Occipital Nerve Blocks for Acute Treatment of Pediatric Migraine
Phase: PHASE3
Conditions: Chronic Migraine, Headache, Episodic Migraine
Sponsor: Children's Hospital of Philadelphia

S T U D Y P R O T O C O L  
Title:  
Occi pital Ner ve Bl oc ks f or Ac ute Treat me nt of Pe diatric Mi grai ne  
S h ort Title  
Occi pital Bl oc ks f or Ac ute Mi grai ne  
Dr u g or De vi ce 
Na me(s):  
Occi pital Ner ve Bl oc k wit h Li d ocai ne  vs Sali ne I njecti o n after 
Li d ocai ne Crea m r u n -i n 
F D A I N D  
N/ A  
Re g ulat or y S p o ns or:  
Nati o nal I nstit utes of Ne ur ol o gical Dis or ders & Str o ke ( NI N D S)  
eI R B N u m ber  
1 8 -0 1 4 9 3 9
Pr ot oc ol Date:  
A pril 2 0, 2 0 1 8  
A me n d me nt 1 Date:  J ul y 2 3, 2 0 1 8 
A me n d me nt 2 Date: Oct o ber 0 4, 2 0 1 8  
A me n d me nt 3 Date: Marc h 2 5, 2 0 1 9  
A me n d me nt 4 Date: A pril 1 6, 2 0 1 9  
A me n d me nt 5 Date: Ja n u ar y 2 2, 2 0 2 1  
A me n d me nt 6 Date: Oct o ber 1 8 , 2 0 2 1 
A me n d me nt 7 Date: J ul y 2 9, 2 0 2 2  
S p o ns or: NI N D S  
Pri nci p al I n vesti g at or : C hristi na Sz per ka, M D, M S C E 
3 5 0 1 Ci vic Ce nter Bl v d  
C T R B 1 0 0 1 9  
P hila del p hia, P A, 1 9 1 0 4  
P h o ne: 2 1 5 -5 9 0 -1 7 1 9  
E mail: sz per ka @ c h o p.e d u 

  
 
 
 
 
 
 
 
ii 
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
T A B L E O F C O N T E N T S  
T A B L E O F C O N T E N T S  ...................................................................................................................................II 
A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  ................................................................................ I V 
A B S T R A C T  ........................................................................................................................................................ V  
P R O T O C O L S Y N O P SI S  ................................................................................................................................ VI  
T A B L E 1: S C H E D U L E O F S T U D Y P R O C E D U R E S  ................................................................................. I X 
FI G U R E 1: S T U D Y DI A G R A M  ...................................................................................................................... X  
1  
B A C K G R O U N D I N F O R M A TI O N A N D R A TI O N A L E  ....................................................................... 1  
1. 1  
R E L E V A N T L I T E R A T U R E A N D D A T A  ..................................................................................................... 1  
1. 2  
N A M E A N D D E S C RI P TI O N O F IN V E S TI G A TI O N A L P R O D U C T O R IN T E R V E N TI O N  ..................................... 2  
1. 3  
F I N DI N G S F R O M C LI NI C A L S T U DI E S  ..................................................................................................... 2  
1. 4  
S E L E C TI O N O F D R U G S A N D D O S A G E S ................................................................................................... 4  
1. 5  
C O M P LI A N C E S T A T E M E N T  .................................................................................................................... 5  
2  
S T U D Y O B J E C TI V E S  .............................................................................................................................. 5  
2. 1  
P RI M A R Y O BJ E C TI V E S (O R A I M)........................................................................................................... 5  
2. 2  
S E C O N D A R Y O BJ E C TI V E S (O R A I M) ...................................................................................................... 5  
3  
I N V E S TI G A TI O N A L P L A N .................................................................................................................... 6  
3. 1  
G E N E R A L S C H E M A O F S T U D Y D E SI G N  ................................................................................................. 6  
3. 1. 1  
Scree ni n g P h ase  .............................................................................................................................. 6  
3. 1. 2  
St u dy Tre at me nt P h ase  .................................................................................................................... 6  
3. 1. 3  
F oll o w -u p P h ase  ............................................................................................................................. 6  
3. 2  
A L L O C A TI O N T O T R E A T M E N T G R O U P S A N D B LI N DI N G  ........................................................................ 6  
3. 3  
S T U D Y D U R A TI O N , E N R O L L M E N T A N D N U M B E R O F S I T E S ................................................................... 7  
3. 3. 1  
D ur ati o n of St u dy P artici p ati o n  ...................................................................................................... 7  
3. 3. 2  
T ot al N u m ber of St u dy Sites/ T ot al N u m ber of S u bjects Pr ojecte d  .................................................. 7  
3. 4  
S T U D Y P O P U L A TI O N  ............................................................................................................................. 7  
3. 4. 1  
I ncl usi o n Criteri a ............................................................................................................................ 7  
3. 4. 2  
Excl usi o n Criteri a  ........................................................................................................................... 8  
4  
S T U D Y P R O C E D U R E S  ............................................................................................................................ 9  
4. 1  
INI TI A L R E C R UI T M E N T A N D S C R E E NI N G F O R T H E S T U D Y O N T H E P H O N E  ............................................ 9  
4. 2  
S C R E E NI N G  ........................................................................................................................................... 9  
4. 2. 1  
I n-pers o n St u dy Visit  ....................................................................................................................... 9  
4. 3  
S T U D Y T R E A T M E N T P H A S E  ................................................................................................................ 1 0  
4. 3. 1  
I n-pers o n St u dy Visit  ..................................................................................................................... 1 0  
4. 4  
F O L L O W -U P P H A S E  ............................................................................................................................. 1 1  
4. 5  
U N S C H E D U L E D V I SI T S ........................................................................................................................ 1 2  
4. 6  
C O N C O MI T A N T M E DI C A TI O N  ............................................................................................................. 1 2  
4. 7  
R E S C U E M E DI C A TI O N A D MI NI S T R A TI O N  ............................................................................................ 1 2  
4. 8  
S U BJ E C T C O M P L E TI O N / WI T H D R A W A L ............................................................................................... 1 3  
5  
S T U D Y E V A L U A TI O N S A N D M E A S U R E M E N T S  ............................................................................ 1 4  
5. 1  
S C R E E NI N G A N D M O NI T O RI N G E V A L U A TI O N S A N D M E A S U R E M E N T S  ................................................ 1 4  
5. 1. 1  
Me dic al Rec or d Revie w  ................................................................................................................. 1 4  
5. 1. 2  
Me dic al Hist ory  ............................................................................................................................. 1 4  
5. 1. 3  
Vit al Si g ns & P hysic al Ex a m  ........................................................................................................ 1 4  
5. 1. 4  
Pre g n a ncy Testi n g  ......................................................................................................................... 1 4  
5. 1. 5  
Ot her Ev al u ati o ns, Me as ures  ........................................................................................................ 1 5  
5. 2  
E F FI C A C Y E V A L U A TI O N S  ................................................................................................................... 1 6  

 
 
 
 
 
 
 
 
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5. 2. 1  
Di a g n ostic Tests, Sc ales, Me as ures, etc.  ....................................................................................... 1 6  
5. 3  
S A F E T Y E V A L U A TI O N  ......................................................................................................................... 1 6  
6  
S T A TI S TI C A L C O N SI D E R A TI O N S  .................................................................................................... 1 6  
6. 1  
P RI M A R Y E N D P OI N T  ........................................................................................................................... 1 6  
6. 2  
S E C O N D A R Y E N D P OI N T S  .................................................................................................................... 1 6  
6. 3  
S T A TI S TI C A L M E T H O D S ...................................................................................................................... 1 7  
6. 3. 1  
B aseli ne D at a  ................................................................................................................................ 1 7  
6. 3. 2  
Effic acy A n alysis  ........................................................................................................................... 1 7  
6. 3. 3  
S afety A n alysis  .............................................................................................................................. 1 7  
6. 4  
S A M P L E S I Z E A N D P O W E R  .................................................................................................................. 1 7  
7  
S T U D Y M E DI C A TI O N ( S T U D Y D E VI C E O R O T H E R S T U D Y I N T E R V E N TI O N)  .................... 1 8  
7. 1  
D E S C RI P TI O N  ...................................................................................................................................... 1 8  
7. 1. 1  
Dr u g Acc o u nt a bility  ...................................................................................................................... 1 8  
8  
S A F E T Y M A N A G E M E N T  ..................................................................................................................... 1 9  
8. 1  
C LI NI C A L A D V E R S E E V E N T S  .............................................................................................................. 1 9  
8. 2  
A D V E R S E E V E N T R E P O R TI N G  ............................................................................................................. 1 9  
8. 3  
D E FI NI TI O N O F A N A D V E R S E E V E N T  .................................................................................................. 1 9  
8. 4  
D E FI NI TI O N O F A S E RI O U S A D V E R S E E V E N T ( S A E) ........................................................................... 2 0  
8. 4. 1  
Rel ati o ns hi p of S A E t o st u dy dr u g or ot her i nterve nti o n  ............................................................... 2 0  
8. 5  
I R B/I E C N O TI FI C A TI O N O F S A E S A N D O T H E R U N A N TI CI P A T E D P R O B L E M S  ...................................... 2 0  
8. 5. 1  
F oll o w -u p re p ort  ........................................................................................................................... 2 1  
9  
S T U D Y A D MI NI S T R A TI O N  ................................................................................................................. 2 2  
9. 1  
T R E A T M E N T A S SI G N M E N T M E T H O D S ................................................................................................. 2 2  
9. 1. 1  
R a n d o miz ati o n ............................................................................................................................... 2 2  
9. 1. 2  
Bli n di n g  ......................................................................................................................................... 2 2  
9. 1. 3  
U n bli n di n g  .................................................................................................................................... 2 2  
9. 2  
D A T A C O L L E C TI O N A N D M A N A G E M E N T  ............................................................................................ 2 2  
9. 3  
C O N FI D E N TI A LI T Y  .............................................................................................................................. 2 3  
9. 4  
R E G U L A T O R Y A N D E T HI C A L C O N SI D E R A TI O N S .................................................................................. 2 3  
9. 4. 1  
D at a a n d S afety M o nit ori n g Pl a n  ................................................................................................. 2 3  
9. 4. 2  
Risk Assess me nt  ............................................................................................................................. 2 4  
9. 4. 3  
P ote nti al Be n efits of Tri al P artici p ati o n  ....................................................................................... 2 4  
9. 4. 4  
Risk -Be n efit Assess me nt  ................................................................................................................ 2 5  
9. 5  
R E C R UI T M E N T S T R A T E G Y  .................................................................................................................. 2 5  
9. 6  
IN F O R M E D C O N S E N T / AS S E N T A N D HI P A A  A U T H O RI Z A TI O N  ............................................................ 2 6  
9. 7  
P A Y M E N T T O S U BJ E C T S / FA MI LI E S  ..................................................................................................... 2 6  
9. 7. 1  
Rei m b urse me nt f or tr avel, p arki n g a n d me als  .............................................................................. 2 6  
9. 7. 2  
P ay me nts t o p are nt f or ti me a n d i nc o nve nie nce (i.e. c o m pe ns ati o n)  ............................................ 2 6  
9. 7. 3  
P ay me nts t o s u bject f or ti me, eff ort a n d i nc o nve nie nce (i.e. c o m pe ns ati o n)  ................................. 2 6  
9. 7. 4  
Gifts  ............................................................................................................................................... 2 6  
1 0  
P U B LI C A TI O N  ........................................................................................................................................ 2 6  
1 1  
R E F E R E N C E S  ......................................................................................................................................... 2 6  
 
 

  
 
 
 
 
 
 
 
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Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
C  
 
De grees ce nti gra de  
A E  
 
A d verse e ve nt  
G O N  
 
Greater Occi pital Ner ve  
C H O P  
 
C hil dre n’s H os pital of P hila del p hia  
V A S  
 
Vis ual A nal o g Scale  
P N B  
 
Peri p heral N er ve Bl oc ks  
I V 
 
I ntr a ve n o us 
A T N  
 
A uric ul ote m p oral N er ve   
S T N  
 
S u pratr oc hlear  Ner ve  
S O N  
 
S u pra or bital  Ner ve  
L O N  
 
Lesser O cci pital Ner ve  
Pe d MI D A S  
 
Pe diatric Mi grai ne Disa bilit y Assess me nt  
P R O MI S  
 
Patie nt -Re p orte d O utc o mes Meas ure m e nt I nf or mati o n 
S yste m  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
v  
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
A B S T R A C T  
C o nte xt :  
Mi grai ne is a c o m m o n  a n d disa bli n g hea dac h e dis or der i n c hil dre n  a n d a d olesce nts , yet fe w 
treat me nt o pti o ns are a vaila ble, a n d t hese are oft e n i neffecti ve.  M ore i n vasi ve treat me nts 
s uc h as ner ve bl oc ks c o ul d be hel pf ul,  b ut m ust be teste d wit h a trial desi g n w hic h  a d dress es 
k n o w n c halle n ges . 
O bjecti ves :  
1.  T o test t he eff ic ac y of li d ocai ne vs sali ne greater occi pital ner ve ( G O N) i njecti o ns t o 
treat pe diatric ac ute mi gr ai ne.  
2.  T o test w het her li d ocai n e crea m lea ds t o s uccessf ul bli n di n g of i njecte d me dicati o n . 
3.  T o c haracteri ze h o w  p ercei ve d treat me nt affects e x pectati o n of be n efit, a n d h o w 
e x pectati o n affects c ha n g e i n pai n sc ore.  
St u d y Desi g n : Ra n d o mize d c o ntr olle d trial  
Setti n g/ Partici pa nts:  U p t o 9 7 s u bjects , a ges 7 t o 2 1 , will be recr ui te d fr o m C H O P 
Ne ur ol o g y , E mer ge nc y De part me nt a n d referrals .  P atie nts wit h a dia g n osis of e pis o dic or 
c hr o nic mi grai ne w h o re q uire escalati o n of care f or ac ute hea dac he flare (lasti n g u p  t o 3 
m o nt hs  a n d u nres p o nsi ve t o ac ute  me dicati o ns ) will later be offere d a n o ut p atie nt st u d y visit  
(if eli gi ble). O n e p are nt or g uar dia n p er c hil d/a d ol esce nt will als o be e nr olle d i n t he st u d y.  
St u d y I nter v e nti o ns a n d Meas ures :  
L i d ocai ne crea m will be a p plie d o ver s u bjects’ bilateral greater occi pital ner ve s ( G O N).  
After a b o ut 3 0 mi n utes, s u bjec ts w h o c o nti n ue t o ha ve si g nifica nt hea dac h e will pr ocee d t o 
ra n d o mize d, bli n de d i njecti o ns o f li d ocai ne or sali ne o ver t he bilateral G O N.  T he pri mar y 
o utc o me will be differe n ce i n mea n c ha n ge i n p ai n sc ore ( pre - t o ~ 3 0  mi n utes p ost -
i njecti o n) bet wee n i njecti o n gr o u ps.   
 
