Clinical trial NCT05561140
Conditions: Sickle Cell Disease Leg Ulcers
Keywords: Sickle Cell Disease, SCD
Sponsor: Pfizer
Start date: 2022-05-30; Completion date: 2024-10-22
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a Phase 3, multicenter, randomized, placebo-controlled study to evaluate the efficacy of voxelotor and standard of care for the treatment of leg ulcers in participants with sickle cell disease. The study is divided into a 5 study periods: Screening, Run-in, Randomized Treatment, Open-label Treatment, and Follow-up/End of Study (EOS).

The study will be conducted in approximately 80 eligible participants at approximately 20 global clinical trial sites.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Voxelotor Oral Tablet intervention 2: Placebo
Intervention descriptions: intervention 1: Synthetic small molecule supplied as 500 mg tablets, administered Orally intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
P FI Z E R C O N FI D E N TI A L
Pa ge 1
C LI NI C A L S T U D Y P R O T O C O L
St u d y Title
A P h ase 3, M ultice nter, R a n d o mize d, D o u ble -Bli n d, 
Pl ace b o -C o ntr olle d Tri al t o E v al u ate t he Effic ac y of V o xel ot or f or 
t he Tre at me nt of Le g Ulcers i n P atie nts wit h Sic kle Cell Dise ase
S h ort Title
Res ol uti o n o f Sic kle Cell Le g Ulcers wit h V o x el ot or ( R E S O L V E)
I n vesti g ati o n al 
Pr o d uct
V o xel ot or ( G B T 4 4 0)
I N D N u m ber
1 2 1 6 9 1
S p o ns or Le g al 
A d dress
Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer 
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
Pr ot oc ol 
A me n d me nt 3. 0
2 2 Dece m ber 2 0 2 3
Pr ot oc ol 
A me n d me nt 2. 0
0 1 Se pte m ber 2 0 2 2 
Pr ot oc ol 
A me n d me nt 1. 0
1 3 Ja n uar y 2 0 2 2
Ori gi n al 
Pr ot oc ol
2 2 Se pte m ber 2 0 2 0
C O N FI D E N TI A L
T he i nf or m ati o n i n t his st u d y pr ot oc ol is strictl y c o nfi de nti al a n d is a v ail a ble f or 
re vie w t o I n vesti g at ors, st u d y ce nter pers o n nel, t he et hics c o m mittee, a n d t he he alt h 
a ut h orities. It will n ot be discl ose d t o t hir d p arties wit h o ut writte n a ut h oriz ati o n fr o m 
t he S p o ns or, e xce pt t o o bt ai 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 
tre at 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 p arties.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 2
S U M M A R Y O F C H A N G E S 
A m e n d me nt 3 ( 2 2 Dece m ber 2 0 2 3)
O ver all R ati o n ale f or t he A me n d me nt: 

T o i nc or p orate c ha n ges pre vi o usl y  i m ple me nte d via pr ot oc ol clarificati o n me m os

T o ali g n t he pr ot oc ol wit h t he Pfizer Pr ot oc ol Te m plate a n d Sta n dar d O perati n g 
Pr oce d ures

N ote: t he c ha n ges bel o w ar e n ot d ue t o a n y i ncrease i n safet y si g nals
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble
Descri pti o n of C h a n ge 
Brief R ati o n ale
Secti o n N u m ber a n d N a me
N o n -S u bst a nti al M o dific ati o ns
Re m o ve d na me of St u d y 
Direct or
Na me of St u d y Direct or is 
c o nsi dere d pers o nal pr otecte d 
data
Title pa ge
Re m o ve d State me nt of 
A p pr o val a n d C o m plia nce
State me nt of A p pr o val a n d 
C o m plia nce is c o nsi dere d
pers o nal pr otecte d data
State me nt of A p pr o val a n d 
C o m plia nce 
A d de d detaile d g ui da nce f or 
re p orti n g A Es 
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms
7. 2. 1 A d verse E ve nt Re p orti n g 
( ge neral)
A d de d la n g ua ge f or re p orti n g 
A Es a n d S A Es after t he e n d 
of A E/ S A E acti ve c ollecti o n 
peri o d
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
p r ocesses a n d s yste ms
7. 3 Seri o us A d verse E ve nts, Seri o us 
A d verse Dr u g Reacti o ns, a n d 
Re q uire me nts f or I m me diate 
Re p orti n g
Re vise d la n g ua ge o n 
re p orti n g o ver d ose
T o ali g n wit h Pfizer’s safet y 
re p orti n g pr ocess
7. 4 Re p orti n g O ver d ose
Re vis e d la n g ua ge re gar di n g 
e n vir o n me ntal a n d 
occ u pati o nal e x p os ure as 
well as e x p os ure d uri n g 
pre g na nc y a n d breastfee di n g
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms
7. 4 Re p orti n g Pre g na nc y ( delete d 
secti o n)
7. 5 E n vir o n me ntal E x p os ure, 
E x p os u re D uri n g Pre g na nc y or 
Breastfee di n g, Occ u pati o nal 
E x p os ure , a n d Lac k of Efficac y ( ne w 
secti o n)
A d de d la n g ua ge re gar di n g 
t he defi niti o n a n d re p orti n g 
of me dicati o n err ors
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms
7. 6 Me dicati o n Err ors ( ne w secti o n)
A d de d la n g ua ge re gar di n g 
ma xi m u m a m o u nt of bl o o d 
t o be dra w n f or pe diatric 
partici pa nts 
T o o pti mize pe diatric bl o o d 
dra ws
6. 1 0 La b orat or y Assess me nts
Ta ble 5
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 3
Descri pti o n of C h a n ge 
Brief R ati o n ale
Secti o n N u m ber a n d N a me
U p date d t he list of e xa m ples 
of m o derate a n d str o n g 
C Y P 3 4 A i n d ucers 
T o pr o vi de u p -t o-date 
g ui da nce t o I n vesti gat ors per 
t he latest list of e xa m ples 
pr o vi de d b y t he F D A a n d 
ali g n wit h ot her v o xel ot or 
cli nical st u d y pr ot oc ols
5. 7. 5 Pr o hi bite d C o nc o mita nt 
Me dicati o ns
E xte n de d t he Visit 3/ Da y 1 
wi n d o w b y o ne a d dit i o nal 
cale n dar da y at Visit 3 
T o all o w a d diti o nal ti me f or 
e nr oll me nt i n t he e ve nt t hat 
ce ntral re vie w a n d re p orti n g 
of res ults t o deter mi ne 
eli gi bilit y f or ra n d o mizati o n is 
n ot recei ve d i n a ti mel y 
ma n ner.
(I m ple me nte d via Pr ot oc ol 
Clarificati o n Letter # 1 – 0 2 
N o ve m ber 2 0 2 2)
3. 1 St u d y Desi g n
A p pe n di x 1 Sc he d ule of Assess me nts
Re vise d ta ble f o ot n ote “ n ” t o 
a d d:
Uri ne pre g na nc y test will be 
perf or me d at Baseli ne ( Da y 
1), Wee k 6, Wee k 1 2, Wee k 
1 8, a n d Wee k 2 4 i n fe male 
partici pa nts w h o ha ve 
e x perie nce d me narc he .
C orrecti o n t o ali g n wit h te xt 
i n Secti o n 6. 1 0, La b orat or y 
Assess me nts
(I m ple me nte d via Pr ot oc ol 
Clarificati o n Letter # 2 – 1 5 
Fe br uar y 2 0 2 3)
A p pe n di x 1 Sc he d ule of Assess me nts
A d de d or re vise d la n g ua ge 
re gar di n g access t o me dical 
m o nit or a n d re g ulat or y 
o bli gati o ns, disse mi nati o n of 
cli nical st u d y data, 
p u blicati o n p olic y, data 
q ualit y ass ura nce, st u d y/site 
start site a n d cl os ure, data 
pr otecti o n, a n d i nf or me d 
c o nse nt
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer Pr ot oc ol Te m plate a n d 
Sta n dar d O perati n g 
Pr oce d ures
1 1. Re g ulat or y, Et hical, Le gal, a n d 
O versi g ht O bli gati o ns (i ncl u des 
se veral ne w s u bsecti o ns)
1 4. P u blicati o n P olic y
A d de d la n g ua ge a n d a ne w 
a p pe n di x f or re p orti n g a n d 
f oll o w-u p assess me nts f or 
p ote ntial dr u g -i n d uce d li ver 
i nj ur y ( DI LI) e ve nts
T o s u p p ort st u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms
7. 2. 3 A b n or mal La b orat or y Val ues
1 0. 4 S p o ns or’s Me dicall y Q ualifie d 
I n di vi d ual ( ne w secti o n)
A p pe n di x 2 Li ver Safet y: S u g geste d 
acti o ns a n d f oll o w -u p assess me nts 
a n d st u d y dr u g rec halle n ge g ui deli nes
Re vise d i nstr ucti o ns f or 
c ollecti o n of bl o o d sa m ples 
f or retesti n g.
All o ws fle xi bilit y i n t he e ve nt 
t hat bl o o d sa m ple ca n n ot be 
re dra w n a n d s u b mitte d f or 
6. 1 0 L a b orat or y Assess me nts
A p pe n di x 1 Sc he d ule of Assess me nts
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 4
Descri pti o n of C h a n ge 
Brief R ati o n ale
Secti o n N u m ber a n d N a me
testi n g wit hi n 7 da ys of t he 
st u d y visit.
U p date d t he list of S C D -
relate d A Es t o i ncl u de 
s ple nic or he patic 
se q uestrati o ns, a n d str o ke
T o pr o vi de a br oa der 
defi niti o n of S C D -relate d A Es 
f or safet y a nal yses
7. 2. 5 W orse ni n g of Sic kle Cell 
D isease
A d de d clarif yi n g la n g ua ge 
re gar di n g le g ulcer 
p h ot o gra p h y a n d 
meas ure me nt pr ocess
T o pr o vi de clarit y t o sites 
re gar di n g pr ocess
6. 7 Ulcer Assess me nts
Re m o ve d clarif yi n g la n g ua ge 
o n P R O MI S meas ures 
P R O MI S data will be 
a nal yze d usi n g t he meas ures 
i ncl u de d i n t he ori gi nal 
P R O MI S i nstr u me nt
Pr ot oc ol S y n o psis
2. 3 E x pl orat or y O bjecti ves
3. 1. 3. 3 E x pl orat or y E n d p oi nts
6. 1 1 Patie nt -Re p orte d O utc o mes
Re vise d st u d y sc he ma t o 
refere nce alter nati ve access
St u d y dr u g ma y be pr o vi de d 
t hr o u g h alter nati ve access 
pr o gra ms
Fi g ure 1 St u d y Sc he ma
A d de d la n g ua ge re gar di n g 
eli gi bilit y re vie w pr ocess
T o pr o vi de clarit y t o sites
re gar di n g pr ocess
6. 3 Eli gi bilit y Assess me nt, 
I ncl usi o n/ E xcl usi o n Re vie w
A d de d la n g ua ge re gar di n g
di gital p h ot o gra p h y re vie w 
pr ocess
T o pr o vi de clarit y re gar di n g 
efficac y a nal ysis of le g ulcers
8. 4 Efficac y A nal ysis
Mi n or a d mi nistrati ve 
c ha n ges were ma de t o 
c orrect t y p o gra p hical err ors
or t o e m p hasize s u btle p oi nts
Im pr o ve i nter nal c o nsiste nc y 
wit h t he pr ot oc ol.
T hr o u g h o ut t he pr ot oc ol
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 5
T A B L E O F C O N T E N T S
S U M M A R Y O F C H A N G E S ..................................................................................................... 2
T A B L E O F C O N T E N T S ........................................................................................................... 5
LI S T O F T A B L E S ..................................................................................................................... 9
LI S T O F FI G U R E S ................................................................................................................. 1 0
A P P E N DI C E S ......................................................................................................................... 1 0
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S ............................................ 1 1
P R O T O C O L  S Y N O P SI S ........................................................................................................ 1 4
1. I N T R O D U C TI O N ............................................................................................................... 2 3
1. 1. Disease Bac k gr o u n d ................................................................................................ 2 3
1. 1. 1. Sic kle Cell Disease ..................................................................................... 2 3
1. 2. V o xel ot or .................................................................................................................2 3
1. 3. S u m mar y  of Rele va nt N o ncli nical Data a n d Cli nical Data..................................... 2 4
1. 3. 1. L e g Ulcers i n Patie nts wit h S C D ................................................................ 2 4
1. 3. 2. N o ncli nical Data ......................................................................................... 2 5
1. 3. 3. Cli nical Data ...............................................................................................2 5
1. 4. S u m mar y  of t he K n o w n a n d P ote ntial Ris ks a n d Be nefits of V o xel ot or................ 2 6
1. 5. Descri pti o n of a n d J ustificati o n f or t he R o ute of A d mi nis trati o n, D osa ge, 
D osa ge Re gi me n, a n d Treat me nt Peri o d(s) ...............................................................2 6
1. 5. 1. D ose Rati o nale f or V o xel ot or ..................................................................... 2 6
1. 5. 2. Use of a Place b o C o ntr ol ............................................................................ 2 7
2. S T U D Y O BJ E C TI V E S ........................................................................................................ 2 7
2. 1. Pri mar y  O bjecti ve ................................................................................................... 2 7
2. 2. Sec o n dar y  O bjecti ves..............................................................................................2 7
2. 3. E x pl orat or y  O bjecti ves............................................................................................ 2 7
2. 4. Safet y O bjecti ve ...................................................................................................... 2 8
3. I N V E S TI G A T I O N A L PL A N ..............................................................................................2 8
3. 1. St u d y  Desi g n........................................................................................................... 2 8
3. 1. 1. St u d y  Treat me nt.......................................................................................... 3 1
3. 1. 2. St u d y  Assess me nts......................................................................................3 1
3. 1. 3. St u d y E n d p oi nts .......................................................................................... 3 1
3. 1. 3. 1. Pri mar y  E n d p oi nt ......................................................................3 1
3. 1. 3. 2. Sec o n dar y  E n d p oi nts................................................................. 3 1
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 6
3. 1. 3. 3. E x pl orat or y  E n d p oi nts...............................................................3 1
3. 1. 3. 4. Safet y E n d p oi nts ....................................................................... 3 2
3. 1. 4. Mi ni mizati o n of Bias .................................................................................. 3 2
3. 2. D urati o n of St u d y  Partici pati o n a n d of t he St u d y ................................................... 3 2
3. 3. St o p pi n g R ules ........................................................................................................ 3 2
3. 3. 1. Earl y Disc o nti n uati o n of t he St u d y ............................................................. 3 2
3. 3. 2. Disc o nti n uati o n of I n di vi d ual Partici pa nts ................................................. 3 3
3. 3. 2. 1. Wit h dra wal of C o nse nt ..............................................................3 3
3. 3. 2. 2. Earl y Disc o nti n uati o n of St u d y Treat me nt ................................ 3 3
3. 4. Ra n d o mizati o n a n d U n bli n di n g .............................................................................. 3 3
3. 4. 1. Ra n d o mizati o n ............................................................................................ 3 3
3. 4. 1. 1. Pre ve nti n g U n bli n di n g d ue t o La b orat or y  Assess me nts........... 3 3
3. 4. 1. 2. U n bli n di n g f or Me dical Nee d ................................................... 3 4
4. S E L E C TI O N O F S T U D Y P A R TI CI P A N T S ...................................................................... 3 4
4. 1. I ncl usi o n Criteria ..................................................................................................... 3 4
4. 2. E xcl usi o n Criteria .................................................................................................... 3 4
5. T R E A T M E N T S A D MI NI S T E R E D .................................................................................... 3 6
5. 1. Treat me nt Re gi me n ................................................................................................. 3 6
5. 1. 1. D ose Fre q ue nc y .......................................................................................... 3 6
5. 1. 2. D ose M o dificati o n ...................................................................................... 3 6
5. 2. P h y sical Descri pti o n of V o xel ot or .......................................................................... 3 7
5. 3. F or m ulati o n ............................................................................................................. 3 8
5. 3. 1. V o xel ot or .................................................................................................... 3 8
5. 3. 2. Place b o ........................................................................................................ 3 8
5. 4. Pac ka gi n g a n d La beli n g .......................................................................................... 3 8
5. 5. I n vesti gati o nal Pr o d uct S u p pl y ............................................................................... 3 8
5. 6. St ora ge a n d Ha n dli n g Pr oce d ure ............................................................................. 3 8
5. 7. C o nc o mita nt a n d Pr o hi bite d Me dicati o ns ...............................................................3 8
5. 7. 1. C o nc o mita nt Me dicati o ns ........................................................................... 3 8
5. 7. 2. Restricti o ns Re gar di n g Usa ge of C o nc o mita nt Me dicati o ns ...................... 3 9
5. 7. 3. Tra nsf usi o n ................................................................................................. 3 9
5. 7. 4. Ot her T hera pies .......................................................................................... 3 9
5. 7. 5. Pr o hi bite d C o nc o mita nt Me dicati o ns ......................................................... 3 9
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 7
5. 8. F ertilit y/ C o ntrace pti ve Re q uire me nts .....................................................................4 1
5. 8. 1. I nstr ucti o ns f or Fe male Partici pa nts of C hil d -Beari n g P ote ntial ................ 4 1
5. 8. 2. Fe male Partici pa nts of N o n -C hil d -Beari n g P ote ntial ................................. 4 1
5. 8. 3. I nstr ucti o ns f or Male Partici pa nts Ca pa ble of Fat heri n g a C hil d
............... 4 1
5. 9. Acce pta ble F or ms of C o ntrace pti o n f or Se x uall y  Acti ve Partici pa nts ................... 4 1
5. 1 0. Assess me nt of Treat me nt C o m plia nce .................................................................. 4 2
6. S T U D Y P R O C E D U R E S A N D A S S E S S M E N T S ...............................................................4 2
6. 1. I nf or me d C o nse nt/ Asse nt ........................................................................................ 4 2
6. 2. Partici pa nt I de ntificati o n N u m ber ........................................................................... 4 3
6. 3. Eli gi bilit y  Assess me nt, Incl usi o n/ E xcl usi o n Re vie w .............................................. 4 3
6. 4. Me dical Hist or y / De m o gra p hics .............................................................................. 4 3
6. 5. P h y sical E xa mi nati o n ..............................................................................................4 3
6. 6. Vital Si g ns ............................................................................................................... 4 4
6. 7. Ulcer Asses s me nts................................................................................................... 4 4
6. 8. A d verse E ve nts a n d C o nc o mita nt Me dicati o ns ...................................................... 4 4
6. 9. Hei g ht a n d Wei g ht .................................................................................................. 4 4
6. 1 0. L a b orat or y Assess me nts........................................................................................ 4 5
6. 1 0. 1. He mat ol o g y ...............................................................................................4 6
6. 1 0. 2. Ser u m C he mistr y ...................................................................................... 4 6
6. 1 0. 3. Pre g na nc y  Testi n g .................................................................................... 4 7
6. 1 1. Patie nt - Re p orte d O utc o mes................................................................................... 4 7
6. 1 2. Cli nical Gl o bal I m pressi o n of C ha n ge .................................................................. 4 7
6. 1 3. Misse d Assess me nts ..............................................................................................4 7
7. A D V E R S E A N D S E RI O U S A D V E R S E E V E N T S ............................................................ 4 7
7. 1. A d verse E ve nts ........................................................................................................ 4 8
7. 1. 1. Defi niti o n of A d verse E ve nts .....................................................................4 8
7. 1. 2. Se verit y  of A d verse E ve nts ........................................................................4 9
7. 1. 3. Relati o ns hi p t o I n vesti gati o nal Pr o d uct ...................................................... 5 0
7. 1. 4. U ne x pecte d A d verse Reacti o ns .................................................................. 5 0
7. 2. A d verse E ve nt Re p orti n g ........................................................................................ 5 0
7. 2. 1. Ge neral ........................................................................................................ 5 0
7. 2. 2. Dia g n os is Vers us Si g ns a n d S ym pt o ms .....................................................5 1
7. 2. 3. A b n or mal La b orat or y  Val ues.....................................................................5 1
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 8
7. 2. 4. Pre -e xisti n g Me dical C o n diti o ns ................................................................5 1
7. 2. 5. W orse ni n g of Sic kle Cell Disease .............................................................. 5 2
7. 3. Seri o us A d verse E ve nts, Seri o us A d verse Dr u g Reacti o ns, a n d Re q uire me nts 
f or I m me diate Re p orti n g ........................................................................................... 5 2
7. 3. 1. Re p or ti n g S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns a n d 
Ur ge nt Safet y Iss ues ........................................................................................ 5 2
7. 4. Re p orti n g O ver d ose ................................................................................................. 5 2
7. 5. E n vir o n me ntal E x p os ure, E x p os ure D uri n g Pre g na nc y  or Breastfee di n g, a n d 
Occ u pati o nal E x p os ure ..............................................................................................5 3
7. 5. 1. E x p os ure D uri n g Pre g na nc y ....................................................................... 5 3
7. 5. 2. E x p os ure D uri n g Breastfee di n g .................................................................. 5 5
7. 5. 3. Occ u pati o nal E x p os ure ............................................................................... 5 5
7. 6. L ac k Of Efficac y ..................................................................................................... 5 5
7. 7. Me dicati o n Err ors .................................................................................................... 5 5
8. 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............................................................ 5 6
8. 1. A nal y sis P o p ulati o ns ...............................................................................................5 6
8. 2. S u m mar y  of St u d y C o n d uct.................................................................................... 5 7
8. 3. S u m mar y  of De m o gra p hics, Baseli ne C haracteristics, a n d C o nc o mita nt 
Me dicati o ns
............................................................................................................... 5 7
8. 4. Efficac y  A nalys is .................................................................................................... 5 7
8. 4. 1. Pri mar y  E n d p oi nt........................................................................................ 5 7
8. 4. 2. Sec o n dar y  E n d p oi nts.................................................................................. 5 8
8. 4. 3. E x pl orat or y E n d p oi nts ................................................................................ 5 8
8. 5. Safet y A nal ys is........................................................................................................ 5 8
8. 6. Deter mi nati o n of Sa m ple Size ................................................................................. 5 8
8. 7. Missi n g Data Ha n dli n g ............................................................................................ 5 9
8. 8. A dj ust me nt f or M ulti ple C o m paris o ns .................................................................... 5 9
9. DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S.................................................. 5 9
9. 1. S o urce Data............................................................................................................. 5 9
9. 2. Data C ollecti o n ........................................................................................................ 5 9
9. 3. Ess e ntial D oc u me ntati o n Re q uire me nts.................................................................. 6 0
1 0. Q U A LI T Y C O N T R O L  A N D Q U A LI T Y A S S U R A N C E .................................................6 0
1 0. 1. M o nit ori n g ............................................................................................................. 6 0
1 0. 2. Q ualit y  C o ntr ol a n d Q ualit y Ass ura nce................................................................ 6 0
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 9
1 0. 3. L a b orat or y Accre ditati o n ......................................................................................6 0
1 0. 4. S p o ns or’s Me dicall y  Q ualifie d I n di vi d ual............................................................ 6 1
1 1. R E G U L A T O R Y, E T HI C A L , L E G A L, A N D O V E RSI G H T O B LI G A TI O N S ................ 6 1
1 1. 1. Re g ulat or y  a n d Et hical C o nsi derati o ns................................................................. 6 1
1 1. 1. 1. Re p orti n g of Safet y  Iss ues a n d Seri o us Breac hes of t he Pr ot oc ol or 
I C H G C P.......................................................................................................... 6 2
1 1. 2. I nf or me d C o nse nt a n d A sse nt ............................................................................... 6 2
1 1. 3. Data Pr otecti o n ...................................................................................................... 6 3
1 1. 4. I n de pe n de nt Et hics C o m mittee a n d Re g ulat or y  A p pr o val.................................... 6 3
1 1. 5. Esse ntial D oc u me ntati o n Re q uire me nts ................................................................ 6 4
1 1. 6. Disse mi nati o n of Cli nical St u d y  Data................................................................... 6 4
1 1. 7. Data Q ualit y Ass ura nce ......................................................................................... 6 5
1 1. 8. St u d y  a n d Site Start a n d Cl os ure........................................................................... 6 6
1 1. 9. C o nfi de ntialit y ....................................................................................................... 6 7
1 1. 1 0. St u d y  D oc u me ntati o n a n d Data St ora ge ............................................................. 6 7
1 2. D A T A H A N D LI N G A N D R E C O R D K E E PI N G ..............................................................6 7
1 2. 1. I ns pecti o n of Rec or ds ............................................................................................ 6 7
1 2. 2. Rete nti o n of Rec or ds ............................................................................................. 6 7
1 3 . I N S U R A N C E A N D FI N AN CI A L DI S C L O S U R E ...........................................................6 9
1 4. P U B LI C A TI O N P O LI C Y ................................................................................................. 6 9
1 5. R E F E R E N C E S .................................................................................................................. 7 0
A P P E N DI X 1. S C H E D U L E O F A S S E S S M E N T S ................................................................. 7 2
A P P E N DI X 2. LI V E R S A F E T Y: S U G G E S T E D A C TI O N S A N D F O L L O W -U P 
A S S E S S M E N T S A N D S T U D Y D R U G R E C H A L L E N G E G UI D E LI N E S...................... 7 6
LI S T O F T A B L E S
Ta ble 1:
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 ....................................................................................................... 3 7
Ta ble 2:
Se nsiti ve C Y P 3 A 4 S u bstrates wit h Narr o w T hera pe utic Ra n ge.............. 4 0
Ta ble 3:
E xa m ples of M o derate a n d Str o n g C Y P I n d ucers .................................... 4 0
Ta ble 4:
A d diti o nal Pr o hi bite d Me dicati o ns ........................................................... 4 0
Ta ble 5:
Bl o o d S peci me n Assess me nt Pri orit y  List ............................................... 4 6
Ta ble 6:
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................4 9
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0
Ta ble 7:
Re p orti n g of Me dicati o n Err ors ................................................................5 5
LI S T O F FI G U R E S
Fi g ure 1:
St u d y  Sc he ma ........................................................................................... 3 0
A P P E N DI C E S
A p pe n di x 1. Sc he d ule of Assess me nts .................................................................................... 7 2
A p pe n di x 2. L i ver Safet y: S u g geste d acti o ns a n d f oll o w-u p assess me nts a n d st u d y  dr u g 
rec halle n ge g ui deli nes .............................................................................. 7 6
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S
A b bre vi ati o n
Descri pti o n
A E
a d verse e ve nt
A F
asse nt f or m
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase
A S T
as partate a mi n otra nsferase
C F R
C o de of Fe deral Re g ulati o ns
C GI - C
Cli nicia n Gl o bal I m pressi o n of C ha n ge
CI O M S
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces
C M H
C oc hra n - Ma ntel-Hae nszel
C R F
case re p ort f or m
C R O
c o ntract researc h or ga nizati o n
C S R
Cli nical St u d y Re p ort
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
DI LI
dr u g -i n d uce d li ver i nj ur y
E C C
e mer ge nc y c o ntact car d
e C R F
electr o nic case re p ort f or m
E D B
e x p os ure d uri n g breastfee di n g
E D C
electr o nic data ca pt ure
E D P
e x p os ure d uri n g pre g na nc y
e G F R
esti mate d gl o mer ular filtrati o n rate
E O S
e n d of st u d y
E U
E ur o pea n U ni o n
E u dra C T/ C TI S
E ur o pea n U ni o n Dr u g Re g ulati n g A ut h orities Cli nical Trials ( E ur o pea n 
Cli nical Trials Data base) / Cli nical Trials I nf or mati o n S yste m
F D A
( U S) F o o d a n d Dr 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
H b
he m o gl o bi n
H b F
fetal he m o gl o bi n
H b S
sic kle he m o gl o bi n
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2
A b bre vi ati o n
Descri pti o n
H b S / β0
sic kle he m o gl o bi n a n d o ne beta t halasse mia ge ne
H b S S
sic kle he m o gl o bi n wit h 2 sic kle cell ge nes
H C
h y dr o x ycar ba mi de
HI V
h u ma n i m m u n o deficie nc y vir us
H R Q O L
healt h -relate d q ualit y of life
H U
h y dr o x y urea
I B
I nvesti gat or's Br oc h ure
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u ma n Use
I D
i de ntificati o n
I E C
I n de pe n de nt Et hics C o m mittee
II D
I nacti ve I n gre die nt Data base
I RB
I nstit uti o nal Re vie w B oar d
I TT
I nte nt t o Treat
I XR S
I nteracti ve Res p o nse S yste m
L D H
lactate de h y dr o ge nase
L F T
li ver f u ncti o n test
M QI
Me dicall y Q ualifie d I n di vi d ual
N CI
Nati o nal Ca ncer I nstit ute 
O 2
o x y ge n
O L E
O pe n -la bel E xte nsi o n
o x y H b
o x y he m o gl o bi n
P D
p har mac o d y na mics
P E
p h ysical e xa mi nati o n
P GI - C
Patie nt Gl o bal I m pressi o n of C ha n ge
P h. E ur.
E ur o pea n P har mac o p oeia
P R O
Patie nt- re p orte d o utc o me
P R O MI S 
Patie nt- Re p orte d O utc o me Meas ure me nts I nf or mati o n S yste m 
P S S A
Pfizer’s Seri o us A d verse E ve nt S u b m issi o n Assista nt
Q O L
q ualit y of life
R B C
re d bl o o d cell
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3
A b bre vi ati o n
Descri pti o n
R SI
Refere nce Safet y I nf or mati o n
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S C A
sic kle cell a ne mia
S C D
sic kle cell disease
S O A
Sc he d ule of Assess me nts
S O C
sta n dar d of care ( w o u n d care per pr ot oc ol f or S C D le g ulcers)
S R S D
Si n gle Refere nce Safet y D oc u me nt
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
T E A E
treat me nt-e mer ge nt a d verse e ve nt
U L N
u p per li mit of n or mal 
U S
U nite d States
V A S
vis ual a nal o g scale
W H O
W orl d Healt h Or ga nizati o n
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4
P R O T O C O L S Y N O P SI S
St u d y N u m ber
G B T 4 4 0- 0 4 2 ( C 5 3 4 1 0 2 6)
St u d y Title
A P hase 3, M ultice nter, Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d Trial t o 
E val uate t he Efficac y of V o xel ot or f or t he Treat me nt of Le g Ulcers i n Patie nts 
wit h Sic kle Cell Disease
S h ort Title
Res ol uti o n o f Sic kle Cell L e g Ulcers wit h V o x el ot or ( R E S O L V E)
S p o ns or
Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer 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 
Descri pti o n
T his st u d y is a P hase 3, m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -
c o ntr olle d trial t o e val uate t he efficac y of v o xel ot or f or t he treat me nt of le g 
ulcers i n partici pa nts wit h sic kle cell disease ( S C D). 
N u m ber of 
Cli nic al Sites
T he st u d y will be c o n d ucte d at a p pr o xi matel y 2 0 gl o bal sites.
N u m ber of 
St u d y 
P artici p a nts
A p pr o xi matel y 8 0 eli gi ble partici pa nts will i nitiate treat me nt i n t his st u d y.
I n vesti g ati o n al 
Pr o d uct
V o xel ot or, 5 0 0 m g ta blets, a d mi nistere d orall y
Matc hi n g
place b o, a d mi nistere d orall y
Tre at me nt
D uri n g t he Ra n d o mize d Treat me nt Peri o d, partici pa nts will be ra n d o mize d i n a 
1: 1 rati o t o recei ve 1 5 0 0 m g of v o xel ot or o nce dail y (a d mi nistere d as t hree 5 0 0 
m g ta blets) or matc hi n g place b o f or 1 2 wee ks. I n t his st u d y, all partici pa nts will 
recei ve t he sta n dar d of care ( S O C) per pr ot oc ol f or S C D le g ulcers d uri n g t he 
R u n -i n, Ra n d o mize d Treat me nt, a n d O pe n-la bel Treat me nt peri o ds. D uri n g t he 
O pe n -la bel Treat me nt Peri o d, all partici pa nts will recei ve 1 5 0 0 m g of v o xel ot or 
o nce dail y (a d mi nistere d as t hree 5 0 0 m g ta blets) f or a mi ni m u m of 1 2 wee ks.
Partici pa nts w h o ha ve c o m plete d 1 2 wee ks i n t he O pe n -la bel Treat me nt Peri o d 
ma y c o nti n ue t o recei ve v o xel ot or as l o n g as t he y c o nti n ue t o recei ve cli nical 
be nefit t hat o ut wei g hs ris k as deter mi ne d b y t he I n vesti gat or or u ntil t he 
partici pa nt has access t o v o xel ot or fr o m a n alter nati ve s o urce n ot ass ociate d wit h 
t his pr ot oc ol (e g, t hro u g h a cli nical O pe n -la bel E xte nsi o n [ O L E] st u d y 
s p o ns ore d b y Pfizer, c o m mercializati o n of t he pr o d uct, or a ma na ge d access 
pr o gra m) . 
O bjecti ves
Pri m ar y
T he pri mar y o bjecti ve of t his st u d y is t o assess t he effect of v o xel ot or a n d S O C 
c o m pare d t o place b o a n d S O C o n le g ulcer heali n g i n partici pa nts ≥1 2 years of 
a ge wit h S C D, as meas ure d b y t he pr o p orti o n of partici pa nts ac hie vi n g 
res ol uti o n of tar get ulcer(s) i n eac h treat me nt gr o u p b y Wee k 1 2. 
Sec o n d ar y
T he sec o n dar y o bjecti ves of t his st u d y are t o e val uate t he effect of v o xel ot or a n d 
S O C c o m pare d t o place b o a n d S O C o n: 

Ti me t o res ol uti o n of tar get ulcer(s)
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5

C ha n ge i n t otal s urface area of tar get ulcer(s)

I nci de nce of ne w ulcers 
E x pl or at or y
T he e x pl orat or y o bjecti ves will assess t he effect of v o xel ot or a n d S O C 
c o m pare d t o place b o i n a d diti o n t o S O C ( or o pe n -la bel v o xel ot or a n d S O C, 
w here a p plica ble) o n:

C orrelati o n bet wee n c ha n ge i n he m o gl o bi n ( H b) a n d tar get ulcer(s) 
heali n g 

C orrelati o n bet wee n c ha n ge i n he m ol ytic para meters ( % retic ul oc ytes, 
i n direct bilir u bi n, lactate de h y dr o ge nase [ L D H]) a n d tar get ulcer(s) 
heali n g

Healt h -relate d q ualit y of life ( H R Q O L) usi n g patie nt-re p orte d o utc o me 
( P R O) meas ures, w he n a vaila ble ( pe n di n g tra nslati o n a n d c ult ural 
vali dati o n re q uire me nts)
o
Patie nt- Re p orte d O utc o me Me as ure me nts I nf or mati o n S yste m 
( P R O MI S) Pe diatric Pr ofile-3 7 v 2. 0/ P R O MI S - 4 3 v 2. 1
o
Vis ual a nal o g scale ( V A S) assess me nt of pai n le vel li n ke d t o tar get 
ulcer(s)
o
Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI -C)

Cli nicia n Gl o bal I m pressi o n of C ha n ge ( C GI -C)
S afet y
T h e safet y o bjecti ve is t o assess t he safet y a n d t olera bilit y of v o xel ot or 
c o m pare d t o place b o base d o n a d verse e ve nts ( A Es), cli nical la b orat or y tests, 
p h ysical e xa mi nati o ns, vital si g ns, a n d ot her cli nical meas ures (e g, 
disc o nti n uati o ns d ue t o A Es, d ose re d ucti o ns).
St u d y Desi g n
T he st u d y is di vi de d i nt o a Scree ni n g Peri o d, a R u n -i n Peri o d, a Ra n d o mize d 
Treat me nt Peri o d, a n O pe n -la bel Treat me nt Peri o d, a n d a F oll o w- u p Peri o d/ E n d 
of St u d y ( E O S) Visit.
Scree ni n g Peri o d ( wit hi n 2 8 d a ys pri or t o R u n -i n Peri o d): 
D uri n g t his peri o d, partici pa nts will si g n t he i nf or me d c o nse nt f or m/asse nt f or m 
(I C F/ A F), after w hic h t he y will c o m plete t he scree ni n g assess me nts, i ncl u di n g 
tar get le g ulcer(s) s urface area meas ure me nt(s) b y di gital p h ot o gra p h y, as 
detaile d i n t he Sc he d ule of Assess me nts ( S O A) i n A p pe n di x 1 a n d i n t he Le g 
Ulcer Assess me nt a n d Meas ure me nt Ma n ual. All Scree ni n g assess me nts m ust be 
c o m plete d wit hi n 2 8 da ys bef ore t he R u n -i n Peri o d.
R u n -i n Peri o d ( 2 wee ks pri or t o R a n d o miz ati o n [ ± 3- d a y wi n d o w]):
Partici pa nts will e nter a 2 -wee k R u n -i n Peri o d ( Da y -1 4 t o Da y -1 [ + 3 da ys]), 
d uri n g w hic h assess me nts, i ncl u di n g tar get le g ulcer(s) s urface area 
meas ure me nt(s) b y di gital p h ot o gra p h y will be c o n d ucte d a n d S O C i nitiate d per 
pr ot oc ol, f oll o wi n g best practice g ui deli nes (see Mi n niti, 2 0 1 4
f or g ui da nce a n d 
t he Le g Ulcer Ma na ge me nt Ma n ual f or a d diti o nal details). T hese assess me nts 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6
m ust be c o m plete d pri or t o ra n d o mizati o n t o e ns ure t hat t he partici pa nt 
c o nti n ues t o q ualif y f or t he st u d y.
R a n d o mize d Tre at me nt Peri o d ( 1 2 wee ks [ ± 3- d a y wi n d o w f or e ac h visit 
af ter D a y 1 Visit]):
After c o m pleti o n of t he 2 -wee k R u n -i n Peri o d, tar get le g ulcer(s) s urface area 
meas ure me nt(s) will be reassesse d t o e ns ure t hat t he partici pa nt c o nti n ues t o 
q ualif y f or t he st u d y b ef ore ra n d o mizati o n. Eli gi ble partici pa nts (tar get  
 
) will be 
ra n d o mize d 1: 1 t o recei ve v o xel ot or 1 5 0 0 m g o nce dail y a n d S O C or place b o 
o nce dail y a n d S O C f or 1 2 wee ks. At t he ti me of ra n d o mizati o n, partici pa nts 
will be stratifie d 
 
 
 
 
 
T he treat me nt peri o d is c o nsi dere d t he c o nti n u o us 1 2 wee ks of v o xel ot or a n d 
S O C or place b o a n d S O C treat me nt fr o m date of ra n d o mizati o n (first d ose, Da y 
1). T he tar get le g ulcer(s) will be assesse d b y vis ual i ns pecti o n a n d s urface area 
meas ure me nt(s) 
 sc he d ule d visits e ver y 2 wee ks 
d uri n g t he 1 2-wee k Ra n d o mize d Treat me nt Peri o d. 
 
