A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Followed by an Open-Label Extension to Evaluate the Efficacy and Safety of Fremanezumab for Preventive Treatment of Migraine in Patients With Major Depressive Disorder
Phase: PHASE4
Conditions: Migraine, Major Depressive Disorder
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

 
 
 
Cli nic al St u d y Pr ot oc ol  
 
 
A M ultice nt er, Ra n d o mize d, D o u ble -Bli n d, Pla ce b o-C o ntr olle d, Parallel -Gr o u p 
St u d y F oll o we d b y a n O pe n -La bel E xte nsi o n t o E val uate t he Efficac y a n d Safet y 
of Fre ma nez u ma b f or Pre ve nti ve Treat me nt of Mi grai ne i n Patie nts wit h Maj or 
De pressi ve Dis or der  
 
 
St u d y N u m ber T V 4 8 1 2 5 - M H-4 0 1 4 2  
 
 
N C T 0 4 0 4 1 2 8 4  
 
 
Pr ot oc ol wit h A me n d me nt 0 4  A p pr o val Date: 0 4 Ma y 2 0 2 0  

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1  
 
 
 
Cli nic al St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y N u m ber  T V 4 8 1 2 5 -M H -4 0 1 4 2  
A M ultice nter, R a n d o mize d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, P ar all el -Gr o u p St u d y 
F oll o w e d b y a n O pe n -L a bel E xte nsi o n t o E v al u ate t he Effic ac y a n d S afet y of 
Fre m a nez u m a b f or Pre ve nti ve Tre at me nt of Mi gr ai ne i n P atie nts wit h M aj or De pressi ve 
Dis or der  
A R a n d o miz e d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d St u d y o n Effic ac y a n d S afet y of 
Fre m a nez u m a b  f or Pre ve nti n g Mi gr ai ne i n P atie nts wit h M D D 
A St u d y t o Assess if Fre m a nez u m a b is Effecti ve i n Pre v e nti n g Mi gr ai ne i n P atie nts wit h 
M aj or De pressi ve Dis or der  
Effic ac y a n d S afet y St u d y ( P h ase 4)  
I N D n u m ber: 1 0 6 5 3 3; 
N D A n u m ber: N ot a p plic a ble;   B L A n u m ber: 7 6 1 0 8 9;  
E u dr a C T n u m ber: 2 0 1 9 -0 0 1 9 8 9 -1 5  
E M A Decisi o n n u m ber of Pe di atric I n vesti g ati o n Pl a n: N ot a p plic a ble  
Article 4 5 o r 4 6 of 1 9 0 1/ 2 0 0 6 d oes n ot a p pl y  
 
Pr ot oc ol A p pr o v al D ate: 0 3 M a y  2 0 1 9  
Pr ot oc ol wit h A me n d me nt  0 1  A p pr o v al D ate: 0 4 J u ne 2 0 1 9  
Pr ot oc ol wit h A me n d me nt  0 2  A p pr o v al D ate: 1 0 Oct o ber 2 0 1 9  
Pr ot oc ol wi t h A me n d me nt 0 3  A p pr o v al  D ate: 0 4 N o ve m ber 2 0 1 9  
Pr ot oc ol wit h A me n d me nt 0 4 A p pr o v al D ate: 0 4  M a y  2 0 2 0  
S p o ns or  
Te v a Br a n de d P h ar m ace utic al  
Pr o d ucts R & D, I nc.  
1 4 5 Br a n d y wi ne P ar k w a y,  
West C hester , Pe n ns yl v a ni a 1 9 3 8 0  
U nite d St ates of A meric a  
I nf or m ati o n re g ar di n g cli nic al l a b or at ories a n d ot her de p art me nts a n d i nstit uti o ns is 
f o u n d i n A p pe n di x  A  
C O VI D -1 9 p a n de mic -rel ate d o per ati o n al u p d ates are pr o vi de d i n A p pe n di x  P   
T his cli nical st u d y will be c o n d ucte d i n acc or da nce wit h c urre nt G o o d Cli nical Practice ( G C P) as directe d 
b y t he pr o visi o ns of t he I nter nati o nal C o u ncil f or Har m o nisati o n (I C H); U nite d States ( U S) C o de of 
Fe deral Re g ulati o ns ( C F R), a n d E ur o pea n U ni o n ( E U) Directi ves a n d Re g ulati o ns (as a p plica ble i n t he 
re gi o n of t he st u d y); nati o nal c o u ntr y le gislati o n; a n d t he s p o ns or’s Sta n dar d O perati n g Pr oce d ures 
( S O Ps). 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
2  
 
C o nfi de nti alit y St ate me nt  
T his d oc u me nt c o ntai ns c o nfi de ntial a n d pr o prietar y i nf or mati o n (i ncl u di n g c o nfi de ntial c o m mercial 
i nf or mati o n p urs ua nt t o 2 1 C F R § 2 0. 6 1) a nd is a c o nfi de ntial c o m m u nicati o n of T e va Bra n de d 
P har mace utical Pr o d ucts Gl o bal Me dical Affairs, I nc. a n d/ or its affiliates. T he reci pie nt a grees t hat n o 
i nf or mati o n c o ntai ne d herei n ma y be p u blis he d or discl ose d wit h o ut writte n a p pr o val fr o m t he s p o ns or. 
© 2 0 2 0  T e va Bra n de d  P har mace utical Pr o d ucts R & D, I nc. All ri g hts reser ve d.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
3  
 
A M E N D M E N T HI S T O R Y  
T he pr ot oc ol f or st u d y T V 4 8 1 2 5 -M H -4 0 1 4 2 ( ori gi nal pr ot oc ol date d 0 3  M a y  2 0 1 9) has bee n 
a me n de d a n d reiss ue d as f oll o ws:  
A me n d me nt 0 4  
0 4  Ma y  2 0 2 0  
2 4  patie nts ra n d o mize d/e nr olle d t o da te 
T he ma na ge m e nt of st u d y acti vities 
d uri n g t he C O VI D -1 9 p a n de mic are 
detaile d i n  A p pe n di x  P . 
T he f oll o wi n g s ecti o ns are affecte d:  
Secti o n 3. 5 Sc he d ule of St u d y Pr oce d ures 
a n d Assess me nts ( Ta bl e 4)  
A p pe n di x D. Et hics  
A d mi nistrati ve Letter  0 2  
1 4 Fe br uar y 2 0 2 0  
A me n d me nt 0 3  
0 4  N o ve m ber  2 0 1 9  
0 patie nts ra n d o mize d/e nr olle d t o date  
A me n d me nt 0 2  
1 0  Oct o ber  2 0 1 9  
0  patie nts ra n d o mize d/e nr olle d t o date  
Letter of Clarificati o n 0 1  
2 6 A u g ust 2 0 1 9  
0  patie nts ra n d o mize d/e nr olle d t o date  
A me n d me nt  0 1  
0 4  J u ne 2 0 1 9  
0  patie nts ra n d o mize d/e nr olle d t o date  
T he S u m mar y of C ha n ges t o t he Pr ot oc ol i ncl u des t he c orres p o n di n g reas o n/j ustificati o n f or 
eac h c ha n ge a n d is pr o vi de d i n Secti o n 1 6 . 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
4  
 
I N V E S TI G A T O R A G R E E M EN T  
Ori gi n al Pr ot oc ol D ate d 0 3 M a y  2 0 1 9  
Cli nic al St u d y Pr ot oc ol wit h A me n d me nt 0 4  
I N D n u m ber: 1 0 6 5 3 3; 
N D A n u m ber: N ot a p plic a ble;  B L A n u m ber: 7 6 1 0 8 9;  E u dr a C T 
n u m ber: 2 0 1 9 -0 0 1 9 8 9 -1 5  
E M A Decisi o n n u m ber of Pe di atric I n vesti g ati o n Pl a n: N ot a p plic a ble  
Article 4 5 o r 4 6 of 1 9 0 1/ 2 0 0 6 d oes n ot a p pl y  
 
A M ultice nter, R a n d o mize d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, P ar all el -Gr o u p St u d y 
F oll o w e d b y a n O pe n -L a bel E xte nsi o n t o E v al u ate t he Effic ac y a n d S afet y of 
Fre m a nez u m a b f or Pre ve nti ve Tre at me nt of Mi gr ai ne i n P atie nts wit h M aj or De pressi ve 
Dis or der  
Pri nci p al I n vesti g at or:   
Title:  
 
A d dress of I n vesti g ati o n al Ce nt er:  
 
 
 
 
 
Tel:  
 
I h a ve rea d t he pr ot oc ol wit h A me n d me nt 0 4  a n d a gree t h at it c o ntai ns all necessar y details f or 
carr yi n g o ut t his st u d y. I a m q ualifie d b y e d ucati o n, e x perie nce, a n d trai ni n g t o c o n d uct t his 
cli nical researc h st u d y. T he si g nat ure bel o w c o nstit utes a gree m e nt wit h t his pr ot oc ol a n d 
attac h me nts, a n d pr o vi d es ass ura nce t hat t his st u d y will be c o n d u cte d acc or di n g t o all 
sti p ulati o ns of t he pr ot oc ol, i ncl u di n g all state me nts re gar di n g c o nfi de ntialit y, a n d acc or di n g t o 
nati o nal or l ocal le gal a n d re g ulat or y re q uire me nts a n d a p plica ble re g ulati o ns a n d g ui d eli nes. 
I will ma ke a vaila ble t h e pr ot oc ol a n d all i nf or mati o n o n t he i n vesti gati o nal me dici nal pr o d uct 
(I M P) t hat were f ur nis he d t o me b y t he s p o ns or t o all p h ysicia ns a n d ot her st u d y pers o n nel 
re p orti n g t o me w h o parti ci pate i n t his st u d y a n d will disc uss t his material wit h t he m t o e ns ure 
t hat t he y are f ull y i nf or me d re gar di n g t he I M P a n d t he c o n d uct of t he st u d y. I a gree t o kee p 
rec or ds o n all patie nt i nf or mati o n, I M P s hi p me nt a n d ret ur n f or ms, a n d all ot her i nf or mati o n 
c ollecte d d uri n g t he st u d y, i n a cc or da nce wit h nati o nal a n d l ocal G o o d Cli nical Practice ( G C P) 
re g ulati o ns as well as all ot her nati o nal a n d i nter n ati o nal la ws a n d re g ulati o ns. 
Pri nci p al I n vesti g at or  
 
Si g n at ure  
D ate   
 
Exec ute d si g n at ure p a g es are m ai nt ai ne d wit hi n t he I nvesti g at or Site File a n d Tri al M aster File .  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
5  
 
S P O N S O R P R O T O C O L A P P R O V A L  
 
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
6  
 
C O O R DI N A TI N G I N V E S TI G A T O R A G R E E M E N T  
Ori gi n al Pr ot oc ol D ate d 0 3 M a y  2 0 1 9  
Cli nic al St u d y Pr ot oc ol wit h A me n d me nt 0 4  
I N D n u m ber: 1 0 6 5 3 3; 
N D A n u m ber: N ot a p plic a ble;  B L A n u m ber: 7 6 1 0 8 9;  
E u dr a C T n u m ber: 2 0 1 9 -0 0 1 9 8 9 -1 5  
E M A Decisi o n n u m ber of Pe di atric I n vesti g ati o n Pl a n: N ot a p plic a ble  
Article  4 5 o r 4 6 of 1 9 0 1/ 2 0 0 6 d oes n ot a p pl y  
A M ultice nter, R a n d o mize d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, P ar all el -Gr o u p St u d y 
F oll o w e d b y a n O pe n -L a bel E xte nsi o n t o E v al u at e t he Effic ac y a n d S afet y of 
Fre m a nez u m a b f or Pre ve nti ve Tre at me nt of Mi gr ai ne i n P atie nts wit h M aj or De pressi ve 
Dis or der  
I h a ve rea d t he pr ot oc ol wit h A me n d me nt 0 4  a n d a gree t h at it c o ntai ns all necessar y details f or 
carr yi n g o ut t his st u d y. I a m q ualifie d b y e d ucati o n, e x perie nce, a n d trai ni n g t o c o n d uct t his 
cli nical researc h st u d y. T he si g nat ure bel o w c o nstit utes a gree m e nt wit h t his pr ot oc ol a n d 
attac h me nts a n d p r o vi d es ass ura nce t hat t his st u d y will be c o n d ucte d acc or di n g t o all sti p ulati o ns 
of t he pr ot oc ol, i ncl u di n g all state me nts re gar di n g c o nfi de ntialit y, a n d acc or di n g t o nati o nal a n d 
l ocal le gal a n d re g ulat or y re q uire me nts a n d a p plica ble re g ulati o ns a n d g ui deli nes.  
I will ma ke a vaila ble t h e pr ot oc ol a n d all i nf or mati o n o n t he i n vesti gati o nal me dici nal pr o d uct 
(I M P) t hat were f ur nis he d t o me b y t he s p o ns or t o all p h ysicia ns a n d ot her st u d y pers o n nel 
re p orti n g t o me w h o parti ci pate i n t his st u d y a n d will disc uss t his material wit h t he m t o e ns ure 
t hat t he y are f ull y i nf or me d re gar di n g t he I M P a n d t he c o n d uct of t he st u d y. I a gree t o kee p 
rec or ds o n p atie nt i nf or m ati o n, I M Ps s hi p me nt a n d ret ur n f or ms, a n d ot her i nf or mati o n c ollecte d 
d uri n g t he st u d y, i n a cc or da nce  wit h m y res p o nsi bilities u n der t he f u ncti o n of t he c o or di nati n g 
i n vesti gat or a n d i n acc or da nce wit h nati o nal a n d l ocal G o o d Cli nical Practi ce ( G C P) re g ulati o ns 
as well as all ot her n ati o nal a n d i nter nati o nal la ws a n d re g ulati o ns. I n a d diti o n, I will ass u m e t he 
res p o nsi bilit y of t he c o or di nati n g i n vesti gat or acc or di n g t o a s e parate c o ntr act. 
C o or di n ati n g I n vesti g at or  
 
Title:  
 
A d dress of I n vesti g ati o n al Ce nter:  
 
 
 
 
 
Tel:  
 
C o or di n ati n g I n vesti g at or  
 
Si g n at ure  
 
  
D ate  
Exec ute d si g n at ure p a g es are m ai nt ai ne d wit hi n t he I nvesti g at or Site File a n d Tri al M aster File .  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
7  
 
C LI NI C A L S T U D Y P R O T O C O L S Y N O P SI S  
wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
Title of St u d y: A M ultice nter, R a n d o mize d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, 
P ar allel -Gr o u p St u d y F oll o w e d b y a n O pe n -L a bel E xte nsi o n t o E v al u ate t he Effic ac y a n d 
S afet y of Fre m a nez u m a b f or Pre v e nti ve Tre at me nt of M i gr ai ne i n P atie nts wit h M aj or 
De pressi ve Dis or der  
S p o ns or:  
Te v a Br a n de d P h ar m ace utic al  
Pr o d ucts R & D, I nc.  
1 4 5 Br a n d y wi ne P ar k w a y,  
West C hester,  Pe n ns yl v a ni a 1 9 3 8 0  
U nite d St ates of A meric a  
I n vesti g ati o n al Ne w Dr u g N u m ber: 1 0 6 5 3 3; Ne w Dr u g A p plic ati o n N u m ber: N ot 
a p plic a ble;  
Bi ol o gic al Lice nse A p plic ati o n N u m ber: 7 6 1 0 8 9;  E u dr a C T 
N u m ber:  2 0 1 9 -0 0 1 9 8 9 -1 5  
E M A Decisi o n n u m ber of Pe di atric I n vesti g ati o n Pl a n: N ot a p plic a ble   
Article 4 5 o r 4 6 of 1 9 0 1/ 2 0 0 6 d oes n ot a p pl y  
N a me of Test I n vesti g ati o n al Me dici n al Pr o d uct (I M P):  Fre ma nez u ma b, T E V -4 8 1 2 5, 
L B R -1 0 1, P F -0 4 4 2 7 4 2 9, a n d R N 3 0 7.  
E u dr a Vi gil a nce c o de f or t he I M P, if a p plic a ble: N ot a p plic a ble  
T y pe of t he St u d y:  Efficac y a n d Safet y St u d y ( P h ase  4)  
I n dic ati o n: Fre ma nez u ma b is i n dicate d f or pre ve nti ve treat me nt of mi grai n e i n a d ults.  
Is t his st u d y c o n d ucte d t o i n vesti g ate t he Ne w Use of a n a p pr o ve d, m ar kete d pr o d uct ?  Yes  
N u m ber of I n vesti g ati o n al Ce nters Pl a n ne d: T he st u d y is pla n ne d t o b e c o n d ucte d i n 
a p pr o xi matel y 6 5  i n vesti gati o nal ce nters.  
C o u ntries Pl a n ne d: T h e st u d y is pla n ne d t o be c o n d ucte d i n a p pr o xi matel y 1 3  c o u ntries.   
Pl a n ne d St u d y Peri o d: T he st u d y is e x pecte d t o start i n a p pr o xi matel y Se pte m ber  2 0 1 9 a n d last 
u ntil a p pr o xi matel y A u g ust  2 0 2 1 .  
N u m ber of P atie nts Pl a n ne d (t ot al):  A p pr o xi matel y 3 4 0 patie nts ( a p pr o xi matel y 1 7 0 patie nts 
per treat me nt gr o u p) are pla n ne d t o be e nr olle d i n t his st u d y t o ha ve a p pr o xi matel y 
2 8 8  c o m pleters (a p pr o xi matel y 1 4 4  c o m pleters p er treat me nt gr o u p). A 1 5 % dr o p -o ut rat e is 
a ntici pate d.  
St u d y P o p ul ati o n:  
T he st u d y p o p ulati o n will be c o m p ose d of fe male a n d male patie nts, a ge d 1 8 t o 7 0  years, 
i ncl usi ve, wit h a dia g n osis of mi grai ne a n d maj or de pressi ve dis or d er ( M D D). Patie nts m ust 
ha ve bee n dia g n ose d wit h mi grai ne (as defi ne d b y t he I nt er nati o nal Classifi cati o n of Hea d ac h e 
Dis or ders, 3 r d re visi o n [I C H D-3] criteria [ I H S, 2 0 1 3], see A p pe n di x  I) at least 1 2 m o nt hs pri or t o 
t he scree ni n g visit ( visit [ V] 1). T he dia g n osis of mi grai ne will be pr os pecti vel y c o nfir me d via a 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
8  
 
re vie w of mi grai ne data rec or de d d ail y d uri n g a 2 8-da y baseli ne p eri o d i n a n electr o nic diar y 
de vice. Patie nts m ust als o ha ve a hist or y of M D D as dia g n ose d acc or di n g t o t he Fift h E diti o n of 
t he Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders ( D S M-V) criteri a at least 1 2 m o nt hs 
pri or t o t he scree ni n g visit ( V 1) a n d ha v e acti ve s y m pt o ms of de pressi o n as assesse d b y a Patie nt 
Healt h Q uesti o n na ir e-9 ( P H Q -9) sc ore of at least 1 0 at t he scree ni n g visit ( V 1). I n vesti gat ors 
m ust d oc u me nt t hat patie nts ha d t he dia g n osis of mi grai ne a n d M D D f or at least 1 2  m o nt hs pri or 
t o t he scree ni n g visit ( V 1). 
F or mi grai ne, p atie nts usi n g n o m or e t ha n 1 pre v e nti ve  me dicati o n at t he ti me of t he scree ni n g 
visit ( V 1) will be all o we d t o re mai n o n t he me dicati o n. T he t otal n u m ber of patie nts recei vi n g 
c o nc o mita nt mi grai ne pre ve nti ve me dicati o n d uri n g t he st u d y will n ot e xcee d 3 0 % of t h e t otal 
sa m ple siz e of t he st u d y. For de pressi o n, patie nts usi n g n o m ore t ha n 1  m e dicati o n f or t he 
treat me nt of de pressi o n at t he ti me of t he scree ni n g visit ( V 1) will be all o we d t o re mai n o n t he 
me dicati o n. Patie nts o n a c o nc o mita nt mi grai ne pre ve nti ve me dicati o n a n d/ or a n a nti de pressa nt 
m ust be o n a sta ble d ose f or at least 8  wee ks of c o nsec uti ve use pri or t o st u d y e ntr y (ie, bef ore 
t he 2 8 -da y bas eli ne peri o d ), wit h o ut a ntici pate d c h a n ges d uri n g t he st u d y. If i n t he cli nical 
j u d g me nt of t he i n vesti gat or or q ualifie d ps yc hiatrist, t he patient’s a nti de pressa nt me dicati o n 
nee ds t o be c h a n ge d or d ose -a dj uste d d uri n g t he 2 8 -da y baseli ne  p eri o d , t h e patie nt will be 
scree n faile d. A n y c ha n ges ma de d uri n g t he treat me nt peri o d will be rec or de d i n t he electr o ni c 
data ca pt ur e s yste m. T he perce nt a ge of patie nts wit h t hese c ha n ges will be a nal yze d at t he e n d of 
t he st u d y. 
All c o nc o mita nt me dicati o ns prescri be d or o ver -t h e-c o u nter me dicati o ns, vita mi ns, or her bal or 
n utriti o nal s u p ple me nts, m ust be rec or de d wit h i n di cati o n, dail y d ose, a n d start a n d st o p dates of 
a d mi nistrati o n. All patie nts will be q uesti o ne d a b o ut c o nc o mita nt me dicati o n use at eac h visit. 
C o m plete disc o nti n uati o n criteria are pr o vi de d i n t he f ull pr ot oc ol i n Secti o n  4. 3 . 
D uri n g t h e 2 8 -da y b aseli ne  peri o d, patie nts m ust f ulfill t he f oll o wi n g criteri a f or mi grai ne:  
•  o n ≥4 da ys, h ea dac he attac ks q ualifie d as mi grai n e base d o n t he f oll o wi n g I C H D -3 
criteria: 
− I C H D-3 dia g n ostic criteria C a n d D f or 1. 1 Mi grai ne wit h o ut a ura  
− I C H D-3 criteria B a n d C f or 1. 2 Mi grai ne wit h a ura  
− pr o ba ble mi grai ne (a mi grai ne s u bt y pe w here o nl y 1 mi grai ne criteri o n is 
missi n g)  
− tri pta n or er g ot deri vati ve use d t o treat a n establis he d hea d ac he  
Patie nts w h o f ulfill t he criteria f or mi grai ne will be f urt her d eli neate d as patie nts wit h c hr o nic 
mi grai ne ( C M) or e pis o dic mi grai n e ( E M), f or str atificati o n a n d ot her a nal ys es.  
C M is defi ne d as:  
Patie nt f ulfills t he f oll o wi n g criteria f or C M i n pr os pecti vel y c ollecte d baseli ne i nf or mati o n 
d uri n g t he 2 8 -da y bas eli ne  peri o d:  
•  hea dac he occ urri n g o n ≥1 5 da ys  
•  o n ≥8 da ys, f ulfilli n g a n y 1 of t he f oll o wi n g:  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
9  
 
− I C H D-3 dia g n ostic criteria C a n d D f or 1. 1 Mi grai ne wit h o ut a ura ( A p pe n di x  I) 
− I C H D-3 criteria B a n d C f or 1. 2 Mi grai ne wit h a ura ( A p pe n di x  I) 
− pr o ba ble mi grai ne (a mi grai ne s u bt y pe w here o nl y 1 mi grai ne criteri o n is 
missi n g)  
− tri pta n or er g ot deri vati ve used t o treat esta blis he d hea dac he  
E M is defi ne d as:  
T he patie nt f ulfills t he f oll o wi n g criteria f or E M i n pr os pecti vel y c ollecte d baseli ne i nf or mati o n 
d uri n g t he 2 8 -da y bas eli ne  peri o d:  
•  hea dac he occ urri n g ≥4  d a ys b ut < 1 5  
•  o n ≥4 da ys, f ulfilli n g a n y 1 of t he f oll o wi n g:  
− I C H D-3 dia g n ostic criteria C a n d D f or 1. 1 Mi grai ne wit h o ut a ura ( A p pe n di x  I) 
− I C H D-3 criteria B a n d C f or 1. 2 Mi grai ne wit h a ura ( A p pe n di x  I) 
− pr o ba ble mi grai ne (a mi grai ne s u bt y pe w here o nl y 1 mi grai ne criteri o n is 
missi n g)  
− tri pta n or er g ot deri vati ve use d t o treat a n esta blis he d hea d ac he 
Pri m ar y a n d Sec o n d ar y O bjecti ves a n d E n d p oi nts  
T he pri mar y a n d s ec o n d ar y st u d y o bje cti ves a n d e n d p o i nts are i n Ta ble  1 . 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 0  
 
T a ble  1 : 
Pri m ar y a n d Sec o n d ar y O bjecti ves a n d E n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri m ar y o bjecti ve:  
T o e val uate t he effi cac y of m o nt hl y 2 2 5  m g s c 
fre ma n ez u ma b i n a d ult patie nts wit h mi grai ne 
a n d M D D  
Mea n c ha n ge i n t he m o nt hl y a v era ge n u m ber 
of mi grai ne da ys fr o m t he 2 8 -da y bas eli ne 
peri o d  d uri n g t he 1 2 -wee k peri o d after t he first 
d ose of st u d y  dr u g  
Ke y sec o n d ar y o bjecti ve:  
T o e val uate t he effi cac y of m o nt hl y 2 2 5  m g s c 
of fre ma n ez u ma b i n a d ult patie nts wit h 
mi grai ne  a n d M D D o n t h e re d ucti o n of M D D 
s y m pt o ms 
Mea n c ha n ge i n de pressi o n s y m pt o ms fr o m 
ra n d o mizati o n ( da y 1) t o wee k 8  after t he first 
d ose of st u d y dr u g as me as ure d b y:  
•  H A M -D 1 7  
Sec o n d ar y o bjecti ve:  
T o e val uate t he effi cac y of m o nt hl y 2 2 5  m g s c 
fre ma n ez u ma b i n a d ult patie nts wit h mi grai ne 
a n d M D D i n ter ms of res p o n der rat es i n 
m o nt hl y mi grai ne da ys  
N u m ber of patie nts wit h 5 0 % or m ore 
re d ucti o n fr o m t he 2 8-da y bas eli ne peri o d i n 
t he m o nt hl y a vera ge n u m ber of mi grai ne da ys 
at 1 2 wee ks after t he first d ose of st u d y dr u g  
Sec o n d ar y o bjecti ve:  
T o e val uate t he effi cac y of m o nt hl y 2 2 5  m g s c 
fre ma n ez u ma b i n a d ult patie nts with mi grai ne 
a n d M D D i n ter ms of i m pr o vi n g q u alit y of life  
Mea n c ha n ge i n q ualit y of life fr o m 
ra n d o mizati o n ( da y 1) t o wee k 1 2 after t he first 
d ose of st u d y dr u g  as me as ure d b y:  
•  M S Q o L q uesti o n nair e, r ole 
f u ncti o n-restricti ve a n d r ole 
f u ncti o n-pre v e nti ve d o m ai ns 
Sec o n d ar y o bjecti ve:   
T o e val uate t he effi cac y of m o nt hl y 2 2 5  m g s c 
fre ma n ez u ma b i n a d ult patie nts wit h mi grai ne 
a n d M D D i n ter ms of i m pr o vi n g disa bilit y  
Mea n c ha n ge fr o m ra n d o mizati o n ( da y 1) i n 
disa bilit y s c ore f or o verall i m pact as meas ure d 
b y C G I-S a n d HI T -6 t o t he f oll o wi n g ti me 
p oi nts after a d mi nistrati o n of t he first d ose of 
st u d y dr u g: 
•  wee ks 4 a n d 8 ( C GI -S)  
•  wee k 1 2 ( C GI -S a n d HI T -6)  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 1  
 
T a ble  1 : 
Pri m ar y a n d Sec o n d ar y O bjecti ves a n d E n d p oi nts ( C o nti n ue d)  
O bjecti ves  
E n d p oi nts  
S afet y a n d t oler a bilit y o bjecti ve  
( Sec o n d ar y o bjecti v e): 
T o e val uate t he s afet y a n d t olera bilit y of 
m o nt hl y 2 2 5  m g sc a n d q uarterl y 6 7 5  m g sc 
fre ma n ez u ma b i n a d ult patie nts wit h mi grai ne 
a n d M D D  
•  occ urre nce of a d v erse e v e nts 
t hr o u g h o ut t he st u d y 
•  c ha n ges fr o m ra n d o mizati o n visit 
( da y 1) i n vital si g ns ( p ulse, s yst olic 
a n d diast olic bl o o d press ure, b o d y 
te m perat ur e, a n d res pirat or y rate) 
meas ure me nts  
•  a b n or mal p h ysical e xa mi nati o n 
fi n di n gs i ncl u di n g b o d y wei g ht 
•  use of c o nc o mita nt me di cati o n f or 
a d verse e ve nts d uri n g t he st u d y 
•  n u m ber ( %) of patie nts w h o di d n ot 
c o m plete t he st u d y d u e t o a d verse 
e ve nts  
•  occ urre nce of se v ere 
h y perse nsiti vit y/a na p h yl a xis 
reacti o ns 
•  s uici dal i deati o n a n d be h a vi or as 
s u g geste d b y e C-S S R S  
C GI -S  =  Cli nical Gl o bal I m pr essi o n -Se verit y; e C -S S R S  =  el ectr o nic C ol u m bia -S uici de Se verit y Rati n g Scale; 
H A M -D 1 7 = Ha milt o n De pressi o n Rati n g Scale -1 7  ite ms; HI T-6  =  6 -ite m Hea dac he I m p act T est; M D D = maj or 
de pressi ve dis or der; M S Q o L = Mi grai ne -S pecific Q ualit y of Life; sc  =  s u bc uta ne o us. 
E x pl or at or y O bjecti ves a n d E n d p oi nts   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
Ge ner al St u d y Desi g n:  
T his is a n a p pr o xi matel y 2 8 -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, 
parallel -gr o u p st u d y t o e val uate t he efficac y a n d s afet y of fre ma nez u ma b self-a d mi nistere d at 
m o nt hl y d os es of 2 2 5  m g sc a n d a q uarterl y d ose of 6 7 5  m g sc (ie,  o ne d os e  usi n g 3  prefille d 
s yri n ges wit h 2 2 5 m g eac h) i n a d ult patie nts wit h mi grai ne a n d M D D. T h e st u d y will c o nsist of a 
2 8 -da y (ie, 4 -wee k) bas eli ne peri o d, a 1 2 -wee k d o u ble -bli n d treat me nt p has e f oll o we d b y a 
1 2 -wee k o p e n -la b el e xte nsi o n p hase, a n d a n e n d-of -treat me nt visit (a p pr o xi matel y 1 2 wee ks 
after t he fi nal d ose of st u d y dr u g) . 
T he t otal d urati o n of pati e nt partici pati o n i n t he st u d y is pla n ne d t o be a p pr o xi matel y 2 8 wee ks. 
Patie nts are e x pecte d t o c o m plete t he e ntire d urati o n of t he st u d y.  
Brief S u m m a r y of St u d y Desi g n f or t he Tri al Re gistr y(s):  
T he mai n p ur p ose of t his st u d y is t o test if fre ma nez u ma b is effecti ve i n pre ve nti n g mi grai ne i n 
patie nts wit h M D D. Researc hers will first l o o k at 2 differe nt gr o u ps of pati e nts: 1 gr o u p of 
patie nts w h o ta ke t he st u d y dr u g a n d 1 gr o u p of patie nts w h o ta ke t he place b o. T his part of t he 
st u d y is “ d o u ble-bli n d,” w hic h mea ns patie nts a n d researc hers will n ot k n o w w h o ta kes 
fre ma n ez u ma b or place b o. T his e ns ures t hat t he res ults are n ot i nfl ue nce d i n a n y wa y. At t he e n d 
of 1 2 wee ks, researc h ers will c o m bi ne t hese gr o u ps a n d gi v e all patie nts t he st u d y dr u g f or 
1 2  m ore wee ks. T his part of t he st u d y will n ot be bli n de d. Researc h ers will test h o w effecti ve t he 
dr u g is at h el pi n g re d uce t he n u m ber of m o nt hl y mi grai n e da ys.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 3  
 
Met h o d of R a n d o miz ati o n a n d Bli n di n g:  
F or t he first p hase of t his st u d y, t h e s p o ns or, i n vesti gat ors, st u d y staff, a n d patie nts will be 
bli n de d t o treat me nt assi g n me nt . A c o m p uter -ge n erate d mast er ra n d o mizati o n list will be 
pr o vi de d t o dr u g pac k a gi n g facilities. T he pac ka gi n g ve n d or(s) will pac ka ge acti ve dr u g a n d 
place b o i nt o si n gle -visit kits acc or di n g t o G o o d Ma n ufact uri n g Practice pr oce d ures. Kits will be 
i de ntical i n a p peara nce a n d c o ntai n 1  prefille d s yri n ge wit h eit her acti ve dr u g or place b o.  
Patie nts will be stratifie d base d o n se x, c o u ntr y, mi grai ne classifi cati o n (ie, C M or E M) , a n d 
P H Q -9 sc ore cate g or y ( 1 0 t o 1 4, 1 5 t o 1 9, a n d ≥2 0) t o e ns ure b ala nce f or t he c o vari ates.  
Pa tie nts will be ra n d o ml y assi g ne d t o treat me nt gr o u ps b y mea ns of a c o m p uter-ge n erate d 
ra n d o mizati o n list usi n g electr o nic i nteracti ve res p o nse tec h n ol o g y (I R T). T his s yste m is use d t o 
e ns ure a b ala nce acr oss tr eat me nt gr o u ps. T he s p ecificati o ns f or ra n d o mi zati o n will be u n der t he 
res p o nsi bilit y a n d o versi g ht of T e va Gl o bal Statistics. 
At t he ra n d o mizati o n visit ( da y  1), eac h patie nt will be ra n d o mize d i n a 1: 1 rati o wit hi n t he 
strat u m t o w hic h he or s h e bel o n gs t o recei ve m o nt hl y 2 2 5 m g s c fre ma nez u ma b or p lace b o, as 
assi g ne d b y t h e I R T. I n t he o pe n -la b el e xte nsi o n p hase starti n g at wee k 1 2, h o we ver, all patie nts 
will recei ve acti ve treat me nt wit h a q uarterl y d os e of 6 7 5  m g sc fre m a nez u ma b.  
T he I R T will ma na ge i nitial dr u g s u p pl y, mai nte na nce of a d e q uate st u d y dr u g s u p plies o n site, 
a n d st u d y ra n d o mizati o n ce ntrall y. At eac h st u d y visit w here st u d y dr u g is a d mi nistere d, t he I R T 
will be q uerie d, t he site p ers o n nel will retrie v e t he st u d y dr u g fr o m refri gerate d st ora ge , a n d t h e 
patie nt will  self-a d mi nister  treat me nt wit h t he 1 or 3 prefille d s yri n ges , de p e n di n g o n t he st u d y 
visit, c o ntai ne d i n t he a p pr o priatel y n u m bere d kit . 
I n vesti g ati o n al Me dici n al Pr o d ucts: D ose, P h ar m a ce utic al F or m, R o ut e of A d mi nistr ati o n, 
a n d A d mi nistr ati o n R ate  
T he safet y a n d t olera bilit y  of fre ma n ez u ma b (i ntra ve n o us [i v] d oses ra n gi n g fr o m 0. 2 t o 
2 0 0 0  m g a n d s c d oses of 2 2 5 m g a n d 9 0 0 m g) has bee n well c h aracterize d i n t he P hase  1 
de vel o p me nt pr o gra m. F urt her m ore, t he s afet y a n d efficac y of fre ma nez u ma b has bee n 
de m o nstrate d i n a ra n d o miz e d d o u ble-bli n d, place b o -c o ntr olle d P hase 2 st u d y of 2 s c d osi n g 
re gi me ns of fre ma nez u m a b ( m o nt hl y 9 0 0 m g fre ma nez u ma b or 6 7 5 m g fre ma nez u ma b f oll o we d 
b y m o nt hl y 2 2 5 m g fre m a nez u ma b) i n patie nts wit h C M a n d a ra n d o mize d, d o u ble -bli n d, 
place b o -c o ntr olle d P h ase 2 st u d y of 2 sc d osi n g re gi me ns of fre ma nez u ma b ( m o nt hl y d ose of 
6 7 5 or 2 2 5  m g fre ma n ez u ma b) i n patie nts wit h E M. F urt her m ore, t he efficac y a n d t olera bilit y 
pr ofile ha ve b ee n c o nfir me d i n t he P hase 3 de vel o p me nt pr o gra m, w hic h i ncl u de d a q uarterl y 
d ose  of 6 7 5  m g.  
A ra n d o mize d, d o u ble -bli n d, parallel -gr o u p, place b o -c o ntr olle d desi g n is a p pr o priate gi ve n t he 
o bjecti ves of t his st u d y. F urt her m ore, t his desi g n is c o nsiste nt wit h t he rec o m me n dati o ns of t he 
Classificati o ns C o m mittee of t he I nter nati o nal Hea d ac he S ociet y f or c o ntr olle d trials of 
pre ve nti ve dr u gs i n mi grai ne . 
Patie nts will recei ve e x peri me ntal me dici nal pr o d uct fre ma nez u ma b ( visit  2, visit  3, a n d visit  4) 
or matc hi n g pl ace b o refere nce m e dici nal pr o d u ct ( visit  2, visit  3, a n d visit  4) i n m o nt hl y  d os es 
fr o m t he s p o ns or. Patie nts will recei ve a q uarterl y d ose of 6 7 5 m g  s c fre ma nez u ma b at visit 5.  
Prefille d s yri n ge s (acti ve or place b o) will be c o ntai ne d i n u ni q uel y n u m bere d kits a n d st ore d 
(refri gerat e d at 2°C t o 8 °C) o n site. ( See details i n Ta ble  2 ). Acti ve prefille d s yri n ges  will 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 4  
 
c o ntai n 2 2 5  m g of T E V -4 8 1 2 5 i n 1. 5 m L s ol uti o n, a n d place b o prefille d s yri n ges  will c o ntai n t he 
sa me ve hicle a n d e x ci pie nts as t h ose f or acti ve i njecti o ns. Eac h kit will c o ntai n 1 prefille d 
s yri n ge.  
A de q uate kit s u p pl y f or u pc o mi n g st u d y visits will be ma na ge d b y t h e I R T a n d ke pt (refri gerate d 
at 2° C t o 8° C) o n site.  
Treat me nt self-a d mi nistrati o n  (acti ve or pl ace b o) will occ ur at visit 2 ( da y 1), visit  3 ( da y  2 9 ), 
a n d visit  4 ( da y  5 7). O nl y acti ve treat me nt will be a d mi nistere d o n visit 5 ( da y 8 5), w hic h is t he 
be gi n ni n g of t he o p e n -la bel e xte nsi o n p hase. Fi nal st u d y assess me nts will be perf or me d at t he 
e n d-of -tr eat me nt visit ( visit 6), a p pr o xi matel y 1 2 wee ks aft er a d mi nistrati o n of t he last d ose of 
st u d y treat me nt. 
T a ble  2 : 
I n vesti g ati o n al Me dici n al Pr o d ucts Us e d i n t he St u d y  
I M P n a me 
Rec o m bi n a nt h u m a nize d 
I g G 2 a/ k a p p a m A b 
Fre m a nez u m a b  
Pl ace b o  
Tr a de n a me a n d I N N, if 
a p plic a ble, or c o m p a n y -assi g ne d 
n u m ber  
AJ O V Y, fre ma nez u ma b  
Als o k n o w n as:  
T E V -4 8 1 2 5, L B R -1 0 1, 
P F -0 4 4 2 7 4 2 9, R N 3 0 7  
Place b o  
F or m ul ati o n  
Prefille d s yri n ges  c o ntai ni n g 1. 5 m L 
s ol uti o n f or i nj ecti o n of 2 2 5 m g of 
t he acti ve i n gre die nt fre ma nez u ma b  
I nacti ve i n gre die nts i ncl u de 
L -histi di ne, L -histi di ne 
h y dr oc hl ori de m o n o h y drate, s ucr ose, 
p ol ys or bate -8 0, E D T A, a n d water f or 
i nj ecti o n 
Prefille d s yri n ges  c o ntai ni n g 1. 5 m L 
s ol uti o n f or i nj ecti o n of t he sa me 
ve hicle a n d e xci pie nts as t h os e f or 
acti ve i nj ecti o n  
I nacti ve i n gre die nts i ncl u de 
L -histi di ne, L -histi di ne 
h y dr oc hl ori de m o n o h y drate, s ucr ose, 
p ol ys or bate -8 0, E D T A, a n d water f or 
i nj ecti o n 
U nit d ose stre n gt h(s)/ D os a ge 
le vel(s) 
2 2 5 m g/ 1. 5 m L per u nit  
N o ne  
R o ute of A d mi nistr ati o n  
sc i nj ecti o n 
sc i nj ecti o n 
D osi n g i nstr ucti o ns  
D o u ble -bli n d tre at me nt p h ase : a 
d ose of 2 2 5 m g fre ma nez u ma b as a n 
acti ve i nj ecti o n ( 2 2 5 m g/ 1. 5  m L) at 
visit 2 ( da y 1), visit  3 ( da y  2 9), a n d 
visit 4 ( da y 5 7)  
O pe n -l a bel e xte nsi o n p h ase: a 
q uarterl y d ose of 6 7 5 m g 
fre ma nez u ma b as 3 acti ve inj ecti o ns 
( 2 2 5 m g/ 1. 5 m L) at visit 5 ( da y 8 5)  
D o u ble -bli n d tre at me nt p h ase : 
1. 5  m L place b o i nj ecti o n at visit 2 
( da y 1), visit 3 ( da y 2 9), a n d visit 4 
( da y 5 7) 
 
O pe n -l a bel e xte nsi o n p h ase: n ot 
a p plica ble 
P ac k a gi n g  
A kit u ni q uel y n u m bere d c o nt ai ni n g 
1 prefille d s yri n ge st ore d 
(refri gerate d at 2° C t o 8° C) o n site 
A kit u ni q uel y n u m bere d c o nt ai ni n g 
1 prefille d s yri n ge st ore d 
(refri gerate d at 2° C t o 8° C) o n site 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 5  
 
T a ble  2 : 
I n vesti g ati o n al Me dici n al Pr o d ucts Us e d i n t he St u d y ( C o nti n ue d) 
I M P n a me 
Rec o m bi n a nt h u m a nize d 
I g G 2 a/ k a p p a m A b 
Fre m a nez u m a b  
Pl ace b o  
M a n uf act urer  
 
Dr u g s u bst a nce : 
 
 
 
 
 
Dr u g pr o d uct : 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E D T A = et h yle ne dia mi netetra acetate; I g G 2a = i m m u n o gl o b uli n G 2a; I M P = i n vesti gati o nal me dici nal pr o d uct; 
I N N =  i nter nati o nal n o n-pr o prietar y na me; m A b = m o n ocl o nal a nti b o d y; sc = s u bc uta ne o us.  
D ur ati o n of P atie nt P artici p ati o n a n d M a xi m al E x p os ure t o I M P:   
T he t otal d urati o n of pati e nt partici pati o n i n t he st u d y is pla n ne d t o be a p pr o xi matel y 2 8 wee ks. 
Patie nts are e x pecte d t o c o m plete t he e ntire d urati o n of t he st u d y.  
Patie nts i nitiall y ra n d o mi ze d t o fre ma nez u ma b will recei ve a t otal of 1 3 5 0 m g sc fre ma nez u ma b 
i n t he st u d y ( o ne 2 2 5 m g d ose m o nt hl y f or 3 m o nt hs i n t he d o u ble-bli n d treat me nt p hase a n d a 
q uarterl y d ose of 6 7 5  m g i n t he o pe n -la bel e xte nsi o n phase). Patie nts i nitiall y ra n d o mize d t o 
place b o will recei ve a q u arterl y d ose of 6 7 5 m g s c i n t he o pe n -la bel e xte nsi o n.  
St u d y D ur ati o n:  T he st u d y d urati o n will be a p pr o xi matel y 2 4 m o nt hs, fr o m a p pr o xi matel y 
Se pte m ber  2 0 1 9 (first patie nt scree n e d) t o a p pr o xi matel y A u g ust  2 0 2 1 (l ast visit of t he last 
patie nt) . 
E n d of St u d y:  E n d of st u d y is defi n e d as t he last visit (e n d-of -treat me nt/earl y wit h dr a wal visit 
[ visit 6]) of t he last patie nt. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 6  
 
Pl a ns f or Tre at me nt or C are after t he P atie nt H as E n de d P artici p ati o n i n t he St u d y:  
N o treat me nt is pla n ne d b y t he s p o ns or after c o m pleti o n of t he st u d y. Pati e nts s h o ul d be treate d 
wit h sta n dar d of care after wit h dra wal fr o m or ter mi nati o n of t he st u d y, as a p pr o priate.  
I ncl usi o n Criteri a: Patie nts ma y be ra n d o mize d/e nr oll e d i n t he st u d y o nl y if t he y meet all of t he 
f oll o wi n g criteria:  
a. T he patie nt is ca p a ble of gi vi n g si g n e d i nf or me d c o nse nt, w hic h i ncl u des c o m plia nce 
wit h t he re q uire me nts a n d restricti o ns liste d i n t his pr ot oc ol . 
b.  T he patie nt is male or fe male a n d 1 8  t o 7 0  years of a ge, i ncl usi ve.  
c. T he patie nt has a di a g n osis of mi grai ne wit h o nset at ≤5 0 years of a ge.  
d.  Pri or t o t he scree ni n g visit ( V 1), t he patie nt has a 1 2 -m o nt h hist or y of eit her:  
− mi grai ne (acc or di n g t o I C H D -3 criteri a [ I H S, 2 0 1 3]) or 
− hea dac he c o nsiste nt wit h mi grai ne (ie, mi grai ne di a g n osis n ot better acc o u nte d f or 
b y a n ot h er I C H D -3 dia g n osis)  
e. T he patie nt f ulfills t he f oll o wi n g criteria f or mi grai ne i n a pr os pecti ve l y c ollecte d 
diar y d uri n g t he 2 8 -da y b aseli ne peri o d:  
− o n ≥4 da ys, h ea dac he attac ks q ualifie d as mi grai n e base d o n t he f oll o wi n g 
I C H D-3 criteria:  
○ I C H D-3 dia g n ostic criteria C a n d D f or 1. 1 Mi grai ne wit h o ut a ura   
hea dac he has at least 2 of t he f oll o wi n g 4 c h aracteristics: u nilateral 
l ocati o n; p ulsati n g q ualit y; m o derate or se v ere pai n i nte nsit y; a n d 
a g gra vati o n b y, or ca usi n g a v oi d a 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)  
d uri n g hea dac he, at least o ne of t he f oll o wi n g: 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  
○ I C H D-3 criteria B a n d C f or 1. 2 Mi grai ne wit h a ura  
1 or m ore of t he f oll o wi n g f ull y re versi ble a ura s y m pt o ms: vis ual, se ns or y, 
s peec h a n d/ or la n g ua ge, m ot or, brai nste m, reti nal 
at least 2 of t he f oll o wi n g 4 c h aracteris tics: at least 1 a ura s y m pt o m 
s prea ds gra d uall y o ver ≥5 mi n utes, a n d/ or 2 or m ore s y m pt o ms occ ur i n 
s uccessi o n; eac h i n di vi d ual a ura s y m pt o m lasts 5 t o 6 0 mi n utes; at least 
1  a ura s y m pt o m is u nilateral; t he a ura is acc o m pa nie d, or f oll o we d wit hi n 
6 0  mi n ute s, b y hea d ac h e n ot better acc o u nte d f or b y a n ot h er I C H D-3 
dia g n osis, a n d tr a nsie nt isc he mic attac k h as bee n e x cl u de d  
○ pr o ba ble mi grai ne (a mi grai ne s u bt y pe w here o nl y 1 mi grai ne criteri o n is 
missi n g)  
○ tri pta n or er g ot deri vati ve use d t o treat a n esta blis he d hea d ac he.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 7  
 
f. T he patie nt a grees n ot t o i nitiate a n y mi grai n e pre ve nti ve me dicati o ns (as d efi ne d i n 
A p pe n di x  G ) d uri n g t he st u d y. U p t o 3 0 % of patie nts, h o we ver, ma y ta ke a si n gle 
s uc h me dicati o n pre vi o usl y pres cri be d f or t he treat me nt of mi grai ne.  
g.  T he patie nt has a hist or y of M D D acc or di n g t o t he D S M -V criteria at least 1 2 m o nt hs 
pri or t o t he scree ni n g visit ( V 1) . Patie nts ma y t a ke a si n gle me di cati o n pres cri be d f or 
t he treat me nt of d e pressi o n as l o n g as t he d ose of t hat me dicati o n has bee n sta ble f or 
at least 8  wee ks pri or t o t he scree ni n g visit ( V 1) a n d e x pects t o re mai n at t he sta ble 
d ose t hr o u g h o ut t he st u d y ( A p pe n di x  G ).  
h.  T he patie nt has a P H Q -9 sc ore of at least 1 0 at t he scree ni n g visit ( V 1).  
i. T he patie nt has a Mi ni M e ntal State E x a mi nati o n sc ore of at least 2 6 p oi nts at t he 
scree ni n g visit ( V 1). 
j. T he patie nt is i n g o o d h ealt h i n t he o pi ni o n of t he i n vesti gat or as deter mi ne d b y 
me dical e val uati o n, i ncl u di n g me dical a n d ps yc hiatric hist or y, p h ysic al e xa mi nati o n, 
la b orat or y tests, a n d car diac m o nit ori n g.  
k.  T he patie nt has a b o d y w ei g ht 4 5  k g a n d a b o d y mass i n de x wit hi n t he ra n ge of 
1 7. 5  t o 3 4. 9 k g/ m 2, i ncl usi ve. 
l. T he patie nt de m o nstrate d c o m plia nce wit h t he electr o nic hea dac he diar y d uri n g t he 
2 8 -da y baseli ne p eri o d  b y e ntr y of hea dac h e data o n a mi ni m u m of 2 1  da ys 
c u m ulati ve d uri n g t h e 2 8 -da y baseli ne  p eri o d  ( ~ 75 % diar y c o m plia nce).  
m.  W o me n ma y be i ncl u d e d o nl y if t he y ha v e a n e gati ve ser u m beta -h u m a n c h ori o nic 
g o na d otr o pi n test at t he scree ni n g visit ( V 1), are st erile or p ost me n o pa us al, a n d are 
n ot lactati n g ( n ot a p plica ble f or patie nts partici pati n g i n safet y f oll o w -u p o nl y). 
Defi niti o ns of sterile a n d p ost me n o pa usal are gi v e n i n A p pe n di x  E . 
n.  W o me n of c hil d -beari n g p ote ntial w h ose male part ners are p ot e ntiall y fertil e (ie, n o 
vasect o m y) m ust use hi g hl y effecti ve birt h c o ntr ol met h o ds f or t he d urati o n of t he 
st u d y a n d f or 6 m o nt hs after disc o nti n uati o n of I M P (f or details see A p pe n di x  E ). 
o.  Me n m ust be sterile or, if t he y are p ote ntiall y fertile/re pr o d ucti vel y c o m pete nt ( n ot 
c o n ge nitall y sterile) a n d  t heir fe mal e part ners are of c hil d-beari n g p ot e ntial, m ust use 
a c o n d o m f or t he d urati o n of t he st u d y a n d f or 6 m o nt hs after disc o nti n uati o n of I M P. 
F or t he p ur p os e of t his st u d y, vas ect o mize d me n m ust use a c o n d o m if t heir part ners 
are of c hil d -beari n g p ote ntial. Defi niti o ns of w o me n of n o n -c hil d-b eari n g p ote ntial, 
sterile a n d p ost me n o pa us al w o me n; male c o ntr ace pti o n; a n d hi g hl y effecti v e birt h 
c o ntr ol met h o ds, i ncl u di n g e x a m ples, are gi ve n i n A p pe n di x  E . 
p.  T he patie nt m ust be willi n g a n d a ble t o c o m pl y wit h st u d y restricti o ns, t o re mai n at 
t he cli nic f or t he re q uire d d urati o n d uri n g t h e st u d y, a n d t o ret ur n t o t he cli nic f or t he 
f oll o w-u p e val uati o ns,  as s pecifie d i n t his pr ot oc ol.  
E xcl usi o n Criteri a: Patie nts will n ot be ra n d o mize d/e nr olle d i n t his st u d y if t he y m eet a n y of 
t he f oll o wi n g criteria: 
a. T he patie nt uses me dicati o ns c o ntai ni n g o pi oi ds (i ncl u di n g c o d ei ne) or bar bit urates 
(i ncl u di n g b utal bital/as piri n/caffei ne [ Fi ori nal ® , Acta vis plc], 
b utal bital/ paracet a m ol/caffei ne [ Fi oricet ® , Car di nal Healt h], or a n y ot h er c o m bi nati o n 
c o ntai ni n g b utal bital) o n m ore t ha n 4 da ys d uri n g t he 2 8 -da y bas eli ne peri o d f or t he 
treat me nt of mi grai ne or f or an y ot her reas o n.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 8  
 
b.  T he patie nt has faile d 4 or m ore differe nt me dicati o n classes t o treat d e pressi o n i n 
t heir lifeti me (A p pe n di x  G ). 
c. If i n t he cli nical j u d g me nt of t he i n vesti gat or or q ualifie d ps yc hiatrist, t he patie nt’s 
a nti de pressa nt me dicati o n nee ds t o be c h a n ge d or d ose -a dj uste d d uri n g t he 2 8 -da y 
baseli ne  peri o d . 
d.  T h e patie nt has use d a n i nter ve nti o n/ de vice (e g, s c he d ule d ner ve bl oc ks, i m pla nta ble 
va gal ner v e sti m ulati o n, a n d tra nscra nial ma g neti c sti m ulati o n) f or mi grai ne or 
de pressi o n d uri n g t he 2 m o nt hs pri or t o scree ni n g . 
e. T he patie nt has use d electr oc o n v ulsi ve t he ra p y at a n y ti me. 
f. T he patie nt s uffers fr o m c o nsta nt or nearl y c o nsta nt hea dac h e , defi n e d as h a vi n g 
hea dac hes f or m ore t ha n 8 0 % of t he ti me he/s he is a wa ke, a n d less t ha n 4 da ys 
wit h o ut hea dac h e per m o nt h. Dail y hea dac he is acce pta ble if p atie nt has hea dac h es 
8 0 % or less of t he ti me h e/s he is a wa k e o n m ost da ys.  
g.  T he patie nt has cli nicall y si g nifica nt h e mat ol o gical, car diac, re n al, e n d ocri n e, 
p ul m o nar y, gastr oi ntesti nal, ge nit o uri nar y, ne ur ol o gic, he patic, oc ular disease,  or 
c o m plicati o ns of a n i nfecti o n,  at t he discreti o n of t he i n vesti gat or. 
h.  T he patie nt has a cli nical hist or y of  a se vere or u nc o ntr olle d ps yc hiatric dis or der, t o 
i ncl u de t he f oll o wi n g, or at t he discreti o n of t he i n vesti gat or f or a n y cli nicall y 
si g nifica nt ps yc hi atric hist or y t hat w o ul d li kel y  i nterfere wit h f ull partici pati o n i n t he 
st u d y: 
− Lif eti me e x cl usi o n:  s uici de atte m pt 
− I n t he p ast 6 m o nt hs e x cl usi o n: s uici dal i deati o n, or ot her ps yc h o acti ve s pectr u m 
dis or ders i ncl u di n g s c hiz oaffecti ve dis or der, del usi o nal dis or der, de pressi o n wit h 
ps yc h otic feat ur es, a n d catat o nic dis or der  
i. T he patie nt has a hist or y of cli nicall y si g nifica nt car di o vasc ular disease or v asc ular 
isc he mia (s uc h as m y o car dial, ne ur ol o gical [ e g, cere bral isc he mia], peri p h eral 
e xtre mit y isc h e mia, or ot her isc he mic e ve nt) or t hr o m b oe m b olic e ve nts (arterial or 
ve n o us t hr o m b otic or e m b olic e ve nts), s uc h as cere br o vasc ul ar acci de nt (i n cl u di n g 
tra nsie nt isc he mic attac ks), dee p vei n t hr o m b osis, or p ul m o nar y e m b olis m.  
j. T he patie nt has a k n o w n i nfecti o n or hist or y of h u ma n i m m u n o deficie nc y vir us, 
t u berc ul osis, a n y hist or y of L y m e disease, or c hr o nic he patitis B or C i nfecti o n. 
k.  T he patie nt has a p ast or c urre nt hist or y of ca ncer, e x ce pt f or a p pr o priatel y treate d 
n o n -mela n o ma s ki n carci n o ma.  
l. T he patie nt is a pre g n a nt or n ursi n g fe male or pla ns t o bec o me pre g n a nt d uri n g t he 
st u d y, i ncl u di n g t h e 6-m o nt h peri o d after t h e a d mi nistrati o n of t he last d ose.  
m.  T he p atie nt has a hist or y of h y p erse nsiti vit y reacti o ns t o i njecte d pr otei ns, i ncl u di n g 
m o n ocl o nal a nti b o dies , or a hist or y of Ste ve n s-J o h ns o n S y n dr o me or t o xic e pi der mal 
necr ol ysis s y n dr o me . 
n.  T he patie nt has partici pat e d i n a cli nical st u d y of a ne w c he mical e n tit y or a 
prescri pti o n me dici ne wit hi n 2 m o nt hs of t he scree ni n g visit ( V 1) or 3 m o nt hs i n case 
of bi ol o gics if t he h alf -life of t he bi ol o gi cs is u n k n o w n or 5 half-li ves, w hi c he ver is 
l o n ger, or is c urre ntl y p artici pati n g i n a n ot her st u d y of a n I M P ( or a me dical de vice).  
o.  T he patie nt has faile d treat me nt ( base d o n t olera bilit y a n d/ or a lac k of efficac y) wit h 
a n y m o n o cl o nal a nti b o dies tar geti n g t he calcit o ni n ge n e -relate d p e pti de pat h wa y 
(ere n u m a b, e pti nez u ma b, gal ca nez u ma b, or fre ma nez u ma b) or ha ve t a ke n t he 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 9  
 
me dicati o ns wit hi n 5 half -li ves of t he scree ni n g visit ( V 1) or ta ke t he m d uri n g t he 
st u d y. 
p.  T he patie nt has a n y fi n di n g i n t he bas eli ne 1 2 -lea d electr ocar di o gra m c o nsi dere d 
cli nicall y si g nifica nt i n t he j u d g me nt of t h e i n vesti gat or.  
q.  T he patie nt has a n y fi n di n g t hat, i n t he j u d g me nt of t he i n vesti gat or, is a cli nicall y 
si g nifica nt a b n or malit y, i ncl u di n g ser u m c he mistr y, he m at ol o g y, c oa g ulati o n, a n d 
uri nal ysis test val ues (a b n or mal tests ma y b e re p eate d f or c o nfir mati o n).  
r. T he patie nt has he p atic e nz y m es (ala ni n e a mi n otr a nsferase, as p artate 
a mi n otra nsferase, a n d al kali ne p h os p hatase) > 1. 5  × t he u p per li mit of t he n or mal 
ra n ge after c o nfir mati o n i n a re peat test or s us pect e d he pat ocell ular da ma ge t hat 
f ulfills t he criteria f or H y’s la w at t he scree ni n g visit ( V1) .  
s. T he patie nt has ser u m creati ni ne > 1. 5  × t h e u p per li mit of n or mal ra n ge, cli nicall y 
si g nifica nt pr ot ei n uria, or e vi de nce of re n al diseas e at t he scree ni n g visit ( V 1).  
t. T he patie nt has a n y cli nicall y si g nifica nt u nc o ntr olle d me dical c o n diti o n (treate d or 
u ntreate d).  
u.  T he patie nt has a hist or y of alc o h ol or dr u g a b use  i n t he o pi ni o n of t he i n vesti gat or.  
v.  T he patie nt ca n n ot p artici pate or s uccessf ull y c o m plete t he st u d y, i n t he o pi ni o n of 
t heir healt hcare pr o vi d er or t he i n vesti gat or, f or a n y of t he f oll o wi n g reas o ns: 
− me ntall y or le gall y i n ca p acitate d or u n a ble t o gi ve c o nse nt f or a n y reas o n  
− i n c ust o d y d ue t o a n a d mi nistrati ve or a le gal decisi o n, u n der t utela ge, or bei n g 
a d mitte d t o a sa nitari u m or s ocial i nstit uti o n  
− u na ble t o be c o nta cte d i n case of  e mer ge nc y 
− has a n y ot her c o n diti o n, w hic h, i n t he o pi ni o n of t he i n vesti gat or, ma kes t h e 
patie nt i na p pr o priate f or i ncl usi o n i n t he st u d y  
w.  T he patie nt is a st u d y ce nter or s p o ns or e m pl o yee w h o is directl y i n v ol ve d i n t he 
st u d y or t he relati ve of s u c h a n e m pl o yee. 
x.  T he patie nt has a n y dis or der t hat ma y i nterfere wit h t he a bs or pti o n, distri b uti o n, 
meta b olis m, or e x creti o n of I M P.  
y.  T he patie nt is v ul nera ble (e g, pe o ple ke pt i n dete nti o n).  
z. T he patie nt has pre vi o usl y partici pate d i n t his st u d y.  
aa.  T he patie nt has e vi d e nce or me dical hist or y of ps yc h otic s y m pt o ms  as per D S M -V 
criteria s uc h as del usi o ns, hall uci nati o ns, or dis or ga nize d s peec h i n t he past 1 m o nt h.  
b b.  Patie nt has recei ve d o na b ot uli n u mt o xi n A f or mi grai ne or f or a n y me dical or c os metic 
reas o ns r e q uiri n g i njecti o ns i n t he hea d, face, or nec k d uri n g t he 3 m o nt hs bef ore 
scree ni n g visit. 
St atistic al C o nsi der ati o ns  
S a m ple Size R ati o n ale:   
A sa m ple siz e of 2 8 8 ( 1 4 4 per treat me nt gr o u p) e v al ua ble patie nts c o m pleti n g t he st u d y will 
pr o vi de 9 0 % p o wer t o detect a treat me nt differe nce of 2 da ys wit h a c o m m o n sta n dar d de viati o n 
of 5. 2 da ys i n c ha n ges fr o m t he 2 8 -da y baseli ne p eri o d i n m o nt hl y a vera ge mi grai ne da ys 
bet wee n acti ve a n d pla ce b o gr o u ps  at a 2-si de d al p ha le vel of 0. 0 5. T his sa m ple siz e will pr o vi de 
a p pr o xi matel y 8 0 % p o w er t o detect a treat me nt differe nce of 2 p oi nts wit h a c o m m o n sta n dar d 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
2 0  
 
de viati o n of 6 p oi nts i n t he c ha n ge fr o m r a n d o mizati o n ( da y  1) i n H A M -D 1 7 t otal sc ore  at a 
2 -si de d al p ha le v el of 0. 0 5. Ass u mi n g a 1 5 % dr o p -o ut rate, a p pr o xi matel y 3 4 0  patie nts  
(a p pr o xi matel y 1 7 0 patie nts per treat me nt gr o u p) will be ra n d o mize d.  
Pri m ar y Effic ac y A n al ysis:  
T he pri mar y effic ac y e n d p oi nt, c ha n ge fr o m t he 2 8 -da y baseli ne p eri o d i n t he m o nt hl y a v era ge 
n u m ber of mi grai ne d a ys, will be a nal yze d usi n g a nal ysis of c o var ia nce m o del wit h se x, re gi o n 
( U nite d States, E ur o pea n, or rest of w orl d), mi grai ne classificati o n (i e, C M or E M), baseli ne 
P H Q -9 sc ore cate g or y, a n d treat me nt as fact ors a n d baseli ne n u m ber of mi grai ne da ys as a 
c o variate. T he treat me nt differe n ce, t he 9 5 %  c o nfi de nce i nter val f or t he treat me nt differe nce, a n d 
t he ass ociate d p-v al ue will be ge n erat e d fr o m t his m o del.  
Se nsiti vit y A n al ysis:  
Se nsiti vit y a n al ysis usi n g m ulti ple i m p utati o n f or missi n g data i m p utati o n ma y b e c o n d uct e d.  
Sec o n d ar y Effic ac y A n al ysis:  
T he c o nti n u o us sec o n dar y effic ac y e n d p oi nts will be a nal yz e d si milarl y as t he pri mar y efficac y 
e n d p oi nt. A nal ys es usi n g t he mi x e d -effect m o del r e peate d m eas ure met h o d will be c o n d ucte d f or 
c o nti n u o us varia bles assesse d at m ulti ple ti me p oi nts. F or t he pr o p orti o n of res p o n ders, defi ne d 
as 5 0 % or m ore re d u cti o n fr o m t he 2 8 -da y b aseli ne peri o d i n t he m o nt hl y a vera ge n u m ber of 
mi grai ne d a ys, a l o gistic re gressi o n m o del will be use d wit h t he f oll o wi n g effects: treat me nt, se x, 
re gi o n ( U nite d States, E ur o pea n, or rest of w orl d), mi grai ne classificati o n (ie, C M or E M), a n d 
baseli ne P H Q -9 sc ore cat e g or y. T he o d ds rati os ( O Rs), 9 5 % c o nfi de n ce i nter vals (f or O Rs), a n d 
p -val ues will be pres e nte d f or fre ma nez u ma b c o m pari n g t o place b o.  
Ot her Effic ac y A n al ysis:  
 
