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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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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.  
                                        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


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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.  
                                        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


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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. 
                                        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


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C O N FI D E N TI A L  
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.  
                                        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


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 0 5  
 
C O N FI D E N TI A L  
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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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 0 6  
 
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.  
                                        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


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 0 7  
 
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.  
                                        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


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 0 8  
 
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.  
                                        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


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 0 9  
 
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.  
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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.  
                                        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


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.  
 
 
                                        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


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 1  
 
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) 
 
 
 
                                        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


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 2  
 
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

SAP_001.pdf: 


Regeneron Pharmaceuticals, Inc. 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 2 of 65 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
See appended electronic signature page 
Study Biostatistician  
 
See appended electronic signature page 
Study Clinical Pharmacology Lead 
 
See appended electronic signature page 
Study Bioanalytical Sciences Lead 
 
See appended electronic signature page 
Study Precision Medicine Lead 
 
See appended electronic signature page 
Study Medical Director 
 
See appended electronic signature page 
Project Biostatistician  
 
See appended electronic signature page 
Head of BDM or designee 
 
                                        VV-RIM-00212243-1.0 Approved - 28 Sep 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 3 of 65 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale for Study Design ......................................................................9 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objective .........................................................................................................9 
1.2.2. 
Secondary and Exploratory Objectives ........................................................................9 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.4. 
Revision History for SAP Amendments .....................................................................11 
2. 
INVESTIGATION PLAN ..........................................................................................12 
2.1. 
Study Design ...............................................................................................................12 
2.2. 
Sample Size Considerations .......................................................................................13 
2.3. 
Study Plan ...................................................................................................................13 
3. 
ANALYSIS POPULATIONS ....................................................................................14 
3.1. 
The Full Analysis Set (FAS) .......................................................................................14 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................14 
3.3. 
The Pharmacokinetic Analysis Set .............................................................................14 
3.4. 
The Immunogenicity Analysis Sets ............................................................................14 
3.5. 
The Exploratory Biomarker Endpoint Analysis Set ...................................................14 
4. 
ANALYSIS VARIABLES .........................................................................................15 
4.1. 
Demographic and Baseline Characteristics ................................................................15 
4.2. 
Medical History ..........................................................................................................16 
4.3. 
Prior/Concomitant Medication and Procedures ..........................................................16 
4.4. 
Prohibited Medication During Study if Applicable ....................................................17 
4.5. 
Efficacy Variables ......................................................................................................17 
4.5.1. 
Primary Efficacy Variables .........................................................................................17 
4.5.2. 
Secondary Efficacy Variables .....................................................................................17 
4.5.3. 
Exploratory Efficacy Variables ..................................................................................22 
4.6. 
Safety Variables ..........................................................................................................24 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................24 
4.6.2. 
Adverse Events of Special Interest .............................................................................26 
4.6.3. 
Laboratory Safety Variables .......................................................................................26 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 4 of 65 
4.6.4. 
Vital Signs ..................................................................................................................27 
4.6.5. 
12-Lead Electrocardiography (ECG) ..........................................................................27 
4.7. 
Pharmacokinetic Variables .........................................................................................27 
4.8. 
Immunogenicity Variables ..........................................................................................27 
4.9. 
Pharmacodynamic Variables ......................................................................................27 
4.10. 
Clinical Outcome Assessments (COAs) .....................................................................27 
5. 
STATISTICAL METHODS .......................................................................................28 
5.1. 
Demographics and Baseline Characteristics ...............................................................28 
5.2. 
Medical History ..........................................................................................................28 
5.3. 
Prior/concomitant Medications ...................................................................................28 
5.4. 
Prohibited Medications ...............................................................................................28 
5.5. 
Patient Disposition ......................................................................................................29 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................29 
5.6.1. 
Measurement of Compliance ......................................................................................29 
5.6.2. 
Exposure to Investigational Product ...........................................................................29 
5.7. 
Analyses of Efficacy Variables ..................................................................................30 
5.7.1. 
Analysis of Continuous Secondary Efficacy Variables ..............................................31 
5.7.2. 
Analysis of Categorical Secondary Efficacy Variables ..............................................31 
5.7.3. 
Analysis of Exploratory Variables ..............................................................................32 
5.8. 
Analysis of Safety Data ..............................................................................................32 
5.8.1. 
Adverse Events ...........................................................................................................33 
5.8.2. 
Analysis of Vital Signs ...............................................................................................33 
5.8.3. 
Analysis of Laboratory Tests ......................................................................................33 
5.8.4. 
Analysis of 12-Lead ECG ...........................................................................................33 
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data ...........................................34 
5.9.1. 
Analysis of Pharmacokinetic Data ..............................................................................34 
5.9.2. 
Analysis of Immunogenicity Data ..............................................................................34 
5.9.2.1. 
Analysis of ADA Data ................................................................................................34 
5.9.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................35 
5.9.3.1. 
Immunogenicity and Exposure ...................................................................................35 
5.9.3.2. 
Immunogenicity and Safety and Efficacy ...................................................................35 
5.10. 
Analysis of Pharmacodynamic and Biomarker Data ..................................................36 
                                        VV-RIM-00212243-1.0 Approved - 28 Sep 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 5 of 65 
6. 
DATA CONVENTIONS ............................................................................................37 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................37 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................37 
6.3. 
Data Handling Convention for Missing Data .............................................................37 
6.3.1. 
Adverse events ............................................................................................................37 
6.3.2. 
PCSV ..........................................................................................................................39 
6.3.3. 
Date of first / last study drug administration ..............................................................39 
6.4. 
Analysis Windows ......................................................................................................39 
6.5. 
Unscheduled Assessments ..........................................................................................41 
7. 
INTERIM ANALYSIS ...............................................................................................42 
8. 
SOFTWARE ...............................................................................................................43 
9. 
REFERENCES ...........................................................................................................44 
10. 
APPENDIX.................................................................................................................45 
10.1. 
Footnotes for the Schedule of Events Tables .............................................................53 
10.1.1. 
Footnotes for Table 3 Schedule of Events (Open-Label Treatment Period) ..............53 
10.1.2. 
Footnotes for Table 4 Schedule of Events (Open-Label Treatment Period for 
Patients on Intensified Therapy) .................................................................................57 
10.1.3. 
Footnotes for Table 5 Schedule of Events (for Optional Open-Label 
Extension Period) ........................................................................................................59 
10.1.4. 
Footnotes for Table 6 Schedule of Events (Post-Treatment Safety Follow-Up 
Period for All Patients) ...............................................................................................61 
10.2. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................62 
 
                                        VV-RIM-00212243-1.0 Approved - 28 Sep 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 6 of 65 
LIST OF TABLES 
Table 1: Efficacy Analysis Windows ............................................................................................40 
Table 2: Safety Analysis Windows ................................................................................................40 
Table 3: Schedule of Events for Open-Label Treatment Period ....................................................45 
Table 4: Schedule of Events for Treatment Period (for Patients on Intensified Treatment 
in the OLTP) ...............................................................................................................48 
Table 5: Schedule of Events (Optional Open-Label Extension Period) ........................................50 
Table 6: Schedule of Events for Post-Treatment Safety Follow-Up Period (All Patients) ...........52 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................12 
 
                                        VV-RIM-00212243-1.0 Approved - 28 Sep 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 7 of 65 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AH50 
Alternative pathway hemolytic activity assay 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
C 
Complement component (e.g., C3, C5) 
CH50 
Total Complement hemolytic activity assay 
CI 
Confidence interval 
COA 
Clinical outcome assessment 
CRF 
Case report form (electronic or paper) 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
dL 
Deciliter 
DTD 
Drug-target-drug 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
EORTC-QLQ-30 
European Organisation for Research and Treatment of Cancer Quality of Life of 
Cancer Patients Questionnaire-30 
EOT 
End of treatment 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FDA 
Food and Drug Administration 
g 
Grams 
GHS 
Global health status 
HRQoL 
Health-related quality of life 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
INR 
International normalized ratio 
IV 
Intravenous 
                                        VV-RIM-00212243-1.0 Approved - 28 Sep 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 8 of 65 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
MAVE 
Major adverse vascular event 
mg 
Milligram 
µg 
Microgram 
mL 
Milliliter 
OLEP 
Open-label extension period (an optional period) 
OLTP 
Open-label treatment period (main study period) 
PD 
Pharmacodynamic 
PGIC 
Patient global impression of change 
PGIS 
Patient global impression of severity 
PK 
Pharmacokinetic 
PNH 
Paroxysmal nocturnal hemoglobinuria 
PT 
Preferred term 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SOC 
System organ class 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 
                                        VV-RIM-00212243-1.0 Approved - 28 Sep 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 9 of 65 
1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the analysis of data for this study. 
1.1. 
Background/Rationale for Study Design 
Background information on paroxysmal nocturnal hemoglobinuria (PNH), pozelimab 
(REGN3918), and cemdisiran (ALN-CC5) may be found in the protocol. This is a single-arm study 
and thus patients and the investigator will be aware of treatment allocation.  
The long-term safety and efficacy of the combination treatment will be assessed by providing the 
patients who complete the main open-label treatment period (OLTP) on combination treatment an 
opportunity to participate in an optional long-term open-label extension period (OLEP), in which 
patients shall continue to receive study treatment for an additional 52 weeks. Patients who opt not 
to participate in the optional OLEP (or those who stop treatment for any reason) will be followed 
for 52 weeks after the last dose of study treatment, to monitor for safety as the study drugs are 
gradually eliminated from the body. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of pozelimab and 
cemdisiran (ALN-CC5) combination therapy in patients with PNH who switch from eculizumab 
therapy. 
1.2.2. 
Secondary and Exploratory Objectives 
The secondary objectives of the study are: 
• To assess the effect of the combination treatment on the following parameters of 
intravascular hemolysis: lactate dehydrogenase (LDH) control, breakthrough 
hemolysis, and inhibition of complement hemolysis activity (CH50) 
• To assess the stability of LDH during the transition period from eculizumab 
monotherapy to combination with pozelimab and cemdisiran  
• To assess the effect of the combination treatment on red blood cell (RBC) transfusion 
requirements 
• To assess the effect of the combination treatment on hemoglobin levels 
• To assess the effect of the combination treatment on clinical outcome assessments 
(COAs) measuring fatigue and health-related quality of life (HRQoL) 
• To assess the concentrations of total pozelimab and eculizumab in serum, and total 
cemdisiran and C5 protein in plasma 
• To assess the immunogenicity of pozelimab and cemdisiran 
• To assess safety after dose intensification 
                                        VV-RIM-00212243-1.0 Approved - 28 Sep 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R3918-PNH-20105 
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• To assess the long-term safety and efficacy of the combination treatment in an 
optional open-label extension period (OLEP) 
The exploratory objectives of the study are: 
• To assess the need for intensified treatment 
• To assess the effect of the combination treatment on clinical thrombosis events 
• To assess the effect of the combination treatment on renal function and renal injury 
biomarkers 
• To assess the effect of the combination treatment on complement activation and 
intravascular hemolysis relevant to PNH and other related diseases 
• To assess the effect of the combination treatment on PNH clone size 
• To assess the effect of the combination treatment on a COA measuring treatment 
satisfaction (TSQM) 
• To assess the effect of the combination treatment on a novel COA measuring PNH-
specific symptoms 
• To assess the effect of the combination treatment on PNH symptoms   
• To assess potential differences in genotype and gene expression that may influence 
efficacy and safety of the combination treatment for further understanding of C5, 
PNH, or other conditions associated with complement-mediated injury (for patients 
who consent to participate in a genomics sub-study) 
o DNA and RNA collected from patients who agree to participate in the 
optional genomics sub-study will be analyzed. Separate analysis plan(s) and 
report(s) will be written. Results will not be included in the CSR. 
• To assess pozelimab and cemdisiran mechanism of action (related to efficacy and/or 
safety), complement pathway biology, PNH, and related complement-mediated 
diseases 
• To assess efficacy after dose intensification with pozelimab and cemdisiran 
• To assess the long-term effects of the combination treatment on clinical and PD 
assessments in an optional OLEP 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
This SAP is based on protocol amendment 3. 
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1.2.4. 
Revision History for SAP Amendments 
Summary of Changes from SAP Version 1 to Version 2 Due to Protocol Amendment 3 
Changes  
Sections changed 
Revised and clarified the following secondary 
endpoints: 
• Proportion of patients who maintain adequate 
control of hemolysis, defined as lactate 
dehydrogenase (LDH) ≤1.5 x upper limit of normal 
(ULN) from post-baseline (on day 1) through day 
225 and from day 57 through day 225, inclusive  
• Proportion of patients with normalization of LDH 
at each visit, defined as LDH ≤1.0 x ULN from 
post-baseline (on day 1) through day 225, inclusive 
Corresponding changes were made to secondary 
endpoints for the optional open-label extension period 
(OLEP) 
Section 4.5.2  
 
