Clinical trial NCT02850406
Conditions: Sickle Cell Disease
Sponsor: Pfizer
Start date: 2016-07-05; Completion date: 2023-10-02
Enrollment: 147 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This study consists of four parts, Parts A, B, C, and D.

* Part A is a single dose pharmacokinetic (PK) study in pediatric participants with Sickle Cell Disease ages 6 to 17 years.
* Part B is a multiple dose, safety, exploratory, efficacy, and PK study in adolescent participants with Sickle Cell Disease ages 12 to 17 years.
* Part C is a multiple dose, safety, tolerability, and PK study, which includes the assessment of hematological effects and the effect on TCD flow velocity of voxelotor in pediatric participants with Sickle Cell Disease ages 4 to 17 years.
* Part D is a multiple dose, safety, tolerability, and PK study, which examines the hematological effects of voxelotor in pediatric participants with Sickle Cell Disease ages 6 months to \< 4 years.

Detailed description:

Arms: arm 1: Subjects to receive daily oral dosing of voxelotor according to which Part (A, B, C, or D), the subject is participating in:

* Part A: Subjects to receive daily oral dosing of voxelotor for 1 day (single dose)
* Part B: Subjects to receive daily oral dosing of voxelotor for up to 24 weeks (multiple dose)
* Part C: Subjects to receive daily oral dosing of voxelotor for up to 48 weeks (1500mg or 1500mg equivalent dose)
* Part D: Subjects to receive daily oral dosing of voxelotor for up to 48 weeks (1500mg equivalent dose)
Interventions: intervention 1: Voxelotor
Intervention descriptions: intervention 1: * Part A: Voxelotor will be administered as oral capsules or tablets
* Part B: Voxelotor will be administered as oral capsules or tablets
* Part C: Voxelotor will be administered as oral dispersible tablets or powder for oral suspension
* Part D: Voxelotor will be administered as oral dispersible tablets or powder for oral suspension

Protocol documents:
Prot_000.pdf: 
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
8 2
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
8 3
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
8 4
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
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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)

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
Study Title:
A Phase 2a, Open-label, Single and Multiple Dose Study to 
Evaluate the Pharmacokinetics, Safety, Tolerability, and 
Exploratory Treatment Effect of GBT440 in Adolescents 
with Sickle Cell Disease
Phase:
2b
Protocol No.:
GBT440-007
Protocol Date:
14June2018 Amendment 5
Analysis Plan Version 
and Date:
Part A and Part B: Version 1.0, 11January2019
CONFIDENTIAL AND PROPRIETARY INFORMATION




Global Blood Therapeutics, Inc. 
Statistical Analysis Plan 
 
GBT440-007 
CONFIDENTIAL 
3 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ................................................2
TABLE OF CONTENTS .................................................................................................................3
LIST OF TABLES ...........................................................................................................................4
1.
GLOSSARY OF ABBREVIATIONS ..........................................................................5
2.
INTRODUCTION AND STUDY OVERVIEW ..........................................................6
3.
OBJECTIVES ...............................................................................................................7
3.1.
Part A Objectives ..........................................................................................................7
3.2.
Part B Objectives ..........................................................................................................7
3.3.
Part C Objectives ..........................................................................................................8
4.
DEFINITIONS AND TERMINOLOGY .....................................................................8
5.
STUDY ENDPOINTS ................................................................................................10
5.1.
Part A Endpoints .........................................................................................................10
5.2.
Part B Endpoints .........................................................................................................10
5.3.
Part C Endpoints .........................................................................................................11
6.
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................11
6.1.
Sample Size Considerations .......................................................................................11
6.2.
Handling of Data .........................................................................................................12
6.2.1. 
Visit Windows ............................................................................................................12
6.2.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................12
6.2.3. 
Missing Start and Stop Dates for Adverse Events ......................................................13
7.
ANALYSIS POPULATIONS ....................................................................................13
7.1.
Efficacy Evaluable Population ...................................................................................13
7.2.
Safety Population ........................................................................................................13
7.3.
PK Population .............................................................................................................13
8.
STATISTICAL METHODS .......................................................................................13
8.1.
Subject Disposition, Demographic and Baseline Characteristics ...............................14
8.1.1. 
Subjects Disposition ...................................................................................................14
8.1.2. 
Demographic and Baseline Characteristics ................................................................14
8.1.3. 
Baseline Sickle Cell Disease Characteristics ..............................................................14
8.1.4. 
Other Medical History ................................................................................................14
8.2.
Efficacy Analysis ........................................................................................................14


Global Blood Therapeutics, Inc. 
Statistical Analysis Plan 
 
GBT440-007 
CONFIDENTIAL 
4 
 
8.2.1. 
Analysis of the Primary Efficacy Endpoint ................................................................14
8.2.2. 
Analysis of the Secondary Efficacy Endpoints ..........................................................15
8.3.
Safety ..........................................................................................................................15
8.3.1. 
Summary of Exposure ................................................................................................15
8.3.2. 
Adverse Events ...........................................................................................................15
8.3.3. 
Concomitant Medications ...........................................................................................16
8.3.4. 
Clinical Laboratory Data ............................................................................................16
8.3.5. 
Vital Signs and Physical Exam...................................................................................17
8.3.6. 
12-Lead Electrocardiogram ........................................................................................17
9.
PROTOCOL DEVIATIONS......................................................................................17
10.
CHANGES IN THE PLANNED ANALYSES ..........................................................17
11.
TABLES, FIGURES, AND LISTINGS.....................................................................18
11.1.
Tables Part A ..............................................................................................................18
11.2.
Listings Part A ............................................................................................................19
11.3.
Tables Part B...............................................................................................................20
11.4.
Listings Part B ............................................................................................................22
LIST OF TABLES 
Table 1: 
Nominal Analysis Visit Windows for PRO Measures ...............................................12


Global Blood Therapeutics, Inc. 
Statistical Analysis Plan 
 
GBT440-007 
CONFIDENTIAL 
5 
 
1. 
GLOSSARY OF ABBREVIATIONS 
AE 
Adverse Event 
ATC
Anatomical Therapeutic Chemical 
BMI
Body Mass Index
CRF
Case Report Form 
Cmax
Maximum Blood Concentration
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data and Safety Monitoring Board 
HU
Hydroxyurea
ICH 
International Conference on Harmonisation 
MedDRA
Medical Dictionary for Regulatory Activities
NCI 
National Cancer Institute
PT 
Preferred Term
RBC
Red Blood Cells 
SAE
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCD 
Sickle Cell Disease
SCDSM
Sickle Cell Disease Severity Measure 
SD
Standard Deviation
SOC 
System Organ Class 
TAMM
Time-Averaged Mean of the Maximum 
TCD
Transcranial Doppler 
TEAE 
Treatment-Emergent Adverse Event
TSS 
Total Symptom Score 
WHO
World Health Organization 


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2. 
INTRODUCTION AND STUDY OVERVIEW 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the interim Clinical Study Report (CSR) for Protocol GBT440-007. 
The SAP will describe the analyses for Part A and Part B of the study only.  
This SAP was developed in accordance with the ICH E9 guideline. All decisions regarding final 
interim analysis, as defined in this SAP, will be made prior to database snapshot. Further 
information can be found in the protocol.  
The statistical analysis methods presented in this document will supersede the statistical analysis 
methods described in the clinical protocol. If additional analyses are required to supplement the 
planned analyses described in this SAP, they may be completed and will be identified in the 
CSR. 
Planned pharmacokinetic (PK) analyses will be described in a separate analysis plan. 
Study Overview: 
This study is a multicenter, open-label study to evaluate the safety, PK and efficacy of GBT440 
in pediatric participants with SCD.  
This study consists of three parts, Part A, Part B and Part C:  
Part A is a single dose PK study of GBT440 in pediatric participants with SCD aged 6 to 17 
years. This study will involve 2 cohorts in this age range, Cohort 1 (12 to 17 years) and Cohort 2 
(6 to 11 years) 
Part B is a multiple dose, safety, PK and efficacy study of GBT440 in pediatric participants with 
SCD aged 12 to 17 years, inclusive. 
Prior to proceeding from the 900 mg dose to the 1500 mg dose in Part B, the following data 
reviews will be conducted: 
A review of the PK data from at least 8 pediatric participants enrolled in Part B of Study 
GBT440-007, following at least 15 days of dosing with GBT440 900 mg.  
DSMB review of safety data from at least 8 pediatric participants enrolled in Part B of Study 
GBT440-007, following the completion of 28 days of dosing with GBT440 900 mg to confirm 
acceptable safety and tolerability. 
DSMB review safety data from the first 6 adult participants 1500 mg dose level from Group 1 of 
Study GBT440-031 (HOPE study), following at least 28 days of dosing with study drug to 
confirm acceptable safety and tolerability.  
Part C will assess the safety, tolerability and PK, as well as the hematological effects and the 
effect on TCD flow velocity of GBT440 in pediatric participants with SCD who are 4 to 17 years 
of age.  
Up to 50 pediatric participants will be enrolled.  
 
