Clinical trial NCT04594213
Conditions: Moderate to Severe Upper Facial Lines (Horizontal Forehead Lines, Glabellar Frown Lines, and Lateral Canthal Lines)
Sponsor: Merz North America, Inc.
Start date: 2020-09-23; Completion date: 2022-05-09
Enrollment: 362 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the safety and efficacy of NT 201 (active ingredient: Botulinum (neuro)toxin type A, free from complexing proteins) in the combined treatment of wrinkles in the upper face (Upper Facial Lines \[UFL\]): Horizontal Forehead Lines \[HFL\], Glabellar Frown Lines \[GFL\], and Lateral Canthal Lines \[LCL\]). It is a prospective, randomized, double-blind, placebo-controlled, multicenter study with a placebo-control main period (MP) followed by an open-label extension (OLEX) period.

Detailed description:

Arms: arm 1: Subjects will receive placebo injection in all three UFL (GFL, HFL and LCL) on Day 1 of main period. arm 2: Subjects will receive a total of 64 Units (U) of NT 201: 20 U of NT 201 injection both in the GFL area and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 of main period. arm 3: Subjects will receive a total of 40 U of NT 201: 20 U of NT 201 injection both in the GFL and HFL area, and placebo injection in the LCL area on Day 1 of main period. arm 4: Subjects will receive a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period. arm 5: Subjects will receive a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period. arm 6: Subjects will receive a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.
Interventions: intervention 1: NT 201 intervention 2: Placebo
Intervention descriptions: intervention 1: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% NaCl. intervention 2: Solution for injection prepared by reconstitution of powder with percent (%) Sodium Chloride (NaCl).

Protocol documents:
Prot_000.pdf: 
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A pr o s p e cti v e, r a n d o mi z e d, d o u bl e -bli n d, pl a c e b o -c o ntr oll e d, m ulti c e nt er 
st u d y wit h a n o p e n -l a b el e xt e n si o n p eri o d t o i n v e sti g at e t h e effi c a c y a n d 
s af et y of N T 2 0 1 i n t h e si m ult a n e o u s tr e at m e nt of u p p er f a ci al li n e s 
( h ori z o nt al f or e h e a d li n e s, gl a b ell ar fr o w n li n e s, a n d l at er al c a nt h al li n e s) 
De vel o p m e nt p h ase:  
P hase 3 
St u d y i de ntifier  
I N D N u m ber 
M 6 0 2 0 1 1 0 7 1  / N C T 0 4 5 9 4 2 1 3 
1 0 0 2 8 8 
I n dic ati o n: 
Si m ulta ne o us treat me nt of h oriz o ntal f ore h ea d li nes, 
gla bellar fr o w n li nes, a n d lateral ca nt hal li nes i n t he 
u p per face 
Pl a n ne d st u d y peri o d : 
F irst s u bject first visit: 
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L ast pri mar y o utc o me visit:   Q 2- 2 0 2 1 
L ast s u bject last visit: 
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I n vesti g ati o n al pr o d uct(s): 
N T 2 0 1, 1 0 0 U nits, p o w der f or s ol uti o n f or i njecti o n 
(acti ve  i n gre die nt:  N T  1 0 1,  B ot uli n u m  ne ur ot o xi n  
t y pe  A  free  fr o m  c o m ple xi n g  pr otei ns,  U S A N:  
i nc o b ot uli n u mt o xi n A)  
Refere n ce pr o d uct: matc hi n g place b o 
S p o ns or : 
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Ec ke n hei mer La n d str. 1 0 0 
6 0 3 1 8 Fra n kf urt/ Mai n G er ma n y 
Tele p h o ne:  
+ 4 9 6 9 1 5 0 3 0 
Telefa x:   
+ 4 9 6 9 1 5 0 3 2 0 0 
Res p o nsi ble f or t he cli nic al 
st u d y pr ot oc ol c o nte nt at t he 
s p o ns or: 
C li nical Pr oject Ma na ger , U S A: 
 
M e dical E x pert : 
 
B i ostatisticia n: 
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T he c o nte nts of t his d oc u me nt are c o nfi de ntial a n d pr o prietar y t o Merz P har mace uticals. 
U na ut h ori ze d use, discl os ure or re pr o d ucti o n is strictl y pr o hi bite d. T his d oc u me nt or parts t here of ma y 
n ot be discl ose d t o parties n ot ass ociate d wit h t he cli nical i n vesti gati o n wit h o ut t he pri or writte n c o nse nt 
of Merz P har mace uticals.  
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SI G N A T U R E P A G E 
T he st u d y will be c o n d u cte d i n c o m plia nce wit h t he cli nical st u d y pr ot oc ol, I C H-G C P 
pri nci ples,  t he  Decl arati o n  of  H elsi n ki,  a n d  re g ulat or y  a ut h orit y  re q uire me nts.  T he 
f oll o wi n g i n di vi d uals are res p o nsi ble f or t he c o nte nt of t he cli nical st u d y pr ot oc ol: 
Date ( d d-M M M -y y y y) 
Si g nat ure  
Date ( d d-M M M -y y y y) 
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T he f oll o w i n g i n di vi d uals als o si g nifica ntl y c o ntri b ute d t o t he d e vel o p me nt of t he cli nical 
st u d y pr ot oc ol: 
Date ( d d-M M M -y y y y) 
Si g nat ure >  
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St at e m e nt o f C o m pli a n c e 
St u d y site (s) 
I ha v e t h or o u g hl y rea d a n d re vie we d t he cli nical st u d y pr ot oc ol. Ha vi n g u n derst o o d t he 
re q uire me nts a n d c o n diti o ns of t he cli nical st u d y pr ot oc ol, I a gree t o perf or m t he cli nical 
st u d y acc or di n g t o t he cli nical st u d y pr ot oc ol, t he case re p ort f or m, I C H-G C P pri nci ples, 
t he Declarati o n of H elsi n ki, a n d re g ulat or y a ut h orit y re q uire me nts. 
I ha v e recei ve d t he c urr e nt i n vesti gat or’s br oc h ure. Ha vi n g bee n a d e q u atel y i nf or me d 
a b o ut t he I P (i n vesti gati o nal pr o d uct) de v el o p me nt t o date, I als o a gree t o:  
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Si g n t his cli nical st u d y pr ot oc ol bef ore t h e st u d y f or mall y starts.
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Wait u ntil I ha v e r e cei ve d a p pr o val fr o m t he a p pr o priate I E C/I R B bef ore
e nr olli n g a n y s u bject i n t his st u d y.
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O btai n i nf or me d c o nse nt f or all s u bjects pri or t o a n y st u d y- relate d acti o n
perf or me d.
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Start t he st u d y o nl y after all le gal re q uire m e nts i n m y c o u ntr y ha ve bee n f ulfille d.
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Per mit st u d y -relate d m o nit ori n g, a u dits, I E C/I R B re vie w, a n d re g ulat or y
i ns pecti o ns.
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Pr o vi de direct access t o all st u d y-relate d rec or ds, s o urce d oc u m e nts, a n d s u bject
files f or t he m o nit or, a u dit or, I E C/I R B, or re g ul at or y a ut h orit y u p o n re q uest.
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Use t he I P a n d all st u d y materials o nl y as s pecifi e d i n t he cli nical st u d y pr ot oc ol.
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Re p ort t o t he res p o nsi ble pr o d uct safet y officer, wit hi n 2 4 h o urs, a n y a d verse
e ve nt of s pecial i nterest a n d a n y a d vers e e v e nt  t hat is seri o us, w het her c o nsi dere d
treat ment relat e d or n ot.
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Pri or t o i nitiati n g t he st u d y, I will pr o vi de t he s p o ns or wit h a writte n discl os ure of
a n y fi na ncial i nter est i n acc or da n ce wit h 2 1 C F R Part 5 4 a n d a si g ne d F D A 1 5 7 2
f orm acc or di n g t o 2 1 C F R Part 3 1 2.
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C ha n ges t o t he cli nical st u d y pr ot oc ol m ust be ma de i n t he f or m of a n a m e n d me nt
t hat has t he pri or writte n a p pr o val of Merz a n d – as a p plica ble – of t he a p pr o priate
I E C/I R B a n d r e g ulat or y a ut h orit y.
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T he c o nte nt of t he cli nical st u d y pr ot oc ol is c o nfi de ntial a n d pr o priet ar y t o Merz.
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A n y de viati o n fr o m t he cli nical st u d y pr ot oc ol ma y lea d t o earl y ter mi nati o n of t he
st u d y site.
Pri nci pal in vesti gat or  ( pri nt na me) 
Date ( d d-M M M -y y y y) 
Si g nat ure >  
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Li st of a b br e vi ati o n s a n d d efi niti o n s of t er m s 
A E  
A d verse e ve nt  
A E SI  
A d v erse e ve nt of s pecial i nterest  
B P  
Bl o o d press ure 
B o N T  
B ot uli n u m ne ur ot o xi n  
B o N T - A 
B ot uli n u m ne ur ot o xi n t y pe A  
C F R  
C o de of Fe deral Re g ulati o n 
CI  
C o nfi de nce i nter val  
Cli n R O  
Cli nicia n -re p orte d o utc o me 
C R O  
Cli nical researc h or ga nizati o n 
e C R F 
Electr o nic case re p ort f or m  
E D C  
Electr o nic data ca pt ure 
F A S  
F ull a nal ysis set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n, U S 
G C P  
G o o d cli nical practice 
G F L  
Gla bella r fr ow n  li nes 
H F L  
H oriz o ntal f ore hea d li nes  
I C E 
I nterc urre nt e ve nts 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n  
I E C 
I n de pe n de nt et hics c o m mittee 
I N D n u m ber 
I n vesti gati o nal ne w dr u g n u m ber, iss ue d b y t he F D A 
I P 
I n vesti gati o nal pr o d uct 
I R B 
I nstit uti o nal re vie w b oar d 
I S F 
I n vesti gat or’s S ite F ile 
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L ateral ca nt hal li nes  
M A S  
Merz Aest hetics Scale s 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M P  
Mai n peri o d  
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N u m ber of s u bjects 
O L E X  
O pe n -la bel e xte nsi o n 
PI  
Pri nci pal i n vesti gat or  
P P S  
Per pr ot oc ol set  
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Patie nt Re p orte d O utc o me  
P T  
Preferre d ter m  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S E S  
Safet y e val uati o n set  
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S yste m or ga n class 
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Sta n dar d o perati n g pr oce d ure  
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Treat me nt -e mer ge nt a d verse e ve nt 
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Treat me nt -e mer ge nt a d verse e ve nt of s pecial i nterest  
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Treat me nt -e mer ge nt seri o us a d verse e ve nt   
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U nit  
U F L  
U p per facial li nes  
W H O- A T C 
cl assific ati o n  
W orl d Healt h Or ga nizati o n A nat o mical T hera pe utic C he mical classificati o n  
 
 
 
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S Y N O P SI S  ................................................................................................................. 1 2 
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S T U D Y A D MI NI S T R A TI V E S T R U C T U R E  ........................................................ 1 8 
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I nter nal r es p o nsi bilities .......................................................................................... 1 8 
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E xter nal res p o nsi bilities  ......................................................................................... 1 9 
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C o m mittees  ............................................................................................................ 2 1 
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E T HI C S  ..................................................................................................................... 2 2 
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I n d e pe n de nt Et hics Co m mittee (I E C)/I nstit uti o nal Re vie w B oar d (I R B)  ............. 2 2 
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Et hical c o n d uct of t he st u d y ................................................................................... 2 2  
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S u bject i nf or mati o n a n d i nf or me d c o ns e nt ............................................................ 2 3  
 
S u bject i nf or mati o n  .......................................................................................... 2 3 
 
I nf or me d c o ns e nt ............................................................................................. 2 3 
 
S u bject car d  ...................................................................................................... 2 4 
 
P ost-st u d y treat me nt......................................................................................... 2 4  
 
S u bject pri vac y ................................................................................................. 2 4 
 
C o ntact p oi nt .................................................................................................... 2 5  
3. 4  
I ns ura nce ................................................................................................................ 2 5 
3. 5  
Fi na nci n g................................................................................................................ 2 5  
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I N T R O D U C TI O N .................................................................................................... 2 6 
4. 1  
St u d y bac k gr o u n d .................................................................................................. 2 6  
4. 2  
St u d y ra ti o nale ....................................................................................................... 2 8 
4. 3  
Ris k -be nefit assess me nt  ......................................................................................... 2 9 
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S T U D Y O B J E C TI V E S  ............................................................................................ 3 1 
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I N V E S TI G A TI ON A L P L A N  .................................................................................. 3 2 
6. 1  
O verall st u d y desi g n .............................................................................................. 3 2  
 
E n d of st u d y ..................................................................................................... 3 2  
 
St u d y fl o w c hart ............................................................................................... 3 3  
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Disc us si o n of st u d y desi g n, i ncl u di n g c h oice of c o ntr ol gr o u ps ........................... 3 3 
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S T U D Y P O P U L A TI O N  ........................................................................................... 3 5 
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Selecti o n of st u d y p o p ulati o n................................................................................. 3 5  
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I n cl usi o n criteria .................................................................................................... 3 5 
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E xcl us i o n criteria ................................................................................................... 3 6 
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Re m o val of s u bjects fr o m treat me nt or assess me nt  ............................................... 4 1 
 
Disc o nti n uati o n of s u bject’s st u d y partici pati o n.............................................. 4 1  
 
Pre mat ure ter mi nati o n or s us pe nsi o n of t he st u d y or 
cl os ure/s us pe nsi o n of a st u d y site .................................................................... 4 2  
 
Pr o visi o n of care f or s u bj ects after disc o nti n uati o n of t he st u d y ..................... 4 3  
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T R E A T M E N T S  ........................................................................................................ 4 4 
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I n v esti gati o nal pr o d uct(s) ...................................................................................... 4 4 
 
Descri pti o n of i n vesti gati o nal pr o d uct(s)......................................................... 4 4  
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I nstr ucti o ns f or pre p ar ati o n ....................................................................... 4 4 
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I nstr ucti o ns f or a d mi nistr ati o n .................................................................. 4 5 
 
Pac ka gi n g a n d la b eli n g .................................................................................... 4 7  
 
St ora ge of i n vesti gati o nal pr o d uct(s) ............................................................... 4 8  
 
Acc o u nta bilit y f or i n vesti gati o nal pr o d uct(s) .................................................. 4 8  
 
Destr ucti o n of i n vesti gati o nal pr o d uct(s)......................................................... 4 9  
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Treat me nts a d mi nistere d  ........................................................................................ 4 9 
 
Met h o ds of assi g ni n g s u bjects t o treat me nt gr o u ps ......................................... 5 0  
 
Selecti o n of d oses i n t he st u d y ......................................................................... 5 1  
 
Selecti o n a n d ti mi n g of d oses f or eac h s u bject ................................................ 5 1  
 
D urati o n of treat me nt per s u bject .................................................................... 5 2  
 
Treat me nt c o m plia nce  ...................................................................................... 5 2 
 
Treat me nt of o v er d ose ..................................................................................... 5 2  
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Pre vi o us a n d c o nc o mita nt t hera pies....................................................................... 5 4  
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Restricti o ns d uri n g t he st u d y ................................................................................. 5 5  
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S T U D Y A S S E S S M E N T S A N D VI SI T S C H E D U L E  ............................................ 5 7 
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Assess me nts  ........................................................................................................... 5 7 
 
Cli nical assess me nts ......................................................................................... 5 7 
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Effic acy assess me nts  .................................................................................. 5 7 
9. 1. 1. 2  
Ge ner al assess me nts  .................................................................................. 6 1 
 
La b orat or y e val uati o ns ..................................................................................... 6 2 
9. 1. 2. 1  
Cli nic al a n d rese arc h l a b or at ory ev al u ati o ns ........................................... 6 2  
 
P har mac o d y na mics  .......................................................................................... 6 3 
 
P har mac o ki netics  ............................................................................................. 6 3 
 
P har mac o ge n etics  ............................................................................................ 6 3 
 
Ta ble of bl o o d v ol u me ..................................................................................... 6 4  
 
S peci me n pre parati o n, ha n dli n g, st ora ge, a n d s hi p pi n g .................................. 6 4  
9. 2  
Visit sc he d ule  ......................................................................................................... 6 4 
9. 2. 1 M o difie d visit sc he d ule d uri n g a pa n de mic .............................................................. 6 5  
1 0  S A F E T Y A S S E S S M E N T S  ....................................................................................... 7 1 
1 0. 1  
Defi niti o n of a n a d v erse e ve nt ............................................................................... 7 1  
 
Defi niti o n of i nte nsit y  ...................................................................................... 7 2 
 
Defi niti o n of ca usal relati o ns hi p wit h i n vesti gati o nal pr o d uct(s) .................... 7 3  
 
Cate g ories of o utc o me ..................................................................................... 7 3  
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Defi niti o n of a seri o us a d verse e v e nt  ..................................................................... 7 4 
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Sta n dar dizati o n pr oce d ures .................................................................................... 7 9  
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S o urce d oc u me ntati o n re q uire me nts ...................................................................... 7 9  
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Data ma na g e me nt ................................................................................................... 8 0 
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M o nit ori n g ............................................................................................................. 8 1  
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A u diti n g ................................................................................................................. 8 2  
1 2  S T A TI S TI C A L M E T H O D S  .................................................................................... 8 3 
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Deter mi nati o n of sa m ple size  ................................................................................. 8 3 
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A nal ysis sets ........................................................................................................... 8 5 
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E n d p oi nts a n d mai n esti ma n ds f or a nal ysis ........................................................... 8 5  
 
Efficac y e n d p oi nts a n d mai n efficac y esti ma n ds ............................................. 8 5  
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Pri m ary effic acy e n d p oi nts a n d m ai n pri m ary effic acy esti m a n ds ............ 8 5  
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Sec o n d ary effic a cy e n d p oi nts a n d m ai n sec o n d ary effic acy 
esti m a n ds.................................................................................................... 8 9  
 
P har mac o d y na mic e n d p oi nts  ........................................................................... 9 2 
 
P har mac o ki netic e n d p oi nts .............................................................................. 9 2  
 
P har mac o ge n etic e n d p oi nts ............................................................................. 9 2  
 
Safet y e n d p oi nts ............................................................................................... 9 2  
1 2. 3. 5. 1  
Pri m ary s afety e n d p oi nt ............................................................................. 9 2  
1 2. 3. 5. 2  
Sec o n d ary s afety e n d p oi nts ........................................................................ 9 3  
1 2. 4  
Statistical a nal ysis met h o ds  ................................................................................... 9 3 
 
Efficac y e n d p oi nts a n d efficac y esti ma n ds ...................................................... 9 3  
1 2. 4. 1. 1  
Pri m ary effic acy e n d p oi nts a n d pri m ary effic acy esti m a n ds ..................... 9 4  
1 2. 4. 1. 2  
Sec o n d ary effic a cy e n d p oi nts a n d sec o n d ary effic acy esti m a n ds .............. 9 6  
 
P har mac o d y na mic e n d p o i nts ........................................................................... 9 7 
 
P har mac o ki netic e n d p oi nts .............................................................................. 9 8  
 
P har mac o ge n etic e n d p oi nts ............................................................................. 9 8  
 
Safet y e n d p oi nts ............................................................................................... 9 8  
1 2. 4. 5. 1  
Pri m ary s afety e n d p oi nt ............................................................................. 9 8  
1 2. 4. 5. 2  
Sec o n d ary s afety e n d p oi nts ........................................................................ 9 8  
 
S pecial statistical/a nal ytical iss ues  .................................................................. 9 9 
C CI
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C CI
C CI
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 0  of 1 2 4  
1 2. 4. 7. 1  
Disc o nti n u ati o ns a n d missi n g d at a ............................................................ 9 9  
1 2. 4. 7. 2  
I nteri m a n alyses ......................................................................................... 9 9 
1 2. 4. 7. 3  
C o m mittees  ................................................................................................. 9 9 
1 2. 4. 7. 4  
M ulti ple c o m p aris o ns/ m ulti plicity  ........................................................... 1 0 0 
1 2. 4. 7. 5  
Ex a mi n ati o n of s u b gr o u ps ....................................................................... 1 0 0  
1 3  D A T A H A N D LI N G A N D R E C O R D K E E PI N G .................................................. 1 0 1 
1 3. 1  
C orrecti o ns t o data ............................................................................................... 1 0 1  
1 3. 2  
Rec or d kee pi n g ..................................................................................................... 1 0 1  
1 3. 3  
Destr ucti o n of st u d y d oc u me nts........................................................................... 1 0 2  
1 4  P U B LI C A TI O N P O LI C Y  ...................................................................................... 1 0 3 
1 5  R E F E R E N C E S  ....................................................................................................... 1 0 4 
1 6  A P P E N DI C E S  ......................................................................................................... 1 0 8 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 1  of 1 2 4  
Li st of Fi g ur e s  
Li st of T a bl e s  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 2  of 1 2 4  
 
