BOTOX® (onabotulinumtoxinA) Treatment of Masseter Muscle Prominence: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study
Phase: PHASE3
Conditions: Masseter Muscle Prominence
Sponsor: AbbVie

 
 
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Title P a ge 
Pr ot oc ol Title:  B O T O X®  ( o na b ot uli n u mt o xi n A) Treat me nt of Masseter M uscle Pr o mi ne nce: A 
P hase 3, M ultice nter, Ra n d o mize d, D o u bl e- Bli n d, Place b o- C o ntr olle d St u d y  
Pr ot oc ol N u m ber:  1 7 8 9- 3 0 1- 0 0 8 
Pr o d uct:  O na b ot uli n u mt o xi n A  
Brief Pr ot oc ol Title:  B O T O X Treat me nt of Masseter M uscle Pr o mi ne nce  
De vel o p me nt P h ase:  3 
S p o ns or N a me a n d Le g al Re gistere d A d dress:   
Aller ga n Sales L L C 
5 Giral da Far ms 
Ma dis o n, NJ 0 7 9 4 0 
U S A 
a n d 
Aller ga n Li mite d, 
1 st Fl o or Marl o w I nter nati o nal, 
T he Par k wa y, Marl o w, B uc ki n g ha ms hire S L 7 1 Y L 
U nite d Ki n g d o m 
Re g ul at or y A ge nc y I de ntif yi n g N u m ber: I N D 1 3 3, 0 3 5 
E mer ge nc y Tele p h o ne N u m ber 
Refer t o t he St u d y C o ntacts List  
S A E Re p orti n g F a x N u m ber/ E m ail: 
 
B usi ness U nit 
/ Le gac y 
Or ga nizati o n
 E mail
  
P h o ne
  
Fa x
 
Aller ga n 
mail t o: 
  
N ot a p plica ble  
+ 1- 7 1 4- 7 9 6- 9 5 0 4 
Bac k u p:  
+ 1- 7 1 4- 2 4 6- 5 2 9 5 
S p o ns or Si g n at or y: 
  
Ass ociate Vice Presi de nt a n d Secti o n Hea d 
Me dical Aest hetics  
Refer t o t he fi nal pa ge of t his pr ot oc ol f o r electr o nic si g nat ure a n d date of a p pr o val. 
 
 
 
N C T 0 4 0 7 3 3 0 3

 
 
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7.  
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al........................................................................................ 3 7  
7. 1.  
Disc o nti n uati o n of St u d y I nter ve nti o n ............................................................................ 3 7  
7. 2.  
Partici pa nt Disc o nti n uati o n/ W it h dra wal fr o m t he St u d y ................................................ 3 7 
7. 3.  
L ost t o F oll o w U p ........................................................................................................... 3 8  
8.  
St u d y Assess me nts a n d Pr oce d ures............................................................................. 3 9  
8. 1.  
Efficac y Assess me nts ..................................................................................................... 3 9  
8. 1. 1.  
Pri mar y Efficac y Assess me nt ......................................................................................... 3 9  
8. 1. 2.  
Sec o n dar y Efficac y Assess me nts .................................................................................... 4 0  
8. 1. 3.  
Ot her Efficac y Assess me nts ........................................................................................... 4 1  
8. 2.  
Safet y Assess me nts ......................................................................................................... 4 2  
8. 2. 1.  
Vital Si g ns ................................................................................................................... .... 4 2 
8. 2. 2.  
Pre g na nc y Testi n g ........................................................................................................... 4 2  
8. 2. 3.  
Scree ni n g f or T MJ D ....................................................................................................... 4 2  
8. 3.  
A d verse E ve nts a n d Seri o us A d verse E ve nts ................................................................. 4 3  
8. 3. 1.  
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E ve nt I nf or mati o n ................................................................................ 4 3  
8. 3. 2.  
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts ........................................................................................................................ ...... 4 3 
8. 3. 3.  
F oll o w- u p of A d verse E ve nts a n d Seri o us A d verse E ve nts ........................................... 4 3  
8. 3. 4.  
Re g ulat or y Re p orti n g Re q uire me nts f o r Seri o us A d verse E ve nts .................................. 4 4 
8. 3. 5.  
Pre g na nc y ..................................................................................................................... ... 4 4 
8. 3. 6.  
A d verse E ve nts of S pecial I nterest ................................................................................. 4 5  
8. 3. 7.  
Me dicati o n Err ors ........................................................................................................... 4 5  
8. 4.  
Treat me nt of O ver d ose ................................................................................................... 4 5  
8. 5.  
P har mac o ki netics ............................................................................................................ 4 5  
8. 6.  
P har mac o d y na mics ......................................................................................................... 4 5  
8. 7.  
Ge netics ...................................................................................................................... .... 4 6 
8. 8.  
Bi o mar kers a n d Ot her Assess me nts ............................................................................... 4 6  
8. 9.  
Healt h Ec o n o mics ........................................................................................................... 4 6  
9.  
St atistic al C o nsi der ati o ns ............................................................................................. 4 6  
9. 1.  
Statistical H y p ot heses ..................................................................................................... 4 6  
9. 2.  
Sa m ple Size Deter mi nati o n ............................................................................................ 4 6  
9. 3.  
P o p ulati o ns f or A nal yses ................................................................................................ 4 6  
9. 4.  
Statistical A nal yses ......................................................................................................... 4 7  
9. 4. 1.  
Efficac y A nal yses ........................................................................................................... 4 7  
9. 4. 1. 1.  
A nal ysis E n d p oi nts ............................................................................................. 4 7  
9. 4. 1. 2.  
Pri mar y A nal yses ............................................................................................... 4 8  
9. 4. 1. 3.  
Sec o n dar y A nal yses ........................................................................................... 4 9  
9. 4. 2.  
Safet y A nal yses ............................................................................................................... 4 9  
9. 4. 2. 1.  
A d verse E ve nts ................................................................................................... 4 9  
9. 4. 2. 2.  
Vital Si g ns .......................................................................................................... 5 0  
9. 4. 3.  
S u b gr o u p A nal yses ......................................................................................................... 5 0  
 
 
 

 
 
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9. 5.  
I nteri m A nal yses ............................................................................................................. 50  
1 0.  
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns .................................. 5 1  
1 0. 1.  
A p pe n di x 1: Re g ulat or y, Et hical, a n d St u d y O versi g ht 
C o nsi derati o ns ................................................................................................................ 5 1  
1 0. 1. 1.  Re g ulat or y a n d Et hical C o nsi derati o ns ........................................................................... 5 1  
1 0. 1. 2.  Fi na ncial Discl os ure ........................................................................................................ 5 1  
1 0. 1. 3.  I nf or me d C o nse nt Pr ocess .............................................................................................. 5 2 
1 0. 1. 4.  Data Pr otecti o n................................................................................................................ 5 2  
1 0. 1. 5.  P osti n g Cli nical St u d y Data ............................................................................................ 5 2  
1 0. 1. 6.  Data Q ualit y Ass ura nce .................................................................................................. 5 3  
1 0. 1. 7.  S o urce D oc u me nts .......................................................................................................... 5 3  
1 0. 1. 8.  St u d y a n d Site Cl os ure .................................................................................................... 5 3  
1 0. 1. 9.  P u blicati o n P olic y ........................................................................................................... 5 4  
1 0. 1. 1 0.  C o m plia nce wit h Pr ot oc ol............................................................................................... 5 4  
1 0. 2.  
A p pe n di x 2: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or 
Rec or di n g, E val uati n g, F oll o w- u p, a n d Re p orti n g ......................................................... 5 5  
Defi niti o n of A E ............................................................................................................................ 5 5  
Defi niti o n of S A E ............................................................................................................. ............. 5 6 
Rec or di n g a n d F oll o w- U p of A Es a n d/ or S A Es ............................................................................ 5 7  
Re p orti n g of S A Es ............................................................................................................. ............ 5 9 
1 0. 3.  
A p pe n di x 3: A b bre viati o ns ............................................................................................. 6 0  
1 0. 4.  
A p pe n di x 4: Sta n dar d Disc o nti n uati o n Criteria.............................................................. 6 2  
1 0. 5.  
A p pe n di x 5: St u d y Ta b ular S u m mar y ............................................................................ 6 3  
1 0. 6.  
A p pe n di x 6: C o ntrace pti ve G ui da nce a n d C ollecti o n of 
Pre g na nc y I nf or mati o n ................................................................................................... 6 5  
Defi niti o ns: .................................................................................................................. .................. 6 5 
C o ntrace pti o n G ui da nce: ....................................................................................................... ........ 6 5 
Pre g na nc y Testi n g: ............................................................................................................ ............. 6 6 
C ollecti o n of Pre g na nc y I nf or mati o n: .......................................................................................... . 6 7 
1 0. 7.  
1 0. 7. 1.  
1 0. 7. 2.  
1 0. 7. 3.  
1 0. 7. 4.  
1 0. 8.  
1 0. 8. 1.  
1 0. 8. 2.  
1 0. 8. 3.  
1 0. 8. 4.  
1 0. 8. 5.  
1 0. 8. 6.  
 
 
 

 
 
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1 1.  
Refere nces .................................................................................................................... .. 8 6 
 
List of Ta bles 
Ta ble 1 – 1  
Sc he d ule of Visits a n d Pr oce d ures .................................................................... 1 1  
Ta ble 6- 1  
St u d y I nter ve nti o ns A d mi nistere d ..................................................................... 2 8  
Ta ble 6- 2  
 
Ta ble 9- 1  
M ulti ple C o m paris o ns Pr oce d ure ...................................................................... 4 7  
Ta ble 1 0- 1  
Hi g hl y Effecti ve a n d Acce pta ble C o ntrace pti ve Met h o ds ................................ 6 6  
 
List of Fi g ures 
Fi g ure 6- 1  
Sc he matic of I njecti o n Area .............................................................................. 3 0  
Fi g ure 1 0- 1  
L o wer Facial Wi dt h Meas ure me nt .................................................................... 7 0  
Fi g ure 1 0- 2  
L o wer Facial V ol u me Meas ure me nt ................................................................. 7 2  
Fi g ure 1 0- 3  
Ma n di b ular Facial A n gle Meas ure me nt ............................................................ 7 3  
 
 
 
 

 
 
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1.  
Pr ot oc ol S u m m ar y 
1. 1.  
S y n o psis 
Pr ot oc ol Title:  B O T O X®  ( o na b ot uli n u mt o xi n A) Treat me nt of Masseter M uscle Pr o mi ne nce: A 
P hase 3, M ultice nter, Ra n d o mize d, D o u bl e- Bli n d, Place b o- C o ntr olle d St u d y  
Pr ot oc ol N u m ber:  1 7 8 9- 3 0 1- 0 0 8 
Brief Title:  B O T O X Treat me nt of Masseter M uscle Pr o mi ne nce  
St u d y R ati o n ale:  
Base d o n t he res ults of t he P hase 2 St u d y 1 9 1 6 2 2- 1 3 0,  t his P hase 3 st u d y is desi g ne d t o f urt her 
e val uate t he efficac y a n d safet y of B O T O X 7 2 U f or t he treat me nt of M M P i n a d ults t o s u p p ort 
mar keti n g a ut h orizati o n.  
O bjecti ves a n d E n d p oi nts: 
T he pri mar y a n d sec o n dar y o bjecti ves of t his st u d y are t o c o m pare t he efficac y a n d safet y of 
B O T O X vers us place b o i n partici pa nts wit h M M P. 
O bjecti ves
 E n d p oi nts
 
Pri mar y
 
 
•  
T o c o m pare t he efficac y of B O T O X 
wit h place b o i n pa rtici pa nts wit h 
bilateral M M P 
 
•  
Pr o p orti o n of res p o n ders w h o ac hie ve ≥ 2- gra de i m pr o ve me nt fr o m 
baseli ne at Da y 9 0, per i n vesti gat or assess me nts of M M P usi n g t he 
M M P S ( 5 se verit y gra des: 1 = mi ni mal, 2 = mil d, 3 = m o derate, 
4 = mar ke d, 5 = ver y mar ke d) 
 
•  
T o c o m pare t he safet y of B O T O X 
wit h place b o i n pa rtici pa nts wit h 
M M P 
•  
I nci de nce of A Es a n d c ha n ge fr o m baseli ne i n vital si g ns 
Sec o n dar y
 
 
•  
T o c o m pare t he efficac y of B O T O X 
wit h place b o i n pa rtici pa nts wit h 
M M P  
•  
Pr o p orti o n of res p o n ders w h o ac hie ve M M P S Gra de ≤ 3 at Da y 9 0, 
acc or di n g t o i n vesti gat or 
•  
Pr o p orti o n of res p o n ders w h o ac hie ve M M P S- P Gra de ≤ 3 at 
Da y 9 0, acc or di n g t o partici pa nt 
•  
Pr o p orti o n of res p o n ders w h o ac hie ve ≥ 2- gra de i m pr o ve me nt fr o m 
baseli ne at Da y 9 0 usi n g t he M M P S- P 
•  
Pr o p orti o n of res p o n ders w h o ac hie ve P S A C Gra de ≥ 1 (at least 
mi ni mall y i m pr o ve d fr o m baseli ne) at Da y 9 0 
•  
C ha n ge fr o m baseli ne i n l o wer facial wi dt h ( m m) at Da y 9 0, 
calc ulate d fr o m sta n dar dize d i ma ges 
 
 
 

 
 
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O bjecti ves
 E n d p oi nts
 
•  
D urati o n of effect f or B O T O X-treate d M M P S res p o n ders  
Ot her ( C O A) 
 
•  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
O ver all St u d y Desi g n: 
T his is a n 1 8- m o nt h, m ultice nter st u d y c o nsisti n g of 2 peri o ds, a d o u ble- bli n d place b o-c o ntr olle d 
si n gle-treat me nt peri o d a n d a n o pe n-la bel peri o d i n w hic h a ma xi m u m of 2 f urt her st u d y 
treat me nts ca n be recei ve d. U p t o 2 0 sc he d ule d visits are pla n ne d: scree ni n g ( Da y - 1 4 t o 
Da y - 1), baseli ne ( Da y 1), f oll o w- u p m o nt hl y t h ereafter ( Da ys 3 0, 6 0, 9 0, 1 2 0, 1 5 0, 1 8 0, 2 1 0, 
2 4 0, 2 7 0, 3 0 0, 3 3 0, 3 6 0, 3 9 0, 4 2 0, 4 5 0, 4 8 0, 5 1 0), a n d st u d y e xit ( Da y 5 4 0). 
Peri o d 1 ( Da ys 1 t hr o u g h 1 8 0) will be a d o u ble- bli n d, ra n d o mize d, place b o-c o ntr olle d, 
si n gle-treat me nt desi g n, w hic h will assess t he safet y a n d efficac y of B O T O X treat me nt of M M P. 
O n Da y 1, partici pa nts will be ra n d o mize d i n  a 3: 1 rati o t o recei ve B O T O X 7 2 U or place b o. 
Ra n d o mizati o n will be stratifie d at eac h i n ves ti gat or site b y t he partici pa nt’s baseli ne M M P S 
Gra de ( 4 or 5). O n Da y 1 8 0, fi nal Peri o d 1 as sess me nts will be c ollecte d, after w hic h all 
partici pa nts will c o nti n ue i nt o Peri o d 2, t he o pe n-la bel treat me nt p orti o n of t he st u d y. 
Peri o d 2 ( Da ys 1 8 0 t hr o u g h 5 4 0) will be o pe n-la bel. All B O T O X a n d place b o-treate d 
partici pa nts fr o m Peri o d 1 are eli gi ble t o re cei ve u p t o 2 o pe n-la bel treat me nts of B O T O X 7 2 U 
i n Peri o d 2 if t he y meet pr ot oc ol-s pecifie d retreat me nt criteria o n or after t he Da y 1 8 0 visit. If t he 
partici pa nt d oes n ot meet t he retreat me nt criteria at t he Da y 1 8 0 visit, he or s he will be 
reassesse d at t he ne xt visit. F or Treat me nt 2, partici pa nts w h o q ualif y ca n be retreate d fr o m t he 
Da y 1 8 0 visit t hr o u g h t he Da y 4 2 0 visit. F or Treat me nt  3, t he earliest visit t hat partici pa nts ma y 
q ualif y a n d recei ve t he t hir d treat me nt is t he Da y 2 7 0 visit ( 3 m o nt hs after t he earliest visit f or 
Treat me nt 2 [ Da y 1 8 0 visit]). T he last visit t hat  partici pa nts ma y q ualify a n d recei ve treat me nt 
 
 
 

 
 
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1. 3.  
Sc he d ule of Acti vities ( S o A) 
St u d y pr oce d ures are rec o m me n de d t o be d o ne i n se q ue nce as liste d i n t he bel o w sc he d ule ( wit h 
e xce pti o ns descri be d i n a f o ot n ote); h o we ver, t he se q ue nce is n ot ma n dat or y. 
 