Screening AND 
 At least 20 participants must be between 4 to 11 years of age 


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To further characterize a potential effect on TCD data for those participants who have a TCD 
 In 
this event, Part C will contain up to 70 pediatric participants. 
3.
OBJECTIVES
3.1. 
Part A Objectives 
Primary Objective:
To characterize the PK of GBT440 in plasma and whole blood following a single dose in 
pediatric participants with SCD  
Secondary Objective: 
To evaluate the safety and tolerability of GBT440 following a single dose in pediatric 
participants with SCD 
3.2. 
Part B Objectives 
Primary Objective:
The primary objective is to assess the efficacy of GBT440 in pediatric participants with SCD as 
measured by improvement in anemia 
Secondary Objectives:
 To provide data on the ePRO measurement in establishing the longitudinal 
measurement properties of the PRO 
To evaluate the effect of GBT440 on clinical measures of hemolysis 
 To characterize the PK of GBT440 in plasma, whole blood and red blood cells 
(RBCs) following multiple doses in pediatric participants with SCD 
To evaluate the safety and tolerability of GBT440 following multiple doses in 
pediatric participants with SCD 
 To evaluate the effect of GBT440 on cerebral hemodynamics as assessed by 
transcranial Doppler (TCD) ultrasonography 
 To evaluate the effects of GBT440 on SCD symptom exacerbation and total symptom 
score (TSS) from PRO measurement  


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3.3. 
Part C Objectives 
Primary Objective: 
To evaluate the effect of GBT440 on cerebral hemodynamics in pediatric participants with SCD 
with elevated or conditional TCD low velocity as assessed by transcranial Doppler (TCD) 
ultrasonography 
Secondary Objectives: 
 To evaluate the effect of GBT440 on clinical measures of anemia and hemolysis 
 To characterize the PK of GBT440 in plasma, whole blood and red blood cells 
(RBCs) following multiple doses in pediatric participants with SCD
 To evaluate the safety and tolerability of GBT440 following multiple doses in 
pediatric participants with SCD  
4. 
DEFINITIONS AND TERMINOLOGY 
Study Day 
Study Day is defined relative to initiation of treatment, i.e., Day 1. Thus, the study day of an 
event is calculated as: 
Study Day = event date –Day 1 date + 1. 
Day 1 is the date that study drug is first initiated. 
Study Visit  
Study Visit is the nominal visit as recorded on the CRF.  
Baseline 
For all endpoints where both Screening and Day 1 pre-dose assessments are collected, baseline is 
defined as average of all assessments prior to the first dose. If there is an unscheduled visit prior 
to first dose, this unscheduled assessment will also be included in the baseline calculation. For 
PRO endpoints specific to SCD, e.g. TSS, the Baseline value is the average of the non-missing 
scores during the 28 to 35-day Screening period (Part B). 
Change from Baseline 
Change from baseline to follow-up visit will be calculated as the baseline measurement 
subtracted from the follow-up measurement for all assessments. Percent change from baseline 
values to post-baseline values will be calculated using the following formula where applicable: 
([post-baseline value – baseline value] / baseline value) × 100% 


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Duration of Exposure to Study Drug  
Duration of exposure to study drug is defined as the number of weeks from Day 1 to the last date 
of dosing of Study drug which excludes days where treatment was entirely missed or 
intermittently stopped as recorded in the CRF. Duration of study drug exposure is calculated as 
follows:
[
 
 
 
 
 
 
+1]×
 
=1
7
, 
where  n is the number of dose modifications during the study and  
= 0,
 
 
 = 0 
 
1,
 
 
  
0 
.
Total Symptom Score (TSS)
For each participant, the TSS will be computed as follows: The Baseline TSS is the average of 
the scores during the 35 Screening period, i.e. the sum of non-missing TSS scores divided by the 
number of non-missing diary entries. Participants in Part B must complete a minimum of 14 days 
during Screening with ePRO to be enrolled in the study. During the treatment period when there is at 
least  or 75% compliance during a 4-week period, the TSS is the average score for each 4-week 
period on treatment. The 4-week periods are Weeks 1-4 (Study Day 1-28), Weeks 5-8 (Study 
Day 29-56), Weeks 9-12 (Study Day 57-84), Weeks 13-16 (Study Day 85-112), Weeks 17-20 
(Study Day 113-140), Weeks 21-24 (Study Day 141-168), and Weeks 25-28 (Study Days 
169-196). If lack of compliance is due to missed diary entries or participant dropout, the TSS 
will be set to missing for that 4-week period or that 4-week period and beyond, respectively.  
Concomitant Medications 
Concomitant medications are those medications taken on or after the initiation of study drug. 
This definition includes medications started prior to the initiation of study drug, but continuing 
concurrently with study drug. 
Prior Medications 
Prior medications are those medications taken prior to the initiation of study drug.
Treatment-emergent Adverse Event  
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges on or after 
initiation of study drug (having been absent pre-treatment), or an AE that existed pre-treatment 
and worsened on treatment (relative to the pre-treatment state) through 28 days after study drug 
discontinuation. AEs occurring on Day 1 are assumed to be treatment-emergent.


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5. 
STUDY ENDPOINTS 
5.1. 
Part A Endpoints 
Primary Endpoint: 
 Cmax, area AUC from time 0 to the time of the last quantifiable concentration (AUC0-
last) and AUC0-inf of GBT440 in whole blood 
Secondary Endpoints:
Cmax, AUC0-last and AUC0-inf of GBT440 in plasma and RBC 
The time that Cmax was observed (tmax), terminal elimination half-life (T
) in RBC, 
whole blood and plasma, and percent Hb occupancy  
Safety Endpoints:
 Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
 Clinical laboratory tests, physical examination findings, vital signs and ECGs 
5.2. 
Part B Endpoints 
Primary Endpoint: 
 Change from baseline to Week 24 in Hb  
Secondary Endpoint: 
 Proportion of days with SCD symptom exacerbation during the first 24 weeks of 
treatment.  
 Change from Baseline to Weeks 21–24 in the (SCDSM) TSS 
Change from baseline to 12 and 24 weeks in LDH, indirect bilirubin and reticulocyte 
count 
 GBT440 PK (Cmax, AUC0-last, AUC0-inf , AUC0-24, T
, accumulation ratio, 
cupancy 
 Change from baseline to 12 and 24 weeks in cerebral blood flow as measured by the 
TAMM TCD velocity 
Safety Endpoints:
 TEAEs and SAEs
 Clinical laboratory tests, physical examination findings, vital signs and ECGs 


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5.3. 
Part C Endpoints 
Primary Endpoint:
Change from baseline to 48 Weeks in cerebral blood flow as measured by the TAMM 
TCD velocity 
Secondary Endpoints: 
 Change from baseline to Weeks 24 and 48 in Hb, LDH, indirect bilirubin and 
reticulocyte count  
 Change from baseline to 24 weeks in cerebral blood flow as measured by the TAMM 
TCD velocity 
 GBT440 PK (Cmax, AUC0-last, AUC0-inf, AUC0-24, T
, accumulation ratio, 
 
Safety Endpoints: 
 TEAEs and SAEs
 Clinical laboratory tests, physical examination findings, vital signs and ECGs 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
6.1. 
Sample Size Considerations 
Part A: A cohort size of up to approximately 6 participants for each age group: 6 to 11 and 12 to 
17 is based on a typical size for a single-dose PK study and is intended to balance the desire to 
minimize exposure of pediatric participants to a novel compound at this stage of GBT440’s 
development with the need to obtain PK, safety and tolerability data. No formal power or sample 
size calculations were performed to determine the cohort size.
Part B:  Approximately 12 participants at 900 mg were selected to determine preliminary safety, 
tolerability, PK, laboratory effects and treatment response of GBT440 in pediatric participants 
with SCD. The number of participants may be increased to approximately 36 to further 
characterize the effect of multiple doses of GBT440.  Upon a favorable review by the DSMB, 
dosing of a minimum of 6 participants at 1500 mg may commence (dependent on how many 
participants were enrolled at 900 mg, i.e. not to exceed a total study size of approximately 36).
For the endpoint of change from baseline to Week 24 in Hb, power calculations assume normally 
 For a two-sided alpha = 0.05 and N = 12, power exceeds 90% with a 
paired t-test to reject the null hypothesis of equality of post-treatment and baseline Hb means. 
 
Day 90 data from Cohorts 16 and (partial data) 17 from the GBT440-001 study.  


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Part C: Up to 50 pediatric participants who are 4 to 17 years of age with SCD will be enrolled. 
For the primary efficacy endpoint, change from baseline in TAMM TCD velocity at Week 48, a 
sample size of 30 participants achieves greater than 95% power to detect a mean difference of 
15
-test 
(two-sided) with a significance level (alpha) of 0.10.  
6.2. 
Handling of Data 
6.2.1. 
Visit Windows   
Visit windows will be defined for Part B PRO measures. PRO measures include ePRO Screening 
and ePRO SCDSM. 
Table 1: 
Nominal Analysis Visit Windows for PRO Measures 
Nominal Visit
Time 
Study Day Range for 
Statistical Analysis 
Screening 
[-28, -1]  
Week 4 
[1, 28] 
Week 8 
[29, 56] 
Week 12 
[57, 84] 
Week 16 
[85, 112] 
Week 20 
[113, 140] 
Week 24 
[141, 168] 
Week 28 
[169, 196] 
Note: ePRO SCDSM is measured every day from the first day of screening to Week 28 post first dose. Participants 
must complete a minimum of 14 days during Screening.  
6.2.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
For missing start day only: Day will be imputed as the first day of the month (i.e., 1) with the 
following exception: If the partial date falls in the same month and year as the treatment start 
date then the concomitant medication start date will be imputed as the treatment start date.  
For missing start day and month: Day and month will be imputed as the first day of the year (i.e., 
1 January) with the following exception: If the partial date falls in the same year as the treatment 
start date then the concomitant medication start date will be imputed as the treatment start date.
For missing stop day only: Day only will be imputed as the last day of the month (i.e., 28, 29, 30, 
or 31). 
For missing stop day and month: Day and month will be imputed as the last day of the year (i.e., 
31 December). 


