A Phase 2, Open-Label Study to Evaluate the Long-term Safety of Oral BCX9930 in Subjects With Paroxysmal Nocturnal Hemoglobinuria (PNH)
Phase: PHASE2
Conditions: Paroxysmal Nocturnal Hemoglobinuria, PNH
Sponsor: BioCryst Pharmaceuticals

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A P H A S E 2,  O P E N-L A B E L S T U D Y T O E V A L U A T E T H E 
L O N G -T E R M S A F E T Y O F O R A L B C X 9 9 3 0 I N 
S U B J E C T S WI T H P A R O X Y S M A L N O C T U R N A L 
H E M O G L O BI N U RI A ( P N H)  
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P h o ne: ( 9 1 9) 8 5 9- 1 3 0 2 
Fa x: ( 9 1 9) 8 5 1- 1 4 1 6 
C O N FI D E N TI A L  
T he i nf or m ati o n i n t his d oc u me nt c o nt ai ns pr o priet ary a n d c o nfi de nti al i nf or m ati o n bel o n gi n g t o 
Bi o Cryst P h ar m ace utic als, I nc. As a res ult, n o p art of t his d oc u me nt s h o ul d be c o pie d, referr e d 
t o, rele ase d, p u blis he d or ot her wise discl ose d i n a ny m a n ner or me di a wit h o ut pri or writte n 
a p pr ov al fr o m Bi o Cryst P h ar m ace utic als, I nc. 

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S p o ns or’s A ut h orize d Si g n at or y: 
 
 
 
 
 
 
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A P H A S E 2, O P E N -L A B E L S T U D Y T O E V A L U A T E T H E L O N G -T E R M 
S A F E T Y O F O R A L B C X 9 9 3 0 I N S U B J E C T S WI T H P A R O X Y S M A L 
N O C T U R N A L H E M O G L O BI N U RI A ( P N H)  
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I h a ve r ecei ve d a n d r ea d t he I n v esti gat or’s Br oc h ure f or B C X 9 9 3 0. I h a ve rea d t he 
B C X 9 9 3 0- 2 0 1 pr ot oc ol a n d a gree t o c o n d uct t he st u d y as o utli ne d. I a gree t o mai ntai n t he 
c o nfi de ntialit y o f all i nf or mati o n recei ve d or de v el o pe d i n c o n necti o n wit h t his pr ot oc ol.  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
Pri nte d Na me of I n v esti gat or 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
Si g nat ure of I n vesti gat or 
 
  
  
  
  
  
  
 
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S T U D Y I N F O R M A TI O N  
Pr ot oc ol N u m ber:  
B C X 9 9 3 0 -2 0 1  
St u d y Title:  
A P hase 2, O pe n -la bel St u d y t o E val uate t he L o n g-ter m Safet y of Oral B C X 9 9 3 0 
i n S u bjects wit h Par o x ys mal N oct ur nal He m o gl o bi n uria ( P N H) 
E u dr a C T N o.  
2 0 2 0 -0 0 0 5 0 1 -9 3  
I n vesti g ati o n al Pr o d uct: 
B C X 9 9 3 0  
I n dic ati o n St u die d: 
Par o x ys mal n oct ur nal he m o gl o bi n uria ( P N H)  
S p o ns or:  
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4 5 0 5 E m per or B o ule var d, S uite 2 0 0  
D ur ha m, N C 2 7 7 0 3, U S A  
S p o ns or Me dic al M o nit or:  
 
 
C o or di n ati n g I n vesti g at or:  
 
C o m pli a nce St ate m e nt:  
T his 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 cli nical researc h g ui deli nes 
esta blis he d b y t he C o de of Fe deral Re g ulati o ns ( Title 2 1, C F R Parts 5 0, 5 6, a n d 
3 1 2) a n d I nter nati o nal C o u ncil f or Har m o ni sati o n G ui deli nes, a n d all l ocall y 
a p plica ble re g ulati o ns . Esse ntial st u d y d oc u me nts are c urre ntl y arc hi ve d i n 
acc or da nce wit h a p plica ble re g ulati o ns.  
Fi n al Pr ot oc ol D ate:  
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Pre vi o us Versi o ns:  
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V ersi o n 1. 0: 2 6 Ma y 2 0 2 0  
 

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2.  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
Bi o Cr yst P har mace uticals I nc. 
N a me of I n vesti g ati o n al Pr o d uct:  
B C X 9 9 3 0 
N a me of Acti ve I n gre die nt:  
  
Title of St u d y:  
A P hase 2, O pe n - La bel St u d y t o E val uate t he L o n g-ter m Safet y of Oral B C X 9 9 3 0 i n S u bjects wit h 
Par o x ys mal N oct ur nal He m o gl o bi n uria ( P N H)  
St u d y ce nters: Ce nters t hat ha ve partici pate d i n a pre vi o us B C X 9 9 3 0 P N H st u d y  
C o - or di n ati n g I n vesti g at or:  
 
P h ase of De vel o p me nt:  2 
Pri m ar y O bjecti ve:  
•  T o assess l o n g -ter m safet y a n d t olera bilit y data i n eli gi ble s u bjects 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 pre vi o usl y recei ve d B C X 9 9 3 0 i n a Bi o Cr yst-s p o ns ore d st u d y a n d 
deri ve d be nefit fr o m B C X 9 9 3 0 treat me nt. 
Sec o n d ar y O bjecti ves:  
•  T o assess t he c o nti n ue d effecti ve ness of B C X 9 9 3 0 i n treat me nt of P N H d uri n g l o n g -ter m 
a d mi nistrati o n .  
•  T o e val uate patie nt-re p orte d o utc o mes ( P R O) of l o n g- ter m B C X 9 9 3 0 treat me nt. 
•  T o c ollect p har mac o ki netic ( P K ), p har mac o d y na mic (P D ), a n d c o m ple me nt bi o mar ker data i n 
s u bjects wit h P N H f or i nc or p orati o n i nt o meta-st u d y m o dels of p o p ulati o n P K a n d P K/ P D.  
•  T o c haracterize t he effects of B C X 9 9 3 0 i n s u bjects wit h P N H b y cli nical meas ure me nts a n d 
P D a n d c o m ple me nt bi o mar kers. 
•  T o e val uate bi o mar kers of c o m ple me nt acti vati o n d uri n g e pis o des of brea kt hr o u g h he m ol ysis 
( B T H).  
Pri m ar y E n d p oi nt:  
•  Meas ure me nt of safet y a n d t olera bilit y b y s u bject i nci de nce of gra de d treat me nt -e mer ge nt 
a d verse e ve nts ( T E A Es), la b orat or y a b n or malities, c ha n ges t o vital si g ns, electr ocar di o gra m 
( E C G) res ults, a n d p h ysical e xa mi nati o n fi n di n gs. 

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Sec o n d ar y E n d p oi nts:  
•  Cli nical P N H s y m pt o m assess me nts i ncl u di n g fati g ue, d ys p nea, c hest pai n/ disc o mf ort, 
diffic ult y s wall o wi n g (es o p ha geal pai n), a b d o mi nal pai n, hea dac he, erectile d ysf u ncti o n, 
he m o gl o bi n uria, ja u n dice, i nci de nce of B T H, a n d i nci de nce of t hr o m b oe m b olic e ve nts . 
•  Cli nical meas ure me nts of P N H ( lactate de h y dr o ge nase [L D H ], he m o gl o bi n, ha pt o gl o bi n, 
retic ul oc ytes, tra nsf usi o n re q uire me nts).  
•  P R O e n d p oi nts will i ncl u de sc ores fr o m t he Q ualit y of Life Q uesti o n naire f or Patie nt s wit h 
A plastic A ne mia/ P N H ( Q L Q - A A/ P N H), F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y 
( F A CI T) fati g ue scale, a n d Treat me nt Satisfacti o n Q uesti o n naire f or Me dicati o n ( T S Q M). 
•  C o nce ntrati o n of B C X 9 9 3 0 i n plas ma at stea d y state i n s u bjects wit h P N H. 
P h ar m a c o d y n a mic ( P D) E n d p oi nt:  
•  
P D a n d c o m ple me nt bi o mar ker meas ure me nts will i ncl u de P N H re d bl o o d cell ( R B C) a n d 
w hite bl o o d cell ( W B C) cl o ne size, plas ma Fact or B b le vels a n d alter nati ve c o m ple me nt 
pat h wa y ( A P ) acti vit y (as assesse d via  A P W ieisla b).  
 
 
St u d y Desi g n:  
T his is a n o pe n-la bel p hase 2 st u d y desi g ne d t o e val uate t he l o n g -ter m safet y of dail y oral treat me nt 
wit h B C X 9 9 3 0 i n s u bjects w h o ha ve partici pate d i n a pre vi o us B C X 9 9 3 0 trial f or P N H a n d s h o we d a 
be nefit of treat me nt as deter mi ne d b y t he I n vesti gat or. T he st u d y all o ws c o nti n ue d access t o 
B C X 9 9 3 0 f or e nr olle d s u bjects. 
Met h o d ol o gy:  
S u bjects w h o meet all of t he i ncl usi o n a n d n o ne of t he e xcl usi o n criteria will be e nr olle d i nt o t he 
st u d y. St u d y visits will occ ur at Scree ni n g, Baseli ne/ Da y 1, Wee k 4, t he n e ver y 4 wee ks u p t o 
Wee k  9 6. O nce s u bjects ha ve reac he d Wee k 9 6 , s u bse q ue nt st u d y visits will occ ur e ver y 8 wee ks u p 
t o Wee k 1 4 4 . A d diti o nal visits will  be re q uire d i n t he case of risi n g ser u m creati ni ne.  
S u bjects will recei ve u p t o 1 4 4 wee ks of dail y B C X 9 9 3 0.  
•  F or s u bjects directl y r olli n g o ver fr o m a n ot her B C X 9 9 3 0 st u d y wit h o ut treat me nt i nterr u pti o n, 
n o scree ni n g visit is re q uire d. T he fi nal o n-st u d y visit assess me nts i n t he pri or B C X 9 9 3 0 st u d y 
will ser ve as t he baseli ne assess me nts f or t his st u d y; h o we ver, a d diti o nal rele va nt baseli ne 
assess me nts f or t his st u d y ma y be perf or me d at t he fi nal o n-treat me nt visit f or t he pri or st u d y 
as nee de d t o satisf y e nr oll me nt criteria. E nr oll me nt wit h o ut treat me nt i nterr u pti o n i nt o t he 
c urre nt st u d y will o b viate t he re q uire me nt f or a f oll o w- u p visit i n t he pre vi o us B C X 9 9 3 0 st u d y. 
•  S u bjects wit h a n i nterr u pti o n of treat me nt of 1 t o 3 0 da ys d urati o n will be re q uire d t o c o m plete 
a f ull baseli ne visit, b ut n o scree ni n g visit.   
•  S u bjects wit h a n i nterr u pti o n of treat me nt of 3 1 da ys or greater will be re q uire d t o c o m plete a 
f ull scree ni n g visit a n d t he n baseli ne visit.  

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Pri or t o t his a me n d me nt, t he  pr ot oc ol -s pecifie d d os i n g re gi me n was 5 0 0 m g B C X 9 9 3 0 t wice dail y 
(BI D ). U n der t his a me n d me nt, s u bjects will recei ve 4 0 0  m g B C X 9 9 3 0 BI D.  
Safet y a n d t olera bilit y will be e val uate d t hr o u g h assess me nts of T E A Es, la b orat or y a nal yses (cli nical 
c he mistr y, he mat ol o g y, c oa g ulati o n a n d uri nal ysis), vital si g ns, E C Gs, a n d p h ysical e xa mi nati o n 
fi n din gs. Safet y e ve nts of s pecial i nterest, i ncl u di n g i nfecti o ns, will be f oll o we d.  
Cli nical effecti ve ness will be assesse d at eac h visit, i ncl u di n g assess me nt of P N H -ass ociate d cli nical 
s y m pt o ms (e g, fati g ue, d ys p nea, c hest pai n/ disc o mf ort, diffic ult y s wall owi n g (es o p ha geal pai n), 
a b d o mi nal pai n, hea dac he, erectile d ysf u ncti o n, he m o gl o bi n uria, ja u n dice), L D H, he m o gl o bi n a n d 
ha pt o gl o bi n le vels, retic ul oc yte c o u nts, n u m ber of bl o o d tra nsf usi o ns, B T H a n d t hr o m b oe m b olic 
e ve nts.  
P K a n d P D sa m ples will be c ollecte d at eac h st u d y visit fr o m baseli ne o n war ds a n d at t he ti me of a n y 
s us pecte d brea kt hr o u g h e ve nts. P D a n d c o m ple me nt bi o mar kers will i ncl u de P N H R B C a n d W B C 
cl o ne size, a n d plas ma Fact or B b a n d A P acti vit y. A d diti o nal e x pl orat or y P D a n d c o m ple me nt 
bi o mar ker s ma y be i ncl u de d, if s uita ble tests are a vaila ble. 
S a m ple Size J ustific ati o n:  
N o sa m ple size calc ulati o ns were c o n d ucte d f or t his o pe n -la bel, l o n g-ter m safet y st u d y. 
A p pr o xi matel y 2 0 0 s u bjects wit h P N H ma y be e nr olle d i n t his st u d y, t o all o w c o nti n ue d acc ess t o 
B C X 9 9 3 0 f oll o wi n g cli nical be nefit i n a pri or B C X 9 9 3 0 trial. 
N u m ber of S u bjects ( pl a n ne d):  
A p pr o xi matel y 2 0 0 s u bjects base d u p o n t he a ntici pate d cli nical pr o gra ms f or B C X 9 9 3 0. 
I ncl usi o n Criteri a: 
1.  A ble t o pr o vi de writte n i nf or me d c o nse nt. 
2.  Male or n o n - pre g na nt, n o n-lactati n g fe male s u bjects.  
3.  S u bjects w h o ha ve s uccessf ull y partici pate d i n a pre vi o us B C X 9 9 3 0 st u d y of P N H a n d w h o 
e x perie nce d a cli nical be nefit, as c o nfir me d b y t he I n vesti gat or. S uccessf ul partici pati o n is 
defi ne d as c o m pleti o n of pla n ne d d urati o n of d osi n g wit h B C X 9 9 3 0 i n t he pri or st u d y, n ot 
i ncl usi ve of a n y e xte nsi o n peri o d. 
4.  Fe male partici pa nts m ust meet at least 1 of t he f oll o wi n g c o ntrace pti o n re q uire me nts:  
a. Be a w o ma n of c hil d beari n g p ote ntial w h o a grees t o use a hi g hl y effecti ve 
c o ntrace pti ve met h o d t hr o u g h o ut t he st u d y a n d f or a d urati o n of 3 0 da ys after t he last 
d ose of st u d y dr u g. 
b.  Alter nati vel y, tr ue a bsti ne nce is acce pta ble f or w o me n of c hil d beari n g p ote ntial w he n 
it is i n li ne wit h t he s u bject’s preferre d a n d us ual lifest yle.  
c. Be a w o ma n of n o nc hil d beari n g p ote ntial. 
5.  Male partici pa nts m ust meet t he f oll o wi n g c o ntrace pti o n re q uire me nts:  
a. S u bjects wit h fe male part ners of c hil d beari n g p ote ntial m ust a gree t o utilize a 
hi g hl y effecti ve c o ntrace pti ve met h o d. 

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b.  Alter nati vel y, tr ue a bsti ne nce is acce pta ble w he n it is i n li ne wit h t he s u bject’s 
preferre d a n d us ual lifest yle.   
6.  I n t he o pi ni o n of t he I n vesti gat or, t he s u bject is e x pecte d t o a de q uatel y c o m pl y wit h all 
re q uire d st u d y pr oce d ures a n d restricti o ns f or t he d urati o n of t he st u d y.  
 
E xcl usi o n Criteri a:  
1.  A n y cli nicall y si g nifica nt me dical or ps yc hiatric c o n diti o n t hat, i n t he o pi ni o n of t he 
I n vesti gat or or S p o ns or, w o ul d i nterfere wit h t he s u bject’s a bilit y t o partici pate i n t he st u d y or 
partici pati o n w o ul d i ncr ease t he ris k f or t hat s u bject . 
2.  A n y cli nicall y si g nifica nt hist or y of a n gi na, k n o w n c or o nar y arter y disease, m y ocar dial 
i nfarcti o n, s y nc o pe, cli nicall y si g nifica nt car diac arr h yt h mias, left ve ntric ular h y pertr o p h y, 
car di o m y o pat h y, a ortic ste n osis, or a n y ot her car di o vasc ular a b n or malit y. 
3.  C hr o nic s yste mic c ortic oster oi d use. N ote: T o pical, i n hale d, oc ular, or nasal s pra ys 
c o ntai ni n g c ortic oster oi ds are all o we d. 
4.  I n vesti gati o nal dr u g e x p os ure, ot her t ha n B C X 9 9 3 0, wit hi n 3 0 da ys of t he baseli ne visit, or 
5. 5 half -li ves of t he i n vesti gati o nal dr u g ( w hic he ver is l o n ger). 
5.  F or s u bjects re q uiri n g  a scree ni n g visit:  
a. Cli nicall y si g nifica nt a b n or mal E C G at t he scree ni n g visit. T his i ncl u des, b ut is n ot 
li mite d t o, a Q T i nter val c orrecte d usi n g Fri dericia's met h o d ( Q Tc F) > 4 5 0 msec i n 
males a n d > 4 7 0 msec i n fe males, or ve ntric ular a n d/ or atrial pre mat ure c o ntracti o ns 
t hat are m ore fre q ue nt t ha n occasi o nal, a n d/ or as c o u plets or hi g her i n gr o u pi n g. 
b.  Ala ni ne a mi n otra nsferase ( A L T) or as partate a mi n otra nsferase ( A S T ) > 3 × u p per 
li mit of n or mal ( U L N) ( E xce pti o n: S u bjects ma y be e nr olle d wit h A L T or A S T 
> 3 × U L N if e x plai ne d b y he m ol ysis. I n t hese cases, A L T a n d A S T m ust be < 5 × 
U L N.)  
c. T otal ser u m bilir u bi n > 2 × u p per li mit of n or mal ( U L N) ( E xce pti o ns: S u bject ma y 
be e nr o lle d wit h t otal ser u m bilir u bi n > 2 × U L N if t he ele vate d bilir u bi n is e x plai ne d 
b y he m ol ysis or i n t he case of Gil bert’s s y n dr o me. I n t he case of he m ol ysis, t otal 
ser u m bilir u bi n m ust be < 5 × U L N a n d i n t he case of Gil bert’s S y n dr o me, t otal 
bilir u bi n m us t be < 7 × U L N).  
6.  Dail y use of me dicati o ns liste d i n t he c urre ntl y a p plica ble pr o hi bite d me dicati o ns list . 
7.  Pre g na nt, pla n ni n g t o bec o me pre g na nt, or ha vi n g bee n pre g na nt wit hi n 9 0 da ys of baseli ne, 
or lactati n g . 
I n vesti g ati o n al Pr o d uct, D os a ge a n d M o de of A d mi nistr ati o n:  
B C X 9 9 3 0 ta blets f or oral a d mi nistrati o n. U n der t his a me n d me nt, s u bjects will ta ke 4 0 0 m g B C X 9 9 3 0 
BI D  orall y . D osa ge f or ms ma y i ncl u de 1 0 0, 2 0 0, a n d/ or 2 5 0 m g ta blets  t o all o w f or d ose a dj ust me nts 
if nee de d f or t he safet y ma na ge me nt of t he s u bject. Cli nical effecti ve ness a n d safet y will be 
m o nit ore d.  

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D ur ati o n of T re at me nt:  
S u bjects will be eli gi ble t o recei ve st u d y dr u g ( B C X 9 9 3 0) f or 1 4 4  wee ks, or u ntil dr u g is a vai la ble b y 
a n ot her mec ha nis m (e g, e x pa n de d or mar ket access)  or u ntil t he S p o ns or disc o nti n ues de vel o p me nt of 
t he pr o d uct f or P N H; w hic he ver c o mes first.  
Refere nce T her a p y, D os a ge a n d M o de of A d mi nistr ati o n:  
N/ A  
Criteri a f or E v al u ati o n: 
S afety: 
Safet y will be e val uate d b y T E A Es, la b orat or y a nal yses (cli nical c he mistr y, he mat ol o g y, c oa g ulati o n, 
uri nal ysis  wit h micr osc o p y), vital si g ns, E C Gs, a n d p h ysical e xa mi nati o n fi n di n gs. A n i n de pe n de nt 
data m o nit ori n g c o m mittee ( D M C) will re vie w safet y data i n acc or da nce wit h a se parate D M C 
C harter.  
Effective ness:  
Cli nical meas ure me nts of P N H i ncl u de L D H, he m o gl o bi n a n d ha pt o gl o bi n le vels, retic ul oc yte c o u nts, 
P N H s y m pt o ms (e g, fati g ue, d ys p nea, c hest pai n/ disc o mf ort, diffic ult y s wall o wi n g (es o p ha geal pai n), 
a b d o mi nal pai n, hea dac he, erectile d ysf u ncti o n, he m o gl o bi n uria, ja u n dice), n u m ber of bl o o d 
tra nsf usi o ns, B T H, a n d t hr o m b oe m b olic e ve nts will be use d t o assess o n g oi n g effecti ve ness. 
P atie nt Re p orte d O utc o mes: 
Q uesti o n naires will be use d t o e val uate q ualit y of life ( Q L Q-A A/ P N H) , effecti ve ness of t hera p y 
( F A CI T fati g ue scale) a n d treat me nt satisfacti o n ( T S Q M). 
P h ar m ac oki netics: 
Plas ma sa m ples f or deter mi nati o n of B C X 9 9 3 0 / meta b olite c o nce ntrati o ns will be c ollecte d at eac h 
st u d y visit. S p ot uri ne sa m ples f or deter mi nati o n of B C X 9 9 3 0/ meta b olite c o nce ntrati o ns will be 
c ollecte d at eac h st u d y visit . T he res ulti n g P K data will be i nc or p orate d i nt o meta-st u d y p o p ulati o n 
P K a n d P K/ P D a nal yses. Meta b olites of B C X 9 9 3 0 will  be a nal yze d as a p pr o priate. 
P h ar m ac o dy n a mics a n d C o m ple me nt Bi o m arkers: 
E x - vi v o P D a n d c o m ple me nt bi o mar ker effects of B C X 9 9 3 0 will be assesse d usi n g e x pl orat or y 
assa ys. Sa m ples c ollecte d f or P D a n d c o m ple me nt bi o mar ker a nal ysis ma y be r u n i n m ore t ha n o ne 
assa y t o el uci date t he P D effects of B C X 9 9 3 0. T hese i ncl u de:  
•  Plas ma Fact or B b  
•  P N H R B C a n d W B C cl o ne size  
•  A P acti vit y  
T he o n g oi n g assess me nt of t he acti vit y of B C X 9 9 3 0 a n d/ or a vaila bilit y of a s uita ble assa y ma y 
c ha n ge t he re q uire d P D assess me nts o ver ti me. 
 
 

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St atistic al M et h o ds: 
A n alysis of S afety  
Safet y e n d p oi nts will be s u m marize d a n d will i ncl u de t he pr o p orti o n of s u bjects: wit h T E A Es; w h o 
disc o nti n ue d ue t o a T E A E; w h o recei ve a re d uce d d ose d ue t o t olera bilit y iss ues; w h o e x perie nce a 
treat me nt-e mer ge nt seri o us a d verse e ve nt ( S A E); w h o e x perie nce a Gra de 3 or 4 T E A E; w h o 
e x perie nce a treat me nt -e mer ge nt, treat me nt -relate d a d verse e ve nt ( A E) c o nsiste nt wit h a dr u g ras h 
(e g, ras h, mac ul o- pa p ular e xa nt he m, pa p ular ras h); a n d w h o e x perie nce Gra de 3 or 4 la b orat or y 
a b n or malities. 
A Es will be ma p pe d t o a Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) preferre d ter m a n d 
s yste m or ga n classificati o n. T he occ urre nce of T E A Es will be s u m marize d usi ng Me d D R A preferre d 
ter ms, s yste m or ga n classificati o ns, a n d se verit y. I n a d diti o n t o se verit y, A Es a n d S A Es will als o be 
s u m marize d base d o n I n vesti gat or assess me nt of relati o ns hi p t o st u d y dr u g.  
Ti me t o d ose re d ucti o n, ti me t o disc o nti n uati o n d ue t o a T E A E, a n d ti me t o de vel o p me nt of 
dr u g- relate d ras h will be esti mate d usi n g t he Ka pla n-Meier met h o d.  F or t h ose wit h a dr u g -relate d 
ras h, cli nical a n d la b orat or y fi n di n gs will be s u m marize d as will t he pr o p orti o n of s u bjects w h o 
s uccessf ull y c o nti n ue t hera p y f oll o wi n g o nset of ras h. 
Descri pti ve statistics f or vital si g ns, wei g ht, a n d cli nical la b orat or y res ults will be prese nte d b y st u d y 
visit. La b orat or y a b n or malities will be gra de d acc or di n g t o t he Di visi o n of Micr o bi ol o g y a n d 
I nfecti o us Diseases (D MI D ) A d ult T o xicit y Ta ble. T he n u m ber a n d perce nta ge of s u bjects 
e x perie nci n g treat me nt -e mer ge nt gra de d t o xicities will be s u m marize d.  
La b orat or y t o xicit y s hifts fr o m baseli ne t o t he w orst p ost- baseli ne val ue as well as t he last visit will 
be s u m marize d. T he n u m ber a n d perce nta ge of s u bjects ha vi n g ele vati o ns i n A L T, A S T, or bilir u bi n 
a b n or malities i n relati o n t o f ol d a b o ve U L N will be s u m marize d acc or di n g t o t he U nite d States F o o d 
a n d Dr u g A d mi nistrati o n's Pre mar keti n g Cli nical E val uati o n o n Dr u g-I n d uce d Li ve r I nj ur y G ui da nce 
f or I n d ustr y. 
Cli nicall y si g nifica nt a b n or mal E C G fi n di n gs will be s u m marize d b y st u d y visit. C ha n ges fr o m 
baseli ne i n E C G para meters will als o be s u m marize d b y st u d y visit. T he n u m ber a n d pr o p orti o n of 
s u bjects wit h cli nicall y i m p orta nt a bs ol ute a n d c ha n ge -fr o m-baseli ne t hres h ol ds i n Q Tc F will be 
s u m marize d. 
A n alysis of Cli nic al Me as ure me nts of P N H  
Cli nical meas ure me nts of P N H (e g, L D H, he m o gl o bi n, a bs ol ute retic ul oc yte c o u nt, ha pt o gl o bi n 
le vels, n u m ber of bl o o d tra nsf usi o ns, i nci de nce of B T H, i nci de nce of t hr o m b oses a n d maj or 
t hr o m b oses, A S T, t otal bilir u bi n, a n d direct bilir u bi n) will be s u m marize d b y s u m mar y statistics, 
i ncl u di n g c ha n ge fr o m baseli ne, b y treat me nt gr o u p a n d st u d y visit. Cate g orical meas ure me nts will be 
s u m marize d wit h fre q ue ncies a n d perce nta ges b y treat me nt gr o u p a n d st u d y visit. 
A n alysis of Effective ness a n d P atie nt Re p orte d O utc o mes 
Effecti ve ness a n d patie nt -re p orte d o utc o mes (P R Os ) will be m o nit ore d wit h disease-s pecific cli nical 
assess me nts, la b orat or y assess me nts, a n d q uesti o n naires. Res p o nses f or s u bjects wit h P N H will be 
cate g orize d usi n g p u blis he d draft criteria (Risita n o, Mar otta, et al. 2 0 1 9 ) i nt o c o m plete res p o nse, 
maj or res p o nse, g o o d res p o nse, partial res p o nse, mi n or res p o nse, a n d n o res p o nse, m o difie d f or st u d y 
d urati o n a n d visit sc he d ule. 

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P R Os will i ncl u de F A CI T fati g ue scale, T S Q M, a n d Q L Q -A A/ P N H q uesti o n naires.  
A n alysis of P h ar m ac oki netic D at a  
Plas ma a n d uri ne c o nce ntrati o ns of B C X 9 9 3 0 a n d meta b olites (as ap p lica ble) will be s u m marize d b y 
d ose re gi me n a n d st u d y visit. T he res ulti n g P K data will be p o ole d i n a meta- a nal ysis of  p o p ulati o n 
P K.  
A n alysis of P h ar m ac o dy n a mic D at a 
Descri pti ve statistics, i ncl u di n g c ha n ge fr o m baseli ne, will be pr o vi de d b y st u d y visit a n d d ose 
re gi me n. T he res ulti n g P D data will be e x pl ore d usi n g m o del - base d tec h ni q ues p o ole d i n 
meta -a nal yses of P K/ P D, as a p plica ble. 

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1 2 
3.  
T A B L E O F C O N T E N T S, LI S T O F T A B L E S, A N D LI S T O F 
FI G U R E S  
T A B L E O F C O N T E N T S  
1.  
TI T L E P A G E  ................................................................................................................ 1 
SI G N A T U R E P A G E  ....................................................................................................................... 2 
I N V E S TI G A T O R’ S A G R E E M E N T ............................................................................................... 3 
S T U D Y I N F O R M A TI O N  ............................................................................................................... 4 
2.  
S Y N O P SI S  ................................................................................................................... 5 
3.  
T A B L E O F C O N T E N T S, LI S T O F T A B L E S, A N D LI S T O F FI G U R E S  ............... 1 2 
4.  
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 8 
5.  
I N T R O D U C TI O N ...................................................................................................... 2 1 
5. 1.  
Bac k gr o u n d ................................................................................................................. 2 1  
5. 2.  
I n dicati o n .................................................................................................................... 2 1 
5. 3.  
N o ncli nical Fi n di n gs f or B C X 9 9 3 0 ............................................................................ 2 3  
5. 4.  
Cli nical Fi n di n gs f or B C X 9 9 3 0 .................................................................................. 2 4  
5. 4. 1.  
Cli nical Safet y a n d T oler a bilit y  .................................................................................. 2 4 
5. 4. 2.  
Effecti ve n ess  ............................................................................................................... 2 5 
5. 5.  
Rati o nale f or St u d y ..................................................................................................... 2 5  
5. 5. 1.  
Rati o nale f or St u d y Desi g n ......................................................................................... 2 5  
5. 5. 2.  
Rati o nale f or St u d y Dr u g D ose a n d Re gi me n ............................................................ 2 5  
5. 5. 2. 1.  
S u m mar y of He mat ol o gic Res p o nse at 4 0 0 a n d 5 0 0 m g BI D – St u dies 1 0 1 
a n d 2 0 1 ........................................................................................................................ 2 6  
5. 5. 2. 2.  
S u m mar y of P P K a n d P K/ P D M o deli n g .................................................................... 2 7  
5. 5. 3.  
St u d y P o p ulati o n Rati o nale ........................................................................................ 2 9  
5. 6.  
Be nefit - Ris k A nal ysis ................................................................................................. 2 9 
5. 6. 1.  
P ote ntial Ris ks f or Bacterial I nfecti o ns  ...................................................................... 2 9 
5. 6. 2.  
P ote ntial Ris ks of S A R S - C o V- 2 I nfecti o n a n d Vacci nati o n W hile Recei vi n g 
B C X 9 9 3 0 T hera p y ...................................................................................................... 3 0  
5. 6. 3.  
P ote ntial Ris ks f or Hea dac he  ...................................................................................... 3 0 
5. 6. 4.  
P ote ntial Ris ks f or Der mat ol o gic Reacti o ns  ............................................................... 3 1 
5. 6. 5.  
P ote ntial Ris ks f or He m ol ysis After B C X 9 9 3 0 Disc o nti n uati o n or 
I nterr u pti o n i n S u bjects wit h P N H ............................................................................. 3 1 
5. 6. 6.  
P ote ntial Ris ks f or He patic Effects  ............................................................................. 3 1 

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5. 6. 7.  
P ote ntial Ris ks f or Re nal Effects  ................................................................................ 3 1 
5. 6. 8.  
O verall Be nefit - Ris k A nal ysis .................................................................................... 3 2 
6.  
T RI A L O BJ E C TI V E S A N D P U R P O S E  .................................................................... 3 2 
6. 1.  
Pri mar y O bjecti ve  ....................................................................................................... 3 2 
6. 2.  
Sec o n dar y O bj ecti ves  ................................................................................................. 3 2 
6. 3.  
Pri mar y E n d p oi nt ........................................................................................................ 3 2  
6. 4.  
Sec o n dar y E n d p oi nts .................................................................................................. 3 3  
6. 5.  
P har mac o d y na mic ( P D) E n d p oi nt  .............................................................................. 3 3 
7.  
I N V E S TI G A TI O N A L P L A N ..................................................................................... 3 3 
7. 1.  
O verall St u d y Desi g n .................................................................................................. 3 3  
7. 2.  
N u m ber of S u bjects .................................................................................................... 3 5  
7. 3.  
Treat me nt D osi n g  ....................................................................................................... 3 5 
7. 4.  
I n di vi d ual a n d St u d y St o p pi n g R ules ......................................................................... 3 5 
7. 4. 1.  
S u bject Disc o nti n uati o n fr o m St u d y Dr u g ................................................................. 3 5  
7. 4. 2.  
St u d y St o p pi n g R ules  ................................................................................................. 3 6 
8.  
S E L E C TI O N A N D WI T H D R A W A L O F S U BJ E C T S  .............................................. 3 7 
8. 1.  
S u bject I n cl usi o n Criteria  ........................................................................................... 3 7 
8. 2.  
S u bject E xcl usi o n Criteria  .......................................................................................... 3 7 
8. 3.  
S u bject Wit h dra wal Criteria  ....................................................................................... 3 8 
8. 4.  
E n d of St u d y Defi niti o n .............................................................................................. 3 9  
9.  
T R E A T M E N T O F S U BJ E C T S  .................................................................................. 3 9 
9. 1.  
C o nc o mita nt Me dicati o ns ........................................................................................... 3 9  
9. 2.  
Pr o hi bite d Me dicati o ns ............................................................................................... 3 9  
9. 3.  
Treat me nt C o m plia nce  ................................................................................................ 4 0 
9. 3. 1.  
S pecial C o nsi derati o ns f or D osi n g, I ncl u di n g I na bilit y t o Ta ke Me dicati o n 
Orall y  .......................................................................................................................... 4 1 
9. 4.  
Ra n d o mizati o n a n d Bli n di n g ...................................................................................... 4 2  
9. 5.  
Vacci n ati o n Re q uire me nts, a n d Vacci n ati o ns d uri n g St u d y, a n d Pr o p h ylactic 
A nti bi otic C o vera ge .................................................................................................... 4 2  
1 0.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T  ........................................... 4 2 
1 0. 1.  
St u d y Dr u g .................................................................................................................. 4 2  
1 0. 2.  
St u d y Dr u g Pac ka gi n g a n d La beli n g .......................................................................... 4 3  

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1 0. 3.  
St u d y Dr u g St ora ge ..................................................................................................... 4 3  
1 0. 4.  
St u d y Dr u g Pre parati o n .............................................................................................. 4 3  
1 0. 5.  
A d mi nistrati o n  ............................................................................................................ 4 3 
1 0. 5. 1.  
Treat me nt I nterr u pti o n a n d D ose Re d ucti o n .............................................................. 4 3  
1 0. 5. 2.  
D ose Ta peri n g ............................................................................................................. 4 3  
1 0. 6.  
St u d y Dr u g Acc o u nta bilit y ......................................................................................... 4 4  
1 0. 7.  
St u d y Dr u g Ha n dli n g a n d Dis p osal ............................................................................ 4 4  
1 1.  
S T U D Y C O N D U C T  ................................................................................................... 4 4 
1 1. 1.  
O ver vie w  ..................................................................................................................... 4 4 
1 1. 2.  
Sc he d ule of Assess me nts  ............................................................................................ 4 4 
1 1. 3.  
St u d y Visits  ................................................................................................................. 5 0 
1 1. 3. 1.  
Scree ni n g a n d Bas eli ne Visit Re q uire me nts  ............................................................... 5 0 
1 1. 3. 2.  
Scree ni n g Visit  ............................................................................................................ 5 0 
1 1. 3. 3.  
Baseli ne Visit ( Da y 1)  ................................................................................................ 5 1 
1 1. 3. 4.  
O n -st u d y Visits ( Wee k 4 a n d e ver y 4 wee ks u p t o Wee k 9 6; Wee k 9 6 a n d 
e ver y 8 w ee ks t o Wee k 1 4 4) ....................................................................................... 5 2 
1 1. 3. 4. 1.  
Safet y Assess me nts f or Re nal E ve nts  ......................................................................... 5 3 
1 1. 3. 5.  
He m ol ysis M o nit ori n g Visits  ...................................................................................... 5 4 
1 1. 3. 6.  
U nsc he d ule d Visit f or Br ea kt hr o u g h H e m ol ysis ........................................................ 5 4  
1 1. 3. 7.  
E n d of St u d y Visit ...................................................................................................... 5 5  
1 1. 4.  
C o ntrace pti o n Re q uire m e nts ...................................................................................... 5 5  
1 1. 4. 1.  
Fe male S u bjects a n d Fe male Part ners of M ale S u bjects  ............................................ 5 5 
1 1. 4. 2.  
Male S u bjects  .............................................................................................................. 5 6 
1 2.  
A S S E S S M E N T O F E F FI C A C Y  ................................................................................ 5 6 
1 2. 1.  
Cli nical Res p o nse Assess me nt  ................................................................................... 5 6 
1 2. 2.  
Bl o o d Tra nsf usi o ns Re vie w ........................................................................................ 5 7  
1 2. 3.  
P har mac o ki netic Bl o o d Sa m ple C ollecti o n  ................................................................ 5 7 
1 2. 4.  
P har mac o d y na mic Bl o o d Sa m ple C ollecti o n  ............................................................. 5 8 
1 2. 5.  
Uri ne C ollecti o n f or Meas ure me nt of Pare nt- Meta b olite C o nce ntrati o n  ................... 5 8 
1 2. 6.  
Patie nt Re p orte d O utc o m es  ........................................................................................ 5 8 
1 3.  
A S S E S S M E N T O F S A F E T Y  ..................................................................................... 5 9 
1 3. 1.  
De m o gra p hic/ Me di cal Hist or y  ................................................................................... 5 9 

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1 3. 2.  
Vital Si g ns  .................................................................................................................. 5 9 
1 3. 3.  
Wei g ht, Hei g ht, a n d B o d y Mass I n d e x ....................................................................... 5 9  
1 3. 4.  
P h ysical E xa mi nati o n  ................................................................................................. 5 9 
1 3. 5.  
Electr ocar di o gra m  ....................................................................................................... 5 9 
1 3. 6.  
La b orat or y Ass ess me nts ............................................................................................. 6 0  
1 3. 6. 1.  
Uri ne C ollecti o ns f or Uri nal ysis, Micr osc o p y, a n d Bi o mar ker Testi n g ..................... 6 2  
1 3. 6. 2.  
Me n o pa use a n d Pr e g na n c y Scree n  ............................................................................. 6 2 
1 3. 7.  
M o nit ori n g f or He m ol ysis at Disc o nti n uati o n of B C X 9 9 3 0 ...................................... 6 2  
1 3. 8.  
Assess me nt of Brea kt hr o u g h He m ol ysis E pis o des ..................................................... 6 3  
1 3. 9.  
A d verse E v e nts  ........................................................................................................... 6 3 
1 3. 9. 1.  
Defi niti o n of A d vers e E v e nts ..................................................................................... 6 3  
1 3. 9. 1. 1.  
A d verse E v e nt  ............................................................................................................. 6 3 
1 3. 9. 1. 2.  
Seri o us A d verse E v e nt ................................................................................................ 6 4  
1 3. 9. 1. 3.  
E ve nts of S pecial I nterest  ........................................................................................... 6 5 
1 3. 9. 1. 4.  
E ve nts of S pecial M o nit ori n g ..................................................................................... 6 5  
1 3. 9. 1. 5.  
Defi niti o n of Se verit y  ................................................................................................. 6 5 
1 3. 9. 1. 6.  
Relati o ns hi p t o St u d y Dr u g ........................................................................................ 6 6  
1 3. 9. 2.  
Rec or di n g A d verse E ve nts ......................................................................................... 6 7  
1 3. 9. 3.  
Met h o d, Fre q u e nc y, a n d Ti me Peri o d f or Det ecti n g A d verse E v e nts a n d 
Re p orti n g Seri o us A d verse E ve nts ............................................................................. 6 7  
1 3. 9. 4.  
Re p orti n g .................................................................................................................... 6 8  
1 3. 9. 4. 1.  
Seri o us A d verse E v e nts a n d S us pecte d U n e x pect e d Seri o us A d vers e 
Reacti o ns  ..................................................................................................................... 6 8 
1 3. 9. 4. 2.  
Re p orti n g E ve nts of S pecial I nterest .......................................................................... 6 8  
1 3. 9. 4. 3.  
Pre g na nc y  ................................................................................................................... 6 9 
1 3. 9. 4. 4.  
Seri o us Breac h es  ......................................................................................................... 6 9 
1 3. 9. 5.  
T o xicit y Ma na ge me nt ................................................................................................. 6 9  
1 3. 9. 5. 1.  
Se vere I nfecti o ns  ........................................................................................................ 6 9 
1 3. 9. 5. 2.  
P ote ntial Dr u g -i n d uce d Li ver I nj ur y: M o nit ori n g, E val uati o n, a n d 
Disc o nti n uati o n Criteria  .............................................................................................. 6 9 
1 3. 9. 5. 3.  
Re nal E ve nts: M o nit ori n g, E val uati o n, a n d Disc o nti n uati o n Criteria ........................ 7 0  
1 3. 9. 5. 4.  
He m ol ysis After Disc o nti n uati o n of B C X 9 9 3 0 .......................................................... 7 1  
1 3. 9. 5. 5.  
Brea kt hr o u g h H e m ol ysis ............................................................................................ 7 2  