 
 
 
 
St u d y Desi g n
(c o nti n ue d)
O pe n -l a bel Tre at me nt Peri o d ( mi ni m u m 1 2 wee ks [ ± 3- d a y wi n d o w 
f or e ac h visit]): 
At t he e n d of t he 1 2 -wee k Ra n d o mize d Treat me nt Peri o d, all partici pa nts ( wit h 
t he e xce pti o n of t h ose de m o nstrati n g i nitial ulcer re-e pit helializati o n at Wee k 
1 2) will recei ve o pe n -la bel v o xel ot or 1 5 0 0 m g per da y a n d S O C f or a n 
a d diti o nal 1 2 wee ks a n d tar get ulcer(s) t hat faile d t o heal d uri n g t he i nitial 
1 2 wee ks will be f oll o we d f or dela ye d heali n g. Assess me nts will c o nti n ue t o be 
perf or me d per t he S O A ( A p pe n di x 1 ).
N ote: P artici p a nts w h o h ave c o m plete d 1 2 weeks i n t he O pe n -l a bel 
Tre at me nt Peri o d m ay c o nti n ue t o receive v oxel ot or as l o n g as t hey 
c o nti n ue t o receive cli nic al be nefit t h at o ut wei g hs risk as deter mi ne d by t he 
I nvesti g at or or u ntil t he p artici p a nt h as access t o v oxel ot or fr o m a n 
alter n ative s o urce (e g, t hr o u g h a cli nic al O L E st u dy s p o ns ore d by P fiz er, 
c o m merci aliz ati o n of t he pr o d uct, or a m a n a ge d access pr o gr a m) . 
P artici p a nts w h o d o n ot pl a n t o c o nti n ue t o receive v oxel ot or fr o m a n 
alter n ative s o urce s h o ul d c o nti n ue t o t he f oll o w -u p peri o d after c o m pleti n g 
1 2 weeks i n t he O pe n -l a bel Tre at me nt Peri o d.
F oll o w -u p Peri o d ( 4 wee ks after l ast d ose [ ± 7- d a y wi n d o w f or E O S visit]):
F oll o wi n g c o m pleti o n of t he O pe n -la bel Treat me nt Peri o d i n t his st u d y, eli gi ble 
partici pa nts will be gi ve n t he o pti o n t o c o nti n ue t o recei ve v o xel ot or ( u n der t his 
pr ot oc ol, u ntil access is pr o vi de d t hr o u g h a n alter nati ve s o urce). Partici pa nts 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)
C CI
C CI
C CI
C CI


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7
w h o d o n ot c o nti n ue v o xel ot or will be f oll o we d f or 4 wee ks after t he last d ose of 
treat me nt a n d i nstr ucte d t o ret ur n t o t he site t o c o m plete t he E O S visit. 
E arl y Ter mi n ati o n Visit: 
If a partici pa nt ter mi nates t he st u d y f or a n y reas o n, t his s h o ul d be d oc u me nte d 
o n t he electr o nic case re p ort f or m (e C R F) a n d t he assess me nts f or t he Earl y 
Ter mi nati o n visit s h o ul d be perf or me d per t he S O A ( A p pe n di x 1 ).
Safet y  a n d t olera bilit y will be m o nit ore d d uri n g t he e ntire st u d y  usi n g 
sta n dar d meas ures, i ncl u di n g t he assess me nt of A Es, cli nical la b orat or y 
tests, p h ysical e xa mi nati o ns, a n d vital si g ns.
D ur ati o n of 
St u d y 
P artici p ati o n
T he a p pr o xi mate st u d y d urati o n f or a n i n di vi d ual partici pa nt i ncl u des t he 
Scree ni n g Peri o d ( wit hi n 2 8 da ys), a R u n -i n Peri o d of 2 wee ks, a Ra n d o mize d 
Treat me nt Peri o d of 1 2 wee ks, a n O pe n -la bel Treat me nt Peri o d of a mi ni m u m of 
1 2 wee ks, a n d a F oll o w -u p Peri o d/ E O S visit ( 4 wee ks [ ± 7 da ys] after t he last 
d ose of st u d y dr u g). 
Partici pa nts w h o ha ve c o m plete d 1 2 wee ks i n t he O pe n -la bel Treat me nt Peri o d 
ma y c o nti n ue t o recei ve v o xel ot or as l o n g as t he y c o nti n ue t o recei ve cli nical 
be nefit t hat o ut wei g hs ris k as deter mi ne d b y t he I n vesti gat or or u ntil t he 
part ici pa nt has access t o v o xel ot or fr o m a n alter nati ve s o urce (e g, t hr o u g h a 
cli nical O L E st u d y s p o ns ore d b y Pfizer c o m mercializati o n of t he pr o d uct, or a 
ma na ge d access pr o gra m) . 
Fr o m Scree ni n g t hr o u g h F oll o w -u p, t otal partici pati o n i n t his st u d y f or a n 
i n di vi d ual partici pa nt ma y last fr o m a p pr o xi matel y 3 1 wee ks t o u p t o 3 4 wee ks 
(if t he partici pa nt d oes n ot c o nti n ue t o recei ve v o xel ot or be y o n d 1 2 wee ks i n t he 
O pe n -la bel Treat me nt Peri o d as state d a b o ve). Partici pa nts will c o nti n ue t o be 
f oll o we d f or efficacy a n d safet y t hr o u g h at least t he pri mar y e n d p oi nt visit 
( Wee k 1 2) re gar dless of treat me nt disc o nti n uati o n. T he st u d y will e n d w he n t he 
last partici pa nt’s last visit occ urs.
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 t he f oll o wi n g criteria will be 
eli gi ble f or e nr oll me nt i n t his st u d y:
1.
Male or fe male partici pa nts wit h d oc u me nte d dia g n osis of S C D (sic kle 
he m o gl o bi n wit h 2 sic kle cell ge nes [ H b S S], sic kle he m o gl o bi n a n d o ne 
beta t halasse mia ge ne [ H b S/ β 0] t halasse mia) 
2.
A ge 1 2 years a n d ol d er 
3.
At least o ne c uta ne o us ulcer o n t he l o wer e xtre mit y (le g, a n kle, or d ors u m 
of f o ot) t hat meets t he f oll o wi n g criteria:

D urati o n: ≥2 wee ks a n d < 6 m o nt hs at Scree ni n g, a n d

Size: > 2 s q uare ce nti meters (c m 2) pri or t o ra n d o mizati o n

N ote: Partici pa nts wit h m ulti ple ulcers are eli gi ble f or t he st u d y. F or 
eac h partici pa nt, tar get ulcer(s) f or e val uati o n i n t his st u d y will be 
i de ntifie d a n d trac ke d. T o q ualif y as a tar get ulcer, t he ulcer m ust meet 
t he criteria a b o ve.
4.
Partici pa nts, w h o if fe male a n d of c hi l d-beari n g p ote ntial, a gree t o use 
hi g hl y effecti ve met h o ds of c o ntrace pti o n fr o m st u d y start t o 3 0 da ys after 
t he last d ose of st u d y dr u g a n d w h o if male, a gree t o use barrier met h o ds of 
c o ntrace pti o n fr o m st u d y start t o 3 0 da ys after t he last d ose of st u d y dr u g.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8
5.
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.
6.
Writte n i nf or me d c o nse nt ( ≥1 8 years) or pare ntal/ g uar dia n c o nse nt a n d 
partici pa nt asse nt ( ≥1 2 – 1 7 years) per I nter nati o nal Et hics C o m mittee (I E C) 
p olic y a n d re q uire me nts, c o nsiste nt wit h I nter nati o nal C o u ncil f or 
Har m o nisati o n (I C H) g ui deli nes.
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.
Tar get ulc er(s) heale d b y ≥2 5 % d uri n g t he S O C R u n -i n pri or t o 
ra n d o mizati o n
N ote: F or p artici p a nts wit h m ulti ple ulcers, t he p artici p a nt is n ot eli gi ble 
f or t he st u dy if all t ar get ulcers h ave he ale d by ≥ 2 5 %  d uri n g t he S O C R u n-
i n.
2.
Acti ve i nfecti o n/ p ur ule nce at ulc er site, or e x p ose d te n d o n or b o ne at t he 
ulcer site, base d o n I n vesti gat or’s cli nical j u d g me nt. 
3.
C urre nt oste o m yelitis at or near t he ulcer site
4.
K n o w n vasc ular a b n or malities t hat w o ul d precl u de heali n g i n t he o pi ni o n 
of t he I n vesti gat or (e g, pre -e xisti n g se vere arterial i ns ufficie nc y i n t he 
affecte d li m b)
5.
Ser u m al b u mi n < 2. 0 g/ d L 
6.
Re d bl o o d cell ( R B C) tra nsf usi o n wit hi n 6 0 da ys of i nitiati o n of st u d y dr u g 
7.
Recei vi n g re g ularl y sc he d ule d R B C tra nsf usi o n t hera p y (als o ter me d 
c hr o nic, pr o p h ylactic, or pre ve nti ve tra nsf usi o n) d uri n g t he st u d y.
8.
Pla n ne d electi ve s ur ger y wit hi n t he ne xt 6 m o nt hs.
9.
A ne mia d ue t o b o ne marr o w fail ure (e g, m yel o d ys plasia)
1 0. A bs ol ute retic ul oc yte c o u nt < 1 0 0 × 1 0 9/ L
1 1. Scree ni n g ala ni ne a mi n otra nsferase ( A L T) > 4 × u p per li mit of n or mal 
( U L N)
1 2. Se vere re nal d ysf u ncti o n (esti mate d gl o mer ular filtrati o n rate [e G F R] 
< 3 0 m L/ mi n/ 1. 7 3 m 2 b y Sc h wartz f or m ula) or is o n c hr o nic dial ysis.
St u d y 
P o p ul ati o n
(c o nti n ue d)
1 3. Cli nicall y si g nifica nt bacterial, f u n gal, parasitic, or viral i nfecti o n t hat 
re q uires t hera p y:

Partici pa nts wit h ac ute bacterial i nfecti o n re q uiri n g s yste mic a nti bi otic 
use s h o ul d dela y Scree ni n g/e nr oll me nt u ntil t he c o urse of a nti bi otic 
t hera p y has bee n c o m plete d.

Partici pa nts wit h k n o w n acti ve he patitis A, B, or C or w h o are k n o w n t o 
be h u ma n i m m u n o deficie nc y vir us ( HI V) p ositi ve.

Partici pa nts wit h acti ve S A R S -C o V -2 i nfecti o n ( C O VI D -1 9) 
1 4. Fe males w h o are breast -fee di n g or pre g na nt
1 5. Hist or y of he mat o p oietic ste m cell tra ns pla nt or ge ne t hera p y
1 6. Partici pate d i n a n ot her cli nical trial of a n i n vesti gati o nal pr o d uct ( or 
me dical de vice) wit hi n 3 0 da ys or 5 half -li ves of date of i nf or me d c o nse nt, 
w hic he ver is l o n ger, or is c urre ntl y partici pati n g i n a n ot her trial of a n 
i n vesti gati o nal pr o d uct ( or me dical de vice)
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9
1 7. Me dical, ps yc h ol o gical, or be ha vi oral
c o n diti o n t hat, i n t he o pi ni o n of t he 
I nvesti 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 
efficac y of t he st u d y dr u g, pre ve nt c o m plia nce wit h t he st u d y pr ot oc ol; 
precl u de i nf or me d c o nse nt; or re n der t he partici pa nt u na ble/ u nli kel y t o 
c o m pl y wit h t he st u d y pr oce d ures.
1 8. T his e xcl usi o n criteri o n ( E C) was re vise d t o E C # 1 8 A i n t he Gl o bal 
Pr ot oc ol A me n d me nt 2. 0.
1 8 A. Use of dr u gs wit h dr u g -dr u g i nteracti o n p ote ntial wit h v o xel ot or, 
i ncl u di n g t he f oll o wi n g cate g ories of dr u gs, wit hi n 3 0 da ys of Da y 1: 

her bal me dicati o ns (e g, St. J o h n’s w ort), or m o derate or str o n g C Y P 3 A 4 
i n d ucers

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 mit a nt 
Me dic ati o ns 
a n d 
Restricti o ns
T he f oll o wi n g c o nc o mita nt me dicati o ns are all o we d : 

H y dr o x y urea ( H U)/ h y dr o x ycar ba mi de ( H C) (sta ble d ose f or at least 
9 0 da ys pri or t o si g ni n g t he I C F a n d wit h n o d ose m o dificati o ns pla n ne d 
or a ntici pate d b y t he I n vesti gat or a n d n o si g n of he mat ol o gical t o xicit y)

L- gl uta mi ne, o ver -t he-c o u nter a nal gesics, a n d o pi oi ds

Er yt hr o p oieti n -sti m ulati n g a ge nts (sta ble d ose f or at least 4 wee ks wit h 
n o d ose m o dificati o ns pla n ne d or a ntici pate d b y t he I n vesti gat or) 
T he f oll o wi n g c o nc o mita nt me dicati o ns are pr o hi bite d : 

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

M o derate a n d str o n g C Y P 3 A 4 i n d ucers

Criza nliz u ma b ( A da k ve o ® )

Ot her e x peri me ntal S C D t hera p y
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0
St u d y 
E n d p oi nts
T he pri mar y efficac y e n d p oi nt will be meas ure d b y t he pr o p orti o n of 
partici pa nts ac hie vi n g res ol uti o n of t he tar get ulcer(s),
 d uri n g t he 
1 2- wee k Ra n d o mize d Treat me nt Peri o d.
 
 
F o r partici pa nts wit h m ore t ha n o ne tar get ulcer, all tar get ulcers m ust be 
c o nfir me d res ol ve d i n or der f or t he partici pa nt t o be c o nsi dere d a res p o n der.
Sec o n dar y e n d p oi nts i n t his st u d y i ncl u de a c o m paris o n of v o xel ot or a n d S O C 
vers us place b o a n d S O C i n: 

Ti me (i n da ys) t o res ol uti o n of tar get ulcer(s) u p t o Wee k 1 2 

C ha n ge fr o m baseli ne i n t otal s urface area of tar get ulcer(s) at Wee k 1 2

I nci de nce of ne w ulcers b y Wee k 1 2
E x pl orat or y e n d p oi nts i ncl u de: 

Pr o p orti o n of pa rtici pa nts ac hie vi n g res ol uti o n of tar get ulcer(s) b y 
Wee k
2 4

Ti me (i n da ys) t o res ol uti o n of tar get ulcer(s) u p t o Wee k 2 4

C ha n ge fr o m baseli ne i n t otal s urface area of tar get ulcer(s) o ver ti me u p 
t o Wee k 2 4

C orrelati o n bet wee n c ha n ge i n H b a n d tar get ul cer(s) heali n g at Wee k 
1 2 a n d Wee k 2 4

C orrelati o n bet wee n c ha n ge i n mar kers of he m ol ysis ( % retic ul oc ytes, 
i n direct bilir u bi n, L D H) a n d tar get ulcer(s) heali n g at Wee k 1 2 a n d 
Wee k
2 4

C ha n ge fr o m baseli ne i n H R Q O L P R O meas ures: P R O MI S -3 7 v 2. 0 
Pe diatric Pr of ile/P R O MI S -4 3 v 2. 1 at Wee k 1 2 a n d Wee k 2 4

C ha n ge fr o m baseli ne i n pai n le vel li n ke d t o tar get ulcer(s) assesse d b y 
V A S at Wee k 1 2 a n d Wee k 2 4

P GI -C sc ore at Wee k 1 2 a n d Wee k 2 4

C GI -C sc ore at Wee k 1 2 a n d Wee k 2 4
Safet y e n d p oi nts: 
Assess me nts of A Es, cli ni cal la b orat or y para meters, p h ysical e xa mi nati o ns, a n d 
vital si g ns.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)
C CI
C CI


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1
St atistic al 
Met h o ds
T he pri mar y st u d y a nal ysis will be base d o n c o m plete data fr o m t he 1 2 -wee k 
treat me nt peri o d of t he st u d y, a n d will be perf or me d at t he earliest after all 
partici pa nts ha ve c o m plete d t he 1 2 -wee k treat me nt peri o d or disc o nti n ue d earl y 
a n d all c orres p o n di n g data ha ve bee n e ntere d i nt o t he data base, re vie we d, a n d 
verifie d. 
T he fi nal st u d y a nal ysis will be base d o n d ata fr o m t he c o m plete st u d y 
(i ncl u di n g t he O pe n-la bel Treat me nt Peri o d a n d 4-wee k F oll o w -u p Peri o d), a n d 
will be perf or me d after all partici pa nts ha ve c o m plete d t he st u d y or disc o nti n ue d 
earl y a n d all data fr o m t he st u d y are i n t he data base a n d t he data bas e is l oc ke d.
A n al ysis P o p ul ati o n
T w o mai n a nal ysis p o p ulati o ns are defi ne d f or t his st u d y: t he i nte nt -t o-treat 
(I T T) p o p ulati o n a n d t he safet y-e val ua ble p o p ulati o n. 
Efficac y a nal yses will be c o n d ucte d o n t he I T T p o p ulati o n, defi ne d as all 
ra n d o mize d partici pa nts. Safet y a nal ysis will be base d o n safet y -e val ua ble 
p o p ulati o n, defi ne d as ra n d o mize d partici pa nts w h o recei ve d at least o ne d ose of 
st u d y treat me nt. 
S a m ple Size
T he sa m ple size of 8 0 partici pa nts ( 4 0 partici pa nts per treat me nt gr o u p) pr o vi des 
a p pr o xi matel y 9 0 % p o wer t o detect a 3 5 % a bs ol ute differe nce bet wee n 
treat me nt gr o u ps ( v o xel ot or 1 5 0 0 m g + S O C vers us place b o + S O C) i n 
pr o p orti o n of partici pa nts e x perie nci n g res ol uti o n of t he tar get ulcer(s) b y 1 2 
wee ks. Calc ulati o ns were base d o n a t w o -si de d al p ha = 5 % test of t he differe nce 
i n t w o bi n o mial pr o p orti o ns ( N or mal a p pr o xi mati o n) a n d ass u me d 5 % dr o p o ut 
b y Wee k 1 2.
Pri m ar y A n al ysis
T he pr o p orti o n of partici pa nts wit h res ol uti o n of tar get le g ulcer(s) b y Wee k 1 2 
will be a nal yze d usi n g a C oc hra n - Ma ntel-Hae nszel ( C M H) test t o c o m pare 
v o xel ot or + S O C wit h place b o + S O C gr o u ps, stratifie d b y tar get ulcer size a n d 
tar get ulcer d urati o n. Ulcer res ol uti o n is 
 
 
 
F or partici pa nts wit h m ore 
t ha n o ne tar get le g ulcer, all ulcers m ust be c o nfir me d res ol ve d i n or der f or t he 
partici pa nt t o be c o nsi dere d a res p o n der.
Partici pa nts w h o are l ost t o f oll o w -u p or ot her wise dr o p o ut of t he st u d y wit h o ut 
c o nfir mati o n of res ol uti o n of all tar get st u d y ulcer(s) pri or t o st u d y dr o p o ut will 
be classifie d as n o n -res p o n ders f or p ur p oses of t he pri mar y a nal ysis.
Sec o n d ar y A n al ysis
Ti me t o res ol uti o n of tar get ulcer(s) u p t o Wee k 1 2: a stratifie d l o g -ra n k test will 
be use d t o c o m pare t he treat me nt gr o u ps. A C o x re gressi o n m o del will be use d 
t o esti mate t he hazar d rati o bet ween v o xel ot or + S O C a n d place b o + S O C 
gr o u ps, as a p pr o priate. 
C ha n ge fr o m baseli ne i n t otal s urface area of tar get ulcer(s) at Wee k 1 2: a 
mi xe d -effect m o del f or re peate d meas ures will be use d t o esti mate a n d c o m pare 
c ha n ge fr o m baseli ne i n s u m of tar get ulcer(s) s urface area bet wee n v o xel ot or + 
S O C a n d place b o + S O C gr o u ps. 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)
C CI


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2
St atistic al 
Met h o ds 
(c o nti n ue d)
I nci de nce of ne w ulcers b y Wee k 1 2: t he pr o p orti o n of partici pa nts wit h ne w 
ulcer occ urre nce wit hi n 1 2 wee ks of treat me nt will be c o m pare d bet wee n 
treat me nt gr o u ps usi n g a C M H test, stratifie d b y tar get ulcer size a n d tar get ulcer 
d urati o n, as a p pr o priate.
S afet y A n al ysis
A d verse e ve nts will be classifie d acc or di n g t o Me dical Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A). T he fre q ue nc y of A Es will be ta b ulate d b y 
s yste m or ga n class, preferre d ter m, se verit y, a n d relati o ns hi p t o st u d y treat me nt. 
C ha n ges i n la b orat or y para meters a n d vital si g ns will be s u m marize d 
descri pti vel y.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3
1. I N T R O D U C TI O N
1. 1. Dise ase B ac k gr o u n d
1. 1. 1. Sic kle Cell Dise ase 
Sic kle cell disease ( S C D) is a n i n herite d bl o o d dis or der ca use d b y a p oi nt m utati o n i n t he 
β gl o bi n ge ne res ulti n g i n t he f or mati o n of “sic kle he m o gl o bi n” ( H b S), w hic h p ol ymerizes i n 
t he de o xy ge nate d state a n d lea ds t o re d bl o o d cell ( R B C) sic kli n g. T he disease is mar ke d b y 
t he pat h o p h ysi ol o gic feat ures of he m olyt ic a ne mia, vas o- occl usi o n, a n d pr o gressi ve e n d-
or ga n da ma g e, wit h a cli nical c o urse c haracterize d b y life -l o n g disa bility a n d earl y deat h 
(Gla d wi n, 2 0 1 4 ; N o uraie, 2 0 1 3 ). I n a d diti o n t o u n pre dicta ble a n d rec urre nt vas o -occl usi ve 
pai n e pis o des, he m ol yt ic a ne mia directl y da ma ges bl o o d vessels, res ulti n g i n a s yste mic 
vasc ul o pat h y t hat lea ds t o c hr o nic a n d pr o gressi ve tiss ue a n d or ga n i nj ur y ( Kat o , 2 0 0 7). Wit h 
i m pr o ve d s ur vi val i n c hil dre n, t he nat ural hist or y of S C D has s hifte d fr o m a disease of 
c hil d h o o d t o a c hr o nic, de bilitati n g disease of y o u n g a n d mi d dle -a ge d a d ults. C u m ulati ve 
i nj ur y t o m ulti ple or ga n s yste ms fr o m re peate d e pis o des of R B C sic kli n g, vas o-occl usi o n, 
a n d c hr o nic he m ol ytic a ne mia e xact a hi g h cli nical b ur de n i n t he a gi n g a d ult, si g nifica ntly 
i m pacti n g q uality of life ( Q O L) a n d o verall f u ncti o ni n g ( S wa ns o n, 2 0 1 1 ). 
1. 2. V o xel ot o r
V o xel ot or ( pre vi o usl y  G B T 4 4 0) is a n H b S p oly m erizati o n i n hi bit or t hat bi n ds t o H b S wit h a 
1: 1 st oic hi o metr y a n d e x hi bits prefere ntial partiti o ni n g t o R B Cs. V o xel ot or bi n ds c o vale ntl y 
a n d re versi bl y t o t he N-ter mi nal vali ne of t he H b α c hai n a n d all ostericall y i ncreases H b S-
o x y ge n ( O 2) affi nit y (Eat o n, 1 9 9 9 ), sta bilizi n g t he o xy h e m o gl o bi n ( o x yH b) state a n d 
i n hi biti n g p ol ymerizati o n ( O kse n ber g, 2 0 1 6 ). T he v o xel ot or bi n di n g site (Kat o, 2 0 0 7 ) is 
dista nt fr o m he me p oc kets a n d it ca n t heref ore i ncrease O 2 affi nit y wit h o ut sterically 
bl oc ki n g t he release of O 2. 
A pri mar y  a n d o bli gat or y e ve nt i n t he m olec ular pat h o ge nesis of S C D is t he p ol ymerizati o n 
of de o x y ge nate d H b S. Beca use o x y H b is a p ote nt i n hi bit or of H b S p ol y merizati o n, 
i ncreasi n g t he pr o p orti o n of o xy H b i n all R B Cs wit h v o xel ot or ca n re d uce H b S 
p ol y meriz ati o n, decrease R B C me m bra ne da ma ge a n d destr ucti o n, a n d has t he p ote ntial t o 
s u bse q ue ntl y ac hie ve l o n g-ter m disease m o dificati o n. T his pri nci ple is s u p p orte d b y t he 
fi n di n g t hat i n patie nts wit h sic kle here ditar y persiste nce of fetal he m o gl o bi n ( H b F), t he
dil uti o n of H b S b y  2 0 % t o 3 0 % H b F i n all R B Cs is s ufficie nt t o i n hi bit H b S p ol ymerizati o n, 
pre ve nti n g R B C da ma ge a n d S C D cli nical se q uelae. T his s u g gests t hat p har mac ol o gicall y  
mai ntai ni n g a p pr o xi matel y  2 0 % t o 3 0 % of H b i n t he n o n p ol ymerizi n g o x y ge nate d s tate i n all 
R B Cs ma y  be a n effecti ve a p pr oac h f or t he treat me nt of S C D. T his t hera pe utic effect was 
de m o nstrate d 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) w here 1 5 0 0 m g of v o xel ot or, 
ac hie vi n g H b m o dificati o n of 2 0 % t o 3 0 %, a d mi nistere d dail y orall y f or 2 4 wee ks s h o we d a 
si g nifica nt a n d cli nically mea ni n gf ul i ncrease i n H b a n d decrease i n he m ol ysis. 
V o xel ot or was a p pr o ve d f or use i n t he U S u n der t he tra de na me O X B R Y T A ® i n 2 0 1 9 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 4 years of a ge a n d ol der ( O x br y ta® U S PI ). Mar keti n g a p pr o val i n ot her 
re gi o ns has bee n recei ve d or is bei n g s o u g ht. F or details o n ot her c o u ntr y a p pr o vals f or 
mar keti n g, please refer t o t he c urre nt I n vesti gat or’s Br oc h ure (I B). H o we ver, f or t his st u d y , 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 2 4
t he st u d y dr u g v o xel ot or is c o nsi dere d a n i n vesti gati o nal dr u g as t he st u dy will be c o n d ucte d 
i n c o u ntries w here v o xel ot or is n ot a p pr o ve d.
V o xel ot or c o nti n ues t o be e val uate d i n o n g oi n g cli n ical st u dies e x pl ori n g t he safety, 
t olera bilit y, p har mac o ki netics, p har mac o d yna mics ( P D), a n d treat me nt res p o nse i n pe diatric 
a n d a d ult partici pa nts wit h S C D 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 nts. 
1. 3. 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. 3. 1. Le g Ulcers i n P atie nts wit h S C D
Le g ulcers are a c o m m o n c o m plicati o n of S C D, partic ularl y a m o n g i n di vi d uals wit h t he m ore 
se vere ge n oty pes (sic kle he m o gl o bi n wit h 2 sic kle cell ge nes [ H b S S] or sic kle he m o gl o bi n 
a n d o ne beta t halasse mia ge ne [ H b S/ β0] t halasse mia) of sic kle cell a ne mia ( S C A) . 
Gl o bal pre vale nce of le g ulcers i n t he S C D p o p ulati o n varies ge o gra p hicall y , wit h esti mates 
of 1 4 % t o 1 8 % i n t he U nite d States ( U S) a n d E ur o pe, 1 0 % t o 3 0 % i n s u b-Sa hara n Africa, 
a n d 3 0 % t o 4 0 % i n Ja maica a n d Brazil. Wit h i ncreasi n g s ur vi val be y o n d c hil d h o o d a n d a 
gr o wi n g p o p ulati o n of a d ults li vi n g wit h c hr o nic ma nifestati o ns of S C D , t he lifeti me 
pre vale nce of l e g ulcers is li kel y t o be m uc h hi g her.
Le g ulcers us uall y  occ ur i n yo u n g a d ults wit h S C A, t y picall y  ma nifesti n g i n t he peri-
malle olar area w hic h is v ul nera ble d ue t o t hi n s ki n a n d little pr otecti ve s u bc uta ne o us fat. U p 
t o 5 0 % of patie nts wit h le g ulcers re p ort prece di n g mi n or tra u ma a n d/ or pr urit us t hat 
pr o v o kes scratc hi n g a n d s ki n brea ka ge (Si n g h, 2 0 1 6 ). O nce f or me d, t hese le g ulcers are sl o w 
t o heal, ha ve a hi g h rate of rec urre nce, a n d are ass ociate d wit h se vere u nre mitti n g pai n. T he 
se q uelae of c hr o nic le g ulcers i n S C D i ncl u de restricte d m o bilit y, de pressi o n, di mi nis he d 
w or k ca pacit y, a n d slee p i m pair me nt, as well as i ncreas e d healt hcare utilizati o n 
(Her ber, 2 0 0 7 ; Pers o o n, 2 0 0 4 ).
T he pat h o ge nesis of le g ulcers i n S C D is c o m ple x a n d n ot f ull y  u n derst o o d. Micr o vasc ular 
occl usi o n b y  de nse sic kle d R B Cs, re d uce d o x yge n -carr yi n g ca pacity fr o m a ne mia, a n d 
vasc ular e n d ot helial da ma ge d ue t o isc he mia, he m ol y sis, a n d de pleti o n of nitric o xi de ha ve 
bee n i m plicate d (Bart ol ucci, 2 0 1 2 ; Ballas, 1 9 9 1 ; Kat o, 2 0 0 7 ). I n di vi d uals wit h S C A a n d le g 
ulcers ha ve e x hi bite d la b orat or y  mar kers of partic ularl y se vere hem ol yt ic a ne mia, i ncl u di n g 
l o wer he m o gl o bi n ( H b) a n d hi g her retic ul oc yte c o u nts, ser u m lactate de h ydr o ge nase ( L D H), 
bilir u bi n, a n d as partate a mi n otra nsferase ( A S T) t ha n S C A patie nts wit h o ut le g ulcers (N ola n, 
2 0 0 6 ; Ta y l or, 2 0 0 8; C u m mi n g, 2 0 0 8 ). T he y  als o ha ve a hi g her i nci de nce of se vere S C D 
c o m plicati o ns, i ncl u di n g str o ke, re nal i m pair me nt, a n d ele vate d tric us pi d jet re g ur gitati o n, 
c o m pare d t o S C A patie nts wit h o ut le g ulcers ( Mi n niti, 2 0 1 4 ). T hese e pi de mi ol o gic 
ass ociati o ns wit h le g ulcers s u p p ort a c o m m o n pat h o ge nesis dri ve n by H b S p ol y merizati o n 
a n d are li n ke d t o a ne mia a n d he m ol y sis-ass ociate d vasc ul o pat h y (Kat o, 2 0 0 7 ).
Hist o pat h ol o gic fi n di n gs i n S C D le g ulcers s h o wi n g bl o o d vessel occl usi o n, acti vate d 
e n d ot heli u m, t hic ke ne d i nti ma a n d l u mi nal dist orti o n as well as ca pillar y pr oliferati o n are 
c o nsiste nt wit h se vere vasc ul o pat h y  (Mi n niti,
2 0 1 4 ). 
Le g ulcers are a well ‐rec o g nize d de bilitati n g c o m plicati o n of S C D, yet t here are still n o 
s pecific g ui deli nes f or ma na ge me nt n or effecti ve treat me nts. T his re mai ns a lar ge u n met 
nee d f or t hese patie nts. I n a C oc hra ne re vie w of fi ve ra n d o mize d trials of i nter ve nti o ns f or 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 2 5
treati n g le g ulcers i n patie nts wit h S C D, n o ne of t he t hera pies res ulte d i n c o m plete ulcer 
heali n g (Marti -Car vajal, 2 0 1 4 ). Alt h o u g h h y dr o x y urea ( H U)/ h y dr o x yc ar ba mi de ( H C) a n d 
c hr o nic tra nsf usi o ns are use d t o treat S C D, n o c o ntr olle d st u dies ha ve de m o nstrate d e fficac y 
of t hese t hera pies i n t he treat me nt of le g ulcers. C urre nt ma na ge me nt of S C D le g ulcers t h us 
relies pri marily o n t he practice a p pr oac h use d f or ot her c uta ne o us ulcers, i n v ol vi n g 
de bri de me n t, wet t o dr y dressi n gs, a n d t o pical a ge nts. 
1. 3. 2. N o ncli nic al D at a
Pri mar y  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 urifi e 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 hese 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 y i n g H b S p ol ymerizati o n at l o w O 2 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 2 e n vir o n me 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 ( D uf u, 2 0 1 8 ). 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 offl oa d O2 fr o m H b 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 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, a n d 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- O2 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 y te c o u nt i n a S C D m o use m o del.
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 n d 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 v o xel ot or I B, 
pr o vi de d se paratel y.
1. 3. 3. Cli nic al D at a
V oxel ot or as a p ote nti al tre at me nt f or le g ulcers
I n a n e x pl orat or y p ost h oc a nalys is of 2 4-wee k data fr o m t he H O P E trial ( St u d y  G B T 4 4 0-
0 3 1), 1 3 partici pa nts ha d a n acti ve le g ulcer at treat me nt i nitiati o n ( 4 i n t he v o xel ot or 
1 5 0 0 m g gr o u p, 6 i n t he v o xel ot or 9 0 0 m g gr o u p, a n d 3 i n t he place b o gr o u p). Of t hese 
1 3 partici pa nts, 3 of 4 ( 7 5 %) i n t he 1 5 0 0 m g gr o u p, 3 of 6 ( 5 0 %) i n t he 9 0 0 m g gr o u p, a n d 0 
of 3 i n t he place b o gr o u p s h o we d c o m plete res ol uti o n of t he le g ulcer d uri n g 2 4 wee ks of 
treat me nt per t he site I n vesti gat or’s assess me nt (Mi n niti, 2 0 1 9 ). A d diti o nall y, n o ne w le g 
ulcers occ urre d i n t he 1 5 0 0 m g gr o u p d uri n g 2 4 wee ks of treat me nt. Res ol uti o n of le g ulcers 
was ass ociate d wit h a n H b occ u pa nc y  of a p pr o xi matel y 2 0 % or hi g her, wit hi n t he tar get 
ra n ge f or i n hi biti o n of H b S p ol y merizati o n. T hese fi n di n gs s u g gest t hat v o xel ot or ma y be a n 
effecti ve treat me nt f or le g ulcers. B y  directly tar geti n g t he u n de rlyi n g mec ha nis m of disease, 
i n hi biti n g H b S p ol ymerizati o n a n d c o nse q ue nt he m ol y sis, v o xel ot or ma y ha ve t hera pe utic 
effects be yo n d le g ulcers f or c oe xisti n g c o m plicati o ns ca use d b y  a ne mia a n d he m ol ysis. 
T he effect of v o xel ot or o n le g ulcer heali n g a n d saf et y will be assesse d i n partici pa nts 1 2 
ye ars of a ge a n d ol der wit h S C D a n d acti ve le g ulcer(s) i n t his st u d y .
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 2 6
Details re gar di n g t he Pfizer 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.
I nf or mati o n re gar di n g t he safety a n d t olera bilit y, a n d efficac y of v o xel ot or is pr o vi de d i n 
Secti o n 1. 4 of t his pr ot oc ol.
1. 4. 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 Be 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 years 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 derl yi 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 verity, were ma na ge d b y d ose re d ucti o n a n d/ or 
s ym 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 p y . 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 verity 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 ysis 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 alt er 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 urt 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. Descri pti o n of a n d J ustific ati o n f or t he R o ute of A d mi nistr ati o n, D os a ge, D os a ge 
Re gi me n, a n d Tre at me nt Peri o d(s)
I n t his st u dy, all partici pa nts will recei ve t he sta n dar d of care ( S O C) per pr ot oc ol f or S C D le g 
ulcers (see t he Le g Ulcer Ma na ge me nt Ma n ual) d uri n g t he R u n -i n, 1 2-wee k Ra n d o mize d 
Treat me nt ( v o xel ot or a n d S O C c o m pare d wit h place b o a n d S O C), a n d t he O pe n -la bel 
Treat me nt ( v o xel ot or a n d S O C) peri o ds.
1. 5. 1. D ose R ati o n ale f or V o xel ot or
V o xel ot or is a vaila ble i n a n oral f or m a n d is i nte n de d f or o nce dail y a d mi nistrat i o n. See 
Secti o n 5. 1 f or a d diti o nal i nf or mati o n re gar di n g t he d ose t o be use d i n t his st u d y. 
T he d ose of v o xel ot or t o be e val uate d i n t his st u d y is 1 5 0 0 m g orall y dail y. T his d ose of 
v o xel ot or is t he c urre ntl y a p pr o ve d d ose f or t he treat me nt of S C D a n d is s u p p orte d b y:  
1) a bse nce of c o ncer ni n g e x p os ure -relate d safety fi n di n gs fr o m t he pi v otal P hase 3 
St u d y G B T 4 4 0 -0 3 1 i n a d ults a n d a d olesce nts wit h S C D; 2) a statisticall y  si g nifica nt a n d 
cli nicall y mea ni n gf ul i ncrease i n H b, a n d re d ucti o ns i n cli nical meas ures of he m ol y sis 
o bser ve d wit h v o xel ot or 1 5 0 0 m g, w hic h were m ore r o b ust t ha n t h ose o bser ve d wit h 
v o xel ot or 9 0 0 m g ( Vic hi ns k y , 2 0 1 8); 3) t he efficac y of t he 1 5 0 0 -m g  d ose i n a d olesce nts is 
als o s u p p orte d b y si milar i m pr o ve me nts i n H b a n d he m ol ysis meas ures o bser ve d i n t he P hase 
2a St u d y G B T 4 4 0- 0 0 7 ( Br o w n, 2 0 1 8 ); 4) e x p os ure-res p o nse a nal yses usi n g data fr o m b ot h 
St u d y G B T 4 4 0 -0 3 1 a n d St u d y  G B T 4 4 0- 0 0 7 de m o nstrati n g d ose- de pe n de nt treat me nt effects 
of v o xel ot or o n H b a n d he m ol y sis meas ures; 5) t he maj orit y of a d ult a n d a d olesce nt 
partici pa nts recei vi n g v o xel ot or 1 5 0 0 m g i n St u d y  G B T 4 4 0-0 3 1 ac hie ve d t he i nte n de d 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 2 7
t hera pe utic tar get of 2 0 % t o 3 0 % mea n % H b occ u pa nc y; a n d 6) t he maj orit y of partici pa nts 
wit h le g ulcers recei vi n g v o xel ot or 1 5 0 0 m g i n St u d y  G B T 4 4 0-0 3 1 ha d heale d le g ulcers at 
2 4 wee ks.
1. 5. 2. Use of a Pl ace b o C o ntr ol
T his st u d y  will use place b o as a c o m parat or o n t he bac k gr o u n d of S O C treat me nt. Place b o 
was c h ose n as t he c o ntr ol beca use it is necessar y  t o deter mi ne t he efficac y of v o xel ot or f or 
t he treat me nt of le g ulcers b y all o wi n g efficac y t o be esti mate d w hile c o ntr olli n g f or 
bac k gr o u n d heali n g rates wit h S O C. T he use of a place b o c o ntr ol will als o all o w safet y 
si g nals t o be disti n g uis he d fr o m A Es occ urri n g d ue t o S C D.
Ra n d o mizati o n t o place b o treat me nt i n t his st u d y  d oes n ot place st u d y partici pa nts at 
i ncrease d ris k, as t he S O C f or patie nts wit h le g ulcers will be pr o vi de d d uri n g t he st u d y .
2. S T U D Y O B J E C TI V E S
See Secti o n 3 f or details re gar di n g t he i n vesti gati o nal pla ns.
2. 1. Pri m ar y O bjecti ve
T he pri mar y  o bjecti ve of t his st u d y is t o assess t he effect of v o xel ot or a n d S O C c o m pare d t o 
place b o a n d S O C o n le g ulcer he ali n g i n partici pa nts ≥1 2 y ears of a ge wit h S C D, as 
meas ure d b y t he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of tar get ulcer(s) i n eac h 
treat me nt gr o u p by Wee k 1 2.
2. 2. Sec o n d ar y O bjecti ves
T he sec o n dar y  o bjecti ves of t his st u d y are t o e val uate t he effect of v o xel ot or a n d S O C 
c o m pare d t o place b o a n d S O C o n: 

Ti me t o res ol uti o n of tar get ulcer(s)

C ha n ge i n t otal s urface area(s) of tar get ulcer(s) 

I nci de nce of ne w ulcers
2. 3. E x pl or at or y O bjecti ves
T he e x pl orat or y  o bjecti ves will assess t he effect of v o xel ot or a n d S O C c o m pare d t o place b o 
a n d S O C ( or o pe n -la bel v o xel ot or a n d S O C, w here a p plica ble) o n:

C orrelati o n bet wee n c ha n ge i n H b a n d tar get ulcer(s) heali n g 

C orrelati o n bet wee n c ha n ge i n he m ol y tic para meters ( % retic ul oc ytes, i n direct 
bilir u bi n, L D H) a n d tar get ulcer(s) heali n g

Healt h -relate d q uality of life ( H R Q O L) usi n g patie nt -re p orte d o utc o me ( P R O) 
meas ures, w he n a vaila ble ( pe n di n g tra nslati o n a n d c ult ural vali dati o n 
re q uire me nts)

Patie nt- Re p orte d O utc o me Meas ure me nts I nf or mati o n S y ste m ( P R O MI S) 
Pe diatric Pr ofile -3 7 v 2. 0/ P R O MI S- 4 3 v 2. 1

Vis ual a nal o g scale ( V A S) assess me nt of pai n le vel li n ke d t o tar get ulcer(s)

Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI -C)
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 2 8

Cli nicia n Gl o bal I m pressi o n of C ha n ge ( C GI -C)
2. 4. S afet y O bjecti ve
T he safet y o bjecti ve is t o assess t he sa fet y a n d t olera bilit y of v o xel ot or c o m pare d t o place b o 
base d o n A Es, cli nical la b orat or y  tests, p h ysical e xa mi nati o ns, vital si g ns, a n d ot her cli nical 
meas ures (e g, disc o nti n uati o ns d ue t o A Es, d ose re d ucti o ns).
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 P hase 3, m ultice nter, ra n d o mize d, place b o-c o ntr olle d st u d y t o e val uate t he 
efficac y of v o xel ot or a n d S O C f or t he treat me nt of le g ulcers i n partici pa nts wit h S C D. T he 
st u d y is di vi de d i nt o a 5 st u d y peri o ds: Scree ni n g, R u n-i n, Ra n d o mize d Treat me nt, Ope n -
la bel Treat me nt, a n d F oll o w-u p/ E n d of St u d y  ( E O S). 
T he st u d y  will be c o n d ucte d i n a p pr o xi matel y 8 0 eli gi ble partici pa nts at a p pr o xi matel y 2 0 
gl o bal cli nical trial sites. T he o verall st u d y  desi g n is ill ustrate d i n t he St u d y Sc he ma pr o vi de d 
i n Fi g ure 1 .
Scree ni n g Peri o d ( wit hi n 2 8 d ays pri or t o t he R u n -i n Peri o d)
D uri n g t his peri o d, partici pa nts will si g n t he i nf or me d c o nse nt f or m/asse nt f or m (I C F/ A F), 
after w hic h t he y will c o m plete t he Scree ni n g assess me nts, i ncl u di n g tar get le g ulcer(s) 
s urface area meas ure me nt(s) b y di gital p h ot o gra p h y, as detaile d i n t he Sc he d ule of 
Assess me nts ( S O A) i n A p pe n di x 1 a n d i n t he Le g Ulcer Assess me nt a n d Meas ure me nt 
Ma n ual . All Scree ni n g assess me nts m ust be c o m plete d wit hi n 2 8 da y s bef ore t he R u n-i n 
Peri o d.
R u n -i n Peri o d ( 2 weeks pri or t o R a n d o miz ati o n [ ± 3- d ay wi n d o w] )
Partici pa nts will e nter a 2 -wee k R u n -i n Peri o d ( Da y -1 4 t o Da y  -1 [ + 3 da y s]), d uri n g w hic h 
assess me nts, i ncl u di n g tar get le g ulcer(s) s urface area meas ure me nt(s) b y di gital p h ot o gra p h y 
will be c o n d ucte d a n d S O C i nitiate d per pr ot oc ol, f oll o wi n g best practi ce g ui deli nes (see 
Mi n niti, 2 0 1 4
f or g ui da nce a n d t he Le g Ulcer Ma na ge me nt Ma n ual f or a d diti o nal details). 
T hese assess me nts m ust be c o m plete d pri or t o ra n d o mizati o n t o e ns ure t hat t he partici pa nt 
co nti n ues t o q ualif y  f or t he st u d y.
R a n d o mize d Tre at me nt Peri o d ( 1 2 weeks [ ± 3- d ay wi n d o w f or e ac h visit after D ay 1 Visit] )
After c o m pleti o n of t he 2 -wee k R u n -i n Peri o d, tar get le g ulcer(s) s urface area 
meas ure me nt(s)
will be reasses se d o n Da y 1 ( + 1 -da y  wi n d o w) t o 
e ns ure t hat t he partici pa nt c o nti n ues t o q ualif y  f or t he st u d y bef ore ra n d o mizati o n. Eli gi ble 
partici pa nts 
) 
will be ra n d o mize d 1: 1 t o recei ve v o xel ot or 1 5 0 0 m g o nce dail y a n d S O C or place b o o nce 
dail y  a n d S O C f or 1 2 wee ks. At t he ti me of ra n d o mizati o n, partici pa nts will be stratifie d 
 
 
 
 
 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)
C CI
C CI
C CI


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 2 9
T he treat me nt peri o d is c o nsi dere d t he c o nti n u o us 1 2 wee ks of v o xel ot or a n d S O C or place b o 
a n d S O C fr o m date of ra n d o mizati o n (first d ose, Da y  1). T he tar get le g ulcer(s) will be 
assesse d b y vis ual i ns pecti o n a n d s urface area meas ure me nt(s)
sc he d ule d visits e ver y 2 wee ks d uri n g t he 1 2-wee k Ra n d o mize d Treat me nt Peri o d.  
 
