A Phase 4 Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Rimegepant in Episodic Migraine Prevention With Multiple Dosing Regimens
Phase: PHASE4
Conditions: Migraine
Sponsor: Pfizer

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 of 1 0 3
P FI Z E R C O N FI D E N TI A L
D R U G:
B H V - 3 0 0 0 (P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
S T U D Y N U M B E R( S):
B H V 3 0 0 0 - 4 0 4 ( C 4 9 51 0 1 0)
P R O T O C O L( S) TI T L E:
A P hase 4 Ra n d o mize d, D o u ble -bli n d, Place b o -c o ntr olle d 
St u d y  t o E val uate t he Efficac y  a n d Safety of Ri me ge pa nt
i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g 
Re gi me ns
I N D N U M B E R:
E u dr a C T N U M B E R:
1 0 9 8 8 6
2 0 2 1- 0 0 5 2 3 9- 2 2
S P O N S O R:
Pfizer I nc. 
6 6 H u ds o n B o ule var d East Ne w Y or k, N Y 1 0 0 0 1
O RI GI N A L P R O T O C O L 
D A T E:
2 2 N o v e m ber 2 0 2 1
V E R SI O N N U M B E R:
5. 0
V E R SI O N D A T E:
2 6 J u ne 2 0 2 3 
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 IR Bs/ E Cs a n d a n y  pr ot oc ol a d mi nistrati ve c ha n ge letter(s).
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 2 of 1 0 3
P FI Z E R C O N FI D E N TI A L
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S 
A m e n d me nt Versi o n 5. 0 
O ver all R ati o n ale f or t he A me n d me nt: C ha n ge i n s p o ns ors hi p fr o m Bi o ha ve n t o Pfizer wit h 
ali g n me nt of t he pr ot oc ol te m plate. 
Descri pti o n of c ha n ge
Brief Rati o nale
Secti o n # a n d Na me
S u bst a nti al M o dific ati o n(s)
Refere nce d st u d y n u m ber 
B H V 3 0 0 0 -4 0 4 t o C 4 9 5 1 0 1 0 a n d 
c o m p o u n d na me B H V -3 0 0 0 t o 
P F -0 7 8 9 9 8 0 1 t o reflect 
i de ntificati o n c ha n ges b y s p o ns or.
Reflects c ha n ge i n 
s p o ns ors hi p pr ot oc ol a n d 
c o m p o u n d i de ntificati o n 
n u m bers
1. 1 Bac k gr o u n d
7. 1. 1 I n vesti gati o nal Pr o d uct
Hea ders
Title pa ge
Re m o ve d t he e xcl usi o n criteri o n 
f or patie nts wit h HI V disease.
Ali g ne d wit h ri me ge pa nt 
prescri bi n g i nf or mati o n w here 
t here is n o e xcl usi o n f or use i n 
patie nts wit h HI V
5. 3. # 2a) E xcl usi o n C riteria
U p date d t he e xcl usi o n criteri o n f or 
patie nts wit h biliar y dis or der.
Ali g ne d wit h ri me ge pa nt 
prescri bi n g i nf or mati o n w here 
t here is n o e xcl usi o n f or use i n 
s u bjects wit h biliar y dis or der
5. 3. # 2f) E xcl usi o n Criteria
Re m o ve d Gil bert's S y n dr o me fr o m 
t he e xcl usi o nar y criteria.
Ali g ne d wit h ri me ge pa nt 
prescri bi n g i nf or mati o n w here 
t here is n o e xcl usi o n f or use i n 
Gil bert’s S y n dr o me
5. 3. # 2 h) E xcl usi o n Criteria
A m e n de d t he e xcl usi o n criteri o n 
f or b o d y mass i n de x t o > 3 5. 0 
k g/ m 2 fr o m 3 3. 0 k g/ m 2.
Ali g ne d defi niti o n t o be 
i ncl usi ve of all Class 1 
O besit y s u bjects
5. 3. # 2 o) E xcl usi o n Criteria
A m e n de d e xcl usi o n criteri o n f or 
H b A 1c t o > 7. 5 %.
All o we d i ncl usi o n of well 
c o ntr olle d dia betics ali g ne d 
wit h ri m ege pa nt prescri bi n g 
i nf or mati o n w here t here is n o 
e xcl usi o n f or s u bjects wit h 
dia betes
5. 3. # 5 g)   E xcl usi o n Criteria
A m e n de d t he he patic e xcl usi o n
criteria t o all o w s u bjects wit h 
1. 5 x U L N of A L T , A S T a n d T otal 
Bilir u bi n .
All o we d f or i ncl usi o n of 
s u bjects wit h mil d L F T 
ele vati o ns c o nsiste nt wit h t he 
prescri bi n g i nf or mati o n w here 
t here is n o e xcl usi o n f or 
s u bjects wit h mil d he patic 
disease 
4. 3. 1. 1 Scree ni n g Visit
4. 3. 1. 2 Pre -ra n d o mizati o n E val uati o n 
Visit
5. 3. # 5 c) & 5 d) E x cl usi o n Criteria
R e m o ve d s pecific e xcl usi o nar y 
E C G criteria
All o we d f or i n vesti gat or 
o pi ni o n o n e xcl usi o nar y E C G 
fi n di n gs
5. 3. # 5 b) E xcl usi o n Criteria
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 3 of 1 0 3
P FI Z E R C O N FI D E N TI A L
C ha n ge d G F R fr o m 4 0 t o 3 0 
ml/ mi n/ 1. 7 3 m 2.
All o we d f or s u bjects wit h 
m o derate re nal i m pair me nt t o 
be i ncl u de d i n t he trial 
c o nsiste nt wit h t he prescri bi n g 
i nf or mati o n
5. 3. # 5a) E xcl usi o n Criteria
A d de d e xcl usi o n criteri o n f or 
i n v ol ve me nt i n t he c o n d uct of t he 
cli nical trial b y staff or fa mil y 
me m bers.
Ali g ne d wit h Pfizer pr ot oc ol 
te m plate
5. 3. # 7 l) E xcl usi o n Criteria
All o we d f or rescree ni n g of 
s u bjects d ue t o pri or faile d 
eli gi bilit y criteria.
All o we d f or rescree ni n g of 
s u bjects w h o pre vi o usl y were 
scree n faile d f or a n a me n de d 
e xcl usi o nar y criteri o n
4. 3. 1. 1 Scree ni n g visit
All o we d d ose of as piri n u p t o 1 0 0 
m g dail y f or car di o vasc ular 
pr o p h yla xis.
Ali g ne d wit h e x -U S d osi n g 
f or l o w d ose 
as piri n pr o p h yla xis
5. 3. # 6 c) b ullet Pr o hi bite d 
Me dicati o ns
5. 4. # 1 4) Pr o hi bite d a n d Restricte d 
C o nc o mita nt Me dicati o ns a n d De vices
Re m o ve d tacr oli m us fr o m t he 
Str o n g C Y P 3 A 4 i n hi bit ors list. 
Re m o ve d gra pefr uit j uice fr o m t he 
M o derate C Y P 3 A 4 i n hi bit ors list .
Ali g ne d wit h n o ncli nical a n d 
cli nical dr u g t o dr u g 
i nteracti o n ( D DI) i nf or mati o n 
a vaila ble o n ri me ge pa nt
1 6. 2 A p pe n di x 2 – I n hi bit ors a n d 
I n d ucers of C Y P 3 A 4
C ha n ge d t he ter m 
o na b ot uli n u mt o xi n A t o b ot uli n u m
t o xi n i njecti o ns.
A d de d br oa der dr u g class 
ter m
5. 4 # 1 & # 3 Pr o hi bite d a n d Restricte d 
C o nc o mita nt Me dicati o ns a n d De vices
C ha n ge d ne ur o m usc ular bl oc ker t o 
B ot uli n u m t o xi n i njecti o ns .
Mai ntai ne d c o nsiste nc y of 
n o me nclat ure wit h secti o n 5. 4
1 6. 4 A p pe n di x 4 Cate g or y # 8. 
Cate g ories of Mi grai ne Pre ve nti o n 
Me dicati o ns 
C ha n ge d ter m n o n -mi grai ne t o 
n o n- hea dac he.
Clarifie d t o i ncl u de br oa der 
defi niti o n of hea dac he w hic h 
i ncl u des n o n-mi grai ne a n d 
mi grai ne hea dac he
5. 4. # 7 a n d 5. 4. # 1 4 Pr o hi bite d a n d 
Restricte d C o nc o mita nt Me dicati o ns 
a n d De vices
Clarifie d t hat i n case of DI LI t he 
PI  s h o ul d deter mi ne if t he patie nt 
ca n safel y c o nti n ue i n t he st u d y
a n d e x pa n de d DI LI defi niti o n t o 
i ncl u de s u bjects wit h a b n or mal 
he pa tic f u ncti o n at st u d y e ntr y.
Ali g ne d wit h c o u ntr y s pecific 
a me n d me nt a n d u p date d 
defi niti o n t o ali g n wit h re vise d 
e xcl usi o n criteria 
8. 4 P ote ntial Dr u g I n d uce d Li ver 
I njur y ( DI LI)
A d de d A p pe n di x f or E C G 
fi n di n gs of P ote ntial Cli nical 
C o ncer n .
Ali g ne d wit h Pfizer pr ot oc ol 
te m plate
1 6. 6 A p pe n di x 6 E C G Fi n di n gs of 
P ote ntial Cli nical C o ncer n
Clarifie d defi niti o n of S p o ns or's 
Me dicall y Q ualifie d I n di vi d ual.
Ali g ne d wit h Pfizer pr ot oc ol 
te m plate
1 0. 6 S p o ns or’s Me dicall y Q ualifie d 
I n di vi d ual
A d de d be nefit ris k assess me nt
Ali g ne d wit h e x -U S c o u ntr y 
s pecific a me n d me nt 
re q uire me nts
1. 4 Be nefit Ris k Assess me nt
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 4 of 1 0 3
P FI Z E R C O N FI D E N TI A L
Defi ne d e n d of st u d y
Ali g ne d wit h c o u ntr y s pecific 
a me n d me nt
4. 1 St u d y Desi g n a n d D urati o n
N o n -s u bst a nti al M o dific ati o n(s)
U p date d Seri o us A d verse E ve nt 
( S A E) re p orti n g desti nati o n a n d 
electr o nic re p orti n g s yste m 
a d mi nistrati ve c ha n ges a n d 
clarificati o ns
I nc or p orati o n of n o n-
s u bsta ntial c ha n ges descri be d 
i n pre vi o us P A C L date d 
2 8 A pr 2 0 2 3
8. 1. 2 C ollecti o n a n d Re p orti n g Seri o us 
A d verse E ve nts
Clarifie d Secti o n 8. 2. 1
Ali g ne d wit h Pfizer pr ot oc ol 
te m plate 
8. 2. 1 C ollecti o n a n d Re p orti n g of N o n -
seri o us A d verse E ve nts
U p date d te xt f or Data Pr otecti o n.
Ali g ne d wit h Pfizer pr ot oc ol 
te m plate
1 5 Data Pr otecti o n
A d de d c o m plia nce ai m f or I P of 
8 0 %
Defi ne d c o m plia nce f or 
clarit y
7. 4 Treat me nt C o m plia nce
A d de d c o ntrace pti o n re q uire me nt
Ali g ne d wit h Ital y c o u ntr y 
s pecific a me n d me nt
1 6. 1 A p pe n di x 1 C o u ntr y S pecific 
Re q uire me nts
Clarifie d t he dis b urse me nt of 
u n use d , n o n-e x pire d partial 
wallets
Ali g ne d wit h details of I P 
Ma n ual
4. 3. 2 D o u ble -bli n d Treat me nt P hase
U p date d t o i ncl u de U S, U K, E U 
refere nce a n d I B refere nce.
A d diti o nal safet y refere nce
1. 3 Pr o d uct De vel o p me nt Bac k gr o u n d
Clarifie d st u d y dr u g destr ucti o n
U p date d desti nati o n f or st u d y 
dr u g destr ucti o n
7. 5 Destr ucti o n a n d Ret ur n of St u d y 
Dr u g
U p date d st u d y s u m mar y 
( S y n o psis)
S y n o psis was c ha n ge d t o 
i ncl u de all rele va nt secti o ns of 
t he E U C T R
St u d y s u m mar y ( S y n o psis)
Re m o ve d Cli nical Pr ot oc ol 
A p pr o val F or m
Ali g ne d wit h Pfizer pr ot oc ol 
te m plate
Pr ot oc ol a p pr o val f or m
Re m o ve d PI  declarati o n pa ge
Ali g ne d wit h Pfizer pr ot oc ol 
te m plate
PI  declarati o n pa ge
Clarifie d defi niti o n of a nal ysis 
sets
Ali g ne d wit h Statistical 
A nal ysis Pla n
9. 2 A nal ysis Sets
A d de d refere nce t o q ualit y 
t olera nce li mits
Ali g ne d wit h Pfizer pr ot oc ol 
te m plate
9. 3. 2 Safet y A nal yses
Clarifie d/c orrecte d statistical 
met h o ds
Ali g ne d wit h Statistical 
A nal ysis Pla n a n d F D A 
G ui da nce f or I n d ustr y 
A dj usti n g f or C o variates i n 
Ra n d o mize d Cli nical Trials 
f or Dr u gs a n d Bi ol o gical 
Pr o d ucts
9. 3. 1. 1 Pri mar y Efficac y E n d p oi nt
9. 3. 1. 2 Sec o n dar y Efficac y E n d p oi nt
9. 3. 1. 3 M ulti plicit y C orrecti o n
Re m o ve d P hase I st u d y e xce pti o n. 
Re m o ve d state me nt re gar di n g 
Pri nci pal I n vesti gat or a n d t he 
S p o ns or’s re prese ntati ve 
si g nat or y. A d de d S p o ns or’s 
Ali g ne d wit h Pfizer pr ot oc ol 
te m plate
1 0. 1 G o o d Cli nical Practice
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 5 of 1 0 3
P FI Z E R C O N FI D E N TI A L
re g ulat or y a n d et hics 
res p o nsi bilities.
A d de d Pfizer sta n dar d t e xt f or 
Disse mi nati o n of Cli nical St u d y 
Data.
Ali g ne d wit h Pfizer pr ot oc ol 
te m plate
1 0. 5 Disse mi nati o n of Cli nical St u d y 
Data
A d de d A E i nf or mati o n o n lac k of 
efficac y a n d me dicati o n err ors
Ali g ne d wit h Pfizer pr ot oc ol 
te m plate
8. 6 Lac k of Efficac y
8. 7 Me dicati o n Err ors
A d de d Pfizer sta n dar d safet y 
la n g ua ge f or 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, e x p os ure d uri n g 
breastfee di n g, occ u pati o nal 
e x p os ure
Ali g ne d wit h Pfizer pr ot oc ol 
te m plate
8. 5 E n vir o n me ntal e x p os ure, E x p os ure 
d uri n g Pre g na nc y, a n d Occ u pati o nal 
e x p os ure
M o ve d pri or Pr ot oc ol A me n d me nt 
S u m mar y of C ha n ges t o 
A p pe n di x
E dit orial
1 6. 7 A p pe n di x 7 Pr ot oc ol A me n d me nt 
Hist or y
U p date d List of a b bre viati o ns ,
E dit orial
List of A b bre viati o ns
C ha n ge d ter m N o n -I nvesti gati o nal 
Pr o d uct, t o C o nc o mita nt T hera p y
E dit orial c ha n ges
7. 1. 2 C o nc o mita nt T hera p y
State d t hat t here is 1 pla n ne d 
data base l oc k a n d n o i nteri m 
a nal ysis is pla n ne d
Clarificati o n
9. 4 Sc he d ule of A nal yses
Re m o ve d n otifie d I R B/I E C wit hi n 
5 da ys
A m e n de d t o all ow f or 
i m me diate acti o n t o be 
i m ple me nte d
1 2 A me n d me nts
Re m o ve d t he s u b hea der ot her
i ncl usi o n criteria # 6.
E dit orial /f or matti n g c ha n ge
5. 2 I ncl usi o n Criteria
C orrecte d i nc o nsiste ncies a n d
t y p o gra p hical err ors t hr o u g h o ut
t he pr ot oc ol.
C orrecti o ns t o pr o vi de clarit y 
a n d c o nsiste nc y t hr o u g h o ut 
t he pr ot oc ol. 
A p plica ble secti o ns of t he pr ot oc ol
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 6 of 1 0 3
P FI Z E R C O N FI D E N TI A L
S T U D Y S U M M A R Y ( S Y N O P SI S)
Pr ot oc ol Title : A P hase 4 Ra n d o mize d, D o u ble -bli n d, Place b o -c o ntr olle d St u d y t o E val uate t he 
Efficac y  a n d Safety of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n wit h M ulti ple D osi n g 
Re gi me ns
Brief Title : T he p ur p ose of t his st u d y  is t o c o m pare t he efficac y a n d safety of dail y  a n d e ver y 
ot her da y  d osi n g of ri me ge pa nt t o place b o as a pre ve nti ve treat me nt f or e pis o dic mi grai ne.
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 0 9 8 8 6
E u dra C T N u m ber:
2 0 2 1- 0 0 5 2 3 9- 2 2
Cli nical Trials. g o v I D:
N C T 0 5 2 1 7 9 2 7
Pr ot oc ol N u m ber:
B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0
P hase:
4
R ati o n ale: T his st u d y  is bei n g c o n d ucte d t o e val uate t he efficac y, safet y, a n d t olera bilit y of 
E O D a n d dail y ri me ge pa nt d osi n g re gi me ns f or t he pre ve nti o n of e pis o dic mi grai ne.
Pri m ar y O bjecti ves:
T o e val uate t he efficac y  of E O D a n d dail y ri me ge pa nt d osi n g re gi me ns relati ve t o place b o as a 
pre ve nti ve treat me nt f or e pis o dic mi grai ne, as meas ure d b y t he mea n re d ucti o n fr o m t he 
O bser vati o n P hase i n t he n u m ber of mi grai ne da y s per m o nt h o ver t he e ntire D o u ble-bli n d 
Treat me nt P hase.
Sec o n d ar y O bjecti ves:
1.
T o e val uate t he pr o p orti o n of s u bjects wit h > 5 0 % re d ucti o n fr o m t he O bser vati o n P hase 
i n t he n u m ber of m o derate t o se vere mi grai ne da ys per m o nt h o ver t he e ntire D o u ble-
bli n d Treat me nt P hase f or t he E O D a n d dail y  ri me ge pa nt d osi n g re gi me ns relati ve t o 
place b o.
2.
T o e val uate t he mea n re d ucti o n fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne 
da y s per m o nt h i n t he last 4 wee ks of t he D o u ble-bli n d Treat me nt P hase f or t he E O D a n d 
dail y  ri me ge pa nt d osi n g re gi me ns relati ve t o place b o.
3.
T o e val uate t he mea n re d ucti o n fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne 
da y s per m o nt h i n t he first 4 wee ks of t he D o u ble-bli n d Treat me nt P hase f or t he E O D a n d 
dail y  ri me ge pa nt d osi n g re gi me ns relati ve t o place b o.
4.
T o e val uate t he mea n n u m ber of ac ute mi grai ne -s pecific me dicati o n d a y s per m o nt h o ver 
t he e ntire D o u ble-bli n d Treat me nt P hase f or t he E O D a n d dail y ri me ge pa nt d osi n g 
re gi me ns relati ve t o place b o.
5.
T o e val uate t he mea n c ha n ge fr o m baseli ne i n t he Mi grai ne- S pecific Q ualit y -of -Life 
Q uesti o n naire v 2. 1 ( M S Q) restricti ve r ole f u ncti o n d o mai n sc ore at Wee k 1 2 of t he 
D o u ble- bli n d Treat me nt P hase f or t he E O D a n d dail y ri me ge pa nt d osi n g re g i me ns 
relati ve t o place b o.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 7 of 1 0 3
P FI Z E R C O N FI D E N TI A L
6.
T o e val uate t he safet y a n d t olera bilit y of ri me ge pa nt d uri n g t he D o u ble- bli n d Treat me nt 
a n d O pe n-la bel E xte nsi o n P hases.
7.
T o e val uate t he fre q ue nc y of A L T or A S T > 3 x u p per li mit of n or mal ( U L N) c o nc urre nt 
wit h t otal bilir u bi n > 2 x U L N i n s u bjects treate d wit h ri me ge pa nt d uri n g t he D o u ble-
bli n d Treat me nt a n d O pe n -la bel E xte nsi o n P hases
8.
T o e val uate t he fre q ue ncies of he patic -relate d a d verse e ve nts ( A Es) a n d he patic-relate d 
A Es lea di n g t o st u d y  dr u g disc o nti n uati o n i n s u bjects treate d wit h ri me ge pa nt d uri n g t he 
D o u ble- bli n d Treat me nt a n d O pe n -la bel
Pri m ar y E n d p oi nt:
Mea n c ha n ge fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da y s per m o nt h o ver t he 
e ntire D o u ble -bli n d Treat me nt P hase ( Wee ks 1 t o 1 2).
Sec o n d ar y E n d p oi nts:
1.
Pr o p orti o n of s u bjects wit h > 5 0 % re d ucti o n t he O bser vati o n P hase i n t he n u m ber of 
m o derate t o se vere mi grai ne da y s per m o nt h o ver t he e ntire D o u ble-bli n d Treat me nt 
P hase ( Wee ks 1 t o 1 2).
2.
Mea n c ha n ge fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne d a y s per m o nt h i n 
t he last 4 wee ks ( Wee ks 9 t o 1 2) of t he D o u ble-bli n d Treat me nt P hase.
3.
Mea n c ha n ge fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da y s per m o nt h i n 
t he first 4 wee ks ( Wee ks 1 t o 4) of t he D o u ble-bli n d Treat me nt P hase.
4.
Mea n n u m ber o f ac ute mi grai ne-s pecific me dicati o n da ys per m o nt h o ver t he e ntire 
D o u ble- bli n d Treat me nt P hase ( Wee ks 1 t o 1 2). Ac ute mi grai ne- s pecific me dicati o ns are 
tri pta ns a n d er g ota mi ne.
5.
Mea n c ha n ge fr o m baseli ne i n t he M S Q restricti ve r ole f u ncti o n d o mai n sc ore at Wee k 
1 2 of t he D o u ble -bli n d Treat me nt P hase.
6.
N u m ber a n d perce nta ge of s u bjects wit h A Es b y i nte nsit y, seri o us a d verse e ve nts ( S A Es), 
A Es lea di n g t o st u d y  dr u g disc o nti n uati o n, a n d gra de 3 t o 4 la b orat or y test a b n or malities 
d uri n g t he D o u ble -bli n d Treat me nt a n d O pe n- la bel E xte nsi o n P hases.
7.
N u m ber a n d perce nta ge of s u bjects treate d wit h ri me ge pa nt wit h A S T or A L T ele vati o ns 
> 3 x U L N c o nc urre nt (i.e., o n t he sa me la b orat or y  c ollecti o n date) wit h t otal bilir u bi n > 
2 x U L N d uri n g t he D o u ble -bli n d Treat me nt a n d O pe n -la bel E xte nsi o n P hases.
8.
N u m ber a n d perce nta ge of s u bjects treate d wit h ri me ge pa nt wit h he patic relate d A Es b y 
i nte nsit y, a n d he patic-relate d A Es lea di n g t o st u d y dr u g disc o nti n uati o n d uri n g t he 
D o u ble -bli n d Treat me nt a n d O pe n -la bel E xte nsi o n P hases.
O ver all Desi g n:
T his is a m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y t o assess t he efficac y 
a n d safet y of ri me ge pa nt i n e pis o dic mi grai ne pre ve nti o n. D uri n g t he D o u ble -bli n d Treat me nt 
P hase, s u bjects will be ra n d o mize d t o dail y  d osi n g (ri me ge pa nt 7 5 m g O D T dail y , ri me ge pa nt 7 5 
m g O D T d ose d e ver y  ot her da y ( E O D) alter nati n g wit h place b o f or matc hi n g ri me ge pa nt 7 5 m g 
O D T d ose d E O D, or place b o).
All s u bjects will partici pate i n a 2 8 -d a y  O bser vati o n P hase. D uri n g t he O bser vati o n P hase, 
s u bjects will treat mi grai nes wit h ac ute sta n dar d of care mi grai ne me dicati o ns. S u bjects will 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 8 of 1 0 3
P FI Z E R C O N FI D E N TI A L
re p ort mi grai ne occ urre nce, mi grai ne pai n feat ures a n d ass ociate d sy m pt o ms (e. g., pai n i nte nsit y , 
na usea, p h ot o p h o bia a n d p h o n o p h o bia), a n d use of ac ute mi grai ne me dicati o n i n a n electr o nic 
diar y  (e Diar y).
At t he Baseli ne Visit, eli gi bilit y  f or c o nti n ue d partici pati o n i n t he st u d y will be assesse d bef ore 
ra n d o mizati o n occ urs a n d bef ore st u dy dr u g is dis pe nse d. S u bjects will be ra n d o mize d 1: 1: 1 
acr oss 3 treat me nt gr o u ps i n t he D o u ble- bli n d Treat me nt P hase: ri me ge pa nt 7 5 m g O D T d ose d 
E O D alter nati n g wit h matc hi n g place b o ( n = 2 2 0); ri me ge pa nt 7 5 m g O D T d ose d dail y  d osi n g ( n 
= 2 2 0); or place b o f or matc hi n g ri me ge pa nt 7 5 m g O D T d ose d dail y ( n = 2 2 0). D uri n g t he 
D o u ble -bli n d Treat me nt P hase, s u bjects will be i nstr ucte d t hat t he y  m ust ta ke 1 ta blet of bli n de d 
st u d y dr u g daily. If s u bjects ha ve a mi grai ne d uri n g t he D o u ble -bli n d Treat me nt P hase, t he n t he y  
ma y  treat t he mi grai ne wit h per mitte d ac ute mi grai ne me dicati o n as nee de d w hile c o nti n ui n g t o 
ta ke t he st u d y dr u g. S u bjects will ta ke t he assi g ne d st u d y dr u g f or 1 2 wee ks. S u bjects will rec or d
mi grai ne occ urre nce, mi grai ne pai n feat ures a n d ass ociate d s y m pt o ms, a n d use of ac ute mi grai ne 
me dicati o n i n t he e Diar y  d uri n g t he D o u ble-bli n d Treat me nt P hase.
At t he c o m pleti o n of t he 1 2 - wee k D o u ble- bli n d Treat me nt P hase, s u bjects will be e val uate d f or 
e ntr y i nt o t he 1 2-wee k O pe n -la bel E xte nsi o n P hase f oll o wi n g la b orat or y res ults wit hi n 
acce pta ble ra n ges per pr ot oc ol. D uri n g t he O pe n-la bel E xte nsi o n P hase, s u bjects will be 
i nstr ucte d t hat t he y m ust ta ke 1 ta blet of ri me ge pa nt 7 5 m g O D T me dicati o n e ver y da y, 
re gar dless of w het her t he y ha ve a mi grai ne t hat da y.
All ra n d o mize d s u bjects will ha ve f oll o w- u p visits at a p pr o xi matel y 2 wee ks a n d 8 wee ks after 
t he last visit i n t he last treat me nt p hase. S u bjects will als o rec or d all c o nc o mita nt me dicati o ns, 
i ncl u di n g ac ute sta n dar d of care mi grai ne me dicati o ns ( b ot h prescri be d a n d O T C), ta ke n 
t hr o u g h o ut t he e ntire st u d y i n t he c o nc o mita nt me dicati o n pa per diar y.
N u m ber of S u bjec ts:
A p pr o xi matel y  2 0 0 0 s u bjects will be scree ne d t o ra n d o mize u p t o a p pr o xi matel y 6 6 0 s u bjects 
wit h a hist or y  of e pis o dic mi grai ne t hat is c o nfir me d i n t he O bser vati o n P hase. S u bjects will be 
ra n d o mize d 1: 1: 1 acr oss 3 treat me nt gr o u ps i n t he D o u ble-bli n d Treat me nt P hase: ri me ge pa nt 7 5 
m g O D T d ose d E O D alter nati n g wit h matc hi n g place b o ( n = 2 2 0) ri me ge pa nt 7 5 m g O D T d ose d 
dail y  ( n = 2 2 0); or place b o f or matc hi n g ri me ge pa nt 7 5 m g O D T d ose d dail y  ( n = 2 2 0). U p t o 
6 6 0 s u bjects (i ncl u di n g u p 2 2 0 s u bjects i n t he dail y d osi n g c o h ort) ma y  e nter t he O pe n-la bel 
E xte nsi o n P hase f or a n a d diti o nal 1 2 wee ks wit h dail y  d osi n g.
St u d y P o p ul ati o n:
T he st u d y  will recruit male a n d fe male s u bjects, 1 8 y ears of a ge or ol der wit h at least a o ne -ye ar 
hist or y  of e pis o dic mi grai ne ( wit h or wit h o ut a ura) c o nsiste nt wit h a dia g n osis acc or di n g t o t he 
I nter nati o nal Classificati o n of Hea dac he Dis or ders, 3r d e diti o n. 4 Per t heir o w n re p ort, s u bjects 
m ust ha ve mi grai ne o nset pri or t o a ge 5 0, mi grai ne attac ks t hat last 4 -7 2 h o urs (if n ot treate d), 
a n d ha ve ha d 4-1 4 mi grai ne attac ks per 4 wee k peri o d wit hi n t he 1 2 wee ks pri or t o t he Scree ni n g 
Visit. S u bjects m ust als o ha ve at least 4 Mi grai ne Da y s a n d n o m ore t ha n 1 4 Hea dac he Da ys 
d uri n g 2 8 da y s i n t he O bser vati o n P hase.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 9 of 1 0 3
P FI Z E R C O N FI D E N TI A L
W O C B P w h o are u n willi n g or u na ble t o use a n acce pta ble c o ntrace pti ve met h o d or a bsti ne nce t o 
a v oi d pre g na nc y f or t he e ntire st u d y a n d f or 6 0 da ys after t he last d ose of st u d y  dr u g, w o me n 
w h o are pre g na nt or breastfee di n g, a n d w o me n wit h a p ositi ve pre g na nc y  test at scree ni n g or 
pri or t o st u d y  dr u g a d mi nistrati o n will be e xcl u de d.
Use of pr o p h yl actic mi grai ne me dicati o n wit hi n 3 0 da y s pri or t o t he Scree ni n g Visit is 
p r o hi bite d. S u bjects wit h a hist or y of use of a nal gesics (e. g., n o n-ster oi dal a nti-i nfla m mat or y 
dr u gs [ N S AI Ds] or aceta mi n o p he n) or use of me dicati o n acce pte d f or treat me nt of ac ute 
mi grai ne f or a n o n mi grai ne i n dicati o n o n ≥ 1 5 da ys per m o nt h d uri n g t he 3 m o nt hs ( 1 2 wee ks) 
pri or t o t he Scree ni n g Visit are e xcl u de d. S u bjects w h o pre vi o usl y disc o nti n ue d bi ol o gic 
mi grai ne me dicati o ns (s uc h as C G R P m o n ocl o nal a nti b o dies) m ust ha ve d o ne s o at least 
6 m o nt hs ( 2 4 wee ks) pri or t o t he Scree ni n g Visit.
St atistic al M et h o ds:
T he st u d y  will ra n d o mize a p pr o xi matel y 2 2 0 s u bjects wit h c o nfir me d e pis o dic mi grai ne per 
treat me nt gr o u p. Base d o n data fr o m st u d y B H V 3 0 0 0 -3 0 5, we esti mate t hat t his will res ult i n 
r o u g hly 2 0 0 s u bjects per treat me nt gr o u p i n t he mi grai ne a nal ysis set. Ass u mi n g ri me ge pa nt 
pr o vi des r o u g hl y a 1. 1 da y a d va nta ge o ver place b o o n t he pri mar y e n d p oi nt, a n d ass u mi n g a 
c o m m o n sta n dar d de viati o n of 3. 5 da y s, t he n t he st u d y will ha ve r o u g hly 8 0 % p o wer o n t he 
pri mar y  e n d p oi nt at a 2-si de d al p ha le vel of 0. 0 2 5.
T he pri mar y  e n d p oi nt, mea n c ha n ge fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da ys 
per m o nt h o ver t he e ntire D o u ble -bli n d Treat me nt P hase ( Wee ks 1 t o 1 2), will be assesse d usi n g 
a li near mi xe d effects m o del wit h re peate d meas ures. 
T he pr o p ort i o n of s u bjects wit h > 5 0 % re d ucti o n fr o m t he O bser vati o n P hase i n t he n u m ber of 
m o derate or se vere mi grai ne da y s per m o nt h o ver t he e ntire D o u ble-bli n d Treat me nt P hase 
( Wee ks 1 t o 1 2) will be assesse d usi n g Ma ntel-Hae nszel ris k esti mati o n. 
T he mea n c ha n g e fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da y s per m o nt h i n t he 
first 4 wee ks ( Wee ks 1 t o 4) a n d t he last 4 wee ks ( Wee ks 9 t o 1 2) of t he D o u ble-bli n d Treat me nt 
P hase will be assesse d fr o m t he sa me m o del use d f or t he pri mar y  efficac y e n d p oi nt.   
T he mea n n u m ber of ac ute mi grai ne- s pecific me dicati o n da ys per m o nt h o ver t he e ntire D o u ble-
bli n d Treat me nt P hase ( Wee ks 1 t o 1 2) will be assesse d usi n g a li near mi xe d effects m o del wit h 
re peate d meas ures. 
T he mea n c ha n ge fr o m baseli ne i n t he M S Q restricti ve r ole f u ncti o n d o mai n sc ore at Wee k 1 2 
will be assesse d usi n g a li near m o del.
Safet y  e n d p oi nts will be assesse d descri pti vel y.
Ris k/ Be nefit Assess me nt:
Ri me ge pa nt is bei n g de vel o pe d f or t he treat me nt of mi grai ne. Effecti ve ness f or t he ac ute 
treat me nt of mi grai ne was i nitiall y de m o nstrate d i n a P hase 2 b d o u ble-bli n d, ra n d o mize d, 
place b o -c o ntr olle d, d ose-ra n gi n g st u dy w here ri me ge pa nt at 7 5 m g s h o we d effica c y o n all f o ur 
tra diti o nal e n d p oi nts: pai n, na usea, p h ot o p h o bia a n d p h o n o p h o bia. 1 Efficac y was c o nfir me d f or 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 0 of 1 0 3
P FI Z E R C O N FI D E N TI A L
t he ac ute treat me nt of mi grai ne i n t hree pi v otal P hase 3 trials usi n g t he c urre nt re gistrati o nal c o-
pri mar y  e n d p oi nts of p ai n free d o m a n d free d o m fr o m m ost b ot hers o me sy m pt o m at 2 h o urs after 
d osi n g. Effecti ve ness f or t he pre ve nti ve treat me nt of e pis o dic mi grai ne was de m o nstrate d i n a 
P hase 2/ 3 d o u ble -bli n d, ra n d o mize d, place b o -c o ntr olle d st u d y of ri me ge pa nt 7 5 m g d ose d e ver y 
ot her da y  ( E O D). 2 E ver y ot her da y  d osi n g was als o well t olerate d wit h n o si g nals of 
h y perse nsiti vit y , car di o vasc ular e ve nts, or he pat ot o xicit y. E ver y ot her da y sc he d ule d d osi n g wit h 
as nee de d d osi n g was s h o w n t o be well t olerate d wit h a fa v ora ble safet y pr ofile
T he res ults of p re vi o us st u dies of ri me ge pa nt s u p p ort t he i n vesti gati o n of ri me ge pa nt i n e pis o dic 
mi grai ne pre ve nti o n wit h m ulti ple d osi n g re gi me ns, a n 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 
s u bjects, t he p ote ntial ris ks ass ociate d wit h ri me ge pa nt 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 s u bjects wit h e pis o dic mi grai ne.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 1 of 1 0 3
P FI Z E R C O N FI D E N TI A L
S T U D Y S C H E M A TI C
Fi g ure 1
1 2 Wee ks of D o u ble -bli n d Tre at me nt wit h D ail y D osi n g, F oll o we d b y 1 2 
Wee ks of O pe n -l a bel Tre at me nt wit h D ail y D osi n g
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 2 of 1 0 3
P FI Z E R C O N FI D E N TI A L
T A B L E O F C O N T E N T S
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S ..................................................... 2
S T U D Y S U M M A R Y ( S Y N O P SI S) .............................................................................................. 6
S T U D Y S C H E M A TI C ................................................................................................................ 1 1
T A B L E O F C O N T E N T S ............................................................................................................ 1 2
LI S T O F T A B L E S ....................................................................................................................... 1 6
LI S T O F FI G U R E S ..................................................................................................................... 1 6
LI S T O F A B B R E VI A TI O N S..................................................................................................... 1 7
1
I N T R O D U C TI O N A N D R A TI O N A L E ............................................................................. 1 9
1. 1
B ac k gr o u n d ...................................................................................................................... 1 9
1. 2
C G R P’s R ole i n Mi gr ai ne ...............................................................................................2 0
1. 3
Pr o d uct De vel o p me nt B ac k gr o u n d ................................................................................ 2 0
1. 4
Be nefit Ris k Assess me nt .................................................................................................. 2 1
1. 5
St u d y R ati o n ale ................................................................................................................ 2 2
1. 5. 1
St u d y Desi g n R ati o n ale ..............................................................................................2 3
1. 5. 2
D ose Selecti o n ............................................................................................................. 2 3
1. 6
Rese arc h H y p ot hesis ........................................................................................................ 2 4
2
S T U D Y O B J E C TI V E S ........................................................................................................ 2 4
2. 1
Pri m ar y ............................................................................................................................. 2 4
2. 2
Sec o n d ar y................................ .......................................................................................... 2 4
2. 3
E x pl or at or y O bjecti ves .................................................................................................... 2 5
3
S T U D Y E N D P OI N T S .......................................................................................................... 2 6
3. 1
Pri m ar y ............................................................................................................................. 2 6
3. 2
Sec o n d ar y................................ .......................................................................................... 2 6
3. 3
Defi niti o n of Mi gr ai ne D a ys ............................................................................................ 2 7
3. 4
Defi niti o n of He a d ac he D a ys ........................................................................................... 2 8
4
S T U D Y P L A N ....................................................................................................................... 2 8
4. 1
St u d y Desi g n a n d D ur ati o n ............................................................................................. 2 8
4. 2
St u d y Sc he m atic ............................................................................................................... 3 1
4. 3
Sc he d ule of Assess me nts .................................................................................................. 3 2
4. 3. 1
O bser v ati o n P h ase ..................................................................................................... 4 0
4. 3. 1. 1
Scree ni n g Visit................................ ......................................................................4 0
4. 3. 1. 2
Pre -r a n d o miz ati o n E v al u ati o n Visit .................................................................. 4 1
4. 3. 2
D o u ble -bli n d Tre at me nt P h ase .................................................................................4 1
4. 3. 2. 1
B aseli ne ( R a n d o miz ati o n) Visit ..........................................................................4 2
4. 3. 2. 2
Wee k 1 2 or E O T Visit .......................................................................................... 4 3
4. 3. 3
O pe n -l a bel E xte nsi o n P h ase......................................................................................4 3
4. 3. 3. 1
Wee k 2 4 or E O T Visit ..........................................................................................4 4
4. 3. 4
F oll o w -u p P h ase .........................................................................................................4 4
4. 3. 4. 1
F oll o w -u p Wee k 2 Visit .......................................................................................4 5
4. 3. 4. 2
F oll o w -u p Wee k 8 Visit .......................................................................................4 5
4. 4 
P ost St u d y Access t o T her a p y (if a p plic a ble)................................ ................................4 5
5
P O P U L A TI O N ......................................................................................................................4 6
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 3 of 1 0 3
P FI Z E R C O N FI D E N TI A L
5. 1  
N u m ber of S u bjects................................ ..........................................................................4 6
5. 2 
I ncl usi o n Criteri a............................................................................................................. 4 6
5. 3
E xcl usi o n Criteri a............................................................................................................ 4 8
5. 4
Pr o hi bite d a n d Restricte d C o nc o mit a nt Me dic ati o ns a n d De vices............................. 5 2
5. 5
St a n d ar d of C are Mi gr ai ne Me dic ati o ns....................................................................... 5 4
5. 5. 1
Ac ute Mi gr ai ne Me dic ati o ns ..................................................................................... 5 4
5. 6
W o me n of C hil d be ari n g P ote nti al
.................................................................................. 5 4
5. 7
Ot her Restricti o ns a n d Prec a uti o ns (if a p plic a ble) ....................................................... 5 6
5. 8
De vi ati o n fr o m I ncl usi o n/ E xcl usi o n Criteri a a n d St u d y Pr oce d ures .......................... 5 6
6
S T U D Y C O N D U C T A N D D E S C RI P TI O N O F S T U D Y P R O C E D U R E S ..................... 5 6
6. 1
St u d y M ateri als ................................................................................................................ 5 6
6. 2
S afet y Assess me nts ........................................................................................................... 5 7
6. 2. 1
Vit al Si g ns a n d P h ysic al Me as ure me nts ( Hei g ht a n d Wei g ht).............................. 5 7
6. 2. 2
Electr oc ar di o gr a m ( E C G) ......................................................................................... 5 8
6. 2. 3
P h ysic al E x a m ............................................................................................................ 5 8
6. 2. 4
L a b or at or y Assess me nts ............................................................................................ 5 8
6. 2. 4. 1
S afet y L a b or at or y Testi n g .................................................................................. 5 8
6. 2. 4. 2
Pre g n a nc y Testi n g ................................................................................................ 5 9
6. 2. 5
C ol u m bi a -S uici de Se verit y R ati n g Sc ale ( C -S S R S) ................................................ 5 9
6. 3
Effic ac y Assess me nts ....................................................................................................... 6 0
6. 4
Ot her Assess me nts ........................................................................................................... 6 0
6. 4. 1
Mi gr ai ne- S pecific Q u alit y - of-Life Q uesti o n n aire ( M S Q) v 2. 1 ............................. 6 0
6. 4. 2
Cli nic al Gl o b al I m pressi o n – C h a n ge ( C GI -c) Sc ale .............................................. 6 0
6. 4. 3
S atisf acti o n wit h Me dic ati o n ( S M) Sc ale ................................................................. 6 0
6. 5
E arl y Disc o nti n u ati o n fr o m t he St u d y........................................................................... 6 0
6. 5. 1
L ost t o F oll o w -u p ....................................................................................................... 6 1
6. 6
Cli nic al Tri al S u bject D at a b ase ( C T S d at a b ase) ........................................................... 6 2
7
S T U D Y D R U G M A N A G E M E N T....................................................................................... 6 3
7. 1
Descri pti o n of St u d y Dr u g ..............................................................................................6 3
7. 1. 1
I n vesti g ati o n al Pr o d uct ............................................................................................. 6 3
7. 1. 2
C o nc o mit a nt T her a p y ................................................................................................ 6 3
7. 1. 3
P ac k a gi n g, S hi p me nt a n d St or a ge ............................................................................ 6 4
7. 2
D ose a n d A d mi nistr ati o n ................................................................................................. 6 4
7. 2. 1
Met h o d of Assi g ni n g S u bject I de ntific ati o n............................................................ 6 4
7. 2. 2
Selecti o n a n d Ti mi n g of D ose a n d A d mi nistr ati o n................................ .................6 4
7. 2. 3  
D ose M o dific ati o n................................ ......................................................................6 5
7. 2. 4
D ose I nterr u pti o ns ..................................................................................................... 6 5
7. 3
Bli n di n g a n d U n bli n di n g .................................................................................................6 5
7. 4 
Tre at me nt C o m pli a nce................................ ....................................................................6 6
7. 5
Destr ucti o n a n d Ret ur n of St u d y Dr u g ..........................................................................6 7
8
A D V E R S E E V E N T S ............................................................................................................6 7
8. 1
S E RI O U S A D V E R S E E V E N T ....................................................................................... 6 9
8. 1. 1
Defi niti o n of Seri o us A d verse E ve nt ( S A E) .............................................................6 9
8. 1. 2
C ollecti o n a n d Re p orti n g Seri o us A d verse E ve nts .................................................7 0
8. 2
N o n -seri o us A d verse E ve nts............................................................................................7 1
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 4 of 1 0 3
P FI Z E R C O N FI D E N TI A L
8. 2. 1
C ollecti o n a n d Re p orti n g of N o n -seri o us A d verse E ve nts .....................................7 1
8. 2. 2
L a b or at or y Test A b n or m alities ................................................................................ 7 1
8. 3
O ver d ose ........................................................................................................................... 7 2
8. 4
P ote nti al Dr u g I n d uce d Li ver I nj ur y ( DI LI) ................................................................ 7 2
8. 5
E n vir o n me nt al E x p os ure, E x p os ure D uri n g Pre g n a nc y or Bre astfee di n g, a n d 
Occ u p ati o n al E x p os ur e ................................................................................................... 7 3
8. 5. 1
E x p os ure D uri n g Pre g n a nc y ..................................................................................... 7 3
8. 5. 2
E x p os ure D uri n g Bre astfee di n g ................................................................................ 7 5
8. 5. 3
Occ u p ati o n al E x p os ure ............................................................................................. 7 6
8. 6
L ac k of Effic ac y ................................................................................................................ 7 6
1 0. 1
Me dic ati o n Err ors ............................................................................................................ 7 6
1 0. 2
A d verse E ve nts of S peci al I nterest ................................................................................. 7 6
9
S T A TI S TI C S ......................................................................................................................... 7 7
9. 1
S a m ple Size ....................................................................................................................... 7 7
9. 2
A n al ysis Sets ..................................................................................................................... 7 7
9. 3
St atistic al Met h o ds ........................................................................................................... 7 8
9. 3. 1
Effic ac y A n al yses ....................................................................................................... 7 8
9. 3. 1. 1
Pri m ar y Effic ac y E n d p oi nt ................................................................................. 7 8
9. 3. 1. 2
Sec o n d ar y Effic ac y E n d p oi nts ............................................................................ 7 8
9. 3. 1. 3
M ulti plicit y C orrecti o n ........................................................................................ 7 9
9. 3. 2
S afet y A n al yses ........................................................................................................... 7 9
9. 4
Sc he d ule of A n al yses ........................................................................................................ 8 0
1 0
E T HI C S A N D R E S P O N SI BI LI TI E S ................................................................................. 8 1
1 0. 1
G o o d Cli nic al Pr actice..................................................................................................... 8 1
1 0. 2
D at a a n d S afet y M o nit ori n g C o m mittee........................................................................ 8 1
1 0. 3
I nf or me d C o nse nt ............................................................................................................ 8 2
1 0. 4
C ase Re p ort F or ms .......................................................................................................... 8 2
1 0. 5
Disse mi n ati o n of Cli nic al St u d y D at a ............................................................................ 8 3
1 0. 5. 1 D at a s h ari n g ...................................................................................................................... 8 4
1 0. 6
S p o ns or’s Me dic all y Q u alifie d I n di vi d u al ..................................................................... 8 4
1 1
R E C O R D S M A N A G E M E N T A N D R E T E N TI O N ........................................................... 8 5
1 1. 1
S o urce D oc u me nt ati o n ..................................................................................................... 8 6
1 1. 2
St u d y Files a n d Rec or d Rete nti o n ..................................................................................8 6
1 2
A M E N D M E N T S ................................................................................................................... 8 7
1 3
P U B LI C A TI O N S P O LI C Y................................ .................................................................8 7
1 4
S T U D Y DI S C O N TI N U A TI O N................................ ...........................................................8 7
1 5
D A T A P R O T E C TI O N ......................................................................................................... 8 7
1 6
A P P E N DI C E S .......................................................................................................................8 9
1 6. 1
A p pe n di x 1 – C o u ntr y S pecific Re q uire me nts ..............................................................8 9
1 6. 1. 1 
It al y ..............................................................................................................................8 9
1 6. 2
A p pe n di x 2 – I n hi bit ors a n d I n d ucers of C Y P 3 A 4 a n d I n hi bit ors of P-
gl yc o pr otei n ( N ot all -i ncl usi ve)....................................................................................... 9 0
1 6. 3
A p pe n di x 3 – Defi niti o n of Mi gr ai ne D a ys ....................................................................9 2
1 6. 4
A p pe n di x 4 – C ate g ories of Mi gr ai ne Pre ve nti o n Me dic ati o ns ( Refere nce f or 
E xcl usi o n Criteri a 7 h) ...................................................................................................... 9 4
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 5 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 6. 5
A p pe n di x 5 – Me dic ati o ns f or Mi gr ai ne Pre ve nti o n Ge ner all y C o nsi dere d t o 
H a ve Effic ac y.................................................................................................................... 9 5
1 6. 6
A p pe n di x 6 - E C G Fi n di n gs of P ote nti al Cli nic al C o ncer n ......................................... 9 7
1 6. 7
A p pe n di x 7 – Pr ot oc ol A me n d me nt Hist or y ................................................................. 9 9
1 7
R E F E R E N C E S ................................................................................................................... 1 0 2
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 6 of 1 0 3
P FI Z E R C O N FI D E N TI A L
LI S T O F T A B L E S
T a ble 1
Sc he d ule of Assess me nts – O bser v ati o n P h ase, D o u ble- bli n d Tre at me nt 
P h ase, E O T, & F oll o w- u p P h ase ........................................................................ 3 3
T a ble 2
Sc he d ule of Assess me nts – O pe n -l a bel E xte nsi o n P h ase, E O T, & F oll o w-u p 
P h ase ...................................................................................................................... 3 7
LI S T O F FI G U R E S
Fi g ure 1
1 2 Wee ks of D o u ble -bli n d Tre at me nt wit h D ail y D osi n g, F oll o we d b y 1 2 
Wee ks of O pe n -l a bel Tre at me nt wit h D ail y D osi n g ......................................... 1 1
Fi g ure 2
1 2 Wee ks of D o u ble -bli n d Tre at me nt wit h D ail y D osi n g, F oll o we d b y 1 2 
Wee ks of O pe n -l a bel Tre at me nt wit h D ail y D osi n g ......................................... 3 1
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 7 of 1 0 3
P FI Z E R C O N FI D E N TI A L
LI S T O F A B B R E VI A TI O N S
A E
A d verse E ve nt
A C E
A L T
A n gi ote nsi n -c o n verti n g e nz ym e
Ala ni ne A mi n otra nsferase
A R B
A S T
A n gi ote nsi n rece pt or bl oc ker
As partate A mi n otra nsferase
A U C
Area U n der t he C ur ve
A V
Atri o ve ntric ular
B H V
Bi o ha ve n
B P
Bl o o d Press ure
B U N
Bl o o d Urea Nitr o ge n
C GI -c
C G R P
Cli nical Gl o bal I m pressi o ns - c ha n ge scale
Calcit o ni n Ge ne -Relate d Pe pti de
CI
C K
C o nfi de nce i nter val
Creati ne Ki nase
C ma x
C O VI D -1 9
Ma xi m u m Plas ma C o nce ntrati o n
C or o na vir us Disease 2 0 1 9
C R F
C R O
C R P S
Case Re p ort F or m
C o ntract Researc h Or ga nizati o n
C o m ple x Re gi o nal Pai n S y n dr o me
C -S S R S
C ol u m bia -S uici de Se verit y  Rati n g Scale
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 y ste m
C T S
Cli nical Trial S u bject
C V
C oefficie nt of Variati o n
C Y P
c yt oc hr o me P 4 5 0
D AI D S
Di visi o n of AI D S
DI LI
Dr u g -I n d uce d Li ver I nj ur y
D DI
dr u g -dr u g i nteracti o n
D S M C
Data a n d Safet y M o nit ori n g C o m mittee
D S M -V
Dia g n ostic a n d Statistical ma n ual of Me ntal Dis or ders Fift h e diti o n
D S U
Dr u g Safet y U nit
E C
E C G
e C R F
E D B
E t hics c o m mittee
Electr ocar di o gra m
Electr o nic Case Re p ort F or m
E x p os ure D uri n g B reastfee di n g
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 8 of 1 0 3
P FI Z E R C O N FI D E N TI A L
E D C
e Diar y
E D P
E O D
Electr o nic Data Ca pt ure
Electr o nic diar y
E x p os ure D uri n g P re g na nc y
E ver y  Ot her Da y
E O T
E n d of Treat me nt
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 C P
G G T
G L P
H D L
H b A 1c
G o o d Cli nical Practice
Ga m ma -Gl uta m yl  Tra nsferase
G o o d La b orat or y  Practices
Hi g h -de nsit y  Li p o pr otei n
He m o gl o bi n A 1 C
HI V
H u ma n I m m u n o deficie nc y  Vir us
H R
Heart Rate
I CF
I nf or me d C o nse nt F or m
I B
I n vesti gat or’s Br oc h ure
I C H
I nter nati o nal C o nfere nce o n Har m o nizati o n
I E C
I n de pe n de nt Et hics C o m mittee
I H S
I nter nati o nal Hea dac he S ociet y
I ND
I n vesti gati o nal Ne w Dr u g
I N R
I nter nati o nal N or malize d Rati o
I RB
I nstit uti o nal Re vie w B oar d
I V
I ntra ve n o us
I W R S
I nteracti ve We b Res p o nse S yste m
k B q
Kil o bec q uerel
k g
Kil o gra m
L
L B B B
L D H
L D L
Liters
left b u n dle bra nc h bl oc k
Lactate De h y dr o ge nase
L o w -de nsit y Li p o pr otei n
L F T
Li ver F u ncti o n Test
M B q
Me ga bec q uerel
M D Z
Mi daz ola m
m g
Milli gra m
M S Q
Mi grai ne -S pecific Q ualit y -of -Life Q uesti o n naire 
mi n
Mi n ute
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 9 of 1 0 3
P FI Z E R C O N FI D E N TI A L
m m H g
Milli meters Merc ur y
N O E L
N o O bser ve d Effect Le vel
N O A E L
N S AI D
O D T
O T C
N o O bser ve d A d verse E ve nt Le vel
N o n -ster oi dal a nti-i nfla m mat or y dr u g
Orall y  Disi nte grati n g Ta blet
O ver t he C o u nter
P A C L
P O
P S S A
P V C
P r ot oc ol A d mi nistrati ve C larificati o n L etter
B y  M o ut h, Orally
Pfizer S A E S u b missi o n Assista nt
pre mat ure ve ntric ular c o ntracti o n
Q D
O nce Dail y
Q Tc
Q Tc F
Q T L
I nter val bet wee n Q-wa ve a n d T -wa ve i n t he car diac c y cle
Q Tc c orrecte d usi n g Fri dericia’s f or m ula
Q ualit y  T olera nce Li mits
S A E
Seri o us A d verse E ve nt
S E
Sta n dar d err or
S M
S R S D
Satisfacti o n wit h Me dicati o n
Si n gle Refere nce Safety D oc u me nt
T bili
t otal bilir u bi n
U L N
U p per Li mit of N or mal
W B C
W hite Bl o o d Cell
W H O
W orl d Healt h Or ga nizati o n
W O C B P
W o me n of C hil d beari n g P ote ntial
1
I N T R O D U C TI O N A N D R A TI O N A L E
1. 1
B ac k gr o u n d
Mi grai ne is a c o m m o n a n d de bilitati n g ne ur ol o gical dis or der t hat affects a p pr o xi matel y  1 5 % of 
t he a d ult p o p ulati o n. It is c haracterize d b y m o derate -t o-se vere e pis o dic u nilateral p ulsati n g 
hea dac hes t hat last f or 4 t o 7 2 h o urs. T y pical c haracteristics of t he hea dac he are u nilateral 
l ocati o n, p ulsati n g q ualit y, m o derate or se vere i nte nsit y, a g gra vati o n b y r o uti ne p h ysical acti vit y, 
a n d ass ociat i o n wit h na usea a n d/ or p h ot o p h o bia a n d p h o n o p h o bia.1
B H V - 3 0 0 0 ( P F-0 7 8 9 9 8 0 1) (ri me ge pa nt) is a calcit o ni n ge ne-relate d pe pti de ( C G R P) rece pt or 
a nta g o nist i n de vel o p me nt f or t he ac ute treat me nt of mi grai ne. T he C G R P rece pt or is l ocate d 
wit hi n pai n -si g nali n g pat h wa ys, i ntracra nial arteries a n d mast cells a n d its acti vati o n is t h o u g ht 
t o pla y a ca usal r ole i n mi grai ne pat h o p h ysi ol o g y. F or e xa m ple, researc h a n d cli nical st u dies 
ha ve s h o w n: ser u m le vels of C G R P are ele vate d d uri n g mi grai ne attac ks, i nf usi o n of i ntra ve n o us 
C G R P pr o d uces persiste nt pai n i n mi grai ne s ufferers a n d n o n -mi gra i ne s ufferers, a n d treat me nt 
wit h a nti- mi grai ne dr u gs n or malize C G R P le vels. A d diti o nall y , m ulti ple cli nical st u dies s h o w 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 2 0 of 1 0 3
P FI Z E R C O N FI D E N TI A L
t hat s mall m olec ule C G R P rece pt or a nta g o nists, w hic h i n hi bit t he bi n di n g of e n d o ge n o us C G R P 
t o C G R P rece pt ors, are effecti ve i n a b ortin g mi grai ne attac ks. Treat me nt wit h a C G R P rece pt or 
a nta g o nist is belie ve d t o relie ve mi grai ne t hr o u g h t he p ossi ble mec ha nis ms of 1) bl oc ki n g 
ne ur o ge nic i nfla m mati o n, 2) decreasi n g arter y  dilati o n, a n d 3) i n hi biti n g pai n tra ns missi o n. 
T here is wi des prea d a gree me nt t hat t his ne w a p pr oac h a v oi ds t he car di o vasc ular effects 
pr o d uce d b y  acti ve vas oc o nstricti o n ass ociate d wit h t he c urre nt sta n dar d tri pta n t hera p y ( n o n-
selecti ve 5-H T 1 B/ 1 D a g o nists (e. g., s u matri pta n [I mitre x ™]) ).
1. 2
C G R P’s R ole i n Mi gr ai ne
Ri me ge pa n t is a selecti ve, hi g h -affi nit y, orally a d mi nistere d, s mall m olec ule calcit o ni n ge ne -
relate d pe pti de (C G R P ) rece pt or a nta g o nist.
C G R P is a n e n d o ge n o us 3 7 a mi n o aci d pe pti de c o ntai ne d wit hi n pai n -si g nali n g n ocice pti ve 
affere nts, a n d is t h o u g ht t o pla y a ca usal r ole i n mi grai ne.5 ,6  M ulti ple li nes of cli nical e vi de nce 
p oi nt t o a r ole f or C G R P i n mi grai ne pat h o p h y si ol o g y: 1) ser u m le vels of C G R P are ele vate d 
d uri n g mi grai ne; 7 2) treat me nt wit h a nti - mi grai ne dr u gs ret ur ns C G R P le vels t o n or mal 
c oi nci de nt wit h pai n relief;7 ,8 a n d 3) i ntra ve n o us C G R P i nf usi o n pr o d uces lasti n g pai n i n n o n -
mi grai ne urs a n d mi grai ne urs. 6 ,9
Treat me nt wit h a C G R P rece pt or a nta g o nist is belie ve d t o relie ve mi grai ne t hr o u g h t he f oll o wi n g 
p ossi ble mec ha nis ms:

