An Open-label Extension Study to Evaluate the Long-term Safety of GBT021601 Administered to Participants With Sickle Cell Disease Who Have Participated in a GBT021601 Clinical Trial
Phase: PHASE2
Conditions: Sickle Cell Disease
Sponsor: Pfizer

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 1
St u d y N u m ber
C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
Pr ot oc ol Title
A n O pe n -la bel E xte nsi o n St u d y t o E val uate t he L o n g-ter m Safet y of 
O si vel ot or A d mi nistere d t o Partici pa nts wit h Sic kle Cell Disease W h o 
Ha ve Partici pate d i n a n O si vel ot or Cli nical Trial
I n vesti g ati o n al 
Pr o d uct
O si vel ot or (als o k n o w n as P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
U S I N D N u m ber
1 5 1 6 7 7
E u dr a C T/ E U C T 
N u m ber
2 0 2 3 -5 0 8 7 6 8 -3 2 -0 0
Cli nic al Tri als. g o v I D
N C T 0 5 6 3 2 3 5 4
Pe di atric 
I n vesti g ati o n al Pl a n 
N u m ber:
E M E A -0 0 3 2 4 1 -PI P 0 1- 2 2 a n d P S P n ot a vaila ble 
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
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 S A
Brief Title
A n O pe n -la bel E xte nsio n St u d y of O si vel ot or i n Partici pa nts wit h 
Sic kle Cell Disease
T his d oc u me nt a n d acc o m pa n yi n g materials c o ntai n c o nfi de ntial i nf or mati o n bel o n gi n g t o Pfizer. 
E x pect as ot her wise a gree d t o i n writi n g, b y acce pti n g or re vie wi n g t hese d oc u me nts, y o u a gree t o 
h ol d t his i nf or mati o n i n c o nfi de nce a n d n ot c o p y or discl ose it t o ot hers (e xce pt w here re q uire d b y 
a p plica ble la w) or use it f or u na ut h orize d p ur p oses. I n t he e ve nt of a n y act ual or s us pecte d breac h 
of t he o bli gati o n, Pfizer m ust be pr o m ptl y n otifie d. 
C LI NI C A L S T U D Y P R O T O C O L
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 2
D oc u me nt Hist or y
D oc u me nt 
Versi o n D ate
A me n d me nt 4
0 8 Fe b 2 0 2 4
A me n d me nt 3
2 2 J u n 2 0 2 3
A me n d me nt 2
1 1 Oct 2 0 2 2
A me n d me nt 1
1 9 J ul 2 0 2 2
Ori gi nal pr ot oc ol
0 9 Ma y  2 0 2 2
T his a me n d me nt i nc or p orates all re visi o ns t o date, i ncl u di n g a me n d me nts ma de at t he 
re q uest of c o u ntr y healt h a ut h orities a n d I R Bs/ E Cs a n d a n y pr ot oc ol a d mi nistrati ve c ha n ge 
letter(s).
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 - A m e n d me nt 4 ( 0 8 Fe b 2 0 2 4)
O ver all R ati o n ale f or t he A me n d me nt: 
T o o pti mize st u d y  desi g n f or o pti mal safety m o nit ori n g a n d t o ali g n wit h pare nt st u d y desi g n 
as well as Pfizer sta n dar ds f or i nter ve nti o nal trials.
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n # & N a me
S u bst a nti al M o dific ati o n(s)
U p date d st u d y desi g n a n d 
m o difie d S o A: a d de d 
c o ntrace pti o n c hec k f or 
re pr o d ucti ve a ge males or 
fe males of c hil d -beari n g a ge, 
a d de d e x pl orat or y bi o mar kers, 
clarifie d partici pa nts s h o ul d 
ret ur n t o t he st u d y site f or a n 
E O S visit a p pr o xi matel y  1 2 
wee ks after t he last d ose of 
st u d y dr u g. A d de d P T, a P T T, 
I N R t o S o A a n d la b orat or y 
tests. Re m o ve d “ ot her S C D -
relate d bi o mar kers”.
S pecificall y f or partici pa nts 
e nr olli n g fr o m C 5 3 5 1 0 0 4 Part 
C: a d de d visit at 2 wee ks a n d 
re m o ve d fl o w a d hesi o n, R B C 
def or ma bilit y  a n d R B C 
mit oc h o n drial c o nte nt. 
O pti mizi n g st u d y  
desi g n f or o pti mal 
safety m o nit ori n g 
a n d t o ali g n wit h 
Pfizer sta n dar ds f or 
i nter ve nti o nal trials
2. 1 S o A; 5. 1 O verall Desi g n; 8. 2 
Disc o nti n uati o n of St u d y 
Treat me nt; 9. 2 Efficac y  
Assess me nts; 9. 3. 3 Cli nical 
La b orat or y  Tests; 9. 7 
P har mac o d y na mics/ Bi o mar kers
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
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 a me
I ncl u de d healt hcare res o urce 
utilizati o n assess me nts f or 
p artici pa nts e nr olli n g fr o m 
C 5 3 5 1 0 0 4 Part B. Re m o ve d 
P R O fr o m pe diatric 
partici pa nts e nr olli n g fr o m 
C 5 3 5 1 0 0 4 Part C. Pr o vi de d 
clarificati o n f or H R Q O L P R O 
assess me nts. 
T o ali g n P R Os wit h 
pare nt st u d y 
C 5 3 5 1 0 0 4.
2. 1 S o A Ta ble 2, Ta ble 3 a n d 
Ta ble 4 ; 7. 7. 1 Hea lt hcare 
Res o urce Utilizati o n f or 
Partici pa nts E nr olli n g fr o m 
C 5 3 5 1 0 0 4 Part B ; 9. 8 Healt h-
Relate d Q ualit y  of Life 
Assess me nts
U p date d a n d i de ntifie d 
o bjecti ves a n d e n d p oi nts as 
pri mar y , sec o n dar y, or 
e x pl orat or y. U p date d efficac y 
assess me nts. 
T o ali g n wit h Pfizer 
sta n dar ds f or 
i nter ve nti o nal trials
2 S y n o psis; 2. 1 S o A; 4 
O bjecti ves, E n d p oi nts a n d 
Esti ma n ds; 9. 2 Efficac y  
Assess me nts
Defi ne d a d ult d ose as 1 5 0 m g
osi vel ot or . A d olesce nt a n d 
pe diatric partici pa nts fr o m 
C 5 3 5 1 0 0 4 Parts B a n d C will 
be a d mi nister e d a d ose t hat 
pr o vi des ge nerall y  e q ui vale nt 
e x p os ure t o a d ult partici pa nts.
U p date d d ose m o dificati o n 
i nstr ucti o ns.
Base d o n e mer gi n g 
data fr o m C 5 3 5 1 0 0 4 
pare nt st u d y
3. 3 St u d y  Rati o nale; 5. 3 
J ustificati o n f or D ose: 7. 5 D ose 
M o dificati o n; 1 1. 3 Detaile d 
D os i n g I nf or mati o n f or 
Osi vel ot or
U p date d 
c o ntrace pti o n/a bsti ne nce 
re q uire me nt t o e xte n d fr o m 
st u d y start t o 8 4 da y s after t he 
last d ose of st u d y dr u g f or 
fe male partici pa nts of c hil d-
beari n g p ote ntial a n d 
re pr o d ucti ve a ge male s.
T his ti me fra me is 
s ufficie nt c o vera ge 
d uri n g osi vel ot or
was h o ut, c o nsi deri n g 
t he half-life i n S C D 
pa tie nts.
2 S y n o psis; 6. 1 I ncl usi o n Criteria; 
9. 3. 5. 1 Fe male Partici pa nts of 
C hil d beari n g P ote ntial ; 9. 3. 5. 2 
I nstr ucti o ns f or Male Partici pa nts 
Ca pa ble of Fa t heri n g a C hil d;
9. 3. 5. 3 Acce pta ble F or ms of 
C o ntrace pti o n f or male 
Partici pa nts wit h Fe male part ners 
Ca pa ble of Re pr o d ucti o n
A d de d males m ust refrai n fr o m 
d o nati n g s per m fr o m st u d y 
start t hr o u g h 8 4 da ys after t he 
fi nal d ose t o i ncl usi o n criteria.
T o ali g n wit h 
c o ntrace pti ve/a bsti ne
nce i ncl usi o n 
criteria.
2 S y n o psis; 6. 1 I ncl usi o n Criteria
U p date d e xcl usi o n criteria 
relate d t o: marij ua na use a n d 
clarifie d ti mi n g of use
 
 
 A d de d 
T o ali g n wit h Pfizer 
sta n dar ds f or 
i nter ve nti o nal trials
6. 2 E xcl usi o n Criteria
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)
C CI

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
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 a me
e xcl usi o n base d o n c urre nt or
rece nt use of criza nliz u ma b.
Pr o vi de d u p date d bl o o d 
v ol u me c ollecti o n li mits. 
Pr o vi de d g ui da nce f or 
mi ni mizi n g fear/ disc o mf ort f or 
pe diatric partici pa nts. Pr o vi de d 
a bl o o d s peci me n assess me nt 
pri orit y list.
T o ali g n wit h Pfizer 
safety g ui da nce 
9 St u d y  Assess me nts a n d 
Pr oce d ures; 9. 3. 3 Cli nical 
La b orat or y  Tests; 9. 3. 3. 1 T otal 
Bl o o d V ol u me; 9. 5 
P har mac o ki netics
Re vise d rec o m me n de d acti o ns 
f or dr u g-relate d a d verse e ve nts 
d ue t o d ose m o dificati o ns i n 
Ta ble 8. Pr o vi de d u p date d 
g ui da nce o n A d verse E ve nts 
t hat are V O C e ve nts. T he ti me 
peri o d f or acti vel y eliciti n g 
a n d c ollecti n g A Es a n d S A Es 
be gi ns at i nf or me d c o nse nt , 
t hr o u g h 6 3 cale n dar da ys after 
t he last a d mi nistrati o n of t he 
st u d y i nter ve nti o n. A d de d 
secti o ns: ‘ U ne x pecte d A d verse 
Reacti o ns’, ‘ Ti me Peri o d a n d 
Fre q ue nc y  f or C ollecti n g A E 
a n d S A E I nf or mati o n’, a n d 
‘ Lac k of Efficac y’.  A d de d 
a d diti o nal re q uire me nts f o r 
re p orti n g E D Ps.
T o ali g n wit h Pfizer 
safety g ui da nce
9. 4. 5 U ne x pecte d A d verse 
Reacti o ns; 9. 4. 7 Ti me Peri o d a n d 
Fre q ue nc y  f or C ollecti n g A E a n d 
S A E I nf or mati o n; 9. 4. 9 Dr u g -
i n d uce d Li ver I nj ur y, 9. 4. 1 2. 1 
(a n d s u bsecti o ns) A d verse E ve nts 
t hat are Vas o-Occl u si ve Crisis 
E ve nts; 9. 4. 1 3. 1 E x p os ure D uri n g 
Pre g na nc y ; 9. 4. 1 4 Lac k of 
Efficac y
A d de d esti ma n ds f or pri mar y  
e n d p oi nt. U p date d Pla n ne d 
Statistical A nal y sis. 
T o ali g n la n g ua ge 
wit h S A P
4 O bjecti ves, E n d p oi nts a n d 
Esti ma n ds; 1 0 Statistical 
C o nsi derati o ns (an d s u bsecti o ns)
N o n -S u bst a nti al M o dific ati o n(s)
A d de d S u m mar y  of C ha n ges 
Ta ble; Re place d S y n o psis; 
Pr o vi de d u p date d f o ot n otes i n 
S o A ; U p date d I ntr o d ucti o n, 
Bac k gr o u n d, a n d Be nefit/ Ris k 
Assess me nt secti o ns; U p date d 
st u d y dr u g i nf or mati o n; A d de d 
Pr ot oc ol A me n d me nt Hist or y  
T o ali g n wit h Pfizer 
sta n dar ds f or 
i nter ve nti o nal trials 
a n d pr o vi de u p t o 
d ate i nf or mati o n
2 S y n o psis; 2. 1 S o A; 3 
I ntr o d ucti o n; 3. 1 Bac k gr o u n d; 3. 2 
Be nefit/ Ris k Assess me nt (a n d 
s u bsecti o ns); 7. 1 St u d y 
Treat me nts A d mi nistere d; 7. 6 
Treat me nt of O ver d ose; 1 1. 7 
Pr ot oc ol A me n d me nt Hist or y ; 
1 1. 8 A b bre viati o ns
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 5
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n # & N a me
A p pe n di x a n d m o ve d list of 
a b bre viati o ns
Re m o ve d refere nce t o 
G B T 0 2 1 6 0 1 -0 1 2 partici pa nts 
e nr olli n g
G B T 0 2 1 6 0 1 - 0 1 2 
st u d y is c o m plete, 
a n d partici pa nts will 
n ot be e nr olli n g i n 
C 5 3 5 1 0 0 5
2. 1 S o A; 3. 2 Be nefit/ Ris k 
Assess me nt; 5. 1 O verall Desi g n ; 
5. 3 J ustificati o n f or D ose; 9. 2 
Efficac y  Assess me nts; 1 1. 3 
Detaile d D osi n g I nf or m ati o n f or 
Osi vel ot or
U p date d visit wi n d o w after 2 4 
wee ks fr o m +/ - 4 wee ks t o
+/ - 14 d a y s
T o preser ve dr u g 
s u p pl y
2. 1 S o A Ta ble 1, Ta ble 2, Ta ble 
3, Ta ble 4
U p date d stat us of 
G B T 0 2 1 6 0 1 -0 1 1 a n d 
G B T 0 2 1 6 0 1 -0 1 2 t o c o m plete d
T o reflect 
c o m pleti o n of 
st u dies.
3. 1 Bac k gr o u n d
U p date d I B pr o vi de d
Reflects 2 0 2 3 
a p pr o ve d versi o n
3. 1 Bac k gr o u n d; 1 2 Refere nces
Re m o ve d “at a p pr o xi matel y  6 0 
gl o bal cli nical sites” a n d 
u p date d t o “ will ha ve a gl o bal 
distri b uti o n”.
T o ali g n wit h Pfizer 
sta n dar ds f or 
i nter ve nti o nal trials
5. 1 O verall Desi g n
Re place d “ male or fe male” i n 
i ncl usi o n criteria. 
M ore i ncl usi vit y  
6. 1 I ncl usi o n Criteria
C o m bi ne d o ver d ose i nt o si n gle 
secti o n a n d re vise d 
i nstr ucti o ns f or re p orti n g 
o ver d ose. Re vise d g ui da nce 
f or C o nc o mita nt Me dicati o ns 
a n d Pr oce d ures a n d a d de d 
a p pe n di x f or Pr o hi bite d 
C o nc o mita nt Me dicati o ns T hat 
Ma y  Res ult i n D DI. A d de d 
ne w secti o ns o n P ote ntial 
Cases of Ac ute Ki d ne y  I nj ur y 
a n d Dr u g -i n d uce d Li ver 
I nj ur y. U p date d g ui da nce f or 
calc ulati n g e Cr Cl or e G F R. 
A d de d a p pe n di x f or Ki d ne y  
Safet y . A d de d clarif yi n g te xt 
t o Li ver Safety a p pe n di x. 
A d de d ser u m c ystati n C , 
ha pt o g l o bi n, he m o pe xi n, a n d 
T o ali g n wit h Pfizer 
safety g ui da nce f or 
i nter ve nti o nal trials
7. 6. Treat me nt of O ver d ose; 7. 7 
C o nc o mita nt Me dicati o ns a n d 
Pr oce d ures; 8. 2. 1 P ote ntial Cases 
of Ac ute Ki d ne y  Inj ur y ; 9. 3. 3 
Cli nical L a b orat or y Tests; 9. 4. 9 
Dr u g -i n d uce d Li ver I nj ur y ; 1 1. 4 
Li ver Safet y : S u g geste d Acti o ns 
a n d F oll o w -U p Assess me nts; 
1 1. 5 Ki d ne y Safet y M o nit ori n g 
G ui deli nes; 1 1. 6 Pr o hi bite d a n d 
Restricte d C o nc o mita nt 
Me dicati o ns T hat Ma y  Res ult i n 
D DI
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 6
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n # & N a me
s ol u ble C 3 c ollecti o n t o 
la b orat or y tests. 
Delete d re d u n da nt ‘ Re p orti n g 
Pre g na nc y ’ secti o n a n d 
u p date d ‘ E x p os ure D uri n g 
Pre g na nc y ’ secti o n. U p date d 
g ui da nce f or ‘ E x p os ure D uri n g 
Breastfee di n g’.
T o ali g n wit h Pfizer 
sta n dar ds f or 
i nter ve nti o nal trials
Delete d pre vi o us 8. 4. 7 Re p orti n g 
Pre g na nc y ; 9. 4. 1 3. 1 E x p os ure 
D uri n g Pre g na nc y ; 9. 4. 1 3. 2 
E x p os ure D uri n g Breastfee di n g
Re vise d/refi ne d 
p har mac o d y n a mics/ bi o mar kers
T o reflect u p date d 
st u d y desi g n
9. 7 
P har mac o d y na mics/ Bi o mar kers
S pecifie d S A Es, E D P a n d 
occ u pati o nal e x p os ure will be 
re p orte d via P S S A. A E or S A E 
m ust be rec or de d o n t he C R F , 
t he S A E re p orte d usi n g P S S A,
a n d pr o vi de d a d diti o nal 
g ui da nce f or i m me diate 
re p orti n g re q uire me nts. 
Me dicati o n err ors will be 
re p orte d via P S S A t o Pfizer 
Safet y  ( o nly if ass ociate d wit h 
a n S A E) a n d clarifie d p ote ntial 
me dicati o n err ors.
I nc or p orate d
P A C L  a p pr o ve d o n 
1 4 J ul 2 0 2 3
9. 4. 6. 1 Ge neral A E Re p orti n g; 
9. 4. 7 Ti me Peri o d a n d Fre q ue nc y  
f or C ollecti n g A E a n d S A E 
I nf or mati o n; 9. 4. 8 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; 9. 4. 1 3. 1 E x p os ure 
D uri n g Pre g na nc y ; 9. 4. 1 3. 3 
Occ u pati o n al E x p os ure; 9. 4. 1 5 
Me dicati o n Err ors
F or t he assess me nt ‘ Dis pe nse 
st u d y dr u g: st u d y dr u g s h o ul d 
be dis pe nse d fr o m t he I RT 
s yste m at Baseli ne visit, St u d y 
Wee k 1 2, Wee k 2 4, a n d E ver y  
1 2 wee ks.
I nc or p orate d P A C L 
a p pr o ve d o n 
0 4 Oct 2 0 2 3
2. 1 S o A Ta ble 1
T he E mer ge nc y  C o ntact Car d 
is bei n g re place d by a st u d y 
i nf or mati o n car d a n d E C C will 
n o l o n ger be refere nce d. 
T he pr ocess f or 
c o ntacti n g a 
me dicall y  q ualifie d 
i n di vi d ual has 
c ha n ge d fr o m a 
me dical escalati o n 
pr ocess via a Pfizer 
Call Ce nter t o direct 
cli nical tea m c o ntact 
usi n g a St u d y Tea m 
C o ntact L ist. 
1 1. 1. 1 0 S p o ns or’s M e dicall y 
Q ualifie d I n di vi d ual
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 7
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n # & N a me
P F - 0 7 9 4 0 36 7 u p date d t o 
ge neric na me, osi vel ot or.
G B T 0 2 1 6 0 1 -0 2 1 u p date d t o 
C 5 3 5 1 0 0 4; G B T 0 2 1 6 0 1 - 0 2 2 
u p date d t o C 5 3 5 1 0 0 5
T o ali g n wit h Pfizer 
sta n dar ds f or 
i nter ve nti o nal trials
T hr o u g h o ut pr ot oc ol
Mi n or e dit orial c ha n ges a n d 
clarificati o ns
T o pr o vi de clarit y
T hr o u g h o ut Pr ot oc ol
1. T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F FI G U R E S 
T A B L E O F C O N T E N T S
1. T A B L E O F C O N T E N T S , LI S T O F T A B L E S, A ND LI S T O F FI G U R E S .......................... 7
LI S T O F T A B L E S ................................................................................................................... 1 2
2. S Y N O P SI S ........................................................................................................................... 1 3
2. 1. Sc he d ule(s) of Assess me nts a n d Pr oce d ures ........................................................... 1 7
A d ult Partici pa nts wit h Dela y e d Start of O pe n La bel E xte nsi o n ( O L E) St u d y  
( > 4 2 da ys) ..................................................................................................................1 7
A d ult Partici pa nts fr o m Part A of C 5 3 5 1 0 0 4 a n d Ot her A p plica ble Osi vel ot or 
O pe n La bel St u dies wit h n o Dela y  of Start...............................................................2 1
Partici pa nts fr o m Part B of C 5 3 5 1 0 0 4 a n d Ot her Osi vel ot or Ra n d o mize d, 
Bli n de d, Place b o C o ntr olle d St u dies ......................................................................... 2 4
Pe diatric Partici pa nts fr o m Part C of C 5 3 5 1 0 0 4 ............................................................ 2 7
3. I N T R O D U C TI O N ............................................................................................................... 3 0
3. 1. Bac k gr o u n d ............................................................................................................. 3 0
3. 2. Be nefit/ Ris k Assess me nt ......................................................................................... 3 2
3. 2. 1. Ris k Assess me nt ......................................................................................... 3 2
3. 2. 2. Be nefit Assess me nt ..................................................................................... 3 3
3. 2. 3. O verall Be nefit/ Ris k C o ncl usi o n ................................................................3 4
3. 3. St u d y  Rati o nale....................................................................................................... 3 4
4. O BJ E C TI V E S, E N D P O I N T S, A N D E S TI M A N D S ........................................................... 3 5
5. S T U D Y D E SI G N .................................................................................................................3 6
5. 1. O verall D esi g n ......................................................................................................... 3 6
5. 2. Scie ntific Rati o nale f or St u d y  Desi g n..................................................................... 3 7
5. 3. J ustificati o n f or D ose ..............................................................................................3 7
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 8
5. 4. E n d of St u d y  Defi niti o n .......................................................................................... 3 8
6. S T U D Y P O P U L A T I ON ...................................................................................................... 3 9
6. 1. I ncl usi o n Criteria ..................................................................................................... 3 9
6. 2. E xcl usi o n Criteria .................................................................................................... 4 0
7. S T U D Y T R E A T M E N T A N D C O N C O MI T A N T T H E R A P Y ........................................... 4 1
7. 1. St u d y  Treat me nts A d mi nistere d.............................................................................. 4 1
7. 2. Pre parati o n, Ha n dli n g, St ora ge, a n d Acc o u nta bilit y ............................................... 4 2
7. 3. Ra n d o mizati o n a n d Bli n di n g ................................................................................... 4 2
7. 4. St u d y  Treat me nt C o m plia nce.................................................................................. 4 2
7. 5. D ose M o dificati o n ................................................................................................... 4 3
7. 5. 1. I n di vi d ual Le vel St o p pi n g R ules f or Partici pa nts E nr olli n g i n 
C 5 3 5 1 0 0 5 fr o m t he 2 0 0 m g Treat me nt Ar m fr o m Part A of C 5 3 5 1 0 0 4 ......... 4 4
7. 6. Treat me nt of O ver d ose ............................................................................................ 4 5
7. 7. C o nc o mita nt Me dicati o ns a n d Pr oce d ures ..............................................................4 5
7. 7. 1. Healt hcare Res o urce Utilizati o n f or Partici pa nts E nr olli n g fr o m 
C 5 3 5 1 0 0 4 Part B ..............................................................................................4 6
8. DI S C O N TI N U A TI O N O F S T U D Y T R E A T M E N T A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L ........................................................................... 4 6
8. 1. Earl y Disc o nti n uati o n of t he St u d y ......................................................................... 4 6
8. 2. Disc o nti n uati o n of St u d y  Treat me nt....................................................................... 4 6
8. 2. 1. P ote ntial Cases of Ac ute Ki d ne y  Inj ur y ..................................................... 4 7
8. 2. 2. Disc o nti n uati o n d ue t o A d verse E ve nts ...................................................... 4 8
8. 3. Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y .......................................................... 4 9
8. 4. L ost t o F oll o w u p .................................................................................................... 4 9
9. S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S ...............................................................5 0
9. 1. De m o gra p hic/ Me dical Hist or y ................................................................................ 5 0
9. 2. Efficac y  Assess me nts..............................................................................................5 0
9. 3. Safet y Assess me nts ................................................................................................. 5 2
9. 3. 1. P h y sical E xa mi nati o n ................................................................................. 5 2
9. 3. 2. Vital Si g ns .................................................................................................. 5 2
9. 3. 3. Cli nical L a b orat or y Tests ........................................................................... 5 2
9. 3. 3. 1. T otal Bl o o d V ol u me .................................................................. 5 4
9. 3. 4. Pre g na nc y  Testi n g ......................................................................................5 5
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 9
9. 3. 5. Fertilit y  a n d C o ntrace pti ve Re q uire me nts.................................................. 5 5
9. 3. 5. 1. Fe male Partici pa nts of C hil d beari n g P ote ntial .......................... 5 5
9. 3. 5. 2. I nstr ucti o n s f or Male Partici pa nts Ca pa ble of Fat heri n g a 
C hil d .................................................................................................. 5 6
9. 3. 5. 3. Acce pta ble F or ms of C o ntrace pti o n f or Male Partici pa nts 
wit h Fe ma le Part ners Ca pa ble of Re pr o d ucti o n................................ 5 6
9. 4. A d verse E ve nts ( A Es) Seri o us A d verse E ve nts ( S A Es), a n d Ot her Safet y  
Re p orti n g ................................................................................................................... 5 6
9. 4. 1. Defi niti o n of A d verse E ve nts ..................................................................... 5 6
9. 4. 2. Defi niti o n of Seri o us A d verse E ve nts or Seri o us S us pecte d A d verse 
Reacti o ns .......................................................................................................... 5 7
9. 4. 3. Se verit y  of A d verse E ve nts ........................................................................5 7
9. 4. 4. Relati o ns hi p t o I n vesti gati o nal Pr o d uct ...................................................... 5 8
9. 4. 5. U ne x pecte d A d verse Reacti o ns .................................................................. 5 8
9. 4. 6. A d verse E ve nt Re p orti n g ............................................................................ 5 9
9. 4. 6. 1. Ge neral A E Re p orti n g ...............................................................5 9
9. 4. 7. Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A E a n d S A E I nf or mati o n....... 5 9
9. 4. 7. 1. Dia g n osis Vers us Si g ns a n d S y m pt o ms .................................... 5 9
9. 4. 7. 2. A b n or mal La b orat or y  Val ues.................................................... 6 0
9. 4. 8. Seri o us A d verse E ve nts, Seri o us A d verse Dr u g Reacti o n s, a n d 
Re q uire me nts f or I m me diate Re p orti n g ...........................................................6 0
9. 4. 8. 1. Re p orti 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 .................................................. 6 0
9. 4. 9. Dr u g -i n d uce d Li ver I nj ur y .......................................................................... 6 1
9. 4. 1 0. Met h o d of Detecti n g A Es a n d S A Es ........................................................ 6 1
9. 4. 1 1. F oll o w -u p of A Es a n d S A Es ..................................................................... 6 1
9. 4. 1 2. Disease -relate d E ve nts or Disease-relate d O utc o mes N ot Q ualif yi n g 
as A Es or S A Es ................................................................................................ 6 1
9. 4. 1 2. 1. A d verse E ve nts t hat are Vas o -Occl usi ve Crisis E ve nts .......... 6 1
9. 4. 1 3. 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 ..................................................... 6 4
9. 4. 1 3. 1. E x p os ure D uri n g Pre g na nc y .................................................... 6 4
9. 4. 1 3. 2. E x p os ure D uri n g Breastfee di n g .............................................. 6 6
9. 4. 1 3. 3. Occ u pati o nal E x p os ure ........................................................... 6 6
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0
9. 4. 1 4. La c k Of Efficac y ....................................................................................... 6 6
9. 4. 1 5. Me dicati o n Err ors ..................................................................................... 6 6
9. 5. P har mac o ki netics .................................................................................................... 6 7
9. 6. Ge netics ................................................................................................................... 6 7
9. 7. P har mac o d y na mics/ Bi o mar kers .............................................................................. 6 8
9. 8. Healt h -Relate d Q ualit y  of Life Assess me nts f or Partici pa nts E nr olli n g fr o m 
C 5 3 5 1 0 0 4 Part A a n d Part B ..................................................................................... 6 8
9. 9. Me dical Res o urce Utilizati o n a n d Healt h Ec o n o mics ............................................. 6 9
9. 1 0. Misse d Assess me nts ..............................................................................................6 9
1 0. S T A TI S TI C A L C O N S I DE R A TI O N S .............................................................................. 7 0
1 0. 1. Statistical H y p ot hesis ............................................................................................ 7 0
1 0. 1. 1. Esti ma n ds .................................................................................................. 7 0
1 0. 1. 2. M ulti plicit y  A dj ust me nt............................................................................ 7 0
1 0. 2. A nal y sis Sets ......................................................................................................... 7 0
1 0. 3. St atistical A nal yses ...............................................................................................7 1
1 0. 3. 1. Ge neral C o nsi derati o ns ............................................................................. 7 1
1 0. 3. 2. Pri mar y  E n d p oi nt(s)/ Esti ma n d(s) A nalys is.............................................. 7 1
1 0. 3. 3. Sec o n dar y  E n d p oi nt(s)/ Esti ma n d(s) A nalysis .......................................... 7 2
1 0. 3. 4. E x pl orat or y  E n d p oi nt A nal ysis................................................................. 7 2
1 0. 3. 5. Ot her A nal ys es .......................................................................................... 7 2
1 0. 4. I nteri m A nalys es ................................................................................................... 7 3
1 0. 5. Sa m ple Size Deter mi nati o n ................................................................................... 7 3
1 1. S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S .......................................................................................................... 7 4
1 1. 1. Re g ulat or y , Et hical, a n d St u d y O versi g ht C o nsi derati o ns.................................... 7 4
1 1. 1. 1. Re g ulat or y  a n d Et hical C o nsi derati o ns .................................................... 7 4
1 1. 1. 2. Fi na ncial Discl os ure .................................................................................7 4
1 1. 1. 3. 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.......................................................................................................... 7 5
1 1. 1. 4. I nf or me d C o nse nt Pr ocess ........................................................................7 5
1 1. 1. 5. Data Pr otecti o n ......................................................................................... 7 6
1 1. 1. 6. Disse mi nati o n of Cli nical St u d y  Data ......................................................7 6
1 1. 1. 7. Data Q ualit y Ass ura nce ............................................................................ 7 7
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1
1 1. 1. 8. St u d y  a n d Site Start a n d Cl os ure ..............................................................7 8
1 1. 1. 9. P u blicati o n P olic y ..................................................................................... 7 9
1 1. 1. 1 0. S p o ns or’s Me dicall y  Q ualifie d I n di vi d ual.............................................. 8 0
1 1. 2. S u p p orti n g D oc u me ntati o n ................................................................................... 8 1
1 1. 3. A p pe n di x 1: Detaile d D osi n g I nf or mati o n F or Osi vel ot or ................................... 8 1
1 1. 4. 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 ....... 8 2
1 1. 4. 1. Dr u g -i n d uce d Li ver I nj ur y ........................................................................ 8 2
1 1. 4. 2. L i ver Safety:  S u g geste d Acti o ns a n d F oll o w-u p Assess me nts ................. 8 2
1 1. 5. A p pe n di x 3: Ki d ne y  Safet y M o nit ori n g G ui deli nes ............................................. 8 5
1 1. 5. 1. La b orat or y  Assess me nt of C ha n ge i n Ki d ne y F u ncti o n a n d 
Detecti o n of Ki d ne y  Inj ur y .............................................................................. 8 5
1 1. 5. 2. A ge -S pecific Ki d ne y  F u ncti o n Calc ulati o n Rec o m me n dati o ns............... 8 5
1 1. 5. 2. 1. A d ults ( 1 8 Years a n d A b o ve) — 2 0 2 1 C K D -E PI 
E q uati o ns[ 1] ...................................................................................... 8 5
1 1. 5. 2. 2. A d olesce nts ( 1 2 Years t o < 1 8 Years) —
C oc kcr oft -Ga ult 
F or m ula ..............................................................................................8 6
1 1. 5. 2. 3. C hil dre n ( 2 Years t o < 1 2 Years) —
( M o difie d) Sc h wartz 
E q uati o n............................................................................................. 8 6
1 1. 5. 2. 4. I nfa nts ( 1 M o nt h t o < 2 Years) a n d Ne o nates ( < 1 M o nt h) 
—
( Be dside) Sc h wartz E q uati o n ....................................................... 8 6
1 1. 5. 3. Ki d ne y  F u ncti o n Calc ulati o n T o ols.......................................................... 8 6
1 1. 5. 4. A d verse E ve nt Gra di n g f or Ki d ne y  Safety La b orat or y  
A b n or malities ................................................................................................... 8 7
1 1. 6. A p pe n di x 5: Pr o hi bite d a n d Restricte d C o nc o mita nt Me dicati o ns T hat Ma y 
Res ult i n D DI ............................................................................................................. 8 8
1 1. 7. A p pe n di x 5: Pr ot oc ol A me n d me nt Hist or y ........................................................... 9 0
1 1. 8. A p pe n di x 6: A b bre viati o ns ................................................................................... 9 4
1 2. R E F E R E N C E S .................................................................................................................. 9 8
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2
LI S T O F T A B L E S
Ta ble 1.
Sc he d ule of Assess me nts f or A d ult Partici pa nts wit h Dela y e d Start 
of O L E ( > 4 2 da y s) .................................................................................... 1 7
Ta ble 2.
Sc he d ule of Assess me nts f or A d ult Partici pa nts fr o m Part A of 
C 5 3 5 1 0 0 4 a n d Ot her A p plica ble Osi vel ot or O pe n L a bel St u dies 
wit h n o Dela y  of Start............................................................................... 2 1
Ta ble 3.
Sc he d ule of Assess me nts f or Partici pa nts fr o m Part B of C 5 3 5 1 0 0 4 
a n d Ot her Osi vel ot or Ra n d o mize d, Bli n de d, Place b o C o ntr o lle d 
St u dies ....................................................................................................... 2 4
Ta ble 4.
Sc he d ule of Assess me nts f or Pe diatric Partici pa nts fr o m Part C of 
C 5 3 5 1 0 0 4 ..................................................................................................2 7
Ta ble 5.
O bjecti ves, E n d p oi nts a n d Esti ma n ds ....................................................... 3 5
Ta ble 6.
D oses Pla n ne d Base d o n Partici pati o n fr o m C 5 3 5 1 0 0 4........................... 3 8
Ta ble 7.
St u d y  Dr u g I nf or mati o n............................................................................ 4 1
Ta ble 8.
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 ....................................................................................................... 4 3
Ta ble 9.
Cli nical Safet y  a n d Ot her La b orat or y Tests ............................................. 5 4
Ta ble 1 0:
Bl o o d S peci me n Assess me nt Pri orit y  List ............................................... 5 5
Ta ble 1 1.
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 ................ 5 8
Ta ble 1 2.
Re p orti n g of Me dicati o n Err o rs................................................................ 6 7
Ta ble 1 3.
D ose f or Partici pa nts E nr olle d Directl y fr o m Part A of C 5 3 5 1 0 0 4 .......... 8 1
Ta ble 1 4.
M o difie d L oa di n g D ose f or T h ose wit h a Ga p i n Treat me nt fr o m 
C 5 3 5 1 0 0 4 Part A, Part B, a n d Part C ....................................................... 8 1
Ta ble 1 5.
D ose f or Partici pa nts E nr olle d fr o m Part B of C 5 3 5 1 0 0 4 ........................ 8 2
Ta ble 1 6.
D ose f or Partici pa nts E nr olle d fr o m Part C of C 5 3 5 1 0 0 4 ........................ 8 2
Ta ble 1 7.
E xa m ples of Pr o hi bite d C o nc o mita nt Me dicati o ns .................................. 8 8
Ta ble 1 8.
E xa m ples of Restricte d C o nc o mita nt Me dicati o ns ...................................8 9
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3
2. S Y N O P SI S
Pr ot oc ol Title: 
A n O pe n -la bel E xte nsi o n St u d y t o E val uate t he L o n g-ter m Safety of O si vel ot or
A d mi nistere d t o Partici pa nts wit h Sic kle Cell Disease W h o Ha ve Partici pate d i n a n
O si vel ot or Cli nical Trial
Brief Title:
A n O pe n -la bel E xte nsi o n St u d y of O si vel ot or i n Partici pa nts wit h Sic kle Cell Disease
Re g ul at or y A ge nc y I de ntific ati o n N u m ber(s):
U S I N D N u m ber:
1 5 1 6 7 7
E u dr a C T/ E U C T N u m ber:
2 0 2 3- 5 0 8 7 6 8- 3 2- 0 0
Cli nic al Tri als. g o v I D:  
N C T 0 5 6 3 2 3 5 4
Pe di atric I n vesti g ati o n al Pl a n 
N u m ber:
E M E A -0 0 3 2 4 1- PI P 0 1 -2 2 a n d P S P n ot a vaila ble 
Pr ot oc ol N u m ber:
C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
P h ase:
2/ 3
R ati o n ale:
T his is a m ultice nter, gl o bal, o pe n -la bel e xte nsi o n st u d y t o e val uate t he l o n g-ter m safet y, 
t olera bilit y, a n d sic kle cell disease ( S C D) relate d c o m plicati o ns of partici pa nts w h o ha ve 
bee n treate d wit h o si vel ot or.
O bjecti ves a n d E n d p oi nts:
O bjecti ves
E n d p oi nt
Pri m ar y:
Pri m ar y:
T o e val uate t he l o n g -ter m safet y of 
osi vel ot or i n partici pa nts wit h S C D.