Added new secondary endpoint on the proportion of 
patients with adequate control of hemolysis at each 
visit 
Section 4.5.2  
Added immunogenicity sample (anti-pozelimab 
antibodies) and D-dimer as part of laboratory analyses 
in the event of suspected breakthrough hemolysis 
Table 3 
Table 4 
Table 5 
Revised sample size language to “up to 12 patients” 
Section 2.1 
Section 2.2 
Updated information about post-trial treatment access 
for patients who complete the optional OLEP 
Figure 3 footnote 
Removed eculizumab concentration from open-label 
extension period (OLEP) analysis 
Section 4.5.2 
Added baseline LDH, time since PNH diagnosis and 
Prior eculizumab dosing regime to baseline 
characteristics 
Section 4.1 
Moved PNH signs and symptoms from baseline to 
medical history 
Sections 4.1 and 4.2 
Clarified on-treatment period definition 
Section 4.6.1 
Added analysis window tables (Tables 1 and 2) 
Section 6.4 
Removed several rows from the List of Abbreviations, 
due to their not being included in this document 
List of Abbreviations and Definition of Terms 
Clarifications and corrections 
Throughout the document 
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2.2. 
Sample Size Considerations 
A total of up to 12 patients with PNH who are currently receiving eculizumab will switch to 
pozelimab and cemdisiran combination therapy. Patients will be switched from eculizumab 
administration at the labeled dosing regimen or at a dose higher than labeled and/or administered 
more frequently than labeled. 
2.3. 
Study Plan 
The study event table is presented in Section 10. 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following populations will be used for 
statistical analysis: 
3.1. 
The Full Analysis Set (FAS) 
The full analysis set (FAS) includes all enrolled patients (i.e., patients for whom the CRF’s subject 
enrollment field was entered as ‘Yes’) who received any study drug and have at least 1 post-
baseline efficacy assessment. Efficacy endpoints will be analyzed using the FAS. 
The OLEP FAS includes all patients who participated in the OLEP who received any amount of 
study drug in the OLEP and have at least 1 post-baseline efficacy assessment in the OLEP. 
3.2. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all enrolled patients who received any amount of study 
drug. Treatment compliance/administration and all clinical safety variables will be analyzed using 
the SAF. 
The OLEP SAF includes all patients who participated in the OLEP who received any amount of 
study drug in the OLEP. 
3.3. 
The Pharmacokinetic Analysis Set 
The pharmacokinetic (PK) analysis set includes all patients who received any amount of study 
drug and who had at least 1 non-missing result following the first dose of study drug. 
The OLEP PK analysis set includes all patients who participated in the OLEP who received any 
amount of study drug in the OLEP and who had at least 1 non-missing result following the first 
dose of study drug in the OLEP. 
3.4. 
The Immunogenicity Analysis Sets 
The ADA analysis set includes all patients who received any amount of study drug and who had 
at least 1 non-missing ADA result following the first dose of study drug. 
The OLEP ADA analysis set includes all patients in the OLEP who received any amount of study 
drug in the OLEP and had at least 1 non-missing ADA result following the first OLEP dose. 
3.5. 
The Exploratory Biomarker Endpoint Analysis Set 
The exploratory biomarker endpoint (pharmacodynamic) analysis set includes all patients who 
received any amount of study drug and who had at least 1 non-missing analyte measurement 
following the first dose of study drug.   
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristic variables will be summarized:  
• Age at screening (years) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic/Latino) 
• Baseline Weight  
• Baseline Height 
• Baseline Body mass index (BMI) calculated from weight and height 
• Baseline hemoglobin 
• Baseline eGFR 
• Baseline creatinine 
• Baseline total C5 
• Baseline PNH clone size 
• Baseline LDH 
• Time since diagnosis of PNH 
• Prior eculizumab dosing regimen (900 mg Q2W vs. >900 mg Q2W) 
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4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
In addition, the following historical data will be summarized: 
• History in the past 12 months of the following: 
o Transfusions 
o Breakthrough hemolysis (numbers of patients and events) 
• All available laboratory parameters for measurement of hemolysis at baseline: 
o LDH 
o Bilirubin 
o Haptoglobin 
o Reticulocyte count 
o Hemoglobin 
• Prior history of thrombosis at any time 
• Prior history of Neisseria infections at any time 
• PNH signs or symptoms in the past 3 months 
• Tuberculosis history 
• Aplastic anemia history 
4.3. 
Prior/Concomitant Medication and Procedures 
Prior medications include detailed eculizumab administration history (past 26 weeks) and N. 
meningitidis vaccination (past 5 years); all other prior medications 12 weeks prior to screening.  
Medications will be recorded by patients from the day of informed consent until their final study 
visit. Medications will be coded to the ATC level 2 (therapeutic main group) and ATC level 4 
(chemical/therapeutic subgroup), according to the latest available version of WHO Drug 
Dictionary (WHODD). Patients will be counted once in all ATC categories linked to the 
medication. 
Prior medications are medications taken prior to administration of the first dose of study drug. 
Concomitant medications are medications taken between the first dose of study drug to the end of 
the safety follow-up period. 
Prior/concomitant medications will include Meningococcal vaccinations and oral antibiotic 
prophylaxes. 
Prior/concomitant procedures will be recorded.  Prior procedures are procedures performed prior 
to administration of the first dose of study drug.  Concomitant procedures are procedures 
performed between the first dose of study drug and the EOS visit. 
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In addition, erythropoietin, immunosuppressive drugs, corticosteroids, anti-thrombotic agents, 
anticoagulants, iron supplements, and folic acid will be summarized. 
4.4. 
Prohibited Medication During Study if Applicable 
The use of the following concomitant medications is not permitted: 
• The use of any other complement inhibitor is prohibited while the patient is taking 
study treatments, with the exception of eculizumab as ongoing background therapy 
during the transition to the combination treatment 
• Other investigational treatments during the course of the study 
4.5. 
Efficacy Variables 
4.5.1. 
Primary Efficacy Variables 
Not Applicable 
4.5.2. 
Secondary Efficacy Variables 
The secondary efficacy endpoints for the OLTP are: 
• The percent change in LDH from pre-treatment (as defined by the mean of the 
LDH values at the screening visit [obtained no more than one day before administration 
with eculizumab] and baseline (day 1 visit, prior to administration of cemdisiran and 
eculizumab) to end-of-treatment period (as defined by the mean of the LDH values at 
days 197 and 225 in the OLTP) 
• The percent change in LDH from pre-treatment to day 29 
• The proportion of patients who are transfusion-free (defined as not requiring an 
RBC transfusion as per protocol algorithm) from baseline through day 225 
• The proportion of patients who are transfusion-free (defined as not requiring an 
RBC transfusion as per protocol algorithm) from day 29 through day 225 
• The rate and number of units of RBCs transfused from baseline through day 225, 
inclusive 
• The rate and number of units of RBCs transfused from day 29 through day 225, 
inclusive 
• The proportion of patients with breakthrough hemolysis from baseline through 
day 225, inclusive 
• The proportion of patients with breakthrough hemolysis from day 29 through day 225, 
inclusive  
• The proportion of patients who maintain adequate control of hemolysis, defined as 
LDH ≤1.5 x ULN from post-baseline (on day 1) through day 225, inclusive 
• The proportion of patients who maintain adequate control of hemolysis, defined as 
LDH ≤1.5 x ULN from day 57 through day 225, inclusive 
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• The proportion of patients with adequate control of hemolysis at each visit from post-
baseline (on day 1) through day 225, inclusive 
• The proportion of patients with normalization of their LDH at each visit, defined as 
LDH ≤1.0 x ULN , from post baseline (on day 1) through day 225, inclusive 
• The area under the curve (AUC) of LDH over time between baseline through day 225, 
inclusive  
• The area under the curve (AUC) of LDH over time between day 57 through day 225, 
inclusive 
• The proportion of patients with hemoglobin stabilization (defined as patients who do 
not receive an RBC transfusion and have no decrease in hemoglobin level of ≥2 g/dL) 
from baseline through day 225, inclusive  
• The proportion of patients with hemoglobin stabilization (defined as patients who do 
not receive an RBC transfusion and have no decrease in hemoglobin level of ≥2 g/dL) 
from day 29 through day 225, inclusive 
• Change in hemoglobin levels from baseline to day 225, inclusive 
• Change in fatigue as measured by the FACIT-Fatigue Scale from baseline to day 225, 
inclusive 
• Change from baseline to day 225 in global health status/QoL scale (GHS) and physical 
function (PF) scores on the European Organization for Research and Treatment of 
Cancer: Quality-of-Life Questionnaire core-30 items (EORTC QLQ-C30)   
• Change in CH50 from baseline to day 225, inclusive   
• Concentrations of total pozelimab and eculizumab in serum, and total cemdisiran in 
plasma assessed throughout the study 
• Change from baseline in concentration of total C5 assessed throughout the study 
• Assessment of immunogenicity to pozelimab and cemdisiran as determined by the 
incidence, titer, and clinical impact of treatment-emergent anti-drug antibody (ADA) 
responses over time 
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The secondary efficacy endpoints for the optional OLEP are: 
• Change and percent change of LDH from day 1e (baseline of the OLEP) to week 24e 
and week 52e (the suffix “e” denoting extension) 
• The proportion of patients who are transfusion-free (defined as not requiring an RBC 
transfusion as per protocol algorithm) from day 1e through week 24e and week 52e 
(i.e., transfusion avoidance) 
• The rate and number of units of RBCs transfused from day 1e through week 24e and 
week 52e. 
• The proportion of patients with breakthrough hemolysis from day 1e through week 24e 
and week 52e  
• The proportion of patients who maintain adequate control of their hemolysis, defined 
as LDH ≤1.5 x ULN between day 1e through week 24e and week 52e, inclusive 
• The proportion of patients with adequate control of hemolysis at each visit from day 1e 
through week 24e and week 52e, inclusive 
• The proportion of patients with normalization of their LDH, defined as 
LDH ≤1.0 x ULN at each visit from day 1e through week 24e and week 52e, inclusive 
• The AUC of LDH over time between day 1e through week 24e and week 52e, inclusive  
• The proportion of patients with hemoglobin stabilization (defined as patients who do 
not receive an RBC transfusion and have no decrease in hemoglobin level of ≥2 g/dL) 
from day 1e through week 24e and week 52e 
• Change in hemoglobin levels from day 1e to week 24e and week 52e of the OLEP 
• Change in fatigue as measured by the FACIT-Fatigue Scale from day 1e to week 52e 
of the OLEP 
• Change from day 1e to week 52e of the OLEP in GHS/QoL scale PF scores on the 
EORTC QLQ-C30   
• Change in CH50 from day 1e to week 16e, week 24e, and week 52e of the OLEP  
• Concentrations of total pozelimab in serum, and total C5 and cemdisiran in plasma, 
assessed over time during the OLEP 
• Assessment of immunogenicity to pozelimab and cemdisiran as determined by the 
incidence, titer, and clinical impact of treatment-emergent ADA responses over time 
during the OLEP 
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The following table summarizes the OLTP and OLEP secondary endpoints: 
OLTP and OLEP 
Measurement 
Metric 
Time Period in OLTP 
Time Period in OLEP 
LDH 
Change 
BL through D225 
Day 1e (BL of the 
OLEP) to week 24e 
 
