Clinical trial NCT03526874
Conditions: Chronic Migraine, Headache Episodic Migraine
Keywords: Pain Chronic Migraine Episodic Migraine Headache Nerve Block
Sponsor: Children's Hospital of Philadelphia
Start date: 2019-04-03; Completion date: 2023-03-10
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Migraine affects 10-28% of children and adolescents and yet 20-30% of patients are ineffectively treated with current oral and nasal options. Peripheral nerve blocks (PNBs), injections of local anesthetics over branches of the occipital and/or trigeminal nerves, have been associated with possible benefit for pediatric headaches in case series, and may be useful for both acute and preventive treatment of migraine for children who fail less invasive treatments. In fact, 80% of pediatric headache specialists reported using peripheral nerve blocks and carry low risk of serious side effects; however, peripheral nerve blocks have never been tested, formally, in a randomized pediatric trial.

By applying a novel design that utilizes lidocaine cream as a run-in step, investigators intend to test the efficacy of the most commonly used peripheral nerve block, the greater occipital nerve (GON) block, as an acute treatment for pediatric migraine and determine whether lidocaine cream leads to successful blinding of the injection.

The GON block is expected to prove effective in decreasing the pain of migraine, with lidocaine being superior to saline and lidocaine cream maintaining blinding.

Detailed description:
There are two substantial hurdles that must be overcome in designing a trial to test the efficacy of PNBs: high placebo response rate and possible unblinding. In order to test the efficacy of this commonly used treatment for children and adolescents with difficult-to-treat headache, we need utilize a trial design which will address the high placebo response rate and the potential lack of blinding.

About 194 children, recruited over a 3.5 year period at Children's Hospital of Philadelphia, will take part in this study. Participation will last about one month and involve one in-person study visit, and then completion of headache-related surveys, at home, for 28 days. Lidocaine cream lead-in will be used open-label for all subjects followed by double-blind randomized injections of active treatment (lidocaine) versus comparator (saline) in subjects who continue to have significant headache.

To accomplish our secondary objectives, we will examine how expectation is affected by perceived treatment, and how expectations, measured in patients, parents, and providers, influence outcomes in pediatric and adolescent acute migraine.

Arms: arm 1: Subjects randomized to this arm receive 2 mL injection of lidocaine 2% over the right and left greater occipital nerve at the baseline study visit.

All subjects then complete daily headache-related questions through a Headache Diary and other assessments for 28 days. arm 2: Subjects randomized to this arm receive 2 mL injection of preservative-free normal saline over the right and left greater occipital nerve at the baseline study visit.

All subjects then complete daily headache-related questions through a Headache Diary and other assessments for 28 days.
Interventions: intervention 1: Lidocaine 4% Topical Application Cream [LMX 4] intervention 2: Lidocaine Hydrochloride 2 mg/mL Injectable Solution intervention 3: Normal Saline
Intervention descriptions: intervention 1: Run-in Step: All subjects receive 32 mg (4 cm ribbon of cream) applied, bilaterally, over greater occipital nerve. intervention 2: Subjects, who continue to experience headache pain after the run-in step, receive 2 (2 mL) injections of the active treatment. intervention 3: Subjects, who continue to experience headache pain after the run-in step, receive 2 (2 mL) injections of the comparator.

Protocol documents:
Prot_SAP_003.pdf: 
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 


  
 
 
 
 
 
 
 
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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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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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
 
 
 
 
 
 
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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.   
 
 
 


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


 
  
 
 