I nci de nce of treat me nt-e mer ge nt a d verse e ve nts 
( T E A Es), c ha n ges i n la b orat or y assess me nts, a n d 
c ha n ges i n vital si g ns.
Sec o n d ar y:
Sec o n d ar y:
T o e val uate fre q ue nc y of S C D-relate d 
c o m plicati o ns.
T o e val uate t he effects of l o n g -ter m use of 
osi vel ot or o n he m ol ytic a ne mia. 

A n n ualize d rate of vas o -occl usi ve crisis ( V O C). 

I nci de nce of S C D-relate d seri o us a d verse e ve nts ( S A Es).

C ha n ge fr o m baseli ne i n he mat ol o gi cal la b orat or y 
para meters, i ncl u di n g he m o gl o bi n, retic ul oc ytes, lactate 
de h y dr o ge nase, a n d u nc o nj u gate d bilir u bi n.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4
O ver all Desi g n:
T his is a m ultice nter, gl o bal, o pe n -la bel e xte nsi o n st u d y i n partici pa nts wit h S C D. T he st u d y 
will i ncl u de partici pa nts 6 m o nt hs of a ge a n d ol der wit h S C D w h o ha ve partici pate d a n d 
recei ve d st u d y dr u g i n an osi vel ot or cli nical st u d y a n d meet eli gi bilit y criteria. 
All partici pa nts will recei ve dail y  osi vel ot or a d mi nistere d orall y.
Eli gi ble partici pa nts will recei ve o pe n -la bel o si vel ot or o n Da y  1. It is i nte n de d t hat Da y 1 
c oi nci des wit h t he fi nal visit fr o m t he ori gi nati n g osi vel ot or st u d y. E n d of Treat me nt ( E O T) 
assess me nts fr o m t he ori gi nati n g st u d y  will ser ve as Baseli ne assess me nts f or t his st u d y. If 
D a y  1 f or t his st u d y is greater t ha n 7 da y s fr o m t he c o m pleti o n of t he ori gi nati n g st u d y, ne w 
baseli ne assess me nts will be o btai ne d. If d uri n g t he peri o d bet wee n Da y  1 of t his st u d y a n d 
c o m pleti o n of t he ori gi nati n g st u d y  n o d ose is recei ve d f or greater t ha n 3 c o nsec uti ve da ys, 
a n a p pr o priate l oa di n g d ose will be a d mi nistere d pri or t o c o nti n ue d mai nte na nce d osi n g.
St u d y P o p ul ati o n: 
I ncl usi o n Criteri a Partici pa nts m ust meet t he f oll o wi n g ke y i ncl usi o n criteria t o be eli gi ble 
f or e nr oll me nt i nt o t he st u d y:
1.
A ge d 6 m o nt hs or ol der wit h S C D w h o partici pate d a n d recei ve d st u d y dr u g i n a n
osi vel ot or cli nical st u d y a n d c o m plete d t he E O T visit.
N ote: Partici pa nts w h o disc o nti n ue d st u d y  dr u g i n t he ori gi nati n g st u d y d ue t o a n A E, b ut 
w h o re mai ne d o n st u d y, ma y be eli gi ble f or treat me nt i n t his st u d y pr o vi de d t he A E d oes 
n ot p ose a ris k f or treat me nt wit h osi vel ot or . Als o, partici pa nts w h o c o m plete d treat me nt 
fr o m t he ori gi nati n g st u d y b ut were n ot a ble t o r oll o ver i nt o C 5 3 5 1 0 0 5 d ue t o dela y i n 
st u d y site acti vati o n will be eli gi ble pr o vi ded ot her eli gi bilit y  criteria are met.
2.
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 uri ne pre g na nc y  test 
pri or t o d osi n g o n Da y 1.
N ote: Fe males w h o bec o me of c hil d -beari n g p ote ntial d uri n g t he st u d y  m ust be willi n g t o 
ha ve a ne gati ve uri ne pre g na nc y  test t o re mai n i n t he st u d y.
3.
If se x uall y acti ve, fe males of c hil d-beari n g p ote ntial m ust c o nsiste ntl y  use hi g hly 
effecti ve met h o ds of c o ntrace pti o n c o nsiste ntl y t hr o u g h o ut t he st u d y a n d f or at least 8 4 
da y s after t he last d ose of st u d y dr u g. Male partici pa nts are eli gi ble t o partici pate if t he y  
a gree t o t he f oll o wi n g re q uire me nts d uri n g t he st u d y  i nter ve nti o n peri o d a n d f or 8 4 da ys 
after t he last d ose of st u d y i nter ve nti o n: 

Refrai n fr o m d o nati n g s per m
P L U S eit her:

Be a bsti ne nt fr o m heter ose x ual i nterc o urse as t heir preferre d a n d us ual 
lifest yle (a bsti ne nt o n a l o n g-ter m a n d persiste nt basis) a n d a gree t o re mai n 
a bsti ne nt. 
O R

M ust a gree t o use a male c o n d o m w he n e n ga gi n g i n a n y  acti vit y t hat all o ws 
f or passa ge of ejac ulate t o a n ot her pers o n. 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5
E xcl usi o n Criteri a Partici pa nts wit h a n y  of t he f oll o wi n g c haracteristics/c o n diti o ns will be 
e xcl u de d:
1.
Fe male w h o is breastfee di n g or pre g na nt.
2.
Wit h dre w c o nse nt or was n o nc o m plia nt fr o m t he ori gi nati n g osi vel ot or cli nical st u d y.
3.
Has a n y me dical, ps y c h ol o gical, safet y, or be ha vi oral c o n diti o ns t hat, i n t he o pi ni o n of 
t he In vesti gat or, ma y  c o nf o u n d safety i nter pretati o n, i nterfere wit h c o m plia nce, or 
precl u de i nf or me d c o nse nt.
St u d y Ar ms:
St u d y Ar ms
Ar m Title
O si vel ot or  (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
A d ults
A d ult partici pa nts e nr olli n g fr o m C 5 3 5 1 0 0 4 Part A a n d Part B will recei ve 1 5 0 m g 
mai nte na nce d ose. D ose a dj ust me nt a n d or l oa di n g d ose will be deter mi ne d base d o n  pre vi o us 
i nter ve nti o n/ d ose recei ve d i n C 5 3 5 1 0 0 4.
A d olesce nts a n d 
Pe diatrics
A d olesce nt a n d pe diatric partici pa nts fr o m C 5 3 5 1 0 0 4 Parts B a n d C will be a d mi nistere d a 
d ose t hat pr o vi des ge nerall y e q ui vale nt e x p os ure t o a d ult partici pa nts.
D ur ati o n of Tre at me nt : Partici pa nts ma y  recei ve st u d y dr u g f or u p t o 2 5 2 da y s, 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 
a n d/ or u ntil t he partici pa nt has access t o osi vel ot or fr o m a n alter nati ve s o urce (e g, t hr o u g h 
c o m mercializati o n, a ma na ge d -access pr o gra m, or a S p o ns ore d i nitiati ve ) or u ntil t he 
S p o ns or deci des t o ter mi nate t he st u d y .
Et hic al C o nsi der ati o ns:
T he res ults of pre vi o us st u dies of osi vel ot or i n healt h y v ol u nteers a n d S C D a d ult partici pa nts 
s u p p ort t he i n vesti gati o n of osi vel ot or f or S C D. T here is a fa v ora ble be nefit -ris k pr ofile t o 
s u p p ort t he rati o nale f or t his st u d y. Ta ki n g i nt o acc o u nt t he meas ures t o mi ni mize ris k t o 
partici pa nts, t he p ote ntial ris ks ass ociate d wit h osi vel ot or are j ustifie d b y t he a ntici pate d 
be nefits t hat ma y  be aff or de d t o partici pa nts wit h S C D.

S C D is a seri o us c o n diti o n c haracterize d b y he m ol ytic a ne mia, c hr o nic or ga n da ma ge, 
a n d V O Cs. Des pite rece nt a d va nces i n t hera p y, t here re mai n li mite d treat me nt o pti o ns f or 
patie nts wit h S C D; t h us a hi g h u n met me dical nee d c o nti n ues t o e xist. O si vel ot or’s
p ote ntial t o a d dress t his u n met me dical nee d is s u p p orte d b y  t he n o ncli nical st u dies a n d 
preli mi nar y  cli nical data w hic h pr o vi de e vi de nce f or a treat me nt effect ( gra d ual i ncrease 
i n he m o gl o bi n (H b ) at b ot h 1 0 0 m g a n d 1 5 0 m g dail y mai nte na nce d osi n g i n C 5 35 1 0 0 4). 
Gi ve n t he mec ha nis m of acti o n ( M O A), it is li kel y t hat hi g her H b le vels (a n d 
c o nse q ue ntl y a cli nicall y si g nifica nt re d ucti o n i n t he i nci de nce of V O Cs) will be 
ac hie ve d, w hic h is s u p p orte d b y data f or H b a n d H b occ u pa nc y fr o m C 5 3 5 1 0 0 2 a n d 
preli mi nar y C 5 3 5 1 0 0 4 data. 

O si vel ot or has i ncrease d affi nit y  f or H b a n d a l o n ger half-life (t1/ 2) c o m pare d t o 
v o xel ot or . Osi vel ot or has t he p ote ntial t o ac hie ve greater % H b occ u pa nc y  a n d attai n 
desire d he mat ol o gical effects at l o wer d oses t ha n v o xel ot or, t heref ore re d uci n g pill 
b ur de n, i ncreasi n g t he d ura bilit y  of res p o nse, a n d i m pr o vi n g cli nical o utc o mes f or 
i n di vi d uals li vi n g wit h S C D.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6

T he c urre nt treat me nt o pti o ns f or pe diatric partici pa nts wit h S C D, partic ularl y  i n c hil dre n 
less t ha n 1 2 years of a ge, are li mite d. S C D re q uires life -l o n g pre ve nti ve mai nte na nce a n d 
ma na ge me nt of ac ute a n d c hr o nic c o m plicati o ns. Ne w b or n scree ni n g, earl y  
i m m u nizati o n, a n d pr o p h ylactic pe nicilli n treat me nt i n i nfa nts a n d c hil dre n as well as 
c o m pre he nsi ve ma na ge me nt f or pai n a n d diseas e c o m plicati o ns ha ve i m pr o ve d o utc o mes 
i n c hil dre n wit h S C D i n certai n parts of t he w orl d. Des pite t hese a d va nces, t he me dia n 
life e x pecta nc y of affecte d i n di vi d uals is o nl y 4 3 years of a ge a n d treat me nt of S C D 
re mai ns a seri o us u n met me dical nee d ( Bra n d o w, A M a n d Lie m, RI. A d va nces i n t he 
dia g n osis a n d treat me nt of sic kle cell disease. J o ur nal of He mat ol o g y  & O nc ol o g y 
2 0 2 2; 1 5: 2 0: 1 -1 3). C 5 3 5 1 0 0 4 Part B will e val uate t he efficac y  a n d safety of t he selecte d 
d ose of o si vel ot or vers us place b o i n a d ult a n d pe dia tric partici pa nts ( 1 2 t o < 1 8 years of 
a ge) wit h S C D. Part C will e val uate t he p har mac o ki netics ( P K ) a n d safet y of si n gle a n d 
m ulti ple d oses of o pe n -la bel o si vel ot or a d mi nistere d t o pe diatric partici pa nts 6 m o nt hs t o 
< 1 8 ye ars of a ge.

F or pe diatric partici p a nts bl o o d dra ws will be mi ni mize d, pai n ma na ge me nt e nc o ura ge d, 
a n d tec h ni q ues will be use d t o mi ni mize fear a n d pr o vi de c o mf ort. A d diti o nall y , eff ort 
will be ma de t o e n ga ge care gi vers t o deter mi ne t he m ost a p pr o priate wa y  t o s o ot he 
partici pa nts. 

Base d o n t he e x perie nce wit h o si vel ot or at t he ti me of t his Pr ot oc ol A me n d me nt, n o 
partici pa nt has e x perie nce d a n y a d verse reacti o n of cli nical si g nifica nce. T he t he oretical 
p ote ntial ris k f or o si vel ot or is decrease d o xy ge n deli ver y , h o we ver t here are n o c urre nt 
a d verse e ve nts attri b ute d t o t he st u d y  dr u g t hat s u p p ort t his t he oretical ris k.