 
 
 

 
 
 
 
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T a ble 1 – 1  
Sc he d ule of Visits a n d Pr oce d ures 
 
 
 

 
 
 
 
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2.  
I ntr o d ucti o n 
B O T O X has bee n use d f or t hera pe utic a n d aest h etic p ur p oses f or 3 deca des, wit h its first 
t hera pe utic a p pr o val (treat me nt of facial s pas m o dic dis or der s) i n 1 9 8 9 a n d first aest hetic 
a p pr o val (treat me nt of gla bellar li nes) i n 2 0 0 2. Si nce t he first re p orts of cli nical res ults wit h 
b ot uli n u m t o xi n t y pe A treat m e nt of M M H ( M o ore 1 9 9 4, S m yt h 1 9 9 4 ), n u mer o us p u blicati o ns 
i n t he me dical literat ure su g gest B O T O X ma y be a l ocall y a p plie d, well-t olerate d, a n d 
pre dicta ble treat me nt t o i m pr o ve t he a p peara n ce of t he masseter m uscles i n t he l o wer face. 
C o m pare d wit h c o nser vati ve a p pr oac hes, B O T O X ma y pr o d uce a relati vel y ra pi d, pre dicta ble, 
a n d desire d effect of re d uci n g t he size a n d s ha pe of t he masseter m uscles; c o m pare d wit h 
s ur gical treat me nt, B O T O X i njecti o ns ma y be less i n vasi ve, ma y lea d t o fe wer si de effects a n d a 
s h orter rec o ver y ti me, a n d t he c he mical de ner vati o n of t he masseter m uscle is te m p orar y.  
2. 1.  
St u d y R ati o n ale 
T he masseter m uscle is 1 of 4 m uscles use d f or masticati o n. Pr o mi ne nce of t he masseter m uscle 
ca n a p pear as a wi de ne d a n d s q uare l o wer f ace s ha pe, w hic h is a n aest hetic c o ncer n f or 
i n di vi d uals w h o prefer a narr o wer a n d m ore o v oi d l o wer face s ha pe. 
W he n B O T O X is i njecte d i nt o a m uscle, it i nterferes wit h ne ur o m usc ular tra ns missi o n, 
pr o d uci n g te m p orar y c he mical de ne r vati o n res ulti n g i n l ocalize d rela xati o n of t he m uscle a n d 
re d ucti o n i n m uscle acti vit y. W he n i njecte d i nt o a masseter m uscle, B O T O X treat me nt has bee n 
o bser ve d t o re d uce t he size of t he m u scle (M o ore 1 9 9 4 ), pr o d uci n g a n effect percei ve d as l o wer 
facial s ha pi n g or sli m min g ( W u  2 0 1 0). 
St u d y 1 9 1 6 2 2- 1 3 0 was t he first Aller ga n-s p o ns ore d st u d y of B O T O X f or t he treat me nt of M M P, 
as a n aest hetic i n dicati o n. T his was a 1 2- m o nt h, m ultice nter, d o u ble- bli n d, ra n d o mize d, place b o-
c o ntr olle d, d ose-escalati o n, P hase 2 st u d y i n w h ic h B O T O X treat me nt of M M P was s h o w n t o be 
safe at d oses ra n gi n g fr o m 2 4 U ( 1 2 U/ masseter) t o 9 6 U ( 4 8 U/masseter). Partici pa nts were 
a d ults < 5 0 years wit h B MI ≤ 3 0 k g/ m2 a n d w h o ha d m arke d  t o very m arke d  M M P, assesse d b y 
t he i n vesti gat or usi n g t he M M P S. F or t he pri mar y a n d ke y sec o n dar y e n d p oi nts (at Da y 9 0), 
statisticall y si g nifica nt p ositi ve efficac y res ults were de m o nstrate d f or all 4 B O T O X d oses 
c o m pare d wit h place b o, wit h a d ose- de pe n de nt  tre n d fa v ori n g t he hi g her 2 d oses ( 7 2 U a n d 
9 6 U). T he be nefit of 7 2 U a n d 9 6 U was si mila r f or d urati o n, v ol u me re d ucti o n, M M P S c ha n ge, 
facial wi dt h, facial a n gle a n d facial s ha pe wit h n o si g nifica nt a d diti o nal be nefit c o nsiste ntl y 
de m o nstrate d wit h 9 6 U o ver 7 2 U. T here were n o sa fet y tre n ds or patter ns i de ntifie d wit h a d ose 
i ncrease, alt h o u g h facial paresis (i ncl u di n g re p orts of wea k or altere d s mile ) was re p orte d i n t he 
hi g hest d ose gr o u p ( 9 6 U) o nl y, as a l ocal effect. F or details of d ose selecti o n a n d j ustificati o n 
f or t he c urre nt P hase 3 st u d y, see Secti o n 4. 3 . 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
1 5 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
St u d y 1 9 1 6 2 2- 1 3 0 safet y meas ures i ncl u de d sta n dar diz e d de ntal a n d C T e xa ms wit h t he g oal t o 
i de ntif y a n d c haracterize B O T O X treat me nt effects o n de ntiti o n, masseter m uscle v ol u me, a n d 
t he ma n di ble. De ntal data yiel de d n o a b n or mal cli nicall y mea ni n gf ul p osttreat me nt fi n di n gs f or 
a n y partici pa nt i n t he st u d y. N o  safet y si g nal or u ne x pecte d new pat h ol o gical de vel o p me nt was 
detecte d fr o m a n y e x pl orat or y ra di ol o gic C T meas ure. T here were n o d ose-relate d tre n ds, A E 
re p orts, or a b n or mal cli nicall y rele vant fi n di n gs o n de ntal e xa mi nati o n. 
Base d o n t he res ults of t he P hase 2 St u d y 1 9 1 6 2 2- 1 3 0,  t his P hase 3 st u d y is desi g ne d t o f urt her 
e val uate t he safet y a n d efficac y of u p t o 3 treat me nt c ycles wit h B O T O X 7 2 U f or t he treat me nt 
of M M P i n a d ults t o s u p p ort mar keti n g a ut h orizati o n as t here is n o ne ur ot o xi n c urre ntl y 
a p pr o ve d f or treat me nt of t his i n dicati o n w orl d w i de. E x pl orat or y C T a n d de ntal e xa mi nati o ns 
de vel o pe d b y Aller ga n i n St u d y 1 9 1 6 2 2- 1 3 0 di d n ot  i de ntif y a n y a d diti o nal p ote ntial safet y 
a n d/ or efficac y si g nals; t h us, t his P hase 3 st u d y uses r o uti ne A E m o n it ori n g t o c haracterize 
safet y. Si milarl y, se veral e x plorat or y efficac y e n d p oi nts a n d res p o n der defi niti o ns use d i n St u d y 
1 9 1 6 2 2- 1 3 0 were de m o nstrate d t o be less relia ble; t heref ore, t his P hase 3 st u d y pr o p oses efficac y 
e n d p oi nts t hat are m ost relia ble a n d li mite d i n n u m ber f or mea ni n gf ul cl i nical a n d statistical 
a nal ysis. 
2. 2.  
B ac k gr o u n d 
T he masseter m uscle f u ncti o ns t o pr otract a n d ele vate t he ma n di ble f or masticati o n. Pr o mi ne nce 
of t he masseter m uscle ca n a p pear as a wi de ne d l o wer face, w hic h is a n aest hetic c o ncer n f or 
i n di vi d uals w h o prefer a narr ower l o wer face s ha pe. I n di vi d uals w h o dee m t his masseter 
pr o mi ne nce as aest heticall y u n desira ble ma y see k  me dical treat me nt t o decrease a wi de, b ul k y, 
or s q uare-a p p eari n g l o wer face ( A h n 2 0 0 4, C hai 2 0 1 1, Ji n 2 0 0 5, Klei n 2 0 1 4, Lie w 2 0 0 8, 
M orris 2 0 0 7, M u 2 0 1 0, P u 2 0 0 9, S hi m 2 0 1 0 ). 
I n me dical literat ure, M M H ca n be defi ne d as e nc o m passi n g b ot h f u ncti o nal a n d aest hetic 
s y m pt o ms of a n e nlar ge d masseter m uscle (Fe d or o wicz 2 0 1 3 ). Aller ga n’s f oc us is t he aest hetic 
i n dicati o n; t o clarif y t his, t he ter m M M P is n o w bei n g use d i nstea d of M M H, t o reflect t his 
f oc us. 
M M P ma y be u nilateral or bilateral. It ma y be i di o pat hic or ma y occ ur i n ass ociati o n wit h 
c o n diti o ns s uc h as br u xis m, occl usal a n d m usc ul ar i m bala nces, T MJ D, or partic ular c he wi n g 
ha bits a n d/ or diets (e g, u nilateral c he wi n g, c he wi n g g u m  or har d f o o ds) (A y dil 2 0 1 2, C h oe 2 0 0 5, 
Misc h k o ws ki 2 0 0 5 ). T he hi g hest i nci de nce of M M P is belie ve d t o occ ur i n t he sec o n d a n d t hir d 
deca des of life, a n d t here is n o ge n der pre dilecti o n ( S m yt h 1 9 9 4 ). Patie nts wit h M M P ma y als o 
ha ve ma n di b ular b o n y pr o mi ne nce (e g, a pr o mi ne nt ma n di b ular a n gle) t hat ma y c o ntri b ute t o t he 
a p peara nce of a wi de l o wer face.  
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
1 6 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
B O T O X has bee n use d t o treat M M P i n cli nical  practice f or 3 deca des, pre d o mi na ntl y i n Asia n 
c o u ntries w here aest hetics fa v or  a sle n der o v oi d facial s ha pe (A h n 2 0 0 4, C ha n g 2 0 1 6, 
Lie w 2 0 0 8, M o ore 1 9 9 4 ). T here is gr o wi n g i nterest i n M M P treat me nt a m o n g n o n- Asia n 
p o p ulati o ns ( Lie w 2 0 0 8 ) a n d p u blis he d re p orts c haracterize t he patie nt p o p ulati o n ( Asia n a n d 
n o n- Asia n), i njecti o n tec h ni q ues utilize d, cli nical res ults ac hie ve d, a n d A Es ( A h n 2 0 0 4, 
A y dil 2 0 1 2, C h oe 2 0 0 5, Lie w 2 0 0 8 , Pe n g 2 0 1 7 ). As a p ote ntiall y l o wer-ris k alter nati ve t o 
s ur gical i nter ve nti o n, t he aest hetic pr oce d ure of treati n g t he masseter m uscle wit h b ot uli n u m 
t o xi n has gai ne d p o p ularit y a m o n g p h ysicia ns a n d patie nts (A h n 2 0 0 4, Xie 2 0 1 4 ). 
2. 3.  
Be nefit/ Ris k Assess me nt 
C urre nt treat me nt o pti o ns f or M M P i ncl u de c o ns er vati ve ( n o ns ur gical) as well as i n vasi ve 
treat me nt m o dalities. C o nser vati ve treat me nts i ncl u de re d uci n g t he m usc ular f u ncti o n a n d 
acti vit y b y be ha vi oral m o dificati o n, occl us al s pli nts, a n d/ or m uscle rela xa nts ( A h n 2 0 0 4, 
A y dil 2 0 1 2, Misc h k o ws ki 2 0 0 5, Ra us o 2 0 1 0, Tartar o 2 0 0 8, T o 2 0 0 1 ). T hese met h o ds ha ve n ot 
bee n ri g or o usl y st u die d f or t his i n dicati o n a n d are belie ve d t o ha ve li mite d efficac y. I n vasi ve 
t hera pies f or treati n g a wi de l o wer face i ncl u de s ur gical pr oce d ures s uc h as oste ot o m y, 
ostect o m y, a n d c orticect o m y t o c ha n ge t he s ha p e of t he ja wli ne tar geti n g t he ma n di ble a n d/ or 
i ncl u di n g e xcisi o n of t he masseter (Bae k 1 9 8 9, C hai 2 0 1 1, De g uc hi 1 9 9 7, Ji n 2 0 0 4, Ji n 2 0 0 5, 
Ki m 2 0 0 1, Ki m 2 0 0 3, Lee 2 0 0 3, Lee 2 0 0 6, M u 2 0 1 0, O niz u ka 1 9 8 3, S u mi ya 2 0 0 4, Ya n g 1 9 9 1 ), 
a n d ra di ofre q ue nc y v ol u metric re d ucti o n of t he masseter (Par k 2 0 0 7 ). Ris ks of s ur gical re d ucti o n 
of t he ma n di ble a n d/ or masseter m uscle i ncl u de  t h ose of a ge neral a nest hetic, pai n a n d 
disc o mf ort, p ost o perati ve he m orr ha ge, e de ma, he mat o ma, i nfecti o n, scarri n g, i nj ur y t o t he 
al ve olar ner ve, fract ure of t he ra m us, c o n d yle, or s u bc o n d yle ma n di b ular b o ne str uct ures , 
as y m metric res ult, a n d facial ner ve da ma ge ( Bae k 1 9 8 9, C hai 2 0 1 1, C h oe 2 0 0 5, De g uc hi 1 9 9 7, 
Ji n 2 0 0 5, M orris 2 0 0 7, M u 2 0 1 0, P u 2 0 0 9, Ya n g 1 9 9 5). B O T O X f or M M P re prese nts a 
p ote ntiall y l o wer-ris k alter nati ve t o s ur gical i n ter ve nti o n a n d hi g her efficaci o us alter nati ve t o 
ot her c o nser vati ve n o ns ur g ical treat me nt o pti o ns. 
I n ge neral, data fr o m t he c o m plete d P hase 2 cli nical st u d y of B O T O X treat me nt of M M P a n d 
fr o m t he me dical literat ure s h o w t hat B O T O X treat me nt of M M P has bee n well t olerate d wit h 
A Es t hat were pri maril y l ocal a n d e x pecte d, ba se d o n t he well-esta blis he d safet y pr ofile of 
B O T O X a n d t he m uscles i njecte d. I n  t he P hase 2 St u d y 1 9 1 6 2 2- 1 3 0, t he m ost 
fre q ue ntl y-re p orte d treat me nt-relate d A Es i ncl u de d c o m m o nl y occ urri n g c o n diti o ns i n t he 
ge neral p o p ulati o n (e g, hea dac he [ 2 . 0 %, 3/ 1 5 0]), e ve nts ass ociate d wit h t he i njecti o n pr oce d ure 
(e g, i njecti o n site pai n [ 3. 3 %, 5/ 1 5 0]), or e ve nts relate d t o l ocal m uscle wea k ness t hat i m pact 
s mili n g or c he wi n g t hat are c o nsiste nt wit h t he k n o w n B O T O X p har mac ol o gical effects 
f oll o wi n g i njecti o n i nt o t he masseter (e g, masticati o n dis or der [ 5. 3 %, 8/ 1 5 0] a n d facial paresis 
[ 2. 7 %, 4/ 1 5 0; re p orte d ver bati m ter ms: wea k ness w he n s mili n g, altere d s mile, ri g ht de press or 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
1 7 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
la bia i nferi or paresis, a n d s u bject n otice d p ossi ble l oss of m o ve me nt al o n g ja wli ne]). I n a d diti o n, 
t here was n o safet y ris k i de ntifie d i n partici pa nts w h o recei ve d 2 B OT O X treat me nts f or M M P 
wit hi n 1 year. 
Si milar safet y res ults ha ve bee n descri be d i n t he me dical literat ure f oll o wi n g B O T O X treat me nt 
of M M P i n 1 1 7 8 partici pa nts wit h vari o us d os es (ra n gi n g fr o m 1 0 t o 1 0 0 U/ masseter) a n d 
n u m bers of treat me nt c ycles ( Secti o n 5. 2. 2 of  t he B O T O X M M P i n vesti gat or br oc h ure). T he 
m ost fre q ue ntl y re p orte d A Es were pai n, disc o mf o rt, or m uscle ac he at t he sites of i njecti o n. 
Beca use t he masseter m uscle is 1 of t he pri mar y m u scles of masticati o n, its treat me nt res ulte d i n 
s o me re p orts of tra nsie nt masticat or y diffic ulties (ie, wea k ness c he wi n g), w hic h was t he ne xt 
m ost fre q ue ntl y re p orte d A E i n t hese p u blica ti o ns. B O T O X i njecti o n of t he masseter a n d/ or 
a djace nt facial m uscles als o res ulte d i n s o me  c os metic c o m plai nts, w hic h were re p orte d less 
fre q ue ntl y. I n ge neral, a d verse reacti o ns occ ur wit hi n t he first fe w da ys t o wee ks f oll o wi n g 
i njecti o n of B O T O X a n d, w hile ge nerall y tra nsie nt, ma y ha ve a d urati o n of se veral m o nt hs or, i n 
rare cases, l o n ger. M ore detaile d i nf or mati o n ab o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks 
a n d reas o na bl y e x pecte d A Es wit h B O T O X tr eat me nt ma y be f o u n d i n  t he i n vesti gat or’s 
br oc h ure a n d pac ka ge i nsert. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
1 8 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
3.  
O bjecti ves a n d E n d p oi nts 
O bjecti ves
 E n d p oi nts
 
Pri mar y
 
 
•  
T o c o m pare t he efficac y of B O T O X 
wit h place b o i n pa rtici pa nts wit h 
bilateral M M P 
 
•  
Pr o p orti o n of res p o n ders w h o ac hie ve ≥ 2- gra de i m pr o ve me nt fr o m 
baseli ne at Da y 9 0, per i n vesti gat or assess me nts of M M P usi n g t he 
M M P S ( 5 se verit y gra des: 1 = mi ni mal, 2 = mil d, 3 = m o derate, 
4 = mar ke d, 5 = ver y mar ke d) 
 
•  
T o c o m pare t he safet y of B O T O X 
wit h place b o i n pa rtici pa nts wit h 
M M P 
•  
I nci de nce of A Es a n d c ha n ge fr o m baseli ne i n vital si g ns 
Sec o n dar y
 
