Clinical trial NCT04702568
Conditions: Paroxysmal Nocturnal Hemoglobinuria PNH
Keywords: BCX9930 Factor D inhibitor PNH paroxysmal Nocturnal Hemoglobinuria oral treatment
Sponsor: BioCryst Pharmaceuticals
Start date: 2020-12-18; Completion date: 2023-10-04
Enrollment: 19 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was designed to evaluate the long-term safety of daily oral treatment with BCX9930 in participants who had participated in a previous BCX9930 trial for PNH and showed a benefit of treatment as determined by the Investigator. The study allowed continued access to BCX9930 for enrolled participants. The study also evaluated the long-term effectiveness and impact on quality of life and general well-being of BCX9930 treatment, and the participant's satisfaction with the medication.

Detailed description:

Arms: arm 1: This group included participants who, prior to enrolling in their previous BCX9930 study, were either naïve to eculizumab or ravulizumab treatment, or naive to treatment with any complement inhibitor therapy (or had received no treatment in the prior 12 months), and with anemia due to ongoing intravascular hemolysis. arm 2: This group included participants who, prior to enrolling in their previous BCX9930 study, were receiving stable treatment with eculizumab or ravulizumab and had an inadequate response to that therapy (ie, residual anemia and/or ongoing need for transfusion). Depending on the prior study, participants may have continued the C5 inhibitor, with BCX9930 provided as an add-on therapy.
Interventions: intervention 1: BCX9930 intervention 2: Eculizumab intervention 3: Ravulizumab
Intervention descriptions: intervention 1: BCX9930 for oral administration intervention 2: Administered at stable dose at the time of study entry intervention 3: Administered at stable dose at the time of study entry

Protocol documents:
Prot_000.pdf: 
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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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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 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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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 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
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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:  
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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.  
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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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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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2.  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
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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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C O N FI D E N TI A L  
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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 6 
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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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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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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. 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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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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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 
st u d y assess me nts. 


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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. 
Pr o hi bite d me dicati o ns c urre ntl y i ncl u de (s ee als o Secti o n 8. 2 ): 
 
 
 
 
 
 
  
 
 
 
 
 
 
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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4 7 
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 
t he cli nical site i n t he La b orat or y Ma n u al. 


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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 
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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 
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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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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 3 
( 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 


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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 
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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 
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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 
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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 
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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 
 
 
  
  
 
  
 
  
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX9930-201 
 
1 of 64 
CONFIDENTIAL 
 
STATISTICAL ANALYSIS PLAN 
Study BCX9930-201 
 
DATE OF PLAN: 
Final Version 1.0 24 May 2023 
BASED ON: 
Protocol Version 5 Date 01 July 2022 
eCRF Date 18 January 2023 
STUDY DRUG: 
BCX9930 
PROTOCOL NUMBER: 
BCX9930-201 
STUDY TITLE: 
A PHASE 2, OPEN-LABEL STUDY TO EVALUATE THE LONG-TERM SAFETY OF ORAL 
BCX9930 IN SUBJECTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) 
SPONSOR: 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Blvd., Suite 200 Durham, NC 27703  
Phone: (919) 859-1302  
Fax: (919) 851-1416 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 
The information in this document contains proprietary and confidential information 
belonging to BioCryst Pharmaceuticals, Inc. As a result, no part of this document should be 
copied, referred to, released, published, or otherwise disclosed in any manner or media 
without prior written approval from BioCryst Pharmaceuticals, Inc. 






Statistical Analysis Plan 
 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX9930-201 
 
4 of 64 
CONFIDENTIAL 
TECHNICAL SUMMARY REPORT (TSR) 
Name of Sponsor/Company 
{Sponsor Name} 
Individual Study Table 
Referring to Part of the 
Dossier: 
 
Volume: 
(For National Authority Use 
Only): 
Name of Investigational 
Product: 
BCX9930 
Page: 
 
Name of Active Ingredient:  
 
 
Title Of Study: A Phase 2, Open-label Study to Evaluate the Long-Term Safety of Oral BCX9930 in 
Subjects with Paroxysmal Nocturnal Hemoglobinuria (PNH)  
Study Center(s): Centers that have participated in a previous BCX9930 PNH study 
Co-ordinating Investigator: 
 
Phase of development: 
2 


Statistical Analysis Plan 
 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX9930-201 
 
5 of 64 
CONFIDENTIAL 
Objectives 
Primary Objective: 
 
To assess long-term safety and tolerability data in eligible subjects with PNH who previously 
received BCX9930 in a BioCryst-sponsored study and derived benefit from BCX9930 treatment.  
Secondary Objectives: 
 
To assess the continued effectiveness of BCX9930 in treatment of PNH during long-term 
administration. 
 
To evaluate patient-reported outcomes (PRO) of long-term BCX9930 treatment 
 
To collect pharmacokinetic (PK), pharmacodynamic (PD), and complement biomarker data in 
subjects with PNH for incorporation into meta-study models of population PK and PK/PD. 
 
To characterize the effects of BCX9930 in subjects with PNH by clinical measurements and PD 
and complement biomarkers. 
 
To evaluate biomarkers of complement activation during episodes of breakthrough hemolysis 
(BTH). 
Primary Endpoint: 
 
Measurement of safety and tolerability by subject incidence of graded treatment-emergent adverse 
events (TEAEs), laboratory abnormalities, changes to vital signs, electrocardiogram (ECG) results, 
and physical examination findings. 
Secondary Endpoints: 
 
Clinical PNH symptom assessments including fatigue, dyspnea, chest pain/discomfort, difficulty 
swallowing (esophageal pain), abdominal pain, headache, erectile dysfunction, hemoglobinuria, 
jaundice, incidence of BTH, and incidence of thromboembolic events  
 
Clinical measurements of PNH (lactate dehydrogenase [LDH], hemoglobin, haptoglobin, 
reticulocytes, transfusion requirements). 
 
PRO endpoints will include scores from the Quality of Life Questionnaire for Patients with 
Aplastic Anemia/PNH (QLQ-AA/PNH), Functional Assessment of Chronic Illness Therapy 
(FACIT) fatigue scale, and Treatment Satisfaction Questionnaire for Medication (TSQM). 
 
Concentration of BCX9930 in plasma at steady state in subjects with PNH. 
Pharmacodynamic (PD) Endpoint: 
 
PD and complement biomarker measurements will include PNH red blood cell (RBC) and white 
blood cell (WBC) clone size, plasma Factor Bb levels and alternative complement pathway (AP) 
activity (as assessed via AP Wieslab). 
Exploratory Endpoints: 
 
 
 




Statistical Analysis Plan 
 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX9930-201 
 
7 of 64 
CONFIDENTIAL 
Number of Subjects (planned):  
Approximately 200 subjects based upon the anticipated clinical programs for BCX9930. 


Statistical Analysis Plan 
 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX9930-201 
 
8 of 64 
CONFIDENTIAL 
Inclusion Criteria: 
1. Able to provide written informed consent 
2. Male or non-pregnant, non-lactating female subjects 
3. Subjects who have successfully participated in a previous BCX9930 study of PNH and who 
experienced a clinical benefit, as confirmed by the Investigator. Successful participation is 
defined as completion of planned duration of dosing with BCX9930 in the prior study, not 
inclusive of any extension period. 
4. Female participants must meet at least 1 of the following contraception requirements: 
a. Be a woman of childbearing potential who agrees to use a highly effective 
contraceptive method throughout the study and for a duration of 30 days after the last 
dose of study drug. 
b. Alternatively, true abstinence is acceptable for women of childbearing potential when 
it is in line with the subject’s preferred and usual lifestyle. 
c. Be a woman of nonchildbearing potential. 
5. Male participants must meet the following contraception requirements: 
a. Subjects with female partners of childbearing potential must agree to utilize a highly 
effective contraceptive method. 
b. Alternatively, true abstinence is acceptable when it is in line with the subject’s 
preferred and usual lifestyle. 
6. In the opinion of the Investigator, the subject is expected to adequately comply with all 
required study procedures and restrictions for the duration of the study. 
Exclusion Criteria: 
1. Any clinically significant medical or psychiatric condition that, in the opinion of the 
Investigator or Sponsor, would interfere with the subject’s ability to participate in the study or 
participation would increase the risk for that subject. 
2. Any clinically significant history of angina, known coronary artery disease, myocardial 
infarction, syncope, clinically significant cardiac arrhythmias, left ventricular hypertrophy, 
cardiomyopathy, aortic stenosis, or any other cardiovascular abnormality. 
3. Chronic systemic corticosteroid use. Note: Topical, inhaled, ocular, or nasal sprays containing 
corticosteroids are allowed. 
4. Investigational drug exposure, other than BCX9930, within 30 days of the baseline visit, or 5.5 
half-lives of the investigational drug (whichever is longer). 
5.  For subjects requiring a screening visit: 
a. Clinically significant abnormal ECG at the screening visit. This includes, but is not limited to, a QT 
interval corrected using Fridericia's method (QTcF) > 450 msec in males and > 470 msec in females, or 
ventricular and/or atrial premature contractions that are more frequent than occasional, and/or as 
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b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × upper limit of normal 
(ULN) (Exception: Subjects may be enrolled with ALT or AST > 3 × ULN if explained by hemolysis. 
In these cases, ALT and AST must be < 5 × ULN.) 
c. Total serum bilirubin > 2 × ULN (Exceptions: Subject may be enrolled with total serum bilirubin > 2 
× ULN if the elevated bilirubin is explained by hemolysis or in the case of Gilbert’s syndrome. In the 
case of hemolysis, total serum bilirubin must be < 5 × ULN and in the case of Gilbert’s Syndrome, 
total bilirubin must be < 7 × ULN). 
6. Daily use of medications listed in the currently applicable prohibited medications list. 
7. Pregnant, planning to become pregnant, or having been pregnant within 90 days of baseline, or 
lactating. 
Investigational Product, Dosage and Mode of Administration: 
BCX9930 tablets for oral administration. Under this amendment, subjects will take 400 mg BCX9930 
BID orally. Dosage forms may include 100, 200, and/or 250 mg tablets to allow for dose adjustments if 
needed for the safety management of the subject. Clinical effectiveness and safety will be monitored. 
Duration of Treatment:  
Subjects will be eligible to receive study drug (BCX9930) for 144 weeks, or until drug is available by 
another mechanism (eg, expanded or market access) or until the Sponsor discontinues development of 
the product for PNH; whichever comes first. 
Reference Therapy, Dosage and Mode of Administration:  
N/A. 


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Criteria for Evaluation: 
Safety: 
Safety will be evaluated by TEAEs, laboratory analyses (clinical chemistry, hematology, coagulation, 
urinalysis with microscopy), vital signs, electrocardiograms (ECGs), and physical examination 
findings. An independent data monitoring committee (DMC) will review safety data in accordance 
with a separate DMC Charter.  
Effectiveness: 
Clinical measurements of PNH include LDH, hemoglobin and haptoglobin levels, reticulocyte counts, 
PNH symptoms (eg, fatigue, dyspnea, chest pain/discomfort, difficulty swallowing (esophageal pain), 
abdominal pain, headache, erectile dysfunction, hemoglobinuria, jaundice), number of blood 
transfusions, BTH, and thromboembolic events will be used to assess ongoing effectiveness. 
Patient Reported Outcomes: 
Questionnaires will be used to evaluate quality of life (QLQ-AA/PNH), effectiveness of therapy 
(FACIT fatigue scale) and treatment satisfaction (TSQM). 
Pharmacokinetics: 
Plasma samples for determination of BCX9930/metabolite concentrations will be collected at each 
study visit. Spot urine samples for determination of BCX9930/metabolite concentrations will be 
collected at each study visit. The resulting PK data will be incorporated into meta-study population PK 
and PK/PD analyses. Metabolites of BCX9930 will be analyzed as appropriate. 
Pharmacodynamics and Complement Biomarkers: 
Ex-vivo PD and complement biomarker effects of BCX9930 will be assessed using exploratory assays. 
Samples collected for PD and complement biomarker analysis may be run in more than one assay to 
elucidate the PD effects of BCX9930. These include: 
• Plasma Factor Bb 
• PNH RBC and WBC clone size 
• AP activity 
The ongoing assessment of the activity of BCX9930 and/or availability of a suitable assay may change 
the required PD assessments over time. 
 