 
 

  
 
 
 
 
 
 
 
vi  
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
P R O T O C O L S Y N O P SI S  
St u d y Titl e  
Occi pital Ner ve Bl oc ks f or Ac ute Treat me nt of Pe diatric Mi grai ne  
F u n d er  
NI N D S  
Cli ni c al P h a s e  
P hase 3  
St u d y R ati o n al e  
•  Mi grai ne affects 1 0 -2 8 % of c hil dre n a n d a d olesce nts, yet 2 0 -3 0 % 
of patie nts are i n effecti vel y treate d wit h c ur re nt or al a n d nasal 
o pti o ns .   
•  Peri p heral ner ve bl oc ks ( P N Bs), i njecti o ns of l ocal a nest hetics 
o ver bra n c hes of t h e occi pital a n d/ or tri ge mi nal ner ves, ha ve b ee n 
ass ociate d wit h p ossi ble be nefit f or p e diatric hea d ac hes i n c ase 
series, a n d ma y be usef ul f or b ot h ac ute a n d pre v e nti ve treat me nt 
of mi grai ne f or c hil dre n w h o fa il less i n vasi ve treat me nts.  P NBs 
are use d b y 8 0 % of pe di atric hea dac he s p ecialists  a n d carr y l o w 
ris k of seri o us si de effects, b ut ha ve ne ver bee n f or mall y teste d i n 
a ra n d o mize d p e diatric trial.  
•  T here are t w o s u bsta ntial h ur dles w hic h m ust be o verc o me i n 
desi g ni n g a trial t o test t he effi cac y of P N Bs –  hi g h place b o 
res p o nse rate a n d p ossi bl e u n bli n di n g.  
•  I n or der t o test t he efficac y of t his c o m m o nl y use d treat me nt f or 
c hil dre n a n d a d ol esce nts wit h diffic ult -t o-treat hea dac he, we nee d 
utilize a trial desi g n w hic h will a d dress t he h i g h place b o res p o nse 
rate a n d t he p ot e ntial lac k of bli n di n g. 
•  T his st u d y will e xa mi ne t he effi cac y of t he m ost c o m m o nl y use d 
P N B, greater o cci pital ner ve ( G O N) bl oc ks, as a n ac ute treat me nt 
f or pe diatric mi gr ai ne usi n g a r u n-i n st u d y desi g n, starti n g wit h 
li d ocai ne crea m a n d pr ocee di n g t o ra n d o mize d i nj ecti o n o nl y f or 
s u bjects w h o are n ot pai n free.  Li d o cai ne crea m is a n a p pr o pri ate 
r u n-i n ste p beca use it is n o n-i n vasi ve, has s o me e vi de nce of 
effic ac y as a hea d ac h e tr eat me n t, a n d ca uses s u perficial n u m b ness 
w hic h s h o ul d facilitate bli n di n g t o t he i njecti o n me dicati o n . 
St u d y O bj e cti v e( s ) 
Pri m ar y   
•  
T o test t he efficac y of li d ocai ne vs sali ne G O N i njecti o ns t o 
treat pe diatric ac ute mi gr ai ne.  
Sec o n d ar y  
•  
T o test w het her li d ocai n e crea m lea ds t o s uccessf ul bli n di n g of 
sali ne vers us li d ocai ne i njecti o n 
•  
T o c haracteri ze h o w percei ve d treat me nt affects e x pectati o n of 
be nefit, a n d h o w e x pect ati o n affects c h a n ge i n pai n sc ore.  
 
T e st Arti cl e( s ) 
Occi pital ner ve bl oc k perf or me d wit h 2 % li d ocai n e  

 
 
 
 
 
 
 
 
 
 
vii  
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
 
St u d y D e si g n  
 
Ra n d o mize d, d o u ble -bli n d greater occi pital ner ve i njecti o n of 
li d ocai ne vers us sali ne after o pe n-la bel li d ocai ne crea m r u n-i n 
S u bj e ct P o p ul ati o n  
k e y crit eri a f or 
I n cl u si o n a n d 
E x cl u si o n:  
I ncl usi o n Criteri a 
  C hil dre ns/ a d olesce nts  
1.  S u bjects , a ges 7 - 2 1 , a ny ge n der, race, or et h nicit y  
2.  Dia g n osis of e pis o dic or c hr o nic mi grai ne  wit h a n ac ute 
hea dac he flare lasti n g u p  t o 3 m o nt hs  a n d u nres p o nsi ve t o 
me dicati o ns  
3.  I nf or me d pare ntal c o nse nt a n d s u bject asse nt 
  P are nts or G u ar di a ns  
1.  Pare nts or g uar di a ns of c hil dre n e nr olle d, w h o s pea k eit her 
E n glis h or S pa nis h, a n d pr o vi de pare ntal/ g uar dia n 
per missi o n (i nf or me d c o nse nt) f or t heir p artici pati o n  
2.  S u bject (c hil d) asse nt  
E xcl usi o n Criteri a  
  C hil dre ns/ a d olesce nt  
1.  S u bjects w h o ha ve pre vi o usl y recei ve d a ner ve bl oc k  less 
t ha n 3 m o nt hs a g o or m ore t ha n 2 pre vi o us ner ve bl oc ks 
2.  Aller g y t o l ocal a nest h etics  
3.  S k ull defect  
  P are nts or G u ar di a ns  
1.  Pare nts or g uar di a ns of c hil dre n e nr olle d w h o d o n ot s pea k 
E n glis h or S pa nis h  
2.  Pare ntal/ g uar dia n per missi o n a n d/ or s u bject (c hil d) asse nt 
has bee n decli ne d  
3.  Pare nts/ g uar dia ns, w h o i n t he o pi ni o n of t he i n vesti gat or, 
ma y be n o n -c o m plia nt or u na ble t o c o m plete t he 
q uesti o n naires  
N u m b er Of S u bj e ct s  
 
A ntici pati n g t hat u p t o 4 2 % of s u bjects will res p o n d t o t he li d ocai ne 
crea m r u n-i n, i n or der t o ac hie ve t h e g oal of 2 9 s u bjects per 
i njecti o n ar m w h o recei v e t he ra n d o mize d ner ve bl oc k i nter ve nti o n , 
u p t o 9 7 s u bjects will be e nr olle d i n t he st u d y.  O n e par e nt or 
g uar dia n per c hil d/a d oles ce nt will als o be e nr olle d i n t he st u d y. T his 
will be a si n gle site st u d y at C H O P.  
St u d y D ur ati o n  
Eac h s u bject’s p artici pati o n will last 2 9 da ys.  
T he e n tire st u d y is e x pecte d t o last 3. 5 years. 
St u d y P h a s e s  
 

 
 
 
 
 
 
 
 
 
 
viii  
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
S cr e e ni n g  
 
 
St u d y Tr e at m e nt  
F oll o w -U p   
( 1) Scree ni n g: I nitial scree ni n g will be d o ne o n t he p h o ne  (aft er 
o btai ni n g ver bal c o nse nt) , w hic h will be as s o o n as p ossi ble .  
Eli gi bilit y criteria will be f urt her c o nfir me d a n d c o nse nt 
o btai ne d at t he i n-pers o n st u d y visit. 
( 2) I nter ve nti o n: St u d y visit will be d o ne o n a si n gle da y. 
( 3) F oll o w -u p will be via te xt messa gi n g/ p h o ne call f or a n 
a d diti o nal 2 8 da ys.   
Effi c a c y E v al u ati o n s  
T he st u d y is p o were d t o detect a  2 -p oi nt differe nce i n t he mea n 
c ha n ge i n pai n sc ore (i m me diatel y pre - t o ~ 3 0 mi n utes  p ost -
i njecti o n) bet wee n t h e li d ocai ne a n d s ali ne i njecti o n gr o u ps. 
S af et y E v al u ati o n s  
Li d ocai ne a n d s ali ne are b ot h wi del y use d me dicati o ns f or i njecti o n.  
Se veral case  series of i nj ecti o n pr oce d ures f or hea dac he i n c hil dr e n 
a n d a d ults ha ve bee n p u blis he d, a n d n o ne ha ve re p orte d seri o us 
a d verse e ve nts ( S A Es).  H o we ver, mi n or si de effects i ncl u di n g 
i njecti o n-relate d p ai n are a si g nifica nt c o ncer n f or c hil dre n a n d 
a d olescents, s o t hese will be rec or de d.  
St ati sti c al A n d 
A n al yti c Pl a n  
T he a vera ge dr o p i n pai n sc ore i n o ur retr os pecti ve st u d y of ner ve 
bl oc ks i n c hil dre n wit h ac ute flare of b ot h e pis o di c a n d c hr o ni c 
mi grai ne was 4 p oi nts ( pre - t o p ost-i njecti o n, o n a n u meric 0-1 0 
scale).   Gi v e n t hat t he mi ni mal cli nicall y si g nifica nt c ha n ge i n pai n 
sc ore acr oss m ulti ple c hr o nic pai n c o n diti o ns is 2 p oi nts[ 4 0], we 
will esti mate t hat t he sali ne i njecti o n gr o u p will dr o p a n a vera ge of 
4 -2 = 2 p oi nts.  Ass u mi n g t hat li d ocai ne i nje cti o ns lea d t o a mea n 
c ha n ge of 4 p oi nts, a n d sali ne i njecti o ns lea d t o a mea n c ha n g e of 2 
p oi nts, wit h a sta n dar d de viati o n of 2. 7, wit h α = 0. 0 5 a n d β = 0. 8, we 
will nee d t o 2 9 s u bjects per i njecti o n ar m t o de m o nstrate efficac y 
usi n g a n u n paire d t -test. 
D A T A A N D S A F E T Y 
M O NI T O RI N G P L A N  
A n I n de pe n d e nt Me dical M o nit or  will re vie w e nr oll me nt, pr ot oc ol 
de viati o ns, a n d a d verse e ve nts a b o ut e ver y 6 m o nt hs, a n d as nee d e d 
if a n y seri o us a d v erse e v e nts ( S A Es) occ ur.  T hes e will als o be 
re p orte d t o t he C H O P I R B per us ual pr ot oc ol.  

 
i x  
 
 
 
 
 
 
 
Pr ot o c ol Versi o n 5 : 04 .1 6 . 2 0 1 8 
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
T A B L E 1: S C H E D U L E O F S T U D Y P R O C E D U R E S  
St u d y P h ase  
Scree ni n g ( Tele p h o ne)  
Scree ni n g/I nter ve nti o n  
F oll o w -u p  
Visit N u m ber  
 
1  
 
 
 
St u d y D a ys  
~ -3  
0  
1 - 6  
7  
8 - 2 8  
I nf or me d C o nse nt / Asse nt  ( Mai n St u d y) 
 
X  
 
 
 
I nf or me d C o nse nt ( Scree ni n g) 
X  
 
 
 
 
Re vie w I ncl usi o n  / E xcl usi o n Criteria  
X  
X  
 
 
 
De m o gra p hics  / Me dical Hist or y  
X  
X  
 
 
 
P h ysical E xa mi nati o n  
 
X  
 
 
 
Ne ur ol o gical E xa mi nati o n (i ncl u di n g a f u n d osc o pic e xa m)  
 
X  
 
 
 
Vital Si g ns: B P, H R  
 
X  
 
 
 
Hei g ht,  Wei g ht , Hea d Circ u mfere nce  
 
X  
 
 
 
Pre g na nc y Test  
 
X  
 
 
 
Pri or/ C o nc o mita nt Me dicati o ns  
 
X  
 
 
 
St u d y I nter ve nti o ns:  
Li d ocai ne Crea m a n d Ra n d o mize d Ner ve Bl oc k I njecti o ns  
 
X  
 
 
 
A d verse E ve nt  Assess me nt  
 
X  
X  
X  
X  
Hea dac he Diar y ( pai n, na usea, p h ot o p h o bia, etc)  
 
 
X  
X  
X  
Pe d MI D A S  
 
X  
 
 
X 1 
P R O MI S Pai n I nterfere nce  
 
X  
 
X  
X 1 
Patie nt Gl o bal I m pressi o n of C ha n ge  
 
X  
X  
 
X  
 
 
1 Da y 2 8 o nl y  

pa ge x  
 
 
 
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
FI G U R E 1: S T U D Y DI A G R A M 2  
Li d o c ai n e 
Cr e a m
P ai n fr e e i n 
3 0 mi n or d e cli n e 
f urt h er 
i nt er v e nti o n s ?
R
C h a n g e i n 
p ai n s c or e 
at 3 0 mi n
C h a n g e i n 
p ai n s c or e at 
3 0 mi n
Li d o c ai n e G O N 
i nj e cti o n
S ali n e G O N 
i nj e cti o n 
N o
N o f urt h er 
i nt er v e nti o n
Y e s ( e sti m at e 4 2 %)
Pri m ar y o ut c o m e:
P ati e nt f e el 
b ett er ?
P ati e nt f e el 
b ett er ?
N o f urt h er 
i nt er v e nti o n
A d diti o n al tr e at m e nt 
p er u s u al c ar e 
( cir c u mf er e nti al 
n er v e bl o c k s, I V 
m e di c ati o n s, et c)
N o
N o f urt h er 
i nt er v e nti o n
N o
Y e s
Y e s
 
 
 
 
 
2 T he ra n d o mize d n otati o n 
refers t o s u bjects pr ocee di n g t o recei ve  t he ra n d o mize d ner ve bl oc k i njecti o n.  T his d oes n ot re prese nt t he act of carr yi n g o ut t he 
Ra n d o mizati o n ste p i n Re d Ca p.  T his o perati o n ta kes place i m me diatel y after t he st u d y tea m has o btai ne d i nf or me d c o nse nt f or t he Mai n St u d y.  

 
  
 
 
 
1  
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
1  
B A C K G R O U N D I N F O R M A TI O N A N D R A TI O N A L E  
1. 1  
Rele v a nt Liter at ure a n d D at a  
Mi gr ai ne Prev ale n ce & Dis a bility  
Mi grai ne is t he sec o n d  le a di n g ca use of disa bilit y w orl d wi de acc or di n g t o t he Gl o bal B ur de n 
of Disease St u d y 2 0 1 6 [1 ].  T he pre vale nce of mi grai ne wit hi n t he pe diatric p o p ulati o n is a 
f u ncti o n of a ge, i ncreasi n g fr o m 1 0. 6 % of c hil dre n a ges 5-1 5 years t o 2 8 % of a d olesce nts a ges 
1 5 -1 9 [2 , 3 ].  C hil dre n wit h mi grai ne miss m ore s c h o ol t ha n t heir p eers[4 ], a n d ha ve i m paire d 
q ualit y of life, si milar t o t hat of c hil dre n wit h r he u mat oi d art hritis or ca ncer [5 ].  I n a d diti o n t o 
t he pr o ble ms of disa bilit y i n c hil d h o o d, u p t o t hr ee-q uarters of c hil dre n wit h mi grai ne will 
c o nti n ue t o ha ve s y m pt o ms i nt o a d ult h o o d [6 -8 ].  
 
Mi gr ai ne  Tre at me nt & Less o ns fr o m Pri or Tri als  
T o miti gate t his disa bilit y we nee d ac ute treat me nts w hic h ca n st o p hea dac he fl ares, a n d 
pre ve nti ve tr eat me nts w hic h ca n c o ntr ol t he fre q ue nc y a n d s e verit y of hea dac hes.  W hile 
se veral treat me nts h a ve l e vel A e vi de nce of be n efit i n t he ac ute a n d pre v e nti ve treat me nt of 
e pis o dic mi grai ne i n a d ults [9 -1 1 ], e vi de nce is l ac ki n g f or c hil dre n.  T h o u g h t he rate of 
res p o nse t o acti ve t hera p y i n pe diatric a n d a d ult trials has bee n si milar ( 6 0-8 5 %), t he hi g h 
pe diatric place b o gr o u p res p o nse ( 5 0 -6 0 %) ma kes it diffic ult t o pr o ve a si g nifica n t differe n ce 
i n t his a ge gr o u p[1 2 -1 4 ].  A p pr o xi matel y 3 0 ra n d o mize d trials ha ve b ee n perf or me d t o 
e val uate t he effect of ac ute mi grai n e treat me nts i n c hil dre n [1 5 ].  After se veral faile d st u dies 
wit h parallel desi g n, tri pta n st u dies w hic h utilize d cr oss o ver desi g n a n d place b o c halle n g e 
pri or t o ra n d o mizati o n [1 6 -1 8 ] de m o nstrate d a si g nifica nt differe ntial be t wee n place b o a n d 
acti ve treat me nts [1 9 ].  Utilizi n g a r u n-i n treat me nt pri or t o ra n d o mizati o n is a p peali n g beca use 
t hat treat me nt, w het her place b o or acti ve, c o ul d be o n e wit h l o w ris k of si de effects, t h us 
e x p osi n g c hil dre n/a d oles ce nts t o t he hi g her ris k e x peri me ntal treat me nt o nl y if nee de d.  Ta ke n 
t o get her, a n i de al trial desi g n w o ul d e na ble de m o nstrati o n of be nefit i n t h ose wit h diffic ult-
t o-treat h ea dac he, a n d w o ul d als o utilize l o w er ris k i nter ve nti o ns f or t h os e w h o are easil y 
treate d.     
 