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6.2.3. 
Missing Start and Stop Dates for Adverse Events 
For missing start day only: Day will be imputed as the first day of the month (i.e., 1) with the 
following exception: If the partial date falls in the same month and year as the treatment start 
date then the adverse event start date will be imputed as the day prior to the treatment start date.  
For missing stop day only – Day only will be imputed as the last day of the month (i.e., 28, 29, 
30, or 31). 
7. 
ANALYSIS POPULATIONS 
7.1. 
Efficacy Evaluable Population 
All participants who received any amount of study drug will be included in the Efficacy 
Evaluable population (EE). All efficacy analyses will be based on the EE population. 
7.2. 
Safety Population 
All participants who received any amount of study drug will be included in the Safety 
population. All safety analyses will be based on the Safety population. The Safety Population is 
defined as all subjects who receive at least one dose of study medication. This population will be 
used in the assessment and reporting of safety data. 
7.3. 
PK Population 
All participants who receive any amount of study drug and who provide PK data from at least 
one post dose sample in plasma will be included in the PK population. Additional details are 
provided  in a separate plan. 
8. 
STATISTICAL METHODS 
The interim data analysis will be performed at the time of the database snapshot. 
Statistical programming and analyses will be performed using SAS® Version 9.4 or higher.  
Select Part A summaries will be presented for the 600 mg dose level by age group (6-11 years 
and 12-17 years) and Overall voxelotor (both age groups).  
Part B summaries will be presented by dose level (900 mg and 1500 mg).  
Continuous variables will be descriptively summarized using number of participants (n), mean, 
standard deviation (SD), median, minimum, maximum, and, as appropriate, geometric mean. 
Categorical variables will be descriptively summarized by presenting the number (frequency) 
and percentage in each category. 


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8.1. 
Subject Disposition, Demographic and Baseline Characteristics  
8.1.1.
Subjects Disposition
Participant disposition will be presented in terms of the numbers and percentages of participants 
who completed the treatment and discontinued from treatment. The reasons for early treatment 
discontinuation will be presented. Similar results will be presented for subjects who discontinue 
study. 
Screen failures along with the reasons for screen failure will be listed only. 
8.1.2. 
Demographic and Baseline Characteristics 
The demographic variables collected in this study include age (years) at Screening, sex, race, and 
ethnicity and will be summarized descriptively. Height (cm), weight (kg) and BMI 
m3 ) at 
Screening will be presented using descriptive statistics. Participants who record more than one 
race will be grouped into a single category denoted as multi-racial.  
8.1.3. 
Baseline Sickle Cell Disease Characteristics 
Number of VOCs including the number of VOCs requiring hospitalization and the number of 
blood transfusion during the previous 12 months will be summarized categorically.  
Additional summaries including the number and percentage of participants who currently use 
HU, who have each genotype (HbSS or HbSBO) and who experienced a sickle cell complication 
prior to study enrollment will be presented. Baseline lab values including Hb, HbF (Part B only),
and reticulocyte count will be summarized using descriptive statistics.  
In Part B, prior HU results including most recent labs prior to initiation of HU, maximum 
tolerated dose of HU and lab results one month post MTD of HU will be provided in a listing. 
8.1.4. 
Other Medical History 
Other medical history will be summarized by System Organ Class (SOC) and Preferred Term 
(PT) according to Medical Dictionary for Regulatory Activities (MedDRA), version 20.0 coding 
dictionary.
8.2. 
Efficacy Analysis 
All efficacy data in Part B will be summarized using the EE population. 
8.2.1. 
Analysis of the Primary Efficacy Endpoint 
Change from baseline in hemoglobin to Week 24 will be summarized descriptively. The changes 
from baseline will be presented including the (absolute) values at each visit. Additionally, a 
responder endpoint defined as an increase in Hb 
compared to Baseline, will be 
summarized descriptively at Week 12 through Week 24. No imputation will be performed for 
this endpoint. 


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8.2.2. 
Analysis of the Secondary Efficacy Endpoints 
Change from baseline to each of the 4 week periods (Section 4, TSS definition) for the sickle cell disease 
severity measure (SCDSM) TSS, will be summarized. If SCDSM compliance is less than 75% for a 
4-week period, the proportion will be considered missing.  
Hematology parameters (reticulocyte count, indirect bilirubin, and LDH) and cerebral blood flow 
as measured by TAMM TCD velocity will be summarized at each visit for observed values and 
changes (absolute and percent) from baseline using appropriate descriptive statistics. If indirect 
bilirubin is missing and direct and total bilirubin are collected, indirect can be calculated as:
8.3.
Safety
All safety analyses will be conducted using the Safety Population.  
8.3.1. 
Summary of Exposure 
Study drug administration in Part B will be summarized with number and percentage of 
participants receiving from 1 to the maximum number of doses by treatment group. Similarly, 
the duration of study drug exposure will be summarized with descriptive statistics. 
The number and percentage of subjects who permanently discontinued study drug, and the 
reason for discontinuation (adverse event (AE) or other) will be summarized. The number and 
percentage of subjects who missed at least 1 dose of study drug or had at least 1 dose reduction 
will be summarized. The summary will include the number and percentage of subjects who had a 
dose reduction or dose interrupted due to an adverse event or other. Additionally, the number and 
percentage of subjects will be summarized in categories of number of interrupted doses and 
number of dose reductions. 
8.3.2.
Adverse Events
Adverse events reported for participants participating in this study will be graded using the 
National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE), 
version 4.03. All AEs will be coded using the using MedDRA, version 20.0. 
TEAE summary tables in both Part A and Part B will exclude sickle cell disease (SCD) related 
events defined as preferred terms of: combined acute chest syndrome and pneumonia, sickle cell 
anemia with crisis, osteonecrosis, and priapism. Additional select TEAE tables (Part B only) will 
summarize SCD related events which only include the preferred terms of acute chest syndrome 
and pneumonia (combined), sickle cell anemia with crisis, osteonecrosis, and priapism. 
An overall summary will be presented which includes the number of TEAEs and the number and 
percentage of participants who experienced at least one TEAE. This summary will also include 
TEAEs Grade 3 or greater, TEAEs possibl
study drug, TEAEs leading to 
study drug reduction, TEAs leading to discontinuation of study drug, serious adverse events 
(SAEs), and deaths. 
Additional summaries of TEAEs will be provided showing the number and percentage of 
participants who experienced at least one TEAE. These summaries will be presented by system 
organ class (SOC), preferred term (PT) and maximum severity. If a participant reports the same 
PT multiple times within the same SOC, that PT will only be counted once within that SOC for 


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that participant. As with the PT, if a participant reports multiple conditions within the same SOC, 
that SOC will only be counted once for that participant. In the summary, SOC will be listed in 
ascending alphabetical order; PTs will be listed in order of descending frequency for all 
participants within each SOC.  
The occurrence of TEAEs possibl
 will be tabulated by SOC, PT 
and maximum severity. Serious adverse events will be presented by system organ class (SOC), 
preferred term (PT) and maximum severity. 
Adverse events recorded in the eCRF which began prior to first dose of study drug will not be 
included in the summary tables.  
8.3.3. 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (Enhanced B2, March, 2016) and summarized to the therapeutic drug class 
(Anatomical Therapeutic Chemical (ATC) 4 classification) and preferred name. 
8.3.4. 
Clinical Laboratory Data 
All hematology and chemistry laboratory assessments were performed by local laboratories.  
The following protocol-specified clinical laboratory findings will be summarized using 
descriptive statistics by dose level. 
1. Hematology: 
a. Hemoglobin 
b. Neutrophils (absolute and %) 
c. Platelets 
d. Reticulocyte % 
e. WBC 
2. Chemistry and Liver Function Tests: 
a. Alkaline phosphatase 
b. ALT 
c. AST 
d. Potassium 
e. Indirect bilirubin 
f. Total bilirubin 
g. Serum Erythropeietin 
Change from baseline and the percent change from baseline will be summarized for the above 
laboratory results. Analyte units will be converted to SI units.  
Participant listings of laboratory data will include a separate listing for clinically significant 
laboratory results. Urinalysis, coagulation and pregnancy results will be listed only. 


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8.3.5. 
Vital Signs and Physical Exam
Part A vital signs and physical exam data will be listed only. 
Part B vital signs, including systolic and diastolic blood pressure, heart rate, and weight will be 
summarized using continuous descriptive statistics at each visit and time point by dose level. 
Change from baseline will also be summarized for each post-baseline visit. 
8.3.6. 
12-Lead Electrocardiogram 
Heart rate, PR interval, QRS interval, QT interval, RR interval, and QTcF (Fridericia’s) interval 
will be summarized along with the change from baseline using descriptive statistics at each visit 
in Part B. The average of the 3 ECGs collected will be used in the summary tables. 
Additionally, in both Part A and Part B, the number and percentage of participants with QTcF 
 450 ms, >450 ms to 
480 ms, >480 ms to 
500 ms, and >500 ms at baseline and as the 
maximum post-baseline measurement will be summarized. The number and percentage of 
participants with maximum increase from baseline where increase in QTcF  30 ms, > 30 ms to 
60 ms and> 60 ms also will be summarized.  If the QTcF interval was not collected, the interval 
will be calculated using the following formula: 
 
 
9. 
PROTOCOL DEVIATIONS 
Protocol deviations as assessed by the study team will be displayed in a data listing and sorted by 
treatment group, subject number, and then by date (where applicable) within each subject 
number. The type of deviation along with a description and any additional comments about the 
deviation will be listed.  
10. 
CHANGES IN THE PLANNED ANALYSES 
The secondary endpoint, proportion of days with SCD symptom exacerbation during the first 
24 weeks of treatment, will not be summarized. The definition for this variable is not defined at 
the time of the analysis. 