1  S Y N O P SI S 
St u d y title  
A pr os pecti ve, ra n d o mi z e d, d o u ble-bli n d, place b o -c o ntr olle d, m ultice nter st u d y wit h a n 
o pe n- la bel  e xte nsi o n  peri o d  t o  i n vesti gate  t he  efficac y  a n d  safet y  of  N T 2 0 1  i n  t he  
si m ulta ne o us treat me nt of u p per faci al li nes ( h oriz o ntal f ore hea d li nes, gla bellar fr o w n 
li nes, a n d lateral ca nt hal li nes) 
St u d y p h ase  
3  
I n dic ati o n 
U p per f acial li nes  
St u d y o bjecti ves  
Pri mar y o bjecti ve(s)  
Efficac y of si m ulta ne o us i ntra m usc ular i njecti o ns of N T  2 0 1 i n s u bjects wit h m o derate t o 
se vere u p p er f acial li nes [ U F L] i n c o m paris o n t o place b o 
Sec o n dar y o bjecti ve(s) 
Efficac y a n d s afet y of si m ulta ne o us si n gle a n d re peat -d ose i ntra m usc ul ar i njecti o ns of 
N T  2 0 1 i n s u bjects wit h m o derate t o se v ere U F L 
St u d y p o p ul ati o n, di a g n osis, a n d m ai n criteri a f or i n- a n d e x cl usi o n 
A t otal of 3 6 0 male a n d f e male a d ults will be recr uite d.  
Key i ncl usi o n criteri a  
•  
O ut patie nts ( male or f e m ale) 1 8 years of a ge or  ol der. 
•  
H oriz o ntal f ore h ea d li nes [ H F L ], gla bellar  fr o w n li nes [G F L ], a n d s y m metrical 
lateral ca nt hal li nes [L C L ] of m o derate ( sc ore 2) t o se vere ( sc ore 3) i nte nsit y at 
ma xi m u m c o ntracti o n as assesse d b y t he i n vesti gat or a n d s u bject acc or di n g t o  Merz 
Aest hetics Scal e s [ M A S]. T he rati n gs of t he i n v esti gat or a n d t he s u bject d o n ot 
ha ve t o c oi nci de as l o n g as all rati n gs at ma xi m u m c o ntracti o n  are m o d erate or 
se vere. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 3  of 1 2 4  
Key e xcl usi o n criteri a  
•  
Pre vi o us treat me nt wit h b ot uli n u m ne ur ot o xi n [ B o N T ] of a n y s er ot y pe i n t he face 
wit hi n t he last 1 2  m o nt hs bef ore i njecti o n. 
•  
A n y facial c os metic pr oce d ure wit hi n t he last 1 2 m o nt hs bef ore baseli ne i njecti o n, 
s uc h  as  der mal  filli n g,  c he mical  peeli n g,  p h ot o  rej u ve nati o n,  mes ot hera p y,  
p h ot o d y na mic  t hera p y,  laser  treat me nt,  ultras o u n d  treat me nt,  tatt o oi n g  of  
e ye br o ws. 
•  
Pre vi o us treat me nt wit h a n y bi o de gra da ble filler i n t he face wit hi n t he last 1 2 
m o nt hs bef ore i njecti o n. 
•  
A n y pre vi o us i nserti o n of per m a ne nt material i n t he face (re g ar dless of t he ti me 
bet wee n pr e vi o us treat m e nt a n d t his st u d y). 
•  
A n y me dical c o n diti o n t hat ma y p ut t he s u bject at i ncrease d ris k wit h e x p os ure t o 
N T 2 0 1,  i ncl u di n g  m yast he nia  gra vis,  La m bert -Eat o n -S y n dr o me,  a m y otr o p hic  
lateral scler osis, or a n y ot her dis or der t hat mi g ht i nterfere wit h ne ur o m usc ular 
f u ncti o n. 
•  
N ursi n g m ot her or pr e g n a nt w o ma n, as verifie d b y a p ositi ve pre g na n c y test. 
St u d y desi g n  
T his  will  be  a  pr os pecti ve,  ra n d o mi z e d,  d o u ble -bli n d,  place b o -c o ntr olle d,  m ultice nter  
st u d y wit h a place b o-c o ntr ol mai n peri o d [M P ] wit h o ne N T 2 0 1 i njecti o n c ycle f oll o we d 
b y a n o pe n-la b el e xte nsi o n peri o d [ O L E X] wit h t w o N T  2 0 1 i njecti o n c ycl es. 
I n t he M P ( C ycle 1) , a t otal of 3 6 0 s u bjects will be ra n d o mize d t o t hree differe nt treat me nt 
gr o u ps: U F L  treat me nt ( Gr o u p U) , G F L a n d H F L  treat me nt ( Gr o u p G& H) , a n d place b o 
( Gr o u p P)  i n a ra n d o mizati o n rati o of 2: 1: 1. D uri n g  t he M P, s u bjects will b e treate d eit her 
wit h a t otal d ose of 6 4  U N T  2 0 1 as si m ulta ne o us i njecti o ns i n all  t hree faci al  areas  
( Gr o u p U), wit h a t otal d ose of 4 0 U N T  2 0 1 i n t he G F L a n d H FL area a n d place b o i n t he 
L C L area  ( Gr o u p G & H) , or wit h place b o i n all t hree faci al areas (Gr o u p P ). All ra n d o mize d 
s u bjects will t he n be f oll o we d u p f or 1 2 0 da ys bef ore t he y ma y e nter t he O L E X peri o d . 
T he d urati o n of t he M P ( C ycle  1) will t h us be 1 2 0  da ys pl us t he d urati o n of i n di vi d ual 
scree ni n g ( u p t o 1 4 d a ys). 
T he O L E X  peri o d will c o m prise t w o a d diti o nal treat me nt c ycles, C ycle  2 a n d C ycle  3 wit h 
d urati o ns of 1 2 0  da ys eac h  pl us u p t o 3 0 da ys f or eli gi bilit y reassess me nts per c ycl e. 
D uri n g eac h c ycle , eli gi ble s u bjects will recei ve si m ulta ne o us i njecti o ns of N T 2 0 1 at a 
t otal d ose of 6 4 U i n all t hree facial areas. Eli gi bilit y criteria will be e v al uate d b ef ore 
rei njecti o n. 
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 4  of 1 2 4  
Pl a n ne d st u d y peri o d  
First s u bject first visit:    
Q 3- 2 0 2 0 
Last pri mar y o utc o me v isit:   Q 2- 2 0 2 1 
Last s u bject last visit:    
Q 2- 2 0 2 2 
D ur ati o n of tre at m e nt per s u bject  
S u bjects will recei ve st u d y me dicati o n at u p t o t hree i njecti o n visits. 
E n d p oi nts f or a n al ysis  
Effic acy e n d p oi nts 
P ri m ary effic acy e n d p oi nts 
•  
Pr o p orti o n of G F L- res p o n ders at Day 3 0 
G F L -res p o nse is defi ne d as a sc ore of 0 ( n o) or 1 ( mil d) a n d at least t w o-gra de i m pr o ve me nt 
fr o m baseli ne t o Da y 3 0 of M P o n M A S f or G F L at ma xi m u m c o ntracti o n as assesse d b y 
b ot h t he i n vesti gat or a n d t he s u bject. 
•  
Pr o p orti o n of H F L- res p o n ders at Da y 3 0 
H F L -res p o nse is defi ne d as a sc ore of 0 ( n o) or 1 ( mil d) a n d at least t w o-gra de i m pr o ve me nt 
fr o m baseli ne t o Da y 3 0 of M P o n M A S f or H F L at ma xi m u m c o ntracti o n as assesse d b y 
b ot h t he i n vesti gat or a n d t he s u bject. 
•  
Pr o p orti o n of L C L -res p o n ders at Da y 3 0 
L C L -res p o nse is defi ne d as a sc ore of 0 ( n o) or 1 ( mil d) a n d at least t w o-gra de i m pr o ve me nt 
fr o m  baseli ne  t o  D a y 3 0  of  M P  o n  M A S  f or  b ot h  left  a n d  ri g ht  L C L  at  ma xi m u m  
c o ntracti o n as assesse d b y b ot h t he i n vesti gat or a n d t he s u bjec t. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 5  of 1 2 4  
Sec o n d ary effic a cy e n d p oi nts 
Ke y sec o n d ar y efficac y e n d p oi nts: 
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or G F L at 
ma xi m u m c o ntracti o n as assesse d b y t he i n vesti gat or at Da y  3 0 of M P.  
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or H F L at 
ma xi m u m c o ntracti o n as assesse d b y t he i n vesti gat or at Da y  3 0 of M P.  
•  
Pr o p orti o n o f s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or b ot h left a n d 
ri g ht L C L at ma xi m u m c o ntracti o n as ass esse d b y t he i n vesti gat or at D a y  3 0 of M P.  
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or G F L at 
ma xi m u m c o ntracti o n as asse sse d b y t he s u bject at Da y 3 0 of M P.  
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or H F L at 
ma xi m u m c o ntracti o n as assesse d b y t he s u bject at Da y  3 0 of M P.  
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or b ot h left a n d 
ri g ht L C L at ma xi m u m c o ntracti o n as assess e d b y t he s u bject at Da y 3 0 of M P. 
•  
Gl o bal Aest hetic I m pr o v e me nt Scale [ G AI S ] as assesse d b y t he s u bject at Da y  3 0 
of M P.  
F urt her s ec o n d ar y efficac y e n d p oi nts: 
•  
Pr o p orti o n of s u bjects wit h at least o ne -gra de i m pr o ve me nt fr o m baseli ne t o Da y 3 0 
of M P o n M A S f or G F L at ma xi m u m c o ntracti o n as assesse d b y t he i n v esti gat or 
•  
Pr o p orti o n of s u bjects wit h at least o ne -gra de i m pr o ve me nt fr o m baseli ne t o Da y  3 0 
of M P o n M A S f or H F L at ma xi m u m c o ntracti o n as assesse d b y t h e i n v esti gat or 
•  
Pr o p orti o n of s u bjects wit h at least o ne -gra de i m pr o ve me nt fr o m baseli ne t o Da y  3 0 
of M P o n M A S f or b ot h left a n d ri g ht L C L at ma xi m u m c o ntracti o n as assesse d b y 
t he i n vesti gat or 
•  
G AI S as assess e d b y t he i n vesti gat or at Da y  3 0 of M P 
S afety e n d p oi nts 
Pri m ary s afety e n d p oi nt 
N o pri mar y saf et y e n d p oi nt was defi ne d. 
Sec o n d ary s afety e n d p oi n ts 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 6  of 1 2 4  
•  
I n ci de nce of r elate d treat me nt-e mer g e nt a d vers e e ve nts ( T E A Es) i n t he M P  
•  
I n ci de nce of r elate d T E A Es i n t he O L E X peri o d  
T ot al n u m ber of s u bjects a n d n u m ber of c o u ntries  
A t otal of 3 6 0  s u bjects will be recr uite d fr o m 1  c o u ntr y, t he U nite d States of A merica 
( U S A). 
N u m ber of st u d y sites  
It is pla n ne d t o c o n d uct t he st u d y i n a p pr o xi matel y 1 0 sites (st u d y ce nters) i n t he U SA.  
N u m ber of visits  
A t otal of 7 st u d y visits are pl a n ne d d uri n g t he M P ( C ycle  1), pl us 5 st u d y visits d uri n g 
C ycle  2 of t he O L E X peri o d ( pl us o pti o nal reassess me nt visit s), a n d 5 st u d y visits d uri n g 
C ycle  3 of t he O L E X p eri o d ( pl us o pti o nal reassess me nt visits).  
I n vesti g ati o n al pr o d uct(s), d ose, a n d r o ute of a d mi nistr ati o n 
N T  2 0 1  (acti ve  i n gr e die nt:  N T  1 0 1, B o N T  t y pe  A  [ B o N T -A],  free  fr o m  c o m ple xi n g  
pr otei ns, U S A d o pte d Na me i nc o b ot uli n u mt o xi n A) or matc hi n g place b o pr o vi de d i n 1 0 0  U 
vials.  
St atistic al a n al ysis m et h o ds 
A de q uate d escri pti ve statistics will be pr o vi de d f or eac h effi cac y e n d p oi nt a n d ti me p oi nt. 
Pri mar y a n d se nsiti vit y a nal yses f or pri mar y efficac y e n d p oi nts will be bas e d o n t he tar get 
p o p ulati o n of mai n pri mar y esti ma n ds  w hic h is defi ne d as “ M ale a n d fe male a d ults ( 1 8 
years of a ge or ol der) wit h H F L, G F L, a n d L C L of m o derat e (sc ore of 2) t o se vere (sc ore 
of 3) i nte nsit y at ma xi m u m c o ntracti o n as assess e d b y t he i n vesti gat or a n d t he s u bject 
acc or di n g t o M A S, as ra n d o mize d i n t his st u d y: S u bset of s u bjects ra n d o mize d t o U F L 
treat me nt  gr o u p  or  t o  Place b o  treat me nt  gr o u p,  gr o u pe d  b y  ra n d o mi ze d  treat me nt  
assi g n me nt.” F urt her efficac y  a nal yses  will  be  base d  o n  t he  f ull  a nal ysis  set  ( F A S)  
i ncl u di n g all ra n d o mize d s u bject s, if n ot ot her wise s pecifie d. 
T he pri mar y a nal ysis of pri mar y e n d p oi nts will be c o m paris o n of pr o p orti o n of G F L -, 
H F L - a n d L C L-res p o n ders i n treat me nt gr o u ps U a n d P b y Ma ntel -Hae nszel tests of t he 
n ull h y p ot hesis t hat t he strat u m -a dj uste d differe n ce i n res p o nse rates at Da y 3 0 is zer o, 
wit h st u d y site ser vi n g as strat u m varia ble . 
T he fa mil y -wise t w o -si d e d t y pe I err or le v el α = 0. 0 5 will be c o ntr olle d b y a hierarc hi cal 
test pr oce d ur e bas e d o n t w o-si de d  tests  wit h  α  =  0. 0 5. First, a test f or s u peri orit y of  U 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 7  of 1 2 4  
vers us P will be c o n d ucte d f or pr o p orti o n of G F L -res p o n ders, t he n f or pr o p orti o n of H F L-
res p o n ders a n d fi nall y f or pr o p orti o n of L C L-res p o n ders. T he t est pr oce d ure will st o p o nce 
statistical si g nifica nce c o ul d n ot be reac h e d. 
Gr o u p G & H will n ot be part of t he pr i mar y efficac y a nal ysis. 
All safet y a nal yses will be perf or me d o n t he S E S.  
Listi n gs a n d ta bles dis pla yi n g i nci de nces of relate d T E A Es  i n M P a n d O L E X will be 
pr o vi de d b y Me dical Dicti o nar y f or Re g ulat or y A cti vities  (Me d D R A ) s yste m or ga n class 
a n d pref err e d ter m b y ra n d o mi ze d st u d y gr o u p a n d o verall, f or t he t otal st u d y peri o d a n d 
b y treat me nt c ycle. F or t h e a nal yses b y treat me nt c ycle , t he de n o mi nat or f or t he i nci de nces 
will be a dj uste d t o all s u bjects bei n g treate d i n t hat treat me nt c y cle.  
C CI








Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 2 1  of 1 2 4  
2. 3  
C o m mitt e e s  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 2 2  of 1 2 4  
3 
E T HI C S  
3. 1  
I n d e p e n d e nt Et hi c s C o m mitt e e (I E C)/I n stit uti o n al R e vi e w B o ar d (I R B) 
T he f oll o wi n g d o c u me nts m ust be s u b mitte d t o t he res p o nsi ble I E C/I R B a n d a p pr o val 
o btai ne d: 
•
T he cli nical st u d y pr ot oc ol.
•
A n y a me n d me nt t o t he cli nical st u d y pr ot oc ol t hat is n ot s olel y of a n a d mi nistrati ve
nat ure.
•
T he i n vesti gat or’s br o c h ure a n d all u p dat es.
•
S u bject i nf or mati o n a n d i nf or me d c o nse nt f or ms, as well as u p d ates (if a p pli ca ble).
•
All s u bject recr uit me nt pr oce d ures a n d a n y a d vertise me nt use d t o recr uit s u bjects
(if a p plica ble).
•
Ot her  d oc u me nts will be pr o vi de d if re q u este d b y t he I E C.
If a p plica ble, a n d i n acc or da nce wit h l ocal le gal re q uire me nts, t he a b o v e d oc u me nts als o 
ma y be s u b mitte d t o t he res pecti ve re g ulat or y a ut h orit y(ies) f or s e parate a p pr o val. 
3. 2  
Et hi c al c o n d u ct of t h e st u d y  
T hi s st u d y will be c o n d ucte d i n acc or da nce wit h t h e et hical pri n ci ples t hat h a ve t heir ori gi n 
i n t he Declar ati o n of Helsi nki, a n d are c o nsiste nt wit h I C H -G C P a n d a p plica ble re g ulat or y 
re q uire me nts. Re g ulat or y a ut h orities will be n otifie d a n d c o ns ulte d as re q uire d pri or t o, 
d uri n g, a n d after t he c o n d uct of t he st u d y. 
All re q uire d a p pr o v als, f a v o ra ble o pi ni o ns, or a d diti o nal re q uire me nts of t he a p pr o pri ate 
I R B, E C, or ot her re g ulat or y a ut h orit y will be o btai ne d pri or t o i nitiati o n of t he trial. 
I n cas e of a pa n de mic disease o ut brea k, e. g. ne w C O VI D -1 9 p u blic healt h e mer ge nc y, 
pr oce d ur es t hat pri oritize t he re p orti n g of pr ot oc ol de viati o ns t hat c o ul d i m pact s u bject 
safet y t o t h e I E C/I R B will be defi ne d. I n a d diti o n, c ha n g es i n pr ot o c ol c o n d uct necessar y 
t o pr o m ptl y ass ure s u bject safet y, s uc h as c o n d ucti n g tele p h o ne or vi de o c o ntact visits f or 
safet y  m o nit ori n g  rat her  t ha n  o n-site  visits,  ca n  be  i m ple me nte d  i m me diatel y  wit h  
s u bse q ue nt re vie w b y t h e I E C/I R B a n d n otificati o n t o re g ulat or y a ut h orities (e. g. F D A, 
Bf Ar M).  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 2 3  of 1 2 4  
3. 3  
S u bj e ct i nf or m ati o n a n d i nf or m e d c o n s e nt  
S u bj e ct i nf or m ati o n  
Pri or t o st u d y e nr oll me nt, t he s u bject will be gi ve n f ull ver bal a n d writte n i nf or mati o n o n 
t he  nat ure,  o bjecti ve,  si g nifica nce,  e x pecte d  b e nefits,  p ote ntial  ris ks,  a n d  e x p ecte d  
c o nse q ue nces of t he st u d y. T his ver b al a n d writte n i nf or mati o n will b e pr o vi de d b y t h e 
i n vesti gat or  ( or  a ut h orize d  desi g nee)  acc or di n g  t o  t he  pr o visi o ns  set  f ort h  i n  t he  
Declar ati o n of Helsi n ki. T he o bli gati o ns of t he i n v esti gat or are set f ort h i n t he c li nical st u d y 
pr ot oc ol, t he I C H -G C P pri nci ples (effecti ve as of 1 7 -J A N- 1 9 9 7 i ncl u di n g I C H re visi o n 
R 2,  2 0 1 7),  a n d  t he  res pecti ve  nati o nal  re g ulati o ns  g o ver ni n g  me dical  researc h  a n d  
e x peri me ntati o n o n h u ma ns. 
Eac h s u bject will ha ve t h e o p p ort u nit y t o q uesti o n t he i n vesti gat or ( or a ut h ori ze d desi g nee) 
a b o ut t he st u d y pri or t o gi vi n g c o nse nt or w he ne v er nee d e d . 
I nf or m e d c o n s e nt 
I nf or me d c o ns e nt will be o btai ne d in writi n g directl y fr o m t he s u bject.  
T he c o ns e nt m ust be c o nfir me d b y t h e i n vesti gat or ( or a ut h ori ze d d esig nee i n acc or d a nce 
wit h l ocal re q uir e me nts)  w h o c o n d u cte d t he i nf or me d c o nse nt briefi n gs. T he i nf or m e d 
c o nse nt pr ocess m ust be tracea ble fr o m t he a v aila ble d oc u me ntati o n. At a mi ni m u m, t his 
d oc u me ntati o n s h o ul d i ncl u de i nf or mati o n a b o ut w he n t he s u bject w as first i nf or me d a b o ut 
t he st u d y a n d w h o s u p pli e d t he i nf or mati o n. T h e s u bject will be gi ve n a c o p y of t he si g ne d 
a n d date d writte n i nf or me d c o nse nt f or m as well as all c o nse nt f or m u p d ates (if a p plica ble).  
D uri n g  t he  c o urse  of  t h e  st u d y,  t he  s u bj ect  will  be  i nf or m e d  i n  a  ti mel y  ma n ner  if  
i nf or mati o n bec o m es a v aila ble t hat ma y be rele v a nt t o t he s u bject’s willi n g ness t o c o nti n ue 
partici pati o n i n t he st u d y. I n case of a d verse e v e nts ( A Es ), or p o or t olera bilit y t o t he 
i n vesti gati o nal pr o d uct (I P), t he s u bject s h o ul d i nf or m t he i n vesti gat or, w h o t he n will ma k e 
a j u d gme nt  w het her c o nti n ui n g i n t he st u d y ser ves t he s u bject’s best i nterests. T he s u bject, 
h o we ver, is free t o wit h dra w c o ns e nt at a n y ti me a n d f or a n y reas o n, w het h er e x presse d or 
n ot. F or c o u ntr y- s pecific re q uire me nts, see Secti o n  1 6. 1 . 
I n case of a pa n de mic disease o ut brea k, e. g. ne w C O VI D-1 9 p u blic healt h e mer ge nc y, if 
re-c o ns e nti n g of t he s u bj ects is dee me d necessar y d ue t o si g nifica nt c h a n g es ma de t o t he 
pr ot oc ol a n d/ or m o nit ori n g pla n t hat c o ul d i m pact t he m: 
•
Alter nati ve wa ys of o btai ni n g c o nse nt will be defi ne d as s u bjects s h o ul d n ot visit
sites f or t he s ole p ur p os e of o btai ni n g re-c o nse nt. S u bjects will be c o ntacte d via
p h o ne or vi de o calls a n d pr o vi de ver b al c o nse nt s u p ple me nte d wit h writte n (e. g. e -
mail) c o nfir mati o n.
•
A p pr o ve d u p date d s u bject i nf or mati o n s heet a n d c o nse nt f or m will be pr o vi de d b y
e-mail, mail or c o u rier t o o btai n a re-c o nse nt.
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 2 4  of 1 2 4  
•
All i nsta nces of c o nse nt t hat are o btai n e d t his wa y will be d oc u me nte d.
T he s u bjects ’ u n d ersta n di n g will be re-c o nfir me d b y wa y of n or mal c o nse nt pr oce d ures at 
t he earliest o p p ort u nit y w he n/if t he s u bjects are a ble t o ret ur n t o t he sites, if a p plica ble. 
S u bj e ct c ar d  
A s u bject car d will be gi ve n t o all s u bjects, w h o will be i nstr ucte d t o kee p it i n t heir 
p ossessi o n at all ti mes. T he s u bject car d will c o ntai n t he f oll o wi n g pri nte d i nf or mati o n: 
Eac h s u bject ’s n u m b er a n d ra n d o mizati o n n u m ber a n d i nf or mati o n t hat t he s u bject is 
ta ki n g part i n a st u d y wit h b ot uli n u m t o xi n A i n t he i n dicati o n U F L  wit h a t otal d ose of u p 
t o 6 4 U. 
I n C ycl e 1 of t he st u d y, s u bjects will recei v e o ne of t he f oll o wi n g 3 treat me nts: 
•
2 0 U i n t he c orr u gat or a n d pr ocer us m uscle, 2 0 U i n t he fr o ntalis m uscle a n d 1 2 U
per si de i n t he later al or bic ularis oc uli m uscle.
•
2 0 U i n t he c orr u gat or a n d pr ocer us, 2 0 U i n t h e fr o ntalis a n d place b o i n t he lateral
or bic ularis oc uli
•
Place b o i n all t hree areas.
I n C ycl e 2 a n d 3, t he s u bjects recei ve a t otal of 6 4 U b ot uli n u m t o xi n A. 
I n case of A Es, treat me nt s h o ul d be s y m pt o matic, si nce n o s pecific treat me nt is a vaila ble. 
T he na me, a d dress, a n d tele p h o ne n u m ber of t he i n vesti gat or or i nstit uti o n, as t he mai n 
c o ntact f or pr o d uct i nf or mati o n a n d e mer ge n c y u n bli n di n g. 
P o st -st u d y tr e at m e nt  
N o s pecifi c p ost -st u d y arra n ge m e nts are ma d e a n d n o s pecific p ost-st u d y care will b e 
pr o vi de d after t his st u d y. After st u d y disc o nti n uati o n, s u bjects will be treate d b y t heir 
p h ysicia n acc or di n g t o t heir me dical c o n diti o n a n d sta n dar d treat me nts i n t he U S.  
S u bj e ct pri v a c y  
T he s u bject will be i nf or me d of pr oce d ures t o pr otect s u bject pri vac y. Alt h o u g h rec or de d 
data will be passe d o n i n a c o de d versi o n ( pse u d o n y miz e d) o nl y t o a ut h orize d i n di vi d uals, 
re-i de ntificati o n b y t he i n vesti gat or (e. g., i n cas e of e mer g e ncies) will be p ossi ble b y t he 
specific  n u m ber assi g ne d t o t he s u bject ( Secti o n  8. 2. 1 ).  
Access t o n o n -c o d e d data will be all o we d s olel y t o c hec k vali dit y, a n d s uc h access will be 
li mite d strictl y t o a ut h orize d i n di vi d uals (e. g., t he s p o ns or or i n di vi d uals a ut h ori ze d b y t he 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 2 5  of 1 2 4  
s p o ns or  (e. g.  ( me dical)  m o nit ors), a u dit ors,  re g ulat or y  a ut h orities,  or  me m bers  of  
I E Cs/I R Bs)  w h o  ha ve  bee n  b o u n d  t o  c o nfi de ntialit y.  If  t h e  res ults  of  t he  st u d y  are  
p u blis he d, t he s u bject’s i de ntit y will re mai n c o nfi de ntial.  
C o nt a ct p oi nt  
All s u bjects will be pr o vi de d i n t he s u bject i nf or m e d c o ns e nt f or m wit h a c o ntact a d dress 
w here t he y m a y o btai n f urt her ge n eral i nf or m ati o n re gar di n g cli nical st u dies. 
3. 4  
I n s ur a n c e 
Fr o m t he be gi n ni n g of t h e st u d y u ntil its ter mi nati o n, eac h s u bject is i ns ure d a gai nst a n y 
healt h i m pair me nt occ urri n g as a res ult of partici pati o n i n t he st u d y i n acc or da nce wit h t he 
la ws a n d re g ul ati o ns of t he c o u ntr y i n w hic h t he st u d y is perf or me d. 
T he s u bject will be i nf or me d b y t he i n vesti gat or a n d t hr o u g h t he s u bject’s i nf or me d c o nse nt 
f or m a b o ut t he e xiste nce of t his i ns ura nce a n d t he res ulti n g o bli gati o ns. T he i ns ura nce 
c o n diti o ns will be ha n de d o ut t o t he s u bject, if re q ueste d or if re q u ire d b y l ocal la w. 
A n y me dical or n o n -m e dical de viati o n fr o m t he cli nical st u d y pr ot oc ol t hat is dee me d t o 
ha ve occ urr e d t hr o u g h t he s u bject’s o w n fa ult ma y n ot be c o vere d b y t his i ns ura nce. 
T he  s p o ns or  is  us uall y  n ot  lia ble  f or  i nj uries/ cases  of  d eat h  t hat  occ ur  s olel y  as  a  
c o nse q ue nce of  t he  s u bject’s  u n derl yi n g  diseas e  or  c o n diti o n,  or  fr o m  dia g n ostic  or  
t hera pe utic meas ures n ot s pecificall y re q uire d b y t he cli nical st u d y pr ot oc ol. T he s p o ns or 
is als o us uall y n ot lia ble f or e ve nts res ulti n g fr o m ne gli ge nce of t he i n vesti gat or, cli nical 
st u d y staff, a n d/ or cli nical researc h or ga nizati o n ( C R O ), i ncl u di n g fail ure t o act acc or di n g 
t o I C H-G C P pri nci ples or t o c o m pl y strictl y wit h t he cli nical st u d y pr ot o c ol.  F or c o u ntr y -
specific r e q uire me nts, see Secti o n 1 6. 1 . 
3. 5  
Fi n a n ci n g  
T he fi na ncial as pects of t he st u d y will be d oc u me nte d i n a n a gree me nt bet w ee n t he s p o ns or, 
t he C R O, a n d eac h i n vesti gat or or a n y ot her i n v ol ve d part y, a n d m ust be c o nfir me d i n 
writi n g bef ore t he st u d y c o m me nces. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 2 7  of 1 2 4  
Me dic al b ac k gr o u n d 
A y o ut hf ul a n d aest heticall y pleasa nt a p peara nce is i ncreasi n gl y i n-f oc us all o ver t he w orl d. 
Effecti ve  ma n a ge me nt  of  facial  li nes  re q uires  a p pr oa c h es t hat  i ncl u de  aest hetic  a n d  
der mat ol o gical tr eat me nts , s uch as peels, l aser res urfaci n g, a n d fillers, as well as s ur gi cal 
treat me nts, s uc h as r h yti dect o m y, e y e br o w lift, a n d ble p har o plast y [Cat h er  2 0 0 2]. Si nce 
s ur gical tec h ni q ues i n v ol ve ris ks a n d rec o ver y ti me, a n d rej u ve nati o n a n d filler tec h ni q ues 
ma y n ot ac hie ve f ull y satisfact or y res ults, mi ni mall y i n vasi ve l ocal i njecti o n treat me nt wit h 
B o N T A - has ra pi dl y bec o me  t he sta n dar d treat me nt w he n t he first re prese ntati ve of t his 
dr u g class was a p pr o ve d f or treat me nt of G F L. 
B o N T -A treat me nt of f acial wri n kles is a safe, effecti ve, pre dicta ble, mi ni mall y i n vasi ve 
aest hetic pr oce d ure a n d was t he lea di n g n o n -s ur gical c os metic pr oce d ure i n 2 0 18 i n t h e 
U S, wit h 7. 4 milli o n a d mi nistrati o ns  [A merica n S ociet y of Plastic S ur ge o ns 2 0 1 8 . Plastic 
S ur ger y Statistics Re p ort 2 0 1 8 ]. 
Treat me nt of G F L pri maril y  tar gets c orr u gat or a n d pr ocer us m uscles [Ca rr ut hers 1 9 9 6]. 
T he us ual n u m ber of i njecti o n sites ra n ges fr o m fi ve t o se ve n, wit h me n t y picall y re q uiri n g 
m ore sites a n d a hi g her d ose. T he a p pr o v e d sta n d ar d d ose of N T  2 0 1 i n t his i n dicati o n is 
2 0 u nits [ U] [X e o mi n U S Prescri bi n g I nf or m ati o n ] b ut t he d ose m a y be i ncreas e d b y t he 
p h ysicia n t o u p t o 3 0 U base d o n i n di vi d ual patie nt nee ds . 
H F L  res ult fr o m c o ntracti o n of t he fr o ntalis m uscle, a n d te n d t o be dee per i n s u bjects w h o 
ha ve  l o w  br o ws  or  bl e p har o pt osis  a n d  w h o  u nc o nsci o usl y  ele vat e t heir  br o ws  t o  
c o m pe nsate. B o N T A - is effecti ve i n s m o ot hi n g o ut t hese li nes b ut d oes s o at t he e x pe ns e 
of br o w h ei g ht. It is r ec o m me n de d t hat s u bjects wit h e xcessi ve br o w pt osis s h o ul d n ot get 
i njecte d i n  t he fr o ntalis m uscle t o a v oi d e xcessi ve desce nt of t he br o ws. If t h e s u bject 
wis hes t o ha ve t he G F L a n d H F L  areas i njecte d, a hi g her d ose ca n be us e d t ha n d uri n g a 
si n gle treat me nt b eca us e t he a nta g o nistic br o w de press ors are wea k e ne d b y G F L i njecti o ns 
a n d t here is less c h a nce of  br o w pt osis de vel o pi n g [Ca rr ut hers 2 0 0 4, K ee n 1 9 9 4]. 
Ra dial li nes at t he later al as pect of t h e or bit, s o -calle d L C L  als o k n o w n as  cr o w’s feet  or  
lateral peri or bital wri n kles/r h yti ds, are pri maril y ca use d b y c o ntracti o n of t he or bic ularis 
oc uli m uscle. H o w e ver, t he z y g o matic m uscles ca n pla y a si g nifica nt r ole i n s u bjects wit h 
cr o w’s f eet. O r bic ularis fi bers are s u perficial a n d ca n be rea dil y i de ntifie d b y ha vi n g t he 
s u bject s mile or s q ui nt. T hree t o fi ve areas wit hi n t he ra dial li nes are us uall y i njecte d  
[H ui 2 0 0 7 , Le v y 2 0 0 4 , L o we  2 0 0 5]. 
T here is a greater c h a nce of br uisi n g i n t his area beca use of t he a b u n da nce of s u perficial 
vessels.  U p per  li p  pt osis  ca n  occ ur  fr o m  paral ysis  of  t he  z y g o mati cus  maj or  m uscle  
a djace nt t o t he or bic ularis oc uli m uscle. T his ca n be pre ve nte d b y a v oi di n g i njecti o n s 
me dial  t o  a  li ne  dri p pe d  fr o m  t he  lateral   ca nt h us  [Carr ut hers  2 0 0 4, Ki m  2 0 0 3, 
Matarass o  2 0 0 1]. 
M ost  s u bjects i n cli nical practice d o n ot s uffer fr o m wri n kles i n is olate d areas. I nstea d m ore 
t ha n o ne t y pe of li ne i n t he u p per face (i. e. G F L, L C L a n d H F L) is us uall y prese nt i n a 
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Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 2 8  of 1 2 4  
si n gle s u bject, a n d c o nse q ue ntl y h olistic treat me nt is bec o mi n g i ncreasi n gl y p o p ular a n d is 
a  c o m m o n  a p pr oac h  i n  cli nical  practice  w orl d wi de  [B litzer 1 9 9 7, Carr ut hers  2 0 0 7, 
C arr ut hers  2 0 0 9 a, Carr ut her s 2 0 0 9 b, L o we  2 0 1 0, Ols o n 2 0 0 7 ]. 
Wri n kle  s m o ot hi n g i n m ore t ha n o ne area at t he sa me ti me pr o vi des a m ore refres he d, 
nat ural , a n d rela x e d a p peara nce a n d i ncreases pati e nt satisfacti o n  [Carr ut hers  2 0 0 5]. T he 
c o m bi ne d treat me nt of differ e nt u p per faci al areas, s uc h as G F L, H F L, a n d L C L d uri n g t he 
sa me treat me nt sessi o n h as bec o me c o m m o n practice. 
4. 2  
St u d y r ati o n al e  
T he c o m bi ne d treat me nt of wri n kles i n t he u p per face pr o d uces a y o u n ger, m ore refres he d, 
nat ural a n d m ore rela x e d a p peara nce a n d is bec o mi n g i ncreasi n gl y p o p ular. Tre at me nt wit h 
B o N T - A i n  t he  u p per  f ace  offers  pre dicta ble  res ults, has  fe w  a d verse  effects , a n d  is  
ass ociate d  wit h  hi g h  p atie nt  satisfacti o n.  T he  s p o ns or  recei ve d U S F D A   a p pr o v al t o 
N T  2 0 1 i n t he tr eat me nt of m o derat e t o se v ere G F L i n 2 0 1 1. T he E U a ut h oritie s a gree d t o 
m ut uall y a p pr o ve t he i n dicati o n U F L (si m ulta ne o us treat me nt of G F L, H F L, a n d L C L) o n 
1 5- M arc h - 2 0 1 6. The s p o ns or  i nte n ds t o br oa d e n t h e e xisti n g U S aest hetic la bel f or X e o mi n
(c urr e ntl y G F L o nl y) t o als o e na ble si m ulta ne o us treat me nt of all t hree u p per facial areas
( G F L, H F L, a n d L C L) i n t he U S.
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M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 2 9  of 1 2 4  
T he fr o nt alis will n ot be treate d al o n e t o re d uce t he ris k of e y ebr o w pt osis . Br o w pt osis  ca n 
be a v oi de d  b y m ai ntai ni n g t he bal a nce bet w ee n e ye br o w ele v at or m uscl e (fr o nt alis) a n d 
de press or m us cles ( pr o cer us a n d c orr u g at or) t h at are i ncl u de d i n t he gla b ellar c o m ple x. 
T heref ore, c o n c o mita nt treat me nt of fr o nt alis a n d t he gla bellar c o m ple x is rec o m me n de d  
[L ore nc 2 0 1 3 , A ni d o 2 0 1 7 , Pai 2 0 1 6 ]. 
M ore o ver, i s olate d treat me nt of f ore hea d li nes fr o m fr o w n li nes ca n ca us e h y per -acti vit y 
i n t he patie nt’s fr o w n li nes, res ulti n g i n t he m  bec o mi n g  m ore pr o mi ne nt . F urt her m ore,  
is olate d f ore hea d treat me nt s h o ul d be a v oi de d as u n o p p ose d br o w de press or acti o n b y t he 
pr ocer us a n d c orr u gat or ma y lea d t o br o w pt osis [ Pai  2 0 1 6]. 
T o ac hie ve a har m o ni o us res ult of a n i m pr o ve d a p peara n ce t hat is satisf yi n g t o t he patie nt , 
it is rec o m me n de d t hat t he fr o ntalis a n d t he br o w de press ors b e treat e d at t he sa me ti me. 
T he pla n ne d st u d y will a d d t o a n u m ber of cli nical st u dies t hat ha ve bee n  c o n d ucte d i n t h e 
fiel d of aest hetics t o s u p p ort data re gar di n g treat me nt of d y na mic facial li nes. T he st u d y 
acc o u nts f or t he c urr e nt tre n d of aest hetic p h ysicia ns treati n g t he a gi n g face h olisticall y  
rat her t ha n treati n g si n gle f ol ds or mi mic m uscle gr o u p s i n or der t o ac hie ve a m ore nat ural 
aest hetic o utc o me, i n li ne wit h s u bjects’ nee ds a n d g oals. 
4. 3  
Ri s k -b e n efit a s s e s s m e nt  
T he treat me nt of G F L, H F L, a n d L C L offers pre dicta ble aest hetic res ults, has fe w a d verse 
effects, a n d is ass ociat e d wit h hi g h patie nt satisfacti o n.  
N T  2 0 1 was safe a n d well t olerate d w h e n all t hree facial areas were treate d i n c o m bi nati o n, 
a n d n o ne w safet y c o ncer ns were i de ntifie d d uri n g t he pi v otal E U U F L st u d y. M ore o ver , 
t here was n o e vi de nce of a n  i ncrease d i nci de n ce of treat me nt-e mer g e nt A Es [T E A Es ], a n d 
es peciall y t h ose of s peci al i nterest [treat me nt-e m er ge nt A E SIs ], i n s u bjects u n der g oi n g 
re peat-d ose treat me nt.  
T o date, a ll cli nical st u di es wit h N T 2 0 1 i n s u bjects wit h m o derate -t o-se vere G F L, L C L or 
U F L  (si m ulta ne o us treat me nt of G F L, H F L a n d L C L) c o n d ucte d wit h ma xi m u m d oses of 
u p t o 6 4  U  N T  2 0 1 per treat me nt, ha ve  s h o w n a g o o d efficac y a n d c o m para ble s afet y 
pr ofile , wit h n o e vi de nce of ne w safet y c o ncer ns. N o ne w safet y iss ues ha ve bee n  detecte d 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 3 0  of 1 2 4  
i n t he o verall safet y d ata base.  T he safet y res ults are c o nsiste nt wit h t he k n o w n safet y 
pr ofile of N T  2 0 1, a n d are s u p p orte d b y e vi de n ce fr o m t he c o m pre he nsi v e o verall safet y 
data base. 
I n  ge neral,  N T  2 0 1  is  well  t olerate d  (see  c urre nt  i n vesti gat or’s br oc h ure).  C o m m o n  
u n desir a ble effects after N T  2 0 1 i njecti o n i ncl u de l ocal, ge neralize d, or pr oce d ural A Es 
s uc h as i njecti o n site he mat o ma, i njecti o n site er yt he ma, a n d ecc h y m osi s. L ocal A Es are 
us uall y mil d a n d te m p orar y i n nat ure. 
A d diti o na l ris ks t hat ma y arise i n case a p a n de mic disease o ut brea k, e. g. n e w C O VI D-1 9 
p u blic healt h e mer ge n c y, ma y affect t he cli nical st u d y c o n d uct. It is o ur pri mar y g oal t o 
ens ure t he pr ot ecti o n of t he safet y a n d well- bei n g of t he partici pati n g s u bjects.  
C halle n ges ma y arise, f or e xa m ple, fr o m q uara nti nes, site cl os ures, tra vel li mitati o ns, 
interr u pti o ns t o t he s u p pl y c hai n f or t he i n vesti gati o nal pr o d uct, or ot her c o nsi derati o ns  if 
site pers o n nel or tri al s u bj ects bec o me i nfect e d. T hese c h alle n ges ma y lea d t o diffic ulties 
i n meeti n g pr ot oc ol-specifie d pr oce d ures, a n d t h us, mi g ht lea d t o pr ot oc ol m o dificati o ns 
( please r efer t o S ecti o n 9 . 2. 1) 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 3 1  of 1 2 4  
5 
S T U D Y O B J E C TI V E S  
T he pri mar y o bjecti ve of t his st u d y is t o assess t he efficac y of si m ulta ne o us i ntra m usc ular 
i njecti o ns of N T 2 0 1 i n s u bjects wit h m o derate t o se vere U F L i n c o m paris o n t o place b o. 
T he sec o n dar y o bjecti ves are t o assess efficac y a n d safet y of si m ulta ne o us si n gle a n d 
re peat- d ose i ntra m usc ular i njecti o ns of N T 2 0 1 i n s u bjects wit h m o derate t o se vere U F L. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 3 2  of 1 2 4  
6 
I N V E S TI G A TI O N A L P L A N 
6. 1  
O v er all s t u d y d e si g n  
T his  will  be  a  pr os pecti ve,  ra n d o mi z e d,  d o u ble -bli n d,  place b o -c o ntr olle d,  m ult ice nter 
st u d y wit h a place b o-c o ntr olle d M P wit h o ne N T  2 0 1 i njecti o n c ycle f oll o we d b y a n o pe n -
la bel e xte nsi o n peri o d [ O L E X] wit h t w o N T 2 0 1 i njecti o n c ycles. 
I n t he M P ( C ycle 1), 3 6 0 s u bjects will be ra n d o mize d 2: 1: 1 t o t hree differe nt treat me nt 
gr o u ps: U F L treat me nt gr o u p ( Gr o u p  U), G F L a n d H F L treat me nt gr o u p ( Gr o u p  G & H), 
a n d place b o gr o u p ( Gr o u p  P) i n a ra n d o mi zati o n rati o of 2: 1: 1. D uri n g t he M P, s u bjects 
will be treate d eit her wit h a t otal d os e of 6 4  U N T  2 0 1 as si m ulta ne o us i njecti o ns i n all 
t hree f acial areas ( Gr o u p U), wit h a t otal d os e of 4 0  U N T  2 0 1 i n t he G F L a n d H F L area 
a n d place b o i n t he L C L area ( Gr o u p  G & H), or wit h place b o i n all t hree facial areas 
( Gr o u p P). F or f urt her details , see 
 All ra n d o mi ze d s u bjects will t he n be f oll o we d 
u p f or 1 2 0  da ys b ef or e t he y ma y e nter i n t o t he O L E X peri o d. T h e d urati o n of t he M P 
( C ycle 1) will t heref ore be 1 2 0  da ys pl us t he d urati o n of i n di vi d ual scree ni n g ( scree ni n g: 
Da ys - 3 t o - 1 4). 
T he O L E X  peri o d will c o m prise t w o a d diti o nal treat me nt c ycles, C ycle  2 a n d C ycle  3, wit h 
d urati o ns of 1 2 0  da ys eac h  pl us u p t o 3 0 da ys f or eli gi bilit y reassess me nts per c ycl e . 
D uri n g eac h c ycle, eli gi ble s u bjects will recei ve si m ulta ne o us i njecti o ns of N T  2 0 1 at a 
t otal d ose of 6 4 U i n all t hree facial areas. Eli gi bilit y criteria are bei n g e v al uate d bef ore 
rei njecti o n. F or f urt h er details see 
 F or details o n t he pla n ne d visits, see Secti o n  9. 2 . 
T his st u d y will be c o n d ucte d i n a p pr o xi matel y 1 0 ce nters i n t he U S A. 
A cli nical st u d y re p ort wit h all res ults fr o m t he M P a n d O L E X peri o d will be pre pare d 
o nce all s u bjects c o m plet e d t he st u d y. 
E n d of st u d y  
T he e n d of st u d y will be defi ne d as t he l ast st u d y visit of t he last s u bject.  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 3 3  of 1 2 4  
6. 2  
Di s c u s si o n of s t u d y d e si g n, in cl u di n g c h oi c e of c o ntr ol g r o u p s 
T h e pr os pecti ve, ra n d o mi ze d, d o u ble-bli n d, place b o -c o ntr olle d, m ultice nter desi g n of t he 
M P of t his P hase  3 st u d y was c h ose n t o i n vesti gate t he efficac y a n d sa fet y of si m ulta ne o us 
treat me nt of U F L  wit h N T  2 0 1 wit h mi ni mi ze d ris k of bias b y i ncl u di n g a place b o c o ntr ol. 
R o b ust res ults are e x pect e d fr o m t he st u d y desi g n.  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 3 4  of 1 2 4  
T he o bser vati o n peri o d of 1 2 0  da ys ( 4  m o nt hs) ( pl us 3 0 da ys if s u bjects ha ve n ot  yet 
rela pse d t o e nter t he O L E X peri o d) b et wee n first i njecti o n a n d rei njecti o n , re pres e nts a 
reas o na bl e ti me t hat t he I P will ha v e w or n off i n m ost of t he treate d s u bjects, s o t hat 
rei njecti o n i n t he O L E X peri o d ca n b e perf or me d safel y.  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 4 1  of 1 2 4  
7. 4  
R e m o v al  of s u bj e ct s fr o m tr e atm e nt or a s s e s s m e nt  
 
Di s c o nti n u ati o n of s u bj e ct ’ s st u d y p arti ci p ati o n  
I n acc or da n ce wit h t he D eclar ati o n of H elsi n ki a n d t he i nf or me d c o nse nt f or m, t he s u bject 
ma y e n d his/ her p artici pati o n i n t he st u d y at a n y ti me wit h o ut a n y pe nalt y or l oss of be n efits 
t o w hic h t he s u b ject is ot her wise e ntitle d (Secti o n  7. 4. 3 ). B ot h t he fact a n d t he reas o n(s) 
w h y t he s u bject’s partici pati o n i n t he st u d y was pre mat urel y disc o nti n ue d m ust be rec or d e d 
i n t he s o urce d o c u me ntati o n (e. g. s u bject file) a n d t he e C R F (electr o ni c Case Re p ort F or m). 
Date a n d disc o nti n uati o n circ u msta nces s h o ul d be state d. 
T he i n vesti gat or m ust disc o nti n ue t he s u bj ect ’s st u d y partici pati o n at a n y ti me, if a n y of 
t he f oll o wi n g occ urs: 
•  
Wit h dra wal of i nf or me d c o nse nt. 
•  
Pre g na nc y  pri or t o i njecti o n of I P . In case of pre g n a nc y aft er a s u bject has recei ve d 
a n i njecti o n, t he s u bject ca n c o nti n ue wit h a p plica ble st u d y visits u ntil t he e n d of 
t he st u d y b ut wit h o ut a n y i n vasi ve pr oce d ure, e. g. i njecti o ns, bl o o d dra w, or a n y 
ot her i nter ve nti o nal pr oce d ure , s ee Secti o n  1 0. 6 ). H o we ver , t he s u bject is free t o 
disc o nti n ue t he st u d y a n y ti me. 
•  
A n y A E f or w hic h treat me nt c o nti n uati o n w o ul d c o nstit ute a n u nacce pta bl y hi g h 
ris k f or t he s u bject. 
•  
I nta k e of a n y ot her i n vesti gati o nal dr u g. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 4 2  of 1 2 4  
•  
A d mi nistrati o n of b ot uli n u m t o xi n of a n y ser ot y pe i n t he f ace e xce pt f or st u d y 
me dicati o n . 
•  
Treat me nt wit h a n y f aci al c os metic pr oce d ure, s uc h as der m al filli n g, c he mical 
peeli n g, p h ot o rej u ve n ati o n, mes ot hera p y, p h ot o d y na mic t hera p y, l aser treat me nt, 
ultras o u n d treat me nt, tatt o oi n g of e ye br o ws, d uri n g t he e ntire c o urse of t he st u d y. 
De viati o ns fr o m t his st u d y pr ot oc ol,  or c o n diti o ns  c o m prisi n g e xcl usi o n crit eria est a blis he d 
i n Secti o n  7. 3  t hat arise after t he s u bject has bee n i ncl u de d i n t he st u d y ma y ( b ut will n ot 
necessaril y) lea d t o t he disc o nti n uati o n  of s u bject’s st u d y partici pati o n. All s uc h c o n diti o ns 
m ust be pr o perl y d oc u me nte d. 
S u bjects w h o disc o nti n ue t he st u d y beca use of  A Es will be treate d acc or di n g t o sta n dar d 
cli nical pr oce d ur es a n d will be f oll o we d  u p u ntil t he e n d  of  st u d y visit as descri be d i n 
Secti o n  1 0. 1 . All perti ne nt i nf or mati o n c o ncer ni n g t he A E will be d oc u me nte d i n t he 
s o urce d oc u m e ntati o n as well as i n t he e C R F A E re p ort f or m.  
I n t he e ve nt of a p u blic healt h e mer ge n c y t he s p o ns or will i nf or m all i n vesti gat ors, t he 
I E C/I R B, a n d t he rele va nt re g ulat or y a ut h orities pr o m ptl y of a n y pla n ne d miti gati o ns t o 
pr otect t he safet y a n d well -bei n g of s u bjects. T his ca n i ncl u de b ut is n ot li mite d t o: p utti n g 
t he st u d y r ecr uit me nt o n h ol d, st o p pi n g or p ost p o ni n g f urt her treat me nts or c h a n gi n g o n-
site visits t o visits b y p h o ne or at a n ot her cli nical site (i n case t he pri mar y sit e is cl ose d e. g. 
d ue t o q uara nti ne). 
F oll o wi n g disc o nti n uati o n , t he e n d of st u d y visit is t o be perf or me d. T he i n vesti gat or is 
re quire d t o ma ke e v er y eff ort t o c o ntact s u bjects l ost t o f oll o w -u p, a n d all s uc h eff orts are 
t o be d oc u me nt e d i n t he s o urce d o c u me ntati o n (e. g., ti mes a n d dat es of t ele p h o ne c o ntact, 
c o pies of letters).  
 
Pr e m at ur e t er mi n ati o n or s u s p e n si o n of t h e st u d y or 
cl o s ur e/ s u s p e n si o n of a st u d y sit e  
T he st u d y or a st u d y site ca n be pre mat urel y ter mi nate d or s us pe n de d b y t he s p o ns or. 
Reas o ns f or ter mi nati o n of t he st u d y or cl os ure of a st u d y site ma y i ncl u de, b ut are n ot 
li mite d t o, t he f oll o wi n g: 
•  
S u bject e nr oll me nt is u nsatisfact or y.  
•  
T he ris ks a n d b e nefits of c o nti n ui n g t he st u d y ha ve bee n reassess e d, a n d t he ris ks 
o ut wei g h a n y p ote ntial b e nefits. 
•  
T he i nci de nce of A Es c o nstit utes a p ote ntial healt h hazar d t o t he s u bj ects. 
•  
Ne w scie ntific d ata o n t h e I P d o n ot j ustif y a c o nti n uati o n of t he st u d y. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 4 3  of 1 2 4  
•  
T he i n vesti gat or or st u d y site e x hi bit s seri o us a n d/ or persiste nt n o n-a d here nce t o 
t he  cli nical  st u d y  pr ot oc ol,  t he  Declarati o n  of  Helsi n ki,  I C H-G C P,  a n d/ or  
a p plica ble r e g ulat or y r e q uire me nts.  
•  
T he s p o ns or deci d es t o ter mi nate t he st u d y at a n y ti me f or a n y ot her reas o n. 
F urt her m ore, t h e st u d y ma y be pre mat urel y e n d e d if t h e re g ulat or y a ut h orit y or t he I E C  / 
I R B has deci d e d t o wit h dra w or s us pe n d a p pr o val f or t h e st u d y, t he st u d y site, or t he 
i n vesti gat or. 
If t he st u d y is pre mat urel y ter mi nate d or s us pe n d e d f or a n y reas o n, t h e i n v esti gat or m ust 
i nf or m t he s u bjects a n d e ns ure a p pr o priate f oll o w-u p treat me nt. Wit hi n t he ti mefra mes 
n ote d i n a p plica ble re g ul ati o ns, t he s p o ns or will pr o m ptl y i nf or m t he i n vesti gat ors, st u d y 
sites, t he I E C/I R B, a n d re g ulat or y a ut h orities of t he ter mi nati o n or s us pe nsi o n of t he st u d y, 
as well as pr o vi de reas o ns f or t he acti o n.  
I n case of a p a n de mic disease o ut brea k, e. g. n e w C O VI D-1 9 p u blic healt h e mer ge n c y,  it 
mi g ht n ot be feasi ble f or a site t o c o nti n ue st u d y partici pati o n. I n t his case, c o nsi derati o n 
s h o ul d be ma de as t o w het her t he trial site cl os ure w o ul d affect t he safet y a n d well- bei n g 
of partici pati n g s u bjects. A d diti o nall y, c o nsi derati o n s h o ul d be ma de ar o u n d i m pact a n d 
mai nt e na nce of data v ali dit y.  
 