 
M ulti ple C o m p aris o ns a n d M ulti plicit y:  
A fi x e d -se q ue nce ( hierarc hical) testi n g pr oce d ure will be i m ple me nte d t o c o ntr ol t he t y pe 1 err or 
rate at 0. 0 5. T h e se q ue n ce of c o m paris o ns is detaile d i n t he statistical a nal ysis pla n. 
S afet y A n al yses:  
Safet y a nal yses will be perf or me d o n t h e safet y a n al ysis set. All a d verse e v e nts wil l be c o de d 
usi n g t he Me dic al Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A). S u m maries will be pres e nte d 
f or all a d verse e v e nts ( o v erall a n d b y se v erit y), a d verse e v e nts deter mi ne d b y t he i n vesti gat or t o 
be relate d t o test I M P, seri o us a d verse e ve nts, a n d a d verse e ve nts c a usi n g wit h dra wal fr o m t he 
st u d y. S u m maries will be prese nte d b y tr eat me nt gr o u p a n d f or all patie nts. Patie nt listi n gs of 
deat hs, seri o us a d v erse e ve nts, a n d a d verse e v e nts lea di n g t o wit h dra wal will be prese nte d. 
C ha n ges i n la b orat or y, ele ctr ocar di o gra m, a n d vital si g ns meas ure me nts data will be s u m marize d 
descri pti vel y.  
T oler a bilit y A n al ysis:  
T olera bilit y fi n di n gs will be liste d a n d s u m marize d descri pti vel y.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
2 1  
 
T A B L E O F C O N T E N T S  
TI T L E P A G E  ...................................................................................................................................1  
A M E N D M E N T HI S T O R Y  .............................................................................................................3  
I N V E S TI G A T O R A G R E E M EN T ...................................................................................................4  
S P O N S O R P R O T O C O L A P P R O V A L  ...........................................................................................5  
C O O R DI N A TI N G I N V E S TI G A T O R A G R E E M E N T  ...................................................................6  
C LI NI C A L S T U D Y P R O T O C O L S Y N O P SI S ...............................................................................7  
LI S T O F A B B R E VI A TI O N S  ........................................................................................................2 9  
1.  
I N T R O D U C TI O N A N D B A CK G R O U N D I N F O R M A TI O N  ..................................3 1  
1. 1.  
I ntr o d u cti o n .................................................................................................................3 1  
1. 1. 1.  
Disease O v er vie w: Mi grai ne  ......................................................................................3 1  
1. 1. 2.  
Disease O v er vie w: Maj or De pressi ve Dis or der  .........................................................3 1  
1. 1. 3.  
Rati o nale f or Fre ma n ez u ma b De vel o p me nt as a Pre ve nti ve Treat me nt f or 
Mi grai n e i n Patie nts wit h C o m or bi d Maj or De pressi ve Dis or der  ..............................3 1  
1. 1. 4.  
St u d y P ur p os e  .............................................................................................................3 3  
1. 2.  
Fi n di n gs fr o m N o ncli nic al a n d Cli nical St u dies  .........................................................3 3  
1. 2. 1.  
N o ncli nical St u dies  .....................................................................................................3 3  
1. 2. 2.  
Cli nical St u dies  ...........................................................................................................3 4  
1. 2. 2. 1.  
Cli nical P har mac ol o g y St u dies  ...................................................................................3 5  
1. 2. 2. 2.  
Cli nical Safet y a n d Efficac y St u dies  ..........................................................................3 5  
1. 3.  
K n o w n a n d P ote ntial  Be nefits a n d Ris ks t o Patie nts  ..................................................3 7  
1. 3. 1.  
K n o w n a n d P ote ntial Be nefits a n d Ris ks of t he Test I n v esti gati o nal 
Me dici nal Pr o d uct(s)  ..................................................................................................3 7  
1. 3. 1. 1.  
I d e ntifie d Ris ks ...........................................................................................................3 8  
1. 3. 1. 2.  
P ote ntial Ris ks  ............................................................................................................3 8  
1. 3. 2.  
O verall Be nefit a n d Ris k Assess me nt f or T his St u d y  ................................................3 9  
2.  
S T U D Y O BJ E C TI V E S A N D  E N D P OI N T S  ..............................................................4 0  
2. 1.  
Pri mar y a n d Sec o n dar y St u d y O bjecti ves a n d E n d p oi nts  ..........................................4 0  
2. 1. 1.  
J ustificati o n of Pri mar y E n d p oi nt ...............................................................................4 1  
2. 2.  
E x pl orat or y O bjecti ve a n d E n d p oi nts  .........................................................................4 2  
3.  
S T U D Y D E SI G N  .......................................................................................................4 3  
3. 1.  
Ge neral St u d y D esi g n a n d St u d y Sc h e matic Dia gra m  ...............................................4 3  
3. 2.  
Pla n ne d N u m ber of Patie nts a n d C o u ntries  ................................................................4 5  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
2 2  
 
3. 3.  
J ustificati o n f or St u d y D esi g n a n d Selecti o n of P o p ulati o n .......................................4 5  
3. 4.  
St o p pi n g R ules f or t he St u d y  ......................................................................................4 6  
3. 5.  
Sc he d ule of St u d y Pr oce d ures a n d Assess me nts  ........................................................4 7  
4.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  ..............................................5 1  
4. 1.  
Patie nt I ncl usi o n Criteria  ............................................................................................5 1  
4. 2.  
Patie nt E x cl usi o n Criteria  ...........................................................................................5 2  
4. 3.  
Wit h dra wal Criteria a n d Pr oce d ures f or t he Patie nt  ...................................................5 4  
4. 4.  
Re place me nt of Patie nts  .............................................................................................5 6  
4. 5.  
Rescree ni n g  .................................................................................................................5 6  
4. 6.  
Scree ni n g Fail ure  ........................................................................................................5 6  
5.  
T R E A T M E N T S  ..........................................................................................................5 7  
5. 1.  
I n v esti gati o nal Me dici nal Pr o d ucts Use d i n t he St u d y ...............................................5 7  
5. 1. 1.  
Test I n v esti gati o nal Me dici nal Pr o d uct  ......................................................................5 7  
5. 1. 1. 1.  
Starti n g D ose a n d D ose Le v els  ...................................................................................5 7  
5. 1. 1. 2.  
D ose M o dificati o n a n d D ose Stratificati o n  ................................................................5 7  
5. 1. 2.  
Place b o I n vesti gati o nal Me dici nal Pr o d uct  ................................................................5 7  
5. 2.  
Pre parati o n, H a n dli n g, La beli n g, St ora ge, a n d Acc o u nta bilit y f or I M Ps  ...................6 0  
5. 2. 1.  
St ora ge a n d Sec urit y  ...................................................................................................6 0  
5. 2. 2.  
La b eli n g  ......................................................................................................................6 0  
5. 2. 3.  
Acc o u nta bilit y  .............................................................................................................6 0  
5. 3.  
J ustificati o n f or I n vesti gati o nal Me dici nal Pr o d ucts ..................................................6 1  
5. 3. 1.  
J ustificati o n f or D ose of Test I n v esti gati o nal Me dici nal Pr o d uct ..............................6 1  
5. 3. 2.  
J ustificati o n f or Use of Place b o I n v esti gati o nal Me dici nal Pr o d uct  ..........................6 1  
5. 4.  
Ot her Me dici n al Pr o d ucts/ N o n -I n vesti gati o nal Me dici nal Pr o d ucts ..........................6 2  
5. 5.  
Treat me nt after t he E n d of t he St u d y  ..........................................................................6 2  
5. 6.  
Restricti o ns  .................................................................................................................6 2  
5. 6. 1.  
Acti vit y  .......................................................................................................................6 2  
5. 6. 2.  
Bl o o d D o nati o n  ...........................................................................................................6 2  
5. 6. 3.  
Pre g n a nc y  ...................................................................................................................6 2  
5. 7.  
Pri or a n d C o nc o mita nt Me dicati o n or T hera p y  ..........................................................6 2  
5. 8.  
Pr oce d ures f or M o nit ori n g Patie nt C o m plia nce  .........................................................6 3  
5. 9.  
Ra n d o mizati o n a n d Bli n di n g  ......................................................................................6 3  
5. 1 0.  
Mai nte na nce of Ra n d o mizati o n a n d Bli n di n g  ............................................................6 4  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
2 3  
 
5. 1 0. 1.  
Mai nte na nce of Ra n d o mizati o n  ..................................................................................6 4  
5. 1 0. 2.  
Bli n di n g a n d U n bli n di n g  ............................................................................................6 5  
5. 1 0. 3.  
Data M o nit ori n g C o m mittee  .......................................................................................6 5  
5. 1 1.  
T otal Bl o o d V ol u me  ...................................................................................................6 5  
6.  
A S S E S S M E N T O F E F FI C A C Y  ................................................................................6 6  
6. 1.  
Assess me nts of Efficac y  .............................................................................................6 6  
6. 1. 1.  
Electr o nic H ea dac he Diar y  .........................................................................................6 6  
6. 1. 2.  
Mi ni Me ntal State E x a mi nati o n  ..................................................................................6 7  
6. 1. 3.  
Patie nt Healt h Q uesti o n naire -9  ...................................................................................6 7  
6. 1. 4.  
Ha milt o n De pressi o n Rati n g Scale -1 7 ........................................................................6 7  
6. 1. 5.  
Ha milt o n A n xiet y Scal e  ..............................................................................................6 7  
6. 1. 6.  
6 -It e m Hea dac h e I m pa ct Test .....................................................................................6 7  
6. 1. 7.  
Cli nical Gl o bal I m pr essi o n -Se verit y Scale  .................................................................6 8  
6. 1. 8.  
Mi grai n e -S pecifi c Q ualit y of Lif e  ..............................................................................6 8  
6. 1. 9.  
W or k Pr o d ucti vit y a n d A cti vit y I m pair me nt Q uesti o n naire Ge n eral Healt h 
V 2. 0  ............................................................................................................................6 8  
7.  
A S S E S S M E N T O F S A F E T Y  .....................................................................................6 9  
7. 1.  
A d verse E v e nts  ...........................................................................................................6 9  
7. 1. 1.  
Defi nit i o n of a n A d verse E ve nt ..................................................................................6 9  
7. 1. 2.  
Rec or di n g a n d Re p orti n g of A d verse E ve nts  .............................................................7 0  
7. 1. 3.  
Se verit y of a n A d v erse E ve nt  .....................................................................................7 1  
7. 1. 4.  
Relati o ns hi p of a n A d verse E ve nt t o t he I n vesti gati o nal Me dici nal Pr o d u ct  .............7 1  
7. 1. 5.  
Seri o us A d verse E v e nts  ..............................................................................................7 2  
7. 1. 5. 1.  
Defi niti o n of a Seri o us A d verse E ve nt  .......................................................................7 2  
7. 1. 5. 2.  
E x pecte d ness  ...............................................................................................................7 3  
7. 1. 5. 3.  
Re p orti n g a Seri o us A d v erse E ve nt  ............................................................................7 3  
7. 1. 6.  
Pr ot oc ol -Defi ne d A d vers e E ve nts of S pecial I nterest  ................................................7 5  
7. 1. 7.  
Pr ot oc ol De viati o ns Beca use of a n A d verse E v e nt  ....................................................7 5  
7. 2.  
Pre g n a nc y  ...................................................................................................................7 5  
7. 3.  
Me dicati o n Err or a n d S pecial Sit uati o ns Relate d t o t he I n v esti gati o nal 
Me dici nal Pr o d uc ts .....................................................................................................7 6  
7. 4.  
Cli nical La b orat or y Tests  ...........................................................................................7 7  
7. 4. 1.  
Ser u m C he mistr y, He m at ol o g y, C oa g ulati o n, a n d Uri nal ysis  ....................................7 7  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
2 4  
 
7. 4. 2.  
F ollicle -Sti m ulati n g H or m o ne  ....................................................................................7 7  
7. 4. 3.  
H u ma n C h ori o nic G o na d otr o pi n Tests  .......................................................................7 7  
7. 5.  
P h ysical E x a mi nati o ns  ................................................................................................7 7  
7. 6.  
V ital Si g ns ..................................................................................................................7 8  
7. 7.  
Electr ocar di o gra p h y  ....................................................................................................7 8  
7. 8.  
Electr o nic C ol u m bia -S uici de Se verit y Rati n g Scal e  ..................................................7 9  
8.  
A S S E S S M E N T O F P H A R M A C O KI N E TI C S / P H A R M A C O D Y N A M I C S / 
BI O M A R K E R S / P H A R M A C O G E N O MI C S / I M M U N O G E NI CI T Y / 
A N CI L L A R Y S T U DI E S  ............................................................................................8 0  
9.  
S T A TI S TI C S  ..............................................................................................................8 1  
9. 1.  
Sa m ple Siz e a n d P o wer C o nsi derati o ns  .....................................................................8 1  
9. 2.  
A nal ysis Sets  ...............................................................................................................8 1  
9. 2. 1.  
I nte nt-t o-Treat A nal ysis Set  ........................................................................................8 1  
9. 2. 2.  
M o difie d I nte nt -t o-Treat A nal ysis Set  ........................................................................8 1  
9. 2. 3.  
Safet y A nal ysis Set  .....................................................................................................8 1  
9. 2. 4.  
Per -Pr ot oc ol A nal ysis Set  ...........................................................................................8 2  
9. 3.  
Data Ha n dli n g C o n ve nti o ns  ........................................................................................8 2  
9. 3. 1.  
Ha n dli n g Wit h dra wals a n d Missi n g Data  ...................................................................8 2  
9. 4.  
St u d y P o p ulati o n  .........................................................................................................8 2  
9. 4. 1.  
Patie nt Dis p ositi o n  ......................................................................................................8 2  
9. 4. 2.  
De m o gra p hic a n d Baseli ne C haracteristics  ................................................................8 2  
9. 5.  
Efficac y A nal ysis  ........................................................................................................8 3  
9. 5. 1.  
Pri mar y E n d p oi nt  ........................................................................................................8 3  
9. 5. 2.  
Sec o n dar y E n d p oi nts  ..................................................................................................8 3  
9. 5. 3.  
E x pl orat or y/ Ot her E n d p oi nts  ......................................................................................8 4  
9. 5. 4.  
Pla n ne d Met h o d of A nal ysis  .......................................................................................8 4  
9. 5. 4. 1.  
Pri mar y Efficac y A nal ysis  ..........................................................................................8 4  
9. 5. 4. 2.  
Se nsiti vit y A nal ysis  ....................................................................................................8 5  
9. 5. 4. 3.  
Sec o n dar y Efficac y A nal ysis  ......................................................................................8 5  
9. 5. 4. 4.  
E x pl orat or y Effi cac y A n al ysis  ....................................................................................8 5  
9. 6.  
M ulti ple C o m paris o ns a n d M ulti plicit y ......................................................................8 5  
9. 7.  
Safet y A nal ysis  ...........................................................................................................8 5  
9. 8.  
T olera bilit y A n al ysis  ..................................................................................................8 6  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
2 5  
 
9. 9.  
Pla n ne d I nteri m A nal ysis  ............................................................................................8 6  
9. 1 0 . 
Re p orti n g D e viati o ns fr o m t he Statistical Pla n  ..........................................................8 6  
1 0.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  .........................................8 7  
1 1.  
C O M P LI A N C E S T A T E M E N T  ..................................................................................8 8  
1 2.  
D A T A  M A N A G E M E N T A N D R E C O R D K E E PI N G  ..............................................8 9  
1 3.  
FI N A N CI N G A N D I N S U R A N C E  .............................................................................9 0  
1 4.  
P U B LI C A TI O N P O LI C Y  ..........................................................................................9 1  
1 5.  
R E F E R E N C E S  ...........................................................................................................9 2  
1 6.  
S U M M A R Y O F C H A N G E S T O P R O T O C O L  .........................................................9 5  
1 6. 1.  
A me n d me nt 0 4 Date d 0 4 Ma y 2 0 2 0  ...........................................................................9 5  
1 6. 2.  
A d mi nistrati ve Letter 0 2 Date d 1 4 Fe br u ar y 2 0 2 0  ...................................................1 0 0  
1 6. 3.  
A me n d me nt 0 3 Date d 0 4  N o ve m ber  2 0 1 9  ...............................................................1 0 1  
1 6. 4.  
A me n d me nt 0 2 Date d 1 0 Oct o ber 2 0 1 9  ...................................................................1 0 8  
1 6. 5.  
Letter of Clarificati o n 0 1 Date d 2 6 A u g ust 2 0 1 9  .....................................................1 1 2  
1 6. 6.  
A me n d me nt 0 1 Date d 0 4 J u ne 2 0 1 9  .........................................................................1 1 4  
A P P E N DI X  A.  C LI NI C A L L A B O R A T O RI E S A N D O T H E R D E P A R T M E N T S A N D 
I N S TI T U TI O N S .......................................................................................................1 1 8  
A P P E N DI X  B.  S T U D Y P R O C E D U R E S A N D  A S S E S S M E N T S B Y VI SI T  .........................1 2 0  
A P P E N DI X  C.  Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  ..............................1 2 6  
A P P E N DI X  D.  E T HI C S  ...........................................................................................................1 2 8  
A P P E N DI X  E.  BI R T H C O N T R O L M E T H O D S A N D P R E G N A N C Y T E S T I N G .................1 2 9  
A P P E N DI X  F.  L O S T T O F O L L O W -U P  .................................................................................1 3 1  
A P P E N DI X  G.  P R E V E N TI V E MI G R AI N E M E DI C A TI O N S A L L O W E D F O R 3 0 % 
O F T H E S T U D Y P O P U L A T I O N A N D A N TI-D E P R E S S A N T 
M E DI C A TI O N S A L L O W E D F O R T H E W H O L E S T U D Y P O P U L A TI O N 
F O R T H E D U R A TI O N O F T H E S T U D Y  ...............................................................1 3 2  
A P P E N DI X  H.  C LI NI C A L C RI T E RI A F O R DI A G N O SI N G A N A P H Y L A XI S  ...................1 3 4  
A P P E N DI X  I. I C H D-3  DI A G N O S TI C C RI T E RI A  .................................................................1 3 5  
A P P E N DI X  J. T O T A L B L O O D V O L U M E .............................................................................1 3 6  
A P P E N DI X  K.  P R O D U C T C O M P L AI N T S  ............................................................................1 3 7  
A P P E N DI X  L.  D A T A M A N A G E M E N T A N D R E C O R D K E E PI N G  ....................................1 3 9  
A P P E N DI X  M.  P U B LI C A TI O N P O LI C Y  ..............................................................................1 4 2  
A P P E N DI X  N.  C LI NI C A L L A B O R A T O R Y T E S T S  .............................................................1 4 3  
A P P E N DI X  O.  I NJ E C TI O N I N S T R U C TI ON S  .......................................................................1 4 4  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
2 6  
 
A P P E N DI X  P.  M A N A G E M E N T O F S T U D Y A C TI VI TI E S D U RI N G C O VI D -1 9  ..............1 5 0  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
2 7  
 
LI S T O F T A B L E S  
Ta ble  1:  
Pri mar y a n d Sec o n dar y O bjecti ves a n d E n d p oi nts  .....................................................1 0  
Ta ble  2:  
I n v esti gati o nal Me dici nal Pr o d ucts Use d i n t he St u d y ...............................................1 4  
Ta ble  3:  
Pri mar y a n d Sec o n dar y St u d y O bjecti ves a n d E n d p oi nts  ..........................................4 0  
Ta ble  4 : 
St u d y Pr oce d ures a n d Assess me nt s ............................................................................4 8  
Ta ble  5:  
I n v esti gati o nal Me dici nal Pr o d ucts Use d i n t he St u d y ...............................................5 8  
Ta ble  6:  
T he Relati o ns hi p of a n A d verse E ve nt t o t he I M P  .....................................................7 1  
Ta ble  7:  
Cli nical La b orat or y Tests  .........................................................................................1 4 3  
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
2 8  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
O verall St u d y Sc h e matic Dia gra m  .............................................................................4 5  
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
2 9  
 
LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n  
Ter m  
β -H C G  
beta -h u ma n c h ori o nic g o na d otr o pi n  
A L T  
ala ni ne a mi n otra nsferase ( S G P T)  
A L P  
al kali ne p h os p hatase  
A S T  
as partate a mi n otra nsferase ( S G O T)  
A U C  
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve 
C D M S  
cli nical data ma na ge me nt s yst e m  
2 1 C F R  
Title 2 1 C o de of Fe deral Re g ulati o ns ( U S A)  
C GI -S  
Cli nical Gl o bal I m pressi o n -Se verit y  
C G R P  
calcit o ni n ge ne -relate d pe pti de 
CI O M S  
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces  
C M  
c hr o nic mi grai ne  
C ma x   
ma xi m u m o bser ve d plas ma dr u g c o nce ntrati o n  
C O VI D -1 9  
C or o na vir us disease 2 0 1 9  
C R O  
c o ntract researc h or ga nizati o n  
C S R  
cli nical st u d y re p ort  
D S M -V  
Fift h E diti o n of t he Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders  
e C-S S R S  
electr o nic C ol u m bia -S uici de S e verit y Rati n g Scale  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic case re p ort f or m  
E C T  
electr oc o n v ulsi ve t hera p y  
E M  
e pis o dic mi grai ne  
G C P  
G o o d Cli nical Practice  
G P S P  
Gl o bal P atie nt Safet y a n d P har mac o vi gila nce  
H A M -A  
Ha milt o n A n xiet y Scale  
H A M -D 1 7  
Ha milt o n De pressi o n Rati n g S cale -1 7 ite ms  
HI T -6  
6 -ite m Hea dac he I m pact T est 
I B 
I n vesti gat or’s Br oc h ure 
I C F 
i nf or me d c o nse nt f or m 
I C H 
T he I nter nati o nal C o u ncil o n Har m o nisati o n 
I C H D-3  
I nter nati o nal Classificati o n of Hea dac he Dis or ders, 3 r d re visi o n 
I E C 
I n de p e n de nt Et hics C o m mitte e 
I H S 
I nter nati o nal Hea dac he S ociet y 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
3 0  
 
A b bre vi ati o n  
Ter m  
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
i nteracti ve res p o nse tec h n ol o g y 
I T T 
i nte nt-t o-treat 
i v 
i ntra ve n o us 
L S O  
l ocal safet y officer 
M D D  
maj or de pressi ve dis or der  
mI T T  
m o difie d i nte nt -t o-treat 
M S Q o L  
Mi grai ne -S pecific Q ualit y of Life  
O R  
o d ds rati o  
P H Q -9  
P atie nt Healt h Q uesti o n naire -9  
P P  
per -pr ot oc ol  
sc 
s u bc uta ne o us 
S O P  
Sta n dar d O perati n g Pr oce d ure  
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n  
t½   
eli mi nati o n half -life 
tma x   
ti me t o ma xi m u m o bser ve d c o nce ntrati o n 
U L N  
u p per li mit of n or mal  
V  
visit  
V z/ F 
a p pare nt t otal v ol u me  of distri b uti o n (e xce pt f or meta b olites)  
W P AI: G H  
W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Q uesti o n naire G e neral Healt h  
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
3 1  
 
1.  
I N T R O D U C TI O N A N D B A CK G R O U N D I N F O R M A TI O N  
1. 1.  
I ntr o d ucti o n 
1. 1. 1.  
Dise ase O ver vie w: Mi g r ai ne  
Mi grai n e is a pre v ale nt disease c h aracterize d b y att ac ks of hea dac h e a n d ass ociate d s y m pt o ms 
(s uc h as na us ea, v o miti n g, p h ot o p h o bia, or p h o n o p h o bia). T he m ost c o m m o n f or m of mi grai ne 
occ urs o n less t ha n 1 5 d a ys per m o nt h a n d is referre d t o as e pis o dic mi grai ne ( E M) ( Li pt o n, 
2 0 0 7 ). H o we v er, 3 % t o 6 % of i n di vi d uals wit h E M e v ol ve, i n a n y gi ve n year, t o a si g nifica ntl y 
m ore disa bli n g c o n diti o n calle d c hr o ni c mi grai ne ( C M) ( Sc her, 2 0 0 3 ). I n di vi d uals wit h C M 
prese nt wit h hea d ac h es of a n y se verit y o n 1 5 or m ore da ys per m o nt h a n d h a ve mi grai ne o n at 
least 8 da ys per m o nt h. A siz a ble pr o p orti o n of i n di vi d uals wit h C M e x perie nce dail y hea dac h es 
a n d, t heref ore, face c o nsi dera ble disa bilit y ( Bi gal, 2 0 0 8 ). 
1. 1. 2.  
Dise ase O ver vie w: M aj or De pressi ve Dis or der  
Mi grai n e a n d maj or d e pressi ve dis or der ( M D D) are fre q ue ntl y c o m or bi d, wit h a lifeti me 
pre vale n ce of M D D i n mi grai n e of 4 0. 7 % a n d a n o d ds rati o ( O R) of 3. 5 1 c o m pare d t o 
n o n mi grai ne c o ntr ols ( Bresla u, 2 0 0 0 ). Patie nts wit h C M are al m ost t wice as li kel y t o ha ve 
recei v e d a me dical dia g n osis of de pressi o n a n d t o meet criteria f or de pressi o n based o n Patie nt 
Healt h Q uesti o n nair e -9 ( P H Q -9) c o m pare d t o t h ose wit h E M ( B use, 2 0 1 3 ). As t he fre q u e nc y of 
attac ks i n mi grai ne i ncreases fr o m l o w -fre q u e nc y E M t hr o u g h hi g h-fre q u e nc y E M a n d o n t o 
C M, t h e fre q ue n c y of de pressi o n s y m pt o ms i ncreases as w ell ( C h u, 2 0 1 8 ). De pressi o n has als o 
bee n i de ntifie d i n m ulti ple st u dies as a ris k fact or f or t he pr o gressi o n fr o m E M t o C M, a n d a 
“ d ose res p o ns e” ha s b ee n n ote d, wit h i ncreas e d se verit y of de pressi o n i ncreasi n g t he ris k f or 
pr o gressi o n ( As hi na, 2 0 1 2 ). A d diti o nall y, t here a p pears t o be a bi directi o nal ass ociati o n bet wee n 
mi grai ne a n d M D D, wit h m i grai ne at baseli ne pre dicti n g o nset of M D D wit hi n 2 years ( O R 5. 8) 
a n d M D D at bas eli ne pre dicti n g o nset of mi grai n e wit hi n 2 years ( O R 3. 4) ( Bresla u, 2 0 0 3 ). 
1. 1. 3.  
R ati o n ale f or Fre m a nez u m a b De v el o p me nt a s a Pre ve nti ve Tre at me nt f or 
Mi gr ai ne i n P atie nts wit h C o m o r bi d M aj or De pressi ve Dis or der  
T he g o als of mi grai ne treat me nt are t o r elie ve pai n, t o rest ore f u ncti o n, t o re d uce hea dac h e 
fre q ue n c y, a n d t o pr e ve nt pr o gressi o n of E M t o C M. P har mac ol o gical i nter ve nti o ns f or t he 
treat me nt of mi grai ne i n cl u de ac ute (s y m pt o matic) treat me nts a n d pre ve nti v e me dicati o ns.  
Pre ve nti ve dr u g treat me nt ma y be a p pr o pri ate i n a n u m ber of i nsta nces, i n cl u di n g w here 
fre q ue n c y of attac ks per m o nt h is 2 or hi g her, or w here a patient’s q ualit y of life is se verel y 
i m paire d (E vers, 2 0 0 9 ). A n u m ber of dr u gs fr o m differe nt p h ar mac ol o gi cal cate g ories (e g,  beta 
bl oc kers, a ntic o n v ulsa nts) ha ve bee n a p pr o ve d f or mi grai ne pre v e nti o n o r ha ve class A e vi de nce 
t o s u p p ort t heir use. H o we ver, a d h ere nce t o a n d persiste nce o n t hese m e dicati o ns ca n be p o or, 
a n d t here is a n ee d f or pre ve nti ve me dicati o ns t hat are m or e effecti ve a n d b etter t olerate d t h a n 
t he c urre nt sta n dar d of care (P ule d da, 2 0 1 7 ). 
Calcit o ni n ge ne -rel ate d p e pti de ( C G R P) is a well-st u die d ne ur o pe pti de i n v ol ve d i n b ot h ce ntral 
a n d peri p heral pr ocesses u n derl yi n g t he pat h o p h ysi ol o g y of mi grai ne ( Efte k hari, 2 0 1 0 ). J u g ular 
le vels of C G R P are i ncrease d d uri n g mi grai ne attac ks, a n d i ntra ve n o us C G R P a d mi nistrati o n 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
3 2  
 
i n d uces mi grai ne-li ke h ea dac h e i n m ost i n di vi d uals wit h mi grai ne (As hi n a, 2 0 0 0 ; Ha nse n, 2 0 1 0 ). 
C G R P is i n v ol ve d i n t he pat h o p h ysi ol o g y of mi grai ne at all le vels, peri p herall y ( ne ur o nal, 
se nsitiz ati o n, vas o dilati o n, i nfla m mati o n a n d pr otei n e xtra vasati o n), at t he tri ge mi nal ga n gli o n, 
a n d i nsi de t he brai n ( H o, 2 0 1 0 ). St u dies ha ve s h o w n t hat i n hi biti o n of C G R P was efficaci o us i n 
t he treat me nt of E M (Bi gal, 2 0 1 5 a; D o dic k, 2 0 1 8 a; D o dic k, 2 0 1 8 b ; Re uter, 2 0 1 8 ) a n d C M 
(Bi gal, 2 0 1 5 a; Sil berstei n, 2 0 0 8 ).  
Fre ma n ez u ma b ( T E V -4 8 1 2 5 [f or merl y L B R -1 0 1, P F -0 4 4 2 7 4 2 9, a n d R N 3 0 7]) is a f ull y 
h u ma nize d I g G 2( delta)  a/ ka p pa m o n ocl o nal a nti b o d y, w hic h h as bee n de vel o pe d f or 
a d mi nistrati o n b y t he s u b c uta ne o us (sc) r o ute f or t he pre ve nti ve treat me nt of mi grai ne. 
Fre ma n ez u ma b was a p pr o ve d i n t he U nite d States i n Se pte m ber 2 0 1 8, recei ve d p ositi ve o pi ni o n 
fr o m E M A/ C H M P i n J a n uar y 2 0 1 9, a n d mar keti n g a ut h orizati o n a p plicati o ns ha ve bee n 
s u b mitte d i n a n u m ber of c o u ntries w orl d wi de. Fre ma nez u ma b p ote ntl y a n d selecti vel y bi n ds t o 
b ot h C G R P is of or ms ( α - a n d β-C G R P)  t o pre ve nt t he m fr o m bi n di n g t o t he C G R P rece pt or. 
Fre ma n ez u ma b  is s pecifi c f or C G R P a n d d oes n ot bi n d t o cl osel y relate d fa mil y m e m bers 
(e g, a m yli n, calcit o ni n, i nter me di n, a n d a dre n o me d ulli n). T w o m utati o ns were i ntr o d uce d i nt o 
t he c o nsta nt re gi o n of t he fre ma n ez u ma b hea v y c h ai n t o li mit a nti b o d y effect or f u ncti o ns. T his 
l oss of f u ncti o n pre ve nts fre ma n ez u ma b fr o m sti m ulati n g a nti b o d y-de p e n de nt cell -me diate d 
c yt ot o xicit y a n d tri g geri n g c o m ple m e nt -me diate d l ysis, w hic h ca n lea d t o u n wa nte d 
c o nse q ue nces s uc h as cell l ysis, o ps o nizati o n, a n d c yt o ki ne release a n d i nfl a m m ati o n (Ar m o ur, 
1 9 9 9 ; Zeller, 2 0 0 8 ). 
T he safet y a n d t olera bilit y of fre ma n ez u ma b (i ntra ve n o us [i v] d oses ra n gi n g fr o m 0. 2 t o 
2 0 0 0  m g a n d s c d oses of 2 2 5 m g a n d 9 0 0 m g) has bee n well c h aracterize d i n t he P hase  1 
de vel o p me nt pr o gra m. A d diti o nal P hase 1 st u dies c o m plete d i ncl u de St u d y T V 4 8 1 2 5 -P K -1 0 0 7 8 
t o assess t he p har mac o ki netics, safet y, a n d t olera bilit y of si n gle-d ose sc a d mi nistrati o n of 
fre ma n ez u ma b i n J a pa nese a n d Ca ucasia n healt h y s u bjects, a n d St u d y  T V 4 8 1 2 5 -B E -1 0 1 1 4 t o 
c o m pare t he p h ar mac o ki netics of fre ma nez u ma b a d mi nistere d sc usi n g a n a ut oi nject or i n 
refere nce t o a prefille d s yri n ge. F urt h er m ore, t h e safet y a n d efficac y of fre ma nez u ma b ha ve bee n 
de m o nstrate d i n a ra n d o mize d d o u ble -bli n d, place b o -c o ntr olle d P hase 2 b st u d y of 
2  fre ma n ez u ma b sc d osi n g re gi me ns (fre ma nez u m a b 9 0 0 m g m o nt hl y or fre ma nez u ma b 6 7 5 m g 
f oll o we d b y 2 2 5 m g m o nt hl y) i n patie nts wit h C M, a n d a ra n d o mize d, d o u ble-bli n d,  
place b o -c o ntr olle d P hase 2 st u d y of 2 fre ma nez u ma b sc d osi n g re gi me ns (fre ma nez u ma b 6 7 5 m g 
m o nt hl y or fre ma nez u ma b 2 2 5 m g m o nt hl y) i n p atie nts wit h E M. F urt her m ore, t he efficac y a n d 
t olera bilit y pr ofile h a ve b ee n c o nfir me d i n t he P hase 3 de vel o p me nt pr o gra m, w hic h i ncl u de d 
fre ma n ez u ma b 2 2 5 m g s c m o nt hl y a n d fre ma nez u ma b 6 7 5 m g sc q u arterl y.  
P ost h oc a nal ys es of data fr o m St u d y T V 4 8 1 2 5 -C N S -3 0 0 4 9 (t he H A L O C M st u d y) 
de m o nstrate d si g nifica nt re d ucti o ns i n mi grai ne a n d hea dac he da ys i n patie nts wit h c o m or bi d 
de pressi o n, si g nifica nt r e d ucti o ns i n disa bilit y, a n d si g nifica nt i m pr o ve m e nts i n q ualit y of life. 
A d diti o nall y, patie nts wit h a baseli ne P H Q -9 of 1 0 t o 1 9 e x perie nce d re d ucti o ns i n P H Q -9 of 9. 5 
t o 1 0. 5 p oi nts o n a vera ge o ver t he 1 2 wee ks of t he st u d y w he n tr eate d wit h fre ma nez u ma b 
q uarterl y or m o nt hl y. Base d o n t hese data a n d t he bi directi o nal relati o ns hi p of mi grai ne a n d 
M D D, fre m a nez u ma b offers t he p ote ntial be n efit of i m pr o ve me nt i n mi grai ne i n patie nts wit h 
c o m or bi d M D D as w ell as t he p ossi bilit y of i m pr o ve me nt i n de pressi o n.  
I n t hes e p ost h oc a n al ys es fr o m t he H A L O C M st u d y, 2 4 1 patie nts wit h mi grai ne a n d P H Q-9 
sc ores of ≥1 0, c o nsiste nt wit h m o derate t o se vere de pressi o n, ha d si milar d e m o gra p hics t o t h ose 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
3 3  
 
wit h sc ores < 1 0, b ut ha d hi g her n u m b ers of h ea d ac he da ys of at least m o derate se v erit y, 
mi grai ne d a ys, a n d 6 -ite m Hea dac he I m pact Test ( HI T-6)  sc ores at baseli n e, s u g gesti n g t hat 
patie nts wit h c o m or bi d m o derate t o se v ere d e pressi o n als o ha d m ore se vere mi grai ne disease 
b ur de n t ha n t h ose wit h mil d or n o  de pressi o n. Patie nts wit h P H Q -9 sc ores of ≥1 0 s h o we d 
si g nifica nt r e d ucti o ns i n mi grai ne d a ys o ver 1 2 wee ks of fre ma nez u ma b treat me nt c o m pare d 
wit h place b o treat me nt  (-5. 4  q uarterl y, -5. 5  m o nt hl y, -2. 4 place b o, p < 0. 0 0 2 f or b ot h m o nt hl y 
a n d q uarterl y d osi n g c o m pare d wit h place b o ). Si g nifica nt re d u cti o ns were als o n ote d f or 
hea dac he da ys of at least m o derate se v erit y, as earl y as 4 wee ks after t h e first d ose. T hese 
re d ucti o ns were greater t ha n t h ose see n i n t he o v erall st u d y p o p ulati o n. A d verse e v e nts i n t his 
s u b gr o u p w ere si milar t o t he o verall st u d y p o p ulati o n, wit h n o seri o us a d verse e ve nts t h o u g ht t o 
be relate d t o treat me nt b y i n vesti gat ors. T h ere were n o cases of s uici de or s uici de atte m pt i n t his 
s u b gr o u p. T h e m ost c o m m o n a d verse e ve nts i n t his s u b gr o u p were i njecti o n site reacti o ns at 
si milar rates see n i n t he o verall p o p ulati o n. 
T he de m o nstrate d effic ac y, fa v ora bl e safet y, a n d t olera bilit y, l o n g ter mi nal eli mi nati o n half -life 
(t½ , a p pr o xi matel y 3 0 da ys), a n d d osi n g re gi me n c h oices ( q uarterl y or m o nt hl y) of 
fre ma n ez u ma b pr o vi de s u bsta ntial t hera pe utic p ot e ntial f or patie nts wit h C M or E M a n d 
c o m or bi d M D D.  
1. 1. 4.  
St u d y P ur p ose  
T he p ur p ose of t h e st u d y is t o  assess if fre ma nez u ma b is effecti ve i n pre v e nti n g mi grai ne i n 
patie nts wit h M D D.  
1. 2.  
Fi n di n gs fr o m N o n cli nic al a n d Cli nic al St u dies  
Brief s u m maries of n o ncli nical p har mac ol o g y, p h ar mac o ki netics, a n d t o xic ol o g y st u dies a n d 
cli nical st u dies are pr o vi de d i n t he f oll o wi n g s ecti o ns. M ore detaile d i nf or mati o n is pr o vi de d i n 
t he I n v esti gat or’s Br oc h ure (I B). 
1. 2. 1.  
N o nc li nic al St u dies 
I n vi v o p h ar mac ol o g y st u dies of fre m a nez u ma b i n a ni mal m o dels i n dicate t hat fre ma nez u ma b 
pre ve nte d a n i ncrease i n bl o o d fl o w i n rat pa w s ki n a n d t he mi d dle me ni n geal arter y aft er 
electrical sti m ulati o n a n d pr o d uce d a d ose -d e pe n d e nt i n hi biti o n of t he ca psaici n -i n d uce d s ki n 
flare res p o nse i n c y n o m ol g us m o n ke y. 
Safet y p h ar mac ol o g y para meters of fre ma nez u ma b were assesse d i n t he pi v otal t o xic ol o g y 
st u dies i n S pra g ue Da wle y rats a n d c y n o m ol g us m o n ke ys a n d a se p arate car di o vasc ular safet y 
p har mac o l o g y st u d y i n male c y n o m ol g us m o n ke ys. T here were n o treat me nt-relate d c ha n ges i n 
electr ocar di o gra ms ( E C Gs) a n d heart rat es i n t he 1 - a n d 3-m o nt h t o xicit y st u dies, a n d a si n gle i v  
d ose of fre ma nez u ma b at 1 0 0 m g/ k g di d n ot res ult i n c ha n ges i n car di o vasc ula r para meters or 
b o d y te m perat ur e i n m o n ke ys. A d diti o nall y, n o tar get or ga n t o xicit y was i d e ntifie d. I n t hese 
refere nce d st u dies, t he n o-o bser ve d -a d verse-effect le vel ra n ge d fr o m 1 0 0 t o 3 0 0  m g/ k g d ose d 
eit her i v or sc. I n a 3 -m o nt h m o n ke y st u d y, peri v asc ula r i nfla m mati o n of t h e ciliar y arter y was 
o bser ve d i n a fe w a ni mals at d oses ≥1 0 0 m g/ k g. T he i nfla m mati o n was s us pecte d t o be t he res ult 
of i m m u ne c o m ple x f or mati o n/ de p ositi o n fr o m t he m o n ke ys’ i m m u n o ge nic res p o nse t o t he dr u g 
(fre ma n ez u ma b). I n t he pi v otal 6 -m o nt h c hr o nic t o xicit y st u d y i n m o n ke ys f oll o wi n g o nce -
wee kl y sc d osi n g at d osa ge l e vels of u p t o 3 0 0  m g/ k g/ wee k, ac hi e vi n g hi g h e x p os ure t hr o u g h o ut 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
3 4  
 
t he st u d y, n o micr osc o pi c fi n di n gs w ere n ote d i n a n y of t he or ga ns, i ncl u di n g t he ciliar y vessels 
of t he  e yes, a n d t he n o -o bser ve d -a d verse-effect le vel of t he c hr o ni c t o xicit y st u d y was 
deter mi ne d t o be t he hi g h est d ose teste d, 3 0 0  m g/ k g/ wee k. T h us, it is belie ve d t hat i n vie w of t he 
l o w fre q ue n c y (ie, o bs er ve d i n ver y fe w a ni mals) a n d mi ni mal se verit y, t he fi n di n g ( peri vasc ul ar 
i nfla m mati o n) t hat was o nl y rec or de d i n t he 3-m o nt h t o xicit y st u d y, a n d h a d bee n res ol v e d 
d uri n g t he rec o v er y peri o d, is a n i nci de ntal fi n di n g.  
T he p har mac o ki netics of fre ma n ez u ma b i n a ni mals (rats a n d m o n ke ys) is t y pical of a h u ma niz e d 
I g G 2 m olec ule, wit h l o w mea n plas ma cleara n ce, l o w v ol u me of distri b uti o n at stea d y state, a n d 
a l o n g t ½ . E x p os ure as defi ne d b y t h e ma xi m u m o bser ve d plas ma dr u g c o n ce ntrati o n ( Cma x ) a n d 
t he area u n der t h e plas ma c o nce ntr ati o n-ti me c ur ve ( A U C) i ncreas e d li nearl y acr oss d oses 
f oll o wi n g si n gle a n d re peate d o nce-wee kl y d osi n g. N o se x differe nces i n e x p os ure were 
o bser ve d i n rats or m o n ke ys.  
A d diti o nall y, pi v otal re pr o d ucti ve a n d de v el o p me ntal t o xicit y st u dies i n ra b bits a n d rats wit h 
fre ma n ez u ma b were c o n d ucte d a n d c o m plet e d. Preli mi nar y d ata s u g gest t h at wee kl y d osi n g wit h 
fre ma n ez u ma b was well t olerate d a n d di d n ot i n d uce a n y o b vi o us mater nal t o xicit y at a n y d ose 
le vel. N o a p pare nt e vi de nce of e m br y o-fetal t o xicit y was n ote d i n a n y d os e gr o u p. 
O verall, n o t o xic ol o gical c o ncer ns were i de ntifie d f oll o wi n g u p t o 6 m o nt hs of d osi n g t o t he 
e x peri me ntal a ni mals.  
F urt her details ma y be f o u n d i n t he c urre nt I n v esti gat or’s Br oc h ure.  
1. 2. 2.  
Cli nic al St u dies  
T he cli nical pr o gra m t o date is c o m p ose d of 7 c o m plete d P hase 1 cli nical st u dies i n healt h y 
s u bjects ( St u dies B 0 1 4 1 0 0 1, B 0 1 4 1 0 0 2, B 0 1 4 1 0 0 6, B 0 1 4 1 0 0 7, L B R -1 0 1 -0 0 8, L B R -1 0 1 -0 1 1, 
a n d T V 4 8 1 2 5 -P K -1 0 0 7 8), 1 c o m plete d P hase 1 bi oe q ui vale nce st u d y ( T V 4 8 1 2 5 -B E -1 0 1 1 4), 
2  c o m plete d P hase 2 b cli nical st u dies i n patie nts wit h mi grai ne  ( St u dies L B R -1 0 1 -0 2 1 a n d 
L B R -1 0 1 -0 2 2), a n d 2 c o m plete d P hase 3 cli nical st u dies i n patie nts wit h mi grai n e 
( St u dies T V 4 8 1 2 5 -C N S -3 0 0 4 9 a n d T V 4 8 1 2 5 -C N S -3 0 0 5 0).  
A t otal of 3 1 9 6 s u bjects/ patie nts ( 3 1 8 healt h y s u bjects a n d 2 8 7 8 patie nts wit h mi grai ne) h a ve 
bee n e nr olle d i n 1 3 st u di es i n t he fre ma nez u ma b mi grai ne cli nical de vel o p me nt pr o gra m. O verall 
i n t he fre ma n ez u ma b cli nical pr o gra m, 2 0 1 3 p atie nts wit h mi grai ne a n d 2 5 6 healt h y s u bjects 
ha ve recei ve d at least 1 d ose of fre ma nez u ma b i n c o m plete d a n d o n g oi n g cl i nical st u dies. T w o 
P hase 3 st u dies ( St u dies T V 4 8 1 2 5 -C N S -3 0 0 5 1 a n d T V 4 8 1 2 5 -C N S -3 0 0 6 8) are c urre ntl y o n g oi n g 
t o f urt her e v al uate t he efficac y, safet y, a n d t olera bilit y of vari o us d ose re gi me ns of 
fre ma n ez u ma b i n t he pre ve nti ve treat me nt of mi grai ne ( C M a n d E M).  
I n a d diti o n, 2 P hase 3 st u dies ( St u dies T V 4 8 1 2 5-C N S -3 0 0 5 6 a n d T V 4 8 1 2 5 -C N S -3 0 0 5 7) a n d 
1  P hase  2 st u d y ( St u d y  T V 4 8 1 2 5 -C N S -2 0 0 2 4 ) are o n g oi n g, a n d 1 P has e 3 st u d y 
( St u d y T V 4 8 1 2 5 -C N S -3 0 0 5 8) is pla n ne d t o e val u ate t he efficac y, safet y, a n d t olera bilit y of 
vari o us d ose re gi me ns of fre ma n ez u ma b i n t he pre ve nti ve treat me nt of cl uster hea d ac h e.  
T w o P hase 2/ 3 st u dies i n J a pa nese a n d K orea n E M a n d C M patie nts ( 4 0 6 -1 0 2 -0 0 0 0 2 a n d 
4 0 6 -1 0 2 -0 0 0 0 1, res p ecti vel y) t o e val u ate t h e efficac y a n d safet y of fre ma nez u ma b as pa rt of t he 
c o m plete cli nical de v el o p me nt pla n, a n d o ne P hase 3 b st u d y ( T V 4 8 1 2 5 -C N S -3 0 0 6 8) t o e val uate 
mi grai ne p atie nts w h o ha d i na de q uate res p o nse t o 2 t o 4 ot her pre vi o us pre ve nti ve treat me nts 
ha ve starte d.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
3 5  
 
A brief s u m mar y of cli nical p har ma c ol o g y a n d cli nical safet y a n d efficac y st u dies of 
fre ma n ez u ma b f oll o ws. 
1. 2. 2. 1.  
Cli nic al P h ar m ac ol o g y St u dies  
A t otal of 1 1 8 healt h y s u bjects recei ve d fre ma nez u ma b acr oss 8 c o m plete d P hase 1 st u dies i n 
d oses ra n gi n g fr o m 0. 2 t o 2 0 0 0 m g.  
Si x of t hese st u dies were 2 si n gle -ascen di n g -d os e p har mac o ki netic a n d p har mac o d y na mic 
st u dies i n healt h y me n ( St u dies B 0 1 4 1 0 0 1 a n d B 0 1 4 1 0 0 2); a 2-c o h ort, place b o -c o ntr olle d 
cr oss o ver st u d y t o e x a mi ne t he ac ut e effects of a d mi nistrati o n of fre ma nez u ma b o n ca psaici n 
flare res p o nse i n healt h y me n ( St u d y B 0 1 4 1 0 0 6); a parallel-gr o u p, re peat -d ose st u d y of 
fre ma n ez u ma b i n healt h y s u bjects ( St u d y B 0 1 4 1 0 0 7); a si n gle-d ose st u d y e val uati n g t he s afet y, 
t olera bilit y, a n d p h ar mac o ki netics of d oses u p t o 2 0 0 0 m g a d mi nistere d i v i n healt h y w o me n 
( St u d y L B R-1 0 1 -0 0 8 [f or merl y referre d t o as St u d y  B 0 1 4 1 0 0 8]); a n d a st u d y ass essi n g t he 
safet y, t olera bilit y, a bs ol ute bi oa vaila bilit y, a n d p har mac o ki netics of si n gl e i v or sc d oses of 
fre ma n ez u ma b i n healt h y s u bjects ( St u d y L B R -1 0 1 -0 1 1). T hese P has e 1 st u dies were a nal yz e d 
usi n g t he ori gi nal bi oa n al ytical met h o d t hat has b ee n deter mi ne d t o be u nrelia ble a n d 
u n deresti mate me as ure d plas ma c o nce ntrati o ns c o m pare d t o t he c urre nt vali date d assa y.  
A n ot her c o m plete d P has e 1 st u d y t hat i n vesti gate d p har mac o ki netics was 
St u d y  T V 4 8 1 2 5 -B E -1 0 1 1 4, a n o pe n -la bel, si n gle-d ose, ra n d o mize d, bi oe q ui vale nce st u d y i n 
healt h y s u bjects desi g ne d t o c o m pare t he p har mac o ki netics of fre m a nez u ma b a d mi nistere d sc 
usi n g 2 m o des of a d mi nistrati o n: t he test a ut oi nject or a n d a prefille d s yri n ge.  
A p ha r mac o ki n etic, safet y, a n d t olera bilit y st u d y was c o n d ucte d i n healt h y J a pa nese a n d 
Ca ucasia n s u bjects ( St u d y T V 4 8 1 2 5 -P K -1 0 0 7 8) d ose d wit h fre ma nez u ma b as a n sc d ose of 2 2 5, 
6 7 5,  or 9 0 0  m g. Plas ma c o nce ntrati o n -ti me pr ofile was meas ure d usi n g t h e c urre nt v ali date d 
bi oa nal ytical met h o d, a n d t he p har mac o ki n etic res ults are descri b e d bel o w. T he 
p har mac o ki netics ( n o n -c o m part me ntal a nal ysis) of fre ma nez u ma b de m o nstrate d a n i ncrease i n 
C ma x  a n d A U C val ues sli g htl y greater t ha n d os e pr o p orti o nalit y o ver sc d os e ra n ge of 2 2 5 t o 
9 0 0  m g. Me dia n ti me t o ma xi m u m o bser ve d c o nce ntrati o n (t ma x ) val ues ge nerall y occ urre d 5 t o 
7  da ys f oll o wi n g s c d oses. Mea n val ues f or a p p are nt v ol u me of distri b uti o n ( V z/ F) after a si n gle 
sc d ose ra n ge d fr o m 5. 7 t o 6. 4 L at 2 2 5 t o 9 0 0 m g sc doses. T he mea n a p pare nt t otal b o d y 
cleara nce ra n ge d fr o m 0. 0 7 7 7 t o 0. 0 8 9 5 m L/ mi n at t his d ose ra n ge. T he mea n t ½  ra n ge d fr o m 
3 2. 2 3 t o 3 6. 1 5  da ys. Fre ma nez u ma b e x p os ure para meters a n d o v erall p har mac o ki netic pr ofile 
were si milar f or healt h y J a pa nese a n d Ca u casia n s u bjects. A bs ol ute bi oa vaila bilit y f oll o wi n g s c 
a d mi nistrati o n of fre ma n ez u ma b was a p pr o xi matel y 5 4 % t o 5 7 %.  
1. 2. 2. 2.  
Cli nic al S afet y a n d Effic ac y St u dies  
T he safet y, t olera bilit y, a n d effic ac y of fre ma nez u ma b ha ve bee n e v al uate d i n 2 c o m plete d 
P hase  2 b st u d ies ( St u dies L B R-1 0 1 -0 2 1 a n d L B R -1 0 1 -0 2 2) i n patie nts wit h mi grai ne ( Bi gal, 
2 0 1 5 a; Bi gal, 2 0 1 5 b ). T h e res ults of b ot h st u dies s h o we d fre ma nez u ma b t o be s u peri or t o 
place b o f or pri mar y a n d sec o n dar y e n d p oi nts ( be n efit at 3  m o nt hs of t hera p y).  
Fre ma n ez u ma b was w ell t olerate d wit h fa v ora ble s afet y pr ofile acr oss t he 8 c o m plete d P hase 1 
st u dies, 2 c o m plete d P hase 2 b st u dies, a n d 2 c o m plete d P hase 3 st u dies i n patie nts wit h mi grai ne. 
T he treat me nt -e mer ge nt a d verse e ve nts r e p orte d i n t he P hase 1, P hase 2 b, a n d P hase 3 st u dies 
were pre d o mi na ntl y mil d t o m o derate i n se verit y. A s pecific “ patter n of a d verse e v e nts” t hat 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
3 6  
 
c o ul d be ass ociat e d wit h a d ose o r a d os e ra n ge of fre ma nez u ma b has n ot bee n i de ntifie d, n or h as 
a ma xi mall y t olerate d d ose bee n i de ntifie d. O verall, t he nat ure a n d occ urre nce of t he re p orte d 
treat me nt-relate d a d v erse e ve nts acr oss t he cli nical pr o gra m ha ve n ot raise d a n y s p ecific s afet y 
c o ncer ns.  
T w o pi v otal P hase 3 st u dies i n C M a n d E M patie nts ( St u dies T V 4 8 1 2 5 -C N S -3 0 0 4 9 a n d 
T V 4 8 1 2 5 -C N S -3 0 0 5 0), c o nfir me d efficac y fi n di n gs i n P hase 2. St u d y T V 4 8 1 2 5 -C N S -3 0 0 4 9 
was a 1 6 -w ee k, m ultice nt er, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, parallel -gr o u p st u d y 
t o c o m pare t he effic ac y, safet y, a n d t olera bilit y of 2 d ose re gi me ns of s c fre ma nez u ma b 
(fre ma n ez u ma b 6 7 5 m g q uarterl y [ 6 7 5  m g/ place b o/ place b o; N = 3 7 9] a n d a starti n g d ose of 
fre ma n ez u ma b 6 7 5 m g f oll o we d b y fre ma nez u ma b 2 2 5  m g m o nt hl y [ 6 7 5/ 2 2 5/ 2 2 5 m g; N = 3 7 6]) 
a n d place b o ( N = 3 7 5) i n a d ults ( 1 8 t hr o u g h 7 0  years of a ge) wit h C M. Patie nts w h o were o n 
m o n ot hera p y ( 7 9 %) a n d patie nts o n sta ble d oses of pre ve nti ve m e dicati o ns ( 2 1 %) were i ncl u d e d 
i n t he st u d y. T he st u d y c o nsiste d of a scree ni n g visit, a baseli ne peri o d lasti n g a p pr o xi matel y 
4  wee ks ( ~ 2 8  d a ys), a n d a treat me nt peri o d lasti n g a p pr o xi matel y 1 2  wee ks.  
T he a nal ysis of t he pri mar y effic ac y e n d p oi nt, t he mea n c ha n ge fr o m b aseli ne i n t he m o nt hl y 
a vera ge n u m ber of hea d ac he da y s of at least m o derate se v erit y d uri n g t he 1 2-wee k p eri o d aft er 
t he 1st d ose of st u d y dr u g, de m o nstrate d statisticall y si g nifica nt differe nces fr o m place b o i n f a v or 
of fre ma n ez u ma b ( p < 0. 0 0 0 1) f or b ot h acti ve treat me nt gr o u ps. T h e me dia n f or t he o verall 
c han ge fr o m baseli ne of -4. 2 a n d -4. 5 ( mea n re d u cti o n of 4. 7 a n d 4. 9  da ys) vers us -2. 5 ( mea n 
re d ucti o n of 2. 9 da ys) hea dac h e da ys of at least m o derate s e verit y f or t h e 
6 7 5  m g/ place b o/ place b o a n d 6 7 5/ 2 2 5/ 2 2 5  m g treat me nt gr o u ps vers us t he place b o gr o u p, 
res pecti vel y. T h e least s q uare ( L S) m ea n differe n ce fr o m place b o was 1. 8 d a ys f or 
6 7 5  m g/ place b o/ place b o a n d 2. 1  da ys f or 6 7 5/ 2 2 5/ 2 2 5  m g.  
Statisticall y si g nifica nt i m pr o ve me nts ( p < 0. 0 0 0 1 f or b ot h c o m paris o ns vers us place b o) were 
e vi de nt as earl y as m o nt h 1 (sec o n dar y e n d p oi nt), 
 