 
•  
T o c o m pare t he efficac y of B O T O X 
wit h place b o i n pa rtici pa nts wit h 
M M P  
•  
Pr o p orti o n of res p o n ders w h o ac hie ve M M P S Gra de ≤ 3 at Da y 9 0, 
acc or di n g t o i n vesti gat or 
•  
Pr o p orti o n of res p o n ders w h o ac hie ve M M P S- P Gra de ≤ 3 at 
Da y 9 0, acc or di n g t o partici pa nt 
•  
Pr o p orti o n of res p o n ders w h o ac hie ve ≥ 2- gra de i m pr o ve me nt fr o m 
baseli ne at Da y 9 0 usi n g t he M M P S- P 
•  
Pr o p orti o n of res p o n ders w h o ac hie ve P S A C Gra de ≥ 1 (at least 
mi ni mall y i m pr o ve d fr o m baseli ne) at Da y 9 0 
•  
C ha n ge fr o m baseli ne i n l o wer facial wi dt h ( m m) at Da y 9 0, 
calc ulate d fr o m sta n dar dize d i ma ges 
•  
D urati o n of effect f or B O T O X-treate d M M P S res p o n ders  
Ot her ( C O A) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
1 9 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
4.  
St u d y Desi g n 
4. 1.  
O ver all Desi g n 
T his is a n 1 8- m o nt h, m ultice nter st u d y c o ns isti n g of 2 peri o ds (see sc he ma, Secti o n 1. 2 ). 
Peri o d 1 ( Da ys 1 t hr o u g h 1 8 0) is a d o u ble- bli n d, ra n d o mize d, place b o-c o ntr olle d, 
si n gle-treat me nt desi g n, w hic h will assess t he safet y a n d efficac y of B O T O X treat me nt of M M P. 
Peri o d 2 ( Da ys 1 8 0 t hr o u g h 5 4 0) is o pe n-la bel  wit h u p t o 2 B O T O X retreat me nts if t he 
partici pa nt meets retrea t me nt criteria ( Secti o n 6. 6 ). O ver t he d urati o n of t he st u d y, a ma xi m u m 
of 3 st u d y treat me nts will be a d mi nistere d t o eac h st u d y partici pa nt. 
A p pr o xi matel y 3 6 0 partici pa nts will be e nr olle d at a p pr o xi matel y 3 0 sites i n or der t o ha ve 
3 0 6 partici pa nts c o m plete t he st u d y base d o n a n a n tici pate d dr o p o ut rate of 1 5 %. Of t he e nr olle d 
partici pa nts, a p pr o xi matel y 2 3 5 will be e nr olle d  fr o m C hi na ( mai nla n d), a p pr o xi matel y 7 5 will 
be e nr olle d fr o m Ca na da, a n d a p pr o xi matel y 5 0 will be e nr olle d fr o m Tai wa n re gi o n. 
O n Da y 1, partici pa nts will be ra n d o mize d i n  a 3: 1 rati o t o recei ve B O T O X 7 2 U or place b o. 
Ra n d o mizati o n will be stratifie d at eac h i n ves ti gat or site b y t he partici pa nt’s baseli ne M M P S 
Gra de ( 4 or 5). F oll o wi n g c o m pleti o n of Peri o d 1, all partici pa nts will c o nti n ue i n Peri o d 2, 
w hic h will assess t he efficac y a n d safet y of re peat a d mi nistrati o n of B O T O X f or t he treat me nt of 
M M P. 
U p t o 2 0 sc he d ule d visits are pla n ne d: scre e ni n g ( Da y - 1 4 t o Da y - 1), baseli ne ( Da y 1), 
f oll o w- u p m o nt hl y t hereafter ( Da ys 3 0, 6 0, 9 0, 1 2 0, 1 5 0, 1 8 0, 2 1 0, 2 4 0, 2 7 0, 3 0 0, 3 3 0, 3 6 0, 3 9 0, 
4 2 0, 4 5 0, 4 8 0, 5 1 0), a n d st u d y e xit ( Da y 5 4 0). 
After verificati o n t hat t he partici pa nts meet all i ncl usi o n a n d e xcl usi o n criteria a n d c o m pleti o n of 
all baseli ne st u d y pr oce d ures, partici pa nts wi ll be ra n d o mize d a n d e nr olle d. O nce e nr olle d, 
partici pa nts will s pe n d a p pr o xi matel y 1 8 m o nt hs i n t he st u d y. 
Peri o d 1 ( Da ys 1 t hr o u g h 1 8 0) 
Treat me nt will be a d mi nistere d i ntra m usc ularl y t o t he bilateral masseter m uscles as 6 t otal 
i njecti o ns ( 0. 3 m L per i njecti o n), wit h 3 i njecti o ns a d mi nistere d per masseter i n t he area of 
ma xi mal m uscle b ul ge  (Fi g ure 6- 1 , Secti o n 6. 1 ), f or a t otal i njecti o n v ol u me of 1. 8 m L. Eac h 
0. 3 m L i njecti o n will c o ntai n B O T O X 1 2 U or  place b o. I n Peri o d 1, treat me nt will be 
a d mi nistere d o n Da y 1, a n d partici pa nts will ret ur n f or f oll o w- u p assess me nts (see Ta ble 1 – 1 ) o n 
Da ys 3 0, 6 0, 9 0, 1 2 0, 1 5 0, a n d 1 8 0. O n Da y 1 8 0, fi nal Peri o d 1 assess me nts will be c ollecte d, 
after w hic h all partici pa nts will c o nti n ue i nt o Peri o d 2, t he o pe n-la bel treat me nt p orti o n of t he 
st u d y. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
2 0 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
Peri o d 2 ( Da ys 1 8 0 t hr o u g h 5 4 0/ St u d y E xit) 
Da y 1 8 0 is c o nsi dere d b ot h t he e n d of Peri o d 1 a n d t he be gi n ni n g of Peri o d 2. After Peri o d 1 
assess me nts are c ollecte d, t he partici pa nt will e nter Peri o d 2 a n d will be assesse d f or retreat me nt. 
If t he partici pa nt d oes n ot meet t he retreat me nt criteria at Da y 1 8 0, he or s he will be reassesse d at 
t he ne xt visit. All B O T O X a n d place b o-treate d partici pa nts fr o m Peri o d 1 are eli gi ble t o recei ve 
u p t o 2 o pe n-la bel treat me nts of B O T O X 7 2 U i n Peri o d 2 if t he y meet t he f oll o wi n g retreat me nt 
criteria (als o see Secti o n 6. 6 ) o n or after t he Da y 1 8 0 visit. 
•  Partici pa nt has bilateral m arke d  ( Gra de 4) or very m arke d  ( Gra de 5) M M P, as assesse d b y t he 
i n vesti gat or usi n g t he M M P S, A N D 
•  Fe males of c hil d beari n g p ote ntial m ust ha ve a ne gati ve pre g na nc y test pri or t o treat me nt, 
A N D 
•  If it is t he t hir d treat me nt, at least 3 m o nt hs ha ve la pse d since t he pre vi o us st u d y treat me nt 
( n o retreat me nt earlier t ha n 8 4 da ys) 
D uri n g Peri o d 2, partici pa nts will atte n d all f oll o w- u p visits ( Da ys 2 1 0, 2 4 0, 2 7 0, 3 0 0, 3 3 0, 3 6 0, 
3 9 0, 4 2 0, 4 5 0, 4 8 0, 5 1 0, a n d 5 4 0). F or Treat me nt 2, partici pa nts w h o q ualif y ca n be retreate d 
fr o m t he Da y 1 8 0 visit t hr o u g h t he Da y 4 2 0 visit. F or Treat me nt 3, t he earliest visit t hat 
partici pa nts ma y q ualif y a n d rece i ve t he t hir d treat me nt is Da y 2 7 0 ( 3 m o nt hs after t he earliest 
visit f or Treat me nt 2 [ Da y 1 8 0]). T he last da y t hat  a partici pa nt ca n recei ve eit her Treat me nt 2 or 
3 is Da y 4 2 0; t his e ns ures a 1 2 0- da y safet y a n d efficac y f oll o w- u p peri o d b y Da y 5 4 0/st u d y e xit. 
A partici pa nt w h o meets retreat me nt criteria ma y decli ne retreat me nt if t he y c h o ose, a n d t heir 
reas o n will be ca pt ure d o n t he e C R F.  If t he partici pa nt still meets retreat me nt criteria at t he ne xt 
visit ( u p t o Da y 4 2 0), he or s he ma y recei ve retreat me nt at t hat ti me. 
I n Peri o d 2, partici pa nts will recei ve u p t o 2 a d diti o nal treat me nts. Base d o n i n di vi d ual 
varia bilit y i n ti me t o meet  retreat me nt criteria n ote d i n t he P hase 2 St u d y 1 9 1 6 2 2- 1 3 0, 
retreat me nt ti me p oi nts are n ot e x pecte d t o be s y nc hr o nize d a m o n g t he partici pa nts i n t he st u d y. 
4. 1. 1.  
Cli nic al H y p ot heses 
B O T O X treat me nt of M M P is m ore effecti ve t ha n place b o as meas ure d b y i n vesti gat or 
assess me nt of M M P se verit y usi n g t he M M P S. 
B O T O X has a n acce pta ble safet y pr ofile after si n gle a n d re peat M M P treat me nt. 
4. 2.  
Scie ntific R ati o n ale f or St u d y Desi g n 
I n t he c urre nt st u d y, all partici pa nts will be assesse d f or a mi ni m u m of 1 8 0 da ys after 
d o u ble- bli n d treat me nt o n Da y 1 ( Peri o d 1). A ra n d o mize d d o u ble- bli n d desi g n i n Peri o d 1 
mi ni mizes i n vesti gat or a n d partici pa nt bias a n d t he place b o c o ntr ol pr o vi des a c o m parat or. After 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
2 1 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
1 bli n de d c ycle of treat me nt i n Peri o d 1, o pe n-la bel treat me nt of B O T O X will be a d mi nistere d t o 
all partici pa nts w h o meet retreat me nt criteria o n or after Da y 1 8 0 i n Peri o d 2. T he o pe n-la bel 
treat me nt of B O T O X i n Peri o d 2 will assess t he efficac y a n d safet y of re peat a d mi nistrati o n of 
B O T O X ( u p t o 2 treat me nts) f or t he treat me nt of M M P. T h us, a ma xi m u m of 3 treat me nts will 
be a d mi nistere d i n t his st u d y a n d all partici pa nts i n t his st u d y will ha ve t he o p p ort u nit y t o recei ve 
at least 1 treat me nt wit h B O T O X. 
Pre vi o us st u dies, i ncl u di n g Aller ga n’s P hase 2 St u d y 1 9 1 6 2 2- 1 3 0, re p orte d pea k efficac y of 
b ot uli n u m t o xi n treat me nt of M M P at 3 m o nt hs ( H o n g 2 0 0 5; Ki m 2 0 0 3; Ki m  2 0 0 7; Par k 2 0 0 3), 
t heref ore, Da y 9 0 has bee n c h ose n as t he pri mar y ti me p oi nt i n t he prese nt st u d y. 
Aller ga n de vel o pe d t he M M P S, a cli nicia n’s assess me nt t o ol f or e val uati o n of M M P. I n t he 
prese nt st u d y, t he M M P S is t o be use d b y trai ne d cli nicia ns t o e val uate a n d gra de t he pr o mi ne nce 
of t he masseter m uscle o n t he left a n d ri g ht si de s of t he face as t he pri mar y e n d p oi nt meas ure. 
T he M M P S is a static meas ure me nt e nc o m passi n g b ot h vis ual a n d pal pa ble e xa mi nati o n of t he 
masseter m uscle at rest a n d at ja w-cle nc h state. T he M M P S s h o we d s u bsta ntial i nter- a n d i ntra-
rater relia bilit y i n t he n on-treat me nt scale vali dati o n St u d y 1 9 1 6 2 2- 1 2 8, c o nfir mi n g its 
acce pta bilit y f or use i n t he prese nt st u d y. St u d y 1 9 1 6 2 2- 1 3 0 was t he first st u d y t o use t he M M P S 
t o assess t he treat me nt effect of B O T O X, a n d it de m o nstrate d statisticall y si g nifica nt greater 
pr o p orti o ns of res p o n ders i n ac hie vi n g b ot h a M M P S Gra de ≤ 3, a n d ≥ 1- gra de or ≥ 2- gra de 
i m pr o ve me nts fr o m baseli ne, as assesse d b y t he in vesti gat or at t he pri mar y ti me p oi nt. Res ults 
fr o m St u d y 1 9 1 6 2 2- 1 3 0 s u p p ort a cli nicia n t o ol ( M M P S) t hat ca n i m me di atel y assess t he 
rele va nt masseter pr o mi ne nce wit h o ut re q uiri n g ra di ol o gical e x p os ure fr o m C T sca ns or 3 D 
sta n dar dize d i ma gi n g t hat re q uires a trai ne d a nalyst t o c o nfir m t he aest hetic c o m plai nt descri be d 
b y t he partici pa nt. T heref ore, t he M M P S has bee n  c o nfir me d as a n vali date d efficac y meas ure 
base d u p o n t he res ults of St u dies 1 9 1 6 2 2- 1 2 8 a n d 1 9 1 6 2 2- 1 3 0. 
I n t he me dical literat ure, vari o us i ma gi n g met h o ds ha ve bee n use d t o assess effects of b ot uli n u m 
t o xi n o n masseter m uscle size a n d l o wer facial s ha pe (refer t o t he i n vesti gat or’s br oc h ure). 
Tec h n ol o gies use d t o meas ure q ua ntitati ve c ha n ges i n masseter m uscle v ol u me ha ve i ncl u de d 
ultras o u n d, C T, a n d M RI. P h ot o gra p hic tec h n ol o g ies de vel o pe d t o pr o vi de 3 D q ua ntitati ve 
a nal ysis of facial m or p h ol o g y i ncl u de i ma ge s u btracti o n tec h ni q ue, m oire t o p o gra p h y, li q ui d 
cr ystal sca n ni n g, li g ht l u mi na nce sca n ni n g, la ser sca n ni n g, stere o-lit h o gra p h y, a n d passi ve 
stere o p h ot o gra m metr y (A driae ns 2 0 1 2; Ki m 2 0 0 5; Tz o u 2 0 1 1 ), w hic h all meas ure c ha n ge t o t he 
l o wer facial c o nt o ur. 
A V E C T R A Stere o p h ot o gra m metr y s yste m ( Ca nfiel d Scie ntific, I nc.; Fairfiel d, Ne w Jerse y, 
U S A) will be use d t o q ua ntif y t he effect of B O T O X o n l o wer facial v ol u me as a n ot her e n d p oi nt 
meas ure i n t he c urre nt st u d y. T his s yste m has pr e vi o usl y bee n vali date d f or use i n t he facial 
re gi o n (de Me nezes 2 0 1 0 ), a n d t he l o wer facial area e nc o m passi n g t he masseter m uscle 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
2 2 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
( M V- Re p ort # 1 8 3 2, M V- Re p ort # 1 8 3 2- A d de n d u m). T he effi cac y meas ures use d t o q ua ntitate 
v ol u me i n St u d y 1 9 1 6 2 2- 1 3 0 de m o nstrate d t hat l o wer facial v ol u me re d ucti o ns usi n g 3 D i ma ges 
( pri mar y e n d p oi nt) c orrelate d well wit h v ol u me re d ucti o ns i n masseter m uscle i n a defi ne d 
re gi o n usi n g C T sca ns. Si milarl y, decreases i n l o wer facial wi dt h usi n g 2 D i ma ge pr ojecti o ns 
s h o we d i m pr o ve me nts c o m para ble wit h t he 3 D i ma ge a n d C T v ol u me res ults. L o wer facial 
wi dt h is a sec o n dar y efficac y e n d p oi nt i n t he c urre nt st u d y. 
 
 
 
 
Safet y assess me nts i ncl u de A Es a n d vital si g ns. I n t he P hase 2 St u d y 1 9 1 6 2 2- 1 3 0, t he m ost 
fre q ue ntl y re p orte d A Es i ncl u de d c o m m o nl y- occ urri n g c o n diti o ns i n t he general p o p ulati o n (e g, 
nas o p har y n gitis [ 8. 0 % of all B O T O X-treate d partici pa nts], hea dac he [ 5. 3 %], a n d u p per 
res pirat or y tract i nfecti o n [ 4. 0 %]) or e ve nts relate d t o c he wi n g t hat are n ot u ne x pecte d f oll o wi n g 
i njecti o n i nt o t he masseter (e g, masticati o n dis or der [ 6. 0 %]) Of t he re p orte d A Es a m o n g t he 
1 1 7 8 partici pa nts treate d wit h B O T O X f or M M P i n  t he p u blis he d me dical literat ure, t he m ost 
fre q ue ntl y re p orte d A Es were pai n, disc o mf ort, or m uscle ac he at t he sites of i njecti o n. Beca use 
t he masseter m uscle is 1 of t he pri mar y m uscles of masticati o n, its treat me nt res ulte d i n s o me 
re p orts of tra nsie nt masticat or y diffic ulties (ie, wea k ness c he wi n g), w hic h was t he ne xt m ost 
fre q ue ntl y re p orte d A E i n t hese p u blicati o ns. B OT O X i njecti o n of t he masseter a n d/ or a djace nt 
facial m uscles als o res ulte d i n s o me c os metic c o m plai nts, w hic h were re p orte d less fre q ue ntl y. I n 
ge neral, t hese A Es ha ve bee n re p orte d as  mil d a n d res ol ve d wit h o ut treat me nt. 
St u d y 1 9 1 6 2 2- 1 3 0 yiel de d n o ne w or mea ni n gf ul safe t y fi n di n gs fr o m de ntal or C T e xa ms; 
rat her, a nal ysis of A Es pr o vi de d t he m ost se nsiti ve assess me nt of safet y. T h us, t his P hase 3 st u d y 
uses r o uti ne A E m o nit ori n g (as well as vita l si g n m o nit ori n g) t o c haracterize safet y. 
4. 3.  
J ustific ati o n f or D ose 
A re vie w of t he me dical literat ure of B O T O X treat me nt of M M P f o u n d a mea n d ose of 
a p pr o xi matel y 3 8 U per masseter (ra n ge: 1 0 U t o 1 0 0 U/ masseter) a d mi nistere d i nt o 1 t o 6 
i njecti o n sites/ masseter (refer t o t he i n vesti gat or’s br oc h ure). I n Aller ga n’s P hase 2 St u d y 
1 9 1 6 2 2- 1 3 0, partici pa nts recei ve d  t otal d oses ra n gi n g fr o m B O T O X 2 4 U t o 9 6 U ( Secti o n 2. 1 ). 
A nal yses of t he data fr o m St u d y 1 9 1 6 2 2- 1 3 0 pr o vi de e vi de nce t o s u p p ort selecti o n of a 7 2 U 
B O T O X d ose ( 3 6 U a d mi nistere d per masseter m uscle) f or treat me nt of M M P. Efficac y of 
B O T O X treat me nt of M M P persiste d at least 6 m o nt hs wit h a me dia n ti me t o l oss of res p o nse 
usi n g t he M M P S u p t o 9 m o nt hs i n s o me partic i pa nts. B O T O X a d mi nistrati o n was s h o w n t o be 
safe t hr o u g h Da y 3 6 0 f or all d oses ( 2 4 U, 4 8 U, 7 2 U, a n d 9 6 U). 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
2 3 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
T he 7 2 U d ose perf or me d as well as 9 6 U o n m ulti ple meas ures of efficac y (e g, M M P S 
res p o n der a nal yses a n d c ha n ges i n l o wer facial v ol u me); t heref ore, t here was n o a d va nta ge 
ass ociate d wit h t he hi g her d ose. Si milarl y, t he 7 2 U d ose de m o nstrate d a g o o d safet y pr ofile a n d 
di d n ot ha ve a n y i nci de nce of facial pa resis, i n c o ntrast t o t he 9 6 U d ose. 
4. 4.  
E n d of St u d y Defi niti o n 
T he e n d of t he st u d y is defi ne d as t he date of t he last visit of t he last partici pa nt. 
A partici pa nt is c o nsi dere d t o ha ve c o m plete d t h e st u d y if he/s he is a ra n d o mize d partici pa nt w h o 
was treate d i n Peri o d 1 a n d retreate d i n Peri o d 2 if eli gi ble, has n ot bee n disc o nti n ue d f or a n y 
reas o n, a n d atte n ds/c o m pletes t he st u d y e xit visit. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
2 4 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
5.  
St u d y P o p ul ati o n 
T he st u d y p o p ulati o n will be a d ult partici pa nts wit h m arke d  ( Gra de 4) or very m arke d  ( Gra de 5) 
M M P, as deter mi ne d b y t he i n vesti gat or usi n g t he M M P S A N D wit h pr o n o u nce d  ( Gra de 4) or 
very pr o n o u nce d  ( Gra de 5) M M P, as deter mi ne d b y t he partici pa nt usi n g t he M M P S- P, a n d w h o 
meet eli gi bilit y criteria f or t his pr ot oc ol as s pecifie d i n Secti o n 5. 1  a n d Secti o n 5. 2 . 
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e n r oll me nt criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d. 
5. 1.  
I ncl usi o n Criteri a 
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g criteria a p pl y: 
1.
 A ge
 