 
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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  
1.  
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a n d ye ars live d wit h dis a bility f or 3 2 8 dise ases a n d i nj uries f or 1 9 5 c o u ntries, 1 9 9 0 -
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, 
2 0 1 7 . 3 9 0 ( 1 0 1 0 0): p. 1 2 1 1-1 2 5 9.  
2.  
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sc h o olc hil dre n. B MJ, 1 9 9 4. 3 0 9 ( 6 9 5 7): p. 7 6 5-9.  
3.  
S plit, W. a n d W. Ne u ma n, E pi de mi ol o gy of mi gr ai ne a m o n g st u de nts fr o m r a n d o mly 
selecte d sec o n d ary sc h o ols i n L o dz. Hea dac he, 1 9 9 9. 3 9 ( 7): p. 4 9 4-5 0 1.  
4.  
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5.  
P o wers, S. W., et al., Q u ality of life i n c hil d h o o d  mi gr ai nes: cli nic al i m p act a n d 
c o m p aris o n t o ot her c hr o nic ill nesses.  Pe diatrics, 2 0 0 3. 1 1 2 ( 1 Pt 1): p. e 1-5.  
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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  
7.  
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Pe di atric Mi gr ai ne.  Pe diatr Ne ur ol, 2 0 1 6. 5 8 : p. 3 7-4 0.  
8.  
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Mi gr ai ne.  N E n gl J Me d, 2 0 1 6.  
9.  
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i n a d ults: t he a meric a n he a d ac he s oci ety evi de nce assess me nt of mi gr ai ne 
p h ar m ac ot her a pies.  Hea dac he, 2 0 1 5. 5 5 ( 1): p. 3-2 0.  
1 0.  
Sil berstei n, S. D., et al., Evi de nce -b ase d g ui deli ne u p d a te: p h ar m ac ol o gic tre at me nt 
f or e pis o dic mi gr ai ne preve nti o n i n a d ults: re p ort of t he Q u ality St a n d ar ds 
S u bc o m mittee of t he A meric a n Ac a de my of Ne ur ol o gy a n d t he A meric a n He a d ac he 
S ociety.  Ne ur ol o g y, 2 0 1 2. 7 8 ( 1 7): p. 1 3 3 7-4 5.  
1 1.  
H olla n d, S., et al., Evi de nce -b ase d g ui d eli ne u p d ate: N S AI Ds a n d ot her 
c o m ple me nt ar y tre at me nts f or e pis o dic mi gr ai ne preve nti o n i n a d ults: re p ort of t he 
Q u ality St a n d ar ds S u bc o m mittee of t he A meric a n Ac a de my of Ne ur ol o gy a n d t he 
A meric a n He a d a c he S o ciety.  Ne ur ol o g y, 2 0 1 2. 7 8 ( 1 7): p. 1 3 4 6-5 3.  
1 2.  
Le wis, D. W., P. Wi n ner, a n d W. Wasie ws ki, T he pl ace b o res p o n der r ate i n c hil dre n 
a n d a d olesce nts.  Hea dac he, 2 0 0 5. 4 5 ( 3): p. 2 3 2-9.  
1 3.  
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2 0 1 5.  
1 4.  
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mi gr ai ne i n c hil dre n a n d a d olesce nts: A r a n d o miz e d cli nic al tri al.  J A M A: J o ur nal of 
t he A merica n M e dical Ass ociati o n, 2 0 1 3. 3 1 0 ( 2 4): p. 2 6 2 2-2 6 3 0.  
1 5.  
Ric her, L., et al. , Dr u gs f or t he ac ute tre at me nt of mi gr ai ne i n c hil dre n a n d 
a d olesce nts.  C oc hra n e D ata base S yst Re v, 2 0 1 6. 4 : p. C D 0 0 5 2 2 0. 
1 6.  
Mace d o, A., J. E. Ba n os, a n d M. Farre, Pl a ce b o res p o nse i n t he pr o p hyl axis of 
mi gr ai ne: a met a -a n alysis.  E ur J Pai n, 2 0 0 8. 1 2 ( 1): p. 6 8 -7 5.  
1 7.  
Le wis, D. W., et al., Effic acy of z ol mitri pt a n n as al s pr ay i n a d olesce nt mi gr ai ne.  
Pe diatrics, 2 0 0 7. 1 2 0 ( 2): p. 3 9 0-6.  
1 8.  
H o, T. W., et al., Effic acy a n d t oler a bility of riz atri pt a n i n pe di atric mi gr ai ne urs: 
res ults fr o m a r a n d o mize d, d o u ble-b li n d, pl ace b o-c o ntr olle d tri al usi n g a n ovel 
a d a ptive e nric h me nt d esi g n.  Ce p halal gia, 2 0 1 2. 3 2 ( 1 0): p. 7 5 0-6 5.  
1 9.  
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Hea dac he Re p, 2 0 1 3. 1 7 ( 7): p. 3 4 2. 
2 0.  
Sc h ul ma n, E., Ref r act ory mi gr ai ne - a revie w.  Hea dac he, 2 0 1 3. 5 3 ( 4): p. 5 9 9-6 1 3.  
2 1.  
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2 2.  
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2 3.  
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C ase Series.  J C hil d Ne ur ol, 2 0 1 4. 


 
  
 
 
