A Phase 2a, Open-label, Single and Multiple Dose Study to Evaluate the Pharmacokinetics, Safety, Tolerability and Treatment Effect of GBT440 in Pediatric Participants With Sickle Cell Disease
Phase: PHASE2
Conditions: Sickle Cell Disease
Sponsor: Pfizer

C LI NI C A L S T U D Y P R O T O C O L
G B T 4 4 0 -0 0 7
St u d y N u m ber
G B T 4 4 0 -0 0 7
St u d y Title
A P hase 2a , O pe n -la bel, Si n gle a n d M ulti ple D ose St u d y t o E val uate t he 
P har mac o ki netics, Safet y, T olera bilit y a n d Treat me nt Effect of G B T 4 4 0 i n 
Pe diatric Partici pa nts wit h Sic kle Cell Disease
I n vesti g ati o n al Pr o d uct
V o xel ot or ( pre vi o usl y G B T 4 4 0 )
I N D N u m ber
1 2 1, 6 9 1
E u dr a C T N u m ber
2 0 1 6 -0 0 4 2 0 9 -1 5
S p o ns or
Gl o bal Bl o o d T hera pe utics, I nc.
1 8 1 O yster P oi nt Bl v d .
S o ut h Sa n Fra ncisc o, C A 9 4 0 8 0
U nite d States of A merica
St u d y Direct or
, P har m D
Gl o bal Bl o o d T hera pe utics, I nc.
1 8 1 O yster P oi nt Bl v d .
S o ut h Sa n Fra ncisc o, C A 9 4 0 8 0
U nite d States of A merica
Tele p h o ne: 
 ( office)
E m ail: 
Pr ot oc ol A m e n d me nt 7
2 8 A pril 2 0 2 1
Pr ot oc ol A m e n d me nt 6
1 5 N o ve m ber 2 0 1 9
Pr ot oc ol A m e n d me nt 5
1 4 J u ne 2 0 1 8
Pr ot oc ol A m e n d me nt 4
0 9 J u ne 2 0 1 7
Pr ot oc ol A m e n d me nt 3
0 6 Marc h 2 0 1 7 
Pr ot oc ol A m e n d me nt 2
1 0 N o ve m b er 2 0 1 6
A m e n d me nt 1
3 0 A u g ust 2 0 1 6
Ori gi n al Pr ot oc ol
0 5 Fe br uar y 2 0 1 6
C O N FI D E N TI A LI T Y S T A T E M E N T
T he i nf or mati o n i n t his st u d y pr ot oc ol is strictl y c o nfi de ntial a n d is a vaila ble f or re vie w t o I n vesti gat ors, st u d y 
ce nter pers o n nel, t he et hics c o m mittee a n d t he healt h a ut h orities. It w ill n ot be discl ose d t o t hir d parties wit h o ut 
writte n a ut h orizati o n fr o m t he S p o ns or, e xce pt t o o btai n i nf or me d c o nse nt fr o m pers o ns recei vi n g t he st u d y 
treat me nt. O nce t he pr ot oc ol is si g ne d, its ter ms are bi n di n g f or all parties.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)
P P D
P P D
P P D
P P D

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
2
S T A T E M E N T O F A P P R O V A L A N D C O M P LI A N C E
A P h ase 2 a , O pe n-l a bel, Si n gle a n d M ulti ple D ose St u d y t o E v al u ate t he P h ar m ac o ki netics, 
S a fet y, T oler a bilit y a n d Tre at me nt Effect of G B T 4 4 0 i n Pe di atric P artici p a nts wit h Sic kle 
Cell Dise ase
Pr ot oc ol A me n d me nt 7 : 2 8 A pril 2 0 2 1
S P O N S O R A P P R O V A L
T he si g nat ure of t he S p o ns or re prese ntati ve bel o w re prese nts t hat t he a b o ve-refere nce d cli nical 
trial is bei n g c o n d ucte d u n der F D A I N D N u m ber 1 2 1 6 9 1 G B T 4 4 0 f or t he treat me nt of sic kle cell 
disease . T his I N D a p plicati o n is hel d b y  G B T. T he pr ot oc ol is bei n g c o n d ucte d i n acc or da nce 
wit h I CH G C P a n d all a p plica ble fe deral, state a n d l ocal re g ulati o ns g o ver ni n g t he c o n d uct of 
t his researc h, i ncl u di n g D H H S 4 5 C F R Part 4 6, F D A 2 1 C F R P arts 5 0, 5 4, 5 6, 3 1 2 a n d 8 1 2 .
G B T will pr o vi de t he I n vesti gat or wit h all i nf or mati o n i ncl u di n g safety i nf or mati o n perti ne nt t o 
t he c o n d uct of t he st u dy.
S p o ns or Re prese nt ati ve ( Pri nt) :
Si g n at ure:
D ate:
Title:
I N V E S TI G A T O R A P P R O V A L
T he si g nat ure of t he I n vesti gat or bel o w c o nstit utes a p pr o val of t his pr ot oc ol as writte n a n d 
reflects t he I n vesti gat or’s c o m mit me nt t o c o n d uct t he st u d y i n acc or da nce wit h t he pr ot oc ol, t he 
ap plica ble la ws a n d re g ulati o ns a n d i n c o m plia nce wit h I CH G C P g ui deli nes a n d t he Declarati o n 
of Helsi n ki .
Pri nci p al I n vesti g at or ( Pri nt):
Si g n at ure:
D ate:
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
3
S Y N O P SI S
Title
A P hase 2a , O pe n-la bel, Si n gle a n d M ulti ple D ose St u d y t o E val uate t he 
P har mac o ki netics, Safet y, T olera bilit y a n d Treat me nt Effect of G B T 4 4 0 i n 
Pe diatric Partici pa nts wit h Sic kle Cell Disease
Pr ot oc ol N u m ber
G B T 4 4 0- 0 0 7
S p o ns or 
Gl o bal Bl o o d T hera pe utics, I nc.
1 8 1 O yster P oi nt Bl v d .
S o ut h Sa n Fra ncisc o, C A 9 4 0 8 0
U nite d States of A merica
St u d y Dr u g
P art A a n d P art B : 
V o xel ot or ( pre vi o usl y G B T 4 4 0) ca ps ules or ta blets : 3 0 0 m g , a d mi nistere d 
orall y
P art C:
V o xel ot or dis persi ble ta ble ts: 1 0 0 a n d/ or 3 0 0 m g, a d mi nistere d orall y
V o xel ot or p o w der f or oral s us pe nsi o n: 3 0 0, 4 0 0, 6 0 0 , a n d/ or 9 0 0 m g, 
a d mi nistere d orall y
P art D:
V o xel ot or p o w der f or oral s us pe nsi o n 3 0 0, 4 0 0, 6 0 0 , a n d/ or 9 0 0 m g ,
a d mi nistere d orall y
V o xel ot or dis persi ble ta blets: 1 0 0 a n d/ or 3 0 0 m g, a d mi nistere d orall y
P art A O bjecti ves
Pri m ar y

T o c haracterize t he p har mac o ki netics ( P K) of v o xel ot or i n plas ma a n d 
w h ole bl o o d f oll o wi n g a si n gle d ose i n pe diatric partici pa nts wit h sic kle 
cell disease ( S C D) 
Sec o n d ar y

T o e val uate t he safet y a n d t olera bilit y of v o xel ot or f oll o wi n g a si n gle 
d ose i n pe diatric partici pa nts wit h S C D 
P art B O bjecti ves
Pri m ar y

T he pri mar y o bjecti ve is t o assess t he efficac y of v o xel ot or i n pe diatric 
partici pa nts wit h S C D as meas ure d b y i m pr o ve me nt i n a ne mia
Sec o n d ar y

T o pr o vi de data o n t he electr o nic Patie nt -Re p orte d O utc o me (e P R O) 
meas ure me nt i n esta blis hi n g t he l o n git u di nal meas ure me nt pr o perties of 
t he P R O 

T o e val uate t he effect of v o xel ot or o n cli nical meas ures of he m ol ysis

T o c haracterize t he P K of v o xel ot or i n plas ma, w h ole bl o o d a n d re d 
bl o o d cells ( R B C s) f oll o wi n g m ulti ple d oses i n pe diatric partici pa nt s 
wit h S C D
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
4

T o e val uate t he safet y a n d t olera bilit y of v o xel ot or f oll o wi n g m ulti ple 
d oses i n pe diatric partici pa nts wit h S C D

T o e val uate t he effect of v o xel ot or o n cere bral he m o d y na mics as 
assesse d b y tra nscra nial D o p pler ( T C D) ultras o n o gra p h y

T o e val uate t he effects of v o xel ot or o n S C D s y m pt o m e xacer bati o n a n d 
total sy m pt o m sc ore ( T S S) fr o m t he P R O meas ure me nt
P art C O bjecti ves
Pri m ar y

T o e val uate t he effect of v o xel ot or o n cere bral he m o d y na mics i n 
pe diatric partici pa nts wit h S C D wit h ele vate d or c o n dit i o nal T C D fl o w 
vel ocit y as assesse d b y T C D ultras o n o gra p h y
Sec o n d ar y

T o e val uate t he effect of v o xel ot or o n cli nical meas ures of a ne mia a n d 
he m ol ysis 

T o c haracterize t he P K of v o xel ot or i n plas ma, w h ole bl o o d a n d R B Cs 
f oll o wi n g m ulti ple d oses i n pe diatric partici pa nts wit h S C D

T o e val uate t he safet y a n d t olera bilit y of v o xel ot or f oll o wi n g m ulti ple 
d oses i n pe diatric partici pa nts wit h S C D

T o e val uate t h e pr o p orti o n of partici pa nts wit h n or mal T C D fl o w 
vel ocit y ( < 1 7 0 c m/sec b y n o ni ma gi n g T C D or < 1 5 5 c m/sec b y T C Di ) at 
Wee k 4 8

T o e val uate t he effect of v o xel ot or o n t he i nci de nce of str o ke a n d v as o-
o ccl usi ve crisis ( V O C)
P art D O bjecti ves
Pri m ar y

T o e val uate t he safet y a n d t olera bilit y of v o xel ot or i n pe diatric 
partici pa nts wit h S C D a ge d 6 m o nt hs t o < 4 years
Sec o n d ar y

T o c haracterize t he P K of v o xel ot or i n plas ma, w h ole bl o o d, a n d R B Cs 
i n pe diatric partici pa nts wit h S C D a ge d 6 m o nt hs t o < 4 years

T o e val uate t he effect of v o xel ot or o n cli nical meas ures of a ne mia a n d 
he m ol ysis i n pe diatric partici pa nts wit h S C D a ge d 6 m o nt hs t o < 4 years

T o e val uate t he effect of v o xel ot or o n t he i nci de nce of str o ke a n d V O C
i n pe diatric partici pa nts wit h S C D a ge d 6 m o nt hs t o < 4 years
St u d y Desi g n
T his st u d y is a m ultice nter, o pe n-la bel st u d y t o e val uate t he safet y, P K a n d 
efficac y of v o xel ot or i n pe diatric partici pa nts wit h S C D.
T his st u d y c o nsists of 4 parts, Part A, Part B, Part C, a n d Part D:
P art A is a si n gle d ose P K st u d y of v o xel ot or i n pe diatric partici pa nts wit h 
S C D a ge d 6 t o 1 7 years. T his st u d y will i n v ol ve 2 c o h orts i n t his a ge ra n ge, 
C o h ort 1 ( 1 2 t o 1 7 years) a n d C o h ort 2 ( 6 t o 1 1 years) .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
5
P art B is a m ulti ple d ose, safet y, P K a n d efficac y st u d y of v o xel ot or i n 
pe diatric partici pa nts wit h S C D a ge d 1 2 t o 1 7 years, i ncl usi ve.
Partici pa nt s’ a ge f or c o h ort assi g n me nt will be base d o n t heir m ost rece nt 
birt h da y . U p o n c o m pleti o n of partici pati o n i n Part A of t he st u d y, 
partici pa nt s fr o m Part A t hat are a ge d 1 2 t o 1 7 years ma y be eli gi ble f or 
partici pati o n i n Part B.
Pri or t o pr ocee di n g fr o m t he 9 0 0 m g d ose t o t he 1 5 0 0 m g d ose i n Part B, t he 
f oll o wi n g data re vie ws will be c o n d ucte d:
A re vie w of t he P K data fr o m at least 8 pe diatric partici pa nts e nr olle d i n 
Part B of St u d y G B T 4 4 0 -0 0 7, f oll o wi n g at least 1 5 da ys of d osi n g wit h 
v o xel ot or 9 0 0 m g.
Data a n d Safet y M o nit ori n g B oar d ( D S M B ) re vie w of safet y data fr o m at 
least 8 pe diatric partici pa nts e nr olle d i n Part B of St u d y G B T 4 4 0 - 0 0 7, 
f oll o wi n g t he c o m pleti o n of 2 8 da ys of d osi n g wit h v o xel ot or 9 0 0 m g t o
c o nfir m acce pta ble safet y a n d t olera bilit y.
D S M B re vie w safet y data fr o m t he first 6 a d ult partici pa nts 1 5 0 0 m g d ose 
le vel fr o m Gr o u p 1 of St u d y G B T 4 4 0-0 3 1 ( H O P E st u d y), f oll o wi n g at least 
2 8 da ys of d osi n g wit h st u d y dr u g t o c o nfir m acce pta ble safet y a n d 
t olera bilit y. 
Sites will be n otifie d w he n t he a b o ve c o n diti o ns ha ve bee n met a n d 
e nr oll me nt i n t he 1 5 0 0 m g c o h ort ma y be gi n.
P art C will assess t he saf et y, t olera bilit y a n d P K , as well as t he 
he mat ol o gical eff ects a n d t he effect o n T C D fl o w vel ocit y of v o xel ot or i n 
pe diatric partici pa nts wit h S C D w h o are 4 t o 1 7 years of a ge.
U p t o 5 0 pe diatric partici pa nts will be e nr olle d. 

At least 3 0 partici pa nts m ust ha ve a T C D vel ocit y ≥1 4 0 a n d 
< 2 0 0 c m/sec b y n o ni ma gi n g T C D ( ≥1 2 5 a n d < 1 8 5 c m/sec b y i ma gi n g 
tra nscra nial D o p pler [ T C Di]) u p o n Scree ni n g A N D

At least 2 0 partici pa nts m ust be bet wee n 4 t o 1 1 years of a ge
P ote nti al M o dific ati o n : T o f urt her c haracterize a p ote ntial effect o n T C D 
data f or t h ose partici pa nts w h o ha ve a T C D vel ocit y ≥1 4 0 a n d < 1 7 0 c m/sec 
b y n o ni ma gi n g T C D ( ≥1 2 5 a n d < 1 5 5 c m/sec b y T C Di) u p o n s cree ni n g, 
a p pr o xi matel y 2 0 partici pa nts ma y be a d de d wit h a T C D vel ocit y t hat falls 
wit hi n t his ra n ge , de pe n di n g o n t he e mer gi n g data. I n t his e ve nt, Part C will 
c o ntai n u p t o 7 0 pe diatric partici pa nts.
Partici pa nts’ a ge will be t he a ge at t he ti me of asse nt/c o nse nt.
D uri n g t he 3 5 -da y scree ni n g peri o d, partici pa nts will u n der g o T C D 
assess me nt a n d t h ose w h o meet t he criteria f or T C D a n d t he rest of t he st u d y 
eli gi bilit y criteria will be eli gi ble f or v o xel ot or treat me nt f or u p t o 4 8 wee ks .
P art D will assess t he safet y, t olera bilit y, a n d P K, as well as t he 
he mat ol o gical effects , of v o xel ot or i n pe diatric partici pa nts wit h S C D 
6 m o nt hs t o < 4 years of a ge.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
6
A p pr o xi matel y 3 0 pe diatric partici pa nts will be e nr olle d.

At least 1 0 partici pa nts m ust be 6 m o nt hs t o < 2 year s of a ge .
D ose
P art A: V o xel ot or 6 0 0 m g (t w o 3 0 0 m g ca ps ules or ta blets) si n gle d ose.
P art B: V o xel ot or 9 0 0 m g (a d mi nistere d as t hree 3 0 0 m g ca ps ules or ta blets) 
or 1 5 0 0 m g (a d mi nistere d as fi ve 3 0 0 m g ca ps ules or ta blets) o nce dail y 
( Q D) f or 2 4 wee ks.
P art C: Partici pa nts w h o are bet wee n 1 2 a n d 1 7 years of a ge will recei ve 
v o xel ot or 1 5 0 0 m g/ da y as dis pers ible ta blets or p o w der f or oral s us pe nsi o n 
f or 4 8 wee ks .
Partici pa nts w h o are bet wee n 4 t o 1 1 years of a ge will recei ve 
v o xel ot or 1 5 0 0 m g/ da y E Q UI V A L E N T base d o n b o d y wei g ht as dis pers ible 
ta blets or p o w der f or oral s us pe nsi o n f or 4 8 wee ks (see Ta ble 3 ).
P art D: Partici pa nts will recei ve v o xel ot or 1 5 0 0 m g/ da y E Q UI V A L E N T 
base d o n b o d y wei g ht as p o w der f or oral s us pe nsi o n f or 4 8 wee ks (see
Ta ble 3 ). If p o w der f or oral s us pe nsi o n is n ot a vaila ble, dis persi ble ta blets 
will be use d .
N u m ber of P artici p a nts
P art A ( Si n gle -D ose P K St u d y)

A p pr o xi matel y 6 pe diatric partici pa nts ( male or fe male) will be e nr olle d 
i nt o t he Part A 1 2 t o 1 7 year a ge gr o u p ( C o h ort 1)

A p pr o xi matel y 6 pe diatric partici pa nts ( male or fe male) will be e nr olle d 
i nt o t he Part A 6 t o 1 1 year a ge gr o u p ( C o h ort 2) . A p pr o xi matel y 
3 partici pa nts e nr olle d i nt o t he st u d y will be bet wee n t he a ges of 6 a n d 
8 years of a ge. A p pr o xi matel y 3 partici pa nts e nr olle d will be bet wee n t he 
a ges of 9 t o 1 1 years of a ge.
P art B ( M ulti ple -D ose P K, S afet y , a n d Effic ac y St u d y)
A p pr o xi matel y 3 6 pe diatric partici pa nts ( male or fe male) a ge d 1 2 t o 1 7 years 
will be e nr olle d i nt o Part B.

A mi ni m u m of 1 2 partici pa nts will be d ose d wit h 9 0 0 m g . E nr oll me nt at 
t he 9 0 0 m g d ose le vel ma y c o nti n ue t o f urt her c haracterize t he effect of 
m ulti p le d oses of v o xel ot or ( n ot t o e xcee d a t otal st u d y size of
a p pr o xi matel y 3 6) . A mi ni m u m of 6 of t he partici pa nts at 9 0 0 m g will be 
1 2 t o 1 4 years ol d.

U p o n a fa v ora ble re vie w b y t he D S M B , d osi n g of a mi ni m u m of 
6 partici pa nts at 1 5 0 0 m g ma y c o m me nce ( de pe n de nt o n h o w ma n y 
partici pa nts were e nr olle d at 9 0 0 m g, ie, n ot t o e xcee d a t otal st u d y size 
of a p pr o xi matel y 3 6). A p pr o xi matel y half of t he partici pa nts at 1 5 0 0 m g 
will be 1 2 t o 1 4 years ol d.
P art C ( M ulti ple -D ose P K, S afet y , a n d Effic ac y St u d y )
A p pr o xi matel y 5 0 pe diatric partici pa nts a n d u p t o 7 0 pe diatric partici pa nts 
( male or fe male) a ged 4 t o 1 7 years will be e nr olle d i nt o Part C.
P art D ( M ulti ple -D ose P K, S afet y, a n d Effic ac y St u d y )
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
7
A p pr o xi matel y 3 0 pe diatric partici pa nts a ge d 6 m o nt hs t o < 4 years will be 
e nr olle d i nt o Part D.
N u m ber of Ce nters
T he st u d y will be c o n d ucte d at a p pr o xi matel y 2 5 cli nical sites
D ur ati o n of St u d y 
P artici p ati o n
P art A: U p t o 4 4 da ys fr o m Scree ni n g t o t he fi nal F oll o w -u p visit
P art B: U p t o 2 3 3 da ys fr o m Scree ni n g t o t he fi nal F oll o w -u p visit
P art C: U p t o 3 9 9 da ys fr o m Scree ni n g t o t he fi nal F oll o w -u p visit
P art D: U p t o 3 9 9 da ys fr o m Scree ni n g t o t he fi nal F oll o w -u p visit
St u d y P o p ul ati o n
I ncl usi o n Criteri a: 
Partici pa nts w h o meet all of t he f oll o wi n g criteria will be eli gi ble f or st u d y 
e nr oll me nt:
1.
Male or fe male partici pa nts wit h h o m oz y g o us he m o gl o bi n S S ( H b S S) or 
he m o gl o bi n S beta 0 t halasse mia ( H b S β0 t hal).
2.
A ge:

Part A – 6 t o 1 7 years of a g e (C o h ort 1 [ 1 2 t o 1 7] a n d C o h ort 2 [ 6 t o 
1 1] as defi ne d i n t he St u d y Desi g n)

Part B – 1 2 t o 1 7 years of a ge

Part C – 4 t o 1 7 years of a ge

Part D – 6 m o nt hs t o < 4 years of a ge
3.
H y dr o x y urea ( H U) t hera p y:

Parts A, B, a n d C – A partici pa nt ta ki n g H U ma y be e nr olle d if t he 
d ose has bee n sta ble f or at least 3 m o nt hs wit h n o a ntici pate d nee d 
f or d ose a dj ust me nts d uri n g t he st u d y a n d n o si g n of he mat ol o gical 
t o xicit y.

Part D – A partici pa nt ta ki n g H U ma y be e nr olle d if t he d ose has 
bee n sta ble f or at least 1 m o nt h. Titrati o n t o t he ma xi m u m t olerate d 
d ose ( M T D) is all o we d d uri n g t he st u d y.
4.
He m o gl o bi n ( H b):

Part A – N o restricti o n

Part B – H b ≤1 0. 5 g/ d L

Part C – H b ≤1 0. 5 g/ d L

Part D – H b ≤1 0. 5 g/ d L
5.
Writte n i nf or me d pare ntal/ g uar dia n c o nse nt a n d partici pa nt asse nt has 
bee n o btai ne d per i nstit uti o nal r e vie w b oar d (I R B)/ Et hics C o m mittee 
( E C) p olic y a n d re q uire me nts, c o nsiste nt wit h I C H g ui deli nes. 
6.
Partici pa nts i n Part B ( o nl y) of t he st u d y m ust c o m plete a mi ni m u m of 
1 4 da ys wit h e P R O t o be e nr olle d. I n vesti gat or discreti o n will be use d t o 
deter mi ne if a partici pa nt w h o has pre vi o usl y bee n scree n faile d d ue t o a 
lac k of baseli ne e P R O data c ollecti o n ca n be i n vite d bac k f or 
re-scree ni n g.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
8
7.
If se x uall y acti ve a n d fe male , m ust a gree t o a bstai n fr o m se x ual 
i nterc o urse or t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n 
t hr o u g h o ut t he st u d y peri o d a n d f or 3 0 da ys after disc o nti n uati o n of 
st u d y dr u g. If se x uall y acti ve a n d male, m ust a gree t o a bstai n fr o m 
se x ual i nterc o urse or willi n g t o use barrier met h o ds of c o ntrace pti o n 
t hr o u g h o ut t he st u d y peri o d a n d f or 3 0 da ys after disc o nti n uati o n of 
st u d y dr u g.
8.
Fe males of c hil d -beari n g p ote ntial are re q uire d t o ha ve a ne gati ve 
pre g na nc y test bef ore t he a d mi nistrati o n of st u d y dr u g.
9.
S ufficie nt ve n o us access t o per mit c ollecti o n of P K sa m ples a n d 
m o nit ori n g of la b orat or y safet y varia bles, i n t he o pi ni o n of t he 
I nvesti gat or.
1 0. F or Part C o nl y , partici pa nts 1 2 t o 1 7 year s of a ge m ust ha ve a T C D 
vel ocit y ≥1 4 0 c m/sec b y n o ni ma gi n g T C D or ≥1 2 5 c m/sec b y T C Di 
meas ure d a n yti me d uri n g scree ni n g .
E xcl usi o n Criteri a:
Partici pa nts meeti n g a n y of t he f oll o wi n g e xcl usi o n criteria will n ot be 
eli gi ble f or st u d y e nr oll me nt:
1.
A n y o ne of t he f oll o wi n g re q uiri n g me dical atte nti o n wit hi n 1 4 da ys 
pri or t o si g ni n g t he i nf or me d c o nse nt f or m (I C F):

Vas o -occl usi ve crisis ( V O C)

Ac ute c hest s y n dr o me ( A C S)

S ple nic se q uestrati o n crisis

Dact ylitis
2.
R e q uires c hr o nic tra nsf usi o n t hera p y .
3.
Hist or y of str o ke or meeti n g criteria f or pri mar y str o ke pr o p h yla xis 
( hist or y of t w o T C D meas ure me nts ≥2 0 0 c m/sec b y n o ni ma gi n g T C D or 
≥1 8 5 c m/sec b y T C Di).

F or t he p o te ntial m o dificati o n , a d diti o n of a p pr o xi matel y 2 0 
partici pa nts e nr olle d i n Part C, T C D ≥1 7 0 c m/sec b y n o ni ma gi n g 
T C D or ≥1 5 5  c m/sec b yT C Di .
4.
T ra nsf usi o n wit hi n 3 0 da ys pri or t o si g ni n g t he I C F.
5.
R e nal d ysf u ncti o n re q uiri n g c hr o nic dial ysis or creati ni ne ≥1. 5 m g/ d L .
6.
H e patic d ysf u ncti o n c haracterize d b y a la ni ne a mi n otra nsferase ( A L T) 
> 4 × u p per li mit of n or mal ( U L N) f or a ge .
7.
C li nicall y rele va nt car diac a b n or malit y, i n t he o pi ni o n of t he 
I nvesti gat or, s uc h as:

He m o d y na micall y si g nifica nt heart disease, e g, c o n ge nital heart 
defect, u nc o m pe nsate d heart fail ure, or a n y u nsta ble car diac 
c o n diti o n

A n arr h yt h mic heart c o n diti o n re q uiri n g me dical t hera p y
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
9
8.
Q Tc F > 4 5 0 msec , c o n ge nital l o n g Q T s y n dr o me, sec o n d or t hir d de gree 
heart bl oc k at rest ( wit h t he e xce pti o n of as y m pt o matic M o bitz t y pe I 
sec o n d de gree heart bl oc k).
9.
Recei ve d a n i n vesti gati o nal dr u g wit hi n 3 0 da ys or 5 half -li ves, 
w hic he ver is l o n ger, of si g ni n g t he I C F .
1 0. Hea v y s m o ker ( defi ne d as s m o ki n g m ore t ha n 1 0 ci garettes/ da y or its 
nic oti ne e q ui vale nt i ncl u di n g e -ci garettes) .
1 1. U nli kel y t o c o m pl y wit h t he st u d y pr oce d ures .
1 2. Ot her me dical, ps yc h ol o gical , or a d dicti ve 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, w o ul d c o nf o u n d or i nterfere wit h e val uati o n of safet y 
a n d/ or P K of t he i n vesti gati o nal dr u g, pre v e nt c o m plia nce wit h t he st u d y 
pr ot oc ol, or precl u de i nf or me d c o nse nt .
1 3. Partici pa nts w h o d o n ot ha ve a T C D wi n d o w ( Part B a n d C o nl y) 
(ie, partici pa nts w h o are u na ble t o ha ve a T C D d ue t o s k ull ossificati o n) .
1 4. F or Part C o nl y , pri or partici pati o n i n Part B.
1 5.
A cti ve s y m pt o matic C O VI D - 1 9 i nfecti o n.
I n a d diti o n, f or Part D o nl y :
1 6. B o d y wei g ht < 5 k g f or 1 m o nt h pri or t o t he scree ni n g visit a n d at t he 
scree ni n g visi t.
1 7.
A n y c o n diti o n affecti n g dr u g a bs or pti o n, s uc h as maj or s ur ger y 
i n v ol vi n g t he st o mac h or s mall i ntesti ne ( pri or c h olec ystect o m y is 
acce pta ble).
1 8.
H ist or y of mali g na nc y wit hi n t he past 2 years pri or t o treat me nt Da y 1 
re q uiri n g c he m ot hera p y a n d/ or ra diati o n ( wit h t he e xce pti o n of l ocal 
t hera p y f or n o n-mela n o ma s ki n mali g na nc y).
1 9. C li nicall y si g nifica nt bacterial, f u n gal, parasitic, or viral i nfecti o n 
c urre ntl y recei vi n g or t hat will re q uire t hera p y.

Partici pa nts wit h ac ute bacterial i nfecti o n re q uiri n g a nti bi otic use 
s h o ul d dela y scree ni n g u ntil t he c o urse of a nti bi otic t hera p y has bee n 
c o m plete d a n d t he i nfecti o n has res ol ve d, i n t he o pi ni o n of t he 
i n vesti gat or.

K n o w n acti ve he patitis A, B, or C i nfecti o n or h u ma n 
i m m u n o deficie nc y vir us ( HI V)-p ositi ve.

K n o w n acti ve malaria.
P h ar m ac o ki netic 
Assess me nts
P art A ( Si n gle -D ose P K St u d y)
Plas ma a n d w h ole bl o o d sa m ples f or P K assess me nt will be c ollecte d as 
f oll o ws: Pre d ose ( wit hi n 6 0 mi n utes pri or t o d osi n g) a n d p ost d ose starti n g o n 
Da y 1 at 2, 8, 2 4 h o urs ( Da y 2), 4 8 h o urs ( Da y 3), 9 6 h o urs ( Da y 5) a n d 
1 6 8 h o urs ( Da y 8) a n d Da y 1 5. 
P art B ( M ulti ple -D ose P K, S afet y , a n d Effic ac y St u d y)
Plas ma a n d w h ole bl o o d sa m ples f or P K assess me nt will be c ollecte d as 
f oll o ws: 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
1 0

Da y 1 (f oll o wi n g t he first v o xel ot or d ose): Pre d ose ( wit hi n 6 0 mi n utes 
bef ore d osi n g) a n d p ost d ose at 2, 8 a n d 2 4 h o urs ( Da y 2) f oll o wi n g t he 
first v o xel ot or d ose 

Wee k 2 ( Da y 1 4): Pre - or p ost d ose 

Wee k 4 ( Da y 2 8): Pre d ose ( wit hi n 3 0
mi n utes bef ore d osi n g) a n d 
bet wee n 1 t o 4 h o urs a n d bet wee n 6 t o 8 h o urs p ost d ose 

Wee ks 8, 1 2, 1 6, 2 0
a n d 2 4: Pre - or p ost d ose 
P art C ( M ulti ple -D ose P K, S afet y , a n d Effic ac y St u d y )
Plas ma a n d w h ole bl o o d sa m ples f or P K assess me nt will be c ollecte d as 
f oll o ws:

Da y 1 : P ost d ose ( wit hi n 1 5 mi n utes t o 2 h o urs p ost d ose)

Wee k 4 ( Da y 2 8) , Wee k 8 ( Da y 5 6) , Wee k 1 2 ( Da y 8 4) , Wee k 1 6 ( Da y 
1 1 2), Wee k 2 0 ( Da y 1 4 0) , Wee k 2 4 ( Da y 1 6 8) , Wee k 3 6 ( Da y 2 5 2) a n d 
Wee k 4 8 ( Da y 3 3 6) : Pre d ose
P art D ( M ulti ple -D ose P K, S afet y , a n d Effic ac y St u d y )
Plas ma a n d w h ole -bl o o d sa m ples f or P K assess me nt will be c ollecte d as 
f oll o ws:

Da y 1 : wit hi n 1 5 mi n utes t o 2 h o urs p ost d ose

Wee k 2 ( Da y 1 4), Wee k 8 ( Da y 5 6), Wee k 1 2 ( Da y
8 4), Wee k 1 6 
( Da y 1 1 2), Wee k 2 4 ( Da y 1 6 8), Wee k 3 6 ( Da y 2 5 2) , a n d Wee k 4 8 
( Da y 3 3 6): Pre d ose
P art s A, B, C, a n d D
I n Part A, n o nc o m part me ntal met h o ds will be use d f or deter mi nati o n of P K 
para meters. All P K para meters will be prese nte d b y i n di vi d ual listi n gs a n d 
s u m mar y statistics (e g, mea n, ge o metric mea n, me dia n, sta n dar d de viati o n, 
9 5 % c o nfi de nce i nter val, c oefficie nt of variati o n, mi ni m u m a n d ma xi m u m, 
a n d n u m ber of partici pa nts). Preli mi nar y meta b olite pr ofili n g of plas ma 
a n d/ or w h ole bl o o d ma y be c o n d ucte d.
I n Part B, R B C c o nce ntrati o ns will be calc ulate d fr o m w h ole bl o o d a n d 
plas ma c o nce ntrati o ns. T he f oll o wi n g plas ma, w h ole bl o o d a n d R B C P K 
para meters will be calc ulate d f or G B T 4 4 0 , as a p pr o priate:
Ma xi m u m o bser ve d c o nce ntrati o n ( C
ma x), Ti me of ma xi m u m c o nce ntrati o n 
( Tma x), Area u n der t he c o nce ntrati o n-ti me c ur ve fr o m zer o ( pre d ose) t o ti me 
of last q ua ntifia ble c o nce ntrati o n ( A U C 0- last), Area u n der t he c o nce ntrati o n-
ti me c ur ve fr o m ti me zer o ( pre d ose ) e xtra p olate d t o i nfi nit y ( A U C0- i nf), Area 
u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o ( pre d ose) t o 2 4 h o urs 
( A U C0 - 2 4) f oll o wi n g t he first a n d last da y of d osi n g (Part B o nl y), 
acc u m ulati o n rati o ( Part B), bl o o d/ plas ma rati o, R B C/ plas ma rati o, ter mi nal 
eli mi nati o n half -life (t1/ 2) a n d perce nt H b occ u pa nc y.
I n Parts C a n d D, p o p ul ati o n P K m o deli n g will be use d t o deter mi ne t he 
w h ole -bl o o d a n d plas ma P K para meters of v o xel ot or i n t he st u d y p o p ulati o n. 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
1 1
T he P K para meters t o be deter mi ne d will i ncl u de C ma x, A U C, t1/ 2,a n d perce nt 
H b occ u pa nc y . 
Plas ma a n d w h ole bl o o d c o nce ntrati o ns will be deter mi ne d usi n g vali date d 
li q ui d c hr o mat o gra p h y/ mass s pectr o metr y ( L C/ M S) met h o ds.
S afet y Assess me nts
Partici pa nt safet y a n d t olera bilit y will be m o nit ore d d uri n g t he st u d y usi n g 
sta n dar d meas ures, i ncl u di n g p h ysical e xa mi nati o ns, vital si g ns (i ncl u di n g 
bl o o d press ure, p ulse rate, b o d y te m perat ure, res pirat or y rate) , 1 2-lea d 
electr ocar di o gra ms ( E C Gs , c ollecte d i n tri plicate) (Parts A, B, a n d C o nl y ), 
cli nical la bora t or y tests, c o nc o mita nt me dicati o n usa ge, a n d a d verse e ve nt 
( A E) m o nit ori n g.
F or Parts B a n d C , T C D meas ure me nts are bei n g o btai ne d t o deter mi ne a 
preli mi nar y treat me nt effect. H o we ver, a b n or mal val ues ca n i n dicate a safet y 
c o ncer n a n d will be f oll o we d u p as a p pr o priate f or sta n dar d cli nical care.
D at a a n d S afet y 
M o nit ori n g B o ar d 
( D S M B)
A n i n de pe n de nt D S M B will m o nit or t he safet y a n d c o n d uct of t he trial. T he 
D S M B me m bers hi p will be c o m po se d of me dical a n d statistical 
re prese ntati ves. T he D S M B ma y pr o vi de rec o m me n dati o ns t o t he S p o ns or 
re gar di n g st o p pi n g t he st u d y or disc o nti n ui n g a treat me nt ar m or ot her wise 
m o dif yi n g t he st u d y desi g n or c o n d uct. 
T he D S M B f or t his st u d y will re vie w:

Safet y d ata fr o m at least 8 pe diatric partici pa nts e nr olle d i n Part B of 
St u d y G B T 4 4 0 -0 0 7, f oll o wi n g t he c o m pleti o n of 2 8 da ys of d osi n g wit h 
v o xel ot or 9 0 0 m g t o c o nfir m acce pta ble safet y a n d t olera bilit y.

Safet y data o n a peri o dic basis as defi ne d i n t he D S M B C ha rter. 
Sites will be i nf or me d of t he D S M B rec o m me n dati o ns o nl y if t he 
rec o m me n dati o ns lea d t o c ha n ges i n t he st u d y c o n d uct. 
T he c o m p ositi o n, res p o nsi bilities, a n d ot her details of t he D S M B will be 
descri be d i n a D S M B C harter as a p pr o priate f or eac h part o f t he st u d y.
Pri or t o pr ocee di n g fr o m t he 9 0 0 m g d ose t o t he 1 5 0 0 m g d ose i n Part B, t he 
f oll o wi n g D S M B re vie w will als o ta ke place:

A re vie w of safet y data fr o m t he first 6 a d ult partici pa nts at t he 1 5 0 0 m g 
d ose le vel fr o m Gr o u p 1 fr o m t he H O P E St u d y, f ol l o wi n g at least 
2 8 da ys of d osi n g wit h st u d y dr u g, t o c o nfir m acce pta ble safet y a n d 
t olera bilit y.
F or Part D, e nr oll me nt of partici pa nts a ge d 2 t o < 4 years will c o m me nce
after D S M B re vie w of safet y, t olera bilit y, a n d P K data fr o m ≥1 2 partici pa nts
fr o m Part C of t his st u d y w h o wei g h < 3 0 k g a n d were treate d wit h v o xel ot or
f or ≥2 8 da ys. I n a d diti o n, enr oll me nt of partici pa nts a ge d 6 m o nt hs t o 
< 2 years will c o m me nce after S p o ns or re vie w of safet y, t olera bilit y, a n d P K 
data fr o m ≥6 partici pa nts a ge d 2 t o < 4 years w h o were treate d wit h 
v o xel ot or f or ≥2 8 da ys fr o m Part D of t his st u d y or ot her G B T st u dies. T he 
D S M B ma y be c o ns ulte d if warra nte d .
Effic ac y Assess me nts
Cli nical meas ures of he m ol ysis are i ncl u de d u n der t he he mat ol o g y a n d 
c he mistr y assess me nts descri be d a b o ve ( H b, retic ul oc yte c o u nt, 
er yt hr o p oieti n, lactate de h y dr o ge nase [ L D H], i n direct bilir u bi n). Cli nical 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
1 2
meas ures of he m ol ysis a n d T C D ti me -a vera ge d mea n of t he ma xi m u m 
( T AM M) bl o o d vel ocit y will be assesse d as meas ures of p ote ntial treat me nt 
effect. T C D meas ure me nts will be perf or me d i n Part s B a n d C of t he st u d y
o nl y .
C o nc o mit a nt 
Me dic ati o ns a n d 
Restricti o ns

Parts A, B, a n d C: H U t hera p y is all o we d, pr o v i de d t hat t he d ose a n d 
re gi me n ha ve bee n sta ble f or at least 3 m o nt hs pri or t o si g ni n g t he I C F
a n d wit h n o a ntici pate d nee d f or d ose a dj ust me nts d uri n g t he st u d y .

Part D: H U t hera p y is all o we d pr o vi de d t hat t he d ose a n d re gi me n ha ve
bee n sta ble f or at least 1 m o nt h pri or t o si g ni n g t he I C F. Titrati o n t o t he 
M T D is all o we d d uri n g t he st u d y .

V o xel ot or s h o ul d be n ot be c oa d mi nistere d wit h se nsiti ve c yt oc hr o me 
P 4 5 0 (C Y P ) 3 A 4 s u bstrates wit h a narr o w t hera pe utic i n de x.