 


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Statistical Methods: 
Analysis of Safety 
Safety endpoints will be summarized and will include the proportion of subjects: with TEAEs; 
who discontinue due to a TEAE; who receive a reduced dose due to tolerability issues; who 
experience a treatment-emergent serious adverse event (SAE); who experience a Grade 3 or 4 
TEAE; who experience a treatment-emergent, treatment-related adverse event (AE) consistent 
with a drug rash (eg, rash, maculo-papular exanthem, papular rash); and who experience 
Grade 3 or 4 laboratory abnormalities. 
AEs will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) preferred 
term and system organ classification. The occurrence of TEAEs will be summarized using 
MedDRA preferred terms, system organ classifications, and severity. In addition to severity, 
AEs and SAEs will also be summarized based on Investigator assessment of relationship to 
study drug. 
Time to dose reduction, time to discontinuation due to a TEAE, and time to development of 
drug-related rash will be estimated using the Kaplan-Meier method. For those with a drug-
related rash, clinical and laboratory findings will be summarized as will the proportion of 
subjects who successfully continue therapy following onset of rash. 
Descriptive statistics for vital signs, weight, and clinical laboratory results will be presented by 
study visit. Laboratory abnormalities will be graded according to the Division of Microbiology 
and Infectious Diseases (DMID) Adult Toxicity Table. The number and percentage of subjects 
experiencing treatment-emergent graded toxicities will be summarized. 
Laboratory toxicity shifts from baseline to the worst post-baseline value as well as the last visit 
will be summarized. The number and percentage of subjects having elevations in ALT, AST, 
or bilirubin abnormalities in relation to fold above ULN will be summarized according to the 
United States Food and Drug Administration's Premarketing Clinical Evaluation on Drug-
Induced Liver Injury Guidance for Industry. 
Clinically significant abnormal ECG findings will be summarized by study visit. Changes 
from baseline in ECG parameters will also be summarized by study visit. The number and 
proportion of subjects with clinically important absolute and change-from-baseline thresholds 
in QTcF will be summarized. 
Analysis of Clinical Measurements of PNH 
Clinical measurements of PNH (eg, LDH, hemoglobin, absolute reticulocyte count, 
haptoglobin levels, number of blood transfusions, incidence of BTH, incidence of thromboses 
and major thromboses, AST, total bilirubin, and direct bilirubin) will be summarized by 
summary statistics, including change from baseline, by treatment group and study visit. 
Categorical measurements will be summarized with frequencies and percentages by treatment 
group and study visit. 
Analysis of Effectiveness and Patient Reported Outcomes 
Effectiveness and PROs will be monitored with disease-specific clinical assessments, 


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laboratory assessments, and questionnaires. Responses for subjects with PNH will be 
categorized using published draft criteria (Risitano, Marotta, et al. 2019) into complete 
response, major response, good response, partial response, minor response, and no response, 
modified for study duration and visit schedule. 
PROs will include FACIT fatigue scale, TSQM, and QLQ-AA/PNH questionnaires. 
Analysis of Pharmacokinetic Data 
Plasma and urine concentrations of BCX9930 and metabolites (as applicable) will be 
summarized by dose regimen and study visit. The resulting PK data will be pooled in a meta-
analysis of population PK. 
Analysis of Pharmacodynamic Data 
Descriptive statistics, including change from baseline, will be provided by study visit and dose 
regimen. The resulting PD data will be explored using model-based techniques pooled in 
meta-analyses of PK/PD, as applicable. 
 
 
 


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Table of Contents 
1. 
LIST OF ABBREVIATIONS.....................................................................................18 
2. 
INTRODUCTION ......................................................................................................20 
3. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ........................................................23 
3.1. 
Study Objective(s) ......................................................................................................23 
3.1.1. 
Primary Objective .......................................................................................................23 
3.1.2. 
Secondary Objectives .................................................................................................23 
3.2. 
Study Endpoint(s) .......................................................................................................23 
3.2.1. 
Primary Endpoints ......................................................................................................23 
3.2.2. 
Secondary Endpoints ..................................................................................................23 
3.2.3. 
Pharmacodynamic (PD) Endpoint ..............................................................................23 
3.3. 
Statistical Hypotheses .................................................................................................24 
3.4. 
Study Design ...............................................................................................................24 
3.5. 
Number of Subjects ....................................................................................................24 
3.6. 
Treatment ....................................................................................................................25 
3.7. 
Clinical Assessments ..................................................................................................25 
4. 
PLANNED ANALYSES ............................................................................................29 
4.1. 
Interim Analyses .........................................................................................................29 
4.1.1. 
Data Monitoring Committee .......................................................................................29 
4.2. 
Final Analysis .............................................................................................................29 
5. 
GENERAL CONSIDERATIONS FOR DATA HANDLING ...................................30 
5.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........30 
5.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................30 
5.3. 
Data Management .......................................................................................................31 
5.4. 
Data Presentation Conventions ...................................................................................31 
5.5. 
Analysis Populations ..................................................................................................32 
5.5.1. 
Safety Population ........................................................................................................32 
5.5.2. 
Modified Intent-to-Treat (mITT) Population ..............................................................32 
5.5.3. 
Pharmacokinetic Population .......................................................................................32 
5.5.4. 
Pharmacodynamic Population ....................................................................................32 


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5.6. 
Baseline Definition .....................................................................................................32 
5.7. 
Derived and Transformed Data ..................................................................................33 
5.7.1. 
Baseline Age ...............................................................................................................33 
5.7.2. 
Study Day ...................................................................................................................33 
5.7.3. 
Change from Baseline .................................................................................................33 
5.7.4. 
Fold Change from Baseline ........................................................................................33 
5.7.5. 
Fold Change from ULN (Fold x ULN) .......................................................................33 
5.7.6. 
Total Time on Dose Level ..........................................................................................34 
5.7.7. 
End of Study ...............................................................................................................34 
5.7.8. 
Treatment-Emergent Adverse Events .........................................................................34 
5.7.9. 
Prior and Concomitant Medications ...........................................................................34 
5.7.10. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................34 
5.7.11. 
Missing Start Date, Stop Date, Severity, or Relationship for Adverse Events ...........35 
5.7.12. 
Windowing and Multiple Lab Values .........................................................................35 
5.7.13. 
Transfusion-impacted Period ......................................................................................36 
5.7.13.1. 
Transfusion-impacted Period for South Africa...........................................................36 
5.7.13.2. 
Transfusion-impacted Period for Other Countries .....................................................37 
5.8. 
Multicenter Studies .....................................................................................................38 
5.9. 
Stratification ...............................................................................................................38 
5.10. 
Examination of Subgroups .........................................................................................38 
5.11. 
Multiple Comparisons and Multiplicity......................................................................38 
5.12. 
Data Handling Conventions ........................................................................................38 
5.12.1. 
Premature Withdrawal and Missing Data ...................................................................38 
5.12.2. 
Dropouts .....................................................................................................................38 
5.13. 
Values of Clinical Concern .........................................................................................38 
5.14. 
Events of Special Interest ...........................................................................................38 
6. 
TREATMENT COMPARISONS ...............................................................................39 
6.1. 
Data Display Treatment and Other Sub-Group Descriptors .......................................39 
6.2. 
Significance Tests .......................................................................................................39 
7. 
STUDY POPULATION .............................................................................................40 
7.1. 
Disposition of Subjects ...............................................................................................40 


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7.2. 
Protocol Deviations ....................................................................................................40 
7.3. 
Demographic and Baseline Characteristics ................................................................40 
7.4. 
Medical History ..........................................................................................................40 
7.5. 
Prior and Concomitant Medications ...........................................................................40 
7.6. 
Exposure and Compliance ..........................................................................................40 
8. 
EFFECTIVENESS .....................................................................................................42 
8.1.1. 
Durability of Response ...............................................................................................42 
8.1.2. 
Hematological Response ............................................................................................42 
8.1.3. 
Patient Reported Outcomes ........................................................................................42 
8.1.3.1. 
Treatment Satisfaction Questionnaire for Medication ................................................42 
8.1.3.2. 
Quality of Life Questionnaire for Patients with Aplastic Anemia/PNH ....................43 
8.1.3.3. 
FACIT-Fatigue Scale ..................................................................................................43 
8.1.4. 
Other Effectiveness Assessments ...............................................................................43 
8.1.4.1. 
Clinical Measurements of PNH ..................................................................................43 
8.1.4.2. 
Subjects with Dose Escalation ....................................................................................43 
8.1.4.3. 
Discontinuation Due to Lack of Efficacy ...................................................................43 
8.1.4.4. 
Disease Severity ..........................................................................................................43 
9. 
SAFETY ANALYSES ...............................................................................................44 
9.1. 
Adverse Events ...........................................................................................................44 
9.1.1. 
Events of Special Monitoring .....................................................................................45 
9.2. 
Clinical Laboratory Evaluations .................................................................................45 
9.2.1. 
Analysis of Abnormal Laboratory Values ..................................................................46 
9.2.2. 
Liver Enzymes ............................................................................................................46 
9.3. 
Bedside ECGs .............................................................................................................47 
9.4. 
Other Safety Measures ................................................................................................48 
10. 
CLINICAL MEASUREMENTS AND SYMPTOMS OF PNH ................................49 
10.1.1. 
Clinical PNH Symptoms.............................................................................................49 
10.1.2. 
Clinical Measurements of PNH ..................................................................................49 
11. 
CLINICAL PHARMACOLOGY DATA ANALYSES .............................................50 
11.1. 
Pharmacokinetic Analyses ..........................................................................................50 
11.2. 
Pharmacodynamic Analyses .......................................................................................50 


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12. 
ATTACHMENTS .......................................................................................................51 
12.1. 
Table of Contents for Data Display Specifications ....................................................51 
12.2. 
Data Display Specifications ........................................................................................54 
12.3. 
Preferred Terms that Qualify as MAVEs and Thrombotic Events .............................55 
12.4. 
FACIT-Fatigue Questionnaire Scoring .......................................................................63 
 
 
 
 


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List of Tables 
Table 1: 
List of Abbreviations ..................................................................................................18 
Table 2: 
Study Design and Schedule of Assessments ..............................................................26 
Table 3: 
Visit Windows ............................................................................................................35 
Table 4: 
Planned Treatment Categories ....................................................................................39 
Table 5: 
Hematological Response Categories ..........................................................................42 
Table 6: 
Example Imputation of Inequalities ............................................................................45 
Table 7: 
Data Displays ..............................................................................................................51 
Table 8: 
FACIT-Fatigue Scale ..................................................................................................63 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations  
Abbreviation 
Term 
ADaM 
Analysis Data Model 
AE 
adverse event 
AKI 
acute kidney injury 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AP  
alternative complement pathway  
ARC 
absolute reticulocyte count 
AST 
aspartate aminotransferase 
BID  
twice daily  
BMI 
body mass index 
BTH 
breakthrough hemolysis 
C3 
complement 3 
C5-INH 
C5 inhibitor 
CI  
confidence interval  
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COVID-19 
coronavirus disease 2019 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV 
coefficient of variation 
DHHS 
Department of Health and Human Services 
DMC 
Data Monitoring Committee  
DMID  
Division of Microbiology and Infectious Diseases  
ECG  
electrocardiogram  
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EOSI 
events of special interest 
EOSM 
events of special monitoring 
EVH 
extravascular hemolysis 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FDA  
United States Food and Drug Administration  
FSH  
follicle-stimulating hormone  
HR 
heart rate 
IB  
investigator’s brochure  
ICH 
International Council on Harmonisation 
IMP  
investigational medicinal product  
INR 
international normalized ratio 
IV 
intravenous 
KIM-1 
kidney injury molecule 1 
LDH 
lactate dehydrogenase 
L-FABP 
liver-type fatty acid-binding protein 
MAVE 
major adverse vascular event 
MedDRA  
Medical Dictionary for Regulatory Activities  
NCI 
National Cancer Institute 
PD  
pharmacodynamic(s)  


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pDILI 
potential drug induced liver injury 
PK  
pharmacokinetic(s)  
PNH  
paroxysmal nocturnal hemoglobinuria  
PT 
preferred term 
pRBC 
packed red blood cell(s) 
PRO 
patient reported outcome 
QLQ-AA/PNH 
Quality of Life Questionnaire for patients with Aplastic Anemia / Paroxysmal 
Nocturnal Hemoglobinuria  
QTcF  
QT interval corrected for heart rate using Fridericia’s formula  
RBC  
red blood cell  
SAE  
serious adverse event  
SAP  
Statistical Analysis Plan  
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
sCr 
serum creatinine 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SE 
standard error of the mean 
SOC  
system organ class 
SOP 
standard operating procedure 
TEAE  
treatment-emergent adverse event  
TSQM 
Treatment Satisfaction Questionnaire for Medication  
uACR 
urine albumin to creatinine ratio 
ULN 
upper limit of (the) normal (range) 
uNGAL 
urine neutrophil gelatinase-associated lipocalin 
WBC  
white blood cell  
WHO 
World Health Organization 
 


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2. 
INTRODUCTION 
Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, non-malignant disorder of the hematopoietic 
stem cells associated with significant morbidity and mortality. Disease control with complement C5 
inhibitors such as eculizumab and ravulizumab is incomplete, with persistent transfusion dependence in 
approximately 50% of patients, development of extravascular hemolysis because of uncontrolled 
opsonization of erythrocytes, and concomitant bone marrow dysfunction. The currently approved 
treatments are administered by repeated intravenous infusions. See the Protocol for references and further 
details. 
BCX9930 is a small molecule inhibitor of human factor D that is being developed as an oral treatment of 
PNH and other complement-mediated diseases. As subjects with PNH successfully complete a BCX9930 
study and show clinical benefit, they will be offered the opportunity to continue treatment with BCX9930 
by participation in this long term open-label study where all subjects will be provided treatment with 
open-label BCX9930 for up to 144 weeks. 
Because PNH is a severely debilitating, life threatening disorder with limited treatment options, it is 
considered reasonable to offer continued dosing with BCX9930 to subjects who demonstrate a clinical 
benefit from treatment as assessed by the site investigator during a prior BCX9930 trial, consistent with 
International Council for Harmonisation (ICH) M3 and the FDA guidance on severely debilitating or life-
threatening hematologic disorders (FDA 2019). 
This open-label safety study is designed to assess the long-term safety and effectiveness of BCX9930 in 
subjects who participated in a previous study of BCX9930. BCX9930-201 offers subjects who 
participated in a BCX9930 study additional or continued access to BCX9930 treatment for 144 weeks or 
until the Sponsor discontinues development of the product, whichever comes first. 
Eligible subjects may enroll in the current study if the investigator assesses that they may benefit from 
continued daily administration of BCX9930. The development of BCX9930 may be of benefit to patients 
with PNH and other complement mediated diseases that are serious, associated with chronic morbidity, 
and are potentially life-threatening. In Study 101, administration of BCX9930 at doses of 400 mg or 500 
mg twice daily (BID), both in subjects who are naïve to C5 inhibitors and in those who are receiving C5 
inhibitors and had an inadequate response, resulted in sustained clinical responses, as measured by 
improvement in Hb levels, and decreases in lactate dehydrogenase (LDH) and C3 opsonization of red 
blood cells (RBC). Subjects participating in this study may similarly derive a benefit with BCX9930 in 
controlling the symptoms and/or improving laboratory parameters related to PNH disease. Thorough 
monitoring and assessment of adverse events (AEs) will be performed for subjects enrolled in this study, 
and protocol-mandated safety assessments include vital sign measurements, physical examination, 
electrocardiograms (ECGs), and clinical laboratory testing. Potential risks associated with complement 
inhibitors for the treatment of PNH, as well as potential risks associated with BCX9930 based on 
nonclinical and clinical data to date are described in the investigator’s brochure (IB) for BCX9930 and 
summarized below. 
 