Partici pa nt will be e x pecte d t o c o m mit ti me a n d ma y  e x perie nce s o me disc o mf ort w hile 
u n der g oi n g st u d y  assess me nts. I n a d diti o n, fe male partici pa nts of c hil d beari n g p ote ntial 
m u st a gree t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n fr o m st u dy start t o 8 4 da y s 
after t he last d ose of st u d y dr u g. Males m ust eit her be a bsti ne nt or use a c o n d o m, i n 
a d diti o n t o t heir fe male part ner of c hil d -beari n g p ote ntial usi n g a hi g hl y effecti v e met h o d 
of c o ntrace pti o n fr o m st u d y  start t o 8 4 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 e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7
2. 1. Sc he d ule(s) of Assess me nts a n d Pr oce d ures
A d ult P artici p a nts wit h Del a ye d St art of O pe n L a bel E xte nsi o n (O L E ) St u d y ( > 4 2 d a ys)
T a ble 1. 
Sc he d ule of Assess me nts f or A d ult P artici p a nts wit h Del a ye d St art of O L E ( > 4 2 d a ys) 
Tre at me nt Peri o d
St u d y Wee k
B aseli ne 
visit 
1 
2 
4 
6 
8 
1 2 
1 6 
2 0 
2 4 
E ver y 
1 2 
wee ks 
E O S 1/ E T
St u d y D a y
1
( ± 3 0)
7
( ± 3)
1 4
( ± 3)
2 8
( ± 3)
4 2
( ± 3)
5 6
( ± 3)
8 4
( ± 7)
1 1 2
( ± 7)
1 4 0
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4
D a ys ) 
I nf or me d c o nse nt/asse nt
X
Eli gi bilit y assess me nt
X
Me dical hist or y
X
P h ysical e xa mi nati o n a
X
X
X  
X  
X
Hei g ht 
X
Wei g ht
X
X
X  
X  
X
Vital si g ns b
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Ser ol o g y ( he patitis A, B, 
C, HI V) o nl y if cli nicall y 
i n dicate d
X
He mat ol o g y i ncl u di n g 
retic ul oc yte c o u nt a n d 
ser u m c he mistr y 
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
a P T T, I N R, P T
X
Ser u m er yt hr o p oieti n
X
X
X  
X  
X
e G F R c
X
X  
X  
X
Uri nal ysis
X
X
X  
X  
X
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8
T a ble 1. 
Sc he d ule of Assess me nts f or A d ult P artici p a nts wit h Del a ye d St art of O L E ( > 4 2 d a ys) 
Tre at me nt Peri o d
St u d y Wee k
B aseli ne 
visit 
1 
2 
4 
6 
8 
1 2 
1 6 
2 0 
2 4 
E ver y 
1 2 
wee ks 
E O S 1/ E T
St u d y D a y
1
( ± 3 0)
7
( ± 3)
1 4
( ± 3)
2 8
( ± 3)
4 2
( ± 3)
5 6
( ± 3)
8 4
( ± 7)
1 1 2
( ± 7)
1 4 0
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4
D a ys ) 
Pre g na nc y test (f or 
fe males, p ost me narc he) d
X
X
X  
X  
X  
X  
X  
X  
X
C o ntrace pti o n c hec k h
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P K sa m ples ( w h ole bl o o d 
a n d plas ma) e
X
X
X  
X  
X  
X  
X  
X  
X
R B C def or ma bilit y a n d 
R B C mit oc h o n drial 
c o nte nt f, i
X
X
X
X  
X
Fl o w a d hesi o n f, i
X
X
X  
X  
X
Peri p heral bl o o d s mear f, i
X
X
X  
X  
X
E x pl orat or y Bi o mar kers j
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P GI -C/ C GI -C f
X
X
X  
X  
X
P GI -S/ C GI -S f
X
X
X  
X  
X
P R O MI S S F Fati g ue 1 3a, 
S F Pai n I nterfere nce 8a, 
a n d N R S Pai n I nte nsit y f
X
X
X  
X  
X
E Q - 5 D- 5 L f
X
X
X  
X  
X
W P AI + CI Q: S C D 
f
X
X
X  
X  
X
Q ualitati ve i nter vie w f,g
X
St u d y dr u g a d mi nistrati o n
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9
T a ble 1. 
Sc he d ule of Assess me nts f or A d ult P artici p a nts wit h Del a ye d St art of O L E ( > 4 2 d a ys) 
Tre at me nt Peri o d
St u d y Wee k
B aseli ne 
visit 
1 
2 
4 
6 
8 
1 2 
1 6 
2 0 
2 4 
E ver y 
1 2 
wee ks 
E O S 1/ E T
St u d y D a y
1
( ± 3 0)
7
( ± 3)
1 4
( ± 3)
2 8
( ± 3)
4 2
( ± 3)
5 6
( ± 3)
8 4
( ± 7)
1 1 2
( ± 7)
1 4 0
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4
D a ys ) 
Dis pe nse st u d y dr u g
X
X
X  
X
Ret ur n u n use d st u d y dr u g 
k
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
C o nc o mita nt me dicati o n
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Seri o us a n d n o nseri o us 
A E m o nit ori n g
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0
T a ble 1. 
Sc he d ule of Assess me nts f or A d ult P artici p a nts wit h Del a ye d St art of O L E ( > 4 2 d a ys) 
Tre at me nt Peri o d
St u d y Wee k
B aseli ne 
visit 
1 
2 
4 
6 
8 
1 2 
1 6 
2 0 
2 4 
E ver y 
1 2 
wee ks 
E O S 1/ E T
St u d y D a y
1
( ± 3 0)
7
( ± 3)
1 4
( ± 3)
2 8
( ± 3)
4 2
( ± 3)
5 6
( ± 3)
8 4
( ± 7)
1 1 2
( ± 7)
1 4 0
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4
D a ys ) 
A b bre viati o ns: C GI -C, Cli nicia n’s Gl o bal I m pressi o n of C ha n ge; C GI - S, Cli nicia n’s Gl o bal I m pressi o n of Se verit y; C K D- E PI, C hr o nic Ki d ne y Disease E pi de mi ol o g y 
C olla b orati o n; 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 O T, e n d of treat me n t; E T, earl y ter mi nati o n; HI V, h u ma n i m m u n o deficie nc y vir us; N R S, n u meric 
rati n g scale; P GI-C, Patie nt’s Gl o bal I m pressi o n of C ha n ge; P GI -S, Patie nt’s Gl o bal I m pressi o n of Se verit y; P K, p har mac o ki netic; P R O MI S, Patie nt -Re p orte d O utc o me 
Meas ure me nt I nf or mat i o n S yste m; R B C, re d bl o o d cell; S F, s h ort f or m; W P AI+ CI Q: S C D , W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt pl us Classr o o m I m pair me nt 
Q uesti o n naire: Sic kle Cell Disease.
a A f ull p h ysical e xa mi nati o n s h o ul d be c o n d ucte d at Baseli ne. All s u bse q ue nt p h ysical e xa mi nati o ns ca n be brief. See Secti o n 9. 3. 1 f or details.
b Vital Si g ns i ncl u de bl o o d press ure, heart rate, res pirati o n rate, b o d y te m perat ure will be o b tai ne d after t he partici pa nt has bee n i n a s u pi ne or rec u m be nt p ositi o n f or at least 
5 mi n utes .
c At Scree ni n g, e G F R will be calc ulate d usi n g 2 0 2 1 C K D -E PI e q uati o ns (f or a d ults 1 8 years a n d a b o ve). 
d Pre g na nc y tests will be perf or me d o n fe male partici pa nts w h o are p ost me narc he a n d of c hil d- beari n g p ote ntial. A ser u m pre g na nc y test will be c o n d ucte d at Baseli ne o nl y if 
t here is a dela y of > 7 da ys i n start of O L E fr o m t he ori gi nati n g st u d y, ot her wise a uri ne pre g na nc y test will be a d mi nistere d a n d uri ne preg na nc y test at all ot her visits. A ser u m 
pre g na nc y test will als o be c o n d ucte d w he n a p ositi ve uri nar y pre g na nc y test occ urs f or c o nfir mati o n.
e At t he Baseli ne Visit ( Da y 1), sa m ples will be o btai ne d at pre d ose a n d bet wee n 1 t o 2 h o urs p ost d ose. Tr o u g h ( p re d ose) sa m ples are t o be o btai ne d o n Wee ks 4, 8, 1 2, 1 6, 2 0 
a n d 2 4, t he n at 1 2 -wee k i nter vals t hereafter. F or t he tr o u g h ( pre d ose) c ollecti o ns t he ti me wi n d o w is 2 4 ± 3 h o urs si nce t he m ost rece nt d ose, b ut t he sa m ple m ust be c ollecte d 
bef ore t he d ose gi ve n at t he cli nic visit. T he date a n d ti me of c ollecti o n f or all P K sa m ples m ust be rec or de d i n t he e C R F. T he ti me of st u d y dr u g a d mi nistrati o n pri or t o P K 
c ollecti o n m ust als o be rec or de d. 
f Assess me nts will be c o n d ucte d o nl y at sites i n re gi o ns w here a vail a ble.
g I n selecte d re gi o ns, q ualitati ve i nter vie ws wit h E n glis h s pea ki n g partici pa nts will be c o n d ucte d d uri n g t he Scree ni n g peri o d a n d ma y i ncl u de m ulti ple i nter vie ws.
h C o ntrace pti o n c hec k f or re pr o d ucti ve a ge males or fe males of c hil d-beari n g a ge. 
i Sa m ples t o be o btai ne d pre d ose f or all visits.
j E x pl orat or y bi o mar kers ma y i ncl u de mar kers of he m ol ysis s uc h as le vels of ha pt o gl o bi n, he m o pe xi n, a n d s ol u ble C 3.
k Dr u g acc o u nta bilit y t o be c o m plete d if baseli ne visit is o n t he sa me da y as E O T assess me nts fr o m t he ori gi nati n g st u d y.
l Partici pa nts s h o ul d ret ur n t o t he st u d y site f or a n E O S visit a p pr o xi matel y 1 2 wee ks after t he last d ose of st u d y dr u g.
N ote: Eli gi ble partici pa nts will recei ve o pe n- la bel osi vel ot or o n Da y 1 ( Baseli ne Visit). It is i nte n de d t hat Da y 1 c oi nci des wit h t he fi nal visit fr o m t he ori gi nati n g osi vel ot or
st u d y. E O T assess me nts fr o m t he ori gi nati n g st u d y will ser ve as Baseli ne assess me nts f or t his st u d y. If Da y 1 f or t his st u d y is greater t ha n 7 da ys fr o m t he c o m pleti o n of t he 
ori gi n ati n g st u d y, ne w Baseli ne assess me nts will be o btai ne d. A d diti o nal assess me nts t hat ma y n ot ha ve bee n i ncl u de d i n t he pri or E O T assess me nts will nee d t o be c o m plete d at 
t he Da y 1 visit pri or t o st u d y dr u g a d mi nistrati o n.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1
A d ult P artici p a nts fr o m P art A of C 5 3 5 1 0 0 4 a n d Ot her A p plic a ble Osi vel ot or O pe n L a bel St u dies wit h n o Del a y of St art
T a ble 2. 
Sc he d ule of Assess me nts f or A d ult P artici p a nts fr o m P art A of C 5 3 5 1 0 0 4 a n d Ot her A p plic a ble Osi vel ot or O pe n 
L a bel St u dies wit h n o Del a y of St art
Tre at me nt Peri o d
St u d y Wee k
B aseli ne visit 
1 2
2 4
E ver y 1 2 wee ks 
E O S k/ E T 
St u d y D a y
1
( ± 3 0)
8 4
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4 D a ys ) 
I nf or me d c o nse nt/asse nt
X
Eli gi bilit y assess me nt
X
Me dical hist or y
X
P h ysical e xa mi nati o n a
X
X
X
X
X
Hei g ht 
X
Wei g ht
X
X
X
X
X
Vital si g ns b
X
X
X
X
X
Ser ol o g y ( he patitis A, B, C, HI V) 
o nl y if cli nicall y i n dicate d
X
He mat ol o g y i ncl u di n g retic ul oc yte 
c o u nt a n d ser u m c he mistr y 
X
X
X
X
a P T T, I N R, P T
X
Ser u m er yt hr o p oieti n
X
X
X
X
X
e G F R (f or a d ults, c hil dre n or 
i nfa nts) or e Cr Cl (a d olesce nts) c
X
X
X
X
Uri nal ysis
X
X
X
X
X
Pre g na nc y test (f or fe males, p ost 
me narc he) d
X
X
X
X
X
C o ntrace pti o n c hec k i
X
X
X
X
X
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2
T a ble 2. 
Sc he d ule of Assess me nts f or A d ult P artici p a nts fr o m P art A of C 5 3 5 1 0 0 4 a n d Ot her A p plic a ble Osi vel ot or O pe n 
L a bel St u dies wit h n o Del a y of St art
Tre at me nt Peri o d
St u d y Wee k
B aseli ne visit 
1 2
2 4
E ver y 1 2 wee ks 
E O S k/ E T 
St u d y D a y
1
( ± 3 0)
8 4
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4 D a ys ) 
P K sa m ples ( w h ole bl o o d a n d 
plas ma) e
X
X
X
X
X
R B C def or ma bilit y a n d R B C 
mit oc h o n drial c o nte nt (at sites 
w here a vaila ble) f, j
X
X
X
X
X
Fl o w a d hesi o n f, j
X
X
X
X
X
Peri p heral bl o o d s mear f, j
X
X
X
X
X
E x pl orat or y Bi o mar kers
l
X
X
X
X
X
P GI -C/ C GI -C f
X
X
X
X
X
P GI -S/ C GI -S f
X
X
X
X
X
P R O MI S S F Fati g ue 1 3a , S F Pai n 
I nterfere nce 8a, a n d N R S Pai n 
I nte nsit y f
X
X
X
X
X
E Q - 5 D- 5 L f
X
X
X
X
X
W P AI + CI Q: S C D 
f
X
X
X
X
X
Q ualitati ve i nter vie w f, g
X
St u d y dr u g a d mi nistrati o n
Dis pe nse st u d y dr u g
X
X
X
X
Ret ur n u n use d st u d y dr u g
h
X
X
X
X
C o nc o mita nt me dicati o n
X
X
X
X
X
Seri o us a n d n o nseri o us A E 
m o nit ori n g
X
X
X
X
X
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3
T a ble 2. 
Sc he d ule of Assess me nts f or A d ult P artici p a nts fr o m P art A of C 5 3 5 1 0 0 4 a n d Ot her A p plic a ble Osi vel ot or O pe n 
L a bel St u dies wit h n o Del a y of St art
Tre at me nt Peri o d
St u d y Wee k
B aseli ne visit 
1 2
2 4
E ver y 1 2 wee ks 
E O S k/ E T 
St u d y D a y
1
( ± 3 0)
8 4
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4 D a ys ) 
A b bre viati o ns: C GI -C, Cli nicia n’s Gl o bal I m pressi o n of C ha n ge; C GI - S, Cli nicia n’s Gl o bal I m pressi o n of Se verit y; C K D- E PI, C hr o nic Ki d ne y Disease E pi de mi ol o g y 
C olla b orati o n; e Cr Cl, esti mate d creati ni ne cleara nce; 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 O T, E n d of Treat me nt; E T, earl y ter mi nati o n; HI V, h u ma n 
i m m u n o deficie nc y vir us; N R S, n u meric rati n g scale; P GI-C, Patie nt’s Gl o bal I m pressi o n of C ha n ge; P GI -S, Patie nt’s Gl o bal I m pressi o n of Se verit y; P K, p har mac o ki netic; 
P R O MI S, Patie n t-Re p orte d O utc o me Meas ure me nt I nf or mati o n S yste m; R B C, re d bl o o d cell; S F, s h ort f or m; W P AI + CI Q: S C D, W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt 
pl us Classr o o m I m pair me nt Q uesti o n naire: Sic kle Cell Disease.
a A f ull p h ysical e xa mi nati o n s h o ul d be c o n d ucte d at Baseli ne. All s u bse q ue nt p h ysical e xa mi nati o ns ca n be brief. See Secti o n 9. 3. 1 f or details.
b Vital Si g ns i ncl u de bl o o d press ure, heart rate, res pirati o n rate, b o d y te m perat ure will be o btai ne d after t he partici pa nt has bee n i n a s u pi ne or rec u m be nt p ositi o n f or at least
5 mi n utes .
c At Scree ni n g, e G F R will be calc ulate d usi n g 2 0 2 1 C K D -E PI e q uati o ns (f or a d ults 1 8 years a n d a b o ve) or e Cr Cl will be calc ulate d usi n g C oc kcr oft -Ga ult f or m ula (f or 
a d olesce nts 1 2 t o < 1 8 years) or e G F R will be calc ulate d usi n g M o difie d Sc h wartz E q uati o n (f or c hil dre n 2 t o < 1 2 years), or Be dsi de Sc h wartz e q uati o n (f or i nfa nts 6 m o nt hs t o 
< 2 years), see S ecti o n 1 1. 5. 2 .
d Pre g na nc y tests will be perf or me d o n fe male partici pa nts w h o are p ost me narc he a n d of c hil d -beari n g p ote ntial. A uri ne pre g na nc y test will be c o n d ucte d at Baseli ne a n d at all 
ot her visits as n ote d i n t he S o A. A ser u m pre g na nc y test will als o be c o n d ucte d w he n a p ositi ve uri na r y pre g na nc y test occ urs f or c o nfir mati o n.
e At t he Baseli ne Visit ( Da y 1), sa m ples will be o btai ne d at pre d ose a n d bet wee n 1 t o 2 h o urs p ost d ose. Tr o u g h ( pre d ose) sa m p les are t o be o btai ne d o n Wee ks 1 2 a n d 2 4, a n d 
t he n at 1 2-wee k i nter vals t hereafter. F or t he tr o u g h ( pre d ose) c ollecti o ns t he ti me wi n d o w is 2 4 ± 3 h o urs si nce t he m ost rece nt d ose, b ut t he sa m ple m ust be c ollecte d bef ore t he 
d ose gi ve n at t he cli nic visit. T he date a n d ti me of c ollecti o n f or all P K sa m ples m ust be rec or de d i n t he e C R F. T he ti m e of st u d y dr u g a d mi nistrati o n pri or t o P K c ollecti o n 
m ust als o be rec or de d. 
f Assess me nts will be c o n d ucte d o nl y at sites i n re gi o ns w here a vaila ble.
g I n selecte d re gi o ns, q ualitati ve i nter vie ws wit h E n glis h s pea ki n g partici pa nts will be c o n d ucte d d uri n g t he Scree ni n g peri o d a n d ma y i ncl u de m ulti ple i nter vie ws. 
h Dr u g acc o u nta bilit y t o be c o m plete d if baseli ne visit is o n t he sa me da y as E O T assess me nts fr o m t he ori gi nati n g st u d y.
i C o ntrace pti o n c hec k f or re pr o d ucti ve a ge males or fe males of c hil d-bear i n g a ge.
j Sa m ples t o be o btai ne d pre d ose f or all visits.
k Partici pa nts s h o ul d ret ur n t o t he st u d y site f or a n E O S visit a p pr o xi matel y 1 2 wee ks after t he last d ose of st u d y dr u g.
l E x pl orat or y bi o mar kers ma y i ncl u de mar kers of he m ol ysis s uc h as le vels of ha pt o gl o bi n, he m o pe xi n, a n d s ol u ble C 3.
N ote: Eli gi ble partici pa nts will recei ve o pe n- la bel osi vel ot or o n Da y 1 ( Baseli ne Visit). It is i nte n de d t hat Da y 1 c oi nci des wit h t he fi nal visit fr o m t he ori gi nati n g osi vel ot or
st u d y. E O T assess me nts fr o m t he ori ginati n g st u d y will ser ve as Baseli ne assess me nts f or t his st u d y. If Da y 1 f or t his st u d y is greater t ha n 7 da ys fr o m t he c o m pl eti o n of t he 
ori gi nati n g st u d y, ne w Baseli ne assess me nts will be o btai ne d. A d diti o nal assess me nts t hat ma y n ot ha ve bee n i ncl u de d i n t he pri or E O T assess me nts will nee d t o be c o m plete d at 
t he Da y 1 visit pri or t o st u d y dr u g a d mi nistrati o n.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 2 4
P artici p a nts fr o m P art B of C 5 3 5 1 0 0 4 a n d Ot her Osi vel ot or R a n d o mize d, Bli n de d, Pl ace b o C o ntr olle d St u dies
T a ble 3. 
Sc he d ule of Assess me nts f or P artici p a nts fr o m P art B of C 5 3 5 1 0 0 4 a n d Ot her Osi vel ot or R a n d o mize d, Bli n de d, 
Pl ace b o C o ntr olle d St u dies
Tre at me nt Peri o d
St u d y Wee k
B aseli ne Visit
8 
1 6 
2 4 
E ver y 1 2 
wee ks 
St u d y D a y
1
( ± 3 0)
5 6
( ± 3)
1 1 2
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4 D a ys ) 
E O S k/ E T
I nf or me d c o nse nt/asse nt
X
Eli gi bilit y assess me nt
X
Me dical hist or y
X
P h ysical e xa mi nati o n a
X
X  
X  
X
X
X
Hei g ht 
X
Wei g ht
X
X
X
X
Vital si g ns b
X
X  
X  
X
X
X
Healt hcare res o urce utilizati o n
X
X  
X  
X
X
X
Ser ol o g y ( he patitis A, B, C, HI V) o nl y if cli nicall y 
i n dicate d
X
He mat ol o g y i ncl u di n g retic ul oc yte c o u nts a n d ser u m 
c he mistr y
X  
X  
X
X
X
a P T T, I N R, P T
X
Ser u m er yt hr o p oieti n
X
X  
X  
X
X
X
e G F R (f or a d ults, c hil dre n or i nfa nts) or e Cr Cl 
(a d olesce nts) c
X
X
X
X
Uri nal ysis
X
X  
X  
X
X
X
Pre g na nc y test (f or fe males, p ost me narc he) d
X
X  
X  
X
X
X
C o ntrace pti o n c hec k
l
X
X  
X  
X
X
X
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 2 5
T a ble 3. 
Sc he d ule of Assess me nts f or P artici p a nts fr o m P art B of C 5 3 5 1 0 0 4 a n d Ot her Osi vel ot or R a n d o mize d, Bli n de d, 
Pl ace b o C o ntr olle d St u dies
Tre at me nt Peri o d
St u d y Wee k
B aseli ne Visit
8 
1 6 
2 4 
E ver y 1 2 
wee ks 
St u d y D a y
1
( ± 3 0)
5 6
( ± 3)
1 1 2
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4 D a ys ) 
E O S k/ E T
P K sa m ples ( w h ole bl o o d a n d plas ma) e
X
X  
X  
X
X
X
R B C def or ma bilit y a n d R B C mit oc h o n drial c o nte nt f, j
X
X  
X  
X
X
X
Fl o w a d hesi o n f, j
X
X  
X  
X
X
X
Peri p heral bl o o d s mear f, j
X
X  
X  
X
X
X
E x pl orat or y Bi o mar kers i
X
X  
X  
X
X
X
P GI -C/ C GI -C f
X
X  
X  
X
X
X
P GI -S/ C GI -S f
X
X  
X  
X
X
X
P R O MI S S F Fati g ue 1 3a, S F Pai n I nterfere nce 8a, a n d 
N R S Pai n I nte nsit y f
X
X  
X  
X
X
X
E Q - 5 D- 5 Lf
X
X  
X  
X
X
X
W P AI + CI Q: S C D 
f
X
X  
X  
X
X
X
Q ualitati ve i nter vie w f,g
X
St u d y dr u g a d mi nistrati o n
Dis pe nse st u d y dr u g
X
X  
X  
X
X
Ret ur n u n use d st u d y dr u g h
X  
X  
X
X
X
C o nc o mita nt me dicati o n
X
X  
X  
X
X
X
Seri o us a n d n o nseri o us A E m o nit ori n g
X
X  
X  
X
X
X
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 2 6
T a ble 3. 
Sc he d ule of Assess me nts f or P artici p a nts fr o m P art B of C 5 3 5 1 0 0 4 a n d Ot her Osi vel ot or R a n d o mize d, Bli n de d, 
Pl ace b o C o ntr olle d St u dies
Tre at me nt Peri o d
St u d y Wee k
B aseli ne Visit
8 
1 6 
2 4 
E ver y 1 2 
wee ks 
St u d y D a y
1
( ± 3 0)
5 6
( ± 3)
1 1 2
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4 D a ys ) 
E O S k/ E T
A b bre viati o ns: C GI -C, Cli nicia n’s Gl o bal I m pressi o n of C ha n ge; C GI - S, Cli nicia n’s Gl o bal I m pressi o n of Se verit y; C K D- E PI, C hr o nic Ki d ne y Disease E pi de mi ol o g y 
C olla b orati o n; e Cr Cl, esti mate d creati ni ne cleara nce; 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 O T, e n d of treat me nt; E T, earl y ter mi nati o n; HI V, h u ma n 
i m m u n o deficie nc y vir us; N R S, n u meric rati n g scale; P GI-C, Patie nt’s Gl o bal I m pressi o n of C ha n ge; P GI -S, Patie nt’s Gl o bal I m pressi o n of Se verit y; P K, p har mac o ki netic; 
P R O MI S, Patie n t-Re p orte d O utc o me Meas ure me nt I nf or mati o n S yste m; R B C, re d bl o o d cell; S F, s h ort f or m; W P AI + CI Q: S C D, W or k Pr o d ucti vit y a n d Act i vit y I m pair me nt 
Q uesti o n naire pl us Classr o o m I m pair me nt Q uesti o ns: Sic kle Cell Disease.
a A f ull p h ysical e xa mi nati o n s h o ul d be c o n d ucte d at Baseli ne. All s u bse q ue nt p h ysical e xa mi nati o ns ca n be brief. See Secti o n 9. 3. 1 f or detail. 
b Vital Si g ns i ncl u de bl o o d press ure, heart rate, res pirati o n rate, b o d y te m perat ure will be o btai ne d after t he partici pa nt has bee n i n a s u pi ne p ositi o n f or at least 5 mi n utes .
c At Scree ni n g, e G F R will be calc ulate d usi n g 2 0 2 1 C K D -E PI e q uati o ns (f or a d ults 1 8 years a n d a b o ve) or e Cr Cl will be calc ulate d usi n g C oc kcr oft -Ga ult f or m ula (f or 
a d olesce nts 1 2 t o < 1 8 years) or e G F R will be calc ulate d usi n g M o difie d Sc h wartz E q uati o n (f or c hil dre n 2 t o < 1 2 years), or Be dsi de Sc h wartz e q uati o n (f or i nfa nts 6 m o nt hs t o 
< 2 years), see S ecti o n 1 1. 5. 2 .
d Pre g na nc y tests will be perf or me d o n fe male partici pa nts w h o are p ost me narc he a n d of c hil d- beari n g p ote ntial. A uri ne pre g na nc y test will be c o n d ucte d at Baseli ne a n d at all 
ot her visits as n ote d i n t he S o A. A ser u m pre g na nc y test will als o be c o n d ucte d w he n a p ositi ve uri nar y pre g na nc y test occ urs f or c o nfir mati o n.
e At t he Baseli ne Visit ( Da y 1), sa m ples will be o btai ne d at pre d ose a n d bet wee n 1 t o 2 h o u rs p ost d ose.  Tr o u g h ( pre d ose) sa m ples are t o be o btai ne d o n Wee ks 8, 1 6, a n d 2 4, a n d 
t he n at 1 2-wee k i nter vals t hereafter. F or t he tr o u g h ( pre d ose) c ollecti o ns t he ti me wi n d o w is 2 4 ± 3 h o urs si nce t he m ost rece nt d ose, b ut t he sa m ple m ust be c ollecte d bef ore t he 
d ose gi ve n at t he cli nic visit. T he date a n d ti me of c ollecti o n f or all P K sa m ples m ust be rec or de d i n t he e C R F. T he ti me of st u d y dr u g a d mi nistrati o n pri or t o P K c ollecti o n 
m ust als o be rec or de d. 
f Assess me nts will be c o n d ucte d o nl y at sites i n re gi o ns w here a vaila ble.
g I n selecte d re gi o ns, q ualitati ve i nter vie ws wit h E n glis h s pea ki n g partici pa nts will be c o n d ucte d d uri n g t he Scree ni n g peri o d a n d ma y i ncl u de m ulti ple i nter vie ws. 
h Dr u g acc o u nta bilit y t o be c o m plete d if baseli ne visit is o n t he sa me da y as E O T assess me nts fr o m t he ori gi nati n g st u d y.
i E x pl orat or y bi o mar kers ma y i ncl u de mar kers of he m ol ysis s uc h as le vels of ha pt o gl o bi n, he m o pe xi n, a n d s ol u ble C 3.
j Sa m ples t o be o btai ne d pre d ose f or all visits.
k Partici pa nts s h o ul d ret ur n t o t he st u d y site f or a n E O S visit a p pr o xi matel y 1 2 wee ks after t he last d ose of st u d y dr u g.
l C o ntrace pti o n c hec k f or re pr o d ucti ve a ge males or fe males of c hil d - beari n g p ote ntial.
N ote: Eli gi ble partici pa nts will recei ve o pe n- la bel osi vel ot or o n Da y 1 ( Baseli ne Visit). It is i nte n de d t hat Da y 1 c oi nci des wit h t he fi nal visit fr o m t he ori gi nati n g osi vel ot or
st u d y. E O T assess me nts fr o m t he ori gi nati n g st u d y will ser ve as Baseli ne assess me nts f or t his st u d y. If Da y 1 f or t his st u d y is greater t ha n 7 da ys fr o m t he c o m pleti o n of t he 
ori gi nati n g st u d y, ne w Baseli ne assess me nts will be o btai ne d. A d diti o nal assess me nts t hat ma y n ot ha ve bee n i ncl u de d i n t he p ri or E O T assess me nts will nee d t o be c o m plete d at 
t he Da y 1 visit pri or t o st u d y dr u g a d mi nistrati o n.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 2 7
Pe di atric P artici p a nts fr o m P art C of C 5 3 5 1 0 0 4
T a ble 4. 
Sc he d ule of Assess me nts f or Pe di atric P artici p a nts fr o m P art C of C 5 3 5 1 0 0 4
Tre at me nt Peri o d
St u d y Wee k
B aseli ne 
Visit 
2 
4 
8 
1 2 
1 6 
2 0 
2 4 
E ver y 1 2 
wee ks 
St u d y D a y
1
( ± 3 0)
1 4 
( ± 3)
2 8
( ± 3)
5 6
( ± 3)
8 4
( ± 3)
1 1 2
( ± 7)
1 4 0
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4
D a ys ) &
E O S h/ E T
I nf or me d c o nse nt/asse nt
X
Eli gi bilit y assess me nt
X
Me dical hist or y
X
P h ysical e xa mi nati o n a
X  
X  
X  
X  
X  
X  
X  
X  
X
Hei g ht 
X
X
X  
X
Wei g ht
X
X
X  
X
Vital si g ns b
X  
X  
X  
X  
X  
X  
X  
X  
X
Ser ol o g y ( he patitis A, B, C, HI V) o nl y if cli nicall y 
i n dicate d
X
He mat ol o g y i ncl u di n g retic ul oc yte c o u nt a n d ser u m 
c he mistr y
X  
X  
X  
X  
X  
X  
X  
X
Ser u m er yt hr o p oieti n
X  
X  
X  
X  
X  
X  
X  
X  
X
e Cr Cl or e G F R c
X
X  
X
Uri nal ysis
X  
X  
X  
X  
X  
X  
X  
X  
X
Pre g na nc y test (f or fe males, p ost me narc he) d
X
X  
X  
X  
X  
X  
X  
X
C o ntrace pti o n c hec k
k
X  
X  
X  
X  
X  
X  
X  
X  
X
P K sa m ples ( w h ole bl o o d a n d plas ma) e
X  
X  
X  
X
X
X  
X
Peri p heral bl o o d s mear f, j
X
X
X
X  
X
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 2 8
T a ble 4. 
Sc he d ule of Assess me nts f or Pe di atric P artici p a nts fr o m P art C of C 5 3 5 1 0 0 4
Tre at me nt Peri o d
St u d y Wee k
B aseli ne 
Visit 
2 
4 
8 
1 2 
1 6 
2 0 
2 4 
E ver y 1 2 
wee ks 
St u d y D a y
1
( ± 3 0)
1 4 
( ± 3)
2 8
( ± 3)
5 6
( ± 3)
8 4
( ± 3)
1 1 2
( ± 7)
1 4 0
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4
D a ys ) &
E O S h/ E T
E x pl orat or y Bi o mar kers i
X
X
X  
X
St u d y dr u g a d mi nistrati o n
Dis pe nse ne w st u d y dr u g
X  
X  
X  
X  
X  
X  
X  
X  
X
Ret ur n u n use d st u d y dr u g g
X  
X  
X  
X  
X  
X  
X  
X
C o nc o mita nt me dicati o n
X  
X  
X  
X  
X  
X  
X  
X  
X
Seri o us a n d n o nseri o us A E m o nit ori n g
X  
X  
X  
X  
X  
X  
X  
X  
X
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 2 9
T a ble 4. 
Sc he d ule of Assess me nts f or Pe di atric P artici p a nts fr o m P art C of C 5 3 5 1 0 0 4
Tre at me nt Peri o d
St u d y Wee k
B aseli ne 
Visit 
2 
4 
8 
1 2 
1 6 
2 0 
2 4 
E ver y 1 2 
wee ks 
St u d y D a y
1
( ± 3 0)
1 4 
( ± 3)
2 8
( ± 3)
5 6
( ± 3)
8 4
( ± 3)
1 1 2
( ± 7)
1 4 0
( ± 7)
1 6 8
( ± 7)
2 5 2 +
( ± 1 4
D a ys ) &
E O S h/ E T
A b bre viati o ns: C GI -C, Cli nicia n’s Gl o bal I m pressi o n of C ha n ge; C GI - S, Cli nicia n’s Gl o bal I m pressi o n of Se verit y; e Cr Cl, esti mate d creati ni ne cleara nce;  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 O T, e n d of treat me nt; E T, earl y ter mi nati o n; HI V, h u ma n i m m u n o deficie nc y vir us; R B C, re d bl o o d cell.
a A f ull p h ysical e xa mi nati o n s h o ul d be c o n d ucte d at Baseli ne. All s u bse q ue nt p h ysical e xa mi nati o ns ca n be brief. See Secti o n 9. 3. 1 f or detail. 
b Vital Si g ns i ncl u de bl o o d press ure, heart rate, res pirati o n rate, b o d y te m perat ure will be o btai ne d after t he partici pa nt has bee n i n a s u pi ne p ositi o n f or at least 5 mi n utes .
c At scree ni n g, e Cr Cl will be calc ulate d usi n g t he C oc kcr oft- Ga ult f or m ula (f or a d olesce nts 1 2 t o < 1 8 years), or e G F R will be calc ulate d us i n g M o difie d Sc h wartz E q uati o n (f or 
c hil dre n 2 t o < 1 2 years), or Be dsi de Sc h wartz e q uati o n (f or i nfa nts 6 m o nt hs t o < 2 years).  See S ecti o n 1 1. 5. 2 .
d Pre g na nc y tests will be perf or me d o n fe male partici pa nts w h o are p ost me narc he a n d of c hil d- beari n g p ote ntial. A ser u m pre g na nc y test will be c o n d ucte d at Baseli ne a n d uri ne 
pre g na nc y test at all ot her visits. A ser u m pre g na nc y test will als o be c o n d ucte d w he n a p ositi ve uri nar y pre g na nc y test occ urs f or c o nfir ma ti o n.
e At t he Baseli ne Visit ( Da y 1), sa m ples will be o btai ne d at pre d ose a n d bet wee n 1 t o 2 h o urs p ost d ose. Tr o u g h ( pre d ose) sa m ples are t o be o btai ne d o n Wee ks 2, 4, 8, 1 6, a n d 2 4, 
a n d t he n at 1 2 -wee k i nter vals t hereafter. F or t he tr o u g h ( pre d ose) c ollecti o ns t he ti me wi n d o w is 2 4 ± 3 h o urs si nce t he m ost rece nt d ose, b ut t he sa m ple m ust be c ollecte d bef ore 
t he d ose gi ve n at t he clinic visit. T he date a n d ti me of c ollecti o n f or all P K sa m ples m ust be rec or de d i n t he e C R F. T he ti me of st u d y dr u g a d mi nistrati o n pri or t o P K c ollecti o n 
m ust als o be rec or de d. 
f Assess me nts will o nl y be c o n d ucte d at sites i n re gi o ns w here a vaila ble. If partici pa nt b o d y wei g ht is < 1 5 k g, d o n ot c ollect at a n y Visit.
g Dr u g acc o u nta bilit y t o be c o m plete d if baseli ne visit is o n t he sa me da y as E O T assess me nts fr o m t he ori gi nati n g st u d y.
h Partici pa nts s h o ul d ret ur n t o t he st u d y site f or a n E O S visit a p pr o xi m atel y 1 2 wee ks after t he last d ose of st u d y dr u g.
i E x pl orat or y bi o mar kers ma y i ncl u de mar kers of he m ol ysis s uc h as le vels of ha pt o gl o bi n, he m o pe xi n, a n d s ol u ble C 3.
j Sa m ples t o be c ollecte d pre d ose f or all visits.
k C o ntrace pti o n c hec k f or re pr o d ucti ve age males or fe males of c hil d - beari n g p ote ntial.
N ote: Eli gi ble partici pa nts will recei ve o pe n- la bel osi vel ot or o n Da y 1 ( Baseli ne Visit). It is i nte n de d t hat Da y 1 c oi nci des wit h t he fi nal visit fr o m t he ori gi nati n g osi vel ot or
st u d y. E O T assess me nts fr o m the ori gi nati n g st u d y will ser ve as Baseli ne assess me nts f or t his st u d y. If Da y 1 f or t his st u d y is greater t ha n 7 da ys fr o m t he c o m pleti o n of t he 
ori gi nati n g st u d y, ne w Baseli ne assess me nts will be o btai ne d. A d diti o nal assess me nts t hat ma y n ot ha ve bee n i n cl u de d i n t he pri or E O T assess me nts will nee d t o be c o m plete d at 
t he Da y 1 visit pri or t o st u d y dr u g a d mi nistrati o n.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 3 0
3. I N T R O D U C TI O N 
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. ( G B T; t he 
S p o ns or) i nte n ds t o de vel o p osi vel ot or (als o k n o w n as P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1), a n oral 
sic kle he m o gl o bi n ( H b S) p ol ymerizati o n i n hi bit or, f or t he treat me nt of sic kle cell disease 
( S C D).
3. 1. B ac k gr o u n d
Sic kle Cell Dise ase
Sic kle cell disease is a n i n herite 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 
lea di n g t o f or mati o n of H b S. 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 y merizati o n of i ntracell ular H b S f oll o wi n g de o x y ge nati o n i n t he 
micr o vasc ulat ure. H b S p ol y merizati o n lea ds t o decrease d re d bl o o d cell ( R B C) 
def or ma bilit y , m or p h ol o gic sic kli n g of R B Cs, decrease d R B C s ur vi val, a n d micr o vasc ular 
o bstr ucti o n (B u n n 1 9 9 7 ). Cli nicall y, S C D is a de vastati n g a n d de bilitati n g disease mar ke d b y 
the pat h o p h y si 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 ge. Des pite c urre nt sta n dar ds of care, i ncl u di n g h y dr o x y u rea ( H U), bl o o d 
tra nsf usi o n, a n d s u p p orti ve care wit h a nal gesia, patie nts wit h S C D c o nti n ue t o s uffer seri o us 
m or bi dit y  a n d pre mat ure m ortalit y.
All o ge neic he mat o p oietic ste m cell tra ns pla ntati o n ( H S C T) re mai ns t he o nl y  c urati ve t hera p y 
f or S C D. H S C T i n c hil dre n wit h S C D is ass ociate d wit h o verall a n d e ve nt-free s ur vi val rates 
of 9 5 % a n d 9 2 %, res pecti vel y . H o we ver, H S C T use is li mite d b y  t he pa ucit y of s uita ble 
d o n ors, t he ris k of graft -vers us -h ost disease, i nfecti o ns, i nfertilit y , a n d ot her l o n g-ter m 
tra ns pla nt-relate d c o m plicati o ns. M ore o ver, H S C T is ge nerally a vaila ble o nl y  i n hi g h-i nc o me 
c o u ntries a n d n o t c o m m o nl y use d i n ol der patie nts wit h si g nifica nt m or bi dit y (Kassi m a n d 
Sa va ni 2 0 1 7 ).
Osi vel ot or
Osi vel ot or s hares t he sa me mec ha nis m of acti o n as O x br yta® ( v o xel ot or) w hic h is a n orally 
a d mi nistere d dr u g i n dicate d f or treat me nt of S C D i n a d ults a n d pe diatri c patie nts 1 2 years of 
a ge a n d ol der. Osi vel ot or is desi g ne d t o o pti mize t he p ote ntial f or cli nical be nefit deri ve d 
fr o m sta bilizi n g o x y-H b as de m o nstrate d b y a c o m paris o n t o v o xel ot or i n a m uri ne m o del of 
S C D w here osi vel ot or was o bser ve d t o be m ore p ote n t, ha ve a l o n ger half-life, a n d ac hie ve 
greater e x p os ure per d ose (D uf u, Alt et al. 2 0 2 0 ). T h us, osi vel ot or has t he p ote ntial t o 
ac hie ve a tar gete d H b occ u pa nc y a n d attai n desire d he mat ol o gical effects at l o wer d oses t ha n 
v o xel ot or, t heref ore re d uci n g pill b ur de n a n d i m pr o vi n g cli nical o utc o mes f or i n di vi d uals 
li vi n g wit h S C D. A m ore p ote nt dr u g t hat i n hi bits H bS p ol y merizati o n i n all R B Cs i n a 
br oa der perce nta ge of patie nts has t he ca pa bilit y  t o pr o vi de s u peri or efficac y t o a vaila ble 
treat me nts. B y a d dressi n g t his u n derlyi n g mec ha nis m of S C D, osi vel ot or has t he p ote ntial t o 
be a disease -m o dif y i n g t hera py, lea di n g t o i m pr o ve d a ne mia, re d uce d he m ol y sis, a n d t he 
p ossi bilit y  of re d uci n g t he e n d-or ga n da ma ge res ulti n g fr o m c hr o nic he m ol y tic a ne mia. 
Base d o n t he cli nical a n d n o ncli nical e x perie nce wit h osi vel ot or , p har mac ol o g y-base d 
he mat ol o gical effects are e x pecte d t o occ ur wit h osi vel ot or treat me nt a n d ma y i ncl u de 
i ncrease d R B Cs, H b, he mat ocrit, a n d decrease d n u m ber of retic ul oc ytes. 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 3 1
N o ncli nic al E x perie nce
N o ncli nical st u dies ha ve bee n c o n d ucte d t o c haracterize osi vel ot or , i ncl u di n g pri mar y a n d 
sec o n dar y p har mac o d yn a mics ( P D), safet y, p har mac ol o g y , p har mac o ki netics ( P K), a n d 
t o xic ol o g y. I n S C D mice treate d wit h osi vel ot or , a H b occ u pa nc y of ~ 6 % res ulte d i n a 
> 1 g/ d L i ncrease i n H b c o nce ntrati o n i n all a ni mals. M ore o ver, at a n osi vel ot or H b 
occ u pa nc y  of ~ 2 9 % (si milar t o t he mea n ac hie ve d b y t he 1 5 0 0 m g  d ose of v o xel ot or i n S C D 
partici pa nts), osi vel ot or ca use d a s ustai ne d a n d al m ost c o m plete eli mi nati o n of circ ulati n g 
sic kle d R B Cs, re d uce d retic ul oc yte c o u nts b y > 5 0 %, i ncrease d R B C half-life by 6. 1 da ys, 
a n d n or malize d H b wit h a 6. 7 g/ d L i ncrease fr o m baseli ne i n S C D mice. A d diti o nal 
i nf or mati o n o n n o ncli nical e x perie nce ma y be f o u n d i n t he In vesti gat or Br oc h ure f or 
osi vel ot or .
Cli nic al E x perie nce
T w o P hase 1 cli nical st u dies ha ve bee n c o m plete d.
A first -i n- h u ma n si n gle asce n di n g a n d m ulti ple asce n di n g d ose ( S A D/ M A D) st u d y  i n healt h y 
partici pa nts ( G B T 0 2 1 6 0 1- 0 1 1) has bee n c o m plete d. Safet y a n d P K data o n si n gle d oses u p t o 
3 0 0 0 m g i n healt h y partici pa nts de m o nstrate d t hat osi vel ot or was well t olerate d wit h a li near 
d ose - depe n de nt i ncrease i n perce nt H b occ u pa nc y . A bs or pti o n f oll o wi n g a si n gle oral d ose 
was relati vel y q uic k i n plas ma, wit h T ma x ge nerall y ra n gi n g 0. 5 - 3 h. Pea k c o nce ntrati o n i n 
w h ole bl o o d was ac hie ve d sl o wer wit h T ma x ge nerall y  ra n gi n g 8-4 8 h. T he ter mi nal 
eli mi nati o n half-life of a p pr o xi matel y 2 5 t o 2 8 da ys i n plas ma a n d bl o o d was o bser ve d i n 
healt h y  v ol u nteers; h o we ver, a p pr o xi matel y 3-f ol d l o wer ter mi nal half-life (a p pr o xi matel y 1 0 
da y s) i n plas ma a n d w h ole bl o o d was o bser ve d i n S C D patie nts. P K e x p os ure is ge nerall y  
d ose -pr o p orti o nal a n d dis pla y s a hi g h partiti o ni n g t o w h ole bl o o d ( bl o o d/ plas ma rati os of 
~ 2 1 3 a n d ~ 6 8 f or healt h y v ol u nteers a n d S C D patie nts, res pecti vel y, f oll o wi n g a si n gle 1 0 0 
m g d ose).
I n a d diti o n, a P hase 1 b St u d y G B T 0 2 1 6 0 1-0 1 2 i n a d ult p artici pa nts wit h S C D was c o n d ucte d 
t o e val uate t he P K, safet y, t olera bilit y, a n d P D of si n gle d ose a n d M A D of osi vel ot or . In t his 
o pe n la bel st u d y , a wit hi n partici pa nt d ose escalati o n was e x pl ore d. Safety,  t olera bilit y, a n d 
a vaila ble P K data after eac h d o se le vel were re vie we d b y t he Safet y Re vie w C o m mittee 
bef ore escalati o n t o t he ne xt d ose le vel. Si x a d ults wit h S C D recei ve d a si n gle 1 0 0 m g d ose 
of osi vel ot or . After a n 8-wee k was h o ut, partici pa nts recei ve d osi vel ot or l oa di n g d oses of 
3 0 0 m g o n Da y  1 a n d 2 0 0 m g o n Da y  2, f oll o we d b y a mai nte na nce d ose of 5 0 m g/ da y  f or 5 
wee ks. D ose escalati o n occ urre d at Wee k 1 3 wit h partici pa nts recei vi n g a 5 0 0 m g d ose o n 
D a y  9 1, 4 0 0 m g d ose o n Da y  9 2, f oll o we d by a mai nte na nce d ose of 1 0 0 m g/ da y  f or 
a p pr o xi matel y 3 wee ks. T he st u d y was a me n de d t o e val uate a n a d diti o nal mai nte na nce d ose 
of 1 5 0 m g/ da y  o ver 6 wee ks.
Preli mi nar y  data fr o m t hese st u dies de m o nstrates t hat osi vel ot or has a n acce pta ble safet y a n d 
t olera bilit y pr ofile i n healt h y v ol u nteers a n d partici pa nts wit h S CD as f urt her descri be d i n 
Secti o n 3. 2 . After si n gle d oses of osi vel ot or , bl o o d a n d plas ma P K a n d t he mea n % H b 
occ u pa nc y  of osi vel ot or i ncrease d i n a li near ma n ner f oll o wi n g a si n gle oral d ose i n healt h y 
v ol u nteers ( St u d y  G B T 0 2 1 6 0 1-0 1 1). I n t he i nitial part of t he G B T 0 2 1 6 0 1 -0 1 2 st u d y  of si x 
S C D partici pa nts, after treat me nt at t w o d ose le vels, 5 0 m g f or 5 wee ks a n d 1 0 0 m g f or 3 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 3 2
wee ks, t h e % H b occ u pa nc y a vera ge d 3 2. 6 % (ra n ge 1 9. 7 % t o 4 1. 8 %) a n d H b le vels 
i ncrease d by u p t o 3. 1 g/ d L  ( mea n i ncrease of 2. 3 g/ d L). Wit hi n t he sa me ti mefra me, all 
partici pa nts de m o nstrate d i m pr o ve me nts i n he mat ol o gic para meters, i ncl u di n g retic ul oc y tes 
a n d a bs ol ute retic ul oc y tes, lactate de h ydr o ge nase ( L D H), a n d i n direct bilir u bi n (Br o w n, 
Re dfer n et al. 2 0 2 1 ). 
G B T 0 2 1 6 0 1 -0 1 3 is a n o n g oi n g P hase 1, si n gle -ce nter, o pe n -la bel st u d y t o assess t he mass 
bala nce, e xcreti o n, a n d P K of a si n gle oral d ose of [ 1 4C] - osi vel ot or i n healt h y partici pa nts.
G B T 0 2 1 6 0 1 -0 1 4 is a n o n g oi n g P hase 1, o pe n -la bel, si n gle-d ose, n o n -ra n d o mize d, parallel 
gr o u p st u d y t o e val uate t he P K, safet y, a n d t olera bilit y  of osi vel ot or i n a d ult partici pa nts wit h 
re nal i m pair me nt. 
C 5 3 5 1 0 0 4 is a t hree -part, m ultice nter, P hase 2/ 3 st u d y  of orally a d mi nistere d osi vel ot or i n 
partici pa nts wit h S C D. Part A will e val uate t he safet y , t olera bilit y, a n d efficac y of 1 2 wee ks 
of osi vel ot or i n ad ult partici pa nts wit h S C D, a n d deter mi ne d t he o pti mal d ose of 1 5 0 m g f or 
Part B. Part B will e val uate t he efficac y  of 1 5 0 m g osi vel ot or vers us place b o i n a d ult a n d 
a d olesce nt partici pa nts wit h S C D f or 4 8 wee ks. Part C is a si n gle -ar m st u d y w hic h will 
e valuate t he P K a n d safet y  of si n gle a n d m ulti ple d oses of o pe n-la bel osi vel ot or a d mi nistere d 
t o pe diatric partici pa nts. T he st u d y is o n g oi n g. 
Partici pa nts wit h S C D w h o partici pate d i n a n osi vel ot or cli nical st u d y ma y be eli gi ble t o 
e nr oll i n t his o pe n- la bel e xte nsi o n st u d y ( C 5 3 5 1 0 0 5).
A detaile d descri pti o n of t he c he mistr y , p har mac ol o g y, efficac y, a n d safety of osi vel ot or is 
pr o vi de d i n t he P F- 0 7 9 4 0 3 6 7 I n vesti gat or’s Br oc h ure (I B) ( Pfizer, 2 0 2 3 ), w hic h is t he Si n gle 
Refere nce Safet y D oc u me nt ( S R S D) f or t his st u d y.
3. 2. Be nefit/ Ris k Assess me nt
3. 2. 1. Ris k Assess me nt
Base d o n t he e x perie nce wit h osi vel ot or at t he ti me of t his Pr ot oc ol A me n d me nt, n o 
partici pa nt has e x perie nce d a n y a d verse reacti o n of cli nical si g nifica nce. T he t he oretical 
p ote ntial ris k f or osi vel ot or is decrease d o xy ge n deli ver y , h o we ver t here are n o c urre nt 
a d verse e ve nts attri b ute d t o t he st u d y  dr u g t hat s u p p ort t his t he oretical ris k.  
P ote nti al Ris k of Cli nic al 
Si g nific a nce
S u m m ar y of D at a/ R ati o n ale 
f or Ris k
Miti g ati o n Str ate g y
St u d y I nter ve nti o n 
Osi vel ot or ( P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Decrease d o x y ge n deli ver y
I ncrease d o x y ge n affi nit y 
ass ociate d wit h t he o si vel ot or
mec ha nis m has a t he oretical 
p ote ntial t o res ult i n decrease d 
o x y ge n deli ver y
Cl ose m o nit ori n g of A Es t hr o u g h T M E 
m o nit ori n g, vital si g ns, E P O le vels, a n d 
he m o xi metr y
Pla n ne d near i nfrare d s pectr osc o p y ( NI R S) 
st u d y t o assess e vi de nce of or ga n 
preser vati o n desi g ne d t o a d dress t his ris k.
St u d y Pr oce d ures
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 3 3
P ote nti al Ris k of Cli nic al 
Si g nific a nce
S u m m ar y of D at a/ R ati o n ale 
f or Ris k
Miti g ati o n Str ate g y
W orse ni n g a ne mia i n
partici pa nt wit h u n derl yi n g 
sic kle cell a ne mia.
Fre q ue nt bl o o d sa m ples will be 
c ollecte d fr o m a ne mic 
partici pa nts d uri n g t he st u d y 
w hic h ma y res ult i n p ote ntial 
l oss of bl o o d v ol u me i n alrea d y 
a ne mic partici pa nts
A re d uce d P K sa m pli n g sc he me is 
i nc or p orate d f or pe diatric partici pa nts s o as 
n ot t o e xcee d bl o o d dra w  li mits ( 0. 8 m L/ k g 
i n a gi ve n 2 4-h o ur peri o d; 2. 4 m L/ k g i n a 
gi ve n 4 -wee k peri o d). C ollecti o n kits t hat 
li mit bl o o d v ol u me dra ws are bei n g use d f or 
pe diatric partici pa nts. I nvesti gat ors are 
all o we d t o li mit bl o o d sa m ple c ollecti o n i n 
c o nsi derati o n of patie nt c o n diti o n, wit h t he 
g ui da nce of a sa m ple pri orit y list (Ta ble 1 0 ).
Bl o o d v ol u me li mits are f oll o wi n g 
g ui deli nes i ncl u de d i n E U g ui da nce f or 
et hical c o nsi derati o ns f or cli nical trials 
c o n d ucte d wit h mi n ors. Best practices f or 
pe diatric bl o o d c ollecti o n are p r o vi de d i n 
Secti o n 9. 3. 3. 1 .
P ote ntial D DI
Base d o n preli mi nar y i n vitr o 
data, o si vel ot or has t he p ote ntial 
t o i nteract wit h 
 
 
 
 
Cl ose m o nit ori n g of t he 
Pr o hi bite d/ Restricte d me dicati o n list
A d ult partici pa nts i n t his st u d y  w h o ha ve c o m plete d Part A of C 5 3 5 1 0 0 4 ( wit h o pe n la bel 
osi vel ot or treat me nt), or a n y ot her o pe n la bel osi vel ot or st u d y, will be assesse d e ver y 
1 2 wee ks f or safet y  a n d res p o nse t o treat me nt. 
Partici pa nts fr o m Part B of C 5 3 5 1 0 0 4, or a n y ot her ra n d o mize d, bli n de d, place b o c o ntr olle d 
osi vel ot or st u d y, will be assesse d e ver y 8 wee ks, f or safety a n d res p o nse f or t he i nitial 
2 4 wee ks a n d t he n e ver y  1 2 wee ks t hereafter. 
Pe diatric partici pa nts fr o m Part C of C 5 3 5 1 0 0 4 will be assesse d at Wee k 2 a n d Wee k 4, t he n 
e ver y 4 wee ks f or t he i nitial 2 4 wee ks, a n d t he n e ver y  1 2 wee ks t hereafter. 
F or partici pa nts w h o ha ve bee n off st u d y dr u g treat me nt pri or t o e nr olli n g i nt o t his st u d y , a n 
a p pr o priate l oa di n g d ose re gi me n will be i nitiate d ( Ta ble 1 4 ), a n d partici pa nts will be 
assesse d e ver y 2 wee ks u p t o Wee k 8, t he n e ver y 4 wee ks u p t o Wee k 2 4, a n d e ver y 
1 2 wee ks t hereafter .
3. 2. 2. Be nefit Assess me nt
Osi vel ot or i ncreases he m o gl o bi n ( H b) o xy ge n affi nit y a n d sta bilizes H b i n t he 
o x y -he m o gl o bi n state t here b y  i n hi biti n g p ol ymerizati o n of H b S i n R B Cs a n d i ncreasi n g R B C 
def or ma bilit y a n d re d uci n g m or p h ol o gic sic kli n g of R B Cs (D uf u, Alt et al. 2 0 2 0 ). I n 
precli nical a ni mal st u dies, osi vel ot or partiti o ne d prefere ntiall y  t o t he R B C c o m part me nt wit h 
a mea n bl o o d/ plas ma rati o of 4 8 – 1 2 2: 1. T h us, si milar t o v o xel ot or, osi vel ot or is e x pecte d t o 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)
C CI

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 3 4
partiti o n prefere ntiall y  i nt o R B Cs i n h u ma ns, w here it s pecificall y bi n ds t o H b, there b y 
mi ni mizi n g plas ma e x p os ures. 