1. 0 1 
Partici pa nt m ust be at least 1 8 years of a ge ( or ol der if le gal a ge of a d ult h o o d is > 1 8 
as per l ocal re g ulati o ns), at t he ti me of si g ni n g t he i nf or me d c o nse nt  
2.  
T y pe of P artici p a nt a n d M asseter C h ar acteristics   
2. 0 1 
Partici pa nt m ust be healt h y as assesse d b y t he i n vesti gat or.  
2. 0 2 
Partici pa nt has a m arke d  ( Gra de 4) or very m arke d  ( Gra de 5) bilateral M M P 
(i de ntical gra des f or left a n d ri g ht masseter), as deter mi ne d at t he Da y 1 visit b y t he 
i n vesti gat or usi n g t he M M P S 
2. 0 3 
Partici pa nt has a pr o n o u nce d ( Gra de 4) or ver y pr o n o u nce d ( Gra de 5) M M P, as 
deter mi ne d at t he Da y 1 visit b y t he partici pa nt usi n g t he M M P S- P 
3.  
B o d y M ass I n de x 
3. 0 1 
B MI ≤ 3 0 k g/ m2 usi n g t he calc ulati o n: B MI = wei g ht ( k g)/[ hei g ht ( m)]2  
4.
 Se x
 
4. 0 1 
Male or fe male  
5.
 C o ntr ace pti ves
 
5. 0 1 
A fe male partici pa nt m ust be willi n g t o mi ni mize t he ris k of i n d uci n g pre g na nc y f or 
t he d urati o n of t he cli nical st u d y a n d f oll o w- u p peri o ds. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
2 5 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
5. 0 2 
A fe male partici pa nt is eli gi ble t o partici pate if s he is n ot pre g na nt ( has a ne gati ve 
pre g na nc y res ult pri or t o ra n d o mizati o n; see A p pe n di x 6 ), n ot breastfee di n g, a n d at 
least o ne of t he f oll o wi n g c o n diti o ns a p plies: 
a. N ot a W O C B P as defi ne d i n A p pe n di x 6 
O R 
b.  A W O C B P w h o a grees t o f oll o w t he c o ntrace pti ve g ui da nce i n A p pe n di x 6 
d uri n g t he treat me nt a n d f oll o w- u p peri o d  
6.
 I nf or me d
 
C o nse nt
 
6. 0 1 
Ca pa ble of gi vi n g si g ne d i nf or m e d c o nse nt as descri be d i n A p pe n di x 1 , w hic h 
i ncl u des c o m plia nce wit h t he re q uire me nts an d restricti o ns liste d i n t he I C F a n d i n 
t his pr ot oc ol. 
6. 0 2 
Writte n i nf or me d c o nse nt fr o m t he partici pa nt has bee n o btai ne d pri or t o a n y 
st u d y-relate d pr oce d ures. 
6. 0 3 
Writte n d oc u me ntati o n has bee n o btai ne d i n acc or da nce wit h t he rele va nt c o u ntr y 
a n d l ocal pri vac y re q uire me nts, w her e a p plica ble.  
7.
 Ot her  
7. 0 1 
A ble, as assesse d b y t he i n vesti gat or, a n d willi n g t o f oll o w st u d y i nstr ucti o ns a n d 
li kel y t o c o m plete all re q uire d st u d y visits. 
5. 2.  
E xcl usi o n Criteri a 
Partici pa nts are e xcl u de d fr o m t he st u d y if  a n y of t he f oll o wi n g criteria a p pl y: 
1.
 Me dic al
 
C o n diti o ns
 
1. 0 1 
A n y me dical c o n diti o n t hat ma y p ut t he par tici pa nt at i ncrease d me dical ris k wit h 
e x p os ure t o B O T O X, i ncl u di n g dia g n ose d m yas t he nia gra vis, Eat o n- La m bert s y n dr o me, 
a m y otr o p hic lateral scler osis, or a n y ot he r c o n diti o n t hat mi g ht i nterfere wit h 
ne ur o m usc ular f u ncti o n  
1. 0 2 
A n y u nc o ntr olle d me dical c o n diti o n  
1. 0 3 
A n a ntici pate d nee d f or s ur ger y or o ver ni g ht h os pitaliza ti o n d uri n g t he st u d y 
2.
 Pri or/ C o nc o mit a nt
 
T her a p y
 
2. 0 1 
A n a ntici pate d nee d f or treat me nt wit h b ot uli n u m t o xi n of a n y ser ot y pe f or a n y i n dicati o n 
d uri n g t he st u d y ( ot her t ha n st u d y i nter ve nti o n) 
2. 0 2 
Hist or y of de ntal or s ur gical pr oce d ure f or l o wer facial s ha pi n g or masseter m uscle 
re d ucti o n 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
2 7 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
5. 0 3 
K n o w n aller g y or se nsiti vit y t o a n y of t h e c o m p o ne nts of t he st u d y treat me nts or a n y 
materials use d i n t he st u d y pr oce d ures 
5. 0 4 
Hist or y of alc o h ol or dr u g a b use wit hi n 1 2 m o nt hs of Da y 1 
5. 0 5 
A n y c o n diti o n or sit uati o n w hic h, i n t h e i n vesti gat or’s o pi ni o n, precl u des t he 
partici pa nt’s a bilit y t o c o m pl y wit h st u d y re q uire me nts, i ncl u di n g c o m pleti o n of t he 
st u d y visits or a n i na bilit y t o rea d, or t hat ma y p ut t he partici pa nt at si g nifica nt ris k, ma y 
c o nf o u n d t he st u d y res ults, or ma y i nterfer e si g nifica ntl y wit h t he partici pa nt’s 
partici pati o n i n t he st u d y  
 
5. 3.  
Lifest yle C o nsi der ati o ns 
N ot a p plica ble; n o restricti o ns are re q uire d. 
5. 4.  
Scree n F ail ures 
Scree n fail ures are defi ne d as partici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are 
n ot s u bse q ue ntl y e ntere d i n t he st u d y. A mi ni mal set of scree n fail ure i nf or mati o n is re q uire d t o 
e ns ure tra ns pare nt re p orti n g of scree n fail ure  partici pa nts t o meet t he C O N S O R T p u blis hi n g 
re q uire me nts a n d t o res p o n d t o q ueries fr o m reg ulat or y a ut h orities. Mi ni mal i nf or mati o n 
i ncl u des de m o gra p h y, scree n fail ure details, eli gi bilit y criteria, a n d a n y S A E. 
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ures) ma y n ot 
be rescree ne d. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI
B O T O X 
G R D- C L N
i njecti o n
a n d t he 
eac h i nj
After c o
s h o ul d ap
e vi de nce
a p plie d u
c o ntralat
t he i njec
I m me di
desi g nee
6. 1. 1.  
T he f oll
•  
•  I
•  e
T he f oll
•  c
•  a
•  
D E N TI A L 
-T- 0 1- 0 1 v 2. 0 
, t he nee dle 
v ol u me s h o u
ecti o n site, a
m pl eti n g t h e
p pl y direct 
 of c uta ne o
u ntil t he ble
eral masset
ti o ns f or A
atel y bef ore 
) will write 
Ot her St
o wi n g will b
T e m perat ure 
m a gi n g e q ui
C O A de vic
o wi n g will b
o tt o n pa ds a
lc o h ol wi pe
m e dical gl o v
directi o n w i
l d be distri b
n  e q ual v olu
 3 i njecti o ns
p ress ure t o th
u s blee di n g o
edi n g st o ps. T
er m uscle. Th
E s. 
d is pe nsi n g th
the partici p a
u d y  S u p plie
e pr o vi de d b
rec or di n g de
p me nt (s u p p
es (s u p plie d b
e pr o vi de d b
n d ma ke u p r
s 
es 
it hi n t he m us
ute d wit hi n 
u me will be a
s of t he mass
h e treat me nt 
or  e mer gi n g 
T he sa me p r
h e partici pan
h e st u d y i nt e
ant’s i de ntifi c
es 
b y t he s p o ns o
evice f or m o
p lied  b y a t hi
b y a t hir d- p a
b y t he st u d y s
re m o ver 
3 0 
scle b ul k s h
t he dee per 
ad mi nistere
seter m uscle
area f or a p p
he mat o ma, 
roce d ure wi
n t s h o ul d be 
er ve nti o n, th
cati o n n u m
or  or desi g ne
o nit ori n g re
ird - part y ve
art y ve n d or)
site: 
o ul d be per
an d m ore s u
d  (see Ta ble
 o n 1 si de o
p r o xi matel y 
c o nti n ue d d
ll be f oll o w
o bser ve d f
h e i n vesti gat
b er a n d t he 
ee: 
fri gerat or tem
n d or) 
Pr ot o c
p e n dic ular a n
p erficial m u s
6- 2 ). 
f t he face, th
3 0 sec o n ds. 
irect press ur
ed f or i njecti
o r at least 3 0
or  ( or a p pr op
d ate o n t he l a
m perat ure 
col 1 7 8 9- 3 0 1
n d n ot o bli q u
scle la yers. F
h e i n vesti gat o
If t here is 
re s h o ul d be 
o n t o t he 
 mi n utes aft
p riatel y train
abel. 
1 - 0 0 8 
u e, 
F or 
o r 
er 
n e d 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
3 1 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
•  ser u m or uri ne pre g na nc y tests i n acc or da nce wit h t he l ocal i nstit uti o nal re q uire me nts. If 
uri ne pre g na nc y test kits are t o be use d, a mi ni m u m se nsiti vit y of 2 5 I U/ m L is re q uire d 
•  sterile s ur gical mar ker pe ns 
•  a p pr o priatel y-size d sterile nee dles a n d s y ri n ges f or st u d y treat me nt rec o nstit uti o n a n d 
i njecti o n 
•  
 
•  l oc ka ble refri gerat or, t o st ore st u d y treatme nt kits acc or di n g t o t he St u d y Ma n ual  
•  c o vere d c o ntai ner f or discar de d me dical waste materials (s har ps b o x) 
•  i nter net c o n necti o n ( hi g h-s pee d c o n necti o n f or e C R F c o m pleti o n) 
6. 2.  
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y 
I n or der t o e ns ure i nject or bli n di n g d uri n g Peri o d 1, a n u n bli n de d I D R will be i de ntifie d pri or t o 
st u d y i nitiati o n, w h o will n ot be i n v ol ve d wit h ot her st u d y acti vities. T he de dicate d I D R will be 
res p o nsi ble f or pre parati o n of bli n de d st u d y i nter ve nti o ns f or Peri o d 1 w hile mai ntai ni n g t he 
bli n d f or all ot her st u d y pers o n ne l a n d t he st u d y partici pa nts.  
F or Peri o d 2, o pe n-la bel st u d y i nter ve nti o ns ( B O T O X) will be pre pare d b y assi g ne d st u d y 
pers o n nel, w hic h ma y be t he I D R or a n ot her desi g nee. 
St u d y i nter ve nti o ns will be rec o nstit ute d wit h 0. 9 % s o di u m c hl ori de ( preser vati ve free). 
T a ble 6- 2 
I njecti o n V ol u me 
St u d y I nter ve nti o n  
T ot al D ose ( U); 
T ot al V ol u me 
( m L) 
M asseter D ose ( U); 
V ol u me per 
M asseter ( m L) 
V ol u me per 
I njecti o n ( m L) 
B O T O X 
 
 
 
Place b o 
 
 
 
Detaile d i nstr ucti o ns o n rec o nstit uti o n a n d s yri n ge pre parati o n are pr o vi d e d i n t he St u d y Ma n ual. 
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y i nter ve nti o n recei ve d a n d a n y discre pa ncies are re p orte d 
a n d res ol ve d bef ore use of t he st u d y i nter ve nti o n. 
O nl y partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y i nter ve nti o n, a n d o nl y a ut h orize d site 
staff ma y s u p pl y or a d mi nister st u d y i nter ve nti o n. All st u d y i nter ve nti o n m ust be st ore d i n a 
sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area i n acc or da nce 
wit h t he la bele d st ora ge c o n diti o ns wit h access li m ite d t o t he i n vesti gat or a n d a ut h orize d site 
staff. 
T he i n vesti gat or, i nstit uti o n, or  t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y i nter ve nti o n acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (ie, 
recei pt, rec o nciliati o n, an d fi nal dis p ositi o n rec or ds). 
 
 
 
  
  
  
  
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
3 2 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
All use d a n d u n use d st u d y i nter ve nti o n m ust be st ore d sec ure d, wit h li mite d access t o a 
desi g nate d u n bli n de d site me m ber, a n d ret ur ne d t o  t he s p o ns or or desi g nee o nce e x pire d or at t he 
ter mi nati o n of st u d y. U nit c o u nts will be perf orme d w he n t he st u d y i nter ve nti o n is ret ur ne d, a n d 
all st u d y i nter ve nti o n m ust be acc o u nte d f or. 
6. 3.  
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g 
At t he Scree ni n g Visit, after t he partici pa nt si g ns  t he I C F, t he site will l o g o n t o t he I W R S t o 
o btai n a partici pa nt n u m ber. O n Da y 1, t he I W R S will be use d t o ma na ge t he ra n d o mizati o n a n d 
assi g n me nt of partici pa nts i nt o  o ne of t he 2 st u d y i nter ve ntio n gr o u ps base d o n a ra n d o mizati o n 
sc he d ule pre pare d t he s p o ns or’s Bi ostatistics depart me nt. T he ra n d o mizati o n will occ ur after all 
baseli ne pr oce d ures ha ve bee n c o m plete d a n d t he i n vesti gat or has verifie d t hat t he partici pa nt 
has met all i ncl usi o n a n d e xcl usi o n criteria. Ra n d o mizati o n will be stratifie d at eac h i n vesti gat or 
site b y t he partici pa nt’s baseli ne ( Da y 1) M M P S Gra de ( 4 or 5), as assesse d b y t he i n vesti gat or. 
F or t he d o u ble- bli n d Peri o d 1, all st u d y i nter ve n ti o ns will be pr o vi de d i n i de ntical vials a n d 
cart o ns t o mai ntai n bli n di n g. I n a d diti o n,  t he i njecti o n v ol u me a n d st u d y i nter ve nti o n 
a d mi nistrati o n will be i de ntical f or b ot h gr o u ps.  
F or o pe n-la bel Peri o d 2, all st u d y i nter ve nti o n will be pr o vi de d i n cart o ns, eac h c o ntai ni n g o ne 
o pe n-la bel vial. 
St u d y i nter ve nti o n will be la bele d wit h kit n u m be rs. T he I W R S will pr o vi de t he site wit h t he 
s pecific kit n u m ber f or eac h ra n d o mize d partici pa nt at t he ti me of ra n d o mizati o n ( Da y 1). T he 
I W R S will als o iss ue t he s pecific kit n u m ber f or eac h partici pa nt w h o q ualifies f or retreat me nt. 
Sites will dis pe nse st u d y i nter ve nti o n acc or di n g t o  t he I W R S i nstr ucti o ns. Sites will recei ve t he 
I W R S c o nfir mati o n n otificati o ns f or eac h tra nsacti o n a n d will mai ntai n  t hese wit h t he st u d y 
s o urce d oc u me nts. 
At eac h st u d y site, a desi g nate d staff me m ber will  ser ve as t he I D R f or t he d o u ble- bli n d Peri o d 1. 
T his pers o n will be res p o nsi ble o nl y f or bli n de d st u d y i nter ve nti o n pre parati o n d uri n g Peri o d 1. 
T his pers o n will be a staff me m ber wit h n o st u d y res p o nsi bilities t hat req uire i nteracti o n wit h 
partici pa nts a n d wit h pa rtici pa nt efficac y or safet y data. F or Peri o d 2, site pers o n nel ot her t ha n 
t he I D R ma y be assi g ne d t o pre pare o pe n-la bel st u d y i nter ve nti o ns ( B O T O X). 
F or Peri o d 1, t he I D R will pre pare t he vial of  st u d y i nter ve nti o n as describe d i n Secti o n 6. 2  a n d 
t he St u d y Ma n ual. O nce t he st u d y i nter ve nti o n vial is rec o nstit ute d, t he I D R will dra w t he 
re q uire d v ol u me i nt o a n a p pr o priatel y size d s yri n ge a n d la bel t he s yri n ge wit h t he partici pa nt’s 
I D n u m ber. T he I D R will t he n pr o vi de t he fille d s yri n ges t o t he i n vesti gat or. T he i n vesti gat or 
will i nject t he partici pa nt acc or di n g t o t he st u d y i nter ve nti o n a d mi nistrati o n i nstr ucti o ns i n 
Secti o n 6. 2 . I n Peri o d 1, o nl y t he I D R will be u n blin de d t o t he st u d y treat me nt; all ot her site 
pers o n nel a n d st u d y partici pa nts will be bli n de d. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
3 4 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
3 5 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
6. 6.  
D ose M o dific ati o n 
D ose m o dificati o n is n ot a p plica ble. 
6. 6. 1.  
Retre at me nt Criteri a 
All partici pa nts e ntere d i nt o t he st u d y will be treate d at Da y 1. A partici pa nt will recei ve 
1 a d diti o nal treat me nt if s he/ he meets retreat me nt criteria, as deter mi ne d b y t he i n vesti gat or. T o 
be eli gi ble f or retreat me nt at t he Da y 1 8 0, 2 1 0, 2 4 0, 2 7 0, 3 0 0, 3 3 0, 3 6 0, 3 9 0, or 4 2 0 visits, t he 
partici pa nt m ust meet all t he f oll o wi n g criteria: 
•  Partici pa nt has prese nce of M M P of at least m arke d  ( Gra de 4) o n eac h si de, as meas ure d b y 
t he i n vesti gat or usi n g t he M M P S, A N D 
•  Fe males of c hil d beari n g p ote ntial m ust ha ve a ne gati ve pre g na nc y test pri or t o treat me nt, 
A N D 
•  
 
 
A sec o n d treat me nt is o nl y all o we d o n or bet wee n t he Da y 1 8 0 a n d Da y 4 2 0 visits. 
 