As BCX9930 blocks the alternative complement pathway (AP) of complement, subjects may 
have increased susceptibility to bacterial infections; subjects receiving BCX9930 will be 
monitored closely for signs and symptoms of infection; infection risk will be mitigated by 
requiring subjects to have up to date vaccinations against appropriate bacterial strains, and if 
required on an individual basis, prophylactic antibiotic administration will be allowed.  


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 
BCX9930 is not expected to increase the risk of contracting coronavirus disease 2019 (COVID-
19) following infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
or to increase the risk of severe illness with COVID-19; Vaccination against SARS-CoV-2, the 
causal agent for COVID-19 infection, is allowed, if authorized and available in country or area, 
and based on investigator’s judgment. 
 
In Phase 3 studies of adult patients with PNH who received eculizumab or ravulizumab, headache 
considered related to ravulizumab and eculizumab commonly occurred early after the initiation of 
treatment; in Study BCX9930-101, early onset headache was the most common treatment-
emergent adverse event (TEAE) in subjects with PNH treated with BCX9930; therefore subjects 
will be monitored closely for signs and symptoms of headache.  
 
A benign maculopapular rash with consistent onset and clinical course has been observed with 
multiple-day dosing of BCX9930 in both healthy subjects and subjects with PNH; resolving with 
no intervention while continuing dosing of BCX9930; although there is no evidence for any 
systemic hypersensitivity, any subject with a rash believed to be related to BCX9930 should be 
evaluated as deemed medically appropriate. 
 
Discontinuation of treatment may result in increased risk of hemolysis of PNH RBCs; 
accordingly, subjects who discontinue or interrupt BCX9930 for any reason will be closely 
monitored to detect serious hemolysis.  
 
 
 
 
 
 
 
Blood will be drawn from study subjects for safety, pharmacokinetic (PK), and pharmacodynamic 
(PD) assessments; to reduce the risk of vasovagal syncope and associated sequelae, venipuncture 
will be performed with the subject seated or supine; and to limit the risk of anemia, blood volume 
collected for study-related procedures will be limited to the minimum necessary. 
 
Subjects will be closely monitored to ensure any local irritation from ECG stickers on chests and 
limbs does not persist. 
Treatment-emergent increases in 
 
 Based on the sponsor’s preliminary investigation, reducing the 
BCX9930 dose to 400 mg BID is anticipated to mitigate the risk of 
 to subjects while 
maintaining the potential for demonstrating clinical benefit in the PNH patient population. 
BCX9930 is expected to provide greater efficacy than the currently available C5 inhibitors by not only 
preventing intravascular hemolysis, but also by preventing C3 mediated extravascular hemolysis (EVH), 
thereby reducing symptom burden, reducing hemolysis, including EVH and breakthrough hemolysis 
(BTH), improving patient function, changing the administration route from intravenous (IV) to oral, and 
improving health-related quality of life. Study subject selection criteria, dose selection, and study 
monitoring assessments have been included to optimize benefit and to minimize the risk of toxicities to 
study participants. Regular monitoring of safety parameters, including AEs, clinical laboratory 
abnormalities, vital signs measurements, ECGs, and physical examination findings, will ensure that the 


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benefit-risk profile supports continued dosing. In addition, an independent, program-wide data monitoring 
committee (DMC) will continue to provide oversight of the ongoing exposure of subjects to BCX9930 in 
this and other clinical studies. The overall benefit-risk balance is therefore considered to be acceptable.  


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3. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) 
3.1. 
Study Objective(s) 
3.1.1. 
Primary Objective 
 
To collect long-term safety and tolerability data in eligible subjects with PNH who previously 
received BCX9930 in a BioCryst-sponsored study and derived benefit from BCX9930 treatment.  
3.1.2. 
Secondary Objectives 
 
To assess the continued effectiveness of BCX9930 in treatment of PNH during long-term 
administration. 
 
To evaluate patient reported outcomes (PROs) of long-term BCX9930 treatment.  
 
To collect PK, PD, and complement biomarker data in subjects with PNH for incorporation into 
meta-study models of population PK and PK/PD. 
 
To characterize the effects of BCX9930 in subjects with PNH by clinical measurements and PD 
and complement biomarkers.  
 
To evaluate biomarkers of complement activation during episodes of BTH.  
3.2. 
Study Endpoint(s) 
3.2.1. 
Primary Endpoints 
 
Measurement of safety and tolerability by subject incidence of graded TEAEs, laboratory 
abnormalities, changes to vital signs, ECG results, and physical examination findings. 
3.2.2. 
Secondary Endpoints 
 
Clinical PNH symptom assessments including fatigue, dyspnea, chest pain/discomfort, difficulty 
swallowing (esophageal pain), abdominal pain, headache, erectile dysfunction, hemoglobinuria, 
jaundice, incidence of BTH, and incidence of thromboembolic events. 
 
Clinical measurements of PNH (LDH, hemoglobin, haptoglobin, reticulocytes, transfusion 
requirements). 
 
PRO endpoints will include scores from the Quality of Life Questionnaire for patients with 
Aplastic Anemia / Paroxysmal Nocturnal Hemoglobinuria (QLQ-AA/PNH), Functional 
Assessment of Chronic Illness Therapy (FACIT) fatigue scale, and Treatment Satisfaction 
Questionnaire for Medication (TSQM). 
 
Concentration of BCX9930 in plasma at steady state in subjects with PNH. 
3.2.3. 
Pharmacodynamic (PD) Endpoint 
 
 
PD and complement biomarker measurements will include PNH RBC and white blood cell 
(WBC) clone size, plasma Factor Bb and AP activity (as assessed via AP Hemolysis and AP 
Wieslab). 


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3.3. 
Statistical Hypotheses 
This is an open-label Phase 2 study without a control group; therefore, estimation is emphasized above 
hypothesis testing.  
3.4. 
Study Design 
This is an open-label phase 2 study designed to evaluate the long-term safety of daily oral treatment with 
BCX9930 in subjects who have participated in a previous BCX9930 trial. The study will also evaluate the 
long-term effectiveness and impact on quality of life or general well-being of BCX9930 treatment, and 
the subject’s satisfaction with the medication. 
Subjects who have provided written informed consent and who have participated in a BCX9930 study 
will require a screening visit if they have interrupted study drug ≥ 31 days,  
Subjects who have provided written informed consent and who have participated in a BCX9930 study 
will not require a screening visit if they have interrupted study drug for between 1 and 30 days. However, 
they will require a baseline visit.  
For subjects who roll over directly from another BCX9930 study without treatment interruption, no 
screening visit will be required. The final on-study visit assessments in the prior BCX9930 study will 
serve as the baseline assessments for this study; however, additional relevant baseline assessments for this 
study may be performed at the final on-treatment visit for the prior study as needed to satisfy enrollment 
criteria. Enrollment without treatment interruption into the current study will obviate the requirement for 
a follow-up visit in the previous BCX9930 study.  
A subject may be enrolled once all eligibility criteria and study requirements are met. On-treatment study 
visits will occur on Day 1, then every 4 weeks up to Week 96 and then every 8 weeks until Week 144. 
Subjects with sCr elevations will be required to complete additional assessments at the investigational 
site, at a laboratory local to the subject, or via a home health service (where permitted and available). An 
independent DMC will review the safety data from this study in concert with the accumulating safety 
information generated across the BCX9930 clinical development program. The DMC convened and 
reviewed safety data once the first 4 subjects enrolled completed 12 weeks of dosing. Subsequent DMC 
meetings were and will be convened as detailed in the DMC Charter. 
3.5. 
Number of Subjects 
No sample size calculations were conducted for this open-label, long-term safety study. Approximately 
200 subjects will be enrolled. Subjects will be eligible to receive BCX9930 for up to 144 weeks or until 
the Sponsor discontinues development of the product; whichever comes first. Both males and females will 
be enrolled. As reproductive toxicology studies have not yet been conducted, women of childbearing 
potential may be enrolled in this trial only if they meet and maintain strict contraceptive and pregnancy 
test requirements as listed in this protocol. 


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3.6. 
Treatment  
The active ingredient for this study is BCX9930, a small molecule inhibitor of Factor D supplied by 
BioCryst as 100, 200, and/or 250mg tablets. Earlier versions of this Protocol supplied a white or off-white 
powder in size 0 hard gelatin capsules. Additional details for the chemical and physical characteristics of 
BCX9930 may be found in the IB and investigational medical product (IMP) dossier (where applicable). 
Subjects on earlier versions of the Protocol started treatment at the same dose level and regimen last 
administered to that subject in the prior study, and individually escalated their dose level as the physician 
felt appropriate. As of Protocol version 5, all subjects will receive 400 mg BID, and subjects on lower or 
higher doses will transition to 400 mg BID for continued participation. Where possible, the BCX9930 
doses should be taken at the same times each day as close as possible to 12 hours apart (eg. 8:00 AM and 
8:00 PM). If a subject does not take a BCX9930 dose at the scheduled time, the missed dose can be taken 
up to 6 hours after the scheduled dose time. Subjects will be instructed to bring all drug kits (both unused 
and used bottles) with them for each study visit. 
3.7. 
Clinical Assessments 
Planned study visits are Screening; Day 1; Weeks 4 through 96 at 4-week intervals, and Weeks 104 
through 144 at 8-week intervals. Safety and tolerability will be evaluated through assessments of TEAEs, 
laboratory analyses (clinical chemistry, hematology, coagulation, and urinalysis), vital signs, ECGs, and 
physical examinations at the study visits indicated in the schedule of assessments (see Table 2).  
 
The questionnaires are to be administered first, then physical exam, then ECG and vital signs 
before lab samples, PNH clone sample, then PK, PD, concomitant medication and AE review, 
PNH symptoms assessment, transfusion review, and finally drug dispensing.   
 
A site is permitted to perform screening assessments over more than one screening visit. 
Rescreening of ineligible subjects will be approved or denied on a case-by-case basis by the 
Sponsor Medical Monitor. Retesting of specific assessments without entirely rescreening a 
subject may be permitted. A screening failure electronic case report form (eCRF) page will be 
completed for those subjects who do not proceed with study dosing.  
 
Subjects who dose escalate (under Protocol versions 1-3) will have an additional Dose Escalation 
visit 2 weeks (± 2 days) after each dose increase.  
 
Following discontinuation of study drug (either following completion of the treatment period or 
on premature discontinuation), subjects will return to the clinic for a minimum of 3 consecutive 
days for Hemolysis Monitoring visits. Following the 3 days of monitoring, if required, subjects 
may continue to be assessed every 2 days thereafter until the subject has stabilized to a new 
hemoglobin baseline.  
 
Subjects who permanently discontinue treatment will return to the clinic for Hemolysis 
Monitoring visits. Subsequently they will return to the clinic 3 weeks (21 ± 3 days) after the date 
of their last dose of BCX9930 for their End of Study assessments. 
 