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1 3. 9. 5. 6.  
O ver d ose ..................................................................................................................... 7 2  
1 3. 1 0.  
Data M o nit ori n g C o m mittee  ....................................................................................... 7 2 
1 4.  
S T A TI S TI C S  .............................................................................................................. 7 2 
1 4. 1.  
Sa m ple Size C o nsi derati o ns  ....................................................................................... 7 2 
1 4. 2.  
Stratificati o n  ............................................................................................................... 7 2 
1 4. 3.  
Statistical Met h o ds  ...................................................................................................... 7 3 
1 4. 3. 1.  
A nal ysis P o p ulati o ns .................................................................................................. 7 3  
1 4. 3. 1. 1.  
Safet y P o p ulati o n ........................................................................................................ 7 3  
1 4. 3. 1. 2.  
I nte nt t o Tr eat P o p ulati o n ........................................................................................... 7 3 
1 4. 3. 2.  
Ge ner al C o nsi derati o ns f or Data A n al ysis  ................................................................. 7 3 
1 4. 3. 3.  
Missi n g Data  ............................................................................................................... 7 3 
1 4. 3. 4.  
S u bject De m o gra p hic a n d Dis p ositi o n Data ............................................................... 7 3  
1 4. 3. 5.  
A nal ysis of Safet y Varia bles ...................................................................................... 7 4  
1 4. 3. 6.  
A nal ysis of Cli nical Meas ure me nts of P N H  ............................................................... 7 5 
1 4. 3. 7.  
A nal ysis of Effecti ve ness Varia bles f or P N H  ............................................................ 7 5 
1 4. 3. 7. 1.  
He mat ol o gical Res p o nse Cate g ories  .......................................................................... 7 5 
1 4. 3. 8.  
I nteri m a n d Fi n al A nal ys es  ......................................................................................... 7 6 
1 4. 3. 9.  
P har mac o ki netic A n al yses  .......................................................................................... 7 6 
1 4. 3. 1 0.  
P har mac o d y na mic A n al yses  ....................................................................................... 7 6 
1 5.  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S ......................................... 7 7 
1 5. 1.  
St u d y M o nit ori n g ........................................................................................................ 7 7  
1 5. 2.  
A u dits a n d I ns p ecti o ns ................................................................................................ 7 7  
1 6.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  ......................................... 7 8 
1 7.  
R E G U L A T O R Y A N D E T HI C A L C O N SI D E R A TI O N S  .......................................... 7 8 
1 7. 1.  
Et hics Re vie w  ............................................................................................................. 7 8 
1 7. 2.  
Et hical C o n d uct of t he St u d y ...................................................................................... 7 8  
1 7. 3.  
Writte n I nf or m e d C o nse nt .......................................................................................... 7 8  
1 7. 4.  
I ns ura nce ..................................................................................................................... 7 9 
1 7. 5.  
Pa y me nt t o S u bjects .................................................................................................... 7 9  
1 7. 6.  
Treat me nt Aft er a S u bject’s St u d y C o m pleti o n or Wit h dra wal ................................. 7 9  
1 8.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  ...................................................... 7 9 
1 8. 1.  
I ns p ecti o n of Rec or ds ................................................................................................. 7 9 

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1 8. 2.  
Rete nti o n of Rec or ds .................................................................................................. 7 9  
1 8. 3.  
C o nfi de ntialit y of I nf or m ati o n a n d Data .................................................................... 7 9  
1 9.  
P U B LI C A TI O N P O LI C Y  .......................................................................................... 8 0 
2 0.  
LI S T O F R E F E R E N C E S  ............................................................................................ 8 1 
2 1.  
A P P E N DI C E S  ............................................................................................................ 8 6 
 
 
LI S T O F T A B L E S  
Ta ble 1:  
A b bre viati o ns a n d S peci alist Ter ms ........................................................................... 1 8  
 
 
 .......................................................................................................... 2 7 
Ta ble  3: 
St u d y B C X 9 9 3 0- 2 0 1: Scree ni n g a n d Bas eli ne Visit Re q uire me nts ........................... 3 4  
Ta ble 4:  
St u d y Desi g n a n d Sc he d ule of Assess me nts .............................................................. 4 6  
Ta ble  5: 
Cli nical La b orat or y E val uati o ns ................................................................................. 6 1  
Ta ble 6:  
Acti o ns Base d o n Ser u m Creati ni ne Le vels  ............................................................... 7 1 
Ta ble  7: 
He mat ol o gical Res p o nse Cate g ories  .......................................................................... 7 5 
 
 
LI S T O F FI G U R E S  
 
 
 .......................................... 2 8 
Fi g ure 2:  
St u d y Sc he ma ............................................................................................................. 3 4  
 
  

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4.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
T he f oll o wi n g a b bre vi ati o ns a n d s pecialist ter ms are use d i n t his st u d y pr ot oc ol. 
T a ble 1: 
A b bre vi ati o ns a n d S peci alist Ter ms  
A b bre vi ati o n or S peci alist T er m  
E x pl a n ati o n  
A CI P  
U S Ce nters f or Disease C o ntr ol a n d Pre ve nti o n A d vis or y 
C o m mittee o n I m m u nizati o n Practices  
A E  
a d verse e ve nt 
A KI  
ac ute ki d ne y i nj ur y 
A P  
alter nati ve c o m ple me nt pat h wa y  
A L P  
al kali ne p h os p hatase  
A L T  
ala ni ne a mi n otra nsferase  
A R C  
a bs ol ute retic ul oc yte c o u nt 
A S T  
as partate a mi n otra nsferase  
A U C  
area u n der t he c o nce ntrati o n vs. ti me c ur ve  
A U C 0- 2 4 
A U C fr o m ti me 0 t hr o u g h 2 4 h o urs  
B C R P  
breast ca ncer resista nce pr otei n  
BI D  
t wice dail y 
B MI  
b o d y mass i n de x  
B P  
b l o o d press ure 
B T H  
brea kt hr o u g h he m ol ysis  
B U N  
b l o o d urea nitr o ge n 
C 3  
c o m ple me nt c o m p o ne nt 3 
C 3 b  
e n d pr o d uct of t he alter nati ve c o m ple me nt pat h wa y  
C 3 b B  
fact or B i n c o m ple x wit h C 3 b 
C 4  
c o m ple me nt c o m p o ne nt 4 
C 5  
c o m ple me nt c o m p o ne nt 5 
C B C  
c o m plete bl o o d c o u nt 
C ma x  
ma xi m u m c o nce ntrati o n o bser ve d  
C O VI D -1 9  
c or o na vir us disease 2 0 1 9  
C P  
classical pat h wa y  
C Y P  
c yt oc hr o me P 4 5 0 
D DI  
dr u g -dr u g i nteracti o n  
D MI D  
Di visi o n of Micr o bi ol o g y a n d I nfecti o us Diseases 
D M C  
Data M o nit ori n g C o m mittee  

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A b bre vi ati o n or S peci alist T er m  
E x pl a n ati o n  
E C G  
electr ocar di o gra m 
e C R F  
electr o nic case re p ort f or m  
e GF R  
esti mate d gl o mer ular filtrati o n rate  
E O SI  
e ve nt of s pecial i nterest  
E O S M  
e ve nts of s pecial m o nit ori n g  
E V H  
e xtra vasc ular he m ol ysis  
F A CI T  
F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y  
F D A  
U S F o o d a n d Dr u g A d mi nistrati o n  
FI H  
first i n h u ma n 
F S H  
f ollicle-sti m ulati n g h or m o ne  
G C P  
G o o d Cli nical Practice  
β H C G  
β  h u ma n c h ori o nic g o na d otr o pi n  
I B 
I n vesti gat or’s Br oc h ure 
I C5 0 
half -ma xi mal i n hi bit or y c o nce ntrati o n  
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 E C 
I n de pe n de nt Et hics C o m mittee 
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I N R 
i nter nati o nal n or malize d rati o 
I R B 
I nstit uti o nal R e vie w B oar d  
KI M - 1 
ki d ne y i nj ur y m olec ule 1  
L D H  
lactate de h y dr o ge nase 
L- F A B P  
li ver-t y pe fatt y aci d-bi n di n g pr otei n  
M A C  
me m bra ne attac k c o m ple x  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
N G A L  
ne utr o p hil gelati nase -ass ociate d li p ocali n 
N R M W G  
Ne p hr ol o g y Ris k Miti gati o n W or ki n g Gr o u p  
P D  
p har mac o d y na mic(s)  
P- g p  
P- gl yc o pr otei n  
P K  
p har mac o ki netic(s)  
P N H  
par o x ys mal n oct ur nal he mat uria  
P R O  
patie nt -re p orte d o utc o mes 
P T  
pr ot hr o m bi n ti me  

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A b bre vi ati o n or S peci alist T er m  
E x pl a n ati o n  
Q L Q -A A/ P N H  
Q ualit y of Life Q uesti o n naire f or patie nts wit h A plastic A ne mia 
/ Par o x ys mal N oct ur nal He m o gl o bi n uria 
Q T  
electr ocar di o gra p hic i nter val bet wee n t he be gi n ni n g of t he Q 
wa ve a n d ter mi nati o n of t he T  wa ve, re prese nti n g t he ti me f or 
b ot h ve ntric ular de p olarizati o n a n d re p olarizati o n t o occ ur  
Q Tc  
c orrecte d Q T i nter val 
Q Tc F  
Q T i nter val c orrecte d f or heart rate usi n g Fri dericia’s f or m ula  
R B C  
re d bl o o d cell 
S A E  
seri o us a d verse e ve nt 
S A P  
Statistical A nal ysis Pla n  
S A R S -C o V - 2 
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2 
S O C  
S yste m Or ga n Classificati o n  
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt 
T S Q M  
Treat me nt S atisfacti o n Q uesti o n naire f or M e dicati o n 
U A C R  
uri ne micr oal b u mi n t o creati ni ne rati o  
U L N  
u p per li mit of (t he) n or mal (ra n ge)  
u N G A L  
uri ne ne utr o p hil gelati nase -ass ociate d li p ocali n 
V Z V  
v aricella z oster vir us 
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  
 

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5.  
I N T R O D U C TI O N 
5. 1.  
B ac k gr o u n d  
C o m ple me nt acti vati o n is a n i n nate defe nse mec h a nis m t hat, w he n u nc o ntr olle d, lea ds t o 
i nfla m mati o n a n d l ocal tiss ue da ma ge. T h e c o m pl e me nt s yste m c o nsists of 3 disti nct pat h wa ys: 
t he classical pat h w a y ( C P), lecti n pat h wa y, a n d alter nati ve pat h w a y ( A P). D ysre g ulati o n of t he 
A P of c o m ple me nt acti vit y b y c o n ge nital or ac q uire d ge netic m utati o ns, ne utralizi n g a nti b o dies 
t o c o m ple me nt re g ulat or y pr otei ns, or sta bilizi n g a nti b o dies t o c o m ple me nt c o m ple xes 
pre dis p oses i n di vi d uals t o di verse dis or ders, i ncl u di n g par o x ys mal n oct ur n al he m o gl o bi n uria 
( P N H), a ge-rel ate d mac ular de ge n erati o n, at y pical he m ol ytic ure mic s y n dr o me, a n d c o m ple me nt 
3 ( C 3) gl o mer ul o ne p hritis (H olers 2 0 0 8 , Br o ds k y 2 0 1 4 , Zi pfel, S ker ka, et al. 2 0 1 5 , Ric kli n, Reis, 
et al. 2 0 1 6). 
T he A P of c o m ple me nt is c o nstit uti vel y acti vate d at l o w le vels via sl o w s p o nta ne o us h y dr ol ysis 
of a n i nter nal t hi oester wit hi n C 3, a ke y c o m p o ne nt of t he c o m ple me nt cas ca de, t hat g e nerates 
C 3( H 2O). T his acti vate d C 3( H 2O) i n s ol uti o n p hase bi n ds fact or B t o ge n erate t he pr oc o n v ertas e 
C 3( H 2O) B, w hic h is pr ocesse d b y t he seri n e pr otease fact or D t o clea ve fact or B a n d ge nerates 
t he A P of c o m ple me nt C 3 c o n vertas e, C 3( H2O) B b. T his C 3 c o n vertase t he n clea ves a d diti o nal 
C 3 m olec ules t o ge nerat e C 3a a n d C 3 b, t he latter of w hic h ca n c o vale ntl y attac h t o a vaila ble 
s urfaces (Pa n g b ur n a n d M uller - E ber h ar d 1 9 8 3). De p osite d C 3 fra g me nts ca n t he n elicit a ra pi d 
l ocalize d a m plificati o n ( descri be d as t he a m plificati o n l o o p), es peciall y w he n c o m ple me nt 
re g ulati o n is i m paire d. D e p osite d C 3 b ca n pair wit h fact or B, w hic h is cl ea v e d b y fact or D t o 
ge nerat e a sec o n d f or m of t he alter n ati ve pat h wa y of c o m ple me nt C 3 c o n vertase, C 3 b B b. 
Me m bra ne - b o u n d C 3 b B b t he n clea v es a d diti o nal C 3 t o ge nerate f urt her C 3 b de p osits, w hic h pair 
wit h a d diti o nal fact or B m olec ules t o re peat t he c ycle. T he res ult of t his a m plificati o n is C 3 b 
o ps o nizati o n, releas e of t he a na p h ylat o xi ns C 3a a n d C 5a, a n d asse m bl y of t he ter mi nal 
c o m ple me nt c o m ple x C 5 b- 9 (als o k n o w n as t he m e m bra ne attac k c o m ple x [ M A C]) o n t he tar g et 
s urface res ulti n g i n cell l ysis (Ric kli n, Reis, et al. 2 0 1 6 ). 
5. 2.  
I n dic ati o n 
Par o x ys mal n oct ur nal he m o gl o bi n uria ( P N H) is a n ac q uire d dis or d er c h aracterize d b y 
destr ucti o n of re d bl o o d cells ( R B Cs) b y u nc o ntr olle d acti vit y of t he c o m ple me nt s yste m. T he 
eti ol o g y of P N H is a s o matic m utati o n i n he mat o p oietic ste m cells t hat lea ds t o a deficie n c y of 
t he c o m ple me nt re g ulat or y pr otei ns C D 5 5 a n d C D 5 9, res ulti n g i n u nrestrai ne d c o m ple me nt 
acti vit y t hat attac ks R B Cs lea di n g t o e pis o des of i ntra vasc ular he m ol ysis, c hr o nic he m ol ytic 
a ne mia, b o ne marr o w f ail ure, a n d t hr o m b osis (Par ker 2 0 0 9 , P u a n d Br o ds k y 2 0 1 1 , Par ker 2 0 1 2 ). 
P N H e q uall y aff ects me n  a n d w o me n b ut is m ore c o m m o n i n pe o ple of Asi a n t ha n Ca ucasi a n 
et h nicit y (Hill, De Zer n, et al. 2 0 1 7 , Jal bert, C ha u d hari, et al. 2 0 1 9). P N H i n ci de nce i n creases 
wit h a ge, wit h a n a v era g e a ge of di a g n osis i n t he earl y 3 0s (S ocie, M ar y, et al. 1 9 9 6 , 
Sc hreze n m eier, M u us, et al. 2 0 1 4 ). 
T he i ntra- a n d e xtra v asc ular he m ol ysis i n P N H is ass ociate d wit h gastr oi nt esti nal, 
car di o vas c ular, p ul m o nar y, ne ur ol o gical, a n d ur o g e nital s y m pt o ms, as well as cl otti n g dis or ders 
(R ot her, Bell, et al. 2 0 0 5 , Sa va ge a n d Br o ds k y 2 0 0 7 ). A classic s y m pt o m e x perie nce d b y 
patie nts wit h P N H is re d disc ol orati o n of t he uri ne d ue t o he m o gl o bi n uria f oll o wi n g 

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i ntra vasc ular h e m ol ysis. Ot her c o m m o n s y m pt o ms relate d t o a n e mia of patie nts wit h P N H are 
t h ose s uc h as de bilitati n g fati g ue, s h ort ness of breat h, a n d pal pitati o ns (Par ker, O mi ne, et al. 
2 0 0 5 ).  
Patie nts wit h P N H als o ha ve a n i ncreas e d  ris k f or s pla nc h nic, p ortal, a n d h e patic vei n 
t hr o m b osis, t he latter lea di n g t o B u d d-C hiari  s y n dr o me (Gra ha m, R osse, et al. 1 9 9 6 , Ha user, 
Bric hta, et al. 2 0 0 3 , Yi n, Li u, et al. 2 0 0 9 , Jai n 2 0 1 0, T orres, D e Vr o e y, et al. 2 0 1 0 ). 
T he mai n n o n he mat ol o gical cli nical fi n di n gs i ncl u de ac ute or c hr o ni c re n al fail ure (Sec hi, 
Mari glia n o, et al. 1 9 8 8 , J ac ks o n, N o ble, et al. 1 9 9 2, C h o w, Lai, et al. 2 0 0 1 , Nair, K haira, et al. 
2 0 0 8 , G uasc h 2 0 1 0 , Hill me n, Ele b ute, et al. 2 0 1 0 ), a n d p ul m o nar y h y perte nsi o n (Heller, 
Gri n ber g, et al. 1 9 9 2 ). Patie nts re p ort attac ks of a b d o mi nal pai n, diffic ult y s wall o wi n g a n d pai n 
d uri n g s wall o wi n g, as well as erectile d ysf u n cti o n i n me n (B or o witz, Crai g, et al. 2 0 1 0 , Rac hi di, 
M usalla m, et al. 2 0 1 0 ). 
P N H is as s ociate d wit h si g nifica nt m or bi dit y a n d m ortalit y (Harris, K osci c k, et al. 1 9 9 9 , Rac hi di, 
M usalla m, et al. 2 0 1 0 ); pri or t o t he a p pr o val of ec uliz u ma b a n d ra v uliz u ma b, t he me dia n 
s ur vi val after di a g n osis of P N H was 1 0 years (Hill me n, Le wis, et al. 1 9 9 5 ). Pri or t o t he a p pr o val 
of ec uliz u ma b, t he o v er all s ur vi val at 1 0 years after dia g n osis wit h P N H was esti mate d t o be 
6 5 % t o 7 7. 6 % (S ocie, M ar y, et al. 1 9 9 6 , Risita n o, N otar o, et al. 2 0 0 9 , G e, Li, et al. 2 0 1 2 ). 
T hr o m b osis is t he lea di n g ca use of d eat h i n P N H a n d, w hile it is relati vel y rare as a prese nti n g 
s y m pt o m, it has hist oricall y occ urre d i n u p t o 4 0 % of patie nts d uri n g t he c o urse of diseas e (P u 
a n d Br o ds k y 2 0 1 1 ). Visceral t hr o m b osis, cere br o v asc ular e ve nts, a n d p ul m o nar y e m b olis m 
pre dict a p o or o ut c o me (Zia kas, P o ul o u, et al. 2 0 0 8 ). S ur vi val of patie nts wit h P N H has 
i m pr o ve d rece ntl y, ass ociate d wit h c o ntr ol of i ntra vasc ular h e m ol ysis a n d re d uce d ris k of 
t hr o m b osis f oll o wi n g t he i ntr o d ucti o n of ec uliz u m a b (Hill, Kell y, et al. 2 0 1 3 , S ocie, 
Sc hreze n m eier, et al. 2 0 1 6 ). 
Disease c o ntr ol wit h c o m ple me nt C 5 i n hi bit ors s uc h as ec uliz u m a b a n d ra v uliz u ma b is 
i nc o m plete, wit h persiste nt tra nsf usi o n de pe n de n ce i n a p pr o xi matel y 5 0 % of patie nts, 
de vel o p me nt of e xtr a vas c ular he m ol ysis beca use of u nc o ntr olle d o ps o nizati o n of er yt hr oc ytes, 
a n d c o nc o mita nt b o ne m arr o w d ysf u n cti o n (Risita n o, N otar o, et al. 2 0 0 9 , Hill, D e Zer n, et al. 
2 0 1 7 ). T he c urre ntl y a p pr o ve d treat me nts are a d mi nistere d b y re peate d i ntra ve n o us i nf usi o ns. 
As of 9 A pril 2 0 2 0, t here were 9 pr o d ucts wit h or p ha n dr u g desi g nati o n f or t he treat me nt of P N H 
i n t he U nite d States ( U S) (F D A 2 0 2 0 ). T hese pr o d ucts i ncl u de S oliris®  (ec uliz u ma b) a n d 
Ult o miris ®  (ra v uliz u ma b), w hic h were  t he o nl y dr u gs a p pr o ve d f or treat me nt of P N H i n t he U S. 
P e gcetac o pl a n is als o a p pr o ve d f or t he treat me nt of P N H i n t he U S a n d f or t he treat me nt of 
a d ults w h o are a ne mic after treat me nt wit h a C 5 i n hi bit or f or 3 m o nt hs i n E ur o pe (A p ellis 2 0 2 1 , 
A pellis 2 0 2 2 ). 
Fact or D is t he rate -li miti n g e nz y me of t he A P. Fact or D is o bli gat or y f or pr o d ucti o n of t he C 3 
c o n vertas e of t he A P ( C 3 b B b) as well as a m plificati o n of C 3 c o n vertase pr o d ucti o n i nitiate d b y 
t he lecti n a n d classical pat h wa ys (Lesa vre a n d M uller - E ber har d 1 9 7 8, V ola na kis a n d Nara ya n a 
1 9 9 6 , X u, Nar a ya na, et al. 2 0 0 1 ). Tar geti n g Fact or D wit h a p har m ac ol o gic i n hi bit or is e x pecte d 
t o bl oc k b ot h t he f or mati o n of M A C (a n d he n ce C 5 b- 9) a n d f or mati o n of C 3 fra g me nts a n d 
o ps o nizati o n, a n d t heref ore pre v e nt b ot h i ntra vasc ular a n d e xtra vasc ul ar he m ol ysis. Fact or D 
i n hi bit ors ha ve a p ote ntial cli nical a d va nta ge o v er a nti - C 5 t hera p y, a n d a n orall y bi oa vaila ble 

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s mall- m olec ule Fact or D i n hi bit or c o ul d p ote ntiall y a br o gate t he n ee d f or lifel o n g i ntra ve n o us 
i nf usi o ns of a nti- C 5 bi ol o gics. T heref ore, tar geti n g Fact or D is a pr o misi n g t hera pe utic strate g y 
t o i n hi bit A P acti vati o n f or t he treat me nt of A P-me diate d diseas es s uc h as P N H.  
Bi o Cr yst P har mace uticals, I n c. ( Bi o Cr yst) has de v el o pe d B C X 9 9 3 0, a n o vel s mall- m olec ule 
i n hi bit or of c o m ple me nt Fact or D. B C X 9 9 3 0 p ote ntl y i n hi bits t he ester ol ytic acti vit y of p urifie d 
h u ma n Fact or D a g ai nst s y nt hetic s u bstrate wit h a mea n 5 0 % of ma xi mal i n hi bit or y 
c o nce ntr ati o n (I C 5 0) of 1 4. 3 n M. B C X 9 9 3 0 als o i n hi bits t he pr ote ol ytic acti vit y of Fact or D 
a gai nst its nat ural s u bstrate C 3 b B wit h a mea n I C 5 0 of 2 8. 1 n M. B C X 9 9 3 0 i n hi bits A P-me diate d 
he m ol ysis of ra b bit er yt hr oc ytes wit h a mea n I C 5 0 of 2 9. 5 n M. Usi n g t he H a m test wit h 
er yt hr oc ytes fr o m P N H p atie nts, B C X 9 9 3 0 s u p presses c o m ple me nt- me diat e d he m ol ysis wit h a 
mea n I C 5 0 of 3 5. 4 n M. F urt her m ore, B C X 9 9 3 0 c o m pletel y s u p presses C 3 fra g me nt de p ositi o n 
o n P N H er yt hr oc ytes wit h a mea n I C 5 0 of 3 9. 3 n M, i n dicati n g B C X 9 9 3 0 has t he p ote ntial t o 
i n hi bit b ot h i ntra vasc ular a n d e xtra v asc ular h e m ol ysis. 
5. 3.  
N o ncli nic al Fi n di n gs f or B C X 9 9 3 0  
T he res ults of n o ncli nical p har mac ol o g y, p har mac o ki netics ( P K), a n d t o xic ol o g y st u dies of 
B C X 9 9 3 0  are descri be d briefl y bel o w; a d diti o nal details ca n be f o u n d i n t he I n vesti gat or’s 
Br oc h ure (I B).  
 
 
 
 
 
I n rats a n d d o gs, B C X 9 9 3 0 is ra pi dl y a bs or be d. I n creas es i n e x p os ure of B C X 9 9 3 0 were 
a p pr o xi matel y pr o p orti o nal t o i ncreas es i n d ose i n b ot h s pecies. 
 
 
 
 
 
 A d diti o nal details ca n be f o u n d i n t he I B.  
T he data fr o m safet y p h ar mac ol o g y st u dies i n dicate t hat B C X 9 9 3 0 has a l o w p ote ntial t o affect 
t he res pirat or y, car di o v as c ular, a n d ce ntral ner v o us s yste ms. 
 B C X 9 9 3 0 has a l o w ris k t o pr ol o n g t he Q T i nter val. 
 
 
 
  

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2 4 
T he wei g ht of e vi d e nce s u g gests B C X 9 9 3 0 has a l o w ris k f or ge n ot o xicit y. B C X 9 9 3 0 is n ot 
fet ot o xic a n d is n ot terat o ge nic i n pre g na nt rats a n d ra b bits. T here is a l o w c o ncer n f or 
p h ot ot o xicit y. 
5. 4.  
Cli nic al Fi n di n gs f or B C X 9 9 3 0  
T he safet y a n d effecti ve n ess of B C X 9 9 3 0 i n P N H was i nitiall y e val uate d i n t he P hase 1, 
t hree-p art, first -i n- h u ma n ( FI H) St u d y B C X 9 9 3 0- 1 0 1 ( St u d y 1 0 1). I n Part 3 of St u d y 1 0 1 a t otal 
of 1 6 s u bjects wit h P N H were e nr olle d. T h is st u d y, B C X 9 9 3 0- 2 0 1 ( St u d y 2 0 1) is a l o n g-ter m 
r oll o ver st u d y f or all P N H s u bjects w h o pre vi o usl y recei v e d B C X 9 9 3 0 i n St u d y 1 0 1 Part 3 a n d 
deri ve d be n efit fr o m B C X 9 9 3 0 treat me nt. Fiftee n s u bjects fr o m St u d y 1 0 1 Part 3 e nr olle d i nt o 
t his st u d y. 
  
 
 
 
 
 
 
 
 
 
5. 4. 1.  
Cli nic al S afet y a n d T oler a bilit y  
I n St u d y 1 0 1 Part 3/ St u d y 2 0 1, a d mi nistrati o n of B C X 9 9 3 0 5 0 t o 5 0 0 m g has bee n ge n erall y 
well t olerate d f or u p t o 7 4 6 da ys (a p pr o xi matel y 1 0 7 wee ks) i n s u bjects wit h P N H. T here h a ve 
bee n n o disc o nti n uati o ns d ue t o dr u g relat e d treat me nt-e mer g e nt a d vers e e ve nts (T E A Es ). T h e 
m ost c o m m o n T E A Es relate d t o B C X 9 9 3 0 ha ve b ee n hea dac h e a n d e ve nts c o nsiste nt wit h a dr u g 
ras h.  
 
 
 
 
 
 
 
 
 
 
 
 
 

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2 5 
 
 
 
 
 
  
5. 4. 2.  
Effect i v e ness 
A d mi nistrati o n of B C X 9 9 3 0 at d oses of 4 0 0 m g or 5 0 0 m g BI D, b ot h i n s u bjects wit h P N H w h o 
are naï v e t o C 5 i n hi bit ors a n d i n t h ose w h o are recei vi n g C 5 i n hi bit ors a n d ha d a n i na de q u ate 
res p o nse, has res ulte d i n s ustai ne d cli nical res p o ns es. M ore o ver, treat me nt wit h B C X 9 9 3 0 at 
d oses of 4 0 0 or 5 0 0 m g BI D res ulte d i n i m pr o ve d a n d s ustai ne d cli nical res p o nses relati ve t o 
d oses of 5 0, 1 0 0, a n d 2 0 0 m g BI D, as m eas ure d b y he m o gl o bi n i n b ot h C 5 treat me nt- naï ve 
s u bjects a n d s u bjects wit h a n i na de q uat e res p o nse t o C 5 i n hi biti o n t hera p y, as well as b y 
decreases i n lact ate de h y dr o ge nase ( L D H ) le vels i n s u bjects naï ve t o C 5 i n hi bit ors. A d diti o nal 
efficac y i nf or m ati o n is pr o vi de d bel o w i n Secti o n  5. 5. 2 .  
5. 5.  
R ati o n ale f or St u d y  
B C X 9 9 3 0 is a s mall m olec ule i n hi bit or of h u ma n fact or D t h at is bei n g de v el o pe d as a n oral 
treat me nt of P N H a n d ot her c o m ple me nt-m e diate d diseases. As s u bjects wit h P N H s uccessf ull y 
c o m plete a B C X 9 9 3 0 st u d y a n d s h o w cli nical be n efit, t he y will be offere d t he o p p ort u nit y t o 
c o nti n ue treat me nt wit h B C X 9 9 3 0 b y partici pati o n i n t his l o n g ter m o pe n -la bel st u d y w here all 
s u bjects will be pr o vi de d treat me nt wit h o pe n-la b el B C X 9 9 3 0 f or 1 4 4 wee ks.  
Beca use P N H is a s e ver el y de bilitati n g, life -t hreat e ni n g dis or der wit h li mite d treat me nt o pti o ns, 
it is c o nsi dere d reas o na bl e t o offer c o nti n ue d d osi n g wit h B C X 9 9 3 0 t o s u bjects w h o de m o nstrate 
a cli nical be nefit fr o m treat me nt as assesse d b y t he site i n vesti gat or d uri n g a pri or B C X 9 9 3 0 
trial, c o nsiste nt wit h I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) M 3 a n d t he F D A g ui da n ce 
o n se verel y d e bilitati n g or li fe-t hreate ni n g he mat ol o gic dis or ders (F D A 2 0 1 9 ).  
5. 5. 1.  
R ati o n ale f or St u d y Desi g n  
T his o pe n-la bel saf et y st u d y is desi g ne d t o assess t he l o n g- ter m safet y a n d effecti ve ness of 
B C X 9 9 3 0 i n s u bjects w h o partici pate d i n a pre vi o us st u d y of B C X 9 9 3 0. B C X 9 9 3 0- 2 0 1 offers 
s u bjects w h o partici pate d i n a B C X 9 9 3 0 st u d y a d diti o nal or c o nti n ue d access t o B C X 9 9 3 0 
treat me nt f or 1 4 4 w ee ks , or u ntil dr u g is a vaila ble b y a n ot her mec h a nis m (e g, e x pa n de d or 
mar ket access) or u ntil t he S p o ns or disc o nti n ues de vel o p me nt of t he pr o d u ct f or P N H, w hic h e ver 
c o mes first.  
Eli gi ble s u bjects ma y e nr oll i n t he c urre nt st u d y if t he i n vesti gat or assesses t hat t he y ma y be nefit 
fr om c o nti n ue d dail y a d mi nistrati o n of B C X 9 9 3 0.  
5. 5. 2.  
R ati o n ale f or St u d y Dr u g D ose a n d Re gi me n  
T he d ose re gi me n f or t his st u d y, pri or t o t his a me n d me nt, was 
 

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2 6 
 
 
 
. T he f oll o wi n g o bser vati o ns s u p p ort t his d osi n g 
re gi me n: 
•  
 
 
 
 
 
 
 
 
 
 
5. 5. 2. 1.  
S u m m ar y of He m at ol o gic Res p o nse at 4 0 0 a n d 5 0 0 m g BI D – St u dies 1 0 1 a n d 
2 0 1 
A vaila ble cli nical efficac y data s u p p ort t he p ote nti al f or l o weri n g t he t ar get d ose of B C X 9 9 3 0 
fr o m 5 0 0 t o 4 0 0 m g BI D i n t he o n g oi n g cli nical st u dies. As d osi n g of B C X 9 9 3 0 was titrate d i n 
t he i nitial c o h ort of s u bjects wit h P N H e nr olle d i n St u d y 1 0 1 Part 3, t hat st u d y a n d t his l o n g-ter m 
e xte nsi o n st u d y ( St u d y 2 0 1) pr o vi de a c o m paris o n of eff icac y d uri n g at least 6 wee ks of i nitial 
treat me nt wit h 4 0 0 m g BI D a n d wit h o n g oi n g treat me nt at 5 0 0 m g BI D (T a ble 2 ). Ni ne s u bjects 
i n St u dies 1 0 1/ 2 0 1 ha ve ha d at least 6 wee ks of d osi n g at 4 0 0 m g BI D pri or t o escalati n g t o 5 0 0 
m g BI D; 7 of t hes e s u bjects were n aï ve t o C 5 i n hi bit ors a n d pr o vi de a mea ni n gf ul c o m parati ve 
dataset. Mea n H b, C F B i n H b, P N H T y pe II +III R B C cl o ne size, its C F B, a n d t he C F B i n t he 
rati o of R B C cl o ne size t o W B C cl o ne size were v er y si milar at b ot h d ose l e vels. N o s u bjects 
re q uire d r e d bl o o d cell tr a nsf usi o ns d uri n g treat m e nt at eit her d ose l e vel. 
 
  

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2 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 5. 2. 2.  
S u m m ar y of P P K a n d P K/ P D M o deli n g  
T he pri mar y  efficac y c o nsi derati o n f or t he d ose s electi o n i n t his st u d y was t he de vel o p me nt of 
P P K a n d P K/ P D m o dels usi n g data fr o m St u d y 1 0 1 a n d t his st u d y. 
P D e n d p oi nts i n t hese m o dels i ncl u de d A P Wiesl a b i n healt h y a n d P N H s u bjects, L D H i n 
s u bjects wit h P N H naï ve t o C 5 i n hi bit ors, a n d C 3 o ps o nizati o n i n P N H s u bjects wit h i na de q uate 
res p o nse t o o n g oi n g C 5 i n hi bit or t hera p y. A P Wiesla b was use d as a real ti me mar ker of o verall 
c o m ple me nt acti vati o n. L D H was use d as a mar k er of I V H (ter mi nal c o m ple me nt i n hi biti o n) a n d 
C 3 o ps o nizati o n was use d as a mar k er of t he p ot e ntial f or E V H ( pr o xi mal c o m ple me nt 
i n hi biti o n) i n P N H s u bjects. Tar get occ u pa n c y of Fact or D is n ot e x pect e d t o be affecte d b y a 
ter mi nal c o mple me nt i n hi bit or, all o wi n g f or m o dels of I V H a n d E V H t o be e xtra p olate d t o all 
s u bjects wit h P N H re gar dless of C 5 i n hi bit or stat us. 
 
 
 
 
 
 
Se parate P K/ P D m o dels were c o nstr ucte d f or A P Wiesla b, L D H, a n d C 3 o ps o nizati o n of R B Cs. 
O verall, t he m o dels perf or me d well a n d w ere a ble t o descri be tre n ds i n t he o bser ve d dat a. 