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11. 
TABLES, FIGURES, AND LISTINGS 
Key planned summary tables and listings are provided below. Additional listings and tables may 
 
11.1. 
Tables Part A 
Item  
Title 
Table 14.1.1.a
Demographics and Baseline Characteristics
Table 14.1.2.a 
Baseline Sickle Cell Disease Characteristics 
Table 14.1.3.a 
Other Medical History 
Table 14.1.4.a 
Participant Follow-up and Termination from Study 
Table 14.1.5.a 
Concomitant Medications 
Table 14.3.1.1.a 
Overview of Treatment-Emergent Adverse Events and Serious Adverse Events 
Table 14.3.1.2.a 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term 
and Maximum Severity  
Table 14.3.2.1.a 
Summary of Hematology and Change from Baseline  
Table 14.3.2.2.a 
Summary of Serum Chemistry and Change from Baseline  
Table 14.3.2.3.a 
Summary of Liver Function Tests and Change from Baseline  
Table 14.3.3.a 
Corrected QT Interval (Fridericia) Maximum Post-Baseline and Maximum 
Increase from Baseline Categories 


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11.2. 
Listings Part A 
Item 
Title 
Listing 16.2.1.a 
Eligibility and Enrollment for Screen Failures 
Listing 16.2.2.a
Protocol Deviations for Safety Population
Listing 16.2.3.a 
Demographics for Safety Population 
Listing 16.2.4.a 
Baseline Characteristics for Safety Population 
Listing 16.2.5.a
Sickle Cell Disease History for Safety Population
Listing 16.2.6.a 
Sickle Cell Disease Complications for Safety Population 
Listing 16.2.7.a 
Participant Follow-Up and Termination from Study for Safety Population 
Listing 16.2.8.a 
Prior and Concomitant Medications for Safety Population 
Listing 16.2.9.a 
Adverse Events for Safety Population 
Listing 16.2.10.a 
Study Drug Administration for Safety Population 
Listing 16.2.11.1.a Clinically Significant Laboratory Results for Safety Population 
Listing 16.2.11.2.a Coagulation Results for Safety Population 
Listing 16.2.11.3.a Urinalysis Results for Safety Population 
Listing 16.2.11.4.a Pregnancy Results for Safety Population 
Listing 16.2.12.a 
Vital Signs for Safety Population  
Listing 16.2.13.a 
Electrocardiogram for Safety Population 
Listing 16.2.14.a 
Physical Examinations for Safety Population 


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11.3. 
Tables Part B 
Item  
Title 
Table 14.1.1.b 
Eligibility and Enrollment 
Table 14.1.2.b
Demographics and Baseline Characteristics
Table 14.1.3.b
Baseline Sickle Cell Disease Characteristics
Table 14.1.4.b 
Other Medical History 
Table 14.1.5.b 
Participant Follow-up and Termination from Study 
Table 14.1.6.b 
Concomitant Medications 
Table 14.1.7.b 
Study Drug Exposure 
Table 14.2.1.1.b 
Summary of Hemoglobin and Measures of Hemolysis 
Table 14.2.1.2.b 
Hemoglobin Responders 
Table 14.2.2.b 
Summary of TCD Velocity and Change from Baseline 
Table 14.2.3.b 
Summary of Sickle Cell Disease Measure Total Symptom Score and Change 
from Baseline 
Table 14.3.1.1.b 
Overview of Treatment-Emergent Adverse Events and Serious Adverse Events 
Table 14.3.1.2.1.b 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term 
and Maximum Severity  
Table 14.3.1.2.2.b 
SCD Related Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Maximum Severity  
Table 14.3.1.3.1.b 
Treatment-Emergent Adverse Events Related to Study Drug by System Organ 
Class, Preferred Term and Maximum Severity  
Table 14.3.1.3.2.b 
SCD Related Treatment-Emergent Adverse Events Related to Study Drug by 
System Organ Class, Preferred Term and Maximum Severity  
Table 14.3.1.4.b 
Treatment-Emergent Adverse Events by Preferred Term  
Table 14.3.1.5.b 
Treatment-Emergent Adverse Events Related to Study Drug by Preferred Term  
Table 14.3.1.6.1.b 
Serious Adverse Events by System Organ Class and Preferred Term and 
Maximum Severity 
Table 14.3.1.6.2.b 
SCD Related Serious Adverse Events by System Organ Class and Preferred 
Term and Maximum Severity 
Table 14.3.2.1.b 
Summary of Hematology and Change from Baseline  


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Item
Title
Table 14.3.2.2.b 
Summary of Serum Chemistry and Change from Baseline  
Table 14.3.2.3.b
Summary of Liver Function Tests and Change from Baseline 
Table 14.3.2.4.b 
Summary of Serum Erythropoietin and Change from Baseline  
Table 14.3.3.b 
Summary of Vital Sign and Weight  
Table 14.3.4.1.b
Summary of Electrocardiograms
Table 14.3.4.2.b 
Corrected QT Interval (Fridericia) Maximum Post-Baseline and Maximum 
Increase from Baseline Categories 


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11.4. 
Listings Part B 
Item 
Title 
Listing 16.2.1.b 
Eligibility and Enrollment for Screen Failures 
Listing 16.2.2.b
Protocol Deviations for Safety Population
Listing 16.2.3.b 
Demographics for Safety Population 
Listing 16.2.4.b 
Baseline Characteristics for Safety Population 
Listing 16.2.5.b
Sickle Cell Disease History for Safety Population
Listing 16.2.6.b 
Sickle Cell Disease Complications for Safety Population 
Listing 16.2.7.b 
Hu History for Safety Population 
Listing 16.2.8.1.b 
Adverse Events for Safety Population 
Listing 16.2.8.2. b 
Serious Adverse Events for Safety Population 
Listing 16.2.9.1.b 
Clinically Significant Laboratory Results for Safety Population 
Listing 16.2.9.2.b 
Coagulation Results for Safety Population 
Listing 16.2.9.3.b 
Urinalysis Results for Safety Population 
Listing 16.2.9.4.b 
Pregnancy Results for Safety Population 
Listing 16.2.9.5.b 
Pregnancy Results for Safety Population 


STATISTICAL ANALYSIS PLAN 
Study Title:
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:
2a
Protocol No.:
GBT440-007
Protocol Date:
28 April 2021, Amendment 7
Analysis Plan 
and Date:
Part C (Final Data), 2 November 2022
CONFIDENTIAL AND PROPRIETARY INFORMATION


Global Blood Therapeutics, Inc.
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Statistical Analysis Plan
GBT440-007 Part C ± Final Data
  
CONFIDENTIAL
2 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL
Prepared by: 
 MS
Global Blood Therapeutics, Inc. 
Date
Reviewed by: 
 MStat
PharPoint Research, Inc.
Date
Approved by: 
, PhD
Global Blood Therapeutics, Inc. 
.
Date
 MStat
 MS
, PhD


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ................................................2 
TABLE OF CONTENTS .................................................................................................................3 
1. 
GLOSSARY OF ABBREVIATIONS ..........................................................................5 
2. 
INTRODUCTION AND STUDY OVERVIEW ..........................................................6 
2.1. 
Objectives .....................................................................................................................6 
2.2. 
Part C (Multiple Dose) ..................................................................................................6 
2.2.1. 
Primary Objective .........................................................................................................6 
2.2.2. 
Secondary Objective .....................................................................................................6 
3. 
ENDPOINTS ................................................................................................................8 
3.1. 
Endpoints for Part C .....................................................................................................8 
3.1.1. 
Primary Endpoint ..........................................................................................................8 
3.1.2. 
Secondary Endpoints ....................................................................................................8 
3.1.3. 
Safety Endpoints ...........................................................................................................8 
4. 
DEFINITIONS AND TERMINOLOGY .....................................................................8 
5. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................10 
5.1. 
Sample Size Considerations .......................................................................................10 
5.2. 
Handling of Missing or Partial Dates .........................................................................10 
5.2.1. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................10 
5.2.2. 
Missing Start and Stop Dates for Adverse Events ......................................................10 
6. 
ANALYSIS POPULATIONS ....................................................................................10 
6.1. 
Efficacy Evaluable Population ...................................................................................10 
6.2. 
Safety Population ........................................................................................................10 
6.3. 
PK Population .............................................................................................................11 
7. 
STATISTICAL METHODS .......................................................................................11 
7.1. 
Subject Disposition, Demographic and Baseline Characteristics ...............................11 
7.1.1. 
Subject Disposition .....................................................................................................11 
7.1.2. 
Demographic and Baseline Characteristics ................................................................11 
7.1.3. 
Baseline Sickle Cell Disease Characteristics ..............................................................11 
7.1.4. 
Medical History Excluding Sickle Cell History .........................................................11 
7.2. 
Efficacy Analysis ........................................................................................................12 
7.3. 
Safety ..........................................................................................................................12 


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7.3.1. 
Summary of Exposure ................................................................................................12 
7.3.2. 
Adverse Events ...........................................................................................................13 
7.3.3. 
Concomitant Medications ...........................................................................................14 
7.3.4. 
Clinical Laboratory Data ............................................................................................14 
7.3.5. 
Vital Signs and Physical Exam ...................................................................................15 
7.3.6. 
12-Lead Electrocardiogram ........................................................................................15 
8. 
PROTOCOL DEVIATIONS ......................................................................................15 


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1.
GLOSSARY OF ABBREVIATIONS
Abbreviation
Description
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical
BMI 
Body Mass Index
CRF 
Case Report Form
Cmin
Trough Concentration
Cmax
Maximum Concentration
CTCAE 
Common Terminology Criteria for Adverse Events
HU
Hydroxyurea
ICH 
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
PT
Preferred Term
RBC 
Red Blood Cells
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCD 
Sickle Cell Disease
SD
Standard Deviation
SOC
System Organ Class
TAMM
Time-Averaged Mean of the Maximum
TCD 
Transcranial Doppler
TEAE
Treatment-Emergent Adverse Event
WHO
World Health Organization