C o nc o mita nt use of str o n g i n d ucers of C Y P 3 A 4 wit h v o xel ot or is n ot 
all o we d.
St atistic al Met h o ds
Sa m ple Size
T he sa m ple size was n ot selecte d base d o n statistical c o nsi derati o ns b ut t o 
deter mi ne preli mi nar y safet y, t olera bilit y, P K, la b orat or y effects a n d 
treat me nt res p o nse of v o xel ot or i n pe diatric partici pa nts wit h S C D. 
P art A: A c o h ort size of a p pr o xi matel y 6 partici pa nts f or eac h a ge gr o u p, 
6 t o 1 1 years a n d 1 2 t o 1 7 ye ars, is base d o n a t y pical size f or a si n gle -d ose 
P K st u d y.
P art B: A p pr o xi matel y 1 2 partici pa nts at 9 0 0 m g w ere selecte d t o deter mi ne 
preli mi nar y safet y, t olera bilit y, P K, la b orat or y effects a n d treat me nt res p o nse 
of v o xel ot or i n pe diatric partici pa nts wit h S C D. T he n u m ber of partici pa nts 
ma y be i ncrease d t o a p pr o xi matel y 3 6 t o f urt her c haracterize t he effect of 
m ulti ple d oses of v o xel ot or . U p o n a fa v ora ble re vie w b y t he D S M B , d osi n g 
of a mi ni m u m of 6 partici pa nts at 1 5 0 0 m g ma y c o m me nce ( de pe n de nt o n 
h o w ma n y partici pa nts were e nr olle d at 9 0 0 m g, ie, n ot t o e xcee d a t otal 
st u d y size of a p pr o xi matel y 3 6).
F or t he e n d p oi nt of c ha n ge fr o m baseli ne t o Wee k 2 4 i n H b, p o wer 
calc ulati o ns ass u me n or mall y distri b ute d data, a mea n treat me nt effect of 
0. 8 g/ d L, wit h a sta n dar d de viati o n ( S D) of 0. 6 g/ d L. F or a 2 -si de d al p ha = 
0. 0 5 a n d N = 1 2 partici pa nts , p o wer e xcee ds 9 0 % wit h a paire d t-test t o 
reject t he n ull h y p ot hesis of e q ualit y of p ost-treat me nt a n d baseli ne H b 
mea ns. T he esti mates of 0. 8 a n d 0. 6 g/ d L f or t he mea n a n d S D, res pecti vel y, 
are base d o n a vaila ble Da y 9 0 data fr o m C o h orts 1 6 a n d ( partial) 1 7 fr o m t he 
G B T 4 4 0- 0 0 1 st u d y.
P art C: U p t o 5 0 pe diatric partici pa nts w h o are 4 t o 1 7 years of a ge wit h 
S C D will be e nr olle d. F or t he pri mar y efficac y e n d p oi nt, c ha n ge fr o m 
baseli ne i n T A M M T C D vel ocit y at Wee k 4 8, a sa m ple size of 
3 0 partici pa nts ac hie ves greater t ha n 9 5 % p o wer t o detect a mea n differe nce 
of 1 5 c m/sec wit h a n esti mate d sa m ple sta n dar d de viati o n of 2 2 c m/sec usi n g 
a paire d t -test (2 -si de d) wit h a si g nifica nce le vel (al p ha) of 0. 1 0.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
1 3
P art D: A p pr o xi ma tel y 3 0 pe diatric partici pa nts wit h S C D w h o are 6 m o nt hs 
t o < 4 years of a ge will be e nr olle d. T he sa m ple size was selecte d t o pr o vi de 
descri pti ve assess me nt of safet y, t olera bilit y, a n d P K effects of v o xel ot or i n 
t his y o u n ger a ge gr o u p wit h n o f or mal statistical ass u m pti o ns.
St u d y E n d p oi nts: P art A
Pri m ar y 

C ma x, area u n der t he c o nce ntrati o n-ti me c ur ve ( A U C) fr o m ti me 0 t o t he 
ti me of t he last q ua ntifia ble c o nce ntrati o n ( A U C0- last) a n d A U C 0- i nf of 
v o xel ot or i n w h ole bl o o d
Sec o n d ar y 

C ma x, A U C0- last a n d A U C 0- i nf of v o xel ot or i n plas ma a n d R B C

T he ti me t hat C ma x was o bser ve d (t ma x), ter mi nal eli mi nati o n half-life (t½ )
i n R B C, w h ole bl o o d a n d plas ma , a n d perce nt H b occ u pa nc y
S afet y

Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) a n d seri o us a d verse e ve nts 
( S A Es) 

Cli nical la b orat or y tests, p h ysical e xa mi nati o n fi n di n gs, vital si g ns , a n d
E C Gs
St u d y E n d p oi nts: P art B
Pri m ar y

C ha n ge fr o m baseli ne t o Wee k 2 4 i n H b 
Sec o n d ar y 

Pr o p orti o n of da ys wit h S C D s y m pt o m e xacer bati o n d uri n g t he first 
2 4 wee ks of treat me nt 

C ha n ge fr o m baseli ne t o Wee ks 2 1 – 2 4 i n t he sic kle cell disease se verit y 
meas ure ( S C D S M) T S S 

C ha n ge fr o m baseli ne t o 1 2 a n d 2 4 wee ks i n L D H, i n direct bilir u bi n , a n d
retic ul oc yte c o unt

V o xel ot or P K t o 2 4 wee ks ( C ma x, A U C0- last, A U C0- i nf, A U C0- 2 4, t1/ 2, 
acc u m ulati o n rati o, bl o o d/ plas ma rati o, R B C/ plas ma rati o, if a p pr o priate) 
a n d perce nt H b occ u pa nc y

C ha n ge fr o m baseli ne t o 1 2 a n d 2 4 wee ks i n cere bral bl o o d fl o w as 
meas ure d b y t he T A M M T C D vel ocit y
S afet y

T E A Es a n d S A Es

Cli nical la b orat or y tests, vital si g ns , a n d E C Gs
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
1 4
St u d y E n d p oi nts
P art C
Pri m ar y E n d p oi nt :

C ha n ge fr o m baseli ne t o 4 8 wee ks i n cere bral bl o o d fl o w as meas ure d b y 
t he T A M M T C D vel ocit y
Sec o n d ar y E n d p oi nts :

C ha n ge fr o m ba seli ne t o W ee ks 2 4 a n d 4 8 i n H b, L D H, i n direct 
bilir u bi n , a n d retic ul oc yte c o u nt

C ha n ge fr o m baseli ne t o 2 4 wee ks i n cere bral bl o o d fl o w as meas ure d b y 
t he T A M M T C D vel ocit y

Ti me t o i nitial H b res p o nse, defi ne d as c ha n ge fr o m baseli ne i n H b 
> 1 g/ d L

W h ole bl o o d a n d plas ma v o xel ot or P K ( Cma x, A U C, a n d t1/ 2,) a n d perce nt 
H b occ u pa nc y

Pr o p orti o n of partici pa nts wit h n or mal T C D fl o w vel ocit y ( < 1 7 0 c m/sec 
b y n o ni ma gi ni n g T C D or < 1 5 5 c m/sec b y T C Di ) at 4 8 wee ks

I nci de nce of str o ke a n d V O C d uri n g t he st u d y
S afet y E n d p oi nts:

T E A Es a n d S A Es

Cli nical la b orat or y tests, vital si g ns , a n d E C Gs
St u d y E n d p oi nts
P art D
Pri m ar y E n d p oi nt s:

T E A Es a n d S A Es
Sec o n d ar y E n d p oi nts :

W h ole bl o o d a n d plas ma v o xel ot or P K ( C m a x,A U C, t1/ 2, if a p pr o priate) 
a n d occ u pa nc y

C ha n ge fr o m baseli ne t o W ee k 2 4 a n d Wee k 4 8 i n H b, L D H, i n direct 
bilir u bi n, a n d retic ul oc yte c o u nt

Ti me t o i nitial H b res p o nse, defi ne d as c ha n ge fr o m baseli ne i n H b 
> 1 g/ d L

I nci de nce of str o ke a n d V O C d uri n g t he st u d y
S afet y E n d p oi nts:

Cli nical la b orat or y tests a n d vital si g ns
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
1 5
T A B L E O F C O N T E N T S
C L I NI CA L S T U D Y P R O T O C O L G B T 4 4 0- 0 0 7............................................................................ 1
S T A T E M E N T O F A P P R O V A L A N D C O M P LI A N C E .................................................................2
S Y N O P SI S 3
T A B L E O F C O N T E N T S ...............................................................................................................1 5
LI S T O F T A B L E S .........................................................................................................................2 1
LI S T O F FI G U R E S .......................................................................................................................2 1
LI S T O F A B B R E VI A TI O N S ........................................................................................................2 2
1.
I NT R O D U C TI O N ......................................................................................................2 6
1. 1.
Disease Bac k gr o u n d ...................................................................................................2 6
1. 2.
V o xel ot or ....................................................................................................................2 8
1. 3.
Rati o nale f or St u d y .....................................................................................................2 8
1. 3. 1.
St u d y  E n d p oi nts..........................................................................................................3 0
1. 4.
S u m mar y  of Rele va nt N o ncli nical Data a n d Cli nical Data........................................3 0
1. 4. 1.
N o ncli nical Data .........................................................................................................3 0
1. 4. 2.
Cli nical Data ...............................................................................................................3 1
1. 5.
D ose Rati o nale ............................................................................................................3 1
1. 5. 1.  
D ose Rati o nale f or Si n gle V o xel ot or D oses t o be E val uate d i n Pe diatric 
Partici pa nts ( 6 t o 1 1 Years) i n Part A................................ .........................................3 1
1. 5. 2. 
Rati o nale f or t he V o xel ot or D ose t o be E val uate d i n Part B................................ ......3 2
1. 5. 3.
Rati o nale f or t he V o xel ot or D ose t o be E val uate d i n C hil dre n 4 t o 1 1 Years 
Ol d i n Part C a n d C hil dre n 6 M o nt hs t o < 4 Years Ol d i n Part D.............................. 3 5
1. 6.
Ris k Assess me nt .........................................................................................................3 6
2.
S T U D Y O BJ E C TI V E S ..............................................................................................3 7
2. 1.
Part A ( S i n gle D ose)...................................................................................................3 7
2. 1. 1.
Pri mar y  O bjecti ve:......................................................................................................3 7
2. 1. 2.
Sec o n dar y  O bjecti ve:..................................................................................................3 7
2. 2. 
P art B ( M ulti ple D ose) ................................................................................................3 7
2. 2. 1.
Pri mar y  O bjecti ve:......................................................................................................3 7
2. 2. 2.
Sec o n dar y  O bjecti ves:................................................................................................3 7
2. 3.
Part C ( M ulti ple D ose)................................ ................................................................3 7
2. 3. 1.
Pri mar y  O bjecti ve.......................................................................................................3 7
2. 3. 2.
Sec o n dar y  O bjecti ve...................................................................................................3 8
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
1 6
2. 4.
Part D ( M ulti ple D ose) ...............................................................................................3 8
2. 4. 1.
Pri mar y  O bjecti ve.......................................................................................................3 8
2. 4. 2. 
S ec o n dar y O bjecti ves .................................................................................................3 8
2. 4. 3.
E x pl orat or y  O bjecti ve.................................................................................................3 8
3.
I NV E S TI G A TI O N A L P L A N .....................................................................................3 9
3. 1.
St u d y Desi g n ...............................................................................................................3 9
3. 1. 1.
Part A ( Si n gle -D ose A d mi nistrati o n) .........................................................................3 9
3. 1. 2.
Part B ( M ulti ple- D ose A d mi nistrati o n) ......................................................................4 0
3. 1. 3.
Part C ( M ulti ple -D ose A d mi nistrati o n) ......................................................................4 1
3. 1. 4.
Part D ( M ulti ple -D ose A d mi nistrati o n) ......................................................................4 2
3. 2.
D urati o n of St u d y .......................................................................................................4 2
3. 3.
E n d - of-St u d y  Visit......................................................................................................4 3
3. 4.
Earl y Ter mi nati o n Visit.............................................................................................. 4 3
3. 5.
O n g oi n g Safet y a n d Data Re vie w ...............................................................................4 3
3. 5. 1.
Part B Safet y  Re q uire me nts f or D ose Escalati o n t o t he 1 5 0 0 m g Treat me nt 
Ar m .............................................................................................................................4 3
3. 5. 2.
Part C................................ ..........................................................................................4 4
3. 5. 3.
Part D................................ ..........................................................................................4 4
3. 6. 
St o p pi n g R ules................................ ............................................................................4 4
3. 7.
Data a n d Safet y M o nit ori n g B oar d .............................................................................4 4
3. 8.
E n d of St u d y ...............................................................................................................4 5
3. 9.
E n d p oi nts ....................................................................................................................4 5
3. 9. 1.
E n d p oi nts f or Part A................................ ...................................................................4 5
3. 9. 2.
E n d p oi nts f or Part B ................................ ...................................................................4 6
3. 9. 3.
E n d p oi nts f or Part C ................................ ...................................................................4 6
3. 9. 4.
E n d p oi nts f or Part D................................ ...................................................................4 7
4.
S T U D Y P O P U L A T I O N.............................................................................................4 8
4. 1.
I ncl usi o n Criteria........................................................................................................ 4 8
4. 2.
E xcl usi o n Criteria .......................................................................................................4 9
5. 
S T U D Y P R O C E D U R E S A N D E V A L U A TI O N S .....................................................5 1
5. 1. 
Partici pa nt Scree ni n g................................ ..................................................................5 1
5. 2.
Electr o nic Patie nt Re p orte d O utc o mes (e P R O) Scree ni n g .........................................5 1
5. 3. 
Cli nical Assess me nts................................ ..................................................................5 1
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
1 7
5. 4.
Safet y  Assess me nts.....................................................................................................5 2
5. 4. 1.
Cli nical L a b orat or y St u dies........................................................................................5 2
5. 4. 2.
He m o gl o bi n Ge n ot y p e ................................................................................................5 4
5. 4. 3.
E x pl orat or y  Assess me nts ( Part C o nl y )......................................................................5 4
5. 4. 4.
Vital Si g ns ..................................................................................................................5 4
5. 4. 5.
Electr ocar di o gra ms ( E C Gs) ........................................................................................5 5
5. 4. 6.
P h y sical E xa mi nati o ns ................................................................................................5 5
5. 4. 7.
Tra nscra nial D o p pler ( Parts B a n d C) ........................................................................5 5
5. 5.
Eli gi bilit y  Assess me nt................................................................................................5 5
5. 6.
Treat me nt Res p o nse Assess me nts ..............................................................................5 6
5. 7.
P har mac o ki netic Assess me nts ....................................................................................5 6
5. 7. 1.
Part A................................ ..........................................................................................5 6
5. 7. 2.
Part B................................ ..........................................................................................5 6
5. 7. 3.
Part C................................ ..........................................................................................5 7
5. 7. 4.
Part D................................ ..........................................................................................5 8
5. 7. 5.
C o nce ntrati o n Meas ure me nts .....................................................................................5 8
5. 8.
Electr o nic Patie nt Re p orte d O utc o mes a n d e Diar y ( Part B o nl y) ..............................5 9
5. 8. 1.
Electr o nic Patie nt Re p orte d O utc o me Sic kle Cell Disease Se verit y  Meas ure...........5 9
5. 8. 2.
e Diar y of St u d y Dr u g C o m plia nce.............................................................................5 9
5. 9.
Taste a n d Palata bilit y  Q uesti o n naire ( Part A C o h ort 2, Part C, a n d Part D) ..............5 9
5. 1 0.
F or m ulati o n Tra nsiti o n Visit ( Part C) .........................................................................5 9
5. 1 1.
Misse d Assess me nts
...................................................................................................6 0
6.
E A R L Y DI S C O N TI N U A TI O N O F T RI A L O R I N DI VI D U A L 
P A R TI CI P A N T S ........................................................................................................6 1
6. 1.
Earl y Disc o nti n uati o n of t he Trial ..............................................................................6 1
6. 2.
Earl y Disc o nti n uati o n of St u d y  Treat me nt.................................................................6 1
6. 3.
Earl y Disc o nti n uati o n of St u d y  Partici pati o n.............................................................6 1
6. 4.
Partici pa nt Re place me nt .............................................................................................6 2
7.
S T U D Y D R U G ...........................................................................................................6 3
7. 1.
I n vesti gati o nal Me dici nal Pr o d uct ..............................................................................6 3
7. 1. 1.
Parts A a n d B ..............................................................................................................6 3
7. 1. 2.
Part C................................ ..........................................................................................6 3
7. 1. 3.
Part D................................ ..........................................................................................6 3
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
1 8
7. 1. 4.
P h y sical Descri pti o n ...................................................................................................6 3
7. 1. 5.
F or m ulati o n .................................................................................................................6 4
7. 1. 6.
Pac ka gi n g a n d La beli n g ..............................................................................................6 4
7. 1. 7.
St ora ge a n d Ha n dli n g Pr oce d ure ................................................................................6 4
7. 2.
Dr u g Acc o u n ta bilit y a n d Rete nti o n............................................................................6 5
8.
D O S A G E A N D T R E A T M E N T A D MI NI S T R A TI O N ..............................................6 6
8. 1.
Treat me nt Re gi me n ....................................................................................................6 6
8. 2.
D ose M o dificati o n f or Parts B, C, a n d D ....................................................................6 7
8. 2. 1.
D ose Fre q ue nc y ..........................................................................................................6 7
8. 2. 2.
D ose M o dificati o n G ui deli nes Parts B a n d C f or Partici pa nts A ge d 1 2 t o 
1 7 Years ......................................................................................................................6 7
8. 2. 3.
D ose M o dificati o n G ui deli nes f or Part C Partici pa nts A ge d 4 t o 1 1 Years 
a n d f or Part D Partici pa nts A ge d 6 M o nt hs t o < 4 Years ...........................................6 9
8. 3.
Treat me nt of O ver d ose ...............................................................................................7 2
8. 4. 
C o nc o mita nt Me dicati o ns................................ ...........................................................7 2
8. 4. 1. 
Restricti o ns Re gar di n g C o nc o mita nt Me dicati o ns................................ .....................7 2
8. 4. 2.
Ot her Restricti o ns .......................................................................................................7 3
8. 5.
Fertilit y / C o ntrace pti ve Re q uire me nts.........................................................................7 3
8. 5. 1. 
I nstr ucti o ns f or Fe male Partici pa nts of C hil d- Beari n g P ote ntial ................................7 3
8. 5. 2. 
Fe male Partici pa nts of N o n- C hil d -Beari n g P ote ntial .................................................7 3
8. 5. 3.
I nstr ucti o ns f or Male Partici pa nts Ca pa ble of Fat heri n g a C hil d............................... 7 3
8. 5. 4.
Acce pta ble F or ms of C o ntrace pti o n ...........................................................................7 4
9.
A D V E R S E E V E N T S ..................................................................................................7 5
9. 1.
Rec or di n g A d verse E ve nts .........................................................................................7 5
9. 2.  
Assess me nt of A d verse E ve nts................................ ...................................................7 5
9. 2. 1.
Seri o us A d verse E ve nt ................................................................................................7 5
9. 2. 2.
I nte nsity of A d verse E ve nts ........................................................................................7 6
9. 2. 3.
Relati o ns hi p t o I n vesti gati o nal Pr o d uct ......................................................................7 7
9. 2. 4.  
U ne x pecte d A d verse Reacti o ns................................ ..................................................7 7
9. 3.
Re p orti n g A d verse E ve nts ..........................................................................................7 7
9. 3. 1.
Dia g n osis vers us Si g ns a n d S y m pt o ms ......................................................................7 7
9. 3. 2.
A d verse E ve nts Occ urri n g Sec o n dar y  t o Ot her E ve nts..............................................7 7
9. 3. 3.
Persiste nt or Rec urre nt A d verse E ve nts .....................................................................7 8
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
1 9
9. 3. 4.
A b n or mal La b orat or y  Val ues.....................................................................................7 8
9. 4.
Disc o nti n uati o n d ue t o A d verse E ve nts ......................................................................7 8
9. 5.
Re p orti n g Seri o us A d verse E ve nts .............................................................................7 8
9. 6.
C h o osi n g A d verse E ve nt Ter ms .................................................................................7 9
9. 7.
Re p orti n g Pre g na nc y ..................................................................................................7 9
9. 8.
Re p orti n g O ver d ose ....................................................................................................8 0
1 0.
D A T A A N A L Y SI S A N D S T A TI S TI C A L  P L A N S...................................................8 1
1 0. 1.
Sa m ple Size ................................................................................................................8 1
1 0. 2.
P o p ulati o ns f or A nal y sis .............................................................................................8 1
1 0. 3.
A nal y ses......................................................................................................................8 2
1 0. 3. 1.
P har mac o ki netic Data .................................................................................................8 2
1 0. 3. 2.
Safet y  Data..................................................................................................................8 2
1 0. 3. 3.
Efficac y  Data..............................................................................................................8 3
1 0. 3. 4.  
Ha n dli n g of Missi n g Data................................ ...........................................................8 3
1 1.
R E G U L A T O R Y, E T HI C A L  A N D L E G A L O B LI G A TI O N S .................................. 8 4
1 1. 1.
Et hical C o nsi derati o n ..................................................................................................8 4
1 1. 2. 
I nstit uti o nal Re vie w B oar d or Et hics C o m mittee a n d Re g ulat or y  A p pr o val.............8 4
1 1. 3.
I ns ura nce a n d Fi na ncial Discl os ure ............................................................................8 4
1 1. 4. 
Esse ntial D oc u me ntati o n Re q uire me nts................................ .....................................8 4
1 1. 5.
I nf or me d C o nse nt a n d Asse nt.....................................................................................8 4
1 1. 6.
C o nfi de ntialit y ............................................................................................................8 5
1 1. 7.
Re g ulat or y , Et hical, a n d Le gal O bli gati o ns................................................................8 5
1 1. 8.
Trial D oc u me ntati o n a n d Data St ora ge ......................................................................8 5
1 1. 9.
St u d y  Rec or d Rete nti o n..............................................................................................8 6
1 1. 1 0.
Discl os ure of I nf or mati o n ...........................................................................................8 6
1 1. 1 1.
P u blicati o n ..................................................................................................................8 7
1 2.
A D MI NI S T R A TI V E O B LI G A TI O N S ......................................................................8 8
1 2. 1.
S o urce Data .................................................................................................................8 8
1 2. 2.  
Data C olle cti o n ...........................................................................................................8 8
1 2. 3.
M o nit ori n g ..................................................................................................................8 8
1 2. 4.
Q ualit y  C o ntr ol, Q uality Ass ura nce a n d Re g ulat or y I ns pecti o ns...............................8 8
1 3.
S T U D Y R E P O R T .......................................................................................................9 0
1 4.
R E F E R E N C E S ...........................................................................................................9 1
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
2 0
A P P E N DI X 1.
P A R T A S C H E D U L E O F A S S E S S M E N T S .....................................................9 4
A P P E N DI X 2.
D E T AI L O F P A R T A B L O O D P K C O L L E C TI O N S....................................... 9 5
A P P E N DI X 3.
P A R T B S C H E D U L E O F A S S E S S M E N T S .....................................................9 6
A P P E N DI X 4.
D E T AI L O F P A R T B B L O O D P K C O L L E C TI O N S ....................................... 9 8
A P P E N DI X 5.
P A R T C S C H E D U L E O F A S S E S S M E N T S .....................................................9 9
A P P E N DI X 6.
P A R T C P H A R M A C O KI N E T I C S A M P LI N G S C H E D U L E .........................1 0 1
A P P E N DI X 7.
P A R T D S C H E D U L E O F A S S E S S M E N T S ...................................................1 0 2
A P P E N DI X 8.
P A R T D P H A R M A C O KI N E T I C S A M P LI N G S C H E D U L E .........................1 0 4
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
2 1
LI S T O F T A B L E S
Ta ble 1:
Si m ulate d He m ol y sis Meas ures O utc o mes Base d o n Data i n A d ult 
Partici pa nts ( % C ha n ge fr o m Baseli ne) f or V o xel ot or 9 0 0 a n d 1 5 0 0 m g ..................3 4
Ta ble 2: 
Para meter Esti mates Fr o m t he W h ole Bl o o d V o xel ot or P o p ulati o n P K 
M o del ( A d ults Vers us A d olesce nts) ...........................................................................3 4
Ta ble 3:  
V o xel ot or Wei g ht- Base d D oses Deter mi ne d f or Pe diatric Partici pa nts..................... 3 5
Ta ble 4:
Parts A, B, a n d C: Cli nical La b orat or y  Tests .............................................................5 3
Ta ble 5:
Part D: Cli nical L a b orat or y Tests...............................................................................5 4
Ta ble 6:
D ose M o dificati o n G ui deli nes f or St u d y  Dr u g– Relate d A d verse E ve nts 
( 1 2- 1 7 years) ...............................................................................................................6 8
Ta ble 7:
D ose M o dificati o n G ui deli nes f or St u d y  Dr u g– Relate d Ras h ( 1 2 – 1 7 y ears) ............ 6 9
Ta ble 8:
Wei g ht -Base d D ose Gr o u ps .......................................................................................6 9
Ta ble 9:
D ose M o dificati o n G ui deli nes f or St u d y  Dr u g Relate d A d verse E ve nts 
( 6 M o nt hs – 1 1 ye ars) ...................................................................................................7 0
Ta ble 1 0:
D ose M o dificati o n G ui deli nes f or St u d y  Dr u g Relate d Ras h 
( 6 M o nt hs - 1 1 ye ars) ....................................................................................................7 1
Ta ble 1 1:
Se nsiti ve C Y P 3 A 4 S u bstrates wit h a Narr o w T hera pe utic Ra n ge .............................7 2
Ta ble 1 2:
E xa m ples of Str o n g C Y P 3 A 4 I n d ucers ......................................................................7 3
Ta ble 1 3:
Gra di n g f or A d verse E ve nts n ot C o vere d i n t he N CI -C T C A E ..................................7 6
LI S T O F FI G U R E S
Fi g ure 1:
Si m ulati o ns of V o xel ot or 9 0 0 m g i n A d ults a n d 6 0 0 m g i n C hil dre n 
( 6 t o 1 1 ye ars) .............................................................................................................3 2
Fi g ure 2:
Part A St u d y  Sc he matic..............................................................................................3 9
Fi g ure 3:
Part B M ulti ple -D ose Safet y  St u d y Sc he matic...........................................................4 0
Fi g ure 4:
Part C M ulti ple -D ose Sc he ma ....................................................................................4 1
Fi g ure 5:
Part D M ulti ple -D ose St u d y  Sc he matic......................................................................4 2
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
2 2
LI S T O F A B B R E VI A TI O N S
A b bre vi ati o n
Descri pti o n
A C S
ac ute c hest s y n dr o me
A D L
acti vities of dail y li vi n g
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
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-ti me c ur ve
A U C 0 - 2 4
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me zer o ( pre d ose) t o 2 4 h o urs
A U C 0 -i nf
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me zer o t o e xtra p olate d t o i nfi nit y
A U C 0 -last
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o t he ti me of t he last 
q ua ntifia ble c o nce ntrati o n
A U C t
area u n der t he c ur ve at desi g nate d ti me
BI D
t wice dail y
B P
bl o o d press ure
B U N
bl o o d urea nitr o ge n
% C V
perce nt c oefficie nt of variati o n
C F R
( U nite d States) C o de of Fe deral Re g ulati o ns
C ma x
ma xi m u m o bser ve d c o nce ntrati o n
C mi n
mi ni m u m dr u g c o nce ntrati o n
C N S
ce ntral ner v o us s yste m
C R A
cli nical researc h ass ociate
C R F
case re p ort f or m
C R O
c o ntract researc h or ga nizati o n
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
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 S M B
data safet y m o nit ori n g b oar d
E C
et hics c o m mittee
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
E D C
electr o nic data ca pt ure
E O S
e n d of st u d y
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
2 3
A b bre vi ati o n
Descri pti o n
F D A
( U nite d States) F o o d a n d D r u g A d mi nistrati o n
G B T
Gl o bal Bl o o d T hera pe utics , I nc.
G C P
G o o d Cli nical Practice
G G T
ga m ma -gl uta m yl tra nsferase
G R A S
( U nite d States) ge nerall y rec o g nize d as safe
H b
he m o gl o bi n
H b A
he m o gl o bi n – a d ult
H b F
he m o gl o bi n – fetal
H b S
sic kle he m o gl o bi n
H b S β 0 t hal
sic kle he m o gl o bi n ( S) a n d o ne beta t halasse mia ge ne ( β 0 t hal)
H b S S
sic kle he m o gl o bi n wit h t w o sic kle cell ge nes ( S S) 
Hct
he mat ocrit
H D P E
hi g h de nsit y p ol yet h yle ne
h E R G
h u ma n ether -á-g o -g o -relate d ge ne
H P F H
here ditar y persiste nce of fetal he m o gl o bi n
hr
h o ur
H U
h y dr o x y urea
I B
I nvesti gat or's Br oc h ure
I C F
inf or me d co nse nt for m
I C H
I nter nati o nal C o u ncil f or Har m o ni sati o n 
II G
( U nite d States) i nacti ve i n gre die nt
I N R
i nter nati o nal n or malize d rati o
I R B
i nstit uti o nal re vie w b oar d
I U D
i ntra uteri ne de vice
I U S
i ntra uteri ne h or m o ne-releasi n g s yste m
L D H
lactate de h y dr o ge nase
L C/ M S
li q ui d c hr o mat o gra p h y/ mass s pectr o metr y
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A
® )
mi n
mi ni m u m
m L
milliliter
M RI
ma g netic res o na nce i ma gi n g
M T D
ma xi m u m t olerate d d ose
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
2 4
A b bre vi ati o n
Descri pti o n
N A U C
A U C 0- ∞n or malize d b y d ose
N CI
Nati o nal Ca ncer I nstit ute
N C ma x
C ma x n or malize d b y d ose
N S AI D
n o n-ster oi dal i nti- i nfla m mat or y dr u g
P D
p har mac o d y na mics
PI
Pri nci pal I n vesti gat or
P K
p har mac o ki netics
P O P
p o p ulati o n
P P
p ol y pr o p yle ne
P R
p ulse rate
P T
pr ot hr o m bi n ti me
P T T
partial t hr o m b o plasti n ti me
Q D
o nce dail y 
Q T
Q T i nter val 
Q Tc
c orrecte d Q T i nter val
Q Tc F
Q T c orrecte d b y Fe derica’s f or m ula
R B C
re d bl o o d cell
R State
rela xe d, or hi g h o x y ge nate d, state of he m o gl o bi n
S A E
seri o us a d verse e ve nt
S C D
sic kle cell disease
S C D S
sic kle cell disease se verit y
S C D S M
sic kle cell disease se verit y meas ure 
S O P
sta n dar d o perati n g pr oce d ure
t1/ 2
ter mi nal eli mi nati o n half -life
T A M M
ti me-a vera ge d mea n of t he ma xi m u m
T ma x
ti me of ma xi m u m c o nce ntrati o n
T C D
tra nscra nial D o p pler
T C Di
i ma gi n g tra nscra nial D o p pler
T E A E
treat me nt-e mer ge nt a d verse e ve nt
TI B C
t otal ir o n-bi n di n g ca pacit y 
T S S
t otal s y m pt o m sc ore
T State
te nse, or l o w o x y ge nate d, state of he m o gl o bi n
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
2 5
A b bre vi ati o n
Descri pti o n
U L N
u p per li mit of n or mal 
V O C
vas o -occl usi ve crisis
Vss 
v ol u me of distri b uti o n at stea d y -state
W B C
w hite bl o o d cell
W H O
W orl d Healt h Or ga nizati o n
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
2 6
1.
I N T R O D U C TI O N
1. 1.
Dise ase B ac k gr o u n d
Sic kle cell disease ( S C D), t he first h u ma n dis or der w h ose m olec ular basis was u nc o vere d, is a n 
a ut os o mal recessi ve c o n diti o n i n w hic h t he gl uta mic aci d resi d ue n or mall y f o u n d at t he 6 t h 
p ositi o n of t he he m o gl o bi n β -s u b u nit ( βA ) is re place d b y a vali ne resi d ue ( βS ) (Ita n o, 1 9 4 9)
(I ngra m, 1 9 5 6 ). F u ncti o nal he m o gl o bi n tetra mers t hat c o ntai n βS s u b u nits ( H b S) bi n d a n d release 
o x y ge n a nal o g o usl y t o n or mal he m o gl o bi n tetra mers ( H b A). H o we ver, de o x y ge n ate d H b S te n ds 
t o p ol ymerize i nt o l o n g c hai ns t hat da ma ge a n d dist ort re d cells . P ol y merizati o n of de o x y H b is 
t he si n gle tri g ger t o all t he pat h ol o gical ma nifestati o ns of S C D w hic h is c haracterize d b y 
he m ol y tic a ne mia a n d vas o-occl usi o n lea di n g t o pr o gressi ve e n d- or ga n da ma ge wit h a cli nical 
c o urse of life-l o n g pai n, disa bilit y a n d early deat h.
A m o n g t he earliest ma nifestati o ns of sic kle-relate d or ga n da ma ge is l oss of s ple nic f u ncti o n i n 
t he first t w o years of life w hic h places c hil dre n at hi g h ris k of se psis, partic ularl y  fr o m 
e nca ps ulate d or ga nis ms s uc h as Stre pt oc occ us p ne u m o ni ae a n d H ae m o p hil us i nfl ue nz ae .
F urt her m ore, re nal c o nce ntrati n g a bilit y is als o i m paire d a n d si g nals t he be gi n ni n g of t he decli ne 
i n re nal f u ncti o n t hat ma y lea d t o c hr o nic re nal fail ure a n d e n d-sta ge re nal disease. Pai n is als o 
a n i m p orta nt c o m p o ne nt of t he disease a n d i n y o u n g c hil dre n, prese nts as dact yl itis or ha n d-f o ot 
s yn dr o me a n d ca n be t he first si g n of S C D . T he m ost de vastati n g c o m plicati o n of pe diatric S C D
is t he de vel o p me nt of ce ntral ner v o us s ys te m ( C N S) e ve nts. T his ma y  prese nt as o vert str o ke or 
sile nt str o kes w hic h are s u bcli nical cere bral i nfarcti o ns detecte d o n brai n ma g netic res o na nce 
i ma gi n g ( M RI). Al m ost 5 0 % of t he S C D p o p ulati o n is pe diatric (Far ber, 1 9 8 5 ) a n d 
a p pr o xi matel y 1 1 % of S C D patie nts ha ve cli nicall y a p pare nt str o kes bef ore t he a ge of 2 0 years .
T he ris k of str o ke is hi g hest d uri n g t he first deca de, a n d it is m ost si g nifica nt bet wee n a ges 2 a n d 
5, w he n i t reac hes 1. 0 2 % per year . I n a d diti o n t o o vert str o kes, a n ot her 1 7% t o 2 2 % of c hil dre n 
s uffer sile nt str o kes w hic h ca n pr o d uce si g nifica nt ne ur o psyc h ol o gical deficits 
(O he ne -Fre m p o n g, 1 9 9 8 ; Ver d uzc o, 2 0 0 9 ). T he pat h o ge nesis of str o ke i n c hil dre n wit h S C D is 
c o m ple x a n d n ot f ull y res ol ve d b ut i n m ost cases i n v ol ves occl usi o n or ste n osis of t he lar ge 
i ntracra nial arteries. Hist o pat h ol o g y  varies, b ut i n ge neral t he patter n is o ne of s m o ot h m uscle 
pr oliferati o n wit h o verl yi n g e n d ot helial da ma ge a n d fi br osis (R ot h ma n, 1 9 8 6 ; K os h y , 1 9 9 0).
S maller arteri oles a n d ca pillaries s h o w diste nti o n, t hr o m b osis a n d vessel wall necr osis 
(T u o h y , 1 9 9 7). Da ma ge d, a berra nt re d cells a d here a b n or mally t o t he vasc ular e n d ot heli u m a n d 
t here by tri g ger e n d ot helial cell acti vati o n. E n d ot helial cell acti vati o n casca des i nt o f urt her 
dist ur ba nces, i ncl u di n g a h y perc oa g ula ble state a n d a b n or mal vas o m ot or t o ne . T he greater ris k of 
str o ke i n yo u n g c hil dre n wit h S C D ma y  be e x plai ne d b y t he hi g her cere bral bl o o d vel ocit y 
o bser ve d i n t his p o p ulati o n ( P o wars, 2 0 0 0 ).
Tra nscra nial D o p pler ( T C D) ultras o n o gra p h y ca n be use d t o assess cere bral bl o o d fl o w a n d 
pre dict C N S e ve nts i n S C D . T C D s h o ws a hi g her me a n i ntracra nial arterial fl o w vel ocit y  i n 
c hil dre n wit h S C D (a b o ut 1 3 0 t o 1 4 0 c m/sec) relati ve t o t h ose wit h o ut S C D (a b o ut 9 0 c m/sec).
T he N ati o nal Heart, L u n g, a n d Bl o o d I nstit ute rec o m me n ds c hr o nic tra nsf usi o n t hera p y  f or 
c hil dre n wit h a T C D vel ocit y e xcee di n g 2 0 0 c m/sec base d o n t he res ults of t he S T O P trial 
(A da ms, 1 9 9 8 ). T C D vel ocities of 1 7 0 t o 2 0 0 c m /sec are desi g nate d as “c o n diti o nal” a n d ca n 
pr o gress i nt o t he a b n or mal ra n ge . C hil dre n i n t his cate g or y  re q uire cl ose o bser vati o n. Base d o n 
t he res ults of t he T Wi T C H st u d y, c hil dre n o n a c hr o nic tra nsf usi o n pr ot oc ol f or ele vate d T C D 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
2 7
vel ocit y  > 2 0 0 c m/sec f or at least 1 2 m o nt hs, ca n be safely tra nsiti o ne d t o h y dr o x y u rea ( H U) 
(Ware,
2 0 1 5 ).
O verall, t he ma na ge me nt strate gies f or S C D ha ve e v ol ve d ver y  sl o wly, a n d treat me nt of 
S C D re mai ns a seri o us u n met me dical nee d. I n c hil dre n, r o uti ne vacci nati o n be gi n ni n g i n t he 
1 9 7 0s c o ntri b ute d t o t he re d ucti o n i n deat h rate as a res ult of i nfecti o us c o m plicati o n . Re d bl o o d 
cell ( R B C) tra nsf usi o ns are a d mi nistere d t o alle viate s ym pt o matic a ne mia as well as f or str o ke 
treat me nt a n d pre ve nti o n. Tra nsf usi o ns are c ostl y,  c u m bers o me, a n d n ot u nif or ml y  accessi ble 
a n d acc o m pa nie d b y ris ks, i ncl u di n g ir o n o verl oa d (Wa hl, 2 0 0 9 ). H U t hera p y f or S C D is li mite d 
b y  its si de effect pr ofile, p o or patie nt a d here nce, varia ble patie nt res p o nses, a n d c o ncer ns of 
l o n g-ter m t o xicit y (Bra n d o w, 2 0 1 0 ). T he o nl y c urati ve treat me nt is b o ne marr o w tra ns pla ntati o n 
fr o m a hist oc om pati ble d o n or, a n o pti o n t hat has bee n a vaila ble si nce t he 1 9 9 0s (Platt, 2 0 1 4 ), b ut 
b o ne marr o w tra ns pla ntati o n carries si g nifica nt ris ks a n d is ass ociate d wit h a ~ 5 % m ortalit y  rate 
(Nat ha n, 2 0 1 3 ). Des pite t he c urre nt sta n dar d of care, i ncl u di n g H U, bl o o d tra nsf usi o n, a n d 
palliati ve t hera p y f or ac ute attac ks, patie nts wit h S C D c o nti n ue t o s uffer seri o us m or bi dit y  a n d 
pre mat ure m ortalit y  (Stei n ber g, 2 0 0 3 ).
T o date, n o dr u gs ha ve bee n a p pr o ve d t hat s pecificall y  tar get t he u n derlyi n g mec ha nis m of S C D .
T he mec ha nis m of acti o n of H U i n v ol ves a hi g hl y varia ble i ncrease i n t he le vel of fetal 
h e m o gl o bi n ( H b F) i n a li mite d s u bset of R B Cs ( F- cells), res ulti n g i n li mite d pr otecti o n fr o m 
sic kli n g. H b F is t he pre d o mi na nt he m o gl o bi n d uri n g fetal de vel o p me nt a n d be gi ns t o decli ne i n 
pr o d ucti o n s h ortl y  after birt h. S y nt hesis of a d ult he m o gl o bi n ( H b A ) be gi ns s h ortl y  bef ore birt h 
a n d nears its a d ult pr o p orti o n a p pr o xi matel y  6 t o 9 m o nt hs p ost part u m. H b F p o werf ull y i n hi bits 
t he p ol ymerizati o n of de o x y H b S d ue t o its hi g h o x y ge n affi nit y as well as i ntri nsic str uct ural 
c haracteristics t hat bl oc k p ol y mer f o r mati o n. I n di vi d uals w h o are h o m oz y g o us f or t he βS ge ne 
s h o w n o disease ma nifestati o ns u ntil late i n t he first year of life w he n t he decli ni n g le vel of H b F 
n o l o n ger pr otects a gai nst de o x y H b S p ol y m erizati o n. T he pr otecti ve effect of H b F has bee n 
f urt her vali date d b y t he o bser vati o n t hat rare i n di vi d uals w h o are c o m p o u n d heter oz y g otes f or 
t he β S ge ne a n d a ge ne deleti o n res ulti n g i n persiste nt H b F e x pressi o n ( H b S- H P F H) d o n ot ha ve 
ma nifestati o ns of S C D . H b S -H P F H is t y picall y  ass ociate d wit h 2 0-3 0 % H b F le vels distri b ute d 
e q uall y a m o n g er yt hr oc ytes ( pa ncell ular). I n a d diti o n, a f or m of deleti o nal H b S -H P F H has bee n 
descri be d wit h pa ncell ular H b F le vels of 1 0 % a n d fe w, if a n y, s ic kle cell-relate d e ve nts
(A ki n s he ye, 2 0 1 1 ). Ta ke n t o get her, t he data fr o m s u bjects wit h H b S -H P F H s u g gests t hat 
pa ncell ular H b F of 2 0 % t o 3 0 % pre ve nts S C D a n d t hat le vels as l o ws as 1 0 % ma y  be s ufficie nt 
f or pr otecti o n.
Beca use o x y h e m o gl o bi n is a p ote nt i n hi bit or of H b S p ol y merizati o n , all osteric m o dificati o n of 
h e m o gl o bi n t o i ncrease t he pr o p orti o n of o xy h e m o gl o bi n is a pr o misi n g strate g y t o ac hie ve 
i n hi biti o n of H b S p ol y merizati o n i n all R B Cs (N o g uc hi, 1 9 8 8 ). Pri or e x peri me ntal 
he m o gl o bi n -m o dif y i n g a ge nts ( B W 1 2 C a n d t ucares ol) ha ve pr o vi de d pr o of of c o nce pt f or t he 
he m o gl o bi n m o dificati o n a p pr oac h b y de m o nstrati n g a n i ncrease i n o x y h e m o gl o bi n a n d a 
decrease i n cli nical bi o mar kers of hae m ol ys is (Kei da n, 1 9 8 6 ; Ar y a, 1 9 9 6). Des pite t he i ncrease 
i n he m o gl o bi n o x y ge n affi nit y , t hese dr u gs were well t olerate d b y healt h y v ol u nteers, a n d t he y 
re mai ne d well-c o m pe nsate d b ot h at near ma xi mal e xercise a n d at rest wit h little c ha n ge i n basal 
o x y ge n c o ns u m pti o n or resti n g heart rate ( Nic h olls, 1 9 8 9 ; N g o, 2 0 1 2 ).
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
2 8
1. 2.
V o xel ot or
Gl o bal Bl o o d T hera pe utics , I nc. ( G B T) has de vel o pe d v o xel ot or ( pre vi o usl y G B T 4 4 0), a s mall 
m ol ec ule all osteric m o d ulat or of h e m o gl o bi n o x yge n affi nit y, f or t he treat me nt of S C D. O n 
2 5 N o ve m ber 2 0 1 9, v o xel ot or w as a p pr o ve d f or use i n t he U nite d States ( U S) u n der t he 
tra de na me Ox br y ta® b y  t he F o o d a n d Dr u g A d mi nistrati o n ( F D A), a n d is i n dicate d f or t he 
treat me nt of S C D i n a d ults a n d pe diatric patie nts 1 2 years of a ge a n d ol der.
T he mec ha nis m of acti o n of v o xel ot or i n v ol ves i n hi biti o n of H b S p ol ymerizati o n b y  i ncreasi n g 
t he affi nity of h e m o gl o bi n f or o x yge n. He m o gl o bi n e xists i n b ot h a rela xe d ( R) a n d a te nse ( T) 
state wit h hi g h a n d l o w affi nit y f or o x yge n, res pecti vel y (Eat o n, 1 9 9 9 ). U p o n bi n di n g t o H b S, 
v o xel ot or effecti vel y mai ntai ns a tar gete d fracti o n of H b S i n t he R state . He m o gl o bi n S 
m olec ules t hat are i n t he R ( o x y ge n ate d) state are p ote nt i n hi bit ors of H b S p ol y merizati o n a n d, 
c o n versel y, o nl y de o x y g e nate d H b S is ca pa ble of p ol y merizi n g t o create sic kli n g of R B Cs . T h us, 
H b S t hat is m o difie d b y  v o xel ot or mi mics H b F a n d pre ve nts S C D ma nifestati o ns b y  mai ntai ni n g 
a n R-state c o nf or mati o n a n d i n hi biti n g de o xy H b S  p ol y merizati o n . Beca use v o xel ot or bi n ds t o 
t he he m o gl o bi n α c hai n, its effects o n t he o x y ge n e q uili bri u m c ur ves are e x pecte d t o be si milar 
i n n or mal a n d sic kle bl o o d. N o ncli nical data a n d data fr o m pri or e x peri me ntal he m o gl o bi n -
m o dif y i n g a ge nts de m o nstrate t hat o nl y a fracti o n of he m o gl o bi n m ust be mai ntai ne d i n t he R 
state i n or der t o i n hi bit sic kli n g. Base d o n data fr o m pri or e x peri me ntal c o m p o u n ds a n d ge netic 
data fr o m hi g h -affi nit y he m o gl o bi n m utati o ns i n h u ma ns, 1 0 % t o 3 0 % he m o gl o bi n m o dificati o n 
b y  v o xel ot or s h o ul d be safely ac hie va ble i n h u ma ns (A ki ns he y e, 2 0 1 1; Ar y a, 1 9 9 6; 
G o nzalez, 2 0 0 9 ).
V o xel ot or was rati o nall y desi g ne d, base d o n k n o wle d ge of t he che mical str uct ure a n d m o de of 
he m o gl o bi n bi n di n g of pri or he m o gl o bi n -m o dif y i n g a ge nts i n or der t o i m pr o ve p ote nc y a n d 
s pecificity f or h e m o gl o bi n (Saf o, 2 0 0 4 ; A b d ul mali k, 2 0 1 1 ). A me dici nal c he mistr y  pr o gra m was 
use d t o o pti mize acti vit y  i n i n vitr o h e m o xi metr y a n d p ol ymerizati o n assa y s a n d t o ac hie ve a 
1: 1 st oic hi o metr y of bi n di n g per he m o gl o bi n tetra mer c o m pare d t o t he 2: 1 st oic hi o metr y  of pri or 
c o m p o u n ds. S u bse q ue ntl y , v o xel ot or was f o u n d t o be c o nsi dera bl y  m ore p ote nt t ha n all re p orte d 
pre decess or c o m p o u n ds i n i n vitr o assa ys a n d t o ha ve s ustai ne d e x p os ure f oll o win g oral d osi n g 
i n m ulti ple a ni mal s pecies.
V o xel ot or is c urre ntl y i n cli nical st u dies e x pl ori n g t he safety, t olera bilit y , p har mac o ki netics
( P K), p har mac o dy na mics ( P D) a n d treat me nt res p o nse i n a d olesce nt a n d a d ult S C D partici pa nt s
as well as i n cli nical p har mac ol o g y  st u dies i n healt h y a d ult partici pa nt s (refer t o Secti o n 1. 4. 2 ).
1. 3.
R ati o n ale f or St u d y
Mec ha nis m -base d t hera pies w hic h ma y  m o dif y t he c o urse of S C D are ur ge ntl y nee de d. Base d 
o n t he o bser vati o n t hat v o xel ot or has bee n well t olerate d i n a d ult a n d a d olesce nt partici pa nts
( 1 4 M a y  2 0 1 8 D S M B re vie w), a n d has s h o w n ra pi d, si g nifica nt a n d s ustai ne d i m pr o ve me nt i n 
he m o gl o bi n a n d he m ol y sis meas ures o ver t hat ac hie ve d o n sta n dar d of care t hera p y i ncl u di n g 
H U (Le hrer -Grai wer, 2 0 1 5 ; H o p pe, 2 0 1 7 ) (refer t o Secti o n 1. 4. 2 ), e x pl orati o n of t he effect of 
v o xel ot or i n pe diatric partici pa nts w h o are dee me d t o p ote ntiall y  ha ve t he greatest be nefit fr o m a 
disease -m o d if yi n g t hera p y is warra nte d. T C D as a pre dict or of str o ke ris k is a n e n d p oi nt of 
partic ular i nterest beca use str o ke has hi g h i nci de nce a n d de vastati n g c o nse q ue nces i n pe diatric 
patie nts wit h S C D. T C D vel ocit y  a n d str o ke ris k are i n versely c orrelate d wit h he m o gl o bi n le vel s; 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
2 9
pre dict or of str o ke ris k i n patie nts wit h S C D w h o ha ve n ot ha d pri or str o ke or tra nsie nt isc he mic 
attac k is he m o gl o bi n le vel (O he ne -Fre m p o n g, 1 9 9 8 ). F or t his reas o n, a n i m p orta nt rati o nale f or 
t his st u d y is t o e x pl ore t he p ote ntial be nefit of v o xel ot or o n re d uci n g T C D vel ocit y  i n pe diatric 
partici pa nts wit h S C D.
T his st u d y  pr o p oses t o e val uate t he safety of v o xel ot or at e x p os ures c o m para ble t o t h ose st u die d 
i n a d ults as well as t o assess t he effect o n T C D fl o w vel ocit y  i n t he ol dest pe diatric a ge gr o u p of 
1 2 t o 1 7 y ears of a ge i n partici pa nts w h o ha ve a T C D wi n d o w ( Part B o nl y) . Part C will i ncl u de 
partici pa nts wit h T C D fl o w vel ocit y i n t he n or mal ra n ge (< 1 4 0 c m/sec b y  n o ni ma gi n g T C D; 
< 1 2 5 c m/sec b y i ma gi n g tra nscra nial D o p pler [ T C Di]), ele vate d T C D fl o w vel ocit y
( 1 4 0- 1 6 9 c m/sec b y  n o ni ma gi n g T C D; 1 2 5 – 1 5 4 c m/sec b y  T C Di), a n d c o n diti o nal T C D fl o w 
vel ocit y ( 1 7 0– 1 9 9 c m/sec b y  n o ni ma gi n g T C D; 1 5 5 – 1 8 4 c m/sec b y T C Di) ( D e Ba u n, 2 0 1 4). T he
a ge ra n ge f or Part C will i ncl u de partici pa nts fr o m 4- 1 7 y ears ol d as t his is t he pri mar y a ge ra n ge
at ris k f or ele vate d T C D vel ocit y a n d f or w hic h a n n ual T C D scree ni n g is alrea d y perf or me d 
base d o n sta n dar d of care g ui d eli nes. G ui deli nes rec o m me n d T C D scree ni n g be gi n ni n g at 2 ye ars 
of a ge (E x pert Pa nel Re p ort, 2 0 1 4) ; h o we ver, t his st u d y will n ot re q uire c hil dre n yo u n ger t ha n 
4 ye ars of a ge t o u n der g o T C D d ue t o t he p ote ntial nee d f or se dati o n . Base d o n t he rece nt D S M B 
safety re vie w of data fr o m a d ults a n d a d olesce nts wit h S C D treate d wit h v o xel ot or i n t he 
o n g oi n g P hase 3 st u d y ( G B T 4 4 0 -0 3 1) a n d a d olesce nts wit h S C D treate d i n t his st u d y 
( G B T 4 4 0- 0 0 7), t he D S M B s u p p orts treati n g c hil dre n d o w n t o 2 ye ars of a ge wit h v o xel ot or .
P artici pa nt s wit h u n e val ua ble T C D at baseli ne ( e g, d ue t o a T C D wi n d o w w hic h is i na de q uate t o 
o btai n a n acc urate meas ure me nt) will n ot be eli gi ble f or e nr oll me nt .
T he rati o nale f or i ncl u di n g t he T C D e n d p oi nt i ncl u des t he f oll o wi n g: 1) base d o n t he mec ha nis m 
of acti o n of v o xel ot or , a decrease i n H b S p oly m erizati o n s h o ul d decrease R B C da ma ge a n d 
res ulti n g or ga n i nj ur y i ncl u di n g cere bral vasc ul o pat h y (refer t o Secti o n 1. 1 ), 2) ele vate d T C D 
c orrelates i n de pe n de ntl y wit h l o w he m o gl o bi n a n d ele vate d lactate de hy d r o ge nase (L D H )
(Ber na u di n, 2 0 0 8 ), a n d b ot h of t hese a b n or mal bi o mar kers ha ve s h o w n i m pr o ve me nt wit h 
v o xel ot or t hera p y. Inter ve nti o nal cli nical st u dies wit h si milar sa m ple size s ha ve de m o nstrate d 
re d ucti o ns i n T C D vel ocit y wit h H U (Krat o vil, 2 0 0 6 ). T he data fr o m t his a ge gr o u p will i nf or m 
f ut ure de vel o p me nt i n pe diatric partici pa nts as well as t he de vel o p me nt of v o xel ot or i n t he 
y o u n ger a ge gr o u ps . I n partic ular, t he P K data a n d effect o n he mat ol o gic bi o mar kers will i nf or m 
d ose selecti o n f or pe diatric partici pa nts i n f ut ure cli nical st u dies. I n a d diti o n, it will be 
i nf or mati ve t o c o m pare t he effect o n he mat ol o gic mar kers after 2 4 wee ks of v o xel ot or treat me nt 
(Part B) or after 4 8 wee ks of v o xel ot or treat me nt (Part C) i n pe diatric partici pa nts in t his st u d y  t o 
effects o bser ve d i n a d ults ( G B T 4 4 0-0 0 1 st u d y ), gi ve n t hat pe diatric partici pa nts d o n ot ha ve as 
m uc h c u m ulati ve b o ne marr o w or re nal da ma ge , w hic h ca n sec o n daril y  affect er yt hr o p oiesis.
Lastl y, t he safet y a n d efficac y of v o xel ot or treat me nt i n t he yo u n ger patie nt p o p ulati o n a ge d 
6 m o nt hs t o < 4 y ears will be e val uate d i n Part D.
T he st u d y  will be c o n d ucte d i n 4 parts: 
Part A will e val uate safet y , t olera bilit y, a n d P K of a si n gle d ose of v o xel ot or i n pe diatric 
partici pa nts a ge d 6 t o 1 7 y ears.
Part B will assess t he safet y , t olera bilit y, a n d P K, as well t he he mat ol o gical effects a n d t he effect 
o n T C D fl o w vel ocit y  of m ulti ple d oses of v o xel ot or f or 2 4 wee ks i n pe diatric partici pa nts a ge d 
1 2 t o 1 7 y ears.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
3 0
Part C will assess t he safet y , t olera bilit y, a n d P K , as well as t he he mat ol o gical effects a n d t he 
effect o n T C D fl o w vel oci t y of m ulti ple d oses of v o xel ot or f or 4 8 wee ks i n pe diatric partici pa nts 
a ge d 4 t o 1 7 years .
Part D will assess t he safet y , t olera bilit y, a n d P K, as well as t he he mat ol o gical effects, of 
m ulti ple d oses of v o xel ot or f or u p t o 4 8 wee ks i n pe diatric partici pa nts a ge d 6 m o nt hs t o 
< 4 ye ars.
1. 3. 1.
St u d y E n d p oi nts
1. 3. 1. 1. 
Sic kle Cell Dise ase Se verit y Me as ure a n d P atie nt -Re p orte d O utc o mes
A ke y  o bjecti ve of t he sic kle cell disease se verit y meas ure ( S C D S M) was t o de vel o p a n 
i nstr u me nt (electr o nic Patie nt-Re p orte d O utc o me, e P R O) t hat meas ures pai n e xacer bati o ns/ pai n 
crisis as e x perie nce d b y partici pa nts , d ue t o t he lac k of se nsiti vit y t hat affects t he tra diti o nall y 
defi ne d vas o -occl usi ve crisis (V O C ) e n d p oi nt. S pecificall y, V O C is a meas ure of healt hcare 
utilizati o n, n ot partici pa nt s ym pt o ms. Pri or researc h has s h o w n t hat V O C is t he “ti p of t he 
ice ber g” i n t hat se vere pai n is ver y fre q ue nt, w hile V O C is rare, a n d t hat t he vast maj orit y  of pai n 
crisis da ys occ ur wit h o ut utilizati o n of me dical care a n d t h us, are n ot classifie d as V O C 
(S mit h, 2 0 0 8 ). This se verit y  sc ore is bei n g i ncl u de d as a ke y sec o n dar y e n d p oi nt i n P hase 3 
St u d y  G B T 4 4 0- 0 3 1, beca use it is a ntici pate d t o be a se nsiti ve, s pecific a n d vali d meas ure of 
S C D crisis pai n a n d o verall S C D se verit y , a n d t heref ore has greater p o wer t o detect a n 
i m pr o ve me nt i n s ym pt o ms t ha n V O C . T he meas ure is bei n g de vel o pe d as a cli nical o utc o mes 
assess me nt i n acc or da nce wit h F D A G ui da nce f or I n d ustr y  o n Patie nt- Re p orte d O utc o me 
Meas ures (F D A V oice, 2 0 1 4 ) a n d fi nal q ualificati o n will be esta blis he d usi n g t he anal ys is of i n 
P hase 3 St u d y  G B T 4 4 0- 0 3 1 (i ncl u di n g l o n git u di nal meas ure me nt pr o perties, a bilit y t o detect 
c ha n ge a n d use f or e n d p oi nt a nal y sis t o esta blis h cli nical be nefit). A n e P R O de vice will be use d 
i n Part B ( o nly) of t his st u d y t o pr o vi de i nf or mati o n relati ve t o t he sec o n dar y e n d p oi nts.
1. 4.
S u m m ar y of Rele v a nt N o ncli nic al D at a a n d Cli nic al D at a
1. 4. 1.  
N o ncli nic al D at a
Pri mar y  p har mac o dy n a mics ( P D) st u dies of v o xel ot or c o nsiste d of i n vitr o a n d i n vi v o st u dies t o 
c haracterize (a) v o xel ot or bi n di n g a n d affi nit y f or H b, ( b) t he effect of v o xel ot or o n H b S 
m o dificati o n usi n g p urifie d H b, was he d R B Cs, a n d w h ole bl o o d, a n d (c) t he efficac y  of 
v o xel ot or i n vi v o i n a m o use m o del of S C D. T hes e i n vitr o assa ys of i ncreasi n g c o m ple xit y 
i ncl u de d meas uri n g H b- O2 via he m o xi metr y , q ua ntif yi n g sta bilizati o n of t he o x yhe m o gl o bi n 
state c o nf or mati o n, dela yi n g H b S p ol ymerizati o n at l o w o x y ge n te nsi o n, pre ve nti n g i n vitr o 
sic kli n g i n d uce d by a l o w o x y ge n e n vir o n m e nt, decreasi n g visc osit y a n d i m pr o vi n g 
def or ma bilit y  of R B Cs i n bl o o d fr o m patie nts wit h S C D. I n a d diti o n, t hese st u dies s h o w t hat 
v o xel ot or -m o difie d H b retai ns t he B o hr Effect, w hic h is t he a bilit y  t o a u g me nt o x yge n deli ver y  
i n meta b olicall y acti ve (l o w p H) tiss ues.
C ollecti vel y , t hese st u dies de m o nstrate t hat v o xel ot or p ote ntl y  i ncreases H b- O2 affi nit y wit h hi g h 
s pecificity of bi n di n g t o H b; sta bilizes t he o x y or R -state c o nf or mati o n of H b; pre ve nts H b S 
p ol y merizati o n a n d R B C sic kli n g i n vitr o; i m pr o ves sic kle bl o o d visc osit y, a n d def or ma bilit y i n 
vitr o. I n a d diti o n, v o xel ot or i ncreases H b S-o x y ge n affi nit y  a n d R B C half-life, w hile decreasi n g 
e x vi v o sic kli n g a n d retic ul oc yte c o u nt i n a S C D m o use m o del. 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
3 1
A d diti o nal i nf or mati o n re gar di n g n o ncli nical p har mac ol o g y  (i ncl u di n g safet y p har mac ol o g y a nd 
meta b olis m) a n d t o xic ol o g y  is pr o vi de d i n t he m ost c urre nt versi o n of t he I nvesti gat or's 
Br oc h ure (IB) f or v o xel ot or , pr o vi de d se parately.
1. 4. 2.
Cli nic al D at a
Details re gar di n g G B T’s cli nical de vel o p me nt pr o gra m f or S C D are a vaila ble i n t he c urre nt 
versi o n of t he I B. 
T he P hase 3 d o u ble -bli n d, ra n d o mize d, place b o -c o ntr olle d st u d y, G B T 4 4 0- 0 3 1, i n w hic h a d ults 
a n d a d olesce nts (a ge d 1 2 – 1 7 y ears) recei ve d place b o, v o xel ot or 9 0 0 m g , or v o xel ot or 1 5 0 0 m g is 
c o m plete d , a n d t he res ults are s u m marize d i n t he m ost c urre nt versi o n of t he v o xel ot or I B.
1. 4. 2. 1.
S u m m ar y of t he K n o w n a n d P ote nti al Ris ks a n d B e nefits of V o xel ot or
V o xel ot or is well t olerate d i n a d ult a n d pe diatric partici pa nts 4 y ears of a ge a n d ol der wit h S C D. 
A d verse e ve nts, pri maril y  ass ociate d wit h u n derlyi n g disease a n d gastr oi ntesti nal e ve nts, were 
ge nerall y l o w gra de i n se verit y , were ma na ge d b y d ose re d ucti o n a n d/ or sy m pt o matic treat me nt, 
a n d sel d o m res ulte d i n disc o nti n uati o n of t hera py. I de ntifie d ris ks, w hic h i ncl u de t he a d verse 
dr u g reacti o ns of diarr hea, a b d o mi nal pai n, na usea, ras h, a n d dr u g h y perse nsiti vit y , were l o w 
gra de i n se verit y  a n d cli nicall y ma na gea ble. 
I n t he pi v otal P hase 3 st u d y, St u d y G B T 4 4 0- 0 3 1, v o xel ot or was s h o w n t o si g nifica ntly i ncrease 
H b, i m pr o ve a ne mia, a n d re d uce cli nical meas ures of he m ol y sis i n a d ult a n d pe diatric 
partici pa nts 1 2 years of a ge a n d ol der wit h S C D.
I n c o ncl usi o n, v o xel ot or has a fa v ora ble be nefit-ris k pr ofile base d o n cli nical data fr o m st u dies 
e nr olli n g partici pa nts 4 years of a ge a n d ol der wit h S C D. O verall, b y i n hi biti n g H b S 
p ol y merizati o n v o xel ot or has t he p ote ntial t o alter t he cli nical c o urse of t he disease b y  i m pr o vi n g 
a ne mia a n d he m ol ysis i n S C D disease.
F ur t her i nf or mati o n re gar di n g t he p ote ntial be nefits a n d ris ks of v o xel ot or a n d g ui da nce f or t he 
i n vesti gat or are pr o vi de d i n t he c urre nt versi o n of t he I B.
1. 5.
D ose R ati o n ale
1. 5. 1.
D ose R ati o n ale f or Si n gle V o xel ot or D oses t o be E v al u ate d i n Pe di atric 
P artici p a nts ( 6 t o 1 1 Ye ars) i n P a rt A
Si n gle d oses ( 3 0 0, 6 0 0 , a n d 9 0 0 m g) of v o xel ot or f or pe diatric partici pa nts 6 t o 1 1 years were 
si m ulate d base d o n t he a d olesce nt P O P P K m o del descri be d i n Ta ble 2 t o c o m pare t o pe diatric 
partici pa nts’ ( 6 t o 1 1 ye ars) e x p os ures t o a d ults a d mi nistere d a si n gle d ose of v o xel ot or 9 0 0 m g .
T he c leara nce i n pe diatric partici pa nts was ass u me d t o be all o metricall y scale d t o t he a d ults 
usi n g t he f oll o wi n g e q uati o n:
      =      ×       7 0   .  ×  W here is ra n d o ml y sa m ple val ue fr o m n or mal distri b uti o n wit h 0 mea n a n d varia nce e q ual t o 
esti mate d C L varia nce i n a d ult a nalys is. Ce nters f or Disease C o ntr ol a n d Pre ve nti o n ( C D C )
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
3 2
gr o wt h c harts (htt p:// w w w.c dc. g o v/ gr o wt hc harts ) were use d t o assi g n pe diatric partici pa nt ’s 
wei g hts t o a ge cate g ories. E x p os ure was calc ulate d acc or di n g t o t he f oll o wi n g e q uati o n:
      × ℎ
 =      (  )
   (ℎ)
Si m ulate d e x p os u res f oll o wi n g a d mi nistrati o n of 6 0 0-m g d ose t o c hil dre n a ge d 6 t o 1 1 years is 
c o m pare d t o t he si m ulate d e x p os ures i n a d ults recei vi n g 9 0 0 -m g  d ose as s h o w n i n Fi g ure 1 .
Fi g ure 1:
Si m ul ati o n s of V o xel ot or 9 0 0 m g i n A d ults a n d 6 0 0 m g i n C hil dre n 
( 6 t o 1 1 ye ars)
A b bre viati o ns: A U C , area u n der t he c o nce ntrati o n -ti me c ur ve; ys , years .
Base d o n t hese si m ulati o ns, a si n gle 6 0 0-m g d ose i n c hil dre n 6 t o 1 1 y ears is m ost c o m para ble t o 
a si n gle 9 0 0 -m g d ose of v o xel ot or i n a d ults. T h us, a si n gle 6 0 0 -m g d ose i n c hil dre n a ge d 6 t o 
1 1 ye ars was selecte d t o be e val uate d i n C o h ort 2 of Part A of t his st u d y .
1. 5. 2.
R ati o n ale f or t he V o xel ot or D ose t o be E v al u ate d i n P art B
Base d o n t he si n gle d ose safet y a n d preli mi nar y P K of v o xel ot or i n a d olesce nts, 9 0 0- a n d 
1 5 0 0 -m g d oses ha ve bee n selecte d t o be e val uate d i n Part B of G B T 4 4 0- 0 0 7. T he d oses of 
v o xel ot or 9 0 0 a n d 1 5 0 0 m g t o be e val uate d i n pe diatric partici pa nts i n Part B of G B T 4 4 0- 0 0 7 are 
t he sa me as t he d oses selecte d t o be e val uate d i n G B T 4 4 0-0 3 1 ( Gr o u p 1, P hase 3 st u d y ). T he 
d oses of v o xel ot or 9 0 0 a n d 1 5 0 0 m g t o be e val uate d i n St u d y  G B T 4 4 0-0 3 1 are bas e d o n t he 2 0 %
t o 3 0 % o pti mal treat me nt tar get f or efficac y base d o n ge netic data ( H b S/ here ditar y  persiste nce 
of fetal he m o gl o bi n [ H P F H]), ge netic data f or safet y ( hi g h affi nity H b m utati o ns t hat are well 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
3 3
t olerate d wit h H b o xy ge n affi nit y c orres p o n di n g t o H b m o dificati o n of 3 0 % or hi g her) , a n d o n 
res p o nse a n d safety data fr o m t he P hase 1/ 2 st u d y G B T 4 4 0 - 0 0 1. T o ac hie ve o pti mal efficac y , 
H b S p ol y merizati o n a n d sic kli n g s h o ul d be i n hi bite d at all ti mes, t heref ore t he efficac y  tar get of 
2 0 % t o 3 0 % is base d o n t he mi ni m u m occ u pa nc y tar get base d o n mi ni m u m dr u g c o nce ntrati o n
( Cmi n ) v o xel ot or bl o o d le vels.