S C D is a seri o us c o n diti o n c haracterize d b y he m ol ytic a ne mia, c hr o nic or ga n da ma ge, 
a n d V O Cs. Des pite rece nt a d va nces i n t hera p y, t here re mai n li mite d treat me nt o pti o ns f or 
patie nts wit h S C D; t h us a hi g h u n met me dical n ee d c o nti n ues t o e xist. Osi vel ot or ’s
p ote ntial t o a d dress t his u n met me dical nee d is s u p p orte d b y  t he n o ncli nical st u dies a n d 
preli mi nar y  cli nical data w hic h pr o vi de e vi de nce f or a treat me nt effect ( gra d ual i ncrease 
i n H b at b ot h 1 0 0 m g a n d 1 5 0 m g daily mai nte na nce d osi n g i n C 5 3 5 1 0 0 4). Gi ve n t he 
M O A, it is li kel y  t hat hi g her H b le vels (a n d c o nse q ue ntl y a cli nicall y si g nifica nt 
re d ucti o n i n t he i nci de nce of V O Cs) will be ac hie ve d, w hic h is s u p p orte d b y data f or H b 
a n d H b occ u pa nc y fr o m C 5 3 5 1 0 0 2 a n d preli mi nar y data f or C 5 3 5 1 0 0 4. 

Osi vel ot or ha s i ncrease d affi nit y f or H b a n d a l o n ger t1/ 2 c o m pare d t o v o xel ot or. 
Osi vel ot or has t he p ote ntial t o ac hie ve greater % H b occ u pa nc y  a n d attai n desire d 
he mat ol o gical effects at l o wer d oses t ha n v o xel ot or, t heref ore re d uci n g pill b ur de n, 
i ncreasi n g t he d ura bilit y of res p o nse, a n d i m pr o vi n g cli nical o utc o mes f or i n di vi d uals 
li vi n g wit h S C D.

T he c urre nt treat me nt o pti o ns f or pe diatric partici pa nts wit h S C D, partic ularl y  i n c hil dre n 
less t ha n 1 2 years of a ge, are li mite d. S C D re q uires life -l o n g pre ve nti ve mai ntena nce a n d 
ma na ge me nt of ac ute a n d c hr o nic c o m plicati o ns. Ne w b or n scree ni n g, earl y  
i m m u nizati o n, a n d pr o p h ylactic pe nicilli n treat me nt i n i nfa nts a n d c hil dre n as well as 
c o m pre he nsi ve ma na ge me nt f or pai n a n d disease c o m plicati o ns ha ve i m pr o ve d o utc o mes 
i n chil dre n wit h S C D. Des pite t hese a d va nces, t he me dia n life e x pecta nc y  of affecte d 
i n di vi d uals is o nl y 4 3 ye ars of a ge a n d treat me nt of S C D re mai ns a seri o us u n met 
me dical nee d ( Bra n d o w, 2 0 2 2 ). C 5 3 5 1 0 0 4 Part B will e val uate t he efficac y a n d safety of 
t he selecte d d ose of osi vel ot or vers us place b o i n a d ult a n d pe diatric partici pa nts ( 1 2 t o 
< 1 8 y ears of a ge) wit h S C D. Part C will e val uate t he P K a n d safet y of si n gle a n d m ulti ple 
d oses of o pe n -la bel osi vel ot or a d mi nistere d t o pe diatric partici pa nts 6 m o nt hs t o 
< 1 8 ye ars of a ge.
3. 2. 3. O ver all Be nefit/ Ris k C o ncl usi o n
T he res ults of pre vi o us st u dies of osi vel ot or i n healt h y v ol u nteers a n d S C D a d ult partici pa nts 
s u p p ort t he i n vesti gati o n of osi vel ot or f or S C D. T here is a fa v ora ble be nefit -ris k pr ofile t o 
s u p p ort t he rati o nale f or t his st u d y. Ta ki n g i nt o acc o u nt t he meas ures t o mi ni mize ris k t o 
partici pa nts, t he p ote ntial ris ks ass ociate d wit h osi vel ot or are j ustifie d b y t he a ntici pate d 
be nefits t hat ma y  be aff or de d t o partici pa nts wit h S C D.
3. 3. St u d y R ati o n ale
T his is a m ultice nter, gl o bal, o pe n -la bel e xte nsi o n st u d y t o e val uate t he l o n g-ter m safet y, 
t olera bilit y a n d S C D relate d c o m plicati o ns of partici pa nts w h o ha ve bee n treate d wit h 
osi vel ot or . Gat heri n g m ore patie nt-ye ars of e x p os ure t o osi vel ot or w ill all o w t he S p o ns or t o 
f urt her u n dersta n d a n d c haracterize t he safet y pr ofile of osi vel ot or . 
All partici pa nts i n t his st u d y are partici pa nts wit h S C D w h o ha ve pre vi o usl y  partici pate d i n 
a n osi vel ot or cli nical st u d y. Partici pati o n i n t his st u d y will pr o vi de c o nti n ue d access t o 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 3 5
treat me nt u ntil t he partici pa nt has access t o osi vel ot or fr o m a n alter nati ve s o urce (e g, t hr o u g h 
c o m mercializati o n, a ma na ge d -access pr o gra m, or a S p o ns ore d i nitiati ve ) or u ntil t he 
S p o ns or deci des t o ter mi nate t he St u d y . S o me partici pa nts i n t his st u d y will ha ve recei ve d 
osi vel ot or or place b o i n a pri or st u d y  i n a bli n de d fas hi o n a n d t heref ore t his st u d y will 
e val uate t he first e x p os ure t o osi vel ot or i n s o me partici pa nts. As s uc h, t he safety of i nitial 
e x p os ure t o osi vel ot or will al s o be e val uate d i n t his st u d y. 
T he dail y  mai nte na nce d ose f or a d ult partici pa nts e nteri n g t he st u d y will be 1 5 0 m g 
osi vel ot or , w hic h is t he o pti mal d ose selecte d fr o m Part A of C 5 3 5 1 0 0 4. T he dail y  
mai nte na nce d ose f or all a d ult partici pa nts w h o ha ve alrea d y  e nr olle d i nt o C 5 3 5 1 0 0 5 pri or t o 
t his a me n d me nt ma y be a dj uste d t o t he selecte d d ose of 1 5 0 m g. A d olesce nt a n d pe diatric 
partici pa nts fr o m C 5 3 5 1 0 0 4 Parts B a n d C will be a d mi nistere d a d ose t hat pr o vi des 
ge nerall y e q ui vale nt e x p os ure t o a d ult partici pa nt s.
4. O B J E C TI V E S, E N D P OI N T S, A N D E S TI M A N D S
T he o bjecti ves of t he st u d y  will be assesse d b y t he e n d p oi nts a n d esti ma n ds as s h o w n i n 
Ta ble 5.
T a ble 5.
O bjecti ves, E n d p oi nts a n d Esti m a n ds
O bjecti ves
E n d p oi nts
Esti m a n ds
Pri m ar y:
Pri m ar y:
Pri m ar y:
T o e val uate t he l o n g -ter m 
safet y of osi vel ot or i n 
partici pa nts wit h S C D.

I nci de nce of T E A Es, c ha n ges i n 
la b orat or y assess me nts, a n d c ha n ges 
i n vital si g ns.
T he safet y esti ma n d f or t he 
pri mar y e n d p oi nts will 
c o nsi der all safet y data 
c ollecte d. S pecificall y, all data 
c ollecte d o n or after o btai ni n g 
i nf or me d c o nse nt will be 
i ncl u de d i n t he a nal ysis. 
Sec o n d ar y:
Sec o n d ar y:
Sec o n d ar y:
T o e val uate fre q ue nc y of 
S C D -relate d c o m plicati o ns.
T o e val uate t he effects of 
l o n g-ter m use of osi vel ot or 
o n he m ol ytic a ne mia. 

A n n ualize d rate of V O C. 

I nci de nce of S C D-relate d S A Es.

C ha n ge fr o m baseli ne i n he mat ol o gical 
la b orat or y para meters, i ncl u di n g 
he m o gl o bi n, retic ul oc ytes, lactate 
de h y dr o ge nase, a n d u nc o nj u gate d 
bilir u bi n.
N ot A p plica ble
E x pl or at or y:
E x pl or at or y:
E x pl or at or y:
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 3 6
T a ble 5 .
O bjecti ves, E n d p oi nts a n d Esti m a n ds
O bjecti ves
E n d p oi nts
Esti m a n ds
T o e val uate t he l o n g -ter m 
effects of osi vel ot or
treat me nt o n i nfla m mati o n, 
er yt hr o p oieti n le vels, 
S C D -s pecific bi o mar kers, 
a n d H R Q O L assess me nts.

C ha n ge fr o m baseli ne i n a d hesi o n of 
w h ole bl o o d t o micr ofl ui dic c ha n nels.

C ha n ge fr o m baseli ne i n R B C sic kli n g 
fr o m peri p heral bl o o d s mears.

C ha n ge fr o m baseli ne i n R B C 
def or ma bilit y a n d R B C mit oc h o n drial 
c o nte nt.

C ha n ge fr o m baseli ne i n al b u mi n -t o-
creati ni ne rati o a n d ki d ne y i nj ur y 
m o lec ule.

C ha n ge fr o m baseli ne i n er yt hr o p oieti n 
le vels.

C ha n ge fr o m baseli ne i n ha pt o gl o bi n, 
he m o pe xi n, a n d s ol u ble C 3.

C ha n ge fr o m baseli ne i n H R Q O L 
assess me nts i ncl u di n g P R O MI S S F 
Fati g ue 1 3a, P R O MI S S F Pai n 
I nterfere nce 8a, P R O MI S N R S Pai n 
i nte nsit y, P GI-C of fati g ue a n d pai n, 
C GI -C of S C D, P GI -S of fati g ue a n d 
pai n, a n d C GI -S of S C D, E ur o Q ol E Q -
5 D -5 L, a n d W P AI + CI Q: S C D. 
N ot A p plica ble
T o e val uate t he P K 
para meters of l o n g -ter m 
e x p os ure t o osi vel ot or

Bl o o d a n d plas ma c o nce ntrati o ns of 
osi vel ot or . 
N ot A p plica ble
A b bre viati o ns: C GI -C, Cli nicia n’s Gl o bal I m pressi o n of C ha n ge; C GI - S, Cli nicia n’s Gl o bal I m pressi o n of Se verit y; P GI-
C, Patie nt’s Gl o bal I m pressi o n of C ha n ge; P GI -S, Patie nt’s Gl o bal I m pressi o n of Se verit y; P K, p har mac o ki netic; 
P R O MI S, Patie nt - Re p orte d O utc o me Meas ure me nt I nf or mati o n S yste m; H R Q O L, healt h-relate d q ualit y of life; R B C, re d 
bl o o d cell; S C D, sic kle cell di sease; S F, s h ort f or m, W P AI + CI Q: S C D, W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt 
Q uesti o n naire pl us Classr o o m I m pair me nt Q uesti o ns: Sic kle Cell Disease.  
5. S T U D Y D E SI G N
5. 1. O ver all Desi g n
T his m ultice nter, gl o bal, o pe n -la bel e xte nsi o n st u d y is desi g ne d t o assess t he safety of l o n g -
ter m treat me nt wit h osi vel ot or i n partici pa nts wit h S C D. T he st u d y  will be c o n d ucte d 
gl o ball y a n d will be a vaila ble t o eli gi ble partici pa nts e nr olle d i n a pri or P fizer-s p o ns ore d 
osi vel ot or cli nical st u d y ( ori gi nati n g st u d y). Partici pa nts m ust meet t he e ntr y criteria f or t his 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 3 7
st u d y t o be eli gi ble f or e nr oll me nt (see Secti o n 6. 1 ). T he st u dy will ha ve a gl o bal 
distri b uti o n, a n d u p t o a p pr o xi matel y  5 0 0 partici pa nts will be e nr olle d.
Eli gi ble partici pa nts will recei ve osi vel ot or a d mi nistere d orall y dail y if 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, u ntil t he 
partici pa nt has access t o osi vel ot or fr o m a n alter nati ve s o urce (e g, t hr o u g h c o m mercializati o n 
or a ma na ge d -access pr o gra m).
Eli gi ble partici pa nts will recei ve o pe n -la bel osi vel ot or at Baseli ne ( Da y 1). It is i nte n de d t hat 
D a y  1 c oi nci des wit h t he fi nal visit fr o m t he ori gi nati n g osi vel ot or st u d y. E n d of Treat me nt 
( E O T) assess me nts fr o m t he ori gi nati n g st u dy will ser ve as Baseli ne assess me nts f or t his 
st u d y. If Da y 1 f or t his st u d y is greater t ha n 7 da ys fr o m the c o m pleti o n of t he ori gi nati n g 
st u d y, ne w baseli ne assess me nts will be o btai ne d. If d uri n g t he peri o d bet wee n Da y 1 of t his 
st u d y a n d c o m pleti o n of t he ori gi nati n g st u dy n o d ose is recei ve d f or greater t ha n 3 
c o nsec uti ve da ys, a n a p pr o priate l oa di n g d ose will be a d mi nistere d pri or t o c o nti n ue d 
mai nte na nce d osi n g (see Secti o n 1 1. 3 f or detail). A d diti o nal assess me nts t hat ma y n ot ha ve 
bee n i ncl u de d i n t he pri or E O T assess me nts are o utli ne d i n t he Sc he d ule of Assess me nts a n d 
will nee d t o be c o m plete d pri or t o st u d y  dr u g a d mi nistrati o n.
Partici pa nts w h o partici pate d i n Part A of C 5 3 5 1 0 0 4 or a n y  ot her o pe n la bel osi vel ot or st u d y, 
will u n der g o safet y a n d o utc o me assess me nts at Baseli ne ( Da y  1) a n d e ver y 1 2 wee ks 
t hereafter (Ta ble 2 ). 
Partici pa nts fr o m Part B of C 5 3 5 1 0 0 4, or a n y ot her ra n d o mize d, bli n d e d, place b o c o ntr olle d 
osi vel ot or st u d y will u n der g o safet y a n d o utc o me assess me nts at Baseli ne ( Da y 1), Wee k 8, 
Wee k 1 6, Wee k 2 4, a n d e ver y  1 2 wee ks t hereafter (Ta ble 3 ). 
Pe diatric partici pa nts fr o m Part C of C 5 3 5 1 0 0 4 will u n der g o safet y a n d o utc o me assess me nts 
at Baseli ne ( Da y 1), Wee k 2, Wee k 4, Wee k 8, Wee k 1 2, Wee k 1 6, Wee k 2 0, Wee k 2 4, a n d 
e ver y 1 2 wee ks t hereafter (Ta ble 4 ). 
Partici pa nts will be f oll o we d f or a p pr o xi matel y  1 2 wee ks after c o m pleti n g d osi n g t o f urt her 
assess safet y. Partici pa nts s h o ul d ret ur n t o t he st u d y site f or a n E O S visit a p pr o xi matel y 1 2 
wee ks after t he last d ose of st u d y  dr u g.
5. 2. Scie ntific R ati o n ale f or St u d y Desi g n
T his st u d y  is a n o pe n-la bel st u d y t o e val uate t he safety of l o n g -ter m a d mi nistrati o n of 
osi vel ot or wit h o ut a c o m parat or. Partici pa n ts i n t his st u d y will ha ve partici pate d i n a 
c o ntr olle d cli nical trial of osi vel ot or ( ori gi nati n g st u d y) i n w hic h t he y will ha ve recei ve d 
osi vel ot or or place b o. Gi ve n t he l o n g half -life of osi vel ot or at t he d ose t o be e val uate d i n t his 
st u d y, m ost of t he partici pa nts are e x pecte d t o mai ntai n tar get c o nce ntrati o ns t hr o u g h o ut t he 
st u d y.
5. 3. J ustific ati o n f or D ose
T he dail y  mai nte na nce d ose f or a d ults i n t he o pe n la bel e xte nsi o n st u d y will be 1 5 0 m g, 
w hic h was t he o pti mal efficaci o us d ose deter mi ne d fr o m Part A of C 5 3 5 1 0 0 4. T he dail y  
mai nte na nce d ose f or all a d ult partici pa nts w h o ha ve alrea d y e nr olle d i n C 5 3 5 1 0 0 5 pri or t o 
t his a me n d me nt ma y be a dj uste d t o 1 5 0 m g.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 3 8
A d olesce nt a n d pe diatric partici pa nts fr o m C 5 3 5 1 0 0 4 Parts B a n d C will be a d mi nistere d a 
d ose t hat pr o vi des ge nerall y  e q ui vale nt e x p os ure t o a d ult partici pa nts. 
F urt her m o dificati o ns t o t he l oa di n g d oses ma y  be ma de base d o n c u m ulati ve data fr o m a 
p o p ulati o n P K ( P P K) m o del. A d diti o nall y , if t here are safety/ t olera bilit y iss ues or lac k of 
bi o mar ker res p o ns e at hi g her d oses i n t he ori gi nati n g st u d y , a dr u g d ose re d ucti o n ma y be 
i nstit ute d as n ote d i n Secti o n 1 1. 3 . 
T he met h o d ol o g y  f or l oa di n g d ose selecti o n use d i n t his o pe n la bel st u d y will differ f or 
partici pa nts c o m pleti n g Parts A, B, a n d C of C 5 3 5 1 0 0 4 a n d are s h o w n i n Secti o n 1 1. 3 a n d
Ta ble 6. F or partici pa nts fr o m t he pare nt st u d y  w h o ha ve bee n off st u d y dr u g treat me nt 
greater t ha n 3 c o nsec uti ve da y s pri or t o e nr olli n g i nt o t his st u d y, a ne w l oa di n g d ose re gi me n 
will be i nitiate d as s h o w n i n Secti o n 1 1. 3 .
T a ble 6.  
D oses Pl a n ne d B ase d o n P artici p ati o n fr o m C 5 3 5 1 0 0 4  
P artici p a nts 
fr o m P art
Pl a n ne d D ose t o I niti ate 
Tre at me nt i n O pe n L a bel 
E xte nsi o n
D ose A dj ust me nt 
A
1 5 0 m g osi vel ot or
If d ose is i ncrease d, a l oa di n g d ose ma y be 
re q uire d. Details o n t he l oa di n g d oses are 
pr o vi de d i n Secti o n 1 1. 3 . T he mai nte na nce d ose 
f or all partici pa nts w h o ha ve alrea d y e nr olle d i n
C 5 3 5 1 0 0 5 pri or t o t his a me n d me nt ma y be 
m o difie d t o 1 5 0 m g.
B
A d ults: I nitiate or c o nti n ue wit h 
Q D osi vel ot or 1 5 0 m g d ose fr o m 
Part B of C 5 3 5 1 0 0 4.
A d olesce nts: I nitiate or c o nti n ue 
wit h Q D d ose of osi vel ot or fr o m 
Part B of C 5 3 5 1 0 0 4.
A d ults: N ot a p plica ble
A d olesce nts: A d olesce nt partici pa nts will be 
a d mi nistere d a d ose t hat pr o vi des ge nerall y 
e q ui vale nt e x p os ure t o a d ult partici pa nts.
C
C o nti n ue wit h Q D assi g ne d d ose 
of osi vel ot or fr o m Part C of 
C 5 3 5 1 0 0 4.
Treat me nt ma y be m o difie d base d o n e mer gi n g 
data fr o m C 5 3 5 1 0 0 4. A d olesce nt a n d pe diatric 
partici pa nts will be a d mi nistere d a d ose t hat 
pr o vi des ge nerall y e q ui vale nt e x p os ure t o a d ult 
partici pa nts. 
A b bre viati o ns: Q D, o nce dail y.
Detaile d i nf or mati o n o n l oa di n g d ose a n d mai nte na nce d ose t o be use d base d o n pri or 
partici pati o n i n C 5 3 5 1 0 0 4 ca n be f o u n d i n Secti o n 1 1. 3 .
5. 4. E n d of St u d y Defi niti o n
T he E O S is defi ne d as t he date w he n t he last partici pa nt has c o m plete d all st u d y  pr oce d ures 
u p t o a n d i ncl u di n g E O S or E T visits, as s pecifie d i n t he Sc he d ules of A ssess me nts a n d 
Pr oce d ures ( Secti o n 2. 1 ).
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 3 9
6. S T U D Y P O P U L A TI O N
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o 
k n o w n as pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
6. 1. I ncl usi o n Criteri a
Partici pa nts m ust meet all i ncl usi o n criteria t o be eli gi ble f or st u d y partici pati o n.
1.
A ge d 6 m o nt hs or ol der wit h S C D w h o partici pate d a n d recei ve d st u d y dr u g i n a n
osi vel ot or cli nical stu d y  a n d c o m plete d t he E O T visit.
N ote: Partici pa nts w h o disc o nti n ue d st u d y  dr u g i n t he ori gi nati n g st u d y d ue t o a n A E, b ut 
w h o re mai ne d o n st u d y, ma y be eli gi ble f or treat me nt i n t his st u d y  pr o vi de d t he A E d oes 
n ot p ose a ris k f or treat me nt wit h osi vel ot or . Als o, partici pa nts w h o c o m plete d treat me nt 
fr o m t he ori gi nati n g st u d y b ut were n ot a ble t o r oll o ver i nt o C 5 3 5 1 0 0 5 d ue t o dela y i n 
st u d y site acti vati o n will be eli gi ble pr o vi de d ot her eli gi bilit y criteria are met.
2.
Fe males of c hil d -beari n g p ote ntial are r e q uire d t o ha ve a ne gati ve uri ne pre g na nc y  test 
pri or t o d osi n g o n Da y 1.
N ote: Fe males w h o bec o me of c hil d -beari n g p ote ntial d uri n g t he st u d y  m ust be willi n g t o 
ha ve a ne gati ve uri ne pre g na nc y  test t o re mai n i n t he st u d y.
3.
If se x uall y acti ve, fe males of c hil d-beari n g p ote ntial m ust c o nsiste ntl y  use hi g hly 
effecti ve met h o ds of c o ntrace pti o n c o nsiste ntl y t hr o u g h o ut t he st u d y a n d f or at least 8 4 
da y s after t he last d ose of st u d y dr u g. Male partici pa nts are eli gi ble t o partici pate if t he y  
a gree t o t he f oll o wi n g re q uire me nts d uri n g t he st u d y i nter ve nti o n peri o d a n d f or 8 4 da ys 
after t he last d ose of st u d y i nter ve nti o n, w hic h c orres p o n ds t o t he ti me nee de d t o 
eli mi nate re pr o d ucti ve safet y ris k of t he st u d y i nter ve nti o n: 

Refrai n fr o m d o nati n g s per m
P L U S eit her:

Be a bsti ne nt fr o m heter ose x ual i nterc o urse as t heir preferre d a n d us ual 
lifest yle (a bsti ne nt o n a l o n g-ter m a n d persiste nt basis) a n d a gree t o re mai n 
a bsti ne nt. 
O R

M ust a gree t o use a male c o n d o m w he n e n ga gi n g i n a n y  acti vit y t hat all o ws 
f or passa ge of ejac ulate t o a n ot her pers o n. 
A male partici pa nt s h o ul d be a d vise d of t he be nefit f or a fe male of c hil d -beari n g 
p ote ntial part ner usi n g a hi g hl y effecti ve met h o d of c o ntrace pti o n wit h a fail ure rate of 
< 1 % per ye ar.
4.
Has pr o vi de d writte n i nf or me d c o nse nt/ass e nt. F or u n dera ge partici pa nts, b ot h t he 
c o nse nt of t he partici pa nt’s le gal re prese ntati ve or le gal g uar dia n a n d t he partici pa nt’s 
asse nt ( w here a p plica ble) m ust be o btai ne d base d o n l ocal re q uire me nts.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 4 0
6. 2. E xcl usi o n Criteri a
Partici pa nts meeti n g a n y of t he f o ll 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.
Fe male w h o is breastfee di n g or pre g na nt.
2.
Wit h dre w c o nse nt or was n o nc o m plia nt fr o m t he ori gi nati n g osi vel ot or cli nical st u d y.
3.
Has a n y me dical, ps yc h ol o gical, safet y, or be ha vi oral c o n dit i o ns t hat, i n t he o pi ni o n of 
t he In vesti gat or, ma y  c o nf o u n d safety i nter pretati o n, i nterfere wit h c o m plia nce, or 
precl u de i nf or me d c o nse nt.
4.
Use of pr o hi bite d prescri pti o n or n o n prescri pti o n dr u gs a n d dietar y  s u p ple me nts 
(i ncl u di n g her bal a n d alter nati ve medicati o ns). Marij ua na a n d all f or ms of i n geste d or 
i n hale d ca n na bi di ol ( C B D) a n d T H C-c o ntai ni n g pr o d ucts usa ge meeti n g D S M- V criteria 
f or s u bsta nce a b use dis or der is pr o hi bite d. H o we ver, occasi o nal marij ua na use is all o we d, 
e xce pt f or 2 4 h o urs pri or t o ne ur oc o g niti ve assess me nt as o utli ne d i n t he S o A.
5.
O n g oi n g or rece nt use of 
 
. Rece nt is defi ne d as wit hi n 5 eli mi nati o n half -li ves or 1 4 da y s, 
w hic he ver is l o n ger pri or t o Da y  1.
6.
O n g oi n g or rece n t use of 
Rece nt is 
defi ne d as wit hi n 5 eli mi nati o n half -li ves or 1 4 da ys, w hic he ver is l o n ger, pri or t o Da y 1.
7.
O n g oi n g or rece nt use of t he
 Rece nt is 
defi ne d a s wit hi n 5 eli mi nati o n half-li ves pri or t o Da y 1. 
8.
C urre nt or rece nt use of v o xel ot or. Rece nt use is defi ne d as wit hi n 1 0 da y s pri or t o Da y 1.
9.
C o ns u m pti o n of gra pefr uit, gra pefr uit j uice, a n d/ or Se ville ora n ges wit hi n 1 4 da y s pri or 
t o Da y 1 a n d is u n willi n g t o a bstai n fr o m c o ns u m pti o n of gra pefr uit, gra pefr uit j uice, 
a n d/ or Se ville ora n ges u ntil t he E O S/ E T.
1 0. Has recei ve d a n i n vesti gati o nal dr u g (i ncl u di n g i n vesti gati o nal vacci nes) wit hi n 5 ti mes 
t he eli mi nati o n half-life (if k n o w n) or wit hi n 3 0 da ys (if t he eli mi nati o n half-life- is 
u n k n o w n) pri or t o st u d y  dr u g a d mi nistrati o n or is c o nc urre ntl y e nr olle d i n a n y researc h 
j u d ge d n ot t o be scie ntificall y or me dically c o m pati ble wit h t his st u d y . 
1 1. C urre nt or rece nt use of criza nliz u ma b. Rece nt use is defi ne d as wit hi n 9 0 da y s pri or t o 
D a y  1. 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)
C CI
C CI
C CI

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 4 1
7. S T U D Y T R E A T M E N T A N D C O N C O MI T A N T T H E R A P Y
7. 1. St u d y Tre at me nts A d mi nistere d
St u d y  dr u g i nf or mati o n is prese nte d bel o w.
T a ble 7 . 
St u d y Dr u g I nf or m ati o n
St u d y I nter ve nti o n
I nter ve nti o n 
N a me
Osi vel ot or ( P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
T y pe
Dr u g
Use
E x peri me ntal
I M P or 
NI M P/ A x M P
I M P
D ose 
F or m ul ati o n
Ta blet ( or a ge a p pr o priate oral f or m ulati o n f or pe diatric partici pa nts < 6 years of a ge)
U nit D ose 
Stre n gt h(s)
1 0 0 m g/ta blet, 2 5 m g/ta blet
D os a ge Le vel(s)
1 0 0 m g, 1 5 0 m g, 2 0 0 m g
R o ute of 
A d mi nistr ati o n
oral
S o urci n g
Pr o vi de d ce ntrall y b y t he s p o ns or.
P ac k a gi n g a n d 
L a beli n g
St u d y i nter ve nti o n will be pr o vi de d i n b ottles, Eac h b ottle will be la bele d as re q uire d per c o u ntr y 
re q uire me nt.
Pr o vi de d bli n de d.
S R S D
P F - 0 7 9 4 0 3 6 7 I n vesti gat or’s Br oc h ure 
S t u d y Ar ms
Ar m Title
Osi vel ot or ( P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
A d ults
A d ult partici pa nts e nr olli n g fr o m C 5 3 5 1 0 0 4 Part A a n d Part B will recei ve 1 5 0 m g mai nte na nce 
d ose. D ose a dj ust me nt a n d or l oa di n g d ose will be deter mi ne d base d o n pre vi o us i nter ve nti o n/ d ose 
recei ve d i n C 5 3 5 1 0 0 4. Details are pr o vi de d i n A p pe n di x 1.
A d olesce nts a n d 
Pe diatrics
A d olesce nt a n d pe diatric partici pa nts fr o m C 5 3 5 1 0 0 4 Parts B a n d C will be a d mi nistere d a d ose 
t hat pr o vi des ge nerall y e q ui vale nt e x p os ure t o a d ult partici pa nts.
See A p pe n di x 1: Detaile d D osi n g I nf or mati o n F or Osi vel ot or f or d ose i nf or mati o n f or partici pa nts r olli n g i nt o t his st u d y.
Osi vel ot or will be a d mi nistere d orall y. St u d y dr u g will be dis pe nse d t o t he partici pa nt f or 
c o m pleti o n of l oa di n g d oses a n d i nitiati o n of mai nte na nce d osi n g at h o me dail y  u ntil t he ne xt 
cli nical site visit. 
St u d y  dr u g s h o ul d be ta ke n t w o h o urs bef ore a meal or o ne h o ur after a meal. Eac h d ose will 
be a d mi nistere d orall y  wit h a p pr o xi matel y 2 4 0 m L of water (a d diti o nal water t o c o m plete 
d osi n g is all o we d). Partici pa nts s h o ul d s wall o w t he ta blets (≥6 y ears ol d) or a ge a p pr o priate 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 4 2
pe diatric f or m ulati o n ( < 6 y ears ol d) wit hi n 5 mi n utes. If t he partici pa nt v o mits, t he d ose 
s h o ul d n ot be re peate d.
O n t he da y s t hat P K sa m ples are t o be ta ke n, st u d y dr u g is t o be ta ke n i n t he cli nic a n d t he 
partici pa nt m ust rec or d t he ti me a n d date of t he last t hree d oses of st u d y dr u g ta ke n at h o me. 
It is a ntici pate d t hat t hese sa m ples are t o be ta ke n 2 4 ± 3 h o urs after t he last d ose at h o me.
7. 2. Pre p ar ati o n, H a n dli n g, St or a ge, a n d Acc o u nt a bilit y
Osi vel ot or will be pr o vi de d i n hi g h de nsit y p ol yet h y le ne b ottles wit h c hil d resista nt ca ps wit h 
i n d ucti o n seal a n d la bele d acc or di n g t o l ocal re g ulati o ns. 
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 5⁰ C t o 2 5⁰ C, eit her 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 sec ure, te m perat ure c o ntr olle d, 
l oc ke d e n vir o n ment wit h restricte d access, or i n a sec ure l ocati o n at t he partici pa nts’ h o me.
N o s pecial c o nsi derati o ns f or safe ha n dli n g of osi vel ot or are re q uire d.
T he I n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g t ra nsit f or all st u d y dr u g recei ve d, a n d a n y discre pa ncies are re p orte d a n d 
res ol ve d bef ore use of t he st u d y i nter ve nti o n.
O nl y  partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y i nter ve nti o n, a n d o nl y a ut h orize d 
site staff ma y s u p pl y or a d mi nister st u d y i nter ve nti o n. 
T he I n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u dy i nter ve nti o n acc o u nta bilit y , rec o nciliati o n, a n d rec or d mai nte na nce (ie, 
recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds).
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y  i nter ve nti o ns are 
pr o vi de d i n t he St u d y  Refere nce Ma n ual or P har mac y Ma n ual. 
7. 3. R a n d o miz ati o n a n d Bli n di n g
T his is a n o pe n -la bel st u d y. Ra n d o mizati o n a n d bli n di n g are n ot a p plica ble.
As t his is a n o pe n -la bel, l o n g-ter m e xte nsi o n st u d y, t he s p o ns or ma y c o n d uct u n bli n de d 
re vie ws a n d/ or s u m maries of t he data d uri n g t he c o urse of t he st u d y f or t he p ur p ose of safety 
assess me nt, s u p p orti n g cli nical de vel o p me nt , a n d/ or s u p p orti n g re g ulat ory re vie w.
7. 4. St u d y Tre at me nt C o m pli a nce
T he first d ose of t he st u d y dr u g will be a d mi nistere d b y cli nical staff at t he st u d y  site. Details 
re gar di n g d osi n g, i ncl u di n g t he d ose a d mi nistere d a n d t he date a n d ti me of d osi n g, will be 
rec or de d. T he partici pa nt / pare nt/le gal g uar dia n/le gall y a ut h orize d re prese ntati ve will be 
re q uire d t o bri n g t he dis pe nse d osi vel ot or b ottle(s) t o t he st u d y  ce nter at eac h visit a n d t he 
I n vesti gat or or desi g nee is t o c o nfir m t he n u m ber of ta blets or a m o u nt of a ge-a p pr o priate 
f or m ulati onta ke n a n d re mai ni n g bef ore t he ne xt dis pe nsati o n. 
T he partici pa nt / pare nt/le gal g uar dia n/le gally a ut h orize d re prese ntati ve will als o be s u p plie d 
wit h a diar y  o n w hic h t o rec or d t he date a n d ti me eac h d ose of st u d y dr u g is ta ke n. Reas o ns 
f or misse d d oses s h o ul d be rec or de d. T he diar y will be dis pe nse d at o nsite visits a n d t he 
partici pa nt will be re q uire d t o bri n g t he diar y  t o eac h visit at t he st u d y ce nter w here t he 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 4 3
I n vesti gat or or desi g nee will re vie w t he rec or ds a n d e nter t he details i nt o t he electr o nic case 
re p ort f or m (e C R F). 
If a partici pa nt misses a d ose, t he partici pa nts s h o ul d res u me n or mal d osi n g t he ne xt da y (ie, 
t he d ose o n t he da y  after a misse d d ose s h o ul d n ot be i ncrease d or decrease d).
7. 5. D ose M o dific ati o n
G ui deli nes f or d ose i nterr u pti o n or dr u g disc o nti n uati o n are pr o vi de d i n Ta ble 8. Decisi o ns 
re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de by t he I n vesti gat or i n c o ns ultati o n 
wit h t he st u d y  me dical m o nit or as nee de d base d o n t he cli nical e val uati o n of t he partici pa nt.
T he Me dical M o nit or s h o ul d be n otifie d of all d ose m o dificati o ns wit hi n 7 2 h o urs.
All i nsta nces of st u d y  dr u g m o dificati o n ( d ose 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 n/e ve nt lea di n g t o t he d ose m o dificati o n has 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. 
T a ble 8.
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 I nterr u pti o n
E ve nt
Rec o m me n de d Acti o n
Gr a de 3 or hi g her A E t hat is ( 1) st u d y -dr u g 
relate d i n t he o pi ni o n of t he I n vesti gat or 
A N D ( 2) t hat precl u des c o nti n ue d d osi n g at 
t he c urre nt d ose le vel d ue t o safet y c o ncer n 
or lac k of t olera bilit y (i n t he I n vesti g at or’s 
j u d g me nt) 
St u d y Dr u g : Ma y be hel d f or 1 0 da ys. 
If, i n t he o pi ni o n of t he I n vesti gat or, a Gra de 3 A E 
has res ol ve d t o ≤ Gra de 1, partici pa nt ma y res u me 
dail y d osi n g of st u d y dr u g at a l o wer d ose ( n ot 
l o wer t ha n 1 0 0 m g) or c o nti n ue wit h t he ori gi nal 
d ose or a l o wer dail y d ose.
Ma xi m u m d ose h ol d is 2 8 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 ns ulte d. 
A L T ≥3 X U L N if A L T W N L at b aseli ne 
O R > 3 X U L N A N D a ≥2 -f ol d i ncre ase 
a b o ve b aseli ne v al ues if ele v ate d A L T 
v al ues at b aseli ne
I n t he a bse nce of a d diti o nal si g ns of 
c o m pr o mise d li ver f u ncti o n s uc h as ele vate d 
P T, a P T T, I N R, ele vate d c o nj u gate d 
bilir u bi n, ja u n dice, or he patic pai n.
St u d y dr u g : C o nfir m b y re peat testi n g wit hi n 4 8 
t o 7 2 h o urs if p ossi ble a n d t he n re peat li ver pa nel 
at least wee kl y u ntil A L T le vels i m pr o ve.  
A d diti o n al Acti o ns : If A L T le vels c o nti n ue t o 
i ncrease h ol d t he st u d y dr u g f or 1 0 da ys a n d n otif y 
t he Me dical M o nit or.
U p o n res ol uti o n of t he ele vate d A L T, t he 
partici pa nt ma y res u me dail y d osi n g of st u d y dr u g 
at t he ori gi nal d ose or a l o wer d ose.
A L T ≥5 X a n d < 8 X U L N (c o nfir me d b y 
re pe at testi n g wit hi n 4 8 t o 7 2 h o urs) 
I n t he a bse nce of a d diti o nal si g ns of 
c o m pr o mise d li ver f u ncti o n s uc h as ele vate d 
P T, a P T T, I N R, ele vate d c o nj u gate d 
bilir u bi n, ja u n dice, or he patic pai n. 
St u d y dr u g : H ol d t he st u d y dr u g f or 1 0 da ys.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 4 4
T a ble 8 .
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
A d diti o n al acti o ns : Re peat li ver pa nel test wit hi n 
4 8 t o 7 2 h o urs if p ossi ble a n d t he n at least wee kl y 
u ntil res ol uti o n t o < 5 X U L N, wit h c o nti n ue d 
m o nit ori n g t hereafter. If A L T c o nti n ues t o i ncrease 
wit hi n 1 wee k after t he me dicati o n is restarte d, 
treat me nt s h o ul d be i nterr u pte d, a n d t he Me dical 
M o nit or s h o ul d be n otifie d.
U p o n res ol uti o n of t he ele vate d A L T, t h e 
partici pa nt ma y res u me dail y d osi n g of st u d y dr u g 
at t he ori gi nal d ose or a l o wer d ose.
Dr u g Disc o nti n u ati o n
E ve nt
Rec o m me n de d Acti o n
Gr a de 3 or Hi g her St u d y Dr u g -Rel ate d 
S A E
St u d y Dr u g : Disc o nti n ue st u d y dr u g. If t he 
I nvesti gat or c o nsi ders t hat t he partici pa nt w o ul d 
be nefit fr o m c o nti n ui n g treat me nt, t he Me dical 
M o nit or s h o ul d be c o ntacte d f or disc ussi o n.
C o nsi der tre at me nt disc o nti n u ati o n if: 

