Clinical trial NCT04041284
Conditions: Migraine Major Depressive Disorder
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2019-09-13; Completion date: 2022-08-31
Enrollment: 353 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to evaluate the efficacy of monthly 225 mg sc fremanezumab in adult participants with migraine and major depressive disorder (MDD)

The secondary objectives are to evaluate the efficacy of monthly 225 mg sc of fremanezumab in adult participants with migraine and MDD on the reduction of MDD symptoms, responder rates in monthly migraine days, improving quality of life, improving disability, and the safety and tolerability of monthly 225 mg sc and quarterly 675 mg sc fremanezumab in adult participants with migraine and MDD.

The total duration of participant participation in the study is planned to be approximately 28 weeks.

Detailed description:

Arms: arm 1: monthly 225 mg. In the open-label extension phase starting at week 12, all participants will receive active treatment with a quarterly dose of 675 mg sc arm 2: None
Interventions: intervention 1: Fremanezumab intervention 2: Placebo
Intervention descriptions: intervention 1: Monthly 225 mg subcutaneous intervention 2: Matching Placebo

Protocol documents:
Prot_000.pdf: 
 
 
 
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.  
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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 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 
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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 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. 
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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 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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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 3  
 
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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St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
7 4  
 
•  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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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 7  
 
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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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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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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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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St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
8 1  
 
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). 
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 3  
 
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 
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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 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.  
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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 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.”  
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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 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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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.  
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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 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  
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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 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. 
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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  
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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. 
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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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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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1 4 5  
 
 
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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  
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St u d y T V 4 8 1 2 5 -M H -4 0 1 4 2  
 
1 4 6  
 
 
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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  
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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  
 
 
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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 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.  
V V- 0 0 0 7 0 7 7 8 v 7. 0

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
 
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 
 
 
Study Number TV48125-MH-40142 
 
 
NCT04041284 
 
 
SAP Approval Date: 15 September 2022 


 
Placebo-Controlled Study–Comorbid Migraine and MDD 
Statistical Analysis Plan 
Study TV48125-MH-40142 
1 
 
 
 
Statistical Analysis Plan 
Study TV48125-MH-40142 
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 
 
A Randomized, Double-Blind, Placebo-Controlled Study on Efficacy and Safety of 
Fremanezumab for Preventing Migraine in Patients with MDD 
 
A Study to Assess if Fremanezumab is Effective in Preventing Migraine in Patients with 
Major Depressive Disorder 
Phase 4 
 
IND number: 106533; 
NDA number: not applicable; 
BLA number: 761089;
 
EudraCT number: 2019-001989-15 
 
 
Approval Date: 15 September 2022 
 
 
Sponsor 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
145 Brandywine Parkway 
West Chester, Pennsylvania 19380 
United States 
 
 
Prepared by: 
 
 
VV-00468145 v1.0


 
Placebo-Controlled Study–Comorbid Migraine and MDD 
Statistical Analysis Plan 
Study TV48125-MH-40142 
2 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
Study No.: 
TV48125-MH-40142 
 
Study Title: 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 
 
 
Statistical Analysis Plan for: 
 
 Interim Analysis  
 
 Integrated Summary of Efficacy 
 
 Final Analysis 
 
 
 Integrated Summary of Safety 
 
Amendment: Final  
 
 
 
Author: 
 
 
 
 
 
 
_____________________________________________________________________________ 
Approver: 
 
 
 
 
 
Date 
 
 
 
______________________________________________________________________________ 
Approver: 
 
 
 
Date 
 
 
 
Executed signature pages are maintained separately within the Trial Master File 
VV-00468145 v1.0


 
Placebo-Controlled Study–Comorbid Migraine and MDD 
Statistical Analysis Plan 
Study TV48125-MH-40142 
3 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................8 
INTRODUCTION .........................................................................................................................10 
1. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................11 
1.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................11 
1.2. 
Exploratory Objectives and Endpoints .......................................................................12 
1.3. 
Estimand for Primary Endpoint ..................................................................................13 
2. 
STUDY DESIGN .......................................................................................................15 
2.1. 
General Design ...........................................................................................................15 
2.2. 
Randomization and Blinding ......................................................................................16 
2.3. 
Data Monitoring Committee .......................................................................................16 
2.4. 
Sample Size and Power Considerations .....................................................................17 
2.5. 
Sequence of Planned Analyses ...................................................................................17 
2.5.1. 
Planned Interim Analyses ...........................................................................................17 
2.5.2. 
Final Analyses and Reporting .....................................................................................17 
3. 
ANALYSIS SETS ......................................................................................................18 
3.1.1. 
Intent-to-Treat Analysis Set ........................................................................................18 
3.1.2. 
Modified Intent-to-Treat Analysis Sets ......................................................................18 
3.1.3. 
Safety Analysis Sets ...................................................................................................18 
3.1.4. 
Per-Protocol Analysis Set ...........................................................................................18 
4. 
GENERAL ISSUES FOR DATA ANALYSIS ..........................................................19 
4.1. 
General ........................................................................................................................19 
4.2. 
Specification of Baseline Values ................................................................................19 
4.3. 
Handling Withdrawals and Missing Data ...................................................................19 
4.4. 
Study Days and Visits .................................................................................................19 
4.5. 
Region of Pooled Countries ........................................................................................20 
5. 
STUDY POPULATION .............................................................................................21 
5.1. 
General ........................................................................................................................21 
5.2. 
Patient Disposition ......................................................................................................21 
5.3. 
Demographics and Baseline Characteristics ...............................................................21 
5.4. 
Medical History ..........................................................................................................21 
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5.5. 
Prior Therapy and Medication ....................................................................................21 
5.6. 
Electrocardiography ....................................................................................................22 
5.7. 
Physical Examinations ................................................................................................22 
5.8. 
Childbearing Potential and Methods of Contraception ..............................................22 
5.9. 
Study Protocol Violations ...........................................................................................22 
6. 
EFFICACY ANALYSIS ............................................................................................23 
6.1. 
General ........................................................................................................................23 
6.2. 
Primary Efficacy Endpoint and Analysis ...................................................................24 
6.2.1. 
Definition ....................................................................................................................24 
6.2.2. 
Primary Efficacy Analysis ..........................................................................................24 
6.2.3. 
Sensitivity Analysis ....................................................................................................25 
6.2.3.1. 
MMRM Analysis ........................................................................................................25 
6.2.3.2. 
Analysis with Multiple Imputation Method ...............................................................25 
6.2.3.3. 
ANCOVA Analysis ....................................................................................................27 
6.3. 
Secondary Efficacy Endpoints and Analysis ..............................................................27 
6.3.1. 
Hamilton Depression Rating Scale-17........................................................................27 
6.3.1.1. 
Definition ....................................................................................................................27 
6.3.1.2. 
Analysis ......................................................................................................................27 
6.3.2. 
Migraine Days ............................................................................................................27 
6.3.2.1. 
Definition ....................................................................................................................27 
6.3.2.2. 
Analysis ......................................................................................................................28 
6.3.3. 
Migraine-Specific Quality of Life ..............................................................................28 
6.3.3.1. 
Definition ....................................................................................................................28 
6.3.3.2. 
Analysis ......................................................................................................................28 
6.3.4. 
Clinical Global Impression-Severity Scale .................................................................28 
6.3.4.1. 
Definition ....................................................................................................................28 
6.3.4.2. 
Analysis ......................................................................................................................28 
6.3.5. 
6-Item Headache Impact Test .....................................................................................28 
6.3.5.1. 
Definition ....................................................................................................................28 
6.3.5.2. 
Analysis ......................................................................................................................29 
6.4. 
Other Efficacy Endpoints Analysis ............................................................................29 
6.4.1. 
Patient Health Questionnaire-9 ...................................................................................29 
6.4.1.1. 
Definition ....................................................................................................................29 
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Placebo-Controlled Study–Comorbid Migraine and MDD 
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Study TV48125-MH-40142 
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6.4.1.2. 
Analysis ......................................................................................................................29 
6.4.2. 
Hamilton Anxiety Scale ..............................................................................................29 
6.4.2.1. 
Definition ....................................................................................................................29 
6.4.2.2. 
Analysis ......................................................................................................................29 
6.4.3. 
Work Productivity and Activity Impairment Questionnaire General Health 
V2.0 ............................................................................................................................29 
6.4.3.1. 
Definition ....................................................................................................................29 
6.4.3.2. 
Analysis ......................................................................................................................30 
6.4.4. 
Other Analysis ............................................................................................................30 
7. 
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................31 
8. 
SAFETY ANALYSIS ................................................................................................32 
8.1. 
General ........................................................................................................................32 
8.2. 
Duration of Exposure to Study Drug ..........................................................................32 
8.3. 
Adverse Events ...........................................................................................................32 
8.4. 
Deaths .........................................................................................................................33 
8.5. 
Clinical Laboratory Tests ...........................................................................................33 
8.5.1. 
Laboratory Values Meeting Hy’s Law Criteria ..........................................................34 
8.5.2. 
Other Clinical Laboratory Tests .................................................................................34 
8.5.2.1. 
Human Chorionic Gonadotropin Test ........................................................................34 
8.5.2.2. 
Follicle-Stimulating Hormone Test ............................................................................34 
8.6. 
Physical Examinations ................................................................................................34 
8.7. 
Vital Signs ..................................................................................................................35 
8.8. 
Electrocardiography ....................................................................................................35 
8.9. 
Concomitant Medications or Therapies ......................................................................36 
8.10. 
Electronic Columbia-Suicide Severity Rating Scale ..................................................36 
9. 
TOLERABILITY VARIABLES AND ANALYSIS..................................................37 
10. 
STATISTICAL SOFTWARE ....................................................................................38 
11. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL ..............39 
APPENDIX A. E-DIARY QUESTIONNAIRE ..........................................................................40 
APPENDIX B. LOGICS FOR ENDPOINTS DERIVATION ...................................................42 
APPENDIX C. HAMILTON DEPRESSION RATING SCALE-17 ..........................................43 
APPENDIX D. MIGRAINE-SPECIFIC QUALITY OF LIFE QUESTIONNAIRE 
(MSQ) (VERSION 2.1) ..............................................................................................46 
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APPENDIX E. SCORING INSTRUCTIONS FOR MSQOL (VERSION 2.1) .........................51 
APPENDIX F. CLINICAL GLOBAL IMPRESSION-SEVERITY SCALE .............................53 
APPENDIX G. HIT-6™ HEADACHE IMPACT TEST ............................................................55 
APPENDIX H. PATIENT HEALTH QUESTIONNAIRE (PHQ-9) .........................................56 
APPENDIX I. HAMILTON ANXIETY SCALE .......................................................................57 
APPENDIX J. WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE: GENERAL HEALTH V2.0 (WPAI:GH) .................................59 
 
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LIST OF TABLES 
Table 1: 
Primary and Secondary Study Objectives and Endpoints ..........................................11 
Table 2: 
The Region of Pooled Countries .................................................................................20 
Table 3: 
Criteria for Potentially Clinically Significant Laboratory Values ..............................33 
Table 4: 
Criteria for Potentially Clinically Significant Vital Signs ..........................................35 
 
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Statistical Analysis Plan 
Study TV48125-MH-40142 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
 
