A Phase 3, Multicenter, Randomized, Open-label Study to Evaluate the Long-term Safety and Tolerability of Oral Atogepant for the Prevention of Migraine in Participants With Episodic Migraine
Phase: PHASE3
Conditions: Episodic Migraine
Sponsor: Allergan

 
     
   
   
  
         N C T 0 3 7 0 0 3 2 0  
 
St u d y I D:  3 1 0 1- 3 0 2- 0 0 2 
 
 
Titl e:  A  P H A S E  3,  M U L TI C E N T E R,  R A N D O MI Z E D,  O P E N -L A B E L  S T U D Y 
T O  E V A L U A T E  T H E  L O N G -T E R M  S A F E T Y  A N D  T O L E R A BI LI T Y  O F 
O R A L  A T O G E P A N T  F O R  T H E  P R E V E N TI O N  O F  MI G R AI N E I N 
P A R TI CI P A N T S  WI T H  E PI S O DI C  MI G R AI N E  
 
                           Pr ot o c ol  D at e:  A pril   2 4,  2 0 2 0 

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1
1 
Title P a ge
A L L E R G A N –
T he f oll o wi n g c o ntai ns 
 pr o prietar y i nf or mati o n 
w hic h is t he pr o pert y of Aller ga n
A P H A S E 3, M U L TI C E N T E R, R A N D O MI Z E D, O P E N -L A B E L  S T U D Y T O E V A L U A T E T H E 
L O N G -T E R M S A F E T Y  AN D T O L E R A BI LI T Y  O F O R A L AT O G E P A N T F O R T H E 
P R E V E N TI O N O F MI G R AI N E I N P A R T I CI PA N T S WI T H E PI S O DI C MI G R AI N E
Pr ot oc ol N u m ber:
3 1 0 1- 3 0 2- 0 0 2
E u dra C T N u m ber (if a p plica ble):
P hase:
3
Na me of St u d y I nter ve nti o n : 
At o ge pa nt
S p o ns or:
Aller ga n P har mace uticals I nter nati o nal Li mite d
Marl o w I nter nati o nal
T he Par k wa y, Marl o w S L 7 1 Y L 
U nite d Ki n g d o m
U S A ge nt
Aller ga n Sales, L L C
2 5 2 5 D u P o nt Dri ve
Irvi ne, Calif or nia U S A
9 2 6 1 2
E mer ge nc y Tele p h o ne N u m ber(s):
Seri o us A d verse E ve nt Re p orti n g 
Fa x N u m ber(s):
Bac k u p fa x n u m ber
E mail
Aller ga n Me dical Safet y P h ysicia n
C o ntact I nf or mati o n:
Refer t o t he St u d y C o ntacts Pa ge
Aller ga n Si g nat or y:
Ori gi nal Pr ot oc ol Date :
A m e n d me nt 1 Date:
A m e n d me nt 2 Date:
2 2 A u g ust 2 0 1 8
1 4 Mar c h 2 0 1 9
A pril 2 0 2 0
  Refer t o t he fi nal pa ge of t his pr ot oc ol f or electr o nic si g nat ure a n d date of a p pr o val.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
2
T he f oll o wi n g i nf or mati o n ca n be f o u n d o n F D A F or m 1 5 7 2 a n d/ or st u d y c o ntacts pa ge: Na me 
a n d c o ntact i nf or mati o n of Aller ga n st u d y pers o n nel a n d E mer ge nc y Tele p h o ne N u m bers; na me, 
a d dress , a n d state me nt of q ualificati o ns of eac h i n vesti gat or; na me of eac h s u bi n vesti gat or 
w or ki n g u n der t he s u per visi o n of t he i n vesti gat or; na me a n d a d dress of t he res earc h facilities t o 
be use d; na me a n d a d dress of eac h re vie wi n g I RB; U S 2 1 C F R 3 1 2. 2 3 secti o n 6(iii) b .
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

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I N V E S TI G AT O R SI G N A T U R E P A G E
I N V E S TI G A T O R:
I a gree t o:

I m ple me nt a n d c o n d uct t his st u d y dili ge ntly a n d i n strict c o m plia nce wit h t he pr ot oc ol, G C P s 
a n d all a p plica ble la ws a n d re g ulati o ns.

Mai ntai n all i nf or mati o n s u p plie d b y  Aller ga n i n c o nfi de nce a n d, w he n t his i nf or mati o n is 
s u b mitte d t o a n IR B, I E C or a n other gr o u p, it will be s u b mitte d wit h a desi g nati o n t hat t he 
material is 

E ns ure t hat all pers o ns assisti n g wit h t he trial are a de q uatel y i nf or me d a b o ut t he pr ot oc ol, t he 
st u d y i nter ve nti o n(s), a n d t heir trial-relate d d uties a n d f u ncti o ns.
I have rea d t his pr ot oc ol i n its e ntiret y  a n d I a gree t o all as pects.
I n vesti gat or Pri nte d Na me 
Si g nat ure
Date
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

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Ta ble of C o nte nts
1
Title P a ge ......................................................................................................... 1
Ta ble of C o nte nts ........................................................................................................................... 4
List of T a bles 
........................................................................................................................... 8
List of Fi g ures 
........................................................................................................................... 8
2
Pr ot oc ol S u m mar y ............................................................................................ 9
1
Bac k gr o u n d a n d Cli nical Rati o nale ................................................................ 1 9
1. 1
Bac k gr o u n d ..................................................................................................... 1 9
1. 2
O ver vie w of At o ge pa nt ................................................................................... 1 9
1. 3
St u d y Rati o nale ............................................................................................... 2 0
1. 4
Rati o nale f or D oses a n d D ose Re gi me ns Selecte d ......................................... 2 0
2
St u d y  O bjecti ve a n d Cli nical H yp ot heses ....................................................... 2 0
2. 1
St u d y  O bjecti ve............................................................................................... 2 0
2. 2
Cli nical H y p ot hesis ......................................................................................... 2 0
3
St u d y  Desi g n................................................................................................... 2 0
3. 1
Str uct ure .......................................................................................................... 2 0
3. 2
Data Safet y M o ni t ori n g B oar d........................................................................ 2 2
3. 3
A dj u dicati o n C o m mittee ................................................................................. 2 2
4
St u d y  P o p ulati o n a n d E ntr y Criteria............................................................... 2 2
4. 1
N u m ber of Partici pa nts ................................................................................... 2 2
4. 2
St u d y  P o p ulati o n C haracteristics.................................................................... 2 2
4. 3
I ncl usi o n Criteria ............................................................................................ 2 3
4. 4
E xcl usi o n Criteria ........................................................................................... 2 4
4. 5
Per mis si ble a n d Pr o hi bite d Me dicati o ns/ Treat me nts...................................... 2 8
4. 5. 1
Per missi ble Me dicati o ns/ T reat me nts .............................................................. 2 8
4. 5. 2
Pr o hi bite d Me dicati o ns/ T reat me nts ................................................................ 2 8
4. 5. 3
Defi niti o n of W o me n of ( N o n- ) C hil d beari n g P ote ntial a n d/ or Acce pta ble 
C o ntrace pti ve Met h o ds ................................................................................... 2 9
4. 5. 4
S pecial Diet or Acti vities ................................................................................ 3 1
4. 6
Scree n Fail ures ................................................................................................ 3 1
5
St u d y  Inter ve nti o n ........................................................................................... 3 1
5. 1
St u d y  In ter ve nti o n a n d F or m ulati o ns.............................................................. 3 1
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

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5. 2
C o ntr ol I nter ve nti o n ........................................................................................ 3 1
5. 3
Met h o ds f or Mas ki n g/ Bli n di n g ....................................................................... 3 1
5. 4
Tr eat me nt All ocati o n Rati o ............................................................................. 3 2
5. 5
Met h o d f or Assi g n me nt t o Tr eat me nt Gr o u ps/ Ra n d o mizati o n ....................... 3 2
5. 6
Tr eat me nt Re gi me n a n d D osi n g ..................................................................... 3 2
5. 6. 1
Partici pa nts Ra n d o mize d t o At o ge pa nt ........................................................... 3 3
5. 6. 2
Partici pa nts Ra n d o mize d t o Oral S O C Mi grai ne Pre ve nti o n Me dicat i o n...... 3 3
5. 6. 3
Me dici nes Rec o g nize d as Safe a n d Ef fecti ve f or t he Pre ve nti o n of Mi grai ne 3 4
5. 7
St ora ge of St u d y  Inter ve nti o n ......................................................................... 3 5
6
Res p o nse Meas ures a n d S u m mar y  of Data C ollecti o n Met h o ds.................... 3 5
6. 4
Safet y  Meas ures.............................................................................................. 4 0
6. 4. 1
A d verse E ve nts ............................................................................................... 4 0
6. 4. 2
A d verse E ve nts of S pecial I nterest ................................................................. 4 0
6. 4. 3
Cli nical L a b orat or y Deter mi nati o ns ............................................................... 4 0
6. 4. 4
Vi tal Si g ns....................................................................................................... 4 2
6. 4. 5
P h y sical E xa mi nati o n...................................................................................... 4 2
6. 4. 6
Electr ocar di o gra ms ......................................................................................... 4 2
6. 4. 7
C o l u m bia-S uici de Se verit y  Rati n g Scale ( C-S S R S) ....................................... 4 2
6. 5
Ot her St u d y  S u p plies ...................................................................................... 4 3
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

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6. 6
S u m mar y  of Met h o ds of Data C ollecti o n....................................................... 4 3
7
Statistical Pr oce d ures ...................................................................................... 4 4
7. 3. 2
Safet y  Anal y ses ............................................................................................... 4 7
7. 5
Sa m ple S ize Calc ulati o n................................................................................. 4 8
8
St u d y  Visit Sc he d ule a n d Pr oce d ures.............................................................. 4 8
8. 1
Partici pa nt E ntr y  Pr oce d ures........................................................................... 4 8
8. 1. 1
O ver vie w of E ntr y  Pr oce d ures........................................................................ 4 8
8. 1. 2
I nf or me d C o nse nt a n d Partici pa nt Pri vac y ..................................................... 4 8
8. 1. 3
Pr oce d ure f or D u plicate Partici pa nt I de ntificati o n – Ve rifie d Cli nical Trials. 4 9
8. 2
Wa s h o ut Inter vals/ R u n -i n ............................................................................... 4 9
8. 3
Pr oce d ures f or Fi nal St u d y  E ntr y.................................................................... 4 9
8. 4
Vi sits a n d Ass ociate d Pr oce d ures .................................................................... 4 9
8. 4. 1
Vi sit 1 ( Scree ni n g/ Baseli ne) Da y -3 5 t o Da y  - 2 8 ........................................... 5 0
8. 4. 2
O pe n -la bel Treat me nt Peri o d ( 5 2 We e ks) ....................................................... 5 1
8. 4. 2. 1 
Vi sit 2 ( Ra n d o mizati o n) Da y 1....................................................................... 5 1
8. 4. 2. 2 
Vi sits 3 t o 1 4 ( Wee k 4 t o 4 8) ........................................................................... 5 2
8. 4. 2. 3 
Vi sit 1 5/ Earl y Ter mi nati o n ( Wee k 5 2) ............................................................ 5 3
8. 4. 3
Safet y  F oll o w-u p Peri o d ( 4 We e ks) ................................................................ 5 4
8. 4. 3. 1 
Vi sit 1 6/ E n d of St u d y ( Wee k 5 6) C o n d ucte d D uri n g I n -Pers o n V isit ( Pri or t o 
t he C O VI D-1 9 Pa n de mic) ............................................................................... 5 4
8. 5
I nstr ucti o ns f or t he Partici pa nts ...................................................................... 5 5
8. 6
U nsc he d ule d V isits.......................................................................................... 5 6
8. 7
C o m pli a nce wit h Pr ot oc ol ............................................................................... 5 6
8. 8
Earl y Disc o nti n uati o n of Partici pa nts ............................................................. 5 6
8. 9
Wi t h dra wal Criteria......................................................................................... 5 7
8. 1 0
St u d y  Ter mi nati o n ........................................................................................... 5 7
9
A d verse E ve nts ............................................................................................... 5 7
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

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9. 1
Defi niti o ns ....................................................................................................... 5 7
9. 1. 1
A d verse E ve nt ................................................................................................. 5 7
9. 1. 2
Seri o us A d verse E ve nt .................................................................................... 5 8
9. 1. 3
I nte nsity ........................................................................................................... 6 0
9. 1. 4
Assess me nt of Ca usalit y ................................................................................. 6 0
9. 1. 5
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts ............................ 6 1
9. 2
Pr oce d ures f or Re p orti n g A d verse E ve nts ...................................................... 6 1
9. 3
Pr oce d ures f or Re p orti n g a Seri o us A d verse E ve nt ........................................ 6 1
9. 3. 1
Re g ulat or y  Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts .................. 6 2
9. 4
E x p os ure t o St u d y  Inter ve nti o n D uri n g Pre g na nc y ........................................ 6 2
9. 5
A L T or A S T  Ele vati o ns................................................................................... 6 3
9. 5. 1
P ote ntial H y ’s La w Cases ............................................................................... 6 4
1 0
A d mi nistrati ve I te ms....................................................................................... 6 5
1 0. 1
Pr ote cti o n of H u ma n Partici pa nts ................................................................... 6 5
1 0. 1. 1
C o m plia nce W it h Inf or me d C o nse nt Re g ulati o ns ( U S 2 1 C F R Part 5 0) a n d 
Rele va nt C o u ntr y  Re g ulati ons ........................................................................ 6 5
1 0. 1. 2
C o m plia nce W it h IR B or I E C Re g ulati o ns ..................................................... 6 6
1 0. 1. 3
C o m plia nce W it h G o o d Cli nical Practice....................................................... 6 6
1 0. 1. 4
C o m plia nce W it h Electr o nic Rec or ds; Electr o nic Si g nat ures Re g ulati o ns ( U S 
2 1 C F R Part 1 1) ............................................................................................... 6 6
1 0. 2
Fi na ncial Discl os ure ........................................................................................ 6 6
1 0. 3
C ha n ges t o t he Pr ot oc ol .................................................................................. 6 6
1 0. 4
Data Pr otecti o n ................................................................................................ 6 6
1 0. 5
Partici pa nt Pri vac y .......................................................................................... 6 7
1 0. 6
D oc u me ntati o n ................................................................................................ 6 7
1 0. 6. 1
S o urce D oc u me nts .......................................................................................... 6 7
1 0. 6. 2
Case Re p ort F or m C o m pleti o n ....................................................................... 6 8
1 0. 6. 3
St u d y  S u m mar y............................................................................................... 6 8
1 0. 6. 4
Rete nti o n of D o c u me ntati o n ........................................................................... 6 8
1 0. 7
La beli n g, Pac ka gi n g, a n d Ret ur n or Dis p osal of St u d y  Inter ve nti o n ............. 6 9
1 0. 7. 1
La beli n g/ Pac ka gi n g ......................................................................................... 6 9
1 0. 7. 2
C li nical S u p pl y In ve nt or y ............................................................................... 6 9
1 0. 7. 3
Ret ur n or Dis p osal of St u d y  Inter ve nti o n a n d/ or S u p plies ............................. 6 9
1 0. 8
M o nit ori n g b y t he S p o ns or ............................................................................. 7 0
1 0. 9
Ha n dli n g of Bi ol o gical S peci me ns ................................................................. 7 0
1 0. 1 0
P u blicati o ns ..................................................................................................... 7 0
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

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1 0. 1 1
C o or di nati n g I n vesti gat or................................ ............................................... 7 0
1 1
Refere nces ....................................................................................................... 7 1
1 2
Attac h me nts .................................................................................................... 7 3
1 2. 1
E xa mi nati o n Pr oce d ures, T ests, E q ui p me nt, a n d Tec h ni q ues ......................... 7 3
1 2. 1. 1  
I nter nati o nal Classificati o n of Hea dac he Dis or ders, 3r d E diti o n ................... 7 3
1 2. 2
E xa m ples of Pr o hi bite d Me dicati o ns .............................................................. 9 2
1 2. 3
Classificati o n of Mi grai ne Pre ve nti ve Me dicati o ns ........................................ 9 5
1 2. 4
Gl ossar y  of A b bre viati o ns ............................................................................... 9 7
1 2. 5
Pr ot oc ol A me n d me nt 1 S u m mar y ................................................................... 9 9
1 2. 6
P r ot oc ol A me n d me nt 2 S u m mar y ................................................................. 1 0 4
List of Ta bles
Ta ble 1. 
Sc he d ule of V isits a n d Pr oce d ures.................................................................. 1 4
Ta ble 5 – 1. 
St u d y  Inter ve nti o n ........................................................................................... 3 3
Ta ble 5 – 2. 
Ef fecti ve/ Pr o ba bly Effecti ve Mi grai ne Pre ve nti ve Me dicati o ns .................... 3 4
Ta ble 6 – 1. 
Cli nical L a b orat or y Para meters ...................................................................... 4 1
List of Fi g ur es
Fi g ure 1. 
St u d y  Dia gra m................................................................................................ 1 3
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

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2
Pr ot oc ol S u m m ar y
St u d y C o m p o u n d: At o ge pa nt
P h ase: 3
St u d y O bjecti ve:
T o e val uate t he safet y a n d t olera bilit y of treat me nt wit h at o ge pa nt 6 0 m g dail y ( Q D ) f or t he pre ve nti o n of mi grai ne 
i n partici pa nt s wit h e pis o dic mi grai ne ( E M ) o ver 5 2 -wee k d urati o n. 
Cli nic al H y p ot heses:
At o ge pa nt 6 0 m g Q D is safe a n d well t olerate d w he n a d mi nistere d o ver 5 2 we e ks f or t he pre ve nti o n of mi grai ne i n 
partici pa nt s wit h E M.
St u d y Desi g n
Str uct ure : M ultice nter, ra n d o mize d, o pe n-la bel, 5 2-wee k l o n g -ter m safet y st u d y c o n d ucte d i n t he U nite d States.
D ur ati o n : T he st u d y will c o nsist of a 4-wee k scree ni n g a n d baseli ne peri o d, a 5 2 -we e k treat me nt peri o d, a n d a 
safet y f oll o w-u p peri o d of a n a d diti o nal 4 wee ks, f or a t otal d urati o n of 6 0 wee ks.
St u dy I nterve nti o n: At o ge pa nt 6 0 m g Q D
C o ntr ol: Oral sta n dar d of care ( S O C) mi grai ne pre ve nti o n me dicati o n 
D os a ge/ D ose Re gi me n : At o ge pa nt 6 0 m g Q D will be a d mi nistere d f or 5 2 w ee ks.
Partici pa nt s ra n d o mize d t o oral S O C mi grai ne pre ve nti o n me dicati o n will be treate d w it h a me dicati o n rec o g nize d 
as safe a n d effecti ve f or t he pre ve nti o n of mi grai ne ( E vers 2 0 0 9 , H off ma n n 2 0 1 4 , Sc h ür ks 2 0 0 8 , Sil berstei n 2 0 1 2 ,
Stei ner 2 0 0 7 ). T he selecti o n of t his i nitial mi grai ne pre ve nti ve me dicati o n will be base d o n i n vesti gat or j u d g me nt i n 
c o ns ultati o n wit h t he partici pa nt .
R a n d o miz ati o n : Partici pa nt s will be ra n d o mize d ( 5: 2) t o t he f oll o wi n g treat me nt gr o u ps: At o ge pa nt 6 0 m g Q D or 
oral S O C mi grai ne pre ve nti o n me dicati o n.
A mi ni m u m of 2 0 0 partici pa nts ra n d o mize d t o at o ge pa nt m ust be classifie d as D e N ov o Partici pa nts (see defi niti o n 
bel o w u n der St u d y P o p ulati o n C haracteristics ).
Visit Sc he d ule : After t he scree ni n g a n d ra n d o mizati o n visits, st u d y visits will occ ur e ver y 4 wee ks f or t he d urati o n of 
t he 5 2-wee k st u d y. F or partici pa nts ra n d o mize d t o t he at o ge pa nt ar m , a safet y f oll o w-u p visit will occ ur 4 w ee ks 
after t he last d ose of at o ge pa nt . F or partici pa nts ra n d o mize d t o oral S O C mi grai ne pre ve nti o n me dicati o n a safet y 
f oll o w-u p visit will occ ur 4 wee ks after t he last visit i n t he treat me nt peri o d. T here w ill be 1 6 sc he d ule d cli nic visits. 
F or details, please see Ta ble 1 , t he Sc he d ule of Visits a n d Pr oce d ures.
T his st u d y will c o nsist of 2 gr o u ps of partici pa nts : De N ov o Partici pa nts a n d St u d y C G P -M D -0 1 C o m pleters ( see 
defi niti o n bel o w  u n der St u d y P o p ulati o n Characteristics).
De N ov o P artici pa nts a n d St u d y C G P -M D -0 1 C o m pleters will c o m plete all 1 6 st u d y v isits, i ncl u di n g t he 2 8-da y 
scree ni n g peri o d.
St u d y P o p ul ati o n C h ar acteristics
N u m ber of P artici p a nt s/ Sites: A p pr o xi matel y 7 0 0 partici pa nt s will be ra n d o mize d ( 5 0 0 partici pa nt s i n t he at o ge pa nt 
ar m a n d 2 0 0 partici pa nt s i n t he oral S O C mi grai ne pre ve nti o n me dicati o n ar m) fr o m a p pr o xi matel y 1 1 5 ce nters i n 
t he U nite d States. T w o gr o u ps of partici pa nt s will be eli gi ble t o partici pate i n t his st ud y . 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
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1 0
 
De N ov o P artici p a nts - Partici pa nt s w h o di d n ot partici pate i n a n y pre vi o us st u d y wit h at o ge pa nt w h o meet t he 
i ncl usi o n criteria a n d d o n ot meet t he e xcl usi o n criteria ma y be e nr olle d i n t his st u d y (referre d t o as D e N ov o 
P artici pa nts).
 
St u d y C G P -M D -0 1 C o m pleters - Partici pa nts w h o c o m plete d St u d y C G P -M D -0 1 ( Visit 8) w it h o ut si g nifica nt 
pr ot oc ol de viati o ns (e g, n o nc o m plia nce t o pr ot oc ol -re q uire d pr oce d ures) a n d wh o meet t he i ncl usi o n criteria 
a n d d o n ot meet t he e xcl usi o n criteria (referre d t o as C G P -M D -0 1 C o m pleters) .
o 
F or partici pa nt s w h o c o m plete d St u d y C G P-M D -0 1, t here will be a ti me ga p fr o m t he ti me of c o m pleti o n 
of St u d y C G P -M D -0 1 t o t he start of t his st u d y. F or t his reas o n, partici pa nt s fr o m St u d y C G P-M D -0 1 will 
nee d t o re -esta blis h st u d y eli gi bilt y. I n a d diti o n, t hese partici pa nts wi ll ha ve t heir baseli ne mi grai ne da ys
re-esta blis he d d uri n g t he scree ni n g peri o d b ut t his will n ot be use d as a n i ncl usi o n/e xcl usi o n criteria f or 
ra n d o mizati o n. 
 
C o n diti o n/ Dise ase : Mi grai ne wit h a ura or mi grai ne wit h o ut a ura (I C H D-3 Secti o n 1. 1 or Secti o n 1. 2 ; see 
Secti o n 1 2. 1. 1 )
Key I ncl usi o n Criteri a:
All partici pa nt s:
 
Partici pa nt is a ca n di date t o be prescri be d at least o ne of t he pr ot oc ol -defi ne d acce pta ble oral S O C mi grai ne 
pre ve nti o n me dicati o ns , a n d t he partici p a nt is willi n g t o acce pt S O C treat me nt.
F or D e N ov o P artici pa nts o nl y:
 
Male or fe male partici pa nts a ge 1 8 t o 8 0 years, i ncl usi ve, at Visit 1
 
At least a 1 -year hist or y of mi grai ne wit h or wit h o ut a ura c o nsiste nt wit h a dia g n osis acc or di n g t o t he 
I nter nati o nal Classificati o n of Hea dac he Dis or ders, 3r d E diti o n ( I C H D-3 2 0 1 8 )
 
A ge of t he partici pa nt at t he ti me of mi grai ne o nset < 5 0 years
 
Hist or y of 4 t o 1 4 mi grai ne da ys per m o nt h (see Secti o n 6. 1. 1 f or defi niti o n) i n t he 3 m o nt hs pri or t o Visit 1 i n 
t he i n vesti gat or’s j u d g me nt 
F or C G P -M D -0 1 C o m pleters o nl y: 
 
Eli gi ble partici pa nts w h o c o m plete d St u d y C G P -M D -0 1 ( Visit 8) w it h o ut si g nifica nt pr ot oc ol de viati o ns (e g, 
n o nc o m plia nce wit h pr ot oc ol -re q uire d pr oce d ures) a n d w h o di d n ot e x perie nce a n A E t hat, i n t he i n vesti gat or’s 
o pi ni o n, ma y i n dicate a n u nacce pta ble safet y ris k
F or D e N ov o P artici pa nts a n d CG P- M D -0 1 C o m pleters : 
 
C o m plete d at least 2 0 o ut of 2 8 da ys i n t he e Diar y d uri n g baseli ne peri o d a n d is a ble t o rea d, u n dersta n d, a n d 
c o m plete t he st u d y q uesti o n naires a n d e Diar y per in vesti gat or’s j u d g me nt
Key Excl usi o n Crit eri a ( all p artici p a nt s exce pt w here n ote d ot her wise):
 
Has a hist or y of mi grai ne acc o m pa nie d b y di pl o pia or decrease d le vel of c o nsci o us ness or reti nal mi grai ne as 
defi ne d b y I C H D -3, 2 0 1 8
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 1
 
Has a c urre nt dia g n osis of c hr o nic mi grai ne ( C M ), ne w dail y persiste nt hea dac he, tri ge mi nal a ut o n o mic 
ce p hal gia (e g, cl uster hea dac he), or pai nf ul cra nial ne ur o pat h y as defi ne d b y I C H D -3, 2 0 1 8
 
Has ≥ 1 5 hea dac he da ys per m o nt h ( see Secti o n 6. 1. 2 f or t he defi niti o n of a hea dac he da y) o n a vera ge acr oss t he 
3 m o nt hs pri or t o Visit 1 i n t he i n vesti gat or’s j u d g me nt (f or D e N ov o P artici p a nt s o nl y)
 
Partici pa nt s wit h cli nicall y si g nifica nt he mat ol o gic, e n d ocri ne, car di o vasc ular, p ul m o nar y, re nal, he patic, 
gastr oi ntesti nal, or ne ur ol o gic disease
Res p o nse Me as ures
S afety — A E s, p h ysical e xa mi nati o ns, cli nical la b orat or y deter mi nati o ns, vital si g n meas ure me nts, E C G para meters, 
a n d t he C ol u m bia -S uici de Se verit y Rati n g Scale ( C- S S R S )
T he safet y para meters will i ncl u de A Es, cli nical la b orat or y e val uati o ns, vital si g n meas ure me nts, E C G para meters, 
a n d t he C -S S R S. F or eac h of t he cli nical la b orat or y, vital si g n, a n d E C G para meters, t he last n o n -missi n g safet y 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 2
assess me nt bef ore t he first d ose of treat me nt will be use d as t he baseli ne f or all a nal yses of t hat safet y para meter. 
C o nti n u o us varia bles will be s u m marize d b y t he n u m ber of partici pa nt s a n d mea n, sta n dar d de viati o n (S D ), me dia n, 
mi ni m u m, a n d ma xi m u m val ues. Cate g orical varia bles will be s u m marize d b y n u m ber a n d perce nta ge of 
partici pa nt s.
S a m ple Size C alc ul ati o n : 
T his st u d y pla ns t o ra n d o mize a t otal of 7 0 0 partici pa nt s. Partici pa nt s will be ra n d o mize d 5: 2 t o recei ve at o ge pa nt 
treat me nt 6 0 m g Q D or oral S O C mi grai ne pre ve nti o n me dicati o n. Base d o n data fr o m pre vi o us st u dies 
(A ur ora, 2 0 1 1; Ra p o p ort , 2 0 0 6), it is esti mate d t hat a p pr o xi matel y 6 0 % of t h ose partici pa nt s will c o m plete 6 m o nt hs 
of at o ge pa nt treat me nt, a n d of t h ose , 6 5 % will c o m plete 1 2 m o nt hs of at o ge pa nt treat me nt.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 3
Fi g ur e 1. 
St u d y Di a gr a m
E T = earl y ter mi nati o n; Q D = dail y; V = visit .
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
Ta ble 1 . 
Sc he d ule of Vi sits a n d Proce d ures
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 5
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 6
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 7
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 8
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 9
1 
B ac k gr o u n d a n d Cli nic al R ati o n ale
1. 1
B ac k gr o u n d
Mi grai ne affects 1 8 % of w o me n a n d 6 % of me n i n t he U nite d S tates wit h pea k pre vale nce 
occ urri n g bet wee n t he a ges of 2 5 a n d 5 5 y ears. A p pr o xi matel y o ne-t hir d of patie nts wit h 
mi grai ne s ha ve 3 or m ore mi grai ne attac ks per m o nt h, a n d o ver half re p ort se vere i m pair me nt 
or t he nee d f or be d rest ( Li pt o n 2 0 0 7 ). I n t he U nite d S tates al o ne, w or k l oss d ue t o mi grai ne 
is esti mate d t o c ost ~ $ 1 3 billi o n a n n uall y  (H u 1 9 9 9 ). Pre vale nce is si milar i n E ur o pe, wit h 
mi grai ne hea dac he affecti n g o n a vera ge 1 7. 6 % of w o me n a n d 8 % of me n ( St o v ner 2 0 1 0 ). 
T he Gl o bal B ur de n of Disease S ur ve y  2 0 1 0 (G B D 2 0 1 0 ) esti mate d t he gl o bal pre vale nce of 
mi grai ne t o be 1 4. 7 %, ma ki n g it t he t hir d m ost c o m m o n disease i n t he w orl d i n b ot h males 
a n d fe males. Mi grai ne was ra n ke d se ve nt h hi g hest a m o n g s pecific ca uses of disa bilit y  
gl o ball y ( Stei ner 2 0 1 3 ).
Mi grai ne is t y picall y  c haracterize d b y attac ks of t hr o b bi n g, u nilateral hea dac he of m o derate 
or se vere pai n i nte nsit y , ass ociate d wit h na usea, v o miti n g, a n d/ or se nsiti vit y t o li g ht 
( p h ot o p h o bia) a n d s o u n d ( p h o n o p h o bia). I n a b o ut 2 5 % of i n divi d uals, t he mi grai ne hea dac he
is prece de d by f ocal ne ur ol o gical d ys f u ncti o n (a ura). I m pr o vi n g dia g n osis a n d o pti mizi n g 
treat me nts f or mi grai ne ha ve bee n rec o g nize d as criticall y i m p orta nt t o o verc o mi n g c urre nt 
barriers t o re d uce t he gl o bal b ur de n of mi gra i ne.
Beca use t here are n o bi ol o gical mar kers f or mi grai ne, dia g n osis is base d o n cli nical hist or y , 
e xa mi nati o n, a n d t he e xcl usi o n of ot her hea dac he dis or ders. P h ysicia ns a p pl y cli nical criteria 
t o g ui de dia g n oses a n d s u bse q ue nt treat me nt. E M is a s yn dr o me dia g n osis a p plie d t o patie nts 
wit h mi grai ne ( wit h or wit h o ut a ura) w h o ha ve 1 t o 1 4 hea dac he da y s per m o nt h. C M is a 
s pecific I C H D-3 dia g n osis a p plie d t o a s u bset of patie nts wit h ≥1 5 hea dac he da y s per m o nt h 
(Katsara va 2 0 1 2 ; Olese n 2 0 0 4 ; I CH D - 3 2 0 1 8).
 