Bl oc ki n g Ne ur o ge nic I nfl a m m ati o n: Bi n di n g of C G R P rece pt or a nta g o nists t o C G R P 
rece pt ors l ocate d o n mast cells w o ul d i n hi bit i nfla m mati o n ca use d b y tri ge mi nal ner ve 
release of C G R P o nt o mast cells wit hi n t he t o u g h o uter c o veri n g of t he brai n, or t he 
me ni n ges.

Decre asi n g Arter y Dil ati o n: B y  bl oc ki n g t he C G R P rece pt ors l ocate d i n s m o ot h m uscle 
cells wit hi n vessel walls i n t he me ni n ges, C G R P rece pt or a nta g o nists w o ul d i n hi bit t he 
pat h ol o gic dilati o n of i ntracra nial arteries wit h o ut t he u n wa nte d effect of acti ve 
vas oc o nstricti o n.

I n hi biti n g P ai n Tr a ns missi o n: Bi n di n g of C G R P rece pt or a nta g o nists t o C G R P 
rece pt ors w oul d s u p press t he tra ns missi o n of pai n b y  i n hi biti n g t he ce ntral rela y of pai n 
si g nals fr o m t he tri ge mi nal ner ve t o t he ca u dal tri ge mi nal n ucle us.
Ri me ge pa nt offers a n o vel t hera pe utic mec ha nis m f or t he ac ute treat me nt of mi grai ne wit h t he 
p ote ntial t o a d dress i m p orta nt u n met nee ds (e. g., si n gle- d ose d ura ble efficac y , efficac y wit h o ut 
me dicati o n o ver use hea dac he, a n d n o c o ntrai n dicati o ns or war ni n gs i n patie nts wit h
car di o vasc ular [C V ] disease).
1. 3
Pr o d uct De vel o p me nt B ac k gr o u n d
Details of t he cli nical a n d precli nical st u dies are pr o vi de d i n t he m ost c urre nt In vesti gat or 
B r oc h ure. A s u m mar y of t he rele va nt data t o t he st u d y are prese nte d bel o w. Ri me ge pa nt is 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 2 1 of 1 0 3
P FI Z E R C O N FI D E N TI A L
a p pr o ve d f or t he treat me nt of ac ute treat me nt a n d pre ve nti o n of e pis o dic mi grai ne i n t he U S, U K 
a n d E U a n d is well t olerate d i n h u ma ns w he n gi ve n as si n gle oral d ose of 7 5 m g t o treat ac ute 
mi grai ne a n d at a d ose of 7 5 m g E O D f or t he pre ve nti o n of e pis o dic mi grai ne .  E ver y  ot her da y 
d osi n g was well t olerate d wit h n o si g nals of h y perse nsiti vit y , car di o vasc ular e ve nts, or 
he pat ot o xicit y .2
Ri me ge pa nt has bee n st u die d u p t o t he ma xi m u m d ose of 1 5 0 0 m g a n d m ulti ple oral d oses u p t o 
t he ma xi m u m dail y d ose of 6 0 0 m g f or 1 4 da ys. 
T he B H V 3 0 0 0 -2 0 1 st u d y is a c o m plete d P hase 2/ 3, 5 2 -wee k, o pe n -la bel, safet y st u d y i n 1 8 0 0
s u bjects ( u p t o o ne year i n d urati o n) wit h ri me ge pa nt 7 5 m g d ose d as nee de d or sc he d ule d E O D 
pl us as nee de d . Ri me ge pa nt 7 5 m g a d mi nistere d i n m ulti ple d oses f or u p t o 5 2 wee ks i n s u bjects 
wit h mi grai ne was well t olerate d . N o cli nicall y  rele va nt tre n ds i n la b orat or y a b n or malities were 
o bser ve d o n -treat me nt or d uri n g f oll o w- u p.
T he B H V 3 0 0 0 -3 0 5 st u d y is a c o m plete d P hase 2/ 3, 6 4 -wee k ( 1 2 wee ks of a d o u ble -bli n d, 
place b o -c o ntr olle d p hase f oll o we d b y 5 2 wee ks of o pe n -la bel treat me nt) st u d y wit h ri me ge pa nt 
7 5 m g or matc hi n g place b o d ose d e ver y  ot her da y ( E OD) f or t he pre ve nti o n of mi grai ne. Duri n g 
t he o pe n-la bel p hase, s u bjects were a ble t o d ose o n n o n-sc he d ule d d osi n g da ys a n d t heref ore 
were a ble t o d ose u p t o o nce dail y.
T he pri mar y  i de ntifie d a d verse e ve nt ( A E ) of i nterest is t he p ote ntial ele vati o n of li ver f u ncti o n 
tests. I nvesti gat ors m ust caref ull y  m o nit or r o uti ne li ver f u ncti o n tests (ala ni ne ami n otra nsferase 
[A L T], as partat e ami n otra nsferase [A S T ], t otal bilir u bi n, a n d A LP) a n d p ote ntiall y  li ver relate d 
s ym pt o ms a n d si g ns. Cli nicia ns s h o ul d als o m o nit or c ha n ges i n he mat ol o g y  a n d ot her la b orat or y 
meas ures. 
1. 4
Be nefit Ris k Assess me nt
Ri me ge pa nt is a p pr o ve d i n t he U S, E U, a n d U K f or t he treat me nt of mi g rai ne i n a d ults, i ncl u di n g 
b ot h ac ute treat me nt of mi grai ne a n d pre ve nti ve treat me nt of e pis o dic mi grai ne. Ri me ge pa nt 
a p pears t o be ge nerall y s afe a n d well t olerate d i n h u ma ns w he n gi ve n as si n gle oral d oses fr o m 
7 5 m g u p t o t he ma xi m u m d ose of 1, 5 0 0 m g a n d m ulti ple oral d oses u p t o t he ma xi m u m dail y  
d ose of 6 0 0 m g f or 1 4 da ys. Ri me ge pa nt 7 5 m g re prese nts a n a d va nce me nt i n mi grai ne 
t hera pe utics, pr o vi di n g t he first C G R P a nta g o nist t o de m o nstrate be nefit f or b ot h t he ac ute 
treat me nt a n d pr o p hyl a xis of mi graine. D ual acti o n t hera p y f or mi grai ne wit h a si n gle a ge nt 
offers patie nts t he p ote ntial f or si g nifica nt cli nical a d va nta ges i ncl u di n g: 1) a si m plifie d 
me dicati o n re gi me n t o treat mi grai ne acr oss t he s pectr u m fr o m ac ute e pis o des t o t he pre ve nti o n 
of f ut ure a ttac ks, w hic h are 2 ma nifestati o ns of t he sa me c o n diti o n; 2) a v oi di n g p ol y p har mac y 
wit h c o nc urre nt use of m ulti ple me dicati o ns eac h wit h t heir o w n si de effects; 3) re d uci n g t he ris k 
of dr u g -dr u g i nteracti o ns; a n d 4) c ost -effecti ve ness of a si n gle me dicati on t hat pr o vi des b ot h 
ac ute a n d pre ve nti ve t hera p y.
Br oa d a n d s ustai ne d efficac y  of ri me ge pa nt 7 5 m g was de m o nstrate d i n 3 pre vi o usl y c o m plete d 
P hase 3 st u dies ( B H V 3 0 0 0 -3 0 1, B H V 3 0 0 0 -3 0 2 a n d B H V 3 0 0 0 -3 0 3). Statisticall y  si g nifica nt 
efficac y was de m o nstrate d on t he c o -pri mar y  e n d p oi nts of free d o m fr o m pai n, a n d free d o m fr o m 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 2 2 of 1 0 3
P FI Z E R C O N FI D E N TI A L
m ost b ot hers o me s y m pt o m at 2 h o urs p ost - d ose. Als o, i n all 3 st u dies, si g nifica nt res ults were 
ac hie ve d o n p h ot o p h o bia free d o m, p h o n o p h o bia free d o m a n d pai n relief at 2 h o urs p ost -d ose. 
Si mi lar res ults were de m o nstrate d i n t he B H V 3 0 0 0-3 1 0 st u d y  rece ntl y c o m plete d i n C hi na a n d 
K orea. I n t he P hase 2/ 3 place b o-c o ntr olle d st u d y ( B H V 3 0 0 0-3 0 5) f or t he pre ve nti ve treat me nt of 
mi grai ne, ri me ge pa nt at a d ose of 7 5 m g e ver y  ot her da y ( E O D) de m o nstrate d statisticall y 
si g nifica nt s u peri orit y t o place b o o n t he pri mar y e n d p oi nt of c ha n ge fr o m t he o bser vati o n peri o d 
i n t he mea n n u m ber of mi grai ne da ys per m o nt h o n treat me nt i n t he last m o nt h of t he d o u ble-
bli n d treat me nt p hase.
A m ultice nter o pe n -la bel, l o n g-ter m st u d y ( B H V 3 0 0 0-2 0 1) was c o n d ucte d t o e val uate t he safet y 
a n d t olera bilit y of ri me ge pa nt 7 5 m g ta blet ta ke n as nee de d (u p t o 1 ta blet per da y u p o n o nset of 
a mi grai ne of mil d, m o derate, or se vere i nte nsit y ) f or t he ac ute treat me nt of mi grai ne f or u p to 5 2 
wee ks. T his m ulti ple -d ose, l o n g -ter m st u d y of ri me ge pa nt 7 5 m g a d mi nistere d f or u p t o 5 2 
wee ks c o nfir me d t he fa v ora ble safet y pr ofile acr oss a variet y of safet y e n d p oi nts, i ncl u di n g A E 
assess me nts, cli nical la b orat or y  testi n g i ncl u di n g L F Ts, vital si gns a n d E C Gs. Safet y data fr o m 
t he d o u ble- bli n d treat me nt a n d t he o pe n-la bel e xte nsi o n p hases of t he pi v otal P hase 2/ 3, 
ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d pre ve nti ve treat me nt of mi grai ne st u d y  
( B H V 3 0 0 0- 3 0 5) s u p p ort a fa v ora ble safety pr ofile of r i me ge pa nt 7 5 m g a d mi nistere d E O D f or 
t he pre ve nti ve treat me nt of mi grai ne. Ri me ge pa nt 7 5 m g a d mi nistere d E O D + P R N f or u p t o 5 2 
wee ks i n t he o pe n -la bel p hase is well t olerate d, wit h n o ne w safet y si g nals o bser ve d i n t he o pe n-
la bel-e xte nsi o n p hase.
T here ar e n o a de q uate data o n t he de vel o p me ntal ris k ass ociate d wit h t he use of ri me ge pa nt i n 
pre g na nt w o me n. W o me n of c hil d beari n g p ote ntial ( W O C B P) m ust ha ve a ne gati ve pre g na nc y  
test a n d W O C B P a n d fertile me n m ust use 2 acce pta ble met h o ds of c o ntrace pti o n t o a v oi d 
pre g na nc y  t hr o u g h o ut t he st u d y i n s uc h a ma n ner t hat t he ris k of pre g na nc y is mi ni mize d. 
S u bjects u n der g o re g ular pre g na nc y  testi n g t hr o u g h o ut t he d urati o n of t he st u d y. Alt h o u g h n o 
safety iss ues i n cli nical trials of ri me ge pa nt were o bser ve d, car di o va sc ular e ve nts, 
cere br o vasc ular e ve nts, h y perte nsi ve e ve nts, a n d seri o us gastr oi ntesti nal e ve nts ass ociate d wit h 
c o nsti pati o n are re vie we d i n eac h a g gre gate re p ort per F D A re q uest. N o ne of t hese re vie ws ha ve 
detecte d a n y safet y si g nal ass ociate d wit h t hese e ve nts. S u bjects are e xcl u de d if t here is 
u nc o ntr olle d, u nsta ble, or rece ntl y dia g n ose d car di o vasc ular disease or h y p erte nsi o n. S u bjects 
are m o nit ore d t hr o u g h m ulti ple safet y  e n d p oi nts, i ncl u di n g A E assess me nts, cli nical la b orat or y 
testi n g, vital si g ns a n d E C Gs.
Re vie w of all data a vaila ble, i ncl u di n g p ost -mar keti n g i nf or mati o n, n o ncli nical, cli nical, a n d 
scie ntific literat ure data, de m o nstrates a fa v ora ble be nefit-ris k pr ofile f or t he use of ri me ge pa nt 
i n t his st u d y. M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d 
reas o na bly e x pecte d A Es of ri me ge pa nt ma y  be f o u n d i n t he I nvesti gat or’s Br oc h ure , w hic h is 
t he S R S D f or t his st u d y.
1. 5
St u d y R ati o n ale
T h e g oal of t his st u d y  is t o assess t he efficac y a n d safety of e ver y ot her da y (E O D ) a n d dail y 
( Q D) d osi n g vs. place b o.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 2 3 of 1 0 3
P FI Z E R C O N FI D E N TI A L
T his st u d y  is bei n g c o n d ucte d t o e val uate t he efficac y, safety, a n d t olera bilit y  of a Q D d osi n g
re gi me n of ri me ge pa nt, as well as t o f urt her e val uate a n E O D re gi me n, f or t he pre ve nti o n of 
e pis o dic mi grai ne. It will als o f urt her defi ne t he safet y pr ofile of ri me ge pa nt a d mi nistrati o n f or 
u p t o 2 4 wee ks. A p pr o xi matel y  6 6 0 s u bjects will d ose wit h d o u ble-bli n d st u d y dr u g e ver y d a y 
f or a peri o d of a p pr o xi matel y 1 2 wee ks, f oll o we d b y a n a d diti o nal 1 2 wee ks wit h o pe n-la bel 
ri me gepa nt d ose d dail y .  
1. 5. 1
St u d y Desi g n R ati o n ale
T his is a 1 2 -wee k , m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d e val uati o n of t he 
efficac y a n d safet y of ri me ge pa nt 7 5 m g ta ke n e ver y ot her da y (E O D ) or dail y  f or t he pre ve nti o n 
of e pis o dic mi grai ne wit h a 1 2 - wee k O pe n -la bel E xte nsi o n P hase . 
A p pr o xi matel y  6 6 0 s u bjects will be ra n d o mize d a n d assi g ne d treat me nt i n t he D o u ble -bli n d 
Treat me nt P hase of t he st u d y .  S u bjects will be ra n d o mize d i n a 1: 1: 1 rati o acr oss 3 treat me nt 
gr o u ps: ri me ge pa nt 7 5 m g d o se d E O D alter nati n g wit h matc hi n g place b o ( n = 2 2 0 ); ri me ge pa nt 
7 5 m g d ose d dail y ( n = 2 2 0 ); or place b o matc hi n g ri me ge pa nt 7 5 m g d ose d dail y ( n = 2 2 0 ). 
R a n d o mizati o n will be stratifie d b y use of pri or pr o p h y lactic mi grai ne me dicati o n ge nerall y  
c o nsi dere d t o ha ve efficac y (yes or n o; see Secti o n 7. 2. 1 ). I n a d diti o n, ra n d o mizati o n of 
pr o p h y lactic mi grai ne treat me nt-naï ve s u bjects (“ n o” cate g or y) will be ca p pe d at 3 0 % i n or der t o 
all o w 7 0 % of ra n d o mize d s u bjects t o be pr o p h yl actic mi grai ne treat me nt-e x perie nce d ( “ yes” 
cate g or y).
D uri n g t he D o u ble -bli n d Treat me nt P hase, s u bjects will be i nstr ucte d t o ta ke o ne ( 1) O D T of 
bli n de d st u d y dr u g e ver y d a y . De pe n di n g o n t he ra n d o mizati o n, bli n de d st u d y dr u g will 
alter nate E O D bet wee n ri me ge pa nt a n d matc hi n g place b o , will be e ntirel y ri me ge pa nt 7 5 m g or 
will be e ntirel y  matc hi n g place b o. 
D uri n g t he O pe n -la bel E xte nsi o n P hase, s u bjects will be re q uire d t o ta ke 1 ta blet of ri me ge pa nt 
7 5 m g O D T e ver y d a y .  
If s u bjects ha ve a mi grai ne , t he y m a y treat t he mi grai ne wit h per mitte d ac ute mi grai ne
me dicati o n as nee de d (see Secti o n 5. 5. 1 ) w hile c o nti n ui n g wit h t he st u d y  dr u g.
1. 5. 2
D ose Selecti o n 
T he P hase 2 b d ose -ra n gi n g st u dy C N 1 7 0 0 0 3 esta blis he d t hat ri me ge pa nt 7 5 m g is t he mi ni m u m 
effecti ve d ose f or t he ac ute treat me nt of mi grai ne. T he t hree P hase 3 st u dies B H V 3 0 0 0 - 3 0 1, 
B H V 3 0 0 0 - 3 0 2, a n d B H V 3 0 0 0- 3 0 3 c o nfir me d t his efficac y usi n g t he c urre nt re gistrati o nal 
e n d p oi nts f or ac ute treat me nt of mi grai ne. T he pi v otal P hase 3 St u d y  B H V 3 0 0 0- 3 0 5 
de m o nstrate d t hat ri me ge pa nt 7 5 m g E O D is effecti ve a n d has a fa v ora ble safet y pr ofile f or t he 
pre ve nti o n of mi grai ne hea dac he. T he c urre nt st u d y will e val uate t he efficac y a n d safety of m ore 
fre q ue nt dail y d osi n g relati ve t o t he E O D re gi me n i n e pis o dic mi grai ne pre ve nti o n.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 2 4 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1. 6
Rese arc h H y p ot hesis
Ri me ge pa nt 7 5 m g O D T is effecti ve a n d well t olerate d w he n ta ke n dail y f or t he pre ve nti o n of 
e pis o dic mi grai ne.
2 
S T U D Y O B J E C TI V E S
A m o nt h is defi ne d as 4 wee ks ( 2 8 da y s) f or t he p ur p ose of t his pr ot oc ol.
2. 1
Pri m ar y
T o e val uate t he efficac y of E O D a n d dail y  ri me ge pa nt d osi n g re gi me ns relati ve t o place b o as a 
pre ve nti ve treat me nt f or e pis o dic mi grai ne, as meas ure d b y t he mea n re d ucti o n fr o m t he 
O bser vati o n P hase i n t he n u m ber of mi grai ne da ys per m o nt h o ver t he e ntire Do u ble -bli n d 
T reat me nt P hase .
2. 2 
Sec o n d ar y
1.
T o e val uate t he pr o p orti o n of s u bjects wit h 5 0 % re d ucti o n fr o m t he O bser vati o n P hase i n 
t he n u m ber of m o derate t o se vere mi grai ne da y s per m o nt h o ver t he e ntire D o u ble-bli n d 
Treat me nt P hase f or t he E O D a n d daily ri me ge pa nt d osi n g re gi me ns relati ve t o place b o .
2.
T o e val uate t he mea n re d ucti o n fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da ys 
per m o nt h i n t he last 4 wee ks of t he D o u ble -bli n d Treat me nt P hase f or t he E O D a n d daily 
ri me ge pa nt d osi n g re gi me ns relati ve t o place b o.
3.
T o e val uate t he mea n re d ucti o n fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da ys 
per m o nt h i n t he first 4 wee ks of t he D o u ble- bli n d Treat me nt P hase f or t he E O D a n d daily 
ri me ge pa nt d osi n g re gi me ns relati ve t o place b o.
4.
T o e val uate t he mea n n u m ber of ac ute mi grai ne -s pecific me dicati o n da ys per m o nt h o ver t he 
e ntire D o u ble -bli n d Treat me nt P hase f or t he E O D a n d dail y ri me ge pa nt d osi n g re gi me ns 
relati ve t o place b o.
5.
T o e val uate t he mea n c ha n ge fr o m baseli ne i n t he Mi grai ne-S pecific Q ualit y -of -Life 
Q uesti o n naire v 2. 1 ( M S Q) restricti ve r ole f u ncti o n d o mai n sc ore at Wee k 1 2 of t he D o u ble -
bli n d Treat me nt P hase f or t he E O D a n d dail y ri me ge pa nt d osi n g regi me ns relati ve t o 
place b o .
6.
T o e val uate t he safet y a n d t olera bilit y of ri me ge pa nt d uri n g t he D o u ble-bli n d Treat me nt a n d 
O pe n -la bel E xte nsi o n P hases.
7.
T o e val uate t he fre q ue nc y of A L T or A S T > 3 x u p per li mit of n or mal ( U L N) c o nc urre nt wit h 
t otal bilir u bi n > 2 x U L N i n s u bjects treate d wit h ri me ge pa nt d uri n g t he D o u ble -bli n d 
Treat me nt a n d O pe n -la bel E xte nsi o n P hases.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 2 5 of 1 0 3
P FI Z E R C O N FI D E N TI A L
8.
T o e val uate t he fre q ue ncies of he patic -relate d a d verse e ve nts ( A Es) a n d he patic-relate d A Es 
lea di n g t o st u dy dr u g disc o nti n uati o n i n s u bjects trea te d wit h ri me ge pa nt d uri n g t he D o u ble-
bli n d Treat me nt a n d O pe n -la bel E xte nsi o n P hases.
2. 3
E x pl or at or y  O bj e cti v e s
1.
T o e val uate t he mea n re d ucti o ns fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da ys 
per m o nt h a n d n u m ber of hea dac he da ys per m o nt h b y pai n i nte nsity (t otal; m o derate or 
se vere) i n eac h m o nt h a n d o ver t he e ntire D o u b le-bli n d Treat me nt P h ase f or t he E O D a n d 
dail y  ri me ge pa nt d osi n g re gi me ns relati ve t o place b o.
2.
T o e val uate t he pr o p orti o n s of s u bjects wit h 5 0 % re d ucti o n , 7 5 % re d ucti o n , a n d 1 00 % 
re d ucti o n fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da y s per m o nt h a n d n u m ber 
of hea dac he da y s per m o nt h b y  pai n i nte nsit y (t otal; m o derate or se vere) i n eac h m o nt h a n d 
o ver t he e ntire D o u b le-bli n d Treat me nt P h ase f or t he E O D a n d dail y ri me ge pa nt d osi n g 
re gi me ns relati ve t o place b o.
3.
T o e val uate t he mea n re d ucti o ns fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da ys 
per wee k a n d n u m ber of hea dac he da ys per wee k b y pai n i nte nsit y (t otal; m o derate or se vere) 
i n eac h wee k of t he first 4 wee k s of t he D o u b le-bli n d Treat me nt P h ase f or t he E O D a n d dail y 
ri me ge pa nt d osi n g re gi me ns relati ve t o place b o.
4.
T o e val uate t he pr o p orti o n s of s u bjects wit h 5 0 % re d ucti o n fr o m t he O bser vati o n P hase i n 
t he n u m ber of mi grai ne da ys per wee k a n d n u m ber of hea dac he da ys per wee k b y  pai n 
i nte nsit y (t otal; m o derate or se vere) i n eac h wee k of t he first 4 wee ks of t he D o u b le-bli n d
Treat me nt P h ase f or t he E O D a n d daily ri me ge pa nt d osi n g re gi me ns relati ve t o place b o .
5.
T o e val uate the pr o p orti o ns of s u bjects wit h a mi grai ne d a y  a n d hea dac he da y b y pai n 
i nte nsit y (t otal; m o derate or se vere) o n eac h d a y  of t he first wee k of t he D o u b le-bli n d
Treat me nt P h ase f or t he E O D a n d daily ri me ge pa nt d osi n g re gi me ns relati ve t o place b o .
6.
T o e val uat e t he mea n n u m ber of ac ute mi grai ne-s pecific me dicati o n da ys per m o nt h i n eac h 
m o nt h a n d o ver t he e ntire D o u ble-bli n d Treat me nt P has e f or t he E O D a n d dail y ri me ge pa nt 
d osi n g re gi me ns relati ve t o place b o .
7.
T o e val uate t he mea n n u m ber of ac ute mi grai ne me dica ti o n da ys per m o nt h i n eac h m o nt h 
a n d o ver t he e ntire D o u ble-bli n d Treat me nt P hase f or t he E O D a n d daily ri me ge pa nt d osi n g 
re gi me ns relati ve t o place b o.
8.
T o e val uate t he fre q ue nc y of li ver f u ncti o n test ( L F T) ele vati o ns ( A S T, A L T, or t otal 
bilir u bi n) base d o n f ol d c ha n ges a b o ve U L N i n s u bjects treate d wit h ri mege pa nt d uri n g t he 
D o u ble -bli n d T reat me nt a n d O pe n-la bel E xte nsi o n P hases.
9.
T o e val uate t he fre q ue nc y of A L T or A S T > 3 x U L N i n te m p oral ass ociati o n wit h na usea, 
v o miti n g, a n ore xia, a b d o mi nal pai n or fati g ue i n s u bjects treate d wit h ri mege pa nt d uri n g t he 
D o u ble -bli n d T reat me nt a n d O pe n-la bel E xte nsi o n P hases.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 2 6 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 0. T o e val uate t he mea n c ha n ges fr o m baseli ne i n M S Q d o mai n sc ores d uri n g t he D o u ble -bli n d 
T reat me nt a n d O pe n -la bel E xte nsi o n P hases.
1 1. T o e val uat e t he Satisfacti o n wit h Me dicati o n ( S M) scale d uri n g t he D o u ble -bli n d T reat me nt
a n d O pe n-la bel E xte nsi o n P hases.
1 2. T o e val uate t he Cli nical Gl o bal I m pressi o n – c ha n ge ( C GI-c) scale d uri n g t he D o u ble -bli n d 
T reat me nt a n d O pe n-la bel E xte nsi o n P hases.
3
S T U D Y E N D P OI N T S 
Mi grai ne da y s per m o nt h a n d ac ute mi grai ne-s pecific me dicati o n da ys per m o nt h are deri ve d 
fr o m e Diar y data.
A E s are deter mi ne d fr o m case re p ort f or ms ( C R Fs). 
M S Q d o mai n sc ores are deri ve d fr o m C R Fs.
Gra de 3 t o 4 la b orat or y  test a b n or malities are deter mi ne d fr o m la b orat or y test val ues gra de d 
usi n g sta n dar dize d criteria. La b orat or y  tests are i de ntifie d fr o m C R Fs a n d ce ntral la b orat or y data.
3. 1
Pri m ar y
Mea n c ha n ge fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da y s per m o nt h o ver t he 
e ntire D o u ble -bli n d Treat me nt P hase ( Wee ks 1 t o 1 2).
3. 2 
Sec o n d ar y
1.
Pr o p orti o n of s u bjects wit h 5 0 % re d ucti o n fr o m t he O bser vati o n P hase i n t he n u m ber of 
m o derate t o se vere mi grai ne da y s per m o nt h o ver t he e ntire D o u ble-bli n d Treat me nt P hase 
( Wee ks 1 t o 1 2).
2.
Mea n c ha n ge fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da ys per m o nt h i n t he 
last 4 wee ks ( Wee ks 9 t o 1 2) of t he Do u ble -bli n d T reat me nt P hase.
3.
Mea n c ha n ge fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da ys per m o nt h i n t he 
first 4 wee ks ( Wee ks 1 t o 4) of t he D o u ble -bli n d T reat me nt P hase.
4.
M ea n n u m ber of ac ute mi grai ne -s pecific me dicati o n da ys per m o nt h o ver t he e ntire Do u ble -
bli n d T reat me nt P hase (Wee ks 1 t o 1 2) . Ac ute mi grai ne -s pecific me dicati o ns are tri pta ns a n d 
er g ota mi ne (see Secti o n 3. 3 ).
5.
M ea n c ha n ge fr o m baseli ne i n t he M S Q restricti ve r ole f u ncti o n d o mai n sc ore at Wee k 1 2 of 
t he D o u ble -bli n d T reat me nt P hase.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 2 7 of 1 0 3
P FI Z E R C O N FI D E N TI A L
6.
N u m ber a n d perce nta ge of s u bjects wit h A E s b y  i nte nsit y, seri o us a d verse e ve nts ( S A Es), 
A E s lea di n g t o st u d y dr u g disc o nti n uati o n , a n d gra de 3 t o 4 la b orat or y test a b n or malities
d uri n g t he D o u ble -bli n d T reat me nt a n d O pe n-la bel E xte nsi o n P hases.
7.
N u m ber a n d perce nta ge of s u bjects treate d wit h ri me ge pa nt wit h A S T or A L T ele vati o ns > 
3 x U L N c o nc urre nt (i.e., o n t he sa me la b orat or y c ollecti o n date) wit h t otal bilir u bi n > 2 x 
U L N d uri n g t he D o u ble -bli n d T reat me nt a n d O pe n -la bel E xte nsi o n P hases. 
8.
N u m ber a n d perce nta ge of s u bjects treate d wit h ri me ge pa nt wit h he patic -relate d A E s b y  
i nte nsit y, a n d he patic-relate d A E s lea di n g t o st u d y dr u g disc o nti n uati o n d uri n g t he D o u ble -
bli n d T reat me nt a n d O pe n -la bel E xte nsi o n P hases.
3. 3
Defi niti o n of Mi gr ai ne D a ys
A m i grai ne d a y is defi ne d as a n y cale n dar da y w hic h t he s u bject e x perie nces a q ualifie d 
mi grai ne hea dac he ( o nset, c o nti n uati o n , or rec urre nce of t he mi grai ne hea dac he).  A q ualifie d 
mi grai ne hea dac he is defi ne d as a mi grai ne wit h or wit h o ut a ura, lasti n g f or ≥3 0 mi n utes, a n d 
meeti n g eit her Criteria A or B bel o w : 
A.
≥ 2 of t he f oll o wi n g pai n feat ures: 