Abbreviation 
Term 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
BMI 
body mass index 
CGI-S 
Clinical Global Impression-Severity 
CI 
confidence interval 
CM 
chronic migraine 
COVID-19 
Coronavirus disease 2019 
CRF 
case report form 
DSM-V 
Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders 
eC-SSRS 
electronic Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
EM 
episodic migraine 
EOT 
end of treatment 
FSH 
follicle-stimulating hormone 
HAM-A 
Hamilton Anxiety Scale 
HAM-D 17 
Hamilton Depression Rating Scale-17 items 
HIT-6 
6-item Headache Impact Test 
ICHD-3 
International Classification of Headache Disorders, 3rd revision 
IMP 
investigational medicinal product 
IRT 
interactive response technology 
ITT 
intent-to-treat 
LS 
least square 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
mITT 
modified intent-to-treat 
MMRM 
mixed-effects model repeated measures 
MSQoL 
Migraine-Specific Quality of Life 
NSAID 
non-steroidal anti-inflammatory drug 
PANSS 
Positive and Negative Syndrome Scale  
VV-00468145 v1.0


 
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Study TV48125-MH-40142 
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Abbreviation 
Term 
PHQ-9 
Patient Health Questionnaire-9 
PP 
per-protocol 
PT 
preferred term 
R&D 
Research and Development  
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SI 
standard international 
SOC 
system organ class 
SOP 
Standard Operating Procedure 
sc 
subcutaneous 
WHO 
World Health Organization 
WPAI:GH 
Work Productivity and Activity Impairment Questionnaire General Health 
VV-00468145 v1.0


 
Placebo-Controlled Study–Comorbid Migraine and MDD 
Statistical Analysis Plan 
Study TV48125-MH-40142 
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INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Teva 
Branded Pharmaceutical Products Research and Development (R&D), Inc. study TV48125-MH-
40142 (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), and was written 
in accordance with Standard Operating Procedure (SOP) GSD_SOP_702 (SAP). 
The reader of this SAP is encouraged to read the study protocol for details on the conduct of this 
study, the operational aspects of clinical assessments, and the timing for completing the 
participation of a patient in this study.  
The SAP is intended to be in agreement with the protocol, especially with regards to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details regarding these particular points of interest, or other types of analyses (e.g. other 
endpoints).When differences exist in descriptions or explanations provided in the study protocol 
and this SAP, the SAP prevails; the differences will be explained in the Clinical Study Report. 
 
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1. 
STUDY OBJECTIVES AND ENDPOINTS 
1.1. 
Primary and Secondary Study Objectives and Endpoints 
The primary and secondary study objectives and endpoints are in Table 1: 
Table 1: 
Primary and Secondary Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary objective: 
To evaluate the efficacy of 
monthly 225 mg subcutaneous 
(sc) fremanezumab in adult 
patients with migraine and 
major depressive disorder 
(MDD) 
Mean change in the monthly average number of migraine days 
from the 28-day baseline period during the 12-week period 
after the first dose of study drug 
Key secondary objective: 
To evaluate the efficacy of 
monthly 225 mg sc of 
fremanezumab in adult patients 
with migraine and MDD on the 
reduction of MDD symptoms 
Mean change in depression symptoms from randomization 
(day 1) to week 8 after the first dose of study drug as measured 
by: 
• Hamilton Depression Rating Scale-17 items 
(HAM-D 17)  
Secondary objective: 
To evaluate the efficacy of 
monthly 225 mg sc 
fremanezumab in adult patients 
with migraine and MDD in 
terms of responder rates in 
monthly migraine days 
Number of patients with 50% or more reduction from the 
28-day baseline period in the monthly average number of 
migraine days during 12 weeks after the first dose of study 
drug 
Secondary objective:  
To evaluate the efficacy of 
monthly 225 mg sc 
fremanezumab in adult patients 
with migraine and MDD in 
terms of improving quality of 
life 
Mean change in quality of life from randomization visit 
(day 1) to week 12 after the first dose of study drug as 
measured by: 
• Migraine-Specific Quality of Life (MSQoL) 
questionnaire, role function-restrictive and role 
function-preventive domains 
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Objectives 
Endpoints 
Secondary objective:  
To evaluate the efficacy of 
monthly 225 mg sc 
fremanezumab in adult patients 
with migraine and MDD in 
terms of improving disability  
Mean change from randomization visit (day 1) in disability 
score for overall impact as measured by Clinical Global 
Impression-Severity (CGI-S) and 6-item Headache Impact 
Test (HIT-6) to the following time points after administration 
of the first dose of study drug: 
• weeks 4 and 8 (CGI-S) 
• week 12 (CGI-S and HIT-6) 
Safety and tolerability 
objective 
(Secondary objective): 
To evaluate the safety and 
tolerability of monthly 225 mg 
sc and quarterly 675 mg sc 
fremanezumab in adult patients 
with migraine and MDD 
• occurrence of adverse events throughout the study 
• changes from randomization visit (day 1) in vital 
signs (pulse, systolic and diastolic blood pressure, 
body temperature, and respiratory rate) 
measurements  
• abnormal physical examination findings including 
body weight 
• use of concomitant medication for adverse events 
during the study 
• number (%) of patients who did not complete the 
study due to adverse events  
• occurrence of severe hypersensitivity/anaphylaxis 
reactions 
• suicidal ideation and behavior as suggested by 
eC-SSRS 
CGI-S = Clinical Global Impression-Severity; eC-SSRS = electronic Columbia-Suicide Severity Rating Scale; 
HAM-D 17 = Hamilton Depression Rating Scale-17 items; HIT-6 = 6-item Headache Impact Test; MDD = major 
depressive disorder; MSQoL = Migraine-Specific Quality of Life; sc = subcutaneous. 
1.2. 
Exploratory Objectives and Endpoints 
 
 
 
 
 
  
 
 
 
 
 
 
 
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1.3. 
Estimand for Primary Endpoint 
The primary estimand for this study is defined by the following attributes: 
1. Target population:  
The study population will be composed of male and female patients, aged 18 to 70 years, 
inclusive, with a diagnosis of migraine (as defined by the International Classification of 
Headache Disorders, 3rd revision [ICHD-3] criteria) and MDD (diagnosed according to 
the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) 
criteria) at least 12 months prior to the screening visit.  Patients who are randomized and 
receive at least 1 dose of IMP and have at least 10 days of postrandomization efficacy 
assessment on the primary endpoint will be the population of interest. 
2. Outcome measures: 
Change in the monthly average number of migraine days from the 28-day baseline period 
during the 12-week period after the first dose of study drug. 
3. Treatment description: 
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Fremanezumab at monthly doses of 225 mg sc, and placebo alternatively, in the 12-week 
double-blind treatment period 
4. Intercurrent events strategy:  
a. Early discontinuation due to lack of efficacy: hypothetical strategy 
b. Early discontinuation due to adverse event: hypothetical strategy 
c. Initiation of prohibited therapy: hypothetical strategy 
d. Impact of COVID-19: hypothetical strategy 
5. Population-level summary for the variables: 
Difference in mean change in the monthly average number of migraine days from the 
28-day baseline period during the 12-week between fremanezumab and placebo. 
 