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2.
INTRODUCTION AND STUDY OVERVIEW
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses of final 
data from GBT44-007 Part C.  
Where applicable, the statistical analysis methods presented in this document supersede the 
statistical analysis methods described in the study protocol.
Study Overview:
GBT440-007 is a multicenter, open-label study to evaluate the safety, PK and efficacy of 
voxelotor in pediatric subjects with SCD. 
This study consists of 4 parts, Part A, Part B, Part C and Part D. The planned analysis of the final 
data from Part C (ages 4 to 17 years) is described in this SAP.  
Part C assesses the safety, tolerability and PK, as well as the hematological effects and the effect 
on transcranial doppler (TCD) flow velocity of voxelotor in pediatric subjects with SCD who are 
4 to 17 years of age.  
Up to 50 pediatric subjects will be enrolled in Part C.
At least 30 subjects must have a TC
 140 and < 200 cm/sec by nonimaging 
 125 and < 185 cm/sec by imaging transcranial Doppler [TCDi]) upon Screening 
AND
At least 20 subjects must be between 4 to 11 years of age 
To further characterize a potential effect on TCD data for those subjects who have a TCD 
 140 and < 170 cm/sec by nonimaging TCD (
 125 and < 155 cm/sec by TCDi) upon 
screening, approximately 20 subjects may be added with a TCD velocity that falls within this 
range, depending on the emerging data. In this event, Part C will contain up to 70 pediatric
subjects. 
2.1.
Objectives
2.2.
Part C (Multiple Dose)
2.2.1.
Primary Objective
To evaluate the effect of voxelotor on cerebral hemodynamics in pediatric subjects
with SCD with elevated or conditional TCD flow velocity as assessed by TCD 
ultrasonography 
2.2.2.
Secondary Objective
To evaluate the effect of voxelotor on clinical measures of anemia and hemolysis  
To characterize the PK of voxelotor in plasma, whole blood and RBCs following 
multiple doses in pediatric subjects with SCD


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To evaluate the safety and tolerability of voxelotor following multiple doses in 
pediatric subjects with SCD  
To evaluate the proportion of subjects with normal TCD flow velocity (< 170 cm/sec 
by nonimaging TCD or < 155 cm/sec by TCDi) at 48 weeks  
To evaluate the effect of voxelotor on the incidence of stroke and vaso-occlusive 
crisis (VOC)


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3.
ENDPOINTS
3.1.
Endpoints for Part C 
3.1.1.
Primary Endpoint
Change from baseline to 48 weeks in cerebral blood flow as measured by the 
TAMM TCD velocity
3.1.2.
Secondary Endpoints
Change from baseline to Weeks 24 and 48 in Hb, LDH, indirect bilirubin, and 
reticulocyte count 
Change from baseline to 24 weeks in cerebral blood flow as measured by the 
TAMM TCD velocity
Time to initial Hb response, defined as change from baseline in Hb > 1g/dL 
Whole blood and plasma voxelotor PK (Cmin, Cmax, AUC), plasma t1/2, and percent Hb 
occupancy 
Proportion of subjects with normal TCD flow velocity (< 170 cm/sec by 
nonimagining TCD or < 155 cm/sec by TCDi) at 48 weeks 
Incidence of stroke and VOC during the study 
3.1.3.
Safety Endpoints
TEAEs and SAEs
Clinical laboratory tests, vital signs, and ECGs
4.
DEFINITIONS AND TERMINOLOGY
Study Day
Study Day is defined relative to initiation of treatment, i.e., Day 1. Thus, the study day of an 
event is calculated as:
Study Day = event date ± Day 1 date + 1. 
Study Visit 
Study Visit is the nominal visit as recorded on the CRF.  
Baseline
For all endpoints where both Screening and Day 1 pre-dose assessments are collected, baseline is 
defined as average of all assessments prior to the first dose. If there is an unscheduled visit prior 
to first dose, this unscheduled assessment will also be included in the baseline calculation.  


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Change from Baseline 
Change from baseline to follow-up visit will be calculated as the baseline measurement 
subtracted from the follow-up measurement for all assessments. Percent change from baseline 
values to post-baseline values will be calculated using the following formula where applicable:
([post-baseline value ± baseline value] / baseline value) × 100% 
Exposure to Study Drug 
Duration of exposure to study drug is defined as the number of weeks from Day 1 to the last date 
of dosing of Study drug. The derivation is as follows:
(Last dose date - First dose date + 1)/7
Actual exposure to study drug is defined as the number of weeks from Day 1 to the last date of 
dosing of Study drug which excludes days where treatment was entirely missed or intermittently 
stopped as recorded in the CRF. The derivation is as follows:
(Last dose date - First dose date - Number of days study drug was not taken +1)/7  
Prior Medications
Prior medications are those medications taken prior to the initiation of study drug.
Concomitant Medications
Concomitant medications are those medications taken on or after the initiation of study drug.
This definition includes medications started prior to the initiation of study drug, but continuing 
concurrently with study drug. 
RBC transfusions are collected as concomitant medications. 
Hemoglobin Response
An Hb response is defined as an increase in Hb > 1 g/dL from Baseline to each week of interest. 
Annualized Incidence Rate
Annualized incidence rate = (total number of events recorded over the treatment period) / (total 
person years) 
Total person-years = sum of subject treatment period in years, which covers the time 
from first dose to last dose
Treatment-emergent Adverse Event 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges on or after 
initiation of study drug (having been absent pre-treatment), or an AE that existed pre-treatment 
and worsened on treatment (relative to the pre-treatment state) through 28 days after study drug 
discontinuation. AEs occurring on Day 1 are assumed to be treatment-emergent.  


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5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Sample Size Considerations
Part C: Up to 50 pediatric subjects who are 4 to 17 years of age with SCD will be enrolled. For 
the primary efficacy endpoint, change from baseline in TAMM TCD velocity at Week 48, 
a sample size of 30 subjects  achieves greater than 95% power to detect a mean difference of 
15 cm/sec with an estimated sample standard deviation of 22 cm/sec using a paired t-test 
(2-sided) with a significance level (alpha) of 0.10.
5.2.
Handling of Missing or Partial Dates 
5.2.1.
Missing Start and Stop Dates for Prior and Concomitant Medication
For missing start day only: day will be imputed as the first day of the month (i.e., 1) with the 
following exception: If the partial date falls in the same month and year as the treatment start 
date then the concomitant medication start date will be imputed as the treatment start date. 
For missing start day and month: day and month will be imputed as the first day of the year 
(i.e., 1 January) with the following exception: If the partial date falls in the same year as the 
treatment start date then the concomitant medication start date will be imputed as the treatment 
start date.
For missing stop day only: day only will be imputed as the last day of the month (i.e., 28, 29, 30, 
or 31). 
For missing stop day and month: day and month will be imputed as the last day of the year 
(i.e., 31 December). 
5.2.2.
Missing Start and Stop Dates for Adverse Events
For missing start day only: day will be imputed as the first day of the month (i.e., 1) with the 
following exception: If the partial date falls in the same month and year as the treatment start 
date then the adverse event start date will be imputed as the treatment start date.  
For missing stop day only: day only will be imputed as the last day of the month (i.e., 28, 29, 30, 
or 31). 
6.
ANALYSIS POPULATIONS
6.1.
Efficacy Evaluable Population
All subjects who received at least one dose of study drug will be included in the Efficacy 
Evaluable population (EE). The EE population will be the primary population for the efficacy 
analyses. 
6.2.
Safety Population
The Safety Population is defined as all subjects who receive at least one dose of study drug. 
This population will be used in the assessment and reporting of safety data. 


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6.3.
PK Population
All subjects who receive any amount of study drug and who provide PK data from at least one 
post dose sample in plasma will be included in the PK population. Additional details are 
provided in a separate plan.
7.
STATISTICAL METHODS
Statistical analyses will be performed using SAS® Version 9.4 or higher.
Data summaries will be presented as: 4-11 years, 12-17 years and overall (4-17 years) age 
groups. 
Continuous variables will be descriptively summarized using number of subjects (n), mean, 
standard deviation (SD), median, quartiles, minimum, maximum, and, as appropriate, 95% 
confidence intervals. Categorical variables will be descriptively summarized by presenting the 
number (frequency) and percentage in each category. 
7.1.
Subject Disposition, Demographic and Baseline Characteristics 
7.1.1.
Subject Disposition
Subject disposition will be presented in terms of the numbers and percentages of subjects who 
completed the treatment and discontinued from treatment. The reasons for early treatment 
discontinuation will be presented. Similar results will be presented for subjects who discontinue 
study. 
7.1.2.
Demographic and Baseline Characteristics
The demographic variables collected in this study include age (years) at Screening, sex, race, and 
ethnicity and will be summarized descriptively. Height (cm), weight (kg) and BMI (kg/m2) at 
Screening will be presented using descriptive statistics. Subjects who record more than one race 
will be grouped into a single category denoted as multi-racial.
7.1.3.
Baseline Sickle Cell Disease Characteristics
Number of VOCs including the number of VOCs requiring hospitalization and the number of 
blood transfusion during the previous 12 months will be summarized categorically. 
Additional summaries including the number and percentage of subjects who currently use HU, 
who have each genotype (HbSS or 
0 thal) and who experienced a sickle cell complication 
prior to study enrollment will be presented. Baseline lab values including Hb, HbF, reticulocyte 
count and Baseline TCD will be summarized using descriptive statistics.
7.1.4.
Medical History Excluding Sickle Cell History
Medical history excluding sickle cell history will be summarized by System Organ Class (SOC) 
and Preferred Term (PT) according to Medical Dictionary for Regulatory Activities (MedDRA), 
coding dictionary (current version).  