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Table 2: 
Study Design and Schedule of Assessments  
 
Assessment  
Screening 
Period a 
Baseline 
Visit b 
Treatment Period 
(Visit Schedule) 
Unscheduled 
Visit Following 
BTH  
(within 48hrs or 
next working 
day) 
Discontinuation 
of Study Drug 
End of 
Study 
Assessment 
Screening 
Visit  
(up to  
Day -28) 
(Day 1) 
Week 4 and 
Every 4 Wks 
up to Wk 96 c 
(± 3 days) 
Week 96 and 
Every 8 wks 
Until Wk 144 d 
(± 6 days) 
Hemolysis 
Monitoring for 
at least 3 
Consecutive 
Days e 
3 Weeks  
(± 3 Days) 
After Last 
Dose of 
Study 
Drug 
Informed consent f 
X 
X 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
X 
 
 
 
 
 
Medical and medication history g 
X 
X 
 
 
 
 
 
Weight/height/BMI h 
X 
X 
X 
X 
 
 
X 
Physical examination i 
X 
X 
X 
X 
X 
X 
X 
ECG j 
X 
X 
X 
X 
 
 
X 
Pregnancy test (women) k 
X 
X 
X 
X 
 
 
X 
FSH test (women) l 
X 
X 
 
 
 
 
 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry m/ hematology/ 
coagulation/ urinalysis with microscopy 
n/ iron, folate, B12 status labs o 
X 
X 
X 
X 
X p 
X p 
X 
Urine for biomarkers q 
 
 
X 
X 
X 
X 
X 
PNH symptoms assessment 
X 
X 
X 
X 
X 
X 
X 
Assessment of blood transfusions 
X 
X 
X 
X 
 
 
X 
Assess AEs, concomitant medications 
X 
X 
X 
X 
X 
X 
X 
PNH RBC and WBC clone size 
X 
X 
X 
X 
 
 
 
FACIT-Fatigue Scale 
 
X 
X r 
X 
 
 
 
QLQ-AA/PNH 
 
X 
X s 
X 
 
 
 
TSQM 
 
X 
X t 
X 
 
 
 
PK blood sample 
 
X 
X 
X 
X 
X u 
 
PK urine collection v 
 
 
X 
X 
X 
X 
 
PD blood sample 
 
X 
X 
X 
X 
X u 
X 
Study drug dosing w 
 
----------------------------------------------- 
X x 
 
 
Study drug accountability/ dispensing 
 
X 
X 
X 
 
 
X 
 
 


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Abbreviations: AE = adverse event; BID = twice daily; BTH = breakthrough hemolysis; BMI = body mass index; ECG = electrocardiogram;  
FSH = follicle-stimulating hormone; FACIT = Functional Assessment of Chronic Illness Therapy; IMP = investigational medicinal product;  
PD = pharmacodynamic; PK = pharmacokinetic; PNH = paroxysmal nocturnal hemoglobinuria; QLQ-AA/PNH = Quality of Life Questionnaire for Patients with 
Aplastic Anemia/PNH; RBC = red blood cell; TSQM = Treatment Satisfaction Questionnaire for Medication; WBC = white blood cell. 
a Screening visit is required for subjects who have interrupted study drug for > 30 days. 
b The baseline visit should be within 28 days of the screening visit. For subjects directly rolling over from another BCX9930 study without treatment 
interruption, the final on-treatment visit in the prior BCX9930 study will be considered the baseline visit for this study. 
c Visits should be every 4 weeks until a subject has completed a total of 96 weeks on treatment with BCX9930 (ie, weeks in this study plus weeks in the previous 
study). 
d Subjects with sCr elevations will be required to complete additional assessments to monitor for potential renal toxicity at the investigational site, at a remote 
laboratory more convenient for the subject, or via a home health service (where permitted and available) as indicated in Protocol Section 11.3.4.1 and Protocol 
Section 13.9.5.3. 
e Monitoring for the onset of hemolysis will be conducted after each subject stops BCX9930 treatment. Depending on the results, additional hemolysis testing 
may continue. 
f Informed consent will be signed at the screening visit for subjects requiring a screening visit and will be signed for all other subjects at the baseline visit or final 
on treatment visit in the prior study (which serves as the subject’s baseline visit in this study). 
g Medical and medication history should include vaccination history status, assess risk of exposure, and arrange for any appropriate vaccinations to be 
administered based on local recommendations as well as individual subject considerations. 
h BMI calculation and height at screening; weight is to be recorded at each in-clinic visit. 
i Full physical examinations will be performed at screening and baseline; symptom-directed physical examinations will be performed at all post-baseline visits. 
j All ECGs during the study will be single assessments. ECGs will be conducted every 12 weeks up to Week 96 (ie, Weeks 12, 24, 36, 48, 60, 72, 84, and 96) and 
every 24 weeks thereafter (ie, Weeks 120 and 144) during the treatment period. 
k For women of childbearing potential, a serum pregnancy test will be administered at screening; urine pregnancy tests will be assessed at all subsequent visits. 
Starting at Week 100, women of childbearing potential will start performing urine pregnancy tests at home every 4 weeks (i.e., in between clinic visits). The 
results will be recorded by the site. If the urine pregnancy test is positive, the subject should contact the site immediately. 
l FSH will be measured at screening for any woman post-menopausal ≤ 2 years (this may be omitted if menopausal status was demonstrated with elevated FSH in 
the prior study). For women who do not undergo a screening visit, FSH may be assessed at baseline. In this case, the subject must have a negative urine 
pregnancy test at baseline prior to receiving study drug. 
m Cholesterol and triglycerides will be measured every 12 weeks up to Week 96 (ie, Weeks 36, 48, 60, 72, 84, and 96) and every 24 weeks thereafter (ie, Weeks 
120 and 144). 
n Urine microscopy will be performed on urine collected at investigative site visits (and, where possible, at remote visits where the lab has appropriate on-site 
testing capability). Urine microscopy should be performed using the site’s local laboratory (assuming appropriate on-site testing capability exists) in lieu of the 
central laboratory. 
o Weeks 48, 96, and 144 only. 
p Only limited hematology and clinical chemistry parameters measured as per Protocol Section 11.3.5 and Protocol Section 11.3.6. 
q Urine will be collected at investigative site visits (ie, excluding remote visits) and aliquots frozen for possible future analysis of urine biomarkers. 
r Completed at all treatment visits through Week 96 only. 


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s Every 6 months through Week 96 only (ie, Weeks 24, 48, 72, and 96 only). 
t Though Week 96 only (ie, at Weeks 12, 24, 48, 72, and 96 only).  
u Single PK and PD sample collected 48 hours after treatment discontinuation.  
v Spot urine samples will be collected for analysis of the concentration of BCX9930 and metabolites at investigational site visits (ie, excluding remote visits).  
w The protocol-specified dosing regimen prior to this amendment was 500 mg BCX9930 BID. Under this amendment, subjects will take 400 mg BCX9930 BID. 
The IMP will be supplied by BioCryst as 100, 200, and/or 250 mg tablets to allow for dose adjustments if needed for the safety management of the subject. 
x BCX9930 dosing should continue following BTH.


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4. 
PLANNED ANALYSES 
4.1. 
Interim Analyses 
Interim analyses may be performed during the course of the study as needed to support regulatory filings 
and safety updates.  
4.1.1. 
Data Monitoring Committee 
An independent DMC has been formed to review data from subjects on a regular basis to ensure the 
continued benefit-risk profile is favorable for each subject. The DMC has convened and reviewed safety 
data once the first 4 subjects enrolled completed 12 weeks of dosing. Subsequent meetings were and will 
be convened as detailed in the DMC Charter. The DMC may meet at any time should a safety issue arise 
that requires DMC input or a partial or full data review. A separate DMC charter maintained in the trial 
master file describes membership, roles, timing of DMC review, and responsibilities of the DMC 
members. 
4.2. 
Final Analysis 
The final analysis will be performed when the last subject has completed the final study visit, the data are 
cleaned, and the database has been authorized for analysis.  


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5. 
GENERAL CONSIDERATIONS FOR DATA HANDLING 
This section addresses the definitions, algorithms, imputations, and conventions that will apply to the 
analysis and handling of the data in general. Rules that are data specific will be addressed in the detailed 
discussions of individual summary tables.  
5.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Summary tables and listings will include “footers” providing: 
1. Date and time of output generation. 
2. SAS® program name that generates the output. 
3. The name(s) and location(s) of any input dataset(s) used in the creation of the output. 
4. Any other output-specific details that require elaboration. 
The BioCryst Style Guide for Tables, Figures, and Listings will be used to guide the appearance of 
output. Version 9.4 or higher of the SAS system will be used to analyze the data and to generate tables, 
figures, and listings. All SAS programs prepared to analyze the data will be properly annotated to permit 
uninvolved outside statistical experts to replicate all the analyses specified in this statistical analysis plan 
(SAP). 
The date of output generation links the output to the locked and archived database to allow replication of 
the results. 
5.2. 
General Post Text Summary Table and Individual Subject Data 
Listing Format Considerations 
Tables and listings will be numbered to reflect main levels of unique tables and listings and sub-levels of 
replicate tables and listings with two digits per level (eg, Table XX.YY.ZZ. …).  
1. The first level number should be consistent with the corresponding Clinical Study Report (CSR) 
appendix in which the tables or listings will appear. Following ICH-E3, all post text tables should 
have first level 14 and data listings should have 16.2.  
2. For tabular presentations, subject accounting and final disposition, baseline, and demographic profile 
should appear as the first sub-level (Table 14.1 series). Efficacy should come next (Table 14.2 series), 
followed by safety, PK/PD, and other special-purpose sections. Similar conventions should be applied 
to the subject data listings (16.2.1 for discontinuation, 16.2.2 for protocol deviations, and so on). 
The title should be complete, accurate, and concise. If convenient, the parameter and unit of measurement 
can appear in parentheses to conserve space in the body of the table. For example, a summary of 
orthostatic vital signs title could read “Summary of Sitting and Standing Blood Pressure (SBP) (mmHg) 
and Heart Rate (HR) (bpm).” Whether in the title or body of a table or listing, units must always be 
specified for all appropriate data. The last line of the title should provide the analysis group being 
summarized (eg, Intent-to-Treat Population or Per-Protocol Population).  
In general, variables summarized and statistics reported should appear in the left-most column of a table. 
The columns for treatment groups should report the data from left to right for each treatment group (see 
Section 7), and (optional) all treated subjects, respectively. Any row with all zeros will not appear except 


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with reasons for disposition events or other similar lists of results (e.g. categorical urinalysis results). 
Summary tables clearly indicate the number of subjects to which the data apply, and unknown or not 
performed are distinguished from missing data.  
In general, the listings should be sorted and presented by treatment group, subject number, parameter 
(where applicable), and date/time. 
All tables and listings must have explanatory notes that give the definition of all derived variables and 
decodes for coded data. Footnotes will be in past tense for ease of incorporation into in-text tables in the 
CSR.  
5.3. 
Data Management 
The standard operating procedures (SOPs) of PharPoint, the selected data management and statistics 
vendor for this study, will be used. A data management plan was developed and approved prior to 
commencement of data entry. Data will be captured using the Medrio electronic data capture system. 
Electronic validation steps (edit checks) will be utilized, and data cleaning will occur in conjunction with 
each site. Prior to transfer of data provided by vendors (eg, laboratory data, PK data), a data transfer 
agreement including specifications for the type of file, definitions of variables, and contact information 
for the sending and receiving parties will be developed and finalized.  
Data will be mapped to Study Data Tabulation Model (SDTM)-compliant datasets prior to creation of 
Analysis Data Model (ADaM)-compliant derived datasets for use in the creation of output. All analyses 
will be generated using SAS version 9.4 or above and in accordance with PharPoint SOPs. 
5.4. 
Data Presentation Conventions 
Continuous data will be summarized using the number of subjects with available data, mean, standard 
deviation (SD), standard error of the mean (SE), median, and minimum and maximum. Categorical data 
will be summarized using counts and percentages. Percentages are calculated using the total number of 
subjects per treatment group unless otherwise specified.  
Unless otherwise specified, means and medians are formatted to one more decimal place than the 
measured value, SDs, SEs, confidence interval (CI) limits, and coefficient of variation (CV) to two more 
decimal places, and minimum and maximum values to the same number of decimal places. For 
categorical variables, the number and percentage of responses will be presented in the form XX (XX.X%) 
where the percentage is in the parentheses, except that 100% will be presented to three digits with no 
decimal. Dates will be formatted DDMMMYYYY and times will be formatted in 24-hour time as 
HH:MM. Partial dates will be handled as described in Sections 5.7.10 and 5.7.11. P-values and CIs will 
use a two-sided 0.05 significance level unless otherwise noted; p-values will be presented with three 
decimal places. Extreme p-values or CIs will be presented as “<0.001” and “>0.999” with the appropriate 
number of places. 
All BCX9930 concentrations will be reported as provided by the concentration vendor.  
Wherever possible, data will be decimal aligned. 