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2. 
STUDY DESIGN 
2.1. 
General Design 
This is an approximately 28-week, multicenter, randomized, double-blind, placebo 
investigational medicinal product (IMP)-controlled, parallel-group study to evaluate the efficacy 
and safety of fremanezumab self-administered at monthly doses of 225 mg sc and a quarterly 
dose of 675 mg sc (ie, one dose using 3 prefilled syringes with 225 mg each) in adult patients 
with migraine and MDD. The study will consist of a 28-day (ie, 4-week) baseline period, a 
12-week double-blind treatment phase followed by a 12-week open-label extension phase, and 
an end-of-treatment visit (approximately 12 weeks after the final dose of study drug). 
The total duration of patient participation in the study is planned to be approximately 28 weeks. 
Patients are expected to complete the entire duration of the study. 
Patients who fulfill the criteria for migraine will be further delineated as patients with chronic 
migraine (CM) or episodic migraine (EM), for stratification and other analyses.  
CM is defined as: 
Patient fulfills the following criteria for CM in prospectively collected baseline information 
during the 28-day baseline period: 
• headache occurring on ≥15 days 
• on ≥8 days, fulfilling any 1 of the following: 
− ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura (Appendix I of 
the study protocol) 
− ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix I of the study 
protocol) 
− probable migraine (a migraine subtype where only 1 migraine criterion is 
missing) 
− triptan or ergot derivative used to treat established headache. 
EM is defined as: 
The patient fulfills the following criteria for EM in prospectively collected baseline information 
during the 28-day baseline period: 
• headache occurring ≥4 days but <15 
• on ≥4 days, fulfilling any 1 of the following: 
− ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura (Appendix I of 
the study protocol) 
− ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix I of the study 
protocol) 
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− probable migraine (a migraine subtype where only 1 migraine criterion is 
missing) 
− triptan or ergot derivative used to treat an established headache 
At the randomization visit (day 1), patients will be randomly assigned to 1 of 2 treatment groups 
of 225 mg sc fremanezumab or placebo in a 1:1 ratio. Patients will receive their assigned study 
treatment on visit 2 (day 1), visit 3 (day 29), and visit 4 (day 57) and then continue into the open-
label extension phase in which all patients will receive a quarterly dose of 675 mg sc 
fremanezumab on visit 5 (day 85). Investigators can contact patients in between study visits per 
their clinical judgment. 
Patients who complete all scheduled visits will have procedures and assessments performed at 
visit 6 (end of treatment [EOT]). Patients who withdraw from the study before completing the 
24-week treatment phase will have visit 6 (EOT) procedures and assessments performed at their 
final visit. The end of study is defined as the last visit (end-of-treatment/early withdrawal visit 
[visit 6]) of the last patient. 
Study procedures and assessments with their timing are summarized in Table 4 of the study 
protocol. 
2.2. 
Randomization and Blinding 
After the 28-day baseline period, the first 12 weeks of this study will be double-blind. Patients 
and investigators will remain blinded to IMP assignment during this part of the study. This will 
be followed by a 12-week open-label extension phase.  
Patients will receive 225 mg sc fremanezumab (visit 2, visit 3, and visit 4) or matching placebo 
(visit 2) in monthly doses.  
For the first phase of this study, the sponsor, investigators, study staff, and patients will be 
blinded to treatment assignment. A computer-generated master randomization list will be 
provided to drug packaging facilities. The packaging vendor(s) will package active drug and 
placebo into single-visit kits according to Good Manufacturing Practice procedures. Kits will be 
identical in appearance and contain 1 prefilled syringe with either active drug or placebo.  
Patients will be stratified based on sex, country, migraine classification (ie, CM or EM), and 
PHQ-9 score category (10 to 14, 15 to 19, and ≥20) to ensure balance for the covariates. 
Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list using electronic interactive response technology (IRT). This system is used to 
ensure a balance across treatment groups. The specifications for randomization will be under the 
responsibility and oversight of Teva Global Statistics. 
At randomization visit (day 1), each patient will be randomized in a 1:1 ratio within the stratum 
to which he or she belongs to receive monthly 225 mg sc fremanezumab or placebo, as assigned 
by the IRT. In the open-label extension phase starting at week 12, however, all patients will 
receive active treatment with a quarterly dose of 675 mg sc fremanezumab. 
2.3. 
Data Monitoring Committee 
There will be no Data and Safety Monitoring Board in this study. 
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2.4. 
Sample Size and Power Considerations 
A sample size of 288 (144 per treatment group) evaluable patients completing the study will 
provide 90% power to detect a treatment difference of 2 days with a common standard deviation 
of 5.2 days in changes from the 28-day baseline period in monthly average migraine days 
between active and placebo groups at a 2-sided alpha level of 0.05. This sample size will provide 
approximately 80% power to detect a treatment difference of 2 points with a common standard 
deviation of 6 points in the change from randomization visit (day 1) in HAM-D 17 total score at 
a 2-sided alpha level of 0.05. Assuming a 15% drop-out rate, approximately 340 patients 
(approximately 170 patients per treatment group) will be randomized. 
2.5. 
Sequence of Planned Analyses 
2.5.1. 
Planned Interim Analyses 
No interim analysis is planned for this study. 
2.5.2. 
Final Analyses and Reporting 
All analyses identified in this SAP will be performed after the final database lock. 
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3. 
ANALYSIS SETS 
3.1.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all randomized patients. 
In the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received. 
3.1.2. 
Modified Intent-to-Treat Analysis Sets 
The double-blind modified intent-to-treat (mITT) analysis set is a subset of the ITT analysis set 
including only patients who receive at least 1 dose of IMP and have at least 10 days of 
postrandomization efficacy assessment on the primary endpoint. The open-label mITT analysis 
set is a subset of the ITT analysis set including only patients who receive at least 1 dose of IMP 
during the open-label treatment period and have at least 10 days of diary entries during the 
open-label period. 
In the double-blind mITT analysis set, treatment will be assigned based on the treatment to 
which patients were randomized, regardless of which treatment they actually received. 
3.1.3. 
Safety Analysis Sets 
The double-blind safety analysis set will include all randomized patients who receive at least 1 
dose of IMP during the double-blind treatment period. The open-label safety analysis set will 
include all patients who receive at least 1 of dose of IMP during the open-label treatment period. 
In the double-blind safety analysis set, treatment will be assigned based on the treatment patients 
actually received, regardless of the treatment to which they were randomized, unless otherwise 
specified. 
Patients who begin prohibited therapies during the study will be included in the safety analysis 
sets but not the per-protocol (PP) analysis set (Section 3.1.4). 
3.1.4. 
Per-Protocol Analysis Set 
The PP analysis set is a subset of the mITT analysis set including only patients without important 
protocol deviations during the double-blind treatment period, including any deviation of the 
inclusion/exclusion criteria or any deviations or omissions of the IMP administration. Patients 
with less than 75% diary compliance during the double-blind treatment period will be excluded 
from the PP analysis set. A blinded data review meeting will be conducted prior to the database 
lock in order to determine the exclusion of the patients from the PP analysis set. After database 
lock and unblindng, patients who received study drug different from the study drug they were 
randomized to will also be excluded from the PP analysis set. 
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4. 
GENERAL ISSUES FOR DATA ANALYSIS 
4.1. 
General 
Descriptive statistics for continuous variables include n, mean, standard deviation (SD), standard 
error (SE), median, minimum, and maximum. Descriptive statistics for categorical variables 
include patient counts and percentages, missing category will be displayed as appropriate. 
4.2. 
Specification of Baseline Values 
For migraine days, the baseline value is the total number of migraine days during the 28-day 
baseline period. If the baseline period is greater or less than 28 days, the baseline value for will 
be normalized to 28 days. In addition, if the baseline period is 28 days but there are days with 
missing diary, the baseline value will be normalized to 28 days. 
For all other assessments, the baseline value is the last observed data prior to the first dose of 
study drug. 
4.3. 
Handling Withdrawals and Missing Data 
If a patient has ≥10 days of electronic headache diary data after 1st dose of the study drug, his/her 
monthly average number of migraine days during the 12-week period or monthly number of 
migraine days during the 4-week period will be prorated to 28 days. 
Multiple imputation (MI) method will be applied on the primary variable as sensitivity analyses. 
The methods will be described in detail in Section 6.2.3. 
A patient’s monthly number of migraine days during the 4-week period after each dose of study 
drug will be calculated for months 1, 2, 3, and 6. If a patient has missing diary days when 
calculating the monthly number of migraine days, the following method will be used to handle 
the missing data. 
• If a patient has ≥10 days of electronic headache  diary data for a month, the monthly 
number of migraine days will be prorated to 28 days for that month.  
• If a patient has <10 days of electronic headache  diary data for a month, the monthly 
number of migraine days will be considered as missing. 
For the HAM-D, HAM-A and HIT-6, if 1 or more items are missing then the total score is 
missing. The missing questionnaire items handling for the MSQOL questionnaire is discussed in 
Appendix E . 
4.4. 
Study Days and Visits 
Study days are numbered relative to the 1st day of study drug administration. The start of 
treatment (day 1) is defined as the date on which a patient takes the 1st dose of study drug, as 
recorded on the study drug administration case report form (CRF). Days will be numbered 
relative to treatment start (ie, ..., –2, –1, 1, 2, ...; with day 1 being the 1st day of study drug 
administration and day –1 being the day before the 1st day of study drug administration). 
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The 4-week (28-day) visit windows for the electronic headache diary based efficacy endpoints 
will be determined based on the actual dosing day. The run-in phase is defined as day -28 to -1 
before the 1st injection on day 1. Treatment phase including month 1, 2, 3, and 6 is from the 
beginning of the 1st injection of study drug to visit 6/day 169 or the EOT visit. The monthly visit 
windows are separated by each dosing date/time. Month 1 is from the date/time of the 1st dose of 
study drug administration on day 1 to the date/time just before the 2nd dose. Month 2 is from the 
date/time of the 2nd dose to the date/time just before the 3rd dose. Month 3 is from the date/time 
of the 3rd dose to the date/time just before the 4th dose. Month 6 is from 57 days after the 
date/time of the 4th dose to the EOT on day 169 approximately.  
Throughout this document, all by month efficacy summaries for the headache data will refer to 
these visit windows. 
For all other by-visit summaries, if there are multiple assessments at a postbaseline visit then the 
last non-missing assessment at that visit will be used for the summary. This includes assessments 
at the scheduled and unscheduled visits.  
For patients who withdraw from the study, their efficacy and safety data at the early termination 
visit will be excluded from the by-visit summaries but will be included in the last assessment 
summaries. 
4.5. 
Region of Pooled Countries 
The countries will be pooled to 3 regions as presented in Table 2 for the analysis.  
Table 2: 
The Region of Pooled Countries 
Region 
Country 
United States 
United States 
Europe 
Czech Republic, Finland, France, Germany, Greece, Italy, Poland, 
Spain, United Kingdom 
Rest of World 
Israel, Russia, Ukraine 
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5. 
STUDY POPULATION 
5.1. 
General 
The ITT analysis set will be used for all study population summaries unless otherwise specified. 
Summaries will be presented by treatment group and for all patients (ie, total). 
5.2. 
Patient Disposition 
Patients screened, patients screened but not randomized, and the reasons the patients were not 
randomized will be summarized only for the total group using patient counts.  
Patients in the ITT analysis set, ITT analysis set but not treated, double-blind safety analysis set, 
double-blind mITT analysis set, double-blind mITT analysis set but not PP analysis set (with 
reason not in the PP set), and PP analysis set, patients who complete and withdraw from the 
double-blind treatment period, patients in the open-label safety analysis set and open-label mITT 
analysis set, and patients who complete and withdraw from the study  will be summarized using 
descriptive statistics. Patients who withdraw from double-blind treatment and patients who 
withdraw from the study will also be summarized using descriptive statistics by reason for 
withdrawal. The denominator for calculating the percentages will be the number of patients in 
the ITT analysis set. 
5.3. 
Demographics and Baseline Characteristics 
The continuous variables of patient age, weight, height, and body mass index (BMI), and time 
since initial migraine diagnosis (years) will be summarized using descriptive statistics. The 
categorical variables of patient sex, race, ethnicity, migraine classification, country, region, 
PHQ-9 score category, patient sex as randomized, migraine classification as randomized, and  
PHQ-9 score category as randomized will be summarized using descriptive statistics for each 
category. Missing categories will be presented if necessary. 
This summary will also be done for the open-label safety analysis set. 
The baseline total number of migraine days, HAM-D 17 total score, MSQOL domain scores, 
CGI-S rating, HIT-6 disability score, PHQ-9 total score, HAM-A total score, and WPAI domain 
scores will be summarized using descriptive statistics. 
5.4. 
Medical History 
All medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of medical history abnormalities will be summarized using 
descriptive statistics by system organ class (SOC) and preferred term (PT). Patients are counted 
only once in each SOC category, and only once in each PT category. 
5.5. 
Prior Therapy and Medication 
Any prior or concomitant medication, treatment, psychotherapy, or procedure a patient has had 
for migraine and/or depression within the past 10 years or for any indication within the past 5 
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months before IMP administration and up to the end of study, including follow-up, will be 
recorded on the eCRF. The sponsor will encode all therapy and medication according to the 
World Health Organization (WHO) drug dictionary (WHO Drug). 
The incidence of prior therapies and medications will be summarized using descriptive statistics 
by therapeutic class and PT. Patients are counted only once in each therapeutic class category, 
and only once in each PT category. Prior therapies and medications will include all medications 
taken and therapies administered before the first day of study drug administration administration. 
The subset of prior therapies and medications for migraine /headache will be summarized for the 
following categories: 
• preventive medication from protocol appendix for migraine/headache 
• opioids for migraine/headache 
• NSAIDS for migraine/headache 
• triptans for migraine/headache 
• ergots for migraine/headache 
• butalbital for migraine/headache 
• medication from protocol appendix for other reason than depression 
• benzodiazepines for other reason than anxiety/insomnia 
• other 
5.6. 
Electrocardiography 
ECG findings (normal, abnormal not clinically significant, and abnormal clinically significant) at 
baseline will be summarized using descriptive statistics. 
5.7. 
Physical Examinations 
Patients with a physical examination, patients with at least 1 abnormal finding, and abnormal 
findings for each category at baseline will be summarized using descriptive statistics. 
5.8. 
Childbearing Potential and Methods of Contraception 
For female patients, information related to childbearing potential and menopause will be 
collected at screening. Data will be listed. 
5.9. 
Study Protocol Violations 
Data from patients with any important protocol deviations during the study will be summarized 
overall and for each category using descriptive statistics. 
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6. 
EFFICACY ANALYSIS 
6.1. 
General 
Migraine days will be defined as follows. If the headache fulfills the criteria for migraine on any 
given day, the consecutive days are part of the same migraine attack and are therefore considered 
to be migraine days as well (even if they do not fulfill the criteria for migraine). These days only 
reflect normal fluctuations in migraine severity that lead to or represent the resolution of a 
full-blown migraine attack. Accordingly, for the purpose of this study, a migraine day is 
endorsed when at least one of the following situations occurs:  
• a calendar day (00:00 to 23:59) demonstrating at least 4 consecutive hours of a 
headache meeting the criteria for migraine with or without aura 
• a calendar day (00:00 to 23:59) demonstrating at least 4 consecutive hours of a 
headache meeting the criteria for probable migraine, a migraine subtype where only 
1 migraine criterion is missing 
• a calendar day (00:00 to 23:59) demonstrating a headache of any duration that was 
treated with migraine-specific medications (triptans and ergot compounds) 
• a calendar day (00:00 to 23:59) that is immediately consecutive (happening 1 day 
before or 1 day after) of any day fulfilling any of the 3 criteria above, where 
individuals report headache of any duration 
The monthly average number of days or hours of efficacy variables (migraine days) during the 
12-week period after the 1st dose of study drug will be derived and normalized to 28 days 
equivalent using the following formula. 
∑𝐷𝑎𝑦𝑠 𝑜𝑟 ℎ𝑜𝑢𝑟𝑠 𝑜𝑓 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒 𝑜𝑣𝑒𝑟 𝑡ℎ𝑒 12 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑  
∑𝐷𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑒𝐷𝑖𝑎𝑟𝑦 𝑓𝑜𝑟 𝑡ℎ𝑒 12 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑 ×  28   (1) 
The monthly number of days or hours of efficacy variables during a 4-week period after each 
dose will be derived and normalized to 28 days equivalent using the following formula, where 
monthly data separated by each visit of study drug dosing will be used.  
∑𝐷𝑎𝑦𝑠 𝑜𝑟 ℎ𝑜𝑢𝑟𝑠 𝑜𝑓 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 4 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑  
∑𝐷𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑒𝐷𝑖𝑎𝑟𝑦 𝑓𝑜𝑟 𝑡ℎ𝑒 4 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑  ×  28    (2) 
The baseline values will be calculated using all data collected in the run-in period. 
∑𝐷𝑎𝑦𝑠 𝑜𝑟 ℎ𝑜𝑢𝑟𝑠 𝑜𝑓 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑟𝑢𝑛−𝑖𝑛 𝑝𝑒𝑟𝑖𝑜𝑑  
∑𝐷𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑒𝐷𝑖𝑎𝑟𝑦 𝑓𝑜𝑟 𝑡ℎ𝑒 𝑟𝑢𝑛−𝑖𝑛 𝑝𝑒𝑟𝑖𝑜𝑑  ×  28   (3) 
The percentage of reduction in the monthly average number of an efficacy variable will be 
calculated as  
𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒−𝑝𝑜𝑠𝑡𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒
𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒
× 100%   (4) 
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where the baseline value is calculated by formula (3) and the postbaseline value in the equation 
is calculated by formula (1) for the variables during the 12-week period or by formula (2) for the 
variables during the 4-week period after each dose for months 1, 2 3, and 6. 
The mITT analysis sets will be used for all efficacy analyses. Summaries will be presented by 
treatment group as randomized, unless otherwise noted. For the double-blind treatment period, 
summaries will be presented by treatment group. For the open-label treatment period, summaries 
will be presented by double-blind treatment group and all patients (ie, total). Descriptive 
statistics for all efficacy data will be presented by month (or week), and over 12-week period for 
the double-blind period, and at month 6 (or week 24) for the open-label treatment period. For 
migraine days and PHQ-9 total score, months 1, 2, and 3 (or weeks 4, 8, and 12) will also be 
included in the open-label treatment period summaries. 
The primary and secondary endpoints analysis listed in section 6.2.1 and section 6.3 will be 
repeated for the PP analysis set. 
6.2. 
Primary Efficacy Endpoint and Analysis 
6.2.1. 
Definition 
The primary efficacy endpoint is the mean change in the monthly average number of migraine 
days from the 28-day baseline period during the 12-week period after the first dose of study 
drug. 
6.2.2. 
Primary Efficacy Analysis 
The hypothesis testing for the primary analysis is:  
 