Change 
Not Applicable 
Day 1e (BL of the 
OLEP) to week 52e 
LDH 
Percent change 
From pre-treatment (as 
defined by the mean of 
the LDH values at the 
screening visit [obtained 
no more than one day 
before administration 
with eculizumab] to 
EOT period (as defined 
by the mean of LDH 
values at D197 and 
D225 in the OLTP) 
Day 1e (BL of the 
OLEP) to week 24e 
 
 
Pre-treatment to D29 
Not Applicable 
Patients who are 
transfusion-free  
Proportion 
BL through D225 
Day 1e through week 
24e 
 
 
D29 through D225 
Day 1e through week 
52e 
Units of RBC’s 
transfused 
Rate and Number 
BL through D225 
Day 1e through week 
24e 
 
 
D29 through D225 
Day 1e through week 
52e 
Breakthrough 
hemolysis 
Proportion 
BL through D225 
Day 1e through week 
24e 
 
 
D29 through D225 
Day 1e through week 
52e 
LDH 
Proportion who maintain 
adequate control of 
hemolysis (defined as 
𝐿𝐷𝐻≤1.5 ∗𝑈𝐿𝑁) 
D1 through D225 
Day 1e through week 
24e 
 
 
D57 through D225 
Day 1e through week 
52e 
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OLTP and OLEP 
Measurement 
Metric 
Time Period in OLTP 
Time Period in OLEP 
LDH 
Proportion with adequate 
control of hemolysis at each 
visit 
D1 through D225 
Day 1e through week 
24e 
 
 
 
Day 1e through week 
52e 
LDH 
Proportion with 
normalization of LDH 
(defined as 𝐿𝐷𝐻≤1.0 ∗
𝑈𝐿𝑁) 
D1 through D225 
Day 1e through week 
24e 
 
 
 
Day 1e through week 
52e 
LDH 
AUC over time 
BL through D225 
Day 1e through week 
24e 
 
 
D57 through D225 
Day 1e through week 
52e 
Hemoglobin 
stabilization 
Proportion of patients who 
do not receive an RBC 
transfusion and have no 
decrease in hemoglobin 
level of ≥2 g/dL) 
BL through D225 
Day 1e through week 
24e 
 
 
D29 through D225 
Not Applicable 
Hemoglobin 
Change 
BL through D225 
Day 1e through week 
24e 
 
 
D29 through D225 
Day 1e through week 
52e 
Fatigue 
Change in FACIT-Fatigue 
Scale 
BL to D225 
Day 1e to week 52e 
Global health status 
 Change in GHS in EORTC 
QLQ-C30 
BL to D225 
Day 1e to week 52e 
Physical Function 
 Change in PF in EORTC 
QLQ-C30 
BL to D225 
Day 1e to week 52e 
CH50 
Change 
BL to D225 
Day 1e to week 16e 
 
 
Not Applicable 
Day 1e to week 24e 
 
 
Not Applicable 
Day 1e to week 52e 
Total Pozelimab in 
serum 
Concentrations 
Whole OLTP 
Whole OLEP 
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OLTP and OLEP 
Measurement 
Metric 
Time Period in OLTP 
Time Period in OLEP 
Total Eculizumab 
in serum 
Concentrations 
Whole OLTP 
Not applicable 
Total Cemdisiran in 
plasma 
Concentrations 
Whole OLTP 
Whole OLEP 
Concentration of 
total C5 
Change 
Whole OLTP 
Whole OLEP 
Immunogenicity to 
pozelimab and 
cemdisiran 
Incidence, titer, and clinical 
impact of treatment-
emergent ADA responses 
over time 
Whole OLTP 
Whole OLEP 
4.5.3. 
Exploratory Efficacy Variables 
The exploratory endpoints for the OLTP are: 
• Proportion of patients who require treatment intensification throughout the study 
• Incidence of MAVE from baseline through day 225 
• Change in renal function as measured by estimated glomerular filtration rate (eGFR) 
from baseline to day 225 
• Percent change in free hemoglobin from baseline to day 225 
• Change in bilirubin from baseline to day 225 
• Change in reticulocyte count from baseline to day 225 
• Change and percent change in AH50 from baseline to day 225 
• Proportion of PNH erythrocytes and granulocytes from baseline to day 225 
• Change from baseline to day 225 in functional scale scores (Role Functioning, 
Emotional Functioning, Cognitive Functioning, and Social Functioning) and symptom 
scale scores (Fatigue, Nausea and vomiting, Pain, Dyspnoea, Insomnia, Appetite Loss, 
Constipation, Diarrhoea) of the EORTC QLQ-C30  
• Proportion of patients with stability in global health status, functioning, and symptoms 
as measured by the EORTC QLQ-C30 from baseline to day 225 
• Comparison of treatment satisfaction (as assessed by the TSQM) at baseline (with 
eculizumab) versus treatment at day 225 (with pozelimab/cemdisiran) 
Note: The exploratory variables PGIC, PGIS and the PNH Symptom Specific Questionnaire will 
not be analyzed for the CSR. 
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Exploratory endpoints will be assessed in the OLEP in the same way as in the OLTP. The following 
table summarizes the OLTP and OLEP exploratory endpoints: 
Measurement 
Metric 
Time Period in OLTP 
Time Period in OLEP 
Treatment 
Intensification 
Proportion 
Whole OLTP 
Whole OLEP 
MAVE 
Proportion 
BL to D225 
Day 1e to week 52e 
Renal functions 
Change measured by eGFR 
BL to D225 
Day 1e to week 52e 
Free hemoglobin 
Percent change 
BL to D225 
Day 1e to week 52e 
Bilirubin 
Change 
BL to D225 
Day 1e to week 52e 
Reticulocyte count 
Change 
BL to D225 
Day 1e to week 52e 
AH50 
Change 
BL to D225 
Day 1e to week 52e 
 