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7.2.
Efficacy Analysis
Efficacy data will be summarized using the EE population.   
The primary endpoint for Part C is change from baseline to 48 weeks in cerebral blood flow as 
measured by the TAMM TCD velocity.
TCD flow velocity will be summarized descriptively at Week 24 and Week 48 for observed 
values and absolute changes. TCD is presented as TCD (non-imaging) in the summary table. 
TCDi (imaging) has been normalized to TCD (non-imaging) by adding 15 cm/sec. 
The proportion of subjects with normal TCD flow velocity (< 170 cm/sec by nonimaging TCD 
or < 155 cm/sec by TCDi) at 48 weeks will be summarized descriptively for the overall 
population and by Baseline TCD category (Normal, Conditional). 
Hb response, defined as an increase in Hb > 1 g/dL, will be summarized descriptively at Week 24
and Week 48. Subjects who drop-out early or do not have a Week 24 or Week 48 visit, are not 
included in the analysis for Hb response at each of the respective visits. Additional response 
assessment at each visit will be summarized descriptively. No missing data imputation or 
adjustment for RBC transfusion will be performed for this endpoint.
Additionally, Hb response at Week 24  and Week 48 will be summarized using the treated 
population.  All subjects treated will be included in the denominator for Hb response.
For subjects who have had a Hb response at least 1 visit, the time to the first response will be 
summarized descriptively.
Hematology parameters (hemoglobin, reticulocyte count, indirect bilirubin, and LDH) and in 
addition to each visit for observed values and changes (absolute and percent) from baseline using 
appropriate descriptive statistics. If indirect bilirubin is missing and direct and total bilirubin are 
collected, indirect can be calculated as:
Indirect Bilirubin = Total Bilirubin ± Direct Bilirubin. 
To evaluate the effect of voxelotor on the incidence of stroke and vaso-occlusive crisis (VOC), 
the annualized incidence rate will be summarized and 95% CI provided. 
Efficacy assessment will be summarized by subgroups defined by subjects¶ sex, baseline HU 
use, and  4-11 age group  (4 to 7 years and 8 to 11 years). Efficacy assessments to be 
summarized by subgroup include Hb response and change from baseline for hematology
parameters and TCD flow velocity.  
7.3.
Safety
All safety analyses will be conducted using the Safety Population.  
7.3.1.
Summary of Exposure
The duration of study drug exposure and actual study drug exposure will be summarized with 
descriptive statistics.


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The number and percentage of subjects who permanently discontinued study drug, and the 
reason for discontinuation (adverse event (AE) or other) will be summarized. The number and 
percentage of subjects who missed at least 1 dose of study drug or had at least 1 dose reduction 
will be summarized. The summary will include the number and percentage of subjects who had a 
dose reduction or dose missed due to an adverse event or other. Additionally, the number and 
percentage of subjects will be summarized in categories of number of missed doses and number 
of dose reductions. 
7.3.2.
Adverse Events
Adverse events reported for subjects participating in this study will be graded using the 
National Cancer Institute¶s (NCI) Common Terminology Criteria for Adverse Events (CTCAE), 
version 4.03. All AEs will be coded using MedDRA (current version).  
All adverse events summaries described below will be presented for both non-SCD and 
SCD-related TEAEs. 
Non-SCD-related TEAE summary tables will exclude sickle cell disease (SCD) related events 
defined as preferred terms of: acute chest syndrome, pneumonia, pneumonia necrotising, sickle 
cell anemia with crisis, osteonecrosis, and priapism. Additional TEAE tables will summarize the 
aforementioned SCD related events.  
Overall summaries will be presented which includes the number of TEAEs and the number and 
percentage of subjects who experienced at least one TEAE. The summaries will also include 
TEAEs Grade 3 or greater, TEAEs possibly/probably related to study drug, TEAEs leading to 
study drug reduction, TEAEs leading to study drug interruption, TEAEs leading to 
discontinuation of study drug, serious adverse events (SAEs) and SAEs possibly/probably related 
to study drug. TEAEs leading to deaths will be summarized together regardless if they are 
SCD-related as cause of death may include multiple TEAEs.
Additional summaries of TEAEs will be provided showing the number and percentage of 
subjects who experienced at least one TEAE. These summaries will be presented by system 
organ class (SOC), preferred term (PT) and maximum severity. If a subject reports the same PT 
multiple times within the same SOC, that PT will only be counted once within that SOC for that 
subject. As with the PT, if a subject reports multiple conditions within the same SOC, that SOC 
will only be counted once for that subject. In the summary, SOC will be listed in ascending 
alphabetical order; PTs will be listed in order of descending frequency for all subjects within 
each SOC.
The occurrence of TEAEs possibly/probably related to voxelotor will be tabulated by SOC, 
PT and maximum severity. Serious adverse events will be presented by system organ class 
(SOC), preferred term (PT) and maximum severity.
Grouped terms for rash and abdominal pain are summarized by PT.  
Adverse events recorded in the eCRF which began prior to first dose of study drug will not be 
included in the TEAE summary tables.


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7.3.3.
Concomitant Medications
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (current version) and summarized to the therapeutic drug class (Anatomical 
Therapeutic Chemical (ATC) 4 classification) and preferred name. 
7.3.4.
Clinical Laboratory Data 
All hematology and chemistry laboratory assessments were performed by local laboratories.  
The following protocol-specified clinical laboratory findings will be summarized using 
descriptive statistics.
1. Hematology: 
a.
Hemoglobin 
b. Neutrophils (absolute and %)
c.
Platelets
d. Reticulocyte count (percent) 
e.
WBC


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2. Chemistry and Liver Function Tests: 
a.
Alkaline phosphatase 
b. ALT
c.
AST
d. Lactate dehydrogenase (LDH)
e.
Potassium
f.
Indirect bilirubin
g. Total bilirubin
h. Serum erythropoietin
Change from baseline and the percent change from baseline will be summarized for the above 
laboratory results. Analyte units will be converted to SI units.  
Subject listings of laboratory data will include a separate listing for clinically significant 
laboratory results. Urinalysis, coagulation and pregnancy results will be listed only.
7.3.5.
Vital Signs and Physical Exam
Vital signs, including systolic and diastolic blood pressure, heart rate, respiratory rate, 
temperature, and weight will be summarized using continuous descriptive statistics at each visit 
and time point. Change from baseline will also be summarized for each post-baseline visit.
7.3.6.
12-Lead Electrocardiogram
Heart rate, PR interval, QRS interval, QT interval, RR interval, and QTcF (Fridericia¶s) interval 
will be summarized along with the change from baseline using descriptive statistics at each visit.
The average of the 3 ECGs collected will be used in the summary tables.
Additionally, the number and percentage of subjects with QTcF  450 ms, >450 ms to 
480 ms, 
>480 ms to 
500 ms, and >500 ms at baseline and as the maximum post-baseline measurement 
will be summarized. The number and percentage of subjects with maximum increase from baseline 
where increase in QTcF
 30 ms, > 30 ms to 60 ms and> 60 ms also will be summarized. If the 
QTcF interval was not collected, the interval will be calculated using the following formula:
QTcF = QT / (60/HR)1/3
8.
PROTOCOL DEVIATIONS
Important protocol deviations and COVID 19 related deviations will be displayed in a data 
listing and sorted by age group, subject number, and then by date (where applicable) within each 
subject number. The type of deviation along with a description and any additional comments 
about the deviation will be listed.  


    
 
 
STATISTICAL ANALYSIS PLAN  
 
 
Study Title: 
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: 
2a 
 
 
Protocol No.: 
GBT440-007 (C5341020) 
 
 
Protocol Date and Version: 
28 April 2021, Amendment 7 
 
 
Investigational Product: 
Voxelotor (GBT440 / PF-06759497) 
 
 
Study Sponsor: 
Global Blood Therapeutics, Inc., a wholly owned 
subsidiary of Pfizer Inc. 
181 Oyster Point Blvd. 
South San Francisco, CA 94080 
United States of America 
 
 
SAP Version: 
Part D, Version 1.0  
 
 
SAP Date: 
03 October 2023 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
 
 
 
DocUUID : 8f6e98d3-06ef-4913-9ba2-5091b14dfcc4
090177e19ecf6ba3\Approved\Approved On: 09-Oct-2023 16:12 (GMT)


GBT, a wholly owned subsidiary of Pfizer
   Voxelotor
Statistical Analysis Plan
GBT440-007 Part D (C5341020)
                                                                    
PFIZER CONFIDENTIAL
2
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL
Prepared by:
MS
Global Blood Therapeutics, Inc., a wholly owned subsidiary of 
Pfizer Inc.
Date
Reviewed by: 
 PhD
Global Blood Therapeutics, Inc., a wholly owned subsidiary of 
Pfizer Inc.
Date
Approved by: 
PhD
Pfizer Inc.
Date
DocUUID : 8f6e98d3-06ef-4913-9ba2-5091b14dfcc4
REASON: I approve this
document as author.
REASON: I approve this
document.
REASON: I approve this
document.
03 Oct 2023 13:46:007-0400
03 Oct 2023 13:46:055-0400
03 Oct 2023 14:45:048-0400
090177e19ecf6ba3\Approved\Approved On: 09-Oct-2023 16:12 (GMT)


GBT, a wholly owned subsidiary of Pfizer 
 
   Voxelotor 
Statistical Analysis Plan 
 
GBT440-007 Part D (C5341020) 
 