where 
and 
are the mean change from baseline in the monthly average number of migraine 
days for the fremanezumab treatment group and the placebo treatment group respectively.  
The primary efficacy endpoint will be analyzed using an analysis of covariance (ANCOVA) 
model with sex, region (United States, European, or rest of world), migraine classification 
(ie, CM or EM), baseline PHQ-9 score category (10 to 14, 15 to 19, and ≥20), and treatment as 
factors and baseline number of migraine days as a covariate. The stratification factors (as 
randomized) will be used in the model. The least square (LS) mean treatment difference 
(fremanezumab - placebo), 95% confidence interval (CI) for the LS mean treatment difference, 
and the associated p-value will be generated from this model. 
The statistical test will be two-sided at the alpha=0.05 level of significance. The SAS code for 
this test is as follows: 
PROC MIXED; 
CLASS TREAT SEX REGION MIGCLASS PHQCAT; 
MODEL CHG= TREAT SEX REGION MIGCLASS PHQCAT  BASE; 
LSMEANS TREAT / DIFF CL; 
  RUN; 
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The normality assumption for the ANCOVA model will be checked to ensure validity of the 
primary analysis. If the model assumptions are not met (p-value <0.01), a nonparametric method 
such as Wilcoxon Rank Sum test will be conducted as a sensitivity analysis. 
6.2.3. 
Sensitivity Analysis 
6.2.3.1. 
MMRM Analysis 
Sensitivity analysis will be performed using a mixed-effects model repeated measures (MMRM) 
analysis model to estimate the mean change from baseline in the monthly average of migraine 
days for the overall 3 months double-blind treatment period and by each month to support the 
primary analysis. 
Each patient’s monthly number of migraine days during the 4-week period will be calculated by 
formula 2 in section 6.1. If a patient is early terminated or has intermittent missing days and has 
fewer than 10 days of electronic headache diary entries for a month, that month’s value will be 
considered as missing as described in section 4.3. 
The MMRM model will include treatment, sex, region, migraine classification, baseline PHQ-9 
score category, month, treatment-by-month interaction as fixed effects, baseline value as a 
covariate, and patient in the repeated statement as a random effect. The stratification factors (as 
randomized) will be used in the model. The unconstructed covariance structure will be used for 
the repeated observations within a patient. The LS mean treatment difference 
(fremanezumab - placebo), 95% CI for the LS mean treatment difference, and the associated 
p-value for fremanezumab versus placebo will be generated from this model for each month and 
overall 3 months. 
The SAS code for this test is as follows: 
PROC MIXED; 
  CLASS USUBJID TREAT SEX REGION MIGCLASS PHQCAT MONTH; 
  MODEL CHG= TREAT SEX REGION MIGCLASS PHQCAT  BASE MONTH TREAT*MONTH; 
  REPEATED MONTH / SUBJECT=USUBJID TYPE=UN; 
  LSMEANS TREAT TREAT*MONTH / DIFF CL; 
RUN; 
This sensitivity analysis will be performed on the mITT analysis set. 
6.2.3.2. 
Analysis with Multiple Imputation Method 
Sensitivity analysis will be performed by imputing missing migraine days of months 1-3 using 
MI method. The data will be processed by the following steps. 
• If a patient has partial electronic headache diary data (ie, <28 days) for a month, that 
month’s value will be considered missing before the MI procedure.  
• For the patients in the fremanezumab treatment group who are early terminated with 
reasons of adverse event (AE) or lack of efficacy, they will be assigned to placebo 
group so their missing values will be imputed using data from the placebo treated 
patients.  
• Run SAS PROC MI procedure to create 100 complete datasets.  
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The following SAS code pertains to the MI analysis: 
PROC MI DATA=XXX SEED=SEED OUT=MI_OUT NIMPUTE=100 MAXIMUM=. . . . . . 28 28 
28 MINIMUM=. . . . . . 0 0 0; 
CLASS TREAT SEX REGION MIGCLASS PHQCAT; 
FCS REG (AVALMI1=TREAT SEX REGION MIGCLASS PHQCAT BASE/DETAILS) 
NBITER=100; 
FCS REG (AVALMI2=TREAT SEX REGION MIGCLASS PHQCAT BASE  
AVALMI1/DETAILS) NBITER=100; 
FCS REG (AVALMI3= TREAT SEX REGION MIGCLASS PHQCAT BASE AVALMI1 
AVALMI2/DETAILS) NBITER=100; 
VAR TREAT SEX REGION MIGCLASS PHQCAT BASE AVALMI1 AVALMI2 AVALMI3; 
RUN; 
• Within each imputed data set, for a patient who has partial, say X (X<28) days, 
electronic headache diary data in a month, the monthly value will be replaced by  
• 
∑(𝑜𝑏𝑠𝑒𝑟𝑣𝑒𝑑 𝑣𝑎𝑙𝑢𝑒) + (28 −𝑋) ∗𝑖𝑚𝑝𝑢𝑡𝑒𝑑 𝑣𝑎𝑙𝑢𝑒/28  
• The monthly average number of migraine days during the 12-week double-blind 
period after the 1st dose of study drug will be the average of month 1, month 2 and 
month 3 values.  
Each dataset will be analyzed using the same ANCOVA model as described in section 6.2.2. The 
LS means and SEs from each analysis will be output to a SAS data set. The SAS code for this 
analysis is as follows:  
ODS OUTPUT DIFFS=MIXED_OUT; 
PROC MIXED DATA=UPDATED_MI_OUT METHOD=REML; 
BY _IMPUTATION_; 
CLASS TREAT SEX REGION MIGCLASS PHQCAT; 
MODEL CHG=TREAT SEX REGION MIGCLASS PHQCAT BASE; 
LSMEANS TREAT / DIFF CL; 
RUN; 
The output dataset from the above SAS code will contain the estimate of the LS mean treatment 
difference and the SE of the estimate from each of the 100 datasets. SAS procedure, PROC 
MIANALYZE, will be used to generate an overall LS mean treatment difference, 95% CI for the 
LS mean treatment difference, and associated p-value. The SAS code is as follows: 
ODS OUTPUT PARAMETERESTIMATES=PARMEST; 
PROC MIANALYZE DATA=MIXED_OUT ALPHA=0-.05 THETA0=0; 
BY TREAT; 
MODELEFFECTS ESTIMATE; 
STDERR=STDERR; 
RUN;  
This sensitivity analysis will be performed on the ITT analysis set. 
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6.2.3.3. 
ANCOVA Analysis 
The ANCOVA analysis defined in section 6.2.2 will be repeated as a sensitivity analysis using 
the actual stratification factors in the model. 
This sensitivity analysis will be performed on the mITT analysis set. 
6.3. 
Secondary Efficacy Endpoints and Analysis 
The key secondary efficacy endpoint is the mean change in depression symptoms from 
randomization visit (day 1) to week 8 after the first dose of study drug as measured by 
HAM-D 17.  
Other secondary endpoints include the following: 
• Number of patients with 50% or more reduction from the 28-day baseline period until 
12 weeks after the first dose of study drug, in the monthly average number of 
migraine days 
• Mean change in quality of life from randomization visit (day 1) to week 12 after the 
first dose of study drug as measured by the MSQoL questionnaire, role 
function-restrictive, role function-preventive, and emotional function domains  
• Mean change from randomization visit (day 1) in disability score for overall impact, 
as measured by CGI-S and HIT-6, to the following time points after administration of 
the first dose of study drug: 
− weeks 4 and 8 (CGI-S) 
− week 12 (CGI-S and HIT-6) 
6.3.1. 
Hamilton Depression Rating Scale-17 
6.3.1.1. 
Definition 
The HAM-D 17 (Appendix C) is a list of 17 items used to determine a patient’s level of 
depression. A total score of 0-7 is generally accepted to be within the normal range (or in clinical 
remission), while a score of 20 or higher (indicating at least moderate severity) is usually 
required for entry into a clinical trial. 
6.3.1.2. 
Analysis 
The HAM-D 17 total score change from baseline to week 8 will be analyzed using the same 
MMRM method as described in section 6.2.3.1. The analysis will also be done at weeks 4 
and 12. 
6.3.2. 
Migraine Days 
6.3.2.1. 
Definition 
The 50% reduction in the monthly average number of migraine days during the 12-week period 
after the first dose of study drug will be calculated by formula 4 in section 6.1. If a patient is 
early discontinued from the study, they will be counted as not having a ≥50% reduction. 
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6.3.2.2. 
Analysis 
For the proportion of patients with ≥50% reduction, a logistic regression model will be used with 
the following effects: treatment, sex, region, migraine classification, and baseline PHQ-9 score 
category. The stratification factors (as randomized) will be used in the model. The odds ratios 
(fremanezumab vs. placebo), 95% CI for the odds ratio, and associated p-value will be generated 
from this model.   
6.3.3. 
Migraine-Specific Quality of Life 
6.3.3.1. 
Definition 
The MSQoL version 2.1 (Appendix D) is a 14-item questionnaire that assesses the impact of 
migraine and migraine treatment on a patient’s quality of life during the previous 4 weeks, which 
has been shown to be a reliable and valid tool for use in CM and EM. The MSQoL measures the 
degree to which performance of normal activities is limited by migraine (Role Function-
Restrictive domain comprising 7 items), the degree to which performance of normal activities is 
prevented by migraine (Role Function-Preventive domain comprising 4 items), and the 
emotional effects of migraine (Emotional Function domain comprising 3 items). Scores range 
from 0 to 100, with higher scores indicating better health-related quality of life. Appendix E 
provides the scoring instructions on how to rescale the raw score to the scales that will be used 
for the analysis. 
6.3.3.2. 
Analysis 
The MSQOL domains (Role Function-Restrictive, Role Function-Preventive, and Emotional 
Function) scores change from baseline to week 12 will be analyzed using the same MMRM 
method as described in section 6.2.3.1. The analysis will also be done at weeks 4 and 8. 
6.3.4. 
Clinical Global Impression-Severity Scale 
6.3.4.1. 
Definition 
The CGI-S (Appendix F) is a short questionnaire filled out by the investigator that rates a 
patient’s mental health from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). 
6.3.4.2. 
Analysis 
The CGI-S rating change from baseline to weeks 4, 8, and 12 will be analyzed using the same 
MMRM method as described in section 6.2.3.1.  
6.3.5. 
6-Item Headache Impact Test 
6.3.5.1. 
Definition 
Migraine related disability will be assessed using the HIT-6 (Appendix G). The questionnaire 
measures the adverse impact of headache on social functioning, role functioning, vitality, 
cognitive functioning, and psychological distress. It also assesses headache severity. Each 
question is answered on the scale ranging with the following response options: 6 points (never), 
8 points (rarely), 10 points (sometimes), 11 points (very often), and 13 points (always). The total 
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score is obtained from summation of the 6 question points. The HIT-6 total score ranges between 
36 and 78, with larger scores reflecting greater impact.  
6.3.5.2. 
Analysis 
The HIT-6 disability score change from baseline to week 12 will be analyzed using the same 
MMRM method as described in section 6.2.3.1. The analysis will also be done at weeks 4 and 8. 
6.4. 
Other Efficacy Endpoints Analysis 
The exploratory efficacy endpoints are listed in section 1.2.  
6.4.1. 
Patient Health Questionnaire-9 
6.4.1.1. 
Definition 
The PHQ (Appendix H) is a 9-item questionnaire with each item corresponding to 1 criterion of 
the Diagnostic and Statistical Manual for Mental Disorders 4th edition diagnostic criteria for 
MDD. Each of the items is scored on a scale of 0 (“not at all”), 1 (“several days”), 2 (“more than 
half the days”), and 3 (“nearly every day”) based on the frequency of symptoms during the past 2 
weeks. The PHQ-9 is a validated measure for detecting and monitoring depression, anxiety, and 
somatization. 
6.4.1.2. 
Analysis 
The PHQ-9 total score change from baseline to weeks 4, 8, and 12 will be analyzed using the 
same MMRM method as described in section 6.2.3.1, except that the baseline value will not be 
included in the model. 
6.4.2. 
Hamilton Anxiety Scale 
6.4.2.1. 
Definition 
The HAM-A Scale (Appendix I)  is a 14-item scale that measuring the severity of a patient’s 
anxiety. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 
0–56, where <17 indicates mild severity, 18–24 mild to moderate severity and 25–30 moderate to 
severe. 
6.4.2.2. 
Analysis 
The HAM-A total score change from baseline to weeks 4, 8, and 12 will be analyzed using the 
same MMRM method as described in section 6.2.3.1. 
6.4.3. 
Work Productivity and Activity Impairment Questionnaire General Health V2.0 
6.4.3.1. 
Definition 
The generic version of the WPAI questionnaire (Appendix J) measures the overall effect of 
health on productivity at work and daily activities. The specific health problems version of the 
WPAI questionnaire allows investigators to attribute productivity and activity impairment issues 
to specific health conditions. After the employment status of a respondent is identified, 3 open 
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ended questions are asked concerning (1) hours absent from work due to health problems (or 
specific condition), (2) hours absent from work due to other reasons, and (3) hours actually 
worked. Two additional questions are included that ask about the impact of health on 
productivity, 1 concerning productivity at work and the other concerning daily activities outside 
of work. The response format of each item of the WPAI questionnaire consists of an 11-point 
scale ranging from 0 (no impairment) to 10 (complete impairment). 
The following scores will be derived based on the WPAI:GH questionnaire. Multiply scores by 
100 to express in percentages. 
• percent work item missed due to health:   
 