Pr o vi si o n of c ar e f or s u bj e ct s aft er di s c o nti n u ati o n  of t h e 
st u d y  
After st u d y disc o nti n uati o n, t he s u bjects will be treate d b y t heir p h ysicia n acc or di n g t o 
t heir me dical c o n diti o n a n d sta n dar d treat me nts i n t he U S . 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 4 4  of 1 2 4  
8 
T R E A T M E N T S  
8. 1  
I n v e sti g ati o n al pr o d u ct( s) 
 
D e s cri pti o n of i n v e sti g ati o n al pr o d u ct( s)  
N T  2 0 1, mar kete d as X e o mi n (acti ve i n gre di e nt: N T 1 0 1, B o N T -A free fr o m c o m ple xi n g 
pr otei ns; U S A N: i nc o b ot uli n u mt o xi n A) will be pr o vi de d i n q ua ntities of 1 0 0  U i n glass 
vials c o ntai ni n g p o w der t o be rec o nstit ute d f or i njecti o n. 
Place b o  i n  glass  vials  c o ntai ni n g p o w der  f or  rec o nstit uti o n , e xci pie nts   o nl y (s ucr ose, 
h u ma n ser u m al b u mi n) wit h o ut N T  10 1. Place b o vials a n d N T  2 0 1 vials ha ve i de ntical 
a p pear a nce  a n d  t he s ol uti o n  pr o perties of  t he  p o w der  wit h  a n d  wit h o ut  N T  2 0 1  are  
i de ntical. 
N T  2 0 1  a n d  place b o  ar e  ma n ufact ure d  b y  Merz  P har ma  G m b H  &  C o.  K Ga A,  A m  
P har ma par k   2 4,  D-0 6 8 6 1  Dessa u -R ossla u,  Ger ma n y,  a n d  rel ease d  b y  Merz  
P har mace uticals G m b H, Ec ke n hei mer La n dstr. 1 0 0, D- 6 0 3 1 8 Fra n kf urt/ Mai n, Ger ma n y. 
8. 1. 1. 1  
I n str u cti o n s f or pr e p ar ati o n 
T here i s a vac u u m i n t he vial w hic h e ns ures t hat t he l y o p hilize d material re mai ns i nte ger 
as a bl oc k u ntil a d diti o n of 0. 9 % s o di u m c hl ori d e . T heref ore, t he r u b b er st o p per m ust n ot 
be pe netrate d wit h a n ee dle wit h o ut fl ui d. Ot her wise t he v ac u u m w o ul d b e release d a n d t he 
p o w der dis pers e d o n t he i n ner walls of t he vials. 
After vertical i nserti o n of t he nee dle t hr o u g h t he r u b ber st o p per t he s ol ve nt is i njecte d 
ge ntl y i nt o t he vial i n or der t o a v oi d f o a m f or mati o n. A 
s h ort be vel nee dle is 
rec o m me n de d f or rec o nstit uti o n. After re m o v al of t he s yri n ge fr o m t h e vial t he pr o d u ct is 
mi xe d wit h t he s ol ve nt b y car ef ull y s wirli n g a n d i n verti n g t he vial a n d s h o ul d n ot be s ha k e n 
vi g or o usl y. If nee d e d, t h e nee dle us e d f or rec o nstit uti o n s h o ul d re mai n i n t he vial a n d t he 
re q uire d a m o u nt of s ol uti o n s h o ul d be dra w n u p wit h a ne w sterile s yri n ge s uita ble f or 
i njecti o n. 
All  i njecta ble  s ol uti o ns  s h o ul d  be  clear,  c ol o rless,  a n d  free  fr o m  partic ulate  matter 
ot her wise it has t o be discar de d . T h e I P(s) s h o ul d be rec o nstit ute d s h ortl y bef ore i njecti o n. 
H o w e ver, t he rec o nstit ute d I P(s) ca n be st ore d i n t he ori gi nal vial f or u p t o 2 4  h o urs i n a 
refri gerat or at 2 t o 8° C ( 3 6  t o 4 6° F). A n y de vi ati o n t o t his will be d oc u me nt e d o n t he dr u g 
acc o u nta bilit y l o g  a n d t he s p o ns or has t o be c o ntacte d . Rec o nstit ute d st u d y me dicati o n 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 4 5  of 1 2 4  
s h o ul d n ot be st ore d i n s yri n ges. A n y use d s yri n g es, s pilla ges, or ot her materials t hat ha ve 
bee n i n c o ntact wit h t he test or refere n ce pr o d uct m ust be a ut ocla ve d. A n y ( partiall y) us e d 
or u n use d I P will be destr o ye d a p pr o pri atel y at t he site, e. g. b y a ut ocla vi n g  (Secti o n  8. 1. 5 ). 
T he s yri n ges f or i njecti o n of  N T  2 0 1 or place b o will be pre p are d b y a p h ar macist , n urse or 
t he i n vesti gat or. T o kee p t he i n vesti gat or a n d s u bject bli n de d i n all t hree treat me nt gr o u ps , 
t he sa me i njecti o n v ol u mes irres pecti ve of acti ve or place b o will be a p plie d. Eit her
nee dl es s h o ul d be use d f or i njecti o n. 
O nl y t he pr o vi de d st u d y material s h o ul d be use d i n t he st u d y. 
8. 1. 1. 2  
I n str u cti o n s f or a d mi ni str ati o n 
O nl y me dical d oct ors tr ai ne d a n d e x p erie n ce d i n aest hetic B o N T treat me nt are all o we d t o 
i nject s u bjects. T he n u m ber of i n vesti gat ors res p o nsi ble f or t his tas k s h o ul d be li mite d t o a 
ma xi m u m of t w o per site i n t his st u d y.  
Bef ore i njecti o ns, t he area t o be treate d will be clea ne d. N o massa ge, pre - or p ost-c o oli n g, 
or l ocal a n est hetics are all o we d. If blee di n g occ urs at t he i njecti o n site, ge ntle press ure 
wit h o ut  r u b bi n g  ca n  be  a p plie d  u ntil  blee di n g  settles.  F or  safet y  reas o ns,  e mer ge nc y  
e q ui p me nt f or treat me nt of a na p h ylactic reacti o ns will be a vaila ble at site.  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 4 6  of 1 2 4  
 T he i n vesti gat or will use t he I P(s) a n d all st u d y 
materials o nl y wit hi n t he fra me w or k of t he cli nical st u d y a n d i n acc or da nce wit h t his 
cli nical st u d y pr ot oc ol. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 4 7  of 1 2 4  
 
 
 will be sent t o t he  sites c o ntai nin g N T 2 0 1 or place b o vials f or t he 
M P . If necessar y d uri n g t he c o urs e of t he st u d y, sites will be re ple nis he d wit h all st u d y 
ma terials. T he site will dis pe nse I P(s) t o eac h s u bject d uri n g t he d o u ble - bli n d a n d o pe n 
la bel treat me nt peri o ds. 
I n cas e of a pa n demic disease o ut brea k, e. g. ne w C O VI D -1 9 p u blic healt h e mer ge nc y, 
c o nsi derati o ns ma y b e ma de t o s u p pl y t he i n vesti gat or wit h s ufficie nt st u d y s u p plies t o 
a v oi d res u p pl y d uri n g t he st u d y. 
T he stu d y me dicati o n  will be 
la bele d acc or di n g t o re g ulat or y re q uire me nts i n t he partici pati n g c o u ntries. T he la bel will 
i ncl u de as mi ni m u m i nf or mati o n t he na m e a n d  a d dress o f t he s p o ns or,  st u d y refere n ce 
n u m ber , I N D n u m ber, m e dicati o n n u m ber,  d osa g e f or m, r o ute of a d mi nistrati o n, q ua ntit y 
of d osa ge u nits, batc h n u m ber, directi o ns f or us e, st ora ge c o n diti o ns  a n d  peri o d of use , a n d 
t he war ni n g ‘ F or cli nical st u d y use o nl y’.  La bels (f or U S A) m ust i ncl u de: ` Ca uti o n: Ne w 
Dr u g – Li mite d b y Fe deral ( or U S) la w t o i n vesti gati o nal use` . Parts of t he st u d y me dicati o n 
ma y be s u bject t o a re d uce d la bel i n g acc or di n g t o t he a p plica ble re g ul ati o ns.  F or t his 
d o u ble- bli n d st u d y, t he test pr o d uct a n d refere nce pr o d uct(s) will ha ve t he sa me pri nte d 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 4 8  of 1 2 4  
 
la bel i nf or mati o n o n t he o uter me dicati o n pac ka gi n g ( b o x) a n d t he  i n ner c o ntainers ( vials). 
See Secti o n 8. 5  f or det ails of t he bli n di n g pr oce d ures pla n ne d f or t his st u d y. 
 
St or a g e of i n v e sti g ati o n al pr o d u ct( s)  
T he I P (s) will be s hi p pe d at a m bie nt te m perat ure  a n d a te m perat ure l o g ger wil l be i ncl u de d 
i n t he s hi p me nt. U n o pe n e d vials s h o ul d be st ore d at a te m p erat ure bet w ee n 2 ° C a n d 2 5° C 
( 3 5. 6° F t o 7 7° F). D uri n g st ora ge, t he mi ni m u m/ ma xi m u m te m perat ure will be rec or de d i n 
a te m per at ure l o g  b y a mi n -/ ma x-t her m o meter pr o vi de d b y t he s p o ns or. D uri n g st ora ge at 
t he site, t he te m perat ur e l o g s h o ul d be mai ntai ne d o n e ver y w or ki n g da y. 
 
A c c o u nt a bilit y f or i n v e sti g ati o n al pr o d u ct( s)  
It is t he res p o nsi bilit y of t he i n vesti gat or or p har macist acc or di n g t o l ocal la w t o e ns ure 
t hat a c urr e nt rec or d of i n ve nt or y/ dr u g acc o u nta bilit y is mai ntai ne d. I n ve nt or y rec or ds m ust 
be r ea dil y a v aila ble f or i ns pecti o n b y t he st u d y m o nit or a n d are o pe n t o i ns pecti o n b y t he 
U S F D A or ot her re g ul at or y a ut h orities at a n y ti me. Eac h s hi p me nt of m aterials f or t h e 
st u d y will c o ntai n a n ‘I P deli ver y f or m’ t o assist t he i n vesti gat or i n mai ntai ni n g u p- t o-date 
a n d  acc urate  i n ve nt or y  rec or ds.  T his  f or m  i ncl u des  t he  f oll o wi n g  i nf or mati o n:  st u d y  
n u m ber,  dat es,  q ua ntities,  batc h  n u m b er,  e x pirati o n  date,  a n d  t he  me di cati o n n u m ber 
assi g ne d t o t he I P. 
U p o n recei pt of t he I P(s), t he i n vesti gat or or p har macist , acc or di n g t o l ocal la w, will 
vis uall y i ns pect t he s hi p me nt a n d verif y t he n u m ber a n d c o n diti o n of t he I P(s) , c hec k a n y  
te m perat ur e l o g ger t hat was se nt wit h t he me dicati o n a n d ac k n o wl e d ge t he recei pt i n t he 
I W R S.  A n  ‘I P deli ver y f or m’ will  be  c o m plet e d  a n d  si g ne d  b y  t he  i n vesti gat or  or  
a ut h orize d site staff or p har macist acc or di n g t o l ocal la w. T he ori gi nal c o m plete d a n d 
si g ne d f or m m ust be file d wit h t he i n ve nt or y/ dr u g acc o u nta bilit y rec or ds. 
T o e ns ure pr o p er st ora g e a n d t o verif y t he i n v e nt or y, a dr u g s u p pl y i ns pecti o n will be 
c o n d ucte d at r e g ular i nt er vals b y t he m o nit or. St u d y rec or ds will be ma de a vaila ble t o 
a p pr o priate  i n di vi d uals  (e. g.,  m o nit or,  a u dit or,  a n d  re g ulat or y  a ut h oriti es)  o n  re q uest  
t hr o u g h o ut t he st u d y. 
A n y st u d y rec or ds will be re vie w e d d uri n g a n a u dit if re q ueste d, w het her it is state d i n t he 
pr ot oc ol or n ot.   
F or f urt her det ails, see Secti o n  8. 2. 5 . 
I n cas e of a pa n de mic disease o ut brea k, e. g. ne w C O VI D -1 9 p u blic healt h e mer ge nc y, 
c o nsi derati o ns ma y be ma de t o perf or m st u d y -acc o u nta bilit y pr oce d ures re m otel y a n d 
ret ur n of u n use d s u p plies ma y be dela y e d u ntil site pers o n nel are a ble t o safel y d o s o. 
 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 4 9  of 1 2 4  
D e str u cti o n  of i n v e s ti g ati o n al pr o d u ct( s) 
A n y use d s yri n ges, s pilla ges, or ot her materi als t hat ha ve b ee n i n c o ntact wit h t he I P m ust 
be  dis p ose d  a de q uatel y.  A n y  rec o nstit ute d  I P  if  ( partiall y)  use d  or  u n use d  m ust  be  
i nacti vate d a p pr o priatel y at t he site b y o ne of t he f oll o wi n g met h o ds: 
•
A ut ocla vi n g.
F or all pr actical p ur p os es, deacti vati o n a n d d e nat urati o n will  occ ur i nsta nta ne o usl y. 
I n cases w her e r ec o nstit ute d pr o d uct has b ee n s pille d, dr y, a bs or be nt m aterial s h o ul d b e 
use d. If t he pr o d uct c o m es i nt o c o ntact wit h s ki n, t he affecte d area s h o ul d be a b u n da ntl y 
ri nse d wit h w ater. If pr o d uct gets i nt o t he e yes, t he y s h o ul d be ri nse d t h or o u g hl y wit h 
ple nt y of wat er or wit h a n o p ht hal mic e ye was h s ol uti o n. If pr o d uct  c o mes i nt o c o ntact wit h 
a w o u n d or d a ma ge d s ki n, t he area s h o ul d be ri nse d t h or o u g hl y wit h ple nt y of water a n d 
a p pr o priate m e dical ste ps acc or di n g t o t he d os e i njecte d s h o ul d be ta k e n. 
U p o n t he c o m pleti o n or ter mi nati o n of t he st u d y, all u n use d a n d/ or partiall y use d I P(s) 
m ust  be ret ur ne d t o t he s p o ns or  or a n ot her a ut h ori ze d  part y. T he s p o ns or or a n ot her  
a ut h orize d p art y will destr o y t he I P(s) after c o m pleti o n of t he cli nical st u d y re p ort t a ki n g 
i nt o acc o u nt l ocal le gislati o n. Destr ucti o n of I P(s) at t he st u d y site ma y be all o we d if 
writte n a ut h ori zati o n is pr o vi de d b y t he s p o ns or. If destr ucti o n at t he st u d y site is a gree d 
u p o n, t he n a certificate of destr ucti o n m ust be gi ve n t o t he s p o ns or. 
8. 2  
Tr e at m e nt s a d mi ni st er e d  
I n t he M P ( C ycle 1) s u bjects will be ra n d o mi ze d t o o ne of t hree treat me nt gr o u ps  
 
•
I n Gr o u p U, s u bjects will recei ve 2 0 U N T  2 0 1 i n t he G F L area, 2 0 U N T  2 0 1 i n
t he H F L area, a n d 2 4 U N T  2 0 1 i n t he L C L area ( 1 2 U per si de).
•
I n t he G & H gr o u p, s u bjects will recei ve 2 0 U N T  2 0 1 i n t he G F L area,  2 0 U
N T  2 0 1 i n t he H F L area, a n d place b o i n t he L C L  area.
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 5 0  of 1 2 4  
•  
I n t he P gr o u p, all t hree areas will be treate d wit h place b o.  
I n t h e O L E X p eri o d ( Cy cles  2 a n d 3) , all s u bjects will recei ve N T  2 0 1 i n all t hree areas  
 
I njecti o ns will be a d mi nistere d as des cri be d i n Secti o n  8. 1. 1. 2 . 
I n case of a p u blic healt h e mer ge n c y f urt her treat me nts ma y be halte d or p ost p o ne d. 
 
M et h o d s of a s si g ni n g s u bj e ct s t o tr e at m e nt gr o u p s  
At baseli ne visit  V 2 , s u bjects will be ra n d o mize d 2: 1: 1 t o o ne of t he t hree treat me nt gr o u ps 
( Gr o u ps U, G & H, or P) . Ra n d o mizati o n will be d o ne b y usi n g a n I W R S . Ra n d o mizati o n 
n u m ber s a n d date of ra n d o mi zati o n will be rec or d e d i n t he e C R F . 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 5 2  of 1 2 4  
After a 1 2 0  d a y o bser vati o n peri o d f oll o wi n g i njecti o ns i n cycle s 1 a n d 2 , eli gi ble s u bjects 
will recei ve  N T  2 0 1 r ei njecti o n 
 at t he n e xt c ycle bas eli ne visit (V 8 f or C ycle  2 
a n d V 1 3 f or C ycle  3) acc or di n g t o t he i nstr ucti o ns detaile d i n Secti o n 8. 1. 1. 2  a n d t he 
i njecti o n sc he me s h o w n i n 
 T he e n d - of-C ycle  1 visit V 7 a n d t he C ycle  2 baseli ne 
visit V 8, as well as t he e n d - of C ycle- 2 visit V 1 2 a n d t he C ycle 3 baseli ne visit V 1 3 s h o ul d 
be o n t he sa me da y if eli g i bilit y criteria are f ulfille d at V 7 a n d V 1 2. 
 
D ur ati o n of tr e at m e nt p er s u bj e ct  
S u bjects will recei ve st u d y me dicati o n at u p t o t hree i njecti o n visits.  
T he o verall st u d y d urati o n will be a p pr o xi matel y 3 6 0  da ys pl us t he i n di vi d ual d urati o n of 
scree ni n g u ntil bas eli ne (u p t o 1 4  da ys) pl us a ma xi m u m of 3 0  da ys aft er C ycle  1 a n d 
C ycle  2, res pecti vel y, f or eli gi bilit y reassess me nt, as a p plica ble. 
I n case of a p u blic healt h e mer ge nc y t he st u d y mi g ht be halte d, recr uit me nt i nterr u pte d, 
a n d/ or st u d y pr ocesses a n d fl o w mi g ht be m o difie d wit h i m pact t o t he st u d y d urati o n/ visit 
sc he d ule de p e n di n g o n t he c urre nt st u d y stat us. T his mi g ht i ncl u de, b ut is n ot li mite d t o, 
e xte n di n g  st u d y visit  wi n d o ws,  perf or mi n g  st u d y visits  b y  p h o ne  or  vi de o,  a n d/ or  
perf or mi n g efficac y assess me nts re m otel y  
 
Tr e at m e nt c o m pli a n c e  
T he  I P(s)  will  be  a d mi nistere d  t o  t he  t hree facial  areas  b y  i ntra m usc ular  i njecti o n  
perf or me d b y t he i n vesti gat or d uri n g t he s u bject’s visits at t he site at st u d y baseli ne ( V 2) 
a n d at c ycle b aseli nes i n t he O L E X peri o d (V 8  f or C ycle  2 a n d V 1 3 f or C ycle  3). T h us, 
f ull treat me nt c o m plia nce is ass ure d f or eac h i n di vi d ual s u bject. 
 