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A table of contents at the end of this SAP provides the expected titles and numbers of the tables, listings, 
and figures of the final report. Changes to titles or numbering in the final report will not necessitate a 
revision to the SAP, nor will it be considered a deviation from planned analyses. Additional data listings 
supporting the tables will not be considered a deviation from planned analyses. 
5.5. 
Analysis Populations  
5.5.1. 
Safety Population 
The safety population will include all subjects who received at least 1 capsule or tablet of study drug. This 
population will be used for all analyses of accountability, demographics, BCX9930 drug concentrations, 
and safety. Subjects will be analyzed according to the treatment received.  
5.5.2. 
Modified Intent-to-Treat (mITT) Population 
The modified intent-to-treat (mITT) population will include all subjects who receive at least 1 capsule or 
tablet of study drug and have post baseline assessment of PNH symptoms and/or laboratory data. The 
mITT population will be the population for effectiveness analyses. Subjects will be analyzed according to 
the treatment intended.  
5.5.3. 
Pharmacokinetic Population 
The PK population will include all subjects included in the Safety population for whom a PK 
concentration was collected. The PK population will be the primary population for the PK listings. 
Subjects will be analyzed according to the treatment received. 
5.5.4. 
Pharmacodynamic Population 
The PD population will include all Safety population subjects for whom at least 1 PD or complement 
biomarker measurement can be obtained. This population will be used for all PD and complement 
biomarker analyses. Subjects will be analyzed according to the treatment received. 
5.6. 
Baseline Definition 
For a given subject and assessment, the baseline result generally will be the Day 1 value. For subjects 
who are directly rolling over from a previous study, the baseline ECG result will be obtained at the 
subject’s final on-treatment visit in the previous study and recorded in the eCRF.  
For determination of Hemoglobin (Hb) baseline, only preferred lab values that were not collected within 
14 days after the subject received a packed red blood cell (pRBC) or whole blood transfusion will be 
used. For South African subjects, the local lab will be the preferred lab, and for all other subjects, the 
central lab will be the preferred lab. All Hb values that meet these criteria and were collected at any time 
from the preferred lab from the Screening visit up to Day 1 pre-dose will be averaged to determine a 
baseline value. Values from different labs will not be averaged together. If no preferred lab values are 
available but there are other lab values that were not collected within 14 days after the subject received 
any RBC or whole blood transfusion, lab values that meet the criteria will be used in place of the 
preferred lab values. If there are no baseline lab values that were collected outside the transfusion-


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impacted period, the average of all (central and local labs) pre-treatment values from the Screening visit 
up to Day 1 pre-dose will be used to determine a baseline value, even if these values are themselves 
impacted by transfusion. This will lead to a conservative estimate of the baseline as the values could be 
impacted by transfusion and may be higher than expected as a result. 
Derivation of the baseline for the following parameters: reticulocytes, PNH RBC (Type II and III red 
blood cells), the ratio of PNH RBC to PNH WBC (Type II and III granulocytes), haptoglobin, and 
FACIT-Fatigue will be as stated for Hb, above. 
5.7. 
Derived and Transformed Data 
5.7.1. 
Baseline Age 
The subject’s baseline age will be the age collected on the eCRF at time of consent. If this is missing, 
baseline age will be calculated as the number of complete years from date of birth through date of 
informed consent. In the case of a partial date, the lowest age consistent with available information will 
be used.  
5.7.2. 
Study Day 
Study Day 1 (or Day 1) is the date of first on-study dose of study drug and values captured on that day 
will generally be used as the baseline (see Section 5.6) If the date of interest occurs on or after the Study 
Day 1, then study day will be calculated as (date of interest – Study Day 1) + 1. If the date of interest 
occurs prior to the date of first dose, then study day will be calculated as (date of interest – Study Day 1). 
There is no Study Day 0.  
5.7.3. 
Change from Baseline 
Change from baseline is calculated as (post-baseline result – baseline result). Percent change from 
baseline is calculated as (100 x change from baseline/baseline result). If either the baseline or the post-
baseline result is missing, the change from baseline and percent change from baseline are set to missing as 
well. If the baseline result is 0, then the percent change from baseline is set to missing. 
5.7.4. 
Fold Change from Baseline 
Fold change from baseline (also known as the ratio to baseline) is calculated as (post-baseline result / 
baseline result). If the baseline result is missing, the fold change is also set to missing. 
5.7.5. 
Fold Change from ULN (Fold x ULN) 
Fold change from the upper limit of normal (ULN) (also known as the ratio to ULN, fold x ULN, or fold 
above the ULN) is calculated as (post-baseline result / ULN). If the ULN is missing, the fold x ULN is 
also set to missing. 


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5.7.6. 
Total Time on Dose Level 
The total time spent on any dose level will be calculated as the sum of the days on each dose level using 
the start and stop dates per dose period, including if another dose level was taken in between periods of 
the particular level in question. 
5.7.7. 
End of Study 
The end of the study is defined as the date when the last subject completes the last protocol-scheduled 
visit or terminates early. 
5.7.8. 
Treatment-Emergent Adverse Events 
An AE is considered treatment-emergent if its start date and time is on or after the date and time of first 
on-study dose of study drug. If the AE start date is missing and the AE stop date and time is after the start 
date and time of the first on-study dose of study drug (or the AE is ongoing) then the AE will be 
considered treatment-emergent. If either or both times are missing, then dates alone will be compared. See 
Section 5.7.11 for incomplete dates or times. 
5.7.9. 
Prior and Concomitant Medications 
A medication will be classified as prior if its end date and time are before the date and time of the first on-
study dose of study drug. Otherwise, the medication will be classified as concomitant; that is, its start date 
and time are on or after the date and time of the first on-study dose of study drug, or its end date and time 
are on or after the start date and time of the first on-study dose of study drug, or the medication is flagged 
as ongoing. If either or both times are missing, then dates alone will be compared. See Section 5.7.10 for 
incomplete dates or times. 
5.7.10. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
For analysis of medications, a complete date should be established to identify medication as occurring 
during treatment or not. For the purposes of handling partially reported start and stop dates for 
medication, the following algorithm will be applied: 
 
Missing start day, but month and year present: 
If study medication had been taken in the same month and year as the occurrence of the 
medication, then the start day of the medication will be assigned to the day of first dose of 
study medication. 
Otherwise the start day will be set to the first day of the month. 
 
Missing start day and month, but year present: 
If study medication had been taken in the same year as the occurrence of the medication, then 
the start date of the medication will be assigned to the date of first application of study 
medication. 


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Otherwise the start day and month will be set to 01 January. 
 
Missing end day, but month and year present: 
The day will be set to the last day of the month. 
 
Missing end day and month, but year present: 
If the year of trial termination is the same year or prior to the year the medication is reported, 
the end day and month will be set to the date of trial termination. 
Otherwise, the end day and month will be set to 31 December. 
5.7.11. 
Missing Start Date, Stop Date, Severity, or Relationship for Adverse Events 
The same conventions to address incomplete dates for prior and concomitant medications will also be 
used for AEs. Should an event have a missing severity or relationship, it will be classified as having the 
highest severity and/or strongest relationship to study treatment. 
5.7.12. 
Windowing and Multiple Lab Values 
Unscheduled and early termination visits will be assigned to an analysis window according to the study 
day of the actual visit date using visit windows described in Table 3 below: 
Table 3: 
Visit Windows 
Visit 
Relative Target 
Day 
Analysis Visit Window 
Screening 
(optional) 
-35 to -1 
Prior to Day 1 
Day 1 (Baseline) 
1 
1 
Week 4 
29 
2 to 43 
Weeks 8 to 92 
Week * 7 +1 
Target Day -13 to Target Day +14 
Week 96 
673 
660 to 701 
Week 104 to 136 
Week * 7 +1 
Target Day -27 to Target Day +28 
Week 144 
1009 
982 and later 
For subjects with multiple lab values on the same day, special rules will be used to choose values eligible 
for display on tables and figures. For South African sites: on days with multiple test results, results from 
the local lab will be used. For other sites: on days with multiple test results, results from the central lab 
will be used. If there are still multiple records on the same date, then the median of available records on 
that date will be used; for these created median records, if applicable, the most frequent toxicity grade of 
the records used to calculate the median will be used. 


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5.7.13. 
Transfusion-impacted Period 
The 14-day period following a transfusion of pRBCs or whole blood is defined as the transfusion-
impacted period (ie, the interval between the transfusion day and the current study day is ≤ 13 days and 
includes the day of transfusion). An exception to this rule is that the transfusion-impacted period for 
haptoglobin is the 3-day period following a transfusion (ie, the interval between the transfusion day and 
the current study day is ≤ 2 days and includes the day of transfusion). Transfusion-impacted periods will 
only be taken into account for effectiveness endpoints. 
The following parameters are impacted by pRBC or whole blood transfusion: 
 
Hemoglobin  
 
Reticulocytes  
 
PNH RBC (Type II and III red blood cells)  
 
Ratio of PNH RBC to PNH WBC 
 
FACIT-Fatigue  
 
Haptoglobin (transfusion-impacted period is limited to 3 days instead of 14) 
5.7.13.1. Transfusion-impacted Period for South Africa 
The algorithm as defined below aims to exclude transfusion impacted lab measurements when possible, 
and acts to select local lab measurements over central lab measurements (for South Africa subjects) or 
central lab measurements over local lab measurements (for subjects outside of South Africa), when 
possible. This is due to a lack of reliable data obtained from the central lab in South Africa.  
For South African sites, the algorithm for determining which values should be used in effectiveness 
analysis are as follows: 
The Hb value to use for a particular visit is provided below. The first item matching the description in the 
list should be used. 
1. Local lab value for Hb at the visit of interest closest to the target day.  
a. If multiple results are equidistant from the target, use the latest. 
b. If multiple records exist on the same day, find the median of the results on that day (for 
grading, set to the most frequent grade or worst grade if two grade have the same frequency). 
2. Central lab value for Hb at the visit of interest closest to the target day.  
a. If multiple results are equidistant from the target, use the latest. 
b. If multiple records exist on the same day, find the median of the results on that day (for 
grading, set to the most frequent grade or worst grade if two grade have the same frequency). 
If the value at the visit of interest was taken during a transfusion-impacted period: 


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3. Local lab pre-transfusion value that itself was not within 14 days after the subject received a 
pRBC or whole blood transfusion.  
a. If multiple results are equidistant from the target, use the latest. 
b. If multiple records exist on the same day, find the median of the results on that day (for 
grading, set to the most frequent grade or worst grade if two grade have the same frequency). 
4. Central lab pre-transfusion value that itself was not within 14 days after the subject received a 
pRBC or whole blood transfusion.  
a. If multiple results are equidistant from the target, use the latest. 
b. If multiple records exist on the same day, find the median of the results on that day (for 
grading, set to the most frequent grade or worst grade if two grade have the same frequency). 
If no value meets the criteria listed, the Hb at the visit of interest will be set to missing and will not be 
summarized. This same algorithm will be used for all other transfusion-impacted parameters (Section 
5.7.13), however haptoglobin will use a period of 3 days after transfusion instead of 14 days. 
5.7.13.2. Transfusion-impacted Period for Other Countries 
The Hb value to use for a particular visit is provided below. The first item matching the description in the 
list should be used. 
5. Central lab value for Hb at the visit of interest closest to the target day. 
a. If multiple results are equidistant from the target, use the latest. 
b. If multiple records exist on the same day, find the median of the results on that day (for 
grading, set to the most frequent grade or worst grade if two grade have the same frequency). 
6. Local lab value for Hb at the visit of interest closest to the target day. 
a. If multiple results are equidistant from the target, use the latest. 
b. If multiple records exist on the same day, find the median of the results on that day (for 
grading, set to the most frequent grade or worst grade if two grade have the same frequency). 
If the value at the visit of interest was taken during the transfusion-impacted period: 
1. Central lab pre-transfusion value that itself was not within 14 days after the subject received a 
pRBC or whole blood transfusion closest to the target day. 
a. If multiple results are equidistant from the target, use the latest. 
b. If multiple records exist on the same day, find the median of the results on that day (for 
grading, set to the most frequent grade or worst grade if two grade have the same frequency). 
2. Local lab pre-transfusion value that itself was not within 14 days after the subject received a 
pRBC or whole blood transfusion 
a. If multiple results are equidistant from the target, use the latest. 
b. If multiple records exist on the same day, find the median of the results on that day (for 
grading, set to the most frequent grade or worst grade if two grade have the same frequency). 
If no value meets the criteria listed, the Hb at the visit of interest will be set to missing and will not be 
summarized. This same algorithm will be used for all other transfusion-impacted parameters, however 
haptoglobin will use a period of 3 days after transfusion instead of 14 days. 


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For FACIT-Fatigue, since the scale is not captured at unscheduled visits, any FACIT-Fatigue occurring 
within a transfusion-impacted period will not be summarized on the tables but will be presented in the 
listings. 
5.8. 
Multicenter Studies 
No adjustment for multiple centers is planned.  
5.9. 
Stratification 
No stratification is planned. 
5.10. 
Examination of Subgroups 
No subgroups are planned. 
5.11. 
Multiple Comparisons and Multiplicity 
No adjustment for multiple comparisons is planned. 
5.12. 
Data Handling Conventions 
5.12.1. 
Premature Withdrawal and Missing Data 
No missing data will be imputed, except dates and times as mentioned above. 
5.12.2. 
Dropouts 
Subjects will not be replaced if they discontinue study drug.  
5.13. 
Values of Clinical Concern 
Values of clinical concern include events of special monitoring (EOSMs), which are AEs or safety topics 
for which special monitoring, additional data collection activities, and/or enhanced signal detection 
activities within BioCryst are considered appropriate for this population and study. EOSMs for this 
study include hemolysis, SARS-CoV-2 infections (asymptomatic and symptomatic), 
 
5.14. 
Events of Special Interest 
For this study, severe infections will be considered events of special interest (EOSIs).  