U nilateral l ocati o n

P ulsati n g q ualit y (t hr o b bi n g)

M o derate or se vere p ai n i nte nsit y

A g gra vati o n b y or ca usi n g a v oi da nce of r o uti ne p h ysical acti vit y (e. g. wal ki n g or cli m bi n g 
stairs)
B.
≥ 1 of t he f oll o wi n g ass ociate d s y m pt o ms: 

Na usea a n d/ or v o miti n g 

P h ot o p h o bia a n d p h o n o p h o bia
D uri n g t he D o u ble -bli n d T reat me nt P hase, i f t he s u bject ta kes a mi grai ne-s pecific me dicati o n 
(i.e. tri pta n) d uri n g a ura or t o treat a hea dac he o n a cale n dar da y , t he n it will be c o u nte d as a 
mi grai ne da y  re gar dless of t he d urati o n a n d pai n feat ures/ass ociate d sy m pt o ms. T he use of 
er g ota mi ne me dicati o n is pr o hi bite d t hr o u g h o ut t he e ntire d urati o n of t his st u d y.  H o we ver, use 
of t his me dicati o n, if ta ke n f or mi grai ne treat me nt, m ust be d oc u me nte d f or t he p ur p oses of 
assessi n g mi grai ne da ys a n d m ust be ca pt ure d as a pr ot oc ol de viati o n.  
A m o derate t o se vere mi grai ne da y  is a mi grai ne da y wit h a mi grai ne re p orte d wit h m o derate or 
se vere pai n i nte nsit y.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 2 8 of 1 0 3
P FI Z E R C O N FI D E N TI A L
F or t he f ull defi niti o n of m i grai ne d a y, please refer t o Secti o n 1 6. 3 A p pe n di x 3 .
3. 4
Defi niti o n of He a d ac he D a ys
A h ea dac he d a y is an y  cale n dar da y i n w hic h t he s u bject e x perie nces a q ualifie d hea dac he (i nitial 
o nset, c o nti n uati o n, or rec urre nce of t he hea dac he). A q ualifie d hea dac he is defi ne d as:

A q ualifie d mi grai ne hea dac he (i ncl u di n g a n a ura- o nl y  e ve nt t hat is treate d wit h ac ute 
mi grai ne -s pecific me dicati o n), or

A q ualifie d n o n -mi grai ne hea dac he, w h ic h is a hea dac he t hat lasts ≥ 3 0 mi n utes a n d is n ot a 
q ualifie d mi grai ne hea dac he, or