 (e x pl orat ory e n d p oi nts). T he 
res ults of t he a nal yses of eac h of t h e ot her sec o n dar y e n d p oi nts f urt her s u p p ort t he efficac y of 
b ot h fre ma nez u ma b d ose re gi me ns; all c o m paris o ns vers us place b o were statisticall y si g nifica nt. 
T h us, patie nts treate d wit h fre ma n ez u ma b were  si g nifica ntl y m or e li kel y t o be res p o n ders 
( ≥5 0 % re d u cti o n i n t he n u m ber of hea dac h e da ys of at least m o derate se v erit y), ha d si g nifica ntl y 
fe wer mi grai ne da ys a n d da ys wit h use of ac ute hea dac h e me dicati o n, a n d re p orte d si g nifica ntl y 
less disa bilit y t ha n p atie nts treate d wit h place b o. I n a d diti o n, t he o verall treat me nt effect o n 
hea dac he da ys of at least m o derate se v erit y was als o o bser ve d i n t he s u bset of patie nts ( 7 9 % of 
patie nts) w h o were n ot recei vi n g c o nc o mita nt pre v e nti ve me dicati o n.  
Fre ma n ez u ma b a t t he d oses teste d was ge n erall y s afe a n d well t olerate d f or 3 m o nt hs i n patie nts 
wit h C M. Seri o us a d verse e ve nts a n d a d verse e ve nts lea di n g t o disc o nti n u ati o n fr o m t he st u d y 
occ urre d i nfre q ue ntl y a n d wit h si milar i nci de nce acr oss t he treat me nt gr o u ps. M os t a d verse 
e ve nts were mil d t o m o derate . I njecti o n site-relate d a d verse e ve nts w ere t h e m ost fre q ue nt 
treat me nt-relate d a d v erse e ve nts a n d w ere o v erall c o m para ble acr oss all treat me nt gr o u ps.  
St u d y T V 4 8 1 2 5 -C N S -3 0 0 5 0  was a 1 6 -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, parallel -gr o u p st u d y t o c o m p are t he efficac y, safet y, a n d t olera bilit y of 
2  d ose re gi me ns of s c fre ma nez u ma b ( q uarterl y d ose of 6 7 5  m g fre m a nez u ma b 
[ 6 7 5-m g/ place b o/ place b o; N = 2 9 1] a n d d oses m o nt hl y 2 2 5  m g fre ma nez u ma b [ 2 2 5/ 2 2 5/ 2 2 5 -m g; 
N = 2 9 0]) a n d place b o ( N = 2 9 4) i n a d ults ( 1 8  t hr o u g h 7 0 years of a ge) wit h E M. Patie nts w h o 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
3 7  
 
were o n m o n ot hera p y ( 7 9 %) a n d patie nts o n sta bl e d oses of pre ve nti ve me dicati o ns ( 2 1 %) were 
i ncl u de d i n t he st u d y. T h e st u d y c o nsiste d of a scree ni n g visit, a baseli ne  p eri o d lasti n g 
a p pr o xi matel y 4  wee ks ( ~ 2 8  da ys), a n d a treat me nt peri o d lasti n g a p pr o xi matel y 1 2 wee ks.  
T he a nal ysis of t he pri mar y effic ac y e n d p oi nt, t he mea n c ha n ge fr o m b aseli ne i n t he m o nt hl y 
a vera ge n u m ber of mi grai ne da ys d uri n g t he 1 2 -wee k peri o d after t h e 1 st d ose of st u d y dr u g, 
de m o nstrate d statisticall y si g nifica nt differe nces fr o m place b o i n fa v or of fre ma nez u ma b 
( p < 0. 0 0 0 1) f or b ot h acti v e treat me nt gr o u ps. T h e me dia n f or t he o verall c h a n ge fr o m b aseli ne 
was -4. 0 a n d -4. 2  da ys ( mea n  re d u cti o n of 3. 9 a n d 4. 0 da ys) vers us -2. 7 d a ys ( mea n re d ucti o n 
2. 6  da ys) f or t he 6 7 5  m g/ place b o/ place b o a n d 2 2 5/ 2 2 5/ 2 2 5  m g treat me nt gr o u ps vers us t he 
place b o gr o u p, res pecti vel y. T h e L S m ea n differe nce fr o m place b o was 1. 3  da ys f or 
6 7 5  m g/ place b o/ place b o a n d 1. 5  da ys f or 2 2 5/ 2 2 5/ 2 2 5  m g.  
Statisticall y si g nifica nt i m pr o ve me nts ( p < 0. 0 0 0 1 f or b ot h c o m paris o ns vers us place b o) were 
e vi de nt as earl y as m o nt h 1 (sec o n dar y e n d p oi nt), 
 
 (e x pl orat or y e n d p oi nts). T he 
res ults of t he a nal yses of eac h of t h e ot her sec o n dar y e n d p oi nts f urt her s u p p ort t he efficac y of 
b ot h fre ma nez u ma b d ose re gi me ns; all c o m paris o ns vers us place b o were statisticall y si g nifica nt. 
T h us, pati e nts treate d wit h fre ma n ez u ma b were si g nifica ntl y m or e li kel y t o be res p o n ders 
( ≥5 0 % re d u cti o n i n t he n u m ber of mi grai ne da ys), ha d si g nifica ntl y fe wer da ys wit h use of ac ute 
hea dac he me dicati o n, a n d re p orte d si g nifica ntl y l ess disa bilit y t h a n patie nts tre ate d wit h place b o. 
I n a d diti o n, t he o verall tr eat me nt effect o n mi grai ne da ys was als o o bser ve d i n t he s u bset of 
patie nts ( 7 9 % of patie nts) w h o were n ot recei vi n g c o nc o mita nt pre ve nti ve me dicati o n.  
Fre ma n ez u ma b at t he d oses teste d was ge n erall y s afe a n d we ll t olerate d f or 3 m o nt hs i n patie nts 
wit h E M. Seri o us a d vers e e ve nts a n d a d verse e ve nts lea di n g t o disc o nti n u ati o n fr o m t he st u d y 
occ urre d i nfre q ue ntl y a n d wit h si milar fre q ue nc y acr oss t he treat me nt gr o u ps.  I njecti o n 
site-relate d a d vers e e ve nts were t he m ost fre q ue nt treat me nt -relate d a d v erse e ve nts a n d were 
c o m para ble acr oss all treat me nt gr o u ps.  
O ne P hase 3 st u d y ( St u d y T V 4 8 1 2 5 -C N S -3 0 0 5 1) was c o n d ucte d t o f urt her e val uate l o n g -ter m 
effic ac y, safet y, a n d t olera bilit y of vari o us d ose re gi me ns of fre ma nez u ma b i n t he pre ve nti ve 
treat me nt of mi grai ne ( C M a n d E M). F or t he place b o r oll o ver a n d t h e ne w patie nts, t he efficac y 
pr ofile d uri n g t he first 3 m o nt h was si milar t o w hat was see n i n St u dies  T V 4 8 1 2 5 -C N S -3 0 0 4 9 
a n d T V 4 8 1 2 5 -C N S -3 3 0 5 0 f or patie nts treate d wit h fre ma nez u ma b. F or all patie nts, efficac y was 
s ustai ne d f or o ver 6 m o nt hs i n t he l o n g-ter m treat me nt peri o d w he n patie nts recei v e d 
fre ma n ez u ma b wit h o ut i nterr u pti o n. 
N o cli nicall y rele v a nt c h a n ges i n cli nical la b orat or y v al ues, vital si g ns meas ure me nts, or E C G 
fi n di n gs ha v e bee n o bs er ve d i n a n y of t he st u dies t o date. 
1. 3.  
K n o w n a n d P ote nti al Be nefits a n d Ris ks t o P atie nts  
1. 3. 1.  
K n o w n a n d P ote nti al Be nefits a n d Ris ks of t he Test I n vesti g ati o n al Me dici n al 
Pr o d uct(s)  
A d diti o nal i nf or mati o n re gar di n g be n efits a n d ris ks t o  patie nts ma y be f o u n d i n t he I B . 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
3 8  
 
1. 3. 1. 1.  
I de ntifie d Ris ks 
1. 3. 1. 1. 1.  Ge ner al Dis or ders a n d A d mi nistr ati ve Sit e C o n diti o ns  
Re p orts of tra nsie nt a d mi nistrati o n site reacti o ns, i ncl u di n g i njecti o n site br uisi n g, i njecti o n site 
s welli n g, i njecti o n site pai n, i njecti o n site pr urit us, i njecti o n site i n d urati o n, i njecti o n site 
er yt h e ma, i njecti o n site i nfla m mati o n, i njecti o n site war mt h, i njecti o n site der matitis, i njecti o n 
site ras h, i njecti o n site e d e ma, i njecti o n site disc o mf ort, i njecti o n site he m orr ha ge, i njecti o n site 
irritati o n, i njecti o n site mass, a n d i njecti o n site he mat o ma, ha ve occ urre d wit h sc a d mi nistrati o n. 
A m o n g t hes e e ve nts, t he f oll o wi n g ha v e bee n i d e ntifie d as a d verse dr u g reacti o ns (i de ntifie d 
ris ks): i njecti o n site er yt h e ma, i njecti o n site i n d urati o n, i njecti o n site pr urit us, i njecti o n site pai n, 
a n d i njecti o n site ras h. N o ne of t he i de ntifie d ris ks were c o nsi dere d i m p ort a nt ris ks.  
1. 3. 1. 1. 2.  I nj ur y, P ois o ni n g, a n d Pr o ce d ur al C o m plic ati o ns/I m m u ne S yste m Dis or ders  
T he ge neral ris ks of i nf usi o n reacti o ns wit h m o n ocl o nal a nti b o d y a d mi nistrati o n i ncl u de fe ver, 
hea dac he, na us ea, v o miti n g, a n d h y p ot e nsi o n. T hese a d verse e ve nts are ge n erall y ascri be d t o 
l ysis of cell ular tar gets, c yt o ki ne releas e, or c o m pl e me nt acti vati o n. 
T y pe I h y pers e nsiti vit y or aller gic reacti o ns (e g, s h ort nes s of breat h, urticaria, a na p h yla xis, a n d 
a n gi o e de ma) are t he oreti call y p ossi ble wit h a n y i njecte d pr otei n.  
T y pe III h y p erse nsiti vit y reacti o ns occ ur as a c o ns e q ue nce of a n a nti b o d y res p o nse t o t he 
i njecte d pr otei n res ulti n g i n i m m u ne c o m ple x f or mati o n. S uch i m m u ne c o m ple x f or mati o n a n d 
s u bse q ue nt de p ositi o n i n tiss ues ma y res ult i n s y m pt o ms, i ncl u di n g ras h, urticaria, p ol yart hritis, 
m yal gias, p ol ys y n o vitis, fe ver, ne uritis, or a n gi oe de ma, a n d if u ntreate d a n d se vere, ca n pr o gress 
t o gl o mer ul o ne p hritis. 
I nf usi o n-relat e d reacti o n a n d dr u g h y perse nsiti vit y ha ve occ urre d rarel y wit h fre ma nez u ma b. I n 
all patie nts i n t he place b o c o ntr olle d st u dies, dr u g h y perse nsiti vit y occ urre d i n 2  patie nts ( < 1 %) 
w h o recei ve d place b o a n d 2 patie nts ( < 1 %) w h o recei ve d fre m a nez u ma b ( 1  m o derate e v e nt a n d 
1 mil d e ve nt). A m o n g all fre ma n ez u ma b -treate d patie nts, 3 a d diti o nal patie nts w h o recei v e d 
fre ma n ez u ma b ha d a d verse e ve nts of dr u g h y p erse nsiti vit y ( 2 m o derate e ve nts a n d 1 mil d e ve nt).  
1. 3. 1. 2.  
P ote nti al Ris ks  
1. 3. 1. 2. 1.  Peri v asc ul ar I nfl a m m ati o n  
I n the 3 -m o nt h m o n ke y t o xic ol o g y st u d y, i nfla m mati o n ar o u n d t he ciliar y vessel of t he e ye was 
o bser ve d. Base d o n t h e l o w -gra d e i ncrease i n i m m u ne c o m ple x de p osits o bser ve d i n t he i nti ma 
a n d/ or me dia of ciliar y v essels i n t he a ni mals wit h peri vasc ular i nfla m mat i o n, t hese e ve nts w ere 
assesse d as b ei n g d u e t o t he m o n ke ys’ i m m u n o ge nic res p o nse t o h u ma nize d m o n ocl o nal 
a nti b o d y rat her t ha n a p h ar mac ol o gic t o xicit y a n d are n ot li kel y t o be rele va nt i n a cli nical 
setti n g. M ore o v er, a c o nfir mat or y 6-m o nt h st u d y c o ul d n o t re peat t he fi n di n gs. 
1. 3. 1. 2. 2.  C o nse q ue nces of C alcit o ni n Ge ne -Rel at e d Pe pti de I n hi biti o n  
Beca use C G R P is a vas o dilat or, t here is a t he oretical ris k of u nfa v ora ble car di o vasc ular effects 
wit h C G R P i n hi biti o n. E xte nsi ve researc h c o n d ucte d wit h t he C G R P rece pt or a nt a g o nists has n ot 
i de ntifie d rele va nt s afet y car di o vas c ular c o n cer ns i n h u ma ns. De dicate d st u dies c o n d ucte d i n 
m o n ke y a n d h u ma ns usi n g fre ma n ez u ma b ha ve n ot i de ntifie d cli nicall y rele va nt c ha n ges i n heart 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
3 9  
 
rate, bl o o d press ure, or ot her car di o vasc ular para m eters. N o rele va nt car di o vasc ular e ve nt has 
bee n see n i n t he c o m plet e d st u dies.  
1. 3. 2.  
O ver all Be nefit a n d Ris k Assess me nt f or T his St u d y  
I n s u m mar y, t he be nefit a n d ris k assess me nt f or fre ma nez u ma b is fa v ora ble f oll o wi n g re vie w of 
t he a vaila ble safet y a n d efficacy data.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
4 0  
 
2.  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S  
2. 1.  
Pri m ar y a n d Sec o n d ar y St u d y O bjecti ves a n d E n d p oi nts  
T he pri mar y a n d s ec o n d ar y st u d y o bje cti ves a n d e n d p oi nts are i n Ta ble  3 : 
T a ble  3 : 
Pri m ar y a n d Sec o n d ar y St u d y O bjecti ves a n d E n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri m ar y o bjecti ve:  
T o e val uate t he effi cac y of 
m o nt hl y 2 2 5  m g s u b c uta ne o us 
(sc) fre ma nez u ma b i n a d ult 
patie nts wit h mi grai ne a n d 
maj or de pressi ve dis or d er 
( M D D) 
Mea n c ha n ge i n t he m o nt hl y a v era ge n u m ber of mi grai n e da ys 
fr o m t he 2 8-da y b aseli ne peri o d d uri n g t he 1 2 -wee k peri o d 
after t he first d ose of st u d y dr u g  
Ke y sec o n d ar y o bjecti ve: 
T o e val uate t he effi cac y of 
m o nt hl y 2 2 5  m g sc of 
fre ma n ez u ma b i n a d ult patie nts 
wit h mi grai ne  a n d M D D o n t he 
re d ucti o n of M D D s y m pt o ms 
Mea n c ha n ge i n de pressi o n s y m pt o ms fr o m ra n d o mizati o n 
( da y 1) t o wee k 8  after t h e first d ose of st u d y dr u g as meas ure d 
b y:  
•  Ha milt o n De pressi o n Rati n g Scale -1 7  ite ms 
( H A M-D 1 7)  
Sec o n d ar y o bjecti ve:  
T o e val uate t he effi cac y of 
m o nt hl y 2 2 5  m g sc 
fre ma n ez u ma b i n a d ult patie nts 
wit h mi grai ne a n d M D D i n 
ter ms of res p o n d er rates in 
m o nt hl y mi grai ne da ys  
N u m ber of patie nts wit h 5 0 % or m ore re d ucti o n fr o m t he 
2 8 -da y baseli ne p eri o d i n t he m o nt hl y a vera ge n u m ber of 
mi grai ne da ys at 1 2 w ee ks after t he first d ose of st u d y dr u g  
Sec o n d ar y o bjecti ve:  
T o e val uate t he effi cac y of 
m o nt hl y 2 2 5  m g sc 
fre ma n ez u ma b i n a d ult patie nts 
wit h mi grai ne a n d M D D i n 
ter ms of i m pr o vi n g q u alit y of 
life 
Mea n c ha n ge i n q ualit y of life fr o m r a n d o mizati o n visit 
( da y 1) t o wee k  1 2 after t he first d ose of st u d y dr u g  as 
meas ure d b y:  
•  Mi grai n e -S pecifi c Q ualit y of L if e ( M S Q o L) 
q uesti o n naire, r ole f u ncti o n-restricti ve a n d r ole 
f u ncti o n-pre v e nti ve d o mai ns  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
4 1  
 
T a ble  3 : 
Pri m ar y a n d Sec o n d ar y St u d y O bjecti ves a n d E n d p oi nts ( C o nti n ue d)  
O bjecti ves  
E n d p oi nts  
Sec o n d ar y o bjecti ve:  
T o e val uate t he effi cac y of 
m o nt hl y 2 2 5  m g sc 
fre ma n ez u ma b i n a d ult patie nts 
wit h mi grai ne a n d M D D i n 
ter ms of i m pr o vi n g disa bilit y  
Mea n c ha n ge fr o m ra n d o mizati o n visit ( da y  1) i n disa bilit y 
sc ore f or o verall i m pact as meas ure d b y Cli nical Gl o bal 
I m pr essio n -Se verit y ( C GI -S) a n d 6 -ite m H ea dac h e I m p act 
Test ( HI T -6) t o t he f oll o wi n g ti me p oi nts after a d mi nistrati o n 
of t he first d ose of st u d y dr u g:  
•  wee ks 4 a n d 8 ( C GI -S)  
•  wee k 1 2 ( C GI -S a n d HI T -6)  
S afet y a n d t oler a bilit y 
o bjecti ve  
( Sec o n d ar y o bjecti v e): 
T o e val uate t he s afet y a n d 
t olera bilit y of m o nt hl y 2 2 5  m g  
sc a n d q uart erl y 6 7 5 m g sc 
fre ma n ez u ma b i n a d ult patie nts 
wit h mi grai ne a n d M D D  
•  occ urre nce of a d v erse e v e nts t hr o u g h o ut t he st u d y  
•  c ha n ges fr o m ra n d o mizati o n visit ( da y 1) i n vital 
si g ns ( p ulse, s ystolic a n d diast olic bl o o d press ure, 
b o d y te m perat ur e, a n d res pirat or y rate) 
meas ure me nts  
•  a b n or mal p h ysical e xa mi nati o n fi n di n gs i ncl u di n g 
b o d y wei g ht  
•  use of c o nc o mita nt me di cati o n f or a d v erse e ve nts 
d uri n g t he st u d y  
•  n u m ber ( %) of patie nts w h o di d n ot c o m pl ete t he 
st u d y d ue t o a d verse e ve nts  
•  occ urre nce of se v ere h y p erse nsiti vit y/a na p h yl a xis 
reacti o ns 
•  s uici dal i deati o n a n d be h a vi or as s u g geste d b y 
e C-S S R S  
C GI -S  =  Cli nical Gl o bal I m pr essi o n -Se verit y; e C -S S R S  =  el ectr o nic C ol u m bia -S uici de Se verit y Rati n g Scal e; 
H A M -D 1 7 = Ha milt o n De pressi o n Rati n g Scale -1 7  ite ms; HI T-6  =  6 -ite m Hea dac he I m p act T est; M D D = maj or 
de pressi ve dis or der; M S Q o L = Mi grai ne -S pecific Q ualit y of Life; sc  =  s u bc uta ne o us. 
2. 1. 1.  
J ustific ati o n of Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt w as c h ose n b ase d o n t h e I nt er nati o nal Hea dac he S oci et y (I H S) g ui deli nes 
f or trials i n mi grai ne, w hic h s u g gest t hat t he m ost a p pr o priate pri mar y e n d p oi nt t o ca pt ure 
effic ac y of treat me nt is t he c ha n ge fr o m bas eli ne i n t he m o nt hl y a vera ge n u m ber of mi grai ne 
da ys ( Sil berstei n, 2 0 0 8 ). 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
4 2  
 
2. 2.  
E x pl or at or y O bjecti ve a n d E n d p oi nts  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
4 3  
 
3.  
S T U D Y D E SI G N  
3. 1.  
Ge ner al St u d y Desi g n a n d St u d y Sc he m atic Di a gr a m  
T his is a n a p pr o xi matel y 2 8 -we e k, m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o 
i n vesti gati o nal me dici nal pr o d uct (I M P)-c o ntr olle d, parallel -gr o u p st u d y t o e val uate t he efficac y 
a n d safet y of fre m a nez u ma b self-a d mi nistere d at m o nt hl y d os es of 2 2 5  m g sc a n d a q uarterl y 
d ose of 6 7 5  m g s c (ie,  o n e d ose  usi n g 3  prefille d s yri n ges wit h 2 2 5 m g eac h) i n a d ult patie nts 
wit h mi grai ne a n d M D D . T he st u d y will c o nsist of a 2 8-da y (i e,  4 -wee k) baseli ne peri o d, a 
1 2 -wee k d o u bl e -bli n d treat me nt p hase f oll o we d b y a 1 2 -wee k o pe n -l a bel e xte nsi o n p hase, a n d 
a n e n d-of -treat me nt visit (a p pr o xi matel y 1 2 wee ks after t he fi nal d ose of st u d y dr u g). 
T he t otal d urati o n of pati e nt partici pati o n i n t he st u d y is pla n ne d t o be a p pr o xi matel y 2 8 wee ks. 
Patie nts are e x pecte d t o c o m plete t he e ntire d urati o n of t he st u d y.  
T his st u d y will i ncl u de fe male a n d male patie nts, a ge d 1 8 t o 7 0 years, i ncl usi ve, wit h a dia g n osis 
of mi grai ne a n d M D D. Patie nts m ust ha ve bee n di a g n os e d wit h mi grai ne at least 1 2  m o nt hs pri or 
t o t he scree ni n g visit ( visit [ V] 1). T he dia g n osis of mi grai ne (as d efi ne d b y t he I nt er nati o nal 
Classificati o n of Hea d ac he Dis or ders, 3 r d re visi o n [I C H D-3] criteria [ I H S, 2 0 1 3], see 
A p pe n di x  I) will be pr os pecti vel y c o nfir m e d via a re vie w of mi grai ne data rec or de d dail y d uri n g 
a 2 8-da y bas eli ne peri o d i n a n electr o nic di ar y de vice. Patie nts m ust als o ha ve a hist or y of M D D 
acc or di n g t o t he Fift h E diti o n of t he Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders 
( D S M-V) criteria at least 1 2 m o nt hs pri or t o t he scree ni n g visit ( V 1) a n d h a ve acti ve s y m pt o ms 
of de pressi o n as assesse d b y a P H Q -9 sc ore of at l east 1 0 at  scree ni n g. I n v esti gat ors m ust 
d oc u me nt t hat patie nts ha d t he dia g n osis of mi grai ne a n d M D D f or at least 1 2  m o nt hs pri or t o 
t he scree ni n g visit ( V 1). 
D uri n g t h e 2 8 -da y b aseli ne  peri o d, patie nts m ust f ulfill t he f oll o wi n g criteri a f or mi grai ne:  
•  o n ≥4 da ys, h ea dac he attac ks q ualifie d as mi grai n e base d o n t he f oll o wi n g I C H D -3 
criteria:  
− I C H D-3 dia g n ostic criteria C a n d D f or 1. 1 Mi grai ne wit h o ut a ura  
− I C H D-3 criteria B a n d C f or 1. 2 Mi grai ne wit h a ura  
− pr o ba ble mi grai ne (a mi grai ne s u bt y pe w here o nl y 1 mi grai ne c riteri o n is 
missi n g)  
− tri pta n or er g ot deri vati ve use d t o treat a n esta blis he d hea d ac he. 
Patie nts w h o f ulfill t he criteria f or mi grai ne will be f urt her d eli neate d as patie nts wit h C M or 
E M, f or stratificati o n a n d ot her a nal yses.  
C M is defi ne d as:  
Patie nt f ulfills t he f oll o wi n g criteria f or C M i n pr os pecti vel y c ollecte d baseli ne i nf or mati o n 
d uri n g t he 2 8 -da y bas eli ne  peri o d:  
•  hea dac he occ urri n g o n ≥1 5 da ys  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
4 4  
 
•  o n ≥8 da ys, f ulfilli n g a n y 1 of t he f oll o wi n g:  
− I C H D-3 dia g n ostic criteria C a n d D f or 1. 1 Mi grai ne wit h o ut a ura ( A p pe n di x  I) 
− I C H D-3 criteria B a n d C f or 1. 2 Mi grai ne wit h a ura ( A p pe n di x  I) 
− pr o ba ble mi grai ne (a mi grai ne s u bt y pe w here o nl y 1 mi grai ne criteri o n is 
missi n g)  
− tri pta n or er g ot deri vati ve use d t o treat esta blis he d hea dac he. 
E M is defi ne d as:  
T he patie nt f ulfills t he f oll o wi n g criteri a f or E M i n pr os pecti vel y c ollecte d baseli ne i nf or mati o n 
d uri n g t he 2 8 -da y bas eli ne  peri o d:  
•  hea dac he occ urri n g ≥4  d a ys b ut < 1 5  
•  o n ≥4 da ys, f ulfilli n g a n y 1 of t he f oll o wi n g:  
− I C H D-3 dia g n ostic criteria C a n d D f or 1. 1 Mi grai ne wit h o ut a ura ( A p pe n di x  I) 
− I C H D-3 criteria B a n d C f or 1. 2 Mi grai ne wit h a ura ( A p pe n di x  I) 
− pr o ba ble mi grai ne (a mi grai ne s u bt y pe w here o nl y 1 mi grai ne criteri o n is 
missi n g)  
− tri pta n or er g ot deri vati ve use d t o treat a n esta blis he d hea d ac he 
At t he ra n d o mizati o n visit ( da y 1) , patie nts will be ra n d o ml y assi g n e d t o 1 of 2 treat me nt gr o u ps 
of 2 2 5  m g sc fre m a nez u ma b or place b o i n a 1: 1  rati o. Patie nts will recei ve t heir assi g n e d st u d y 
treat me nt o n visit 2 ( da y 1), visit 3 ( da y  2 9), a n d visit  4 ( da y  5 7) a n d t he n c o nti n ue i nt o t he 
o pe n -la bel e xte nsi o n p hase i n w hic h all patie nts will recei ve a q u arterl y d os e of 6 7 5 m g sc 
fre ma n ez u ma b o n visit 5 ( da y 8 5). I n v esti gat ors ca n c o ntact patie nts i n bet w ee n st u d y visits per 
t heir cli nical j u d g m e nt. 
Patie nts w h o c o m plete all sc he d ule d visits  will ha ve pr oce d ures a n d assess me nts perf or me d at 
visit  6 (e n d of treat me nt). Patie nts w h o wit h dra w fr o m t he st u d y bef ore c o m pleti n g t he 2 4 -wee k 
treat me nt p hase will ha ve visit 6 (e n d of treat me nt) pr oce d ures a n d assess me nts perf or me d at 
t heir fi nal visit.  
St u d y pr oce d ures a n d ass ess me nts wit h t heir ti me p oi nts are s h o w n i n Ta bl e  4 . T he st u d y 
sc he matic dia gra m is s h o w n i n Fi g ure  1 . 
T he e n d of st u d y is defi n e d as t he last visit (e n d -of -treat me nt/earl y wit h dra wal visit [ visit 6]) of 
t he last patie nt. 
T he st u d y d urati o n will be a p pr o xi matel y 2 4 m o nt hs, f r o m a p pr o xi matel y S e pte m ber 2 0 1 9 (first 
patie nt scree ne d) t o a p pr o xi matel y A u g ust  2 0 2 1 (last visit of t he last patie nt) . 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
4 5  
 
Fi g ure  1 : 
O ver all St u d y Sc he m ati c Di a gr a m  
 
E O T = e n d of treat me nt; P B O = place b o; sc = s u bc uta ne o us; V = visit. 
A re d circle i n dicates a st u d y site visit w he n st u d y me dicati o n is self-a d mi nistere d . A bl ue s q uare i n dicates a st u d y 
site visit w he n st u d y me dicati o n is n ot a d mi nistere d. 
3. 2.  
Pl a n ne d N u m ber of P atie nts a n d C o u ntries  
A p pr o xi matel y 3 4 0 p atie nts (a p pr o xi matel y 1 7 0 p atie nts per treat me nt gr o u p) are pl a n ne d t o be 
e nr olle d i n t his st u d y t o ha ve a p pr o xi matel y 2 8 8  c o m pleters ( 1 4 4  c o m pleters per treat me nt 
gr o u p). A 1 5 % dr o p -o ut rate is a ntici pate d.  
Details o n defi niti o n of e val ua ble patie nts a n d s a m ple siz e are gi ve n i n Secti o n 9 . 
T he st u d y is pla n ne d t o b e c o n d ucte d i n a p pr o xi matel y 1 3  c o u ntries i n a p pr o xi matel y 
6 5  i n vesti gati o nal c e nters. T he st u d y is e x pecte d t o start i n a p pr o xi matel y Se pte m ber 2 0 1 9 a n d 
last u ntil a p pr o xi matel y A u g ust 2 0 2 1.  
3. 3.  
J ustific ati o n f or St u d y Desi g n a n d Selecti o n of P o p ul ati o n  
T he st u d y p o p ulati o n will be c o m p ose d of fe male a n d male patie nts, a ge d 1 8 t o 7 0  years, 
i ncl usi ve, wit h a dia g n osis of mi grai ne a n d M D D. Patie nts m ust ha ve bee n dia g n ose d wit h 
mi grai ne (as defi ne d b y t he I C H D -3 criteria [ I H S, 20 1 3 ], see A p pe n di x  I) at least 1 2 m o nt hs 
pri or t o t he scree ni n g visit ( V 1). T he dia g n osis of mi grai ne will be pr os pecti vel y c o nfir me d via a 
re vie w of mi grai ne data rec or de d d ail y d uri n g a 2 8-da y baseli ne p eri o d i n a n electr o nic diar y 
de vice. Patie nts m ust als o ha ve a hist or y of M D D acc or di n g t o t he D S M -V criteria at least 
1 2  m o nt hs pri or t o t he scree ni n g visit ( V 1) a n d h a ve acti ve s y m pt o ms of de pressi o n as assesse d 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
4 6  
 
b y a P H Q -9 sc ore of at least 1 0 at t he scree ni n g visit ( V 1). I n vesti gat ors m ust d oc u me nt t hat 
patie nts ha d t he dia g n osis of mi grai ne a n d M D D f or at least 1 2  m o nt hs pri or t o t he scree ni n g 
visit ( V 1). M D D is a c o m m o n c o m or bi dit y wit h mi grai ne.  P ost h oc a nal yses of t he H A L O C M 
st u d y i n dicate d t hat d e pressi ve s y m pt o ms i m pr o v e d i n mi grai n e patie nts wit h baseli ne P H Q -9 of 
1 0 t o 1 9. T his st u d y is desi g ne d t o f urt her e v al uate t he efficac y of fre m a nez u ma b i n t his 
p o p ulati o n.  
C o m merciall y a p pr o ve d d os i n g re gi me ns will be i n vesti gate d i n t he d o u bl e-bli n d treat me nt 
p hase. B ot h t he m o nt hl y d ose of 2 2 5 m g a n d q uarterl y d os e of 6 7 5  m g, w hi c h will be use d i n t he 
c urre nt st u d y i n t he d o u ble -bli n d a n d t he o pe n -l a b el peri o ds, res p ecti vel y, were e q uall y 
effic aci o us i n t he pi v otal trials. F or treat me nt details, see Secti o n  5. 1 . 
O ne o bjecti ve of t his st u d y is t o deter mi ne w het h er mi grai ne a n d de pressi o n are af fecte d 
i n de pe n de ntl y b y fre ma n ez u ma b or w het her i m pr o ve me nt i n o ne disease prece d es a n d ma y 
ca usall y i m pr o ve t he ot h er disease vi a t heir bi directi o nal ass ociati o n (see Secti o n  1. 1. 2  f or 
f urt her bac k gr o u n d i nf or mati o n). B y assessi n g b ot h mi grai ne a n d de pressi o n s y m pt o ms at 
m ulti ple ti me p oi nts a n d b y ha vi n g pla ce b o p atie nts cr oss o ver t o acti ve treat me nt, we will ha ve 
m ore data p oi nts b y w hic h t o ma ke t his assess me nt. A d diti o nall y, t h e o pe n-la bel e xte nsi o n p hase  
is i nte n de d t o pr o vi de t he place b o-tr eate d patie nts t he o p p ort u nit y t o recei v e p ote ntial be nefit 
fr o m t hera p e utic d oses. It als o pr o vi des a n o p p ort u nit y t o f urt her e x pl ore efficac y a n d t olera bilit y 
in t his patie nt p o p ulati o n  a n d t o ge nerate data o n s witc hi n g fr o m t he m o nt hl y t o t he q uart erl y 
d ose.  
T o pr o vi de a d diti o nal e x pertise i n de pressi o n, a n xiet y, a n d s uici d alit y ass ess me nts a n d 
ma na ge me nt, ps yc hiatrists will be i ncl u de d i n t he st u d y tea m at t he i n vesti gati o nal site. 
A ra n d o mize d, d o u ble -bli n d, parallel -gr o u p, place b o -c o ntr olle d desi g n is a p pr o priate gi ve n t he 
o bjecti ves of t his st u d y. F urt her m ore, t his desi g n is c o nsiste nt wit h t he rec o m me n dati o ns of t he 
Classificati o ns C o m mittee of t he I H S f or c o ntr olle d trials of pre ve nti ve dr u gs i n mi grai ne ( Tfelt -
Ha nse n, 2 0 1 2 ). 
3. 4.  
St o p pi n g R ules f or t he St u d y  
T here are n o f or mal r ules f or earl y t er mi nati o n of t his st u d y. D uri n g t he c o n d uct of t he st u d y, 
seri o us a d vers e e v e nts will be re vie we d ( Secti o n 7. 1 . 5) as t he y are re p orte d fr o m t he 
i n vesti gati o nal c e nters t o i de ntif y safet y c o n cer ns.  
T he st u d y  ma y b e ter mi n ate d b y t he s p o ns or f or a n y reas o n at a n y ti me. F or e x a m ple, t he 
s p o ns or s h o ul d ter mi nate t he st u d y i n t he e v e nt of: 
•  ne w t o xic ol o gical or p har mac ol o gical fi n di n gs or safet y iss ues i n vali date t he earlier 
p ositi ve be nefit -ris k assess me nt 
A pati e nt ma y disc o nti n ue partici pati o n i n t he st u d y at a n y ti me f or a n y reas o n (e g, lac k of 
effic ac y, c o ns e nt wit h dra w n, or a d verse e v e nt). T he i n vesti gat or a n d/ or s p o ns or ca n wit h dr a w a 
patie nt fr o m t he st u d y at a n y ti me f or a n y reas o n (e g,  i m p orta nt pr ot oc ol de viati o n s as defi ne d i n 
A p pe n di x  C , n o nc o m plia nce, or a d v erse e ve nt). I n a d diti o n, patie nts wit h p ositi ve s uici dalit y 
fi n di n gs or a b n or mal he p atic la b orat or y v al ues (e g, ala ni ne a mi n otra nsferase [ A L T], as part ate 
a mi n otra nsferase [ A S T], al kali ne p h os p hatase [ A L P], ga m ma gl uta m yl tra ns pe pti dase, bilir u bi n 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
4 7  
 
[t otal, direct, or i n direct], or i nter nati o nal n or malize d rati o) ma y meet t he criteria f or 
disc o n ti n uati o n fr o m t he I M P ( Secti o n 7. 1. 1  a n d Secti o n  7. 1. 5. 1 ). 
3. 5.  
Sc he d ule of St u d y Pr oce d ures a n d Assess me nts  
St u d y pr oce d ures a n d ass ess me nts wit h t heir ti me p oi nts are pres e nte d i n T a ble  4 . Detaile d 
descri pti o ns of eac h met h o d of pr oce d ures a n d assess me nts are pr o vi d e d i n Secti o n  6  (efficac y 
assess me nts) a n d Secti o n  7  (safet y ass ess me nts). St u d y pr oce d ures a n d ass ess me nts b y visit are 
liste d i n A p pe n di x  B . I n v esti gat ors ca n c o nt act patie nts i n bet wee n st u d y visits per t heir cli nical 
j u d g me nt. 
F or C or o na vir us disease 2 0 1 9 ( C O VI D -1 9 ) u p dat es, see A p pe n di x  P . 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
4 8  
 
T a ble  4 : 
St u d y Pr oce d ures a n d Assess me nts  
St u d y pe ri o d  
Pretre at me nt 
(scree ni n g 
a n d b aseli ne)  
D o u ble -bli n d tre at me nt p h ase  
O pe n -l a bel 
e xte nsi o n 
p h ase  
E n d of 
tre at me nt/ 
E arl y 
ter mi n ati o na/ 
F oll o w -u p 
peri o d  
Visit n u m ber  
V 1  
V 2 b 
V 3  
V 4  
V 5 c 
V 6  
D a y a n d all o w e d ti me 
wi n d o ws  
D a ys -2 8 
t o -1  
D a y  1  
+ 3  d a y(s)  
D a y  2 9  
± 3  d a y(s)  
D a y  5 7 
± 3  d a y(s)  
D a y  8 5  
± 3  d a y(s)  
D a y  1 6 9  
± 3  d a y(s)  
Pr oce d ures a n d 
assess me nts  
Scree ni n g  
R a n d o miz ati o n  
We e k 4  
We e k 8  
We e k  1 2  
We e k 2 4  
I nf or me d c o nse nt 
X  
 
 
 
 
 
I ncl usi o n a n d e xcl usi o n 
criteria 
X  
X  
 
 
 
 
Assi g n 
ra n d o mizati o n/treat me nt 
n u m ber  
 
X  
 
 
 
 
Me dical a n d ps yc hiatric 
hist or y  
X  
 
 
 
 
 
Rec or d de m o gra p hic 
c haracteristics  
X  
 
 
 
 
 
Pri or me dicati o n a n d 
treat me nt hist or yd 
X  
 
 
 
 
 
P h ysical e xa mi n ati o n, 
i n cl u di n g hei g ht a n d 
wei g ht e 
X f 
X  
X  
X  
X  
X  
1 2 -Lea d E C G  
X  
X g 
X g 
X g 
X g 
X  
Vital si g ns meas ure me nt h 
X  
X  
X  
X  
X  
X  
Safet y la b orat or y 
assess me nts  
X  
X  
X  
X  
X  
X  
Ser u m β -H C G test i 
X  
 
 
 
 
 
Uri ne β -H C G test i,j 
 
X  
X  
X  
X  
X  
F S H k 
X  
 
 
 
 
 
I nf or m patie nts of st u d y 
restricti o ns a n d c o m plia nce 
re q uire me nts 
X  
 
 
 
 
 
Re vie w st u d y c o m plia nce l 
 
X  
X  
X  
X  
X  
M M S E j 
X  
 
 
 
 
 
P H Q -9 j 
X  
 
X  
X  
X  
X  
e C-S S R S j,m  
X  
X  
X  
X  
X  
X  
H A M -D 1 7 j,n 
 
X  
X  
X  
X  
X  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
4 9  
 
T a ble  4 : 
St u d y Pr oce d ures a n d Assess me nts  ( C o nti n ue d) 
St u d y pe ri o d  
Pretre at me nt 
(scree ni n g 
a n d b aseli ne)  
D o u ble -bli n d tre at me nt p h ase  
O pe n -l a bel 
e xte nsi o n 
p h ase  
E n d of 
tre at me nt/ 
E arl y 
ter mi n ati o na/ 
F oll o w -u p 
peri o d  
Visit n u m ber  
V 1  
V 2 b 
V 3  
V 4  
V 5 c 
V 6  
D a y a n d all o w e d ti me 
wi n d o ws  
D a ys -2 8 
t o -1  
D a y  1  
+ 3  d a y(s)  
D a y  2 9  
± 3  d a y(s)  
D a y  5 7 
± 3  d a y(s)  
D a y  8 5  
± 3  d a y(s)  
D a y  1 6 9  
± 3  d a y(s)  
Pr oce d ures a n d 
assess me nts  
Scree ni n g  
R a n d o miz ati o n  
We e k 4  
We e k 8  
We e k 1 2  
We e k 2 4  
H A M -A j,n  
 
X  
X  
X  
X  
X  
HI T -6 j 
 
X  
X  
X  
X  
X  
C GI -S j 
 
X  
X  
X  
X  
X  
M S Q o L j 
 
X  
X  
X  
X  
X  
W P AI: G H
j 
 
X  
X  
X  
X  
X  
Pr o vi d e electr o nic 
hea dac he diar y o  
X  
 
 
 
 
 
C o m plete electr o nic 
hea dac he diar y e ntries p  
X  
 
X  
Re vie w ele ctr o nic 
hea dac he diar y l 
 
X  
X  
X  
X  
X  
Ret ur n hea dac he diar y  
 
 
 
 
 
X  
A d verse e ve nts a n d  healt h 
care res o urce utilizati o n 
i n q uir yl 
X q 
X  
X  
X  
X  
X  
Dis pe nsi n g of I M P  
 
X  
X  
X  
X  
 
A d mi nistrati o n of I M P r 
 
X  
X  
X  
X  
 
H y perse nsiti vit y/ 
a na p h yla xis s 
 
X  
X  
X  
X  
X  
C o nc o mita nt me dicati o n 
a n d t hera p y i n q uir y l 
X  
X  
X  
X  
X  
X  
a I n t he case of earl y ter mi nati o n, site pers o n nel s h o ul d perf or m a f oll o w-u p p h o ne call t o e ns ure t he patie nt d oes 
n ot re p ort s uici dal i deati o n or be ha vi or. P h o ne calls s h o ul d be perf or me d o nce wee kl y f or 2 wee ks. If si g ns of 
s uici dalit y are i de ntifie d d uri n g t he f oll o w-u p p h o ne call, t he site pers o n nel s h o ul d pr o vi de directi o n t o t he patie nt 
f or f urt her ps yc hiatric e val uati o n at t he site or at a c o m m u nit y ps yc hiatrist refere nced b y t he site.  Rele va nt 
e mer ge nc y ps yc hiatric care ser vices s h o ul d be n otifie d i n t he e ve nt t hat t he patie nt is dee me d t o be a t hreat t o 
t he mself. 
b P atie nts will c o m plete t he scree ni n g visit n ot  m ore t ha n 2 8 ( + 3) da ys bef ore t he ra n d o mizati o n visit ( V 2 [ da y 1]). 
All visit 2 pr oce d ures m ust b e perf or me d bef ore st u d y dr u g a d mi nistrati o n.  
c P atie nts will c o nti n ue i nt o t he o pe n -la bel e xte nsi o n p hase at wee k 1 2 a n d will all recei ve a q uarterl y d ose of 
6 7 5  m g sc fre ma nez u ma b.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
5 0  
 
d C ollecti o n of pri or me dicati o ns  f or mi grai ne a n d/ or de pressi o n is li mite d t o t h ose me dicati o ns a d mi nistere d wit hi n  
t he past 1 0 years or f or a n y i n dicati o n wit h t he past 5 m o nt hs bef ore scree ni n g ( V 1). 
e I n a d diti o n, i n q uire a n d rec or d start/st o p date of me nstr ual peri o d f or w o me n of c hil d -beari n g p ote ntial o nl y at 
eac h visit as part of p h ysical e xa mi nati o n assess me nts.  
f Hei g ht will be meas ure d o nl y at t he scree ni n g visit ( V 1).  
g T his assess me nt will be d o ne pre d ose. A si n gle E C G will be perf or me d. If res ults are a b n or mal, t he E C G will be 
re p eate d 1 ti me. 
h B ef ore p ulse a n d bl o o d press ure are meas ure d, t he patie nt m ust be i n a s u pi ne or se mi -erect/seate d p ositi o n a n d 
resti n g f or at least 5 mi n utes. T he sa me p ositi o n a n d ar m s h o ul d be use d eac h ti me vital si g ns are meas ure d f or a 
gi ve n patie nt.  
i F or details see  A p pe n di x  E . 
j O n d osi n g da ys, t he test or q uesti o n naire s h o ul d be c o m plet e d bef ore st u d y dr u g a d mi nistr ati o n.  
k T he F S H  assess me nt a p plies o nl y t o w o me n t h o u g ht t o be p ost me n o pa usal  at t he scree ni n g visit ( V 1).  If t he res ults 
s h o w a n ele vate d F S H ( > 3 5 U/ L) a n d t he patie nt has ha d n o me nses f or at least 1 2 m o nt hs, t he y d o n ot nee d uri ne  
pre g na nc y testi n g.   
l T his is a re q uire d pr oce d ure f or u nsc he d ule d visits. See f urt her details i n A p pe n di x  B . 
m  P atie nts will c o m plete t he e C -S S R S Lifeti me  versi o n at V 1 a n d will c o m plete t he e C -S S R S Si nce Last Visit 
versi o n at all ot her visits. T he e C -S S R S will be use d i n c o nj u ncti o n wit h a q ualifie d cli nici a n’s  cli nical j u d g me nt 
t o assess t he patie nt’s s uici dal i deati o n (se verit y a n d i nte nsit y) a n d be ha vi or. 
n A q ualifie d staff me m ber (ie, t he i n vesti gat or or a me dicall y q ualifie d pers o n desi g nate d b y t he i n vesti gat or) will 
perf or m t his assess me nt.   
o Eli gi ble patie nts will be gi ve n a n electr o nic hea dac he diar y de vice a n d will be trai ne d i n its use a n d c o m plia nce 
re q uire me nts o n t he da y of t he scree ni n g visit ( V 1). 
p P atie nts will c o m plete electr o nic hea dac he diar y e ntries a b o ut t he pre vi o us da y dail y be gi n ni n g o n da y -2 7 t hr o u g h 
t he E O T/earl y wit h dra wal visit. 
q I n q uiries a b o ut a d verse e ve nts will be ma d e bef ore a d minist eri n g q uesti o n naires o n n o n -d osi n g da ys a n d bef ore 
a n d after st u d y dr u g a d mi nistrati o n o n d osi n g da ys. P ost -d ose i n q uiries will be ma de bef ore t he patie nt lea ves t he 
st u d y ce nter. 
r P atie nts will b e assesse d f or se vere h y perse nsiti vit y/a na p h yla xis reacti o n d uri n g a n d after a d mi nistrati o n of t he 
I M P. O x y ge n sat urati o n a n d res pirat or y rate will be meas ure d i n cases of s us pecte d a na p h yla xis a n d se vere 
h y perse nsiti vit y. See f urt her detail s i n A p pe n di x  H . 
β -H C G = beta -h u ma n c h ori o nic g o na d otr o pi n; E C G = electr ocar di o gra p h y; e C R F  =  electr o nic case re p ort f or m; 
C T  =  electr oc o n v ulsi ve t he ra p y; e C-S S R S  =  electr o nic C ol u m bia -S uici de Se verit y Rati n g Scale; E O T  =  e n d of 
treat me nt; F S H = f ollicle-sti m ulati n g h or m o ne; H A M-A  =  Ha milt o n A n xiet y Scale; H A M -D  1 7  =  Ha milt o n 
De pressi o n Rati n g Scale -1 7  it e ms; HI T-6  =  6 -ite m Hea dac he I m pact T est; I M P =  i n vesti gati o nal me dici nal pr o d uct; 
M M S E  =  Mi ni Me ntal State E xa mi nati o n; M S Q o L  =  Mi grai ne -S pecific Q ualit y of Life; P H Q -9  =  P atie nt Healt h 
Q uesti o n naire -9; W P AI: G H  =  W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Q uesti o n naire Ge neral Healt h V 2. 0; 
V  =  visit.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
5 1  
 
4.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  
Pr os pecti ve wai vers (e x ce pti o ns) fr o m st u d y i ncl usi o n a n d e x cl usi o n criteria t o all o w patie nts t o 
be ra n d o mize d/e nr olle d are n ot gra nte d b y T e va ( A p pe n di x  C ). 
C ha n ges t o i ncl usi o n or e x cl usi o n criteria are i n dicate d bel o w a n d d etaile d i n Secti o n  1 6 . 
4. 1.  
P atie nt I ncl usi o n Criteri a  
Patie nts ma y be ra n d o mi ze d/e nr olle d i n t his st u d y o nl y if t he y meet all of t he f oll o wi n g criteria:  
a. T he patie nt is ca p a ble of gi vi n g si g n e d i nf or me d c o nse nt, w hic h i ncl u des c o m plia nce 
wit h t he re q uire me nts a n d restricti o ns liste d i n t his pr ot oc ol . 
b.  T he patie nt is male or fe male a n d 1 8  t o 7 0  years of a ge, i ncl usi ve.  
c. T he patie nt has a di a g n osis of mi grai ne wit h o nset at ≤5 0 years of a ge.  
d.  Pri or t o t he scree ni n g visit ( V 1) , t he patie nt has a 1 2-m o nt h hist or y of eit her:  
− mi grai ne (acc or di n g t o I C H D -3 criteri a [ I H S, 2 0 1 3]) or 
− hea dac he c o nsiste nt wit h mi grai ne (ie, mi grai ne di a g n osis n ot better acc o u nte d f or 
b y a n ot h er I C H D -3 dia g n osis)  
e. [ Re visi o n 1] T he patie nt f ulfills t he  f oll o wi n g crit eria f or mi grai ne i n pr os p ecti vel y 
c ollecte d bas eli ne i nf or m ati o n d uri n g t he 2 8 -da y b aseli ne  peri o d:  
− o n ≥4 da ys, h ea dac he attac ks q ualifie d as mi grai n e base d o n t he f oll o wi n g 
I C H D-3 criteria:  
○ I C H D-3 dia g n ostic criteria C a n d D f or 1. 1 Mi grai ne wit h o ut a ura  
hea dac he has at least 2 of t he f oll o wi n g 4 c h aracteristics: u nilateral 
l ocati o n; p ulsati n g q ualit y; m o derate or se v ere pai n i nte nsit y; a n d 
a g gra vati o n b y, or ca usi n g a v oi d a nce of, r o uti ne p h ysical acti vit y 
(e g, wal ki n g or cli m bi n g sta irs) 
d uri n g hea dac he, at least o ne of t he f oll o wi n g: 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  
○ I C H D-3 criteria B a n d C f or 1. 2 Mi grai ne wit h a ura  
1 or m ore of t he f oll o wi n g f ull y re versi ble a ura s y m pt o ms: vis ual, se ns or y, 
s peec h a n d/ or la n g ua ge, m ot or, brai nste m, reti nal  
at least 2 of t he f oll o wi n g 4 c h aracteristics: at least 1 a ura s y m pt o m 
s prea ds gra d uall y o ver ≥5 mi n utes, a n d/ or 2 or m ore s y m pt o ms occ ur i n 
s uccessi o n; eac h i n di vi d ual a ura s y m pt o m lasts 5 t o 6 0 mi n utes; at least 
1  a ura s y m pt o m i s u nilateral; t he a ura is acc o m pa nie d, or f oll o we d wit hi n 
6 0  mi n utes, b y hea d ac h e n ot better acc o u nte d f or b y a n ot h er I C H D -3 
dia g n osis, a n d tr a nsie nt isc he mic attac k h as bee n e x cl u de d  
○ pr o ba ble mi grai ne (a mi grai ne s u bt y pe w here o nl y 1 mi grai ne criteri o n is  
missi n g)  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
5 2  
 
○ tri pta n or er g ot deri vati ve use d t o treat a n esta blis he d hea d ac he. 
f. T he patie nt a grees n ot t o i nitiate a n y mi grai n e pre ve nti ve me dicati o ns (as d efi ne d i n 
A p pe n di x  G ) d uri n g t he st u d y. U p t o 3 0 % of patie nts , h o we ver, ma y ta ke s uc h a 
si n gle me dic ati o n pre vi o usl y pres cri be d f or t he treat me nt of mi grai ne.  
g.  T he patie nt has a hist or y of M D D acc or di n g t o t he D S M -V criteria at least 1 2 m o nt hs 
pri or t o  t he scree ni n g visit ( V 1). Patie nts ma y t a ke a si n gle me di cati o n pres cri be d f or 
t he treat me nt of d e pressi o n as l o n g as t he d ose of t hat me dicati o n has bee n sta ble f or 
at least 8  wee ks pri or t o t he scree ni n g visit ( V 1)  a n d e x pects t o re mai n at t he sta ble 
d o se t hr o u g h o ut t he st u d y (A p pe n di x  G ). 
h.  T he patie nt has a P H Q -9 sc ore of at least 1 0 at t he scree ni n g visit ( V 1).  
i. T he patie nt has a Mi ni M e ntal State E x a m i nati o n sc ore of at least 2 6 p oi nts at t he 
scree ni n g visit ( V 1). 
j. T he patie nt is i n g o o d h ealt h i n t he o pi ni o n of t he i n vesti gat or as deter mi ne d b y 
me dical e val uati o n, i ncl u di n g me dical a n d ps yc hiatric hist or y, p h ysic al e xa mi nati o n, 
la b orat or y tests, a n d car diac m o nit ori n g.  
k.  T he patie nt has a b o d y w ei g ht 4 5  k g a n d a b o d y mass i n de x wit hi n t he ra n ge of 
1 7. 5  t o 3 4. 9 k g/ m 2, i ncl usi ve. 
l. [ Re visi o n 2 ] T he patie nt de m o nstrate d c o m plia nce wit h t he electr o ni c hea dac he diar y 
d uri n g t he 2 8 -da y bas eli ne  peri o d b y e ntr y of hea d ac he d ata o n a mi ni m u m of 2 1  da ys 
c u m ulati ve d uri n g t h e 2 8 -da y baseli ne  p eri o d ( ~ 7 5 % diar y c o m plia nce).  
m.  W o me n ma y be i ncl u d e d o nl y if t he y ha v e a n e gati ve ser u m beta -h u m a n c h ori o nic 
g o na d otr o pi n ( β -H C G) test at t he scree ni n g visit (V 1) , are sterile or p ost me n o pa usal, 
a n d are n ot lactati n g ( n ot a p plica ble f or patie nts p artici pati n g i n s afet y f oll o w -u p 
o nl y). Defi niti o ns of sterile a n d p ost me n o pa usal are gi v e n i n A p pe n di x  E . 
n.  W o me n of c hil d -beari n g p ote ntial w h ose male part ners are p ot e ntiall y fertil e (ie, n o 
vasect o m y) m ust use hi g hl y effecti ve birt h c o ntr ol met h o ds f or t he d urati o n of t he 
st u d y a n d f or 6 m o nt hs after disc o nti n uatio n of I M P (f or details see A p pe n di x  E ). 
o.  Me n m ust be sterile or, if t he y are p ote ntiall y fertile/re pr o d ucti vel y c o m pete nt ( n ot 
c o n ge nitall y sterile) a n d t heir fe mal e part ners are of c hil d -beari n g p ot e ntial, m ust use 
a c o n d o m f or t he d urati o n of t he st u d y a n d f or 6 m o nt hs after disc o nti n uati o n of I M P. 
F or t he p ur p os e of t his st u d y, vas ect o mize d me n m ust use a c o n d o m if t heir part ners 
are of c hil d -beari n g p ote ntial. Defi niti o ns of w o me n of n o n -c hil d-b eari n g p ote ntial, 
sterile a n d p ost me n o pa us al w o me n; male c o ntr ace pti o n; a n d hi g hl y effecti v e birt h 
co ntr ol met h o ds, i ncl u di n g e x a m ples, are gi ve n i n A p pe n di x  E . 
p.  T he patie nt m ust be willi n g a n d a ble t o c o m pl y wit h st u d y restricti o ns, t o re mai n at 
t he cli nic f or t he re q uire d d urati o n d uri n g t h e st u d y a n d t o r et ur n t o t he cli nic f or t he 
f oll o w-u p e val uati o ns, as s pecifie d i n t his pr ot oc ol.  
4. 2.  
P atie nt E xcl usi o n Criteri a  
Patie nts will n ot be ra n d o mize d/e nr olle d i n t his st u d y if t he y meet a n y of t h e f oll o wi n g  criteria:  
a. [ Re visi o n 1] T he patie nt uses me dicati o ns c o ntai ni n g o pi oi ds (i ncl u di n g c o dei ne) or 
bar bit urates (i n cl u di n g b utal bital/as piri n/caffei ne [ Fi ori nal ® , Acta vis plc], 
b utal bital/ paracet a m ol/caffei ne [ Fi oricet ® , Car di nal Healt h], or a n y ot h er c o m bi nati o n 
c o ntai ni n g b utal bital) o n m ore t ha n 4 da ys d uri n g t he 2 8 -da y bas eli ne peri o d  f or t he 
treat me nt of mi grai ne or f or a n y ot her reas o n. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
5 3  
 
b.  [ Re visi o n 1] T he patie nt has faile d 4 or m or e differe nt me dicati o n class es t o treat 
de pressi o n i n t heir lifeti me (A p pe n di x  G ). 
c. [ Re visi o n 1] If i n t he cli nical j u d g me nt of t h e i n vesti gat or or q u alifie d ps yc hiatrist, 
t he patie nt’s a nti de pressa nt me dicati o n nee ds t o be c ha n ge d or d ose -a dj uste d d uri n g 
t he 2 8-da y bas eli ne peri o d.  
d.  [ Re visi o n 1] T he patie nt has use d a n i nter ve nti o n/ de vice (e g, sc he d ul e d ner ve bl oc ks,  
i m pla nta ble va gal ner v e sti m ulati o n, a n d tra nscra nial ma g n etic sti m ulati o n) f or 
mi grai ne or de pressi o n d uri n g  t he 2 m o nt hs pri or t o scree ni n g. 
e. T he patie nt has use d electr oc o n v ulsi ve t hera p y ( E C T) at a n y ti me.  
f. T he patie nt s uffers fr o m c o nsta nt or nearl y c o nsta nt hea dac h e, defi n e d as h a vi n g 
hea dac hes f or m ore t ha n 8 0 % of t he ti me he/s he is a wa ke, a n d less t ha n 4 da ys 
wit h o ut hea dac h e per m o nt h. Dail y hea dac he is acce pta ble if t he p atie nt has 
hea dac hes 8 0 % or less of t he ti me he/s he is a wa k e o n m ost da ys.  
g.  [ Re visi o n 1] T he patie nt has cli nicall y si g nifica nt he mat ol o gical, car diac, re nal, 
e n d ocri ne, p ul m o nar y, gastr oi n testi nal, ge nit o uri nar y, n e ur ol o gic, he p atic, o c ular 
disease,  or c o m plic ati o ns of a n i nfecti o n,  at t he discreti o n of t he i n vesti gat or.  
h.  [ Re visi o n 2 ] T he patie nt has a cli nical hist or y of  a se vere or u nc o ntr olle d ps yc hiatric 
dis or der, t o i ncl u de  t he f oll o wi ng, or at t he discreti o n of t he i n vesti gat or f or a n y 
cli nicall y si g nifica nt  ps yc hiatric hist or y t hat w o ul d li kel y i nterfere wit h f ull 
partici pati o n i n t he st u d y : 
− Lif eti me e x cl usi o n:  s uici de atte m pt 
− I n t he p ast 6 m o nt hs e x cl usi o n: s uici dal i deati o n, or ot her ps yc h o acti ve s pectr u m 
dis or ders i ncl u di n g s c hiz oaffecti ve dis or der, del usi o nal dis or der, de pressi o n wit h 
ps yc h otic feat ur es, a n d catat o nic dis or der  
i. T he patie nt has a hist or y of cli nicall y si g nifica nt car di o vasc ular disease or vasc ular 
isc he mia (s uc h as m y o car dial, ne ur ol o gical [ e g, cere bral isc he mia], peri p h eral 
e xtre mit y isc h e mia, or ot her isc he mic e ve nt) or t hr o m b oe m b olic e ve nts (arterial or 
ve n o us t hr o m b otic or e m b olic e ve nts), s uc h as cere br o vasc ul ar acci de nt (i n cl u di n g 
tra nsie nt isc he mic attac ks), dee p vei n t hr o m b osis, or p ul m o nar y e m b olis m.  
j. T he patie nt has a k n o w n i nfecti o n or hist or y of h u ma n i m m u n o deficie nc y vir us, 
t u berc ul osis, a n y hist or y of L y m e disease, or c hr o nic he patitis B or C i nfecti o n . 
k.  T he patie nt has a p ast or c urre nt hist or y of ca ncer,  e x ce pt f or a p pr o priatel y treate d 
n o n -mela n o ma s ki n carci n o ma.  
l. T he patie nt is a pre g n a nt or n ursi n g fe male or pla ns t o bec o me pre g n a nt d uri n g t he 
st u d y, i ncl u di n g t h e 6-m o nt h peri o d after t h e a d mi nistrati o n of t he last d ose.  
m.  [ Re visi o n 1] T he patie nt has a hist or y of h y perse nsiti vit y reacti o ns t o i nject e d 
pr otei ns, i ncl u di n g m o n o cl o nal a nti b o dies , or a hist or y of Ste v e ns-J o h ns o n S y n dr o me 
or t o xic e pi der mal necr ol ysis s y n dr o me. 
n.  T he patie nt has partici pat e d i n a cli nical st u d y of a ne w c he mical e ntit y or a 
pre scri pti o n me dici ne wit hi n 2 m o nt hs of t he scree ni n g visit ( V 1), or 3 m o nt hs i n case 
of bi ol o gics if t he h alf -life of t he bi ol o gi cs is u n k n o w n or 5 half-li ves, w hi c he ver is 
l o n ger, or is c urre ntl y p artici pati n g i n a n ot her st u d y of a n I M P ( or a me dical de vice).  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
5 4  
 
o.  [ Re visi o n 1] T he patie nt has faile d treat me nt ( bas e d o n t olera bilit y a n d/ or a lac k of 
effic ac y) wit h a n y m o n o cl o nal a nti b o dies tar geti n g t he C G R P pat h wa y (ere n u ma b, 
e pti nez u ma b, galc a nez u ma b, or fre m a nez u ma b) or ha ve ta ke n t he me dicati o ns wit hi n 
5 half -li ves of t he scree ni n g visit ( V 1) or t a ke t he m d uri n g t he st u d y. 
p.  T he patie nt has a n y fi n di n g i n t he bas eli ne 1 2 -lea d E C G c o nsi dere d cli nicall y 
si g nifica nt i n t he j u d g me nt of t he i n vesti gat or.  
q.  T he patie nt has a n y fi n di n g t hat, i n t he j u d g me nt of t he i n ves ti gat or, is a cli nicall y 
si g nifica nt a b n or malit y, i ncl u di n g ser u m c he mistr y, he m at ol o g y, c oa g ulati o n, a n d 
uri nal ysis test val ues (a b n or mal tests ma y b e re p eate d f or c o nfir mati o n).  
r. T he patie nt has he p atic e nz y m es ( A L T, A S T, a n d A L P) > 1. 5  × t he u p per li mit o f t he 
n or mal ra n ge after c o nfir mati o n i n a re peat test or s us pecte d he p at ocell ular da ma ge 
t hat f ulfills t he criteria f or H y’s la w at t he scree ni n g visit ( V 1).  
s. T he patie nt has ser u m creati ni ne > 1. 5  × t h e u p per li mit of n or mal ra n ge, cli nicall y 
si g nifica nt pr ot ei n uria, or e vi de nce of re n al diseas e at t he scree ni n g visit ( V 1).  
t. T he patie nt has a n y cli nicall y si g nifica nt u nc o ntr olle d me dical c o n diti o n (treate d or 
u ntreate d).  
u.  [ Re visi o n 1] T he patie nt has a hist or y of alc o h ol or dr u g a b use  i n t he o pi ni o n of t he 
i n vesti gat or.  
v.  T he patie nt ca n n ot p artici pate or s uccessf ull y c o m plete t he st u d y, i n t he o pi ni o n of 
t heir healt hcare pr o vi d er or t he i n vesti gat or, f or a n y of t he f oll o wi n g reas o ns: 
− me ntall y or le gall y i n ca p acitate d or u n a ble t o gi ve c o nse nt f or a n y reas o n  
− i n c ust o d y d ue t o a n a d mi nistrati ve or a le gal decisi o n, u n der t utela ge, or bei n g 
a d mitte d t o a sa nitari u m or s ocial i nstit uti o n  
− u na ble t o be c o nta cte d i n case of e mer ge nc y  
− has a n y ot her c o n diti o n, w hic h, i n t he o pi ni o n of t he i n vesti gat or, ma kes t h e 
patie nt i na p pr o priate f or i ncl usi o n i n t he st u d y  
w.  T he patie nt is a st u d y ce nter or s p o ns or e m pl o yee w h o is directl y i n v ol ve d i n t he 
st u d y or t he relati ve of s u c h a n e m pl o yee. 
x.  T he patie nt has a n y dis or der t hat ma y i nterfere wit h t he a bs or pti o n, distri b uti o n,  
meta b olis m, or e x creti o n of I M P.  
y.  T he patie nt is v ul nera ble (e g, pe o ple ke pt i n dete nti o n).  
z. T he patie nt has pre vi o usl y partici pate d i n t his st u d y.  
aa.  T he patie nt has e vi d e nce or me dical hist or y of ps yc h otic s y m pt o ms as per D S M -V 
criteria s uc h as del usi o ns, hall uci nati o ns, or dis or ga nize d s peec h i n t he past 1 m o nt h.  
b b.  Patie nt has recei ve d o na b ot uli n u mt o xi n A f or mi grai ne or f or a n y me dical or c os metic 
reas o ns r e q uiri n g i njecti o ns i n t he hea d, face, or nec k d uri n g t he 3 m o nt hs bef ore 
scree ni n g visit. 
4. 3.  
Wit h dr a w al C riteri a a n d Pr oce d ures f or t he P atie nt  
Eac h patie nt is free t o wit h dra w fr o m t he st u d y or disc o nti n ue fr o m I M P at a n y ti me, wit h o ut 
prej u dice t o t heir c o nti n ue d care. Patie nts m ust be wit h dra w n fr o m t he I M P if a n y of t he 
f oll o wi n g e v e nts occ ur: 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
5 5  
 