1. 2
O ver vie w of At o ge p a nt
At o ge pa nt is a p ote nt, selecti ve oral C G R P rece p t or a nta g o nist bei n g de vel o pe d f or mi grai ne 
pre ve nti o n. A d diti o nal i nf or mati o n o n n o n -cli nical p har mac ol o g y, t o xic ol o g y, a n d P K 
pr o perties of at o ge pa nt ca n be f o u n d i n t he in vesti gat or’s b r oc h ure. 
A P hase 2/ 3 cli nical st u d y  was c o n d ucte d, w hic h c o m pare d at o ge pa nt 1 0 m g Q D, at o ge pa nt 
3 0 m g Q D , at o ge pa nt 3 0 m g BI D, at o ge pa nt 6 0 m g Q D a n d at o ge pa nt 6 0 m g BI D t o place b o. 
O verall, all t he at o ge pa nt d oses teste d were well t olerate d. F or t he pri mar y ef ficac y e n d p oi nt 
of c ha n ge fr o m baseli ne i n mea n m o nt hl y  mi graine da y s acr oss t he 1 2- wee k treat me nt peri o d, 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
2 0
all at o ge pa nt d oses de m o nstrate d a statisticall y  si g nifica nt re d ucti o n c o m pare d wit h place b o 
i n patie nts wit h E M .
1. 3
St u d y R ati o n ale
T he p ur p ose of t his st u d y is t o e val uate t he safet y a n d t olera bilit y of at o ge pa nt 6 0 m g Q D , 
w he n ta ke n f or 5 2 wee ks f or t he pre ve nti o n of E M .
1. 4
R ati o n ale f or D oses a n d D ose Re gi me ns Selecte d
T he P hase 3 pi v otal st u dies t o e val uate at o ge pa nt will test a ma xi m u m d ose of 6 0 m g Q D. 
F or t his reas o n, t he sa me d ose of 6 0 m g Q D has bee n selecte d f or t his st u d y t o e val uate t he 
l o n g-ter m safety a n d t olera bilit y of at o ge pa nt f or t he pre ve nti o n of E M.
2 
St u d y O bjecti ve a n d Cli nic al H y p ot heses 
2. 1
St u d y O bjecti ve
T o e val uate t he safet y a n d t olera bilit y of treat me nt wit h at o ge pa nt 6 0 m g Q D w he n 
a d mi nistere d o ver 5 2 wee ks f or t he pre ve nti o n of mi grai ne i n partici pa nt s wit h E M.
2. 2
Cli nic al H y p ot hesis
At o ge pa nt 6 0 m g Q D is safe a n d well t olerate d w he n a d mi nistere d o ver 5 2 wee ks f or t he 
pre ve nti o n of mi grai ne i n partici pa nt s wit h E M.
3 
St u d y Desi g n
3. 1
Str uct ure
T his is a m ultice nter, ra n d o mize d, o pe n- la bel, 5 2-wee k , l o n g-ter m safety st u d y  c o n d ucte d i n 
t he U nite d States a n d will e nr oll a p pr o xi matel y 7 0 0 partici pa nt s fr o m a p pr o xi matel y 
1 1 5 sites. P artici pa nt s will be ra n d o mize d ( 5: 2) t o t he f oll o wi n g treat me nt gr o u ps: at o ge pa nt 
6 0 m g Q D or oral S O C mi grai ne pre ve nti o n me dicati o n. 
All partici pa nt s ra n d o mize d t o oral SO C mi grai ne pre ve nti o n me dicati o n will be treate d wit h 
a me dicati o n rec o g nize d as safe a n d ef fecti ve f or t he pre ve nti o n of mi grai ne. T he selecti o n of 
t his i nitial mi grai ne pre ve nti ve me dicati o n is base d o n i n vesti gat or j u d g me nt i n c o ns ultati o n 
wit h t he partici pa nt . F or partici pa nt s w h o d o n ot t olerate t his i nitial pre ve nti ve me dicati o n or 
f or w h o m t he me dicati o n is n ot s ufficie ntl y effecti ve ( per i n vesti gat or j u d g me nt), t he 
i n vesti gat or ma y c h o ose t o: 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
2 1
1.
Prescri be a n alter nati ve me dicati o n fr o m t he me dici nes rec o g nize d as safe a n d 
eff ecti ve f or t he pre ve nti o n of mi grai ne ( Secti o n 5. 6. 3 ), O R
2.
Prescri be a n alter nati ve mi grai ne pre ve nti ve me dicati o n n ot liste d i n t he me dici nes 
rec o g nize d as safe a n d effecti ve f or t he pre ve ntio n of mi grai ne (e g, ri b ofla vi n,
car ba maze pi ne, ga ba pe nti n), O R
3.
N ot prescri be a n alter nati ve mi grai ne pre ve nti ve me dicati o n. 
T he p ur p ose of t he S O C ar m is t o c ollect c o m parati ve safet y data f or 5 2 wee ks. T heref ore, a 
partici pa nt w h o d oes n ot t olerate t he i nitiall y  selecte d mi grai ne pre ve nti o n me dicati o n, or f or 
w h o m t he me dicati o n is n ot s ufficie ntl y  effecti ve ( per i n vesti gat or j u d g me nt), ma y  c o nti n ue 
i n t he st u d y re gar dless of w hic h alter nati ve o pti o n ( 1, 2, or 3) liste d a b o ve the in vesti gat or 
selects. I n a d diti o n, after t he i nitial mi grai ne pre ve nti o n me dicati o n trial, partici pa nt s w h o are 
prescri be d a n alter nati ve me dicati o n ( o pti o ns 1 or 2), b ut d o n ot t olerate t he alter nati ve 
mi grai ne pre ve nti o n me dicati o n , or f or w h o m t his m e dicati o n is n ot s ufficie ntl y  effecti ve,
ma y  c o nti n ue i n t he st u d y re gar dless of w hic h alter nati ve o pti o n ( 1, 2, or 3) liste d a b o ve t he 
in vesti gat or selects. F urt her m ore, partici pa nt s f or w h o m in vesti gat ors c h o ose n ot t o prescri be 
a n alter nati ve pre ve nti o n me dicati o n ma y  be prescri be d a n alter nati ve me dicati o n 
( o pti o n 1 or 2) at a n y ti me d uri n g t he st u d y. T his ma y be re peate d as nee de d t hr o u g h o ut 
partici pati o n i n t he st u d y per in vesti gat or j u d g me nt.
T he st u d y  will c o nsist of a 4- wee k scree ni n g a n d baseli ne peri o d, a 5 2 -wee k treat me nt 
peri o d, a n d a safet y f oll o w -u p peri o d of 4 wee ks. De N ov o P artici pa nts a n d 
St u d y C G P- M D - 0 1 C o m pleters will c o m plete all 1 6 st u d y v isits, i ncl u di n g t he 2 8-da y  
scree ni n g peri o d.
F or clarit y , n ote t hat t he partici pa nt m ust n ot be ra n d o mize d u ntil Visit 2 w he n eli gi bilit y has 
bee n c o nfir me d. 
After t he ra n d o mizati o n visit, t he st u d y  visits will occ ur e ver y 4 wee ks f or t he d urati o n of t he 
5 2- wee k treat me nt peri o d. P artici pa nts will ret ur n t o t he cli nic f or safety assess me nts at 4, 8,
1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, 4 8, a n d 5 2 wee ks relati ve t o t heir ra n d o mizati o n visit. A 
safety f oll o w - u p visit will occ ur 4 wee ks after t he last d ose of at o ge pa nt 6 0 m g Q D or after 
t he last st u d y visit f or t he S O C ar m. F or details, please see Ta ble 1 , Sc he d ule of Vi sits a n d 
Pr oce d ures.
T he pri mar y  o bjecti ve of t he st u d y is t o assess t he safety a n d t olera bilit y of l o n g-ter m 
at o ge pa nt treat me nt. T he pla n ne d safet y  assess me nts i ncl u de c ollecti o n of A Es , cli nical 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
2 2
la b orat or y deter mi nati o ns, E C Gs, vital si g n meas ure me nts, p h ysical e xa mi nati o ns, a n d t he 
C- S S R S. 
3. 2
D at a S afet y M o nit ori n g B o ar d
A n i n de pe n de nt D S M B will be esta blis he d t o re vie w safet y data a n d s u m mar y re p orts, 
i de ntif y a ny s afet y iss ues a n d tre n ds, a n d ma ke rec o m me n dati o ns t o Aller ga n, i ncl u di n g 
m o dificati o n or E T of a trial, if e mer gi n g data s h o w u ne x pecte d a n d cli nica ll y si g nifica nt 
A Es . 
Details of t he D S M B me m bers hi ps, sta n dar d o perati o nal pr oce d ures f or data 
m o nit ori n g/re vie w , fre q ue nc y of re vie w, a n d ot her perti ne nt details will be pr o vi de d i n a 
se parate D S M B C harter .
3. 3
A dj u dic ati o n C o m mittee
A n A dj u dicati o n C harter will be esta blis he d a n d will descri be t he pr ocess f or t he 
s ur veilla nce, m o nit ori n g, a n d a dj u dicati o n by t he Cli nical A dj u dicati o n C o m mittee of e ve nts 
of p ost -treat me nt ele vati o ns of A L T a n d/ or A S T  ≥ 3 × U L N. T he p ur p ose of t his c harter will 
be t o pr o vi de a sta n dar dize d pr ocess f or t he a dj u dica ti o n of t he e ve nts i n or der t o deter mi ne 
w het her t he ele vati o n was relate d t o at o ge pa nt.
4 
St u d y P o p ul ati o n a n d E ntr y Criteri a
4. 1
N u m ber of P artici p a nts
A p pr o xi matel y  7 0 0 partici pa nt s will be ra n d o mize d ( 5: 2) t o at o ge pa nt 6 0 m g Q D
( 5 0 0 partici pa nt s) or oral S O C mi grai ne pre ve nti o n me dicati o n ( 2 0 0 partici pa nt s) at 
a p pr o xi matel y 1 1 5 ce nters i n t he Unite d S tates. A mi ni m u m of 2 0 0 partici pa nt s ra n d o mize d 
t o at o ge pa nt m ust be classifie d as D e N ov o Partici pa nts (see defi niti o n bel o w).
4. 2
St u d y P o p ul ati o n C h ar acteristics
T here will be 2 gr o u ps of partici pa nt s eli gi ble t o partici pate i n t his st u d y. 

De N ov o P artici pa nt s: partici pa nt s wit h n o pre vi o us e x p os ure t o at o ge pa nt a n d w h o 
meet t he i ncl usi o n criteria a n d d o n ot meet t he e xcl usi o n criteria (referre d t o as 
De N ov o Part ici pa nts)

St u d y  C G P-M D - 0 1 C o m pleters: partici pa nt s w h o c o m plete d St u d y C G P-M D - 0 1 
( Visit 8) wit h o ut si g nifica nt pr ot oc ol de viati o ns (e g, n o nc o m plia nce t o 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
2 3
pr ot oc ol -re q uire d pr oce d ures) a n d w h o meet t he i ncl usi o n criteria a n d d o n ot meet t he 
e xcl usi o n criteri a (referre d t o as C G P-M D - 0 1 C o m pleters)
o
F or partici pa nt s w h o c o m plete d St u d y C G P-M D - 0 1, t here will be a ti me 
ga p fr o m t he ti me of c o m pleti o n of St u d y C G P -M D -0 1 t o t he start of t his 
st u d y. F or t his reas o n, partici pa nts fr o m St u d y  C G P-M D -0 1 will nee d 
nee d t o re-esta blis h st u d y eli gi bilt y. I n a d diti o n, t hese partici pa nts will 
ha ve t heir baseli ne mi grai ne da y s re-esta blis he d d uri n g t he scree ni n g 
peri o d b ut t his will n ot be use d as a n i ncl usi o n/e xcl usi o n criteria f or 
ra n d o mizati o n. 
4. 3
I ncl usi o n Criteri a
T he f oll o w i n g are i ncl usi o n criteri a f or all p artici p a nt s:
1.
Wr itte n i nf or me d c o nse nt a n d partici pa nt pri vac y  i nf or mati o n (e g, writte n 
a ut h orizati o n f or use a n d release of healt h a n d researc h st u d y i nf or mati o n) o btai ne d 
fr o m t he partici pa nt pri or t o i nitiati o n of a n y  st u d y-s pecific pr oce d ures
2.
P artici pa nt is a ca n di date t o be prescri be d at least o ne of t he pr ot oc ol-defi ne d 
acce pta ble oral S O C mi grai ne pre ve nti o n me dicati o ns a n d t he partici pa nt is willi n g t o 
acce pt SO C treat me nt
3.
P artici pa nt s m ust be usi n g a m e dicall y acce pta ble a n d eff ecti ve m et h o d of birt h c o ntr ol 
d uri n g t he c o urse of t he e ntire st u d y, as defi ne d i n Secti o n 4. 5. 3
T he f oll o wi n g are i ncl usi o n criteri a f or D e N ov o P artici p a nt s o nly:
4.
Male or fe male partici pa nt s a ge d 1 8 t o 8 0 y ears, i ncl usi ve, at Vi sit 1
5.
At least a 1 -ye ar hist or y of mi grai ne wit h or wit h o ut a ura c o nsiste nt wit h a dia g n osis 
acc or di n g t o t he I CH D - 3, 2 0 1 8
6.
A ge of t he partici pa nt at t he ti me of mi grai ne o nset < 5 0 y ears
7.
Hist or y  of 4 t o 1 4 mi grai ne d a y s per m o nt h (see Secti o n 6. 1. 1 f or defi niti o n) o n 
a vera ge i n t he 3 m o nt hs pri or t o Vi sit 1 i n t he in vesti gat or ’s j u d g me nt
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
2 4
4. 4
E xcl usi o n Criteri a
T he f oll o wi n g are criteri a f or e xcl usi o n fr o m p artici p at i n g i n t he st u dy f or De N ov o 
P artici p a nt s o nly:
1.
Dif fic ulty disti n g uis hi n g mi grai ne hea dac hes fr o m te nsi o n -t ype or ot her hea dac hes
2.
Has a hist or y  of mi grai ne acc o m pa nie d by di pl o pia or decrease d le vel of 
c o nsci o us ness or reti nal mi grai ne as defi ne d b y I C H D- 3, 2 0 1 8
3.
Has a c urre nt dia g n osis of C M , ne w persiste nt dail y hea dac he, tri ge mi nal a ut o n o mic 
ce p hal gia (e g, cl uster hea dac he), or pai nf ul cra nial ne ur o pat h y as defi ne d b y 
I C H D- 3, 2 0 1 8
4.
≥ 1 5 hea dac he da y s per m o nt h (see Secti o n 6. 1. 2 f or defi niti o n of hea dac he da y) o n 
a vera ge acr oss t he 3 m o nt hs pri or t o Vi sit 1 i n t he i n vesti gat or’s j u d g me nt
6.
U sa ge of o pi oi ds or bar bit urates > 2 da y s/ m o nt h, tri pta ns or er g ots ≥1 0 da ys/ m o nt h, or 
si m ple a nal gesics (e g, as piri n, N S AIDs, aceta mi n o p he n) ≥1 5 da y s/ m o nt h i n t he 
3 m o nt hs pri or t o Vi sit 1 per i n vesti gat or’s j u d g me nt, or d uri n g t he baseli ne peri o d. 
F or all partici pa nts, b ar bit urates are e xcl u de d 3 0 da y s pri or t o scree ni n g a n d d uri n g t he 
baseli ne peri o d . F or partici pants ra n d o mize d t o at o ge pa nt , bar bit urates are e xcl u de d 
t hr o u g h t he d urati o n of t he st u d y as well (see Secti o n 4. 5. 2 ).
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
2 5
T he f oll o wi n g are criteri a f or e xcl usi o n fr o m p artici p ati n g i n t he st u dy f or all p artici p a nt s 
u nless n ote d ot her wise:
8.
Fe male partici pa nt is pre g na nt, pla n ni n g t o bec o me pre g na nt d uri n g t he c o urse of t he 
st u d y, or c urre ntly lactati n g. Wo me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve 
uri ne pre g na nc y  test at Visit 1 a n d Vi sit 2
1 2. H y perte nsi o n as defi ne d b y  sitti n g sys t olic B P > 1 6 0 m m H g or sitti n g diast olic 
B P > 1 0 0 m m H g at Vi sits 1 or Vi sit 2. Vi tal si g n meas ure me nts t hat e xcee d t hese 
li mits ma y be re peate d o nl y o nce
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
2 6
1 4. A n y  cli nicall y si g nifica nt he mat ol o gic, e n d ocri ne, p ul m o nar y, re nal, he patic, GI , or 
ne ur ol o gic disease
2 0. Hist or y  of a n y GI pri or pr oce d ures or GI c o n diti o ns (e g, diarr hea sy n dr o mes, 
i nfla m mat or y b o wel disease) t hat ma y affect t he a bs or pti o n or meta b olis m of 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
2 7
at o ge pa nt; partici pa nt s wit h pri or gastric bariatric i nter ve nti o ns (e g, La p Ba n d) w hic h 
ha ve bee n re verse d are n ot e xcl u de d
2 1. At V isit 1, a user of recreati o nal or illicit dr u gs or has ha d a hist or y wit hi n t he past 
ye ar of dr u g or alc o h ol a b use or de pe n de nce
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
2 8
4. 5
Per missi ble a n d Pr o hi bite d Me dic ati o ns/ T re at me nts
4. 5. 1
Per missi ble Me dic ati o ns/ Tre at me nts
4. 5. 2
Pr o hi bite d Me dic ati o ns/ T re at me nts
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
2 9
4. 5. 3
Defi n iti o n of Wo me n of ( N o n -) C hil d be ari n g P ote nti al a n d/ or 
Acce pt a ble C o ntr ace pti ve Met h o ds
F or p ur p oses of t his st u d y, w o me n will be c o nsi dere d of c hil d beari n g p ote ntial u nless t he y 
are nat urall y p ost me n o pa usal (ie, n o me nses f or 2 years) or per ma ne ntl y steril ize d (ie, 
bilateral t u bal li gati o n, bilateral t u bal occl usi o n [e g, Ess ure ® place me nt wit h H S G 
c o nfir mati o n], bilateral sal pi n gect o m y , bilateral o o p h orect o my, or h ys terect o m y). F or w o me n 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
3 0
of c hil d - beari n g p ote ntial w h o ma y  partici pate i n t he st u d y, t he f oll owi n g met h o ds of 
c o ntrace pti o n, if pr o perl y use d, are ge nerall y c o nsi dere d hi g hl y effecti ve:

C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n s uc h as 
oral, i ntra va gi nal, or tra ns der mal (ie , pill, va gi nal ri n g, patc h)

Pr o gest o ge n - o nly h or m o nal c o ntrace pti o n ( wit h i n hi biti o n of o v ulati o n) t hat are oral, 
i njecta ble, or i m pla nta ble

I UD or I U S

Vasect o mize d part ner ( pr o vi de d t hat t he part ner is t he s ole se x ual part ner of st u d y  
partici pa nt a n d t hat t he vasect o mize d part ner has recei ve d me dica l assess me nt of t he 
s ur gical s uccess)

Se x ual a bsti ne nce ( defi ne d as refrai ni n g fr o m heter ose x ual i nterc o urse f or t he 
d urati o n of t he st u d y )
Acce pta ble birt h c o ntr ol met h o ds w hic h ma y  n ot be c o nsi dere d as hi g hl y effecti ve:

Pr o gest o ge n - o nly oral h or m o nal c o n trace pti o n ( w here i n hi biti o n of o v ulati o n is n ot 
t he pri mar y m o de of acti o n)

Male or fe male c o n d o m wit h or wit h o ut s per mici de ( fe male a n d male c o n d o ms 
s h o ul d n ot be use d t o get her)

Ca p, dia p hra g m or s p o n ge wit h s per mici de

A c o m bi nati o n of male c o n d o m wit h eit her ca p, dia p hra g m or s p o n ge wit h s per mici de 
( d o u ble barrier met h o ds) are als o c o nsi dere d acce pta ble, b ut n ot hi g hly effecti ve, birt h 
c o ntr ol met h o ds
F or males w h o ma y  partici pate i n t he st u d y, t he f oll o wi n g met h o ds of c o ntrace pti o n, if 
pr o perl y use d, a re ge nerall y c o nsi dere d relia ble: p ost-bilateral vasect o m y , barrier 
c o ntrace pti o n or se x ual a bsti ne nce. Male partici pa nts m ust als o refrai n fr o m d o nati n g s per m 
d uri n g t he c o urse of t he st u d y .
T he i n vesti gat or a n d eac h partici pa nt will deter mi ne t he a p pr o pr iate met h o d of c o ntrace pti o n 
f or t he partici pa nt d uri n g partici pati o n i n t he st u d y.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
3 1
If a w o ma n bec o mes pre g na nt d uri n g t he st u dy, t he i n vesti gat or will n otif y Aller ga n 
i m me diatel y after t he pre g na nc y is c o nfir me d a n d t he partici pa nt will be disc o nti n ue d fro m 
t he st u d y after a p pr o priate safety f oll o w -u p. T he i n vesti gat or will ( 1) n otif y  t he partici pa nt’s 
p h y sicia n t hat t he partici pa nt was bei n g treate d wit h at o ge pa nt or t he S O C mi grai ne 
pre ve nti o n me dicati o n a n d ( 2) f oll o w t he pr o gress of t he pre g na nc y . T he i n vesti gat or m ust 
d oc u me nt t he o utc o me of t he pre g na nc y  a n d pr o vi de a c o py of t he d oc u me ntati o n t o 
Aller ga n.
4. 5. 4
S peci al Diet or Acti vities
P artici pa nt s s h o ul d refrai n fr o m c o ns u mi n g gra pefr uit or gra pefr uit j uice fr o m t he ti me t he 
I CF is si g ne d u ntil c o m pletio n of t he st u d y . Partici pa nt s s h o ul d als o refrai n fr o m ma ki n g 
si g nifica nt c ha n ges t o t heir diet or caffei ne i nta ke d uri n g t he st u dy.
Alc o h ol i nta ke s h o ul d be li mite d t o n o m ore t ha n 1 dri n k per da y  t hr o u g h o ut t he st u d y. A 
dri n k is defi ne d as a 1 2 -o u nce ca n / b ottle of beer, a 4-o u nce glass of wi ne, or 1 o u nce of 
li q u or.
4. 6
Scree n F ail ures
Scree n fail ures are defi ne d as partici pa nts w h o c o nse nt t o partici pate i n t he st u d y  b ut are n ot 
s u bse q ue ntl y ra n d o mize d t o treat me nt. Rescree ni n g of scree n fail ures is per mitted i n certai n 
sit uati o ns. H o we ver, partici pa nts wit h cli nicall y  si g nifica nt la b orat or y val ues at Visit 1 
(i ncl u di n g A L T or A S T > 1 × U L N, t otal bilir u bi n > 1 x U L N or ser u m al b u mi n < 2. 8 g/ d L), 
or t h ose wit h a p ositi ve res ult o n t he Visit 1 uri ne dr u g scree n f or recreati o nal (i ncl u di n g 
marij ua na re gar dless of le galit y ) or illicit dr u gs or n o n-discl ose d c o nc o mita nt me dicati o ns,
are n ot all o we d t o be rescree ne d.
5 
St u d y I nter ve nti o n
5. 1
St u d y I nter ve nti o n a n d F or m ul ati o ns
Ta blets c o ntai ni n g at o ge pa nt 6 0 m g ( F or m ulati o n N u m ber 
)
5. 2
C o ntr ol I nter ve nti o n 
Aller ga n will n ot be pr o vi di n g oral S O C mi grai ne pre ve nti o n me dicati o ns. See Secti o n 5. 6. 2
f or details o n acce pta ble oral S O C mi grai ne pre ve nti o n me dicati o ns.
5. 3
Met h o ds f or M as ki n g/ Bli n di n g
T his is a n o pe n -la bel st u d y. 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
3 2
5. 4
Tr e at me nt All oc ati o n R ati o
P artici pa nt s will be ra n d o mize d t o t he f oll o wi n g 2 ar ms i n a 5: 2 rati o:

At o ge pa nt 6 0 m g Q D ( n = 5 0 0)
o
N ote: A mi ni m u m of 2 0 0 partici pa nts ra n d o mize d t o at o ge pa nt m ust be classifie d 
as D e N ov o Partici pa nts

Oral S O C mi grai ne pre ve nti o n me dicati o n ( n = 2 0 0)
N o stratificati o n will be perf or me d.
5. 5
Met h o d f or Assi g n me nt t o Tr e at me nt Gro u ps/ R a n d o miz ati o n
Pri or t o i nitiati o n of at o ge pa nt or oral S O C mi grai ne pre ve nti o n me dicati o n , eac h partici pa nt
w h o pr o vi des i nf or me d c o nse nt will be assi g ne d a partici pa nt n u m ber t hat will ser ve as t he 
partici pa nt i de ntificati o n n u m ber o n all st u d y d oc u me nts. C G P -M D -0 1 C o m pleters will 
mai ntai n t he ir lea d-i n st u d y partici pa nt i de ntificati o n n u m ber. 
At ra n d o mizati o n ( Visit 2), eli gi ble partici pa nt s will be ra n d o ml y assi g ne d t o 1 of 2 treat me nt 
ar ms i n a 5: 2 rati o t o recei ve a t o ge pa nt 6 0 m g Q D or oral S O C mi grai ne pre ve nti o n 
me dicati o n.
All partici pa nts will be ce ntrall y  assi g ne d t o ra n d o mize d at o ge pa nt or oral S O C mi grai ne 
pre ve nti o n me dicati o n 
 
 
 
 
 
 
 
5. 6
Tr e at me nt Re gi me n a n d D osi n g
Partici pa nts w h o meet all of t he st u d y  e ntr y criteria at Visit 2 will be ra n d o mize d.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
3 3
5. 6. 1
P artici p a nts R a n d o mize d t o At o ge p a nt
O nl y partici pa nt s ra n d o mize d t o at o ge pa nt will be pr o vi de d wit h at o ge pa nt t o be ta ke n o n a n 
o ut patie nt basis. At o ge pa nt t o be use d i n t his trial is liste d i n (Ta ble 5 – 1 ). P artici pa nts will 
ta ke t heir first d ose of at o ge pa nt at t he cli nic at Visit 2. 
P artici pa nt s will be i nstr ucte d t o ta ke t heir at o ge pa nt at a p pr o xi matel y t he sa me ti me eac h 
da y . At o ge pa nt will be a d mi nistere d orall y  f or 5 2 wee ks, a n d partici pa nt s will be f oll o we d 
f or 4 wee ks f oll o wi n g c o m pleti o n or disc o nti n uati o n of t he at o ge pa nt.
Ta ble 5 – 1. 
St u d y I nter ve nti o n
Dr u g/ D ose
St u d y I nter ve nti o n Fre q ue nc y 
R o ute of A d m i nistr ati o n
A t o ge pa nt 6 0 m g
Q D
Oral
Q D = dail y.
5. 6. 2
P artici p a nts R a n d o mize d t o Or al S O C Mi gr ai ne Pre ve nti o n 
Me dic ati o n
All partici pa nt s ra n d o mize d t o oral SO C mi grai ne pre ve nti o n me dicati o n will be treate d wit h 
a me dicati o n rec o g nize d as safe a n d effecti ve f or t he pre ve nti o n of mi grai ne. T he selecti o n 
of t his i nitial mi grai ne pre ve nti o n me dicati o n is base d o n i n vesti gat or j u d g me nt i n 
c o ns ultati o n wit h t he partici pa nt . 
 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
3 4
At t he e n d of t he o pe n-la bel treat me nt peri o d, partici pa nts d o n ot nee d t o disc o nti n ue oral 
S O C me dicati o n. Oral S O C me dicati o n ma y  be c o nti n ue d d uri n g t he safet y f oll o w-u p peri o d. 
Alter nati vel y, t he i n vesti gat or ma y c h o ose t o disc o nti n ue oral S O C me dicati o n. 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
3 5
5. 7
St or a ge of St u d y I nter ve nti o n
6   
Res p o nse Me as ures a n d S u m m ar y of D at a C ollecti o n Met h o ds
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
3 6
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
3 7
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
3 8
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
3 9
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
4 0
6. 4
S afet y Me as ures
6. 4. 1
A d verse E ve nts
A d verse e ve nt s will be c ollecte d fr o m t he ti me of c o nse nt t hr o u g h t he last visit. F or all A Es, 
t he i n vesti gat or m ust pr o vi de a n assess me nt of t he se verit y, ca usal relati o ns hi p t o t he 
i n vesti gati o nal pr o d uct, start a n d st o p date, a n d seri o us ness of t he e ve nt (e g, S A E), d oc u me nt 
all acti o ns ta ke n wit h re gard t o t he st u d y or c o ntr ol i nter ve nti o n, a n d detail a n y ot her 
treat me nt meas ures ta ke n f or t he A E. F or e ve nts n ote d as S A Es, Aller ga n m ust be n otifie d 
i m me diatel y t o meet t heir re p orti n g o bli gati o ns t o a p pr o priate re g ulat or y a ut h orities.
6. 4. 2
A d verse E ve nts of S peci al I nterest
Selecte d n o n -seri o us a n d seri o us a d verse e ve nts are of s pecial i nterest a n d will re q uire 
i m me diate re p orti n g, rec or di n g a n d f oll o w-u p. T he f oll o wi n g e ve nts will be cl osel y 
m o nit ore d:

Treat me nt -e mer ge nt suici dal i deati o ns wit h i nte nt, wit h o r wit h o ut a pla n, (ie, T y pe 4 or 5 
o n t he C -S S R S) or a n y  s uici dal be ha vi ors 

Treat me nt -e mer ge nt ele vate d A L T or A S T la borat or y val ue t hat is ≥ 3 x U L N