A hea dac he of a n y d urati o n f or w hic h ac ute hea dac he treat me nt is a d mi nistere d.
F or t he f ull defi niti o n of hea dac he d a ys, please refer t o Secti o n 1 6. 3 A p pe n di x 3 .
4
S T U D Y P L A N
4. 1
St u d y Desi g n a n d D ur ati o n
T his is a m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y t o assess t he efficac y 
a n d safet y of t w o differe nt d osi n g re gi me ns of ri me ge pa nt 7 5 m g O D T i n e pis o dic mi grai ne
pre ve nti o n wit h a n o pe n -la bel e xte nsi o n p hase.
T he 2 8 -d a y  O bser vati o n Phase i ncl u des t he Scree ni n g Visit a n d Pre-ra n d o m izati o n E val uati o n 
Visit . To be eli gi ble f or t he st u d y , s u bjects m ust ha ve re p orte d ha vi n g ha d 1). 4- 1 4 mi gr ai ne 
att ac ks per m o nt h i n t he 3 m o nt hs ( 1 2 wee ks) pri or t o t he Scree ni n g Visit, a n d 2). at least 4
mi gr ai ne d ays a n d n o m ore t ha n 1 4 he a d ac he d ays d uri n g 2 8 d a y s i n t he O bser vati o n P hase ,
w hic h will be d oc u me nte d i n t he e Diar y .
U p o n t he c o m pleti o n of t he S cree ni n g Visit, s u bjects will be pr o vi de d a n electr o nic diar y 
(e Diar y) t o d oc u me nt t he f oll o wi n g o n eac h da y of t he O bser vati o n Phase: mi grai ne oc c urrence; 
mi grai ne pai n feat ures a n d ass ociate d s y m pt o ms (see Secti o n 3. 3 ); a n d use of ac ute mi grai ne
me dicati o n (i.e., tri pta ns; see Secti o n 5. 5. 1 ). I n a d diti o n, s u bjects will rec or d all c o nc o mita nt 
me dicati o ns, i ncl u di n g ac ute sta n dar d of care mi grai ne me dicati o ns ta ke n i n t he c o nc o mita nt 
me dicati o n pa per diar y (see S ecti o n 5. 5. 1 ). After c o m pleti n g t he O bser vati o n P hase , t he s u bject 
will ret ur n t o t he cli nic wit h t he e Diar y a n d c o nc o mita nt me dicati o n pa per diar y f or t he Baseli ne 
( Ra n d o mizati o n) Visit.
S u bjects will ha ve bl o o d dra w n a n d a uri nal ys is perf or me d f or baseli ne pr ofiles, a n E C G 
perf or me d, a n d ot her pr oce d ures as n ote d i n Ta ble 1 at t he Pre-ra n d o mizati o n E val uati o n Visit . 
S u bjects will t he n ret ur n f or t he Baseli ne ( Ra n d o mizati o n) Visit.  
At t he Baseli ne Visit, eli gi bilit y  f or c o nti n ue d partici pati o n i n t he st u d y will be assesse d bef ore 
ra n d o mizati o n occurs a n d bef ore st u d y dr u g is dis pe nse d.  S u bjects will be ra n d o mize d 1: 1: 1
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 2 9 of 1 0 3
P FI Z E R C O N FI D E N TI A L
acr oss 3 treat me nt gr o u ps i n t he D o u ble -bli n d T reat me nt P hase: ri me ge pa nt 7 5 m g O D T d ose d 
E O D alter nati n g wit h matc hi n g place b o ( n = 2 2 0 ); ri me ge pa nt 7 5 m g O D T d ose d dail y  ( n = 
2 2 0 ); or place b o f or matc hi n g ri me ge pa nt 7 5 m g O D T d ose d dail y ( n = 2 2 0 ). Ra n d o mizati o n will 
be stratifie d b y use of pri or pr o p h y lactic mi grai ne me dicati o n ge nerall y  c o nsi dere d t o ha ve 
efficac y ( yes or n o; see Secti o n 7. 2. 1 ). I n a d diti o n, ra n d o mizati o n of pr o p h ylactic mi grai ne 
treat me nt-naï ve s u bjects (“ n o” cate g or y) will be ca p pe d at 3 0 % i n or der t o all o w 7 0 % of 
ra n d o mize d s u bjects t o be pr o p hyl actic mi grai ne treat me nt-e x perie nce d ( “ yes” cate g or y).
D uri n g t he D o u ble -bli n d T reat me nt P hase, s u bjects will be i nstr ucte d t hat t he y  m ust ta ke 1 ta blet 
of bli n de d st u d y dr u g dail y . If s u bjects ha ve a mi grai ne d urin g t he D o u ble -bli n d Treat me nt 
P hase, t he n t he y m a y treat t he mi grai ne wit h per mitte d ac ute mi grai ne me dicati o n as nee de d (see 
Secti o n 5. 5. 1 ) w hile c o nti n ui n g t o ta ke t he st u dy dr u g . If a d ose of st u d y dr u g f or a gi ve n da y is 
misse d, l ost, or ot her wise u na ble t o be ta ke n, t he s u bject s h o ul d d oc u me nt t hat as a misse d d ose 
o n t he st u d y dr u g wallet a n d s h o ul d N O T ta ke t he f oll o wi n g da y ’s assi g ne d d ose u ntil t he ne xt 
cale n dar da y at t he s pecifie d ti me.  
At t he c o m pleti o n of t he 1 2-wee k D o u ble -bli n d Treat me nt P hase, s u bjects will be e val uate d f or 
e ntr y i nt o t he 1 2-wee k O pe n -la bel E xte nsi o n P hase f oll o wi n g la b or at or y test res ults wit hi n 
acce pta ble ra n ges per pr ot oc ol ( Secti o ns 5. 2 a n d 5. 3 ). D uri n g t he O pe n -la bel E xte nsi o n P hase, 
s u bjects will be i nstr ucte d t hat t he y m ust ta ke 1 ta blet of ri me ge pa nt 7 5 m g O D T daily.  
D uri n g t he D o u ble -bli n d Treat me nt P hase, s u bjects will rec or d t heir mi grai ne occ urre nce, 
mi grai ne pai n feat ures a n d ass ociate d s y m pt o ms, a n d use of ac ute mi grai ne me dicati o n o n eac h 
da y  i n t he e Diar y. 
S u bjects will als o rec or d all c o nc o mita nt me dicati o ns, i ncl u di n g ac ute sta n dar d of care mi grai ne 
me dicati o ns ( b ot h prescri be d a n d O T C ), ta ke n d uri n g t he e ntire st u d y i n t he c o nc o mita nt 
me dicati o n pa per diar y .
At select st u d y  visits, s u bjects will c o m plete or will be a d mi nistere d t he M i grai ne-S pecific
Q ualit y -of - Life Q uesti o n naire v 2. 1 ( M S Q v 2. 1), Cli nical Gl o bal I m pressi o n – c ha n ge (C GI -c) 
scale, t he Satisfacti o n wit h Me dicati o n ( S M) scale, a n d t he C ol u m bia -S uici de Se verit y Rati n g 
Scale ( C -S S R S) o n pa per f or ms.
A d diti o nal a ssess me nts a n d visit sc he d ule are o utli ne d i n t he pr oce d ural ta bles i n Secti o n 4. 3 . 
Pr oce d ures i ncl u de st u d y pers o n nel re vie w of t he e Diar y ( d uri n g t he D o u ble -bli n d T reat me nt 
P hase) a n d c o nc o mita nt me dicati o n pa per diar y wit h t he s u bject , assess me nt of st u d y dr u g
c o m plia nce, m o nit ori n g of t olera bilit y a n d safet y (i ncl u di n g vital si g ns, lab orat or y  tests, a n d 
electr ocar di o gra p h y).  
D uri n g t he O bser vati o n P hase, s t u d y visits will occ ur at Scree ni n g ( E nr oll me nt) a n d Pre -
ra n d o mizati o n E val uati o n . 
D uri n g t he D o u ble -bli n d Treat me nt P hase, st u d y  visits will occ ur at Baseli ne ( Ra n d o mizati o n), 
Wee k 2, Wee k 4, Wee k 8, a n d Wee k 1 2
or E n d of Treat me nt ( E O T) f or earl y  disc o nti n uati o n.  
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y a n d 
Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 3 0 of 1 0 3
P FI Z E R C O N FI D E N TI A L
At t he c o m pleti o n of t he 1 2 -wee k D o u ble - bli n d Treat me nt P hase, su bjects ma y  e nter t he 1 2-
wee k O pe n -la bel E xte nsi o n P hase if t he y c o nti n ue t o meet st u d y e ntr y criteria an d la b orat or y  test 
res ults are acce pta ble per pr ot oc ol (Secti o ns 5. 2 a n d 5. 3 ). St u d y  visits will occ ur at Wee k 1 4, 
Wee k 1 6, Wee k 2 0, a n d Wee k 2 4 or E O T f or earl y disc o nti n uati o n.  
D uri n g t he F oll o w -u p P hase, st u d y  visits will occ ur at F oll o w-u p Wee k 2 a n d F oll o w -u p Wee k 8 
f or assess me nt of A Es a n d la b orat or y  assess me nts.  All ra n d o mize d s u bjects s h o ul d c o m plete t he 
F oll o w -u p Wee k 2 a n d F oll o w -u p Wee k 8 Visit s.
T he e n d of t he st u d y is defi ne d as t he last visit of t he last s u bject.
T o cl osel y  m o nit or f or p ote ntial dr u g i n d uce d li ver i nj ur y ( DI LI), g ui da nce o n re p orti n g p ote ntial 
DI LI e ve nts is pr o vi de d i n t he pr ot oc ol. La b res ults t hat meet pre defi ne d L F T a b n or malit y 
criteria as DI LI s h o ul d be re p orte d as a seri o us a d verse e ve nt ( S A E). See Secti o n 8. 4 , P ote ntial 
Dr u g I n d uce d Li ver I nj ur y ( DI LI).
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -co ntr olle d St u d y t o E val uate t h e Efficac y a n d Safet y of Ri me ge pa nt i n E pis o dic 
Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 3 1 of 1 0 3
P FI Z E R C O N FI D E N TI A L
4. 2
St u d y Sc he m atic
Fi g ure 2 
1 2 W ee ks of D o u ble -b li n d T re at me nt wit h D ail y D osi n g, F oll o we d b y 1 2 W ee ks of O pe n-l a bel T re at me nt wit h 
D ail y D osi n g
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -co ntr olle d St u d y t o E val uate t h e Efficac y a n d Safet y of Ri me ge pa nt i n E pis o dic 
Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 3 2 of 1 0 3
P FI Z E R C O N FI D E N TI A L
4. 3
Sc he d ule of Assess me nts
E ver y  eff ort s h o ul d be ma de t o c o n d uct t he st u d y visits as pla n ne d. C o ncer ns relate d t o t he C or o na vir us disease 2 0 1 9 ( C O VI D - 1 9) 
pa n de mic, ot her nat ural catastr o p hes (e. g., h urrica ne), a n d a n y a d diti o nal case -b y -case sit uati o ns ma y be disc usse d f or a p pr o val wit h 
t he S p o ns or. F oll o wi n g a p pr o val, pr o visi o ns ma y be i m ple me nte d t o mi ni mize p ote ntial hazar ds t o st u d y s u bjects a n d t o mai ntai n 
c o m plia nce wit h l ocal g o ver n me nt a n d i nstit uti o nal g ui da nce (e. g., st u dy ce nter has a p olic y  t hat a cli nical researc h visit m ust be 
dela y e d).  T hese pr o visi o ns ma y  all o w alter nati ves t o i n-pers o n st u d y  visits a n d i ncl u de, b ut are n ot li mite d t o , t he f oll o wi n g: 
c o n d ucti n g re m ote st u d y visits via p h o ne/tele me dici ne vi de o, f oc usi n g o n safet y assess me nts d uri n g re m ote visits, or perf or mi n g 
safety la bs via l ocal la b orat or y or pr ofessi o nal i n -h o me p hle b ot o m y  ve n d ors. A n y p ote ntial iss ues s h o ul d be disc usse d wit h 
S p o ns or/ C R O a n d will be a d dresse d o n a n i n di vi d ualize d basis. T he Scree ni n g , Pre-Baseli ne E val uati o n, Baseli ne , a n d F oll o w - u p 
Wee k 8
Safet y visits m ust be d o ne i n pers o n. Ot her visits ma y  be c o n d ucte d u n der t he pr o visi o ns me nti o ne d a b o ve (re m ote via 
p h o ne/tele m e dici ne, l ocal la bs, etc.) .
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -co ntr olle d St u d y t o E val uate t h e Efficac y a n d Safet y of Ri me ge pa nt i n E pis o dic 
Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 3 3 of 1 0 3
P FI Z E R C O N FI D E N TI A L
T a ble 1
Sc he d ule of Assess me nts – O bser v ati o n P h ase, D o u ble- bli n d Tre at me nt P h ase, E O T, & F oll o w -u p P h ase
O bser v ati o n P h ase
( 2 8 d a ys + 3 d a ys) 1
D o u ble - bli n d Tre at me nt P h ase2 , 3 , 4
F oll o w -u p 
P h ase 3 , 4
Pr oce d ure
Scree ni n g 
Visit
Pre -
ra n d o miz a -
ti o n 
E v al u ati o n
Visit
B aseli ne 
(R a n d o miz a -
ti o n) Visit
( Da y 1)
Wee k 2
Visit   
( Da y 1 4 +/ - 2 
da ys)
Wee k 4 ( Da y 
2 8) a n d Wee k 
8 ( Da y 5 6)
Visit s
(b ot h visits +/-
2 da ys)
Wee k 1 2 (Da y 
8 6 + 3 da ys) or
E O T Visit f or 
earl y 
disc o nti n u ati o n
F U Wee k 2 
a n d F U Wee k 
8 Visits ( b ot h 
visits +/ -2 
da ys) f or all 
s u bjects4
Eli gi bilit y Assess me nts
I nf or me d C o nse nt
X
D u plicate S u bject C hec k (i n 
C T S data base)
X
I ncl usi o n/ E xcl usi o n Criteria
X
X
Me dical Hist or y
X
Mi grai ne Hist or y 
(si g ns/s y m pt o ms/ pri or 
treat me nt/fre q ue nc y/i nte nsit y)
X
C o nc o mita nt m e dicati o n 
pa per diar y 5
X
X
X
X
X
X
X
Ra n d o mize s u bject / I W R S 6
X
S afet y Assess me nts
P h y sical E xa mi nati o n7
X
X
X
Vital Si g ns / P h ysical 
Meas ure me nts
8
X
X
X
X 
X
X
X
Cli nical Safet y La b orat or y 
Testi n g 9
X
X
X
X
X
Li ver F u ncti o n Test ( L F Ts) 9
X
X
X
X
X
X
X
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -co ntr olle d St u d y t o E val uate t h e Efficac y a n d Safet y of Ri me ge pa nt i n E pis o dic 
Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 3 4 of 1 0 3
P FI Z E R C O N FI D E N TI A L
O bser v ati o n P h ase
( 2 8 d a ys + 3 d a ys) 1
D o u ble - bli n d Tre at me nt P h ase2 , 3 , 4
F oll o w -u p 
P h ase 3 , 4
Pr oce d ure
Scree ni n g 
Visit
Pre -
ra n d o miz a -
ti o n 
E v al u ati o n
Visit
B aseli ne 
(R a n d o miz a -
ti o n) Visit
( Da y 1)
Wee k 2
Visit   
( Da y 1 4 +/ - 2 
da ys)
Wee k 4 ( Da y 
2 8) a n d Wee k 
8 ( Da y 5 6)
Visit s
(b ot h visits +/-
2 da ys)
Wee k 1 2 (Da y 
8 6 + 3 da ys) or
E O T Visit f or 
earl y 
disc o nti n u ati o n
F U Wee k 2 
a n d F U Wee k 
8 Visits ( b ot h 
visits +/ -2 
da ys) f or all 
s u bjects4
Li pi d Pa nel 9
X
X
E C G
X
X
X
X
X
Uri nal ysis
X
X
Uri ne Dr u g Scree n f or dr u gs 
of a b use
X
F S H, if a p plica ble, t o 
deter mi ne W O C B P stat us
X
Pre g na nc y Test
X ( uri ne)
X (ser u m)
X (uri ne )
X ( uri ne)  
X ( uri ne)
X: F U W 2
( uri ne) & F U 
W 8
(ser u m)
A E , S A E , a n d C o nc o mita nt 
Pr oce d ure assess me nt 1 0
X
X
X
X
X
X
X
C ol u m bia -S uici de Se verit y 
Rati n g Scale ( C -S S R S)
X
X
X
X
X
X ( F U W 2 
o nl y)
Cli nic al Dr u g S u p plies / 
St u d y S u p plies
Dis pe nse st u d y dr u g1 1
X
X
X ( O L dr u g 
dis pe nse d f or 
s u bjects 
pla n ni n g t o 
e nter O L 
P hase)
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -co ntr olle d St u d y t o E val uate t h e Efficac y a n d Safet y of Ri me ge pa nt i n E pis o dic 
Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 3 5 of 1 0 3
P FI Z E R C O N FI D E N TI A L
O bser v ati o n P h ase
( 2 8 d a ys + 3 d a ys) 1
D o u ble - bli n d Tre at me nt P h ase2 , 3 , 4
F oll o w -u p 
P h ase 3 , 4
Pr oce d ure
Scree ni n g 
Visit
Pre -
ra n d o miz a -
ti o n 
E v al u ati o n
Visit
B aseli ne 
(R a n d o miz a -
ti o n) Visit
( Da y 1)
Wee k 2
Visit   
( Da y 1 4 +/ - 2 
da ys)
Wee k 4 ( Da y 
2 8) a n d Wee k 
8 ( Da y 5 6)
Visit s
(b ot h visits +/-
2 da ys)
Wee k 1 2 (Da y 
8 6 + 3 da ys) or
E O T Visit f or 
earl y 
disc o nti n u ati o n
F U Wee k 2 
a n d F U Wee k 
8 Visits ( b ot h 
visits +/ -2 
da ys) f or all 
s u bjects4
A d mi nister st u d y dr u g1 1 , 1 2
X
X
X
Dis pe nse / C ollect Electr o nic 
Diar y (e Diar y) 1 3
X ( Dis pe nse 
e Diar y)
X ( C ollect 
e Diar y)
Ret ur n use d a n d u n use d st u d y 
dr u g t o site f or c o m plia nce 
c hec k
X
X
X
e Diar y ret ur ne d / re vie we d 
f or c o m plet ness1 3
X
X
X
X
X
Ot her Assess me nts
Dail y re p ort of mi grai ne 
occ urre nce a n d pai n i nte nsit y
re p orte d b y s u bject i n 
e Diar y 1 3
X
X
X
X
X
Mi grai ne -S pecific Q ualit y -of -
Life Q uesti o n naire ( M S Q )       
v 2. 1
X
X 
Satisfacti o n wit h Me dicati o n 
( S M) 
X 
Cli nical Gl o bal I m pressi o n -
C ha n ge ( C GI -c)
X
1. T he O bser vati o n P hase t o deter mi ne eli gi bilit y is 2 8 da ys + 3 da ys. T he “ + 3” da ys wi n d o w is i ncl u de d f or sc he d uli n g p ur p oses o nl y.  S u bjects wit h less t ha n 
2 4 c o m plete d e Diar y re p orts d uri n g 2 8 da ys i n t he O bser vati o n P hase will n ot be c o nsi dere d f or partici pati o n d ue t o n o n-c o m plia nce wit h t he e Diar y.  S u bjects i n 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -co ntr olle d St u d y t o E val uate t h e Efficac y a n d Safet y of Ri me ge pa nt i n E pis o dic 
Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 3 6 of 1 0 3
P FI Z E R C O N FI D E N TI A L
t he D o u ble-bli n d Treat me nt P hase w h o de m o nstrate p o or c o m plia nce will be disc usse d wit h t he S p o ns or, c orrecti ve trai ni n g will be c o m plete d b y t he site w it h 
t he s u bject a n d ma y n ot be c o nsi dere d f or t he O pe n-la bel E xte nsi o n P hase.  
2. W hile o n -st u d y, all visit wi n d o ws are use d f or sc he d uli n g p ur p oses a n d all eff orts s h o ul d be ma de t o ret ur n s u bjects t o t heir ori gi nal visit sc he d ule b y
calc ulati n g t he visit wi n d o w i nter val fr o m t he Baseli ne/ Ra n d o mizati o n Visit.
3 . All ra n d o mize d s u bjects w h o disc o nti n ue e arly fr o m t he D o u ble -bli n d Tre at me nt P h ase s h o ul d c o m plete t he E O T Visit a n d e nter t he F oll o w-u p P hase (t he y 
s h o ul d n ot e nter t he O pe n-la bel E xte nsi o n P hase). All ra n d o mize d s u bjects s h o ul d c o m plete t he F oll o w-u p Wee k 2 a n d F oll o w -u p Wee k 8 Visits.
4 . F or s u bjects w h o d o n ot e nter t he O pe n -la bel E xte nsi o n P hase, t he f oll o w-u p visits s h o ul d be sc he d ule d base d o n date of t he Wee k 1 2 or E O T Visit. T he visit 
wi n d o w  f or t he F oll o w-u p Wee k 2 Visit is 1 4 da ys +/ - 2 da ys.  T he visit wi n d o w  f or t he F oll o w-u p Wee k 8 Visit is 5 6 da ys +/ - 2 d a y s; h o we ver, i n cases of a 
dela ye d visit d ue t o restricti o ns res ulti n g fr o m t he C O VI D -1 9 pa n de mic, + 1 4 da ys m a y be utilize d i nstea d of + 2 da ys i n or der t o e ns ure t his fi nal visit is 
c o m plete d i n pers o n.
5 . C o nc o mita nt me dicati o ns, i ncl u di n g ac ute sta n dar d of care mi grai ne me dicati o ns ( b ot h prescri be d a n d O T C), ta ke n d uri n g t he O bser vati o n, D o u ble -bli n d 
Treat me nt , a n d F oll o w-u p P hase s h o ul d be rec or de d i n t he s u bject’s c o nc o mita nt me dicati o n pa per diar y, re vie we d b y st u d y pers o n nel at eac h visit, a n d a c o p y 
ma de at eac h st u d y visit t o be mai ntai ne d i n s o urce rec or ds. At e n d of st u d y, t he c o nc o mita nt me dicati o n pa p er diar y s h o ul d be c ollecte d at t he F oll o w-u p Wee k 
8 Visit.  
6. T he act ual Baseli ne Visit date s h o ul d be use d f or I W R S e nr oll me nt date a n d eli gi bilit y date.
7. Per Secti o n 6. 2. 3 , a f ull P h ysical E xa m ( P E) is re q uire d at scree ni n g O N L Y a n d brief s y m pt o m-directe d P Es are re q uire d at all ot her visits.
8 Hei g ht will be meas ure d at t he Scree ni n g Visit o nl y.  Wei g ht, b o d y te m perat ure, res pirat or y rate, bl o o d press ure, a n d heart r ate will be c ollecte d at all 
ti mep oi nts w here i n dicate d.  Sitti n g arterial s yst olic a n d diast olic bl o o d press ure a n d ra dial arter y p ulse rate will be meas ure d .
9 If p ossi ble, s ubjects s h o ul d be fasti n g f or a mi ni m u m of 8 h o urs bef ore la b orat or y tests . H o w e ver, if a s u bject is n ot fasti n g, t he bl o o d dra w s h o ul d still be 
perf or me d, a n d t he n o n -fasti n g stat us s h o ul d be d oc u me nte d. H b A 1c is o nl y c ollecte d at Scree ni n g, Re peat or U nsc he d ule d Visit.
1 0 S A Es, A Es, a n d C o nc o mita nt Pr oce d ures m ust be re p orte d after s u bject si g ns i nf or me d c o nse nt.  S A Es a n d C o nc o mita nt Pr oce d ures s h o ul d be re p orte d fr o m 
si g ni n g of c o nse nt t hr o u g h t he F oll o w-u p Wee k 8 Visit.  N o n -seri o us A Es s h o ul d be re p orte d fr o m si g ni n g of c o nse nt t hr o u g h t he F oll o w-u p Wee k 2 Visit.
1 1 S u bjects m ust fi nis h a wallet of st u d y dr u g be f ore starti n g a ne w wallet.  St u d y dr u g will be dis pe nse d at m o nt hl y (e ver y 4 wee ks) st u d y visits, as nee de d.  Site 
staff s h o ul d mar k eac h wallet wit h t he sc he d ule d date of eac h d ose t o be ta ke n w he n dis pe nsi n g t he st u d y dr u g.  At t he Wee k 12 / E O T Visit, all d o u ble-bli n d 
st u d y dr u g s h o ul d be c ollecte d, o pe n-la bel st u d y dr u g s h o ul d be dis pe nse d, a n d s u bjects m ust be i nstr ucte d t hat d osi n g wit h o pe n-la bel st u d y dr u g ca n n ot i nitiate 
u ntil eli gi bilit y has bee n c o nfir me d via la b res ults (tele p h o ne visit).
1 2 S u bjects m ust ta ke st u d y dr u g dail y re gar dless of w het her t he y ha ve a mi grai ne.  D oses are n ot re q uire d t o be ta ke n i n t he offi ce o n da ys of a st u d y visit, 
h o we ver d osi n g re q uire me nts a n d c o m plia nce s h o ul d be disc usse d w it h s u bjects at all visits.  D uri n g t he D o u ble -bli n d Treat me nt P hase, if a d ose of st u d y dr u g 
f or a gi ve n da y is misse d, l ost, or ot her wise u na ble t o be ta ke n, t he s u bject s h o ul d d oc u me nt t hat as a misse d d ose o n t he stu d y dr u g wallet a n d s h o ul d N O T ta ke 
t he f oll o wi n g da y’s assi g ne d d ose u ntil t he ne xt cale n dar da y at t he s pecifie d ti me.  
1 3 T he e Diar y will be dis pe nse d at t he Scree ni n g Visit, after all scree ni n g pr oce d ures are c o m plete d.  T he s u bject w ill be trai ne d o n t he use of t he e Diar y.  T he 
s u bject will use t he e Diar y e ver y da y d uri n g the O bser vati o n a n d D o u ble -bli n d Treat me nt P hases t o re p ort mi grai ne occ urre nce, mi grai ne i nte nsit y a n d use of 
ac ute mi grai ne me dicati o n. T he e Diar y m ust be c ollecte d at t he Wee k 1 2 or E O T Visit.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -co ntr olle d St u d y t o E val uate t h e Efficac y a n d Safet y of Ri me ge pa nt i n E pis o dic 
Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 3 7 of 1 0 3
P FI Z E R C O N FI D E N TI A L
T a ble 2
Sc he d ule of Assess me nts – O pe n -l a bel E xte nsi o n P h ase, E O T, & F oll o w-u p P h ase
P h o ne visit t o c o nfir m 
eli gi bilit y base d o n 
la b orat or y criteria1
O pe n -l a bel E xte nsi o n P h ase 2 ,3
F oll o w -u p P h ase 3 ,4
Pr oce d ure
Wee k 1 4
Visit   
( Da y 9 8 +/- 3 
da ys)
Wee k 1 6 ( Da y 1 1 2 )
a n d Wee k 2 0 ( Da y 
1 4 0 ) Visits
( b ot h visits +/- 2 
da ys)
Wee k 2 4 ( Da y 
1 6 8 +/ - 2 da ys) 
or E O T Visit f or 
earl y 
disc o nti n u ati o n
F U Wee k 2 a n d F U Wee k 8 
Visits ( b ot h visits +/-2 da ys) 
f or all s u bjects4
C o nfir m Wee k 1 2 La b orat or y 
Res ults
X
C o nc o mita nt Me dicati o n 
pa per diar y 5
X
X
X
X 
S afet y Assess me nts
P h y sical E xa mi nati o n 6
X ( Wee k 1 6 o nl y)
X
Vital Si g ns / P h ysical 
Meas ure me nts
7
X 
X
X
X 
Cli nical Safet y La b orat or y 
Testi n g 8
X
X
Li ver F u ncti o n Test ( L F Ts) 8
X
X
X
X
Li pi d Pa nel 8
X
E C G
X
X
Uri nal ysis
X
Pre g na nc y Test
X ( uri ne)
X ( uri ne)
X ( uri ne)
X: F U W 2 ( uri ne) & F U W 8 
(ser u m)
A E , S A E , a n d C o nc o mita nt 
Pr oce d ure assess me nt 9
X
X
X
X
C ol u m bia -S uici de Se verit y 
Rati n g Scale ( C -S S R S)
X
X
X
X ( F U W 2 o nl y)
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -co ntr olle d St u d y t o E val uate t h e Efficac y a n d Safet y of Ri me ge pa nt i n E pis o dic 
Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 3 8 of 1 0 3
P FI Z E R C O N FI D E N TI A L
P h o ne visit t o c o nfir m 
eli gi bilit y base d o n 
la b orat or y criteria1
O pe n -l a bel E xte nsi o n P h ase 2 ,3
F oll o w -u p P h ase 3 ,4
Pr oce d ure
Wee k 1 4
Visit   
( Da y 9 8 +/- 3 
da ys)
Wee k 1 6 ( Da y 1 1 2 )
a n d Wee k 2 0 ( Da y 
1 4 0 ) Visits
( b ot h visits +/- 2 
da ys)
Wee k 2 4 ( Da y 
1 6 8 +/ - 2 da ys) 
or E O T Visit f or 
earl y 
disc o nti n u ati o n
F U Wee k 2 a n d F U Wee k 8 
Visits ( b ot h visits +/-2 da ys) 
f or all s u bjects4
Cli nic al Dr u g S u p plies / 
St u d y S u p plies
Dis pe nse st u d y dr u g1 0
X
A d mi nister st u d y dr u g1 0 , 1 1
X
X
X
Ret ur n use d a n d u n use d st u d y 
dr u g t o site f or c o m plia nce 
c hec k
X
X
X
Ot her Assess me nts
Mi grai ne -S pecific Q ualit y -of -
Life Q uesti o n naire ( M S Q )       
v 2. 1
X
Satisfacti o n wit h Me dicati o n 
( S M) 
X
Cli nical Gl o bal I m pressi o n -
C ha n ge ( C GI -c)
X
1. St u d y eli gi bilit y m ust be c o nfir me d b y Wee k 1 2
la b orat or y res ults pri or t o first d ose of o pe n -la bel st u d y dr u g, w hic h is dis pe nse d at t he Wee k 1 2 visit. Sites 
m ust c o ntact s u bject b y  p h o ne t o c o nfir m st u d y eli gi bilit y pri or t o s u bject ta ki n g first d ose.
2 .W hile o n -st u d y, all visit wi n d o ws are use d f or sc he d uli n g p ur p oses a n d all eff orts s h o ul d be ma de t o ret ur n s u bjects t o t heir ori gi nal visit sc he d ule b y 
calc ulati n g t he visit wi n d o w i nter val fr o m t he Baseli ne/ Ra n d o mizati o n Visit.
3. All ra n d o mize d s u bjects w h o disc o nti n ue e arly fr o m t he O pe n -l a bel E xte nsi o n P h ase s h o ul d c o m plete t he E O T Visit. All ra n d o mize d s u bjects s h o ul d 
c o m plete t he F oll o w-u p Wee k 2 a n d F oll o w-u p Wee k 8 Visits.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 ( C 4 9 5 1 0 1 0) Versi o n 5. 0 
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -co ntr olle d St u d y t o E val uate t h e Efficac y a n d Safet y of Ri me ge pa nt i n E pis o dic 
Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 3 9 of 1 0 3
P FI Z E R C O N FI D E N TI A L
4. F or s u bjects w h o e nter t he O pe n -la bel E xte nsi o n P hase, t he f oll o w-u p visits s h o ul d be sc he d ule d base d o n date of t he Wee k 2 4 or E O T Visit.  T he visit 
wi n d o w  f or t he F oll o w-u p Wee k 2 Visit is 1 4 da ys +/ - 2 da ys.  T he visit w i n d o w f or t he F oll o w-u p Wee k 8 Visit is 5 6 da ys +/ - 2 d a y s; h o we ver, i n cases of a 
dela ye d visit d ue t o restricti o ns res ulti n g fr o m t he C O VI D -1 9 pa n de mic, + 1 4 da ys ma y be utilize d i nstea d of + 2 da ys i n or der t o e ns ure t his fi nal visit is 
c o m plete d i n per s o n.
5. C o nc o mita nt me dicati o ns, i ncl u di n g ac ute sta n dar d of care mi grai ne me dicati o ns ( b ot h prescri be d a n d O T C), ta ke n d uri n g t he O pe n -la bel E xte nsi o n P hase a n d 
F oll o w -u p P hase s h o ul d be rec or de d i n t he s u bject’s c o nc o mita nt me dicati o n pa per diar y, re vie w e d b y st u d y pers o n nel at eac h visit, a n d a c o p y ma de at eac h 
st u d y visit t o be mai ntai ne d i n s o urce rec or ds. At e n d of st u d y, t he c o nc o mita nt me dicati o n pa per diar y s h o ul d be c ollecte d at t he F oll o w-u p Wee k 8 Visit.
6. Per Secti o n 6. 2. 3 , a f ull P h ysical E xa m ( P E) is re q uire d at scree ni n g O N L Y a n d brief s y m pt o m-directe d P Es are re q uire d at all ot her visits.   
7. Hei g ht will be meas ure d at t he Scree ni n g Visit o nl y.  Wei g ht, b o d y te m perat ure, res pirat or y rate, bl o o d press ure, a n d heart rate will be c ollecte d at all 
ti me p oi nts w here i n dicate d.  Sitti n g arterial s yst olic a n d diast olic bl o o d press ure a n d ra dial arter y p ulse rate will be measure d.
8. If p ossi ble, su bjects s h o ul d be fasti n g f or a mi ni m u m of 8 h o urs bef ore la b orat or y tests. H o w e ver, if a s u bject is n ot fasti n g, t he bl o o d dra w  s h o ul d still be 
perf or me d, a n d t he n o n -fasti n g stat us s h o ul d be d oc u me nte d. H b A 1c is o nl y c ollecte d at Scree ni n g, Re peat or U nsc he d ule d Visit.
9. S A Es, A Es, a n d C o nc o mita nt Pr oce d ures m ust be re p orte d after s u bject si g ns i nf or me d c o nse nt.  S A Es a n d C o nc o mita nt Pr oce d ures s h o ul d be re p orte d fr o m 
si g ni n g of c o nse nt t hr o u g h t he F oll o w-u p Wee k 8 Visit.  N o n -seri o us A Es s h o ul d be re p orte d fr o m si g ni n g of c o nse nt t hr o u g h t he F oll o w-u p Wee k 2 Visit.
1 0 . S u bjects s h o ul d fi nis h a wallet of st u d y dr u g bef ore starti n g a ne w wallet.  St u d y dr u g will be dis pe nse d at m o nt hl y (e ver y 4 wee ks) st u d y visits, as nee de d.  
Site staff s h o ul d mar k eac h wallet wit h t he sc he d ule d date of eac h d ose t o be ta ke n w he n dis pe nsi n g t he st u d y dr u g.
1 1. S u bjects m ust ta ke st u d y dr u g dail y re gar dless of w het her t he y ha ve a mi grai ne.  D oses are n ot re q uire d t o be ta ke n i n t he of fice o n da ys of a st u d y visit, 
h o we ver d osi n g re q uire me nts a n d c o m plia nce s h o ul d be disc usse d w it h s u bjects at all visits.  If a d ose of st u d y dr u g f or a gi ve n da y is misse d, l ost, or ot her wise 
u na ble t o be ta ke n, t he s u bject s h o ul d d oc u me nt t hat as a misse d d ose o n t he st u d y dr u g wallet.    
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 4 0 of 1 0 3
P FI Z E R C O N FI D E N TI A L
4. 3. 1
O bser v ati o n P h ase
T he O bser vati o n P hase will be 2 8 da y s + 3 da ys. N ote t hat the “ + 3 d a y s” wi n d o w is i ncl u de d 
f or sc he d uli n g p ur p oses o nly. 
T he O bser vati o n P hase will ha ve 2 sc he d ule d visits, Scree ni n g a n d Pre- ra n d o mizati o n 
E val uati o n, w hic h s h o ul d be c o m plete d i n pers o n.   
S u bjects will re p ort mi grai ne occ urre nce, mi grai ne pai n feat ures a n d ass ociate d s y m pt o ms, a n d 
use of ac ute mi grai ne me dicati o n i n t he e Diar y  e ver y da y d uri n g t he O bser vati o n P hase. 
All s u bjects will c o nti n ue t o use t heir ac ute sta n dar d of care mi grai ne me dicati o ns d uri n g t he
O bser vati o n P hase. S u bjects will rec or d all c o nc o mita nt me dicati o ns, i ncl u di n g ac ute sta n dar d of 
care mi grai ne me dicati o ns ( b ot h prescri be d a n d O T C ), ta ke n d uri n g t he e ntire O bser vati o n P hase 
in a co nc o mita nt m e dicati o n pa per diar y. 
After c o m pleti n g t he O bser vati o n P hase, s u bjects will ret ur n t o t he st u d y site f or t he Baseli ne 
( Ra n d o mizati o n) Visit, a n d b ot h t heir e Diar y a n d pa per diar y will be re vie we d f or c o m plete ness.
4. 3. 1. 1
Scree ni n g Visit
Bef ore a n y st u d y pr oce d ures are perf or me d, s u bje cts m ust pr o vi de d oc u me nte d i nf or me d 
c o nse nt.  After i nf or me d c o nse nt, s u bjects will be e nr olle d i n t he I W R S s y ste m. T he s u bject’s 
mi grai ne hist or y  a n d me dical hist or y will be c ollecte d at t he Scree ni n g Visit, w hic h starts at d a y  
1 of t he O bser vati o n P hase .
S u bjects will u n der g o all scree ni n g pr oce d ures as detaile d i n Ta ble 1 .  After c o m pleti o n of all 
scree ni n g pr oce d ures, s u bjects will be pr o vi de d a n e Diar y. 
If t he s u bject meets st u d y e ntr y criteria (i.e., i ncl usi o n/e xcl usi o n criteria), t he n t he s u bject will 
ret ur n t o t he st u d y site f or t he Pre-ra n d o mizati o n Eval uati o n Visit . 
If t he s u bject d oes n ot meet st u d y e ntr y criteria, t he n t he s u bject will be c o nsi dere d a scree n 
fail ure a n d s h o ul d be rec or de d as s uc h i n I W R S. T he s u bject m ust ret ur n t o t he st u d y site t o 
ret ur n t he e Diar y.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 4 1 of 1 0 3
P FI Z E R C O N FI D E N TI A L
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y  (scree n fail ure) ma y b e
c o nsi dere d f or re -scree ni ng i n select circ u msta nces (e. g., pre vi o usl y pre g na nt, scree ni n g wi n d o w 
t o o l o n g). S u bjects w h o were c o nsi dere d scree n fail ures ma y als o be c o nsi dere d f or re -scree ni n g 
pr o vi de d t he i neli gi bilit y was d ue t o 1 of t he eli gi bilit y  criteria t hat ma y ha ve c ha n ge d d ue t o 
me dical i nter ve nti o n or 1 of t he eli gi bilit y  criteria m o difie d i n a pr ot oc ol a me n d me nt. A de q uate 
d oc u me ntati o n i n s o urce rec or ds m ust s u p p ort t he pre vi o usl y  faile d criteria. I n all p ossi ble re-
scree ni n g circ u msta nces, t he sit uati o n m ust be disc ussed wit h t he S p o ns or pri or t o re -scree ni n g, 
wit h a p pr o val i n writi n g fr o m t he S p o ns or pri or t o re- scree ni n g.  If a s u bject is a p pr o ve d f or re-
scree ni n g, a ne w s u bject n u m ber m ust be o btai ne d fr o m t he a p pr o priate st u d y-relate d sys te m. 
Re -scree ni n g will o nl y be per mitte d o ne ti me.
4. 3. 1. 2
Pre - ra n d o miz ati o n E v al u ati o n Visit
S u bjects m ust ret ur n t o t he st u d y site f or t he Pre -ra n d o mizati o n E val uati o n Visit wit hi n 4 da y s   
+ 2 da y s of t he Baseli ne Visit. N ote t hat t he “ + 2 da y s” wi n d o w is i ncl u de d f or sc he d uli n g 
p ur p oses o nly . E ver y eff ort s h o ul d be ma de t o c o m plete t he Pre-ra n d o mizati o n E val uati o n Visit 
as cl ose t o, a n d wit hi n, t he 4 da ys pri or t o t he Baseli ne Visit as p ossi ble. H o we ver, f or 
sc he d uli n g c o n ve nie nce, t his wi n d o w ma y be u p t o 6 da ys bet wee n t he Pre-ra n d o mizati o n 
E val uati o n Visit a n d t he Baseli ne Visit.
Safet y  la bs, a n d a n assess me nt of h o w t he s u bject is feeli n g will be perf or me d, a uri nalys is will 
be c o m plete d, a ser u m pre g na nc y test, w here a p plica ble, will be o btai ne d, a n E C G will be 
perf or me d, a brief p h y sical e xa m ( P E) will be perf or me d u nless a f ull P E is cli nicall y warra nte d, 
vital si g ns a n d p h ys ical meas ure me nts will be perf or me d acc or di n g t o Ta ble 1 , a n d c o m plia nce 
wit h t he c o nc o mita nt me diati o n pa per diar y  a n d e Diar y will be assesse d.  
If t he s u bject c o nti n ues t o meet st u d y e ntr y criteria a n d la b orat or y test res ults are acce pta ble per 
pr ot oc ol, t he n t he s u bject will be ra n d o mize d at t he Baseli ne Visit i nt o t he D o u ble -bli n d 
T reat me nt P hase. 
If t he la b orat or y res ults are n ot acce pta ble per pr ot oc ol, t he n t he s u bject is deter mi ne d t o be a 
scree n fail ure a n d s h o ul d be rec or de d as s uc h i n I W R S. T he s u bject m ust ret ur n t o t he st u d y site 
t o ret ur n t he e Diar y.
4. 3. 2
D o u ble -bli n d Tre at me nt P h ase
T he D o u ble -bli n d Treat me nt P hase will be u p t o 1 2 wee ks fr o m t he Baseli ne ( Ra n d o mizati o n) 
Visit t hr o u g h t he Wee k 1 2 or E O T Visit .
D uri n g t he D o u ble -bli n d Treat me nt P hase, s u bjects will be i nstr ucte d t hat t he y  m ust ta ke 1 ta blet 
of bli n de d st u d y dr u g dail y . If s u bjects ha ve a mi grai ne d uri n g t he D o u ble -bli n d Treat me nt 
P hase, t he n t he y m a y treat t he mi grai ne wit h per mitte d ac ute mi grai ne me dicati o n as nee de d (see 
Secti o n 5. 5. 1 ) w hile c o nti n ui n g t o ta ke t he st u dy dr u g .
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 4 2 of 1 0 3
P FI Z E R C O N FI D E N TI A L
S u bjects will c o nti n ue t o re p ort mi grai ne occ urre nce, mi grai ne pai n feat ures a n d ass ociate d 
s ym pt o ms, a n d u se of ac ute mi grai ne me dicati o n i n t he e Diar y e ver y d a y d uri n g t he D o u ble-
bli n d Treat me nt P hase.
T he M S Q, S M, C GI -c, a n d C- S S R S will be c o m plete d, or a d mi nistere d b y t he i n vesti gat or, o n 
pa per at s pecifie d st u d y visits ( Ta ble 1 ).
S u bjects will c o nti n ue t o rec or d all c o nc o mita nt me dicati o ns, i ncl u di n g ac ute sta n dar d of care 
mi grai ne me dicati o ns ( b ot h prescri be d a n d O T C ), ta ke n d uri n g t he e ntire D o u ble -bli n d 
Treat me nt P hase in a co nc o mita nt m e dicati o n pa per diar y.
After t he Baseli ne Visit, st u d y  visits will be a p pr o xi matel y e ver y 2 wee ks d uri n g t he first m o nt h,
a n d t he n e ver y 4 wee ks u ntil t he Wee k 1 2 or E O T Visit (Ta ble 1 ). At eac h visit, t he e Diar y will 
be re vie we d b y site staff f or c o m plete ness a n d c o m plia nce. C o nc o mita nt me dicati o n use will be 
re vie we d a n d c o m pare d bet wee n t he e Diar y a n d c o nc o mita nt me dicati o n pa per diar y  e ntries, 
w here a p plica ble at eac h visit . St u d y dr u g c o m plia nce will be re vie we d at eac h visit usi n g t he 
ret ur ne d st u d y dr u g wallets . Un use d , n o n-e x pire d, partial wallets will be ret ur ne d t o t he s u bjects 
f or c o m pleti o n pri or t o starti n g a ne w wallet. S u bjects will be dis pe nse d a d diti o nal st u d y dr u g as 
nee de d , as per t he I P ma n ual. A d diti o nal safet y tests (i ncl u di n g la b orat or y tests a n d E C Gs) will 
be perf or me d per t he sc he d ule o utli ne d i n Ta ble 1 . S u bjects i n t he D o u ble-bli n d Treat me nt P hase 
w h o de m o nstrate p o or c o m plia nce will be disc usse d wit h t he S p o ns or, c orrecti ve trai ni n g will be 
c o m plete d b y  t he site wit h t he s u bject a n d ma y n ot be c o nsi dere d f or t he Ope n -la bel E xte nsi o n 
P hase.
Certai n pr o visi o ns ma y  be i m ple me nte d, i n or der t o mi ni mize p ote ntial hazar ds t o st u d y 
s u bjectss d ue t o C O VI D-1 9. T hese pr o visi o ns ma y  all o w alter nati ves t o i n-pers o n st u d y  visits 
a n d i ncl u de b ut are n ot li mite d t o t he f oll o wi n g: c o n d ucti n g re m ote st u d y  visits via 
p h o ne/tele me dici ne vi de o, f oc usi n g o n safet y assess me nts d uri n g re m ote visits, perf or mi n g 
safety la bs via l ocal la bs or pr ofessi o nal i n -h o me p hle b ot o m y  ve n dors, a n d s hi p pi n g of st u d y 
dr u g directl y t o st u d y s u bjects if nee de d. A n y p ote ntial iss ues s h o ul d be disc usse d wit h 
S p o ns or/ C R O a n d will be a d dresse d o n a n i n di vi d ualize d basis. All pr oce d ures n ot a ble t o be 
c o m plete d d ue t o a visit bei n g c o n d ucte d re m otel y m ust be re p orte d as a pr ot oc ol de viati o n a n d 
ca n be perf or me d at t he ne xt visit, w here a p pr o priate t o d o s o base d o n s u bject prese ntati o n.
4. 3. 2. 1
B aseli ne ( R a n d o miz ati o n) Visit
O nce c o m pleti n g t he O bser vati o n P hase , su bjects will ret ur n t o t he st u d y  site f or t he Baseli ne 
( Ra n d o mizati o n) Visit , w hic h s h o ul d be c o m plete d i n pers o n.   Su bjects w h o c o nti n ue t o meet all 
st u d y e ntr y criteria a n d ha ve bee n c o m plia nt wit h t he e Diar y m a y  e nter t he D o u ble- bli n d 
Treat me nt P hase , pe n di n g re vie w of a d diti o nal la b orat or y test res ults; see Secti o n 4. 3. 1. 2 . 
S u bjects wit h fe wer t ha n 2 4 c o m plete d e Diar y  re p orts d uri n g 2 8 da y s i n t he O bser vati o n P hase 
will n ot be c o nsi dere d f or partici pati o n d ue t o n o n -c o m plia nce wit h t he e Diar y. Beca use 
la b orat or y res ults fr o m t he Baseli ne Visit will be a vaila ble after t he s u bject ma y ha ve bee n 
deter mi ne d t o be ot her wise eli gi ble f or t he st u d y, ha d bee n ra n d o mize d , a n d starte d treat me nt, 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 4 3 of 1 0 3
P FI Z E R C O N FI D E N TI A L
t here is t he p ossi bilit y t hat e xcl usi o nar y la b orat or y res ults fr o m t he Baseli ne Visit ma y  res ult i n 
earl y disc o nti n uati o n fr o m t he st u d y.
At t he Baseli ne Visit, s u bjects will be ra n d o mize d 1: 1: 1 acr oss 3 treat me nt gr o u ps: ri me ge pa nt 
7 5 m g O D T d ose d E O D alter nati n g wit h matc hi n g place b o ( n = 2 2 0 ); ri me ge pa nt 7 5 m g O D T 
d ose d dail y  ( n = 2 2 0); or place b o f or matc hi n g ri me ge pa nt 7 5 m g O D T d ose d dail y ( n = 2 2 0).   
Ra n d o mizati o n will be stratifie d b y use of pri or pr o p h y lactic mi grai ne me dicati o n ge nerall y  
c o nsi dere d t o ha ve efficac y ( yes or n o; see Secti o n 7. 2. 1 ). I n a d diti o n, ra n d o mizati o n of 
pr o p h y lactic mi grai ne treat me nt-naï ve s u bjects (“ n o” cate g or y) will be ca p pe d at 3 0 % i n or der t o 
all o w 7 0 % of ra n d o mize d s u bjects t o be pr o p h yl actic mi grai ne treat me nt-e x perie nce d (“ yes” 
cate g or y).
N O T E : D uri n g t he D o u ble -bli n d T reat me nt P hase, i f a d ose of st u d y dr u g f or a gi ve n da y is 
misse d, l ost, or ot her wise u na ble t o be ta ke n, t he s u bject s h o ul d d oc u me nt t hat as a misse d d ose
o n t he st u d y dr u g wallet a n d s h o ul d N O T ta ke t he f oll o wi n g da y’s assi g ne d d ose u ntil t he ne xt 
cale n dar da y at t he s pecifie d ti me.  
4. 3. 2. 2
Wee k
1 2 or E O T Visit
S u bjects will ret ur n t o t he st u d y  site at t he Wee k 1 2 Visit ( Da y  8 6 + 3 d a y s), or at t he E O T Visit 
f or earl y disc o nti n uati o n, f or re vie w of t he eD iar y, assess me nt of me dicati o n c o m plia nce a n d 
assess me nt of t olera bilit y a n d safet y (i ncl u di n g vital si g ns, la b orat or y  tests, a n d 
electr ocar di o gra p h y) (Ta ble 1 ). S u bjects m ust ret ur n t he u n use d st u d y dr u g a n d eD iar y t o t he 
st u d y site. S u bjects i n t he D o u ble- bli n d Treat me nt P hase w h o de m o nstrate p o or c o m plia nce will 
be disc usse d wit h t he S p o ns or, c or recti ve trai ni n g will be c o m plete d b y t he site wit h t he s u bject
an d ma y  n ot be c o nsi dere d f or t he Ope n -la bel E xte nsi o n P hase . 
All r a n d o mize d s u bjects w h o disc o nti n ue e arly fr o m t he D o u ble-bli n d Tre at me nt P h ase s h o ul d 
c o m plete t he E O T Visit. Ot her wise, s u bjects s h o ul d c o m plete t he Wee k 1 2 Visit.
I n cases w here a ( 1) Wee k 1 2 or E O T Visit occ urs re m otel y i n or der t o be c o m plete d d uri n g t he 
pr ot oc ol re q uire d wi n d o w a n d d ue t o t he C O VI D - 1 9 pa n de mic a n d ( 2) t he s u bject d oes n ot e nter 
t he O pe n-la bel E xte nsi o n P hase, t he s u bject s h o ul d ret ur n t o t he site f or t he F oll o w-u p Wee k 2
Visit ( 2 wee ks after t he Wee k 1 2
or E O T Visit , -2 t o + 1 4 da y s), t o c o m plete all pr oce d ures t hat 
were n o t a ble t o be c o m plete d re m otely.   Pr oce d ures c o m plete d at t he Wee k 1 2 o r E O T Visit 
occ urri n g re m otel y d o n ot nee d t o be re peate d.  
4. 3. 3
O p e n -l a b el E xt e n si o n P h a s e
U p t o 6 6 0 s u bjects (i ncl u di n g u p t o 2 2 0 s u bjects i n t he dail y  d osi n g c o h ort) ma y be e ntere d i nt o 
t he O pe n -la bel E xte nsi o n P hase f or a n a d diti o nal 1 2 wee ks wit h dail y d osi n g.
As i n dicate d i n Ta ble 1 , la b orat or y tests will be perf or me d at t he Wee k 1 2 visit (fi nal visit of t he 
D o u ble -bli n d T reat me nt P hase). S u bjects w h o ( 1) c o m plete t he D o u ble-bli n d Tre at me nt 
P h ase, ( 2) c o nti n ue t o meet all i ncl usi o n/e xcl usi o n criteri a , a n d ( 3) h a ve bee n c o m pli a nt 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 4 4 of 1 0 3
P FI Z E R C O N FI D E N TI A L
wit h t he e Di ar y m a y e nter t he O pe n- l a bel E xte nsi o n P h ase, pe n di n g re vie w of l a b or at or y 
test res ults. S u bjects will be dis pe ns e d st u d y dr u g (ri me ge pa nt 7 5 m g O D T) me dicati o n a n d 
m ust be i nstr ucte d t hat t he y  ca n n ot ta ke st u d y dr u g u ntil la b orat or y  res ults c o nfir m st u d y 
eli gi bilit y. S u bjects ma y be c o ntacte d b y tele p h o ne; a n office st u d y visit is n ot re q uire d.
S u bjects will be i nstr ucte d t hat t he y  m ust ta ke 1 ta blet of ri me ge pa nt 7 5 m g O D T e ver y da y, 
re gar dless of w het her t he y ha ve a mi grai ne o n t hat da y. If s u bjects ha ve a mi grai ne d uri n g t he 
O pe n -la bel E xte nsi o n Phase, t he n t he y m a y treat t he mi grai ne wit h per mitte d ac ute mi grai ne 
me dicati o n as nee de d (see Secti o n 5. 5. 1 ) w hile c o nti n ui n g t o ta ke t he st u dy dr u g .
St u d y  visits will be a p pr o xi matel y e ver y 2 wee ks d uri n g t he first m o nt h a n d t he n e ver y  4 wee ks, 
u ntil Wee k 2 4 (Ta ble 2 ). St u d y  dr u g c o m plia nce a n d c o nc o mita nt me dicati o n use will be
re vie we d, a n d s u bjects will be dis pe nse d a d diti o nal st u d y dr u g as nee de d. A d diti o nal safet y 
(i ncl u di n g la b orat or y tests a n d E C Gs) will be perf or me d per t he sc he d ule o utli ne d i n Ta ble 2 .
Certai n pr o visi o ns ma y be i m ple me nte d i n or der t o mi ni mize p ote ntial hazar ds t o st u d y s u bjects
d ue t o C O VI D -1 9. T hese pr o visi o ns ma y  all o w alter nati ves t o i n-pers o n st u d y  visits a n d i ncl u de 
b ut are n ot li mite d t o t he f oll o wi n g: c o n d ucti n g re m ote st u d y  visits via p h o ne/tele me dici ne 
vi de o, f oc usi n g o n safet y assess me nts d uri n g re m ote visits, perf or mi n g safet y  la bs via l ocal la bs 
or pr ofessi o nal i n -h o me p hle b ot o m y  ve n d ors, a n d s hi p pi n g of st u d y dr u g directl y  t o st u d y 
s u bjects if nee de d. A n y p ote ntial iss ues s h o ul d be disc usse d wit h S p o ns or/ C R O a n d will be 
a d dresse d o n a n i n di vi d ualize d basis. All pr oce d ures n ot a ble t o be c o m plete d d ue t o a visit bei n g 
c o n d ucte d re m otel y m ust be re p orte d as a pr ot oc ol de viati o n a n d ca n be perf or me d at the ne xt 
visit, w here a p pr o priate t o d o s o base d o n s u bject prese ntati o n.
4. 3. 3. 1  
Wee k 2 4 or E O T Visit 
S u bjects will ret ur n t o t he st u d y  site at t he Wee k 2 4 Visit ( Da y 1 6 8 +/- 3 da y s), or at t he E O T 
Visit f or earl y disc o nti n uati o n, f or assess me nt of me dicati o n c o m plia nce a n d assess me nt of 
t olera bilit y a n d safety (i ncl u di n g vital si g ns, la b orat or y tests, a n d electr ocar di o gra p h y) (Ta ble 1 ).  
S u bjects m ust ret ur n t he u n use d st u d y dr u g t o t he st u d y site. 
All ra n d o mize d s u bjects w h o disc o nti n ue e arly fr o m t he O pe n -l a bel E xte nsi o n P h ase s h o ul d 
c o m plete t he E O T Visit. Ot her wise, s u bjects s h o ul d c o m plete t he Wee k 2 4 Visit.
I n cases w here a Wee k 2 4 or E O T Visit occ urs re m otel y i n or der t o be c o m plete d d uri n g t he 
pr ot oc ol re q uire d wi n d o w a n d d ue t o t he C O VI D - 1 9 pa n de mic, t he s u bject s h o ul d ret ur n t o t he 
site f or t he F oll o w- u p Wee k 2 Visit ( 2 wee ks after t he Wee k 2 4
or E O T Visit , -2 t o + 1 4 da y s), t o 
c om plete all pr oce d ures t hat were n o t a ble t o be c o m plete d re m otely. Pr oce d ures c o m plete d at 
t he Wee k 2 4 or E O T Visit occ urri n g re m otel y d o n ot nee d t o be re peate d.  
4. 3. 4
F oll o w -u p P h ase
T he F oll o w -u p P hase will ha ve 2 sc he d ule d visits , F oll o w-u p Wee k 2 a n d F oll o w -u p Wee k 8 .
T hese visits s h o ul d occ ur a p pr o xi matel y 2 wee ks a n d 8 wee ks , res pecti vely, after t he last visit i n 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 4 5 of 1 0 3
P FI Z E R C O N FI D E N TI A L
t he last treat me nt p hase (i.e., Wee k 1 2/E O T Visit if t he s u bject di d n ot e nter t he O pe n-la bel 
E xte nsi o n P hase; Wee k 2 4 /E O T Visit if t he s u bject e ntere d t he O pe n-la bel E xte nsi o n P hase). All 
ra n d o mize d s u bjects s h o ul d c o m plete b ot h f oll o w-u p visits , re gar dless of c o m pleti n g eit her 
treat me nt p hase.  
S u bjects will c o nti n ue t o rec or d all c o nc o mita nt me dicati o ns, i ncl u di n g ac ute sta n dar d of care 
mi grai ne me dicati o ns ( b ot h prescri be d a n d O T C ), ta ke n d uri n g t he e ntire F oll o w -u p P hase in a 
co nc o mita nt m e dicati o n pa per diar y.
4. 3. 4. 1
F oll o w -u p Wee k 2 Visit
S u bjects will ret ur n t o t he st u d y site a p pr o xi matel y 2 wee ks ( 1 4 da y s +/ - 2 da y s) after t he last 
visit i n t he last treat me nt p hase t o c ollect vital si g ns, L F Ts , assess me nt of A Es /S A Es , t o ha ve t he 
C - S S R S perf or me d, a n d t o ha ve a uri ne pre g na nc y test perf or me d ( W O C B P). 
I n vesti gat ors s h o ul d assess su bjects f or A Es c o nsiste nt wit h dr u g de pe n de nc y or wit h dra wal 
effects a n d re p ort as a p pr o priate (see Secti o n 7. 4 ).
4. 3. 4. 2
F oll o w -u p Wee k 8 Visit
S u bjects will ret u r n t o t he st u d y site a p pr o xi matel y 8 wee ks ( 5 6 da y s +/ - 2 da y s) after t he last 
visit i n t he last treat me nt p hase t o c ollect vital si g ns, L F Ts , assess me nt of S A Es , a n d t o ha ve a 
ser u m pre g na nc y test perf or me d ( W O C B P).  S u bjects will ret ur n t he co nc o mita nt m e dicati o n 
pa per diar y f or d oc u me nti n g c o nc o mita nt me dicati o ns.
T he visit wi n d o w f or t he F oll o w -u p Wee k 8 Visit is 5 6 da y s +/ - 2 da y s; h o we ver, i n cases of a 
dela y e d visit d ue t o restricti o ns res ulti n g fr o m t he C O VI D -1 9 pa n de mic, + 1 4 da y s m a y be 
utilize d i nstea d of + 2 da y s i n or der t o e ns ure t his fi nal visit is c o m plete d i n pers o n.
4. 4 
P ost St u d y Access t o T her a p y (if a p plic a ble ) 
At t he c o ncl usi o n of t his st u d y , s u bjects or i n vesti gat ors will n ot ha ve access t o t he st u d y dr u g.  
T he i n vesti gat or s h o ul d e ns ure t hat t he s u bject recei ves a p pr o priate sta n dar d of care t o treat t he 
c o n diti o n u n der st u d y.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 4 6 of 1 0 3
P FI Z E R C O N FI D E N TI A L
5
P O P U L A TI O N
5. 1  
N u m ber of S u bjects
It is a ntici pate d t hat u p t o a p pr o xi matel y 2 0 0 0 s u bjects m a y  be scree ne d i n or der t o ra n d o mize u p 
t o a p pr o xi matel y 6 6 0 s u bjects t o st u d y dr u g (ri me ge pa nt or place b o).  S u bjects will be 
ra n d o mize d 1: 1: 1 acr oss 3 treat me nt gr o u ps i n t he D o u ble -bli n d T reat me nt P hase: ri me ge pa nt 7 5 
m g O D T d ose d E O D alter nati n g wit h matc hi n g place b o ( n = 2 2 0 ); ri me ge pa nt 7 5 m g O D T 
d ose d dail y  ( n = 2 2 0); or place b o f or matc hi n g ri me ge pa nt 7 5 m g O D T d ose d dail y  ( n = 2 2 0 ).
Ra n d o mizati o n will be stratifie d b y use of pri or pr o p h y lactic mi grai ne me dicati o n ge nerall y  
c o nsi dere d t o ha ve efficac y ( yes or n o; see Secti o n 7. 2. 1 ). I n a d diti o n, ra n d o mizati o n of 
pr o p h y lactic mi grai ne treat me nt-naï ve s u bjects (“ n o” cate g or y) will be ca p pe d at 3 0 % i n or der t o 
all o w 7 0 % of ra n d o mize d s u bjects t o be pr o p h yl actic mi grai ne treat me nt-e x perie nce d (“ yes” 
cate g or y).
U p t o 6 6 0 s u bjects (i ncl u di n g u p t o 2 2 0 s u bjects i n t he dail y  d osi n g c o h ort) ma y be e ntere d i nt o 
t he O pe n -la bel E xte nsi o n P hase f or a n a d diti o nal 1 2 wee ks wit h dail y d osi n g.
5. 2 
I ncl usi o n Criteri a
1.
Si g ne d Writte n I nf or me d C o nse nt
a)
Writte n i nf or me d c o nse nt m ust be o btai ne d fr o m t he s u bject i n acc or da nce wit h 
re q uire me nts of t he st u d y ce nter’s i nstit uti o nal re vie w b oar d (IR B) or et hics c o m mittee, 
pri or t o t he i nitiati o n of a n y  pr ot oc ol-re q uire d pr oce d ures.
2.
Tar get P o p u lati o n
S u bject has at least 1 ye ar hist or y of e pis o dic mi grai ne ( wit h or wit h o ut a ura) c o nsiste nt wit h 
a dia g n osis acc or di n g t o t he I nter nati o nal Classificati o n of Hea dac he Dis or ders, 3 r d E diti o n 4, 
i ncl u di n g t he f oll o wi n g:
a)
A ge of o nset of mi grai nes pri or t o 5 0 y ears of a ge .
b)
Mi grai ne attac ks, o n a vera ge, lasti n g 4 - 7 2 h o urs if u ntreate d .
c)
Per s u bject re p ort , 4- 1 4 mi grai ne attac ks per m o nt h wit hi n t he last 3 m o nt hs pri or t o t he 
Scree ni n g Visit ( m o nt h is defi ne d as 4 wee ks f or t he p ur p ose of t his pr ot oc ol).
d)
4 or m ore mi gr ai ne d ays d uri n g 2 8 da y s i n t he O bser vati o n P hase .
e)
N ot m ore t ha n 1 4 he a d ac h e d ays d uri n g 2 8 da y s i n t he O bser vati o n Phase .
f)
A bilit y t o disti n g uis h mi grai ne attac ks fr o m te nsi o n/cl uster hea dac hes.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 4 7 of 1 0 3
P FI Z E R C O N FI D E N TI A L
g)
S u bjects wit h c o ntrai n dicati o ns f or use of tri pta ns ma y  be i ncl u de d pr o vi de d t he y meet all 
ot her st u d y  e ntr y criteria.
3.
A ge a n d Re pr o d ucti ve Stat us
a)
Male a n d fe male su bjects ≥ 1 8 y ears.
b)
W o me n of c hil d beari n g p ote ntial ( W O C B P) a n d n o n- sterile me n m ust be usi n g t w o 
acce pta ble met h o ds of c o ntrace pti o n t o a v oi d pre g na nc y  t hr o u g h o ut t he st u d y i n s uc h a 
ma n ner t hat t he ris k of pre g na nc y  is mi ni mize d. See Secti o n 5. 6 f or t he defi niti o n of 
W O C B P. Males wit h vasect o m y  are c o nsi dere d s ur gicall y sterile pr o vi de d t he pr oce d ure 
occ urre d greater t ha n 6 m ont hs ( 2 4 wee ks) pri or t o st u d y partici pati o n.
c)
At t he Baseli ne Visit , W O C B P m ust ha ve a ne gati ve pre g na nc y  test ( mi ni m u m se nsiti vit y 
2 5 I U/ L  or e q ui vale nt u nits of H C G) bef ore d osi n g wit h st u d y dr u g.
4.
N o cli nicall y  si g nifica nt a b n or malit y i de ntifie d o n t he me dical or la b orat or y e val uati o n. A 
s u bject wit h a cli nical a b n or malit y or la b orat or y para meters o utsi de t he refere nce ra n ge ma y 
be i ncl u de d o nl y if t he i n vesti gat or c o nsi ders t he fi n di n g n ot cli nical l y si g nifica nt, t hat it will 
n ot i ntr o d uce a d diti o nal ris k fact ors, n or i nterfere wit h t he st u d y  pr oce d ures ( n ot i ncl u di n g 
e xcl usi o n criteria liste d i n Secti o n 5. 3 ).
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 4 8 of 1 0 3
P FI Z E R C O N FI D E N TI A L
5. 3 
E xcl usi o n Criteri a
1.
Tar get Disease E xcl usi o n
a)
S u bject has a hist or y  of basilar mi grai ne, he mi ple gic mi grai ne , reti nal mi grai ne or 
mi grai ne acc o m pa nie d b y di pl o pia or decrease d le vel of c o nsci o us ness as defi ne d b y 
I nter nati o nal Classificati o n of Hea dac he Dis or ders, 3r d E diti o n.4
b)
S u bjects wit h hea dac he s occ urri n g 1 5 or m ore da ys per m o nt h (mi grai ne or n o n -
mi grai ne) i n a n y of t he 3 m o nt hs pri or t o t he Scree ni n g Visit.
2.
Me dical Hist or y  a n d C o nc urre nt Diseases
a)
S u bject hist or y  wit h c urre nt e vi de nce of u nc o ntr olle d, u nsta ble or rece ntl y dia g n ose d 
car di o vasc ular disease, s uc h as isc he mic heart disease, c or o nar y arter y vas os pas m, a n d 
cere bral isc he mia. S u bjects wit h m y ocar dial i nfarcti o n ( MI), ac ute c or o nar y  s yn dr o m e 
( AC S), perc uta ne o us c or o nar y  i nter ve nti o n (P CI ), car diac s ur ger y, str o ke or tra nsie nt 
isc he mic attac k ( TI A) d uri n g t he 6 m o n t hs ( 2 4 wee ks) pri or t o t he Scree ni n g Visit . 
b)
U nc o ntr olle d h y perte nsi o n ( hi g h bl o o d press ure) or u nc o ntr olle d dia betes . Ho we ver, 
su bjects ca n be i ncl u de d w h o ha ve sta ble h y p erte nsi o n a n d/ or dia betes f or 3 m o nt hs ( 1 2 
wee ks) pri or t o t he Scree ni n g Visit . Bl o o d press ure greater t ha n 1 5 0 m m H g s yst olic or 
1 0 0 m m H g diast olic after 1 0 mi n utes of rest is e xcl usi o nar y . T his ma y  be re peate d o nce 
at scree ni n g o nce d uri n g visit t o c o nfir m re pr o d uci bilit y .
c)
S u bjects wit h maj or de pressi ve ( M D D) or a n y a n xiet y dis or der ( A D) w hic h re q uire m ore 
t ha n 1 dail y me dicati o n f or eac h dis or der or s u bjects wit h maj or de pressi ve e pis o de 
( M D E) wit hi n last 1 2 m o nths. Me dicati o ns t o treat maj or de pressi ve dis or der or a n 
a n xiet y dis or der m ust ha ve bee n at a sta ble d ose f or at least 3 m o nt hs ( 1 2 wee ks) pri or t o 
t he Scree ni n g V isit. 
d)
Acti ve c hr o nic pai n s y n dr o mes (s uc h as fi br o m yal gia , c hr o nic pel vic pai n , c o m ple x
re gio nal pai n s y n dr o me [ C R P S] ).
e)
S u bjects wit h ot her pai n s y n dr o mes (i ncl u di n g tri ge mi nal ne ural gia), ps yc hiatric 
c o n diti o ns, de me ntia, or si g nifica nt ne ur ol o gical dis or ders ( ot her t ha n mi grai ne) t hat, i n 
t he In vesti gat or’s o pi ni o n, mi g ht i nterfere wit h st u d y  assess me nts of safet y or efficac y .
f)
Dia g n osis of acti ve biliar y dis or der (e g., gallst o nes).
g)
S u bject has a hist or y  of gastric, or s mall i ntesti nal s ur ger y (i ncl u di n g Gastric B ypass, 
Gastric Ba n di n g, Gastric Slee ve, Gastric Ball o o n, etc.), or has a disease or c o n diti o n 
(e. g., c hr o nic pa ncreatitis, ulcerati ve c olitis, etc.) t hat ca uses mala bs or pti o n.
h)
S u bject has a hist or y or dia g n osis of a n y acti ve he patic dis or der .
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 4 9 of 1 0 3
P FI Z E R C O N FI D E N TI A L
i)
T he s u bject has a hist or y  or c urre nt e vi de nce of a n y u nsta ble me dical c o n diti o ns (e. g., 
hist or y of c o n ge nital heart disease or arr h yt h mia, k n o w n or s us pecte d i nfecti o n, he patitis 
B or C, or ca ncer) t hat, i n t he i n vesti gat or’s o pi ni o n, w o ul d e x p ose t he m t o u n d ue ris k of 
a si g nifica nt a d verse e ve nt ( A E) or i nterfere wit h assess me nts of safet y  or efficac y d uri n g 
t he c o urse of t he st u d y.
j)
Hist or y  of, treat me nt f or, or e vi de nce of, alc o h ol or dr u g a b use wit hi n t he past 1 2 m o nt hs 
( 4 8 wee ks) or su bjects w h o ha ve met D S M -V criteria1 0 f or a ny si g nifica nt s u bsta nce use 
dis or der wit hi n t he past 1 2 m o nt hs (4 8 wee ks) fr o m t he S cree ni n g V isit acc or di n g t o PI 
assess me nt .
k)
Hist or y  of use of narc otics, s uc h as o pi oi d s (e. g., m or p hi ne, c o dei ne, o xyc o d o ne, 
h y dr oc o d o ne) or bar bit urate s (e. g., b utal bital) f or 4 da y s per m o nt h d uri n g t he 3 m o nt hs 
( 1 2 wee ks) pri or t o t he Scree ni n g Visit. 
l)
S u bjects s h o ul d be e xcl u de d if t he y ha ve a p ositi ve dr u g scree n f or dr u gs of a b use t hat i n 
t he i n vesti gat or’s j u d g me nt is me dicall y si g nifica nt, i n t hat it w o ul d i m pact t he safety of 
t he s u bject or t he i nter pretati o n of t he st u d y res ults. In a d diti o n:
i.
Detecta ble le vels of c ocai ne, a m p heta mi ne a n d p he nc y cli di ne ( P C P) i n t he dr u g 
scree n are e xcl usi o n ar y . Retesti n g is n ot all o we d. 
ii.
S u bjects w h o are p ositi ve f or a m p heta mi nes, a n d w h o are o n a prescri be d 
a m p heta mi ne me dicati o n f or a n a p pr o ve d i n dicati o n ( e. g., A D H D) will be 
all o we d i nt o t he st u d y at t he In vesti gat or’s discr eti o n.  T his deter mi nati o n b y t he 
I n vesti gat or m ust be well d oc u me nte d i n t he s u bject’s s o urce me dical rec or ds.  
T he sti m ula nt d ose m ust be sta ble fr o m 3 m o nt hs ( 1 2 wee ks) pri or t o t he Baseli ne 
Visit u ntil t he Wee k 1 2
or E O T Visit occ urs.   
iii.
Detecta ble le v els of marij ua na i n t he dr u g scree n are n ot e xcl usi o n ar y , if i n t he 
i n vesti gat or’s d oc u me nte d o pi ni o n t he s u bject d oes n ot meet D S M -V  criteria
1 0
f or s u bsta nce use dis or der, a n d t he p ositi ve test d oes n ot si g nal a cli nical 
c o n diti o n t hat w o ul d i m pact t he safet y of t he s u bject or i nter pretati o n of t he st u d y 
res ults.  S u bject m ust a gree t o refrai n fr o m marij ua na use d uri n g t he st u d y.
m)
He mat ol o gic or s oli d mali g na nc y  dia g n osis wit hi n 5 years pri or t o t he Scree ni n g Visit . 
S u bjects wit h a hist or y  of l ocalize d basal cell or s q ua m o us cell s ki n ca ncer are eli gi ble 
f or t he st u dy if t he y are ca ncer -free pri or t o t he S cree ni n g V isit i n t his st u d y.
n)
S u bject has c urre nt dia g n osis of maj or de pressi ve dis or der re q uiri n g treat me nt wit h 
at ypical a nti ps y c h otics, sc hiz o p hre nia, bi p olar dis or der , or b or derli ne pers o nalit y  
dis or der .
o)
B o d y mass i n de x > 3 5. 0 k g / m2.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 5 0 of 1 0 3
P FI Z E R C O N FI D E N TI A L
3.
Hist or y  of a na p hyl a xis t o a n y s u bsta nce or a cli nicall y i m p orta nt reacti o n t o a n y dr u g.
4.
Se x a n d Re pr o d ucti ve Stat us
a)
W O C B P
w h o are u n willi n g or u na ble t o use a n acce pta ble c o ntrace pti ve met h o d or 
a bsti ne nce t o a v oi d pre g na nc y  f or t he e ntire st u d y a n d f or 6 0 da ys after t he last dose of 
st u d y dr u g.
b)
W o me n w h o are pre g na nt or breastfee di n g. 
c)
W o me n wit h a p ositi ve pre g na nc y  test at scree ni n g or pri or t o st u d y dr u g a d mi nistrati o n .
5.
E C G a n d La b orat or y  Test Fi n di n gs
a)
Esti mate d gl o mer ular filtrati o n rate (e G F R) acc or di n g t o t he re -e x presse d a b bre viate d 
(f o ur-varia ble) M o dificati o n of Diet i n Re nal Disease ( M D R D ) St u d y e q uati o n ≤ 3 0
ml/ mi n/ 1. 7 3 m 2.
b)
A b n or mal E C G t hat i n t he i n vesti gat or’s o pi ni o n ma kes t he s u bject u ns uita ble f or a 
cli nical trial (e. g. C orrecte d Q T i nter val > 4 7 0 msec , Left B u n dle Bra nc h bl oc k)
c)
T otal ser u m bilir u bi n > 1 . 5 x U L N .
d)
A S T or A L T > 1. 5 x U L N . 
e)
Ser u m al b u mi n < 2. 8 g/ d L .
f)
Ne utr o p hil c o u nt ≤ 1 0 0 0/ μ L  ( or e q ui vale nt )
g)
H b A 1c > 7. 5 %
6.
Pr o hi bite d Me dicati o ns
a)
M e dicati o n f or mi grai ne pr o p h y la xis ge nerall y c o nsi dere d t o ha ve efficac y, re gar dless of 
i n dicati o n, ta ke n wit hi n 3 0 da y s pri or t he Scree ni n g Visit (see Secti o n 1 6. 5 A p pe n di x 5 ).
b)
A nal gesics ( e. g., n o nster oi dal a nti -i nfla m mat or y dr u gs [ N S AI Ds] or aceta mi n o p he n) 
ta ke n ≥ 1 5 da y s per m o nt h d uri n g t he 3 m o nt hs ( 1 2 wee ks) pri or t o t he Scree ni n g Visit.
c)
M e dicati o n acce pte d f or treat me nt of ac ute mi grai ne ( Secti o n 5. 5. 1 ) f or a n o n-mi grai ne 
i n dicati o n ta ke n 1 5 da ys per m o nt h d uri n g t he 3 m o nt hs ( 1 2 wee ks ) pr i or t o t he 
Scree ni n g Visit.