 
 
 
 
O pe n -l a bel Tre at me nt Peri o d ( mi ni m u m 1 2 weeks [ ± 3- d ay wi n d o w f or e ac h visit] )
At t he e n d of t he 1 2 - wee k Ra n d o mize d Treat me nt Peri o d, all partici pa nts ( wit h t he e xce pti o n 
of t h ose de m o nstrati n g i nitial ulcer re -e pit helializati o n at Wee k 1 2) will recei ve o pe n-la bel 
v o xel ot or 1 5 0 0 m g per da y  a n d S O C f or a mi ni m u m of 1 2 wee ks a n d tar get ulcers t hat faile d 
t o heal d uri n g t he i nitial 1 2 wee ks will be f oll o we d f or dela ye d heali n g. Assess me nts will 
c o nti n ue t o be perf or me d per t he S O A ( A p pe n di x 1 ). 
N ote: P artici p a nts w h o h ave c o m plete d 1 2 weeks i n t he O pe n -l a bel Tre at me nt Peri o d m ay c o nti n ue t o 
receive v oxel ot or as l o n g as t hey c o nti n ue t o receive cli nic al be nefit t h at o ut wei g hs risk as deter mi ne d 
by t he I nvesti g at or or u ntil t he p artici p a nt h as access t o v oxel ot or fr o m a n alter n ative s o urce (e g, 
t hr o u g h a cli nic al O L E st u dy s p o ns ore d by Pfizer, c o m merci aliz ati o n of t he pr od uct, or a m a n a ge d 
access pr o gr a m). P artici p a nts w h o d o n ot pl a n t o c o nti n ue t o receive v oxel ot or fr o m a n alter n ative 
s o urce s h o ul d c o nti n ue t o t he f oll o w-u p peri o d after c o m pleti n g 1 2 weeks i n t he O pe n -l a bel Tre at me nt 
Peri o d. 
F oll o w -u p Peri o d ( 4 weeks af ter l ast d ose [ ± 7- d ay wi n d o w f or E O S Visit ])
F oll o wi n g c o m pleti o n of t he O pe n -la bel Treat me nt Peri o d, eli gi ble partici pa nts will be gi ve n 
t he o pti o n t o c o nti n ue t o recei ve v o xel ot or ( u n der t his pr ot oc ol, u ntil access is pr o vi de d 
t hr o u g h a n alter nati ve s o urce). Partici pa nts w h o d o n ot c o nti n ue t o recei ve v o xel ot or fr o m a n 
alter nati ve s o urce will be f oll o we d f or 4 wee ks after t he last d ose of treat me nt a n d i nstr ucte d 
t o ret ur n t o t he site t o c o m plete t he E O S visit. 
E arly Ter mi n ati o n Visit
If a partici pa nt ter mi nates t he st u d y f or a n y reas o n, t his s h o ul d be d oc u me nte d o n t he 
electr o nic case re p ort f or m (e C R F) a n d t he assess me nts f or t he Earl y Ter mi nati o n visit 
s h o ul d be perf or me d per t he S O A (A p pe n di x 1 ).
Safet y  a n d t olera bilit y will be m o nit ore d d uri n g t he e ntire st u d y usi n g sta n dar d meas ures, 
i ncl u di n g t he assess me nt of A Es, cli nical la b orat or y tests, p hys ical e xa mi nati o ns, a n d vital 
si g ns.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)
C CI
C CI


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 3 0
Fi g ure 1:
St u d y Sc he m a
A b bre viati o ns: S O C, sta n dar d of care
* Partici pa nts w h o ha ve c o m plete d 1 2 wee ks i n t he O pe n -la bel Treat me nt Peri o d ma y c o nti n ue t o recei ve v o xel ot or as l o n g 
as t he y c o nti n ue t o recei ve cli nical be nefit t hat o ut wei g hs ris k as deter mi ne d b y t he I n vesti gat or or u ntil t he partici pa nt has 
access t o v o xel ot or fr o m a n alter nati ve s o urce (e g, t hr o u g h a cli nical O L E st u d y s p o ns ore d b y Pfizer, c o m mercializati o n of 
t he pr od uct, or a ma na ge d access pr o gra m). Partici pa nts w h o d o n ot pla n t o c o nti n ue t o recei ve v o xel ot or fr o m a n alter nati ve 
s o urce s h o ul d c o nti n ue t o t he f oll o w-u p peri o d after c o m pleti n g 1 2 wee ks i n t he O pe n -la bel Treat me nt Peri o d.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 3 1
3. 1. 1. St u d y Tre at me nt 
See Secti o n 5 f or d osa ge a n d treat me nt a d mi nistrati o n of v o xel ot or a n d place b o.
3. 1. 2. St u d y Assess me nts 
St u d y  pr oce d ures a n d assess me nts are descri be d i n Secti o n 6 . T he ti mi n g f or t he st u d y  
pr oce d ures a n d assess me nts is pr o vi de d i n t he S O A ( A p pe n di x 1 ). 
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 ys ical e xa mi nati o ns, vital si g ns (i ncl u di n g te m perat ure, bl o o d 
press ure, a n d p uls e rate), cli nical la b orat or y tests, a n d A E m o nit ori n g.
3. 1. 3. St u d y E n d p oi nts
Tar get le g ulcer i ma ges will be se nt f or ce ntral re vie w (see Secti o n 6. 7 ).
3. 1. 3. 1. Pri m ar y E n d p oi nt
T he pri mar y  e n d p oi nt will be meas ure d b y t he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n 
of t he tar get ulcer(s), 
 
 d uri n g t he 1 2-we e k Ra n d o mize d Treat me nt Peri o d. 
 
 
 
F or partici pa nts wit h m ore t ha n o ne tar get ulcer, all tar get ulcers m ust be c o nfir me d res ol ve d 
i n or der f or t he partici pa nt t o be c o nsi dere d a res p o n der.
3. 1. 3. 2. Sec o n d ar y E n d p oi nts
Sec o n dar y  e n d p oi nts i n t his st u d y i ncl u de a c o m paris o n of v o xel ot or a n d S O C vers us 
place b o a n d S O C i n: 

Ti me (i n da y s) t o res ol uti o n of tar get ulcer(s) u p t o Wee k 1 2

C ha n ge fr o m baseli ne i n t otal s urface area of tar get ulcer(s) at Wee k 1 2

I nci de nce of ne w ulcers b y Wee k 1 2
3. 1. 3. 3. E x pl or at or y E n d p oi nts
E x pl orat or y  e n d p oi nts i ncl u de: 

Pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of tar get ulcer(s) b y Wee k 2 4

Ti me (i n da y s) t o res ol uti o n of tar get ulcer(s) u p t o Wee k 2 4

C ha n ge fr o m baseli ne i n t otal s urface area of tar get ulcer(s) o ver ti me u p t o 
Wee k
2 4

C orrelati o n bet wee n c ha n ge i n H b a n d tar get ulcer(s) heali n g at Wee k 1 2 a n d 
Wee k
2 4

C orrelati o n bet wee n c ha n ge i n mar kers of he m ol ysis ( % retic ul oc yt es, i n direct 
bilir u bi n, L D H) a n d tar get ulcer(s) heali n g at Wee k 1 2 a n d Wee k 2 4 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)
C CI
C CI


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 3 2

C ha n ge fr o m baseli ne i n P R O H R Q O L  meas ures: P R O MIS- 3 7 v 2. 0 Pe diatric 
Pr ofile/ P R O MI S- 4 3 v 2. 1 at Wee k 1 2 a n d Wee k 2 4

C ha n ge fr o m baseli ne i n pai n le vel li n ke d t o tar get ulcer( s) assesse d by V A S at 
Wee k
1 2 a n d Wee k 2 4

P GI -C sc ore at Wee k 1 2 a n d Wee k 2 4

C GI -C sc ore at Wee k 1 2 a n d Wee k 2 4
3. 1. 3. 4. S afet y E n d p oi nts
T he safet y e n d p oi nts i ncl u de assess me nts of A Es, cli nical la b orat or y  para meters, p h ysical 
e xa mi nati o ns, a n d vital si g ns.
3. 1. 4. Mi ni mi z ati o n of Bi as
T his st u d y uses a d o u ble-bli n d, ra n d o mize d, m ultice nter desi g n t o mi ni mize bias.
3. 2. D ur ati o n of St u d y P artici p ati o n a n d of t he St u d y
T he a p pr o xi mate st u d y  d urati o n f or a n i n di vi d ual partici pa nt i ncl u des t he Scree ni n g Peri o d 
( wit hi n 2 8 da ys), a R u n -i n Peri o d of 2 wee ks, a Ra n d o mize d Treat me nt Peri o d of 1 2 wee ks, 
a n O pe n -la bel Treat me nt Peri o d of a mi ni m u m of 1 2 wee ks, a n d a F oll o w-u p Peri o d/ E O S 
visit ( 4 wee ks [ ± 7 da y s] after t he last d ose of st u d y dr u g). Fr o m Scree ni n g t hr o u g h F oll o w -
u p, t otal p artici pati o n i n t his st u d y f or a n i n di vi d ual partici pa nt ma y last fr o m a p pr o xi matel y 
3 1 wee ks t o u p t o 3 4 wee ks, e xce pt f or partici pa nts w h o c o nti n ue t o recei ve v o xel ot or 
be y o n d 1 2 wee ks i n t he O pe n -la bel Treat me nt Peri o d (see bel o w). Partici pa nts will c o nti n ue 
t o be f oll o we d f or efficac y a n d safety t hr o u g h at least t he pri mar y  e n d p oi nt visit ( Wee k 1 2) 
re gar dless of treat me nt disc o nti n uati o n. 
Partici pa nts w h o ha ve c o m plete d 1 2 wee ks i n t he O pe n- la bel Treat me nt Peri o d ma y c o nti n ue 
t o recei ve v o xel ot or as l on g as t he y  c o nti n ue t o recei ve cli nical be nefit t hat o ut wei g hs ris k as 
deter mi ne d b y t he I n vesti gat or or u ntil t he partici pa nt has access t o v o xel ot or fr o m a n 
alter nati ve s o urce (e g, t hr o u g h a cli nical O L E st u d y  s p o ns ore d b y Pfizer, c o m mercializati o n 
of t he pr o d uct, or a ma na ge d access pr o gra m). 
Partici pa nts w h o c h o ose n ot t o c o nti n ue v o xel ot or after 1 2 wee ks i n t he O pe n -la bel 
Treat me nt Peri o d will be f oll o we d f or 4 wee ks after t he last d ose of treat me nt a n d i nstr ucte d 
t o ret ur n t o t he site t o c o m plete t he E O S visit ( Visit 1 6 -B, A p pe n di x 1 ). 
T he st u d y  will e n d w he n t he last partici pa nt’s last visit occ urs.
F or partici pa nts w h o ter mi nate t he st u d y  pri or t o t heir last visit, refer t o Secti o n 3. 3. 1.
3. 3. St o p pi n g R ules 
3. 3. 1. E arl y Disc o nti n u ati o n of t he St u d y
T he S p o ns or has t he ri g ht t o ter mi nate t his st u d y  at a n y ti me. Reas o ns f or ter mi nati n g t he 
st u d y ma y i ncl u de, b ut are n ot li mite d t o, t he i nci de nce or se verity of T E A Es i n t his or ot her 
st u dies wit h v o xel ot or i n dicati n g a p ote ntial healt h ris k t o partici pa nts.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 3 3
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, re g ulat or y a ut h orities, a n d I n de pe n de nt Et hics C o m mittees (I E Cs) a n d will 
s pecif y t he reas o n(s) f or ter mi nati o n.
3. 3. 2. Disc o nti n u ati o n of I n di vi d u al P artici p a nts
3. 3. 2. 1. Wit h dr a w al of C o nse nt
Partici pa nts a n d/ or t heir care gi ver/le gal re prese ntati ve will be i nf or me d partici pati o n is 
v ol u ntar y  a n d t hat t he y ma y disc o nti n ue treat me nt or wit h dra w fr o m t he st u d y at a ny ti me 
a n d f or a n y reas o n. A ny partici pa nt w h o re q uests t o be wit h dra w n or w h ose care gi ver/le gal 
g uar dia n re q uests wit h dra wal will be wit h dra w n fr o m t he st u d y  b y t he I n vesti gat or.
3. 3. 2. 2. E arl y Disc o nti n u ati o n of St u d y Tre at me nt
Partici pa nts ma y  be disc o nti n ue d fr o m st u d y treat me nt f or a n y of t he f oll o wi n g reas o ns:

Partici pa nt is l ost t o f oll o w- u p

A d verse e ve nt(s)

Re peate d s ur gical de bri de me nt of tar get ulcer(s) nee de d t o a d dress w o u n d 
deteri orati o n

Discreti o n of t he I n vesti gat or

Discreti o n of t he S p o ns or

Pre g na nc y
T he partici pa nt s h o ul d ret ur n t o t he st u d y  site f or a n E O S/ Early Ter mi nati o n visit 
a p pr o xi mat el y 2 8 da ys ( ± 7 da ys) after t he last d ose of st u d y  treat me nt, as i n dicate d i n t he 
S O A. 
3. 4. R a n d o miz ati o n a n d U n bli n di n g
3. 4. 1. R a n d o miz ati o n
Ra n d o mizati o n will be carrie d o ut t hr o u g h a n I nteracti ve Res p o nse Sys te m (I X R S). 
Per m ute d bl oc ks wit hi n ra n d o mizati o n strata will be use d. Eli gi bilit y  of t he partici pa nt will 
be c o nfir me d b y t he I n vesti gat or pri or t o ra n d o mizati o n.
3. 4. 1. 1. Pre ve nti n g U n bli n di n g d ue t o L a b or at or y Assess me nts
Beca use k n o wle d ge of certai n la b orat or y assess me nts ( H b, he mat ocrit, R B C c o u nt, t otal a n d 
u nc o nj u gate d bilir u bi n, or a bs ol ute a n d % retic ul oc y te c o u nt) ma y s u g gest t he treat me nt 
assi g n me nt i n t he Ra n d o mize d Treat me nt Peri o d, t hese meas ure me nts will be re dacte d t o t he 
I n vesti gat or. 
Res ults of re dacte d la b orat or y  tests will be c o m m u nicate d t o t he I n vesti gat or if a 
partici pa nt’s a bs ol ute retic ul oc y te c o u nt decli nes t o < 8 0 × 1 0 9/ L, or H b decli nes 
t o < 5. 0 g/ d L, or if t he H b decli nes ≥2 g/ d L  fr o m Scree ni n g. T his d oes n ot re q uire brea ki n g 
of t he treat me nt assi g n me nt bli n d. T his is t o e ns ure partici pa nt sa fety b y all o wi n g t he 
I n vesti gat or t o m o nit or f or p ote ntial b o ne marr o w s u p pressi o n, as descri be d i n H U 
m o nit ori n g g ui deli nes ( Mc Ga n n, 2 0 1 5 ; Ya w n, 2 0 1 4 ). De -i de ntifie d la b orat or y res ults will be 
a vaila ble t o t he S p o ns or.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 3 4
3. 4. 1. 2. U n bli n di n g f or Me dic al Nee d
If a me dical c o n diti o n s h o ul d arise f or w hic h a p pr o priate treat me nt ca n n ot be deci de d 
wit h o ut k n o wle d ge of t he st u d y  treat me nt assi g n me nt, t he In ves ti gat or ma y u n bli n d a st u d y 
partici pa nt. T he I n vesti gat or s h o ul d pr o m ptl y  d oc u me nt a n d n otif y t he S p o ns or of a n y 
pre mat ure st u d y treat me nt u n bli n di n g (e g, acci de ntal u n bli n di n g, u n bli n di n g d ue t o a seri o us 
a d verse e ve nt [ S A E]). Pre g na nc y is c o nsi dere d a n e ve nt t hat re q uires u n bli n di n g. U n bli n di n g 
pr oce d ures s pecifie d i n t he I X R S Ma n ual will be f oll o we d a n d d oc u me nte d i n t he 
I n vesti gat or site file.
4. S E L E C TI O N O F S T U D Y P A R TI CI P A N T S
Eli gi bilit y  will be base d o n assess me nts perf or me d d uri n g t he Scree ni n g Peri o d a n d R u n-I n 
Peri o d. A partici pa nt will be e nr olle d after si g ni n g t he I C F or A F f or t his st u d y . I nf or me d 
c o nse nt/asse nt m ust be pr o perl y e xec ute d pri or t o t he perf or ma nce of a n y pr ot oc ol -re q uire d 
assess me nts or pr oce d ures.
4. 1. 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 d oc u me nte d dia g n osis of S C D ( H b S S, H b S/ β 0 
t halasse mia) 
2.
A ge 1 2 years a n d ol der 
3.
At least 1 c uta ne o us ulcer(s) o n t he l o wer e xtre mit y  (le g, a n kle, or d ors u m of f o ot) 
t hat meets t he f oll o wi n g criteria:

D urati o n: ≥2 wee ks a n d < 6 m o nt hs at Scree ni n g, a n d

Size: > 2 c m 2 pri or t o ra n d o mizati o n
N ote: Partici pa nts wit h m ulti ple ulcers are eli gi ble f or t he st u d y. F or eac h partici pa nt, 
tar get ulcer(s) f or e val uati o n i n t his st u d y will be i de ntifie d a n d trac ke d. T o q ualif y as 
a tar get ulcer, t he ulcer m ust meet t he criteria a b o ve.
4.
Partici pa nts, w h o if fe male a n d of c hil d -beari n g p ote ntial, a gree t o use hi g hl y  
effecti ve met h o ds of c o ntrace pti o n fr o m st u d y  start t o 3 0 da ys after t he last d ose of 
st u d y dr u g a n d w h o if male, a gree t o use barrier met h o ds of c o ntrace pti o n fr o m st u d y  
start t o 3 0 da ys after t he last d ose of st u d y dr u g
5.
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
6.
Writte n i nf or me d c o nse nt ( ≥1 8 y ears) or pare ntal/ g uar dia n c o nse nt a n d partici pa nt 
asse nt (≥1 2 – 1 7 y ears) per I E C p olic y a n d re q uire me nts, c o nsiste nt wit h Inter nati o nal 
C o u ncil f or Har m o nisati o n (I C H) g ui deli nes
4. 2. 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.
Tar get ulcer(s) heale d b y ≥2 5 % d uri n g t he S O C R u n -i n pri or t o ra n d o mizati o n
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 3 5
N ote: F or partici pa nts wit h m ulti ple ulcers, t he partici pa n t is n ot eli gi ble f or t he st u d y 
if all tar get ulcers ha ve heale d by ≥2 5 % d uri n g t he S O C R u n -i n.
2.
Acti ve i nfecti o n/ p ur ule nce at ulcer site, or e x p ose d te n d o n or b o ne at t he ulcer site, 
base d o n I n vesti gat or’s cli nical j u d g me nt 
3.
C urre nt oste o m y elitis at or near t he ulcer site
4.
K n o w n vasc ular a b n or malities t hat w o ul d precl u de heali n g i n t he o pi ni o n of t he 
I n vesti gat or (e g, pre-e xisti n g se vere arterial i ns ufficie nc y  i n t he affecte d li m b)
5.
Ser u m al b u mi n < 2. 0 g/ d L 
6.
R B C tra nsf usi o n wit hi n 6 0 da y s of i nitiati o n of st u d y dr u g 
7.
Recei vi n g re g ularl y  sc he d ule d R B C tra nsf usi o n t hera p y (als o ter me d c hr o nic, 
pr o p h y lactic, or pre ve nti ve tra nsf usi o n) d uri n g t he st u d y
8.
Pla n ne d electi ve s ur ger y  wit hi n t he ne xt 6 m o nt hs
9.
A ne mia d ue t o b o ne marr o w fail ure (e g, m yel o d ys plasia)
1 0. A bs ol u te retic ul oc yte c o u nt < 1 0 0 × 1 0 9/ L
1 1. Scree ni n g ala ni ne a mi n otra nsferase (A L T) > 4 × u p per li mit of n or mal ( U L N)
1 2. Se vere re nal d ys f u ncti o n (esti mate d gl o mer ular filtrati o n rate [e G F R] 
< 3 0 m L / mi n/ 1. 7 3 m 2 b y  Sc h wartz f or m ula) or is o n c hr o nic dialys is
1 3. Cli nical l y si g nifica nt bacterial, f u n gal, parasitic, or viral i nfecti o n t hat re q uires 
t hera py:

Partici pa nts wit h ac ute bacterial i nfecti o n re q uiri n g s ys te mic a nti bi otic use s h o ul d 
dela y  scree ni n g/e nr oll me nt u ntil t he c o urse of a nti bi otic t hera p y has bee n 
c o m plete d . 

Partici pa nts wit h k n o w n acti ve he patitis A, B, or C or w h o are k n o w n t o be 
h u ma n i m m u n o deficie nc y vir us ( HI V) p ositi ve

Partici pa nts wit h acti ve S A R S- C o V -2 i nfecti o n ( C O VI D -1 9) 
1 4. Fe males w h o are breast -fee di n g or pre g na nt
1 5. Hist or y  of he mat o p oietic ste m cell tra ns pla nt or ge ne t hera p y
1 6. Partici pate d i n a n ot her cli nical trial of a n i n vesti gati o nal pr o d uct ( or me dical de vice) 
wit hi n 3 0 da y s or 5 half-li ves of date of i nf or me d c o nse nt, w hic he ver is l o n ger, or is 
c urre ntl y partici pati n g i n a n ot her trial of a n i n vesti gati o nal pr o d uct ( or me dical 
de vice)
1 7. Me dical, ps yc h ol o gical, or be ha vi oral 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 safety a n d/ or efficac y of 
t he st u d y dr u g, pre ve nt c o m plia nce wit h t he st u d y pr ot oc ol; precl u de i nf or me d 
c o nse nt; or re n der t he partici pa nt u na ble/ u nli kel y  t o c o m pl y wit h t he st u d y 
pr oce d ures
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 3 6
1 8. T his e xcl usi o n criteri o n ( E C) was re vise d t o E C # 1 8 A i n t he Gl o bal Pr ot oc ol 
A me n d me nt 2. 0.
1 8 A. Use of dr u gs wit h dr u g - dr u g i nteracti o n p ote ntial wit h v o xel ot or, i ncl u di n g t he 
f oll o wi ng cate g ories of dr u gs, wit hi n 3 0 da y s of Da y 1:

her bal me dicati o ns (e g, St. J o h n’s w ort), or m o derate or str o n g C Y P 3 A 4 i n d ucers

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
5. T R E A T M E N T S A D MI NI S T E R E D
5. 1. Tre at me nt Re gi me n
D uri n g t he Ra n d o mize d Treat me nt Peri o d, partici pa nts will be ra n d o mize d i n a 1: 1 rati o t o 
recei ve 1 5 0 0 m g of v o xel ot or o nce daily (a d mi nistere d as t hree 5 0 0 m g ta blets) or matc hi n g 
place b o f or 1 2 wee ks. I n t his st u d y , all partici pa nts will recei ve t he S O C per pr otoc ol f or 
S C D le g ulcers (see t he Le g Ulcer Ma na ge me nt Ma n ual ) d uri n g t he R u n-i n, Ra n d o mize d 
Treat me nt, a n d O pe n -la bel Treat me nt peri o ds. D uri n g t he O pe n-la bel Treat me nt Peri o d, all 
partici pa nts will recei ve 1 5 0 0 m g of v o xel ot or o nce dail y (a d mi nistere d as t hree 5 0 0 m g 
ta blets) f or a mi ni m u m of 1 2 wee ks.
I n a d diti o n, partici pa nts w h o ha ve c o m plete d 1 2 wee ks i n t he O pe n-la bel Treat me nt Peri o d 
ma y  c o nti n ue t o recei ve v o xel ot or as l o n g as t he y c o nti n ue t o recei ve cli nical be nefit t hat 
o ut wei g hs ris k as deter mi ne d b y  t he I n vesti gat or or u ntil t he partici pa nt has access t o 
v o xel ot or fr o m a n alter nati ve s o urce n ot ass ociate d wit h t his pr ot oc ol (e g, t hr o u g h a cli nical 
O L E st u d y  s p o ns ore d b y Pfizer, c o m mercializati o n of t he pr o d uct, or a ma na ge d access 
pr o gra m).
5. 1. 1. D os e Fre q ue nc y
Partici pa nts will recei ve a v o xel ot or d osa ge f or m or matc hi n g place b o 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 t he da y of a misse d d ose, s h o ul d n ot be i ncrease d or 
decrease d). 
5. 1. 2. D ose M o dific ati o n
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, re d uci n g or h ol di n g t he 
d ose f or a s h ort peri o d of ti me d uri n g t he st u d y m a y be use d f or A Es t hat i m pact t he 
partici pa nt’s saf et y a n d t olera bilit y. All i nsta nces of st u d y dr u g d ose m o dificati o n ( d ose 
re d ucti o n, i nterr u pti o n, or disc o nti n uati o n) s h o ul d be d oc u me nte d i n t he partici pa nts’ me dical 
rec or d a n d rec or de d i n t he e C R F. If t he c o n diti o ns/e ve nt lea di n g t o t he d ose m o dificatio 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 
I n vesti gat or, t his ca n n ot be d o ne safely. D ose m o dificati o ns ma y be deter mi ne d b y  t he 
I n vesti gat or i n c o ns ultati o n wit h t he S p o ns or’s Me dical M o nit or 
. 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)
C CI


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 3 7
T a ble 1 :
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
D ose Re d ucti o n
E ve nt
Rec o m me n de d Acti o n
Gr a de ≥2 ( N CI gr a di n g sc ale) A E d e e m e d 
c o nsi dere d relate d t o st u d y dr u g b y t he 
I n vesti gat or 
A N D 
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 uced b y o ne ( 1) 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 s h o ul d c o ntact t he Me dical 
M o nit or.
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 ( N CI gr a di n g sc ale) A E d e e m e d 
c o nsi dere d relate d t o st u d y dr u g b y t he 
I n vesti gat or 
A N D 
Precl u des c o nti n ue d d osi n g at t h e 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 ≤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 f or f urt her disc ussi o n. 
If t he A E rec urs or worse 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.
N O T E: St u d y dr u g -rel ate d r as h
Gra de 2 st u d y dr u g -relate d ras h t hat persists after 
a d ose re d ucti o n
Ma na 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 after a d ose re d ucti o n, c o nsi der a d ose h ol d. 
O nce t he ras h has res ol ve d or i m pr o ve d, d osi n g ma y be 
res u me d at t he re d uce d le vel or if, i n t he o pi ni o n of t he 
I n vesti gat or, partici pa nt ma y res u me st u d y dr u g at t he 
ori gi nal d ose. T he Me dical M o nit or ma y be c o ntacte d 
f or f urt her disc ussi 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 n ti n u ati o n
Gr a de ≥3 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 mpr 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.
A b bre viati o ns: A E, a d verse e ve nt; N CI, Nati o nal Ca ncer I nstit ute.
5. 2. P h ysic al Descri pti o n of V o xel ot or
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 p yl- 1H -p y raz ol-5- yl ) pyri di n -3- yl ) met h o xy) 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. 4 g/ m ol. 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 3 8
5. 3. F or m ul ati o n
5. 3. 1. V o xel ot or
V o xel ot or ( 5 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 of t he e xci pie nts use d i n t he f or m ulati o ns are liste d i n t he F D A I nacti ve 
I ngre die nt Data base (II D) or are p har mace utical e xci pie nt mi xt ures e ntirel y  c o m p ose d of 
F D A II D c o m p o ne nts).
All of t he e xci pie nts use d i n t he f or m ulati o ns are eit her c o m pe n dial per E ur o pea n 
P har mac o p oeia ( P h. E ur.) or are c o m p ose d of mi xt ures w hic h are c o m pe n dial per P h. E ur. or 
acce pte d b y E n u m ber or E ur o pea n C o m missi o n re g ulati o n. 
A d diti o nal details are pr o vi de d i n t he P har mac y  Ma n ual.
5. 3. 2. Pl ace b o
T he place b o matc hi n g ta blets c o ntai n se veral f or m ulati o n e xci pie nts. All of t he e xci pie nts 
use d i n t he f or m ulati o ns are liste d i n t he F D A II D or are p har mace utical e xci pie nt mi xt ures 
e ntirel y c o m p ose d of F D A II D c o m p o ne nts.
All of t he e xci pie nts use d i n t he f or m ulati o ns are eit her c o m pe n dial per P h. E ur. or are 
c o m p ose d of mi xt ures w hic h are c o m pe n dial per P h. E ur. or acce pte d b y E n u m ber or 
E ur o pea n C o m missi o n re g ulati o n. T he matc hi n g place b os d o n ot c o ntai n a n y v o xel ot or dr u g 
s u bsta nce.
5. 4. P ac k a gi n g a n d L a beli n g 
V o xel ot or ta blet dr u g pr o d uct a n d place b os will be s u p plie d t o cli nical sites i n hi g h -de nsit y 
p ol y et h yl e ne 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. A d diti o nal 
details are pr o vi de d i n t he P har mac y  Ma n ual.
5. 5. I n vesti g ati o n al Pr o d uct S u p pl y 
Pfizer 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. Partici pa nts will recei ve a 3-m o nt h ( 9 0 -d a y ) s u p ply of i n vesti gati o nal 
pr o d uct at t he Da y  1 a n d Wee k 1 2 visits. Partici pa nts w h o c o nti n ue t o recei ve v o xel ot or 
be y o n d 1 2 wee ks i n t he O pe n -la bel Treat me nt peri o d will recei ve a 3-m o nt h s u p pl y  of 
v o xel ot or e ver y  1 2 wee ks. Ad diti o nal details are pr o vi de d i n t he P har mac y Ma n ual.
5. 6. St or a ge a n d H a n dli n g Pr oce d ure
All st u d y  dr u g will be st ore d at c o ntr olle d r o o m te m perat ure bet wee n 1 5° C t o 2 5° C ( 5 9° F t o 
7 7° F), 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 is a secure, 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. 
T he S p o ns or or its re prese ntati ves 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, pr o vi de d t hat t he bli n d of t he st u d y is n ot 
c o m pro mise d.
5. 7. C o nc o mit a nt a n d Pr o hi bite d Me dic ati o ns
5. 7. 1. 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.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 3 9
I n t he i nterests of partici pa nt safety a n d acce pta ble sta n da r 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 st u d y partici pa nts w h o 
i nitiate treat me nt, 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 c o nse nt/asse nt 
u ntil 2 8 da y s ( 4 wee ks) 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 o n 
t he partici pa nt’s e C R F.
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 orl d Healt h Or ga nizati o n ( W H O) Dr u g Dicti o nar y .
5. 7. 2. Restricti o ns Re g ar di n g Us a ge of C o nc o mit a nt Me dic ati o ns
C o nc o mita nt treat me nt wit h H U/ H C is all o we d, pr o vi de d t hat t he d ose has bee n sta ble f or at 
least 9 0 d a y s pri or t o si g ni n g t he I C F/ A F. Partici pa nts w h o are o n H U/ H C ma y  ha ve t heir 
d ose a dj uste d ( base d o n c ha n ge i n t heir wei g ht) if t he m g/ k g d ose is sta ble, i n t he o pi ni o n of 
t he In vesti gat or. If H U/ H C treat me nt is i nitiate d after a partici pa nt has bee n scree ne d or after 
bei n g ra n d o mize d, t he eli gi bilit y  of t he partici pa nt t o c o nti n ue i n t he st u d y m ust be disc usse d 
wit h t he S p o ns or’s Me dical M o nit or. 
5. 7. 3. Tr a nsf usi o n
Partici pa nts w h o re q uire i nitiati o n of c hr o nic tra nsf usi o n will be disc o nti n ue d fr o m st u d y  
treat me nt a n d 2 8 d a y s later will u n der g o t he E O S/ Early Ter mi nati o n visit. E pis o dic 
tra nsf usi o ns f or ac ute S C D i n dicati o ns, pre- operati ve pr oce d ures, s ur ger y , or tra u ma are 
per mitte d.
N ote: P artici p a nts w h o c o nti n ue t o receive v oxel ot or bey o n d 1 2 weeks i n t he O pe n -l a bel 
Tre at me nt Peri o d ( see Secti o n 5. 1 ) m ay i niti ate c hr o nic tr a nsf usi o ns wit h o ut bei n g 
disc o nti n ue d fr o m st u dy tre at me nt.
5. 7. 4. Ot her T her a pies
Pe nicilli n pr o p h y la xis a n d vacci nati o ns are all o we d as per S O C. 
Ot her c o nc o mita nt me dicati o ns are all o we d, u nless t he restricti o ns i n Secti o n 5. 7. 5 a p pl y. 
Per mitte d c o nc o mita nt me dicati o ns i ncl u de f olic aci d, L -gl uta mi ne, a n d o ver -t he-c o u nter 
a nal gesics, a n d o pi oi ds, w hic h are a m o n g t he c hr o nic me dicati o ns c o m m o nl y  ta ke n by 
partici pa nts wit h S C D. Er y t hr o p oieti n-sti m ulati n g a ge nts (sta ble d ose f or at least 4 wee ks wit h 
n o d ose m o dificati o ns pla n ne d or a ntici pate d b y t he I n vesti gat or) are all o we d.
Partici pa nts w h o are alrea d y  o n malaria pr o p h yla xis t hera p y ma y be all o we d t o partici pate i n 
t he st u d y at t he discreti o n of t he I n vesti gat or. Partici pa nts ma y als o be i nitiate d o n malaria 
pr o p h y la xis t hera p y d uri n g st u d y, at t he discreti o n of t he I n vesti gat or a n d as per S O C. 
Partici pa nts w h o test p ositi ve f or ac ute malaria d uri n g t he st u d y s h o ul d be pr o vi de d S O C 
treat me nt a n d ma y c o nti n ue i n t he st u d y, at t he discreti o n of t he I n vesti gat or a n d t he S p o ns or.
Partici pa nts w h o test p ositi ve f or ac ute he patitis or HI V d uri n g t he st u d y  will be disc o nti n ue d 
fr o m st u d y dr u g a n d will ret ur n f or t he E O S/ Early Ter mi nati o n visit ( 2 8 da ys after t he last 
d ose of st u d y  dr u g).
5. 7. 5. Pr o hi bite d C o nc o mit a nt Me dic ati o ns
Use of a n i n vesti gati o nal pr o d uct ot her t ha n t hat u n d er st u d y i n t his trial, re gar dless of its 
i nte n de d use, is pr o hi bite d t hr o u g h o ut t he trial a n d f or 2 8 da ys after t he last d ose. 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 4 0
A d diti o nall y , c o nc o mita nt me dicati o ns (e g, criza nliz u ma b) t hat c o nf o u n d t he a bilit y t o 
i nter pret data fr o m t he st u d y are pr o hi bite d.
V o xel ot or is a m o derate C Y P 3 A 4 i n hi bit or a n d s h o ul d 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 2 f or e xa m ples).
T a ble 2:
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
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
A b bre viati o ns: C Y P, c yt oc hr o me P 4 5 0 .
N ote: T his is n ot a n e x h a usti ve list. C o u ntr y -s pecific lists ma y be use d if a vaila 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 urces/ Dr u gI nteracti o ns La beli n g
/ uc m 0 9 3 6 6 4. ht m #ta ble 3-2.
C o nc o mita nt use of v o xel ot or a n d m o derate or str o n g i n d ucers of C Y P 3 A 4 is n ot all o we d 
wit hi n 3 0 da y s of Da y 1 or d uri n g t he st u d y  (refer t o Ta ble 3 f or e xa m ples). In t he e ve nt t hat 
c o nc o mita nt use of v o xel ot or wit h a m o derate or str o n g C Y P 3 A 4 i n d ucer is u na v oi da ble, t he 
I n vesti gat or s h o ul d c o ntact t he Me dical M o nit or.
T a ble 3: 
E x a m ples of M o der ate a n d Str o n g C Y P I n d ucers
C Y P 3 A 4
E x a m ples
M o derate C Y P 3 A 4 i n d ucers
Ce n o ba mate, da brafe nic, efa vire nz, b ose nta n, etra viri ne, l orlati ni b, 
pe xi darti ni b, p he n o bar bital, pri mi d o ne, a n d s ot orasi b
Str o n g C Y P 3 A 4 i n d ucers
Rifa m pi n, a pal uta mi de, p he n yt oi n, car ba maze pi ne, e nzal uta mi de, 
i v osi de ni b, l u macaft or, St J o h n’s w ort, a n d mit ota ne
A b bre viati o ns: C Y P, c yt oc hr o me P 4 5 0.
N ote: T his is n ot a n e x h a usti ve list. C o u ntr y -s pecific lists ma y be use d if a vaila 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 urces/ Dr u gI nteracti o ns La beli n g
/ uc m 0 9 3 6 6 4. ht m #ta ble 3-3 (last accesse d 3 0 Marc h 2 0 2 3).
A d diti o nal pr o hi bite d me dicati o ns are s h o w n i n Ta ble 4.
T a ble 4:
A d diti o n al Pr o hi bite d Me dic ati o ns
Pr o hi bite d Me dic ati o ns
Criza nliz u ma b
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 4 1
5. 8. 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. Pre g na nc y is 
c o nsi dere d a me dical c o n diti o n t hat re q uires u n bli n di n g (refer t o Secti o n 1. 1 ).
5. 8. 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
F or 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 hl y 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 o r 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 or. Hi g hl y effecti ve mea ns of 
c o ntrace pti o n are liste d bel o w i n Secti o n 5. 9 . 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 1. 1 .
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.
5. 8. 2. Fe m ale P artici p a nts of N o n -C hil d -Be ari n g P ote nti al
A fe male partici pa nt of n o n -c hil d-beari n g p ote ntial is defi ne d as o ne w h o: 1) has reac he d 
nat ural me n o pa use ( defi ne d as 1 2 m o nt hs of s p o nta ne o us a me n orr hea wit h o ut a n alt er nati ve 
me dical ca use); 2) is 6 wee ks p ost -s ur gical bilateral o o p h orect o my wit h or wit h o ut 
h y sterect o my;  or 3) has u n der g o ne bilateral t u bal li gati o n. S p o nta ne o us a me n orr hea d oes n ot 
i ncl u de cases f or w hic h t here is a n u n derlyi n g disease t hat ca uses a me n o rr hea (ie, a n ore xia 
ner v osa).
5. 8. 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 ys after t he male partici pa nt 
has ta ke n t he last d ose of v o xel ot or.
As a preca uti o n, all male partici 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 
b y  eit her true a bsti ne nce or t he use of barrier met h o ds of c o ntrace pti o n ( Secti o n 5. 9 ).
5. 9. Acce pt a ble F or ms of C o ntr ace pti o n f or Se x u all y Acti ve P artici p a nts
F or fe male partici pa nts: 
Hi g hl y effecti 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. Hi g hl y effecti ve 
met h o ds of birt h c o ntr ol are as f oll o ws:
1.
H or m o nal c o ntrace pti ves ( m ust be s u p ple me nte d wit h a barrier met h o d, prefera bl y 
male c o n d o m).
a.
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:
o
Oral
o
I ntra va gi nal
o
Tra ns der mal
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 4 2
b.
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:
o
Oral
o
I njecta ble
o
I m pla nta ble
2.
I ntra uteri ne de vice 
3.
I ntra uteri ne h or m o ne-releasi n g sys te m 
4.
Bilateral t u bal occl usi o n
5.
Se x ual a bsti ne nce: 
a.
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 x ual 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 st u d y  a n d t he preferre d a n d 
us ual lifest y le of t he partici pa nt.
F or male partici pa nts 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 wit h 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 f or fe male part ner. 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. 
N ote: As t he effects of v oxel ot or o n pre g n a ncy are n ot c o m pletely k n o w n, t he 
fe m ale p art ner of m ale st u dy p artici p a nts s h o ul d c o nsi der usi n g a n effective 
c o ntr ace ptive met h o d (see a b ove) w hile t he p artici p a nt is t aki n g st u dy tre at me nt 
a n d f or 3 0 d ays after t he l ast d ose of st u dy tre at me nt.
5. 1 0. Assess me nt of Tre at me nt C o m pli a nce
Dr u g dis p ositi o n rec or ds will be mai ntai ne d, s pecif y i n g t he a m o u nt dis pe nse d t o eac h 
partici pa nt a n d t he date of dis pe nsati o n. T his rec or d will be a vaila ble f or S p o ns or re vie w at 
a n y ti me.
C o m plia nce will be deter mi ne d b y  ret ur ne d ta blets. A d osi n g diar y will be dis pe nse d f or 
partici pa nts t o c o m plete.
6. S T U D Y P R O C E D U R E S A N D A S S E S S M E N T S
T he ti mi n g f or t he re q uire d st u d y  pr oce d ures a n d assess me nts are o utli ne d i n t he S O A 
(A p pe n di x 1 ).
T he Scree ni n g Peri o d f or a 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. All scree ni n g assess me nts m ust be 
c o m plete d wit hi n 2 8 da ys bef ore t he R u n- i n Peri o d.
6. 1. I nf or me d C o nse nt/ Asse nt
A si g ne d a n d date d c o nse nt a n d/ or asse nt f or m will be o btai ne d bef ore a n y pr ot oc ol -s pecifie d 
scree ni n g pr oce d ures are perf or me d. 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 4 3
F or pe diatric partici pa nts, c o nse nt s h o ul d be o btai ne d fr o m a t least o ne pare nt ( or b ot h if it is 
re q uire d per I n vesti gati o nal Site p olic y) or t he partici pa nt’s le gal re prese ntati ve. G ui deli nes 
f or t he i nf or me d c o nse nt/asse nt pr ocess are o utli ne d i n Secti o n 1 1. 2 .
6. 2. P artici p a nt I de ntific ati o n N u m ber
U p o n e xec uti o n of c o nse nt/asse nt, all partici pa nts will be gi ve n a u ni q ue partici pa nt 
i de ntificati o n 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 I X R S user ma n ual c o ntai ns t he i nf or mati o n nee de d f or re gisteri n g partici pa nt stat us 
(e g, assi g ni n g partici pa nt n u m bers, i n dicati n g scree n fail ure, te m p orar y s us pe nsi o n of 
treat me nt, a n d e n d of treat me nt).
6. 3. Eli gi bilit y Assess me nt, I ncl usi o n/ E xcl usi o n Re vie w
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 f oll o wi n g t he R u n-i n Peri o d, 
pri or t o recei vi n g st u d y dr u g o n treat me nt Da y 1 . B ot h at Scree ni n g a n d pri or t o 
ra n d o mizati o n, t he In vesti gat or s h o ul d deter mi ne t hat t he partici pa nt is i n sta ble cli nical 
c o n diti o n at t heir stea d y state. 
Ra n d o mizati o n m ust occ ur o n t he sa me da y  as treat me nt, Da y 1 (t he first d ose of st u d y dr u g). 
If a partici pa nt is ra n d o mize d a n d wit h dra w n fr o m t he st u d y  pri or t o t he first d ose of st u d y 
dr u g, t he y  m a y n ot be re-scree ne d.
Pfizer will re vie w eli gi bilit y  criteria verifie d b y t he i n vesti gat or or q ualifie d desi g nee t o 
c o nfir m t hat partici pa nts meet st u d y eli gi bilit y criteria bef ore t he y are ra n d o mize d i nt o t he 
st u d y. T he ra n d o mizati o n a p pr o val pr ocess will be i nitiate d f or a partici pa nt after a n 
i nf or me d c o nse nt d oc u me nt has bee n si g ne d a n d t he i n vesti gat or or q ualifie d desi g nee has 
assesse d t he partici pant as eli gi ble. T he ra n d o mizati o n a p pr o val will be base d o n re vie w of 
C R F/s y ste m data.
6. 4.
Me dic al Hist or y/ De m o gr a p hics 
Cli nicall y  si g nifica nt me dical hist or y (as deter mi ne d b y t he I n vesti gat or), i ncl u di n g hist or y of 
pre vi o us ulcers, c haracteristics, a n d d ur ati o n will be rec or de d at t he ti me of t he Scree ni n g. 
De m o gra p hics a n d baseli ne c haracteristics (i ncl u di n g ge n der, race, et h nicit y , a n d a ge) will 
als o be rec or de d at t he ti me of t he Scree ni n g. 
6. 5. P h ysic al E x a mi n ati o n 
T he p h y sical e xa mi nati o n ( P E) will be a c o m plete P E acc or di n g t o t he sta n dar d at t he site 
a n d a detaile d l o wer e xtre mit y e xa mi nati o n at t he Scree ni n g visit. P h ysical e xa mi nati o ns 
after t he Scree ni n g visit ma y  be a b bre viate d P Es. A n a b bre viate d P E will be c o n d ucte d at t he 
sc he d ule d st u dy visits: Wee k - 2 ( R u n-i n), Da y 1 ( Baseli ne), Wee k 1 2, Wee k 2 4, a n d 
E O S/ Earl y  Ter mi nati o n. F or partici pa nts w h o c o nti n ue t o recei ve v o xel ot or be y o n d 1 2 wee ks 
i n t he O pe n-la bel Treat me nt Peri o d ( See Secti o n 5. 1 ), t he P E will be c o n d ucte d e ver y 
4 8 wee ks (A p pe n di x 1 ).