Nerve bl ocks  
Peri p heral ner ve bl oc ks ( P N Bs), i n w hic h l ocal a nest hetic me dicati o ns are i njecte d o ver 
bra nc hes of t he occi pital a n d tri ge mi nal ner ves, m a y be effecti ve i n refract or y hea dac he [2 0 ].   
Retr os pecti ve, u nc o ntr oll e d pe diatric case s eries h a ve descri be d be n efit fr o m P N Bs as b ot h 
ac ute a n d pre ve nti ve treat me nt f or c hr o nic mi g rai n e a n d p ost-tra u matic hea d ac he[2 1 -2 3 ].  O ur 
o w n retr os pective st u dy of nerve bl ocks, i n w hic h i njecti o ns were t ail ore d t o t he i n divi d u al 
res p o nse of te e n a gers wit h he a d ac hes u nres p o nsi ve t o pri or tr e at me nts, f o u n d t h at 8 6 % of 
t h ose wit h ac ute he a d ac he fl are h a d at le ast tr a nsie nt i m pr ove me nt i n p ai n severity [2 4 ].  
Des pite t he lac k of c o ntr olle d trials, ner ve bl oc ks are use d c o m m o nl y a m o n g pe diatric 
hea dac he s pecialists.  O ur rece nt s ur ve y of t he Pe diatric & A d oles ce nt Secti o n of t he 
A merica n H ea d ac he S ociet y f o u n d t hat 8 0 % of res p o n de nts eit her perf or m or refer patie nts 
f or P N Bs[2 5 ].  C o nsiste nt wit h t he varia bilit y de m o nstrate d i n a d ult hea d ac he care[2 6 ], P N Bs 
are use d f or m ulti ple differe nt hea d ac he c o n diti o ns i n c hil dre n, a n d t here is wi de varia bilit y 
i n t he me dicati o n use d, site(s) i njecte d, a n d use of re peate d i njecti o ns[1 2 ].  Res p o n de nts 
e x presse d i nterest i n c o n d ucti n g a m ulti -site trial t o deter mi ne efficac y a n d clarif y i njecti o n 
tec h ni q ue.  T h e st u dies i n t his pr o p osal will utilize t he r u n-i n d esi g n whic h was effecti ve f or 
tri pta n st u dies t o st u d y ner ve bl o c ks.   O ur pri mar y o bjecti ve is t o d eter mi ne t he efficac y of 
occi pital ner ve bl o c ks f or t he treat me nt of ac ute mi grai ne u nres p o nsi ve t o pri or t hera pies.    
 
Bli n di n g  

 
  
 
 
 
2  
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
Sali ne i njecti o ns will be use d as t he c o m parat or t o li d ocai ne i njecti o ns i n t his st u d y.  H o we ver, 
li d ocai ne i njecti o ns ca use i m me diate pai n f oll o we d b y l ocal n u m b ness, w hereas sali ne 
i njecti o ns d o n ot ca use l o cal n u m b ness.  T his differe nce ma y ha v e ca use d u n bli n di n g i n s o me 
of t he a d ult  ner ve bl oc k trials, w hic h c o ul d e x plai n t heir c o ntra dict or y o utc o mes [2 7 -3 0 ].  
L ocal a nest hetic crea m s h o ul d mai ntai n bli n di n g , si nce t hese crea ms ca us e l ocal n u m b ness, 
a n d o ne has bee n s h o w n t o decrease t he pai n of l u m bar p u nct ur e [3 1 ]. Ba n g’s bli n di n g i n de x 
will be use d beca use it p er mits assess me nt of bli n di n g of eac h treat me nt ar m se paratel y [3 2 ]. 
A sec o n dar y o bjecti ve is t o assess w het her li d ocai ne crea m ca n bli n d s u bjects t o li d ocai ne 
vers us sali ne i njecti o n . 
 
S u bject c h ar acteristics w hic h affect pl ace b o gr o u p res p o nse  
I n pla n ni n g f ut ure trials of ner ve bl oc ks a n d ot her treat me nts, it will be hel pf ul t o k n o w patie nt 
c haracteristics w hi c h pre dict res p o nse.  P ost -h o c a nal yses of d ata fr o m efficac y tri als i n 
pe diatric mi gr ai n e ha v e s h o w n t hat c haract eristics s uc h as a ge, s e x, a n d nat ural hist or y of 
disease d o n ot c o nsist e ntl y affect res p o ns e t o treat me nt[ 5, 1 2 -1 5].  Ne ur o be h a vi oral 
c haracteristics s uc h as e x pectati o n of b e nefit ma y pla y a r ole.  A st u d y of c orrectl y a n d 
i ncorrectl y la bele d rizatri pta n a n d place b o f or ac ut e mi grai ne treat me nt i n a d ults de m o nstrate d 
differe ntial p ai n free d o m res p o nse t o ri zatri pta n b ut n ot place b o b ase d o n l a beli n g, i n dicati n g 
i m p orta nce of b ot h treat me nt a n d e x pect ati o n of be nefit[3 3 ].  I n c o ntrast, scri pte d la n g ua g e 
desi g ne d t o alter e x p ectati o n of be nefit di d n ot i nfl ue nce res p o nse t o i ntra ve n o us sali ne  i n 
c hil dre n wit h mi grai n e i n t he e mer ge n c y de p art me nt [3 4 ].   W e will meas ure e x p ectati o n of 
be nefit usi n g a m o difie d versi o n of t he Sta nf or d E x pectati o ns of Treat me nt Scale, a 6 -ite m 
scale 
me as uri n g p ositi ve a n d n e gati ve tr eat me nt e x pecta ncies[3 5 ]. T o acc o m plis h o ur 
sec o n dar y obje cti ves, w e will e xa mi ne h o w e x pectati o n is affecte d b y percei ve d treat me nt, 
a n d h o w it i nfl ue nces o ut c o me i n pe diatric a n d a d olesce nt ac ut e mi grai ne.   
 
I n c o n cl usi o n, i n t hese st u dies we will test t he efficac y of occi pital ner ve b l oc ks utilizi n g a 
r u n-i n desi g n.  We will si m ulta ne o usl y test w het her li d ocai ne crea m will bli n d s u bjects t o 
i njecte d me dicati o n, a n d e xa mi ne t he rel ati o ns hi p bet wee n percei ve d treat me nt , e x pectati o n, 
a n d o utc o me.  
 
1. 2  N a m e a n d D e s cri pti o n of I n v e sti g ati o n al Pr o d u ct or I nt er v e nti o n 
Ra n d o mize d  Occi pital N er ve Bl oc k wit h i njecti o n of 2 % Li d ocai ne vs Sali ne  
1. 3  Fi n di n g s fr o m Cli ni c al St u di e s  
1. 3. 1. 1  H u m a n P h ar m ac o ki netics  
O nset of Acti o n  of Li d oc ai ne :  
-Crea m 3 -5 mi n utes, wit h rec o m me n de d 3 0 mi n ute a p plicati o n ti me [3 6 , 3 7 ] 
-I njecti o n 1-5  mi n utes [3 6 , 3 8 ] 
D urati o n of Acti o n:  
-Crea m: 6 0 mi n after re m o val [3 7 ] 
-I ntra der mal I nje cti o n: 1 0-2 0 0  mi n utes [3 6 , 3 9 ] 

 
  
 
 
 
3  
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
D ose : T otal a m o u nt of li d ocai ne (c o m bi ne d crea m a n d i njecti o n) use d s h o ul d n o t e xcee d 
4. 5 m g/ k g, ma x 3 0 0 m g [3 6 ] 
1. 3. 1. 2  Cli nic al St u dies i n A d ults  
Ner ve bl oc ks ca n b e use d as  a n ac ut e hea d ac h e  treat me nt, a n d re p eate d ner ve bl oc ks ma y 
als o be use d f or pre v e nti ve hea d ac he tr eat me nt .   Ner ve bl oc ks h a ve b ee n descri be d i n t he 
treat me nt of ma n y h ea dac he t y pes i n a d ults i ncl u di n g Mi grai ne, Cl uster hea dac he, C hr o nic 
Dail y Hea d ac he (i ncl u di n g C hr o nic M i grai ne), He micra nia C o nti n ua, Cer vic o ge nic 
Hea dac he, P ost -Tra u matic Hea d ac h e, P ost -D ural P u nct ure Hea dac h e, a n d Cra nial 
Ne ural gias [3 8 ].  Greater occi pital ner ve i njecti o ns ha ve bee n st u die d m ost c o m m o nl y, b ut 
t he lesser occi pital ner ve a n d se veral bra n c hes of t he tri ge mi nal ner v e (a uric ul ote m p oral, 
s u pra or bital, s u pratr o c hle ar) are s o meti mes i ncl u d ed [2 6 ]. 
1. 3. 1. 3  Cli nic al St u dies i n C hil dre n  
Retr os pecti ve, u nc o ntr oll e d pe diatric case s eries h a ve descri be d be n efit fr o m P N Bs as 
treat me nt f or c hr o nic mi grai ne a n d p ost-tr a u matic hea dac he[2 1 -2 3 ].  O ur o w n retr os pecti ve 
st u d y of ner ve bl oc ks, i n w hic h i njecti o ns were tail ore d t o t he i n di vi d ual res p o nse of 
tee na gers wit h hea d ac hes u nres p o nsi ve t o pri or treat me nts, f o u n d t hat 8 6 % of t h ose wit h 
ac ute hea dac he flare ha d at least tra nsie nt i m pr o ve me nt i n pai n se verit y  [2 4 ].  
B ot h t he literat ure, a n d t he e x peri e nce of t he Hea dac he Pr o gra m cli nicians w h o ha ve 
perf or me d h u n dre ds of n er ve bl oc k pr oce d ures o v er t he past f e w years ha v e de m o nstrate d 
e xcelle nt safet y.  I n o ur retr os pecti ve st u d y, 1 9. 5 % of s u bjects e x p erie nce d mi n or si de 
effects wit h  first ner ve bl oc k[2 4 ].  Si de effects, t y picall y mil d ( gra de 1 a n d gra de 2 ), fall i nt o 
t hree mai n gr o u ps –  pai n, n u m b ness, a n d a n xiet y:  
P ai n : I nje cti o n-relate d disc o mf ort is relati vel y c o m m o n, b ut ver y brief i n d urati o n.  
Cli nicall y , hea da c he cli nicia ns s o meti mes use li d ocai ne crea m or  ice t o tr y t o re d uce 
t his i m me diate disc o mf ort, a n d t hat e x perie n ce c o ntri b ute d t o t he st u d y desi g n here.  
Inje cti o n site di sc o mf ort after t he pr oce d ure  o cc urre d i n ~ 8 % of s u bjects i n o ur 
retr os pecti ve st u d y.  I n m ost cases n o i nter ve nti o n is re q uire d f or t his.  If i nter ve nti o n 
is re q uire d, it is us uall y li mite d t o use of t o pical ice at t he site, a n d/ or use of a n a nti-
i nfla m mat or y me dicati o n s uc h as i b u pr ofe n.  W hile rare patie nts fr o m o ur cli nic ha ve 
bee n h os pitalize d after ner ve bl oc k, t he y h a ve b ee n h os pitalize d f or es calati o n of 
hea dac he treat me nt beca use t he ner ve bl oc k was i neffecti ve  i n pre v e nti n g t he 
h os pitalizati o n , n ot beca use it was ca us ati ve.   
N u m b ness : Ma n y patie nts d o re p ort altere d se ns ori u m, i ncl u di n g feeli n gs of 
n u m b ness.  T his res ol ves wit h ti me.  Ver y rarel y p atie nts w h o are n u m b d e vel o p 
dizzi ness.  I n t hese cases t he patie nts are o bs er ve d u ntil t he y are a ble t o a m b ulate 
safel y. 
A nxiety : Feeli n gs of b ot h a n xiet y a n d gi d di ness are c o m m o n, li kel y relate d t o a n xiet y 
a n d relief fr o m a n xiet y ass oc iate d wit h t he pr oce d ure.  Pa nic attac ks a n d s y nc o pe 
relate d t o pr o ce d ural a n xiet y are ver y rare ( 1 cas e of s y nc o pe i n o ur retr os p ecti ve 
st u d y of 1 2 5 first ner ve bl oc ks[2 4 ]), a n d res ol ve wit h cessati o n of pr oce d ures, ti me, 
a n d reass ura nce.   

 
  
 
 
 
4  
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
Des pite t he lac k of c o ntr olle d trials, ner ve bl oc ks are use d c o m m o nl y a m o n g pe diatric 
hea dac he s pecialists.  O ur rece nt s ur ve y of t h e Pe diatric & A d olesce nt Se cti o n of t he 
A merica n H ea d ac he S oci et y f o u n d t hat 8 0 % of res p o n de nts eit her perf or m or refer patie nts 
f or P N Bs[2 5 ].  H o we ver, healt h i ns ura nce d oes n ot al wa ys c o ver ner ve bl oc ks beca use t h e y 
are c o nsi d ere d e x peri me ntal d ue t o t he a bse nce of c o nt r olle d trials i n c hil dre n a n d 
a d olesce nts.  T he st u d y d escri be d h ere will a d dress t hat ga p of k n o wle d ge.  
1. 4  S el e cti o n of Dr u g s a n d D o s a g e s  
Lea d -i n li d ocai ne 4 % crea m: 
Selecti o n of Dr u g : Li d ocai ne crea m is a n a p pr o pri ate r u n -i n ste p.  It is n o n-i n vasi ve, has 
so me e vi de nce of efficac y as a hea d ac h e treat me n t, a n d ca uses s u p erficial n u m b ness w hic h 
s h o ul d decrease i njecti o n -relate d disc o mf ort a n d facilitate bli n di n g t o t he injecti o n 
me dicati o n .  A s mall st u d y of li d ocai ne crea m as treat me nt f or mi grai ne hea dac h e 
d e m o nstrate d t hat 7 of 3 0 s u bjects ( 2 3 %, 9 5 % CI 9 -4 2 %) were p ai n -free at 2 h o urs[4 0 , 4 1 ], 
a n d li d ocai ne crea m h as bee n use d t o r e d uce t h e p ai n of ner ve bl oc k i njecti o ns [4 2 ].  
Li d ocai ne crea m has a fast o nset of acti o n, ca n b e use d o n hair y s ki n, a n d d oes n ot re q uire 
occl usi o n wit h a n airti g ht dressi n g.   F urt her m ore, li d ocai ne crea m ca uses n u m b ness, w hic h 
s h o ul d mi mic t he l ocal n u m b ness cause d b y li d ocai ne i njecti o n, a n d per mit bli n di n g of 
li d ocai ne vers us sali ne i njecti o n.  I n t his st u d y we will a p pl y t he li d ocai ne crea m o ver t he 
G O N distri b uti o n f or 3 0 mi n utes, w hic h is s ufficie nt ti me t o ac hie ve l ocal n u m b ness a n d 
re d uce t h e disc o mf ort of i njecti o ns.  I n t he PI ’s cli nical e x peri e nce t h at d ur ati o n ca n als o 
re d uce h ea d ac he p ai n, w hereas l o n g er d urati o n of a p plicati o n ca n ca use a b ur ni n g se nsati o n.  
We will use t he li d ocai ne crea m o p e n -la bel t o ma xi mize e x pectati o n of p ai n relief a n d 
n u m b nes s.  Li d ocai ne crea m  is F D A-a p pr o ve d i n c hil dre n > 2 years [3 7 ]. 
D os a ge : 4 c m ri b b o n of crea m = 3 2 m g li d ocai n e  
Ra n d o mize d G O N i njecti o n wit h 2 % li d ocai ne or sali ne:  
Selecti o n of Dr u g :  
-Li d ocai ne 2 %: O ur practice patter n s ur v e y de m o nstrate d  t hat li d ocai ne a n d b u pi vacai ne are 
t he m ost c o m m o nl y use d l ocal a nest hetics i n ner ve bl oc ks perf or me d i n c hil dre n[2 5 , 4 3 ].  
U ntil 2 0 1 4 at C H O P we use d a c o m bi nati o n of b ot h u ntil o ur p har mac y raise d c o ncer ns t hat 
b u pi vacai ne carries a hi g her ris k of ca usi n g L ocal A nest hetic S yste mic T o xicit y.  Si nce t he n, 
o ur retr os pecti ve case series di d n ot de m o nstrate a n y differe n ce i n o utc o me wit h li d ocai ne 
vs li d ocai ne + b u pi vacai ne [2 4 ], s o w e ha ve c o nti n ue d t o use li d ocai ne o nl y.  W hile ma n y 
case series  ha v e als o i ncl u de d c ortic oster oi d [2 1 , 4 4 ], t here was n o clear be nefit t o a d di n g 
c ortic oster oi d t o li d ocai n e + b u pi vacai ne i n c hr o ni c mi grai ne [4 5 ].  F or t h ese reas o ns 
li d ocai ne will be t he acti ve a ge nt. 
-Sali ne: Sali ne i njecti o ns will be use d as a c o m p arat or i n t his trial, rec o g nizi n g t hat t he y ma y 
be place b o or a n acti ve  tr eat me nt.   
 