I n di vi d uals wit h t he deleti o nal f or m of H b S/ H P F H ha ve H bF le vels i n t he ra n ge of 
a p pr o xi matel y 20 % t o 3 0 % wit h n o cli nical ma nifestati o ns of S C D (N g o, 2 0 1 2 ). 
Beca use i n vitr o e x peri me nts ha ve s h o w n t hat v o xel ot or m o difie d H b dela ys H b S 
p ol y merizati o n wit h si milar p ote nc y  t o he m o gl o bi n fetal ( H b F), 2 0 % t o 3 0 % is a 
reas o na ble tar get f or v o xel ot or H b occ u pa nc y .

T he tar get ra n ge of 2 0 % t o 3 0 % H b m o dificati o n is s u p p orte d b y  treat me nt res p o nse 
data fr o m st u d y G B T 4 4 0 - 0 0 1. Partici pa nt s wit h S C D treate d i n st u d y G B T 4 4 0-0 0 1 at 
7 0 0 m g , 9 0 0 m g a n d 1 0 0 0 m g per da y  ac hie ve d H b occ u pa nc y  i n t he ra n ge of 
a p pr o xi matel y 2 0% t o 3 0 %. He mat ol o gic res p o nses ( o n he m ol ys is mar kers a n d sic kle 
cell c o u nts) were see n at all d ose le vels teste d, a n d a d ose res p o nse was e vi de nt f or 
s o me he m ol ysis meas ures ( bilir u bi n a n d retic ul oc ytes). T he greatest H b i ncrease was 
see n i n c o h orts d ose d f or 9 0 da ys. Partici pa nt s w h o ac hie ve d > 2 0 % H b occ u pa nc y  
s h o we d a n i m pr o ve d he mat ol o gic res p o nse c o m pare d t o t h ose w h o di d n ot. In 
a d diti o n, i n di vi d ual partici pa nt s wit h d ose re d ucti o ns ga ve e vi de nce of i m pr ove d 
res p o nse w hile mai ntai ni n g H b occ u pa nc y > 2 0 %.

E x p os ure res p o nse a nal ysis a n d P K/ P D m o deli n g of G B T 4 4 0 -0 0 1 data de m o nstrate a 
hi g hl y si g nifica nt a n d li ner relati o ns hi p bet wee n e x p os ure a n d i m p r o ve me nt i n 
he m ol y sis meas ures (ie, at t he d oses teste d, a platea u o n i m pr o ve me nt i n he m ol ysis 
meas ures has n ot bee n reac he d) 

M o deli n g a n d si m ulati o n pre dicti o ns base d o n data deri ve d fr o m G B T 4 0 0 -0 0 1 f or t he 
he m ol y sis meas ures, i n direct bilir u bi n, retic ul oc y te c o u nts, L D H a n d H b f or 
v o xel ot or d oses of 9 0 0 a n d 1 5 0 0 m g are s u m marize d i n Ta ble 1 . T o date, d oses u p t o 
1 0 0 0 m g ha ve bee n e val uate d cli nicall y. Si nce 1 5 0 0 m g has n ot bee n pre vi o usl y 
e val uate d, t he e x p os u re res p o nse a nalys is a n d si m ulati o ns were base d o n an E ma x
m o del.
M o deli n g a n d si m ulati o n base d o n a d ult data pre dict t hat v o xel ot or 9 0 0 - a n d 1 5 0 0 -m g d oses will 
ac hie ve v o xel ot or bl o o d c o nce ntrati o ns at C mi n i n t he me dia n partici pa nt e q ui vale nt t o H b 
m o dificati o n of 1 6 % ( 2 . 5t h t o 9 7. 5t h perce ntile 7 % t o 3 1 %) a n d 2 6 % ( 2. 5t h t o 9 7. 5t h perce ntile 
1 2 % t o 5 2 %), res pecti vel y . Base d o n t his pre dicti o n, 2 5 % of partici pa nts at 9 0 0 m g, a n d 7 6 % of 
partici pa nts at 1 5 0 0 m g, will mai ntai n > 2 0 % H b occ u pa nc y , res pecti vely.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
3 4
T a ble 1 :
Si m ul ate d He m ol ysis Me as ures O utc o mes B ase d o n D at a i n A d ult 
P artici p a nts ( % C h a n ge fr o m B aseli ne) f or V o xel ot or 9 0 0 a n d 1 5 0 0 m g
H e m ol ysis Me as ure
D ose of V o xel ot or
9 0 0 m g
1 5 0 0 m g
Bilir u bi n ( %)
-4 7 ( 2 7 – 8 4)
-6 6 ( 5 1 – 7 8) a
Retic ul oc ytes ( %)
-5 3 ( 3 0 – 9 3)
-8 4 ( 6 1 – 9 4) a
L D H ( %)
-3 0 ( 1 7 – 5 4)
-6 4 ( 3 7 – 8 4) a
H e m o gl o bi n ( %)
1 1. 9 ( 6. 7 – 2 1. 1)
—
b
H e m o gl o bi n (c ha n ge fr o m b aseli ne)c
1. 0 6 ( 0. 6 0 – 1. 9)
—
b
A b bre viati o n: L D H , lactate de h y dr o ge nase.
N ote: Val ues re prese nt me dia n ( 2. 5t h t o 9 7. 5t h perce ntiles) .
a Base d o n E ma x m o del.
b T he E ma x m o del u n deresti mate d t he c ha n ge i n H b a n d ca n n o t be use d a n d t he li near m o del ma y o veresti mate.
c Base d o n a Baseli ne H b of 9 g/ d L.
A p o p ulati o n ( P O P) P K m o del was de vel o pe d f or a d olesce nts usi n g t he sa me m o del str uct ure
( 2-c o m part me nt m o del wit h first or der a bs or pti o n) as t he a d ult P O P P K m o de l. V o xel ot or P K 
para meters were esti mate d a n d c o m pare d t o t he a d ult val ues. O verall, all maj or ( e g, cleara nce, 
v ol u me ) P K para meters f or t he w h ole bl o o d v o xel ot or are pr ojecte d t o be si milar (Ta ble 2 ) 
bet wee n a d ult a n d a d olesce nt partici pa nts i n dicati n g t hat t here is n o si g nifica nt differe nce 
bet wee n t hese t w o partici pa nt p o p ulati o ns. Base d o n t hese data, t he sa me d oses are 
rec o m me n de d f or a d olesce nts a n d a d ults.
T a ble 2 : 
Par a meter Esti m ates Fr o m t he W h ole Bl o o d V o xel ot or P o p ul ati o n P K M o del
(A d ults V ers us A d olesce nts )
P K P ar a m eters
V o xel ot or W h ole Bl o o d
A d ults ( R S E %)
V o xel ot or W h ole Bl o o d
A d olesce nts ( R S E %)
C L ( L/ h) 
0. 4 3 ( 5)
0. 3 7 ( 1 3)
V ( L)
2 1. 4 ( 6)
1 5 ( 1 7)
K A ( 1/ h)
0. 3 4 ( 1 3)
0. 1 9 ( 3 0)
Pr o p orti o nal err or ( %)
2 8 ( 8)
7 0 ( 8)
A d diti ve err or ( n g/ m L)
4. 6 ( 4 1)
-
A b bre viati o ns: C L , cleara nce ; K A , a bs or pti o n rate c o nsta nt ; R S E , relati ve sta n dar d err or; V , v ol u me of distri b uti o n .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
3 5
1. 5. 3.  
R ati o n ale f or t he V o xel ot or D ose t o be E v al u ate d i n C hil dre n 4 t o 1 1 Y e ars O l d 
i n P art C a n d C hil dre n 6
M o nt hs t o < 4 Y e ars O l d i n P art D
Partici pa nts (a ge d 1 2 t o < 1 8 y ears) i n Part B recei ve d 1 5 0 0 m g. C urre ntl y , partici pa nts i n Part C 
are recei vi n g v o xel ot or 1 5 0 0 m g o nce dail y or, if y o u n ger t ha n 1 2 ye ars of a ge or wit h wei g ht 
< 4 0 m g, a 1 5 0 0 -m g  e q ui vale nt o nce dail y usi n g a wei g ht-base d desi g n (see Ta ble 3 ). 
Partici pa nts i n Part D will recei ve a 1 5 0 0- m g  e q ui vale nt o nce dail y usi n g a wei g ht-base d desi g n 
(see Ta ble 3 ).
T a ble 3 :
V o xel ot or Wei g ht -B ase d D oses Deter mi ne d f or Pe di atric P artici p a nts 
P o p ul ati o n
V o xel ot or D oses
1 5 0 0 m g- E q ui v ale nt A d ult D ose
5 t o < 1 0 k g
4 0 0 m g
1 0 t o < 2 0 k g
6 0 0 m g
2 0 t o < 4 0 k g
9 0 0 m g
≥4 0 k g
1 5 0 0 m g
T he d oses of v o xel ot or t o be e val uate d i n Part s C a n d D of t his st u d y are base d o n tar geti n g 
cli nical efficac y i n a d ult a n d a d olesce nt partici pa nts, c o m bi ne d wit h p o p ulati o n P K ( P P K) 
m o deli n g, p h y si ol o gicall y base d P K ( P B P K) m o deli n g, a n d all o metric scali n g a n d are e x pecte d 
t o pr o vi de e x p os ures of v o xel ot or e q ui vale nt t o e x p os ures o bser ve d i n a d ults a n d a d olesce nts 
( St u d y G B T 4 4 0- 0 3 1) a n d a d olesce nts ( St u d y G B T 4 4 0- 0 0 7) f oll o wi n g m ulti ple d oses of 
1 5 0 0 m g.
T o esti mate a p pr o priate d oses t o be e val uate d i n pe diatric partici pa nts ( 6 m o nt hs t o < 1 2 y ears) 
wit h S C D, m ulti ple d oses of v o xel ot or we re si m ulate d b y  wei g ht gr o u p ( 1 0 t o < 2 0 k g a n d 2 0 t o 
< 4 0 k g). T he d ose si m ulati o ns were base d o n a v o xel ot or w h ole bl o o d P P K m o del , i ncl u di n g 
data fr o m a d ults, a d olesce nts, a n d c hil dre n a ge 6 t o 1 1 y ears ol d. T he m o del use d t he sa me 
m o del str uct ure ( 2 -c o m part me nt m o del wit h first - or der a bs or pti o n) as t he a d ult P P K m o del. T he 
cleara nce (C L ) a n d ce ntral v ol u me ( Vc) were scale d all o metrically (e x p o ne nts of 0. 7 5 f or C L  
a n d 1 f or Vc) base d o n partici pa nt wei g hts sa m ple d fr o m a ge- stratifie d n or mal distri b uti o ns f or 
c hil dre n wit h h o m oz yg o us S C D ( T h o mas, 2 0 0 0 ). S u m mar y e x p os ure metrics ( A U C, Cma x,ss , a n d 
mi ni m u m dr u g c o nce ntrati o n [ C mi n ],ss) i n c hil dre n ( 9 m o nt hs t o < 1 2 ye ars) were c o m pare d t o t he 
i nter q uartile ra n ge of e x p os ures si m ulate d f or t he e q ui vale nt d ose i n a d olesce nt partici pa nts . 
Wei g ht -base d gr o u ps were i de ntifie d t o tar get me dia n e x p os ures wit hi n t he a d olesce nt 
i nter q uartile ra n ge. Base d o n si m ulati o ns i n t he pe diatric p o p ulati o n, d oses of 4 0 0, 6 0 0, a n d 
9 0 0 m g, res pecti vel y, are s u p p orte d t o pr o vi de e x p os ures si milar t o a d olesce nt partici pa nts at 
1 5 0 0 m g. Pa rtici pa nts wit h wei g hts > 4 0 k g will recei ve t he sa me d ose as a d olesce nt or a d ult 
partici pa nts .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
3 6
1. 6.
Ris k Assess me nt
Base d o n t he mec ha nis m of acti o n of v o xel ot or a n d fi n di n gs i n t he n o ncli nical safet y  t o xic ol o g y 
st u dies, v o xel ot or c o ul d ca use tiss ue h y p o xia . I n G LP t o xic ol o g y  st u dies, rats d ose d f or 2 8 da ys 
wit h ≥2 5 0 m g/ k g/ da y  de m o nstrate d i ncrease d er yt hr op oieti n a n d re d cell mass ( he mat ocrit 
[Hct ], R B C, or H b) wit h e xtra me d ullar y he mat o p oiesis a n d b o ne marr o w h ypercell ularit y . T hese 
fi n di n gs are c o nsiste nt wit h e x pecte d p h ysi ol o gic c o m pe nsati o n t o h yp o xia, were well t olerate d 
i n t he rat, were n ot c o nsi dere d a d verse, a n d were re versi ble.
I n pri or cli nical e x perie nce wit h ot her a ge nts, n o a d verse reacti o ns relate d t o tiss ue h yp o xia were 
re p orte d at t he hi g hest teste d d oses of t ucares ol a d mi nistere d i n eit her healt h y partici pa nts
( ma xi m u m 4 0 % H b -m o dificati o n) or partici pa nts wit h S C D ( ma xi m u m 2 4 % H b -m o dificati o n), 
or B W 1 2 C i nf usi o ns i n eit her healt h y partici pa nts ( ma xi m u m 4 0 % H b -m o dificati o n) or 
partici pa nts wit h S C D ( 2 3 % H b m o dificati o n) (Ar y a, 1 9 9 6 ; Kei da n, 1 9 8 6 ; Nic h olls, 1 9 8 9 ;
R ola n, 1 9 9 5 ). A p pr o priate ac ute a n d c hr o nic c o m pe nsat or y  p h ysi ol o gic res p o nses t o tiss ue 
h y p o xia were o bser ve d, i ncl u di n g a n i ncrease i n heart rate d uri n g m o derate e xercise a n d a sli g ht 
i ncrease i n retic ul oc yte c o u nts at hi g h d oses (Nic h olls, 1 9 8 9 ; (R ola n, 1 9 9 5 ; R ola n, 1 9 9 3 ).
I m p orta ntl y, healt h y partici pa nts were well -c o m pe nsate d b ot h at rest a n d at near ma xi mal 
e xercise wit h little c ha n ge i n resti n g heart rate (Nic h olls, 1 9 8 9 ). P ote ntial tiss ue h y p o xia ca n be 
m o nit ore d b y he mat ol o g y  la b orat or y st u dies, er yt hr o p oieti n le vels, a n d car di o vasc ular 
para meters.
Gastr oi ntesti nal effects ( pri maril y  e mesis, a n d s oft or li q ui d feces) were o bser ve d i n all s pecies 
a n d were d ose-li miti n g i n d o gs a n d m o n ke y s. Gastr oi ntesti nal er osi o ns, ulcers, or e pit helial 
h y per plasia were o bser ve d at hi g h d oses i n rats.
T he m ost c o m m o n A E s wit h a n i nci de nce of at least 2 0 % were hea dac he a n d diarr hea
(Vic hi ns k y , 2 0 1 9). T he maj orit y  of t hese T E A Es were Gra de 1 or 2 i n se verit y. T he perce nta ges 
of partici pa nts w h o ha d a Gra de 3 e ve nt, a seri o us a d verse e ve nt ( S A E), a n d/ or treat me nt 
disc o nti n uati o n d ue t o a n A E di d n ot differ s u bsta ntiall y  a m o n g t he 3 treat me nt ar ms ( 1 5 0 0 m g 
v o xel ot or, 9 0 0 m g v o xel ot or , or place b o ). 
I n a d diti o n, t he decli ne i n er yt hr o p oieti n le vels s u g gest a n i m pr o ve me nt i n o x yge n deli ver y  
eit her b y i ncrease i n he m o gl o bi n or i m pr o ve me nt i n micr o vasc ular bl o o d fl o w, or b ot h
(Vic hi ns k y , 2 0 1 9; H o war d , 2 0 1 9).
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
3 7
2.
S T U D Y O B J E C TI V E S
2. 1.
P art A ( Si n gle D ose)
Part A of t he st u d y will i ncl u de partici pa nts 6 t o 1 7 years of a ge (i ncl usi ve). Part A will be 
di vi de d i nt o 2 c o h orts i n t his a ge ra n ge, C o h ort 1 ( 1 2 t o 1 7 y ears) a n d C o h ort 2 ( 6 t o 1 1 y ears).
2. 1. 1.
Pri m ar y O bjecti ve:

T o c haracterize t he P K of v o xel ot or i n plas ma a n d w h ole bl o o d f oll o wi n g a si n gle 
d ose i n pe diatric partici pa nt s wit h S C D 
2. 1. 2.
Sec o n d ar y O bjecti ve :

T o e val uate t he safet y a n d t olera bilit y of v o xel ot or f oll o wi n g a si n gle d ose i n 
pe diatric partici pa nt s wit h S C D
2. 2.
P art B ( M ulti ple D ose)
2. 2. 1.
Pri m ar y O bjecti ve:

T he pri mar y  o bjecti ve is t o assess t he efficac y of v o xel ot or i n pe diatric partici pa nt s 
wit h S C D as meas ure d b y  i m pr o ve me nt i n a ne mia
2. 2. 2.
Sec o n d ar y O bjecti ves :

T o pr o vi de data o n t he e P R O meas ure me nt i n esta blis hi n g t he l o n git u di nal 
meas ure me nt pr o perties of t he P R O 

T o e val uate t he effect of v o xel ot or o n cli nical meas ures of he m ol ys is 

T o c haracterize t he P K of v o xel ot or i n plas ma, w h ole bl o o d a n d re d bl o o d cells 
( R B Cs) f oll o wi n g m ulti ple d oses i n pe diatric partici pa nt s wit h S C D

T o e val uate t he safet y a n d t olera bilit y of v o xel ot or f oll o wi n g m ulti ple d oses i n 
pe diatric partici pa nt s wit h S C D

T o e val uate t he effect of v o xel ot or o n cere bral he m o d y na mics as assesse d b y  T C D 
ultras o n o gra p h y

T o e val uate t he effects of v o xel ot or o n S C D s y m pt o m e xacer bati o n a n d t otal 
s ym pt o m sc ore ( T S S) fr o m P R O meas ure me nt 
2. 3.
P art C ( M ulti ple D ose)
2. 3. 1.
Pri m ar y O bjecti ve

T o e val uate t he effect of v o xel ot or o n cere bral he m o d y na mics i n pe diatric 
partici pa nts wit h S C D wit h ele vate d or c o n di tio nal T C D fl o w vel ocit y as assesse d b y 
T C D ultras o n o gra p h y
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
3 8
2. 3. 2.
Sec o n d ar y O bjecti ve

T o e val uate t he effect of v o xel ot or o n cli nical meas ures of a ne mia a n d he m ol y sis

T o c haracterize t he P K of v o xel ot or i n plas ma, w h ole bl o o d a n d R B C s f oll o wi n g 
m ulti ple d oses i n pe diatric partici pa nt s wit h S C D

T o e val uate t he safet y a n d t olera bilit y of v o xel ot or f oll o wi n g m ulti ple d oses i n 
pe diatric partici pa nts wit h S C D

T o e val uate t he pr o p orti o n of partici pa nts wit h n or mal T C D fl o w vel ocit y  
( < 1 7 0 c m/sec b y n o ni ma gi n g T C D or < 1 5 5 c m/sec b y  T C Di) at 4 8 wee ks

T o e val uate t he effect of v o xel ot or o n t he i nci de nce of str o ke a n d vas o-occl usi ve 
crisis ( V O C)
2. 4.
P art D ( M ulti ple D ose)
2. 4. 1.
Pri m ar y O bjecti ve

T o e val uate t he safet y a n d t olera bilit y of v o xel ot or i n pe diatric partici pa nts wit h S C D
a ge d 6 m o nt hs t o < 4 y ears
2. 4. 2.
Sec o n d ar y O bjecti ve s

T o c haracterize t he P K of v o xel ot or i n plas ma, w h ole bl o o d , a n d R B Cs i n pe diatric 
partici pa nts wit h S C D a ge d 6 m o nt hs t o < 4 y ears

T o e val uate t he effect of v o xel ot or o n cli nical meas ures of a ne mia a n d he m ol y sis i n 
pe diatric partici pa nts wit h S C D a ge d 6 m o nt hs t o < 4 y ears

T o e val uate t he effect of v o xel ot or o n t he i nci de nce of str o ke a n d V O C i n pe diatric 
partici pa nts wit h S C D a ge d 6 m o nt hs t o < 4 y ears
2. 4. 3.
E x pl or at or y O bj ecti ve

T o e val uate t he effect of v o xel ot or o n gr o wt h a n d de vel o p me nt i n pe diatric 
partici pa nts wit h S C D a ge d 6 m o nt hs t o < 4 y ears
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
3 9
3.
I N V E S TI G A TI O N A L P L A N
3. 1.
St u d y Desi g n 
T his st u d y  is a n i nte grate d P hase 2a pr ot oc ol c o nsisti n g of 4 parts, Parts A , B, C , a n d D, w hic h 
will e x pl ore si n gle a n d m ulti ple d oses of v o xel ot or i n pe diatric partici pa nts wit h S C D. Pe diatric 
partici pa nts w h o are 6 t o 1 7 y ears of a ge will be i ncl u de d i n Part A, 1 2 t o 1 7 y ears of a ge i n 
Part B, 4 t o 1 7 years of a ge i n Part C, a n d 6 m o nt hs t o < 4 ye ars of a ge i n Part D.
3. 1. 1.
P art A ( Si n gle -D ose A d mi nistr ati o n ) 
T he St u d y  Sc he matic f or Part A is pr o vi de d i n Fi g ure 2 . A p pr o xi matel y  1 2 pe diatric partici pa nt s 
wit h S C D will partici pate i n Part A . 

A p pr o xi matel y  6 pe diatric partici pa nt s will be e nr olle d i nt o C o h ort 1: a ge 1 2 t o 
1 7 ye ars, i ncl usi ve.