Tr e at m e nt of o v er d o s e  
A n o ver d os e is d efi ne d as a n y d e viati o n fr o m t h e s pecifie d d os e i n t he pr ot oc ol ( d oses t hat 
are hi g her t ha n rec o m me n de d).  A n y o ver d ose m ust be rec or de d i n t he I P s ecti o n a n d t he 
A E secti o n of t he e C R F a n d t he s o urce d o c u me nts. A n y case of o ver d os e lea di n g t o seri o us 
a d verse e ve nts ( S A Es ) or A Es  of s pecial i nterests ( A E SI)  m ust be re p orte d t o t he C R O i n 
a n e x pe dite d ma n n er usi n g t he a p pr o priat e re p orti n g f or m (Secti o n  1 0. 1 ). 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 5 3  of 1 2 4  
As treat me nt wit h I P is p erf or me d e x cl usi vel y i n a cli nical s etti n g u n der t he s u per visi o n of 
trai ne d me dical pers o n n el, t he ris k of o ver d ose i n t his st u d y is esti mate d t o be ver y l o w.  
F or t h e I P use d i n t his st u d y, n o a nti d ote has b ee n i de ntifie d t o d ate, a n d t here is n o k n o w n 
t hera p y r ec o m me n de d f or a n o ver d os e. 
T here is n o si g nifica nt i nf or mati o n re g ar di n g o ver d ose fr o m cli nical st u dies i n a d ults wit h 
G F L. I n t h e e ve nt of a n o ver d ose, t he i n vesti gat or  or treati n g p h ysicia n is a d vise d t o use 
best cli nical j u d g eme nt  a n d s h o ul d cl osel y m o nit or t he s u bject f or a n y A E a n d S A E a n d 
d oc u me nt t he q ua ntit y of t he e xcess d ose. E xcessi ve d oses of N T  2 0 1 ma y be e x pecte d t o 
pr o d uce ne ur o m usc ular wea k ness wit h a v ariet y of s y m pt o ms. 
Si g ns i ncl u de ac ute s y m metric, desce n di n g flacci d paral ysis wit h pr o mi ne nt b ul bar palsies 
s uc h as di pl o pia, d ys p h o nia, a n d d ys p ha gia, w hic h w o ul d t y picall y occ ur 1 2 t o 7 2  h o urs 
after e x p os ur e [Ar n o n 2 0 0 1 ]. F urt her m ore, si g ns a n d s y m pt o ms of o ver d ose ca n res ult i n 
pt osis,  ge nerali ze d  m uscle  wea k n ess , a n d  paral ysis  of  res pirat or y  m uscle  lea di n g  t o  
as pirati o n p ne u m o nia. Cli nical cases of iatr o ge ni c b ot ulis m after B o N T  i njecti o n were 
re p orte d f or f o ur a d ult patie nts w h ose cli nical si g ns were c o nsiste nt wit h t h ose of nat urall y 
occ urri n g b ot ulis m [ C hert o w 2 0 0 6 ]. 
S y m pt o ms of o ver d ose are n ot i m me diatel y a p p are nt f oll o wi n g i njecti o n. B y t he ti me 
s y m pt o ms of i nt o xicati o n are o bs er ve d, treat me nt wit h a nti t o xi n will n o l o n ger be eff ecti ve 
beca use  t h e  ne ur ot o xi n  has  alrea d y  irre vers i bl y  bl oc ke d  t he  tra ns mitter  release.  
C o m p o u n ds releasi n g acet ylc h oli ne (e. g., p h ys osti g mi ne, g ua ni di ne, 3, 4 - di a mi n o p yri di ne) 
mi g ht  be hel pf ul. H o we ver, t here is n o  e x p erie nce wit h a s pecific a nti d ote t o B o N T  
i ncl u di n g  N T 2 0 1  i n  t he  cli nical  ma na ge me nt  of  o ver d ose.  A  p u blis he d  case  re p ort  
descri bes  t he  s uccessf ul  treat me nt  of  d ys p ha gia  wit h  i ntra nasal  ne osti g mi ne  
[Marc hi ni  1 9 9 7]. 
S u bjects  s h o ul d  be  a d vise d  t o  see k  i m me diate  me dical  care  if  s y m pt o ms  s uc h  as  
s wall o wi n g diffic ulties, s peec h or breat hi n g pr o ble ms occ ur. S u bjects will recei ve a s u bject 
car d  wit h  c o ntact  i nf or mati o n  i n  case  of  e mer ge nc y  ( Secti o n  3. 3. 3 )  if  a d diti o nal 
i nf or mati o n o n t he sc o pe of t he st u d y s h o ul d be re q uire d. 
S h o ul d  acci de ntal  i njecti o n  or  oral  i n gesti o n  occ ur,  t he  s u bject  s h o ul d  be  me dicall y  
s u per vise d f or se veral w ee ks f or si g ns a n d s y m pt o ms of e xcessi ve m uscle wea k n ess or 
paral ysis. S y m pt o matic treat me nt ma y b e necessar y. Res pirat or y s u p p ort ma y be re q uire d 
w here e x cessi ve d oses ca use paral ysis of t he res pirat or y m uscles. A ntit o xi n w o ul d n ot 
re vers e a n y B o N T -i n d uce d effects alrea d y a p p are nt b y t he ti me of a ntit o xi n a d mi nistrati o n. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 5 5  of 1 2 4  
s ucci n ylc h oli ne,  or  t hat  mi g ht  i nterfere  wit h  t he  acti o n  of  B o N T-,  s uc h  as  
c hl or o q ui ne, wit hi n 1 4  da ys pri or t o i njecti o n a n d d uri n g t he e ntire c o urs e of t he 
st u d y) (e xcl usi o n criteri o n n o. 2 5). 
•
Ot her a g e nts t hat mi g ht i nterfere wit h ne ur o m us c ular f u ncti o n, i.e. dr u gs liste d i n
W orl d  Healt h  Or g a nizati o n  A nat o mical  T hera pe utic  C he mical  ( W H O-A T C)
classificati o n class M 0 3  A ge nts t hat mi g ht i n d uce t he pr o d u cti o n of a nti b o dies
a gai nst  acet ylc h oli ne  rec e pt ors  (e. g.,  D -pe nicilla mi ne) , wit hi n  1 4  da y  pri or  t o
i njecti o n a n d d uri n g t he e ntire c o urse of t he st u d y8.
•
Reti n oi ds (e xcl usi o n criteri o n n o. 4)
•
B o N T treat me nt of a n y ser ot y pe at a n y b o d y re gi o n  d uri n g t he e ntire c o urse of t he
st u d y.
•
A n y ot her i n vesti gati o nal dr u g d uri n g t he e ntire c o urse of t he st u d y.
T hera p y c h a n ges (i ncl u di n g c ha n ges of re gi me n) d uri n g t he st u d y are t o be d oc u me nte d i n 
t he s o urce d o c u me ntati o n a n d i n t he e C R F. 
8. 4  
R e stri cti o n s d uri n g t h e st u d y  
N ot  a p plica ble.  F or  restricti o ns  re gar di n g  pre vi o us  a n d  c o nc o mita nt  t hera pies,  s ee  
Secti o n  8. 3 . 
8 Pre vi o us treat me nt wit hi n 1 4  da ys pri or t o i njecti o n wit h a ge nts t hat mi g ht i nterfere wit h ne ur o m usc ular 
f u ncti o n or wit h t he acti o n of B o N T is a n e xcl usi o n criteri o n (e xcl usi o n criteri o n n o. 2 5).  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 5 6  of 1 2 4  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 5 7  of 1 2 4  
9 
S T U D Y A S S E S S M E N T S A N D VI SI T S C H E D U L E  
9. 1  
A s s e s s m e nt s  
I nstr u cti o ns f or us e of t he cli nical o utc o m e ass ess me nts  at site visits i n t his st u d y will be 
descri be d i n a res p ecti ve o utc o me ma n ual. All ass ess me nts will be perf or me d as sc h e d ule d 
acc or di n g t o t he st u d y fl o w c hart  pr o vi d e d i n  
 i n Secti o n  9. 2 . A n o verall 
descri pti o n  of  t he  st u d y  pla n  is  pr o vi de d  i n  Secti o n  6. 1  a n d  i n  t he  fl o w  c hart  i n  
Secti o n  6. 1. 2 . 
Cli ni c al a s s e s s m e nt s  
9. 1. 1. 1  
Effi c a c y a s s e s s m e nt s  
A ssess me nts perf or m e d b y t he s u bject s h o ul d al wa ys be d o ne i n de p e n d e ntl y fr o m t he 
i n vesti gat or a n d st u d y staff at t h e be gi n ni n g of a st u d y visit bef ore a n y i n vesti gat or’s 
assess me nts ta ke place t o g uara ntee i n de pe n d e nce of self -rati n gs. 
T o e nsure c o nsiste nt c o n diti o ns f or all s u bjects, all ma ke- u p a n d e vi de nt je welr y has t o be 
re m o ve d fr o m t he face pri or t o a n y sta n dar dize d p h ot o gra p h y, t he cli nical assess me nts a n d 
self-assess me nts. T h e st u d y staff will e ns ure t hat t he s u bject a n d i n vesti gat or ca n perf or m 
assess me nts i n de pe n de ntl y at a place wit h a de q uat e li g hti n g a n d wit h o ut dis t ur ba nce at t he 
be gi n ni n g of t he res pecti ve st u d y visit. F urt her m ore, a mirr or will be pr o vi de d s o t hat 
s u bjects ca n c o ntr ol res p ecti vel y f or t heir faci al a p peara n ce. 
E ntries i n t he s o urce d o c u me nt s nee d t o be date d a n d si g ne d b y t he i n vesti gat or or b y t he  
s u bject. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 5 8  of 1 2 4  
C CI
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 5 9  of 1 2 4  
C CI
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 6 0  of 1 2 4  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 6 1  of 1 2 4  
9. 1. 1. 2  
G e n er al a s s e s s m e nt s  
Ge ner al assess me nts i ncl u de t he f oll o wi n g: 
• 
Me dical hist or y a n d c o nc o mita nt diseases, pri or a n d c o nc o mita nt me dicati o n, pri or 
a n d c o nc o mita nt n o n- dr u g t hera pies. 
•  
S u bject dis p ositi o n. 
• 
De m o gra p hic d ata.  
• 
B o d y hei g ht at V 1 ( scree ni n g) a n d wei g ht at V 1 ( scree ni n g) a n d V 1 7 E n d of St u d y 
Visit.  
At t he be gi n ni n g of t he st u d y, t he s u bject’s de m o gra p hic dat a, rele va nt me dical hist or y, 
c o nc o mita nt diseases, all pri or me dicati o n ( wit hi n 3 0  da ys bef ore scree ni n g) a n d all c urre nt 
a n d c o nc o mita nt me dicati o ns a n d n o n -dr u g treat me nts pla n ne d d uri n g t he st u d y will be 
rec or d e d. Pre vi o us treat me nts wit h a n y facial c os metic pr oce d ure a n d 
 
 m ust  be  rec or de d  re gar dl ess  of  ti me  of  a p plicati o n.  F or  
pr o hi bite d pri or a n d c o n c o mita nt t hera pies, see Secti o n  8. 3 . A re vie w of t his i nf or mati o n 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 6 2  of 1 2 4  
will all o w t he i n v esti gat or t o ass ess w h et her t he s u bject s h o ul d be e nr olle d. Ot her d ata will 
be c ollecte d as re q uire d, i ncl u di n g i nf or mati o n o btai ne d fr o m p h ysical e xa mi nati o ns a n d 
vital si g ns. If c o u ns eli n g of s u bjects is d ee me d necess ar y, eit her b ef ore e nr oll me nt or 
d uri n g t he st u d y, c o u nsel i n g will be ma de  a vaila ble b y t he i n vesti gat or i n v ol vi n g ot her 
me dical s pecialists, if necessar y . 
 
L a b or at or y e v al u ati o n s  
9. 1. 2. 1  
Cli ni c al a n d r e s e ar c h l a b or at or y e v al u ati o n s  
Bl o o d sa m ples f or e val u ati o n of cli nical bi oc he mistr y a n d h e mat ol o g y will be dra w n a n d 
pre g na nc y testi n g p erf or me d as d escri b e d i n t h e st u d y visit sc he d ules f or t he M P 
 
a n d  O L E X  peri o d  
.  T he  sa m ples  f or  he mat ol o g y a n d  cli nical  bi oc he mistr y,  
i ncl u di n g ser u m pre g na nc y test i n g, will be a nal yze d at a ce ntral la b orat or y . Details wit h 
re gar d t o t he met h o ds of sa m pli n g as well as t he a m o u nt of bl o o d t o be ta ke n will be 
descri be d i n t he r es pecti ve la b orat or y m a n ual. See als o Secti o n 9. 1. 6 . 
If la b or at or y e v al uati ons are missi n g or are u n relia ble (e. g. d ue t o faile d a nal ysis) a re-test 
of t hese para meters has t o be perf or me d i n t he ce ntral la b orat or y. Relia ble   la b orat or y 
res ults f or all re q uir e d para meters ha ve t o be a vail a ble pri or t o t he s u bject’s baseli ne visit. 
T he res ults of t he r e- test will be e ntere d i n t he st u d y data base.  
A n a d diti o nal safet y la b orat or y assess me nt ca n be perf or me d i n t he c o urse of a n A E if 
dee me d n ecess ar y b y t h e i n vesti gat or a n d ca n b e e val uate d eit her i n a l ocal or t he ce ntral 
la b orat or y. Res ults of t hese a d diti o nal ass ess me nts will n ot be e ntere d i n t he st u d y data base 
b ut ca n be a d d e d t o t he s afet y data b ase o pti o nall y if val ues are part of s afet y re p orti n g. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 6 3  of 1 2 4  
 
P h ar m a c o d y n a mi c s  
N ot a p plica ble f or t his st u d y. 
 
P h ar m a c o ki n eti c s  
N ot a p plica ble f or t his st u d y.  C urre ntl y, t here are n o  tests s e nsiti ve e n o u g h t o meas ure 
B o N T i n peri p heral bl o o d. 
 
P h ar m a c o g e n eti c s  
N ot a p plica ble f or t his st u d y. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 6 4  of 1 2 4  
 
T a bl e of bl o o d v ol u m e  
T he bl o o d a m o u nt c orr es p o n ds t o r o uti ne la b orat or y practice. 
A d diti o nal bl o o d sa m pli n g ma y be necessar y i n case of missi n g val ues e. g. d ue t o faile d 
a nal ysis. 
 
S p e ci m e n pr e p ar ati o n, h a n dli n g, st or a g e, a n d s hi p pi n g  
Bl o o d sa m ples f or cli nical c he mistr y, h e m at ol o g y , a n d ß-H C G will be d eter mi ne d b y a 
ce ntral la b orat or y a n d will be ha n dle d acc or di n g t o t he ma n ual of t he ce ntral la b orat or y.  
Bl o o d sa m ples will be st ore d at t h e ce ntral la b u ntil t he e n d of t he st u d y a n d destr o ye d after 
st u d y c o m pleti o n. 
9. 2  
Vi sit s c h e d ul e  
T he M P c o nsists of a scr ee ni n g visit V 1, w hic h will be perf or me d b et wee n Da y -1 4 a n d 
Da y - 3 pri or t o r a n d o mizati o n at baseli ne ( V 2; D a y 1). 
T he p ur p ose of t he scree ni n g visit is t o deter mi ne s u bject eli gi bilit y f or st u d y partici pati o n.  
S u bjects w h o fail scree ni n g are all o we d t o be re-s cree n e d o n e ti me. S u bjects w h o are re-
scree n e d will be assi g ne d a ne w scree ni n g n u m ber. 
Baseli ne is defi ne d as Da y  1, w hic h is t he da y of ra n d o mizati o n a n d first a d mi nistrati o n of 
t he I P. 
D uri n g t he d o u ble- bli n d M P , s u bjects will recei v e N T  2 0 1 or matc hi n g place b o  o nce at 
baseli ne  a n d will be f oll o we d u p d uri n g fi ve  s u bse q ue nt c o ntr ol visits ( V 3 t o V 7). V 7 is 
als o t he e n d - of C ycl e - 1 visit . 
T o ca pt ure l o n g -ter m- s afet y a n d efficac y dat a f or t his i n dicati o n, eli gi ble s u bjects of all 
t hree r a n d o mizati o n gr o u ps fr o m t he M P ( C ycle  1) will c o nti n ue i n C ycle  2, w here t he y 
will recei v e treat me nt wit h N T  2 0 1 f or all t hree  facial areas at t h e C ycle 2 baseli ne visit 
V 8. T he e n d - of C ycle - 1 visit V 7 a n d t he C ycle  2 baseli ne rei njecti o n visit V 8 ca n be 
perf or me d o n t h e sa me da y  if all re q uire d eli gi bilit y criteria a n d n o ne of t he e xcl usi o n 
criteria of t he O L E X peri o d  (Secti o n  7. 3 ) are met  at V7. R eassess me n t f or eli gi bilit y is 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 6 5  of 1 2 4  
p ossi ble wit hi n 3 0  da ys after V 7  (Secti o n  8. 2. 3 ). After treat me nt i n C ycle 2, s u bjects will 
be f oll o we d u p d uri n g f o ur  c o ntr ol visits ( V 9 t o V 1 2) f or 1 2 0  da ys. C o ntr ol visit V 1 2 is 
als o t he e n d - of C ycl e - 2 visit.  
After c o m pleti o n of C ycle  2, eli gi ble s u bjects will c o nti n ue i n C ycle 3, w here t he y will 
recei v e treat me nt wit h N T 2 0 1 f or all t hree  facial areas at t he C ycl e 3 baseli ne visit V 1 3. 
T he  e n d-of -C y cle 2  visit  V 1 2  a n d  t he  C ycle  3 baseli ne  rei njecti o n  visit  V 1 3  ca n  b e  
perf or me d o n t h e sa me da y if all re q uire d eli gi bilit y criteria a n d n o ne of t he e xcl usi o n 
criteria of t he O L E X p eri o d (Secti o n 7. 3 ) are met  at V 1 2. Reassess me nt f or eli gi bilit y is 
p ossi ble wit hi n 3 0  da ys after V 1 2  (Secti o n  8. 2. 3 ). After treat me nt i n C ycle 3, s u bjects will 
be f oll o we d u p d uri n g f o ur  c o ntr ol visits ( V 1 4 t o V 1 7) f or 1 2 0 da ys. C o ntr ol visit V 1 7 is 
als o t he e n d - of C ycl e  3 a n d -e n d- of st u d y- visit.  
T he st u d y acti vities a n d visit sc he d ule s are s h o w n i n 
 f or t he M P a n d i n 
 f or 
t he  O L E X  peri o d. T he  cli nical  st u d y  pr ot oc ol  all o ws  f or  a  wi n d o w  of  ± 7 da ys  i n  
sc he d uli n g of st u d y visits f or all p ost- baseli ne visits, e xce pt V 3 w here o nl y a ± 3-da y 
wi n d o w is all o we d.   The I P(s) m ust be i njecte d b y t he i n vesti gat or, w h o is  trai ne d a n d 
e x perie n ce d i n aest h etic B o N T  treat me nt, at t he st u d y site . F oll o wi n g a d mi nistrati o n of 
I P(s), s u bjects will be o bser ve d f or a mi ni m u m of 3 0 mi n utes at t he site a n d will be as ke d 
b y t he i n vesti gat or if a n y A Es ha ve o cc urre d si nce a d mi nistrati o n . Vital si g ns will be ta ke n 
at t he be gi n ni n g of eac h st u d y visit t o e ns ure s u bject safet y. 
T he last pri mar y o utc o me visit will occ ur at Da y 3 0  ± 7 ( V 4) f or eac h s u bject. F or s u bjects 
n ot f ulfilli n g t he rei njecti o n criteria, als o n ot  at t he reassess me nt visit, t he e n d- of st u d y visit 
will be perf or me d directl y a n d t he s u bject will be disc o nti n ue d fr o m t he st u d y. F or all ot her 
s u bjects, t he -e n d-of  st u d y- visit V 1 7 will occ ur at Da y  1 2 0 ± 7 after last a d mi nistrati o n of 
t he I P i n C ycle 3. U ns c h e d ule d visits ma y be re q uire d i n t he case of  A Es or  pre mat ure 
disc o nti n uati o n of t he st u d y. I n t his case, t he fi nal assess me nts as descri be d f or V 1 7 , will 
be perf or me d as s o o n as p ossi ble. If a d diti o nal safet y f oll o w -u p is necessar y after t his visit , 
s u bjects ma y be c o ntacte d b y tele p h o ne or be assesse d i n t he cli nic, de p e n di n g o n t he nat ure 
of t he f oll o w- u p r e q uire d. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 6 6  of 1 2 4  
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 6 7  of 1 2 4  
 
C CI
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 6 8  of 1 2 4  
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
C O N FI D E N TI A L  
Pa ge 6 9  of 1 2 4  
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 7 0  of 1 2 4  
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 7 1  of 1 2 4  
1 0  S A F E T Y A S S E S S M E N T S  
Safet y assess me nts  i ncl u de A Es , A E SIs , sta n dar d cli nical bi oc he mistr y an d h e mat ol o g y, 
v ital  si g ns,  p h ysical  e xa mi nati o n,  pre g na nc y t est as  descri be d  i n  Secti o n  1 2. 3. 5   a n d 
acc or di n g t o t he visit sc h e d ules of t he M P 
 a n d O L E X p eri o d 
 
1 0. 1  D efi niti o n of a n a d v er s e e v e nt  
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject a d mi nistere d a p har mace utical 
pr o d uct. A n  A E d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t he treat me nt. T h us, 
a n  A E  ca n  be  a n y  u nf a v o ra ble a n d  u ni nte n de d  si g n,  s y m pt o m,  or  disease  (i n cl u di n g  
i nterc urr e nt ill ness); deteri orati o n of a pre-e xisti n g i ll ness; acci de nt; a n y s us pecte d dr u g 
reacti o n; or a cli nicall y rele va nt c h a n ge of la b orat or y val ues w het her or n ot c o nsi dere d 
relate d t o t he I P(s) or st u d y pr oce d ure. 
C ha n ges i n efficac y e n d p oi nt s (e. g., s u bject-re p orte d o utc o me e n d p oi nt s ( q uesti o n naires 
an d scales ) d uri n g t he c o urse of t he st u d y) nee d n ot be d oc u m e nte d as A Es, beca use t h ese 
c ha n ges  will  be  r ec or d e d  as  effi cac y  e n d p oi nt s. Electi ve  treat me nts  pla n ne d  bef ore  
scree ni n g a n d w hic h ar e d oc u me nte d i n t he s u bject’s s o urce data are us uall y n ot re garde d 
as A Es.  
F or scr ee ni n g fail ures A Es are n ot t o be d oc u me nte d i n t he e C R F. F or ra n d o mi ze d s u bjects 
t hat e x perie n ce d A Es d uri n g t he scree ni n g p eri o d t hese ha ve t o b e e ntere d i nt o t he e C R F. 
A n y  u nt o war d me dical occ urr e nce t hat ha p pe ns bet wee n t he ti me w he n  t he i nf or me d 
c o nse nt  f or m  is  si g ne d  a n d  t he  first  a d mi nistrati o n  of  I P(s)  is  a n  A E  a n d  has  t o  be  
d oc u me nte d i n t he s u bject’s file a n d i n t he e C R F A E re p ort f or m. T hes e A Es are calle d 
n o n- T E A Es .  
T E A Es ar e defi ne d as A Es wit h o nset or w orse ni n g d uri n g or a fter t he first a d mi nistrati o n 
of I P(s) u p t o a n d i ncl u di n g fi nal st u d y visit. I n case n o fi nal visit is perf or me d, all A Es 
re p orte d d uri n g a ti me p eri o d c orres p o n di n g t o t he e x pect e d c ycl e le n gt h will be re gar de d 
as treat me nt -e mer ge nt.  
Ne w  A Es  r e p orte d  t o  t he  i n vesti gat or  d uri n g  t he  o bser vati o n   peri o d after  t he  l ast  
a d mi nistrati o n of I P(s) m ust be d oc u me nte d, treate d, a n d f oll o we d u p li ke all ot her A Es. 
N o n -seri o us A Es will n ot be f oll o we d u p after t he fi nal st u d y visit, w hic h is sc he d ul e d 
1 2 0 ± 7 da ys after l ast a d mi nistrati o n of I P(s). 
Pre -e xisti n g  c o n diti o ns  n ote d  i n  t he  me dical  hist or y  a n d  pre vi o us  t o  st u d y  dr u g  
a d mi nistrati o n  s h o ul d n ot be re p orte d as a n A E, u nl ess t he c o n diti o n w orse ns or t he disease 
re occ urs d uri n g t he o bser vati o n peri o d. T o d eter mi ne w het her a c o n diti o n h as w orse n e d, it 
is c o m pare d t o t he c o n diti o n of t he s u bject at scree ni n g. A b n or mal l a b orat or y v al ues 
o bt ai ne d d uri n g t he s u bject’s scree ni n g peri o d will o nl y meet A E criteria if ne wl y detecte d 
a n d if c o nsi der e d cli nicall y si g nifica nt. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 7 2  of 1 2 4  
Data pertai ni n g t o A Es will be c ollecte d d uri n g eac h st u d y visit o n t he  basis of t he  s u bject’s 
s p o nta ne o us  r e p ort,  t hr o u g h  i n vesti gat or  i n q uir y,  or  dis c o vere d  i n  t he  c o urse  of  
e xa mi nati o ns perf or me d d uri n g t he visit. T he i n vesti gat or will assess a n d rec or d a n y A E 
i n detail i n t he s o urce d oc u me ntati o n a n d o n t he e C R F A E re p ort f or m. T he f oll o wi n g 
i nf or mati o n m ust be rec or de d: 
•  
A E dia g n osis or mai n s y m pt o m. 
•  
Date of o nset.  
•  
Date of w orse ni n g  ( e. g. if a n A E t ur ns fr o m mil d t o m o derate, t he date h as t o be 
gi ve n). 
•  
I nte nsit y (s ee Secti o n 1 0. 1. 1 ). 
•  
Ca usal relati o ns hi p ( n ot relate d, rel ate d).  
•  
Ca usal relati o ns hi p t o C O VI D- 1 9 ( n ot relate d, rel ate d)  
•  
Seri o us ( yes or n o). 
•  
O utc o me ( Secti o n 1 0. 1. 4 ). 
•  
A E lea di n g t o disc o nti n uati o n of t he st u d y ( yes or n o). 
•  
St o p date. 
After c o m pleti o n of all sc he d ule d visit assess me nts , t he i n vesti gat or m ust d oc u me nt a n y 
A Es arisi n g fr o m t hese assess me nts . 
I n case of an S A E or A E SI (alert ter m, as defi n e d i n Secti o n  1 0. 3 ) t he i n vesti gat or m ust 
als o  c o m plete  a n  S A E  re p ort  f or m  or  A E SI  re p ort  f or m  a n d  re p ort  it  t o  t he C R O  
i m me diatel y, as descri be d i n Secti o n  1 0. 2 . 
Treat me nt of o v er d ose wit h I P(s) is descri be d i n Secti o n  8. 2. 6 . 
 