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T he L D H m o del i n C 5 i n hi bit or- naï ve P N H s u bjects was c haracterize d b y i n direct i n hi biti o n, 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 

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A b bre viati o ns: A P = alter nati ve pat h wa y; BI D = t wice dail y; CI = c o nfi de nce i nter val; C ta u = tr o u g h c o n ce ntrati o n; 
I C = i n hi bit or y c o nce ntrati o n; L D H = lactate de h y dr o ge nase; P K/ P D = p har mac o ki netic/ p har mac o d y na mic; P P K 
= p o p ulati o n p har mac o ki netic(s).  
N otes: P P K si m ulati o n ass u mes perfect a d here nce a n d o pti mal s paci n g of BI D d oses (ie, e ver y 1 2 h o urs).  
I nitiall y, a ma xi m u m d ose of 5 0 0 m g BI D was s electe d f or t his st u d y d ue t o a s mall p ote ntial 
be nefit rel ati ve t o 4 0 0 m g BI D i n P K/ P D m o del pre dicti o ns i n t he a bse nce of a n y safet y si g nal i n 
h u ma ns. Gi ve n t he a vaila ble safet y dat a a n d o verla p pi n g c o nfi de nce i nter vals i n m o del esti mates 
vs. 5 0 0 m g BI D, a B C X 9 9 3 0 d ose of 4 0 0 m g BI D is s u p p orte d b y P P K a n d P K/ P D m o deli n g 
pre dicti o ns t o reac h a si milar cli nical effi cac y i n P N H s u bjects.  
5. 5. 3.  
St u d y P o p ul ati o n R ati o n ale  
T he st u d y p o p ulati o n is defi ne d b y t he pri or B C X 9 9 3 0 trial i n P N H fr o m w hic h t he s u bjects are 
eli gi ble f or t his pr ot oc ol. B ot h males a n d fe males will be e nr olle d. As re pr o d ucti ve t o xic ol o g y 
st u dies ha ve bee n c o n d ucte d, w o me n of c hil d beari n g p ote ntial ma y be e nr olle d i n t his trial o nl y 
if t he y meet a n d mai ntai n strict c o ntrace pti ve a n d pre g na nc y t est re q uire me nts as liste d i n t his 
pr ot oc ol.  
5. 6.  
Be nefit- Ris k A n al ysis  
T he de vel o p me nt of B C X 9 9 3 0 ma y be of b e nefit t o patie nts wit h P N H a n d ot her c o m ple me nt 
me diate d diseases t hat ar e seri o us, ass oci ate d wit h c hr o nic m or bi dit y, a n d are p ote ntiall y 
life-t hreat e ni n g. I n St u d y 1 0 1, a d mi nistrati o n of B C X 9 9 3 0 at d oses of 4 0 0 m g or 5 0 0 m g BI D, 
b ot h i n s u bjects w h o are naï ve t o C 5 i n hi bit ors a n d i n t h ose w h o are recei vi n g C 5 i n hi bit ors a n d 
ha d a n i na de q u ate r es p o nse, res ulte d i n s ustai ne d cli nical res p o nses, as meas ure d b y 
i m pr o ve me nt i n H b le vels, a n d decr eases i n L D H a n d C 3 o ps o nizati o n of R B C cells. S u bjects 
partici pati n g i n t his st u d y ma y si milarl y deri ve a b e nefit wit h B C X 9 9 3 0 i n c o ntr olli n g t he 
s y m pt o ms a n d/ or i m pr o vi n g la b orat or y para meters relate d t o P N H diseas e. T h or o u g h m o nit ori n g 
a n d assess me nt of A Es will be perf or me d f or s u bjects e nr olle d i n t his st u d y, a n d 
pr ot oc ol- ma n date d s afet y assess me nts i ncl u de vital si g n me as ure me nts, p h ysical e xa mi nati o n, 
electr ocar di o gr a ms ( E C Gs ), a n d cli nical la b orat or y testi n g. 
P ote ntial ris ks ass ociate d wit h c o m ple me nt i n hi bit ors f or t he treat me nt of P N H, as well as 
p ote ntial ris ks ass ociate d wit h B C X 9 9 3 0 base d o n n o ncli nical a n d cli nic al data t o date are 
descri be d i n t he I B f or B C X 9 9 3 0 a n d s u m marize d bel o w. 
5. 6. 1.  
P ote nti al Ris ks f or  B act eri al  I nfecti o ns 
T he m ost si g nifica nt ris k ass ociate d wit h c o m ple m e nt i n hi bit or t hera pies is t he ris k of 
life-t hreat e ni n g or fat al me ni n g oc occal i nfecti o ns (Fi g uer o a a n d D e nse n 1 9 9 1 , Hill me n, Y o u n g, 
et al. 2 0 0 6). T his ris k is well- k n o w n a n d i ncl u de d as a war ni n g i n t he rele v a nt la bels f or b ot h 
S oliris (ec uliz u ma b) a n d Ult o miris (ra v uliz u ma b)  (Ale xi o n P har mace uticals 2 0 2 0 , 
Ale xi o n P har mace uticals 2 0 2 1 ). 
As B C X 9 9 3 0 bl oc ks t he A P of c o m ple me nt, s u bjects ma y ha ve i ncreas e d s usce pti bilit y t o 
bacterial i nfecti o ns, es peciall y i n fecti o ns wit h e nca ps ulate d or ga nis ms, s uc h as Neisseri a 
me ni n giti dis,  Stre pt oc occ us p ne u m o ni ae , a n d H a e m o p hil us i nfl ue nz ae , b ut als o wit h 
u ne nca ps ulate d str ai ns of N. me ni n giti dis  a n d ot her bacteria s uc h as  N. g o n orr h oe ae (Ra m, 

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3 0 
Le wis, et al. 2 0 1 0 ). St u d y s u bjects recei vi n g B C X 9 9 3 0 will be m o nit ore d cl osel y f or si g ns a n d 
s y m pt o ms of i nfecti o n; i nfecti o n ris k will be miti gate d b y re q uiri n g s u bjects t o ha ve u p t o date 
vacci nati o ns a g ai nst a p pr o priate bact erial strai ns. If re q uire d o n a n i n di vi d ual basis, pr o p h ylactic 
a nti bi otic a d mi nistrati o n will be all o we d.  
5. 6. 2.  
P ote nti al Ris ks of S A R S -C o V - 2 I nfecti o n a n d V acci n ati o n W hile Recei vi n g 
B C X 9 9 3 0 T her a p y 
C o m ple me nt i n hi bit ors d o n ot i n hi bit cell ular or h u m oral i m m u nit y. T heref ore, B C X 9 9 3 0 is n ot 
e x pecte d t o i ncreas e t he ris k of c o ntracti n g  c or o na vir us disease 2 0 1 9 (C O VI D - 1 9) f oll o wi n g 
i nfecti o n wit h t he se ver e ac ute r es pirat or y s y n dr o me c or o na vir us 2 ( S A R S- C o V-2) or t o i ncreas e 
t he ris k of se vere ill ness wit h C O VI D- 1 9. 
All st u d y acti vit y will be c o n d ucte d i n acc or d a nce wit h rele va nt l ocal, re gi o nal, a n d nati o nal 
g ui da nce ar o u n d C O VI D- 1 9. I n or der t o mi ni mize t he ris k of C O VI D- 1 9 tra ns missi o n, a d diti o nal 
pr oce d ur es or ass ess me nts ( w hic h ma y i ncl u de b ut are n ot li mite d t o s y m pt o m assess me nt, 
te m perat ur e, viral ri b o n u cleic aci d [ R N A] testi n g, a n d a nti b o d y testi n g) ma y be i m ple me nte d at 
t he discreti o n of t he i n vesti gat or a n d s p o ns or me dical m o nit or be y o n d t h ose re q uire d f or t his 
pr ot oc ol. 
Vacci n ati o n a gai nst S A R S - C o V-2, t he ca usal a ge nt f o r C O VI D- 1 9 i nfecti o n, is all o we d, if 
a ut h orize d a n d a vaila ble i n c o u ntr y or area, a n d b ase d o n i n vesti gat or’s j u d g me nt. 
T he s p o ns or’s c urre nt ris k assess me nt, relati ve t o C O VI D- 1 9 vacci nati o n i n cli nical trials wit h 
B C X 9 9 3 0, is t hat a ut h orize d or a v aila ble C O VI D - 1 9 vacci nati o ns are u nli k el y t o ha ve a n y 
p ote ntial i nteracti o n or a d de d safet y ris k, if gi ve n i n c o m bi nati o n wit h B C X 9 9 3 0. Als o, c urre ntl y 
t here is n o t he oretical c o ncer n or d ata t o s u g gest t hat c o m ple me nt i n hi biti o n wit h o n g oi n g 
B C X 9 9 3 0 treat me nt w o ul d i m pact t he p ote ntial efficac y of vacci nati o ns a g ai nst S A R S - C o V- 2. 
W hile t here is a k n o w n or e x pect e d hi g her ris k of s o me bacteri al i nfecti o ns i n patie nts treate d 
wit h c o m ple me nt i n hi biti o n a n d i n patie nts wit h certai n here ditar y c o m ple me nt deficie nci e s, 
t here is n o clear k n o w n i ncreas e d or c o m p o u n d e d ris k wit h vacci nati o ns i n t he setti n g of 
c o m ple me nt i n hi biti o n; h o we ver, t here h a ve bee n re p orts of he m ol ysis i n patie nts wit h P N H after 
S A R S - C o V-2 vacci nati o n (Ger b er, Y u a n, et al. 2 0 2 1 ). 
5. 6. 3.  
P ote nti al Ris ks f or He a d ac he  
I n P has e 3 st u dies of a d ult patie nts wit h P N H w h o recei v e d ec uliz u m a b or ra v uliz u ma b, 
hea dac he w as o ne of t he m ost fre q ue ntl y re p ort e d a d verse dr u g reacti o ns (Ale xi o n 
P har mace uticals 2 0 2 0 ). Hea dac hes t hat w ere c o nsi dere d rel ate d t o ra v uliz u ma b a n d ec uliz u m a b 
c o m m o nl y occ urr e d earl y after t he i nitiati o n of treat me nt . T hese h ea dac hes  ma y be ass ociate d 
wit h a tra nsie nt s ur ge i n plas ma nitric o xi de le vels i n d uce d b y t he cess ati o n of t he de pleti o n of 
nitric o xi de b y free he m o gl o bi n (Hill me n, Y o u n g, et al. 2 0 0 6 , Br o ds k y, Y o u n g, et al. 2 0 0 8 , 
Hill me n, M u us, et al. 2 0 1 3 , R ot h, R otti n g ha us, et al. 2 0 1 8 ). I n St u d y B C X 9 9 3 0- 1 0 1, earl y o ns et 
hea dac he w as t he m ost c o m m o n T E A E i n s u bjects wit h P N H treate d wit h B C X 9 9 3 0, li kel y 
c o nsiste nt wit h rest orati o n of nitric o xi de h o me ostasis d ue t o i m pr o ve d c o ntr ol of he m ol ysis wit h 
B C X 9 9 3 0.  

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5. 6. 4.  
P ote nti al Ris ks f or Der m at ol o gic Re acti o ns 
A be ni g n mac ul o pa p ular ras h wit h c o nsiste nt o nset a n d cli nical c o urs e has bee n o bser v e d wit h 
m ulti ple - da y d osi n g of B C X 9 9 3 0 i n b ot h healt h y s u bjects a n d s u bjects wit h P N H. Cli nical 
e x perie n ce t o date i n dicates t hat t his ras h res ol ves wit h n o i nter ve nti o n w hile c o nti n ui n g d osi n g 
of B C X 9 9 3 0. Alt h o u g h t here is n o e vi de n ce f or a n y s yste mic h y perse nsiti vit y, m ore se vere 
reacti o ns ma y b e p ossi ble, a n d a n y s u bject wit h a ras h belie ve d t o b e relat e d t o B C X 9 9 3 0 s h o ul d 
be e val uat e d, a s dee me d me dicall y a p pr o pri ate. C urre ntl y, t he ris k of disc o nti n ui n g B C X 9 9 3 0 i n 
P N H patie nts is greater t ha n t he p ote ntial ris k of c o nti n ui n g wit h treat me nt; all P N H s u bjects 
wit h ras h ha ve rec o v ere d w hile c o nti n ui n g d osi n g a n d i n t he sa me ti mefra me as healt h y s u bjects 
w h o st o p pe d d osi n g of B C X 9 9 3 0. 
5. 6. 5.  
P ote nti al Ris ks f or He m ol ysis After B C X 9 9 3 0 Disc o nti n u ati o n or I nterr u pti o n i n 
S u bjects wit h P N H  
Si milar t o a vaila ble c o m ple me nt i n hi bit ors use d t o treat P N H, disc o nti n uati o n of B C X 9 9 3 0 ma y 
res ult i n i ncreas e d ris k of he m ol ysis of P N H R B Cs (Ale xi o n P har mace uticals 2 0 2 0 , 
Ale xi o n P har mace uticals 2 0 2 1 ). Acc or di n gl y, s u bjects w h o disc o nti n ue or i nterr u pt B C X 9 9 3 0 
ma y be at ris k of he m ol ysis. S u bjects s h o ul d be i nstr ucte d t o i m me diatel y c o ntact t he 
i n vesti gati ve site pri nci pal i n vesti gat or if t he y miss a n y B C X 9 9 3 0 d oses a n d e x perie n ce ne w or 
w orse ni n g s y m pt o ms of he m ol ysis. I n a d diti o n, s u bjects w h o disc o nti n ue per ma ne ntl y B C X 9 9 3 0 
will be m o nit ore d f or p ote ntial he m ol ysis. Assess me nts t o detect he m ol ysis s h o ul d be perf or m e d 
acc or di n g t o t he s c he d ule i n Secti o n  1 1. 3. 5 . 
5. 6. 6.  
P ote nti al Ris ks f or He p atic Effects  
Ser u m c he mistries, i ncl u di n g li ver tra nsa mi nases, bilir u bi n, a n d al kali ne p h os p hatase ( A L P), will 
be f oll o we d cl osel y i n t his st u d y t o m o nit or f or a n y he pat ocell ular a n d biliar y s yste m c ha n ges. 
He patic s y nt hetic f u n cti o n will be m o nit ore d b y pr ot hr o m bi n ti me, i nter nati o nal n or malize d rati o 
(I N R), al b u mi n, a n d t otal pr otei n le vels i n bl o o d.  
5. 6. 7.  
P ote nti al Ris ks f or Re n al Effects  
 
 
 
 
 
 
 
 
  
M o nit ori n g of re nal f u ncti o n will be u n derta ke n i n t he st u d y usi n g sta n dar d meas ures (e g, s Cr, 
esti mate d gl o mer ular filtr ati o n rate [e G F R], a n d uri nal ysis i ncl u di n g micr osc o p y a n d bi o mar ker 
a nal ysis). F urt h er i nf or m ati o n ca n be f o u n d i n Secti o n  1 3. 6 . A n y re nal e ve nts occ urri n g o n st u d y 
s h o ul d be e val uate d as detaile d i n Secti o n  1 3. 9. 5. 3 .  

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5. 6. 8.  
O ver all Be nefit -Ris k A n al ysis  
Treat me nt -e mer ge nt i ncr eases i n 
 
 Base d o n t he s p o ns or’s preli mi nar y i n v esti gati o n, re d uci n g 
t he B C X 9 9 3 0 d ose t o 4 0 0 m g BI D is a ntici pate d t o miti gate t he ris k of  
 t o s u bjects 
w hile mai ntai ni n g t he p ote ntial f or de m o nstrati n g cli nical be nefit i n t he P N H patie nt p o p ulati o n .  
B C X 9 9 3 0 is e x pecte d t o pr o vi de greater efficac y t ha n t he c urre ntl y a vaila bl e C 5 i n hi bit ors b y 
n ot o nl y pre ve nti n g I V H, b ut als o b y pre ve nti n g C 3 me diate d e xtra v asc ular he m ol ysis ( E V H ), 
t here b y r e d uci n g s y m pt o m b ur de n, re d u ci n g he m ol ysis, i ncl u di n g E V H a n d brea kt hr o u g h 
he m ol ysis ( B T H ), i m pr o vi n g patie nt f u ncti o n, c ha n gi n g t he a d mi nistrati o n r o ute fr o m I V t o oral, 
a n d i m pr o vi n g healt h -rel ate d q ualit y of life . St u d y s u bject selecti o n criteria, d ose selecti o n, a n d 
st u d y m o nit ori n g assess me nts ha ve bee n i n cl u de d t o o pti mize be nefit a n d t o mi ni mize t he ris k of 
t o xicities t o st u d y partici pa nts. Re g ular m o nit ori n g of safet y para met ers, i n cl u di n g A Es, cli nical 
la b orat or y a b n or malities, vital si g ns meas ure me nts, E C Gs, a n d p h ysical e x a mi nati o n fi n di n gs, 
will e ns ure t hat t he be n efit -ris k pr ofile s u p p orts c o nti n ue d d osi n g. I n a d diti o n, a n i n de pe n de nt, 
pr o gra m- wi de data m o nit ori n g c o m mittee ( D M C) will c o nti n ue t o pr o vi de o versi g ht of t he 
o n g oi n g e x p os ure of s u bj ects t o B C X 9 9 3 0 i n t his a n d ot her cli nical st u dies. T he o verall be nefit -
ris k bala nce is t heref ore c o nsi dere d t o be acce pta ble. 
6.  
T RI A L O B J E C TI V E S A N D P U R P O S E  
6. 1.  
Pri m ar y O bjecti ve 
•  T o c ollect l o n g- ter m safet y a n d t olera bilit y data i n eli gi ble s u bjects wit h P N H w h o 
pre vi o usl y recei ve d B C X 9 9 3 0 i n a Bi o Cr yst-s p o ns ore d st u d y a n d deri ve d b e nefit 
fr o m B C X 9 9 3 0 treat me nt. 
6. 2.  
Sec o n d ar y O bjecti ves  
•  T o assess t he c o nti n ue d effecti ve n ess of  B C X 9 9 3 0 i n treat me nt of P N H d uri n g 
l o n g-ter m a d mi nistrati o n. 
•  T o e val uate p atie nt -re p orte d o utc o mes ( P R Os) of l o n g-ter m B C X 9 9 3 0 treat me nt.  
•  T o c ollect P K, P D, a n d c o m ple me nt bi o mar ker data i n s u bjects wit h P N H f or 
i nc or p orati o n i nt o meta-st u d y m o dels of p o p ulati o n P K a n d P K/ P D.  
•  T o c har acteri ze t he eff ects of B C X 9 9 3 0 i n s u bjects wit h P N H b y cli nical 
meas ure me nts a n d P D a n d c o m ple me nt bi o mar ker s. 
•  T o e val uate bi o mar kers of c o m ple me nt acti vati o n d uri n g e pis o des of B T H. 
6. 3.  
Pri m ar y E n d p oi nt  
•  Meas ure me nt of saf et y a n d t olera bilit y b y s u bject i nci de nce of gra d e d T E A Es, 
la b orat or y a b n or malities, c ha n ges t o vital si g ns, E C G res ults, a n d p h ysical 
e xa mi nati o n fi n di n gs. 

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6. 4.  
Sec o n d ar y E n d p oi nts  
•  Cli nical P N H s y m pt o m assess me nts i ncl u di n g fati g ue, d ys p nea, c hest 
pai n/ disc o mf ort, diffic ult y s wall o wi n g (es o p ha g eal pai n), a b d o mi nal pai n, hea dac he, 
erectile d ysf u n cti o n, he m o gl o bi n uria, ja u n dice , i nci de nce of B T H, a n d i nci d e nce of 
t hr o m b oe m b olic e ve nts.  
•  Cli nical meas ure me nts of P N H ( L D H, he m o gl o bi n, ha pt o gl o bi n, retic ul oc ytes, 
tra nsf usi o n re q uir e me nts). 
•  P R O e n d p oi nts will i ncl u de sc ores fr o m t he Q u alit y of Life Q uesti o n naire f or Patie nts 
wit h A plastic A ne mia/ P N H ( Q L Q - A A/ P N H), F u ncti o nal Assess me nt of C hr o nic 
Ill ness T h era p y ( F A CI T) fati g ue scal e, a n d Treat me nt Satisfacti o n Q uesti o n naire f or 
Me dicati o n ( T S Q M).  
•  C o nce ntrati o n of B C X 9 9 3 0 i n plas ma at stea d y state i n s u bjects wit h P N H. 
6. 5.  
P h ar m ac o d y n a mic ( P D) E n d p oi nt  
•  P D a n d c o m ple me nt bi o mar ker meas ure m e nts will i ncl u de P N H R B C a n d w hite 
bl o o d cell ( W B C ) cl o ne size, plas ma Fact or B b , a n d A P acti vit y (as assesse d via A P 
Wi esla b).  
 
 
 
7.  
I N V E S TI G A TI O N A L P L A N 
7. 1.  
O ver all St u d y Desi g n  
T his is a n o pe n-la bel p hase 2 st u d y desi g ne d t o e v al uate t he l o n g- ter m s afet y of dail y oral 
treat me nt wit h B C X 9 9 3 0 i n s u bjects w h o ha ve partici pate d i n a pre vi o us B C X 9 9 3 0 trial. T he 
st u d y will als o e val uate t he l o n g -ter m effecti ve ness a n d i m pact o n q ualit y of life or ge n eral 
well - bei n g of B C X 9 9 3 0 treat me nt, a n d t he s u bj ect’s satisfacti o n wit h t he me dicati o n.  
S u bjects w h o ha ve pr o vi de d writte n i nf or me d c o nse nt a n d w h o ha v e partici pate d i n a B C X 9 9 3 0 
st u d y will re q uire a scr ee ni n g visit if t he y ha ve i nterr u pte d st u d y dr u g f or ≥ 3 1 da ys.  
S u bjects w h o ha ve pr o vi de d writte n i nf or me d c o nse nt a n d w h o ha v e partici pate d i n a B C X 9 9 3 0 
st u d y will n ot re q uire a s cree ni n g visit if t he y ha v e i nterr u pte d st u d y dr u g f or bet wee n 1 a n d 
3 0 da ys. H o we v er, t he y will re q uire a b aseli ne visit. 
F or s u bjects w h o r oll o ver directl y fr o m a n ot her B C X 9 9 3 0 st u d y wit h o ut treat me nt i nterr u pti o n, 
n o scree ni n g visit will be re q uire d. T h e fi nal o n- st u d y visit assess me nts i n t he pri or B C X 9 9 3 0 
st u d y will ser ve as t he baseli ne assess me nts f or t his st u d y; h o we ver, a d diti o nal rele va nt b aseli ne 
assess me nts f or t his st u d y ma y be perf or me d at t h e fi nal o n- treat me nt visit f or t he pri or st u d y as 
nee de d t o satisf y e nr oll me nt criteria. E nr oll me nt wit h o ut treat me nt i nterr u pti o n i nt o t he c urre nt 
st u d y will o b viate t he re q uire me nt f or a f oll o w- u p visit i n t he pre vi o us B C X 9 9 3 0 st u d y. 

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T he scree ni n g a n d bas eli ne visit re q uire me nts are de picte d i n  Ta ble  3.  
T a ble 3:  
St u d y B C X 9 9 3 0- 2 0 1: Scree ni n g a n d B aseli ne Visit Re q uire me nts  
Visit Re q uire d  
I nterr u pte d St u d y 
Dr u g  ≥ 3 1 D a ys  
I nterr u pte d St u d y 
Dr u g 1 t o 3 0 D a ys  
N o I nterr u pti o n of 
St u d y Dr u g  
Scree ni n g visit  
Yes  
N o  
N o  
Baseli ne visit  
Yes  
Yes  
N o  a 
a N o baseli ne visit re q uire d if t he s u bject r olls fr o m t he pre vi o us st u d y wit h o ut d ose i nterr u pti o n; t he fi nal 
o n -treat me nt visit fr o m t he pre vi o us B C X 9 9 3 0 st u d y will ser ve as t he baseli ne visit f or t he c urre nt st u d y, alt h o u g h 
a d diti o nal assess me nts ma y be re q uire d.  
A s u bject ma y be e nr olle d o nce all eli gi bilit y criteria a n d st u d y re q uire me nts are met. 
O n -treat me nt st u d y visits will occ ur o n Da y 1, t he n e ver y 4 w ee ks u p t o Wee k 9 6 a n d t he n e ver y 
8 wee ks  u ntil Wee k 1 4 4. S u bjects wit h s Cr ele vati o ns will be re q uire d t o c o m plete a d diti o nal 
assess me nts at t he i n vesti gati o nal site , at a la b orat or y l ocal t o t he s u bject , or via a h o me healt h 
ser vice ( w her e per mitte d a n d a vaila ble) as i n dicate d i n Secti o n  1 1. 3. 4. 1  a n d Secti o n  1 3. 9. 5. 3 . A n 
i n de pe n de nt D M C will c o nti n ue t o re vie w t he safet y data fr o m t his st u d y i n c o ncert wit h t he 
acc u m ulati n g saf et y i nf or mati o n ge nerate d acr oss t he B C X 9 9 3 0 cli nical de v el o p me nt pr o gra m. 
T he D M C c o n ve n e d a n d re vie we d s afet y d ata o nce t he first 4 s u bjects e nr olle d c o m pleted 1 2 
wee ks of d osi n g. S u bse q ue nt D M C meeti n gs were  a n d will be c o n v e ne d as detaile d i n t he D M C 
C harter.  
U p t o a p pr o xi matel y 2 0 0 s u bjects ma y be e nr olle d i nt o t he st u d y. S u bjects will be eli gi ble t o 
recei v e B C X 9 9 3 0 f or u p t o 1 4 4 wee ks , or u ntil dr u g is a vaila ble b y a n ot her mec ha nis m (e g, 
e x pa n de d or m ar ket access) or u ntil t he S p o ns or disc o nti n ues de vel o p me nt of t he pr o d uct f or 
P N H ; w hic he ver c o mes first.  
A st u d y sc he ma is s h o w n i n Fi g ure 2 .  
Fi g ure  2: 
St u d y Sc he m a  
 
A b bre viati o ns: E O T  = e n d of  treat me nt; W k = wee k.  
a S u bjects wit h s Cr ele vati o ns will be re q uire d t o c o m plete a d diti o nal assess me nts t o m o nit or f or p ote ntial re nal 
t o xicit y at t he i n vesti gati o nal site, at a re m ote la b orat or y m ore c o n ve nie nt f or t he s u bject, or via a h o me healt h 
ser vice ( w here per mitte d a n d a vaila ble) as i n dicate d i n Secti o n  1 1. 3. 4. 1  a n d Secti o n  1 3. 9. 5. 3 . 
b F oll o wi n g disc o nti n uati o n of st u d y dr u g, eit her f oll o wi n g c o m pleti o n of t he treat me nt peri o d or o n pre mat ure 
disc o nti n uati o n, s u bjects will ret ur n t o t he cli nic f or a mi ni m u m of 3 c o nsec uti ve da ys t o m o nit or f or t he o nset of 
he m ol ysis . 
c  S u bjects will ret ur n t o t he cli nic 3 wee ks ( 2 1 ± 3 da ys) after t he date of t h eir last d ose of B C X 9 9 3 0 f or t heir e n d of 
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Safet y a n d t oler a bilit y will be e val uate d t hr o u g h assess me nts of T E A Es, la b orat or y a n al yses 
(cli nical c he mistr y, he m at ol o g y, c oa g ulati o n, a n d uri nal ysis), vital si g ns, E C Gs, a n d p h ysical 
e xa mi nat i o ns at t he st u d y visits i n dicate d i n t he sc he d ule of assess m e nts (see Ta ble 4 ).  
Disease -s p ecific assess m e nts will be perf or m e d at st u d y visits as i n dicate d i n t he sc he d ule of 
assess me nts (see  T a ble 4 ). 
7. 2.  
N u m ber of S u bjects  
U p t o a p pr o xi matel y 2 0 0 s u bjects are pla n n e d t o b e e nr olle d i n t he st u d y base d u p o n t he 
a ntici pate d cli nical pr o gr a ms f or B C X 9 9 3 0. 
7. 3.  
Tre at me nt D os i n g  
T he pr ot oc ol-s pe cifie d d ose pri or t o t his a me n d me nt was 5 0 0 m g B C X 9 9 3 0 BI D. U n d er t his 
a me n d me nt, s u bjects will ta ke 4 0 0 m g  B C X 9 9 3 0 BI D  orall y  .  
7. 4.  
I n di vi d u al a n d St u d y St o p pi n g R ules 
7. 4. 1.  
S u bject Disc o nti n u ati o n fr o m St u d y Dr u g  
A s u bject will be per ma n e ntl y wit h dra w n fr o m st u d y dr u g f or a n y of t he f oll o wi n g reas o ns: 
•  S u bject re q uest t o disc o nti n ue f or a n y reas o n. 
•  Pre g na nc y i n a fe male s u bject.  
•  E mer ge nce of a n A E, i ncl u di n g a la b orat or y a b n or malit y, or ot her u nacce pt a ble 
t o xicit y t hat, i n t he j u d g ment of t he i n vesti gat or, c o m pr o mises t he a bilit y of t he 
s u bject t o c o nti n ue st u d y-s pecific pr oce d ures or it is c o nsi dere d n ot t o be i n t he 
s u bject’s best i nterest t o c o nti n ue d ue t o a n altere d be nefit-ris k pr ofile. 
•  I nterc urre nt ill ness or t he e mer ge n ce of a ne w m e dical c o n diti o n t hat w o ul d, i n t he 
j u d g me nt of t he i n vesti gat or, affect assess me nts of cli nical stat us t o a si g nifica nt 
de gree.  
•  Treat me nt -e mer ge nt A L T > 3 × u p per li mit of n or mal ( U L N ) (c o nfir me d b y re peat 
testi n g) c o m bi ne d wit h eit her: 
− la b orat or y ab n or malities i n dicati ve of si g nifica nt he patic t o xicit y (ie, meeti n g 
H y’s la w, t otal bilir u bi n > 2 × U L N or wit h a ne w i ncreas e i n I N R > 1. 5 i n t he 
a bse nce of warfari n t hera p y) 
O R  
− s y m pt o mat ol o g y of ac ute he patitis (ie, se vere fati g ue, na usea, v o miti n g, ri g ht 
u p per q ua dr a nt pai n a n d t e n der ness, fe ver, ras h, a n d/ or e osi n o p hilia [ > 5 %] t hat 
has n ot bee n part of t he s u bject’s hist or y of P N H s y m pt o mat ol o g y) 
A N D  
− assesse d as pr o b a bl y or d efi nitel y relate d t o B C X 9 9 3 0 

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A N D  
− wit h o ut cli nical a n d/ or la b orat or y e vi de n ce of h e m ol ysis or a n y ot her p ote ntial 
alter nati ve eti ol o g y.  
•  Treat me nt -e mer ge nt i ncr ease i n s Cr ≥ 3 × U L N (c o nfir me d b y re p eat testi n g)  wit h o ut 
cli nical a n d/ or la b or at or y e vi de nce of he m ol ysis or a n y ot her p ote ntial ca us e of re n al 
d ysf u ncti o n. 
•  I n v asi ve me ni n g oc o ccal i nfecti o n or i n vasi ve e nca ps ulate d bacterial i nfecti o n. 
Disc o nti n uati o n of B C X 9 9 3 0 ma y occ ur after s u bject sta bilizati o n t o pre ve nt 
u nc o ntr olle d he m ol ysis. 
•  I n t he i n v esti gat or’s o pi ni o n it is i n t he best i nterest of t he s u bject t o disc o nti n ue fr o m 
f urt her d osi n g. 
•  S u bject n o nc o m plia nce ( e g, pr ot oc ol de viati o n), as assesse d b y t he s p o ns or or 
i n vesti gat or, t o be detri me ntal t o st u d y or s u bject be nefit-ris k pr ofile. 
•  Disc o nti n uati o n at t he re q uest of t he s p o ns or, rel e va nt c o m pete nt a ut h orit y, or t he 
g o ver ni n g i nstit uti o nal re vie w b oar d (I R B), researc h et hics b oar d ( R E B), or 
i n de pe n de nt et hics c o m mittee (I E C), c ollecti vel y referre d t o as “et hics c o m mittee”. 
W he ne v er p ossi ble, t he i n vesti gat or will c o ns ult wit h t he s p o ns or me dical m o nit or ( or desi g nee) 
bef ore disc o nti n ui n g st u d y treat me nt. T he reas o n f or disc o nti n uati o n of st u d y treat me nt will be 
rec or d e d i n t he s o urce d o c u me nts a n d electr o nic case re p ort f or m (e C R F). 
S u bjects w h o disc o nti n ue st u d y dr u g f or a n y reas o n will be m o nit ore d f or h e m ol ysis (see 
Secti o n  1 1. 3. 5  a n d Secti o n  1 1. 3. 6 ).  
7. 4. 2.  
St u d y St o p pi n g R ules  
T he f oll o wi n g st u d y st o p pi n g r ules will be use d t o ter mi nate eit her t he w h ole st u d y or ter mi nate 
a partic ular site:  
•  Re q uest of a c o m pet e nt a ut h orit y or t he s u per visi n g I E C 
•  E mer ge nce of u nacce pta ble ris k, t o xicit y, or ne gati ve c ha n ge i n t he b e nefit- ris k 
assess me nt  
•  Rec o m me n dati o n of t he D M C 
•  I n acc urate or i nc o m plete rec or d k ee pi n g 
•  N o n -c o m plia nce wit h t he st u d y pr ot oc ol t hat je o par dizes t he scie ntifi c i nte grit y of 
st u d y assess me nts or s u bject safet y 
Bi o Cr yst reser ves t he ri g ht t o disc o nti n ue t he trial pri or t o i ncl usi o n of t he i nte n de d n u m ber of 
s u bjects b ut i nte n ds o nl y t o e xercise t his ri g ht f or vali d scie ntific or a d mi nistrati ve reas o ns. After 
s uc h a decisi o n, t he I n v esti gat or m ust c o ntact all partici pati n g s u bjects i m me diatel y after 
n otificati o n. As directe d b y Bi o Cr yst, all st u d y materials m ust be c ollect e d a n d all e C R Fs 
c o m plete d t o t he greatest e xte nt p ossi ble. 

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If t he trial is halte d d ue t o safet y c o n cer ns or base d o n a D M C decisi o n, re-start of t he trial will 
occ ur f oll o wi n g t he a p pr o priate a ut h oriz ati o n via a s u bsta ntial a me n d me nt.  
8.  
S E L E C TI O N A N D WI T H D R A W A L O F S U B J E C T S  
8. 1.  
S u bject I ncl usi o n Criteri a  
S u bjects m ust meet all  of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or p artici pati o n i n t his 
st u d y: 
1.  A ble  t o pr o vi de writte n i nf or me d c o ns e nt. 
2.  Male or n o n- pr e g na nt, n o n- lactati n g fe mal e s u bjects. 
3.  S u bjects w h o ha ve s uccessf ull y partici pate d i n a pre vi o us B C X 9 9 3 0 st u d y of P N H a n d 
w h o e x perie n ce d a cli nical be nefit, as c o nfir me d b y t he I n v esti gat or. S uccessf ul 
partici pati o n is defi ne d as c o m pleti o n of pla n ne d d urati o n of d osi n g wit h B C X 9 9 3 0 i n t he 
pri or st u d y, n ot i ncl usi ve of a n y e xte nsi o n peri o d.  
4.  Fe male p artici pa nts m ust meet at least 1 of t he f oll o wi n g c o ntrace pti o n re q uire me nts (f or 
details see Secti o n  1 1. 4. 1 ): 
a. Be a w o ma n of c hil d beari n g p ote ntial w h o a grees t o use a hi g hl y effecti ve 
c o ntrace pti ve met h o d t hr o u g h o ut t he st u d y a n d f or a d urati o n of 3 0 d a ys af ter t he last 
d ose of st u d y dr u g. 
b.  Alter nati vel y, tr ue a bsti ne nce is acce pt a ble f or w o me n of c hil d beari n g p ote ntial w he n 
it is i n li ne wit h t he s u bject’s preferre d a n d us ual lifest yle.  
c. Be a w o ma n of n o n c hil d beari n g p ote ntial. 
5.  Male partici pa nts m ust meet t he f oll o wi n g c o ntrace pti o n re q uire me nts (f or details see 
Secti o ns  1 1. 4. 1  a n d 1 1. 4. 2 ): 
a. S u bjects wit h fe male part ners of c hil d beari n g p ote ntial m ust a gree t o utilize a hi g hl y 
effecti ve c o ntr ace pti ve m et h o d.  
b.  Alter nati vel y, tr ue a bsti ne nce is acce pt a ble w he n it is i n li ne w it h t he s u bject’s 
preferre d a n d us ual lifest yle.  
6.  I n t he o pi ni o n of t h e I n vesti gat or, t he s u bject is e x pecte d t o a d e q uatel y c o m pl y wit h all 
re q uire d st u d y pr o ce d ur es a n d restricti o ns f or t he d urati o n of t he st u d y. 
8. 2.  
S u bject E xcl usi o n Criteri a  
S u bjects m ust meet n o ne of t he f oll o wi n g e xcl usi o n criteria t o be eli gi ble f or partici pati o n i n t he 
st u d y: 
1.  A n y cli nicall y si g nifica nt me dical or ps yc hiatri c c o n diti o n t hat, i n t he o pi ni o n of t he 
I n v esti gat or or S p o ns or, w o ul d i nterfere wit h t he s u bject’s abilit y t o partici pate i n t he 
st u d y, or partici pati o n w o ul d i ncrease t h e ris k f or t hat s u bject. 

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2.  A n y cli nicall y si g nifica nt hist or y of a n gi na, k n o w n c or o nar y arter y disease, m y ocar dial 
i nfarcti o n, s y nc o pe, cli nicall y si g nifica nt car diac arr h yt h mias, left ve ntri c ular 
h y pertr o p h y, car di o m y o pat h y, a ortic ste n osis, or a n y ot her car di o vasc ular a b n or malit y. 
3.  C hr o nic s yste mic c ortic oster oi d use. N ote: T o pical, i n hale d, oc ular, or n asal s pra ys 
c o ntai ni n g c ortic oster oi ds are all o w e d.  
4.  I n v esti gati o nal dr u g e x p os ure, ot her t ha n B C X 9 9 3 0, wit hi n 3 0 da ys of t he baseli ne visit, 
or 5. 5 half-li ves of t he i n vesti gati o nal dr u g ( w hic h e ver is l o n ger). 
5.  F or s u bjects r e q uiri n g a s cree ni n g visit: 
a. Cli nicall y si g nifica nt a b n or mal E C G at t he scree ni n g visit. T his i ncl u des, b ut is n ot 
li mite d t o, a Q Tc F > 4 5 0 msec i n males a n d > 4 7 0 msec i n fe males, or ve ntric ular 
a n d/ or atrial pr e mat ure c o ntracti o ns t hat are m ore fre q ue nt t ha n o ccasi o nal, a n d/ or as 
c o u plets or hi g her i n gr o u pi n g. 
b.  A L T or A S T > 3 × U L N ( E xce pti o n: S u bjects ma y be e nr olle d wit h A L T or A S T 
> 3 × U L N if e x plai ne d b y he m ol ysis. I n t hese cas es, A L T a n d A S T m ust b e 
< 5 × U L N).  
c. T otal ser u m bilir u bi n > 2 × U L N ( E x ce pti o ns: S u bject ma y be e nr olle d wit h t otal 
ser u m bilir u bi n > 2 × U L N if t he ele vat e d bilir u bi n is e x plai ne d b y he m ol ysis or i n 
t he case of Gil bert’s s y n dr o me. I n t he case of h e m ol ysis, t otal ser u m bilir u bi n m ust be 
< 5 × U L N a n d i n t he cas e of Gil bert ’s S y n dr o me, t otal bilir u bi n m ust be < 7 × U L N).  
6.  Dail y use of me dicati o ns liste d i n t he c urre ntl y a p plica ble pr o hi bite d me dicati o ns list 
( See Secti o n 9. 2 ). 
7.  Pre g na nt, pla n ni n g t o bec o me pre g na nt, or h a vi n g bee n pre g n a nt wit hi n 9 0 da ys of 
baseli ne, or lactati n g . 
8. 3.  
S u bject Wit h dr a w al Criteri a  
Partici pati o n i n t he st u d y is strictl y v ol u ntar y. S u bjects ha ve t he ri g ht t o wit h dra w fr o m st u d y 
dr u g or fr o m t he st u d y at a n y ti me a n d f or a n y reas o n. A s u bject’s partici p ati o n ma y be 
ter mi nate d f or a n y of t he reas o ns deli neate d i n Secti o n 7. 4 . W he ne ver p ossi ble, t he I n vesti gat or 
will c o ns ult wit h t he S p o ns or Me dical M o nit or bef ore halti n g a s u bject’s p artici pati o n i n t he 
st u d y. 
I n all cases, t he reas o n f or wit h dra wal fr o m st u d y dr u g m ust be rec or de d i n t he s u bject’s me dical 
rec or ds (s o urce d oc u me nts). If t he reas o n is n ot k n o w n, t he s ubject m ust be f oll o we d t o esta blis h 
w het her t he reas o n was d ue t o a n A E, a n d if s o, t his m ust be re p orte d i n acc or da nce wit h t he 
pr oce d ur es o utli ne d i n Secti o n  7. 4. 1  a n d Secti o n  1 3. 9. 3 . Vi g or o us atte m pts will be ma de f or 
f oll o w- u p of all s u bjects w h o miss a st u d y visit. I n ge neral, alt h o u g h st u d y dr u g ma y be st o p pe d, 
s u bjects will be str o n gl y e nc o ura g e d t o c o nti n ue t o c o m plete t he sc he d ul e d st u d y visits f or 
he m ol ysis m o nit ori n g (see Secti o n  1 1. 3. 5 ). If t he s u bject is wit h dra w n fr o m t he st u d y pri or t o 
sc he d ule d st u d y c o m pleti o n, a n earl y ter mi nati o n visit t o c o m plete all e n d- of-st u d y e val uati o ns 
will be re q uire d. If a s u bj ect’s partici p ati o n i n t his st u d y is ter mi nate d, t he res p o nsi ble 
I n v esti gat or/cli nical staff me m ber will d oc u me nt ter mi nati o n i n t he s o urce d oc u me nts. 