A p pr o xi matel y  6 pe diatric partici pa nts will be e nr olle d i nt o C o h ort 2: a ge 6 t o 
1 1 ye ars, i ncl usi ve. A p pr o xi matel y  3 partici pa nts e nr olle d i nt o t he st u d y will be 
bet wee n t he a ges of 6 t o 8 y ears of a ge. A p pr o xi matel y  3 partici pa nts e nr olle d will be 
bet wee n t he a ges of 9 t o 1 1 years of a ge .
Partici pa nt s’ a ge will be t he a ge at t he ti me of t he asse nt/c o nse nt.
F oll o wi n g a 2 8 -d a y  Scree ni n g P eri o d, v o xel ot or will be a d mi nistere d orall y  o n Da y 1 a n d 
partici pa nt s will u n der g o P K sa m pli n g as i n dicate d i n t he S c he d ule of A ssess me nts 
(A p pe n di x 1 ).
Fi g ure 2:
P art A St u d y Sc he m atic
U p o n c o m pleti o n of partici pati o n of C o h ort 1 ( 1 2 – 1 7 y ear a ge gr o u p ) a n d C o h ort 2 ( 6 – 1 1 ye ar 
a ge gr o u p) i n Part A ( Si n gle D ose) of t he st u d y , partici pa nts ma y be eli gi ble f or partici pati o n i n 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
4 0
Part B or Part C. If a partici pa nt fr o m Part A wis hes t o partici pate i n Part B or Part C, t he y will 
be re q uire d t o c o m plete scree ni n g pr oce d ures f or Part B or Part C as a p pr o priate . T his will 
i ncl u de re-c o nse nti n g of eli gi ble partici pa nts f or partici pati o n i n Part B or Part C of t he st u d y . 
Part B partici pa nts will n ot be eli gi ble f or partici pati o n i n Part C. Please c o ns ult t he I nteracti ve 
Res p o nse S y ste m ma n ual f or f urt her i nf or mati o n.
3. 1. 2.
P art B ( M ulti ple-D ose A d mi nistr ati o n ) 
U p o n satisfact or y  re vie w of t he safety a n d P K data i n Part A as o utli ne d i n Secti o n 3. 5. 1 , Part B 
ma y  c o m me nce. A p pr o xi matel y 3 6 pe diatric partici pa nts wit h S C D w h o are 1 2 t o 1 7 ye ars of 
a ge will be e val uate d.

A mi ni m u m of 1 2 partici pa nts will be d ose d wit h 9 0 0 m g. E nr oll me nt at t he 9 0 0 m g 
d ose le vel ma y  c o nti n ue t o f urt her c haracterize t he effect of m ulti ple d oses of
v o xel ot or ( n ot t o e xcee d a total st u d y  size of a p pr o xi matel y 3 6). A mi ni m u m of 6 of 
t he partici pa nts at 9 0 0 m g will be 1 2 t o 1 4 y ears ol d.

U p o n a fa v ora ble re vie w b y t he D S M B , d osi n g a mi ni m u m of 6 partici pa nts at 
1 5 0 0 m g ma y  c o m me nce ( de pe n de nt o n h o w ma n y  partici pa nts were e nr olle d at 
9 0 0 m g, ie, n ot t o e xcee d a t otal st u d y  size of a p pr o xi matel y 3 6). A p pr o xi matel y  half 
of t he partici pa nts at 1 5 0 0 m g will be 1 2 t o 1 4 y ears ol d.
Partici pa nt s’ a ge will be t he a ge at t he ti me of t he asse nt/c o nse nt.
Partici pa nt s will recei ve m ulti ple d oses of v o xel ot or ( u p t o 2 4 wee ks ). F oll o wi n g a 3 5- d a y  
Scree ni n g P eri o d, pe diatric partici pa nt s will ret ur n t o t he cli nic o n Da y s 1, 2 a n d 8 a n d Wee ks
2, 
4, 8, 1 2, 1 6, 2 0 , a n d 2 4 (refer t o A p pe n di x 3 ). O n St u d y  D a y 1, partici pa nts will recei ve t heir first 
oral d ose of v o xel ot or (Fi g ure 3 ).
Fi g ure 3:
P art B M ulti ple -D ose S afet y St u d y Sc he m atic
Vo xe l ot or 9 0 0 oral QD f or 
2 4 we e k s
L a st 
D o s e
E O S  Visit 
( 4 we e k s 
af ter l ast 
do s e)
E O S = e n d of  st u d y; P K = p h a r ma c o ki netics ; 
Q D = o n c e d a il y
Tr e at me nt Pe rio d
S c re e ni ng Pe rio d
F o ll ow- U p
Vo xe l ot or 1 5 0 0 mg  oral Q D  
f or 2 4 we e k s
1 5 0 0 mg  dos i ng g a ted by  PK,   
a n d Safet y D at a Re vi e w
D a y - 3 5
D a y 1
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
4 1
3. 1. 3.
P art C ( M ulti ple-D ose A d mi nistr ati o n)
T he St u d y  Sc he matic f or Part C is pr o vi de d i n Fi g ure 4 . U p t o 5 0 pe diatric partici pa nt s w h o are 
4 t o 1 7 years of a ge wit h S C D will be e nr olle d.

At least 3 0 partici pa nts m ust ha ve a T C D vel ocit y ≥1 4 0 a n d < 2 0 0 c m/sec b y  
n o ni ma gi n g T C D ( ≥1 2 5 a n d < 1 8 5 c m/sec b y  T C Di) u p o n Scree ni n g A N D

At least 2 0 partici pa nts m ust be bet wee n 4 t o 1 1 years of a ge
Partici pa nt s’ a ge will be t he a ge at t he ti me of t he asse nt/c o nse nt.
D uri n g t he 3 5 -d a y scree ni n g peri o d, partici pa nts will u n der g o T C D assess me nt a n d t h ose w h o 
meet t he criteria f or T C D a n d t he rest of t he st u d y eli gi bilit y criteria will be eli gi ble f or treat me nt 
a n d will recei ve m ulti ple d oses of v o xel ot or ( u p t o 4 8 wee ks ).
F oll o wi n g c o m pleti o n of st u d y  treat me nt i n Part C , eli gi ble partici pa nts ma y be gi ve n t he o pti o n 
t o e nr oll i n a n o pe n-la bel e xte nsi o n st u d y ( u n der a se parate pr ot oc ol) t o recei ve v o xel ot or .
Fi g ure 4:
P art C M ulti ple -D ose Sc he m a
P art C : P ote nti al M o dific ati on
T o f urt her c haracterize a p ote ntial effect o n T C D data f or t h ose partici pa nts w h o ha ve a T C D 
vel ocit y  ≥1 4 0 a n d < 1 7 0 c m/sec b y  n o ni ma gi n g T C D ( ≥1 2 5 a n d < 1 5 5 c m/sec b y T C Di ) u p o n 
scree ni n g, a p pr o xi matel y 2 0 partici pa nts ma y  be a d de d wit h a T C D vel ocit y t hat falls wit hi n t his
ra n ge, de pe n di n g o n t he e mer gi n g data. I n t his e ve nt, Part C will c o ntai n u p t o 7 0 pe diatric 
partici pa nts.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
4 2
3. 1. 4.
P art D ( M ulti ple-D ose A d mi nistr ati o n)
T he St u d y  Sc he matic f or Part D is pr o vi de d i n Fi g ure 5 . A p pr o xi matel y 3 0 pe diatric partici pa nts 
w h o are 6 m o nt hs t o < 4 ye ars of a ge wit h S C D will be e nr olle d.

At least 1 0 partici pa nts m ust be 6 m o nt hs t o < 2 ye ars of a ge .
Partici pa nts’ a ge s will be deter mi ne d at t he ti me of t he asse nt/c o nse nt.
D uri n g t he 3 5 -d a y  scree ni n g peri o d, partici pa nts w h o meet t he st u d y eli gi bilit y criteria will be 
eli gi ble f or treat me nt a n d will recei ve m ulti ple d oses of v o xel ot or (f or u p t o 4 8 wee ks).
F oll o wi n g c o m pleti o n of st u d y  treat me nt i n Part D, eli gi ble partici pa nts ma y be gi ve n t he o pti o n 
t o e nr oll i n a n o pe n-la bel e xte nsi o n st u d y ( u n der a se parate pr ot oc ol) t o recei ve v o xel ot or .
Fi g ure 5:
P art D M ulti ple - Dose St u d y Sc he m atic
3. 2.
D ur ati o n of St u d y
F or Part A (si n gle d ose), partici pa nt partici pati o n is e x pecte d t o last u p t o 4 4 da y s, i ncl u di n g a 
2 8 -d a y  Scree ni n g P eri o d, o ne d osi n g da y, a n d t he 1 5 -d a y f oll o w-u p visit .
F or Part B ( m ulti ple d ose ), partici pa nt partici pati o n is e x pecte d t o last a p pr o xi matel y 3 3 wee ks
(i ncl u di n g a 3 5 -d a y  Scree ni n g P eri o d, a 2 4 -wee k d osi n g peri o d a n d a n E n d -of -St u d y (E O S) visit 
a p pr o xi matel y 4 wee ks after t he last d ose of st u d y dr u g ).
F or Part C ( m ulti ple d ose), partici pati o n is e x pecte d t o last a p pr o xi matel y 5 7 wee ks ( i ncl u di n g a 
3 5 -d a y  Scree ni n g P eri o d, a 4 8 -wee k d osi n g peri o d a n d a n E O S visit a p pr o xi matel y  4 wee ks after 
t he last d ose of st u d y dr u g f or partici pa nts w h o d o n ot e nr oll i n t he o pe n -la bel e xte nsi o n st u d y).
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
4 3
F or Part D ( m ulti ple d ose), partici pati o n is e x pecte d t o last a p pr o xi matel y 5 7 wee ks (i ncl u di n g a 
3 5 -da y  Scree ni n g Peri o d, a 4 8-wee k d osi n g peri o d , a n d a n E O S visit a p pr o xi matel y 4 wee ks after 
t he last d ose of st u d y dr u g f or partici pa nts w h o d o n ot e nr oll i n t he o pe n -la bel e xte nsi o n st u d y).
3. 3.
E n d -of -St u d y Visit
E O S pr oce d ures will be perf or me d at t he f oll o w- u p visit o n Da y  1 5 ± 1 da y  f or Part A ( si n gle-
d ose p orti o n ), at 4 wee ks ± 2 da ys after t he last d ose of st u d y dr u g (t he E O S vi sit) f or Part B a n d 
Part C ( m ulti ple-d ose p orti o n ), a n d at 4 wee ks ± 7 da y s after t he last d ose of st u d y dr u g (t he E O S 
v isit) f or Part D ( m ulti ple-d ose p orti o n) . F or Parts C a n d D, t he E O S visit will be perf or me d f or
partici pa nts w h o d o n ot e nr oll i nt o t he o pe n -la bel e xte nsi o n st u d y.
3. 4.
E arl y Ter mi n ati o n Visit
Partici pa nt s w h o ter mi nate fr o m t he st u d y earl y (earl y ter mi nati o n) will ha ve E O S pr oce d ures 
perf or me d at t he ti me of disc o nti n uati o n. Partici pa nt s wit h o n g oi n g cli nicall y si g nifica nt cli nical 
or la b orat or y  fi n di n gs will be f oll o we d u ntil t he fi n di n g is res ol ve d or me dicall y sta ble; 
reas o na ble atte m pts will be ma de t o f oll o w-u p wit h partici pa nt s. T he partici pa nt ’s partici pati o n 
will e n d o nce all st u d y  assess me nts a n d f oll o w-u p has bee n c o m plete d.
3. 5.
O n g oi n g S afet y a n d D at a Re vie w 
P K a n d safet y data fr o m st u d y  G B T 4 4 0-0 0 7 will be re vie we d o n a n o n g oi n g basis.
T he S p o ns or will re vie w P K a n d safet y data fr o m 6 partici pa nts e nr olle d i n Part A ( i n t he a ge 
gr o u p of 1 2 t o 1 7 y ears) after t he partici pa nts ha ve u n der g o ne a mi ni m u m of 8 da ys  of P K a n d 
safety data c ollecti o n pri or t o pr ocee di n g t o Part B of t he st u d y. I n t he e ve nt t he P K e x p os ure is 
n ot c o nsiste nt wit h tar get e x p os ure descri be d i n Secti o n 1. 5 , t he d ose f or Part B ma y  be 
m o difie d. Part B will n ot pr ocee d u ntil a f or mal re vie w of t he c o m plete d 8 da y s of P K a n d safety 
data of partici pa nts fr o m Part A ( i n t he a ge gr o u p of 1 2 t o 1 7 years) occ urs. 
T he S p o ns or will als o re vie w P K a n d safet y  data fr o m 6 partici pa nts e nr olle d i n Part A ( i n t he 
a ge gr o u p of 6 t o 1 1 ye ars) after t he partici pa nts ha ve u n der g o ne a mi ni m u m of 8 da y s of P K a n d 
safety data c ollecti o n.
3. 5. 1.
P art B S afet y Re q uire me nts f or D ose Esc al ati o n t o t he 1 5 0 0 m g Tre at me nt Ar m
Pri or t o pr ocee di n g fr o m t he v o xel ot or 9 0 0 m g d ose t o t he 1 5 0 0 m g d ose i n Part B, t he f oll o wi n g 
will ta ke place wit h data re vie ws c o nfir mi n g t he selecte d d ose t o be ge nerall y well t olerate d:

A re vie w of t he P K data fr o m at least 8 pe diatric partici pa nts e nr olle d i n Part B of 
St u d y  G B T 4 4 0-0 0 7 will ta ke place, f oll o wi n g at least 1 5 d a y s of d osi n g wit h 
v o xel ot or 9 0 0 m g .

D S M B re vie w of safety data fr o m at least 8 pe diatric partici pa nts e nr olle d i n Part B 
of St u d y G B T 4 4 0 -0 0 7 will ta ke place, f oll o wi n g t he c o m pleti o n of 2 8 d a y s of d osi n g 
wit h v o xel ot or 9 0 0 m g t o c o nfir m acce pta ble safet y a n d t olera bilit y.

D S M B re vie w of safety data fr o m t he first 6 a d ult partici pa nts at t he 1 5 0 0 m g d ose 
le vel fr o m Gr o u p 1 of St u d y G B T 4 4 0-0 3 1 ( H O P E st u d y ) will ta ke place, f oll o wi n g at 
least 2 8 da ys of d osi n g wit h st u d y dr u g t o c o nfir m acce pta ble safet y a n d t olera bilit y. 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
4 4
T he decisi o n t o pr ocee d fr o m t he v o xel ot or 9 0 0 m g d ose t o t he 1 5 0 0 m g d ose will be rec or de d i n 
a d ose decisi o n d oc u me nt t hat will be si g ne d b y  t he G B T 4 4 0-0 0 7 St u d y  Direct or/ Me dical 
M o nit or a n d rele va nt G B T pers o n nel .
3. 5. 2.
P art C
A D S M B m o nit ors t he safet y  a n d c o n d uct of a n o n g oi n g P hase 3, G B T 4 4 0- 0 3 1 i n a d ults a n d 
a d olesce nts (a ge d 1 2 – 1 7 y ears) o n a peri o dic basis. At a rece nt D S M B meeti n g safet y data fr o m 
1 5 4 partici pa nts treate d i n G B T 4 4 0 - 0 3 1 (ra n d o mize d t o place b o, 9 0 0 m g or 1 5 0 0 m g) a n d 
3 2 a d olesce nts e nr olle d i n t his o n g oi n g st u d y , G B T 4 4 0- 0 0 7 ( 2 5 at 9 0 0 m g a n d 7 at 1 5 0 0 m g)
were re vie we d . T his safet y re vie w i ncl u de d 3 4 a d olesce nts fr o m G B T 4 4 0 - 0 3 1. T he D S M B 
a gree d t hat t he safet y data s u p p orts c o nti n ue d treat me nt wit h b ot h v o xel ot or 9 0 0 m g a n d 
v o xel ot or 1 5 0 0 m g i n G B T 4 4 0 -0 3 1 a n d i n t his st u d y . T he D S M B als o a gree d t hat t he c u m ulati ve 
safety data fr o m a d ults a n d a d olesce n ts s u p p orts t he i nitiati o n of treat me nt of partici pa nts 4 t o 
< 1 2 y ears ol d wit h v o xel ot or . 
Safet y  data fr o m c hil dre n a ge d 4 t o 1 1 y ears of a ge will be m o nit ore d o n a n o n g oi n g basis b y 
G B T . A d diti o nall y, t he D S M B has re vie we d safet y data fro m Part C..
3. 5. 3.
P art D
Safet y  data fr o m c hil dre n a ge d 6 m o nt hs t o < 4 ye ars will be m o nit ore d o n a n o n g oi n g basis b y  
t he S p o ns or. 
I n a d diti o n, a D S M B ma y re vie w safety data fr o m Part D i n c o ns ultati o n wit h t he S p o ns or if 
warra nte d (see Secti o n 3. 7 ).
3. 6.
St o p pi n g R ules
I n di vi d u al P artici p a nt D isc o nti n u ati o n
D osi n g f or a n y i n di vi d ual partici pa nt will be st o p pe d if t he partici pa nt e x perie nces a S A E or a 
cli nicall y si g nifica nt n o nseri o us A E, w hic h i n t he o pi ni o n of t he Pri nci pal I n vesti gat or or 
S p o ns or’s Me dical M o nit or, warra nts disc o nti n uati o n of t he st u d y  f or t hat partici pa nt ’s well-
bei n g.
St u d y Disc o nti n u ati o n
T he occ urre nce of si g nifica nt safet y e ve nts will re q uire t hat f urt her d osi n g of partici pa nts be 
e val uate d b y t he Me dical M o nit or
t o deter mi ne st u d y disc o nti n uati o n. Si g nifica nt safet y  e ve nts 
ma y  i ncl u de t h ose w hic h are dee me d t o be relate d t o st u d y dr u g, ha ve n ot bee n descri be d i n t he 
v o xel ot or I B or ot her wise re prese nt a c o ncer n t o t he In vesti gat or or t he S p o ns or.
3. 7.
D at a a n d S afet y M o nit ori n g B o ar d
A n i n de pe n de nt D S M B will m o nit or t he safet y  a n d c o n d uct of t he trial. T he D S M B me m bers hi p 
will be c o m po se d of me dical a n d statist ical re prese ntati ves. T he D S M B ma y  pr o vi de 
rec o m me n dati o ns t o t he S p o ns or re gar di n g st o p pi n g t he st u dy or disc o nti n ui n g a treat me nt ar m 
or ot her wise m o dif y i n g t he st u d y desi g n or c o n d uct. 
T he D S M B f or t his st u d y will re vie w:
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
4 5

Safet y  data fr o m at least 8 pediatric partici pa nts e nr olle d i n Part B of St u d y  
G B T 4 4 0 -0 0 7, f oll o wi n g t he c o m pleti o n of 2 8 da ys of d osi n g wit h v o xel ot or 9 0 0 m g 
t o c o nfir m acce pta ble safet y a n d t olera bilit y.

Safet y  data o n a peri o dic basis as defi ne d i n t he D S M B C harter. 
Sites will be i nf or me d of t he D S M B rec o m me n dati o ns o nl y if t he rec o m me n dati o ns lea d t o 
c ha n ges i n t he st u d y c o n d uct. 
T he c o m p ositi o n, res p o nsi bilities, a n d ot her details of t he D S M B will be descri be d i n a D S M B 
C harter as a p pr o priate f or eac h part of t he st u d y .
Pri or t o pr ocee di n g fr o m t he 9 0 0 m g d ose t o t he 1 5 0 0 m g d ose i n Part B, t he f oll o wi n g D S M B 
re vie w will als o ta ke place:

A re vie w of safet y  data fr o m t he first 6 a d ult partici pa nts at t he 1 5 0 0 m g d ose le vel 
fr o m Gr o u p 1 fr o m t he H O P E St u d y , f oll o wi n g at least 2 8 d a y s of d osi n g wit h st u d y 
dr u g, t o c o nfir m acce pta ble safet y a n d t olera bilit y.
P art C: T he D S M B re vie we d safet y data a n d a gree d t hat t he c u m ulati ve safet y data fr o m a d ults 
a n d a d olesce nts e nr olle d i n G B T 4 4 0 -0 3 1 a n d G B T 4 4 0 -0 0 7 s u p p orts t he i nitiati o n of tre at me nt of 
partici pa nts 4 t o < 1 2 y ears ol d wit h v o xel ot or . 
P art D: T he D S M B has re vie we d safet y data fr o m Part C a n d a gree d t hat t he c u m ulati ve data 
s u p p ort t he i nitiati o n of treat me nt i n partici pa nts a ge d 2 t o < 4 y ears. I n a d diti o n, e nr oll me nt of 
partic i pa nts a ge d 6 m o nt hs t o < 2 y ears will c o m me nce after S p o ns or re vie w of safety, 
t olera bilit y, a n d P K data fr o m ≥6 partici pa nts a ge d 2 t o < 4 y ears w h o were treate d wit h 
v o xel ot or f or ≥2 8 da y s fr o m Part D of t his st u d y  or ot her G B T st u dies. T he D S M B ma y  be 
c o ns ulte d if warra nte d.
3. 8.
E n d of St u d y
T he e n d of st u d y ( E O S) is defi ne d as t he date w he n t he last partici pa nt has c o m plete d all st u d y  
pr oce d ures u p t o a n d i ncl u di n g t he fi nal st u d y/ earl y ter mi nati o n visit as o utli ne d i n t he Sche d ule 
of Assess me nts ( A p pe n di x 1 f or Part A, A p pe n di x 3 f or Part B, A p pe n di x 5 f or Part C , a n d 
A p pe n di x 7 f or Part D).
3. 9.
E n d p oi nts
3. 9. 1.
E n d p oi nts f or P art A
3. 9. 1. 1.
Pri m ar y E n d p oi nts

Ma xi m u m o bser ve d c o nce ntrati o n ( C ma x ), area u n der t he c o nce ntrati o n -ti me c ur ve
fr o m ti me zer o t o t he ti me of t he last q ua ntifia ble c o nce ntrati o n ( A U C 0- last), a n d area 
u n der t he c o nce ntrati o n- ti me c ur ve fr o m ti me zer o e xtra p olate d t o i nfi nit y (A U C 0- i nf)
of v o xel ot or i n w h ole bl o o d 
3. 9. 1. 2.
Sec o n d ar y E n d p oi nts

C ma x , A U C0- last, a n d A U C 0- i nf of v o xel ot or i n plas ma a n d R B C
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
4 6

T he ti me of ma xi m u m c o nce ntrati o n ( Tma x ), ter mi nal eli mi nati o n half-life (t1/ 2), 
perce nt H b occ u pa nc y
3. 9. 1. 3.
S afet y E n d p oi nts

T E A Es a n d S A Es

Cli nical la b orat or y  tests, p h ysical e xa mi nati o n fi n di n gs, vital si g ns, a n d E C Gs
3. 9. 2.
E n d p oi nts f or P art B
3. 9. 2. 1.
Pri m ar y E n d p oi nts

C ha n ge fr o m baseli ne t o Wee k 2 4 i n H b
3. 9. 2. 2.
Sec o n d ar y E n d p oi nts

Pr o p orti o n of d a y s wit h S C D s y m pt o m e xacer bati o n d uri n g t he first 2 4 wee ks of 
treat me nt. 

C ha n ge fr o m Baseli ne t o Wee ks 2 1 – 2 4 i n t he S C D S M T S S; f or eac h partici pa nt, t he 
T S S will be c o m p ute d as f oll o ws: T he Baseli ne T S S is t he a vera ge of t he sc ore 
d uri n g t he 3 5- d a y  Scree ni n g peri o d; d uri n g t he treat me nt peri o d, t he T S S is t he 
a vera ge sc ore eac h 4 - wee k peri o d o n treat me nt. T he 4 -wee k peri o ds are Wee ks 1 – 4, 
5 – 8, 9 – 1 2, 1 3 – 1 6, 1 7 – 2 0 a n d 2 1 – 2 4 (a n d f oll o ws si m ilarl y f or partici pa nts w h ose 
partici pati o n e xcee ds 2 4 wee ks).

C ha n ge fr o m baseli ne t o Wee k 2 4 i n
L D H, i n direct bilir u bi n a n d retic ul oc y te c o u nt 

V o xel ot or P K ( C ma x , A U C0- last, A U C 0- i nf, A U C 0- 2 4, t1/ 2, acc u m ulati o n rati o, 
bl o o d/ plas ma rati o, R B C/ plas ma ra ti o, if a p pr o priate), a n d perce nt H b occ u pa nc y

C ha n ge fr o m baseli ne t o 1 2 a n d 2 4 wee ks i n cere bral bl o o d fl o w as meas ure d b y t he 
ti me-a vera ge d mea n of t he ma xi m u m ( T A M M ) T C D vel ocit y
3. 9. 2. 3.
S afet y E n d p oi nts 

T E A Es a n d S A Es

Cli nical la b orat or y  tests, vital si g ns, a n d E C Gs
3. 9. 3.
E n d p oi nts f or P art C
3. 9. 3. 1. 
P ri m ar y E n d p oi nt

C ha n ge fr o m baseli ne t o 4 8 wee ks i n cere bral bl o o d fl o w as meas ure d by t he 
T A M M T C D vel ocit y
3. 9. 3. 2. 
Sec o n d ar y E n d p oi nts

C ha n ge fr o m baseli ne t o Wee k s 2 4 a n d 4 8 i n H b, L D H, i n direct bilir u bi n , a n d 
retic ul oc yte c o u nt 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
4 7

C ha n ge fr o m baseli ne t o 2 4 wee ks i n cere bral bl o o d fl o w as meas ure d by t he 
T A M M T C D vel ocit y

Ti me t o i nitial H b res p o nse, defi ne d as c ha n ge fr o m baseli ne i n H b > 1 g/ d L

W h ole bl o o d a n d plas ma v o xel ot or P K ( C ma x , A U C, t1/ 2,), a n d perce nt H b occ u pa nc y

Pr o p orti o n of partici pa nts wit h n or mal T C D fl o w vel ocit y  ( < 1 7 0 c m/sec b y  
n o ni ma gi ni n g T C D or < 1 5 5 c m/sec b y T C Di ) at 4 8 wee kI nci de nce of str o ke a n d 
V O C d uri n g t he st u d y
3. 9. 3. 3.
S afet y E n d p oi nts

T E A Es a n d S A Es

Cli nical la b orat or y  tests, vital si g ns, a n d E C Gs
3. 9. 4.
E n d p oi nts f or P art D
3. 9. 4. 1.
Pri m ar y E n d p oi nts

T E A Es a n d S A Es
3. 9. 4. 2.
Sec o n d ar y E n d p oi nts

W h ole bl o o d a n d plas ma v o xel ot or P K ( C ma x , A U C, t1/ 2, if a p pr o priate) a n d perce nt 
H b occ u pa nc y

C ha n ge fr o m baseli ne t o Wee k 2 4 a n d Wee k 4 8 i n H b, L D H, i n direct bilir u bi n, a n d 
retic ul oc yte c o u nt

Ti me t o i nitial H b res p o nse, defi ne d as c ha n ge fr o m baseli ne i n H b > 1 g/ d L

I nci de nce of str o ke a n d V O C d uri n g t he st u d y
3. 9. 4. 3.
E x pl or at or y E n d p oi nts

Gr o wt h a n d de vel o p me nt as assesse d b y c ha n ge fr o m baseli ne t o Wee ks 2 4 a n d 4 8 i n 
hei g ht, wei g ht , a n d hea d circ u mfere nce
3. 9. 4. 4.
S afet y E n d p oi nts

Cli nical la b orat or y  tests a n d vital si g ns
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
4 8
4.
S T U D Y P O P U L A TI O N
4. 1.
I ncl usi o n Criteri a
All partici pa nt s m ust meet t he f oll o wi n g i ncl usi o n criteria:
1.
Male or fe male
wit h h o m oz y g o us he m o gl o bi n S S ( H b S S) or he m o gl o bi n S beta 0
t halasse mia ( H b S β0 t hal).
2.
A ge:

Part A – 6 t o 1 7 y ears of a ge ( C o h ort 1 [ 1 2- 1 7] a n d C o h ort 2 [ 6- 1 1] as defi ne d i n t he 
St u d y  Desi g n)

Part B – 1 2 t o 1 7 y ears of a ge

Part C – 4 t o 1 7 years of a ge

Part D – 6 m o nt hs t o < 4 ye ars of a ge
3.
H U t hera p y:

Parts A, B , a n d C – A partici pa nt ta ki n g H U m a y  be e nr olle d if t he d ose has bee n 
sta ble f or at least 3 m o nt hs wit h n o a ntici pate d nee d f or d ose a dj ust me nts d uri n g t he 
st u d y a n d n o si g n of he mat ol o gical t o xicit y.

Part D – A partici pa nt ta ki n g H U ma y  be e nr olle d if t he d ose has bee n sta ble f or at 
least 1 m o nt h. Titrati o n t o t he ma xi m u m t olerate d d ose ( M T D) is all o we d d uri n g t he 
st u d y.
4.
He m o gl o bi n ( H b):

Part A – N o restricti o n

Part B – H b ≤1 0. 5 g/ d L

Part C – H b ≤1 0. 5 g/ d L

Part D – H b ≤1 0. 5 g/ d L
5.
Writte n i nf or me d pare ntal /g uar dia n c o nse nt a n d partici pa nt asse nt has bee n o btai ne d per 
i nstit uti o nal re vie w b oar d (IR B) / Et hics C o m mittee ( E C) p olic y  a n d re q uire me nts, 
c o nsiste nt wit h I C H g ui deli nes .
6.
Partici pa nts i n Part B ( o nl y) of t he st u d y m ust c o m plete a mi ni m u m of 1 4 da y s wit h 
e P R O t o be e nr olle d. I n vesti gat or discreti o n will be use d t o deter mi ne if a partici pa nt 
w h o has pre vi o usl y bee n scree n faile d d ue t o a lac k of baseli ne e P R O data c ollecti o n ca n 
be i n vite d bac k f or re -scree ni n g.
7.
If se x uall y acti ve a n d fe male, m ust a gree t o a bstai n fr o m se x ual i nterc o urse or t o use a 
hi g hl y effecti ve met h o d of c o ntrace pti o n t hr o u g h o ut t he st u d y peri o d a n d f or 3 0 d a y s 
after disc o nti n uati o n of st u d y  dr u g. If se x uall y acti ve a n d male, m ust a gree t o a bstai n 
fr o m se x ual i nterc o urse or willi n g t o use barrier met h o ds of c o ntrace pti o n t hr o u g h o ut t he 
st u d y peri o d a n d f or 3 0 da ys after disc o nti n uati o n of st u d y dr u g. Refer t o Secti o n 8. 5 .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
4 9
8.
Fe males of c hil d -beari n g p ote ntial are re q uire d t o ha ve a ne gati ve pre g na nc y  test bef ore 
t he a d mi nistrati o n of st u d y dr u g.
9.
S ufficie nt ve n o us access t o per mit c ollecti o n of P K sa m ples a n d m o n it ori n g of la b orat or y 
safety varia bles, i n t he o pi ni o n of t he I n vesti gat or.
1 0. F or Part C o nl y:  partici pa nts 1 2 t o 1 7 years of a ge m ust ha ve a T C D vel ocit y  ≥
1 4 0 c m/sec b y  n o ni ma gi n g T C D or ≥1 2 5 c m/sec b y T C Di meas ure d a n yt i me d uri n g 
scree ni n g.
4. 2.
E xcl usi o n Cri teri a
A n y  partici pa nt w h o meets o ne or m ore of t he f oll o wi n g criteria will be e xcl u de d fr o m 
partici pati o n:
1.
A n y  o ne of t he f oll o wi n g re q uiri n g me dical atte nti o n wit hi n 1 4 da y s of si g ni n g t he 
i nf or me d c o nse nt f or m (I C F):

Vas o -occl usi ve crisis ( V O C)

Ac ute c hest s yn dr o me ( A C S)

S ple nic se q uestrati o n crisis

Dact yl itis
2.
R e q uires c hr o nic tra nsf usi o n t hera p y.
3.
Hist or y  of str o ke or meeti n g criteria f or pri mar y str o ke pr o p h yla xis ( hist or y of t w o T C D 
meas ure me nts ≥2 0 0 c m/sec b y  n o ni ma gi n g T C D or ≥1 8 5 c m/sec b y T C Di).

F or t he p ote ntial m o dificati o n , a d diti o n of a p pr o xi matel y 2 0 partici pa nts e nr olle d i n 
Part C, T C D ≥1 7 0 c m/sec b y  n o ni ma gi n g T C D or ≥1 5 5  c m/sec by T C Di
4.
Tra nsf usi o n wit hi n 3 0 da y s pri or t o si gni n g t he I C F .
5.
Re nal d y sf u ncti o n re q uiri n g c hr o nic dialys is or creati ni ne ≥1. 5 m g/ d L .
6.
He patic d ys f u ncti o n c haracterize d by ala ni ne a mi n otra nsferase ( A L T) > 4 × u p per li mit of 
n or mal ( U L N) f or a ge .
7.
C li nicall y rele va nt car diac a b n or mality, i n t he o pi ni o n of t he I n vesti gat or, s uc h as:

He m o d y na micall y si g nifica nt heart disease, e g, c o n ge nital heart defect, 
u nc o m pe nsate d heart fail ure, or a n y u nsta ble car diac c o n diti o n .

A n arr h yt h mic heart c o n diti o n re q uiri n g me dical t hera p y.
8.
Q Tc F > 4 5 0 msec , c o n ge nital l o n g Q T s y n dr o me, sec o n d or t hir d de gree heart bl oc k at 
rest ( wit h t he e xce pti o n of asy m pt o matic M o bitz t y p e I  sec o n d de gree heart bl oc k).
9.
Recei ve d a n i n vesti gati o nal dr u g wit hi n 3 0 da y s or 5 half-li ves, w hic he ver is l o n ger, of 
si g ni n g t he I C F.
1 0. H ea v y s m o ker ( defi ne d as s m o ki n g m ore t ha n 1 0 ci garettes/ da y  or its nic oti ne e q ui vale nt
i ncl u di n g e-ci garettes).
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
5 0
1 1. U nli kel y  t o c o m ply wit h t he st u d y pr oce d ures .
1 2. O t her me dical, psyc h ol o gical or a d dicti ve c o n diti o n t hat, i n t he o pi ni o n of a n 
I n vesti gat or, w o ul d c o nf o u n d or i nterfere wit h e val uati o n of safet y a n d/ or P K of t he 
i n vesti gati o nal dr u g, pre ve nt c o m plia nce wit h t he st u d y pr ot oc ol, or precl u de i nf or me d 
c o nse nt.
1 3. Partici pa nt s w h o d o n ot ha ve a T C D wi n d o w (Part B a n d Part C o nl y) (ie, partici pa nts
w h o are u na ble t o ha ve a T C D d ue t o s k ull ossificati o n) .
1 4. F or Part C o nl y, p ri or partici pati o n i n Part B.
1 5. A cti ve s ym pt o matic C O VI D -1 9 i nfecti o n.
I n a d diti o n, f or Part D o nl y :
1 6. B o d y  wei g ht < 5 k g f or 1 m o nt h pri or t o t he scree ni n g visit a n d at t he scree ni n g visit.
1 7. A n y  c o n diti o n affecti n g dr u g a bs or pti o n, s uc h as maj or s ur ger y  i n v ol vi n g t he st o mac h or 
s mall i ntesti ne ( pri or c h olec ystect o my is acce pta ble).
1 8. Hist or y  of mali g na nc y wit hi n t he past 2 years pri or t o treat me nt Da y 1 re q uiri n g 
c he m ot hera p y a n d/ or ra diati o n ( wit h t he e xce pti o n of l ocal t h era p y f or n o n -mela n o ma 
s ki n mali g na nc y).
1 9. Cli nicall y  si g nifica nt bacterial, f u n gal, parasitic, or viral i nfecti o n c urre ntly recei vi n g or 
t hat will re q uire t hera p y.

Partici pa nts wit h ac ute bacterial i nfecti o n re q uiri n g a nti bi otic use s h o ul d dela y  
scree ni n g until t he c o urse of a nti bi otic t hera p y has bee n c o m plete d a n d t he i nfecti o n 
has res ol ve d, i n t he o pi ni o n of t he i n vesti gat or.

K n o w n acti ve he patitis A, B, or C i nfecti o n or h u ma n i m m u n o deficie nc y  vir us 
( HI V)-p ositi ve.

K n o w n acti ve malaria.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
5 1
5.
S T U D Y P R O C E D U R E S A N D E V A L U A TI O N S
5. 1.
P artici p a nt Scree ni n g
A si g n e d a n d date d i nf or me d pare ntal/ g uar dia n c o nse nt a n d partici pa nt asse nt m ust be o btai ne d 
bef ore a n y scree ni n g pr oce d ures or st u d y -s pecific tests ma y be perf or me d. E val uati o ns o btai ne d 
as part of r o uti ne me dical ca re a n d perf or me d d uri n g t he Scree ni n g P eri o d ma y be use d i n place 
of t he st u d y -s pecific e val uati o ns, pr o vi de d t he y meet t he ti me wi n d o ws descri be d bel o w.
Partici pa nt s will ac k n o wle d ge a n d a gree t o t he p ossi ble use of t his i nf or mati o n f or t he st u d y b y 
gi vi n g i nf or me d c o nse nt.
All partici pa nt s w h o si g n c o nse nt will be gi ve n a u ni q ue st u d y n u m ber. T his n u m ber will be use d 
t o i de ntif y t he partici pa nt t hr o u g h o ut t he cli nical st u d y a n d m ust be use d o n all st u d y 
d oc u me ntati o n relate d t o t hat partici pa nt .
T he Scree ni n g P eri o d f or a partic ular partici pa nt c o m me nces at t he p oi nt at w hic h t he partici pa nt
u n der g oes t he first st u d y -s pecific scree ni n g assess me nt a n d m ust be c o m plete d wit hi n 2 8 d a y s 
after si g ni n g t he I C F f or Part A, wit hi n 3 5 da y s after si g ni n g t he I C F f or Part s B, C, a n d D.
All st u d y  visits are t o be sc he d ule d relati ve t o t he Da y 1 visit date.
5. 2.
Electr o ni c P atie nt R e p orte d O utc o mes (e P R O) Scree ni n g
Partici pa nts i n Part B ( o nl y ) of t he st u d y will be gi ve n a n eP R O de vice d uri n g t he S cree ni n g
Peri o d. T o esta bli s h a baseline e P R O Sic kle Cell Disease Se verit y  (S C D S ) Meas ure, 
partici pa nt s m ust c o m plete a mi ni m u m of 1 4 da y s wit h e P R O t o be e nr olle d . In vesti gat or 
discreti o n will be use d t o deter mi ne if a partici pa nt w h o has pre vi o usl y bee n scree n faile d d ue t o 
a lac k of baseli ne e P R O data c ollecti o n ca n be i n vite d bac k f or re -scree ni n g.
5. 3.
Cli nic al Assess me nts
Scree ni n g assess me nt m ust be c o n d ucte d wit hi n 2 8 da y s pri or t o i nitiati o n of d osi n g f or Part A, 
a n d wit hi n 3 5 da y s pri or t o i nitiati o n of d osi n g f or Parts B, C, a n d D. La b orat or y assess me nts, 
vital si g ns a n d p h ys ical e xa mi nati o ns c o n d ucte d o n Da y 1 pre d ose m a y  be c o n d ucte d o n Da y - 1.
Refer t o A p pe n di x 1 , A p pe n di x 3 , A p pe n di x 5 , a n d A p pe n di x 7 f or a d diti o nal details.
Cli nical assess me nts, i ncl u di n g wei g ht, vital si g ns, E C Gs, A E s, a n d c o nc o mita nt me dicati o ns 
will be c o n d ucte d at s pecifie d ti me p oi nts d uri n g t he st u d y  (refer t o A p pe n di x 1 , A p pe n di x 3 , 
A p pe n di x 5 , a n d A p pe n di x 7 ). Vital si g ns data t o be c ollecte d i ncl u de s u pi ne s yst olic a n d 
diast ol ic bl o o d press ure, p ulse rate, res pirati o n rate a n d te m perat ure (i n º C). 1 2-lea d E C Gs will 
be c ollecte d i n tri plicate. A n y  ot her me dical c o n diti o n prese nt at baseli ne s h o ul d be f oll o we d 
d uri n g t he st u d y, a n d a c ha n ge fr o m t he baseli ne stat us (i nte nsit y  or fre q ue nc y) s h o ul d be 
re p orte d as a n A E if dee me d cli nicall y si g nifica nt b y t he In vesti gat or ( refer t o Secti o n 9 ).
Hei g ht a n d wei g ht will be rec or de d as o utli ne d i n A p pe n di x 1 ,A p pe n di x 3 , A p pe n di x 5 , a n d 
A p pe n di x 7 . T here is n o wei g ht restricti o n f or Parts A, B, or C of t he st u d y. Hei g ht (i n 
ce nti meters) a n d wei g ht (i n kil o gra ms) s h o ul d be meas ure d wit h t he partici pa nt’s s h oes off. Hea d 
circ u mfere nce will be rec or de d i n Part D as o utli ne d i n A p pe n di x 7 .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
5 2
5. 4.
S afet y Assess me nts
5. 4. 1.  
Cli nic al L a b or at or y St u dies
It is t he res p o nsi bilit y of t he In vesti gat or t o assess t he cli nical si g nifica nce of all a b n or mal
cli nical la b orat or y val ues as defi ne d b y t he list of n or mal val ues o n file f or t he l ocal cli nical 
la b orat or y. All cli nically si g nifica nt la b orat or y val ue a b n ormalities are t o be rec or de d as A Es.
F or t he p ur p ose of t his st u d y, a cli nicall y si g nifica nt la b orat or y val ue will be a n y a b n or mal res ult 
t hat, i n t he j u d g me nt of t he I n vesti gat or, is a n u ne x pecte d or u ne x plai ne d la b orat or y val ue or if 
me dical i nter ve nti o n or c orrecti ve acti o n (tra nsf usi o n, h y drati o n, i nitiati o n of a nti bi otics or ot her 
c o nc o mita nt me dicati o n) is re q uire d. A n y a b n or mal val ues t hat persist s h o ul d be f oll o we d at t he 
discreti o n of t he I n vesti gat or.
A d diti o nal a n d re peat la b orat or y  safety testi n g f or t he e val uati o n of a b n or mal res ults a n d/ or A E s 
d uri n g t he st u d y ma y be perf or me d at t he discreti o n of t he I n vesti gat or or u p o n re q uest of t he 
S p o ns or. Re peat la b orat or y  testi n g of a b n or mal p ote ntiall y cli nically si g nifica nt or cli nical l y 
si g nifica nt res ults f or t he s cree ni n g e val uati o n of t he partici pa nt m a y  be re peate d o nce at t he 
discreti o n of t he I n vesti gat or.
All la b orat or y  safety testi n g will be perf or me d b y t he l ocal la b orat or y .
Refer t o A p pe n di x 1 , A p pe n di x 3 , A p pe n di x 5 , a n d A p pe n di x 7 , Sc he d ule (s) of St u d y  
Assess me nts, f or all ti me p oi nts.
T he cli nical l a b orat or y tests t hat will be perf or me d are liste d i n Ta ble 4 f or Parts A, B, a n d C,
a n d i n Ta ble 5 f or Part D.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
5 3
T a ble 4 :
P art s A, B, a n d C: Cli nic al L a b or at or y Tests
H e m at ol o g y
Ser u m C he mistr y
Uri ne
Ot her

H e m at ocrit

H e m o gl o bi n

M C V

Platelet c o u nt

R B C c o u nt

R B C distri b uti o n 
wi dt h

Retic ul oc yte c o u nt 
( perce nt)