A c o m plete P E will i ncl u de at a mi ni m u m: Hei g ht, wei g ht, ge neral a p peara nce, 
e xa mi nati o n of hea d, e yes, ears, n ose, a n d t hr oat, s ki n, car di o vasc ular a n d 
res pirat or y sys te ms, a b d o mi nal e xa mi nati o n, ne ur ol o gic, m usc ul os keletal, a n d a 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 4 4
detaile d l o wer e xtre mit y  e xa mi nati o n i ncl u di n g: vasc ular — pe dal p ulses, c ol or of 
s ki n, te m perat ure, e de ma; der mat ol o gical— cli nical descri pti o n of t he ulcer, s ki n 
i nte grity (call uses, dr y ness); m usc ul os keletal — f o ot def or mities s uc h as b u ni o n, 
ha m mert oe, b o n y pr o mi ne nce, fat pa d atr o p h y, altere d gait; ne ur ol o gical —
a bse nce or prese nce of se nsati o n, refle xes.

A n a b bre viate d P E will i ncl u de at a mi ni m u m: E xa mi nati o n of e y es, s ki n, 
car di o vasc ular a n d res pirat or y sys te ms, a b d o mi nal e xa mi nati o n, ne ur ol o gic, 
a n d tar get ulcer(s) e xa mi nati o n.
6. 6. Vit al Si g ns
Vital si g ns ( bl o o d press ure, heart rate, a n d te m perat ure) will be meas ure d at e ver y visit 
d uri n g t he st u d y, as o utli ne d i n t he S O A ( A p pe n di x 1 ), after a partici pa nt has reste d 
c o mf orta bl y f or at least 5 mi n utes i n t he s u pi ne or sitti n g p ositi o n, as a ge a p pr o priate a n d 
feasi ble. A re peate d meas ure me nt of a ny of t he vital si g ns para meters will be ta ke n wit hi n 
5 mi n utes if t he first rea di n g is o uts i de t he n or mal ra n ge a n d dee me d cli nicall y si g nifica nt.
6. 7. Ulcer Assess me nts
Tar get ulcer(s) assess me nts will be perf or me d b y vis ual i ns pecti o n a n d meas ure me nt of t he 
s urface area by di gital p h ot o gra p h y a n d will be c o m plete d at e ver y visit d uri n g t he st u d y as
detaile d i n t he S O A ( A p pe n di x 1 ). T he site will meas ure tar get ulcers usi n g di gital 
p h ot o gra p hs. T he di gital p h ot o gra p hs ta ke n b y t he site will be se n t t o a ce ntral e xter nal 
re vie wer f or re vie w a n d t o deter mi ne meas ure me nts. T he meas ure me nts pr o vi de d b y t he 
ce ntral e xter nal re vie wer ( n ot t he site) will be use d t o i nf or m eli gi bilit y  of partici pa nts, a n d 
assess me nt of i nitial re-e pit helializati o n at t he W ee k 1 2 visit. In a d diti o n, t he meas ure me nts 
pr o vi de d b y ce ntral e xter nal re vie wer will be use d f or assessi n g st u d y efficac y  e n d p oi nts.
F urt her details o n t hese meas ure me nts will be pr o vi de d i n t he Le g Ulcer Assess me nt a n d 
Meas ure me nt Ma n ual.
6. 8. A d verse E ve nt s a n d C o nc o mit a nt Me dic ati o ns
A d verse e ve nts a n d c o nc o mita nt me dicati o ns will be rec or de d at e ver y  visit d uri n g t he st u d y, 
as detaile d i n t he S O A ( A p pe n di x 1 ). See Secti o n 7. 2 f or details re gar di n g A E re p orti n g 
peri o d f or t his st u d y . 
6. 9. Hei g ht a n d Wei g ht
Hei g ht will be c ollecte d at t he Scree ni n g visit o nl y a n d wei g ht will be c ollecte d at Scree ni n g 
a n d Wee k 1 2 (A p pe n di x 1 ).
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 4 5
6. 1 0. L a b or at or y Assess me nts
All la b orat or y  assess me nts will be perf or me d t hr o u g h a ce ntral la b orat or y. He mat ol o g y a n d 
ser u m c he mistr y will be c ollecte d at t he Scree ni n g visit, Baseli ne ( Da y 1), Wee k 1 2, Wee k 
2 4, a n d E O S/ Earl y Ter mi nati o n. Ser u m pre g na nc y test will be perf or me d at t he Scree ni n g 
visit, a n d a uri ne pre g n a nc y test will be perf or me d at Baseli ne ( Da y 1), Wee k 6, Wee k 1 2, 
Wee k 1 8, a n d Wee k
2 4 i n fe male partici pa nts w h o ha ve e x perie nce d me narc he (see Secti o n 
6. 1 0. 3 f or m ore i nf or mati o n o n pre g na nc y testi n g). F or partici pa nts w h o c o nti n ue t o recei ve 
v o xel ot or be y o n d 1 2 wee ks i n t he O pe n -la bel Treat me nt Peri o d (see Secti o n 5. 1 ), 
he mat ol o g y  a n d ser u m c he mistr y assess me nts will be c o n d ucte d e ver y 1 2 wee ks, a n d uri ne 
pre g na nc y  testi n g will be c o n d ucte d e ver y 2 4 wee ks. Refer t o t he S O A ( A p pe n di x 1 ) f or t he 
a d diti o nal details of la b orat or y tests.
It is t he res p o nsi bilit y of t he In vesti gat or or desi g nee t o assess t he cli nical si g nifica nc e of all 
a b n or mal cli nical la b orat or y  val ues, as defi ne d b y t he a p plica ble list of n or mal val ues o n file 
(ie, l ocal or ce ntral la b orat or y). 
F or t he p ur p ose of t his st u d y , a cli nically 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 ju 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. All cli nicall y si g nifica nt la b orat or y 
val ue a b n or malities are t o be rec or de d as A Es.
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 Es 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; it is preferre d f or t he a nal y ses t o be c o n d ucte d by t he ce ntral la b orat or y  
u nless me dical nee d necessitates ur ge nt res ults re p orti n g. Re peat la b orat or y testi n g of 
a b nor mal p ote ntiall y  cli nicall y si g nifica nt or cli nicall y si g nifica nt res ults f or t he scree ni n g 
e val uati o n of t he partici pa nt ma y be re peate d at t he discreti o n of t he I n vesti gat or.
Bl o o d s peci me ns c ollecte d at t he Da y  1 visit a n d Wee k 1 2 visit a n d f o u n d t o be i na de q uate 
f or la b orat or y testi n g s h o ul d be re dra w n a n d s u b mitte d f or la b orat or y testi n g wit hi n 7 da ys of 
t he st u d y visit.
T ot al Bl o o d V ol u me 
O n st u d y  bl o o d v ol u me c ollecti o ns f or partici pa nts < 1 8 years ol d will n ot e xcee d 1 % t otal 
bl o o d v ol u me ( 0. 8 m L /k g base d o n 8 0 m L / k g bl o o d v ol u me i n a n y gi ve n 2 4-h peri o d a n d 3 % 
t otal bl o o d v ol u me ( 2. 4 m L/ k g base d o n 8 0 m L/ k g bl o o d v ol u me) i n a ny gi ve n 4 -wee k 
peri o d. S pecific bl o o d s peci me ns ma y  be o mitte d at t he discreti o n of t he I n vesti gat or if 
warra nte d s uc h as i n t he c o nte xt of bl o o d l oss ass ociate d wit h sta n dar d cli nical care, blee di n g 
e ve nts, or if ot her wise dee me d a p pr o priate. See Ta ble 5 f or bl o o d s peci men assess me nt 
pri orit y  list. 
D ue t o v ol u me restricti o ns i n pe diatric researc h, assess me nts will be pri oritize d i n t he 
f oll o wi n g or der:
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 4 6
T a ble 5 : 
Bl o o d S peci me n Assess me nt Pri orit y List
Pri orit y
Test
1
He m at ol o g y
2
C he mistr y
3
H b S S , H b S /0 t halasse mia test
6. 1 0. 1. He m at ol o g y
He mat ol o g y  assess me nts i ncl u de t he f oll o wi n g:

R B Cs

He mat ocrit

H b

Platelets

W hite bl o o d cells wit h differe ntial ( bas o p hils, e osi n o p hils, ne utr o p hils, 
m o n oc y tes, a n d l ym p h oc y tes)

% a n d a bs ol ute retic ul oc y tes

R B C distri b uti o n wi dt h 

Mea n c or p usc ular v ol u me 

Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n 

H b S S, H b S/ β 0 t halasse mia test (at Scree ni n g o nl y f or me dical dia g n osis of S C D, 
if dia g n osis is n ot d oc u me nte d i n me dical c hart)
6. 1 0. 2. Ser u m C he mistr y
C he mistr y  assess me nts i ncl u de t he f oll o wi n g:

A L T

Al b u mi n

Al kali ne p h os p hatase ( A L P)

A S T

Bicar b o nate

Bl o o d urea nitr o ge n 

C hl ori de

Calci u m

Creati ni ne

Gl uc ose

L D H

S o di u m
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 4 7

P otassi u m

Bilir u bi n (t otal, direct, a n d i n direct)
6. 1 0. 3. Pre g n a nc y Testi n g
Fe male st u d y partici pa nts w h o ha ve n ot e x perie nce d me narc he will n ot u n der g o pre g na nc y  
testi n g. S h o ul d a fe male partici pa nt e x perie nce me narc he d uri n g t he st u dy,  t he partici pa nt 
will be c o nsi dere d a fe male of c hil d -beari n g p ote ntial a n d will u n der g o uri ne pre g na nc y  
testi n g as per t he S O A (A p pe n di x 1 ).
If a uri ne pre g na nc y test is p ositi ve, t he res ult m ust be c o nfir me d per l ocal sta n dar ds at eac h 
site (e g, ultras o u n d, ser u m pre g na nc y  test). See Secti o n 1. 1 f or re p orti n g a pre g na nc y.
6. 1 1. P atie nt -Re p orte d O utc o mes
P R Os (eit her electr o nic or pa per) will be e val uate d b y t he f oll o wi n g meas u res w hic h will be 
pr o vi de d b y t he S p o ns or, w he n a vaila ble ( pe n di n g tra nslati o n a n d c ult ural vali dati o n 
re q uire me nts):

Nati o nal I nstit ute of Healt h P R O MI S- 3 7 v 2. 0 Pe diatric Pr ofile/ P R O MI S- 4 3 v 2. 1: 
Pr ofile I nstr u me nt at Wee k 0, Wee k 1 2, a n d Wee k 2 4

V A S ( pai n le vel li n ke d t o tar get ulcer[s]) at Wee k 0, Wee k 1 2, a n d Wee k 2 4

T he P GI -C assess me nt will be perf or me d usi n g a 7 -p oi nt scale t o meas ure t he 
partici pa nt’s o verall i m pr o ve me nt at Wee k 1 2 a n d Wee k 2 4.
T hese assess me nts will be self- a d mi nistere d b y st u d y partici pa nts at visits s pecifie d i n t he 
S O A ( A p pe n di x 1 ).
6. 1 2. Cli nic al Gl o b al I m pressi o n of C h a n ge
I n vesti gat or’s assess me nt of c ha n ge i n t he o verall healt h c o n diti o n of t he partici pa nt. T he 
C GI -C assess me nt will be a d mi nistere d b y t he I n vesti gat or usi n g a 7 -p oi nt scale t o meas ure 
t he partici pa nt’s o verall i m pr o ve me nt at Wee k 1 2 a n d Wee k 2 4, as s pecifie d i n t he S O A 
(A p pe n di x 1 ).
6. 1 3. 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 nall y 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 me s, 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.
7. A D V E R S E A N D S E RI O U S A D V E R S E E V E N T S
Safet y  assess me nts will c o nsist of rec or di n g all A Es a n d S A Es, pr ot oc ol -s pecifie d 
he mat ol o g y  a n d cli nical c he mistr y varia bles, cli nical e xa mi nati o n fi n di n gs, meas ure me nt of 
pr ot oc ol -s pecifie d vital si g ns, a n d t he res ults fr o m ot her pr ot oc ol-s pecifie d tests t hat are 
dee me d critical t o t he safet y e val uati o n of v o xel ot or.
T he deter mi nati o n, e val uati o n, re p orti n g, a n d f oll o w- u p of A Es will be perf or me d, as 
o utli ne d i n Secti o n 7. 1 . At eac h visit, t he st u d y partici pa nt or partici pa nt care gi ver will be 
as ke d a b o ut a n y ne w or o n g oi n g A E si nce t he pre vi o us visit. Assess me nts of A Es will occ ur 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 4 8
at eac h st u d y visit. See Secti o n 7. 2 f or details re gar di n g t he re q uire d ti me peri o ds f or A E 
re p orti n g.
Cli nicall y  si g nifica nt c ha n ges fr o m st u d y baseli ne i n P E fi n di n gs, wei g ht, vital si g ns, a n d 
cli nical la b orat or y para meters will be rec or de d as A Es or S A Es, as a p pr o priate.
7. 1. A d verse E ve nts
7. 1. 1. Defi niti o n of A d verse E ve nts
A n A E is defi ne d as a n y u nt o war d me dical occ urre nce ass ociate d wit h t he use of a dr u g i n 
h u ma ns, w het her or n ot c o nsi dere d dr u g relate d. 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. A n A E ma y  als o 
c o nstit ute c o m plicati o ns occ urri n g as a res ult of pr ot oc ol -ma n date d i nter ve nti o ns (e g, 
i n vasi ve pr oce d ures s uc h as bi o psies) or S O C pr oce d ures (e g, s ur gical de bri de me nt of ulcer), 
i ncl u di n g t he peri o d pri or t o recei vi n g t he first d ose of t he st u dy dr u g (e g, me dicati o n was h 
o ut). 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 xisti 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 is c o nsi dere d a n A E. T his i ncl u des 
a n y si de effect, i nj ur y, t o xicit y, or se nsiti vit y reacti o n.
A s us pecte d a d verse reacti o n is a n y  A E f or w hic h t here is a reas o na ble p ossi bilit y t hat t he 
dr u g ca use d t he A E. F or t he p ur p oses of e x pe dite d safet y re p orti n g, “ Reas o na ble p ossi bilit y ” 
mea ns t here is e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n t he dr u g a n d t he A E. 
S us pecte d a d verse reacti o n i m plies a lesser de gree of certai nty a b o ut ca usalit y  t ha n a d verse 
reacti o n, w hic h mea ns a n y A E ca use d by a dr u g.
Life -t hreate ni n g A E or life-t hreate ni n g s us pecte d a d verse reacti o n is a n A E or s us pecte d 
a d verse reacti o n t hat, i n t he vie w of eit her t he I n ves ti gat or or Pfizer, places t he st u d y 
partici pa nt at i m me diate ris k of deat h. It d oes n ot i ncl u de a n A E or s us pecte d a d verse 
reacti o n t hat, ha d it occ urre d i n a m ore se vere f or m, mi g ht ha ve ca use d deat h.
A n A E or s us pecte d a d verse reacti o n is c o nsi dere d “ u ne x pecte d” if it is n ot liste d i n t he 
Refere nce Safet y I nf or mati o n ( R SI) secti o n of t he c urre nt I B or is n ot liste d at t he s pecificity 
or se verit y t hat has bee n o bser ve d.
A n S A E or seri o us s us pecte d a d verse reacti o n is a n A E or s us pecte d a d verse reacti o n t ha t at 
a n y d ose, i n t he vie w of t he eit her t he I n vesti gat or or Pfizer, 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 E

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 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 4 9

Persiste nt or si g nifica nt i nca pacit y  or disa bilit y (s u bsta ntial disr u pti o n of t he 
a bilit y t o c o n d uct n or mal life f u ncti o ns)

A c o n ge nital a n o mal y/ 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 i m me diatel y life
t hreate ni n g, or re q uire h os pitalizati o n ma y be c o nsi dere d seri o us w he n base d 
u p o n me dical j u d g me nt, t he y  m a y je o par dize t he st u d y 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 o ne of t he o utc o mes liste d i n 
t his defi niti o n
N O T E: H os pitalizati o n pla n ne d pri or t o st u d y e nr oll me nt (e g, f or electi ve s ur g eries) are n ot 
c o nsi dere d S A Es. H os pitalizati o ns t hat occ ur f or pre- e xisti n g c o n diti o ns t hat are sc he d ule d 
after st u d y e nr oll me nt are c o nsi dere d S A Es.
T he I n vesti gat or will assess eac h A E f or seri o us ness, se verit y, a n d relati o ns hi p t o 
i n vesti gati o nal pr o d uct.
7. 1. 2. Se verit y of A d verse E ve nts
W he ne ver p ossi ble, t he se verit y of all A Es will be gra de d usi n g t he 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 ( N CI C T C A E), Versi o n 5. 0.
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 Ver si o n 5. 0, t he f oll o wi n g criteria 
s h o ul d be use d ( Ta ble 6 ).
T a ble 6:
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 n -i 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 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 pitali zati 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 
T er m i n ol o g y Criteria f or A d verse E ve nts.
T o ma ke s ure t here is n o c o nf usi o n or mis u n dersta n di n g bet wee n t he ter ms “seri o us” a n d 
“se vere,” w hic h are n ot s y n o n y m o us, t he f oll o wi n g n ote of clarificati o n is pr o vi de d. T he 
ter m “se vere” is ofte n use d t o descri be t he i nte nsit y  (se verity) of a s pecific e ve nt (ie, mil d, 
m o derate, or se vere); t he e ve nt itself, h o we ver, ma y be of relati vel y  mi n or me dical 
si g nifica nce (e g, se vere hea dac he). T his is n ot t he sa me as “seri o us” w hic h is base d o n t he 
st u d y partici pa nt/e ve nt o utc o me or acti o n criteria ass ociate d wit h e ve nts t hat p ost a t hreat t o a 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 5 0
partici pa nt’s life or f u ncti o ni n g. Seri o us ness ( n ot se verit y) ser ves as a g ui de f or defi ni n g 
re g ulat or y re p orti n g o bli gati o ns.
7. 1. 3. Rel ati o ns hi p t o I n v esti 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 n vesti gati o nal pr o d uct s h o ul d be deter mi ne d b y  t he 
I n vesti gat or acc or di n g t o t he f oll o wi n g defi niti o ns:

N O T R E L A T E 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 a n d/ or t he te m p oral relati o ns hi p of t he A E/ S A E t o t he i n vesti gati o nal 
pr o d uct a d mi nistrati o n ma kes t he relati o ns hi p u nli kel y . If a n S A E is n ot 
c o nsi dere d relate d t o st u d y  dr u g, 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.

R E L A T E D: A te m p oral relati o ns hi p e xist s bet wee n t he e ve nt o nset a n d t he 
a d mi nistrati o n of t he st u d y dr u g ma kes a ca usal relati o ns hi p p ossi ble or pr o ba ble. 
It ca n n ot be rea dil y e x plai ne d b y t he partici pa nt’s cli nical state or c o nc o mita nt 
t hera pies a n d ma y a p pear, 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. G o o d cli nical 
j u d g me nt s h o ul d be use d f or deter mi ni n g ca usal assess me nt.
7. 1. 4. U ne x pecte d A d verse Re acti o ns
A n A E is “ u ne x pecte d” if its nat ure a n d se verit y are n ot c o nsiste nt wi t h t he i nf or mati o n 
a b o ut t he st u d y dr u g pr o vi de d i n t he R SI i n t he v o xel ot or IB.
7. 2. A d verse E ve nt Re p orti n g
7. 2. 1. Ge ner al
All A Es/ S A Es will be rec or de d fr o m t he ti me t he st u d y partici pa nt si g ns t he IC F/asse nt u ntil 
2 8 da y s after last d ose of st u d y dr u g ( E O S/ Early Ter mi nati o n). All A Es/ S A Es m ust be 
rec or de d o n t he A E e C R F via t he electr o nic data ca pt ure ( E D C) sys te m. T he I n vesti gat or is 
res p o nsi ble f or e val uati n g all A Es/ S A Es, o btai ni n g s u p p orti n g d oc u me nts, a n d e ns uri n g 
d oc u me ntati o n of t he e ve nt is c o m plete. Detai ls of eac h re p orte d A E m ust i ncl u de, at 
mi ni m u m, se verit y , relati o ns hi p t o st u d y treat me nt, d urati o n, a n d o utc o me. All A Es ( b ot h 
seri o us a n d n o nseri o us) 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 oluti o n of t he e ve nt are e x ha uste d.
A n y  partici pa nt w h o e x perie nces a n A E/ S A E ma y be disc o nti n ue d fr o m st u d y treat me nt at 
a n y ti me, at t he discreti o n of t he I n vesti gat or. T he S p o ns or a n d t he c o ntract researc h 
or ga nizati o n ( C R O)’s Me dical M o nit or m ust be n oti fie d of t he st u d y partici pa nt 
disc o nti n uati o n.
W he n a cli nicall y  i m p orta nt A E re mai ns o n g oi n g at t he e n d of t he acti ve c ollecti o n peri o d, 
f oll o w-u p b y  t he i n vesti gat or c o nti n ues u ntil t he A E or S A E or its se q uelae res ol ve or 
sta bilize at a le vel acce pta ble t o t he i n vesti gat or a n d Pfizer c o nc urs wit h t hat assess me nt.
F or partici pa nts w h o are scree n fail ures, t he acti ve c ollecti o n peri o d e n ds w he n scree n fail ure 
stat us is deter mi ne d.
If t he partici pa nt wit h dra ws fr o m t he st u d y a n d als o wit h dra ws c o nse nt f or the c ollecti o n of 
f ut ure i nf or mati o n, t he acti ve c ollecti o n peri o d e n ds w he n c o nse nt is wit h dra w n.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 5 1
If a partici pa nt per ma ne ntl y disc o nti n ues or te m p orarily disc o nti n ues st u d y dr u g beca use of 
a n A E or S A E, t he A E or S A E m ust be rec or de d o n t he e C R F a n d t he S A E re p orte d t o Pfizer 
Safet y  via Pfizer’s Seri o us A d verse E ve nt S u b missi o n Assista nt (P S S A ).
I n vesti gat ors are n ot o bli gate d t o acti vely see k i nf or mati o n o n A Es or S A Es after t he 
partici pa nt has c o ncl u de d st u d y  partici pati o n. H o we ver, if t he i n vesti gat or lear ns of a n y S A E, 
i ncl u di n g a deat h, at a ny ti me after a partici pa nt has c o m plete d t he st u dy, a n d t he y c o nsi der 
t he e ve nt t o be reas o na bl y relate d t o st u dy dr u g , t he i n vesti gat or m ust pr o m ptl y re p ort t he 
S A E t o t he S p o ns or via P S S A .
7. 2. 2. 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 i n t he e C R F rat her t ha n i n di vi d ual si g ns a n d 
s ym pt o ms (e g, rec or d o nl y  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/ o r sy 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 sy 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 se parately i 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 ma ti o n.
7. 2. 3. 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 will be rec or de d o n 
t he A E e C R F (e g, a b n or malities t hat ha ve cli nical se q uelae, re q uire st u dy 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). If t he cli nicall y si g nifica nt la b orat or y a b n or malit y is a si g n 
of a disease or s y n dr o me (e g, A L P 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 i 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 i 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. 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 “ h y per 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 recor de d o n t he A E 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.
N ote: P ote ntial dr u g- i n d uce d li ver i nj ur y ( DI LI; H y’s la w) cases are t o be re p orte d as S A Es 
(Secti o n 7. 3 ). F or s u g geste d acti o ns a n d f oll o w-u p assess me nts i n t he e ve nt of p ote ntial 
DI LI, refer t o A p pe n di x 2 .
7. 2. 4. Pre -e xisti n g Me dic al C o n diti o ns
A pre -e xisti n g me dical c o n diti o n is o ne t hat is prese nt at t he start of t he st u d y . S uc h 
c o n diti o ns s h o ul d be rec or de d o n t he Me dical Hist or y  a n d Baseli ne C o n diti o ns e C R F.
If a pre-e xisti n g me dical c o n diti o n i ncreases i n fre q ue nc y  or se verity, or if t he c haracter 
of t he c o n diti o n w orse ns d uri n g t he st u dy, t he c o n diti o n s h o ul d be rec or de d as a n A E or 
S A E. W he n rec or di n g s uc h e ve nts o n t he A E e C R F, it is i m p orta nt t o c o n ve y  t he c o nce pt t hat 
t he pre-e xisti n g co n diti o n has c ha n ge d b y  i ncl u di n g a p plica ble descri pt ors (e g, “m ore 
fre q ue nt hea dac hes”).
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 5 2
7. 2. 5. W orse ni n g of Sic kle Cell Dise ase
S C D -relate d A Es t hat are c o m m o n c o m plicati o ns ass ociate d wit h t he st u dy partici pa nt’s 
S C D ma y  n ot be c o nsi dere d relate d t o v o xel ot or u nless j u d ge d b y t he I n vesti gat or t o ha ve 
w orse ne d i n se verit y a n d/ or fre q ue nc y or c ha n ge d i n nat ure d uri n g t he st u d y. S C D -relate d 
A Es i ncl u de: S C D wit h vas o- occl usi ve pai n crisis, ac ute c hest s y n dr o me, p ne u m o nia, 
pria pis m, s ple nic or he patic se q uestrati o n s, str o ke, a n d oste o necr osis (Kat o, 2 0 1 8 ). 
7. 3. Seri o us A d verse E ve nts, Seri o us A d verse Dr u g Re acti o ns, a n d Re q uire me nts f or 
I m me di ate Re p orti n g
All S A Es, re gar dless of ca usal attri b uti o n, m ust be re p orte d by t he I n vesti gat or/ desi g nee or 
site pers o n nel wit hi n 2 4 h o urs of S A E a ware ness o n t he A E e C R F a n d re p orte d t o Safet y via 
P S S A. I n t he e ve nt P S S A is n ot a vaila ble, pa per C T S A E Re p ort F or ms will be use d t o re p ort 
t he S A E a n d fa xe d or e maile d t o Pfizer Safet y. T he i nf or mati o n re p orte d o n t he pa per S A E 
re p ort f or m s h o ul d be e ntere d i nt o P S S A o nce a vaila ble.
T he S p o ns or ma y  re q uest a d diti o nal i nf or mati 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. F oll o w-u p re p orts m ust be s u b mitte d wit hi n 2 4 h o urs of a ware ness as 
a d diti o nal i nf or mati o n bec o mes a vaila ble.
All S A Es re gar dless of ca usal attri b uti o n m ust be f oll o we d t o res ol uti o n, sta bilizati o n, or 
u ntil reas o na ble atte m pts t o deter mi ne res ol uti o n of t he S A E are perf or me d.
7. 3. 1. Re p orti n g S us pecte d U ne x pecte d Seri o us A d verse Re acti o ns a n d Ur ge nt S afet y 
Iss ues
T he S p o ns or is res p o nsi ble f or re p orti n g s us pecte d u ne x pecte d seri o us a d verse reacti o ns 
( S U S A Rs) t o re g ulat or y a ge ncies, c o m pete nt a ut h orities, IE Cs, a n d I n vesti gat ors as per l ocal 
la ws a n d re g ulati o ns. Fatal a n d life-t hreate ni n g S U S A Rs will be s u b mitte d n o later t ha n 
7 cale n dar da ys of t he S p o ns or’s first k n o wle d ge of t he e ve nt a n d f oll o w-u p i nf or mati o n 
s u b mitte d wit hi n a n a d diti o nal 8 cale n dar da ys, or as ot her wise re q uire d per l ocal la ws a n d 
re g ulati o ns. All ot her S U S A Rs will be s u b mitte d wit hi n 1 5 cale n dar da ys of t he S p o ns or’s 
first k n o wle d ge of t he e ve nt. T he I n vesti gat or is res p o nsi ble f or n otif y i n g t he l ocal I E Cs of 
all S A Es t hat occ ur at his/ her site as re q uire d b y l ocal re g ulati o ns or I E C policies, if t his 
res p o nsi bilit y resi des wit h t he site.
I n vesti gat ors are re q uire d t o re p ort a ny ur ge nt safet y matters t o t he S p o ns or wit hi n 2 4 h o urs 
of a ware ness. T he S p o ns or will i nf or m re g ulat or y  a ut h orities, I E Cs, a n d I n vesti gat ors, as 
a p plica ble, of a n y e ve nts (e g, c ha n ge t o t he safet y pr ofile of v o xel ot or, maj or safet y fi n di n gs 
t hat ma y place st u d y partici pa nts at ris k) t hat ma y occ ur d uri n g t he cli nical trial t hat d o n ot 
fall wit hi n t he defi niti o n of a S U S A R b ut ma y a d versely affect t he safet y of st u d y 
partici pa nts.
7. 4. 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 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 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 st u d y  dr u g e x p os ure wit h t he 
partici pa nt. Pare nts, g uar dia ns, or partici pa nts are t o be i nstr ucte d t o c o ntact t heir st u d y  site 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 5 3
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 A Es m ust be 
f oll o we d u ntil t he 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.
I n t he e ve nt of a n o ver d ose, t he I n vesti gat or or treati n g p h ysicia n s h o ul d:

C o ntact t he st u d y  Me dical M o nit or wit hi n 2 4 h o urs.

Cl osel y  m o nit or t he partici pa nt f or a ny A Es/ S A Es a n d la b orat or y  a b n or malities as 
me dicall y  a p pr o priate a n d f oll o w u p u ntil res ol uti o n, sta bilizati o n, t he e ve nt is 
ot her wise e x pl ai ne d, or t he partici pa nt is l ost t o f oll o w - u p. 

D oc u me nt t he q ua ntit y of t he e xcess d ose as well as t he d urati o n of t he o ver d ose 
i n t he e C R F.

O ver d ose is re p orta ble t o Pfizer Safet y  o nl y w he n ass oci ate d wit h a n S A E.
7. 5. E n vir o n me nt al E x p os ure, E x p os ure D uri n g Pre g n a nc y or Bre astfee di n g, a n d 
Occ u p ati o n al E x p os ure
E n vir o n me ntal e x p os ure occ urs w he n a pers o n n ot e nr olle d i n t he st u d y as a partici pa nt 
recei ves u n pla n ne d direct c o ntact wit h or e x p os ure t o v o xel ot or. S uc h e x p os ure ma y or ma y 
n ot lea d t o t he occ urre n ce of a n A E or S A E. Pers o ns at ris k f or e n vir o n me ntal e x p os ure 
i ncl u de healt hcare pr o vi ders, fa mily me m bers, a n d ot hers w h o ma y  be e x p ose d. A n 
e n vir o n me ntal e x p os ure ma y  i ncl u de e x p os ure d uri n g pre g na nc y ( E D P), e x p os ure d uri n g 
breastfee di n g ( E D B), a n d occ u pati o nal e x p os ure.
A n y  s uc h e x p os ures t o v o xel ot or u n der st u d y are re p orta ble t o t he S p o ns or or desi g nee 
wit hi n 2 4 h o urs of I n vesti gat or a ware ness.
7. 5. 1. E x p os ure D uri n g Pre g n a nc y
A n E D P occ urs if:

A fe male partici pa nt is f o u n d t o be pre g na nt w hile recei vi n g or after disc o nti n ui n g 
v o xel ot or.

A male partici pa nt w h o is recei vi n g or has disc o nti n ue d v o xel ot or i nse mi nates a 
fe male part ner.

A fe male n o n partici pa nt is f o u n d t o be pre g na nt w hile bei n g e x p ose d or ha vi n g 
bee n e x p ose d t o v o xel ot or beca use of e n vir o n me ntal e x p os ure. Bel o w is a n 
e xa m ple of e n vir o n me ntal E D P:

A fe male fa mil y  me m ber of healt hcare pr o vi der re p orts t hat s he is pre g na nt 
after ha vi n g bee n e x p ose d t o v o xel ot or b y  all p ossi ble r o utes of e x p os ure, e g, 
i n gesti o n, i n halati o n, or s ki n c o ntact.

A male fa m il y me m ber or healt hcare pr o vi der w h o has bee n e x p ose d t o 
v o xel ot or b y  all p ossi ble r o utes of e x p os ure, e g, i n gesti o n, i n halati o n, or s ki n 
c o ntact, t he n i nse mi nates his fe male part ner pri or t o or ar o u n d t he ti me of 
c o nce pti o n.
T he I n vesti gat or m ust re p ort E D P t o t he S p o ns or or desi g nee wit hi n 2 4 h o urs of t he 
I n vesti gat or’s a ware ness, irres pecti ve of w het her a n S A E has occ urre d. T he i nitial 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 5 4
i nf or mati o n s u b mitte d s h o ul d i ncl u de t he a ntici pate d date of deli ver y (see bel o w of 
i nf or mati o n relate d t o ter mi nati o n of pre g na nc y ). 

If E D P occ urs i n a partici pa nt/ partici pa nt’s part ner, t he In vesti gat or m ust re p ort 
t his i nf or mati o n t o Pfizer Safet y usi n g P S S A re gar dless of w het her a n S A E has 
occ urre d. Details of t he pre g na nc y  will be c ollecte d after t he start of v o xel ot or 
a n d u ntil at least 1 4 0 da ys after t he last d ose.

If E D P occ urs i n t he setti n g of e n vir o n me ntal e x p os ure, t he I n vesti gat or m ust 
re p ort i nf or mati o n t o Pfizer Safety usi n g P S S A . Si nce t he e x p os ure i nf or mati o n 
d oes n ot pertai n t o t he partici pa nt e nr o lle d i n t he st u d y, t he i nf or mati o n is n ot 
rec or de d o n a C R F; h o we ver, a c o py of t he c o m plete d re p ort is mai ntai ne d i n t he 
I n vesti gat or site file.
F oll o w -u p is c o n d ucte d t o o btai n ge neral i nf or mati o n o n t he pre g na nc y  a n d its o utc o me f or 
all E D P re p orts wit h a n u n k n o w n o utc o me. T he I n vesti gat or will f oll o w t he pre g na nc y  u ntil 
c o m pleti o n ( or u ntil pre g na nc y  ter mi nati o n) a n d n otif y Pfizer Safety of t he o utc o me as a 
f oll o w-u p t o t he i nitial re p ort. I n t he case of a li ve birt h, t he str uct ural i nte grit y  of t he ne onate 
ca n be assesse d at t he ti me of birt h. 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 will be f oll o we d f or 3 m o nt hs after deli ver y . I n t he 
e ve nt of a ter mi nati o n, t he reas o n(s) f or ter mi nati o n s h o ul d be s p ecifie d a n d, if cli nicall y 
p ossi ble, t he str uct ural i nte grit y of t he ter mi nate d fet us s h o ul d be assesse d b y gr oss vis ual 
i ns pecti o n ( u nless pre-pr oce d ure test fi n di n gs are c o ncl usi ve f or a c o n ge nital a n o mal y a n d 
t he fi n di n gs are re p orte d).
A b n or mal pre g na n c y o utc o mes are c o nsi dere d S A Es. If t he o utc o me of t he pre g na nc y meets 
t he criteria f or a n S A E (ie, ect o pic pre g na nc y, s p o nta ne o us a b orti o n, i ntra uteri ne fetal 
de mise, ne o natal deat h, or c o n ge nital a n o mal y i n a li ve -b or n ba b y, a ter mi nate d fet us, a n 
i ntra uteri ne fetal de mise, or a ne o natal deat h), t he I n vesti gat or s h o ul d f oll o w t he pr oce d ures 
f or re p orti n g S A Es. A d diti o nal i nf or mati o n a b o ut pre g na nc y o utc o mes t hat are re p orte d t o 
t he S p o ns or or desi g nee as S A Es f oll o ws:

S p o nta ne o us a b orti o n i ncl u di n g miscar ria ge a n d misse d a b orti o n s h o ul d be 
re p orte d as a n S A E;

Ne o natal deat hs t hat occ ur wit hi n 1 m o nt h of birt h s h o ul d be re p orte d, wit h o ut 
re gar d t o ca usality, as S A Es. I n a d diti o n, i nfa nt deat hs after 1 m o nt h s h o ul d be 
re p orte d as S A Es w he n t he I n vesti gat or assesses t he i nfa nt deat h as relate d or 
p ossi bl y  relate d t o e x p os ure t o v o xel ot or.
A d diti o nal i nf or mati o n re gar di n g t he E D P ma y  be re q ueste d b y t he S p o ns or. F urt her f oll o w-
u p of birt h o utc o mes will be ha n dle d o n a case -b y -case basis (e g, f oll o w-u p o n preter m 
i nfa nts t o i de ntif y de vel o p me ntal dela ys). I n t he case of pater nal e x p os ure, t he In vesti gat or 
will pr o vi de t he partici pa nt wit h t he Pare ntal Part ner: I nf or mati o n S heet a n d I nf or me d 
C o nse nt F or m t o deli ver t o his part ner. T he I n vesti gat or m ust d oc u me nt i n t he s o urce 
d oc u me nts t hat t he partici pa nt was gi ve n t he Pre g na nt Part ner Release of I nf or mati o n F or m 
t o pr o vi de t o his part ner. 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 5 5
7. 5. 2. E x p os ure D uri n g Bre astfee di n g
A n E D B occ urs if:

A fe male partici pa nt is f o u n d t o be breastfee di n g w hile recei vi n g or after 
dis c o nti n ui n g v o xel ot or.

A fe male n o n partici pa nt is f o u n d t o be breastfee di n g w hile e x p ose d or ha vi n g 
bee n e x p ose d t o v o xel ot or (ie, e n vir o n me ntal e x p os ure). A n e xa m ple of 
e n vir o n me ntal E D B is a fe male fa mil y me m ber or healt hcare pr o vi der w h o 
re p orts t hat s he is breastfee di n g after ha vi n g bee n e x p ose d t o v o xel ot or b y all 
p ossi ble r o utes of e x p os ure, e g, i n gesti o n, i n halati o n, or s ki n c o ntact.
T he I n vesti gat or m ust re p ort E D B t o Pfizer Safet y wit hi n 2 4 h o urs of t he I n vesti gat or’s 
a ware ness, irres pecti ve of w het her a n S A E has occ urre d. T he i nf or mati o n m ust be re p orte d 
usi n g t he P S S A. W he n E D B occ urs i n t he setti n g of e n vir o n me ntal e x p os ure, t he e x p os ure 
i nf or mati o n d oes n ot pertai n t o t he partici pa nt e nr olle d i n t he st u d y, s o t he i nf or mati o n is n ot 
rec or de d o n a C R F. H o we ver, a c o p y  of t he c o m plete d re p ort is mai ntai ne d i n t he 
I n vesti gat or site file.
7. 5. 3. Occ u p ati o n al E x p os ure
T he I n vesti gat or m ust re p ort a n y i nsta nce of occ u pati o nal e x p os ure t o Pfizer Safet y wit hi n 2 4 
h o urs of t he I n vesti gat or’s a ware ness via P S S A re g ar dless of w het her t here is a n ass ociate d 
S A E. Si nce t he i nf or mati o n a b o ut t he occ u pati o nal e x p os ure d oes n ot pertai n t o a partici pa nt 
e nr olle d i n t he st u d y, t he i nf or mati o n is n ot rec or de d o n a C R F; h o we ver, a c o p y  of t he 
c o m plete d re p ort is mai ntai ne d i n t he I n vesti gat or site file.
7. 6. L ac k Of Effic ac y 
T he i n vesti gat or m ust re p ort si g ns, s y m pt o ms, a n d/ or cli nical se q uelae res ulti n g fr o m lac k of 
efficac y.  Lac k of efficac y or fail ure of e x pecte d p har mac ol o gical acti o n is re p orta ble t o Pfizer 
Safet y  o nl y if ass oci ate d wit h a n S A E.
7. 7. Me dic ati o n Err ors
Me dicati o n err ors ma y  res ult fr o m t he a d mi nistrati o n or c o ns u m pti o n of v o xel ot or b y t he 
wr o n g partici pa nt, or at t he wr o n g ti me, or at t he wr o n g d osa ge stre n gt h.
Me dicati o n err ors are rec or de d a n d re p orte d as f oll o ws:
T a ble 7:
Re p orti n g of Me dic ati o n Err ors
Rec or de d o n t he Me dic ati o n 
P a ge of t he C R F
Rec or de d o n t he A d verse 
E ve nt P a ge of t he C R F
Re p orte d vi a P S S A t o Pfizer 
S afet y Wit hi n 2 4 H o urs of 
A w are ness
All (re gar dless of w het her 
ass ociate d wit h a n A E)
A n y A E or S A E ass ociate d wit h 
t he me dicati o n err or
O nl y if ass ociate d wit h a n S A E
Me dicati o n err ors i ncl u de:

Me dicati o n err ors i n v ol vi n g partici pa nt e x p os ure t o t he st u d y  dr u g
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 5 6

P ote ntial me dicati o n err ors or uses o utsi de of w hat is f oresee n i n t he pr ot oc ol t hat d o or 
d o n ot i n v ol ve t he st u d y  partici pa nt;

T he a d mi nistrati o n of a n i nc orrect d osa ge;

T he a d mi nistrati o n of e x pire d st u d y  dr u g;

T he a d mi nistrati o n of a n i nc orrect st u d y  dr u g;

T he a d mi nistrati o n of st u d y  dr u g t hat has u n der g o ne te m perat ure e xc ursi o n fr o m 
t he s pecifie d st ora ge ra n ge u nless it is deter mi ne d b y t he S p o ns or t hat t he st u d y 
dr u g u n der q uesti o n is acce pta ble t o use.
W het her or n ot t he me dicati o n err or is acc o m pa ni e d b y a n A E, as deter mi ne d b y t he 
I n vesti gat or, s uc h me dicati o n err ors occ urri n g t o a st u d y partici pa nt are rec or de d o n t he 
me dicati o n err or pa ge of t he C R F, w hic h is a s pecific versi o n of t he A E pa ge a n d, if 
a p plica ble, a n y ass ociate d seri o us a n d n o nseri o us A E(s) are rec or de d o n t he A E pa ge of t he 
C R F.
I n t he e ve nt of a me dicati o n d osi n g err or, t he S p o ns or or desi g nee s h o ul d be n otifie d wit hi n 
2 4 h o urs.
Me dicati o n err ors s h o ul d be re p orte d t o Pfizer Safet y wit hi n 2 4 h o urs usi n g P S S A o nl y w he n 
ass oci ate d wi t h a n S A E.
8. 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
T he pri mar y  st u d y a nal ysis will be base d o n c o m plete data fr o m t he 1 2-wee k treat me nt 
peri o d of t he st u d y, a n d will be perf or me d at t he earliest after all partici pa nts ha ve c o m plete d 
t he 1 2-wee k treat me nt peri o d or disc o nti n ue d earl y, a n d all c orres p o n di n g data ha ve bee n 
e ntere d i nt o t he data base, re vie we d, a n d verifie d. 
T he fi nal st u d y  a nalys is will be base d o n data fr o m t he c o m plete st u d y (i ncl u di n g t he O pe n-
la bel Treat me nt Peri o d a n d 4-wee k F oll o w -u p Peri o d) , a n d will be perf or me d after all 
partici pa nts ha ve c o m plete d t he st u d y  or disc o nti n ue d early a n d all data fr o m t he st u d y are i n 
t he data base a n d t he data base is l oc ke d.
8. 1. A n al ysis P o p ul ati o ns
T w o mai n a nal ys is p o p ulati o ns are defi ne d f or t his st u d y: t he i nte nt-t o-treat (I T T) p o p ulati o n 
a n d t he safet y-e val ua ble p o p ulati o n.
T he I T T p o p ulati o n i ncl u des all ra n d o mize d partici pa nts. F or a nal y ses base d o n t his 
p o p ulati o n, partici pa nts will be gr o u pe d acc or di n g t o t he treat me nt assi g ne d at 
ra n d o mizati o n. T his is t he pri mar y a nalys is p o p ulati o n f or efficac y, de m o gra p hics, a n d 
baseli ne c haracteristics data.
T he safet y- e val ua ble p o p ulati o n i ncl u des all partici pa nts w h o recei ve at least 1 d ose of st u d y 
dr u g. F or a nal ys es base d o n t his p o p ulati o n, partici pa nts will be gr o u pe d acc or di n g t o t he 
act ual st u d y treat me nt recei ve d. T his is t he pri mar y a nal ysis p o p ulati o n f or safety a n d 
e x p os ure data.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 5 7
8. 2. S u m m ar y of St u d y C o n d uct
T he n u m ber of partici pa nts ra n d o mize d will be ta b ulate d b y  c o u ntr y, st u d y site, a n d 
treat me nt gr o u p. Partici pa nt dis p ositi o n (t he n u m ber of partici pa nts ra n d o mize d, recei vi n g at 
least 1 d ose of st u d y treat me nt , c o m pleti n g t he st u d y t hr o u g h t he 1 2-wee k bli n de d 
Ra n d o mize d Treat me nt Peri o d, c o m pleti n g t he st u d y t hr o u g h t he O pe n -la bel Treat me nt 
Peri o d a n d F oll o w- u p Visit) will be s u m marize d b y  treat me nt gr o u p. Reas o ns f or earl y 
disc o nti n uati o n fr o m st u d y  treat me nt a n d earl y disc o nti n uati o n fr o m t he st u d y will be 
s u m marize d. I mp orta nt pr ot oc ol de viati o ns will be liste d a n d e val uate d f or p ote ntial i m pact 
o n t he i nter pretati o n of st u d y  res ults.
8. 3. S u m m ar y of De m o gr a p hics, B aseli ne C h ar acteristics, a n d C o nc o mit a nt 
Me dic ati o ns
De m o gra p hic a n d baseli ne c haracteristics s uc h as a ge, se x, race, a n d baseli ne disease 
c haracteristics (i ncl u di n g n u m ber of tar get le g ulcer(s), t otal s urface area of tar get le g 
ulcer(s), a n d ma xi m u m d urati o n of tar get le g ulcer(s) will be s u m marize d f or t he I T T 
p o p ulati o n b y  treat me nt gr o u p. Baseli ne will be defi ne d as t he Da y 1 assess me nt of t he tar get 
le g ulcer(s) ( p ost 2-wee k R u n -i n Peri o d). C o nc o mita nt me dicati o ns will be c o de d usi n g t he 
W H O Dr u g Dicti o nar y  a n d s u m marize d.
8. 4. Effic ac y A n al ysis
T he site will meas ure tar get ulcers usi n g di gital p h ot o gra p hs. T he di gital p h ot o gra p hs ta ke n 
b y  t he site will be se nt t o a ce ntral e xter nal re vie wer f or re vie w a n d t o deter mi ne 
meas ure me nts. T he meas ure me nts pr o vi de d b y t he ce ntral e xter nal re vie wer ( n ot t he site) 
will be use d t o i nf or m eli gi bilit y  of partici pa nts, a n d assess me nt of i nitial re-e pit helializati o n 
at t he Wee k 1 2 visit. In a d diti o n, t he meas ure me n ts pr o vi de d b y ce ntral e xter nal re vie wer 
will be use d f or assessi n g st u d y  efficac y e n d p oi nts. 
8. 4. 1. Pri m ar y E n d p oi nt 
T he pri mar y  e n d p oi nt will be meas ure d b y t he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n 
of t he tar get ulcer(s),
 
 d uri n g t he 1 2-wee k Ra n d o mize d Treat me nt Peri o d.
T he pr o p orti o n of partici pa nts wit h res ol uti o n of tar get le g ulcer(s) b y Wee k 1 2 will be 
a nal yz e d usi n g a C oc hra n -Ma ntel -Hae nszel ( C M H) test t o c o m pare v o xel ot or + S O C wit h 
place b o + S O C gr o u ps, stratifie d b y tar get ulcer size a n d tar get ulcer d urati o n. 
 