D os a ge :  
-L i d ocai ne 2 % : will use 2 m L li d ocai ne  o ver eac h ri g ht a n d left Greater Occi pital Ner ve  x 
2 0 m g/ m L = 8 0 m g li d ocai ne  
-S ali ne: will use 2 m L of sali ne o ver eac h ri g ht a n d left Greater Occi pital Ner ve f or bli n de d 
c o m parat or  

 
  
 
 
 
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Selecti o n of I njecti o n Site  
T he cli nical practice i n o ur hea dac he gr o u p has bee n t o tail or i njecti o n sites t o patie nt 
res p o nse, wit h m ost patie nts i n o ur retr os pecti ve st u d y recei vi n g b ot h occi pital a n d 
tri ge mi nal i njecti o ns[2 4 ].  H o we ver, ot her st u dies ha ve de m o nstrat e d efficac y wit h greater 
occi pital ner ve bl o c k al o ne.  Si nce fe wer i njecti o ns are cl earl y less i n vasi ve, a n d w o ul d be 
m ore desira ble if s ufficie nt, we  will  test efficac y of G O N i njecti o ns i n t his st u d y (see 
pict ure s bel o w) .  H o we v er, f or s u bjects w h o d o n ot o btai n s ufficie nt relief fr o m st u d y 
pr oce d ures we will offer a d diti o nal ner ve bl oc ks p er us ual  cli nical pr actice as o ne o pti o n f or 
resc ue tr eat me nt, a n d we will c ollect o bser vati o nal data fr o m t h ose s u bjects. 
 
1. 5  C o m pli a n c e St at e m e nt  
T his st u d y will be c o n d ucte d i n f ull acc or da nce all a p plica ble C hil dre n’s H os pital of 
P hila del p hia Researc h P olicies a n d Pr oce d ures a n d all a p plica ble Fe deral a n d state la ws a n d 
re g ulati o ns i ncl u di n g 4 5 C FR 4 6  a n d 2 1 C F R 5 0, 5 6  , a n d t he HI P A A Pri v ac y R ule. All  
e pis o des of n o nc o m plia n ce will be d oc u me nt e d.  
T he i n vesti gat ors will perf or m t he st u d y i n acc or da nce wit h t his pr ot oc ol, will o btai n 
c o nse nt a n d ass e nt, a n d will re p ort u na ntici pate d pr o ble ms i n v ol vi n g ris ks t o s u bjects or 
ot hers  i n acc or da nce wit h T he C hil dre n’s H os pital of P hila del p hia I R B P olicies a n d 
Pr oce d ures a n d all fe d eral re q uire me nts. C ollecti o n, rec or di n g, a n d re p orti n g of data will be 
acc urate a n d will e ns ure t he pri vac y, h ealt h, a n d welfa re of researc h s u bjects d uri n g a n d 
after t he st u d y.  
2  
S T U D Y O B J E C TI V E S  
T his st u d y will e xa mi ne t he effi cac y of t he m ost c o m m o nl y use d peri p heral ner ve bl oc ks, 
greater occi pital ner ve ( G O N) bl oc ks, as a n ac ute treat me nt f or pe diatric mi grai ne usi n g a 
r u n-i n st u d y desi g n, starti n g wit h li d ocai ne crea m a n d pr ocee di n g t o ra n d o mize d i njecti o n 
o nl y f or s u bjects w h o are n ot pai n free  or nearl y s o .  We will utilize t his desi g n t o test 
w het her li d ocai n e crea m r u n -i n bli n ds s u bjects t o i njecte d me dicati o n, a n d t o st u d y t he 
relati o ns hi p bet wee n p ercei ve d treat me nt, e x pectati o n, a n d o utc o me. 
2. 1  Pri m ar y O bj e cti v e s ( or Ai m)  
T o t est t he effic ac y of li d ocai ne v ers us  s ali ne G O N i njecti o ns t o treat pe di atric ac ut e mi grai ne.  
  
2. 2  S e c o n d ar y O bj e cti v e s ( or Ai m)  
T o test w het her li d ocai ne crea m lea ds t o s uccessf ul bli n di n g of sali ne vers us li d ocai ne 
i njecti o n 
 
T o c haracteri ze h o w p ercei ve d treat me nt affects e x pectati o n of be n efit, a n d h o w e x pect ati o n 
affects c ha n g e i n pai n sc ore.  
 

 
  
 
 
 
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3  
I N V E S TI G A TI O N A L P L A N 
3. 1  G e n er al S c h e m a of St u d y D e si g n  
T he st u d y sc he ma is a r u n -i n desi g n (li d ocai ne crea m) f oll o we d b y d o u ble-bli n d ra n d o mize d 
i njecti o n of acti ve treat me nt (li d ocai ne) v ers us c o m parat or (s ali ne) i n s u bjects w h o c o nti n ue 
t o ha ve si g nifica nt he a dac he aft er r u n -i n. 
3. 1. 1  Scree ni n g P h ase  
P atie nts wit h e pis o dic or c hr o nic mi grai ne w h o co ntac t t he Ne ur ol o g y cli nic re q uesti n g 
escalati o n of care f or ac ute hea dac he fl are refract or y t o h o me treat me nt will be i n vite d b y 
cli nical staff t o recei ve a d diti o nal i nf or mati o n a b o ut t his cli nical trial o pti o n.  S u bjects ma y 
als o be recr uite d fr o m t h e E mer ge n c y De p art me nt. I ntereste d p atie nts will t he n be c o ntacte d 
a n d descri b e d t he st u d y , usi n g t he mai n c o nse nt f or m t o g ui d e t he c o n versati o n.  A me m ber 
of t he st u d y tea m ( via tel e p h o ne) will t he n scree n p ote ntial  fa milies, wit h a c o nti n ue d 
i nterest.  Scree ni n g will n ot  occ ur  u ntil  after o btai ni n g ver bal pare ntal/ g uar dia n i nf or me d 
c o nse nt a n d HI P A A a ut h orizati o n .  I nitial scree ni n g pr oce d ures i ncl u de a me dical c hart 
re vie w a n d q u esti o ns a b o ut healt h hist or y t hat will hel p deter mi ne eli gi bilit y base d o n 
pr ot oc ol i ncl usi o n / e xcl usi o n criteria.  T h ose w h o are i ntereste d  will be offere d a st u d y visit 
as s o o n as p ossi bl e.  P atie nts w h o decli ne partici p ati o n will be directe d bac k t o cli nical care.   
O n t he da y of t he visit , p are ntal/ g uar dia n i nf or me d c o nse nt a n d c hil d asse nt, will be 
o btai ne d pri or t o a n y st u d y relate d pr oce d ures bei n g perf or me d  f or t he mai n st u d y.  P ote n tial 
s u bjects will be f urt her s cree n e d usi n g t he pr ot oc ol i ncl usi o n a n d e xcl usi o n criteria.  
Fe males , w h o ha ve reac h e d me narc he , will ha ve a uri ne pre g n a nc y test. O n e pare nt or 
g uar dia n per c hil d/a d oles ce nt will als o be e nr olle d i n t he st u d y.  
3. 1. 2  St u d y Tre at me nt P h ase  
St u d y treat me nt will i n v ol ve t w o ste ps:  
-li d ocai ne crea m r u n-i n f or all s u bjects 
-s u bjects w h o are n ot pai n free or s uffici e ntl y i m pr o ve d t hat t he y decli ne f urt her pr oce d ures 
will recei ve ra n d o mize d i njecti o n of li d ocai ne or s ali ne o ver t he Great er Occi pital Ner ves.    
S u bjects w h o re p ort i ns ufficie nt i m pr o ve me nt ( per t heir deter mi nati o n) ~ 3 0 mi n utes after 
G O N i njecti o ns  will be offere d a d diti o nal treat me nts per us ual cli nical care, o utsi de t he 
st u d y, b ut t heir i m me diate o utc o mes a n d f oll o w-u p da ta will be rec or de d. 
3. 1. 3  F oll o w -u p P h ase  
T he f oll o w -u p p has e will c o nti n ue f or 2 8 da ys.   
3. 2  All o c ati o n t o Tr e at m e nt Gr o u p s a n d Bli n di n g  
Li d ocai ne crea m lea d -i n will be use d o pe n-la bel f or all s u bjects. 
I nje cti o n me dicati o n (li d ocai ne vers us sali ne) - R a n d o mizati o n will be d o ne usi n g R E D Ca p, 
stratifie d base d o n dia g n osis of e pis o dic vers us c hr o nic mi grai ne.  T he i n v esti gat or w h o 

 
  
 
 
 
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perf or ms t he i nje cti o n a n d t he s u bject will be bli n de d t o me dicati o n.  T he st u d y tea m will 
use researc h p h ar mac y (I D S) t o dis pe nse i njecta bl e me dicati o ns.  Researc h p har mac y (I D S) 
will be u n bli n de d i n or der t o ma na ge a n d pre p are t he ra n d o mize d i njecta ble me dicati o ns.   
3. 3  St u d y D ur ati o n, E nr oll m e nt a n d N u m b er of Sit e s  
3. 3. 1  D ur ati o n of St u d y P artici p ati o n  
T he st u d y d urati o n per s u bject will be u p t o 2 9 da ys, wit h a si n gle visit f or scree ni n g, 
e nr oll me nt, a n d st u d y pr oce d ures, a n d 2 8 da ys f oll o w -u p.  
3. 3. 2  T ot al N u m ber of St u d y Sites/ T ot al N u m ber of S u bjects Pr ojecte d  
T he st u d y will be c o n d ucte d  o nl y at t he C hil dre n’s H os pital of P hila del p hia.  Per disc ussi o n 
wit h researc h p har mac y i n Se pte m ber of 2 0 1 6, beca use all of t h e me dicati o ns (li d ocai ne 
crea m, i nje cta ble li d ocai ne, sali ne) are alrea d y st ore d i n ne ur ol o g y cli nic a n d use d cli nicall y, 
n o I N D wil l be re q uire d a n d t he st u d y me dicati o ns d o  n ot necessaril y nee d t o be dis pe nse d 
b y researc h p har mac y.  H o we ver, t he st u d y tea m will be usi n g researc h p har mac y (I D S) a n d 
w e d o n ot e x pect t his t o li mit e nr oll me nt t o o ur mai n ca m p us. 
Recr uit me nt will st o p w he n a p pr o xi matel y 5 8  su bj ects ha ve recei ve d t he ra n d o mize d t o 
li d ocai ne vers us sali ne i njecti o n.  It is e x p ecte d t h at a p pr o xi matel y 9 7 pri m ar y c hil d s u bjects 
will be e nr olle d t o pr o d u ce 5 8 e v al ua ble s u bjects  f or t he pri mar y o bj ecti ve (t h o u g h data 
fr o m all e nr olle d s u bjects will be use d f or ot her o bjecti ves). 9 7 pare nt/ g uar dia n s u bjects, o ne 
per c hil d/a d olesce nt , will als o be e nr olle d i n t he st u d y.  
3. 4  St u d y P o p ul ati o n  
3. 4. 1  I ncl usi o n Criteri a 
C hil dre n/ A d olesce nts  
1)  Males o r fe males, a g e s 7 - 2 1 , of a n y ge n d er, race, or et h nicit y.   
2)  Dia g n osis of e pis o dic or c hr o nic mi grai n e wit h ac ute hea dac he flare lasti n g u p  t o 3 
m o nt hs  u nres p o nsi ve t o ac ute me dicati o ns.   Patie nts w h o re p ort t hat ac ut e me dicati o ns were 
n ot use d d uri n g t his hea dac he fl are b ec a use t h ose me dicati o n s ha ve bee n i n effecti ve f or 
se veral pri or hea d ac h e fl ares will be i ncl u de d. 
3)  I nf or me d p are nt al c o nse nt a n d s u bject asse nt.   
4)  Girls w h o ha ve reac he d me narc h e m ust ha ve a ne gati ve uri ne/ser u m pre g na nc y test  
beca use li d ocai ne is Pre g na nc y Class B.  
5)  Wei g ht > 2 5 k g  
 
T o ma xi mize a p plica bilit y of t he res ults, we will i ncl u de a n y pat ie nts a g es 7 t hr o u g h 2 1 , as 
l o n g as t he c hil d is ol d e n o u g h t o u n dersta n d t he st u d y a n d pr o vi de ass e nt.  Base d o n cli nical 
e x perie n ce, it is rare f or a c hil d y o u n ger t ha n 1 1 years t o asse nt t o i njecti o ns.  H o we ver, 
t here is n o i n here nt s afet y c o ncer n bel o w a s p ecifi c a ge, a n d n o reas o n t o specificall y 
e xcl u de c hil dre n if t he y are willi n g t o u n der g o t he pr oce d ure a n d u n d ersta n d t he st u d y well 
e n o u g h t o gi ve asse nt .   
 