A L T > 8 X × U L N 

A L T > 3 X U L N wi t h a d diti o n al 
si g ns of c o m pr o mise d li ver 
f uncti o n s uc h as ele vate d P T, a P T T, 
I N R, ele vate d c o nj u gate d bilir u bi n, 
ja u n dice, or he patic pai n, a p peara nce 
of fati g ue, na usea, v o miti n g, ri g ht 
u p per q ua dra nt pai n or te n der ness, 
fe ver, ras h, a n d/ or e osi n o p hilia 
St u d y dr u g : H ol d d ose. 
A d diti o n al acti o ns : S p o ns or rec o m me n ds 
c o nfir mati o n b y re peat testi n g wit hi n 4 8 t o 7 2 
h o urs a n d assess p ote ntial re versi ble ca uses of li ver 
f u ncti o n test a b n or malities. C o ntact t he Me dical 
M o nit or f or disc ussi o n of st u d y dr u g 
dis c o nti n uati o n.
A b bre viati o ns: A E, a d verse e ve nt; A L T, Ala ni ne a mi n otra nsferase; a P T T, acti vate d partial t hr o m b o plasti n 
ti me; I N R, i nter nati o nal n or malize d rati o; P T, pr ot hr o m bi n ti me; S A E, seri o us a d verse e ve nt; U L N, u p per 
li mit of n or mal; W N L, wit hi n n or m al li mits.
7. 5. 1. I n di vi d u al Le vel St o p pi n g R ules f or P artici p a nts E nr olli n g i n C 5 3 5 1 0 0 5 fr o m t he 
2 0 0 m g Tre at me nt Ar m fr o m P art A of C 5 3 5 1 0 0 4
C o nti n ue d d osi n g of t he res pecti ve i n di vi d ual at t he 2 0 0 m g d ose le vel ma y  be pa use d f or 
re vie w if a ny of t he f oll o wi n g occ urs:

If a partici pa nt reac hes t he U L N f or H b or he mat ocrit ( base d o n l ocal la b orat or y 
refere nce ra n ges f or ge n der) a n d a Gra de 2 or hi g her se verit y T E A E t hat is relate d t o 
osi vel ot or .

If a partici pa nt has si g ns of i m paire d tiss ue offl oa di n g of o xy ge n ( ne w or i ncrease d 
fr o m baseli ne hea dac he, dizzi ness, fati g ue). 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 4 5
7. 6. Tre at me nt of O ver d ose
F or t his st u d y , a n y d ose of osi vel ot or greater t ha n t he pr ot oc ol defi ne d d ose of st u d y  
i nter ve nti o n wit hi n a 2 4- h o ur ti me peri o d will be c o nsi dere d a n o ver d ose. Base d o n t he 
mec ha nis m of acti o n of osi vel ot or , a n e xtre me o ver d ose mi g ht decrease o xy ge n deli ver y t o 
tiss ues. Tra nsf usi o n, e xc ha n ge tra nsf usi o n, a n d/ or h yper baric o x y ge n t hera p y  ma y be 
c o nsi dere d i n t he e ve nt of a me dical e mer ge nc y  d ue t o a s us pecte d osi vel ot o r o ver d ose.
T he I n vesti gat or will disc uss t he ris ks a n d c o ncer ns of i n vesti gati o nal a ge nt e x p os ure wit h 
t he partici pa nt/ pare nt/le gal g uar dia n/le gally a ut h orize d re prese ntati ve .
Partici pa nt / pare nt/le gal g uar dia n/le gally a ut h orize d re prese ntati ve are t o be i nstr ucte d t o 
c o ntact t heir st u d y site i m me diatel y if a n o ver d ose of st u d y dr u g is s us pecte d. 
If a partici pa nt ta kes m ore t ha n t he pr ot oc ol-defi ne d d ose of st u d y  dr u g i n a da y a n d
e x perie nces a dr u g relate d A E/ S A E, t his will be re p orte d as a n o ver d ose ( A Es/ S A Es m ust be 
rec or de d o n t he A E e C R F a n d S A Es re p orte d t o Pfizer Safety) 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/ S A Es, t his will o nl y be re p orte d as a 
pr ot oc ol de viati o n. A n o ver d ose wit h A Es m ust be f o ll o we d u ntil a n y a d verse effects are 
res ol ve d or sta bilize d, or u ntil reas o na ble atte m pts t o deter mi ne res ol uti o n of t he e ve nt are 
e x ha uste d.
I n t he e ve nt of a n o ver d ose, t he I n vesti gat or/treati n g p hys icia n s h o ul d:
1.
C o ntact t he st u d y  me dical m o nit or wit hi n 2 4 h o urs.
2.
Cl osel y  m o nit or t he partici pa nt f or a ny A E/ S A E 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 plai ne d, or t he partici pa nt is l ost t o f oll o w - u p.
3.
D oc u me nt t he q ua ntit y o f 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 C R F.
4.
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 .
5.
O btai n a bl o o d sa m ple f or P K a nal ys is wit hi n 1 da y fr o m t he date of t he last d ose of 
st u d y dr u g i nter ve nti o n if re q ueste d by t he me dical m o nit or ( deter mi ne d o n a case -b y -
case basis).
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y  t he I n vesti gat or i n 
c o ns ultati o n wit h t he st u d y  me dical m o nit or as nee de d base d o n t he cli nical e val uati o n of t he
partici pa nt. 
7. 7. C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures
St u d y  partici pa nts will be all o we d t o ta ke ot her me dicati o ns as nee de d e xce pt f or t h ose 
descri be d i n Secti o n 1 1. 6 . Vacci nes are all o we d d uri n g t he st u dy. All c o nc o mita nt 
me dicati o ns will be d oc u me nte d. 
I n t he i nterests of partici pa nt safety a n d acce pta ble sta n dar ds of me dical care, t he I n vesti gat or 
will be per mitte d t o prescri be treat me nt(s) at t heir discreti o n. Treat me nt wit h sta ble d oses of 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 4 6
H U, L - gl uta mi ne are all o we d. H o we ver, i nitiati o n of ne w S O C a ge nts (e g, criza nliz u ma b a n d 
v o xel ot or) d uri n g treat me nt is str o n gl y disc o ura ge d. All ot her sta n dar d t hera pe utic 
i nter ve nti o ns f or S C D a n d its c o m plicati o ns (e g, hy d rati o n, a nal gesia, ac ute tra nsf usi o ns) are 
all o we d u n der t his pr ot oc ol.
All c o nc o mita nt treat me nts a n d/ or pr oce d ures m ust be rec or de d i n t he partici pa nts’ e C R F 
( pr oce d ure, me dicati o n, d ose, treat me nt d urati o n a n d i n dicati o n).
7. 7. 1. He alt hc are Res o urce Utiliz at i o n f or P artici p a nts E nr olli n g fr o m C 5 3 5 1 0 0 4 P art B
Healt hcare res o urce utilizati o n data (e g, h os pitalizati o ns, n o n -pr ot oc ol s pecifie d me dical 
visits, etc.) will be c ollecte d f or all ra n d o mize d partici pa nts. S pecificall y, healt hcare res o urce 
utilizati o n is e val uate d base d o n t he n u m ber of me dical care e nc o u nters s uc h as h os pital 
a d missi o ns a n d t heir d urati o n, o ut patie nt visits, dia g n ostic tests a n d pr oce d ures, c o nc o mita nt 
me dicati o ns, a n d reas o ns f or t he e nc o u nters. T his data will be self -re p orte d b y partici pa nts at 
t he fre q ue nc y descri be d i n t he sc he d ule of assess me nts. Partici pa nts s h o ul d recall a n y 
h os pitalizati o ns or n o n -pr ot oc ol re q uire d healt hcare visits (ie, pa rtici pa nt see ki n g me dical 
atte nti o n f or a n y reas o n) t hat occ urre d bet wee n visits. T his data ma y  als o be o btai ne d 
t hr o u g h electr o nic s o urces s uc h as electr o nic me dical rec or ds, w here a vaila ble. 
8. DI S C O N TI N U A TI O N O F S T U D Y T R E A T M E N T A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L
Disc o nti n uati o n of s pecific sites or of t he st u d y  are detaile d i n Secti o n 1 1. 1. 8 .
8. 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 A Es i n t his st u d y  or 
ot her st u dies wit h osi vel ot or i n dicati n g a p ote ntial healt h ris k t o partici pa nts. 
I n t he 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 nstit uti o nal Re vie w B oar ds/I n de pe n de nt Et hics 
C o m mittees (I R Bs/I E Cs) a n d will s pecif y  t he reas o ns(s) f or t he ter mi nati o n.
8. 2. Disc o nti n u ati o n of St u d y Tre at me nt
Partici pa nts will be disc o nti n ue d fr o m st u d y  dr u g f or a ny 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 partici pa nt t hat d oes n ot ta ke t he f ull l oa di n g d ose assi g ne d ma y  be disc o nti n ue d 
f oll o wi n g a disc ussi o n wit h t he Me dical M o nit or. 

At t he discreti o n of t he I n vesti gat or.

Partici pa nt is n o nc o m plia nt. 

Pre g na nc y .

Wit h dra wal of c o nse nt ( partici pa nts are free t o disc o nti n ue treat me nt or wit h dra w 
fr o m t he st u d y at a n y ti me a n d f or a ny reas o n. T he I n vesti gat or m ust wit h dra w 
partici pa nts fr o m t he st u d y  w h o re q uest t o be wit h dra w n). A d diti o nall y, pare nt/le gal 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 4 7
g uar dia n/le gall y a ut h orize d re prese ntati ve ca n wit h dra w c o nse nt at a n y ti me a n d f or 
a n y reas o n.
Partici pa nts s h o ul d ret ur n t o t he st u d y  site f or a n E O S visit a p pr o xi matel y 1 2 wee ks after t he 
last d ose of st u d y dr u g per t he Sc he d ule of Assess me nts ( S o A) a n d Pr oce d ures ( Secti o n 2. 1 ).
8. 2. 1. P ote nti al C ases of Ac ute Ki d ne y I nj ur y
Partici pa nts e x p ose d t o I M P de m o nstrati n g tra nsie nt or s ustai ne d i ncrease i n Screat ( wit h 
decrease i n Screat- base d e G F R or e Cr Cl) re q uire e x pe dite d e val uati o n t o differe ntiate A KI 
fr o m DI CI. DI CI is defi ne d as tra ns p orter- me diate d effect relate d t o altere d re nal t u b ular 
creati ni ne ha n dli n g wit h o ut hist ol o gical i nj ur y . 
A KI m ay be d ue t o o ne or m ore ty pes of i nj ury, i ncl u di n g DI KI. Differe nti ati o n of DI KI fr o m 
ot her c a uses of A KI a n d fr o m DI CI m ay re q uire cli nic al, r a di o gr a p hic, hist o p at h ol o gic, a n d 
l a b or at ory assess me nts, as well as ne p hr ol o gy c o ns ult ati o n.
F oll o w -U p Asses s me nts
T he partici pa nt s h o ul d ret ur n t o t he site f or e val uati o n as s o o n as p ossi ble, prefera bl y wit hi n 
4 8 h o urs of a ware ness of t he a b n or mal res ults. 
E val uati o n s h o ul d i ncl u de p h y sical e xa mi nati o n, la b orat or y tests, detaile d me dical a n d 
s ur gical hist or y, re vie w of all me dicati o ns (i ncl u di n g recreati o nal dr u gs a n d s u p ple me nts 
[ her bal]), fa mil y hist or y, se x ual hist or y, tra vel hist or y, bl o o d tra nsf usi o n, a n d p ote ntial 
occ u pati o nal e x p os ure t o c he micals.
La b orat or y  assess me nts s h o ul d i ncl u de si m ulta ne o us seru m c y stati n C ( Sc ys) a n d ser u m 
creati ni ne ( Screat) tests. Esti mates of e G F R, e Cr Cl a n d Screat -base d e G F R a n d c o m bi ne d 
Screat -S c y s-base d e G F R s h o ul d als o be deri ve d usi n g t he a p pr o priate e q uati o n descri be d i n 
Secti o n 1 1. 5 .
Assess me nts of uri ne al b u mi n -t o-creati ni ne rati o or uri ne v ol u me ma y  als o be perf or me d as 
a p pr o priate.
If a p pr o priate, ne p hr ol o g y c o ns ultati o n ma y be rec o m me n de d t o facilitate differe ntiati o n of 
renal pare nc h y m al disease, pre-re nal az ote mia, a n d p ost-re nal o bstr ucti o n. 
Differe nti ati n g Ac ute Ki d ne y I nj ur y fr o m DI CI 
A c o nfir me d Screat i ncrease is defi ne d as:
(i) ≥0. 3 m g/ d L ( ≥2 6. 5 µ m ol/ L) wit hi n 4 8 h o urs O R 
(ii) c o nfir me d Screat i ncrease ≥1. 5 ti mes baseli ne ( k n o w n or s us pecte d t o ha ve occ urre d 
wit hi n t he pri or 7 da y s). 
Base d o n t he assess me nts perf or me d, s us pecte d A KI (i ncl u di n g DI KI) ma y be differe ntiate d 
fr o m DI CI as f oll o ws.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 4 8
Pe di atric P artici p a nts
A KI (i ncl u di n g DI KI) 
A n y o ne of t he bel o w
DI CI
Sc ys & Screat
Si m ulta ne o us, c o nfir me d Sc ys i ncrease a n d 
c o nfir me d Screat i ncrease 
C o nfir me d Screat i ncrease wit h o ut 
c o nfir me d i ncrease i n refle x Sc ys
Al b u mi n uria
C o nfir me d al b u mi n uria i ncrease (see Secti o n 
1 1. 5 f or Gra des A 1 t o A 3 q ua ntitati o n) 
Uri ne v ol u me
Uri ne v ol u me < 0. 5 m L/ k g/ h f or 6 c o nsec uti ve 
h o urs
A d ult P artici p a nts
A KI (i ncl u di n g DI KI)
A n y o ne of t he bel o w
DI CI
Sc ys & Screat
Si m ulta ne o us, c o nfir me d ser u m c ystati n C 
( Sc ys) i ncrease a n d c o nfir me d Screat i ncrease 
C o nfir me d Screat i ncrease wit h o ut 
c o nfir me d i ncrease i n refle x Sc ys 
A N D 
C o nfir me d Screat -base d e G F R 
decrease w it h o ut c o nfir me d c o m bi ne d 
Screat -Sc ys -base d e G F R decreas e.
e G F R
Decrease i n Screat -base d e G F R a n d c o m bi ne d 
Screat -Sc ys -base d e G F R ( w he n a vaila ble)
Al b u mi n uria or 
pr otei n uria
C o nfir me d al b u mi n uria i ncrease (see Secti o n 
1 1. 5 f or Gra des A 1 t o A 3 q ua ntitati o n)
Uri ne v ol u me
Uri ne v ol u me < 0. 5 m L/ k g/ h f or 6 c o nsec uti ve 
h o urs
Re gar dless of t he prese nce or a bse nce of i ncrease i n Screat, DI KI a n d ot her ca uses of A KI
ma y  be s us pecte d if eit her (i) ne w-o nset or w orse ni n g al b u mi n uria or pr otei n uria are detecte d 
or (ii) uri ne v ol u me (if meas ure d) is < 0. 5 m L / k g/ h f or 6 c o nsec uti ve h o urs.
All c o nfir me d cases of cli nicall y  rele va nt decrease i n ki d ne y f u ncti o n s h o ul d be c o nsi dere d 
p ote ntial cases of DI KI if n o ot her reas o n f or t he ki d ne y  f u ncti o n a b n or malities has bee n 
f o u n d.
See A p pe n di x 2: L i ver Safety:  S u g geste d Acti o ns a n d F oll o w-U p Assess me nts f or 
i nstr ucti o ns f or la b orat or y testi n g t o m o nit or ki d ne y f u ncti o n a n d re p orti n g la b orat or y test 
a b n or malities.
8. 2. 2. Disc o nti n u ati o n d ue t o A d verse E ve nts
I n a d diti o n t o t he d ose m o dificati o n a n d st u d y st o p pi n g r ules pre vi o usl y o utli ne d i n 
Secti o n 7. 5 a n d Secti o n 8. 1 , res pecti vely, a n y partici pa nt w h o e x perie nces a n A E ma y  be 
wit h dra w n at a n y ti me fr o m t he st u d y  at t he discreti o n of t he I n vesti gat or. Partici pa nts 
wit h dra w n fr o m t he st u d y d ue t o a n A E, w het her seri o us or n o nseri o us, s h o ul d be f oll o we d 
b y  t he I n vesti gat or u ntil t he cli nical o utc ome of t he A E is deter mi ne d (ie, t he e ve nt has 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 4 9
res ol ve d or has sta bilize d). T he A E(s) s h o ul d be n ote d o n t he a p pr o priate e C R Fs. T he 
S p o ns or a n d/ or c o ntract researc h or ga nizati o n ( C R O) Me dical M o nit or m ust be n otifie d of 
t he st u d y partici pa nt disc o nti n uati o n. If t he A E relates t o o ver d ose of st u d y treat me nt, see 
Secti o n 7. 6 f or details of s pecific acti o ns t o be ta ke n.
8. 3. Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y

A partici pa nt ma y  wit h dra w fr o m t he st u d y at a ny ti me at t heir o w n re q uest or ma y be 
wit h dra w n at a n y ti m e at t he discreti o n of t he I n vesti gat or f or safet y , be ha vi oral, or 
c o m plia nce reas o ns.

At t he ti me of disc o nti n ui n g fr o m t he st u d y, if p ossi ble, a n earl y disc o nti n uati o n visit 
s h o ul d be c o n d ucte d, as s h o w n i n t he Sc he d ule of Assess me nts ( S o A) Secti o n 2. 1 . 
T he S o A details t he data t o be c ollecte d at t he ti me of st u d y  disc o nti n uati o n a n d 
f oll o w-u p a n d f or a n y f urt her e val uati o ns t hat nee d t o be c o m plete d.

T he partici pa n t will be per ma ne ntly disc o nti n ue d fr o m t he st u d y treat me nt a n d t he 
st u d y at t hat ti me.

If t he partici pa nt / pare nt/le gal g uar dia n/le gall y a ut h orize d re prese ntati ve wit h dra ws 
c o nse nt f or discl os ure of f ut ure i nf or mati o n, t he S p o ns or ma y  retai n a n d c o nti n ue to 
use a n y data c ollecte d bef ore s uc h a wit h dra wal of c o nse nt.

If a partici pa nt wit h dra ws fr o m t he st u d y, t he y ma y re q uest destr ucti o n of a n y 
sa m ples ta ke n a n d n ot teste d, a n d t he I n vesti gat or m ust d oc u me nt t his i n t he site 
st u d y rec or ds.
8. 4. L ost t o F oll o w u p
A partici pa nt will be c o nsi dere d l ost t o f oll o w- u p if t he y  re peate dly fail t o ret ur n f or 
sc he d ule d visits a n d are u na ble t o be c o ntacte d by t he st u d y  site.
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d 
st u d y visit:

T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as 
s o o n as p ossi ble, c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he 
assi g ne d visit sc he d ule a n d ascertai n w het her t he partici pa nt wis hes t o a n d/ or s h o ul d 
c o nti n ue i n t he st u d y.

Bef ore a partici pa nt is dee me d l ost t o f oll o w- u p, t he I n vesti gat or or desi g nee m ust 
ma ke e ver y  eff ort t o re gai n c o ntact wit h t he partici pa nt ( w here p ossi ble, tele p h o ne 
calls, a n d if necessar y, a certifie d letter t o t he partici pa nt’s last k n o w n maili n g 
a d dress or l ocal e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d 
i n t he partici pa nt’s me dical rec or d.

S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, t he y  will be disc o nti n ue d fr o m t he 
st u d y. 

Site pers o n nel wil l atte m pt t o c ollect t he vital stat us of t he partici pa nt wit hi n le gal a n d 
et hical b o u n daries f or all partici pa nts. P u blic s o urces ma y  be searc he d f or vital stat us 
i nf or mati o n. If vital stat us is deter mi ne d as decease d, t his will be d oc u me nte d, a n d 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 5 0
t he partici pa nt will n ot be c o nsi dere d l ost t o f oll o w-u p. S p o ns or pers o n nel will n ot be 
i n v ol ve d i n a n y atte m pts t o c ollect vital stat us i nf or mati o n.
9. S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S

St u d y  pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A. Pr ot oc ol wai vers or 
e xe m pti o ns are n ot all o we d.

I m me diate safet y c o ncer ns s h o ul d be disc usse d wit h t he Me dical M o nit or 
i m me diatel y u p o n occ urre nce or a ware ness t o deter mi ne if t he partici pa nt s h o ul d 
c o nti n ue or disc o nti n ue st u d y  i nter ve nti o n.

A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is 
esse ntial a n d re q uire d f or st u d y c o n d uct.

Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne cli nical ma na ge me nt (e g, 
bl o o d c o u nt) a n d o btai ne d bef ore si g ni n g of t he i nf or me d c o nse nt f or m (I C F) ma y be 
utilize d f or scree ni n g or baseli ne p ur p oses pr o vi de d t he pr oce d ures met t he pr ot oc ol -
s pecifie d criteria a n d were perf or me d wit hi n t he ti mefra me defi ne d i n t he S o A.

C ollecti o n, pr ocessi n g, a n d s hi p pi n g details f or w h ole bl o o d, plas ma, ser u m, a n d 
ot her s a m ples will be o utli ne d i n a se parate la b orat or y  ma n ual. 

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 ny 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 n y gi ve n 4-wee k peri o d. S pecific bl o o d s peci me ns (e g, e x pl orat or y  meas ures) 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 nic al care, blee di n g e ve nts, or if ot her wise 
dee me d a p pr o priate. See Ta ble 1 0 f or t he bl o o d s peci me n assess me nt pri orit y list.
9. 1. De m o gr a p hic/ Me dic al Hist or y
T he I n vesti gat or or desi g nee will c ollect a c o m plete me dical hist or y  at t he Baseli ne Visit. 
De m o gra p hics (se x, date of birt h, race, et h nicit y, hei g ht, a n d wei g ht), S C D hist or y, a n d 
c urre nt me dicati o ns will be rec or de d. 
9. 2. Effic ac y Assess me nts
Efficac y  will be assesse d t hr o u g h t he f oll o wi n g e n d p oi nts: a n n ualize d rate of V O C, c ha n ge 
fr o m baseli ne i n he mat ol o gical la b orat or y para meters (e g, he m o gl o bi n, retic ul oc ytes, lactate 
de h y dr o ge nase, a n d u nc o nj u gate d bilir u bi n), effects o n i nfla m mati o n, E P O le vels, H R Q O L 
assess me nts, a n d e x pl orat or y  bi o mar kers ( mar kers of he m ol ysis i ncl u di n g ha pt o gl o bi n, 
he m o pe xi n, a n d s ol u ble C 3) . Pla n ne d ti me p oi nts f or all efficac y  assess me nts are pr o vi de d i n 
t he S o A ( Secti o n 2. 1 ).
A V O C is defi ne d as a n ac ute e pis o de of pai n t hat:

Has n o me dicall y deter mi ne d ca use ot her t ha n a vas o -occl usi ve e ve nt, a n d

Res ults i n a visit t o a me dical facilit y ( h os pitalizati o n, e mer ge nc y de part me nt, ur ge nt 
care ce nter, o ut patie nt cli nic, or i nf usi o n ce nter), a n d
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 5 1

Re q uires pare nteral narc otic a ge nts, pare nteral n o nster oi dal a nti -i nfla m mat or y dr u gs 
( N S AI Ds), or a n i ncrease i n treat me nt wit h oral narc otics.
Partici pa nt / pare nt/le gal g uar dia n/le gally a ut h oriz e d re prese ntati ve will be i nstr ucte d t o visit 
t he cli nical site f or V O Cs re q uiri n g a visit t o a healt hcare facilit y. H o we ver, i n cases w here 
visits t o ot her healt hcare facilities are re q uire d f or treat me nt of t heir V O Cs (e g, e mer ge nc y 
r o o m, h os pital, ur ge nt care ce nter, o ut patie nt cli nic or i nf usi o n ce nter), 
partici pa nt / pare nt/le gal g uar dia n/le gally a ut h orize d re prese ntati ve will be i nstr ucte d t o n otif y  
t he cli nical site wit hi n 4 8 h o urs w he n o ne of t hese visits occ urs.
V O Cs are cate g orize d as:

U nc o m plicate d V O C: a V O C t hat is N O T classifie d as a n A C S, he patic se q uestrati o n, 
s ple nic se q uestrati o n, pria pis m, or dactyl itis.

C o m plicate d V O Cs:

Ac ute C hest S y n dr o me, defi ne d as a fi n di n g of a ne w p ul m o nar y i nfiltrate, b ut 
e xcl u di n g atelectasis (as i n dicate d b y c hes t X-ra y). M ust als o prese nt wit h at least 
o ne of t he f oll o wi n g si g ns or s y m pt o ms: partici pa nt -re p orte d c hest pai n, b o d y 
te m perat ure of m ore t ha n 3 8. 5° C, tac h yp nea, w heezi n g, or c o u g h.

He patic se q uestrati o n, defi ne d as fi n di n gs of ri g ht u p per q ua dra nt pai n, a n 
e nlar ge d li ver, a n d a n ac ute decrease i n H b c o nce ntrati o n.

S ple nic se q uestrati o n, defi ne d as fi n di n gs of left u p per q ua dra nt pai n, a n e nlar ge d 
s plee n, a n d a n ac ute decrease i n H b c o nce ntrati o n.

Pria pis m, defi ne d as ha vi n g a s ustai ne d pe nile erecti o n re q uiri n g a visit t o a 
me dical facilit y .

Dact yl itis, defi ne d as t he gl o bal s welli n g of a fi n ger or a t oe gi vi n g it a cli nical 
sa usa ge-s ha pe prese ntati o n. 
I nstr ucti o ns f or rec or di n g V O C e ve nts a n d s o urce d oc u me nt c ollecti o n f or V O C e ve nt
a dj u dicati o n are pr ovi de d i n Secti o n 9. 4. 1 2. 1 .
F or partici pa nts wit h a ga p i n d osi n g > 4 2 c o nsec uti ve da y s fr o m c o m pleti n g t he ori gi nati n g 
st u d y, o utc o me meas ures will be e val uate d at t he e n d of t he l oa di n g d ose peri o d ( Wee k 1), 
t he n e ver y 2 wee ks f or t he first 2 m o nt hs ( u p t o Wee k 8), t he n e ver y 4 wee ks f or 4 m o nt hs 
( u p t o Wee k 2 4), t he n e ver y 1 2 wee ks t hereafter. 
F or partici pa nts fr o m Part A of C 5 3 5 1 0 0 4 or a n y ot her o pe n la bel osi vel ot or st u d y, o utc o me 
meas ures will be e val uate d e ver y  1 2 wee ks. 
F or partici pa nts fr o m Part B of C 5 3 5 1 0 0 4, or a n y ot her r a n d o mize d, bli n de d, place b o 
c o ntr olle d osi vel ot or st u d y, o utc o me meas ures will be e val uate d e ver y 8 wee ks f or t he first 
2 4 wee ks of treat me nt i n t he o pe n la bel st u d y, a n d e ver y 1 2 wee ks t hereafter. 
F or pe diatric partici pa nts fr o m Part C of C 5 3 5 1 0 0 4, o utc o me meas ures will be e val uate d at 
Wee k 2 a n d Wee k 4, t he n e ver y  4 wee ks f or t he first 2 4 wee ks of treat me nt, a n d t he n e ver y 
1 2 wee ks t hereafter.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 5 2
9. 3. S afet y Assess me nts
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n t he S o A ( Secti o n 2. 1 ).
9. 3. 1. P h ysic al E x a mi n ati o n
A f ull p h y sical e xa mi nati o n will be c o n d ucte d at t he Baseli ne Visit. All s u bse q ue nt p h ysical 
e xa mi nati o ns will be brief p h y sical e xa mi nati o ns. F ull p h ysical e xa mi nati o n will i ncl u de 
e xa mi nati o n of t he f oll o wi n g: ge neral a p peara nce, hea d, ears, e y es, n ose, t hr oat, nec k, s ki n, 
car di o vasc ular s ys te m, res pirat or y sys te m, gastr oi ntesti nal s yste m, m usc ul os keletal s yste m, 
l ym p h n o des, a n d ner v o us s y ste m. Brief p hys ical e xa mi nati o ns will i ncl u de ge neral 
a p peara nce; e yes, s ki n, car di o vasc ular a n d res pirat or y  sys te m e xa mi nati o ns; a b d o mi nal 
e xa mi nati o n, a n d as nee de d, a s y m pt o m -directe d e xa mi nati o n.
A n a b n or mal p h ys ical e xa mi nati o n fi n di n g d uri n g t he o n-st u d y peri o d (ie, f oll o wi n g d ose 
a d mi nistrati o n) t hat is c o nsi dere d cli nicall y si g nifica nt a n d ( 1) re q uires t he partici pa nt t o be 
disc o nti n ue d fr o m t he st u d y , or ( 2) re q uires t he partici pa nt t o recei ve treat me nt will be 
rec or de d as a n A E.
9. 3. 2. Vit al Si g ns
Vital si g ns assess me nts will i ncl u de res pirat or y  rate ( breat hs per mi n ute), s yst olic a n d 
diast olic bl o o d press ure ( m m H g), heart rate ( beats per mi n ute), a n d b o d y te m perat ure, w hic h 
will be meas ure d after a partici pa nt has reste d f or at least 5 mi n utes i n t he s u pi ne or 
rec u mbe nt p ositi o n, as a ge a p pr o priate a n d feasi ble, a n d will be c ollecte d as per Secti o n 2. 1 .
A n y  cli nicall y si g nifica nt a b n or mal vital si g n assess me nt re q uires at least o ne re peat 
meas ure me nt.
Vital si g ns a b n or malities t hat are ( 1) c o nsi dere d cli nicall y  si g nifica nt i nitiall y a n d o n 
c o nfir mati o n, ( 2) re q uire a partici pa nt t o be disc o nti n ue d fr o m t he st u d y, ( 3) re q uire a 
partici pa nt t o recei ve treat me nt, or ( 4) re q uire a c ha n ge or disc o nti n uati o n fr o m t he st u d y  
dr u g (if a p plica ble) will be rec or de d as A Es.
9. 3. 3. Cli nic al L a b or at or y Tests
Bl o o d a n d uri ne f or cli nical la b orat or y  tests (Ta ble 9 ) will be c ollecte d as o utli ne d i n t he S o A 
( Secti o n 2. 1 ). A certifie d ce ntral la b orat or y will be utilize d t o pr ocess a n d pr o vi de res ults f or 
t he cli nical la b orat or y tests. T he Baseli ne la b orat or y  test res ults f or cli nical assess me nt f or a 
partic ular test will be defi ne d as t he last meas ure me nt pri or t o t he first d ose of st u d y  dr u g.
Pri or t o i nitiati o n of treat me nt, if a partici pa nt has a n o ut -of- ra n ge val ue f or a cli nical 
la b orat or y para meter t hat t he In vesti gat or belie ves is n ot cli nicall y  si g nifica nt or t hat t he 
I n vesti gat or d oes n ot belie ve is c orrect (e g, la b orat or y or s peci me n pr ocessi n g err or), b ut t he 
I n vesti gat or wa nts t o c o nfir m wit h a re peat la b orat or y test, a si n gle re peat is all o we d t o 
c o nfir m t he i nitial res ult.
All o ut of -ra n ge val ues will be assesse d by t he I n vesti gat or as cli nicall y si g nifica nt or n ot 
cli nicall y si g nifica nt. F or a n y la b orat or y test val ue o utsi de t he refere nce ra n ge t hat t he 
I n vesti gat or co nsi ders cli nicall y  si g nifica nt d uri n g t he o n-st u d y peri o d (ie, f oll o wi n g d ose 
a d mi nistrati o n), t he I n vesti gat or will re peat t he test t o verif y  t he o ut- of-ra n ge val ue a n d 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 5 3
cli nical si g nifica nce. Cli nicall y si g nifica nt la b orat or y a b n or malities will be rec or de d i n t he 
A E e C R F ( see Secti o n 9. 4. 7. 2 ). 
F or pe diatric partici pa nts, 

Bl o o d dra ws will be mi ni mize d (see Secti o n 9. 3. 3. 1 ). 