W B C c o u nt wit h 
differe ntial ( bas o p hils, 
e osi n o p hils, 
ne utr o p hils, 
m o n oc ytes, 
l y m p h oc ytes)

H b electr o p h oresis d

Al b u mi n

Al kali ne p h os p hatase

A L T

A S T

Bicar b o nate

Bilir u bi n ( t otal, direct, 
a n d i n direct )

B U N

Calci u m c

C hl ori de

C h olester ol
c

C P K c

Creati ni ne

Ferriti n c

G G T c

Gl uc ose

Ir o n c

L D H

Ma g nesi u m
c

P h os p h or us c

P otassi u m

Ser u m er yt hr o p oieti n

S o di u m

TI B C c

T otal pr otei n

Tra nsferri n c

Tri gl yceri des
c

Uric aci d
c

p H

S pecific gra vit y

B l o o d

G l uc ose

P r otei n

K et o nes

B ilir u bi n

U r o bili n o ge n

N itrite

L e u k oc ytes

M icr osc o pic 
e xa mi nati o n of 
se di me nt, if 
cli nicall y 
i n dicate d

C oa g ulati o n pa nel 
( P T, P T T, I N R) a

P re g na nc y test b
A b bre viati o ns: A L T, a la ni ne a mi n otra nsferase; A S T, as partate a mi n otra nsferase; B U N, bl o o d urea nitr o ge n; 
C P K, creati ne p h os p h o ki nase; G G T, ga m ma -gl uta m yl tra nsferase; H b, he m o gl o bi n; I N R, i nter nati o nal n or malize d 
rati o; L D H, lactate de h y dr o ge nase; M C V, m ea n c or p usc ular v ol u me ; P T, pr ot hr o m bi n ti me; P T T, partial 
t hr o m b o plasti n ti me; R B C, red bl o o d cell; TI B C, t otal ir o n -bi n di n g ca pacit y ; W B C, w hite bl o o d cell.
a C oa g ulati o n pa nel will o nl y be c ollecte d at Scree ni n g i n Parts A a n d B a n d n ot i n Part C.
b Pre g na nc y tests will be perf or me d f or fe male partici pa nts w h o are p ost me narc he. A ser u m β-h u ma n c h ori o nic 
g o na d otr o pi n pre g na nc y test will be perf or me d at Scree ni n g a n d uri ne pre g na nc y tests will be perf or me d pri or t o 
t he first d ose of st u d y dr u g a n d at ot her ti mes d uri n g t he st u d y.
c T hese tests will be perf or me d at Scree ni n g a n d more fre q ue ntl y if cli nicall y i n dicate d .
d H b electr o p h oresis w ill be perf or me d at Scree ni n g o nl y.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
5 4
T a ble 5 :
P art D: Cli nic al L a b or at or y Tests
H e m at ol o g y
Ser u m C he mistr y

H e m at ocrit

H e m o gl o bi n

M C V

Platelet c o u nt

R B C c o u nt

R B C distri b uti o n wi dt h

Retic ul oc yte c o u nt (a bs ol ute a n d perce nt)

W B C c o u nt wit h differe ntial ( bas o p hils, e osi n o p hils, 
ne utr o p hils, m o n oc ytes, l y m p h oc ytes)

H b electr o p h oresis a

Al b u mi n

Al kali ne p h os p hatase

A L T

A S T

Bicar b o nate

Bilir u bi n ( t otal, direct, a n d i n direct)

B U N

Calci u m b

C hl ori de

Creati ni ne

G G T
b

Gl uc ose

L D H

Ma g nesi u m
b

P h os p h or us b

P otassi u m

Ser u m er yt hr o p oieti n

S o di u m

T otal pr otei n
A b bre viati o ns: A L T, a la ni ne a mi n otra nsferase; A S T, as partate a mi n otra nsferase; B U N, bl o o d urea nitr o ge n; 
G G T, ga m ma -gl uta m yl tra nsferase; H b, he m o gl o bi n; L D H, lactate de h y dr o ge nase; M C V, m ea n c or p usc ular 
v ol u me ; R B C, re d bl o o d cell; W B C, w hite bl o o d cell.
a H b electr o p h oresis will be perf or me d at Scree ni n g o nl y.
b T hese tests will be perf or me d at Scree ni n g a n d m ore fre q ue ntl y if cli nicall y i n dicate d.
5. 4. 2.
He m o gl o bi n Ge n ot y pe
T he In vesti gat or or desi g nee will rec or d t he partici pa nt’s hist orical H b ge n ot y pe.
5. 4. 3.
E x pl or at or y Assess me nts (P art C o nl y)
Pri or t o i m ple me ntati o n of Pr ot oc ol A me n d me nt 7, bl o o d sa m ples f or t he assess me nt of rele va nt 
meas ures of S C D pat h o p h y si ol o g y (e g, R B C def or ma bilit y , R B C p h os p hati d y lseri ne, a n d de nse 
cells) were c ollecte d at select st u d y ce nters. U n der Pr ot oc ol A me n d me nt 7, t hese assess me nts 
will n o l o n ger be perf or me d.
5. 4. 4.
Vit al Si g ns
Vital si g ns will be meas ure d at t he ti me p oi nts s pecifie d i n A p pe n di x 1 , A p pe n di x 3 , 
A p pe n di x 5 , a n d A p pe n di x 7 .
Bl o o d press ure a n d p ulse rate will be meas ure d after t he partici pa nt has bee n resti n g f or at least 
5 mi n utes i n t he seate d or s u pi ne p ositi o n. S y st olic a n d diast olic bl o o d press ure will be meas ure d 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
5 5
usi n g a cali brate d ma n ual or a ut o matic bl o o d press ure de vi ce. P ulse rate will be rec or de d by 
pal pati o n of t he ra dial p ulse o ver a 6 0 -sec o n d peri o d or b y t he a ut o mate d bl o o d press ure de vice.
B o d y te m perat ure will be meas ure d ( oral, t y m pa nic, or a xillar y ) usi n g a di gital t her m o meter a n d 
rec or de d i n de grees Celsi us.
A n y  scree ni n g or pre d ose vital si g n o utsi de t he n or mal ra n ge ma y  be re peate d o nce (i n d u plicate) 
at t he discreti o n of t he In vesti gat or.
5. 4. 5.
Electr oc ar di o gr a ms ( E C Gs)
T wel ve -lea d E C Gs will be c ollecte d i n tri plicate (at least 1 mi n ute a part) at eac h sc he d ule d ti me 
p oi nt as s pecifie d i n A p pe n di x 1 , A p pe n di x 3 , A p pe n di x 5 , a n d A p pe n di x 7 after t he partici pa nt
has bee n resti n g i n t he s u pi ne p ositi o n f or at l east 1 0 mi n utes. If t he Scree ni n g tri plicate E C Gs 
are c ollecte d less t ha n 2 4 h o urs bef ore st u d y  dr u g d osi n g, t he tri plicate E C Gs pri or t o d osi n g 
ma y  be o mitte d.
E C Gs will be c ollecte d at scree ni n g a n d as cli nicall y i n dicate d f or partici pa nts e nr olle d i n Pa rt D.
5. 4. 6.
P h ysic al E x a mi n ati o ns
P h y sical exa mi nati o ns will i ncl u de ge neral a p peara nce ; e yes, s ki n, a n d car di o vasc ular a n d 
res pirat or y sys te m e xa mi nati o ns; a b d o mi nal e xa mi nati o n , a n d s ym pt o m -directe d e xa mi nati o n.
5. 4. 7.
Tr a nscr a ni al D o p pler ( P arts B a n d C )
T C D res ults fr o m t he 3 years pri or t o si g ni n g I C F, if a vaila ble, will be rec or de d as part of t he 
Me dical hist or y  f or partici pa nts i n Part C.
T C D T A M M bl o o d fl o w vel ocit y  is als o bei n g o btai ne d (i n acc or da nce wit h t he T C D refere nce 
ma n ual) as a n assess me nt t o deter mi ne treat me nt effect (refer t o Secti o n 5. 5 a n d A p pe n di x 3 a n d
A p pe n di x 5 ); h o we ver , a b n or mal val ues ca n i n dicate a safety c o ncer n a n d will be f oll o we d u p as 
a p pr o priate. S pecificall y,  sta n dar d cli nical practice f or pri mar y str o ke pre ve nti o n will be 
f oll o we d (e g, a n y T C D val ues ≥2 0 0 c m/sec b y  n o ni ma gi n g T C D or ≥1 8 5 c m/sec b y  T C Di will 
re q uire re peat T C D wit hi n 4 wee ks . I n t he case of a sec o n d TC D val ue ≥2 0 0 c m/sec b y  
n o ni ma gi n g T C D or ≥1 8 5 c m/sec b y  T C Di, t he site I n vesti gat or m a y offer t he partici pa nt
treat me nt wit h a str o ke pre ve nti o n pr ot oc ol utilizi n g pr o p hyl actic tra nsf usi o n as per sta n dar d 
cli nical care if i n place at t hat site’s h os pital or cli nic).
5. 5.
Eli gi bilit y Assess me nt
Eli gi bilit y  assess me nt will be c o n d ucte d d uri n g Scree ni n g a n d als o pri or t o recei vi n g st u d y dr u g 
o n treat me nt Da y  1. If a partici pa nt is f o u n d t o meet i ncl usi o n/e xcl usi o n criteria at the scree ni n g
visit , b ut t he n has a cli nicall y  si g nifica nt c ha n ge i n stat us pri or t o a d mi nistrati o n of t he first d ose 
of st u d y  dr u g (f or e xa m ple is h os pitalize d f or sic kle cell crisis), t he partici pa nt s h o ul d be 
wit h dra w n fr o m t he st u d y. Re -scree ni n g ma y be c o nsi dere d at t he discreti o n of t he I n vesti gat or 
a n d i n c o ns ultati o n wit h t he S p o ns or . Partici pa nts w h o re -scree n will ha ve all assess me nts re d o ne 
e xce pt f or ir o n testi n g ( Parts A, B, a n d C o nl y).
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
5 6
5. 6.
Tre at me nt Res p o nse Assess me nts
Cli nical meas ures of he m ol y sis a n d T C D T A M M bl o o d fl o w vel ocit y ( Parts B a n d C,
A p pe n di x 3 a n d A p pe n di x 5 ) will be assesse d as meas ures of p ote ntial efficac y. Details of 
re q uire me nts f or T C D meas ure me nts will be descri be d i n a se parate st u dy ma n ual. He m ol ys is 
mar kers are i ncl u de d u n der t he he mat ol o g y  a n d c he mistr y assess me nts descri be d a b o ve (H b ,
retic ul oc yte c o u nt, er yt hr o p oieti n, LD H, i n direct bilir u bi n). 
5. 7.
P h ar m ac o k i netic Assess me nts
5. 7. 1.
P art A
Bl o o d sa m ples f or plas ma (if a p plica ble) a n d w h ole bl o o d P K assess me nts will be c ollecte d at 
t he f oll o wi n g ti me p oi nts liste d bel o w (refer t o A p pe n di x 2 ):

D a y 1

Pre d ose ( wit hi n 6 0 mi n utes pri or t o d osi n g) 

P o st d ose at 2 h o urs ( ± 1 5 mi n utes) a n d 8 h o urs ( ± 3 0 mi n utes)

D a y 2

At 2 4 h o urs ( ± 1 h o ur)

D a y 3

At 4 8 h o urs ( ± 2 h o urs)

D a y 5

At 9 6 h o urs ( ± 2 h o urs)

D a y 8

At 1 6 8 h o urs ( ± 2 h o urs)

D a y 1 5 ( ± 1 da y)

E arl y Ter mi n ati o n/ Wit h dr a w al 
W h ole bl o o d a n d plas ma c o nce ntrati o ns of v o xel ot or will be meas ure d usi n g a vali date d assa y.
5. 7. 2.
P art B
Bl o o d sa m ples f or plas ma (if a p plica ble) a n d w h ole bl o o d P K assess me nts will be c ollecte d at 
t he f oll o wi n g ti me p oi nts liste d bel o w (refer t o A p pe n di x 4 ):

D a y 1

Pre d ose ( wit hi n 6 0 mi n utes pri or t o d osi n g) 

P ost d ose at 2 h o urs ( ± 1 5 mi n utes) a n d 8 h o urs ( ± 3 0 mi n utes)

D a y 2

P ost d ose at 2 4 h o urs ( ± 1 h o ur)
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
5 7

Wee k 2
( Da y 1 4) ( ± 2 da y s)

Pre or p ost d ose ( ± 2 h o urs of t he d ose) 

Wee k 4
(D a y  2 8) ( ± 3 da y s)

Pre d ose ( wit hi n 3 0 mi n utes pri or t o d osi n g)

Bet wee n 1 t o 4 h o urs p ost d ose

Bet wee n 6 t o 8 h o urs p ost d ose

Wee k 8
( Da y 5 6) ( ± 3 da y s)

Wee k 1 2
( Da y 8 4) ( ± 3 d a y s)

Wee k 1 6
( Da y 1 1 2) ( ± 3 da y s)

Wee k 2 0
( Da y 1 4 0) ( ± 3 da y s)

Wee k 2 4
( Da y 1 6 8) ( ± 3 da y s) 

F oll o w -u p

E arl y Ter mi n ati o n/ Wit h dr a w al
5. 7. 3.
P art C
Bl o o d sa m ples f or plas ma a n d w h ole bl o o d P K assess me nts will be c ollecte d at t he f oll o wi n g 
ti me p oi nts liste d bel o w (refer t o A p pe n di x 6 ).

D a y 1

P ost d ose ( wit hi n 1 5 mi n utes t o 2 h o urs p ost d ose ) 

Wee k 4
(D a y  2 8) ( ± 3 da y s): Pre d ose

Wee k 8
( Da y 5 6) ( ± 3 da y s): Pre d ose

Wee k 1 2
( Da y 8 4) ( ± 3 d a y s): Pre d ose

Wee k 1 6
( Da y 1 1 2) ( ± 5 da y s): Pre d ose

Wee k 2 0
( Da y 1 4 0) ( ± 5 da y s): Pre d ose

Wee k 2 4 ( Da y 1 6 8) ( ± 5 da y s): Pre d ose

Wee k 3 6 ( Da y 2 5 2) ( ± 5 da y s): Pre d ose

Wee k 4 8 ( Da y 3 3 6) ( ± 5 da y s): Pre d ose

E arl y Ter mi n ati o n/ Wit h dr a w al
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
5 8
5. 7. 4.
P art D
Bl o o d sa m ples f or plas ma a n d w h ole -bl o o d P K assess me nts will be c ollecte d at t he f oll o wi n g 
ti me p oi nts (refer t o A p pe n di x 8 ):

D a y 1

P ost d ose ( wit hi n 1 5 mi n utes t o 2 h o urs p ost d ose )

Wee k 2
( Da y 1 4) ( ± 3 da y s): pre d ose

Wee k 8
( Da y 5 6) ( ± 3 da y s): pr e d ose

Wee k 1 2
( Da y 8 4) ( ± 5 d a y s): pre d ose

Wee k 1 6
( Da y 1 1 2) ( ± 5 da y s): pr e d ose

Wee k 2 4 ( Da y 1 6 8) ( ± 5 da y s): pre d ose

Wee k 3 6 ( Da y 2 5 2) ( ± 5 da y s): pr e d ose

Wee k 4 8 ( Da y 3 3 6) ( ± 5 da y s): pre d ose

E arl y Ter mi n ati o n/ Wit h dr a w al
5. 7. 5.
C o nce ntr ati o n Me as ure me nts
W h ole bl o o d a n d plas ma c o nce ntrati o ns of v o xel ot or will be meas ure d usi n g vali date d assa y s.
T he f oll o wi n g P K para meters will be calc ulate d, if a p pr o priate: 
R B C C o nce ntrati o n
R B C c o nce ntrati o n of v o xel ot or ( µ g/ m L) at eac h ti me p oi nt will be calc ulate d fr o m 
w h ole bl o o d a n d plas ma c o nce ntrati o n data usi n g t he f oll o wi n g e q uati o n:
Hct
C
Hct
C
R B C
p
b
]
*
)
1
[(



W here
C b = w h ole bl o o d c o nce ntrati o n i n µ g/ m L
C p = Plas ma c o nce ntrati o n i n µ g/ m L
Hct = He mat ocrit val ue meas ure d o n or pri or t o P K sa m pli n g da y
C ma x
Ma xi m u m o bser ve d c o nce ntrati o n
f or w h ole bl o o d a n d plas ma
tma x
T he ti me t hat C ma x was o bser ve d f or wh ole bl o o d a n d plas ma
A U C 0 -last
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he ti me of t he last 
q ua ntifia ble c o nce ntrati o n; calc ulate d usi n g t he li near/l o g tra pez oi d r ule f or w h ole 
bl o o d a n d plas ma
A U C 0 - 2 4
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 2 4 h o urs f or w h ole bl o o d 
a n d plas ma
A U C 0 -i nf
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 e xtra p olate d t o i nfi nit y; 
calc ulate d as A U C t + C t/z, w here Ct is t he last q ua ntifia ble c o nce ntrati o n f or w h ole 
bl o o d a n d plas ma
t1/ 2
T er m i nal eli mi nati o n half -life; calc ulate d as l n( 2)/z f or w h ole bl o o d a n d plas ma
Bl o o d/ Plas ma Rati o
Rati o of bl o o d A U C 0 -2 4 t o plas ma A U C0- 2 4 at stea d y-state ( Da y 2 8)
R B C/ Plas ma Rati o
Rati o of R B C A U C 0 - 2 4 t o plas ma A U C0- 2 4 at stea d y-state ( Da y 2 8)
Acc u m ulati o n Rati o
Rati o of A U C 0- 2 4 at stea d y-state ( Da y 2 8) t o A U C0- 2 4 o n Da y 1
% He m o gl o bi n Occ u pa nc y
Rati o of R B C c o nce ntrati o n i n m M at C m a x o n Da y 2 8 m ulti plie d b y 2 0
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
5 9
T he met h o d ol o g y  f or c ollecti o n, ha n dli n g, st ora ge a n d s hi p pi n g of w h ole bl o o d a n d plas ma P K 
sa m ples will be pr o vi de d i n a se parate la b orat or y ma n ual.
5. 8.
E lectr o nic P atie nt Re p orte d O utc o mes a n d e Di ar y (P art B o nl y)
Secti o n 5. 8. 1 a n d Secti o n 5. 8. 2 descri be t he i nf or mati o n t hat will be ca pt ure d daily usi n g t he 
ha n d h el d st u d y-s pecific de vice.
5. 8. 1.
Electr o nic P atie nt Re p orte d O utc o me Sic kle Cell Dise ase Se verit y Me as ure
A self -a d mi nistere d partici pa nt q uesti o n naire of S C D c ore s y m pt o ms i ncl u di n g pai n se verit y, 
fre q ue nc y a n d ty pe as well as fati g ue a n d me ntal ac uit y will be c o m plete d dail y b y  partici pa nts
i n Part B ( o nl y) of t he st u d y .
5. 8. 2.
e Di ar y of St u d y Dr u g C o m pli a nce
Partici pa nts i n Part B ( o nl y ) of t he st u d y will rec or d w het her or n ot t he y t o o k t heir prescri be d 
st u d y dr u g daily.
5. 9.
T aste a n d P al at a bilit y Q uesti o n n aire ( P art A C o h ort 2 , P art C , a n d 
P art D)
F or Part A, C o h ort 2: A Taste a n d Palata bilit y  Q uesti o n naire will be pr o vi de d a n d use d t o 
e val uate t he pe diatric partici pa nts ’ taste a n d palata bilit y e x perie nce after ta ki n g t he d ose.
F or Part C: F or t he d is persi ble ta blets, a Taste a n d Palata bilit y  Q uesti o n naire will be 
a d mi nistere d t o t he care gi ver/le gal g uar dia n a n d/ or c hil dre n ( ≥6 y ears ol d) at W ee k 2 a n d 
W ee k 1 2 d uri n g t he st u d y.
F or Part C: F or t he p o w der f or oral s us pe nsi o n f or m ulati o n, a Taste a n d Palata bilit y  
Q uesti o n naire will be a d mi nistere d t o t he care gi ver/le gal g uar dia n a n d/ or c hil dre n (all a ges) a t 
t he Tra nsiti o n Visit a n d at t he ne xt sc he d ule d st u d y visit.
F or Part D: A Taste a n d Palata bilit y  Q uesti o n naire will be a d mi nistere d t o t he care gi ver/le gal 
g uar dia n at W ee k 2, Wee k 4, a n d W ee k 1 2 d uri n g t he st u d y .
5. 1 0.
F or m ul ati o n Tr a nsiti o n Visit ( P art C)
A Tra nsiti o n Visit will be c o n d ucte d t o tra nsiti o n Part C partici pa nts w h o are recei vi n g v o xel ot or 
as dis persi ble ta blets t o v o xel ot or p o w der f or oral s us pe nsi o n, pac ka ge d as stic k pac ks. A si g ne d 
a n d date d u p date d i nf or me d pare ntal/ g uar dia n c o nse nt a n d partici pa nt asse nt m ust be o btai ne d at 
t he F or m ulati o n Tra nsiti o n Visit if t he partici pa nt has n ot si g ne d t he u p date d I C F f or t he 
tra nsiti o n visit. Assess me nts t o be c o m plete d at t his visit i ncl u de t he f oll o wi n g: p h ys ical 
e xa mi nati o n (as descri be d i n Secti o n 5. 4. 6 ), wei g ht, c o nc o mita nt me dicati o n an d A E re vie w, P K 
sa m pli n g, i n-cli nic st u d y dr u g d osi n g ( p o w der f or oral s us pe nsi o n), Taste a n d Palata bilit y 
Q uesti o n naire, a n d dis pe nsi n g of st u d y dr u g ( pac ka ge d as stic k pac ks). 
T his visit s h o ul d occ ur wit hi n 3 0 da ys of S p o ns or n otificati o n of a vaila bili t y of t he p o w der f or 
oral s us pe nsi o n f or m ulati o n. D ue t o t he C O VI D -1 9 i m pact o n cli nical sites, t he tra nsiti o n visit 
ma y  occ ur at a sc he d ule d st u d y visit. 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
6 0
A tele p h o ne f oll o w - u p visit s h o ul d be c o n d ucte d wit hi n 1 t o 2 wee ks after t he tra nsiti o n t o assess 
tolera bilit y  of t he p o w der f or oral s us pe nsi o n f or m ulati o n.
5. 1 1.
Misse d Assess me nts
Misse d assess me nts s h o ul d be resc he d ule d a n d perf or me d as cl ose t o t he ori gi nal sc he d ule d date 
as p ossi ble. A n e xce pti o n is ma de w he n resc he d uli n g bec o mes, i n t he I n vesti gat or’s o pi ni o n, 
me dicall y  u n necessar y or u nsafe beca use it is t o o cl ose i n ti me t o t he ne xt sc he d ule d e val uati o n.
I n t hat case, t he misse d e val uati o n s h o ul d be a ba n d o ne d.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
6 1
6.
E A R L Y DI S C O N TI N U A TI O N O F T RI A L O R I N DI VI D U A L 
P A R TI CI P A N T S
6. 1.
E arl y Disc o nti n u ati o n of t he Tri al
T he S p o ns or has t he ri g ht t o ter mi nate t his st u d y  at a n y ti me a n d f or a ny reas o n, i ncl u di n g d ue t o 
t he i nci de nce or se verit y of A E s i n t his or ot her st u dies i n dicati n g a p ote ntial healt h hazar d t o 
partici pa nt s. St o p pi n g r ules are o utli ne d i n Secti o n 3. 6 of t he pr ot oc ol.
I n a ny i nsta nce of earl y ter mi nati o n of t he st u d y, t he S p o ns or will n otif y, i n writi n g, t he 
I n vesti gat ors a n d will s pecif y t he reas o n(s) f or ter mi nati o n. T he I n vesti gat or will i nf or m t he I RB
or E C . 
6. 2.
E arl y Disc o nti n u ati o n of St u d y Tre at me nt
Partici pa nt s ma y be disc o nti n ue d fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns:

A d verse E ve nt(s)

Wit h dra wal of c o nse nt

Discreti o n of t he I n vesti gat or

Partici pa nt is l ost t o f oll o w- u p

Partici pa nt is n o n-c o m plia nt

Pre g na nc y
Partici pa nt s will be i nf or me d t hat t he y are free t o wit h dra w fr o m t he st u d y at a n y ti me a n d f or 
a n y reas o n. I n a d diti o n, t he I n vesti gat or ma y re m o ve a partici pa nt fr o m t he st u d y if, i n t he 
I n vesti gat or’s o pi ni o n, it is n ot i n t he best me dical i nterest of t he partici pa nt t o c o nti n ue t he 
st u d y.
T he date t he partici pa nt is wit h dra w n fr o m t he st u d y a n d t he reas o n f or wit h dra wal will be 
d oc u me nte d. 
Wit h t he e xce pti o ns
of ‘ wit h dra wal of c o nse nt’ a n d ‘l ost t o f oll o w - u p,’ partici pa nts w h o are 
disc o nti n ue d fr o m st u d y  treat me nt f or a n y of t he af ore me nti o ne d reas o ns will c o nti n ue t o 
parti ci pate i n t he st u d y assess me nts . If a partici pa nt fails t o ret ur n f or sc he d ule d visits, a
d oc u me nte d eff ort ( e g, at least 2 p h o ne calls t o t he partici pa nt a n d a certifie d letter) m ust be 
ma de t o deter mi ne t he reas o n.
6. 3.
E arl y Disc o nti n u ati o n of St u d y P artici p ati o n
A n y  partici pa nt ( or his or her le gally a ut h orize d re prese ntati ve) ma y  wit h dra w t heir c o nse nt t o 
partici pate i n t he st u d y at  a n y ti me wit h o ut prej u dice. T he In vesti gat or m ust wit h dra w fr o m t he 
st u d y a ny partici pa nt w h o re q uests t o be wit h dra w n. A partici pa nt ’s partici pati o n i n t he st u d y 
ma y  be disc o nti n ue d at a n y ti me at t he discreti o n of t he S p o ns or or t he In vesti gat or a n d i n 
acc or da nce wit h his or her cli nical j u d g me nt . H o we ver, all eff orts m ust be ma de t o f oll o w 
partici pa nt s f or t he f ull d urati o n of t he stu d y  a n d t o e nc o ura ge all partici pa nt s w h o as k t o lea ve 
t he st u d y early t o u n der g o t he tests a n d e val uati o ns liste d f or t he earl y ter mi nati o n visit . If a 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
6 2
partici pa nt wit h dra ws bef ore c o m pleti n g t he st u d y , t he reas o n f or wit h dra wal is t o be 
d oc u me nte d o n t he C R F.
6. 4.
P artici p a nt Re pl ace me nt
O nce d ose d, partici pa nt s w h o disc o nti n ue st u d y dr u g d ue t o a n A E will n ot be re place d.
Partici pa nt s w h o disc o nti n ue st u d y dr u g d ue t o reas o ns ot her t ha n a n A E or w h o ha ve 
n o n -e val ua ble P K sa m ples ma y be re place d at t he discret i o n of t he S p o ns or.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
6 3
7.
S T U D Y D R U G
7. 1.
I n vesti g ati o n al Me dici n al Pr o d uct
7. 1. 1.
P art s A a n d B
F or partici pa nts w h o are a ges 1 2 t o 1 7 years ol d, t he st u d y m a y be perf or me d wit h v o xel ot or
c o m m o n ble n d 3 0 0 m g ca ps ules or v o xel ot or ta blets. F or partici pa nts w h o are a ges 6 t o 1 1 years 
ol d, t he gra n ulati o n fr o m t he v o xel ot or c o m m o n ble n d ca ps ules will be mi xe d wit h f o o d a n d 
a d mi nistere d t o t he partici pa nt . Res ults are a vaila ble fr o m a relati ve bi oa vaila bilit y  st u d y w hic h 
s h o we d c o m para ble P K of v o xel ot or 3 0 0 m g ta blets wit h v o xel ot or ca ps ules. T hese data s h o w 
t hat t he w h ole bl o o d P K f or v o xel ot or ta blets a n d ca ps ules are si milar. T he 9 0 % c o nfi de nce 
inter vals f or C ma x a n d f or A U C fall wit hi n t he 8 0 % t o 1 2 5 % (t he acce pta ble ra n ge f or 
bi oe q ui vale nce) .
7. 1. 2.
P art C
Partici pa nts w h o are bet wee n 1 2 a n d 1 7 y ears of a ge will recei ve v o xel ot or , 1 5 0 0 m g/ da y  as 
dis pers ible ta blets or p o w der f or oral s us pe nsi o n.
Partici pa nts w h o are bet wee n 4 t o 1 1 y ears of a ge will recei ve v o xel ot or , 1 5 0 0 m g/ da y 
E Q UI V A L E N T base d o n b o d y  wei g ht as dis pers ible ta blets or p o w der f or oral s us pe nsi o n. T he 
partici pa nt’s wei g ht at scree ni n g will be use d t o deter mi ne t he i nitial treat me nt d ose ( Ta ble 3 ). 
Details re gar di n g pre parati o n f or a d mi nistrati o n are pr o vi de d i n t he P har mac y  Ma n ual ( pr o vi de d 
se paratel y). Detaile d i nstr ucti o ns will be pr o vi de d t o partici pa nts a n d t heir care gi ver/le gal 
g uar dia n pri or t o t he first d ose of st u d y  dr u g.
7. 1. 3.
P art D
Partici pa nts w h o are 6 m o nt hs t o < 4 y ears of a ge will recei ve v o xel ot or 1 5 0 0 m g/ da y  
E Q UI V A L E N T base d o n b o d y  wei g ht as p o w der f or oral s us pe nsi o n. If p o w der f or oral 
s us pe nsi o n is n ot a vaila ble, dis persi ble ta blets will be use d. T he partici pa nt’s wei g ht at scree ni n g 
will be us e d t o deter mi ne t he i nitial treat me nt d ose ( Ta ble 3 ). T he d ose s h o ul d be a dj uste d if t he 
partici pa nt’s wei g ht i ncreases or decreases a n d t he i n vesti gat or deter mi nes t hat t he wei g ht 
c ha n ge is sta ble. T he partici pa nt’s wei g ht will be meas ure d acc or di n g t o t he Sc he d ule of 
Assess me nts ( A p pe n di x 7 ), a n d d ose a dj ust me nts ma de as nee de d, as i n dicate d i n Ta ble 8 .
Details re gar di n g pre parati o n f or a d mi nistrati o n are pr o vi de d i n t he P har mac y  Ma n ual ( pr o vi de d
se paratel y). Detaile d i nstr ucti o ns will be pr o vi de d t o partici pa nts a n d t heir care gi ver/le gal 
g uar dia n pri or t o t he first d ose of st u d y  dr u g.
7. 1. 4.
P h ysic al Descri pti o n
V o xel ot or is a s ynt hetic s mall m olec ule beari n g t he c he mical na me 2- h y dr o x y - 6-(( 2-( 1-
is o pr o pyl - 1 H-p y raz ol- 5-yl ) p y ri di n- 3-yl ) met h o x y) be nzal de h y de. T he c he mical f or m ula is 
C 1 9H 1 9N 3O 3 a n d t he m olec ular wei g ht is 3 3 7. 3 8.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
6 4
7. 1. 5.
F or m ul ati o n
V o xel ot or C a ps ules: V o xel ot or 3 0 0 m g ca ps ules c o ntai n gra n ulati o n c o nsisti n g of v o xel ot or
dr u g s u bsta nce al o n g wit h se veral f or m ulati o n e xci pie nts i n S we dis h ora n ge, o pa q ue, size 0, 
H y pr o mell ose ca ps ules. All t he e xci pie nts use d f or t he f or m ulati o n are G R A S ( Ge nerall y  
rec o g nize d as safe) materials a n d are als o F D A II G (I nacti ve I n gre die nts G uide) liste d.
V o xel ot or T a blets: T he v o xel ot or 3 0 0 m g ta blets c o ntai n v o xel ot or dr u g s u bsta nce al o n g wit h 
se veral f or m ulati o n e xci pie nts. All t he e xci pie nts use d f or t he f or m ulati o n are F D A I nacti ve 
I ngre die nts Data base ( II D) liste d a n d c o m plia nt wit h E ur o pe a n Re g ulati o ns.
V o xel ot or Dis pers ible T a blets : V o xel ot or will be s u p plie d as 1 0 0 or 3 0 0 m g dis persi ble ta blets.
V o xel ot or P o w der f or Or al S us pe nsi o n : V o xel ot or will be s u p plie d as 3 0 0-, 4 0 0-, 6 0 0-, or 
9 0 0 -m g p o w der f or oral s us pe nsi o n pac ka ge d as stic k pac ks .
7. 1. 6.
P ac k a gi n g a n d L a beli n g
F or Part A a n d Part B: V o xel ot or dr u g pr o d uct will be s u p plie d t o cli n ical sites i n 3 0-c o u nt 
b ottles. V o xel ot or ca ps ules will be pac ka ge d i n 1 0 0 cc hi g h de nsit y p olyet h yle ne ( H D P E) b ottles 
wit h i n d ucti o n seale d p ol y pr o p y le ne chil d -resista nt caps. V o xel ot or ta blets will be pac ka ge d i n 
6 0 cc H D P E b ottles wit h i n d ucti o n seale d P P C R ca ps .
F or Part C : V o xel ot or dis persi ble ta blets will be s u p plie d t o cli nical sites i n H D P E b ottles wit h 
i n d ucti o n seale d p ol y pr o p y le ne c hil d-resista nt ca ps. V o xel ot or als o will be s u p plie d t o cli nical 
sites i n a ta m per-seale d cart o n c o ntai ni n g stic k pac ks. A d diti o nal details are pr o vi de d i n t he 
P har mac y  M a n ual.
F or Part D: V o xel ot or will be s u p plie d t o cli nical sites i n a ta m per -seale d cart o n c o ntai ni n g stic k 
pac ks.
If p o w der f or oral s us pe nsi o n is n ot a vaila ble, dis persi ble ta blets will be use d . V o xel ot or as 
dis persi ble ta blets will als o be s u p plie d t o cli nical sites i n H D P E b ottles wit h i n d ucti o n seale d 
p ol y pr o p yl e ne c hil d -resista nt ca ps. A d diti o nal d etails are pr o vi de d i n t he P har mac y  Ma n ual.
At assi g ne d visit s, partici pa nts will be s u p plie d a sufficie nt q ua ntit y of v o xel ot or t o e ns ure 
c o nti n u o us d osi n g t hr o u g h t o t he ne xt dis pe nsi n g visit. All st u d y  dr u g pac ka gi n g m ust be 
ret ur ne d at desi g nate d visit s, re gar dless of w het her t he y are e m pty or c o ntai n u n use d st u d y dr u g. 
G B T or t heir re prese ntati ve will s u p pl y  t he pac ka ge d a n d la bele d dr u g pr o d uct t o t he 
i n vesti gati o nal sites.
7. 1. 7.
St or a ge a n d H a n dli n g Pr oce d ure
All st u d y  me dicati o ns will be st ore d at c o ntrolle d r o o m te m perat ure bet wee n 1 5° C t o 2 5° C 
pr otecte d fr o m li g ht i n t he st ora ge area of t he i n vesti gati o nal site p har mac y, w hic h m ust be a 
sec ure, te m perat ure-c o ntr olle d, l oc ke d e n vir o n me nt wit h restricte d access.
N o s pecial pr oce d ures f or t he safe ha n dli n g of v o xel ot or are re q uire d. T he S p o ns or will be 
per mitte d u p o n re q uest t o a u dit t he s u p plies, st ora ge, dis pe nsi n g pr oce d ures a n d rec or ds.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
6 5
7. 2.
Dr u g Acc o u nt a bilit y a n d Rete nti o n
I n acc or da nce wit h G C P, t he I n vesti gati o nal Site will acc o u nt f or all s u p plies of v o xel ot or . 
Details of recei pt, st ora ge, asse m bl y a n d ret ur n will be rec or de d. 
T he l ot n u m bers f or t he I M P will be pr o vi de d t o t he site b y  t he s u p plier/ ma n ufact urer as s o o n as 
a vaila ble.
T he I n vesti gat or ( or desi g nee) will mai ntai n a n acc urate rec or d of t he recei pt of t he I M P as 
s hi p pe d b y t he S p o ns or ( or desi g nee), i ncl u di n g t he date recei ve d a n d st ora ge 
c o n diti o ns/l ocati o n. I n a d diti o n, a n acc urate dr u g dis p ositi o n rec or d will be ke pt, s pecif yi n g t he
f oll o wi n g: a m o u nt dis pe nse d t o eac h partici pa nt, t he date of dis pe nsati o n, t he date of ret ur n, t he 
n u m ber of ca ps ules/ta blets / p o w der f or oral s us pe nsi o n stic k pac ks ret ur ne d, a n d destr ucti o n 
rec or ds. Partici pa nts will be i nstr ucte d t o kee p t he use d ca ps ule s hells f or st u d y  dr u g 
acc o u nta bilit y p ur p oses.
T he In vesti gat or m ust mai ntai n acc urate rec or ds of t he recei pt of all I M P s hi p pe d b y t he S p o ns or 
or t heir re prese ntati ve, i ncl u di n g b ut n ot li mite d t o t he date recei ve d, st ora ge c o n diti o ns/l ocati o n, 
l ot n u m ber, a m o u nt recei ve d, a n d t he dis p ositi o n of t he I M P. A c o p y of t his rec or d will be 
ret ur ne d t o t he S p o ns or w he n t he c o nte nts a n d c o n diti o n of t he I MP s hi p me nt ha ve bee n verifie d.
C urre nt dis pe nsi n g rec or ds will als o be mai ntai ne d i ncl u di n g t he date a n d a m o u nt of I M P
dis pe nse d a n d t he partici pa nt recei vi n g t he dr u g. T his dr u g acc o u nta bilit y rec or d will be 
a vaila ble f or i ns pecti o n at a n y ti me.
All u n use d s u p plies of v o xel ot or will eit her be destr o ye d b y t he i n vesti gati o nal site or ret ur ne d t o 
t he st u d y S p o ns or t hr o u g h o ut a n d at t he e n d of t he st u d y i n acc or da nce wit h i nstr ucti o n b y t he 
S p o ns or. 
A d diti o nal details are p r o vi de d i n t he P har mac y  Ma n ual ( pr o vi de d se paratel y).
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
6 6
8.
D O S A G E A N D T R E A T M E N T A D MI NI S T R A TI O N
8. 1.
Tre at me nt Re gi me n
I n Part A, partici pa nt s will recei ve a si n gle oral d ose of v o xel ot or 6 0 0 m g (t w o 3 0 0 m g ca ps ules 
or ta blets ).
I n Part B, partici pa nt s will recei ve v o xel ot or a d mi nistere d eac h da y f or 2 4 wee ks ( 1 6 8 d a y s).
V o xel ot or will be a d mi nistere d as 3 0 0 m g ca ps ules or ta blets .
I n Part C, partici pa nt s will recei ve v o xel ot or a d mi nistere d eac h da y f or 4 8 wee ks ( 3 3 6 d a y s).
Partici pa nts w h o are bet wee n 1 2 t o 1 7 y ears of a ge will recei ve v o xel ot or , 1 5 0 0 m g/ da y as 
dis persi ble ta blets or p o w der f or oral s us pe nsi o n . Partici pa nts w h o are bet wee n 4 t o 1 1 ye ars of 
a ge will recei ve v o xel ot or 1 5 0 0 m g/ da y  E Q UI V A L E N T as dis persi ble ta blets or p o w der f or oral 
s us pe nsi o n base d o n b o d y  wei g ht. Eit her dis persi ble ta blets (1 0 0 or 3 0 0 m g ) or p o w der f or oral 
s us pe nsi o n ( 3 0 0, 4 0 0, 6 0 0, or 9 0 0 m g) will be use d base d o n Ta ble 3 .
I n Part D, partici pa nt s will recei ve v o xel ot or a d mi nistere d eac h da y f or 4 8 wee ks ( 3 3 6 d a y s).
Partici pa nts will recei ve v o xel ot or 1 5 0 0 m g/ da y  E Q UI V A L E N T as p o w der f or o ral s us pe nsi o n
base d o n b o d y wei g ht. V o xel ot or p o w der f or oral s us pe nsi o n ( 3 0 0, 4 0 0, 6 0 0, or 9 0 0 m g) will be 
use d base d o n Ta ble 3 . If p o w der f or oral s us pe nsi o n is n ot a vaila ble, dis persi ble ta blets will be 
use d a n d will be s u p plie d as 1 0 0 or 3 0 0 m g ta blets. 
I nstr ucti o ns f or a d mi nistrati o n of st u d y dr u g f or ca ps ules ( Part B) :

V o xel ot or will be self -a d mi nistere d b y t he partici pa nt i n t he m or ni n g . W he n
necessar y , a pare nt or g uar dia n ma y be prese nt t o assist wit h t his pr ocess.

e xce pt o n st u d y  visit da ys w he n t he partici pa nt m ust n ot ta ke st u d y  dr u g at h o me. 
It will be a d mi nistere d at t he site after c o m pleti o n of a p pr o priate assess me nts.

Partici pa nts s h o ul d ta ke v o xel ot or wit h water or ot her n o n -alc o h olic be vera ge.
I nstr ucti o ns f or a d mi nistrati o n of st u d y dr u g as dis persi ble ta blets or p o w der f or oral s us pe nsi o n
( Parts C a n d D):

Details re gar di n g t he d osi n g pre parati o n a n d oral a d mi nistrati o n of t he dis persi ble 
ta blets or p o w der f or oral s us pe nsi o n are pr o vi de d i n t he P har mac y Ma n ual ( pr o vi de d 
se paratel y).