 
  
 
 
 
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P are nts  or G u ar di a ns  
1) Pare nts or g uar dia ns of c hil dre n e nr olle d, w h o s pea k eit her E n glis h or S pa nis h, a n d 
pr o vi de pare ntal/ g uar dia n per missi o n (i nf or me d c o nse nt)  f or t heir p artici pati o n 
2)  S u bject (c hil d) asse nt  
 
3. 4. 2  E xcl usi o n Criteri a  
C hil dre n/ A d olesce nts  
1)  Pre vi o us ner ve bl oc k  less t ha n 3 m o nt hs a g o or m ore t ha n 2 pre vi o us ner ve bl oc ks 
2)  Aller g y t o l ocal a nest h etics  
3)  S k ull defect  or brea k i n t he s ki n at t he pla n ne d sit e of crea m a p plicati o n or G O N 
i njecti o n 
4)  A n y i n vesti gati o nal dr u g use wit h i n 3 0 da ys pri or t o e nr oll me nt, or 9 0 da ys pri or t o 
e nr oll me nt f or me dicati o ns tar gete d at Calcit o ni n Ge ne -Rel ate d Pe pti de.  
5)  Pre g na nt or lact ati n g f e m ales.  
6)  Pare nts/ g uar dia ns or s u bj ects w h o, i n t he o pi ni o n of t he I n vesti gat or, ma y be n o n -
c o m plia nt wit h st u d y sc he d ules or pr oce d ures.  
7)  Si g nifica nt a d verse e ve nt wit h pri or i njecti o n or pr oce d ure.  
8)  Ne w a b n or malities o n p h ysical or ne ur ol o gical e xa mi nati o n.  
9)  Ne wl y re p orte d re d fla gs i n hea dac h e hist or y w hic h pr o m pt i n vesti gati o n f or sec o n dar y 
hea dac he.  
1 0)  N o n -E n glis h a n d N o n -S p a nis h s pea ki n g  
1 1)  N o n -E n glis h s pea ki n g wit h n o S pa nis h i nter preter a vaila ble.  T his is u nli kel y si nce 
C H O P I nter preter Ser vic es pr o vi des assista nce wit h researc h visits.  
P are nts  
1)  Pare nts or g uar dia ns of c hil dre n e nr olle d w h o d o n ot s pea k E n glis h or S pa nis h  
2) Pare ntal/ g uar di a n per missi o n a n d/ or s u bject (c hil d) asse nt has bee n d ec li ne d 
3 ) Pare nts/ g uar dia ns, w h o i n t he o pi ni o n of t he i n vesti gat or, ma y be n o n -c o m plia nt or 
u na ble t o c o m plete t he q uesti o n naires  
S u bjects t hat d o n ot meet all of t he e nr oll me nt crit eria ma y n ot be e nr olle d. A n y vi olati o ns 
of t hese criteria m ust be re p orte d i n acc or da nce wit h I R B P olicies a n d Pr oce d ures.  

 
  
 
 
 
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4  
S T U D Y P R O C E D U R E S  
4. 1  I niti al R e cr uit m e nt a n d S cr e e ni n g f or t h e St u d y o n t h e P h o n e  
•  St u d y tea m me m ber pr o vi des a descri pti o n of st u d y t o p ote ntial s u bjects a n d / or 
pare nts  ( Recr uit me nt) 
•  Ver bal I nf or me d C o nse nt f o r Scree ni n g, if still i ntereste d 
•  Scree ni n g Q u esti o ns, i n v ol vi n g me dical hist or y, t o preli mi nar y assess eli gi bilit y 
( base d o n I n cl usi o n/ E xcl usi o n Criteria)  
•  I ntereste d ca n di dates are offere d st u d y visit, c o nti n ge nt o n i nitial c o nfir mati o n of 
eli gi bilit y bas e d o n i n vesti gat or re vie w of i n cl usi o n/e xcl usi o n criteria a n d me dical 
rec or d re vie w 
4. 2  S cr e e ni n g 3   
4. 2. 1  I n-pers o n St u d y Visit  
•  I nf or me d C o nse nt a n d Asse nt 
•  Pre g na nc y T est (fe mal es of a ge of m e narc he o nl y)  
•  If meeti n g t his criteria a n d t he st u d y tea m has alrea d y o btai ne d c o nse nt t o t his 
pr oce d ure d uri n g t he tele p h o ne scree ni n g , t he n a uri ne sa m ple ca n be c ollecte d  as 
earl y as t he b e gi n ni n g of t he st u d y visit.  
•  If s u bject is e nr olle d w hil e a d mitte d t o t he  i n patie nt u nit, t he res ults fr o m t he 
cli nicall y perf o r m e d pre g na nc y test will be use d f or t he researc h visit. N o 
a d diti o nal pre g na nc y t est will be perf or me d.  
•  If s u bject is fe mal e se x assi g ne d at birt h b ut  i de ntifies as ge n der n o n -c o nf or mi n g, 
we will gi ve t he s u bject t he o pti o n t o s ki p t he pre g na nc y test.  Uri nar y pre g n a nc y 
test is t y picall y d o ne i n t his st u d y as pre g na nc y w o ul d c ha n ge differe ntial 
dia g n osis of hea dac he.  B ot h li d ocai ne a n d sali ne ca n be use d i n pre g na n c y 
safel y.    
•  Re vie w I ncl usi o n/ E xcl usi o n Criteria a n d c o nfir m eli gi bi lit y 
•  If s u bject is n ot naï ve t o ner ve bl oc k  or has recei v e d I V me dicati o ns , i nf or mati o n o n 
treat me nt be nefit, si de effects a n d  n er ve  pr oce d ure use d will be c ollect e d.  
•  De m o gra p hics/ Me dical Hist or y  
 
3 If hist orical data p oi nts (e. g. vital si g ns, hei g ht, wei g ht, hea d circ u mfere nce, etc.) are a vaila ble fr o m earlier 
t hat da y, t he n t he st u d y tea m d oes n ot h a ve t o re peat t hese pr oce d ures f or scree ni ng a n d e nr oll me nt.  

 
  
 
 
 
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•  Re p ort of hea d ac he dis a bilit y usi n g Pe d MI D A S a n d c hil d P R O MI S Pai n I nt erfere nce  
•  P h ys ical E xa m 
•  Ne ur ol o gical e x a m i nati o n i ncl u di n g f u n d osc o pic e xa m 
•  Vital Si g ns  
•  Hei g ht, Wei g ht, Hea d Circ u mfere nce  
•  Re vie w of Pri or/ C o nc o mita nt Me dicati o ns  
4. 3  St u d y Tr e at m e nt P h a s e  
4. 3. 1  I n-pers o n St u d y Visit  
•  Assess  pai n usi n g Vis ual A nal o g Scale re pres e nti n g 0 -1 0  a n d Nu meri c Rati n g S cale 
( N R S) 
•  I n v esti gat or will a p pl y 4 c m ri b b o n  ( 3 2 m g) of li d o cai ne crea m o v er t he bilateral 
great er occi pital ner ve a n d its distri b uti o n  ( gree n area of fi g ure):  
[4 6 ] 
•  I n a d diti on t o Z he n g’s e x pectati o n q uesti o n, s u bject, p are nt, a n d i nject or c o m plete 
m o difie d Sta nf or d E x pectati o ns of Treat me nt Scal e ( S E T S) t o re p ort e x p ect e d 
be nefit of li d ocai n e c rea m  
•  After li d ocai n e crea m has bee n i n place f or ~ 3 0 mi n utes, assess pai n usi n g Vi s ual 
A nal o g Scale re pres e nti n g 0 -1 0  a n d N u meri c Rati n g Scale ( N R S)  
•  If pai n is 0, or s uffi cie ntl y better s uc h t hat s u bject/ pare nt decli ne f urt her 
i nter ve nti o ns t he n n o a d diti o nal pr oce d ures at St u d y Visit, pr ocee d t o F oll o w-U p 
P hase  
•  F or n o n -res p o n ders, t he i n vesti gat or will perf or m i njecti o n wit h ra n d o mize d 
li d ocai ne or sali ne o v er t he bilateral gr eater occi pital ner ve  at t he l o cati o n 
de m o nstrate d o n t he fi g ure bel o w.  T h e i njecti o n site l ocati o n w ill be deter mi ne d b y 

 
  
 
 
 
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Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
pal pati o n, 1/ 3 of t he dista nce laterall y  fr o m t he occi pital pr ot u bera nce t o war d t he 
mast oi d pr ocess, at t he sit e of ma xi mal te n der ness.  T he nee dle will be i nserte d at 
t hat l ocati o n, p oi nti n g t o war d t he verte x of t he h ea d.  1cc will be i njecte d directl y.  
T he nee dle will be sli g htl y wit h dra w n a n d rei nsert e d 4 5 de grees eac h directi o n fr o m 
t he i nitial site, i njecti n g a n a d diti o nal 0. 5cc eac h laterall y a n d me diall y.  Beca use t he 
occi pital arter y us u all y c o urses lateral t o t he great er occi pital ner ve, after n ee dle 
i nserti o n a n d bef ore i njecti o n of sali ne or li d ocai ne eac h ti me  t he i n vesti gat or will 
dra w bac k o n t he s yri n ge t o c o nfir m t hat t he nee dl e is n ot i ntra-arterial.   If t he nee dle 
is i ntra-arteri al it will be re p ositi o ne d.   
[4 6 ] 
•  S u bject, p are nt , a n d i nject or will re p ort percei ve d me dicati o n a n d c o m plete m o difie d 
Sta nf or d E x pectati o ns of Treat me nt Scale ( S E T S) t o re p ort e x pecte d be n efit of 
i njecti o n ( will be d o ne i m me diatel y bef ore n u m b ness sets i n). 
•  A b o ut 3 0 mi n utes after i njecti o n s u bject, pare nt, a n d i nject or a g ai n re p ort percei v e d 
me dicati o n  a n d t he s u bject will als o c o m plete t he P GI C  scale 
•  Assess pai n usi n g Vis ual A nal o g Scale re pres e nti n g 0 -1 0  a n d N u meri c Rati n g Scale 
( N R S) 
•  A d verse E v e nt Assess me nt  
 
4. 4  F oll o w -u p P h a s e  
S u bjects will be as ke d t o mai ntai n electr o nic h ea d ac he diar y t o re p ort p ai n , disa bilit y, use of 
resc ue m e dicati o ns, a n d ot her mi grai ne s y m pt o ms f or 2 8 da ys.  T he y will als o be as ke d 
a b o ut a d vers e e ve nts , use of ot her me dicati o ns , a n d a b o ut satisfacti o n wit h treat me nt .  O n 
da y 7  a n d da y 2 8 , s u bjects will be as ke d t o c o m plete t he P R O MI S Pai n I nterfere nce s cale. 
T he Pe d MI D A S will be a d mi nistere d at da y 2 8 w hile t he P GI C will be wee kl y.   L i n ks t o 
Re dca p s ur ve y s will be se nt via te xt messa ge.   

 
  
 
 
 
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Pa per versi o ns of t h ese f or ms a n d t he hea d ac h e diar y will als o be at ha n d i n case access t o 
t he re q uire t ec h n ol o g y t o fill t hese f or ms o n-li ne is n ot a vaila ble or fa milies decli ne t o use 
electr o nic platf or ms.  
4. 5  U n s c h e d ul e d Vi sit s  
A d diti o nal visits will be sc he d ule d as n ee de d f or a n y s u bjects w h o re p ort s u ne x pecte d 
a d verse e ve nts.  
4. 6  C o n c o mit a nt M e di c ati o n  
All pri or a n d c o nc o mi ta nt hea dac h e pre v e nti ve me dicati o ns use d wit hi n 3 0 da ys pri or t o t he 
Visit 1 a n d t hr o u g h t he e n d of t he st u d y will be rec or de d. All pri or a n d c o n c o mita nt ac ute 
hea dac he me dicati o ns a n d n o n -hea dac he me di cati o ns use d wit hi n 7 da ys pri or t o t he Visit 1 
a n d t hr o u g h t he e n d of t h e st u d y will be rec or de d. T he dates of a d mi nistrati o n, d osa ge, a n d 
reas o n f or use will be i ncl u de d.  
4. 7  R e s c u e M e di c ati o n A d mi ni str ati o n  
S u bjects w h o re p ort i na de q uate relief fr o m st u d y treat me nts ~ 3 0 mi n utes after i njecti o n will 
be offere d a d diti o nal tr eat me nt per us ual cli nical care .  T h ese o pti o ns c o ul d i ncl u de:   
-i ntra ve n o us me dic ati o ns 
-n o a d diti o nal treat me nt  
-o pe n -la b el circ u mf ere nti al ner ve bl oc k i njecti o ns of li d ocai ne.  I n or der t o li mit t he 
ma xi m u m p ossi ble d ose of li d ocai ne t o 4. 5 m g/ k g, i ncl u di n g t he crea m, ra n d o mize d 
i njecti o n, a n d o pe n-la b el i njecti o ns, t he a m o u nt of li d ocai ne use d will be wei g ht-base d:  
Wei g ht  
V ol u me of 2 % li d ocai ne  
D ose of li d ocai ne  
T otal d ose li d ocai ne 
fr o m all pr oce d ures 
6 4 k g +  
8. 8 m L :  
2 m L o ver eac h G O N  
1 m L o ver eac h L O N  
1 m L o ver eac h A T N  
0. 2 m L o ver eac h S O N  
0. 2 m L o ver eac h S T N  
1 7 6 m g  
2 8 8 m g  
5 9. 5 k g -6 3. 9 k g  
7. 8 m L :  
1. 5 m L o ver eac h G O N  
1 m L o ver eac h L O N  
1 m L o ver eac h A T N  
0. 2 m L o ver eac h S O N  
0. 2 m L o ver eac h S T N  
1 5 6 m g  
2 6 8 m g  
5 5. 1 k g -5 9. 4 k g  
6. 8 m L : 
1 m L o ver eac h G O N  
1 m L o ver eac h L O N  
1 m L o ver eac h A T N  
1 3 6 m g  
2 4 8 m g  

 
  
 
 
 
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Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
0. 2 m L o ver eac h S O N  
0. 2 m L o ver eac h S T N  
5 0. 6 k g -5 5 k g  
5. 8 m L : 
1 m L o ver eac h G O N  
1 m L o ver eac h L O N  
0. 5 m L o ver eac h A T N  
0. 2 m L o ver eac h S O N  
0. 2 m L o ver eac h S T N  
1 1 6 m g  
2 2 8 m g  
4 6. 2 k g -5 0. 5 k g  
4. 8 m L : 
1 m L o ver eac h G O N  
0. 5 m L o ver eac h L O N  
0. 5 m L o ver eac h A T N  
0. 2 m L o ver eac h S O N  
0. 2 m L o ver eac h S T N  
9 6 m g  
2 0 8 m g  
4 1. 7 k g -4 6. 1 k g  
3. 8 m L : 
0. 5 m L o ver eac h G O N  
0. 5 m L o ver eac h L O N  
0. 5 m L o ver eac h A T N  
0. 2 m L o ver eac h S O N  
0. 2 m L o ver eac h S T N  
7 6 m g  
1 8 8 m g  
2 5 -4 1. 7 k g  
T B D base d o n hea dac he 
l ocati o n 
T B D  
T B D, ma x 4. 5 m g/ k g  
 
 
4. 8  S u bj e ct C o m pl eti o n/ Wit h dr a w al  
S u bjects ma y wit h dra w fr o m t he st u d y at a n y ti me wit h o ut prej u dice t o t heir care.  T he y 
ma y als o be disc o nti n ue d fr o m t he st u d y at t he discreti o n of t he I n v esti gat or f or A Es.  T h e 
I n v esti gat or ma y als o wit h dra w s u bjects w h o vi olate t he st u d y pla n, or t o pr otect t he s u bject 
f or reas o ns of safet y or f or a d mi nistrati ve reas o ns.  It will be d oc u m e nte d w het her or n ot 
eac h s u bject c o m pletes t he cli nical st u d y. If t he I n vesti gat or bec o mes a ware of a n y s eri o us, 
relate d a d v erse e ve nts after t he s u bject c o m pletes or wit h dra ws fr o m t he st u d y, t he y will be 
rec or de d i n t he s o urce d o c u me nts a n d o n t he C R F. 