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8. 4.  
E n d of St u d y Defi niti o n  
T he e n d of t he st u d y will be defi ne d as t he date w he n t he last s u bject c o m pletes t he last pr ot oc ol-
sc he d ule d visit. 
9.  
T R E A T M E N T O F S U B J E C T S  
T hr o u g h o ut treat me nt wit h B C X 9 9 3 0, s u bjects s h o ul d mai ntai n a de q uate h y drati o n t o pre ve nt 
t he f or mati o n of hi g hl y c o nce ntrate d uri ne. 
9. 1.  
C o nc o mit a nt Me dic ati o ns  
D uri n g t he c o urs e of t he st u d y, t he i n vesti gat or s h o ul d re vie w t he s u bject’s me dicati o n list f or 
p ote ntiall y ne p hr ot o xic me dicati o ns a n d c o nsi der, w he n me dicall y feasi ble, w het her t hes e 
me dicati o ns ma y be st o p pe d or s u bstit ute d wit h n o n- or less ne p hr ot o xic m e dicati o ns. Ca uti o n 
s h o ul d be e xer cise d wit h t he c hr o nic use of n o n-st er oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds) 
w hile ta ki n g B C X 9 9 3 0. S u bjects ma y ta ke t heir n or mal me dicati o ns, wit h t he e xce pti o n of a n y 
c ha n ges t o ne p hr ot o xic me dicati o ns a n d pr o hi bite d me dicati o ns detaile d b el o w ( Secti o n  9. 2 ).  
Vacci n ati o n a gai nst N. me ni n giti dis  t y pes A, C, W, Y, a n d B, S. p ne u m o ni a e,  H. i nfl ue nz ae  t y pe 
B ( Hi b) a n d vari cella z oster vir us ( V Z V) will be all o we d u p t o at least 1 4 da ys pri or t o Da y 1.  
As part of t heir tr eat me nt f or P N H, s u bjects s h o ul d be assesse d b y t he i n v esti gat or f or i nfecti o n 
ris k as descri b e d i n Secti o n 1 1. 3. 2 . Pr o p h ylactic a nti bi otic a n d/ or a nti viral me dicati o ns ma y be 
c o nsi dere d if cli nicall y i n dicate d (e g,  v alac y cl o vir/ac ycl o vir if s u bject is ser o p ositi ve f or V Z V or 
te n of o vir/la mi v u di ne if at ris k f or reacti vati o n of H B V). 
S u bjects ma y be e nc o ura ge d t o be gi n ta peri n g or t o disc o nti n ue me dicati o ns t hat s u p press t he 
i m m u ne s yste m if cli nicall y i n dicate d. 
Base d u p o n t he mec h a nis m of acti o n of pr o xi mal A P i n hi biti o n tar geti n g Fact or D a n d 
de m o nstrati o n t hat B C X 9 9 3 0 m o n ot hera p y is s ufficie nt t o c o ntr ol he m ol ysis i n P N H i n C 5 
i n hi bit or- naï ve s u bjects (see Secti o n  5. 4 ), s u bjects w h o c o m me nce t h e st u d y wit h a bac k gr o u n d 
treat me nt of ec uliz u ma b or ra v uliz u ma b s h o ul d be c o nsi dere d f or a disc o nti n uati o n of t hese 
me dicati o ns. T he treati n g I n v esti gat or s h o ul d disc o nti n ue t he C 5 i n hi bit or o nce t he s u bject is o n 
a n o pti mize d d ose of B C X 9 9 3 0. It is e x pect e d t h at all s u bjects will disc o nti n ue bac k gr o u n d C 5 
i n hi bit or t hera p y as t her e s h o ul d be n o p har mac ol o gical be nefit t o ter mi nal A P i n hi biti o n wit h 
effecti ve pr o xi mal A P i n hi biti o n via B C X 9 9 3 0, u nless t here is a me dical reas o n n ot t o d o s o. I n 
t his case, disc o nti n uati o n fr o m t he st u d y s h o ul d be c o nsi dere d if t he m e dical reas o n is 
n o nres p o nse t o B C X 9 9 3 0 t hera p y. 
Details of all pri or ( wit hi n 3 0 da ys of Scree ni n g) a n d c o nc o mita nt me dicati o n use, i ncl u di n g all 
me dicati o ns a d mi nistere d f or t he treat me nt of A Es, will be rec or d e d i n t he s o urce 
d oc u me ntati o n/case re p ort f or m (e C R F).  
9. 2.  
Pr o hi bite d Me dic ati o ns  
All s u bjects i n t he st u d y s h o ul d refrai n fr o m dail y use of ta ki n g pr o hi bite d me dicati o ns 
t hr o u g h o ut t heir st u d y partici pati o n. A list of pr o hi bite d me dicati o ns will be pr o vi de d t o sites. If 

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d uri n g t he c o urse of t his st u d y, a d diti o nal i nf or mati o n a b o ut t he i nteracti o n of B C X 9 9 3 0 wit h 
pr o hi bite d me dicati o ns bec o mes a v aila ble fr o m P hase 1 dr u g i nteracti o n st u dies, t he list will be 
u p date d.  
T hr o u g h o ut t he c o urse of t he st u d y, I n v esti gat ors s h o ul d i n q uire a b o ut ne w l y i nitiate d dail y 
me dicati o ns; t he I n vesti gat or s h o ul d c o m pare t h es e me dicati o ns t o t he pr o hi bite d me dicati o n list.  
S i milarl y, s u bjects s h o ul d be ma de a ware t hat t he re ma y be restricte d m e dicati o n i n t his st u d y 
a n d s h o ul d i nf or m t heir treati n g p h ysicia ns of t he p ossi bilit y of p ote ntial i nteracti o ns.  
S u bjects a n d i n vesti gat ors s h o ul d w or k wit h treati n g p h ysicia ns t o e ns ure t hat ne wl y i nitiate d 
dail y me dicati o ns are n ot i ncl u de d i n t he pr o hi bite d me dicati o n list. If t he i nitiati o n of s uc h a 
me dicati o n is u na v oi da ble (ie, me dicall y necess ar y a n d wit h o ut a n acce pta ble alter nati ve), t h e 
Me dical M o nit or s h o ul d be c o ntact e d t o disc uss t he c o nti n ue d eli gi bilit y of t he s u bject. 
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9. 3.  
Tre at me nt C o m pli a nce  
F or s u bjects w h o h a ve h a d a d ose i nterr u pti o n si nce t he pre vi o us B C X 9 9 3 0 st u d y, t he first d ose 
o n Da y 1 will be gi ve n i n t he cli nic. All ot her d oses a n d all d oses f or s u bjects c o nti n ui n g fr o m 
t he pri or st u d y wit h o ut i nterr u pti o n, will be ta ke n at h o me d uri n g t he d osi n g peri o d f oll o wi n g t he 
i nstr ucti o ns pr o vi de d b y t he st u d y site staff. B C X 9 9 3 0 ma y be ta ke n wit h or wit h o ut f o o d. 
W here p ossi ble, t he B C X 9 9 3 0 d oses s h o ul d be ta k e n at t he sa me ti mes eac h da y as cl ose as 
p ossi ble t o 1 2 h o urs a part (e g. 8: 0 0 A M a n d 8: 0 0 P M). C o nsi derati o n s h o ul d be gi ve n t o 
strate gies t hat will hel p r ei nf orce t hese be h a vi ors, s uc h as as ki n g s u bjects t o v ol u ntaril y set u p 
re mi n der al ar ms o n t heir m o bile p h o nes or at t heir h o mes t o re mi n d t he m t o ta ke t heir d oses, at 
least u ntil t he y bec o me a dj uste d t o t heir ne w treat me nt re gi me n. I n vesti gat ors s h o ul d re mi n d 
partici pa nts w h o re g ul arl y miss d oses of B C X 9 9 3 0 a b o ut t he i m p orta nce of treat me nt 
c o m plia nce.   

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I n-Cli nic D osi n g : 
I n v esti gati o nal pr o d uct a d mi nistere d i n t he cli nic will be gi ve n directly b y t he i n vesti gat or, or 
q ualifie d staff me m b er, u n der me dical s u p er visi o n t o c o nfir m c o m plia nce. T he date a n d ti me of 
t he a d mi nistere d d ose i n t he cli nic will be rec or de d i n t he s u bject’s s o urce d oc u me nts a n d e C R F.  
At - H o me D osi n g: 
S u bjects will be pr o vi de d i nstr ucti o ns f or ta ki n g dail y d oses of i n vesti gati o nal pr o d uct at h o me, 
i ncl u di n g fre q ue n c y a n d ti me of a d mi nistrati o n. S u bjects will be i nstr ucte d t o mai ntai n 
a p pr o xi matel y t he sa me d osi n g i nter val bet wee n st u d y dr u g d oses eac h da y. 
Misse d D oses:  
I d eall y, B C X 9 9 3 0 d oses s h o ul d be ta ke n 1 2 h o urs a part at t he s a me ti mes eac h da y wit h o ut 
missi n g d oses. If a s u bj ect d oes n ot ta ke a B C X 9 9 3 0 d ose at t he sc he d ul e d ti me, t he misse d d ose 
ca n be ta k e n u p t o 6 h o urs after t he s c he d ule d d os e ti me. If m ore t ha n 6 h o urs has passe d, t he 
misse d d ose s h o ul d n ot be ta ke n. Re gar dless of w het her t he misse d d ose w as ma de u p, d osi n g 
s h o ul d res u me wit h t he ne xt d ose ta ke n at t he s c he d ule d ti me. F or e x a m ple, a s u bject w h o 
n or mall y ta kes t he B C X 9 9 3 0 d oses at 8: 0 0 A M/ P M eac h da y ca n ta k e a misse d m or ni n g d ose as 
late as 2: 0 0 P M wit h t he e ve ni n g d ose a d mi nistere d o n sc he d ule at 8: 0 0 P M. A misse d e ve ni n g 
d ose ca n be t a ke n as l ate as 2: 0 0 A M t he ne xt da y, wit h t he ne xt d ose ta ke n o n sc he d ule at 
8: 0 0 A M.  
S u bjects s h o ul d be i nstr ucte d t o i m me diatel y c o ntact t he i n vesti gat or if t he y miss a n y B C X 9 9 3 0 
d oses a n d ha ve n e w or w orse ni n g si g ns or s y m pt o ms c o nsiste nt wit h ac ute s y m pt o matic 
he m ol ysis.  
S u bjects will be i nstr ucte d t o bri n g all dr u g kits ( b ot h u n use d a n d use d b ottles) wit h t he m f or 
eac h st u d y visit. Acc o u nt a bilit y a n d a d here n ce will be re vie w e d at eac h cli nic visit. S u bjects d o 
n ot nee d t o wit h h ol d a n y d oses o n cli nic da ys or ta ke a d ose at t he cli nic, u nless t he cli nic visit 
falls d uri n g t he s u bject’s n or mal ti me of d osi n g. 
9. 3. 1.  
S pec i al C o nsi der ati o ns f or D osi n g, I ncl u di n g I n a bilit y t o T a ke Me dic ati o n 
Or all y  
It is i m perati ve t h at st u d y s u bjects ta ke st u d y dr u g as sc he d ule d wit h o ut missi n g d oses. U n der 
certai n circ u msta nces, w he n a s u bject ca n n ot ta ke or a bs or b B C X 9 9 3 0 (i ncl u di n g ac ut e ill ness 
wit h v o miti n g, d ys p ha gia d ue t o s y m pt o matic he m ol ysis, a n d u n pla n ne d circ u msta nces re q uiri n g 
h os pitalizati o n), t here are pr o visi o ns t hat ca n be ta ke n. 
F or ac ute v o miti n g, treat me nt of na usea a n d/ or v o miti n g wit h a n oral, orall y diss ol vi n g, or rec tal 
s u p p osit or y a nti-e metic 3 0 mi n utes t o a n h o ur (as a s u g gesti o n) bef ore atte m pti n g t o s wall o w t he 
B C X 9 9 3 0 ta blets c o ul d be atte m pte d. If a s u bject v o mits after recei vi n g a d ose of B C X 9 9 3 0, t he 
s u bject ma y be r e d ose d (i e, ta ke t w o ne w ta blets) if t he i ntact ta blets or pieces of t he ta blets are 
see n i n t he v o mit us ( v o mit c o nte nts).  
Please ref er als o t o t he I M P ma n ual f or s pecific i nstr ucti o ns.  

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9. 4.  
R a n d o miz ati o n a n d Bli n di n g  
T his is a n o pe n-la bel, n o n-ra n d o mize d st u d y. All s u bjects e nr olle d i n t he st u d y will r ecei ve 
B C X 9 9 3 0 orall y f or u p t o 1 4 4 wee ks , u ntil dr u g is a vaila ble b y a n ot her mec ha nis m 
(e g, e x pa n d e d or mar ket access) or u ntil t he S p o ns or disc o nti n ues de vel o p me nt of t he pr o d uct f or 
P N H , w hic he ver c o mes first. 
9. 5.  
V acci n ati o n Re q uire me nts, a n d V acci n ati o ns d uri n g St u d y, a n d 
Pr o p h yl actic A nti bi otic C o ver a ge  
U nless l ocal g ui deli nes are m ore stri n ge nt, t he A d vis or y C o m mittee o n I m m u nizati o n Practices 
( A CI P) rec o m me n dati o ns f or me ni n g oc occal vacci nati o n a n d A CI P g ui da n ce f or altere d 
i m m u n oc o m pete nce (i ncl u di n g c o m ple me nt i n hi biti o n t hera p y) s h o ul d be f oll o we d (M bae yi 
2 0 2 0 , Kr o ger, Ba ht a, et al. 2 0 2 1 ). F or vacci nes a g ai nst ser o gr o u ps A, C, W, a n d Y, a b o oster 
vacci ne s h o ul d be gi v e n e ver y 5 years w hile o n c o m ple me nt i n hi bit or t hera p y; t he a vaila ble 
vacci nes are i nterc ha n g ea ble. F or vacci nes a g ai nst ser o gr o u p B, a b o oster vacci ne s h o ul d be 
gi ve n 1 year after t h e seri es c o m pleti o n a n d e ver y 2 t o 3 years t hereaft er; t he a vaila ble v acci n es 
are n ot i nter c ha n gea ble (M bae yi 2 0 2 0 ). 
I n v esti gat ors will  re vie w eac h s u bject’s vacci nati o n stat us at peri o dic i nter v als t o e ns ure t hat a n y 
nee de d b o oster vacci nati o ns are a d mi nistere d at t he o pti mal ti mi n g d uri n g t he st u d y. Please 
c o ntact t he s p o ns or me di cal m o nit or or desi g nee f or a n y q uesti o ns. 
If a li ve vacci ne n ee ds t o be gi ve n d uri n g t he st u d y, please c o ntact t he s p o ns or me dical m o nit or 
or desi g nee. 
L ocal treat me nt g ui deli nes s h o ul d be f oll o we d f or pr o p h ylactic a nti bi otic t hera p y f or patie nts 
wit h P N H at t he discreti o n of t he i n vesti gat or f or t h ose recei vi n g treat me nt wit h c o m ple me nt 
i n hi biti o n. 
1 0.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T  
1 0. 1.  
St u d y Dr u g  
B C X 9 9 3 0 is a s mall m olec ule i n hi bit or of Fact or D. T he I M P will  be s u p plie d b y Bi o Cr yst as 
1 0 0, 2 0 0, a n d/ or 2 5 0 m g  ta blets t o all o w f or d ose a dj ust me nts if nee de d f or t he safet y 
ma na ge me nt of t he s u bj ect.  
T he acti ve i n gr e die nt f or t his st u d y is B C X 9 9 3 0, s u p plie d b y Bi o Cr yst. B C X 9 9 3 0 is a w hite or 
off - w hite p o w d er.  
T he I M P will be a d mi nistere d b y t he oral r o ute. 
A d diti o nal details f or t he c he mical a n d p h ysical c haract eristics of B C X 9 9 3 0 ma y be f o u n d i n t he 
I B a n d I M P Ma n ual. 

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1 0. 2.  
St u d y Dr u g P ac k a gi n g a n d L a beli n g  
T he st u d y dr u g will be pac ka g e d i n t he a p pr o priat e size b ottle. Eac h b ottle will be la bele d wit h 
t he i nf or mati o n re q uir e d per l ocal la w a n d ma y i n cl u de: S p o ns or na me, st u d y pr ot oc ol n u m ber, 
descri pti o n of t he c o nte nts, a state me nt re g ar di n g t he i n vesti gati o nal (cli nical trial) use of t he 
st u d y dr u g a n d e x pir y dat e.  
1 0. 3.  
St u d y Dr u g St or a ge  
St u d y dr u g will be st ore d bet wee n 1 5° C a n d 2 5° C (r o o m te m perat ure). 
1 0. 4.  
St u d y Dr u g Pre p ar ati o n  
N o st u d y dr u g pre parati o n is re q uire d. Ta bl ets  will be ta ke n fr o m t he pr o vi de d b ottles. 
1 0. 5.  
A d mi nistr ati o n  
S u bjects will ta ke B C X 9 9 3 0 orall y, eit her wit h or wit h o ut f o o d. S u bjects will be treate d f or u p t o 
1 4 4 wee ks.  S u bjects s h o ul d be e nc o ur a ge d t o mai ntai n a n e ver y - 1 2- h o ur re gi me n a n d re mi n de d 
of t he i m p orta nce of a d h ere nce t o t he d ose sc h e d ule . 
S u bjects will ta ke 4 0 0 m g  B C X 9 9 3 0 BI D . T hr o u g h o ut treat me nt wit h B C X 9 9 3 0, s u bjects s h o ul d 
mai ntai n a de q uate h y drati o n t o pre ve nt t he f or mati o n of hi g hl y c o nce ntrate d uri ne. 
1 0. 5. 1.  
Tre at m e nt I nterr u pti o n a n d D ose Re d ucti o n  
Treat me nt i nterr u pti o n or d ose re d ucti o n as a res ult of i n vesti gat or ma na ge me nt of A Es 
p ote ntiall y relate d t o st u d y dr u g is per missi ble wit h a p pr o priate m o nit ori n g f or p ote ntial 
he m ol ysis as descri be d i n Secti o n  1 3. 9. 5. 4 . D ose re d ucti o n s h o ul d be d o ne i n c o ns ultati o n wit h 
t he s p o ns or me dical m o nit or ( or desi g nee). A n y treat me nt i nterr u pti o n or d ose re d ucti o n will be 
rec or d e d i n t he e C R F a n d s o urce d oc u m e nts, i ncl u di n g t he reas o n f or t he i nterr u pti o n or 
re d ucti o n. Res u m pti o n of st u d y dr u g a d mi nistrati o n is als o per missi ble u p o n res ol uti o n of t he 
e ve nt, as assess e d b y t he i n vesti gat or, wit h a pla n f or m o nit ori n g of t he s u bject f or rec urre nce of 
t he A E, as a p pr o priate. S ee Secti o n 1 0. 5. 2  f or p ot e ntial d ose ta peri n g o pti o ns. 
1 0. 5. 2.  
D ose T a peri n g  
I n t he e ve nt of p er ma n e nt disc o nti n uati o n of B C X 9 9 3 0, 
 
 
 
 
 
 
T he decisi o n t o ta per t h e d ose a n d d urati o n of a n y ta per will be bas e d o n t he i n vesti gat or’s 
me dical j u d ge me nt, ta ki n g i nt o acc o u nt t he reas o n f or disc o nti n uati o n of t he dr u g, t he se v erit y of 

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a n y re p ort e d si g ns or s y m pt o ms, a n d/ or a n y re p orte d w orse ni n g of si g ns or s y m pt o ms. T he 
ta peri n g sc he d ul e s h o ul d be disc usse d wit h t he s p o ns or me dical m o nit or ( or desi g nee), i deall y 
pri or t o i m ple me ntati o n, a n d a dj uste d, as a p pr o pri ate, f or t he i n di vi d ual s u bject. 
1 0. 6.  
St u d y Dr u g Acc o u nt a bilit y  
T he I n vesti gat or m ust mai ntai n acc urate rec or ds o n a dr u g acc o u nta bilit y f or m of t he dis p ositi o n 
of all st u d y dr u gs recei ve d fr o m t he S p o ns or, directl y a d mi nistere d t o t he s u bject (i ncl u di n g date 
a n d ti me) or dis pe nse d t o t he s u bject. At t he e n d of t he st u d y, i nf or mati o n descri bi n g st u d y dr u g 
s u p plies (e g, l ot n u m bers) a n d dis p ositi o n of s u p plies m ust be pr o vi de d, si g ne d b y t he 
I n v estigat or or desi g nee, a n d c ollecte d b y t h e st u d y m o nit or. 
1 0. 7.  
St u d y Dr u g H a n dli n g a n d Dis p os al  
All me dicati o n n ot a d mi nistere d a n d use d p ac ka gi n g materials will be ret ur ne d t o t he S p o ns or or 
destr o ye d o n site as i nstr ucte d b y t he S p o ns or f oll o wi n g I M P acc o u nta bilit y b y t he st u d y 
m o nit or, a bi di n g b y a p pr o priate Sta n dar d O p erati n g Pr oce d ure at t he parti ci pati n g i nstit uti o n.  
1 1.  
S T U D Y C O N D U C T  
1 1. 1.  
O ver vie w  
T his is a n o pe n-la bel, n o n-ra n d o mize d st u d y t o e v al uate t he l o n g-ter m s afet y a n d effecti ve n ess of 
dail y oral B C X 9 9 3 0.  
S u bjects will be eli gi ble t o recei v e st u d y dr u g ( B C X 9 9 3 0) f or u p t o 1 4 4 w ee ks , u ntil dr u g is 
a vaila ble b y a n ot h er mec ha nis m (e g, e x pa n d e d or mar ket  access) or u ntil t he S p o ns or 
disc o nti n ues de vel o p me nt of t he pr o d uct f or P N H ( See Secti o n 7. 4 ), w hic h e ver c o m es first. 
St u d y dr u g will be disc o nti n ue d f or s u bjects w h o are deri vi n g n o cli nical b e nefit, are i nt olera nt 
of st u d y dr u g, or e x perie nce a n u n acce pta ble dr u g- relate d T E A E as d efi ne d i n m ore detail i n 
Secti o n  7. 4 . T he St u d y will be disc o nti n ue d if o n g oi n g re g ulat or y or I nstit uti o nal Re vie w 
B oar d/ Et hics C o m mittee (I R B/ E C) a p pr o val is wit h dra w n, or i n t he e ve nt t hat tec h nical or 
l o gistical fact ors pre v e nt t he o n g oi n g c o n d uct of t he st u d y. S u bjects w h o disc o nti n ue st u d y dr u g 
will ha ve a mi ni m u m of 3 da ys he m ol ysis testi n g a n d t he n ret ur n t o t he cli nic f or a n e n d- of-st u d y 
visit 3  wee ks after t h e last d ose of st u d y dr u g.  
1 1. 2.  
Sc he d ule of Assess me nts  
T he sc he d ule of assess m e nts f or t his st u d y is prese nte d i n Ta ble 4  a n d pr oce d ures are des cri be d 
bel o w. W her e p ossi ble, it is preferre d t hat pr o ce d ures are perf or me d i n t he f oll o wi n g se q ue nce 
d uri n g eac h cli nic visit: 
1.  Q uesti o n nair es  
2.  1 2- lea d E C G 
3.  Bl o o d press ure ( B P), te m perat ure, a n d p ulse rate 
4.  Bl o o d sa m pli n g; t he preferre d or der f or bl o o d sa m pli n g is:  

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a. He mat ol o g y 
b.  C oa g ulati o n 
c. Cli nical c he mistr y a n d ot her la b orat or y assess me nts  
d.  P K bl o o d sa m ple  

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T a ble 4: 
St u d y Desi g n a n d Sc he d ule of Assess me nts  
Assess m e nt  
Scree ni n g 
Peri o d  a   
B aseli ne 
Visit  b   
Tre at me nt Peri o d  
( Visit Sc he d ule) 
U nsc he d ule d 
Visit 
F oll o wi n g 
B T H  
( wit hi n 
4 8  hrs or 
ne xt 
w or ki n g 
d ay)  
Disc o nti n u ati o n 
of St u dy Dr u g  
E n d of 
St u dy 
Assess me nt  
Scree ni n g 
Visit  
( U p t o 
D a y -2 8)  
( D a y 1) 
Wee k 4 a n d 
E ver y 4 w ks u p 
t o W k 9 6 c 
( ± 3 d a ys)  
Wee k 9 6  a n d 
E ver y 8 w ks 
U ntil W k 1 4 4  d   
( ± 6 d a ys)  
He m ol ysis 
M o nit ori n g f or 
at le ast 
3 C o nsec uti ve 
D a ys  e   
 
3 Wee ks 
( ± 3 D a ys) 
After L ast 
D ose of 
St u d y 
Dr u g  
I nf or me d c o nse nt f   
X 
X 
 
 
 
 
 
I ncl usi o n-e xcl usi o n 
criteria  
X 
X 
 
 
 
 
 
Me dical a n d me dicati o n 
hist or y  g   
X 
X 
 
 
 
 
 
Wei g ht/ hei g ht/ B MI  h   
X 
X 
X 
X 
 
 
X 
P h ysical e xa mi nati o n  i   
X 
X 
X 
X 
X 
X 
X 
E C G  j   
X 
X 
X 
X 
 
 
X 
Pre g na nc y test ( w o me n) 
k   
X 
X 
X 
X 
 
 
X 
F S H test ( w o me n)  l   
X 
X 
 
 
 
 
 
Vital si g ns  
X 
X 
X 
X 
X 
X 
X 
Cli nical c he mistr y  m / 
he mat ol o g y/c oa g ulati o n/  
u ri nal ysis wit h 
micr osc o p y  n/ir o n, 
f olate, vita mi n  B1 2 stat us 
la bs o  
X 
X 
X 
X 
X p   
X p 
X 
Uri ne f or bi o mar kers  q  
 
 
X 
X 
X 
X 
X 

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Assess m e nt  
Scree ni n g 
Peri o d  a   
B aseli ne 
Visit  b   
Tre at me nt Peri o d  
( Visit Sc he d ule) 
U nsc he d ule d 
Visit 
F oll o wi n g 
B T H  
( wit hi n 
4 8  hrs or 
ne xt 
w or ki n g 
d ay)  
Disc o nti n u ati o n 
of St u dy Dr u g  
E n d of 
St u dy 
Assess me nt  
Scree ni n g 
Visit  
( U p t o 
D a y -2 8)  
( D a y 1) 
Wee k 4 a n d 
E ver y 4 w ks u p 
t o W k 9 6 c 
( ± 3 d a ys)  
Wee k 9 6  a n d 
E ver y 8 w ks 
U ntil W k 1 4 4  d   
( ± 6 d a ys)  
He m ol ysis 
M o nit ori n g f or 
at le ast 
3 C o nsec uti ve 
D a ys  e   
 
3 Wee ks 
( ± 3 D a ys) 
After L ast 
D ose of 
St u d y 
Dr u g  
P N H s y m pt o ms 
assess me nt  
X 
X 
X 
X 
X 
X 
X 
Assess me nt of bl o o d 
tra nsf usi o ns 
X 
X 
X 
X 
 
 
X 
Assess A Es, 
c o nc o mita nt 
me dicati o ns  
X 
X 
X 
X 
X 
X 
X 
P N H R B C a n d W B C 
cl o ne size  
X 
X 
X 
X 
 
 
 
F A CI T fati g ue scale  
 
X 
X r 
X  
 
 
 
Q L Q -A A/ P N H  
 
X 
X s 
X  
 
 
 
T S Q M  
 
X 
X t 
X  
 
 
 
P K bl o o d sa m ple  
 
X 
X 
X 
X 
X u   
 
P K uri ne c ollecti o n  v 
 
 
X 
X 
X 
X 
 
P D bl o o d sa m ple 
 
X 
X 
X 
X 
X u 
X 
St u d y dr u g d osi n g  w  
 
 
X x  
 
 
St u d y dr u g 
acc o u nta bilit y/ 
dis pe nsi n g  
 
X 
X 
X 
 
 
X 

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4 8 
A b bre viati o ns: A E  = a d verse e ve nt; BI D  = t wice dail y; B T H = brea kt hr o u g h he m ol ysis; B MI = b o d y mass i n de x; E C G = electr ocar di o gra m; 
F S H  = f ollicle-sti m ulati n g h or m o ne; F A CI T = F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y; I M P = i n vesti gati o nal me dici nal pr o d uct; 
P D  = p har mac o d y na mic; 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; Q L Q -A A/ P N H  = Q ualit y of Life Q uesti o n naire f or P atie nts 
wit h A plastic A ne mia/ P N H ; R B C  = re d bl o o d cell; T S Q M = T reat me nt S atisfacti o n Q uesti o n naire f or M e dicati o n ; W B C = w hite bl o o d cell . 
a Scree ni n g visit is re q uire d f or s u bjects w h o ha ve i nterr u pte d st u d y dr u g f or > 3 0 da ys.  
b T he baseli ne visit s h o ul d be wit hi n 2 8 da ys of t he  scree ni n g visit. F or s u bjects directl y r olli n g o ver fr o m a n ot her B C X 9 9 3 0 st u d y wit h o ut treat me nt 
i nterr u pti o n, t he fi nal o n-treat me nt visit i n t he pri or B C X 9 9 3 0 st u d y will be c o nsi dere d t he baseli ne visit f or t his st u d y. 
c Visits s h o ul d be e ver y 4 wee ks u ntil a s u bject has c o m plete d a t otal of 9 6 wee ks o n treat me nt wit h B C X 9 9 3 0 (ie, wee ks i n t his  st u d y pl us wee ks i n t he pre vi o us 
st u d y). 
d S u bjects will s Cr ele vati o ns will be re q uire d t o c o m plete a d diti o nal assess me nts t o m o nit or f or p ote ntial re nal t o xicit y at t he i n vesti gati o nal site, at a re m o te 
la b orat or y m ore c o n ve nie nt f or t he s u bject, or via a h o me healt h ser vice ( w here per mitte d an d a vaila ble)  as i n dicate d i n Secti o n  1 1. 3. 4. 1  a n d Secti o n 1 3. 9. 5. 3 . 
e M o nit ori n g f or t he o nset of he m ol ysis will be c o n d ucte d after eac h s u bject st o ps B C X 9 9 3 0 treat me nt. De pe n di n g o n t he res ults,  a d diti o nal he m ol ysis testi n g 
ma y c o nti n ue.  
f I nf or me d c o nse nt will be si g ne d at t he scree ni n g visit f or s u bjects re q uiri n g a scree ni n g visit a n d will be si g ne d f or all ot her s u bjects at t he baseli ne visit or fi nal 
o n treat me nt visit i n t he pri or st u d y ( w hic h ser ves as t he s u bject’s baseli ne visit i n t his st u d y).  
g Me dical a n d me dicati o n hist or y s h o ul d i ncl u de vacci nati o n hist or y stat us, assess ris k of e x p os ure, a n d arra n ge f or a n y a p pr o p riate vacci nati o ns t o be 
a d mi nistere d base d o n l ocal rec o m me n dati o ns as well a s i n di vi d ual s u bject c o nsi derati o ns. 
h B MI calc ulati o n a n d hei g ht at scree ni n g; wei g ht is t o be rec or de d at eac h i n -cli nic visit. 
i F u ll p h ysical e xa mi nati o ns will be perf or me d at scree ni n g a n d baseli ne; s y m pt o m-directe d p h ysical e xa mi nati o ns will be perf or me d at all p ost -baseli ne visits.  
j All E C Gs d uri n g t he st u d y will be si n gle assess me nts. E C Gs will be c o n d ucte d e ver y 1 2 wee ks u p t o Wee k 9 6 (ie, Wee ks 1 2, 2 4, 3 6, 4 8, 6 0, 7 2, 8 4, a n d 9 6) 
a n d e ver y 2 4 wee ks t hereafter (ie, Wee ks 1 2 0 a n d 1 4 4) d uri n g t he treat me nt peri o d.  
k F or w o me n of c hil d beari n g p ote ntial, a ser u m pre g na nc y test will be a d mi nistere d at scree ni n g; uri ne pre g na nc y tests will be assesse d at all s u bse q ue nt visits. 
Starti n g at Wee k 1 0 0, w o me n of c hil d beari n g p ote ntial will start perf or mi n g uri ne pre g na nc y tests at h o me e ver y 4 wee ks (i.e., i n bet wee n cli nic visits). T he 
res ults will be rec or de d b y t he site. If t he uri ne pre g na nc y test is p ositi ve, t he s u bject s h o ul d c o ntact t he site i m me diately. 
l F S H will be meas ure d at scree ni n g f or a n y w o ma n p ost -me n o pa usal ≤ 2 years (t his ma y be o mitte d if me n o pa usal stat us was de m o nstrate d wit h ele vate d F S H 
i n t he pri or st u d y). F or w o me n w h o d o n ot u n der g o a scree ni n g visit, F S H ma y be assesse d at baseli ne. I n t his case, t he s u bject m ust ha ve a ne gati ve uri ne 
pre g na nc y test at baseli ne pri or t o recei vi n g st u d y dr u g.  
m  C h olester ol a n d tri gl y ceri des will be meas ure d e ver y 1 2 wee ks u p t o Wee k 9 6 (ie, Wee ks 3 6, 4 8, 6 0, 7 2, 8 4, a n d 9 6) a n d e ver y 2 4 wee ks t hereafter (i e, Wee ks 
1 2 0 a n d 1 4 4).  
n Uri ne micr osc o p y will be perf or me d o n uri ne c ollecte d at i n vesti gati ve site visits (a n d, w here p ossi ble, at re m ote visits w here t he la b has a p pr o priate o n -site 
testi n g ca pa bilit y). Uri ne micr osc o p y s h o ul d be perf or me d usi n g t he site’s l ocal la b orat or y (ass u mi n g a p pr o priate o n-site testi n g ca pa bilit y e xists) i n lie u of t he 
ce ntral la b orat or y. 
o Wee ks 4 8, 9 6, a n d 1 4 4 o nl y.  
p O nl y li mite d he mat ol o g y a n d cli nical c he mistr y para meters m eas ure d as per Secti o n  1 1. 3. 5  a n d Secti o n  1 1. 3. 6 . 
q Uri ne will be c ollecte d at i n vesti gati ve site visits (ie, e xcl u di n g re m ote visits) a n d ali q u ots fr oze n f or p ossi ble f ut ure a n al ysis of uri ne bi o mar kers.  
r C o m plete d at all treat me nt visits t hr o u g h Wee k 9 6 o nl y.  
s E ver y 6 m o nt hs t hr o u g h Wee k 9 6 o nl y (ie, Wee ks 2 4, 4 8, 7 2, a n d 9 6 o nl y).  

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t T h o u g h Wee k 9 6 o nl y (ie, at Wee ks 1 2, 2 4, 4 8, 7 2, a n d 9 6 o nl y).  
u Si n gle P K a n d P D sa m ple c ollecte d 4 8 h o urs after treat me nt disc o nti n uati o n.  
v S p ot uri ne sa m ples will be c ollecte d f or a nal ysis of t he c o nce ntrati o n of B C X 9 9 3 0 a n d meta b olites  at i n vesti gati o nal site visits (ie, e xcl u di n g re m ote visits ). 
w  T he pr ot oc ol -s pecifie d d os i n g re gi me n pri or t o t his a me n d me nt was 5 0 0 m g B C X 9 9 3 0 BI D. U n der t his a me n d me nt, s u bjects will ta ke 4 0 0 m g B C X 9 9 3 0 BI D. 
T he I M P will be s u p plie d b y Bi o Cr yst as 1 0 0, 2 0 0, a n d/ or 2 5 0 m g ta blets t o all o w f or d ose a dj ust me nts if nee de d f or t he safet y ma na ge me nt of t he s u bject.  
x B C X 9 9 3 0 d osi n g s h o ul d c o nti n ue f oll o wi n g B T H.  
 
 

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1 1. 3.  
St u d y Visits  
Writte n i nf or me d c o ns e nt m ust be o btai ne d fr o m eac h s u bject bef ore i nitiati o n of a n y scree ni n g 
( or baseli ne, if n o s cree ni n g visit) assess me nts or pr oce d ures. Eac h s u bject will recei ve a c o p y of 
t he si g ne d a n d date d st u d y-s pecific i nf or me d c o ns e nt f or m (I C F). S u bjects w h o ha ve si g ne d a n 
I C F w h o are i nter este d i n partici pati n g i n t he st u d y will t he n u n der g o assess me nts at a scree ni n g 
visit t o deter mi ne eli gi bilit y (as a p plica ble). Si g ni n g of t he I C F ma y  o cc ur pri or t o t he first 
o n- st u d y visit, w hic h is defi ne d as t he visit w here site-c o n d ucte d pr o ce d ures are first perf or m e d. 
F or s u bjects w h o dir ectl y r oll o ver fr o m a pre vi o us st u d y wit h o ut i nterr u pti o n of d osi n g, t he 
writte n i nf or me d c o ns e nt will be o btai ne d at t he fi nal o n-st u d y visit of t he pri or st u d y. 
1 1. 3. 1.  
Scree ni n g a n d B aseli ne Visit Re q uire me nts  
If s u bjects ha v e i nterr u pt e d treat me nt f or ≥ 3 1 da ys si nce last treat me nt i n t he pri or B C X 9 9 3 0 
st u d y, t he y will nee d t o be scree ne d f or partici p ati o n i n t his st u d y. Eac h s u bject will be 
deter mi ne d as eli gi ble f or t he st u d y base d u p o n scree ni n g e v al uati o ns.  
A baseli ne visit is necess ar y f or s u bjects w h o ha v e ha d a n i nterr u pti o n of treat me nt of 1 t o 
3 0 da ys. T h ose w h o r oll o ver directl y fr o m t he pri or st u d y wit h o ut i nterr u pti o n m ust e ns ure all 
baseli ne assess me nts liste d i n Secti o n  1 1. 3. 3  bel o w are c o m plete d at t he fi nal o n -treat me nt visit 
i n t he pri or st u d y. 
1 1. 3. 2.  
Scree ni n g Visit  
T he I n vesti gat or ( or desi g nee) will c o n d uct t he f oll o wi n g assess me nts at t he scree ni n g visit, 
i ncl u di n g: 
•  Si g ni n g of I C F 
•  Re vie w of i ncl usi o n a n d e xcl usi o n criteria  
•  Me dical a n d me dicati o n hist or y i ncl u di n g c o nfir mati o n of a de q uat e vacci nati o n  
•  C o m plete p h ysical e xa mi nati o n  
•  1 2- lea d E C G  
•  Hei g ht/ wei g ht/ b o d y mass i n de x ( B MI) esti mati o n  
•  Vit al si g ns ( B P, te m perat ure, a n d p ulse rate) 
•  Ser u m pre g na n c y test f or fe male s u bjects of c hil d - beari n g p ote ntial 
•  Bl o o d c ollecti o n f or f ollicle-sti m ulati n g h or m o ne (F S H ) f or a n y w o ma n p ost-
me n o pa usal ≤ 2 years (t his ma y be o mitte d if me n o pa usal stat us was de m o nstrate d 
wit h ele vate d F S H i n t he pri or st u d y) 
•  Bl o o d c ollecti o n f or cli nical c he mistr y, he m at ol o g y, c oa g ulati o n 
•  Bl o o d c ollecti o n f or P N H cl o ne ( R B C a n d W B C)  
•  Uri ne c ollecti o n f or uri nal ysis  

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•  Rec or di n g of A Es a n d c o nc o mita nt me dicati o ns  
•  Disease -s p ecific assess m e nts 
− Assess me nt of P N H s y m pt o ms ( fati g ue, d ys p nea, c hest pai n/ disc o mf ort, diffic ult y 
s wall o wi n g (es o p ha g eal pai n), a b d o mi nal pai n, hea dac h e, erectile d ysf u ncti o n, 
he m o gl o bi n uria, ja u n dic e)  
− Re vie w of bl o o d tra nsf usi o n hist or y 
I n t he cas e of ti me li mitati o ns f or c o n d uct of t he s cree ni n g visit, a site is per mitte d t o perf or m 
scree ni n g assess me nts o v er m ore t ha n o n e scree ni n g visit. 
As part of ge n eral g o o d me dical practice, i n vesti gat ors s h o ul d i ncl u de vacci nati o n hist or y stat us 
as part of t he me di cal hist or y, assess ris k of e x p os ure, a n d arra n g e f or a n y a p pr o priate 
vacci nati o ns t o be a d mi nistere d base d o n l ocal rec o m me n dati o ns as well as i n di vi d ual s u bject 
c o nsi derati o ns.  
Rescree ni n g of i neli gi ble s u bjects, w here t here is a reas o n a ble e x p ectati o n t hat t he s u bject will 
bec o me eli gi ble, will be a p pr o ve d or d e nie d o n a case- b y-cas e basis b y t he S p o ns or Me dical 
M o nit or. Retesti n g of s pecific assess me nts wit h o ut e ntirel y rescree ni n g a s u bject ma y be 
per mitte d.  
A scree ni n g fail ure e C R F pa ge will be c o m plete d f or t h ose s u bjects w h o d o n ot pr ocee d wit h 
st u d y d osi n g, rec or di n g t he reas o n f or scree ni n g fail ure. 
1 1. 3. 3.  
B aseli ne Visit ( D a y 1) 
F or all s u bjects, I nf or me d C o nse nt a n d I ncl usi o n/ E xcl usi o n criteria will be re vie we d t o e ns ure 
c o nti n ue d s u bject eli gi bilit y.  
Bef ore a n y st u d y dr u g is a d mi nistere d t he f oll o wi n g assess me nts will be c o m plete d: 
•  Si g ni n g of I C F (if n o scr ee ni n g visit) 
•  Re vie w  of i ncl usi o n a n d e xcl usi o n criteria a n d pr o hi bite d me dicati o ns 
•  Re vie w of me dical a n d me dicati o n hist or y 
•  A d mi nistrati o n of q uesti o n naires:  
− F A CI T f ati g ue scale  
− Q L Q -A A/ P N H  
− T S Q M  
•  S u bject wei g ht 
•  C o m plete p h ysical e xa mi nati o n  
•  Vital si g ns ( B P, te m perat ure, a n d p ulse rate)  
•  1 2- lea d E C G  
•  Bl o o d c ollecti o n f or cli nical c he mistr y, he m at ol o g y, a n d c oa g ulati o n 

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•  Bl o o d sa m ple f or P N H cl o ne ( R B C a n d W B C) 
•  Uri ne pre g n a nc y test f or fe male s u bjects of c hil d - beari n g p ote ntial. A ne g ati ve uri ne 
pre g na nc y res ult m ust be rec or d e d i n or der f or t he s u bject t o recei ve st u d y dr u g.  
•  Uri ne c ollecti o n f or uri nal ysis  wit h micr osc o p y  
•  P K bl o o d sa m ple  
•  P D bl o o d sa m ple 
•  Re vie w of c o n c o mita nt me dicati o ns a n d A Es 
•  Disease -s p ecific assess m e nts 
− Assess me nt of P N H s y m pt o ms ( fati g ue, d ys p nea, c hest pai n/ disc o mf ort, diffic ult y 
s wall o wi n g (es o p ha g eal pai n), a b d o mi nal pai n, hea dac h e, erectile d ysf u ncti o n, 
he m o gl o bi n uria, ja u n dice ) 
− Re vie w of bl o o d tra nsf usi o ns 
•  St u d y dr u g dis pe nsi n g 
W here p ossi ble, t he q u esti o n naires s h o ul d be c o m plete d b y t he s u bje ct pri or t o ot her assess me nts 
(e xce pt si g ni n g of t he I C F) t o pre v e nt i nfl ue nci n g s u bject perce pti o ns. 
1 1. 3. 4.  
O n -st u d y Visits ( Wee k 4 a n d e ver y 4 wee ks u p t o Wee k 9 6 ; Wee k 9 6 a n d e ver y 
8 wee ks t o Wee k 1 4 4) 
S u bjects will ret ur n t o t he cli nic d uri n g Wee k 4 ( St u d y Da y 2 9 ± 3 da ys) a n d e ver y 4 w ee ks u p t o 
Wee k 9 6 ( St u d y D a y 6 7 3, ± 3 da ys ). Visits s h o ul d be e ver y 4 wee ks u ntil a s u bject has 
c o m plete d a t otal of 9 6 w ee ks o n treat me nt wit h B C X 9 9 3 0 (ie, wee ks i n t his st u d y pl us wee ks i n 
t he pre vi o us st u d y). Starti n g at Wee k  9 6 ( St u d y D a y 6 7 3, ± 3 da ys), s u bjects will ret ur n t o t he 
cli nic e ver y 8 w ee ks t o Wee k 1 4 4 ( St u d y D a y 1 0 0 9, ± 6 da ys ).  
S u bjects d o n ot nee d t o wit h h ol d a n y d oses o n cli nic da ys or ta ke a d ose i n t he cli nic, u nless t he 
cli nic visit falls d uri n g t he s u bject’s n or mal ti me of d osi n g.  
T he f oll o wi n g assess me nts will be perf or me d: 
•  A d mi nistrati o n of q uesti o n naires. W h ere p ossi ble, t he q uesti o n naires s h o ul d be 
c o m plete d b y t he s u bject pri or t o ot her assess me nts: 
− F A CI T f ati g ue scale at eac h visit  t hr o u g h Wee k 9 6 o nl y 
− T S Q M q uesti o n naire at Wee ks 1 2, 2 4, 4 8, 7 2, a n d 9 6 o nl y 
− Q L Q -A A/ P N H at Wee ks 2 4 , 4 8, 7 2, a n d 9 6 o nl y 
•  Tar gete d p h ysical e xa mi nati o n  
•  S u bject wei g ht 
•  Vital Si g ns ( B P, te m perat ure, a n d p ulse rate) 