P ote ntial H y ’s la w cases: ele vate d A L T or A S T la borat or y val ue t hat is ≥ 3 x U L N a n d a n 
ele vate d t otal bi lir u bi n la borat or y val ue t hat is ≥ 2 x U L N a n d, at t he sa me ti me, a n 
al kali ne p h os p hatase la b orat or y val ue t hat is < 2 x U L N.
Re p orti n g re q uire me nts f or A L T or A S T ele vati o ns a n d p ote ntial H y ’s la w cases are o utli ne d 
i n Secti o ns 9. 5 a n d 9. 5. 1 . Res p o nses t o t he C-S S R S t hat meet t he a b o ve criteri o n will be 
ca pt ure d i n t he e Ta blet a n d m o nit ore d b y Aller ga n. T hese A Es or e ve nts deter mi ne d t o be 
S A Es m ust be re p orte d a p pr o priatel y via t he desi g nate d e C R F s a n d safety f or ms.
6. 4. 3
Cli nic al L a b or at or y Deter mi n ati o ns
Bl o o d a n d uri ne sa m ples f or cli nical la b orat or y  tests will be c ollecte d at t he visits o utli ne d i n 
Ta ble 1 . He mat ol o g y, c he mistr y, I N R, a n d uri nalys is will be c o n d ucte d at t hese visits. 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
4 1
Ser ol o g y  a n d t he uri ne dr u g scree n will o nl y be c o n d ucte d at scree ni n g ( Visit 1). T he 
i n vesti gat or will assess t he cli nical si g nifica nce of a ny val ues o utsi de t he refere nce ra n ges 
pr o vi de d b y t he ce ntral la b orat or y. Partici pa nts wit h a b n or malities j u d ge d t o be cli nicall y 
si g nifica nt, la b orat or y val ues t hat meet e xcl usi o nar y criteria, or p ositi ve res ults o n t he uri ne 
dr u g scree n at scree ni n g ( Visit 1) will be e xcl u de d fr o m t he st u d y. Wo me n of c hil d beari n g 
p ote ntial will be re q ui re d t o ha ve a uri ne pre g na nc y test at all visits. A p ositi ve pre g na nc y  test 
at Visit 1 or Vi sit 2 will e xcl u de t he partici pa nt fr o m t he st u d y.
I n vesti gat ors ma y als o perf or m u nsc he d ule d cli nical la b orat or y deter mi nati o ns at a n y ti me f or 
t he p ur p ose of part ici pa nt safet y. 
P artici pa nt s are n ot re q uire d t o fast o ver ni g ht bef ore c o mi n g i n f or t heir a p p oi nt me nts.
T he cli nical la b orat or y  para meters t o be meas ure d are s h o w n i n Ta ble 6 – 1.
Ta ble 6 – 1.
Cli nic al L a b or at or y P ar a m eters
C ate g or y
P ar a m eter
C he mistr y
S o di u m, p otassi u m, c hl ori de, bicar b o nate, gl uc ose, bl o o d urea nitr o ge n, 
creati ni ne, t otal bilir u bi n, al kali ne p h os p hatase, as partate a mi n otra nsferase, 
ala ni ne a mi n otra nsferase, lactate de h y dr o ge nase, creati ne ki nase, t otal pr otei n, 
al b u mi n, calci u m, p h os p h or us, uric aci d, t otal c h olester ol. T he esti mate d 
gl o mer ular filtrati o n rate will be calc ulate d b y t h e ce ntral la b orat or y
He m at ol o g y
He m o gl o bi n, he mat ocrit, re d bl o o d cell c o u nt, re d bl o o d cell i n dices ( mea n 
c or p usc ular v ol u me, mea n c or p usc ular he m o gl o bi n, mea n c or p us c ular 
he m o gl o bi n c o nce ntrati o n), w hite bl o o d cell c o u nt, i ncl u di n g differe ntial 
( ne utr o phils, l y m p h oc ytes, m o n oc ytes, e osi n o p hils, a n d bas o p hils), platelet c o u nt
Uri nal ysis
Uri ne di pstic k f or s pecific gra vit y, p H, pr otei n, gl uc ose, ket o nes, bilir u bi n, a n d 
bl o o d; micr osc o pic e xa m i nati o n i ncl u di n g re d bl o o d cells/ hi g h-p o wer fiel d, w hite 
bl o o d cells/ hi g h -p o wer fiel d, a n d casts/l o w -p o wer fiel d
C oa g ulati o n
I N R
Ser ol o g y
At Visit 1 o nl y: a nti -he patitis A I g M a nti b o d y, he patitis B s urface a nti ge n, 
a nti -he patitis C a nti b o d y , a nti-he patitis E I g M a nti b o d y
Uri ne Dr u g Scree n
Scree ni n g f or dr u gs of a b use (e g, marij ua na, c ocai ne, p he nc ycli di ne, 
a mp heta mi nes, be nz o diaze pi nes, bar bit urates, o piates) w ill be c o n d ucte d usi n g a 
uri ne dr u g scree n at Visit 1. T h ose wit h a p ositi ve res ult o n t he Visit 1 uri ne dr u g 
scree n f or recreati o nal (i ncl u di n g marij ua na re gar dless of le galit y) or illicit dr u gs 
or n o n -discl ose d c o nc o mita nt me dicati o ns are n ot all o we d t o be re peate d. F or all 
ot her p ositi ve res ults, t he uri ne dr u g scree n ma y be re peate d wit h per missi o n 
fr o m Aller ga n; a ne gati ve res ult or a n e x pla nati o n of a p ositi ve res ult d ue t o
c o nc o mita nt me dicati o n use (e g, o pi oi ds prescri be d f or mi grai ne pai n) will be 
re q uire d f or ra n d o mizati o n.
I g M = i m m u n o gl o b uli n M; I N R = I nter nati o nal N or malize d Rati o
A ce ntral la b orat or y will be use d t o e val uate all uri ne a n d bl o o d sa m ples, w hic h will be 
c ollecte d, pr ocesse d , a n d st ore d acc or di n g t o t he i nstr ucti o ns pr o vi de d b y t he la b orat or y.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
4 2
6. 4. 4
Vi t al Si g ns
Vi tal si g n meas ure me nts, i ncl u di n g sitti n g a n d sta n di n g B P, sitti n g a n d sta n di n g p ulse rate, 
res pirat or y rate, te m perat ure, wei g ht, a n d hei g ht (at Vi sit 1 o nl y), will be perf or me d at e ver y 
visit. Sitti n g a n d sta n di n g B P  a n d p ulse rate will be deter mi ne d as f oll o ws: B P a n d p ulse 
meas ure me nts will be perf or me d after t he partici pa nt sits q uietl y f or 5 mi n utes, f oll o we d b y  a 
sec o n d set of meas ure me nts ta ke n after t he partici pa nt sta n ds f or at least 3 mi n utes ( b ut n o 
l o n ger t ha n 1 0 mi n utes).
6. 4. 5
P h ysic al E x a mi n ati o n
A c o m plete p h ys ical e xa mi nati o n will be perf or me d at t he visits o utli ne d i n Ta ble 1 . A 
pr ofessi o nall y trai ne d p h ysicia n or healt hcare pr ofessi o n al lice nse d t o perf or m p h y sical 
e xa mi nati o ns will e xa mi ne t he partici pa nt f or a ny detecta ble a b n or malities of t he f oll o wi n g 
b o d y  sys te ms: ge neral a p peara nce; nec k (i ncl u di n g t h yr oi d); hea d, e yes, ears, n ose, a n d 
t hr oat; l u n gs; heart/car di o vasc ular; a b d o me n; ne ur ol o gic; e xtre mities; bac k; m usc ul os keletal; 
l ym p hatic; s ki n; a n d ot her . T he ne ur ol o gic e xa mi nati o n s h o ul d be c o n d ucte d t o detect t he 
prese nce of a n y si g nifica nt se ns or y / m ot or a b n or malities.
6. 4. 6
Electr oc ar di o gr a ms
A 1 2- lea d E C G will be perf or me d at t he visits o utli ne d i n Ta ble 1 . All E C Gs s h o ul d be 
perf or me d after t he partici pa nt has bee n s u pi ne f or at least 5 mi n utes. All E C G s perf or me d
will be sa ve d as a s o urce d oc u me nt. E C Gs will be tra ns mitte d electr o nicall y t o t he ce ntral 
E C G la b orat or y  f or a nalysis acc or di n g t o t he i nstr ucti o ns pr o vi de d b y t he la b orat or y t o be 
ce ntrall y rea d b y a car di ol o gist. T he o verall i nter pretati o n of t he cli nical si g nifica nce of t he 
E C G will be deter mi ne d b y  t he i n vesti gat or a n d rec or de d i n t he partici pa nt ’s e C R F.
6. 4. 7
C ol u m bi a -S uici de Se verit y R ati n g Sc ale ( C-S S R S)
T he C - S S R S is a cli nicia n-rate d i nstr u me nt t hat re p orts t he se verity of b ot h s uici dal i deati o n 
a n d be ha vi or. S uici dal i deati o n is classifie d o n a 5 -ite m scale: 1 ( wis h t o be dea d), 
2 ( n o ns pecific acti ve s uici dal t h o u g hts), 3 (acti ve s uici dal i deati o n wit h a n y met h o ds [ n ot 
pla n] wit h o ut i nte nt t o act), 4 (acti ve s uici dal i deati o n wit h s o me i nte nt t o act, wit h o ut 
s pecific plan), a n d 5 (acti ve s uici dal i deati o n wit h s pecific pla n a n d i nte nt). T he C -S S R S als o 
ca pt ures i nf or mati o n a b o ut t he i nte nsit y  of i deati o n, s pecifically t he fre q ue nc y, d urati o n, 
c o ntr olla bilit y, deterre nts, a n d reas o ns f or t he m ost se vere ty pes of i deati o n. S uici dal be ha vi or 
is classifie d o n a 5-ite m scale: 0 ( n o s uici dal be ha vi or), 1 ( pre parat or y acts or be ha vi or), 
2 (a b orte d atte m pt), 3 (i nterr u pte d atte m pt), a n d 4 (act ual atte m pt). M ore t ha n 1 classificati o n 
ca n be selecte d pr o vi de d t he y  re prese nt se parate e pis o des. F or act ual atte m pts o nl y, t he act ual 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
4 3
or p ote ntial let halit y  is classifie d f or t he i nitial, m ost let hal, a n d m ost rece nt atte m pts. T he 
C- S S R S will be c o m plete d at all st u d y  visits. At scree ni n g (Vi sit 1) f or D e N ov o Partici pa nts
a n d C G P -M D -0 1 C o m pleters t he C-S S R S will be c o m plete d f or t he partici pa nt ’s lifeti me 
hist or y  of s uici dal i deati o n a n d be ha vi or. At all ot her visits t he C -S S R S will be c o m plete d f or 
i deati o n a n d be ha vi or si nce last visit f or all partici pa nts. T he C - S S R S will be c o m plete d o n 
t he e Ta blet b y t he i n vesti gat or or desi g nee wit h c urre nt a n d vali d trai ni n g i n a d mi nisteri n g 
t he assess me nt. A partici pa nt s h o ul d n ot be release d fr o m t he st u dy ce nter u ntil t he res ults of 
C- S S R S are re vie we d a n d it is c o nfir me d t hat t he partici pa nt is n ot c o nsi dere d t o be at ris k.
Partici pa nts w h o re pl y wit h “yes ” t o q uesti o ns 4 or 5 i n t he s uici dal i deati o n secti o n or “ yes ” 
t o a n y q uesti o n i n t he s uici dal be ha vi or secti o n of t he C-S S R S at Vi sits 3 t hr o u g h 1 4 m ust be 
wit h dra w n fr o m t he st u d y a n d s h o ul d recei ve a p pr o priate f oll o w-u p as i n r o uti ne cli nical 
practice, i ncl u di n g t he E T (Vi sit 1 5) a n d t he safet y foll o w - u p (Vi sit 1 6).
6. 5
Ot her St u d y S u p plies
6. 6
S u m m ar y of Met h o ds of D at a C ollecti o n
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
4 4
7 
St atistic al Pr oce d ur es
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
4 5
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
4 6
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
4 7
7. 3. 2
S afet y A n al yses
T he safet y a nal ys es will be perf or me d usi n g t he safet y p o p ulati o n. T he safet y para meters will 
i ncl u de A Es, cli nical la b orat or y  e val uati o ns, vital si g n meas ure me nts, E C G para meters, a n d 
t he C- S S R S. F or eac h of t he cli nical la b orat or y, vital si g n, a n d E C G para meters, t he last 
n o n- missi n g safet y  assess me nt bef ore t he first d ose of treat me nt will be use d as t he baseli ne 
f or all a nalys es of t hat safet y para meter. 
C o nti n u o us varia bles will be s u m marize d b y  t he n u m ber of partici pa nt s, a n d mea n, S D, 
me dia n, mi ni m u m, a n d ma xi m u m val ues. Cate g orical varia bles will be s u m marize d b y  
n u m ber a n d perce nta ge of partici pa nt s.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
4 8
7. 5
S a m ple Size C alc ul ati o n
T his st u d y  pla ns to ra n d o mize a t otal of 7 0 0 partici pa nt s. P artici pa nts will be ra n d o mize d 5: 2 
t o recei ve at o ge pa nt 6 0 m g Q D or oral S O C mi grai ne pre ve nti o n me dicati o n . Base d o n data 
fr o m pre vi o us st u dies (A ur ora 2 0 1 1 ; Ra p o p ort 2 0 0 6 ), it is estimate d t hat a p pr o xi matel y  6 0 % 
of t h ose partici pa nt s will c o m plete 6 m o nt hs of treat me nt, a n d of t h ose, 6 5 % will c o m plete 
1 2 m o nt hs of treat me nt. 
7. 6
I nteri m A n al yses
N o ne.
8
St u d y Vi sit Sc he d ule a n d Pr oce d ur es
Pl ease see Ta ble 1 f or a s ch e matic of t he S c he d ule of Vi sits a n d Pr oc e d ur es an d Fi g ure 1 f or a 
st ud y visit fl o wc hart.
8. 1
P artici p a nt E ntr y Pr oce d ures
8. 1. 1
O ver vie w of E ntr y Pr oce d ures
Pr os pecti ve partici pa nt s as defi ne d by t he crit eria i n Secti o ns 4. 3 a n d 4. 4 (i ncl usi o n/e xcl usi o n 
criteria) will be c o nsi dere d f or e ntr y i nt o t his st u d y.
8. 1. 2
I nf or me d C o nse nt a n d P artici p a nt Pri v ac y
T he st u d y  will be disc usse d wit h t he partici pa nt , a n d a partici pa nt wis hi n g t o partici pate m ust 
gi ve i nf or me d c o nse nt pri or t o a n y  st u d y-relate d pr oce d ures or c ha n ge i n treat me nt. T he 
partici pa nt m ust als o gi ve a ut h orizati o n, a n d ot her writte n d oc u me ntati o n i n acc or da nce wit h 
t he rele va nt c o u ntr y a n d l ocal pri vac y re q uire me nts ( w here a p plica ble) pri or t o a n y 
st u d y-relate d pr oce d ures or c ha n ge i n treat me nt.
Eac h partici pa nt t hat pr o vi des i nf or me d c o nse nt will be assi g ne d a partici pa nt i de ntificati o n 
n u m ber t hat will be use d o n partici pa nt d oc u me ntati o n t hr o u g h o ut t he st u d y . C G P -M D - 0 1 
C o m pleters will mai ntai n t heir lea d -i n st u d y partici pa nt i de ntificati o n n u m ber.
T he i n vesti gat or or q ualif ie d desi g nee will e x plai n t he f ut ure bi o me dical researc h s u b-st u d y 
c o nse nt (De N ov o Partici pa nts o nl y ) t o t he partici pa nt a n d a ns wer all of his/ her q uesti o ns. 
Partici pa nts will si g n a se parate c o nse nt f or m t o partici pate i n t he f ut ure bi o me dical researc h
s u b-st u d y bef ore perf or mi n g a n y pr oce d ure relate d t o t he s u b-st u dy.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
4 9
8. 1. 3
Pr oce d ure f or D u plic ate P artici p a nt I de ntific ati o n – Ve rifie d Cli nic al 
Tr i als
A ce ntral ve n d or will be use d t o verif y  partici pa nts c urre nt a n d past researc h st u d y stat us i n 
or der t o miti gat e safet y c o ncer ns ass ociate d wit h d u plicate e nr oll me nt a n d pr ot oc ol 
de viati o ns ass ociate d wit h m ulti ple trial e nr oll me nt. T he use of t his ce ntral ve n d or will be 
ma n dat or y  f or U S sites. F oll o wi n g pr o per i nf or me d c o nse nt a n d after iss ui n g a partici pa nt
n u m be r, eac h partici pa nt will be c hec ke d i n t he V C T data base, i n dicate d i n t he Sc he d ule of 
Vi sits a n d Pr oce d ures (Ta ble 1 ). Partial i de ntifiers will be utilize d. Partici pa nt s w h o are 
i de ntifie d as verificati o n fail ures by V C T s h o ul d n ot be e nr olle d wit h o ut d oc u me nte d 
a p pr o val fr o m Aller ga n .
8. 2
Wa s h o ut I nter v als/ R u n-i n
T his st u d y  will n ot i ncl u de a was h o ut peri o d.
8. 3
Pr oce d ures f or Fi n al St u d y E ntr y
At t he scree ni n g a n d ra n d o mizati o n visits ( Visits 1 a n d 2) partici pa nt s m ust meet all of t he 
i ncl usi o n criteria a n d m ust n ot meet a n y of t he e xcl usi o n criteria. Rescree ni n g of partici pa nts 
ma y  be c o nsi dere d wit h per missi o n fr o m Aller ga n. Als o, all fe males of c hil d beari n g p ote ntial 
m ust ha ve ne gati ve res ults o n t he uri ne pre g na nc y  test at t he scree ni n g a n d ra n d o mizati o n 
visits ( Visits 1 a n d 2, pri or t o t he first a d mi nistrati o n of at o ge pa nt or oral S O C mi grai ne 
pre ve nti o n me dicati o n ).
Pri or t o ra n d o mizati o n , it m ust be c o nfir me d t hat t he partici pa nt ha d 4 t o 1 4 mi grai ne d a y s 
per m o nt h i n t he 3 m o nt hs pri or t o Vi sit 1 i n t he o pi ni o n of t he i n vesti gat or (f or D e N ov o
P artici pa nts o nl y ), a n d 4 t o 1 4 mi grai ne d a y s d uri n g t he 4-wee k scree ni n g/ baseli ne peri o d per 
t he e Diar y (f or De N ov o P artici pa nts o nl y [see Secti o n 6. 1. 1 f or defi niti o n] ), a n d co m plete d 
t he e Diar y f or at least 2 0 of t he 2 8 da y s (f or D e N ov o Partici pa nts a n d C G P -M D - 0 1 
C o m pleters o nl y ).
See S ecti o n 5. 5 f or t he met h o d f or assi g n me nt t o treat me nt gr o u ps/ra n d o mizati o n.
8. 4
Vi sits a n d Ass oci ate d Pr oce d ures
T here will be 1 6 sc he d ule d cli nic visits: Vi sit 1 (scree ni n g/ baseli ne), Visit 2 (ra n d o mizati on), 
Vi sit 3 ( Wee k 4 ), Visit 4 ( Wee k 8 ), Visit 5 ( Wee k 1 2 ), Visit 6 ( Wee k 1 6 ), Visit 7 (We e k 20 ), 
Vi sit 8 ( Wee k 2 4), Visit 9 ( Wee k 2 8), Visit 1 0 ( Wee k 3 2), Visit 11 ( Wee k 3 6), Visit 1 2 
( Wee k 4 0), Visit 1 3 ( Wee k 4 4), Visit 1 4 ( Wee k 4 8), Visit 1 5/ E T ( Wee k 5 2), a n d Visit 1 6
(safety f oll o w -u p). F or details, please see Ta ble 1 , Sc he d ule of Vi sit a n d Pr oce d ures.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
5 0
8. 4. 1
Vi sit 1 ( Scree ni n g/ B aseli ne) D a y -3 5 t o D a y -2 8
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
5 1
8. 4. 2
O pe n- l a bel Tr e at me nt Peri o d ( 5 2 We e ks)
8. 4. 2. 1 Vi sit 2 ( R a n d o miz ati o n) D a y 1
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
5 2
8. 4. 2. 2 Vi sits 3 t o 1 4 (We e k 4 t o 4 8)
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
5 3
8. 4. 2. 3 Vi sit 1 5/ E arl y Te r mi n ati o n ( Wee k 5 2)
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
5 4
8. 4. 3
S afet y F oll o w -u p Peri o d ( 4 We e ks)
Refer t o Secti o n 8. 4. 3. 1. 1 a n d Ta ble 1 f or assess me nts t o be c o n d ucte d re m otel y d ue t o t he 
C O VI D -1 9 pa n de mic.
8. 4. 3. 1 Vi sit 1 6/ E n d of St u d y ( Wee k 5 6 ) C o n d ucte d D uri n g I n -Pers o n V isit 
( Pri or t o t he C O VI D-1 9 P a n de mic)
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
5 5
8. 4. 3. 1. 1 Vi sit 1 6/ E n d of St u d y ( Wee k 5 6) C o n d ucte d Re m otel y ( D ue t o t he 
C O VI D -1 9 P a n de mic)
8. 5
I nstr ucti o ns f or t he P artici p a nt s
Secti o n 4. 5. 4 pr o vi des diet a n d acti vit y  i nstr ucti o ns f or partici pa nts e nr olle d i n t he st u d y.
Partici pa nts will be pr o vi de d wit h i nstr ucti o ns o n dail y  c o m pleti o n of t he e Diar y. A practice 
sessi o n wit h a h yp ot hetical sce nari o s h o ul d be a d mi nistere d t o e ns ure t he partici pa nt ’s 
c o m pre he nsi o n of t he q uesti o ns a n d t he i nf or mati o n t o be e ntere d. I n a d diti o n, pr o hi bite d 
me dicati o ns s h o ul d be re vie we d wit h t he partici pa nts. Partici pa nts will be i nstr ucte d t o bri n g 
t heir e Diar y t o eac h cli nic visit a n d ret ur n t heir at o ge pa nt b ottle(s), b ot h use d a n d u n use d.
Partici pa nts s h o ul d be i nstr ucte d t o ta ke at o ge pa nt 6 0 m g Q D at a p pr o xi matel y t he sa me ti me 
eac h da y (a p pr o xi matel y 2 4 h o urs bet wee n d oses). F or d osi n g o n Da y  1 (Vi sit 2), t he first 
d ose is t o be ta ke n at t he st u d y  site. F or partici pa nts ra n d o mize d t o oral S O C mi grai ne 
pre ve nti o n me dicati o n, t he first d ose s h o ul d be ta ke n o n Da y  1.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
5 6
8. 6
U nsc he d ule d Vi sits
A d diti o nal e xa mi nati o ns a n d la b orat or y  assess me nts ma y be perf or me d as necessar y t o 
ens ure t he safet y a n d well -bei n g of t he partici pa nts d uri n g t he st u d y peri o d. U nsc he d ule d 
visit e C R Fs s h o ul d be c o m plete d f or eac h u nsc he d ule d visit.
8. 7
C o m pli a nce wit h Pr ot oc ol
All assess me nts will be c o n d ucte d at t he a p pr o priate visits as o utli ne d i n Ta ble 1 , a n d t he 
ti mi n g of t he visits s h o ul d occ ur as cl ose as p ossi ble t o t he da y s pecifie d. At eac h visit, t he 
partici pa nt will be as ke d if t he partici pa nt c ha n ge d t he d ose/re gi me n of a n y e xisti n g 
c o nc o mita nt me dicati o ns or i nitiate d t he use of a n y ne w c o nc o mita nt me dicati o ns si nce t he 
last visit, t o e ns ure c o m plia nce wit h t he pr ot oc ol. 
At o ge pa nt c o m plia nce d uri n g a n y peri o d will be cl osel y  m o nit ore d by c o u nti n g t he n u m ber 
of ta blets dis pe nse d a n d ret ur ne d. E ver y eff ort will be ma de t o c ollect all u n use d at o ge pa nt.
8. 8
E arl y Disc o nti n u ati o n of P artici p a nt s
A pre mat ure disc o nti n uati o n will occ ur w he n a partici pa nt w h o si g ne d t he I C F a n d has bee n 
ra n d o mize d ceases partici pati o n i n t he st u d y, re gar dless of circ u msta nces, bef ore c o m pleti o n 
of t he st u d y. Partici pa nt s ca n be pre mat urel y disc o nti n ue d fr o m t he st u d y f or o ne of t he
f oll o wi n g reas o ns:

A E

Lac k of efficac y

L ost t o f oll o w - u p

N o n -c o m plia nce wit h st u d y i nter ve nti o n (ie, at o ge pa nt)

Pre g na nc y

Pr ot oc ol de viati o n

Site ter mi nate d b y  Aller ga n

St u d y  ter mi nate d b y Aller ga n

Wit h dra wal b y  partici pa nt
Partici pa nt s ma y v ol u ntaril y wit h dra w fr o m t he st u d y at a n y ti me.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
5 7
N otificati o n of earl y  partici pa nt disc o nti n uati o n fr o m t he st u d y  a n d t he reas o n f or 
disc o nti n uati o n will be ma de t o t he s p o ns or a n d will be clearl y d oc u me nte d o n t he 
a p pr o priate eC R F . All ra n d o mize d partici pa nt s w h o pre mat urely disc o nti n ue fr o m t he st u d y, 
re gar dless of ca use, s h o ul d be see n f or fi nal st u d y assess me nts. T he fi nal assess me nts will be 
defi ne d as c o m pleti o n of t he e val uati o ns sc he d ule d f or Visit 1 5 /E T a n d Visit 1 6 (safet y 
foll o w - u p), 4 wee ks p ost t he last d ose of at o ge pa nt or af ter t he last st u d y visit f or oral S O C
mi grai ne pr e ve nti o n ar m.
8. 9
Wi t h dr a w al Criteri a
Wo me n w h o bec o me pre g na nt (Secti o n 9. 4 ) a n d partici pa nts w h o meet at o ge pa nt or oral S O C 
mi grai ne pre ve nti o n me dicati o n disc o nti n uati o n criteria relate d t o a b n or mal li ver f u ncti o n 
tests (Secti o n 9. 5 ), a n d a d vise d n ot t o be rec halle n ge d , will be wit h dra w n fr o m t he st u d y a n d 
s h o ul d refrai n fr o m ta ki n g at o ge pa nt or oral S O C mi grai ne pre ve nti o n me dicati o n . T he 
partici pa nt s h o ul d ret ur n t o t he cli nic f or E T pr oce d ures ( Visit 1 5) a n d t he safet y f oll o w - u p 
( Visit 1 6). Partici pa nt s w h o re pl y wit h “ yes ” t o q uesti o ns 4 or 5 i n t he s uici dal i deati o n 
secti o n or “ yes ” t o a ny q uesti o n i n t he s uici dal be ha vi or secti o n of t he C -S S R S at Vi sits 3 
t hr o u g h 1 4 m ust be wit h dra w n fr o m t he st u d y  a n d s ho ul d recei ve a p pr o priate f oll o w -u p as i n 
r o uti ne cli nical practice, i ncl u di n g t he E T ( Visit 1 5) a n d t he safet y f oll o w -u p ( Visit 1 6).
A partici pa nt wit h a c o n diti o n a n d/ or a sit uati o n t hat, i n t he i n vesti gat or's o pi ni o n, ma y  p ut 
t he partici pa nt at si g nifica nt ris k, ma y c o nf o u n d t he st u d y res ults, or ma y i nterfere 
si g nifica ntly wit h t he partici pa nt’s partici pati o n i n t he st u d y  ma y be wit h dra w n fr o m 
treat me nt.
8. 1 0 St u d y Te r mi n ati o n
T he st u d y  ma y be st o p pe d at his/ her st u d y site at a n y ti me b y t he site i n vesti gat or. Aller ga n 
ma y  st o p t he st u d y (a n d/ or t he st u d y site) f or a ny reas o n wit h a p pr o priate n otificati o n.
9
A d verse E ve nts
A E s occ u rri n g d uri n g t he st u d y will be rec or de d o n a n A E eC R F . If A E s occ ur, t he first 
c o ncer n will be t he safet y of t he st u d y partici pa nts.
9. 1
Defi niti o ns
9. 1. 1
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a cli nical st u d y  partici pa nt ass ociate d wit h t he 
use of at o ge pa nt or oral S O C mi grai ne pre ve nti o n me dicati o n , w het her or n ot c o nsi dere d 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
5 8
relate d. A n A E ca n t heref ore be a n y  u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), sy m pt o m, or disease ( ne w or e xacer bate d) te m p orall y ass ociate d wit h t he 
use of at o gepa nt or oral S O C mi grai ne pre ve nti o n me dicati o n . I n a d diti o n, d uri n g t he 
scree ni n g peri o d, A Es will be assesse d re gar dless of t he a d mi nistrati o n of a p har mace utical 
pr o d uct.
A Es will be re p orte d b y t he partici pa nt ( or , w he n a p pr o priate, b y a care gi ver, s urr o gate, or t he 
partici pa nt ’s le gally a ut h orize d re prese ntati ve).
T he i n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble f or 
f oll o wi n g u p A Es t hat are seri o us, c o nsi dere d relate d t o at o ge pa nt or st u d y  pr oce d ures, or t hat 
ca use d t he partici pa nt t o disc o nti n ue at o ge pa nt or oral S O C mi grai ne pre ve nti o n me dicati o n
or st u d y  (see Secti o n 8. 8 ).
All A Es fr o m t he si g ni n g of t he I C F u ntil t he safet y f oll o w-u p visit ( Visit 1 6 ), or 3 0 da ys after 
t he last d ose of at o ge pa nt ( or 3 0 d a y s after t he last st u d y visit f or t he oral S O C mi grai ne
pre ve nti o n me dicati o n ar m) if t he safety f oll o w-u p visit is n ot d o ne, will be c ollecte d at t he 
ti me p oi nts s pecifie d i n t he Sc he d ule of Visits a n d Pr oce d ures (Ta ble 1 ), a n d as o bser ve d or 
re p orte d s p o nta ne o usl y b y st u d y partici pa nts.
I n vesti gat ors are n ot o bli gate d t o acti vely see k A E i nf or mati o n after c o ncl usi o n of t he st u d y  
partici pati o n.
A Es will be assesse d, d oc u me nte d, a n d rec or de d i n t he e C R F t hr o u g h o ut t he st u d y  (ie, after 
i nf or me d c o nse nt has bee n o btai ne d). At eac h visit, t he i n vesti gat or will be gi n b y  q uer yi n g 
f or A Es b y as ki n g eac h partici pa nt a ge neral, n o n -directe d q uesti o n s uc h as “H o w ha ve y o u 
bee n feeli n g si nce t he last visit? ” O pe n -e n de d a n d n o n-lea di n g ver bal q uesti o ni n g of t he 
partici pa nt is t he preferre d met h o d t o i n q uire a b o ut A E occ urre nces. Care will be ta ke n n ot t o 
i ntr o d uce bias w he n detecti n g A Es a n d/ or S A Es. All re p orte d A Es will be d oc u me nte d o n t he 
a p pr o priate eC R F .
9. 1. 2
Seri o us A d verse E ve nt
A n S A E is a n y  AE occ urri n g at a n y  d ose t hat res ults i n a n y of t he f oll o wi n g o utc o mes:
A n S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:
a. 
Res ults i n de at h
b. 
Is life t hre ate ni n g
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
5 9
T he ter m life t hre ate ni n g i n t he defi niti o n of seri o us refers t o a n e ve nt i n w hic h t he 
partici pa nt was at ris k of deat h at t he ti me of t he e ve nt. I t d oes n ot refer t o a n e ve nt, w hic h 
h y p ot heticall y  mi g ht ha ve ca use d deat h, if it were m ore se vere.
c. 
Re q uir es i n p atie nt h os pit aliz ati o n or prol o n g ati o n of e xisti n g h os pit aliz ati o n
I n ge neral, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n detai ne d ( us uall y 
i n v ol vi n g at least a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or o bser vati o n 
a n d/ or i nter ve nti o n t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h ys icia n’s office or 
o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are A Es. If a 
c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, t he e ve nt is 
seri o us. W he n i n d o u bt as t o w het her h os pitalizati o n occ urre d or was necessar y, t he A E 
s h o ul d be c o nsi dere d seri o us.
H os pitalizati o n f or electi ve i nter ve nti o n of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n 
fr o m baseli ne is n ot c o nsi dere d a n A E.
d. 
Res ults i n persiste nt dis a bilit y/i nc a p acit y
T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n ’s a bilit y t o c o n d uct n or mal 
life f u ncti o ns.
T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, a n d 
acci de ntal tra u ma (e g, s prai ne d a n kle) w hic h ma y  i nterfere wit h or pre ve nt e ver yda y  life 
f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n.
e. 
Is a c o n ge nit al a n o m al y/ birt h defect
f. 
Ot her  sit u ati o ns:
Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E re p orti n g is 
a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat ma y  n ot be 
i m me diatel y life t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he 
partici pa nt or ma y  re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he ot her 
o utc o mes liste d i n t he a b o ve defi niti o n. T hese e ve nts s h o ul d us uall y  be c o nsi dere d seri o us.
E xa m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve i nter ve nti o n i n 
a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or c o n v ulsi o ns 
t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.
Aller ga n c o nsi ders all ca ncer A Es as S A Es. I n a d diti o n, Aller ga n c o nsi ders a n y a b orti o n 
(s p o nta ne o us or electi ve) as a n S A E.
Pre -pla n ne d s ur geries or pr oce d ures f or pre -e xisti n g, k n o w n me dical c o n diti o ns f or w hic h a 
partici pa nt re q uires h os pitalizati o n is n ot re p orta ble as a n S A E.
A n y  pre -pla n ne d s ur ger y  or pr oce d ure s h o ul d be clearly d oc u me nte d i n t he site s o urce 
d oc u me nts b y  t he me dicall y q ualifie d i n vesti gat or at t he ti me of t he partici pa nt’s e ntr y i nt o 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
6 0
t he st u d y. If it has n ot bee n d oc u me nte d at t he ti me of t he partici pa nt’s e ntr y int o t he st u d y, 
t he n it s h o ul d be d oc u me nte d as a S A E a n d re p orte d t o Aller ga n.
9. 1. 3
I nte nsit y
T he i nte nsit y  assess me nt f or a cli nical A E m ust be c o m plete d usi n g t he f oll o wi n g defi niti o ns 
as g ui deli nes:
Assess me nt of I nte nsit y
MI L D 
A t ype of A E t hat is us uall y  tra nsie nt a n d ma y re q uire o nl y mi ni mal 
treat me nt or t hera pe utic i nter ve nti o n. T he e ve nt d oes n ot ge nerall y 
i nterfere wit h us ual acti vities of dail y li vi n g.
M O D E R A T E
A t ype of A E t hat is us uall y  alle viate d wit h a d diti o nal s pecific 
t hera pe utic i nter ve nti o n. T he e ve nt i nterferes wit h us ual acti vities of 
dail y  li vi n g, ca usi n g disc o mf ort b ut p oses n o si g nifica nt or per ma ne nt 
ris k of har m t o t he researc h partici pa nt.
S E V E R E
A t ype of A E t hat i nterr u pts us ual acti vities of dail y  li vi n g, or 
si g nifica ntly affects cli nical stat us, or ma y re q uire i nte nsi ve t hera pe utic 
i nter ve nti o n.
A n e ve nt is defi ne d as seri o us w he n it meets at least o ne of t he pre defi ne d o utc o mes as 
descri be d i n t he defi niti o n of a n S A E, N O T  w he n it is rate d as se vere.
9. 1. 4
Assess me nt of C a us alit y
Assess me nt of C a us alit y
 
T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n at o ge pa nt or oral S O C 
mi grai ne pre ve nti o n me dicati o n a n d eac h occ urre nce of eac h A E or S A E .
 
A reas o n a ble p ossi bility of a relati o ns hi p c o n ve y s t hat t here are facts, evi de nce, a n d/ or 
ar g u me nts t o s u g gest a ca usal relati o ns hi p, rat her t ha n a relati o ns hi p ca n n ot be r ule d 
o ut.
 
T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.
 
Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y,  an d ot her ris k 
fact ors, as well as t he te m p oral relati o ns hi p of t he e ve nt t o at o ge pa nt a d mi nistrati o n or 
oral S O C mi grai ne pre ve nti o n me dicati o n will be c o nsi dere d a n d i n vesti gate d.
 
T he i n vesti gat or will als o c o ns ult t he i n vesti gat or ’s br oc h ure i n his/ her assess me nt.
 
F or eac h A E or S A E, t he i n vesti gat or m ust d oc u me nt i n t he me dical n otes t hat he/s he 
has re vie we d t he A E or S A E a n d has pr o vi de d a n assess me nt of ca usalit y .
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
6 1
 
T here ma y be sit uati o ns i n w hic h a n S A E has occ urre d, a n d t he i n vesti gat or has 
mi ni mal i n f or mati o n t o i ncl u de i n t he i nitial re p ort t o Aller ga n . H o we ver, it is ver y 
i m p ort a nt t h at t he i n vesti g at or al w a ys m a ke a n assess me nt of c a us alit y f or e ver y 
e ve nt bef ore t he i niti al tr a ns missi o n of t he S A E d at a t o Aller g a n .
 
T he i n vesti gat or ma y  c ha n ge his/her o pi ni o n of ca usalit y  i n li g ht of f oll o w- u p 
i nf or mati o n a n d se n d a n S A E f oll o w-u p re p ort wit h t he u p date d ca usalit y  assess me nt.

T he ca usalit y  assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y 
re p orti n g re q uire me nts.
9. 1. 5
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h 
partici pa nt at s u bse q ue nt visits/c o ntacts. All A Es/ S A Es a n d n o n -seri o us A Es of s pecial 
i nterest (as defi ne d i n Secti o n 6. 4. 2 ) will be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he e ve nt 
is ot her wise e x plai ne d, or t he partici pa nt is l ost t o f oll o w-u p (as defi ne d i n Secti o n 8. 8 ).
T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as me dicall y i n dicate d or as re q ueste d b y Aller ga n t o 
el uci date t he nat ure a n d/ or ca usalit y of t he A E or S A E as f ull y  as p ossi ble. T his ma y  i ncl u de 
a d diti o nal la b orat or y tests or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n 
wit h ot her healt h care p r ofessi o nals.
Pri or t o data base l oc k, ne w or u p date d i nf or mati o n will be rec or de d i n t he ori gi nall y
c o m plete d e C R F. If t he e ve nt is a n S A E, it will als o nee d t o be re p orte d o n t he S A E re p orti n g
f or m. P ost data base l oc k, ne w or u p date d S A E i nf or mati o n will o nl y  be re p orte d o n t he S A E
re p orti n g f or m.
T he i n vesti gat or will s u b mit a n y  u p date d S A E data t o Aller ga n wit hi n 2 4 h o urs of recei pt of 
t he i nf or mati o n.
9. 2
Pr oce d ures f or Re p orti n g A d verse E ve nts
All A E s m ust be rec or de d o n t he a p pr o priate e C R F .
All A Es t hat are at o ge pa nt -relate d a n d u ne x pecte d ( n ot liste d as treat me nt-relate d i n t he 
c urre nt i n vesti gat or's br oc h ure) m ust be re p orte d t o t he g o ver ni n g I R B/I E C as re q uire d b y t he 
I RB/I E C, l ocal re g ulati o ns, a n d t he g o ver ni n g healt h a ut h orities. A n y A E t hat is mar ke d 
‘o n g oi n g ’ at t he e xit visit m ust be f oll o we d -u p as a p pr o priate.
9. 3
Pr oce d ures f or Re p orti n g a Seri o us A d verse E ve nt
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
6 2
A n y  S A E occ urri n g d uri n g t he st u d y peri o d ( be gi n ni n g wit h i nf or me d c o nse nt) u ntil t he 
safety f oll o w-u p visit ( Visit 1 6 ) or 3 0 da ys after t he last d ose of at o ge pa nt ( or 3 0 da y s after 
t he last st u d y visit f or t he S O C ar m) if t he safet y f oll o w- u p visit is n ot d o ne m ust be 
i m me diatel y re p orte d b ut n o later t ha n 2 4 h o urs after lear ni n g of a n S A E. S A Es m ust be 
re p orte d t o Aller ga n as liste d o n t he Aller ga n St u d y C o ntacts Pa ge a n d rec or de d o n t he S A E 
f or m. All partici pa nt s wit h a n S A E m ust be f oll o we d u p a n d t he o utc o mes re p orte d. T he 
i n vesti gat or m ust s u p pl y  Aller ga n a n d t he I R B/I E C wit h a n y a d diti o nal re q ueste d i nf or mati o n 
(e g, a ut o ps y re p orts a n d disc har ge s u m maries).
9. 3. 1
Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts

Pr o m pt n otificati o n b y  t he i n vesti gat or t o Aller ga n of a n S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of partici pa nts a n d t he 
safety of a st u d y i nter ve nti o n (ie, at o ge pa nt) u n der cli nical i n vesti gati o n are met. 

Aller ga n has a le gal res p o nsi bilit y  t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d 
ot her re g ulat or y  a ge ncies a b o ut t he safety of a st u d y  i nter ve nti o n (ie, at o ge pa nt) u n der 
cli nical i n vesti gati o n. Aller ga n will c o m pl y wit h c o u ntr y -s pecific re g ulat or y 
re q uire me nts relati n g t o safety re p orti n g t o t he re g ulat or y a ut h orit y, I RBs/ I E Cs, a n d 
i n vesti gat ors

I n vesti gat or safet y re p orts m ust be pre pare d f or S U S A Rs acc or di n g t o l ocal 
re g ulat or y re q uire me nts a n d Aller ga n p olic y  a n d f or war de d t o i n vesti gat ors as 
necessar y .

A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a n S A E or ot her 
s pecific safety i nf or mati o n (e g, s u m mar y or listi n g of S A Es fr o m Aller ga n ) will 
re vie w a n d t he n file it al o n g wit h t he i n vesti gat or’s br oc h ure a n d will n otif y t he 
I RB/I E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.
9. 4
E x p os ure t o St u d y I nter ve nti o n D uri n g Pre g n a nc y
Details of all pre g na ncies i n fe male partici pa nts a n d fe male part ners of male partici pa nts will 
be c ollecte d after t he st ar t of at o ge pa nt a n d oral S O C mi grai ne pre ve nti o n me dicati o n a n d 
u ntil t he safet y f oll o w-u p visit ( Visit 1 6) or 3 0 da ys after t he last d ose of at o ge pa nt ( or 
3 0 da y s after t he last st u d y visit f or t he oral S O C mi grai ne pre ve nti o n me dicati o n ar m) if t he 
safety f oll o w-u p visit is n ot d o ne. St u d y  ce nter pers o n nel m ust re p ort e ver y pre g na nc y o n t he 
Pre g na nc y  F orm ( wit hi n 2 4 h o urs of lear ni n g of t he pre g na nc y  t o t he Seri o us A d verse E ve nt 
Re p orti n g Fa x N u m ber
 
, e ve n if n o A E has occ urre d. T he pre g na nc y m ust be 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
6 3
f oll o we d t o ter m a n d t he o utc o me re p orte d by c o m pleti n g a f oll o w -u p Pre g na nc y  F or m. 
A b n or mal pre g na nc y  o utc o mes (e g, s p o nta ne o us or electi ve a b orti o n, fetal deat h, still birt h, 
c o n ge nital a n o malies, ect o p ic pre g na nc y) are c o nsi dere d S A Es. F or pre g na nc y  relate d S A Es, 
i n a d diti o n t o t he Pre g na nc y F or m, a se parate S A E F or m m ust be file d as descri be d i n 
Secti o n 9. 3 wit h t he a p pr o priate seri o us criteri o n (e g, h os pitalizati o n) i n dicate d.
9. 5
A L T or A S T Ele v ati o ns
A treat me nt-e merge n t A L T ≥ 3 × U L N a n d/ or A S T ≥3 × U L N is c o nsi dere d a n A E SI. 
 