 
  
 
 
 
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5  
S T U D Y E V A L U A TI O N S A N D M E A S U R E M E N T S  
5. 1  S cr e e ni n g a n d M o nit ori n g E v al u ati o n s a n d M e a s ur e m e nt s  
5. 1. 1  Me dic al Rec o r d Re vie w  
T he f oll o wi n g varia bles will be a bstracte d fr o m t he me dical c hart: 
•  Date of birt h  
•  Wei g ht  
•  Aller gies  
•  Hea dac he feat ur es a n d di a g n osis, pri or p h ysical e xa m fi n di n gs  
•  Pri or hea dac he treat me nts i ncl u di n g ner ve bl oc k a n d ot her pr oce d ures, as well as 
a d verse e ve nts  
•  S ur gical hist or y  
•  Rec or d of rece nt i n vesti gati o nal dr u g st u d y partici pati o n  
5. 1. 2  Me dic al Hist or y  
Me dical hist or y will be gat here d i n a s e mi -str uct ur e d i nter vie w bas e d o n patie nt a ns wers 
pr o vi de d i n o ur Hea dac h e Q uesti o n naire .  Beca us e a ver y si milar Q uesti o n nai re is use d f or 
cli nical care, t he a ns w ers pr o vi de d f or cli nical care will be use d if a v aila ble, a n d c o nfir me d 
i n t he i nter vie w. 
De m o gra p hics i ncl u di n g a ge, ge n d er, race, a n d et h nicit y will be c ollecte d.   
5. 1. 3  Vit al Si g ns  & P h ysic al E x a m  
Vital si g ns will be mea s ure d f oll o wi n g t he sa me st a n dar d of care f or all ne ur ol o g y patie nts 
see n cli nicall y.  T his i ncl u des meas ure m e nt  of hei g ht a n d wei g ht, hea d circ u mfere n ce, p ulse, 
a n d bl o o d press ure .  Bl o o d press ure will be meas ure d usi n g a n a ut o mate d de vice i n a seate d 
p os iti o n, usi n g eit her left or ri g ht ar m, wit h rec hec k d o ne wit h s p h y g m o ma n o meter if t he 
a ut o mate d rea di n g is o utsi de t he a ge -a p pr o pri ate n or mal ra n ge.  
F ull ge neral me dical a n d ne ur ol o gical e xa mi nati o n will be perf or me d, i n cl u di n g f u n d usc o pic 
e xa mi nati o n a n d hea dac h e -s pecifi c e xa mi nati o n ( pal pati o n f or all o d y nia, te n der ness o ver 
ner ves, ti g ht ness a n d te n der ness of m uscl es of nec k a n d bac k, a usc ultati o n f or br uits).   T hes e 
e xa mi nati o ns are i d e ntical t o t he e xa mi nati o n t hat t he Pri nci pal I n vesti gat or perf or ms as p art 
of us ual cli nical c are.  
5. 1. 4  Pre g n a nc y Testi n g  
A uri ne pre g n a nc y test will b e perf or me d f or fe male s u bjects w h o ha ve reac he d me narc he . 

 
  
 
 
 
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5. 1. 5  Ot her E v al u ati o ns, Me as ures  
•  He a d ac he Q uesti o n n aire ( H Q)  
o  Beca use a si milar q uesti o n naire is use d f or cli nical care, t h e a ns w ers 
pr o vi de d f or cli nic al care will be use d (if a vaila bl e) a n d c o nfir m e d d uri n g t he 
st u d y visit. 
o  T hese q uesti o ns are base d o n t he NI N D S C o m m o n Data Ele me nts f or 
hea dac he. T he “ Hea dac h e Q uesti o n naire” will i ncl u de t he f oll o wi n g:    
▪ C urre nt Hea d ac h e C o n dit i o n a n d Hea d ac he Hist or y  
•  I n cl u des q uesti o ns relat e d t o d urati o ns a n d ti mi n g of 
hea dac hes, se verit y or i nte nsit y, tri g gers, faile d a n d c urre nt 
treat me nts, n o n -me dicati o n treat me nts, use of s u p ple me nts or 
vita mi ns, a ge of o nset, fre q ue nc y a n d patter n of hea dac he 
pai n, c haracterizati o n of pai n, re d fla gs f or sec o n d ar y 
hea dac he (i.e. rece nt i nj ur y or tra u ma, stress ors), alle viati n g or 
a g gra vati n g fact ors, a ura a n d/ or pre m o nit or y s y m pt o ms, 
c haracteri zati o n of hea dac he flar e, dia g n osis 
▪ C urre nt a n d Past Me dical H ist or y  
•  I n cl u des q uesti o ns relat e d t o birt h a n d de vel o p me ntal hist or y, 
s ur geries, i m m u nizati o ns, fa mil y hist or y, pre vi o us or c urre nt 
healt h pr o ble ms, pre vi o us or c urre nt me dicati o ns  
▪ S ocial Hist or y a n d Sc h o ol Life  
•  I n cl u des q uesti o ns s uc h as w h o li ves wit h t he s u bject, a n y 
rece nt c ha n ges or stress ors t o h o me life, s u bject gr a de le vel 
a n d sc h o oli n g e n vir o n me nt, a n y c o ncer ns wit h aca de mic 
perf or ma n ce  
•  Pe d MI D A S  
•  P R O MI S Pe di atric S F v 2. 0 - P ai n I nterfere nce   
•  Z he n g’s ex pec t ati o n questi o n : a si n gle q uesti o n a b o ut e x pect ati o n as d o ne i n 
Z he n g’s ac u p u nct ure st u d y i n mi grai ne [ 5 3] 
•  M o difie d S E T S  
•  P atie nt Gl o b al I m pressi o n of C h a n ge ( P GI C) Sc ale [ 5 4]: A si n gle -ite m r es p o nse 
meas ure i n w hic h p atie nts use a 7 -p oi nt n u merical rati n g sc ale t o self -re p ort t heir 
de gree of o verall c ha n g e or t heir percei ve d i m pr o v e me nt wit h treat me nt.  T his t o ol 
has bee n use d wi del y i n pai n researc h as a sta n dar d meas ure of o utc o me. I n 
c o nsi derati o n of o ur t ar gete d patie nt p o p ulati o n, t he scale i ncl u d es sli g ht re visi o ns t o 
w or di n g: “ m y hea dac hes are” re places “ m y o v erall stat us  is”; “a little” re places 
“ mi ni mall y”; “ better” re places “i m pr o ve d.”  
•  Bli n di n g q uesti o ns : Base d o n t he a p pr oac h of B yi n gt o n[4 7 ], s u bjects will be as ke d: 
“ W hat treat me nt d o y o u t hi n k y o u recei ve d i n t his st u d y? ( A) I a m certai n li d ocai ne 
was use d; ( B) I t hi n k li d ocai ne was pr o ba bl y use d; ( C ) I ha ve a bs ol utel y n o i dea 
w hic h me dicati o n was us e d; ( D) I t hi n k sali ne was pr o ba bl y use d; ( E) I a m certai n 
sali ne was use d.  
S u bjects w h o a ns wer c h oice ( C) will be as k e d, w hic h me dicati o n w o ul d y o u g uess? ( A) 
li d ocai ne; ( B) sali ne. 

 
  
 
 
 
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5. 2  Effi c a c y E v al u ati o n s  
5. 2. 1  Di a g n ostic Tests, Sc ales, Me as ures, etc.  
Pai n sc ore will be assess e d usi n g a Vis ual A nal o g Scale wit h a nc h ors at 0 a n d 1 0  a n d a 
N u meric Rati n g Scale ( N R S) .  Pai n will be assesse d wit h t his at t he f oll o wi n g ti mes: 
- P ri or t o a p plicati o n of li d ocai ne crea m 
- A b o ut 3 0  mi n utes after a p plicati o n of li d ocai ne crea m/j ust pri or t o i njecti o n  
- A b o ut e ver y 5 mi n utes after t he i njecti o n, if perf or me d (i.e. ~ 5, 1 0, 1 5, 2 0, 2 5, a n d 3 0 
mi n utes ) 
Hea dac he diar y, base d o n t he NI N D S Hea dac he C o m m o n Data Ele me nts, will be us e d t o 
c ollect o utc o mes f or 2 8 d a ys of f oll o w -u p.  T his will be a dail y, pr os pecti ve t o ol use d t o 
ca pt ure t he prese n ce or a bse nce of hea d ac he. If prese nt, t he n a d diti o nal q uesti o ns will be 
as ke d t o c ollect i nf or m ati o n t hat f urt her c h aracteri zes it, s uc h as h ea dac h e i nte nsit y, use of 
resc ue m e dicati o ns o n eac h da y, disa bilit y ass ociate d wit h hea dac he pai n, a n d ot her 
s y m pt o ms.  If n ot pres e nt, t he n a d diti o nal q uesti o ns will be as ke d t o c ollect i nf or mati o n 
a b o ut t he use of pre ve ntati ve me dicati o ns a n d t he use of me dicati o ns f or a n y ot her pai n.  
 
5. 3  S af et y E v al u ati o n  
S u bject safet y will be m o nit ore d b y a d verse e ve nts  a n d p h ysical e xa mi nati o ns .  
 
6  
 S T A TI S TI C A L C O N SI D E R A TI O N S  
6. 1  Pri m ar y E n d p oi nt  
C ha n ge i n pai n sc ores, meas ure d b y s u btracti n g t he 3 0 mi n p ost -i njecti o n sc ore fr o m t he pre-
i njecti o n sc ore, b ot h m eas ure d b y t he Vis ual A nal o g Scale[4 8 ] a n d N u m eric Rati n g Scal e 
( N R S),  will be use d as t h e pri mar y o ut c o me meas ure.  A co nti n u o us o utc o m e meas ure e n a bles 
us t o e xa mi ne t he varia bilit y of t he o utc o me, a n d a c ha n g e of 2 p oi nts has bee n pre vi o usl y 
s h o w n t o be cli nicall y rel e va nt.   
6. 2  S e c o n d ar y E n d p oi nt s  
Per t he g ui deli nes of c o ntr olle d trials of dr u gs i n mi grai ne, sec o n d ar y o utc o me meas ures will 
i ncl u de pai n free d o m, p ai n relief (i m pr o ve me nt of pai n fr o m m o derate/se v ere t o n o n e/ mil d), 
2 4 -h o ur s ustai ne d pai n free d o m a n d relief, free d o m fr o m all s y m pt o ms of mi grai ne (i ncl u di n g 
p h ot o p h o bia, na usea), us e of res c ue tr eat me nts, a n d dis a bilit y[4 9 ].   

 
  
 
 
 
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Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
6. 3  St ati sti c al M et h o d s  
6. 3. 1  B aseli ne D at a  
Baseli ne a n d de m o gr a p hic c haracteristics will be s u m marize d b y sta n dar d descri pti ve 
statistics (e. g. mea ns a n d sta n dar d de viati o ns f or c o nti n u o us varia bles s uc h as a ge a n d 
perce nt a ges f or cat e g orical varia bles s uc h as ge n d er).  
6. 3. 2  Effic ac y A n al ysis  
T he pri mar y  a n al ysis will be base d o n a n i nte nti o n t o treat a p pr o ac h .  F or O bjecti ve 1 t his 
will i ncl u de all s u bjects w h o recei ve t he ra n d o mize d li d ocai ne vers us sali ne i njecti o n at t he 
St u d y Visit .  Differe nce i n mea n c ha n g e i n pai n sc ore i n t he li d ocai ne i njecti o n a n d sali ne 
i njecti o n gr o u ps will be c o m pare d usi n g a n i n de pe n de nt t -test.   
6. 3. 3  S afet y A n al ysis  
All s u bjects w h o ha ve li d ocai ne crea m a p plie d at t he St u d y Visit  will be i ncl u de d i n t he 
safet y a n al ysis. T he fre q ue ncies of A Es b y t y p e, b o d y s yste m, se verit y a n d relati o ns hi p t o 
st u d y dr u g will be s u m marize d. S A Es (if a n y) will be descri be d i n d etail. 
A E i nci de nce will be s u m marize d al o n g wit h t he c orres p o n di n g e xact bi n o mial 9 5 % t w o -
si de d c o nfi de nce i nter vals. 
6. 4  S a m pl e Si z e a n d P o w er  
S a m ple size f or r a n d o mize d ste p:  T he mea n dr o p i n pai n sc ore i n o ur retr os pecti ve st u d y of 
ner ve bl oc ks i n c hil dre n wit h ac ute flare of b ot h e pis o dic a n d c hr o nic mi grai ne was 4 p oi nts 
(i m me diatel y pre- t o a fe w mi n utes p ost-i njecti o n, as meas ure d o n a n u meric 0-1 0 scale).   
Si milarl y, Dr . Y o u n g & Os hi ns k y’s st u d y of t he effects of G O N bl oc k i n t he first fi ve mi n utes 
f o u n d a n a vera ge dr o p of 3. 3 p oi nts o n a Vis ual A nal o g Scale[5 0 ], a n d wit h t he ti mi n g of 
acti o n of l ocal a nest hetics, it is reas o na ble t o esti mate t hat c o nti n ue d ti me w o ul d ha ve l e d t o 
a dr o p of ~ 4 p oi nts.  Gi ve n t hat t he mi ni mal cli nicall y si g nifica nt c ha n ge i n pai n sc ore acr oss 
m ulti ple c hr o nic pai n c o n diti o ns is 2 p oi nts [5 1 ], we will esti mate t hat t h e sali ne i njecti o n 
gr o u p will dr o p a n a v era ge of 4 -2 = 2 p oi nts.  T he sta n dar d de viati o n of c h a n ge i n p ai n sc ore 
i n o ur o bser vati o nal st u d y was 2. 5, a n d i n Dr. Y o u n g’s s maller st u d y was 2. 7, s o we will use 
t he latter t o esti mate sa m ple size.  Ass u mi n g t hat li d ocai ne i njecti o ns lea d t o a mea n c ha n g e 
of 4 p oi nts, a n d sali ne i nj ecti o ns lea d t o a m ea n c h a n ge of 2 p oi nts, wit h a sta n dar d de vi ati o n 
of 2. 7, t w o -si d e d α = 0. 0 5 a n d 8 0 % po wer, we will nee d 2 9 pri mar y c hil d/a d olesce nt s u bjects 
t o recei ve t h e ra n d o mize d ner ve bl oc k treat me nt, per i njecti o n ar m, f or a t otal of 5 8.   
 
7  
E F F E C T O F LI D O C AI N E C R E A M R U N -I N O N O V E R A L L S A M P L E SI Z E: A 
S M A L L S T U D Y O F LI D O C AI N E C R E A M A S T R E A T M E N T F O R MI G R AI N E 
H E A D A C H E D E M O N S T R A T E D T H A T 7 O F 3 0 S U B J E C T S, O R 2 3 % ( 9 5 % 
C O N FI D E N C E I N T E R V A L: 9 -4 2 %), W E R E P AI N -F R E E A T 2 H O U R S [4 0 , 4 1 ].  
W E WI L L P L A N T H A T T H E U P P E R E N D O F T HI S C O N FI D E N C E I N T E R V A L, 
4 2 % O F S U B J E C T S  WI L L D R O P -O U T D U E T O P AI N F R E E D O M WI T H 
LI D O C AI N E C R E A M ( O R S U F FI CI E N T I M P R O V E M E N T S U C H T H A T T H E Y 
D E C LI N E F U R T H E R I N T E R V E N TI O N S).  A S A R E S U L T, W E E S TI M A T E 

 
  
 
 
 
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T H A T W E WI L L N E E D T O E N R O L L U P T O 9 7 P RI M A R Y 
C HI L D/ A D O L E S C E N T S U B J E C T S I N O R D E R T O  A C HI E V E T H E G O A L O F 
P RI M A R Y C HI L D A D O L E S C E N T 5 8 S U B J E C T S R E C EI VI N G T H E 
R A N D O MI Z E D  N E R V E B L O C K I N J E C TI O N.  S T U D Y M E DI C A TI O N ( S T U D Y 
D E VI C E O R O T H E R S T U D Y I N T E R V E N TI O N) 
7. 1  D e s cri pti o n  
St u d y me dicati o ns will i ncl u de li d ocai ne crea m, i njecta ble 2 % li d ocai ne s ol uti o n, a n d sali ne.  
Per disc ussi o n wit h researc h p har m ac y i n J ul y 2 0 1 8 , t he st u d y tea m ca n ma na ge t he 
li d ocai ne crea m. T h is st u d y me dicati o n will be ke pt se parate fr o m t he cli ni cal s u p pl y i n a 
l oc ke d cl oset i n cli nic.  T he st u d y tea m will use researc h p h ar mac y (I D S) t o pre pare a n d 
dis pe nse t he i njecta ble m e dicati o ns.  Researc h p har mac y will re mai n u n bli n de d.  
7. 1. 1  Dr u g Acc o u nt a bilit y  
A de q uate rec or ds of st u d y dr u g recei pt a n d dis p ositi o n  f or t he li d ocai ne crea m will be 
mai ntai ne d b y t he st u d y tea m.  Researc h p har mac y (I D S) will ma na ge acc o u nta bilit y of t he 
i njecta ble st u d y me dicati o ns.   