 
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Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
2 4.  
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Tre at me nt of He a d ac hes i n C hil dre n & A d olesce nts . 2 0 1 6: A merica n Hea d ac he 
S ociet y 5 8t h A n n ual Scie ntific Meet i n g. 
2 5.  
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Bl ocks a n d Tri g ger P oi nt I njecti o ns f or Pe di atric He a d ac he: Res ults of a s urvey of 
t he A meric a n He a d ac he S ociety Pe di atric & A d ol esce nt Secti o n 2 0 1 6 ( Acce pte d f or 
p u b licati o n 6/ 8/ 1 6): Hea dac he. 
2 6.  
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2 7.  
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2 8.  
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bli n d r a n d o mize d c o ntr olle d cli nic al tri al.  Pai n Pract, 2 0 0 6. 6 ( 2): p. 8 9-9 5.  
2 9.  
I n a n, L. E., et al., Gr e ater occi pit al nerve bl ock a de f or t he tre at me nt of c hr o nic 
mi gr ai ne: a r a n d o mize d, m ultice nter, d o u ble -bli n d, a n d pl ace b o -c o ntr olle d st u dy.  
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3 0.  
Pala mar, D., et al., Ultr as o u n d -g ui de d gre ater occi pit al nerve bl ock: a n efficie nt 
tec h ni q ue i n c hr o nic refr act ory mi gr ai ne wit ho ut a ur a ?  Pai n P h ysicia n, 2 0 1 5. 1 8 ( 2): 
p. 1 5 3 -6 2.  
3 1.  
Si m m o ns, K., et al., P ai n a n d pl ace b o i n pe di atrics: a c o m pre h e nsive revie w of 
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3 2.  
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3 3.  
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3 4.  
Ric her, L., W. Crai g, a n d B. R o we, R a n d o mize d c o ntr olle d tri al of tre at me nt 
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1 4 9 6 -5 0 5.  
3 5.  
Y o u n ger, J., et al., D evel o p me nt of t he St a nf or d Ex pect ati o ns of Tre at me nt Sc ale 
( S E T S): a t o ol f or me as uri n g p atie nt o utc o me ex p ect a ncy i n cli nic al tri als. Cli n 
Trials, 2 0 1 2. 9 ( 6): p. 7 6 7-7 6.  
3 6.  
Lexic o m p O nli ne F or m ul ary f or t he C hil dre n's H os pit al of P hil a del p hi a . 
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]; 
A vaila ble fr o m: ht t ps://w w w.ci nci n natic hil dre ns. or g/ healt h/l/l m x 4 . 
3 8.  
Bl u me nfel d, A., et al., Ex pert c o nse ns us rec o m me n d ati o ns f or t he perf or m a nce of 
peri p her al nerve bl oc ks f or he a d ac hes --a n arr ative revie w.  Hea dac he, 2 0 1 3. 5 3 ( 3): 
p. 4 3 7 -4 6.  
3 9.  
S ures h, S. a n d C.J. C oté, C h a pter 4 7: L oc al A nest hetic S ol uti o ns f or Re gi o n al 
A nest hesi a i n I nf a nts, C hil dre n, a n d A d olesce nts , i n Ne o n at al a n d Pe di atric 
P h ar m ac ol o gy : T her a pe utic Pri nci ples i n Pr actice , S.J. Yaffe, E dit or. 2 0 1 0, 
W olters Kl u wer, Pr o Q uest E b o o k Ce ntral.  


 
  
 
 