• percent impairment while working due to health:  
  
• percent overall work impairment due to health:   
 
• percent activity impairment due to health:   
 
6.4.3.2. 
Analysis 
For the patients who are currently employed, their scores of 
• percent work item missed due to health 
• percent impairment while working due to health  
• percent overall work impairment due to health 
• percent activity impairment due to health 
change from baseline to week 12 will be analyzed using the same MMRM method as described 
in section 6.2.3.1. The analysis will also be done at weeks 4 and 8. 
6.4.4. 
Other Analysis 
Correlation between the change from baseline in the PHQ-9 total score and the change from 
baseline in the monthly average number of migraine days will be presented with all visits 
combined through the 24-week period after the first dose of study drug. All visits will be 
combined and both treatments will be combined in the analysis. The open-label mITT analysis 
set will be used for the analysis. A scatter plot will also be presented. 
To assess whether improvements in headaches precede changes in depression, a graph of mean 
change from baseline in monthly number of migraine days versus mean change from baseline in 
PHQ-9 total score during the 6-month treatment period will be presented by month and 
double-blind treatment group. The open-label mITT analysis set will be used for the graph. 
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7. 
MULTIPLE COMPARISONS AND MULTIPLICITY 
A fixed-sequence (hierarchical) testing procedure will be implemented to control the type 1 error 
rate at 0.05. The primary endpoint will be tested first at a type I error rate of 5%. If the analysis is 
statistically significant (p-value <0.05), then the key secondary hypothesis will be tested. If not 
statistically significant, confirmatory hypothesis testing will not be carried out on the remaining 
hypotheses. This process will repeat accordingly to the order of the secondary endpoints as 
specified in section 6.3. 
 
  
 
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8. 
SAFETY ANALYSIS 
8.1. 
General 
The safety analysis sets will be used for all safety analyses. Summaries will be presented 
separately for the double-blind treatment period and open-label treatment period. For the 
double-blind treatment period, summaries will be presented by treatment group, unless otherwise 
stated. For the open-label treatment period, summaries will be presented by double-blind 
treatment group and all patients (ie, total). 
8.2. 
Duration of Exposure to Study Drug  
Duration of treatment (days treated) for the double-blind treatment period is the number of days 
on treatment started from the 1st study drug administration day to the week 12 or double-blind 
early withdrawal visit day (week 12 or double-blind early withdrawal visit day – first day of 
study drug + 1). For patients who are lost to follow-up during the double-blind treatment period, 
the EOT visit date is defined as the last study drug administration + 27. 
Duration of treatment (days treated) for the open-label treatment period is the number of days on 
treatment started from the 1st study drug administration day in the open-label treatment period to 
the week 24 or open-label early withdrawal visit day (week 24 or open-label early withdrawal 
visit day – first day of study drug in the open-label treatment period + 1). For patients who are 
lost to follow-up during the open-label treatment period, the EOT visit date is defined as the last 
study drug administration + 27. 
Number (%) of patients receiving 1 dose, 2 doses, and 3 doses during the double-blind treatment 
period will be summarized using descriptive statistics. Duration of treatment (days) during the 
double-blind and open-label periods will also be summarized using descriptive statistics. 
8.3. 
Adverse Events 
All AEs will be coded using MedDRA. 
The following are considered protocol-defined AEs of special interest: events of anaphylaxis and 
severe hypersensitivity reactions and ophthalmic events of at least moderate severity.   
Summaries will be presented for all treatment-emergent AEs (overall and by severity), AEs 
determined by the investigator to be treatment-related AEs (defined as related or with missing 
relationship (overall and by severity), serious AEs, protocol-defined AEs of special interest, AEs 
causing withdrawal from treatment, and non-serious AEs. Additionally the injection site 
reactions recorded as AEs will be summarized separately. 
The incidence of AEs will be summarized using descriptive statistics by SOC and PT (all 
treatment-emergent AEs overall will also be presented by just PT category). Patients are counted 
only once in each SOC category, and only once in each PT category. For the summaries by 
severity, patients are counted at the greatest severity. AEs with the missing flag indicating 
serious will be excluded from the summary of serious AEs but included in the summary of non-
serious AEs. 
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Listings for deaths, AEs, serious AEs, AEs causing withdrawal from treatment, injection 
site-related AEs, and protocol defined AEs of special interest will be presented. 
8.4. 
Deaths 
If any patient dies during the study all relevant information will be discussed in the patient’s 
narratives included in the CSR. 
8.5. 
Clinical Laboratory Tests 
Laboratory test results will be presented in standard international (SI) units.  
Summary statistics for chemistry, hematology, urinalysis, and coagulation laboratory tests will 
be presented at baseline, weeks 4, 8, 12, and 24, and last on study assessment (double-blind and 
open-label). Laboratory values and changes from baseline to each visit and last on study 
assessment will be summarized using descriptive statistics. Listings of all individual patients’ 
laboratory tests will be presented. 
Shifts (below, within, and above the normal range) from baseline to each visit and last on study 
assessment will be summarized using patient counts. 
Summaries of potentially clinically significant abnormal values will include all postbaseline 
values (including scheduled, unscheduled, and early termination visits). The incidence of 
potentially clinically significant abnormal values will be summarized for laboratory variables 
using descriptive statistics with the criteria specified in Table 3.  
Table 3: 
Criteria for Potentially Clinically Significant Laboratory Values 
Test 
Criterion value 
Serum chemistry 
 
ALT 
3x ULN 
AST 
3x ULN 
ALP 
3x ULN 
GGT 
3x ULN 
LDH 
3x ULN 
BUN 
10.71 mmol/L 
Creatinine 
177 mol/L 
Uric acid 
Men 
625 mol/L 
 
Women 
506 mol/L 
Bilirubin (total) 
34.2 mol/L 
Hematology 
 
Hematocrit 
Men 
<0.37 L/L 
 
Women 
<0.32 L/L 
Hemoglobin 
Men 
115 g/L 
 
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Test 
Criterion value 
 
Women 
95 g/L 
WBC counts 
3 x 109/L  
20 x 109/L 
Eosinophils 
10% 
ANC 
1 x 109/L 
Platelet counts 
75 x 109/L  
700 x 109/L 
Urinalysis 
 
HGB 
2 unit increase from baseline 
Glucose 
2 unit increase from baseline 
Ketones 
2 unit increase from baseline 
Total protein 
2 unit increase from baseline 
Coagulation 
 