 
  
 
 
 
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8  
S A F E T Y M A N A G E M E N T  
Base d o n cli nical e x p erie nce a n d pri or st u dies, we c o nsi der t his st u d y t o be a mil d i ncrease 
a b o ve mi ni mal ris k a n d d o n ot a ntici pate a n y S A Es.   
•  Li d ocai ne crea m is a p pr o ve d b y  t he F o o d & Dr u g A d mi nistrati o n as a safe a n d 
effecti ve dr u g  f or mi n or s ki n irritati o n o ver 2 years of a ge [3 7 ].   
•  Sali ne ner ve bl oc ks h a ve bee n use d i n m ulti ple pri or st u dies wit h s o me be nefit a n d 
wit h o ut re p ort of har m.  S u bjects will be e x p ose d t o a ma xi m u m of 2 sali ne 
i njecti o ns i n t his st u d y.   
•  I n o ur retr os p ecti ve st u d y of ner ve bl o c ks wit h li d ocai ne a n d b u pi v acai n e, 8 6 % of 
t h ose wit h ac ute hea dac h e flare ha d at least tra nsie nt i m pr o ve me nt i n pai n se verit y 
[2 4 ], a n d t here were n o s eri ous a d verse e v e nts.  T here were cases i n w hi c h ner ve 
bl oc k was use d u ns uccessf ull y t o pre ve nt h os pitalizati o n, b ut it was t he hea dac he, 
n ot t he ner ve bl oc k, t hat l e d t o h os pitalizati o n.  A  s mall p orti o n of s u bjects re p orte d 
i ncreas e d pai n, n u m b ness, or a n xiet y us uall y d uri n g a n d i m me diatel y f oll o wi n g 
i njecti o n, b ut t hese s y m pt o ms were self-res ol ve d.   
8. 1  Cli ni c al A d v er s e E v e nt s  
Cli nical a d verse e v e nts ( A Es) will be m o nit ore d t hr o u g h o ut t he st u d y  directl y b y t he PI a n d 
st u d y tea m,    
8. 2  A d v er s e E v e nt R e p orti n g  
U na ntici pate d  pr o ble ms r elate d t o t he res earc h i n v ol vi n g ris ks t o s u bjects or ot hers t hat 
occ ur d uri n g t he c o urse of t his st u d y (i ncl u di n g S A Es) will be re p orte d t o t he I R B i n 
acc or da nce wit h C H O P I R B S O P 4 0 8: U na ntici pate d Pr o ble ms I n v ol vi n g Ris ks t o S u bjects. 
A Es t hat are n ot seri o us b ut t hat are n ota ble a n d c o ul d i n v ol ve ris ks t o s u bjects will be 
s u m marize d i n narrati ve or ot her f or m at a n d s u b mitte d t o t he I R B at t he ti me of c o nti n ui n g 
re vie w.  
8. 3  D efi niti o n of a n A d v er s e E v e nt  
A n a d vers e e ve nt  is a n y u nt o war d me dical o cc urre nce i n a s u bject w h o has recei v e d a n 
i nter ve nti o n ( dr u g, bi ol o gic, or ot her i nter ve nti o n).  T he occ urre nce d o es n ot necessaril y 
ha ve t o ha ve a ca usal rel ati o ns hi p wit h t he treat me nt.  A n A E ca n t heref ore be a n y 
u nfa v ora bl e o r u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g, f or e xa m ple), 
s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a m e dici nal pr o d uct, w het her or 
n ot c o nsi dere d relate d t o t he me dici nal pr o d uct.  
All A Es (i ncl u di n g seri o us A Es) will be n o te d i n t he st u d y rec or ds a n d o n t he case re p ort 
f or m wit h a f ull descri pti o n i ncl u di n g t he nat ure, date a n d ti me of o nset, d eter mi nati o n of 
n o n -seri o us vers us seri o us, i nte nsit y ( mil d, m o derate, se vere), d urati o n, ca usalit y, a n d 
o utc o me of t he e v e nt.   

 
  
 
 
 
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8. 4  D efi niti o n of a S eri o u s A d v er s e E v e nt ( S A E)  
A n S A E is a n y a d vers e dr u g e x peri e nce o cc 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:  
•  deat h,  
•  a life-t hreate ni n g e v e nt ( at ris k of deat h at t he ti m e of t he e v e nt),  
•  re q uires u ne x pecte d  i n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n,  
•  a persiste nt or si g nifica nt disa bilit y/i nca pacit y, or  
•  a c o n ge nital a n o m al y/ birt h defect i n t he offs pri n g of a s u bject.   
I m p ort a nt me dical e v e nts t hat ma y n ot res ult i n deat h, be life-t hr eate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d a seri o us a d verse dr u g e ve nt w h e n, bas e d u p o n 
a p pr o priate m e dical j u d g me nt, t he y ma y je o par dize t he s u bject a n d ma y re q uire me dical or 
s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o m es liste d i n t his defi niti o n. 
Beca use t he c urre nt sta n dar d of care f or patie nts wit h ac ute, se vere h ea dac he is i ntra ve n o us 
me dicati o ns, it is e x pecte d t hat s o me s u bjects i n t his st u d y will be treate d i n t he E mer ge n c y 
De part me nt or h os pitaliz e d.  T his re prese nts a fail ure of be n ef it of t he st u d y treat me nt, 
rat her t ha n a n a d v erse effect of t he st u d y treat me nt.  T hese h os pitalizati o ns will n ot be 
treate d as Seri o us A d vers e E ve nts beca use t he y are e x pecte d i n t he c o urse of t he hea d ac he 
flare i n a s mall p orti o n of patie nts, e ve n w he n ap pr o priate treat me nts are us e d t o tr y t o 
pre ve nt h os pitalizati o n . 
Si milarl y, ma n y c hil dre n wit h se vere, refract or y h ea dac h es ha ve m ulti ple me dical a n d 
ps yc hiatric c o m or bi dities.  H os pitalizati o ns w hic h are n ot r elate d t o t he st u d y i nter ve nti o ns 
will n ot be  c o nsi dere d S A Es.  
8. 4. 1  Rel ati o ns hi p of S A E t o st u d y dr u g or ot her i nter ve nti o n  
T he relati o ns hi p of eac h S A E t o t he st u d y i nter ve nti o n s h o ul d be c haracterize d usi n g o ne of 
t he f oll o wi n g ter ms i n acc or da nce wit h C H O P I R B G ui deli nes: defi nitel y, pr o ba bl y, 
p ossi bl y, u nli kel y or u nrelate d.  
8. 5  I R B/I E C N otifi c ati o n of S A E s a n d Ot h er U n a nti ci p at e d Pr o bl e m s  
T he I n vesti gat or will pr o m ptl y n otif y t he I R B of all u na ntici pate d, seri o us A d verse E v e nts 
t hat are relate d t o t he res earc h acti vit y. Ot her u na ntici pate d pr o ble ms relat e d t o t he researc h 
i n v ol vi n g ris k t o s u bjects or ot hers will als o be re p orte d pr o m ptl y. Writte n re p orts will be 
file d usi n g t he eI R B s yste m a n d i n acc or da n ce wit h t he ti meli ne bel o w.  
T y p e of U n a nti ci p at e d 
Pr o bl e m  
I niti al N otifi c ati o n  
( P h o n e, E m ail, F a x) 
Writt e n R e p ort  
I nt er n al ( o n-sit e) S A E s  
D e at h or Lif e T hr e at e ni n g  
2 4 h o ur s  
Wit hi n 2 c al e n d ar d a y s  
I nt er n al ( o n-sit e) S A E s  
7 d a y s  
Wit hi n 7 b u si n e s s d a y s  

 
  
 
 
 
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All ot h er S A E s  
U n a nti ci p at e d Pr o bl e m s 
R el at e d t o R e s e ar c h  
7 d a y s  
Wit hi n 7 b u si n e s s d a y s  
All ot h er A E s  
N/ A  
Bri ef S u m m ar y of i m p ort a nt 
A E s m a y b e r e p ort e d at ti m e 
of c o nti n ui n g r e vi e w  
8. 5. 1  F oll o w -u p re p ort  
If a n S A E has n ot res ol ve d at t he ti me of t he i nitial re p ort a n d n e w i nf or m ati o n arises t hat 
c ha n ges t he i n vesti gat or’s assess me nt of t he e v e nt, a f oll o w -u p re p ort i ncl u di n g all rele va nt 
ne w or reassesse d i nf or m ati o n (e. g., c o nc o mita nt me dicati o n, me dical hist or y) s h o ul d be 
s u b mitte d t o t he I R B. T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat all S A E are f oll o we d 
u ntil eit her res ol ve d or st a ble.  

 
  
 
 
 
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9  
S T U D Y A D MI NI S T R A TI O N  
9. 1  Tr e at m e nt A s si g n m e nt M et h o d s  
9. 1. 1  R a n d o miz ati o n  
Ra n d o mizati o n will be d o ne usi n g R E D Ca p, w hic h ca n stratif y t he ra n d o mizati o n.  T hat 
i nf or mati o n will be ke pt se parat el y fr o m ot her s u bject rec or ds i n R E D Ca p. 
9. 1. 2  Bli n di n g  
T he i n vesti gat or w h o perf or ms t he i njecti o n, t he s u bject a n d his/ her pare nt(s) will be bli n de d 
t o me dicati o n.  Researc h p har mac y will be  u n bli n de d a n d will pre pare a n d dis pe nse t he 
i njecta ble st u d y me dicati o ns.  
9. 1. 3  U n bli n di n g  
I n t he e ve nt of a seri o us S A E i n w hic h t here is a c o ncer n f or partici p a nt safet y a n d it is 
i m perati ve t o k n o w w het her t he partici pa nt recei v e d li d ocai ne or s ali ne , we will u n bli n d t he 
treat me nt f or t he s p ecific partici pa nt wit h o ut brea ki n g t he bli n d  f or ot her p artici pa nts .  
F or t hat, t he Pri nci pal I n vesti gat or will c o ntact t he Researc h P har mac y t o r e q uest t he 
u n bli n de d treat me nt i nf or mati o n f or t he s pecifi c s u bject.  
9. 2  D at a C oll e cti o n a n d M a n a g e m e nt  
Data will be ma na g e d a n d st ore d usi n g t he researc h -f oc use d electr o ni c we b-base d dat a 
ca pt ure s yste m R E D Ca p, u n der a n a gree me nt wit h t he s oft war e’s de v el o p me nt c o ns orti u m, 
le d b y Va n der bilt U ni versit y.  I de ntifia ble i nf or mati o n of s u bjects will be e ntere d i nt o 
R E D Ca p, w hic h will be accessi ble o nl y t o t he i n vesti gat ors, researc h c o or di nat or, a n d 
I n d e pe nde nt M e dical M o nit or.  I d e ntifier fiel ds will be re m o ve d  w he n e x p orti n g data f or 
a nal ysis . 
Data bac k u p is perf or me d ni g htl y via a de dicate d bac k u p s yste m.  T he bac k u p e n vir o n me nt 
is mai ntai ne d b y a de dicate d staff usi n g de dicate d res o urces.  Access t o t he bac k u p 
e n vir o n me nt is restricte d t o Researc h I nf or mati o n S yste ms staff.  
R E D Ca p has t he ca p a bilit y t o se n d S M S te xt messa ges t o s ur ve y res p o n de nts b y usi n g a 
t hir d-part y we b s er vice n a me d T wili o ( w w w.t wili o.c o m). T wili o pr o vi des s pecific H T T P 
hea ders t h at are e nc o d e d a n d are v erifia bl e t o e ns ure t hat t he y are tr ul y c o mi n g fr o m t he 
T wili o ser ver. R E D Ca p utilizes t hese hea ders t o a ut he nticate t o t he re q u est t o R E D Ca p fr o m 
T wili o. R E D Ca p uses a tec h nical met h o d ol o g y e n a bli n g near -i nsta nta ne o us re m o val of t he 
mi ni mal tra nsacti o n l o g gi n g –  esse ntiall y re m o vi n g c o ntacts a n d d urati o n l o gs wit hi n 
sec o n ds of t he S M S or p h o ne tra nsacti o n occ urri n g. All l o gs are scr u b be d ; n ot hi n g else is 
ca pt ure d o n T wili o, a n d t he R E D Ca p i m ple me ntati o n e ns ures si g nifica nt c o ntr ols t o warra nt 
a ut h orit y t o o perate. T h e w o ul d li ke t o  utilize t he R E D Ca p -T wili o i nte grati o n t o ol f or 
se n di n g a s ur ve y li n k via S M S (te xt messa ge) t o a R E D Ca p s ur ve y. 
I n c o nsi derati o n of t h e ma n dat or y rete nti o n p olicies f or researc h rec or ds s et f ort h b y C H O P, 
o ur tea m w o ul d li ke t o sca n a n d st ore t he writte n p a per c o ns e nt a n d ot her p a per s o urce 

 
  
 
 