1.  Patie nt wit h dra ws c o nse nt or re q uests disc o nti n uati o n fr o m t he I M P or wit h dra wal fr o m 
t he st u d y f or a n y reas o n. 
2.  Patie nt de vel o ps a n ill ness t hat w o ul d i nterfere wit h his/ her c o nti n ue d partici pati o n.  
3.  Patie nt is n o nc o m plia nt wit h t he st u d y pr oce d ures a n d ass ess me nts or a d mi nistrati o n of 
I M Ps i n t he o pi ni o n of t he i n vesti gat or. 
4.  Patie nt ta kes pr o hi bite d c o nc o mita nt me dicati o ns or recei ves pr o hi bite d t hera pies as 
defi ne d i n t his pr ot oc ol.  
5.  A fe male p atie nt has a c o nfir mati o n of pre g n a nc y d uri n g t he st u d y fr o m a p ositi ve uri ne  
pre g na nc y t est.  
6.  T he s p o ns or re q u ests wit h dra wal of t h e patie nt.  
7.  Patie nt e x perie nces a n a d verse e v e nt or ot her m e dical c o n diti o n t hat i n dicates t o t he 
i n vesti gat or t hat c o nti n ue d partici pati o n is n ot i n t he best i nterest of t he patie nt. 
Patie n ts s h o ul d be treate d wit h sta n dar d of care after wit h dra wal fr o m or ter mi nati o n of t he st u d y 
as a p pr o priat e.  
I n v esti gat ors s h o ul d atte m pt t o o btai n i nf or mati o n o n patie nts i n t he case of wit h dra wal fr o m t he 
st u d y or disc o nti n uati o n fr o m I M P. Res ults of a n y e val uati o ns a n d o bser vati o ns, t o get her wit h a 
narrati ve d escri bi n g t he reas o n(s) f or wit h dra wal fr o m t he st u d y or disc o nti n uati o n fr o m I M P, 
m ust be rec or de d i n t he s o urce d oc u m e nts. T he el ectr o nic case re p ort f or m (e C R F) m ust 
d oc u me nt t he pri mar y reas o n f or wit h dra wal fr o m t he st u d y or disc o nti n uati o n fr o m I M P.  
See A p pe n di x  F  f or i nf or mati o n re gar di n g h o w t h e st u d y will defi n e a n d a d dress l ost t o 
f oll o w-u p patie nts t o hel p li mit t he a m o u nt a n d i m pact of missi n g data.  
If t he reas o n f or wit h dra wal fr o m t he st u d y or dis c o nti n uati o n fr o m I M P is a n a d verse e v e nt 
a n d/ or cli nicall y si g nifi ca nt a b n or mal la b orat or y t est res ult, m o nit ori n g will be c o nti n ue d as 
a p plica ble (e g, u ntil t he e ve nt has res ol ve d or sta bilize d, u ntil t he patie nt is referre d t o t he care of 
a healt h care pr ofessi o nal, or u ntil a deter mi nati o n of a ca us e u nrel ate d t o t he I M P or st u d y 
pr oce d ure is ma de). T h e s pecific e v e nt or test res ult (i ncl u di n g re p eate d test res ults, as 
a p plica ble) m ust be rec or de d o n b ot h t he s o urce d oc u me ntati o n a n d t he e C R F; b ot h t he a d verse 
e ve nts pa ge a n d t he rele v a nt pa ge of t he e C R F will be c o m plete d at t hat ti me . 
T he patie nt will be m o nit ore d as a p plica ble (e g,  u ntil t he e ve nt has res ol ve d or sta bilize d, u ntil 
t he patie nt is referre d t o t he care of a healt h care pr ofessi o nal, or u ntil a det er mi nati o n of a ca use 
u nrelate d t o t he test I M P or st u d y pr oce d ure is ma de). T he i n vesti gat or m ust i nf or m t he St u d y 
Lea der a s s o o n as p ossi bl e of eac h patie nt w h o is b ei n g c o nsi dere d f or wit h dra wal d ue t o a d verse 
e ve nts. A d diti o nal re p orts m ust be pr o vi de d w he n re q ueste d.  
If a patie nt is wit h dra w n fr o m t he st u d y or disc o nti n ues I M P f or m ulti ple reas o ns t hat als o 
i ncl u de a d vers e e v e nts, t he rele v a nt pa ge of t he e C R F s h o ul d i n dicate t hat t he wit h dra wal w as 
relate d t o a n a d vers e e ve nt. A n e x ce pti o n t o t his re q uire me nt will be t he occ urre n ce of a n 
a d verse e ve nt t hat, i n t he o pi ni o n of t he i n vesti gat or, is n ot se vere e n o u g h t o warra n t 
disc o nti n uati o n b ut t hat re q uires t he use of a pr o hi bite d me dicati o n, t here b y re q uiri n g 
disc o nti n uati o n of t he patie nt. I n s u c h a case, t he reas o n f or disc o nti n uati o n w o ul d be “ nee d t o 
ta ke a pr o hi bite d me dic ati o n,” n ot t he a d verse e ve nt. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
5 6  
 
I n t he cas e of patie nts l ost t o f oll o w -u p, atte m pts t o c o ntact t he patie nt m ust be ma de. A patie nt 
s h o ul d o nl y be desi g nat e d as l ost t o f oll o w u p if t he site is u na ble t o esta blis h c o ntact wit h t he 
patie nt after 3  d o c u me nte d atte m pts via 2 differe nt met h o ds (tele p h o ne, t e xt, e mail, certifie d 
letter, etc). 
4. 4.  
Re pl ace me nt of P atie nts  
A patie nt w h o is ra n d o mi ze d/e nr olle d b ut d oes n ot c o m plete t he treat me nt p hase will n ot be 
re place d wit h a n ot her eli gi ble patie nt. 
4. 5.  
Rescree ni n g  
A patie nt w h o is scree ne d b ut n ot e nr olle d (e g, beca u se st u d y eli gi bilit y criteria were n ot met 
[i ncl usi o n criteria n ot met or e x cl usi o n criteria met]) d ue t o a n y of t he f oll o wi n g reas o ns: 
tec h nical iss ues (e g, diar y malf u n cti o n), o ut of visit 2 wi n d o w d ue t o a n e m er ge nc y sit uati o n, or 
re q uire t o scree n fail as directe d b y t he s p o ns or d u e t o a n e mer ge nc y sit uati o n (e g, pa n de mic or 
p ote ntial pa n de mic), ma y be c o nsi dere d f or rescree ni n g 1 ti me.  
I n v esti gat ors ma y c o nta ct t he s p o ns or’s me dical m o nit ors or me dical e x pert f or a d diti o nal 
g ui da n ce o n rescree ni n g. If t he patie nt is res cree ne d, a n i nf or me d c o ns e nt f or m (I C F) will nee d 
t o be re-si g ne d, a n d a ne w scree ni n g n u m b er will be assi g n e d. 
4. 6.  
Scree ni n g F ail ure  
Scree ni n g fail ures are defi ne d as partici p a nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut 
are n ot s u bse q u e ntl y ra n d o mize d. Mi ni mal i nf or mati o n i ncl u des b ut is n ot li mite d t o 
de m o gra p h y, scree ni n g fail ure details, eli gi bilit y criteria, a n d a n y seri o us a d verse e v e nts.  
 
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
5 7  
 
5.  
T R E A T M E N T S  
5. 1.  
I n vesti g ati o n al Me dici n al Pr o d ucts Use d i n t he St u d y 
I n v esti gati o nal me dici nal pr o d uct is defi ne d as t h e test I M P a n d matc hi n g place b o I M P t o t he 
res pecti ve t est I M P.  
Patie nts will recei ve e x peri me ntal me dici nal pr o d uct fre ma nez u ma b ( visit  2, visit  3, a n d visit  4) 
or matc hi n g pl ace b o refere nce m e dici nal pr o d u ct ( visit  2, visit  3, a n d visit 4) i n m o nt hl y d os es 
fr o m t he s p o ns or. Patie nts will recei ve a si n gle q uarterl y d ose of fre ma nez u ma b at visit 5.  
5. 1. 1.  
Test I n vesti g ati o n al Me dici n al Pr o d uct  
Refer t o t he P har m ac y M a n ual f or f ull i nstr ucti o ns f or pre p arati o n a n d  a d mi nistrati o n f or t he test 
I M P a n d pla ce b o I M P. 
Prefille d s yri n ges  (acti ve or place b o) will be c o ntai ne d i n u ni q uel y n u m bere d kits a n d st ore d 
(refri gerat e d at 2°C t o 8 °C) o n site. Acti ve prefille d s yri n ges  will c o ntai n 2 2 5  m g of T E V -4 8 1 2 5 
i n 1. 5 m L s ol uti o n, a n d place b o prefille d s yri n ges  will c o ntai n t he sa me ve hicle a n d e x ci pie nts as 
t h ose f or acti ve i njecti o ns. Eac h kit will c o ntai n 1 prefille d s yri n ge . 
A de q uate kit s u p pl y f or u pc o mi n g st u d y visits will be ma na ge d b y i nteracti ve re s p o nse 
tec h n ol o g y (I R T) a n d k e pt (refri gerate d at 2° C t o 8° C) o n site. 
Treat me nt self-a d mi nistrati o n  (acti ve or pl ace b o) will occ ur at visit 2 ( da y 1), visit  3 ( da y  2 9), 
a n d visit  4 ( da y  5 7). O nl y acti ve treat me nt will be a d mi nistere d o n visit 5 ( da y 8 5), w hic h is t he 
be gi n ni n g of t he o p e n -la bel e xte nsi o n p hase. Fi nal st u d y assess me nts will be perf or me d at t he 
e n d-of -tr eat me nt visit ( visit 6), a p pr o xi matel y 1 2 wee ks after a d mi nistrati o n of t he last d ose of 
st u d y treat me nt. 
I M Ps are defi ne d as t he t est I M P an d pl ace b o I M P ( Ta ble  5 ). A d diti o nal details ma y be f o u n d i n 
t he I B f or fre ma nez u ma b. 
5. 1. 1. 1.  
St arti n g D ose a n d D ose Le vels  
T he starti n g d os e will be 2 2 5  m g fr e ma nez u ma b as a n acti ve i njecti o n ( 2 2 5  m g/ 1. 5  m L) , or a 
1. 5  m L place b o i njecti o n. Treat me nt self-a d mi nistrati o n  (acti ve or place b o) will occ ur at visit 2 
( da y 1), visit  3 ( da y  2 9), a n d visit  4 ( da y  5 7). O nl y acti ve treat me nt (a q uarterl y d os e of 6 7 5  m g 
sc [ie, o ne d ose usi n g 3  prefille d s yri n ges wit h 2 2 5 m g eac h]) will be a d mi nistere d o n visit  5 
( da y 8 5), w hic h is t he b e gi n ni n g of t he o pe n -la bel e xte nsi o n p hase.  
5. 1. 1. 2.  
D ose M o dific ati o n a n d D ose Str atific ati o n  
N o d ose m o dificati o ns are all o we d.  
5. 1. 2.  
Pl ac e b o I n vesti g ati o n al Me dici n al Pr o d uct 
T he place b o I M P is a place b o t o t he test I M P. Det ails o n t he place b o I M P are f o u n d i n 
Secti o n  5. 1. 1 .  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
5 8  
 
T a ble  5 : 
I n vesti g ati o n al Me dici n al Pr o d ucts Us e d i n t he St u d y  
I M P n a me 
Rec o m bi n a nt h u m a nize d 
I g G 2 a/ k a p p a m A b  
Fre m a nez u m a b  
Pl ace b o  
Tr a de n a me a n d I N N, if 
a p plic a ble, or c o m p a n y -assi g ne d 
n u m ber  
AJ O V Y, fre ma nez u ma b  
Als o k n o w n as:  
T E V -4 8 1 2 5, L B R -1 0 1, 
P F -0 4 4 2 7 4 2 9, R N 3 0 7  
Place b o  
F or m ul ati o n  
Prefille d s yri n ges  c o ntai ni n g 1. 5 m L 
s ol uti o n f or i nj ecti o n of 2 2 5 m g of 
t he acti ve i n gre die nt fre ma nez u ma b  
I nacti ve i n gre die nts i ncl u de 
L -histi di ne, L -histi di ne 
h y dr oc hl ori de m o n o h y drate, s ucr ose, 
p ol ys or bate -8 0, E D T A, a n d water f or 
i nj ecti o n 
Prefille d s yri n ges  c o ntai ni n g 1. 5 m L 
s ol uti o n f or i nj ecti o n of t he sa me 
ve hicle a n d e xci pie nts as t h os e f or 
acti ve i nj ecti o n  
I nacti ve i n gre die nts i ncl u de 
L -histi di ne, L -histi di ne 
h y dr oc hl ori de m o n o h y d rate, s ucr ose, 
p ol ys or bate -8 0, E D T A, a n d water f or 
i nj ecti o n 
U nit d ose stre n gt h(s)/ D os a ge 
le vel(s) 
2 2 5 m g/ 1. 5 m L per u nit  
N o ne  
R o ute of a d mi nistr ati o n  
sc i nj ecti o n 
sc i nj ecti o n 
D osi n g i nstr ucti o ns  
D o u ble -bli n d, tre at me nt p h ase : a 
d ose of m o nt hl y 2 2 5 m g sc 
fre ma nez u ma b as a n acti ve i nj ecti o n 
( 2 2 5 m g/ 1. 5 m L) at visit 2 ( da y 1), 
visit  3 ( da y 2 9), a n d visit  4 ( da y  5 7)  
O pe n -l a bel e xte nsi o n p h ase: a 
q uarterl y d ose of 6 7 5  m g 
fre ma nez u ma b as 3 acti ve i nj ecti o ns 
( 2 2 5 m g/ 1. 5  m L) at visit 5 ( da y 8 5)  
D o u ble -bli n d, t re at me nt p h ase : 
m o nt hl y 1. 5  m L place b o i nj ecti o n at 
visit 2 ( da y 1), visit  3 ( da y 2 9), a n d 
visit  4 ( da y  5 7)  
 
O pe n -l a bel e xte nsi o n p h ase: n ot 
a p plica ble  
P ac k a gi n g  
 
A kit u ni q uel y n u m bere d c o nt ai ni n g 
1 prefille d s yri n ge st ore d 
(refri gerate d at 2° C t o 8° C) o n site  
A kit u ni q uel y n u m bere d c o nt ai ni n g 
1 prefille d s yri n ge st ore d 
(refri gerate d at 2° C t o 8° C) o n site 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
5 9  
 
T a ble  5 : 
I n vesti g ati o n al Me dici n al Pr o d ucts Us e d i n t he St u d y  ( C o nti n ue d) 
I M P n a me 
Rec o m bi n a nt h u m a nize d 
I g G 2 a/ k a p p a m A b  
Fre m a nez u m a b  
Pl ace b o  
M a n uf act urer  
 
Dr u g s u bst a nce : 
 
 
 
 
 
Dr u g pr o d uct : 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
E D T A = et h yle ne dia mi netetra acetate; I g G 2a = i m m u n o gl o b uli n G 2a; I M P = i n vesti gati o nal me dici nal pr o d uct; I N N 
= i nter nati o nal n o n -pr o prietar y na me; m A b = m o n ocl o nal a nti b o d y; sc = s u bc uta ne o us.  
Pre p arati o n, Ha n dli n g, La b eli n g, St ora ge, a n d Acc o u nta bilit y f or I M Ps  
 
I n di vi d ual, u ni q uel y n u m bere d visit kits c o ntai ni n g 1 prefille d s yri n ge wit h a sta ke d 2 7-G, 
½ -i nc h nee dle will be pr o vi de d.  
At t he ti me of eac h st u d y visit, t he I R T will be q uerie d, a n d site staff will retrie ve  t he I M P a n d 
o versee p atie nt self -a d mi nist rati o n of 1. 5 m L  fr o m eac h prefille d s yri n ge c o ntai ne d i n t he 
a p pr o priatel y n u m bere d kit(s).  Rec o m me n de d sc i njecti o n sites f oll o w t he  Nati o nal I nstit utes of 
Healt h Patie nt E d ucati o n G ui deli nes of J u ne  2 0 1 2 (see A p pe n di x  O ). 
T he s u g geste d sites of i nj ecti o n are b ac k of u p per ar ms, l o wer a b d o me n/ bell y/ waistli ne, a n d 
fr o nt of t hi g hs. E ac h of t he i njecti o ns s h o ul d be gi ve n i n a differe nt l ocati o n (e g, n ot i n precisel y 
t he sa me place/ n ot o n t o p of t he pre vi o us i njecti o n site), a n d st u d y staff me m ber(s) are 
res p o nsi ble f or o v erseei n g patie nt self -a d mi nistrati o n  of i njecti o ns  a n d i ns pecti n g pre vi o us 
injecti o n sites t o e ns ure t hat t he y are free of br uisi n g a n d t e n der ness a n d t h at pr o per r ot ati o n of 
sites is perf or me d. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
6 0  
 
St u d y dr u g s h o ul d be re m o ve d fr o m t he refri gerat or a n d all o we d t o e q uili brate at r o o m 
te m perat ur e f or 3 0  mi n ut es bef ore st u d y dr u g self-ad mi nistrati o n . A 1. 5-m L v ol u me fr o m eac h 
prefille d s yri n ge i n e ac h visit’s kit(s) m ust be i njecte d sc f or d osi n g t o be c o nsi dere d c o m plete. 
T he t otal n u m ber of sc i njecti o ns a n d t heir l ocati o ns will be rec or de d o n t he e C R F f or eac h 
d osi n g visit ( visits 2, 3, 4, a n d 5).  
5. 2.  
Pre p ar ati o n, H a n dli n g, L a beli n g, St or a ge, a n d Acc o u nt a bilit y f or 
I M Ps 
5. 2. 1.  
St or a ge a n d Sec urit y  
T he i n vesti gat or or desi g nee m ust c o nfir m t hat a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d f or all I M Ps r ecei ve d a n d a n y discre pa ncies are re p orte d a n d res ol ve d bef ore use of 
t he I M Ps. 
T he I M Ps (test I M P a n d place b o I M P) m ust be st ore d refri gerate d at 2° C t o 8° C, pr otecte d fr o m 
t he li g ht. T he i n vesti gati o nal ce nter m ust ha v e a pr ocess f or m o nit ori n g I M P st ora ge 
te m perat ur e. 
Di versi o n is c o nsi dere d t o ha ve occ urre d w he n t h e le gal s u p pl y c hai n of prescri pti o n a nal gesic 
me dici nal pr o d ucts is br o ke n, a n d me dici nal pr o d u cts are tr a nsferre d fr o m a licit t o a n illicit 
c ha n nel of distri b uti o n or use.  
5. 2. 2.  
L a beli n g  
S u p plies of I M Ps will be la bele d acc or di n g  t o t he c urre nt I nt er nati o nal C o u ncil f or 
Har m o nisati o n (I C H) g ui deli nes o n G o o d Cli nical Practice ( G C P) a n d G o o d Ma n ufact uri n g 
Practice a n d will i ncl u de a n y l o call y re q uir e d state me nts. If necessar y, la bels will be tra nslate d 
i nt o t he l ocal la n g u a ge. 
5. 2. 3.  
Acc o u nt a bilit y  
Eac h I M P s hi p me nt will i ncl u de a pac ki n g sli p listi n g t he c o nt e nts of t he s hi p me nt, ret ur n 
i nstr ucti o ns, a n d a n y a p plica ble f or ms. 
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat d eli veries of I M Ps a n d ot h er st u d y m aterials 
fr o m t he s p o ns or are c orrectl y recei ve d, rec or de d, ha n dle d, a n d st ore d s afel y a n d pr o perl y i n 
acc or da nce wit h t he nati o nal a n d l ocal r e g ulati o ns, a n d use d i n acc or da n ce wit h t his pr ot oc ol.  
O nl y patie nts e nr olle d i n t he st u d y ma y recei ve  a n d self-a d mi nister I M Ps, a n d onl y  a ut h orize d 
site staff at t he i n vesti gati o nal ce nter ma y s u p pl y I M Ps. All I M Ps m ust be st ore d i n a sec ure, 
e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n u al or a ut o mate d) area i n acc or da n ce wit h t he 
la bele d st ora ge c o n diti o ns or a p pr o priat e i nstr ucti o ns wit h access li mite d t o t he i n vesti gat or a n d 
a ut h orize d  site staff at t h e i n vesti gati o nal ce nter. 
T he i n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or I M P acc o u nta bilit y, rec o n ciliati o n, a n d rec or d mai ntena n ce (ie, recei pt, 
rec o nciliati o n, a n d fi nal dis p osal rec or ds). 
A rec or d of I M P acc o u nt a bilit y (ie, I M P a n d ot her st u d y materi als recei ve d, use d, retai ne d, 
ret ur ne d, or d estr o ye d) m ust be pre pare d a n d si g ne d b y t he pri nci pal i n vesti gat or or desi g nee, 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
6 1  
 
wit h  a n acc o u nt gi ve n f or a n y discre p a ncies. Prefille d s yri n ges s h o ul d ne ver be use d partiall y. 
E m pt y s yri n ges s h o ul d b e destr o ye d at t he i n vesti gati o nal ce nter after rec o nciliati o n is 
perf or me d. If t he i n vesti gati o nal ce nter d o es n ot ha ve t he ca p a bilit y t o de str o y t he e m pt y 
s yri n ges, t h e y s h o ul d be se nt bac k t o t he s p o ns or. U n use d prefille d s yri n ges of I M P will be 
ret ur ne d t o t he s p o ns or or desi g n ee. 
5. 3.  
J ustific ati o n f or I n vesti g ati o n al Me dici n al Pr o d ucts  
5. 3. 1.  
J ustific ati o n f or D ose of Test I n vesti g ati o n al Me dici n al P r o d uct  
T hree d ose re gi me ns of fre ma nez u ma b a d mi nistere d sc were teste d d uri n g 2 P hase 3 pi v otal 
st u dies i n t he E M a n d C M patie nt p o p ulati o ns. C hr o nic mi grai ne d oses w ere 6 7 5 m g l oa di n g 
d ose/ m o nt hl y 2 2 5 m g or q uarterl y 6 7 5 m g a n d E M d oses were m o nt hl y 2 2 5 m g or q uarterl y 
6 7 5  m g.  
D uri n g t h e P hase 2 b st u dies, 4 d ose re gi me ns (ie, E M: m o nt hl y 2 2 5 m g or 6 7 5 m g, a n d 
C M:  m o nt hl y 6 7 5 m g f oll o we d b y 2 2 5 m g or m o nt hl y 9 0 0 m g s c fre ma nez u ma b) were teste d 
a n d s h o w n t o be effecti ve, safe, a n d well t olerate d at t he 3 -m o nt h treat me nt peri o d. Beca us e it is 
c o nsi dere d b est practice t o select t he l o wer d ose f or a d mi nistrati o n fr o m 2 d oses t hat s h o w 
e q ui vale nce i n efficac y (t o a v oi d hi g her d ose t ha n necessar y), t he 2 m o nt hl y d ose re gi me ns of 
m o nt hl y 2 2 5 m g wit h 6 7 5 m g l oa di n g  d ose ( C M) or wit h o ut l oa di n g d ose ( E M) were use d as 
1  acti ve ar m i n eac h of t he P hase 3 st u dies. A sec o n d acti ve ar m i ncl u d e d i n b ot h t he E M a n d 
C M st u dies was 6 7 5  m g sc fre ma n ez u ma b a d mi nistrati o n o nce e v er y 3 m o nt hs. He nce, eac h 
st u d y ret ai ne d t he l o west effecti ve d ose fr o m P hase 2 w hile e x pl ori n g differe nt i nter vals of 
a d mi nistrati o n. F urt her m ore, t he a d diti o n of t he q uarterl y d ose re gi me n, w hic h was a s hare d d ose 
le vel acr oss t he mi grai ne c o nti n u u m, e na ble d t he e x pl orati o n of t he c h oice of treat me nt 
c on ve nie nce a n d fl e xi bilit y f or p atie nts a n d p h ysicia ns, t he c ha n ge i n prefere nce, a n d t he 
li keli h o o d of patie nts’ de ma n d f or differe nt treat m e nt o pti o ns. 
T he res ults of t he P hase 3 st u dies, na mel y statisticall y si g nifica nt differe n ces, e q uall y fa v ori n g 
m o nt hl y a n d q uart erl y fre ma nez u ma b c o m pare d wit h place b o f or all pri mar y a n d sec o n dar y 
e n d p oi nts, de m o nstrate t he effi cac y of fre ma nez u ma b as a pre ve nti ve treat me nt f or E M a n d C M 
i n a d ults. I n a d diti o n, all acti ve d ose re gi me ns s h o we d n o si g nifi ca nt differe nce i n safet y 
para meters.  
T he d ose re gi me ns i n cl u de d i n t his st u d y are m o nt hl y 2 2 5 m g s c a n d q uart erl y 6 7 5 m g s c. T he 
o pe n -la bel e xte nsi o n p hase wit h a q uarterl y d os e of 6 7 5 m g sc fre m a nez u ma b is i nte n de d t o 
pr o vi de t he place b o -treat e d patie nts t he o p p ort u nit y t o recei ve p ot e ntial be nefit fr o m t hera pe utic 
d oses. It als o pr o vi des a n o p p ort u nit y t o f urt her e x pl ore effi cac y a n d t olera bilit y i n t his patie nt 
p o p ulati o n a n d t o ge n erat e data o n s witc hi n g fr o m t he m o nt hl y t o t he q uarterl y d ose.  
5. 3. 2.  
J ustific ati o n f or Use of Pl ace b o I n vesti g ati o n al Me dici n al Pr o d uct  
A place b o -c o ntr olle d desi g n is a p pr o priate, gi ve n t he p ur p ose a n d o bjecti ves of t his cli nical 
st u d y. I ncl usi o n of a place b o c o ntr ol gr o u p is c o nsiste nt wit h g ui deli nes f or c o ntr olle d trials of 
pr o p h yla ctic treat me nt of mi grai ne i n a d ults ( Sil berstei n, 2 0 0 8 ) a n d t he Classificati o n C o m mittee 
of t he I H S g ui deli nes f or c o ntr olle d trials of dr u gs i n mi grai ne, 3 r d e diti o n ( Tfelt -Ha ns e n, 2 0 1 2 ). 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
6 2  
 
5. 4.  
Ot her Me dici n al Pr o d ucts/ N o n -I n vesti g ati o n al Me dici n al Pr o d ucts 
N ot a p plica ble.  
5. 5.  
Tre at me nt after t he E n d of t he St u d y  
At t he e n d of t he last st u d y visit, patie nts will ret ur n t o t he care of t heir treati n g p h ysicia ns.  
N o treat me nt is pla n ne d b y t he s p o ns or after c o m pleti o n of t he st u d y. Pati e nts s h o ul d be treate d 
wit h sta n dar d of care after wit h dra wal fr o m or ter mi nati o n of t he st u d y, as a p pr o priate.  
5. 6.  
Restricti o ns  
Patie nts will be re q uire d t o c o m pl y wit h t he f oll o wi n g restricti o ns.  
5. 6. 1.  
Acti vit y  
Patie nts m ust re mai n at t he site, f or safet y o bser vati o n, at least 6 0 mi n utes after i njecti o n or 
acc or di n g t o me dic al j u d g me nt.  
5. 6. 2.  
Bl o o d D o n ati o n  
Patie nts ma y n ot d o nate bl o o d w hile ta ki n g I M P a n d f or 5 half -li ves ( 6. 0 m o nt hs) after t he l ast 
I M P a d mi nistrati o n. 
5. 6. 3.  
Pre g n a nc y  
Restricti o ns i n re gar d t o pre g na nc y a n d re q uire d l a b orat or y v al ues (ie, ser u m a n d uri ne β -H C G 
tests) are pr o vi d e d i n t he i ncl usi o n a n d e x cl usi o n criteria ( Secti o n 4. 1  a n d S ecti o n  4. 2 , 
res pecti vel y). R estricti o ns i n re gar d t o c o ntr ace pti o n met h o ds are re vie we d i n A p pe n di x  E . 
5. 7.  
Pri or a n d C o nc o mit a nt Me dic ati o n o r T her a p y 
A n y pri or or c o n c o mita nt me dicati o n, treat me nt,  ps yc h ot hera p y,  or pr oce d ure a patie nt h as ha d  
f or mi grai ne a n d/ or de pressi o n wit hi n t he past 1 0  years  or f or a n y i n dicati o n wit hi n t he past 5 
m o nt hs  bef ore I M P a d mi nistrati o n a n d u p t o t he e n d of st u d y, i ncl u di n g f oll o w-u p, will be 
rec or de d o n t he e C R F. Tra de na m e a n d i nter nati o nal n o n pr o prietar y n a me (if a vaila ble), 
i n dicati o n, d ose, a n d start a n d e n d dates of t h e a d mi nistere d me dicati o n or treat me nt will be 
rec or de d. I n a d diti o n, mi grai ne a n d d e pressi o n pre ve nti ve me dicati o n liste d i n A p pe n di x  G  t hat a 
patie nt t o o k bef ore st u d y dr u g a d mi nistrati o n will be rec or de d o n t he e C R F. Ge neric or tra d e 
na me, i n dicati o n, a n d d osa ge will be rec or de d. T h e s p o ns or will e nc o de all me dicati o n acc or di n g 
t o t he W orl d Healt h Or ga niz ati o n dr u g dicti o nar y ( W H O Dr u g).  
F or mi grai ne, p atie nts usi n g n o m or e t ha n 1 pre v e nti ve me dicati o n at t he ti me of t he scree ni n g 
v isit ( V 1) will be all o we d t o re mai n o n t he me dicati o n. T he t otal n u m ber of patie nts recei vi n g 
c o nc o mita nt mi grai ne pre ve nti ve me dicati o n d uri n g t he st u d y will n ot e xcee d 3 0 % of t h e t otal 
sa m ple siz e of t he st u d y. F or de pressi o n, patie nts usi n g n o m ore t ha n 1 m e dicati o n f or t he 
treat me nt of de pressi o n at t he ti me of t he scree ni n g visit ( V 1) will be all o we d t o re mai n o n t he 
me dicati o n. Patie nts o n a c o nc o mita nt mi grai ne pre ve nti ve me dicati o n a n d/ or a n a nti de pressa nt 
m ust be o n a sta ble d ose f or at least 8 w ee ks of c o nsec uti ve use pri or t o st u d y e ntr y (ie, bef ore 
t he 2 8-da y bas eli ne  peri o d), wit h o ut a ntici pate d c h a n ges d uri n g t he st u d y. If i n t he cli nical 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
6 3  
 
j u d g me nt of t he i n vesti gat or or q ualifie d ps yc hiatrist, t he patie nt’s a nti de pressa nt me dicati o n 
nee ds t o be  c h a n ge d or d ose -a dj uste d d uri n g t he 2 8 -da y baseli ne  p eri o d , t h e patie nt will be 
scree n faile d. A n y c ha n ges ma de d uri n g t he treat me nt peri o d will be rec or de d i n t he electr o ni c 
data ca pt ur e s yste m. T he perce nt a ge of patie nts wit h t hese c ha n ges will be a nal y ze d at t he e n d of 
t he st u d y. 
All c o nc o mita nt me dicati o ns prescri be d or o ver -t h e-c o u nter me dicati o ns, vita mi ns, or her bal or 
n utriti o nal s u p ple me nts, m ust be rec or de d wit h i n dicati o n, dail y d ose, a n d start a n d st o p dates of 
a d mi nistrati o n. All patie nts will  be q uesti o ne d a b o ut c o nc o mita nt me dicati o n use at eac h visit. 
C o m plete disc o nti n uati o n criteria are pr o vi de d i n Secti o n  4. 3 . 
A list of pre ve nti ve m i gr ai ne me dicati o ns t hat are all o we d f or  u p t o 3 0 % of t he st u d y p o p ulati o n 
a n d a nti de press a nt me dic ati o ns all o we d f or  t he w h ole st u d y p o p ulati o n f or  t he d urati o n of t he 
st u d y are gi ve n i n A p pe n di x  G .  
C o nc o mita nt me dicati o ns t hat are n ot all o we d f or t he d urati o n of t he st u d y i ncl u de ot her 
m o n ocl o nal a nti b o dies t hat tar get t he C G R P pat h wa y (ere n u ma b, e pti nez u ma b, or 
gal ca nez u ma b), as desc ri be d i n Secti o n 4. 2 . 
If cli nicall y i n dicate d, p atie nts’ a nti de pressa nt me dicati o ns a n d ps yc h ot hera p y m a y be c h a n ge d 
at a n y ti me d uri n g t h e treat me nt peri o d at t he discreti o n of t he i n vesti gat or, a n d all c ha n ges will 
be rec or de d i n t he e C R F. I n s u c h cas e, t he patie nt’s c o nti n ue d partici pati o n i n t he st u d y will be 
re vie we d b y t h e me dical m o nit ors. 
At eac h visit at t he i n vesti gati o nal c e nter after t h e scree ni n g visit ( V 1) , t he i n vesti gat or will as k 
patie nts w het her t he y h a ve ta ke n a n y m e dicati o ns ( ot her t ha n I M P), i ncl u di n g o ver -t he-c o u nter 
me dicati o ns, vita mi ns, or her bal or n utriti o nal s u p ple me nts, or recei ve d a n y t hera pies (e g, E C T) 
si nce t he pre vi o us visit.  
C o nc o mita nt me dicati o n a n d treat me nt , i ncl u di n g ps yc h ot h era p y, will be rec or de d u ntil visit  6, 
da y 1 6 9.  
5. 8.  
Pr oce d ures f or M o nit ori n g P atie nt C o m pli a nce  
T he i n vesti gat or will be res p o nsi ble f or m o nit ori n g patie nt c o m plia nce u ntil c o m pleti o n of t he 
I M P a d mi nistrati o n acc or di n g t o t he pr ot oc ol or disc o nti n uati o n fr o m I M P. If t he i n vesti gat or or 
t he s p o ns or deter mi nes t hat t he patie nt is n ot i n c o m plia nce with t he st u d y pr ot oc ol, t he 
i n vesti gat or a n d t he s p o ns or s h o ul d deter mi ne w het her t he patie nt s h o ul d b e wit h dra w n fr o m t he 
st u d y. T he I n de pe n d e nt Et hics C o m mittee/I nstit uti o nal Re vie w B oar d (I E C/I R B) s h o ul d be 
n otifie d.  
5. 9.  
R a n d o miz ati o n a n d Bli n di n g  
After t he 2 8 -d a y bas eli ne peri o d, t he first 1 2  wee ks of t his st u d y will be d o u ble -bli n d. Patie nts 
a n d i n vesti gat ors will re mai n bli n de d t o I M P assi g n me nt d uri n g t his part of t he st u d y. T his will 
be f oll o we d b y a 1 2 -wee k o pe n -la bel e xte nsi o n p hase.  
Patie nts will rece i ve 2 2 5 m g sc fre ma n ez u ma b ( visit  2, visit  3, a n d visit  4) or matc hi n g pl ace b o 
( visit 2) i n m o nt hl y d oses.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
6 4  
 
F or t he first p hase of t his st u d y, t he s p o ns or, i n vesti gat ors, st u d y staff, a n d patie nts will be 
bli n de d t o treat me nt assi g n me nt. A c o m p uter -ge n erat e d mast er ra n d o mizati o n list will be 
pr o vi de d t o dr u g pac k a gi n g facilities. T he pac ka gi n g ve n d or(s) will pac ka ge acti ve dr u g a n d 
place b o i nt o si n gle -visit kits acc or di n g t o G o o d Ma n ufact uri n g Practice pr oce d ures. Kits will be 
i de ntical i n a p peara nce a n d c ontai n 1  prefille d s yri n ge wit h eit her acti ve dr u g or place b o.  
Patie nts will be stratifie d base d o n se x, c o u ntr y, mi grai ne classifi cati o n (ie, C M or E M) , a n d 
P H Q -9 sc ore cate g or y ( 1 0 t o 1 4, 1 5 t o 1 9, a n d ≥2 0) t o e ns ure b ala nce f or t he c o vari ates.  
Patie nts will be ra n d o ml y assi g ne d t o treat me nt gr o u ps b y mea ns of a c o m p uter -ge n erate d 
ra n d o mizati o n list usi n g electr o nic I R T. T his s yst e m is use d t o e ns ure a b ala nce acr oss treat me nt 
gr o u ps. T h e s pecificati o ns f or ra n d o mizati o n will be u n der t he res p o nsi bilit y a n d o v ersi g ht of 
Te va Gl o bal Statistics.  
At ra n d o mizati o n visit ( da y 1) , eac h patie nt will b e ra n d o mize d i n a 1: 1 rati o wit hi n t he strat u m 
t o w hic h he or s he b el o n gs t o recei ve m o nt hl y 2 2 5 m g sc fre ma nez u ma b or place b o, as assi g ne d 
b y t he I R T. I n t he o pe n -la bel e xte nsi o n p hase starti n g at wee k 1 2, h o we v er, all patie nts will 
recei v e acti ve tr eat me nt wit h a q uarterl y d ose of 6 7 5 m g sc fre ma nez u ma b.  
T he I R T will ma na ge i nitial dr u g s u p pl y, mai nte na nce of a d e q uate st u d y dr u g s u p plies o n site, 
a n d st u d y ra n d o miza ti o n ce ntrall y. At eac h st u d y visit w here st u d y dr u g is a d mi nistere d, t he I R T 
will be q uerie d, t he site p ers o n nel will retrie v e t he st u d y dr u g fr o m refri gerate d st ora ge , a n d t h e 
patie nt will self -a d mi nister  treat me nt wit h t he 1 or 3 prefille d s yri n ges , de pe n di n g o n t he st u d y 
visit, c o ntai ne d i n t he a p pr o priatel y n u m bere d kit . 
T he s p o ns or’s cli nical p ers o n nel (a n d d ele gates) i n v ol ve d i n t he st u d y will be bli n de d t o t he 
i de ntit y of t he I M Ps u ntil t he data base is l oc k e d f or a nal ysis a n d the I M P assi g n me nt is k n o w n. 
H o we ver, if a pri oritiz e d sa m ple a nal ysis is nee de d, bi oa nal ytical a n d cli ni cal p har mac ol o g y 
pers o n nel ma y be u n bli n de d.  
I n t he e ve nt of a n e mer ge nc y, it will be p ossi ble t o deter mi ne t o w hic h treat me nt gr o u p a n d d ose 
t he patie nt has bee n all ocate d by accessi n g t he I R T s yste m. All i n vesti gati o nal ce nters will be 
pr o vi de d wit h details o n h o w t o access t he s yst e m f or c o de brea ki n g at t he start of t he st u d y. T h e 
Me dical M o nit or or e q ui vale nt s h o ul d be n otifie d f oll o wi n g u n bli n di n g. A n y u n bli n di n g of t he 
I M P perf or me d b y t h e i n vesti gat or m ust be rec or de d i n t he s o urce d o c u me nts. 
T he ra n d o mizati o n list will be assi g ne d t o t he rele va nt treat me nt gr o u ps t hr o u g h a q u alifie d 
ser vice pr o vi d er, e g, vi a I R T s yste m. T he ge n erati o n of t he ra n d o mizati o n list a n d ma na ge me nt 
of t he I R T s yst e m will be d o ne b y a q ualifie d s er vi ce pr o vi der u n der t he o v ersi g ht of t he 
res p o nsi ble f u ncti o n at T e va. 
5. 1 0.  
M ai nte n a nce of R a n d o miz ati o n a n d Bli n di n g  
5. 1 0. 1.  
M ai nte n a nce of R a n d o miz ati o n  
Patie nt ra n d o mizati o n c o des will be mai ntai ne d i n a sec ure  l ocati o n at t he s er vice pr o vi der 
c o ntracte d t o ge nerate t h e c o des. At t he ti me of a nal ysis (after t he e n d of st u d y), after recei vi n g 
u n bli n di n g re q uest fr o m Te va statisticia n, t he ser vice pr o vi der will pr o vi de t he u n bli n de d I M P 
assi g n me nt acc or di n g t o t he  pr ocesses d efi ne d i n t he rele va nt Sta n dar d O p erati n g Pr oce d ure 
( S O P). 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
6 5  
 
5. 1 0. 2.  
Bli n di n g a n d U n bli n di n g  
D o u ble -Bli n d Tre at me nt P h ase  
I n case of a seri o us a d verse e ve nt, pr e g na nc y, or i n cases w h e n k n o wle d ge of t he I M P 
assi g n me nt is nee d e d t o ma ke treat me nt d ecisi o ns, t he i n vesti gat or m a y u n bli n d t he patie nt’s 
I M P assi g n me nt as d ee m e d necessar y, mai nl y i n e mer ge nc y sit uati o ns, t hr o u g h s pecialize d 
access i n t he I R T s yste m. Brea ki n g of t he tr eat me nt c o de ca n al wa ys be p erf or me d b y t h e 
i n vesti gat or wit h o ut pri or a p pr o val b y t he s p o ns or; h o we ver, t he s p o ns or s h o ul d be n otifie d t hat 
t he c o de w as br o ke n, b ut t he patie nt treat me nt assi g n me nt s h oul d n ot be re v eale d t o t he s p o ns or . 
W he n a bli n d is br o ke n, t he patie nt will be wit h dra w n fr o m t he st u d y, a n d t he e ve nt will be 
rec or de d o n t he e C R F. T he circ u msta n ces lea di n g t o t he brea ki n g of t he c o de s h o ul d be f ull y 
d oc u me nte d i n t he i n vesti gat or’s st u d y files a n d i n t he patie nt’s s o urce d oc u me ntati o n. 
Assi g n me nt of I M P s h o ul d n ot be rec or de d i n a n y st u d y d oc u me nts or s o urce d oc u me nt.  
I n bli n de d st u dies, f or a n a d verse e ve nt defi ne d as a s us pecte d u ne x pecte d seri o us a d verse 
reacti o n ( S U S A R) (i e, reas o nable p ossi bilit y; s ee Secti o n  7. 1. 4 ), Gl o bal Patie nt Safet y a n d 
P har mac o vi gila nce ( G P S P) ma y i n de p e n de ntl y re q uest t hat t he bli n d c o de be br o ke n ( o n a 
case-b y -cas e basis) t o c o m pl y wit h re g ulat or y re q uire me nts. T he re p ort will be pr o vi de d i n a n 
u n bli n de d ma n ner f or re g ulat or y s u b missi o n. If t his occ urs, bli n di n g will be mai ntai ne d f or t he 
i n vesti gat or a n d f or ot her pers o n nel 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 he a nal ysis a n d 
re p orti n g of t he dat a. 
O pe n -L a bel E xte nsi o n P h ase  
T he o pe n -la b el e xte nsi o n p hase has n o bli n di n g. 
5. 1 0. 3.  
D at a M o nit ori n g C o m mittee  
T here will be n o D ata a n d Safet y M o nit ori n g B oar d i n t his st u d y.  
5. 1 1.  
T ot al Bl o o d V ol u me  
T he t otal bl o o d v ol u me t o be c ollecte d f or eac h p atie nt i n t his st u d y is a p pr o xi matel y 6 4. 2  m L 
f or sc he d ule d t ests. Details o n t otal bl o o d v ol u me are pr o vi d e d i n A p pe n di x  J. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
6 6  
 
6.  
A S S E S S M E N T O F E F FI C A C Y  
Data fr o m a n y efficac y assess me nts perf or me d aft er t he s pecifie d ti me will n ot be c ollecte d o n 
t he e C R F; i n t he e ve nt, h o we ver, t hat s u c h data are c ollecte d, t hes e data will n ot be a nal yze d. 
6. 1.  
Assess me nts of Effic ac y  
See A p pe n di x  B  f or a det aile d descri pti o n of ass ess me nts a n d pr oce d ures. Q uesti o n naires a n d t he 
hea dac he diar y will be c ollecte d wit h a n electr o nic ha n d hel d de vice.  
6. 1. 1.  
Electr o nic H e a d ac he D i ar y 
Patie nts will kee p a dail y hea dac he diar y t o rec or d t he n u m ber of mi grai ne da ys a n d hea d ac h es 
da ys t he y e x perie nce. T h ese diar y e ntries will be re vie we d at cli nic visits o n visit 2 
(ra n d o mizati o n), visit 3 ( da y 2 9), visit 4 ( da y 5 7), visit 5 ( da y 8 5), a n d visit 6 ( da y  1 6 9) (see 
Ta ble  4 ). 
T he pri mar y effic ac y e n d p oi nt (a n d sec o n dar y a n d e x pl orat or y efficac y e n d p oi nts  as well) will 
be deri ve d fr o m hea d ac h e varia bles c ollecte d dail y usi n g a n electr o nic h ea dac he diar y de vic e. 
Eli gi ble patie nts will recei ve c o m pre h e nsi ve trai ni n g fr o m site pers o n nel o n t he use of t he 
electr o nic h ea dac he diar y de vice. Site pers o n nel will a ls o i nstr uct patie nts o n t he re q uire m e nt f or 
ti mel y a n d dail y c o m pleti o n of t he electr o ni c diar y. A p pr o xi matel y 7 5 % c o m plia nce is nee de d 
after t he ra n d o mizati o n peri o d. Site pers o n nel will m o nit or patie nt’s c o m plia nce t hat 
a p pr o xi matel y 7 5 % diar y e ntr y is met d uri n g t he d o u ble -bli n d treat me nt p h ase a n d o pe n -la bel 
e xte nsi o n p hase . 
O n eac h d a y, t he patie nt will be as ke d t o rec or d di ar y data f or t he pre vi o us 2 4 -h o ur peri o d. 
Patie nts ma y be as ke d a b o ut t heir perf or m a nce at w or k, at sc h o ol, a n d w he n d oi n g h o use h ol d 
c h ores (ie, f u ncti o nal ass ess me nts). Patie nts w h o re p ort hea d ac he o n t h e pre vi o us da y will 
a ns wer q uesti o ns a b o ut t he hea d ac he (ie, t he n u m ber of h o urs wit h he a dac he, prese n ce of 
ass ociate d s y m pt o ms, a n d use of ac ut e mi grai ne me dicati o ns). A d diti o nal d etails re gar di n g t he 
q uesti o ns t hat t he patie nts will a ns wer ca n be f o u n d i n t he electr o nic h ea dac he diar y trai ni n g 
ma n ual.  
If a patie nt f ails t o c o m plete t he diar y f or t he prece di n g d a y, t he patie nt will be pr o m pte d t o e nter 
t he misse d da y’s i nf or mati o n the ne xt ti me he/s he accesses t he electr o nic di ar y pr o vi de d n o m ore 
t ha n 4 8 h o urs ha ve ela ps e d si nce c o m pleti o n of t h at da y. If m ore t ha n 4 8 h o urs ha ve el a pse d 
si nce c o m pleti o n of a diar y d a y, t he patie nt will n ot be all o we d t o e nter di ar y i nf or mati o n f or t hat 
da y, a n d it will be c o nsi dere d a misse d da y.  
Rati n g of hea dac he se v erit y a n d d urati o n of hea d ac he f or eac h da y will be c o m plete d i n t he 
electr o nic diar y. O verall hea dac he d urati o n will be rec or de d n u mericall y (i n h o urs) as well as 
n u m ber of h o urs wit h hea dac h e of at least m o derate se verit y.  
If hea d ac h e is re p orte d, t he n hea d ac he s e verit y will be s u bjecti vel y rate d b y t he patie nt as 
f oll o ws: 
•  mil d hea dac he  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
6 7  
 
•  m o derate hea dac he  
•  se vere h ea d ac he 
Patie nts will als o rec or d w het her p h ot o p h o bia, p h o n o p h o bia, na usea, a n d/ or v o miti n g are 
prese nt, a n d t he y will rec or d a n y mi grai ne me di cati o ns ( na me of dr u g, n u m ber of 
ta blets/ca ps ules, a n d t he d ose i n milli gra ms per ta blet/ca ps ule) ta ke n o n eac h da y. 
6. 1. 2.  
Mi ni Me nt al St ate E x a mi n ati o n  
Patie nts will c o m plete Mi ni Me ntal State E x a mi nati o n at t he ti me p oi nts detaile d i n Ta ble  4 . T his 
is a 3 0-p oi nt q uesti o n naire t o meas ure c o g niti ve f u nc ti o n.  
6. 1. 3.  
P ati e nt He alt h Q uesti o n n aire -9  
T he P H Q is a 9 -ite m q uesti o n naire wit h eac h ite m c orres p o n di n g t o 1 criteri o n of t he Dia g n ostic 
a n d Statistical Ma n ual f or Me ntal Dis or ders 4 t h e diti o n dia g n ostic criteri a f or M D D. Eac h of t he 
ite ms is sc ore d o n a scale of 0 (“ n ot at all”), 1 (“s e veral da ys ”), 2 (“ m ore t h a n half t he da ys ”), 
a n d 3 (“ nearl y e v er y da y”) base d o n t h e fre q ue nc y of s y m pt o ms d uri n g t he past 2 wee ks ( S pitzer, 
1 9 9 9 ). T he P H Q -9 is a v ali da te d meas ure f or d etecti n g a n d m o nit ori n g de pressi o n, a n xiet y, a n d 
s o matizati o n (Kr oe n ke, 2 0 1 0 ). 
Patie nts will c o m plete t he P H Q -9 at t he ti me p oi nts detaile d i n Ta ble  4 .  
6. 1. 4.  
H a milt o n De pressi o n R ati n g Sc ale -1 7  
A q ualifie d staff m e m ber (ie, t he i n vesti gat or or a me dicall y q u alifie d pers o n desi g nat e d b y t he 
i n vesti gat or) will a d mi nister  a n d rec or d the H A M -D 1 7 at t he ti me p oi nts detaile d i n Ta ble  4 . 
T he H A M -D 1 7 is a list of 1 7  ite ms use d t o deter mi ne a patie nt’s le vel of de pressi o n. T he 
H A M -D 1 7 q uesti o n nair e s h o ul d be gi ve n at t he s a me ti me of da y f or eac h visit.  A  ps yc hiatrist 
will be a me m ber of t h e site st u d y tea m a n d s h o ul d be c o ns ulte d as a p pr o pri ate .  
6. 1. 5.  
H a milt o n A n xiet y Sc ale  
A q ualifie d staff m e m ber (ie, t he i n vesti gat or or a me dicall y q u alif ie d pers o n desi g nat e d b y t he 
i n vesti gat or) will a d mi nister  a n d rec or d the H A M -A at t he ti me p oi nts detaile d i n Ta ble  4 . T he 
H A M -A Scale is a t o ol f or meas uri n g t he se v erit y of a patie nt’s a n xiet y. A  ps yc hiatrist will be a 
me m ber of t he site st u d y tea m a n d s h o ul d be c o ns ulte d as a p pr o priat e . 
6. 1. 6.  
6 -Ite m He a d ac he I mp a ct Test  
T he HI T -6 was de v el o pe d b y K osi ns ki et al, 2 0 0 3  as a s h ort f or m f or relia bl y assessi n g t he 
a d verse h ea d ac he i m pact i n cli nical practice a n d cli nical researc h setti n gs. T he q uesti o n naire 
me as ures t he a d vers e i m pact of hea dac h e o n s oci al f u ncti o ni n g, r ole f u ncti o ni n g, vitalit y, 
c o g niti ve f u n cti o ni n g, a n d ps yc h ol o gical distress. It als o assesses hea dac he se verit y. T he HI T -6 
has bee n s h o w n t o be a relia ble a n d vali d t o ol f or assess me nt of hea da c h e i m pact i n patie nts wit h 
mi grai ne (Ya n g, 2 0 1 1 ). 
Patie nts will c o m plete t he HI T -6 at t he ti me p oi nts detaile d i n Ta ble  4 . 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
6 8  
 
6. 1. 7.  
Cli nic al Gl o b al I m pressi o n -Se verit y Sc ale  
Patie nts will c o m plete t he C GI -S scale at t he ti me p oi nts detaile d i n Ta ble  4 . T he C GI-S is a 
s h ort q uesti o n naire fille d o ut b y t he i n vesti gat or t hat rates a p atie nt’s me nt al healt h fr o m 1 
( n or mal, n ot at all ill) t o 7 (a m o n g t he m ost e xtre mel y ill patie nts; G u y, 1 9 7 6 ). 
6. 1. 8.  
Mi gr ai ne -S pecific Q u alit y of Life  
T he M S Q o L v ersi o n 2. 1 is a 1 4 -ite m q uesti o n nair e t hat assesses t he i m pact of mi grai ne a n d 
mi grai ne treat me nt o n a patie nt’s q ualit y of life d uri n g t he pre vi o us 4 wee ks, w hic h has bee n 
s h o w n t o be a relia bl e a n d vali d t o ol f or use i n C M a n d E M ( Ba gle y, 2 0 1 2 ). T he M S Q o L 
meas ures t he d e gree t o w hic h perf or m a nce of n or mal acti vities is li mite d b y mi grai ne ( R ole 
F u ncti o n -Restricti ve d o mai n c o m prisi n g 7 ite ms), t he de gree t o w hic h perf or ma nce of n or mal 
acti vities is pre ve nte d b y mi grai ne ( R ole F u n cti o n -Pre ve nti ve d o mai n c o m prisi n g 4 ite ms), a n d 
t he e m oti o nal effects of mi grai ne ( E m oti o nal F u n cti o n d o mai n c o m prisi n g 3 ite ms). Sc ores ra n ge 
fr o m 0 t o 1 0 0, wit h hi g her sc ores i n dicati n g b etter healt h-rel ate d q ualit y of life. 
Patie nts will c o m plete t he M S Q o L at t he ti me p oi nts detaile d i n Ta ble  4 .  
6. 1. 9.  
W or k Pr o d ucti vit y a n d Acti vit y I m p air me nt Q uesti o n n aire Ge ner al H e alt h V 2. 0  
T he ge neric versi o n of t h e W P AI q uesti o n nair e meas ures t he o v erall effect of healt h o n 
pr o d ucti vit y at w or k a n d dail y acti vities. T he s pecific healt h pr o ble ms versi o n of t he W P AI 
q uesti o n naire all o ws i n vesti gat ors  t o attri b ute pr o d ucti vit y a n d acti vit y i m pair me nt iss ues t o 
s pecific healt h c o n diti o ns. After t he e m pl o y me nt stat us of a res p o n d e nt is i de ntifie d, 3 o pe n 
e n de d q uesti o ns are as ke d c o ncer ni n g ( 1) h o urs a bse nt fr o m w or k d ue t o h ealt h pr o ble ms ( or 
s pecific co n diti o n), ( 2) h o urs a bse nt fr o m w or k d ue t o ot her reas o ns, a n d ( 3) h o urs act uall y 
w or ke d. T w o a d diti o nal q uesti o ns are i ncl u de d t h at as k a b o ut t he i m pact of healt h o n 
pr o d ucti vit y, 1 c o n cer ni n g pr o d u cti vit y at w or k a n d t he ot her c o ncer ni n g dail y acti vitie s o utsi de 
of w or k. T he res p o nse f or mat of eac h ite m of t he W P AI q uesti o n naire c o nsists of a n 1 1 -p oi nt 
scale ra n gi n g fr o m 0 ( n o i m pair me nt) t o 1 0 (c o m plete i m pair me nt) (Reill y, 1 9 9 3 ).  
Patie nts will c o m plete t he W P AI q uesti o n nair e at  t he ti me p oi nts detaile d i n Ta ble  4 . 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
6 9  
 
7.  
A S S E S S M E N T O F S A F E T Y  
I n t his st u d y, safet y will be assesse d b y q u alifie d st u d y pers o n nel b y e val u ati n g re p orte d a d verse 
e ve nts , cli nical la b orat or y test r es ults, vital si g ns meas ure me nts, E C G fi n di n gs, p h ysical 
e x a mi nati o n fi n di n gs (i ncl u di n g hei g ht a n d wei g ht meas ure me nts), e C -S S R S sc ores, use of 
c o nc o mita nt me dicati o n a n d t hera p y, a n d occ urre nce of se v ere h y p erse nsiti vit y/ a na p h ylactic 
reacti o ns. 
7. 1.  
A d verse E ve nts  
7. 1. 1.  
Defi niti o n of a n A d verse E ve nt  
A n y u nt o w ar d me dic al occ urre nce i n a patie nt or cli nical i n vesti gati o n s u bject a d mi nistere d a 
p har mace utical pr o d uct a n d w hic h d oes n ot necess ari l y h a ve t o ha ve a ca us al relati o ns hi p wit h 
t his treat me nt. 
A n a d vers e e ve nt ca n, t h eref ore, be a n y u nfa v ora ble a n d u ni nte n de d p h ysi cal si g n, s y m pt o m, or 
la b orat or y para meter t hat de vel o ps or w orse ns i n se verit y d uri n g t he c o urse of t his st u d y, or 
si g nificant w orse ni n g of t he disease u n der st u d y, or of a n y c o n c urre nt disease, w het her or n ot 
c o nsi dere d relate d t o t he I M P, fre ma nez u ma b. A n e w c o n diti o n or t he w ors e ni n g of a 
pre -e xisti n g c o n diti o n will be c o nsi dere d a n a d verse e ve nt. Sta ble c hr o nic c o n diti o ns ( s uc h as 
art hritis) t hat are prese nt bef ore st u d y e ntr y a n d d o n ot w orse n d uri n g t his st u d y will n ot be 
c o nsi dere d a d vers e e ve nts.  
Acc or di n gl y, a n a d vers e e ve nt ca n i n cl u de a n y of t he f oll o wi n g:  
•  i nterc urre nt ill nesses 
•  p h ysical i nj uries  
•  e ve nts p ossi bl y relate d t o c o nc o mita nt me dicati o n 
•  si g nifica nt w orse ni n g (c h a n ge i n nat ure, s e verit y, or fre q u e nc y) of t he dise ase u n der 
st u d y or ot her pre-e xisti n g c o n diti o ns  
•  dr u g i nteracti o ns  
•  e ve nts occ urri n g d uri n g dia g n ostic pr o ce d ures or d uri n g a n y was h o ut p has e of t his 
st u d y 
•  la b orat or y or dia g n ostic t est a b n or malities t hat res ult i n t he wit h dra wal of t he patie nt 
fr o m t he st u d y, are ass ociate d wit h cli nical si g ns a n d s y m pt o ms or a seri o us a d verse 
e ve nt, re q uir e me dical treat me nt or f urt her dia g n ostic w or k -u p, or are c o nsi dere d b y 
t he i n vesti gat or t o b e cli nicall y si g nifica nt. 
( N ote: A b n or mal la b orat or y or dia g n ostic test res ults at t he scree ni n g visit ( V 1) t hat 
precl u de a patie nt fr o m e nteri n g t he st u d y or recei vi n g st u d y treat me nt are n ot 
c o nsi dere d a d vers e e ve nts.)  
•  all e ve nts of p ossi ble dr u g -i n d uce d li ver i nj ur y wit h h y per bilir u bi ne mia ( defi ne d as 
A S T or A L T ≥3 ti mes t he u p per li mit of n or mal [ U L N], pl us eit her t otal bilir u bi n 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
7 0  
 