INR 
>1.5 
 ALP=alkaline phosphatase; ALT=alanine aminotransferase; ANC=absolute neutrophil count AST=aspartate 
aminotransferase; BUN=blood urea nitrogen; GGT=gamma-glutamyl transpeptidase; HGB=hemoglobin; 
INR=international normalized ratio; LDH=lactate dehydrogenase; ULN=upper limit of normal range; WBC=white 
blood cell. 
8.5.1. 
Laboratory Values Meeting Hy’s Law Criteria 
All occurrences of possible drug-induced liver injury that meet Hy's law criteria as defined in the 
protocol Section 7.1.5.1 will be included in adverse events reporting. 
8.5.2. 
Other Clinical Laboratory Tests 
8.5.2.1. 
Human Chorionic Gonadotropin Test 
Serum beta-human chorionic gonadotropin (β-HCG) tests will be performed for all women of 
childbearing potential at screening. Urine pregnancy tests will be performed for all women of 
childbearing potential at the randomization visit, weeks 1, 2, and 3, and the EOT/early 
termination visit. Pregnancy test results will be listed. 
8.5.2.2. 
Follicle-Stimulating Hormone Test 
Postmenopausal women will have a follicle-stimulating hormone (FSH) test at screening. Results 
will be listed. 
8.6. 
Physical Examinations 
Any physical examination finding that is judged by the investigator as a clinically significant 
change (worsening) compared with a baseline value will be considered an adverse event, 
recorded on the CRF, and monitored as described in Section 7.1.2 of the study protocol. Shifts 
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from baseline to weeks 4, 8, 12, and 24, and last on study assessment (double-blind and open-
label) will be summarized using patient counts. 
Descriptive statistics for weight and height will be provided. 
8.7. 
Vital Signs 
Summary statistics for vital signs (pulse, systolic and diastolic blood pressure, body temperature, 
and respiratory rate) will be presented at baseline, weeks 4, 8, 12, and 24, and last on study 
assessment (double-blind and open-label). Vital signs values and changes from baseline to each 
visit and last on study assessment will be summarized using descriptive statistics. 
Summaries of potentially clinically significant abnormal values will include all postbaseline 
values (including scheduled, unscheduled, and early termination visits). The incidence of 
potentially clinically significant abnormal values will be summarized using descriptive statistics 
with the criteria specified in Table 4.  
Table 4 specifies the criteria for identifying vital signs as potentially clinically significant 
abnormal values. Note that in order to qualify as potentially clinically significant abnormal, a 
value needs to meet both criteria below: ie, have a value beyond the criterion value and a change 
of at least the magnitude specified in the change relative to baseline column. 
Table 4: 
Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign 
Criterion value 
Change relative to baseline 
Pulse 
120 bpm 
Increase of 15 bpm 
 
50 bpm 
Decrease of 15 bpm 
Systolic blood pressure 
180 mm Hg 
Increase of 20 mm Hg 
 
90 mm Hg 
Decrease of 20 mm Hg 
Diastolic blood pressure 
105 mm Hg 
Increase of 15 mm Hg 
 
50 mm Hg 
Decrease of 15 mm Hg 
Respiratory rate 
<10 breaths/min 
 
Body temperature 
≥38.3C 
Change of 1.1C 
bpm=beats per minute 
8.8. 
Electrocardiography 
Any ECG finding that is judged by the investigator as clinically significant (except at the 
screening visit) will be considered an adverse event. 
Shifts (normal and abnormal) from baseline to overall result interpretation, weeks 4, 8, 12, and 
24, and last on study assessment (double-blind and open-label) will be summarized using patient 
counts. For overall result interpretation the worst postbaseline finding for the patient (the 
abnormal finding if there are both normal and abnormal findings) will be used in the summaries. 
Summary statistics for ECG variables will be presented at baseline, weeks 4, 8, 12, and 24, and 
last on study assessment (double-blind and open-label). Actual values and changes from baseline 
to each visit and last on study assessment will be summarized using descriptive statistics. 
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8.9. 
Concomitant Medications or Therapies  
Concomitant therapies and medications, including medications that are taken on an as needed 
basis and occasional therapies, will be monitored during the study. Details of prohibited 
medications may be found in Section 5.7 of the study protocol. All concomitant medications will 
be coded using the WHO Drug. 
The incidence of concomitant therapies and medications will be summarized using descriptive 
statistics by therapeutic class category and PT. Patients are counted only once in each therapeutic 
class and only once in each PT category. Concomitant therapies and medications will include all 
medications up to the end of study as defined in the study protocol. 
The subset of concomitant pain medication and medication or therapy for migraine/headache will 
be summarized by the following indication categories. 
• preventive medication from protocol appendix for migraine/headache 
• opioids for migraine/headache 
• NSAIDS for migraine/headache 
• triptans for migraine/headache 
• ergots for migraine/headache 
• butalbital for migraine/headache 
• medication from protocol appendix for other reason than depression 
• benzodiazepines for other reason than anxiety/insomnia 
• other 
8.10. 
Electronic Columbia-Suicide Severity Rating Scale 
As part of the overall safety evaluation, the eC-SSRS will be used in conjunction with a qualified 
clinician’s (ie, the investigator or a medically qualified person designated by the investigator) 
clinical judgment to assess the patient’s suicidal ideation (severity and intensity) and behavior. 
The eC-SSRS Lifetime version will be completed by the patient at visit 1, and the eC-SSRS 
Since Last Visit version will be completed by the patient at all other time points. 
The results from the eC-SSRS will be listed. 
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9. 
TOLERABILITY VARIABLES AND ANALYSIS 
Tolerability is summarized with patient disposition. 
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10. 
STATISTICAL SOFTWARE 
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later. 
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11. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL 
There are no changes to analyses specified in the study protocol. 
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Appendix A. 
E-DIARY QUESTIONNAIRE 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
  
 
 
  
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
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Appendix B. 
LOGICS FOR ENDPOINTS DERIVATION 
  
 
 
  
  
  
  
  
 
  
  
 
  
  
  
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
  
  
  
  
 
 
 
  
  
 
  
 
  
 
 
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
  
  
  
  
  
  
  
  
 
  
 
  
 
 
 
 
  
  
  
  
  
  
 
 
 
  
 
 
 
  
 
  
  
  
 
  
 
  
  
 
 
 
 
 
  
  
  
  
 
  
 
 
 
 
 
  
 
  
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
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APPENDIX C. HAMILTON DEPRESSION RATING SCALE-17 
 
Hamilton Depression Rating Scale (HDRS)  
 
Reference: Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 
1960; 23:56–62  
Rating Clinician-rated  
Administration time 20–30 minutes  
Main purpose To assess severity of, and change in, depressive symptoms  
Population Adults  
 
Commentary  
The HDRS (also known as the Ham-D) is the most wide- ly used clinician-administered depression assessment 
scale. The original version contains 17 items (HDRS17) pertaining to symptoms of depression experienced over the 
past week. Although the scale was designed for completion after an unstructured clinical interview, there are now 
semi-structured interview guides available. The HDRS was originally developed for hospital inpatients, thus the 
emphasis on melancholic and physical symptoms of depression. A later 21-item version (HDRS21) included 4 items 
intended to subtype the depression, but which are sometimes, incorrectly, used to rate severity. A limitation of the 
HDRS is that atypical symptoms of depression (e.g., hypersomnia, hyperphagia) are not assessed (see SIGH-SAD, 
page 55). 
 
Scoring  
Method for scoring varies by version. For the HDRS17, a score of 0–7 is generally accepted to be within the normal 
range (or in clinical remission), while a score of 20 or higher (indicating at least moderate severity) is usually 
required for entry into a clinical trial.  
 
Versions  
The scale has been translated into a number of languages including French, German, Italian, Thai, and Turkish. As 
well, there is an Interactive Voice Response version (IVR), a Seasonal Affective Disorder version (SIGH-SAD, see 
page 55), and a Structured Interview Version (HDS-SIV). Numerous versions with varying lengths include the 
HDRS17, HDRS21, HDRS29, HDRS8, HDRS6, HDRS24, and HDRS7 (see page 30).  
 
Additional references  
Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6(4):278–96.  
Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry 1988; 
45(8):742–7. 
Address for correspondence  
The HDRS is in the public domain.  
 
Hamilton Depression Rating Scale (HDRS)  
PLEASE COMPLETE THE SCALE BASED ON A STRUCTURED INTERVIEW  
Instructions: for each item select the one “cue” which best characterizes the patient. Be sure to record the answers in 
the appropriate spaces (positions 0 through 4). 
 
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1 DEPRESSED MOOD (sadness, hopeless, helpless, worthless)  
0 |__| Absent.  
1 |__| These feeling states indicated only on questioning.  
2 |__| These feeling states spontaneously reported verbally.  
3 |__| Communicates feeling states non-verbally, i.e. through facial expression, posture, voice and tendency to weep.  
4 |__| Patient reports virtually only these feeling states in his/her spontaneous verbal and non-verbal communication.  
 
2 FEELINGS OF GUILT  
0 |__| Absent.  
1 |__| Self reproach, feels he/she has let people down.  
2 |__| Ideas of guilt or rumination over past errors or sinful deeds.  
3 |__| Present illness is a punishment. Delusions of guilt.  
4 |__| Hears accusatory or denunciatory voices and/or experiences threatening visual hallucinations. 
 
3 SUICIDE  
0 |__| Absent.  
1 |__| Feels life is not worth living.  
2 |__| Wishes he/she were dead or any thoughts of possible death to self.  
3 |__| Ideas or gestures of suicide.  
4 |__| Attempts at suicide (any serious attempt rate 4).  
 
4 INSOMNIA: EARLY IN THE NIGHT  
0 |__| No difficulty falling asleep.  
1 |__| Complains of occasional difficulty falling asleep, i.e. more than 1⁄2 hour.  
2 |__| Complains of nightly difficulty falling asleep.  
 
5 INSOMNIA: MIDDLE OF THE NIGHT  
0 |__| No difficulty.  
1 |__| Patient complains of being restless and disturbed during the night.  
2 |__| Waking during the night – any getting out of bed rates 2 (except for purposes of voiding).  
 
6 INSOMNIA: EARLY HOURS OF THE MORNING  
0 |__| No difficulty.  
1 |__| Waking in early hours of the morning but goes back to sleep.  
2 |__| Unable to fall asleep again if he/she gets out of bed.  
 
7 WORK AND ACTIVITIES  
0 |__| No difficulty.  
1 |__| Thoughts and feelings of incapacity, fatigue or weakness related to activities, work or hobbies.  
2 |__| Loss of interest in activity, hobbies or work – either directly reported by the patient or indirect in listlessness, indecision and vacillation 
(feels he/she has to push self to work or activities).  
3 |__| Decrease in actual time spent in activities or decrease in productivity. Rate 3 if the patient does not spend at least three hours a day in 
activities (job or hobbies) excluding routine chores.  
4 |__| Stopped working because of present illness. Rate 4 if patient engages in no activities except routine chores, or if patient fails to perform 
routine chores unassisted.  
 
8 RETARDATION (slowness of thought and speech, impaired ability to concentrate, decreased motor activity)  
0 |__| Normal speech and thought.  
1 |__| Slight retardation during the interview.  
2 |__| Obvious retardation during the interview.  
3 |__| Interview difficult.  
4 |__| Complete stupor.  
 
9 AGITATION  
0 |__| None.  
1 |__| Fidgetiness.  
2 |__| Playing with hands, hair, etc.  
3 |__| Moving about, can’t sit still.  
4 |__| Hand wringing, nail biting, hair-pulling, biting of lips.  
 
 
10 ANXIETY PSYCHIC  
0 |__| No difficulty.  
1 |__| Subjective tension and irritability.  
2 |__| Worrying about minor matters.  
3 |__| Apprehensive attitude apparent in face or speech.  
4 |__| Fears expressed without questioning.  
 
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11 ANXIETY SOMATIC (physiological concomitants of anxiety) such as:  
gastro-intestinal – dry mouth, wind, indigestion, diarrhea, cramps, belching  
cardio-vascular – palpitations, headaches  
respiratory – hyperventilation, sighing  
urinary frequency  
sweating  
0 |__| Absent.  
1 |__| Mild.  
2 |__| Moderate.  
3 |__| Severe.  
4 |__| Incapacitating.  
 