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6. 
TREATMENT COMPARISONS 
6.1. 
Data Display Treatment and Other Sub-Group Descriptors 
Planned treatment categories to be displayed on the summary tables are defined by whether the subject 
was naïve to both eculizumab and ravulizumab (C5 inhibitor [C5-INH] naïve) or had an inadequate 
response to either eculizumab or ravulizumab (C5-INH inadequate response). Subjects who have not 
taken either eculizumab or ravulizumab within the previous calendar year are considered naïve. Subjects 
whose parent study is BCX9930-202 are considered inadequate response subjects, and subjects whose 
parent study is BCX9930-203 are considered naïve subjects. These categories may be changed; if so, the 
final treatment categories will be used in the data displays.  
Table 4: 
Planned Treatment Categories 
C5-INH Naïve 
C5-INH Inadequate Response 
6.2. 
Significance Tests 
If performed, unless otherwise specified, by-treatment significance tests will use a two-sided 0.05 
significance level for p-values and confidence intervals (CIs).  


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7. 
STUDY POPULATION 
7.1. 
Disposition of Subjects 
Subject disposition will be presented for all subjects. The number and percentage of subjects who 
completed the study and discontinued from the study will be provided. The reasons for early 
discontinuation at any point also will be presented by planned treatment category. These data will also be 
listed by treatment and subject. Duration on study treatment during Study 201 and from the beginning of 
the previous study will also be provided. 
The number and percentage of subjects included in the Safety, PK, and PD populations will be presented 
by treatment category. 
7.2. 
Protocol Deviations 
Protocol deviations will be identified and displayed in data listings by treatment, subject, and (where 
applicable) date of deviation. Deviation category, major or minor status, and importance will be listed if 
included in the received deviation data.  
7.3. 
Demographic and Baseline Characteristics 
Demographic data and baseline characteristics including age, race, ethnicity, sex, height (if available), 
weight, and body mass index (BMI) (if available) will be summarized using descriptive statistics for the 
Safety population, presented by treatment category. If not collected, baseline BMI will be calculated as 
BMI = weight (kg)/[height (m)2] to one decimal place. Time from last BCX9930 dose to baseline will be 
summarized and listed as applicable. 
7.4. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Affairs (MedDRA) 
version 24.0 and listed. 
7.5. 
Prior and Concomitant Medications 
Medications will be classified as prior or concomitant and coded using the World Health Organization 
(WHO) drug dictionary version B3 March 2021. Concomitant medications will be summarized, and prior 
medications may be summarized, by descending frequency of Class 4 term, preferred term (PT), and 
treatment. Medications will be listed by treatment category and subject.  
7.6. 
Exposure and Compliance 
Subjects will receive kits containing BCX9930 per the schedule of assessments for self-administration at 
home. The number and percentage of subjects exposed to BCX9930, and the number of days of exposure 
to BCX9930 in Study 201 and including the parent study will be summarized by treatment category. 
Individual kit data will be listed by treatment, subject, and date issued. 


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Compliance will be determined from the Study 201 Study Drug Accountability form kit data as tablets 
dispensed minus tablets returned, multiplied by 100, divided by the total number of tablets of study drug 
which should have been taken according to the Protocol and dose escalation and reduction records. 
Compliance data will be summarized by treatment and listed by treatment and subject. 




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8.1.3.2. 
Quality of Life Questionnaire for Patients with Aplastic Anemia/PNH 
The QLQ-AA/PNH will be completed at Baseline and at the Week 24, 48, 72, and 96 visits. It has 54 
items in 12 domains: body image (BI), cognitive functioning (CF), emotional functioning (EF), fatigue 
(FA), illness intrusiveness (II), fear of progression (PAF), infections (IN), other symptoms (OS), physical 
functioning (PF), role functioning (RF), social support (SS), and stigmatization (ST). The individual 
question data from the QLQ-AA/PNH will be listed. Domain scores will not be calculated.  
8.1.3.3. 
FACIT-Fatigue Scale 
The Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale will be administered at 
Baseline and each clinic visit through Week 96. The FACIT-Fatigue scale has 13 items scored 0-4. A 
total score will be calculated with range 0 to 52 where 52 indicates complete functionality. See Section 
12.4 for the scoring algorithm. The FACIT-Fatigue scale score and change from baseline will be 
summarized by treatment category and visit. Note that assessments within a transfusion-impacted period 
will not be summarized but will be presented on the listings.  
8.1.4. 
Other Effectiveness Assessments 
8.1.4.1. 
Clinical Measurements of PNH 
Assessment of clinical measurements of PNH are described in Section 10.1.2. 
8.1.4.2. 
Subjects with Dose Escalation 
The number of subjects who were on each dose level at any time during the study and the total length of 
time on each dose level will be summarized using descriptive statistics by treatment category. Changes in 
subject dosing will be listed. 
8.1.4.3. 
Discontinuation Due to Lack of Efficacy 
Discontinuation due to lack of efficacy was not captured in the eCRF and so cannot be summarized 
specifically. Captured discontinuation reasons will be summarized on the disposition table. 
8.1.4.4. 
Disease Severity 
Disease severity will be summarized by treatment category, visit, and by PNH symptom category 
(fatigue, dyspnea, chest pain/discomfort, difficulty swallowing, abdominal pain, headache, 
erectile dysfunction, hemoglobinuria, jaundice). The number of subjects with a symptom at each 
visit will be presented, along with a summary of the number of days with symptoms and the 
severity. 


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9. 
SAFETY ANALYSES 
Safety endpoints that will be summarized, include the proportion of subjects 1) with TEAEs; 2) who 
discontinue BCX9930 due to TEAEs; 3) with treatment-emergent serious adverse events (SAEs); 4) with 
treatment-emergent Grade 3 or 4 AEs; and 5) with treatment-emergent Grade 3 or 4 laboratory 
abnormalities.  
9.1. 
Adverse Events 
AEs will be assessed and recorded from the time of signing of the informed consent through the 
appropriate follow-up period. AEs will be mapped to a MedDRA version 24.0 PT and system organ class 
(SOC). Relationship to study drug will be assessed as not related, unlikely related, possibly related, 
probably related, or definitely related. AEs will be graded according to the Division of Microbiology and 
Infectious Diseases (DMID) Adult Toxicity Table (draft version November 2007, see Protocol Appendix 
1). AEs not covered by DMID criteria will be assessed for severity as mild, moderate, severe, or life-
threatening, corresponding to toxicity Grades 1 through 4. EOSIs include severe infections that will be 
identified using the SOC “Infections and infestations” and a reported severity of grade 3 or higher (or 
missing). In this study the disease related events of BTH and thromboembolic events will be reported as 
AEs, even if deemed related to the disease under investigation.  
If the relationship between the AE or SAE and the study drug is determined to be ‘possibly’, ‘probably’, 
or ‘definitely’ related, the event will be considered related to the study drug for the purposes of expedited 
regulatory reporting. Conversely, both events deemed ‘unlikely’ and those judged ‘not related’ will be 
considered not related for regulatory reporting purposes. 
TEAEs will be summarized by SOC, PT, and treatment category. TEAEs will also be summarized by 
SOC, PT, severity, and treatment category. SAEs will be summarized by SOC, PT, and treatment. TEAEs 
deemed related to study drug, grade 3 and 4 TEAEs, TEAEs leading to treatment interruption or treatment 
discontinuation, EOSIs, and major adverse vascular events (MAVEs) will be summarized separately by 
SOC, PT, and treatment category. Summaries will be sorted by descending frequency of SOC and PT. 
Summaries will be presented chiefly by subject counts, and event counts will also be provided. 
AEs, SAEs, MAVEs, and EOSIs will be listed separately by treatment, subject, and start date, showing 
SOC, PT, and verbatim term.  
The duration of AEs in days will be derived and presented in all listings; this value is calculated as 
(AE stop date/time – AE start date/time). Both start and stop dates must be present to calculate a duration. 
If an AE start time or end time is missing then include the entire day, but if the AE start date is the 
treatment start date, then the treatment start time will be used. 
Time to first dose reduction either associated with an AE or otherwise, time to discontinuation due to a 
TEAE, and time to development of drug-related rash will be estimated using the Kaplan-Meier method. 
Subjects who do not experience a particular event will be censored at the date of the last study visit.  
Clinical findings for cutaneous eruptions requiring assessment will be listed.  


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9.1.1. 
Events of Special Monitoring 
EOSMs for this study include hemolysis, SARS-CoV-2 infections (asymptomatic and symptomatic), 
 
 
 
 
 
 
Time to each subject’s first SARS-CoV-2 infection, 
 
 will be estimated separately using the Kaplan-Meier method. The results will be displayed in 
summary tables as well as in a Kaplan-Meier plot. Subjects who do not experience the event will be 
censored at the date of the most recent dose of BCX9930. 
 
Duration of SARS-CoV-2 infection will be summarized as well as displayed in a Kaplan-Meier plot, with 
the event as the unit of interest rather than the subject. Ongoing durations will be censored at the most 
recent examination date. The summary display will provide the median duration of event by treatment 
category. 
These summaries and plots will be presented by treatment category. 
9.2. 
Clinical Laboratory Evaluations 
Non-PK/PD blood and urine samples will be obtained per the schedule of assessments in Table 2.  
Laboratory test results and change from baseline will be summarized by panel, parameter, time point, and 
treatment. Laboratory results, including lab normal ranges, will be listed by treatment category, subject, 
parameter, and time point.  
For continuous laboratory data that are reported using “<” or “≤”, a value of the number presented less 
one level of precision will be used for tables and figures. If the resulting value is equal to zero, the value 
will be adjusted by an additional level of precision. Similarly, “>” or “≥” will result in adding one at the 
level of precision for use in tables and figures. Actual results will be presented in the data listings. Table 6 
provides example imputations. 
Table 6: 
Example Imputation of Inequalities 
Reported Value 
Imputed Values 
< 23 
22 
< 2.3 
2.2 
< 2 
1 
< 1 
0.9* 


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< 0.23 
0.22 
< 0.1 
0.09* 
< 0.10 
0.09 
< 0.0200 
0.0199 
> 1.030 
1.031 
> 8 
9 
*value precision adjusted 
Hemoglobin and other transfusion-impacted parameters will be summarized using the rules for 
transfusion-impacted periods as described in Section 5.7.13. 
Select lab parameters including but not limited to serum creatinine and urine albumin/creatinine ratio will 
be plotted versus time from Day 1 to last visit. 
9.2.1. 
Analysis of Abnormal Laboratory Values 
Laboratory abnormalities will be graded according to DMID Adult Toxicity Table (draft version 
November 2007, see Protocol Appendix 1), with the exception of creatinine clearance and glomerular 
filtration rate, which will be graded using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.  
Any graded abnormality that occurs following the initiation of study drug and represents at least 1-grade 
increase from the baseline assessment is defined as treatment emergent. The number and percentage of 
subjects who experience treatment-emergent graded toxicities will be summarized by panel, parameter, 
time point, and treatment category. Laboratory toxicity shifts from baseline to worst post-baseline grade 
will be summarized by panel, parameter, toxicity grade, and treatment.  
9.2.2. 
Liver Enzymes 
The number and percentage of subjects having elevations in liver enzyme abnormalities (alanine 
aminotransferase [ALT] or aspartate aminotransferase [AST], or bilirubin) in relation to fold above the 
ULN will be summarized according to the FDA’s Premarketing Clinical Evaluation on Drug-Induced 
Liver Injury Guidance for Industry (DHHS 2009).  
Both fold change from ULN and fold change from baseline will be summarized by visit for ALT, ALP, 
AST, and bilirubin. 
The following categories of abnormal hepatic laboratory values will be evaluated for any occurrence 
among all post-baseline assessments (where “and” indicates elevations occurring at the same visit). 
Treatment-emergent elevations will also be summarized. Within each treatment group and laboratory 
parameter grouping, a subject may be counted once per elevation criteria using the worst-case result. That 
is, a subject with a worst-case ALT elevation >3 × ULN for a given treatment group would be counted 
once in the ALT > 1.5 × ULN category and once in the ALT > 3 × ULN category, regardless of how 
many ALT elevations the subject had that met the > 3 × ULN and > 1.5 × ULN elevation criteria. 