 
2 9  
Pr ot o c ol Versi o n  7 : 07 . 29 . 2 0 22  
4 0.  
Freita g, F., S. Dia m o n d, a n d E. L oc k hart, 2 0 0 1 A n n u al Meeti n g of t he A meric a n 
S ociety f or Cli nic al P h ar m ac ol o gy a n d T her a pe utics. Orl a n d o, Fl ori d a, U S A. M arc h 
6 -1 0, 2 0 0 1. A bstr acts.  Cli n P har mac ol T her, 2 0 0 1. 6 9 ( 2): p. P 1-1 2 8.  
4 1.  
S uria n o, R. P atc h O n F ore he a d C o ul d St o p Mi gr ai nes . [ ne ws pa p er article] 2 0 0 1  
A u g ust 1 6, 2 0 1 6]; A vaila ble fr o m: htt p://articles. orla n d ose nti nel.c o m/ 2 0 0 1 -0 3 -
0 8/ ne ws/ 0 1 0 3 0 8 0 0 8 6 _ 1 _treat -mi grai nes -patc h -a n est hesia. 
4 2.  
Sz per ka, C. L., A. A. Gelf a n d, a n d A. D. Hers he y, P atter ns of Use of Peri p her al Nerve 
Bl ocks a n d Tri g ger P oi nt I njecti o ns f or Pe di atric He a d ac he: Res ults of a S urvey of 
t he A meric a n He a d ac he S ociety Pe di atric a n d A d olesce nt Secti o n. Hea dac he, 2 0 1 6. 
5 6 ( 1 0): p. 1 5 9 7-1 6 0 7.  
4 3.  
As h ke nazi, A., et al., Peri p her al nerve bl ocks a n d tri g ger p o i nt i njecti o ns i n 
he a d ac he m a n a g e me nt - a syste m atic revie w a n d s u g gesti o ns f or f ut ure rese arc h.  
Hea dac he, 2 0 1 0. 5 0 ( 6): p. 9 4 3-5 2.  
4 4.  
See ger, T. A., et al., Occi pit al Nerve Bl ocks f or Pe di atric P osttr a u m atic He a d ac he: A 
C ase Series.  J C hil d Ne ur ol, 2 0 1 5. 3 0 ( 9): p. 1 1 4 2-6.  
4 5.  
As h ke nazi, A., et al., Gre ater occi pit al nerve bl ock usi n g l oc al a n aest hetics al o ne or 
wit h tri a mci n ol o ne f or tr a nsf or me d mi gr ai ne: a r a n d o mise d c o m p ar ative st u dy.  J 
Ne ur ol Ne ur os ur g Ps yc hi atr y, 2 0 0 8. 7 9 ( 4): p. 4 1 5-7.  
4 6.  
cli nical gate. c o m, f 1 0 5 -0 1 -9 7 8 1 4 5 5 7 7 5 7 7 4.j p g, E dit or.  
4 7.  
B yi n gt o n, R. P., J. D. C ur b, a n d M. E. Matts o n, Assess me nt of d o u ble -bli n d ness at t he 
c o ncl usi o n of t he bet a -Bl ocker H e art Att ack Tri al.  J A M A, 1 9 8 5. 2 5 3 ( 1 2): p. 1 7 3 3-6.  
4 8.  
Sti ns o n, J. N., et al., Syste m atic revie w o f t he psyc h o metric pr o perties, 
i nter pret a bility a n d fe asi bility of self-re p ort p ai n i nte nsity me as ures f or use i n 
cli nic al tri als i n c hil dre n a n d a d olesce nts.  Pai n, 2 0 0 6. 1 2 5 ( 1-2): p. 1 4 3 -5 7.  
4 9.  
Tfelt -Ha ns e n, P., et al., G ui deli nes f or c o ntr olle d tri als o f dr u gs i n mi gr ai ne: t hir d 
e diti o n. A g ui de f or i nvesti g at ors.  Ce p halal gia, 2 0 1 2. 3 2 ( 1): p. 6-3 8.  
5 0.  
Y o u n g, W., et al., T he first 5 mi n utes after gre ater occi pit al nerve bl ock.  Hea dac he, 
2 0 0 8. 4 8 ( 7): p. 1 1 2 6-8.  
5 1.  
Farrar, J. T., et al., Cli nic al i m p ort a nc e of c h a n ges i n c hr o nic p ai n i nte nsity me as ure d 
o n a n 1 1 -p oi nt n u meric al p ai n r ati n g sc ale.  Pai n, 2 0 0 1. 9 4 ( 2): p. 1 4 9-5 8.  
5 2.  
Aller ga n. A St u dy Usi n g B ot uli n u m T oxi n Ty pe A as He a d ac he Pr o p h yl axis i n 
A d olesce nts Wit h C hr o nic Mi gr ai ne .  2 0 1 7 9/ 4/ 1 7 1 0/ 2 8/ 1 7]; A vaila ble fr o m: 
htt ps://cli nicaltrials. g o v/ct 2/ s h o w/res ults/ N C T 0 1 6 6 2 4 9 2?ter m =a d ol esce nt + b ot o x &c o
n d = Mi grai ne &ra n k = 1 &s ect = X 4 3 0 1 2 5 6 # ot hr.  
5 3.  
Z he n g, H., et al., Ass oci ati o n of pre - a n d p ost -tre at me nt ex pect ati o ns wit h 
i m pr ove me nts after ac u p u nct ure i n p atie nts wit h mi gr ai ne . Ac u p u nct Me d, 2 0 1 5. 
3 3 ( 2): p. 1 2 1-8.  
5 4.  
G u y, W. E C D E U ass ess me nt ma n ual f or ps yc h o p har mac ol o g y. U S De part me nt of 
Healt h, E d ucati o n, a n d Welfare, R oc k ville, M D, 1 9 7 6.  
 
 

ICF_002.pdf: 
CHOP IRB#: IRB 18-014939
Effective Date: 3/3/2021
Expiration Date: 3/2/2022
Page 1 of 13
Main Study Informed Consent Form and HIPAA Authorization
  Study Title: 
Occipital Nerve Blocks for Acute Treatment of Pediatric Migraine
Version Date:  
February 3, 2021
Principal Investigator:
Dr. Christina Szperka
(215) 590-1719
Emergency Contact:
Dr. Christina Szperka
(215) 590-1000
Ask to page the Neurology 
Fellow on call
You and your child may be eligible to take part in a research study. This form gives you 
important information about the study. It describes the purpose of this research study, and 
the risks and possible benefits of participating. 
If there is anything in this form you do not understand, please ask questions. Please take 
your time. You do not have to take part in this study if you do not want to. If you take 
part, you can leave the study at any time. 
In the sections that follow, the word “we” means the study doctor and other research 
staff. If you are a parent or legal guardian who is giving permission for a child, please 
note that the word “you” refers to your child. 
Parents or guardians may also be eligible to participate in this study and its research 
questionnaire/survey portion.  Please note that this study does not require 
parents/guardians to undergo any other research procedure.  
Why are you being asked to take part in this study?
You are being asked to take part in this research study because you have a bad headache 
that has not gone away with usual medicines, and additional treatment might help. 
What is the purpose of this research study? 
The purpose of this research study is to see if occipital nerve blocks can treat children 
with bad headaches. Occipital nerve blocks will put medicine over the nerves in the back 
of your head. 
How many people will take part? 
Up to 97 primary child subjects will be enrolled and 97 parents/legal guardians will also 
be enrolled. 194 subjects will be enrolled in total.
What is involved in the study?
During the study, we will ask you to describe your headache.  We will also ask you, and 
your parent or guardian, how you feel about the treatments. In this study, once you have 
signed consent, to make sure you are eligible, we will first start with some additional 
screening procedures (if not already done): pregnancy test, interview, and/or medical 