D efi niti o n of i nt e n sit y 
T he cli nical i nte nsit y of a n A E will be classifie d o n t he basis of its ass ociate d si g ns a n d 
s y m pt o ms, as f oll o ws: 
Mil d:  
Si g ns a n d s y m pt o ms t hat ca n b e easil y t olerat e d. S y m pt o ms ca n be i g n ore d 
a n d disa p pear w he n t he s u bject is distracte d. 
M o der ate:  
Si g ns  a n d  s y m pt o ms  t hat  ca use  disc o mf ort  a n d  i nterfere  wit h  n or mal  
f u ncti o ni n g, b ut are t olera ble. T he y ca n n ot b e i g n ore d a n d d o n ot disa p pear 
w he n t he s u bject is distracte d. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 7 3  of 1 2 4  
Severe:  
Si g ns a n d s y m pt o ms t hat affect us ual d ail y acti vit y a n d i nca pac itate t he 
s u bject, t here b y i nterr u pti n g his/ her dail y acti vities. 
T he  defi niti o ns  a b o ve  are  diffic ult  t o  a p pl y  f or  s o me  data  (e. g.,  cli nicall y  rele va nt  
la b orat or y v al ues t hat are d oc u me nte d a n d e val uat e d o n t he e C R F A E re p ort f or m). I n s uc h 
sit uati o ns, t he i n vesti gat or s h o ul d ma ke a j u d gme nt  base d o n cli nical e x p eri e nce.  
D efi niti o n of c a u s al r el ati o n s hi p wit h i n v e sti g ati o n al 
pr o d u ct( s ) 
A n A E is c o nsi der e d t o b e “r elate d” t o I P(s) if a ca usal relati o ns hi p bet w ee n t he I P(s) a n d 
a n A E is at least a reas o n a ble p ossi bilit y (i.e., t he relati o ns hi p ca n n ot be r ul e d o ut). 
T he e x pr essi o n “reas o n a ble ca us al rel ati o ns hi p” is mea nt t o i m pl y t hat t here are facts 
(e vi de nce) or ar g u me nts t o s u g gest a ca usal relati o ns hi p (I C H E 2 A g ui deli ne). Ot her wise, 
t he A E s h o ul d be c o nsi dere d as “ n ot relate d. ” 
 
C at e g ori e s of o ut c o m e  
T he re p ort a ble o utc o mes a n d/ or se q u elae of a n A E are as f oll o ws:  
•
Rec o ver e d/res ol ve d.
•
Rec o veri n g/res ol vi n g.
•
N ot rec o vere d/ n ot res ol v e d.
•
Rec o ver e d/res ol ve d wit h se q uelae.
•
Fatal.
•
U n k n o w n.
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 7 4  of 1 2 4  
If t her e is m or e t ha n o ne A E, o nl y t he A E lea di n g t o deat h will be rec or d e d as h a vi n g a 
“fatal” o ut c o me.  
1 0. 2   Defi niti o n of a s eri o u s a d v er s e e v e nt  
A n S A E is a n y u nt o war d me dical occ urre n ce, at a n y d ose, t hat: 
•  
Res ults i n deat h. 
•  
Is life-t hreate ni n g.9 
•  
Re q uires i n patie nt h os pitalizati o n, or pr ol o n gati o n of e xisti n g h os pitalizati o n. 
•  
Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y.  
•  
Is a c o n ge nital a n o mal y/ birt h defect. 
•  
C o nsists of a n y ot her me dicall y i m p orta nt c o n diti o n. 1 0 
I n case of d eat h, a n a ut o ps y re p ort s h o ul d be s u b mitte d (if a vaila ble). T he date a n d ca us e 
of deat h s h o ul d be r ec or d e d. 
H os pitalizati o ns  f or  el ecti ve  treat me nts  pla n n e d  bef ore  scree ni n g  a n d  w hic h  are  
d oc u me nte d i n t he s u bject’s s o urce dat a are us uall y n ot re gar d e d as S A Es. 
All S A Es t ha t occ ur d uri n g t he st u d y peri o d w het her c o nsi dere d t o be relate d t o I P(s) or 
n ot, m ust be re p orte d i m me diatel y a n d u n d er n o circ u msta nces later t ha n 2 4 h o urs aft er 
lear ni n g of t he e ve nt b y telefa x, tele p h o ne or email . S A E re p ort f or ms are pr o vi de d i n t he 
I n v esti gat or’s Site F ile (I S F). 
Alt h o u g h all i nf or mati o n re q uire d f or c o m pleti o n of a n S A E re p ort f or m ma y n ot be 
a vaila ble wit hi n t he s pecifie d ti me peri o d, a n i nitial re p ort s h o ul d be s u b mitte d if t he 
f oll o wi n g mi ni mu m i nf or mati o n is a vaila ble: 
•  
A n i de ntifia ble s u bject ( n u m ber). 
 
9 T he ter m “life -t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h t he s u bject was at ris k 
of deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt t hat h y p ot heticall y mi g ht ha ve ca use d deat h if 
it were m ore se vere. 
1 0 Acc or di n g t o I C H E 2 A, C P M P/I C H/ 3 7 7/ 9 5: “ Me dical a n d scie ntific  j u d g me nt s h o ul d be e xercise d i n 
deci di n g w het her e x pe dite d re p orti n g is a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat 
ma y  n ot  be  i m me diatel y  life -t hreate ni n g  or  res ult  i n  deat h  or  h os pitalizati o n  b ut  ma y  je o par dize  t he  
patie nt/s u b ject or ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he defi niti o n a b o ve. 
T hese s h o ul d als o us uall y be c o nsi dere d seri o us. E xa m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n 
e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m; bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n 
h os pitalizati o n; or de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.”  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 7 5  of 1 2 4  
•
A s us pect pr o d uct.
•
A n i de ntifia ble re p orti n g s o urce (i n vesti gat or/ st u d y site i de ntificati o n).
•
A n e ve nt or o utc o me t h at ca n be i de ntifie d as seri o us.
T he re p ort m ust be d eli vere d t o t he i n di vi d ual(s) liste d bel o w. 
T he a d dr ess f or S A E r e p orti n g is: 
T he  i n vest i gat or  m ust  s u p pl y  f urt her  s u p p orti n g  i nf or mati o n  wit hi n  t hree da ys  of  
k n o wle d ge of t he S A E, a n d a detaile d S A E descri pti o n is a n i nte gral part of t his s u p p orti n g 
i nf or mati o n. F oll o w-u p r e p orts are t o be se nt wit h o ut dela y t o t he C R O as a n S A E re p ort 
f or m  ( mar ke d  as  a  “f oll o w- up”  re p ort)  a n d  acc o m pa nie d  b y  a p pr o priate  s u p p orti n g  
d oc u me ntati o n (e. g., h os pital re p orts). T he S A E is t o be f oll o we d u p u ntil t he S A E is 
res ol ve d/rec o ver e d or a pla usi ble e x pla nati o n is a vaila ble. T hese S A Es will be f oll o we d u p 
o nl y i n t he pr o d uct safet y data base after fi nal S A E rec o nciliati o n is c o m plet e d.  
M ore o ver, S A E s ar e t o be d oc u me nte d o n t he ge n eral pa ges of t he A E e C R F as well as i n 
t he  s u bject’s  file. T he  e C R F  pa ges  f or  me di cal  hist or y/c o nc o mita nt  diseases  a n d  f or  
pre vi o us/c o nc o mita nt me dicati o n a n d n o n -dr u g treat me nt are t o be fa xe d/s e nt al o n g wit h 
t he S A E re p orti n g f or m. 
S A Es occ urri n g  after fi nal st u d y visit ( V 1 7)  nee d o nl y be re p ort e d if t he i n vest i gat or 
c o nsi ders t he e ve nt t o be relate d t o I P(s). T hes e re p orts will  ge n erall y n ot be e ntere d i nt o 
t he cli nical st u d y data bas e. T hese re p orts will be e ntere d i nt o t he Safet y D ata base.  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 7 6  of 1 2 4  
1 0. 3   AE SI s  / al ert t er m s  
A Es occ urri n g after treat me nt t hat are t h o u g ht t o p ossi bl y i n dicate t o xi n s prea d are defi ne d 
as A E SI . T he s u bject will be acti vel y as ke d b y t he i n vesti gat or at eac h visit after s cree ni n g 
(starti n g wit h baseli ne visit V 2) if a n y of t he A E SI ter ms liste d i n 
 bel o w occ urre d 
si nce t he last c o ntact. A E SI q uesti o ni n g at V 2 will facilitate rec or di n g of pre -e xisti n g 
c o n diti o ns a n d/ or p ossi bl y u n detecte d ( S) A Es t hat c o ul d c o nf o u n d A E SI q uesti o ni n g p ost 
i njecti o n of I P. T he q uesti o ni n g a n d d oc u me ntati o n of a ns wers will be sta n dar dize d.  
A E SIs are c o nsi dere d t o ha ve a s pecial mea ni n g or i m p orta nce f or a p artic ul ar dr u g or class 
of dr u gs. T h e y ma y b e n o n -seri o us a n d prec urs ors ( pr o dr o mes) of m ore s eri o us me dical 
c o n diti o ns. T h us t he y s h o ul d be cl osel y m o nit ore d a n d re p orte d t o t he s p o ns or wit hi n 2 4 
h o urs. 
T he site m ust r e p ort all A E SIs t hat occ ur d uri n g t he st u d y peri o d, w het her c o nsi dere d t o 
be rel ate d t o I P(s) or n ot, b y telefa x or e mail  t o t he res p o nsi ble C R O wit hi n 2 4 h o urs of 
k n o wle d ge of t he e v e nt. T he C R O will tra ns mit t hese A E SIs t o M erz P har mace uticals 
G m b H. Eac h A E SI m ust be re p ort e d b y t he site o n t he A E SI re p orti n g f or m. M ore o ver, 
A E SIs are t o be d o c u me nte d o n t he ge n eral p a ges of t he A E e C R F as well as i n t he s u bject’s 
file. 
T he
 e C R F
 pa ges
 f or
 m e dical 
hist or y/c o nc o mita nt  d iseases
 a n d
 f or
 
pre vi o us/c o nc o mita nt m e dicati o n a n d n o n- dr u g t reat me nt are t o be fa xe d/s e nt al on g wit h 
t he A E SI re p orti n g f or m. The A Es i n 
 are defi ne d as A E SIs  f or t his st u d y. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 7 7  of 1 2 4  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 7 8  of 1 2 4  
1 0. 4  E x p e ct e d a d v er s e e v e nt s  
E x pecte d A Es are t h ose descri be d i n  Secti o n 7. 1 C o m p a ny C ore S afety I nf or m ati o n  of t he 
i n vesti gat or’s br oc h ur e f or N T  2 0 1. 
1 0. 5  U n e x p e ct e d a d v er s e e v e nt s  
U ne x pect e d A Es ar e t h ose n ot descri be d i n  Secti o n 7. 1 C o m p a ny C ore S afety I nf or m ati o n  
of t he i n vesti gat or’s br o c h ure f or N T  2 0 1. 
1 0. 6  Pr e g n a n c y  
Eac h pr e g na n c y t hat starts d uri n g t he st u d y m ust be re p orte d b y t he i n vesti gat or t o t he 
pr o d uct safet y  d e part me nt of t he C R O wit hi n 2 4 h o urs of lear ni n g of its occ urre nce. 
Pre g na ncies a n d pre g n a n c y f oll o w -u p s h o ul d be re p orte d o n a pre g na n c y m o nit ori n g f or m. 
Pre g na nc y  f oll o w -u p  s h o ul d  descri be  t he  o utc o me  of  t he  pre g na n c y,  i ncl u di n g  a n y  
v ol u ntar y or s p o nta ne o us disc o nti n uati o n; details of t he birt h; t he prese nce or a bse nce of 
a n y c o n ge nital a b n or malities, birt h defects, mater nal or ne w b or n c o m plicati o ns, a n d t heir 
relati o n t o t he I P(s). Eac h n or mal pre g na nc y is t o be re p orte d as a n o n-seri o us A E ( dr u g 
e x p os ure b ef or e or d uri n g pre g na n c y). A n y a b n or mal pre g na n c y or pre g na nc y o utc o me is 
t o be re p orte d as S A E  (o n a n S A E  f or m). I n cas e a pre g na nc y o cc urs pri or t o first i njecti o n, 
t he s u bject m ust n ot b e ra n d o mize d. If a pre g na nc y occ urs after a s u bject has recei ve d 
i njecti o n,  t he  s u bject  ca n  c o nti n ue  wit h  a p plica ble  st u d y  visits  u ntil  t he  e n d  of  t h e  
c orres p o n di n g c ycl e b ut wit h o ut a n y i n vasi ve pr oce d ure (e. g. i njecti o ns, bl o o d dra wi n g)  
a n d  n o  f urt her  i njecti o n  treat me nts  will  be  gi ve n.  H o we ver,  t he  s u bject  is  free  t o  
disc o nti n ue t he st u d y at a n y ti me. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 7 9  of 1 2 4  
1 1  D A T A Q U A LI T Y A S S U R A N C E  
I ns p ecti o ns b y re g ulat or y a ut h orit y re prese ntati ves a n d I E Cs/I R Bs are p ossi ble at a n y ti me, 
e ve n aft er t he e n d of st u d y. T he i n vesti gat or is t o n otif y t he s p o ns or i m me diatel y of a n y 
s uc h i ns pecti o n. T he i n vesti gat or a n d i nstit uti o n will per mit st u d y-related m o nit ori n g, 
a u dits, re vie ws b y t h e I E C/I R B a n d/ or re g ul at or y a ut h orities a n d  will all o w direct access 
t o s o urce data a n d s o urce d oc u me nts f or s uc h m o nit ori n g, a u dits, a n d re vie ws. 
1 1. 1  St a n d ar di z ati o n pr o c e d ur e s  
Sta n dar diz ati o n pr oce d ur es will be i m ple me nte d t o e ns ure acc urate, c o nsistent, c o m plete, 
a n d relia ble d ata, i ncl u di n g met h o ds t o e ns ure sta n dar dizati o n a m o n g sites (e. g., trai ni n g, 
ne wsletters,  i n vesti gat or  meeti n gs,  m o nit ori n g,  ce ntral  la b orat ories,  ce ntrali ze d 
e val uati o ns, a n d vali dati o n met h o ds). 
T h is st u d y will be m o nit ore d re g ularl y b y a q ualifie d m o nit or fr o m t he C R O acc or di n g t o 
I C H- GC P a n d t he res p ecti ve S O Ps ( Secti o n 1 1. 4 ). 
1 1. 2  S o ur c e d o c u m e nt ati o n r e q uir e m e nt s  
All data c ollecte d fr o m a s u bject d uri n g t he c o urse of t his cli nical st u d y s h o ul d be retai ne d 
i n t he res p ecti ve s o ur ce d oc u me ntati o n (e. g. s u bject file). T his i n cl u des a c o p y of t he l etter 
se nt  t o  t he  s u bject’s  pri mar y  p h ysicia n  a b o ut  t he  s u bject’s  partici pati o n  i n  t he  st u d y  
( pr o vi de d t he s u bject h as a pri mar y p h ysicia n a n d has a gree d t o t he ge n eral practiti o ner  
bei n g i nf or me d). 
T he s o urce  d oc u me ntati o n m ust als o c o ntai n a descri pti ve state me nt o n t he i nf or me d 
c o nse nt pr oce d ur e ( Secti o n  3. 3. 2 ). T he i n vesti gat or m ust als o c o nfir m b y wri tte n state me nt 
i n t he s o urce d oc u m e ntati o n t hat  all  i ncl usi o n criteria a n d  all  e xcl usi o n  criteria were 
c hec k e d pri or t o i ncl usi o n of t he s u bject. I n a d diti o n t o t his state me nt, t he s u bject’s meeti n g 
or n o n- meeti n g of t he i n- a n d e xcl usi o n criteria a n d eli g i bilit y criteria ha ve t o be tracea ble 
o n t he basis of t he d o c u me ntati o n i n t he s u bjects file. T he c hil d beari n g p ote ntial of fe male 
s u bjects m ust be n ote d i n t he s o urce d o c u me ntati o n. 
T he site will kee p a s o urce d ata l ocati o n list w hic h will o utli ne f or t he  differe nt data 
cate g ories i ncl u di n g electr o nic data (e. g. de m o gra p hics, me dical hist or y, a n d A Es  et c.) 
w hic h d oc u me nt ser ves as s o urce f or t h ese dat a (e. g. s u bject file, s u bject diar y, la b orat or y 
re p ort). Scal es assesse d b y t he i n vesti gat ors a n d s u bjects o n pa per f or ms 
 
 will be c o nsi dere d as s o urce data a n d will be tra nsferre d 
i nt o t he e C R F b y t he site. 
If a st u d y site is usi n g a n electr o nic s yste m f or d o c u me nti n g s o urce dat a, a me m ber of t he 
site staff m ust pri nt-o ut t he s o urce dat a after eac h visit. T he pa per pri nt -o uts m ust o verla p, 
if p ossi ble (i.e., m ust c o ntai n at least t h e last r o w of data fr o m t he s u bject’s pre vi o us visit). 
If it is n ot p ossi ble t o o bt ai n o verl a p pi n g pa p er pri nt-o uts, t he c o m plete n ess  of s o urce data 
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C O N FI D E N TI A L  
Pa ge 8 0  of 1 2 4  
 
m ust be e ns ure d b y ot her s uita ble mea ns. T h e pri nt -o ut m ust be si g ne d a n d date d b y a 
me m ber of t he site staff w h o ca n c o nfir m t he acc urac y a n d c o m plete n ess of data i n t he 
pa per pri nt- o ut. 
T he m o nit or will als o si g n a n d d ate after verif yi n g t he s o urce d ata. T h e pa per pri nt- o ut 
s h o ul d be st ore d i n t h e I S F. If s o urce dat a i nf or mati o n is e ntere d retr os p ecti vel y, t his m ust 
be d o ne dir ectl y o n t he p a per pri nt -o ut a n d s h o ul d be i nitial e d a n d d ate d. T he sa me a p plies 
t o a n y c orr ecti o ns of i nitial data. 
If t he site is usi n g a vali d ate d c o m p uter s yste m i ncl u di n g a u dit trail wit h a s e parat e access 
f or t he m o nit or (i.e., t he m o nit or ca n o nl y access t he data of t he st u d y s u bjects), t he n n o 
s uc h pa per pri nt- o uts are re q uire d. 
1 1. 3  D at a m a n a g e m e nt  
Data re q uire d acc or di n g  t o t his pr ot oc ol  are t o be rec or de d i n t he w e b-base d  e C R Fs  
(electr o ni c data ca pt ure [ E D C] s yste m) pr o vi d e d b y t he C R O. All users  w h o will e nter d ata 
i nt o t he e C R F will be pr e vi o usl y trai ne d. S uccessf ul c o m pleti o n of t he t rai ni n g will be a  
prere q uisite f or t he access t o t he e C R F. T he access t o t he e C R F is pass w or d-c o ntr olle d a n d 
c o nf or ms wit h 2 1 C F R p art 1 1 . 
Pla usi bilit y c hec ks will be perf or m e d acc or di n g t o a data vali dati o n pla n. I nc o ns iste ncies 
i n t he data will be q uerie d t o t he i n vesti gat ors via t he electr o nic data ca pt ure s yste m; 
a ns wers t o q ueries or c h a n ges t o t he data will als o be d oc u me nte d i n t his s yste m directl y 
b y a n a ut h orize d m e m ber of t he i n vesti gat or’s site staff. 
T he a u dit  trail i n t he electr o nic data ca pt ure s yst e m d oc u me nts all c h a n g es. E dit c hec ks 
ge nerat e a ut o matic q ueri es d uri n g data e ntr y w h e n a fiel d is n ot p o p ulate d acc or di n g t o 
s pecificati o ns defi ne d i n t he data vali dati o n pla n. Ma n ual q ueries (t o be a ns were d b y site 
staff) ca n be raise d d uri n g s o urce d ata verificati o n, me dical or safet y re vie w a n d dat a 
ma na ge me nt r e vie w.  
La b orat or y dat a will be recei v e d electr o nicall y a n d mer ge d wit h t he e C R F data ( b ut n ot 
u pl oa de d i nt o t he E D C s yste m). Pla usi bilit y c hec ks will be perf or me d t o e ns ure c orrect ness 
a n d c o m plete ness of t hes e data. T he C R O ’s data ma na ge me nt f u ncti o n (s ee Secti o n  2. 2 ) 
will be res p o nsi ble f or cli nical data - pr ocessi n g, i n acc or da n ce wit h t he s p o ns or’s dat a 
ma na ge me nt pr o ce d ur es as far as p ossi ble . 
Data fr o m t he i n d e pe n de nt rater pa nel will be recei ve d electr o nicall y a n d m er ge d wit h t he 
e C R F data ( b ut n ot u pl oa de d i nt o t he E D C s yste m). F urt her d etails will be s pecifie d i n t h e 
Data Ma na g e me nt Pla n.  
After all data are e ntere d a n d all q ueri es are s ol ve d, t he data b ase will b e cl ose d. After 
data base cl ose, u n bli n di n g will ta ke place. I n case of a n y c ha n g es t o t he d at a aft er d ata base 
cl ose, t hese c h a n ges will be d oc u me nte d.  
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M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 8 1  of 1 2 4  
I n cas e of a pa n d e mic disease o ut brea k, e. g. ne w C O VI D-1 9 p u blic healt h e mer ge nc y, a n d 
b y t his, if data e ntr y a n d clea ni n g is li mite d or n ot p ossi ble d ue t o site cl os ures, tra vel 
li mitati o ns,  or  ot her  c o nsi derati o ns  if  site  p ers o n nel  bec o me  i nfecte d,  t he  f oll o wi n g  
miti gati o ns s h o ul d be c o nsi dere d f or d ata cl ea ni n g pr ocesses: 
•  Data e ntr y a n d r es p o nse t o data clarificati o ns will  pr ocee d d e pe n di n g o n a vaila bilit y 
of st u d y n urses, c o or di nat ors a n d i n vesti gat ors.  
•  De pe n di n g o n t he c o nt e nt of data clarificati o ns, t h e necessit y of s o urce d ata re vie w 
of t he res p o nse will be re-assesse d b y t he s p o ns or.  
•  Self -e vi de nt c orr ecti o ns of o b vi o us q uer y res p o nses mi g ht be all o we d. T hese will 
be  d oc u me nte d  t h or o u g hl y  (e. g.  usi n g  a  list  of  self -e vi de nt  c orrecti o ns  t o  be  
a p pr o ve d bef ore Data b as e L oc k).  
•  If a p plica ble, ris k-b ase d assess me nt of cl osi n g l o n g o pe n q ueries will b e d o ne 
c o nsi deri n g t heir i m pact o n trial c o ncl usi o n a n d d ata vali dit y. 
•  Assess me nt will be d o ne if data clarificati o ns a n d/ or e C R F pa ges are t o be si g ne d 
b y staff t hat is n ot yet o n t he dele gati o n l o g. T he d ele gati o n l o g is t o be u p date d, if 
a p plica ble.  
1 1. 4  M o nit ori n g  
T his st u d y will be m o nit ore d re g ularl y b y a q ualifie d m o nit or fr o m t he C R O acc or di n g t o 
G C P g ui deli nes a n d t he res pecti ve S O Ps. D uri n g t hese visits, t he m o nit or will pre pare t he 
st u d y site f or t he c o n d uct of t he st u d y, c h ec k f or s u bject eli gi bilit y, f or c o m pleti o n of t he 
e ntries i n t he s o urce data a n d o n t he  e C R Fs; f or c o m plia nce wit h t he cli nical st u d y pr ot oc ol, 
I C H-G C P pri nci ples, t he Declarati o n of Helsi n ki, a n d re g ulat or y a ut h orit y re q uire m e nts . 
M o nit ori n g will als o be ai me d at detecti n g a n y misc o n d uct or fra u d. 
I n  a d diti o n,  t he  m o nit or  will  c hec k  w het her  all  A Es  a n d  S A Es  ha ve  bee n  re p orte d  
a p pr o priatel y wit hi n t he ti me peri o ds re q uire d. 
T he i n vesti gat or a n d all staff will be e x pecte d t o c o o perate wit h t he m o nit or b y pr o vi di n g 
a n y missi n g i nf or mati o n w he ne ver p ossi ble. T he i n vesti gat or m ust be  a vaila ble t o a ns wer 
q uesti o ns arisi n g d uri n g re g ular m o nit ori n g visits. I n a d diti o n, t he i n vesti gat or is re q uire d 
t o: 
•  
Ha ve all data pr o perl y rec or de d i n t he  s o urce d oc u me ntati o n a n d t he e C R F pri or t o 
eac h m o nit ori n g visit. 
•  
Ha ve t he s o ur ce d o c u me ntati o n a vaila ble at t he m o nit ori n g visits.  
•  
Rec or d all I P(s) dis pe ns e d i n t he e C R F a n d t he dr u g i n ve nt or y rec or ds. 
All s u bjects w h o are scree ne d, b ut n ot i ncl u de d i n t he st u d y, will be liste d o n t he s u bject 
scree ni n g/e nr oll me nt  l o g. M o nit ori n g  will  b e  s yste matic,  pri oriti ze d,  a n d  ris k - base d. 
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M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 8 2  of 1 2 4  
F urt her det ails of m o nit ori n g  acti vities will be pr o vi de d i n t he m o nit ori n g ma n ual, w hic h 
descri bes t he pr oce d ures t o i de ntif y, e val uate, c o ntr ol, a n d re p ort ris ks t o critical pr ocesses 
a n d data o n a n o n g oi n g b asi s t hr o u g h o ut all sta ges of t he trial’s life-c ycle.  
I n cas e of a pa n d e mic disease o ut brea k, e. g. ne w C O VI D-1 9 p u blic healt h e mer ge nc y, a n d 
b y t his, if o n -site visits are n ot p ossi ble d ue t o site cl os ures, tra v el li mitati o ns, or ot her 
c o nsi derati o ns if site pers o n nel or trial s u bjects bec o me i nfecte d, t he f oll o wi n g miti gati o ns 
s h o ul d be c o nsi dere d a n d assesse d i n a n u p dat e d m o nit ori n g pla n: 
•  O n -site m o nit ori n g visits mi g ht be ca ncelle d a n d/ or t he peri o d bet wee n m o nit ori n g 
visits e xte n de d. W he n pla n ne d o n -site m o nit ori n g visits are n ot p ossi ble, t he reas o n 
s h o ul d be clearl y d oc u me nte d a n d ma de a vaila ble f or re vie w d uri n g a u dits a n d/ or 
i ns pecti o ns. 
•  P h o ne a n d/ or vi de o visits will be i m ple me nte d w he n feasi ble, c o nsi deri n g site 
cl os ures, re d u ce d staff a n d a n y ot her circ u msta nces.  
•  Re m ote m o nit ori n g or ce ntral m o nit ori n g c o ul d s u bstit ute o n -site m o nit ori n g, w he n 
tec h nicall y feasi ble.  
•  Pr ot oc ol de viati o ns will be trac k e d a n d d o c u me nt e d if de viati o ns occ urre d d ue t o 
t he p u blic healt h e mer g e nc y.  
C urre nt l ocal re g ulati o ns, i ncl u di n g data pri v ac y re g ulati o ns will be c o nsi dere d w h e n 
accessi n g s o urce d ata re m otel y.  
 