L o w d ose as piri n (u p t o 1 0 0 m g dail y) f or d oc u me nte d car di o vasc ular pr o p h yla xis 
is all o we d.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 5 1 of 1 0 3
P FI Z E R C O N FI D E N TI A L
d)
B i ol o gic mi grai ne me dicati o n (s uc h as C G R P m o n ocl o nal a nti b o dies liste d i n 
Secti o n 1 6. 5 A p pe n di x 5 ) ta ke n d uri n g t he 6 m o nt hs ( 2 4 wee ks) pri or t o t he Scree ni n g 
Visit.
e)
P r o hi bite d me dicati o n or de vice use d d uri n g t he O bser vati o n P hase (see Secti o n 5. 4 ). 
7.
Ot her E xcl usi o n Criteria
a)
Pris o ners or s u bjects w h o are i n v ol u ntaril y i ncarcerate d.
b)
S u bjects w h o are c o m p uls oril y  detai ne d f or treat me nt of eit her a ps yc hiatric or p h ysical 
(e. g., i nfecti o us disease) ill ness.
c)
N o n -co m plia nce wit h or i na bilit y  t o c o m plete e Diar y d uri n g O bser vati o n Phase . S u bjects 
wit h less t ha n 2 4 c o m plete d e Diar y re p orts d uri n g 2 8 da y s i n t he O bser vati o n Phase will 
n ot be c o nsi dere d f or partici pati o n d ue t o n o n -c o m plia nce wit h t he e Diar y.  
d)
E x p os ure t o n o n- bi ol o gical i n vesti gati o nal a ge nts wit hi n t he 3 0 da y s pri or t o t he 
Scree ni n g V isit.
e)
E x p os ure t o bi ol o gical i n vesti gati o nal a ge nts s uc h as m o n ocl o nal a nti b o dies wit hi n t he 6 
m o nt hs ( 2 4 wee ks) pri or t o t he Scree ni n g V isit.
f)
S u bjects w h o meet criteria f or C -S S R S S uici dal I deati o n I te ms 4 or 5 wit hi n t he last 1 2 
m o nt hs pri or t o t he Scree ni n g Visit , O R s u bjects w h o e n d orse a ny of t he 5 C -S S R S 
S uici dal Be ha vi or Ite ms (act ual atte m pt, i nterr u pte d atte m pt, a b orte d atte m pt, pre parat or y  
acts, or be ha vi or) wit hi n t he last 1 0 y ears pri or t o t he Scree ni n g Visit , O R s u bjects w h o, 
i n t he o pi ni o n of t he i n vesti gat or, prese nt a seri o us ris k of s uici de ( See Secti o n 6. 2. 5 ).
g)
Pre vi o us e nr oll me nt i n a n y m ulti ple d ose B H V 3 0 0 0 (ri me ge pa nt) st ud y , s uc h as 
B H V 3 0 0 0- 2 0 1, B H V 3 0 0 0 -3 0 5, B H V 3 0 0 0 -4 0 5 , B H V 3 0 0 0-4 0 6, or B H V 3 0 0 0 - 4 0 7, 
re gar dless of t he n u m ber of d oses ta ke n. Su bjects ma y  be c o nsi dere d f or B H V 3 0 0 0- 4 0 4 if 
t he s u bject partici pate d i n a n y of t he f oll o wi n g si n gle d ose st u dies: B H V 3 0 0 0 - 3 0 1, 
B H V 3 0 0 0 -3 0 2, B H V 3 0 0 0 - 3 0 3, b ut di d n ot partici pate i n a n y m ulti ple d ose ri me ge pa nt 
st u d y. N ote t hat s u bjects w h o were c o nsi dere d scree n fail ures i n a past B H V 3 0 0 0 st u d y 
ma y  be c o nsi dere d after disc ussi o n wit h t he S p o ns or a n d writte n a p pr o val is recei ve d .  
h)
S u bjects are e xcl u de d if t he y  ha ve ha d n o t hera pe utic res p o nse wit h > 2 of t he 8
me dicati o n c ate g ories f or pr o p h ylactic treat me nt of mi grai ne liste d i n A p pe n di x 4 after 
a n a de q uate t hera pe utic trial.  A d diti o nal details ca n be f o u n d i n Secti o n 1 6. 4
A p pe n di x 4 .
i) P artici pati o n i n a n y ot her i n vesti gati o nal cli nical st u d y w hile partici pati n g i n t his cli nical 
st u d y. Partici pati o n i n a C O VI D -1 9 m R N A vacci ne st u d y  ( vacci ne m ust be a ut h orize d 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 5 2 of 1 0 3
P FI Z E R C O N FI D E N TI A L
u n der F D A e mer ge nc y  use a ut h orizati o n or a p pr o val) w h o are at le ast 3 0 d ays p ost l ast 
d ose of t he vacci ne are per mitte d t o be scree ne d f o r t his st u d y.
j)    Past partici pati o n i n a cli nical st u d y wit hi n 3 0 da y s pri or t o t he Scree ni n g Visit.  N ote: 
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) 
ma y  be c o nsi dere d f or re- scree ni n g i n select circ u msta n ces (e. g., pre vi o usl y pre g na nt, 
scree ni n g wi n d o w t o o l o n g, i neli gi bilit y was d ue t o 1 of t he eli gi bilit y  criteria t hat ma y 
ha ve c ha n ge d d ue t o me dical i nter ve nti o n or 1 of t he eli gi bilit y  criteria m o difie d i n a 
pr ot oc ol a me n d me nt ). I n all p ossi ble re-screeni n g circ u msta nces , t he sit uati o n m ust be 
disc usse d wit h t he S p o ns or pri or t o re -scree ni n g, wit h a p pr o val i n writi n g fr o m t he 
S p o ns or pri or t o re -scree ni n g.
k)   T he s u bject is, i n t he i n vesti gat or’s o pi ni o n, u nli kel y  t o c o m ply wit h t he pr ot oc ol or is 
u ns uita ble f or a n y reas o n (i ncl u di n g a n y k n o w n, s us pecte d, or c o nfir me d i nfecti o ns i n t he 
s u bject t hat ma y p ut t he s u bject or st u d y staff at ris k).
l)
I n vesti gat or site staff directl y i n v ol ve d i n t he c o n d uct of t he st u d y a n d t heir fa mil y 
me m bers, site staff ot her wise s u per vise d b y t he i n vesti gat or, a n d s p o ns or a n d s p o ns or 
dele gate e m pl o y ees directl y i n v ol ve d i n t he c o n d uct of t he st u d y a n d t heir fa mil y 
me m bers.
5. 4
Pr o hi bite d a n d Restricte d C o nc o mit a nt Me dic ati o n s a n d De vices
All me dicati o ns ta ke n b y s u bjects a t t he Scree ni n g Visit u ntil t he last st u d y  da y will be 
d oc u me nte d as c o nc o mita nt me dicati o ns i ncl u di n g vacci nati o ns. 
T he me dicati o ns a n d de vices liste d bel o w are pr o hi bite d or restricte d d uri n g t he e ntire st u d y , 
i.e., starti n g at t he Scree ni n g V isit a n d t hr o u g h t he F oll o w-u p Wee k 8 Visit, u nless ot her wise 
s pecifie d. 
1.
M e dicati o n f or mi grai ne pr o p h y la xis ge nerall y c o nsi dere d t o ha ve efficac y, re gar dless of 
i n dicati o n (see Secti o n 1 6. 5 A p pe n di x 5 ). N ote t hese are als o pr o hi bite d 3 0 da y s pri or t o t he 
Scree ni n g Visit (see Secti o n 5. 3 ), wit h e xce pti o ns n ote d f or C G R P m o n ocl o nal a nti b o dies i n 
ite m 2 bel o w a n d b ot uli n u m t o xi n i njecti o ns i n ite m 3 bel o w.
2.
C G R P a nta g o nists ( m o n ocl o nal a nti b o dies [e. g., Ai m o vi g ® or Aj o v y ® ] or s mall m olec ule
[e. g., N urtec® O D T or U brel v y T M ]) ot her t ha n ri me ge pa nt pr o vi de d f or t his cli nical st u d y .
N ote t hat C G R P m o n ocl o nal a nti b o dies liste d i n Secti o n 1 6. 5 A p pe n di x 5 are als o pr o hi bite d 
wit hi n 6 m o nt hs ( 2 4 wee ks) pri or t o t he Scree ni n g Visit (see Secti o n 5. 3 ).
3.
B ot uli n u m t o xi n i njecti o ns (e g, B ot o x ® ) use d f or t he pre ve nti o n of mi grai ne, liste d i n 
Secti o n 1 6. 5 A p pe n di x 5 . N ote t hat t his is als o pr o hi bite d wit hi n 3 m o nt hs ( 1 2 wee ks ) pri or 
t o t he Scree ni n g Visit.
4.
St. J o h n’s W ort
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 5 3 of 1 0 3
P FI Z E R C O N FI D E N TI A L
5.
Er g ota mi ne. N ote t h e f oll o wi n g:
a.
Re p orti n g of er g ota mi ne use is re q uire d f or t he p ur p ose of defi ni n g mi grai ne da y s.
b.
U se of er g ota mi ne o n 1 0 da y s per m o nt h o n a re g ular basis f or 3 m o nt hs ( ≥1 2 wee ks)
i n t he year pri or t o t he Scree ni n g Visit is als o pr o hi bite d. 
6.
N arc otics, s uc h as o pi oi ds ( e. g., m or p hi ne , c o dei ne, o x yc o d o ne, h y dr oc o d o ne ) or bar bit urates
(e. g., b utal bital). N ote t hat use of narc otics f or 4 da y s per m o nt h d uri n g t he 3 m o nt hs ( 1 2 
wee ks) pri or t o t he Scree ni n g Visit is als o pr o hi bite d.
7.
A ceta mi n o p he n or aceta mi n o p he n-c o ntai ni n g pr o d ucts f or n o n-hea dac he i n dicati o ns. N ote 
t hat aceta mi n o p he n as ac ute mi grai ne me dicati o n as descri be d i n Secti o n 5. 5. 1 is all o we d 
d uri n g t he st u d y. 
8.
M arij 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
9.
M o derate t o str o n g C Y P 3 A 4 i n hi bit ors. I f use of a m o derate or str o n g C Y P 3 A 4 i n hi bit or is 
re q uire d, t he n d osi n g wit h st u d y dr u g s h o ul d be st o p pe d a n d s h o ul d n ot start a gai n u ntil 1 4 
da y s after t he last d ose of t he m o derate or str o n g C Y P 3 A 4 i n hi bit or.  Please see Secti o n 1 6. 2
A p pe n di x 2 .
1 0. M o derate t o str o n g C Y P 3 A 4 i n d ucers. If use of a m o derate o r str o n g C Y P 3 A 4 i n d ucer is 
re q uire d, t he n d osi n g wit h st u d y  dr u g s h o ul d be st o p pe d a n d s h o ul d n ot start a gai n u ntil 1 4 
da y s after t he last d ose of t he m o derate or str o n g C Y P 3 A 4 in d ucer . Please see Secti o n 1 6. 2
A p pe n di x 2 .
1 1. S tr o n g i n hi bit ors of t he P-g p tra ns p orter. If use of a str o n g i n hi bit or of t he P-g p tra ns p orter is 
re q uire d, t he n d osi n g wit h st u d y  dr u g s h o ul d be st o p pe d a n d s h o ul d n ot start a gai n u ntil 1 4 
da y s after t he last d ose of t he str o n g i n hi bit or of t he P- g p tra ns p orter . Please see Secti o n 1 6. 2
A p pe n di x 2 .
1 2. A t ypical a nti ps y c h otics s uc h as A bilif y (ari pi praz ole), Z ypre xa ( ola nza pi ne), Ser o q uel
(q uetia pi ne ), Ge o d o n (zi prasi d o ne), or Ris per dal (ris peri d o ne) or De pa k ote / De pa ke ne 
(val pr oic aci d / val pr oate).
1 3. L A M I CT A L (la m otri gi ne)
1 4. A nal gesics ot her t ha n aceta mi n o p he n f or n o n -hea dac he use (e. g. n o nster oi dal a nti -
i nfla m mat or y dr u gs [ N S AI Ds]) o n ≥1 5 da y s per m o nt h. A ceta mi n o p he n a n d aceta mi n o p he n 
c o ntai ni n g pr o d ucts f or n o n- hea dac he i n dicati o ns are pr o hi bite d (see ite m 7 a b o ve). L o w 
d ose as piri n (u p t o 0 0 m g dail y ) f or d oc u me nte d car di o vasc ular pr o p h yla xis is all o we d.
1 5. Cefal y T M or a n y ot her de vice f or mi grai ne pre ve nti o n or treat me nt. N ote t hat t h ese de vices 
are als o pr o hi bite d wit hi n 1 2 wee ks pri or t o t he Scree ni n g Visit. 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 5 4 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 6. A n y  i n vesti gati o nal a ge nt ot her t ha n ri me ge pa nt ( pr o vi de d f or t he p ur p ose of t his cli nical 
st u d y).
5. 5 
St a n d ar d of C are Mi gr ai ne Me dic ati o ns 
Use of ac ute sta n dar d of care mi grai ne me dicati o n d uri n g t he O bser vati o n P hase t hr o u g h t he 
F oll o w - u p Wee k 8 Visit will be rec or de d b y t he s u bject in t he c o nc o mita nt me dicati o n pa per 
diar y  a n d re p orte d t o t he site. Mi grai ne
me dicati o ns i ncl u de b ot h prescri be d a n d O T C, a c ute 
mi grai ne me dicati o ns.
5. 5. 1
Ac ute Mi gr ai ne
Me dic ati o ns
S u bjects ma y  use t heir per mitte d sta n dar d of care me dicati o n if nee de d f or ac ute treat me nt of a 
mi grai ne t hr o u g h o ut t he st u d y . Ac ute mi gr ai ne me dic ati o ns t h at are per mitte d d uri n g t he 
st u d y i ncl u de t he f oll o wi n g: 

tri pta ns, 

as piri n, 

i b u pr ofe n, 

bacl ofe n, 

aceta mi n o p he n u p t o 1 0 0 0 m g/ da y  f or a ma xi m u m of 2 c o nsec uti ve da ys at a ti me (t his 
i ncl u des E xce dri n Mi grai ne), 

Na pr os y n ( or a n y ot her t y pe of n o n -ster oi dal a nti-i nfla m mat or y ( N S AI D)), 

a ntie metics (e. g. met ocl o pra mi de or pr o met hazi ne),

m uscle rela xa nts
T he a b o ve liste d me dic ati o ns are t he o nl y ac ute mi gr ai ne me dic ati o ns all o we d
If a s u bject ta kes a ta blet of st u d y dr u g a n d e x perie nces a mi grai ne later t hat da y , after d osi n g 
wit h st u d y dr u g f or t he da y, t he s u bject ma y ta ke t heir per mitte d ac ute mi gr ai ne me dic ati o n as 
descri be d i n t his secti o n of t he pr ot oc ol. D uri n g t he st u dy, s u bjects are n ot all o we d t o t a ke m ore 
t h a n 1 t a blet of st u dy dr u g per d ay .
5. 6  
W o me n of C hil d be ari n g P ote nti al
W o me n of c hil d beari n g p ote ntial ( W O C B P) i ncl u des a n y fe male w h o has e x perie nce d me narc he
a n d w h o has n ot u n der g o ne s uccessf ul s ur gical sterilizati o n ( h y sterect o m y, bilateral 
sal pi n gect o m y, or bilateral o o p h orect o my) or is n ot p ost me n o pa usal. T u bal li gati o n is c o nsi dere d 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 5 5 of 1 0 3
P FI Z E R C O N FI D E N TI A L
o ne f or m of c o ntrace pti o n; t heref ore, o ne a d diti o nal f or m of c o ntrace pti o n m ust be use d t o f ulfill 
c o ntrace pti o n re q uire me nts f or t he st u d y . Ess ure, t u bal occl usi o n a n d e n d o metrial a blati o n are 
n ot acce pta ble met h o ds of c o ntrace pti o n.  Me n o p a use is defi ne d as:

A me n orr hea greater t ha n or e q ual t o 1 2 c o nsec uti ve m o nt hs wit h o ut a n ot her ca use a n d a
d oc u me nte d ser u m f ollicle sti m ulati n g h or m o ne ( F S H) le vel > 3 5 mI U/ m L

N O T E: F S H le vel testi n g is n ot re q uire d f or w o me n greater t ha n or e q ual t o 6 2 ye ars ol d wit h
a me n orr hea of greater t ha n or e q ual t o 1 ye ar
O R

W o ma n o n h or m o ne re place me nt t hera p y ( H R T) w h o n o l o n ger me nstr uate.
W o me n of c hil d beari n g p ote ntial ( W O C B P) a n d all me n m ust u n dersta n d t he f oll o wi n g 
re q uire me nts a n d use a n acce pta ble met h o d of c o ntrace pti o n t o a v oi d pre g na nc y  t hr o u g h o ut t he 
st u d y a n d f or u p t o 6 0 da y s (f or W O C B P ) a n d 9 0 da ys (f or me n) after t he last d ose of 
i n vesti gati o nal pr o d uct i n s uc h a ma n ner t hat ris k of pre g na nc y is mi ni mize d. 
It is re q uire d t hat all W O C B P use 2 met h o ds of c o ntrace pti o n t o pre ve nt pre g na nc y, f or t he 
d urati o n of t he st u d y  (i.e., t his st u d y be gi ns wit h si g ne d c o nse nt f or m t hr o u g h 60 da y s (f or 
W O C B P ) a n d 9 0 da ys (f or me n) after d osi n g wit h st u d y dr u g). T he 2 met h o ds s h o ul d i ncl u de 1
barrier met h o d ( e. g., C o n d o m wit h s per mici dal gel, n o n- h or m o nal i ntra uteri ne de vices, cer vical 
ca p etc.) a n d 1 ot her met h o d. T he ot her met h o d c o ul d i ncl u de a n ot her barrier met h o d or 
h or m o nal c o ntrace pti ves (e .g., oral c o ntrace pti ves, i njecta ble c o ntrace pti ves, patc h, or 
c o ntrace pti ve i m pla nt [e. g., h or m o nal i ntra uteri ne de vice]) use d si nce at least 4 wee ks pri or t o 
se x ual i nterc o urse.  
W O C B P a n d all male s u bjects m ust be c o u nsele d o n t he re q uire me nts t o a v oi d pre g na nc y 
t hr o u g h o ut t he st u dy a n d f or 6 0 da y s (f or W O C B P ) a n d 9 0 days  (f or me n) after t he last d ose of 
st u d y dr u g, as well as acce pta ble met h o ds of c o ntrace pti o n t o use d uri n g t he st u d y.  S u bjects w h o 
re p ort a bsti ne nce, or w h o re p ort e xcl usi vel y bei n g i n sa me-se x relati o ns hi ps are still re q uire d t o 
u n dersta n d t he c o ntracepti o n re q uire me nts i n t his st u d y  t o pre ve nt pre g na nc y. If s u bjects w h o 
re p ort a bsti ne nce, or w h o re p ort e xcl usi vel y bei n g i n a sa me-se x relati o ns hi p e n ga ge i n 
heter ose x ual acti vit y , t he n t he c o ntrace pti o n re q uire me nts m ust be f oll o we d.  
Males wit h vasect o m y  are c o nsi dere d s ur gically sterile pr o vi de d t he pr oce d ure occ urre d greater 
t ha n 6 m o nt hs ( 2 4) wee ks pri or t o t he scree ni n g visit. Vasect o m y is c o nsi dere d o ne f or m of 
c o ntrace pti o n; t heref ore, o ne a d diti o nal f or m of c o ntrace pti o n m ust be use d t o f ulfill t he 
c o ntrace pti o n re q uire me nts f or t he st u d y .  Male s u bjects m ust n ot d o nate s per m u ntil 9 0 da y s 
f oll o wi n g t he last st u d y dr u g a d mi nistrati o n .
All W O C B P m ust c o m plete t he pre g na nc y test sc he d ule i n Ta ble 1 a n d Ta ble 2 .
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 5 6 of 1 0 3
P FI Z E R C O N FI D E N TI A L
5. 7
Ot her Restricti o ns a n d Prec a uti o ns (if a p plic a ble)
N ot A p plica ble
5. 8
De vi ati o n fr o m I ncl usi o n/ E xcl usi o n Criteri a a n d St u d y Pr oce d ures
A n y  si g nifica nt e ve nt t hat d oes n ot c o m pl y wit h t he i ncl usi on / e xcl usi o n criteria, st u d y c o n d uct, 
or st u d y  pr oce d ures will be d oc u me nte d as a de viati o n. De viati o ns will be d oc u me nte d a n d 
re p orte d t hr o u g h t he cli nical m o nit ori n g of t he st u d y. De viati o ns will be re p orte d t o t he IR B/ E C 
at t he fre q ue nc y re q uire d b y yo ur I RB/ E C. 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
S T U D Y C O N D U C T A N D D E S C RI P TI O N O F S T U D Y P R O C E D U R E S
6. 1
St u d y M ateri als 
T he f oll o wi n g st u d y materials will be pr o vi de d at t he st u d y  start:

I n vesti gat or File/ Re g ulat or y Bi n der

P har mac y  Bi n der

Dr u g Acc o u nta bilit y  Lo gs

Sa m ple s o urce d oc u me nts, w here a p plica ble

C o nc o mita nt me dicati o n pa per diar y (ta ke h o me f or s u bject) 

I n vesti gat or Br oc h ure

I nteracti ve We b- base d Res p o nse S yste m (IW R S)

Electr o nic Case Re p ort F or m (e C R F) i nstr ucti o ns
o
Electr o nic Case Re p ort F or ms (e C R Fs) will be pre pare d f or all data c ollecti o n fiel ds
o
All sites will use a n Electr o nic Data Ca pt ure ( E D C) t o ol t o s u b mit st u d y  data t o t he C R O.
Electr o nic Case Re p ort F or ms (e C R Fs) will be pre pare d f or all data c ollecti o n fiel ds 
i ncl u di n g Seri o us A d verse E ve nts ( S A E) Re p orti n g. S A E data (i ncl u di n g q ueries) will be 
s u b mitte d t o t he C R O usi n g eC R Fs. 

Electr o nic D i ar y (e Diar y): ha nd- hel d electr o nic de vice ( 1 will be gi ve n t o eac h s u bject)
○
I nstr ucti o ns f or t he e Diar y de vice a n d access t o t he p ortal
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 5 7 of 1 0 3
P FI Z E R C O N FI D E N TI A L
○
D uri n g t he D o u ble -bli n d T reat me nt P hase, t he e Diar y will be use d dail y t o rec or d 
mi grai ne occ urre nce, mi grai ne pai n feat ures a n d ass ociate d s y m pt o ms a n d use of ac ute 
mi grai ne me dicati o n (i.e., tri pta ns, er g ota mi ne, or ot her). Use of er g ota mi ne me dicati o n 
is pr o hi bite d t hr o u g h o ut t he e ntire d urati o n of t he st u d y, h o we ver re p orti n g of a n y use of 
er g ota mi ne me dicati o n is re q uire d f or t he p ur p ose of defi ni n g m i grai ne da ys.  

La b orat or y  Kits a n d La b orat or y Ma n ual
○
Safet y  la b orat or y, plas ma, a n d ser u m i nstr ucti o ns f or all s peci me ns c ollecte d will be 
pr o vi de d b y  a desi g nate d ce ntral la b orat or y.

E C G Mac hi ne a n d I nstr ucti o ns
○
E C G e q ui p me nt, s u p plies, i nstr ucti o ns a n d trai ni n g materials will be s u p plie d b y a 
ce ntralize d E C G ve n d or.

Bac k -u p f or ms f or C T S A E re p ort, E x p os ure D uri n g Pre g na nc y  a n d Pre g na nt Part ner 
Release of I nf or mati o n

C ol u m bia -S uici de Se verit y  Rati n g Scale ( C-S S R S) f or ms

Satisfacti o n wit h Me dicati o n ( S M) f or ms 

M S Q v 2. 1 f or ms

C GI -c f or ms

St u d y  sys te m access:
○
Electr o nic Data Ca pt ure ( E D C) t o ol t o s u b mit st u d y  data t o S p o ns or / C R O
○
I W R S
○
Ce ntral La b orat or y  ve n d or p ortal
○
Ce ntral E C G ve n d or p ortal
○
e Diar y ve n d or p ortal
6. 2
S afet y Assess me nts
6. 2. 1
Vit al Si g ns a n d P h ysic al Me as ure me nts
( Hei g ht a n d Wei g ht)
Vital si g ns, b o d y  wei g ht a n d hei g ht will be rec or de d at t he sc he d ule d visits as o utli ne d i n Ta ble 1
a n d Ta ble 2 .
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 5 8 of 1 0 3
P FI Z E R C O N FI D E N TI A L
6. 2. 2
Electr oc ar di o gr a m ( E C G)
A sta n dar d 1 2 -lea d E C G will be rec or de d d uri n g t he Scree ni n g P hase a n d at all sc he d ule d visits 
as o utli ne d i n Ta ble 1 a n d Ta ble 2 . A ce ntral E C G ser vice will be utilize d f or rea di n g all E C Gs.  
T he o ver rea d fr o m t he ce ntral E C G ve n d or s h o ul d be use d t o deter mi ne eli gi bilit y  f or t he st u d y. 
T he i n vesti gat or will deter mi ne if a n y E C G a b n or malities are cli nicall y si g nifica nt or n ot (see 
S ecti o n 1 6. 6 A p pe n di x 6 )
6. 2. 3
P h ysic al E x a m
S u bjects will u n der g o a r o uti ne p h y sical e xa mi nati o n d uri n g t he Scree ni n g P hase a n d brief a n d 
s ym pt o m -directe d p h y sical e xa m at all sc he d ule d visits as o utli ne d i n Ta ble 1 a n d Ta ble 2 .
P h y sical e xa mi nati o ns t o i ncl u de at mi ni m u m e xa mi nati o n of heart, a b d o me n a n d l u n gs, a n d 
ne ur ol o gic s ys te m wit h re vie w of a ny ot her s ys te m t o be g ui de d by s y m pt o ms .
6. 2. 4
L a b or at or y Assess me nts
T he i n vesti gat or m ust re vie w t he la b orat or y  re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y i n t he A E secti o n of t he C R F. T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d oc u me nts. Cli nicall y si g nifica nt a b n or mal 
la b orat or y test fi n di n gs are t h ose w hic h are n ot ass ociate d wit h t he u n derlyi n g disease, u nless 
j u d ge d by t he i n vesti gat or t o be m ore se vere t ha n e x pecte d f or t he s u bject’s c o n diti o n.
6. 2. 4. 1
S afet y L a b or at or y Testi n g
Bl o o d a n d uri ne sa m ples will be o btai ne d as o utli ne d i n Ta ble 1 a n d Ta ble 2 f or cli nical 
la b orat or y e val uati o ns. A ce ntral la b orat or y ve n d or will be utilize d f or t his st u d y a n d a 
la b orat or y ma n ual will be pr o vi de d t o eac h site. If p ossi ble, su bjects s h o ul d be f asti n g f or a 
mi ni m u m of 8 h o urs bef ore l a b or at or y tests. H o we ver, if a s u bject is n ot fasti n g at a gi ve n 
visit, t he bl o o d dra w s h o ul d still be perf or me d, a n d t he n o n- fasti n g stat us s h o ul d be d oc u me nte d.
1 7. Cli nical safet y  la bs:
He m at ol o g y : He m o gl o bi n, he mat ocrit, re d bl o o d cell c o u nt, w hite bl o o d cell c o u nt wit h 
differe ntial, a n d platelets
C he mistr y : S o di u m, p otassi u m, c hl ori de, bicar b o nate, calci u m; gl uc ose, H bA 1c ( o nly 
c ollecte d at Scree ni n g, Re peat or U nsc he d ule d Visit) , B U N ( urea), ser u m creati ni ne, uric 
aci d, L D H, t otal pr otei n, al b u mi n, C K
e G F R usi n g t he esti mate d M D R D f or m ula (calc ulate d at central la b)
1 8. L F Ts : A S T, A L T, Al kali ne P h os p hatase a n d Bilir u bi n ( T otal, Direct, I n direct).  A d diti o nal 
tests ma y be o btai ne d t o e val uate la b orat or y a b n or malities a n d/ or a d verse e ve nts ; please refer 
t o t he La b orat or y ma n ual
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 5 9 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 9. Li pi d P a nel: C h olester ol, L D L, H D L, tri glyc eri des
2 0. Uri n al ysis: p H, s pecific gra vit y , ket o nes, nitrites, ur o bili n o ge n, le u k oc yte esterase, pr otei n, 
gl uc ose, a n d bl o o d. If bl o o d, pr otei n or le u k oc y tes are p ositi ve, refle x t o micr osc o pic
e xa mi nati o n.
2 1. Uri ne Dr u g Scree n: F or dr u gs of a b use
2 2. F S H: At scree ni n g i n fe male s u bjects t o c o nfir m p ost me n o pa usal stat us, if a p plica ble
2 3. Refle x / a d d- o n tests:
If A L T or A S T ≥ 3 x U L N O R t otal bilir u bi n ≥ 2 x U L N at a n y visit after t he B aseli ne V isit, 
a d diti o nal refle x or a d d -o n tests ma y  be perf or me d t hat ma y i ncl u de: C K, G G T, a n d a nti-
viral ser ol o gies. S u bjects ma y  ha ve t o ret ur n t o t he st u d y site t o pr o vi de a d diti o nal bl o o d 
sa m ples f or t hese la b orat or y tests. See secti o n o n p ote ntial Dr u g I n d uce d Li ver I nj ur y  
(Secti o n 8. 4 ).
A d diti o n al tests m a y be o bt ai ne d t o e v al u ate l a b or at or y a b n or m alities a n d/ or a d verse 
e ve nts; ple ase refer t o t he L a b or at or y M a n u al.
6. 2. 4. 2
Pre g n a nc y Testi n g
W O C B P will c o m plete p re g na nc y tests (ser u m a n d / or uri ne) at s pecifie d st u d y visits, pri or t o
ta ki n g st u d y dr u g, a n d as o utli ne d i n Ta ble 1 a n d Ta ble 2 .
6. 2. 5
C ol u m bi a -S uici de Se verit y R ati n g Sc ale ( C -S S R S)
T he C ol u m bia -S uici de Se veri t y Rati n g Scale ( C-S S R S) is a q uesti o n naire use d f or s uici de
Assess me n t.1 1 T he C -S S R S “Scree ni n g versi o n ” will be use d at t he Scree ni n g Visit a n d t he
“Si nce Last Visit versi o n ” 1 2 will be use d at s u bse q ue nt visits i n t his st u d y .
T he C -S S R S Assess me nt is i nte n de d t o hel p esta blis h a pers o n’s i m me diate ris k of s uici de. T he 
C- S S R S is a cli nicia n a d mi nistere d scale t hat s h o ul d be a d mi nistere d by a certifie d rater. T his 
scale will be c ollecte d o n site wit h a pa per f or m. T he C -S S R S s h o ul d be re vie we d b y t he 
I n vesti gat or or desi g nee bef ore t he s u bject is all o we d t o lea ve cli nic.
At t he Scree ni n g Visit, t he recall peri o d f or c o m pleti n g is 1 2 m o nt hs f or s uici dal i deati o n a n d 1 0 
ye ars f or s uici dal be ha vi or ; at all ot her visits, t he recall peri o d f or c o m pleti n g t he C -S S R S is 
si nce t he last visit (refere nce Ta ble 1 a n d Ta ble 2 ).
A n y  “ Yes” res p o nses m ust be i m me diatel y e val uate d b y t he i n vesti gat or. If t he In vesti gat or 
deter mi nes t hat a s u bject is at ris k of s uici de, self-har m, a p pr o priate meas ures t o e ns ure t he 
s u bject’s safety a n d o btai n me ntal healt h e val uati o n m ust be i m ple me nte d. I n s uc h 
circ u msta nces, t he s u bject m ust i m me diatel y  be disc o nti n ue d fr o m t he st u d y. T he e ve nt s h o ul d 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 6 0 of 1 0 3
P FI Z E R C O N FI D E N TI A L
be rec or de d as eit her a n A E or S A E as deter mi ne d b y  t he I n vesti gat or a n d re p orte d wit hi n 2 4 
h o urs t o t he S p o ns or .
6. 3
Effic ac y Assess me nts
T he e Diar y will be use d dail y  t o rec or d ac ute me dicati o n d osi n g occ urre nces (i.e., wit h tri pta ns,
er g ota mi ne, or ot her), a n d mi grai ne pai n feat ures a n d ass ociate d s y m pt o ms d uri n g t he 
O bser vati o n P hase a n d t he D o u ble -bli n d Treat me nt P hase.
Efficac y  assess me nts will be deri ve d fr o m e Diar y data a n d will i ncl u de t he n u m ber of mi grai ne 
da y s per m o nt h b y pai n i nte nsit y (t otal; m o derate or se vere), a n d n u m ber of ac ute mi grai ne -
s pecific me dicati o n da y s per m o nt h, i n eac h m o nt h b y st u d y peri o d. Please refer t o Ta ble 1 .
6. 4
Ot her Assess me nts
6. 4. 1  
M i gr ai ne-S pecific Q u alit y - of-Life Q uesti o n n aire ( M S Q) v 2. 1
I m pact of treat me nt o n s u bject-re p orte d q uality of life will be assesse d usi n g the Mi grai ne -
S pecific Q ualif y -of -Life Q uesti o n naire versi o n 2. 1 ( M S Q v 2. 1) . T he M S Q v 2. 1 is a 1 4- ite m 
i nstr u me nt t hat has bee n vali date d i n 3 d o mai ns: r ole f u ncti o n - restricti ve, r ole f u ncti o n -
pre ve nti ve, a n d e m oti o nal f u ncti o n .1 3 T he M S Q will be c o m plete d o n a pa per f or m at t he site.
6. 4. 2
Cli nic al Gl o b al I m pressi o n – C h a n ge ( C GI -c) Sc ale
T he Cli nical Gl o bal I m pres si o n-c ha n ge ( C GI-c) scale is an o bser ver- rate d, 7-p oi nt scale t hat 
meas ures s u bject t otal i m pr o ve me nt relati ve t o t he i n vesti gat or’s past e x perie nce wit h ot her 
s u bjects wit h t he sa me dia g n osis, wit h or wit h o ut c ollateral i nf or mati o n. 1 4  T he C GI -c will be 
ad mi nistere d b y t he i n vesti gat or or desi g nee a n d will be c o m plete d o n a pa per f or m at t he site.
6. 4. 3
S atisf acti o n wit h Me dic ati o n ( S M) Sc ale
T he Satisfacti o n wit h Me dicati o n ( S M) scale is a s u bject-rate d, 7-p oi nt scale t hat meas ures 
satisfacti o n wit h t he st u d y me dicati o n t o treat mi grai ne hea dac hes. T he S M will be c o m plete d o n 
a pa per f or m at t he site.
6. 5
E arl y Disc o nti n u ati o n fr o m t he St u d y
S u bjects M U S T disc o nti n ue i n vesti gati o nal pr o d uct (a n d n o n -i n vesti gati o nal pr o d uct at t he 
discreti o n of t he i n vesti gat or) f or a n y of t he f oll o wi n g reas o ns.  