F or y o u n ger partici pa nts , v o xel ot or a d mi nistrati o n s h o ul d be s u per vise d by a pare nt 
or g uar dia n . Detaile d i nstr ucti o ns will be pr o vi de d t o partici pa nts a n d t heir 
care gi vers/le gal g uar dia ns pri or t o t he first d ose of st u d y  dr u g.
Partici pa nt s m ust be i nstr ucte d n ot t o ta ke st u d y dr u g t he da y of t heir sc he d ule d visits (refer t o 
A p pe n di x 1 f or Part A , A p pe n di x 3 f or Part B , A p pe n di x 5 f or Part C , a n d A p pe n di x 7 f or 
Part D). St u d y  dr u g will be a d mi nistere d at t he site o n t hese da ys, after c o m pleti o n of all t he 
assess me nts sc he d ule d f or t hat visit .
Treat me nt c o m plia nce will be base d o n c o m paris o n of t h e dis pe nse d vers us ret ur ne d st u d y dr u g.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
6 7
8. 2.
D ose M o dific ati o n f or P art s B, C, a n d D
Partici pa nts s h o ul d a d here t o t heir assi g ne d d ose le vel. H o we ver, d ose m o dificati o n ma y  be 
c o nsi dere d if warra nte d a n d as o utli ne d bel o w i n Secti o n 8. 2. 1 , Secti o n 8. 2. 2 , a n d Secti o n 8. 2. 3 .
All i nsta nces of st u d y dr u g m o dificati o n ( d ose re d ucti o n, i nterr u pti o n, i ncrease, or 
disc o nti n uati o n) are t o be ca pt ure d i n t he partici pa nt researc h rec or d a n d o n t he C R F, a n d t he 
Me dical M o nit or s h o ul d be n otifie d wit hi n 7 2
h o urs. If t he c o n diti o ns/e ve nt lea di n g t o a d ose 
m o dificati o n ha ve res ol ve d, t he ori gi nal d ose le vel s h o ul d be res u me d, u nless i n t he j u d g me nt of 
t he In vesti gat or, t his ca n n ot be d o ne safel y .
8. 2. 1.
D ose Fre q ue nc y
P art B: Partici pa nt s recei vi n g v o xel ot or 9 0 0 m g will recei ve t hree 3 0 0 m g ca ps ules or ta blets
a dmi nistere d orall y, o nce dail y . Partici pa nts recei vi n g v o xel ot or 1 5 0 0 m g will recei ve fi ve 
3 0 0 m g ca ps ules or ta blets, a d mi nistere d orall y, o nce dail y. If a partici pa nt misses a d ose, t he
partici pa nt s h o ul d res u me n or mal d osi n g t he ne xt da y (ie, t he d ose o n t he da y after a da y of a 
misse d d ose s h o ul d n ot be i ncrease d or decrease d).
P art C : Partici pa nt s a ges 1 2 t o 1 7 years of a ge recei vi n g v o xel ot or 1 5 0 0 m g will recei ve 
dis persi ble ta ble ts or p o w der f or oral s us pe nsi o n a dmi nistere d orall y, o nce dail y . Partici pa nts 
a ges 4 t o 1 1 years of a ge recei vi n g v o xel ot or 1 5 0 0 m g e q ui vale nt will recei ve dis persi ble ta blets
or p o w der f or or al s us pe nsi o n, a dmi nistere d orall y , o nce daily. If a partici pa nt misses a d ose, t he
partici pa nt s h o ul d res u me n or mal d osi n g t he ne xt da y (ie, t he d ose o n t he da y after a da y of a 
misse d d ose s h o ul d n ot be i ncrease d or decrease d).
P art D: Partici pa nts recei vi n g v o xel ot or 1 5 0 0 m g e q ui vale nt will recei ve p o w der f or oral 
s us pe nsi o n, a dmi nistere d orall y  o nce daily. If p o w der f or oral s us pe nsi o n is n ot a vaila ble, 
dis persi ble ta blets will be use d . If a partici pa nt misses a d ose, t he partici pa nt s h o ul d res u me
n or mal d osi n g t he ne xt da y  (ie, t he d ose o n t he da y after a da y of a misse d d ose s h o ul d n ot be 
i ncrease d or decrease d).
8. 2. 2.
D ose M o dific ati o n G ui del i nes P art s B a n d C f or P artici p a nts A ge d 1 2 t o 
1 7 Y e ars
G ui deli nes f or re d ucti o n, h ol d, or per ma ne nt disc o nti n u ati o n of st u d y dr u g are pr o vi de d a b o ve,
i n Ta ble 6 (st u d y dr u g relate d A Es) a n d Ta ble 7 (st u d y dr u g relate d ras h). T he Me dical M o nit or 
s ho ul d be n otifie d of all d ose m o dificati o ns wit hi n 7 2 h o urs .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
6 8
T a ble 6 :
D ose M o dific ati o n G ui deli nes f or St u d y Dr u g – Rel ate d A d verse E ve nts
( 1 2- 1 7 ye ars)
D ose Re d ucti o n
E ve nt
Rec o m me n de d Acti o n
Gr a de 2 or hi g her A E t hat is ( 1) st u d y dr u g relate d i n 
t he o pi ni o n of t he I n vesti gat or, a n d ( 2) t hat precl u des 
c o nti n ue d d osi n g at t he c urre nt d ose le vel d ue t o safet y 
c o ncer n or lac k of t olera bilit y (i n t he I n vesti gat or’s 
j u d g me nt) 
St u d y dr u g : Ma y be re d uce d b y o ne ta blet 
If i n t he o pi ni o n of t he I n vesti gat or, a Gra de 2 A E has res ol ve d 
t o ≤Gra de 1, partici pa nt ma y res u me st u d y dr u g at t he ori gi nal 
d ose.
If, i n t he o pi ni o n of t he I n vesti gat or, t he A E p oses a si g nifica nt 
safet y c o ncer n s uc h t hat a d ose h ol d is c o nsi dere d, t he 
I n vesti gat or ma y c o nsi der a d ose i nterr u pti o n ( h ol d), Ma xi m u m 
d ose h ol d is 5 c o nti n u o us da ys. If, i n t he o pi ni o n of t he 
I n vesti gat or, a l o n ger d ose h ol d is cli nicall y nee de d, t he 
Me dical M o nit or s h o ul d be c o ntacte d f or disc ussi o n
A L T ≥3 x U L N if A L T W N L at b aseli ne O R 
> 3 × U L N A N D a ≥2- f ol d i ncre ase a b o ve b aseli ne 
v al ues if ele v ate d A L T v al ues at b aseli ne
I n t he a bse nce of a d diti o nal si g ns of c o m pr o mise d li ver 
f u ncti o n s uc h as ele vate d P T, P T T, I N R, ele vate d 
c o nj u gate d bilir u bi n, ja u n dice, or he patic pai n.
St u d y dr u g : C o nfir m b y re peat testi n g wit hi n 4 8-7 2 h o urs if 
p ossi ble, t he n re peat li ver pa nel at least wee kl y u ntil A L T le vels 
i m pr o ves. A d diti o n al Acti o ns : If A L T le vels c o nti n ue t o 
i ncrease re d uce b y o ne ta blet.a n d n otif y t he Me dical M o nit or
A L T ≥5 × a n d < 8 × U L N (c o nfir me d b y re pe at 
testi n g wit hi n 4 8-7 2 h o urs) I n t he a bse nce of a d diti o nal 
si g ns of c o m pr o mise d li ver f u ncti o n s uc h as ele vate d P T, 
P T T, ele vate d c o nj u gate d bilir u bi n, ja u n dice, or he patic 
pai n. 
St u d y dr u g: Re d uce d ose b y o ne ta blet.
A d diti o nal acti o ns: Re peat li ver pa nel test wit hi n 4 8 t o 7 2 h o urs 
if p ossi ble a n d t he n at least wee kl y u ntil res ol uti o n t o 
< 5 × U L N; if A L T test d oes n ot i m pr o ve wit hi n 2 wee ks of 
d ose re d ucti o n, t he Me dical M o nit or s h o ul d be n otifie d. If A L T 
c o nti n ues t o i ncrease wit hi n 1 wee k after a d ose re d ucti o n, d ose 
s h o ul d be i nterr u pte d a n d t he Me dical M o nit or s h o ul d be 
n otifie d.
D ose I nterr u pti o n ( H ol d)
E ve nt
Rec o m me n de d Acti o n
Gr a de 3 or hi g her A E t hat is ( 1) st u d y dr u g relate d i n 
t he o pi ni o n of t he I n vesti gat or, a n d ( 2) t hat precl u des 
c o nti n ue d d osi n g at t he c urre nt d ose le vel d ue t o safet y 
c o ncer n or lac k of t olera bilit y i n t he I n vesti gat or’s 
j u d g me nt
St u d y dr u g : H ol d d ose u ntil ≤Gr a de 2, t he n r es u me st u d y dr u g 
at ori gi nal d ose. If, i n t he o pi ni o n of t he I n vesti gat or, d osi n g 
s h o ul d be res u me d at a l o wer d ose, c o ntact t he Me dical 
M o nit or. If t he A E rec urs or w orse ns, re d uce d ose b y o ne ta blet. 
Ma xi m u m d ose h ol d is 5 c o nti n u o us da ys. If, i n t he o pi ni o n of 
t he I n vesti gat or, a l o n ger d ose h ol d is cli nicall y nee de d, t he 
Me dical M o nit or s h o ul d be c o ntacte d f or disc ussi o n.
Dr u g Disc o nti n u ati o n
E ve nt
Rec o m me n de d Acti o n
Gr a de 3 or hi g her st u d y dr u g rel ate d S A E
St u d y dr u g : Disc o nti n ue st u d y dr u g. If t he I n vesti gat or 
c o nsi ders t hat t he partici pa nt w o ul d be nefit fr o m c o nti n ui n g 
treat me nt, t he Me dical M o nit or s h o ul d be c o ntacte d f or 
disc ussi o n.
Gr a de 3 or hi g her st u d y dr u g rel ate d A E t hat, at t he 
discreti o n of t he I n vesti gat or, warra nts disc o nti n uati o n of 
st u d y dr u g (e g, has n ot i m pr o ve d or res ol ve d after d ose 
h ol d)
St u d y dr u g : Disc o nti n ue st u d y dr u g. If t he I n vesti gat or 
c o nsi ders t hat t he partici pa nt w o ul d be nefit fr o m c o nti n ui n g 
treat me nt, t he Me dical M o nit or s h o ul d be c o ntacte d f or 
disc ussi o n.
C o nsi der tre at me nt disc o nti n u ati o n if: 

A L T > 8 U L N 
A L T > 3 × U L N or 2) A L T ≥3 x A N D ≥2- f ol d i ncre ase 
a b o ve b aseli ne v al ues if ele v ate d A L T v al ues at 
b aseli ne wit h a d diti o nal si g ns of c o m pr o mise d li ver 
f u ncti o n s uc h as ele vate d P T, P T T, I N R, ele vate d 
c o nj u gate d bilir u bi n, ja u n dice, or he patic pai n , 
a p peara nce of 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 der ness, fe ver, ras h, a n d/ or 
e osi n o p hilia
St u d y dr u g : H ol d d ose, c o nfir m b y re peat testi n g wit hi n 4 8 -7 2 
h o urs if p ossi ble, a n d assess f or p ote ntial re versi ble ca uses of 
li ver f u ncti o n test a b n or malities. C o ntact t he Me dical M o nit or 
f or disc ussi o n of st u d y dr u g disc o nti n uati o n.
A b bre viati o ns: A E , a d verse e ve nt; A L T , ala ni ne a mi n otra nsferase; S A E , seri o us a d verse e ve nt; U L N, u p per li mit of n or mal.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
6 9
T a ble 7 :
D ose M o dific ati o n G ui deli nes f or St u d y Dr u g – Rel ate d R as h ( 1 2– 1 7 ye ars)
D ose Re d ucti o n
E ve nt
Rec o m me n de d Acti o n
Gr a de 1 or 2 St u d y Dr u g Rel ate d R as h
M a n a ge me nt:
C o nsi der a nti hista mi nes, t o pical ster oi ds as 
cli nicall y i n dicate d .
St u d y dr u g : If ras h d oes n ot res ol ve or i m pr o ve t o Gra de 1 wit hi n 
4 da ys after oral a nti hista mi nes a n d/ or t o pical ster oi ds, t he d ose 
ma y be re d uce d b y o ne ca ps ule/ta blet ( 3 0 0 m g). T he d ose ma y be 
re d uce d f urt her b y o ne ca ps ule/ta blet ( 3 0 0 m g) if t he e ve nt d oes n ot 
res ol ve.
If i n t he o pi ni o n of t he I n vesti gat or, a Gra de 2 A E has res ol ve d t o 
≤Gra de 1, partici pa nt ma y res u me st u d y dr u g at t he ori gi nal d ose.
D ose I nterr u pti o n ( H ol d)
E ve nt
Rec o m me n de d Acti o n
Gr a de 1 or 2 St u d y Dr u g Rel ate d R as h t h at Persists 
after D ose Re d ucti o n
M a n a ge me nt:
C o nsi der a nti hista mi nes, t o pical ster oi ds as 
cli nicall y i n dicate d. C o nsi der a Der mat ol o g y C o ns ult if cli nicall y 
i n dicate d.
St u d y dr u g : If ras h d oes n ot res ol ve or i m pr o ve t o Gra de 1 o n t he 
l o wer d ose, c o nsi der a d ose h ol d u ntil res ol uti o n or ret ur ns t o Gra de 
1 or Baseli ne. O nce ras h has res ol ve d or i m pr o ve d t o 
G ra de 1 d osi n g ma y be res u me d at t he re d uce d le vel. Ma xi m u m 
d ose h ol d is 5 c o nti n u o us da ys. If, i n t he o pi ni o n of t he 
I n vesti gat or, a l o n ger d ose h ol d is cli nicall y nee de d, t he Me dical 
M o nit or s h o ul d be c o ntacte d f or disc ussi o n.
If i n t he o pi ni o n of t he I n vesti gat or, a Gra de 2 A E has res ol ve d t o 
< Gra de 1, partici pa nt ma y res u me st u d y dr u g at t he ori gi nal d ose.
Dr u g Disc o nti n u ati o n
E ve nt
Rec o m me n de d Acti o n
Gr a de 3 or Hi g her St u d y Dr u g Rel ate d R as h
St u d y dr u g : Disc o nti n ue st u d y dr u g
C o nsi der a Der mat ol o g y C o ns ult if cli nicall y i n dicate d
A b bre viati o ns: A E , a d verse e ve nt; A L T , ala ni ne a mi n otra nsferase; S A E , seri o us a d verse e ve nt; U L N, u p per li mit of n or mal.
8. 2. 3.  
D ose M o dific ati o n G ui deli nes f or P art C P artici p a nts A ge d 4 t o 1 1 Y e ars a n d f or 
P art D P artici p a nts A ge d 6 M o nt hs t o < 4 Ye ars
Partici pa nts s h o ul d a d here t o t heir d ose le vel assi g ne d at Da y  1. H o we ver, d ose m o dificati o n will 
be c o n d ucte d i n acc or da nce wit h t he partici pa nts wei g ht gr o u ps . If t he partici pa nt gai ns or l oses 
wei g ht a n d m o ves fr o m o ne wei g ht -base d d osi n g gr o u p t o a n ot h er d uri n g t he st u d y, a dj ust me nts 
i n t he dr u g d ose will be ma de acc or di n g t o Ta ble 8 . Partici pa nt’s wei g ht will be c hec ke d as 
i n dicate d i n A p pe n di x 5 .
T a ble 8 :
Wei g ht -B ase d D ose Gr o u ps
a F or partici pa nts w h o wei g h 5 t o < 1 0 k g a n d are ta ki n g v o xel ot or p o w der f or oral s us pe nsi o n, o nl y 1 d ose 
re d ucti o n is p ossi ble.
Wei g ht
V o xel ot or 1 5 0 0 m g
D ose E q ui v ale nt
D ose R e d ucti o n 1 -
N e w D ose
D ose R e d ucti o n 2 -
N e w D ose
5 t o < 1 0 k g
4 0 0 m g
3 0 0 m g
2 0 0 m g a
1 0 t o < 2 0 k g
6 0 0 m g
4 0 0 m g
3 0 0 m g
2 0 t o < 4 0 k g
9 0 0 m g
6 0 0 m g
4 0 0 m g
≥4 0 k g
1 5 0 0 m g
1 2 0 0 m g
9 0 0 m g
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
7 0
G ui deli nes f or re d ucti o n, h ol d, or per ma ne nt disc o nti n uati o n of st u d y  dru g are pr o vi de d bel o w , 
i n Ta ble 9 (st u d y dr u g – relate d A Es) a n d Ta ble 1 0 (st u d y dr u g– relate d ras h). T he Me dical 
M o nit or s h o ul d be n otifie d of all d ose m o dificati o ns wit hi n 7 2 h o urs .
T a ble 9 :
D ose M o dific ati o n G ui deli nes f or St u d y Dr u g Rel ate d A d verse E ve nts
( 6 M o nt hs – 1 1 ye ars )
D ose Re d ucti o n
a
E ve nt
Rec o m me n de d Acti o n
Gr a de 2 or hi g her A E t hat is ( 1) st u d y dr u g-relate d i n 
t he o pi ni o n of t he I n vesti gat or A N D ( 2) t hat precl u des 
c o nti n ue d d osi n g at t he c urre nt d ose le vel d ue t o safet y 
c o ncer n or lac k of t olera bilit y (i n t he I n vesti gat or’s 
j u d g me nt) 
St u d y Dr u g : Ma y be re d uce d b y o ne d ose re d ucti o n. 
If, i n t he o pi ni o n of t he I n vesti gat or, a Gra de 2 A E has res ol ve d t o 
≤Gra de 1, t he partici pa nt ma y res u me st u d y dr u g at t he ori gi nal 
d ose.
If, i n t he o pi ni o n of t he I n vesti gat or, t he A E p oses a si g nifica nt 
safet y c o ncer n s uc h t hat a d ose h ol d is c o nsi dere d, t he I n vesti gat or 
s h o ul d c o ntact t he Me dical M o nit or.
A L T ≥3 × U L N if A L T is W N L at b aseli ne O R 
> 3 × U L N A N D a ≥2- f ol d i ncre ase a b o ve b aseli ne 
v al ues if ele v ate d A L T v al ues at b aseli ne
I n t he a bse nce of a d diti o nal si g ns of c o m pr o mise d li ver 
f u ncti o n s uc h as ele vate d P T, P T T, I N R, ele vate d 
c o nj u gate d bilir u bi n, ja u n dice, or he patic pai n.
St u d y dr u g : Ma y c o nti n ue c urre nt d ose u ntil c o nfir me d b y re peat 
testi n g wit hi n 4 8- 7 2 h o urs if p ossi ble, t he n re peat li ver pa nel at 
least wee kl y u ntil A L T le vels i m pr o ves. 
A d diti o n al Acti o ns : If A L T le vels c o nti n ue t o i ncrease, re d uce b y 
o ne d ose re d ucti o n a n d n otif y t he Me dical M o nit or
A L T ≥5 × a n d < 8 × U L N (c o nfir me d b y re pe at 
testi n g wit hi n 4 8-7 2 h o urs) I n t he a bse nce of 
a d diti o nal si g ns of c o m pr o mise d li ve r f u ncti o n s uc h as 
ele vate d P T, P T T, ele vate d c o nj u gate d bilir u bi n, 
ja u n dice, or he patic pai n. 
St u d y dr u g : Re d uce d ose b y o ne d ose re d ucti o n
A d diti o n al acti o ns : Re peat li ver pa nel test wit hi n 4 8 t o 7 2 h o urs if 
p ossi ble a n d t he n at least wee kl y u ntil res ol uti o n t o < 5 × U L N; if 
A L T test d oes n ot i m pr o ve wit hi n 2 wee ks of d ose re d ucti o n, t he 
Me dical M o nit or s h o ul d be n otifie d. If A L T c o nti n ues t o i ncrease 
wit hi n 1 wee k after a d ose re d ucti o n, d ose s h o ul d be i nterr u pte d 
a n d t he Me dical M o nit or s h o ul d be n otifi e d.
D ose I nterr u pti o n ( H ol d)
E ve nt
Rec o m me n de d Acti o n
Gr a de 3 or hi g her A E t hat is ( 1) st u d y dr u g -relate d i n 
t he o pi ni o n of t he I n vesti gat or A N D ( 2) t hat precl u des 
c o nti n ue d d osi n g at t he c urre nt or at a re d uce d d ose 
le vel d ue t o safet y c o ncer n or lac k of t olera bilit y i n t he 
I n vesti gat or’s j u d g me nt
St u d y Dr u g : H ol d d ose u ntil AE res ol ves t o ≤Gra de 2, t he n 
res u me st u d y dr u g at ori gi nal d ose. If, i n t he o pi ni o n of t he 
I n vesti gat or, d osi n g s h o ul d be res u me d at a l o wer d ose, c o ntact t he 
Me dical M o nit or. If t he A E rec urs or w orse ns, re d uce d ose b y o ne 
d ose re d ucti o n. Ma xi m u m d ose h ol d is 5 c o nti n u o us da ys. If, i n t he 
o pi ni o n of t he I n vesti gat or, a l o n ger d ose h ol d is cli nicall y nee de d, 
t he Me dical M o nit or s h o ul d be c o ntacte d f or disc ussi o n.
Dr u g Disc o nti n u ati o n
E ve nt
Rec o m me n de d Acti o n
Gr a de 3 or Hi g her, St u d y Dr u g -Rel ate d S A E
St u d y Dr u g : Disc o nti n ue st u d y dr u g (see Secti o n 6. 2 ). If t he 
I n vesti gat or c o nsi ders t hat t he partici pa nt w o ul d be nefit fr o m 
c o nti n ui n g treat me nt, t he Me dical M o nit or s h o ul d be c o ntacte d f or 
disc ussi o n.
Gr a de 3 or hi g her st u d y dr u g -Rel ate d A E t hat, at 
t he discreti o n of t he I n vesti gat or, warra nts 
disc o nti n uati o n of st u d y dr u g (e g, has n ot i m pr o ve d or 
res ol ve d after d ose h ol d) 
St u d y dr u g : Disc o nti n ue stu d y dr u g ( see Secti o n 6. 2 ). If t he 
I n vesti gat or c o nsi ders t hat t he partici pa nt w o ul d be nefit fr o m 
c o nti n ui n g treat me nt, t he Me dical M o nit or s h o ul d be c o ntacte d .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
7 1
D ose Re d ucti o n
a
C o nsi der tre at me nt disc o nti n u ati o n if: 
A L T > 8 × U L N 
A L T > 3 × U L N or 2) A L T ≥3 × A N D ≥2- f ol d 
i ncre ase a b o ve b aseli ne v al ues if ele v ate d A L T 
v al ues at b aseli ne wit h a d diti o nal si g ns of 
c o m pr o mise d li ver f u ncti o n s uc h as ele vate d P T, P T T, 
I N R, ele vate d c o nj u gate d bilir u bi n, ja u n dice, or he patic 
pai n , a p peara nce of 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 der ness, fe ver, ras h, a n d/ or 
e osi n o p hilia 
St u d y dr u g : H ol d d ose, c o nfir m b y re peat testi n g wit hi n 4 8-7 2 
h o urs if p ossi b le, a n d assess p ote ntial re versi ble ca uses of li ver 
f u ncti o n test a b n or malities. C o ntact t he Me dical M o nit or f or 
disc ussi o n of st u d y dr u g disc o nti n uati o n.
A b bre viati o ns: A E , a d verse e ve nt; A L T , ala ni ne a mi n otra nsferase; I N R, i nter nati o nal n or malize d rati o; P T, pr ot hr o m bi n ti me; 
P T T , partial t hr o m b o plasti n ti me; S A E , seri o us a d verse e ve nt; U L N, u p per li mit of n or mal ; W N L = wit hi n n or mal li mits .
a F or partici pa nts w h o wei g h 5 t o < 1 0 k g a n d are ta ki n g v o xel ot or p o w der f or oral s us pe nsi o n, o nl y 1 d ose re d ucti o n is p ossi ble.
T a ble 1 0 :
D ose M o dific ati o n G ui deli nes f or St u d y Dr u g Rel ate d R as h
( 6 M o nt hs - 1 1 ye ars)
D ose Re d ucti o n
a
E ve nt
Rec o m me n de d Acti o n
Gr a de 1 or 2 St u d y Dr u g Rel ate d R as h
M a n a ge me nt:
C o nsi der a nti hista mi nes, t o pical ster oi ds as 
cli nicall y i n dicate d .
St u d y dr u g : If ras h d oes n ot res ol ve or i m pr o ve t o Gra de 1 wit hi n 
4 da ys after oral a nti hista mi nes a n d/ or t o pical ster oi ds, t he d ose 
ma y be re d uce d b y o ne d ose re d ucti o n. T he d ose ma y be r e d uce d 
b y a sec o n d d ose re d ucti o n if t he e ve nt d oes n ot res ol ve.
If i n t he o pi ni o n of t he I n vesti gat or, a Gra de 2 A E has res ol ve d t o 
≤Gra de 1, partici pa nt ma y res u me st u d y dr u g at t he ori gi nal d ose.
D ose I nterr u pti o n ( H ol d)
E ve nt
Rec o m me n de d Acti o n
Gr a de 1 or 2 St u d y Dr u g Rel ate d R as h t h at Persists 
after D ose Re d ucti o n
M a n a ge me nt:
C o nsi der a nti hista mi nes, t o pical ster oi ds as 
cli nicall y i n dicate d. C o nsi der a Der mat ol o g y C o ns ult if cli nicall y 
i n dicate d.
St u d y dr u g : If ras h d oes n ot res ol ve or i m pr o ve to Gra de 1 
f oll o wi n g t he sec o n d d ose re d ucti o n, c o nsi der a d ose h ol d u ntil 
res ol uti o n or A E ret ur ns t o Gra de 1 or Baseli ne. O nce ras h has 
res ol ve d or i m pr o ve d t o G ra de 1 d osi n g ma y be res u me d at t he 
re d uce d le vel ( d ose re d ucti o n 2 d ose). Ma xi m u m d ose h ol d is 
5 c o nti n u o us da ys. If, i n t he o pi ni o n of t he I n vesti gat or, a l o n ger 
d ose h ol d is cli nicall y nee de d, t he Me dical M o nit or s h o ul d be 
c o ntacte d f or disc ussi o n.
If i n t he o pi ni o n of t he I n vesti gat or, a Gra de 2 A E has res ol ve d t o 
Gra de 1, partici pa nt ma y res u m e st u d y dr u g at t he ori gi nal d ose.
Dr u g Disc o nti n u ati o n
E ve nt
Rec o m me n de d Acti o n
Gr a de 3 or hi g her St u d y Dr u g Rel ate d R as h
St u d y dr u g : Disc o nti n ue st u d y dr u g
C o nsi der a Der mat ol o g y C o ns ult if cli nicall y i n dicate d
A b bre viati o ns: A E , a d verse e ve nt.
a F or partici pa nts w h o wei g h 5 t o < 1 0 k g a n d are ta ki n g v o xel ot or p o w der f or oral s us pe nsi o n, o nl y 1 d ose re d ucti o n is p ossi ble.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
7 2
8. 3.
Tre at me nt of O ver d ose
Base d o n t he mec ha nis m of acti o n of v o xel ot or , a n e xtre me o ver d ose mi g ht decrease o x y ge n 
deli ver y  t o tissues. Tra nsf usi o n, e xc ha n ge tra nsf usi o n a n d/ or h yper baric o x y ge n t hera p y ma y be 
a d mi nistere d i n t he e ve nt of a me dical e mer ge nc y  d ue t o a s us pecte d v o xel ot or o ver d ose .
G ui deli nes f or re p orti n g a s us pecte d treat me nt o ver d ose are pr o vi de d i n Secti o n 9. 8 . 
8. 4.
C o nc o mit a nt Me dic ati o ns
A c o nc o mita nt me dicati o n is defi ne d as a n y prescri pti o n or o ver -t he-c o u nter pre parati o n, 
i ncl u di n g vita mi ns a n d s u p ple me nts. 
I n t he i nterests of partici pa nt safety a n d acce pta ble sta n dar ds of me dical care , t he I n vesti gat or 
will be per mitte d t o prescri be treat me nt(s) at his/ her discreti o n. F or all e nr olle d partici pa nt s, all 
a d mi nistere d c o nc o mita nt me dicati o ns fr o m si g ni n g t he i n f or me d c o nse nt u ntil 3 0 da ys after t he 
partici pa nt ’s last d ose of st u d y dr u g, m ust be rec or de d i n t he partici pa nt s’ case re p ort f or m 
( C R F) ( me dicati o n, d ose, treat me nt d urati o n a n d i n dicati o n).
Pe nicilli n pr o p h y la xis a n d vacci nati o ns (i ncl u di n g t he C O VI D-1 9 vacci ne) are all o we d i n 
acc or da nce wit h sta n dar d of care.
All re p orte d pri or a n d c o nc o mita nt me dicati o ns will be c o de d usi n g t he c urre nt versi o n of t he 
W H O Dr u g Dicti o nar y .
8. 4. 1.
Restricti o ns Re g ar di n g C o nc o mit a nt M e dic ati o ns
8. 4. 1. 1.
H y dr o x y ure a

Parts A, B, a n d C: C o nc urre nt treat me nt wit h H U is all o we d if t he d ose a n d re gi me n 
ha ve bee n sta ble f or at least 3 m o nt hs pri or t o si g ni n g t he I C F a n d wit h n o a ntici pate d 
nee d f or d ose a dj ust me nts d uri n g t he st u d y a n d n o si g n of he mat ol o gical t o xicit y .

Part D: C o nc urre nt treat me nt wit h H U is all o we d if t he d ose a n d re gi me n ha ve bee n 
sta ble f or at least 1 m o nt h pri or t o si g ni n g t he I C F. Titrati o n t o t he M T D is all o we d 
d uri n g t he st u d y.
8. 4. 1. 2.
Pr o hi bite d C o nc o mit a nt Me dic ati o ns
V o xel ot or is a m o derate c yt oc hr o me P 4 5 0 (C Y P ) 3 A 4 i n hi bit or a n d s h o ul d be n ot be 
c oa d mi nistere d wit h se nsiti ve C Y P 3 A 4 s u bstrates wit h a narr o w t hera pe utic i n de x (refer t o
Ta ble 1 1 f or e xa m ples).
T a ble 1 1 :
Se nsiti ve C Y P 3 A 4 S u bstr ates wit h a N arr o w T her a pe utic R a n ge
Se nsiti ve C Y P 3 A 4 S u bstr ates wit h N arr o w T her a pe utic R a n ge
Alfe nta nil, sir oli m us, a n d tacr oli m us
C o nc o mita nt use of str o n g i n d ucers of C Y P 3 A 4 wit h v o xel ot or is n ot all o we d (refer t o Ta ble 1 2
f or e xa m ples).
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
7 3
T a ble 1 2 :
E x a m ples of Str o n g C Y P 3 A 4 I n d ucers
C Y P 3 A 4 I n d ucer
E x a m ples
Str o n g
R ifa m pi n, mit ota ne, a vasi m be, rifa pe nti ne, a pal uta mi de, i v osi de ni b, 
p he n yt oi n, cara ba maze pi ne, e nzal uta mi de, St. J o h n’s w ort e xtract, 
l u macaft or, p he n o bar bital
Ple ase n ote t he f oll o wi n g: T his is n ot a n e x h a usti ve list . C o u ntr y -s pecific lists m a y be use d if a v ail a ble.
F or a n u p date d list, refer t o t he f oll o wi n g li n k: 
htt ps:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urc es/ Dr u gI nteracti o ns La beli n g/ uc m 0 9 3 6 6 4. ht m #ta
ble 3 -3.
A n y  ot her e x peri me ntal S C D t hera p y is n ot all o we d d uri n g t he e ntire st u d y peri o d. A ny
me dicati o n w hic h is n ot a p pr o ve d f or t he i n dicati o n of S C D a n d is n ot s u g geste d i n t he c urre nt 
g ui deli nes f or t he tre at me nt of S C D is c o nsi dere d “e x peri me ntal”.
8. 4. 2.
Ot her Restricti o ns
P artici pa nt s m ust a bstai n fr o m all alc o h ol fr o m 2 da ys pri or t o Da y  1 u ntil t he e n d of t he st u d y .
8. 5.
Fertilit y/ C o ntr ace pti ve Re q uire me nts
All fe male partici pa nts of c hil d beari n g p ote ntial ( p ost me narc he ) s h o ul d a v oi d pre g na nc y, a n d 
all se x uall y acti ve male partici pa nts s h o ul d a v oi d fat heri n g a c hil d.
8. 5. 1.
I nstr ucti o ns f or Fe m ale P artici p a nts of C hil d-Be ari n g P ote nti al
I n fe male partici pa nts of c hil d -beari n g p ote ntial ( p ost-me narc he) a n d se x uall y  acti ve, pre g na nc y 
s h o ul d be a v oi de d b y eit her a bsti ne nce fr o m se x/se x ual i nterc o urse or t he use of hi g hly effecti ve 
mea ns of c o ntrace pti o n f or t he d urati o n of t he st u d y , a n d f or a t otal peri o d of 3 0 da y s after t he 
partici pa nt has ta ke n her last d ose of v o xel ot o r. Hi g hly effecti ve mea ns of c o ntrace pti o n are 
liste d bel o w i n Secti o n 8. 5. 4 . Pre g na nc y re p orti n g re q uire me nts are o utli ne d i n Secti o n 9. 7 .
Fe male partici pa nts w h o bec o me pre g na nt d uri n g t he st u d y  will be wit h dra w n fr o m t he st u d y.
8. 5. 2. 
Fe m ale P artici p a nts of N o n -C hil d -Be ari n g P ote nti al
Fe male partici pa nts of n o n -c hil d-beari n g p ote ntial are defi ne d as t h ose w h o ha ve n ot starte d t heir 
me narc he.
8. 5. 3.
I nstr ucti o ns f or M ale P artici p a nts C a p a ble of F at heri n g a C hil d
T here is n o i nf or mati o n a b o ut effects t hat v o xel ot or c o ul d ha ve o n t he de vel o p me nt of t he fet us 
i n h u ma ns. T heref ore, it is i m p orta nt t hat t he part ners of male partici pa nts d o n ot bec o me 
pre g na nt d uri n g t he st u d y  a n d f or a t otal peri o d of 3 0 da y s after t he male partici pa nt has ta ke n 
t he last d ose of G B 4 4 0. 
As a preca uti o n, all male partic i pa nts w h o are se x uall y  acti ve s h o ul d a v oi d fat heri n g a c hil d by 
eit her tr ue a bsti ne nce or t he use of barrier met h o ds of c o ntrace pti o n .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
7 4
8. 5. 4.
Acce pt a ble F or ms of C o ntr ace pti o n
Hi g hl y e ffecti ve met h o ds of birt h c o ntr ol are defi ne d as t h ose w hic h res ult i n a l o w fail ure rate 
(ie, less t ha n 1 % per year) w he n use d c o nsiste ntl y a n d c orrectl y. E ffecti ve met h o ds of birt h 
c o ntr ol are as f oll o ws:

C o m bi ne d (estr o ge n - a n d pr o gest o ge n -c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n:

Oral

I ntra va gi nal

Tra ns der mal

Pr o gest o ge n - o nly 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:

Oral

I njecta ble

I m pla nta ble

H or m o nal c o ntrace pti o n m ust be s u p ple me nte d wit h a barrier met h o d ( prefera bl y a 
male c o n d o m)

I ntra uteri ne de vice (I U D)

I ntra uteri ne h or m o ne -releasi n g sys te m (I U S)

Bilateral t u bal occl usi o n

Vasect o mize d part ner : N ote t hat vasect o mize d part ner is a hi g hl y effecti ve birt h 
c o ntr ol met h o d pr o vi de d t hat part ner is t he s ole se x ual part ner of t he w o ma n of c hil d -
beari n g p ote ntial trial partici pa nt a n d t hat t he vasect o mize d part ner has recei ve d 
me dical assess me nt of t he s ur gical s uccess.

Se x ual a bsti ne nce : Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y  if 
t he partici pa nt is refrai ni n g fr o m heter ose xual i nterc o urse d uri n g t he e ntire peri o d of 
ris k ass ociate d wit h t he st u d y treat me nts. T he relia bilit y  of se x ual a bsti ne nce nee ds t o 
be e val uate d i n relati o n t o t he d urati o n of t he cli nical trial a n d t he preferre d a n d us ual 
lifest yle of t he partici pa nt .
F o r male partici pa nt s wit h fe male part ners ca pa ble of re pr o d ucti o n :

Barrier met h o ds of c o ntrace pti o n: C o n d o m or occl usi ve ca p ( dia p hra g m or 
cer vical/ va ult ca ps) wit h s per mici dal f oa m/ gel/fil m/crea m/s u p p osit or y . T he use of 
barrier c o ntrace pti ves s h o ul d al wa y s be s u p ple me nte d wit h t he use of a s per mici de.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
7 5
9.
A D V E R S E E V E N T S
A n A E is defi ne d as a n y u nt o war d me dical occ urre nce i n a partici pa nt a d mi nistere d a 
p har mace utical pr o d uct d uri n g t he c o urse of a cli nical i n vesti gati o n . A n A E ca n t heref ore be a n y  
u nfa v ora ble a n d u ni nte n de d si g n, s y m pt o m, or disease te m p orall y  ass ociate d wit h t he use of a n 
i n vesti gati o nal pr o d uct, w het her or n ot t h o u g ht t o be relate d t o t he i n vesti gati o nal pr o d uct. I n 
a d diti o n t o ne w e ve nts, a n y i ncrease i n t he se verit y  or fre q ue nc y of a pre-e x isti n g c o n diti o n t hat 
occ urs after t he partici pa nt si g ns t he I C F f or partici pati o n is c o nsi dere d a n A E. T his i ncl u des a ny 
si de effect, i nj ur y, t o xicit y or se nsiti vit y reacti o n.
Partici pa nt s will be m o nit ore d t hr o u g h o ut t he st u d y f or A Es, fr o m t he ti me i nfor me d c o nse nt is 
o btai ne d t hr o u g h t he E O S visit . A E s t hat are i de ntifie d at t he last assess me nt visit ( or t he early 
ter mi nati o n visit) as s pecifie d i n t he pr ot oc ol m ust be rec or de d o n t he A E e C R F. All e ve nts t hat 
are o n g oi n g at t his ti me will be rec or de d as o n g oi n g o n t he e C R F . All ( b ot h seri o us a n d 
n o nseri o us) A Es m ust be f oll o we d u ntil t he y  are res ol ve d or sta bilize d, or u ntil reas o na ble 
atte m pts t o deter mi ne res ol uti o n of t he e ve nt are e x ha uste d . T he In vesti gat or s h o ul d use his/ her 
discreti o n i n or deri n g a d diti o nal tests as necessar y t o m o nit or t he res ol uti o n of s uc h e ve nts. 
All re p orte d A Es will be c o de d usi n g t he c urre nt versi o n of t he Me dical Dicti o nar y  f or 
Re g ulat or y  Acti vities ( Me d D R A).
T he pr oce d ures s pecifie d i n Secti o n 9. 5 are t o be f oll o we d f or re p orti n g S A Es.
9. 1.
Rec or di n g A d verse E ve nts
A E s are t o be rec or de d o n t he A E pa ge of t he e C R F. T he f oll o wi n g i nf or mati o n will be rec or de d:

Assess me nt of w het her or n ot t he A E is a n S A E ( Secti o n 9. 2. 1 )

Assess me nt of A E i nte nsit y ( Secti o n 9. 2. 2 )

Assess me nt of A E relati o ns hi p t o i n vesti gati o nal pr o d uct ( Secti o n 9. 2. 3 )

Acti o n ta ke n - cate g orize d as n o ne, i n vesti gati o nal pr o d uct disc o nti n ue d, re q uire d 
c o nc o mita nt me dicati o n, re q uire d pr oce d ure, or ot her

O utc o me - rec or de d as e ve nt res ol ve d, res ol ve d wit h se quelae, o n g oi n g, or deat h
9. 2.
Assess me nt of A d verse E ve nts
T he In vesti gat or will assess eac h A E f or seri o us ness, i nte nsit y a n d relati o ns hi p t o i n vesti gati o nal 
pr o d uct.
9. 2. 1.
Seri o us A d verse E ve nt
T he I n vesti gat or is res p o nsi ble f or deter mi ni n g w het her a n A E meets t he defi niti o n of a n S A E .
A n S A E is a n y  A E occ urri n g fr o m I C F si g ni n g t hr o u g h t he E O S visit t hat res ults i n a n y of t he 
f oll o wi n g o utc o mes:

Deat h

A life -t hreate ni n g a d verse dr u g e x perie nce

I n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
7 6

A persiste nt or si g nifica nt disa bilit y  or i nca pacit y

A c o n ge nital a n o mal y or birt h defect

I m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y  be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate me dical 
j ud g me nt, je o par dizes t he partici pa nt a n d ma y re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt a n y of t he o utc o mes liste d i n t his defi niti o n. E x a m ples of s uc h 
me dical e ve nts 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 nc y r o o m or at h o me, bl o o d d y scrasias or c o n v ulsi o ns t hat d o n ot res ult i n 
i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.

Electi ve s ur ger y , pre-pla n ne d s ur ger y  or h os pitalizati o n less t ha n 2 4 h o urs will n ot be 
c o nsi dere d an S A E u nle ss dee me d b y t he In vesti gat or t o be a si g nifica nt me dical 
e ve nt as descri be d a b o ve.
N ote: S A Es re q uire i m me diate re p orti n g t o t he C o ntract R esearc h O r ga nizati o n ( C R O) S afet y 
D e part me nt. Refer t o “ Re p orti n g Seri o us A d verse E ve nts” ( Secti o n 9. 5 ) f or details.
9. 2. 2. 
I nte nsit y of A d verse E ve nts
T he i nte nsit y  of a n e ve nt descri bes t he de gree of i m pact u p o n t he partici pa nt a n d/ or t he nee d f or 
me dical care necessar y  t o treat t he e ve nt. A E s re p orte d f or partici pa nt s partici pati n g i n t his st u d y 
will be gra de d pri maril y  usi n g t he Nati o nal Ca ncer I nstit ute’s ( N CI) C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E ve nts ( C T C A E), versi o n 4. 0 3 .
F or A Es n ot a de q uatel y a d dresse d i n t he N CI -C T C A E Versi o n 4. 0 3 , t he f oll o wi n g criteria 
s h o ul d be use d (Ta ble 1 3 ).
T a ble 1 3 :
Gr a di n g f or A d verse E ve nts n ot C o vere d i n t he N CI -C T C A E
Se verit y
Descri pti o n
Gra de 1 – Mil d
As y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns 
o nl y; i nter ve nti o n n ot i n dicate d
Gra de 2 – M o derate
Mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li mite d a ge -
a p pr o priate i nstr u me ntal acti vities of dail y li vi n g ( A D L)
Gra de 3 – Se vere
Me dicall y si g nifica nt b ut n ot i m me diatel y life t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; 
li miti n g self-care A D L
Gra de 4 – Life -t hreate ni n g
Life -t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d
Gra de 5 – Fatal
Deat h
A b bre viati o ns: A D L , acti vities of dail y li vi n g; N CI -C T C A E , Nati o nal Ca ncer I nstit ute - C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E ve nts .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
7 7
9. 2. 3.
Rel ati o ns hi p t o I n vesti g ati o n al Pr o d uct
T he relati o ns hi p of a n A E t o t he I MP s h o ul d be deter mi ne d b y t he In vesti gat or acc or di n g t o t he 
f oll o wi n g defi niti o ns:

N ot Rel ate d: E vi de nce e xists t hat t he A E has a n eti ol o g y  ot her t ha n t he st u d y dr u g 
(s uc h as a pree xisti n g c o n diti o n, u n derl yi n g disease, interc urre nt ill ness, or 
c o nc o mita nt me dicati o n).