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Expiration Date: 3/2/2022
Page 2 of 13
chart review.  Then, we will apply numbing cream on the back of your head. This step 
may make the headache go away and may decrease the pain of injection.  After 30 
minutes, if your headache is gone, or so low that you do not want any more treatment, we 
will not do any more research treatments. If you still have a headache, we will inject the 
nerves on the back of your head with either lidocaine or saline.  The choice of medicine 
will be decided at random, like the toss of a coin.  There is an equal chance that you will 
receive either study medicine.  
If the research treatments do not make your headache go away, the study doctor will 
discuss non-study treatments that can be tried. If you decide not to participate in the 
study, we will discuss with you the same non-study treatments.
How long will you be in this study?
If you agree to take part, your participation will last about 1 month. You will have to 
complete 1 in-person study visit and then, when you go home, you will be asked to 
answer questions, daily, in a headache diary and other surveys for 28 days.
What are the study procedures? 
Some of the procedures in this study will be repeated several times. The study involves 
the following tests and procedures. 
Interviews: A team member will take your medical history, along with a listing of any 
medications you are taking. Throughout the study, you will be asked to report if 
you think that anything bad has happened as a result of the study. 
Medical Record Review: We will review your medical records throughout the study to 
collect information about your medical history, current health, headache 
diagnosis, treatments, and medications.
Physical Examination: Exams will be conducted during the study including complete 
medical and neurological examinations as well as measurements of height, 
weight, blood pressure, heart rate, and head circumference.  These exams will also 
include a fundoscopic exam in which we will look at your eyes using different 
instruments. The light from the instruments used may seem very bright. 
   Nerve Block Procedure: You will have numbing cream applied to the back of your 
head. In a clinic room, the study doctor will have you sit on a chair in front of the 
exam table and lay your forehead on the table. She will apply the cream onto your 
scalp under your hair on the back of your head. You can then sit up and move 
around while the cream takes effect. After 30 minutes, the cream will be wiped 
off with gauze. 
If you still have a headache after 30 minutes, the study doctor will perform 
occipital nerve blocks. She will have you sit in a chair and put your forehead on 
the exam table again. She will feel for the bones in the back of your head, and 
push to find a sore spot, which corresponds to the occipital nerve. She will then 
inject lidocaine or saline with a small needle over the nerve. She will repeat this 
on the other side of your head. Each injection will take a few seconds. During that 
time, you need to hold still, but then you can move around again. 
Pregnancy Test (Female subjects only): We will collect urine to complete a pregnancy 
test. If you are female and have already started having periods, you will be asked 


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Effective Date: 3/3/2021
Expiration Date: 3/2/2022
Page 3 of 13
to take a urine pregnancy test before starting the study. The results will be shared 
with you and not with your parent(s). If you are found to be pregnant, you will not 
be able to participate/continue participating in the study. We encourage you to 
share the results of a positive pregnancy test with your parents but we cannot 
make you.  
Questionnaires: You will be asked to complete a few questionnaires throughout the study. 
We will ask you how the pain affects your life and your opinion about the study 
treatment(s). We will also ask your parent or guardian to complete some of these 
questionnaires. These short questionnaires will take about 5 minutes to complete. 
Headache Diary: You will be asked to keep a daily diary of headache symptoms for 28 
days following the Study Visit. Each day, answering the questions will take about 
5 - 7 minutes to complete. 
You can choose to answer the questions on paper or electronically through text 
messages.  If you prefer to keep a paper diary, then, weekly, we will ask you to 
fax or scan and email the pages.  If you prefer to use texting, then our CareBot 
will text you questions every day. Some of these text messages will include links. 
You will be asked to click on the link and answer more questions. 
If you forget to respond, our CareBot will remind you. If you do not respond to 
CareBot or you do not send us any completed questions on paper, then our study 
team will call you.  
What are the risks of this study? 
Taking part in a research study involves inconveniences and risks. If you have any 
questions about any of the possible risks listed below, you should talk to your study 
doctor or your regular doctor. 
While in this study, you are at risk for side effects. Based on both the experience at 
CHOP and studies from other places, minor side effects are common but major side 
effects are very rare. 
Risks associated with lidocaine cream:

Numbness or abnormal sensation at the site of the cream is common

Redness or irritation at the site of the cream can occur

Rash is uncommon
Risks associated with a nerve block procedure:

Mild nervousness is common. Some people also feel silly or giddy after the 
procedure ends. 

Panic feelings including nervousness, breathing fast, racing heart, and hot 
flashes occur slightly more often, but go away after the procedure stops or 
ends. 