12 SOMATIC SYMPTOMS GASTRO-INTESTINAL  
0 |__| None.  
1 |__| Loss of appetite but eating without staff encouragement. Heavy feelings in abdomen.  
2 |__| Difficulty eating without staff urging. Requests or requires laxatives or medication for bowels or medication for gastro-intestinal symptoms.  
 
13 GENERAL SOMATIC SYMPTOMS  
0 |__| None.  
1 |__| Heaviness in limbs, back or head. Backaches, headaches, muscle aches. Loss of energy and fatigability.  
2 |__| Any clear-cut symptom rates 2.  
 
14 GENITAL SYMPTOMS (symptoms such as loss of libido, menstrual disturbances)  
0 |__| Absent.  
1 |__| Mild.  
2 |__| Severe.  
 
15 HYPOCHONDRIASIS  
0 |__| Not present.  
1 |__| Self-absorption (bodily).  
2 |__| Preoccupation with health.  
3 |__| Frequent complaints, requests for help, etc.  
4 |__| Hypochondriacal delusions.  
 
16 LOSS OF WEIGHT (RATE EITHER a OR b)  
a) According to the 
patient:  
0 |__| No weight loss.  
1 |__| Probable weight loss 
associated with present 
illness.  
2 |__| Definite (according to 
patient) weight loss.  
3 |__| Not assessed.  
b) According to weekly 
measurements:  
0 |__| Less than 1 lb weight 
loss in week.  
1 |__| Greater than 1 lb 
weight loss in week.  
2 |__| Greater than 2 lb 
weight loss in week.  
3 |__| Not assessed.  
 
17 INSIGHT  
0 |__| Acknowledges being depressed and ill.  
1 |__| Acknowledges illness but attributes cause to bad food, climate, overwork, virus, need for rest, etc.  
2 |__| Denies being ill at all.  
 
Total score: |__|__| 
 
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APPENDIX D. MIGRAINE-SPECIFIC QUALITY OF LIFE 
QUESTIONNAIRE (MSQ) (VERSION 2.1) 
 
 
While answering the following questions, please think about all migraine attacks you may have had in 
the past 4 weeks. 
 
1. 
In the past 4 weeks, how often have migraines interfered with how well you dealt with family, 
friends and others who are close to you?  (Select only one response.) 
 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
 
2. 
In the past 4 weeks, how often have migraines interfered with your leisure time activities, such as 
reading or exercising?  (Select only one response.) 
 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
 
3. 
In the past 4 weeks, how often have you had difficulty in performing work or daily activities 
because of migraine symptoms?  (Select only one response.) 
 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
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4. 
In the past 4 weeks, how often did migraines keep you from getting as much done at work or at 
home?  (Select only one response.) 
 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
 
5. 
In the past 4 weeks, how often did migraines limit your ability to concentrate on work or daily 
activities?  (Select only one response.) 
 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
 
6. 
In the past 4 weeks, how often have migraines left you too tired to do work or daily activities? 
(Select only one response.) 
 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
7. 
In the past 4 weeks, how often have migraines limited the number of days you have felt energetic? 
(Select only one response.) 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
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8. 
In the past 4 weeks, how often have you had to cancel work or daily activities because you had a 
migraine? (Select only one response.) 
 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
 
9. 
In the past 4 weeks, how often did you need help in handling routine tasks such as every day 
household chores, doing necessary business, shopping, or caring for others, when you had a 
migraine? (Select only one response.) 
 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
 
10. 
In the past 4 weeks, how often did you have to stop work or daily activities to deal with migraine 
symptoms? (Select only one response.) 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
 
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11. 
In the past 4 weeks, how often were you not able to go to social activities such as parties, dinner 
with friends, because you had a migraine? (Select only one response.) 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
 
12. 
In the past 4 weeks, how often have you felt fed up or frustrated because of your migraines? (Select 
only one response.) 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
 
13. 
In the past 4 weeks, how often have you felt like you were a burden on others because of your 
migraines?  (Select only one response.) 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
 
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14. 
In the past 4 weeks, how often have you been afraid of letting others down because of your 
migraines? (Select only one response.) 
 
 
1❑  None of the time 
 
2❑  A little bit of the time 
 
3❑  Some of the time 
 
4❑  A good bit of the time 
 
5❑  Most of the time 
 
6❑  All of the time 
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APPENDIX E. SCORING INSTRUCTIONS FOR MSQOL (VERSION 2.1) 
MSQOL (Version 2.1) is a 14-item self-administered questionnaire. Patients are asked to provide 
responses to each item using a standard six-point Likert type scale. The specific items which 
make up each dimension are presented in Appendix D.  
Scoring 
Each of the three MSQOL dimensions is scored independently. For each dimension, a higher 
score indicates a better health status. The 14 MSQOL items used in scoring are worded with a 
negative perspective, therefore must be recoded before the dimension scores are calculated.  
The scoring of the MSQOL is completed in 3 steps: 
1. Recoding of MSQOL items (final item value assignment) 
2. Computation of raw dimension scores 
3. Transformation of raw dimension scores to a 0 to 100 scale 
Final item value assignment  
The precoded and final item values for each MSQOL item response is shown in Table 1. All item 
values range from 1 to 6.  
How to handle missing values 
In the event that responses on one or more items within a dimension are missing, a missing item 
value may be estimated using the average of the other items within the same dimension.  
The general rule of thumb for handling missing data similar to the SF-36 Health Survey is 
applied. If a respondent answered at least half of the items in a multi-item scale (or half plus one 
in the case of scales with an odd number of items), a missing item value can be estimated. 
Therefore, when the number of missing items is fewer than or equal to 3 for the Role Function-
Restrictive, fewer than or equal to 2 for the Role Function-Preventive, and fewer than or equal to 
1 for the Emotional Function dimension, the value of missing item(s) can be estimated using the 
average of the other completed items within the same dimension.  
For example, if a respondent leaves one item (e.g. item 4) within the 7-item Role Function-
Restrictive dimension blank, substitute the respondent’s average score across the six completed 
Role Function-Restrictive items (e.g. item 1, 2, 3, 5, 6, 7) for that one item. 
It is important to note that the psychometric properties of the MSQOL dimension are based on 
the assumption that all items within the dimension are answered. Therefore, when the number of 
missing responses exceeds the limits as noted above, a dimension score may not be estimated 
and should be considered as missing.  
Raw score computation 
Once a final item value has been assigned to each item, a raw score can be computed for each 
MSQOL dimension. The raw score for each dimension is simply the algebraic sum of the final 
item value for all items in that dimension. The range of each raw dimension score is shown in 
Table 2.  
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Transformation of dimension scores 
After the raw score for each MSQOL dimension is computed, the each score is transformed to a 
0 to 100 scale. The transformation formula for each dimension is provided in Table 2. The 
transformation process allows each dimension score to reflect the percentage of the total possible 
score achieved (since 100 equal the highest score). 
Scoring checks 
The following scoring checks are recommended to ensure accuracy in data entry and processing: 
1) After recoding items to their final item values, inspect the frequency distribution to verify 
all item values are within the range of 1 to 6.  
2) Inspect frequency distributions for raw scores and transformed scores to verify that all 
scores are within the expected ranges.  
Table 1 Precoded and final item values for MSQOL item responses 
Item No.  
Response categories 
Precoded items value Final item value 
1-14  
None of the time 
1 
6 
 
A little bit of the time 
2 
5 
 
Some of the time 
3 
4 
 
A good bit of the time 
4 
3 
 
Most of the time 
5 
2 
 
All of the time 
6 
1 
Table 2 Raw score and transformation formula for each MSQOL dimension 
MSQOL dimension 
Item No. 
Raw score range 
Transformation formula 
Role Function - Restrictive 
1-7 
7 to 42 
(𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒−7) × 100
35
 
Role Function - Preventive 
8-11 
4 to 24 
(𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒−4) × 100
20
 
Emotional Function 
12-14 
3 to 18 
(𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒−3) × 100
15
 
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APPENDIX F.  CLINICAL GLOBAL IMPRESSION-SEVERITY SCALE 
 
Clinical Global Impression (CGI) 
Reference: Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 1976. Rockville, 
MD, U.S. Department of Health, Education, and Welfare 
Rating Clinician-rated 
Administration time Varies with familiarity with 
patient 
Main purpose To provide a global rating of illness 
severity, improvement and response to treatment 
Population  Adults 
Commentary 
Amongst the most widely used of extant brief 
assessment tools in psychiatry, the CGI is a 3-item 
observer-rated scale that measures illness severity 
(CGIS), global improvement or change (CGIC) and 
therapeutic response. The illness severity and 
improvement sections of the instrument are used more 
frequently than the therapeutic response section in both 
clinical and research settings. The Early Clinical Drug 
Evaluation Program (ECDEU) ver- sion of the CGI 
(reproduced here) is the most widely used format, and 
asks that the clinician rate the patient relative to their 
past experience with other patients with the same 
diagnosis, with or without collateral information. 
Several alternative versions of the CGI have been 
developed, how- ever, such as the FDA Clinicians’ 
Interview-Based Impression of Change (CIBIC), which 
uses only informa- tion collected during the interview, 
not collateral. The CGI has proved to be a robust 
measure of efficacy in  many clinical drug trials, and is 
easy and quick to admin- ister, provided that the 
clinician knows the patient well. 
Scoring 
The CGI is rated on a 7-point scale, with the severity of 
illness scale using a range of responses from 1 (normal) 
through to 7 (amongst the most severely ill patients). 
CGI-C scores range from 1 (very much improved) 
through to 7 (very much worse). Treatment response 
ratings should take account of both therapeutic efficacy 
and treatment-related adverse events and range from 0 
(marked improvement and no side-effects) and 4 
(unchanged or worse and side-effects outweigh the 
thera- peutic effects). Each component of the CGI is 
rated sepa- rately; the instrument does not yield a 
global score. 
Versions 
CGI for bipolar disorder (CGI-BD), FDA Clinicians’ 
Interview-Based Impression of Change (CIBIC), 
Clinicians’ Interview-Based Impression of Change-
Plus (CIBIC+), NYU CIBIC+, Parke-Davis 
Pharmaceuticals Clinical Interview-Based Impression 
(CIBI); the CGI has been translated into most 
languages. 
Additional references 
Leon AC, Shear MK, Klerman GL,  Portera  L, 
Rosenbaum JF, Goldenberg I. A comparison of  
symptom determinants of patient and clinician global 
ratings in patients with panic disorder and depression. J 
Clin Psychopharmacol 1993; 13(5):327–31. 
Spearing MK, Post RM, Leverich GS, Brandt D, Nolen 
W. Modification of the Clinical Global Impressions 
(CGI) Scale for use in bipolar illness (BP): the CGI-
BP. Psychiatry Res 1997; 73(3):159–71. 
Zaider TI, Heimberg RG, Fresco DM, Schneier FR, 
Liebowitz MR. Evaluation of the clinical global 
impression scale among individuals with social anxiety 
disorder. Psychol Med 2003; 33(4):611–22. 
Address for correspondence 
Not applicable – the CGI is in the public domain. 
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1. Severity of illness 
Considering your total clinical experience with this particular population, how mentally ill is the patient at 
this time?  
0  = Not assessed 
4 = Moderately ill 
1 = Normal, not at  all ill 
5 = Markedly ill  
2 = Borderline mentally ill   6 = Severely ill 
3 = Mildly ill 
7 = Among the most extremely ill patients 
 
2. Global improvement: Rate total improvement whether or not, in your judgement, it is due entirely to drug 
treatment. Compared to his condition at admission to the project, how much has he changed? 
0 = Not assessed 
4 = No change 
1 = Very much improved 
5 = Minimally worse  
2 = Much improved 
6 = Much worse 
3 = Minimally improved 
7 = Very much worse 
 
3. Efficacy index: Rate this item on the basis of drug effect only. 
Select the terms which best describe the degrees of therapeutic effect and side effects and record the number in the box where the 
two items intersect. 
EXAMPLE: Therapeutic effect is rated as ‘Moderate’ and side effects are judged ‘Do not significantly interfere with patient’s functioning’. 
 