 
PFIZER CONFIDENTIAL 
3 
 
  
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ................................................2 
TABLE OF CONTENTS .................................................................................................................3 
1. 
GLOSSARY OF ABBREVIATIONS ..........................................................................5 
2. 
INTRODUCTION AND STUDY OVERVIEW ..........................................................7 
3. 
STUDY OBJECTIVES FOR PART D .........................................................................7 
3.1. 
Primary .........................................................................................................................7 
3.2. 
Secondary .....................................................................................................................7 
3.3. 
Exploratory ...................................................................................................................7 
4. 
ENDPOINTS FOR PART D ........................................................................................8 
4.1. 
Primary .........................................................................................................................8 
4.2. 
Secondary .....................................................................................................................8 
4.3. 
Exploratory ...................................................................................................................8 
4.4. 
Safety ............................................................................................................................8 
5. 
DEFINITIONS AND TERMINOLOGY .....................................................................8 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................10 
6.1. 
Sample Size Considerations .......................................................................................10 
6.2. 
Handling of Missing or Partial Dates .........................................................................10 
6.2.1. 
Missing Start Dates for Prior and Concomitant Medication.......................................10 
6.2.2. 
Missing Start Dates for Adverse Events .....................................................................10 
7. 
ANALYSIS POPULATIONS ....................................................................................10 
7.1. 
Efficacy Evaluable Population....................................................................................10 
7.2. 
Safety Population ........................................................................................................10 
7.3. 
PK Population .............................................................................................................10 
8. 
STATISTICAL METHODS .......................................................................................11 
8.1. 
Subject Disposition, Demographic and Baseline Characteristics ...............................11 
8.1.1. 
Subject Disposition .....................................................................................................11 
8.1.2. 
Demographic and Baseline Characteristics ................................................................11 
8.1.3. 
Baseline Sickle Cell Disease Characteristics ..............................................................11 
8.1.4. 
Medical History Excluding Sickle Cell History .........................................................11 
8.2. 
Efficacy Analysis ........................................................................................................12 
8.3. 
Safety ..........................................................................................................................12 
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8.3.1. 
Summary of Exposure ................................................................................................12 
8.3.2. 
Adverse Events ...........................................................................................................13 
8.3.3. 
Concomitant Medications ...........................................................................................13 
8.3.4. 
Clinical Laboratory Data ............................................................................................13 
8.3.5. 
Vital Signs and Physical Exam ...................................................................................14 
8.3.6. 
12-Lead Electrocardiogram ........................................................................................14 
9. 
PROTOCOL DEVIATIONS ......................................................................................14 
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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the concentration-time curve 
BMI 
Body Mass Index 
CI 
Confidence Interval 
cm 
Centimeter 
CRF 
Case Report Form 
Cmax 
Maximum Blood Concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EE 
Efficacy Evaluable 
g/dL 
gram per deciliter 
Hb 
Hemoglobin 
HbF 
hemoglobin ± fetal 
HbS 
0 thal 
sickle hemoglobin (S) and one beta thalassemia gene (
0 thal) 
HbSS 
sickle hemoglobin with two sickle cell genes (SS)  
HU 
Hydroxyurea 
kg 
Kilogram 
kg/m2 
kilogram per meter squared 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
n 
number of subjects 
NCI 
National Cancer Institute 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
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Abbreviation 
Description 
SAS® 
Statistical Analysis Software 
SCD 
Sickle Cell Disease 
SD 
Standard Deviation 
SI 
Systeme International 
SOC 
System Organ Class 
t1/2 
terminal elimination half-life 
TEAE 
Treatment-Emergent Adverse Event 
VOC 
vaso-occlusive crisis 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 
 
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2. 
INTRODUCTION AND STUDY OVERVIEW 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses of data 
from GBT440-007 Part D.  
Where applicable, the statistical analysis methods presented in this document will supersede the 
statistical analysis methods described in the study protocol.  
Study Overview: 
GBT440-007 is a multicenter, open-label study to evaluate the safety, pharmacokinetics (PK) 
and efficacy of voxelotor in pediatric subjects with Sickle Cell Disease (SCD).  
This study consists of 4 parts, Part A, Part B, Part C, and Part D. The planned analyses of data 
from Part D are described in this SAP. 
Part D assesses the safety, tolerability, and PK, as well as the hematological effects of voxelotor 
in pediatric subjects with SCD who are 6 months to < 4 years of age. Approximately 30 pediatric 
subjects will be enrolled into Part D.  
3. 
STUDY OBJECTIVES FOR PART D 
3.1. 
Primary 
 To evaluate the safety and tolerability of voxelotor in pediatric subjects with SCD 
aged 6 months to < 4 years 
3.2. 
Secondary 
 To characterize the PK of voxelotor in plasma, whole blood, and red blood cells 
(RBCs) in pediatric subjects with SCD aged 6 months to < 4 years  
 To evaluate the effect of voxelotor on clinical measures of anemia and hemolysis in 
pediatric subjects with SCD aged 6 months to < 4 years 
 To evaluate the effect of voxelotor on the incidence of stroke and vaso-occlusive 
crisis (VOC) in pediatric subjects with SCD aged 6 months to < 4 years 
3.3. 
Exploratory 
 To evaluate the effect of voxelotor on growth and development pediatric subjects 
with SCD aged 6 months to < 4 years 
 
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4. 
ENDPOINTS FOR PART D 
4.1. 
Primary 
 Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) 
4.2. 
Secondary 
 Whole blood and plasma voxelotor PK (maximum blood concentration [Cmax], area 
under the concentration-time curve [AUC], terminal elimination half-life [t1/2], if 
appropriate) and percent hemoglobin (Hb) occupancy 
 Change from baseline to Week 24 and Week 48 in Hb, lactate dehydrogenase (LDH), 
indirect bilirubin, and reticulocyte count 
 Time to initial Hb response, with Hb response defined as change from baseline in  
Hb > 1g/dL 
 Time to initial Hb response is defined as time from first dose of study treatment to 
first occurrence of change from baseline in Hb > 1g/dL 
 Incidence of stroke and VOC during the study 
 In addition to the protocol-specified secondary endpoints, Hb response (defined as a 
change from baseline in Hb > 1g/dL) will be assessed at both Week 24 and Week 48.   
4.3. 
Exploratory 
 Growth and development as assessed by change from baseline to Weeks 24 and 48 in 
height, weight, and head circumference 
4.4. 
Safety 
 Clinical laboratory tests and vital signs  
5. 
DEFINITIONS AND TERMINOLOGY 
Study Day 
Study Day is defined relative to initiation of treatment, i.e., Day 1. Thus, the study day of an 
event is calculated as: 
Study Day = event date ± Day 1 date + 1. 
Study Visit  
Study Visit is the nominal visit as recorded on the Case Report Form (CRF).  
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Baseline 
For all endpoints where both Screening and Day 1 pre-dose assessments are collected, baseline is 
defined as average of all assessments prior to the first dose. If there is an unscheduled visit prior 
to first dose, this unscheduled assessment will also be included in the baseline calculation.  
 