Syncope (passing out) related to anxiety happens in less than 1 per 100 people


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Expiration Date: 3/2/2022
Page 4 of 13
Risks associated with lidocaine or saline injection for nerve block:

Pain or burning with injection

Numbness of the skin

Dizziness

Worsened headache 
Reproductive Risks: 
There are no known reproductive risks involved in this study. The lidocaine and saline 
used in the nerve block injections are not known to cause any complications in pregnancy 
for either the pregnant woman or fetus. Neither substance is expected to cause problems 
for breast-fed infants. 
Risks of Breach of Privacy and Confidentiality:
As with any study involving collection of data, there is the possibility of breach of 
confidentiality of data. Every precaution will be taken to secure participants' personal 
information to ensure confidentiality.
At the time of participation, each participant will be assigned a study identification 
number. This number will be used on data collection forms and in the database instead of 
names and other private information. A separate list will be maintained that will link each 
participant’s name to the study identification number for future reference and 
communication.
Risks associated with completing questionnaires and interviews:
There are no physical risks but you might experience momentary embarrassment or 
discomfort. You do not have to answer any questions that make you too uncomfortable.
Risks associated with physical exams:
There are no physical risks but you might experience momentary embarrassment or 
discomfort. The exam is similar to those that are performed as part of routine medical 
care.  There is very little risk of harm from the eye examination.
When blood pressure is taken during physical exams, the blood pressure cuff may cause 
discomfort or bruising to the upper arm.


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Expiration Date: 3/2/2022
Page 5 of 13
Are there any benefits to taking part in this study?
Your headache might get better with the study procedures. Data from previous studies 
show that nerve blocks usually help headache, regardless of what medicine is used.  
However, we cannot guarantee or promise that you will receive any direct benefit by 
participating in this study. The knowledge gained from this research may help doctors 
determine if occipital nerve blocks with either numbing medicine or saline are helpful as 
an acute headache treatment in children. 
Do you need to give your consent in order to participate? 
If you decide to participate in this study, you must sign this form. A copy will be given to 
you to keep as a record. 
What are your responsibilities?
Please consider the study time commitments and responsibilities as a research subject 
when making your decision about participating in this study. You will need to remain still 
for a few seconds during the injections and follow the study doctor’s instructions. 
What happens if you decide not to take part in this study? 
Participation in this study is voluntary. You do not have to take part in order to receive 
care at CHOP.  If you decide not to take part or if you change your mind later there will 
be no penalties or loss of any benefits to which you are otherwise entitled. 
Can you stop your participation in the study early?
You can stop being in the study at any time. You do not have to give a reason.
Can the study doctor take you out of the study early?

You cannot meet all of the requirements of the study.  

You have a bad reaction to the cream or the first nerve block injection. If this 
happens we will not do any more study treatments, but we will ask you to 
keep a diary of symptoms for 28 days after the Study Visit.
What choices do you have other than this study?
There are options for you other than this study including: 

Receiving usual care for your headache outside this study

Not participation in this study. 

You may discuss other options available to you with your doctor.
What about privacy, authorization for use of Personal Health Information (PHI) 
and confidentiality? 
As part of this research, health information about you will be collected. This will include 
information from medical records, procedures, interviews, tests and questionnaires that 
you and your parent or guardian complete. Information related to your medical care at 
CHOP will go in your medical record. This could include physical exams or tests done in 
the clinical lab. Medical records are available to CHOP staff. Staff will view your records 


CHOP IRB#: IRB 18-014939
Effective Date: 3/3/2021
Expiration Date: 3/2/2022
Page 6 of 13
only when required as part of their job. Staff are required to keep your information 
private. Information that could identify you will not be shared with anyone - unless you 
provide your written consent, or it is required or allowed by law. Laboratory test results 
will appear in your medical record.  We will do our best to keep your personal 
information private and confidential. However, we cannot guarantee absolute 
confidentiality. Your personal information may be disclosed if required by law. 
The results of this study may be shown at meetings and published in journals to inform 
other doctors and health professionals. We will keep your identity private in any 
publication or presentation.
Several people and organizations may review or receive your identifiable information. 
They will need this information to conduct the research, to assure the quality of the data, 
or to analyze the data. These groups include: 

Members of the research team and other authorized staff at Children’s Hospital 
of Philadelphia (CHOP).

People from agencies and organizations that perform independent accreditation 
and/or oversight of research; such as the Department of Health and Human 
Services, Office for Human Research Protections.

An Independent Medical Monitor performing data and safety monitoring for 
this study

The National Institutes of Health who is sponsoring this research

Researchers at outside hospitals including University of Pennsylvania and 
Cincinnati Children’s Hospital who will help with the analysis of study data.  
The data will be labeled with a unique code and these researchers will not 
know who you are.  Private information such as name, birth date or medical 
record number will not be shared.