 Retreat me nts m ust 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
3 6 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
occ ur d uri n g n or mall y sc he d ule d visit wi n d o ws a n d are pre pare d a n d a d mi nistere d as descri be d 
i n Secti o n 6. 2  f or B O TO X. 
Tre at me nt
 St u d y
 
Visit
 
Descri pti o n
 
Treat me nt 1  
Da y 1 ( Visit 2)  
D o u ble bli n d, ra n d o mize d 
Treat me nt 2 
( Retreat me nt 1) 
Da ys 1 8 0 t o 4 2 0 
( Visit 8 t o 1 6) 
O pe n-la bel; partici pa nt m ust q ualif y f or retreat me nt 
Treat me nt 3 
( Retreat me nt 2) 
Da ys 2 7 0 t o 4 2 0 
( Visits 1 1 t o 1 6) 
O pe n-la bel; partici pa nt m ust q ualif y f or retreat me nt; 
m ust be 8 4 da ys fr o m t he pre vi o us treat me nt 
 
If a partici pa nt q ualifies f or retreat me nt i n Peri o d 2 a n d decli nes it, retreat me nt will n ot be 
a d mi nistere d at t hat visit a n d t he partici pa nt’s reas o n f or decli ni n g retreat me nt will be ca pt ure d 
o n t he e C R F. If t he partici pa nt sti ll meets retreat me nt criteria at t he ne xt visit ( u p t o Da y 4 2 0), he 
or s he ma y recei ve retreat me nt at t hat ti me.  
6. 7.  
I nter ve nti o n after t he E n d of t he St u d y 
N o i nter ve nti o ns after t he e n d of t he st u d y are pla n ne d. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
3 7 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
7.  
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al 
Partici pa nts ma y v ol u ntaril y wit h dra w fr o m t h e st u d y at a n y ti me. A pr e mat ure disc o nti n uati o n 
will occ ur if a partici pa nt w h o si g ns t he I C F a n d is d ose d ceases partici pati o n i n t he st u d y, 
re gar dless of circ u msta nces, bef ore t he c o m pletio n of t he pr ot oc ol- defi n e d st u d y pr oce d ures. 
N otificati o n of earl y partici pa nt disc o n ti n uati o n fr o m t he st u d y a n d t he reas o n f or 
disc o nti n uati o n will be ma de t o t he s p o ns or a n d will be clearl y d oc u me nte d o n t he a p pr o priate 
e C R F. 
Reas o ns f or disc o nti n uati o n fr o m t he st u d y treat me nt a n d/ or t he st u d y ma y i ncl u de t he f oll o wi n g 
c o m m o nl y use d or ot her acce pta ble ter ms: 
C o m m o nl y Use d Ter ms 
Ot her Acce pt a ble Ter ms 
A d verse e ve nt 
Deat h 
Lac k of efficac y 
 
L ost t o f oll o w- u p 
 
Ot her
 
 
P h ysicia n decisi o n 
 
Pre g na nc y
 
 
Pr ot oc ol de viati o n 
 
Site ter mi nate d b y s p o ns or 
 
St u d y ter mi nate d b y s p o ns or 
 
Wit h dra wal b y s u bject 
 
 
Defi niti o ns of t he sta n dar d ter m s are pr o vi de d i n A p pe n di x 4 . 
7. 1.  
Disc o nti n u ati o n of St u d y I nter ve nti o n 
See t he S o A 
 f or data t o be c ollecte d at t he ti me of disc o nti n uati o n fr o m t he st u d y 
i nter ve nti o n a n d f oll o w- u p a n d f or a n y f urt her e val uati o ns t hat nee d t o be c o m plete d. 
If a pre g na nc y is c o nfir me d after t he partici pa nt has recei ve d stu d y i nter ve nti o n, t he partici pa nt 
will n ot recei ve a d diti o nal treat me nt a n d ma y c h o ose t o e xit t he st u d y after a p pr o priate safet y 
f oll o w- u p or t o re mai n i n t he st u d y f or all safet y a n d efficac y f oll o w- u p assess me nts t hr o u g h t he 
e n d- of-st u d y visit. 
7. 2.  
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y 
•  A partici pa nt ma y wit h dra w fr o m t he st u d y at a n y ti me at his/ her o w n re q uest or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he i n vesti gat or f or safet y, be ha vi oral, c o m plia nce, 
or a d mi nistrati ve reas o ns. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
3 9 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
8.  
St u d y Assess me nts a n d Pr oce d ures 
•  St u d y pr oce d ures a n d t heir ti mi n g ar e s u m marize d i n t he S o A ( Secti o n 1. 3 ). Pr ot oc ol wai vers 
or e xe m pti o ns are n ot all o we d. 
•  E val uati o ns are t o be perf or me d b y t he sa me e val uat or t hr o u g h o ut t he st u d y w he ne ver 
p ossi ble. If it is n ot p ossi ble t o use t he sa me e val uat or t o f oll o w t he partici pa nt, t he n 
e val uati o ns s h o ul d o verla p (e xa mi ne  t he partici pa nt t o get her a n d disc uss fi n di n gs) f or at least 
1 visit. 
•  I m me diate safet y c o ncer ns s h o ul d be disc usse d wit h t he s p o ns or i m me diatel y u p o n 
occ urre nce or a ware ness t o dete r mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y 
i nter ve nti o n. 
•  A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is esse ntial 
a n d re q uire d f or st u d y c o n d uct. 
•  All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y criteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all partici pa nts scree ne d an d t o c o nfir m eli gi bilit y or rec or d reas o ns f or 
scree ni n g fail ure, as a p plica ble. 
8. 1.  
Effic ac y Assess me nts 
Pla n ne d ti me p oi nts f or all efficac y assess me n ts are pr o vi de d i n t he S o A (see Secti o n 1. 3 ). T he 
m eas ures are descri be d i n detail i n A p pe n di x 7  a n d A p pe n di x 8 . 
8. 1. 1.  
Pri m ar y Effic ac y Assess me nt 
T he pri mar y efficac y assess me nt is t o be c o m plete d at scree ni n g, baseli ne, a n d at eac h sc he d ule d 
visit t hereafter u ntil st u d y e xit. 
N ote: T he Da y 1 i ma ges will be use d as baseli ne  i ma ges. If t he baseli ne i ma ges are n ot of 
acce pta ble q ualit y, t he scree ni n g i ma ges will be use d i nstea d. Ca nfiel d Scie ntific, I nc. m ust 
a p pr o ve eac h partici pa nt’s scree ni n g i ma ges t o e ns u re a q ualit y baseli ne i ma ge is a vaila ble if t he 
Da y 1 i ma ges are n ot of acce pta ble q ualit y. If t he scree ni n g i ma ges are n ot acce pta ble, 1 reta ke is 
per mitte d a n d m ust be ta ke n bef ore Da y 1. 
Masseter M uscle Pr o mi ne nce S cale – I n vesti gat or ( M M P S) 
T he pri mar y efficac y assess me nt is masseter m uscle pr o mi ne nce assesse d b y t he i n vesti gat or 
usi n g t he M M P S ( 1 = mi ni mal, 2 = mil d, 3 = m o derate, 4 = mar ke d, 5 = ver y mar ke d 
 
 
 
 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
4 0 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
8. 1. 2.  
Sec o n d ar y Effic ac y Assess me nts 
M M P S- P a n d l o wer facial wi dt h assess me nts will be c o m plete d at scree ni n g, baseli ne, a n d at 
eac h sc he d ule d visit t hereafter u ntil st u d y e xit. T he P S A C will be c o m plete d at all sc he d ule d 
p ost baseli ne visits. Partici pa nts will be trai ne d o n h o w t o pr o perl y c o m plete t he M M P S- P a n d 
P S A C assess me nts usi n g i ma ges, at t he Scree ni n g Visit (a n d at ot her visits if nee de d). 
Masseter M uscle Pr o mi ne nce Scale – Partici pa nt ( M M P S- P) 
M M P assesse d b y t he partici pa nt is a sec o n dar y  efficac y assess me nt de vel o pe d b y t he s p o ns or 
t hr o u g h c o nce pt elicitati o n a n d co g niti ve de briefi n g. Partici pa nts will be as ke d t o assess t he 
se verit y of t heir masseter pr o mi ne nce usi n g a si n gle q uesti o n c o m p ose d of 5 gra des ( 1 = n ot at 
all pr o n o u nce d, 2 = mil dl y pr o n o u nce d, 3 = m o deratel y pr o n o u nce d, 4 = pr o n o u nce d, 5 = ver y 
pr o n o u nce d; 
 
 
  
 
 
  
Partici pa nt Self- Assess me nt of C ha n ge ( P S A C) 
T he P S A C is a c o m m o nl y use d assess me nt of c ha n ge scale t hat has bee n a da pte d f or use wit h 
M M P b y t he s p o ns or usi n g c o nce pt elicitati o n a n d c o g niti ve de briefi n g. Partici pa nts will be 
as ke d t o assess c ha n ge of t heir l o wer face s h a pe usi n g 2 D i ma ges c ollecte d bef ore st u d y 
i nter ve nti o n (ie, baseli ne, or scree ni n g if t he baseli ne i ma ge is n ot of acce pta ble q ualit y) a n d 
after st u d y i nter ve nti o n (ie, t he c u rre nt st u d y visit) 
 
 
  
T he partici pa nt will a ns wer t he q uesti o ns o n t h e acc o m pa n yi n g assess me nts via electr o nic ta blet 
t hat will be pr o vi de d t o t he stu d y partici pa nt at t he st u d y site. 
L o wer Facial Wi dt h 
T he l o wer facial wi dt h ( m m) will be calc ulate d fr o m 2 D pr ojecti o ns of 3 D i ma ges. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
4 1 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
8. 1. 3.  
Ot her Effic ac y Assess me nts 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
4 3 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
8. 3.  
A d verse E ve nts a n d S eri o us A d verse E ve nts 
T he defi niti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x 2 . 
A Es will be re p orte d b y t he partici pa nt ( or, w h e n a p pr o priate, b y a care gi ver, s urr o gate, or t he 
partici pa nt’s le gall y a ut h orize d re prese ntati ve). 
T he i n vesti gat or a n d a n y q ualifie d desi g nees ar e res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble f or f oll o wi n g 
u p A Es t hat are seri o us, c o nsi dere d relate d t o t h e st u d y i nter ve nti o n or st u d y pr oce d ures, or t hat 
ca use d t he partici pa nt t o disc o nt i n ue t he st u d y i nter ve nti o n (ie, re peat treat me nt) or st u d y (see 
Secti o n 7 ). 
8. 3. 1.  
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A d verse E ve nt a n d Seri o us A d verse 
E ve nt I nf or m ati o n  
All S A Es fr o m t he si g ni n g of t he I C F will be c o llecte d at t he ti me p oi nts s pecifie d i n t he S o A 
( Secti o n 1. 3 ), a n d as o bser ve d or re p orte d s p o nta ne o usl y b y stu d y partici pa nts. 
All A Es fr o m t he si g ni n g of t he I C F will be c o llecte d at t he ti me p oi nts s pecifie d i n t he S o A 
( Secti o n 1. 3 ), a n d as o bser ve d or re p orte d sp o nta ne o usl y b y st u d y partici pa nts. 
Me dical occ urre nces t hat be gi n bef ore t he start of st u d y i nter ve nti o n, b ut after o btai ni n g 
i nf or me d c o nse nt, will be rec or de d i n t he A E secti o n of t he e C R F a n d will be c o nsi dere d 
pretreat me nt A Es. 
All S A Es will be rec or de d a n d re p orte d t o t he s p o ns or or desi g nee wit hi n 2 4 h o urs, as i n dicate d 
i n A p pe n di x 2 . T he i n vesti gat or will s u b mit a n y u p dated S A E data t o t he s p o ns or wit hi n 
2 4 h o urs of it bei n g a vaila ble. 
I n vesti gat ors are n ot o bli gate d t o acti vel y see k A E or S A E i nf or mati o n after c o ncl usi o n of t he 
st u d y partici pati o n. H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a deat h, at a n y 
ti me after a partici pa nt has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt t o be 
reas o na bl y relate d t o t he st u d y i nter ve nti o n or st u d y partici pati o n, t he i n vesti gat or m ust pr o m ptl y 
n otif y t he s p o ns or. 
T he met h o ds of rec or di n g, e val uati n g, a n d a ssessi n g ca usalit y of A Es a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n A p pe n di x 2. 
8. 3. 2.  
Met h o d of Detecti n g A d verse E ve n ts a n d Seri o us A d verse E ve nts 
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A Es a n d/ or S A Es. O pe n-e n de d a n d 
n o n-lea di n g ver bal q uesti o ni n g of  t he partici pa nt is t he preferre d met h o d t o i n q uire a b o ut 
A E occ urre nces. 
8. 3. 3.  
F oll o w- u p of A d verse E ve nts a n d Seri o us A d verse E ve nts 
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h partici pa n t 
at s u bse q ue nt visits/c o n tacts. All S AEs a n d a n y A E SI as defi ne d i n A p pe n di x 2  will be f oll o we d 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
4 4 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
u ntil res ol uti o n, sta biliz ati o n, t he e ve nt is ot her wise e x plai ne d, or t he partici pa nt is l ost t o f oll o w-
u p (as defi ne d i n Secti o n 7. 3 ). 
T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as me dicall y i n dicate d or as re q ueste d b y t he s p o ns or t o 
el uci date t he nat ure a n d/ or ca usa lit y of t he A E or S A E as f ull y as p ossi ble. T his ma y i ncl u de 
a d diti o nal la b orat or y tests or i n ve sti gati o ns, hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n wit h 
ot her healt h care pr ofessi o nals. If a partici pa nt dies d uri n g partici pati o n i n t he st u d y, t he 
i n vesti gat or will pr o vi de t he s p o ns or wit h a c o p y of a n y p ost m orte m fi n di n gs i ncl u di n g 
hist o pat h ol o g y. 
Ne w or u p date d i nf or mati o n will be rec or d e d i n t he ori gi nall y c o m plete d e C R F. 
T he i n vesti gat or will s u b mit a n y u p date d S A E data t o t he s p o ns or wit hi n 2 4 h o urs of recei pt of 
t he i nf or mati o n. 
8. 3. 4.  
Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts 
•  Pr o m pt n otificati o n b y t he i n vesti gat or t o t he s p o ns or of a n S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bil ities t o war ds t he safet y of partici pa nts a n d t he safet y of a 
st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met.  
•  T he s p o ns or has a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a ge ncies a b o ut t he safet y of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n. T he 
s p o ns or will c o m pl y wit h c o u ntr y-s pecific reg ulat or y re q uire me nts relati n g t o safet y 
re p orti n g t o t he re g ulat or y a ut h orit y, I R Bs/ I E Cs, a n d i n vesti gat ors.  
•  I n vesti gat or safet y re p orts m ust be pre pare d f or S U S A Rs acc or di n g t o l ocal re g ulat or y 
re q uire me nts a n d s p o ns or p olic y a n d f or warde d t o i n vesti gat ors as necessar y. 
•  A n i n vesti gat or w h o recei ves a n i n vesti gat or  safet y re p ort descri bi n g a n S A E or ot her 
s pecific safet y i nf or mati o n (e g, s u m mar y or listi n g of S A Es) fr o m t he s p o ns or will re vie w 
a n d t he n file it al o n g wit h t he i n vesti gat or’s  br oc h ure a n d will n otif y t he I R B/I E C, if 
a p pr o priate acc or di n g t o l ocal re q uire me nts. 
8. 3. 5.  
Pre g n a nc y 
•  If a pre g na nc y is c o nfir me d after t he partici pa nt has recei ve d t he st u d y i nter ve nti o n, t he 
partici pa nt ma y c h o ose t o e xit t h e st u d y after a p pr o priate safet y f oll o w- u p or t o re mai n i n t he 
st u d y f or all safet y a n d efficac y f oll o w- u p assess me nts t hr o u g h t he e n d- of-st u d y visit. 
•  Details of all pre g na ncies i n fe male partici pa n ts will be c ollecte d fr o m t he si g ni n g of t he I C F 
a n d t hr o u g h t he d urati o n of t he pre g na nc y . 
•  If a pre g na nc y is re p orte d, t he i n vesti gat or s h o ul d i nf or m t he s p o ns or wit hi n 2 4 h o urs of 
lear ni n g of t he pre g na nc y a n d s h o ul d f oll o w t he pr oce d ures o utli ne d i n A p pe n di x 6 . 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
4 5 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
•  A b n or mal pre g na nc y o utc o mes (e g, s p o nta ne o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g na nc y) or ge netic a b n or malities ( w het her lea di n g t o a n electi ve 
a b orti o n or n ot) are c o nsi dere d S A Es. 
8. 3. 6.  
A d verse E ve nts of S peci al I nterest 
A E SIs will be rec o r de d as i n dicate d i n A p pe n di x 2 . 
8. 3. 7.  
Me dic ati o n Err ors 
Me dicati o n err or refers t o a n y u ni nte n de d err or i n t he d osi n g a n d/ or a d mi nistrati o n of t he st u d y 
i nter ve nti o n as per i nstr ucti o ns i n t he pr ot oc ol, f or e xa m ple: 
•  Wr o n g st u d y dr u g 
•  Wr o n g d ose (i ncl u di n g d osi n g re gi me n, c o nce ntrati o n, a m o u nt) 
•  Wr o n g partici pa nt (ie, n ot a d mi nister e d t o t he i nte n de d partici pa nt) 
8. 4.  
Tre at me nt of O ver d ose 
T he L D 5 0 f or B O T O X i n h u ma ns is esti mate d fr o m  pri mate st u dies t o be a p pr o xi matel y 3 0 0 0 U. 
T his ma kes acci de ntal i njecti o n of a let hal d ose  hi g hl y u nli kel y, b ut si g nifica nt A Es ma y still 
occ ur at d oses bel o w t he L D 5 0 ( Herrer o 1 9 6 7, Sc ott 1 9 8 9 ). 
E xcessi ve d oses ma y pr o d uce l ocal or dista n t, ge neralize d, a n d pr of o u n d ne ur o m usc ular 
paral ysis. S h o ul d acci de ntal i njecti o n or oral i n gesti o n occ ur, or o ver d ose be s us pecte d, t he 
partici pa nt s h o ul d be me dicall y m o nit ore d f or u p t o se veral wee ks f or pr o gressi ve si g ns or 
s y m pt o ms of s yste mic m usc ular wea k ness t hat c o ul d be l ocal or dista nt fr o m t he site of i njecti o n, 
a n d w hic h ma y i ncl u de pt osis, di pl o pia, d ys p ha gia, d ysart hria, ge neralize d wea k ness, or 
res pirat or y fail ure. Please refer t o t he ge neral Secti o n 6. 5 of t he B OT O X M M P i n vesti gat or’s 
br oc h ure f or f urt her details. 
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or s h o ul d: 
1.  
C o ntact t he me dical safe t y p h ysicia n i m me diatel y. 
2.  
Cl osel y m o nit or t he partici pa nt f or A Es a n d S A Es. 
3.  
D oc u me nt t he q ua ntit y of t he e xcess d ose as  well as t he d urati o n of t he o ver d ose i n t he 
e C R F as well as ot her details t hat le d t o t he o ver d ose. 
8. 5.  
P h ar m ac o ki netics 
P har mac o ki netic para meters are n ot e val uate d i n t his st u d y. 
8. 6.  
P h ar m ac o d y n a mics 
P har mac o d y na mic para meters are n ot e val uate d i n t his st u d y. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
4 6 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
8. 7.  
Ge netics 
Ge netics are n ot e val uate d i n t his st u d y. 
8. 8.  
Bi o m ar kers a n d Ot her Assess me nts 
Bi o mar kers are n ot e val uate d i n t his st u d y. 
8. 9.  
He alt h Ec o n o mics  
Healt h ec o n o mics para meters are n ot e val uate d i n t his st u d y. 
9.  
St atistic al C o nsi der ati o ns 
9. 1.  
St atistic al H y p ot heses 
T he f oll o wi n g set of h y p ot heses will be use d t o  c o m pare t he B O T O X 7 2 U gr o u p wit h place b o: 
•  N ull h y p ot hesis: B O T O X a n d place b o are e q uall y effecti ve i n re d uci n g M M P as 
meas ure d b y t he pr o p orti o n of res p o n ders ac hie vi n g ≥ 2- gra de i m pr o ve me nt fr o m 
baseli ne at Da y 9 0 usi n g t he M M P S. 
•  Alter nati ve h y p ot hesis: B O T O X a n d place b o are n ot e q uall y effecti ve i n re d uci n g M M P 
as meas ure d b y t he pr o p orti o n of res p o n ders ac hie vi n g ≥ 2- gra de i m pr o ve me nt fr o m 
baseli ne at Da y 9 0 usi n g t he M M P S. 
9. 2.  
S a m ple Size Deter mi n ati o n 
 