 
 
 
 
 
 
All A E S Is m ust be re p orte d t o Aller ga n wit hi n 2 4 h o urs of t he ti me t he i n vesti gat or bec o mes 
a ware of t he e ve nt usi n g t he a bn or mal li ver f u ncti o n re p orti n g f or m a n d t he A E e C R F. All 
ne w ele me nts of hist or y, p h ysical e xa mi nati o n, dia g n ostic testi n g res ults, a n d ot her rele va nt 
me dical re p orts are t o be re p orte d f or eac h A E S I.
If a n A L T or A S T ≥3 × U L N is c o nfir me d , cl ose me dic al f oll ow- u p is re q uire d:
At o ge p a nt a n d or al S O C mi gr ai ne pre ve nti o n me dic ati o n
m ust be disc o nti n ue d if a n y of 
t he f oll o wi n g criteri a are met:

A L T or A S T ≥ 3 × U L N a n d t he partici pa nt is s ym pt o matic wit h t he a p peara nce of 
fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt pai n or te n der ness, fe ver, ras h, or 
e osi n o p hilia ( > 5 %)
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
6 4

A L T or A S T ≥ 3 × U L N a n d t otal bilir u bi n > 2 × U L N

A L T or A S T ≥ 3 × U L N a n d I N R > 1. 5 

A L T or A S T ≥ 5 × U L N f or m ore t ha n 2 wee ks

A L T or A S T ≥ 8 × U L N
T he partici pa nt m a y  be rec halle n ge d wit h at o ge pa nt or oral S O C mi grai ne pre ve nti o n 
me dicati o n o nl y  after c o ns ultati o n wit h t he Aller ga n Me dical M o nit or . F or partici pa nt s w h o 
are n ot rec halle n ge d wit h oral S O C mi grai ne pre ve nti o n me dicati o n , t he partici pa nt s h o ul d be 
disc o nti n ue d fr o m t he st u d y  a n d c o m plete a n E T visit a n d 4-wee k safet y foll o w - u p visit. 
Partici pa nt s s h o ul d recei ve a p pr o priate f oll o w-u p as per sta n dar d of care.
T he i n vesti g at or m ust c o nt act t he Aller g a n Me dic al M o nit or t o disc uss all c ases of 
c o nfir me d A L T/ A S T ele v ati o n ≥ 3 x U L N. All A L T/ A S T ele v ati o ns m ust be f oll o we d 
u ntil A L T a n d A S T ret ur n t o < 1. 5 x U L N a n d t here is f ull cli nic al res ol uti o n.
9. 5. 1
P ote nti al H y ’s L a w C ases
Sites m ust re p ort e ver y partici pa nt w h o meets t he f oll o wi n g p ote ntial H y ’s la w criteria if t his 
occ urs wit hi n t he ti me t he partici pa nt si g ns t he I C F u ntil 3 0 da ys after t he last d ose of 
at o ge pa nt or oral S O C mi grai ne pre ve nti o n me dicati o n :

A L T or A S T ≥ 3 x U L N A N D

T otal bilir u bi n ≥ 2 x U L N A N D

Al kali ne p h os p hatase < 2 x U L N
St u d y  site pers o n nel m ust re p ort e ver y partici pa nt w h o meets t hese criteria. Ty picall y, all 
3 a nal yt es will be o btai ne d fr o m t he sa me sa m ple, b ut t he y  ma y c o me fr o m m ulti ple sa m ples 
ta ke n wit hi n a 2 4-h o ur peri o d. T his re q uire me nt a p plies fr o m t he ti me t he partici pa nt si g ns 
t he IC F f or t he st u d y  u ntil 3 0 da ys after t he fi nal pr ot oc ol-defi ne d st u d y visit or t he last 
k n o w n d ose of at o ge pa nt or oral S O C mi grai ne pre ve nti o n me dicati o n (if t he fi nal visit d oes 
n ot occ ur).
A la b orat or y alert f or p ossi ble H y’s la w cases will be i n place a n d m ust n otif y  i n vesti gat ors 
a n d Aller ga n i m me diatel y w he n t he a b o ve criteria ha ve bee n met. A p ossi ble H y ’s la w case 
m ust be fa xe d t o Aller ga n o n a n a b n or mal li ver f u ncti o n re p orti n g f or m as s o o n as p ossi ble 
( wit hi n 2 4 h o urs of lear ni n g of t he p ossi ble H y ’s la w case) t o t he S A E/ Pre g na nc y fa x 
n u m ber , e ve n if n o A E has occ urre d. If t he e ve nt is seri o us, please c o m plete t he A E SI/ S A E 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
6 5
f or m. T he e C R F f or p ossi ble H y ’s la w cases m ust be c o m plete d wit hi n 7 cale n dar da ys. 
E ver y ef f ort t o deter mi ne t he ca use of t he li ver e nz yme a b n or malities m ust be ma de, a n d 
cl ose m o nit ori n g s h o ul d be i nitiate d i n c o nj u ncti o n wit h t he me dical m o nit or a n d me dical 
safety p h ys icia n a n d i n acc or da nce wit h t he F D A G ui da nce f or I n d ustr y, Dr u g-I n d uce d Li ver 
I nj ur y: Pre mar keti n g Cli nical E val uati o n, J ul y 2 0 0 9. T he partici pa nt s h o ul d ret ur n t o t he 
st u d y site a n d be e val uate d as s o o n as p ossi ble, prefera bly wit hi n 4 8 h o urs fr o m t he ti me t he 
i n vesti gat or bec o mes a ware of t he a b nor mal res ults. T his e val uati o n s h o ul d i ncl u de 
la b orat or y tests, detaile d hist or y, a n d p h ysical assess me nt.
1 0 A d mi nistr ati ve Ite ms
T his pr ot oc ol is t o be c o n d ucte d i n acc or da nce wit h t he a p plica ble G C P  re g ulati o ns a n d 
g ui deli nes (e g, t he I C H G ui deli ne o n G C P).
1 0. 1 Pr otecti o n of H u m a n P artici p a nt s
1 0. 1. 1 C o m pli a nce W it h I nf or me d C o nse nt Re g ul ati o ns ( U S 2 1 C F R 
P art 5 0) a n d Rele v a nt C o u ntr y Re g ul ati o ns
Wr itte n i nf or me d c o nse nt is t o be o btai ne d fr o m eac h partici pa nt pri or t o a n y st u d y-relate d 
acti vities or pr oce d ures i n t he st u d y, a n d/ or fr o m t he partici pa nt's le gall y a ut h orize d 
re prese ntati ve.
T he f oll o wi n g pr ocess will be f oll o we d:

T he i n vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t he 
partici pa nt or his/ her le gall y  a ut h orize d re prese ntati ve a n d a ns wer all q uesti o ns 
re gar di n g t he st u dy. 

Partici pa nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y . Partici pa nts or t heir 
le gall y a ut h orize d re prese ntati ves will be re q uire d t o si g n a state me nt of i nf or me d 
c o nse nt t hat meets t he re q uire me n ts of 2 1 C F R 5 0, l ocal re g ulati o ns, I C H g ui deli nes, 
HI P A A re q uire me nts, w here a p plica ble, a n d t he I R B/I E C or st u d y  ce nter. 

T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was 
o btai ne d bef ore t he partici pa nt was e nr olle d i n t he st u d y  a n d t he date t he writte n 
c o nse nt was o btai ne d. T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust 
als o si g n t he I C F.

Partici pa nts m ust be rec o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir 
partici pati o n i n t he st u d y if re q uire d by t he I RB. 

A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gall y 
a ut h orize d re prese ntati ve.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
6 6
1 0. 1. 2 C o m pli a nce W it h I R B or  I E C Re g ul ati o ns
T his st u d y  is t o be c o n d ucte d i n acc or da nce wit h I R B re g ulati o ns ( U S 2 1 C F R Part 5 6. 1 0 3) 
or a p plica ble I E C re g ulati o ns. T he i n vesti gat or m ust o btai n a p pr o val fr o m a pr o perly 
c o nstit ute d IR B/I E C pri or t o i nitiati n g t he st u d y  a n d re-a p pr o val or re vie w at least a n n uall y. 
Aller ga n is t o be n otifie d i m me diatel y if t he res p o nsi ble I R B/I E C has bee n dis q ualifie d or if 
pr ocee di n gs lea di n g t o dis q ualificati o n ha ve be g u n. C o pies of all I R B/I E C c orres p o n de nce 
wit h t he i n vesti gat or s h o ul d be pr o vi de d t o Aller ga n.
1 0. 1. 3 C o m pli a nce W it h G o o d Cli nic al Pr actice
T his pr ot oc ol is t o be c o n d ucte d i n acc or da nce wit h t he a p p lica ble GC P re g ulati o ns a n d 
g u i deli nes.
1 0. 1. 4 C o m pli a nce W it h Electro nic Rec or ds; Electr o nic Si g n at ures 
Re g ul ati o ns ( U S 2 1 C F R P art 1 1)
T his st u d y  is t o be c o n d ucte d i n c o m plia nce wit h t he re g ulati o ns o n electr o nic rec or ds a n d 
electr o nic si g nat ures.
1 0. 2 Fi n a nci al Dis cl os ure
I n vesti gat ors a n d s u bi n vesti gat ors will pr o vi de Aller ga n wit h s uf ficie nt, acc urate fi na ncial 
i nf or mati o n as re q ueste d t o all o w Aller ga n t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y  a ut h orities. In vesti gat ors 
are res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y 
a n d f or 1 ye ar after c o m pleti o n of t he st u d y.
1 0. 3 C h a n ges t o t he Pr ot oc ol
T he i n vesti gat or m ust n ot i m ple me nt a n y de viati o n fr o m or c ha n ges t o t he pr ot oc ol wit h o ut 
a p pr o val b y Aller ga n a n d pri or re vie w a n d d oc u me nte d a p pr o val/fa v ora ble o pi ni o n fr o m t he 
I RB/I E C of a pr ot oc ol a me n d m e nt, e xce pt w here necessar y  t o eli mi nate i m me diate hazar ds t o 
st u d y partici pa nt s, or w he n t he c ha n ges i n v ol ve o nl y l o gistical or a d mi nistrati ve as pects of 
t he st u d y (e g, c ha n ge i n m o nit ors, c ha n ge of tele p h o ne n u m bers).
1 0. 4 D at a Pr otecti o n
Partici pa nts will be assi g ne d a u ni q ue i de ntifier. A n y  partici pa nt rec or ds or datasets t hat are 
tra nsferre d t o Aller ga n will c o ntai n t he i de ntifier o nl y; partici pa nt na mes or a n y  i nf or mati o n 
w hic h w o ul d ma ke t he partici pa nt i de ntifia ble will n ot be tra nsferre d. 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
6 7
T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d data will be use d b y 
Aller ga n i n acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl os ure m ust als o be 
e x plai ne d t o t he partici pa nt. 
T he partici pa nt m ust be i nf or me d t hat his/ her me dical re c or ds ma y be e xa mi ne d b y Cli nical 
Q ualit y  Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y Aller ga n , b y 
a p pr o priate I RB/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities.
1 0. 5 P artici p a nt Pri v ac y
Wr itte n a ut h orizati o n a n d ot her d oc u me ntati o n i n acc or da nce wit h t he rele va nt c o u ntr y  a n d 
l ocal pri vac y re q uire me nts ( w here a p plica ble) is t o be o btai ne d fr o m eac h partici pa nt pri or t o 
e nr oll me nt i nt o t he st u d y, a n d/ or fr o m t he partici pa nt's le gally a ut h orize d re prese ntati ve i n 
acc or da nce wit h t he a p plica ble pri vac y re q uire me nts (e g, HIP A A).
I n acc or da nce wit h HI PA A  re q uire me nts, a d diti o nal p ur p oses of t his st u d y ma y  i ncl u de 
p u blis h i n g of a n o n y m o us partici pa nt data fr o m t he st u d y.
1 0. 6 D oc u me nt ati o n
1 0. 6. 1 S o ur ce D oc u me nts
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
6 8
1 0. 6. 2 C ase Re p ort F or m C o m pleti o n
1 0. 6. 3 St u d y S u m m ar y
A n i n vesti gat or's s u m mar y  will be pr o vi de d t o Aller ga n wit hi n a s h ort ti me after t he 
c o m pleti o n of t he st u d y, or as desi g nate d by Aller ga n. A s u m mar y is als o t o be pr o vi de d t o 
t he res p o nsi ble I R B/I E C.
1 0. 6. 4 Rete nti o n of D oc u me n t ati o n
All st u d y  relate d c orres p o n de nce, partici pa nt rec or ds, c o nse nt f or ms, partici pa nt pri vac y 
d oc u me ntati o n, rec or ds of t he distri b uti o n a n d use of all at o ge pa nt, a n d c o pies of eC R Fs 
s h o ul d be mai ntai ne d o n file.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
6 9
1 0. 7 L a beli n g, P ac k a gi n g , a n d Ret ur n or Dis p os al of St u d y I nter ve nti o n
1 0. 7. 2 Cli nic al S u p pl y I n ve nt or y
 
 
 