 
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d oc u me nts electr o ni call y, w hic h w o ul d n ot re q uir e t he st u d y tea m t o retai n t he p h ysical 
pa per c o pi es.  
9. 3  C o nfi d e nti alit y  
A ll data a n d rec or ds ge n erate d d uri n g t his st u d y will be ke pt c o nfi de ntial i n acc or da nce wit h 
I nstit uti o nal p olicies a n d HI P A A o n s u bject pri vac y.  The I n vesti gat or a n d ot her site 
pers o n nel will n ot use s uc h data a n d rec or ds f or a n y p ur p ose ot her t ha n c o n d ucti n g t he 
st u d y.  
N o i de ntifia ble data will be use d f or f ut ure st u d y wit h o ut first o btai ni n g I R B a p p r o val. T he 
i n vesti gat or will o btai n a data use a gree m e nt bet wee n t he pr o vi der (t he PI) of t he data a n d 
a n y reci pie nt researc h ers (i ncl u di n g ot hers at C H O P) bef ore s h ari n g a li mite d dataset ( P HI 
li mite d t o dates a n d zi p c o des).  
9. 4  R e g ul at or y a n d Et hi c al C o n si d er ati o n s  
9. 4. 1  D at a a n d S afet y M o nit o ri n g Pl a n  
T he Office of Res earc h C o m plia nce ( O R C) pr o vi des q ualifie d a n d tr ai ne d staff t o s u p p ort 
t he m o nit ori n g pla n. T he O R C ta kes a ris k-bas e d a p pr oac h t o m o nit ori n g. T he p ur p oses of 
trial m o nit ori n g are t o verif y t he pr otecti o n of t h e ri g hts, safet y a n d well-bei n g of h u ma n 
s u bjects are pr otecte d, as well as, t o e ns ure t he q ualit y a n d i nte grit y of data res ulti n g fr o m 
t his i n vesti gati o n. A d diti o nall y, m o nit ori n g will be c o n d ucte d t o v erif y t he c o n d uct of t he 
trial is i n c o m plia nce wit h t he c urre ntl y a p pr o ve d pr ot ocol/a me n d me nt(s), a n d wit h t he 
a p plica ble re g ulat or y re q uire me nt(s).  
Pri or t o i nitiati o n of recr uit me nt acti vities, t he O R C will c o n d uct a re vie w of re g ulat or y 
d oc u me nts t o c o nfir m cli nical trial rea di n ess. T hereafter, t he O R C will perf or m t he first 
m o nit o ri n g visit after t he first s u bject is e nr olle d a n d c o m pletes a d mi nistrati o n of t he 
i n vesti gati o nal pr o d uct. T hereafter, t h e I n vesti gat or will c o ntact O R C t o arra n ge a 
m o nit ori n g visit. S u bse q ue nt m o nit ori n g acti vities will c o nsist of 1 0 0 % re vie w of re g ul at or y 
rec or ds a n d c o nse nt d o c u me ntati o n, a n d re vie w of a s u bset of s u bject dat a after a n a d diti o nal 
6 -m o nt hs of researc h acti vit y. At t hat ti me, a rec o m me n dati o n f or t he c o nti n ue d m o nit ori n g 
fre q ue n c y will be deter mi ne d base d u p o n t he o bser vati o ns a n d/ or fi ndi n gs n ote d. M o nit ori n g 
ma y c o nti n ue at 6 -m o nt h i nter vals, or ma y be ta pere d.  
T he st u d y will be m o nit ore d b y a n I n d e pe n d e nt Me dical M o nit or (I M M) b eca use it i n v ol ves 
o nl y a mi n or i ncreas e a b o ve mi ni mal ris k wit h direct p ossi bilit y of be nefit, a n d will be 
c o n d ucte d at a si n gle site.  Dr. A m y Gelf a n d, w h o has p u blis he d o n t he use of ner ve bl o c ks 
i n c hil dre n, has a gree d t o ser ve as I M M.  S he will ha ve access t o all data i n R E D Ca p, 
i ncl u di n g patie nt i de ntifiers, w hic h will be n ote d i n t he i nf or me d c o nse nt d oc ume nt.  
C o nsiste nt wit h t he res p o nsi bilities of a n I M M o utli ne d b y NI N D S, a b o ut e ver y 6 m o nt hs 
s he will re vie w t he researc h pr ot oc ol a n d o n g oi n g st u d y acti vities wit h e m p hasis o n data 
i nte grit y, pr ot oc ol a d here nce, a n d st u d y partici pa nt safet y iss ues.  T he I M M’s re vie w will 
f oc us o n a d verse e v e nts a n d reas o ns f or l osses t o f oll o w u p, raisi n g a n y c o n cer ns or iss ues 
wit h t he NI N D S a n d t he PI, a n d rec o m me n di n g t o t he NI N D S a n d PI t he c o nti n uati o n, 
m o dificati o n, or c o ncl usi o n of t he trial, w hile pr ot ecti n g t he c o nfi de ntialit y of t he trial data 

 
  
 
 
 
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a n d t he res ults of m o nit ori n g.  I n a d diti o n, b ot h Dr. Gelfa n d a n d t he I R B will be n otifie d if 
a n y seri o us a d v erse e ve nts ( S A Es) occ ur per t he ti meli ne o utli ne d i n t he pr ot oc ol.  
Beca use t he pl a n ne d st u d y i ncl u des a rel ati vel y s mall n u m ber of s u bjects, a n d t he 
i nter ve nti o ns i n v ol ve o nl y a mi n or i ncrease a b o v e mi ni mal ris k wit h direct p ossi bilit y of 
be nefit, t here is n o pla n f or i nteri m a nal ysis or pre mat ure st o p pi n g base d o n efficac y.  
9. 4. 2  Ris k Assess m e nt  
T he st u d y pr oce d ures will be perf or m e d i n ne ur ol o g y cli nic, wit h t he sa me s afe g uar ds we 
o bser ve as p art of us ual cli nical care.  T h e me dicati o ns are ke pt i n a l oc ke d st ora ge cl oset, 
a n d a 2-staff pers o n “ti me o ut” is perf or me d pri or t o all i njecti o n pr oce d ures.   
C o m pleti o n of st u d y sur ve ys are n ot gr eater t ha n mi ni mal ris k.  M ost of t he s ur ve ys are use d 
c o m m o nl y i n r o uti ne me dical care, a n d n o n e as k u nc o mf orta ble or pri vate q uesti o ns.  
A p plicati o n of li d ocai ne crea m is n ot greater t h a n mi ni mal ris k.  T he li d ocai ne crea m is 
act uall y a n o ver-t he-c o u nter crea m s ol d f or tr eat m e nt of he m orr h oi ds a n d mi n or s ki n 
irritati o n, s o ca n be use d i n e ver y da y life.   
Sali ne i njecti o n o ver t he greater occi pital ner ves is als o mi ni mal ris k, si milar t o a bl o o d 
dra w.  A s mall v ol u me ( 2cc) of s ali ne will  be i njecte d o ver eac h ner ve, usi n g a 3 0 ga u ge 
nee dle, w hic h is s maller t ha n nee dles t y picall y use d f or p hle b ot o m y.  T he n ee dle will be 
i nserte d o nl y s u perfici all y i nt o t he s ki n.  T here is n o k n o w n ris k t o s mall i njecti o ns of sali ne, 
a n d t his has bee n use d as t he place b o c o m parat or i n n u mer o us trials of ner ve bl oc ks i n 
a d ults[2 7 -3 0 ].  Multi ple sali ne i njecti o ns were use d as t he place b o treat me nt i n t he rece ntl y -
c o m plete d trial  o n  a b ot uli n u m t o xi n f or c hr o nic mi grai ne i n a d olesce nts [5 2 ]. 
Li d ocai ne greater o cci pit al ner ve i njecti o n i n v ol ves a mi n or i ncreas e a b o v e mi ni mal ris k 
wit h direct pr os pect of be nefi t.  We c o m m o nl y perf or m ner ve bl o c ks wit h li d ocai ne i n o ur 
hea dac he cli nic , a n d n er ve bl oc ks else w h ere o n t h e b o d y are p erf or me d pri or t o pai nf ul 
pr oce d ures ver y c o m m o nl y i n me dical care (cat het er place me nt, stitc hes, et c) .  Base d o n o ur 
retr os pecti ve cli nical dat a, 8 5 % of patie nts w h o recei ve d ner ve bl oc k s wit h l ocal a nest hetic 
f or hea d ac h e deri ve d s o me be nefit.  T he m ost fre q ue ntl y re p orte d n e gati ve o utc o me was 
mi n or disc o mf ort.  N o s u bjects e x peri e nces s eri o us har m or re p orte d w hat w o ul d be 
c o nsi dere d a seri o us ne g ati ve o utc o me.  I n a d diti o n, i n t his st u d y we are s ee ki n g t o utilize 
t he li d ocai ne crea m r u n-i n t o mi ni mize t he i njecti o n disc o mf ort.  A lar ge p orti o n of patie nts 
i n o ur retr os pecti ve st u d y a n d i n a n ot her p u blis he d pe diatric st u d y electe d t o recei v e 
re peat e d ner ve bl oc k s, i n dicati n g t hat be nefit o ut wei g he d ris ks i n t he o pi ni o n of t he patie nt. 
9. 4. 3  P ote nti al Be nefits of Tri al P artici p ati o n  
Direct be n efits: S u bjects w h o partici pate i n t he st u d y ma y ha ve i m pr o ve me nt i n t heir 
hea dac he treat me nt.  As descr i be d a b o ve, a pri or st u d y de m o nstrate d t hat t hat 7 of 3 0 
s u bjects ( 2 3 %, 9 5 % CI 9-4 2 %)  treate d wit h li d ocai ne crea m ha d res ol uti o n of hea dac he [4 0 , 
4 1 ].  All s u bjects will be treate d wit h li d ocai ne crea m as t he first st u d y treat me nt.  T h ose 
w h o d o n ot deri ve s uffi cie nt be nefit fr o m t he li d ocai ne crea m will recei ve ra n d o mize d, 
bli n de d sali ne or li d ocai n e G O N i njecti o ns.  Base d o n o ur retr os pecti ve cli nical data,  8 5 % of 
patie nts w h o recei ve d ner ve bl oc k s wit h l ocal a nest hetic deri ve d s o me be n efit.  If s u bjects 
c o nti n ue t o ha ve si g nifica nt hea dac he at t he e n d of st u d y pr oce d ures t he y will be offere d 

 
  
 
 
 
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Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
a d diti o nal treat me nts per us ual cli nical care (I V m e dicati o ns, o pe n -la bel ner ve bl oc ks wit h 
li d ocai ne, etc). 
I n dir ect be n efits: T he c urre nt sta n dar d of care f or ac ute, se v ere h ea d ac he refract or y t o 
oral/ nasal me dicati o ns is i ntra ve n o us me dicati o ns.  T he a d mi nistrati o n of I V me dicati o ns 
c o mes wit h si g nifica nt b ur de n t o t he i n di vi d ual a n d t he me dical s yste m.  If we de m o nstr ate 
t hat occi pital ner ve bl o c ks are a n effecti ve met h o d of treati n g ac ute, se vere hea dac he t he n 
we will a d d a n ot her treat me nt o pti o n w hic h is m ore c o n ve ni e nt f or patie nts a n d less c ostl y 
f or t he me dic al s yste m. 
9. 4. 4  Ris k -Be nefit Assess m e nt  
Base d o n cli nical e x p erie nce, t he p ote ntial be nefits of t his treat me nt s u bsta ntiall y o ut wei g h 
t he mi n or ris ks. 
9. 5  R e cr uit m e nt Str at e g y  
P atie nts wit h e pis o dic or c hr o nic mi grai ne w h o re q uire escalati o n of care f or disa bli n g ac ute 
mi grai ne hea d ac he refract or y t o h o me treat me nt will be i n vite d t o recei ve a d diti o nal 
inf or mati o n a b o ut t his cli nical trial  o pti o n . O ur preli mi nar y data i n dicate t hat we will 
pri maril y recr uit tee na ge girls, c o nsiste nt wit h t he distri b uti o n of mi grai ne i n c hil dre n a n d 
a d olesce nts, wit h risi n g i nci de nce i n girls after p u bert y.  
A d diti o nall y, to e n ha nce recr uit me nt eff orts, as n ee de d we will:  
1.  T he Recr uit me nt E n ha n ce me nt Ce nter will e mail  patie nts w h o ha ve bee n s ee n i n 
Ne ur ol o g y or t he E D f or treat me nt of mi grai ne wit hi n t he past year.  I n a d diti o n, 
patie nts w h o ha ve bee n s ee n rece ntl y f or ac ute tr eat me nt ma y be c o ntacte d b y 
tele p h o ne t o offer t he o pti o n t o e nr oll in  t he ner ve bl oc k st u d y f or t heir ne xt 
pr ol o n ge d mi grai ne  flare.  
2.  We will ha n d o ut r ecr uit me nt material s t o p ote ntiall y eli gi ble patie nts i n Ne ur ol o g y 
cli nic, i n t he E D, a n d at Hea dac he E d u cati o n e ve nts .    
3.  We will als o disc uss t his st u d y wit h patie nts ( b ot h C H O P a n d n o n-C H O P) w h o 
c o ntact us as ki n g a b o ut p ote ntial st u dies.  
4.  We will reac h o ut t o t he p ote ntial s u bjects t hr o u g h m y C H O P t o as k if t he y’re 
i ntereste d t o hear a b o ut t he st u d y a n d we’ll f oll o w u p wit h a p h o ne call if t he y are. 
5.  We will p ost i nf or mati o n a b o ut t he st u d y i n C H O P we bsite  a n d ge neral C H O P 
Face b o o k.  
 
6.  We will use t he Recr uit me nt E n ha nce m e nt C ore Ser vices t o hel p us i ncreas e o ur 
recr uit me nt n u m bers. 
7.  I n or der t o alle vi ate t he E D l oa d , t he di visi o n of Ne ur ol o g y will se n d Ne ur ol o g y 
patie nts a c o m m u nicati o n wit h alter nati ve treat me nts f or hea d ac h e flares t hat d o n't 
i n v ol ve a visit t o t he E D. Partici pati o n i n t his st u d y will be o ne of t he o pti o ns liste d. 
 

 
  
 
 
 
2 6  
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
9. 6  I nf or m e d C o ns e nt/ A s s e nt  a n d HI P A A A ut h ori z ati o n  
A n a p pr o ve d st u d y te a m me m ber will o btai n ver bal c o nse nt a n d HI P A A a ut h orizati o n pri or 
t o s oliciti n g i nf or mati o n fr o m i ntereste d p ote ntial fa milies d uri n g t he i nitial tele p h o ne call . 
T he I n vesti gat or will o bt ai n writte n i nf or me d c o nse nt/asse nt a n d HI P A A a ut h orizati o n f or 
t he mai n st u d y at t he i n-pers o n s t u d y v isit.  T he s u bject a n d pare nt will be gi ve n 
a p pr o xi matel y 3 0 mi n utes t o ma ke a decisi o n a b o ut partici pati o n o n t he st u d y.   
9. 7  P a y m e nt t o S u bj e ct s/ F a mili e s  
9. 7. 1  Rei m b urse me n t f or tr a vel, p ar ki n g a n d me als 
Rei m b urse me nt of par ki n g/tra vel c ost per s u bject, i ncl u di n g scree n fail ures = $ 2 0  
9. 7. 2  P a y me nts t o p are nt f or ti me a n d i nc o n ve nie nce (i.e. c o m pe ns ati o n) 
N o ne  
9. 7. 3  P a y me nts t o s u bject f or ti me, eff ort a n d i nc o n ve nie nce  (i.e. c o m pe ns ati o n) 
$ 2 5 f or st u d y visit + $ 2 5 f or 2 8 -da y h ea dac he diar y  
9. 7. 4  Gifts  
N o ne  
 
1 0  P U B LI C A TI O N  
We a ntici pate s e veral p u blicati o ns fr o m t hese st u dies.  We pla n t o p u blis h t he efficac y of 
ner ve bl oc ks, effecti ve ness of li d ocai ne crea m lea d -i n, a n d s u bject pre di ct ors of res p o nse t o 
li d ocai ne i njecti o n a n d crea m wit hi n 6-1 2 m o nt hs of st u d y c o m pleti o n.  St u dies of bli n di n g 
a n d e x pectati o n will be p u blis he d i n t he f oll o wi n g year.  
1 1  R E F E R E N C E S  
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2 0 1 6: a syste m atic a n alysis f or t he Gl o b al B ur de n of Dise ase St u dy 2 0 1 6.  La ncet, 
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a n alysis.  J A M A Pe diatr, 2 0 1 3. 1 6 7 ( 3): p. 2 5 0-8.  

 
  
 
 
 
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Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
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2 2.  
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Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
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2 5.  
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3 1.  
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3 6.  
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3 7.  
L. M. X. 4 ( Li d oc ai ne 4 %) . Ci nci n nati C hil dre n's Healt h T o pics  9/ 2 0 1 6 1 0/ 1 9/ 1 7]; 
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3 8.  
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3 9.  
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W olters Kl u wer, Pr o Q uest E b o o k Ce ntral.  

 
  
 
 
 
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Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
4 0.  
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