Therapeutic effect 
Side effects
None 
Do not significantly 
Significantly interferes 
Outweighs 
interfere with 
patient’s functioning 
with patient’s 
functioning 
therapeutic 
effect 
Marked 
Vast improvement. Complete or nearly complete 
remission of all symptoms 
01 
02 
03 
04 
Moderate 
Decided improvement. Partial remission of 
symptoms 
05 
06 
07 
08 
Minimal 
Slight improvement which doesn’t alter status 
of care of patient 
09 
10 
11 
12 
Unchanged or worse 
13 
14 
15 
16 
Not assessed = 00 
Reproduced from Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 1976. Rockville, MD, U.S. Department of Health,  
Education, and Welfare 
 
Clinical Global Impression (CGI) 
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APPENDIX G. HIT-6™ HEADACHE IMPACT TEST 
HIT is a tool used to measure the impact headaches have on your ability to function on the job, at school, 
at home and in social situations. Your score shows you the effect that headaches have on normal daily life 
and your ability to function. HIT was developed by an international team of headache experts from 
neurology and primary care medicine in collaboration with the psychometricians who developed the SF-
36® health assessment tool. This questionnaire was designed to help you describe and communicate the 
way you feel and what you cannot do because of headaches. 
To complete, please circle one answer for each question. 
When you have headaches, how often is the pain severe? 
never 
rarely 
sometimes 
very often 
always 
How often do headaches limit your ability to do usual daily activities including household work, 
work, school, or social activities? 
never 
rarely 
sometimes 
very often 
always 
When you have a headache, how often do you wish you could lie down? 
never 
rarely 
sometimes 
very often 
always 
In the past 4 weeks, how often have you felt too tired to do work or daily activities because of your 
headaches? 
never 
rarely 
sometimes 
very often 
always 
In the past 4 weeks, how often have you felt fed up or irritated because of your headaches? 
never 
rarely 
sometimes 
very often 
always 
In the past 4 weeks, how often did headaches limit your ability to concentrate on work or daily 
activities? 
never 
rarely 
sometimes 
very often 
always 
 
 
+ 
 
+ 
 
+ 
 
+ 
 
COLUMN 1 
6 points each 
 
 
COLUMN 2 
8 points each 
 
 
COLUMN 3 
10 points each 
 
COLUMN 4 
11 points each 
 
COLUMN 5 
13 points each 
To score, add points for answers in each column. 
If your HIT-6 is 50 or higher: 
You should share your results with your doctor. Headaches that stop you from enjoying 
the important things in life, like family, work, school or social activities could be migraine 
 
 
 
 
TOTAL 
SCORE 
©2001 QualityMetric, Inc. and GlaxoSmithKline Group of Companies. All rights reserved. 
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APPENDIX H. PATIENT HEALTH QUESTIONNAIRE (PHQ-9)  
PATIENT HEALTH QUESTIONNAIRE-9 
(PHQ-9) 
Over the last 2 weeks, how often have you been 
bothered by any of the following problems? 
(Use “✔” to indicate your answer)  
 
Not at all 
 
Several 
days 
 
More 
than half 
the days 
 
Nearly 
every 
day 
 
1.  Little interest or pleasure in doing things  
0 
1 
2 
3 
2.  Feeling down, depressed, or hopeless  
0 
1 
2 
3 
3.  Trouble falling or staying asleep, or sleeping too much  
0 
1 
2 
3 
4.  Feeling tired or having little energy  
0 
1 
2 
3 
5.  Poor appetite or overeating  
0 
1 
2 
3 
6.  Feeling bad about yourself — or that you are a failure 
or have let yourself or your family down 
0 
1 
2 
3 
7.  Trouble concentrating on things, such as reading the 
newspaper or watching television  
0 
1 
2 
3 
8.  Moving or speaking so slowly that other people could 
have noticed? Or the opposite — being so fidgety or 
restless that you have been moving around a lot more 
than usual 
0 
1 
2 
3 
9.  Thoughts that you would be better off dead or of 
hurting yourself in some way  
0 
1 
2 
3 
FOR OFFICE CODING                 0     +  ______ +  _______  + ______  
=Total Score: ______ 
 
If you checked off any problems, how difficult have these problems made it for you to do your work,  
take care of things at home, or get along with other people? 
Not difficult 
at all 
⸮ 
Somewhat 
difficult 
⸮ 
Very 
difficult 
⸮ 
Extremely 
difficult 
⸮ 
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APPENDIX I. HAMILTON ANXIETY SCALE 
 
Hamilton Depression Rating Scale (HAM-A) 
Reference: Hamilton M.The assessment of anxiety states by rating. Br J Med Psychol 1959; 
32:50–55 
Rating Clinician-rated 
Administration time 10-15 minutes 
Main purpose To assess the severity of symptoms of 
anxiety 
Population Adults, adolescents and children 
 
Commentary 
The HAM-A was one of the first rating scales 
developed to measure the severity of anxiety 
symptoms, and is still widely used today in both 
clinical and research settings. The scale consists of 14 
items, each defined by a series of symptoms, and 
measures both psychic anxiety (mental agitation and 
psychological distress) and somatic anxiety (physical 
complaints related to anxiety). Although the HAM-A 
remains widely used as an outcome measure in clinical 
trials, it has been criticized for its sometimes poor 
ability to discriminate between anxiolytic and 
antidepressant effects, and somatic anxiety versus 
somatic side effects. The HAM-A does not provide any 
standardized probe questions. Despite this, the reported 
levels of interrater reliability for the scale appear to be 
acceptable. 
Scoring 
Each item is scored on a scale of 0 (not present) to 4 
(severe), with a total score range of 0–56, where <17 
indicates mild severity, 18–24 mild to moderate 
severity and 25–30 moderate to severe. 
 
Versions 
The scale has been translated into: Cantonese for 
China, French and Spanish. An IVR version of the 
scale is available from Healthcare Technology 
Systems. 
 
Additional references 
Maier W, Buller R, Philipp M, Heuser I. The Hamilton 
Anxiety Scale: reliability, validity and sensitivity to 
change in anxiety and depressive disorders. J Affect 
Disord 1988;14(1):61–8. 
Borkovec T and Costello E. Efficacy of applied 
relaxation and cognitive behavioral therapy in the 
treatment of generalized anxiety disorder. J Clin 
Consult Psychol 1993; 61(4):611–19 
 
Address for correspondence 
The HAM-A is in the public domain. 
 
 
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Below is a list of phrases that describe certain feeling that people have. Rate the patients by finding the answer which best describes the extent to 
which he/she has these conditions. Select one of the five responses for each of the fourteen questions. 
 
0 = Not present, 
1 = Mild, 
2 = Moderate, 
3 = Severe, 
4 = Very severe. 
 
1 
Anxious mood 
0 1 
2 
3 
4 
Worries, anticipation of the worst, fearful anticipation, irritability. 
2 
Tension 
0 1 
2 
3 
4 
Feelings of tension, fatigability, startle response, moved to 
tears easily, trembling, feelings of restlessness, inability to 
relax. 
3 
Fears 
0 1 
2 
3 
4 
Of dark, of strangers, of being left alone, of animals, of 
traffic, of crowds. 
4 
Insomnia 
0 1 
2 
3 
4 
Difficulty in falling asleep, broken sleep, unsatisfying sleep and 
fatigue on waking, dreams, nightmares, night terrors. 
5 
Intellectual 
0 1 
2 
3 
4 
Difficulty in concentration, poor memory. 
6 
Depressed mood 
0 1 
2 
3 
4 
Loss of interest, lack of pleasure in hobbies, depression, early 
waking, diurnal swing. 
7 
Somatic (muscular) 
0 1 
2 
3 
4 
Pains and aches, twitching, stiffness, myoclonic jerks, grinding 
of teeth, unsteady voice, increased muscular tone. 
 
 
8 
Somatic (sensory) 
0 1 
2 
3 
4 
Tinnitus, blurring of vision, hot and cold flushes, feelings of 
weakness, pricking sensation. 
9 
Cardiovascular symptoms 
0 1 
2 
3 
4 
Tachycardia, palpitations, pain in chest, throbbing of vessels, 
fainting feelings, missing beat. 
10 
Respiratory symptoms 
0 1 
2 
3 
4 
Pressure or constriction in chest, choking feelings, 
sighing, dyspnea. 
11 
Gastrointestinal symptoms 
0 1 
2 
3 
4 
Difficulty in swallowing, wind abdominal pain, burning 
sensations, abdominal fullness, nausea, vomiting, borborygmi, 
looseness of bowels, loss of weight, constipation. 
12 
Genitourinary symptoms 
0 1 
2 
3 
4 
Frequency of micturition, urgency of micturition, amenorrhea, 
menorrhagia, development of frigidity, premature ejaculation, loss 
of libido, impotence. 
13 
Autonomic symptoms 
0 1 
2 
3 
4 
Dry mouth, flushing, pallor, tendency to sweat, giddiness, 
tension headache, raising of hair. 
14 
Behavior at interview 
0 1 
2 
3 
4 
Fidgeting, restlessness or pacing, tremor of hands, furrowed 
brow, strained face, sighing or rapid respiration, facial pallor, 
swallowing, 
 
etc. 
Hamilton Anxiety Rating Scale (HAM-A) 
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APPENDIX J. WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE: GENERAL HEALTH V2.0 (WPAI:GH) 
 
The following questions ask about the effect of your health problems on your ability to work and perform 
regular activities. By health problems we mean any physical or emotional problem or symptom. Please 
fill in the blanks or circle a number, as indicated. 
 
1. 
Are you currently employed (working for pay)?  
____  NO 
____  YES 
 
If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
 
2. 
During the past seven days, how many hours did you miss from work because of your health 
problems? Include hours you missed on sick days, times you went in late, left early, etc., because of 
your health problems. Do not include time you missed to participate in this study. 
_____HOURS 
 
3. 
During the past seven days, how many hours did you miss from work because of any other reason, 
such as vacation, holidays, time off to participate in this study? 
_____HOURS 
 
4. 
During the past seven days, how many hours did you actually work? 
_____HOURS (If “0”, skip to question 6.) 
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5. 
During the past seven days, how much did your health problems affect your productivity while you 
were working?  
 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as usual. If 
health problems affected your work only a little, choose a low number. Choose a high number if 
health problems affected your work a great deal.  
 
Consider only how much health problems affected  
productivity while you were working. 
Health problems 
had no effect on 
my work 
 
 
 
 
 
 
 
 
 
 
 
Health problems 
completely 
prevented me from 
working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 
6. 
During the past seven days, how much did your health problems affect your ability to do your 
regular daily activities, other than work at a job?  
 
By regular activities, we mean the usual activities you do, such as work around the house, 
shopping, childcare, exercising, studying, etc. Think about times you were limited in the amount or 
kind of activities you could do and times you accomplished less than you would like. If health 
problems affected your activities only a little, choose a low number. Choose a high number if health 
problems affected your activities a great deal.  
 
Consider only how much health problems affected your ability  
to do your regular daily activities, other than work at a job. 
Health problems 
had no effect on my 
daily activities 
 
 
 
 
 
 
 
 
 
 
 
Health problems 
completely 
prevented me from 
doing my daily 
activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 
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