Patiently, Inc. and its representatives, who will help with setting up our texting 
CareBot for this study.
By law, CHOP is required to protect your health information. The research staff will only 
allow access to your health information to the groups listed above.  By signing this 
document, you are authorizing CHOP to use and/or release your health information for 
this research. Some of the organizations listed above may not be required to protect your 
information under Federal privacy laws. If permitted by law, they may be allowed to 
share it with others without your permission.  
There is no set time for destroying the information that will be collected for this study. 
Your permission to use and share the information and data from this study will continue 
until the research study ends and will not expire. Researchers continue to analyze data for 
many years and it is not possible to know when they will be completely done. 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from 
the National Institutes of Health. With this Certificate, the researchers cannot be forced to 
disclose information that may identify you, even by a court subpoena, in any federal, 
state, or local civil, criminal, administrative, legislative, or other proceedings. The 


CHOP IRB#: IRB 18-014939
Effective Date: 3/3/2021
Expiration Date: 3/2/2022
Page 7 of 13
researchers will use the Certificate to resist any demands for information that would 
identify you, except as explained below.
The Certificate cannot be used to resist a demand for information from personnel of the 
United States Government that is used for auditing or evaluation of Federally funded 
projects or for information that must be disclosed in order to meet the requirements of the 
federal Food and Drug Administration (FDA).
You should understand that a Certificate of Confidentiality does not prevent you or a 
member of your family from voluntarily releasing information about yourself or your 
involvement in this research. If an insurer, medical care provider, or other person obtains 
your written consent to receive research information, then the researchers will not use the 
Certificate to withhold that information.
The Certificate of Confidentiality does not prevent the researchers from disclosing, 
without your consent, information that they are required by law to disclose to government 
authorities. For example, researchers must comply with laws requiring the reporting of 
suspected child abuse and neglect and communicable diseases. 
Can you change your mind about the use of personal information?
You may change your mind and withdraw your permission to use and disclose your 
health information at any time. To take back your permission, it is preferred that you 
inform the investigator in writing. 
Dr. Christina Szperka
The Children’s Hospital of Philadelphia
Division of Neurology
34th Street and Civic Center Blvd.
Philadelphia, PA 19104
In the letter, state that you changed your mind and do not want any more of your health 
information collected. The personal information that has been collected already will be 
used if necessary for the research. No new information will be collected. If you withdraw 
your permission to use your personal health information, you will be withdrawn from the 
study.
Additional Information 
An Independent Medical Monitor will be reviewing the data from this research through 
the study.  
You will be informed if changes to the study are needed to protect your health. You will be 
told about any new information that could affect your willingness to stay in the study, such as 
new risks, benefits or alternative treatments.


CHOP IRB#: IRB 18-014939
Effective Date: 3/3/2021
Expiration Date: 3/2/2022
Page 8 of 13
Financial Information 
While you are in this study, the cost of your usual medical care – procedures, medications 
and doctor visits – will continue to be billed to you or your insurance.  If your headache 
does not get better with study treatments, or gets worse with study treatments, you will be 
offered other usual care options.  Those non-study treatments will be billed to you or your 
insurance.
Will there be any additional costs? 
There may be additional costs to you by taking part in this study; standard message and 
data rates or charges may apply when receiving or sending text messages or completing 
the web-based questionnaires on a mobile device.  Check with your wireless carrier if 
you have any questions or concerns about your plan or possible costs. You will not be 
reimbursed for any of these associated or additional costs.  
The NIH is providing financial support and material for this study.  The following 
research procedures, study drugs and study visits will be paid by the NIH: 

Cost of parking

Cost of study drug

Study doctor’s time to perform procedures

Urine pregnancy tests for pregnancy, if applicable
Will you be paid for taking part in this study? 
Parents will be reimbursed a per diem of $20 to offset the cost of travel and parking. 
Participants will be paid $25 for their time and effort for the study visit, and an additional 
$25 if at least 23 days (out of 28) worth of the headache diary and survey questions are 
completed. 
If you receive payment using a bankcard, the bank will have access to identifiable 
information.  The bank will not have access to any medical information.  
We may share your data with third parties (other researchers/institutions or for profit 
companies). If there are patents or products that result from the research, the third parties 
may make money from the research. You will not receive any financial benefit from 
research done on your data.
Who is funding this research study?
The National Institutes of Health is providing funding for this study. 
What if you have questions about the study?
If you have questions about the study, call the study doctor, Dr. Szperka at 215-590-1719. 
You may also talk to your own doctor if you have questions or concerns.
The Institutional Review Board (IRB) at The Children’s Hospital of Philadelphia has 
reviewed and approved this study. The IRB looks at research studies like these and makes 
sure research subjects’ rights and welfare are protected. If you have questions about your 
rights or if you have a complaint, you can call the IRB Office at 215-590-2830. 


CHOP IRB#: IRB 18-014939
Effective Date: 3/3/2021
Expiration Date: 3/2/2022
Page 9 of 13
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time. 
What happens if you are injured during the study? 
If you are hurt or get sick from something that was done as part of this study, doctors at 
the clinic or hospital can arrange for emergency medical care. The Hospital does not offer 
financial compensation or payment for injuries due to participation in this research. 
You and your insurance company will be billed for the costs of any care or injuries. 
If you think you have been injured from taking part in this study, call Dr. Szperka at 215-
590-1719. She can go over things with you, let you know of resources that may be 
available and give you information on what you need to do.
In case of injury resulting from this study, you will not lose any legal rights by signing 
this form.
Consent for Use of Data for Future Research 
As part of the study, we will collect data.  We may wish to use this information in a 
future study about headache or other conditions. Your information will be given a unique 
code and will not include information that can identify you. Any identifiable data will be 
stored on a secure electronic server at CHOP.  A master list linking the code to 
information that can identify you may be kept permanently in a computer database at 
CHOP. Only the study doctors and those working with them on this study will be able to 
see information that can identify you.
If you leave the study, you can ask to have the data collected about you removed. You 
can also ask us to remove information that identifies you from the data. 
Please indicate whether you will allow the data to be used for future research by putting 
your initials next to one of the following choices: 
_____ (initials)  The data may be used for this study only.
_____ (initials)  The data may be used for other future research studies. If the data are 
shared outside of CHOP, no identifiable information will be included. 
(Note: For Spanish speaking subjects, initialing will be performed by the study team 
member obtaining consent.)