Percent change 
BL to D225 
Day 1e to week 52e 
PNH erythrocytes 
Change 
BL to D225 
Day 1e to week 52e 
PNH granulocytes 
Change 
BL to D225 
Day 1e to week 52e 
Role Functioning 
Change in Functional Scale 
Scores: EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
Emotional 
Functioning 
Change in Functional Scale: 
EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
Cognitive 
Functioning 
Change in Functional Scale: 
EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
Social Functioning 
Change in Functional Scale: 
EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
Fatigue 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
Nausea 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
Vomiting 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
Pain 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
Dyspnea 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
Insomnia 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
Appetite Loss 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
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Measurement 
Metric 
Time Period in OLTP 
Time Period in OLEP 
Constipation 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
Diarrhea 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to D225 
Day 1e to week 52e 
Stability in global 
health status 
Proportion with stability as 
measured by EORTC QLQ-
C30 
BL to D225 
Day 1e to week 52e 
Stability in 
functioning, and 
symptoms 
Proportion with stability as 
measured by EORTC QLQ-
C30 
BL to D225 
Day 1e to week 52e 
Stability in 
symptoms 
Proportion with stability as 
measured by EORTC QLQ-
C30 
BL to D225 
Day 1e to week 52e 
Treatment 
satisfaction 
Comparison between two 
therapies as assessed by 
TSQM 
BL to D225 
Not applicable 
4.6. 
Safety Variables 
The safety variables are 
• TEAEs 
• Body weight 
• Vital signs 
• Electrocardiogram (ECG) 
• Physical examination 
• Routine safety laboratory tests (hematology, chemistry, urinalysis) 
4.6.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of the study. All adverse events are to be coded to a 
“Preferred Term (PT)” and associated primary “System Organ Class (SOC)” according to the 
Medical Dictionary for Regulatory Activities (MedDRA, the most current available version). 
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
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For safety variables, there are three observation periods: 
• The pre-treatment period is defined as the time from signing the ICF to before the 
first dose of the study drug 
• The on-treatment period is defined as the day from first dose of the study drug to 
either: 
o The last dose of study drug in the OLTP plus 52 weeks for those not continuing in 
the OLEP, 
o The last dose of study drug in the OLEP plus 52 weeks for those continuing in the 
OLEP but not the post-trial access program, or 
o The last dose of study drug in the OLEP for those continuing in the OLEP and the 
post-trial access program 
• The post-treatment period is defined as the time after the end of the on-treatment 
period 
Pre-treatment AEs are defined as AEs that developed or worsened during the pre-treatment 
period.  
Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened during the 
on-treatment period. 
Post-treatment AEs are AEs that developed or worsened during the post-treatment period.     
Treatment-emergent adverse events (TEAE) are defined as those that are not present at baseline or 
represent the exacerbation of a pre-existing condition during the on-treatment period 
A Serious Adverse Event is an adverse event (AE) that is classified as serious according to the 
criteria specified in the protocol. They include  
• Results in death 
• Is life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
• Important medical event 
The severity of AEs and of infusion reaction AEs are graded according to the criteria given in the 
protocol.  
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
investigator to determine their clinical significance. Isolated abnormal laboratory results, vital sign 
findings, or other diagnostic findings (i.e., not part of a reported diagnosis) should be reported as 
AEs if they are symptomatic, lead to study drug discontinuation, require corrective treatment, or 
constitute an AE in the investigator’s clinical judgement.  
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Pregnancy and symptomatic overdose of study drug events require expedited reporting to the 
sponsor, and they will be described. 
4.6.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner as described in the protocol. In 
this study, AESIs are listed below (as provided in the protocol): 
• Suspected Neisseria infection 
• Moderate or severe infusion reactions 
• Major adverse vascular events (MAVE) 
• Moderate or severe hypersensitivity reactions potentially related to study treatment 
• Adverse events potentially due to suspected large DTD immune complexes 
• Liver transaminase elevations as evidenced by one or more of the following: 
o ALT or AST>8 × ULN, or 
o ALT or AST>5 × ULN for more than 2 weeks, or 
o ALT or AST>3 × ULN and total bilirubin >2 × ULN (or international normalized 
ratio [INR] > 1.5) not related to PNH 
The following events are also AESIs but do not require expedited safety reporting to the sponsor: 
• Mild infusion reactions to study treatment 
• Mild hypersensivity reactions to study treatment 
• Injection site reactions due to study treatment 
4.6.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of serum chemistry, hematology, urinalysis, and other. 
Clinical laboratory values will be grouped by function in summary tables. Conventional units may 
be provided. Laboratory tests are categorized in the protocol as follows: 
• Titers to measure N. Meningitidis (only if required per local practice/regulations) 
• Hematology 
• Coagulation panel 
• Chemistry, including LDH 
• Hepatitis B and C testing 
• Pregnancy test (for applicable patients) 
• Urinalysis 
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4.6.4. 
Vital Signs 
Temperature, pulse, systolic and diastolic blood pressure will be collected. 
4.6.5. 
12-Lead Electrocardiography (ECG) 
Heart rate will be recorded from the ventricular rate and the PR, QRS, and QT, QTcF, and ECG 
status (normal, abnormal not clinically significant or abnormal clinical significant) will also be 
recorded. 
4.7. 
Pharmacokinetic Variables  
The PK endpoints are concentrations of total pozelimab, cemdisiran and eculizumab.  Target 
engagement will be assessed by the concentration of total C5. The sampling time points are 
specified in Section 10. 
4.8. 
Immunogenicity Variables  
The immunogenicity variables are ADA status and titer at nominal sampling time point/visit. 
Samples in this study will be collected at the clinic visits specified in Section 10. 
4.9. 
Pharmacodynamic Variables 
Pharmacodynamic and other biomarker variables include, but are not limited to, the following:  
• Serum CH50, an assay assessing the activity of the classical pathway of complement, 
will be used to measure C5 activity. It is the principal PD marker for the study and is 
also an efficacy variable in this study 
• Free hemoglobin 
• Parameters of intravascular hemolysis: i.e., haptoglobin, reticulocyte count, and 
bilirubin 
• AH50 (serum)   
• Complement activation markers: i.e., sC5b-9 
• PNH clone size: i.e., PNH erythrocytes and granulocytes 
The list may be altered or expanded, as it is recognized that more relevant or novel biomarkers 
may be discovered during the course of this study. 
4.10. 
Clinical Outcome Assessments (COAs) 
COAs include the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), 
the EORTC-QLQ-C30, the Treatment Satisfaction Questionnaire for Medication (TSQM), and the 
de novo PNH Symptom-Specific Questionnaire.  
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, Q1, Q3, minimum, and 
maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by subgroup (switched 
from eculizumab administration at the labeled dosing regimen or switched from eculizumab at a 
dose higher than labeled and/or more frequently than labeled), and for all patients combined for 
the FAS. Baseline is defined as the last available value prior to study drug administration unless 
otherwise specified.  
5.2. 
Medical History 
Medical history will be descriptively summarized overall for the study in safety analysis set. 
All reported patient medical history will be presented by primary SOC and PT.  The tables will be 
presented by SOC sorted alphabetically and decreasing patient frequency of PT.  In addition, all 
medical history of specific interest will be summarized by patient incidence and percentage. 
5.3. 
Prior/concomitant Medications  
All prior medications, dictionary coded by WHODD, will be descriptively summarized for the 
study, for patients in the safety set. Summaries will present patient counts (and percentages) for 
all prior medications, by decreasing frequency of the overall incidence of ATC followed by 
therapeutic class.  In the case of equal frequency across anatomic or therapeutic categories, 
alphabetical order will be used. Patients will be counted once in each ATC category (anatomic or 
therapeutic) linked to the medication but may be counted again for a different category if the same 
medication falls under multiple categories.   
All concomitant medications during the treatment period, dictionary coded by WHODD, will be 
descriptively summarized for patients in the safety set.  In the case of equal frequency across 
anatomic or therapeutic categories, alphabetical order will be used. Patients will be counted once 
in each ATC category (anatomic or therapeutic) linked to the medication, and hence may be 
counted again for a different category if the same medication falls under multiple categories. 
5.4. 
 Prohibited Medications  
A listing of prohibited medications, found in Section 4.4, will be provided for the patients in the 
safety analysis set for the treatment period . 
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5.5. 
Patient Disposition 
The following displays will be provided: 
• The total number of screened patients who signed the ICF 
• The total number of enrolled patients 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation, by study period 
• The total number of patients who discontinued from the study treatment, and the 
reasons for discontinuation, by study period 
• A listing of patients prematurely discontinued from treatment, along with reasons 
discontinuation 
• Total number of patients who received treatment intensification, by study period 
• Total number of patients who continued into the OLEP and who completed the OLEP 
5.6. 
Extent of Study Treatment Exposure and Compliance 
5.6.1. 
Measurement of Compliance 
Compliance with each protocol-defined investigational product and background eculizumab will 
be calculated for each study period as follows: 
Treatment Compliance = (Number of investigational product doses or background 
eculizumab taken during study period)/(Number of investigational product or background 
eculizumab doses prescribed to be taken during period) x 100%, 
where temporary dose discontinuation is ignored. Separate summaries will be provided for 
pozelimab and cemdisiran. 
5.6.2. 
Exposure to Investigational Product 
Treatment exposure will be presented separately for pozelimab and cemdisiran. 
The duration of study drug exposure for a study period is calculated as: 
(Date of last administration of study drug – date of the first administration of study drug 
for the study period) + 28 days (for Q4W dosing), and 
(Date of last administration of study drug – date of the first administration of study drug 
for the study period) + 14 days (for Q2W dosing) 
Summaries (including the number of patients exposed, the duration of exposure, and the dose 
regimen to which patients were exposed) will be provided for pozelimab and cemdisiran. 
The total number of complete and incomplete study drug administrations will be summarized. 
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In addition, the number of patients exposed to the investigational product will be presented by 
specific time period. The time periods of interest are as follows: 
For OLTP: 
• ≥ Day 29 (Week 4) 
• ≥ Day 57 (Week 8) 
• ≥ Day 85 (Week 12)  
• ≥ Day 113 (Week 16)  
• ≥ Day 141 (Week 20) 
• ≥ Day 169 (Week 24) 
• ≥ Day 197 (Week 28) 
• ≥ Day 225 (Week 32) 
For OLEP: 
• ≥ Day 57 (Week 8) 
• ≥ Day 113 (Week 16) 
• ≥ Day 169 (Week 24)  
• ≥ Day 225 (Week 32)  
• ≥ Day 281 (Week 40) 
≥ Day 365 (Week 52) 
Few patients are expected to be in the intensified OLTP; their exposure information will be listed. 
5.7. 
Analyses of Efficacy Variables 
The analysis of secondary and exploratory efficacy variables is determined by type of variable 
(i.e., continuous or binary). Secondary efficacy analysis for the optional OLEP will be performed 
using the same approach described for corresponding analyses in the OLTP but using OLEP data. 
Analyses will be performed on the FAS. Levels of LDH in serum will be analyzed by a central 
laboratory. Efficacy analysis of LDH will be based on central laboratory data.  LDH values will 
be excluded from the analysis if the LDH was ≥ 2 x ULN and potassium was ≥ 6 mmol/L, in the 
absence of an event of breakthrough hemolysis (LDH values will be included in the analysis if 
there is an associated breakthrough hemolysis). 
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5.7.1. 
Analysis of Continuous Secondary Efficacy Variables 
For visit-oriented, continuous secondary efficacy variables in Section 4.5.2, descriptive statistics 
for change from baseline and/or percent change from baseline to each time point will be presented 
by patient subgroup (switched from eculizumab administration at the labeled dosing regimen or 
switched from eculizumab at a dose higher than labeled and/or more frequently than labeled) and 
overall, and visit. 
In addition, for LDH, hemoglobin and CH50, spaghetti plots will be provided for patients who did 
not have intensified treatment, patients who received intensified treatment, patients who 
discontinued treatment due to lack of efficacy, and patients who stopped treatment for other 
reasons, if numbers permit. 
For the AUC of LDH over time from baseline through day 225, from day 57 through day 225 
during OLTP, and from day 225 and onward during OLEP, inclusive, the analysis set will 
include all treated patients. The AUC will be computed using available LDH values using the 
trapezoidal rule. The mean AUC, 95% CI, and other summary statistics will be provided. 
For the rate and number of units of RBCs transfused from baseline through day 225, and from day 
29 through day 225, the analysis set will consist of all treated patients who never received the 
intensified regimen during treatment. For the rate of transfusion (number of transfusions of RBCs 
through day 225), the rate and 95% confidence interval will be calculated, based on an assumption 
of a negative binomial distribution, adjusted for time on study. The number of units of transfusion 
for a patient will be calculated based on the duration of treatment exposure of the patient. 
Descriptive statistics will be reported for all patients and for the 2 patient subgroups, if sample size 
allows. A transfusion will be counted only if it follows the pre-defined transfusion algorithm.  
5.7.2. 
Analysis of Categorical Secondary Efficacy Variables 
Proportions and 95% confidence intervals by the Clopper Pearson exact method for the endpoints 
will be reported for all patients and for the 2 patient subgroups separately. 
For the secondary variable of the rate of breakthrough hemolysis through day 225, defined as the 
measurement of LDH ≥ 2 x ULN concomitant with associated signs or symptoms at any time 
subsequent to an initial achievement of disease control (i.e., LDH ≤ 1.5 x ULN), the proportion of 
patients with breakthrough hemolysis will be calculated, along with a 95% confidence interval by 
the exact Clopper Pearson method.  Signs and symptoms will be tabulated, as will number of 
breakthrough hemolyses per patient. 
For the secondary variable of the proportion of patients who maintain adequate control of 
hemolysis (defined as LDH ≤1.5 x ULN from post-baseline (on day 1) through day 225, and from 
day 57 through day 225, inclusive), patients who have one or more of the following will be 
considered as not maintaining adequate control of their intravascular hemolysis:  