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 
ALT or AST and total bilirubin 
 
ALT > 3 × ULN and bilirubin > 1.5 × ULN 
 
ALT > 3 × ULN and bilirubin > 2 × ULN 
 
AST > 3 × ULN and bilirubin > 1.5 × ULN 
 
AST > 3 × ULN and bilirubin > 2 × ULN 
 
(ALT > 3 × ULN or AST > 3 × ULN) and bilirubin > 1.5 × ULN 
 
(ALT > 3 × ULN or AST > 3 × ULN) and bilirubin > 2 × ULN 
 
AST > 1.5, 3, 5, 10, or 20 × ULN 
 
ALT > 1.5, 3, 5, 10, or 20 × ULN 
 
Total bilirubin > 1, 1.5, or 2 × ULN 
 
ALP > 1.5 × ULN 
Profiles of hemoglobin, liver enzymes (ALT, ALP, AST) and bilirubin over time will be graphically 
displayed for subjects with any Grade 3 or 4 abnormality in ALT, ALP, AST, or total bilirubin. In 
addition, a listing of all liver function test (ALT, AST, bilirubin, ALP) results for subjects experiencing a 
treatment-emergent Grade 3 or 4 liver function test will be provided. 
In addition, a Hy’s law plot, a shift plot showing liver safety panel tests over time (baseline vs. on-study), 
and distribution plots of ALT, AST, ALP, bilirubin, cholesterol, and triglycerides over time will be 
produced using the format recommended by the FDA/Industry/Academia Safety Graphics working group 
(https://www.ctspedia.org/do/view/CTSpedia/StatGraphHome). The plots to be included are the scatter 
plot of maximum transaminase versus maximum bilirubin, the liver test safety panel over time, and the 
distribution of ALT by time and treatment. Distribution plots for AST, ALP, bilirubin, cholesterol, and 
triglycerides will use the same format as is used for ALT. 
9.3. 
Bedside ECGs 
Bedside ECGs are obtained as scheduled in Table 2.  
Descriptive summaries of bedside ECG parameters (PR, QRS, QT, RR, and QTcF) and change from 
baseline will be presented by parameter, time point, and treatment category. ECG interpretation (normal, 
abnormal, abnormal clinically significant) will be presented by time point and treatment including “worst 
post baseline” (defined as Abnormal if ever Abnormal post-baseline, and otherwise Normal if always 
Normal post-baseline).  
The number and percentage of subjects with QTcF ≤ 450, > 450 to ≤ 480, > 480 to ≤ 500, and > 500 
msec; or changes of ≤ 30, > 30 to ≤ 60, or > 60 msec will be summarized by treatment category and visit 
along with worst post-baseline result. Unscheduled ECG results will be included in this summary table. 
ECG results will be listed by treatment category, subject, parameter, and time point.  


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9.4. 
Other Safety Measures 
Descriptive summaries of vital signs and change from baseline in vital signs will be presented by 
parameter, time point, and treatment category. Vital signs and physical examination results will each be 
listed by treatment, subject, and time point.  


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10. 
CLINICAL MEASUREMENTS AND SYMPTOMS OF PNH 
10.1.1. 
Clinical PNH Symptoms 
The following clinical parameters will be summarized with counts and percentages by treatment category 
and study visit:  fatigue, dyspnea, chest pain/discomfort, difficulty swallowing (esophageal pain, 
dysphagia), abdominal pain, headache, erectile dysfunction, hemoglobinuria, and jaundice.  
10.1.2. 
Clinical Measurements of PNH 
Continuous clinical measurements of PNH (LDH, hemoglobin, haptoglobin levels, absolute reticulocyte 
count, AST, total bilirubin, and direct bilirubin) will be summarized by summary statistics including 
change from baseline and percent change from baseline, by treatment category and study visit. Note that 
LDH, hemoglobin, haptoglobin, and absolute reticulocyte count that occur within a transfusion-impacted 
period will not be included in summaries but will be presented in respective listings. Categorical clinical 
measurements of PNH (number of blood transfusions, incidence of  major thromboses) will be 
summarized with counts and percentages by treatment category (see Section 12.3 for a list of thrombosis 
events). Incidence of breakthrough hemolysis will be analyzed by the sponsor. 
 
 


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11. 
CLINICAL PHARMACOLOGY DATA ANALYSES 
11.1. 
Pharmacokinetic Analyses 
Sparse plasma and spot urine samples for determination of BCX9930 concentrations are planned to be 
collected at each study visit to the investigative site and 48 hours after evidence of BTH.  
Plasma and urine concentrations of BCX9930 and BCX13559—a metabolite of BCX9930—will be listed 
with the time of sample collection and time of prior dose along with other available information. Any 
analysis of PK data including the calculation and assessment of PK parameters will be performed under a 
separate analysis plan. 
11.2. 
Pharmacodynamic Analyses 
In this study, PD assessments include PNH clone size (RBC and WBC), Factor Bb, serum AP activity as 
assessed by AP Wieslab, and additional exploratory assays.  
Descriptive summaries of the above assessments including change from baseline will be presented by 
treatment category, dose regimen, and study visit. AP Wieslab (and other similar assays, if applicable) 
will be reported only as percent of baseline, not as actual value or percent change from baseline. Data 
values will be listed.  
If PD assessments are reported with inequalities (<, ≤, >, or ≥), the same conventions used for laboratory 
values as described in Section 9.2 will be used. 
Any further analysis of PD data including the relationship to PK concentrations will be performed under a 
separate analysis plan. 


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12. 
ATTACHMENTS 
12.1. 
Table of Contents for Data Display Specifications 
This table of contents provides the expected titles and numbers of the tables, listings, and figures of the 
final report. Changes to titles or numbering in the final report, additional data listings supporting the 
tables, or displays being split into multiple smaller displays for clarity will not necessitate a revision to 
the SAP, nor will they be considered a deviation from planned analyses. 
Table 7: 
Data Displays 
Table 
Number  
Title  
Population  
14.1.1 
Subject Disposition  
All 
14.1.2 
Analysis Populations  
All  
14.1.3.1 
Demographic and Baseline Characteristics  
mITT  
14.1.3.2 
Demographic and Baseline Characteristics  
Safety  
14.1.4.1 
Prior Medication  
Safety  
14.1.4.2 
Concomitant Medication  
Safety  
14.1.5 
Treatment Exposure and Compliance 
Safety  
14.2.1 
Durability of Response – Hemoglobin (g/dL) 
mITT 
14.2.2.1 
Hematological Response 
mITT 
14.2.3 
Functional Assessment of Chronic Illness Therapy 
(FACIT) Fatigue Scale 
mITT 
14.2.4 
Total Time on Dose Level 
mITT 
14.2.5 
Disease Severity 
mITT 
14.3.1 
Overall Summary of Treatment-emergent Adverse 
Events 
Safety  
14.3.2.1 
Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
Safety  
14.3.2.2 
Treatment-emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term, and Severity 
Safety  
14.3.2.3 
Serious Treatment-emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety  
14.3.2.4 
Treatment-emergent Adverse Events Related to Study 
Drug by MedDRA System Organ Class and Preferred 
Term 
Safety  
14.3.2.5 
Grade 3 or 4 Treatment-emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety  
14.3.2.6 
Treatment-emergent Adverse Events Leading to 
Treatment Discontinuation by MedDRA System Organ 
Class and Preferred Term 
Safety  
14.3.2.7 
Treatment-emergent Adverse Events Leading to 
Treatment Interruption by MedDRA System Organ 
Class and Preferred Term 
Safety  
14.3.2.8 
Treatment-emergent Major Adverse Vascular Events 
(MAVEs) by MedDRA System Organ Class and 
Preferred Term 
Safety 
14.3.2.9 
Treatment-emergent Events of Special Interest (EOSIs) 
by MedDRA System Organ Class and Preferred Term 
Safety 
14.3.2.10.1 
Time to First Dose Reduction – Kaplan-Meier 
Safety  
14.3.2.11.1 
Time to Discontinuation Due to a Treatment-Emergent 
Adverse Event – Kaplan-Meier 
Safety 


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14.3.2.12.1 
Time to First Drug-Related Rash – Kaplan-Meier 
Safety  
14.3.2.13.1 
Time to First SARS-CoV-2 Infection – Kaplan-Meier 
Safety 
14.3.2.13.3 
Duration of SARS-CoV-2 Infection – Kaplan-Meier 
Safety 
14.3.2.14.1 
Time to First Potential Drug-Induced Liver Injury 
(pDILI) Event – Kaplan-Meier 
Safety 
14.3.2.15.1 
Time to First Increase in Serum Creatinine > ULN – 
Kaplan-Meier 
Safety 
14.3.3.1.1 
Laboratory Results by Visit – Clinical Chemistry 
Safety 
14.3.3.2 
Laboratory Results by Visit – Hematology, PNH Clone 
Size, and Coagulation 
Safety 
14.3.3.3.1 
Laboratory Results by Visit – Continuous Urinalysis 
Parameters 
Safety 
14.3.3.3.2 
Laboratory Results by Visit – Categorical Urinalysis 
Parameters 
Safety 
14.3.3.4 
Laboratory Results by Visit – Complement Factors 
Safety 
14.3.3.5 
Laboratory Results by Visit – Iron Assessments 
Safety 
14.3.3.6 
Treatment-emergent Graded Laboratory Abnormalities 
by Visit 
Safety 
14.3.3.7 
Treatment-emergent Grade 3 or 4 Laboratory 
Abnormalities by Visit 
Safety 
14.3.3.8 
Treatment-emergent Graded Laboratory Toxicity Grade 
Increases from Baseline 
Safety 
14.3.3.9 
Shift from Baseline to Worst Post-baseline Assessment: 
Clinical Chemistry 
Safety 
14.3.3.10 
Shift from Baseline to Worst Post-baseline Assessment: 
Hematology 
Safety 
14.3.3.11 
Shift from Baseline to Worst Post-baseline Assessment: 
Urinalysis 
Safety 
14.3.3.12 
Fold x ULN for Liver Function Tests 
Safety 
14.3.3.13 
Fold Change from Baseline for Liver Function Tests 
Safety 
14.3.3.14.1 
Post-baseline Elevations in Liver Function Tests 
Safety 
14.3.3.15 
Treatment-emergent Elevations in Liver Function Tests 
Safety 
14.3.4 
Vital Signs by Visit 
Safety 
14.3.5.1 
12-Lead ECG Results by Visit 
Safety 
14.3.5.2 
12-Lead ECG Findings by Visit 
Safety 
14.3.5.3 
12-Lead ECG QTcF Interval Abnormalities 
(Categorical) by Visit 
Safety 
14.4.1.1 
Clinical PNH Symptoms 
mITT 
14.4.1.2 
Clinical Measurements of PNH: Blood Transfusions and 
Major Thromboses 
mITT 
14.4.1.3 
Continuous Clinical Measurements of PNH 
mITT 
14.5.1 
PD Assessment Summary Statistics  
PD  
Figure 
Number  
Title  
Population  
14.2.2.2 
Bar Chart of Hematological Response over Time 
 
(Note to programmers: Present each time point on its 
own page.) 
 
14.3.2.10.2 
Kaplan-Meier Plot of First Dose Reduction 
Safety  
14.3.2.11.2 
Kaplan-Meier Plot of Discontinuation Due to a 
Treatment-Emergent Adverse Event 
Safety 
14.3.2.12.2 
Kaplan-Meier Plot of First Drug-Related Rash 
Safety  
14.3.2.13.2 
Kaplan-Meier Plot of First SARS-CoV-2 Infection 
Safety 


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14.3.2.13.4 
Kaplan-Meier Plot of Duration of SARS-CoV-2 
Infection 
Safety 
14.3.2.14.2 
Kaplan-Meier Plot of First Potential Drug-Induced Liver 
Injury (pDILI) Event 
Safety 
14.3.2.15.2 
Kaplan-Meier Plot of First Increase in Serum Creatinine 
> ULN 
Safety 
14.3.3.1.2 
Distribution of Cholesterol and Triglycerides over Time 
Safety 
14.3.3.1.3 
Selected Laboratory Parameters by Time  
Safety  
14.3.3.14.2 
Hy’s Law Plot of Maximum Total Bilirubin vs. 
Maximum ALT 
Safety 
14.3.3.14.3 
Liver Test Safety Panel over Time, Baseline vs. On-
study 
Safety 
14.3.3.14.4 
Individual Patient Profile of ALT, ALP, AST, 
Hemoglobin, and Total Bilirubin 
(Note to programmers: display ALT, ALP, AST, and 
total bilirubin as the fold x ULN on a semi-log axis (left-
hand y-axis). Display hemoglobin on a linear scale using 
the right-hand axis and display lines and symbols in red) 
Safety:  
Subjects with 
Treatment-
Emergent 
Grade 3 or 4 
ALT, ALP, 
AST, or Total 
Bilirubin  
14.3.3.14.5 
Distribution of Liver Tests over Time: ALT, AST, ALP, 
and Bilirubin 
Safety 
14.4.3.2 
Plot of Clinical Measurements of PNH  
 
(Note to programmers: display LDH, hemoglobin, 
haptoglobin, absolute reticulocyte count, AST, total 
bilirubin, and direct bilirubin on the same plot if 
possible. Display hemoglobin on a linear scale (on each 
page, if multiple pages are needed) using the right-hand 
axis and display lines and symbols in red.) 
mITT 
  
14.4.3.3 
Plot of Clinical Measurements of PNH Change from 
Baseline  
 
(Note to programmers: display LDH, hemoglobin, 
haptoglobin, absolute reticulocyte count, AST, total 
bilirubin, and direct bilirubin on the same plot if 
possible. Display hemoglobin on a linear scale (on each 
page, if multiple pages are needed) using the right-hand 
axis and display lines and symbols in red.) 
mITT 
14.4.3.4 
Plot of Clinical Measurements of PNH Percent Change 
from Baseline  
 
(Note to programmers: display LDH, hemoglobin, 
haptoglobin, absolute reticulocyte count, AST, total 
bilirubin, and direct bilirubin on the same plot if 
possible. Display hemoglobin on a linear scale (on each 
page, if multiple pages are needed) using the right-hand 
axis and display lines and symbols in red.) 
mITT 
Listing 
Number  
Title  
Population  
16.2.1.1 
Informed Consent  
All  
16.2.1.2 
Subject Registry 
 