≥2  ti mes t he U L N or i nter nati o nal n or malize d rati o > 1. 5) or H y’s La w e ve nts re q uire 
i m me diate st u d y treat me nt cessati o n.  
Mi grai n e e x acer bati o ns, i ncl u di n g ac ute hea dac he re q uiri n g hea d ac h e me di cati o ns, will be 
c ollecte d as p art of t he efficac y assess me nt i n t his st u d y. Mi grai ne e x acer bati o ns (i ncl u di n g ac ut e 
hea dac he) s h o ul d be rec or de d as a n a d verse e v e nt o nl y if t he prese ntati o n a n d/ or o utc o me is 
m ore se vere t ha n w o ul d t y pic all y b e e x pecte d fr o m t he n or mal c o urse of t he disease i n a 
partic ular p atie nt or if t he y are se v ere e n o u g h t o re q uire h os pitalizati o n of t he patie nt, i n w hic h 
case t he y are rec or de d as seri o us a d verse e v e nts. 
W orse ni n g of de pressi o n will be c ollecte d as p art of t he effi cac y assess me nt i n t his st u d y  a n d 
s h o ul d be rec or de d as a n a d verse e ve nt o nl y if t he prese ntati o n or o utc o me is m ore se vere t ha n 
w o ul d n or mall y be e x pecte d fr o m t he n or mal c o urse of t he diseas e i n a partic ular patie nt. 
7. 1. 2.  
Rec or di n g a n d Re p orti n g of A d verse E ve nts  
F or rec or di n g of a d verse e ve nt, t he st u d y p eri o d is defi ne d f or eac h patie nt as t he ti me peri o d 
fr o m si g n at ure of t he I C F t o t he e n d of t he f oll o w-u p p eri o d. T he f oll o w -u p peri o d of rec or di n g 
of a d vers e e ve nts is defi ne d as 1 2  wee ks aft er t he l ast d ose of I M P. T he peri o d f or re p orti n g 
treat me nt-e mer ge nt a d v erse e ve nts is defi ne d as t he peri o d after t he first d ose of I M P is 
a d mi nistere d  a n d u ntil e n d of f oll o w -u p peri o d o n da y  1 6 9 ( ± 3 da ys).  
All a d verse e ve nts t hat o cc ur d uri n g t he defi ne d st u d y peri o d m ust be rec or de d o n b ot h t he 
s o urce d oc u m e ntati o n a n d t he e C R F, re gar dless of t he se verit y of t he e ve nt or j u d ge d 
relati o ns hi p t o t he I M P. F or seri o us a d vers e e ve nts, t he seri o us a d verse e v e nt f or m m ust be 
c o m plete d a n d t he seri o us a d verse e ve nt m ust be re p orte d i m me diatel y ( Secti o n  7. 1. 5. 3. 1 ). T he 
i n vesti gat or d o es n ot nee d t o acti vel y m o nit or pati e nts f or a d verse e ve nts after t he defi n e d 
peri o d. Seri o us a d verse e ve nts a n d a d verse e v e nts of s pecial i nterest occ urri n g i n a patie nt after 
t he defi ne d st u d y peri o d s h o ul d be re p orte d t o t he s p o ns or if t he i n vesti gat or bec o mes a ware of 
t he m, f oll o wi n g t he pr o ce d ures des cri be d i n Secti o n 7. 1. 5. 3. 1 . 
At eac h c o ntact wit h t he patie nt, t he i n vesti gat or or desi g n ee m ust q uesti o n t he patie nt a b o ut 
a d verse e ve nts b y as ki n g a n o pe n -e n d e d q uesti o n s uc h as “ Ha ve y o u h a d a n y u n us ual s y m pt o ms 
or me dical pr o ble ms si nce t he last visit? If yes, please descri be.” All r e p orte d or o bser ve d si g ns 
a n d s y m pt o ms will be rec or de d  i n di vi d uall y, e x ce pt w he n c o nsi dere d ma nifestati o ns of a 
me dical c o n diti o n or dise ase state. A precise di a g n osis will be rec or de d w he ne ver p ossi ble. 
W he n s uc h a dia g n osis is ma de, all relat e d si g ns, s y m pt o ms, a n d a n y test fi n di n gs will be 
rec or de d c ollecti vel y as a si n gle dia g n osis o n t he e C R F a n d, if it is a seri o us a d verse e ve nt, o n 
t he seri o us a d verse e v e nt f or m. 
T he cli nical c o urs e of eac h a d vers e e v e nt will be m o nit ore d at s uita ble i nter vals u ntil res ol ve d, 
sta bilize d, or ret ur ne d t o baseli ne; or u ntil t he patie nt is referre d f or c o nti n u e d care t o a healt h 
care pr ofessi o nal; or u ntil a deter mi nati o n of a ca use u nrelate d t o t he I M P or st u d y pr oce d ure is 
ma de.  
T he o nset a n d e n d d ates, d urati o n (i n case of a d v erse e ve nt d ur ati o n of less t ha n 2 4  h o urs), ac ti o n 
ta ke n re gar di n g I M P, treat me nt a d mi nistere d, a n d o utc o me f or eac h a d verse e ve nt m ust be 
rec or de d o n b ot h t he s o ur ce d oc u me nt ati o n a n d t he e C R F. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
7 1  
 
T he relati o ns hi p of eac h a d verse e ve nt t o I M P a n d st u d y pr oce d ures, a n d t h e se verit y a n d 
seri o us ness of each a d v erse e ve nt, as j u d ge d b y t h e i n vesti gat or, m ust be rec or de d as d escri b e d 
i n Secti o n 7. 1. 3  a n d Secti o n  7. 1. 4 . 
F urt her details are gi ve n i n t he Safet y M o nit ori n g Pla n.  
7. 1. 3.  
Se verit y of a n A d verse E ve nt  
T he se verit y of eac h a d v erse e v e nt m ust be rec or de d as o ne of t h e f oll o wi n g:  
Mil d:  
N o li mitati o n of us ual a cti vities 
M o der ate:  S o me li mitati o n of us ual acti vities  
Se vere:  
I n a bilit y t o carr y o ut us u al acti vities 
7. 1. 4.  
Rel ati o ns hi p of a n A d verse E ve nt t o t he I n vesti g ati o n al Me dici n al Pr o d uct  
T he relati o ns hi p of a n a d verse e v e nt t o t he I M P is c haracterize d as f oll o ws:  
T a ble  6 : 
T he Rel ati o ns hi p of a n A d verse E ve nt t o t he I M P  
Ter m  
Defi niti o n  
Cl arific ati o n  
N o reas o na ble 
p ossi bilit y  
( n ot relate d) 
T his cate g or y a p plies t o a d verse 
e ve nts t hat, after caref ul 
c o nsi derati o n, are clearl y d ue  t o 
e xtra ne o us ca uses ( disease, 
e n vir o n me nt, etc) or t o a d verse 
e ve nts t hat, after caref ul me di cal 
c o nsi derati o n at t he ti me t he y are 
e val uate d, are j u d ge d t o be u nrelate d 
t o t he I M P. 
T he relati o ns hi p of a n a d verse e ve nt ma y be c o nsi dere d 
“ n o reas o na ble p o ssi bilit y” if it is clearl y d ue t o 
e xtra ne o us ca uses or if at least 2 of t he f oll o wi n g a p pl y:  
•  
It d oes n ot f oll o w a reas o na bl e te m p oral se q ue nce 
fr o m t he a d mi nistrati o n of t he I M P. 
•  
It c o ul d rea dil y ha ve bee n pr o d uce d b y t he patie nt’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 patie nt.  
•  
It d oes n ot f oll o w a k n o w n patter n of res p o nse t o t he 
I M P. 
•  
It d oes n ot rea p pear or w orse n w he n t he I M P is 
re-a d mi nistere d.  
Reas o na ble 
p ossi bilit y  
(relate d) 
T his cate g or y a p plies t o a d verse 
e ve nts f or w hic h, after caref ul 
me dical c o nsi derati o n at t he ti me 
t he y are e val uate d, a c o n necti o n wit h 
t he a d mi nistrati o n of I M P ca n n ot be 
r ule d o ut wit h certai nt y. 
T he relati o ns hi p of a n a d verse e ve nt ma y be c o nsi dere d 
“reas o na ble p oss i bilit y” if at l east 2 of t he f oll o wi n g 
a p pl y:  
•  
It f oll o ws a reas o na ble te m p or al se q ue nce fr o m 
a d mi nistrati o n of t he I M P.  
•  
It ca n n ot be reas o na bl y e x plai ne d b y t he k n o w n 
c haracteristics of t he patie nt’s cli nical state, 
e n vir o n me ntal or t o xic fact ors, or ot he r m o des of 
t hera p y a d mi nistere d t o t he patie nt. 
•  
It disa p pears or decreases o n cessati o n or re d ucti o n i n 
d ose. T here are i m p orta nt e xc e pti o ns w he n a n 
a d verse e ve nt d oes n ot disa p pear after 
disc o nti n uati o n of t he I M P, yet a n I M P relati o ns hi p 
clearl y e xists.  
•  
It f oll o ws a k n o w n patter n of res p o nse t o t he I M P. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
7 2  
 
7. 1. 5.  
Seri o us A d verse E ve nts  
F or rec or di n g of s eri o us a d verse e ve nt, t he st u d y peri o d is defi ne d f or eac h patie nt as t hat ti me 
peri o d fr o m si g nat ure of t he I C F t o t he e n d of t h e f oll o w -u p peri o d. Seri o us a d vers e e ve nts 
occ urri n g i n a p atie nt aft er t he e n d of t he f oll o w -u p peri o d s h o ul d be re p orte d t o t he s p o ns or if 
t he i n vesti gat or b ec o mes a ware of t he m, f oll o wi n g t he pr oce d ures des cri be d i n Secti o n 7. 1. 5. 3. 1 . 
7. 1. 5. 1.  
Defi niti o n of a Seri o us A d verse E ve nt  
A seri o us a d verse e v e nt is a n a d vers e e ve nt o cc urri n g at a n y d os e t hat res ults i n a n y of t he 
f oll o wi n g o utc o mes or acti o ns: 
•  res ults i n deat h 
•  is life-t hreate ni n g ad vers e e ve nt (ie, t h e patie nt w as at ris k of deat h at t he ti me of t he 
e ve nt); it d oes n ot refer t o a n e ve nt w hic h h y p ot h eticall y mi g ht ha ve ca us e d deat h if it 
were m or e se vere  
•  re q uires 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, w hic h 
mea ns t hat h os pital i n patie nt a d missi o n or pr ol o n gati o n of h os pital sta y were re q uire d 
f or treat me nt of a n a d v erse e ve nt, or t hat t he y o cc urre d as a c o nse q u e nce of t he e ve nt 
H os pitalizati o ns sc he d ule d bef ore t he patie nt si g n e d t he I C F will n ot be c o nsi dere d 
seri o us a d vers e e v e nts, u nless t here was w orse ni n g of t he pree xisti n g c o n diti o n 
d uri n g t he p atie nt’s parti ci pati o n i n t his st u d y.  
•  res ults i n persiste nt or si g nifica nt disa bilit y/i n ca pacit y (refers t o a s u bsta nti al 
disr u pti o n of o ne’s a bilit y t o c o n d u ct n or mal life f u ncti o ns)  
•  is a c o n ge nital a n o mal y/ birt h defect 
•  a n i m p orta nt me dical e v e nt t hat ma y n ot res ult i n deat h, be life -t hreat e ni n g, or re q uire 
h os pitaliz ati o n, b ut ma y j e o par dize t he patie nt a n d ma y re q uire m e dical i nter ve nti o n 
t o pre ve nt o ne of t h e o utc o mes liste d i n t his defi niti o n  
E x a m ples of s uc h e ve nts are 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 n c h os pas m; bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n 
h os pitaliz ati o n; or t he de vel o p me nt of dr u g de p e n de n c y or dr u g a b use. N ot e: A n y 
s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a me dici nal pr o d uct is c o nsi dere d a n 
i m p orta nt me dical e ve nt. 
All occ urre nces of p ossi ble dr u g -i n d uce d li ver i nj ur y t hat meet H y’s la w criteria, defi n e d as all  
of t he bel o w, m ust be re p orte d b y t h e i n vesti gat or t o t he s p o ns or as a seri o us a d verse e ve nt:  
•  A L T or A S T i ncrease of > 3 ×  U L N  
•  t otal bilir u bi n i ncrease of > 2×  U L N  
•  a bse nce of i nitial fi n di n gs of c h olestasis (ie, n o s u bsta ntial i ncrease of A L P)  
A n a d vers e e ve nt t hat d o es n ot meet a n y of t he criteria f or seri o us ness liste d a b o ve will be 
re gar de d as a n o ns eri o us a d verse e ve nt. 
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Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
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7. 1. 5. 2.  
E x pecte d ness  
A seri o us a d verse e v e nt t hat is n ot i ncl u de d i n t he A d verse Reacti o n secti o n of t he rele va nt 
refere nce safet y i nf or mati o n b y its s pecificit y, se v erit y, o utc o m e, or fre q ue nc y is c o nsi dere d a n 
u ne x pecte d a d vers e e v e nt. T he refere n ce safet y i nf or mati o n f or t his st u d y is t he  l ocall y a p pr o ve d 
prescri bi n g i nf or mati o n f or c o u ntries w here  fre ma nez u ma b is a p pr o ve d f or t he pre ve nti ve 
treat me nt of mi grai ne. F or c o u ntries w here  fre ma nez u ma b is n ot yet a p pr o v e d, t he refere nce 
safet y i nf or mati o n f or t his st u d y is t he I B. 
T he s p o ns or’s G P S P will deter mi ne t he e x pecte d ness f or all seri o us a d verse e ve nts.  
F or t he p ur p os e of S U S A R re p orti n g, i n c o u ntries w here fre ma nez u ma b is a p pr o ve d f o r t he 
pre ve n ti ve tr eat me nt of mi grai ne, t h e l ocall y a p pr o ve d pres cri bi n g i nf or m ati o n will be use d. F or 
c o u ntries w here t he I B is t he refere n ce safet y i nf or mati o n, t he c urre nt versi o n of t he I B at t he 
ti me of occ urr e nce of t he S U S A R a p plies.  
7. 1. 5. 3.  
Re p orti n g a Seri o us A d verse E ve nt  
7. 1. 5. 3. 1.  I n vesti g at or Res p o nsi bilit y 
T o satisf y re g ulat or y re q uire me nts, a ll seri o us a d v erse e v e nts t hat occ ur d uri n g t he st u d y, 
re gar dl ess of j u d ge d relati o ns hi p t o a d mi nistrati o n of t he I M P, m ust be re porte d t o t he s p o ns or 
b y t he i n vesti gat or. T h e e ve nt m ust be re p orte d wit hi n 2 4  h o urs of w he n t he i n vesti gat or lear ns 
a b o ut it. C o m pleti n g t he seri o us a d vers e e v e nt f or m a n d re p orti n g t he e v e nt m ust n ot be dela ye d, 
e ve n if n ot all t he i nf or m ati o n is a vaila b le. T he i n vesti gat or d o es n ot nee d t o acti vel y m o nit or 
patie nts f or a d verse e v e nts o nce t his st u d y has e n d e d.  
Seri o us a d verse e ve nts o cc urri n g t o a patie nt after t he last a d mi nistrati o n of I M P of t hat p atie nt 
has e n de d s h o ul d be re p orte d t o t he s p o ns or if t he i n vesti gat or b ec o mes a ware of t h e m. 
T he seri o us a d v erse e ve nt f or m s h o ul d be se nt t o t he l ocal safet y officer ( L S O) or desi g nee (a 
c o ntract r esearc h or ga niz ati o n [ C R O] i n a c o u ntr y wit h o ut a s p o ns or L S O) (c o ntact  i nf or m ati o n 
is i n t he Cli nical St u d y Pe rs o n nel C o ntact I nf or mati o n secti o n); t he L S O will f or war d t he re p ort 
t o t he s p o ns or’s G P S P de part me nt. 
T he f oll o wi n g i nf or mati o n s h o ul d be pr o vi de d t o rec or d t he e ve nt acc uratel y a n d c o m pletel y:  
•  st u d y n u m ber 
•  i n vesti gat or a n d i n vesti gati o nal ce nter i d e ntificati o n 
•  patie nt n u m ber  
•  o nset date a n d det aile d d escri pti o n of a d verse e v e nt  
•  i n vesti gat or’s assess me nt of t he relati o ns hi p of t he a d verse e ve nt t o t he I M P ( n o 
reas o na bl e p ossi bilit y, reas o na ble p ossi bilit y) 
A d diti o nal i nf or mati o n i ncl u des:  
•  a ge a n d se x of patie nt  
•  date of first d ose of I M P  
•  date a n d a m o u nt of last a d mi nistere d d ose of I M P  
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•  acti o n ta ke n  
•  o utc o me, if k n o w n  
•  se verit y 
•  e x pla nati o n of assess me nt of relate d n ess  
•  c o nc o mita nt me dicati o n (i ncl u di n g d oses, r o utes of a d mi nistrati o n, a n d re gi me ns) a n d 
treat ment of t he e ve nt  
•  perti ne nt la b orat or y or ot her dia g n ostic test data  
•  me dical hist or y  
•  res ults of dec h alle n ge/rec halle n ge, if k n o w n 
•  f or a n a d v erse e ve nt r es ulti n g i n deat h 
− ca use of deat h ( w het her or n ot t he deat h was relat e d t o I M P)  
− a ut o ps y fi n di n gs (if a vail a ble)  
Eac h re p ort of a s eri o us a d verse e v e nt will be re vi e we d a n d e val uat e d b y t he i n vesti gat or a n d t he 
s p o ns or t o assess t he nat ure of t he e ve nt a n d t he relati o ns hi p of t he e ve nt t o t he I M P, st u d y 
pr oce d ures, a n d t o u n derl yi n g diseas e.  
A d diti o nal i nf or mati o n (f oll o w -u p) a b o ut a n y seri o us a d verse e ve nt u na vaila ble at t he i nitial 
re p orti n g s h o ul d be f or w ar de d b y t he i n vesti gat or wit hi n 2 4 h o urs of w he n it bec o mes k n o w n t o 
t he sa me a d dress as t he i nitial re p ort. 
F or all c o u ntri es, t he s p o ns or’s G P S P de part me nt  will distri b ute t he C o u ncil f or I nter n ati o nal 
Or ga niz ati o ns of Me dical Scie nces ( CI O M S) f or m/ E xte nsi ble Mar k u p La n g ua ge file t o t he 
L S O/ C R O f or s u b missi o n t o t he c o m pete nt a ut h orities, I E C/I R Bs, a n d i n vesti gat ors, acc or di n g t o 
re g ulati o ns. T he i n vesti gat o r m ust e ns ure t hat t he I E C/I R B is als o i nf or me d of t he e ve nt, i n 
acc or da nce wit h nati o nal a n d l ocal re g ul ati o ns. 
F or d o u ble -bli n d st u dies, bli n di n g will be mai ntai ne d f or all st u d y pers o n nel. T heref ore, i n case 
of a S U S A R, o nl y t he L S O/ C R O will recei ve t he  u n bli n de d re p ort f or re g ul at or y s u b missi o n; t he 
ot hers will recei v e a bli n de d re p ort.  
7. 1. 5. 3. 2.  S p o ns or Res p o nsi bilit y  
If a seri o us u ne x pecte d a d verse e v e nt is belie ve d t o be relate d t o t he I M P or st u d y pr oce d ures, 
t he s p o ns or will ta ke a p pr o priate ste ps t o n otif y all i n vesti gat ors partici pati n g i n s p o ns ore d 
cli nical st u dies of fre m a n ez u ma b a n d t he a p pr o priate c o m pete nt a ut h orities (a n d I E C/I R B, as 
a p pr o priate).  
I n a d diti o n t o n otif yi n g t he i n vesti gat ors a n d c o m pete nt a ut h orities (a n d I E C/I R B, as 
a p pr o priate), ot her  acti o n ma y b e re q uir e d, i ncl u di n g t he f oll o wi n g:  
•  alteri n g e xisti n g researc h b y m o dif yi n g t he pr ot oc ol  
•  disc o nti n ui n g or s us pe n di n g t he st u d y  
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Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
7 5  
 
•  m o dif yi n g t he e xisti n g c o nse nt f or m a n d i nf or mi n g all st u d y partici p a nts of ne w 
fi n di n gs 
•  m o dif yi n g t he listi n gs of e x pecte d t o xicities t o i ncl u de a d verse e ve nts ne wl y 
i de ntifie d as relat e d t o fre ma nez u ma b 
7. 1. 6.  
Pr ot oc ol -D efi ne d A d verse E ve nts of S peci al I nterest  
F or  p ur p os es of t his pr ot oc ol, t he f oll o wi n g are c o nsi dere d pr ot oc ol -d efi n e d a d verse e v e nts of 
s pecial i nterest t o be s e nt t o t he s p o ns or’s G P S P f or e val uati o n:  
•  e ve nts of a n a p h yl a xis a n d se vere h y p erse nsiti vit y reacti o ns.  
•  o p ht hal mic e ve nts of at l east m o derat e se verit y.  
A na p h yl a xis a n d se vere h y perse nsiti vit y will be m o nit ore d usi n g t he dia g n ostic criteria f or 
a na p h yla xis as o utli ne d b y t he 2 0 0 6 J oi nt Nati o nal I nstit ute of Aller g y a n d I nfecti o us 
Disease/ F o o d Aller g y a n d A na p h yl a xis Net w or k Sec o n d S y m p osi u m o n A na p h yl a xis ( Sa m ps o n, 
2 0 0 6 ) (als o see A p pe n di x  H ). I n t he e v e nt of s us p ecte d a n a p h yla xis a n d se vere h y perse nsiti vit y, 
vital si g ns, i ncl u di n g o x y ge n s at urati o n a n d res pir ati o n rate, will be meas ure d. Ot her ass ess me nts 
will be perf or me d at t he discreti o n of t he i n vesti gat or. As a preca uti o n, eac h site s h o ul d ha ve a 
res uscitati o n cart near b y. 
T he pr ocess f or re p orti n g a pr ot oc ol -defi ne d a d v erse e ve nt of i nterest is t he sa me as t hat f or 
re p orti n g a seri o us a d verse e ve nt ( Secti o n 7. 1. 5. 3 ). Pr ot oc ol-defi ne d a d v erse e ve nts of s p ecial 
i nterest t o be re p orte d t o G P S P ca n be eit her seri o us or n onseri o us, acc or di n g t o t he criteria 
o utli ne d i n Secti o n  7. 1. 5. 1 . 
7. 1. 7.  
Pr ot oc ol D e vi ati o ns Bec a use of a n A d verse E ve nt  
If a patie nt e x perie nces a n a d verse eve nt or me di cal e mer ge n c y, de viati o ns fr o m t he pr ot oc ol 
ma y b e all o we d o n a cas e -b y -case basis. T o e ns ure patie nt safet y, after t h e e ve nt has sta bilize d or 
treat me nt has bee n a d mi nistere d ( or b ot h), t he i n v esti gat or or ot her p h ysici a n i n atte n da nce m ust 
c ontact t he p h ysicia n i de ntifie d i n t he Cli nical St u d y Pers o n nel C o ntact I nf or mati o n secti o n of 
t his pr ot oc ol as s o o n as p ossi ble t o disc uss t he sit uati o n. T he i n vesti gat or, i n c o ns ultati o n wit h 
t he s p o ns or, will deci de w het her t he p atie nt s h o ul d c o nti n ue t o partici pate i n t he st u d y.  
7. 2.  
Pre g n a nc y  
A n y fe male p atie nt bec o mi n g pre g n a nt d uri n g t he st u d y will disc o nti n ue I M P. A ll pre g na n cies of 
w o me n partici pati n g i n t he st u d y a n d fe mal e part ners of me n partici pati n g i n t he st u d y t hat occ ur 
d uri n g t he st u d y or wit hi n  at least 6 m o nt hs after t he last d ose of I M P are t o be re p ort e d 
i m me diatel y t o t he i n di vi d ual i de ntifie d i n t he Cli nical St u d y Pers o n nel C o ntact I nf or mati o n 
secti o n of t his pr ot oc ol, a n d t he i n vesti gat or m ust pr o vi de t he s p o ns or ( L S O/ C R O) wit h t he 
c o m plet e d pre g n a nc y f or m. T he pr ocess f or re p orti n g a pre g na n c y is t he sa me as t hat f or 
re p orti n g a seri o us a d verse e ve nt b ut usi n g t h e pre g na n c y f or m ( S ecti o n 7. 1. 5. 3 ). T he 
i n vesti gat or is n ot re q uir e d t o re p ort patie nts w h o are f o u n d t o b e pre g n a nt bet wee n t he s cree ni n g 
visit ( V 1) a n d ra n d o mizati o n visit ( V 2 o n da y  1), pr o vi de d n o pr ot oc ol -relate d pr oce d ures were 
a p plie d. 
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Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
7 6  
 
All fe male patie nts ( or fe male part ners of me n partici pati n g i n t he st u d y) w h o bec o me pre g na nt 
will be m o nit ore d f or t he o utc o me of t he pre g na nc y (i ncl u di n g s p o nta n e o us or electi ve a b orti o n). 
Fe male p art ners of me n p artici pati n g i n t he st u d y w h o bec o me pre g na nt will be as ke d t o si g n a n 
I C F. If t he pre g n a nc y c o nti n ues t o ter m, t he o utc o me ( healt h of t he i nf a nt u p t o 8 wee ks of a ge), 
i ncl u di n g details of birt h a n d prese n ce or a bse n ce of a n y birt h defect, c o n ge nital a b n or malities, 
or mater nal a n d ne w b or n c o m plicati o ns, will be re p orte d t o t he s p o ns or. A n y c o m plicati o n of 
pre g na nc y d uri n g t he st u d y a n d a n y c o m plicati o n of pre g na n c y t hat t he i n v esti gat or b ec o mes 
a ware of after wit h dra wal fr o m t he st u d y will be re p orte d as a n a d verse e v e nt or seri o us a d verse 
e ve nt, as a p pr o priate.  
If t he pre g n anc y i n t he w o ma n partici pati n g i n t he st u d y a n d/ or t he fe male part ners of m e n 
partici pati n g i n t he st u d y d oes n ot c o nti n ue t o ter m, o ne of t he f oll o wi n g acti o ns will be ta ke n:  
•  F or a s p o nta n e o us a b orti o n, re p ort as a seri o us a d verse e v e nt.  
•  F or a n electi ve a b orti o n d ue t o de vel o p me ntal a n o malies, re p ort as a seri o us a d verse 
e ve nt.  
•  F or a n electi ve a b orti o n n ot  d ue t o de vel o p me ntal a n o malies, re p ort o n t he pre g na nc y 
f or m; d o n ot re p ort as a n a d verse e ve nt. 
7. 3.  
Me dic ati o n Err or a n d S peci al Sit u ati o ns Rel ate d t o t he 
I n vesti g ati o n al Me dici n al Pr o d ucts 
A n y a d mi nistrati o n of I M P t hat is n ot i n acc or da nce wit h t he st u d y pr ot oc ol s h o ul d be re p orte d 
i n t he patie nts s o urce d oc u me nts, re gar dless of w h et her or n ot a n a d verse e ve nt occ urs as a 
res ult. 
T he f oll o wi n g are t y p es of  me dicati o n err ors a n d s pecial sit uati o ns:  
1.  Me dicati o n err or: A n y u ni nte nti o nal err or i n t he prescri bi n g, dis pe nsi n g, or 
a d mi nistrati o n of a me dici nal pr o d uct w hile i n t he c o ntr ol of t he healt hcare pr ofessi o nal, 
patie nt, or c o ns u mer.  
2.  O ver d ose: A d mi nistrati o n of a q ua ntit y of a me di ci nal pr o d uct gi ve n per a d mi nistrati o n 
or c u m ulati vel y w hic h is a b o ve t he ma xi m u m rec o m me n de d d ose acc or di n g t o t he 
a ut h orize d pr o d uct i nf or mati o n. Cli nical j u d g me nt s h o ul d al wa ys b e a p plie d. A n y d os e of 
I M P ( w h et her t he t est I M P, refere nce I M P, or place b o I M P), w het her ta ke n i nte nti o nall y 
or u ni nte nti o nall y, i n e x cess of t hat pres cri be d m ust be i m me diatel y re p orte d t o t he 
s p o ns or. 
3.  Mis use: Sit uati o ns w here t he I M P is i nte nti o nall y a n d i na p pr o priat el y us e d n ot i n 
acc or da nce wit h t he a ut h orize d pr o d uct i nf or mati o n.  
4.  A b use: Persiste nt or s p ora dic, i nte nti o nal e x cessi ve use of I M P w hic h is a cc o m pa nie d b y 
har mf ul p h ysical or ps yc h ol o gical effects.  
5.  Off -la b el use: Sit uati o ns w here a n I M P is i nte nti o nall y use d f or a me di cal p ur p ose n ot i n 
accor da nce wit h t he a ut h orize d pr o d uct i nf or mati o n.  
6.  Occ u pati o nal e x p os ure: E x p os ure t o a n I M P, as a res ult of o ne’s pr ofessi o nal or 
n o n -pr ofessi o nal o cc u pati o n.  
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7.  Breastfee di n g: S us pect e d a d verse reacti o ns w hic h occ ur i n i nfa nts f oll o wi n g e x p os ure t o 
a me dici nal pr o d uct fr o m breast mil k. 
7. 4.  
Cli nic al L a b or at or y Tests  
All cli nical la b orat or y test res ults o utsi de of t he refere nce ra n ge will be j u d ge d b y t h e 
i n vesti gat or as bel o n gi n g t o o ne of t he f oll o wi n g cate g ories: 
•  a b n or mal a n d n ot cli nicall y si g nifica nt  
•  a b n or mal a n d cli nic all y si g nifica nt  
A la b orat or y test r es ult t hat is j u d ge d b y t he i n vesti gat or as cli nicall y si g nifi ca nt will be rec or de d 
o n b ot h t he s o urce d oc u me ntati o n a n d t he e C R F as a n a d verse e v e nt a n d m o nit ore d as descri b e d 
i n Secti o n 7. 1. 2 . A n e ve nt ma y i ncl u de a la b orat or y or dia g n ostic test a b n or malit y ( o nce 
c o nfir me d b y re peat e d testi n g) t hat res ults i n t he wit h dra wal of t he p atie nt fr o m t he st u d y, t he 
te m p orar y or per ma n e nt wit h dra wal of I M P or m e dical treat me nt, or f urt her dia g n ostic w or k-u p. 
( N ote: A b n or mal la b orat or y or dia g n ostic test res ults at t he scree ni n g visit ( V 1) t hat precl u de a 
patie nt fr o m e nteri n g t he st u d y or recei vi n g I M P are n ot c o n si dere d a d verse e ve nts.) 
I n a d diti o n, p ote ntiall y cli nicall y si g nifica nt val u es will be pre defi ne d b y t h e s p o ns or f or sel ecte d 
la b orat or y para meters a n d will be detaile d i n t he statistical a nal ysis pla n. 
7. 4. 1.  
Ser u m C he mistr y, He m at ol o g y, C o a g ul ati o n, a n d Uri n al ysis  
Cli nical la b orat or y tests (ser u m c he mistr y, he mat ol o g y, c o a g ulati o n, a n d uri nal ysis) will be 
perf or me d at t he ti me p oi nts detaile d i n Ta ble  4 . Cli nical la b orat or y tests will be perf or me d usi n g 
t he ce ntral la b orat or y. H o we ver, i n case of a b n or mal c oa g ulati o n d uri n g t he 2 8-da y bas eli ne 
peri o d, a l ocal retest ca n be a ut h orize d b y t h e s p o ns or o n a cas e -b y -case b asis. S pecific 
la b orat or y tests t o be perf or me d are pr o vi de d i n A p pe n di x  N . 
7. 4. 2.  
F ollicle -Sti m ul ati n g H or m o ne  
F ollicle -sti m ulati n g h or m o ne will be assesse d at t he ti me p oi nts detaile d i n Ta ble  4 . T his 
assess me nt a p plies o nl y t o w o me n t h o u g ht t o be p ost me n o pa usal  at t he scree ni n g visit ( V 1) . If 
t he res ults s h o w a n ele v ate d F S H ( > 3 5 U/ L) a n d t he pa tie nt has ha d n o me nses f or at least 
1 2  m o nt hs, t he y d o n ot n ee d uri ne  pre g na n c y testi n g.  
7. 4. 3.  
H u m a n C h ori o nic G o n a d otr o pi n Tests  
Ser u m β -H C G test will be a d mi nistere d at visit 1 (scree ni n g)  f or w o m e n of c hil d-beari n g 
p ote ntial a n d w o me n t h o u g ht t o be p ost me n o pa us al . Uri ne β-H C G test will be a d mi nistere d at 
visit 2 (ra n d o mizati o n), visit 3 ( da y 2 9), visit 4 ( da y 5 7), visit 5 ( da y 8 5), a n d visit  6 ( da y 1 6 9) 
f or w o me n of c hil d-beari n g p ote ntial a n d f or w o m e n t h o u g ht t o be p ost me n o pa usal w h ose F S H 
res ults at t he scree ni n g visit  di d n ot s h o w a n ele vati o n ( ≤3 5 U/ L)  (see T a ble  4 ). O n d osi n g d a ys, 
t he test s h o ul d be c o m plete d bef ore st u d y dr u g a d mi nistrati o n .  
7. 5.  
P h ysic al E x a mi n ati o ns  
P h ysical e x a mi nati o ns, i ncl u di n g hei g ht (t o be o btai ne d at t he scree ni n g visit [ V 1] o nl y) a n d 
wei g ht, will be p erf or m e d at t he ti me p oi nts detaile d i n Ta ble  4 . A f ull p h ysical e xa mi nati o n will 
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Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
7 8  
 
i ncl u de, at a mi ni m u m, ge neral a p peara n ce; hea d, e yes, ears, n ose, a n d t hr oat; c hest a n d l u n gs; 
heart; a b d o me n; m usc ul os keletal; s ki n; l y m p h n o d es; a n d ne ur ol o gical . I n v esti gat ors s h o ul d pay 
s pecial atte nti o n t o cli nical si g ns r elate d t o pre vi o us seri o us diseases. A n y p h ysical e x a mi nati o n 
fi n di n g t hat is j u d ge d b y t he i n vesti gat or as cli nicall y si g nifi ca nt (e x ce pt at t he scree ni n g visit 
[ V 1]) will be c o nsi dere d a n a d vers e e v e nt, rec or de d o n t he e C R F, a n d m o nit ore d as descri be d i n 
Secti o n  7. 1. 2 . F or w o me n of c hil d -beari n g p ot e ntial o nl y, i n q uire a n d rec or d start/st o p date of 
me nstr ual peri o d at e ac h visit as part of p h ysic al e x a mi nati o n assess me nts . 
7. 6.  
Vit al Si g ns  
Vital si g ns ( bl o o d press ure [s yst olic/ diast olic] , te m perat ure, res pirat or y rat e, a n d p ulse) will be 
meas ure d at t he ti me p oi nts detaile d i n Ta ble  4 . All vital si g ns res ults o utsi de of t he refere nce 
ra n ges will be j u d ge d b y t he i n vesti gat or as bel o n gi n g t o o ne of t he f oll o wi n g cate g ories: 
•  a b n or mal a n d n ot cli nicall y si g nifica nt  
•  a b n or mal a n d cli nic all y si g nifica nt  
Bef ore bl o o d pr ess ure a n d p ulse are meas ure d, t h e patie nt m ust rest i n a s u pi ne or 
se mi-erect/seate d p ositi o n f or at least 5  mi n utes. ( T he sa me p ositi o n a n d ar m s h o ul d be use d eac h 
ti me vital si g ns are me as ure d f or a gi ve n patie nt.) F or  a n y a b n or mal vital si g n val u e, t he 
meas ure me nt s h o ul d be re peate d as s o o n as p ossi ble. A n y vital si g n val ue t hat is j u d ge d b y t he 
i n vesti gat or as cli nicall y si g nifica nt will be rec or de d o n b ot h t he s o urce d o c u me ntati o n a n d t he 
e C R F as a n a d vers e e ve nt a n d m o nit ore d as descri be d i n Secti o n  7. 1. 2 . 
7. 7.  
Electr oc ar di o gr a p h y  
A si n gle 1 2 -l ea d E C G will be rec or de d at t he ti me p oi nts detaile d i n Ta ble  4 .  
A q ualifie d p h ysicia n at a ce ntr al dia g n ostic ce nter will be i nter preti n g t he E C G. E C Gs s h o ul d be 
perf or me d a n d tra ns mitte d acc or di n g t o t he ce ntr al E C G rea di n g i nstr ucti o ns pr o vi de d i n t he 
E C G user ma n ual. E C G e q ui p me nt will be pr o vi de d t o all cli nical sites. Alt h o u g h t he E C G 
i nter pretati o n will be perf or me d ce ntrall y, t he cli nical e val uati o n r e mai ns t he i n vesti gat or’s 
res p o nsi bilit y. 
A n y u ns c he d ule d E C Gs m ust als o be s u b mitte d f or ce ntr al E C G rea di n g.  
All E C G res ults o utsi de of t he refere nce ra n ges will be j u d ge d b y t he i n vesti gat or as b el o n gi n g t o 
o ne of t he f oll o wi n g cate g ories:  
•  a b n or mal a n d n ot cli nicall y si g nifica nt  
•  a b n or mal a n d cli nic all y si g nifica nt 
If res ults are a b n or mal, t he E C G will be re peate d 1 ti me.  
T he E C G will be e val uat e d b y t h e i n vesti gat or at t he ti me of rec or di n g (si g ne d a n d date d), a n d 
t he pri nt o ut s h o ul d be ke pt i n t he s o urce d oc u me ntati o n file. W he n p ote ntiall y cli nicall y 
si g nifica nt fi n di n gs are d etecte d b y t he i n v esti gat or, a car di ol o gist s h o ul d b e c o ns ulte d f or a 
defi niti ve i nter pretati o n. All c o m m u nicati o ns a n d dia g n oses s h o ul d b e file d i n t he s o urce 
d oc u me ntati o n file. T he i n vesti gat or’s i nter pretati o n will be rec or de d  o n t h e e C R F re gar dless of 
t he ce ntral rea di n g i nter pretati o n. A n y E C G fi n di n g t hat is j u d ge d b y t he i n vesti gat or as 
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Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
7 9  
 
cli nicall y si g nifica nt (e x ce pt at t he scree ni n g visit [ V 1]) will be c o nsi dere d a n a d verse e v e nt, 
rec or de d o n t he s o urce d oc u me ntati o n a n d the e C R F a n d m o nit ore d as des cri be d i n 
Secti o n  7. 1. 2 .  
O bjecti ve alerts are pre d efi ne d as d escri be d i n t he ce ntral E C G rea di n g ma n ual. I n t h ese cases,  
t he site a n d t he s p o ns or will be i nf or me d i m me diatel y.  
7. 8.  
Electr o nic C ol u m bi a -S uici de Se verit y R ati n g Sc ale  
As part of t he o v erall safet y e val uati o n, t he electr o nic C ol u m bia -S uici de Se verit y Rati n g Scale 
(e C-S S R S) (P os ner, 2 0 1 6 ) will be use d i n c o nj u n cti o n wit h a q ualifie d cli nicia n’s  (ie, t he 
i n vesti gat or or a me dicall y q ualifie d p ers o n desi g n ate d b y t he i n vesti gat or) cli nical j u d g me nt t o 
assess t he patie nt’s s uici dal i deati o n (se verit y a n d i nte nsit y ) a n d b e ha vi or. T he e C-S S R S 
Lif eti me versi o n will be c o m plete d b y t he patie nt at visit 1, a n d t he e C -S S R S Si nce Last Visit 
versi o n will be c o m plete d b y t he p atie nt at all ot her ti me p oi nts, as descri b e d i n Ta ble  4 . A n y 
p ositi ve fi n di n gs o n t he e C -S S R S Si nce Last Visit versi o n re q uir e e val u ati o n b y a q u alifie d 
ps yc hiatrist f or p ote ntial e x cl usi o n a n d/ or disc o nti n uati o n fr o m t he st u d y. Base d o n his/ her 
me dical j u d g m e nt, a q ualifie d ps yc hiatrist will deter mi ne if t he patie nt s h o ul d be referre d f or 
f urt her e v al uati o n t o a n ot her me ntal healt h s pecialist a n d if t he patie nt s h o ul d c o nti n ue 
partici pati o n i n t he st u d y.  
A n y p atie nt s h o ul d be e x cl u de d if a n y s uici dal b e ha vi ors are re p ort e d. 
A n y p atie nt wit h lifeti me s uici dal be ha vi ors (act ual, i nterr u pte d, a n d a b orte d atte m pts a n d 
pre parat or y acti o ns) s h o ul d be e x cl u de d a n d/ or disc o nti n ue d fr o m t he st u d y.  
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Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
8 0  
 
8.  
A S S E S S M E N T O F P H A R M A C O KI N E TI C S / 
P H A R M A C O D Y N A M I C S / BI OM A R K E R S / 
P H A R M A C O G E N O MI C S / I M M U N O G E NI CI T Y / A N CI L L A R Y 
S T U DI E S  
N ot a p plica ble.  
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Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
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9.  
S T A TI S TI C S  
T his st u d y is a P hase 4, m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, 
parallel -gr o u p st u d y t o e val uate t he efficac y a n d s afet y of fre ma nez u ma b m o nt hl y  d osi n g 
c o m pare d wit h place b o f or pre ve nti ve tr eat me nt of E M a n d C M. Eli gi ble p atie nts will be 
ra n d o mize d i n a 1: 1 rati o t o recei ve m o nt hl y 2 2 5 m g sc fre ma nez u ma b or matc hi n g place b o. 
Patie nts will be stratifie d b y se x, c o u ntr y, mi grai ne classificati o n (ie, C M or E M), a n d baseli ne 
P H Q -9 sc ore cate g or y ( 1 0 t o 1 4, 1 5 t o 1 9, a n d ≥2 0).  
9. 1.  
S a m ple Size a n d P o wer C o nsi der ati o ns  
A sa m ple siz e of 2 8 8 ( 1 4 4 per treat me nt gr o u p) e v al ua ble patie nts c o m pleti n g t he st u d y will 
pr o vi de 9 0 % p o wer t o detect a treat me nt differe nc e of 2 da ys wit h a c o m m o n sta n dar d de viati o n 
of 5. 2 da ys i n c ha n ges fr o m t he 2 8 -da y baseli ne p eri o d i n m o nt hl y a vera ge mi grai ne da ys 
bet wee n acti ve a n d pla ce b o gr o u ps  at a 2-si de d al p ha le vel of 0. 0 5. T his sa m ple siz e will pr o vi de 
a p pr o xi matel y 8 0 % p o w er t o detect a treat me nt differe nce of 2 p oi nts wit h a c o m m o n sta n dar d 
de viati o n of 6 p oi nts i n t he c ha n ge fr o m r a n d o mizati o n visit ( da y  1) i n H A M -D 1 7 t otal sc ore  at 
a 2-si de d al p ha l e vel of 0. 0 5. Ass u mi n g a 1 5 % dr o p -o ut rate, a p pr o xi matel y 3 4 0  patie nts 
(a p pro xi matel y 1 7 0  patie nts per treat me nt gr o u p) will be ra n d o mize d.  
9. 2.  
A n al ysis Sets  
9. 2. 1.  
I nte nt-t o-Tre at A n al ysis Set  
T he i nte nt -t o-treat (I T T) a nal ysis s et will i ncl u de all ra n d o mize d patie nts. 
I n t he I T T a n al ysis set, treat me nt will be assi g ne d base d o n t he treat ment t o w hic h patie nts were 
ra n d o mize d, re gar dl ess of w hic h treat me nt t he y act uall y recei ve d. 
Data c ollecte d fr o m patie nts after treat me nt disc o nti n uati o n will be i ncl u de d i n t he I T T a nal ysis 
set. 
9. 2. 2.  
M o difie d I nte nt -t o-Tre at A n al ysis Set  
T he m o difie d i nte nt -t o-tr eat ( mI T T) a nal ysis set is a s u bset of t he I T T a nal ysis set i ncl u di n g o nl y 
patie nts w h o recei ve at least 1 d ose of I M P a n d ha ve at least 1 0 da ys of p ostra n d o mizati o n 
effic ac y ass ess me nt o n t he pri mar y e n d p oi nt.  
I n t he mI T T a n al ysis set, treat me nt will be assi g ne d base d o n t he treat me nt t o w hic h patie nts 
were ra n d o mize d, re gar dless of w hic h treat me nt t he y act uall y recei v e d.  
9. 2. 3.  
S afet y A n al ysis Set  
T he safet y a nal ysis set will i ncl u de all ra n d o mize d patie nts w h o recei ve at least 1 d ose of I M P.  
I n t he s afet y a nal ysis set, treat me nt will be assi g ne d base d o n t he treat me nt patie nts act uall y 
recei v e d, re gar dless of t h e treat me nt t o w hic h t he y were ra n d o mize d, u nless ot her wise s pecifie d. 
Patie nts w h o be gi n pr o hi bite d t hera pies d uri n g t he st u d y will be i ncl u de d i n t he  safet y a n al ysis 
set b ut n ot t he per-pr ot oc ol a nal ysis set ( Secti o n  9. 2. 4 ). 
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9. 2. 4.  
Per -Pr ot oc ol A n al ysis Set  
T he per -pr ot oc ol ( P P) a n al ysis set is a s u bset of t h e I T T a n al ysis set i ncl u di n g o nl y patie nts 
wit h o ut i m p orta nt pr ot oc ol de viati o ns , i ncl u di n g a n y de vi ati o n of t he i ncl usi o n/e x cl usi o n criteria 
or a n y de viati o ns or o missi o ns of t he I M P a d mi nistrati o n.  
I n t he P P a n al ysis set, treat me nt will be assi g n e d b ase d o n t he treat me nt patie nts act uall y 
recei v e d, re gar dless of t h e treat me nt t o w hic h t he y were ra n d o mize d. 
9. 3.  
D at a H a n dli n g C o n ve nti o ns  
Efficac y vari a bles fr o m p atie nts w h o d o n ot ha ve t he electr o ni c hea d ac h e diar y c o m plete d f or t he 
e ntire st u d y p eri o d will be i m p ute d usi n g a pr orate d a p pr oac h. S e nsiti vit y a nal ysis f or t h e 
pri mar y efficac y varia bl e will be perf or me d us i n g m ulti ple i m p utati o n met h o ds f or missi n g data. 
T he detaile d dat a i m p utati o n r ules will be descri be d i n t he statistical a nal ysis pla n.  
9. 3. 1.  
H a n dli n g Wit h dr a w als a n d Missi n g D at a  
Details f or missi n g dat a i m p utati o n will be pr o vi de d i n t he statistical a nal ysis  pla n.  
9. 4.  
St u d y P o p ul ati o n  
T he I T T a n al ysis set ( Secti o n  9. 2 ) will be use d f or all st u d y p o p ulati o n s u m maries u nless 
ot her wise s pecifie d. S u m maries will be pres e nte d b y treat me nt gr o u p a n d f or all patie nts.  
9. 4. 1.  
P ati e nt Dis p ositi o n  
Data fr o m p atie nts scree n e d; patie nts scree ne d b ut n ot ra n d o mize d a n d reas o n f or n ot 
ra n d o mize d; patie nts w h o are ra n d o mize d; patie nts ra n d o mize d b ut n ot treate d; patie nts i n t he 
I T T, mI T T, safet y, a n d P P a nal ysis sets; patie nts w h o c o m plete t he st u d y; a n d patie nts w h o 
wit h dra w fr o m t he st u d y will be s u m marize d usi n g des cri pti ve statistics. Data fr o m patie nts w h o 
wit h dra w fr o m t he st u d y will als o be s u m marize d b y reas o n f or wit h dra wal usi n g descri pti ve 
statistics. 
9. 4. 2.  
De m o gr a p hic  a n d B aseli ne C h ar acteristics  
Patie nt de m o gra p hic a n d bas eli ne c haracteristics, i ncl u di n g me dical hist or y, pri or me dicati o ns 
a n d t hera pies, a n d E C G fi n di n gs, will be s u m marize d usi n g descri pti ve statistics. F or c o nti n u o us 
varia bles, des cri pti ve statistics ( n u m ber [ n], mea n, sta n dar d de viati o n, me di a n, mi ni m u m, a n d 
ma xi m u m) will be pr o vi de d. F or cate g orical varia bles, patie nt c o u nts a n d p erce nt a ges will be 
pr o vi de d. Cate g ories f or missi n g data will be pres e nte d if necessar y.  
Treat me nt gr o u ps will be c o m pare d f or all c o nti n u o us varia bles, usi n g a n a nal ysis of varia nce 
wit h treat me nt gr o u p as a fact or. T h e cat e g orical v aria bles of p atie nt se x a n d race will be 
s u m marize d usi n g descri pti ve statistics f or eac h v aria ble cate g or y. Missi n g cate g ories will be 
prese nte d if n ecess ar y. Treat me nt gr o u ps will be c o m pare d f or all  cate g orical varia bles usi n g a 
Pears o n’s c hi -s q u are t est ( or Fis her’s e x act test if cell siz es are t o o s mall). 
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St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
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9. 5.  
Effic ac y A n al ysis  
Mi grai n e da ys will be defi ne d as f oll o ws. If t h e hea dac h e f ulfills t he criteri a f or mi grai ne o n a n y 
gi ve n d a y, t he c o nsec uti ve da ys are part of t he sa m e mi grai ne attac k a n d are t heref ore c o nsi dere d 
t o be mi grai n e da ys as w ell (e ve n if t he y d o n ot f ulfill t he criteria f or mi grai ne). T hese d a ys o nl y 
reflect n or mal fl uct uati o ns i n mi grai ne se v erit y t hat lea d t o or re prese nt t he res oluti o n of a 
f ull-bl o w n mi grai n e attac k ( I H S, 2 0 0 4). Acc or di n gl y, f or t h e p ur p ose of t his st u d y, a mi grai ne 
da y is e n d orse d w h e n at l east o ne of t he f oll o wi n g sit uati o ns occ urs:  
•  a cale n d ar da y ( 0 0: 0 0  t o 2 3: 5 9) de m o nstrati n g at least 4 c o nsec uti ve h o urs of a 
hea dac he me eti n g t he criteria f or mi grai ne wit h or wit h o ut a ura  
•  a cale n d ar da y ( 0 0: 0 0 t o 2 3: 5 9) de m o nstrati n g at least 4 c o nsec uti ve h o urs of a 
hea dac he me eti n g t he criteria f or pr o ba ble mi grai ne, a mi grai ne s u bt y pe w here o nl y 
1  mi grai ne criteri o n is missi n g  
•  a cale n d ar da y ( 0 0: 0 0 t o 2 3: 5 9) de m o nstrati n g a h ea dac he of a n y d urati o n t hat was 
treate d wit h mi grai ne-s pecific me dicati o ns (tri pta ns a n d er g ot c o m p o u n ds) 
•  a cale n d ar da y ( 0 0: 0 0 t o 2 3: 5 9) t hat i s i m me diatel y c o ns ec uti ve ( ha p pe ni n g 1 da y 
bef ore or 1 da y after) of a n y d a y f ulfilli n g t h e 3 criteria a b o ve, w here i n di vi d uals 
re p ort hea dac h e of a n y d urati o n 
9. 5. 1.  
Pri m ar y E n d p oi nt  
T he pri mar y effic ac y e n d p oi nt is t he mea n c ha n ge i n t he m o nt hl y a vera ge n u m ber of mi grai ne 
da ys fr o m t he 2 8 -d a y bas eli ne peri o d  d uri n g t he 1 2 -wee k p eri o d aft er t he first d ose of st u d y 
dr u g.  
9. 5. 2.  
Sec o n d ar y E n d p oi nts  
T he ke y sec o n dar y effic ac y e n d p oi nt is t he mea n c ha n ge i n de pressi o n s y m pt o ms fr o m 
ra n d o mizati o n visit ( da y 1) t o wee k  8 afte r t he first d ose of st u d y dr u g as m eas ure d b y 
H A M -D  1 7.  
Ot her sec o n d ar y e n d p oi nts i ncl u de t he f oll o wi n g:  
•  N u m ber of patie nts wit h 5 0 % or m ore re d ucti o n fr o m t he 2 8 -da y baseli ne p eri o d u ntil 
1 2 wee ks after t he first d ose of st u d y dr u g, i n t he m o nt hl y a vera g e n u m ber of 
mi grai ne d a ys  
•  Mea n c ha n ge i n q ualit y of life fr o m r a n d o mizati o n visit ( da y  1) t o wee k 1 2  after t he 
first d ose of st u d y dr u g as meas ure d b y t he M S Q o L q uesti o n nair e, r ole f u ncti o n-
restricti ve a n d r ole f u ncti o n -pre ve nti ve d o m ai ns  
•  Mea n c ha n ge fr o m ra n d o mizati o n visit ( da y 1) i n disa bilit y s c ore f or o verall i m pact, 
as meas ure d b y C GI -S a n d HI T -6, t o t he f oll o wi n g ti me p oi nts after a d mi nistrati o n of 
t he first d ose of st u d y dr u g: 
− wee ks 4 a n d 8 ( C GI -S)  
− wee k 1 2 ( C GI -S a n d HI T -6)  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
8 4  
 
9. 5. 3.  
E x pl or at or y/ Ot her E n d p oi n ts 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. 5. 4.  
Pl a n ne d Met h o d of A n al ysis  
T he I T T a n al ysis set ( Secti o ns  9. 2. 1 , 9. 2. 2 , a n d 9. 2. 4 , res pecti vel y) will be use d f or all efficac y 
a nal ys es. S u m maries will be prese nt e d b y treat me nt gr o u p.  
9. 5. 4. 1.  
Pri m ar y Effic ac y A n al ysis  
T he pri mar y effic ac y e n d p oi nt, c ha n ge fr o m t he 2 8 -da y baseli ne p eri o d i n t he m o nt hl y a v era ge 
n u m ber of mi grai ne d a ys, will be a nal yze d usi n g a nal ysis of c o varia n ce m o del wit h se x, re gi o n 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
8 5  
 
( U nite d States, E ur o pea n, or rest of w orl d), mi grai ne classificati o n (i e, C M or E M), baseli ne 
P H Q -9 sc ore cate g or y, a n d treat me nt as fact ors a n d baseli ne n u m ber of mi grai ne da ys as a 
c o variate. T he treat me nt differe n ce, t he 9 5 % c o nfi de nce i nter val f or t he treat me nt dif fere nce, a n d 
t he ass ociate d p-v al ue will be ge n erat e d fr o m t his m o del.  
9. 5. 4. 2.  
Se nsiti vit y A n al ysis  
Se nsiti vit y a n al ysis usi n g m ulti ple i m p utati o n f or missi n g data i m p utati o n ma y b e c o n d uct e d.  
9. 5. 4. 3.  
Sec o n d ar y Effic ac y A n al ysis  
T he c o nti n u o us sec o n dar y effic ac y e n d p oi nts  will be a nal yz e d si milarl y as t he pri mar y efficac y 
e n d p oi nt. A nal ys es usi n g t he mi x e d -effect m o del r e peate d m eas ure met h o d will be c o n d ucte d f or 
c o nti n u o us varia bles assesse d at m ulti ple ti me p oi nts. F or t he pr o p orti o n of res p o n ders, defi ne d 
as 5 0 % or m or e re d u cti o n fr o m t he 2 8 -da y b aseli ne peri o d i n t he m o nt hl y a vera ge n u m ber of 
mi grai ne d a ys, a l o gistic re gressi o n m o del will be use d wit h t he f oll o wi n g effects: treat me nt, se x, 
re gi o n ( U nite d States, E ur o pea n, or rest of w orl d), mi grai ne classificati o n (ie, C M or E M), a n d 
baseli ne P H Q -9 sc ore cat e g or y. T he O Rs, 9 5 % c o nfi de nce i nter vals (f or O Rs), a n d p -val ues will 
be prese nt e d f or fre ma n ez u ma b c o m pari n g t o place b o . 
9. 5. 4. 4.  
E x pl or at or y Effic ac y A n al ysis  
 
 
9. 6.  
M ulti ple C o m p aris o ns a n d M ulti plicit y  
A fi x e d -se q ue nce ( hierarc hical) testi n g pr oce d ure will be i m ple me nte d t o c o ntr ol t he t y pe  1 err or 
rate at 0. 0 5. T h e se q ue n ce of c o m paris o ns is detaile d i n t he statistical a nal ysis pla n. 
9. 7.  
S afet y A n al ysis  
Safet y a nal yses will be perf or me d o n t h e safet y a n al ysis set ( Secti o n  9. 2. 3 ). 
Safet y assess me nts a n d ti me p oi nts are pr o vi de d i n Ta ble  4 . 
All a d verse e ve nts will be c o de d usi n g t he Me di cal Dicti o nar y f or Re g ulat or y Acti vities. Eac h 
patie nt will be c o u nte d o nl y o nce i n eac h preferre d ter m or s yst e m or ga n cl ass cate g or y f or t he 
a nal ys es of safet y. S u m maries will be pres e nte d f or all a d verse e ve nts ( o v erall a n d b y s e v erit y), 
a d verse e ve nts deter mi ne d b y t he i n vesti gat or t o b e relate d t o test I M P (ie, reas o na bl e p ossi bilit y; 
see Secti o n 7. 1. 4 ) ( d efi ne d as relate d or wit h missi n g relati o ns hi p) ( o verall a n d b y s e verit y), 
seri o us a d vers e e v e nts, a n d a d verse e ve nts c a usi n g wit h dra wal fr o m t he st u d y. S u m maries will 
be prese nt e d b y treat me nt gr o u p a n d f or all patie nts. Patie nt listi n gs of seri o us a d verse e ve nts a n d 
a d verse e ve n ts lea di n g t o wit h dra wal will be prese nte d. 
C ha n ges i n la b orat or y, E C G, e C -S S R S, a n d vital si g ns meas ure me nts data will be s u m mariz e d 
descri pti vel y. All val ues will be c o m pare d wit h t h e pre defi ne d criteria t o i d e ntif y p ote ntiall y 
cli nicall y si g nifica nt v al ues or c ha n ges, a n d s uc h v al ues will be liste d.  
T he use of c o nc o mita nt me dicati o ns will be s u m marize d b y t hera pe utic class usi n g des cri pti ve 
statistics. C o nc o mita nt me dicati o ns will i ncl u de E C T a n d all me dicati o ns ta ke n w hile t he p atie nt 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
8 6  
 
is treate d wit h I MP. Patie nts w h o be gi n pr o hi bite d t hera pies d uri n g t he st u d y will be 
disc o nti n ue d fr o m t he st u d y (e g, E C T, va g us ner ve sti m ulati o n, direct c urre nt t hera p y, 
tra nsc uta ne o us s u pra or bital sti m ulati o n, a n d ot her f or ms of electrical sti m ulati o n). C o m plete 
disc o nt i n uati o n criteria are pr o vi de d i n Secti o n  4. 3 . 
Safet y d ata will be s u m m arize d descri pti vel y o verall, b y treat me nt gr o u p, a n d b y st u d y p hase. 
F or c o nti n u o us varia bles, descri pti ve statistics ( n, mea n, sta n dar d de viati o n, me dia n, mi ni m u m, 
a n d ma xi m u m) will be pr o vi de d f or act ual val ues a n d c ha n ges fr o m ra n d o mizati o n visit ( da y 1) 
t o eac h ti me p oi nt. F or cate g ori cal varia bles, patie nt c o u nts a n d perce nta ges will be pr o vi de d. 
Descri pti ve s u m maries of seri o us a d verse e v e nts a n d patie nt wit h dra wals d ue t o a d verse e ve nts 
will be pr o vi de d as well.  
If a n y patie nt dies d uri n g t he st u d y, a listi n g of deat hs will be pr o vi de d a n d all rele va nt 
i nf or mati o n will be disc usse d i n t he patie nt narrati ve i ncl u de d i n t he C S R. 
9. 8.  
T oler a bilit y A n al ysis  
T olera bilit y fi n di n gs will be liste d a n d s u m marize d descri pti vel y.  
9. 9.  
Pl a n ne d I nteri m A n al ysis  
T here will be n o f or mal i nteri m a nal ysis.  
9. 1 0.  
Re p orti n g De vi ati o ns fr o m t he St atistic al Pl a n  
De viati o ns fr o m t he statistical pla n, al o n g wit h t he reas o ns f or t he de viati o ns, will be descri be d 
i n pr ot oc ol a me n d me nts, t he statistical a nal ysis pla n, t he C S R, or a n y c o m bi nati o n of t hese, as 
a p pr o priate, a n d i n acc or da nce wit h a p plica ble nati o nal, l ocal, a n d re gi o n al re q uire me nts a n d 
re g ulati o ns. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
8 7  
 