 
 
a p pr o xi ma tel y 3 6 0 partici pa nts ( 2 7 0 B O T O X a n d 9 0 place b o) will pr o vi de 
> 9 0 % p o wer
 
. 
9. 3.  
P o p ul ati o ns f or A n al yses 
T he a nal ysis p o p ulati o ns will c o nsist of partici pa nts as defi ne d i n bel o w: 
•  T he mI T T p o p ulati o n i ncl u des all ra n d o mize d partici pa nts wit h ≥ 1 p ost baseli ne M M P S 
assess me nt. Partici pa nts will be s u m marize d acc or di n g t o t he ra n d o mize d st u d y 
i nter ve nti o n. 
•  T he safet y p o p ulati o n i ncl u des all treate d partici pa nts w h o recei ve ≥ 1 a d mi nistrati o n of 
st u d y i nter ve nti o n. Partici pa nts will be s u m mari ze d acc or di n g t o t he st u d y i nter ve nti o n 
t he y recei ve d. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
4 7 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
9. 4.  
St atistic al A n al yses 
T he S A P will be de vel o pe d a n d fi nalize d bef ore data base l oc k a n d u n bli n di n g a n d will descri be 
t he partici pa nt p o p ulati o ns t o be i ncl u de d i n t he a nal yses, a n d pr oce d ures f or acc o u nti n g f or 
missi n g, u n use d, a n d s p uri o us data. T his secti o n is  a s u m mar y of t he pla n ne d statistical a nal yses 
of t he pri mar y a n d sec o n dar y e n d p oi nts. Pla n ne d a nal yses of ot her efficac y e n d p oi nts a n d ot her 
c ollecte d cli nical a n d safet y data fr o m t his st u d y will be f ull y d oc u me nte d i n t he st u d y S A P. 
9. 4. 1.  
Effic ac y A n al yses 
T he efficac y a nal yses will be base d o n t he mI T T p o p ulati o n. Baseli ne f or efficac y is defi ne d as 
t he last n o n missi n g effi cac y assess me nt bef ore t he first d ose of st u d y i nter ve nti o n. All statistical 
tests will be 2-si de d h y p ot hesis tests perf or me d at t he 5 % le vel of si g nifica nce f or mai n effects. 
T he o verall fa mil y wise err or rate will be c o ntr olle d at α  = 0. 0 5 f or t he set of pri mar y a n d 
sec o n dar y e n d p oi nt c o m paris o ns bet wee n B OT O X 7 2 U vs place b o. T he o verall serial 
gate kee pi n g M C P is defi ne d i n Ta ble 9- 1 . 
 
9. 4. 1. 1.  
A n al ysis E n d p oi nts 
T he pri mar y a n d sec o n dar y efficac y e n d p oi nts are lis te d bel ow, a n d a nal yses will be defi ne d i n 
t he f oll o wi n g secti o ns. All a nal yses f or ot her efficac y e n d p oi nts liste d bel o w will be defi ne d i n 
t he S A P. 
Pri m ar y effic ac y e n d p oi nt: 
•  Pr o p orti o n of res p o n ders w h o ac hie ve ≥ 2- gra de i m pr o ve me nt fr o m baseli ne at Da y 9 0, 
per i n vesti gat or assess me n ts of M M P usi n g t he M M P S 
 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
4 8 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
Sec o n d ar y effic ac y e n d p oi nts: 
•  Pr o p orti o n of res p o n ders w h o ac hie ve M M P S Gra de ≤ 3 at Da y 9 0, acc or di n g t o 
i n vesti gat or 
•  Pr o p orti o n of res p o n ders w h o ac hie ve M M P S- P Gra de ≤ 3 at Da y 9 0, acc or di n g t o 
partici pa nt 
•  Pr o p orti o n of res p o n ders w h o ac hie ve ≥ 2- gra de i m pr o ve me nt fr o m baseli ne at Da y 9 0 
usi n g t he M M P S- P 
•  Pr o p orti o n of res p o n ders w h o ac hie ve P S A C Gra de ≥ 1 (at least mi ni mall y i m pr o ve d 
fr o m baseli ne) at Da y 9 0 
•  C ha n ge fr o m baseli ne i n l o wer facial wi dt h ( m m) at Da y 9 0 
•  D urati o n of effect f or B O T O X-treate d  M M P S res p o n ders
 
 
Ot her e n d p oi nts: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
9. 4. 1. 2.  
Pri m ar y A n al yses 
T he pri m ar y efficac y e n d p oi nt will be t he pr o p orti o n of res p o n ders w h o ac hie ve ≥ 2- gra de 
i m pr o ve me nt fr o m baseli ne at Da y 9 0, per i n vesti gat or assess me nts of M M P usi n g t he M M P S 
a n d will be a nal yze d usi n g C M H m o del stratifi e d b y baseli ne M M P S Gra de ( 4 or 5). Missi n g 
M M P S val ues i n Peri o d 1 will be i m p ute d us i n g m ulti ple i m p utati o n met h o ds. A se nsiti vit y 
a nal ysis will be base d o n o bser ve d data. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
5 1 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
1 0.  
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns 
1 0. 1.  
A p pe n di x 1: Re g ul at or y, Et hic al, a n d St u d y O versi g ht 
C o nsi der ati o ns 
1 0. 1. 1.  
Re g ul at or y a n d Et hic al C o nsi der ati o ns 
•  T his st u d y will be c o n d ucte d i n acc or da nce w it h t he pr ot oc ol a n d wit h t he f oll o wi n g: 
o  C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d CI O M S I nter nati o nal Et hical G ui deli nes 
o  A p plica ble I C H/I S O/ G C P g ui deli nes 
o  A p plica ble la ws a n d re g ulati o ns 
•  T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, i n vesti gat or’s br oc h ure, a n d ot her rele va nt 
d oc u me nts (e g, a d vertise me nts) m ust be s u b mitte d t o a n I R B/I E C b y t he i n vesti gat or a n d 
re vie we d a n d a p pr o ve d b y t he I R B/I E C bef ore t he st u d y is i nitiate d.  
•  A n y a me n d me nts t o t he pr ot oc ol will re q uir e I R B/I E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n ges necessar y t o e li mi nate a n i m me diate 
hazar d t o st u d y partici pa nts.  
•  T he i n vesti gat or will be re s p o nsi ble f or t he f oll o wi n g: 
o  Pr o vi di n g writte n s u m maries of t he stat us of  t he st u d y t o t he I R B/I E C a n n uall y or m or e 
fre q ue ntl y i n acc or da nce wit h t he re q uire me nts, p olicies, a n d pr oce d ures esta blis he d b y 
t he I R B/I E C 
o  N otif yi n g t he I R B/I E C of S A Es or ot her si g n ifica nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ures 
o  Pr o vi di n g o versi g ht of t he o verall c o n d uct of t he st u d y at t he site a n d a d here nce t o 
re q uire me nts of a p plica ble l ocal re g ulati o ns, f or e xa m ple 2 1 C F R, I C H g ui deli nes, t he 
I R B/I E C, a n d E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble) 
1 0. 1. 2.  
Fi n a nci al Discl os ure 
I n vesti gat ors a n d s u bi n vesti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mati o n as re q ueste d t o all o w t he s p o ns or t o s u b mit c o m pl ete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y a ut h or ities. I n vesti gat ors are 
res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y a n d f or 
1 year after c o m pleti o n of t he st u d y. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
5 2 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
1 0. 1. 3.  
I nf or me d C o nse nt Pr ocess 
•  T he i n vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure  of t he st u d y t o t he 
partici pa nt or his/ her le gall y a ut h orize d re pres e ntati ve a n d a ns wer all q uesti o ns re gar di n g t he 
st u d y.  
•  Partici pa nts m ust be i nf or me d t hat t heir part ici pati o n is v ol u ntar y. Partici pa nts will be 
re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets t he re q uire me nts of 2 1 C F R 5 0, 
l ocal re g ulati o ns, I C H g ui deli nes, HI P A A re q uire me nts, w here a p plica ble, a n d t he I R B/I E C 
or st u d y ce nter.  
•  T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d 
bef ore t he partici pa nt was e nr olle d i n t he st u d y a n d t he date t he writte n c o nse nt was o btai ne d. 
T he a ut h orize d pers o n o btai n i n g t he i nf or me d c o nse nt m ust als o si g n t he I C F. 
•  Partici pa nts m ust be re-c o nse nte d t o t he m ost  c urre nt versi o n of t he I C F(s) d uri n g t heir 
partici pati o n i n t he st u d y, if a p plica ble.  
•  A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gall y 
a ut h orize d re prese ntati ve.  
1 0. 1. 4.  
D at a Pr otecti o n 
•  Partici pa nts will be assi g ne d a u ni q ue i de ntifier . A n y partici pa nt rec or ds or datasets t hat are 
tra nsferre d t o t he s p o ns or will c o ntai n t he i de ntifier o nl y; partici pa nt na mes or a n y 
i nf or mati o n w hic h w o ul d ma ke t he partici pa nt i de ntifia ble will n ot be tra nsferre d.  
•  T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y-relate d data will be use d b y t he 
s p o ns or i n acc or da nce wit h l ocal data pr otectio n la w. T he le vel of discl os ure m ust als o be 
e x plai ne d t o t he partici pa nt.  
•  T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y be e xa mi ne d b y Cli nical 
Q ualit y Ass ura nce a u dit ors or ot her a ut h or ize d pers o n nel a p p oi nte d b y t he s p o ns or, b y 
a p pr o priate I R B/I E C me m bers, a n d b y i n s pect ors fr o m re g ulat or y a ut h orities. 
1 0. 1. 5.  
P osti n g Cli nic al St u d y D at a 
•  St u d y data a n d i nf or mati o n ma y be p u blis he d i n  n o n pr o m oti o nal, peer-re vie we d p u blicati o ns 
eit her b y or o n be half of t he s p o ns or.  
•  Cli nical st u d y re p orts, safet y u p dates, a n d a n n ual re p orts will be pr o vi de d t o re g ulat or y 
a ut h orities as re q uire d. 
•  C o m pa n y-s p o ns ore d st u d y i nf or mati o n a n d ta b ul ar st u d y res ults will be p oste d o n t he U S 
Nati o nal I nstit utes of Healt h's  we bsite w w w. Cli nical Trials. g o v a n d ot her p u blicl y accessi ble 
sites. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
5 3 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
1 0. 1. 6.  
D at a Q u alit y Ass ur a nce 
•  All partici pa nt data relati n g t o t he st u d y will be rec or de d o n pri nte d or electr o nic C R Fs 
u nless tra ns mitte d t o t he s p o ns or or desi g nee elec tr o nicall y. T he i n vesti gat or is res p o nsi ble 
f or verif yi n g t hat data e ntries are acc urate an d c orrect b y p h ysicall y or  electr o nicall y si g ni n g 
t he C R F.  
•  T he i n vesti gat or m ust mai ntai n acc urate d o c u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t he C R F.  
•  T he i n vesti gat or m ust per mit st u d y-relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts.  
•  T he s p o ns or or desi g nee is res p o nsi ble f or t he data ma na ge me nt of t his st u d y i ncl u di n g 
q ualit y c hec ki n g of t he data.  
•  St u d y m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d 
i nt o t he C R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m s o urce 
d oc u me nts; t hat t he safet y a n d ri g hts of partici pa nts are bei n g pr otecte d; a n d t hat t he st u d y is 
bei n g c o n d ucte d i n acc or da nce wit h t he c urre n tl y a p pr o ve d pr ot oc ol a n d a n y ot her st u d y 
a gree me nts, I C H G C P, a n d all a p p lica ble re g ulat or y re q uire me nts.  
•  Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pe rtai ni n g t o t he c o n d uct of t his st u d y m ust 
be retai ne d b y t he i n vesti gat or as state d i n t h e cli nical trial a gree me nt. N o rec or ds ma y be 
destr o ye d d uri n g t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of t he s p o ns or. N o rec or ds 
ma y be tra nsferre d t o a n ot her l ocati o n or part y wit h o ut writte n n otific ati o n t o t he s p o ns or.  
1 0. 1. 7.  
S o urce D oc u me nts 
•  S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grit y of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or’s site. 
•  Data re p orte d o n t he C R F or e ntere d i n t he e C R F t hat are tra nscri be d fr o m s o urce d oc u me nts 
m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he 
i n vesti gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer  rec or ds, de pe n di n g o n 
t he st u d y. 
•  Defi niti o n of w hat c o nstit utes s o urce data ca n  be f o u n d i n Secti o n 4. 0 of I C H E 6, G o o d 
Cli nical Practice: C o ns oli date d G ui da nce a n d m ust f oll o w A L C O A, ie, rec or ds m ust be 
attri b uta ble, le gi ble, c o nte m p or a ne o us, ori gi nal, a n d acc urate. 
1 0. 1. 8.  
St u d y a n d Site Cl os ure 
T he s p o ns or desi g nee reser ves t he ri g ht t o cl ose t he st u d y site or ter mi nate t he st u d y at a n y ti me 
f or a n y reas o n at t he s ole discreti o n of t he s p o ns or. St u d y sites will be cl ose d u p o n st u d y 
c o m pleti o n. A st u d y site is c o nsi dere d cl ose d  w he n all re q uire d d oc u me nts a n d st u d y s u p plies 
ha ve bee n c ollecte d a n d a st u d y-site  cl os ure visit has bee n perf or me d. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
5 4 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
T he i n vesti gat or ma y i nitiate st u d y-site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n. 
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he s p o ns or or i n vesti gat or ma y i ncl u de b ut are 
n ot li mite d t o: 
•  Fail ure of t he i n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C or 
l ocal healt h a ut h orities, t he s p o ns or’s pr oce d ures, or G C P g ui deli nes 
•  I na de q uate recr uit me nt of partici pa nts b y t he i n vesti gat or 
•  Disc o nti n uati o n of f urt her st u d y i nter ve nti o n de vel o p me nt 
1 0. 1. 9.  
P u blic ati o n P olic y 
•  Aller ga n as t he s p o ns or has pr o prietar y i ntere st i n t his st u d y. A ut h ors hi p a n d ma n uscri pt 
c o m p ositi o n will reflect j oi nt c o o perati o n bet w ee n m ulti ple i n vesti gat ors a n d sites a n d 
Aller ga n pers o n nel. A ut h ors hi p will be esta blis he d pri or t o t he writi n g of t he ma n uscri pt. As 
t his st u d y i n v ol ves m ulti ple ce nters, n o i n di vi d ual p u blicati o ns will be all o we d pri or t o 
c o m pleti o n of t he fi nal re p ort of t he m ultice n ter st u d y e xce pt as a gree d wit h Aller ga n. 
•  T he s p o ns or will c o m pl y wit h t he re q uire m e nts f or p u blicati o n of st u d y res ults. I n 
acc or da nce wit h sta n dar d e dit orial a n d et hica l practice, t he s p o ns or will ge nerall y s u p p ort 
p u blicati o n of m ultice nter st u dies o nl y i n t heir e ntiret y a n d n ot as i n di vi d ual site data. 
•  A ut h ors hi p will be deter mi ne d b y m ut ual a gre e me nt a n d i n li ne wit h I nter nati o nal C o m mittee 
of Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts. 
1 0. 1. 1 0.  
C o m pli a nce wit h Pr ot oc ol 
T he i n vesti gat or is res p o nsi ble f or c o m plia nce wi t h t he pr ot oc ol at t he i n vesti gati o nal site. A 
re prese ntati ve of t he s p o ns or will ma ke fre q ue nt c o ntact wit h t he i n vesti gat or a n d his/ her 
researc h staff a n d will c o n d uct re g ular m o nit ori n g visits at t he site t o re vie w partici pa nt a n d 
st u d y i nter ve nti o n acc o u nta bilit y rec or ds f or c o m pliance wit h t he pr ot oc ol. Pr ot oc ol de viati o ns 
will be disc usse d wit h t he i n vesti gat or u p o n i de ntificati o n. T he use of t he data c ollecte d f or t he 
partici pa nt will be disc usse d t o deter mi ne if t h e data are t o be i ncl u de d i n t he a nal ysis. T he 
i n vesti gat or will e nter data t hat ma y be e xclu de d fr o m a nal ysis as defi ne d b y t he pr ot oc ol 
de viati o n s pecificati o ns. Si g nifi ca nt pr ot oc ol de viati o ns will  be re p orte d t o t he I R B/I E C 
acc or di n g t o t he I R B/I E C’s re p orti n g re q uire me nts. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
6 0 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
1 0. 3.  
A p pe n di x 3: A b bre vi ati o ns 
 