 
. F or partici pa nts wit h m ore t ha n o ne 
tar get le g ulcer, all ulcers m ust be c o nfir me d res ol ve d i n or der f or t he partici pa nt t o be 
c o nsi dere d a res p o n der.
Partici pa nts w h o are l ost t o f oll o w -u p or ot her wise dr o p o ut of t he st u d y  wit h o ut 
c o nfir mati o n of res ol uti o n of all tar get st u d y ulcer(s) pri or t o st u d y  dr o p o ut will be classifie d 
as n o n-res p o n ders f or p ur p oses of t he pri mar y a nal ysis.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)
C CI
C CI


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 5 8
8. 4. 2. Sec o n d ar y E n d p oi nts
Ti me t o res ol uti o n of tar get ulcer(s) u p t o Wee k 1 2: a stratifie d l o g -ra n k test will be use d t o 
c o m pare t he treat me nt gr o u ps. A C o x re gressi o n m o del will be use d t o esti mate t he hazar d 
rati o bet wee n v o xel ot or + S O C a n d place b o + S O C gr o u ps, as a p pr o priate. Ti me t o res ol uti o n 
will be meas ure d (i n da ys) fr o m Da y  1 t o date of i nitial cl os ure of t he tar get ulcer. F or 
partici pa nts wit h m ore t ha n o ne tar get ulcer, ti me t o res ol uti o n will be base d o n t he ti me t o 
cl os ure of all tar get ulcers (ie, i nitial cl os ure of t he last tar get ulcer t o res ol ve).
C ha n ge fr o m baseli ne i n s u m of s urface area of tar get ulcer(s) at Wee k 1 2: a mi xe d -effect 
m o del f or re peate d meas ures will be use d t o esti mate a n d c o m pare c ha n ge fr o m baseli ne i n 
s u m of tar get ulcer(s) s urface area bet ween v o xel ot or + S O C a n d place b o + S O C gr o u ps. T he 
m o del will i ncl u de ter ms f or treat me nt gr o u p, st u d y visit, treat me nt -b y -st u d y visit i nteracti o n, 
as well as t he stratificati o n fact ors. Wit hi n- partici pa nt varia bilit y  will be m o dele d usi n g a n 
u nstr uct ure d c o v aria nce matri x. 
I nci de nce of ne w ulcers b y Wee k 1 2: t he pr o p orti o n of partici pa nts wit h ne w ulcer 
occ urre nce wit hi n 1 2 wee ks of treat me nt will be c o m pare d bet wee n treat me nt gr o u ps usi n g a 
C M H test, stratifie d b y  tar get ulcer size, a n d tar get ulcer d urati on, as a p pr o priate. 
8. 4. 3. E x pl or at or y E n d p oi nts
E x pl orat or y  e n d p oi nts will be s u m marize d b y descri pti ve statistics. Details will be pr o vi de d 
i n t he statistical a nal ysis pla n ( S A P).
8. 5. S afet y A n al ysis
Safet y  a nalys is will be perf or me d o n all partici pa nts recei vi n g at least 1 d ose of st u d y dr u g.
A d verse e ve nts will be classifie d acc or di n g t o Me dical Dicti o nar y  f or Re g ulat or y Acti vities 
( Me d D R A). T he fre q ue nc y of A Es will be ta b ulate d b y sys te m or ga n class, preferre d ter m, 
se verity, a n d relati o ns hi p t o st u d y treat me nt.
C ha n ges i n la b orat or y  para meters a n d vital si g ns will be s u m marize d descri pti vel y. 
8. 6. Deter mi n ati o n of S a m ple Size 
A p pr o xi matel y  8 0 partici pa nts will be e nr olle d i n t he st u d y. Partici pa nts will be ra n d o mize d 
i n a 1: 1 rati o t o recei ve treat me nt wit h v o xel ot or 1 5 0 0 m g or place b o f or 1 2 wee ks . T he 
pri mar y  e n d p oi nt will be meas ure d b y t he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of 
t he tar get ulcer(s), 
 
 d uri n g t he 1 2 - wee k Ra n d o mize d Treat me nt Peri o d.
 
F or t he pri mar y  e n d p oi nt, t he sa m ple size of 8 0 partici pa nts ( 4 0 partici pa nts per treat me nt 
gr o u p) pr o vi des a p pr o xi matel y  9 0 % p o wer t o detect a 3 5 % a bs ol ute differe nce bet wee n 
treat me nt gr o u ps ( v o xel ot or 1 5 0 0 m g + S O C vers us place b o + S O C) i n pr o p orti o n of 
partici pa nts e x perie nci n g res ol uti o n of t he tar get ulcer(s) b y Wee k 1 2. Calc ulati o ns were 
base d o n a t w o -si de d al p ha = 5 % test of t he differe nce i n t w o bi n o mial pr o p orti o ns ( N or mal 
a p pr o xi mati o n) a n d ass u me d 5 % dr o p o ut b y Wee k 1 2 ( P A S S versi o n 1 1).
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)
C CI
C CI


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 5 9
8. 7. Missi n g D at a H a n dli n g
Partici pa nts w h o are l ost t o f oll o w - u p or ot her wise dr o p o ut of t he st u d y  wit h o ut 
c o nfir mati o n of res ol uti o n of all tar get st u d y ulcer(s) pri or t o st u d y dr o p o ut, will be classifie d 
as n o n-res p o n ders f or p ur p oses of t he pri mar y a nal ysis.
Detaile d c o nsi derati o ns of missi n g data ha n dli n g will be descri be d i n t he S A P.
8. 8. A dj ust me nt f or M ulti ple C o m p aris o ns
 
 
 
 
9. DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S
9. 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, micr ofic hes, p h ot o gra p hic ne gati ves, micr ofil m or ma g netic me dia, X -r a ys, 
partici pa nt files, tra nsf usi o n rec or ds, a n d rec or ds ke pt at t he p har mac y , at t he la b orat ories, 
a nd at me dic o -tec h nical de part me nts i n v ol ve d i n t he cli nical st u d y), 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 st u d y  
c o nstit ute s o urce d oc u me nts.
T he c o m plete d e 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 
st u d y-relate d m o nit ori n g, a u dits, IE C re vie w, a n d re g ulat or y  i ns pecti o n by pr o vi di n g direct 
access t o s o urce d oc u me nts.
9. 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 uat e 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 t o e 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 Es, a c hec klist of i ncl usi o n a n d e xcl usi o n 
criteria, i n vesti gati o nal treat me nt 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(s). T he m o nit or (cli nical researc h ass ociate [ C R A]) 
will re vie w all e 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 nts’ 
s o urce d oc u me nts/ me dical rec or ds.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)
C CI


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 6 0
Data f or eac h partici pa nt will be rec or de d i n t he e C R F. A n e C R F m ust be c o m plete d f or 
e ver y partici pa nt e nr olle d i n t he st u d y. W he n data are c o m plete, t he I n vesti gat or or me dicall y 
q ualifie d s u b -I n vesti gat or liste d o n F or m F D A 1 5 7 2 ( or I n vesti gat or’s A gree me nt if 
a p plica ble) will a p pl y  his/ her si g nat ure i n t he e C R F i n dicati n g he/s he has re vie we d a n d 
a p pr o ves of t he data c ollecte d i n t he e C R F.
9. 3. Esse nti al D oc u me nt ati o n Re q uire me nts
T he S p o ns or or S p o ns or’s re prese ntati ve 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 0. Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E
1 0. 1. M o nit ori n g
Site pers o n nel will be pr o vi de d wit h trai ni n g o n h o w t o c ollect q ualit y  data f or t he st u d y, a n d a 
S p o ns or m o nit or ( C R A) will be c o ntacti n g t he site peri o dicall y t o re vie w st u d y  c o n d uct a n d 
data rec or de d at t he site. At t he S p o ns or’s discreti o n, o n -site m o nit orin g visits ma y  be 
c o n d ucte d pre-st u d y, d uri n g t he st u d y, a n d f oll o wi n g st u d y c o m pleti o n. T hese visits are t o 
pr o vi de t he S p o ns or wit h t he o p p ort u nit y  t o e val uate st u d y pr o gress; verif y t he acc urac y a n d 
c o m plete ness of s o urce data a n d e C R Fs; a n d e ns ure t hat all pr ot oc ol a n d G o o d Cli nical 
Practice ( G C P) re q uire me nts, a p plica ble U S F D A or c o u ntr y -s pecific re g ulati o ns, a n d 
I n vesti gat or o bli gati o ns are bei n g f ulfille d. T he S p o ns or ma y ter mi nate st u d y partici pati o n b y a 
cli nical st u d y site if st u d y-site pers o n nel d o n ot f oll o w t he pr ot oc ol or G C Ps. A d diti o nall y , 
i n di vi d ual partici pa nts ma y be e xcl u de d if a me dical rec or ds re vie w i n dicates pr ot oc ol 
de viati o ns or if ot her fact ors a p pear t o je o par dize t he vali dit y  of t he st u dy.
T he I n vesti gat or a grees t o c o o perate wit h t he m o nit or ( C R A) 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 0. 2. Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce
Pfizer ma y  c o n d uct a q ualit y ass ura nce a u dit(s) of t his st u d y. If s uc h a n a u dit occ urs, t he 
I n vesti gator a grees t o all o w t he a u dit or direct access t o all rele va nt d oc u me nts (e g, all 
partici pa nt rec or ds, me dical rec or ds a n d e C R Fs) a n d access t o all c orres p o n di n g p orti o ns of 
t he office, cli nic, la b orat or y, or p har mac y w hic h ma y ha ve bee n i n v ol ve d wit h t he stu d y . T he 
I n vesti gat or will all ocate his/ her ti me a n d t hat of t he st u d y-site pers o n nel t o t he a u dit or t o 
disc uss fi n di n gs a n d a n y rele va nt iss ues. I n a d diti o n, re g ulat or y a ge ncies ma y c o n d uct a 
re g ulat or y i ns pecti o n of t his st u d y. If s uc h a n i ns pecti o n occ urs, t he I n vesti gat or a grees t o 
n otif y  Pfizer u p o n n otificati o n b y t he re g ulat or y a ge nc y. T he I n vesti gat or a grees t o all o w t he 
i ns pect or direct access t o all rele va nt d oc u me nts a n d t o all ocate his/ her ti me a n d t hat of t he 
st u d y-site pers o n nel t o t he i ns pector t o disc uss fi n di n gs a n d a n y  rele va nt iss ues. T he 
I n vesti gat or will all o w Pfizer pers o n nel t o be prese nt as a n o bser ver d uri n g a re g ulat or y 
i ns pecti o n, if re q ueste d.
1 0. 3. L a b or at or y Accre dit ati o n
T he la b orat or y  facilit y use d f or a nalys is of cli nical la b orat or y sa m ples m ust pr o vi de e vi de nce 
of a de q uate lice ns ure or accre ditati o n. C o pies of la b orat or y  certificati o n, lice ns ure, a n d 
refere nce ra n ges (as a p pr o priate) will be s u p plie d t o t he S p o ns or pri or t o st u d y i nitiati o n. T he 
S p o ns or or desi g nee s h o ul d be n otifie d of a n y c ha n ges i n refere nce ra n ge val ues or 
certificati o n/lice nse re ne wal d uri n g t he c o urse of t he st u d y .
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 6 1
1 0. 4. S p o ns or’s Me dic all y Q u alifie d I n di vi d u al
T he c o ntact i nf or mati o n f or t he s p o ns or’s M e dicall y Q ualifie d I n di vi d ual ( M QI; ie, Me dical 
M o nit or) f or t he st u d y is d oc u me nte d i n t he st u d y c o ntact list l ocate d i n t he St u d y  Bi n der. 
T o facilitate access t o t heir I n vesti gat or a n d t he S p o ns or’s M QI f or st u d y -relate d me dical 
q uesti o ns or pr o ble ms fr o m n o nst u d y  healt hcare pr ofessi o nals, partici pa nts are pr o vi de d wit h 
a n e mer ge nc y c o ntact car d ( E C C) at t he ti me of i nf or me d c o nse nt. T he E C C c o ntai ns, at a 
mi ni m u m (a) pr ot oc ol a n d st u d y  dr u g i de ntifiers, ( b) partici pa nt’s st u d y i de ntificati o n 
n u m ber, a n d (c) site e mer ge nc y p h o ne n u m ber acti ve 2 4 h o urs/ da y, 7 da ys per wee k.
T he E C C is i nte n de d t o a u g me nt, n ot re place, t he esta blis he d c o m m u nicati o n pat h wa y s 
bet wee n t he partici pa nt a n d t heir I n vesti gat or a n d site staff, a n d bet wee n t he I n vesti gat or a n d 
S p o ns or st u d y  tea m. T he E C C is o nl y t o be use d b y healt hcare pr ofessi o nals n ot i n v ol ve d i n 
t he researc h st u d y, as a mea ns of reac hi n g t he I nvesti gat or or site staff relate d t o t he care of a 
partici pa nt.
1 1. R E G U L A T O R Y, E T HI C A L, L E G A L, A N D O V E R SI G H T O B LI G A TI O N S 
T he st u d y will c o m ply wit h t he Ge neral Data Pr otecti o n Re g ulati o n 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 pa rtici 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 h e 
patie nt i nf or mati o n s heet/i nf or me d c o nse nt f or t he st u d y  will i nf or m t he partici pa 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. 1. Re g ul at or y a n d Et hic al C o nsi der ati o ns
T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes, i ncl u di n g t he 
Declarati o n of Helsi n ki a n d CI O M S I nter nati o nal Et hical G ui deli nes;

A p plica ble I C H G C P g ui deli nes;

A p plica ble la ws a n d re g ulati o ns, i ncl u di n g a p plica ble pri vac y la ws.
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F , S R S D(s), a n d ot her rele va nt d oc u me nts (e g, 
a d vertise me nts) m ust be re vie we d a n d a p pr o ve d b y t he s p o ns or, s u b mitte d t o a n I R B/ E C b y  
t he i n vesti gat or, a n d re vie we d a n d a p pr o ve d by t he I RB/ E C bef ore t he st u d y  is i nitiate d.
A n y  a me n d me nts t o t he pr ot oc ol will re q uire I R B/ E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n ges necessar y  t o eli mi nate a n i m me diate 
hazar d t o st u d y  partici pa nts.
Pr ot oc ols a n d a n y s u bsta ntial a me n d me nts t o t he pr ot oc ol will re q uire healt h a ut h orit y  
a p pr o val pri or t o i nitiati o n e xce pt f or c ha n ges necessar y t o eli mi nate a n i m me diate hazar d t o 
st u d y partici pa nts.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 6 2
T he i n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:

Pr o vi di n g wr itte n s u m maries of t he stat us of t he st u d y t o t he I R B/ E C a n n uall y or 
m ore fre q ue ntl y  i n acc or da nce wit h t he re q uire me nts, p olicies, a n d pr oce d ures 
esta blis he d b y t he I R B/ E C;

N otif y i n g t he I R B/ E C of S A Es or ot her si g nifica nt safety fi n di n gs as re q uire d b y 
IR B/ E C pr oce d ures;

Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at t he site a n d a d here nce t o 
re q uire me nts of 2 1 C F R, I C H G C P g ui deli nes, t he IR B/ E C, E ur o pea n re g ulati o n 
5 3 6/ 2 0 1 4 f or cli nical st u dies, E ur o pea n Me dical De vice Re g ulati o n 2 0 1 7/ 7 4 5 f or 
cli nical de vice researc h, a n d all ot her a p plica ble l ocal re g ulati o ns.
1 1. 1. 1. Re p orti n g of S afet y Iss ues a n d Seri o us Bre ac hes of t he Pr ot oc ol or I C H G C P
I n t he e ve nt of a ny pr o hi biti o n or restricti o n i m p ose d (ie, cli nical h ol d) b y a n a p plica ble 
re g ulat or y a ut h ority i n a n y  area of t he w orl d, or if t he i n vesti gat or is a ware of a n y ne w 
i nf or mati o n t hat mi g ht i nfl ue nce t he e val uati o n of t he be nefits a n d ris ks of t he st u d y dr u g , 
Pfizer s h o ul d be i nf or me d i m me diatel y . 
I n a d diti o n, t he i n vesti gat or will i nf or m Pfizer i m me diatel y of a n y ur ge nt safety meas ures 
ta ke n by t he i n vesti gat or t o pr otect t he st u d y partici pa nts a gai nst a n y i m me diate hazar d, a n d 
of a n y seri o us breac hes of t his pr ot oc ol or of t he I C H G C P g ui deli nes t hat t he i n vesti gat or 
bec o mes a ware of.
1 1. 2. I nf or me d C o nse nt a nd Asse nt
T he I n vesti gat or or t he I n vesti gat or’s re prese ntati ve will e x plai n t he nat ure of t he st u d y , 
i ncl u di n g t he ris ks a n d be nefits, t o t he partici pa nt ( or t heir le gally a ut h orize d re prese ntati ve) 
a n d a ns wer all q uesti o ns re gar di n g t he st u d y. T he partici pa nt ( or t heir le gall y  a ut h orize d 
re prese ntati ve) s h o ul d be gi ve n s ufficie nt ti me a n d o p p ort u nit y t o as k q uesti o ns a n d t o deci de 
w het her or n ot t o partici pate i n t he trial.
Partici pa nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y . Partici pa nts ( or t heir 
le gall y a ut h orize d re prese ntati ve [if all o we d b y l ocal re g ulati o n]) will be re q uire d t o si g n a 
state me nt of i nf or me d c o nse nt t hat meets t he re q uire me nts of 2 1 C F R 50, l ocal re g ulati o ns, 
I C H g ui deli nes, pri vac y a n d data pr otecti o n re q uire me nts, w here a p plica ble, a n d t he I R B/ E C 
or st u d y  ce nter. 
T he I n vesti gat or m ust e ns ure t hat eac h partici pa nt ( or t heir le gall y a ut h orize d re prese ntati ve) 
is f ull y i nf or me d a b o ut t he nat ure a n d o bjecti ves of t he st u d y , t he s hari n g of data relate d t o 
t he st u d y, a n d p ossi ble ris ks ass ociate d wit h partici pati o n, i ncl u di n g t he ris ks ass ociate d wit h 
t he pr ocessi n g of t he partici pa nt’s pers o nal data.
T he partici pa nt ( or t heir le gall y  a ut h orize d re prese ntati ve) m ust be i nf or me d t hat t heir 
pers o nal st u d y -relate d data will be use d b y t he S p o ns or i n acc or da nce wit h l ocal data 
pr otecti o n la w. T he le vel of discl os ure m ust als o be e x plai ne d t o t he partici pa nt ( or t heir 
le gall y a ut h orize d re prese ntative).
T he partici pa nt ( or t heir le gall y  a ut h orize d re prese ntati ve) m ust be i nf or me d t hat t heir 
me dical rec or ds ma y  be e xa mi ne d b y Cli nical Q ualit y Ass ura nce a u dit ors or ot her a ut h orize d 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 6 3
pers o n nel a p p oi nte d b y t he S p o ns or, b y  a p pr o priate IR B/ E C me m bers, a n d b y  i ns pect ors 
fr o m re g ulat or y a ut h orities.
T he I n vesti gat or f urt her m ust e ns ure t hat eac h st u d y  partici pa nt ( or t heir le gally a ut h orize d 
re prese ntati ve) is f ully i nf or me d a b o ut t heir ri g ht t o access a n d c orrect t heir pers o nal data a n d 
t o wit h dra w c o nse nt for t he pr ocessi n g of t heir pers o nal data.
T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d 
bef ore t he partici pa nt was e nr olle d i n t he st u d y  a n d t he date o n w hic h t he writte n c o nse nt was 
o btai ne d. T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.
Partici pa nt ( or t heir le gall y  a ut h orize d re prese ntati ve) m ust be rec o nse nte d t o t he m ost 
c urre nt versi o n of t he I R B/ E C -a p pr o ve d I C F(s) d uri n g t heir partici pati o n i n t he st u d y  as 
re q uire d per l ocal re g ulati o ns.
A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt ( or t heir le gall y a ut h orize d 
re prese ntati ve).
1 1. 3. D at a Pr otecti o n
All parties will c o m pl y  wit h all a p plica ble la ws, i ncl u di n g la ws re gar di n g t he i m ple me ntati o n 
of or ga nizati o nal a n d tec h nical meas ures t o e ns ure pr otecti o n of partici pa nt data.
Partici pa nt’s pers o nal data will be st ore d 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 pare nt or le gal g uar dia n’s res p o nsi bilit y t o c o m m u nicate t he st u d y site i n e ncr ypte d 
electr o nic a n d/or pa per f or m a n d will be pass w or d pr otecte d or sec ure d i n a l oc ke d r o o m t o 
e ns ure t hat o nl y a ut h orize d st u d y staff ha ve access. T he st u d y site will i m ple me nt a p pr o priate 
tec h nical a n d or ga nizati o nal meas ures t o e ns ure t hat t he pers o nal data ca n be rec o vere d i n t he 
e ve nt of disaster. I n t he e ve nt of a p ote ntial pers o nal data breac h, t he st u dy site will be 
res p o nsi ble f or deter mi ni n g w het her a pers o nal data breac h has i n fact occ urre d a n d, if s o, 
pr o vi di n g breac h n otificati o ns as re q uire d b y la w.
T o pr otect t he ri g hts a n d free d o ms of partici pa nts wit h re gar d t o t he pr ocessi n g of pers o nal 
data, partici pa nts will be assi g ne d a si n gle, partici pa nt -s pecific n u merical c o de. A n y 
partici pa nt rec or ds or data sets t hat are tra nsferre d t o t he S p o ns or will c o ntai n t he n u merical 
c o de; partici pa nt na mes will n ot be tra nsferre d. All ot her i de ntifia ble data tra nsferre d t o t he 
S p o ns or will be i de ntifie d b y  t his si n gle, partici pa nt-s pecific c o de. T he st u d y site will 
mai ntai n a c o nfi de ntial list of partici pa nts w h o partici pate d i n t he st u d y, li n ki n g eac h 
partici pa nt’s n u merical c o de t o t heir act ual i de ntit y  a n d me dical rec or d I D. I n case of data 
tra nsfer, t he S p o ns or will pr otect t he c o nfi de ntialit y of partici pa nt’ pers o nal data c o nsiste nt 
wit h t he cli nical st u d y  a gree me nt a n d ap plica ble pri vac y  la ws.
I nf or mati o n tec h n ol o g y s yste ms use d t o c ollect, pr ocess, a n d st ore st u d y-relate d data are 
sec ure d by t ec h nical a n d or ga nizati o nal sec urit y meas ures desi g ne d t o pr otect s uc h data 
a gai nst acci de ntal or u nla wf ul l oss, alterati o n, or u na ut h orize d discl os ure or access.
T he S p o ns or mai ntai ns sta n dar d o perati n g pr oce d ures o n h o w t o res p o n d i n t he e ve nt of 
u na ut h orize d access, use, or discl os ure of S p o ns or i nf or mati o n or s y ste ms.
1 1. 4. I n de pe n de nt 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 ves ti 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 E C f or t he c o n d uct of t he st u d y 
at na me d sites, f or t he pr ot oc ol, t he Partici pa nt I C F, a n d a n y ot her writte n i nf or mati o n t hat 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 6 4
will be pr o vi de d t o t he partici pa nts 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 nts i nt o t he st u d y a n d s hi p me nt of 
st u d y 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 d oc u me nts m ust be disc usse d wit h 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 E C f or a p pr o val as w ell as s u b mitte d t o re g ulat or y  
a ut h orities f or a p pr o val pri or t o i m ple me ntati o n. A me n d me nts ma y  be i m ple me nte d o nly 
after a c o p y of t he I 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 nts ma y be i m ple me nte d 
pri or t o recei vi n g S p o ns or or I E C 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 n t t o t he I E C t o 
facilitate t heir c o nti n ui n g re vie w of t he st u d y (if nee de d) a n d t hat t he I E C 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. T he I n vesti gat or will i nf or m t he IE C of a n y re p orta ble A Es.
1 1. 5. Esse nti al D oc u me nt ati o n Re q uire me nts
T he S p o ns or or S p o ns or’s re prese ntati ve 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. 6. Disse mi n ati o n of Cli nic al St u d y D at a
T he S p o ns or f ulfills its c o m mit me nt t o p u blicl y  discl ose cli nical st u d y res ults t hr o u g h 
p osti n g t he res ults of st u dies o n w w w.cli nicaltrials. g o v ( Cli nical Trials. g o v), t he 
E u dra C T/ C TI S, a n d/ or w w w. pfizer.c o m, a n d ot her p u blic re gistries a n d we bsites i n 
acc or da nce wit h a p plica ble l ocal la ws/re g ulati o n. I n a d diti o n, t he S p o ns or re p orts st u d y  
res ults o utsi de of t he re q uire me nt of l ocal la ws/re g ulati o ns p urs ua nt t o its sta n dar d o perati n g 
pr oce d ures.
I n all cases, st u dy res ults are re p orte d b y t he S p o ns or i n a n o bjecti ve, acc urate, bala nce d, a n d 
c o m plete ma n ner a n d are re p orte d re gar dless of t he o utc o me of t he st u d y or t he c o u ntr y i n 
w hic h t he st u d y  was c o n d ucte d.
w w w.cli nicaltrials. g o v
T he S p o ns or p osts cli nical trial res ults o n w w w.c li nicaltrials. g o v f or G B T/ Pfizer-s p o ns ore d 
i nter ve nti o nal st u dies (c o n d ucte d i n patie nts) t hat e val uate t he safety a n d/ or efficac y of a 
pr o d uct, re gar dless of t he ge o gra p hical l ocati o n i n w hic h t he st u d y is c o n d ucte d. T hese 
res ults are s u b mitte d f or p osti ng i n acc or da nce wit h t he f or mat a n d ti meli nes set f ort h b y U S 
la w.
E u dra C T/ C TI S
T he S p o ns or p osts cli nical trial res ults o n E u dra C T/ C TI S f or G B T/ Pfizer -s p o ns ore d 
i nter ve nti o nal st u dies i n acc or da nce wit h t he f or mat a n d ti meli nes set f ort h b y E U 
re q uire me nts.
w w w. pfizer.c o m
T he S p o ns or p osts cli nical st u d y  re p ort ( C S R) s yn o pses a n d plai n -la n g ua ge st u d y res ults 
s u m maries o n w w w. pfizer.c o m f or G B T/ Pfizer-s p o ns ore d i nter ve nti o nal st u dies at t he sa me 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 6 5
ti me t he c orres p o n di n g st u d y res ults are p oste d t o w w w.cli nicaltrials. g o v. C S R s y n o pses will 
ha ve pers o nall y  i de ntifia ble i nf or mati o n a n o n ymize d.
D oc u me nts wit hi n mar keti n g a p plicati o ns
T he S p o ns or c o m plies wit h a p plica ble l ocal la ws/re g ulati o ns t o p u blis h cli nical d oc u me nts 
i ncl u de d i n mar keti n g a p plicatio ns. Cli nical d oc u me nts i ncl u de s u m mar y  d oc u me nts a n d 
C S Rs i ncl u di n g t he pr ot oc ol a n d pr ot oc ol a me n d me nts, sa m ple C R Fs, a n d S A Ps. Cli nical 
d oc u me nts will ha ve pers o nall y  i de ntifia ble i nf or mati o n a n o n ymize d.
Data s hari n g
T he S p o ns or pr o vi des researc hers sec ure access t o partici pa nt -le vel data or f ull C S Rs f or t he 
p ur p oses of “ b o na -fi de scie ntific researc h” t hat c o ntri b utes t o t he scie ntific u n dersta n di n g of 
t he disease, tar get, or c o m p o u n d class. T he S p o ns or will ma ke data fr o m t hese trials a vaila ble 
1 8 m o nt hs after st u d y  c o m pleti o n. Partici pa nt-le vel data will be a n o ny m ize d i n acc or da nce 
wit h a p plica ble pri vac y  la ws a n d re g ulati o ns. C S Rs will ha ve pers o nally i de ntifia ble 
i nf or mati o n a n o ny m ize d.
Data re q uests are c o nsi dere d fr o m q ualifie d researc hers wit h t he a p pr o priate c o m pete ncies t o 
perf or m t he pr o p ose d a nal yses. Researc h tea ms m ust i ncl u de a bi ostatisticia n. Data will n ot 
be pr o vi de d t o a p plica nts wit h si g nifica nt c o nflicts of i nterest, i ncl u di n g i n di vi d uals 
re q uesti n g access f or c o m mercial/c o m petiti ve or le gal p ur p oses.
1 1. 7. D at a Q u alit y Ass ur a nce
All partici pa nt data relati n g t o t he st u d y will be rec or de d o n pri nte d or electr o nic C R F u nless 
tra ns mitte d t o t he S p o ns or or desi g nee electr o nicall y (e g, la b orat or y data). T he I n vesti gat or is 
res p o nsi ble f or verif yin g t hat data e ntries are acc urate a n d c orrect b y  p h ysicall y or 
electr o nicall y si g ni n g t he C R F.
G ui da nce o n c o m pleti o n of C R Fs will be pr o vi de d i n t he C R F C o m pleti o n Re q uire me nt 
d oc u me nt.
T he I n vesti gat or m ust e ns ure t hat t he C R Fs are sec urel y st ore d at t he st u d y site i n e ncr ypte d 
electr o nic a n d/ or pa per f or m a n d are pass w or d - pr otecte d or sec ure d i n a l oc ke d r o o m t o 
pre ve nt access b y u na ut h orize d t hir d parties.
T he I n vesti gat or m ust per mit st u d y -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 a ge ncy i ns pecti o ns a n d pr o vi de direct access t o s o urce rec or ds a n d d oc u me nts. 
T his verificati o n ma y  als o occ ur after st u d y c o m pleti o n. It is i m p orta nt t hat t he 
I n vesti gat or(s) a n d t heir rele va nt pers o n nel are a vaila ble d uri n g t he m o nit ori n g visits a n d 
p ossi ble a u dits or i ns pecti o ns a n d t hat s ufficie nt ti me i n de v ote d t o t he pr ocess.
M o nit ori n g details descri bi n g strate g y , i ncl u di n g defi niti o n of st u d y-critical data ite ms a n d 
pr ocesses (e g, ris k -base d i nitiati ves i n o perati o ns a n d q ualit y  s uc h as ris k ma na ge me nt a n d 
miti gati o n strate gies a n d a nal yt ical ris k-base d m o nit ori n g), met h o ds, res p o nsi bilities, a n d 
re q uire me nts, i ncl u di n g ha n dli n g of n o nc o m plia nce iss ues a n d m o nit ori n g tec h ni q ues 
(ce ntral, virt ual, or o n-site m o nit ori n g), are pr o vi de d i n t he data ma na ge me nt pla n mai ntai ne d 
a n d utilize d b y t he S p o ns or or desi g nee.
T he S p o ns or or desi g nee is res p o nsi ble f or t he data ma na ge me nt of t his st u d y , i ncl u di n g 
q ualit y  c hec ki n g of t he data.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 6 6
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his st u d y m ust 
be retai ne d b y t he I n vesti gat or f or 1 5 ye ars after st u d y c o m pleti o n u nless l ocal re g ulati o ns or 
i nstit uti o nal p olicies re q uire a l o n ger rete nti o n peri o d. N o rec or ds ma y be destr o ye d d uri n g 
t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of t he s p o ns or. N o rec or ds ma y  be 
tra nsferre d t o a n ot her l ocati o n or party wit h o ut writte n n otificati o n t o t he S p o ns or. T he 
I n vesti gat or m ust e ns ure t hat t he rec or ds c o nti n ue t o be st ore d sec urely f or as l o n g as t he y are 
mai ntai ne d.
W he n partici pa nt data are t o be delete d, t he I n vesti gat or will e ns ure t hat all c o pies of s uc h 
data are pr o m ptl y  a n d irre v oca bly delete d fr o m all s yste ms.
T he I n vesti gat or(s) will n otif y  t he S p o ns or or its a ge nts i m me diately of a n y re g ulat or y 
i ns pecti o n n otificati o n i n relati o n t o t he st u d y. F urt her m ore, t he I n vesti gat or will c o o perate 
wit h t he S p o ns or or its a ge nts t o pre pare t he I n vesti gat or site f or t he i ns pecti o n a n d will all o w 
t he S p o ns or or its a ge nt, w he ne ver feasi ble, t o be prese nt d uri n g t he i ns pecti o n. T he 
I n vesti gat or site an d I n vesti gat or will pr o m ptl y  res ol ve a n y discre pa ncies t hat are i de ntifie d 
bet wee n t he st u d y data a n d t he partici pa nt’s me dical rec or ds. T he I n vesti gat or will pr o m ptl y 
pr o vi de c o pies of t he i ns pecti o n fi n di n gs t o t he S p o ns or or its a ge nt. Bef ore res p o nse 
s u b missi o n t o t he re g ulat or y a ut h orities, t he I n vesti gat or will pr o vi de t he S p o ns or or its 
a ge nts wit h a n o p p ort u nit y t o re vie w a n d c o m me nt o n res p o nses t o a n y s uc h fi n di n gs. 
1 1. 8. St u d y a n d Site St art a n d Cl os ure
T he st u d y  start date is t he date of t he first partici pa nt’s first visit.
T he S p o ns or desi g nee reser ves t he ri g ht t o cl ose t he st u d y  site or ter mi nate t he st u d y at a ny 
ti me f or a ny reas o n at t he s ole discreti o n of t he S p o ns or, i ncl u di n g ( b ut n ot li mite d t o) 
re g ulat or y a ut h ority decisi o n, c ha n ge i n o pi ni o n of t he I R B/ E C, or c ha n ge i n be nefit -ris k 
assess me nt. St u d y sites will be cl ose d u p o n st u d y c o m pleti o n. A st u d y site is c o nsi dere d 
cl ose d w he n all re q uire d d oc u me nts a n d st u d y  s u p plies ha ve bee n c ollecte d a n d a st u d y-site 
cl os ure visit has bee n perf or me d .
T he I n vesti gat or ma y  i nitiate st u d y-site cl os ure at a n y ti me u p o n n otificati o n t o t he S p o ns or 
or desi g nee/ C R O if re q ueste d t o d o s o b y  t he res p o nsi ble IR B/ E C or if s uc h ter mi nati o n is 
re q uire d t o pr otect t he healt h of st u d y partici pa nts.
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or ma y i ncl u de b ut are n ot li mite d 
t o:

Fail ure of t he I n vesti gat or t o c o m pl y  wit h t he pr ot oc ol, t he re q uire me nts of t he 
I RB/ E C or l ocal healt h a ut h orities, t he S p o ns or’s pr oce d ures, or t he I CH G C P 
g ui deli nes;

I na deq uate recr uit me nt of partici pa nts b y  t he I n vesti gat or;