o Having at least one measurement of LDH  > 1.5 x ULN 
o Discontinuing from study treatment early 
o Having 2 consecutive missing values of the scheduled LDH measurements 
o Having 3 or more missing values of the scheduled LDH measurements 
o Having received intensified treatment  
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Patients who complete study treatment, have no more than 2 consecutive missing values of the 
scheduled LDH measurements between day 57 and day 225, have fewer than 3 missing values of 
the scheduled LDH measurements between day 57 and day 225 and have no breakthrough 
hemolysis will be evaluated based on their non-missing LDH measurements. The analysis will be 
based on scheduled central laboratory data. If the LDH value at the scheduled central lab 
assessment is missing, the LDH value from the unscheduled central lab within the analysis visit 
window (see Section 6.4) that is the closest to the visit date will be used. The proportion of patients 
maintaining adequate control of their intravascular hemolysis will be calculated, along with a 95% 
confidence interval, by the exact Clopper Pearson method. In addition, proportion of patients with 
LDH ≤1.50 x ULN at each scheduled assessment timepoint will be summarized. 
Percentages of patients with LDH ≤ 1.5 x ULN and LDH ≤ 1.0 x ULN will be tabulated and plotted 
at each visit. 
5.7.3. 
Analysis of Exploratory Variables 
For categorical exploratory variables, such as  “Incidence of MAVE through week 32” the 
proportion of patients with at least one MAVE will be presented along with  95% confidence 
interval using the exact Clopper-Pearson method. 
For continuous, visit-oriented exploratory variables, the change and/or percent change from 
baseline will be assessed in the same way as the secondary variables of this type.  
For patients who received intensified treatment, safety data after intensified treatment will be 
listed. 
Results of exploratory endpoint analyses may be reported separately from the CSR. 
5.8. 
Analysis of Safety Data 
The primary endpoint in this study is the incidence and severity of TEAEs through day 225 of the 
OLTP. Safety analysis will be conducted when all patients (including patients on treatment 
intensification) complete the 32-week treatment period or prematurely discontinue study. 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®). 
The analysis of safety data will be performed on the SAF, as defined in Section 3.2. 
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations, vital signs, and 12-lead ECG).  
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables, vital signs 
and ECG are defined in Section 10.2 . 
The summary of safety results will be presented overall. 
For patients who received intensified treatment, safety data after intensified treatment will be 
listed. 
For patients who enter the OLEP, safety data will be summarized in a similar manner. 
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5.8.1. 
Adverse Events  
Summaries of frequencies and proportions of patients reporting AEs will include the PTs and the 
SOCs.  Summaries will be presented for the OLTP (overall and separately for the eculizumab + 
cemdisiran and pozelimab + cemdisiran treatment periods) and for the OLEP. 
 Summaries of all TEAEs will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 4.6.1), 
presented by SOC and PT 
• Study drug related TEAEs, presented by SOC and PT 
• Treatment-emergent AESIs (defined by experiencing a prespecified PT or 
prespecified grouping of PTs, or by being put in a grouping specified in the CRF) 
• Non-serious TEAEs by SOC and PT 
Deaths and other SAEs will be listed and summarized. 
Treatment-emergent adverse events leading to permanent treatment discontinuation and leading to 
study discontinuation will be listed and summarized. 
5.8.2. 
Analysis of Vital Signs 
Vital signs (temperature, pulse, blood pressure) will be summarized by baseline and change from 
baseline to each scheduled assessment time point with descriptive statistics. Listings will be 
provided with flags indicating treatment-emergent PCSVs. 
5.8.3. 
Analysis of Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time point with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-treatment time point will be summarized for each clinical laboratory test . 
For samples with LDH ≥ 2 x ULN and potassium ≥ 6 mmol/L in the absence of an event of 
breakthrough hemolysis, the potassium, ALT, AST, magnesium, and phosphorous will not be used 
in the analysis due to hemolysis possibly caused by sample mishandling.   
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
5.8.4. 
Analysis of 12-Lead ECG 
ECG parameters (PR interval, QT interval, QTcF interval, QRS interval, and heart rate [from 
ventricular rate]) will be summarized by visit and change from Baseline to each scheduled and 
collected assessment time. 
Listings will be provided with flags indicating PCSVs. 
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5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data 
5.9.1. 
Analysis of Pharmacokinetic Data  
Summary of concentrations of total pozelimab, cemdisiran, eculizumab and total C5 will be 
presented by nominal time point (i.e., the time points specified in the protocol). Individual data 
will be presented by actual time. Plots of the concentrations of pozelimab and total C5 will be 
presented over time (linear and log scales). When the scale is linear, concentrations below the 
lower limit of quantification (LLOQ) will be set to zero. In the log-scaled figures, concentrations 
below the LLOQ will be imputed as LLOQ/2. Summary statistics of concentrations of total 
pozelimab and total C5 may include, but are not limited to arithmetic mean, standard deviation, 
standard error of the mean, coefficient of variation (in %), minimum, Q1, median, Q3, and 
maximum. 
No formal statistical analysis will be performed. 
Descriptive concentration-response (AH50, CH50 and total C5) analysis will be performed as 
appropriate. 
5.9.2. 
Analysis of Immunogenicity Data 
5.9.2.1. 
Analysis of ADA Data 
Analyses will be performed separately for ADA against cemdisiran and ADA against pozelimab 
in this study unless otherwise specified. The immunogenicity variables described in Section 4.8 
will be summarized using descriptive statistics.   
Immunogenicity will be characterized by ADA status, ADA category and maximum titer observed 
in patients in the ADA analysis set. 
The ADA status of each patient may be classified as one of the following:  
− Positive 
− Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as 4-fold (for anti-cemdisiran) and 9-fold (for anti-pozelimab) over the baseline 
titer value 
− Negative - If all samples are found to be negative in the ADA assay. 
The ADA category of each positive patient is classified as:  
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥4-fold (for anti-cemdisiran) and ≥9-fold (for anti-
pozelimab) over the baseline titer value .  
• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Patients that are treatment-emergent 
will be further categorized as follows: 
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Treatment-emergent is further sub-categorized as: 
− Persistent - A positive result in the ADA assay detected in at least 2 
consecutive post baseline samples separated by at least a 16-week post baseline 
period [based on nominal sampling time], with no ADA-negative results in-
between, regardless of any missing samples 
− Transient - Not persistent or indeterminate, regardless of any missing samples  
− Indeterminate - A positive result in the ADA assay at the last collection time 
point only, regardless of any missing samples  
The maximum titer category of each patient is classified as: 
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer >10,000) 
The following listings will be provided: 
˗ 
Number (n) and percent (%) of ADA-negative patients 
˗ 
Number (n) and percent (%) of pre-existing patients 
˗ 
Number (n) and percent (%) of treatment-emergent ADA positive patients 
˗ 
Number (n) and percent (%) of persistent treatment-emergent ADA positive patients 
˗ 
Number (n) and percent (%) of indeterminate treatment-emergent ADA positive patients 
˗ 
Number (n) and percent (%) of transient treatment-emergent ADA positive patients 
˗ 
Number (n) and percent (%) of treatment-boosted ADA positive patients  
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent, 
and treatment-boosted ADA response. 
5.9.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.9.3.1. 
Immunogenicity and Exposure 
Association between immunogenicity and systemic exposure to pozelimab will be analyzed. Plots 
of pozelimab concentration may be provided to examine the potential impact of ADA category 
and maximum titer on these profiles.  
5.9.3.2. 
Immunogenicity and Safety and Efficacy 
Association between immunogenicity variables and safety may be explored with a primary focus 
on the following safety events during the TEAE period:  
• 
Injection site reaction (serious or severe and lasting 24 hours or longer) 
• 
Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• 
Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
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Association between immunogenicity variables and efficacy endpoints may be explored (e.g., 
scatter plot or spaghetti plot).  
The above-mentioned safety and efficacy analyses will be conducted using the following 
categories: 
• ADA Positive 
− Treatment-emergent 
− Treatment-boosted 
• Maximum post-baseline titer category in ADA positive patients 
5.10. 
Analysis of Pharmacodynamic and Biomarker Data 
Pharmacodynamic and biomarker variable listed in Section 4.9 may be analyzed and summarized.  
For each biomarker variable, time profile and percent of change from baseline  at each time point 
will be summarized over time. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product. If the 
scheduled baseline day 1 measurements are not available, screening assessments may be used; 
when scores are used, this rule applies to scores, not individual variables. 
6.2. 
Data Handling Convention for Efficacy Variables  
6.3. 
Data Handling Convention for Missing Data 
Rules for handling missing data for secondary efficacy variables are described in Section 5.7. 
For categorical variables, patients with missing data are not included in calculations of percentages 
unless otherwise specified. When relevant, the number of patients with missing data is presented. 
Missing data will not be imputed in listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
6.3.1. 
Adverse events 
If the severity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
severity of TEAE. If the measurement of relationship of a TEAE to the investigational product is 
missing, it will be classified as “related” in the frequency tables by relation to the investigational 
product. 
Adverse event start date  
AE start date will be used for AE classification and analysis. If AE start date is not complete, then 
the character variable will keep the original incomplete date, the numerical date variable will be 
imputed, and an imputation flag will indicate which date component is missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and the AE start month is the same as the first dose month then impute AE 
start day using the day of first dose. If this leads to a date after the AE end date, use AE end date 
instead. Otherwise impute the AE start day using the first day of the month. If this leads to a date 
before informed consent, the informed consent date will be used. Imputation flag is ‘D’. 
If AE start month is missing, and AE start year is not missing: If AE start year is less than the first 
dose year, use the informed consent day and month. If AE start year is equal to the first dose year, 
use the first dose day and month. If this leads to a date after the AE end date, use AE end date 
instead. If AE start year is after the first dose year, use 01 January. Imputation flag is ‘M’. 
If AE start year is missing: Impute AE start date using the day of first dose. If this leads to a date 
after the AE end date, use AE end date instead. Imputation flag is ‘Y’. 
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Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for AE starting date imputation, in order to carry through the logic for programming, the 
following intermediate step will be used. Afterwards, only the original character/numeric date 
recorded in CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: Impute AE end date using 
the last day of the month. If this leads to a date after end of study follow up date, use the last study 
visit date instead. 
If AE end month is missing, and AE end year is not missing: Impute AE end date using 31 
December as the day and month. If this leads to a date after end of study follow up date, use the 
last study visit date instead. 
If AE end year is missing: Impute AE end date using the end of follow up date. 
Medication start and end date missing 
To determine whether a medication is pre-treatment (described in Section 5.8 ) medication or 
concomitant medication or both, the missing medication start date is estimated as early as possible, 
and the missing medication end date is estimated as late as possible. If the medication start date is 
missing, the onset day will not be calculated in medication listings. 
Prior medication start date  
If start day is missing, and start month and year are not missing: Impute the start day using the first 
day of the month. Imputation flag is ‘D’. 
If start month is missing, and start year is not missing: Impute the day and month using 01 January. 
Imputation flag is ‘M’. 
If start year is missing: Impute start date using 2 years before informed consent date. Imputation 
flag is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However, in 
order to simplify the programming flow, the imputation is proposed to align with the protocol 
which specifies to collect up to 2 years prior medication. Since the start date of prior medication 
will not be used in any analysis, the rule will not impact the analysis result.  
Prior medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date on or after first dose intake date, use first dose intake date -1 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date on or after first dose intake date, use first dose intake date -
1 instead. Imputation flag is ‘M’ 
If end year is missing: Impute end date using the first dose intake date –1. Imputation flag is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
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Concomitant medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date after end of study follow up date, use the last visit study date 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date after end of study follow up date, use the last study visit date 
instead. Imputation flag is ‘M’. 
If end year is missing: Impute date using the end of last study visit date. Imputation flag is ‘Y’. 
Medication coding 
No imputations for missing laboratory data, ECG data, vital sign data, or physical examination 
data will be made. 
6.3.2. 
PCSV 
Patients who had post-baseline PCSV, but missing baseline value will be regarded as having 
treatment emergent PCSV. 
6.3.3. 
Date of first / last study drug administration 
Date of first study drug administration is the first non-missing start date of dosing filled in the CRF 
“Investigational Product” module. 
If a patient’s date of the last dose is totally missing or unknown, his/her last visit date will be 
substituted.  
6.4. 
Analysis Windows 
Data analyzed by visit (including efficacy, laboratory data, vital signs, ECG) will be summarized 
by the study scheduled visits described in Appendix 10.1 (Schedule of Time and Events). Analysis 
visit windows will be constructed using ranges applied to the number of days in study (study days) 
when the measure is collected, according to the analysis windowing  described in the tables below. 
Analysis visit windows will be exhaustive so that all available values obtained from unscheduled 
visits, early termination visit (ETV) and end of treatment (EOT)/end of study (EOS) have the 
potential to be summarized. No analysis visit windows will be applied to the study scheduled visits.  
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Table 1: Efficacy Analysis Windows 
Visit 
Targeted 
Study Day 
Haptoglobin 
PNH Eryth, 
PNH Gran 
CH50, 
AH50, sC5b-
9 
FACIT-Fatigue, 
EORTC-QLQ-
C30, TSQM 
Screening 1 
 