P ossi bl y/ Pr o b a bl y Rel ate d : A te m p oral relati o ns hi p e xists bet wee n t he e ve nt o nset 
a n d a d mi nistrati o n of t he st u d y  dr u g. It ca n n ot be rea dily e x plai ne d b y t he 
partici pa nt ’s cli nical state or c o nc o mita nt t herapies a n d a p pears wit h s o me de gree of 
certai nt y t o be relate d base d o n t he k n o w n t hera pe utic a n d p har mac ol o gic acti o ns of 
t he dr u g. I n case of cessati o n or re d ucti o n of t he d ose, t he e ve nt a bates or res ol ves 
a n d rea p pears u p o n rec halle n ge. It s h o ul d be e m p hasize d t hat i neffecti ve treat me nt 
s h o ul d n ot be c o nsi dere d as ca usally relate d i n t he c o nte xt of A E re p orti n g.
T hese criteria i n a d diti o n t o g o o d cli nical j u d g me nt s h o ul d be use d as a g ui de f or deter mi ni n g t he 
ca usal assess me nt. If it is felt t hat t he e ve nt is n ot relate d t o st u d y dr u g t hera p y, t he n a n 
alter nati ve e x pla nati o n s h o ul d be pr o vi de d.
9. 2. 4.
U ne x pecte d A d verse Re acti o ns
A n a d verse reacti o n is ‘ u ne x pecte d’ if its nat ure a n d se verit y are n ot c o nsiste nt wit h t he 
i nf or mati o n a b o ut t he me dici nal pr o d uct i n q uesti o n set o ut:

I n t he case of a pr o d uct wit h a mar keti n g a ut h orizati o n, i n t he s u m mar y of pr o d uct 
c haracteristics f or t hat pr o d uct;

I n t he case of a ny ot her I M P, i n t he I n vesti gat or’s Br oc h ure relati n g t o t he trial i n 
q uesti o n. 
9. 3.
Re p orti n g A d verse E ve nts
9. 3. 1.
Di a g n osis vers us Si g ns a n d S y m pt o ms
If k n o w n, a dia g n osis s h o ul d be rec or de d o n t he e C R F rat her t ha n i n di vi d ual si g ns a n d sy m pt o ms 
(e g, rec or d o nly li ver fail ure or he patitis rat her t ha n ja u n dice, asteri xis a n d ele vate d 
tra nsa mi nases). H o we ver, if a c o nstellati o n of si g ns a n d/ or s y m pt o ms ca n n ot be me dicall y  
c haracterize d as a si n gle dia g n osis or s y n dr o me at t he ti me of re p orti n g, eac h i n di vi d ual e ve nt 
s h o ul d be rec or de d as a n A E or S A E o n t he e C R F. If a dia g n osis is s u bse q ue ntl y esta blis he d, it 
s h o ul d be re p orte d as f oll o w-u p i nf or mati o n.
9. 3. 2.  
A d verse E ve nts Occ urri n g Sec o n d ar y t o Ot her E ve nts
I n ge neral, A Es occ urri n g sec o n dar y t o ot her e ve nts (e g, casca de e ve nts or cli nical se q uelae) 
s h o ul d be i de ntifie d b y t heir pri mar y ca use. F or e xa m ple, if se vere diarr h ea is k n o w n t o ha ve 
res ulte d i n de hy drati o n, it is s ufficie nt t o rec or d o nl y diarr hea as a n A E or S A E o n t he e C R F. 
H o we ver, me dicall y si g nifica nt A Es occ urri n g sec o n dar y  t o a n i nitiati n g e ve nt t hat are se parate d 
i n ti me s h o ul d be rec or de d as i n de pe n de nt eve nts o n t he e C R F. F or e xa m ple, if a se vere 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
7 8
gastr oi ntesti nal he m orr ha ge lea ds t o re nal fail ure, b ot h e ve nts s h o ul d be rec or de d se paratel y o n 
t he e C R F.
9. 3. 3.
Persiste nt or Rec urre nt A d verse E ve nts
A persiste nt A E is o ne t hat e xte n ds c o nti n u o usl y , wit h o ut res ol utio n bet wee n partici pa nt
e val uati o n ti me p oi nts. S uc h e ve nts s h o ul d o nl y be rec or de d o nce i n t he e C R F u nless t heir 
se verity i ncreases. If a persiste nt A E bec o mes m ore se vere, it s h o ul d be rec or de d a gai n o n 
a n A d verse E ve nt e C R F.
A rec urre nt A E is o ne t hat occ urs a n d res ol ves bet wee n partici pa nt e val uati o n ti me p oi nts a n d 
s u bse q ue ntl y rec urs. All rec urre nt A Es s h o ul d be rec or de d o n a n A d verse E ve nt e C R F.
9. 3. 4.
A b n or m al L a b or at or y V al ues
O nl y  cli nicall y si g nifica nt la b orat or y a b n or malities t hat re q uire acti ve ma na ge me nt will be 
rec or de d as A Es or S A Es o n t he e C R F (e g, a b n or malities t hat re q uire st u d y dr u g d ose 
m o dificati o n, disc o nti n uati o n of st u d y  treat me nt, m ore fre q ue nt f oll o w-u p assess me nts, f urt her 
dia g n ostic i n vesti gati o n, etc.).
If t he cli nically si g nifica nt l a b orat or y a b n or malit y is a si g n of a disease or s yn dr o me ( e g, al kali ne 
p h os p hatase a n d bilir u bi n 5 × t he U L N ass ociate d wit h c h olec ystitis), o nl y t he dia g n osis 
(e g, c h olec ystitis) nee ds t o be rec or de d o n t he e C R F.
If t he cli nically si g nifica nt la b orat or y a b n or malit y is n ot a si g n of a disease or s y n dr o me, t he 
a b n or malit y itself s h o ul d be rec or de d as a n A E or S A E o n t he e C R F. If t he la b orat or y 
a b n or malit y ca n be c haracterize d b y a precise cli nical ter m, t he cli nical ter m s h o ul d be rec or de d 
as t he A E or S A E. F or e xa m ple, a n ele vate d ser u m p otassi u m le vel of 7. 0 m E q/ L  s h o ul d be 
rec or de d as “ hy p er kale mia.”
O bser vati o ns of t he sa me cli nicall y  si g nifica nt la b orat or y a b n or malit y fr o m visit t o visit s h o ul d 
n ot be re peate dl y rec or de d as A Es or S A Es o n t he A d verse E ve nt e C R F, u nless t heir se verit y, 
seri o us ness, or eti ol o g y c ha n ges. 
9. 4.
Disc o nti n u ati o n d ue t o A d verse E ve nts
I n a d diti o n t o t he d ose m o dificati o n a n d st u d y st o p pi n g r ules pre vi o usl y o utli ne d i n Secti o n 6. 2
a n d Secti o n 8. 2 a n d a n y partici pa nt w h o e x perie nces a n A E ma y  be wit h dra w n at a ny t i me fr o m 
t he st u d y at t he discreti o n of t he I n vesti gat or. Partici pa nt s wit h dra w n fr o m t he st u d y d ue t o a n 
A E, w het her seri o us or n o nseri o us, s h o ul d be f oll o we d b y t he In vesti gat or u ntil t he cli nical 
o utc o m e of t he A E is deter mi ne d, ie, t he e ve nt has res ol ve d or has sta bilize d. T he A E(s) s h o ul d 
be n ote d o n t he a p pr o priate e C R Fs , a n d t he partici pa nt ’s pr o gress s h o ul d be f oll o we d u ntil t he 
A E is res ol ve d or sta bilize d as deter mi ne d b y t he In vesti gat or . T he S p o ns or a n d t he C R O 
M e dical M o nit ors m ust be n otifie d . If t he A E relates t o o ver d ose of st u dy treat me nt, t he 
v o xel ot or I B s h o ul d be c o ns ulte d f or details of a n y s pecific acti o ns t o be ta ke n.
9. 5.
Re p orti n g Seri o us A d verse E ve nts
S A Es occ urri n g o n t his st u d y  will be re p orte d t o G B T P har mac o vi gila nce or desi g nate d C R O
wit hi n 2 4 h o urs of t he I n vesti gat or, desi g nee, or site pers o n nel’s k n o wle d ge of t he e ve nt. T he 
S A E will be re p orte d b y c o m pleti n g t he pa per S A E re p ort f or ms f or Part A, B a n d C partici pa nts 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
7 9
or i n t he E D C f or Part D partici pa nts a n d s u b mitte d t o G B T P har mac o vi gila nce or desi g nate d 
C R O wit hi n 2 4 h o urs of bec o mi n g a ware of t he e ve nt. F oll o w -u p re p orts m ust be s u b mitte d i n a 
ti mel y fas hi o n as a d diti o nal i nf or mati o n bec o mes a vaila ble.
T he In vesti gat or is res p o nsi ble f or n otif y i n g t he I R B or E C i n acc or da nce wit h l ocal re g ulati o ns, 
of all S A Es. T he S p o ns or or desi g nee ma y re q uest a d diti o nal s o urce d oc u me ntati o n pertai ni n g t o 
t he S A E fr o m t he i n vesti gati o nal site. If a partici pa nt is per ma ne ntly wit h dra w n fr o m t he st u d y 
d ue t o a S A E, t his i nf or mati o n m ust be i nc l u de d i n t he i nitial or f oll o w-u p S A E re p ort.
Pr o perl y  a n o n ymize d a n d de- i de ntifie d d oc u me nts (e g, h os pital disc har ge s u m maries, a ut o ps y  
re p orts a n d/ or deat h certificates) as a vaila ble will be pr o vi de d t o G B T P har mac o vi gila nce or 
desi g nate d C R O f or all re porte d S A Es.
9. 6.
C h o osi n g A d verse E ve nt Ter ms
W he ne ver p ossi ble, re p orte d e ve nt ter ms f or A Es (i ncl u di n g S A Es) s h o ul d be t he na mes of 
me dical e ve nts, n ot lists of s y m pt o ms or e ve nt o utc o mes. Bel o w are s o me e xa m ples of ter ms t o 
a v oi d a n d m ore acc urate alter nati ves. A b bre viati o ns are n ot per mitte d.
E x a m ples of Ter ms t o A v oi d
E x a m ples of M ore Acc ur ate Ter ms
Deat h (t his is a n o utc o me)
Fatal m y ocar dial i nfarcti o n ( best c h oice)
Deat h d ue t o u n k n o w n ca use, a ut o ps y res ults pe n di n g (if 
n o ot her i nf or mati o n is a vaila ble)
H os pitalize d (t his is a seri o us criteri o n)
M y ocar dial i nfarcti o n ( best c h oice)
H os pitalize d wit h c hest pai n, r ule o ut m y ocar dial 
i nfarcti o n (if n o ot her i nf or mati o n is a vaila ble)
C hest pai n, s h ort ness of breat h, 
dia p h oresis, a n xiet y, left ar m pai n
M y ocar dial i nfarcti o n ( best c h oice)
H os pitalize d, r ule o ut m y ocar dial i nfarcti o n (if n o ot her 
i nf or mati o n is a vaila ble)
9. 7.
Re p orti n g Pre g n a nc y
If a partici pa nt bec o mes pre g na nt w hile ta ki n g st u d y  dr u g, t he st u d y treat me nt will be 
i m me diatel y disc o nti nue d , a n d t he pre g na nc y m ust be re p orte d t o t he S p o ns or or desi g nee wit hi n 
2 4 h o urs of a ware ness . T he In vesti gat or will disc uss t he ris ks a n d c o ncer ns of st u d y dr u g 
e x p os ure t o a de vel o pi n g fet us a n d c o u nsel t he partici pa nt a n d/ or pre g na nt part ner ( or e ns ur e 
s uc h c o u nselli n g is pr o vi de d).
Re p orte d pre g na nc y  of a partici pa nt or a partici pa nt’s part ner, w hile partici pati n g i n t his st u d y, 
will be m o nit ore d f or t he f ull d urati o n of t he pre g na nc y  a n d/ or f oll o we d t hr o u g h a defi niti ve 
o utc o me ( ie, birt h or s p o nta ne o us or electi ve a b orti o n) .
A n u nc o m plicate d pre g na nc y  will n ot be c o nsi dere d a n A E or S A E. Pre g na nc y c o m plicati o ns 
s uc h as s p o nta ne o us a b orti o n/ miscarria ge a n d c o n ge nital a n o malies are c o nsi dere d S A Es a n d 
m ust be re p orte d as descri be d i n Secti o n 9. 5 . N ote t hat a n electi ve a b orti o n is n ot c o nsi dere d a n 
S A E. Pre g na nc y  a n d pre g na nc y o utc o mes m ust be re p orte d o n a Pre g na nc y  N otificati o n F or m or 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
8 0
Pre g na nc y  O utc o me F or m, res pecti vely, a n d se nt t o t he S p o ns or or desi g nee wit hi n 2 4 h o urs of 
t he In vesti gat or or site pers o n nel lear ni n g of t he pre g na nc y or pre g na nc y  o utc o me. 
T he c hil d b or n t o a fe male partici pa nt or part ner of a male partici pa nt e x p ose d t o st u d y dr u g m a y
be f oll o we d f or 3 m o nt hs after deli ver y if c o nse nt is pr o vi de d. T he o utc o me of a ny pre g na nc y 
a n d t he prese nce or a bse nce of a n y c o n ge nital a b n or malit y will be rec or de d i n t he Pre g na nc y 
O utc o me F or m a n d re p orte d t o t he S p o ns or or desi g n ee. An y  c o n ge nital a b n or malities i n t he 
offs pri n g will be re p orte d as a n S A E a n d m ust be re p orte d as descri be d i n Secti o n 9. 5 .
I nf or mati o n re gar di n g pre g na nc y testi n g (i ncl u di n g defi niti o n of fe males of c hil d beari n g 
p ote ntial) is pr o vi de d i n Secti o n 8. 5 . Hi g hly effecti ve mea ns of c o ntrace pti o n are liste d i n 
Secti o n 8. 5. 4 .
9. 8.
Re p orti n g O ver d ose
If a partici pa nt ta kes m ore t ha n t he pr ot oc ol-defi ne d d ose of a st u d y dr u g i n a da y a n d 
e x perie nces a dr u g relate d A E, t his will be re p orte d as a n o ver d ose ( A Es m ust be rec or de d o n t he 
A E e C R F) a n d a pr ot oc ol de viati o n. H o we ver, if t he partici pa nt di d n ot e x perie nce a n y A Es, t his 
will o nl y  be re p orte d as a pr ot oc ol de viati o n. 
T he I n vesti gat or will disc uss t he ris ks a n d c o ncer ns of i n vesti gati o nal a ge nt e x p os ure wit h t he 
partici pa nt. Partici pa nts are t o be i nstr ucte d t o c o ntact t heir st u d y site i m me diatel y if a n o ver d ose 
of st u d y  dr u g is s us pecte d. A n o ver d ose wit h ass ociate d A Es m ust be re p orte d wit hi n 2 4 h o urs of 
t he In vesti gat or, desi g nee, or site pers o n nel lear ni n g of t he o ver d ose a n d re p orte d t o t he St u d y  
Direct or/ Me dical M o nit or. A n o ver d ose m ust be f oll o we d u ntil a n y  a d verse effects are res ol ve d 
or sta bilize d, or u ntil reas o na ble atte m pts t o deter mi ne res ol uti o n of t he e ve nt are e x ha uste d.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
8 1
1 0.
D A T A A N A L Y SI S A N D S T A TI S TI C A L P L A N S
1 0. 1.
S a m ple Size
Part A: A c o h ort size of u p t o a p pr o xi matel y 6 partici pa nts f or eac h a ge gr o u p: 6 t o 1 1 a n d 1 2 t o 
1 7 is base d o n a t y pical size f or a si n gle-d ose P K st u d y  a n d is i nte n de d t o bala nce t he desire t o 
mi ni mize e x p os ure of pe diatric partici pa nt s t o a n o vel c o m p o u n d at t his sta ge of v o xel ot or ’s 
de vel o p me nt wit h t he nee d t o o btai n P K, safet y a n d t olera bilit y data. N o f or mal p o wer or sa m ple 
size calc ulati o ns were perf or me d t o deter mi ne t he c o h ort size.
Part B: A p pr o xi matel y  1 2 partici pa nts at 9 0 0 m g were selecte d t o deter mi ne preli mi nar y  safety, 
t olera bilit y, P K, la b orat or y effects a n d treat me nt res p o nse of v o xel ot or i n pe diatric partici pa nts 
wit h S C D. T he n u m ber of par tici pa nts ma y be i ncrease d t o a p pr o xi matel y 3 6 t o f urt her 
c haracterize t he effect of m ulti ple d oses of v o xel ot or. U p o n a fa v ora ble re vie w b y t he D S M B, 
d osi n g of a mi ni m u m of 6 partici pa nts at 1 5 0 0 m g ma y  c o m me nce ( de pe n de nt o n h o w ma n y 
partici pa nts were e nr olle d at 9 0 0 m g, ie, n ot t o e xcee d a t otal st u d y  size of a p pr o xi matel y 3 6).
T he st u d y  wit h N = 1 2 f or 9 0 0 m g is a de q uately p o were d f or t he pri mar y e n d p oi nt of c ha n ge 
fr o m baseli ne t o Wee k 2 4 i n H b. P o wer calc ulatio ns ass u me n or mall y  distri b ute d data, a mea n 
treat me nt effect (c ha n ge fr o m baseli ne) of 0. 8 g/ d L, wit h a sta n dar d de viati o n ( S D) of 
0. 6 g/ d L. F or a 2-si de d al p ha = 0. 0 5 a n d N = 1 2, p o wer e xcee ds 9 0 % wit h a paire d t- test t o reject 
t he n ull h yp ot hesis of e q u alit y of p ost-treat me nt a n d baseli ne H b mea ns. T he esti mates of 
0. 8 a n d 0. 6 g/ d L f or t he mea n a n d S D, res pecti vel y , are base d o n a vaila ble Da y 9 0 data fr o m 
C o h orts 1 6 a n d ( partial data ) 1 7 fr o m t he G B T 4 4 0-0 0 1 st u d y .
Part C: U p t o 5 0 pe diatric partici pa nts w h o are 4 t o 1 7 y ears of a ge wit h S C D will be e nr olle d. 
F or t he pri mar y  efficac y e n d p oi nt, c ha n ge fr o m baseli ne i n T A M M T C D vel ocit y at Wee k 4 8, 
a sa m ple size of 3 0 partici pa nts ac hie ves greater t ha n 9 5 % p o wer t o detect a mea n differe nce of 
1 5 c m/sec wit h a n esti mate d sa m ple sta n dar d de viati o n of 2 2 c m/sec usi n g a paire d t -test 
( 2-si de d) wit h a si g nifica nce le vel (al p ha) of 0.1 0.
Part D: A p pr o xi matel y  3 0 pe diatric partici pa nts wit h S C D w h o are 6 m o nt hs t o < 4 ye ars of a ge
will be e nr olle d . T he sa m ple size was selecte d t o pr o vi de descri pti ve assess me nt of safety, 
t olera bilit y, a n d P K effects of v o xel ot or i n t his y o u n ger a ge gr o u p wit h n o f or mal statistical 
ass u m pti o ns .
1 0. 2.
P o p ul ati o ns f or A n al ysis
T w o a nal ys is p o p ulati o ns will be defi ne d:

Safet y  p o p ulati o n : all partici pa nt s w h o recei ve a ny a m o u nt of st u d y dr u g.