S u bjects w h o disc o nti n ue earl y fr o m t he D o u ble -bli n d Treat me nt P hase are n ot eli gi ble t o 
e nter t he O pe n-la bel E xte nsi o n P hase.

Wit h dra wal of i nf or me d c o nse nt (s u bject’s decisi o n t o wit h dra w f or a n y  reas o n)
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 6 1 of 1 0 3
P FI Z E R C O N FI D E N TI A L

A n y  cli nical a d verse e ve nt ( A E), la b orat or y a b n or malit y or i nterc urre nt ill ness w hic h, i n t he 
o pi ni o n of t he i n vesti gat or, i n dicates t hat c o nti n ue d partici pati o n i n t he st u d y  is n ot i n t he 
best i nterest of t he s u bject

E xcl usi o nar y  la b orat or y a b n or malit y i de ntifie d o n t he Ra n d o mizati o n / Baseli ne La b orat or y  
Re p ort.  

Pre g na nc y

Ter mi nati o n of t he st u d y b y  Pfizer I nc.

L oss of a bilit y  t o freely pr o vi de c o nse nt t hr o u g h i m pris o n me nt or i n v ol u ntar y i ncarcerati o n 
f or treat me nt of eit her a ps yc hiatric or p h ys ical (e. g., i nfecti o us disease) ill ness

P o or c o m plia nce wit h st u d y  pr oce d ures a n d visits, i ncl u di n g p o or c o m pleti o n c o m plia nce 
wit h e ve ni n g re p orts i n e Diar y . 
i.
S u bjects wit h less t ha n 2 4 c o m plete d e Diar y re p orts d uri n g 2 8 da y s i n t he O bser vati o n 
P hase will n ot be c o nsi dere d f or partici pati o n d ue t o n o n -c o m plia nce wit h t he e Diar y.  
ii.
S u bjects i n t he D o u ble- bli n d Treat me nt P hase will be m o nit ore d cl osel y f or c o m plia nce 
wit h t he e Diar y  a n d ma y n ot be c o nsi dere d f or t he O pe n -la bel E xte nsi o n P hase, base d 
o n PI  a n d/ or S p o ns or discreti o n if c o m plia nce is l o w.  S u bjects w h o de m o nstrate p o or 
c o m plia nce will be disc usse d wit h t he S p o ns or a n d c orrecti ve trai ni n g will be 
c o m plete d b y t he site wit h t he s u bject.

Please see Secti o n 6. 2. 5 f or g ui da nce o n st u dy disc o nti n uati o n base d o n res ults fr o m t he      
C -S S R S.

All s u bjects w h o disc o nti n ue s h o ul d c o m pl y  wit h pr ot oc ol-s pecifie d Wee k 1 2/ E O T or Wee k 
2 4/ E O T Visit pr oce d ures as o utli ne d i n Ta ble 1 or Ta ble 2 . T he o nl y e xce pti o n t o t his 
re q uire me nt is w he n a s u bject wit h dra ws c o nse nt f or all st u d y pr oce d ures or l oses t he a bilit y 
t o c o nse nt freel y (i.e., is i m pris o ne d or i n v ol u ntaril y  i ncarcerate d f or t he treat me nt of eit her a 
ps y c hiatric or p h ys ical ill ness). 
6. 5. 1
L ost t o F oll o w - up
A s u bject will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peate dl y  fails t o ret ur n f or sc he d ule d 
visits a n d is u na ble t o be c o ntacte d b y t he st u d y site.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 6 2 of 1 0 3
P FI Z E R C O N FI D E N TI A L
T he f oll o wi n g acti o ns m ust be ta ke n if a s u bject 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 s u bject a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he s u bject 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 or n ot t he s u bject 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 s u bject 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 s u bject ( w here p ossi ble, 3 tele p h o ne calls a n d, if necessar y, a 
certifie d letter t o t he s u bject’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 s u bject’s me dical rec or d.

S h o ul d t he s u bject c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve wit h dra w n 
fr o m t he st u d y.
6. 6
Cli nic al Tri al S u bject D at a b ase ( C T S d at a b ase)
C T S data base is a cli nical trial s u bject re gistr y  t hat mai ntai ns t he pri vac y a n d sec urity of researc h 
s u bjects w hile pr o vi di n g s p o ns ors a n d i n vesti gat ors wit h cr ucial i nf or mati o n a b o ut s u bjects’ 
c urre nt a n d/ or pre vi o us st u d y  partici pati o n. 
C T S data base has bee n s h o w n t o re d uce t he n u m ber of d u plicate a n d pr ofessi o nal s u bjects 
e nteri n g cli nical trials.
T he use of t his data base m ust be prese nte d t o all s u bjects partici pati n g i n t his pr ot oc ol, w here 
a p pr o ve d l ocall y. If s u bjects ref use t o pr o vi de a ut h orizati o n, t he st u d y tea m s h o ul d be n otifie d.  
A t t he ti me of pr o vi di n g t he Inf or me d C o nse nt f or t he st u d y , t he I n vesti gat or or desi g nee will 
e x plai n t he IR B -a p pr o ve d S u bject Data base A ut h orizati o n t o t he s u bject a n d wit ness t he 
si g nat ure.
D uri n g scree ni n g, s ite staff t hat ha ve recei ve d trai ni n g a n d l o gi n i nf or mati o n s h o ul d access 
w w w.cts data ba se.c o m a n d e nter t he last 7 di gits of t he s u bject st u d y ID a n d a ut h orize d s u bject 
i de ntifiers. A n i m me diate re p ort detaili n g matc hes is ge nerate d a n d s h o ul d be pri nte d f or s o urce 
d oc u me ntati o n. T he re p ort will s pecif y  eit her ( 1) n o matc hes f o u n d, ( 2) a matc h was f o u n d wit h 
a s u bject partici pati n g i n a n ot her st u d y  wit hi n 3 0 da y s or ( 3) t he s u bject matc hes wit h a s u bject 
w h o has pre -scree ne d at a n ot her site.  
At t he last s u bject c o ntact, C T S data base staff will a ut o maticall y cl ose o ut s u bjects ( S F, E T, or 
C o m pleter) base d o n I W R S i nf or mati o n.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 6 3 of 1 0 3
P FI Z E R C O N FI D E N TI A L
7 
S T U D Y D R U G M A N A G E M E N T
7. 1
Descri pti o n of St u d y Dr u g
7. 1. 1
I n vesti g ati o n al Pr o d uct
A n i n vesti gati o nal pr o d uct, als o k n o w n as i n vesti gati o nal me dici nal pr o d uct i n s o me re gi o ns, is 
defi ne d as f oll o ws:

A p har mace utical f or m of a n acti ve s u bsta nce or place b o bei n g teste d or use d as a refere nce 
i n a cli nical st u d y, i ncl u di n g pr o d ucts alrea dy wit h a mar keti n g a ut h orizati o n b ut use d or 
asse m ble d (f or m ulate d or pac ka ge d) i n a wa y  differe nt fr o m t he a ut h orize d f or m, or use d f or 
a n u na ut h orize d i n dicati o n, or w he n u se d t o gai n f urt her i nf or mati o n a b o ut t he a ut h orize d 
f or m.

T he i n vesti gati o nal pr o d uct s h o ul d be st ore d i n a sec ure area acc or di n g t o l ocal re g ulati o ns. It 
is t he res p o nsi bilit y of t he i n vesti gat or t o e ns ure t hat i n vesti gati o nal pr o d uct is o nl y  
dis pe nse d t o st u d y  s u bjects. T he i n vesti gati o nal pr o d uct m ust be dis pe nse d o nl y  fr o m official 
st u d y sites b y a ut h orize d pers o n nel acc or di n g t o l ocal re g ulati o ns.

D uri n g t he D o u ble -bli n d T reat me nt P hase, i n vesti gati o nal pr o d uct (st u d y dr u g) is ri me ge pa nt 
(B H V - 3 0 0 0) ( PF -0 7 8 9 9 8 0 1) 7 5 m g O D T d ose d E O D alter nati n g wit h matc hi n g place b o , 7 5 
m g O D T d ose d dail y, or matc hi n g place b o d ose d dail y.   

D uri n g t he O pe n -la bel E xte nsi o n P hase, i n vesti gati o nal pr o d uct (st u d y dr u g) is o pe n -la bel 
ri me ge pa nt (B H V - 3 0 0 0) ( P F-0 7 8 9 9 8 0 1) 7 5 m g O D T d ose d dail y. 

All s u bjects , re gar dless of t he treat me nt p hase, will ta ke st u d y  dr u g e ver y da y.
N O T E : D uri n g t he D o u ble -bli n d T reat me nt P hase , if a d ose of st u d y dr u g f or a gi ve n da y is 
misse d, l ost, or ot her wise u na ble t o be ta ke n, t he s u bject s h o ul d d oc u me nt t hat as a misse d d ose 
o n t he st u d y dr u g wallet a n d s h o ul d N O T ta ke t he f oll o wi n g da y ’s assi g ne d d ose u ntil t he ne xt 
cale n dar da y at t he s pecifie d ti me.  D uri n g t he O pe n -la bel E xte nsi o n P hase , if a d ose of st u d y 
dr u g f or a gi ve n da y is misse d, l ost, or ot her wise u na ble t o be ta ke n, t he s u bject s h o ul d d oc u me nt 
t hat as a misse d d ose o n t he st u d y dr u g wallet .
7. 1. 2
C o nc o mit a nt T her a p y
Ot her me dicati o ns use d as s u p p ort or resc ue me dicati o n f or dia g n ostic, or t hera pe utic reas o ns, as 
c o m p o ne nts of t he sta n dar d of care f or a gi ve n dia g n osis, ma y be c o nsi dere d as c o nc o mita nt 
t hera py.
I n t his pr ot oc ol, c o nc o mita nt t hera p y( ies) is/are sta n dar d of care f or ac ute treat me nt a n d resc ue 
me dicati o n f or mi grai ne treat me nt.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 6 4 of 1 0 3
P FI Z E R C O N FI D E N TI A L
7. 1. 3
P ac k a gi n g, S hi p me nt a n d St or a ge
T he pr o d uct st ora ge ma na ger s h o ul d e ns ure t hat t he st u d y  dr u g is st ore d i n acc or da nce wit h t he 
e n vir o n me ntal c o n diti o ns (te m perat ure, li g ht, a n d h u mi dit y) as deter mi ne d b y  t he s p o ns or. 
Please s ee t he P har mac y Ma n ual f or s pecific c o n diti o ns. If c o ncer ns re gar di n g t he q ualit y or 
a p peara nce of t he st u d y dr u g arise, d o n ot dis pe nse t he st u d y dr u g a n d c o ntact t he s p o ns or / C R O
i m me diatel y.
7. 2
D ose a n d A d mi nistr ati o n
7. 2. 1
Met h o d of Assi g ni n g
S u bject I de ntific ati o n
Im me diatel y  after writte n i nf or me d c o nse nt is o btai ne d a n d bef ore perf or mi n g a n y st u d y-relate d 
pr oce d ures, t he site staff m ust o btai n a s u bject i de ntificati o n b y  a d di n g a ne w s u bject i n t he 
a p pr o priate st u d y- relate d s yste m. In t his st u d y , an I W R S/ R T S M
s yste m will be utilize d f or 
o btai ni n g s u bject i de ntificati o n a n d as t he electr o nic data ca pt ure (E D C ) syste m . Eac h s u bject 
will be assi g ne d a u ni q ue 8- di git s u bject n u m ber t hr o u g h t he a p pr o priate st u d y-relate d sys te m. 
T he s u bject n u m ber will c o nsist of t he 3- di git s ite n u m ber, a h yp he n, a n d a u ni q ue 4- di git s u bject 
n u m ber . T his s u bject n u m ber m ust n ot be re use d f or a n y ot her s u bject i n t he st u d y. S u bjects will 
mai ntai n t heir s u bject n u m ber assi g ne d at scree ni n g t hr o u g h o ut t he st u d y e xce pt i n cas es of re -
scree ni n g, w here per mitte d, i n w hic h case a ne w s u bject n u m ber m ust be assi g ne d. 
At t he Baseli ne Visit, eli gi ble s u bjects will be ra n d o mize d i n a 1: 1: 1 rati o t o ri me ge pa nt 7 5 m g O D T 
d ose d E O D alter nati n g wit h matc hi n g place b o , ri me ge pa nt 7 5 m g O D T d ose d dail y , or place b o 
f or matc hi n g ri me ge pa nt 7 5 m g O D T d ose d dail y.
Ra n d o mizati o n will be stratifie d b y use of pri or pr o p h y lactic mi grai ne me dicati o n ge nerall y  
c o nsi dere d t o ha ve efficac y ( yes or n o). I n a d diti o n, ra n d o mizati o n of pr o p h y lactic mi grai ne 
treat me nt-naï ve s u bjects (“ n o” cate g or y ) will be ca p pe d at a p pr o xi matel y 3 0 % i n or der t o all o w
a p pr o xi matel y 7 0 % of ra n d o mize d s u bjects t o be pr o p h y lactic mi grai ne treat me nt-e x perie nce d 
(“ yes” cate g or y”). S u bjects s h o ul d be cate g orize d as “ yes” if t he y ha ve e ver ta ke n an y s pecifie d 
pr o p h y lactic mi grai ne me dicati o n ge nerall y c o nsi dere d t o ha ve efficac y  pri or t o i nf or me d 
c o nse nt, i.e., t he me dicati o n start date is bef ore t he i nf or me d c o nse nt date . Ot her wise, s u bjects 
s h o ul d be cate g orize d as “ n o”. See Secti o n 1 6. 5 A p pe n di x 5 f or a list of pr o p h y lactic mi grai ne 
me dicati o n s ge nerall y  c o nsi dere d t o ha ve efficac y.
After c o nfi rmi n g s u bject eli gi bilit y, r e gisteri n g a s u bject for Baseli ne ( Ra n d o mizati o n) will 
tri g ger a c o ntai ner n u m ber f or t he st u d y dr u g . St u d y dr u g will be dis pe nse d at t he Baseli ne Visit 
a n d as nee de d at t he st u d y visits.
7. 2. 2
Selecti o n a n d Ti mi n g of D ose a n d A d mi nistr ati o n
St u d y  dr u g (ri me ge pa nt or matc hi n g place b o ) will be assi g ne d via t he a p pr o priate st u d y-relate d 
s yste m. T here are n o d ose a dj ust me nts i n t his st u d y a n d su bjects will recei ve 8 ta blets of st u d y 
dr u g i n a blister car d heat-seale d i nt o a wallet; s u bjects will be assi g ne d a p pr o priate s u p pl y 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 6 5 of 1 0 3
P FI Z E R C O N FI D E N TI A L
bet wee n visits . S u bjects will be dis pe nse d st u d y dr u g at t he Baseli ne Visit, a n d t he su bjects will 
be i nstr ucte d t hat t he y m ust ta ke 1 t a blet d aily re g ar dless of w het her t hey h ave a mi gr ai ne o n 
t h at d ay. T his is t he sc he d ule d d osi n g re gi me n f or t he D o u ble -bli n d T reat me nt P hase a n d t he 
O pe n -la bel E xte nsi o n P hase . Site staff s h o ul d mar k eac h wallet wit h t he sc he d ule d date of eac h 
d ose t o be ta ke n w he n dis pe nsi n g t he st u d y dr u g.
D osi n g s h o ul d occ ur ar o u n d t he sa me ti me f or eac h sc he d ule d d ose.  It is preferre d t hat s u bjects 
d ose i n t he m or ni n g ; h o we ver, it is m ore i m p orta nt t hat t he s u bject c o nsiste ntl y d ose at 
a p pr o xi matel y t he sa me ti me f or eac h sc he d ule d d ose.  T he ti me of d osi n g s h o ul d be c o nsiste nt 
t hr o u g h o ut t he st u d y.  If t he s u bject has a mi grai ne o n a da y w he n t h e y alre a dy t o o k st u dy dr u g , 
t he n t he s u bject ca n ta ke per mitte d ac ute mi grai ne me dicati o n as nee de d (see Secti o n 5. 5. 1 ). 
S u bject s m ust be i nstr ucte d t hat t he y C A N N O T ta ke m ore t ha n 1 ta blet of st u d y  dr u g dail y
d uri n g t he st u d y.  
D uri n g t he D o u ble -bli n d T reat me nt P hase, if a d ose of st u d y dr u g f or a gi ve n da y is misse d, l ost, 
or ot her wise u na ble t o be ta ke n, t he s u bject s h o ul d d oc u me nt t hat as a misse d d ose o n t he st u d y  
dr u g wallet a n d s h o ul d N O T ta ke t he f oll o wi n g da y ’s assi g ne d d ose u ntil t he ne xt cale n dar da y  at 
t he s pecifie d ti me.  
D uri n g t he O pe n -la bel E xte nsi o n P hase , if a d ose of st u d y dr u g f or a gi ve n da y is misse d, l ost, or 
ot her wise u na ble t o be ta ke n, t he s u bject s h o ul d d oc u me nt t hat as a misse d d ose o n t he st u d y  
dr u g wallet .
7. 2. 3  
D ose M o dific ati o n
T here will be n o d ose a dj ust me nts i n t his st u d y.
7. 2. 4
D ose I nterr u pti o ns
If a s u bject e x perie nces a n A E t hat re q uires i nterr u pti o n i n st u d y dr u g, t he i n vesti gat or s h o ul d 
c o ns ult wit h t he S p o ns or me dical m o nit or t o e val uate t he nee d f or a n y a d diti o nal tests pri or t o 
re-starti n g st u d y dr u g. 
7. 3
Bli n di n g a n d U n bli n di n g 
Bli n di n g is critical t o t he i nte grit y of t his cli nical st u d y . H o we ver, i n t he e ve nt of a me dical 
e mer ge nc y or pre g na nc y i n a n i n di vi d ual s u bject, i n w hic h k n o wle d ge of t he i n vesti gati o nal 
pr o d uct is critical t o t he s u bject’s ma na ge me n t, t he bli n d f or t hat s u bject ma y be br o ke n b y t he 
treati n g p hys icia n. 
Bef ore brea ki n g t he bli n d of a n i n di vi d ual s u bject’s treat me nt, t he i n vesti gat or s h o ul d ha ve 
deter mi ne d t hat t he i nf or mati o n is necessar y , (i.e., t hat it will alter t he s u bject’s i m me diate 
ma na ge me nt). I n ma ny cases, partic ularl y w he n t he e mer ge nc y is clearl y n ot i n vesti gati o nal 
pr o d uct relate d, t he pr o ble m ma y  be pr o perly ma na ge d b y ass u mi n g t hat t he s u bject is recei vi n g 
acti ve pr o d uct wit h o ut t he nee d f or u n bli n di n g. 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 6 6 of 1 0 3
P FI Z E R C O N FI D E N TI A L
I n cases of accide ntal u n bli n di n g, c o ntact t he Me dical M o nit or
a n d e ns ure e ver y atte m pt t o 
preser ve t he bli n d is ma de.
7. 4
Tre at me nt C o m pli a nce
Res p o nsi ble st u d y  pers o n nel will dis pe nse t he st u d y dr u g.  S u bjects are re q uire d t o fi nis h a 
wallet of st u d y dr u g bef ore starti n g a ne w wallet . Acc o u nta bilit y  a n d c o m plia nce verificati o n 
s h o ul d be d oc u me nte d i n t he s u bject’s st u d y rec or ds.  
S u bjects m ust be c o u nsele d o n t he i m p orta nce of ta ki n g t he st u d y dr u g as directe d (see 
Secti o n 7. 2. 2 ). Treat me nt c o m plia nce a n d re vie w of st u d y dr u g d oses t hr o u g h re vie w of ret ur ne d 
st u d y dr u g s h o ul d be assesse d b y site staff at eac h st u d y visit. Discre pa ncies bet wee n re vie w of 
st u d y dr u g a n d i nf or mati o n pr o vi de d b y s u bject m ust be d oc u me nte d i n t he s o urce rec or d. 
I n vesti gat ors s h o ul d i nf or m su bjects t hat i n v ol u ntar y ter mi nati o n fr o m t he st u d y will occ ur i n 
cases w here n o n -c o m plia nce is i de ntifie d. St u d y  staff s h o ul d c o ntact a s u bject bet wee n t he 
m o nt hl y  st u d y visits if t he s u bject de m o nstrates n o n -c o m plia nce wit h t he e Diar y a n d d oc u me nt 
t he c o ntact i n t he s o urce, t o i de ntif y p ote ntial l ost t o f oll o w- u p su bjects as earl y as p ossi ble. 
I n vesti gat ors m ust m o nit or su bjects f or p ossi ble cases of a b use of st u d y dr u g (su bjects ta ki n g 
st u d y dr u g f or n o n-t hera pe utic p ur p oses, e. g. f or ps yc h oacti ve effects s uc h as hi g h or e u p h oria). 
I n vesti gat ors s h o ul d als o assess st u d y dr u g acc o u nta bilit y discre pa ncies (e. g. missi n g st u d y dr u g,
l oss of me dicati o n , or n o n-c o m plia nce cases i n w hic h m ore st u d y dr u g was use d, as c o m pare d t o 
e x pecte d). I n vesti gat ors s h o ul d o btai n m ore i nf or mati o n a n d e x pla nati o n fr o m su bjects w he n 
t here are st u d y dr u g acc o u nta bilit y discre pa ncies. (See Secti o n 8. 1. 1 .)
Cases of p ote ntial st u d y  dr u g a b use or o ver d ose (i ncl u di n g cases of n o n -c o m plia nce wit h st u d y 
dr u g d osi n g i nstr ucti o ns or su bjects w h o disc o nti n ue treat me nt wit h o ut ret ur ni n g st u d y dr u g) 
s ho ul d be d oc u me nte d i n t he s o urce rec or d a n d re p orte d as a n A E or S A E as a p pr o priate. D osi n g 
err ors (e. g. acci de ntall y t a ki n g 2 ta blets i n o ne cale n dar da y) s h o ul d be re p orte d as de viati o ns. 
C o m plia nce wit h st u d y  i nter ve nti o n will be defi ne d as:

≥8 0 % (a n d i deally, u p t o 1 0 0 %) of st u d y- s u p plie d i nter ve nti o n fr o m Da y 1 
t hr o u g h t he Treat me nt P hase are e x pecte d t o be c o ns u me d.

P ost ra n d o mizati o n, at eac h dis pe nsati o n visit (refer t o Ta ble 1 ), s u bjects w h o are 
< 8 0 % c o m plia nt m ust be re -e d ucate d o n t he i m p orta nce of daily 
selfa d mi nistrati o n of st u d y i nter ve nti o n .

O verall ai m: mai ntai n ≥8 0 % c o m plia nce o ver t he d urati o n of d osi n g wit h 
ra n d o mize d st u d y i nter ve nti o n.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 6 7 of 1 0 3
P FI Z E R C O N FI D E N TI A L
7. 5
Destr ucti o n a n d Ret ur n of St u d y Dr u g
All u n use d a n d/ or partiall y  use d st u d y dr u g ca n be se nt t o t he pre deter mi ne d dr u g destr ucti o n
facilit y o nl y after bei n g i ns pecte d a n d rec o ncile d b y  t he res p o nsi ble St u d y m o nit or or t he 
s p o ns or’s desi g nee. If it is site p olic y t o destr oy st u d y dr u g o n site, it is t he I n vesti gat or’s 
res p o nsi bilit y t o e ns ure t hat arra n ge me nts ha ve bee n ma de f or t he dis p osal, pr oce d ures f or pr o per 
dis p osal ha ve bee n esta blis he d acc or di n g t o t he a p plica ble re g ulati o ns, g ui deli nes a n d 
i nstit uti o nal pr oce d ures, a n d a p pr o priate rec or ds of t he dis p osal ha ve bee n d oc u me nte d. 
Destr ucti o n at a st u d y site ma y o nl y occ ur after bei n g i ns pecte d a n d rec o ncile d b y t he 
res p o nsi ble St u d y m o nit or or t he s p o ns or’s desi g nee.
8
A D V E R S E E V E N T S
A n A d verse E ve nt ( A E) is defi ne d as a n y ne w u nt o war d me dic al occ urre nce or w orse ni n g of a 
pre -e xisti n g me dical c o n diti o n i n a s u bject or cli nical i n vesti gati o n s u bject a d mi nistere d a n 
i n vesti gati o nal ( me dici nal) pr o d uct a n d t hat d oes n ot necessarily ha ve a ca usal relati o ns hi p wit h 
t his treat me nt. A n A E ca n t herefore be a n y  u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g f or e xa m ple) s ym pt o m, or disease te m p orall y  ass ociate d wit h t he 
use of t he i n vesti gati o nal pr o d uct, w het her or n ot c o nsi dere d relate d t o t he i n vesti gati o nal 
pr o d uct. 
A d ve rse e ve nts ca n be s p o nta ne o usl y re p orte d or elicite d d uri n g a n o pe n-e n de d q uesti o ni n g, 
e xa mi nati o n, or e val uati o n of a s u bject. I n or der t o pre ve nt re p orti n g bias, su bjects s h o ul d n ot be 
q uesti o ne d re gar di n g t he s pecific occ urre nce of o ne or m ore A Es.
If a s pecific dia g n osis or s yn dr o me is i de ntifie d b y t he I n vesti gat or, t his s h o ul d be rec or de d as 
t he A E, rat her t ha n rec or di n g (as se parate A Es) t he i n di vi d ual si g ns/s ym pt o ms or cli nicall y  
si g nifica nt la b orat or y a b n or malities k n o w n t o be ass ociate d wit h an d c o nsi dere d b y t he 
I n vesti gat or t o be a c o m p o ne nt of, t he disease/sy n dr o me.
Defi niti o n of ter ms rel ate d t o all A Es (seri o us a n d n o n-seri o us):
Mil d : Is us uall y tra nsie nt a n d ma y re q uire o nly mi ni mal treat me nt or t hera pe utic 
i nter ve nti o n. T he e ve nt d oes n ot ge nerall y  i nterfere wit h us ual acti vities of dail y li vi n g.
M o derate : Is us uall y alle viate d wit h a d diti o nal s pecific t hera pe utic i nter ve nti o n. T he e ve nt 
i nterferes wit h us ual acti vities of dail y li vi n g, ca usi n g disc o mf ort b ut p oses n o si g nifica nt or 
pe r ma ne nt ris k of har m t o t he s u bject.
Se vere : I nterr u pts us ual acti vities of dail y li vi n g, si g nifica ntly affects cli nical stat us, or ma y 
re q uire i nte nsi ve t hera pe utic i nter ve nti o n.
Life t hreate ni n g : A n A E is life t hreate ni n g if t he s u bject was at i m me diate ris k of deat h fr o m t he 
e ve nt as it occ urre d, i.e., it d oes n ot i ncl u de a reacti o n t hat if it ha d occ urre d i n a m ore seri o us 
f or m mi g ht ha ve ca use d deat h. F or e xa m ple, dr u g i n d uce d he patitis t hat res ol ve d wit h o ut 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 6 8 of 1 0 3
P FI Z E R C O N FI D E N TI A L
e vi de nce of he patic fail ure w o ul d n ot be c o n si dere d life t hreate ni n g e ve n t h o u g h dr u g i n d uce d 
he patitis ca n be fatal.
H os pitalizati o n : A Es re q uiri n g h os pitalizati o n s h o ul d be c o nsi dere d S A Es. H os pitalizati o n f or 
electi ve s ur ger y or r o uti ne cli nical pr oce d ures t hat are n ot t he res ult of A E (e. g., electi ve s ur ger y 
f or a pre-e xisti n g c o n diti o n t hat has n ot w orse ne d) nee d n ot be c o nsi dere d A Es or S A Es. If 
a n yt hi n g u nt o war d is re p orte d d uri n g t he pr oce d ure, t hat occ urre nce m ust be re p orte d as a n A E, 
eit her 'seri o us' or ' n o n -seri o us' acc or di n g t o t he us ual criteria.
Assess me nt f or Deter mi ni n g Rel ati o ns hi p of A E t o St u d y Dr u g :
T he relate d ness of eac h A E t o st u d y  dr u g m ust be classifie d base d o n me dical j u d ge me nt a n d 
acc or di n g t o t he f oll o wi n g cate g ories. T he defi niti o ns are as f oll o ws:
Relate d : T his cate g or y a p plies t o A Es t hat are c o nsi dere d, wit h a hi g h de gree of certai nt y , t o be 
relate d t o t he st u d y dr u g. A n A E ma y be c o nsi dere d relate d w he n it f oll o ws a te m p oral se q ue nce 
fr o m t he a d mi nistrati o n of st u d y dr u g, it ca n n ot reas o na bl y be e x plai ne d b y t he k n o w n
c haracteristics of t he s u bject’s cli nical state, e n vir o n me nt, or t o xic fact ors, or ot her m o des of 
t hera py a d mi nistere d t o t he s u bject. A n A E ma y be c o nsi dere d relate d w he n it f oll o ws a k n o w n 
patter n of res p o nse t o t he st u d y  dr u g, or if t he A E rea p pears u po n re -c halle n ge.
P ossi bl y  relate d ( n o n-seri o us A Es o nl y): T his cate g or y a p plies t o A Es t hat are c o nsi dere d t o ha ve 
a n u nli kel y c o n necti o n t o st u d y dr u g, b ut a relati o ns hi p ca n n ot be r ule d o ut wit h certai nty.
U nli kel y  relate d ( n o n-seri o us A Es o nl y): T his cate g or y a p plies t o A Es t hat d o n ot f oll o w a 
reas o na ble te m p oral se q ue nce fr o m t he a d mi nistrati o n of t he st u d y dr u g. T he A E ma y rea dily 
ha ve bee n pr o d uce d b y t he s u bject’s cli nical state, e n vir o n me ntal or t o xic fact ors, or ot her m o des 
of t hera p y a d mi nistere d t o t he s u bject.
U nrelate d: T his cate g or y  a p plies t o A Es t hat are c o nsi dere d wit h a hi g h de gree of certai nt y t o be 
d ue o nl y  t o e xtra ne o us ca uses (e. g. s u bject’s cli nical state, e n vir o n me nt, t o xic fact ors, disease 
u n der st u d y , etc.) a n d d oes n ot meet t he criteria of ot her cate g ories a b o ve.
T here are t w o t y pes of a d verse e ve nts, Seri o us A d verse E ve nts ( S A E) a n d N o n -seri o us A d verse 
E ve nts ( A Es).
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 6 9 of 1 0 3
P FI Z E R C O N FI D E N TI A L
8. 1
S E RI O U S A D V E R S E E V E N T
8. 1. 1
Defi niti o n of Seri o us A d verse E ve nt ( S A E)
A n S A E is a n y  e ve nt t hat meets a n y of t he f oll o wi n g criteria at a n y d ose:

Deat h

Life -t hreate ni n g

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 disa bilit y /i nca pacity

C o n ge nital a n o mal y/ birt h defect i n t he offs pri n g of a s u bject w h o recei ve d ri me ge pa nt

Ot her: I m p orta nt me dical e ve nts t hat ma y  n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n, ma y  be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate me dical j u d g me nt, 
t he y ma y je o par dize t he s u bject 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. E xa m ples of s uc h e ve nts are ( b ut n ot li mite d t o):
○
I nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m
○
Bl o o d d ys crasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n
○
De vel o p me nt of dr u g de pe n de nc y  or dr u g a b use
○
P ote ntial dr u g i n d uce d li ver i nj ur y  (see S ecti o n 8. 4 )
○
A b use or o ver d ose of st u d y dr u g
▪
P ote ntial st u d y  dr u g a b use (i ncl u di n g cases of e xcessi ve n o n -c o m plia nce wit h st u d y 
dr u g d osi n g i nstr ucti o ns or su bjects w h o disc o nti n ue st u d y dr u g wit h o ut ret ur ni n g 
st u d y dr u g ) s h o ul d be d oc u me nte d i n t he s o urce rec or d a n d re p orte d as a n A E or S A E 
as a p pr o priate. I n vesti gat ors m ust m o nit or su bjects f or p ossi ble cases of a b use of 
st u d y dr u g (su bjects ta ki n g st u dy dr u g f or n o n -t hera pe utic p ur p oses, e. g. f or 
ps y c hoacti ve effects s uc h as hi g h or e u p h oria). I n vesti gat ors s h o ul d o btai n m ore 
i nf or mati o n a n d e x pla nati o n fr o m su bjects w he n t here are st u d y dr u g acc o u nta bilit y  
discre pa ncies
▪
P ote ntial st u d y  dr u g o ver d ose is defi ne d i n Secti o n 8. 3
I n ge neral, h os pitalizati o n si g nifies t hat t he s u bject has bee n detai ne d ( us uall y i n v ol vi n g at least 
a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or o bser vati o n a n d/ or treat me nt t hat w o ul d 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 7 0 of 1 0 3
P FI Z E R C O N FI D E N TI A L
n ot ha ve bee n a p pr o priate i n t he p h y sicia n's office or o ut patie nt setti n g. W he n i n d o u bt as t o 
w het her ' h os pitalizati o n' occ urre d or was necessar y, t he A E s h o ul d be c o nsi dere d seri o us.
T he f oll o wi n g h os pita lizati o ns are n ot c o nsi dere d S A Es i n Pfizer cli nical st u dies ( b ut ma y be 
c o nsi dere d n o n -seri o us A Es):
1.
A visit t o t he e mer ge nc y  r o o m or ot her h os pital de part me nt < 2 4 h o urs t hat d oes n ot res ult i n 
a n a d missi o n ( u nless c o nsi dere d “i m p orta nt me dical e ve nt” or e ve nt t hat is life t hreate ni n g ).
2.
Electi ve s ur ger y pla n ne d pri or t o si g ni n g c o nse nt;
3.
A d missi o ns as per pr ot oc ol f or a pla n ne d me dical/s ur gical pr oce d ure;
4.
R o uti ne healt h assess me nt re q uiri n g a d missi o n (i.e., r o uti ne c ol o n osc o p y);
5.
A d missi o n e nc o u ntere d f or a n ot her life circ u msta nce t hat carries n o beari n g o n healt h a n d 
re q uires n o me dical i nter ve nti o n (i.e., lac k of h o usi n g, care-gi ver res pite, fa mil y  
circ u msta nces).
Disa bilit y /i nca pacitati n g: A n A E is i nca pacitati n g or disa bli n g if t he e x perie nce res ults i n a
s u bsta ntial a n d/ or per ma ne nt disr u pti o n of t he s u bject's a bilit y t o carr y o ut n or mal life f u ncti o ns.
8. 1. 2
C ollecti o n a n d Re p orti n g Seri o us A d verse E ve nts
F oll o wi n g t he s u bject’s writte n c o nse nt t o partici pate i n t he st u d y, all S A Es, w het her relate d or 
n ot rela te d t o st u d y dr u g, m ust be c ollecte d, i ncl u di n g t h ose t h o u g ht t o be ass ociate d wit h 
pr ot oc ol -s pecific pr oce d ures. All S A Es m ust be c ollecte d t hat occ ur fr o m t he ti me t he IC F is 
si g ne d t hr o u g h t he F oll o w - u p Wee k 8 Visit . T he i n vesti gat or s h o ul d re p ort a n y  SA E occ urri n g 
after t his ti me peri o d t hat is belie ve d t o be relate d t o st u d y dr u g or pr ot oc ol-s pecific pr oce d ures.  
All S A Es s h o ul d be f oll o we d t o res ol uti o n or sta bilizati o n.
A n S A E re p ort s h o ul d be c o m plete d f or a n y  e ve nt w here d o u bt e xists re gar di n g its stat us of 
seri o us ness.  
If t he i n vesti gat or belie ves t hat a n S A E is n ot relate d t o t he st u d y dr u g b ut is p ote ntiall y relate d 
t o t he c o n diti o ns of t he st u d y (s uc h as a wit h dra wal of pre vi o us t hera py or a c o m plicati o n relate d 
t o st u d y pr oce d ure), t he relati o ns hi p s h o ul d be s pecifie d i n t he narrati ve secti o n of t he S A E 
Re p ort. 
S A Es, w het her relate d or n ot relate d t o st u d y dr u g, o ver d ose (see Secti o n 8. 3 ), p ote ntial dr u g 
i n d uce d li ver i nj ur y (see Secti o n 8. 4 ) a n d pre g na ncies (see S ecti o n Err or! Refere nce s o urce n ot f
o u n d. ) m ust be re p orte d wit hi n 2 4 h o urs of t he I n vesti gat or bec o mi n g a ware of t he e ve nt. F or 
t his st u d y we will be ca pt uri n g S A Es t hr o u g h electr o nic data ca pt ure ( E D C) a n d o n t he S A E 
re p ort.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 7 1 of 1 0 3
P FI Z E R C O N FI D E N TI A L
T he I n vesti gat or is res p o nsi ble f or s u b mitti n g all a p plica ble e ve nts t o t he I n de pe n de nt Re vie w 
B oar d (I R B) as per t he I R B’s re p orti n g re q uire me nts. A d diti o nall y , t he I n vesti gat or, or 
desi g nate d staff, is res p onsi ble f or e nteri n g t he S A E i nf or mati o n i nt o t he Case Re p ort F or m 
( C R F) a n d safety re p orti n g s yste m (i.e., e ve nt ter m, start/st o p dates, ca usalit y , a n d i nte nsit y).
A n y  seri o us a d verse e ve nt m ust be re p orte d i m me diately or n o later t ha n 2 4 h o urs after 
a ware ness of t he e ve nt t o Pfizer D S U eit her via t he Pfizer S A E S u b missi o n Assista nt ( P S S A) 
t o ol or usi n g t he Pfizer C T S A E re p ort, t hat m ust be se nt b y  facsi mile (fa x or e Fa x ), t o yo ur 
c o u ntr y’s Pfizer D S U. If o nl y  li mite d i nf or mati o n is i nitiall y a vaila ble, f oll o w-u p re p orts are 
re q uire d. If a n o n g oi n g S A E c ha n ges i n its i nte nsit y or relati o ns hi p t o st u d y dr u g or if ne w 
i nf or mati o n bec o mes a vaila ble, a f oll o w- u p S A E re p ort s h o ul d be se nt wit hi n 2 4 h o urs of t he 
I n vesti gat or bec o mi n g a ware of t he u p date d i nf or mati o n usi n g t he sa me pr oce d ure use d f or t he 
tra ns missi o n of t he i nitial S A E a n d t he sa me e ve nt ter m s h o uld be use d.
T he mi ni m u m i nf or mati o n re q uire d f or a n i nitial S A E re p ort is:

Se n der of re p ort ( Site n u m ber, I n vesti gat or na me)

S u bject i de ntificati o n (s u bject n u m ber)