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•  1 2- lea d E C G e v ery 1 2 w ee ks u p t o Wee k 9 6 (ie, Wee ks 1 2, 2 4, 3 6, 4 8, 6 0, 7 2, 8 4, 
a n d 9 6) a n d e ver y 2 4 w ee ks t hereafter (ie, Wee ks 1 2 0 a n d 1 4 4)  
•  Bl o o d c ollecti o n f or cli nical c he mistr y, he m at ol o g y, c oa g ulati o n, a n d ir o n, f olate, B1 2 
stat us la bs (ir o n, f olate, vita mi n B 1 2 stat us la bs at Wee ks 4 8 , 9 6, a n d 1 4 4 o nl y)  
•  Bl o o d sa m ple f or P N H cl o ne ( R B C a n d W B C) 
•  P K plas ma sa m ple  
•  P K uri ne c ollecti o n   
•  P D bl o o d sa m ple 
•  Uri ne c ollecti o n f or uri nal ysis  wit h micr osc o p y a n d uri ne pre g n a nc y test f or fe male 
s u bjects of c hil d-beari n g p ote ntial  
•  Uri ne c ollecti o n f or bi o mar ker t esti n g  
•  Re vie w of c o n c o mita nt me dicati o ns a n d A Es 
•  Disease -s p ecific assess m e nts 
− Assess me nt of P N H s y m pt o ms ( fati g ue, d ys p nea, c hest pai n/ disc o mf ort, diffic ult y 
s wall o wi n g (es o p ha g eal pai n), a b d o mi nal pai n, hea dac h e, erectile d ysf u ncti o n, 
he m o gl o bi n uria, ja u n dice ) 
− Re vie w of bl o o d tra nsf usi o ns 
•  St u d y dr u g acc o u nta bilit y a n d st u d y dr u g dis pe nsi n g ( w here necessar y) 
1 1. 3. 4. 1.  S afet y  Assess m e nts  f or Re n al E ve nts 
S u bjects wit h s Cr ele vati o ns  as descri be d i n Secti o n  1 3. 9. 5. 3  will be re q uire d t o c o m plete 
a d diti o nal assess me nts  t o m o nit or f or p ote ntial re n al t o xicit y at t he i n vesti gati o nal site , at a 
re m ote la b or at or y m ore c o n ve nie nt f or t he s u bject, or via a h o me healt h ser vice. T he mi ni m u m 
pr oce d ur es t o be c o m plet e d at eac h assess me nt will de pe n d o n w het her t he s u bject is assesse d at 
t he i n vesti gati ve site or r e m otel y.  
F or s u bjects assesse d at t he i n vesti g ati o nal site:  
•  Re vie w/rec or d A Es, c o n c o mita nt me dicati o n use, a n d bl o o d tra nsf usi o ns 
•  Vital si g ns (resti n g bl o o d press ure, p ulse rate, a n d te m perat ure) 
•  Bl o o d c ollecti o n f or cli nical la b orat or y e val uati o ns 
-  Cli nical c he mistr y  
•  Bl o o d c ollecti o n f or P K 
•  Uri ne c oll ecti o n f or cli nical la b orat or y e val uati o ns:  
-  Uri nal ysis i ncl u di n g micr osc o p y 
-  Uri ne c ollecti o n f or bi o mar ker t esti n g  

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•  Uri ne c ollecti o n f or P K  
F or s u bjects assesse d r e m otel y:  
•  Bl o o d c ollecti o n f or cli nical la b orat or y e val uati o ns: 
-  Cli nical c he mistr y (t o i ncl u de at a mi ni m u m: s Cr, e G F R, bl o o d urea nitr o ge n, 
A L T, A S T, A L P, a n d bilir u bi n [t otal a n d direct]) 
•  Uri ne c ollecti o n f or cli nical la b orat or y e val uati o ns:  
-  Uri nal ysis (t o i ncl u de at a mi ni m u m s pecific gra vit y, p H, pr otei n, a n d bl o o d) 
-  Uri ne micr osc o p y ( o nl y if t he facilit y is dee me d s ufficie ntl y q ualifie d t o perf or m 
t his a nal ysis) 
-  Uri ne al b u mi n t o creati ni ne rati o ( u A C R)  
1 1. 3. 5.  
He m ol ysis M o nit ori n g Visits  
F oll o wi n g disc o nti n uati o n of st u d y dr u g, eit her f oll o wi n g c o m pleti o n of t he treat me nt peri o d or 
o n pre mat ure disc o nti n uati o n, s u bjects will ret ur n t o t he cli nic f or a mi ni m u m of 3 c o nsec uti ve 
da ys t o m o nit or f or t he o nset of he m ol ysis. T he f oll o wi n g assess me nts will be perf or me d:  
•  Tar gete d p h ysical e xa mi nati o n  
•  Vital si g ns ( B P, te m perat ure, a n d p ulse rate) 
•  Bl o o d c ollecti o n f or cli nical c he mistr y a n d h e mat ol o g y 
•  Re vie w of P N H s y m pt o ms 
•  Re vie w of c o n c o mita nt me dicati o ns a n d A Es 
•  A si n gle bl o o d sa m ple f or P K a n d P D assess me nts will be c ollecte d 4 8 h o urs after 
treat me nt disc o nti n uati o n 
F oll o wi n g t he 3 da ys of m o nit ori n g, if re q uire d, s u bjects ma y c o nti n ue t o be assesse d e ver y 
2 da ys t hereafter u ntil t he s u bject has sta bilize d t o a ne w he m o gl o bi n baseli ne ( See 
Secti o n  1 3. 7 ). 
1 1. 3. 6.  
U nsc he d ule d Visit f or Bre a kt hr o u g h He m ol ysis  
If s u bjects atte n d a n u nsc he d ule d visit t o assess B T H ( See Secti o n 1 3. 9. 5. 5 ), t he f oll o wi n g 
para meters s h o ul d be ass esse d:  
•  Tar gete d p h ysical e xa mi nati o n 
•  Vital si g ns ( B P, te m perat ure, a n d p ulse rate)  
•  Re vie w of P N H s y m pt o ms  
•  Re vie w of c o n c o mita nt me dicati o ns a n d A Es 
•  Bl o o d c ollecti o n f or he m at ol o g y a n d cli nical c he mistr y  
•  P K plas ma sa m ple  

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•  Uri ne c ollecti o n f or bi o mar ker t esti n g  
•  P K uri ne c ollecti o n  
•  P D bl o o d sa m ple 
1 1. 3. 7.  
E n d of St u d y Visit  
S u bjects w h o per ma ne ntl y disc o nti n ue treat me nt will ret ur n t o t he cli nic f or t he he m ol ysis 
m o nit ori n g visits detaile d i n Secti o n  1 1. 3. 5 . S u bse q ue ntl y t he y will ret ur n t o t he cli nic 3 wee ks 
( 2 1 ± 3 da ys) after t he d ate of t heir last d ose of B C X 9 9 3 0 f or t heir e n d- of-st u d y assess me nts.  
T he f oll o wi n g assess me nts will be perf or me d at t he e n d of st u d y visit: 
•  S u bject wei g ht 
•  Tar gete d p h ysical e xa mi nati o n  
•  Vital si g ns ( B P, te m perat ure, a n d p ulse rate) 
•  1 2- lea d E C G 
•  Bl o o d c ollecti o n f or cli nical c he mistr y, he m at ol o g y, c oa g ulati o n 
•  Uri ne c ollecti o n f or uri nal ysis  wit h micr osc o p y, uri ne pre g na n c y test f or fe male 
s u bjects of c hil d beari n g p ote ntial 
•  Uri ne c ollecti o n f or bi o mar ker t esti n g  
•  Disease -s p ecific assess m e nts: 
− Assess me nt of P N H s y m pt o ms ( fati g ue, d ys p nea, c hest pai n/ disc o mf ort, diffic ult y 
s wall o wi n g (es o p ha g eal pai n), a b d o mi nal pai n, hea dac h e, erectile d ysf u ncti o n, 
he m o gl o bi n uria, ja u n dice ) 
− Re vie w of bl o o d tra nsf usi o ns 
•  P D bl o o d sa m ple 
•  Re vie w of c o n c o mita nt me dicati o ns a n d A Es 
•  St u d y dr u g acc o u nta bilit y (f or earl y wit h dra wal visit o nl y) 
If a n A E is o n g oi n g at t h e e n d- of-st u d y visit, a d diti o nal cli nic visit(s) or tele p h o ne c o ntact(s) 
ma y be warra nte d (see S ecti o n  1 3. 9. 3 ). 
1 1. 4.  
C o ntr ace pti o n Re q uire me nts  
1 1. 4. 1.  
Fe m ale S u bjects a n d Fe m ale P art ners of M ale S u bjects  
A w o ma n of c hil d beari n g p ote ntial ( W O C B P) is defi ne d as a n o n me n o pa usal fe male w h o h as n ot 
ha d a h ysterect o m y, bilateral sal pi n gect o m y or bilateral o o p h orect o m y.  
W O C B P m ust a gree t o use a hi g hl y eff ecti ve c o ntrace pti ve m et h o d t hr o u g h o ut t he st u d y a n d f or 
a d urati o n of 3 0 da ys after t he last d ose of st u d y dr u g. T he f oll o wi n g met h o ds are acce pta ble:  

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•  S ur gical steri lizati o n (ie, h ysterect o m y, bilateral sal pi n gect o m y or bilateral 
o o p h orect o m y)  
•  Vasect o m y of t he s ole m ale part ner, a n d t he v asect o mize d part ner h as recei ve d 
me dical assess me nt of s ur gical s uccess  
•  Place me nt of a n i ntr a uteri ne de vice or i ntra uteri ne s yste m  
•  H or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n (i m pla nta ble, 
i njecta ble, patc h or oral c o ntrace pti ves) 
Tr ue a bsti ne nce is acce pt a ble w he n it is i n li ne wit h t he s u bject’s preferre d a n d us ual lifest yle. If 
a s u bject is us uall y n ot se x uall y acti ve b ut bec o mes acti ve, s he, wit h her p art ner, m ust meet t he 
re q uire me nts liste d a b o v e. 
A w o ma n of n o nc hil d beari n g p ote ntial is defi ne d as p ost me n o pa usal ( wit h o ut me nses f or 
≥ 1 2 m o nt hs [ wit h o ut a n alter nati ve me dical ca us e] wit h f ollicle -sti m ulati n g h orm o ne ( F S H) 
> 4 0 mI U/ m L, or w h o ha ve ha d a h ysterect o m y, bilateral sal pi n gect o m y or bilateral 
o o p h orect o m y. 
Fe male p artici pa nts m ust a bstai n fr o m e g g d o nati o n f or a peri o d of u p t o 9 0 da ys after l ast d ose 
of st u d y dr u g.  
1 1. 4. 2.  
M ale S u bjects  
Hi g hl y effecti ve c o ntrace pti ve met h o ds f or male s u bjects are:   
•  S ur gical sterilizati o n (ie, vasect o m y t hat has bee n c o nfir me d t o be s uccessf ul), or 
h ysterect o m y, bilater al sal pi n gect o m y or bilateral o o p h orect o m y of a fe male part ner 
•  Part ner’s use of a n i ntra uteri ne de vice or i ntra uteri ne s yste m 
•  Part ner’s use of h or m o nal c o ntrace pti o n ass o ciate d wit h i n hi biti o n of o v ulati o n ( oral, 
i njecta ble, i m pla nta ble, or patc h) 
Tr ue a bsti ne nce is acce pt a ble w he n it is i n li ne wit h t he s u bject’s preferre d a n d us ual lif est yle. If 
a s u bject is us uall y n ot se x uall y acti ve b ut bec o mes acti ve, he, wit h his fe m ale part ner, m ust 
meet t he re q uir e me nts liste d a b o ve.  
Male s u bjects m ust a bstai n fr o m s per m d o nati o n f or a peri o d of 9 0 da ys after last d ose of st u d y 
dr u g a n d if t he s u bject h as a fe male p art ner, he m ust a gree t o use a barrier met h o d of 
c o ntrace pti o n f or at least 9 0 da ys after l ast d ose of st u d y dr u g.  
1 2.  
A S S E S S M E N T O F E F FI C A C Y  
1 2. 1.  
Cli nic al Res p o nse Assess me nt  
T he f oll o wi n g cli nical para meters will be assesse d at baseli ne a n d ea c h st u d y visit: 
•  Re d or blac k ( c ola) c ol or e d uri ne 
•  D ys p nea 

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•  Diffic ult y s wall o wi n g (es o p ha geal pai n) 
•  A b d o mi nal pai n 
•  Erectile d ysf u n cti o n  
•  Fati g ue 
•  Hea dac he  
•  Ja u n dice 
•  C hest pai n/ disc o mf ort  
1 2. 2.  
Bl o o d Tr a nsf usi o ns Re vie w  
At scree ni n g, t he n u m b er of bl o o d tra nsf usi o ns si nce t he e n d of t he pri or tri al will be rec or de d. 
D uri n g t he trial, all bl o o d tra nsf usi o ns will be d oc u me nte d, i ncl u di n g t he n u m ber of u nits a n d t he 
bl o o d pr o d uct a d mi nistere d.    
1 2. 3.  
P h ar m ac o ki netic Bl o o d S a m ple C ollecti o n  
A si n gle bl o o d sa m ple f or P K a nal yses (ie, “s pars e sa m pli n g” t o s u p p ort p o p ulati o n P K a n d 
P K/ P D m o deli n g) will be dra w n fr o m all s u bjects at baseli ne a n d e ver y st u d y visit t o t he 
i n vesti gati ve site t hereaft er, at a n y B T H visit t o t he i n vesti gati ve site, a n d 4 8 h o urs after 
treat me nt disc o nti n uati o n at t he he m ol ysis m o nit ori n g visit.  
S parse P K bl o o d sa m ples ma y be dra w n at a n y ti me wit h o ut re gar d t o B C X 9 9 3 0 d osi n g. 
H o we ver, w her e f easi ble, i n vesti gat ors are re q uest e d t o var y t he ti mi n g of visits t o facilitate P K 
sa m pli n g at differe nt ti mes relati ve t o t he pre vi o us d ose. It is preferre d t h at t he c u m ulati ve s parse 
P K data f or eac h s u bject will c o ntai n sa m ples dra w n wit hi n eac h of t he f oll o wi n g i nter vals (all 
relati ve t o t he pre vi o us d ose f or BI D d osi n g): 0. 5 t o 2 h o urs, 2 t o 5 h o urs, a n d 1 0 t o 1 2 h o urs 
p ost d ose. 
S u bjects d o n ot nee d t o wit h h ol d a n y st u d y dr u g/ B C X 9 9 3 0 d oses o n cli nic da ys or ta k e a d ose i n 
t he cli nic, u nless t he cli nic visit falls d uri n g t he s u bject’s n or mal ti me of d osi n g.  
F or eac h sa m ple c ollecte d, t he act ual date  a n d ti me of sa m ple c ollecti o n, t he act ual d ate a n d ti me 
of t he last t w o B C X 9 9 3 0 d oses ta ke n pri or t o t he bl o o d dra w ( w h ere a p plica ble), a n d w het her 
t h ose d oses wer e ta ke n wit h or wit h o ut f o o d will be rec or de d i n t he e C R F.  
Plas ma sa m ples f or deter mi nati o n of B C X 9 9 3 0 will be a nal yze d usi n g vali d ate d li q ui d 
c hr o mat o gra p h y- mass s p ectr o metr y assa ys. T he pl as ma c o nce ntrati o n of B C X 9 9 3 0 meta b olites 
ma y als o be a nal y ze d usi n g t hese sa m ples.  
A n y u n use d p orti o n of t h e plas ma sa m ples c ollecte d f or P K p ur p oses will be retai ne d f or 
p ossi ble re peat or f ut ure P K a nal ysis of B C X 9 9 3 0 a n d/ or i de ntifie d meta b olites. S u bjects ca n 
re q uest f or t h ese sa m ples t o be destr o ye d at t he e n d of t he st u d y, b ut a n y data pre vi o usl y 
c ollecte d will be r etai ne d.  
I nstr u cti o ns f or c ollecti o n, pr ocessi n g, st ora g e, a n d s hi p me nt of P K sa m ples will be pr o vi de d t o 
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1 2. 4.  
P h ar m ac o d y n a mic Bl o o d S a m ple C ollecti o n  
Ve n o us bl o o d sa m ples will be wit h dra w n via a n i n d welli n g ca n n ula or b y ve ni p u nct ure at 
Baseli ne a n d eac h  s u bse q ue nt visit d uri n g t he treat me nt peri o d. W here feasi ble, a n d as 
a p plica ble, bl o o d sa m ples f or P D a nal yses s h o ul d be c ollecte d at t he sa me ti me as s parse P K 
sa m ples. A d diti o nal details of sa m ple t u bes a n d pr ocessi n g will be c o ntai ne d i n t he La b orat or y 
Ma n ual.  
Bl o o d sa m ples will be c ollecte d f or plas ma Fact or B b, P N H cl o ne size ( R B C a n d gra n ul oc yte), 
A P acti vit y as assesse d via A P W iesla b, a n d a d diti o nal e x pl orat or y ass a ys at baseli ne a n d 
s u bse q ue nt visits. A n ali q u ot of ser u m a n d plas m a will be retai ne d f or p ot e ntial e x pl orat or y P D 
assa ys t o el uci date t he P D pr o perties of B C X 9 9 3 0. 
F or t h ose s u bjects w h o disc o nti n ue st u d y dr u g t hera p y, a sa m ple of bl o o d f or P D a nal ysis ( w hic h 
ma y i ncl u de Fact or B b, P N H cl o ne size ( R B C a n d gra n ul oc yte), A P acti vit y a n d e x pl orat or y 
assa ys) will be c ollecte d 4 8 h o urs after t h e last d ose of B C X 9 9 3 0. T his ma y be s plit i nt o m ulti ple 
sa m ples, if nee de d. 
F or s u bjects b ei n g e val uate d f or B T H, a si n gle bl o o d sa m ple f or P D a n al ysis ( w hic h ma y i ncl u de 
Fact or B b, P N H cl o ne si ze ( R B C a n d gra n ul oc yt e), A P acti vit y, a n d e x pl orat or y assa ys) will be 
c ollecte d.  
1 2. 5.  
Uri ne C ollecti o n f or Me as ure me nt of P are nt -Met a b olite 
C o nce ntr ati o n  
S p ot uri ne sa m ples will be c o llecte d f or a n al ysis of t he c o nce ntrati o n of B C X 9 9 3 0 a n d 
meta b olites.  
Uri ne sa m ples f or deter mi nati o n of B C X 9 9 3 0 will be a nal yze d usi n g vali dat e d li q ui d 
c hr o mat o gra p h y- mass s p ectr o metr y assa ys. T he c o nce ntrati o n of B C X 9 9 3 0 meta b olites ma y als o 
be a nal yze d usi n g t hese s a m ples. 
F or eac h sa m ple c ollecte d, t he act ual date a n d ti me of sa m ple c ollecti o n, t he act ual d ate a n d ti me 
of t he last t w o B C X 9 9 3 0 d oses ta ke n pri or t o t he uri ne c ollecti o n ( w h ere a p plica ble), a n d 
w het her t h ose d os es wer e ta ke n wit h or wit h o ut f o o d will be rec or d e d i n t he e C R F. 
1 2. 6.  
P atie nt Re p orte d O utc o mes  
T he f oll o wi n g q uesti o n naires will be c o m plete d b y st u d y s u bjects t hr o u g h Wee k 9 6 o nl y: 
T he Q L Q -A A/ P N H will be c o m plete d at Bas eli ne a n d at t he Wee k  2 4, 4 8, 7 2, a n d 9 6 visits  o nl y.  
T he T S Q M q uesti o n naire will be c o m plete d at Bas eli ne a n d at t he Wee k 1 2, 2 4, 4 8, 7 2, a n d 9 6 
visits  o nl y. 
T he F A CI T fati g ue scale will be c o m plete d at Bas eli ne a n d s u bse q ue nt treat me nt visits  t hr o u g h 
Wee k 9 6 o nl y. 
Eac h q uesti o n nair e will be tra nslate d i nt o t he l ocal la n g ua ge as re q uire d. F or all 
s u bject-c o m plete d f or ms, cli nic staff s h o ul d e ns ure t he s u bject rea ds t he i nstr ucti o ns a n d 
c o m pletes t he q uesti o n naire i n f ull. T he I n vesti gat or or cli nic staff is n ot per mitte d t o pr o vi de 

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a n y assista nce, i nter pretati o n or clarificati o n of i nf or mati o n or q uesti o ns c o ntai ne d i n t he 
q uesti o n naires. W here p ossi ble, t he q uesti o n naires s h o ul d be c o m plete d b y t he s u bject pri or t o 
ot her assess me nts f or t h at visit t o pre ve nt assess me nts fr o m i nfl ue nci n g s u bject perce pti o ns. 
1 3.  
A S S E S S M E N T O F  S A F E T Y  
1 3. 1.  
De m o gr a p hic/ Me dic al Hist or y  
De m o gra p hic i nf or mati o n, i ncl u di n g year of birt h, se x, race a n d et h nicit y, a n d me dical a n d 
me dicati o n hist or y will be ca pt ur e d f or eac h s u bj ect partici pati n g i n t he st u d y at t he Scree ni n g 
visit, or Baseli ne visit if Scre e ni n g visit is o mitte d. Me dical hist or y, me dicati o n re vie w, a n d 
re vie w of i n cl usi o n a n d e xcl usi o n criteria a n d pr o hi bite d me dicati o ns will als o be rec hec k e d as 
o utli ne d i n Secti o n 1 1 .  
1 3. 2.  
Vit al Si g ns  
Vital si g ns c o m prise d of te m perat ur e, B P, a n d p ulse rate will be ta k e n per t he sc he d ule of 
assess me nts s pecifie d i n  Ta ble 4 . 
Vital si g n meas ure me nts s h o ul d be o btai ne d after resti n g at least 5 mi n utes i n a q uiet r o o m at a 
c o mf orta ble te m p erat ur e, wit h t he s u bject's ar m u n c o nstrai ne d b y cl ot hi n g or ot her materi al. B P 
meas ure me nts will be o btai ne d wit h t he a p pr o pri ate c uff size, wit h t he s u bject’s ar m s u p p orte d at 
t he le vel of t he heart, w hile t he s u bject is resti n g i n a se mi-s u pi ne p ositi o n. It is acce pta ble t o 
o btai n a p ulse rate fr o m t he B P or E C G mac hi ne. 
1 3. 3.  
Wei g ht, Hei g ht, a n d B o d y M ass I n de x  
Hei g ht a n d wei g ht s h o ul d be deter mi ne d as o utli ne d i n Ta ble 4  a n d Secti o n 1 1 . B ot h hei g ht a n d 
wei g ht are meas ure d at s cree ni n g. F or all s u bse q ue nt visits, o nl y wei g ht is meas ure d. 
F or deter mi nati o n of hei g ht a n d wei g ht, s u bjects s h o ul d be dresse d, wit h o ut s h oes. B MI s h o ul d 
be calc ul ate d usi n g t he f oll o wi n g f or m ula: 
B MI = wei g ht ( k g)/ hei g ht ( m) 2 
1 3. 4.  
P h ysic al E x a mi n ati o n  
S u bjects will u n der g o a p h ysical e xa mi nati o n at per t he sc he d ule of assess m e nts s pecifie d i n 
Ta ble 4 . A f ull p h ysical e xa mi nati o n s h o ul d be c o n d ucte d at Scree ni n g (if a p plica ble) a n d 
baseli ne. All s u bse q ue nt p h ysical e xa mi nati o ns ma y be tar g ete d (ie, s y m pt o m- dri ve n). 
Ge nit o uri nar y a n d breast e xa mi nati o ns ma y be o mitte d w he n n ot re q uire d b y n or mal site 
practice. S u bjects recei vi n g i m m u n os u p pressi ve t hera p y s h o ul d be m o nit ore d f or si g ns a n d 
s y m pt o ms of i nfecti o n. 
1 3. 5.  
Electr oc ar di o gr a m  
A sta n dar d be dsi d e 1 2- lea d E C G mac hi ne or t ele metr y s yste m t hat calc ulates H R a n d meas ures 
t he P R, Q R S, Q T, R R, a n d c orrecte d Q T ( Q Tc F) i nter vals will be utilize d. T wel ve-lea d E C Gs 

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will be meas ure d after t h e s u bject has bee n i n t he s u pi ne p ositi o n f or a mi ni m u m of 1 0 mi n utes 
as detaile d i n  Ta ble 4  a n d Secti o n  1 1 . All E C Gs will be si n gle assess me nts.  
Q ualifie d site pers o n n el s h o ul d re vie w t he E C Gs a n d a ut o mate d fi n di n gs i n real ti me f or gr oss 
a b n or malities a n d i nter val meas ure me nts of c o ncer n (a bs ol ute rea di n gs a n d c ha n ge fr o m 
baseli ne). A n E C G s h o ul d be re peate d after a n a d diti o nal 1 0- mi n ute rest i n a s u pi ne p ositi o n i n 
t he e ve nt of a c ha n g e fr o m baseli ne i n Q Tc F > 6 0 msec or a Q T c F i nter val >  5 0 0 msec.  
F or all E C Gs, t he cli nical i nter pretati o n of t he E C G s h o ul d be rec or de d (i n cl u di n g 
re-a dj u dicati o n of a n y a ut o matic fi n di n gs) directl y o n a har d c o p y of t he E C Gs. C o pies of t he 
E C Gs ma y be re q u este d b y t he S p o ns or. 
1 3. 6.  
L a b or at or y Assess me nts  
Bl o o d a n d uri ne sa m ples will be o btai ne d per t he s c he d ule of assess me nts i n Ta ble 4 . A list of 
t he la b orat or y p ara met ers meas ure d is prese nte d i n Ta ble  5.  
Sa m ples will be c ollecte d i nt o a p pr o priate t u bes, as s pecifie d b y t he cli nical la b orat or y. All 
la b orat or y sa m ples, wit h t he e xce pti o n of h e m ol ysis testi n g at st u d y dr u g disc o nti n uati o n, will be 
a nal yze d b y a ce ntral la b orat or y. L ocal la b orat ori es ma y be use d i n place of t he ce ntral 
la b orat or y at t he i n v esti gat or’s discreti o n f or l o gistical reas o ns (e g, s uc h as dela ys i n tra ns p ort 
d ue t o C O VI D- 1 9), t h e y ma y als o be utilize d f or a nal ysis of sa m ples c ollecte d f or assess me nt of 
p ossi ble A Es. Uri ne micr osc o p y f or sa m ples c ollecte d at t he i n vesti gati ve site will be perf or me d 
at t he site’s l ocal la b or at or y, w her e a p pr o priate o n -site testi n g ca pa bilit y e xists (see 
Secti o n  1 3. 6. 1 ). T he a d diti o nal re nal a n d he p atic s afet y assess m e nts ma y be perf or me d at t he 
i n vesti gati ve site or re m otel y at a l ocati o n m ore c o n ve nie nt f or t he s u bject or via a h o me healt h 
ser vice. If t he use of a h o me healt h ser vice is per mitte d, testi n g ma y be perf or me d at t he ce ntral 
la b orat or y or at a r e m ote la b orat or y. T he res ults fr o m la b orat or y testi n g perf or me d at a l o cal or 
re m ote la b or at or y m ust be pr o vi de d t o t he i n vesti g ati onal site. Refere nce ra n ges f or eac h l ocal 
la b orat or y will be pr o vi d e d t o t he S p o ns or a n d i ncl u de d i n data listi n gs. F or o ut- of-ra n g e 
la b orat or y fi n di n gs, t he i nter pretati o n of cli nicall y si g nifica nt or n ot cli nicall y si g nifica nt s h o ul d 
be de n ote d i n t he s o ur ce rec or ds. Cli nicall y si g nifica nt la b orat or y fi n di n gs i n t he o pi ni o n of t he 
I n v esti gat or s h o ul d be rec or de d as a n A E a n d ha n dle d as descri b e d i n Secti o n 1 3. 9 .  

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T a ble 5:  
Cli nic al L a b or at or y E v al u ati o ns 
C he mistr y  
C o a g ul ati o n  
•  
Al b u mi n  
•  
Al kali ne p h os p hatase ( A L P)  
•  
Ala ni ne a mi n otra nsferase ( A L T)  
•  
As partate a mi n otra nsfe rase ( A S T) 
•  
Bilir u bi n (t otal a n d direct)  
•  
Bl o o d gl uc ose  
•  
Bl o o d urea nitr o ge n ( B U N)  
•  
Calci u m  
•  
S o di u m  
•  
P otassi u m  
•  
C hl ori de  
•  
Creati ne ki nase  
•  
Creati ni ne  (s Cr) a n d esti mate d gl o mer ular 
filtrati o n rate (e G F R) 
•  
Lactate de h y dr o ge nase ( L D H)  
•  
T otal ser u m pr otei n  
•  
Uric aci d  
•  
A m ylase  
•  
Li pase (refle x test if a m ylase ele vate d)  
•  
C h olester ol (t otal, hi g h - a n d l o w-de nsit y 
li p o pr otei n) 
•  
Ma g nesi u m   
•  
Tri gl yceri des  
•  
Pr ot hr o m bi n ti me ( P T) a n d i nter nati o nal 
n or malize d rati o (I N R)  
•  
Acti vate d partial t hr o m b o plasti n ti me (a P T T)  
•  
T hr o m bi n ti me  
•  
D- di mer  
•  
Pr ot hr o m bi n fra g me nt 1 + 2  
Pre g n a nc y Test  
Ser u m (scree ni n g) a n d uri ne ( ot her sc he d ule d visits) 
β H C G f or w o me n of c hil d beari n g p ote ntial o nl y  
He m at ol o g y  
•  
He m o gl o bi n  
•  
He mat ocrit  
•  
Er yt hr oc ytes ( R B C)  
•  
Mea n c or p usc ular he m o gl o bi n ( M C H)  
•  
Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n 
( M C H C) 
•  
Mea n c or p usc ular v ol u me ( M C V)  
•  
W hite bl o o d cell c o u nt, wit h differe ntial 
(l y m p h oc ytes, m o n oc ytes, ne utr o p hils, 
e osi n o p hils, a n d bas o p hils)  
•  
A bs ol ute retic ul oc yte c o u nt  
•  
Platelets  
•  
P N H R B C cl o ne  
•  
P N H W B C cl o ne  
Uri n al ysis  wit h micr osc o p y  
•  
S pecific gra vit y  
•  
Bl o o d  
•  
Bilir u bi n  
•  
Gl uc ose  
•  
Le u k oc ytes  
•  
Ket o nes  
•  
Nitrites  
•  
p H  
•  
Pr otei n  
•  
Ur o bili n o ge n  
•  
Micr oal b u mi n t o creati ni ne rati o  
 
A d diti o n al Tests  
•  
F S H f or w o me n wit h n o me nses f or ≥ 1 2 
m o nt hs  
•  
C 3 a n d C 4 (at baseli ne)  
•  
Ha pt o gl o bi n  
•  
C- reacti ve pr otei n 
•  
C ystati n C (i n bl o o d)  
He m ol ysis m o nit ori n g at disc o nti n u ati o n of st u d y 
dr u g or f oll o wi n g B T H  
Ir o n, F ol ate, a n d Vit a mi n B 1 2  
•  
Lactate de h y dr o ge nase ( L D H)  
•  
Ser u m creati ni ne  
•  
Bl o o d urea nitr o ge n ( B U N)  
•  
R B C  
•  
He m o gl o bi n  
•  
C o m plete bl o o d c o u nt  
•  
P K a n d P D bl o o d sa m ples  
•  
Ferriti n  
•  
F olate  
•  
He pci di n  
•  
Ir o n 
•  
T otal ir o n bi n di n g ca pacit y  
•  
Tra nsferri n  
•  
Vita mi n B 1 2 
 

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Uri ne Bi o m ar k ers   
•  
β -2 -micr o gl o b uli n  
•  
C ystati n C (i n uri ne)  
•  
Ki d ne y i nj ur y m olec ule 1 ( KI M -1)  
•  
Li ver -t y pe fatt y aci d -bi n di n g pr otei n ( L -F A B P)  
•  
Uri ne al b u mi n t o creati ni ne rati o ( u A C R)  
•  
Uri ne ne utr o p hil gelati nase -ass ociate d li p ocali n ( u N G A L)  
•  
Uri ne ali q u ots f or st ora ge  ( uri ne will be ali q u ote d, fr oze n a n d se nt t o t he ce ntral la b orat or y f or p ossi ble 
f ut ure a nal ysis of uri ne bi o mar kers) 
1 3. 6. 1.  
Uri ne C ollecti o ns f or U ri n al ysis, Micr osc o p y, a n d Bi o m ar ker Testi n g  
I n v esti gat ors s h o ul d e m p hasize t o staff a n d t he s u bjects t he i m p orta nce of c ollecti n g fres h, 
hi g h- q ualit y uri ne s peci me ns (clea n -cat c h, mi d- v oi d, etc.) a n d e ns uri n g a p pr o priate ha n dli n g a n d 
pr o m pt a nal ysis of t he sa m ples f or uri nal ysis. Uri ne micr osc o p y will be perf or me d o n all uri n e 
sa m ples c ollecte d f or uri nal ysis at i n vesti gati ve site visits. Beca use of t he p ote ntial f or e xte n d e d 
tra nsit ti mes t o t he ce ntral la b orat or y, w here p ossi ble, t he uri ne micr osc o p y s h o ul d be perf or m e d 
usi n g t he site’s l ocal la b orat or y ( w h ere a p pr o pri ate o n- site testi n g ca pa bilit y e xists) i n lie u of t he 
desi g nate d ce ntral la b or at or y. Uri ne micr osc o p y s h o ul d als o be perf or me d at a n y re m ote 
la b orat or y w h ere a p pr o priate o n-site testi n g ca pa bilit y e xists. If t he l ocal la b orat or y d oes n ot 
ha ve o n- site testi n g ca p a bilit y, t he sa m ple ma y be se nt t o t he desi g nate d ce ntral la b orat or y. 
Uri ne will be c ollect e d at all i n vesti gati ve site visits f or a nal ysis of u A C R, β - 2- micr o gl o b uli n, 
c ystati n C, u N G A L, KI M - 1, a n d L- F A B P. I n a d diti o n, ali q u ots of uri ne will be fr oze n a n d 
s hi p pe d t o t he ce ntral la b orat or y f or st ora ge f or p ossi ble f ut ure a nal ysis of uri ne bi o mar kers. 
1 3. 6. 2.  
Me n o p a use a n d Pre g n a nc y Scree n  
F S H will be meas ur e d at scree ni n g f or a n y w o m a n p ost-me n o pa usal ≤ 2 years (t his ma y be 
o mitte d if me n o pa usal stat us was de m o nstrate d wit h ele vate d F S H i n t he pri or st u d y).  F or 
w o me n w h o d o n ot u n der g o a scree ni n g visit, F S H ma y be assesse d at baseli ne. I n t his case, t he 
s u bject m ust ha ve a ne g ati ve uri ne pre g n a nc y test at baseli ne pri or t o recei vi n g st u d y dr u g. 
F or w o me n of c hil d beari n g p ote ntial, a ser u m pre g na nc y test will be a d mi nistere d at scree ni n g. 
Uri ne pre g n a nc y tests will be assesse d at all s u bse q ue nt visits. A ser u m pre g na nc y test s h o ul d 
i m me diatel y be dra w n a n d se nt f or a nal ysis f or a n y p ositi ve uri ne pre g na n c y test. 
Uri ne pre g n a nc y test kits will be pr o vi de d b y t he ce ntral la b orat or y b ut will be res ulte d l ocall y. 
Starti n g at Wee k 1 0 0, w o me n of c hil d beari n g p ote ntial will  start perf or mi n g uri ne pre g n a nc y 
tests at h o me e ver y 4 w ee ks (i.e., i n bet wee n cli ni c visits). T he res ults will be rec or de d b y t he 
site. If t h e uri ne pr e g na n c y test is p ositi ve, t he s u bject s h o ul d c o ntact t he site i m mediatel y.  
1 3. 7.  
M o nit ori n g f or He m ol ysis at Disc o nti n u ati o n of B C X 9 9 3 0  
B y i n hi biti n g t he alter nati ve pat h wa y of c o m ple me nt, t he fact or D i n hi bit or B C X 9 9 3 0 ma y 
i m pr o ve he m o gl o bi n le vels b y re d uci n g t he h e m ol ysis of P N H R B Cs. T h us, f oll o wi n g 
disc o nti n uati o n of B C X 9 9 3 0 treat me nt, s u bjects ma y be at ris k of seri o us he m ol ysis. 

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Base d o n a vaila ble d ata r e gar di n g t he P K a n d P D of B C X 9 9 3 0, seri o us he m ol ysis, if it occ urs, 
w o ul d be e x pecte d t o prese nt wit hi n da ys after dis c o nti n uati o n of t hera p y, t heref ore w h e n 
s u bjects sto p st u d y dr u g t hera p y, eit her at t he sc h e d ule d e n d of treat me nt or o n pre mat ure 
disc o nti n uati o n, t he y m ust be m o nit ore d f or he m ol ysis, as descri be d bel o w. Sa m ples ma y be 
a nal yze d at a l ocal la b orat or y.  
He m ol ysis will be m o nit ore d b y dail y la b orat or y assess me nt of L D H, h e m o gl o bi n, c o m plete 
bl o o d c o u nt ( C B C), a n d ser u m c he mistr y (ser u m creati ni ne, bl o o d urea nitr o ge n [ B U N]), al o n g 
wit h vital si g ns a n d a tar gete d p h ysical e x a mi nati o n, f or at least 3 c o ns ec uti ve da ys after 
disc o nti n ui n g B C X 9 9 3 0. Sa m ple(s) f or P D bi o mar ker a n al ysis a n d P K will be c ollecte d 4 8 h o urs 
after t he l ast d ose of B C X 9 9 3 0. 
F oll o wi n g t he 3 da ys of m o nit ori n g, a d diti o nal la b orat or y m o nit ori n g ma y be necessar y, bas e d 
u p o n t he safet y ass ess me nt of t he I n vesti gat or a n d t he S p o ns or Me dical M o nit or.  
1 3. 8.  
Assess me nt of Bre a kt hr o u g h He m ol ysis E pis o des  
It is p ossi ble t hat s u bjects ma y e x perie n ce e pis o des of B T H w hile o n st u d y dr u g. S y m pt o ms of 
B T H ma y i ncl u de fati g ue, he m o gl o bi n uria, a b d o mi nal pai n, d ys p ha gia, s h ort ness of breat h, or 
t hr o m b osis. S u bjects w h o e x perie n ce s uc h s y m pt o ms s h o ul d c o ntact t heir st u d y I n vesti gat or 
u p o n first a war e ness a n d s h o ul d be assesse d f or B T H wit hi n 4 8 h o urs of t his c o ntact, or o n t he 
first w or ki n g da y f oll o wi n g t his c o ntact.  
Assess me nt of e pis o des of B T H will i ncl u de L D H, he m o gl o bi n, C B C, a n d ser u m c he mistr y 
(ser u m cr eati ni ne, B U N), al o n g wit h vital si g ns a n d a tar gete d p h ysi cal e x a mi nati o n. I n a d diti o n, 
sa m ple(s) f or P D a n d P K will be c ollecte d. 
L ocal la b or at or y tests ma y be use d f or p arts of he m ol ysis m o nit ori n g, as necess ar y. 
1 3. 9.  
A d verse E ve nts  
A Es will be assesse d a n d rec or d e d fr o m t he ti me of si g ni n g of t he i nf or me d c o nse nt t hr o u g h t he 
a p pr o priate f oll o w - u p peri o d. F ull details o n rec or di n g a n d re p orti n g A Es are pr o vi de d i n 
Secti o ns  1 3. 9. 3  a n d 1 3. 9. 4 . 
1 3. 9. 1.  
Defi niti o n of A d verse E ve nts  
1 3. 9. 1. 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 cli nical st u d y s u bject. N o ca usal relati o ns hi p 
wit h t he st u d y dr u g/I M P or wit h t he cli nical st u d y itself is i m plie d. A n A E ma y be a n 
u nfa v ora bl e a n d u ni nte n d e d si g n, s y m pt o m, s y n dr o me, or ill ness t hat de vel o ps or w orse ns d uri n g 
t he cli nical st u d y. Cli nicall y rele va nt a b n or m al res ults of dia g n ostic pr oce d ures i ncl u di n g 
a b n or mal la b or at or y fi n di n gs (e g, re q uiri n g u nsc h e d ule d dia g n ostic pr oce d ures or treat me nt 
meas ures, or res ulti n g i n wit h dra wal fr o m t he st u d y) are c o nsi dere d t o be A Es. A b n or mal res ults 
of dia g n ostic pr oce d ures t hat are i nci de nt al or n ot cli nicall y rele va nt are n ot re p orta ble as A Es.  