 
 At o ge pa nt m ust be dis pe nse d or a d mi nistere d o nl y b y a n a p pr o priatel y q ualifie d 
pers o n t o partici pa nts i n t he st u d y . At o ge pa nt is t o be use d i n acc or da nce wit h t he pr ot oc ol f or 
partici pa nts w h o are u n der t he direct s u per visi o n of a n i n vesti gat or .
1 0. 7. 3 Ret ur n or Dis p os al of St u d y I nter ve nti o n a n d/ or S u p plies
 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
7 0
1 0. 8
M o nit ori n g b y t he S p o ns or
A re prese ntati ve of Aller ga n will m o nit or t he st u d y o n a peri o dic basis. T he deter mi nati o n of 
t he e xte nt a n d nat ure of m o nit ori n g will be base d o n c o nsi derati o ns s uc h as t he o bjecti ve, 
p ur p ose, desi g n, c o m ple xit y, bli n di n g, size, a n d e n d p oi nts of t he st u d y.
A ut h orize d re prese ntati ves of Aller ga n or re g ulat or y a ut h orit y re prese ntati ves will c o n d uct 
o n- site visits t o re vie w, a u dit, a n d c o p y st u d y-relate d d oc u me nts. T hese re prese ntati ves will 
meet wit h t he i n vesti gat or(s) a n d a p pr o priate staf f at m ut uall y c o n ve nie nt ti mes t o disc uss 
st u d y-relate d data a n d q uesti o ns.
1 0. 9 H a n dli n g of Bi ol o gic al S peci me ns
1 0. 1 0 P u blic ati o ns
Aller ga n as t he s p o ns or , has pr o prietar y i nterest i n t his st u d y. A ut h ors hi p a n d ma n uscri pt 
c o m p ositi o n will reflect j oi nt c o o perati o n bet wee n m ulti ple i n vesti gat ors a n d sites a n d 
Aller ga n pers o n nel. A u t h ors hi p will be esta blis he d pri or t o t he writi n g of t he ma n uscri pt. As 
t his st u d y i n v ol ves m ulti ple ce nters, n o i n di vi d ual p u blicati o ns will be all o we d pri or t o 
c o m pleti o n of t he fi nal re p ort of t he m ultice nter st u d y  e xce pt as a gree d wit h Aller ga n.
1 0. 1 1 C o or di n ati n g I n vesti g at or
A si g nat or y C o or di nati n g In vesti gat or will be desi g nate d pri or t o t he writi n g of t he cli nical 
st u d y re p ort.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
7 1
1 1 Refere nces
A ur ora S K, W i n ner P, Free ma n M C, S pieri n gs E L, Heiri n g J O, De Gr yse R E, et al. 
O na b ot uli n u mt o xi n A  f or treat me nt of c hro nic mi grai ne: p o ole d a nal y ses of t he 5 6-wee k 
P R E E M P T  cli nical pr o gra m. Hea dac he. 2 0 11 Oct; 5 1( 9): 1 3 5 8 - 1 3 7 3.
E vers S, Afra J, Frese A, G oa ds b y PJ, L i n de M, Ma y A, Sá n d or P S. E F N S g ui deli nes 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 J Ne ur ol 2 0 0 9 Se p; 
1 6( 9): 9 6 8 - 9 8 1.
H of f ma n n J, A ker ma n S, G oa ds b y PJ. Ef ficac y a n d mec ha nis m of a ntic o n v ulsa nt dr u gs i n 
mi grai ne. E x pert Re vie w of Cli nical P har mac ol o g y . Ta yl or & Fra ncis; 2 0 1 4 
Mar; 7( 2): 1 9 1 - 2 0 1.
H u X H, Mar ks o n
L E , Li pt o n R B, Ste wart W F , Ber ger M L.
B ur de n of mi grai ne
i n t he 
U nite d States. Arc h I nter n Me d. 1 9 9 9; 1 5 9: 8 1 3- 8 1 8.
I C H D-3: Hea dac he Classificati o n C o m mittee of t he I nter nati o nal Hea dac he S ociet y  (IH S). 
T he I nter nati o nal Classificati o n of Hea dac he Dis or ders, 3r d e diti o n. Ce p halal gia. 
2 0 1 8 ; 38 ( 1):1- 2 1 1.
Katsara va Z, B use D C, Ma nac k A N, L i pt o n R B. Defi ni n g t he Differe nces Bet wee n E pis o dic 
Mi grai ne a n d C hr o nic Mi grai ne. C urr Pai n Hea dac he Re p. 2 0 1 2; 1 6: 8 6 – 9 2 .
Ke n war d M G, R o ger J H. S mall sa m ple i nfere nce f or fi xe d ef fects fr o m restricte d ma xi m u m 
li keli h o o d. Bi o metrics 1 9 9 7; 5 3: 9 8 3 – 9 9 7. 
Li pt o n R B, Bi gal M E, Dia m o n d M, Freita g F , Ree d M L, Ste wart W F . Mi grai ne pre vale nce, 
disease b ur de n, a n d t he nee d f or pre ve nti ve t hera p y . Ne ur ol o g y 2 0 0 7; 6 8: 3 4 3- 3 4 9.
Olese n J, Die ne r H-C, H usste dt I W, G oa ds b y PJ , Hal l D, Meie r U, et al. Calcit o ni n ge ne -
relate d pe pti de rece pt or a nta g o nist BI B N 4 0 9 6 B S f or t he ac ute treat me nt of mi grai ne.
N E n gl J Me d. 2 0 0 4; 3 5 0: 1 1 0 4- 1 1 1 0.
Ra p o p ort A, Ma us k o p A, Die ner H C, Sc h wale n S, Pfeil J. L o n g -ter m mi grai ne pre ve nti o n 
wit h t o pira mate: o pe n -la bel e xte nsi o n of pi v otal trials. Hea dac he. 
2 0 0 6 J ul-A u g; 4 6( 7): 1 1 5 1 -1 1 6 0.
Sc h ür ks M, Die ner H C, G oa ds b y P.  U p date o n t he Pr o p h yla xis of Mi grai ne. C urre nt 
Tr eat me nt O pti o ns i n Ne ur ol o g y. S pri n ger U S [ Ne w Yo r k]; 2 0 0 8 Ja n; 1 0( 1): 2 0- 2 9.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
7 2
Sil berstei n S D, H olla n d S, Freita F , D o dic k D W, Ar g off C, a n d As h ma n E. E vi de nce -base d 
g ui deli ne u p date: p har mac ol o gic treat me nt f or e pis o dic mi grai ne pre ve nti o n i n a d ults. 
Ne ur ol o g y  2 0 1 2; 7 8: 1 3 3 7- 1 3 4 5.
Stei ner TJ, Pae meleire K, Je nse n R, V ala de D, Sa vi L, Lai nez MJ A, et al. E ur o pea n pri nci ples 
of ma na ge me nt of c o m m o n hea dac he dis or ders i n pri mar y  care. J Hea dac he Pai n 2 0 0 7; Oct; 8
S u p pl 1: S 3 - 4 7.
Stei ner TJ, St o v ner L J, a n d Bir bec k G L. Mi grai ne: t he se ve nt h disa bler. J Hea dac he Pai n 
2 0 1 3; 1 4( 1): 1 -2.
St o v ner L J, A n dree C. Pre vale nce of hea dac he i n E ur o pe: a re vie w f or t he E ur oli g ht Pr oject. 
J Hea dac he Pai n. 2 0 1 0; 1 1: 2 8 9 – 2 9 9.
Vo s T,  Fla x ma n A D, Na g ha vi M, L oza n o R, Mic ha u d C, Ezzati M, et al. Ye ars li ve d wit h 
disa bilit y  ( Y L Ds) f or 11 6 0 se q uelae of 2 8 9 diseases a n d i nj uries 1 9 9 0 -2 0 1 0: a s y ste mic 
a nal ys is f or t he Gl o bal B ur de n of Disease St u d y 2 0 1 0. La n cet. 2 0 1 3; 1 4( 9 8 5 9): 2 1 6 3 - 2 1 9 6.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
7 3
1 2 Att ac h me nts
1 2. 1 E x a mi n ati o n Pr oce d ures, Te sts, E q ui p me nt, a n d Te c h ni q ues
1 2. 1. 1 I nter n ati o n al Cl assific ati o n of He a d ac he Dis or ders, 3r d E diti o n
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
7 4
1.
Mi gr ai n e
1. 1
Mi grai ne wit h o ut a ura
1. 2
Mi gr ai n e wit h a ur a
1. 2. 1
Mi gr ai n e wit h t y pi c al 
a ura
1. 2. 1. 1
T y pi c al a ur a wit h h e a d a c h e
1. 2. 1. 2
T y pi c al a ur a wit h o ut h e a d a c h e
1. 2. 2
Mi gr ai n e wit h br ai nst e m a ur a
1. 2. 3
H e mi pl e gi c mi gr ai n e
1. 2. 3. 1
F a mili al h e mi pl e gi c mi gr ai n e
( F H M)
1. 2. 3. 1. 1
F a mili al h e mi pl e gi c 
mi gr ai n e t y p e 1 ( F H M 1)
1. 2. 3. 1. 2
F a mili al h e mi pl e gi c 
mi gr ai n e t y p e 2 ( F H M 2)
1. 2. 3. 1. 3
F a mili al h e mi pl e gi c 
mi gr ai n e t y p e 3 ( F H M 3)
1. 2. 3. 1. 4
F a mili al h e mi pl e gi c 
mi gr ai n e, ot h er l o ci
1. 2. 3. 2
S p or a di c h e mi pl e gi c mi gr ai n e
( S H M)
1. 2. 4
R eti n al mi gr ai n e
1. 3
C hr o ni c mi gr ai n e
1. 4
C o m pli c ati o ns of mi gr ai n e
1. 4. 1
Stat us mi gr ai n os us
1. 4. 2
Persiste nt a ura wit h o ut i nfarcti o n
1. 4. 3
Mi gr ai n o us i nf ar cti o n
1. 4. 4
Mi gr ai n e a ur a -tri g g er e d s ei z ur e
1. 5
Pr o b a bl e mi gr ai n e
1. 5. 1
Pr o ba ble mi grai ne wit h o ut a ura
1. 5. 2
Pr o ba ble mi grai ne wit h
a ura
1. 6
E pis o di c s y n dr o m es t h at m a y b e ass o ci at e d
wit h mi gr ai n e
1. 6. 1
R e c urr e nt g astr oi nt esti n al
dist ur b a n c e
1. 6. 1. 1
C y cli c al v o miti n g s y n dr o m e
1. 6. 1. 2
A b d o mi n al mi gr ai n e
1. 6. 2
B e ni g n p ar o x ys m al v erti g o
1. 6. 3
B e ni g n p ar o x ys m al t orti c ollis
C o de d else w here:
Mi gr ai n e -li k e h e a d a c h e s e c o n d ar y
t o a n ot h er 
dis or d er (s y m pt o m ati c mi gr ai n e ) is c o d e d as a 
s e c o n d ar y h e a d- a c h e attri b ut e d t o t h at dis or d er.
Ge ner al c o m me nt
Pri m ar y or s e c o n d ar y h e a d a c h e or b ot h ? T hr e e 
r ul es a p pl y t o mi gr ai n e-li k e h e a d a c h e, a c c or di n g 
t o cir c u mst a n c es.
1.
W h e n a n e w h e a d a c h e wit h t h e 
c h ar a ct eristi cs of mi gr ai n e o c c urs f or t h e ﬁrst 
ti m e i n cl os e t e m p or al r el ati o n t o a n ot h er 
dis or d er k n o w n t o c a us e h e a d - a c h e, or f ul ﬁls 
ot h er crit eri a f or c a us ati o n b y t h at dis or d er, 
t h e n e w h e a d a c h e is c o d e d as a s e c o n d ar y 
h e a d a c h e attri b ut e d t o t he c a us ati v e
dis or d er.
2.
W h e n
pr e -e xisti n g mi gr ai n e b e c o m es c hr o ni c
i n cl ose t e m p or al r el ati o n t o s u c h a ca usati ve 
dis or der, b ot h t h e i nitial mi gr ai n e dia g n osis 
a n d t h e sec o n dar y di a g n osis s h o ul d b e gi v e n. 
8. 2 M e di c ati o n -o v er us e
h e a d -
a c h e 
is a 
p arti c ul arl y i m p orta nt e x a m pl e of t his:b ot h t h e 
mi gr ai n e dia g n osis ( e pis o di c or c hr o ni c) a n d 
t he  
dia g n osis 
8. 2
M e di c ati o n -o v er us e
h e a d a c h e s h o ul d b e gi v e n w h e n m e di c ati o n 
o v er us e is pr es e nt.
3.
W h e n 
pr e -e xisti n g  
mi gr ai n e 
is  m a d e 
si g niﬁc a ntl y  w ors e 
( us u all y 
m e a ni n g  a 
t w of ol d or gr e at er i n cr e as e i n fr e q u e n c y a n d/ or 
s e v erit y) i n cl os e t e m p or al r el ati o n t o s u c h a 
c a us ati v e dis or d er, b ot h t h e i nitial mi gr ai n e 
di a g n osis  a n d  t h e 
s e c o n d ar y  h e a d a c h e 
di a g n osis s h o ul d b e gi v e n, pr o vi d e d t h at t h er e 
is g o o d e vi d e n c e t h at t h e dis or d er c a n c a us e
h e a d a c h e.
I ntr o d ucti o n
Mi grai ne is a c o m m o n disa bli n g pri mar y hea dac he 
dis - or der. Ma n y  e pi de mi ol o gical st u dies ha ve  
d oc u me nte d 
its hi g h 
pre vale nce 
a n d s oci o-
ec o n o mic a n d pers o nal i m pacts. I n t he Gl o b al 
B ur de n of Dise ase St u d y 2 0 1 0 ( G B D 2 0 1 0), it was 
ra n ke d as t h e t hir d m ost pre vale nt dis or der i n t h e 
w orl d. I n G B D 2 0 1 5, it w as ra n ke d t h e t hir d-hi g hest 
ca use of disa bilit y w orl d wi de i n b ot h males a n d 
fe males u n d er t h e a g e of 5 0 years.
Mi gr ai n e h as t w o m aj or t y p es: 1. 1 Mi gr ai n e
wit h o ut a ur a is a cli nical s y n dr o m e c h ar a ct eri z e d 
b y h e a d a c h e wit h s p e ci ﬁc f e at ur es a n d ass o ci at e d 
s y m pt o ms; 1. 2 Mi gr ai n e wit h a ur a is pri m aril y 
c h ar a ct eri z e d b y t he tr a nsi e nt f o c al n e ur ol o gi c al 
s y m pt o ms t hat us u all y pr e c e d e or s o m eti m es 
acc o m pa n y t h e h e a d a c h e. S o m e p ati e nts als o 
e x p eri e n c e a pr o dr o mal p h as e, o c c urri n g h o urs or 
d a ys b ef or e t h e h e a d a c h e, a n d/ or a p ost dr o mal 
p h as e f oll o wi n g hea dac he r es ol uti o n. Pr o dr o mal 
a n d p ost dr o mal s y m pt o ms i n cl u d e h y p er a cti vit y, 
h y p oacti v it y, d e pr essi o n, cr a vi n gs f or p a rti c ul ar 
f o o ds, r e p etiti v e y a w ni n g, f ati g u e a n d n e c k 
sti n ess a n d/ or p ai n.
W h e n 
a p ati e nt f ulﬁls crit eri a f or m or e t h a n
o n e t y p e, s u bt y p e or s ubf or m of mi gr ai n e, all 
s h o ul d b e di a g n os e d a n d c o d e d. F or e x a m pl e, a 
p ati e nt w h o h as fr e q u e nt att a c ks wit h a ur a b ut als o 
s o m e att a c ks wit h o ut a ur a s h o ul d b e c o d e d as 1. 2 
Mi gr ai n e 
wit h
a ur a a n d 1. 1 Mi gr ai n e 
wit h o ut
a ur a .H o w e v er, si n c e t hedi a g n osti c crit eri a f or 1. 3 
C hr o ni c mi gr ai n e s u bs u m e att a c ks of all t y p es, 
s u bt y p es or 
s u bf or ms, a d diti o n al c o di n g is 
u n n e c ess ar y f or e pis o di c s u bt y p es of mi gr ai n e.
1. 1 
Mi gr ai ne wit h o ut a ur a
Pr e vi o usl y  us e d 
t er ms: C o m m o n  
mi gr ai n e; 
h e mi cr a ni a si m pl e x
D es cri pti o n: R e c urr e nt h e a d a c h e dis or d er 
m a nif esti n g i n att a c ks l asti n g 4 – 7 2 h o urs T y pi c al 
c h ar a ct eristi cs of t h e h e a d a c h e ar e u nil at er al 
l o c ati o n, p uls ati n g q u alit y, m o d er at e or s e v er e 
i nt e nsit y, a g gr a v ati o n b y r o uti n e p h ysi c al a cti vit y 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
7 5
a n d ass o ci ati o n wit h n a us e a a n d/ or p h ot o p h o bi a 
a n d p h o n o p h o bi a.
Di a g n ostic criteri a:
A.
At l e ast ﬁv e att a c ks 1 f ulﬁlli n g crit eri a B – D
B.
H e a d a c h e att a c ks l asti n g 4 – 7 2 h o urs 
( w h e n u ntr e at e d or u ns u c c essf ull y
treate d)2, 3
C.
H e a d a c h e h as at l e ast t w o of t h e f oll o wi n g 
f o ur c h ar a ct eristi cs:
1.
u nil at er al l o c ati o n
2.
p uls ati n g q u alit y
3.
m o d er at e or s e v er e p ai n
i nt e nsit y
4.
a g gr a v ati o n b y or c a usi n g a v oi d a n c e of 
r o uti n e p h ysi c al a cti vit y ( e. g. w al ki n g 
or cli m bi n g st airs)
D.
D uri n g 
h e a d a c h e at 
l e ast
o n e 
of 
t h e
f oll o wi n g:
1.
n a us e a a n d/ or v o miti n g
2.
p h ot o p h o bia a n d p h o n o p h o bia
E.
N ot b ett er a c c o u nt e d f or b y a n ot h er 
I C H D-3 di a g n osis.
N otes:
1.
O ne or a fe w mi grai ne attac ks ma y be d iffic ult 
t o disti n g uis h fr o m s y m pt o m ati c mi gr ai n e-li k e 
att a c ks. F urt h er m or e, t h e n at ur e of a si n gl e or 
a f e w att a c ks m a y b e di ffic ult t o u n d erst a n d. 
T h er ef or e, at l e ast ﬁv e att a c ks ar e r e q uir e d. 
I n di vi d u als w h o ot h er wis e m e et crit eri a f or 1. 1 
Mi gr ai n e wit h o ut a ur a b ut h a v e h a d f e w er t h a n 
ﬁv e att a c ks s h o ul d b e c o d e d 1. 5. 1 Pr o b a bl e 
mi gr ai n e wit h o ut
a ur a .
2.
W h e n t h e p ati e nt f alls asl e e p d uri n g a mi gr ai n e 
att a c k a n d w a k es u p wit h o ut it, d ur ati o n of t h e 
attac k 
is r e c k o n e d 
u ntil 
t he ti m e of
a w a k e ni n g.
3.
I n c hil dre n a n d a d olesce nts (a ge d u n der 1 8 years), 
att a c ks m a y last 2 – 7 2 h o urs (t h e e vi d e n c e f or 
u ntr e at e d d ur ati o ns of l ess t h a n t w o h o urs i n
c hil dr e n h as n ot b e e n s u bst a nti at e d).
C o m me nts: Mi gr ai n e  hea dac he i n c hil dre n a n d
a d ol es c e nts (a ge d u n der 1 8 y e ars) is m ore ofte n
bil at er al t ha n is t he c as e i n a d ults; u nilateral p ai n
us uall y e m er g es i n l at e a d olesce nce or earl y a d ult
life. Mi grai ne
hea dac he is us uall y fr o nt ote m p oral. 
O c ci pit al hea dac he i n c hil dre n is rare a n d calls f or 
dia g n ostic ca uti o n. A s u bset of ot her wise t y pical 
patie nts ha ve facial l ocati o n of pai n, w hic h is calle d
‘facial mi grai ne’ 
i n t he literat ure; t here is n o
e vi d e n c e t h at t hese patie nts f or m
a se parate 
s u b gr o u p of mi gr ai n e
p ati e nts. Pr o dr o m al s y m pt o ms 
m a y b e gi n h o urs or a d a y or t w o b ef or e t h e ot h er
s y m pt o ms of a mi gr ai n e
attac k wit h - o ut a ura. T h e y 
i n cl u d e v ari o us c o m bi n ati o ns of f ati g u e, di  c ult y i n 
c o n c e ntr ati n g, n e c k sti n ess,  s e nsiti vit y t o li g ht 
a n d/ or s o u n d, n a us e a, bl urr e d visi o n, y a w ni n g  an d 
p all or. P ost dr o m al s y m pt o ms, m ost c o m m o nl y
f e eli n g  tir e d  or  
w e ar y,  
diffi c ult y  
wit h 
c o n c e ntr ati o n a n d n e c k stiffn ess, m a y f oll o w 
r es ol uti o n of
t he h e a d a c h e, p ersisti n g f or u p t o 
4 8 h o urs; t h es e ar e l ess w ell st u di e d.
Mi gr ai n e  
att a c ks c a n b e ass o ci at e d wit h 
cr a ni al a ut o n o mi c s y m pt o ms a n d s y m pt o ms of 
c ut a n e o us all o d y ni a.
I n 
y o u n g  c hil dre n,  p h ot o p h o bia  a n d 
p h o n o p h o bia ma y  b e i nferre d fr o m t heir 
be ha vi o ur.
A mi n orit y ( < 1 0 %) of w o m e n h a v e att a c ks of 
mi grai ne i n ass ociati o n wit h t he maj orit y of t heir 
m e nstr u al c y cl es; m ost s u c h att a c ks ar e wit h o ut 
a ura. Att a c ks d uri n g m e nstr u ati o n t e n d t o b e 
l o n ger a n d a c c o m p a ni e d b y m ore s e v er e n a us e a 
t h a n att a c ks o ut - si de t h e m e nstr u al c y cl e. I C H D-
3 off ers criteria f or A 1. 1. 1 
P ur e m e nstr u al 
mi gr ai n e  wit h o ut  a ur a , A 1. 1. 2 
M e nstr u all y 
r el at e d mi gr ai n e wit h o ut a ur a a n d A 1. 1. 3 N o n -
m e nstr u al mi gr ai n e wit h o ut a ur a , b ut i n t h e 
A p p e n di x b e c a us e of u n c ert ai nt y o v er w h et h er 
t h e y s h o ul d b e r e g ar d e d as s e p ar at e e ntiti es. 
Crit eri a ar e  als o off er e d f or A 1. 2. 0. 1 
P ur e 
m e nstr u al  
mi gr ai n e  
wit h  
a ur a , 
A 1. 2. 0. 2 
M e nstr u all y  r el at e d mi gr ai n e 
wit h a ur a a n d 
A 1. 2. 0. 3 N o n -m e nstr u al mi gr ai n e wit h a ur a t o 
e n c o ur a g e 
b ett er  c h ar a ct eri z ati o n 
of  t h es e 
u n c o m m o n s u bf or ms if t h e y ar e s e p ar at e e ntiti es.
V er y fr e q u e nt mi gr ai n e att a c ks ar e 
disti n g uis h e d as 1. 3 C hr o ni c mi gr ai n e . W h e n 
t h er e is ass o ci at e dm e di c ati o n o v er us e, b ot h of
t he di a g n os es 1. 3 C hr o ni c mi gr ai n e a n d 8. 2
M e di c ati o n -o v er us e h e a d a c h e s h o ul d b e a p pli e d. 
1. 1 Mi gr ai n e
wit h o ut a ur a is t he dis e as e m ost
pr o n e t o a c c el er at e wit h fr e q u e nt us e of
s y m pt o m ati c m e di c ati o n. R e gi o n al c er e br al
bl o o d ﬂo w i m a gi n g s h o ws n o c h a n g es 
s u g g esti v e of c orti c al s pr e a di n g d e pr essi o n
( C S D) d uri n g att a c ks of 1. 1 Mi gr ai n e wit h o ut
a ur a , alt h o u g h bl o o d ﬂo w c h a n g es i n t he
br ai nst e m m a y o c c ur, as m a y c orti c al c h a n g es 
s e c o n d ar y t o p ai n a cti v ati o n. T his c o ntr asts
wit h
t h e p at h o g n o m o ni c s pr e a di n g oli g a e mi a of
1. 2 Mi gr ai n e wit h a ur a .W hil e t h eb ul k of t he
lit er at ur e s u g g ests t h at C S D d o es n ot o c c ur i n
1. 1 Mi gr ai n e wit h o ut a ur a , s o m e r e c e ntst u di es
dis a gr e e. F urt h er m or e, it h as b e e n s u g g est e d
t h at gli al w a v es or ot h er c orti c al p h e n o m e n a 
m a y b e i n v ol v e d
i n 1. 1 Mi gr ai n e wit h o ut a ur a . 
T h e m ess e n g er m ol e c ul es nitric o xi d e ( N O), 
s er ot o ni n ( 5-h y dr o x ytr y pt a mi n e; 5- H T) a n d
c al cit o ni n g e n e -r el at e d p e pti d e ( C G R P) ar e
i n v ol v e d. W hil e t h e dis e as e w as pr e vi o usl y 
r e g ar d e d as pri m aril y v as c ul ar, t h e i m p ort a n c e 
of s e nsiti z ati o n of p ai n p at h - w a ys, a n d t h e
p ossi bilit y t h at attac ks m a y ori gi n at e i n t he
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
7 6
c e ntr al n er v o us s yst e m, h a v e g ai n e d i n cr e asi n g
atte nti o n o v er t h e l ast d e c a d es. 
At t h e s a m e ti m e, t h e circ uitr y of mi gr ai n e p ai n,
t he tri g e mi n o v as c ul ar s yst e m, a n d s e v er al
as p e cts of its n e ur otr a ns missi o n p eri p h er all y 
a n d i n t he tri g e mi n al n u cl e us c a u d alis, c e ntr al
m es e n c e p h ali c gr e y a n d t h al a m us, h a v e b e e n
r e c o g ni z e d. Hi g hl y
r e c e pt or- s p e ciﬁc a c ut e 
m e di c ati o ns i n cl u di n g 5- H T 1 B/ D r e c e pt or
a g o nists (tri pt a ns), 5 -H T 1 F r e c e pt or a g o nists
a n d C G R P r e c e pt or a nt a g o nists h a v e
d e m o nstr at e d effic a c y i n t h e a c ut e tr e at m e nt of 
mi gr ai n e att a c ks. B e c a us e of t h eir hi g h r e c e pt or-
s p e ciﬁcit y, t heirm e c h a nis ms of acti o n pr o - vi d e 
n e w i nsi g ht i nt o mi gr ai n e m e c h a nis ms. It is n o w 
clear t h at 1. 1 Mi gr ai n e wit h o ut a ur a is a
n e ur o bi ol o gi c al dis or d er, w hil e cli ni c al as w ell
as b asi c n e ur os ci e n c e st u- di es c o nti n u e t o 
a d v a n c e o ur k n o wl e d g e of mi gr ai n e 
m e c h a nis ms.
1. 2 
Mi gr ai ne wit h a ur a
Pr e vi o usl y us e d t er ms: Cl assi c or cl assi c al mi gr ai n e; 
o p ht h al mi c, h e mi p ar a est h eti c, h e mi pl e gi c or a p h asi c 
mi gr ai n e; 
mi gr ai n e 
acc o m pa g ne´
e; c o m pli c at e d
mi grai ne.
D es cri pti o n: R e c urr e nt att a c ks, l asti n g mi n ut es, of 
u nil at er al f ull y r e v ersi bl e vis u al, s e ns or y or ot h er 
c e ntr al n er v o us s yst e m s y m pt o ms t h at us u all y 
d e v el o p gr a d u all y a n d ar e us u all y f oll o w e d b y 
h e a d a c h e a n d ass o ci at e d mi gr ai n e s y m pt o ms.
Di a g n ostic criteri a:
A.
At l e ast t w o att a c ks f ulﬁlli n g crit eri a B a n d C
B.
O n e or m or e of t h e f oll o wi n g f ull y r e v ersi bl e 
a ur a s y m pt o ms:
1.
vis u al
2.
s e ns or y
3.
s p e e c h a n d/ or l a n g u a g e
4.
m ot or
5.
br ai nst e m
6.
r eti n al
C.
At l e ast t hr e e of t he f oll o wi n g si x
c h ar a ct eristi cs:
1.
at least o ne a ura s y m pt o m s prea ds gra d uall y 
o ver 5 mi n utes
2.
t w o orm or e a ura s y m pt o ms o c c ur i n
s u c c essi o n
3.
e a c h i n di vi d u al a ur a s y m pt o m l asts 5 – 6 0 
mi n ut es 1
4.
at least o ne a ura s y m pt o m is u nilateral 2
5.
at l e ast o n e a ura s y m pt o m is p ositi v e 3
6.
t h e a ur a is a c c o m p a ni e d, or f oll o w e d 
wit hi n 6 0 mi n ut es, b y h e a d a c h e
D.
N ot b ett er a c c o u nt e d f or b y a n ot h er I C H D -3 
di a g n osis.
N otes:
1.
W he n, f or e xa m ple, t hree s y m pt o ms o c c ur d uri n g 
a n a ura, t h e a c c e pt a bl e m a xi m al d ur ati o n is 3 x 6 0 
mi n ut es. 
M ot or 
s y m pt o ms m a y 
last u p t o 7 2
h o urs.
2.
A p h asi a is al w a ys r e g ar d e d as a u nil at er al 
s y m pt o m; d ys art hri a m a y or m a y n ot b e.
3.
S ci ntill ati o ns a n d pi ns a n d n e e dl es ar e p ositi v e 
s y m pt o ms of a ur a.
C o m m e nts: M a n y 
p ati e nts w h o h a v e mi gr ai n e 
att a c ks wit h a ur a als o h a v e att a c ks wit h o ut a ur a; 
t h e y s h o ul d  b e c o d e d as b ot h 1. 2 Mi gr ai n e wit h 
a ur a a n d 1. 1 Mi gr ai n e wit h o ut a ur a .
Fi el d t esti n g h as c o m p ar e d t h e di a g n osti c crit eri a 
f or 1. 2 Mi gr ai n e wit h a ur a i n t h e m ai n b o d y of 
I C H D-3 b et a wit h t h os e f or A 1. 2 Mi gr ai n e wit h a ur a 
i n t h e A p p e n di x. T h e l att er p erf or m e d b ett er i n 
disti n g uis hi n g mi gr ai n e wit h a ur a fr o m tr a nsi e nt 
is c h a e mi c att a c ks. T h es e ar e n o w a d o pt e d i n I C H D -
3, w hi c h n o l o n g er  h as A p p e n di x crit eri a f or t his
dis or d er.
T h e a ur a is t h e c o m pl e x of n e ur ol o gi c al 
s y m pt o ms t h at o c c urs 
us u all y 
b ef or e 
t h e 
h e a d a c h e of 1. 2 Mi gr ai n e wit h a ur a , b ut it m a y 
b e gi n aft er t h e h e a d a c h e p h as e has c o m m e n c e d
or c o nti n u e i nt o t he h e a d a c h e p h as e.
Vis u al a ura is t h e m ost c o m m o n t y p e of a ur a, 
o c c ur - ri n g i n o v er 9 0 % of p ati e nts wit h 1. 2 
Mi gr ai n e wit h a ur a , at l e ast i n s o m e att a c ks. It 
oft e n pr es e nts as a f ortiﬁc ati o n s p e ctr u m:  a 
zi g z a g ﬁg ure near t he  p oi nt  of ﬁxati o n t hat ma y 
gr a d u all y s pr e a d ri g ht or l eft a n d ass u m e a 
laterall y c o n v e x 
s ha pe wit h  
a n 
a n g ul at e d 
s ci ntill ati n g e d g e, l e a vi n g a bs ol ut e or v ari a bl e 
d e gr e es of r el ati v e s c ot o m a i n its w a k e. I n ot h er 
c as es, s c ot o m a wit h o ut p ositi v e p h e n o m e n a m a y 
occ ur; t his is oft e n p er c ei v e d as b ei n g of a c ut e 
o ns et  b ut,  o n  s cr uti n y, 
us u all y  e nl ar g es 
gr a d u all y. I n c hil dr e n a n d a d ol es c e nts, l ess 
t y pi c al bil at er al vis u al s y m pt o ms o c c ur t h at m a y 
r e pr es e nt a n a ur a. A vis u al a ur a r ati n g s c al e wit h 
hi g h  s p e ciﬁcit y  a n d 
s e nsiti vit y 
h as  b e e n 
d e v el o p e d a n d v ali d at e d.
N e xt i n fr e q u e n c y ar e s e ns or y dist ur b a n c es, i n 
t h e f or m of pi ns a n d n e e dl es m o vi n g sl o wl y fr o m 
t he p oi nt of or i gi n a n d a  e cti n g a gr e at er or
s m all er p art of o n e si de of t h e b o d y, f a c e a n d/ or
t o n g u e. N u m b n ess
ma y
o c c ur i n its w a k e, b ut 
n u m b n ess m a y als o b e t h e o nl y s y m pt o m.
L ess  fr e q u e nt ar e 
s p e e c h 
dist ur b a n c es, 
us u all y a p h asi c b ut oft e n h ar d t o c at e g ori z e.
S yst e m ati c st u di es h a v e d e m o nstr at e d t h at 
m a n y p ati e nts wit h vis u al a ur a o c c asi o n all y h a v e 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
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s y m pt o ms i n t h e e xtr e miti es a n d/ or s p e e c h 
s y m pt o ms. C o n v ers el y, p ati e nts wit h s y m pt o ms 
i n t h e e xtr e miti es a n d/ or s p e e c h or l a n g u a g e 
s y m pt o ms al m ost al w a ys als o e x p er i e n c e vis u al 
a ura s y m pt o ms at  least  d uri n g  s o me  attac ks. A 
disti n cti o n b et w e e n mi gr ai n e wit h vis u al a ura, 
mi gr ai n e  
wit h  
h e mi p ar a est h eti c  
a ur a  a n d 
mi gr ai n e wit h s p e e c h a n d/ or la n g ua ge a ur a is 
pr o b a bl y arti ﬁci al, a n d t h er ef or e n ot r e c o g ni z e d
i n t his classiﬁcati o n: t h e y ar e all c o d e d as 1. 2. 1 
Mi gr ai n e wit h t y pi c al a ur a .
W h e n  
a ur a s y m pt o ms ar e m ulti pl e,  t h e y 
us u all y 
f oll o w o n e 
a n ot h er i n s u c c essi o n, 
b e gi n ni n g 
wit h  
vis u al, 
t h e n s e ns or y, t h e n 
a p h asi c; b ut t h e r e v ers e a n d ot h er or d ers h a v e 
bee n n ote d. T he acce pte d d urati o n  f or m ost a ura 
s y m pt o ms is o n e h o ur, b ut m ot or s y m pt o ms ar e 
oft e n l o n g er l asti n g.
Patie nts wit h a ura s y m pt o ms arisi n g fr o m t h e 
brai n - st e m ar e c o de d as 1. 2. 2 Mi gr ai ne wit h
br ai nste m a ur a , b ut
t he y al m ost al wa ys h a v e 
a d diti o nal t y pical a ura s y m pt o ms. W h e n t he a ur a 
i ncl u des m ot or wea k ness, t h e dis - or der s h o ul d b e 
c o de d as 1. 2. 3 He mi ple gic mi gr ai ne or o ne of its 
s u bf or ms. 1. 2. 3 He mi ple gic mi gr ai ne is classiﬁe d 
as a se parate s u bt y pe beca use of ge netic a n d 
pat h o p h ysi ol o gical 
di ffere nces 
fr o m 
1. 2. 1
Mi gr ai ne wit h ty pic al a ur a . Patie nts wit h 1. 2. 3 
He mi ple gic  
mi gr ai ne 
oft e n  ha ve  brai nste m 
s y m pt o ms i n a d diti o n.
P ati e nts oft e n ﬁn d it har d t o d es cri b e t heir a ura
s y m pt o ms, i n w hi c h c as e t h e y s h o ul d b e i nstr u ct e d 
t o ti me a n d r e c or d t h e m pr os pecti vel y. T he cli nical  
pi ct ur e  th e n b e c o m es cl e ar er. C o m m o n mist a k es 
ar e i nc orrect r e p orts of lateralizati o n, of s u d d e n 
r at h er t h a n gr a d u al o ns et a n d of m o n o c ul ar r at h er 
t h a n h o m o n y m o us vis u al dist ur b a n c es, as w ell as 
of d ur ati o n of a ur a a n d mist a ki n g s e ns or y l oss f or 
w e a k n ess. Aft er a n i niti al c o ns ultati o n, us e of a n
a ura di ar y m a y
cl arif y t h e di a g n osis.
Mi gr ai n e a ur a is s o m eti m es ass o ci at e d wit h a 
h e a d - a c h e t h at d o es n ot f ulﬁl l crit eri a f or 1. 1
Mi gr ai n e wit h o ut a ur a , b ut t his is still r e g ar d e d as 
a mi gr ai n e h e a d a c h e b e c a us e of its r el ati o n t o t h e 
a ur a. I n ot h er cases, mi gr ai n e a ur a m a y o c c ur 
wit h o ut
h e a d a c h e.
B ef or e or si m ult a n e o usl y wit h t h e o ns et of a ur a 
s y m pt o ms, r e gi o n al c er e br al 
bl o o d 
ﬂo w  is 
d e cr e as e d   in t h e c ort e x c o rr es p o n di n g t o t h e 
cli ni c all y aff e ct e d ar e a a n d oft e n o v er a wi d er ar e a. 
Bl o o d ﬂo w r e d u cti o n us u all y st arts p ost eri orl y a n d 
s pr e a ds a nt eri orl y, a n d is us u all y a b o v e t h e 
is c h a e mi c t hr es h ol d. Aft er o n e t o s e v er al h o urs, 
gr a d u al tr a nsiti o n i nt o h y p er a e mi a  oc c urs i n t h e 
s a m e r e gi o n. C orti c al s pr e a di n g d e pr essi o n of Lea˜
o is t he li k el y u n d erl yi n g m e c h a nis m.
T h e pr e vi o usl y d e ﬁn e d s y n dr o m es, mi gr ai n e 
wit h pr ol o n g e d a ur a a n d mi gr ai n e wit h a c ut e -
o ns et a ur a , ha ve bee n a ba n d o ne d. It is n ot rare f or 
a ur a t o  l ast m or e t h a n o n e h o ur b ut, i n m ost s u c h 
cases, p ati e nts h a v e at l e ast t w o of t h e ot h er 
c h ar a ct eristi cs of crit eri o n
C. E v e n w h e n m ost of a p ati e nt’s att a c ks d o n ot 
f ulﬁl criteri o n C, it is us ual t hat ot her attac ks f ul ﬁl 
criteria  for o n e of t h e r e c o g ni z e d s u bt y p es or 
s u bf or ms of 1. 2 Mi gr ai n e 
wit h a ur a , a n d t his 
s h o ul d b e t h e di a g n osis. T he fe w ot her cases s h o ul d 
be c o ded t o 1. 5. 2 Pr o b a ble mi gr ai ne wit h a ur a , 
s pecif yi n g t he at y pical feat ure ( pr o- l o n ge d a ura or 
ac ute-o nset a ura) i n pare nt hesis. T he dia g n osis is 
us uall y e vi de nt after a caref ul hist or y al o ne, alt h o u g h 
t here are rare sec o n dar y mi mics i ncl u di n g car oti d 
dissecti o n, arteri o ve n o us malf or mati o n a n d seiz ure.
Pr o dr o m al s y m pt o ms ma y b e gi n h o urs or a d a y
or t w o b ef or e t h e ot h er s y m pt o ms of a mi gr ai n e 
att a c k  
wit h  
a ur a.  
T h e y  
i n cl u d e  v ari o us 
c o m bi n ati o ns  
of  
f ati g u e,  
dif ﬁc ult y 
i n
co n c e ntr ati n g, n e c k sti n ess, s e nsiti vit y t o li g ht 
a n d/ or s o u n d, na usea, bl urre d visi o n, y a w ni n g a n d 
p all or. T he t er m ‘ pr o dr o m e’, w hi c h h as r e pl a c e d 
‘ pr e- m o nit or y p h as e’ or ‘ pr e m o nit or y s y m pt o ms’, 
d o es n ot i n cl u d e a ur a. P ost dr o m al s y m pt o ms, m ost 
c o m m o nl y f e eli n g tir e d or w e ar y, diffi c ult y wit h 
c o n c e ntr ati o n 
a n d n e c k stiffn ess, m a y 
f oll o w 
r es ol uti o n of t h e h e a d a c h e, p ersisti n g f or u p t o 4 8 
h o urs; t h es e ar e l ess w ell st u di e d.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
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1. 2. 1 Mi gr ai ne wit h ty pic al a ur a
D es cri pti o n: Mi gr ai n e 
wit h a ura, i n w hi c h a ur a 
c o nsists  
of  
vis u al  
a n d/ or  
s e ns or y  a n d/ or 
s p e e c h/l a n g u a g e  s y m pt o ms, 
b ut  
n o  
m ot or 
w e a k n ess,  
a n d 
is c h ar a ct eri z e d 
b y  gr a d u al 
d e v el o p m e nt, d ur ati o n of e a c h s y m pt o m n o l o n g er 
t h a n o n e h o ur, a mi x of p ositi v e a n d n e g ati v e 
f e at ur es a n d c o m pl et e r e v ersi bilit y
Di a g n o stic criteri a:
A.
Att a c ks f ul ﬁlli n g crit eri a f or 1. 2 Mi gr ai n e 
wit h a ur a a n d crit eri o n B b el o w
B.
A ur a wit h b ot h of t h e
f oll o wi n g:
1.
f ull y r e v ersi bl e vis u al, s e ns or y a n d/ or 
s p e e c h/ l a n g u a g e s y m pt o ms
2.
n o m ot or, brai nste m or reti nal
s y m pt o ms.
1. 2. 1. 1 Ty pic al a ur a wit h he a d ac he
D es cri pti o n: Mi gr ai n e wit h t y pi c al a ur a i n w hi c h 
a ur a is a c c o m p a ni e d or f oll o w e d wit hi n 6 0 mi n ut es 
b y  h e a d - 
a c h e  wit h  
or  wit h o ut  
mi gr ai n e 
c h ar a ct eristi cs.
Di a g n ostic criteri a:
A.
Att a c ks f ul ﬁlli n g crit eri a f or 1. 2. 1 Mi gr ai n e 
wit h t y pi c al a ur a a n d crit eri o n B b el o w
B.
H e a d a c h e, wit h or wit h o ut mi gr ai n e
c h ar a ct eristi cs, a c c o m p a ni es or f oll o ws t h e
a ura wit hi n 6 0 mi n ut es.
1. 2. 1. 2 Ty pic al a ur a wit h o ut he a d ac he
D es cri pti o n: Mi grai ne wit h t y pical a ura i n w hic h 
a ura is neit her acc o m pa nie d n or f oll o we d b y 
hea dac he of a n y s ort.
Di a g n ostic criteri a:
A.
Att a c ks f ul ﬁlli n g crit eri a f or 1. 2. 1 Mi gr ai n e 
wit h t y pi c al a ur a a n d crit eri o n B b el o w
B.
N o h e a d a c h e a c c o m p a ni es or f oll o ws t h e 
a ur a wit hi n 6 0 mi n ut es.
C o m m e nts: I n s o m e p ati e nts, a t y pi c al a ur a is 
al w a ys f oll o w e d b y mi gr ai n e h e a d a c h e, b ut m a n y 
p ati e nts h a v e, i n a d diti o n, att a c ks wit h a ur a 
f oll o w e d b y a l ess disti n ct h e a d a c h e or e v e n 
wit h o ut h e a d a c h e. A n u m b er of p ati e nts h a v e, 
e x cl usi v el y, 1. 2. 1. 2 T y pi c al a ur a wit h- o ut
h e a d a c h e .
I n t h e a bs e n c e of h e a d a c h e f ulﬁlli n g crit eri a f or 
1. 1 Mi gr ai n e wit h o ut a ur a , t he pr e cis e di a g n osis of
a ura a n d its disti n cti o n fr o m mi mi cs t h at m a y 
si g n al s eri o us dis- e as e ( e. g. tr a nsi e nt is c h a e mi c 
att a c k) b e c o m es m or e dif ﬁc ult a n d oft e n r e q uir es 
i n v esti g ati o n. W h e n a ur a o c c urs f or t h e ﬁrst ti m e 
aft er a g e 4 0, w h e n s y m pt o ms ar e e x cl usi v el y 
n e g ati v e ( e. g. h e mi a n o pi a) or w h e n a ur a is 
pr ol o n g e d or v er y s h ort, ot h er c a us es, p arti c ul arl y 
tr a nsi e nt is c h a e mi c att a c ks, s h o ul d b e r ul e d o ut.
1. 2. 2 Mi gr ai ne wit h br ai nste m a ur a
Pr e vi o usl y us e d t er ms: B asil ar art er y mi gr ai n e; 
b asil ar mi gr ai n e; b asil ar -t y p e mi gr ai n e.
D es cri pti o n: Mi gr ai n e wit h a ur a s y m pt o ms cl e arl y 
ori gi n ati n g fr o m t h e br ai nst e m, b ut n o m ot or 
w e a k n ess.
Di a g n ostic criteri a:
A.
Att a c ks f ul ﬁlli n g crit eri a f or 1. 2 Mi gr ai n e wit h 
a ur a a n d crit eri o n B b el o w
B.
A ur a wit h b ot h of t h e
f oll o wi n g:
1.
at l e ast t w o of t h e f oll o wi n g f ull y 
r e v ersi bl e br ai nst e m s y m pt o ms:
a.
d ysart hria 1
b.
v erti g o 2
c.
ti n nit us
d.
h y p a c usis 3
e.
di pl o pia 4
f.
ata xia n ot attri b uta ble t o se ns or y
de ﬁcit
g.
d e cr e as e d l e v el of c o ns ci o us n ess
( G C S ≤1 3) 5
2.
n o m ot or 6 or reti nal s y m pt o ms.
N otes:
1.
D ys art hri a s h o ul d b e disti n g uis h e d fr o m a p h asi a.
2.
V erti g o d o es n ot e m br a c e a n d s h o ul d b e 
disti n g uis h e d fr o m di z zi n ess.
3.
T his crit eri o n is n ot f ul ﬁll e d b y s e ns ati o ns of e ar 
f ull n ess.
4.
Di pl o pi a d o es n ot e m br a c e ( or e x cl u d e) bl urr e d 
visi o n.
5.
T h e Gl as g o w C o m a S c al e ( G C S) s c or e m a y h a v e 
b e e n ass ess e d d uri n g a d missi o n; alt er n ati v el y, 
d efi cits cl e arl y d es cri b e d b y t h e p ati e nt all o w 
G C S esti m ati o n.
6.
W h e n m ot or s y m pt o ms ar e pr es e nt, c o d e as 1. 2. 3
He mi ple gic mi gr ai ne .
C o m m e nts: 
Ori gi n all y  t h e t er ms b asil ar art er y 
mi gr ai n e or b asil ar mi gr ai n e w er e us e d b ut, si n c e 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
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i n v ol v e m e ntof t he basilar arter y is u nli kel y, t he ter m 
mi gr ai n e wit h br ai nst e m a ur a is pr ef err e d.
T h er e are t y pi c al a ur a s y m pt o ms i n a d diti o n 
t o t h e br ai nst e m s y m pt o ms d uri n g m ost att a c ks. 
M a n y p ati e nts w h o h a v e att a c ks wit h br ai nst e m 
a ur a als o r e p ort ot h er att a c ks wit h t y pi c al a ur a 
a n d s h o ul d b e c o d e d
f or b ot h
1. 2. 1
Mi gr ai n e
wit h 
t y pi c al a ur a
a n d 1. 2. 2 Mi gr ai ne 
wit h 
br ai nste m a ur a .
M a n y of t h e s y m pt o ms list e d u n d er crit eri o n 
B 1 ma y occ ur wit h a n xiet y a n d h y per ve ntilati o n, 
a n d ar e t h er ef or e s u bj e ct t o misi nt er pr et ati o n.
1. 2. 3 He mi ple gic 1 mi gr ai ne
D es cri pti o n: Mi gr ai n e
wit h a ur a i n cl u di n g m ot or 
w e a k n ess.
Di a g n ostic criteri a:
A.
Att a c ks f ul ﬁlli n g crit eri a f or 1. 2 Mi gr ai n e 
wit h a ur a a n d crit eri o n B b el o w
B.
A ur a c o nsisti n g of b ot h of t he f oll o wi n g:
1.
f ull y r e v ersi bl e m ot or w e a k n ess 2
2.
f ull y r e v ersi bl e vis u al, s e ns or y a n d/ or 
s p e e c h/ l a n g u a g e s y m pt o ms.
N otes:
1.
T h e t er m pl e gi c m e a ns 
p ar al ysis i n m ost 
l a n g u a g es, b ut m ost att a c ks ar e c h ar a ct eri z e d 
b y m ot or w e a k n ess.
2.
M ot or  s y m pt o ms g e n er all y l ast l ess t h a n 
7 2 h o urs 
b ut, 
i n s o m e p ati e nts, 
m ot or 
w e a k n ess m a y p ersist f or w e e ks.
C o m m e nt: It m a y b e diffic ult t o disti n g uis h 
w e a k n ess fr o m s e ns or y l oss.
1. 2. 3. 1 F a mili al he mi ple gic mi gr ai ne ( F H M)
D es cri pti o n: Mi gr ai n e wit h a ur a i n cl u di n g m ot or 
w e a k - n ess, a n d at l e ast o n e ﬁrst - or s e c o n d-
d e gr e e r el ati v e h as mi gr ai n e  a ur a i n cl u di n g 
m ot or w e a k n ess.
Di a g n ostic criteri a:
A.
Att a c ks f ul ﬁlli n g crit eri a f or 1. 2. 3 
H e mi pl e gi c mi gr ai n e
B.
At least o ne ﬁrst - or s e c o n d-d e gr e e r el ati v e 
h as h a d att a c ks f ulﬁlli n g crit eri a f or 1. 2. 3 
H e mi pl e gi c mi gr ai n e .
C o m m e nts: N e w g e n eti c d at a h a v e all o w e d a m or e
pr e cis e d e ﬁniti o n of 1. 2. 3. 1 F a mili al h e mi pl e gi c 
mi gr ai n e t h a n w as pr e vi o usl y p ossi bl e. S p e ci ﬁc 
g e n eti c s u bf or ms h a v e b e e n i d e ntiﬁe d: i n F H M 1 
t h er e ar e m ut ati o ns i n t he
C A C N A 1 A g e n e ( c o di n g  for a c al ci u m  ch a n n el)  
o n c hr o m os o m e 1 9; i n F H M 2 t h er e ar e m ut ati o ns 
i n t he A T P 1 A 2 g e n e ( c odi n g f or a K/ N a -A T P as e) 
o n c hr o m o - s o m e 1; a n d i n F H M 3 t h er e are 
m ut ati o ns i n t h e S C N 1 A g e n e ( c o di n g f or a s o di u m 
c h a n n el) o n c hr o m os o m e 2. T h er e m a y
b e ot h er
l o ci n ot y et i d e ntiﬁe d. W h e n 
g e n eti c testi n g is
d o n e, t heg e n eti c s u bf or m (if dis c o v er e d) s h o ul d b e
s p e ciﬁe d at t he ﬁft h di git.
It h as b e e n s h o w n t hat 1. 2. 3. 1 F a mili al 
h e mi pl e gi c mi gr ai n e 
v er y oft e n pr es e nts wit h 
br ai nst e m s y m pt o ms i n a d diti o n t o t he t y pi c al a ur a 
s y m pt o ms, a n d t h at h e a d a c h e al m ost al w a ys 
o c c urs. R ar el y, d uri n g F H M att a c ks, dist ur b a n c es 
of c o ns ci o us n ess (s o m eti m es i n cl u di n g c o m a), 
c o nf usi o n, f e v er a n d c er e br os pi n al ﬂui d ( C S F) 
pl e o c yt osis c a n o c c ur.
1. 2. 3. 1 F a mili al h e mi pl e gi c mi gr ai n e
ma y
b e
mist a k e n f or e pil e ps y a n d tr e at e d ( u ns u c c essf ull y) 
as s u c h. F H M att a c ks c a n b e tri g g er e d b y ( mil d) 
h e a d tr a u m a. I n a p pr o xi m at el y 5 0 % of F H M 
f a mili es, c hr o ni c pr o gr essi v e c er e b ell ar at a xi a 
o c c urs i n d e p e n d e ntl y of t h e mi gr ai n e att a c ks.
1. 2. 3. 1. 1 F a mili al h e mi pl e gi c mi gr ai n e t y p e 1
( F H M 1)
Di a g n ostic criteri a:
A.
Attac ks f ul ﬁlli n g criteria f or 1. 2. 3. 1 F a mili al 
he mi ple gic mi gr ai ne
B.
A m utati o n o n t he C A C N A 1 A g e n e h as
bee n de m o nstrate d.
1. 2. 3. 1. 2 F a mili al h e mi pl e gi c mi gr ai n e t y p e 2
( F H M 2)
Di a g n ostic criteri a:
A.
Attac ks f ul ﬁlli n g criteria f or 1. 2. 3. 1 F a mili al 
he mi ple gic m i gr ai ne
B.
A m utati o n o n t he A T P 1 A 2 ge ne has bee n 
de m o nstrate d.
1. 2. 3. 1. 3 F a mili al h e mi pl e gi c mi gr ai n e t y p e 3
( F H M 3)
Di a g n ostic criteri a:
A.
Attac ks f ul ﬁlli n g criteria f or 1. 2. 3. 1 F a mili al 
he mi ple gic mi gr ai ne
B.
A m utati o n o n t he S C N 1 A ge ne has bee n 
de m o nstrate d.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
8 0
1. 2. 3. 1. 4 F a mili al h e mi pl e gi c mi gr ai n e, ot h er l o ci
Di a g n ostic criteri a:
A.
Attac ks f ul ﬁlli n g criteria f or 1. 2. 3. 1 F a mili al 
he mi ple gic mi gr ai ne
B.
Ge netic testi n g has de m o nstrate d n o 
m utati o n o n t he C A C N A 1 A , A T P 1 A 2 or 
S C N 1 A ge nes.
1. 2. 3. 2 S p or a dic he mi ple gic mi grai ne ( S H M)
D es cri pti o n: Mi gr ai n e wit h a ur a i n cl u di n g m ot or 
w e a k - n ess, a n d n o ﬁrst - or s e c o n d-d e gr e e r el ati v e 
h as mi gr ai n e a ur a i n cl u di n g m ot or w e a k n ess.
Di a g n ostic criteri a:
A.
Att a c ks f ul ﬁlli n g crit eri a f or 1. 2. 3 
H e mi pl e gi c mi gr ai n e
B.
N o ﬁrst - or s e c o n d -d e gr e e r el ati v e f ul ﬁls 
crit eri a f or 1. 2. 3 H e mi pl e gi c
mi gr ai n e.
C o m m e nts: E pi d e mi ol o gi c al st u di es h a v e s h o w n 
t h at s p or a di c c as es o c c ur wit h a p pr o xi m at el y t h e 
s a m e pr e v al e n c e as f a mili al c as es.
T h e attac ks i n 1. 2. 3. 2 S p or a di c h e mi pl e gi c 
mi gr ai n e h a v e t h e s a m e cli ni c al c h ar a ct eristi cs as 
t h os e i n 1. 2. 3. 1 F a mili al
h e mi pl e gi c mi gr ai n e .
S o m e a p p ar e ntl y s p or a di c c as es h a v e k n o w n F H M 
m ut ati o ns a n d, i n s o m e, a ﬁrst - or s e c o n d-d e gr e e 
r el ati v e l at er d e v el o ps h e mi pl e gi c mi gr ai n e , t h us
c o m pl eti n g f ulﬁl m e nt of t h e crit eri a f or
1. 2. 3. 1 F a mili al h e mi pl e gi c mi gr ai n e a n d r e q uiri n g 
a c h a n g e of di a g n osis.
S p or a di c c as es us u all y r e q uir e n e ur oi m a gi n g 
a n d ot h er tests t o r ul e o ut ot h er c a us es. A l u m b ar 
p u n ct ur e m a y  b e n e c ess ar y t o r ul e o ut 7. 3. 5 
S y n dr o m e of tr a nsi e nt h e a d a c h e a n d n e ur ol o gi c al
d e ﬁcits wit h c er e br os pi n al ﬂui d l y m p h o c yt osis
( H a N D L).
1. 2. 4 Reti n al mi gr ai ne
D es cri pti o n: R e p e at e d att a c ks of m o n o c ul ar vis u al 
dist ur b a n c e, i n cl u di n g s ci ntill ati o ns, s c ot o m at a or 
bli n d n ess, ass o ci at e d wit h mi gr ai n e h e a d a c h e.
Di a g n ostic criteri a:
A.
Att a c ks f ul ﬁlli n g crit eri a f or 1. 2 Mi gr ai n e 
wit h a ur a a n d crit eri o n B b el o w
B.
A u r a c h ar a ct eri z e d b y b ot h of t he f oll o wi n g:
1.
f ull y r e v ersi bl e, m o n o c ul ar,  p ositi v e 
a n d/ or n e g ati v e vis u al p h e n o m e n a ( e. g. 
s ci ntill ati o ns, s c ot o m at a or bli n d n ess) 
c o n ﬁr m e d d uri n g a n att a c k b y eit her or
b ot h of t he f oll o wi n g:
a.
cli ni c al vis u al ﬁel d e x a mi n ati o n
b.
t h e p ati e nt’s dr a wi n g of a 
m o n o c ul ar ﬁel d d ef e ct ( m a d e aft er 
clear i nstr u cti o n)
2.
at l e ast t w o of t h e f oll o wi n g:
a. s pr e a di n g gr a d u all y o v er ≥ 5
mi n ut es
b.
s y m pt o ms l ast 5– 6 0 mi n ut es
c.
a c c o m p a ni e d, or f oll o w e d wit hi n 6 0 
mi n ut es, b y h e a d a c h e
C.
N ot b ett er a c c o u nt e d f or b y a n ot h er I C H D-3 
di a g n osis, a n d ot h er c a us es of a m a ur osis f u g a x 
h a v e b e e n e x cl u d e d.
C o m m e nts: 
S o m e  p ati e nts  w h o  
c o m pl ai n  of 
m o n o c ul ar  
vis u al  
dist ur b a n c e  
i n 
f a ct  h a v e 
he mia n o pia. S o me cases wit h o ut h e a d a c h e h a v e b e e n 
r e p ort e d, b ut mi gr ai n e as t h e u n d erl yi n g a eti ol o g y 
c a n n ot b e as c ert ai n e d.
1. 2. 4 R eti n al mi gr ai n e is a n e xtr e m el y r ar e c a us e 
of 
tr a nsi e nt m o n o c ul ar  
vis u al 
l oss. C as es  of 
p er m a n e nt m o n o c ul ar 
vis u al l oss ass o ci at e d wit h 
mi gr ai n e  
h a v e  
b e e n  
d es cri b e d.  
A p pr o pri at e 
i n v esti g ati o ns ar e r e q uir e d t o e xcl u de ot her ca uses of 
tr a nsi e nt m o n o c ul ar bli n d n ess.
1. 3 
C hr o nic mi gr ai ne
Descri pti o n: H e a d a c h e occ urri n g o n 1 5 or m ore 
da ys/ m o nt h f or m or e t ha n t hree m o nt hs, w hic h, o n 
at least ei g ht da ys/ m o nt h, h as t hefeat uresof mi grai ne
hea dac he.
Di a g n ostic criteri a:
A.
H e a d a c h e ( mi gr ai n e-li k e or t e nsi o n-t y p e-li k e1) 
o n 1 5 d a ys/ m o nt h f or > 3 m o nt hs, a n d f ul ﬁlli n g
crit eri a B a n d C
B.
O c c urri n g i n a p ati e nt w h o h as h a d at l e ast ﬁv e 
att a c ks f ulﬁlli n g crit eri a B – D f or 1. 1 Mi gr ai n e
wit h - o ut a ur a a n d/ or criteria B a n d C f or 1. 2 
Mi gr ai n e wit h
a ur a
C.
O n 8 d a ys/ m o nt h f or > 3 m o nt hs, f ulﬁlli n g a n y 
of t he f oll o wi n g2:
1.
crit eri a C a n d D f or 1. 1 Mi gr ai n e wit h o ut
a ur a
2.
crit eri a B a n d C f or 1. 2 Mi gr ai n e
wit h
a ur a
3.
b eli e v e d b y t h e p ati e nt t o b e mi gr ai n e at 
o ns et a n d r eli e v e d b y a tri pt a n or er g ot
d eri v ati v e
D.
N ot better a c c o u nt e d f or b y a n ot h er I C H D-3 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
8 1
dia g n osis. 3 – 5
N otes:
1.
T h e r e as o n f or si n gli n g o ut 1. 3 C hr o ni c mi gr ai n e
fr o m t y p es of e pis o di c mi gr ai n e 
is t h at it is 
i m p ossi bl e t o disti n g uis h t h e i n di vi d u al e pis o d es 
of h e a d a c h e i n p ati e nts wit h s u c h fr e q u e nt or 
c o nti n u o us h e a d a c h es. I n f a ct, t h e c h ar a ct eristi cs 
of t h e h e a d a c h e m a y c h a n g e n ot o nl y fr o m d a y t o 
d a y b ut e v e n wit hi n  t h e s a m e d a y. S u c h p ati e nts 
ar e e xtr e m el y di  c ult t o k e e p m e di c ati o n-fr e e i n 
or d er t o o bs e r v e t h e n at ur al hist or y of t h e 
hea dac he. I n t his sit uati o n, attac ks wit h a n d t h ose 
wit h o ut 
a ur a ar e b ot h c o u nt e d, as ar e b ot h 
mi gr ai n e -li k e a n d t e nsi o n-t y p e-li k e h e a d a c h es 
( b ut n ot s e c o n d ar y h e a d a c h es).
2.
C h ar a ct eri z ati o n 
of fre q ue ntl y rec urri n g 
hea dac he ge nerall y
re q uires a hea dac he
diar y t o rec or d i nf or mati o n o n pai n a n d 
ass o ci at e d s y m pt o ms da y b y da y f or at l e ast 
o ne m o nt h.
3.
B e c a us e t e nsi o n -t y pe-li k e h e a d a c h e is wit hi n 
t he di a g n osti c 
criteria f or 1. 3 
C hr o ni c 
mi gr ai n e , t his 
di a g n osis  e x cl u d es  t h e 
di a g n osis of 2. T e nsi o n -t y p e h e a d a c h e or its
t y p es.
4.
4. 1 0 N e w d ail y p ersist e nt h e a d a c h e m a y h a v e
f e at ur es s u g g esti v e of 1. 3 C hr o ni c mi gr ai n e .
T h e latterdis or d er e v ol v es o v er ti m efr o m 1. 1
Mi gr ai n e wit h o ut a ur a a n d/ or 1. 2 Mi gr ai n e 
wit h a ur a ; t heref ore, w he n t hese criteria A – C 
ar e  
f ulﬁll e d  
b y  
h e a d a c h e  
t hat, 
u n a m bi g u o usl y, is d ail y a n d u nr e mitti n g 
fr o m < 2 4 h o urs aft er its ﬁrst o ns et, c o d e as
4. 1 0 N e w d ail y p ersist e nt h e a d - a c h e . W h e n
t he m a n n er
of o ns et is n ot r e m e m b er e d or is
ot h er wis e
u n c ert ai n,
c o d e as 1. 3
C hr o ni c
mi gr ai n e .
5.
T h e 
m ost  c o m m o n c a us e of s y m pt o ms 
s u g g esti v e of c hr o ni c mi gr ai n e is m e di c ati o n
o v er us e, as d e ﬁn e d u n d er 8. 2 M e di c ati o n -
o v er us e h e a d a c h e . Ar o u n d 5 0 % of p ati e nts 
a p p ar e ntl y wit h 1. 3 C hr o ni c mi gr ai n e r e v ert 
t o a n e pis o di c mi gr ai n e  t y p e after dr u g 
wit h dr a w al; 
s u c h p ati e nts ar e i n a s e ns e 
wr o n gl y di a g n os e d as 1. 3 C hr o ni c mi gr ai n e . 
E q u all y, m a n y p ati e nts a p p ar e ntl y o v er usi n g 
m e di c ati o n  
d o 
n ot 
i m pr o v e aft er dr u g 
wit h dr a w al; t h e di a g n osis of 8. 2 M e di c ati o n -
o v er us e h e a d a c h e m a y b e i n a p pr o pri at e f or 
t hese ( ass u mi n g t h at c hr o ni cit y i n d u c e d b y 
dr u g o v er us e is al w a ys r e v ersi bl e). F or t h es e 
r e as o ns, a n d b e c a us e of t h e g e n er al r ul e t o 
a p pl y all r el e v a nt di a g n os es, p ati e nts m e eti n g 
criteria f or 1. 3 C hr o ni c mi gr ai n e a n d f or 8. 2 
M e di c ati o n -o v er us e 
h e a d a c h e 
s h o ul d b e 
c o d e d f or b ot h. Aft er  dr u g wit h dr a w al, 
mi gr ai n e will eit h er r e v ert t o a n e pis o di c t y p e 
or r e m ai n c hr o ni c a n d s h o ul d b e re-di a g n os e d 
a c c or di n gl y; i n t h e l att er c as e, t h e di a g n osis 
of 8. 2 M e di c ati o n -o v er us e h e a d a c h e ma y b e
r es ci n d e d.
1. 4 
C o m plic ati o ns of mi gr ai ne
C o m m e nt: C o d e s e p ar at el y f or b ot h t h e mi gr ai n e 
t y p e, s u bt y p e or s u bf or m a n d f or t h e c o m pli c ati o n.
1. 4. 1 St at us mi gr ai n os us
D es cri pti o n: A d e bilit ati n g mi gr ai n e att a c k 
l asti n g f or m or e t h a n 7 2 h o urs.
Di a g n ostic criteri a:
A.
A h e a d a c h e att a c k f ul ﬁlli n g crit eri a B a n d C
B.
O c c urri n g i n a p ati e nt wit h 1. 1 Mi gr ai n e 
wit h o ut a ur a a n d/ or 1. 2 Mi gr ai n e  wit h 
a ur a , a n d t y pi c al of pr e vi o us att a c ks e x c e pt
f or its d ur ati o n a n d se verit y
C.
B ot h of t h e f oll o wi n g c h ar a ct eristi cs:
1.
u nr e mitti n g f or > 7 2 h o urs 1
2.
p ai n 
a n d/ or 
ass o ci at e d
s y m pt o ms 
are de bilitati n g 2
D.
N ot b ett er a c c o u nt e d f or b y a n ot h er I C H D -
3 di a g n osis.
N otes:
1.
R e missi o ns of u p t o 1 2 h o urs d u e t o 
m e di c ati o n or sl e e p ar e a c c e pt e d.
2.
Mil d er 
cases, n ot meeti n g crit eri o n C 2,
ar e
c o d e d
1. 5. 1 Pr o b a ble mi gr ai ne wit h o ut a ur a .
C o m m e nt: Hea dac he wit h t he feat ures of 1. 4. 1 
St at us mi gr ai n os us 
ma y  
ofte n b e 
ca use d b y 
me dicati o n  
o ver use. W he n  
hea dac he i n t hese 
circ u msta nces meets t he criteria f or 8. 2 Me dic ati o n -
over use he a d ac he , c o de f or t his dis - or der a n d t he 
rele va nt t y pe or s u bt y pe  of mi grai ne  b ut n ot f or 
1. 4. 1 
St at us  mi gr ai n os us . W he n  
o ver use  of 
me dicati o n is of s h orter d urati o n t ha n t hree m o nt hs, 
c o de f or t he a p pr o priate mi grai ne t y pe or s u bt y pe(s)
o nl y.
1. 4. 2 Pe rsiste nt a ur a wit h o ut i nf arcti o n
D es cri pti o n: A ur a s y m pt o ms p ersisti n g f or o n e 
w e e k or m or e wit h o ut e vi d e n c e of i nf ar cti o n o n 
n e ur oi m a gi n g.
Di a g n ostic criteri a:
A.
A ur a f ul ﬁlli n g crit eri o n B
B.
O c c urri n g i n a p ati e nt wit h 1. 2 Mi gr ai n e 
wit h a ur a a n d t y pical of pr e vi o us a ur as 
e x c e pt t hat o n e or m or e 
a ura s y m pt o ms 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
8 2
p ersists f or 1 w e e k
C.
N e ur oi m a gi n g s h o ws n o e vi d e n c e of
i nf ar cti o n
D.
N ot b ett er a c c o u nt e d f or b y a n ot h er I C H D -
3 di a g n osis.
C o m m e nts: P ersist e nt a ur a s y m pt o ms ar e r ar e b ut 
w ell d o c u m e nt e d. T h e y ar e oft e n bil a teral a n d m a y 
last f or m o nt hs or y e ars. T h e o n e -w e e k mi ni m u m 
i n crit eri o n B is b as e d o n t h e o pi ni o n of e x p erts 
a n d s h o ul d b e f or m all y st u di e d.
Di a g n osti c 
w or k -u p m ust  disti n g uis h 1. 4. 2
P ersist e nt a ur a wit h o ut i nf ar cti o n fr o m 1. 4. 3 
Mi gr ai n o us i nf ar cti o n a n d e x cl u d e s y m pt o m ati c 
a ur a d u e t o c er e br al i nf ar cti o n of ot her c a us es. 
Attac ks wit h  pr ol o n ge d  a ura lasti n g less t ha n o ne 
w e e k a n d n ot f ulﬁlli n g criteria f or 1. 2. 1 Mi gr ai n e 
wit h 
t y pi c al a ur a ar e c o d e d 1. 5. 2 Pr o b a bl e 
mi gr ai n e wit h
a ur a.
1. 4. 3 Mi gr ai n o us i nf arcti o n
D es cri pti o n: O n e or m or e mi gr ai n e a ur a 
s y m pt o ms o c c urri n g i n ass o ci ati o n wit h a n 
is c h a e mi c br ai nl esi o n i n t h e a p pr o pri at e t errit or y 
d e m o nstr at e d b y n e ur oi m a gi n g, wit h o ns et d uri n g 
t h e c o urs e of a t y pi c al mi gr ai n e wit h a ur a att a c k.
Di a g n ostic criteri a:
A.
A mi gr ai n e att a c k f ul ﬁlli n g crit eri a B a n d C
B.
O c c urri n g i n a p ati e nt wit h 1. 2 Mi gr ai n e wit h 
a ur a a n d t y pi c al of pr e vi o us att a c ks e x c e pt 
t h at o n e or m or e a ur a s y m pt o ms p ersists f or 
> 6 0 mi n ut es 1
C.
N e ur oi m a gi n g d e m o nstr at es is c h a e mi c 
i nf ar cti o n i n a r el e v a nt ar e a
D.
N ot b ett er a c c o u nt e d f or b y a n ot h er I C H D -3 
di a g n osis.
N ote:
1. T h er e m a y b e a d diti o n al s y m pt o ms attri b ut a bl e 
t o  t h e i nf ar cti o n.
C o m m e nts: Isc hae mic str o ke i n a mi grai ne s uff er er 
m a y b e c at e g ori z e d as c er e br al i nf ar cti o n of ot h er 
c a us e c o e xis ti n g wit h  1. 
Mi gr ai n e , c er e br al 
i nf ar cti o n of 
 