Disc o nti n uati o n of f urt her st u d y  dr u g de vel o p me nt.
If t he st u dy is pre mat urel y ter mi nate d or s us pe n de d, t he S p o ns or s hall pr o m ptl y  i nf or m t he 
I n vesti gat ors, t he E Cs/IR Bs, t he re g ulat or y  a ut h orities, a n d a n y C R O(s) use d i n t he st u d y of 
t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y t he a p plica ble re g ulat or y 
re q uire me nts. T he I n vesti gat or s hall pr o m ptl y i nf or m t he partici pa nt a n d s h o ul d ass ure 
a p pr o priate partici pa nt t hera p y a n d/ or f oll o w -u p.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 6 7
St u d y  ter mi nati o n is als o pr o vi de d f or i n t he cli nical st u d y a gree me nt. If t here is a n y c o nflict 
bet wee n t he c o ntract a n d t his pr ot oc ol, t he c o ntract will c o ntr ol as t o ter mi nati o n ri g hts. 
1 1. 9. 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. I n t he e C R F a n d 
ot her d oc u me nts s u b mitte d t o t he S p o ns or, partici pa nts will be i de ntifie d b y  a partici pa nt 
st u d y n u m ber o nly. 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 nti al 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 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. 1 0. St u d y 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 s ys te m of all st u d y-
relate d d oc u me ntati o n t hat is s uita ble f or 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 ntial d oc u me nts as detaile d i n Secti o n 1 2. 2 . 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 , st u d y 
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 st u d y ) 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 s uc h a wa y t hat the 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 st u d y  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 I n vesti gat or. S h o ul d t he I n vesti gat or wis h t o assi g n t he st u d y  rec or ds t o a n ot her party 
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 2. D A T A H A N D LI N G A N D R E C O R D K E E PI N G
1 2. 1. I ns pecti o n of Rec or ds
Pfizer will be all o we d t o c o n d uct site visits t o t he i n vesti gati o n f acilities f or t he p ur p ose of 
m o nit ori n g a n y as pect of t he st u d y. T he I n vesti gat or a grees t o all o w t he m o nit or ( C R A) t o 
i ns pect t he dr u g st ora ge area, st u dy dr u g st oc ks, dr u g acc o u nta bilit y rec or ds, partici pa nt 
c harts, st u d y s o urce d oc u me nts, a n d ot her rec o r ds relati ve t o st u d y c o n d uct.
T he I n vesti gat or a grees t o mai ntai n a re g ulat or y  bi n der i n a c urre nt, or ga nize d fas hi o n; t his 
bi n der will c o ntai n d oc u me ntati o n s u p p orti ve of t he pr ot oc ol - a n d G C P -c o m plia nce of t he 
st u d y. T he c o nte nts of t he bi n der will be or ga nize d acc or di n g t o t he sta n dar ds of I C H E 6, 
Secti o n 8 ( Esse ntial D oc u me nts). T he I n vesti gat or a grees t o ma ke t his bi n der accessi ble t o 
t he m o nit or ( C R A), a u dit or, a n d re prese ntati ves of re g ulat or y a ge ncies a n d t he I E C.
1 2. 2. Rete nti o n of Rec or ds
T he I n vesti ga t 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 ny ot her perti ne nt 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 6 8
da ta. All st u d y rec or ds m ust be retai ne d f or 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 t he U S 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 or a n I C H re gi o n or ( 2) at least 2 ye ars ha ve 
ela pse d si nce t he f or mal 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 nvesti 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 disc 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 or b y t he S p o ns or. Pfizer 
m ust be n otifie d wit h rete nti o n if t he I n vesti gat or/i nstit uti o n is 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 I n vesti gat ors m ust retai n pr ot oc ols, a me n d me nts, I E C a p pr o vals, c o pies of t he F or m 
F D A 1 5 7 2 ( or I n vesti gat or’s A gree me nt if a p plica ble), 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 st u d y.
If t he 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 n y pr ot oc ol 
rec or ds.
Discl os ure of I nf or mati o n
Partici pa nts’ me dical i nf or mati o n o btai ne d as a re s ult of t his st u d y is c o nsi dere d c o nfi de ntial, 
a n d discl os ure t o t hir d parties, ot her t ha n t h ose n ote d i n t his pr ot oc ol, is pr o hi bite d. S u bject 
t o a n y a p plica ble a ut h orizati o n(s), all re p orts a n d c o m m u nicati o ns relati n g t o partici pa nts i n 
t his st u d y will ide ntif y  partici pa nts o nl y b y i nitials a n d n u m ber. Me dical i nf or mati o n 
res ulti n g fr o m a partici pa nt’s partici pati o n i n t his st u d y ma y be gi ve n t o t he partici pa nt’s 
pers o nal p h ys icia n, ot her a ut h orize d parties, or t o t he a p pr o priate me dical pers o n nel 
res p o nsi ble f or t he partici pa nt’s partici pati o n i n t his cli nical st u d y. Data ge nerate d i n t his 
st u d y will be a vaila ble f or i ns pecti o n o n re q uest b y t he F D A or ot her g o ver n me nt re g ulat or y 
a ge nc y a u dit ors, t he S p o ns or, t he S p o ns or’s Me dical M o nit or ( or desi g nee), an d t heir 
desi g nate d re prese ntati ves, t he I E C, a n d ot her a ut h orize d parties. All i nf or mati o n c o ncer ni n g 
t he st u d y dr u g a n d t he S p o ns or’s o perati o ns (s uc h as pate nt a p plicati o ns, f or m ulas, 
ma n ufact uri n g pr ocesses, basic scie ntific data, or ot her i nf or mati o n s u p plie d b y t he S p o ns or 
a n d n ot pre vi o usl y p u blis he d) are c o nsi dere d c o nfi de ntial a n d s hall re mai n t he s ole pr o perty 
of t he S p o ns or. T he I n vesti gat or a grees t o use t his i nf or mati o n o nl y  i n c o n d ucti n g t his st u d y 
a n d t o n ot use it f or ot her p ur p oses wit h o ut t he S p o ns or’s pri or writte n c o nse nt. T he 
i nf or mati o n de vel o pe d i n t his cli nical st u d y will be use d by t he S p o ns or i n t he cli nical 
de vel o p me nt of v o xel ot or a n d t heref ore, ma y  be discl ose d b y t he S p o ns or as re q uire d, t o 
a ut h orize d parties (i ncl u di n g its c or p orate part ners f or t he st u d y  dr u g, if a ny,  a n d t heir 
desi g nate d re prese ntati ves), ot her cli nical I n vesti gat ors, p har mace utical c o m pa nies, t he F D A, 
a n d ot her g o ver n me nt a ge ncies. A n y i nf or mati o n, i n ve nti o ns, disc o veries ( w het her pate nta ble 
or n ot), i n n o vati o ns, s u g gesti o ns, i deas, a n d re p orts ma de or de vel o pe d b y  t he In vesti gat or(s) 
as a res ult of c o n d ucti n g t his st u d y s hall be pr o m ptl y discl ose d t o t he S p o ns or a n d s hall be 
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 6 9
t he s ole pr o perty of t he S p o ns or. T he I n vesti gat or a grees, u p o n t he S p o ns or’s re q uest a n d at 
t he S p o ns or’s e x pe nse, t o e xec ute s uc h d oc u me nts a n d t o ta ke s uc h ot her acti o ns as t he 
S p o ns or dee ms necessar y or a p pr o priate t o o btai n pate nts i n t he S p o ns or’s na me c o veri n g 
a n y of t he f ore g oi n g.
1 3. I N S U R A N C E A N D FI N A N CI A L DI S C L O S U R E
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 plicable 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 4. P U B LI C A TI O N P O LI C Y
F or m ultice nter trials, t he pri mar y p u blicati o n will be a j oi nt p u blicati o n de vel o pe d by t he 
I n vesti gat or a n d t he S p o ns or re p orti n g t he pri mar y e n d p oi nt(s) of t he st u d y c o veri n g all st u d y 
sites. T he I n vesti gat or a grees t o refer t o t he pri mar y p u blicati o n i n a ny s u bse q ue nt
p u blicati o ns. T he S p o ns or will n ot pr o vi de a n y fi na ncial c o m pe nsati o n f or t he I n vesti gat or’s 
partici pati o n i n t he pre parati o n of t he pri mar y  c o n gress a bstract, p oster, prese ntati o n, or 
pri mar y  ma n uscri pt f or t he st u d y.
I n vesti gat ors are free t o p u blis h i ndi vi d ual ce nter res ults t hat t he y  dee m t o be cli nicall y 
mea ni n gf ul after p u blicati o n of t he o verall res ults of t he st u d y  or 1 2 m o nt hs after pri mar y 
c o m pleti o n date or st u d y c o m pleti o n at all sites, w hic he ver occ urs first, s u bject t o t he ot her 
re q uire me nts descri be d i n t his secti o n.
T he I n vesti gat or will pr o vi de t he S p o ns or a n o p p ort u nit y  t o re vie w a ny pr o p ose d p u blicati o n 
or a n y ot her t y pe of discl os ure of t he st u d y res ults (c ollecti vel y, “ p u blicati o n”) bef ore it is 
s u b mitte d or ot her wise discl ose d a n d will s u b mit all p u blicati o ns t o t he S p o ns or 3 0 da ys 
bef ore s u b missi o n. If a n y pate nt acti o n is re q uire d t o pr otect i ntellect ual pr o pert y ri g hts, t he 
I n vesti gat or a grees t o dela y t he discl os ure f or a peri o d n ot t o e xcee d a n a d diti o nal 6 0 da ys 
u p o n re q uest fr o m t he S p o ns or. T his all o ws t he S p o ns or t o pr otect pr o prietar y i nf or mati o n 
a n d t o pr o vi de c o m me nts, a n d t he I n vesti gat or will, o n re q uest, re m o ve a n y pre vi o usl y 
u n discl ose d c o nfi de ntial i nf or mati o n bef ore discl os ure, e xce pt f or a n y st u d y i nter ve nti o n or 
S p o ns or relate d i nf or mati o n necessar y  f or t he a p pr o priate scie ntific prese ntati o n or 
u n dersta n di n g of t he st u d y  res ults. F or j oi nt p u blicati o ns, s h o ul d t here be disa gree me nt 
re gar di n g i nter pretati o n a n d/ or prese ntati o n of s pecific a nalys is res ults, res ol uti o n of, a n d 
res p o nsi bilit y f or, s uc h disa gree me nts will be t he c ollecti ve res p o nsi bilit y of all a ut h ors of 
t he p u blicati o n.
F or all p u blicati o ns relati n g t o t he st u d y, t he i n vesti gat or a n d t he S p o ns or will c o m pl y wit h 
rec o g nize d et hical sta n dar ds c o ncer ni n g p u blicati o ns a n d a ut h ors hi p, i ncl u di n g t h ose 
esta blis he d b y t he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors. T he I n vesti gat or will 
discl ose a n y relati o ns hi p wit h t he S p o ns or a n d a n y rele va nt p ote ntial c o nflicts of i nterest, 
i ncl u di n g a ny fi na ncial or p ers o nal relati o ns hi p wit h t he S p o ns or, i n a n y  p u blicati o ns. All 
a ut h ors will ha ve access t o t he rele va nt statistical ta bles, fi g ures, a n d re p orts (i n t heir ori gi nal 
f or mat) re q uire d t o de vel o p t he p u blicati o n.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 7 0
1 5. R E F E R E N C E S
Ballas S K. Sic kle cell a ne mia wit h fe w pai nf ul crises is c haracterize d by decrease d re d 
cell def or ma bilit y a n d i ncrease d n u m ber of de nse cells. A m J He mat ol. 1 9 9 1; 3 6( 2): 1 2 2 -
3 0.
Bart ol ucci P, Br u g nara C, Tei xeira -Pi nt o A, Pissar d S, M ora d k ha ni K, J o ua ult H, et al. 
Er y t hr oc yte de nsity i n sic k le cell sy n dr o mes is ass ociate d wit h s pecific cli nical 
ma nifestati o ns a n d he m ol y sis. Bl o o d. 2 0 1 2; 1 2 0( 1 5): 3 1 3 6-4 1. d oi: 1 0. 1 1 8 2/ bl o o d - 2 0 1 2-
0 4- 4 2 4 1 8 4.
Br o w n C, H o p pe C, I nati A, A b b o u d M R, Wa n g W, L ie m R, et al. Efficac y a n d safety of 
1 5 0 0 m g v o xel ot or i n a P hase 2a st u d y ( G B T 4 4 0 -0 0 7) i n a d olesce nts wit h sic kle cell 
disease. Bl o o d. 2 0 1 8; 1 3 2( S u p pl 1): 5 0 9.
C u m mi n g V, Ki n g L, Fraser R, Rei d M. Ve n o us i nc o m pete nce, p o vert y a n d lactate 
de h y dr o ge nase i n Ja maica are i m p orta nt pre dict ors of le g ulcerati o n i n sic kle cell 
a nae mia. Br J Hae mat ol. 2 0 0 8; 1 4 2( 1): 1 1 9 -2 5. d oi: 1 0. 1 1 1 1/j. 1 3 6 5 - 2 1 4 1. 2 0 0 8. 0 7 1 1 5.
D uf u K, Patel M, O kse n ber g D, Ca brales P. G B T 4 4 0 i m pr o ves re d bl o o d cell 
def or m a bilit y a n d re d uces visc osit y of sic kle cell bl o o d u n der de o xy ge nate d c o n diti o ns. 
Cli n He m or he ol Micr ocirc. 2 0 1 8; 7 0( 1): 9 5 -1 0 5. d oi: 1 0. 3 2 3 3/ C H - 1 7 0 3 4 0.
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.
Gla d wi n M T, Barst RJ, Gi b bs J S R, Hil des hei m M, Sac h de v V, N o uraie M, et al. Ris k 
fact ors f or deat h i n 6 3 2 patie nts wit h sic kle cell disease i n t he U nite d States a n d U nite d 
Ki n g d o m. P L o S O N E. 2 0 1 4; 9( 7):e 9 9 4 8 9. d oi: 1 0. 1 3 7 1/j o ur nal. p o ne. 0 0 9 9 4 8 9.
Her ber O R, Sc h ne p p W, Rie ger M A. A s ys te matic re vie w o n t he i m pact of le g ulcerati o n 
o n patie nts’ q ualit y  of life. Healt h Q ual Life O utc o mes. 2 0 0 7; 5: 4 4. d oi: 1 0. 1 1 8 6/ 1 4 7 7-
7 5 2 5- 5- 4 4.
Kat o GJ, Gla d wi n M T, Stei n ber g M H. Dec o nstr ucti n g sic kle cell disease: rea p praisal of 
t he r ole of he m olys is i n t he de vel o p me nt of cli nical s u b p he n ot ypes. Bl o o d Re v. 
2 0 0 7; 2 1( 1): 3 7 -4 7.
Kat o GJ, Piel F B, Rei d C D, Gast o n M H, O he ne- Fre m p o n g K, Kris h na m urti L , et al. 
Sic kle cell disease. Nat Re v Dis Pri mers. 2 0 1 8; 4: 1 8 0 1 0. d oi: 1 0. 1 0 3 8/ nr d p. 2 0 1 8. 1 0.
Marti - Car vajal AJ, K ni g ht- Ma d de n J M, Marti nez-Za pata MJ. I nter ve nti o ns f or treati n g 
le g ulcers i n pe o ple wit h sic kle cell disease. C oc hra ne Data base Sys t Re v. 
2 0 1 4( 1 2): C D 0 0 8 3 9 4. d oi: 1 0. 1 0 0 2/ 1 4 6 5 1 8 5 8. C D 0 0 8 3 9 4. p u b 3.
Mc Ga n n P T, Ware R E. H y dr o x y urea t hera p y  f or sic kle cell a ne mia. E x pert O pi n Dr u g 
Saf. 2 0 1 5; 1 4( 1 1): 1 7 4 9 -5 8. d oi: 1 0. 1 5 1 7/ 1 4 7 4 0 3 3 8. 2 0 1 5. 1 0 8 8 8 2 7.
Mi n niti C P, Dela ne y  K M H, G or bac h A M, X u D, Lee C C R, Mali k N, et al. Vasc ul o pat hy, 
i nfla m mati o n, a n d bl o o d fl o w i n le g ulcers of patie nts wit h sic kle cell a ne mia. A m J 
He mat ol. 2 0 1 4; 8 9( 1): 1 – 6. D oi: 1 0. 1 0 0 2/aj h. 2 3 5 7 1.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 7 1
Mi n niti C P, K ni g ht -Ma d de n J, T o n da M, L e hrer -Grai wer J, Bie m o n d BJ. T he i m pact of 
v o xel ot or treat me nt o n le g ulcers i n patie nts wit h S C D: a nal y sis fr o m the P hase 3 H O P E 
st u d y. A n n ual Sic kle Cell Disease a n d T halassae mia C o nfere nce ( A S C A T) 2 0 1 9; 
2 1- 2 3 Oct o ber 2 0 1 9; L o n d o n, U K. P oster # 0 4 6.
N ola n V G, A de w o ye A, Bal d wi n C, Wa n g L, Ma Q, W ysz y ns ki D F, et al. Sic kle cell le g 
ulcers: ass ociati o ns wit h hae m ol y sis a n d S N Ps i n Kl ot h o, T E K a n d ge nes of t he T G F -
beta/ B M P pat h wa y . Br J Hae mat ol. 2 0 0 6; 1 3 3( 5): 5 7 0– 8. d oi: 1 0. 1 1 1 1/j. 1 3 6 5-
2 1 4 1. 2 0 0 6. 0 6 0 7 4. x.
N o uraie M, Lee J S, Z ha n g Y, Ka nias T, Z ha o X, Xi o n g Z. T he relati o ns hi p bet wee n t he 
se verity of he m ol ys is, cli nical ma nifestati o ns a n d ris k of deat h i n 4 1 5 patie nts wit h sic kle 
cell a ne mia i n t he U S a n d E ur o pe. Hae mat ol o gica. 2 0 1 3; 9 8( 3): 4 6 4- 7 2. d oi: 
1 0. 3 3 2 4/ hae mat ol. 2 0 1 2. 0 6 8 9 6 5.
O kse n ber g D, D uf u K, Patel M P, C h ua n g C, Li Z, X u Q, et al. G B T 4 4 0 i ncreases 
he m o gl o bi n o x y ge n affi nit y, re d uces sic kli n g a n d pr ol o n gs R B C half-life i n a m uri ne 
m o del of sic kle cell disease. Br J Hae mat ol. 2 0 1 6; 1 7 5( 1): 1 4 1- 5 3.
O x br y t a® ( v o xel ot or ta blets) [ pac ka ge i nsert]. S o ut h Sa n Fra ncisc o, C A: Gl o bal Bl o o d 
T hera pe utics, I nc. htt ps:// w w w. o x br y ta.c o m/ p df/ prescri bi n g-i nf or mati o n. p df
Pers o o n A, Hei ne n M M, va n der Vle ute n CJ M, de R o oij MJ, va n de Ker k h of P C M, va n 
Ac hter ber g T. Le g ulcers: a re vie w of t heir i m pact o n dail y  life. J Cli n N urs. 
2 0 0 4; 1 3( 3); 3 4 1 - 5 4.
Si n g h A P, Mi n niti C P. Le g ulcerati o n i n si c kle cell disease: a n earl y a n d visi ble si g n of 
e n d-or ga n disease. I n Sic kle Cell Disease--Pai n a n d C o m m o n C hr o nic C o m plicati o ns, 
B P D I n usa (e d). N o ve m ber 2 0 1 6. d oi: htt p:// d x. d oi. or g/ 1 0. 5 7 7 2/ 6 4 2 3 4.
S wa ns o n M E, Gr osse S D, K ul kar ni R. Disa bilit y  a m o n g i n di vi d uals wit h sic kle cell 
disease: literat ure re vie w fr o m a p u blic healt h pers pecti ve. A m J Pre v Me d. 
2 0 1 1; 4 1( 6 S u p pl 4): S 3 9 0 -7. d oi: 1 0. 1 0 1 6/j.a me pre. 2 0 1 1. 0 9. 0 0 6.
Ta y l or J G, N ola n V G, Me n dels o h n L, Kat o GJ. C hr o nic h yper -he m ol y sis i n sic kle cell 
a ne mia: ass ociati o n of vasc ular c o m plicati o ns a n d m ortalit y  wit h less fre q ue nt 
vas o occl usi ve pai n. P L o S O ne. 2 0 0 8; 3( 5): e 2 0 9 5. d oi: 1 0. 1 3 7 1/j o ur nal. p o ne. 0 0 0 2 0 9 5.
Vic hi ns k y  E, H o p pe C, H o war d J, Ata ga K, N d u ba V, El-Bes hla w y  A, et al. Res ults fr o m 
Part A of t he He m o gl o bi n O x y ge n Affi nit y M o d ulati o n t o I n hi bit H b S P ol y merizati o n 
( H O P E) Trial ( G B T 4 4 0-0 3 1), a place b o -c o ntr olle d ra n d o mize d st u d y e val uati n g 
v o xel ot or ( G B T 4 4 0) i n a d ults a n d a d olesce nts wit h sic kle cell disease. A S H 2 0 1 8 
a bstract # 5 0 5, oral prese ntati o n.
Ya w n B P, B uc ha na n G R, Afe n yi - A n na n A N, Ballas S K, Hassell K L, Ja mes A H, et al. 
Ma na ge me nt of sic kle cell disease. S u m mar y  of t he 2 0 1 4 e vi de nce-base d re p ort b y  e x pert 
pa nel me m bers. J A M A. 2 0 1 4; 3 1 2( 1 0): 1 0 3 3 -4 8. d oi: 1 0. 1 0 0 1/ja ma. 2 0 1 4. 1 0 5 1 7.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 7 2
A p pe n di x 1. Sc he d ule of Assess me nts
Peri o d
Scree ni n g
R u n -i n
1 2 -Wee k R a n d o mize d Tre at me nt
O pe n -l a bel Tre at me nt 
( mi ni m u m 1 2 wee ks)
F oll o w -
u p/ E O S 
Visit a , v
E arl y 
Ter mi n ati o n 
Visit
Visit N u m ber ( Wee k)
Visit 1
( Wee k -6 t o -
2)
Visit 2
( Wee k -2)
Visit 3
( Wee k 0)
Visits 4 - 8b
( Wee k 2-1 0)
Visit 9
( Wee k 1 2)
Visits 1 0 -1 4 c
( Wee k 1 4-
2 2)
Visit 1 5
( Wee k 
2 4)
Visit 1 6 -A 
& o n w ar d d
( Wee k 2 8)
Visit 1 6 - B
( Wee k 2 8) 
Visit D ay
-4 2 t o -1 4
-1 4
D ay 1
D ay 1 4 -7 0
D ay 8 4  
D ay 9 6 -1 5 4
D ay 1 6 8
D ay 1 9 6 & 
o n w ar d
D ay 1 9 6
Visit Wi n d o w
—
+ 3 d a ys
+ 1 d a y
± 3 d a ys 
± 3 d a ys 
± 3 d a ys 
± 3 d a ys 
± 5 d a ys 
± 7 d a ys
—
I nf or me d c o nse nt/asse nt
X
H b S S, H b S/ β 0
t halasse mia teste
X
I ncl usi o n/e xcl usi o nf
X
X  
X g
Me dical hist or y
X
Hei g ht a n d wei g ht
X
X h
P h y sical e xa mi nati o ni
X
X  
X
X
X  
X j
X  
X
Vital si g ns k
X
X  
X  
X  
X  
X  
X  
X l
X  
X
Ser u m pre g na nc y test m
X
Uri ne pre g na nc y test n
X  
X  
X  
X  
X  
X o
H e m at ol o g y p
X
X
X
X  
X l
X  
X
Ser u m c he mistr y q
X
X
X
X  
X l
X  
X
P R O MI S -4 3 v 2. 1 
P R O MI S -3 7 v 2. 0 
Pe diatric Pr ofile r
X
X
X
V A S r
X g
X
X
P GI - Cr
X
X
C GI - C
X
X
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 7 3
Peri o d
Scree ni n g
R u n -i n
1 2 -Wee k R a n d o mize d Tre at me nt
O pe n -l a bel Tre at me nt 
( mi ni m u m 1 2 wee ks)
F oll o w -
u p/ E O S 
Visit a, v
E arl y 
Ter mi n ati o n 
Visit
Visit N u m ber ( Wee k)
Visit 1
( Wee k -6 t o -
2)
Visit 2
( Wee k -2)
Visit 3
( Wee k 0)
Visits 4 - 8b
( Wee k 2-1 0)
Visit 9
( Wee k 1 2)
Visit 1 0 -1 4 c
( Wee k 1 4-
2 2)
Visit 1 5
( Wee k 
2 4)
Visit 1 6- A 
& o n w ar d d
( Wee k 2 8)
Visit 1 6 - B
( Wee k 2 8)
Visit D ay
-4 2 t o -1 4
-1 4
D ay 1
D ay 1 4 -7 0
D ay 8 4  
D ay 9 6 -1 5 4
D ay 1 6 8
D ay 1 9 6 & 
o n w ar d
D ay 1 9 6
Visit Wi n d o w
—
+ 3 d a ys
+ 1 d a y
± 3 d a ys 
± 3 d a ys 
± 3 d a ys 
± 3 d a ys 
± 5 d a ys 
± 7 d a ys
—
Tar get ulcer(s) 
assess me nt s
X
X  
X g
X  
X  
X  
X
X  
X
S O C
X
X  
X  
X  
X  
X  
X  
X l
X  
X
Ra n d o mizati o n
X
Dis pe nse st u d y dr u g t
X  
X  
X u
X
X l
C ollect st u d y dr u g
X  
X  
X  
X  
X l
X w
X
Dis pe nse d osi n g diar y
X
X
C ollect d osi n g diar y
X  
X  
X  
X
X w
X
C o nc o mita nt me dicati o ns
X
X  
X  
X  
X  
X  
X  
X l
X  
X
A d verse e ve nts
X
X  
X  
X  
X  
X  
X  
X l
X  
X
A b bre viati o ns: A L T, ala 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 GI -C, Cli nicia n Gl o bal I m pressi o n of C ha n ge; 
E O S, E n d of st u d y; H b, he m o gl o bi n; H b S/ β 0, sic kle he m o gl o bi n a n d o ne beta t halasse mia ge ne; H b S S, sic kle he m o gl o bi n wit h 2 sic kle cell ge nes; L D H, 
lactate de h y dr o ge nase; M C H, mea n cell he m o gl o bi n; M C H C, mea n c or p usc ular he m o gl o bi n c o nce ntrati o n; M C V, mea n c or p usc ular v ol ume; P GI -C, Patie nt 
Gl o bal I m pressi o n of C ha n ge; P R O MI S, Patie nt -Re p orte d O utc o me Meas ure me nts I nf or mati o n S yste m; R B C, re d bl o o d cell; R D W, re d bl o o d cell distri b uti o n 
wi dt h; S O C, sta n dar d of care; V A S, vis ual a nal o g scale; W B C, w hite bl o o d cell.
a.
Wee k 2 8 ( Visit 1 6 -B) will be f or partici pa nts w h o c h o ose n ot t o e nr oll or are i neli gi ble f or t he pr o visi o n of v o xel ot or t hr o u g h a n alter nati ve s o urce st u d y. 
At t his visit, safet y a n d efficac y assess me nts will be c ollecte d.
b.
Visits at Wee ks 2, 4, 6, 8, a n d 1 0.
c.
Visits at Wee ks 1 4, 1 6, 1 8, 2 0, a n d 2 2.
d.
F or partici pa nts w h o ha ve c o m plete d 1 2 w ee ks i n t he O pe n -la bel Treat me nt Peri o d a n d c o nti n ue t o recei ve v o xel ot or u ntil t he y ha ve access t o v o xel ot or 
fr o m a n alter nati ve s o urce (e g, t hr o u g h a cli nical O L E st u d y s p o ns ore d b y Pfizer, c o m mercializati o n of t he pr o d uct, or a ma na ge d access pr o gra m; See 
Secti o n 5. 1 ). T he fi nal st u d y visit f or t hese partici pa nts will occ ur o n t he da y of access t o v o xel ot or fr o m a n alter nati ve s o urce.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 7 4
Peri o d
Scree ni n g
R u n -i n
1 2 -Wee k R a n d o mize d Tre at me nt
O pe n -l a bel Tre at me nt 
( mi ni m u m 1 2 wee ks)
F oll o w -
u p/ E O S 
Visit a ,v
E arl y 
Ter mi n ati o n 
Visit
Visit N u m ber ( Wee k)
Visit 1
( Wee k -6 t o -
2)
Visit 2
( Wee k -2)
Visit 3
( Wee k 0)
Visits 4 - 8b
( Wee k 2-1 0)
Visit 9
( Wee k 1 2)
Visit 1 0 -1 4 c
( Wee k 1 4-
2 2)
Visit 1 5
( Wee k 
2 4)
Visit 1 6- A 
& o n w ar d d
( Wee k 2 8)
Visit 1 6 - B
( Wee k 2 8)
Visit D ay
-4 2 t o -1 4
-1 4
D ay 1
D ay 1 4 -7 0
D ay 8 4  
D ay 9 6 -1 5 4
D ay 1 6 8
D ay 1 9 6 & 
o n w ar d
D ay 1 9 6
Visit Wi n d o w
—
+ 3 d a ys
+ 1 d a y
± 3 d a ys 
± 3 d a ys 
± 3 d a ys 
± 3 d a ys 
± 5 d a ys 
± 7 d a ys
—
e.
T his test will be perf or me d at Scree ni n g o nl y f or t he me dical dia g n osis of S C D, if t his dia g n osis is n ot d oc u me nte d i n t he partici pa nt’s me dical c hart.
f.
All Scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d bef ore t he R u n -i n Visit t o c o nfir m all eli gi bilit y criteria are met. I ncl usi o n a n d e xcl usi o n criteria 
s h o ul d be re vie we d at Scree ni n g, R u n -i n, a n d j ust pri or t o ra n d omizi n g eac h partici pa nt t o e ns ure st u d y eli gi bilit y is met.
g.
T hese assess me nts m ust be c o m plete d bef ore partici pa nts are ra n d o mize d t o st u d y treat me nt.
h.
O nl y wei g ht will be meas ure d.
i.
P h y sical 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 used 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, t he tar get le g 
ulcer(s), a n d as relate d t o a d verse e ve nts.
j.
E ver y 4 8 w ee ks
k.
Vital si g ns ( heart rate, bl o o d press ure, a n d b o d y te m perat ure) w ill be meas ure d after a partici pa nt has reste d f or at least 5 mi n utes i n t he s u pi ne or sitti n g 
p ositi o n. A re peate d meas ure me nt of a n y of t he vital si g ns para meters will be ta ke n wit hi n 5 mi n utes if t he first rea di n g is o utsi de t he n or mal ra n ge a n d 
dee me d cli nicall y si g nifica nt.
l.
E ver y 1 2 w ee ks 
m.
Fe m ales of c hil d - beari n g p ote ntial a n d p ost me n o pa usal fe males will ha ve a ser u m pre g na nc y test at Scree ni n g.
n.
Uri ne pre g na nc y tests will be perf or me d at sc he d ule d visits f or w o m e n of c hil d -beari n g p ote ntial a n d p ost me n o pa usal fe males. If a uri ne pre g na nc y test is 
p ositi ve, t he res ult m ust be c o nfir me d wit h a ser u m pre g na nc y test. Uri ne pre g na nc y test will be perf or me d at Baseli ne ( Da y 1), Wee k 6, Wee k 1 2, Wee k 
1 8, a n d Wee k 2 4 i n fe male partici pa nts w h o ha ve e x perie nce d me narc he.
o.
E ver y 2 4 w ee ks f or wo m e n of c hil d -beari n g p ote n tial.
p.
H e m at ol o g y assess me nts will i ncl u de W B C ( w it h differe ntial), R B C c o u nt, H b, he mat ocrit, R D W, M C H, M C H C, M C V, platelet c o u nt, retic ul oc yte 
perce nta ge, a n d a bs ol ute retic ul oc yte c o u nt. Bl o o d s peci me ns c ollecte d at t he Da y 1 visit a n d Wee k 1 2 visit a n d f o u n d t o be i na de q uate f or la b orat or y 
testi n g s h o ul d be re dra w n a n d s u b mitte d f or la b orat or y testi n g wit hi n 7 da ys of t he st u d y visit.
q.
Ser u m c he mistr y will i ncl u de s o di u m, p otassi u m, bicar b o nate, c hl ori de, calci u m, p h os p h or us, B U N, creati ni ne, gl uc ose, bil ir u bi n (t otal, direct, a n d 
i n direct), t otal pr otei n, al b u mi n, A L T, al kali ne p h os p hatase, A S T, a n d L D H.
r.
T he P R O assess me nts will be e val uate d w he n a vaila ble ( pe n di n g tra nslati o n a n d c ult ural vali dati o n re q uire me nts).
s.
Tar get ulcer(s) assess me nts will be perf or me d b y vis ual i ns pecti o n (i ncl u di n g t he l o wer e xtre mit y e xa mi nati o n a n d detaile d descri pti o n of t he tar get 
ulcer[s]’ c haracteristics) a n d meas ure me nt of t he s urface area b y di gital p h ot o gra p h y. See t he Le g Ulcer Assess me nt a n d Meas u r e me nt Ma n ual f or 
a d diti o nal details.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 7 5
Peri o d
Scree ni n g
R u n -i n
1 2 -Wee k R a n d o mize d Tre at me nt
O pe n -l a bel Tre at me nt 
( mi ni m u m 1 2 wee ks)
F oll o w -
u p/ E O S 
Visit a , v
E arl y 
Ter mi n ati o n 
Visit
Visit N u m ber ( Wee k)
Visit 1
( Wee k -6 t o -
2)
Visit 2
( Wee k -2)
Visit 3
( Wee k 0)
Visits 4 - 8b
( Wee k 2-1 0)
Visit 9
( Wee k 1 2)
Visit 1 0 -1 4 c
( Wee k 1 4-
2 2)
Visit 1 5
( Wee k 
2 4)
Visit 1 6- A 
& o n w ar d d
( Wee k 2 8)
Visit 1 6 - B
( Wee k 2 8)
Visit D ay
-4 2 t o -1 4
-1 4
D ay 1
D ay 1 4 -7 0
D ay 8 4  
D ay 9 6 -1 5 4
D ay 1 6 8
D ay 1 9 6 & 
o n w ar d
D ay 1 9 6
Visit Wi n d o w
—
+ 3 d a ys
+ 1 d a y
± 3 d a ys 
± 3 d a ys 
± 3 d a ys 
± 3 d a ys 
± 5 d a ys 
± 7 d a ys
—
t.
St u d y dr u g will be dis pe nse d at t he Da y 1, Wee k 6, Wee k 1 2, a n d Wee k 1 8 visits. F or partici pa nts w h o c o nti n ue t o recei ve v o xe l ot or be y o n d 1 2 wee ks i n 
t he O pe n-la bel Treat me nt Peri o d ( See Secti o n 5. 1 ), st u d y dr u g will be dis pe nse d e ver y 1 2 wee ks.
u.
Partici pa nts de m o nstrati n g i nitial ulcer -re-e pit helizati o n at Wee k 1 2 will c o nti n ue treat me nt i n t heir assi g ne d treat me nt gro u p f or a n a d diti o nal 2 w ee ks t o    
c o nfir m ulcer res ol uti o n.
v.
Partici pa nts tra nsiti o ni n g t o a pr o gra m pr o vi di n g v o xel ot or t hr o u g h a n alter nati ve s o urce will c o m plete assess me nts o n t he da y t he y tra nsiti o n t o t hat 
pr o gra m. St u d y dr u g f or t his st u d y s h o ul d n ot be ta ke n o n t he da y of t hat visit ( d ose w ill be ta ke n o n t hat da y as part of t he alter nati ve s o urce pr o gra m).   
w.
O nl y re q uire d f or partici pa nts tra nsiti o ni n g t o a pr o gra m pr o vi di n g v o xel ot or t hr o u g h a n alter nati ve s o urce
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 7 6
A p pe n di x 2. Li ver S afet y: S u g geste d acti o ns a n d f oll o w- u p assess me nts a n d st u d y dr u g 
rec h alle n ge g ui deli nes
P ote nti al C ases of Dr u g -I n d uce d Li ver I nj ur y
H u ma ns e x p ose d t o a dr u g w h o s h o w n o si g n of li ver i nj ur y  (as deter mi ne d b y ele vati o ns i n 
tra nsa mi nases) are ter me d “t olerat ors,” w hile t h ose w h o s h o w tra nsie nt li ver i nj ur y  b ut a da pt 
are ter me d “a da pt ors.” I n s o me partici pa nts, tra nsa mi nase ele vati o ns are a har bi n ger of a 
m ore seri o us p ote ntial o utc o me. T hese partici pa nts fail t o a da pt a n d t heref ore are 
“s usce pti ble” to pr o gressi ve a n d seri o us li ver i nj ur y , c o m m o nl y referre d t o as DI LI. 
Partici pa nts w h o e x perie nce a tra nsa mi nase ele vati o n a b o ve 3 × t he u p per li mit of n or mal 
( U L N) s h o ul d be m o nit ore d m ore fre q ue ntl y t o deter mi ne if t he y are “a da pt ors ” or are 
“s usce pti ble.”
Li ver f u ncti o n tests ( L F Ts) are n ot re q uire d as a r o uti ne safet y m o nit ori n g pr oce d ure i n t his 
st u d y. H o we ver, s h o ul d a n i n vesti gat or dee m it necessar y t o assess L F Ts beca use a 
partici pa nt prese nts wit h cli nical si g ns/s y m pt o ms, s uc h L F T res ults s h o ul d be ma na ge d a n d 
f oll o we d as descri be d bel o w.
I n t he maj orit y of DI LI cases, ele vati o ns i n A S T  (as partate a mi n otra nsa mi nase) a n d/ or A L T 
(ala ni ne a mi n otra nsa mi nase) prece de t otal bilir u bi n ele vati o ns ( > 2 × U L N) b y  se veral da ys 
or wee ks. T he i ncrease i n t otal b ilir u bi n t ypicall y  occ urs w hile A S T/ A L T is/are still ele vate d 
a b o ve 3 × U L N (ie, A S T/ A L T a n d t otal bilir u bi n val ues will be ele vate d wit hi n t he sa me 
la b orat or y sa m ple). I n rare i nsta nces, b y t he ti me t otal bilir u bi n ele vati o ns are detecte d, 
A S T/ A L T val ues mi g ht ha ve decrease d. T his occ urre nce is still re gar de d as a p ote ntial DI LI. 
T heref ore, a b n or mal ele vati o ns i n eit her A S T  or A L T i n a d diti o n t o t otal bilir u bi n t hat meet 
t he criteria o utli ne d bel o w are c o nsi dere d p ote ntial DI LI (assesse d per H y’s la w criteria) 
cases a n d s h o ul d al wa y s be c o nsi dere d i m p orta nt me dical e ve nts, e ve n bef ore all ot her 
p ossi ble ca uses of li ver i nj ur y  ha ve bee n e xcl u de d.
T he t hres h ol d of la b orat or y  a b n or malities f or a p ote ntial DI LI case de pe n ds o n t he 
partici pa nt ’s i n di vi d ual baseli ne val ues a n d u n derl yi n g c o n diti o ns. Partici pa nts w h o prese nt 
wit h t he f oll o wi n g la b orat or y  a b n or malities s h o ul d be e val uate d f urt her as p ote ntial DI LI 
( Hy ’s la w) cases t o defi niti vel y deter mi ne t he eti ol o g y of t he a b n or mal la b orat or y val ues:

Partici pa nts wit h A S T/ A L T a n d t otal bilir u bi n val ues wit hi n t he n or mal ra n ge 
w h o s u bse q ue ntl y  prese nt wit h A S T/ A LT val ues ≥3 × U L N A N D a t otal 
bilir u bi n val ue ≥2 × U L N wit h n o e vi de nce of he m ol y sis a n d a n al kali ne 
p h os p hatase val ue < 2 × U L N or n ot a vaila ble.

F or pa rtici pa nts wit h baseli ne A S T O R A L T O R t otal bilir u bi n val ues a b o ve t he 
U L N, t he f oll o wi n g t hres h ol d val ues are use d i n t he defi niti o n me nti o ne d a b o ve, 
as nee de d, de pe n di n g o n w hic h val ues are a b o ve t he U L N at baseli ne:

Pree xisti n g A S T/ A L T baseli ne val ues a b o ve t he n or mal ra n ge: A S T/ A L T 
val ues ≥2 ti mes t he baseli ne val ues A N D ≥3 × U L N; or ≥8 × U L N 
( w hic he ver is s maller).
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


Gl o bal Bl o o d T hera pe utics, I nc., a w h oll y o w ne d s u bsi diar y of Pfizer, I nc .
V o xel ot or
Pr ot oc ol A me n d me nt 3. 0
G B T 4 4 0 -0 4 2/ C 5 3 4 1 0 2 6
P FI Z E R C O N FI D E N TI A L
Pa ge 7 7

Pree xisti n g val ues of t otal bilir u bi n a b o ve t he n or mal ra n ge: t otal bilir u bi n 
le vel i ncrease d fr o m baseli ne val ue by a n a m o u nt of ≥1 × U L N o r if t he val ue 
reac hes ≥3 × U L N ( w hic he ver is s maller).
Rises i n A S T/ A L T a n d t otal bilir u bi n se parate d b y m ore t ha n a fe w wee ks s h o ul d be assesse d 
i n di vi d uall y base d o n cli nical j u d g me nt; a n y case w here u ncertai nt y re mai ns as t o w het her it 
re prese nts a p ote ntial H y’s la w case s h o ul d be re vie we d wit h t he s p o ns or. 
T he partici pa nt s h o ul d ret ur n t o t he i n vesti gat or site a n d be e val uate d as s o o n as p ossi ble, 
prefera bl y wit hi n 4 8 h o urs fr o m a ware ness of t he a b n or mal res ults. T his e val uati o n s h o ul d 
i ncl u de la b orat or y tests, detaile d hist or y, a n d p hys ical assess me nt.
I n a d diti o n t o re peati n g meas ure me nts of A S T a n d A LT a n d t otal bilir u bi n f or s us pecte d 
H y ’s la w cases, a d diti o nal la b orat or y tests s h o ul d i ncl u de al b u mi n, creati ne ki nase, direct a n d 
i n direct bilir u bi n, ga m ma-gl uta m yl  tra nsferase, pr ot hr o m bi n ti me/i nter nati o nal n or malize d 
rati o, e osi n o p hils ( %), a n d al kali ne p h os p hatase. C o nsi derati o n s h o ul d als o be gi ve n t o 
dra wi n g a se parate t u be of cl otte d bl o o d a n d a n a ntic oa g ulate d t u be of bl o o d f or f urt her 
testi n g, as nee de d, f or f urt her c o nte m p ora ne o us a nal yses at t he ti me of t he rec o g nize d i nitial 
a b n or malities t o deter mi ne eti ol o g y . A detaile d hist or y, i ncl u di n g rele va nt i nf or mati o n, s uc h 
as re vie w of et ha n ol, aceta mi n o p he n/ paraceta m ol (eit her b y itself or as a c of or m ulate d 
pr o d uct i n prescri pti o n or o ver -t he-c o u nter me dicati o ns), recreati o nal dr u g, or s u p ple me nt 
( her bal) use a n d c o ns u m pti o n, fa mil y hist or y, se x ual hist or y, tra vel hist or y, hist or y of c o ntact 
wit h a ja u n dice d pers o n, s ur ger y , bl o o d tra nsf usi o n, hist or y of li ver or aller gic disease, a n d 
p ote ntial occ u pati o nal e x p os ure t o c he micals, s h o ul d be c ollecte d. F urt her testi n g f or ac ute 
he patitis A, B, C, D, a n d E i nfecti o n , t otal bile aci ds, li ver i ma gi n g (e g, biliar y tract), a n d 
c ollecti o n of ser u m sa m ples f or aceta mi n o p he n/ paraceta m ol dr u g a n d/ or pr otei n a d d uct 
le vels ma y be warra nte d. 
All cases de m o nstrate d o n re peat testi n g as meeti n g t he la b orat or y  criteria of A S T/ A L T a n d 
t otal bilir u bi n ele vati o n defi ne d a b o ve s h o ul d be c o nsi dere d p ote ntial DI LI ( Hy’ s la w) cases 
if n o ot her reas o n f or t he L F T a b n or malities has yet bee n f o u n d. S uc h p ote nti al DI LI ( H y’s 
l a w) c ases are t o be re p orte d as S A Es, irres pecti ve of a v ail a bilit y of all t he res ults of t he 
i n vesti g ati o ns perf or me d t o deter mi ne eti ol o g y of t he L F T a b n or m alities.
A p ote ntial DI LI ( H y ’s la w) case bec o mes a c o nfir me d case o nly after all res ults of 
reas o na ble i n vesti gati o ns ha ve bee n recei ve d a n d ha ve e xcl u de d a n alternati ve eti ol o g y.
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)


D o c u m e nt A p pr o v al R e c or d
D o c u m e nt N a m e:
D o c u m e nt Titl e:
Si g n e d B y:
D at e( G M T)
Si g ni n g C a p a cit y
0 9 0 1 7 7 e 1 9f 8 8 e 0 0 9\ A p pr o v e d\ A p pr o v e d O n: 2 5- D e c- 2 0 2 3 1 4: 4 6 ( G M T)
P P D
P P D

SAP_001.pdf: 
Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 of 4 3
A P h ase 3 , M ultice nter, R a n d o mize d, D o u ble-Bli n d, Pl ace b o --C o ntr olle d Tri al t o 
E v al u ate t he Effic ac y of V o xel ot or f or t he Tre at me nt of Le g Ulcers i n P atie nts wit h 
Sic kle Cell Dise ase
St atistic al A n al ysis Pl a n f or Pr ot oc ol G B T 4 4 0 - 0 4 2 (C 5 3 4 1 0 2 6 )
( S A P)
Versi o n : 
<4 >   
D A T E:
1 6 -D E C - 2 0 2 4  
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 of 4 3
T A B L E O F C O N T E N T S
LI S T O F T A B L E S .....................................................................................................................3
LI S T O F FI G U R E S ...................................................................................................................3
A P P E N DI C E S ...........................................................................................................................4
1. V E R SI O N HI S T O R Y ............................................................................................................5
2. I N T R O D U C TI O N ...............................................................................................................1 0
2. 1. M o dificati o ns t o t he A nal y sis Pla n Descri be d i n t he Pr ot oc ol................................1 0
2. 2. St u d y  O bjecti ves a n d E n d p oi nts .............................................................................1 0
2. 3. St u d y  Desi g n...........................................................................................................1 1
2. 3. 1. Sa m ple Size Deter mi nati o n........................................................................ 1 3
2. 3. 2. Treat me nt Gr o u p a n d Re p orti n g Peri o d f or A nal y sis .................................1 3
2. 3. 3. Defi niti o ns a n d Ter mi n ol o g y ......................................................................1 4
3. E N D P OI N T S A N D B A S E LI N E V A RI A B L E S:  D E FI N I TI O N S A N D 
C O N V E N TI O N S................................ ................................................................................1 6
3. 1. Pri mar y  E n d p oi nt(s)................................................................................................1 6
3. 2. Sec o n dar y  E n d p oi nt(s)............................................................................................1 6
3. 3. E x pl orat or y E n d p oi nt(s) ..........................................................................................1 7
3. 4. Baseli ne Varia bles ...................................................................................................1 8
3. 4. 1. Stratificati o n Varia ble................................................................................. 1 8
3. 4. 2. Ot her Baseli ne Varia bles t o be S u m marize d ..............................................1 8
3. 5. Safet y E n d p oi nts .....................................................................................................1 9
3. 5. 1. A d verse E ve nts ...........................................................................................1 9
3. 5. 2. L a b orat or y Data..........................................................................................1 9
3. 5. 3. Ot her Safet y E n d p oi nts ...............................................................................2 0
4. A N A L Y SI S S E T S ( P O P U L A T I O N S F OR A N A L Y SI S) ...................................................2 0
5. G E N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S ....................................................2 1
5. 1. H y p ot heses a n d Decisi o n R ules ..............................................................................2 1
5. 2. Ge neral Met h o ds .....................................................................................................2 1
5. 2. 1. A nal y ses f or Bi nar y E n d p oi nts...................................................................2 1
5. 2. 2. A nal y ses f or C o nti n u o us E n d p oi nts ...........................................................2 1
5. 2. 2. 1. Mi xe d M o del Re peate d Meas ures ( M M R M)............................ 2 1
5. 2. 3. A nal y ses f or Ti me-t o E ve nt E n d p oi nts.......................................................2 2
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 of 4 3
5. 2. 4. C orrelati o n A nal ys is Bet wee n C o nti n u o us a n d Bi nar y E n d p oi nts.............2 2
5. 3. Met h o ds t o Ma na ge Missi n g Data ..........................................................................2 3
5. 3. 1. Stat us of Tar get St u d y  Ulcer(s) ..................................................................2 3
5. 3. 2. I m p utati o n of I nc o m plete Dates .................................................................2 3
6. A N A L Y S E S A N D S U M M A RI E S ......................................................................................2 4
6. 1. Pri mar y  E n d p oi nt ....................................................................................................2 4
6. 2. Sec o n dar y  E n d p oi nts...............................................................................................2 4
6. 3. E x pl orat or y  Efficac y E n d p oi nts..............................................................................2 5
6. 4. S u bset A nal y ses.......................................................................................................2 8
6. 4. 1. S u bset a nal y sis f or efficac y e n d p oi nts........................................................2 8
6. 4. 1. 1. Pri mar y  E n d p oi nt ......................................................................2 8
6. 4. 1. 2. Sec o n dar y  E n d p oi nt ..................................................................2 8
6. 4. 2. S u bset a nal y sis f or safety e n d p oi nts ...........................................................2 9
6. 5. Baseli ne a n d Ot her S u m maries a n d A nal ys es .........................................................2 9
6. 5. 1. Baseli ne S u m maries ....................................................................................2 9
6. 5. 2. St u d y  C o n d uct a n d Partici pa nt Dis p ositi o n................................................3 0
6. 5. 3. C o nc o mita nt Me dicati o ns a n d N o n dr u g T reat me nts..................................3 0
6. 6. Safet y S u m maries a n d A nal yses .............................................................................3 0
6. 6. 1. A d verse E ve nts ...........................................................................................3 0
6. 6. 2. L a b orat or y Data..........................................................................................3 1
6. 6. 3. Vital Si g ns ..................................................................................................3 1
7. I N T E RI M A N A L Y S E S .......................................................................................................3 2
8. R E F E R E N C E S ....................................................................................................................3 2
A P P E N DI C E S .........................................................................................................................3 3
LI S T O F T A B L E S
Ta ble 1.
S u m mar y  of C ha n ges..................................................................................5
Ta ble 2.
Pr ot oc ol -Re q uire d Safet y L a b orat or y Assess me nts .................................2 0
LI S T O F FI G U R E S
Fi g ure 1.
St u d y  Sc he ma ...........................................................................................1 2
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 of 4 3
A P P E N DI C E S
A p pe n di x 1. S u m mar y  of Efficac y A nalys es ........................................................................... 3 3
A p pe n di x 2. Data Deri vati o n Details ....................................................................................... 3 5
A p pe n di x 2. 1. Defi niti o n a n d Use of Visit Wi n d o ws i n Re p orti n g ......................................... 3 5
A p pe n di x 2. 2. Pr ot oc ol De viati o ns t hat Relate d t o Statistical A nal yses/ P o p ulati o ns ............. 3 7
A p pe n di x 3. Data C o n versi o n .................................................................................................. 3 8
........................................................... 4 1
A p pe n di x 5. L ist of A b bre viati o ns........................................................................................... 4 2
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C CI


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 5 of 4 3
1. V E R SI O N HI S T O R Y
T a ble 1 .
S u m m ar y of C h a n ges
Versi o n /
D ate
Ass oci ate d 
Pr ot oc ol 
A m e n d me nt
R ati o n ale
S pecific C h a n ges
4 /
1 6 -Dec - 2 0 2 4
Pr ot oc ol 
A me n d me nt 3 
2 2 Dece m ber 
2 0 2 3
U p date f or t he
fi nal C S R 
Secti o n 2:
A d de d a se nte nce a b o ut d ose pa use a n d 
st u d y ter mi nati o n.
Secti o n 2. 3. 2 :

Re place d t he o pe n la bel treat me nt 
peri o d wit h t he o pe n la bel treat me nt 
e xte nsi o n peri o d 

Clarifie d t he a nalys is peri o d
Secti o n 2. 3. 3:
Clarifie d t he baseli ne defi niti o n f or la bs 
a n d vital si g ns
Secti o n 3. 4. 2:
A d de d baseli ne disease c haracteristics, 
sic kle cell disease ge n ot y pe a n d 
H y dr o x y urea use.
Secti o n 3. 5. 1:
Clarifie d Me d D R A versi o n
Secti o n 3. 5. 3:
Re m o ve d t he ne ur ol o gical e xa mi nati o n.
Secti o n 4:
Clarifie d a nal ys is p o p ulati o n.
Secti o n 6. 4:
M o difie d Secti o n title a n d a d de d safet y 
s u b gr o u p a nalys is
Secti o n 6. 6:

A d de d a se nte nce f or O pe n -la bel 
treatme nt e xte nsi o n peri o d 

U p date d t he w or di n gs t o S C D -relate d 
a n d n o n -S C D relate d e ve nts.