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A Es i n cl u de t he f oll o wi n g: 
•  A Es n ot pre vi o usl y o bser ve d i n t he s u bject t hat e mer ge d uri n g t he pr ot o c ol- s pecifie d 
A E re p orti n g peri o d (see Secti o n  1 3. 9. 3 ). 
•  Fi n di n gs fr o m pr ot oc ol- ma n date d i nter ve nti o ns. T his ca n i ncl u de la b orat or y 
assess me nts perf or me d i n t he cli nical st u d y. A Es s h o ul d o nl y be re p orte d if t he 
a b n or malities are c ha n g es fr o m baseli ne a n d are cli nicall y si g nifica nt as descri be d 
a b o ve. 
•  Pre -e xisti n g me dical c o n diti o ns ( ot her t ha n t he c o n diti o n bei n g st u die d) j u d ge d b y t he 
I n v esti gat or t o ha ve w ors e ne d i n se verit y or fre q u e nc y or c ha n g e d i n c haracter d uri n g 
t he pr ot oc ol-s pecifie d A E re p orti n g peri o d. 
•  I n a d diti o n, i n t his st u d y t he disease-relate d e ve nts of B T H a n d t hr o m b oe m b olic 
e ve nts will be re p ort e d as A Es, e ve n if d ee me d rel ate d t o t he disease u n d er 
i n vesti gati o n. 
A n a d vers e reacti o n is defi ne d i n I C H Har m o nise d Tri partite G ui deli ne E 2 A as f oll o ws: all 
u nt o war d a n d u ni nte n de d res p o nses t o a st u d y dr u g/I M P rel ate d t o a n y d os e a d mi nistere d. T he 
defi niti o n c o vers als o me dicati o n err ors a n d uses o utsi de w hat is f oresee n i n t he pr ot oc ol, 
i ncl u di n g mis use a n d a b use of t he pr o d u ct. T he defi niti o n i m plies a reas o na ble p ossi bilit y of a 
ca usal r elati o ns hi p bet wee n t he e ve nt a n d t he st u d y dr u g/I M P. T his mea ns t hat t here are facts 
(e vi de nce) or ar g u me nts t o s u g gest a ca usal relati o ns hi p. 
S ur gical pr oce d ures s h o ul d n ot be re p orte d as A Es. T he c o n diti o n f or w hic h t he s ur ger y is 
re q uire d s h o ul d be re p ort e d as t he A E if it occ urs or is detecte d d uri n g t he st u d y peri o d. Pla n ne d 
s ur gical meas ur es per mitte d b y t he cli nical st u d y pr ot oc ol a n d t he c o n diti o ns(s) lea di n g t o t hese 
meas ures are n ot A Es if t he c o n diti o n(s) was ( were) k n o w n bef ore t h e start of st u d y treat me nt. I n 
t he latter cas e, t he c o n diti o n s h o ul d be re p orte d as me dical hist or y. 
A Es are d esi g nate d as “ n o nseri o us” or “s eri o us.”  
1 3. 9. 1. 2.  Seri o us A d verse E ve nt  
A n S A E is a n A E/reacti o n t hat res ults i n a n y of t he f oll o wi n g o utc o mes: 
•  Deat h  
•  Is life-t hreate ni n g (s u bject is at i m me diate ris k of deat h at t he ti me of t he e ve nt; it 
d oes n ot refer t o a n e v e nt t hat h y p ot heticall y mi g ht ha ve ca us e d deat h if it were m ore 
se vere) 
•  Re q uires s u bject h os pitalizati o n (f or mal a d missi o n t o a h os pital f or me dical  reas o ns) 
or pr ol o n gati o n of e xisti n g h os pitalizati o n 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y (ie, t here is a s u bsta ntial 
disr u pti o n of a pers o n's a bilit y t o carr y o ut n or mal life f u ncti o ns) 
•  Is a c o n ge nital a n o mal y/ birt h defect 

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I m p ort a nt me dical e v e nts t hat ma y n ot res ult i n deat h, are n ot life -t hreat e ni n g, or d o n ot re q uire 
h os pitalizati o n ma y be c o nsi dere d a S A E w h e n, b ase d u p o n a p pr o priate m e dical j u d g me nt, t he y 
ma y je o par dize t he s u bject’s healt h or ma y re q uire me dical or s ur gi cal i nter ve nti o n t o pre ve nt 
o ne of t he o utc o mes liste d i n t his defi niti o n. E xa m ples of s uc h e v e nts ma y i ncl u de aller gic 
br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me, bl o o d d yscrasias, 
or c o n v ulsi o ns t hat d o n ot res ult i n s u bject h os pitalizati o n.  
I n a d diti o n, a b orti o n (s p o nta ne o us or i n d uce d), fet al de mise, a n d still birt h al o n g wit h c o n ge nital 
a b n or malities i n t he ne w b or n, s h o ul d be re p ort e d as se parate S A Es (see Secti o n 1 3. 9. 4. 3 ). 
O ver d ose will be c o nsi dere d a n S A E o nl y if a n y of t he seri o us ness criteria are met. A n y cli nical 
c o m plicati o n i n ass ociati o n wit h t he o ver d ose s h o ul d be re p orte d as a n A E or S A E (as 
a p plica ble) al o n g wit h t he o ver d ose (see Secti o n  1 3. 9. 5. 6 ) Details of si g ns or s y m pt o ms, cli nical 
ma na ge me nt, a n d o ut c o me s h o ul d be re p orte d, if a vaila ble. O v er d ose wit h o ut ass ociate d si g ns or 
s y m pt o ms s h o ul d n ot be rec or d e d as A Es b ut s h o ul d be rec or de d as pr ot oc ol de viati o ns. 
1 3. 9. 1. 3.  E ve nts of S peci al I nterest  
F or t his pr ot oc ol, se vere i nfecti o ns will be c o nsi dere d e v e nts of s pecial i nterest ( E O SIs). 
At eac h visit, s u bjects will be assesse d f or E O SIs t hat ma y ha ve o cc urre d si nce t he last visit. All 
E O SI are c o nsi der e d A Es a n d s h o ul d be re p ort e d o n t he A E e C R F. F or eac h E O SI re p orte d, sites 
will be pr o m pte d t o c o m plete a n E O SI Tar gete d Assess me nt. (I n case a n E O SI meets criteri a t o 
be re p ort e d as a n S A E, pl ease f oll o w pr oce d ures as descri be d i n Secti o n 1 3. 9. 3 ). 
1 3. 9. 1. 4.  E ve nts of S peci al M o nit ori n g  
E ve nts of s pecial m o nit ori n g ( E O S M) are A Es or safet y t o pics f or w hic h s pecial m o nit ori n g, 
a d diti o nal data c ollecti o n acti vities, a n d/ or e n ha n ce d si g nal detecti o n acti vities wit hi n Bi o Cr yst 
are c o nsi d ere d a p pr o priat e f or t his p o p ulati o n a n d st u d y. I de ntifie d E O S Ms ca n be of p artic ular 
c o ncer n b ase d o n fi n di n gs fr o m t he I M P cli nical pr o gra m t o date, p ote ntial a n d/ or k n o w n ris ks 
ge nerall y ass o ciate d wit h t he u n derl yi n g disease, or c o m or bi dities a n d ris k fact ors pre v ale nt i n 
t he st u d y p o p ulati o n. 
E O S M f or t his st u d y i ncl u de he m ol ysis, S A R S- C o V - 2 i nfecti o ns (as y m pt o matic a n d 
s y m pt o matic),  
 
 
1 3. 9. 1. 5.  Defi niti o n of Se verit y  
All A Es will be assesse d ( gra de d) f or s e verit y b y t he I n vesti gat or a n d classifie d usi n g t he D MI D 
criteria f or gra di n g A Es ( N o ve m ber 2 0 0 7, see A p p e n di x 1). A n y A Es n ot c o vere d b y t he D MI D 
criteria will be ass esse d a n d classifie d i nt o 1 of t he 4 clearl y  defi ne d cate g ories as f oll ows:  

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Mil d:  
( Gra de 1): Tra nsie nt or mil d s y m pt o ms; n o li mitati o n i n acti vit y; n o i nter ve nti o n re q uire d. 
T he A E d oes n ot i nterfere wit h t he partici pa 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 nce. 
M o der ate:  
( Gra de 2): S y m pt o m res ults i n mil d t o m o derate li mitati o n i n acti vit y; n o or mi ni mal 
i nter ve nti o n re q uire d. T he A E pr o d uces s o me i m pair me nt of f u ncti o ni n g, b ut it is n ot 
hazar d o us t o healt h. It is u nc o mf orta ble or a n e m barrass me nt.  
Se vere:  
( Gra de 3): S y m pt o m res ults i n si g nifica nt li mitati o n i n acti vit y; me dical i nter ve nti o n ma y be 
re q uire d. T he A E pr o d uces si g nifica nt i m pair me nt of f u ncti o ni n g or i nca pacitati o n. 
Life -
t hre ate ni n g: 
( Gra de 4): E xtre me li mitati o n i n acti vit y, si g nifica nt assista nce re q uire d; si g nifica nt me dical 
i nter ve nti o n/t hera p y re q uire d t o pre ve nt deat h, h os pitalizati o n or h os pice care pr o ba ble.  
1 3. 9. 1. 6.  Rel ati o ns hi p t o St u d y Dr u g  
A n I n vesti gat or w h o is q ualifie d i n me dici ne m ust ma ke t he deter mi nati o n of relati o ns hi p t o t he 
i n vesti gati o nal pr o d uct f or eac h A E ( n ot relate d, u nli kel y relate d, p ossi bl y relate d, pr o b a bl y 
relate d, defi nitel y relate d). T he I n vesti gat or s h o ul d deci de w h et her, i n his or her me dical 
j u d g me nt, t here is a reas o na ble p ossi bilit y t hat t he e ve nt ma y h a ve bee n ca use d b y t he 
i n vesti gati o nal pr o d uct. If n o vali d reas o n e xists f or s u g gesti n g a relati o ns hi p, t he n t he A E 
s h o ul d be classifie d as “ n ot relate d.” If t here is a n y vali d reas o n, e v e n if u n d eter mi ne d, f or 
s us pecti n g a p ossi ble ca use-a n d- eff ect relati o ns hi p bet wee n t he i n v esti gati o nal pr o d uct a n d t he 
occ urr e nce of t he A E, t h e n t he A E s h o ul d be c o nsi dere d “relate d. ” 
N ot Rel ate d:  
T he e ve nt ca n be rea dil y e x plai ne d b y ot her fact ors s uc h as t he s u bject’s u n derl yi n g me dical 
c o n diti o n, c o nc o mita nt t hera p y, or acci de nt, a n d n o te m p oral relati o ns hi p e xists bet wee n t he 
st u d y dr u g/I M P a n d t he e ve nt. 
U nli k el y 
Rel ate d:  
T he e ve nt d oes n ot f oll o w a reas o na ble te m p oral se q ue nce fr o m dr u g a d mi nistrati o n a n d is 
rea dil y e x plai ne d b y t he s u bject’s cli nical state or b y ot her m o des of t hera p y a d mi nistere d t o 
t he s u bject. 
P os si bl y 
Rel ate d:  
T here is s o me te m p oral relati o ns hi p bet wee n t he e ve nt a n d t he a d mi nistrati o n of t he st u d y 
dr u g/I M P a n d t he e ve nt is u nli kel y t o be e x plai ne d b y t he s u bject’s me dical c o n diti o n, ot her 
t hera pies, or acci de nt. 
Pr o b a bl y 
Rel ate d:  
T he e ve nt f oll o ws a reas o na ble te m p oral se q ue nce fr o m st u d y dr u g/I M P a d mi nistrati o n, 
a bates u p o n disc o nti n uati o n of t he st u d y dr u g/I M P, a n d ca n n ot be reas o na bl y e x plai ne d b y 
t he k n o w n c haracteristics of t he s u bject’s cli nical state. 
Defi nitel y 
Rel ate d:  
T he e ve nt f oll o ws a reas o na ble te m p oral se q ue nce fr o m st u d y dr u g/I M P a d mi nistrati o n, 
f oll o ws a k n o w n or s us pecte d res p o nse patter n t o t he st u d y dr u g/I M P, is c o nfir me d b y 
i m pr o ve me nt u p o n st o p pi n g t he st u d y dr u g/I M P ( dec halle n ge), a n d rea p pears u p o n re peate d 
e x p os ure  (rec halle n ge, if rec halle n ge is me dicall y a p pr o priate). 
If t he rel ati o ns hi p bet wee n t he A E/ S A E a n d t he i n vesti gati o nal pr o d uct is deter mi ne d t o be 
“ p ossi ble,” “ pr o b a ble,” or “ defi nite, ” t he e ve nt will be c o nsi dere d t o b e relate d t o t he 
i n vesti gati o nal pr o d uct f or t he p ur p oses of e x pe dite d re g ulat or y re p orti n g. 

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1 3. 9. 2.  
Rec or di n g A d verse E ve nts  
A Es s p o nta ne o usl y re p orte d b y t he s u bject a n d/ or i n res p o nse t o a n o pe n q u esti o n fr o m t he st u d y 
pers o n nel or r e veale d b y o bser vati o n will be rec or de d d uri n g t he st u d y at t he i n vesti gati o nal site. 
O nl y cli nicall y si g nifica nt c ha n ges fr o m b aseli ne i n pr ot oc ol- ma n date d assess me nts s uc h as vital 
si g ns, la b orat or y val ues, a n d E C Gs s h o ul d be re p orte d as A Es. I nf or mati o n a b o ut A Es a n d S A Es 
will be c ollecte d fr o m t he si g ni n g of c o nse nt f or m u ntil t he e n d of t he st u d y. T he A E ter m s h o ul d 
be re p ort e d i n sta n dar d m e dical ter mi n ol o g y a n d as a dia g n osis ( n ot s y m pt o ms) w he n p ossi ble. 
F or eac h A E, t h e I n vesti gat or will e val uate a n d re p ort t he o nset ( date a n d ti me), res ol uti o n ( date 
a n d ti me), se verit y, ca usalit y, acti o n ta ke n wit h st u d y dr u g, seri o us ness, a n d o utc o me,  
Se verit y will be assesse d b y t he I n vesti gat or usi n g t he D MI D scale.  
It is i m p orta nt t o disti n g uis h bet wee n seri o us a n d s e vere A Es. Se verit y is a meas ure of i nte nsit y, 
defi ne d i n Secti o n 1 3. 9. 1. 5 , w hereas seri o us ness is defi ne d b y t he criteria u n der Secti o n 1 3. 9. 1. 2  
A n A E of se v ere i nte nsit y ma y or ma y n ot be c o nsi dere d seri o us. 
S h o ul d a pre g na nc y o cc ur, it m ust be re p orte d a n d rec or d e d o n Bi o Cr yst’s pre g n a nc y f or m. 
Pre g na nc y is n ot re g ar de d as a n A E u nless t here is a s us pici o n t hat a n i n vesti gati o nal pr o d uct 
ma y ha ve i nterfer e d wit h t he eff ecti ve ness of a c o ntrace pti ve me di cati o n.  
T he o utc o me of all pre g n a ncies (s p o nta n e o us miscarria g e, electi ve ter mi nati o n, n or mal birt h, or 
c o n ge nital a b n or malit y) m ust be f oll o we d u p a n d d oc u me nte d, e v e n if t he s u bject was 
disc o nti n ue d fr o m t he st u d y. 
All re p orts of c o n g e nital a b n or malities/ birt h defects are S A Es. S p o nta ne o us miscarria ges, 
electi ve a b orti o ns, a n d still - birt hs s h o ul d als o be re p orte d a n d ha n dle d as S A Es.  
1 3. 9. 3.  
Met h o d, Fre q ue nc y, a n d Ti me Peri o d f or Detecti n g A d verse E ve nts a n d 
Re p orti n g Seri o us A d verse E ve nts  
Re p orts of all A Es a n d S A Es, re gar dless of I n v esti gat or attri b uti o n, are t o be c ollecte d fr o m t he 
ti me of si g ni n g of t he i nf or me d c o nse nt. All A Es a n d S A Es are t o b e re p orte d o n t he A E e C R F.  
A Es s h o ul d be d oc u me nt e d o n e C R Fs as I n v esti gat ors bec o me a ware of t he m. A Es are t o be 
f oll o we d u ntil t he e ve nt r es ol ves. If a n e ve nt is o n g oi n g at t he last f oll o w- u p visit, Gra de 1 a n d 
2 e ve nts d o n ot nee d t o b e f oll o we d if t he e ve nt is dee me d u nli kel y t o be relate d or n ot rel ate d t o 
st u d y dr u g/I M P (see Secti o n 1 3. 9. 1. 5  f or A E gra di n g). F or all Gra d e 3 a n d 4 e ve nts or e v e nts 
dee me d p ossi bl y, pr o ba bl y, or defi nitel y relate d t o use of st u d y dr u g/I M P, t he e ve nt s h o ul d be 
f oll o we d u ntil t he A E is res ol ve d or t he s u bject is i n a cli nicall y sta ble c o n diti o n wit h re gar ds t o 
t he A E. 
T he I n vesti gat or s hall r e p ort all S A Es i m me diatel y a n d n o later t ha n 2 4 h o urs of t heir k n o wle d g e 
of t he e ve nt t o t he S p o ns or b y c o m m u nicati n g wit h t he Me dical M o nit or ( p h o ne or e mail) a n d b y 
s u b missi o n of a n S A E re p ort f or m via e mail a n d e nteri n g t he e ve nt o nt o t he A E e C R F. T he S A E 
re p ort f or m is a d etaile d, writte n re p ort o n t he S A E. T he I n vesti gat or s h o ul d f oll o w all 
u nres ol ve d S A Es o bser v e d d uri n g t he st u d y u ntil t he y are res ol ve d, or are j u d ge d me dicall y 
sta ble, or are ot her wise me dicall y e x plaine d. 

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T he I n vesti gat or s h o ul d atte m pt, if p ossi ble, t o esta blis h a dia g n osis base d o n t he prese nti n g 
si g ns a n d s y m pt o ms. I n s uc h cases, t h e dia g n osis s h o ul d be d oc u me nte d as t he A E a n d n ot t he 
i n di vi d ual si g n/s y m pt o m. If a cl ear dia g n osis ca n n ot be esta blis he d, eac h si g n a n d s y m pt o m m ust 
be rec or de d i n di vi d uall y. O nce a di a g n osis is ma de d uri n g e val uati o n or treat me nt, t he 
I n v esti gat or will u p date t he A E rec or d wit h t his dia g n osis. 
1 3. 9. 4.  
Re p orti n g  
1 3. 9. 4. 1.  Seri o us A d verse E ve nts a n d S us pecte d U ne x pecte d Seri o us A d verse R e acti o ns  
All S A Es re gar dless of relati o ns hi p t o st u d y dr u g m ust be re p orte d wit hi n 2 4 h o urs t o t he 
S p o ns or. E mail or p h o ne call t o t he S p o ns or Me dical M o nit or s h o ul d be f oll o we d b y s u b missi o n 
of t he S A E re p ort f or m ( c o m plete d wit h as m uc h i nf or mati o n as a vai la ble) via e mail a n d e ntr y of 
t he e ve nt o n t he e C R Fs. T he S A E re p ort f or ms s h o ul d be se nt t o t he f oll o wi n g e mail a d dress: 
 
E mail: safet y @ bi ocr yst.c o m  
I m me diat e re p orti n g s h o ul d all o w Bi o Cr yst t o ta ke t he a p pr o priate meas ures t o a d dress p ote ntial 
ne w ris ks i n a cli nical st u d y. T heref ore, t he i nitial re p ort s h o ul d be s u b mitte d b y t he I n vesti gat or 
wit hi n a ver y s h ort peri o d of ti me a n d u n der n o circ u msta nces s h o ul d t his peri o d e xcee d 2 4 h o urs 
f oll o wi n g a war e ness of t he S A E.  
T he f oll o w- u p r e p ort s h o ul d all o w Bi o Cr yst t o deter mi ne w het her t he S A E re q uires a 
reassess me nt of t h e be nefit-ris k pr ofile of t he st u d y dr u g/I M P i n cli nical st u d y, if t he rele v a nt 
i nf or mati o n was n ot alrea d y a vaila ble a n d pr o vi d e d i n t he initial re p ort.  
I n v esti gat ors or desi g nees at eac h site are res p o nsi ble f or ret ai ni n g c o pies of all s us pecte d 
u ne x pecte d s eri o us a d verse reacti o n ( S U S A R) re p orts (i nitial a n d f oll o w- u p) a n d ot her s afet y 
i nf or mati o n (e g, r e vise d I B) i n t heir I n v esti gat or site files. 
Bi o Cr yst s hall e ns ure t hat all rele va nt i nf or mati o n a b o ut S U S A Rs t hat are fatal or 
life-t hreat e ni n g is rec or d e d a n d re p orte d as s o o n as p ossi ble t o all c o m pete nt a ut h orities, a n d t o 
t he I E C/I R Bs i n a n y case n o later t ha n 7 cale n dar da ys after k n o wle d ge b y Bi o Cr yst of s uc h a 
case, a n d t h at rele v a nt f oll o w - u p i nf or mati o n is s u bse q ue ntl y c o m m u nicate d wit hi n a n a d diti o nal 
8 da ys. All ot her S U S A Rs s hall be re p orte d t o t he c o m pete nt a ut h orities c o ncer ne d a n d t o t he 
I E C/I R Bs, as a p plica ble acc or di n g t o l ocal re g ulati o ns, as s o o n as p ossi ble b ut i n n o case later 
t ha n 1 5 cale n d ar da ys of first k n o wle d ge b y Bi o Cr yst. Bi o Cr yst or desi g nee s hall als o i nf or m t he 
I n v esti gat or. Alt h o u g h ac ute ki d ne y i nj ur y is c o nsi dere d a n e x pecte d e v e nt (see Secti o n 6. 1 1 of 
t he IB), t h e e ve nt will be re p orte d i n a n e x pe dite d ma n ner. 
1 3. 9. 4. 2.  Re p orti n g E ve nts of S peci al I nterest  
All E O SIs are c o nsi d ere d A Es a n d s h o ul d be re p orte d o n t he A E e C R F. F or eac h E O SI re p ort e d, 
sites will be pr o m pte d t o c o m plete a n E O SI Ass ess me nt F or m. T he E O SI Assess me nt F or m will 
c ollect tar get e d i nf or mati o n s uc h as s pecifi c p h ysical e xa m fi n di n gs a n d rel e va nt i n vesti gati ve 
st u dies a n d pr oce d ures. 

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1 3. 9. 4. 3.  Pre g n a nc y  
A n y fe male s u bject w h o bec o mes pr e g na nt d uri n g t he c o urse of t h e st u d y s h o ul d ha ve st u d y 
dr u g/I M P disc o nti n u e d i m me diatel y a n d m ust be f oll o we d t hr o u g h t he e n d of t he pre g n a nc y. 
W hile pre g na n c y is n ot c o nsi dere d a n A E, all cas es of fetal dr u g e x p os ure via t he pare nt as a 
st u d y partici pa nt (i ncl u di n g part ners of st u d y p artici pa nts) are t o be re p orte d i m me diatel y t o 
Bi o Cr yst or its desi g nee. C o nse nt fr o m st u d y part ners w h o bec o me pre g na nt will be o btai ne d 
pri or t o re p orti n g a n y d etails of t he pre g na n c y. I nf or mati o n relate d t o t he pre g na nc y m ust be 
gi ve n o n a “ Pre g n a nc y C o nfir mati o n a n d O utc o m e” f or m t hat will be pr o vi de d b y t he S p o ns or or 
its desi g nee s o t hat t he pr e g na nc y ma y b e f oll o we d a n d a n o utc o me d eter mi ne d. A n y A Es or 
S A Es e x perie n ce d b y a pre g na nt s u bject are t o be re p orte d as direct e d i n Secti o n  1 3. 9. 3  a n d 
Secti o n  1 3. 9. 4 . A n y c o m plicati o ns re p orte d i n a s u bject’s pre g n a nt part ner s h o ul d be re p orte d o n 
t he Pre g na nc y C o nfir m ati o n a n d O utc o me f or m. All pre g na ncies m ust be f oll o we d t o o utc o me, 
w hic h occ urs w he n a n i nfa nt is deli vere d (li ve or still b or n), t here is fetal d e mise, or t here is a n 
a b orti o n (s p o nta ne o us or i n d uce d). A b orti o n (s p o nta ne o us or i n d uce d), fet al de mise, a n d still 
birt h, al o n g wit h c o n ge nital a b n or malities i n t he ne w b or n, s h o ul d be re p ort e d as se parate S A Es. 
1 3. 9. 4. 4.  Seri o us Bre ac hes  
It is t he r es p o nsi bilit y of t he S p o ns or t o n otif y t he c o m pete nt a ut h orit y of a n y seri o us breac h of 
G o o d Cli nic al Practice ( G C P), w hic h is li kel y t o affect, t o a si g nifica nt de gree, t he s afet y or 
me ntal i nte grit y of t he s u bjects of t he st u d y or t he scie ntific val ue of t h e st u d y. All seri o us 
breac h es will be n otifie d t o t he rele va nt c o m p ete nt a ut h orit y i n acc or d a nce  wit h l ocall y 
a p plica ble r e g ulati o ns. T he re p orti n g t o t he S p o ns or will be perf or me d b y t he part y w h o s us pects 
t he seri o us breac h.  
1 3. 9. 5.  
T o xicit y M a n a ge m e nt 
T he I n vesti gat or ( or q ualifie d desi g nee) will gra de cli nicall y si g nificant e ve nts a n d la b orat or y 
a b n or malities (if c o nsi dere d A Es) acc or di n g t o t hat detaile d i n Secti o n  1 3. 9. 1. 5 . Gra de 3 a n d 4 
cli nicall y si g nifica nt la b orat or y a b n or m alities s h o ul d be c o nfir me d b y re peat testi n g a n d bef ore 
a n y c o nte m plate d st u d y dr u g/I M P disc o nti n uati o n, u nless s uc h a dela y is n ot c o nsiste nt wit h 
g o o d me dical practice.  
1 3. 9. 5. 1.  Se vere I nfecti o ns  
S pecial e val uati o n of all st u d y dr u g- relate d s e vere i nfecti o ns is re quire d as per Secti o n  1 3. 9. 1. 3  
a n d re p orti n g per Secti o n  1 3. 9. 4. 2 . S u bjects s h o ul d be i nstr ucte d re g ar di n g t he ris k of i nfecti o ns 
a n d c o ntact t he I n vesti gat or i m me diatel y o n bec o mi n g a ware of a n y ne w or w orse ni n g 
s y m pt o ms. Ma na ge me nt of i nfecti o ns s h o ul d be b ase d o n best me dical practice a n d a d dres s t he 
s u bject’s pres e ntati o n.  
1 3. 9. 5. 2.  P ote nti al Dr u g -i n d uce d Li ver I nj ur y: M o nit ori n g, E v al u ati o n, a n d 
Disc o nti n u ati o n Criteri a  
All treat me nt -e mer ge nt A L T ele vati o ns > 3 × U L N s h o ul d be c o nfir me d, prefera bl y wit hi n 7 2 
h o urs, wit h re peat assess me nt of A L T, A S T, t otal bilir u bi n, A L P, pr ot hr o m bi n ti me/I N R, a n d 
c o m plete bl o o d c o u nt wit h differe ntial. T h ese ma y be re peate d at a l ocal la b orat or y as l o n g as t he 

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res ults are r e p orte d t o t he i n vesti gat or w he n a v aila ble a n d t he i n vesti gati ve site c o ntacts t he 
s u bject t o ascert ai n a n y s y m pt o ms. 
S u bjects wit h A L T ele vati o n > 3 × U L N m ust be assesse d t o deter mi ne w h et her st u d y dr u g m ust 
be wit h hel d or disc o nti n ue d. I n a d diti o n, a n y p ote ntiall y c o ntri b uti n g me dicati o ns, s u p ple me nts, 
or o ver-t he-c o u nter me di cati o ns t hat are n ot me di call y necessar y s h o ul d be disc o nti n ue d if 
me dicall y feasi ble.  
Disc o nti n uati o n of treat me nt s h o ul d be c o nsi dere d f or a n y of t h e f oll o wi n g, a n d s h o ul d be 
disc usse d wit h t he s p o ns or me dical m o nit or pri or t o B C X 9 9 3 0 disc o nti n uati o n, c o nsi deri n g t he 
be nefit r is k of disc o nti n ui n g B C X 9 9 3 0: 
•  A L T or A S T > 8 × U L N  
•  A L T or A S T > 5 × U L N f or m ore t ha n 2 wee ks 
•  A L T or A S T > 3 × U L N a n d (t otal bilir u bi n > 2 × U L N [ u nless t here is e vi de nce t hat t he 
i ncreas e i n bilir u bi n is d ue t o he m ol ysis or Gil bert’s s y n dr o me] or I N R > 1. 5 × U L N i n 
t he a bse nce of w arf ari n t hera p y) 
A L T or A S T > 3 × U L N wit h t he a p peara nce of fati g ue ( o ver bas eli ne fati g ue), na usea, 
v o miti n g, ri g ht u p per q ua dra nt pai n or te n d er ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %) 
If s u bjects ar e as y m pt o m atic wit h n o ot her perti ne nt la b orat or y a b n or m alit y, st u d y dr u g ma y be 
c o nti n ue d u n der cl os e o bser vati o n. Tra ns a mi nases, t otal bilir u bi n, A L P, a n d I N R s h o ul d be 
re peat e d at least t wice w ee kl y. Fr e q ue n c y of retesti n g ca n decreas e t o o nce per wee k or less if 
a b n or malities sta bilize or t he st u d y dr u g has bee n disc o nti n ue d a n d t he s u bject is as y m pt o matic. 
A d diti o nall y, se veral ot h er ite ms s h o ul d be c o nsi d ere d, i ncl u di n g o btai ni n g a m ore detaile d 
hist or y of s y m pt o ms a n d pri or or c o nc urre nt diseases; o btai ni n g a hist or y of c o nc o mita nt use of 
n o n prescri pti ve me dicati o ns, her bal a n d diet ar y s u p ple me nts, alc o h ol i nta ke, recreati o nal dr u g 
use, or s pecial diets; e v al uati o n f or ac ut e viral he p atitis A, B, C, D, a n d E a n d p ote ntiall y ot her 
ser ol o gies; e val uati o n f or ot hers as cli nicall y i n dicate d i ncl u di n g alc o h olic a n d a ut oi m m u ne 
he patitis, n o n alc o h olic steat o he patitis ( N A S H), a n d biliar y tract diseas e.  
T he a b o ve criteria will be a p plie d t o i ncreases i n A S T u nless t here is e vi de nce t hat t he i ncrease is 
d ue t o he m ol ysis. If b ot h A L T a n d A S T are ele v at e d, s u bjects will be ma na ge d base d o n t heir 
A L T le vel, re g ar dless of w het her t heir A S T i ncrease is t h o u g ht t o be d ue t o he m ol ysis. 
If H y’s L a w criteri o n is met a n d is assesse d as pr o ba bl y or defi nitel y rel ate d per treat me nt 
disc o nti n uati o n criteri o n i n Secti o n 7. 4. 1 , t he n st u d y dr u g m ust be disc o nti n ue d. Pri or t o 
disc o nti n uati o n fr o m st u d y dr u g/ B C X 9 9 3 0, t he i n vesti gat or s h o ul d c o n tact t he s p o ns or me dical 
m o nit or f or a disc ussi o n re gar di n g t he e ve nt a n d assess me nt. If me dicall y i n dicate d, t he 
i n vesti gat or ca n disc o nti n ue t he s u bject i m me diat el y a n d f oll o w u p wit h t he s p o ns or wit hi n 
2 4 h o urs. 
1 3. 9. 5. 3.  Re n al E ve nts: M o nit ori n g, E v al u ati o n, a n d Disc o nti n u ati o n Criteri a 
T here are m ulti ple p ote ntial reas o ns t hat s Cr ca n i ncreas e i n t h ose wit h P N H, i ncl u di n g 
he m ol ysis. F or s u bjects w h o ha ve a c o nfir me d treat me nt- e mer g e nt i ncreas e i n s Cr, e val uati o ns t o 
i n vesti gate p ote ntial eti ol o g y s h o ul d be c h ose n c o nsi deri n g baseli ne re nal f u ncti o n, hist or y of 

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pri or re nal e ve nts i ncl u di n g t h ose d ue t o P N H, ot her c o m or bi dities, c o nc o mita nt me dicati o ns, 
a n d ot her r ele va nt f act ors. I n a d diti o n:  
•  F or all s u bjects, e ns ure a de q uate h y drati o n, st o p or s u bstit ute p ote ntiall y ne p hr ot o xic 
me dicati o ns, a n d e val u ate f or t u berc ul osis if sterile p y uria is pres e nt if p ote ntial e x p os ure 
•  F or treat me nt-e mer ge nt i ncreas es i n s Cr > U L N c o nfir me d b y re p eat testi n g, n otif y 
s p o ns or me dical m o nit or 
•  A re nal ultras o u n d wit h d o p pler s h o ul d be c o nsi dere d t o e xcl u de re n al vei n t hr o m b osis or 
ot her i nci de ntal ca uses  
•  S u bject data ma y be r e vi e we d b y t he N R M W G f or a d diti o nal rec o m me n d ati o ns, 
i ncl u di n g d ose re d ucti o n, i nterr u pti o n of d osi n g, a n d per ma ne nt disc o nti n u ati o n 
•  If a bi o ps y is perf or me d, a re dacte d c o p y of t he bi o ps y re p ort a n d a vaila ble i ma ges 
( w h ole sli de i ma ges of li g ht micr osc o p y or electr o n micr osc o p y s peci me ns, 
i m m u n ofl u oresce nce, i m m u n o hist oc he mistr y, etc.) s h o ul d be ma de a v aila ble 
T a ble 6 pr o vi des a d diti o nal g ui da nce b ase d o n s Cr le vels. 
T a ble 6: 
Acti o ns B ase d o n Ser u m Cre ati ni ne Le vels  
s Cr > U L N b ut ≤ 1. 5 × U L N  
•  
Assess me nt fre q ue nc y base d o n t he ma g nit u de of t he s Cr rise u ntil s Cr ≤ 
U L N (ie , e ver y 2 t o 4 wee ks) . 
•  
C o nsi der e val uati o n b y ne p hr ol o gist  
s Cr > 1. 5  × U L N b ut <  3 × 
U L N  
•  
Assess me nt fre q ue nc y  wee kl y u ntil s Cr  ≤ U L N  
•  
E val uati o n b y ne p hr ol o gist  
s Cr ≥ 3 × U L N  
•  
B C X 9 9 3 0 s h o ul d be disc o nti n ue d, wit h ta per  (see Secti o n 1 0. 5. 2 ), after 
c o nfir mati o n  
•  
If he m ol ysis or a n y ot her p ote ntiall y re versi ble ca use is s us pecte d, c o ntact 
s p o ns or me dical m o nit or 
A b bre viati o ns: s Cr = ser u m creati ni ne; U L N = u p per li mit of n or mal.  
1 3. 9. 5. 4.  He m ol ysis After Disc o nti n u ati o n of B C X 9 9 3 0 
S u bjects s h o ul d be i nstr ucte d re g ar di n g t he ris k of he m ol ysis t hat ma y occ ur after t h e 
disc o nti n uati o n or i nterr u pti o n of B C X 9 9 3 0. S u bjects will c o me t o t he cli nic f or he m ol ysis 
m o nit ori n g f or at least 3 da ys f oll o wi n g B C X 9 9 3 0 disc o nti n uati o n or i nterr u pti o n a n d s h o ul d 
c o ntact t he I n v esti gat or if t he y e x perie nce a n y w orse ni n g of t heir P N H s y m pt o ms, s uc h as 
fati g ue, he m o gl o bi n uria, a b d o mi nal pai n, d ys p ha gia, s h ort ness of breat h, or t hr o m b osis, after t he 
disc o nti n uati o n or i nterr u pti o n of B C X 9 9 3 0. M o nit ori n g para meters f or h e m ol ysis after st u d y 
dr u g disc o nti n uati o n or i nterr u pti o n are liste d i n S ecti o n  1 3. 7 . 
If he m ol ysis occ urs after disc o nti n uati o n of B C X 9 9 3 0, treat me nt c o nsi derati o ns ma y i ncl u de 
bl o o d tra nsf usi o n ( pac k e d R B Cs), e xc ha n ge tra nsf usi o n, a ntic oa g ulati o n, or l ocal sta n dar d of 
care, as deter mi ne d b y t he I n vesti gat or. 

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1 3. 9. 5. 5.  Bre a kt hr o u g h He m ol ysis 
S u bjects s h o ul d be i nstr ucte d re g ar di n g t he ris k of B T H. S u bjects s h o ul d c o ntact t he I n vesti gat or 
i m me diatel y after bec o mi n g a ware of a n y w orse ni n g of t heir P N H s y m pt o ms, s uc h as fati g ue, 
he m o gl o bi n uria, a b d o mi nal pai n, d ys p ha gia, s h ort ness of breat h, or t hr o m b osis w hile c o nti n ui n g 
d osi n g of B C X 9 9 3 0. St u d y assess me nts f or B T H are des cri be d i n Secti o n  1 3. 8 .  
B T H, if it occ urs, s h o ul d be treate d acc or di n g t o l ocal sta n dar d of care, as deter mi ne d b y t he 
I n v esti gat or. S u bjects s h o ul d c o nti n ue d osi n g wit h B C X 9 9 3 0 u nless i nstr ucte d t o disc o nti n ue b y 
t he I n v esti gat or.  
Ma na ge me nt of t hr o m b otic e ve nts s h o ul d be acc or di n g t o l ocal sta n dar d of care. 
1 3. 9. 5. 6.  O ver d ose  
T o date, t her e is n o e x perie nce wit h o ver d os e of B C X 9 9 3 0. I n t he e ve nt t hat st u d y pers o n nel 
bec o me a war e of a n o v er d ose of st u d y dr u g/I M P t hat is ass ociate d wit h a n A E, b ot h t he o ver d ose 
a n d t he res ulta nt e v e nt s h o ul d be re p orte d as A Es. O ver d ose wit h o ut a n y s y m pt o ms (ie, A Es) 
d oes n ot nee d t o be r e p orte d as a n A E. If o ver d ose occ urs wit h or wit h o ut ass ociate d A Es, 
s u bjects s h o ul d u n der g o cli nical a n d la b orat or y m o nit ori n g as a p pr o priate f or t heir cli nical 
c o n diti o n a n d, if i n dicate d, s h o ul d recei ve cli nicall y i n dicate d s u p p orti ve t hera p y. 
1 3. 1 0.  
D at a M o nit ori n g C o m mittee  
A n i n de pe n de nt D M C will be asse m ble d f or t his st u d y. T he D M C c o n ve n e d a n d re vie w e d  safet y 
data o nce t h e first 4 s u bjects e nr olle d c o m plete d 1 2 wee ks of d osi n g. S u bs e q ue nt meeti n gs were  
c o n ve ne d as detaile d i n t he D M C C harter.  
T he D M C ma y meet at a n y ti me s h o ul d a safet y iss ue arise t hat re q uires D M C i n p ut or a partial 
or f ull data re vi e w. A se p arate D M C c h arter mai ntai ne d i n t he trial master file descri bes 
me m bers hi p, r oles, ti mi n g of D M C re vie w, a n d res p o nsi bilities of t he D M C me m bers.  
A N R M W G will re vie w a n d a d vise o n s u bjects wit h treat me nt -e mer ge nt i n creas es i n s Cr a n d 
ot her re n al e ve nts . T he s pecific r es p o nsi bilities a n d c o m p ositi o n of t he N R M W G will be  o utli ne d 
i n a se par ate c h arter. 
1 4.  
S T A TI S TI C S  
1 4. 1.  
S a m ple Size  C o nsi der ati o ns  
N o sa m ple size calc ulati o ns were c o n d ucte d f or t his o pe n-la bel, l o n g-ter m safet y st u d y. 
A p pr o xi matel y 2 0 0 s u bjects ma y be e nr olle d i n t his st u d y, t o all o w c o nti n ue d access t o 
B C X 9 9 3 0 f oll o wi n g a s u bject’s partici pati o n i n a pri or B C X 9 9 3 0 st u d y.  
1 4. 2.  
Str atific ati o n  
N ot a p plica ble.  