P K p o p ulati o n : all partici pa nts w h o recei ve a n y a m o u nt of st u d y dr u g a n d w h o 
pr o vi de P K data fr o m at least o ne p ost d ose sa m ple i n plas ma.
If a ny partici pa nt s are f o u n d t o be n o n-c o m plia nt wit h res pect t o d osi n g or ha ve i nc o m plete data, 
pr ot oc ol vi olati o ns, or cli nical e ve nts t hat affect P K, a decisi o n will be ma de o n a case -b y -case 
basis as t o t heir i ncl usi o n i n t he a nal ys is. Partici pa nt s i n t his p o p ulati o n will be use d f or all P K 
s u m maries.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
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1 0. 3.
A n al yses
Details of all pla n ne d a nal y ses will be s pecifie d i n a se parate S tatistical A nal y sis P la n ( S A P).
T he S A P will be fi nalize d pri or t o fi nal data base l oc k. Data will be prese nte d b y  eac h st u d y part 
( Parts A a n d B) a n d d ose le vel. F or Part C , data will be prese nte d b y a ge gr o u p ( 4 – 1 1 ye ars a n d
1 2 – 1 7 ye ars). Part D data will be prese nte d b y a ge gr o u p ( 6 m o nt hs t o < 2 years a n d 2 t o < 4 
ye ars).
De m o gra p hic a n d baseli ne c haracteristics, pri mar y a n d sec o n dar y  e n d p oi nts, a n d safety 
para meters will be s u m marize d usi n g descri pti ve statistics a n d prese nte d i n select i n di vi d ual 
listi n gs. 
1 0. 3. 1. 
P h ar m ac o ki netic D at a
F or Part A, n o nc o m part me ntal met h o ds will be use d f or deter mi nati o n of P K para meters. All P K 
para meters will be prese nte d b y  i n di vi d ual listi n gs a n d s u mmar y  statistics (e g, mea n, ge o metric 
mea n, me dia n, sta n dar d de viati o n, 9 5 % c o nfi de nce i nter val, c oefficie nts of variati o n, mi ni m u m 
a n d ma xi m u m, a n d n u m ber of partici pa nts). Preli mi nar y  meta b olite pr ofili n g of plas ma a n d/ or 
w h ole bl o o d ma y  be c o n d ucte d.
I n Part B, R B C c o nce ntrati o ns will be calc ulate d fr o m w h ole -bl o o d a n d plas ma c o nce ntrati o ns. 
T he f oll o wi n g plas ma, w h ole -bl o o d, a n d R B C P K para meters will be calc ulate d f or v o xel ot or, as 
a p pr o priate:
C ma x , Tma x , A U C0- last, A U C0- i nf, area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me zer o ( pre d ose) 
t o 2 4 h o urs ( A U C0- 2 4) f oll o wi n g t he first a n d last da y of d osi n g, acc u m ulati o n rati o, 
bl o o d/ plas ma rati o, R B C/ plas ma rati o, ter mi nal half- life (t1/ 2) a n d perce nt H b occ u pa nc y.
I n Parts C a n d D, p o p ulati o n PK m o deli n g will be use d t o deter mi ne t he w h ole -bl o o d a n d plas ma 
P K para meters of v o xel ot or i n t he st u d y  p o p ulati o n. T he P K para meters t o be deter mi ne d will 
i ncl u de Cma x , A U C, t1/ 2,a n d perce nt H b occ u pa nc y.
1 0. 3. 2.
S afet y D at a
All safet y assess me nts will be c o n d uc te d o n t he Safety p o p ulati o n.
A T E A E is defi ne d as a n A E t hat e mer ges o n or after i nitiati o n of st u d y  dr u g ( ha vi n g bee n a bse nt 
pretreat me nt), or a n A E t hat e xiste d pretreat me nt a n d w orse ne d o n treat me nt (relati ve t o t he 
pretreat me nt state) . T he n u m ber a n d perce nta ge of partici pa nt s re p orti n g T E A Es will be 
ta b ulate d by Me d D R A ® (c urre nt versi o n) sys te m or ga n class a n d preferre d ter m, se verit y a n d
relati o ns hi p t o st u d y me dicati o n. Seri o us T E A Es a n d T E A Es res ulti n g i n disc o nti n uati o n of 
st u d y dr u g will be s u m marize d se parately.
C o nc o mita nt me dicati o ns will be ma p pe d usi n g t he W H O D R U G dicti o nar y (c urre nt versi o n).
T he n u m ber a n d perce nta ge of partici pa nt s ta ki n g eac h c o nc o mita nt me dicati o n will be 
ta b ulate d.
A nal y sis of la b orat or y res ults will be base d o n t hose re p orte d b y t he local la b orat or y at eac h site.
C o nti n u o us la b orat or y  meas ure me nts will be descri pti vel y s u m marize d at eac h visit f or o bser ve d 
val ues a n d c ha n ges fr o m baseli ne.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
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Vital si g ns a n d E C G para meters ( base d o n a vera ge of tri plicate meas ure me nts ) will be 
s u m marize d at eac h visit f or o bser ve d val ues a n d c ha n ges fr o m baseli ne. I n a d diti o n, Q T a n d 
Q Tc i nter vals will be s u m marize d cate g oricall y  as n u m ber a n d perce nta ge of partici pa nt s wit h 
a b n or mal val ues or i ncreases.
1 0. 3. 3.
Effic ac y D at a
T he la b orat or y p a ra meters (H b , retic ul oc yte c o u nt, er yt hr o p oieti n, L D H a n d i n direct bilir u bi n )
a n d cere bral bl o o d fl o w as meas ure d b y T A M M T C D vel ocit y ( Parts B a n d C o nl y ) will be liste d 
a n d s u m marize d at eac h visit f or o bser ve d val ues a n d c ha n ges fr o m baseli ne usi n g a p pr o priate 
descri pti ve statistics . Ti me t o i nitial H b res p o nse will be s u m marize d descri pti vel y  ( Parts C 
a n d D). T he pr o p orti o n of partici pa nts wit h n or mal T C D at 4 8 wee ks will be s u m marize d 
(Part C).
F or Part s C a n d D, t he i nci de nce of str o ke a n d a n n ualize d i nci de nce of V O C will be s u m marize d 
descri pti vel y. 
F or Part B o nl y, c ha n ge fr o m Baseli ne t o Wee ks 2 1 – 2 4 i n t he S C D S M T S S; f or eac h partici pa nt, 
t he T S S will be c o m p ute d as f oll o ws: T he Baseli ne T S S is t he a vera ge of t he sc ore d uri n g t he 
3 5 -d a y  Scree ni n g peri o d; d uri n g t he treat me nt peri o d, t he T S S is t he a vera ge sc ore eac h 4- wee k 
peri o d o n treat me nt. T he 4 -wee k peri o ds are Wee ks 1 – 4, 5 – 8, 9 – 1 2, 1 3 – 1 6, 1 7 – 2 0 a n d 2 1 – 2 4 
(a n d f oll o ws si milarl y f or partici pa nts w h ose partici pati o n e xcee ds 2 4 wee k s). C ha n ge fr o m 
baseli ne i n t he T S S a n d t he pr o p orti o n of da y s wit h S C D s ym pt o m e xacer bati o n will 
s u m marize d usi n g descri pti ve statistics (Part B) .
1 0. 3. 4.
H a n dli n g of Missi n g D at a
Missi n g data will n ot be i m p ute d. T he details o n efficac y  a nalys is f or partici pa nt s t hat ha ve bee n 
tra nsf use d will be detaile d i n t he Statistical A nal ysis Pla n.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
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1 1.
R E G U L A T O R Y, E T HI C A L A N D L E G A L O B LI G A TI O N S
1 1. 1.
Et hic al C o nsi der ati o n
It is t he res p o nsi bilit y of t he In vesti gat or t o ass ure t hat t he st u d y  is c o n d ucte d i n acc or da nce wit h 
c urre nt c o u ntr y a n d l ocal re g ulati o ns, F D A, I CH G C P a n d t he Declarati o n of Helsi n ki.
1 1. 2.
I nstit uti o n al Re vie w B o ar d or Et hics C o m mittee a n d Re g ul at or y 
A p pr o v al
T he I n vesti gat or m ust i nf or m, a n d o btai n a p pr o val fr o m, t he I R B / E C f or t he c o n d uct of t he st u dy 
at na me d sites, f or t he pr ot oc ol, t he I CF , a n d a n y ot her writte n i nf or mati o n t hat will be pr o vi de d 
t o t he partici pa nt s a n d a n y a d vertise me nts t hat will be use d. Writte n a p pr o val m ust be o btai ne d 
pri or t o recr uit me nt of partici pa nt s i nt o t he st u d y a n d s hi p me nt of i n vesti gati o nal dr u g.
Pr o p ose d a me n d me nts t o t he pr ot oc ol a n d af ore me nti o ne d d oc u me nts m ust be disc usse d a m o n g 
t he S p o ns or a n d C R O, a n d t he n s u b mitte d t o t he I R B/ E C f or a p pr o val, as well as s u b mitte d t o 
re g ulat or y a ut h orities pri or t o i m ple me ntati o n. A me n d me nts may be i m ple me nte d o nl y after a 
c o p y of t he I RB / E C a p pr o val letter has bee n tra ns mitte d t o t he S p o ns or. A me n d me nts t hat are 
i nte n de d t o eli mi nate a n a p pare nt i m me diate hazar d t o partici pa nt s ma y be i m ple me nte d pri or t o 
recei vi n g S p o ns or or I RB a p pr o val. H o we ver, i n t his case, a p pr o val m ust be o btai ne d as s o o n as 
p ossi ble after i m ple me ntati o n.
T he I n vesti gat or will be res p o nsi ble f or e ns uri n g t hat a n a n n ual u p date is se nt t o t he I RB / E C t o 
facilitate t heir c o nti n ui n g re vie w of t he trial (if nee de d), a n d t hat t he IR B is i nf or me d a b o ut t he 
e n d of t he st u d y. C o pies of t he u p date, s u bse q ue nt a p pr o vals a n d fi nal letter m ust be se nt t o t he 
S p o ns or.
1 1. 3.
I ns ur a nce a n d Fi n a nci al Discl os ure
T he S p o ns or has s u bscri be d t o a n i ns ura nce p olic y  c o veri n g, i n its ter ms a n d pr o visi o ns, its le gal 
lia bilit y f or i nj uries ca use d t o partici pati n g pers o ns a n d arisi n g o ut of t his researc h perf or me d 
strictl y i n acc or da nce wit h t he scie ntific pr ot oc ol as well as wit h a p plica ble la w a n d pr ofessi o nal 
sta n dar ds.
Fi na ncial Discl os ure state me nts will be ha n dle d i n a se parate a gree me nt a part fr o m t he pr ot oc ol, 
ke pt o n file a n d s u b mitte d as a p plica ble wit h a n y s u bse q ue nt lice nse a p plicati o n.
1 1. 4.
Esse nti al D oc u me nt ati o n Re q uire me nts
T he S p o ns or will c ollect fr o m t he i n vesti gati o nal site t he re q uire d esse ntial re g ulat or y  d oc u me nts 
per I C H g ui da nce pri or t o v o xel ot or s hi p me nt t o t he site.
1 1. 5.
I nf or me d C o nse nt a n d Asse nt
It is t he I n vesti gat or’s res p o nsi bilit y t o o btai n writte n i nf or me d c o nse nt/asse nt fr o m t he 
partici pa nt after a de q uate e x pla nati o n of t he o bjecti ves, met h o ds, a ntici pate d be nefits, a n d 
p ote ntial ris ks of t he st u d y a n d bef ore a n y st u d y pr oce d ures are c o m me nce d. T he partici pa nt
s h o ul d be gi ve n a c o p y of t he IC F i n t heir nati ve la n g ua ge. T he i nf or me d c o nse nt pr ocess s h o ul d 
be rec or de d i n t he s o urce d oc u me ntati o n . T he ori gi nal c o p y  of t he si g ne d a n d date d i nf or me d 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
8 5
c o nse nt m ust be retai ne d i n t he i nstit uti o n’s rec or ds, a n d is s u bject t o i ns pecti o n b y  
re prese ntati ves of t he S p o ns or, or re prese ntati ves fr o m re g ulat or y a ge ncies.
Partici pa nt s u nable t o si g n t he I C F ma y  partici pate i n t he st u d y if a le gal re prese ntati ve or 
wit ness pr o vi des t he c o nse nt (i n acc or da nce wit h t he pr oce d ures of I CH- G C P a n d l ocal 
re g ulati o ns) a n d t he partici pa nt c o nfir ms his/ her i nterest i n st u d y  partici pati o n. T he partic i pa nt
will be i nf or me d t hat he/s he ca n freel y wit h dra w c o nse nt a n d st o p partici pati o n i n t he st u d y  at 
a n y ti me wit h n o prej u dice t o f urt her treat me nt. It is t he partici pa nt ’s res p o nsi bilit y t o 
c o m m u nicate t his decisi o n t o t he In vesti gat or.
Partici pa nt s w h o i nitiall y si g n t he Asse nt F or m a n d s u bse q ue ntl y le gall y bec o me a n a d ult w hile 
acti vel y partici pati n g i n t he st u d y ( bef ore t he E O S visit) s h o ul d be re- c o nse nte d usi n g t he A d ult 
I CF s o o n after t heir stat us c ha n ges.
1 1. 6.
C o nfi de nti alit y
T he I n vesti gat or m ust e ns ure t hat t he partici pa nt ’s pri vac y is mai ntai ne d. O n t he C R F or ot her 
d oc u me nts s u b mitte d t o t he S p o ns or, partici pa nt s will be i de ntifie d b y a partici pa nt st u d y n u m ber 
o nl y . D oc u me nts t hat are n ot s u b mitte d t o t he S p o ns or ( e g, si g ne d I CF ) s h o ul d be ke pt i n a 
strictl y c o nfi de ntial file b y t he I n vesti gat or.
T he I n vesti gat or s hall per mit a ut h orize d re prese ntati ves of t he S p o ns or, re g ulat or y a ge ncies a n d 
I RBs / E Cs t o re vie w t he p orti o n of t he partici pa nt ’s me dical rec or d t hat is directly relate d t o t he 
st u d y. As part of t he re q uire d c o nte nt of i nf or me d c o nse nt, t he partici pa nt m ust be i nf or me d t hat 
his/ her rec or ds will be re vie we d i n t his ma n ner.
1 1. 7.
Re g ul at or y, E t hic al, a n d L e g al O bli g ati o ns
T he st u d y  will c o m ply wit h Ge neral Data Pr otecti o n Re g ulati o n ( G D P R) 2 0 1 8 a n d a p plica ble 
l ocal data pr otecti o n re g ulati o ns. Data c ollecte d will be pse u d o n ymize d. 
T he pr ocessi n g of t he pers o nal data of partici pa nts will be mi ni mize d b y  ma ki n g use of a u ni q ue 
partici pa nt st u d y  n u m ber o nl y o n st u d y d oc u me nts a n d electr o nic data base(s).
All st u d y  d oc u me nts will be st ore d sec urely a n d o nl y accessi ble b y st u d y staff a n d a ut h orize d 
pers o n nel. T he st u d y staff will safe g uar d t he pri vac y of partici pa nts’ pers o nal data. T he patie nt 
i nf or mati o n s heet/I CF f or t he st ud y  will i nf or m t he patie nt of t heir ri g hts a n d pr o vi de a p pr o priate 
c o ntact details of t he Data Pr otecti o n Officer.
1 1. 8.
Tri al D oc u me nt ati o n a n d D at a St or a ge
T he I n vesti gat or m ust retai n a c o m pre he nsi ve a n d ce ntralize d fili n g sys te m of all esse ntial trial-
related d oc u me ntati o n as o utli ne d i n I C H G C P Secti o n 8. T his I n vesti gat or Site File m ust be 
asse m ble d a n d mai ntai ne d i n a ti mel y  ma n ner i n or der t o e na ble i ns pecti o n b y  t he S p o ns or a n d 
re prese ntati ves of re g ulat or y a ut h orities.
T he I n vesti gat or m ust retai n esse n tial d oc u me nts u ntil at least 2 years after t he last a p pr o val of a 
mar keti n g a p plicati o n i n a n y  IC H re gi o n . Partici pa nt files a n d ot her s o urce data (i ncl u di n g c o pies 
of pr ot oc ols, ori gi nal re p orts of test res ults, i n vesti gati o nal dr u g dis pe nsi n g l o gs, c orres p o n de nce, 
rec or ds of i nf or me d c o nse nt, a n d ot her d oc u me nts pertai ni n g t o t he c o n d uct of t he trial) m ust be 
ke pt f or t he ma xi m u m peri o d of ti me per mitte d b y t he i nstit uti o n. D oc u me nts s h o ul d be st ore d i n 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
8 6
s uc h a wa y t hat t he y ca n be accesse d/ data retrie ve d at a later date. C o nsi derati o n s h o ul d be gi ve n 
t o sec urit y a n d e n vir o n me ntal ris ks.
N o trial d oc u me nt will be destr o ye d wit h o ut pri or writte n a gree me nt bet wee n t he S p o ns or a n d 
t he In vesti gat or. S h o ul d t he I n vesti gat or wis h t o assi g n t he trial rec or ds t o a n ot her part y or m o ve 
t he m t o a n ot her l ocati o n, writte n a gree me nt m ust be o btai ne d fr o m t he S p o ns or.
1 1. 9.
St u d y Rec or d Rete nt i o n
T he I n vesti gat or will mai ntai n a de q uate rec or ds, i ncl u di n g partici pa nts’ me dical rec or ds, 
la b orat or y re p orts, si g ne d c o nse nt f or ms, dr u g acc o u nta bilit y rec or ds, safet y re p orts, i nf or mati o n 
re gar di n g partici pa nts w h o disc o nti n ue d t he pr ot oc ol, a n d a n y ot her perti ne nt data. All st u d y 
rec or ds m ust be retai ne d f or at least 2 ye ars after t he last a p pr o val of a mar keti n g a p plicati o n i n 
t he U S A or a n I C H re gi o n a n d u ntil ( 1) t here are n o pe n di n g or c o nte m plate d mar keti n g 
a p plicati o ns i n t he U S A or a n I C H re gi o n or ( 2) at least 2 years ha ve ela pse d si nce t he f or m al 
disc o nti n uati o n of cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct u n der st u d y . T he 
I n vesti gat or/i nstit uti o n s h o ul d retai n partici pa nt i de ntifiers f or at least 1 5 years after t he 
c o m pleti o n or dis c o nti n uati o n of st u d y. St u d y partici pa nt files a n d ot her res o urce data m ust be 
ke pt f or t he ma xi m u m peri o d of ti me per mitte d b y t he h os pital, i nstit uti o n b ut n ot less t ha n 
1 5 ye ars. T hese d oc u me nts s h o ul d be retai ne d f or a l o n ger peri o d, if re q uire d b y t he a p plica ble 
re g ulat or y re q uire me nts. G B T m ust be n otifie d s h o ul d t he In vesti gat or/i nstit uti o n be u na ble t o 
c o nti n ue wit h t he mai nte na nce of st u d y partici pa nt files f or t he f ull 1 5 years. All st u d y  rec or ds 
m ust be st ore d i n a sec ure a n d safe facilit y .
T he In vesti gat or m ust ret ai n pr ot oc ols, a me n d me nts, IR B/ E C a p pr o vals, c o pies of t he F or m F D A 
1 5 7 2, si g ne d a n d date d c o nse nt f or ms, me dical rec or ds, e C R Fs, dr u g acc o u nta bilit y  rec or ds, all 
c orres p o n de nce a n d a n y ot her d oc u me nts pertai ni n g t o t he c o n d uct of t he s t u d y.
If t he Pri nci pal I n vesti gat or m o ves, wit h dra ws fr o m a n i n vesti gati o n or retires, t he res p o nsi bilit y 
f or mai ntai ni n g t he rec or ds ma y be tra nsferre d t o a n ot her pers o n w h o will acce pt res p o nsi bilit y.
N otice of tra nsfer m ust be ma de t o a n d a gree d b y t he S p o ns or. T he I n vesti gat or m ust n otif y  t he 
S p o ns or i m me diatel y  i n t he e ve nt of acci de ntal l oss or destr ucti o n of a ny pr ot oc ol rec or ds.
1 1. 1 0.
Discl os ure of I nf or m ati o n
I nf or mati o n c o ncer ni n g t he st u d y, pate nt a p plicati o ns, pr ocesses, scie ntific data or ot her perti ne nt 
i nf or mati o n is c o nfi de ntial a n d re mai ns t he pr o pert y of t he S p o ns or. T he I n vesti gat or ma y  use 
t his i nf or mati o n f or t he p ur p oses of t he st u dy o nl y.
It is u n derst o o d b y t he I nvesti gat or t hat t he S p o ns or will use i nf or mati o n de vel o pe d i n t his 
cli nical st u d y i n c o n necti o n wit h t he de vel o p me nt of v o xel ot or a n d, t heref ore, ma y discl ose it as 
re q uire d t o ot her cli nical i n vesti gat ors a n d t o re g ulat or y a ge ncies. I n or der t o all o w t he use of t he 
i nf or mati o n deri ve d fr o m t his cli nical st u d y, t he I n vesti gat or u n dersta n ds t hat he/s he has a n 
o bli gati o n t o pr o vi de c o m plete test res ults a n d all data de vel o pe d d uri n g t his st u d y  t o t he 
S p o ns or.
Ver bal or writte n disc ussi o n of res ults pri or t o st u d y  c o m pleti o n a n d f ull re p orti n g s h o ul d o nl y 
be u n derta ke n wit h writte n c o n se nt fr o m t he S p o ns or.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
8 7
1 1. 1 1.
P u blic ati o n
It is i nte n de d t o p u blis h t he res ults of t he st u d y as a w h ole o nce all partici pa nt s ha ve c o m plete d 
t he st u d y, t he cli nical data base has bee n l oc ke d, a n d t he st u d y has bee n a nal yze d.
T he I n vesti gat or or t he S p o ns or ma y  n ot s u b mit f or p u blicati o n or prese nt t he res ults of t his 
st u d y wit h o ut all o wi n g eac h of t he ot her parties 3 0 da ys i n w hic h t o re vie w a n d c o m me nt o n t he 
pre -p u blicati o n ma n uscri pt.
T he In vesti gat or ma y  n ot s u b mit t he res ults of t he st u d y f or p u blicati o n wit h out t he pri or c o nse nt 
of t he S p o ns or.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
8 8
1 2.
A D MI NI S T R A TI V E O B LI G A TI O N S
1 2. 1.
S o urce D at a
Ori gi nal d oc u me nts, data, rec or ds ( e g, cli nic rec or ds, la b orat or y n otes, me m ora n da, partici pa nt
diaries or e val uati o n c hec klists, p har mac y  dis pe nsi n g rec or ds, rec or de d data fr o m a ut o mate d 
i nstr u me nts, c o pies or tra nscri pti o ns certifie d after verificati o n as bei n g acc urate a n d c o m plete, , 
X- ra ys, partici pa nt files, a n d rec or ds ke pt at t he p har mac y, at t he la b orat ories, a n d at 
me dic o -tec h nical de part me nts i n v ol ve d i n t he cli nical trial) a n d all rele va nt secti o ns of t he 
partici pa nt ’s me dical rec or ds a n d all ot her data c ollecti o n ma de s pecific t o t his trial c o nstit ute 
s o urce d oc u me nts.
T he c o m plete d C R F is n ot a s o urce d oc u me nt. T he I n vesti gat or/i nstit uti o n will per mit 
trial-relate d m o nit ori n g, a u dits, I R B / E C re vie w a n d re g ulat or y i ns pecti o n b y pr o vi di n g direct 
access t o s o urce d oc u me nts.
1 2. 2.
D at a C ollecti o n
T he I n vesti gat or will be res p o nsi ble f or mai ntai ni n g acc urate a n d a de q uate case rec or ds (s o urce 
d oc u me nts) fr o m w hic h data will be tra nscri be d ( or if E D C , s o urce data, tra nsferre d) t o C R Fs 
desi g ne d t o rec or d data perti ne nt t o t his st u d y . All rele va nt o bser vati o ns a n d data relate d t o t he 
st u d y will be rec or de d. T his will i ncl u de me dical a n d me dicati o n hist or y , p h ysical e xa mi nati o ns, 
a chec klist of i ncl usi o n a n d e xcl usi o n criteria, I MP a d mi nistrati o n, a rec or d of sa m ple c ollecti o n, 
cli nical assess me nts, A Es a n d fi nal e val uati o n. T he cli nical site Cli nical Researc h Ass ociate 
( C R A) will re vie w all C R Fs a n d c o m pare data t o t hat c o ntai ne d i n cli nic n otes a n d partici pa nt s’ 
s o urce d oc u me nts/ me dical rec or ds.
Data c ollecte d re gar di n g eac h partici pa nt will be e ntere d i nt o t he C R F i n a ti mel y  ma n ner 
( ge nerall y wit hi n 5 b usi ness da ys of data ca pt ure). T he In vesti gat or will be res p o nsi ble f or t he 
ti meli ness, c o m plete ness, a n d acc urac y of t he d oc u me ntati o n e ntere d i nt o t he C R Fs.
1 2. 3.
M o nit ori n g
It is u n derst o o d t hat m o nit ors, a n d a n y a ut h orize d pers o n nel c o ntracte d t o S p o ns or ma y c o ntact 
a n d visit t he In vesti gat or, a n d t hat t he y  will be all o we d t o i ns pect t he vari o us rec or ds of t he trial 
o n re q uest ( ori gi nal s o urce rec or ds a n d ot her perti ne nt trial data), pr o vi de d t hat partici pa nt
c o nfi de ntialit y is mai ntai ne d, a n d t hat t he i ns pecti o n is c o n d ucte d i n acc or da nce wit h l ocal 
re g ulati o ns.
It is t he m o nit or’s res po nsi bilit y  t o i ns pect t he C R Fs at re g ular i nter vals t hr o u g h o ut t he trial t o 
verif y  a d here nce t o t he pr ot oc ol, t he c o m plete ness, acc urac y a n d c o nsiste nc y of t he data, a n d 
a d here nce t o G C P re g ulati o ns a n d g ui deli nes.
T he I n vesti gat or a grees t o c o -o perate wi t h t he m o nit or t o e ns ure t hat a n y pr o ble ms detecte d 
d uri n g t he c o urse of t hese m o nit ori n g visits are res ol ve d.
1 2. 4.
Q u alit y C o ntr ol , Q u alit y Ass ur a nce a n d Re g ul at or y I ns pecti o ns
Q ualit y  C o ntr ol will be perf or me d acc or di n g t o S p o ns or a n d C R O i nter nal pr oce d ures. A Q ualit y  
Ass ura nce re prese ntati ve of t he S p o ns or a n d/ or C R O ma y  a u dit t he st u d y. In a d diti o n, t he 
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
8 9
i n vesti gati ve site ma y be i ns pecte d b y a re prese ntati ve of a re g ulat or y a ut h orit y. T he In vesti gat or 
c o m mits t o ma ki n g all necessar y data/ d oc u me nts a n d ke y pers o n nel a vaila ble t o s u p p ort t he 
i ns pecti o n or a u dit.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
9 0
1 3.
S T U D Y R E P O R T
A cli nical st u d y  re p ort, c o m plia nt wit h t he re q uire me nts of IC H E 3, will be pre pare d b y  t he 
S p o ns or or desi g nee .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
9 1
1 4.
R E F E R E N C E S
1.
A b d ul mali k O, G hat ge M S, M usa y e v F N, Pari k h A, C he n Q, Ya n g J, et al. 
Cr y stall o gra p hic a nalys is of h u ma n he m o gl o bi n el uci dates t he str uct ural basis of t he 
p ote nt a n d d ual a ntisic kli n g acti vit y  of pyri d yl  deri vati ves of va nilli n. Acta Cr yst. 
2 0 1 1; D 6 7: 9 2 0 – 9 2 8.
2.
A da ms RJ, Mc Kie V , Hsu L , Files B, Vic hi ns k y E, Pe gel o w C H, et al. Pre ve nti o n of a 
first str o ke by tra nsf usi o ns i n c hil dre n wit h s ic kle cell ane mia a n d ab n or mal res ults o n 
tra nscra nial d o p pler ultras o n o gra p h y . Ne w E n gl J Me d. 1 9 9 8; 3 3 9:5 – 1 1.
3.
A ki ns he y e I, Als ulta n A, S ol o vieff N, N g o D, Bal d wi n C T, Se bastia ni P, et al. Fetal 
he m o gl o bi n i n sic kle cell a ne mia. Bl o o d. 2 0 1 1; 1 1 8( 1): 1 9 – 2 7.
4.
Ar y a R, R ola n P E, W o ott o n R, P os ner J, Belli n g ha m AJ . T ucares ol i ncreases o xy ge n 
affi nit y a n d re d uces hae m ol ysis i n s u bjects wit h sic kle cell a nae mia. Britis h J o ur nal of 
Hae mat ol o g y . 1 9 9 6; 9 3( 4): 8 1 7 – 2 1. 
5.
Ber na u di n F, Verl hac S, C he vret S, T orres M, C oic L , Ar na u d C, et al. G 6 P D deficie nc y , 
a bse nce of al p ha -t halasse mia, a n d he m ol ytic rate at baseli ne are si g nifica nt i n de pe n de nt 
ris k fact ors f or a b n or mall y hi g h cere bral vel ocities i n patie nts wit h sic kle cell a ne mia. 
Bl o o d. 2 0 0 8; 1 1 2: 4 3 1 4.
6.
Bra n d o w A M, Pa ne pi nt o J A. H y dr o x y u rea use i n sic kle cell disease: t he battle wit h l o w 
prescri pti o n rates, p o or patie nt c o m plia nce a n d fears of t o xicities. E x pert Re vie w of 
He mat ol o g y . 2 0 1 0; 3( 3): 2 5 5– 2 6 0.
7.
De Ba u n M R, G or d o n M, Mc Ki nstr y  R C, N oetzel MJ, W hite D A, Sar nai k S A, et al., 
C o ntr olle d trial of tra nsf usi o ns f or sile nt cere bral infarcts i n sic kle cell ane mia . N E n gl J 
Me d . 2 0 1 4; 3 7 1: 8 - 6 9 9.
8.
Eat o n W A, He nr y  E R, H ofric hter J, M ozzarelli A. Is c o o perati ve o x yge n bi n di n g b y  
he m o gl o bi n reall y  u n derst o o d? Nat Str uct Bi ol. 1 9 9 9;6( 4): 3 5 1 – 8 .
9.
Far ber M D, K os h y M, Ki n ne y T R . C o o perati ve st u d y of sic kle cell disease: De m o gra p hic 
a n d s oci oec o n o mic c haracteristics of patie nts a n d fa milies wit h sic kle cell disease. J 
C hr o n Dis. 1 9 8 5; 3 8( 6): 4 9 5 – 5 0 5.
1 0. F D A T he V oice of t he Patie nt A series of re p orts fr o m t he U. S. F o o d an d Dr u g 
A d mi nistrati o n’s ( F D A’s ) Patie nt- F oc use d Dr u g De vel o p me nt I nitiati ve Sic kle Cell 
Disease P u blic Meeti n g: Fe br uar y  7, 2 0 1 4 Re p ort Date: Oct o ber 2 0 1 4 Ce nter f or Dr u g 
E val uati o n a n d Researc h ( C D E R) a n d Ce nter f or Bi ol o gics E val uati o n a n d Researc h 
( C B E R) U. S. F o o d a n d Dr u g A d mi nistrati o n ( F D A).
1 1. G o nzalez F A, Ville gas A, R o per o P, Carre n o M D, A n q uita E, P ol o M, et al. 
Hae m o gl o bi n o pat hies wit h hi g h o x y ge n affi nit y. E x perie nce of Er yt hr o pat h ol o g y
C o o perati ve S pa nis h Gr o u p. A n n He mat ol. 2 0 0 9; 8 8: 2 3 5 – 2 3 8.
1 2. H o war d J, He m ma wa y CJ, Telfer P, La yt o n D M, P o rter J, A w o g ba de M,
et al. A p hase 
1/ 2 asce n di n g d ose st u d y a n d o pe n -la bel e xte nsi o n st u d y of v o xel ot or i n patie nts wit h 
sic kle cell disease. Bl o o d. 2 0 1 9; 1 3 3( 1 7): 1 8 6 5 -1 8 7 5 .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
9 2
1 3. H o p pe C, I n ati A, Br o w n C, Wa n g W, G or de u k V, L ie m R, et al. I nteri m res ults f or m a 
c o h ort i n a P hase 2a st u d y ( G B T 4 4 0 -0 0 7) e val uati n g a d olesce nts wit h S C D treate d wit h 
m ulti ple d oses of v o xel ot or ( G B T 4 4 0). A S H 5 9t h A n n ual Meeti n g a n d E x p ositi o n. 0 9 - 1 2 
Dece m ber 2 0 1 7. Atla nta G A. Oral prese ntati o n/ A bstract # 6 8 9.
1 4. I ngra m V M . " A S pecific C he mical Differe nce bet wee n Gl o bi ns of N or mal a n d Sic kle-
cell A ne mia He m o gl o bi ns". Nat ure. 1 9 5 6; 1 7 8 ( 4 5 3 7): 7 9 2 – 7 9 4.
1 5. Ita n o H , Pa uli n g L. A ra pi d dia g n ostic tes t f or sic kle cell a ne mia. Bl oo d. 1 9 4 9; 1 1 8 6: 6 6 –
6 8. 
1 6. Kei da n AJ, Fra n kli n I M, W hite R D, J o y  M, H ue h ns E R, St uart J. Effect of B W 1 2 C o n 
o x y ge n affi nit y of he m o gl o bi n i n sic kle -cell disease. La ncet. 1 9 8 6; 1( 8 4 8 5): 8 3 1 – 4 .
1 7. K os h y  M, T h o mas C , G o o d wi n J . J o ur nal of Pe diatric He mat ol o g y/ O nc ol o g y: Vasc ular 
lesi o ns i n t he ce ntral ner v o us s yste m i n sic kle cell disease ( ne ur o pat h ol o g y). J o ur nal of 
t he Ass ociati o n f or Aca de mic Mi n orit y P h ysicia ns: t he Official P u blicati o n of t he 
Ass ociati o n f or Aca de mic Mi n orit y  P h ysicia ns. 1 9 9 0; 1( 3): 7 1 – 7 8.
1 8. Krat o vil T, B ulas D, Drisc oll M C, S peller -Br o w n B, Mc Carter R, Mi n niti C P. 
H y dr o x y urea t hera p y  l o wers T C D vel ocities i n c hil dre n wit h sic kle cell disease. Pe diatr 
Bl o o d Ca ncer. 2 0 0 6; 4 7: 8 9 4 – 9 0 0. d oi: 1 0. 1 0 0 2/ p bc. 2 0 8 1 9.
1 9. Le hrer -Grai we r J, H o war d J, He m ma wa y CJ, A w o g ba de M, Telfer P, La yt o n M, et al. 
G B T 4 4 0, a p ote nt a nti -sic kli n g he m o gl o bi n m o difier re d uces he m olys is, i m pr o ves 
a ne mia a n d nearl y eli mi nates sic kle cells i n peri p heral bl o o d of patie nts wit h sic kle cell 
disease. Oral prese ntati o n: A merica n S ociet y of He mat ol o g y A n n ual Meeti n g; Orla n d o, 
F L. 2 0 1 5.
2 0. Nat ha n D G. He m o gl o bi n dis or ders: A l o o k t o t he f ut ure. Bl o o d . 2 0 1 3; 1 2 2( 6): 8 5 9– 6 0.
2 1. N g o D A, A u g y n D, A ki ns he y e I, Ha n ki ns J S, B ha n I, et al. Fetal hae m o gl o bi n le vels a n d 
hae mat ol o gica l c haracteristics of c o m p o u n d heter oz yg otes f or hae m o gl o bi n S a n d 
deleti o nal here ditar y  persiste nce of fetal hae m o gl o bi n. Britis h J Hae mat ol. 2 0 1 2; 1 5 6: 2 5 9-
2 6 4.
2 2. Nic h olls AJ, Par ker J E, P os ner JJ. I ncrease d H b- O 2 affi nit y  i n d uce d b y B W 1 2 C i n 
healt h y  v ol u nteers: effect o n heart rate. Br J Cli n P har mac ol. 1 9 8 9; 2 8: 2 1 5 P.
2 3. N o g uc hi, C T, R o d gers G P, Serjea nt G, Sc hec hter A N. Le vels of fetal he m o gl o bi n 
necessar y  f or treat me nt of sic kle cell disease. N E n gl J Me d. 1 9 8 8; 3 1 8( 2): 9 6– 9 .
2 4. O he ne -Fre m p o n g K, Wei ner SJ, Slee per L A, Miller S T, E m b ur y  S, M o o hr J W, et al. 
Cere br o vasc ular acci de nts i n sic kle cell dis ease: rates a n d ris k fact ors. Bl o o d. 1 9 9 8; 
9 1: 2 8 8.
2 5. Platt O S , G ui na na E C. B o ne Marr o w tra ns pla ntati o n i n sic kle cell a nae mia - T he 
dile m ma of c h oice. Ne w E n gla n d J o ur nal of Me dici ne. 2 0 1 4; 3 3 5: 4 2 6 – 4 2 8.
2 6. P o wars, D. Ma na ge me nt of cere bral vasc ul o pat h y i n c hil dre n wit h sic kle cell a ne mia. 
Britis h J o ur nal of Hae mat ol o g y . 2 0 0 0; 1 0 8( 4): 6 6 6– 6 7 8.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
P r ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
9 3
2 7. R ola n P E, Mercer AJ, W o ott o n R, P os ner J. P har mac o ki netics a n d p har mac o d y na mics of 
t ucares ol, a n a ntisic kli n g a ge nt, i n healt hy v ol u nteers. Br J Cli n P har mac ol. 
1 9 9 5; 3 9( 4): 3 7 5 – 8 0 .
2 8. R ola n P E, Par ker J E, Gra y  SJ, Weat herle y B C, I n gra m J, Lea ve ns W, et al. T he
p har mac o ki netics, t olera bilit y  a n d p har mac o d yna mics of t ucares ol ( 5 8 9 C 8 0; 4[ 2 -f or m yl-
3 -h y dr o x y p he n o x y m et h yl] be nz oic aci d), a p ote ntial a nti -sic kli n g a ge nt, f oll o wi n g oral
a d mi nistrati o n t o healt h y s u bjects. Br J Cli n P har mac ol. 1 9 9 3; 3 5( 4): 4 1 9 – 2 5 .
2 9. R ot h ma n S M, F ulli n g K H, Nels o n J S. Sic kle cell a ne mia a n d ce ntral ner v o us s y ste m 
i nfarcti o n: A ne ur o pat h ol o gical st u d y. A n n Ne ur ol. 1 9 8 6; 2 0: 6 8 4– 6 9 0. 
d oi: 1 0. 1 0 0 2/a na. 4 1 0 2 0 0 6 0 6.
3 0. S af o M K, A b d ul mali k O, Da ns o -Da n q ua h R, B ur nett J C, N o k uri S, J os hi G S, et al. 
Str uct ural basis f or t he p ote nt a ntisic kli n g effect of a n o vel class of fi ve -me m bere d 
heter oc y clic al de h ydic c o m p o u n ds. J Me d C he m. 2 0 0 4; 4 7: 4 6 6 5 – 4 6 7 6.
3 1. S mit h W R, Pe n bert h y  L T, B o vbjer g V E, Mc Clis h D K, R o berts J D, Da h ma n B, et al. 
Dail y assess me nt of pai n i n a d ults wit h sic kle cell disease. A n n I nter n Me d . 
2 0 0 8; 1 4 8( 2): 9 4 - 1 0 1.
3 2. Stei n ber g M H, Bart o n F, Castr o O, Pe gel o w C H, Ballas S K, K utlar
A, et al. Effect of 
h y dr o x y u rea o n m ortalit y a n d m or bi dit y i n a d ult sic kle cell a ne mia: ris ks a n d be nefits u p 
t o 9 ye ars of treat me nt. J A M A. 2 0 0 3; 2 8 9( 1 3): 1 6 4 5 – 5 1.
3 3. T u o h y  A M, Mc Kie V, Ma nci E A, A da ms RJ. Inter nal car oti d arter y  occl usi o n i n a c hil d 
wit h sic kle cell disease: Case re p ort a n d i m m u n o hist oc he mical st u d y . J Pe diatr He mat ol 
O nc ol. 1 9 9 7;( 1 9) 5 .
3 4. U S De part me nt of Healt h a n d H u ma n Ser vices. Nati o nal I nstit utes of Healt h. Nati o nal 
Heart, L u n g, a n d Bl o o d I nstit ute. E vi de nce - base d ma na ge me nt of sic kle cell disease. 
E x pert Pa nel Re p ort 2 0 1 4. htt p:// w w w. n hl bi. ni h. g o v/ g ui deli nes.
3 5. Ver d uzc o L A, Nat ha n D G. Sic kle cell disease a n d str o ke. Bl o o d. 2 0 0 9; 1 1 4: 5 1 1 7.
3 6. Vic h i ns k y E, H o p pe C C, Ata ga KI, Ware R E, N d u ba V, El -Bes hla w y  A. et al. A p hase 3 
ra n d o mize d trial of v o xel ot or i n sic kle cell disease. N E n gl J Me d. 2 0 1 9; 3 8 1: 5 0 9 - 5 1 9.
3 7. Wa hl S , Q uir ol o K C. C urre nt iss ues i n bl o o d tra nsf usi o n f or sic kle cell disease. 
C urr O pi n Pe diatr. 2 0 0 9; 2 1( 1): 1 5 – 2 1 .
3 8. Ware R E, Da vis B R, Sc h ultz W H, Br o w n C, A y g u n B, Sar nai k S A, et al. T C D wit h 
tra nsf usi o ns c ha n gi n g t o h ydr o x y u rea ( T Wi T C H): h ydr o x y u rea t hera py as a n alter nati ve 
t o tra nsf usi o ns f or pri mar y str o ke pre ve nti o n i n c hil dre n wit h sic kle cell a ne mia. Bl o o d. 
2 0 1 5; 1 2 6: 3.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
Pr ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
Pa ge 9 4
A P P E N DI X 1.
P A R T A S C H E D U L E O F A S S E S S M E N T S
Pr oce d ure
Scree ni n g
( U p t o 2 8 D a ys 
Bef ore D osi n g)
D a y 1 h
F oll o w -u p P eri o d
E arl y
Ter mi n ati o n/
Wit h dr a w al
D a y 2
D a y 3
D a y 5  
D a y 8
D a y 1 5
(± 1 D a y )
Asse nt (if ap pr o priate ) & I nf or me d C o nse nt
X
Re vie w I ncl usi o n/ E xcl usi o n Criteria
X
X
Me dicati o n &
Me dical Hist or y
X
X
Hei g ht a
X
B o d y Wei g ht
X
X
X
X
Vital Si g ns b
X
X
X
X
X
X
E C G c
X
X
X
X
P h ysical E xa mi nati o n d
X
X
X
X
Ser u m Pre g na nc y Test e
X
Uri ne Pre g na nc y Test e
X
X
X
He mat ol o g y, Ser u m C he mistr y , Li ver
F u ncti o n , Uri nal ysisf
X
X
X
X
X
C oa g ulati o n Pa nel
X
V o xel ot or Dr u g D osi n g
X
P K Sa m pli n g ( Plas ma & W h ole Bl o o d)
g
X
X
X  
X  
X
X
X
C o nc o mita nt Me dicati o ns
X
X
X
X  
X  
X
X
X
A d verse E ve nts
X
X
X
X  
X  
X
X
X
Taste & Palata bilit y Q uesti o n naire
( onl y 6 – 1 1 y ears o l d)
X
A b bre viati o ns: E C G , electr ocar di o gra m; P K , p har mac o ki netics .
a Hei g ht will be rec or de d at Scree ni n g o nl y.
b Vital si g ns ( p ulse rate ( PR) , bl o o d press ure [ B P], res pirat or y rate a n d b o d y te m perat ure) will be meas ure d o n Da y 1 pre d ose a n d at 8 a n d 2 4 h o urs p ost d ose ( Da y 2). P R a n d B P 
will be meas ure d after a partici pa nt has reste d f or at least 5 mi n utes i n t he seat e d or s u pi ne p ositi o n.
c E C Gs ( 1 2 -lea d) will be rec or de d after a partici pa nt has reste d f or at least 1 0 mi n utes i n t he s u pi ne p ositi o n. E C Gs will be c ollecte d i n tri plicate wit hi n a 5- mi n ute ti mefra me.
Tri plicate E C Gs will be c ollecte d o n Da y 1 b ot h pre - a n d p ost d ose . If t he Scree ni n g tri plicate E C Gs are c ollecte d less t ha n 2 4 h o urs bef ore st u d y dr u g d osi n g, t he tri plicate E C Gs 
pri or t o d osi n g ma y be o mitte d. T he E C G o n Da y 1 p ost d ose ma y b e c ollecte d bet wee n 1. 5 a n d 2. 5 h o urs relati ve t o v o xel ot or a d mi nist rati o n.
d P h ysical e xa mi nati o ns after t he Scree ni n g Peri o d ma y be a b bre viate d, f oc usi n g o n a b n or malities i de ntifie d o n t he Scree ni n g e xa mi nati o n a n d as relate d t o a d verse e ve nts
e Pre g na nc y tests will be perf or me d o n fe male partici pa nts w h o are of c hil d- beari n g p ote ntial .
f All la bs t o be d o ne via l ocal la b orat ories e xce pt P K dra ws .
g Bl o o d sa m ples f or plas ma a n d w h ole bl o o d P K a nal ysis of v o xel ot or will be c ollecte d as o utli ne d i n A p pe n di x 2 .
h La b orat or y assess me nts, vital si g ns a n d p h ysical e xa mi nati o ns c o n d ucte d o n Da y 1 pre d ose ma y be c o n d ucte d o n Da y - 1.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
Pr ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
Pa ge 9 5
A P P E N DI X 2.
D E T AI L O F P A R T A B L O O D P K C O L L E C TI O N S
Pr oce d ure
S a m pli n g Ti me P oi nts ( H o urs) Rel ati ve t o D a y 1
E arl y
Ter mi n ati o n/
Wit h dr a w al
Pre d ose a
2 b
8 c
2 4 d
( D a y 2)
4 8 e
( D a y 3)
9 6 e
( D a y 5)
1 6 8 e
( D a y 8)  
D a y 1 5f
P K Sa m pli n g
( plas ma & w h ole b l o o d)
X  
X  
X  
X  
X  
X
X
X
X
N ote: F or pr oce d ures sc he d ule d t o be perf or me d at c o m m o n ti mes, pri orit y is t o be gi ve n t o c ollecti o n of t he P K sa m ples at t he desi g nate d ti me.
a Ca n be c ollecte d u p t o a n h o ur pri or t o d osi n g .
b Ca n be c ollecte d wit hi n ± 1 5 mi n utes of ti me p oi nt .
c Ca n be c ollecte d wit hi n ± 3 0 mi n utes of ti me p oi nt .
d Ca n be c ollecte d wit hi n ± 6 0 mi n utes of ti me p oi nt.
e Ca n be c ollecte d wit hi n ± 2 h o urs of ti me p oi nt .
f Ca n be c ollecte d wit hi n ± 1 da y of ti me p oi nt .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
Pr ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
Pa ge 9 6
A P P E N DI X 3.
P A R T B S C H E D U L E O F A S S E S S M E N T S
Pr oce d ure
Scree ni n g
( U p t o 3 5
D a ys
Bef ore
D osi n g)
Tre at me nt Peri o d
F oll o w -U p
E arl y
Ter mi n ati o n /
Wit h dr a w al
D a y 1 i
D a y 2  
D a y 8
Wee k 2
( D a y 1 4 )
Wee k 4
( D a y 2 8)
Wee k 8
(D a y 5 6)
Wee k 1 2 
( D a y 8 4)
Wee k 1 6
(D a y 1 1 2)
& Wee k 2 0
( D a y 1 4 0)
Wee k 2 4
( D a y 1 6 8)
E O S
(l ast d ose +
4 Wee ks)
( ± 2 d a ys)
( ± 3 d a ys)
( ± 3 d a ys)
( ± 3 d a ys)
( ± 3 d a ys)
( ± 3 d a ys)
( ± 2 d a ys)
Asse nt (if ap pr o priate )
& I nf or me d C o nse nt
X
Re vie w I ncl usi o n/
E xcl usi o n Criteria
X  
X
e P R O Scree ni n g
(Part B o nl y)
X
Me dicati o n &
Me dical Hist or y
X  
X
Hei g ht a
X
B o d y Wei g ht
X  
X
X  
X  
X  
X  
X  
X
X
Vital Si g ns b
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
E C G c
X  
X
X  
X  
X  
X  
X  
X
X
P h ysical E xa mi nati o n
X  
X
X  
X  
X  
X  
X  
X
X
Ser u m Pre g na nc y Test d
X
Uri ne Pre g na nc y Test d
X
X  
X  
X  
X  
X  
X  
X
X
He m o gl o bi n 
Electr o p h oresis
X
He mat ol o g y, Ser u m
C he mistr y, Li ver
F u ncti o n, Uri nal ysis e
X f
X
X  
X  
X  
X  
X  
X  
X  
X
X
Ser u m Er yt hr o p oieti n
X
X
X
X  
X
X
C oa g ulati o n Pa nel
X
V o xel ot or Dr u g D osi n g
( dail y fr o m Da y 1 t o
Wee k 2 4)
h
X  
X  
X  
X  
X  
X  
X  
X  
X
P K Sa m pli n g ( plas ma
& w h ole b l o o d)g
X  
X
X  
X  
X  
X  
X  
X  
X
X
Tra nscra nial D o p pler
X  
X
X
X  
X
X
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
Pr ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
Pa ge 9 7
Pr oce d ure
Scree ni n g
( U p t o 3 5
D a ys
Bef ore
D osi n g)
Tre at me nt Peri o d
F oll o w -U p
E arl y
Ter mi n ati o n/
Wit h dr a w al
D a y 1 i
D a y 2  
D a y 8
Wee k 2
( D a y 1 4 )
Wee k 4
( D a y 2 8)
Wee k 8 
(D a y 5 6)
Wee k 1 2 
( D a y 8 4)
Wee k 1 6
(D a y 1 1 2)
& Wee k 2 0
( D a y 1 4 0)
Wee k 2 4
( D a y 1 6 8)
E O S
(L ast D ose +
4 Wee ks)
( ± 2 d a ys)
( ± 3 d a ys)
( ± 3 d a ys)
( ± 3 d a ys)
( ± 3 d a ys)
( ± 3 d a ys)
( ± 2 d a ys)
Dis pe nsi n g of S t u d y
D r u g f or H o me U se
X
X  
X  
X  
X
C o nc o mita nt
Me dicati o ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
A d verse E ve nts
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
e P R O S C D S Meas ure
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
e Diar y
X  
X  
X  
X  
X  
X  
X  
X  
X
A b bre viati o ns: E C G , electr ocar di o gra m; P K , p har mac o ki netic ; E O S, en d of stu d y; e P R O , electr o nic patie nt re p orte d o utc o mes; S C D S , sic kle cell disease se verit y.
a
Hei g ht will be rec or de d at Scree ni n g o nl y.
b
Vital si g ns ( p ulse rate ( PR) , bl o o d press ure [ B P], res pirat or y rate a n d b o d y te m perat ure) will be meas ure d o n Da y 1 pre d ose a n d at 8 a n d 2 4 h o urs p ost d ose ( Da y 2). P R a n d 
B P will be meas ure d after a partici pa nt has reste d f or at least 5 mi n utes i n t he seate d or s u pi ne p ositi o n.
c
E C Gs ( 1 2 -lea d) will be rec or de d after a partici pa nt has reste d f or at least 1 0 mi n utes i n t he s u pi ne p ositi o n. E C Gs will be c ollecte d i n tri plicate wit hi n a 5 -mi n ute ti mefra me.
Tri plicate E C Gs will be c ollecte d o n Da y 1 b ot h pre - a n d p ost d ose . If t he Scree ni n g tri plicate E C Gs are c ollecte d less t ha n 2 4 h o urs bef ore st u d y dr u g d osi n g, t he tri plicate 
E C Gs pri or t o d osi n g ma y be o m itte d. T he E C G o n Da y 1 p ost d ose ma y be c ollecte d bet wee n 1. 5 a n d 2. 5 h o urs relati ve t o v o xel ot or a d mi nistrati o n.
d
Pre g na nc y tests will be perf or me d o n fe male partici pa nts w h o are of c hil d -beari n g p ote ntial .
e
All la bs t o be d o ne via l ocal la b orat ories e xce pt P K dra ws .
f
Ir o n st u dies at Scree ni n g o nl y: Ferriti n, tra nsferri n , t otal ir o n bi n di n g ca pacit y (TI B C) a n d ser u m ir o n.
g
Bl o o d sa m ples f or plas ma (if a p plica ble) a n d w h ole bl o o d P K a nal ysis of v o xel ot or will be c ollecte d as o utli ne d i n A p pe n di x 4 .
h
St u d y dr u g a d mi nistrati o n o n st u d y visit da ys is t o be p ost p o ne d i n or der t o e na ble a d mi nistrati o n i n t he cli nical setti n g.
i
La b orat or y assess me nts, vital si g ns, p h ysical e xa mi nati o ns a n d T ra nscra nial D o p pler c o n d ucte d o n Da y 1 pre d ose ma y be c o n d ucte d o n Da y - 1.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
Pr ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
Pa ge 9 8
A P P E N DI X 4.
D E T AI L O F P A R T B B L O O D P K C O L L E C TI O N S
Pr oce d ure
S a m pli n g Ti me P oi nts
( Ho urs) Rel ati ve t o D a y 1
Wee k 2
( D a y 1 4)f
S a m pli n g Ti me
P oi nts ( Ho urs)
Rel ati ve t o
Wee k 4 ( D a y 2 8) 
Wee k 8
( D a y 5 6)
Wee k 1 2 
( D a y 8 4)
Wee k 1 6
( D a y 1 1 2)
Wee k 2 0
( D a y 1 4 0)
Wee k 2 4
( D a y 1 6 8)
F oll o w -U p
E arl y
Ter mi n ati o n/
Wit h dr a w al
Pre -
d ose a
2 c
8 d
2 4 e
Pre
d ose b
1 – 4
P ost -
d ose
6 – 8
P ost -
d ose
Pre - or
P ost -
D ose
Pre - or
P ost -
D ose
Pre - or
P ost -
D ose
Pre - or
P ost -
D ose
Pre - or
P ost -
D ose
E O S
( Last D ose
+ 4 W ee ks)
( D a y 2)
P K 
Sa m pli n g 
( plas ma &
w h ole 
b l o o d)
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
a Ca n be c ollecte d u p t o a n h o ur pri or t o d osi n g .
a Ca n be c ollecte d wit hi n 3 0 mi n utes pri or t o d osi n g .
b Ca n be c ollecte d wit hi n ± 1 5 mi n utes of ti me p oi nt .
c Ca n be c ollecte d wit hi n ± 3 0 mi n utes of ti me p oi nt .
d Ca n be c ollecte d wit hi n ± 6 0 mi n utes of ti me p oi nt .
e Ca n be c ollecte d pre or p ost d ose, wit hi n ± 2 h o urs of t he d ose .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
Pr ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
Pa ge 9 9
A P P E N DI X 5.
P A R T C S C H E D U L E O F A S S E S S M E N T S
Pr oce d ure
Scree ni n g
( U p t o 3 5
D a ys
Bef ore
D osi n g)
D a y 1 a
Tre at me nt Peri o d
F oll o w -U p
F or m ul ati o n 
Tr a nsiti o n 
Visit b
E arl y
Ter mi n ati o n/
Wit h dr a w al
Wee k 2 
( D a y 1 4)
Wee k 4
( D a y 2 8)
Wee k 8 
( D a y 5 6)
Wee k 1 2 
( D a y 8 4)
Wee k 1 6
( D a y 1 1 2) &
Wee k 2 0
( D a y 1 4 0)
Wee k 2 4
( D a y 1 6 8)
Wee k 3 6
( D a y 2 5 2)
Wee k 4 8
( D a y 3 3 6)
E O S
(l ast d ose +
4 Wee ks)
( ± 2 d a ys)
( ± 3 d a ys)
( ± 5 d a ys)
( ± 2 d a ys)
Asse nt (if a p pr o priate) &
I nf or me d C o nse nt
X
X b
Re vie w I ncl usi o n/
E xcl usi o n Criteria
X  
X
Me dicati o n &
Me dical Hist or y
X  
X
Hei g ht c
X
B o d y Wei g ht
X  
X
X  
X  
X  
X  
X  
X  
X  
X
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
E C G d
X
X
X
X
X  
X
X
P h y sical E xa mi nati o n
X  
X
X  
X  
X  
X  
X  
X  
X  
X
X
X
Ser u m Pre g na nc y Test e
X
Uri ne Pre g na nc y Test e
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
He m o gl o bi n 
Electr o p h oresis
X
He mat ol o g y, Ser u m
C he mistr y, Li ver F u ncti o n,
Uri nal ysis f
X g
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
Ser u m E r yt hr o p oieti n
X
X  
X
P K Sa m pli n g
( plas ma & w h ole b l o o d)h
X
X  
X  
X  
X  
X  
X  
X
X
V o xel ot or Dr u g
D osi n g i n Cli nic i
X
X  
X  
X  
X  
X  
X  
X
X
Tra nscra nial D o p pler
( wit h o ut se dati o n)
X
X
X
X
P ost d ose Taste a n d 
Palata bilit y Q uesti o n naire j
X
X
X
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
Pr ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
Pa ge 1 0 0
Pr oce d ure
Scree ni n g
( U p t o 3 5
D a ys Bef ore
D osi n g)
Tre at me nt Peri o d
F oll o w -U p
F or m ul ati o n 
Tr a nsiti o n
Vi sitb
E arl y
Ter mi n ati o n/
Wit h dr a w al
D a y 1 a
Wee k 2
( D a y 1 4 )
Wee k 4
( D a y 2 8)
Wee k 8 
(D a y 5 6)
Wee k 1 2 
( D a y 8 4)
Wee k 1 6
(D a y 1 1 2)
& Wee k 2 0
( D a y 1 4 0)
Wee k 2 4
( D a y 1 6 8)
Wee k 3 6
( D a y 2 5 2)
Wee k 4 8
( D a y 3 3 6 )
E O S
(l ast d ose +
4 Wee ks)
( ± 2 d a ys)
( ± 3 d a ys)
( ± 5 d a ys)
( ± 2 d a ys)
Dis pe nsi n g of St u d y Dr u g
f or H o me Use
X
X  
X  
X  
X  
X  
X
X
C o nc o mita nt Me dicati o ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X
A d verse E ve nts
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X
A b bre viati o ns: E C G , electr ocar di o gra m; P K , p har mac o ki netic; E O S , e n d of st u d y; e P R O , electr o nic patie nt re p orte d o utc o mes; S C D S , sic kle cell disease se verit y.
a La b orat or y assess me nts, vital si g ns, a n d p h ysical e xa mi nati o ns c o n d ucte d o n Da y 1 pre d ose ma y be c o n d ucte d o n Da y -1.
b T he F or m ulati o n Tra nsiti o n V isit s h o ul d occ ur f or all partici pa nts wit hi n 3 0 da ys of p o w der f or oral s us pe nsi o n a vaila bilit y. A si g ne d a n d date d u p date d i nf or me d pare ntal/ g uar dia n 
c o nse nt a n d partici pa nt asse nt m ust be o btai ne d at t he F or m ulati o n Tra nsiti o n Visit if t he partici pa nt has n ot si g ne d t he u p date d I C F f or t he tra nsiti o n visit. D ue t o t he C O VI D - 1 9 
i m pact o n cli nical sites, t he tra nsit o n visit ma y occ ur at a sc he d ule d st u d y visit. A tele p h o ne F oll o w -U p Visit s h o ul d be c o n d ucte d 1 t o 2 wee ks after t his visit t o assess t olera bilit y of t he 
ne w st u d y dr u g f or m ulati o n.
c Hei g ht will be rec or de d at Scree ni n g o nl y.
d E C Gs ( 1 2 -lea d) will be rec or de d after a partici pa nt has reste d f or at least 1 0 mi n utes i n t he s u pi ne p ositi o n , as a ge a p pr o priate. E C Gs will be c ollecte d i n tri plicate wit hi n a 5- mi n ute 
ti mefra me. 
e Pre g na nc y tests will be perf or me d f or fe male partici pa nts w h o are of c hi l d- beari n g p ote ntial.
f All cli nical la borat or y tests will be perf or me d at t he l ocal la b orat ories e xce pt f or a nal ysis of P K sa m ples. 
g Ir o n st u dies will be perf or me d at Scree ni n g o nl y: ferriti n, tra nsferri n, t otal ir o n bi n di n g ca pacit y ( TI B C), a n d ser u m ir o n.
h Bl o o d sa m ples f or plas ma a n d w h ole bl o o d P K a nal ysis of v o xel ot or will be c ollecte d as o utli ne d i n A p pe n di x 6 .
i St u d y dr u g a d mi nistrati o n o n st u d y visit da ys will be p ost p o ne d i n or der t o e na ble a d mi nistrati o n i n t he cli nic.
j T he P ost d ose Taste a n d Palata bilit y Q uesti o n naire will be a d mi nistere d f or b o t h st u d y dr u g f or m ulati o ns after i n-cli nic d osi n g. F or t he dis persi ble ta blets, it will be a d mi nistere d t o t he 
care gi ver/le gal g uar dia n a n d/ or c hil dre n ( ≥6 y ears ol d) at Wee k 2 a n d Wee k 1 2 ( or a n y ti me after 3 m o nt hs of st u d y dr u g treat me nt). F or t he p o w der f or oral s us pe nsi o n f or m ulati o n, it will be 
a d mi nistere d t o t he care gi ver/le gal g uar dia n a n d/ or c hil dre n (all a ges) at t he F or m ulati o n Tra nsiti o n V isit a n d at t he ne xt sc he d ule d st u d y visit.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
Pr ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
Pa ge 1 0 1
A P P E N DI X 6.
P A R T C P H A R M A C O KI N E TI C S A M P LI N G S C H E D U L E
Pr oce d u re
D a y 1
Wee k 4  
Wee k 8
Wee k 1 2  
Wee k 1 6  
Wee k 2 0  
Wee k 2 4
Wee k 3 6  
Wee k 4 8
E arl y
Ter mi n ati o n/
Wit h dr a w al
D a y 2 8
± 3 d a ys
D a y 5 6
± 3 d a ys
D a y 8 4
± 3 d a ys
D a y 1 1 2
± 5 d a ys 
D a y 1 4 0
± 5 d a ys 
D a y 1 6 8
± 5 d a ys
D a y 2 5 2
± 5 d a ys
D a y 3 3 6
± 5 d a ys
P K Sa m pli n g
( Plas ma
a n d W h ole
Bl o o d)
1 5 m i n t o 2 h
p ost d ose
Pre d ose a
Pre d ose a
Pre d ose a
Pre d ose a
Pre d ose a
Pre d ose a
Pre d ose a
Pre d ose a
X
X
X
X
X
X
X
X
X
X
a Ca n be c ollecte d u p t o a n h o ur pri or t o d osi n g .
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
Pr ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
Pa ge 1 0 2
A P P E N DI X 7.
P A R T D S C H E D U L E O F A S S E S S M E N T S
Pr oce d ure
Scree ni n g
( U p t o 3 5
D a ys
Bef ore
D osi n g)
Tre at me nt Peri o d
F oll o w - U p
E arl y
Ter mi n ati o n/
Wit h dr a w al
D a y 1 a
Wee k 2
( D a y 1 4)
Wee k 4
( D a y 2 8)
Wee k 8
( D a y 5 6)
Wee k 1 2
( D a y 8 4)
Wee k 1 6
( D a y 1 1 2) 
a n d
Wee k 2 0
( D a y 1 4 0)
Wee k 2 4
( D a y 1 6 8)
Wee k 3 6
( D a y 2 5 2)
Wee k 4 8
( D a y 3 3 6)
E O S
(L ast D ose
+ 2 8 d a ys)
( ± 3 d a ys)
( ± 5 d a ys)
( + 7 d a ys)
Asse nt ( If A ppr o priate) 
a n d I nf or me d C o nse nt
X
Re vie w I ncl usi o n/
E xcl usi o n Criteria
X  
X
Me dical Hist or y
X
Hei g ht
X
X  
X  
X  
X  
X  
X  
X  
X
X
B o d y Wei g ht
X  
X
X  
X  
X  
X  
X  
X  
X  
X
X
Hea d Circ u mfere nce
X
X
X  
X  
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
E C G b
X
P h ysical E xa mi nati o n
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
H b Electr o p h oresis
X
He mat ol o g y, Ser u m 
C he mistr y, Li ver 
F u ncti o n c
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
Hist orical H b Ge n ot y pe
X
Ser u m Er yt hr o p oieti n
X
X
X  
X
X
P K Sa m pli n g
( Plas ma a n d W h ole 
B l o o d)d
See A p pe n di x 8
V o xel ot or Dr u g D osi n g
i n Cli nice
X  
X  
X  
X  
X  
X  
X  
X  
X
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
Pr ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
Pa ge 1 0 3
Pr oce d ure
Scree ni n g
( U p t o 3 5
D a ys
Bef ore
D osi n g)
Tre at me nt Peri o d
F oll o w - U p
E arl y
Ter mi n ati o n/
Wit h dr a w al
D a y 1 a
Wee k 2
( D a y 1 4)
Wee k 4
( D a y 2 8)
Wee k 8
( D a y 5 6)
Wee k 1 2
( D a y 8 4)
Wee k 1 6
( D a y 1 1 2) 
a n d
Wee k 2 0
( D a y 1 4 0)
Wee k 2 4
( D a y 1 6 8)
Wee k 3 6
( D a y 2 5 2)
Wee k 4 8
( D a y 3 3 6)
E O S
(L ast D ose
+ 2 8 d a ys)
( ± 3 d a ys)
( ± 5 d a ys)
( + 7 d a ys)
P ost d ose Taste a n d 
Palata bilit y Q uesti o n naire
X  
X
X f
St u d y Dr u g Dis pe nsi n g
X
X
X  
X
C o nc o mita nt Me dicati o ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
A d verse E ve nts
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
A b bre viati o ns: E C G , electr ocar di o gra m; H b , he m o gl o bi n; P K , p har mac o ki netic.
a La b orat or y assess me nts, vital si g ns, a n d p h ysical e xa mi nati o ns c o n d ucte d o n Da y 1 pre d ose ma y be c o n d ucte d o n Da y -1.
b E C Gs ( 1 2-lea d) will be rec or de d after a partici pa nt has reste d f or at least 1 0 mi n utes i n t he s u pi ne p ositi o n, as a ge a p pr o priate. E C Gs will be c ollecte d i n tri plicate wit hi n a 
5- mi n ute ti mefra me. 
c All cli nical la b orat or y tests will be perf or me d at t he l ocal la b orat ories e xce pt f or a nal ysis of P K sa m ples. 
d Bl o o d sa m ples f or plas ma a n d w h ole bl o o d P K a nal ysis of v o xel ot or will be c ollecte d as o utli ne d i n A p pe n di x 8 .
e St u d y dr u g a d mi nistrati o n o n st u d y visit da ys will be p ost p o ne d i n or der t o e na ble a d mi nistrati o n i n t he cli nic.
f Ma y be perf or me d a n y ti me after 3 m o nt hs of treat me nt.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)

Gl o bal Bl o o d T hera pe utics , I nc.
Pr ot oc ol A me n d me nt 7
Pr ot oc ol G B T 4 4 0 -0 0 7
C O N FI D E N TI A L
Pa ge 1 0 4
A P P E N DI X 8.
P A R T D P H A R M A C O KI N E TI C S A M P LI N G S C H E D U L E
Pr oce d ure
D a y 1
Wee k 2  
Wee k 8
Wee k 1 2  
Wee k 1 6  
Wee k 2 4  
Wee k 3 6  
Wee k 4 8
E arl y
Ter mi n ati o n/
Wit h dr a w al
D a y 1 4
± 3 d a ys
D a y 5 6 
± 3 d a ys
D a y 8 4
± 5 d a ys
D a y 1 1 2
± 5 d a ys
D a y 1 6 8
± 5 d a ys
D a y 2 5 2
± 5 d a ys
D a y 3 3 6
± 5 d a ys
S a m ple 1
P K Sa m ple ( Plas ma &
W h ole Bl o o d)
1 5 m i n t o
2 h p ost d ose
Pre d ose a
Pre d ose a
Pre d ose a
Pre d ose a
Pre d ose a
Pre d ose a
Pre d ose a
X
X  
X  
X
X
X  
X  
X
X
A b bre viati o n: P K , p har mac o ki netic .
a Ca n be c ollecte d u p t o a n h o ur pri or t o d osi n g.
0 9 0 1 7 7 e 1 9 e 5 8 1 cf 9\ A p pr o v e d\ A p pr o v e d O n: 2 0- A pr- 2 0 2 1 1 8: 3 2 ( G M T)