Change from Baseline 
Change from baseline to follow-up visit will be calculated as the baseline measurement 
subtracted from the follow-up measurement for all assessments. Percent change from baseline 
values to post-baseline values will be calculated using the following formula where applicable: 
([post-baseline value ± baseline value] / baseline value) × 100% 
Exposure to Study Drug  
Duration of exposure to study drug is defined as the number of weeks from Day 1 to the last date 
of dosing of study drug. The derivation is as follows: 
(Last dose date - First dose date + 1)/7 
Actual exposure to study drug is defined as the number of weeks from Day 1 to the last date of 
dosing of study drug which excludes days where treatment was entirely missed or intermittently 
stopped as recorded in the CRF. The derivation is as follows: 
(Last dose date - First dose date - Number of days study drug was not taken +1)/7  
Prior Medications 
Prior medications are those medications taken prior to the initiation of study drug.  
Concomitant Medications 
Concomitant medications are those medications taken on or after the initiation of study drug. 
This definition includes medications started prior to the initiation of study drug, but continuing 
concurrently with study drug. 
RBC transfusions are collected as concomitant medications. 
Hemoglobin Response  
Hb response is defined as an increase in Hb > 1 g/dL from Baseline and will be assessed at both 
Week 24 and Week 48.  
Treatment-Emergent Adverse Event  
A treatment-emergent adverse event (TEAE) is defined as an adverse event (AE) that emerges on 
or after initiation of study drug (having been absent pre-treatment), or an AE that existed pre-
treatment and worsened on treatment (relative to the pre-treatment state) through 28 days after 
study drug discontinuation.  
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PFIZER CONFIDENTIAL 
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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
Sample Size Considerations 
Approximately 30 pediatric subjects with SCD who are 6 months to < 4 years of age will be 
enrolled in GBT440-007 Part D. The sample size was selected to provide descriptive assessment 
of safety, tolerability, and PK effects of voxelotor in this younger age group with no formal 
statistical assumptions. 
6.2. 
Handling of Missing or Partial Dates 
6.2.1. 
Missing Start Dates for Prior and Concomitant Medication 
For missing start day only: day will be imputed as the first day of the month (i.e., 1) with the 
following exception: If the partial date falls in the same month and year as the treatment start 
date then the concomitant medication start date will be imputed as the treatment start date.  
For missing start day and month: day and month will be imputed as the first day of the year 
(i.e., 1 January) with the following exception: If the partial date falls in the same year as the 
treatment start date then the concomitant medication start date will be imputed as the treatment 
start date. 
6.2.2. 
Missing Start Dates for Adverse Events 
For missing start day only: day will be imputed as the first day of the month (i.e., 1) with the 
following exception: If the partial date falls in the same month and year as the treatment start 
date then the adverse event start date will be imputed as the day prior to the treatment start date.  
7. 
ANALYSIS POPULATIONS 
7.1. 
Efficacy Evaluable Population 
All subjects who receive at least one dose of study drug will be included in the Efficacy 
Evaluable population (EE). All efficacy analyses will be based on the EE population. 
In this study (GBT440-007 Part D), the EE population is the same as the Safety Population (see 
Section 7.2). 
7.2. 
Safety Population 
The Safety Population is defined as all subjects who receive at least one dose of study drug. 
This population will be used in the assessment and reporting of safety data. 
7.3. 
PK Population 
For the Population PK analysis, an individual will be defined as evaluable if both of the 
following criteria are satisfied: 
1. Received at least 1 dose of voxelotor with associated dosing date and time  
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2. Has at least 1 measurable voxelotor concentration observation in plasma or whole blood 
with associated sampling time and dosing information 
Details on PK analyses, as well as Hb occupancy, are provided in a separate analysis plan.   
8. 
STATISTICAL METHODS 
Statistical analyses will be performed using SAS® Version 9.4 or higher.  
Continuous variables will be descriptively summarized using number of subjects (n), mean, 
standard deviation (SD), median, minimum, maximum, and, as appropriate, 95% confidence 
intervals (CIs). Categorical variables will be descriptively summarized by presenting the number 
(frequency) and percentage in each category. 
In general, results for Part D will be presented by age group (6 months to < 2 years and 2 years to 
< 4 years) and overall, as appropriate.  
8.1. 
Subject Disposition, Demographic and Baseline Characteristics  
8.1.1. 
Subject Disposition 
Subject disposition will be presented in terms of the numbers and percentages of subjects who 
completed the treatment and discontinued from treatment. The reasons for early treatment 
discontinuation will be presented. Similar summaries will be presented for subjects who 
discontinue study. 
8.1.2. 
Demographic and Baseline Characteristics 
The demographic variables collected in this study include age (months or years) at Screening, 
sex, race, and ethnicity and will be summarized descriptively. Height (cm), weight (kg), and 
BMI (kg/m2) at Day 1 will be presented using descriptive statistics. Subjects who record more 
than one race will be grouped into a single category denoted as multi-racial.  
8.1.3. 
Baseline Sickle Cell Disease Characteristics 
Number of VOCs including the number of VOCs requiring hospitalization and the number of 
blood transfusions during the previous 12 months will be summarized categorically.  
Additional summaries including the number and percentage of subjects who currently use HU, 
who have each genotype (homozygous hemoglobin SS [HbSS] or hemoglobin S beta0 
thalassemia [HbS 
0 thal]), and who experienced a sickle cell complication prior to study 
enrollment will be presented. Baseline lab values including Hb, hemoglobin ± fetal (HbF), and 
reticulocyte count will be summarized using descriptive statistics.  
8.1.4. 
Medical History Excluding Sickle Cell History 
Medical history excluding sickle cell history will be summarized by System Organ Class (SOC) 
and Preferred Term (PT) according to Medical Dictionary for Regulatory Activities (MedDRA), 
coding dictionary (current version).  
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8.2. 
Efficacy Analysis 
All efficacy data will be summarized using the EE population.   
Hematology and hemolysis parameters (hemoglobin, reticulocyte count, indirect bilirubin, and 
LDH) will be summarized at Week 24 and Week 48 in addition to each visit for observed values 
and changes (absolute and percent, as appropriate) from baseline using appropriate descriptive 
statistics. If indirect bilirubin is missing and direct and total bilirubin are collected, indirect can 
be calculated as: 
Indirect Bilirubin = Total Bilirubin ± Direct Bilirubin. 
Hb response, defined as an increase in Hb > 1 g/dL, will be summarized descriptively at Week 24 
and Week 48 with 95% confidence intervals provided for the response rates.  Subjects who drop-
out early or do not have a Week 24 or Week 48 assessment, are not included in the analysis for 
Hb response. Additional response assessments at each visit will be summarized descriptively. No 
missing data imputation or adjustment for RBC transfusion will be performed for this endpoint. 
Additionally, Hb response at Week 24 and Week 48 with 95% confidence intervals will be 
summarized using the treated population.  All subjects treated will be included in the 
denominator for Hb response, and subjects without a Week 24 or Week 48 assessment will be 
counted as non-responders at each relevant timepoint. 
For subjects who had a Hb response at least 1 visit, the time to the first response will be 
summarized descriptively (ie, median, first quartile, third quartile, and range). 
The annualized incidence rates for VOC and stroke and the associated 95% CIs will be 
presented. Annualized rate is defined as the total number of events divided by total person years. 
Total person-years is defined as the sum of subject treatment period in years which covers the 
time from first dose to last dose. VOC is defined based on clinical review of adverse event 
MedDRA preferred terms (eg, sickle cell anemia with crisis, acute chest syndrome, and 
pneumonia). 
Exploratory analysis for change from baseline to Weeks 24 and 48 in height, weight, and head 
circumference, will be summarized using continuous descriptive statistics at each visit.  
8.3. 
Safety 
All safety analyses will be conducted using the Safety Population.  
8.3.1. 
Summary of Exposure 
The duration of study drug exposure and actual study drug exposure will be summarized with 
descriptive statistics. 
The number and percentage of subjects who permanently discontinued study drug, and the 
reason for discontinuation (AE or other) will be summarized. The number and percentage of 
subjects who missed at least 1 dose of study drug or had at least 1 dose reduction will be 
summarized. The summary will include the number and percentage of subjects who had a dose 
reduction or dose missed due to an adverse event or other reason. Additionally, the number and 
percentage of subjects will be summarized in categories of number of missed doses and number 
of dose reductions. 
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8.3.2. 
Adverse Events 
Adverse events reported for subjects participating in this study were primarily graded for 
severity using the National Cancer Institute¶s (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.03. For adverse events not covered in the NCI-CTCAE, grading was 
performed per the criteria outlined in Table 13 of the protocol.  
All adverse events will be coded using MedDRA (current version).  
All adverse events summaries described below will be presented for both non-SCD and 
SCD-related TEAEs.  
Non-SCD-related TEAE summary tables will exclude sickle cell disease (SCD) related events 
defined as preferred terms of: acute chest syndrome, pneumonia, sickle cell anemia with crisis, 
osteonecrosis, and priapism. Additional TEAE tables will summarize the aforementioned SCD 
related events.  
Overall summaries will be presented which include the number of TEAEs and the number and 
percentage of subjects who experienced at least one TEAE. The summaries will also include 
TEAEs Grade 3 or greater, TEAEs possibly/probably related to study drug, TEAEs leading to 
study drug reduction, TEAEs leading to study drug interruption, TEAEs leading to 
discontinuation of study drug, and serious adverse events (SAEs). TEAEs leading to deaths will 
be summarized together regardless if they are SCD-related, as cause of death may include 
multiple TEAEs.  
Additional summaries of TEAEs will be provided showing the number and percentage of 
subjects who experienced at least one TEAE. These summaries will be presented by system 
organ class (SOC), preferred term (PT) and maximum severity. If a subject reports the same PT 
multiple times within the same SOC, that PT will only be counted once within that SOC for that 
subject. As with the PT, if a subject reports multiple conditions within the same SOC, that SOC 
will only be counted once for that subject. In the summary, SOC will be listed in ascending 
alphabetical order; PTs will be listed in order of descending frequency for all subjects within 
each SOC.  
The occurrence of TEAEs possibly/probably related to voxelotor will be tabulated by system 
organ class (SOC), preferred term (PT), and maximum severity. Serious adverse events will be 
presented by system organ class (SOC), preferred term (PT), and maximum severity. 
Grouped terms for rash and abdominal pain will be summarized.  
Adverse events recorded in the electronic case report form (eCRF) which began prior to first 
dose of study drug will not be included in the summary tables.  
8.3.3. 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (current version) and summarized to the therapeutic drug class, Anatomical 
Therapeutic Chemical (ATC) 4 classification, and preferred name. 
8.3.4. 
Clinical Laboratory Data 
All hematology and chemistry laboratory assessments were performed by local laboratories.  
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The following protocol-specified clinical laboratory findings will be summarized using 
descriptive statistics. 
1. Hematology: 
a. Hemoglobin 
b. Neutrophils (absolute and %) 
c. Platelets 
d. Reticulocyte count (percent and absolute reticulocyte) 
e. White blood cells (WBCs) 
2. Chemistry and Liver Function Tests: 
a. Alkaline phosphatase 
b. Alanine aminotransferase (ALT) 
c. Aspartate aminotransferase (AST) 
d. Indirect bilirubin 
e. Total bilirubin 
f. Lactate dehydrogenase (LDH) 
g. Serum Erythropoietin 
Change from baseline and the percent change from baseline will be summarized for the above 
laboratory results. Analyte units will be converted to International System of Units (SI) units.  
Subject listings of laboratory data will include a separate listing for clinically significant 
laboratory results.  
8.3.5. 
Vital Signs and Physical Exam 
Vital signs, including systolic and diastolic blood pressure and heart rate, will be summarized 
using continuous descriptive statistics at each visit. Change from baseline will also be 
summarized for each post-baseline visit. 
8.3.6. 
12-Lead Electrocardiogram 
Data from ECG assessments (collected at Screening only) will be listed. 
9. 
PROTOCOL DEVIATIONS 
Protocol deviations as assessed by the study team will be displayed in a data listing and sorted by 
subject number, and then by date (where applicable) within each subject number. The type of 
deviation along with a description and any additional comments about the deviation will be 
listed.  
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