 
Scr 1 
 
 
Screening 2 
 
 
 
 
 
Day 1 
1 
1 
 
1 
1 
Week 1 
8 
 
 
[2, 12] 
 
Week 2 
15 
 
 
[13, 25] 
[2, 25] 
Week 4 
29 
[2, 81] 
 
[26, 53] 
[26, 53] 
Week 6 
43 
 
 
 
 
Week 8 
57 
 
[2,217] 
[54, 81] 
[54, 81] 
Week 10 
71 
 
 
 
 
Week 12 
85 
[82, 217] 
 
[82, 105] 
[82, 105] 
Week 16 
113 
 
 
[106, 133] 
[106, 133] 
Week 20 
141 
 
 
[134, 161] 
[134, 161] 
Week 24 
169 
 
 
[162, 189] 
[162, 189] 
Week 28 
197 
 
 
[190, 217] 
[190, 217] 
Week 32 
225 
[218, 232] 
[218, 232] 
[218, 232] 
[218, 232] 
OLEP-1 (Week 0e) 
1e 
1e 
1e 
1e 
1e 
OLEP-2 (Week 8e) 
57e 
 
 
 
 
OLEP-3 (Week 16e) 
113e 
 
 
[2e, 217e] 
 
OLEP-4 (Week 24e) 
169e 
 
[2e, 357e] 
 
[2e, 357e] 
OLEP-5 (Week 32e) 
225e 
 
 
[218e, 357e] 
 
OLEP-6 (Week 40e) 
281e 
 
 
 
 
OLEP-7 (Week 52e) 
365e 
[2e, 368e] 
[358e, 368e] 
[358e, 368e] 
[358e, 368e] 
 
Table 2: Safety Analysis Windows 
Visit 
Targeted 
Study Day 
Blood 
Chem 
(Including 
LDH), 
Coagulatio
n 
Hematolog
y 
(Including 
Hemoglobi
n) 
Urinalysis 
Vital Signs 
ECG 
Body 
Weight 
Screening 1 
  
  
  
  
Scr 1 
  
Scr 1 
Screening 2 
  
  
  
  
  
  
  
Day 1 
1 
1 
1 
1 
  
1 
  
Week 1 
8 
[2, 12] 
[2, 12] 
[2, 12] 
  
  
  
Week 2 
15 
[13, 25] 
[13, 25] 
[13, 25] 
[2, 25] 
  
  
Week 4 
29 
[26, 39] 
[26, 53] 
[26, 53] 
[26, 53] 
  
[2, 53] 
Week 6 
43 
[40, 53] 
  
  
  
  
  
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Visit 
Targeted 
Study Day 
Blood 
Chem 
(Including 
LDH), 
Coagulatio
n 
Hematolog
y 
(Including 
Hemoglobi
n) 
Urinalysis 
Vital Signs 
ECG 
Body 
Weight 
Week 8 
57 
[54, 67] 
[54, 81] 
[54, 81] 
[54, 81] 
  
[54, 81] 
Week 10 
71 
[68, 81] 
  
  
  
  
  
Week 12 
85 
[82, 105] 
[82, 105] 
[82, 105] 
[82, 105] 
  
[82, 105] 
Week 16 
113 
[106, 133] 
[106, 133] 
[106, 133] 
[106, 133] 
  
[106, 133] 
Week 20 
141 
[134, 161] 
[134, 161] 
[134, 161] 
[134, 161] 
  
[134, 161] 
Week 24 
169 
[162, 189] 
[162, 189] 
[162, 217] 
[162, 217] 
[2, 217] 
[162, 217] 
Week 28 
197 
[190, 217] 
[190, 217] 
  
  
  
  
Week 32 
225 
[218, 232] 
[218, 232] 
[218, 232] 
[218, 232] 
[218, 232] 
[218, 232] 
OLEP-1 
(Week 0e) 
1e 
1e 
1e 
1e 
1e 
1e 
1e 
OLEP-2 
(Week 8e) 
57e 
[2e, 105e] 
[2e, 105e] 
[2e, 105e] 
[2e, 105e] 
  
[2e, 105e] 
OLEP-3 
(Week 16e) 
113e 
[106e, 161e] [106e, 161e] [106e, 161e] [106e, 161e] 
  
[106e, 161e] 
OLEP-4 
(Week 24e) 
169e 
[162e, 217e] [162e, 217e] [162e, 217e] [162e, 217e] 
  
[162e, 217e] 
OLEP-5 
(Week 32e) 
225e 
[218e, 273e] [218e, 273e] [218e, 273e] [218e, 273e] 
  
[218e, 273e] 
OLEP-6 
(Week 40e) 
281e 
[274e, 357e] [274e, 357e] [274e, 357e] [274e, 357e] 
  