16.2.1.3 
Subject Disposition  
All  
16.2.2 
Protocol Deviations  
All  
16.2.3 
Analysis Populations  
All  


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16.2.4.1 
Demographic and Baseline Characteristics  
All  
16.2.4.2 
Medical History  
All  
16.2.4.3 
Prior and Concomitant Medications  
All  
16.2.5.1 
Study Drug Accountability 
Safety  
16.2.5.2 
Overall Compliance 
Safety 
16.2.6.1 
PNH Characteristics and Symptoms 
All 
16.2.6.2 
Clinical Measurements of PNH 
All 
16.2.7 
QLQ-AA/PNH Individual Question Responses 
All 
16.2.8.1 
FACIT-Fatigue Scale Individual Question Responses 
All 
16.2.8.2 
FACIT-Fatigue Scale Score 
All 
16.2.9 
TSQM Individual Question Responses 
All 
16.2.10.1 
Hemolysis Monitoring 
All  
16.2.10.2 
Renal Events 
All 
16.2.10.3 
Transfusions 
All 
16.2.11.1 
Adverse Events  
All  
16.2.11.2 
Serious Adverse Events  
All  
16.2.11.3 
Adverse Events Leading to Study Discontinuation  
All  
16.2.11.4 
Adverse Events Related to Study Drug  
All  
16.2.11.5 
Adverse Events with Grade 3 or Grade 4 Severity  
All  
16.2.11.6 
Major Adverse Vascular Events (MAVEs) 
All 
16.2.11.7 
Events of Special Interest (EOSIs) 
All 
16.2.11.8 
Hemolysis Adverse Events 
All  
16.2.11.9 
Rash-related Adverse Events 
All  
16.2.11.10 
Acute Kidney Injuries 
All 
16.2.12 
Cutaneous Eruption Assessments 
All 
16.2.13.1 
Laboratory Results - Clinical Chemistry  
All  
16.2.13.2 
Laboratory Results - Hematology  
All  
16.2.13.3 
Laboratory Results - Coagulation  
All  
16.2.13.4 
Laboratory Results - Urinalysis  
All  
16.2.13.5 
Laboratory Results - Other Laboratory Tests  
All  
16.2.14 
Bedside 12-lead Electrocardiogram  
All  
16.2.15 
Vital Signs, Height, and Weight  
All  
16.2.16 
Physical Examinations  
All  
16.2.17.1 
Plasma BCX9930 Pharmacokinetic Concentrations  
All  
16.2.17.2 
Urine BCX9930 Pharmacokinetic Concentrations 
All  
16.2.18.1 
Plasma BCX13559 Pharmacokinetic Concentrations  
All  
16.2.18.2 
Urine BCX13559 Pharmacokinetic Concentrations 
All  
16.2.19 
Individual PD Assessments and Biomarkers 
All  
12.2. 
Data Display Specifications 
Specifications for data displays will be provided in a separate document. 
 


Statistical Analysis Plan 
 
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12.3. 
Preferred Terms that Qualify as MAVEs and Thrombotic Events 
MAVE Term 
PT 
SOC 
Thrombotic 
Event? 
deep vein 
thrombosis 
Deep vein thrombosis 
Vascular disorders 
YES 
Deep vein thrombosis postoperative 
Injury, poisoning and procedural complications 
YES 
Deep vein thrombosis postoperative 
Vascular disorders 
YES 
Pelvic venous thrombosis 
Vascular disorders 
YES 
pulmonary embolus 
Pulmonary embolism 
Respiratory, thoracic and mediastinal disorders 
YES 
Pulmonary embolism 
Vascular disorders 
YES 
myocardial infarction 
Myocardial infarction 
Cardiac disorders 
YES 
Myocardial infarction 
Vascular disorders 
YES 
Acute myocardial infarction 
Cardiac disorders 
YES 
Acute myocardial infarction 
Vascular disorders 
YES 
ECG signs of myocardial infarction 
Investigations 
NO 
Periprocedural myocardial infarction 
Injury, poisoning and procedural complications 
YES 
Periprocedural myocardial infarction 
Cardiac disorders 
YES 
Dressler's syndrome 
Cardiac disorders 
NO 
Dressler's syndrome 
Immune system disorders 
NO 
Dressler's syndrome 
Respiratory, thoracic and mediastinal disorders 
NO 
Post procedural myocardial infarction 
Injury, poisoning and procedural complications 
YES 


Statistical Analysis Plan 
 
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MAVE Term 
PT 
SOC 
Thrombotic 
Event? 
Post procedural myocardial infarction 
Cardiac disorders 
YES 
Silent myocardial infarction 
Cardiac disorders 
YES 
Silent myocardial infarction 
Vascular disorders 
YES 
transient ischemic 
attack 
Transient ischaemic attack 
Nervous system disorders 
YES 
Transient ischaemic attack 
Vascular disorders 
YES 
unstable angina 
Angina unstable 
Cardiac disorders 
YES 
Angina unstable 
Vascular disorders 
YES 
renal vein 
thrombosis 
Renal vein thrombosis 
Renal and urinary disorders 
YES 
Renal vein thrombosis 
Vascular disorders 
YES 
Renal vein embolism 
Renal and urinary disorders 
YES 
Renal vein embolism 
Vascular disorders 
YES 
acute peripheral 
vascular occlusion 
Vascular occlusion 
Vascular disorders 
YES 
Cerebral vascular occlusion 
Nervous system disorders 
YES 
Cerebral vascular occlusion 
Vascular disorders 
YES 
Coronary vascular graft occlusion 
Injury, poisoning and procedural complications 
YES 
Coronary vascular graft occlusion 
Cardiac disorders 
YES 
Coronary vascular graft occlusion 
Vascular disorders 
YES 
Mesenteric vascular occlusion 
Gastrointestinal disorders 
YES 


Statistical Analysis Plan 
 
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MAVE Term 
PT 
SOC 
Thrombotic 
Event? 
Mesenteric vascular occlusion 
Vascular disorders 
YES 
Retinal vascular occlusion 
Eye disorders 
YES 
Retinal vascular occlusion 
Vascular disorders 
YES 
Vascular access site occlusion 
Injury, poisoning and procedural complications 
YES 
Vascular access site occlusion 
Vascular disorders 
YES 
Vascular access site occlusion 
General disorders and administration site 
conditions 
YES 
Vascular device occlusion 
General disorders and administration site 
conditions 
NO 
Vascular device occlusion 
Vascular disorders 
YES 
Vascular graft occlusion 
Injury, poisoning and procedural complications 
NO 
Vascular graft occlusion 
Vascular disorders 
YES 
Vascular stent occlusion 
General disorders and administration site 
conditions 
YES 
Vascular stent occlusion 
Vascular disorders 
YES 
mesenteric/visceral 
vein thrombosis or 
infarction 
Mesenteric vein thrombosis 
Gastrointestinal disorders 
YES 
Mesenteric vein thrombosis 
Vascular disorders 
YES 
Portosplenomesenteric venous 
thrombosis 
Hepatobiliary disorders 
YES 


Statistical Analysis Plan 
 
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MAVE Term 
PT 
SOC 
Thrombotic 
Event? 
Portosplenomesenteric venous 
thrombosis 
Gastrointestinal disorders 
YES 
Portosplenomesenteric venous 
thrombosis 
Vascular disorders 
YES 
Intestinal infarction 
Gastrointestinal disorders 
YES 
Intestinal infarction 
Vascular disorders 
YES 
Visceral venous thrombosis 
Gastrointestinal disorders 
YES 
Visceral venous thrombosis 
Vascular disorders 
YES 
mesenteric/visceral 
arterial thrombosis 
or infarction 
Mesenteric artery thrombosis 
Gastrointestinal disorders 
YES 
Mesenteric artery thrombosis 
Vascular disorders 
YES 
Intestinal infarction 
Gastrointestinal disorders 
YES 
Intestinal infarction 
Vascular disorders 
YES 
hepatic/portal vein 
thrombosis (Budd-
Chiari syndrome) 
Budd-Chiari syndrome 
Hepatobiliary disorders 
YES 
Budd-Chiari syndrome 
Vascular disorders 
YES 
cerebral arterial 
occlusion/cerebrovas
cular accident 
Cerebral artery occlusion 
Nervous system disorders 
YES 
Cerebral artery occlusion 
Vascular disorders 
YES 
Intraoperative cerebral artery occlusion 
Injury, poisoning and procedural complications 
YES 
Intraoperative cerebral artery occlusion 
Nervous system disorders 
YES 
Intraoperative cerebral artery occlusion 
Vascular disorders 
YES 


Statistical Analysis Plan 
 
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MAVE Term 
PT 
SOC 
Thrombotic 
Event? 
Precerebral artery occlusion 
Nervous system disorders 
YES 
Precerebral artery occlusion 
Vascular disorders 
YES 
Cerebrovascular accident 
Nervous system disorders 
YES 
Cerebrovascular accident 
Vascular disorders 
YES 
Cerebrovascular accident prophylaxis 
Surgical and medical procedures 
NO 
cerebral venous 
occlusion 
Cerebral venous thrombosis 
Nervous system disorders 
YES 
Cerebral venous thrombosis 
Vascular disorders 
YES 
renal arterial 
thrombosis 
Renal artery thrombosis 
Renal and urinary disorders 
YES 
Renal artery thrombosis 
Vascular disorders 
YES 
gangrene 
(nontraumatic; 
nondiabetic) 
Gangrene 
Infections and infestations 
NO 
Gangrene 
Vascular disorders 
YES 
Gangrene 
Skin and subcutaneous tissue disorders 
NO 
Arteriosclerotic gangrene 
Infections and infestations 
YES 
Arteriosclerotic gangrene 
Vascular disorders 
YES 
Arteriosclerotic gangrene 
Skin and subcutaneous tissue disorders 
YES 
Peripheral arterial occlusive disease 
Vascular disorders 
YES 
Femoral hernia gangrenous 
Infections and infestations 
NO 
Femoral hernia gangrenous 
Gastrointestinal disorders 
NO 


Statistical Analysis Plan 
 
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Version 1.0 
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MAVE Term 
PT 
SOC 
Thrombotic 
Event? 
Femoral hernia gangrenous 
Vascular disorders 
YES 
Inguinal hernia gangrenous 
Infections and infestations 
NO 
Inguinal hernia gangrenous 
Vascular disorders 
YES 
Inguinal hernia gangrenous 
Gastrointestinal disorders 
NO 
Dry gangrene 
Vascular disorders 
YES 
Dry gangrene 
Skin and subcutaneous tissue disorders 
NO 
Gas gangrene 
Infections and infestations 
NO 
Gas gangrene 
Vascular disorders 
YES 
Gas gangrene 
Skin and subcutaneous tissue disorders 
NO 
Fournier's gangrene 
Infections and infestations 
NO 
Fournier's gangrene 
Musculoskeletal and connective tissue disorders 
NO 
Fournier's gangrene 
Reproductive system and breast disorders 
NO 
Penile gangrene 
Infections and infestations 
NO 
Penile gangrene 
Reproductive system and breast disorders 
NO 
Penile gangrene 
Vascular disorders 
YES 
Scrotal gangrene 
Infections and infestations 
NO 
Scrotal gangrene 
Vascular disorders 
YES 
Scrotal gangrene 
Reproductive system and breast disorders 
NO 


Statistical Analysis Plan 
 
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MAVE Term 
PT 
SOC 
Thrombotic 
Event? 
Scrotal gangrene 
Skin and subcutaneous tissue disorders 
NO 
Umbilical hernia gangrenous 
Infections and infestations 
NO 
Umbilical hernia gangrenous 
Vascular disorders 
YES 
Umbilical hernia gangrenous 
Gastrointestinal disorders 
NO 
Abdominal hernia gangrenous 
Infections and infestations 
NO 
Abdominal hernia gangrenous 
Gastrointestinal disorders 
NO 
Incisional hernia gangrenous 
Infections and infestations 
NO 
Incisional hernia gangrenous 
Vascular disorders 
YES 
Incisional hernia gangrenous 
Gastrointestinal disorders 
NO 
amputation 
(nontraumatic; 
nondiabetic) 
Amputation 
Surgical and medical procedures 
NO 
Hemipelvectomy 
Surgical and medical procedures 
NO 
Leg amputation 
Surgical and medical procedures 
NO 
Amputation of penis 
Surgical and medical procedures 
NO 
Arm amputation 
Surgical and medical procedures 
NO 
Foot amputation 
Surgical and medical procedures 
NO 
Cervix colporrhaphy with amputation 
Surgical and medical procedures 
NO 
Finger amputation 
Surgical and medical procedures 
NO 
Interscapulothoracic amputation 
Surgical and medical procedures 
NO 


Statistical Analysis Plan 
 
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Version 1.0 
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CONFIDENTIAL 
MAVE Term 
PT 
SOC 
Thrombotic 
Event? 
Hand amputation 
Surgical and medical procedures 
NO 
Limb amputation 
Surgical and medical procedures 
NO 
Spontaneous amputation 
Vascular disorders 
NO 
Spontaneous amputation 
Skin and subcutaneous tissue disorders 
NO 
Toe amputation 
Surgical and medical procedures 
NO 
dermal thrombosis 
Thrombophlebitis superficial 
Vascular disorders 
YES 
Vascular skin disorder 
Skin and subcutaneous tissue disorders 
NO 
Vascular skin disorder 
Vascular disorders 
YES