1 1. 5  A u diti n g  
A u dits will be perf or me d acc or di n g t o t h e c orres p o n di n g a u dit pr o gra m, w hi c h will i ncl u de 
t he p ossi bilit y t hat a me m ber of t he s p o ns or’s q u alit y ass ura nce f u n cti o n ma y arra n g e t o 
visit t he i n vesti gat or i n or der t o a u dit t he p erf or ma nce of t he st u d y at t he st u d y site, a n d  all 
st u d y d oc u me nts ori gi nati n g t here. A u dit ors will  c o n d uct t heir w or k i n de pe n de ntl y of t he 
cli nical st u d y a n d its perf or ma nce. A u dits ma y als o be p erf or me d b y c o ntract a u dit ors. I n 
t his case, t he s p o ns or’s q ualit y ass ura nce f u n cti o n will a gree wit h t he c o ntract a u dit or 
re gar di n g t he ti mi n g a n d e xte nt of t he a u dit(s). F or  a u dits at t he st u d y site, t he m o nit or will 
us uall y acc o m pa n y t he a u dit or(s).  
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M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 8 3  of 1 2 4  
1 2  S T A TI S TI C A L M E T H O D S  
T his  secti o n  descri bes  t he statistical  a nal yses  i nte n de d at  t he ti me of st u d y pla n ni n g. 
F urt her d etails o n t he statistical a n d a nal ytical as p ects will be prese nt e d i n t he S A P.  
A n y  de viati o ns  fr o m  pl a n ne d  a n al yses,  t he  reas o n(s) f or  s u c h  de viati o n(s),  a n d  all  
alter nati ve or a d diti o nal statistical a nal yses t hat ma y be perf or me d bef ore data bas e cl ose 
or u n bli n di n g, res pecti vel y, will be descri b e d i n a me n d me nts t o t he cli nical st u d y pr ot oc ol 
or t he S A P. All de viati o ns a n d/ o r alterati o ns will be s u m marize d i n t h e cli nical st u d y 
re p ort. 
I n case of a pa n de mic disease o ut brea k, e. g. ne w C O VI D-1 9 p u blic healt h e mer ge nc y, if 
o n- site visits are n ot p ossi ble d ue t o site cl os ures, tra vel li mitati o ns, or ot her c o nsi derati o ns 
if site pers o n nel or trial s u bjects bec o me i nfecte d, t he f oll o wi n g miti gati o ns s h o ul d be 
c o nsi dere d a n d assesse d i n a n u p date d statistical a nal ysis pla n: 
•  Descri be  c ha n g es  t o  pla n ne d  a n d  a d diti o nal  a nal yses  d ue  t o  t he  p u blic  healt h  
e mer ge n c y. T h or o u g hl y assess a m o u nt a n d patter ns of missi n g val ues a n d s o urces 
of bias s uc h as missi n g val ues a n d virt ual i nstea d of li ve assess me nts (if a p plica ble).  
•  I n cl u de s yste matic i de ntificati o n of pr ot oc ol d e viati o ns d ue t o t he p u blic healt h 
e mer ge n c y . 
•  C o nsi der t he nee d f or i n v ol ve me nt of a n i n de pe n d e nt Data M o nit ori n g C o m mittee 
partic ularl y if trial sa m pl e size c h a n ges are a ntici p ate d.  
1 2. 1  D et er mi n ati o n of s a m pl e si z e  
O verall, 3 6 0 s u bjects ar e pla n ne d  t o  be  ra n d o mi ze d  t o  t hree  treat me nt  gr o u ps  ( U F L, 
G F L & H F L  or Place b o)  wit h a ra n d o mizati o n rati o of 2: 1: 1 at baseli ne visit V 2 . 
T hese s a m ple sizes pr o vi de s uffici e nt p o wer als o t o assess efficac y u n d er c o nser vati ve 
ass u m pti o ns. F or pr o p orti o ns of 2 0 % L C L -res p o n ders i n Gr o u p U a n d 5 % i n Gr o u p P , a 
p o wer of 9 3 % is ac hie v e d f or o ne -si de d  Fis her’s  e xact  test  at  α =  2. 5 %. M ore o v er, if 
pr o p orti o ns of H F L- a n d G F L-res p o n ders of at least 4 0 % f or Gr o u p U a n d at m ost 5 % f or 
Gr o u p P are ass u me d , t he sa m ples sizes pr o vi de p o wer cl ose t o 1 0 0 %. 
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M 6 0 2 0 1 1 0 7 1  
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C O N FI D E N TI A L  
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I n  c o n cl usi o n,  w he n  ra n d o mizi n g  1 8 0 s u bjects  t o  Gr o u p U  a n d  9 0  s u bjects  eac h t o 
Gr o u ps G & H a n d P, t he st u d y will ha ve at least 9 0 % p o wer t o est a blis h effi cac y of N T  2 0 1 
usi n g a hierarc hical  pr oce d ure  f or  c o m paris o ns  of  pr o p orti o ns  of  G F L -,  H F L-, a n d 
L C L -res p o n ders bet wee n Gr o u ps U a n d P. Ass u mi n g t hat a b o ut 1 5 % of s u bjects will n ot 
c o m plete t he M P peri o d, t he pr o p ose d sa m ple size will res ult i n m ore t ha n 1 5 0  c o m plete d 
s u bjects i n Gr o u p U i n t his st u d y. T his n u m ber of c o m plete d patie nts i n t his st u d y is 
c o nsi dere d s uffi cie nt t o s u p p ort t he o verall safet y pr ofile of N T  2 0 1 f or si m ulta ne o us 
treat me nt of U F L. 
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Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 8 5  of 1 2 4  
1 2. 2  A n al y si s s et s  
T he f oll o wi n g a nal ysis sets will be defi ne d f or t he statistical a nal ysis of t his st u d y:  
S afet y e v al u ati o n s et ( S E S) 
T he S E S is t he s u bset of all s u bjects w h o were e x p ose d t o st u d y me dicati o n at least o nce. 
S u bjects  i n t he S E S a nal yses will be a nal y ze d as treate d.  
F ull a n al ysis s et ( FA S)  
T he F A S will c o nsist of all ra n d o mi ze d s u bjects.  S u bjects i n F A S  a n al yses  will be a nal y ze d 
as ra n d o mize d.  
Per p r ot o c ol set ( P P S) 
T he P P S is t he s u bset of s u bjects i n t he F A S wit h o ut maj or pr ot oc ol de viati o ns. Maj or 
pr ot oc ol de viati o ns will be defi ne d d uri n g t he bli n de d data re vie w meeti n g. 
1 2. 3  E n d p oi nt s a n d m ai n e sti m a n d s f or a n al y si s 
 
Effi c a c y e n d p oi nt s a n d m ai n effi c a c y e sti m a n d s  
1 2. 3. 1. 1   
Pri m ar y effi c a c y e n d p oi nt s a n d m ai n pri m ar y effi c a c y e sti m a n d s  
T he f oll o wi n g t hree e n d p oi nts will be use d f or pri mar y effi cac y a nal ysis d uri n g t he M P: 
•  
Pr o p orti o n of G F L- res p o n ders at Da y 3 0 
G F L -res p o nse is defi ne d as a sc ore of 0 ( n o) or 1 ( mil d) a n d at least t w o- gra de 
i m pr o ve me nt  fr o m  baseli ne  t o  Da y 3 0  of  M P  o n  M A S  f or  G F L  at  ma xi m u m  
c o ntracti o n as assesse d b y b ot h t he i n vesti gat or a n d t he s u bject. 
•  
Pr o p orti o n of H F L- res p o n ders at Da y 3 0 
H F L -res p o nse is defi ne d as a sc ore of 0 ( n o) or 1 ( mil d) a n d at least t w o- gra de 
i m pr o ve me nt  fr o m  baseli ne  t o  Da y 3 0  of  M P  o n  M A S  f or  H F L  at  ma xi m u m  
c o ntracti o n as assesse d b y b ot h t he i n vesti gat or a n d t he s u bject. 
•  
Pr o p orti o n of L C L- res p o n ders at Da y 3 0 
L C L -res p o nse is defi ne d as a sc ore of 0 ( n o) or 1 ( mil d) a n d at lea st t w o- gra de 
i m pr o ve me nt fr o m bas eli ne t o Da y 3 0 of M P o n M A S f or b ot h left a n d ri g ht L C L 
at ma xi m u m c o ntracti o n as assesse d b y b ot h t he i n vesti gat or a n d t he s u bject. 
Mai n esti ma n ds f or pri mar y efficac y e n d p oi nts (see 
 f or G F L, 
 f or H F L, 
 f or L C L) descri be t he treat me nt effects of i nterest f or t he t hree treat me nt areas. 
C CI
C CI
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 8 6  of 1 2 4  
F or  eac h  mai n  pri mar y esti ma n d,  t he  v aria ble  attri b ute  c orres p o n ds t o  t he  res pecti ve 
pri mar y e n d p oi nt. 
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 8 7  of 1 2 4  
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 8 8  of 1 2 4  
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 8 9  of 1 2 4  
1 2. 3. 1. 2  
S e c o n d ar y effi c a c y e n d p oi nt s a n d m ai n s e c o n d ar y effi c a c y 
e sti m a n d s  
Ke y sec o n d ar y efficac y e n d p oi nts: 
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or G F L at 
ma xi m u m c o ntracti o n as assesse d b y t he i n vesti gat or at Da y  3 0 of M P.  
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or H F L at 
ma xi m u m c o ntracti o n as assesse d b y t he i n vesti gat or at Da y  3 0 of M P.  
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or b ot h left a n d 
ri g ht L C L at ma xi m u m c o ntracti o n as ass esse d b y t he i n vestigat or at D a y  3 0 of M P.  
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or G F L at 
ma xi m u m c o ntracti o n as assesse d b y t he s u bject at Da y  3 0 of M P. 
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or H F L at 
ma xi m u m c o ntracti o n as assesse d b y t he s u bject at Da y  3 0 of M P. 
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or b ot h left a n d 
ri g ht L C L at ma xi m u m c o ntracti o n as assess e d b y t he s u bject at Da y 3 0 of M P. 
•  
G AI S as assess e d b y t he s u bject at Da y  3 0 of M P. 
Mai n esti ma n ds f or M A S -base d k e y sec o n dar y efficac y e n d p oi nts are  s pecifie d i n f ull 
detail i n 
. All  ke y sec o n d ar y esti ma n ds per treat me nt  area were deri ve d fr o m 
t he  res p ecti ve m ai n  pri mar y  esti ma n d  as  s p ecifie d  i n Secti o n  1 2. 3. 1. 1 .  Defi niti o ns  of 
attri b utes  treat me nt,  tar get p o p ulati o n,  ot her i nterc urre nt  e v e nts  a n d  p o p ulati o n  le vel  
s u m mar y are i de ntical . The varia ble attri b ute s of ke y sec o n dar y esti ma n ds were a da pt e d  
acc or di n g t o t he a b o v e- d efi ne d ke y sec o n dar y e n d p oi nt s f or t he res pecti ve treat me nt area 
base d o n t he i n vesti gat or/ s u bject assess me nt o n t he M A S at ma xi m u m c o ntracti o n. F or 
e xa m ple, t he v aria ble attri b utes of t he mai n  esti ma n ds f or t he t w o ke y s ec o n dar y efficac y 
e n d p oi nt s f or treat me nt area G F L are defi ne d as “ G F L res p o nse defi n e d as a sc ore of 0 ( n o) 
or 1 ( mil d) o n M A S f or G F L at ma xi m u m c o ntracti o n as assesse d b y t he i n vesti gat or at 
Da y 3 0”  a n d “ G F L res p o nse defi ne d as a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or G F L at 
ma xi m u m c o ntracti o n as assesse d b y t he s u bject at Da y 3 0”, res pecti vel y. 
T he mai n  esti ma n d f or t h e ke y s ec o n dar y e n d p oi nt  base d o n s u bject’s G AI S at Da y  3 0 of 
M P is prese nte d i n 
  
C CI
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 9 0  of 1 2 4  
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 9 1  of 1 2 4  
F u rt her s ec o n d ar y efficac y e n d p oi nts: 
•  
Pr o p orti o n of s u bjects wit h at least o ne -gra de i m pr o ve me nt fr o m baseli ne t o Da y  3 0 
of M P o n M A S f or G F L at ma xi m u m c o ntracti o n as assesse d b y t he i n v esti gat or. 
•  
Pr o p orti o n of s u bjects wit h at least o ne -gra de i m pr o ve me nt fr o m baseli ne t o Da y  3 0 
of M P o n M A S f or H F L at ma xi m u m c o ntracti o n as assesse d b y t he i n v esti gat or. 
•  
Pr o p orti o n of s u bjects wit h at least o ne -gra de i m pr o ve me nt fr o m baseli ne t o Da y  3 0 
of M P o n M A S f or b ot h left a n d ri g ht L C L at ma xi m u m c o ntracti o n as assesse d b y 
t he i n vesti gat or. 
•  
G AI S as assess e d b y t he i n vesti gat or at Da y  3 0 of M P. 
N o esti ma n ds are d efi ne d f or f urt her sec o n d ar y e n d p oi nts. 
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 9 2  of 1 2 4  
 
P h ar m a c o d y n a mi c e n d p oi nt s 
N ot a p plica ble.  
 
P h ar m a c o k i n eti c e n d p oi nt s 
N ot a p plica ble.  
 
P h ar m a c o g e n eti c e n d p oi nt s 
N ot a p plica ble.  
 
S af et y e n d p oi nt s 
1 2. 3. 5. 1  
Pri m ar y s af et y e n d p oi nt  
N o pri mar y saf et y e n d p oi nt has bee n defi n e d.  
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 9 3  of 1 2 4  
1 2. 3. 5. 2  
S e c o n d ar y s af et y e n d p oi nt s 
•  
I n ci de nce of r elate d T E A Es i n M P 
•  
I n ci de nce of r elate d T E A Es i n O L E X peri o d  
F or t he d efi niti o n of T E A Es, see Secti o n 1 0. 1 . 
1 2. 4  St ati sti c al a n al y si s m et h o d s  
 
Effi c a c y e n d p oi nt s a n d effi c a c y e sti m a n d s  
Pri mar y a n d se nsiti vit y a nal yses f or pri mar y efficac y e n d p oi nts  (see Secti o n  1 2. 4. 1. 1 ) will 
be base d o n t h e tar g et p o p ulati o n of t he t hree mai n pri mar y esti ma n ds as defi ne d  i n 
Secti o n  1 2. 3. 1. 1 . F urt h er  effi cac y a n al yses will be bas e d o n t h e F A S if n ot ot herwise 
s pecifie d.  Statistical  tests  will  be  t w o-si de d  h y p ot hesis  tests  f or  bet wee n treat me nt 
differe n ces i n ge n eral. A de q uate d escri pti ve statistics will be pr o vi d e d f or all e n d p oi nts. 
C o nti n u o us e n d p oi nt s ( val ues a n d c ha n g es fr o m baseli ne) will be s u m marize d b y n u m ber 
of s u bjects ( N) , mea n, sta n dar d de viati o n, me dia n, q uartiles, mi ni m u m, a n d ma xi m u m. F or 
q ualitati ve e n d p oi nt s, a bs ol ute a n d perce nt fre q u e ncies ( N, %) a n d, if a p plica ble, s hift 
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 9 4  of 1 2 4  
ta bles will be dis pla ye d. C o nfi de nce li mits a n d descri pti ve p-val ues will be gi ve n, w here 
a p pr o priate. 
1 2. 4. 1. 1  
Pri m ar y effi c a c y e n d p oi nt s a n d pri m ar y effi c a c y e sti m a n d s  
T he pri mar y e n d p oi nts will be pr o p orti o ns of G F L -, H F L- a n d L C L-res p o n ders as defi n e d 
i n S ecti o n 1 2.3. 1. 1 . T hese pr o p orti o ns will be c o m pare d f or treat me nt gr o u ps U a n d P ( as 
descri be d i n
 It s h o ul d be n ote d t hat Gr o u p G & H is n ot part of t he pri mar y efficac y 
a nal ysis w hic h has t he o bjecti ve t o c o m pare efficac y of si m ulta ne o us treat me nt of U F L  
wit h N T 2 0 1 vers us place b o. Gr o u p  G & H will be c o nsi dere d i n t he sec o n dar y a n d ot her 
a nal yses.  
T he t hree m ai n pri mar y efficac y esti ma n ds are defi ne d i n Secti o n  1 2. 3. 1. 1  (see 
 f or 
G F L, 
 f or H F L, a n d 
 f or L C L). 
Mai n esti mat ors f or mai n pri mar y esti ma n ds: P ri mary a nal ysis of pri mar y e n d p oi nts 
F or c o m p aris o n of pr o p orti o n of G F L -, H F L- a n d L C L-res p o n ders i n treat me nt gr o u ps U 
a n d P , Ma ntel -Hae ns zel strat u m wei g hts  a n d t he Sat o varia nce esti mat or will be use d  t o 
calc ulate t he str at u m -a dj uste d ris k differe n ce, wit h st u d y site ser vi n g as strat u m varia ble.  
F or eac h a nat o mical re gi o n , t he strat u m-a dj uste d (c o m m o n) differe n ce i n res p o nse rates 
bet wee n treat me nt Gr o u p U a n d Gr o u p P (refere nce) will be pr o vi de d wit h t w o-si de d 
p- val ue a n d 9 5 % M a ntel -Hae ns zel c o nfi de nce i nter val ( CI) . T he n ull h y p ot hesis of t he 
Ma ntel -Hae nszel test is t hat t he c o m m o n differe n ce i n res p o nse rates is zer o. T he fa mil y -
wise t w o-si de d t y pe I err or le vel α =  0. 0 5 will be c o ntr olle d b y a hiera rc hical test pr oce d ure 
base d o n t w o-si de d tests wit h α =  0. 0 5 as des cri be d i n Secti o n  1 2. 4. 7. 4 .  
C CI
C CI
C CI
C CI
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 9 5  of 1 2 4  
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 9 6  of 1 2 4  
1 2. 4. 1. 2  
S e c o n d ar y effi c a c y e n d p oi nt s a n d s e c o n d ar y effi c a c y e sti m a n d s  
Sec o n dar y efficac y e n d p oi nt s a n d esti ma n ds f or ke y sec o n dar y e n d p oi nts are descri be d i n 
Secti o n  1 2. 3. 1. 2 . Defi niti o ns  of M A S -bas e d k e y  sec o n d ar y esti ma n ds are pr o vi de d  i n 
 a n d of t h e s u bject’s G AI S-b ase d ke y sec o n dar y esti ma n d i n 
 N o 
esti ma n ds are defi ne d f or f urt her sec o n dar y e n d p oi nts. 
1 2. 4. 1. 2. 1  
K e y s e c o n d ar y effi c a c y e n d p oi nt s a n d  k e y s e c o n d ar y effi c a c y 
e sti m a n d s  
Mai n esti mat ors f or mai n k e y sec o n dar y dic h ot o m o us M A S -base d effi cac y esti ma n ds 
c orres p o n d t o mai n esti mat ors f or mai n pri mar y esti ma n ds (see Secti o n  1 2. 4. 1. 1 ). F or all 
t hree a nat o mical re gi o ns a n d f or i n vesti gat or’s as well as s u bject’s assess me nts o n t he 
M A S , strat u m-a dj uste d differe n ces i n pr o p orti o ns f or o verall c o m paris o ns of treat me nt 
gr o u p U v ers us P (ref ere nce) wit h c orres p o n di n g 9 5 % Ma ntel H ae ns zel  CIs a n d p -v al ues 
will be pr o vi de d.  
Mai n  esti mat or  f or  t he  mai n  ke y  sec o n d ar y  esti ma n d  base d  o n  s u bject’s  G AI S   
 
 will be a n al ysis of c o v aria n ce wit h fact ors treat me nt gr o u p a n d site, a n d m ea n of 
baseli ne M A S f or H F L, G F L, a n d L C L at m a xi m u m c o ntracti o n ass esse d b y s u bject as 
c o variate. M issi n g data o n su bject’s G AI S at Da y  3 0 will be ha n dle d f oll o wi n g t he sa me 
c o nser vati ve i m p utati o n strate g y as defi ne d f or missi n g M A S data at Da y  3 0 i n  t he mai n 
esti mat or of mai n pri mar y esti ma n ds (see Secti o n  1 2. 4. 1. 1 ).  
M ulti plicit y a dj ust me nt strate g y f or c o m paris o ns of treat me nt gr o u ps U a n d P o n ke y 
sec o n dar y e n d p oi nts is descri be d i n Secti o n 1 2. 7. 4. 7.  
S u p ple me ntar y a n al yses of ke y s ec o n d ar y e n d p oi nts f or all t hree re gi o ns will be perf or me d 
usi n g t he sa me met h o ds as descri be d f or s u p pl e me ntar y a nal yses of pri mar y e n d p oi nts o n 
t he F A S, t he P P S a n d o n o bser ve d cases i n F A S a n d P P S  (see Secti o n  1 2. 4. 1. 1 ).  
1 2. 4. 1. 2. 2  
F urt h er  s e c o n d ar y e n d p oi nt s  
S i milar a nal ysis strate g y b y re gi o n as descri be d f or s u p ple me ntar y a nal ysis of pri mar y 
e n d p oi nts o n o bser ve d cases i n F A S/ P P S  (see S ecti o n  1 2. 4. 1. 1 ) will be a p plie d f or t he 
C CI
C CI
C CI
C CI
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 9 7  of 1 2 4  
f urt her sec o n d ar y dic h ot o m o us M A S-base d efficac y e n d p oi nts  defi ne d f or t he M P . I n 
partic ular, pr o p orti o ns of s u bjec ts wit h at least o ne-p oi nt i m pr o ve me nt i n  treat me nt gr o u ps 
U  a n d  P  will  be  c o m pare d   b y strat u m-a dj uste d differe n ce s i n  pr o p orti o ns  wit h  
c orres p o n di n g 9 5 % Ma nt el Hae nszel CIs  a n d p-v al ues . M ore o ver, 9 5 % CIs f or pr o p orti o ns 
a n d u na dj uste d differe n ce i n pr o p orti o ns will be pr o vi de d.  
Gr o u p G & H will o nl y be c o nsi dere d f or statistical a nal yses of M A S of t he G F L a n d H F L 
re gi o ns b ut n ot of t he L C L re gi o n.  
G AI S as ass esse d b y t he i n vesti gat or at Da y  3 0 of t he M P will be a nal yze d usi n g a nal ysis 
of c o varia nce wit h f act ors treat me nt gr o u p a n d sit e, a n d mea n of baseli ne M A S f or H F L, 
G F L, a n d L C L at ma xi m u m c o ntracti o n assesse d b y i n vesti gat or as c o variate.  
Res ults f or a ll f urt her sec o n dar y e n d p oi nts will o nl y be i nter prete d d escripti vel y. 
F or f urt her s ec o n dar y e n d p oi nts o nl y o bser ve d cases will be a n al yze d. A n al yses will be 
pr o vi de d f or F A S a n d P P S. 
 
P h ar m a c o d y n a mi c e n d p oi nt s 
N ot a p plica ble.  
C CI
C CI


Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 9 8  of 1 2 4  
 
P h ar m a c o ki n eti c e n d p oi nt s 
N ot a p plica ble.  
 
P h ar m a c o g e n eti c e n d p oi nt s 
N ot a p plica ble.  
 