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1 4. 3.  
St atistic al Met h o ds  
A detaile d statistical a nal ysis pla n ( S A P) will be de vel o pe d t o descri be t he met h o ds of a nal yses 
a n d s u m maries, i ncl u di n g all e n d p oi nts, ti me p oi nts, p o p ulati o ns, missi n g data, etc. D e viati o ns 
fr o m the a nal yses o utli ne d i n t he S A P will be descri be d i n t he cli nical st u d y re p ort.  
1 4. 3. 1.  
A n al ysis P o p ul ati o ns 
T he a nal ysis p o p ulati o ns are defi ne d bel o w. 
1 4. 3. 1. 1.  S afet y P o p ul ati o n 
T he safet y p o p ulati o n will i ncl u de all s u bjects w h o recei v e d at least 1  ta blet of st u d y dr u g. T his 
p o p ulati o n will be use d f or all a nal yses of acc o u nta bilit y, de m o gra p hics, B C X 9 9 3 0 dr u g 
c o nce ntr ati o ns, a n d saf et y. 
1 4. 3. 1. 2.  I nte nt t o Tre at P o p ul ati o n 
T he i nte nt t o treat (I T T) p o p ulati o n will i ncl u de all s u bjects w h o recei v e at least 1  ta blet of st u d y 
dr u g a n d ha ve p ost baseli ne assess me nt of P N H s y m pt o ms a n d/ or la b orat or y data. T he I T T 
p o p ulati o n will be t he p o p ulati o n f or effecti ve n ess a nal yses. 
1 4. 3. 2.  
Ge ner al C o nsi der ati o ns f or D at a A n al ysis 
I n g e ner al, descri pti ve s u m maries will i ncl u de n, mea n, sta n dar d d e viati o n, me dia n, mi ni m u m, 
a n d ma xi m u m f or c o nti n u o us varia bles a n d n a n d perce nt f or cate g orical varia bles. S u m maries 
will be prese nte d b y st u d y visit. 
F or s u bjects dir ectl y r olli n g o ver fr o m a n ot her B C X 9 9 3 0 st u d y wit h o ut treat me nt i nterr u pti o n,  
t he c ha n ge fr o m baseli ne a nal yses will use t he bas eli ne val ue as re p orte d i n t he pri or st u d y. 
All i n di vi d ual s u bject data will be liste d as meas ure d. All statistical s u m maries a n d a nal yses will 
be perf or me d usi n g S A S ®  s oft ware ( S A S I nstit ute, Car y, N ort h Car oli na, U S A). 
1 4. 3. 3.  
Missi n g D at a 
F or s u bjects w h o pre mat urel y disc o nti n ue t he st u d y, all a vaila ble data will be i ncl u de d f or t h e 
ke y safet y a n d effecti ve n ess a nal yses.  
1 4. 3. 4.  
S u bject De m o gr a p hic a n d Dis p ositi o n D at a  
De m o gra p hic d ata a n d b aseli ne c haracteristics i ncl u di n g a ge, ge n der, race or et h nicit y, hei g ht, 
wei g ht, B MI, a n d P N H hist or y will be s u m marize d. Ti me fr o m last B C X 9 9 3 0 d ose t o baseli ne 
will be s u m marize d a n d liste d as a p plica ble.  
S u bject dis p ositi o n will be prese nt e d f or all s u bjects. T he n u m ber of s u bjects w h o c o m plete d 
t hr o u g h eac h st u d y visit a n d t h ose t hat disc o nti n ue d fr o m t he st u d y will be pr o vi de d. T he reas o ns 
f or earl y disc o nti n uati o n als o will be prese nte d. A ta b ulati o n of t he n u m ber of s u bjects e x p ose d 
t o st u d y dr u g a n d d urati o n of e x p os ure will als o be prese nt e d. Treat me nt a d here nce, d ose 
i nterr u pti o ns, a n d reas o n f or d ose i nterr u pti o ns will be pr o vi de d as s u m mari es or liste d as 
a p pr o priate. 

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1 4. 3. 5.  
A n al ysis of S afet y V ari a bles 
Safet y e n d p oi nts t hat will be s u m marize d, at a mi ni m u m, i ncl u de t he pr o p orti o n of s u bjects 
1) wit h T E A Es; 2) w h o disc o nti n ue B C X 9 9 3 0 d ue t o T E A Es; 3) wit h treat me nt- e mer g e nt S A Es; 
4) wit h treat me nt -e m er ge nt Gra de 3 or 4 A Es; a n d 5) wit h treat me nt-e m er g e nt Gra de 3 or  4 
la b orat or y a b n or malities. I n a d diti o n, t he pr o p orti o n of s u bjects w h o recei v e d a re d u ce d d os e d ue 
t o t olera bilit y iss ues at t he f ull d ose will be s u m marize d.  
Ti me t o d ose re d ucti o n, ti me t o disc o nti n uati o n d ue t o a T E A E, a n d ti me t o de vel o p me nt of 
dr u g- relat e d ras h will be esti mate d usi n g t he Ka pl a n- Meier m et h o d. F or t h ose wit h a dr u g-r elate d 
ras h, cli nical a n d l a b orat or y fi n di n gs will be s u m marize d a n d t h e pr o p orti o n of s u bjects w h o 
s uccessf ull y c o nti n ue d t h era p y f oll o wi n g o nset of ras h. 
A Es will be ma p pe d t o a Me dical Dicti o nar y f or R e g ulat or y Acti vities ( Me d D R A) pr eferre d 
ter m a n d s yste m or ga n class ( S O C). T he occ urre n ce of T E A Es will be s u m marize d usi n g 
Me d D R A pref err e d ter ms, S O Cs, a n d se verit y. Se parate s u m mari es of T E A Es, 
treat me nt-e mer ge nt S A Es, A Es c o nsi dere d relate d t o st u d y dr u g, a n d A Es lea di n g t o st u d y dr u g 
i nterr u pti o n will be ge ner ate d. All A Es will be liste d f or i n di vi d ual s u bjects s h o wi n g b ot h 
ver bati m a n d pr eferre d ter ms.  
Descri pti ve s u m maries f or vital si g ns, wei g ht, be dsi de E C G para met ers, a n d cli nical la b orat or y 
res ults will be prese nte d. La b orat or y a b n or malities will be gra de d acc or di n g t o t he D MI D A d ult 
T o xicit y Ta ble ( P u blis h Date: Draft, N o ve m ber 2 0 0 7; A p pe n di x 1).  
A n y gra de d a b n or malit y t hat occ urs f oll o wi n g t he i nitiati o n of st u d y dr u g a n d re pres e nts at least 
1- gra de i n crease fr o m t he baseli ne ass ess me nt is defi ne d as treat me nt e mer ge nt. T he n u m ber a n d 
perce nt a ge of s u bjects e x perie nci n g tr eat me nt -e m er ge nt gra de d t o xicities will be s u m marize d . 
La b orat or y t o xicit y s hifts fr o m baseli ne t o w orst p ost- baseli ne assess me nts will be s u m marize d.  
T he n u m ber a n d p erce nta ge of s u bjects ha vi n g el e vati o ns i n li ver e nz y me a b n or malities ( A L T, 
A S T, or bilir u bi n) i n relati o n t o f ol d a b o ve U L N will be s u m marize d acc or di n g t o t he 
Pre mar keti n g Cli nical E val uati o n o n Dr u g- I n d u ce d Li ver I nj ur y G ui da n ce f or I n d ustr y. 
Cli nicall y si g nifica nt a b n or mal m or p h ol o gical E C G fi n di n gs will be s u m marize d.  
T he c ha n g e fr o m bas eli ne i n Q Tc F will be deter mi ne d b y r o uti ne E C Gs. At eac h ti me p oi nt 
E C Gs are a n al yze d, a n i n di vi d ual s u bject’s c ha n ge fr o m baseli ne will be cal c ulate d as:  
∆i k= ( Q Tc F f or s u bject at ti me p oi nt k – Baseli ne Q Tc F)  
F or s u bjects w h o are directl y r olli n g o ver fr o m a pre vi o us st u d y, t he pretreat me nt E C G val ue 
o btai ne d at t he fi nal o n- tr eat me nt visit i n t he pre vi o us st u d y will ser ve as t he baseli ne E C G 
val ue.  
F or r o uti ne E C Gs, t he n u m ber a n d pr o p orti o n of s u bjects wit h Q Tc F ≤ 4 5 0, > 4 5 0 t o ≤ 4 8 0, 
> 4 8 0 t o ≤ 5 0 0, a n d > 5 0 0 msec; or c ha n g es of ≤ 3 0, > 3 0 t o ≤ 6 0, or > 6 0 msec will be 
s u m marize d.  
P h ysical e xa mi nati o n fi n di n gs will be liste d.  

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C o nc o mita nt me dicati o ns a n d t h ose disc o nti n ue d d uri n g t he st u d y will be c o de d usi n g t he W orl d 
Healt h Or ga ni zati o n dr u g dicti o nar y a n d s u m marize d. S u bjects wit h me dicati o ns c ha n ges pri or 
t o baseli ne ma y als o be s u m marize d.  
1 4. 3. 6.  
A n al ysis of Cli nic al Me as ure me nts of P N H  
Cli nical meas ure me nts of P N H (e g, L D H, h e m o gl o bi n, a bs ol ute retic ul oc yt e c o u nt, ha pt o gl o bi n 
le vels, n u m ber of bl o o d tra nsf usi o ns, i nci de nce of B T H, i nci de nce of t hr o m b oses a n d maj or 
t hr o m b oses, A S T, t otal bilir u bi n, a n d direct bilir u bi n) will be s u m marize d b y s u m mar y statistics, 
i ncl u di n g c ha n ge fr o m baseli ne, b y treat me nt gr o u p a n d st u d y visit. Cate g orical meas ure me nts 
will be s u m marize d wit h fre q ue n cies a n d p erce nta ges b y treat me nt gr o u p a n d st u d y visit. 
Brea kt hr o u g h he m ol ysis is defi ne d as ≥ 1 ne w or w orse ni n g s y m pt o m/si g n of i ntra vasc ular 
he m ol ysis (fati g ue, he m o gl o bi n uria, a b d o mi nal pai n, d ys p nea, a ne mia [ he m o gl o bi n < 1 0 g/ d L], 
maj or a d vers e vasc ul ar e ve nt [i ncl u di n g t hr o m b osis], d ys p ha gia, or erectile d ysf u ncti o n) i n t he 
prese nce of lactate de h y dr o ge na se ( L D H) ≥ 2 ti mes t he u p per li mit of n or mal ( U L N). Fre q ue nc y 
of B T H a n d ti me t o first B T H will be s u m marize d b y treat me nt gr o u p.  
1 4. 3. 7.  
A n al ysis of Effecti ve ness V ari a bles f or P N H  
T he f oll o wi n g eff ecti ve n ess e n d p oi nts will be s u m marize d a n d liste d: 
•  D ura bilit y of res p o nse  
•  Cate g orizati o n of r es p o nse acc or di n g t o t he criteria i n Secti o n 1 4. 3. 7. 1  
•  P R Os: Q L Q -A A/ P N H, F A CI T fati g ue scale, T S Q M sc ores  
•  Cli nical meas ur e me nts of P N H ( L D H, he m o gl o bi n, ha pt o gl o bi n, retic ul oc ytes, 
tra nsf usi o n re q uir e me nts) 
•  S u bjects wit h d ose escalati o n  
•  Disc o nti n uati o ns d ue t o lac k of efficac y 
•  Disease se v erit y  
 Details of t hese a n al yses will be pr o vi de d i n t he S A P. 
1 4. 3. 7. 1.  He m at ol o gic al Res p o nse C a te g o ries 
He mat ol o gical res p o ns e will be assesse d e v er y 6 m o nt hs acc or di n g t o t he criteria pr o p os e d b y 
Risita n o a n d c ollea g ues (Risita n o, Mar otta, et al. 2 0 1 9 ). He m o gl o bi n a n d R B C tra nsf usi o ns will 
be pri maril y use d t o assess res p o nse. A d diti o nall y, L D H a n d a bs ol ute retic ul oc yte c o u nt ( A R C) 
will be use d t o disti n g uis h bet wee n c o m plete a n d maj or res p o nse (Ta ble  7): 
T a ble 7:  
He m at ol o gic al Res p o nse C ate g o ries 
Res p o nse 
C ate g or y  
R B C 
Tr a nsf usi o ns  
He m o gl o bi n 
( g/ d L) a 
L D H × U L N a 
A R C (/ μ L)a 
C o m plete res p o nse  
N o ne  
≥ 1 2  
≤ 1. 5  
≤ 1 5 0, 0 0 0  
Maj or res p o nse  
N o ne  
≥ 1 2  
> 1. 5  
Or > 1 5 0, 0 0 0  

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1 5.  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  
1 5. 1.  
St u d y M o nit ori n g  
Bef ore a n i n v esti gati o nal site ca n e nter a s u bject i nt o t he st u d y, a re pres e nt ati ve of Bi o Cr yst will 
visit t he i n vesti gati o nal st u d y site t o:  
•  Deter mi ne t he a de q uac y of t he facilities  
•  Disc uss wit h t he i n vesti gat or(s) a n d ot h er pers o n n el t heir res p o nsi bilities wit h re gar d 
t o pr ot oc ol a d her e nce, a n d t he res p o nsi bilities of Bi o Cr yst or its re prese ntati ves. T his 
will be d oc u me nte d i n a Cli nical St u d y A gree me nt bet wee n Bi o Cr yst a n d t he 
i n vesti gat or. 
D uri n g t he st u d y, a m o nit or fr o m Bi o Cr yst or re prese ntati ve will ha ve re g u lar c o ntacts wit h t he 
i n vesti gati o nal site, f or t he f oll o wi n g: 
•  Pr o vi de i nf or mati o n a n d s u p p ort t o t he i n vesti gat or(s) 
•  C o nfir m t hat facilities re mai n acce pta ble  
•  C o nfir m t hat t he i n vesti gati o nal tea m is a d heri n g t o t he pr ot oc ol, t hat data are bei n g 
acc ur atel y r ec or d e d i n t he case re p ort f or ms, a n d t hat i n vesti gati o nal pr o d uct 
acc o u nta bilit y c hec ks ar e bei n g perf or m e d 
•  Perf or m s o urce data v erificati o n. T his i ncl u des a c o m paris o n of t he data i n t he case 
re p ort f or ms wit h t he s u bject’s me dical rec or ds at t he h os pital or practice, a n d ot her 
rec or ds rele v a nt t o t he st u d y. T his will re q uire direct access t o all ori gi nal rec or ds f or 
eac h s u bject (e g, cli nic c harts).  
•  Rec or d a n d r e p ort a n y pr ot oc ol de viati o ns n ot pre vi o usl y se nt t o Bi o Cr yst. 
•  C o nfir m A Es a n d S A Es ha ve bee n pr o perl y d oc u me nte d o n e C R Fs a n d c o nfir m a n y 
S A Es ha ve bee n f or w ar d e d t o Bi o Cr yst. 
T he m o nit or will be a vaila ble bet wee n visits if t he i n vesti gat or(s) or ot her st aff nee ds 
i nf or mati o n or a d vice.  
1 5. 2.  
A u dits a n d I ns pecti o ns  
A ut h orize d r e pres e ntati ves of Bi o Cr yst, a re g ulat or y a ut h orit y, a n I E C or a n I R B ma y visit t he 
site t o perf or m a u dits or i ns pecti o ns, i ncl u di n g s o urce dat a verifi cati o n. T he p ur p ose of a 
Bi o Cr yst a u dit or i ns pecti o n is t o s yste maticall y a n d i n de pe n de ntl y e xa mi n e all st u d y- relate d 
acti vities a n d d oc u me nts t o deter mi ne w het her t hese acti vities were c o n d ucte d, a n d data w ere 
rec or d e d, a n al yze d, a n d acc urat el y re p ort e d acc or di n g t o t he pr ot oc ol, G C P g ui deli nes of t he 
I C H, a n d a n y a p plica ble re g ulat or y r e q uire me nts. T he i n vesti gat or s h o ul d c o ntact Bi o Cr yst 
i m me diatel y if c o ntacte d b y a re g ulat or y a ge n c y a b o ut a n i ns pecti o n. 

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1 6.  
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  
T o e ns ure c o m plia n ce wit h G o o d Cli nical Practices a n d all a p plica ble re g ul at or y re q uire me nts, 
Bi o Cr yst ma y c o n d uct a q ualit y ass u ra nce a u dit. Please see Secti o n 1 5. 2  f or m ore details 
re gar di n g t he a u dit pr ocess. 
1 7.  
R E G U L A T O R Y A N D E T HI C A L C O N SI D E R A TI O N S  
1 7. 1.  
Et hics Re vie w  
Bef ore i nitiati o n of t he st u d y at t he i n vesti gati o nal site, t he pr ot oc ol, I C F, s u bject i nf or mati o n 
s heet (if a p plica ble), writte n i nf or mati o n pr o vi de d t o s u bjects a n d a n y ot her rele va nt st u d y 
d oc u me ntati o n will be s u b mitte d t o t he a p pr o priate I R B/I E C. Writte n a p pr o val of t he st u d y m ust 
be o btai ne d bef ore t he i n vesti gati o nal me dici nal pr o d uct is releas e d t o t he I n vesti gat or a n d t he 
st u d y site ma y be o pe ne d f or e nr oll me nt. A n y necessar y e xte nsi o ns or re n e wals of I R B/I E C 
a p pr o val m ust be o btai ne d f or c ha n g es t o t he st u d y s uc h as m o dificati o n of t he pr ot oc ol, I C F, 
writte n i nf or mati o n pr o vi de d t o s u bjects, a n d/ or ot her pr oce d ures. After t h e pr ot oc ol has bee n 
s u b mitte d, a n y a me n d me nt m ust be a gree d b y t he I n v esti gat or aft er disc ussi o n wit h t he S p o ns or 
a n d will be f or mall y d oc u me nte d. All s u bsta ntial a me n d me nts will be s u b mitte d f or a n o pi ni o n 
as re q uire d b y c urre nt re g ulati o ns.  
Writte n re p orts of cli nical st u d y stat us will be s u b mitte d t o t he I R B/I E C i n acc or d a nce wit h t he 
a p plica ble r e g ulati o ns. T he I R B/I E C will be pr o m ptl y pr o vi de d a n y ne w i nf or mati o n t hat ma y 
a d versel y aff ect t he safet y of t he s u bjects or t he c o n d uct of t he st u d y. T he st u d y will be 
c o nsi dere d t o be c o m plet e d o nce t he l ast s u bject c o m pletes t he last st u d y visit (f oll o w- u p visit 
after t he l ast st u d y d ose). A fi nal st u d y n otificati o n will als o be f or war de d t o t he I R B/I E C a n d 
c o m pete nt a ut h orit y after t he st u d y is c o m plete d or i n t he e ve nt of pre mat ure ter mi nati o n of t he 
st u d y i n acc or da n ce wit h t he a p plica ble re g ulati o ns.  
C o pies of all c o ntacts wit h t he I R B/I E C s h o ul d be mai ntai ne d i n t he st u d y file. C o pies of cli nical 
st u d y stat us re p orts (i ncl u di n g ter mi nati o n) s h o ul d be pr o vi de d t o Bi o Cr yst. 
1 7. 2.  
Et hic al C o n d uct of t he St u d y  
T he st u d y will be perf or me d i n acc or d a nce wit h t he pr ot oc ol a n d et hical pri nci ples t hat ha ve 
t heir ori gi n i n t he Declar ati o n of Helsi n ki a n d are c o nsiste nt wit h I C H/ G C P, a p plica ble 
re g ulat or y r e q uire me nts a n d Bi o Cr yst’s p olic y o n Bi oet hics. 
1 7. 3.  
Writte n I nf or me d C o nse nt  
T he I n vesti gat or(s) at eac h ce nter will e ns ure t hat t he s u bject is gi ve n f ull a n d a de q uate oral a n d 
writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p ossi ble ris k a n d be nefit of t he st u d y. S u bjects 
m ust als o be n otifie d t hat t he y are free t o disc o nti n ue fr o m t he st u d y at a n y ti me. T he s u bject 
s h o ul d be gi ve n t he o p p ort u nit y t o as k q uesti o ns a n d all o we d ti me t o c o nsi der t he i nf or mati o n 
pr o vi de d. 

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T he s u bject’s si g ne d a n d date d i nf or me d c o nse nt m ust be o btai ne d bef ore c o n d ucti n g a n y st u d y 
pr oce d ur es. 
T he I n vesti gat or(s) m ust mai ntai n t he ori gi nal, si g ne d I C F. 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 s u bject. 
1 7. 4.  
I ns ur a nce 
I ns ura nce c o vera g e s hall be pr o vi de d i n acc or d a nce wit h t he re g ulati o ns of eac h i n di vi d ual 
c o u ntr y f or all s u bjects e nr olle d i n t he trial fr o m t he ti me of t he s u bject’s i ncl usi o n i nt o t he trial 
(ie, fr o m t he ti me i nf or m e d c onse nt is gi ve n). A p pr o priate i ns ura n ce c o vera ge is pr o vi de d b y t he 
S p o ns or, i n li ne wit h le gal re q uire m e nts a n d I C H- G C P g ui da nce a n d i n acc or da nce wit h t he 
(l ocal) r e g ulati o ns of eac h i n di vi d ual c o u ntr y. 
1 7. 5.  
P a y me nt t o S u bjects  
Reas o na ble c o m p e nsati o n t o st u d y s u bjects a n d rei m b urse me nt of tra vel e x pe nses ( w h ere 
a p plica ble) will be pr o vi de d as a p pr o v e d b y t he I R B/I E C res p o nsi ble f or t he st u d y at t he 
I n v esti gat or’s site. 
1 7. 6.  
Tre at me nt After a S u bject’s St u d y C o m pleti o n or Wit h dr a w al  
F oll o wi n g c o m pleti o n of t he pla n ne d st u d y treat m e nt, or f oll o wi n g earl y wit h dra wal, s u bjects 
will be offer e d t he sta n dar d car e off ere d b y t h eir st u d y ce nter. 
1 8.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  
1 8. 1.  
I ns pecti o n of Rec or ds 
Bi o Cr yst will be all o we d t o c o n d uct site visits t o t he i n vesti gati o n facilities f or t he p ur p ose of 
m o nit ori n g a n y as pect of t he st u d y. T he I n vesti gat or a grees t o all o w t he m o nit or t o i ns pect t he 
dr u g st ora ge area, st u d y dr u g st oc ks, dr u g acc o u nta bilit y rec or ds, s u bject c harts a n d st u d y s o urce 
d oc u me nts, a n d ot her r ec or ds relati ve t o st u d y c o n d uct. 
1 8. 2.  
Rete nti o n of Rec or ds  
T he Pri nci pal I n vesti gat or m ust mai ntai n all d oc u me ntati o n relati n g t o t he st u d y f or a peri o d of 
2 years after t he l ast mar keti n g a p plicati o n a p pr o v al, or if n ot a p pr o ve d 2 y ears f oll o wi n g t he 
disc o nti n ua nce of t he t est article f or i n v esti gati o n. If it bec o mes necessar y f or Bi o Cr yst or t he 
Re g ulat or y A ut h orit y t o re vie w a n y d o c u me ntati o n relati n g t o t he st u d y, t he I n vesti gat or m ust 
per mit access t o s uc h rec or ds.  
1 8. 3.  
C o nfi de nti alit y of I nf or m ati o n a n d D at a  
Bi o Cr yst affir ms t he s u bject’s ri g ht t o pr otecti o n a gai nst i n vasi o n of pri vac y a n d sec ure 
mai nte na nce of t he c o nfi de ntial nat ure of his/ her pers o nal data. O nl y a s u bject i de ntificati o n 
n u m ber a n d s u bject i de ntifiers per mitte d b y l ocal re g ulati o n will i de ntif y s u bject data retrie ve d 
b y Bi o Cr yst. H o we ver, i n c o m plia nce wit h fe d eral re g ulati o ns, Bi o Cr yst re q uires t he I n vesti gat or 

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t o per mit Bi o Cr yst’s re prese ntati ves a n d, w h e n necessar y, re prese ntati ves of t he F D A or ot her 
re g ulat or y a ut h orities t o r e vie w a n d/ or c o p y a n y m e dical rec or ds rele va nt t o t he st u d y, 
mai ntai ni n g pse u d o a n o n y mit y. 
All parties will a bi de b y all a p plica ble la ws a n d re g ulati o ns re gar di n g s u bject pri vac y a n d 
c o nfi de ntialit y, i ncl u di n g t he Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A), 
w here t his r ule is a p plica ble, a n d t he re q uire me nts of t he Ge neral D ata Pr otecti o n Re g ulati o n i n 
t he E U, w her e a p plica ble. A vali d a ut h orizati o n a n d c o nse nt m ust meet t he s pecificati o ns of t he 
a p plica ble la ws a n d re g ul ati o ns relati n g t o s uc h pers o nal data a n d h ealt h i nf or mati o n. It is t he 
res p o nsi bilit y of t he I n v esti gat or a n d i nstit uti o n t o o btai n s uc h wai ver/ a ut h orizati o n i n writi n g 
fr o m t he a p pr o priate i n di vi d ual. HI P A A a ut h orizati o ns are re q uire d f or U S sites o nl y. 
1 9.  
P U B LI C A TI O N P O LI C Y  
All da ta ge ner ate d fr o m t his st u d y are t he pr o pert y of Bi o Cr yst a n d s hall be hel d i n strict 
c o nfi de nce al o n g wit h all i nf or mati o n f ur nis he d b y Bi o Cr yst. E xce pt as pr o vi de d t hr o u g h writte n 
a gree m e nt bet wee n Bi o Cr yst, i n de pe n de nt a n al ysis a n d/ or p u blicati o n of t he se data b y t he 
I n v esti gat or or a n y m e m ber of his/ her staff is n ot per mitte d wit h o ut pri or writte n c o nse nt of 
Bi o Cr yst. S uc h c o nse nt will n ot be wit h hel d u nreas o na bl y. Bi o Cr yst is i n a gree m e nt wit h t he 
pri nci ple of f ull discl os ur e of cli nical trial res ults.  
 

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2 0.  
LI S T O F R E F E R E N C E S  
Ale xi o n P har mace uticals, I. ( 2 0 2 0). S oliris (ec uliz u ma b) i njecti o n f or i ntra ve n o us use U S 
Prescri bi n g I nf or m ati o n, Ale xi o n P har mace uticals, I n c. 
Ale xi o n P har mace uticals, I. ( 2 0 2 1). Ult o miris (ra v uliz u ma- c w vz) i njecti o n, f or i ntra ve n o us us e 
U S prescri bi n g i nf or mati o n, Ale xi o n P har mace uti cals, I nc. 
A pellis ( 2 0 2 1). E m pa veli ™ ( pe gcet ac o pla n) i njecti o n, f or s u bc uta ne o us us e. F ull prescri bi n g 
i nf or mati o n. 
A pellis ( 2 0 2 2). A S P A V E LI S M P C. 
B or o witz, M. J., F. E. Cr ai g, J. A. Di gi use p pe, A. J. Illi n g w ort h, W. R osse, D. R. S ut herla n d, C. 
T. Witt wer, S. J. Ric har ds, a n d S. Cli nical C yt o metr y ( 2 0 1 0). " G ui deli nes f or t he dia g n osis a n d 
m o nit ori n g of par o x ys mal n oct ur nal he m o gl o bi n uria a n d relat e d dis or ders b y fl o w c yt o metr y." 
C yt o metr y  B Cli n C yt o m  7 8 ( 4): 2 1 1- 3 0. 
Br o ds k y, R. A. ( 2 0 1 4). " Par o x ys mal n oct ur nal he m o gl o bi n uria." Bl o o d 1 2 4 ( 1 8): 2 8 0 4- 1 1. 
Br o ds k y, R. A., N. S. Y o u n g, E. A nt o ni oli, A. M. Risita n o, H. Sc hreze n mei er, J. Sc h u bert, A. 
Ga ya, L. C o yle, C. de Castr o, C. L. F u, J. P. Macieje ws ki, M. Bessler, H. A. Kr o o n, R. P. R ot her, 
a n d P. Hill me n ( 2 0 0 8). " 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 p atie nts wit h par o x ys mal n oct ur n al he m o gl o bi n uria." Bl o o d 1 1 1 ( 4): 1 8 4 0- 7. 
C h o w, K. M., F. M. Lai, A. Y. Wa n g, Y. L. C ha n, N. L. Ta n g, a n d P. K. Li ( 2 0 0 1). " Re versi ble 
re nal f ail ure i n par o x ys m al n oct ur nal he m o gl o bi n uria." A m J Ki d ne y Dis  3 7 ( 2): E 1 7. 
F D A ( 2 0 1 9). " Se ver el y De bilitati n g or Life- T hreate ni n g He mat ol o gic Dis or ders: N o ncli nical 
De vel o p me nt of P har m ace uticals." F D A G ui da nce f or I n d ustr y  
P h ar m ac ol o g y/ T o xic ol o g y ( D H H S C D E R). 
F D A, U. ( 2 0 2 0, 0 9 A pril 2 0 2 0). " Or p ha n Dr u g Desi g nati o ns a n d A p pr o vals." Retrie ve d A pril 9, 
2 0 2 0, fr o m htt ps:// w w w.access data.f d a. g o v/scri pts/ o p dlisti n g/ o o p d/i n de x.cf m . 
Fi g uer oa, J. E., a n d P. De nse n ( 1 9 9 1). "I nfecti o us diseases ass oci ate d wit h c o m ple me nt 
deficie nci es." Cli n Micr o bi ol Re v  4 ( 3): 3 5 9- 9 5. 
Ge, M., X. Li, J. S hi, Y. S ha o, a n d Y. Z he n g ( 2 0 1 2). " Cli nical feat ures a n d pr o g n ostic fact ors of 
Asia n patie nts wit h par o x ys mal n oct ur nal he m o gl o bi n uria: res ults fr o m a si n gle ce nter i n C hi na." 
A n n He mat ol 9 1 ( 7): 1 1 2 1- 8. 
Ger ber, G. F., X. Y ua n, J. Y u, B. A. Y. C her, E. M. Bra u nstei n, S. C hat ur ve di, a n d R. A. 
Br o ds k y ( 2 0 2 1). " C O VI D- 1 9 Vacci nes I n d u ce Se vere H e m ol ysis i n Par o x ys mal N oct ur nal 
He m o gl o bi n uria." Bl o o d. 
Gra ha m, M. L., W. F. R osse, E. C. Hal peri n, C. R. Miller, a n d R. E. Ware ( 1 9 9 6). " Res ol uti o n o f 
B u d d- C hiari s y n dr o me f oll o wi n g b o ne marr o w tra ns pla ntati o n f or par o x ys mal n oct ur nal 
hae m o gl o bi n uria." Br J Hae mat ol  9 2 ( 3): 7 0 7- 1 0. 
G uasc h, A. ( 2 0 1 0). "I m pr o vi n g re nal o utc o mes i n c hr o nic a n e mia: lear ni n g fr o m par o x ys mal 
n oct ur nal he m o gl o bi n uri a." A m J He mat ol  8 5 ( 8): 5 5 1- 2. 

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Harris, J. W., R. K osci c k, H. M. Lazar us, J. R. Es hle ma n, a n d M. E. Me d of ( 1 9 9 9). " Le u k e mia 
arisi n g o ut of par o x ys mal n oct ur nal he m o gl o bi n uria." Le u k L y m p h o ma 3 2 ( 5- 6): 4 0 1- 2 6. 
Ha user, A. C., A. Bri c hta, I. Pa bi n g er- Fasc hi n g, a n d U. Ja ger ( 2 0 0 3). " Fi bri n ol ytic t hera p y wit h 
rt- P A i n a patie nt wit h par o x ys mal n oct ur nal he m o gl o bi n uria a n d B u d d- C hiari s y n dr o me." A n n 
He mat ol  8 2 ( 5): 2 9 9- 3 0 2. 
Heller, P. G., A. R. Gri n ber g, M. Le nci o ni, M. M. M oli na, a n d A. J. R o nc or o ni ( 1 9 9 2). 
" P ul m o nar y h y perte nsi o n i n par o x ys mal n oct ur nal he m o gl o bi n uria." C hest  1 0 2 ( 2): 6 4 2- 3. 
Hill, A., A. E. De Zer n, T. Ki n os hita, a n d R. A. Br o ds k y ( 2 0 1 7). " Par o x ys mal n oct ur nal 
hae m o gl o bi n uria." Nat R e v Dis Pri mers  3 : 1 7 0 2 8. 
Hill, A., R. J. Kell y, a n d P. Hill me n ( 2 0 1 3). " 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 1 2 1 ( 2 5): 4 9 8 5- 9 6; q uiz 5 1 0 5. 
Hill me n, P., M. Ele b ute, R. Kell y, A. Ur ba n o-Is piz ua, A. Hill, R. P. R ot her, G. K h ursi gara, C. L. 
F u, M. O mi ne, P. Br o w n e, a n d W. R osse ( 2 0 1 0). " L o n g- ter m effect of t h e c o m ple me nt i n hi bit or 
ec uliz u ma b o n ki d ne y f u ncti o n i n patie nts wit h par o x ys mal n oct ur nal he m o gl o bi n uria." A m J 
He mat ol  8 5 ( 8): 5 5 3- 9. 
Hill me n, P., S. M. Le wis, M. Bessler, L. L uzzatt o, a n d J. V. Dacie ( 1 9 9 5). " Nat ural hist or y of 
par o x ys mal n oct ur nal h e m o gl o bi n uria." N E n gl J Me d 3 3 3 ( 1 9): 1 2 5 3- 8. 
Hill me n, P., P. M u us, A. R ot h, M. O. Ele b ute, A. M. Risita n o, H. Sc hreze n meier, J. Szer, P. 
Br o w ne, J. P. Macieje ws ki, J. Sc h u bert, A. Ur ba n o-Is piz ua, C. de Castr o, G. S ocie, a n d R. A. 
Br o ds k y ( 2 0 1 3). " L o n g- t er m safet y a n d efficac y of s ustai ne d ec uliz u ma b treat me nt i n patie nts 
wit h par o x ys mal n oct ur n al hae m o gl o bi n uria." Br J Hae mat ol  1 6 2 ( 1): 6 2- 7 3. 
Hill me n, P., N. S. Y o u n g, J. Sc h u bert, R. A. Br o ds k y, G. S ocie, P. M u us, A. R ot h, J. Szer, M. O. 
Ele b ute, R. Na ka m ur a, P. Br o w ne, A. M. Risita n o, A. Hill, H. Sc hreze n meier, C. L. F u, J. 
Macieje ws ki, S. A. R olli ns, C. F. M ojci k, R. P. R ot her, a n d L. L uzzatt o ( 2 0 0 6). " T he 
c o m ple me nt i n hi bit or ec uliz u ma b i n par o x ys mal n oct ur nal he m o gl o bi n uri a." N E n gl J Me d 
3 5 5 ( 1 2): 1 2 3 3- 4 3. 
H olers, V. M. ( 2 0 0 8). " T he s pectr u m of c o m ple me nt alter nati ve p at h wa y- me diate d diseases." 
I m m u n ol Re v 2 2 3 : 3 0 0- 1 6. 
Jac ks o n, G. H., R. S. N o ble, Z. T. Ma u n g, J. Mai n, S. R. S mit h, a n d M. M. Rei d ( 1 9 9 2). " Se vere 
hae m ol ysis a n d re nal fail ure i n a patie nt wit h par o x ys mal n oct ur nal hae m o gl o bi n uria." J Cli n 
Pat h ol 4 5 ( 2): 1 7 6- 7. 
Jai n, P. ( 2 0 1 0). " A n u n us ual ca use of B u d d- C hiari s y n dr o me: par o x ys mal n oct ur nal 
he m o gl o bi n uria." J Gastr oi ntesti n Li ver Dis 1 9 ( 1): 1 0 7- 8. 
Jal bert, J. J., U. C ha u d hari, H. Z ha n g, J. We y ne, a n d J. M. S ha m m o ( 2 0 1 9). " E pi de mi ol o g y of 
P N H a n d Real - W orl d Tr eat me nt Patter ns F oll o wi n g a n I nci de nt P N H Di a g n osis i n t he U S." 
Bl o o d 1 3 4 ( S u p ple me nt _ 1): 3 4 0 7-. 
Kell u m, J. A., N. La mier e, P. As peli n, R. S. Bars o u m, E. A. B ur d ma n n, S. L. G ol dstei n, C. A. 
Hertz o g, M. J oa n ni dis, A. Kri b be n, A. S. Le ve y, A. M. Mac Le o d, R. L. M e hta, P. T. M urra y, S. 
Naic ker, S. M. O p al, F. S c haef er, M. Sc het z, a n d S. Uc hi n o ( 2 0 1 2). "I m pr o vi n g gl o bal o utc o mes 

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( K DI G O) ac ute ki d ne y i nj ur y w or k gr o u p. K DI G O cli nical practice g ui deli ne f or ac ute ki d ne y 
i nj ur y." Ki d ne y I nt S u p pl 2 ( 1): 1 4- 1 3 8. 
Kr o ger, A., L. Ba hta, a n d P. H u nter. ( 2 0 2 1). " Ge n eral Best Practice G ui deli nes f or 
I m m u nizati o n. Best Practices G ui da nce of t he A d vis or y C o m mittee o n I m m u nizati o n Practices 
( A CI P)." Retrie ve d Marc h 1 1, 2 0 2 1, fr o m w w w.c dc. g o v/ vacci n es/ hc p/aci p- recs/ ge n eral-
recs/ d o w nl oa ds/ ge n eral-r ecs. p df. 
Lesa vre, P. H., a n d H. J. M uller- E ber h ar d ( 1 9 7 8). " Mec ha nis m of acti o n of fact or D of t he 
alter nati ve c o m ple m e nt pat h wa y." J E x p Me d 1 4 8 ( 6): 1 4 9 8- 5 0 9. 
M bae yi, S. A. B., C. H.; D uff y, J.; R u bi n, L. G.; Hariri, S.; Ste p he ns, D. S.; Mac Neil, J. R. ( 2 0 2 0). 
Me ni n g oc occal Vacci nati o n: Rec o m me n dati o ns of t he A d vis or y C o m mittee o n I m m u nizati o n 
Practices, U nite d States, 2 0 2 0. C D C M or bi dit y a n d M ortalit y Wee kl y Re p ort. C. K. Ke nt. 6 9: 1-
3 2. 
Nair, R. K., A. K haira, A. S har ma, S. Ma haja n, a n d A. K. Di n da ( 2 0 0 8). " S pectr u m of re nal 
i n v ol ve me nt i n par o x ys mal n oct ur nal he m o gl o bi n uria: re p ort of t hree cases a n d a brief re vie w of 
t he literat ure." I nt Ur ol N e p hr ol 4 0 ( 2): 4 7 1- 5. 
Pa n g b ur n, M. K., a n d H. J. M uller- E ber h ar d ( 1 9 8 3). "I nitiati o n of t he alter n ati ve c o m ple me nt 
pat h wa y d ue t o s p o nta ne o us h y dr ol ysis of t he t hi oester of C 3." A n n N Y A ca d Sci  4 2 1 : 2 9 1- 8. 
Par ker, C., M. O mi ne, S. Ric har ds, J. Nis hi m ura, M. Bessler, R. Ware, P. Hill me n, L. L uzzatt o, 
N. Y o u n g, T. Ki n os hita, W. R osse, G. S ocie, a n d P. N. H. I. G. I nter n ati o nal ( 2 0 0 5). " Dia g n osis 
a n d ma na ge m e nt of par o x ys mal n oct ur nal he m o gl o bi n uria." Bl o o d 1 0 6 ( 1 2): 3 6 9 9- 7 0 9. 
Par ker, C. J. ( 2 0 0 9). " B o ne marr o w fail ure s y n dr o mes: par o x ys mal n oct ur n al he m o gl o bi n uria." 
He mat ol O nc ol Cli n N ort h A m  2 3 ( 2): 3 3 3- 4 6. 
Par ker, C. J. ( 2 0 1 2). " Par o x ys mal n oct ur nal he m o gl o bi n uria." C urr O pi n He mat ol 1 9 ( 3): 1 4 1- 8. 
P u, J. J., a n d R. A. Br o ds k y ( 2 0 1 1). " Par o x ys mal n oct ur nal he m o gl o bi n uri a fr o m be n c h t o 
be dsi de." Cli n Tra nsl Sci  4 ( 3): 2 1 9- 2 4. 
Rac hi di, S., K. M. M usalla m, a n d A. T. Ta h er ( 2 0 1 0). " A cl oser l o o k at p ar o x ys mal n oct ur nal 
he m o gl o bi n uria." E ur J I nter n Me d  2 1 ( 4): 2 6 0- 7. 
Ra m, S., L. A. Le wis, a n d P. A. Rice ( 2 0 1 0). "I nfecti o ns of pe o ple wit h c o m ple me nt deficie nci es 
a n d patie nts w h o ha ve u n der g o ne s ple n ect o m y." Cli n Micr o bi ol Re v  2 3 ( 4): 7 4 0- 8 0. 
Ric kli n, D., E. S. Reis, a n d J. D. La m bris ( 2 0 1 6). " C o m ple me nt i n disease: a defe n ce s yste m 
t ur ni n g offe nsi ve." Nat R e v Ne p hr ol 1 2 ( 7): 3 8 3- 4 0 1. 
Risita n o, A. M., S. Mar otta, P. Ricci, L. Mara n o, C. Frieri, F. Cacace, M. Sica, A. K ulase k araraj, 
R. T. Cala d o, P. Sc hei n ber g, R. N otar o, a n d R. Peffa ult de Lat o ur ( 2 0 1 9). " A nti- c o m ple me nt 
Treat me nt f or Par o x ys mal N oct ur nal He m o gl o bi n uria: Ti me f or Pr o xi mal C o m ple me nt 
I n hi biti o n? A P ositi o n Pa per Fr o m t he S A A W P of t he E B M T." Fr o nt I m m u n ol  1 0 : 1 1 5 7. 
Risita n o, A. M., R. N otar o, L. Mara n d o, B. Seri o, D. Ra nal di, E. Se neca, P. Ricci, F. Alfi nit o, A. 
Ca mera, G. Gi a nfal d o ni, A. A me n d ola, C. B osc hetti, E. Di B o na, G. Fr atell a nza, F. Bar b a n o, F. 
R o de g hier o, A. Za n ella, A. P. I ori, C. Selleri, L. L uzzatt o, a n d B. R ot oli ( 2 0 0 9). " C o m ple me nt 