1 0.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
Refer t o A p pe n di x  C  f or i nf or mati o n re gar di n g q u alit y c o ntr ol a n d q u alit y ass ura nce. T his 
i ncl u des i nf or mati o n a b o ut pr ot oc ol a me n d me nts, de viati o ns, res p o nsi bilities of t he i n vesti gat or 
t o st u d y pers o n n el, st u d y m o nit ori n g, a n d a u dit a n d i ns pecti o n.  
Refer t o A p pe n di x  K  f or t he defi niti o n of a cli nical pr o d uct c o m plai nt a n d i n vesti gat or 
res p o nsi bilities i n t he ma na ge me nt of a cli nical pr o d uct c o m plai nt.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
8 8  
 
1 1.  
C O M P LI A N C E S T A T E M E N T  
T his st u d y will be c o n d u cte d i n f ull acc or da nce wit h t he I C H Har m o nise d Tri partite G ui deli ne, 
G ui deli ne f or G C P E 6 a n d a n y a p plica ble nati o nal a n d l ocal la ws a n d re g ul ati o ns (e g, Title  2 1 
C o de of Fe d eral Re g ul ati o ns [ 2 1 C F R] Parts  1 1, 5 0, 5 4, 5 6, 3 1 2, a n d  3 1 4, Directi ve 2 0 0 1/ 2 0/ E C 
of t he E u r o pea n Parlia me nt a n d of t he C o u ncil o n t he a p pr o xi mati o n of t he la ws, re g ulati o ns a n d 
a d mi nistrati ve pr o visi o ns of t he Me m ber States rel ati n g t o t he i m ple me ntati o n of G C P i n t he 
c o n d uct of cli nical trials o n me dici nal pr o d ucts f or h u ma n use). A n y e pis o de of n o nc o m plia nce 
will be d oc u me nte d.  
T he i n vesti gat or is res p o nsi ble f or perf or mi n g t h e cli nical st u d y i n acc or da nce wit h t his pr ot oc ol 
a n d t he a p plica ble G C P g ui deli nes refere n ce d a b o ve f or c ollecti n g, rec or di n g, a n d re p orti n g t he 
data acc urat el y a n d pr o p erl y. A gree me nt of t he i n vesti gat or t o c o n d uct a n d a d mi nister t his 
cli nical st u d y i n a cc or da nce wit h t he pr ot oc ol will be d oc u me nte d i n se parate cli nical st u d y 
a gree m e nts wit h t he s p o ns or a n d ot her f or ms as re q uire d b y nati o nal c o m pete nt a ut h orities  i n t he 
c o u ntr y w here eac h i n vesti gati o nal ce nt er is l ocate d.  
T he i n vesti gat or is res p o n si ble f or e ns uri n g t he pri vac y, healt h, a n d welfare of t he patie nts d uri n g 
a n d after t he cli nical st u d y a n d m ust e ns ure t hat tr ai ne d pers o n nel are i m m e diatel y a vaila ble i n 
t he e ve nt of a m e dical e mer ge nc y. T h e i n vesti gat or a n d t he i n v ol ve d cli nical st u d y p ers o n nel 
m ust be fa miliar wit h t he bac k gr o u n d a n d re q uir e me nts of t he st u d y a n d wit h t he pr o perties of 
t he I M Ps as d escri be d i n t he I B or pres cri bi n g i nf or mati o n. 
T he pri nci pal i n vesti gat or at eac h i n vesti gati o nal ce nter  has t he o v erall res p o nsi bilit y f or t h e 
c o n d uct a n d a d mi nistrati o n of t he cli nical st u d y at t hat i n vesti gati o nal ce nter  a n d f or c o ntacts 
wit h st u d y ma na ge m e nt, wit h t he I E C/I R B, a n d wit h c o m pete nt a ut h orities.  
See A p pe n di x  D  f or t he et hics e x pectati o ns of i nf or me d c o nse nt or asse nt, c o m pete nt a ut h orities 
a n d I E C/I R B, c o nfi de ntialit y re gar di n g st u d y pati e nts, a n d re q uir e me nts f or re gistrati o n of t he 
cli nical st u d y.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
8 9  
 
1 2.  
D A T A M A N A G E M E N T A N D R E C O R D K E E PI N G  
See A p pe n di x  L  f or i nf or mati o n re gar di n g dat a ma na ge me nt a n d rec or d kee pi n g. T his i ncl u des 
direct access t o s o urce data a n d d oc u me nts, d ata c ollecti o n, data q ualit y c o ntr ol, a n d arc hi vi n g of 
e C R Fs a n d s o urce d oc u me nts.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
9 0  
 
1 3.  
FI N A N CI N G A N D I N S U R A N C E  
A se parate cli nical st u d y a gree m e nt, i ncl u di n g a st u d y b u d get, will be si g ne d bet wee n eac h 
pri nci pal i n vesti gat or a n d t he s p o ns or ( or t he C R O desi g na t e d b y t he s p o ns or) bef ore t he I M P is 
deli vere d.  
T he patie nts i n t his cli nical st u d y are i ns ure d i n acc or da nce wit h a p plica bl e le gal pr o visi o ns. T he 
p olic y c o v era ge is s u bject t o t he f ull p olic y ter ms, c o n diti o ns, e xte nsi o ns, a n d e x cl usi o ns. 
E x cl u de d fr o m t he i ns ura nce c o v era ge are, e g, d a ma ges t o healt h a n d w orse ni n g of pre vi o us 
e xisti n g disease t hat w o ul d ha ve occ urre d or c o nti n ue d if t he patie nt ha d n ot ta ke n part i n t he 
cli nical st u d y.  
T he p olic y of Cli nical Trials I ns ur a nce will be pr o vi de d t o t he i n ve sti gati o n al ce nters b y t h e 
s p o ns or. 
F or c o v ere d cli nical st u dies (see 2 1 C F R 5 4), t he i n vesti gat or will pr o vi de t he s p o ns or wit h 
fi na ncial i nf or mati o n r e q uire d t o c o m plete F o o d a n d Dr u g A d mi nistrati o n 3 4 5 4 f or m. Eac h 
i n vesti gat or will n otif y t he s p o ns or of an y rele va nt c ha n ges d uri n g t he c o n d uct of t he st u d y a n d 
f or 1 year aft er t he st u d y has bee n c o m plet e d.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
9 1  
 
1 4.  
P U B LI C A TI O N P O LI C Y  
See A p pe n di x  M  f or i nf or mati o n re gar di n g t he p u blicati o n p olic y. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
9 2  
 
1 5.  
R E F E R E N C E S  
Ar m o ur K L, Clar k M R, Ha dle y A G, Willia ms o n L M. Rec o m bi na nt h u ma n I g G m olec ules 
lac ki n g Fc ga m ma rece pt or I bi n di n g a n d m o n oc yt e tri g geri n g acti vities. E ur J I m m u n ol 
1 9 9 9; 2 9( 8): 2 6 1 3 – 2 4.  
As hi na M, Be n dtse n L, Je nse n R, Sc hifter S, J a nse n -Olese n I, Olese n J. Plas ma le vels of 
calcit o ni n ge ne-relate d p e pti de i n c hr o nic te nsi o n-t y pe h ea dac he. Ne ur ol o g y 
2 0 0 0; 5 5( 9): 1 3 3 5 -4 0.  
As hi na S, Serra n o D, Li pt o n R B, Maiz els M, Ma nac k A N, T ur kel C C, Ree d M L, B use D C.  
De pressi o n a n d ris k of tr a nsf or mati o n of e pis o dic t o c hr o nic mi grai ne. J Hea dac h e Pai n 
2 0 1 2; 1 3( 8): 6 1 5 -2 4.  
Ba gle y C L, Re n d as -Ba u m R, Ma gli nte G A, Ya n M, Var o n S F, Lee J, et al. Vali dati n g Mi grai ne -
s pecific Q u alit y of Lif e q uesti o n naire v 2. 1 i n e pis o dic a nd c hr o nic mi grai n e. Hea d ac h e 
2 0 1 2; 5 2( 3): 4 0 9 -2 1.  
Bi gal M E, D o dic k D W, Ra p o p ort A M, Sil berstei n S D, Ma Y, Ya n g R, et al. Safet y, t olera bilit y, 
a n d effi cac y of T E V -4 8 1 2 5 f or pre v e nti ve treat me nt of hi g h -fre q u e nc y e pis o dic mi grai n e: a 
m ultice ntre, ra n d o mise d, d o u ble -bli n d, place b o -c o ntr olle d, p hase 2 b st u d y. La n cet N e ur ol 
2 0 1 5a; 1 4: 1 0 8 1 -9 0.  
Bi gal M E, E d vi nss o n L, Ra p o p ort A M, Li pt o n R B, S pieri n gs E L H, Die ner H, et al. Safet y, 
t olera bilit y, a n d effic ac y of T E V-4 8 1 2 5 f or pre v e nti ve treat me nt of c hr o nic mi grai ne: a  
m ultice ntre, ra n d o mise d, d o u ble -bli n d, place b o -c o ntr olle d, p hase 2 b st u d y. La n cet N e ur ol 
2 0 1 5 b; 1 4: 1 0 9 1 -1 0 0.  
Bi gal M E, Li pt o n R B. Cli nical c o urse i n mi grai ne: c o nce pt ualizi n g mi grai n e tra nsf or m ati o n. 
Ne ur ol o g y 2 0 0 8; 7 1( 1 1): 8 4 8 -5 5.  
Bresla u N, Li pt o n R B, Ste w art W F, Sc h ultz L R, Welc h K M. C o m or bi dit y of mi grai ne a n d 
de pressi o n: i n vesti gati n g p ote ntial eti ol o g y a n d pr o g n osis. Ne ur ol o g y. 2 0 0 3; 6 0( 8): 1 3 0 8 -1 2.  
Bresla u N, Sc h ultz L R, Ste wart W F, Li pt o n R B, L ucia V C, Welc h K M. Hea dac h e a n d maj or 
de pressi o n: is t he ass ociati o n s pecific t o mi grai ne? Ne ur ol o g y 2 0 0 0; 5 4( 2): 3 0 8 -1 3.  
B use D C, Sil berstei n S D, Ma nac k A N, Pa pa petr o p o ul os S, Li pt o n R B. Ps yc hiatric c o m or bi dities 
of e pis o dic a n d c hr o nic mi grai ne. J Ne ur ol 2 0 1 3; 2 6 0( 8): 1 9 6 0 -9.  
C h u H T, Lia n g C S, Lee J T, Ye h T C, Lee M S,  S u n g Y F, Ya n g F C. Ass ociati o ns bet wee n 
de pressi o n/a n xiet y a n d h ea dac he fre q ue n c y i n mi grai ne urs: a cr oss -secti o nal st u d y. Hea dac he 
2 0 1 8; 5 8( 3): 4 0 7 -1 5.  
D o dic k D W, As hi na M, Le wis Bra n des J, K u dr o w D, La nteri -Mi n et M, Osi p o va V, et al. 
A RI S E: A p has e 3 ra n d o mize d trial of ere n u ma b f or e pis o dic mi grai ne. Ce p halal gi a 
2 0 1 8a; 3 8( 6): 1 0 2 6 -3 7.  
D o dic k D W, Sil berstei n S D, Bi gal M E, Ye u n g P P, G oa ds b y PJ, Bla n ke n biller T, et al. Effect of 
fre ma n ez u ma b c o m pare d wit h place b o f or pre ve nti o n of e pis o dic mi grai ne: a ra n d o mized 
cli nical trial. J A M A 2 0 1 8 b; 3 1 9( 1 9): 1 9 9 9 -2 0 0 8.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
9 3  
 
Efte k hari S, E d vi nss o n L. P ossi ble sites of acti o n of t he ne w calcit o ni n ge n e -rel ate d pe pti de 
rece pt or a nta g o nists. T her A d v Ne ur ol Dis or d 2 0 1 0; 3( 6): 3 6 9– 7 8.  
E vers S, Afra J, Frese A, G oa ds b y PJ, Li n de M, M a y A, et a. E F N S g ui deli ne o n t he dr u g 
treat me nt of mi grai ne— re vise d re p ort of a n E F N S tas k f orce. E ur o p J Ne ur ol 2 0 0 9; 1 6: 9 6 8-8 1.  
G u y W, e d. E C D E U Assess me nt Ma n ual f or Ps yc h o p har mac ol o g y, Re vise d, 1 9 7 6. R oc k ville, 
M D, U. S. De part me nt of Healt h a n d H u ma n Ser v ices, 1 9 7 6: 2 1 8 2 2. 
Ha nse n J M, Ha u ge A W, Olese n J, As hi na M. Calcit o ni n ge ne -relate d pe pti de tri g gers mi grai ne 
li ke attac ks i n patie nts wit h mi grai ne wit h a ura. Ce p halal gi a 2 0 1 0; 3 0( 1 0): 1 1 7 9– 8 6.  
H o T W, E d vi nss o n L, G oa ds b y PJ. C G R P a n d its rece pt ors pr o vi de ne w i nsi g hts i nt o mi grai ne 
pat h o p h ysi ol o g y. Nat Re v Ne ur ol 2 0 1 0; 6( 1 0): 5 7 3 – 8 2.  
I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors (I C MJ E). Rec o m me n dati o ns f or t he 
C o n d uct, Re p orti n g, E diti n g, a n d P u blicati o n of S c h olarl y W or k i n Me dical J o ur nals. A vaila ble 
at htt p:// w w w.ic mje. or g/r ec o m me n dati o ns/. U p dat e d Dece m ber 2 0 1 8.  
I nter nati o nal H ea dac he S ociet y. T h e I nter nati o nal Classificati o n of Hea d ac he Dis or ders, 3r d 
e diti o n ( beta versi o n). Ce p halal gi a 2 0 1 3; 3 3( 9): 6 2 9 -8 0 8.  
I nter nati o nal H ea dac he S ociet y. T h e I nter nati o nal Classificati o n of Hea d ac he Dis or ders, 2 n d 
e diti o n ( beta versi o n). Ce p halal gi a 2 0 0 4; 2 4(s u p pl 1): 1 -1 6 0.  
K osi ns ki M, Ba yliss M S, Bj or ner J B, Ware J E Jr, Gar ber W H, Bate n h orst A, et al. A si x -ite m 
s h ort-f or m s ur ve y f or me as uri n g h ea d ac he i m pact: t he HI T-6. Q ual Life Res 2 0 0 3; 1 2( 8) 9 6 3 -7 4.  
Kr oe n ke K, S pitz er R L, Willia ms J B, L ö we B. T he Patie nt Healt h Q uesti o n naire s o matic, 
a n xiet y, a n d de pressi ve s y m pt o m scales: a s yste m atic re vie w. Ge n H os p Ps yc hi atr y 
2 0 1 0; 3 2( 4): 3 4 5 -5 9.  
Li pt o n R B, Bi gal M E, Di a m o n d M, Fr eita g F, Ree d M L, Ste wart W F. Mi grai ne pre v ale nce, 
disease b ur de n, a n d t he n ee d f or pre ve nti ve t h era p y. Ne ur ol o g y 2 0 0 7; 6 8( 5): 3 4 3 – 9.  
P os ner K, Br o w n G K, St a nle y B, Bre nt D A, Yers h o va K V, O q ue n d o M A, et al. 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 Ps yc hiatr y 2 0 1 1; 1 6 8( 1 2): 1 2 6 6 -7 7.  
P ule d da F, Messi na R, G oa ds b y PJ. A n u p date o n mi grai ne: c urre nt u n derst a n di n g a n d f ut ure 
directi o ns. J Ne ur ol 2 0 1 7: 2 0 3 1 -9.  
Reill y M C, Z br oze k A S, D u kes E M. T he vali dit y a n d re pr o d uci bilit y of a w or k pr o d ucti vit y a n d 
acti vit y i m pair me nt i nstr u me nt. P har mac o Ec o n o mics 1 9 9 3; 4( 5): 3 5 3 -6 5.  
Re uter U, G oa ds b y PJ, La nteri -Mi net M, We n S, H o urs -Zesi ger P, Ferrari M D, et al. Effic ac y 
a n d t olera bilit y of ere n u ma b i n patie nts wit h e pis o dic mi grai n e i n w h o m t w o -t o-f o ur pre vi o us 
pre ve nti ve tr eat me nt were u ns uccessf ul: a ra n d o mise d, d o u ble -bli n d, place b o -c o ntr olle d, p hase 
3 b st u d y. La n cet 2 0 1 8; 3 9 2( 1 0 1 6 1): 2 2 8 0 -7.  
Sa m ps o n H A, M u n oz -F url o n g A, Ca m p b ell R L, A d ki ns o n N F, Jr, B oc k S A, Bra n u m A, et al. 
Sec o n d s y m p osi u m o n t he defi niti o n a n d ma na ge me nt of a na p h yla xis: s u m mar y re p ort -Sec o n d 
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseas e/ F o o d Aller g y a n d A na p h yla xis Net w or k 
S y m p osi u m. J Alle r g y Cli n I m m u n ol 2 0 0 6; 1 1 7( 2): 3 9 1-7.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
9 4  
 
Sc her AI, Ste wart W F, Ricci J A, Li pt o n R B. Fact ors ass ociate d wit h t he o nset a n d re missi o n of 
c hr o nic dail y hea dac h e i n a p o p ulati o n -base d st u d y. Pai n 2 0 0 3; 1 0 6( 1 -2): 8 1 – 9.  
Sil berstei n S, Tfelt -Ha ns e n P, D o dic k D Q, Li m mr ot h V, Li pt o n R B, Pasc u al J, et al. G ui deli nes 
f or c o ntr olle d trials of pr o p h yla ctic treat me nt of c hr o nic mi grai ne i n a d ults. Ce p halal gi a 
2 0 0 8; 2 8: 4 8 4 -9 5.  
S pitzer R L, Kr oe n ke K, Willia ms J B W. Vali dati o n a n d utilit y of self -re p ort versi o n of P RI M E 
M D: t he P H Q pri mar y care st u d y. J A M A 1 9 9 9; 2 8 2( 1 8): 1 7 3 7 -4 4.  
Tfelt -Ha ns e n P, Pasc ual J, Ra ma da n N, Da hl öf C, D o me nic o D, Die ner H -C, et al. G ui deli nes f or 
c o ntr olle d trials of dr u gs i n mi grai ne: t hir d e diti o n. A g ui de f or i n vesti gat ors. Ce p halal gi a 
2 0 1 2; 3 2( 1): 6 -3 8.  
Ya n g M, Re n das -Ba u m R, Var o n S F, K osi ns ki M. Vali dati o n of t he Hea dac he I m pact Test 
( HI T-6 ™) acr oss e pis o dic a n d c hr o ni c mi grai ne. Ce p halal gi a 2 0 1 1; 3 1( 3): 3 5 7 -6 7.  
Zeller J, P o ulse n K T, S utt o n J E, A b dic he Y N, C ollier S, C h o pra R, et al. C G R P f u ncti o n 
bl oc ki n g a nti b o dies i n hi bit ne ur o ge nic vas o dilatati o n wit h o ut affecti n g heart rate or arterial 
bl o o d press ure i n t he rat. Br J P har mac ol 2 0 0 8; 1 5 5( 7): 1 0 9 3 – 1 0 3.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
9 5  
 
1 6.  
S U M M A R Y O F C H A N G E S T O P R O T O C O L  
1 6. 1.  
A me n d me nt 0 4 D ate d 0 4  M a y  2 0 2 0  
T he pri mar y reas o n f or t his a me n d me nt i s t o re vise a n e x cl usi o n criteri o n t o e x cl u de patie nts 
wit h a hist or y of Ste ve n s-J o h ns o n S y n dr o me or t o xic e pi der mal necr ol ysis s y n dr o me a n d t o 
all o w rescree ni n g of patie nts 1 ti me . T hese c ha n g es are refl ecte d i n t he ta ble bel o w.  
A d diti o nall y, C O VI D -1 9 pa n de mic -relate d o perati o nal u p dates were a d d e d t o t he st u d y as a n e w 
a p pe n di x (A p pe n di x  P ). A d mi nistrati ve c ha n ges h a ve bee n a p plie d i ncl u di n g u p dati n g t he Ta ble 
of C o nte nts.  
T he a me n d me nt is c o nsi dere d t o be s u bsta ntial (i e, re q uir es a p pr o val b y c o m pete nt a ut h orities, 
I E C, a n d/ or I R B) b y t he s p o ns or’s A ut h orize d Re prese ntati ve. Ot h er n o ns u bsta ntial c ha n ges 
ha ve bee n ma de t o t he pr ot oc ol (a n d pr ot oc ol s y n o psis, as a p pr o priate). T h ese c ha n ges are 
u nli kel y t o affect t he s afet y or ri g hts ( p h ysic al or me ntal i nte grit y) of t he p atie nts i n t his cli nical 
st u d y or t he s cie ntific val ue of t he cli nical st u d y. 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/  
j ustific ati o n f or c h a n ge 
TI T L E P A G E ( Ot her secti o ns affecte d b y t his c h a n ge: A me n d me nt Hist or y, I n vesti g at or A gree me nt, 
C o or di n ati n g I n vesti g at or A gree me nt)  
Pr ot oc ol A p pr o v al D ate: 0 3 
M a y  2 0 1 9  
Pr ot oc ol wit h A me n d me nt  0 1 
A p pr o v al D ate: 0 4 J u ne 2 0 1 9  
Pr ot oc ol wit h A me n d me nt  0 2 
A p pr o v al D ate: 1 0 Oct o ber 2 0 1 9  
Pr ot oc ol wit h A me n d me nt  0 3 
A p pr o v al D ate: 0 4 N o ve m be r 2 0 1 9  
Pr ot oc ol wit h A me n d me nt 0 4 
A p pr o v al D ate: 0 4  M a y  2 0 2 0  
Pr ot oc ol A p pr o v al D ate: 0 3 
M a y  2 0 1 9  
Pr ot oc ol wit h A me n d me nt  0 1 
A p pr o v al D ate: 0 4 J u ne 2 0 1 9  
Pr o t oc ol wit h A me n d me nt 0 2 
A p pr o v al D ate: 1 0 Oct o ber 2 0 1 9  
Pr ot oc ol wit h A me n d me nt  0 3 
A p pr o v al D ate: 0 4 N o ve m be r 2 0 1 9  
Pr ot oc ol wit h A me n d me nt 0 4 
A p pr o v al D ate: 0 4  M a y 2 0 2 0  
U p date d  f or A me n d me nt 0 4 
C O VI D -1 9 p a n de mic -rel ate d 
o per ati o n al u p d ates are pr o vi de d 
i n A p pe n di x P   
C O VI D -1 9 p a n de mic -rel ate d 
o per ati o n al u p d ates are pr o vi de d 
i n A p pe n di x P   
U p date d t o ma na ge st u d y c o n d uct 
d uri n g t he C O VI D -1 9 pa n de mic.  
© 2 0 1 9  2 0 2 0  T e va Bra n de d 
P har mace utical Pr o d ucts R & D, I nc. 
All ri g hts reser ve d.  
© 2 0 2 0 T e va Bra n de d 
P h ar mace utical Pr o d ucts R & D, I nc. 
All ri g hts reser ve d.  
U p date d f or A me n d me nt 0 4  
Te v a B r a n de d P h ar m ace utic al  
Pr o d ucts R & D, I nc.  
1 4 5 B r a n d y wi ne P ar k w a y,  
West C hester, Pe n ns yl v a ni a 1 9 3 8 0  
4 1 M o ores R o a d  
Fr a zer, Pe n ns yl v a ni a 1 9 3 5 5  
U nite d St ates of A meric a  
Te v a Br a n de d P h ar m ace utic al  
Pr o d ucts R & D, I nc.  
1 4 5 B r a n d y wi ne P ar k w a y,  
West C hester, Pe n ns yl v a ni a 1 9 3 8 0  
U nite d St ates of A meric a  
U p date d as o utli ne d i n 
A d mi nistrati ve Letter 0 2  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
9 6  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/  
j ustific ati o n f or c h a n ge 
3. 5 Sc he d ule of St u d y Pr o ce d ures a n d Assess me nts ( T a ble 4) a n d A p pe n di x D. Et hics  
F or C or o na vir us disease 2 0 1 9 
(C O VI D -1 9 ) u p dates, see 
A p pe n di x  P.  
F or C or o na vir us disease 2 0 1 9 
(C O VI D -1 9 ) u p dates, see 
A p pe n di x  P.  
U p date d secti o ns t o cr oss -refere nce 
t he a d diti o n of A p pe n di x P. 
3. 5. Sc he d ule of St u d y Pr o ce d ures a n d Assess me nts  ( T a ble 4) 
a. I n t he case of earl y ter mi nati o n, 
site pers o n nel s h o ul d perf or m a 
f oll o w-u p p h o ne call t o e ns ure t he 
patie nt d oes n ot re p ort s uici dal 
i deati o n or be ha vi or. P h o ne calls 
s h o ul d be perf or me d o nce wee kl y 
f or 2 wee ks. If si g ns of s uici dalit y 
are i de ntifie d d uri n g t he f oll o w -u p 
p h o ne call, t he site pers o n nel s h o ul d 
pr o vi de directi o n t o t he patie nt f or 
f urt her ps yc hiatric e val uati o n at t he 
site or at a c o m m u nit y ps yc hiatrist 
refere nce d b y t he site. Rele va nt 
e mer ge nc y ps yc hiatric care ser vices 
s h o ul d be n otified i n t he e ve nt t hat 
t he patie nt is dee me d t o be a t hreat 
t o t he mself. 
a. I n t he case of earl y ter mi nati o n, 
site pers o n nel s h o ul d perf or m a 
f oll o w-u p p h o ne call t o e ns ure t he 
patie nt d oes n ot re p ort s uici dal 
i deati o n or be ha vi or. P h o ne calls 
s h o ul d be perf or me d o nce wee kl y 
f or 2 wee ks. If si g ns of s uici dalit y 
are i de ntifie d d uri n g t he f oll o w -u p 
p h o ne call, t he site pers o n nel s h o ul d 
pr o vi de directi o n t o t he patie nt f or 
f urt her ps yc hiatric e val uati o n at t he 
site or at a c o m m u nit y ps yc hiatrist 
refere nce d b y t he site. Rele va nt 
e mer ge nc y ps yc hiatric care ser vices 
s h o ul d be n otifie d i n t he e ve nt t hat 
t he patie nt is dee me d t o be a t hreat 
t o t he mself. 
A d diti o nal f oll o w -u p f or patie nts 
w h o earl y ter mi nate were a d de d t o 
e ns ure t he safet y of t hese pati e nts.  
d . C ollecti o n of pri or me dicati o ns 
f or mi grai ne a n d/ or de pressi o n is 
li mite d t o t h ose me dicati o ns 
a d mi nistere d wit hi n t he past 1 0 
years or f or a n y i n dicati o n wit h t he 
past  5 m o nt hs bef ore scree ni n g ( V 1). 
d . C ollecti o n of pri or me dicati o ns 
f or mi grai ne a n d/ or de pressi o n is 
li mite d t o t h ose me dicati o ns 
a d mi nistere d wit hi n t he past 1 0 
years or f or a n y i n dicati o n wit h t he 
past 5 m o nt hs bef ore scree ni n g ( V 1).  
Clarificati o n  
4. 2.  P atie nt E xcl usi o n Criteri a  
g.  [ Re visi o n 1] T he patie nt has 
cli nicall y si g nifica nt he mat ol o gical, 
car diac, re nal, e n d ocri ne, 
p ul m o nar y, gastr oi ntesti nal, 
ge nit o uri nar y, ne ur ol o gic, he p atic, 
or  oc ular disease, or c o m plicati o ns 
of a n i nfecti o n, at t he discreti o n of 
t he i n vesti gat or. 
g.  [ Re visi o n 1] T he patie nt has 
cli nicall y si g nifica nt he mat ol o gical, 
car diac, re nal, e n d ocri ne, 
p ul m o nar y, gastr oi ntesti nal, 
ge nit o uri nar y, ne ur ol o gic, he p atic, 
oc ular disease, or c o m plicati o ns of 
a n i nfecti o n, at t he discreti o n of t he 
i n vesti gat or. 
It has bee n s pecifie d t hat patie nts 
wit h cli nicall y si g nifica nt 
c o m plicati o ns of a n i nfecti o n ma y be 
e xcl u de d at t he discreti o n of t he 
i n vesti gat or 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
9 7  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/  
j ustific ati o n f or c h a n ge 
h.  T he patie nt has a cli nical hist or y 
of  a se vere or u nc o ntr olle d 
ps yc hiatric dis or der, t o i ncl u de  t he 
f oll o wi n g, or at t he discreti o n of t he 
i n vesti gat or f or a n y cli nicall y 
si g nifica nt ps yc hiatric hist or y t hat 
w o ul d li kel y i nterfere wit h f ull 
partici pati o n i n t he st u d y : e vi de nce 
or me dical hist or y of ot her cli nicall y 
si g nifica nt ps yc hiatric iss ues t hat, i n 
t he o pi ni o n of t he i n vesti gat or, c o ul d 
j e o par dize or w o ul d c o m pr o mise t he 
patie nt’s a bilit y t o partici pate i n t his 
st u d y i ncl u di n g pa nic dis or der, 
bi p olar dis or der, sc hiz o p hre nia,  or  
a n y  
- Lifeti me e xcl usi o n:  s uici de 
atte m pt i n t he past,  
- I n t he p ast 6 m o nt hs e xcl usi o n: 
s uici dal i deati o n, or ot her 
ps yc h oacti ve s pectr u m dis or d ers 
i ncl u di n g sc hiz oaffecti ve dis or der, 
del usi o nal dis or der, de pressi o n wit h 
ps yc h otic feat ures, a n d catat o nic 
dis or der i n t he past 6 m o nt hs. 
h.  T he patie nt has a cli nical hist or y 
of a se vere or u nc o ntr olle d 
ps yc hiatric dis or der, t o i ncl u de t he 
f oll o wi n g, or at t he discreti o n of t he 
i n vesti gat or f or a n y cli nicall y 
si g nifica nt ps yc hiatric hist or y t hat 
w o ul d li kel y i nterfere wit h f ull 
partici pati o n i n t he st u d y:  
- Lifeti me e xcl usi o n: s uici de atte m pt  
- I n t he past 6 m o nt hs e xcl usi o n: 
s uici dal i deati o n, or ot her 
ps yc h oacti ve s pectr u m dis or d ers 
i ncl u di n g sc hiz oaffecti ve dis or der, 
del usi o nal dis or der, de pressi o n wit h 
ps yc h otic feat ures, a n d catat o nic 
dis or der  
U p date d  to  clarif y e xcl usi o n of 
ps yc hiatric dis or ders i ncl u di n g 
s uici de atte m pt a n d i deati o n 
m.  T he patie nt has a hist or y of 
h y perse nsiti vit y reacti o ns t o i nj ecte d 
pr otei ns, i ncl u di n g m o n ocl o nal 
a nti b o dies , or a hist o r y of Ste ve ns-
J o h ns o n S y n dr o me or  t o xic 
e pi der mal necr ol ysis s y n dr o me . 
m.  T he patie nt has a hist or y of 
h y perse nsiti vit y reacti o ns t o i nj ecte d 
pr otei ns, i ncl u di n g m o n ocl o nal 
a nti b o dies, or a hist o r y of Ste ve ns-
J o h ns o n S y n dr o me or  t o xic 
e pi der mal necr ol ysis s y n dr o me.  
U p date d t o  e xcl u de patie nts wi t h 
hist or y of St e ve n s-J o h ns o n 
S y n dr o me or  t o xic e pi der mal 
necr ol ysis s y n dr o me  per safet y 
u p dates  
b b.  P atie nt has recei ve d 
o na b ot uli n u mt o xi n A f or mi gr ai ne or 
f or a n y me dical or c os metic re as o ns 
re q uiri n g i nj ecti o ns i n t he hea d, face, 
or nec k d uri n g t he 3 m o nt hs b ef ore 
scree ni n g visit. 
b b.  P atie nt has recei ve d 
o na b ot uli n u mt o xi n A f or mi gr ai ne or 
f or a n y me dical or c os metic re as o ns 
re q uiri n g i nj ecti o ns i n t he hea d, face, 
or nec k d uri n g t he 3 m o nt hs b ef ore 
scree ni n g visit. 
U p date d t o e xcl u de patie nts t hat 
receive d o na b ot uli n u mt o xi n A f or 
mi grai ne or f or a n y me dical or 
c os metic reas o ns re q uiri n g i nj ecti o ns 
i n t he hea d, face, or nec k d uri n g t he 
3 m o nt hs bef ore scree ni n g visit p er 
safet y u p dates 
4. 5 .  Rescree ni n g  
A patie nt w h o is scree ne d a n d d oes 
n ot meet st u d y i ncl usi o n a n d 
e xcl usi o n criteria will n ot b e 
c o nsi dere d f or scree ni n g a gai n.  A 
patie nt w h o is scree ne d b ut n ot 
e nr olle d (e g, beca use st u d y 
eli gi bilit y criteria were n ot met 
[i ncl usi o n criteria n ot met or 
e xcl usi o n criteria met]) d ue t o a n y of 
t he f oll o wi n g reas o ns: tec h nic al 
iss ues (e g, diar y malf u ncti o n), o ut of 
A patie nt w h o is scree ne d b ut n ot 
e nr olle d (e g, beca use st u d y 
eli gi bilit y criteria were n ot met 
[i ncl usi o n criteria n ot met or 
e xcl usi o n criteria met]) d ue t o a n y of 
t he f oll o wi n g reas o ns: tec h nic al 
iss ues (e g, diar y malf u ncti o n), o ut of 
visit 2 wi n d o w  d ue t o a n e mer ge nc y 
sit uati o n, or re q uire t o scree n fail as 
directe d b y t he s p o ns or d ue t o a n 
e mer ge nc y sit uati o n (e g, pa n de mic 
U p date d  rescree ni n g criteri o n t o 
acc o u nt f or e xtra or di nar y sit uati o ns  
a n d tec h nical pr o ble ms  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
9 8  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/  
j ustific ati o n f or c h a n ge 
visit 2 wi n d o w d ue t o a n e mer ge nc y 
sit uati o n, or re q uire t o scree n fail as 
directe d b y t he s p o ns or d ue t o a n 
e mer ge nc y sit uati o n (e g, pa n de mic 
or p ote ntial p a n de mic), ma y b e 
c o nsi dere d f or rescree n i n g 1 ti me. 
I n vesti gat ors ma y c o ntact t he 
s p o ns or’s me dical m o nit ors or 
me dical e x pert f or a d diti o nal 
g ui da nce o n rescree ni n g. If t he 
patie nt is rescree ne d, a n i nf or me d 
c o nse nt f or m (I C F) will nee d t o be 
re-si g ne d, a n d a ne w scree ni n g 
n u m ber will be assi g n e d. 
or p ote ntial pa n de mic), ma y b e 
c o nsi dere d f or rescree ni n g 1 ti me.  
I n vesti gat ors ma y c o ntact t he 
s p o ns or’s me dical m o nit ors or 
m e dical e x pert f or a d diti o nal 
g ui da nce o n rescree ni n g. If t he 
patie nt is rescree ne d, a n i nf or me d 
c o nse nt f or m (I C F) will nee d t o be 
re-si g ne d, a n d a ne w scree ni n g 
n u m ber will be assi g ne d.  
5. 7. Pri or a n d C o nc o mit a nt M e dic ati o n or T her a p y  
A n y pri or or c o nc o mita nt 
me dicati o n, treat me nt, 
ps yc h ot hera p y, or pr oce d ure a 
patie nt has ha d  f or mi grai ne a n d/ or 
de pressi o n  wit hi n t he past 1 0  years  
or f or a n y i n dicati o n wit hi n t he past 
5 m o nt hs  bef ore I M P a d mi nistrati o n 
a n d u p t o t he e n d of st u d y, i ncl u di n g 
f oll o w-u p, will be rec or de d o n t he 
e C R F. 
A n y pri or or c o nc o mita nt 
me dicati o n, treat me nt, 
ps yc h ot hera p y, or pr oce d ure a 
patie nt has ha d f or mi grai ne a n d/ or 
de pressi o n wit hi n t he past 1 0 years 
or f or a n y i n dicati o n wit hi n t he past 
5 m o nt hs bef ore I M P a d mi nistrati o n 
a n d u p t o t he e n d of st u d y, i ncl u di n g 
f oll o w u p, will be rec or de d o n t he 
e C R F. 
Clarificati o n  
6. 1. 4. H a milt o n De pressi o n R ati n g Sc ale -1 7  
T he H A M -D 1 7 is a list of 2 1  
1 7  ite ms use d t o deter mi ne a 
patie nt’s le vel of de pressi o n.  
T he H A M D 1 7 is a list of 1 7 ite ms 
use d t o deter mi ne a patie nt’s l e vel of 
de pressi o n.  
Clarificati o n  
7. 7. Electr o c ar di o gr a p h y  
A si n gle 1 2 -lea d E C G will be 
rec or de d at t he ti me p oi nts detaile d 
i nT a ble 4 . T his pr oce d ure will be 
perf or me d bef ore ot her assess me nts 
(e g, bl o o d dra ws a n d a d mi nistrati o n 
of q uesti o n naires).  
A si n gle 1 2 -lea d E C G will be 
rec or de d at t he ti me p oi nts detaile d 
i nT a ble 4 . 
U p date d t o re m o ve w or di n g 
i n v ol vi n g w he n t he pr oce d ure is 
perf or me d  
A p pe n di x A. Cli nic al L a b or at ories a n d Ot her De p art me nts a n d I nstit uti o ns  
 
 
 
 
T e va Bra n de d P har mace utical 
Pr o d ucts R & D, I n c.  
T el: 
 
Cell: 
 
 
 
 
 
 
T e va Bra n de d P har mace utical 
Pr o d ucts R & D, I nc.  
Cell: 
 
 
U p date d as o utli ne d i n 
A d mi nistrati ve Letter 0 2.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
9 9  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/  
j ustific ati o n f or c h a n ge 
 
 
 
T e va Bra n de d P har mace utical 
Pr o d ucts R & D, I nc.  
T el: 
 a n d 
 
Cell: 
 
 
 
 
 
T e va Bra n de d P har mace utical 
Pr o d ucts R & D, I nc.  
T el: 
 a n d 
 
Cell: 
 
 
U p date d as o utli ne d i n 
A d mi nistrati ve Letter 0 2.  
A p pe n di x B. St u d y Pr o ce d u re s s a n d Assess me nts b y Visit 
I n t he case of earl y ter mi nati o n, site 
pers o n nel s h o ul d perf or m a f oll o w -
u p p h o ne call t o e ns ure t he patie nt 
d oes n ot re p ort s uici dal i deati o n or 
be ha vi or. P h o ne calls s h o ul d be 
perf or me d o nce wee kl y f or 2 wee ks. 
If si g ns of s uici dalit y are i de ntifie d 
d uri n g t he f oll o w -u p p h o ne call, t he 
site pers o n nel s h o ul d pr o vi de 
directi o n t o t he patie nt f or f urt her 
ps yc hiatric e v al uati o n at t he site or 
at a c o m m u nit y ps yc hiatrist 
refere nce d b y t he site. Rele va nt 
e mer ge nc y ps yc hiatric care ser vices 
s h o ul d be n otifie d i n t he e ve nt t hat 
t he patie nt is dee me d t o be a t hreat 
t o t he mself. 
I n t he case of earl y ter mi nati o n, site 
pers o n nel  s h o ul d perf or m a f oll o w-
u p p h o ne call t o e ns ure t he patie nt 
d oes n ot re p ort s uici dal i deati o n or 
be ha vi or. P h o ne calls s h o ul d be 
perf or me d o nce wee kl y f or 2 wee ks. 
If si g ns of s uici dalit y are i de ntifie d 
d uri n g t he f oll o w -u p p h o ne call, t he 
site pers o n nel s h o ul d pr o vi de 
directi o n t o t he patie nt f or f urt her 
ps yc hiatric e val uati o n at t he site or 
at a c o m m u nit y ps yc hiatrist 
refere nce d b y t he site. Rele va nt 
e mer ge nc y ps yc hiatric care ser vices 
s h o ul d be n otifie d i n t he e ve nt t hat 
t he patie nt is dee me d t o be a t hreat 
t o t he mself. 
A d diti o nal f oll o w -u p f or patie nts 
w h o earl y ter mi nate were a d de d t o 
e ns ure t he safet y of t hese pati e nts.  
A p pe n di x G. Pre ve nti ve Mi gr ai ne M e dic ati o ns All o w e d f or 3 0 % of t he St u d y P o p ul ati o n a n d A nti 
De press a nt M e dic ati o ns All o w e d f or t he W h ole St u d y P o p ul ati o n f or t he D ur ati o n of t he St u d y  
P atie nts are n ot p er mitte d t o use 
o na b ot uli n u mt o xi n A f or a n y 
i n dicati o n f or t he d urati o n of t he 
st u d y. 
P atie nts are n ot per mitte d t o use 
o na b ot uli n u mt o xi n A f or a n y 
i n dicati o n f or t he d urati o n of t he 
st ud y.  
Clarificati o n.  
A p pe n di x P. M a n a ge me nt o f St u d y Acti vities D uri n g C O VI D-1 9  
Ne w a p pe n di x a n d te xt.  
A d diti o nal te xt t o o n u mer o us t o 
i ncl u de i n t his ta ble; refer t o 
A p pe n di x P of t his pr ot oc ol.  
U p date d t o ma na ge st u d y c o n d uct 
d uri n g t he C O VI D -1 9 pa n de mic.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 0 0  
 
1 6. 2.  
A d mi nistr ati ve Letter  0 2 D ate d 1 4 Fe br u ar y 2 0 2 0  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 0 1  
 
1 6. 3.  
A me n d me nt 0 3 D ate d 0 4  N o ve m ber  2 0 1 9  
T he pri mar y reas o ns f or t his a me n d me nt are t o u p date t he pr ot oc ol t o all o w a q ualifie d staff 
me m ber t o c o m plete t he H A M -A a n d H A M -D  1 7 assess me nts a n d t o all o w a q ualifie d 
cli nicia n’s j u d g m e nt t o be use d i n c o nj u ncti o n wit h t he e C -S S R S i ns tea d of a ps yc hiatrist. T his 
a me n d me nt is c o nsi dere d t o be s u bsta ntial (ie, re q uires a p pr o val b y c o m pet e nt a ut h orit y, I E C, 
a n d/ or I R B) b y t he s p o ns or’s A ut h orize d Re pres e ntati ve. Ot her n o ns u bsta ntial c ha n ges ha v e 
bee n ma de t o t he pr ot oc ol (a n d pr ot oc ol s y n o psis, as a p pr o priat e). T hes e c h a n ges are u nli kel y t o 
affect t he safet y or ri g hts ( p h ysic al or me ntal i nte grit y) of t h e patie nts i n t his cli nical st u d y or t he 
scie ntific val ue of t h e cli nical st u d y. 
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/  
j ustific ati o n f or 
c h a n ge  
TI T L E P A G E ( Ot her secti o ns affecte d b y t his c h a n ge: pr ot oc ol he a der, A me n d me nt Hist or y, I n vesti g at or 
A gree me nt, C o or di n ati n g I n vesti g at or A gree me nt)  
Cli nic al St u d y Pr ot oc ol wit h A me n d me nt 
0 2 0 3  A p pr o v al D ate: 1 0 Oct o ber 2 0 1 9 
0 4  N o ve m ber  2 0 1 9  
Cli nic al St u d y Pr ot oc ol wit h A me n d me nt 
0 3 A p pr o v al D ate: 0 4  N o ve m b er  2 0 1 9  
T o u p date f or 
A me n d me nt 0 3  
3.  S T U D Y D E SI G N  
3. 2.  Pl a n ne d N u m ber of P atie nts a n d C o u ntries  
T he st u d y is pla n ne d t o be c o n d ucte d i n 
a p pr o xi matel y 1 0 1 3  c o u ntries i n 
a p pr o xi matel y 6 5 i n vesti gati o nal ce nters. 
T he st u d y is e x pecte d t o start i n 
a p pr o xi matel y Se pte m ber 2 0 1 9 a n d last 
u ntil a p pr o xi matel y A u g ust 2 0 2 1.  
T he st u d y is pla n ne d t o be c o n d ucte d i n 
a p pr o xi matel y 1 3 c o u ntries i n a p pr o xi matel y 
6 5 i n vesti g ati o nal ce nters. T he st u d y is 
e x pecte d t o start i n a p pr o xi matel y Se pte m ber 
2 0 1 9 a n d last u ntil a p pr o xi mat el y A u g ust 
2 0 2 1.  
T o u p date t he 
pla n ne d n u m ber of 
c o u ntries.  
3. 5.  Sc he d ule of St u d y Pr o ce d ures a n d Assess me nts ( T a ble 4) ( Ot her secti o ns affecte d b y t his c h a n ge: 7. 4. 2, 
A p pe n di x B, A p pe n di x J)  
j O n d osi n g da ys, t he test or  q uesti o n naire  
s h o ul d be a d mi nistere d  pre d ose  
c o m plete d bef ore st u d y dr u g 
a d mi nistrati o n.  
j O n d osi n g da ys, t he test or q uesti o n naire 
s h o ul d be c o m plete d bef ore st u d y dr u g 
a d mi nistrati o n.  
Clarificati o n  
k T he F S H  t his assess me nt a p plies o nl y t o 
w o me n t h o u g ht t o be p ost me n o pa usal at 
t he scree ni n g visit ( V 1). If t he res ults 
s h o w a n ele vate d F S H ( > 3 5 U/ L) a n d t he 
patie nt has ha d n o me nses f or at least 1 2 
m o nt hs, t he y d o n ot nee d uri ne  pre g na nc y 
testi n g.  
k T he F S H assess me nt a p plies o nl y t o 
w o me n t h o u g ht t o be p ost me n o pa usal at 
t he scree ni n g visit ( V 1). If t he res ults s h o w 
a n ele vate d F S H ( > 3 5  U/ L) a n d t he patie nt 
has ha d n o me nses f or at least 1 2 m o nt hs, 
t he y d o n ot nee d uri ne pre g na nc y testi n g.  
T o clarif y a n d u p date 
t he F S H assess me nt  
n A q ualifie d ps yc hiatrist  staff me m ber (ie, 
t he i n vesti gat or or a me dicall y q ualifie d 
pers o n desi g nate d b y t he i n ve sti gat or) 
will p erf or m t his assess me nt.  
n A q ualifie d staff me m ber (ie, t he 
i n vesti gat or or a me dicall y q ualifie d pers o n 
desi g nate d b y t he i n vesti gat or) will 
perf or m t his assess me nt.  
T o u p date w h o ca n 
a d mi nister t he H A M -
A/  
D  1 7  
4.  S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  
4. 1.  P atie nt I ncl usi o n Criteri a  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 0 2  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/  
j ustific ati o n f or 
c h a n ge  
l. [ Re visi o n 1  2 ] T he patie nt d e m o nstrate d 
c o m plia nce wit h t he electr o ni c hea dac he 
diar y d uri n g t he 2 8 -da y baseli ne peri o d b y 
e ntr y of hea dac he data o n a mi ni m u m of 2 1  
4  da ys c u m ulati ve d uri n g t he 2 8 -da y 
baseli ne peri o d ( ~ 7 5 % diar y c o m plia nce).  
l. [ Re visi o n 2] T he patie nt de m o nstrate d 
c o m plia nce wit h t he electr o ni c hea dac he 
diar y d uri n g t he 2 8 -da y baseli ne peri o d b y 
e ntr y of hea dac he data o n a mi ni m u m of 2 1 
da ys c u m ulati ve d uri n g t he 2 8 -da y baseli ne 
peri o d ( ~ 7 5 % diar y c o m plia nc e).  
T o c orrect t he 
mi ni m u m a m o u nt of 
da ys t o 2 1  
4. 2.  P atie nt E xcl usi o n Criteri a  
b. [ Re visi o n 1] T he patie nt has faile d 4 or 
m ore differe nt me dicati o n classes t o treat 
de pressi o n i n t heir lifeti me 
b. [ Re visi o n 1] T he patie nt has faile d 4 or 
m ore differe nt me dicati o n classes t o treat 
de pressi o n i n t heir lifeti me  
Clarificati o n  
d.  [ Re visi o n 1] T he patie nt has use d a n 
i nter ve nti o n/ de vice (e g, sc he d ule d ner ve 
bl oc ks, i m pla nta ble va gal ner ve sti m ulati o n, 
a n d tra nscra nial ma g netic sti m ulati o n) f or 
mi grai ne or de pressi o n at a n y ti me d uri n g 
t he 2 m o nt hs pri or t o scree ni n g. 
d.  [ Re visi o n 1] T he patie nt has use d a n 
i nter ve nti o n/ de vice (e g, sc he d ule d ner ve 
bl oc ks, i m pla nta ble va gal ner ve sti m ulati o n, 
a n d tra nscra nial ma g netic sti m ulati o n) f or 
mi grai ne or de pressi o n d uri n g t he 2 m o nt hs 
pri or t o scree ni n g.  
T o u p date t he 
re q uire me nts f or 
patie nts t hat ha ve 
use d a n 
i nter ve nti o n/ de vice. 
o. [ Re visi o n 1] T he patie nt has faile d 
treat me nt ( base d o n t olera bilit y a n d/ or a 
lac k of efficac y) wit h a n y m o n ocl o nal 
a nti b o dies tar geti n g t he C G R P pat h wa y 
(ere n u ma b, e pti nez u ma b, galc a nez u ma b, or 
fre ma nez u ma b) or ha ve ta ke n t he 
me dicati o ns wit hi n 5 half -li ves of t he 
scree ni n g visit ( V 1) or ta ke t he m d uri n g t he 
st u d y. 
o. [ Re visi o n 1] T he patie nt has faile d 
treat me nt ( base d o n t olera bilit y a n d/ or a lac k 
of efficac y) wit h a n y m o n ocl o nal a nti b o dies 
tar geti n g t he C G R P pat h wa y ( ere n u ma b, 
e pti nez u ma b, galca nez u ma b, or 
fre ma nez u ma b) or ha ve ta ke n t he 
me dicati o ns wit hi n 5 half -li ves of t he 
scree ni n g visit ( V 1) or ta ke t he m d uri n g t he 
st u d y. 
Clarificati o n  
4. 3. Wit h dr a w al Criteri a a n d Pr o ce d ures f or t he P atie nt  
5.  A fe male patie n t has a c o nfir mati o n of 
pre g na nc y d uri n g t he st u d y fr o m a p ositi ve 
uri ne  pre g na nc y test.  
5.  A fe male patie nt has a c o nfir mati o n of 
pre g na nc y d uri n g t he st u d y fr o m a p ositi ve 
uri ne pre g na nc y test.  
Clarificati o n  
5.  T R E A T M E N T S  
5. 1. 1. 2.  D ose M o dific ati o n a n d  D ose Str atific ati o n  
N o d ose m o dificati o ns were are  all o we d.  
N o d ose m o dificati o ns are all o we d.  
Clarificati o n  
5. 1. 2.  
Pl ace b o I n vesti g ati o n al M e dici n al Pr o d uct ( Ot her secti o ns affecte d b y t his c h a n ge: 3. 1, 5. 1. 1, 5. 9)  
At t he ti me of eac h st u d y visit, t he I R T will 
be q uerie d, a n d site pers o n nel  staff will 
retrie ve t he I M P a n d o versee patie nt self -
a d mi nistrati o n of  1. 5 m L fr o m eac h 
prefille d s yri n ge c o ntai ne d i n t he 
a p pr o priatel y n u m bere d kit(s).  
At t he ti me of eac h st u d y  visit, t he I R T will 
be q uerie d, a n d site staff will r etrie ve t he 
I M P a n d o versee patie nt self-a d mi nistrati o n 
of 1. 5 m L fr o m eac h prefille d s yri n ge 
c o ntai ne d i n t he a p pr o priatel y n u m bere d 
kit(s).  
Clarificati o n  
St u d y dr u g s h o ul d be re m o ve d fr o m t he 
refri gerat or a n d all o we d t o e q uili brate at 
r o o m te m perat ure f or 4 5 t o 6 0  3 0 mi n utes 
bef ore st u d y dr u g self-a d mi nistrati o n.  
St u d y dr u g s h o ul d be re m o ve d fr o m t he 
refri gerat or a n d all o we d t o e q uili brate at 
r o o m te m perat ure f or 3 0 mi n utes bef ore 
st u d y dr u g self-a d ministrati o n.  
U p date t he I P 
e q uili brati o n ti me t o 
be i n li ne wit h t he 
U S PI a n d t he S m P C  
5. 2. 3.  
Acc o u nt a bilit y  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 0 3  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/  
j ustific ati o n f or 
c h a n ge  
O nl y patie nts e nr olle d i n t he st u d y ma y 
recei ve a n d self -a d mi nister  I M Ps, a n d o nl y 
a ut h orize d site staff at t he i n vesti gati o nal 
ce nter ma y s u p pl y I M Ps. All I M Ps m ust b e 
st ore d i n a sec ure, e n vir o n me ntall y 
c o ntr olle d, a n d m o nit ore d ( ma n ual or 
a ut o mate d) area i n acc or da nce wit h t he 
la bele d st ora ge c o n diti o ns or a p pr o priate 
i nstr ucti o ns wit h access li mited t o t he 
i n vesti gat or a n d a ut h orize d sit e staff at t he 
i n vesti gati o nal ce nter. 
O nl y patie nts e nr olle d i n t he st u d y ma y 
recei ve a n d self-a d mi nister I M Ps, a n d o nl y 
a ut h orize d site staff at t he i n vesti gati o nal 
ce nter ma y s u p pl y I M Ps. All I M Ps m ust be 
st ore d in a sec ure, e n vir o n me ntall y 
c o ntr olle d, a n d m o nit ore d ( ma n ual or 
a ut o mate d) area i n acc or da nce wit h t he 
la bele d st ora ge c o n diti o ns or a p pr o priate 
i nstr ucti o ns wit h access li mite d t o t he 
i n vesti gat or a n d a ut h orize d sit e staff at t he 
i n vesti gati o nal ce nter. 
Clarificati o n  
5. 1 1.  
T ot al Bl o o d V ol u me ( Ot her secti o ns affecte d b y t his c h a n ge: A p pe n di x J)  
T he t otal bl o o d v ol u me t o be c ollecte d f or 
eac h patie nt i n t his st u d y is a p pr o xi matel y 
4 5  6 4. 2  m L f or sc he d ule d tests. Details o n 
t otal bl o o d v ol u me are pr o vi de d i n 
A p pe n di x J.  
T he t otal bl o o d v ol u me t o be c ollecte d f or 
eac h patie nt i n t his st u d y is a p pr o xi matel y 
6 4. 2 m L f or sc he d ule d tests. Details o n t otal 
bl o o d v ol u me are pr o vi de d i n A p pe n di x J.  
T otal bl o o d v ol u me 
u p date d  
6.  A S S E S S M E N T O F E F FI C A C Y  
6. 1. 4.  
H a milt o n De pressi o n R ati n g Sc ale -1 7 ( Ot her secti o ns affecte d b y t his c h a n ge: A p pe n di x B)  
P atie nts will c o m plete A q ualifie d staff 
me m ber (ie, t he i n vesti gat or or a me dicall y 
q ualifie d pers o n desi g nate d b y t he 
i n vesti gat or) will a d mi nister a n d rec or d t he 
H A M -D 1 7 at t he ti me p oi nts detaile d i n 
T a ble 4.  T he H A M D -1 7 is a list of 2 1 
ite ms use d t o deter mi ne a patie nt’s le vel of 
de pressi o n. T he H A M -D 1 7 q uesti o n naire 
s h o ul d be gi ve n at t he sa me ti me of da y f or 
eac h visit. A ps yc hiatrist will be a me m ber 
of t he s ite st u d y tea m a n d s h o ul d be 
c o ns ulte d as a p pr o priate.  
A q ualifie d staff me m ber (ie, t he i n vesti gat or 
or a me dicall y q ualifie d pers o n desi g nate d 
b y t he i n vesti gat or) will a d mi nister a n d 
rec or d t he H A M-D 1 7 at t he ti me p oi nts 
detaile d i n T a ble 4.  T he H A M D -1 7 is a list 
of 2 1 ite ms use d t o deter mi ne a patie nt’s 
le vel of de pressi o n. T he H A M-D 1 7 
q uesti o n naire s h o ul d be gi ve n at t he sa me 
ti me of da y f or eac h visit. A ps yc hiatrist will 
be a me m ber of t he site st u d y tea m a n d 
s h o ul d be c o ns ulte d as a p pr o priate. 
T o  u p date w h o ca n 
a d mi nister t he H A M -
D  1 7  
6. 1. 5.  
H a milt o n A n xiet y Sc ale ( Ot her secti o ns affecte d b y t his c h a n ge: A p pe n di x B)  
P atie nts will c o m plete A q ualifie d staff 
me m ber (ie, t he i n vesti gat or or a me dicall y 
q ualifie d pers o n desi g nate d b y t he 
i n vesti gat or) will a d mi nister a n d rec or d t he 
H A M -A at t he ti me p oi nts detaile d i n T a ble 
4. T he H A M -A Scale is a t o ol f or 
meas uri n g t he se verit y of a patie nt’s 
a n xiet y. A ps yc hiatrist will be a me m ber of 
t he site st u d y tea m a n d s h o ul d be c o ns ulte d 
as a p pr o p riate. 
A q ualifie d staff me m ber (ie, t he i n vesti gat or 
or a me dicall y q ualifie d pers o n desi g nate d 
b y t he i n vesti gat or) will a d mi nister a n d 
rec or d t he H A M-A at t he ti me p oi nts 
detaile d i n T a ble 4. T he H A M -A Scale is a 
t o ol f or meas uri n g t he se verit y of a patie nt’s 
a n xiet y. A ps yc hiatrist will be a me m ber of 
t he site st u d y tea m a n d s h o ul d be c o ns ulte d 
as a p pr o priate.  
T o u p date w h o ca n 
a d mi nister t he H A M -
A  
7.  A S S E S S M E N T O F S A F E T Y  
7. 3.  M e dic ati o n Err or a n d S peci al Sit u ati o ns Rel ate d t o t he I n vesti g ati o n al M e di ci n al Pr o d ucts  
A n y a d mi nistrati o n of I M P t hat is n ot i n 
acc or da nce wit h t he st u d y pr ot oc ol s h o ul d 
A n y a d mi nistrati o n of I M P t hat is n ot i n 
acc or da nce wit h t he st u d y pr ot oc ol s h o ul d be 
T o u p date w or di n g 
fr o m vi olati o n t o 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 0 4  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/  
j ustific ati o n f or 
c h a n ge  
be re p orte d o n t he e C R F eit her as a 
vi olati o n, if it meets t he vi olati o n criteria 
s pecifie d i n t he pr ot oc ol ( A p pe n di x C), or 
as a de viati o n,  i n t he patie nts s o urce 
d oc u me nts, re gar dless of w het her or n ot a n 
a d verse e ve nt o cc urs as a res ult.  
re p orte d i n t he patie nts s o urce d oc u me nts, 
re gar dless of w het her or not a n a d verse e ve nt 
occ urs as a res ult.  
i m p orta nt pr ot oc ol 
de viati o n.  
7. 4. 3.  H u m a n C h ori o nic G o n a d otr o pi n Tests ( Ot her secti o ns affecte d b y t his c h a n ge: A p pe n di x B a n d 
A p pe n di x J.  
Ser u m β -H C G test will b e a d mi nistere d  at 
visit 1 (scree ni n g) f or w o me n of c hil d-
beari n g p ote ntial a n d w o me n t h o u g ht t o be 
p ost me n o pa usal.  Uri ne β -H C G test will be 
a d mi nistere d at visit 2 (ra n d o mizati o n), 
visit 3 ( da y 2 9), visit 4 ( da y 5 7), visit 5 ( da y 
8 5), a n d visit  6 ( da y  1 6 9) f or w o me n of 
c hil d-beari n g p ote ntial a n d f or w o me n 
t h o u g ht t o be p ost me n o pa usal w h ose F S H 
res ults at t he scree ni n g visit di d n ot s h o w a n 
ele vati o n ( ≤3 5 U/ L)  (see T a ble 4). O n 
d osi n g da ys, t he test s h o ul d be c o m plete d 
bef ore st u d y dr u g a d mi nistrati o n.  
Ser u m β -H C G test w ill be a d mi nistere d at 
visit 1 (scree ni n g) f or w o me n of c hil d -
beari n g p ote ntial a n d w o me n t h o u g ht t o be 
p ost me n o pa usal. Uri ne β -H C G test will be 
a d mi nistere d at visit 2 (ra n d o mizati o n), visit 
3 ( da y 2 9), visit 4 ( da y 5 7), visit 5 ( da y 8 5), 
a n d visit 6 ( da y  1 6 9) f or w o me n of c hil d -
beari n g p ote ntial a n d f or w o me n t h o u g ht t o 
be p ost me n o pa usal w h ose F S H res ults at t he 
scree ni n g visit di d n ot s h o w a n ele vati o n 
( ≤3 5 U/ L) (see T a ble 4). O n d osi n g da ys, t he 
test s h o ul d be c o m plete d bef ore st u d y dr u g 
a d mi nistrati o n.  
Clarificati o n  
7. 8.  
Electr o nic C ol u m bi a -S uici d e Se verit y R ati n g Sc ale ( Ot her secti o ns affecte d b y t his c h a n ge: Secti o n  3. 5 
( T a ble 4, F o ot n ote l) a n d A p pe n di x B) 
As part of t he o verall safet y e val uati o n, t he 
electr o nic C ol u m bia -S uici de S e verit y 
Rati n g Scale (e C -S S R S) (P os ner, 2 0 1 6 ) will 
be use d i n c o nj u ncti o n wit h a q ualifie d 
ps yc hiatrist’s  cli nicia n’s (ie, t he 
i n vesti gat or or a me dicall y q ualifie d pers o n 
desi g nate d b y t he i n vesti gat or) cli nical 
j u d g me nt t o assess t he patie nt’s s uici dal 
i deati o n (se verit y a n d i nte nsit y) a n d 
be ha vi or.  
As part of t he o verall safet y e val uati o n, t he 
electr o nic C ol u m bia -S uici de S e verit y Rati n g 
Scale (e C -S S R S) (P os ner, 2 0 1 6 ) will be use d 
i n c o nj u ncti o n wit h a q ualifie d cli nicia n’s 
(ie, t he i n vesti gat or or a me dic all y q ualifie d 
pers o n desi g nate d b y t he i n vesti gat or) 
cli nical j u d g me nt t o assess t he patie nt’s 
s uici dal i deati o n (se verit y a n d i nte nsit y) a n d 
be ha vi or.  
Clarificati o n   
A P P E N DI X A.  C LI NI C A L L A B O R A T O RI E S A N D O T H E R D E P A R T M E N T S A N D I N S TI T U TI O N S  
S p o ns or’s A ut h orize d Re prese nt ati ve  
 
 
 
 
 
T e va Bra n de d P har mace utical Pr o d ucts 
R & D, I nc.  
T el: 
 
Cell: 
 
 
 
  
T e va Bra n de d P har mace utical Pr o d ucts 
R & D, I nc.  
  