E nc o ura ge pai n ma na ge me nt tec h ni q ues, f or e xa m ple, c ol d s pra y , li d ocai ne crea m, 
B uzz y  Bee, massa ge, g ui de d i ma ger y, heat/c ol d pac ks.

Re d uce fear b y pr o vi di n g c o mf ort ite ms/s wa d dli n g, pare nt al prese nce, me dical pla y 
t hera py s o c hil dre n k n o w w hat t o e x pect, distracti o n (t o ys, vi de os, m usic), a n d/ or 
pr o vi de a re war d sys te m after necessar y pai nf ul pr oce d ures.
See Secti o n 1 1 . 4 f or s u g geste d acti o ns a n d f oll o w-u p assess me nts re gar di n g li ver safet y i n 
t he e ve nt of p ote ntial DI LI.
See Secti o n 1 1 . 5 f or g ui deli nes o n la b orat or y testi n g t o m o nit or ki d ne y f u ncti o n a n d 
re p orti n g la b orat or y test a b n or malities.
A d diti o nal safet y la b orat or y tests ma y be c o n d ucte d as nee de d b y t he I n vesti gat or t o e val uate 
partici pa nt safet y .
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 5 4
T a ble 9 .
Cli nic al S afet y a n d Ot her L a b or at or y Tests
H e m at ol o g y
C he mistr y
Uri n al ysis
Ot her
H e m at ocrit
H b
R B C c o u nt
Mea n c or p usc ular 
v ol u me
Mea n c or p usc ular H b
Mea n c or p usc ular H b 
c o nce ntrati o n
Retic ul oc yte c o u nt 
(a bs ol ute a n d %)
Platelet c o u nt (esti mate 
n ot acce pta ble)
W hite bl o o d cell c o u nt 
i ncl u di n g differe ntial 
c o u nt ( perce nt a n d 
a bs ol ute):
Ne utr o p hils 
L y m p h oc ytes 
M o n oc ytes 
Bas o p hils 
E osi n o p hils 
P T
a P T T
I N R
A L T
Al b u mi n
Al kali ne p h os p hatase
A S T
Bicar b o nate
Bl o o d urea nitr o ge n
Calci u m
C hl ori de
Creati ne p h os p h o ki nase 
Creati ni ne
Fasti n g gl uc ose
Gl o b uli n
Lactate de h y dr o ge nase 
Ma g nesi u m
P h os p h or o us
P otassi u m
S o di u m
T otal bilir u bi n ( direct 
a n d i n direct)
T otal pr otei n
Uric aci d 
e G F R a
Al b u mi n
Bilir u bi n
Bl o o d
Creati ni ne
Gl uc ose
Ket o nes
Le u k oc ytes
Micr osc o pic a nal ysis of 
se di me nt if cli nicall y 
i n dicate d
Nitrite
p H
Pr otei n
S pecific gra vit y
Ur o bili n o ge n
E P O
F S H ( p ost me n o pa usal 
fe males o nl y)
Pre g na nc y – ser u m a n d 
uri ne (fe males w h o are 
p ost me narc he a n d of 
c hil d-beari n g p ote ntial) b
R B C def or ma bilit y
Fl o w  Ad hesi o n 
R B C Mit oc h o n drial 
C o nte nt
Peri p heral S mear
Ser u m c ystati n C
Ha pt o gl o bi n
He m o pe xi n
S ol u ble C 3
Ser ol o g y P a nel (if 
cli nic all y i n dic ate d):
HI V a nti b o d y 
He patitis A vir us I g M 
a nti b o d y
He patitis B vir us s urface 
a nti ge n
He patitis C vir us 
a nti b o d y
A b bre viati o ns: A L T, ala ni ne a mi n otra nsferase; a P T T, acti vate d partial t hr o m b o plasti n ti me; A S T, as partate 
a mi n otra nsferase; C K D-E PI, c hr o nic ki d ne y disease e pi de mi ol o g y; e G F R, esti mate d gl o mer ular filtrati o n 
rate; E P O, er yt hr o p oieti n; F S H, f ollicle sti m ulati n g h or m o ne; H b, he m o gl o bi n; HI V, h u ma n 
i m m u n o deficie nc y vir us; I g M, i m m u n o gl o b uli n M; I N R, I nter nati o nal N or malize d Rati o; P T, pr ot hr o m bi n 
ti me; R B C, re d bl o o d cells.
a Usi n g C K D -E PI e q uati o ns (f or a d ults 1 8 years a n d a b o ve), C oc kcr oft -Ga ult f or m ula (f or a d olesce nts 1 2 t o 
< 1 8 years), M o difie d Sc h wartz E q uati o n (f or c hil dre n 2 t o < 1 2 years), or Sc h wartz e q uati o n (f or i nfa nts 6 
m o nt hs t o < 2 years), see Secti o n 1 1. 5. 2 .
b Tests w ill be c o n d ucte d at t he cli nic.
9. 3. 3. 1. 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 n y gi ve n 4-wee k 
peri o d. S pecific bl o o d s peci me ns (e g, e x pl orat or y  meas ures) 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 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 5 5
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 1 0 f or t he bl o o d 
s peci me n 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:
T a ble 1 0:
Bl o o d S peci me n Assess me nt Pri orit y List
Pri orit y
Test
1
He mat ol o g y
2 
C he mistr y
3 
P har mac o ki netics
4
Er yt hr o p oieti n
5
Bl o o d S mear a n d R B C Def or ma bilit y
6
E x pl orat or y bi o mar kers
9. 3. 4. Pre g n a nc y Testi n g
Pre g na nc y  tests will be perf or me d o n fe male partici pa nts w h o are p ost me narc he a n d of 
c hil d-beari n g p ote ntial as i n dicate d i n t he Sc he d ule of Assess me nts ( Secti o n 2. 1 ). A w o ma n 
is c o nsi dere d of c hil d- beari n g p ote ntial, ie. fertile, f oll o wi n g me narc he a n d u ntil bec o mi n g 
p ost -me n o pa usal u nless pe r ma ne ntly sterile. A ser u m pre g na nc y  test will be c o n d ucte d at 
Baseli ne o nl y if t here is a dela y  of > 7 da ys i n start of O L E fr o m t he ori gi nati n g st u d y, 
ot her wise a uri ne pre g na nc y test will be c o n d ucte d at Baseli ne wit h uri ne pre g na nc y  tests 
c o n d ucte d t her eafter as i n dicate d i n t he Sc he d ule of Assess me nts. If t he Da y  1 uri ne test is 
p ositi ve, a pre -d ose ser u m pre g na nc y  test s h o ul d be perf or me d a n d d osi n g s h o ul d be 
p ost p o ne d u ntil a ne gati ve res ult is c o nfir me d; if p ositi ve, t he partici pa nt will be c o nsi dere d a 
scree n fail ure.
Fe male partici pa nts will n ot be c o nsi dere d of c hil d- beari n g p ote ntial if t he y are s ur gicall y  
sterile ( hys terect o m y, bilateral sal pi n gect o m y, t u bal li gati o n, or bilateral o o p h orect o my) or 
p ost me n o pa usal ( n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical ca use, c o nfir me d 
b y  f ollicle-sti m ulati n g h or m o ne test res ults).
9. 3. 5. Fertilit y a n d C o ntr ace pti ve Re q uire me nts
9. 3. 5. 1. Fe m ale P artici p a nts of C hil d be ari n g P ote nti al
Fe male partici pa nts w h o are of c hil d - beari n g p ote ntial are re q uire d t o use hi g hly e ffecti ve 
met h o ds of c o ntrace pti o n or practice a bsti ne nce fr o m st u d y  start t o 8 4 da ys after t he last d ose 
of st u d y  dr u g.
Hi g hl y effecti ve c o ntrace pti o n met h o ds are defi ne d as t he f oll o wi n g:
a.
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 ociat e d wit h 
i n hi biti o n of o v ulati o n O R pr o gest o ge n o nl y 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 b y oral, i m pla nta ble, or i njecta ble r o ute of a d mi nistrati o n
b.
A n i ntra uteri ne de vice 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 5 6
c.
A n i ntra uteri ne h or m o ne -releasi n g sys te m
d.
Fe males wit h bilateral t u bal occl usi o n
e.
S ur gicall y sterile male part ner (e g, vasect o m y)
f.
Tr ue se x ual a bsti ne nce, defi ne d as 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. Peri o dic a bsti ne nce 
(e g, cale n dar, o v ulati o n, s y m pt o m -t her mal, p ost-o v ulati o n met h o ds), a n d wit h dra wal 
are n ot acce pta ble met h o ds of c o ntrace pti o n.
9. 3. 5. 2. 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
It is i m p orta nt t hat t he fe male part ners of male partici pa nts d o n ot bec o me preg na nt d uri n g 
t he st u d y a n d f or a t otal peri o d of 8 4 d a y s after t he male partici pa nt has ta ke n t he last d ose of
osi vel ot or .
As a preca uti o n, all male partici pa nts w h o are se x uall y  acti ve a n d n ot s ur gicall y sterile 
s h o ul d a v oi d fat heri n g a c hil d b y eit her tr ue a bsti ne nce or t he use of barrier met h o ds of 
c o ntrace pti o n pl us hi g hl y effecti ve c o ntrace pti o n f or t heir fe male part ner if of c hil d beari n g 
p ote ntial.
9. 3. 5. 3. Acce pt a ble F or ms of C o ntr ace pti o n f or M ale P artici p a nts wit h Fe m ale P art ners 
C a p a ble of Re pr o d ucti o n
M ale partici pa nts w h o are n ot s ur gicall y sterile wit h part ners of c hil d beari n g p ote ntial m ust 
a gree t o use a hi g hl y effecti ve met h o d of birt h c o ntr ol d uri n g t he st u d y a n d f or 8 4 d a y s after 
t he last d ose of st u d y dr u g. A hi g hly effecti ve met h o d of c o ntrace pt i o n is defi ne d as o ne t hat 
res ults i n a l o w d oc u me nte d fail ure rate w he n use d c o nsiste ntl y a n d c orrectl y s uc h as: 
c o n d o m pl us use of a n i ntra uteri ne de vice; i ntra uteri ne s ys te m or h or m o nal met h o d of 
c o ntrace pti o n ( oral, i njecte d, i m pla nte d, or tra ns der mal) f or t heir fe male part ner; or se x ual 
a bsti ne nce.
Male partici pa nts w h o are n ot s ur gicall y sterile wit h a part ner w h o is pre g na nt m ust a gree t o 
c o n d o m use or mai ntai n se x ual a bsti ne nce d uri n g t he st u d y  a n d f or 8 4 d a y s after t he last d ose 
of st u d y  dr u g.
9. 4. A d ve rse E ve nts ( A Es) Seri o us A d verse E ve nts ( S A Es), a n d Ot her S afet y Re p orti n g
9. 4. 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 i n a partici pa nt a d mi nistere d a 
p har mace utical pr o d uct d uri n g t he c o urse of a cli nical i n vesti gati o n . A n A E ca n t heref ore be 
a n y u nfa v ora ble a n d u ni nte n de d si g n, sy m pt o m, or disease te m p orall y ass ociate d wit h t he use 
of a n i n vesti gati o nal pr o d uct, w het her or n ot t h o u g ht t o be relate d t o t he i n vesti gati o nal 
pr o d uct. I n a d diti o n t o ne w e ve nts, a n y i ncrease i n t he se verity 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 / pare nt/le gal g uar dia n/le gally a ut h orize d 
re prese ntati ve si g ns t he I C F f or partici pati o n is c o nsi dere d a n A E. T his i ncl u des a ny si de 
effect, i nj ur y, t o xicit y, or se nsiti vit y reacti o n.  
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 ort i 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. 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 5 7
S us pecte d a d verse reacti o n i m plies a lesser de gree of certai nt y 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 vesti gat or or S p o ns or, 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 pe cte 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 t o be “ 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 secti o n of t he c urre nt I B or is n ot liste d at t he s pecificity or 
se verity t hat has bee n o bser ve d.
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.
9. 4. 2. Defi niti o n of Seri o us A d verse E ve nts or Seri o us S us pecte d A d verse Re acti o ns
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 hat, 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 S p o ns or, 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  

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  

Dr u g -i n d uce d li ver i nj ur y

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  ma 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 geries) is n ot 
c o nsi dere d t o be a n S A E. A n y c o m plicati o ns arisi n g fr o m a pla n ne d h os pitalizati o n ma y  be 
c o nsi dere d a n A E a n d s h o ul d be r e p orte d as a p plica ble. 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.  
9. 4. 3. 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, Versi o n 5. 0, t he criteria prese nte d i n
Ta ble 1 1 s h o ul d be use d.  
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 5 8
T a ble 1 1 .
Gr a di n g f or A d verse E ve nts n ot C o vere d i n t he N CI-C T C A E
Se verit y
Descri pti o n
Gra de 1 – Mil d 
As y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns 
o nl y; i nter ve nti o n n ot i n dicate d 
Gra de 2 – M o derate 
Mi ni mal, l ocal, or n o ni n vasi ve i nter ve nti o n i n dicate d; li mite d a ge -
a p pr o priate i nstr u me ntal acti vities of dail y li vi n g 
Gra de 3 – Se v ere 
Me dicall y si g nifica nt b ut n ot i m me diatel y life t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; 
li miti n g self-care acti vities of dail y li vi n g 
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: N CI -C T C A E, Nati o nal Ca ncer I nstit ute - C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts.
T o ma ke s ure t hat 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 ose a t hreat t o 
a 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.  
9. 4. 4. Rel ati o ns hi p t o I n vesti g ati o n al Pr o d uct  
T he relati o ns hi p of a n A E t o t he st u d y  dr u g s h o ul d be deter mi ne d by 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 t o be 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 xists 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 a n d 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 nty,  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.
9. 4. 5. U ne x pecte d A d v erse Re acti o ns
A n a d verse reacti o n is “ u ne x pecte d” if its nat ure a n d se verity are n ot c o nsiste nt wit 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 P F-0 7 9 4 0 3 6 7 I B (Pfizer, 2 0 2 3 ).
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 5 9
9. 4. 6. A d verse E ve nt Re p orti n g
9. 4. 6. 1. Ge ner al A E Re p orti n g
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/ pare nt/le gal 
g uar dia n/le gall y a ut h orize d re prese ntati ve si g ns t he IC F/asse nt f or m u ntil t he E O S Visit or 
E T Visit, w hic he ver c o mes first. T he A E or S A E m ust be rec or de d o n t he C R F a n d t he S A E 
re p orte d usi n g P S S A. 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 t hat d oc u me ntati o n of t he e ve nt is c o m plete. Details of 
eac h re p orte d A E/ S A E m ust i ncl u de at a 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.
9. 4. 7. Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d S A E I nf or m ati o n
T he ti me peri o d f or acti vel y  eliciti n g a n d c ollecti n g A Es a n d S A Es (“acti ve c ollecti o n 
peri o d”) f or eac h partici pa nt be gi ns fr o m t he ti me t he partic i pa nt/ pare nt/le gal 
g uar dia n/le gall y a ut h orize d re prese ntati ve pr o vi des i nf or me d c o nse nt, w hi c h is o btai ne d 
bef ore u n der g oi n g a n y st u d y relate d pr oce d ure a n d/ or recei vi n g st u d y i nter ve nti o n, t hr o u g h 
a n d i ncl u di n g a mi ni m u m of 6 3 cale n dar da y s after t he last a d mi nistrati o n of t he st u d y 
i nter ve nti o n. F oll o w-u p b y  t he i n vesti gat or c o nti n ues t hr o u g h o ut t he acti ve c ollecti o n peri o d 
a n d 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.
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 t he 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.
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 i nter ve nti o n 
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 C R F a n d t he S A E 
re p orte d usi n g P S S A Pfizer’s Seri o us A d verse E ve nt S u b missi o n Ass ista nt. T he 
S p o ns or/ Me dical M o nit or(s) m ust be n otifie d of t he st u d y  partici pa nt disc o nti n uati o n.
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 ncl u de d st u dy partici pati o n, 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 t he st u d y  i nter ve nti o n, t he i n vesti gat or m ust 
pr o m ptl y  re p ort t he S A E t o Pfizer usi n g P S S A .
9. 4. 7. 1. Di a g n osis Vers us Si g ns a n d S y m pt o ms  
If k n o w n, a dia g n osis s h o ul d be rec or de d o n t he e C R F rat her t ha n i n di vi d ual si g ns a n d 
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/ or s y m pt o ms ca n n ot be 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 6 0
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 
in di vi d ual e ve nt s h o ul d be rec or de d se paratel y o n t he e C R F. If a dia g n osis is s u bse q ue ntl y 
esta blis he d, it s h o ul d be re p orte d as f oll o w -u p i nf or mati o n.
9. 4. 7. 2. A b n or m al L a b or at or y V al ues  
Cli nicall y  si g nifica nt la b orat or y test res ults will be rec or de d o n t he A E e CR F (e g, 
a b n or malities t hat ha ve cli nical se q uelae, m ore fre q ue nt f oll o w- u p assess me nts, or 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, al kali ne p h os p hatase a n d bilir u bi n 5 × t he u p per li mit of n or mal 
ass ociate d wit h c h olec ystitis), o nl y t he dia g n osis (e g, c h olec ystitis) s h o ul d be rec or de d o n t he 
e C R F.  
If t he cli nically si g nifica nt la b orat or y a b n or malit y is n ot a si g n of a disease or s y n dr o me, t he 
a b n or malit y itself s h o ul d be rec or de d o n t he e C R F. If t he la b orat or y  a b n or malit y ca n be 
c haracterize d b y a precise cli nical ter m, t he cli nical ter m s h o ul d be rec or de d. 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 yper kale mia”.  
O bser vati o ns o f t he sa me cli nicall y si g nifica nt la b orat or y a b n or malit y fr o m visit t o visit 
s h o ul d n ot be re peate dl y rec or de d 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. 
9. 4. 8. 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 nt s 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 b y 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 Pfizer 
Safet y  via P S S A. In t he e ve nt t hat P S S A is n ot a v aila ble, pa per 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 t he S p o ns or or C R O desi g nee. T he 
i nf or mati o n re p orte d o n pa per S A E re p ort f or m s h o ul d be e ntere d i nt o t he E D C o nce 
a vaila ble.
T he S p o ns or or desi g nee ma y  re q uest a d diti onal s o urce d oc u me ntati o n pertai ni n g t o t he S A E 
fr o m t he i n vesti gati o nal site. 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 a n d partici pa nt i de ntifier i nf or mati o n (e g, na me, me dical rec or d n u m ber) m ust be 
re dacte d i n t he h os pital disc harge s u m maries, a ut o ps y  re p orts, a n d/ or deat h certificates.  
F oll o w - u p S A E i nf or mati o n 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 or 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.
9. 4. 8. 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 reac ti 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, IR Bs/ E 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 y s 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 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 6 1
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 yi n g t he l ocal I R Bs or 
E Cs of all S A Es t hat occ ur at his or her site as re q uire d b y  l ocal re g ulati o ns or IR B/ E C 
p olicies, 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, IR Bs/ 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 osi vel ot or , maj or safety 
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. 
9. 4. 9. Dr u g -i n d uce d Li ver I nj ur y
Partici pa nts will be m o nit ore d f or si g ns of dr u g- i n d uce d li ver i nj ur y ( DI LI). 
P ote ntial e ve nts of DI LI will be defi ne d as meeti n g all t he f oll o wi n g criteria (as s pecifie d i n t he 
F D A G ui da nce f or Dr u g -I n d uce d Liver I nj ury: Pre m arketi n g Cli nic al Ev al u ati o n 2 0 0 9 [F D A, 
2 0 0 9 ]).
P ote ntial e ve nts of DI LI will be re p orte d as S A Es ( Secti o n 9. 4. 8 ). All partici pa nts wit h 
p ote ntial DI LI will be cl osel y  f oll o we d u ntil a b n or malities ret ur n t o n or mal or baseli ne or 
u ntil all 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.
See A p pe n di x 2: L i ver Safety:  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.
9. 4. 1 0. Met h o d of Detecti n g A Es a n d S A Es
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A Es a n d/ or S A Es. O pe n -e n de d a n d 
n o nlea di n g ver bal q uesti o ni n g of t he partici pa nt / pare nt/le gal g uar dia n/le gall y a ut h orize d 
re prese ntati ve is t he preferre d met h o d t o i n q uire a b o ut A E occ urre nces.
9. 4. 1 1. F oll o w -u p of A Es a n d S A Es
After t he i nitial A E/ S A E re p ort, t he I n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h 
partici pa nt at s u bse q ue nt visits/c o ntacts. All S A Es will be f oll o we d u ntil res ol uti o n, 
sta bilizati o n, t he e ve nt is ot her wise e x plai ne d, or t he partici pa nt is l ost t o f oll o w-u p (as 
defi ne d i n Secti o n 8. 4 ).
9. 4. 1 2. Dise ase -rel ate d E ve nts or Dise ase -rel ate d O utc o mes N ot Q u alif yi n g as A Es or 
S A Es
9. 4. 1 2. 1. A d verse E ve nts t h at are V as o -Occl usi ve Crisis E ve nts
V O C e ve nts are n ot re p orte d as a n A E/ S A E a n d m ust be re p orte d o n t he V O C pa ge. 
If the u n derl yi n g ca use of a n S A E is deter mi ne d t o be a V O C, t he n t he S A E will be e ntere d 
o n t he V O C pa ge a n d n ot re p orte d as a n S A E.
If t he u n derlyi n g ca use of a n S A E is deter mi ne d n ot t o be a V O C, t he n t he S A E m ust be 
rec or de d i n t he S A E pa ge a n d re p orte d as a n S A E.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 6 2
T he f oll o wi n g disease -relate d e ve nts are c o m m o n i n partici pa nts wit h S C D, i n de pe n de nt of 
e x p os ure t o st u d y i nter ve nti o n, ca n be seri o us/life-t hreate ni n g, a n d are defi ne d as e n d p oi nts 
i n t his pr ot oc ol:

U nc o m plicate d V O C ( defi ne d as a n ac ute e pis o de of pai n wit h n o me dicall y  
deter mi ne d ca use ot her t ha n a vas o -occl usi ve e ve nt, res ults i n a visit t o a me dical 
facilit y ( h os pitalizati o n, e mer ge nc y de part me nt, ur ge nt care ce nter, o ut patie nt cli nic, 
or i nf usi o n ce nter), a n d re q ui res pare nteral narc otic a ge nts, pare nteral n o nster oi dal 
a nti-i nfla m mat or y dr u gs ( N S AI Ds), or a n i ncrease i n treat me nt wit h oral narc otics, 
b ut is N O T classifie d as a n ac ute c hest s y n dr o me, he patic se q uestrati o n, s ple nic 
se q uestrati o n, dact yl itis, or pria pis m.)

C o m plicate d V O C:

Ac ute c hest s y n dr o me

He patic se q uestrati o n

S ple nic se q uestrati o n

Pria pis m re q uiri n g a visit t o a me dical facilit y

Dact yl itis
Beca use t hese e ve nts are t y picall y ass ociate d wit h t he disease u n der st u d y, t he y will n ot be 
re p orte d acc or din g t o t he sta n dar d pr ocess f or e x pe dite d re p orti n g of S A Es e ve n t h o u g h t he 
e ve nt ma y meet t he defi niti o n of a n S A E. T hese e ve nts will be rec or de d o n t he V O C pa ge i n 
t he partici pa nt’s C R F wit hi n 7 2 h o urs. T hese disease -relate d e ve nts will be m o nit ore d b y a n
i n de pe n de nt data m o nit ori n g c o m mittee a n d safet y re vie w tea m o n a r o uti ne basis.  
N ote: H o we ver , if eit her of t he f oll o wi n g c o n diti o ns a p plies, t he n t he e ve nt m ust be rec or de d 
a n d re p orte d as a n S A E (i nstea d of disease -relate d e ve nts):

T he e ve nt is, i n t he i n vesti gat or’s o pi ni o n, of greater i nte nsit y, fre q ue nc y, or d urati o n 
t ha n e x pecte d f or t he i n di vi d ual partici pa nt.
O R

T he i n vesti gat or c o nsi ders t hat t here is a reas o na ble p ossi bilit y  t hat t he e ve nt was 
relate d t o st u dy i nter ve nti o n.
9. 4. 1 2. 1. 1. Pr oce d ures f or Re p orti n g a n d D oc u me nti n g V O C E ve nt D at a
All V O Cs, as defi ne d i n Secti o n 9. 4. 1 2. 1 , are t o be d oc u me nte d wit hi n t he e C R F wit hi n 
5 da y s of a site bec o mi n g a ware of s uc h e ve nt. Eac h V O C is t o be rec or de d o nl y  o nce o n t he 
“ Vas o-Occl usi ve E ve nt” e C R F pa ge. All V O Cs are t o be rec or de d t hr o u g h o ut t he e ntire 
treat me nt peri o d, u p t o Wee k 4 8, a n d s h o ul d c o nti n ue u ntil t he F oll o w -U p Visit at Wee k 6 0 
f or partici pa nts w h o d o n ot e nroll i n t he O L E st u d y  ( or earlier if partici pa nt disc o nti n ues 
fr o m t he st u d y). T he I n vesti gat or will classif y a n d pr o vi de all t he f oll o wi n g i nf or mati o n f or 
eac h V O C as f oll o ws:
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 6 3

Dia g n osis, w hic h will be li mite d t o o ne of t he pre -defi ne d V O C e ve nts as descri b e d 
i n Secti o n 9. 4. 1 2. 1 :

U nc o m plicate d V O Cs

Ac ute c hest s y n dr o me

He patic se q uestrati o n 

S ple nic se q uestrati o n

Pria pis m (re q uiri n g a visit t o a me dical facilit y )

Dact yl itis

O nset date,

St o p date,

Acti o n ta ke n ( n o ne, re q uire d c o nc o mita nt me dicati o n, te m p oraril y wit h hel d st u d y  
dr u g, per ma ne nt disc o nti n uati o n of st u d y  dr u g, or ot her [e x plai n]),

W het her or n ot h os pitalizati o n or a visit t o e mer ge nc y  de part me nt, ur ge nt care ce nter, 
o ut patie nt cli nic, or i nf usi o n ce nter was re q uire d,

C o nc o mita nt me dicati o ns gi ve n, a n d 

O utc o me (rec o vere d wit h o ut se q uelae, res ol ve d wit h se q uelae, o n g oi n g, u n k n o w n, 
deat h).
If a partici pa nt is h os pitalize d d ue t o a V O C a n d d uri n g h os pitalizati o n de vel o ps a n o n -V O C 
e ve nt t hat meets t he criteria f or a S A E, t he n t hat e ve nt s h o ul d be re p orte d as a S A E. A n y  
pr ol o n gati o n of a h os pitalizati o n d ue t o a n o n -V O C e ve nt (e ve n t h o u g h t he y ma y ha ve 
i nitiall y bee n h os pitalize d d ue t o a V O C) is rep orta ble as a S A E i n t he e C R F.
9. 4. 1 2. 1. 2. S o urce D oc u me nt C ollecti o n f or V O C E ve nt A dj u dic ati o n
F or eac h re p orte d V O C, bli n de d s o urce d oc u me ntati o n t o s u p p ort t he re p orte d dia g n osis will 
be s u b mitte d b y  t he site t o t he V O C a dj u dicati o n c o m mittee. A dj u dicati o n of all p ote ntial 
V O C e ve nts re p orte d b y t he In vesti gat or will be perf or me d b y  a st u d y A dj u dicati o n 
C o m mittee – a n i n de pe n de nt, bli n de d pa nel c o m prise d of e x perts i n S C D. Res p o nsi bilities of 
t he A dj u dicati o n C o m mittee a n d defi niti o n of V O Cs f or a dj u dicati o n will be pr o vi de d i n t he 
A dj u dicati o n C o m mittee C harter.
S o urce d oc u me nts ma y  i ncl u de ( b ut are n ot li mite d t o) t he f oll o wi n g:

Cli nical n otes (i ncl u di n g hist or y  a n d p hys ical e xa mi nati o n [ P E] fi n di n gs),

E mer ge nc y  De part me nt n otes (i ncl u di n g hist or y a n d P E fi n di n gs),

H os pital disc har ge s u m mar y ,
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 6 4

Cli nical la b orat or y  val ues (e g, H b c o nce ntrati o n val ues f or dia g n oses of he patic or 
s ple nic se q uestrati o n),

P h y sical e xa mi nati o n fi n di n gs,

C o nc o mita nt me dicati o ns, a n d 

C hest X -ra y (re q uire d f or re p orti n g a n A C S).
E n d p oi nts wi ll be a dj u dicate d by a n i n de pe n de nt e n d p oi nt a dj u dicati o n c o m mittee. A n y  S A E 
t hat is a dj u dicate d by t he e n d p oi nt a dj u dicati o n c o m mittee N O T t o meet e n d p oi nt criteria is 
re p orte d bac k t o t he i n vesti gat or site of i nci de nce. T he i n vesti gat or m ust re p ort t he SA E t o 
Pfizer Safet y  wit hi n 2 4 h o urs of bei n g ma de a ware t hat t he S A E di d n ot meet e n d p oi nt 
criteria. T he i n vesti gat or’s S A E a ware ness date is t he date o n w hic h t he i n vesti gat or site of 
i nci de nce recei ves t he S A E bac k fr o m t he e n d p oi nt a dj u dicati o n c o m mittee.
9. 4. 1 3. 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 t he st u d y i nter ve nti o n. S uc h e x p os ure 
ma y  or ma y n ot lea d t o t he occ urre nce 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 mil y 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 t he st u d y i nter ve nti o n 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.
9. 4. 1 3. 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 
st u d y i nter ve nti o n.

A male partici pa nt w h o is recei vi n g or has disc o nti n ue d st u d y  i nter ve nti o n 
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 st u d y i nter ve nti o n 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 t he st u d y i nter ve nti o n b y i n gesti o n, i n halati o n, or s ki n 
c o ntact.

A male fa mil y me m ber or healt hcare pr o vi der w h o has bee n e x p ose d t o osi vel 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.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 6 5
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 
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 st u d y  i nter ve nti o n a n d 
u ntil at least 1 4 0 da y s 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 Safet y 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 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.
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 t he S p o ns or or desi g nee of t he 
o utc o me as a f oll o w -u p t o t he i nitial re p ort. 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 case of a li ve birt h, t he str uct ural i nte grity of t he ne o nate ca n be assesse d at t he ti me of 
birt h. 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 pecifie d a n d, if 
cli nicall y p ossi ble, t he str uct ural i nte grity 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 nc 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 criterial 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 miscarria 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 usalit y, 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 t he st u d y i nter ve nti o n.
A d diti o nal i nf or mati o n re gar di n g t he E D P m a 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 Pre g na nt Part ner Release of I nf or mati o n 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 e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 6 6
9. 4. 1 3. 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 
disc o nti n ui n g st u d y  i nter ve nti o n.