Bi o Cr yst P har mace uticals, I n c.  
Pr ot oc ol Versi o n 5. 0 
C O N FI D E N TI A L  
B C X 9 9 3 0- 2 0 1 
 
8 4 
fracti o n 3 bi n di n g o n er yt hr oc ytes as a d diti o nal mec ha nis m of disease i n p ar o x ys mal n oct ur nal 
he m o gl o bi n uria patie nts treate d b y ec uliz u ma b." Bl o o d 1 1 3 ( 1 7): 4 0 9 4- 1 0 0. 
R ot h, A., S. T. R otti n g ha us, A. Hill, E. S. Bac h ma n, J. S. Ki m, H. Sc hreze n meier, L. Terri o u, A. 
Ur ba n o-Is pi z ua, R. A. Wells, J. H. Ja n g, A. G. K ulase kararaj, J. Szer, R. A g uzzi, A. I. 
Da m o k os h, L. S haf ner, a n d J. W. Lee ( 2 0 1 8). " Ra v uliz u ma b ( A L X N 1 2 1 0) i n patie nts wit h 
par o x ys mal n oct ur nal h e 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 ( 1 7): 2 1 7 6-
8 5. 
R ot her, R. P., L. Bell, P. Hill me n, a n d M. T. Gla d wi n ( 2 0 0 5). " T he cli nical se q uelae of 
i ntra vasc ular h e m ol ysis an d e xtracell ular plas ma h e m o gl o bi n: a n o vel mec h a nis m of h u ma n 
disease." J A M A 2 9 3 ( 1 3): 1 6 5 3- 6 2. 
Sa va ge, W. J., a n d R. A. Br o ds k y ( 2 0 0 7). " Ne w i nsi g hts i nt o par o x ys mal n oct ur nal 
he m o gl o bi n uria." He mat ol o g y 1 2 ( 5): 3 7 1- 6. 
Sc hreze n m eier, H., P. M u us, G. S ocie, J. Szer, A. Ur ba n o-Is pi z ua, J. P. Macieje ws ki, R. A. 
Br o ds k y, M. Bessler, Y. Ka na k ur a, W. R osse, G. K h ursi gara, C. Be dr osi a n, a n d P. Hill me n 
( 2 0 1 4). " Baseli ne c h aracteristics a n d disease b ur de n i n patie nts i n t he I nter n ati o nal Par o x ys mal 
N oct ur nal He m o gl o bi n uria Re gistr y." Hae mat ol o gica  9 9 ( 5): 9 2 2- 9. 
Sec hi, L. A., A. Mari glia n o, a n d R. Te d de ( 1 9 8 8). " Ve n o us t hr o m b osis a n d ac ute re nal fail ure i n 
par o x ys mal n oct ur nal h ae m o gl o bi n uria." Ne p hr ol Dial Tra ns pla nt 3 ( 5): 7 0 8- 9. 
S ocie, G., J. Y. Mar y, A. de Gra m o nt, B. Ri o, M. Le p orrier, C. R ose, P. He u dier, H. R oc ha nt, J. 
Y. Ca h n, a n d E. Gl uc k m a n ( 1 9 9 6). " Par o x ys mal n oct ur nal hae m o gl o bi n uria: l o n g- ter m f oll o w-
u p a n d pr o g n ostic fact ors. Fre n c h S ociet y of H ae mat ol o g y." La ncet  3 4 8 ( 9 0 2 7): 5 7 3- 7. 
S ocie, G., H. Sc hreze n m eier, P. M u us, I. Lis u k o v, A. R ot h, A. K ulase kararaj, J. W. Lee, D. 
Arate n, A. Hill, R. Br o ds k y, A. Ur ba n o-Is piz ua, J. Szer, A. Wils o n, P. Hill me n, a n d P. N. H. 
Re gistr y ( 2 0 1 6). " C ha n gi n g pr o g n osis i n par o x ys mal n oct ur nal hae m o gl o bi n uria disease 
s u bcate g ories: a n a nal ysis of t he I nter n ati o nal P N H Re gistr y." I nter n Me d J 4 6 ( 9): 1 0 4 4- 5 3. 
T orres, J., B. De Vr oe y, M. P. N oel, B. N otte g he m, a n d J. F. C ol o m bel ( 2 0 1 0). " Rec urre nt s mall 
b o wel isc he mia i n a patie nt wit h par o x ys mal n oct ur nal he m o gl o bi n uria." Nat Re v Gastr oe nter ol 
He pat ol  7 ( 7): 4 1 0- 4. 
V ola na kis, J. E., a n d S. V. L. Nar a ya na ( 1 9 9 6). " C o m ple me nt fact or D, a n o vel seri ne pr otease." 
Pr otei n Sci  5 ( 4): 5 5 3- 6 4. 
X u, Y., S. V. Nar a ya na, a n d J. E. V ola na kis ( 2 0 0 1). " Str uct ural bi ol o g y of t he alter nati ve 
pat h wa y c o n v ertase." I m m u n ol Re v 1 8 0 : 1 2 3- 3 5. 
Yi n, D. L., L. X. Li u, S. G. Z ha n g, L. T. Tia n, Z. Y. L u, a n d H. C. Jia n g ( 2 0 0 9). " P ortal 
h y perte nsi o n res ulte d fr o m par o x ys mal n oct ur nal he m o gl o bi n uria: a cas e re p ort a n d re vie w of 
literat ure." I nt J He m at ol 8 9 ( 3): 3 0 2- 4. 
Zia kas, P. D., L. S. P o ul o u, a n d A. P o m o ni ( 2 0 0 8). " 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 at a gla n ce: a cli nical re vie w." C urr Vas c P har mac ol  6 ( 4): 3 4 7- 5 3. 

Bi o Cr yst P har mace uticals, I n c.  
Pr ot oc ol Versi o n 5. 0 
C O N FI D E N TI A L  
B C X 9 9 3 0- 2 0 1 
 
8 5 
Zi pfel, P. F., C. S ker ka, Q. C he n, T. Wiec h, T. G o o ds hi p, S. J o h ns o n, V. Fre mea u x- Bacc hi, C. 
Nester, S. R. de C or d o ba, M. N oris, M. Pic keri n g, a n d R. S mit h ( 2 0 1 5). " T he r ole of 
c o m ple me nt i n C 3 gl o mer ul o pat h y." M ol I m m u n ol 6 7 ( 1): 2 1- 3 0. 

Bi o Cr yst P har mace uticals, I n c.  
Pr ot oc ol Versi o n 5. 0 
C O N FI D E N TI A L  
B C X 9 9 3 0- 2 0 1 
8 6 
2 1.  
A P P E N DI C E S
A P P E N DI X 1: D MI D A D U L T T O XI CI T Y T A B L E ( D R A F T: N O V E M B E R 2 0 0 7)  
C o pies of t he D MI D T o xicit y Ta ble will be a vaila ble t o me dical staff t hr o u g h o ut t he pr oject.  

DI VI SI O N O F MI C R O BI O L O G Y A N D I N F E C TI O U S 
DI S E A S E S ( D MI D) A D U L T T O XI CI T Y T A B L E  
N O V E M B E R 2 0 0 7  
D R A F T  
 
 
A B B R E VI A TI O N S :  A b bre viatio ns utilize d i n t he Ta ble:  
U L N = U p p er Li mit of N or mal             L L N = Lo wer Li mit of N or mal  
R x   = T hera p y                                         Re q = Re q uire d  
M o d = M o dera te                                     I V  = I ntra ve no us  
A D L =  A cti vities of Dail y Li vi n g          De c = Decreas e d  
 
E S TI M A TI N G S E V E RI T Y G R A D E  
F or  a b nor malities  N O T  fo u nd  else w here  i n  t he  To xicit y  T a bles  use  t he  scale  belo w  t o 
esti mate gra de of s e verit y: 
G R A D E 1  
Mil d     
 
Tra nsie nt or mil d disc o mf ort  
 
( < 4 8 ho urs); no medical i nter ve nti o n/t hera p y re q uir e d  
G R A D E 2  
M o de rate   
 
Mild  t o  
mo derate  li mitatio n  i n 
acti vit y - s o me  assista nce  ma y  be  nee de d;  no  or  mi ni mal 
me dical i nter ve ntio n/t hera p y re q uire d  
G R A D E 3  
Se ve re    
 
Mar ke d  li mit atio n  i n  acti vit y,  s o me 
assista nce  us uall y  r e q u ire d;  me dical  i nter ve nti o n/t hera p y 
re q uire d, hos pit alizati o ns p ossi ble 
G R A D E 4  
Life -t hre ate ni ng 
E xtre me  
li mitatio n  
i n  
acti vit y, 
si g nifica nt  assist a nce  re q uire d;  si g nifica nt  
me dical 
i nter ve ntio n/t hera p y  re q uire d,  hos pitalizati o n  or  hos pice 
care pr o ba ble  
 
S E RI O U S O R LI F E -T H R E A T E NI N G  A Es  
 
A N Y  cli nical  e ve n t  dee me d  b y  t he  cli nicia n  t o  be  seri o us  or  life-t hr eate ni n g  s ho uld  be 
c o nsi dere d  a  gra de  4  e ve nt.    Cli nical  e ve nts  c o nsi dere d  t o  be  seri o us  or  life -t hreate ni n g 
i ncl ude,  b ut  are  not  li mit e d  t o:   seiz ures,  c o ma,  tet a n y,  dia betic  ket oacid osis, 
disse mi nat e d  i ntra vasc ular  c oa g ulati o n,  diff use  petec hiae,  paral ysis,  ac ute  ps yc hosis, 
se vere de pressio n.  
 
C O M M E N T S R E G A R DI N G T H E  U S E O F  T H E S E  T A B L E S  
 
• 
Sta nd ar dize d  a nd  c o m m o nl y  use d  t o xicit y  ta bles  ( Di visi o n  of  AI D S,  N CI’ s 
C o m m o n T o xicit y  Criteria ( C T C), a nd W orl d Healt h Or ga nizati o n ( W H O))  ha ve 
bee n  a da pte d  for  use  b y  t he  Di visi o n  of  Micr o bi olo g y  a nd  I nfectio us  Dis eases 
( D MI D) a nd m o difie d t o better meet t he nee ds of partici pa nts i n D MI D trials.  
 
•  
F or para meter s not i ncl u de d i n t he foll o wi n g To xicit y Ta bles, sites s ho uld refer t o 
t he “ G ui de F or Esti mati n g Se verit y Gra de ”  lo cate d a b o ve. 
 
• 
Criteria are ge n erall y gr o upe d b y b o d y s yste m.  
 
• 
S o me pr ot oc ols ma y ha ve a d ditio nal pr ot oc ol s p ecific gra di n g criteria, w hic h will 
superce de t he use of t hese ta bles f or s pe cifie d criteria.  

DI VI SI O N O F MI C R O BI O L O G Y A N D I N F E C TI O U S 
DI S E A S E S ( D MI D) A D U L T T O XI CI T Y T A B L E  
N O V E M B E R 2 0 0 7  
D R A F T  
 
 
H E M A T O L O G Y  
 
 
 
 
Gra d e 1  
 
Gra d e 2  
 
Gra d e 3  
 
Gra d e 4  
 
He mo gl o bi n  
 
9. 5 - 1 0. 5 g  m/ d L  
 
8. 0  - 9. 4 g  m/ d L  
 
 6. 5 - 7. 9 g  m/ d L  
 
< 6. 5 g  m/ d L  
 
A bs ol ut e Ne utr o p hil Co u nt  
 
1 0 0 0 -1 5 0 0/  m m 3  
 
7 5 0 -9 9 9/  m m 3  
 
5 0 0 - 74 9/  m m 3  
 
< 5 0 0/ m m 3  
 
Plat elets  
 
7 5, 0 0 0 -
9 9, 9 9 9/ m m 3  
 
5 0, 0 0 0 -
7 4, 9 9 9/ m m 3  
 
2 0, 0 0 0 -4 9, 9 9 9/ m m 3  
 
< 2 0, 0 0 0/  m m 3  
W B Cs  
1 1, 0 0 0 -1 3, 0 0 0 / 
m m 3  
1 3, 0 0 0 - 
1 5, 0 0 0 / m m 3  
1 5, 0 0 0 - 
3 0, 0 0 0/ m m 3  
> 3 0, 0 0 0 or 
< 1, 0 0 0 / m m 3  
% P ol y mor p h o n u cle ar 
Le u c o c yt es + Ba n d Cells  
 > 8 0 %  
9 0 –  9 5 %  
> 9 5 %  
---------- 
 
 
A b n or mal  
Fi bri n o g e n  
Lo w :  
1 0 0 -2 0 0 mg/ d L  
 
Hi g h:  
4 0 0 -6 0 0 mg/ d L  
Lo w :  
< 1 0 0 mg/ d L  
 
Hi g h:  
> 6 0 0 mg/ d L  
Lo w :  
< 5 0 mg/ d L  
 
 
    ---------- 
Fi bri n o g e n 
ass o ciat e d wit h 
gr oss ble e di n g or 
wit h 
dis s e mi n at e d 
c o a g ulati o n 
 
Fi bri n S plit Pr o d u ct  
 
2 0 -4 0 mc g/ ml  
 
4 1 - 50  mc g / ml  
 
5 1 -6 0 mc g/ ml  
 
>  6 0   mc g / ml  
 
Pr ot hr o mbi n  
Ti me  ( P T )  
 
1. 0 1 - 1. 2 5 x U L N  
 
1. 2 6 -1. 5 x U L N  
 
1. 5 1 -3. 0 x U L N  
 
> 3 x U L N  
 
A cti v at e d Partial 
T hr o mb o plasti n ( A P P T)  
 
1. 0 1 -1. 6 6 x U L N  
 
1. 6 7 - 2. 3 3 x 
U L N  
 
2. 3 4 - 3 x U L N  
 
> 3 x U L N  
 
M et h e mo gl o bi n  
 
5. 0 - 9. 9 % 
 
1 0. 0 - 1 4. 9 %  
 
1 5. 0 - 1 9. 9 %  
 
> 2 0. 0 %  

DI VI SI O N O F MI C R O BI O L O G Y A N D I N F E C TI O U S 
DI S E A S E S ( D MI D) A D U L T T O XI CI T Y T A B L E  
N O V E M B E R 2 0 0 7  
D R A F T  
 
 
C H E MI S T RI E S  
   
 
Gra d e 1  
 
Gra d e 2  
 
Gra d e 3  
 
Gra d e 4  
 
H y p o n atre mia  
 
1 3 0 -1 3 5 m Eq/ L  
 
 1 2 3 -1 2 9 
m Eq / L  
 
1 1 6 -1 2 2 m Eq/ L  
 
< 1 1 6 m Eq/ L or 
a b n or mal s o di u m 
wit h  me nt al 
st at us c h a n ges or 
s eizures  
 
H y p er n atre mia  
 
1 4 6 -1 5 0 m Eq/ L  
 
1 5 1 -1 5 7 m Eq/ L  
 
1 5 8 -1 6 5 m Eq/ L  
 
> 1 6 5 m Eq/ L or 
a b n or mal s o di u m 
wit h me nt al 
st at us c h a n ges or 
s eizures  
 
H y p o kale mia  
 
3. 0 - 3. 4 m Eq/ L  
 
2. 5 - 2. 9 m Eq/ L  
 
2. 0 - 2. 4 m Eq/ L  
or i nt e nsi v e 
re pla c e me nt 
t h era p y or 
h os pit ali zati o n 
re q uire d 
 
< 2. 0 m Eq/ L  or 
a b n o r ma l 
p ot assi u m wit h  
 p ares is , ile us  or 
life-t hre at e ni n g 
arr h yt h mia  
 
H y p er ka le  mia  
 
5. 6 - 6. 0 m Eq/ L  
 
6. 1 - 6. 5 m Eq/ L  
 
6. 6 - 7. 0 m Eq/l  
 
> 7. 0 m Eq/ L  
or a b n or mal 
p ot assi u m  wit h 
life-t hre at e ni n g 
arr h yt h mia  
 
H y p o gl y c e mia  
 
5 5 -6 4 m g/ d L  
 
4 0 -5 4 m g/ d L  
 
3 0 -3 9 m g/ d L  
 
< 3 0 mg/ d L or 
a b n or mal gl u c os e 
wit h  me nt al 
st at us c h a n ges or 
c o ma  
 
H y p er gl y c e mia  
( n o nfasti n g a n d n o pri or 
dia b et es) 
 
1 1 6 - 1 6 0 m g/ d L  
 
1 6 1 - 2 5 0 
mg / d L  
 
2 5 1 - 5 0 0 m g/ d L  
 
> 5 0 0 mg/ d L  or  
a b n or mal gl u c os e 
wit h ket o a ci d osis  
 or s ei zures  
 
H y p o c alc e mia  
(c orre ct e d f or al b u mi n) 
 
8. 4 - 7. 8 mg/ d L  
 
7. 7 - 7. 0 mg/ d L  
 
6. 9 - 6. 1 mg/ d L  
 
< 6. 1 mg/ d L  
or a b n or mal 
c alci u m wit h  life 
t hre at e ni n g 
arr h yt h mia or 
t et a n y 
 
 
 
 
 
 

DI VI SI O N O F MI C R O BI O L O G Y A N D I N F E C TI O U S 
DI S E A S E S ( D MI D) A D U L T T O XI CI T Y T A B L E  
N O V E M B E R 2 0 0 7  
D R A F T  
 
C H E MI S T RI E S (c o nti n ue d)  
 
 
 
Gra d e 1  
 
Gra d e 2  
 
Gra d e 3  
 
Gra d e 4  
 
H y p erc alc e mia  
(c orre ct f or al b u  mi n) 
 
1 0. 6 - 1 1. 5 mg/ d L  
 
1 1. 6 - 1 2. 5 
mg / d L  
 
1 2. 6 - 1 3. 5 mg/ d L  
 
> 1 3. 5 mg/ d L or  
a b n or mal c alci u m 
wit h life 
t hre at e ni n g 
arr h yt h mia  
 
H y p o ma g n es e mia  
 
1. 4 - 1. 2 m Eq/ L  
 
1. 1 - 0. 9 m Eq/ L  
 
0. 8 - 0. 6 m Eq/ L  
 
<  0. 6  m Eq / L o r  
a b n or mal 
ma g n e s i u m wit h 
life-t hre at e ni n g 
arr h yt h mia 
 
H y p o p h os p h at e mia  
 
2. 0 - 2. 4 mg/ d L  
 
1. 5 -1. 9 m g/ d L 
or  
re pla c e me nt R x 
re q uire d 
 
1. 0 -1. 4 m g/ d L  
i nt e nsi v e t h era p y  
or  
h os pit ali zati o n 
re q uire d 
 
< 1. 0 mg/ d L or 
a b n or mal 
p h os p hat e wit h 
life-t hre at e ni n g 
arr h yt h mia  
 
H y p er bilir u bi n e mia  ( w h e n 
a c c o mp a nie d b y a n y i n cre as e 
i n ot h er li v er f u n cti o n t est) 
 
1. 1 - <1. 2 5 x U L N  
 
1. 2 5  - < 1 . 5 x 
U L N  
 
1. 5  – 1. 7 5  x U L N  
 
> 1. 7 5  x U L N  
 
H y p er bilir u bi n e mia ( w h e n 
ot h er li v er f u n cti o n are i n t h e  
n or mal ra n g e ) 
 
1. 1 - < 1. 5 x U L N  
 
1. 5 - < 2. 0 x 
U L N  
 
2. 0 – 3. 0 x U L N  
 
> 3. 0 x U L N  
 
B U N 
 
1. 2 5 - 2. 5 x U L N  
 
2. 6 - 5 x U L N  
 
5. 1 - 1 0 x U L N  
 
> 1 0 x U L N  
H y p er uric e mia ( uric a ci d)  
7. 5 –  1 0. 0 mg/ d L  
1 0. 1 –  1 2. 0 
mg / d L  
1 2. 1 –  1 5. 0 mg/ d L  
> 1 5. 0 mg/ d L  
 
 
 
Cre at i ni n e  
 
1. 1 - 1. 5 x U L N  
 
1. 6 - 3. 0 x U L N  
 
3. 1 - 6 x U L N  
 
> 6 x U L N or  
dial ys is  re q uire d  

DI VI SI O N O F MI C R O BI O L O G Y A N D I N F E C TI O U S 
DI S E A S E S ( D MI D) A D U L T T O XI CI T Y T A B L E  
N O V E M B E R 2 0 0 7  
D R A F T  
 
 
E N Z Y M E S  
 
 
 
Gra d e 1  
 
Gra d e 2  
 
Gra d e 3  
 
Gra d e 4  
 
A S T ( S G O T)  
 
1. 1 - < 2. 0 x U L N  
 
2. 0 – < 3. 0  x U L N  
 
3. 0  – 8. 0  x  U L N  
 
> 8 x  U L N  
 
A L T  ( S G P T )  
 
1. 1 - < 2. 0 x U L N  
 
2. 0 – < 3. 0 x U L N  
 
3. 0 – 8. 0 x U L N  
 
> 8 x U L N  
 
G G T  
 
1. 1 - < 2. 0 x U L N  
 
2. 0 – < 3. 0 x U L N  
 
3. 0 – 8. 0 x U L N  
 
> 8 x U L N  
 
Al kali n e P h os p hat as e  
 
1. 1 - < 2. 0 x U L N  
 
2. 0 – < 3. 0 x U L N  
 
3. 0 – 8. 0 x U L N  
 
> 8 x U L N  
 
A my la s e  
 
1. 1 - 1. 5 x U L N  
 
1. 6 - 2. 0 x U L N  
 
2. 1 - 5. 0 x U L N  
 
> 5. 1 x U L N  
Li p as e  
 
1. 1 - 1. 5 x U L N  
 
1. 6 - 2. 0 x U L N  
 
2. 1 - 5. 0 x U L N  
 
> 5. 1 x U L N  
 
 
U RI N A L Y SI S  
 
 
 
Gra d e 1  
 
Gra d e 2  
 
Gra d e 3  
 
Gra d e 4  
Pr ot ei n uria  
 
1 +  
 or  
2 0 0 mg  - 1  g m 
l os s/ d a y 
 
2- 3 +  
or  
1- 2 g  m 
l os s/ d a y 
 
4 +  
 or  
2- 3. 5 g  m l os s / d ay  
 
n e p hr otic 
s y n dr o me  
or  
>  3. 5 g  m  l os s / d a y  
He ma t u ria  
 
micr os c o pic o nl y  
< 1 0 r b c/ h pf  
 
gr oss, n o cl ots  
> 1 0 r b c/ h pf  
 
gr oss, wit h or 
wit h o ut cl ots, O R 
re d bl o o d c ell c asts 
 
o bstr u cti v e or 
re q uire d 
tra nsf usi o n 

DI VI SI O N O F MI C R O BI O L O G Y A N D I N F E C TI O U S 
DI S E A S E S ( D MI D) A D U L T T O XI CI T Y T A B L E  
N O V E M B E R 2 0 0 7  
D R A F T  
 
 
C A R DI O V A S C U L A R  
 
 
 
Gra d e 1  
 
Gra d e 2  
 
Gra d e 3  
 
Gra d e 4  
 
Car dia c Rh yt h m  
 
 
 
as y mpt o matic, 
tra nsie nt si g ns, 
n o  
R x re q uire d  
 
re c urre nt/ p ersist ent; 
s y mpt o matic R x 
re q uire d 
 
u nst a ble 
d ysr yt h mia; 
h os pit ali zati o n 
a n d tre at me nt 
re q uire d 
 
H y p ert e nsi o n  
 
tra nsie nt i n cre as e 
> 2 0 m m/ H g; n o 
tre at me nt 
 
re c urre nt, 
c hr o nic 
i n cre as e 
 > 2 0 m m/ H g.  
/tre at me nt 
re q uire d 
 
a c ut e tre at me nt 
re q uire d; o ut p atie nt 
tre at me nt or 
h o s pit ali zati o n 
p ossi ble  
 
e n d or g a n 
d a ma g e or 
h os pit ali zati o n 
re q uire d 
 
H y p ot e nsi o n  
 
tra nsie nt 
ort h ost atic 
h y p ot e nsi o n wit h 
h e art rat e i n cre as e d 
b y < 2 0 b e at/ mi n or 
d e cre as e d b y < 1 0 
m m H g s yst olic 
B P, N o tre at me nt 
re q uire d 
 
s y mpt o ms d u e 
t o ort h ost atic 
h y p ot e nsi o n or 
B P d e cre as e d 
b y < 2 0 m m H g 
s ys t olic; 
c orre ct a ble 
wit h ora l  fl u i d 
tre at me nt 
 
re q uires I V fl ui ds; 
n o h os pit ali zati o n 
re q uire d 
 
me a n art erial 
press ure  
< 6 0 m m/ H g  or 
e n d or g a n 
d a ma g e or s h o c k;   
re q uires 
h os pit ali zati o n 
a n d v as o press or 
tre at me nt 
 
Peri c a r dit is  
 
mi ni mal eff usi o n  
 
mil d/ mo d erat e 
as y mpt o matic 
eff usi o n, n o 
tre at me nt 
 
s y mpt o matic 
eff usi o n; p ai n; 
E K G c h a n g es  
 
t a mp o n a d e; 
p eric ar di o c e nt esis 
or s ur g er y 
re q uire d 
 
He morr h a g e, Bl o o d Los s  
 
micr os c o pic/ o c c ult  
 
mil d, n o 
tra nsf usi o n 
 
gr oss bl o o d l oss;  
1- 2 u nits tra nsf us ed  
 
mas si v e bl o o d 
l os s; > 3 u nits 
tra nsf us e d 

DI VI SI O N O F MI C R O BI O L O G Y A N D I N F E C TI O U S 
DI S E A S E S ( D MI D) A D U L T T O XI CI T Y T A B L E  
N O V E M B E R 2 0 0 7  
D R A F T  
 
 
R E S PI R A T O R Y  
  
 
 
Gra d e 1  
 
Gra d e 2  
 
Gra d e 3  
 
Gra d e 4  
 
Co u g h  
 
tra nsie nt- n o 
tre at me nt 
 
p ersist ent 
c o u g h; 
tre at me nt 
res p o nsi v e 
 
Par o xys mal c o u g h; 
u n c o ntr olle d wit h 
tre at me nt 
-------------------- 
 
Br o n c h os p as m, A c ut e  
 
tra nsie nt; n o 
tre at me nt; 
7 0 %  - 8 0 % F E V1  
of p e a k fl o w  
 
re q uires 
tre at me nt; 
n or mali zes wit h 
br o n c h o dilat or;  
F E V 1  5 0 %  - 
7 0 %  
( of p e a k fl o w) 
 
n o n or mali zati o n 
wit h 
br o n c h o dilat or;  
F E V 1  2 5 %  - 5 0 %  
of p e a k fl o w; or  
retra cti o ns present 
 
c y a n os is : F E V1  
< 2 5 %  
of p e a k fl o w or 
i nt u b ati o n 
n e c ess ar y  
D ys p n e a  
 
d ys p n e a o n 
e xe rt i o n  
d ys p n e a wit h 
n or ma l a cti v it y  
d ys p n e a at rest  
d ys p n e a re q uiri n g 
O xy g e n t h era p y  

DI VI SI O N O F MI C R O BI O L O G Y A N D I N F E C TI O U S 
DI S E A S E S ( D MI D) A D U L T T O XI CI T Y T A B L E  
N O V E M B E R 2 0 0 7  
D R A F T  
 
 
G A S T R OI N T E S TI N A L  
 
 
 
Gra d e 1  
 
Gra d e 2  
 
Gra d e 3  
 
Gra d e 4  
 
Na us e a  
 
mil d or tra nsie nt; 
ma i nt ai ns  
re as o n able i nt a ke 
 
mo d erat e 
dis c o mf ort; 
i nt a ke 
d e cre as e d 
s i g nific a ntl y; 
s o me a cti vit y 
li mit e d 
 
n o si g nific a nt 
i nt a ke; re q uires I V 
fl u i ds 
h os pit ali zati o n 
re q uire d; 
 
Vo  mit i n g  
 
1 e pis o d e i n 2 4 
h o urs  
2 -5 e pis o d es i n 
2 4 h o urs  
> 6 e pis o d es i n 2 4 
h o urs or n e e di n g 
I V  fl ui ds 
 
 
 
p h ysi ol o gic 
c o ns e q u en c es 
re q uiri n g 
h os pit ali zati o n or 
re q uiri n g 
p are nt eral 
n utriti o n  
 
Co nsti p ati o n  
 
re q uiri n g st o ol 
s oft e n er or diet ar y 
mo dific ati o n  
re q uiri n g 
la xat i v es 
o bsti p ati o n 
re q uiri n g ma n u al 
e v a c u ati o n or 
e n e ma  
 
o bst r u cti o n or 
t o xic me g a c ol o n 
 
Dia rr h e a  
 
mil d or tra nsie nt; 
3- 4 l o os e 
st o ols/ da y or mil d 
diarr h e a last < 1 
we e k  
 
mo d erat e or 
p ersist ent; 5 -7 
l o os e st o ols/ d a y 
or diarr h e a 
las ti n g > 1  we e k 
> 7 l o os e st o ols/ da y 
or bl o o d y diarr h e a; 
or ort h ostatic 
h y p ot e nsi o n or 
ele ctr ol yt e 
i mb ala n c e or > 2 L 
I V fl ui ds re q uire d  
 
 
h y p ot e nsi v e 
s h oc k or 
p h ysi ol o gic 
c o ns e q u en c es 
re q uiri n g 
h os pit ali zati o n   
 
Oral Dis c o mf ort/ D ys p h a gia  
 
mil d dis c o mf ort; 
n o diffic ult y 
s wall o wi n g  
 
s o me li mits o n 
e ati n g/ dri n ki n g  
 
e ati n g/t al ki n g v er y 
li mit e d; u n a ble t o 
s wall o w s oli d 
f o o ds 
 
u n a ble t o dri n k 
fl u i ds ; re q uires  
I V  fl ui ds 
 
 

DI VI SI O N O F MI C R O BI O L O G Y A N D I N F E C TI O U S 
DI S E A S E S ( D MI D) A D U L T T O XI CI T Y T A B L E  
N O V E M B E R 2 0 0 7  
D R A F T  
 
 
N E U R O L O GI C A L  
  
 
 
Gra d e 1  
 
Gra d e 2  
 
Gra d e 3  
 
Gra d e 4  
 
Ne ur o -Cere b ellar  
 
s li g ht 
i n c o or di n ati o n 
d ys dia d o c h o ki n esis  
 
i nt e nti o n 
tre mo r, 
d ys metria, 
sl urre d s p e e c h; 
n yst a g mus  
 
lo c o mot or at a xia  
 
i n c a p a cit at e d 
 
Ps y c hiatric  
 
mil d a n xiet y or 
d e pressi o n  
 
mo d erat e 
a n xiet y or 
d e pressi o n; 
t h era p y 
re q uire d; 
c h a n g e i n 
n or mal r o uti n e  
 
s e v ere mo o d 
c h a n g es re q uiri n g  
t h era p y; or s uici d al 
i d e ati o n;  or 
a g gressi v e i d e ati o n  
 
a c ut e ps y c h osis 
re quiri n g 
h os pit ali zati o n;  
or s uici d al 
g est ure/ atte mpt 
or h all u ci n ati o ns  
 
M us cle Stre n gt h  
 
s u bje cti v e 
we a k n es s  
n o o bje cti v e 
s y mpt o ms/ si g ns 
 
mil d o bje cti v e  
si g ns/s y mpt o ms  
n o d e cre as e i n 
f u n cti o n 
 
o bje cti v e we a k n es s 
f u n cti o n li mit e d  
 
p aral ys is  
Parest h esia ( b ur ni n g, ti n gli n g, 
et c.) 
mil d dis c o mf ort; 
n o tre at me nt  
re q uire d 
mo d erat e 
dis c o mf ort; 
n o n -n arc otic 
a n al g esia 
re q uire d 
s e v ere dis c o mf ort; 
or n arc otic 
a n al g esia re q uire d 
wit h s y mpt o matic 
i mpr o v e me nt 
i n c a p a cit ati n g; or 
n ot res p o nsi v e t o 
n arc otic a n al g esia  
N e ur o -s e ns or y 
mil d i m p air me nt i n 
s e ns ati o n 
( d e cre as e d 
s e ns ati o n, e. g., 
vi brat or y, pi n pric k, 
h ot/ col d i n gre at 
t o es) i n f o c a l are a  
or s y m metric al 
distri b uti o n; or 
c h a n g e i n t ast e, 
s  mell,  vis i o n 
a n d/ or h e ari n g 
mo d erat e 
i mp air me nt 
( mo d d e cre as e d 
s e ns ati o n, e. g., 
vi brat or y, 
pi n pric k, 
h ot/ col d t o 
a n kles) a n d/ or 
j oi nt p ositi o n or 
mil d 
i mp air me nt t h at 
is n ot 
s y m metric al 
s e v ere i mp air me nt 
( d e cre as e d or l os s 
of s e ns ati o n t o 
k n e es or wrists) or 
l os s of s ensati o n of 
at le ast mo d d e gre e 
i n  mult i ple  
differe nt b o d y 
are as (i.e., u p p er 
a n d l o wer 
e xtre  mities )  
s e ns or y l oss 
i n v ol v es li mbs 
a n d tr u n k; 
p aral ysis;  or  
s eizures  

DI VI SI O N O F MI C R O BI O L O G Y A N D I N F E C TI O U S 
DI S E A S E S ( D MI D) A D U L T T O XI CI T Y T A B L E  
N O V E M B E R 2 0 0 7  
D R A F T  
 
 
M U S C U L O S K E L A T E L  
 
 
 
Gra d e 1  
 
Gra d e 2  
 
Gra d e 3  
 
Gra d e 4  
Art hral gia  
(j o i nt p ai n) 
mil d p ai n n ot 
i nt erferi n g wit h 
f u n cti o n 
mo d erat e p ai n, 
a n al g esics 
a n d / or p ai n 
i nt erferi n g wit h 
f u n cti o n b ut n ot 
wit h a cti v ities  
of d ail y li vi n g  
s e v ere p ai n; p ai n 
a n d/ or a n al g esics 
i nt erferi n g wit h 
a cti vities  of d ail y 
li v i n g 
dis a bli n g p ai n  
Art hritis  
mil d p ai n wit h 
i nfla  m mat i o n, 
er yt h e ma or j oi nt 
s welli n g – b ut n ot 
i nt erferin g wit h 
f u n cti o n 
mo d erat e p ai n 
wit h 
i nfla  m mat i o n, 
er yt h e ma or 
j oi nt s welli n g – 
i nt erferi n g wit h 
f u n cti o n, b ut 
n ot wit h 
a cti vities  of 
d ail y  li v i n g  
s e v ere p ai n wit h 
i nfla  m mat i o n, 
er yt h e ma or j oi nt 
s welli n g – a n d 
i nt erferi n g wit h 
a cti vities  of d ail y 
li v i n g 
p er ma n e nt a n d/ or 
dis a bli n g j oi nt 
distr u cti o n  
M y al gia  
my al gia  wit h  n o 
li mit at i o n of  
a cti vit y  
mus cle 
t e n d er n ess (at 
ot h er t h a n 
i nje cti o n s it e) 
or wit h 
mo d erat e 
i mp air me nt of 
a cti vit y  
s e v ere mus cle 
t e n d er n ess wit h 
ma r ke d   i mp a ir me n t 
of a cti vit y  
fra n k 
my o n e cr osi s 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DI VI SI O N O F MI C R O BI O L O G Y A N D I N F E C TI O U S 
DI S E A S E S ( D MI D) A D U L T T O XI CI T Y T A B L E  
N O V E M B E R 2 0 0 7  
D R A F T  
 
S KI N  
 
 
 
Gra d e 1  
 
Gra d e 2  
 
Gra d e 3  
 
Gra d e 4  
M u c o c ut a n e o us  
er yt h e ma; pr urit us  
diff us e, ma c ul o 
p a p ular ras h, 
dr y 
d es q u a mati o n  
v es ic ulati o n  or 
mo is t 
d es q u a mati o n or 
ulc erati o n  
e xf oliati v e 
d er mat itis , 
mu c o us 
me mb ra n e 
i n v ol v e me nt or 
er yt h e ma, 
mu lt i f o r me o r  
s us p e ct e d 
St e v e ns -J o h ns o n 
or  n e cr osis 
re q uiri n g s ur g er y 
I n d urati o n 
< 1 5 m m  
1 5 -3 0 m m  
> 3 0 m m  
 
Er yt h e ma  
< 1 5 m m  
1 5 -3 0 m m  
> 3 0 m m  
 
Ed e ma  
< 1 5 m m  
1 5 -3 0 m m  
> 3 0 m m  
 
Ras h at I nje cti o n S it e  
< 1 5 m m  
1 5 -3 0 m m  
> 3 0 m m  
 
Pr urit us  
s li g ht it c hi ng at 
i nje cti o n s it e 
mo d erat e 
it c hi n g at 
i nje cti o n 
e xtre mit y  
it c hi n g o v er e ntire 
b o d y  
 
 
 
 
S Y S T E M I C  
 
 
Gra d e 1  
 
Gra d e 2  
 
Gra d e 3  
 
Gra d e 4  
 
Aller gic Re a cti o n  
 
pr urit us wit h o ut 
ras h 
 
l o c ali ze d 
urtic aria  
 
g e n erali ze d 
urtic aria; 
a n gi o e d e ma  
 
a n a p h yla xis  
He a d a c h e  
mil d, n o tre at me nt 
re q uire d 
tra nsie nt, 
mo d erat e; 
tre at me nt 
re q uire d 
s e v ere; res p o n ds t o 
i nitia l n arc otic  
t h era p y 
i ntra ct a ble; 
re q uires re p e at e d 
n arc otic t h era p y  
 
Fe v er: oral  
 
3 7. 7 - 3 8. 5 C or  
1 0 0. 0 - 1 0 1. 5 F  
 
3 8. 6 - 3 9. 5 C or  
1 0 1. 6 - 1 0 2. 9 F  
 
3 9. 6  - 4 0. 5 C or  
1 0 3 - 1 0 5 F  
 
> 4 0 C or  
> 1 0 5 F  
 
Fati g u e  
 
n or ma l a cti v it y 
re d u c e d < 4 8 h o urs 
 
 n or mal a cti vit y 
d e cre as e d 2 5 - 
5 0 % > 4 8 h o urs  
 
n or ma l a cti v it y 
d e cre as e d > 5 0 % 
c a n’t w or k  
 
u n a ble t o c are f or 
s elf