A d de d listi n g of S C D a n d n o n-S C D 
relate d n o n-T E A Es.

M o difie d vital si g ns will be e val uate d 
t hr o u g h e n d of st u dy visit.
3/
0 2 -J ul- 2 0 2 4
Pr ot oc ol 
A me n d me nt 3 
2 2 Dece m ber 
2 0 2 3
U p d ate t o 
Secti o n he a ders 
t o reflect 
e n d p oi nts a n d 
pr o vi de cl arit y
f or t he a n al ysis.
Secti o n 3. 1:
A d de d t he defi niti o n of tar get ulcers.
Secti o n 3. 3:
A d de d P GI -C a n d C GI -C q uesti o n naire.
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 6 of 4 3
Secti o n 6. 3

A d de d t he a nal y sis f or t he ra w sc ore of 
P R O MI S e n d p oi nts.

M o difie d t he a nal ys is f or P GI-C a n d 
C GI -C.
A p pe n di x 1:
A d de d t hr ee e x pl orat or y e n d p oi nts.
A p pe n di x 2. 1:
A d de d a f o ot n ote of visit wi n d o wi n g t o 
clarif y t he Da y 1 le g ulcer assess me nt.
2/
2 6- Ja n-2 0 2 4
Pr ot oc ol 
A me n d me nt 3
2 2 Dece m ber
2 0 2 3
U p date d t o 
matc h pr ot oc ol 
a me n d me nt 3.

Secti o ns 2. 2, 3. 3 a n d 6. 3 a n d A p pe n di x 
1 -  Re m o ve d detail w or di n gs o n 
P R O MI S meas ures

Secti o n 2. 3 -  U p date d Fi g ure 1 St u d y  
sc he ma
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C CI


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 7 of 4 3
U p date t o 
Secti o n 
hea ders t o 
reflect 
e n d p oi nts a n d 
pr o vi de clarit y
f or t he 
a nal ys is.

Secti o n 2. 2 – A d de d e x pl orat or y
e n d p oi nts.   

Secti o n 2. 3. 2 - A d de d m ore detail o n 
t he sce nari o f or s u bjects w h o ha ve t he 
i nitial s ki n re-e pit helializati o n 
c o nfir me d at Wee k 1 2

Secti o n 3. 1 - Ad de d a defi niti o n of t he 
tar get ulcer(s).

Secti o n 3. 3 - C ha n ge d ‘ Ot her ’ t o 
‘E x pl orat or y ’ i n t he Secti o n title a n d 
ad de d details o n h eali n g at Wee k 1 2 
a n d Wee k 2 4 a n d m o difie d he m ol y tic 
para meter . 
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 8 of 4 3

Secti o n 3. 4. 1 - Ad de d details o n 
stratificati o n fact ors.

Secti o n 3. 4. 2 - A d de d c o u ntr y a n d site 
i n t he baseli ne varia bles t o be 
s u m marize d.

Secti o n 3. 5. 2 - A d de d T otal pr otei n s
a n d P h os p h or us i n t he Ser u m 
C he mistr y  la b orat or y assess me nt i n 
Ta ble 2.  

Secti o n 5. 2. 1 - A d de d details o n 
pr o p orti o n differe nce

Secti o n 5. 2. 2. 1 - Re m o ve d 
stratificati o n fact ors a n d re m o ve d a 
se nte nce of differe nce i n L S mea ns as 
it is me nti o ne d i n Secti ons 6. 2 a n d 6. 3.  

Secti o n 5. 2. 3 - M o difie d w or di n gs f or 
t he stratifie d C o x re gressi o n m o del.

Secti o n 5. 2. 4 – U p date d A p pe n di x 4 
fr o m 4. 2 

Secti o n 6. 1 - Re m o ve d A p pe n di x 4. 1 . 

Secti o ns 6. 2 a n d 6. 3 - A d de d details o n 
t he M M R M a n d C o x re gressi o n m o del, 
ad de d ‘fr o m baseli ne’ t o clarif y t he 
e n d p oi nt, m o difie d descri pti o n of 
c o variates , ad de d M M R M a nal ysis f or 
P R O MI S a n d V A S e x pl orat or y  
e n d p oi nts a n d re m o ve d t he se nte nce 
‘ N ote t hat …’ as it is n ot nee de d.  

Secti o n 6. 4 - A d de d Secti o ns 6. 4. 1 a n d 
6. 4. 2 f or t he s u b gr o u p a nal ysis of 
pri mar y  a n d sec o n dar y e n d p oi nts, 
sec o n dar y e n d p oi nts f or t he s u b gr o u p 
a nal ys is a n d a ge gr o u p a n d c o u ntr y i n 
t he s u b gr o u p a nalys is a n d a d de d f orest 
pl ot f or t he s u b gr o u p a nal y sis a n d p-
val ues w ill n ot be pr o vi de d.
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 9 of 4 3

Secti o n 6. 5 - A d de d si te a n d re gi o n i n 
t he baseli ne s u m mar y ta ble a n d act uall 
e x p os ure t o st u d y dr u g will be 
s u m marize d.

Secti o n 6. 6. 1 - A d de d S C D - relate d 
A Es i n t he re p orti n g a n d re m o ve d 
safety data base as t he ta ble are base d 
o n cli nical data base.

Secti o n 6. 6. 2 - Re vise d la b u nit t o SI , 
re m o ve d t he a p pr oac h of ha n d li n g
e xtre me la b val ues, re m o ve d treat me nt -
e mer ge nt gra de d a b n or mal A Es a n d 
s hift ta ble f or o ne gra de or m ore fr o m 
baseli ne a n d ad de d H y ’s La w a n d E-
DI S H pl ot.

Secti o n 8 – U p date d t he refere nce f or 
stratifie d C o x m o del a n d re m o ve d 
refere nce # 7 as n ot nee de d.

A p pe n di x 1 – A d de d s u b gr o u p a nal ys is
a n d L S  mea ns f or P R O P R O MI S a n d 
V A S e n d p oi nts i n t he a nal ysis ty pe a n d 
m ore detail s i n t he mai n a nalys is 
m o del .  

A p pe n di x 2 - A d de d safet y  e n d p oi nts 
a n d m o difie d visit wi n d o ws a n d visit 
wi n d o ws f or la b orat or y  assess me nts. 

A p pe n di x 3 - A d de d P R O MI S T -sc ore 
c o n versi o n ta ble.

A p pe n di x 4 – Re m o ve d A p pe n di x 4. 1 
a n d m o difie d A p pe n di x 4. 2 t o 4.

A p pe n di x 5 – A d de d I R T , SI  a n d 
T E S A E a n d re m o ve d C D A R S, H R, 
Q T a n d Q Tc F fr o m t he ta ble.
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 0 of 4 3
2. I N T R O D U C TI O N
T his S A P pr o vi des t he detaile d met h o d ol o g y  f or s u m mar y a n d statistical a nal yses of t he data 
c ollecte d i n S t u d y G B T 4 4 0 -0 4 2 f or t he fi nal C S R after last s u bject last visit ( LS L V) . T his 
d oc u me nt ma y  m o dif y t he pla ns o utli ne d i n t he pr ot oc ol; h o we ver, a n y maj or m o dificati o ns 
of t he pri mar y  e n d p oi nt defi niti o n or its a nal ysis will als o be reflecte d i n a pr ot oc ol 
a me n d me nt. Statistical a nal y ses will be perf or me d usi n g clea ne d case re p ort f or m ( C R F) data 
as well as n o n -C R F data (i.e., bl o o d sa m ples data a n d ba n ke d bi os peci me ns) . 
T he a d mi nistrati o n of t he st u d y i nter ve nti o n was v ol u ntaril y  pa use d b y  t he S p o ns or o n 
1 0 Ma y
2 0 2 4 d ue t o t he o verall n u m ber of deat hs o bser ve d i n t he st u d y . The decisi o n was 
ma de b y  t he s p o ns or t o ter mi nate t he st u d y o n 2 5 Se pte m ber 2 0 2 4 a n d t he L S L V w a s o n 2 2 
Oct o ber 2 0 2 4.
2. 1. M o dific ati o ns
t o t he A n al ysis Pl a n Descri be d i n t he Pr ot oc ol
N ot a p plica ble.
2. 2. St u d y O bjecti ves a n d E n d p oi nts
T y pe
O bjecti ve
E n d p oi nt
Pri m ar y
Pri m ar y
Pri m ar y
Efficac y
C haracterize t he effect of 
v o xel ot or a n d S O C
(sta n dar d of care)
c o m pare d t o place b o a n d 
S O C o n le g ulcer heali n g 
i n partici pa nts ≥ 1 2 y ears 
of a ge wit h S C D b y Wee k 
1 2
T he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of t he tar get 
ulcer(s), 
 
 d uri n g t he 1 2-wee k 
Ra n d o mize d Treat me nt Peri o d. 
 
 
Sec o n d ar y 
Sec o n d ar y
Sec o n d ar y
Efficac y
C haracterize t he effect of 
v o xel ot or a n d S O C 
c o m pare d t o place b o a n d 
S O C o n sec o n dar y 
e n d p oi nts

Ti m e (i n da ys) t o res ol uti o n of tar get ulcer(s) u p t o 
Wee k 1 2

C ha n ge i n t otal s urface area(s) of tar get ulcer(s) at 
Wee k 1 2

I nci de nce of ne w ulcers b y  Wee k 1 2
E x pl or at or y 
E x pl or at or y
E x pl or at or y
Efficac y
C haracterize t he effect of 
v o xel ot or a n d S O C 
c o m pare d t o place b o a n d 
S O C o n e x pl orat or y 
e n d p oi nts

Pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of 
tar get ulcer(s) b y Wee k 2 4

Ti m e (i n da ys) t o res ol uti o n of tar get ulcer(s) u p t o 
Wee k 2 4

C ha n ge fr o m baseli ne i n t otal s urface area of tar get 
ulcer(s) o ver ti me u p t o Wee k 2 4
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C CI
C CI


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 1 of 4 3
T y pe
O bjecti ve
E n d p oi nt

C orrelati o n bet w ee n c ha n ge i n H b a n d tar get ulcer(s) 
heali n g at Wee k 1 2 a n d Wee k 2 4

C orrelati o n bet wee n c ha n ge i n he m ol yti c para meters 
( % retic ul oc ytes, i n direct bilir u bi n, L D H) a n d tar get 
ulcer(s) heali n g at Wee k 1 2 a n d Wee k 2 4

Healt h -relate d q ualit y of life ( H R Q O L) usi n g patie nt-
re p orte d o utc o me ( P R O) meas ures, w he n a vaila ble 
( pe n di n g tra nslati o n a n d c ult ural vali dati o n 
re quire me nts)
o
C ha n ge fr o m baseli ne i n P R O H R Q O L 
meas ures: P R O MI S -3 7 v 2. 0 Pe diatric 
Pr ofile/ P R O MI S -4 3 v 2. 1 at Wee k 1 2 a n d 
Wee k 2 4
o
C ha n ge fr o m baseli ne i n pai n le vel li n ke d t o 
tar get ulcer(s) assesse d b y V A S at Wee k 1 2 
a n d Wee k 2 4
o
Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI -
C) sc ore at Wee k 1 2 a n d Wee k 2 4

Cli nicia n Gl o bal I m pressi o n of C ha n ge ( C GI -C) sc ore 
at Wee k 1 2 a n d Wee k 2 4
Safet y
A ssess t he safet y a n d 
t olera bilit y of v o xel ot or 
c o m pare d t o place b o

A E s

Cli nical la b orat or y tests

P h y sical e xa mi nati o ns

Vital si g ns

Ot her cli nical meas ures (e g. disc o nti n uati o n d ue t o 
A E s, d ose re d ucti o ns) 
2. 3. St u d y Desi g n
T his st u d y  is a P hase 3, m ultice nter, ra n d o mize d, place b o-c o ntr olle d st u d y t o e val uate t he 
efficac y of v o xel ot or a n d S O C f or t he treat me nt of le g ulcers i n partici pa nts wit h S C D. T he 
st u d y is di vi de d i nt o 5 st u d y peri o ds: Scree ni n g, R u n-i n, Ra n d o mize d Treat me nt, O pe n-la bel 
Treat me nt, a n d F oll o w -u p/ E n d of St u d y  ( E O S). 
T he st u d y  will be c o n d ucte d i n a p pr o xi matel y 8 0 eli gi ble partici pa nts at a p pr o xi matel y 2 0 
gl o bal cli nical trial sites. Partici pa nts i n t his st u d y  will ha ve safety a n d efficac y assess me nts 
perf or me d at t he i n vesti gati ve cli nic per t he pr ot oc ol Sc he d ule of Assess me nts .  T he o verall 
st u d y desi g n is ill ustrate d i n t he St u d y Sc he ma pr o vi de d i n Fi g ure 1 .
St u d y Sc he ma
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 2 of 4 3
Fi g ure 1.
St u d y Sc he m a
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 3 of 4 3
2. 3. 1. S a m ple Size Deter mi n ati o n
A p pr o xi matel y  8 0 partici pa nts will be e nr olle d i n t he st u d y. Partici pa nts will be ra n d o mize d 
i n a 1: 1 rati o t o recei ve treat me nt wit h v o xel ot or 1 5 0 0 m g or place b o f or 1 2 wee ks . T he 
pri mar y  e n d p oi nt will be meas ure d b y t he pr o p ortio n of partici pa nts ac hie vi n g res ol uti o n of 
t he tar get ulcer(s), 
 
d uri n g t he 1 2 - wee k Ra n d o mize d Treat me nt Peri o d.
 
F or t he pri mar y  e n d p oi nt, t he sa m ple size of 8 0 partici pa nts ( 4 0 partici pa nts per treat me nt 
gr o u p) pr o vi des a p pr o xi matel y  9 0 % p o wer t o detect a 3 5 % a bs ol ute differe nce bet wee n 
treat me nt gr o u ps ( v o xel ot or 1 5 0 0 m g + S O C vers us place b o + S O C) i n pr o p orti o n of 
partici pa nts e x perie nci n g res ol uti o n of t he tar get ulcer(s) b y Wee k 1 2. Calc ulati o ns were 
base d o n a t w o -si de d al p ha = 5 % test of t he differe nce i n t w o bi n o mi al pr o p orti o ns ( N or mal 
a p pr o xi mati o n).
2. 3. 2. Tr e at me nt Gr o u p a n d Re p orti n g Peri o d f or A n al ysis
I n t he st u dy s c he matic i n Fi g ure 1.
St u d y Sc he ma , t he st u d y peri o d a n d treat me nt gr o u ps t o 
b e i ncl u de d i n t he pri mar y a n d o pe n -la bel a nalys is.
Efficac y  a n d Safety:  Pri mar y  a nalys is (Ra n d o mize d Treat me nt Peri o d):

Treat me nt gr o u ps:
1.
V o xel ot or : partici pa nts ra n d o mize d t o v o xel ot or .
2.
Place b o : partici pa nts ra n d o mize d t o p lace b o.

Re p orti n g Peri o d:

Fr o m D a y  1 t hr o u g h Wee k 1 2 f or s u bjects w h o eit her d o n ot ac hie ve c o nfir me d re-
e pit helializati o n or ac hie ve it bef ore or at Wee k 1 2 visit .

Fr o m Da y  1 t hr o u g h Wee k 1 4 f or s u bjects w h o ha ve t he i nitial s ki n re-
e pit helializati o n c o nfir me d at Wee k 1 2 a n d t he n t he 1 4- wee k visit will be use d t o 
c o nfir m res ol uti o n.
D a y  1 is defi ne d as t he date of ra n d o mizati o n. T he last da y  (i.e. Wee k 1 2 visit or Wee k 
1 4 ) of ra n d o mize d treat me nt p eri o d is defi ne d as t he last da y  e ntere d o n t he dis p ositi o n 
pa ge f or e n d of ra n d o mize d treat me nt p eri o d.
Efficac y : O pe n -la bel a nal ysis ( O pe n-La bel Treat me nt Peri o d):

Treat me nt gr o u ps:
1.
V o xel ot or : partici pa nts ra n d o mize d t o v o xel ot or w h o recei ved a t least o ne d ose of 
v o xel ot or .
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C CI
C CI


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 4 of 4 3
2.
Dela y e d v o xel ot or: partici pa nts ra n d o mize d t o place b o d uri n g Ra n d o mize d T reat me nt 
P eri o d (t hr o u g h Wee k 1 2) a n d w h o recei ve d at least o ne d ose of v o xel ot or o n or after 
t he Wee k 1 2
visit .
3.
T otal: partici pa nts w h o recei ve d at least o ne d ose of v o xel ot or .

Re p orti n g Peri o d:

After Wee k 1 2
(o ne da y  after Wee k 1 2 visit) t hro u g h Wee k 2 4 f or s u bjects w h o eit her 
d o n ot ac hie ve c o nfir me d re -e pit helializati o n or ac hie ve d it bef ore or at Wee k 1 2 
visit.

After Wee k 1 4 ( o ne da y  after Wee k 14 visit) t hr o u g h Wee k 2 4 f or s u bjects w h o ha ve 
t he i nitial s ki n re-e pit helializati o n c o nfir me d at Wee k 1 2 a n d t he n t he 1 4-wee k visit 
will be use d t o c o nfir m res ol uti o n.
Safet y : O pe n-la bel a nalysis ( O pe n -La bel Treat me nt E xte nsi o n Peri o d w hic h is c o m bi ni n g t he 
e ntire O pe n -La bel Treat me nt Peri o d a n d t he F oll o w -u p Peri o d ):

Treat me nt gr o u ps:
1.
V o xel ot or: partici pa nts ra n d o mize d t o v o xel ot or a n d recei ve d at least o ne d ose of 
v o xel ot or .
2.
Dela y e d v o xel ot or: partici pa nts ra n d o mize d t o place b o a n d w h o di d n ot recei ve 
v o xel ot or d uri n g Ra n d o mize d Treat me nt Peri o d (t hr o u g h Wee k 1 2) a n d w h o recei ve d 
at least o ne d os e of v o xel ot or o n d uri n g t he o pe n -la bel peri o d (or after t he Wee k 1 2 ).
3.
T otal: partici pa nts w h o recei ve d at least o ne d ose of v o xel ot or.

Re p orti n g Peri o d:

After Wee k 1 2 ( o ne da y after Wee k 1 2 visit) t hr o u g h e n d of st u d y  f or s u bjects w h o 
eit her d o n ot ac hie v e c o nfir me d re -e pit helializati o n or ac hie ve d it bef ore or at Wee k 
1 2 visit.

After Wee k 1 4 ( o ne da y after Wee k 1 4 visit) t hr o u g h e n d of st u d y  f or s u bjects w h o 
ha ve t he i nitial s ki n re -e pit helializati o n c o nfir me d at Wee k 1 2 a n d t he n t he 1 4 -wee k 
visit will be use d t o c o nfir m res ol uti o n.
2. 3. 3. Defi niti o ns a n d Ter mi n ol o g y
St u d y  Dr u g
T he ter m st u d y  dr u g refers t o eit her v o xel ot or or place b o. 
Baseli ne Val ue
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 5 of 4 3
Baseli ne f or all assess me nts ot her t ha n la b orat or y  or vital si g n para meters, will be defi ne d as 
t he last a vaila ble pre-treat me nt val ue ta ke n o n or bef ore t he da y of ra n d o mizati o n a n d will be 
use d f or s u m mar y  of baseli ne c haracteristics a n d c ha n ge fr o m baseli ne a nal yses, as 
a p pr o priate. 
Baseli ne f or a gi ve n la b orat or y para meter will be defi ne d as t he a vera ge of all n o n -missi n g 
la b orat or y val ues o n or pri or t o t he ra n d o mizati o n Date . 
Baseli ne f or a gi ve n vital si g n para meter will be defi ne d as t he a vera ge of all n o n -missi n g 
vital si g n val ue o n or pri or t o ra n d o mizati o n Date .
St u d y  D a y 
St u d y  D a y is defi ne d relati ve t o t he date of ra n d o mizati o n. 
F or st u d y assess me nts or e ve nts t hat occ ur o n or after t he date of ra n d o mizati o n, st u d y  d a y is 
calc ulate d as:
St u d y  D a y = E ve nt Date – Da y  1 date + 1.
F or st u d y assess me nts or e ve nts t hat occ ur bef ore t he date of ra n d o mizati o n, st u d y  da y is 
calc ulate d as:
St u d y  D a y = E ve nt Date – Da y  1 date. 
St u d y  Visit 
St u d y  Visit is t he n o mi nal visit as rec or de d o n t he C R F.
C h an ge fr o m Baseli ne
C ha n ge fr o m baseli ne f or a gi ve n e n d p oi n t is defi ne d as the St u d y  D a y val ue mi n us t he 
Baseli ne val ue.
O n -treat me nt peri o d:
O n -treat me nt peri o d is defi ne d as t he ti me fr o m t he first d ose of st u d y dr u g t hr o u g h 
mi ni m u m of 2 8 da y s + last d ose of st u d y dr u g a n d t he date of st u d y 
c o m pleti o n/ disc o nti n uati o n.
E xte nt of e x p os ure t o st u d y dr u g
E xte nt of e x p os ure t o st u d y  dr u g is defi ne d as t he n u m ber of wee ks fr o m i nitiati o n of st u d y 
dr u g t o t he e n d of st u d y dr u g treat me nt. E xte nt of e x p os ure is calc ulate d as f oll o ws:
(               −              + 1)
7
.
Act ual e x p os ure t o st u d y  dr u g
Act ual e x p os ure t o st u d y  dr u g is defi ne d as t he n u m ber of wee ks fr o m i nitiati o n of st u d y 
dr u g t o t he last date of d osi n g of st u d y dr u g w hic h e xcl u des da y s w here treat me nt was 
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 6 of 4 3
e ntirel y misse d or i nter mitte ntl y st o p pe d as rec or de d i n t he C R F. D urati o n of st u d y dr u g 
e x p os ure is calc ulate d as f oll o ws:
∑
(             −             + 1) ×        7
,
w here n is t he n u m ber of d ose m o dificati o ns d uri n g t he st u d y a n d 
I     =  0, if tr e at m e nt d os e i = 0 m g
1, if tr e at m e nt d os e i
≠0 m g ,i = 1, 2, …, n.
3. E N D P OI N T S A N D B A S E LI N E V A RI A B L E S: D E FI NI TI O N S A N D 
C O N V E N TI O N S
3. 1. Pri m ar y E n d p oi nt(s)
T he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of t he tar get ulcer(s), 
d uri n g t he 1 2 - wee k 
Ra n d o mize d Treat me nt Peri o d. 
 
F or partici pa nts wit h m ore t ha n o ne tar get ulcer, all tar get ulcers m ust be c o nfir me d res ol ve d 
i n or der f or t he partici pa nt t o be c o nsi dere d a res p o n der.
A tar get ulcer ca n be defi ne d as f oll o wi n g criteria:

Size: > 2 c m 2 at a n y visit, pri or t o ra n d o mizati o n ( Visits 1, 2, a n d 3, usi n g ce ntral 
rea der meas ure me nt)
If t he ulcer d oes n ot meet t he criteria a b o ve, it will n ot be use d as t he tar get ulcer f or t he 
efficac y a nal ys is. 
3. 2. Sec o n d ar y E n d p oi nt(s)
o
Ti me (i n da ys) t o res ol uti o n of tar get ulcer(s) u p t o Wee k 1 2
Ti me t o res ol uti o n of tar get ulcer(s) is defi ne d as 
Date of res ol uti o n – Date of ra n d o mizati o n + 1,
w here t he d ate of res ol uti o n is defi ne d as t he first ti me of t he o bser ve d ulcer was 
res ol ve d. F or partici pa nts wit h m ore t ha n o ne tar get ulcer, ti me t o res o l uti o n of tar get 
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C CI
C CI
C CI


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 7 of 4 3
ulcer(s) is defi ne d as ti me t o t he last tar get ulcer c o nfir me d res ol ve d. F or partici pa nts 
w h o d o n ot ha ve t he last tar get ulcer c o nfir me d res ol ve d b y  Wee k 1 2 or w h o are 
disc o nti n ue d fr o m st u d y , t he ti me t o res ol uti o n will be ce ns ore d. 
o
C ha n ge fr o m baseli ne i n t otal s urface area of tar get ulcer(s) at Wee k 1 2
o
I nci de nce of ne w ulcers b y  Wee k 1 2
3. 3. E x pl or at or y E n d p oi nt (s)
Pr ot oc ol s pecifie d e x pl orat or y  efficac y e n d p oi nts i nclu de:   

Pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of tar get ulcer(s) b y  Wee k 2 4

Ti me (i n da y s) t o res ol uti o n of tar get ulcer(s) u p t o Wee k 2 4

C ha n ge fr o m baseli ne i n t otal s urface area of tar get ulcer(s) o ver ti me u p t o Wee k 
2 4

C orrelati o n bet wee n c ha n ge i n H b a n d tar get ulcer(s) heali n g at Wee k s 1 2 a n d 2 4
Heali n g at Wee k 1 2 a n d 2 4 is defi ne d as ac hie vi n g c o nfir me d re-e pit helializati o n
b y Wee k
1 2 a n d Wee k 2 4 w hic h is defi ne d as partici pa nts ac hie vi n g res ol uti o n of 
t he tar get ulcer(s),
 
d uri n g t he 1 2-wee k Ra n d o mize d Treat me nt Peri o d a n d 
d uri n g t he 2 4 -wee k treat me nt peri o d, res pecti vel y . 
 
 
 
 
 
 

C orrelati o n bet wee n c ha n ge i n he m ol y tic para meter ( % retic ul oc ytes, i n direct 
bilir u bi n, L D H) a n d tar get ulcer(s) heali n g at Wee k s 1 2 a n d 2 4 

C ha n ge fr o m baseli ne i n P R O H R Q O L  meas ures: P R O MIS -3 7 v 2. 0 Pe diatric 
Pr ofile/ P R O MI S- 4 3 v 2. 1 at Wee ks 1 2 a n d 2 4

C ha n ge fr o m baseli ne i n pai n le vel li n ke d t o tar get ulcer(s) assesse d b y V A S at 
Wee k s 1 2 a n d 2 4

P GI -C sc ore at Wee k s 1 2 a n d 2 4
P GI -C q uesti o n naire i ncl u des 7 res p o nses w hic h are 1) ver y  m uc h i m pr o ve d, 2) 
m uc h i m pr o ve d, 3) mi ni mal i m pr o ve d, 4) n o c ha n ge, 5) mi ni mal w orse, 6) m uc h 
w orse a n d 7) ver y  m uc h w orse. 

C GI -C sc ore at Wee ks 1 2 a n d 2 4
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C CI
C CI


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 8 of 4 3
C GI -C q uesti o n naire i ncl u des 7 res p o nses w hic h are 1) ver y  m uc h i m pr o ve d, 2) 
m uc h i m pr o ve d, 3) mi ni mal i m pr o ve d, 4) n o c ha n ge, 5) mi ni mal w orse, 6) m uc h 
w orse a n d 7) ver y  m uc h w orse.
3. 4. B aseli ne V ari a bles
Ra n d o mize d T reat me nt P eri o d:

V o xel ot or: Baseli ne peri o d is defi ne d as Da y 1 of t he st u d y.

Place b o: Baseli ne peri o d is defi ne d as D a y  1 of t he st u d y.
O pe n - La bel T reat me nt P eri o d:

V o xel ot or: Baseli ne peri o d is defi ne d as Da y 1 of t he st u d y.

Dela y e d v o xel ot or: Baseli ne peri o d is defi ne d as Da y 1 of t he st u dy.
3. 4. 1. Str atific ati o n V ari a ble
Stratificati o n fact ors ( varia bles) are defi ne d as f oll o we d:

Ulcer size: t otal tar get ulcer s urface area (ie, s u m of all tar get ulcer s urface areas) at 
baseli ne visit ( Da y 1).

D urati o n of ulcer(s): l o n gest d urati o n of a n y i n di vi d ual tar get ulcer(s) prese nt at 
baseli ne visit ( Da y 1).
 
N ote t hat t he stratificati o n varia ble s will be deri ve d base d o n t he baseli ne visit ( Da y  1) i n t he 
cli nical data base. If t he deri ve d stratificati o n varia bles are n ot matc he d wit h I R T stratifie d 
ra n d o mizati o n fact ors, t he deri ve d stratificati o n variables fr o m cli nical data base will be use d 
f or t he a nal ysis. If d urati o n of ulcer(s) or ulcer size n ot are a vaila ble i n t he cli nical data base, 
t he data fr o m I R T will be use d f or t he a nalys is.
3. 4. 2. Ot her B aseli ne V ari a bles t o be S u m m arize d

De m o gra p hic c haracteristics i ncl u de ge n der, race, et h nicit y, ge o gra p hical re gi o n, 
c o u ntr y, site, a n d a ge at Scree ni n g visit .

B aseli ne dise ase c haracteristics (i ncl u di n g n u m ber of tar get le g ulcer(s), t otal s urface area 
of tar get le g ulcer(s), a n d ma xi m u m d urati o n of tar get le g ulcer(s))
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C CI
C CI
C CI


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 9 of 4 3

P h y sical e xa mi nati o n at Scree ni n g i ncl u de hei g ht (c m), wei g ht ( k g) a n d B MI 
( k g/ m2) = wei g ht ( k g)/[ hei g ht ( m)]2

Sic kle cell disease ge n ot y pe 

H y dr o x y urea use 
3. 5. S afet y E n d p oi nts
3. 5. 1. A d verse E ve nts
Me d D R A will be use d t o c o de all A Es ( n o n -seri o us a n d seri o us) wit h res pect t o s yste m or ga n 
class a n d preferre d ter m ( P T) usi n g m ost c urre nt versi o n of t he Me d D R A dicti o nar y . 
T E A E is defi ne d as a n A E t hat occ urs or w orse ns d uri n g t he o n-treat me nt peri o d as defi ne d 
i n Secti o n 2. 3. 3 .
3. 5. 2. L a b or at or y D at a
T he f oll o wi n g safety la b orat or y  tests (Ta ble 2 ) will be c ollecte d. A nal y ses f or ba n ke d 
bi os peci me ns are o ut of sc o pe f or t his S A P.
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 0 of 4 3
T a ble 2 .
Pr ot oc ol -Re q uire d S afet y L a b or at or y Assess me nts
H e m at ol o g y
Ser u m C he mistr y

R B Cs

H e m at ocrit

H e m o gl o bi n

Platelet

W hite bl o o d cells w it h differe ntial ( bas o p hils, 
e osi n o p hils, ne utr o p hils, m o n oc ytes, a n d 
l y m p h oc ytes)

% a n d a bs ol ute retic ul oc ytes

R B C distri b uti o n wi dt h 

Mea n c or p usc ular v ol u me 

Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n 

H b S S, H b S/ β 0 t halasse mia test (at Scree ni n g o nl y 
f or me dical dia g n osis of S C D, if dia g n osis is n ot 
d oc u me nte d i n me dical c hart)

A L T

Al b u mi n

Al kali ne p h os p hatase ( A L P)

A S T

Bicar b o nate

Bl o o d urea nitr o ge n 

C hl ori de

Calci u m

Creati ni ne

Gl uc ose

L D H

S o di u m

P otassi u m

Bilir u bi n (t otal, direct, a n d i n direct)

T otal pr otei ns

P h os p h or us
3. 5. 3. Ot her S afet y E n d p oi nts

C o m plete p h y sical e xa mi nati o n a n d brief p hys ical e xa mi nati o n: if a n y fi n di n g o n t he 
p h y sical e xa mi nati o n is c o nsi dere d b y t he i n vesti gat or t o be ‘cli nicall y si g nifica nt’, 
t he e ve nt is t o be rec or de d as me dical hist or y or a n A E, as a p pr o priate.

Vital Si g ns: vital si g n para meters i ncl u de bl o o d press ure, heart rate, a n d te m perat ure.
4. A N A L Y SI S S E T S ( P O P U L A TI O N S F O R A N A L Y SI S )
F or p ur p oses of a nal y sis, tw o mai n a nal ys is p o p ulati o ns are defi ne d f or t his st u d y as bel o w.
P o p ul ati o n
Descri pti o n
I T T P o p ulati o n
All ra n d o mize d partici pa nts acc or di n g t o t he treat me nt gr o u p t o 
w h ic h t he y were ra n d o mize d, re gar dless of t he treat me nt recei ve d
Safet y - Eval ua ble
P o p ulati o n
All ra n d o mize d partici pa nts w h o recei ve d at least o ne d ose of st u dy 
dr u g , re gar dless of t he gr o u p t o w hic h t he y were ra n d o mize d
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 1 of 4 3
5. G E N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S
5. 1. H y p ot heses a n d Decisi o n R ules
T he h y p ot hesis testi n g f or t he pri mar y  e n d p oi nt is t o c o m pare t he pr o p orti o n of partici pa nts
ac hie vi n g res ol uti o n of t he tar get ulcer(s) b y Wee k 1 2 i n v o xel ot or vs. place b o gr o u p as 
f oll o ws:
H 0: pv= p c vs. H 1: pv≠p c,
w here p v a n d p c are t he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of t he tar get ulcer(s) 
b y  Wee k 1 2 i n v o xel ot or a n d place b o gr o u p, res pecti vel y.  
5. 2. Ge ner al Met h o ds
5. 2. 1. A n al yses f or Bi n ar y E n d p oi nts
T he e xact C M H
5 ,6 ge neral ass ociati o n test will be use d f or bi nar y e n d p oi nts. T he esti mate d 
pr o p orti o ns wit h 9 5 % CI  b y treat me nt gr o u p, t he esti mate d pr o p orti o n differe nce ( v o xel ot or 
vs. place b o) wit h 9 5 % CI a n d t he p -val ue will be pr o vi de d.  
Descri pti ve statistics i ncl u di n g t he n u m ber of partici pa nts ( N) a n d perce nta ge ( %) will be 
pr o vi de d b y  treat me nt gr o u p. 
5. 2. 2. A n al yses f or C o nti n u o us E n d p oi nts
5. 2. 2. 1. Mi xe d M o del Re pe ate d Me as ures ( M M R M)
T he M M R M m o del will be use d f or t he s pecific e n d p oi nt a n d will i ncl u de fi xe d effects ter ms 
f or:

Treat me nt gr o u p (as a cate g orical varia ble);

Sc he d ule d visit ti me p oi nt (as a n or dere d cate g orical varia ble);
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C CI


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 2 of 4 3

I nteracti o n bet wee n treat me nt gr o u p a n d sc he d ule d visit ti me p oi nt.
T he restricte d ma xi m u m li keli h o o d ( R E M L ) esti mati o n met h o d will be use d wit h a n 
u nstr uct ure d c o varia nce matri x t o descri be t he c orrelati o n a m o n g differe nt visits fr o m t he 
sa me partici pa nt.  If t here are c o n ver ge nce iss ues wit h t he m o del, t he f oll o wi n g str uct ures 
will be c o nsi dere d i n t he or der liste d bel o w u ntil c o n ver ge nce is o btai ne d: 
1.
S patial P o wer ( S P);
2.
A ut ore gressi ve - 1 ( A R( 1));
3.
C o m p o u n d S y m metr y  ( C S).  
T he Ke n war d -R o ger 2 de grees of free d o m will be use d. 
T he m o del a dj uste d esti mates f or t he e n d p oi nt f or eac h treat me nt gr o u p at eac h s pecifie d 
ti me p oi nt will be pr o vi de d usi n g t he least s q uares ( L S) mea ns a n d t heir 9 5 % c o nfi de nce 
i nter vals ( CIs). 
Descri pti ve statistics i ncl u di n g t he n u m ber of partici pa nts ( N) , mea n, sta n dar d de viati o n 
( S D), me dia n, first q uartile ( Q 1), t hir d q uartile ( Q 3), mi ni m u m, a n d ma xi m u m will be 
pr o vi de d.
5. 2. 3. A n al yses f or Ti me -t o E ve nt E n d p oi nts
Ti me -t o e ve nt e n d p oi nt will als o be s u m marize d usi n g t he Ka pla n-Meier met h o d
( pr o d uct-
li mit esti mates) a n d esti mate d s ur vi val c ur ves will be dis pla y e d gra p hicall y w he n 
a p pr o priate.  Gra p hs will descri be t he n u m ber of partici pa nts at ris k o ver ti me.  T he me dia n, 
q uartiles , a n d pr o ba bilities of a n e ve nt at partic ular p oi nts i n ti me will be esti mate d b y  t he 
Ka pla n - Meier met h o d.  C o nfi de nce i nter vals f or me dia ns a n d q uartiles are base d o n t he 
Br o o k me y er-Cr o wle y  met h o d.  C o nfi de nce i nter vals f or t he esti mate d pr o ba bilit y of a n eve nt
at a partic ular ti me p oi nt will be ge nerate d usi n g t he Gree n w o o d f or m ula .
A stratifie d l o g -ra n k test wit h stratificati o n fact ors will be perf or me d t o test f or differe nces 
bet wee n t he v o xel ot or a n d place b o treat me nt gr o u ps.
A stratifie d C o x re gressi o n m o del 3 wit h treat me nt gr o u p as t he c o variate will be use d t o 
esti mate t he treat me nt gr o u p hazar d rati o ( v o xel ot or vs. place b o ) a n d t he c orres p o n di n g t w o-
si de d 9 5 % c o nfi de nce i nter val.
C o u nts a n d perce nta ges of s u bjects w h o e x perie nce d t he e ve nt as well as t he c o u nts a n d 
perce nta ges of s u bjects w h o were ce ns ore d a n d t he t y pe of ce ns ori n g (e g, deat h or missi n g 
data) will be re p orte d f or eac h of t he treat me nt gr o u ps.
5. 2. 4. C orrel ati o n A n al ysis Bet wee n C o nti n u o us a n d Bi n ar y E n d p oi nts 
 Pears o n4 c orrelati o n wit h o ne 
dic h ot o m o us varia ble will be use d
.
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C CI
C CI


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 3 of 4 3
5. 3.
Met h o ds t o M a n a ge Missi n g D at a
G ui deli nes re gar di n g h o w missi n g data will be ha n dle d are descri be d bel o w .
5. 3. 1. St at us of T ar get St u d y Ul cer(s) 
Partici pa nts w h o are l ost t o f oll o w -u p or ot her wise dr o p o ut of t he st u d y  wit h o ut 
c o nfir mati o n of res ol uti o n of all tar get st u d y ulcer(s) pri or t o Wee k 1 2, will be classifie d as 
n o n -res p o n ders f or p ur p oses of t he pri mar y a nalys is.
5. 3. 2. I m p ut ati o n of I nc o m plete D ates
A n i nc o m plete date is a n y  date f or w hic h eit her t he da y, m o nt h or year is u n k n o w n, b ut all 
t hree fiel ds are n ot u n k n o w n. A n i nc o m plete date occ urs w he n t he e xact date a n e ve nt 
occ urre d or e n de d ca n n ot be o btai ne d fr o m a s u bject. F or ma n y of t he a nal yses, a c o m plete 
date is necessar y  t o deter mi ne if the e ve nt s h o ul d be i ncl u de d i n t he a nal y sis (i.e., if t he e ve nt 
is treat me nt-e mer ge nt) or t o esta blis h t he d urati o n of a n e ve nt. I n s uc h cases, i nc o m plete 
dates will be i m p ute d as f oll o ws.
F or c o nc o mita nt me dicati o ns, t he case re p ort f or m per mits t he start date t o ha ve a n u n k n o w n 
da y  a n d/ or m o nt h.
Start dates f or c o n c o mita nt me dicati o n

F or missi n g start da y  o nl y – D a y  will be i m p ute d as t he first da y of t he m o nt h (i.e., 1) 
wit h t he f oll o wi n g e xce pti o n: I f t he partial date falls i n t he sa me m o nt h a n d year as
t he treat me nt start date t he n t he c o nc o mita nt me dicati o n start date will be i m p ute d as 
t he treat me nt start date.