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 st u d y i nter ve ntio n (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 t he st u d y i nter ve nti o n b y 
i n gesti o n, i n halati o n, or s ki n c o ntact.
T he I n ves ti 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 C T S A E Re p ort F or m. 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.
A n E D B re p ort is n ot create d w he n a Pfizer dr u g s pecificall y a p pr o ve d f or use i n 
breastfee di n g w o me n (e g, vita mi ns) is a d mi nistere d i n acc or da nce wit h a ut h orize d use. 
H o we ver, if t he i nfa nt e x perie nces a n S A E ass ociate d wit h s uc h a dr u g, t he S A E is re p orte d 
t o get her wit h t he E D B.
9. 4. 1 3. 3. Occ u p ati o n al E x p o s 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 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 usi n g P S S A re gar 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 nt ai ne d i n t he I n vesti gat or site file.
9. 4. 1 4. L a c 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.
9. 4. 1 5. 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 t he st u d y 
i nter ve nti o n 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:
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 6 7
T a ble 1 2 . 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 
Err or 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
A b bre viati o ns: A E, a d verse e ve nt; C T, cli nical trial; C R F, case re p ort f or m; P S S A, Pfizer’s Seri o us A d verse 
E ve nt S u b missi o n Assista nt; S A E, seri o us a d verse e ve nt.
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  i nter ve nti o n;

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 e x pire d st u d y  i nter ve nti o n;

T he a d mi nistrati o n of a n i nc orrect st u d y  i nter ve nti o n;

T he a d mi nistrati o n of st u d y  i nter ve nti o n 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 i nter ve nti o n u n der q uesti o n is acce pta ble f or use;

T he a d mi nistrati o n of a n i nc orrect d osa ge.
W het her or n ot t he me dicati o n err or is acc o m pa nie 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 urrin 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, Pfizer Safet y 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 via P S S A o nl y w he n 
ass oci ate d wit h a n S A E.
9. 5. P h ar m ac o ki netics
Plas ma a n d w h ole bl o o d P K sa m ples (1 x 4 m L  per ti me p oi nt f or partici pa nts fr o m 
C 5 3 5 1 0 0 4 Parts A a n d B; 1 x 2 m L  per ti me p oi nt f or partici pa nts fr o m C 5 3 5 1 0 0 4 Part C)
will be c ollecte d acc or di n g t o t he ti me p oi nts as s pecifie d i n t he S o A ( Secti o n 2. 1 ). 
I nstr ucti o ns f or t he c ollecti o n a n d ha n dli n g of bi ol o gical sa m ples will be pr o vi de d by t he 
S p o ns or. T he act ual date a n d ti me ( 2 4 - h o ur cl oc k ti me) of eac h sa m ple will be rec or de d. 
9. 6. Ge netics
Ge netics is n ot e val uate d i n t his st u d y .
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 6 8
9. 7. P h ar m ac o d y n a mics/ Bi o m ar kers
Pre d ose bl o o d sa m ples f or t he f oll o wi n g P D assess me nts will be c ollecte d at t he ti me p oi nts 
s pecifie d i n t he S o A Secti o n 2. 1 :

Peri p heral bl o o d s mears (t o vis uall y  e val uate c ha n ge i n R B C sic kli n g)

R B C def or ma bilit y  

R B C mit oc h o n drial c o nte nt

Fl o w a d hesi o n (a d hesi o n of w h ole bl o o d t o micr ofl ui dic c ha n nels c oate d wit h 
vasc ular cell a d hesi o n m olec ule or P -selecti n)

E x pl orat or y  bi o mar kers ( mar kers of he m ol ysis i ncl u di n g ha pt o gl o bi n, he m o pe xi n, 
a n d s ol u ble C 3) 
T hese will be perf or me d o n sa m ples fr o m partici pa nts e nr olle d at sites i n re gi o ns w here t hese 
assess me nts are a vaila ble. 
Bi ol o gical sa m ples f or bi o mar kers will be retai ne d b y  t he S p o ns or f or u p t o 1 0 years, u nless 
l ocal re g ulat or y re q uire me nts are f or l o n ger st ora ge. T hese st ore d sa m ples ma y be use d b y 
t he S p o ns or or t heir researc h part ners t o hel p a ns wer q uesti o ns a b o ut t he st u d y dr u g, S C D 
a n d its ass ociate d c o n diti o ns, or cli nical la b orat or y  testi n g t o pr o vi de a d diti o nal safety data. 
N o h u ma n ge netic testi n g will be perf or me d wit h o ut e x press c o nse nt of t he st u d y  partici pa nt. 
T he sa m ples will be ha n dle d s uc h t hat neit her t he partici pa nt’s na me n or ot her i de ntif y i n g 
i nf or mati o n will be rec or de d i n t he data bel o n gi n g t o t he sa m ple.
9. 8. He alt h -Rel ate d Q u alit y of Life Assess me nts f or P artici p a nts E nr olli n g fr o m 
C 5 3 5 1 0 0 4 P art A a n d P art B
P R O assess me nts will be c o m plete d electr o nicall y b y t he st u d y partici pa nt at t he be gi n ni n g 
of t he sc he d ule d visit, bef ore a n y m e dical pr oce d ures or i nteracti o ns wit h t he cli nical staff 
ta ke place. 
Partici pa nts will be as ke d t o pr o vi de res p o nses t o ni ne H R Q O L s ur ve y s at sites w here 
a p plica ble. T hese s ur ve y meas ures i ncl u de P R O MI S S F Fati g ue 1 3a, P R O MIS S F Pai n 
I nterfere nce 8a, P R O MI S N R S Pai n Inte nsit y, P GI -S of fati g ue, P GI -S of pai n, P GI -C of 
fati g ue, P GI-C of pai n, E ur o Q ol E Q - 5 D-5 L , a n d W P AI + CI Q: S C D at sites w here a vaila ble. 
Cli nicia ns will als o c o m plete t w o H R Q O L assess me nts ( Cli nical Gl o bal I m pressi o n of 
C ha n ge [ C GI-C] a n d Cli nical Gl o bal I m pressi o n of Se verit y [ C GI -S]) o n t heir gl o bal 
i m pressi o n of partici pa nt i m pr o ve me nt. 
Q ualitati ve i nter vie ws will be c o n d ucte d wit h a s u bset of st u d y  partici pa nts b y tele p h o ne or 
o nli ne/ we b c o nfere n ce after c o m pleti o n of st u d y  treat me nt as i n dicate d i n t he Sc he d ule(s) of 
Assess me nts a n d Pr oce d ures . I nter vie ws will be tar gete d f or c o m pleti o n wit hi n 
a p pr o xi matel y 2 1 da ys after e n d of Part B st u d y treat me nt. It will n ot be c o nsi dere d a 
pr ot oc ol de viati o n if t hese i nter vie ws are c o n d ucte d o utsi de of t his ti mefra me. T hese 
i nter vie ws are re q uire d f or all eli gi ble partici pa nts, i ncl u di n g t h ose w h o ter mi nate earl y. 
Eli gi bilit y  f or partici pati o n will be o utli ne d i n a se parate q ualitati ve i nter vie w pr oce d ure 
d oc u me nt. 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 6 9
T he g oal of t he i nter vie ws i s t o c ollect data re gar di n g partici pa nts’ disease- a n d treat me nt -
relate d e x perie nces, i ncl u di n g t he f oll o wi n g:

Disease -relate d sy m pt o ms a n d i m pacts pri or t o e nr olli n g i n t he st u d y

Percei ve d c ha n ges i n s y m pt o ms a n d i m pacts d uri n g t he st u d y

Pers pecti ves o n r ele va nce a n d clarit y of H R Q O L s ur ve y meas ure (e g, P R O MIS, 
P GI -C a n d P GI -S s ur ve y  meas ures).

Mea ni n gf ul ness of a n y c ha n ges e x perie nce d
T he i nter vie ws will be c o n d ucte d b y trai ne d m o derat ors/i nter vie ws w h o are n ot e m pl o ye d or 
c o ntracte d b y t he st u d y  site. T he d urati o n of eac h i nter vie w will be a p pr o xi matel y  6 0- 9 0 
mi n utes a n d will be a u di o rec or de d, tra nscri be d, a n d de -i de ntifie d. F oll o wi n g a nal ys is of t he 
q ualitati ve data (ie, i nter vie w tra nscri pts a n d fiel d n otes), a s u m mar y  re p ort t hat descri bes t he 
st u d y o bjecti ves, met h o ds, sa m ple, a n d a g gre gate d res ults of t he q ualitati ve i nter vie ws will 
be de vel o pe d se paratel y fr o m t he C S R. T hese q ualitati ve data will n ot be i ncl u de d i n t he 
C S R.
Pla n ne d ti me p oi nts f or all H R Q O L assess me nts are pr o vi de d i n t he S o A ( Sect i o n 2. 1 ). 
9. 9. Me dic al Res o urce Utiliz ati o n a n d He alt h Ec o n o mics
Me dical res o urce utilizati o n a n d healt h ec o n o mics para meters
are n ot e val uate d i n t his st u d y.
9. 1 0. Misse d Asse ss me nts
Misse d assess me nts s h o ul d be resc he d ule d a n d perf or me d as cl ose t o t he ori gi nal sc he d ule d 
date as p ossi ble. A n e xce pti o n is ma de w he n resc he d uli n g bec o mes, i n t he I n vesti gat or’s 
o pi ni o n, me dicall y  u n necessar y or u nsafe beca use it is t o o cl ose i n time t o t he ne xt sc he d ule d 
e val uati o n. I n t hat case, t he misse d e val uati o n s h o ul d be a ba n d o ne d.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 7 0
1 0. S T A TI S TI C A L C O N SI D E R A TI O N S
Met h o d ol o g y f or s u m mar y  a n d statistical a nalys es of t he data c ollecte d i n t his st u d y is 
o utli ne d here a n d f urt her detaile d i n t he S A P , w hic h will be mai ntai ne d b y t he S p o ns or. T he 
S A P ma y  m o dif y w hat is o utli ne d i n t he pr ot oc ol w here a p pr o priate; 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 ns or t heir a nalys es will als o be reflecte d i n a 
pr ot oc ol a me n d me nt.
1 0. 1. St atistic al H y p ot hesis
N o f or mal h y p ot hesis will be assesse d.
1 0. 1. 1. Esti m a n ds
T he pri mar y  esti ma n d is defi ne d as f oll o ws:
P o p ul ati o n: Patie nts wit h S C D as defi ne d b y t he i ncl usi o n/e xcl usi o n criteria.
E n d p oi nt(s): 

I nci de nce of T E A Es

C ha n ges i n la b orat or y  assess me nts

C ha n ges i n vital si g ns
I nterc urre nt E ve nts a n d H a n dli n g Str ate g y: N o I C E is defi ne d f or t his esti ma n d . All data 
c ollecte d o n or after o btai ni n g i nf or me d c o nse nt will be i ncl u de d i n t he a nal y sis. 
P o p ul ati o n -le vel S u m m ar y:

I nci de nce of T E A Es – a bs ol ute a n d relati ve fre q ue nc y

C ha n ges i n la b orat or y  assess me nts – descri pti ve s u m mar y  of o bser ve d val ues at eac h 
visit a n d c ha n ge fr o m baseli ne.

C ha n ges i n vital si g ns – descri pti ve s u m mar y  of o bser ve d val ues at eac h visit a n d 
c ha n ge fr o m baseli ne.
1 0. 1. 2.
M ulti plicit y A dj ust me nt
N o f or mal h y p ot hesis will be teste d a n d t heref ore n o a dj ust me nts f or m ulti plicit y  are 
pla n ne d.
1 0. 2. A n al ysis Sets
T he a nal ys is p o p ulati o n f or re p orti n g are defi ne d i n t he f oll o wi n g ta ble:
P artici p a nt A n al ysis Set
Descri pti o n
E nr olle d
All partici pa nts w h o si g n t he i nf or m c o nse nt d oc u me nt a n d 
e nr oll i n t his O LE st u d y .
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 7 1
P artici p a nt A n al ysis Set
Descri pti o n
Safet y  A nalys is Set
All e nr olle d partici pa nts w h o ha ve recei ve d at least o ne 
d ose of st u d y  dr u g i n t his O LE st u d y . Partici pa nts will be 
a nal yz e d o verall a n d acc or di n g t o t he st u d y treat me nt 
recei ve d i n t he pare nt st u d y.
T his a nal y sis set will be use d f or all safety, efficac y, 
P D/ bi o mar ker, H R Q O L a nal ys es.
P K A nal y sis Set
All e nr olle d partici pa nts w h o recei ve at least o ne d ose of 
st u d y dr u g a n d ha ve at least o ne c o nce ntrati o n data p oi nt 
( plas ma or w h ole bl o o d) p ost d ose.
1 0. 3. St atistic al A n al yses
T he S A P will be de vel o pe d a n d fi nalize d bef ore a n y  a nalys es are perf or me d a n d will 
descri be t he a nal ys es of t he st u d y e n d p oi nts a n d ha n dli n g of missi n g, u n-use d, a n d s p uri o us 
data. T his secti o n is a s u m mar y of t he pla n ne d statistical a nal yses of t he pri mar y a n d 
sec o n dar y e n d p oi nts.
1 0. 3. 1. Ge ner al C o nsi der ati o ns
Data will be s u m marize d usi n g descri pti ve statistics as descri be d i n Secti o ns 1 0. 3. 2 a n d 
1 0. 3. 3 . Data will be re p orte d o verall a n d als o base d o n patie nt p o p ulati o n a n d treat me nt 
recei ve d i n t he pare nt st u dies.
1 0. 3. 2. Pri m ar y E n d p oi nt(s)/ Esti m a n d(s) A n al ysis
Pri m ar y E n d p oi nts
St atistic al A n al ysis Met h o d

I nci de nce of T E A Es

C ha n ges i n la b orat or y assess me nts

C ha n ges i n vital si g ns
Descri pti ve statistics of T E A Es, safet y la b orat or y data 
a n d vital si g ns o bser ve d val ues a n d c ha n ge fr o m baseli ne
will be pr o vi de d. Safet y data will be prese nte d i n ta b ular 
or gra p hical f or mat a n d s u m marize d descri pti vel y, w here 
a p pr o priate.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 7 2
1 0. 3. 3. Sec o n d ar y E n d p oi nt(s)/ Esti m a n d(s) A n al ysis
Sec o n d ar y E n d p oi nts
St atistic al A n al ysis Met h o d

A n n ualize d rate of V O C
A n n ualize d rate of V O C will be s u m marize d usi n g 
descri pti ve statistics a n d a ne gati ve bi n o mial m o del.
V O C data will be ce ns ore d fr o m t he a nal ysis after t he 
f oll o wi n g e ve nts: 

Ne w  H U use p ost baseli ne;

P ost baseli ne usa ge of pr o hi bite d/restricte d 
me dicati o ns k n o w n t o affect H b/ V O C;

R B C e xc ha n ge tra nsf usi o n p ost base li ne.

I nci de nce of S C D relate d S A Es
Descri pti ve statistics of S C D relate d S A Es will be 
pr o vi de d.

C ha n ge fr o m baseli ne i n he mat ol o gical 
la b orat or y para meters, i ncl u di n g 
he m o gl o bi n, retic ul oc ytes, lactate 
de h y dr o ge nase, a n d u nc o nj u gate d bilir u bi n.
C ha n ge fr o m baseli ne i n he m o gl o bi n, retic ul oc ytes, 
lactate de h y dr o ge nase, a n d u nc o nj u gate d bilir u bi n will be 
s u m marize d usi n g descri pti ve statistics.

T he f oll o w i n g data will be e xcl u de d fr o m t he 
a nal ysis: Data c ollecte d o n or after t he start of ne w 
H U use p ost baseli ne;

Data c ollecte d o n or after t he p ost baseli ne usa ge of 
pr o hi bite d/restricte d me dicati o ns k n o w n t o affect 
H b/ V O C;

Data c ollecte d o n or after start of p ost baseli ne R B C 
e xc ha n ge tra nsf usi o n;

Data c ollecte d fr o m t he start of p ost baseli ne R B C 
n o n- e xc ha n ge tra nsf usi o n f or 1 8 wee ks. ( Data 
c ollecte d after t he 1 8 wee ks will be i ncl u de d i n t he 
a nal ysis.)
1 0. 3. 4. E x pl or at or y E n d p oi nt A n al ysis
Res ults of e x pl orat or y  e n d p oi nt a nal yses will be descri be d i n t he C S R t o t he e xte nt p ossi ble. 
D ue t o t he e x pl orat or y nat ure of t he e n d p oi nts, t he ass ociate d data a nal ys es ma y n ot be 
c o m plete at t he ti me of C S R pre parati o n. If res ults of e x pl orat or y  e n d p oi nt a nalys es ca n n ot 
be i ncl u de d i n t he C S R, t he y  will be disse mi nate d t o t he scie ntific c o m m u nit y t o t he e xte nt 
p ossi b le t hr o u g h prese ntati o n at scie ntific meeti n gs a n d/ or p u blicati o n i n peer-re vie we d 
scie ntific j o ur nals.
All plas ma a n d w h ole bl o o d c o nce ntrati o n vers us ti me data will be s u m marize d usi n g 
descri pti ve statistics a n d will be liste d a n d s u m marize d i n ta b ular f or mat. Gra p hical dis pla y s
of mea n a n d/ or me dia n c o nce ntrati o n vers us ti me pl ots ma y  be pre pare d.
1 0. 3. 5. Ot her A n al yses
P K para meters will be assesse d b y p o p ulati o n P K a nal ys is usi n g n o nli near mi xe d-effects 
m o deli n g a n d will be re p orte d se paratel y.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 7 3
P har mac o ge n o mi c or bi o mar ker data fr o m Retai ne d Researc h Sa m ples ma y  be c ollecte d 
d uri n g or after t he trial a n d retai ne d f or f ut ure a nal yses; t he res ults of s uc h a nal ys es are n ot 
pla n ne d t o be i ncl u de d i n t he C S R. 
1 0. 4. I nteri m A n al yses
N o f or mal i nteri m a nal ys is will be c o nd ucte d f or t his st u d y . 
1 0. 5. S a m ple Size Deter mi n ati o n
T he sa m ple size is base d o n t he n u m ber of partici pa nts w h o will c o m plete t he pare nt st u dies 
a n d c o nse nt t o c o nti n ue t o t his st u d y . T heref ore, a p pr o xi matel y 5 0 0 partici pa nts are 
a ntici pate d t o e nr oll i n t his l o n g-ter m f oll o w-u p st u d y .
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 7 4
1 1. S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L C O N SI D E R A TI O N S
1 1. 1. Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns
1 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 C o u ncil f or I nter nati o nal Or ga nizati o ns of 
Me dical Scie nces i nter nati o nal et hical g ui deli nes

A p plica ble 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 C H) G o o d Cli nical 
Practice ( G C P) g ui deli nes

A p plica ble l ocal la ws a n d re g ulati o ns

T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I B, a n d ot her rele va nt d oc u me nts (e g, 
a d vertise me nts) m ust be s u b mi tte d t o a n IR B/I n de pe n de nt Et hics C o m mittee (I E C) b y  
t he In vesti gat or a n d re vie we d a n d a p pr o ve d b y  t he IR B/I 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/IE 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 dy de si 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.

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 writte n s u m maries of t he stat us of t he st u d y t o t he I R B/I 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 est a blis he d b y t he I R B/I E C

N otif y i n g t he I R B/I 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 I R B/I 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 ui deli nes, t he I RB/I 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 (if a p plica ble), 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 (if a p plica ble), a n d all ot her 
a p plica ble l ocal re g ulati o ns
1 1. 1. 2. Fi n a nci al Discl os ure
I n vesti gat ors a n d s u b-i n vesti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate 
fi na ncial i nf or mati o n as re q ueste d t o all o w t he S p o ns or t o s u b mit c o m plete a n d acc urate 
fi na ncial certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y a ut h orities. 
I n vesti gat ors are res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he 
c o urse of t he st u d y a n d f or 1 year after c o m pleti o n of t he st u d y.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 7 5
1 1. 1. 3. 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 n y pr o hi biti o n or restricti o n i m p ose d (ie, cli nical h ol d) by 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 
i nter ve nti o n, t he S p o ns or s h o ul d be i nf or me d i m me diately.
I n a d diti o n, t he I n vesti gat or will i nf or m t he S p o ns or i m me diatel y of a n y ur ge nt safety 
meas ures ta ke n b y 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 hi s 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. 1. 4. I nf or me d C o nse nt Pr ocess
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 gall y 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 5 0, 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 med 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 g all 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 ntati ve).
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 
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 f or 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 o rize 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.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 7 6
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. 1. 5. 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 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 nly 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 d y  site will be resp 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 a p 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. 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 n icaltrials. 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.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 7 7
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.cli 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 n g i n acc or da nce wit h t he f or mat a n d ti meli nes set f ort h by 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 
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 plicati o 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 ni cal 
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 n y 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. 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 yi n 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 wi ll 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.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 7 8
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 y pte 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.
Q ualit y  t olera nce li mits ( Q T Ls) are pre defi ne d para meters t hat are m o nit ore d d uri n g t he 
st u d y. I m p orta nt de viati o ns fr o m t he Q T Ls a n d a n y re me dial acti o ns ta ke n will be 
s u m marize d i n t he C S R.
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 nc y 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.
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 yed 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 diatel y 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 a n 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. 1. 8. St u d y a n d Site S t 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 u t n ot li mite d t o) 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 7 9
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 ori ties, 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 de q 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  i nter ve nti o n 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.
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 h ts. 
1 1. 1. 9. P u blic ati o n P olic 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 n y 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 stu d y .
I n vesti gat ors are free t o p u blis h i n di 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 d a y s 
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 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 8 0
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 pers 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.
1 1. 1. 1 0. S p o ns or’s Me dic all y Q u alifie d I n di vi d u al
T he S p o ns or will desi g nate a me dicall y q ualifie d i n di vi d ual ( M QI, als o k n o w n as t he me dical 
m o nit or) t o a d vise t he i n vesti gat or o n st u d y- relate d me dical q uesti o ns. T he c o ntact 
i nf or mati o n f or t he st u dy me dical m o nit or is d oc u me nte d i n t he St u d y  Tea m C o ntact List 
l ocate d i n t he I n vesti gat or Site File. 
Partici pa nts are pr o vi de d wit h a Pfizer st u d y  i nf or mati o n car d at t he ti me of i nf or me d c o nse nt 
w hic h i ncl u des c o ntact i nf or mati o n f or t heir i n vesti gat or i n case of st u d y- relate d me dical 
q uesti o ns. T he st u d y  i nf or mati o n car d c o ntai ns, at a mi ni m u m, (a) st u d y n u m ber, ( b) 
partici pa nt’s st u d y i de ntificati o n n u m ber, a n d (c) pri nci pal i n vesti gat or c o ntact i nf or mati o n. 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 8 1
1 1. 2. S u p p orti n g D oc u me nt ati o n
1 1. 3. A p pe n di x 1: Det aile d D osi n g I nf or m ati o n F or Osi vel ot or
D ose f or P artici p a nts E nr olli n g fr o m P art A of C 5 3 5 1 0 0 4
T a ble 1 3.
D ose f or P artici p a nts E nr olle d Directl y fr o m P art A of C 5 3 5 1 0 0 4
M ai nte n a nce D ose i n P art A of C 5 3 5 1 0 0 4  
M ai nte n a nce D ose i n C 5 3 5 1 0 0 5
a
1 0 0 m g Q D
Sta y at 1 0 0 m g Q D
I ncrease t o 1 5 0 m g Q D
1 5 0 m g Q D
Sta y at 1 5 0 m g Q D
Decrease t o 1 0 0 m g Q D
U p t o 2 0 0 m g Q D
Sta y at u p t o 2 0 0 m g Q D
Decrease t o 1 5 0 m g Q D
Decrease t o 1 0 0 m g Q D
A b bre viati o ns: Q D , o nce dail y. 
a U ntil t he a nal ysis is c o m plete d fr o m Part A of C 5 3 5 1 0 0 4, t he ori gi nal d ose fr o m Part A of C 5 3 5 1 0 0 4 s h o ul d be 
c o nti n ue d i n C 5 3 5 1 0 0 5. After t he o pti mal efficaci o us d ose is deter mi ne d i n C 5 3 5 1 0 0 4, partici pa nts ma y ha ve t heir d ose 
a dj uste d t o t he o pti mal efficaci o us d ose i n C 5 3 5 1 0 0 5.
If t here is a dela y i n d osi n g f or partici pa nts fr o m Part A of t he C 5 3 5 1 0 0 4 st u d y pri or t o e ntr y 
i nt o t his O LE st u d y , a m o difie d l oa di n g d ose will be a d mi nistere d de pe n di n g o n t he d ose 
recei ve d i n t he pre vi o us st ud y  as f oll o ws:
T a ble 1 4.
M o difie d L o a di n g D ose f or T h ose wit h a G a p i n Tre at me nt fr o m 
C 5 3 5 1 0 0 4 P art A, P art B, a n d P art C
A m o u nt of 
C o nsec uti ve D a ys 
wit h Misse d D oses
1 0 0 m g M ai nte n a nce 
D ose 
1 5 0 m g M ai nte n a nce 
D ose 
2 0 0 m g M ai nte n a nce 
D ose 
> 3 t o < 7 c o nsec uti ve 
da ys of misse d d oses
2 0 0 m g Q D x 3 da ys 
3 0 0 m g Q D x 3 da ys 
3 0 0 m g Q D x 4 da ys
7 t o < 1 4 c o nsec uti ve 
da ys of misse d d oses
2 0 0 m g Q D x 5 da ys 
3 0 0 m g Q D x 5 da ys 
3 0 0 m g Q D x 7 da ys
1 4 t o < 4 2 c o nsec uti ve 
da ys of misse d d oses
2 0 0 m g Q D x 7 da ys 
3 0 0 m g Q D x 7 da ys
3 0 0 m g Q D x 1 0 da ys
4 2 c o nsec uti ve da ys of 
misse d d oses or 
greater
2 0 0 m g Q D x 7 da ys 
3 0 0 m g Q D x 7 da ys
3 0 0 m g Q D x 1 4 da ys
A b bre viati o ns: BI D, t wice dail y; Q D, o nce dail y. 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 8 2
D ose f or P artici p a nts E nr olle d fr o m P art B of C 5 3 5 1 0 0 4
T a ble 1 5.
D ose f or P artici p a nts E nr olle d fr o m P art B of C 5 3 5 1 0 0 4
M ai nte n a nce D ose i n P art B of 
C 5 3 5 1 0 0 4
M ai nte n a nce D ose i n C 5 3 5 1 0 0 5
L o a di n g D ose i n C 5 3 5 1 0 0 5
1 5 0 m g d ose or place b o
1 5 0 m g d ose selecte d f or Part B of 
C 5 3 5 1 0 0 4 
N ot a p plica ble
D ose f or P artici p a nts E nr olle d fr o m P art C of C 5 3 5 1 0 0 4
T a ble 1 6.
D ose f or P artici p a nts E nr olle d fr o m P art C of C 5 3 5 1 0 0 4
M ai nte n a nce D ose i n P art C of 
C 5 3 5 1 0 0 4
M ai nte n a nce D ose i n C 5 3 5 1 0 0 5
L o a di n g D ose i n C 5 3 5 1 0 0 5
Partici pa nts will be a d mi nistere d a 
d ose t hat pr o vi des ge nerall y 
e q ui vale nt e x p os ure t o 1 5 0 m g 
Q D i n a d ult S C D partici pa nts 
Re mai n o n t he d ose selecte d i n 
Part C of C 5 3 5 1 0 0 4 
N ot a p plica ble
A b bre viati o ns: T B D, t o be deter mi ne d.
1 1. 4. 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
1 1. 4. 1. Dr u g -i n d uce d Li ver I nj ur y
Partici pa nts will be m o nit ore d f or si g ns of dr u g- i n d uce d li ver i nj ur y ( DI LI).
P ote ntial e ve nts of DI LI will be defi ne d as meeti n g all of t he f oll o wi n g criteria (as s pecifie d 
i n t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) G ui da nce f or Dr u g -I n d uce d Liver I nj ury: 
Pre m arketi n g Cli nic al Ev al u ati o n 2 0 0 9 [F D A, 2 0 0 9 ]).

A L T > 4 × U L N or as partate a mi n otra nsferase ( A S T) > 3 × U L N

N o ot her reas o n ca n be f o u n d t o e x plai n t he c o m bi nati o n of la b orat or y  val ue 
i ncreases (e g, ac ute viral he patitis; alc o h olic a n d a ut oi m m u ne he patitis; he pat o biliar y  
dis or ders; n o nalc o h olic steat o he patit is; car di o vasc ular ca uses; c o nc o mita nt 
treat me nts)
P ote ntial e ve nts of DI LI will be re p orte d as S A Es. All partici pa nts wit h p ote ntial DI LI will 
be cl osel y f oll o we d u ntil a b n or malities ret ur n t o n or mal or baseli ne or u ntil all 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.
1 1. 4. 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
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 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 8 3
“s usce pti ble” t o 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 × 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 test ( L F T)s 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 a n d/ or A L T prece de T bili ele vati o ns ( > 2 × 
U L N) b y se veral da ys or wee ks. T he i ncrease i n T bili 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 bili 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 bili 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  O R A L T i n a d diti o n t o T bili 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 ho 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. I n S C D, h y per bilir u bi ne mia is d ue t o a c o m bi nati o n of ac ute 
he pat o biliar y  disease (ie, ac ute S C he patic crisis, ac ute he patic se q uestrati o n or ac ute 
i ntra he patic c h olestasis) as well as c hr o nic he pat o biliar y ma nifestati o ns (ie, c h olelit hiasis, 
c h ole d oc h olit hiasis, a n d S C D c h ola n gi o pat h y) (S ha h, R 2 0 1 7 ).
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 bili baseli ne 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 O R A LT val ues ≥3 × U L N A N D a T bili val ue 
≥2 × U L N wit h n o e vi de nce of he m ol ys is 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 partici pa nts wit h baseli ne A S T O R A L T O R T bili 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 n e:

Pree xisti n g A S T or A L T baseli ne val ues a b o ve t he n or mal ra n ge: A S T or 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).

Pree xisti n g val ues of T bili a b o ve t he n or mal ra n ge: T bili le vel i ncrease d fr o m 
baseli ne val ue b y a n a m o u nt of ≥1 × U L N or if t he val ue reac hes ≥3 × U L N 
( w hic he ver is s maller).
Beca use k n o wle d ge of t he t otal a n d u nc o nj u gate d bilir u bi n, ma y  s u g gest t he treat me nt 
assi g n me nt, t hese meas ure me nts will be re dacte d t o t he I n vesti gat or a n d m o nit ore d o n a 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 8 4
re g ular basis b y a n u n bli n de d tea m. Rises i n A S T/ A L T a n d T bili 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 ni ne ki nase, direct 
a n d i n direct bilir u bi n, ga m ma -gl uta m yl tra nsferase, P T/IN R, 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 ys es 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 p ti 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 for 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 ( Hy’s la w) case bec o mes a c o nfir me d case o nl y 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 alter nati ve eti ol o g y.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 8 5
1 1. 5. A p pe n di x 3: Ki d ne y S afet y M o nit ori n g G ui deli nes
1 1. 5. 1. L a b or at or y Assess me nt of C h a n ge i n Ki d ne y F u ncti o n a n d Detecti o n of Ki d ne y 
I nj ur y
Sta n dar d ki d ne y  safet y m o nit ori n g re q uires assess me nt of baseli ne a n d p ost baseli ne Screat 
meas ure me nt t o esti mate ki d ne y f u ncti o n [ Screat -base d e G F R] or creati ni ne cleara nce 
[e Cr Cl]). Baseli ne a n d p ost baseli ne Sc ys ma kes it feasi ble t o disti n g uis h A KI fr o m ot her 
ca uses of Screat i ncrease. If Screat i ncrease is c o nfir me d after baseli ne, t he n refle x 
meas ure me nt of Sc y s is i n dicate d. 
A D U L T S: C urre ntl y, 2 0 2 1 C K D -E PI  e G F R e q uati o ns ( Screat- o nly base d a n d c o m bi ne d 
Screat pl us Sc y s-base d) are vali d f or use i n a d ults o nl y . At baseli ne Screat a n d Sc ys val ues 
are nee de d t o calc ulate 2 0 2 1 C K D- E PI  e G F R b y Screat- o nly base d e q uati o n (see Ta ble i n 
Secti o n 1 1. 5. 2. 1 ) a n d by c o m bi ne d Screat pl us Sc ys -base d e q uati o n. W he n p ost -baseli ne 
Screat i ncrease ≥0. 3 m g/ d L  is c o nfir me d, t he n refle x Sc ys meas ure me nt is nee de d t o e na ble 
p ost - baseli ne c o m paris o n of e G F R c ha n ges ( Screat-o nl y  base d e G F R a n d c o m bi ne d Screat 
pl us Sc y s e G F R). 
P E DI A T RI C S: C urre ntl y, n o Screat pl us Sc y s e G F R e q uati o ns ha ve bee n u ni versall y 
a d o pte d f or pe diatrics. T heref ore, c o m paris o n of baseli ne Screat a n d Sc y s t o p ost-baseli ne 
Screat a n d refle x Sc ys are utilize d t o s u p p ort differe ntiati o n o f A KI fr o m DI CI. 
Re gar dless of w het her ki d ne y  f u ncti o n m o nit ori n g tests are re q uire d as a r o uti ne safety 
m o nit ori n g pr oce d ure i n t he st u d y , if t he i n vesti gat or or s p o ns or dee ms it necessar y t o f urt her 
assess ki d ne y safet y a n d q ua ntif y ki d ne y f u ncti o n, t hen t hese test res ults s h o ul d be ma na ge d 
a n d f oll o we d per sta n dar d of care.
1 1. 5. 2. A ge -S pecific Ki d ne y F u ncti o n C alc ul ati o n Rec o m me n d ati o ns
At Scree ni n g, e G F R will be calc ulate d usi n g 2 0 2 1 C K D -E PI  e G F R e q uati o ns (f or a d ults 
1 8 ye ars a n d a b o ve), e Cr Cl will be calc ul ate d usi n g C oc kcr oft -Ga ult f or m ula (f or a d olesce nts 
1 2 t o < 1 8 y ears), a n d e G F R will be calc ulate d usi n g M o difie d Sc h wartz E q uati o n (f or 
c hil dre n 2 t o < 1 2 ye ars), or Be dsi de Sc h wartz e q uati o n (f or i nfa nts 6 m o nt hs t o < 2 y ears). 
1 1. 5. 2. 1. A d ults ( 1 8 Ye ars a n d A b o ve) — 2 0 2 1 C K D- E P I E q u ati o ns (I nker, E nea n y a et al. 
2 0 2 1 )
e G F R ( m L/ mi n/ 1. 7 3 m²)
2 0 2 1 C K D -
E PI            
Scre at O nl y
Scre at
( m g/ d L)
Sc ys
( m g/ L)
Rec o m me n de d e G F R E q u ati o n
Fe male
if ≤0. 7
N A
e G F R = 1 4 3 × ( Screat/ 0. 7) -0. 2 4 1 × ( 0. 9 9 3 8) A ge
Fe male
if > 0. 7
N A
e G F R = 1 4 3 × ( Screat/ 0. 7) -1. 2 0 0 × ( 0. 9 9 3 8) A ge
Male
if ≤0. 9
N A
e G F R = 1 4 2 × ( Screat/ 0. 9) -0. 3 0 2 × ( 0. 9 9 3 8) A ge
Male
if > 0. 9
N A
e G F R = 1 4 2 × ( Screat/ 0. 9) -1. 2 0 0 × ( 0. 9 9 3 8) A ge
2 0 2 1 C K D -
E PI           
Scre at -Sc ys 
C o m bi ne d
Scre at
( m g/ d L)
Sc ys
( m g/ L)
Rec o m me n de d e G F R E q u ati o n
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 8 6
Fe male
if ≤0. 7
if ≤0. 8
e G F R = 1 3 0 × ( Screat/ 0. 7) -0. 2 1 9 ×
( Sc ys/ 0. 8)-0. 3 2 3 ×
( 0. 9 9 6 1)A ge
Fe male
if ≤0. 7
if > 0. 8
e G F R = 1 3 0 × ( Screat/ 0 . 7)-0. 2 1 9 ×
( Sc ys/ 0. 8)-0. 7 7 8 ×
( 0. 9 9 6 1)A ge
Fe male
if > 0. 7
if ≤0. 8
e G F R = 1 3 0 × ( Screat/ 0. 7) -0. 5 4 4 ×
( Sc ys/ 0. 8)-0. 3 2 3 ×
( 0. 9 9 6 1)A ge
Fe male
if > 0. 7 
if > 0. 8
e G F R = 1 3 0 × ( Screat/ 0. 7) -0. 5 4 4 ×
( Sc ys/ 0. 8)-0. 7 7 8 ×
( 0. 9 9 6 1)A ge
Male
if ≤0. 9
if ≤0. 8
e G F R = 1 3 5 × ( Screat/ 0 . 9)-0. 1 4 4 ×
( Sc ys/ 0. 8)-0. 3 2 3 ×
( 0. 9 9 6 1)A ge
Male
if ≤0. 9
if > 0. 8
e G F R = 1 3 5 × ( Screat/ 0 . 9)-0. 1 4 4 ×
( Sc ys/ 0. 8)-0. 7 7 8 ×
( 0. 9 9 6 1)A ge
Male
if > 0. 9
if ≤0. 8
e G F R = 1 3 5 × ( Screat/ 0. 9) -0. 5 4 4 ×
( Sc ys/ 0. 8)-0. 3 2 3 ×
( 0. 9 9 6 1)A ge
Male
if > 0. 9 
if > 0. 8
e G F R = 1 3 5 × ( Screat/ 0 . 9)-0. 5 4 4 ×
( Sc ys/ 0. 8)-0. 7 7 8 ×
( 0. 9 9 6 1)A ge
1 1. 5. 2. 2. A d olesce nts ( 1 2 Ye ars t o < 1 8 Ye ars) —
C oc kcr oft -G a ult F or m ul a
e Cr Cl ( m L/ mi n) 
Males: e Cr Cl = [( 1 4 0 -
a ge) × b o d y wei g ht (i n k g)] / [ Screat (i n m g/ d L) × 7 2]
Fe males: e Cr Cl = 0. 8 5 × [( 1 4 0 - a ge) × b o d y wei g ht (i n k g)] / [ Screat (i n m g/ d L) × 7 2]
1 1. 5. 2. 3. C hil dre n ( 2 Ye ars t o < 1 2 Ye ars) —
( M o difie d) Sc h w artz E q u ati o n
e Cr Cl n or malize d t o B S A ( m L/ mi n/ 1. 7 3 m2) 
e Cr Cl = ( K × Ht) / Screat
Ht i n c m; Screat i n m g/ d L.
K ( pr o p orti o nalit y  c o nsta nt): Fe male c hil d < 1 2 years: K = 0. 5 5. Male c hil d < 1 2 years: K = 
0. 7 0.
1 1. 5. 2. 4. I nf a nts ( 1 M o nt h t o < 2 Ye ars) a n d Ne o n ates ( < 1 M o nt h) — ( Be dsi de) Sc h w artz 
E q u ati o n
e G F R ( m L/ mi n/ 1. 7 3 m 2) = 0. 4 1 3 × ( Ht/ Screat)
Ht i n c m; Screat i n m g/ d L.
1 1. 5. 3. Ki d ne y F u ncti o n C alc ul ati o n T o ols
T he s p o ns or has pr o vi de d t he f oll o wi n g res o urces t o i n vesti gati o nal sites w he n re q uire d t o 
calc ulate a ge -s pecific ki d ne y f uncti o n at Scree ni n g, Baseli ne, a n d p ost -Baseli ne visits. Site 
calc ulati o ns of ki d ne y f u ncti o n ca n be perf or me d ma n uall y, usi n g t he a ge a p pr o priate 
f or m ulae (see Secti o n 1 1. 5. 2 ) a n d ca n use rec o m me n de d o nli ne ki d ne y f u ncti o n calc ulat ors 
t o re d uce t he li keli h o o d of a calc ulati o n err or. 
T he U nite d States Nati o nal Ki d ne y  F o u n dati o n O nli ne Calc ulat ors. 