Pr ot oc ol n u m ber

S A E ter m (if a n S A E is bei n g re p orte d)
8. 2
N o n -seri o us A d verse E ve nts
A n o n -serio us a dverse eve nt is a n A E n ot classifie d as seri o us. 
8. 2. 1
C ollecti o n a n d Re p orti n g of N o n -seri o us A d verse E ve nts
All n o n -seri o us A Es m ust be c ollecte d t hat occ ur fr o m si g ni n g t he I C F t hr o u g h t he F oll o w- u p
Wee k 8 Visit. N o n -seri o us A E s s h o ul d be f oll o we d u ntil c o ncl usi o n or sta bilizati o n or re p orte d 
as S A Es if t he y bec o me seri o us.  F oll o w-u p is als o re q uire d f or n o n -seri o us A Es t hat ca use 
i nterr u pti o n or disc o nti n uati o n of st u d y dr u g or t h ose t hat are prese nt at t he e n d of st u d y 
treat me nt. 
8. 2. 2 
L a b or at or y Test A b n o r m alities
T he f oll o wi n g la b orat or y test a b n or malities s h o ul d be ca pt ure d o n t he n o n -seri o us A E C R F pa ge 
or S A E Re p ort F or m ( pa per or electr o nic) as a p pr o priate:
1.
A n y  la b orat or y test res ult t hat is cli nicall y si g nifica nt or meets t he defi niti o n of a n S A E;
2.
A n y la b orat or y  a b n or malit y t hat re q uire d t he s u bject t o ha ve t he st u d y dr u g disc o nti n ue d or 
i nterr u pte d;
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 7 2 of 1 0 3
P FI Z E R C O N FI D E N TI A L
3.
A n y  la b orat or y a b n or malit y t hat re q uire d t he s u bject t o recei ve s pecific c orrecti ve t hera p y.
8. 3
O ver d ose
A n o ver d ose is defi ne d as t he acci de ntal or i nte nt i o nal a d mi nistrati o n of a n y d ose of a
pr o d uct t hat is c o nsi dere d b ot h e xcessi ve a n d me dic all y i m p ort a nt.  
All occ urre nces of o ver d ose (s us pecte d or c o nfir me d ) m ust be c o m m u nicate d t o Pfizer or a 
s pecifie d desi g nee wit hi n 2 4 h o urs a n d be f ully d oc u me nte d as a n S A E. Details of a n y si g ns or 
s ym pt o ms a n d t heir ma na ge me nt s h o ul d be rec or de d i ncl u di n g details of a n y  treat me nts
a d mi nistere d.
As y m pt o matic d osi n g err ors (e. g. , acci de ntall y ta ki n g 2 ta blets i n o ne cale n dar da y) s h o ul d be 
re p orte d as de viati o ns.
8. 4 
P ote nti al Dr u g I n d uce d Li ver I nj ur y ( DI LI)
W here ver p ossi ble, ti mel y  c o nfir mati o n of t he i nitial li ver-relate d la b orat or y a b n or malities 
s h o ul d occ ur pri or t o t he re p orti ng of a p ote ntial DI LI e ve nt.  All occ urre nces of p ote ntial DI LIs, 
meeti n g t he defi ne d criteria, m ust be re p orte d as S A Es as per Secti o n 8. 1. 2 . 
P ote ntial dr u g i n d uce d li ver i nj ur y  is defi ne d as: 
1.
A L T or A S T ele vati o n > 3 ti mes t he u p per li mit of n or mal ( U L N)
A N D
2.
T otal bilir u bi n > 2 ti mes U L N, wit h o ut i nitial fi n di n gs of c h olestasis (ele vate d ser u m 
al kali ne p h os p hatase)
A N D
3.
N o ot her i m me diatel y a p pare nt p ossi ble ca uses of A L T or A S T ele vati o n a n d 
h y per bilir u bi ne mia, i ncl u di n g b ut n ot li mite d t o, viral he patitis, pre -e xisti n g c hr o nic or 
ac ute li ver disease, or t he a d mi nistrati o n of ot her dr u g(s) k n o w n t o be he pat ot o xic. 
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 s u bject’s
i n di vi d ual baseli ne val ues a n d u n derlyi n g c o n diti o ns. S u bjects 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 pote ntial DI LI ( H y ’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:
F or s u bjects 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 ne:
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 7 3 of 1 0 3
P FI Z E R C O N FI D E N TI A L

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).
If a n y p ote ntial DI LI is i de ntifie d a n d meets t he criteria a b o ve, t he Pfizer Me dical M o nit or ( or 
desi g nee) s h o ul d i m me diatel y  be c o ntacte d f or f urt her i nstr ucti o n a n d w het her t he s u bject m ust 
disc o nti n ue fr o m t he st u d y a n d a p pr o priate f oll o w u p re q uire me nts . As wit h a n y  a d verse e ve nt, 
as state d per Secti o n 6. 5 , t he Pri nci pal I n vesti gat or has t he a bilit y a n d t he res p o nsi bilit y t o 
deter mi ne w het her a s u bject ca n safel y c o nti n ue i n t he st u d y.
Pr ocess f or a b n or mal li ver f u ncti o n test s: If at a n y visit after i nitiati o n of st u d y dr u g t he A S T or 
A L T is > 3 x U L N, t he f oll o wi n g ste ps s h o ul d be ta ke n as s o o n as t he i n vesti gat or is a ware: 1. 
T he s u bject m ust be i nf or me d of t he res ults a n d i nstr ucte d t o st o p st u d y  dr u g, 2. T he s u bject 
m ust be i nstr ucte d t o ret ur n t o t he cli nic wit hi n 3-5 da y s f or U nsc he d ule d visit f or re peat L F T 
pa nel a n d f urt her cli nical e val uati o n a n d testi n g as a p pr o priate ( wit h c o ns ultati o n wit h t he 
Me dical M o nit or ), a n d 3. T he Pfizer Me dical M o nit or s h o ul d i m me diatel y be c o ntacte d. 
G ui da nce will be pr o vi de d t o a u g me nt ma na ge me nt as a p pr o priat e. 
8. 5
E n vir o n me nt al E x p os ure, E x p os ure D uri n g Pre g n a nc y or Bre astfee di n g, a n d 
Occ u p ati o n al E x p os ure
E n vir o n me ntal e x p os ure occ urs w he n a pers o n n ot e nr olle d i n t he st u d y as a s u bject 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 b e 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 D P, 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 Pfizer Safet y wit hi n 
2 4 h o urs of i n vesti gat or a ware ness.
8. 5. 1
E x p os ure D uri n g Pre g n a nc y
If, f oll o wi n g t he Baseli ne Visit it is s u bse q ue ntl y disc o vere d t hat a st u d y s u bject is pre g na nt or 
ma y  ha ve bee n pre g na nt at t he ti me of t he i n vesti gati o nal pr o d uce e x p os ure, i ncl u di n g d uri n g at 
least 6 half-li ves after t he pr o d uct a d mi nistrati o n, t he i n vesti gati o nal pr o d uct will be per ma ne ntly 
disc o nti n ue d i n a n a p pr o priate ma n ner ( ie, d ose ta peri n g if necessar y f or s u bject safety).  
Pr ot oc ol -re q uire d pr oce d ures f or t he st u dy disc o nti n ue d a n d t he f oll o w -u p m ust be perf or me d o n 
t he s u bject u nless c o ntrai n dicate d by t he pre g na nc y  (ie, x-ra y st u dies).  Ot her a p pr o priate
pre g na nc y  f oll o w- u p pr oce d ures s h o ul d be c o nsi dere d if i n dicate d.  T he i n vesti gat or m ust 
i m me diatel y n otif y t he Pfizer  Me dical M o nit or ( or desi g nee) a n d re p ort t he e ve nt b y eit her usi n g 
t he C T S A E Re p or t F or m or via P S S A t o ol or b y  c o m pleti n g a n E x p os ure D uri n g Pre g na nc y 
( E D P) S u p ple me ntal F or m f oll o wi n g t he S A E re p orti n g pr oce d ures as descri be d i n Secti o n 8. 1. 2 . 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 7 4 of 1 0 3
P FI Z E R C O N FI D E N TI A L
F oll o w -u p i nf or mati o n re gar di n g t he c o urse of t he pre g na nc y , i ncl u di n g peri natal a n d ne o natal 
o utc o me a n d, w here a p plica ble offs pri n g i nf or mati o n m ust als o be re p orte d o n a n E D P 
S u p ple me nta l F or m.
A n y  pre g na nc y t hat occ urs i n a fe male part ner of a male st u d y s u bject s h o ul d be re p orte d t o t he
Pfizer D S U.  I nf or mati o n o n t his pre g na nc y  will be c ollecte d o n a n E D P S u p ple me ntal F or m, as 
a p pr o priate.   
A n E D P  occ urs if:

A fe male s u bject 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 s u bject 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 s u bject 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 are 
e xa m ples of e n vir o n me ntal E D P:  

A fe male fa mil y  me m ber or 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 gestio 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 t he st u d y 
i nter ve nti o n b y i n gesti o n or s ki n c o ntact t he n i nse mi nates his fe male part ner pri or t o 
or ar o u n d t he ti me of c o nce pti o n.
T he i n vesti gat or m ust re p ort E D P  t o 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 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 f or 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 s u bject/s u bject’s part ner, t he i n vesti gat or m ust re p ort t his i nf or mati o n t o 
Pfizer Safet y  usi n g t he C T S A E Re p ort F or m or via 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 dy i nter ve nti o n a n d u ntil 
6 6 h o urs 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 t he C T S A E Re p ort F or m or via P S S A. Si nc e t he e x p os ure i nf or mati o n 
d oes n ot pertai n t o t he s u bject 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 m ati o n o n t he pre g na nc y a n d its o utc o me f or all 
E D P  re p orts wit h a n u n k n o w n o utc o me. T he i n vesti gat or will f oll o w t he pre g na nc y u ntil 
c o m pleti o n ( or u ntil pre g na nc y  ter mi nati o n) a n d n otif y Pfizer Safety of t he o utc o me as a 
f oll o w-u p t o t he i nitial re p ort. I n t he case of a li ve birt h, t he str uct ural i nte grit y  of t he ne o nate 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 7 5 of 1 0 3
P FI Z E R C O N FI D E N TI A L
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 grit y of t he ter mi nat e d fet us 
s h o ul d be assesse d by 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 maly 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 
criteria f or a n S A E (ie, ect o pic pre g na nc y, s p o nta ne o us a b orti o n, i ntra uteri ne fetal de mise, 
ne o natal deat h, or c o n ge nital a n o mal y i n a li ve-b or n ba b y , a ter mi nate d fet us, a n i ntra uteri ne 
fetal de mise, or a ne o natal deat h), t he i n vesti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g 
S A Es. A d diti o nal i nf or mati o n a b o ut pre g na nc y o utc o mes t hat are re p orte d t o Pfizer Safet y  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 dea t 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 ma y  be re q ueste d by 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 i n vesti gat or will pr o vi de t he 
s u bject 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 s u bject was gi ve n t he Pre g na nt 
Part ner Relea se of I nf or mati o n F or m t o pr o vi de t o his part ner.
8. 5. 2
E x p os ure D uri n g Bre astfee di n g
A n E D B occ urs if: A fe male s u bject 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 s u bject is f o u n d t o be breastfee di n g 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 (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.  
T he i n vesti gat or m ust re p ort E D B t o Pfizer Safet y wit hi n 2 4 h o urs of t he i n vesti gat or’s 
a ware ness, irres pecti ve of w het her a n S A E has occ urre d. T he i nf or mati o n m ust be re p orte d usi n g 
t he C T S A E Re p ort F or m or via P S S A . W he n E D B occ urs i n t he setti n g of e n vir o n me ntal 
e x p os ure, t he e x p os ure i nf or mati o n d oes n ot pertai n t o t he s u bject 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.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 7 6 of 1 0 3
P FI Z E R C O N FI D E N TI A L
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.
8. 5. 3
Occ u p ati o n al E x p os ure
T he i n vesti gat or m ust re p ort a n y  i nsta nce of occ u pati o nal e x p os ure t o Pfizer Safet y wit hi n 2 4 
h o urs of t he i n vesti gat or’s a ware ness usi n g t he C T S A E Re p ort F or m or via 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 s u bject e nrolle 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 .
8. 6
L ac k of Effic ac y
T he i n vesti gat or m ust re p ort si g ns, s y m pt o ms, a n d/ or cli nical se q uelae res ulti n g fr o m lac k o f 
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 . 
8. 7
Me dic ati o n Err o rs
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 s u bject, 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:
Rec or de d o n t he 
Me dic ati o n E rr 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 o n t he C T S A E 
Re p ort F or m or 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
8. 8
A d v er s e E v e nt s of S p e ci al I nt er e st
N ot a p plica ble f or t his st u d y .
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 7 7 of 1 0 3
P FI Z E R C O N FI D E N TI A L
9
S T A TI S TI C S
C o m plete details o n t he statistical met h o ds f or t his st u d y  ma y be f o u n d t he Statistical A nal ysis 
Pla n ( S A P).
9. 1
S a m ple Size
T he st u d y  will ra n d o mize a p pr o xi matel y 2 2 0 s u bjects wit h c o nfir me d e pis o dic mi grai ne per 
treat me nt gr o u p.  Base d o n data fr o m st u d y B H V 3 0 0 0-3 0 5, we esti mate t hat t his will res ult i n 
r o u g hly 2 0 0 s u bjects per treat me nt gr o u p i n t he mi grai ne a nal ysis set.  Ass u mi n g ri me ge pa nt 
pr o vi des r o u g hl y a 1 . 1 da y  a d va nta ge o ver place b o o n t he pri mar y e n d p oi nt, a n d ass u mi n g a 
c o m m o n sta n dar d de viati o n of 3. 5 d a y s, t he n t he st u d y will ha ve r o u g hly 8 0 % p o wer o n t he 
pri mar y  e n d p oi nt at a 2- si de d al p ha le vel of 0. 0 2 5. 
I n st u d y B H V 3 0 0 0-3 0 5, ri me ge pa nt pr o vi de d a 0. 8 da y  a d va nta ge o ver place b o. Wit h dail y 
d osi n g, we e x pect t he treat me nt effect t o i ncrease.  Usi n g t he data fr o m st u d y  B H V 3 0 0 0-3 0 5, t he 
sta n dar d de viati o n of t he pri mar y e n d p oi nt was esti mate d t o be r o u g hl y 3. 5 da y s. 
9. 2
A n al ysis Sets
T he f oll o wi n g a nal ys is sets will be use d i n t his st u d y:

E nr olle d: S u bjects w h o si g n i nf or me d c o nse nt a n d are assi g ne d a s u bject i de ntificati o n 
n u m ber

F ull: S u bjects i n t he e nr olle d a nal ys is set w h o recei ve a ra n d o mize d treat me nt gr o u p 
assi g n me nt (ri me ge pa nt or place b o)

D o u ble - bli n d treat me nt safety:  S u bjects i n t he e nr olle d a nalys is set w h o ta ke 1 d ose of 
d o u ble -bli n d st u d y  dr u g (ri me ge pa nt or place b o)

O pe n -la bel ri me ge pa nt safety:  S u bjects i n t he e nr olle d a nalys is set w h o ta ke 1 d o se of 
o pe n -la bel ri me ge pa nt

D o u ble -bli n d or o pe n -la bel ri me ge pa nt safety:  S u bjects i n t he e nr olle d a nal ysis set w h o ta ke 
1 d ose of d o u ble -bli n d or o pe n -la bel ri me ge pa nt

D o u ble- bli n d treat me nt efficac y : S u bjects i n t he f ull a nal ysis set w h o are ra n d o mize d o nl y  
o nce, a n d ta ke 1 d ose of d o u ble -bli n d st u d y dr u g

Mi grai ne: S u bjects i n t he d o u ble- bli n d treat me nt efficac y  a nalys is set wit h 1 4 da y s of 
e Diar y efficac y data ( n ot necessaril y c o nsec uti ve) i n b ot h t he O bser vati o n P hase a n d 1 
m o nt h ( 4 -wee k i nter va l) i n t he D o u ble-bli n d Treat me nt P hase
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 7 8 of 1 0 3
P FI Z E R C O N FI D E N TI A L
9. 3
St atistic al Met h o ds
Res ults will be s u m marize d b y  treat me nt gr o u p.
9. 3. 1
Effic ac y A n al yses
9. 3. 1. 1
Pri m ar y Effic ac y E n d p oi nt
T he pri mar y  e n d p oi nt will be assesse d f or t he mi grai ne a nal ysis set usi n g a li near mi xe d effects
m o del wit h re peate d meas ures t hat will incl u de t he f oll o wi n g varia bles: c ha n ge fr o m t he 
O bser vati o n P hase i n t he n u m ber of mi grai ne da ys per m o nt h as t he de pe n de nt varia ble; n u m ber 
of mi grai ne da y s per m o nt h i n t he O bser vati o n P hase as a c o variate; a n d fixe d effects f or 
treat me nt gr o u p, ra n d o mizati o n strat u m (i.e., use of pri or pr o p h yl actic mi grai ne me dicati o n 
ge nerall y c o nsi dere d t o ha ve efficac y ), m o nt h, a n d m o nt h-b y -treat me nt gr o u p i nteracti o n. 
Mi grai ne da y s are of a n y pai n i nte nsit y. M o nt hs are defi ne d usi n g 4 -wee k i nter vals as M o nt h 1 
( Wee ks 1 t o 4), M o nt h 2 ( Wee ks 5 t o 8), a n d M o nt h 3 ( Wee ks 9 t o 1 2). T he n u m ber of mi grai ne 
da y s per m o nt h is pr orate d t o 2 8 da ys acc o u nt f or da ys wit h missi n g mi grai ne data. T he 
differe nce esti mate (ri me ge pa nt – place b o) , sta n dar d err or ( S E), p- val ue a n d 9 7. 5 % c o nfi de nce 
i nter val ( CI) will be re p orte d f or t he e ntire D o u ble-bli n d Treat me nt P hase ( Wee ks 1 t o 1 2) f or 
eac h ri me ge pa nt treat me nt gr o u p vers us place b o. 
T he re peate d meas ures err or str uct ure is ass u me d t o be c o nst a nt acr oss treat me nt gr o u ps a n d will 
be i nitiall y s pecifie d as u nstr uct ure d. If t he m o del fails t o c o n ver ge or ca n n ot be fit wit h a n 
u nstr uct ure d err or str uct ure, t he n a heter o ge ne o us T oe plitz err or str uct ure will be atte m pte d. If 
t he T oe plitz fails, t he n a n a ut ore gressi ve or der 1 err or str uct ure will be atte m pte d. 
T he H u ber - W hite r o b ust “sa n d wic h” esti mat or will be use d f or t he esti mati o n of S Es, w hic h 
d oes n ot re q uire c o nsta nt res p o nse varia nces bet wee n treat me nt gr o u ps a n d differe nt baseli ne 
c o variate val ues .
9. 3. 1. 2
Sec o n d ar y Effic ac y E n d p oi nt s
T he pr o p orti o n of s u bjects wit h 5 0 % re d ucti o n fr o m t he O bser vati o n P hase i n t he n u m ber of 
m o derate or se vere mi grai ne da y s per m o nt h o ver t he e ntire D o u ble-bli n d Treat me nt P hase 
( Wee ks 1 t o 1 2) will be a nal yze d usi n g Ma ntel- Hae nszel ris k esti mati o n wit h stratificati o n b y  
ra n d o mizati o n strat u m f or t he mi grai ne a nalys is set. Missi n g data are i m p ute d as n o n-res p o nse 
(i.e., fail ure). T he differe nce esti mate (ri me ge pa nt – place b o), S E, p- val ue a n d 9 7. 5 % CI will be 
re p orte d f or eac h ri me ge pa nt treat me nt gr o u p vers us place b o.
T he mea n c ha n ge fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da y s per m o nt h i n t he 
last 4 wee ks ( Wee ks 9 t o 1 2) of t he Do u ble -bli n d T reat me nt P hase will be assesse d f or t he 
mi grai ne a nal ys is set fr o m t he sa me m o del use d f or t he pri mar y  efficac y e n d p oi nt.   
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 7 9 of 1 0 3
P FI Z E R C O N FI D E N TI A L
T he mea n c ha n ge fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da y s per m o nt h i n t he 
first 4 wee ks ( Wee ks 1 t o 4) of t he Do u ble -bli n d T reat me nt P hase will be assesse d f or t he 
mi grai ne a nal ys is set fr o m t he sa me m o del use d f or t he pri mar y  efficac y e n d p oi nt.
T he mea n n u m ber of ac ute mi grai ne -s pecific me dicati o n d a y s per m o nt h o ver t he e ntire D o u ble -
bli n d T reat me nt P hase ( Wee ks 1 t o 1 2) will be assesse d f or t he mi grai ne a nal ysis set usi n g a 
m o del t hat is si milar i n str uct ure t o t hat use d f or t he pri mar y efficac y e n d p oi nt, e xce pt t hat t he 
n u m ber of ac ute mi grai ne -s pecific me dicati o n da y s per m o nt h is t he de pe n de nt varia ble a n d 
t here is n o c o variate. Ac ute mi grai ne-s pecific me dicati o ns are tri pta ns a n d er g ota mi ne.
T he mea n c ha n ge fr o m baseli ne i n t he M S Q restricti ve r ole f u ncti o n d o mai n sc ore at Wee k 1 2 
wi ll be a nalyz e d f or t he d o u ble -bli n d treat me nt efficac y a nalys is set usi n g a li near m o del t hat 
will i ncl u de t he f oll o wi n g varia bles: Wee k 1 2 c ha n ge fr o m baseli ne i n t he sc ore as t he de pe n de nt 
varia ble; baseli ne sc ore as a c o variate; a n d fi xe d effects f or treat me nt gr o u p a n d ra n d o mizati o n 
strat u m. T he Wee k 1 2 differe nce esti mate (ri me ge pa nt – place b o), S E, p- val ue a n d 9 7. 5 % CI 
will be re p orte d f or eac h ri me ge pa nt treat me nt gr o u p vers us place b o.
9. 3. 1. 3
M ulti plicit y C orrecti o n
T y pe 1 err or is c o ntr olle d b y  s plitti n g t he al p ha le vel bet wee n t he 2 ri me ge pa nt treat me nt gr o u ps 
a n d t he use of hierarc hical testi n g. T he si g nifica nce of t he pri mar y e n d p oi nt f or eac h treat me nt 
gr o u p is e val uate d at a 2-si de d al p ha le vel of 0. 0 2 5. If t he pri mar y  e n d p oi nt is si g nifica nt f or a 
treat me nt gr o u p, t he n t he sec o n dar y efficac y a n d o utc o mes researc h e n d p oi nts f or t hat treatme nt 
gr o u p will be teste d hierarc hicall y, eac h at a 2- si de d al p ha le vel of 0. 0 2 5 , i n t he f oll o wi n g or der:

Pr o p orti o n of s u bjects wit h 5 0 % re d ucti o n fr o m t he O bser vati o n P hase i n t he n u m ber of 
m o derate t o se vere mi grai ne da y s per m o nt h o ver t he e ntire D o u ble-bli n d Treat me nt P hase 
( Wee ks 1 t o 1 2).

Mea n c ha n ge fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da ys per m o nt h i n t he 
last 4 wee ks ( Wee ks 9 t o 1 2) of t he D o u ble-bli n d Treat me nt P hase.

Mea n c ha n ge fr o m t he O bser vati o n P hase i n t he n u m ber of mi grai ne da ys per m o nt h i n t he 
first 4 wee ks ( Wee ks 1 t o 4) of t he D o u ble-bli n d Treat me nt P hase.

Mea n n u m ber of ac ute mi grai ne -s pecific me dicati o n da ys per m o nt h o ver t he e ntire D ou ble -
bli n d Treat me nt P hase ( Wee ks 1 t o 1 2) . Ac ute mi grai ne-s pecific me dicati o ns are tri pta ns a n d 
er g ota mi ne.

Mea n c ha n ge fr o m baseli ne i n t he M S Q restricti ve r ole f u ncti o n d o mai n sc ore at Wee k 1 2 of 
t he D o u ble-bli n d Treat me nt P hase.
9. 3. 2
S afet y A n al yses
Deat hs will be liste d re gar dless of o nset f or t he e nr olle d a nal ys is set.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 8 0 of 1 0 3
P FI Z E R C O N FI D E N TI A L
T he fre q ue ncies of safet y e n d p oi nts will be assesse d descri pti vel y as t he n u m ber a n d perce nta ge 
of s u bjects wit h e ve nts/fi n di n gs se parately f or t he 3 safety a nal ysis set s.
T he fre q ue ncies of t he f oll o wi n g safet y e n d p oi nts will be ta b ulate d o n treat me nt: A Es b y  
i nte nsit y ( mil d, m o derate, se vere, t otal); A Es b y  relati o ns hi p t o st u d y dr u g (relate d, p ossi bl y 
relate d, u nli kely relate d, n ot relate d); S A Es; A Es lea di n g t o st u d y dr u g disc o nti n uati o n ; he patic -
relate d A E s b y i nte nsity;  he patic -relate d A Es lea di n g t o st u d y dr u g disc o nti n uati o n ; la b orat or y 
test a b n or malities b y  t o xicit y gra de; a n d L F T ele vati o ns base d o n f ol d c ha n ges a b o ve U L N, 
i ncl u di n g A L T or A S T > 3 x U L N c o nc urre nt ( o n t he sa me la b orat or y test c ollecti o n date) wit h 
t otal bilir u bi n > 2 x U LN.
T he i n vesti gat ors will deter mi ne t he i nte nsit y of A Es a n d t he relati o ns hi p of A Es t o st u d y dr u g . 
T he i n vesti gat ors’ ter ms will be c o de d usi n g t he latest versi o n of t he Me dical Dicti o nar y  f or 
Re g ulat or y  Acti vities ( Me d D R A). A Es will be ta b ulate d b y  sys te m or ga n class a n d preferre d 
ter m. In ta bles b y i nte nsit y, if a s u bject has a n A E wit h differe nt i nte nsities o ver ti me, t he n o nl y 
t he greatest i nte nsit y will be re p orte d. In ta bles b y relati o ns hip t o st u d y  dr u g, if a s u bject ha s a n
A E wit h differe nt relati o ns hi ps o ver ti me, t he n t he hi g hest de gree of relate d ness t o st u d y dr u g 
will be re p orte d .
L a b orat or y test res ults will be gra de d acc or di n g t o n u meric la b orat or y test criteria i n C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) Versi o n 5. 0 ( 2 0 1 7), if a vaila ble. Ot her wise, 
if C T C A E gra des are n ot a vaila ble, t he n res ults will be gra de d acc or di n g t o n u meric la b orat or y 
test criteria i n Di visi o n of AI D S ( D AI D S) Ta ble f or Gra di n g t he Se verit y of A dult a n d Pe diatric 
A d verse E ve nts C orrecte d Versi o n 2. 1 ( 2 0 1 7) . If a s u bject has a la b orat or y test a b n or malit y wit h 
differe nt t o xicit y  gra des o ver ti me, t he n o nl y t he hi g hest t o xicit y gra de will be re p orte d.
I n a d diti o n, 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 L s a n d a n y re me dial acti o ns ta ke n will be 
s u m marize d.
9. 4
Sc he d ule of A n al yses
T here is 1 pla n ne d data base l oc k at t he e n d of t he st u d y . T he fi nal cli nical st u d y re p ort will be 
pr o d uce d t o s u p p ort re g ulat or y  re q uire me nts after t he  data base l oc k at t he e n d of t he st u d y. N o 
i nteri m a nal ysis is pla n ne d.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 8 1 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 0
E T HI C S A N D R E S P O N SI B I LI TI E S
1 0. 1  
G o o d Cli nic al Pr actice
T his st u d y  will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, G o o d Cli nical Practice ( G C P), 
G o o d La b orat or y  Practice ( G L P), Inter nati o nal C o nfere nce o n Har m o nizati o n g ui deli nes , a n d all 
a p plica ble re g ulati o ns, i ncl u di n g t he Fe deral F o o d, Dr u g a n d C os metic Act, U. S. a p plica ble 
C o de of Fe deral Re g ulati o ns (title 2 1), a n y  In de pe n de nt Et hics C o m mittee (I E C) re q uire me nts 
relati ve t o cli nical st u dies. T he st u d y will als o be c o n d ucte d i n c o m plia nce wit h t he 
rec o m me n dati o ns lai d d o w n i n t he m ost rece nt versi o n of t he Declarati o n of Helsi n ki . T his st u d y 
will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol. T he pr ot oc ol a n d a n y a me n d me nts a n d t he 
s u bject i nf or me d c o nse nt will recei ve I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee 
(IR B/I E C) a p pr o val/fa v ora ble o pi ni o n pri or t o i nitiati o n of t he st u d y .   
T he S p o ns or is res p o nsi bl e f or e ns uri n g t hat all u p date d rele va nt i nf or mati o n relate d t o t he
pr ot oc ol be s u b mitte d t o re g ulat or y  a ut h orities a n d In de pe n de nt Et hics C o m mittees i n
acc or da nce wit h l ocal la ws a n d re g ulati o ns. T his i ncl u des e x pe dite d re p orti n g of s us pecte d
u ne x pecte d s eri o us a d verse reacti o ns per re g ulat or y  g ui deli nes.
All seri o us breac hes m ust be re p orte d t o Pfizer ( or desi g nee) i m me diately.  A Seri o us breac h is a 
breac h of t he c o n diti o ns a n d pri nci ples of G C P i n c o n necti o n wit h t he st u d y or pr ot oc ol, w hic h is 
li kel y to affect, t o a si g nifica nt de gree, t he safet y or p h y sical or me ntal i nte grity of t he s u bjects 
of t he st u d y  or t he scie ntific val ue of t he st u d y. 
St u d y  pers o n nel i n v ol ve d i n c o n d ucti n g t his st u d y will be q ualifie d b y e d ucati o n, trai ni n g, a n d 
e x perie nce t o perf or m t heir res pecti ve tas k(s). 
T his st u d y  will n ot use t he ser vices of st u d y pers o n nel w here sa ncti o ns ha ve bee n i n v o ke d or 
w here t here has bee n scie ntific misc o n d uct or fra u d (e. g., l oss of me dical lice ns ure, de bar me nt).
It is t he S p o ns or’s res p o nsi bilit y t o s u b mit t he pr ot oc ol a n d its a me n d me nts (if a n y), a n d t he 
I CFs t o re g ulat or y  a ut h orities w he n necessar y.
1 0. 2  
D at a a n d S afet y M o nit ori n g C o m mittee
T his st u d y  will n ot ma ke use of a Data Safety M o nit ori n g C o m mittee ( D S M C). T he st u d y  dr u g
ri me gepa nt has bee n teste d a n d f o u n d t o be well t olerate d .  Safet y will be cl osel y m o nit ore d via 
o versi g ht b y t he i n vesti gat ors, S p o ns or a n d C R O/ desi g nee a n d a n I nstit uti o nal Re vie w 
B oar d/I n de pe n de nt Et hics C o m mittee .
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 8 2 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 0. 3
I nf or me d C o nse nt
I n vesti gat ors m ust e ns ure that su bjects , or, i n t h ose sit uati o ns w here c o nse nt ca n n ot be gi ve n by 
su bjects , t heir le gall y acce pta ble re prese ntati ves, are clearly a n d f ull y i nf or me d a b o ut t he 
p ur p ose, p ote ntial ris ks, a n d ot her critical iss ues re gar di n g cli nical st u dies i n w hic h t he y
v ol u nteer t o partici pate. 
Pfizer ( or desi g nee) will pr o vi de t he i n vesti gat or wit h a n a p pr o priate (i.e., Gl o bal or L ocal) 
sa m ple i nf or me d c o nse nt f or m w hic h will i ncl u de all ele me nts re q uire d by I C H, G C P a n d 
a p plica ble re g ulat or y re q uire me nts.  T he sa m ple i nf or me d c o nse nt f or m will a d here t o t he et hical 
pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki.
Bef ore t he p ote ntial s u bject has u n der g o ne a n y st u d y -relate d scree ni n g pr oce d ures, t he nat ure of 
t he st u d y a n d t he p ote ntial ris ks ass ociate d wit h it will be e x plai ne d t o t he s u bject, a n d t he 
s u bject will be gi ve n a n o p p ort u nit y t o as k q uesti o ns t o his or her satisfacti o n. After t he 
q uesti o ns are a ns were d, b ut bef ore pr ocee di n g f urt her, if t he s u bject has n ot o pte d o ut of t he 
C T S data base p orti o n of t he st u d y , t he y m ust rea d, si g n a n d date a n I R B/I E C a p pr o ve d writte n 
i nf or me d c o nse nt f or m f or st u d y partici pati o n a n d C T S data base partici pati o n. T he si g ne d a n d 
date d I C F will be retai ne d at t he I n vesti gat or’s site, wit h a c o p y pr o vi de d t o t he st u d y s u bject a n d 
date will be e ntere d i n his or her C R F or a p pr o priate s y ste m. T he I R B/I E C m ust re vie w a n d 
a p pr o ve all pr ot oc ol versi o ns a n d i nf or me d c o nse nt f or m versi o ns a n d a c o p y  of eac h versi o n of 
t he IR B/I E C a p pr o ve d pr ot oc ol a n d i nf or me d c o nse nt f or m is t o be retai ne d i n t he St u d y Master 
file. A n y  re visi o ns t o t he pr ot oc ol or I C F will be re vie we d a n d a p pr o ve d b y t he I R B/I E C a n d 
s u bjects will be i nf or me d of IC F c ha n ges a n d d oc u me nt c o nti n ui n g c o nse nt b y  si g ni n g a n d 
dati n g t he re vise d versi o n of t he I C F.
If a re vise d I C F is i ntr o d uce d d uri n g t he st u d y , eac h s u bject’s f urt her c o nse nt m ust be o btai ne d. 
T he ne w versi o n of t he I C F m ust be a p pr o ve d b y t he I RB/ I E C, pri or t o s u bse q ue ntl y o btai ni n g 
eac h s u bject’s c o nse nt. 
If i nf or me d c o nse nt is i nitiall y gi ve n by a s u bject’s le gal g uar dia n or le gall y acce pta ble 
re prese ntati ve, a n d t he s u bject s u bse q ue ntly bec o mes ca pa ble of ma ki n g a n d c o m m u nicati n g 
t heir i nf or me d c o nse nt d uri n g t he st u d y, t he n t he c o nse nt m ust a d diti o nall y be o btai ne d fr o m t he 
s u bject. 
T he i nf or me d c o nse nt f or m m ust als o i ncl u de a state me nt t hat Pfizer a n d its re prese ntati ves a n d 
re g ulat or y a ut h orities ma y ha ve direct access t o s u bject rec or ds.  
1 0. 4
C ase Re p ort F or ms
A n I n vesti gat or is re q uire d t o pre pare a n d mai ntai n a de q uate a n d acc urate case hist ories desi g ne d 
t o rec or d all o bser vati o ns a n d ot her data perti ne nt t o t he i n vesti gati o n of eac h st u d y s u bject. Data 
re p orte d o n t he C R F t hat are deri ve d fr o m s o urce d oc u me nts m ust be c o nsiste nt wit h t he s o urce 
d oc u me nts or t he discre pa ncies m ust be e x plai ne d.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 8 3 of 1 0 3
P FI Z E R C O N FI D E N TI A L
Electr o nic C R Fs will be pre pare d f or all data c ollecti o ns fiel ds w he n electr o nic data ca pt ure 
(E D C ) is bei n g use d.   
T he c o nfi de ntialit y of rec or ds t hat c o ul d i de ntif y su bjects m ust be pr otecte d, res pecti n g t he 
pri vac y  a n d c o nfi de ntialit y r ules i n acc or da nce wit h t he a p plica ble re g ulat or y re q uire me nt(s). 
T he In vesti gat or m ust retai n a c o p y of t he C R Fs i ncl u di n g rec or ds of c ha n ges a n d c orrecti o ns.   
If E D C is bei n g use d, si g nat ures will be o btai ne d electr o nicall y a n d a c o py of t he electr o nic 
C R Fs will be pr o vi de d ( or t he data fr o m t he C R Fs) f or f ut ure refere nce.
1 0. 5
Di s s e mi n ati o n of Cli ni c al St u d y  D at a
Pfizer f ulfills its c o m mit me nt t o p u blicl y  discl ose cli nical st u d y res ults t hr o u g h p osti n g t he 
res ults of st u dies o n w w w.cli nicaltrials. g o v ( Cli nical Trials. g o v), t he E u dra C T/ C TIS, 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 ns. I n a d diti o n, Pfizer re p orts st u d y res ults o utsi de of t he re q uire me nts of l ocal 
la ws/re g ulati o ns p urs ua nt t o its S O Ps.
I n all cases, st u dy res ults are re p orte d b y Pfizer 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 h e o utc o me of t he st u d y or t he c o u ntr y i n w hic h t he st u d y 
was c o n d ucte d.
w w w.cli nicaltrials. g o v
Pfizer p osts cli nical trial res ults o n w w w.cli nicaltrials. g o v f or Pfizer s p o ns ore d i nter ve nti o nal 
st u dies (co n d ucte d i n patie nts) t hat e val uate t he safet y  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 b y U S la w.
E u dra C T/ C TI S
Pfizer p osts cli nical trial res ults o n E u dra C T/ C TI S f or 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
Pfizer p osts C S R s y n 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 
Pfiz er 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 yn 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
Pfizer 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 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 8 4 of 1 0 3
P FI Z E R C O N FI D E N TI A L
pr ot oc ol a n d pr ot oc ol a me n d me nts, sa m ple C R Fs, a n d S A Ps. Cli nical d oc u me nts will ha ve 
pers o nall y i de ntifia ble i nf or mati o n a n o n y m ize d.
1 0. 5. 1 D at a s h ari n g
Pf izer pr o vi des researc hers sec ure access t o s u bject
le vel data or f ull C S Rs f or t he p ur p oses of “ b o nafi 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. Pfizer 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. S u bje ct le vel data will be a n o n ymize d i n 
acc or da nce wit h a p plica ble pri vac y  la ws a n d re g ulati o ns. C S Rs will ha ve pers o nally i de ntifia ble 
i nf or mati o n a n o ny m ize d.
Data re q uests are c o nsi dere d fr o m q ualifie d researc hers wit h t he a p pr o priate c o m pete ncies t o 
perf or m t he pr o p ose d a nal yses. Researc h tea ms m ust i ncl u de a bi ostatisticia n. Data will n ot be 
pr o vi de d t o a p plica nts wit h si g nifica nt c o nflicts of i nterest, i ncl u di n g i n di vi d uals re q uesti n g 
access f or c o m mercial/c o m petiti ve or le gal p ur p oses.
1 0. 6
S p o ns or’s Me dic all y Q u alifie d I n di vi d u al 
T he c o ntact i nf or mati o n f or t he s p o ns or’s M QI f or t he st u d y  is d oc u me nte d i n t he st u d y c o ntact 
list l ocate d i n t he pri nci pal i n vesti gat or I SF .
T o facilitate access t o t heir i n vesti gat or a n d t he s p o ns or’s M QI f or st u d y relate d me dical
q uesti o ns or pr o ble ms fr o m n o n -st u d y healt hcare pr ofessi o nals, s u bjects are pr o vi de d wit h a n 
E C C at t he ti me of i nf or me d c o nse nt. T he E C C c o ntai ns, at a mi ni m u m, (a) pr ot oc ol a n d st u d y 
i nter ve nti o n i de ntifiers, ( b) s u bject’s st u d y i de ntificati o n n u m ber, (c) site e mer ge nc y p h o ne 
n u m ber acti ve 2 4 h o urs/ da y , 7 da ys per wee k, a n d ( d) Pfizer Call Ce nter n u m ber.
T he E C C is i nte n de d t o a u g me nt, n ot re place, t he esta blis he d c o m m u nicati o n pat h wa y s bet wee n 
t he s u bject a n d t heir i n vesti gat or a n d site staff, a n d bet wee n t he i n vesti gat or a n d s p o ns or st u d y 
tea m. T he E C C is o nl y t o be use d b y healt hcare pr ofessi o nals n ot i n v ol ve d i n t he researc h st u d y, 
as a mea ns of reac hi n g t he i n vesti gat or or site staff relate d t o t he car e of a s u bject. T he Pfizer 
Call Ce nter n u m ber is t o be use d w he n t he i n vesti gat or a n d site staff are u na vaila ble. T he Pfizer 
Call Ce nter n u m ber is n ot f or use b y t he s u bject directl y;  if a s u bject calls t hat n u m ber directl y, 
t he y will be directe d bac k t o the i n vesti gat or site.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 8 5 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 1
R E C O R D S M A N A G E M E N T A N D R E T E N TI O N
I n acc or da nce wit h t he pri nci ples of G C P a n d G LP, t he st u d y  ma y be i ns pecte d b y re g ulat or y 
a ut h orities, t he S p o ns or a n d C R O. T he S p o ns or is e ntitle d t o access i nf or mati o n a b o ut t he stat us 
of t he st u d y  a n d t o re vie w t he ori gi nal d oc u me nts of t he st u d y .
T he In vesti gat or m ust retai n all st u d y  rec or ds a n d s o urce d oc u me nts f or t he ma xi m u m re q uire d 
b y  t he a p plica ble re g ulati o ns a n d g ui deli nes, or i nstit uti o n pr oce d ures or f or t he peri o d of ti me 
s pecifie d by t he s p o ns or, w hic he ver is l o n ger.  T he In vesti gat or m ust c o ntact t he S p o ns or pri or t o 
destr o y i n g a n y rec or ds ass ociate d wit h t his st u d y. 
Pfizer will n otif y  t he In vesti gat ors w he n t he st u d y files f or t his st u d y  are n o l o n ger nee de d. 
If t he In vesti gat or wit h dra ws fr o m t he st u d y (i.e., retire me nt, rel ocati o n), t he rec or ds s hall be 
tra nsferre d t o a m ut ually a gree d u p o n desi g nee.  N otice of s uc h tra nsfer will be gi ve n i n writi n g 
t o Pfizer
It is t he res p o nsi bilit y of t he In vesti gat or t o e ns ure t hat t he c urre nt d is p ositi o n rec or d of 
i n vesti gati o nal pr o d uct (t h ose s u p plie d b y t he s p o ns or) is mai ntai ne d at eac h st u d y site w here t he 
st u d y dr u g is i n ve nt orie d a n d dis pe nse d.  Rec or ds or l o gs m ust c o m pl y wit h a p plica ble 
re g ulati o ns a n d g ui deli nes a n d s h o ul d i ncl u de:
1.
a m ou nt of st u d y  dr u g recei ve d a n d place d i n st ora ge area
2.
la bel I D n u m ber or batc h n u m ber or Kit n u m ber as s pecifie d f or t he pr ot oc ol
3.
a m o u nt dis pe nse d t o a n d ret ur ne d fr o m eac h s u bject
4.
a m o u nt tra nsferre d t o a n ot her area or site f or dis pe nsi n g or st ora ge if a p plica ble
5.
a m o u nt of dr u g l ost or waste d
6.
a m o u nt destr o ye d at t he site, if a p plica ble
7.
a m o u nt ret ur ne d t o s p o ns or, if a p plica ble
8.
retai n sa m ple d f or bi oa vaila bilit y/ bi oe q ui vale nce, if a p plica ble
9.
rec or d of dates a n d i nitials of pers o n nel res p o nsi ble f or I M dispe nsi n g a n d acc o u nta bilit y   
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 8 6 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 1. 1
S o urce D oc u me nt ati o n
A n I n vesti gat or is re q uire d t o pre pare a n d mai ntai n a de q uate a n d acc urate case hist ories desi g ne d 
t o rec or d all o bser vati o ns a n d ot her data perti ne nt f or all s u bjects o n st u d y.  
If s o urce d oc u me nts are create d t o s u p p ort t he c ollecti o n of st u d y i nf or mati o n, t his m ust be 
retai ne d wit h t he ot her perti ne nt me dical rec or ds f or eac h s u bject f or verificati o n of data p oi nts,
u nless ot her wise i nstr ucte d b y t he S p o ns or or desi g nee t o e nter data directl y  o n t he e C R F.
St u d y  m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d i nt o 
t he C R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m s o urce 
d oc u me nts; t hat t he safet y a n d ri g hts of s u bjects are bei n g pr otecte d; a n d t hat t he st u d y  is bei n g 
c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her st u d y  a gree me nts, 
I C H G C P, a n d all a p plica ble re g ulat or y re q uire me nts.
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/I 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 data d oc u me nts.
1 1. 2
St u d y Files a n d Rec or d Rete nti o n
T he S p o ns or d oes n ot re q uire ori gi nal d oc u me nts t hat ha ve alrea d y bee n sca n ne d a n d e ntere d 
i nt o t he e T M F sys te m t o be f or war de d t o t he S p o ns o r. A n y ori gi nal d oc u me nts (i.e. 1 5 7 2, si g ne d 
fi na ncial discl os ure, si g ne d IC F, etc.) will be retai ne d i n t he re g ulat or y  bi n der at t he st u d y site. 
T he C R O will c o n d uct a fi nal T M F rec o nciliati o n t o e ns ure all st u d y  files a n d re g ulat or y 
d oc u me nts ha ve bee n c orrectl y u pl oa de d t o t he T M F pri or t o t he cl ose or ter mi nati o n of t he 
st u d y. A ny materials or d oc u me nts t o s u p p ort t he cli nical st u d y o utsi de of t he e T M F (i.e. rater 
trai ni n g ta pes) s h o ul d be mai ntai ne d b y t he C R O. T he S p o ns or will be c o ntacte d t o deter mi ne 
w het her t he st u d y d oc u me nts/ materials t hat are retai ne d o utsi de of t he T M F will be f or war de d t o 
t he S p o ns or, destr o ye d or ke pt at t he C R O or at a n ot her facilit y f or a l o n ger peri o d of ti me at t he 
S p o ns or ’s e x pe nse.
T he C R O will mai ntai n a de q uate st u d y rec or ds after c o m pleti o n or ter mi nati o n of st u d y. After 
t hat peri o d, t he S p o ns or will be c o ntacte d t o deter mi ne w het her t he st u dy rec or ds will be 
f or war de d t o t he S p o ns or, destr o ye d or ke pt at C R O or at a n ot her facilit y f or a lo n ger peri o d of 
ti me at t he S p o ns or’s e x pe nse.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 8 7 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 2
A M E N D M E N T S
Pr ot oc ol m o dificati o ns, e xce pt t h ose i nte n de d t o re d uce i m me diate ris k t o st u d y  s u bjects, ma y be 
ma de o nl y  b y Pfizer . A pr ot oc ol c ha n ge i nte n de d t o eli mi nate a n a p pare nt i m me diate hazar d t o 
s u bjects ma y be i m ple me nte d i m me diately . A n y per ma ne nt c ha n ge t o t he pr ot oc ol m ust be 
ha n dle d as a pr ot oc ol a me n d me nt. T he writte n a me n d me nt m ust be s u b mitte d t o t he I R B/I E C 
a n d t he i n vesti gat or m ust a wait a p pr o val bef ore i m ple me nti n g t he c ha n ges. Pfizer will s u b mit 
pr ot oc ol a me n d me nts t o t he a p pr o priate re g ulat or y a ut h orities f or a p pr o val.
If i n t he j u d g me nt of t he I R B/I E C, t he i n vesti gat or, a n d/ or Pfizer , t he a me n d me nt t o t he pr ot oc ol 
s u bsta ntiall y c ha n ges t he st u d y desi g n a n d/ or i ncreases t he p ote ntial ris k t o t he s u bject a n d/ or has 
a n i m pact o n t he s u bject ’s i n v ol ve me nt as a st u d y s u bject, t he c urre ntl y a p pr o ve d writte n 
i nf or me d c o nse nt f or m will re q uire si milar m o dificati o n. I n s uc h cases, i nf or me d c o nse nt will be 
re ne we d f or s u bjects e nr olle d i n t he st u d y before c o nti n ue d partici pati o n.
1 3
P U B LI C A TI O N S P O LI C Y
T he p u blicati o n p olic y  of Pfizer is disc usse d i n t he i n vesti gat or’s Cli nical Researc h A gree me nt.
1 4
S T U D Y DI S C O N TI N U A TI O N 
B ot h Pfizer a n d t he Pri nci pal In vesti gat or reser ve t he ri g ht t o ter mi nate t he st u d y  at t he 
i n vesti gat or’s site at a ny ti me. S h o ul d t his be necessar y, Pfizer or a s pecifie d desi g nee will 
i nf or m t he a p pr o priate re g ulat or y a ut h orities of t he ter mi nati o n of t he st u d y if nee de d a n d t he 
reas o ns f or its ter mi nati o n, a n d t he Pri nci pal I n vesti gat or will i nf or m t he I R B/I E C of t he sa me. 
I n ter mi nati n g t he st u d y, Pfizer a n d t he Pri nci pal I n vesti gat or will ass ure t hat a de q uate 
c o nsi derati o n is gi ve n t o t he pr otecti o n of t he s u bjec ts’ i nterests.
1 5
D A T A P R O T E C TI 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 s u bject data.
S u bjects’ 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 nl y  a ut h orize d st u d y 
staff ha ve access. T he st u d y site will i m ple me nt a p pr o priate tec h nical a n d or ga nizati o nal 
meas ures t o e ns ure t hat t he pers o nal data ca n be rec o vere d i n t he e ve nt of disaster. I n t he e ve nt 
of a p ote ntial pers o nal data breac h, t he st u d y site will be res p o nsi ble f or deter mi ni n g w het her a 
pers o nal data breac h has i n fact occ urre d a n d, if s o, pr o vi di n g breac h n otificati o ns as re q uire d b y  
la w.
T o pr otect t he ri g hts a n d free d o ms of s u bjects wit h re gar d t o t he pr ocessi n g of pers o nal data, 
s u bjects will be assi g ne d a si n gle, s u bject s pecific n u merical c o de. A n y s u bject 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; s u bject na mes will n ot be 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 8 8 of 1 0 3
P FI Z E R C O N FI D E N TI A L
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, 
s u bject s pecific c o de. T he st u d y site will mai ntai n a c o nfi de ntial list of s u bjects w h o partici pate d 
i n t he st u d y, li n ki n g eac h s u bject’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 ntiality of s u bjects’ 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 
b y  tec h nical a n d or ga nizati o nal sec urity 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 S O Ps 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.
W he n s u bject data are t o be delete d, t he i n ves ti 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 bl y delete d fr o m all s yste ms.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 8 9 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 6
A P P E N DI C E S
1 6. 1
A p pe n di x 1 – C o u ntr y S pecific Re q uire me nts
1 6. 1. 1 
It al y
C o ntrace pti ve Use
T he pri mar y  met h o d s h o ul d be a birt h c o ntr ol met h o d w hic h ma y  be c o nsi dere d hi g hly effecti ve.
T his i ncl u des:

C o m bi ne d 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 (c o ntai ni n g 
estr o ge n a n d pr o gester o ne), t ypes: oral, i ntra va gi nal, a n d tra ns der mal.

H or m o nal c o ntrace pti o n ( pr o gester o ne- o nl y) ass ociate d wit h i n hi biti o n of o v ulati o n, 
t ypes: oral, i njecta ble, a n d i m pla nta ble ( pr o gester o ne -o nl y -c o ntai ni n g dr u gs t hat d o n ot 
i n hi bit o v ulati o n a n d pre g na nc y are n ot per mitte d)

Ot her t y pes: i ntra uteri ne de vice (I U D), i ntra uteri ne h or m o ne -releasin g s ys te m (I U S), 
bilateral t u bal occl usi o n, a n d vasect o mize d part ner ( m ust be s ole se x ual part ner a n d ha ve 
s ur gical pr o of of vasect o m y’s s uccess)
T he sec o n dar y  met h o d s h o ul d i ncl u de a barrier met h o d (eg . C o n d o m wit h or wit h o ut s per mici dal 
gel, cer vical ca p , dia p hra g m, or s p o n ge wit h s per mici de)
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 9 0 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 6. 2
A p pe n di x 2 – I n hi bit ors a n d I n d ucers of C Y P 3 A 4 a n d I n hi bit ors of P-gl yc o pr otei n 
( N ot all-i ncl usi ve)
T he f oll o wi n g me dicati o ns a n d me dicati o n c o m bi nati o ns are m o derate t o str o n g i n hi bit ors of 
C Y P 3 A 4 T his list s h o ul d n ot be c o nsi dere d all -i ncl usi ve. As descri be d i n t he st u d y pr ot oc ol, 
c o nc o mita nt use of m o derate t o str o n g C Y P 3 A 4 i n hi bit ors is pr o hi bite d. In di vi d ual dr u g la bels 
s h o ul d be re vie we d f or s pecific i nf or mati o n o n pr o pe nsit y t o ca use m o derate t o str o n g i n hi biti o n 
of t he C Y P 3 A 4 e nz yme f or a s pecific c o m p o u n d.
Str o n g C Y P 3 A 4 i n hi bit ors
B oce pre vir, c o bicistat, c o ni va pta n, da n o pre vir a n d rit o na vir, el vite gra vir a n d rit o na vir, 
i n di na vir a n d rit o na vir, itrac o naz ole, ket oc o naz ole, l o pi na vir a n d rit o na vir, parita pre vir a n d 
rit o na vir a n d ( o m bitas vir a n d/ or dasa b u vir), p osac o naz ole, rit o na vir, sa q ui na vir a n d rit o na vir, 
tela pre vir, ti pra na vir a n d rit o na vir, tr olea n d o myci n, v oric o naz ole, clarit hr o m yci n, nefaz o d o ne, 
nelfi na vir, mife prist o ne, mi befra dil.  
M o der ate C Y P 3 A 4
i n hi bit ors
A m pre na vir, a pre pita nt, cas o pita nt, ci meti di ne, ci pr ofl o xaci n, diltiaze m, dr o ne dar o ne, 
er yt hr o m y ci n, fl uc o naz ole, Se ville ora n ge, isa v uc o naz ole, lefa m uli n, leter m o vir, net u pita nt, 
ra v uc o naz ole, vera pa mil
T he f oll o wi n g me dicati o ns a n d s u p ple me nts are m o derate t o str o n g i n d ucers of C Y P 3 A 4. As 
descri be d i n t he st u d y pr ot oc ol, c o nc o mita nt use of m o derate t o str o n g C Y P 3 A 4 i n d ucers is 
pr o hi bite d. T his list s h o ul d n ot be c o nsi dere d all- i ncl usi ve. I n di vi d ual pr o d uct la bels s h o ul d be 
re vie we d f or s pecific i nf or mati o n o n pr o pe nsit y t o ca use m o derate t o str o n g i n d ucti o n of t he
C Y P 3 A 4 e nz y me f or a s pecific c o m p o u n d.
M o der ate C Y P 3 A 4 i n d ucers
B ose nta n, rifa b uti n, m o dafi nil, nafcilli n, efa vire nz, etra viri ne, l o pi na vir
T he f oll o wi n g me dicati o ns are str o n g P -gl yc o pr otei n ( P -g p) i n hi bit ors as descri be d i n t he st u dy 
pr ot oc ol, c o nc o mita nt use of str o n g P- g p i n hi bit ors is pr o hi bite d. T his list s h o ul d n ot be 
c o nsi dere d all -i ncl usi ve. I n di vi d ual pr o d uct la bels s h o ul d be re vie we d f or s pecific i nf or mati o n 
o n pr o pe nsit y  t o str o n gly i n hi bit P -g p f or a s pecific c o m p o u n d .
Str o n g P -g p I n hi bit ors
A m i o dar o ne, clarit hr o m yci n, c ycl os p ori ne, dr o ne dar o ne, itrac o naz ole, la pati ni b, pr o pafe n o ne, 
q ui ni di ne, rit o na vir, vera pa mil
Str o n g C Y P 3 A 4 i n d ucers
Car ba maze pi ne, p he n yt oi n, rifa m pi n, St. J o h n’s W ort, rifa pe nti ne, p he n o bar bital, a pal uta mi de
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 9 1 of 1 0 3
P FI Z E R C O N FI D E N TI A L
Res o urces: 
htt ps:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI nteracti
o ns L a beli n g/ uc m 0 9 3 6 6 4. ht m #ta ble 3 - 2
htt ps:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI nteracti
o ns L a beli n g/ uc m 0 9 3 6 6 4. ht m #ta ble 3 - 3
Hac ha d H, Ra g ue nea u -Majlessi I , Le v y R H. A usef ul t o ol f or dr u g i nteracti o n e val uati o n: t he 
U ni versit y  of Was hi n gt o n Meta b olis m a n d Tra ns p ort Dr u g I nteracti o n Data base. H u m 
Ge n o mics. 2 0 1 0 Oct; 5( 1): 6 1- 7 2.
U ni versit y  of Was hi n gt o n Meta b olis m a n d Tra ns p ort Dr u g I nteracti o n Data base accessi ble at 
htt ps:// w w w. dr u gi nteracti o ni nf o. or g/
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 9 2 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 6. 3
A p pe n di x 3 – Defi niti o n of Mi gr ai ne D a ys
Mi gr ai ne D a y:
A n y cale n dar da y i n w hic h t he s u bject e x perie nces a q ualifie d mi grai ne
hea dac he ( o nset, c o nti n uati o n, or rec urre nce of t he mi grai ne hea da c he). A q ualifie d mi grai ne 
hea dac he is defi ne d as a mi grai ne wit h or wit h o ut a ura, lasti n g f or ≥ 3 0 mi n utes, a n d meeti n g 
eit her Criteria A or B bel o w:
A.
≥ 2 of t he f oll o wi n g pai n feat ures:

U nilateral l ocati o n

P ulsati n g q ualit y (t hr o b bi n g)

M o derate or se vere pai n i nte nsit y

A g gra vati o n b y or ca usi n g a v oi da nce of r o uti ne p h ysical acti vit y (e. g. wal ki n g or cli m bi n g 
stairs)
B.
≥ 1 of t he f oll o wi n g ass ociate d s y m pt o ms:

Na usea a n d/ or v o miti n g

P h ot o p h o bia a n d p h o n o p h o bia
If t he s u bject t o o k a mi grai ne-s pecific me dicati o n (i.e., tri pta n) d uri n g a ura or t o treat hea dac he, 
t he n it will be c o u nte d as a mi grai ne da y re gar dless of t he d urati o n a n d pai n feat ures/ass ociate d 
s ym pt o ms. Use of er g ota mi ne me dicati o n is pr o hi bite d t hr o u g h o ut t he e ntire d urati o n of t he 
st u d y. H o we ver, use of t his me dicati o n, if ta ke n f or mi grai ne treat me nt, m ust be d oc u me nte d f or 
t he p ur p oses of assessi n g mi grai ne da ys a n d m ust be ca pt ure d as a pr ot oc ol de viati o n.  
A m o derate t o se vere mi grai ne da y  is a mi grai ne da y wit h a mi grai ne re p orte d wit h m o derate or 
se vere pai n i nte nsit y.
He a d ac he D a y: A n y cale n dar da y i n w hic h t he s u bject e x perie nces a q ualifie d hea dac he (i nitial 
o nset, c o nti n uati o n, or rec urre nce of t he hea dac he). A q ualifie d hea dac he is defi ne d as:

a q ualifie d mi grai ne hea dac he (i ncl u di n g a n a ura-o nl y  e ve nt t hat is treate d wit h ac ute 
mi grai ne -s pecific me dicati o n), or

a q ualifie d n o n - mi grai ne hea dac he, w hic h is a hea dac he t hat lasts ≥ 3 0 mi n utes a n d is 
n ot a q ualifie d mi grai ne hea dac he, or

a hea dac he of a n y d urati o n f or w hic h ac ute hea dac he treat me nt is a d mi nistere d.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 9 3 of 1 0 3
P FI Z E R C O N FI D E N TI A L
Ac ute Mi gr ai ne -s pecific Me dic ati o n D a y: A n y cale n dar da y d uri n g w hic h t he s u bject t o o k a 
mi grai ne -s pecific me dicati o n (i.e., tri pta n or er g ota mi ne). Use of er g ota mi ne me dicati o n is 
pr o hi bite d t hr o u g h o ut t he e ntire d urati o n of t he st u d y , h o we ver re p orti n g of a n y use of 
er g ota mi ne me dicati o n is re q uire d f or t he p ur p ose of defi ni n g mi grai ne da ys. 
M o nt hl y e Di ar y D at a:
Data c ollecte d b y t he e Diar y base d o n t he s u bject’s m o nt hl y
i n vesti gati o nal pr o d uct d osi n g sc he d ule w he n at least 1 4 da ys of e Diar y data are c ollecte d wit hi n 
t hat i nter val. M o nt hl y fre q ue nc y meas ure me nts will be pr orate d t o 2 8- d a y  e q ui vale nts.
Mi gr ai ne Att ac k:
A n e pis o de of a n y q ualifie d mi gr ai ne hea dac he. T he f oll o wi n g r ules will be
use d t o disti n g uis h a n attac k of l o n g d urati o n fr o m t w o attac ks, or t o disti n g uis h bet wee n attac ks 
a n d rela pses:
a)
A mi grai ne attac k t hat is i nterr u pte d b y slee p, or te m p oraril y re mits, a n d t he n rec urs 
wit hi n 4 8 h o u rs (i.e., ≤ 4 8 h o urs bet wee n t he start of t he mi grai ne attac k t o t he ti me of 
t he rec urre nce) will be c o nsi dere d as o ne attac k a n d n ot t w o.
b)
A n attac k treate d s uccessf ull y  wit h me dicati o n b ut wit h rela pse wit hi n 4 8 h o urs (i .e., 
≤ 4 8 h o urs bet wee n t he start o f t he mi grai ne attac k t o t he ti me of t he rec urre nce) will 
be c o nsi dere d as o ne attac k.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 9 4 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 6. 4
A p pe n di x 4 – C ate g ories of Mi gr ai ne Pre ve nti o n Me dic ati o ns ( Refere nce f or 
E xcl usi o n Criteri a 7 h)
N o t hera pe utic res p o nse wit h > 2 of t he f oll o wi n g 8 me dicati o n cate g ories f or pr o p h yl actic 
treat me nt of mi grai ne after a n a de q uate t hera pe utic trial. T hese me dicati o n cate g ories are:
○
C ate g or y 1 : A ntie pile ptics (f or e xa m ple: d i val pr oe x s o di u m, s o di u m val pr oate)
○
C ate g or y 2 : A ntie pile ptics (f or e xa m ple: t o pira mate, car b a maze pi ne, ga ba pe nti n )
○
C ate g or y 3 : Beta bl oc kers (f or e xa m ple: ate n ol ol, bis o pr ol ol, met o pr ol ol, na d ol ol, 
ne bi v ol ol, pi n d ol ol, pr o pra n ol ol, ti m ol ol)
○
C ate g or y 4 : Tric yclic a nti de pressa nts (f or e xa m ple: a mitri pt y li ne, n ortri pt yli ne, 
pr otri pt y li ne)
○
C ate g or y 5 : Ser ot o ni n-n ore pi ne p hri ne re u pta ke i n hi bit ors (f or e xa m ple: ve nlafa xi ne, 
des ve nlafa xi ne, d ul o xeti ne, mil naci pra n)
○
C ate g or y 6 : Calci u m c ha n nel bl oc kers (f or e xa m ple: f l u narizi ne, vera pa mil)
○
C ate g or y 7 : A n gi ote nsi n c o n verti n g e nz y me ( A C E) i n hi bit or/a n gi ote n si n rece pt or 
bl oc ker ( A R B): (f or e xa m ple: l isi n o pril, ca n desarta n)
○
C ate g or y 8 : B ot uli n u m t o xi n i njecti o ns : (f or e xa m ple: B ot o x ® [ o na b ot uli n u mt o xi n A])
N o t hera pe utic res p o nse is defi ne d as n o r e d ucti o n i n hea dac he fre q ue nc y, d urati o n, or i nte nsit y 
after a d mi nistrati o n of t he me dicati o n f or at least 6 wee ks at t he ge nerall y  acce pte d t hera pe utic 
d ose(s) base d o n t he i n vesti gat or’s assess me nt.
T he f oll o wi n g sce nari os d o n ot c o nstit ute lac k of t hera pe utic res p o nse:
○
Lac k of s ustai ne d res p o nse t o a me dicati o n
○
Fail ure t o t olerate a t hera pe utic d ose
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 9 5 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 6. 5
A p pe n di x 5 – Me dic ati o ns
for Mi gr ai ne Pre ve nti o n Ge ner all y C o nsi dere d t o H a ve 
Effic ac y

A nti h y perte nsi ves
o
Bet a bl ockers

Pr o pr a n ol ol

Met o pr ol ol

N a d ol ol

Ate n ol ol

Ti m ol ol

Bis o pr ol ol
o
C alci u m c h a n nel bl ockers

Ver a p a mil

Fl u n arizi ne

Nife di pi ne

Ni m o di pi ne
o
A C E i n hi bit ors/ A R Bs

Lisi n o pril

C a n des art a n

A nti de press a nts
o
Tricyclic a nti de press a nt

A mitri ptyli ne

N ortri ptyli ne
o
Ser ot o ni n -n ore pi ne p hri ne re u pt ake i n hi bit or

Ve nl af axi ne

Desve nl af axi ne

A nti -e pile ptics
o
Div al pr oex s o di u m, s o di u m v al pro ate
o
T o pir a m ate
o
G a b a pe nti n

C G R P a nt a g o nists
o
Ere n u m a b ( Ai m ovi g ® )
o
Fre m a nez u m a b ( Aj ovy ® )
o
G alc a nez u m a b ( E m g ality ® )
o
E pti nez u m a b ( Vye pti ® )
o
Ri me ge p a nt ( N urtec ® )
o
At o ge p a nt ( Q uli pt a T M )
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 9 6 of 1 0 3
P FI Z E R C O N FI D E N TI A L

O n a b ot uli n u mt o xi n A ( B ot ox ® )

B utter b ur r o ot or e xtracts

Fe verfe w

Piz otife n 

O xetr o ne
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 9 7 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 6. 6
A p pe n di x 6 - E C G Fi n di n gs of P ote nti al Cli nic al C o ncer n
E C G Fi n di n gs T h at M a y
Q u alif y as A Es

Mar ke d si n us bra d yc ar dia (rate < 4 0 b p m) lasti n g mi n utes.

Ne w P R i nter val pr ol o n gati o n > 2 8 0 ms.

Ne w pr ol o n gati o n of Q Tc F t o > 4 8 0 ms (a bs ol ute).

Ne w pr ol o n gati o n of Q Tc F b y > 6 0 ms fr o m baseli ne.

Ne w ‑ o nset atrial fl utter or fi brillati o n, wit h c o ntr olle d ve ntric ular res p o nse rate: ie, 
rate < 1 2 0 b p m.

Ne w ‑ o nset ty pe I sec o n d‑ de gree ( We nc ke bac h) A V bl oc k of > 3 0-sec o n d d urati o n.

Fre q ue nt P V Cs, tri plets, or s h ort i nter vals ( < 3 0 sec o n ds) of c o nsec uti ve ve ntric ular 
c o m ple xes.
E C G Fi n di n gs T h at M a y
Q u alif y as S A Es

Q Tc F pr ol o n gati o n > 5 0 0 ms.

A bs ol ute val ue of Q Tc F > 4 5 0 ms A N D Q Tc F c ha n ge fr o m baseli ne > 6 0 ms.

Ne w S T ‑ T c ha n ges s u g gesti ve of m yocar dial isc he mia.

Ne w ‑ o nset L B B B ( Q R S c o m ple x > 1 2 0 ms).

Ne w ‑ o nset ri g ht b u n dle bra nc h bl oc k ( Q R S c o m ple x > 1 2 0 ms).

S y m pt o matic bra d y car dia. 

As y st ole

I n a wa ke, sy m pt o m ‑free s u bjects i n si n us r h yt h m, wit h d oc u me nte d asys t olic pa uses 
≥3 sec o n ds or a n y esca pe rate < 4 0 b p m, or wit h a n esca pe r h y t h m t hat is bel o w t he 
A V n o de;

I n a wa ke, sy m pt o m ‑free s u bjects wit h atrial fi brillati o n a n d bra d yc ar dia wit h 1 or 
m ore as ys t olic pa uses of at least 5 sec o n ds or l o n ger. 

Atrial fl utter or fi brillati o n, wit h ra pi d ve ntric ular res p o nse rate: ra pi d = rate > 1 2 0 
b p m.

S ustai ne d s u pra ve ntric ular tac h yc ar dia (rate > 1 2 0 b p m) (“s ustai ne d” = s h ort d urati o n 
wit h rele va nt s y m pt o ms or lasti n g > 1 mi n ute).

Ve ntric ular r h y t h ms > 3 0 sec o n d d urati o n, i ncl u di n g i di o ve ntric ular r h yt h m ( H R < 4 0 
b p m), accelerate d i di o ve ntric ular r h yt h m ( H R 4 0 b p m t o < 1 0 0 b p m), a n d 
m o n o m or p hic/ p ol y m or p hic ve ntric ular tac h y car dia ( H R > 1 0 0 b p m [s uc h as t orsa des 
de p oi ntes]).

T y pe II sec o n d‑ de gree ( M o bitz II) A V bl oc k.

C o m plete (t hir d ‑ de gree) heart bl oc k.
E C G Fi n di n gs T h at Q u alif y as S A Es

C ha n ge i n patter n s u g gesti ve of ne w m y ocar dial i nfarcti o n. 

S ustai ne d ve ntric ular tac h y arr h yt h mias ( > 3 0-sec o n d d urati o n).
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 9 8 of 1 0 3
P FI Z E R C O N FI D E N TI A L

Sec o n d ‑ or t hir d‑ de gree A V bl oc k re q uiri n g pace ma ker place me nt.

As y st olic pa uses re q uiri n g pace ma ker place me nt.

Atrial fl utter or fi brillati o n wit h ra pi d ve ntric ular res p o nse re q uiri n g car di o versi o n.

Ve ntric ular fi brillati o n/fl utter.

At t he discreti o n of t he i n vesti gat or, a n y arr h yt h mia c lassifie d as a n a d verse 
e x perie nce.
T he maj or e ve nts of p ote ntial cli nical c o ncer n liste d a b o ve are rec o m me n de d as “alerts” or n otificati o ns fr o m 
t he c ore E C G la b orat or y t o t he i n vesti gat or a n d Pfizer st u d y tea m, a n d n ot t o be c o nsi dere d as all-i ncl usi ve of 
w hat is t o be re p orte d as A Es/ S A Es.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 9 9 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 6. 7
A p pe n di x 7 – Pr ot oc ol A me n d me nt Hist or y
Versi o n N u m ber
Brief Descri pti o n of C ha n ge
Date
Versi o n 1. 0 -
Ori gi nal
N ot A p plica ble
2 2 N o ve m ber 2 0 2 1
Versi o n 2. 0
U p date d f or mat of “ S u m mar y of C ha n ges” pa ge.
U p date d Secti o n 4. 3, t he Sc he d ule of Assess me nts / Ta ble 1 t o 
r e mo ve t he refere nce t o “( vital si g ns o nl y)” fr o m t he Vital 
Si g ns/ P h ysical Meas ure me nts pr oce d ure at: Baseli ne 
( Ra n d o mizati o n) Visit, Wee k 2 Visit, a n d F oll o w-u p Wee k 2 a n d 
F oll o w -u p Wee k 8 Visits.
U p date d Secti o n 4. 3, t he Sc he d ule of Assess me nts / Ta ble 2 t o 
r e mo ve t he refere nce t o “( vital si g ns o nl y)” fr o m t he Vital 
Si g ns/ P h ysical Meas ures pr oce d ure at Wee k 1 4 Visit, a n d 
F oll o w -u p Wee k 2 a n d F oll o w -u p Wee k 8 Visits.
U p date d Secti o n 5. 2, i ncl usi o n c riteria # 3 a n d re m o ve d refere nce 
t o u n dersta n di n g E n glis h a n d S pa nis h.
U p date d Secti o n 5. 3, e xcl usi o n criteria # 7, se parati n g e xcl usi o n 
criteria # 7i a n d # 7j.
C orrecte d i nc o nsiste ncies a n d t y p o gra p hical err ors t hr o u g h o ut t he 
pr ot oc ol.
0 4 Ja n uar y 2 0 2 2
V ersi o n 3. 0
U p date d Secti o n 4. 3, t he Sc he d ule of Assess me nts / Ta ble 1 a n d 
Ta ble 2 t o clarif y p h ysical e xa m pr oce d ure a n d H b A 1c c ollecti o n.
U p date d Secti o n 5. 3, e xcl usi o n criteria 5 b a n d re m o ve d refere nce 
t o “at scree ni n g”.
1 7 Marc h 2 0 2 2
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 0 0 of 1 0 3
P FI Z E R C O N FI D E N TI A L
Versi o n N u m ber
Brief Descri pti o n of C ha n ge
Date
U p date d Secti o n 5. 3, e xcl usi o n criteri o n; 2l, 6a -6e, a n d 7e t o 
clarif y restricti o ns ar o u n d pr o hi bite d me dicati o n use.
U p date d Secti o n 5. 3 a n d re m o ve d e xcl usi o n criteria 7 k.
U p date d Secti o n 5. 4 t o clarif y restricti o ns ar o u n d pr o hi bite d 
me dicati o n use.
U p date d Secti o n 6. 2. 4. 1 t o clarif y H b A 1c c ollecti o n.
U p date d Secti o n 9. 2 t o clarif y o ne of t he A nal ysis Sets.
C orrecte d i nc o nsiste ncies a n d t y p o gra p hical err ors t hr o u g h o ut t he 
pr ot oc ol.
Versi o n 4. 0
U p date d Secti o n 5. 3, e xcl usi o n criteri o n 6c t o clarif y l o w d ose 
as piri n use f or car di o vasc ular pr o p h yla xis.
U p date d Secti o n 5. 3, e xcl usi o n criteri o n 7 g t o i ncl u de a d diti o nal 
st u dies; B H V 3 0 0 0-4 0 6 a n d B H V 3 0 0 0 -4 0 7.
U p date d Secti o n 5. 3, a d de d e xcl usi o n criteri o n 7 k.
U p date d Secti o n 5. 4, # 1 4 t o clarif y l o w d ose as piri n use f or 
car di o vasc ular pr o p h yla xis.
0 1 J ul y 2 0 2 2
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 0 1 of 1 0 3
P FI Z E R C O N FI D E N TI A L
Versi o n N u m ber
Brief Descri pti o n of C ha n ge
Date
U p date d Secti o n 6. 6, C T S data base t o clarif y t hat t his a p plies 
o nl y “ w here a p pr o ve d l ocall y”.
U p date d secti o n 8. 2. 1 t o c orrect t y p o gra p hical err or a n d ali g n t he 
c ollecti o n of N o n -seri o us A d verse E ve nts t hr o u g h t he F oll o w - u p 
Wee k 2 Visit as n ote d i n Ta ble 1 a n d Ta ble 2 f o ot n otes.
U p date d secti o n 9. 2 t o clarif y t he defi niti o n of t he “ Mi grai ne” 
A nal ysis Set.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 0 2 of 1 0 3
P FI Z E R C O N FI D E N TI A L
1 7 R E F E R E N C E S
1.
Marc us R, G oa ds b y PJ, D o dic k D, St oc k D, Ma n os G, Fisc her T Z. B M S -9 2 7 7 1 1 f or t he ac ute 
treat me nt of mi grai ne: a d o u ble-bli n d, ra n d o mize d, place b o c o ntr olle d, d ose -ra n gi n g trial. 
Ce p h al al gi a. 2 0 1 4; 3 4( 2): 1 1 4 - 1 2 5.
2.
B H V 3 0 0 0 - 3 0 5-Fi nal -Wee k - 1 2-C S R. A P hase 2/ 3, Ra n d o mize d, D o u ble -bli n d, Place b o -
c o ntr olle d St u d y t o E va l uate t he Efficac y a n d Safet y of Ri me ge pa nt i n Mi grai ne Pre ve nti o n. 
Bi o h ave n P h ar m ace utic als, I nc;. 2 0 2 0.
3.
B H V 3 0 0 0 - 2 0 1-C S R. A M ultice nter, O pe n -la bel, L o n g-ter m Safet y St u d y of B H V-3 0 0 0 i n t he 
Ac ute Treat me nt of Mi grai ne. Bi o h ave n P h ar m ace utic als, I nc;. 2 0 1 9.
4.
Hea dac he Classificati o n C o m mittee of t he I nter nati o nal Hea dac he S ociet y (I H S) T he 
I nter nati o nal Classificati o n of Hea dac he Dis or ders, 3r d e diti o n. Ce p h al al gi a. 2 0 1 8; 3 8( 1): 1 - 2 1 1.
5.
E d vi nss o n L. Bl oc ka de of C G R P rece pt ors i n t he i ntracra nial vasc ul at ure: a ne w tar get i n t he 
treat me nt of hea dac he. Ce p h al al gi a. 2 0 0 4; 2 4( 8): 6 1 1 - 6 2 2.
6.
Lasse n L H, Ha dersle v P A, Jac o bse n V B, I verse n H K, S perli n g B, Olese n J. C G R P ma y pla y a 
ca usati ve r ole i n mi grai ne. Ce p h al al gi a. 2 0 0 2; 2 2( 1): 5 4 - 6 1.
7.
G oa ds b y PJ, E d vi nss o n L, E k ma n R. Vas oacti ve pe pti de release i n t he e xtracere bral circ ulati o n of 
h u ma ns d uri n g mi grai ne hea dac he. A n n als of ne ur ol o gy. 1 9 9 0; 2 8( 2): 1 8 3 - 1 8 7.
8.
G oa ds b y PJ, E d vi nss o n L. T he tri ge mi n o vasc ular s yste m a n d mi grai ne: st u dies c harac terizi n g 
cere br o vasc ular a n d ne ur o pe pti de c ha n ges see n i n h u ma ns a n d cats. A n n als of ne ur ol o gy. 
1 9 9 3; 3 3( 1): 4 8 - 5 6.
9.
Peterse n K A, Lasse n L H, Bir k S, Les k o L, Olese n J. BI B N 4 0 9 6 B S a nta g o nizes h u ma n al p ha -
calcit o ni n ge ne relate d pe pti de -i n d uce d hea dac he a n d e xtracere bral arter y dilatati o n. Cli n 
P h ar m ac ol T her. 2 0 0 5; 7 7( 3): 2 0 2 - 2 1 3.
1 0.
A P A. Di a g n ostic a n d St atistic al M a n u al of Me nt al Dis or ders, 5t h E diti o n: D S M -5 5t h E diti o n.
5t h e d: A merica n Ps yc hiatric P u blis hi n g; 2 0 1 3.
1 1.
P os ner K, Br o w n G K, Sta nle y B, et a l. T he C ol u m bia-S uici de Se verit y Rati n g Scale: i nitial 
vali dit y a n d i nter nal c o nsiste nc y fi n di n gs fr o m t hree m ultisite st u dies wit h a d olesce nts a n d a d ults. 
A m J Psyc hi atry. 2 0 1 1; 1 6 8( 1 2): 1 2 6 6 - 1 2 7 7.
1 2.
P os ner K, Bre nt D, L ucas C, et al. C ol u m bia - S uici de Se verit y Rati n g Scale. T he Rese arc h 
F o u n d ati o n f or Me nt al Hy gie ne, i nc. 2 0 0 9; Versi o n 1/ 1 4/ 0 9.
1 3.
Marti n B C, Pat ha k D S, S harf ma n MI, et al. Vali dit y a n d relia bilit y of t he mi grai ne -s pecific 
q ualit y of life q uesti o n naire ( M S Q Versi o n 2. 1). He a d ac he. 2 0 0 0; 4 0( 3) : 2 0 4- 2 1 5.
1 4.
G u y W. E C D E U Assess me nt Ma n ual f or ps yc h o p har mac ol o g y. I n: R oc k ville, M d. : U. S. De pt. of 
Healt h, E d ucati o n, a n d Welfare, P u blic Healt h Ser vice, Alc o h ol, Dr u g A b use, a n d Me ntal Healt h 
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

Pr ot oc ol B H V 3 0 0 0 -4 0 4 (C 4 9 5 1 0 1 0 ) Versi o n 5. 0
A P hase 4 Ra n d o m ize d, D o u ble-bli n d, Place b o -c o ntr olle d St u d y t o E val uate t h e Efficac y 
a n d Safet y of Ri me ge pa nt i n E pis o dic Mi grai ne Pre ve nti o n
wit h M ulti ple D osi n g Re gi me ns
Pa ge 1 0 3 of 1 0 3
P FI Z E R C O N FI D E N TI A L
A d mi nistrati o n, Nati o nal I nstit ute of Me ntal Healt h, Ps yc h o p har mac ol o g y Researc h Bra nc h, 
Di visi o n of E xtra m ural Researc h Pr o gra ms; 1 9 7 6.
0 9 0 1 7 7 e 1 9 d d 9 5 d a c\ A p pr o v e d\ A p pr o v e d O n: 2 7- J u n- 2 0 2 3 1 2: 1 3 ( G M T)

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