[274e, 357e] 
OLEP-7 
(Week 52e) 
365e 
[358e, 368e] [358e, 368e] [358e, 368e] [358e, 368e] 
[2e, 368e] 
[358e, 368e] 
6.5. 
Unscheduled Assessments 
The determination of baselines and values at the end of treatment for both efficacy and safety 
variables will be based on scheduled available assessments and unscheduled available 
assessments.  
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing adverse events) will be included in listings, 
but not summaries except for the endpoint determination.  If more than one unscheduled laboratory 
value is available for a given visit, the observation closest to the target visit date will be used in 
summaries and all observations will be presented in listings. 
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7. 
INTERIM ANALYSIS  
An interim analysis may be conducted after 6 patients have completed at least 16 weeks of the 
OLTP. Additional/other interim analyses may be performed to support regulatory interactions. 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
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9. 
REFERENCES 
1. 
ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use.
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10.1. 
Footnotes for the Schedule of Events Tables 
10.1.1. 
Footnotes for Table 3 Schedule of Events (Open-Label Treatment Period) 
1. Study procedures: when multiple procedures are performed on the same day, the sequence of procedures is as follows: COA 
assessments, ECG and/or vital signs, blood collection, study treatment administration, and any pre-specified post-dose sample 
collection.  
2. Screening visit 1b can be combined with visit 1a, if LDH can be obtained one day before or on the day of eculizumab 
administration. Visit 1b and additional interim visits may also be needed for repeat blood collection, vaccination, etc.  
3. Medical history: transfusions, breakthrough hemolysis history, and laboratory parameters for measurement of hemolysis (such 
as LDH, bilirubin, haptoglobin, reticulocyte count, and hemoglobin) should be obtained for the past 1 year, if possible. Prior 
history at any time of thrombosis and Neisseria infections will be collected if feasible. Ongoing PNH symptoms and signs will 
also be collected. 
4. Prior medications: including detailed eculizumab administration history (past 26 weeks) and N. meningitidis vaccination (past 5 
years); all other prior medications 12 weeks prior to screening 
5. Patients will require administration with meningococcal vaccination unless documentation is provided of prior immunization in 
the past 5 years prior to screening, or less than 5 years if required according to national vaccination guidelines for vaccination 
use with complement inhibitors or local practice. For patients who require administration with meningococcal vaccination(s) 
during the screening period, administration should occur preferably at least 2 weeks prior to day 1, or at another time point 
according to local practice or national guidelines.   
6. Tuberculosis history and assessment. Screening by tuberculin skin test or T-cell interferon-gamma release assay may be 
performed according to local practice or guidelines at the discretion of the investigator. 
7. A risk factor assessment for N. gonorrhea is recommended, and counseling is advised for at-risk patients.  
8. Patient safety card: provide the patient safety card for N. meningitidis infection to the patient on day 1 or any other visit when 
needed. Site should review the instructions on the safety card with the patient at each visit.   
9. Cemdisiran administration: the first day of dosing of cemdisiran will take place at the patient’s usual schedule of administration 
for eculizumab.   
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10. Pozelimab IV administration: administration at day 29 should precede SC administration. After completion of IV administration, 
the patient should be observed for at least 30 minutes and if no clinical concern, then SC administration of the combination 
should proceed. Patients should be monitored for at least another 30 minutes after the first SC dosing. 
11. The SC doses of pozelimab and cemdisiran should be given Q4W (every 28 days) starting at day 29 (week 4). From day 57 
(week 8) onward, cemdisiran and pozelimab SC administration may either be continued by the site personnel or another 
healthcare professional at the patient’s home, or administration by the patient or designated person at the patient’s preferred 
location after adequate training. The final SC dosing of the combination during the OLTP is at week 28. 
During the Q4W dose administration interval starting at day 57, the dose of cemdisiran and pozelimab SC should be given on 
the day of the corresponding study visit whenever possible. Study treatment administration should always be the last procedure 
after all blood sample collection and study assessments have been completed unless otherwise specified.  If pozelimab or 
cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 7 
days before or up to 7 days after the planned dosing date, provided that the dosing takes place after the corresponding study visit 
has been completed. For example, the day 57 (week 8) visit can take place from day 54 to day 60 given the visit window. The 
corresponding dose of pozelimab and cemdisiran can be given from day 54 to day 64, but only after the week 8 visit assessments 
have been performed. Similarly, the day 113 (week 16) visit can take place from day 106 to day 120 given the visit window. The 
corresponding dose of pozelimab and cemdisiran can be given from day 106 to day 120, but only after the week 16 visit 
assessments have been performed. Pozelimab and cemdisiran should be administered on the same day whenever possible. Care 
must be taken to coordinate dosing for visits where a post-dose sample is collected to measure the concentration of cemdisiran 
and its metabolites.   
12. Eculizumab administration: continue patient’s eculizumab administration at the usual dose and dosing interval. Administration 
of eculizumab at day 1 (when first dose of cemdisiran is administered) may occur up to 2 days later.  
NOTE: the week 2 visit should be scheduled relative to the patient’s typical dosing frequency. For patients taking eculizumab 
with a frequency of: 
• Every 12 days  
− The visit should be scheduled on day 13 (±2 days). 
• Every 13 days  
− The visit should be scheduled on day 14 (±2 days). 
• Every 14 days  
− The visit should be scheduled on day 15 (±2 days). 
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The dose of eculizumab should be administered according to the usual dose frequency and must be dosed on or after the visit 
and corresponding assessments have been performed. 
13. Injection training will be provided to patients who desire self-injection or injection by a designated person. Site staff should 
observe patient’s self-injection or injection by a designated person and confirm adequacy. Patient instruction materials will be 
provided. 
14. If needed, based on patient self-administration/administration by a designated person, the patient will complete a diary for 
recording data on study treatment administration starting at the day 57 visit or a subsequent visit. If patient diary is provided to 
the patient, then it should be reviewed at each clinic visit and data collected into the case report forms (CRFs). On the final visit, 
the diary should be collected by the site. 
15. Daily oral antibiotic prophylaxis against N. meningitidis is recommended starting on the first day of dosing with study treatment 
and continuing until 52 weeks after discontinuation of pozelimab/cemdisiran. If vaccination for N. meningitidis occurs less than 
2 weeks prior to day 1, then antibiotic prophylaxis must be administered for at least 2 weeks from the time of vaccination.    
16. Patients will complete the PNH Symptom-Specific Questionnaire on a daily basis for at least 14 days prior to the day 1 visit. 
Patients should try to complete the PNH Symptom-Specific Questionnaire at the same time each day whenever possible. 
17. Breakthrough hemolysis assessment: if a patient is suspected of having a breakthrough hemolysis event, then in addition to the 
required laboratory collection, additional samples for coagulation parameters, chemistry, hematology, reticulocyte count, D-
dimer, total C5, CH50, ADA (against pozelimab), and drug concentrations of pozelimab and eculizumab will be collected unless 
already noted in the Schedule of Events for that visit. If the suspected event does not occur at a scheduled visit, then an 
unscheduled visit should occur with an evaluation of the patient and collection of coagulation parameters, chemistry, hematology, 
reticulocyte count, total C5, CH50 and drug concentrations of pozelimab and eculizumab.  
18. During lab collection, handling, and processing, the same methodology will be applied across study visits, as best as possible, to 
preserve the quality of sample and avoid hemolysis. The coagulation blood sample (tube) must always be collected first, followed 
by the blood chemistry sample (tube). If the investigator or sponsor suspects that the lab result is not an accurate reflection of 
the patient’s condition, the lab sample should be repeated. 
19. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. The coagulation blood sample (tube) 
must always be collected first, followed by the blood chemistry sample (tube). During screening, obtain chemistry including 
LDH prior to eculizumab administration on the day of (or if not possible, one day before) eculizumab administration. On day 1 
and all subsequent visits, obtain chemistry including LDH prior to any study treatment administration.   
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20. Pregnancy test for WOCBP: a serum test will be done at the screening visit and a urine test will be done at all other visits 
indicated. Any positive urine test should be confirmed with a serum pregnancy test. 
21. Blood sample collection for concentrations of pozelimab, eculizumab, total C5, CH50 (efficacy endpoint), and AH50: obtain 
samples prior to any study drug administration (pre-dose). On day 29, obtain blood samples prior to IV administration of 
pozelimab and also within 15 minutes after the end of the IV infusion.  
22. Blood samples for concentrations of cemdisiran and its metabolites will be collected prior to any study treatment administration 
(pre-dose) and at 2 to 6 hours post-cemdisiran administration. The post-dose sample should be carefully coordinated with the 
dosing of cemdisiran and may be collected at the clinic or by a visiting healthcare professional.  
23. Blood samples for immunogenicity will be collected before the administration of any study drug (pre-dose). At the visits where 
immunogenicity samples are to be taken, the sample should be collected with the drug concentration sample. In the event of 
suspected SAEs, such as anaphylaxis or hypersensitivity, additional samples for drug concentration and immunogenicity may be 
collected at or near the event. 
24. Future research serum and plasma (optional): samples should be collected, as permitted by patient consent and local regulatory 
policies. They may be stored for up to 15 years or as permitted by local regulatory policies, whichever is shorter, for future 
biomedical research. 
25. Whole blood samples (optional) for DNA extraction should be collected on day 1 (pre-dose) but can be collected at a later study 
visit.  
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10.1.2. 
Footnotes for Table 4 Schedule of Events (Open-Label Treatment Period for Patients on Intensified Therapy) 
1. Study procedures: When multiple procedures are performed on the same day, the sequence of procedures is as follows: COA 
assessments, ECG and/or vital signs, blood collection, study treatment administration, and any pre-specified post-dose sample 
collection.  
2. Patients should be monitored for at least 30 minutes after completion of pozelimab 30 mg/kg IV. Subsequent SC doses will be 
administered Q2W (pozelimab) and Q4W (cemdisiran) and may either be performed by the site personnel or another healthcare 
professional at the patient’s home, or administered by the patient or by a designated person. For patients on intensified treatment 
in the OLTP, the final SC dose of cemdisiran is at day 197r, week 28r, and the final SC dose of pozelimab is at day 211r 
(week 30r).  
3. Pozelimab and cemdisiran SC administration: the dose of pozelimab SC should be given Q2W (every 14 days) and cemdisiran 
should be given Q4W (every 28 days) and on the day of the corresponding study visit whenever possible and as applicable. Study 
treatment administration should always be the last procedure after all blood sample collection and study assessments have been 
completed unless otherwise specified. If administration of pozelimab or cemdisiran cannot be administered on the day of the 
corresponding study visit, the dose may be administered up to 3 days before or up to 3 days after the planned dosing date as long 
as the dosing takes place after the corresponding study visit has been completed. For example, the day 29r (week 4r) visit can 
take place from day 26r to day 32r given the visit window. The dose of pozelimab and cemdisiran therefore can be given from 
day 26r to day 32r, but only on or after the week 4r visit assessments have been performed. Similarly, the day 113r (week 16r) 
visit can take place from day 106r to day 116r given the visit window. The dose of pozelimab and cemdisiran can be given from 
day 110r to day 116r, but only on or after the week 16r visit assessments have been performed. Whenever possible, the dose of 
cemdisiran should be administered on the same day as the Q4W dose of pozelimab. The final dose of cemdisiran is at week 28r 
and the final dose of pozelimab is at week 30r. 
4. Injection training will be provided to patients who desire self-injection or injection by a designated person. The site should 
observe patient self-injection or injection by a designated person and confirm adequacy. Patient instruction materials will be 
provided. 
5. If needed, based on patient self-administration/administration by a designated person, the patient will complete a diary for 
recording data on study treatment administration. If the patient diary is provided to the patient, then it should be reviewed at each 
clinic visit and data collected into the CRFs. On the final visit, the diary should be collected by the site. 
6. Daily oral antibiotic prophylaxis against N. meningitidis is recommended until 52 weeks after discontinuation of 
pozelimab/cemdisiran.  
7. Patients should try to complete the PNH Symptom-Specific Questionnaire at the same time each day whenever possible. 
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8. Patient safety card: the site should review the instructions on the safety card with the patient at each visit.   
9. Breakthrough hemolysis assessment: if a patient is suspected of having a breakthrough hemolysis event, then in addition to the 
required laboratory collection, additional samples for coagulation parameters, chemistry, hematology, reticulocyte count, D-
dimer, total C5, CH50, ADA (against pozelimab) and drug concentrations of pozelimab will be collected unless already noted 
in the Schedule of Events for that visit. If the suspected event does not occur at a scheduled visit, then an unscheduled visit 
should occur with an evaluation of the patient and collection of coagulation parameters, chemistry, hematology, reticulocyte 
count, total C5, CH50 and drug concentrations of pozelimab.  
10. During lab collection, handling, and processing, the same methodology will be applied across study visits, as best as possible, to 
preserve the quality of the sample and avoid hemolysis. The coagulation blood sample (tube) must always be collected first, 
followed by the blood chemistry sample (tube). 
11. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis.     
12. Pregnancy test for WOCBP: a urine test will be done at all visits indicated.   
13. Blood sample collection for concentrations of pozelimab, total C5, CH50 (efficacy endpoint), and AH50: obtain samples prior 
to any study drug administration (pre-dose). On day 1, obtain blood sample for pozelimab concentration and total C5 prior to IV 
administration of pozelimab and also within 15 minutes after the end of the IV infusion.  
14. Blood samples for concentrations of cemdisiran and its metabolites will be collected prior to any study treatment administration 
(pre-dose) and at 2 to 6 hours post-cemdisiran dosing. The post-dose sample should be carefully coordinated with the dosing of 
cemdisiran and may be collected at the clinic or by a visiting healthcare professional.  
15. Blood samples for immunogenicity will be collected before the administration of any study drug (pre-dose). At the visits where 
immunogenicity samples are to be taken, the sample should be collected with the drug concentration sample. In the event of 
suspected SAEs, such as anaphylaxis or hypersensitivity, additional samples for drug concentration and immunogenicity may be 
collected at or near the event. 
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10.1.3. 
Footnotes for Table 5 Schedule of Events (for Optional Open-Label Extension Period) 
1. Visits may be at the clinical site or another preferred location, such as the patient’s home. The location will depend on the 
availability of a home healthcare visiting professional as well as the preferences of the investigator and patient. In the event of 
travel restrictions due to a global pandemic, alternative mechanisms such as but not limited to telemedicine visits may be 
implemented to maintain continuity of study conduct. 
2. Study procedures (visits): when multiple procedures are performed on the same day, the sequence of procedures is as follows: 
COA assessments, ECG and/or vital signs, blood collection, study treatment administration, and any pre-specified post-dose 
sample collection.  
3. Day 1e of OLEP should be scheduled on the same day as week 32 (or week 32r for patients on intensified treatment) of the 
OLTP, and any common assessments will be performed once for both the OLTP and OLEP visits. 
4. During the OLEP, the dose of cemdisiran and pozelimab SC should be given on the day of the corresponding study visit whenever 
possible. Study treatment administration should always be the last procedure after all blood sample collection and study 
assessments have been completed unless otherwise specified. If pozelimab or cemdisiran cannot be administered on the day of 
the corresponding study visit, the combination may be administered up to 3 days before or up to 3 days after the planned dosing 
date for patients in an intensified treatment regimen (pozelimab Q2W dosing) or up to 7 days before or 7 days after the planned 
dosing date for patients on a maintenance treatment regimen (pozelimab Q4W dosing), provided that the dosing takes place after 
the corresponding study visit has been completed. Care must be taken to coordinate dosing for visits where a post-dose sample 
is collected to measure concentration of cemdisiran and its metabolites.  
5. For patients who did not receive intensified treatment during OLTP: at any time during the OLEP, patients who meet pre-
specified criteria will receive intensified treatment consisting of a pozelimab 30 mg/kg IV loading dose followed 30 minutes 
later by the initiation of pozelimab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W.  Patients will continue their visit schedule 
at the next OLEP visit. 
6. Study treatment administration should always be the last procedure after all blood sample collection and study assessments have 
been completed unless otherwise specified. For patients whose treatment is not intensified during the OLEP, the last doses of 
cemdisiran and pozelimab are administered at week 52e. For patients whose treatment was intensified during the OLEP, the last 
doses of study treatment will be determined based on the time of treatment intensification. 
7. Injection training will be provided to patients who desire self-injection or injection by a designated person. The site should 
observe patient self-injection or injection by a designated person and confirm adequacy. Patient instruction materials will be 
provided. 
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8. If study treatment is given by the patient or by a designated person, the patient will complete a diary for recording compliance 
with study treatment administration. If the patient diary is provided to the patient, then it should be reviewed at each clinic visit 
and data collected into the CRFs. On the final visit, the diary should be collected by the site. 
9. Daily oral antibiotic prophylaxis against N. meningitidis is recommended until 52 weeks after discontinuation of study treatment. 
10. Patient safety card: the site should review the instructions on the safety card with the patient at each visit. 
11. Breakthrough hemolysis assessment: if a patient is suspected of having a breakthrough hemolysis event, then in addition to the 
required laboratory collection, additional samples for coagulation parameters, chemistry, hematology, reticulocyte count, D-
dimer, total C5, CH50, ADA (against pozelimab) and drug concentrations of pozelimab will be collected unless already noted 
in the Schedule of Events for that visit. If the suspected event does not occur at a scheduled visit, then an unscheduled visit 
should occur with an evaluation of the patient and collection of coagulation parameters, chemistry, hematology, reticulocyte 
count, total C5, CH50 and drug concentrations of pozelimab. 
12. Clinical lab samples will be collected prior to any study drug administration (pre-dose) unless otherwise specified. The 
coagulation blood sample (tube) must always be collected first, followed by the blood chemistry sample (tube). During lab 
collection, handling, and processing, the same methodology will be applied across study visits, as best as possible, to preserve 
the quality of the sample and avoid hemolysis. 
13. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. The blood chemistry sample should be 
collected before study treatment administration (pre-dose). If the investigator or sponsor suspects that the lab result is not an 
accurate reflection of the patient’s condition, the lab sample should be repeated. 
14. Hemoglobin and free hemoglobin will be assessed as part of the hematology analysis. A separate sample for hemoglobin and 
free hemoglobin is not required if a hematology sample is collected on the same day. The hematology sample should be collected 
before study treatment administration (pre-dose). 
15. Pregnancy test for WOCBP: a urine test will be done at all visits indicated. Any positive urine pregnancy test should be confirmed 
with a serum pregnancy test. 
16. Blood samples for pozelimab concentration analysis and total C5 analysis will be obtained on the specified days prior to any 
study treatment administration (pre-dose).  If the patient receives treatment intensification during the open-label extension period, 
a PK sample should be obtained prior to IV pozelimab administration and 15 minutes post-dose. 
17. Blood samples for cemdisiran concentration analysis and concentrations of its metabolites will be collected on the specified days 
prior to any study treatment administration (pre-dose) and 2 to 6 hours post-cemdisiran administration. The post-dose sample 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 61 of 65 
should be carefully coordinated with the dosing of cemdisiran and may be collected at the clinic or by a visiting healthcare 
professional.  
18. Blood samples for immunogenicity will be collected on the specified days prior to any study treatment administration (pre-dose). 
At the visits where immunogenicity samples are to be taken, the sample should be collected with the drug concentration sample. 
In the event of suspected treatment-related SAEs, such as anaphylaxis or hypersensitivity, additional drug concentration and 
immunogenicity samples may be collected at or near the onset and the resolution of the event. 
19. Blood samples for CH50 (efficacy endpoint) and AH50 will be obtained prior to any study treatment administration (pre-dose). 
10.1.4. 
Footnotes for Table 6 Schedule of Events (Post-Treatment Safety Follow-Up Period for All Patients) 
Patients who discontinue study treatment in either the OLTP or the intensified OLTP will be asked to remain in the study until 
week 32 EOT (or week 32r EOT) and follow the original Schedule of Events as applicable. After the week 32 or week 32r EOT visit, 
the entry point into the safety follow-up schedule will depend on the number of weeks that have elapsed since patient’s last dose (e.g., 
a patient who is 20 weeks after his/her final dose of study treatment at EOT will enter into the safety follow-up period at Visit FU-4 [26 
weeks after last dose]).Patients who completed week 32r in the OLTP who choose not to continue treatment in the OLEP, patients who 
complete the optional OLEP but do not continue study treatment in a post-trial access program, and patients who permanently 
discontinue treatment during the OLEP will enter into the safety follow-up period at FU-1. 
1. Patient safety card: Site should review the instructions on the safety card with the patient at each visit. Replacement cards may 
be given to the patient as needed. 
2. Daily oral antibiotic prophylaxis against N. meningitidis is recommended until 52 weeks after discontinuation of study treatment. 
                                        VV-RIM-00212243-1.0 Approved - 28 Sep 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 62 of 65 
10.2. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
PCSV 
Comments 
Clinical chemistry 
ALT 
By distribution analysis: 
> 3 ULN 
> 5 ULN 
> 10 ULN 
> 20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007 
Internal DILI WG Oct 2008 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be deleted. 
AST 
By distribution analysis: 
> 3 ULN 
> 5 ULN 
> 10 ULN 
> 20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007 
Internal DILI WG Oct 2008 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be deleted. 
Alkaline Phosphatase 
> 1.5 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008 
Total Bilirubin 
> 1.5 ULN 
> 2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L.  
Concept paper on DILI – FDA draft Guidance Oct 2008 
Internal DILI WG Oct 2008 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be deleted. 
Conjugated bilirubin 
> 35% total bilirubin (when total bilirubin 
>1.5 ULN) 
Conjugated bilirubin dosed on a case-by-case basis 
ALT and Total Bilirubin 
ALT > 3 ULN and Total Bilirubin > 2 
ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007 
Internal DILI WG Oct 2008 
To be counted within the same treatment phase, whatever the interval between 
measurement 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 63 of 65 
Parameter 
PCSV 
Comments 
CPK 
> 3 ULN 
>10 ULN 
FDA Feb 2005 
Am J Cardiol April 2006 
Categories are cumulative 
First row is mandatory. Rows following one mentioning zero can be deleted. 
Creatinine 
 150 mol/L (adults) 
   90 mol/L (6-12 year-old) 
 30% from baseline 
 100% from baseline 
Benichou C., 1994 
 