ot h er c a us e 
pr es e nti n g 
wit h 
s y m pt o ms r es e m bli n g 1. 2 Mi gr ai n e wit h a ur a , or 
c er e br al i nf ar cti o n o c c urri n g d uri n g t h e c o urse of a 
t y pical att a c k of 1. 2 Mi gr ai n e wit h a ur a. O nl y t h e 
last f ulﬁls crit eri a f or 1. 4. 3 Mi gr ai n o us
i nf ar cti o n.
1. 4. 3 Mi gr ai n o us i nf ar cti o n m ostl y o c c urs i n 
t hep ost eri or cir c ul ati o n a n d i n y o u n g er w o m e n.
A t w of ol d i n cr e as e d ris k of is c h a e mi c str o k e i n 
p ati e nts wit h 1. 2 Mi gr ai n e 
wit h a ur a h as b e e n 
d e m o nstr at e d i n s e v er al p o p ul ati o n -b as e d st u di es. 
H o w e v er, it s h o ul d b e n ot e d t h at t hese i nf ar cti o ns 
are n ot mi grai n o us i nfarcti o ns. T he mec ha nis ms of 
t h e i n cr e as e d ris k of is c h a e mi c str o k e i n mi gr ai n e 
s uffer ers r e m ai n u n cl e ar; li k e wis e, t h e r el at i o ns hi p 
b et w e e n i n cr e as e d ris k a n d fr e q u e n c y of a ur a a n d 
t h e n at ur e of a ur a s y m pt o ms d e n oti n g t h e i n cr e as e 
i n ris k ar e u n k n o w n. M ost st u di es h a v e s h o w n a 
l a c k of ass o ci ati o n b et w e e n 1. 1 Mi gr ai n e wit h o ut 
a ur a a n d is c h a e mi c str o k e.
1. 4. 4 Mi gr ai ne a ur a -tri g gere d seiz ure
D es cri pti o n: A s ei z ur e tri g g er e d b y a n att a c k of 
mi gr ai n e wit h a ur a.
Di a g n ostic criteri a:
A.
A s ei z ur e f ul ﬁlli n g di a g n osti c crit eri a f or 
o n e t y p e of e pil e pti c att a c k, a n d crit eri o n B
b el o w
B.
O c c urri n g i n a p ati e nt wit h 1. 2 Mi gr ai n e wit h
a ur a , a n d d uri n g or wit hi n o n e h o ur aft er a n 
att a c k of mi gr ai n e wit h a ura
C.
N ot b ett er a c c o u nt e d f or b y a n ot h er I C H D -3 
di a g n osis.
C o m m e nt: Mi gr ai n e 
a n d e pil e ps y ar e pr ot ot y pi c al 
e x a m pl es of p ar o x ys m al br ai n dis or d ers. W hil e
mi gr ai n e -li k e h e a d a c h es are q uit e fr e q u e ntl y s e e n i n 
t he e pil e pti c p ost -ictal p eri o d, s o m eti m es a  seiz ure  
o c c urs  duri n g or f oll o wi n g a mi gr ai n e att a c k. T his 
p he n o me n o n, s o meti mes referre d t o as mi gr al e ps y , is 
a r ar e e v e nt, ori gi n all y d es cri b e d i n p ati e n ts wit h 1. 2 
Mi gr ai n e wit h a ur a . E vi d e n c e of a n ass o ci ati o n wit h 
1. 1 Mi gr ai n e wit h o ut a ur a is l a c ki n g.
1. 5 
Pr o b a ble mi gr ai ne
Previ o usly use d ter m: Mi grai n o us dis or der.
C o d e d els e w h er e: Mi gr ai n e -li k e h e a d a c h e s e c o n d ar y 
t o a n ot h er dis or d er (s y m pt o m ati c mi gr ai n e ) is c o d e d 
a c c or di n g t o t h at dis or d er.
D es cri pti o n: Mi gr ai n e -li k e att a c ks missi n g o n e of t he 
f e at ur es re q uire d t o f ulﬁl all criteria f or a t y p e or s u b-
t y p e of mi gr ai n e 
c o d e d a b o v e, a n d n ot f ulﬁlli n g 
crit eri a f or a n ot h er h e a d a c h e dis or d er.
Di a g n ost ic criteri a:
A.
Att a c ks
f ulﬁlli n g all b ut o n e of crit eri a A – D
f or
1. 1 Mi gr ai n e wit h o ut a ur a , or all b ut o n e of
criteria A – C f or 1. 2 Mi gr ai n e wit h
a ur a
B.
N ot f ul ﬁlli n g I C H D -3 crit eri a f or a n y ot h er 
h e a d - a c h e dis or d er
C.
N ot b ett er a c c o u nt e d f or b y a n ot h er I C H D -3 
di a g n osis.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
8 3
C o m m e nt: I n m a ki n g a h e a d a c h e di a g n osis, att a c ks 
t h at f ulﬁl criteria f or b ot h 2. T e nsi o n -t y p e h e a d a c h e 
a n d 1. 5 Pr o b a bl e mi gr ai n e are c o de d as t he f or mer i n 
a c c or d a n c e wit h t h e g e n er al r ul e t h at a d e ﬁnit e 
di a g n osis al w a ys tr u m ps a pr o b a bl e di a g n o sis. 
H o w e v er, i n p ati e nts w h o alr e a d y h a v e a mi gr ai n e 
dia g n osis, a n d w here t he iss ue is t o c o u nt t he n u m ber 
of att a c ks t h e y ar e h a vi n g ( e. g. as a n o ut c o m e 
m e as ur e i n a dr u g tri al), att a c ks f ul ﬁlli n g crit eri a f or 
1. 5 
Pr o b a bl e  mi gr ai n e 
s h o ul d b e 
c o u nt e d as 
m i gr ai n e. T h e r e as o n f or t his is t h at mil d mi gr ai n e 
att a c ks, or att a c ks tr e at e d e arl y, oft e n d o n ot a c hi e v e 
all c h ar a ct eristi cs n e c ess ar y f or a mi gr ai n e attac k 
di a g n osis 
b ut 
n e v ert h el ess 
r es p o n d t o s p e ciﬁc 
mi gr ai n e
tr e at m e nts.
1. 5. 1 Pr o b a ble mi gr ai ne wit h o u t a ur a Di a g n ostic
criteri a:
A.
Att a c ks
f ulﬁlli n g all b ut o n e of crit eri a A – D
f or 1. 1 Mi gr ai ne wit h o ut a ur a
B.
N ot f ul ﬁlli n g I C H D -3 crit eri a f or a n y 
ot h er h e a d - a c h e dis or d er
C.
N ot b ett er a c c o u nt e d f or b y a n ot h er 
I C H D-3 di a g n osis.
1. 5. 2 Pr o b a ble mi gr ai ne wit h a ur a
Di a g n ostic criteri a:
A.
Att a c ks f ulﬁlli n g all b ut o n e of crit eri a A – C f or
1. 2
Mi gr ai n e wit h a ur a or a n y of its s u bt y p es
B.
N ot f ul ﬁlli n g I C H D -3 crit eri a f or a n y 
ot h er h e a d - a c h e dis or d er
C.
N ot b ett er a c c o u nt e d f or b y a n ot h er 
I C H D-3 di a g n osis.
1. 6 
E pis o dic sy n dr o mes t h at m ay be ass oci ate d 
wit h mi gr ai ne
Pr e vi o usl y  us e d t er ms: 
C hil d h o o d  p eri o di c 
s y n dr o m es; p eri o di c s y n dr o m es of c hil d h o o d.
C o m m e nts: T his gr o u p of dis or d ers o c c urs i n 
p ati e nts w h o als o h a v e 1. 1 Mi gr ai n e 
wit h o ut 
a ur a or 1. 2 Mi gr ai n e wit h a ur a , or w h o h a v e a n 
i n cr e as e d li k eli h o o d t o d e v el o p eit h er of t hese 
dis or d ers. Alt h o u g h hist ori c all y n ot e d t o o c c ur i n 
c hil d h o o d,  t h e y  m a y  als o o c c ur i n a d ults.
A d diti o n al c o n diti o ns t h at m a y als o o c c ur i n 
t hese p ati e nts 
i n cl u d e e pis o d es of 
m oti o n 
si c k n ess a n d p eri o di c sl e e p dis or d ers i n cl u di n g 
slee p w al ki n g, sl e e p t al ki n g, ni g ht t err ors a n d 
br u xis m.
1. 6. 1 Rec urre nt g astr oi ntesti n al dist ur b a nce
Pr e vi o usl y us e d t er ms: C hr o ni c a b d o mi n al p ai n; 
f u n cti o n al a b d o mi n al pai n; f u ncti o nal d ys p e psi a; 
irrita ble b o w el s y n dr o m e; f u n cti o n al a b d o mi n al 
p ai n s y n dr o m e.
D es cri pti o n: 
R e c urr e nt  e pis o di c 
att a c ks 
of 
a b d o mi n al p ai n a n d/ or dis c o mf ort, n a us e a a n d/ or 
v o miti n g, o c c urri n g i nfr e q u e ntl y, c hr o ni c all y or 
at pr e di ct a bl e i nt er v als, t hat m a y b e ass o ci at e d 
wit h mi gr ai n e.
Di a g n o stic criteri a:
A.
At l e ast ﬁv e att a c ks wit h disti n ct e pis o d es 
of a b d o mi n al p ai n a n d/ or dis c o mf ort a n d/ or 
n a us e a a n d/ or v o miti n g
B.
N or mal gastr oi ntesti nal e xa mi nati o n a n d 
e v al u ati o n
C.
N ot attri b ute d t o a n ot her
dis or der.
1. 6. 1. 1 Cyclic v o miti n g sy n dr o me
D es cri pti o n: R e c urr e nt e pis o di c att a c ks of i nt e ns e 
n a us e a a n d v o miti n g, us u all y st er e ot y pi c al i n t h e 
i n di vi d u al a n d wit h pr e di ct a bl e ti mi n g of e pis o d es. 
Att a c ks  m a y  b e ass o ci at e d wit h  p all or a n d 
l et h ar g y. T h er e  
is c o m pl et e  r es ol uti o n 
of 
s y m pt o ms b et w e e n att a c ks.
Di a g n ostic criteri a:
A.
At l e ast ﬁv e att a c ks of i nt e ns e n a us e a a n d 
v o miti n g, f ul ﬁlli n g crit eri a B a n d C
B.
St er e ot y pi c al i n t h e i n di vi d u al p ati e nt a n d 
r e c ur- ri n g wit h pr e di ct a bl e p eri o di cit y
C.
All of t h e
f oll o wi n g:
1.
n a us e a a n d v o miti n g o c c ur at l e ast f o ur 
ti m es p er h o ur
2.
att a c ks last f or ≥ 1 h o ur, u p t o 1 0
da ys
3.
att a c ks occ ur ≥ 1 w e e k a part
D.
C o m pl et e fr e e d o m fr o m s y m pt o ms b et w e e n 
att a c ks
E.
N ot attri b ute d t o a n ot her dis or der. 1
N ote:
1. I n p arti c ul ar, hist or y a n d p h ysi c al e x a mi n ati o n 
d o n ot s h o w si g ns of g astr oi nt esti n al dis e as e.
C o m m e nts: 1. 6. 1. 1 C y cli c v o miti n g s y n dr o m e is 
t y pi c all y a s elf-li miti n g e pis o di c c o n diti o n 
o c c urri n g i n c hil d- h o o d, wit h p eri o ds of 
c o m pl et e n or m alit y b et w e e n e pis o d es. T h e c y cli c 
n at ur e is t h e h all m ar k, a n d att a c ks ar e 
pr e di ct a bl e.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
8 4
T his dis or d er w as ﬁrst i n cl u d e d as a c hil d h o o d 
p eri o di c s y n dr o m e i n I C H D -II. T h e cli ni c al 
f e at ur es of t his s y n dr o m e r es e m bl e t h os e f o u n d i n 
ass o ci ati o n wit h mi gr ai n e h e a d a c h es, a n d 
m ulti pl e t hr e a ds of r es e ar c h o v er t h e l ast y e ars 
h a v e s u g g est e d t h at 1. 6. 1. 1 C y cli c v o miti n g 
s y n dr o m e is a c o n diti o n r el at e d t o mi gr ai n e.
1. 6. 1. 2 A b d o mi n al mi gr ai ne
D es cri pti o n: A n i di o p at hi c dis or d er s e e n m ai nl y 
i n c hil dr e n as r e c urr e nt att a c ks of m o d er at e t o 
s e v er e mi dli n e a b d o mi n al p ai n, ass o ci at e d wit h 
v as o m ot or s y m pt o ms, n a us e a a n d v o miti n g, 
l asti n g 2– 7 2 h o urs a n d wit h n or m alit y b et w e e n 
e pis o d es. H e a d a c h e d o es n ot o c c ur d uri n g t h es e 
e pis o d es.
Di a g n ostic criteri a:
A.
At l e ast ﬁv e att a c ks of a b d o mi n al p ai n, 
f ulﬁlli n g crit eri a B – D
B.
P ai n h as at l e ast t w o of t h e f oll o wi n g t hr e e 
c h ar a ct eristi cs:
1.
mi dli n e l o c ati o n, p eri u m bili c al or 
p o orl y l o c ali z e d
2.
d ull or ‘j ust s or e’ q u alit y
3.
m o d er at e or s e v er e i nte nsit y
C.
At l e ast t w o of t h e f oll o wi n g f o ur ass o ci at e d 
s y m pt o ms or si g ns:
1.
a n or e xi a
2.
n a us e a
3.
v o miti n g
4.
pall or
D.
Attac ks l ast 2 – 7 2 h o urs w he n u ntreate d or
u ns uccessf ull y tr e at e d
E.
C o m pl et e fr e e d o m fr o m s y m pt o ms b et w e e n 
att a c ks
F.
N ot attri b ute d t o a n ot her dis or der. 1
N ote:
1.
I n p arti c ul ar, hist or y a n d p h ysi c al e x a mi n ati o n 
d o n ot s h o w si g ns of g astr oi nt esti n al or r e n al 
disease, or s u c h dis e as e h as b e e n r ul e d o ut b y 
a p pr o pri at e i n v esti g ati o ns.
C o m m e nts: P ai n of 1. 6. 1. 2 A b d o mi n al mi gr ai n e is 
s e v er e e n o u g h t o i nt erf er e wit h n or m al d ail y 
a cti viti es.
I n y o u n g c hil dr e n, t h e pr es e n c e of h e a d a c h e is 
oft e n o v erl o o k e d. A c ar ef ul hist or y of pr es e n c e or 
a bs e n c e of h e a d a c h e m ust b e t a k e n a n d, w h e n 
h e a d a c h e or h e a d p ai n d uri n g att a c ks is i d e nti ﬁe d, 
a di a g n osis of 1. 1 Mi gr ai n e wit h o ut a ur a s h o ul d 
b e c o nsi d er e d.
C hil dr e n m a y ﬁn d it diffi c ult t o disti n g uis h 
a n or e xi a fr o m n a us e a. P all or is oft e n a c c o m p a ni e d 
b y d ar k s h a d o ws u n d er t h e e y es. I n a f e w p ati e nts, 
ﬂus hi n g is t h e pr e d o mi n a nt v as o m ot or 
p h e n o m e n o n.
M ost 
c hil dr e n wit h a b d o mi n al mi gr ai n e will 
d e v el o p mi gr ai n e h e a d a c h e l at er i n lif e.
1. 6. 2 Be ni g n p ar oxys m al verti g o
D es cri pti o n: A dis or d er c h ar a ct eri z e d b y r e c urr e nt 
bri ef att a c ks of v erti g o, o c c urri n g wit h o ut w ar ni n g 
a n d r es ol vi n g s p o nt a n e o usl y, i n ot h er wis e h e alt h y 
c hil dr e n.
Di a g n ostic criteri a:
A.
At l e ast ﬁv e attac ks f ulﬁlli n g crit eri a B a n d C
B.
V erti g o 1 o c c urri n g wit h o ut w ar ni n g, m a xi m al 
at o ns et a n d r es ol vi n g s p o nt a n e o usl y aft er 
mi n ut es t o h o urs wit h o ut l oss of
c o ns ci o us n ess
C.
At l e ast o n e of t h e f oll o wi n g ﬁv e ass o ci at e d 
s y m pt o ms or si g ns:
1.
n yst a g m us
2.
at a xi a
3.
v o miti n g
4.
pall or
5.
f e arf ul n ess
D.
N or m al n e ur ol o gi c al e x a mi n ati o n a n d 
a u di o m etri c a n d v esti b ul ar f u n cti o ns b et w e e n
att a c ks
E.
N ot attri b ute d t o a n ot her dis or der. 2
N otes:
1.
Y o u n g c hil dr e n wit h v erti g o m a y n ot b e a bl e t o 
d es cri b e  
v erti gi n o us  
s y m pt o ms.  
P ar e nt al 
o bs er v ati o n of e pis o di c p eri o ds of u nst e a di n ess 
m a y b e i nt er pr et e d as v erti g o i n y o u n g c hil dr e n.
2.
I n p arti c ul ar, p ost eri or f oss a t u m o urs, s ei z ur es 
a n d v esti b ul ar dis or d ers h a v e b e e n e x cl u d e d.
C o m m e nt: T h e r el ati o ns hi p b et w e e n 1. 6. 2 B e ni g n
p ar o x ys m al v erti g o a n d A 1. 6. 6 V esti b ul ar mi gr ai n e 
(s e e A p p e n di x) n e e ds t o b e f urt h er e x a mi n e d.
1. 6. 3 Be ni g n p ar oxys m al t ortic ollis
D es cri pti o n: R e c urr e nt e pis o d es of h e a d tilt t o o n e 
si de, p er h a ps wit h  sli g ht r ot ati o n, w hi c h 
r e mit 
s p o nt a n e o usl y. T he c o n diti o n o c c urs i n i nfants a n d 
s m all c hil dr e n, wit h o ns et i n t h e ﬁrst y e ar.
Di a g n ostic criteri a:
A.
R e c urr e nt att a c ks 1 i n a y o u n g c hil d, f ulﬁlli n g 
crit eri a B a n d C
B.
Tilt of t h e h e a d t o eit h er si d e, wit h or wit h o ut 
sli g ht r ot ati o n, r e mitti n g s p o nt a n e o usl y after 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
8 5
mi n ut es t o
d a ys
C.
At l e ast o n e of t h e f oll o wi n g ﬁv e ass o ci at e d 
s y m pt o ms or si g ns:
1.
pall or
2.
irrita bilit y
3.
m al ais e
4.
v o miti n g
5.
at a xi a 2
D.
N or m al n e ur ol o gi c al e x a mi n ati o n b et w e e n
att a c ks
E.
N ot attri b ute d t o a n ot her dis or der. 3
N otes:
1.
Attac ks te n d t o rec ur
m o nt hl y.
2.
Ata xia is m ore li kel y i n ol der c hil dre n wit hi n 
t he affe ct e d a g e gr o u p.
3.
T h e  diff ere ntial 
di a g n osis i n cl u d es 
g astr o -
o es o p h a g e al r eﬂu x, i di o p at hi c t orsi o n al d yst o ni a 
a n d c o m- pl e x p arti al s ei z ur e, b ut p arti c ul ar 
att e nti o n m ust b e p ai d t o t h e p ost eri or f oss a a n d 
cr a ni o c er vi c al j u n cti o n w h er e  c o n g e nit al or 
a c q uir e d l esi o ns m a y pr o - d u c e t ortic ollis.
C o m m e nts: T h e c hil d’s h e a d c a n b e r et ur n e d t o 
t h e n e utr al p ositi o n d uri n g att a c ks: s o m e 
r esist a n c e m a y b e e n c o u nt er e d b ut c a n b e 
o v er c o m e.
T h es e o bs er v ati o ns n e e d f urt h er v ali d ati o n b y 
p ati e nt di ari es, str u ct ur e d i nt er vi e ws a n d 
l o n git u di n al d at a c oll e cti o n.
1. 6. 3 B e ni g n p ar o x ys m al t orti c ollis m a y e v ol v e 
i nt o
1. 6. 2 B e ni g n p ar o x ys m al v erti g o or 1. 2 Mi gr ai n e 
wit h 
a ur a ( p arti c ul arl y 1. 2. 2 Mi gr ai n e  wit h 
br ai nst e m  
a ur a ) or 
c e as e 
wit h o ut  
f urt h er 
s y m pt o ms.
Bi bli o gr a p h y
1 Mi gr ai ne i n ge ner al
Arr u d a M A, G ui d etti V, G alli F, et al. Pri m ar y 
h e a d - a c h es i n c hil d h o o d – a p o p ul ati o n -
b as e d st u d y. C e p h al al gi a 2 0 1 0; 3 0: 1 0 5 6 –
1 0 6 4.
Di e n er H C  a n d  Sil b erst ei n  S D.  M e di c ati o n 
o v er -  us e h e a d a c h e. I n: Ol es e n J, G o a ds b y 
PJ, R a m a d a n N M, et al. ( e ds) T h e 
h e a d a c h es, 3r d e diti o n . P hil a d el p hi a: 
Li p pi n c ott Willi a ms & Wil ki ns, 2 0 0 6, 
p p. 9 7 1 – 9 7 9.
G B D 2 0 1 5 Dis e as e a n d I nj ur y I n ci d e n c e a n d 
Pr e v al e n c e C oll a b or at ors. Gl o b al, r e gi o n al, 
a n d n a ti o n al i n ci d e n c e, pr e v al e n c e, a n d 
y e ars  li v e d  wit h dis a bilit y f or 3 1 0 dis e as es 
a n d i nj uri es, 1 9 9 0 – 2 0 1 5: a s yst e m ati c 
a n al ysis f or t h e Gl o b al B ur d e n of Dis e as e 
St u d y 2 0 1 5. L a n c et 2 0 1 6; 3 8 8: 1 5 4 5 – 1 6 0 2.
G elf a n d A A, F ull ert o n HJ a n d G o a ds b y PJ. 
C hil d n e ur ol o g y: mi gr ai n e wit h a ur a i n 
c hil dr e n. N e ur ol o g y 2 0 1 0; 7 5( 5): e 1 6 – e 1 9.
G o a ds b y PJ. Mi gr ai n e p at h o p h ysi ol o g y. H e a d a c h e
2 0 0 5; 4 5( S u p pl 1): S 1 4 – S 2 4.
G o a ds b y PJ. R e c e nt a d v a n c es i n t he di a g n osis 
a n d m a n - a g e m e nt of mi gr ai n e. B M J 2 0 0 6; 
3 3 2: 2 5 – 2 9.
K ats ar a v a Z, M a n a c k A, Y o o n M S, et al. C hr o ni c 
mi gr ai n e:  cl assi ﬁc ati o n a n d c o m p aris o ns. 
C e p h al al gi a 2 0 1 1; 3 1: 5 2 0 – 5 2 9.
Li pt o n R B, Bi g al M E, 
 St ei n er  TJ,  et  al.  
Cl assi ﬁc ati o n  
of  
pri m ar y  
h e a d a c h es. 
N e ur ol o g y 2 0 0 4; 6 3: 4 2 7 – 4 3 5.
M art ell etti P, Hai ma n ot  R T,  Lai n e z  MJ,  et  al.  
T he Gl o bal Ca m pai g n ( G C) t o R e d u c e t he
B ur de n  
of 
H e a d a c h e  
W orl d wi de.  
T he 
I nter nati o nal T e a m f or S p e ci alist E d ucati o n 
(I T S E). J He a d ac he P ai n 2 0 0 5; 6: 2 6 1 – 2 6 3.
Sil b erst ei n S D. Mi gr ai n e. L a n c et 2 0 0 4; 3 6 3: 3 8 1 –
3 9 1.
V et vi k K G, M a c gr e g or E A, L u n d q vist C, et al. 
Pr e v al e n c e  
of  
m e nstr u al 
mi grai ne :  a 
p o p ul ati o n - b as e d st u d y. C e p h al al gi a 2 0 1 4; 
3 4: 2 8 0 – 2 8 8.
V et vi k K G, B e nt h J Sˇ , M a c Gr e g or E A, et al. 
M e nstr u al 
v ers us n o n -m e nstr u al  att a c ks of mi gr ai n e 
wit h o ut 
a ur a i n w o m e n 
wit h 
a n d wit h o ut 
m e nstr u al 
mi grai ne. 
C e p h al al gi a 2 0 1 5; 3 5:
1 2 6 1 – 1 2 6 8.
V os T, Fl a x m a n A D, N a g h a vi M, et al. Y e ars li v e d 
wit h dis a bilit y ( Y L D) f or 1 1 6 0 s e q u el a e of 2 8 9 
dis - 
e as es  a n d  i nj uri es 
1 9 9 0 – 2 0 1 0:  a 
syst e m ati c a n al ysis f or t h e gl o b al b ur d e n of 
dis e as e st u d y 2 0 1 0. L a n c et 2 0 1 2; 3 8 0: 2 1 6 3 –
2 1 9 6.
1. 2 Mi gr ai ne
wit h a ur a
C a o Y, W el c h 
K M, A ur or a S, et al. F u n cti o n al 
M RI - B O L D of vis u all y tri g g er e d h e a d a c h e i n 
p ati e nts wit h mi gr ai n e. Ar c h N e ur ol 1 9 9 9; 5 6: 
5 4 8 – 5 5 4.
C h arl es A a n d Br e n n a n K. C orti c al s pr e a di n g 
d e pr essi o n – n e w i nsi g hts a n d p ersist e nt 
q u esti o ns. C e p h al al gi a 2 0 0 9; 2 9: 1 1 1 5 – 1 1 2 4.
C ol o g n o D, T or elli P a n d M a n z o ni G C. Mi gr ai n e 
wit h a ur a: a r e vi e w of 8 1 p ati e nts at 1 0 – 2 0 
years’ f oll o w - u p. C e p h al al g i a 1 9 9 8; 1 8: 6 9 0 –
6 9 6.
C utrer F M, S or e ns e n A G, W eiss k o  R M, et al.
P erf usi o n -  w ei g ht e d i m a gi n g d ef e cts d uri n g 
s p o nt a n e o us  mi gr ai n o us a ur a. A n n N e ur ol 
1 9 9 8; 4 3: 2 5 – 3 1.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
8 6
Eri ks e n M K, 
T h o ms e n L L, A n d ers e n I, et al. 
Cli ni c al c h ar a ct eristi cs of 3 6 2 p ati e nts wit h
f a mili al mi gr ai n e
wit h a ura. Ce p h al al gi a 2 0 0 4; 2 4: 5 6 4 – 5 7 5.
Eri ks e n M K, 
T h o ms e n L L a n d Ol es e n J. T h e 
Vis u al  
A ur a  
R ati n g  
S c al e ( V A R S)  f or 
mi gr ai n e a ur a di a g n osis. C e p h al al gi a 2 0 0 5; 
2 5: 8 0 1 – 8 1 0.
Gi  n  NJ,   Li pt o n   R B,   Sil b erst ei n   S D,   et  
al. T h e mi gr ai n e p ost dr o m e: a n el e ctr o ni c 
di ar y st u d y. N e ur ol o g y 2 0 1 6; 8 7: 3 0 9 – 3 1 3.
Ha dji k ha ni N, Sa nc hez del Ri o M, 
W u 
O, et al. 
Mec ha nis ms  
of mi grai ne  a ura re veale d b y 
f u ncti o nal M RI i n h u ma n vis ual c orte x. P N A S 
2 0 0 1; 9 8: 4 6 8 7 – 4 6 9 2.
H a ns e n J M, Li pt o n R, D o di c k D, et al. Mi gr ai n e 
h e a d - a c h e is pr es e nt i n t h e a ur a p h as e – a 
pr os p e cti v e st u d y. N e ur ol o g y 2 0 1 2; 7 9: 2 0 4 4 –
2 0 4 9.
J e ns e n K, Tf elt -H a ns e n P, L a urit z e n M, 
et al. 
Cl assi c mi gr ai n e. A pr os p e cti v e r e c or di n g of 
s y m pt o ms. A ct a N e ur ol S c a n d 1 9 8 6; 7 3: 3 5 9 –
3 6 2.
K all el a M, W ess m a n M, F ar k kil a M, et al. Cli ni c al 
c h ar a ct eristi cs of mi gr ai n e i n a p o p ul ati o n -
b as e d  
t wi n  
s a m pl e:  
si mil ariti es  
a n d 
di  er e n c es b et w e e n
mi grai ne wit h a n d wit h o ut 
a ura. Ce p h al al gi a  1 9 9 9; 1 9: 1 5 1 – 1 5 8.
K el m a n  
L.  
T h e  
pr e m o n it or y  
s y m pt o ms 
( pr o dr o m e): a t erti ar y care st u d y of 8 9 3 
mi gr ai n e urs. H e a d a c h e 2 0 0 4; 4 4: 8 6 5 – 8 7 2.
L a urit z e n M.  P at h o p h ysi ol o g y of t h e mi gr ai n e 
a ur a. T h e s pr e a di n g d e pr essi o n t h e or y. Br ai n 
1 9 9 4; 1 1 7( Pt 1): 1 9 9 – 2 1 0.
L e a o A A P. S pr e a di n g d e pr essi o n of a cti vit y i n t h e 
c er e- br al c ort e x. J N e ur o p h ysi ol 1 9 4 4; 7: 3 5 9 –
3 9 0.
L e b e d e v a E R, G ur ar y 
N M, 
Gil e v 
D V, 
et al.  
Pr os p e cti v e testi n g of I C H D-3 b et a di a g n osti c 
crit eri a f or mi gr ai n e wit h a ur a a n d mi gr ai n e 
wit h t y pi c al a ur a i n p ati e nts wit h tr a nsi e nt 
is c h e mi c att a c ks. C e p h al al gi a . E p u b a h e a d of 
pri nt 
1  
J a n u ar y  
2 0 1 7.  
D OI:
1 0. 1 1 7 7/ 0 3 3 3 1 0 2 4 1 7 7 0 2 1 2 1.
Li D, C hrist e ns e n A F a n d Ol es e n J. Fiel d -t esti n g of 
t h e I C H D-3 b et a/ pr o p os e d I C D-1 1 di a g n osti c 
crit eri a f or mi gr ai n e wit h a ur a. C e p h al al gi a
2 0 1 5; 3 5: 7 4 8 – 7 5 6.
Ol es e n J, Fri b er g L, Ols e n T S, et al. Ti mi n g a n d 
t o p o gr a p h y of c er e br al bl o o d ﬂo w, a ur a, a n d 
h e a d a c h e d uri n g mi gr ai n e att a c ks. A n n N e ur ol 
1 9 9 0; 2 8: 7 9 1 – 7 9 8.
Q u eir o z L P, Fri e d m a n DI, R a p o p ort A M, et al. 
C h ar a ct eristi cs 
of mi gr ai n e vis u al a ur a i n 
S o ut h er n  
Br a zil  
a n d  
N ort h er n  
U S A. 
C e p h al al gi a 2 0 1 1; 3 1: 1 6 5 2 – 1 6 5 8.
R as m uss e n B K a n d Ol es e n J. Mi gr ai n e wit h a ur a 
a n d mi gr ai n e wit h o ut a ur a: a n e pi d e mi ol o gi c al 
st u d y. 
C e p h al al gi a 
1 9 9 2;  
1 2:  
2 2 1 – 2 2 8 
( dis c ussi o n 1 8 6).
S al h of er -P ol a n yi S, Fr a nt al S, Br a n n at h W, et al. 
Pr os p e cti v e 
a n al ysis of f a ct ors r el at e d t o 
mi gr ai n e  
a ur a  – 
T h e  
P A MI N A  St u d y. 
H e a d a c h e 2 0 1 2; 5 2: 1 2 3 6 – 1 2 4 5.
S c h o o n m a n G G, E v ers DJ, T er wi n dt G M, et al. 
T h e pr e v al e n c e of pr e m o nit or y s y m pt o ms i n 
mi gr ai n e: a q u esti o n n air e st u d y i n 4 6 1 p ati e nts. 
C e p h al al gi a 2 0 0 6; 2 6: 1 2 0 9 – 1 2 1 3.
Ulri c h V, G er vil M, K y vi k K O, et al. E vi d e n c e of 
a g e n eti c f a ct or i n mi gr ai n e 
wit h 
a ur a: A 
p o p ul ati o n -b as e d D a nis h  t wi n st u d y. A n n  
N e ur ol  1 9 9 9; 4 5: 2 4 2 – 2 4 6.
1. 2. 1 Mi gr ai ne wit h ty pic al a ur a
Eri ks e n  M K,  
T h o ms e n  L L  a n d 
Ol es e n  
J. 
I m pli c ati o ns of cli nical s u bt y p es of mi gr ai n e 
wit h a ur a. H e a d a c h e 2 0 0 6; 4 6: 2 8 6 – 2 9 7.
H a ns e n  J M, G o a ds b y  PJ 
a n d C h arl es  A C. 
V ari a bilit y  of cli nical f e at ur es i n att a c ks of 
mi gr ai n e 
wit h a ur a. C e p h al al gi a 2 0 1 6; 3 6:
2 1 6 – 2 2 4.
M at h ar u  
M J a n d G o a ds b y  PJ. P ost -tr a u m ati c 
c hr o ni c p ar o x ys m al h e mi cr a ni a ( C P H) wit h 
a ur a. N e ur ol o g y 2 0 0 1; 5 6: 2 7 3 – 2 7 5.
M orris o n  D P . A b n or mal 
perce pt ual e x perie nces i n 
mi grai ne. Ce p h al al gi a 1 9 9 0; 1 0: 2 7 3 – 2 7 7.
Sil b erst ei n S D, Ni k n a m R, R o z e n T D, et al. Cl ust er 
h e a d a c h e wit h a ur a. N e ur ol o g y 2 0 0 0; 5 4: 2 1 9 –
2 2 1.
Vi a n a M, Li n d e M, S a n c es G, et al. Mi gr ai n e a ura 
s y m pt o ms: d ur ati o n, s u c c essi o n a n d t e m p or al 
r el ati o ns hi p t o h e a d a c h e. C e p h al al gi a 2 0 1 6; 3 6: 
4 1 3 – 4 2 1.
Wij m a n C A, W olf P A, K as e C S, et al. Mi gr ai n o us 
vis ual a c c o m p a ni m e nts are n ot r ar e i n late life: 
t h e Fr a mi n g h a m St u d y. Str o k e 1 9 9 8; 2 9:
1 5 3 9 –
1 5 4 3.
1. 2. 2 Mi gr ai ne wit h br ai nste m a ur a
A m br osi ni 
A, 
D’ O n ofri o 
M,  Gri e c o 
G S, 
et al. 
F a mili al b asil ar mi gr ai n e ass o c i at e d wit h a n e w 
m ut ati o n i n t h e A T P 1 A 2 g e n e. N e ur ol o g y 2 0 0 5; 
6 5: 1 8 2 6 – 1 8 2 8.
Bi c k erst aff E R. B asil ar art er y mi gr ai n e. L a n c et 1 9 6 1; 
i:1 5 – 1 7.
Ca pla n L R. Mi grai ne a n d verte br o basilar 
is c h e mi a. Ne ur ol o gy 1 9 9 1; 4 1: 5 5 – 6 1.
Eri ks e n M K, T h o ms e n L L a n d Ol es e n J. I m pli c ati o ns 
of cli nical s u bt y p es of mi gr ai n e  wit h 
a ur a.
H e a d a c h e 2 0 0 6; 4 6: 2 8 6 – 2 9 7.
Kir c h m a n n M, T h o ms e n L L a n d Ol es e n J. B asil ar -
t y p e mi gr ai n e:  
cli ni c al, 
e pi d e mi ol o gi c, 
a n d 
g e n eti c f e at ur es. N e ur ol o g y 2 0 0 6; 6 6: 8 8 0 – 8 8 6.
Le m pert T, Ne u ha user H a n d Dar off R B. Verti g o 
as a s y m pt o m of mi grai ne.
A n n N Y Ac a d S ci
2 0 0 9; 1 1 6 4: 2 4 2 – 2 5 1.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
8 7
Li D, C hrist e ns e n A F a n d Ol es e n J. Fiel d -t esti n g of 
t he I C H D-3 b et a/ pr o p os e d I C D-1 1 di a g n osti c 
crit eri a f or mi gr ai n e wit h a ur a. C e p h al al gi a 2 0 1 5;
3 5: 7 4 8 – 7 5 6.
St ur z e n e g g er M H a n d M ei e n b er g O. B asil ar art er y 
mi gr ai n e:  
a f oll o w-u p 
st u d y of 
8 2 
c as es. 
H e a d a c h e 1 9 8 5; 2 5: 4 0 8 – 4 1 5.
S w a ns o n J W a n d Vic k N A. B asil ar art er y mi gr ai n e 
1 2  
p ati e nts,  
wit h  
a n  
att a c k  
r e c or d e d 
el e ctr o e n c e p h al o gr a p hi c all y. 
N e ur ol o g y 
1 9 7 8; 
2 8: 7 8 2 – 7 8 6.
T h o ms e n  L L,  Eri ks e n   M K,   R o e m er   S F,   et   al.   
A p o p ul ati o n -b as e d st u d y of f a mili al h e mi pl e gi c 
mi gr ai n e  s u g g ests r e vis e d di a g n osti c criteria. 
Br ai n 2 0 0 2; 1 2 5: 1 3 7 9 – 1 3 9 1.
T h o mse n L L, Oster gaar d E, Olese n J, et al. E vi de nce 
f or a s e p ar at e t y p e of mi gr ai n e wit h a ur a: s p or a di c 
h e mi pl e gi c mi gr ai n e. N e ur ol o g y 2 0 0 3; 6 0: 5 9 5 –
6 0 1.
1. 2. 3 He mi ple gic mi gr ai ne
A m br osi ni A, D’ O n ofri o M, Gri e c o G S, et al. 
F a mili al b asil ar mi gr ai n e ass o ci at e d wit h a n e w 
m ut ati o n i n t h e A T P 1 A 2 g e n e. N e ur ol o g y 2 0 0 5; 
6 5: 1 8 2 6 – 1 8 2 8.
D e F us c o M, M ar c o ni R, Sil v estri L, et al. 
H a pl oi ns u  ci e n c y of A T P 1 A 2 e n c o di n g t h e 
N a þ/K þ p u m p a 2 s u b u nit ass o ci at e d wit h f a mili al 
h e mi pl e gi c mi gr ai n e t y p e 2. N at G e n et 2 0 0 3; 3 3:
1 9 2 – 1 9 6.
D e  Vri es  B,  Fr a nts  R R,  F err ari  M,  et  al.  
M ol e c ul ar g e n eti cs of mi gr ai n e. H u m G e n et 
2 0 0 9; 1 2 6: 1 1 5 – 1 3 2.
Di c h g a ns M, Fr eili n g er T, E c kst ei n G, et al. 
M ut ati o n i n t h e n e ur o n al v olt a g e -g at e d 
s o di u m c h a n n el S C N 1 A i n f a mili al 
h e mi pl e gi c mi gr ai n e. L a n c et 2 0 0 5; 3 6 6:
3 7 1 – 3 7 7.
Dr ei er J P, J ur k at-R ott K, P et z ol d G C, et al. 
O p e ni n g    
of t h e bl o o d – br ai n 
b arri er 
pr e c e di n g c orti c al e d e m a i n a s e v er e att a c k of 
F H M t y p e II. N e ur ol o g y 2 0 0 5; 6 4: 2 1 4 5 –
2 1 4 7.
Eri ks e n 
M K,  
T h o ms e n 
L L 
a n d Ol es e n  J. 
I m pli c ati o ns of cli ni c al s u bt y p es of mi gr ai n e 
wit h a ur a. H e a d a c h e 2 0 0 6; 4 6: 2 8 6 – 2 9 7.
H a ns e n J M, S c h yt z H W, L ars e n V A, et al. 
H e mi pl e gi c  
mi gr ai n e  
a ur a 
b e gi ns 
wit h 
c er e br al h y p o p erf usi o n: i m a gi n g i n t h e a c ut e 