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Effective Date: 3/3/2021
Expiration Date: 3/2/2022
Page 10 of 13
Consent to Take Part in this Research Study and Authorization to Use and 
Disclose Health Information for the Research
The research study and consent form have been explained to you by:
Person Obtaining Consent
Signature of Person Obtaining Consent
Date
By signing this form, you are indicating that you have had your questions answered, you agree to 
take part and to allow your child to take part in this research study, and you are legally 
authorized to consent to your and your child’s participation. You are also agreeing to let CHOP 
use and share the health information that will be collected for this study, as explained above. If 
you don’t agree to the collection, use, and sharing of health information, you and your child 
cannot participate in this study. 
NOTE: A foster parent is not legally authorized to consent for a foster child’s participation.
Consent for Child’s Participation
Name of Subject
Signature of Subject 
(18 years or older)
Date
Name of Authorized Representative 
Relation to subject:
 Parent   
 Legal Guardian
Signature of Authorized Representative
Date
Consent for Parent’s Participation
Name of Parent or Guardian
Signature of Parent or Guardian
Date


CHOP IRB#: IRB 18-014939
Effective Date: 3/3/2021
Expiration Date: 3/2/2022
Page 11 of 13
Child Assent to Take Part in this Research Study
For children capable of providing assent:
I have explained this study and the procedures involved to __________________ in 
terms he/she could understand and that he/she freely assented to take part in this study.
Person Obtaining Assent
Signature of Person Obtaining Assent
Date
This study has been explained to me and I agree to take part.
Signature of Subject (optional)
Date


CHOP IRB#: IRB 18-014939
Effective Date: 3/3/2021
Expiration Date: 3/2/2022
Page 12 of 13
STUDY SUMMARY DOCUMENT (NON-ENGLISH SPEAKERS)
Consent to Take Part in this Research Study and Authorization to Disclose Health 
Information for Research
Name of Child Subject
Name of Parent or Guardian Subject
Name of Authorized Representative 
(if different than child subject)
Relation to subject:
 Parent  
 Legal Guardian
The research study and consent form have been explained to the subject and parent/guardian.
By signing this form, you are indicating that you have answered the subject’s or parent’s/legal 
guardian’s questions, they have agreed to take part in this research study and they are legally 
authorized to consent to their and their child’s participation. They have also agreed to let CHOP 
use and share their and their child’s health information as explained above. If they don’t agree to 
the collection, use and sharing of their  and their child’s health information, they cannot 
participate in this study.
Person Obtaining Consent
Signature of Person Obtaining Consent
Date:
Witness/Interpreter
By signing this form, you are indicating that 

The information in the Summary Document as well as any additional information conveyed 
by the person obtaining consent was presented to the subject in a language preferred by and 
understandable to the subject; and

The subject’s questions were interpreted and the responses of the person obtaining consent 
were presented in a language preferred by and understandable to the subject.

At the conclusion of the consent conference, the subject was asked in a language preferred by 
and understandable to the subject if s/he understood the information in the Summary 
Document as well as any additional information conveyed by the person obtaining consent 
(including responses to the subject's questions) and responded affirmatively.
Name of Witness/Interpreter
Signature of Witness/Interpreter
Date:


CHOP IRB#: IRB 18-014939
Effective Date: 3/3/2021
Expiration Date: 3/2/2022
Page 13 of 13
Child Assent to Take Part in this Research Study 
For children capable of providing assent:
I have explained this study and the procedures involved to __________________ in terms he/she 
could understand and that he/she freely assented to take part in this study.
Person Obtaining Assent
Signature of Person Obtaining Assent
Date
Witness/Interpreter
By signing this form, you are indicating that 

The information in the Summary Document as well as any additional information conveyed 
by the person obtaining assent was presented to the subject in a language preferred by and 
understandable to the subject; and

The subject’s questions were interpreted and the responses of the person obtaining assent 
were presented in a language preferred by and understandable to the subject.
At the conclusion of the consent conference, the subject was asked in a language preferred by 
and understandable to the subject if s/he understood the information in the Summary Document 
as well as any additional information conveyed by the person obtaining assent (including 
responses to the subject's questions) and responded affirmatively.
Name of Witness/Interpreter
Signature of Witness/Interpreter
Date