eGFR 
(Chronic Kidney Disease 
– Epidemiology 
Collaboration Equation 
2009) 
< 30 ml/min (severe renal impairment) 
30 - < 59 ml/min (moderate renal 
impairment) 
60 - <89 ml/min (mild renal impairment) 
90 ml/min (no renal impairment) 
 
Uric Acid 
Hyperuricemia: 
Hypouricemia: 
 
>408 µmol/L 
<120 µmol/L 
Harrison- Principles of internal Medicine 17th Ed. 2008 
Sodium 
129 mmol/L 
 160 mmol/L 
 
Potassium 
< 3  mmol/L 
 5.5 mmol/L 
FDA Feb 2005 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
 3.9 mmol/L and < LLN 
  7 mmol/L (fasted);  11.1 mmol/L 
(unfasted) 
 
ADA May 2005 
ADA Jan 2008 
 
CRP 
> 2 ULN or 
 >10 mg/L, if ULN not provided 
 FDA Sept 2005 
 
Hematology 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 64 of 65 
Parameter 
PCSV 
Comments 
WBC 
< 3.0 Giga/L (3000/mm3) 
< 2.0 Giga/L (2000/mm3) (Black) 
Increase in WBC: not relevant 
To be interpreted only if no differential count available. 
Neutrophils 
< 1.5 Giga/L (1500/mm3) 
< 1.0 Giga/L (1000/mm3) Black 
International Consensus meeting on drug-induced blood cytopenias, 1991. 
FDA criteria 
Eosinophils 
> 0.5 Giga/L (500/mm3) 
or > ULN if ULN  0.5 Giga/L 
Gallin 1989, Harrisson 13th Ed, 1994. 
Hemoglobin 
At least 20 g/L (1.24 mmol/L) decrease 
versus baseline 
Criteria based upon decrease from baseline are more relevant than based on 
absolute value.  
Other categories for decrease from baseline can be used ( 30 g/L,  40 g/L, 
 50 g/L) 
Platelets 
< 100 Giga/L (100 000/mm3) 
International Consensus meeting on drug-induced blood cytopenias, 1991. 
Vital signs 
HR 
 40 bpm and decrease from baseline  20 
bpm 
 100 bpm and increase from baseline  
20 bpm 
Proposed change: To be applied for all positions (including missing) except 
STANDING 
SBP 
 95 mmHg and decrease from baseline  
20 mmHg 
 140 mmHg and increase from baseline  
20 mmHg 
Proposed change: To be applied for all positions (including missing) except 
STANDING 
DBP 
Young and elderly subjects 
 45 mmHg and decrease from baseline  
10 mmHg 
 90 mmHg and increase from baseline  
10 mmHg 
 
Proposed change: To be applied for all positions (including missing) except 
STANDING 
Weight 
 5 % increase versus baseline 
5% decrease versus baseline 
FDA Feb 2007  
ECG parameters 
CPMP 1997 guideline 
                                        VV-RIM-00212243-1.0 Approved - 28 Sep 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-20105 
Statistical Analysis Plan 
 
Date: 26 Sep 2022 
 
CONFIDENTIAL 
Page 65 of 65 
Parameter 
PCSV 
Comments 
HR 
 40 bpm and decrease from baseline  20 
bpm 
 100 bpm and increase from baseline  
20 bpm 
 
PR 
 220 ms 
 
QRS 
 120 ms 
 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms) 
                Males           Females 
Borderline  
           431-450 ms     451-470 ms 
Prolonged* 
           > 450 ms         > 470 ms 
QTc   ≥500 ms           ≥ 500 ms 
 
Increase versus baseline (Males and 
Females) 
Borderline 
 30-60 ms 
Prolonged * 
 > 60 ms 
To be applied to any kind of QT correction formula  
 
*QTc prolonged and QTc > 60 ms are the PCSA to be identified in individual 
subjects/patients listings. 
 
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