F or missi n g start da y  a n d m o nt h – Da y  a n d m o nt h will be i m p ute d as t he first da y of 
t he year (i.e., 1 Ja n uar y) wit h t he f oll o wi n g e xce pti o n: If t he partial date falls i n t he 
sa me year as t he treat me nt start date t he n t he c o nc o mita nt me dicati o n start date will 
be i m p ute d as t he treat me nt start date.
St o p d ates f or co nc o mita nt m e dicati o ns

F or missi n g st o p da y  o nl y – D a y  o nl y will be i m p ute d as t he last da y of t he m o nt h 
(i.e., 2 8, 2 9, 3 0, or 3 1).

F or missi n g st o p da y  a n d m o nt h – Da y  a n d m o nt h will be i m p ute d as t he last da y of 
t he year (i.e., 3 1 Dece m ber).
F or a d verse e ve nts, t he case re p ort f or m per mits t he date t o ha ve a n u n k n o w n da y . If da y is 
mi ssi n g, t he n a q uesti o n o n t he case re p ort f or m as ks w het her t he e ve nt starte d pri or t o t he 
first d ose.
Start d ates f or a d verse eve nts w here t he e ve nt occ urs pri or t o t he first d ose
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 4 of 4 3
F or missi n g start da y  o nl y – D a y  will be i m p ute d as t he first da y of t he m ont h (i.e., 1) wit h 
t he f oll o wi n g e xce pti o n: If t he partial date falls i n t he sa me m o nt h a n d year as t he treat me nt 
start date t he n t he a d verse e ve nt start date will be i m p ute d as t he da y pri or t o t he treat me nt 
start date.
Start d ates f or a d verse eve nts w her e t he e ve nt is n ot pri or t o t he first d ose
F or missi n g start da y  o nl y – If t he partial date falls i n t he sa me m o nt h a n d year as t he 
treat me nt start date t he n t he a d verse e ve nt start date will be i m p ute d as t he treat me nt start 
date. Ot her wise, t he da y  will be i m p ute d as t he first da y  of t he m o nt h (i.e., 1) as l o n g as t he 
i m p ute d date d oes n ot occ ur bef ore t he treat me nt start date.
St o p Dates f or A d verse E ve nts
F or missi n g st o p da y  o nl y – D a y  o nl y will be i m p ute d as t he last da y of t he m o nt h (i.e., 2 8, 
2 9, 3 0 , or 3 1).
F or st u d y dr u g e x p os ure, t he case re p ort f or m per mits t he date t o ha ve a n u n k n o w n da y. 
H o we ver, d ue t o dail y d osi n g, partial dates will n ot be i m p ute d. A n y partial dates will be 
dis pla y e d i n data listi n gs wit h o ut i m p utati o n of missi n g da y s a n d/ or m o nt hs.  
6. A N A L Y S E S A N D S U M M A RI E S
A nal yses base d o n I T T partici pa nts will be gr o u pe d acc or di n g t o t he treat me nt assi g ne d at 
ra n d o mizati o n a n d f or S afet y- Eval ua ble p o p ulati o ns, partici pa nts will be gr o u pe d acc or di n g t o 
t he act ual st u d y dr u g ta ke n.
6. 1. Pri m ar y E n d p oi nt
T he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of t he tar get ulcer(s) b y  Wee k 1 2.
P o p ulati o n: I T T p o p ulati o n as descri be d i n Secti o n 4 . 
Pri mar y  anal ys is:
T he e xact C M H 5 ,6 test as descri be d i n Secti o n 5. 2. 1 stratifie d b y stratificati o n fact ors of 
tar get ulcer size a n d d urati o n wit h i m p utati o n r ules o utli ne d i n Secti o n 5. 3 will be use d. 
6. 2. Sec o n d ar y E n d p oi nts
1.
E n d p oi nt: Ti me (i n da y s) t o res ol uti o n of tar get ulcer(s) u p t o Wee k 1 2
P o p ulati o n: I T T P o p ulati o n as descri be d i n Secti o n 4 . 
A nal y sis:
T he a nal ys is as descri be d i n Secti o n 5. 2. 3 c o nsists of a stratifie d l o g -ra n k test t o test t he 
differe nce i n t his e n d p oi nt bet wee n t he v o xel ot or a n d place b o gr o u ps, w here t he 
stratificati o n fact ors are tar get ulcer size a n d d urati o n, will be perf or me d a n d t he p-val ue 
f or l o g-ra n k test will be re p orte d. A stratifie d C o x re gressi o n m o del wit h t he strata 
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 5 of 4 3
i ncl u di n g tar get ulcer size (cate g orical) a n d tar get ulcer d urati o n (cate g orical) a n d t he 
treat me nt gr o u p as t he c o variate will be use d t o esti mate t he hazar d rati o ( v o xel ot or vs. 
place b o) a n d t he c orres p o n di n g t w o -si de d 9 5 % c o nfi de nce i nter val.
2.
E n d p oi nt: C ha n ge fr o m baseli ne i n t otal s urface area of tar get ulcer(s) at Wee k 1 2
P o p ulati o n: I T T P o p ulati o n as descri be d i n Secti o n 4 . 
A nal y sis: 
M M R M a nal y sis as descri be d i n Secti o n 5. 2. 2. 1 will be use d wit h tar get ulcer size
(cate g orical ) a n d tar get ulcer d urati o n (cate g orical ) as c o variates a n d t he c ha n ge fr o m 
baseli ne i n t otal s urface area of tar get ulcer(s) at Wee k 1 2 as a res p o nse v aria ble. T he L S 
mea ns differe nce ( v o xel ot or vs. place b o) wit h 9 5 % CI  a n d p-val ue f or L S mea n differe nce at 
Wee k 1 2 will be pr o vi de d.  
3.
E n d p oi nt: I nci de nce of ne w ulcers b y Wee k 1 2
P o p ulati o n: I T T P o p ulati o n as descri be d i n Secti o n 4 . 
A nal y sis:
T he e xact C M H ge neral ass ociati o n test as descri be d i n Secti o n 5. 2. 1 wit h i m p utati o n r ules 
o utli ne d i n Secti o n 5. 3 will be use d. 
V o xel ot or will be c o m pare d t o place b o w hile stratif y i n g f or t he stratificati o n fact ors of tar get 
ulcer size a n d d urati o n . 
6. 3. E x pl or at or y Effic ac y E n d p oi nts
E n d p oi nt: T he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of t he tar get ulcer(s) b y  Wee k 
2 4
P o p ul ati o n: I T T p o p ulati o n as descri be d i n Secti o n 4 . 
A nal y sis: Descri pti ve statistics i ncl u di n g t he n u m ber of partici pa nts ( N) a n d perce nta ge ( %) 
will be pr o vi de d b y  V o xel ot or a n d dela ye d V o xel ot or gr o u ps. 
E n d p oi nt: Ti me (i n da y s) t o res ol uti o n of tar get ulcer(s) u p t o Wee k 2 4
P o p ulati o n: I T T p o p ulati o n as descri be d i n Secti o n 4 . 
A nal y sis: N u m ber of partici pa nts ( N) w h o ac hie ve d res ol uti o n of tar get ulcer , media n, first 
q uartile ( Q 1), t hir d q uartile ( Q 3) , mi ni m u m, a n d ma xi m u m will be pr o vi de d b y V o xel ot or
a n d Del a ye d V o xel ot or gr o u ps . 
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 6 of 4 3
E n d p oi nt: C ha n ge fr o m Baseli ne i n t otal s urface area of tar get ulcer(s) o ver ti me u p t o 
Wee k
2 4
P o p ulati o n: I T T p o p ulati o n as descri be d i n Secti o n 4 . 
A nal y sis: Descri pti ve statistics i ncl u di n g t he n u m ber of partici pa nts ( N) , mea n, sta n dar d 
de viati o n ( S D) , me dia n, first q uartile ( Q 1), t hir d q uartile ( Q 3), mi ni m u m, a n d ma xi m u m will 
be pr o vi de d b y  V o xel ot or a n d D ela ye d V o xel ot or gr o u ps .
E n d p oi nt: C orrelati o n bet wee n c ha n ge fr o m Baseli ne i n H b a n d target ulcer(s) heali n g at 
Wee k 1 2 a n d Wee k 2 4.
P o p ulati o n: I T T P o p ulati o n as descri be d i n Secti o n 4 . 
A nal y sis: T he p oi nt biserial c orrelati o n   will be pr o vi de d as descri be d i n Secti o n 5. 2. 4 b y  
treat me nt gr o u ps. 
E n d p oi nt: 

C orrelati o n bet wee n c ha n ge i n he m ol y tic para meter, % retic ul oc y tes a n d tar get 
ulcer(s) heali n g at Wee k 1 2 a n d Wee k 2 4

C orrelati o n bet wee n c ha n ge i n he m ol y tic para meter, i n direct bilir u bi n a n d tar get 
ulcer(s) heali n g at Wee k 1 2 a n d Wee k 2 4

C orrelati o n bet wee n c ha n ge i n he m ol y tic para meter, L D H a n d tar get ulcer(s) heali n g 
at Wee k 1 2 a n d Wee k 2 4
P o p ulati o n: I T T P o p ulati o n as descri be d i n Secti o n 4 . 
A nal y sis: T he p oi nt biserial c orrelati o n   will be pr o vi de d as descri be d i n Secti o n 5. 2. 4 b y  
treat me nt gr o u ps.
Healt h -relate d q uality of life ( H R Q O L) usi n g patie nt -re p orte d o utc o me ( P R O) meas ures 
en d p oi nt s: 
E n d p oi nt: C ha n ge fr o m baseli ne i n P R O H R Q O L  meas ures: P R O MIS- 3 7 v 2. 0 Pe diatri c 
Pr ofile/ P R O MI S- 4 3 v 2. 1 at Wee k 1 2 a n d Wee k 2 4 .
P R O MI S- 3 7 v 2. 0 Pe diatric Pr ofile d o mai ns i ncl u de d P h y sical F u ncti o n M o bilit y, A n xiet y, 
De pressi ve S y m pt o ms, Fati g ue, Peer Relati o ns hi ps, Pai n I nterfere nce a n d Pai n I nte nsit y. 
P R O MI S- 4 3 v 2. 1 A d ult Pr ofile d o mai ns i ncl u de d P h y sical F u ncti o ni n g, Pai n Interfere nce, 
Slee p Dist ur ba nce , Fati g ue, A n xiet y, De pressi o n, A bilit y t o Partici pate i n S ocial R oles a n d 
Acti vities a n d Pai n Inte nsit y .
T he P R O MI S- 3 7 v 2. 0 a n d P R O MI S- 4 3 v 2. 1 ra w sc ore f or eac h d o mai n will be c on verte d t o 
T- sc ore (see A p pe n di x 3 ) e xce pt pai n i nte nsit y d o mai n i n b ot h P R O MI S- 3 7 v 2. 0 a n d 
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 7 of 4 3
P R O MI S- 4 3 v 2. 1. All a nal y sis will be base d o n b ot h ra w sc ore a n d T- sc ore b y  d o mai n 
i ncl u di n g pai n i nte nsit y  sc ore.   
P o p ulati o n: I T T P o p ulati o n as descri be d i n Secti o n 4 . 
A nal y sis:

M M R M a nal y sis as descri be d i n Secti o n 5. 2. 2. 1 will be use d wit h tar get ulcer size
(cate g orical ) a n d tar get ulcer d urati o n (cate g orical ) as c o variates a n d t he c ha n ge fr o m 
baseli ne i n P R O MI S d o mai n T- sc ore a n d ra w sc ore at Wee k 1 2 as a res p o nse 
varia ble . T he p-val ue f or L S mea ns differe nce ( v o xel ot or vs. place b o) at Wee k 1 2 
will be pr o vi de d f or eac h of d o mai ns. 

Descri pti ve statistics i ncl u di n g t he n u m ber of partici pa nts ( N), mea n, sta n dar d 
de viati o n ( S D), me dia n, first q uartile ( Q 1), t hir d q uartile ( Q 3), mi ni m u m, a n d 
ma xi m u m will be pr o vi de d b y  treat me nt gr o u p at Wee ks 1 2 a n d 2 4.
E n d p oi nt: C ha n ge fr o m baseli ne i n pai n le vel li n ke d t o tar get ulcer(s) assesse d b y V A S at 
Wee k 1 2 a n d Wee k 2 4
P o p ulati o n: I T T P o p ulati o n as descri be d i n Secti o n 4 . 
A nal y sis:

M M R M a nal y sis as descri be d i n Secti o n 5. 2. 2. 1 will be use d wit h tar get ulcer size
(cate g orical ) a n d tar get ulcer d urati o n (cate g orical ) as c o variates a n d t he c ha n ge fr o m 
baseli ne i n pai n le vel li n ke d t o tar get ulcer(s) assess e d b y V A S at Wee k 1 2 as a 
res p o nse varia ble. T he p -val ue f or L S mea ns differe nce ( v o xel ot or vs. place b o) at 
Wee k 1 2 will be pr o vi de d. 

Descri pti ve statistics i ncl u di n g t he n u m ber of partici pa nts ( N) , mea n, sta n dar d 
de viati o n ( S D) , me dia n, first q uartile ( Q 1), t hir d q uartile ( Q 3), mi ni m u m, a n d 
ma xi m u m will be pr o vi de d b y treat me nt gr o u p at Wee ks 1 2 a n d 2 4.
E n d p oi nt: Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI- C) sc ore at Wee k 1 2 a n d Wee k 2 4
P o p ulati o n: I T T P o p ulati o n as descri be d i n Secti o n 4 . 
A nal y sis: Descri pti ve statistics i ncl u di n g t he p erce nta ge of patie nts f or eac h res p o nse will be 
pr o vi de d b y treat me nt gr o u p at Wee ks 1 2 a n d 2 4.
E n d p oi nt: Cli nicia n Gl o bal I m pressi o n of C ha n ge ( C GI -C) sc ore at Wee k 1 2 a n d Wee k 2 4
P o p ulati o n: I T T P o p ulati o n as descri be d i n Secti o n 4 . 
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 8 of 4 3
A nal y sis: Descri pti ve statistics i ncl u di n g t he n u m ber a n d p erce nta ge of patie nts f or eac h 
res p o nse will be pr o vi de d b y  treat me nt gr o u p at Wee ks 1 2 a n d 2 4.
6. 4. S u bset A n al yses
6. 4. 1. S u b set a n al ysis f or effic ac y e n d p oi nts
Efficac y  s u b gr o u p a nal yses will be perf or me d f or t he pri mar y a n d sec o n dar y efficac y 
e n d p oi nts f or t he f oll o wi n g s u bsets u nless ot her wise n ote d. T he f orest pl ots f or all s u bset
a nal ys is b y  e n d p oi nt will be pr o vi de d . P-val ues will n ot be pr o vi de d f or a n y s u b gr o u p 
a nal ys is.
3.
A ge gr o u p wit h < 1 8 ye ars of a ge a n d ≥1 8 y ears of a ge
4.
C o u ntr y ( Ni geria, Ke n ya a n d Brazil)
6. 4. 1. 1. Pri m ar y E n d p oi nt
T he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of t he tar get ulcer(s) b y  Wee k 1 2
P o p ulati o n: I T T p o p ulati o n as descri be d i n Secti o n 4
A nal y sis:
T he pr o p orti o n differe nce ( v o xel ot or vs. place b o) a n d 9 5 % CI  will be pr o vi d e d b y  
s u b gr o u p. 
6. 4. 1. 2. Sec o n d ar y E n d p oi nt
1.
E n d p oi nt: Ti me (i n da y s) t o res ol uti o n of tar get ulcer(s) u p t o Wee k 1 2
P o p ulati o n: I T T p o p ulati o n as descri be d i n Secti o n 4
A nal y sis:
A C o x re gressi o n m o del wit h t he treat me nt gr o u p as a c o variate will be use d t o 
esti mate t he hazar d rati o ( v o xel ot or vs. place b o) a n d t he c orres p o n di n g t w o -si de d 
9 5 % CI b y  s u b gr o u p.
2.
E n d p oi nt: C ha n ge fr o m baseli ne i n t otal s urface area of tar get ulcer(s) at Wee k 1 2
P o p ulati o n: I T T p o p ulati o n as descri be d i n Secti o n 4
A nal y sis:
M M R M a nal y sis as descri be d i n Secti o n 5. 2. 2. 1 will be use d a n d t he c ha n ge fr o m 
baseli ne i n t otal s urface area of tar get ulcer(s) at Wee k 1 2 as a res p o nse var ia ble. T he 
L S mea ns differe nce ( v o xel ot or vs. place b o) wit h 9 5 % CI  f or L S mea n differe nce at 
Wee k 1 2 will be pr o vi de d
b y s u b gr o u p.  
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C CI


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 9 of 4 3
3.
E n d p oi nt: I nci de nce of ne w ulcers b y Wee k 1 2
P o p ulati o n: I T T p o p ulati o n as descri be d i n Secti o n 4
A nal y sis:
T he pr o p orti o n differe nce ( v o xel ot or vs. place b o) a n d 9 5 % CI  will be pr o vi de d b y  
s u b gr ou p s of a ge gr o u p a n d c o u ntr y o nl y. 
6. 4. 2. S u bset a n al ysis f or s afet y e n d p oi nts
Safet y  s u b gr o u p a nal yses will be perf or me d o n safet y  a nalys is set f or S C D -relate d T E A E s
a n d T E S A Es i n t he ra n d o mize d treat me nt p eri o d o n t he f oll o wi n g s u bgr o u p s.
1)
Malaria 
a.
S u bjects wit h at least o ne T E A E of Malaria b y  Wee k 1 2 ( Yes, N o)
b.
S u bjects wit h at least o ne T E A E of Malaria b y  Wee k 2 4 ( Yes, N o)
2)
C ha n ge fr o m Baseli ne i n He m o gl o bi n at Wee k 1 2 ( < 0 g/ d L, 0 - 1 g/ d L , > 1 g/ d L ) 
3)
He m o gl o bi n at Wee k 1 2 ( < 7 g/ d L, > = 7 g/ d L a n d < 9 g/ d L , > = 9 g/ d L )
4)
N u m ber of V O Cs i n t he past 1 2 M o nt hs ( 0 V O Cs, > = 1 V O Cs)
5)
N u m ber of V O Cs i n t he past 1 2 M o nt hs ( 1 V O C, > = 2 V O Cs)
6)
C o u ntr y  ( Ni geria, Ke n ya, Brazil)
6. 5. B aseli ne a n d Ot her S u m m aries a n d A n al yses
6. 5. 1. B aseli ne S u m m aries
1.
De m o gra p hic c haracteristics will be s u m marize d b y  treat me nt gr o u p. 
De m o gra p hic a n d baseli ne c haracteristics s uc h as a ge, se x, race, a n d baseli ne disease 
c haracteristics (i ncl u di n g n u m ber of tar get le g ulcer(s), t otal s urface area of tar get le g 
ulcer(s), a n d ma xi m u m d urati o n of tar get le g ulcer(s))
2.
Baseli ne p h ys ical meas ure me nts (i ncl u di n g hei g ht a n d wei g ht) will be s u m marize d b y  
treat me nt gr o u p.
3.
T he bel o w will be s u m marize d usi n g n u m ber ( %) of partici pa nts b y  treat me nt gr o u p:

Sic kle cell disease ge n ot y pe ; a n d 

E nr oll m e nt site, c o u ntr y a n d re gi o n .
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 0 of 4 3
4.
Ge neral me dical hist or y  will be s u m marize d b y  treat me nt gr o u p.
5.
H y dr o x y urea use b y  treat me nt g r o u p.
6. 5. 2. St u d y C o n d uct a n d P artici p a nt Dis p ositi o n
1.
T he bel o w partici pa nt p o p ulati o n will be s u m marize d b y  treat me nt gr o u p.

I T T P o p ulati o n .

Safet y -E val ua ble P o p ulati o n .
2.
Partici pa nt dis p ositi o n (e g, disc o nti n uati o n fr o m st u d y, reas o n f or disc o nti n uati o n, 
c o m plete d st u d y, a n d o n g oi n g) will be s u m marize d b y  treat me nt gr o u p at Wee k 1 2 a n d 
2 4 .
3.
Act ual e x p os ure t o st u d y dr u g will be s u m ma rize d b y treat me nt gr o u p at Wee k 1 2 a n d 
2 4.
4.
I m p orta nt pr ot oc ol de viati o ns will be s u m marize d b y  treat me nt gr o u p.
6. 5. 3. C o nc o mit a nt Me dic ati o ns a n d N o n dr u g T re at me nts
T he m ost c urre nt W orl d Healt h Or ga nizati o n ( W H O) -Dr u g c o di n g dicti o nar y  will be use d t o 
classif y c o nc o mita nt me dicati o ns.
T he n u m ber ( %) of partici pa nts w h o t o o k eac h c o nc o mita nt me dicati o n will be pr o vi de d b y  
treat me nt gr o u p.
6. 6. S afet y S u m m aries a n d A n al yses
All safet y a nal ys is will be perf or me d base d o n Safet y-E val ua ble P o p ulati o n as descri be d i n 
Secti o n 4 a n d O pe n-La bel Treat me nt E xte nsi o n Peri o d f or Safet y as descri be d i n Secti o n 
2. 3. 2 .
6. 6. 1. A d verse E ve nts
S C D -relate d a d verse e ve nts, defi ne d as Me d D R A P Ts
of sic kle cell a nae mia wit h crisis, 
ac ute c hest s yn dr o me, p ne u m o nia, pria pis m ( male partici pa nts o nl y), s ple nic or he patic 
se q uestrati o ns, str o ke, a n d oste o necr osis , are i ncl u de d i n t he s u m mar y. N o n -S C D -relate d 
a d verse e ve nts are all ot her a d verse e ve nts.  T he T E A Es / T E S A Es a n d treat me nt -relate d 
A Es / S A Es will be dis pla y e d b y S C D-relate d a n d n o n-S C D -relate d.  
T he t otal n u m ber a n d perce nta ge of s u bjects wit h T E A Es will be prese nte d b y  s yste m or ga n 
class a n d preferre d ter m b y treat me nt gr o u p. T E A Es will be prese nte d by se verity ( C T C A E 
gra de or pr ot oc ol defi ne d se veri t y). T E A Es will be ta b ulate d prese nti n g t he s yste m or ga n 
class al p ha beticall y a n d wit hi n eac h sys te m t he preferre d ter m will be prese nte d b y  treat me nt 
gr o u p. T he t otal n u m ber a n d perce nta ge of s u bjects disc o n ti n ue d fr o m st u d y d ue t o A Es will 
b y  prese nte d by treat me nt gr o u p.
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 1 of 4 3
T he fre q ue nc y  of s u bjects w h o e x perie nce eac h T E A E or treat me nt-relate d A E will be 
deter mi ne d as f oll o ws: A s u bject e x perie nci n g t he sa me A E m ulti ple ti mes will o nl y  be 
c o u nte d o nce f or t he preferre d ter m. Si milarl y , if a s u bject e x perie nces m ulti ple A Es wit hi n 
t he sa me s yste m or ga n class, t hat s u bject will be c o u nte d o nl y o nce f or t hat s yste m. If 
c ha n ges i n t he se verit y of a n A E are rec or de d i n t he e C R F, o nl y t he m ost se vere i nci de nce of 
t he A E will be c o u nte d. If a s u bject e x perie nces m ulti ple occ urre nces of a T E A E, o nl y  t he 
relate d e ve nt or t he w orst se verity (a nal ysis de pe n de nt), will be c o u nte d f or eac h s u bject 
wit hi n eac h s yste m or ga n class or preferre d ter m f or t he s u m maries of treat me nt- relate d A Es.
Missi n g o nset dates will be i m p ute d as pre vi o usl y o utli ne d i n Secti o n 5 . 3. 2 as re q uire d t o 
deter mi ne treat me nt -e mer ge nt e ve nts. S h o ul d a n e ve nt ha ve a missi n g se verit y  or relati o ns hi p 
t o st u d y me dicati o n, t he n t he se verit y or relati o ns hi p, res pecti vel y, will be classifie d as 
missi n g f or s u m mar y  ta b ulati o n p ur p oses.
Listi n gs of A Es lea di n g t o disc o nti n uati o n of t he st u d y , S A Es a n d deat hs, if a n y, will be 
pr o vi de d.
Listi n g of all A Es, i ncl u di n g A Es occ urre d after 2 8 da y s of t he last treat me nt date.
Deat hs a n d S A Es will be liste d a n d i nci de nce of S A Es (all ca usalities a n d treat me nt -relate d) 
will be s u m marize d b y  s yste m or ga n class a n d P T b y  treat me nt gr o u p.
Seri o us a d verse e ve nts ( S A Es) will be s u m marize d wit h c o u nts a n d perce nta ge. S A E 
i nf or mati o n will be rec o ncile d bet wee n t he cli nical a n d safety data bases pri or t o t he data base 
l oc k f or data base release.
6. 6. 2. L a b or at or y D at a
All he mat ol o g y  a n d c he mistr y la b orat or y assess me nts were perf or me d b y a ce ntral la b orat or y. 
La b orat or y  data will be c o n verte d i nt o SI f or t he a nal ysis. T he pr ot oc ol-s pecifie d cli nical 
la b orat or y (Ta ble 2 ) fi n di n gs will be s u m marize d usin g descri pti ve statistics b y treat me nt gr o u p, 
wit h o ut a n y  i m p utati o n. 
Descri pti ve statistics will be prese nte d f or baseli ne, eac h e val uati o n p ost baseli ne, a n d c ha n ge 
fr o m baseli ne f or eac h p ost baseli ne e val uati o n t hr o u g h 2 8 da y s after last d ose date . 
La b orat or y  a b n or malities will be gra de d via t he C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nt ( C T C A E) or pr ot oc ol defi ne d se verit y classificati o n . La b orat or y a b n or malit y s hifts fr o m 
baseli ne will be s u m marize d b y treat me nt gr o u p a n d b y re p orti n g peri o ds. 
T o assess li ver i nj ur y , a listi n g of t he partici pa nts p ote ntiall y meeti n g H y’s La w criteria a n d 
E- DI S H pl ots will be pr o d uce d.
6. 6. 3. Vit al Si g ns
Vital si g ns ( b o d y te m perat ure, heart rate, a n d s yst olic/ diast olic bl o o d press ure) will be 
s u m marize d usi n g descri pti ve statistics f or baseli ne a n d c ha n ge fr o m baseli ne f or eac h p ost -
baseli ne e val uati o n t hr o u g h 2 8 da y s after t he last d ose date. 
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 2 of 4 3
7. I N T E RI M A N A L Y S E S
N o i nteri m a nal ys is is pla n ne d f or t his st u d y. 
8. R E F E R E N C E S
1.
Je n nis o n C, T ur n b ull B ( 2 0 0 0) Gr o u p Se q ue ntial Met h o ds wit h A p plicati o ns t o Cli nical 
Trials. C ha p ma n & Hall/ C R C.
2.
Ke n war d, M G a n d R o ger, J H. ( 1 9 9 7). S mall Sa m ple I nfere nce f or Fi xe d Effects fr o m 
Restricte d Ma xi m u m L i keli h o o d. Bi o metrics, 5 3: 9 8 3- 9 9 7
3.
Kal bfleisc h, J. D., Pre ntice, R. L ., 2 0 0 2. T h e Statistical A nal ys is of Fail ure Ti me Data, 
sec o n d e d. Wile y Series i n Pr o ba bilit y a n d Statistics. Wile y, Ne w Y or k. .
4.
Pears o n, Karl ( 1 8 9 5). " N otes o n re gressi o n a n d i n herita nce i n t he case of t w o 
pare nts" . Pr ocee di n gs of t he R oy al S ociety of L o n d o n. 5 8: 2 4 0 – 2 4 2 .
5.
C oc hra n, Willia m G. 1 9 5 4. “ S o me Met h o ds f or Stre n gt he ni n g t he C o m m o n C hi- S q uare d 
Tests.” Bi o metrics 1 0 ( 4). [ Wile y , I nter nati o nal Bi o metric S ociet y]: 4 1 7– 5 1. 
htt p:// w w w.jst or. or g/sta ble/ 3 0 0 1 6 1 6.
6.
Ma ntel, N., a n d W. Hae nszel. 1 9 5 9. “ Statistical As pects of t he A nal y sis of Data fr o m 
Retr os pecti ve St u dies of Disease.” J o ur nal of t he Nati o nal Ca ncer I nstit ute 2 2 ( 4): 7 1 9 –
4 8. 
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 3 of 4 3
A P P E N DI C E S
A p pe n di x 1. S u m m ar y o f Effic ac y A n al yses
E n d p oi nt
A n al ysis
T y pe
P o p ul ati o n
D at a I ncl usi o n a n d 
R ules f or H a n dli n g 
I nterc urre nt E ve nts 
a n d Missi n g D at a
M ai n A n al ysis M o del
Pri m ar y 
T he stat us of 
partici pa nts 
ac hie vi n g 
res ol uti o n of t he 
tar get ulcer(s) b y 
Wee k 1 2
E xact 
C M H test
Descri pti ve 
s u m mar y 
statistics
S u b gr o u p
a nal ysis
I T T
Partici pa nts w h o are l ost 
t o f oll o w-u p or 
ot her wise dr o p o ut of t he 
st u d y wit h o ut 
c o nfir mati o n of 
res ol uti o n of all tar get 
st u d y ulcer(s) pri or t o 
Wee k 1 2, w ill be 
classifie d as n o n -
res p o n der. 
E xact C M H test wit h 
stratificati o n fact ors of tar get 
ulcer size a n d d urati o n
Sec o n d ar y
Ti m e (i n da ys) t o 
res ol uti o n of 
tar get ulcer(s) u p 
t o Wee k 1 2
L o g -ra n k 
a n d C o x 
re gressi o n 
m o del
Descri pti ve 
s u m mar y 
statistics
S u b gr o u p 
a nal ysis
I T T
F or partici pa nts w h o d o 
n ot ha ve t he last tar get 
ulcer c o nfir me d res ol ve d 
b y Wee k 1 2 or w h o are 
disc o nti n ue d fr o m st u d y, 
t he ti me t o res ol uti o n 
will be ce ns ore d
Ka pla n -Meier met h o d 
( pr o d uct-li mit esti mates) 
a n d esti mate d s ur vi val 
c ur ves will be dis pla ye d 
gra p hicall y w he n 
a p pr o priate.  Gra p hs will 
descri be t he n u m ber of 
partici pa nts at ris k o ver ti me.
A stratifie d l o g -ra n k test 
wit h stratificati o n fact ors 
will be perf or me d t o test f or 
differe nces bet wee n t he 
v o xel ot or a n d place b o 
treat me nt gr o u ps
C ha n ge fr o m 
baseli ne i n t otal 
s urface area of 
tar get ulcer(s) at 
Wee k 1 2
L S mea ns 
( 9 5 % CI)
L S mea ns 
differe nce 
Descri pti ve 
s u m mar y 
statistics
S u b gr o u p 
a nal ysis
I T T
N A
M M R M a nal ysis will be 
use d as descri be d i n Secti o n 
5. 2. 2. 1 wi t h t he stratificati o n 
fact ors i ncl u di n g tar get ulcer 
size (cate g orical) a n d tar get 
ulcer d urati o n (cate g orical) 
as c o variates a n d . T he p-
val ue f or L S mea ns 
differe nce ( v o xel ot or vs. 
place b o) at Wee k 1 2 w ill be 
pr o vi de d .
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 4 of 4 3
E n d p oi nt
A n al ysis
T y pe
P o p ul ati o n
D at a I ncl usi o n a n d 
R ules f or H a n dli n g 
I nterc urre nt E ve nts 
a n d Missi n g D at a
M ai n A n al ysis M o del
I nci de nce of ne w 
ulcers b y Wee k 
1 2
E xact 
C M H test
Descri pti ve 
s u m mar y 
statistics
S u b gr o u p 
a nal ysis
(a ge gr o u p 
a n d 
c o u ntr y)
I T T
N A
E xact C M H test wit h 
stratificati o n fact ors of tar get 
ulcer size a n d d urati o n
E x pl or at or y 
T he pr o p orti o n 
of partici pa nts 
ac hie vi n g 
res ol uti o n of t he 
tar get ulcer(s) b y 
Wee k 2 4
Descri pti ve 
s u m mar y 
statistics
I T T
N A
Descri pti ve statistics
Ti m e (i n da ys) t o 
res ol uti o n of 
tar get ulcer(s) u p 
t o Wee k 2 4
Descri pti ve 
s u m mar y 
statistics
I T T
N A
Descri pti ve statistics
C ha n ge fr o m 
Baseli ne i n t otal 
s urface area of 
tar get ulcer(s) 
o ver ti me u p t o 
Wee k 2 4
Descri pti ve 
s u m mar y 
statistics
I T T
N A
Descri pti ve statistics
C orrelati o n 
bet w ee n c ha n ge 
i n H b a n d target 
ulcer(s) heali n g 
at Wee k 1 2 a n d 
Wee k 2 4
P oi nt 
biserial 
c orrelati o n 
I T T
N A
T he p oi nt biserial c orrelati o n 
 C orrelati o n 
bet w ee n c ha n ge 
i n he m ol ytic 
para meters ( % 
retic ul oc ytes, 
i n direct bilir u bi n, 
L D H) a n d tar get 
ulcer(s) heali n g 
at Wee k 1 2 a n d 
Wee k 2 4
P oi nt 
biserial 
c orrelati o n
I T T
N A
T he p oi nt biserial c orrelati o n 
 0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 5 of 4 3
E n d p oi nt
A n al ysis
T y pe
P o p ul ati o n
D at a I ncl usi o n a n d 
R ules f or H a n dli n g 
I nterc urre nt E ve nts 
a n d Missi n g D at a
M ai n A n al ysis M o del
C ha n ge fr o m 
baseli ne i n P R O 
H R Q O L 
meas ures: 
P R O MI S -3 7 v 2. 0 
Pe diatric 
Pr ofile/ P R O MI S -
4 3 v 2. 1 at Wee k 
1 2 a n d Wee k 2 4
L S mea ns 
( 9 5 % CI)
L S mea ns 
differe nce
Descri pti ve 
s u m mar y 
statistics
I T T
N A
Descri pti ve statistics
M M R M a nal ysis will be 
use d as descri be d i n Secti o n
5. 2. 2. 1 wi t h t he stratificati o n 
fact ors i ncl u di n g tar get ulcer 
size (cate g orical) a n d tar get 
ulcer d urati o n (cate g orical) 
as c o variates.
C ha n ge fr o m 
baseli ne i n pai n 
le vel li n ke d t o 
tar get ulcer(s) 
assesse d b y V A S 
at Wee k 1 2 a n d 
Wee k 2 4
L S mea ns 
( 9 5 % CI)
L S mea ns 
differe nce
Descri pti ve 
s u m mar y 
statistics
I T T
N A
Descri pti ve statistics
M M R M a nal ysis will be 
use d as descri be d i n Secti o n 
5. 2. 2. 1 t he stratificati o n 
fact ors i ncl u di n g tar get ulcer 
size (cate g orical) a n d tar get 
ulcer d urati o n (cate g orical) 
as c o variates.
Patie nt Gl o bal 
I mpressi o n of 
C ha n ge ( P GI - C) 
sc ore at Wee k 1 2 
a n d Wee k 2 4
Descri pti ve 
s u m mar y 
statistics
I T T
N A
Descri pti ve statistics
Cli nicia n Gl o bal 
I mpressi o n of 
C ha n ge ( C GI - C) 
sc ore at Wee k 1 2 
a n d Wee k 2 4
Descri pti ve 
s u m mar y 
statistics
I T T
N A
Descri pti ve statistics
A p pe n di x 2. D at a Deri v ati o n Det ails
A p pe n di x 2. 1. Defi niti o n a n d U se of V isit W i n d o ws i n R e p orti n g
N o mi nal a nal ys is visit wi n d o ws f or t he efficac y a n d safet y e n d p oi nts will be defi ne d bel o w. 
N o mi nal Visit Ti me
Tar get St u d y  D a y
Pr ot oc ol St u d y  D a y 
Ra n ge
St u d y  D a y Ra n ge f or 
Statistical A nal y sis 
D a y  1
1
[ 1, 1]
[ 1, 1]*
Wee k 2
1 4
[ 1 1, 1 7]
[ 2, 2 1]
Wee k 4
2 8
[ 2 5, 3 1]
[ 2 2, 3 5]
Wee k 6
4 2
[ 3 9, 4 5]
[ 3 6, 4 9]
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 6 of 4 3
Wee k 8
5 6
[ 5 3, 5 9]
[ 5 0, 6 3]
Wee k 1 0
7 0
[ 5 7, 6 3]
[ 6 4, 7 7]
Wee k 1 2
8 4
[ 8 1, 8 7]
[ 7 8, 9 1]
Wee k 1 4
9 8
[ 9 5, 1 0 1]
[ 9 2, 1 0 5]
Wee k 1 6
1 1 2
[ 1 0 9, 1 1 5]
[ 1 0 6, 1 1 9]
Wee k 1 8
1 2 6
[ 1 2 3, 1 2 9]
[ 1 2 0, 1 3 3 ]
Wee k 2 0
1 4 0
[ 1 3 7, 1 4 3]
[ 1 3 4, 1 4 7]
Wee k 2 2
1 5 4
[ 1 5 1, 1 5 7]
[ 1 4 8, 1 6 1]
Wee k 2 4
1 6 8
[ 1 6 5, 1 7 1]
[ 1 6 2, 1 7 5]
Wee k 2 8
1 9 6
[ 1 9 1, 2 0 1]
[ 1 7 6, 2 1 6]
*: F or t he le g ulcer Da y 1 assess me nt , t he wi n d o wi n g D a y  1 visit is defi ne d as [- 1, 1]
N o mi nal a nal ys is visit wi n d o ws f or t he la b orat or y assess me nts will be defi ne d bel o w.  
N o mi nal Visit Ti me
Tar get St u d y  D a y
Pr ot oc ol St u d y  D a y 
Ra n ge
St u d y  D a y Ra n ge f or 
Statistical A nal y sis 
D a y  1 
1
[ 1, 1]
[ 1, 1 ]
Wee k 1 2
8 4
[ 8 1, 8 7]
[ 2, 1 2 5]
Wee k 2 4
1 6 8
[ 1 6 5, 1 7 1]
[ 1 2 6, 2 1 6 ]
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 7 of 4 3
A p pe n di x 2. 2. Pr ot oc ol De vi ati o ns t h at Rel ate d t o St atistic al A n al yses/ P o p ul ati o ns
F or t he pri mar y  e n d p oi nt, t he sa m ple size of 8 0 partici pa nts ( 4 0 partici pa nts per treat me nt 
gr o u p) pr o vi des a p pr o xi matel y  9 0 % p o wer t o detect a 3 5 % a bs ol ute differe nce bet wee n 
treat me nt gr o u ps ( v o xel ot or 1 5 0 0 m g + S O C vers us place b o + S O C) i n pr o p orti o n of 
partici pa nts e x perie nci n g res ol uti o n of t he tar get ulcer(s) b y Wee k 1 2. Calc ulati o ns were 
base d o n a t w o -si de d al p ha = 5 % test of t he differe nce i n t w o bi n o mial pr o p orti o ns ( N or mal 
a p pr o xi mati o n). If t he dr o p o ut rate of 5 % is ass u me d, t he sa m ple size s h o ul d be 8 4 
partici pa nts.
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 8 of 4 3
A p pe n di x 3.
D at a C o n ver si o n
P R O MI S- 4 3 v 2. 1 A d ult Pr ofile T -sc ore c o n versi o n ta ble
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C O P Y RI G H T E D M A T E RI A L


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 9 of 4 3
P R O MI S- 3 7 v 2. 0 Pe diatric Pr ofile T -sc ore c o n versi o n ta ble
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C O P Y RI G H T E D M A T E RI A L
C O P Y RI G H T E D M A T E RI A L


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 0 of 4 3
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C O P Y RI G H T E D M A T E RI A L


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 1 of 4 3
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)
C CI


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 2 of 4 3
A p pe n di x 5. List o f A b bre vi ati o ns
A b bre vi ati o n
Ter m
A E
a d verse e ve nt
A L P
al kali ne p h os p hatase
A L T
ala ni ne tra nsa mi nase
A S T
as partate tra nsferase
A R( 1)
first or der a ut ore gressi ve 
C GI -C
cli nical gl o bal i m pressi o n of cha n ge
CI
c o nfi de nce i nter val
C M H
C oc hra n – Ma ntel – Hae nszel
C R F
case re p ort f or m
C S
c o m p o u n d s ym metr y
C S R
cli nical st u d y re p ort
C T C A E
co m m o n ter mi n ol o g y criteria f or ad verse eve nt
E O S
en d of st u d y
H R Q O L
h ealt h-relate d q ualit y of life
I R T
i nterati ve res p o nse tec h n ol o g y
I T T
i nte nt-t o-treat
L D H
lactate de hy d r o ge nase
L S
least s q uare d 
Me d D R A
m e dical d icti o nar y f or re g ulat or y acti vities
M M R M
mi xe d m o del re peate d meas ures
N/ A
n ot a p plica ble
O L E
o pe n -la bel e xte nsi o n
P GI -C
patie nt gl o bal i m pressi o n of cha n ge
P R O
patie nt -re p orte d o utc o me
P R O MI S
p atie nt-re p orte d o utc o mes m eas ure me nt inf or mati o n sys te m
P T
preferre d ter m
Q 1
first q uartile
Q 3
t hir d q uartile
R E M L
restricte d ma xi m u m li keli h o o d
R B C
re d bl o o d cell
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S C D
sic kle cell disease 
S D
sta n dar d de viati o n
SI
inter nati o nal sys te m of u nits
S O C
sta n dar d of care
S O P
sta n dar d o perati n g pr oce d ure
S P
s patial p o wer
T E A E
treat me nt-e mer ge nt a d verse e ve nt
T E S A E
treat me nt-e mer ge nt seri o us a d verse e ve nt
V A S
vis ual a nal o g ue scale
0 9 0 1 7 7 e 1 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)


Pr ot oc ol V o xel ot or G B T 4 4 0 -0 4 2 (C 5 3 4 1 0 2 6 )
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 3 of 4 3
A b bre vi ati o n
Ter m
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 a 2 6 b 4 5 2 b\ A p pr o v e d\ A p pr o v e d O n: 1 7- D e c- 2 0 2 4 1 9: 2 0 ( G M T)