A d ults ( 1 8 y ears a n d a b o ve) - 2 0 2 1 C K D -E PI  Creati ni ne O nli ne Calc ulat or (e G F R): 
htt ps:// w w w. ki d ne y . or g/ pr ofessi o nals/ K D O QI/ gfr _calc ulat or
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 8 7

A d olesce nts ( 1 2 ye ars t o < 1 8 years) - C oc kcr oft -Ga ult F or m ula (e Cr Cl): 
htt ps:// w w w. ki d ne y . or g/ pr ofessi o nals/ k d o qi/ gfr _calc ulat or C oc

I n vesti gati o nal sites are res p o nsi ble to e ns ure t hat t he acc urate a ge -s pecific e q uati o n is 
selecte d a n d t hat t he c orrect u nits are use d f or ser u m creati ni ne ( m g/ d L o nl y), ser u m c ystati n 
C ( m g/ L o nl y ), t otal b o d y wei g ht ( k g o nl y), a n d a ge ( years). I n vesti gat ors are e x pecte d t o (i) 
re vie w a n d c o nfir m c orrect ness of t he ki d ne y f u ncti o n calc ulati o n res ults a n d (ii) e val uate t he 
calc ulate d val ue wit hi n t he c o nte xt of hist orical i nf or mati o n a vaila ble t o t he m i n t he 
partici pa nt’s me dical rec or d. I n vesti gat ors are res p o nsi ble f or t he cli nical o versi g ht of t he 
partici pa nt eli gi bilit y  pr ocess, ki d ne y f u ncti o n calc ulati o n, a n d d ose selecti o n a n d 
a dj ust me nts per st u d y pr ot oc ol. In vesti gat ors are e nc o ura ge d t o direct q uesti o ns or 
u ncertai nties re gar di n g ki d ne y f u ncti o n a n d d osi n g t o t he Pfizer Cli nical Tea m a n d Me dical 
M o nit or, if nee de d.
1 1. 5. 4. A d verse E ve nt Gr a di n g f or Ki d ne y S afet y L a b or at or y A b n or m alities
A E gra di n g f or decli ne i n ki d ne y  f u ncti o n (ie, e G F R or e Cr Cl) will be acc or di n g t o C T C A E
criteria f or b ot h pe diatric a n d a d ul t partici pa nts.
C T C A E Ter m 
( 2 0 1 7)
Gr a de 1
Gr a de 2
Gr a de 3
Gr a de 4
Gr a de 5
A KI
N A
N A
H os pitalizati o n 
i n dicate d
Life -
t hreate ni n g 
c o nse q ue nces; 
dial ysis 
i n dicate d
Deat h
A KI: A dis or der c haracterize d b y ac ute l oss of ki d ne y f u ncti o n ( w it hi n 2 wee ks) a n d is tra diti o nall y 
classifie d as pre -re nal (l o w bl o o d fl o w i nt o ki d ne ys), re nal ( ki d ne y da ma ge), or p ost-re nal ca uses ( ureteral or 
bla d der o utfl o w o bstr ucti o n.
Cre ati ni ne 
i ncre ase d
> U L N t o 1. 5 x 
U L N
> 1. 5 t o 3. 0 x 
baseli ne O R  
> 1. 5 t o 3. 0 x 
U L N
> 3. 0 t o 6. 0 x 
b aseli ne O R 
> 3. 0 t o 6. 0 x 
U L N
> 6. 0 x U L N
N A
C K D
e G F R ≥6 0 t o 
8 9 
m L/ mi n/ 1. 7 3 m² 
O R                 
e Cr Cl ≥6 0 t o 
8 0 m L/ mi n 
e G F R 3 0 t o 5 9 
m L/ mi n/ 1. 7 3 m² 
O R                  
e Cr Cl 3 0 t o 5 9 
m L/ mi n
e G F R 1 5 t o 2 9 
m L/ mi n/ 1. 7 3 m² 
O R                
e Cr Cl 1 5 t o 2 9 
m L/ mi n
e G F R < 1 5 
m L/ mi n/ 1. 7 3 m² 
O R               
e Cr Cl < 1 5 
m L/ mi n            
O R            
dial ysis 
i n dicate d
Deat h
Pr otei n uri a
A D U L T S: 
Pr otei n uria 1 + 
O R                
Pr otei n uria 
> 0. 5 t o < 1. 0 
g/ 2 4 h
A D U L T S: 
Pr otei n uria 2 + 
or 3 +               
O R                
Pr otei n uria 1. 0 
t o < 3. 5 g/ 2 4 h
P E DI A T RI C S:  
Uri ne Pr otei n -
A D U L T S: 
Pr otei n uria 4 +               
O R                
Pr otei n uria 
≥3. 5 g/ 2 4 h
P E DI A T RI C S: 
Uri ne Pr otei n -
t o-Creati ni ne 
N A
N A
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 8 8
C T C A E Ter m 
( 2 0 1 7)
Gr a de 1
Gr a de 2
Gr a de 3
Gr a de 4
Gr a de 5
t o-Creati ni ne 
Rati o ( U P C R) 
0. 5 t o 1. 9
Rati o ( U P C R) 
> 1. 9
C K D: A dis or der c haracterize d b y gra d ual a n d us uall y per ma ne nt l oss of ki d ne y f u ncti o n res ulti n g i n ki d ne y 
fail ure.
1 1. 6. A p pe n di x 4 : Pr o hi bite d a n d Restricte d C o nc o mit a nt Me dic ati o ns T h at M a y 
Res ult i n D DI  
T he pr o hi bite d c o nc o mita nt me dicati o ns liste d bel o w ( Ta ble 1 7 ) s h o ul d n ot be ta ke n wit h 
osi vel ot or f or the peri o d of ti me at least e q ual t o t he re q uire d was h o ut peri o d liste d i n t he 
ta ble a n d t hr o u g h o ut t he c o n d uct of t he st u d y. Restricte d c o nc o mita nt me dicati o ns ma y be 
use d b ut wit h t he f oll o wi n g restricti o ns ( Ta ble 1 8 ).
T he Pfizer st u d y tea m is t o be n otifie d of a n y  pr o hi bite d or restricte d me dicati o ns ta ke n 
d uri n g t he st u d y. After c o ns ulti n g wit h t he s p o ns or, t he i n vesti gat or will ma ke a j u d g me nt o n 
t he o n g oi n g partici pati o n of a ny partici pa nt wit h pr o hi bite d or restricte d me dicati o n use 
d uri n g t he st u d y.
T his list of dr u gs pr o hi bite d a n d restricte d f or p ote ntial D DI c o ncer ns wit h t he I M P ma y  be 
re vise d d uri n g t he c o urse of t he st u d y wit h writte n n otificati o n fr o m t he s p o ns or t o i ncl u de or 
e xcl u de s pecific dr u gs or dr u g cate g ories f or vari o us reas o ns (e g, e mer gi n g D DI res ults f or 
t he IM P, a vaila bilit y  of ne w i nf or mati o n i n literat ure o n t he D DI p ote ntial of ot her dr u gs) if 
t he o verall be nefit/ris k assess me nt is n ot i m pacte d or if t he c ha n ges d o n ot si g nifica ntly 
i m pact t he safety of partici pa nts or t he scie ntific val ue of t he trial.  
T his is n ot a n all -i ncl usi ve list. Site staff s h o ul d c o ns ult wit h t he s p o ns or or desi g nee wit h 
a n y q uesti o ns re gar di n g p ote ntial D DI.
T a ble 1 7.
E x a m ples of Pr o hi bite d C o nc o mit a nt Me dic ati o ns
Dr u g C ate g or y 
Dr u gs
W as h o ut Peri o d 
Re q uire me nt Pri or t o First 
D ose of Osi vel ot or
Her b al Pre p ar ati o ns a n d 
Diet ar y S u p ple me nts
Pre parati o ns o btai ne d b y 
s u bjecti n g her bal s u bsta nces t o 
treat me nts s uc h as e xtracti o n, 
distillati o n, e x pressi o n, 
fracti o nati o n, p urificati o n, 
c o nce ntrati o n or fer me ntati o n. 
N ote: prescri pti o n or 
n o n prescri pti o n vita mi ns are a n 
e xce pti o n
1 4 da ys pri or t o first d ose of 
osi vel ot or
5 eli mi nati o n half -li ves or 1 4 
da ys, w hic he ver is l o n ger
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)
C CI

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 8 9
T a ble 1 7 . E x a m ples of Pr o hi bite d C o nc o mit a nt Me dic ati o ns
Dr u g C ate g or y 
Dr u gs
W as h o ut Peri o d 
Re q uire me nt Pri or t o First 
D ose of Osi vel ot or
5 eli mi nati o n half -li ves or 1 4 
da ys, w hic he ver is l o n ger
5 eli mi nati o n half -li ves or 1 4 
da ys, w hic he ver is l o n ger
Pr o hi bite d J uices
Partici pa nts are n ot per mitte d 
t o c o ns ume gra pefr uit, 
gra pefr uit j uice, a n d/ or Se ville 
ora n ges
1 4 da ys pri or t o first d ose of 
osi vel ot or
A b bre viati o ns:
N ote: T his is n ot a n e x ha 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/ dr u g -i nteracti o ns-la beli n g/ dr u g-
de vel o p me nt -a n d -dr u g -i nteracti o ns-ta ble-s u bstrates-i n hi bit ors-a n d -i n d ucers.
T a ble 1 8 .
E x a m ples of Restricte d C o nc o mit a nt Me dic ati o ns
Dr u g C ate g or y 
Dr u gs 
Restricti o ns
Osi vel ot or m ust be a d mi nistere d at 
least 4 h o urs bef ore 
 
 are a d mi nistere d
Partici pa nts s h o ul d a v oi d se nsiti ve 
 If n ot 
p ossi ble, c o nsi der d ose a dj ust me nt.
Use ca uti o n wit h se nsiti ve 
 
a n d c o nsi der d ose 
a dj ust me nt, as nee de d.
A b bre viati o ns:
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/ dr u g -i nteracti o ns-la beli n g/ dr u g-
de vel o p me nt -a n d -dr u g -i nteracti o ns-ta ble -s u bstrates-i n hi bit ors-a n d -i n d ucers.
I n vesti gat ors s h o ul d c o ns ult t he pr o d uct la bel f or a n y ot her me dicati o n use d d uri n g t he st u d y 
f or i nf or mati o n re gar di n g me dicati o n t hat is pr o hi bite d f or c o nc o mita nt use. 
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 9 0
1 1. 7. A p pe n di x 5: Pr ot oc ol A me n d me nt Hist or y
T he pr ot oc ol a me n d me nt s u m mar y  of c ha n ges ta ble f or t he c urre nt a me n d me nt is l ocate d 
directl y  bef ore t he Ta ble of C o nte nts . T he pr ot oc ol a me n d me nt s u m mar y of c ha n ges ta bles 
f or past a me n d me nts ca n be f o u n d bel o w:
A m e n d me nt 3. 0 ( 2 2 J u ne 2 0 2 3)
C h a n ge
R ati o n a le
Secti o n(s) affecte d 
Re m o ve d t he pers o nal i de ntifia ble 
i nf or mati o n f or t he s p o ns or’s me dical 
officer fr o m t he title pa ge a n d re m o ve d 
t he state me nt of a p pr o val a n d 
c o m plia nce
Per pfizer pr ot oc ol te m plates, 
t here s h o ul d be n o pers o nal 
i de ntifia ble i nf or mati o n i n t he 
pr ot oc ol. T hat i nf or mati o n will 
be d oc u me nte d se paratel y. 
Title pa ge
State me nt of a p pr o val 
a n d c o m plia nce 
I ncrease d t he n u m ber of st u d y sites t o 
a p pr o xi matel y 6 0 gl o ball y
F or c o nsiste nc y wit h t he n u m ber 
of sites i n t he ori gi nati n g st u dies
S y n o psis
A d de d pr o mis sf -fati g ue 1 3a, pr o mis sf-
pai n i nterfere nce 8a, pr o mis n u meric 
rati n g scale-pai n i nte nsit y, e ur o q ol e q -
5 d- 5l, a n d w or k pr o d ucti vit y a n d 
acti vit y i m pair me nt assess me nts t o t he 
q ualit y - of-life assess me nts
T his i nf or mati o n is bei n g 
c ollecte d i n t he ori gi nati n g st u d y 
( g bt 0 2 1 6 0 1-0 2 1) a n d will 
c o nti n ue t o be c ollecte d i n t he 
o pe n -la bel e xte nsi o n st u d y t o 
m o nit or patie nt re p orte d 
o utc o mes
S y n o psis
Sc he d ule of 
assess me nts a n d 
pr oce d ures
Secti o n 3
Secti o n 8. 8
A d de d s pecific detail t hat t he p gi -c a n d 
p gi -s assess me nts will be f or fati g ue 
a n d pai n, a n d t hat t he c gi -c a n d c gi -s 
assess me nts will be f or sc d
F or c o nsiste nc y wit h t he 
ori gi nati n g st u d y
S y n o psis
Sc he d ule of 
assess me nts a n d 
pr oce d ures
Secti o n 3
Secti o n 8. 8
Re vise d t he o utc o me meas ure of 
“tr o u g h a n d 1 - t o 2- h o ur bl o o d a n d 
plas ma c o nce ntrati o ns” t o “ bl o o d a n d 
plas ma c o nce ntrati o ns”
T o pr o vi de f or assess me nt of p k 
at vari o us ti me p oi nts as o utli ne d 
i n t he sc he d ule of assess me nts
S y n o psis
Sc he d ule of 
assess me nts a n d 
pr oce d ures
Secti o n 3
A d de d t hat e ve nts re prese nti n g sc d -
relate d c o m plicati o ns s uc h as vas o-
occl usi ve crisis ( v oc), (ie, ac ute c hest 
s y n dr o me (acs), he patic se q uestrati o n, 
s ple nic se q uestrati o n, pria pis m, a n d 
dact ylitis) will als o be re p orte d as 
meas ures of efficac y
F or clarit y o n t he meas ures of 
efficac y
S y n o psis
Secti o n 8. 2
Re m o ve d t he criteria t hat if t he da y 1 
visit d oes n ot occ ur o n t he sa me da y as 
t he e n d of treat me nt visit fr o m t he 
ori gi nati n g st u d y, t he da y 1 visit m ust 
occ ur wit hi n 3 0 cale n dar da ys of 
c o m pleti o n of t h e ori gi nati n g st u d y
T here ha ve bee n site acti vati o n 
dela ys t hat li mite d t he a bilit y of 
partici pa nts t o e nr oll i n t he o pe n 
la bel e xte nsi o n st u d y s o i n or der 
t o all o w t h ose partici pa nts t o 
S y n o psis
S c he d ule of 
assess me nts a n d 
pr oce d ures
Secti o n 4. 1
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 9 1
C h a n ge
R ati o n a le
Secti o n(s) affecte d 
c o nti n ue o n st u d y dr u g, t he 3 0 -
da y wi n d o w is bei n g re m o ve d
Secti o n 5. 1
A d de d t hat if d uri n g t he peri o d bet wee n 
da y 1 of t his st u d y a n d c o m pleti o n of 
t he ori gi nati n g st u d y, n o d ose is 
recei ve d f or greater t ha n 3 c o nsec uti ve 
da ys, a n a p pr o priate l oa di n g d ose 
s h o ul d be a d mi nistere d pri or t o 
c o nti n ue d mai nte na nce d osi n g
Bl o o d c o nce ntrati o n of dr u g will 
dr o p bel o w stea d y state le vels 
f oll o wi n g a ga p i n d osi n g. I n 
or der t o bri n g partici pa nts bac k 
u p t o stea d y state le vels (t he 
t hera pe utic wi n d o w), a ne w 
l oa di n g d ose will be a d mi nistere d 
S y n o psis 
Secti o n 2. 2
Secti o n 4. 1
Secti o n 4. 3
A p pe n di x 1
A d de d a visit at wee k 1 (t he e n d of t he 
l oa di n g d ose peri o d) f or partici pa nts 
wit h a ga p i n d osi n g > 4 2 c o nsec uti ve 
da ys fr o m c o m pleti n g t he ori gi nati n g 
st u d y
T o dis pe nse ne w st u d y dr u g a n d 
s witc h fr o m t he l oa di n g d ose t o 
t he mai nte na nce d ose
S y n o psis
Sc he d ule of 
assess me nts a n d 
pr oce d ures
Secti o n 4. 1
Secti o n 8. 2
A d de d t o t he i ncl usi o n criteria 1 t hat 
partici pa nts w h o c o m plete d treat me nt 
fr o m t he ori gi nati n g st u d y b ut were n ot 
a ble t o r oll o ver i nt o st u d y g bt 0 2 1 6 0 1 -
0 2 2 d ue t o a dela y i n st u d y site 
acti vati o n will be eli gi ble pr o vi de d 
ot her eli gi bilit y criteria are m et
F or c o nsiste nc y wit h t he re m o val 
of t he re q uire me nt t o ha ve bee n 
o n t he pre vi o us st u d y wit hi n 3 0 
cale n dar da ys 
S y n o psis
Secti o n 5. 1
Re vise d t he pre g na nc y testi n g t o be a 
uri ne test at baseli ne u nless t here is a 
dela y i n start of ole of > 7 da ys (i n 
w hic h case a ser u m pre g na nc y test 
w o ul d be a d mi nistere d)
T o clarif y t hat ser u m pre g na nc y 
tests are o nl y re q uire d if t here is a 
ga p of > 7 da ys i n start of ole or t o 
c o nfir m a p ositi ve uri ne test
Sc he d ule of 
assess me nts a n d 
pr oce d ures
A d de d a q ualitati ve i n ter vie w t o t he 
q ualit y - of-life meas ure me nts w hic h will 
be c o n d ucte d wit h partici pa nts b y 
tele p h o ne or o nli ne/ we b c o nfere nce at 
t he baseli ne visit
T o c ollect data re gar di n g 
partici pa nts’ disease - a n d 
treat me nt-relate d e x perie nces
Sc he d ule of 
assess me nts a n d
pr oce d ures
Secti o n 8. 8
A d de d t hat a d diti o nal n o ncli nical 
i nf or mati o n ca n be f o u n d i n t he 
i n vesti gat or br oc h ure
F or clarit y o n w here t o fi n d m ore 
i nf or mati o n
Secti o n 2. 1
U p date d t he cli nical e x perie nce secti o n
T o pr o vi de m ore u p t o date 
i nf or mati o n o n t he cli nical 
st u dies
Secti o n 2. 1
A d de d i n di vi d ual le vel st o p pi n g r ules 
f or partici pa nts r olli n g o ver fr o m t he 
2 0 0 m g treat me nt ar m fr o m part a of 
st u d y g bt 0 2 1 6 0 1- 0 2 1
F or c o nsiste nc y wit h t he 
ori gi nati n g st u d y
Secti o n 6. 5. 1
Re vise d t he la n g ua ge i n t he treat me nt 
of o ver d ose
F or c o nsiste nc y wit h pfizer 
pr ocesses
Secti o n 6. 6
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 9 2
C h a n ge
R ati o n a le
Secti o n(s) affecte d 
A d de d a ta ble wit h e xa m ples of 
pr o hi bite d or restricte d c o nc o mita nt 
me dicati o ns
F or clarit y
Secti o n 6. 7. 1 ta ble 9
A d de d a secti o n re gar di n g 
e n vir o n me ntal e x p os ure, e x p os ure 
d uri n g pr e g na nc y or breastfee di n g, 
occ u pati o nal e x p os ure, a n d me dicati o n 
err ors
F or c o nsiste nc y wit h pfizer 
pr ocesses a n d f or a d diti o nal 
clarif y
Secti o n 8. 4. 1 3
Secti o n 8. 4. 1 3. 1
Secti o n 8. 4. 1 3. 2
Secti o n 8. 4. 1 3. 3
Secti o n 8. 4. 1 4
A d de d t o t he o utc o me meas ures “it is 
inte n de d t hat da y 1 c oi nci des wit h t he 
fi nal visit fr o m t he ori gi nati n g 
g bt 0 2 1 6 0 1 st u d y. E n d of treat me nt (e ot) 
assess me nts fr o m t he ori gi nati n g st u d y 
will ser ve as baseli ne assess me nts f or 
t his st u d y. If da y 1 f or t his st u d y is 
greater t ha n 7 da ys fr o m t he c o m pleti o n 
of t he ori gi nati n g st u d y, ne w baseli ne 
assess me nts will be o btai ne d. 
A d diti o nal assess me nts t hat ma y n ot 
ha ve bee n i ncl u de d i n t he pri or e ot 
assess me nts are o utli ne d i n t he sc he d ule 
of assess me nts a n d will nee d t o be 
c o m plete d pri or t o st u d y dru g 
a d mi nistrati o n.” 
T o clarif y t hat t here are t w o 
p ote ntial baseli ne assess me nts 
(eit her fr o m t he ori gi nati n g st u d y, 
or at t he start of t he ole)
Secti o n 9. 2. 1
A d de d a secti o n o n re p orti n g of safet y 
iss ues a n d seri o us breac hes of pr ot oc ol 
F or c o nsiste nc y wit h pfizer 
pr ocesses a n d f or a d diti o nal 
clarif y
Secti o n 1 0. 1. 3
Re vise d t he i nf or me d c o nse nt pr ocess, 
data pr otecti o n, disse mi nati o n of 
cli nical st u d y data, data q ualit y 
ass ura nce, st u d y a n d site start a n d 
cl os ure, p u blicati o n p olic y, s p o n s or’s 
me dicall y q ualifie d i n di vi d ual
F or c o nsiste nc y wit h pfizer 
te m plate la n g ua ge a n d pr ocesses
Secti o n 1 0. 1. 4
Secti o n 1 0. 1. 5
Secti o n 1 0. 1. 6
Secti o n 1 0. 1. 7
Secti o n 1 0. 1. 8
Secti o n 1 0. 1. 9
Secti o n 1 0. 1. 1 0
U p date d a p pe n di x 1 g ui deli nes f or d ose 
f or partici pa nts r olli n g o ver wit h a ga p 
i n d osi n g
F or a d diti o nal clarit y o n d ose 
i nf or mati o n
A p pe n di x 1
A d de d a p pe n di x 2 o n li ver safet y
T o pr o vi de g ui da nce o n 
m o nit ori n g, re p orti n g, a n d 
ma na gi n g p ote ntial dr u g -i n d uce d 
li ver i nj ur y
A p pe n di x 2
A b bre viati o ns: p gi -c, patie nt gl o bal i m pressi o n of c ha n ge; p gi -s, patie nt gl o bal i m pressi o n of se verit y; pr o mis, 
patie nt -re p orte d o utc o me meas ure me nt i nf or mati o n s yste m; sc d, sic kle cell disease; sf, s h ort f or m.
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 9 3
A m e n d me nt 2. 0 ( 1 1 Oct 2 0 2 2)
C h a n ge
R ati o n a le
Secti o n(s) affecte d 
C ha n ge d t he s p o ns or c o ntact 
fr o m
 t o  
 
.
Dr. 
is t he ne w cli nical 
scie nce lea d f or t he g bt 0 2 1 6 0 1-
0 2 2 st u d y.
Title pa ge
State me nt of a p pr o val a n d 
si g nat ure
I ncrease d t he fre q ue nc y of st u d y 
visits f or partici pa nts r olli n g i nt o 
t he g bt 0 2 1 6 0 1-0 2 2 st u d y fr o m 
t he g bt 0 2 1 6 0 1-0 1 2 st u d y.
D ue t o q ualit y iss ues at t he site 
of t he g bt 0 2 1 6 0 1 -0 1 2 st u d y, 
a d diti o nal visits a n d assess me nts 
f or t hese partici pa nts r olli n g i nt o 
t he o pe n la bel e xte nsi o n st u d y 
fr o m t he g bt 0 2 1 6 0 1-0 1 2 st u d y 
were i ncl u de d t o cl osel y m o nit or 
t he safet y a n d p k of t he 
partici pa nts.  
Secti o n 1. 1 
Secti o n 1. 2 
Secti o n 2. 2 
Secti o n 2. 3 
Secti o n 4. 1
Secti o n 4. 3
Secti o n 8. 2
A p pe n di x 1 – ta ble 1 2
U p date d t he test pr o d uct 
i nf or mati o n fr o m g bt 0 2 1 6 0 1 
ma y be pr o vi de d as a c oate d 
dis persi ble ta blet t o “a n 
a p pr o priate oral f or m ulati o n f or 
pe diatric partici pa nts w h o 
ca n n ot s wall o w t he re g ular 
ta blet”
T he pe diatric f or m ulati o n is still 
bei n g de vel o pe d.
Sec ti o n 1. 1 
Secti o n 6. 1
Re vise d t he seri o us a d verse 
e ve nt re p orti n g fr o m pa per 
f or ms t o t he electr o nic case 
re p ort f or ms via t he electr o nic 
data ca pt ure s yste m.
All a d verse e ve nt re p orti n g 
s h o ul d n o w be ca pt ure d 
electr o nicall y t o mi ni mize err or.
Secti o n 8. 4. 6
A m e n d me nt 1. 0 ( 1 9 J ul y 2 0 2 2)
C h a n ge
R ati o n ale
Secti o n(s) affecte d 
Re vise d t he baseli ne visit t o 
c oi nci de wit h t he da y 1 visit a n d 
a d de d clarificati o n la n g ua ge t o 
assess me nts d o ne at t hat visit.
It is i nte n de d f or t he da y 1 
baseli ne visit t o c oi nci de wit h 
t he fi nal visit fr o m t he 
ori gi nati n g g bt 0 2 1 6 0 1 st u d y.
Secti o n 1. 1 s y n o psis
Secti o n 1. 2 sc he d ule of 
assess me nts (ta ble 1, ta ble 2, 
ta ble 3)
Secti o n 4. 1 o verall desi g n
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)
P P D
P P D
P P D

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 9 4
1 1. 8. A p pe n di x 6: A b bre vi ati o ns
A b bre vi ati o n 
Ter m
A 1 t o A 3
al b u mi n uria ( K DI G O al b u mi n uria se verit y sta n dar dizati o n)
A C S
ac ute c hest s y n dr o me
A E
a d verse e ve nt
A KI
ac ute ki d ne y i nj ur y
A L T
ala ni ne a mi n otra nsferase
a P T T
acti vate d partial t hr o m b o plasti n ti me
A S T
as partate a mi n otra nsferase
BI D
t wice dail y
B S A
b o d y s urface area
C B D
ca n na bi di ol
C GI - C
Cli nical Gl o bal I m pressi o n of C ha n ge
C GI - S
Cli nical Gl o bal I m pressi o n of Se verit y
C K D
C hr o nic Ki d ne y Disease
C K D -E PI
C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n
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
cli nical trial
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 TI S
Cli nical Trial I nf or mati o n S yste m
D DI
dr u g - dr u g i nteracti o n
DI CI
dr u g -i n d uce d creati ni ne i ncrease
DI KI
dr u g -i n d uce d ki d ne y i nj ur y
DI LI
dr u g -i n d uce d li ver i nj ur y
D S M - V
Criteria f or S u bsta nce Use Dis or ders
E C
Et hics C o m mittee
E C C
E mer ge nc y C o ntact Car d
e Cr Cl
esti mate d creati ni ne cleara nce
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
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)
C CI

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 9 5
A b bre vi ati o n 
Ter m
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 M E A
E ur o pe, Mi d dle East, a n d Africa
E O S
e n d of st u d y
E O T
e n d of treat me nt
E P O
er yt hr o p oieti n
E T
earl y ter mi nati o n
E U
E ur o pea n U ni o n
E u dra C T
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)
F D A
F o o d a n d Dr u g A d mi nistrati o n
F S H
f ollicle-sti m ulati n g h or m o ne
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
h o ur
H b
he m o gl o bi n
H b S
sic kle he m o gl o bi n
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 S C T
he mat o p oietic ste m cell tra ns pla ntati o n
Ht
hei g ht
H U
h y dr o x y urea
I B
I nvesti gat or’s Br oc h ure
I C E
I nterc urre nt e ve nts
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
I g M
I m m u n o gl o b uli n M
I N D
I nvesti gati o nal Ne w Dr u g
I M P
I nvesti gati o nal me dici nal pr o d uct  
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 9 6
A b bre vi ati o n 
Ter m
I N R
I nter nati o nal N or malize d Rati o
I R B
I nstit uti o nal Re vie w B oar d
I R T
I nteracti ve res p o nse tec h n ol o g y
K
Pr o p orti o nalit y c o nsta nt
L D H
lactate de h y dr o ge nase
L F T
li ver f u ncti o n test
M A D
M ulti ple asce n di n g d ose
M O A
Mec ha nis m of acti o n
M QI 
Me dicall y Q ualifie d I n di vi d ual 
N A
N ot a p plica ble
N CI C T C A E
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
NI R S
near i nfrare d s pectr osc o p
NI M P/ A x M P
N o n I n vesti gati o nal Me dici nal Pr o d uct/ A u xiliar y Me dici nal Pr o d uct
N R S
n u meric rati n g scale
N S AI Ds
n o nster oi dal a nti -i nfla m mat or y dr u gs
O L E
o pe n -la bel e xte nsi o n
O x y -H b
O x y ge n -he m o gl o bi n
P A C L
Pr ot oc ol A d mi nistrati ve C ha n ge Letter
P D
p har mac o d y na mic
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 GI - S
Patie nt Gl o bal I m pressi o n of Se verit y
PI P
Pe diatric I n vesti gati o n Pla n
P K
p har mac o ki netic
P P K
p o p ulati o n p har mac o ki netic
P R O
Patie nt- R e 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 nt I nf or mati o n S yste m
P S P
Pe diatric St u d y Pla n
P S S A
Pfizer’s Seri o us A d verse E ve nt S u b missi o n Assista nt
P T
pr ot hr o m bi n ti me
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)
C CI
C CI

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 9 7
A b bre vi ati o n 
Ter m
Q D
o nce dail y
Q T Ls
Q ualit y t olera nce li mits
R B C
re d bl o o d cell
S A D
si n gle asce n di n g d ose
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S C
sic kle cell
S C D
sic kle cell disease
Screat
ser u m creati ni ne
Sc ys
ser u m c ystati n C
S F
s h ort f or m
S o A
sc he d ule of assess me nts
S O C
Sta n dar d of care
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 ns
t1/ 2
Half -life
T bili
t otal bilir u bi n
T E A E
treat me nt-e mer ge nt a d verse e ve nt
T H C
tetra h y dr oca n na bi n ol
T ma x
ti me of ma xi m u m c o nce ntrati o n
T M E
tar gete d me dical e ve nts
U L N
u p per li mit of n or mal
U S
U nite d States
V O C
vas o -occl usi ve crisis
W P AI + CI Q: S C D
W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt pl us Classr o o m I m pair me nt 
Q uesti o n naire: Sic kle Cell Disease v 2. 0
0 9 0 1 7 7 e 1 9f e 1 d 2 c b\ A p pr o v e d\ A p pr o v e d O n: 0 8- F e b- 2 0 2 4 1 4: 5 6 ( G M T)

Osi vel ot or (P F -0 7 9 4 0 3 6 7 or G B T 0 2 1 6 0 1)
Pr ot oc ol C 5 3 5 1 0 0 5 ( G B T 0 2 1 6 0 1 -0 2 2)
A me n d me nt 0 4, 0 8 Fe b 2 0 2 4
P FI Z E R C O N FI D E N TI A L
Pa ge 9 8
1 2. R E F E R E N C E S
Bra n d o w, A M a n d Lie m, RI . A d va nces i n t he dia g n osis a n d treat me nt of sic kle cell disease. 
J o ur nal of He mat ol o g y & O nc ol o g y 2 0 2 2; 1 5: 2 0: 1-1 3. d oi: 1 0. 1 1 8 6/s 1 3 0 4 5 - 0 2 2- 0 1 2 3 7-z.
Br o w n, R., A. Re dfer n, E. L is b o n, C. Was hi n gt o n, I. A g o d oa a n d K. S mit h -W hitle y  ( 2 0 2 1). 
G B T 0 2 1 6 0 1, a Ne xt Ge nerati o n H b S P ol y merizati o n I n hi bit or: Res ults of Safet y, 
T olera bilit y , P har mac o ki netics a n d P har mac o d yna mics i n A d ults L i vi n g wit h Sic kle Cell 
Disease a n d Healt h y V ol u nteers. A merica n S ociet y  of He mat ol o g y.
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