p h as e. H e a d a c h e 2 0 1 1; 5 1: 1 2 8 9 – 1 2 9 6.
H a ns e n 
J M, T h o ms e n L L, Ol es e n 
J, et al. 
C o e xisti n g  t y pi c al
mi gr ai n e  
i n f a mili al 
h e mi pl e gi c mi gr ai n e. N e ur ol o g y 2 0 1 0; 7 4: 
5 9 4 – 6 0 0.
Ii z u k a T,  T a k a h as hi  Y,  
S at o  M,  
et 
al. 
N e ur o v as c ul ar  
c h a n g es  
i n  
pr ol o n g e d 
mi gr ai n e a ur a i n F H M wit h a n o v el A T P 1 A 2 
g e n e  
m ut ati o n. 
J  
N e ur ol  
N e ur os ur g 
Ps y c hi atr y 2 0 1 2; 8 3: 2 0 5 – 2 1 2.
J ur k at-R ott K, Fr eili n g er T, Dr ei er J P, et al. 
V ari a bilit y of f a mili al h e mi pl e gi c mi gr ai n e 
wit h n o v el A 1 A 2 N a þ/ Kþ-A T P as e v ari a nts. 
N e ur ol o g y 2 0 0 4; 6 2:
1 8 5 7 – 1 8 6 1.
Kir c h m a n n 
M,  T h o ms e n L L a n d Ol es e n 
J. 
B asil ar -t y p e  
mi gr ai n e:  
cli ni c al, 
e pi d e mi ol o gi c,  
a n d  
g e n eti c  
f e at ur es. 
N e ur ol o g y 2 0 0 6; 6 6: 8 8 0 – 8 8 6.
L e o L, G h er ar di ni L, B ar o n e V, et al. I n cr e as e d 
s us c e pti bilit y  
t o  
c orti c al  
s pr e a di n g 
d e pr essi o n i n t h e m o us e m o d el of f a mili al 
h e mi pl e gi c mi gr ai n e 
t y p e 2. Pl o S G e n et 
2 0 1 1; 7: e 1 0 0 2 1 2 9.
T h o ms e n L L, Eri ks e n M K, R o e m e S F, et al. A 
p o p ul ati o n -b as e d  
st u d y  
of  
f a milial 
h e mi pl e gi c  
mi gr ai n e  
s u g g ests  
r e vis e d 
di a g n osti c criteria. Br ai n 2 0 0 2; 1 2 5: 1 3 7 9 –
1 3 9 1.
T h o ms e n L L, Kir c h m a n n M, Bj or nss o n A, et al. 
T h e g e n eti c s p e ctr u m of a p o p ul ati o n -b as e d 
s a m pl e of f a mili al h e mi pl e gi c mi gr ai n e. 
Br ai n 2 0 0 7; 1 3 0: 3 4 6 – 3 5 6.
T h o ms e n L L , Ost er g a ar d E,  Ol es e n  J,  et  al.  
E vi d e n c e f or a s e p ar at e t y p e of  mi gr ai n e  
wit h  aur a: s p or a di c h e mi pl e gi c mi gr ai n e. 
N e ur ol o g y 2 0 0 3; 6 0: 5 9 5 – 6 0 1.
Va n m ol k ot K RJ, K ors E E, T ur k U, et al. T w o d e 
n o v o m ut ati o ns i n t h e N a, K -A T P as e g e n e 
A T P 1 A 2 
ass o ci at e d 
wit h  
p ur e  f a mili al 
h e mi pl e gi c mi gr ai n e. E ur J H u m G e n et 2 0 0 6; 
1 4: 5 5 5 – 5 6 0.
1. 2. 4 Reti n al mi gr ai ne
C arr oll D. R eti n al mi gr ai n e. H e a d a c h e 1 9 7 0; 1 0: 
9 – 1 3. C hr o ni cl e 
E P 
a n d M ull e n ers  
W M. 
Vis u al 
s yst e m d ysf u n cti o n i n mi gr ai n e:  a 
r e vi e w of cli ni c al a n d ps y c h o p h ysi c al ﬁn di n gs. 
C e p h al al gi a 1 9 9 6; 1 6: 5 2 5 – 5 3 5.
Gr os b er g B M, S ol o m o n S, Fri e d m a n DI, et al. 
R eti n al  mi gr ai n e 
r e a p pr ais e d. C e p h al al gi a 
2 0 0 6; 2 6:  1 2 7 5 – 1 2 8 6.
H e d g es T R. Is ol at e d o p ht h al mi c mi gr ai n e i n t h e 
di  er e nti al  
di a g n osis  
of  
c er e br o o c ul ar 
is c h emia. Str o k e 1 9 7 6; 7: 3 7 9 – 3 8 1.
Hill  DL,  Dar off   R B,  Du cr os  A,   et  al.  Most  
c as es la bele d as ‘‘r eti n al mi gr ai n e’’ ar e n ot
mi gr ai n e. J N e ur o o p ht h al m ol 2 0 0 7; 2 7: 3 – 8.
Marti n TJ a n d C or bett JJ. Dis or ders of t he e ye. I n: 
Sil b erst ei n S D, Li pt o n R B a n d D al essi o DJ 
( e ds) W olff ’s h e a d a c h e a n d ot h er h e a d p ai n . 
N e w Y or k: O xf or d U ni v ersit y Pr ess, 2 0 0 1, 
p p. 4 5 9 – 4 7 4.
Tr o ost 
T 
a n d Z a g a mi 
A S.  O p ht h al m o pl e gi c 
mi gr ai n e a n d r eti n al mi gr ai n e. I n: Ol es e n J, 
Tf elt -H a ns e n P a n d W el c h 
K M A ( e ds) T h e 
h e a d a c h es,  
2 n d  
e diti o n .  
P hil a d el p hi a: 
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
8 8
Li p pi n c ott Willi a ms & Wil ki ns, 2 0 0 0, p p. 5 1 1 –
5 1 6.
1. 3 C hr o nic mi gr ai ne
A ur or a S K. Is c hr o ni c mi gr ai n e o n e e n d of a 
s p e ctr u m of mi gr ai n e or a s e p ar at e e ntit y ? 
C e p h al al gi a 2 0 0 9; 2 9: 5 9 7 – 6 0 5.
Bi g al M E a n d Li pt o n R B. C o n c e pts a n d 
m e c h a nis ms of mi gr ai n e c hr o ni ﬁc ati o n. 
H e a d a c h e 2 0 0 8; 4 8: 7 – 1 5.
Bi g al M, Ra p o p ort A, S h eft ell F, et al. T h e 
I nt er n ati o n al Cl assiﬁc ati o n of H e a d a c h e 
Dis or d ers r e vis e d crit eri a f or c hr o ni c 
mi gr ai n e – ﬁel d t esti n g i n a hea dac he  
s p e ci alt y cli ni c. C e p h al al gi a 2 0 0 7; 2 7: 2 3 0 –
2 3 4.
Bi g al M E, S err a n o D, R e e d M, et al. C hr o ni c 
mi gr ai n e i n t h e p o p ul ati o n: b ur d e n, di a g n osis, 
a n d s atisf a cti o n wit h tr e at m e nt. N e ur ol o g y 
2 0 0 8; 7 1: 5 5 9 – 5 6 6.
Bi g al M E, 
S heftell F D, Ra p o prt A M, et al. 
C hr o nic d ail y h e a d a c h e i n a tertiar y c ar e
p o p ulati o n: 
c orr el ati o n  
bet wee n  
t he 
I nter nati o nal Hea dac he S ociet y dia g n ostic
criteria a n d pr o p ose d re visi o ns of criteria f or 
c hr o nic dail y h e a d a c h e. Ce p h al al gi a 2 0 0 2;
2 2: 4 3 2 – 4 3 8.
Bl o u d e k L M, St o k es M, B us e D C, et al. C ost of 
healt h - c ar e f or p ati e nts wit h mi gr ai n e i n ﬁv e 
E ur o p e a n  
c o u ntri es:  
r es ults  fr o m  
t h e 
I nt er n ati o n al B ur d e n  
of 
Mi gr ai n e  
St u d y 
(I B M S). J H e a d a c h e P ai n 2 0 1 2; 1 3: 3 6 1 -3 7 8.
B us e 
D C, 
M a n a c k  A N, 
F a n ni n g K M, 
et al. 
C hr o n ic mi gr ai n e pr e v al e n c e, dis a bilit y, a n d 
s o ci o d e m o gr a p hi c f a ct ors. R es ults fr o m t h e 
A m eri c a n Mi gr ai n e Pr e v al e n c e a n d Pr e v e nti o n 
St u d y. H e a d a c h e 2 0 1 2; 5 2: 1 4 5 6 -1 4 7 0.
B us e D, M a n a c k A, S err a n o D, et al. H e a d a c h e 
i m p a ct of c hr o ni c a n d e pis o di c mi gr ai n e: 
r es ults fr o m t h e A m eri c a n Mi gr ai n e Pr e v al e n c e 
a n d Pr e v e nti o n st u d y. H e a d a c h e 2 0 1 2; 5 2: 3 –
1 7.
Di a m o n d S. A vi e w of c hr o ni c d ail y h e a d a c h e.
He a d ac he Q 2 0 0 0; 1 1: 1 7 7.
Di e n er H C, D o di c k D W, G o a ds b y PJ, et al. 
C hr o ni c mi gr ai n e – cl assi ﬁc ati o n, 
c h ar a ct eristi cs a n d tr e at m e nt. N at R e v N e ur ol 
2 0 1 2; 8: 1 6 2 – 1 7 1.
G o a ds b y PJ a n d H ar gr e a v es R. R efr a ct or y  
mi gr ai n e a n d c hr o ni c mi gr ai n e: 
p at h o p h ysi ol o gi c al m e c h a nis ms. H e a d a c h e 
2 0 0 8; 4 8: 7 9 9 – 8 0 4.
K ats ar a v a Z, M a n a c k A, Y o o n M S, et al. C hr o ni c 
mi gr ai n e: cl assi ﬁc ati o n a n d c o m p aris o ns. 
C e p h al al gi a 2 0 1 1; 3 1: 5 2 0 – 5 2 9.
M a n z o ni G C, B o n a vit a V, B uss o n e G, et al.;  
A NI R C E F ( Ass o ci a zi o n e N e ur ol o gi c a It ali a n a 
Ri c er c a C ef al e e). C hr o ni c mi gr ai n e 
cl assi ﬁc ati o n: c urr e nt k n o wl e d g e a n d f ut ur e 
p ers p e cti v es. J H e a d a c h e P ai n 2 0 0 1; 1 2:
5 8 5 – 5 9 2.
M at h e w  
N T,  St u bits 
E 
 an d   Ni g a m M P. 
Tr a nsf or m e d or e v ol uti v e mi gr ai n e. H e a d a c h e 
1 9 8 7; 2 7: 1 0 2 – 1 0 6. 
N at oli J L, M a n a c k  A, 
D e a n B, et al. Gl o b al 
pr e v al e n c e of c hr o ni c mi gr ai n e: a s yst e m ati c 
r e vi e w. C e p h al al gi a 2 0 1 0; 3 0: 5 9 9– 6 0 9.
S c h er 
AI,  St e w art 
W F,  
Li b er m a n 
J, et al. 
Pr e v al e n c e  
of  fr e q u e nt 
h e a d a c h e  
i n 
a 
p o p ul ati o n s a m pl e.  H e a d a c h e 1 9 9 8; 3 8: 4 9 7 –
5 0 6.
S c h er AI, St e w art W F, 
Ri c ci J A, et al. F a ct ors 
ass o ci at e d wit h t h e o ns et a n d r e missi o n of 
c hr o ni c d ail y h e a d a c h e i n a p o p ul ati o n -b as e d 
st u d y. P ai n 2 0 0 3; 1 0 6: 8 1 – 8 9.
Sil b erst ei n S D, Li pt o n R B 
a n d Sli wi ns ki M. 
Cl assi ﬁc ati o n  
of  
d ail y  
a n d  
n e ar -d ail y 
h e a d a c h es: ﬁel d tri al of r e vis e d I H S crit eri a. 
N e ur ol o g y 1 9 9 6; 4 7: 8 7 1 – 8 7 5.
Sil b erst ei n S D , Li pt o n R B, S ol o m o n S, et al. 
Cl assi ﬁc ati o n  
of  
d ail y  
a n d  
n e ar -d ail y 
h e a d a c h es: pr o p os e d r e visi o ns t o t h e I H S 
criteria. H e a d a c h e 1 9 9 4; 3 4: 1 – 7.
St e w art W F, S c h er AI a n d Li pt o n R B. Str essf ul lif e 
e ve nts a n d ris k of c hr o ni c d ail y h e a d a c h e: 
r es ults  
fr o m  
t h e  
fr e q u e nt   
h e a d a c h e 
e pi d e mi ol o g y st u d y. C e p h al al gi a 2 0 0 1; 2 1: 
2 7 9. A bstr a ct n o: O R 3 2.
Y alı n  O O ¨   ,  Ul u d u z  D,  O ¨  z ge  A,  et  al.  Phenotypic
f e at ur es  of  chr o ni c  mi gr ai n e.  J  He a d a c h e  
P ai n 2 0 1 6; 1 7: 2 6.
Z e e b er g P, Ol es e n J a n d J e ns e n R. Pr o b a bl e 
m e di c ati o n -o v er us e h e a d a c h e: t h e eff e ct of a 
2- m o nt h dr u g - fr e e p eri o d. N e ur ol o g y 2 0 0 6; 
6 6: 1 8 9 4 – 1 8 9 8.
Z e e b er g P, Ol es e n J a n d J e ns e n R. M e di c ati o n 
o v er us e h e a d a c h e a n d c hr o ni c mi gr ai n e i n a 
s p e ci ali z e d h e a d a c h e c e ntr e: ﬁel d -t esti n g 
pr o p os e d n e w a p p e n - di x crit eri a. C e p h al al gi a 
2 0 0 9; 2 9: 2 1 4 – 2 2 0.
1. 4. 1 St at us mi gr ai n os us
A k ht ar N D, M urr a y 
M A 
a n d R ot h n er A D. St at us 
mi gr ai n os us i n c hil dr e n a n d a d ol es c e nts. S e mi n 
P e di atr N e ur ol 2 0 0 1; 8: 2 7 – 3 3.
B eltr a m o n e M a n d D o n n et A. St at us mi gr ai n os us a n d 
mi gr ai n e a ur a st at us i n a Fr e n c h  terti ar y -c ar e 
c e nt er:  A n  
1 1 -y e ar  r etr os p e cti v e 
a n al ysis. 
C e p h al al gi a 2 0 1 4; 3 4: 6 3 3 – 6 3 7 .
C o u c h 
J R a n d Di a m o n d 
S. St at us mi gr ai n os us. 
C a us ati v e 
a n d t h er a p e uti c as pects. H e a d a c h e 
1 9 8 3; 2 3: 9 4 – 1 0 1.
C ur e J a n d R ot hr o c k J. Pr ol o n g e d st at us mi gr ai n os us 
c o m pli c at e d b y c er e b ell ar i nf ar cti o n. H e a d a c h e 
2 0 0 7; 4 7: 1 0 9 1 – 1 0 9 2.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
8 9
G e ntil e S, R ai n er o I, D a ni el e D, et al. R e v ersi bl e M RI 
a b n or m aliti es i n a p ati e nt wit h r e c urr e nt st at us 
mi gr ai n os us. C e p h al al gi a 2 0 0 9; 2 9: 6 8 7 -6 9 0.
L a nfr a n c o ni S, C orti S, B ers a n o A, et al. A p h asi c a n d 
vis u al a ur a wit h i n cr e as e d v as o g e ni c l e a k a g e: a n 
at y pi c al mi gr ai n os us st at us. J N e ur ol  Sci  2 0 0 9; 
2 8 5: 2 2 7 – 2 2 9.
P er u c c a P, T er z a g hi M  a n d M a n ni  R. 
 St at us  
e pil e pti c us  
mi gr ai n os us:  
cli ni c al, 
el e ctr o p h ysi ol o gi c, a n d i m a gi n g c h ar a ct eristi cs. 
N e ur ol o g y 2 0 1 0; 7 5: 3 7 3 – 3 7 4.
R as ki n N H. Tr e at m e nt of st at us mi gr ai n os us: t he 
A m eri c a n e x p eri e n c e. H e a d a c h e 1 9 9 0; 3 0( S u p pl 
2): 5 5 0 – 5 5 3.
1. 4. 2 Persiste nt a ur a wit h o ut i nf arcti o n
A m br osi ni A, d e N o or d h o ut A M a n d S c h o e n e n J. 
N e ur o m us c ul ar tr a ns missi o n i n mi gr ai n e p ati e nts 
wit h pr ol o n g e d a ur a. A ct a N e ur ol Bel g 2 0 0 1; 1 0 1: 
1 6 6 – 1 7 0.
B e nt o M S a n d Es p er a n c a P. Mi gr ai n e wit h pr ol o n g e d 
a ur a. H e a d a c h e 2 0 0 0; 4 0: 5 2 – 5 3.
C h e n W T, F u h J L, L u S R, et al. P ersist e nt mi gr ai n o us 
vis u al 
p h e n o m e n a 
mi g ht  
b e 
r es p o nsi v e t o 
l a m otri gi n e. H e a d a c h e 2 0 0 1; 4 1: 8 2 3 – 8 2 5.
C h e n W T, Li n  YY,  Fu h  JL,  et  al.  Sust ai n e d  vis ual 
c ort e x  h y p er e x cit a bilit y  
i n 
mi gr ai n e  
wit h 
p ersist e nt vis u al a ur a. Br ai n 2 0 1 1; 1 3 4( Pt 8): 
2 3 8 7 – 2 3 9 5.
E v a ns R W a n d L a y C L. A p ersist e nt mi gr ai n e a ur a.
He a d ac he 2 0 0 0; 4 0: 6 9 6 – 6 9 8.
H a a n J, Sl uis P, Sl uis I H, et al. A c et a z ol a mi d e 
tr e at m e nt f or mi gr ai n e 
a ur a st at us. N e ur ol o g y 
2 0 0 0; 5 5: 1 5 8 8 – 1 5 8 9.
H a as D C. Pr ol o n g e d mi gr ai n e a u r a st at us. A n n 
N e ur ol 1 9 8 2; 1 1: 1 9 7 – 1 9 9.
L e b e d e v a E R, G ur ar y N M, Gil e v D V, et al.  
Pr os p e cti v e t esti n g of I C H D -3 b et a di a g n osti c 
crit eri a f or mi gr ai n e wit h a ur a a n d mi gr ai n e wit h
t y pi c al a ur a i n p ati e nts wit h tr a nsi e nt is c h e mi c 
att a c ks. C e p h al al gi a . E p u b a h e a d of pri nt  1  
J a n u ar y 2 0 1 7. D OI:
1 0. 1 1 7 7/ 0 3 3 3 1 0 2 4 1 7 7 0 2 1 2 1.
Li u G T, S c h at z NJ, G al ett a S K, et al. P ersist e nt 
p ositi v e vis u al p h e n o m e n a 
i n mi gr ai n e. 
N e ur ol o g y 1 9 9 5; 4 5: 6 6 4 – 6 6 8.
L u d a E, B o E, Si c ur o L, et al. S ust ai n e d vis u al 
a ur a: a t ot all y n e w v ari ati o n of mi gr ai n e. 
H e a d a c h e 1 9 9 1; 3 1: 5 8 2 – 5 8 3.
Relja G, Gr a n at o A, U k m ar M, et al. P ersist e nt 
a ur a wit h o ut i nf ar cti o n: d es cri pti o n of t h e 
ﬁrst c as e st u di e d wit h b ot h br ai n S P E C T a n d 
p erf usi o n M RI. C e p h al al gi a 2 0 0 5; 2 5: 5 6 –
5 9.
R ot hr o c k J F. S u c c essf ul tr e at m e nt of p ersist e nt 
mi gr ai n e  
a ur a wit h  
di v al pr o e x 
s o di u m. 
N e ur ol o g y 1 9 9 7; 4 8: 2 6 1 – 2 6 2.
Sa n- J ua n O D a n d Zer me n˜ o P F. Mi grai ne wit h 
persiste nt a ura  in  a  Me xica n  patie nt:  case  
re p ort a n d  re vie w of t he literat ure. Ce p halal gia 
2 0 0 7; 2 7: 4 5 6 – 4 6 0 .
S mit h M, Cr os D a n d S h e e n V. H y p er p erf usi o n 
wit h v as o g e ni c l e a k a g e b y f M RI i n mi gr ai n e 
wit h pr o - l o n g e d a ur a. N e ur ol o g y 2 0 0 2; 5 8: 
1 3 0 8 – 1 3 1 0.
W a n g Y F, F u h J L, C h e n W T, et al. T h e vis u al 
a ur a r ati n g s c al e as a n o ut c o m e pr e di ct or f or 
p ersist e nt vis u al a ura
wit h o ut 
i nf ar cti o n.
C e p h al al gi a 2 0 0 8; 2 8: 1 2 9 8 – 1 3 0 4.
1. 4. 3 Mi gr ai n o us i nf arcti o n
B o n o G, Mi n o n zi o G, M a uri M,  et al. 
C o m pli c ati o ns  of mi gr ai n e: mi gr ai n o us 
i nf ar cti o n. Cli n E x p H y p ert e ns 2 0 0 6; 2 8:
2 3 3 – 2 4 2.
B o uss er  M G,  
C o n ar d  J, Kitt n er  S, 
et al. 
R e c o m m e n d ati o ns o n t h e ris k of is c h e mi c 
str o k e ass o ci at e d wit h us e of c o m bi n e d or al 
c o ntr a c e pti v es a n d h or m o n e r e pl a c e m e nt 
t h er a p y i n w o m e n  wit h  mi gr ai n e.  
T h e 
I nt er n ati o n al H e a d a c h e S o ci et y T as k F or c e 
o n  C o m bi n e d  
Or a l 
C o ntr a c e pti v es  
& 
H or m o n e  
R e pl a c e m e nt  
T h er a p y. 
C e p h al al gi a 2 0 0 0; 2 0: 1 5 5 – 1 5 6.
C h a n g C L, D o n a g h y M a n d P o ult er N. Mi gr ai n e 
a n d str o k e i n y o u n g w o m e n: c as e – c o ntr ol 
st u d y. T h e W orl d H e alt h Or g a ni z ati o n 
C oll a b or ati v e St u d y of C ar di o v as c ul ar 
Dis e as e a n d St er oi d H or m o n e 
C o ntr a c e pti o n. B M J 1 9 9 9; 3 1 8: 1 3 – 1 8.
C o n n or C C R. C o m pli c at e d mi gr ai n e. A st u d y of 
p er m a n e nt n e ur ol o gi c al a n d vis u al d ef e cts. 
L a n c et 1 9 6 2; ii: 1 0 7 2 – 1 0 7 5.
L a ur ell K, Artt o V, B e n dts e n L, et al. 
Mi gr ai n o us i nf ar cti o n: a N or di c m ulti c e nt er 
st u d y. E ur   J  N e ur ol 2 0 1 1; 1 8: 1 2 2 0 – 1 2 2 6.
M a c Gr e g or E A a n d G uill e b a u d J. C o m bi n e d or al 
c o ntr a c e pti v es,  
mi gr ai n e  
a n d  
is c h e mi c 
str o ke. Cli ni c al a n d S ci e nti ﬁc C o m mitt e e of 
t h e F a c ult y  
of 
F a mil y  
Pl a n ni n g  
a n d 
R e pr o d u cti v e H e alt h C ar e a n d t h e F a mil y 
Pl a n ni n g Ass o ci ati o n. Br J F a m Pl a n n 1 9 9 8; 
2 4: 5 5 – 6 0.
Ol es e n J, Fri b er g L, Ols e n T S, et al. Is c h a e mi a-
i n d u c e d (s y m pt o m ati c) mi gr ai n e att a c ks m a y 
b e m or e  fr e q u e nt t h a n mi gr ai n e  i n d u c e d  
is c h e mi c  ins ults. Br ai n 1 9 9 3; 1 1 6: 1 8 7 – 2 0 2.
R ot hr oc k J F, Walic ke P, S we ns o n M R, et al.
Mi gr ai n o us str o k e. Ar c h N e ur ol 1 9 8 8; 4 5:
6 3 – 6 7.
S c h ul z U G, Bl a mir e A M, D a vi es P, et al. N or m al 
c ortical  en er g y m et a b olis m 
i n mi gr ai n o us 
str o k e: A 
3 1P- M R s p e ctr os c o p y st u d y. Str o k e 
2 0 0 9; 4 0: 3 7 4 0 – 3 7 4 4.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
9 0
Ti etj e n G E. T h e r el ati o ns hi p of mi gr ai n e a n d 
str o k e.
Ne ur oe pi de mi ol o gy 2 0 0 0; 1 9: 1 3 – 1 9.
T z o uri o 
C, 
Kitt n er  SJ, B o uss er 
M G,  
et al. 
Mi gr ai n e  
 an d str o k e i n y o u n g w o m e n. 
C e p h al al gi a 2 0 0 0; 2 0: 1 9 0 – 1 9 9.
V oll br a c ht  
S,  R o b bi ns  
M S  
a n d 
K ister I. 
Cl assi ﬁc ati o n  
c h all e n g e  
i n  
mi gr ai n o us 
i nf ar cti o n. H e a d a c h e 2 0 1 4; 5 4: 1 7 0 – 1 7 1.
W olf M E, S z a b o K, Gri e b e M, et al. Cli ni c al a n d 
M RI  
c h ar a ct eristi cs of 
a c ut e 
mi gr ai n o us 
i nf ar cti o n. N e ur ol o g y 2 0 1 1; 7 6: 1 9 1 1 – 1 9 1 7.
1. 4. 4 Mi gr ai ne a ur a -tri g gere d seiz ure
B el c astr o  V Stri a n o  P,  K ast el eij n -N olst  Tre nite´ 
D G et al.  Mi gr al e ps y, h e mi cr a ni a e pil e pti c a, 
p osti ct al  h e a d a c h e  a n d  ‘‘i ct al 
e pil e pti c 
h e a d a c h e’’: a pr o p os al f or t er mi n ol o g y a n d 
cl assi ﬁc ati o n r e visi o n. J H e a d a c h e P ai n 2 0 1 1; 
1 2: 2 8 9 – 2 9 4.
D a vi es P T a n d P a n a yi ot o p o ul os C P.  
Mi gr ai n e 
tri g g er e d s ei z ur es a n d e pile ps y tri g g er e d
h e a d a c h e a n d mi gr ai n e att a c ks: a n e e d f or 
re-ass ess m e nt. J H e a d a c h e P ai n 2 0 1 1; 1 2:
2 8 7 – 2 8 8.
Fri e d e n b er g 
S 
a n d D o di c k  
D W.  
Mi gr ai n e -
ass o ci at e d s ei z ur e: a c as e of r e v ersi bl e  MRI  
a b n or m aliti es  an d p ersist e nt n o n d o mi n a nt 
h e mis p h er e s y n dr o m e. H e a d a c h e 2 0 0 0; 4 0:
4 8 7 – 4 9 0.
M a g gi o ni  F, M a m pr es o  E, R u atti 
S, et al. 
Mi gr al e ps y:  
is t h e c urr e nt de ﬁniti o n 
to o 
n arr o w ? H e a d a c h e 2 0 0 8; 4 8: 1 1 2 9 – 1 1 3 2.
M ar ks D A a n d E hr e n b er g B L. Mi gr ai n e -r el at e d 
s ei z ur es i n a d ults wit h e pil e ps y, wit h E E G 
c orr el ati o n. N e ur ol o g y 1 9 9 3; 4 3: 2 4 7 6 – 2 4 8 3.
M erli n o G, V al e nt e M R, D’ A n n a S, et al. S ei z ur es
wit h
pr ol o n g e d E E G a b n or m aliti es d u ri n g a n
attac k 
of mi gr ai n e wit h o ut
a ur a. H e a d a c h e
2 0 0 7; 4 7: 9 1 9 – 9 2 2.
arisi P 
a n d K ast el eij n -N olst  Tre nite` 
D G A. 
‘‘ Mi gr al e ps y’’: a
c all
f or r e visi o n of t he
de ﬁniti o n. E pile psi a 2 0 1 0; 5 1: 9 3 2 – 9 3 3.
R o g a ws ki  
M A.  
C o m m o n  
p at h o p h ysi ol o gi c 
m e c h a n is ms i n mi gr ai n e a n d e pil e ps y. Ar c h 
N e ur ol 2 0 0 8; 6 5: 7 0 9 – 7 1 4.
S a n c es 
G,  G u as c hi n o  E, 
P er u c c a 
P, 
et al. 
Mi gr al e ps y: a c all
f or r e visi o n of t he d e ﬁniti o n.
E pil e psi a 2 0 0 9; 5 0: 2 4 8 7 – 2 4 9 6.
Ter B er g H W. Mi gr ai n e -ass ociate d s ei z ur e: a c as e 
of r e v ersi bl e M RI a b n or m aliti es a n d p ersist e nt 
n o n - 
d o mi n a nt  
h e mis p h er e  
s y n dr o m e. 
H e a d a c h e 2 0 0 1; 4 1: 3 2 6 – 3 2 8.
V eli o gl u S K a n d O z m e n o gl u M. Mi gr ai n e -r el at e d 
s ei z ur es i n a n e pil e pti c p o p ul ati o n. 
C e p h al al gi a 1 9 9 9; 1 9: 7 9 7 – 8 0 1.
V err otti A, C o p p ol a G, Di F o n z o A, et al. S h o ul d 
‘‘ mi gr al e ps y’’ b e c o nsi d er e d a n o bs ol et e 
c o n c e pt ?  A m ulti c e nt er r etr os p e cti v e 
cli ni c al/ E E G st u d y a n d r e vi e w of t h e 
literat ure. E pil e ps y B e h a v 2 0 1 1; 2 1: 5 2 – 5 9.
1. 5 Pr o b a ble mi gr ai ne
Gr a n ell a F, Al ess a n dr o R D, M a n z o ni G C, et al. 
I nt er n ati o n al H e a d a c h e S o ci et y cl assi ﬁc ati o n: 
i nter- o bs er v er r eli a bilit y i n t h e di a g n osis of 
pri m ar y h e a d - a c h es. C e p h al al gi a 1 9 9 4; 1 4: 
1 6 – 2 0.
R ai ns  J C, P e n zi e n 
D B,  Li p c hi k 
G L,  et al. 
Di a g n osis of mi gr ai n e: e mpiri c al a n al ysis of a 
l ar g e cli nical s a m pl e of at y pical mi gr ai n e 
(I H S 1. 7) p ati e nts a n d pr o p os e d r e visi o n of t h e 
I H S crit eri a. C e p h al al gi a 2 0 0 1, 2 1: 5 8 4 – 5 9 5.
Ras m usse n B K, J e ns e n R a n d Olese n 
J. A
p o p ulati o n- base d a nal ysis of t h e dia g n ostic 
criteria  of  t h e 
I nter nati o nal Hea dac he
S o ci et y. Ce p h al al gi a 1 9 9 1; 1 1: 1 2 9 – 1 3 4.
R ussell M B a n d Ol es e n J. Mi gr ai n o us dis or d er a n d 
its r el ati o n t o mi gr ai n e  wit h o ut 
a ur a a n d 
mi gr ai n e wit h a ur a. A g e n eti c e pi d e mi ol o gi c al 
st u d y. C e p h al al gi a 1 9 9 6; 1 6: 4 3 1 – 4 3 5.
1. 6. 1 Rec urre nt g astr oi ntesti n al dist ur b a nce
A b u -Ar af e h 
I a n d R uss el 
G. 
Pr e v al e n c e a n d 
cli ni c al  f e at ur es 
of  a b d o mi n al  mi gr ai n e 
c o m p ar e d wit h  th os e of mi gr ai n e h e a d a c h e. 
Ar c h Dis C hil d 1 9 9 5; 7 2: 4 1 3 – 4 1 7.
Al -T w aijri W A a n d S h e v ell MI. P e di atri c mi gr ai n e 
e q ui v al e n ts: o c c urr e n c e a n d cli ni c al f e at ur es i n 
prac - tice. P e di atr N e ur ol 2 0 0 2; 2 6: 3 6 5 – 3 6 8.
Di g n a n 
F, A b u -Ar af e h 
I a n d R uss ell G. 
T h e 
pr o g n osis of c hil d h o o d a b d o mi n al mi gr ai n e. 
Ar c h Dis C hil d 2 0 0 1; 8 4: 4 1 5 – 4 1 8.
Dr oss m a n  D A  a n d  D u mitr as c u  D L.  R o m e   III:   
n e w st a n d ar d f or f u n cti o n al g astr oi nt esti n al 
dis or d ers. J G astr oi nt esti n Li v er Dis 2 0 0 6; 1 5: 
2 3 7 – 2 4 1.
Far q uar H A. A b d o mi nal mi grai ne i n c hil dre n. 
B M J 1 9 5 6; i: 1 0 8 2 – 1 0 8 5.
Fl eis h er D R. C y cli c v o miti n g s y n dr o m e a n d 
mi gr ai n e. J Pe di atr 1 9 9 9; 1 3 4: 5 3 3 – 5 3 5.
H a a n J, K ors E E a n d F err ari M D. 
F a mili al c yclic 
v o miti n g 
s y n dr o m e.
C e p h al al gi a
2 0 0 2; 
2 2:
5 5 2 -5 5 4.
Li B U. C y cli c v o miti n g s y n dr o m e:  ag e -ol d  sy n -
dr o m e a n d n e w i nsi g hts. S e mi n P e di atr N e ur ol 
2 0 0 1; 8: 1 3 – 2 1.
Li B U K, L ef e vr e F, C h eli ms k y G G, et al. N ort h 
A m eri c a n S o ci et y f or P e di atri c 
G astr o e nt er ol o g y, H e p at ol o g y, a n d N utriti o n 
c o ns e ns us st at e m e nt o n t h e di a g n osis a n d 
m a n a g e m e nt of c y cli c v o miti n g s y n dr o m e. J 
P e di atr G astr o e nt er ol N utr 2 0 0 8; 4 7: 3 7 9 – 3 9 3.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
9 1
R as h e d H, A b ell T L, F a mil o ni B O, et al. A ut o n o mi c 
f u n cti o n i n c y cli c v o miti n g s y n dr o m e a n d cl assi c 
mi gr ai n e. 
Di g  Dis  S ci 1 9 9 9; 4 4( S u p pl 8): 
7 4 S -7 8 S.
R ussell G, A b u -Arafe h I a n d S y m o n D N. A b d o mi nal 
mi gr ai n e: e vi d e n c e f or e xist e n c e a n d tr e at m e nt 
o pti o ns. P a e di atr Dr u gs 2 0 0 2; 4: 1 – 8.
T hi ess e n P N. R e c urr e nt a b d o mi n al p ai n. P e di atr R e v
2 0 0 2; 2 3: 3 9 – 4 6.
W el c h K M. S ci e nti ﬁc b asis of mi gr ai n e: s p e c ul ati o n 
o n t he r el ati o ns hi p t o c y cli c v o miti n g. Di g Dis S ci
1 9 9 9; 4 4( S u p pl 8): 2 6 S – 3 0 S.
1. 6. 2 Be ni g n p ar o xys m al verti g o
Dri g o P, C arli G a n d L a v er d a A M. B e ni g n 
p ar o x ys m al v erti g o of c hil d h o o d. Br ai n D e v 
2 0 0 1; 2 3: 3 8 – 4 1.
D u n n D W a n d S n y d er C H.  B e ni g n  p ar o x ys m al  
v erti g o of c hil d h o o d. A m J Dis C hil d 1 9 7 6; 
1 3 0: 1 0 9 9 – 1 1 0 0.
F e ni c h el G M. Mi gr ai n e 
as a c a us e of b e ni g n
p ar o x ys m al v erti g o of c hil d h o o d. J P e di atr 
1 9 6 7; 7 1: 1 1 4 – 1 1 5.
1. 6. 3 Be ni g n p ar o xys m al t ortic ollis
Dri g o P, C arli G a n d L a v er d a A M. B e ni g n 
p ar o x ys m al t ortic ollis of i nf a n c y. Br ai n D e v 
2 0 0 0; 2 2: 1 6 9 – 1 7 2. 
Giffi n NJ, B e nt o n S a n d G o a ds b y PJ. B e ni g n 
p ar o x ys m al t ortic ollis of i nf a n c y: f o ur n e w 
c as es a n d li n k a g e t o C A C N A 1 A m ut ati o n. 
D e v M e d C hil d N e ur ol 2 0 0 2; 4 4: 4 9 0 – 4 9 3.
R os m a n N P, D o u gl ass L M, S h arif U M, et al. T h e 
n e ur ol o g y of b e ni g n p ar o x ys m al t orti c ollis of 
i nf a n c y: r e p ort of 1 0 n e w cases a n d r e vi e w of 
t h e lit er at ur e. J C hil d N e ur ol 2 0 0 9; 2 4: 1 5 5 –
1 6 0.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
9 2
1 2. 2 E x a m ples of Pr o hi bite d Me dic ati o ns
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
9 3
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
9 4
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
9 5
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
9 6
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
9 7
1 2. 4 Gl oss ar y of A b br e vi ati o ns
Ter m / A b bre vi ati o n 
Defi niti o n
A E
a d verse e ve nt
A E SI
a d verse e ve nt of s pecial i nterest
A L T
ala ni ne a mi n otra nsferase
A S C -1 2
all o d y nia s y m pt o m c hec klist
A S T
as partate a mi n otra nsferase
BI D
t wice dail y
B P
bl o o d press ure
C G R P
calcit o ni n ge ne -relate d pe pti de
C O VI D -1 9
c or o na vir us disease 2 0 1 9
C M
c hr o nic mi grai ne
C- S S R S 
C ol u m bia -S uici de Se verit y Rati n g Scale
C Y P 3 A 4
c yt oc hr o me P 4 5 0 3 A 4
D S M B
Data Safet y M o nit ori n g B oar d
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
e Diar y
electr o nic diar y
E M
e pis o dic mi grai ne
E T
earl y ter mi nati o n
e Ta blet
electr o nic ta blet
F D A
F o o d a n d Dr u g A d mi nistrati o n
G B D 2 0 1 0
Gl o bal B ur de n of Disease S ur ve y 2 0 1 0
G C P
G o o d Cli nical Practices
GI
gastr oi ntesti nal
HI P A A
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act
HI V
h u ma n i m m u n o deficie nc y vir us
H S G
h yster osal pi n g o gra m
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o nfere nce o n H ar 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, 3r d e diti o n
I E C
I n de pe n de nt Et hics C o m mittee
I g M
i m m u n o gl o b uli n M
I N R
i nter nati o nal n or malize d rati o
I R B
I nstit uti o nal Re vie w B oar d
I U D
i ntra uteri ne de vice
I U S
i ntra uteri ne h or m o ne releasi n g s yste m
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
9 8
Ter m / A b bre vi ati o n 
Defi niti o n
I V
i ntra ve n o us
I W R S
i nteracti ve we b res p o nse s yste m
mI T T
m o difie d i nte nt -t o-treat
M M R M
mi xe d -effects m o del f or re peate d meas ures
N S AI D
n o nster oi dal a nti -i nfla m mat or y dr u g
O A T P 1 B 1
or ga nic a ni o n tra ns p orti n g p ol y pe pti de 1 B 1
P K
p har mac o ki netic
P R O
patie nt re p orte d o utc o mes
Q D
dail y
Q Tc F
Q T i nter val c orrecte d f or heart rate usi n g Fri dericia f or m ula ( Q Tc F = 
Q T/( R R) ⅓)
R O W
rest of worl d
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S N RI
ser ot o ni n n ore pi ne p hri ne re u pta ke i n hi bit or
S O C
sta n dar d of care
S S RI
selecti ve ser ot o ni n re u pta ke i n hi bit or
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
U L N
u p per li mit of n or mal
V A S
Vis ual A nal o g ue Scale
V C T
V erifie d C li nical T rials
W H O
W orl d Healt h Or ga nizati o n
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
9 9
1 2. 5 Pr ot oc ol A me n d me nt 1 S u m m ar y
Ti tle: A P hase 3, M ultice nter , Ra n d o mize d, O pe n-La bel St u d y  to E val uate the L o n g -T er m 
Safet y  an d Tolera bilit y  of Oral At o ge pa nt for the Pre ve nti o n o f Mi grai ne in Partici pa nts W it h 
E pis o dic Mi grai ne
Pr ot oc ol 3 1 0 1 - 3 0 2- 0 0 2
Date of A me n d me nt: 1 4 Mar 2 0 1 9
A m e n d me nt S u m m ar y
T his a me n d me nt i ncl u des c ha n ges ma de t o Pr ot oc ol 3 1 0 1- 3 0 2- 0 0 2 date d 2 2 A u g ust 2 0 1 8 . T he 
pr ot oc ol was a me n de d t o:

Delete t he i ncl usi o n of partici pa nts fr o m St u d y  3 1 0 1 -3 0 1- 0 0 2 (r oll o ver partici pa nts) 
fr o m t his l o n g-ter m st u d y a n d delete a n y i nstr ucti o ns s pecific f or t his p o pulati o n 
t hr o u g h o ut t he pr ot oc ol.

A d d t he e xcl usi o n of partici pa nts wit h cli nicall y  si g nifica nt re nal disease t o t he 
Pr ot oc ol S u m mar y , t o be c o nsiste nt wit h E xcl usi o n Criteria # 1 4 i n Secti o n 4. 4.

A d d pr o gest o ge n - o nly h or m o nal c o ntrace pti o n ( wit h i n hi biti o n of o v ulati o n) t hat are 
oral, i njecta ble, or i m pla nta ble as acce pta ble hi g hl y  effecti ve c o ntrace pti ve met h o ds.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 0 0

A d d t hat t he assess me nt of ca usality of a n y A E or S A E a p plies t o t he partici pa nts 
recei vi n g oral S O C mi grai ne pre ve nti o n me dicati o n as well as th ose recei vi n g 
ato ge pa nt.

Clarif y  h o w ne w a n d u p date d i nf or mati o n will be rec or de d i n t he e C R F pri or t o 
data base l oc k; if a n e ve nt is a n S A E, t he n it will als o be re c or de d o n a n S A E re p orti n g 
f or m. If ne w or u p date d S A E i nf or mati o n bec o mes a vaila ble after data base l oc k, t he n 
t he e ve nt is o nl y rec or de d o n a n S A E re p orti n g.

Clarif y  w hic h f or m t hat s h o ul d be use d i n t he e ve nt of treat me nt-e mer ge nt ele vati o ns 
i n A L T or A S T  e nz yme le vels ≥ 3 x U L N.

Clarif y  t hat if a partici pa nt meets t he H y ’s la w criteria a n d has a n ass ociate d A E t hat 
is seri o us, t he n a n A E SI/ S A E f or m is t o be c o m plete d.

Ma ke Secti o n 1 2. 2 E xa m ples of Pr o hi bite d Me di cati o ns c o nsiste nt wit h Secti o n 4. 5. 2 
Pr o hi bite d Me dicati o ns/ T reat me nts

A d d ti mi n g of pr o hi bite d n o n- p har mac ol o gical hea dac he i nter ve nti o ns t o be 
c o nsiste nt wit h Secti o n 4. 5. 2
T he ta ble bel o w pr o vi des details relate d t o c o nte nt c ha n ges t hat were ma de i n t he pr ot oc ol, 
a n d a brief rati o nale f or t hese c ha n ges. Mi n or e dit orial a n d d oc u me nt f or matti n g re visi o ns 
ha ve n ot bee n s u m marize d.
Secti o n
Re visi o n
R ati o n ale
Pr ot oc ol Title P a ge 
A d de d A me n d me nt 1 Date
T o i n dicate t hat t he 
i nitial pr ot oc ol has bee n 
a me n de d a n d w he n
Gl o bal Pr ot oc ol Deleti o n
Secti o ns affecte d are:
o Pr ot oc ol S u m mar y a n d 
Ta ble 1 Sc he d ule of 
Visits a n d Pr oce d ures
o Secti o n 3. 1
o Secti o n 4. 2
o Secti o n 4. 3 ( I ncl usi o n 
Criteria # 1 1)
o Secti o n 4. 4 ( E xcl usi o n 
Cri teria # 1 0 , # 1 3, a n d 
# 2 3 )
o Secti o n 5. 5
o Secti o n 5. 6. 1
Delete d t he i ncl usi o n of partici pa nts fr o m St u d y 
3 1 0 1 - 3 0 1-0 0 2 (r oll o ver partici pa nts) as eli gi ble 
partici pa nts i n t his l o n g -ter m st u d y a n d deleted a n y 
i nstr ucti o ns s pecific f or t his p o p ulati o n t hr o u g h o ut 
t he pr ot oc ol
T he scree ni n g peri o d f or 
t his st u d y is pr ojecte d t o
e n d pri o r t o partici pa nts 
i n St u d y 3 1 0 1 -3 0 1 -0 0 2 
c o m pleti n g Visit 7 , t he 
visit w here t he y c o ul d 
r oll o ver i nt o t his st u d y. 
F or t his rea s o n, t he 
i ncl usi o n of r oll o ver 
partici pa nts fr o m St u d y 
3 1 0 1 - 3 0 1-0 0 2 has bee n 
eli mi nate d
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 0 1
o Secti o n 7. 3. 1
o Secti o n 7. 3. 2
o Secti o n 8. 1. 2
o Secti o n 8. 3
o Secti o n 8. 4
o Secti o n 8. 4. 1
o Secti o n 8. 4. 2. 1
Pr ot oc ol S u m mar y, Key 
Excl usi o n Criteri a
A d de d “re nal” t o t he list of cli nicall y si g nifica nt 
diseases t h at e xcl u de partici pa nts fr o m e nr olli n g i n 
t his st u d y; see 
C orrecti o n t o be 
c o nsiste nt wit h 
Secti o n 4. 4 , E xcl usi o n 
Criteria # 1 4
Secti o n 4. 5. 2 Pr o hi bite d 
Me dicati o ns/ Treat me nts
(all t hree ite ms) a n d 
A d de d C B D oil as a pr o hi bite d 
me dicati o n/treat me nt 3 0 da ys pri or t o Visit 1 f or all 
partici pa nts a n d t hr o u g h o ut t he st u d y f or 
partici pa nts ra n d o mize d t o recei ve at o ge pa nt o nl y
A d d e d M y c o bl oc ® a n d Je uve ua ™
as a pr o hi bite d 
t hera pe utic or c os metic b ot uli n u m t o xi n i njecti o n 
i nt o areas of t he hea d, face, or nec k wit hi n 6 
m o nt hs pri or t o Visit 1 a n d t hr o u g h o ut t he st u d y 
per i o d
A d d e d i njecta ble a nti b o dies bl oc ki n g t he C G R P 
pat h wa y (e g, Ai m o vi g ™, E m galit y ™, Aj o v y ®) as 
pr o hi bite d me dicati o ns/treat me nts wit hi n 6 m o nt hs 
pri or t o Visit 1 a n d t hr o u g h t he st u d y peri o d
T he p ur p ose of listi n g 
t he ad diti o n al pr o hi bite d 
me di cati o ns/treat me nts 
wa s t o pr o vi de a m ore 
i ncl usi ve list t o assist 
in vesti gat ors c o n d ucti n g 
t he st u d y
Secti o n 4. 5. 3 Defi niti o n of 
W o m e n of 
( N o n-)C hil d beari n g 
P ote ntial a n d/ or 
Acce pta ble C o ntrace pti ve 
Met h o ds
A d d e d pr o gest o ge n -o nl y  h or m o nal c o ntrace pti o n 
( wit h i n hi biti o n of o v ulati o n) t hat are oral, 
i njecta ble, or i m pla nta ble as acce pta ble hi g hl y 
effecti ve c o ntrace pti ve met h o ds
S o m e pr o gest o ge n -o nl y 
h or m o nal c o ntrace pti ves
are c o nsi dere d hi g hl y 
effecti ve, t heref ore 
w o me n w h o meet ot her 
st u d y criteria ca n use 
t hese effecti ve 
c o ntrace pti ve a n d 
partici pate i n t his st u d y
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 0 2
Secti o n 9. 1. 4 Assess me nt 
of Ca usalit y
A d de d “ or oral S O C mi grai ne pre ve nti o n 
me dicati o n” t o 1 st a n d 4 t h b ullet.
Clarificati o n ; all o ws f or 
a ge neral safet y 
c o m paris o n bet wee n 
partici pa nts w h o 
recei ve d at o ge pa nt 
vers us S O C mi grai ne 
pre ve nti o n me dicati o n
Secti o n 9. 1. 5 F oll o w -u p of 
A d verse E ve nts a n d 
Seri o us A d verse E ve nts
Re place d “ Ne w or u p date d i nf or mati o n will be 
rec or de d i n t he ori gi nall y c o m plete d e C R F.” w it h 
“Pri or t o d at a b ase l oc k, ne w or u p d ate d 
i nf or mati o n will be rec or de d i n t he ori gi n all y 
c o mplete d e C R F. If t he e ve nt is a n S A E, it will 
als o nee d t o be re p orte d o n t he S A E re p orti n g 
f o r m. P ost d at a b ase l oc k, ne w or u p d ate d S A E 
i nf or mati o n will o nl y be re p orte d o n t he S A E 
re p orti n g f or m.”
Clarificati o n
Secti o n 9. 5 A L T or A S T 
Ele vati o ns
Last para gra p h: re place d “ A E SI F or m” wit h 
“a b n or m al li ver f u ncti o n re p orti n g f or m ”
C orrecti o n
Secti o n 9. 5. 1 P ote ntial 
H y’s La w Cases
Last para gra p h: re place d “ A E SI F or m” wit h 
“a b n or m al li ver f u ncti o n re p orti n g f or m ” a n d 
a d de d “If t he e ve nt is seri o us, ple ase c o m plete t he 
A E SI/ S A E f or m .”
C orrecti o n a n d 
clarificati o n
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 0 3
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 0 4
1 2. 6 Pr ot oc ol A me n d me nt 2 S u m m ar y
Ti tle: A P hase 3, M ultice nter , Ra n d o mize d, O pe n-La bel St u d y  t o E val uate t he Lo n g -Te r m 
Safet y  a n d To lera bilit y of Oral At o ge pa nt f or t he Pre ve nti o n of Mi grai ne i n Partici pa nts Wi t h 
E pis o dic Mi grai ne
Pr ot oc ol 3 1 0 1 - 3 0 2- 0 0 2
Date of A me n d me nt: A pril 2 0 2 0
A m e n d me nt S u m m ar y
T his a me n d me n t i ncl u des c ha n ges ma de t o Pr ot oc ol 3 1 0 1- 3 0 2- 0 0 2 A me n d me nt 1 date d 
1 4 Marc h 2 0 1 9 . 
To  eli mi nate i m me diate p ote ntial hazar ds t o partici pa nts a n d st u d y staff d ue t o t he C O VI D- 1 9 
pa n de mic w hile e ns uri n g partici pa nt safet y  a n d mai ntai ni n g data i nte grit y, t he pr ot oc ol was 
u p date d t o all o w i n vesti gat ors/a p pr o priatel y  desi g nate d st u d y staff t o perf or m Vi sit 1 4, 
Vi sit 1 5/ E T, a n d Visit 1 6/ S F U as re m ote st u d y visits (e g, c o n d ucte d via p h o ne, vi de o 
c o nfere nce) , as f oll o ws:

In vesti gat ors/a p pr o priatel y  desi g nate d st u dy staf f are all o we d t o perf or m Vi sit 1 4 a n d 
Vi sit 1 5/ E T  as re m ote st u d y visits. 

In vesti gat ors/a p pr o priatel y  desi g nate d st u dy staf f s h o ul d c o n d uct Visit 1 6/ S F U Vi sit 
re m otel y f or all partici pa nts i n all cases.

Safet y  assess me nts t o be c o m plete d at re m ote st u d y visits i ncl u de assess me nt of A E s, 
c o nc o mita nt me dicati o ns, pre g na nc y  test results re vie w, a n d t he C-S S R S .
T he pr ot oc ol als o was a me n de d t o:

U p date t he defi niti o n of safet y p o p ulati o n. 

Re m o ve s u b gr o u p a nal ys is b y pri or treat me nt fail ure wit h oral me dicati o ns.
T he ta ble bel o w pr o vi des details relate d t o c o nte nt c ha n ges t hat were ma de i n t he pr ot oc ol, 
a n d a brief rati o nal e f or t hese c ha n ges. Mi n or e dit orial a n d d oc u me nt f or matti n g re visi o ns 
ha ve n ot bee n s u m marize d.
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 0 5
Secti o n
Re visi o n
R ati o n ale
Ta ble 1 Sc he d ule of Visits 
a n d Pr oce d ures;
8. 4. 2. 2 Visits 3 t o 1 4 
( Wee k 4 t o 4 8)
Secti o n 8. 4. 2. 3
Visit 1 5/ Earl y Ter mi nati o n 
( Wee k 5 2)
8. 4. 3. 1 Visit 1 6/ E n d of 
St u d y ( Wee k 5 6) 
C o n d ucte d D uri n g 
I n-Pers o n Visit ( Pri or t o 
t he C O VI D-1 9 Pa n de mic)
Secti o n 8. 4. 3. 1. 1 Visit 1 6/ 
E n d of St u d y ( Wee k 5 6) 
C o n d ucte d Re m otel y ( D ue 
t o t he C O VI D-1 9 
Pa n de mic)
I n vesti gat ors/a p pr o priatel y desi g nate d st u d y staff 
are all o we d t o perf or m Visit 1 4 a n d Visit 1 5/ E T 
Visit as re m ote st u d y visit s (e g, c o n d ucte d via 
p h o ne, vi de o c o nfere nce). 
I n vesti gat ors/a p pr o priatel y desi g nate d st u d y staff 
will perf or m Visit 1 6/ S F U V isit as a re m ote st u d y 
visit (e g, c o n d ucte d via p h o ne, vi de o c o nfere nce).
Ta ble 1 f o ot n otes t, u, v, w were a d de d f or clarit y.
Safet y assess me nts t o be c o m plete d at re m ote st u d y 
visit s i ncl u de assess me nt of A Es, c o nc o mita nt 
me dicati o ns, pre g na nc y test res ults re vie w, a n d t he 
C- S S R S. 
P h y sical e xa mi nati o n, E C G, vital si g n 
meas ure me nts, cli nical la b orat or y deter mi nati o ns, 
a n d P R O m eas ures will n ot be perf or me d at t he 
r e motel y c o n d ucte d visits.
Secti o n 8. 4. 3. 1. 1 Visit 1 6/ E n d of St u d y ( Wee k 5 6) 
C o n d ucte d Re m otel y ( D ue t o t he C O VI D-1 9 
Pa n de mic) a d de d f or clarit y.
T o eli mi nate i m me diate 
p ote ntial hazar ds t o 
partici pa nts a n d st u d y 
staff d ue t o t he 
C O VI D -1 9 pa n de mic 
w hile e ns uri n g 
partici pa nt safet y a n d 
mai ntai ni n g data 
i nte grit y
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

Aller ga n 
Pr ot oc ol 3 1 0 1 -3 0 2 -0 0 2 A me n d me nt 2
1 0 6
Secti o n
Re visi o n
R ati o n ale
A p pr o v al D at e: 2 4- A pr- 2 0 2 0 1 8: 3 2: 1 9 ( G M T)

El e ctr o ni c Si g n at ur e s
U s er
D at e
J u stifi c ati o n
2 4- A pr- 2 0 2 0
1 8: 3 2: 1 5
( G M T)
M a n a g er A p pr o v al