 
 
 
T e va Bra n de d P har mace utical Pr o d ucts 
R & D, I nc.  
T el: 
 
Cell: 
 
 
T o u p date S p o ns or’s 
A ut h orize d 
Re prese ntati ve  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 0 5  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/  
j ustific ati o n f or 
c h a n ge  
T el: 
 
Cell: 
 
 
Le gal Re prese ntati ve of t he S p o ns or i n t he 
E U a n d C o ntact P ers o n  
Le gal Re prese ntati ve of t he S p o ns or i n t he 
E U a n d C o ntact P ers o n  
Clarificati o n  
S p o ns or’s M e dic al E x pert/ C o nt a ct P oi nt Desi g n ate d b y t he S p o ns or f or F urt her I nf o r m ati o n o n t he St u d y  
 
 
 
T e va Bra n de d P har mace utical Pr o d ucts 
R & D, I nc.  
T el: 
 
Cell: 
 
 
 
  
T e va Bra n de d P har mace utical Pr o d ucts 
R & D, I nc.  
T el: 
 
Cell: 
 
 
 
 
 
T e va Bra n de d P har mace utical Pr o d ucts 
R & D, I nc.  
T el: 
 
Cell: 
 
 
T o u p date S p o ns or’s 
Me dical 
E x pert/ C o ntact P oi nt 
Desi g nate d b y t he 
S p o ns or f or F urt her 
I nf or mati o n o n t he 
St u d y  
A p pe n di x B.   
S T U D Y P R O C E D U R E S A N D A S S E S S M E N T S B Y VI SI T  
•  
a d mi nister c o m plete  Mi ni 
Me ntal State E xa mi nati o n  
•  
a d mi nister  c o m plete P atie nt 
Healt h Q uesti o n naire -9 ( P H Q -
9)  
•  
a d mi nister  c o m plete t he 
e C-S S R S Lifeti me versi o n 
( use d i n c o nj u ncti o n wit h 
q ualifie d 
ps yc hiatrist ’scli nicia n’s 
cli nical j u d g me nt t o assess t he 
patie nt’s s uici dal i deati o n 
[se verit y a n d i nte nsit y] a n d 
be ha vi or)   
•  
c o m plete Mi ni Me ntal State 
E xa mi nati o n  
•  
c o m plete P atie nt Healt h 
Q uesti o n naire -9 ( P H Q -9)  
•  
c o m plete t he e C -S S R S 
Lifeti me versi o n ( use d i n 
c o nj u ncti o n wit h q ualifie d 
cli nicia n’s cli nical j u d g me nt t o 
assess t he patie nt’s s uici dal 
i deati o n [se verit y a n d i nte nsit y] 
a n d be ha vi or)  
 
Clarificati o n  
si mil ar c h a n ges 
a p plie d t o ot her 
sc ales/ q uesti o n n aires 
i n A p pe n dix B 
A p pe n di x C.   
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E ( Ot her secti o ns affecte d: Secti o n 3. 4 
a n d 9. 2. 4)  
I m p orta nt Pr ot oc ol De viati o ns Pr ot oc ol 
Vi olati o ns  
I m p orta nt Pr ot oc ol De viati o ns 
Re w or di n g of 
pr ot oc ol vi olati o n t o 
i m p orta nt pr ot oc ol 
de viati o n  
A n y de viati o n fr o m t he pr ot oc ol t hat 
affects, t o a si g nifica nt d e gree, (a) t he 
safet y, p h ysical, or me ntal i nte grit y of t he 
patie nts i n t he st u d y a n d/ or ( b) t he scie ntific 
val ue of t he st u d y will be c o nsi dere d a 
pr ot oc ol vi olati o n  a n i m p orta nt pr ot oc ol 
A n y de viati o n fr o m t he pr ot oc ol t hat affects, 
t o a si g nifica nt de gree, (a) t he safet y, 
p h ysical, or me ntal i nte grit y of t he patie nts 
i n t he stu d y a n d/ or ( b) t he scie ntific val ue of 
t he st u d y will be c o nsi dere d a n i m p orta nt 
Re w or di n g of 
pr ot oc ol vi olati o n t o 
i m p orta nt pr ot oc ol 
de viati o n  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 0 6  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/  
j ustific ati o n f or 
c h a n ge  
de vi ati o n. Pr ot oc ol vi olati o ns I m p orta nt 
pr ot oc ol de viati o ns  ma y i ncl u de n o n -
a d here nce o n t he part of t he patie nt, t he 
i n vesti gat or, or t he s p o ns or t o pr ot oc ol-
s pecific i ncl usi o n a n d e xcl usi o n criteria, 
pri mar y o bj ecti ve varia ble criteria, or G o o d 
Cli nical Pra ctice ( G C P) g ui deli nes; 
n o nc o m plia nce t o I M P a d mi nistrati o n; a n d 
use of pr o hi bite d me dicati o ns. Pr ot oc ol 
vi olati o ns  I m p orta nt pr ot oc ol d e viati o ns 
will b e i de ntifie d a n d rec or de d b y 
i n vesti gati o nal ce nter pers o n nel o n t he 
electr o nic case re p ort f or m (e C R F).  All 
pr ot oc ol vi olati o ns  i m p orta nt pr ot oc ol 
de viati o ns  will be re p orte d t o t he 
res p o nsi ble I E C/I R B, as re q uire d.  
pr ot oc ol de viati o n. I m p orta nt pr ot oc ol 
de viati o ns ma y i ncl u de n o n -a d here nce o n t he 
part of t he patie nt, t he i n vesti gat or, or t he 
s p o ns or t o pr ot oc ol-s pecific i ncl usi o n a n d 
e xcl usi o n criteria, pri mar y o bj ecti ve varia ble 
criteria, or G o o d Cli nical Practice ( G C P) 
g ui deli nes; n o nc o m plia nce t o I M P 
a d mi nistrati o n; a n d use of pr o hi bite d 
me dicati o ns. I m p orta nt pr ot oc ol de viati o ns 
will be i de ntifie d a n d rec or de d b y 
i n vesti gati o nal ce nter pers o n nel o n t he 
electr o nic case re p ort f or m (e C R F). All 
i m p orta nt pr ot oc ol de viati o ns will be 
re p orte d t o t he res p o nsi ble I E C/I R B, as 
re q uire d. 
W he n a pr ot oc ol vi olati o n  a n i m p orta nt 
pr ot o c ol de viati o n is re p orte d, t he s p o ns or 
will d eter mi ne w het her t o wit h dra w t he 
patie nt fr o m t he st u d y or per mit t he patie nt 
t o c o nti n ue i n t he st u d y, wit h d oc u me nte d 
a p pr o val fr o m t he me dical e x p ert.  
W he n a n i m p orta nt pr ot oc ol de viati o n is 
re p orte d, t he s p o ns or will deter mi ne w het her 
t o wit h dra w t he patie nt fr o m t he st u d y or 
per mit t he patie nt t o c o nti n ue i n t he st u d y, 
wit h d oc u me nte d a p pr o val fr o m t he me dical 
e x pert.  
Re w or di n g of 
pr ot oc ol vi olati o n t o 
i m p orta nt pr ot oc ol 
de viati o n  
If i n vesti gati o nal ce nter pers o n nel lear n t hat 
a patie nt w h o di d n ot meet t he pr ot oc ol 
i ncl usi o n a n d e xcl usi o n criteri a was e ntere d 
i n a st u d y, t he y m ust i m me diatel y i nf or m 
t he s p o ns or of t he pr ot oc ol vi olati o n  
i m p orta nt pr ot oc ol d e viati o n. If s uc h patie nt 
has alrea d y c o m plete d t he st u d y or has 
wit h dra w n earl y, n o acti o n will b e ta ke n b ut 
t he vi olati o n  de viati o n  will be rec or de d.  
If i n vesti gati o nal ce nter pers o n nel lear n t hat 
a patie nt w h o di d n ot meet t he pr ot oc ol 
i ncl usi o n a n d e xcl usi o n criteri a was e ntere d 
i n a st u d y, t he y m ust i m me diatel y i nf or m t he 
s p o ns or of t he i m p orta nt pr ot oc ol de viati o n. 
If s uc h patie nt has alrea d y c o m plete d t he 
st u d y or has wit h dra w n earl y, n o acti o n will 
be ta ke n b ut t he de viati o n will be rec or de d.  
 
Re w or di n g of 
pr ot oc ol vi olati o n t o 
i m p orta nt pr ot oc ol 
de viati o n  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 0 7  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/  
j ustific ati o n f or 
c h a n ge  
A p pe n di x J.   
T O T A L B L O O D V O L U M E  
T y pe of 
s a m ples 
V ol u me 
per 
s a m ple 
( m L) 
T ot al 
n u m ber 
of 
s a m ples 
T ot al 
v ol u me 
( m L) 
Ser u m 
c he mistr y, 
he mat ol o g y, 
a n d 
c oa g ulati o n, 
ser u m 
β -H C G test a 
a n d F S H b 
6. 5 1 0. 7  
6 1  
3 9 1 0. 7  
Ser u m 
β H C G 
testaSer u m 
c he mistr y, 
he mat ol o g y, 
a n d 
c oa g ulati o n 
3 1 0. 7  
1 5  
3 5 3. 5  
F S H b  
3  
1  
3  
T ot al  
 
8 6  
4 5 6 4. 2   
 
T y pe of 
s a m ples 
V ol u me  
per 
s a m ple 
( m L) 
T ot al 
n u m ber 
of 
s a m ples 
T ot al 
v ol u me 
( m L) 
Ser u m 
c he mistr y, 
he mat ol o g y, 
c oa g ulati o n, 
ser u m 
β -H C G test a 
a n d F S H b 
1 0. 7  
1  
1 0. 7  
Ser u m 
c he mistr y, 
he mat ol o g y, 
a n d 
c oa g ulati o n 
1 0. 7  
5  
5 3. 5  
T ot al  
 
6  
6 4. 2  
 
U p date t o t he 
v ol u me of bl o o d 
ta ke n d uri n g t he 
s o urce of t he st u d y. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 0 8  
 
1 6. 4.  
A me n d me nt 0 2 D ate d 1 0 Oct o ber 2 0 1 9  
T he pri mar y reas o n f or t his a me n d me nt is t o u p date t he pr ot oc ol base d o n fee d bac k recei ve d 
fr o m t he V ol u ntar y H ar m o nisati o n Pr oce d ure. T his a me n d me nt is c o nsi dere d t o be s u bsta ntial 
(ie, re q uir es a p pr o val b y c o m pete nt a ut h orit y, I E C, a n d/ or I R B) b y t he s p o ns or’s A ut h orize d 
Re prese ntati ve. Ot h er n o ns u bsta ntial c ha n ges ha v e bee n ma de t o t he pr ot o c ol (a n d pr ot oc ol 
s y n o psis, as a p pr o priate). T hese c h a n ges are u nli k el y t o affect t he safet y or ri g hts ( p h ysic al or 
me ntal i nte grit y) of t he p atie nts i n t his cli nical st u d y or t he s cie ntific val u e of t he cli nical st u d y.  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ 
j ustific ati o n 
f or c h a n ge 
TI T L E P A G E ( Ot her secti o ns affecte d b y t his c h a n ge: pr ot oc ol he a der, A me n d me nt Hist or y, I n vesti g at or 
A gree me nt, C o or di n ati n g I n vesti g at or A gree me nt)  
Cli nic al St u d y Pr ot oc ol wit h A me n d me nt 
0 1 0 2  A p pr o v al D ate: 0 4 1 0  Oct o ber  2 0 1 9  
Cli nic al St u d y Pr ot oc ol wit h A me n d me nt 0 2 
A p pr o v al D ate: 1 0  Oct o ber  2 0 1 9  
T o u p date f or 
A me n d me nt 0 2  
2.  S T U D Y O B J E C TI V E S A N D E N D P OI N T S  
2. 1.  Pri m ar y a n d Sec o n d ar y St u d y O bjecti ves a n d E n d p oi nt  
Ke y sec o n d ar y o bjecti ve:  
T o e val uate t he efficac y of m o nt hl y 2 2 5 m g sc 
of fre ma nez u ma b i n a d ult p atie nts wit h 
mi grai ne a n d M D D  o n t he re d ucti o n of M D D 
s y m pt o ms 
Ke y sec o n d ar y o bjecti ve:  
T o e val uate t he efficac y of m o nt hl y 2 2 5 m g sc 
of fre ma nez u ma b i n a d ult patie nts wit h 
mi grai ne a n d M D D o n t he re d ucti o n of M D D 
s y m pt o ms 
T o fi x a n 
e dit orial 
mista ke.  
4.  S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  
4. 2.  P atie nt E xcl usi o n Criteri a  
h. [ Re visi o n 1] T he patie nt has e vi de nce or 
me dical hist or y of ot her cli nic all y si g nifica nt 
ps yc hiatric iss ues t hat, i n t he o pi ni o n of t he 
i n vesti gat or, c o ul d j e o par dize or w o ul d 
c o m pr o mise t he patie nt’s a bilit y t o partici pate 
i n t his st u d y i ncl u di n g pa nic dis or der, bi p olar 
dis or der, sc hiz o p hre nia, or a n y s uici de atte m pt 
i n t he past, or s uici dal i deati o n, or ot her 
ps yc h oacti ve s pectr u m dis or d ers i ncl u di n g 
sc hiz oaffecti ve dis or der, del usi o nal dis or der, 
de pressi o n wit h ps yc h otic feat ures, a n d 
catat o nic dis or der  i n t he past 6 m o nt hs. 
h. [ Re visi o n 1] T he patie nt has e vi de nce or 
me dical hist or y of ot her cli nic all y si g nifica nt 
ps yc hiatric iss ues t hat, i n t he o pi ni o n of t he 
i n vesti gat or, c o ul d j e o par dize or w o ul d 
c o m pr o mise t he patie nt’s a bilit y t o partici pate 
i n t his st u d y i ncl u di n g pa nic dis or der, bi p olar 
dis or der, sc hiz o p hre nia, or a n y s uici de atte m pt 
i n t he past, s uici dal i deati o n, or ot her 
ps yc h oacti ve s pectr u m dis or d ers i ncl u di n g 
sc hiz oaffecti ve dis or der, del usi o nal dis or der, 
de pressi o n wit h ps yc h otic feat ures, a n d 
catat o nic dis or der i n t he past 6 m o nt hs.  
Clarificati o n t o 
e ns ure n o 
patie nts wit h 
e vi de nce of 
ps yc h osis are 
i ncl u de d i n t his 
st u d y. 
u. [ Re visi o n 1] T he patie nt has a hist or y of 
alc o h ol or dr u g a b use i n t he o pi ni o n of t he 
i n vesti gat or. 
u. [ Re visi o n 1] T he patie nt has a hist or y of 
alc o h ol or dr u g a b use i n t he o pi ni o n of t he 
i n vesti gat or.  
Clarificati o n  
aa. T he patie nt has e vi de nce or me dical hist or y 
of ps yc h otic s y m pt o ms as per D S M -V criteria 
s uc h as del usi o ns, hall uci nati o ns, or 
dis or ga nize d s peec h i n t he past 1 m o nt h.  
aa. T he patie nt has e vi de nce or me dical hist or y 
of ps yc h otic s y m pt o ms as per D S M -V criteria 
s uc h as del usi o ns, hall uci nati o ns, or 
dis or ga nize d s peec h i n t he past 1 m o nt h.  
E xcl usi o n 
criteri o n “aa” 
was a d de d t o 
e ns ure n o 
pat ie nts wit h 
e vi de nce of 
ps yc h osis are 
i ncl u de d i n t his 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 0 9  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ 
j ustific ati o n 
f or c h a n ge 
st u d y. 
5. 7.  Pri or a n d C o nc o mit a nt M e dic ati o n or T her a p y  
A n y pri or or c o nc o mita nt me dicati o n, 
treat me nt, ps yc h ot hera p y , or pr oce d ure a 
patie nt has ha d wit hi n t he past 1 0 years bef ore 
I M P a d mi nistrati o n a n d u p t o t he e n d of st u d y, 
i ncl u di n g f oll o w u p, will be rec or de d o n t he 
e C R F. Tra de na me a n d i nter nati o nal 
n o n pr o prietar y na me (if a vaila ble), i n dicati o n, 
d ose, a n d start a n d e n d dates of t he 
a d mi nistere d me dicati o n or treat me nt will be 
rec or de d. I n a d diti o n, mi grai ne a n d de pressi o n 
pre ve nti ve me dicati o n liste d i n A p pe n di x G 
t hat a patie nt t o o k bef ore st u d y dr u g 
a d mi nistrati o n will be rec or de d o n t he e C R F. 
Ge neric or tra d e na me, i n dicati o n, a n d d osa ge 
will b e rec or de d. T he s p o ns or will e nc o de all 
me dicat i o n acc or di n g t o t he W orl d Healt h 
Or ga nizati o n dr u g dicti o nar y ( W H O Dr u g).  
A n y pri or or c o nc o mita nt me dicati o n, 
treat me nt, ps yc h ot hera p y, or pr oce d ure a 
patie nt has ha d wit hi n t he past 1 0 years bef ore 
I M P a d mi nistrati o n a n d u p t o t he e n d of st u d y, 
i ncl u di n g f oll o w u p, will be rec or de d o n t he 
e C R F. Tra de na me a n d i nter nati o nal 
n o n pr o prietar y na me (if a vaila ble), i n dicati o n, 
d ose, a n d start a n d e n d dates of t he 
a d mi nistere d me dicati o n or treat me nt will be 
rec or de d. I n a d diti o n, mi grai ne a n d de pressi o n 
pre ve nti ve me dicati o n liste d i n A p pe n di x G 
t hat a patie nt t o o k bef ore st u d y dr u g 
a d mi nistrati o n will be rec or de d o n t he e C R F. 
Ge neric or tra de na me, i n dicati o n, a n d d osa ge 
will be rec or de d. T he s p o ns or will e nc o de all 
me dicati o n acc or di n g t o t he W orl d Healt h 
Or ga nizati o n dr u g dicti o nar y ( W H O Dr u g). . 
Clarifie d t hat 
a n y o n g oi n g 
ps yc h ot he ra p y 
or c ha n ges t o 
t he patie nts’ 
ps yc h ot hera p y 
is t o be 
rec or de d 
t hr o u g h o ut t he 
st u d y. 
A list of pre ve nti ve mi grai ne me dicati o ns t hat 
are all o we d f or u p t o 3 0 % of t he st u d y 
p o p ulati o n a n d a nti de pressa nt me dicati o ns 
all o we d f or t he w h ole st u d y p o p ulati o n f or t he 
d urati o n of t he st u d y are gi ve n i n A p pe n di x G.  
C o nc o mita nt me dicati o ns t hat are n ot all o we d 
f or t he d urati o n of t he st u d y i ncl u de ot her 
m o n ocl o nal a nti b o dies t hat tar get t he C G R P 
pat h wa y (ere n u ma b, e pti nez u ma b, or 
galca nez u ma b), as descri be d i n Sec ti o n 4. 2. 
If cli nicall y i n dicate d, patie nts’ a nti de pressa nt 
me dicati o ns a n d ps yc h ot hera p y ma y be 
c ha n ge d at a n y ti me d uri n g t he treat me nt p eri o d 
at t he discreti o n of t he i n vesti gat or, a n d all 
c ha n ges will be rec or de d i n t he e C R F. I n s uc h 
case, t he patie nt’ s c o nti n ue d partici pati o n i n t he 
st u d y will be re vie we d b y t he me dical 
m o nit ors.  
A list of pre ve nti ve mi grai ne me dicati o ns t hat 
are all o we d f or u p t o 3 0 % of t he st u d y 
p o p ulati o n a n d a nti de pressa nt me dicati o ns 
all o we d f or t he w h ole st u d y p o p ulati o n f or t he 
d urati o n of t he st u d y are gi ve n i n A p pe n di x G.  
C o nc o mita nt me dicati o ns t hat are n ot all o we d 
f or t he d urati o n of t he st u d y i ncl u de ot her 
m o n ocl o nal a nti b o dies t hat tar get t he C G R P 
pat h wa y (ere n u ma b, e pti nez u ma b, or 
galca nez u ma b), as descri be d i n Secti o n 4. 2.  
If cli nicall y i n dicate d, patie nts’ a nti de pressa nt 
me dicati o ns a n d ps yc h ot hera p y ma y be 
c ha n ge d at a n y ti me d uri n g t he treat me nt peri o d 
at t he discreti o n of t he i n vesti gat or, a n d all 
c ha n ges will be rec or de d i n t he e C R F. I n s uc h 
case, t he patie nt’s c o nti n ue d partici pati o n i n t he 
st u d y will be re vie we d b y t he me dical 
m o nit ors.  
Clarificati o n of 
me dicati o ns 
t hat are 
all o we d a n d 
disall o we d f or 
t he d urati o n of 
t he st u d y a n d 
t hat patie nts 
ma y c ha n ge 
t heir 
a nti de pressa nt 
me dicati o n or 
ps yc h ot hera p y 
d uri n g t he 
stu d y.  
C o nc o mita nt me dicati o n a n d treat me nt, 
i ncl u di n g ps yc h ot hera p y, will be rec or de d u ntil 
visit 6, da y 1 6 9.  
C o nc o mita nt me dicati o n a n d treat me nt, 
i ncl u di n g ps yc h ot hera p y, will be rec or de d u ntil 
visit 6, da y 1 6 9.  
Clarifie d t hat 
a n y c ha n ges t o 
t he patie nts’ 
ps yc h ot hera p y 
is t o be 
rec or de d 
t hr o u g h o ut t he 
st u d y. 
7.  A S S E S S M E N T O F S A F E T Y  
7. 1. 5. 2.  E x pecte d ness  
A seri o us a d verse e ve nt t hat is n ot i ncl u de d i n 
A seri o us a d verse e ve nt t hat is n ot i ncl u de d i n 
Clarificati o n of 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 1 0  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ 
j ustific ati o n 
f or c h a n ge 
t he A d verse Reacti o n secti o n of t he rele va nt 
refere nce safet y i nf or mati o n b y its s pecificit y, 
se verit y, o utc o me, or fre q ue nc y is c o nsi dere d 
a n u ne x pecte d a d verse e ve nt. T he refere nce 
safet y i nf or mati o n f or t his st u d y is t he I B a n d 
De vel o p me nt Safet y U p date R e p ort l ocall y 
a p pr o ve d prescri bi n g i nf or mati o n f or c o u ntries 
w here fre ma nez u ma b is a p pr o ve d f or t he 
pre ve nti ve treat me nt of mi grai ne. F or c o u ntries 
w here fre ma nez u ma b is n ot yet a p pr o ve d, t he 
refere nce safety i nf or mati o n f or t his st u d y is 
t he I B. 
T he s p o ns or’s G P S P will deter mi ne t he 
e x pecte d ness f or all seri o us a d verse e ve nts.  
F or t he p ur p ose of S U S A R re p orti n g, i n 
c o u ntries w here fre ma nez u ma b is a p pr o ve d f or 
t he pre ve nti ve treat me nt of mi grai ne, t he 
l ocall y a p pr o ve d prescri bi n g i nf or mati o n will 
be use d. F or c o u ntries w here t he I B is t he 
refere nce safet y i nf or mati o n, t he c urre nt 
versi o n of t he I B at t he ti me of occ urre nce of 
t he S U S A R a p plies. 
t he A d verse Reactio n secti o n of t he rele va nt 
refere nce safet y i nf or mati o n b y its s pecificit y, 
se verit y, o utc o me, or fre q ue nc y is c o nsi dere d 
a n u ne x pecte d a d verse e ve nt. T he refere nce 
safet y i nf or mati o n f or t his st u d y is t he l ocall y 
a p pr o ve d prescri bi n g i nf or mati o n f or c o u nt ries 
w here fre ma nez u ma b is a p pr o ve d f or t he 
pre ve nti ve treat me nt of mi grai ne. F or c o u ntries 
w here fre ma nez u ma b is n ot yet a p pr o ve d, t he 
refere nce safet y i nf or mati o n f or t his st u d y is 
t he I B. 
T he s p o ns or’s G P S P will deter mi ne t he 
e x pecte d ness f or all seri o u s a d verse e ve nts. 
F or t he p ur p ose of S U S A R re p orti n g, i n 
c o u ntries w here fre ma nez u ma b is a p pr o ve d f or 
t he pre ve nti ve treat me nt of mi grai ne, t he 
l ocall y a p pr o ve d prescri bi n g i nf or mati o n will 
be use d. F or c o u ntries w here t he I B is t he 
refere nce safet y i nf or mati o n, t he c urre nt 
versi o n of t he I B at t he ti me of occ urre nce of 
t he S U S A R a p plies. 
w hat d oc u me nt 
s h o ul d be use d 
as t he 
refere nce 
safet y 
i nf or mati o n. 
9.  S T A TI S TI C S  
9. 1.  S a m ple Size a n d P o w er C o nsi der ati o ns  
A sa m ple size of 2 8 8 ( 1 4 4 per  treat me nt gr o u p) 
e val ua ble patie nts c o m pleti n g t he st u d y will 
pr o vi de 9 0 % p o wer t o detect a treat me nt 
differe nce of 2 da ys wit h a c o m m o n sta n dar d 
de viati o n of 5. 2 da ys i n c ha n ges fr o m t he 
2 8 -da y baseli ne peri o d i n m o nt hl y a vera ge 
mi grai ne da ys bet wee n act i ve a n d place b o 
gr o u ps at a 2 -si de d al p ha le vel of 0. 0 5. T his 
sa m ple size will pr o vi de a p pr o xi matel y 8 0 % 
p o wer t o detect a treat me nt differe nce of 
2  p oi nts wit h a c o m m o n sta n dar d de viati o n of 
6  p oi nts i n t he c ha n ge fr o m ra n d o mizati o n visit 
( da y 1) i n H A M-D  1 7 t otal sc ore at a 2 -si de d 
al p ha le vel of 0. 0 5 . Ass u mi n g a 1 5 % dr o p-o ut 
rate, a p pr o xi matel y 3 4 0 patie nts 
(a p pr o xi matel y 1 7 0 patie nts p er treat me nt 
gr o u p) will be ra n d o mize d.  
A sa m ple size of 2 8 8 ( 1 4 4 per treat me nt gr o u p) 
e val ua ble patie nts c o m pleti n g t he  st u d y will 
pr o vi de 9 0 % p o wer t o detect a treat me nt 
differe nce of 2 da ys wit h a c o m m o n sta n dar d 
de viati o n of 5. 2 da ys i n c ha n ges fr o m t he 
2 8 -da y baseli ne peri o d i n m o nt hl y a vera ge 
mi grai ne da ys bet wee n acti ve a n d place b o 
gr o u ps at a 2 -si de d al p ha le vel of 0. 0 5. T his 
sa m ple size will pr o vi de a p pr o xi matel y 8 0 % 
p o wer t o detect a treat me nt differe nce of 
2  p oi nts wit h a c o m m o n sta n dar d de viati o n of 
6  p oi nts i n t he c ha n ge fr o m ra n d o mizati o n visit 
( da y 1) i n H A M-D 1 7 t otal sc ore at a 2 -si de d 
al p ha le vel of 0. 0 5. A ss u mi n g a 1 5 % dr o p-o ut 
rate, a p pr o xi matel y 3 4 0 patie nts 
(a p pr o xi matel y 1 7 0 patie nts p er treat me nt 
gr o u p) will be ra n d o mize d.  
Clarificati o n 
t hat t he sa m ple 
size was 
deter mi ne d 
usi n g a 2 -si de d 
al p ha le vel of 
0. 0 5.  
A P P E N DI X G.  P R E V E N TI V E 
MI G R AI N E M E DI C A TI O N S A L L O W E D 
F O R 3 0 % O F T H E S T U D Y P O P U L A TI O N 
A N D A N TI -D E P R E S S A N T 
M E DI C A TI O N S A L L O W E D F O R T H E 
W H O L E S T U D Y P O P U L A TI O N  F O R T H E 
D U R A TI O N O F T H E S T U D Y  
A P P E N DI X G.  P R E V E N TI V E 
MI G R AI N E M E DI C A TI O N S A L L O W E D 
F O R 3 0 % O F T H E S T U D Y P O P U L A TI O N 
A N D A N TI -D E P R E S S A N T 
M E DI C A TI O N S A L L O W E D F O R T H E 
W H O L E S T U D Y P O P U L A TI O N F O R T H E 
D U R A TI O N O F T H E S T U D Y  
Clarificati o n of 
t he A p pe n di x 
title t o better 
reflect t he 
i nf or mati o n 
prese nte d.  
A nti de pressa nt me dicati o ns all o we d f or t he 
A nti de pressa nt me dicati o ns all o we d f or t he 
Clarificati o n.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 1 1  
 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ 
j ustific ati o n 
f or c h a n ge 
w h ole st u d y p o p ulati o n f or t he  d urati o n of t he 
st u d y s pecificall y i ncl u de t he f oll o wi n g (if t he y 
were pre vi o usl y prescri be d f or de pressi o n or 
f or a n ot her i n dicati o n): 
w h ole st u d y p o p ulati o n f or t he d urati o n of t he 
st u d y s pecificall y i ncl u de t he f oll o wi n g (if t he y 
were pre vi o usl y prescri be d f or de pressi o n or 
f or a n ot her i n dicati o n): 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 1 2  
 
1 6. 5.  
Letter of Cl arific ati o n 0 1 D ate d 2 6 A u g ust 2 0 1 9  
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 1 3  
 
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 1 4  
 
1 6. 6.  
A me n d me nt 0 1 D ate d 0 4  J u ne 2 0 1 9  
T he pri mar y reas o n f or t his a me n d me nt is t o s pecif y t hat t he s uici d alit y ass ess me nt t o be use d 
will be t he e C -S S R S i n c o nj u ncti o n wit h t he cli nical j u d g m e nt of a q ualifi e d ps yc hiatrist. T his 
a me n d me nt is c o nsi dere d t o be s u bsta ntial (ie, re q uires a p pr o val b y c o m pet ent a ut h orit y , I E C, 
a n d/ or I R B) b y t he s p o ns or’s A ut h oriz e d Re pres e ntati ve. Ot her n o ns u bsta ntial c ha n ges ha v e 
bee n ma de t o t he pr ot oc ol (a n d pr ot oc ol s y n o psis, as a p pr o priat e). T hes e c h a n ges are u nli kel y t o 
affect t he safet y or ri g hts ( p h ysic al or me ntal i nte grit y) of t h e patie nts i n t his cli nical st u d y or t he 
scie ntific val ue of t h e cli nical st u d y. 
Ta ble  4  ( St u d y Pr oce d ures a n d Assess me nts) h as bee n re vis e d t o refl ect c ha n ges descri be d 
bel o w.  
Ori gi n al te xt wit h c h a n ges s h o w n 
Ne w w or di n g  
Re as o n/j ustific ati o n f or c h a n ge  
TI T L E P A G E ( Ot her secti o ns affecte d b y t his c h a n ge: pr ot oc ol he a der, A me n d me nt Hist or y, I n vesti g at or 
A gree me nt, C o or di n ati n g I n vesti g at or A gree me nt)  
Cli nic al St u d y Pr ot oc ol wit h 
A me n d me nt 0 1  
Cli nic al St u d y Pr ot oc ol wit h 
A me n d me nt 0 1  
T o u p date f or A me n d me nt 0 1  
© 2 0 1 8 2 0 1 9  T e va Bra n de d 
P har mace utical Pr o d ucts R & D, I nc. All 
ri g hts reser ve d. 
© 2 0 1 9 T e va Bra n de d 
P har mace utical Pr o d ucts R & D, 
I nc. All ri g hts reser ve d. 
C orrecti o n  
F O O T E R P A G E 1 ( Ot her se cti o ns affecte d b y t his c h a n ge: all ot her f o oters)  
Pr ot oc ol A p pr o val Date 0 4 J u n 2 0 1 9  
Pr ot oc ol A p pr o val Date 0 4 J u n 
2 0 1 9  
F or matti n g u p date  
C O O R DI N A TI N G I N V E S TI G A T O R A G R E E M E N T  
Si g n at ure  Si g ne d p a ge is ret ai ne d i n t he 
s p o ns or’s offici al re p osit ory. 
Si g n at ure Si g ne d p a ge is 
ret ai ne d i n t he s p o ns or’s 
offici al re p osit ory.  
Clarificati o n  
2.  S T U D Y O B J E C TI V E S A N D E N D P OI N T S  
2. 2.  E x pl or at or y O bjecti ve a n d E n d p oi nts ( Ot her secti o ns affecte d b y t his c h a n ge: Secti o n 6. 1. 9., 
Secti o n  9. 5. 3. a n d A p pe n di x  B)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.  S T U D Y D E SI G N  
3. 1.   Ge ner al St u d y Desi g n a n d St u d y Sc he m atic Di a gr a m  
T he patie nt f ulfills t he f oll o wi n g criteria 
f or E M i n pr os pecti vel y c ollecte d baseli ne 
i nf or mati o n d uri n g t he 2 8-da y baseli ne 
T he patie nt f ulfills t he 
f oll o wi n g criteria f or E M i n 
pr os pecti vel y c ollecte d 
C orrecti o n t o ali g n wit h scree ni n g 
criteria  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 1 5  
 
Ori gi n al te xt wit h c h a n ges s h o w n 
Ne w w or di n g  
Re as o n/j ustific ati o n f or c h a n ge  
peri o d:  
•  
hea dac he occ urri n g ≥4 6  da ys b ut 
< 1 5  
baseli ne i nf or mati o n d uri n g t he 
2 8 -da y baseli ne peri o d:  
1.  hea da c he occ urri n g 
≥4  da ys b ut < 1 5  
3. 5  Sc he d ule of St u d y Pr o ce d ures a n d Assess me nts  
k 
T his is a re q uire d pr oce d ure f or 
u nsc he d ule d visits. See f urt her details i n  
A p pe n di x B .  
k 
T his is a re q uire d 
pr oce d ure f or u nsc he d ule d 
visits. See f urt her details i n  
A p pe n di x B .  
Clarificati o n  
4.  S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  
4. 1.  P atie nt I ncl usi o n Criteri a  
l. [ Re visi o n 1] T he patie nt d e m o nstrate d 
c o m plia nce wit h t he electr o ni c hea dac he 
diar y d uri n g t he 2 8 -da y baseli ne  peri o d b y 
e ntr y of hea dac he data o n a mi ni m u m of 
2 4 da ys c u m ulati ve d uri n g t he 2 8 -da y 
baseli ne  peri o d ( ~ 8 5  7 5 % diar y 
c o m plia nce).  
[ Re visi o n 1] T he patie nt 
de m o nstrate d c o m plia nce wit h 
t he electr o nic hea dac he diar y 
d uri n g t he 2 8 -da y baseli ne  
peri o d  b y e ntr y of hea dac he 
data o n a mi ni m u m of 2 4 da ys 
c u m ulati ve d uri n g t he 2 8 -da y 
baseli ne  peri o d ( ~ 7 5 % diar y 
c o m plia nce).  
A dj uste d c o m plia nce criteria f or 
patie nt p o p ulati o n nee ds  
6.  A S S E S S M E N T O F E F FI C A C Y  
6. 1.  Assess me nts of Effic ac y  
6. 1. 1.  
Electr o nic He a d ac he Di ar y  
A p pr o xi matel y 8 5  7 5 % c o m plia nce is 
nee de d after t he ra n d o mizati o n peri o d. 
Site pers o n nel will m o nit or patie nt’s 
c o m plia nce t hat a p pr o xi matel y 8 5  7 5 % 
diar y e ntr y is met d uri n g t he d o u ble -bli n d 
treat me nt p hase a n d o pe n-la bel e xte nsi o n 
p hase . 
A p pr o xi matel y 7 5 % 
c o m plia nce is nee de d after t he 
ra n d o mizati o n peri o d. Site 
pers o n nel will m o nit or 
patie nt’s c o m plia nce t hat 
a p pr o xi matel y 7 5 % diar y e ntr y 
is met d uri n g t he d o u ble-bli n d 
treat me nt p hase a n d o pe n-la bel 
e xte nsi o n p hase . 
A dj uste d c o m plia nce cr iteria f or 
patie nt p o p ulati o n nee ds  
6. 1. 9. W or k Pr o d ucti vit y a n d Acti vit y I m p air me nt Q uesti o n n aire Ge ner al He alt h V 2. 0  ( Ot her secti o ns 
affecte d b y t his c h a n ge: Secti o n 1 5.)  
P atie nts will c o m plete t he 
W P AI: MI G R AI N E V 2. 0 at t he ti me 
p oi nts detaile d i n T a ble 4. T he 
W P AI: MI G R AI N E q uesti o n naire is use d 
t o assess t he effect of hea dac he o n a 
patie nt’s a bilit y t o w or k a n d perf or m 
re g ular acti vities. 
T he ge neric versi o n of t he W P AI 
q uesti o n naire meas ures t he o verall effect 
of healt h o n pr o d ucti vit y at w or k a n d  
dail y acti vities. T he s pecific healt h 
pr o ble ms versi o n of t he W P AI 
q uesti o n naire all o ws i n vesti gat ors t o 
T he ge neric versi o n of t he 
W P AI q uesti o n naire meas ures 
t he o verall effect of healt h o n 
pr o d ucti vit y at w or k a n d dail y 
acti vities. T he s pecif ic healt h 
pr o ble ms versi o n of t he W P AI 
q uesti o n naire all o ws 
i n vesti gat ors t o attri b ute 
pr o d ucti vit y a n d acti vit y 
i m pair me nt iss ues t o s pecific 
healt h c o n diti o ns. After t he 
e m pl o y me nt stat us of a 
res p o n de nt is i de ntifie d, 3 o pe n 
e n de d q uesti o ns are as ke d 
T o select a n e q ui vale nt t o ol wit h 
m ore a vaila ble la n g ua ges  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 1 6  
 
Ori gi n al te xt wit h c h a n ges s h o w n 
Ne w w or di n g  
Re as o n/j ustific ati o n f or c h a n ge  
attri b ute pr o d ucti vit y a n d acti vit y 
i m pair me nt iss ues t o s pecific healt h 
c o n diti o ns. After t he e m pl o y me nt stat us 
of a res p o n de nt is i de ntifie d, 3 o pe n  e n de d 
q uesti o ns are as ke d c o ncer ni n g ( 1) h o urs 
a bse nt fr o m w or k d ue t o healt h pr o ble ms 
( or s pecific c o n diti o n), ( 2) h o urs a bse nt 
fr o m w or k d ue t o ot her reas o ns, a n d ( 3) 
h o urs act uall y w or ke d. T w o a d diti o nal 
q uesti o ns are i ncl u de d t hat as k a b o ut t he 
i m pact of healt h o n pr o d ucti vit y, 1 
c o ncer ni n g pr o d ucti vit y at w or k a n d t he 
ot her c o ncer ni n g dail y acti viti es o utsi de 
of w or k. T he res p o nse f or mat of eac h 
ite m of t he W P AI q uesti o n naire c o nsists 
of a n 1 1 -p oi nt scale ra n gi n g fr o m 0 ( n o 
i m pair me nt) t o 1 0 (c o m plete i m pair me nt) 
(Reill y, 1 9 9 3 ).  
P atie nts will c o m plete t he W P AI 
q uesti o n naire at t he ti me p oi nts detaile d i n 
T a ble 4 . 
c o ncer ni n g ( 1) h o urs a bse nt 
fr o m w or k d ue t o healt h 
pr o ble ms ( or s pecific 
c o n diti o n), ( 2) h o urs a bse nt 
fr o m w or k d ue t o ot her 
reas o ns, a n d ( 3) h o urs act uall y 
w or ke d. T w o a d diti o nal 
q uesti o ns are i ncl u de d t hat as k 
a b o ut t he i m pact of healt h o n 
pr o d ucti vit y, 1  c o ncer ni n g 
pr o d ucti vit y at w or k a n d t he 
ot her c o ncer ni n g dail y 
acti vities o utsi de of w or k. T he 
res p o nse f or mat of eac h ite m of 
t he W P AI q uesti o n naire 
c o nsists of a n 1 1 -p oi nt scale 
ra n gi n g fr o m 0 ( n o 
i m pair me nt) t o 1 0 (c o m plete 
i m pair me nt) ( Reill y, 1 9 9 3).  
P atie nts will c o m plete t he 
W P AI q uesti o n naire at t he ti me 
p oi nts detaile d i n T a ble 4.  
7.  A S S E S S M E N T O F S A F E T Y  
7. 8.  Electr o nic C ol u m bi a -S uici d e Se verit y R ati n g Sc ale ( Ot her secti o ns affecte d b y t his c h a n ge: Secti o n 2. 1., 
Secti o n  9. 7., Secti o n 1 5., a n d A p pe n di x B)  
7. 8.  Electr o nic C ol u m bi a -S uici d e 
Se verit y R ati n g Sc ale Assess me nt of 
S uici d alit y  
7. 8.  Electr o nic C ol u m bi a -
S uici de Se verit y R ati n g Sc ale  
T o s pecif y w hic h t o ol t o use i n 
a d diti o n t o cli nical j u d g me nt of 
q ualifie d ps yc hiatrist  
S uici dalit y will b e assesse d a A s part of 
t he o verall safet y e val uati o n, w hic h will 
be assesse d at t he ti me p oi nts i n dicate d i n  
T a ble  4 . t he electr o nic C ol u m bia -S uici de 
Se verit y Rati n g Scale (e C -S S R S ) ( P os ner 
et al, 2 0 1 1) will be use d i n c o nj u ncti o n 
wit h a q ualifie d ps yc hiatrist’s cli nical 
j u d g me nt t o assess t he patie nt’s s uici dal 
i deati o n (se verit y a n d i nte nsit y) a n d 
be ha vi or. T he e C -S S R S Lifeti me  versi o n 
will b e c o m plete d b y t he patie nt at visit 1, 
a n d t he e C -S S R S Si nce Last Visit versi o n 
will b e c o m plete d b y t he patie nt at all 
ot her ti me p oi nts, as descri be d i n T a ble  4  
A n y p ositi ve fi n di n gs o n t he e C -S S R S 
Si nce Last Visit versi o n re q uire 
e val uati o n b y a q ualifie d ps yc hiatrist  A 
q ualifie d ps yc hiatrist will assess t he 
patie nts. A n y p ositi ve fi n di n gs i n t he 
assess me nt re q uire e val uati o n b y a 
p h ysicia n or d oct oral le vel ps yc h ol o gist 
f or p ote ntial e xcl usi o n a n d/ or 
disc o nti n uati o n fr o m t he st u d y.  
As part of t he o verall safet y 
e val uati o n t he electr o nic 
C ol u m bia -S uici de S e verit y 
Rati n g Scale (e C -S S R S) 
(P os ner et al, 2 0 1 1 ) will be 
use d i n c o nj u ncti o n wit h a 
q ualifie d ps yc hiatrist’s cli nical 
j u d g me nt t o assess t he patie nt’s 
s uici dal i deati o n (se verit y a n d 
i nte nsit y) a n d be ha vi or. T he 
e C-S S R S Lifeti me  versi o n will 
be c o m plete d b y t he patie nt at 
visit 1, a n d t he e C -S S R S Si nc e 
Last Visit versi o n will be 
c o m plete d b y t he patie nt at all 
ot her ti me p oi nts, as descri be d 
i n T a ble  4 . A n y p ositi ve 
fi n di n gs o n t he e C-S S R S Si nc e 
Last Visit versi o n re q uire 
e val uati o n b y a q ualifie d 
ps yc hiatrist  f or p ote ntial 
e xcl usi o n a n d/ or 
disc o nti n uati o n fr o m t he st u d y.  
T o s pecif y w hic h t o ol t o use i n 
a d diti o n t o cli nical j u d g me nt of 
q ualifie d ps yc hiatrist  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 1 7  
 
Ori gi n al te xt wit h c h a n ges s h o w n 
Ne w w or di n g  
Re as o n/j ustific ati o n f or c h a n ge  
A P P E N DI X B.   S T U D Y P R O C E D U R E S A N D A S S E S S M E N T S B Y VI SI T  
( Ot her secti o ns affecte d b y t his c h a n ge: Secti o n 2. 1., 2. 2., 3. 1., 3. 3., 4. 1., 4. 2., 5. 7., 5. 9., 7. 1. 2., 7. 4. 1., 9. 5. 1. t o 
9. 5. 3., 9. 5. 4. 1, a n d 9. 5. 4. 3.)  
1. Pr o ce d ures f or Scree ni n g ( Visit  1, 
D a ys  -2 8 t o -1 [ + 3 d a y wi n d o w]) 
1. Pr oce d ures f or Scree ni n g 
( Visit 1, D a ys  -2 8 t o -1)  
C orrecti o n  
3. Pr o ce d ures D uri n g A d mi nistr ati o n 
of I n vesti g ati o n al M e dici n al Pr o d uct 
( Visit 3, D a y 2 9 + ± 3 d a ys) 
( D o u ble-Bli n d Tre at me nt P h ase)  
3. Pr oce d ures D uri n g 
A d mi nistr ati o n of 
I n vesti g ati o n al M e dici n al 
Pr o d uct ( Visit  3, D a y 2 9 ± 3 
d a ys) ( D o u ble -Bli n d 
Tre at me nt P h ase)  
C orrecti o n  
4. Pr o ce d ures D uri n g A d mi nistr ati o n 
of I n vesti g ati o n al M e dici n al Pr o d uct 
( Visit 4, D a y 5 7 + ± 3 d a ys) 
( D o u ble-Bli n d Tre at me nt P h ase)  
4. Pr oce d ures D uri n g 
A d mi nistr ati o n of 
I n vesti g ati o n al M e dici n al 
Pr o d uct ( Visit  4, D a y 5 7  ± 3 
d a ys) ( D o u ble -Bli n d 
Tre at me nt P h ase)  
C orrecti o n  
O pe n -L a bel E xte nsi o n P h as e ( Visit  5, 
D a y 8 5 + ± 3  d a ys)  
O pe n -L a bel E xte nsi o n P h as e 
( Visit 5, D a y 8 5 ± 3  d a ys)  
C orrecti o n  
F oll o w -u p/ E n d of Tre at me nt/ E arl y 
Ter mi n ati o n ( Visit  6, D a y 1 6 9 + ± 3 
d a ys)  
F oll o w -u p/ E n d of 
Tre at me nt/ E arl y 
Ter mi n ati o n ( Visit  6, D a y 1 6 9 
± 3 d a ys)  
C orrecti o n  
 
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 1 8  
 
A P P E N DI X  A.  C LI NI C A L L A B O R A T O RI E S A N D O T H E R 
D E P A R T M E N T S A N D I N S T I T U TI O N S 
S p o ns or’s A ut h orize d Re prese nt ati ve  
 
 
 
T e va Bra n de d P har mace utical Pr o d ucts R & D, I nc.  
Cell: 
 
 
Le g al Re prese nt ati ve of t he S p o ns or i n t he E U  a n d 
C o nt a ct Pers o n  
 
 
 
Merc kle G m b H  
T el: 
 
 
S p o ns or’s M e dic al E x pert/ C o nt a ct P oi nt Desi g n ate d 
b y t he S p o ns or f or F urt her I nf o r m ati o n o n t he 
St u d y  
 
 
T e va Bra n de d P har mace utical Pr o d ucts R & D, I nc.  
T el: 
 a n d 
 
Cell: 
 
 
C o or di n ati n g I n vesti g at or  
 
 
 
 
 
 
 
T el: 
 
 
S p o ns or’s Re prese nt ati ve of Gl o b al P atie nt S afet y 
a n d P h ar m ac o vi gil a nce  
F or seri o us a d verse e v e nts: 
Se n d b y e mail t o t he l ocal safet y officer/c o ntract 
researc h or ga nizati o n ( L S O/ C R O). T he e mail a d dress 
will b e pr o vi de d i n t he seri o us a d verse e ve nt re p ort 
f or m. I n t he e ve nt of diffic ult y tra ns mitti n g t he f or m, 
c o ntact t he s p o ns or’s st u d y pers o n nel i de ntifie d a b o ve 
f or f urt her i nstr ucti o n. 
 
 
T e va P har mace utical I n d ustries Lt d.  
T el: 
 
Cell: 
 
 
C o ntr act Rese arc h Or g a niz ati o n  
P har mace utical Researc h Ass ociates, I nc.  
4 1 3 0 P ar kla ke A ve n ue  
S uite 4 0 0  
Ralei g h, N ort h Car oli na 2 7 6 1 2  
U S A  
Ce ntr al Cli nic al L a b or at or y  
P P D Gl o bal Ce ntral La b orat ories  
2 T esse neer Dri ve  
Hi g hla n d Hei g hts, K Y 4 1 0 7 6  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 1 9  
 
Ce ntr al Electr o c a r di o gr a m E v al u ati o n  
e Researc h T ec h n ol o g y, I nc.  
1 8 1 8 Mar ket Street  
S uite 1 0 0 0  
P hila del p hia, P A 1 9 1 0 3  
U S A  
Bi o a n al ytic al P h ar m ac o ki netics E v al u ati o n  
N ot a p plica ble  
Bi o a n al ytic al I m m u n o ge nicit y E v al u ati o n  
N ot a p plica ble  
P h ar m ac o ge n o mics/ Bi o m ar ker E v al u ati o n  
N ot a p plica ble  
I nter a cti ve res p o nse tec h n ol o g y ve n d or 
P are xel H o use, Castle W harf, 4 Ca nal St.  
N otti n g ha m N G 1 7 E h  
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 2 0  
 
A P P E N DI X  B.  S T U D Y P R O C E D U R E S A N D  A S S E S S M E N T S B Y VI SI T  
1.  Pr o ce d ures f or Scree ni n g ( Visit  1, D a ys  -2 8 t o -1)  
T he scree ni n g visit ( V 1 ) will ta ke place n ot m ore t ha n 2 8 ( + 3) d a ys bef ore t he ra n d o mizati o n 
visit ( visit  2) . T he f oll o wi n g pr oce d ures will be perf or me d at visit  1:  
•  o btai n writte n i nf or me d c o nse nt bef ore a n y st u d y -relate d pr oce d ures are perf or me d 
•  re vie w i ncl usi o n a n d e x cl usi o n criteria 
•  re vie w me dical a n d ps yc hiatric hist or y 
•  rec or d de m o gra p hic c haracteristics 
•  re vie w pri or m e dicati o ns a n d treat me nt hist or y 
•  perf or m f ull p h ysical e x a mi nati o n (i ncl u di n g hei g ht a n d wei g ht)  
•  perf or m 1 2 -l ea d el ectr ocar di o gra m ( E C G) 
•  perf or m vital si g ns meas ure me nts  
•  perf or m safet y la b orat or y assess me nts  
•  perf or m ser u m beta -h u m a n c h ori o nic g o na d otr o pi n ( β -H C G) pre g na nc y t est (f or 
w o me n of c hil d -beari n g p ote ntial  a n d w o me n t h o u g ht t o be p ost me n o pa us al ) at t he 
scree ni n g visit ( V 1) a n d f ollicle-sti m ulati n g h or m o ne test (f or w o m e n t h o u g ht t o be 
p ost me n o pa usal)  
•  i nf or m patie nts of st u d y restricti o ns a n d c o m plia nce re q uir e me nts 
•  c o m pl ete Mi ni Me ntal State E x a mi nati o n  
•  c o m plete Patie nt Healt h Q uesti o n naire -9  ( P H Q-9)  
•  c o m plete t he e C-S S R S Lifeti me  versi o n  (use d i n c o nj u ncti o n wit h q ualifie d 
cli nicia n’s cli nical j u d g me nt  t o assess t he patie nt’s s uici dal i deati o n [se verit y a n d 
i nte nsit y] a n d b e ha vi or ) 
•  pr o vi de electr o nic hea dac he diar y  
•  c o m plete electr o nic hea d ac he diar y e ntries  
•  perf or m a d v erse e ve nts a n d healt h care res o urce utilizati o n i n q uir y  
•  perf or m c o n c o mita nt me dicati o n a n d t hera p y i n q uir y  
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 2 1  
 
2.  Pr o ce d ures Bef ore A d mi nistr ati o n of I n vesti g ati o n al Me dici n al Pr o d uct(s) 
( R a n d o miz ati o n [ Visit 2, D a y 1 + 3 d a ys]) ( D o u ble -Bli n d Tre at me nt P h ase)  
Patie nts w h o meet t he i ncl usi o n a n d e x cl usi o n criteria at visit  1 will c o nti n ue t o visit  2, w he n 
baseli ne assess me nts will be c o n d ucte d.  
T he f oll o wi n g pr oc e d ures will be perf or me d at visit  2:  
•  re vie w i ncl usi o n a n d e x cl usi o n criteria 
•  assi g n ra n d o mizati o n/treat me nt n u m bers a n d e nt er i n t he electr o nic cas e re p ort f or m 
(e C R F) 
•  perf or m p h ysic al e x a mi nati o n  
•  perf or m 1 2 -l ea d E C G 
•  perf or m vital si g ns meas ure me nt  
•  perf or m  safet y la b orat or y assess me nts 
•  perf or m uri n e β -H C G pre g n a nc y test (f or w o me n of c hil d -beari n g p ot e ntial ) 
•  re vie w st u d y c o m plia nce 
•  c o m plete t he e C-S S R S Si nce Last Visit versi o n  ( use d i n c o nj u ncti o n wit h q ualifie d 
cli nicia n’s cli nical j u d g me nt t o assess t he p atie nt’s s uici dal i deati o n [se verit y a n d 
i nte nsit y] a n d b e ha vi or)  
•  c o m plete Ha milt o n De pressi o n Rati n g Scale -1 7 ite ms ( H A M -D  1 7) ( q ualifie d staff 
me m ber t o a d mi nister  a n d rec or d ) 
•  c o m plete Ha milt o n A n xiet y Scale  ( H A M-A) ( q ualifie d staff me m ber t o a d mi nister 
a n d rec or d) 
•  c o m plete 6 -ite m Hea dac he I m p act T est ( HI T-6)  
•  c o m plete Cli nical Gl o bal I m pr essi o n -Se verit y ( C GI -S)  
•  c o m plete Mi grai ne -S pecific Q ualit y of Life ( M S Q o L)  
•  c o m plete W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Q uesti o n naire Ge neral Healt h 
( W P AI-G H)  
•  c o m plete electr o nic hea d ac he diar y 
•  re vie w el ectr o nic h ea dac he diar y 
•  perf or m a d v erse e ve nts a n d healt h care res o urce utilizati o n i n q uir y  
•  dis pe nse i n vesti gati o nal me dici nal pr o d uct (I M P)  
•  patie nt self -a d mi nistrati o n of I M P  
•  assess f or h y perse nsiti vit y/ a n a p h yl a xis  
•  perf or m c o n c o mita nt me dicati o n a n d t hera p y i n q uir y  
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 2 2  
 
3.  Pr o ce d ures D uri n g A d mi nistr ati o n of I n vesti g ati o n al Me dici n al Pr o d uct ( Visit  3, 
D a y 2 9 ± 3 d a ys) ( D o u ble -Bli n d Tre at me nt P h ase)  
T he f oll o wi n g pr oce d ures/assess me nts will be perf or me d at visit 3:  
•  perf or m p h ysic al e x a mi nati o n  
•  perf or m 1 2 -l ea d E C G 
•  perf or m vital si g ns meas ure me nt  
•  perf or m safet y la b orat or y assess me nts  
•  perf or m uri n e β -H C G pre g n a nc y test (f or w o me n of c hil d -beari n g p ot e ntial)  
•  re vie w st u d y c o m plia nce 
•  c o m plete P H Q -9  
•  c o m plete t he e C-S S R S Si nce Last V isit versi o n ( use d i n c o nj u ncti o n wit h q ualifie d 
cli nicia n’s cli nical j u d g me nt t o assess t he patie nt’s s uici dal i deati o n [se verit y a n d 
i nte nsit y] a n d b e ha vi or)  
•  c o m plete H A M -D  1 7 ( q ualifie d staff me m b er t o a d mi nister a n d rec or d ) 
•  c o m plete H A M -A ( q ualifie d staff me m ber t o a d mi nister a n d rec or d ) 
•  c o m plete HI T -6  
•  c o m plete C GI -S  
•  c o m plete M S Q o L  
•  c o m plete W P AI -G H  
•  c o m plete electr o nic hea d ac he diar y  
•  re vie w el ectr o nic h ea dac he diar y 
•  perf or m a d v erse e ve nts a n d healt h care res o urce utilizati o n i n q uir y  
•  dis pe nse I M P  
•  patie nt self -a d mi nistrati o n of I M P  
•  assess f or h y perse nsiti vit y/ a n a p h yl a xis  
•  perf or m c o n c o mita nt me dicati o n a n d t hera p y i n q uir y  
 
4.  Pr o ce d ures D uri n g A d mi nistr ati o n of I n vesti g ati o n al Me dici n al Pr o d uct ( Visit  4, 
D a y 5 7 ± 3 d a ys) ( D o u ble -Bli n d Tre at me nt P h ase)  
T he f oll o wi n g pr oce d ures/assess me nts will be perf or me d at visit 4:  
•  perf or m p h ysic al e x a mi nati o n  
•  perf or m 1 2 -l ea d E C G 
•  perf or m vital si g ns meas ure me nt  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 2 3  
 
•  perf or m safet y la b orat or y assess me nts  
•  perf or m uri n e β -H C G pre g n a nc y test (f or w o me n of c hil d -beari n g p ot e nti al) 
•  re vie w st u d y c o m plia nce 
•  c o m plete P H Q -9  
•  c o m plete t he e C-S S R S Si nce Last Visit versi o n  ( use d i n c o nj u ncti o n wit h q ualifie d 
cli nicia n’s cli nical j u d g me nt t o assess t he patie nt’s s uici dal i deati o n [se verit y a n d 
i nte nsit y] a n d b e ha vi or)  
•  c o m plete H A M -D  1 7 ( q u alifie d staff me m b er t o a d mi nister a n d rec or d ) 
•  c o m plete H A M -A ( q ualifie d staff me m ber t o a d mi nister a n d rec or d ) 
•  c o m plete HI T -6  
•  c o m plete C GI -S  
•  c o m plete M S Q o L  
•  c o m plete W P AI -G H  
•  c o m plete electr o nic hea d ac he diar y  
•  re vie w el ectr o nic h ea dac he diar y 
•  perf or m a d v erse e ve nts a n d healt h care res o urce utilizati o n i n q uir y  
•  dis pe nse I M P  
•  patie nt self -a d mi nistrati o n of I M P  
•  assess f or h y perse nsiti vit y/ a n a p h yl a xis  
•  perf or m c o n c o mita nt me dicati o n a n d t hera p y i n q uir y  
 
5.  O pe n -L a bel E xte nsi o n P h ase ( Visit  5, D a y 8 5 ± 3  d a ys)  
T h e f oll o wi n g pr oce d ures/assess me nts will be perf or me d at visit 5:  
•  perf or m p h ysic al e x a mi nati o n  
•  perf or m 1 2 -l ea d el ectr ocar di o gra m 
•  perf or m vital si g ns meas ure me nt  
•  perf or m safet y la b orat or y assess me nts  
•  perf or m uri n e β -H C G pre g n a nc y test (f or w o me n of c hil d -bea ri n g p ot e ntial) 
•  re vie w st u d y c o m plia nce 
•  c o m plete P H Q -9  
•  c o m plete t he e C-S S R S Si nce Last Visit versi o n  ( use d i n c o nj u ncti o n wit h q ualifie d 
cli nicia n’s cli nical j u d g me nt t o assess t he patie nt’s s uici dal i deati o n [se verit y a n d 
i nte nsit y] a n d b e ha vi or)  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 2 4  
 
•  c o m plete H A M -D  1 7 ( q ualifie d staff me m b er t o a d mi nister a n d rec or d ) 
•  c o m plete H A M -A ( q ualifie d staff me m ber t o a d mi nister a n d rec or d ) 
•  c o m plete HI T -6  
•  c o m plete C GI -S  
•  c o m plete M S Q o L  
•  c o m plete W P AI -G H  
•  c o m plete electr o nic hea d ac he diar y  
•  re vie w el ectr o nic h ea dac he diar y 
•  perf or m a d v erse e ve nts a n d healt h care res o urce utilizati o n i n q uir y  
•  dis pe nse of I M P  
•  patie nt self -a d mi nistrati o n of I M P  
•  assess f or h y perse nsiti vit y/ a n a p h yl a xis  
•  perf or m c o n c o mita nt me dicati o n a n d t hera p y i n q uir y  
 
6.  F oll o w -u p/ E n d of Tre at me nt/ E arl y Ter mi n ati o n ( Visit  6, D a y 1 6 9 ± 3 d a ys)  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d at t he f oll o w -u p visit 6 or 
d uri n g t he earl y ter mi nati o n visit:  
•  perf or m p h ysic al e x a mi nati o n  
•  perf or m 1 2 -l ea d el ectr ocar di o gram  
•  perf or m vital si g ns meas ure me nt  
•  perf or m safet y la b orat or y assess me nts  
•  perf or m uri n e β -H C G pre g n a nc y test (f or w o me n of c hil d -beari n g p ot e ntial ) 
•  re vie w st u d y c o m plia nce 
•  c o m plete P H Q -9  
•  c o m plete t he e C-S S R S Si nce Last Visit versi o n  ( use d i n c o nj u ncti o n wit h q ualifie d 
cli nicia n’s cli nical j u d g me nt t o assess t he patie nt’s s uici dal i deati o n [se verit y a n d 
i nte nsit y] a n d b e ha vi or)  
•  c o m plete H A M -D  1 7 ( q ualifie d staff me m b er t o a d mi nister a n d rec or d ) 
•  c o m plete H A M -A ( q ualifie d staff me m ber t o a d mi nister a n d rec or d ) 
•  c o m plete HI T -6  
•  c o m plete C GI -S  
•  c o m plete M S Q o L  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 2 5  
 
•  c o m plete W P AI -G H  
•  c o m plete electr o nic hea d ac he diar y  
•  re vie w el ectr o nic h ea dac he diar y 
•  ret ur n hea dac h e diar y d e vice 
•  perf or m a d v erse e ve nts a n d healt h care res o urce utilizati o n i n q uir y  
•  assess f or h y perse nsiti vit y/ a n a p h yl a xis  
•  perf or m c o n c o mita nt me dicati o n a n d t hera p y i n q uir y  
I n t he cas e of earl y ter mi nati o n, site pers o n nel s h o ul d perf or m a f oll o w-u p p h o ne call t o e ns ure 
t he patie nt d oes n ot re p ort s uici dal i deati o n or be h a vi or. P h o ne calls s h o ul d be perf or me d o nce 
wee kl y f or 2 wee ks. If si g ns of s uici d alit y are i de ntifie d d uri n g t he f oll o w -u p p h o ne call, t he site 
pers o n nel s h o ul d pr o vi de directi o n t o t he patie nt f or f urt her ps yc hiatric e val uati o n at t he site or at 
a c o m m u nit y ps yc hiatrist refere nce d b y t he site.  R el e va nt e mer ge nc y ps yc hiatric care ser vices 
s h o ul d be n otifie d i n t he e ve nt t hat t he patie nt is d ee me d t o be a t hreat t o t h e mself.  
 