A b bre vi ati o n/ Ter m
 Defi niti o n
 
2 D
 2- di me nsi o nal
 
3 D
 3- di me nsi o nal
 
A E
 a d verse
 
e ve nt
 
A E SI 
a d verse e ve nt of s pecial i nterest 
A L C O A 
attri b uta ble, le gi ble, c o nte m p ora ne o us, ori gi nal, a n d acc urate 
A N C O V A 
a nal ysis of c o varia nce 
B MI 
b o d y mass i n de x 
B O T O X 
B ot uli n u m t o xi n t y pe A p urifie d ne ur ot o xi n 
C DI S C 
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m 
C F B
 c ha n ge
 
fr o m
 
baseli ne
 
CI O M S 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces 
C M H
 C oc hra n- Ma ntel- Hae nszel
 
C O A 
cli nical o utc o me assess me nt (f or merl y de scri be d as patie nt-re p orte d o utc o mes 
[ P R O]) 
C O N S O R T 
C o ns oli date d Sta n dar ds of Re p orti n g Trials 
C R F 
case re p ort f or m 
C T
 c o m p ute d
 
t o m o gra p h y
 
e C O A
 electr o nic
 
cli nical o utc o me assess me nt 
e C R F 
electr o nic case re p ort f or m 
F S H
 f ollicle
 
sti m ulati n g
 
h or m o ne
 
G C P
 G o o d
 
Cli nical
 
Practice
 
HI P A A 
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
H R T 
h or m o nal re place me nt t hera p y 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil o n Har m o nisati o n 
I D R
 i n de pe n de nt
 
dr u g
 
rec o nstit ut or
 
I E C 
i n de pe n de nt et hics c o m mittee 
I R B 
i nstit uti o nal re vie w b oar d 
I S O 
I nter nati o nal Or ga nizati o n f or Sta n dar dizati o n 
I U D
 i ntra uteri ne
 
de vice
 
I U S
 i ntra uteri ne
 
s yste m
 
I W R S 
i nteracti ve we b res p o nse s yste m 
L D 5 0
 let hal
 
d ose,
 
5 0 %
 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
6 1 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
M C P
 m ulti ple
 
c o m paris o ns
 
pr oce d ure
 
mI T T
 m o difie d
 
i nte nt-t o-treat
 
M M H 
masseter m uscle h y pertr o p h y 
M M P 
masseter m uscle pr o mi ne nce 
M M P S 
Masseter M uscle Pr o mi ne nce Scale 
M M P S- P
 M M P S- partici pa nt
 
M RI 
ma g netic res o na nce i ma gi n g 
N CI 
Nati o nal Ca ncer I nstit ute  
N o.
 n u m ber
 
P C S 
p ote ntiall y cli nicall y si g nifica nt 
 
 
P S A C 
Partici pa nt Self-assess me nt of C ha n ge 
S A E 
seri o us a d verse e ve nt 
S A P 
statistical a nal ysis pla n 
S o A 
sc he d ule of acti vities  
S O P
 sta n dar d
 
o perati n g
 
pr oce d ure
 
S U S A Rs
 s us pecte d
 
u n e x pecte d seri o us a d verse reacti o ns 
T E A E 
treat me nt-e mer ge nt a d verse e ve nt 
T E S A E 
treat me nt-e mer ge nt seri o us a d verse e ve nt 
T MJ D
 te m p or o ma n di b ular
 
j oi nt
 
dis or ders
 
U
 u nit
 
W O C B P 
w o ma n of c hil d beari n g p ote ntial 
 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
6 2 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
1 0. 4.  
A p pe n di x 4: St a n d ar d Di sc o nti n u ati o n Criteri a 
T his ta ble pr o vi des partici pa nt di sc o nti n uati o n criteria f or t his pr ot oc ol. C DI S C ter mi n ol o g y is 
use d,  a n d  t h us  s u bject or  p atie nt  is  use d  i nstea d  of  p artici p a nt  (as  use d  else w here  i n  t his  
pr ot oc ol). T hese ter ms are i nterc ha n gea ble. 
C DI S C S u b missi o n Val ue 
C DI S C Defi niti o n 
A d verse e ve nt 
A n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
s u bject a d mi nistere d a p har mace utical pr o d uc t a n d w hic h d oes n ot 
necessaril y ha ve a ca usal relati o ns hi p wit h t his treat me nt. A n A E ca n 
t heref ore be a n y 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), 
s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal 
(i n vesti gati o nal) pr o d uct, w het her or n ot relate d t o t he me dici nal 
(i n vesti gati o nal) pr o d uct. F or f urt her i nf or mati o n, see t he I C H G ui deli ne f or 
Cli nical Safet y Data Ma na ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d 
Re p orti n g ( m o difie d fr o m I C H E 2 A)  S y n o n y ms: si de effect, a d verse 
e x perie nce. See als o seri o us a d verse e ve nt, seri o us a d verse e x perie nce. 
( C DI S C gl ossar y) 
C o m plete d 
T o p ossess e ver y necessar y or n or mal part or c o m p o ne nt or ste p; ha vi n g 
c o me or bee n br o u g ht t o a c o ncl usi o n ( N CI) 
Deat h 
T he a bse nce of life or state of bei n g dea d ( N CI) 
Lac k of efficac y 
T he lac k of  e x pecte d or desire d effect relate d t o a t hera p y ( N CI) 
L ost t o f oll o w- u p 
T he l oss or lac k of c o nti n uati o n of a s u bject t o f oll o w- u p 
Ot her 
Differe nt t ha n t he o ne(s) pre vi o usl y s pecifie d or me nti o ne d ( N CI) 
P h ysicia n decisi o n 
A p ositi o n, o pi ni o n or j u d g me nt reac he d after c o nsi derati o n b y a p h ysicia n 
wit h refere nce t o s u bject ( N CI) 
Pre g na nc y 
Pre g na nc y is t he state or c o n diti o n of ha vi n g a de vel o pi n g e m br y o or fet us i n 
t he b o d y ( uter us), after u ni o n of a n o v u m a n d s per mat oz o o n, d uri n g t he 
peri o d fr o m c o nce pti o n t o birt h. ( N CI) 
Pr ot oc ol de viati o n 
A n e ve nt or decisi o n t hat sta n ds i n c o ntrast t o t he g ui deli nes set o ut b y t he 
pr ot oc ol ( N CI) 
Site ter mi nate d b y s p o ns or 
A n i n dicati o n t hat a cli nical st u d y was st o p pe d at a partic ular site b y its 
s p o ns or ( N CI) 
St u d y ter mi nate d b y s p o ns or  
A n i n dicati o n t hat a cli nical st u d y was st o p pe d b y its s p o ns or ( N CI) 
Wit h dra wal b y s u bject 
A n i n dicati o n t hat a st u d y partici pa nt has re m o ve d itself fr o m t he st u d y 
( N CI) 
 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
6 3 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
1 0. 5.  
A p pe n di x 5: St u d y T a b ul ar S u m m ar y 
T his ta ble is i nte n de d f or use i n p osti n g st u d y i nf or m ati o n t o re gistries (e g, Cli nical Trials. g o v). 
P ar a meter Gr o u p 
P ar a meter 
V al ue 
Trial i nf or mati o n  
Trial Title 
B O T O X ®  ( o na b ot uli n u mt o xi n A) 
Treat me nt of Masseter M uscle 
Pr o mi ne nce: A P hase 3, M ultice nter, 
Ra n d o mize d, D o u ble- Bli n d, 
Place b o- C o ntr olle d St u d y 
 
Cli nical St u d y S p o ns or 
Aller ga n Sales, L L C / Aller ga n Li mite d 
 
Trial P hase Classificati o n 
P hase 3 Trial 
 
Trial I n dicati o n 
Masseter M uscle Pr o mi ne nce 
 
Trial I n dicati o n T y pe 
Treat me nt 
 Trial
 T y pe
 
Efficac y
 
Safet y 
 
Trial Le n gt h 
5 4 0 da ys pl us t he 1 4- da y scree ni n g peri o d 
 
Pla n ne d C o u ntr y of I n vesti gati o nal Sites  
C o u ntr y/ Re gi o n:  
Ca na da, C hi na ( mai nla n d), Tai wa n 
 
Pla n ne d N u m ber of S u bjects 
3 6 0 
 
F D A- Re g ulate d De vice St u d y 
N o 
 F D A- Re g ulate d
 Dr u g
 
St u d y
 Yes
 
 Pe diatric
 St u d y
 
N o
 
Partici pa nt 
i nf or mati o n 
Dia g n osis Gr o u p 
Masseter M uscle Pr o mi ne nce 
 
Healt h y S u bject I n dicat or 
Yes 
 
Pla n ne d Mi ni m u m A ge of S u bjects 
1 8 
 
Pla n ne d Ma xi m u m A ge of S u bjects 
N ot s pecifie d 
 Se x
 of
 
Partici pa nts
  
B ot h
 
 
Sta ble Disease Mi ni m u m D urati o n 
N ot s pecifie d 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
6 5 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
1 0. 6.  
A p pe n di x 6: C o ntr ace pti ve G ui d a n ce a n d C ollecti o n of Pre g n a nc y 
I nf or m ati o n 
Defi niti o ns: 
W o ma n of C hil d beari n g P ote ntial 
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma ne ntl y sterile (see bel o w). 
W o me n i n t he f oll o wi n g c ate g ories are n ot c o nsi dere d W O C B P:  
1.  Pre me narc hal 
2.  Pre me n o pa usal fe male wit h 1 of t he f oll o wi n g: 
•  D oc u me nte d h ysterect o m y 
•  D oc u me nte d bilateral sal pi n gect o m y 
•  D oc u me nte d bilateral o o p h orect o m y 
N ote: D oc u me ntati o n ca n c o me fr o m t he site  pers o n nel’s: re vie w of t he partici pa nt’s 
me dical rec or ds, me dical e xa mi nati o n, or me dical hist or y i nter vie w. 
3.  P ost me n o pa usal fe male 
•  A p ost me n o pa usal state is defi ne d as n o me ns es f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca use. A hi g h F S H le vel i n t he p ost me n o pa usal ra n ge ma y be use d t o c o nfir m a 
p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal c o ntrace pti o n or H R T. H o we ver, i n 
t he a bse nce of 1 2 m o nt hs of a me n orr hea, a si n gle F S H meas ure me nt is i ns ufficie nt.  
C o ntr ace pti o n G ui d a nce: 
Fe male Partici pa nts 
Fe male partici pa nts of c hil d beari n g p ote ntial are eli gi ble t o partici pate if t he y a gree t o use a 
hi g hl y effecti ve or acce pta ble m et h o d of c o ntrace p ti o n c o nsiste ntl y a n d c orrectl y as descri be d i n 
Ta ble 1 0- 1 . 
C o ntrace pti ve met h o ds usi n g C hi nese tra diti o nal me dici ne or ot her her bal re me dies are n ot 
c o nsi dere d acce pta ble met h o ds of c o ntrace pti o n i n t his st u d y. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
6 6 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
T a ble 1 0- 1  
Hi g hl y Effecti ve a n d Acce pt a ble C o ntr ace pti ve Met h o ds 
Hi g hl y Effecti ve C o ntr ace pti ve Met h o ds T h at Are User De pe n de nt
a  
F ail ure r ate of < 1 % per ye ar w he n use d c o nsiste ntly a n d c orrectly   
C o m bi ne d (estr o ge n- a n d pr o gest o ge n-c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h  i n hi biti o n of o v ulati o n 
•  
Oral  
•  
I ntra va gi nal  
•  
Tra ns der mal  
Pr o gest o ge n- o nl y h or m o nal c o ntrace pti o n ass ociate d wit h  i n hi biti o n of o v ulati o n 
•  
Oral  
•  
I njecta ble  
Hi g hl y Effecti ve Met h o ds T h at Are User I n de pe n de nt a  
•  
I m pla nta ble pr o gest o ge n- o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 
•  
I U D 
•  
I U S 
•  
Et o n o gestrel i m pla nt (ie, Ne x pla n o n ® ) 
•  
Bilateral t u bal occl usi o n (e g. Ess ure, bilateral t u bal li gati o n) 
•  
I ntra uteri ne c o p per c o ntrace pti ve (ie, Para Gar d® ) 
V asect o mize d P art ner  
A v asect o mize d p art ner is a hi g hly effective c o ntr ace pti o n met h o d pr ovi de d t h at t he p art ner is t he s ole m ale 
sex u al p art ner of t he W O C B P a n d t he a bse nce of s per m h as bee n c o nfir me d. If n ot, a n a d diti o n al hi g hly effective 
met h o d of c o ntr ace pti o n s h o ul d be use d.   
Se x u al A bsti ne nce  
Sex u al a bsti ne nce is c o nsi dere d a hi g hly effective met h o d o nly if defi ne d as refr ai ni n g fr o m heter osex u al 
i nterc o urse d uri n g t he e ntire peri o d of risk ass oci ate d wit h t he st u dy i nterve nti o n. T he reli a bility of sex u al 
a bsti ne nce nee ds t o be ev al u ate d i n rel ati o n t o t he d ur ati o n of t he st u dy a n d t he preferre d a n d us u al lifestyle of 
t he p artici p a nt.  
Acce pt a ble Met h o ds   
Acce pt a ble birt h c o ntr ol met h o ds t h at res ult i n a f ail ure of m ore t h a n 1 % per ye ar i ncl u de: 
•  
Pr o gest o ge n- o nl y oral h or m o nal c o ntrace pti o n, w here i n hi biti o n of o v ulati o n is n ot t he pri mar y m o de of 
acti o n 
•  
Male or fe male c o n d o m wit h or wit h o ut s per mici de  
•  
Ca p, dia p hra g m, or s p o n ge wit h s per mici de 
•  
N o n h or m o nal i ntra uteri ne de vice  
A c o m bi nati o n of male c o n d o m wit h eit her ca p, dia p hra g m, or s p o n ge wit h s per mici de  ( d o u ble- barrier met h o ds) 
are als o c o nsi dere d acce pta ble, b ut n ot hi g hl y effecti ve, birt h c o ntr ol met h o ds. 
a  T y pical use fail ure rates ma y differ fr o m t h ose w he n use d c o nsiste ntl y a n d c orrectl y. Use s h o ul d be c o nsiste nt 
wit h l ocal re g ulati o ns re gar di n g t he use of c o ntrace pti ve met h o ds f or partic i pa nts partici pati n g i n cli nical 
st u dies.  
 