7.  U nsc he d ule d Visits  
A n u nsc he d ule d visit ma y be p erf or me d at a n y ti me d uri n g t he st u d y (i e, pre -treat me nt, 
d o u ble -bli n d treat me nt p hase, o pe n -l a bel e xte nsi o n, a n d f oll o w-u p peri o d) at t he patie nt’s 
re q uest a n d as dee me d n ecessar y b y t he i n vesti gat or. T he date a n d reas o n f or t he 
u nsc he d ule d visit will be rec or de d o n t he e C R F as well as a n y ot her d ata o btai ne d fr o m 
pr oce d ures a n d as s ess me nts. 
Pr oce d ures p erf or me d d uri n g u nsc h e d ule d visits i ncl u de t he f oll o wi n g:  
•  re vie w st u d y c o m plia nce 
•  re vie w el ectr o nic h ea dac he diar y  
•  perf or m a d v erse e ve nt a n d healt h care res o urce utilizati o n i n q uir y  
•  perf or m c o n c o mita nt me dicati o n a n d t hera p y i n q uir y  
Ot her pr oce d ures a n d ass ess me nts ma y b e perf or me d at t he discreti o n of t he i n vesti gat or a n d 
s h o ul d be d oc u me nte d i n t he e C R F. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 2 6  
 
A P P E N DI X  C.  Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
Pr ot oc ol A me n d me nts a n d Pr ot oc ol D e vi ati o ns  
Pr ot oc ol A me n d me nts  
N o c ha n ges fr o m t he fi nal a p pr o ve d (si g ne d) pr ot o c ol will be i nitiate d wit h o ut t he pri or writte n 
a p pr o val or fa v ora ble o pi ni o n of a writte n a me n d me nt b y t he I n d e pe n d e nt Et hics 
C o m mittee/I nstit uti o nal Re vie w B o ar d (I E C/I R B)  a n d nati o nal a n d l ocal c o m pete nt a ut h orities, 
as a p plica ble , e x ce pt w he n necessar y t o a d dress i m me diate safet y c o ncer ns t o t he patie nts or 
w he n t he c h a n ge i n v ol ves o nl y n o ns u bsta ntial l o gistics or a d mi nistrati o n. T he pri nci pal 
i n vesti gat or at eac h i n vesti gati o nal ce nt er, t he c o or di nati n g i n vesti gat or (if a p plica ble), a n d t he 
s p o ns or will si g n t he pr ot oc ol a me n d me nt. 
I m p ort a nt Pr ot oc ol De vi ati o ns 
A n y d e viati o n fr o m t he pr ot oc ol t hat affects, t o a si g nifica nt d e gree, (a) t he safet y, p h ysical, or 
me ntal i nte grit y of t he p atie nts i n t he st u d y a n d/ or ( b) t he scie ntific v al ue of t he st u d y will be 
c o nsi dere d a n i m p orta nt pr ot oc ol de viati o n . I m p orta nt pr ot oc ol de viati o ns ma y i ncl u d e n o n -
a d here n ce o n t he p art of t he patie nt, t he i n vesti gat or, or t he s p o ns or t o pr ot oc ol -s pecific i n cl usi o n 
a n d e x cl usi o n criteria, pri mar y o bj ec ti ve varia ble criteria, or G o o d Cli nical Practice ( G C P) 
g ui deli nes; n o nc o m plia n ce t o I M P a d mi nistrati o n; a n d use of pr o hi bite d m e dicati o ns. I m p orta nt 
pr ot oc ol de viati o ns  will be i de ntifie d a n d rec or de d b y i n vesti gati o nal ce nter pers o n nel o n t he 
electr o nic case re p ort f or m (e C R F). All i m p orta nt pr ot oc ol de viati o ns  will be re p ort e d t o t he 
res p o nsi ble I E C/I R B, as re q uire d. 
W he n a n i m p orta nt pr ot oc ol de viati o n  is re p orte d, t he s p o ns or will deter mi ne w het her t o 
wit h dra w t he patie nt fr o m t he st u d y or per mit t he p atie nt t o c o nti n ue i n t he st u d y, wit h 
d oc u me nte d a p pr o val fr o m t he me dical e x pert. T he decisi o n will be base d o n e ns uri n g t h e safet y 
of t he patie nt a n d preser vi n g t he i nte grit y of t he st u d y.  
C ha n ges i n t he i n cl usi o n a n d e x cl usi o n criteria of t he pr ot oc ol a re n ot  pr os pecti vel y gra nte d b y 
t he s p o ns or. If i n vesti gati o nal ce nter p ers o n nel lear n t hat a patie nt w h o di d n ot meet t he pr ot oc ol 
i ncl usi o n a n d e x cl usi o n criteria was e ntere d i n a st u d y, t he y m ust i m me diatel y i nf or m t he 
s p o ns or of t he i m p orta nt pr ot oc ol de viati o n . If s uc h patie nt has alrea d y c o m plete d t he st u d y or 
has wit h dra w n earl y, n o acti o n will be ta ke n b ut t he de viati o n  will be rec or de d.  
I nf or m ati o n t o St u d y Pers o n nel 
T he i n vesti gat or is res p o nsi ble f or gi vi n g i nf or m ati o n a b o ut t he st u d y t o all pers o n nel me m bers 
i n v ol ve d i n t he st u d y or i n a n y ele me nt of p atie nt ma na ge me nt, b ot h bef ore starti n g t he st u d y a n d 
d uri n g t he c o urse of t he st u d y (e g, w he n n e w pers o n nel bec o me i n v ol ve d). T he i n vesti gat or m ust 
e ns ure t hat all st u d y pers o n nel are q u alifie d  b y e d ucati o n, e x perie nce, a n d trai ni n g t o perf or m 
t heir s pecific tas k. T h ese st u d y pers o n nel me m bers m ust be liste d o n t he i n vesti gati o nal ce nter 
a ut h orizati o n f or m, w hic h i ncl u des a clear des cri pti o n of eac h pers o n nel m e m ber’s 
res p o nsi bilities. T his list m ust be u p date d t hr o u g h o ut t he st u d y, as necessar y.  
T he st u d y m o nit or is res p o nsi ble f or e x plai ni n g t he pr ot oc ol t o all st u d y p ers o n nel, i ncl u di n g t he 
i n vesti gat or, a n d f or e ns uri n g t he y c o m pl y wit h t h e pr ot oc ol. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 2 7  
 
St u d y M o nit ori n g  
T o e ns ure c o m plia n ce wit h  G C P g ui deli nes, t he st u d y m o nit or or re pres e ntati ve is res p o nsi ble 
f or e ns uri n g t hat patie nts ha ve si g n e d t he i nf or m e d c o nse nt f or m a n d t he st u d y is c o n d u cte d 
acc or di n g t o a p plic a ble sta n dar d o perati n g pr oce d ures, t he pr ot oc ol, a n d ot her writte n 
i nstr uctio ns a n d re g ulat or y g ui deli nes.  
T he st u d y m o nit or is t he pri mar y ass ociati o n bet w ee n t he s p o ns or a n d t he i n vesti gat or. T he mai n 
res p o nsi bilities of t he st u d y m o nit or are t o visit t he i n vesti gat or bef ore, d uri n g, a n d after t h e 
st u d y t o e ns ure a d here nce t o t he pr ot oc ol, t hat all data are c orrectl y a n d c o m pletel y rec or de d a n d 
re p orte d, a n d t hat i nf or m e d c o nse nt is o btai ne d a n d rec or de d f or all patie nts bef ore t he y 
partici pate i n t he st u d y a n d w he n c ha n ges t o t he c o nse nt f or m are warra nte d, i n acc or da nce wit h 
I EC/I R B a p pr o vals.  
T he st u d y m o nit or will c o ntact t he i n vesti gat or a n d visit t he i n vesti gati o nal ce nter acc or di n g t o 
t he m o nit ori n g pla n. T he st u d y m o nit or will be per mitte d t o re vie w a n d verif y t he vari o us 
rec or ds (cas e re p ort f or ms a n d ot her perti ne nt s o urce data rec or ds, i ncl u di n g s pecific el ectr o nic 
s o urce d oc u m e nt relati n g t o t he st u d y) t o verif y a d here nce t o t he pr ot oc ol a n d t o e ns ure t he 
c o m plete ness, c o nsiste nc y, a n d acc urac y of t he d ata bei n g rec or de d.  
As part of t he s u per visi o n of st u d y pr o gress, ot her s p o ns or pers o n nel ma y, o n re q uest, 
acc o m pa n y t h e st u d y m o nit or o n visits t o t he i n vesti gati o nal ce nt er. T he i n vesti gat or a n d 
assisti n g pers o n n el m ust a gree t o c o o perate wit h t he st u d y m o nit or t o res ol ve a n y pr o ble ms, 
err ors, or p ossi ble mis u n dersta n di n gs c o ncer ni n g t he fi n di n gs det ecte d d uri n g t he c o urse of t hese 
m o nit ori n g visits or pr o vi de d i n f oll o w -u p writte n c o m m u nicati o n.  
A u dit a n d I ns pecti o n  
T he s p o ns or ma y a u dit t h e i n vesti gati o nal ce nter t o e val uate st u d y c o n d u ct a n d c o m plia nce wit h 
pr ot oc ols, sta n dar d o perati n g pr oce d ures, G C P g ui deli nes, a n d a p plica bl e re g ulat or y 
re q uire me nts. T h e s p o ns or’s Gl o bal Cli nical Q ualit y Ass ura n ce, i n de pe n de nt of Gl o bal S pecialt y 
De vel o p me nt, is res p o nsi ble f or deter mi ni n g t he nee d f or (a n d ti mi n g of) a n i n vesti gati o nal 
ce nter a u dit.  
T he i n vesti gat or m ust acce pt t hat c o m pete nt a ut h orities a n d s p o ns or re prese ntati ves ma y c o n d uct 
i ns pecti o ns a n d a u dits t o verif y c o m plia nce wit h G C P g ui deli nes. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 2 8  
 
A P P E N DI X  D.  E T HI C S  
I nf or me d C o nse nt 
T he i n vesti gat or, or a q u alifie d pers o n desi g n ate d b y  t he i n vesti gat or, s h o ul d f ull y i nf or m t he 
patie nt of all perti ne nt as pects of t he st u d y, i ncl u di n g t he writte n i nf or mati o n a p pr o ve d b y t he 
I n d e pe n de nt Et hics C o m mittee/I nstit uti o nal Re vie w B oar d (I E C/I R B). All writte n a n d oral 
i nf or mati o n a b o ut t he st u d y will be pr o vi de d i n a la n g u a ge as n o ntec h nical as practical t o be 
u n derst o o d b y t h e patie nt. T he patie nt s h o ul d be gi ve n a m ple ti me a n d o p p ort u nit y t o i n q uire 
a b o ut t he details of t he st u d y a n d t o d eci de w h et her or n ot t o partici pate i n t he st u d y. T h e a b o v e 
s h o ul d be detaile d i n t he s o urce d oc u m e nts. 
Writte n i nf or me d c o nse nt will be o btai ne d fr o m eac h patie nt bef ore a n y st u d y -s p ecific 
pr oce d ures or ass ess me nts are d o ne a n d aft er t he ai ms, met h o ds, a ntici pate d be nefits, a n d 
p ote ntial hazar ds are e x plai ne d. T he patie nt’s willi n g ness t o partici pate i n t he st u d y will be 
d oc u me nte d i n t he i nf or me d c o nse nt f or m, w hic h will be si g ne d a n d p ers o nall y dat e d b y t he 
patie nt a n d b y t he pers o n w h o c o n d ucte d t he i nf or me d c o nse nt disc ussi o n. T he i n vesti gat or will 
kee p t he o ri gi nal i nf or m e d c o nse nt f or ms, a n d c o pies will be gi ve n t o t he patie nts. It will als o be 
e x plai ne d t o t he patie nts t hat t he patie nt is free t o ref use p artici pati o n i n t he st u d y a n d free t o 
wit h dra w fr o m t he st u d y at a n y ti me wit h o ut prej u dice t o f ut ure tr eat me nt.  
F or C O VI D -1 9 u p dates, see A p pe n di x  P . 
C o m pete nt A ut h oriti es a n d I n de pe n de nt Et hics C o m mittees/I nstit uti o n al Re vie w B o ar ds  
Bef ore t his st u d y s tarts, t he pr ot oc ol will be s u b mitte d t o t he nati o nal c o m pete nt a ut h orit y a n d t o 
t he res pecti ve I E C/I R B f or re vie w. As re q uir e d, t he st u d y will n ot start at a gi v e n i n vesti gati o nal 
ce nter b ef ore t he I E C/I R B a n d c o m p ete nt a ut h orit y (as a p plica bl e) f or t h e i n vesti gati o nal ce nter 
gi ve writte n a p pr o val or a fa v ora ble o pi ni o n.  
C o nfi de nti alit y Re g ar di n g St u d y P atie nts  
T he i n vesti gat or m ust e ns ure t hat t he pri vac y of t he patie nts, i ncl u di n g t heir i de ntit y a n d all 
pers o nal me dic al i nf or mati o n, will be mai ntai ne d at  all ti mes. I n C R Fs a n d ot her d oc u me nts or 
i ma ge m aterial s u b mitte d t o t he s p o ns or, patie nts will be i de ntifie d n ot b y t heir na mes, b ut b y a n 
i de ntificati o n n u m ber. 
Pers o nal me dical i nf or m ati o n ma y b e re vie we d f or t he p ur p ose of patie nt safet y or f or verif yi n g 
data i n t he s o urce a n d t he e C R F. T his re vie w ma y be c o n d ucte d b y t h e st u d y m o nit or, pr o perl y 
a ut h orize d pers o ns o n be half of t he s p o ns or, Gl o b al Q ualit y Ass ura nce, or c o m pete nt a ut h orities. 
Pers o nal me dical i nf or m ati o n will al wa ys b e treate d as c o nfi d e ntial. 
Re gistr ati o n of t he Cli nic al St u d y  
I n c o m plia nce wit h nati o nal a n d l ocal r e g ulati o ns a n d i n acc or da nce wit h T e va sta n dar d 
pr oce d ures, t his cli nical st u d y will be re gistere d o n trial re gistr y we bsites.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 2 9  
 
A P P E N DI X  E.  BI R T H C O N T R O L M E T H O D S A N D P R E G N A N C Y 
T E S TI N G  
C o ntrace pti o n rec o m me n dati o ns a n d pre g na n c y testi n g s h o ul d e nc o m pass  all I M Ps as well as 
n o n -i n vesti gati o nal me di ci nal pr o d ucts, e g, b ac k gr o u n d t hera p y, a n d t he m eas ures t o be f oll o we d 
s h o ul d be base d o n t he m e dici nal pr o d uct wit h hi g hest ris k. 
Assess me nt of li keli h o o d of p ossi ble i nteracti o n b et wee n i n vesti gati o nal m e dici nal pr o d uct 
(I M P) or c o n c o mita nt me dicati o ns a n d h or m o nal c o ntrace pti o n s h o ul d be c o n d ucte d. H or m o nal 
c o ntrace pti o n ma y b e s us ce pti ble t o i nteracti o n wit h t he I M P, w hic h ma y re d uce t he eff icac y of 
t he c o ntrace pti o n met h o d, e g, c yt oc hr o me P 4 5 0 ( C Y P) 4 A i n d ucers.  
Dr u g i nteracti o n st u dies ha ve n ot bee n c o n d ucte d wit h fre ma nez u ma b. Li k e ot her t hera pe utic 
a nti b o dies, fre ma n ez u ma b is e x pecte d t o be pri maril y meta b olize d via pr ot e ol ytic cata b olis m. 
T heref ore, i nteracti o n wit h a n d i m pact o n dr u g meta b olizi n g e nz y mes (e g, C Y P is of or ms) is 
c o nsi dere d u nli kel y i n h u ma ns.  
I n a d diti o n, fre ma n ez u ma b is n ot e x pecte d t o i n directl y i nfl ue nce t he C Y P e nz y mes. I n ge neral, 
pr otei n pr o d ucts t hat are c yt o ki ne m o d ulat ors h a v e bee n re p orte d t o affect t he meta b olis m or 
dis p ositi o n of c o -a d mi nistere d me dicati o n b y alteri n g C Y P e nz y mes/tra ns p orters. 
Fre ma n ez u ma b is a n i m m u n o gl o b uli n G 2 is ot y pe t hat is directe d a gai nst a n o n -i m m u n ol o gic a n d 
s ol u ble ( n ot cell b o u n d) target. T h us, t he ris k of c yt o ki ne releas e is c o nsi dere d t o be l o w i n t he 
cli nical setti n g. F urt her m ore, fre ma nez u ma b was t este d f or sti m ulati o n of pr o -i nfla m mat or y 
c yt o ki ne rele ase i n h u ma n w h ole bl o o d ( St u d y 1 1 1 3 2 0). Fre ma nez u ma b di d n ot elicit si g nifica nt 
c yt o ki ne rele ase (t u m or n ecr osis fact or -α, i nterle u ki n -6, i nterfer o n -γ, or i nt erle u ki n -1 β) i n a n y 
d o n or i ncl u di n g at c o nce ntrati o ns u p t o 1 0 0  μ g/ m L. As s u c h, t here is n o reas o n t o s us pect t hat 
fre ma n ez u ma b ma y i nfl u e nce C Y P acti vit y. 
W o me n of n o n -c hil d -be a ri n g p ote nti al are defi ne d as:  
•  S ur gicall y ( d oc u me nte d h ysterect o m y, bilateral o o p h orect o m y, or bilateral 
sal pi n gect o m y) or c o n ge nitall y sterile 
•  P ost me n o pa usal  
P ost me n o p a us al w o me n:  
•  1  year p ost me n o pa us al ( n o me nses f or 1 2  m o nt hs wit h o ut a n alter nati ve m e dic al 
ca use pl us a n i ncreas e d c o nce ntrati o n of f ollicle sti m ulati n g h or m o ne [ F S H] of m ore 
t ha n 3 5 U/ L) i n w o me n n ot usi n g h or m o nal c o ntrace pti o n or h or m o nal r e place me nt 
t hera p y 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 3 0  
 
Descri pti o n of differe nt birt h c o ntr ol met h o ds  
Hi g hl y effecti ve birt h c o ntr ol met h o ds:  
Hi g hl y effecti ve birt h c o ntr ol met h o ds are met h o ds t hat ca n ac hi e ve a fail ure rat e of less t ha n 1 % 
per year w he n us e d c o nsiste ntl y a n d c orrectl y are c o nsi dere d. S uc h met h o ds i ncl u de t he 
f oll o wi n g: 
•  C o m bi ne d estr o ge n a n d pr o gest o ge n h or m o nal c o ntrace pti o n ( oral, i ntra va gi nal, 
tra ns der mal) ass ociate d wit h i n hi biti o n of o v ulati o n; t hese s h o ul d be i nitiate d at least 
7  da ys b ef ore t he first d ose of I M P  
•  Pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n ( oral, i njecta ble, or i m pla nta ble) ass ociate d 
wit h i n hi b iti o n of o v ulati o n; t hese s h o ul d be i nitiate d at least 7 da ys bef ore t he first 
d ose of I M P  
•  I ntr a uteri ne d e vice a n d i ntra uteri ne h or m o n e-releasi n g s yste m nee d t o be i n place at 
least 2 m o nt hs bef ore t he scree ni n g visit ( V 1). 
•  Bilateral t u bal occl usi o n  
•  Se x ual  a bsti ne nce is o nl y  c o nsi dere d a hi g hl y effecti ve met h o d if defi ne d as 
refrai ni n g fr o m heter ose x ual i nterc o urse i n t he d efi ne d peri o d. T he relia bilit y of 
se x ual a bsti ne nce nee ds t o be e val uat e d i n relati o n t o t he d urati o n of t he cli nical st u d y 
a n d t he preferre d a n d us u al lifest yle of t he patie nt.  
U n acce pt a ble birt h c o ntr ol met h o ds:  
Peri o dic a bsti ne nce (cal e n dar, s y m pt ot her mal, p ost -o v ulati o n met h o ds), wit h dra wal ( c oit us 
i nterr u pt us), s per mici des o nl y, a n d la ctati o nal a me n orr h oea m et h o d are n ot acce pta ble met h o ds 
of c o ntrace pti o n. Fe male c o n d o m a n d male c o n d o m s h o ul d n ot be use d t o get her.  
M ale c o ntr a ce pti o n  
Male patie nts m ust al wa ys use a c o n d o m i ncl u di n g vas ect o mize d me n if t heir part ners are of 
c hil d-beari n g p ote ntial . 
V asect o m y:  
Use of c o ntr ace pti ve m et h o d s als o a p plies t o vasect o mize d me n.  
Pre g n a nt fe m al e p art ners of m ale st u d y p artici p a nts:  
Male st u d y p artici pa nts m ust use c o n d o ms d uri n g i nterc o urse if t h eir fe m ale part ners are 
pre g na nt.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 3 1  
 
A P P E N DI X  F.  L O S T T O F O L L O W -U P  
A patie nt will be c o nsi dere d l ost t o f oll o w -u p if  he/s he re p eate dl y fails t o ret ur n f or sc h e d ule d 
visits a n d is u na ble t o be c o ntacte d b y t he i n v esti gati o nal ce nter.  
T he f oll o wi n g acti o ns m ust be ta ke n if a p atie nt f ails t o ret ur n t o t he i n vesti gati o nal ce nter f or a 
re q uire d st u d y visit: 
•  T he i n vesti gati o nal ce nter m ust atte m pt t o c o ntact t he patie nt a n d res c he d ul e t he 
misse d visit as s o o n as p ossi ble a n d c o u nsel t he p atie nt o n t he i m p orta nce of 
mai ntai ni n g t he assi g ne d visit sc he d ule a n d ascertai n w het her or n ot t he p atie nt 
wis hes t o a n d/ or s h o ul d c o nti n u e i n t he st u d y.  
•  I n cases i n w hi c h t he pati e nt is dee me d l ost t o f oll o w-u p, t he i n vesti gat or or desi g n ee 
m ust ma ke e ver y eff ort t o re gai n c o ntact wit h t he patie nt ( w here p ossi ble, 
3  d oc u me nte d atte m pts via 2 differe nt met h o ds [tele p h o ne, te xt, e mail, certif ie d letter, 
etc]). T hese c o nt act atte m pts s h o ul d be d oc u me nte d i n t he patie nt’s me dical rec or d.  
•  S h o ul d t he patie nt c o nti n ue t o be u nreac ha bl e, 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 wit h a pri mar y reas o n of “l ost t o f oll o w -u p.”  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 3 2  
 
A P P E N DI X  G.  P R E V E N TI V E MI G R AI N E M E DI C A TI O N S A L L O W E D 
F O R 3 0 % O F T H E S T U D Y  P O P U L A TI O N  A N D 
A N TI -D E P R E S S A N T M E DI C A TI O N S A L L O W E D F O R 
T H E W H O L E S T U D Y P O P U L A TI O N F O R T H E  
D U R A TI O N O F T H E S T U D Y   
T he use of u p t o 1 pr e ve nti ve mi grai ne m e dicati o n is all o we d f or t he d urati o n of t he st u d y f or u p 
t o 3 0 % of t he t otal p o p ulati o n of patie nts (see Secti o n 5. 7 ). 
Pre ve nti ve mi grai ne me dicati o ns all o we d f or t he d urati o n of t he st u d y s p ecificall y i n cl u de t he 
f oll o wi n g (if t he y were pre vi o usl y prescri be d f or mi grai ne or f or a n ot her i n dicati o n): 
•  beta -bl oc kers: ate n ol ol, pr o pra n ol ol, met o pr ol ol, na d ol ol, a n d ti m ol ol  
•  calci u m c ha n n el bl oc kers/ be nz oc ycl o h e pte nes: fl u narizi ne a n d piz otife n  
•  a nti de pressa nts: a mitri pt yli ne, ve nl afa xi ne, n ortri pt yli ne, a n d d ul o x eti ne 
•  a nti-e pile ptic me dicati o ns: t o pira mate, val pr oate, a n d di val pr oate  
Patie nts are n ot per mitte d t o use o na b ot uli n u mt o xi n A f or a n y i n dicati o n f or t he d urati o n of t he 
st u d y. 
A nti de pressa nt me dicati o ns all o we d f or t he w h ole st u d y p o p ulati o n f or t he d urati o n of t he st u d y 
s pecificall y i ncl u de t he f oll o wi n g (if t he y were pre vi o usl y prescri be d f or d e pressi o n or f or 
a n ot her i n dicati o n):  
•  selecti ve ser ot o ni n r e u pta ke i n hi bit ors  
− fl u o xeti ne 
− par o xeti ne  
− sertrali ne 
− cital o pra m  
− fl u v o x a mi ne 
− escital o pra m  
•  ser ot o ni n a n d n ore pi ne p hri ne re u pta ke i n hi bit ors  
− ve nlafa xi ne  
− d ul o x eti ne  
− des ve nlafa xi ne  
− mil naci pra n  
− le v o mil naci pra n 
•  tric ycli c a nti de pressa nts 
− a mitri pt yli n e  
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Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 3 3  
 
− desi pra mi ne  
− a m o x a pi ne  
− cl o mi pra mi ne  
− n ortri pt yli ne  
− i mi pra mi ne 
− pr otri pt yli ne  
− tri mi pra mi ne 
− d o x e pi n  
•  at y pic al a nti de pressa nts  
− b u pr o pi o n  
− mirtaza pi ne  
− traz o d o ne 
− v orti o x eti ne  
− vilaz o d o ne  
− fl u o x eti ne a n d ola nza pi ne 
 
Ma y o Cli nic. A nti de pressa nts: Selecti n g o ne t h at’s ri g ht f or y o u. A vaila ble at: 
htt ps:// w w w. ma y ocli nic. or g/ diseases -c o n diti o ns/ de pressi o n/i n -de pt h/a nti de pressa nts/art -
2 0 0 4 6 2 7 3. U p date d N o v e m ber 1 7, 2 0 1 7. Access e d Fe br uar y 2 2, 2 0 1 9.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 3 4  
 
A P P E N DI X  H.  C LI NI C A L C RI T E RI A F O R DI A G N O SI N G 
A N A P H Y L A XI S  
As detaile d b y Sa m ps o n, 2 0 0 6 , a na p h yla xis is br oa dl y defi n e d as “a seri o us aller gic reacti o n t hat 
is ra pi d i n o nset a n d ma y ca use deat h.” Dia g n ostic criteria d efi ne d b y t he Nati o nal I nstit ute of 
Aller g y a n d I nfecti o us Disease/ F o o d Aller g y a n d A na p h yl a xis Ne t w or k d uri n g t he s ec o n d 
s y m p osi u m o n t he defi niti o n a n d ma na ge me nt of a na p h yl a xis, m o difie d fr o m Sa m ps o n, 2 0 0 6 , 
are as f oll o ws:  
A na p h yl a xis is hi g hl y li kel y w h e n a n y o n e of t he f oll o wi n g 3 criteria is f ulfille d: 
1.  ac ute o nset of a n ill ness ( mi n utes t o se veral h o urs) wit h i n v ol ve me nt of t he s ki n, m uc osal 
tiss ue, or b ot h (e g, ge neralize d hi ves, pr urit us or fl us hi n g, s w olle n li ps-t o n g ue-u v ula) a n d 
at least o ne of t he f oll o wi n g:  
a. res pirat or y c o m pr o mise (e g, d ys p n ea, w heeze -br o nc h os pas m, stri d or, re d u ce d pea k 
e x pirat or y fl o w, h y p o x e mia)  
b.  re d uce d bl o o d press ur e or ass ociate d s y m pt o ms of e n d-or ga n d ysf u ncti o n 
(e g, h y p ot o nia [c olla pse], s y nc o p e, i nc o nti ne nce)  
2.  t w o or m ore of t he f oll o wi n g t hat occ ur ra pi dl y after e x p os ure t o a likely aller ge n f or t h at 
p atie nt ( mi n utes t o se veral h o urs): 
a. i n v ol ve me nt of t he s ki n-m uc osal tiss ue (e g, ge n eralize d hi ves, itc h -fl us h, s w olle n 
li ps-t o n g ue-u v ula)  
b.  res pirat or y c o m pr o mise (eg, d ys p n ea, w heeze -br o nc h os pas m, stri d or, re d u ce d pea k 
e x pirat or y fl o w, h y p o x e mia)  
c. re d uce d bl o o d press ur e or ass ociate d s y m pt o ms (e g, h y p ot o nia [c olla pse], s y n c o p e, 
i nc o nti ne nce) 
d.  persiste nt gastr oi ntesti nal s y m pt o ms (e g, cra m p y a b d o mi nal pai n, v o miti n g)  
3.  red uce d bl o o d press ur e after e x p os ure t o k n o w n  aller ge n f or t h at p atie nt  ( mi n utes t o 
se veral h o urs): 
a. a d ults: s yst olic bl o o d press ure of < 9 0 m m H g or > 3 0 % decrease fr o m t hat p ers o n’s 
baseli ne  
I n t he e ve nt of s us p ecte d a na p h yla xis, vital si g ns, i ncl u di n g o x y gen s at urati o n a n d res pirati o n 
rate, will be meas ure d. Ot her assess me nts will be perf or me d at t he discreti o n of t he i n vesti gat or. 
As a preca uti o n, eac h i n v esti gati o nal site s h o ul d h a ve a res uscitati o n cart n ear b y.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 3 5  
 
A P P E N DI X  I. I C H D-3 DI A G N O S TI C C R I T E RI A 
F or f urt her det ai ls, refer t o I H S, 2 0 1 3. 
Mi gr ai ne wit h o ut A ur a  
a. at least 5 attac ks f ulfilli n g criteria B t hr o u g h D  
b.  hea dac he attac ks lasti n g 4 t o 7 2 h o urs ( u ntreate d or u ns uccessf ull y tr eate d)  
c. hea dac he has at least 2 of t he f oll o wi n g 4 c h aracteristics:  
− u nilateral l ocati o n  
− p ulsati n g q ualit y  
− m o derate or s e vere pai n i nte nsit y  
− a g gra vati o n b y, or ca usi n g a v oi d a 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)  
d.  d uri n g hea dac he, at least o ne of t he f oll o wi n g:  
− 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  
e. n ot better acc o u nte d f or b y a n ot h er I nter nati o nal Classificati o n of Hea d ac he 
Dis or ders, 3 r d re visi o n (I C H D-3) criteria dia g n osis  
Mi gr ai ne wit h A ur a  
a. at least 2 attac ks f ulfilli n g criteria B a n d C  
b.  o ne or m or e of t he f oll o wi n g f ull y re versi ble a ura s y m pt o ms:  
− vis ual  
− se ns or y 
− s peec h a n d/ or la n g ua ge 
− m ot or  
− brai nste m  
− reti nal 
c. at least 2 of t he f oll o wi n g 4 c h aracteristics:  
− at least 1 a ura s y m pt o m s prea ds gra d uall y o ver ≥5 mi n utes, a n d/ or 2 or m or e 
s y m pt o ms occ ur i n s uccessi o n  
− eac h i n di vi d ual a ura s y m pt o m lasts 5 t o 6 0 mi n utes  
− at least 1 a ura s y m pt o m is u nilateral  
− t he a ura is a cc o m pa nie d, or f oll o we d wit hi n 6 0 mi n utes, b y h ea dac he n ot b etter 
acc o u nte d f or b y a n ot h er I C H D -3 dia g n osis, a n d tr a nsie nt isc he mic attac k h as 
be e n e x cl u de d  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 3 6  
 
A P P E N DI X  J.  T O T A L B L O O D V O L U M E  
T otal bl o o d v ol u me t o be c ollecte d f or eac h patie nt i n t his st u d y is a p pr o xi matel y 6 4. 2  m L.  
T ot al Bl o o d V ol u mes  
T y pe of s a m ples  
V ol u me per s a m ple ( m L)  
T ot al n u m ber of s a m ples  
T ot al v ol u me ( m L)  
Ser u m c he mistr y, 
he mat ol o g y, c o a g ulati o n, 
ser u m β-H C G test a a n d 
F S H b  
1 0. 7  
1  
1 0. 7  
Ser u m c he mistr y, 
he mat ol o g y, a n d 
c o a g ulati o n  
1 0. 7  
5  
5 3. 5  
T ot al  
 
6  
6 4. 2  
a A ser u m pre g na nc y test will b e perf or me d f or w o me n of c hil d -beari n g p ote ntial  a n d w o me n t h o u g ht t o be 
p ost me n o pa usal  at t he scree ni n g visit ( V 1 ). 
b A n F S H test will b e perf or me d  o nl y f or w o me n t h o u g ht t o b e p ost me n o pa usal at t he scree ni n g visit ( V 1 ). 
β -H C G  =  beta -h u ma n c h ori o nic g o na d otr o pi n; F S H  =  f ollicl e sti m ulati n g h or m o ne. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 3 7  
 
A P P E N DI X  K.  P R O D U C T C O M P L AI N T S  
Cli nic al Pr o d uct C o m pl ai nts  
A cli nical pr o d uct c o m pl ai nt is defi ne d as a pr o ble m or p ote ntial pr o ble m wit h t he p h ysical 
q ualit y or c h aracteristics of cli nical i n vesti gati o nal me dici nal pr o d uct (I M P) s u p plies or cli nical 
de vice s u p plies use d i n a cl i nical researc h st u d y s p o ns ore d b y Te v a. E x a m ples of a pr o d u ct 
c o m plai nt i ncl u de b ut are n ot li mite d t o:  
•  s us pecte d c o nta mi nati o n 
•  q uesti o na ble sta bilit y (e g, c ol or c ha n ge, fla ki n g, cr u m bli n g, etc)  
•  defecti ve c o m p o ne nts  
•  missi n g or e xtra u nits (e g, pri mar y c o n tai ner is recei ve d at t he i n vesti gati o n al ce nter 
wit h m ore or less t ha n t h e desi g n ate d n u m ber of u nits i nsi de)  
•  i nc orrect pac k a gi n g, or i nc orrect or missi n g la beli n g/la bels 
•  u ne x pecte d or u na ntici pate d taste or o d or, or b ot h  
•  de vice n ot w or ki n g c orrectl y or a p pears defecti ve i n s o me ma n ner  
Eac h i n vesti gati o nal ce nt er will be res p o nsi ble f or re p orti n g a p ossi ble cli ni cal pr o d uct c o m plai nt 
b y c o m pleti n g t he pr o d u ct c o m plai nt f or m pr o vi d e d b y T e va a n d e maili n g it t o 
 wit hin 4 8  h o urs of bec o mi n g a ware of t he iss ue.  
F or c o m plai nts i n v ol vi n g a de vice or ot her retrie v a ble ite m, it is re q uire d t hat t he de vice ( or 
ite m) be se nt bac k t o t he s p o ns or f or i n vesti gati ve testi n g w he n e ver p ossi bl e. F or c o m plai nts 
i n v ol vi n g a n I M P, all rel e va nt sa m ples (e g, t h e re mai n der of t he patie nt’s I M P s u p pl y) s h o ul d be 
se nt bac k t o t he s p o ns or f or i n vesti gati ve t esti n g w he ne ver p ossi ble.  
1.  Pr o d uct C o m pl ai nt I nf or m ati o n Nee de d fr o m t he I n vesti g ati o n al Ce nter  
I n t he e ve nt t hat t he pr o d uct c o m plai nt f orm ca n n ot be c o m plete d, t he i n vesti gat or will pr o vi de 
t he f oll o wi n g i nf or m ati o n, as a vaila ble: 
•  i n vesti gati o nal c e nter n u m ber a n d pri nci p al i n vesti gat or n a me 
•  na me, p h o ne n u m ber, a n d a d dress of t he s o urce of t he c o m plai nt  
•  cli nical pr ot oc ol n u m ber  
•  patie nt i de n tifier ( patie nt st u d y n u m ber) a n d c orres p o n di n g visit n u m bers, if 
a p plica ble  
•  pr o d uct na me a n d stre n gt h f or o pe n -la bel st u dies 
•  patie nt n u m ber, b ottle, a n d kit n u m bers (if a p plica ble) f or d o u bl e -bli n d or o pe n -la bel 
st u dies 
•  pr o d uct a vaila ble f or ret ur n Yes/ N o  
•  pr o d uct was ta k e n or use d acc or di n g t o pr ot o c ol Yes/ N o  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 3 8  
 
•  descri pti o n or nat ur e of c o m plai nt  
•  ass ociate d seri o us a d vers e e ve nt Y es/ N o  
•  cli nical s u p plies u n bli n de d (f or bli n de d st u dies) Yes/ N o  
•  date a n d na m e of pers o n recei vi n g t he c o m plai nt  
N ote: Re p orti n g a pr o d uct c o m plai nt m ust n ot be dela ye d e v e n if n ot all t he re q uire d i nf or mati o n 
ca n be o btai n e d i m me diatel y. K n o w n i nf or mati o n m ust be re p orte d i m me di atel y. T h e s p o ns or 
will c olla b orate wit h t he i n vesti gat or t o o btai n a n y o utsta n di n g i nf or mati o n.  
2.  H a n dli n g o f I n vesti g ati o n al Me dici n al Pr o d uct(s) at t he I n vesti g ati o n al Ce nter(s) 
T he i n vesti gat or is res p o nsi ble f or retai ni n g t he pr o d uct i n q uesti o n i n a l ocati o n se parat e fr o m 
t he i n vesti gat or’s cli nical st u d y s u p plies. T he s p o ns or ma y re q uest t hat t he i n vesti gat or ret ur n t he 
pr o d uct f or f urt her e val u ati o n a n d/ or a nal ysis. If t his is necessar y, t he cli nical st u d y m o nit or or 
desi g nee will pr o vi de t he i nf or mati o n nee de d f or ret ur ni n g t he I M P.  
If it is deter mi ne d t hat t he i n vesti gati o nal ce nter m ust ret ur n all I M P, t he s p o ns or will pr o vi de t he 
i nf or mati o n nee de d t o h a n dle t he ret ur n. 
T he i nte grit y of t he ra n d o mizati o n c o de a n d c orres p o n di n g bli n de d cli nical s u p plies will be 
mai ntai ne d w he ne v er p ossi ble. A seri o us a d verse e ve nt or t he p ote ntial f or a pr o d uct q ualit y 
p r o ble m e xisti n g be y o n d t he sc o pe of t he c o m plai nt ma y be a reas o n t o u n bli n d t he cli nical 
s u p plies f or a n affecte d p atie nt. 
3.  A d verse E ve nts or Seri o us A d verse E ve nts Ass oci ate d wit h a Pr o d uct C o m pl ai nt  
If t here is a n a d verse e v e nt or seri o us a d verse e v e nt due t o pr o d uct c o m plai nt, t he pr ot oc ol 
s h o ul d be f oll o we d f or rec or di n g a n d re p orti n g ( Secti o n 7. 1. 2  a n d Secti o n  7. 1. 5. 3 , res pecti vel y). 
4.  D oc u me nti n g a Pr o d uct C o m pl ai nt  
T he i n vesti gat or will rec or d i n t he s o urce d o c u me ntati o n a descri pti o n of t he pr o d uct c o m plai nt, 
a n d a n y acti o ns ta ke n t o res ol ve t h e c o m plai nt a n d t o preser ve t h e safet y of t he patie nt. O nce t he 
c o m plai nt has bee n i n vesti gate d b y t he s p o ns or a n d t he i n vesti gat or, if necessar y, a n e v e nt 
cl os ure letter ma y b e se nt t o t he i n vesti gati o nal ce nter w here t he c o m plai nt ori gi nate d or t o all 
i nvesti gati o nal c e nters usi n g t he pr o d u ct.  
Me dical de vice i nci de nts, i ncl u di n g t h ose res ulti n g fr o m malf u ncti o ns of t he de vice, m ust be 
detecte d, d o c u me nte d, a n d re p orte d b y t he i n v esti gat or t hr o u g h o ut t he st u d y.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 3 9  
 
A P P E N DI X  L.  D A T A M A N A G E M E N T A N D R E C O R D K E E PI N G  
Direct Access t o S o urce D at a a n d D oc u me nts  
All patie nt data m ust ha ve s u p p orti ve ori gi nal s o urce d oc u m e ntati o n i n t he me dical rec or ds, or 
e q ui vale nt, bef ore t he y are tra nscri b e d t o t he electr o nic case re p ort f or m (e C R F). Data m a y n ot 
be rec or de d dir ectl y o n t he e C R F a n d c o nsi dere d as s o urce d ata u nless t he s p o ns or pr o vi des 
writte n i nstr ucti o ns s pecif yi n g w hi c h data are p er mitte d t o be rec or de d dir ectl y t o t he e C R F.  
If data are pr ocess e d fr o m ot her i nstit uti o ns or b y ot her mea ns (e g, cli nical la b orat or y, ce ntral 
i ma ge ce nter, or ele ctr o ni c diar y data), t he res ults will be se nt t o t he i n vesti gati o nal ce nter, w here 
t he y will be retai ne d b ut n ot tra nscri be d t o t he e C R F, u nless ot her wise n ot e d i n t he pr ot oc ol. 
T hese data m a y als o be s e nt electr o nicall y t o t he s p o ns or ( o r or ga nizati o n perf or mi n g data 
ma na ge me nt).  
T he me dical e x perts, st u d y m o nit ors, a u dit ors, I n de pe n de nt Et hics C o m mittee/I nstit uti o nal 
Re vie w B o ar d (I E C/I R B), a n d i ns pect ors fr o m c o m pete nt a ut h orit y ( or t heir a ge nts) will be 
gi ve n direct a ccess t o s o urce da t a a n d d oc u m e nts ( e g, m e dical c harts/rec or ds, la b orat or y test 
res ults, pri nt o uts, vi de ota pes) f or s o urce d ata verificati o n, pr o vi de d t hat patie nt c o nfi de ntialit y is 
mai ntai ne d i n acc or da nce wit h nati o nal a n d l ocal r e q uire me nts.  
T he i n vesti gat or m ust mai nta i n t he ori gi nal rec or ds (ie, s o urce d o c u me nts) of eac h p atie nt’s data 
at all ti mes.  T he i n vesti gat or m ust mai ntai n a c o nfi de ntial patie nt i de ntificati o n list t hat all o ws 
t he u na m bi g u o us i de ntifi cati o n of eac h patie nt. 
D at a C ollecti o n  
Data will be c ollecte d  usi n g case re p ort f or ms ( C R Fs) t hat are s pecificall y d esi g ne d f or t his 
st u d y. T he d ata c ollecte d o n t he C R Fs will be ca pt ure d i n a cli nical d ata ma na ge me nt s yste m 
( C D M S) t hat meets t he tec h nical r e q uire me nts d escri be d i n 2 1 C F R Part  1 1 ( U nite d States of 
A m erica) a n d d oc u m e nts of ot her c o n cer ne d c o m p ete nt a ut h orities. Bef ore usi n g t he C D M S, it 
will be f ull y vali date d a n d all users will recei ve trai ni n g o n t he s yste m a n d st u d y -s pecific 
trai ni n g. After t he y are tr ai ne d, users will be pr o vi de d wit h i n di vi d ual syste m access ri g hts.  
Data will be c ollecte d at t he i n vesti gati o nal ce nter b y a p pr o priatel y d esi g n ate d a n d trai ne d 
pers o n nel, a n d C R Fs m ust be c o m plete d f or eac h patie nt w h o pr o vi de d i nf or me d c o nse nt. Patie nt 
i de ntit y s h o ul d n ot be discer ni ble fr o m t he data pr o vi de d o n t he e C R F.  
If data are pr ocess e d fr o m ot her s o urces (e g, ce ntral la b orat or y, bi o a nal ytical la b orat or y, ce ntr al 
i ma ge ce nter, ele ctr o nic diar y d ata, el ectr o nic p atie nt-re p ort e d o utc o me ta blet), t hese data will be 
se nt t o t he i n vesti gati o nal ce nter, w h ere t h e y will be retai ne d b ut n ot tr a nscri be d t o t he e C R F, 
u nless ot her wise n ote d i n t he pr ot oc ol. T hese d ata ma y als o be se nt electr o nicall y t o t he s p o ns or 
( or or ga niz ati o n perf or mi n g dat a ma na ge me nt). All patie nt data m ust ha ve s u p p orti ve ori gi n al 
s o urce d oc u m e ntati o n i n t he me dical rec or ds, or e q ui vale nt, bef ore t he y are tra nscri be d t o t he 
e C R F. Data ma y n ot b e rec or de d directl y o n t he e C R F a n d c o nsi dere d as s o urce dat a u nless t he 
s p o ns or pr o vi des writte n i nstr ucti o ns s pecif yi n g w hic h data are per mitte d t o be rec or de d dir ectl y 
t o t he e C R F. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 4 0  
 
F or patie nts w h o e nter a st u d y b ut d o n ot meet t he e ntr y criteri a, at a mi ni m u m, data f or 
scree ni n g fail ure reas o n, de m o gra p h y, a n d a d verse e ve nts fr o m t he ti me of i nf or me d c o nse nt will 
be e ntere d i n t he e C R F.  
D at a Q u alit y C o ntr ol  
Data Ma na ge me nt is res p o nsi ble f or t he acc urac y, q ualit y, c o m plete ness, a n d i nter nal 
c o nsiste nc y of t he dat a fr o m t his st u d y. O versi g ht will be carri e d o ut as des cri be d i n t he 
s p o ns or’s S O Ps f or cli nic al st u dies. Da y-t o-da y d ata ma na ge me n t tas ks f or t his st u d y are 
dele gate d t o a c o ntract or ga niz ati o n, a n d t hese f u ncti o ns ma y be carrie d o ut as descri be d i n t he 
S O Ps f or cli nical st u dies at t hat or ga nizati o n. T hese S O Ps will be re vie we d b y t he s p o ns or b ef ore 
t he start of data ma n a ge me nt acti vities. 
Data will be verifie d b y t he st u d y m o nit or usi n g t he data s o urce a n d re vie we d b y Data 
Ma na ge me nt usi n g b ot h a ut o mate d l o gi cal c hec ks a n d ma n ual re vi e w. Dat a i de ntifie d as 
err o ne o us, or data t hat are missi n g, will be referre d t o t he i n vesti gati o nal c e nter f or res ol uti o n 
t hr o u g h d ata q ueri es. A n y necessar y c ha n ges will be ma de i n t he cli nical d ata base, a n d data 
re vie w a n d v ali dati o n pr oce d ures will be re peate d as nee de d. Data fr o m e xter nal s o urces will be 
c o m pare d wit h t he i nf or mati o n a vaila ble i n t he C D M S, a n d a n y discre p a n cies will be q uerie d.  
A p plica ble ter ms will be c o de d acc or di n g t o t he c o di n g c o n v e nti o ns f or t his st u d y.  
At t he c o ncl usi o n of t he st u d y, t he C D M S a n d all ot her st u d y d ata will be l oc ke d t o f urt her 
a d diti o ns or c orrecti o ns. L oc ki n g t h e st u d y d ata re prese nts t he ac k n o wle d ge me nt t hat all data 
ha ve bee n ca pt ur e d a n d c o nfir me d as acc urate. All data c ollecte d will be a p pr o ve d b y t he 
i n vesti gat or at t he i n vesti gati o nal ce nter. T his a p pr o val ac k n o wle d ges t he i n vesti gat or’s re vie w 
a n d acce pta n ce of t he d at a as bei n g c o m plete a n d acc urate.  
Arc hi vi n g of C ase Re p ort F or ms a n d S o urce D oc u me nts  
S p o ns or Res p o nsi bilities  
T he ori gi nal C R Fs will be arc hi v e d b y t he s p o ns or. I n v esti gati o nal ce nter -s pecific C R Fs will be 
pr o vi de d t o t he res pecti ve i n vesti gati o nal ce nters f or arc hi vi n g. 
I n v esti gat or Res p o nsi bilities 
T he i n vesti gat or m ust mai ntai n all writte n a n d electr o nic rec or ds, acc o u nts, n ot es, re p orts, a n d 
data relat e d t o t he st u d y a n d a n y a d diti o nal rec or ds re q uire d t o be mai ntai n e d u n der c o u nt r y, 
state/ pr o vi nce, or nati o nal a n d l ocal la ws, i ncl u di n g, b ut n ot li mite d t o: 
•  f ull case hist ories 
•  si g ne d i nf or me d c o nse nt f or ms 
•  patie nt i de ntificati o n lists  
•  case re p ort f or ms f or eac h patie nt o n a per -visit basis  
•  data fr o m ot her s o urces (e g, ce ntr al la b or at or y, bi oa nal yti cal la b orat or y, ce ntral i ma ge 
ce nter, electr o nic di ar y)  
•  safet y re p orts 
•  fi na ncial discl os ure re p orts/f or ms 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 4 1  
 
•  re p orts of recei pt, use, a n d dis p osal of t he I M Ps 
•  c o pies of all c orres p o n de nce wit h s p o ns or, t he I E C/I R B, a n d a n y c o m p ete nt a ut h orit y  
T he i n vesti gat or will retai n all rec or ds relate d t o t he st u d y a n d a n y a d diti o nal rec or ds re q uir e d, as 
i n dicate d b y t he pr ot oc ol a n d acc or di n g t o a p plica ble la ws a n d re g ulati o ns, u ntil t he c o ntract 
researc h or ga niz ati o n or s p o ns or n otifies t he i nstit uti o n i n writi n g t hat rec or ds ma y b e destr o ye d. 
If, after 2 5 years fr o m st u d y c o m pleti o n, or earlier i n t he case of t h e i n vesti gati o nal ce nter 
cl osi n g or g oi n g o ut of b usi ness, t he i n vesti gat or reas o na bl y deter mi nes t hat st u d y rec or d 
rete nti o n has bec o me u n d ul y b ur de ns o me, a n d t h e s p o ns or has n ot pr o vi de d writte n n otificati o n 
of destr ucti o n, t he n t he i n vesti gat or m a y s u b mit a writte n re q uest t o t he s p o ns or at least 6 0  da ys 
bef ore a n y pla n ne d dis p osal of st u d y rec or ds. After recei pt of s uc h re q uest, t he s p o ns or ma y 
ma ke arra n ge m e nts f or a p pr o priate arc hi val or dis p osal, i ncl u di n g re q uiri n g t hat t he i n vesti gat or 
deli ver s uc h rec or ds t o t h e s p o ns or. T he i n vesti gat or s hall n otif y t he s p o ns or of a n y acci de nt al 
l oss or destr ucti o n of st u d y rec or ds. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 4 2  
 
A P P E N DI X  M.  P U B LI C A TI O N P O LI C Y  
Al l u n p u blis he d i nf or mati o n gi ve n t o t he i n vesti gat or b y t he s p o ns or s h all n ot be p u blis he d or 
discl ose d t o a t hir d part y wit h o ut t he pri or writte n c o nse nt of t he s p o ns or.  
T he res ults of t his st u d y ma y b e p u blis he d or pres e nte d at scie ntific meeti n gs. If t hi s is f oresee n, 
t he i n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he s p o ns or bef ore s u b missi o n. 
T his all o ws t he s p o ns or t o pr otect pr o priet ar y i nf or mati o n a n d t o pr o vi de c o m me nts.  
T he s p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults: 
“ Rec o m me n dati o ns  f or t he C o n d uct, Re p orti n g, E diti n g, a n d P u blicati o n of Sc h olarl y W or k i n 
Me dical J o ur nals” ( w w w.I C MJ E. or g). P u blicati o n of t he res ults will occ ur i n a ti mel y ma n ner 
acc or di n g t o a p plic a ble re g ul ati o ns. I n acc or da n ce wi t h sta n dar d e dit orial a n d et hical practice, 
t he s p o ns or will ge n erall y s u p p ort p u blicati o n of m ultice nter st u dies o nl y i n t heir e ntiret y a n d n ot 
as i n di vi d ual i n vesti gati o nal ce nter d ata. I n t his case, a c o or di n ati n g i n vesti gat or will be 
desi g nat e d b y m ut u al a gree me nt.  
A ut h ors hi p will be deter mi ne d b y m ut ual a gree m e nt a n d i n li ne wit h I nt er nati o nal C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p re q uire m e nts:  
•  s u bsta ntial c o ntri b uti o ns t o t he c o nce pti o n or desi g n of t he w or k; or t he ac q uisiti o n, 
a nal ysis, or  i nter pret ati o n of data f or t h e w or k 
•  drafti n g t he w or k or re visi n g it criticall y f or i m p ort a nt i ntellect ual c o nte nt  
•  fi nal a p pr o val of t h e versi o n t o be p u blis he d 
•  a gree m e nt t o be acc o u nta ble f or all as pects of t he w or k i n e ns uri n g t hat q uesti o ns 
relate d t o t he acc urac y or i nte grit y of a n y part of t he w or k are a p pr o priatel y 
i n vesti gate d a n d res ol ve d 
T he p u blicati o ns c o m mittee esta blis he d b y t he s p o ns or will o versee t his pr ocess. A d diti o nal 
p u blicati o ns ma y f oll o w. P olicies re gar di n g t he p u blicati o n of t he st u d y res ults are defi ne d i n t he 
fi na ncial a gree me nt. 
N o pate nt a p plicati o ns base d o n t he res ults of t he st u d y ma y be m a de b y t he i n vesti gat or, n or 
ma y assista nce be gi v e n t o a n y t hir d part y t o ma ke s uc h a n a p plicati o n wit h o ut t he writte n 
a ut h orizati o n of t he  s p o ns or. 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 4 3  
 
A P P E N DI X  N.  C LI NI C A L L A B O R A T O R Y T E S T S  
Ta ble  7  pr o vi des t he cli nical la b orat or y assess me nts t o be perf or m e d i n t he st u d y.  
T a ble  7 : 
Cli nic al L a b or at or y Tests  
Ser u m C he mistr y  
He m at ol o g y a n d C o a g ul ati o n  
Uri n al ysis  
Calci u m  
P h os p hate  
S o di u m  
P otassi u m  
C hl ori de  
Creati ni ne  
Gl uc ose  
B U N  
L D L  
H D L  
Tri gl yceri des  
Urate  
A L T  
A S T  
L D H  
G G T  
Al kali ne p h os p hatase  
Bicar b o nate  
Car b o n di o xi de  
Pr otei n  
Al b u mi n  
Bilir u bi n  
Direct bilir u bi n  
He m o gl o bi n  
He mat ocrit  
Er yt hr oc ytes  
Platelets  
Le uc oc ytes  
− Ne utr o p hils  
− L y m p h oc ytes  
− E osi n o p hils  
− M o n oc ytes  
− Bas o p hils  
L y m p h oc ytes at y pical  
Pr ot hr o m bi n I N R  
Pr otei n  
Gl uc ose  
Ket o nes  
He m o gl o bi n  
p H  
S pecific gra vit y  
Micr osc o pic tests  
− Bacteria  
− Er yt hr oc ytes  
− Le uc oc ytes  
− Cr ystals  
− Casts  
A L T  =  ala ni ne a mi n otra nsferase; A S T  =  as partate a mi n otra nsferase; B U N  =  bl o o d urea nitr o ge n; G G T  =  ga m ma 
gl uta m yl tra ns pe pti dase; H D L  =  hi g h de nsit y li p o pr otei n; I N R =  I nter nati o nal N or malize d Rati o; L D H =  lactate 
de h y dr o ge nase; L D L  =  l o w de nsit y li p o pr otei n. 
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Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 4 4  
 
A P P E N DI X  O.  I N J E C TI O N I N S T R U C TI ON S  
 
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Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 4 5  
 
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 4 6  
 
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 4 7  
 
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 4 8  
 
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 4 9  
 
 
V V- 0 0 0 7 0 7 7 8 v 7. 0

 
Place b o -C o ntr olle d St u d y – C o m or bi d Mi grai ne a n d M D D  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 4  
St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 5 0  
 
A P P E N DI X  P.  M A N A G E M E N T O F S T U D Y A C TI VI TI E S D U RI N G 
C O VI D -1 9  
T his a p pe n di x is t o a d dress t he m o dificati o n s i n st u d y c o n d u ct d uri n g t he C or o na vir us diseas e 
2 0 1 9 ( C O VI D -1 9) pa n de mic.  
T he c ha n ges  s pecifi e d i n t his a p pe n di x will be effecti ve f or t he d urati o n  of t he C O VI D -1 9 
pa n de mic . O nce t he pa n d e mic res ol ves a n d ce nters /c o u ntries are a ble t o res u me n or mal 
f u ncti o ni n g, t his a p pe n di x will bec o me v oi d . 
T he f oll o wi n g s ecti o ns are affecte d:  
Secti o n 3. 5 Sc he d ule of St u d y Pr oce d ures a n d Assess me nts ( T a ble 4)  
H o me visits are per mitte d f or patie nts w h o are n ot a ble t o g o t o t he i n vesti gati o nal ce nter f or 
t heir visit(s) or if t he i n vesti gati o nal ce nter staff are n ot a ble t o se e patie nts at t he i n vesti gati o nal 
ce nter d u e t o t he C O VI D -1 9 pa n de mic.  H o me visits m ust be c o m plete d b y t he pri nci pal 
i n vesti gat or or a s u bi n vesti gat or a n d m a y als o i ncl u de trai ne d st u d y staff (ie, a me dicall y 
q ualifie d pers o n desi g n ate d b y t h e i n vesti gat or  or a h o me care ser vice pr o vi der  f or certai n 
assess me nts), as r e q uire d, t o c o m plete all visit assess me nts/ pr oce d ures.   
Visits s h o ul d be c o n d ucte d i n acc or da nce wit h t he ti meli nes s pecifie d i n t he pr ot oc ol (see 
Ta ble  4 ). 
A p pe n di x D. Et hics  
F or h o me visits, a ver bal  c o nse nt  pr ocess  will be a p plie d  f or eac h patie nt pri or t o t he h o me visit 
a n d will f oll o w writte n i nf or me d c o nse nt as per l o cal re g ulati o ns bef ore a n y st u d y pr oce d ures or 
assess me nts  are p erf or me d.  
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