Pre g n a nc y Testi n g: 
•  
W O C B P s h o ul d o nl y be i ncl u de d after a c o nfir me d me nstr ual peri o d a n d a ne gati ve hi g hl y 
se nsiti ve pre g na nc y test at scree ni n g a n d als o a ne gati ve test at baseli ne. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
6 7 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
•  
A d diti o nal pre g na nc y testi n g s h o ul d be perf or me d pri or t o retr eat me nt a n d at st u d y e xit, a n d 
as re q uire d l ocall y. 
•  
Pre g na nc y testi n g will be perf or me d w he ne v er a me nstr ual c ycle is misse d or w he n 
pre g na nc y is ot her wise s us pecte d.  
•  
Uri ne pre g na nc y testi n g will be use d u nless t he st u d y site re q uires t he use of ser u m testi n g, 
i n w hic h case ser u m testi n g will be use d. 
C ollecti o n of Pre g n a nc y I nf or m ati o n: 
Fe m ale P artici p a nts W h o Bec o me Pre g n a nt  
•  
T he i n vesti gat or will c ollect pre g na nc y i nf or mati o n o n a n y fe male partici pa nt w h o bec o mes 
pre g na nt w hile partici p ati n g i n t his st u d y. I nf or mati o n wi ll be rec or de d o n t he a p pr o priate 
f or m a n d s u b mitte d t o Aller ga n wit hi n 2 4 h o urs of lear ni n g of a partici pa nt’s pre g na nc y. 
T he partici pa nt will be f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y. T he 
i n vesti gat or will c ollect f oll o w- u p i nf or mati o n o n t he partici pa nt a n d t he ne o nate, a n d t he 
i nf or mati o n will be f or war de d t o Aller ga n. Ge nerall y, f oll o w- u p will n ot be re q uire d f or 
l o n ger t ha n 6 t o 8 wee ks be y o n d t he esti mate d deli ver y date. A n y ter mi nati o n of pre g na nc y 
will be re p orte d, re gar dless of fetal stat us ( prese nce or a bse nce of a n o malies) or i n dicati o n 
f or t he pr oce d ure. 
•  
W hile pre g na nc y itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na nc y c o m plicati o n 
will be re p orte d as a n A E or S A E. A s p o nta ne o us a b orti o n is al wa ys c o nsi dere d t o be a n 
S A E a n d will be re p orte d as s uc h. A n y p os tst u d y pre g na nc y-relate d S A E c o nsi dere d 
reas o na bl y relate d t o t he st u d y i nter v e nti o n b y t he i n vesti gat or will be re p orte d t o Aller ga n 
as descri be d i n Secti o n 8. 3. 4 . W hile t he i n vesti gat or is n ot o bli gate d t o acti vel y see k t his 
i nf or mati o n i n f or mer st u d y partici pa nts, he or s he ma y lear n of a n S A E t hr o u g h 
s p o nta ne o us re p orti n g.  
•  
If a pre g na nc y is c o nfir me d after t he partici pa nt has recei ve d st u d y i nter ve nti o n, t he 
partici pa nt ma y c h o ose t o e xit t he st u d y after a p pr o priate safet y f oll o w- u p or t o re mai n i n 
t he st u d y f or all safet y a n d efficac y f oll o w- u p assess me nts t hr o u g h t he e n d- of-st u d y visit.   
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
6 8 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
1 0. 7.  
A p pe n di x 7: Effic ac y Me as ures 
1 0. 7. 1.  
M asseter M uscle Pr o mi ne nce Sc ale – I n vesti g at or Assess me nt 
I nstr ucti o ns 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
6 9 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
7 2 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
7 4 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
1 0. 8.  
A p pe n di x 8: E x a m ple Cli nic al O utc o me Assess me nt Q uesti o n n aires, 
Descri pti o ns, a n d I nstr ucti o ns 
T his a p pe n di x pr o vi des c o m plete sa m ples of eac h  C O A q uesti o n naire; h o we ver, partici pa nts will 
pr o vi de res p o nses i n electr o nic ta bl ets (ie, e C O A) at t he st u d y site. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI
B O T O X 
G R D- C L N
1 0. 8. 1.  
D E N TI A L 
-T- 0 1- 0 1 v 2. 0 
M assete r M uscle Pro mi ne nce S
7 5 
c ale – P art ici p a nt ( M
Pr ot o c
M P S- P) 
col 1 7 8 9- 3 0 1 - 0 0 8 
  
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI
B O T O X 
G R D- C L N
1 0. 8. 2.  
D E N TI A L 
-T- 0 1- 0 1 v 2. 0 
M assete r Pr o mi ne nce P artici p a
7 6 
a nt Self- Ass ess me nt of 
Pr ot o c
C h a n g e ( PS
col 1 7 8 9- 3 0 1
S A C) 
1 - 0 0 8 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI
B O T O X 
G R D- C L N
D E N TI A L 
-T- 0 1- 0 1 v 2. 0 
7 7 
Pr ot o c ol 1 7 8 9- 3 0 1 - 0 0 8 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
7 8 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI
B O T O X 
G R D- C L N
D E N TI A L 
-T- 0 1- 0 1 v 2. 0 
7 9 
Pr ot o c ol 1 7 8 9- 3 0 1 - 0 0 8 
  
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI
B O T O X 
G R D- C L N
D E N TI A L 
-T- 0 1- 0 1 v 2. 0 
8 0 
Pr ot o c ol 1 7 8 9- 3 0 1 - 0 0 8 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
8 1 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI
B O T O X 
G R D- C L N
D E N TI A L 
-T- 0 1- 0 1 v 2. 0 
8 2 
Pr ot o c ol 1 7 8 9- 3 0 1 - 0 0 8 
  
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
8 3 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI
B O T O X 
G R D- C L N
D E N TI A L 
-T- 0 1- 0 1 v 2. 0 
8 4 
Pr ot o c ol 1 7 8 9- 3 0 1 - 0 0 8 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI
B O T O X 
G R D- C L N
D E N TI A L 
-T- 0 1- 0 1 v 2. 0 
8 5 
Pr ot o c ol 1 7 8 9- 3 0 1 - 0 0 8 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
8 6 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
1 1.  
Refere nces 
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stere o p h ot o gra m metric met h o d of q ua ntif yi n g t he effect of b ot uli n u m t o xi n t y pe A i njecti o ns o n 
masseter h y pertr o p h y.  Plast Rec o ns tr S ur g.  2 0 1 2; 1 3 0( 2): 3 7 6e- 3 7 8e. 
A h n J, H or n C, Blitzer A.  B ot uli n u m t o xi n f or ma sseter re d ucti o n i n Asia n patie nts.  Arc h Facial 
Plast S ur g.  2 0 0 4; 6( 3): 1 8 8- 1 9 1. 
Ay dil B, Basara n B, U nsaler S, S u o gl u Y.  T he use of b ot uli n u m t o xi n t y pe A i n masseteric 
m uscle h y pertr o p h y:  l o n g-ter m effects a n d la sti n g i m pr o ve me nt.  K ula k B ur u n B o g gaz I htis 
Der g (J o ur nal of Ear, N ose a n d T hr oat).  2 0 1 2; 2 2( 5): 2 4 9- 2 5 3. [ E n glis h tra nslati o n fr o m T ur kis h] 
Bae k S M, Ki m S S, Bi n di ger A. T he pr o mi ne nt ma n di b ular a n gle: pre o perati ve ma na ge me nt, 
o perati ve tec h ni q ue, a n d res ults i n 4 2 pa tie nts. Plast Rec o nstr S ur g. 1 9 8 9; 8 3: 2 7 2- 2 7 8. 
C hai G, Z ha n g Y, Z h u M, Ma X, Yu Z, M u X, Qi Z. E val uati o n of d y na mic m or p h ol o gic c ha n ges 
i n t he masseter m uscle i n patie nts u n der g oi n g ma n di b ular a n gle sa gittal s plit oste ot o m y. Arc h 
Facial Plast S ur g. 2 0 1 1; 1 3: 3 0 1- 3 0 4. 
C ha n g C S, Ka n g G C- W. Ac hie vi n g i deal l o we r face aest hetic c o nt o urs: c o m bi nati o n of 
tri di me nsi o nal fat grafti n g t o t he c hi n wit h masseter b ot uli n u m t o xi n i njecti o n. Aest hetic S ur ger y 
J o ur nal, 2 0 1 6; 3 6( 1 0): 1 0 9 3 – 1 1 0 0. 
C h oe S W, C h o WI, Lee C K, Se o SJ.  Effects of b ot uli n u m t o xi n t y pe A o n c o nt o uri n g of t he 
l o wer face.  Der mat ol S ur g.  2 0 0 5; 3 1( 5): 5 0 2- 5 0 8. 
de Me nezes M, R osati R, Ferrari o V F, Sf or za C.  Acc urac y a n d re pr o d uci bilit y of a 
3- di me nsi o nal stere o p h ot o gra m metric i ma g i n g s yste m.  J Oral Ma xill ofac S ur g.  
2 0 1 0; 6 8: 2 1 2 9- 2 1 3 5. 
De g uc hi M, Ii o Y, K o ba yas hi K, S hira ka be T. A n gle-s plitti n g ostect o m y f or re d uci n g t he wi dt h 
of t he l o wer face. Plast Rec o nstr S ur g. 1 9 9 7; 9 9: 1 8 3 1- 1 8 3 9. 
Fe d or o wicz Z, va n Z u ure n EJ, Sc h o o nes J. B ot u li n u m t o xi n f or masseter h y pertr o p h y. C oc hra ne 
Data base S yst Re v. 2 0 1 3;( 9): C D 0 0 7 5 1 0. Re vie w. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
8 7 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
Herrer o B A, Ec kl u n g A E, Streett C S, F or d D F, Ki n g J K. E x peri me ntal b ot ulis m i n m o n ke ys: a 
cli nical pat h ol o gical st u d y. E x p M ol Pat h ol. 1 9 6 7; 6: 8 4- 9 5. 
H o n g H S, Ka n g S C, Ki m C- Y, Ki m S T.  L o n g-ter m e v al uati o n of t he effect of b ot uli n u m t o xi n A 
i njecti o n i n patie nts wit h masseteric h y pertr o p h y.  K orea n J Oral Me d.  2 0 0 5; 3 0( 1): 1 2 1- 1 2 9. 
Ji n H. Misc o nce pti o ns a b o ut ma n di ble re d ucti o n pr oce d ures. Aest hetic Plast S ur g. 
2 0 0 5; 2 9: 3 1 7- 3 2 4. 
Ji n H, Ki m B G. Ma n di ble re d ucti o n vers us ma n dib ular a n gle re d ucti o n. Plast Rec o nstr S ur g. 
2 0 0 4; 1 1 4: 1 2 6 3- 1 2 6 9. 
Ki m HJ, Yu m K- W, Lee S- S, He o M- S, Se o K.  Ef fects of b ot uli n u m t o xi n t y pe A o n bilateral 
masseteric h y pertr o p h y e val uate d wit h c o m p ute d t o m o gra p hic meas ure me nt.  Der mat ol S ur g.  
2 0 0 3; 2 9: 4 8 4- 4 8 9. 
Ki m J- H, S hi n J H, Ki m S T, Ki m C- Y.  Effects of  t w o differe nt u nits of b ot uli n u m t o xi n t y pe A 
e val uate d b y c o m p ute d t o m o gra p h y a n d elec tr o m y o gra p hic meas ure me nt of h u ma n masseter 
m uscle.  Plast Rec o nstr S ur g.  2 0 0 7; 1 1 9( 2): 7 1 1- 7 1 7. 
Ki m N- H, C h u n g J- H, Par k R- H, Par k J- B.  T h e use of b ot uli n u m t o xi n t y pe A i n aest hetic 
ma n di b ular c o nt o uri n g.  Plast Rec o nstr S ur g.  2 0 0 5; 1 1 5( 3): 9 1 9- 9 3 0. 
Ki m S K, Ha n JJ, Ki m J T. Classifica ti o n a n d treat me nt of pr o mi ne nt ma n di b ular a n gle. Aest hetic 
Plast S ur g. 2 0 0 1; 2 5: 3 8 2 – 3 8 7. 
Klei n F H, Bre n ner F M, Sat o M S, R o bert F M, Hel mer K A. L o wer facial re m o deli n g wit h 
b ot uli n u m t o xi n t y pe A f or t he treat me nt of  masseter h y pertr o p h y. A n Bras Der mat ol. 
2 0 1 4; 8 9( 5): 8 7 8- 8 8 4. 
Lee J G, Par k Y W. I ntra oral a p pr oac h f or re d ucti o n malar plast y: a si m ple met h o d. Plast Rec o nstr 
S ur g. 2 0 0 3; 1 1 1: 4 5 3- 4 6 0. 
Lee K C, Ha S U, Par k J M, Ki m S K, Par k S H, Ki m J H. Re d ucti o n malar plast y b y 3- m m 
perc uta ne o us oste ot o m y. Aest hetic Plast S ur g. 2 0 0 6; 3 0: 3 3 3 – 3 4 1. 
Lie w S, Dart A.  N o ns ur gical res ha pi n g of t h e l o wer face.  Aest het S ur g J.  2 0 0 8; 2 8( 3): 2 5 1- 2 5 7. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
8 8 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
Misc h k o ws ki R A, Siesse g ger M, Lazar F, Z oller J E .  [ C he m o de ner vati o n wit h b ot uli n u m t o xi n 
i n masseteric h y pertr o p h y].  M u n d-, Kiefer- u n d Gesic htsc hir.  2 0 0 5; 9( 2): 1 0 1- 1 0 8. 
M o ore A P, Wo o d G D.  T he me dical ma na ge me nt of masseter h y pertr o p h y wit h b ot uli n u m t o xi n 
t y pe A.  Br J Oral Ma xill ofac S ur g.  1 9 9 4; 3 2( 1): 2 6- 2 8. 
M orris D E, M oa ve ni Z, L o L-J. Aest hetic facial s keletal c o nt o uri n g i n t he Asia n patie nt. Cli n 
Plastic S ur g. 2 0 0 7; 3 4: 5 4 7 – 5 5 6. 
M u X. E x perie nce i n East Asia n facial re c o nt o uri n g: re d ucti o n mala r plast y a n d ma n di b ular 
res ha pi n g. Arc h Facial Plast S ur g. 2 0 1 0; 1 2: 2 2 2- 2 2 9. 
O niz u ka T, Wata na be K, Ta kas u K, Ke ya ma A. Re d ucti o n malar plast y. Aest hetic Plast S ur g. 
1 9 8 3; 7: 1 2 1- 1 2 5. 
Par k M Y, A h n K Y, J u n g D S.  B ot uli n u m t o xi n t y pe  A treat me nt f or c o nt o urin g of t he l o wer face.  
Der mat ol S ur g.  2 0 0 3; 2 9: 4 7 7- 4 8 3. 
Par k YJ, J o Y W, Ba n g SI, Ki m HJ, Li m S Y, M u n G H, et al. Ra di ofre q ue nc y v ol u metric 
re d ucti o n f or masseteric h y pertr o p h y. Aest hetic Plast S ur g. 2 0 0 7; 3 1: 4 2- 5 2. 
Pe n g H- L P, Pe n g J- H. C o m plicati o ns of b ot u li n u m t o xi n i njecti o n f or masseter h y pertr o p h y: 
i nci de nce rate fr o m 2 0 3 6 treat me nts a n d s u m mary of ca uses a n d pre ve nti o ns. J C os met Der mat ol. 
2 0 1 7; 0 0: 1- 6 
P u Z, Z ha n g Y, Ya n g J, Li u T, Z ha n g Y, Ya n g Q, et al. Ma n di b ular a n gle ostect o m y f or C hi nese 
w o me n: a p pr oac hes a n d e xte nt deter mi ne d b y ce p hal o metric a nal ysis. J Cra ni ofac S ur g. 
2 0 0 9; 2 0: 1 0 5- 1 1 0. 
Ra us o R, Sa nta gata M, C olella G. Ca n occl usal de vices pr ol o n g t he effect of b ot uli n u m t o xi n 
t y pe A i n t he c o nt o uri n g of t he l o wer face? E ur J Plast S ur g. 2 0 1 0; 3 3: 3 5- 4 0. 
Sc ott A B. Cl ostri dial t o xi ns as t hera pe utic a ge n ts. I n: Si m ps o n L L, e dit or. B ot uli n u m ne ur ot o xi n 
a n d teta n us t o xi n. Ne w Yor k, Aca de mic Press. 1 9 8 9; 3 9 9- 4 1 2. 
S hi m W H, Yo o n S H, Par k J H, C h oi Y- C, Ki m S T. Effect of b ot uli n u m t o xi n t y pe A i njecti o n o n 
l o wer facial c o nt o uri n g e val uate d usi n g a t hree- di me nsi o nal laser sca n. Der mat ol S ur g. 
2 0 1 0; 3 6( S u p pl 4): 2 1 6 1- 2 1 6 6. 
 
 
 

 
 
A p pr o v al D at e : 
 
 
1 7- D e c- 2 0 1 8
 
C O N FI D E N TI A L
 Pr ot oc ol 1 7 8 9- 3 0 1- 0 0 8
B O T O X 
8 9 
G R D- C L N- T- 0 1- 0 1 v 2. 0 
S m yt h A G. B ot uli n u m t o xi n treat me nt of bilate ral masseteric h y pertr o p h y. Br J Oral Ma xill ofac 
S ur g. 1 9 9 4; 3 2: 2 9- 3 3. 
S u mi ya N, Yos hi n ori I, Oz u mi K. Re d ucti o n malar plast y. Plast Rec o nstr S ur g. 2 0 0 4; 1 1 3: 1 4 9 7 –
1 4 9 9. 
Tartar o G, Ra us o R, Sa nta gata M, Sa ntill o V, Itr o A. L o wer facial c o nt o uri n g wit h b ot uli n u m 
t o xi n t y pe A. J Cra ni ofac S ur g. 2 0 0 8; 1 9: 1 6 1 3- 1 6 1 7.  
To E W H, A h uja A T, H o W S, Ki n g W W K, Wo n g W K , Pa n g P C W, et al. A pr os pecti ve st u d y of 
t he effect of b ot uli n u m t o xi n A o n masseteric m uscle h y pertr o p h y wit h  ultras o n o gra p hic a n d 
electr o m y o gra p hic meas ure me nt. Br J Plast S ur g. 2 0 0 1; 5 4: 1 9 7- 2 0 0. 
Tz o u C- H J, Fre y M.  E v ol uti o n of 3 D s urface i ma g i n g s yste ms i n facial plastic s ur ger y. Facial 
Plast S ur g Cli n N ort h A m.  2 0 1 1; 1 9: 5 9 1- 6 0 2. 
W u W T L. B ot o x facial sli m mi n g/fa cial sc ul pti n g: t he r ole of b ot uli n u m t o xi n- A i n t he treat me nt 
of h y pertr o p hic masseter m uscle a n d par oti d e n lar ge me nt t o narr o w t he l o wer facial wi dt h. 
Facial Plastic S ur ger y Cli nics of  N ort h A merica 2 0 1 0; 1 8( 1): 1 3 3- 1 4 0. 
Xie Y, Z h o u J, Li H, C he n g C, Herrler T, Li  Q. Classificati o n of Masseter H y pertr o p h y f or 
Tail ore d B ot uli n u m To xi n Ty pe A Tr eat me nt. Plast Rec o nstr S ur g. 2 0 1 4; 1 3 4: 2 0 9e- 2 1 8e. 
Ya n g D B, Par k C G. Ma n di b ular c o nt o uri n g s ur ger y f or p urel y aest hetic reas o ns. Aest hetic Plast 
S ur g. 1 9 9 1; 1 5: 5 3 – 6 0. 
Ya n g D B, S o n g H S, Par k C G. U nfa v ora ble res ults a n d t heir res ol uti o n i n ma n di b ular c o nt o uri n g 
s ur ger y. Aest hetic Plast S ur g. 1 9 9 5; 1 9: 9 3- 1 0 2.