S af et y e n d p oi nt s 
All safet y a nal yses will be perf or m e d o n t he S E S. T he a nal ysis of safet y e n d p oi nt s will be 
base d o n o bser v e d cases  a n d o nl y T E A Es will be a nal y ze d. A Es will be c o de d acc or di n g 
t o t he Me d D R A versi o n i n effect at t he ti me t he data base is cl ose d.  O nl y T E A Es will be 
a nal yze d, w hi c h ar e defi ne d as A Es wit h o nset or w orse ni n g o n or aft er date of t he first 
a d mi nistrati o n of I P u p t o e n d of st u d y visit. 
1 2. 4. 5. 1  
Pri m ar y s af et y e n d p oi nt  
N o pri mar y saf et y e n d p oi nt has bee n defi n e d.  
1 2. 4. 5. 2  
S e c o n d ar y s af et y e n d p oi nt s 
Listi n gs a n d ta bles dis pla yi n g i nci de nces of relate d T E A Es i n M P a n d O L E X will be 
pr o vi de d b y s yste m or ga n class a n d preferre d ter m b y st u d y gr o u p a n d o v erall, f or t he t otal 
st u d y peri o d a n d b y treat me nt c ycle. F or t he a nal yses b y treat me nt c y cle, t h e de n o mi nat or 
f or t he i nci de n ces will be a dj uste d t o all s u bjects bei n g treate d i n t hat treat me nt c ycle. 
C CI
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 9 9  of 1 2 4  
S p e ci al st ati sti c al/ a n al yti c al i s s u e s  
1 2. 4. 7. 1  
Di s c o nti n u ati o n s a n d mi s si n g d at a  
Reas o ns  f or  pre m at ure  disc o nti n uati o n  of  st u d y  will  be  s u m mari ze d  descri pti vel y.  
Disc o nti n ue d s u bjects will n ot be re place d. 
1 2. 4. 7. 2  
I nt eri m a n al y s e s 
N ot pla n ne d. 
1 2. 4. 7. 3   
Co m mitt e e s 
C CI
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C CI
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 0 0  of 1 2 4  
1 2. 4. 7. 4  
M ulti pl e c o m p ari s o n s/ m ulti pli cit y  
T he fa mil y -wise t w o-si de d t y pe I err or le vel α =  0. 0 5 f or c o m paris o ns of treat me nt gr o u ps 
U a n d P o n t he pri mar y a n d ke y sec o n d ar y e n d p oi nts will be c o ntr olle d b y a hierarc hical 
test pr oce d ur e base d o n t w o-si de d tests wit h α =  0. 0 5.  
T he hier arc hical pr o ce d ure  f or pri mar y a nal ysis (Secti o n 1 2. 4. 1. 1 ) will be perf or me d as 
descri be d b el o w. First, usi n g t he Ma ntel -Hae ns zel test of t he n ull h y p ot hesis t hat t he 
c o m m o n differe n ce i n res p o nse rates at Da y 3 0 is zer o, Gr o u p U v ers us Gr o u p  P will be 
teste d f or s u peri orit y f or pr o p orti o n of G F L-res p o n ders,  sec o n d f or pr o p orti o n of H F L-
res p o n ders, a n d t hir d f or pr o p orti o n of L C L-res p o n ders. T he test pr oce d ure will st o p o nce 
statistical si g nifica nce c o ul d n ot be reac h e d. 
I n cas e statistical si g nifica nce ca n b e esta blis he d f or all t hree pri mar y efficac y e n d p oi nts, 
t he pr oce d ur e will pr ocee d t o ke y sec o n dar y e n d p oi nts (Secti o n 1 2. 4. 1. 2. 1 ): A s ne xt ste ps , 
Ma ntel -Hae nszel test s f or s u peri orit y of Gr o u p U vers us Gr o u p  P will  be c o n d ucte d f or 
pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S  at ma xi m u m c o ntracti o n 
as assesse d b y t he i nvesti g at or at Da y 3 0 f or GF L, t he n H F L a n d fi nall y L C L a nat o mical 
re gi o n. T hereafter, Ma nt el -Hae ns zel t ests f or s u p eri orit y of Gr o u p  U vers us Gr o u p  P will 
be c o n d ucte d f or pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S at 
ma xi m u m c o ntracti o n as assesse d b y t he s u bject at Da y 3 0 f or G F L, t he n H F L a n d fi nall y 
L C L  a nat o mical re gi o n.  
Fi nall y,  G AI S  as assesse d b y t he s u bject at Da y 3 0 of M P will be teste d  as descri be d i n 
Secti o n 1 2. 4. 1. 2. 1 .  
T he hierar c hical tes t pr oce d ure will st o p o nce statistical si g nifica nce c o ul d n ot be reac he d. 
F or a n y ot her statistical tests o n pri mar y or ke y s ec o n dar y e n d p oi nts (e. g. c o m paris o n of 
treat me nt gr o u ps G & F a n d P), n o t y pe I err or a dj ust me nt will be perf or m e d . The sa me 
acc o u nts f or a n y statistical a nal yses of f urt her s ec o n dar y a n d ot her e n d p oi nts. 
1 2. 4. 7. 5  
E x a mi n ati o n of s u b gr o u p s  
T he pri mar y a nal ysis of pri mar y e n d p oi nts will be c o n d ucte d f or t w o  s u b gr o u ps acc or di n g 
t o pre-tr eat me nt stat us. S u bjects will be disti n g uis he d o n w h ether t he y h a v e bee n treate d 
wit h B o N T A - pri or t o r a n d o mi zati o n at a n y ti me f or a n y treat me nt i n dicati o n or n ot 
(treat me nt naï ve). 
Dic h ot o mize d e n d p oi nts w hic h are bas e d o n M A S at rest will be a n al y ze d i n s u b gr o u ps of 
s u bjects wit h bas eli ne sc ore of at least 2 o n t he c orres p o n di n g M A S at rest  as assess e d b y 
b ot h s u bject a n d i n vesti gat or. Si nce s c ores at rest are i n ge neral l o w er t ha n sc ores at 
ma xi m u m c o ntracti o n, s o me s u bjects ma y h a ve a s c ore of 0 ( n o) or 1 ( mil d) at baseli ne o n 
M A S at r est. T hes e s u b gr o u p a nal yses will be m ore mea ni n gf ul a n d se nsiti ve t o treat me nt 
effects t ha n a nal yses of t he t otal F A S as t he y c o nsi der effects i n ‘s y m pt o matic’ s u bjects, 
i.e. s u bjects wit h 0 ( n o) or 1 ( mil d) o n c orres p o n di n g M A S will n ot be a nal yze d. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 0 1  of 1 2 4  
1 3  D A T A H A N D LI N G A N D R E C O R D K E E PI N G 
B y si g ni n g a n d dati n g t he e C R F, t he i n vesti gat or will c o nfir m t hat all i n vesti gati o ns ha ve 
bee n c o m plete d a n d c o n d ucte d i n c o m plia nce wit h t h is cli nical st u d y pr ot oc ol, a n d t hat 
relia ble a n d c o m plete dat a ha ve b ee n e nt ere d i nt o t he e C R F. 
1 3. 1  C orr e cti o n s t o d at a  
All data re q uire d b y t his cli nical st u d y pr ot oc ol are t o be rec or de d i n t he e C R F as s o o n as 
p ossi ble. H o we ver, direct e ntries are n ot all o we d; d ata m ust be tra nscri be d fr o m t he s o urce  
d oc u me ntati o n (e. g., s u bj ect file) t o t he e C R F. 
If c orrecti o ns are n ecessar y, a n a ut h orize d me m ber of t he i n vesti gat or’s site staff will e nter 
t he c orrect data i nt o t he we b-bas e d electr o nic C R F. T he a u dit trail i n t he electr o nic data 
ca pt ure s yste m will d oc u me nt all c ha n ges.  
If c orrecti o ns i n t he s u bject diar y or s u bject scales are n ecessar y, t h e s u bject will be 
i nstr ucte d t o ma ke a c orrecti o n b y dra wi n g o nl y a si n gle li ne t hr o u g h t he err or, lea vi n g t he 
i nc orrect e ntr y le gi ble. T he s u bject is t o date t he c orrecti o n a n d si g n it off . T he i n vesti gat or 
is n ot all o we d t o ma ke a n y c ha n ges t o t hese d o c u me nts. 
D ata base cl os i n g will occ ur o nl y after q ualit y ass ura nce pr oce d ures h a ve b ee n c o m plete d. 
1 3. 2  R e c or d k e e pi n g  
Esse ntial d oc u me nts s h o ul d be retai ne d u ntil at least t w o years afte r t he last a p pr o val of a 
mar keti n g a p plicati o n ( w het her p e n di n g or c o nte m plate d) i n a n I C H re gi o n, or at least t w o 
years h a ve ela pse d si n ce t he f or mal disc o nti n uati o n of I P cli nical d e vel o p me nt. T hese 
d oc u me nts are t o  be retai ne d f or a l o n ger peri o d, h o we ver, if re q uire d b y a p plica ble 
re g ulat or y r e q uire me nts or b y a gree me nt wit h t he s p o ns or. 
Esse ntial d oc u me nts at t he st u d y site i ncl u de (a m o n g ot her d oc u me nts): 
•  
S o urce d oc u me ntati o n (e. g. s u bject file ). 
•  
S u bject i de ntificati o n c o de list ( res p ecti ve t e m plate  pr o vi de d t o t he i n vesti gat or 
al o n g wit h t he I S F, at t h e be gi n ni n g of t he st u d y), w hic h i de ntifies t he s u bject b y 
n u m ber, na me, a n d d ate of birt h. 
•  
A si g ne d c o p y of t he fi nal cli nical st u d y pr ot oc ol a n d a n y a me n d me nt. 
•  
Dis ks (e. g. D V D/ C D, U S B) wit h P D F -files c o ntai ni n g s u bjects’ e C R F d ata a n d 
a u dit trail ( prefer a bl y pr o vi de d t o site d uri n g cl ose -o ut visit),  a n d a n y ass ociate d 
s u bject-relat e d s o urce dat a ( or, w here a p plica ble, a ut h orize d c o pies of s o urce data).  
•  
Si g ne d i nf or me d c o nse nt f or ms. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 0 2  of 1 2 4  
•  
C o pies of site i n vesti gat ors’ a n d c o- w or k ers' c urri c ula vitae.  
•  
C o pies of all direct c orres p o n de nce wit h t he I E C/I R B a n d wit h t he re g ulat or y 
a ut h orit y(ies). 
•  
C o pies of la b orat or y n or mal ra n ges a n d m et h o ds. 
•  
C o pies of st u d y s u p pl y recei pt f or ms a n d dr u g i n v e nt or y f or ms. 
•  
C o pies  of  all  c orres p o n de nce  b et wee n  t he  i n vesti gat or  a n d  t he  m o nit or,  a n d  
bet wee n t he i n v esti gat or a n d t he s p o ns or. 
•  
C o pies  of  safet y  i nf or mati o n  re p orte d  d uri n g  t he  st u d y  a n d  s u b mitte d  b y  t he  
s p o ns or. 
1 3. 3  D e str u cti o n of st u d y d o c u m e nt s  
St u d y d oc u me nts ma y n ot be destr o ye d b y st u d y site pers o n nel bef ore e n d of t he rete nti o n 
peri o d s pecifi e d a b o ve wit h o ut t he pri or writte n c o nse nt of t he s p o ns or. T h e PI  m ust i nf or m 
t he s p o ns or i n d ue ti me if t he PI lea ves t he i nstit uti o n d uri n g t he rete nti o n peri o d. T his r ule 
als o a p plies if t he i nstit uti o n cl oses wit hi n t he rete nti o n peri o d. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 0 3  of 1 2 4  
1 4  P U B LI C A TI O N P O LI C Y  
T he st u d y res ults will be p u blis he d i n t he p u blic d o mai n, a n d p u blis hi n g details will be 
gi ve n  i n  t he  cli nical  st u d y  a gree me nt.  P u blicati o ns  c o ncer ni n g  st u d y  res ults  m us t  be  
a p pr o ve d i n a d v a nce b y t he s p o ns or i n writi n g. 
T he r es ults of t his st u d y a n d a n y disc o veri es relat e d t o t his st u d y, re gar dl ess of w h et her 
t he y ha ve tec h nical or m e dical c h aracter, are t he pr o pert y of t he s p o ns or. 
T he s p o ns or e ns ur es t hat t he st u d y is re gistere d a n d st u d y res ults are discl ose d i n at least 
o ne  p u blic  cli nical  st u d y  re gistr y  (s uc h  as  cli nicaltrials. g o v),  i n  acc or da nce  wit h  
nati o nal/i nter nati o nal re g ulati o ns a n d ot her re q uire me nts. St u d y re gistrati o n ma y i ncl u de a 
list of t he st u d y sites, as a p plica ble.  
 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 0 4  of 1 2 4  
1 5  R E F E R E N C E S  
A merica n  S ociet y  of  Plastic  S ur ge o ns  2 0 1 8.  Plastic  S ur ger y  Statistics  Re p ort  2 0 1 8.  
A vaila ble  fr o m:  htt ps:// w w w. plastics ur ger y. or g/ d oc u me nts/ Ne ws/ Statistics/ 2 0 1 8/ plastic -
s ur ger y-statistics-f ull-r e p ort- 2 0 1 8. p df. Accesse d 2 8 -Ja n- 2 0 2 0. 
A ni d o J, Are nas D, Arr u a barr e na C, et al. Tail ore d b ot uli n u m t o xi n t y pe A i njecti o ns i n 
aest hetic me dici ne: c o ns e ns us pa nel rec o m me n d ati o ns f or treati n g t he f ore hea d bas e d o n 
i n di vi d ual facial a n at o m y a n d m uscle t o ne. Cli n C os met I n vesti g D er mat ol. 2 0 17; 1 0: 4 1 3-
4 2 1. 
Ar n o n S S, Sc hec hter R, I n gles b y T V, et al. B ot uli n u m t o xi n as a bi ol o gical wea p o n: 
Me dical a n d p u blic healt h ma na ge me nt. J A M A. 2 0 0 1; 2 8 5( 8): 1 0 5 9- 1 0 7 0. 
Blitzer A, Bi n der WJ, A vi v J E, et al. T he ma na ge me nt of h y perf u ncti o nal facial li nes wit h 
b o t uli n u m  t o xi n.  A  c olla b orati ve  st u d y  of  2 1 0  i njecti o n  sites  i n  1 6 2  patie nts.  Arc h  
Ot olar y n g ol Hea d Nec k S ur g . 1 9 9 7; 1 2 3( 4): 3 8 9- 3 9 2. 
B ot o x ( o na b ot uli n u mt o xi n A) Hi g hli g hts of Prescri bi n g I nf or m ati o n. Re vise d O ct  2 0 1 9. 
A vaila ble at: htt ps:// w w w.aller ga n. c o m/ pr o d ucts/ b ot o x- c ns. Accesse d 1 1 - Dec- 2 0 1 9. 
B ur ge n A S V, Dic ke ns F, Zat ma n LJ. T he acti o n of b ot uli n u m t o xi n o n t he ne ur o m usc ular 
j u ncti o n. J P h ysi ol. 1 9 4 9; 1 0 9: 1 0- 2 4. 
Carr ut hers A, Carr ut hers J, Sai d S. D ose -ra n gi n g st u d y of b ot uli n u m t o xi n t y pe A i n t he 
treat me nt of gla b ellar r h yti ds i n fe males. Der mat ol S ur g. 2 0 0 5; 3 1( 4): 4 1 4-2 2; disc ussi o n 
4 2 2. 
Carr ut hers A, Carr ut hers J. Patie nt -re p orte d o utc o mes wit h b ot uli n u m ne ur ot o xi n t y pe A. 
J C os met Laser T her. 2 0 0 7; 9 S u p pl 1: 3 2- 3 7. 
Carr ut hers A, Carr ut hers J. A si n gle- ce nter, d ose -c o m paris o n, pil ot st u d y of b ot uli n u m 
ne ur ot o xi n t y pe A i n fe male patie nts wit h u p per faci al r h yti ds: safet y a n d efficac y. J A m 
Aca d D er mat ol. 2 0 0 9a; 6 0( 6): 9 7 2- 9 7 9. 
Carr ut hers  A,  Carr ut hers  J.  A  si n gle -ce nter  d ose-c o m paris o n  st u d y  of  b ot uli n u m 
ne ur ot o xi n t y pe A i n fe males wit h u p per faci al r h yti ds: assessi n g patie nts' perce pti o n of 
treat me nt o utc o mes. J Dr u gs Der mat ol. 2 0 0 9 b; 8( 1 0): 9 2 4- 9 2 9. 
Carr ut hers A, Carr ut hers J, C ole ma n W P, 3r d, et al. M ultice nter, ra n d o mize d, p hase III 
st u d y of a si n gle d os e of i nc o b ot uli n u mt o xi n A, free fr o m c o m ple xi n g pr otei ns, i n t he 
treat me nt of gla bellar fr o w n li nes. Der mat ol S ur g. 2 0 1 3; 3 9( 4): 5 5 1- 8. 
Carr ut hers  J,  Fa gie n  S,  Matarass o  S L.  C o nse ns us  rec o m me n d ati o ns  o n  t he  use  of  
b ot uli n u m t o xi n t y pe A i n facial a est hetics. Plast Rec o nstr S ur g . 2 0 0 4; 1 1 4( 6): 1- 2 2. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 0 5  of 1 2 4  
Carr ut hers A, Kie n e K, Carr ut hers J. B ot uli n u m A e x ot o xi n use i n cli nical der mat ol o g y. J 
A m Aca d D er mat ol. 1 9 9 6; 3 4( 5 Pt 1): 7 8 8- 7 9 7. 
Cat her J C, Me nter A. U p date o n b ot uli n u m t o xi n f or faci al aest h etics. Der m at ol Cli n. 
2 0 0 2; 2 0( 4): 7 4 9- 7 6 1. 
C hert o w  D S,  Ta n  E T,  Masla n ka  S E,  et  al.  B ot ulis m  i n  4  a d ults  f oll o wi n g  c os metic  
i njecti o ns  wit h  a n  u nli ce nse d,  hi g hl y  c o nce ntrate d  b ot uli n u m  pre parati o n.  J A M A. 
2 0 0 6; 2 9 6( 2 0): 2 4 7 6- 2 4 7 9. 
De B o ulle K, Wersc hler W P, G ol d M H, et al . P hase 3 St u d y of O na b ot uli n u mt o xi n A 
Distri b ute d  Bet wee n  Fr o ntalis,  Gla bellar  C o m ple x,  a n d  Lateral  Ca nt hal  Areas  f or  
Treat me nt of U p p er Facial Li nes.  Der mat ol o gic S ur ger y. 2 0 1 8; 4 4( 1 1): 1 4 3 7- 1 4 4 8.  
Fl y n n T C, Carr ut hers A, Carr ut hers J, et al. Vali date d a ssess me nt scal es f or t he u p per face. 
Der mat ol S ur g. 2 0 1 2; 3 8( 2 S pec N o.): 3 0 9- 1 9. 
H ui JI, Lee W W. Efficac y of fr es h vers us refri gerate d b ot uli n u m t o xi n i n t he treat me nt of 
lateral peri or bital r h yti ds. O p ht hal Plast Rec o nstr S ur g. 2 0 0 7; 2 3( 6): 4 3 3- 4 3 8. 
I m h of M, K u h ne U. I ntr o d ucti o n of t he Micr o dr o plet Tec h ni q ue wit h I nc o b ot uli n u mt o xi n 
A f or t he Tr eat me nt of Cr o w's Feet. J Cli n Aest het Der mat ol. 2 0 1 3; 6( 7): 4 0 – 4 4. 
J o nes, D. C o m me ntar y: Are Aest hetic Gra di n g Scales o nl y a Researc h T o ol?. Der mat ol 
S ur g. 2 0 1 0; 3 6: 1 8 1 7- 1 8 1 8 
J ost W H, Bl ü mel J, Gr af e S. B ot uli n u m Ne ur ot o xi n T y pe A Free of C o m ple xi n g Pr otei ns 
( X E O MI N ®) i n F ocal D yst o nia. Dr u gs. 2 0 0 7; 6 7( 5): 6 6 9- 6 8 3. 
Kee n M, Blitzer A, A vi v J E, et al. B ot uli n u m t o xi n A f or h y per ki n etic facial li nes: res ults 
of a d o u ble- bli n d, place b o -c o ntr olle d st u d y. Plast Rec o nstr S ur g. 1 9 9 4; 9 4( 1): 9 4- 9 9. 
Kersc h er M, Rza n y B, Pr a ger W, T ur n b ull C, Tre vi dic P, I n glefiel d C. Efficac y a n d safet y 
of i nc o b ot uli n u mt o xi na i n t he treat me nt of u p per facial li nes: res ults fr o m a ra n d o mize d, 
d o u ble- bli n d, place b o- c o ntr olle d, P hase III st u d y. Der mat ol S ur g. 2 0 1 5; 4 1( 1 0): 1 1 4 9- 5 7. 
Ki m H S, H wa n g J H, J e o n g S T, et al. Effect of m uscle acti vit y a n d b ot uli n u m t o xi n dil uti o n 
v ol u me o n m uscle paral ysis. De v Me d C hil d Ne ur ol. 2 0 0 3 Mar; 4 5( 3): 2 0 0- 6. 
Le v y J L, Ser va nt JJ, J o u ve E. B ot uli n u m t o xi n A: a 9 -m o nt h cli nical a n d 3 D i n vi v o 
pr ofil o metric cr o w's feet wri n kle f or mati o n st u d y. J C os met Laser T her. 2 0 0 4; 6( 1): 1 6- 2 0. 
L ore nc Z P, S mit h S, Nest or M, et al. U n dersta n di n g t he f u ncti o nal a nat o m y of t he fr o ntalis 
a nd gla bellar c o m ple x f or o pti mal aest hetic b ot uli n u m t o xi n t y pe A t hera p y. Aest hetic Plast 
S ur g. 2 0 1 3; 3 7( 5): 9 7 5- 8 3.  
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 0 6  of 1 2 4  
L o we NJ, Asc h er B, Hec k ma n n M, et al. D o u ble -bli n d, ra n d o mize d, place b o -c o ntr olle d, 
d ose- res p o ns e st u d y of t he saf et y a n d efficac y of b ot uli n u m t o xi n t y pe A i n s u bjects wit h 
cr o w's f eet. Der mat ol S ur g. 2 0 0 5; 3 1( 3): 2 5 7- 2 6 2. 
L o we NJ, S ha h A, L o we P L, et al. D osi n g, efficac y a n d safet y pl us t he use of c o m p uterize d 
p h ot o gra p h y f or b ot uli n u m t o xi ns t y pe A f or u p per facial li nes. J C os met Laser T her . 
2 0 1 0; 1 2( 2): 1 0 6- 1 1 1. 
Marc hi ni C. I ntra nas al ne osti g mi ne t hera p y of b ot uli n u m t o xi n ( B T X) treat me nt d ys p ha gia 
[letter]. Cli n Ne ur o p h ar mac ol. 1 9 9 7; 2 0( 3): 2 7 9- 2 8 0. 
Matarass o S L, Matarass o A. Treat me nt g ui deli nes f or b ot uli n u m t o xi n t y pe A f or t he 
peri oc ular re gi o n a n d a r e p ort o n partial u p per li p pt osis f oll o wi n g i njecti o ns t o t he lateral 
ca nt hal r h yti ds. Plast Rec o nstr S ur g. 2 0 0 1; 1 0 8( 1): 2 0 8- 1 4; disc ussi o n 2 1 5- 7. 
Merz P har ma ce uticals G m b H. I n vesti gat or´s br oc h ure N T  2 0 1 ( Cl ostri di u m B ot uli n u m 
Ne ur ot o xi n T y pe A  ( 1 5 0 k D), free fr o m c o m ple xi n g pr otei ns (i nc o b ot uli n u mt o xi nt y pe A). 
E diti o n: X VIII . 
Nest or M S, A bl o n G R. D urati o n of acti o n of a b o b ot uli n u mt o xi na a n d o na b ot uli n u mt o xi na: 
a r a n d o mize d, d o u bl e -bli n d st u d y usi n g a c o ntralateral fr o ntalis m o del. J Cli n Aest het 
Der mat ol. 2 0 1 1; 4( 9): 4 3 – 4 9. 
Nettar K D, Y u K C Y, Ba p na S, et al. A n i nter nall y c o ntr olle d, d o u ble-bli n d c o m paris o n of 
t he  efficac y  of  o na b ot uli n u mt o xi na  a n d  a b o b ot uli n u mt o xi na.  Arc h  Facial  Plast  S ur g.  
2 0 1 1; 1 3( 6): 3 8 0 – 3 8 6. 
Ols o n JJ. Bala nce d b ot o x c he m o de ner vati o n of t he u p per face: s y m metr y i n m oti o n. Se mi n 
Plast S ur g . 2 0 0 7; 2 1( 1): 4 7- 5 3. 
Pai 2 0 1 6. C o m plicati o ns i n C os metic Der mat ol o g y: Crafti n g C ures b y Ga nes h S, pa ge 1 1 9; 
Ja y pee Br ot hers Me dical P u blis hers ( p) Lt d  
Pra ger W, Bee E K, Ha v er ma n n I, et  al. O nset, l o n ge vit y, a n d patie nt satisfacti o n wit h 
i nc o b ot uli n u mt o xi n A f or t he treat me nt of gla bellar fr o w n li nes: a si n gle-ar m, pr os pecti ve 
cli nical st u d y. Cli n I nter v A gi n g. 2 0 1 3; 8: 4 4 9- 5 6. 
Pra ger W, Wiss m üller E, K oll h orst B, et al. C o m paris o n of t w o b ot uli n u m t o xi n t y pe A 
pre par ati o ns f or tr eati n g cr o w's feet: a s plit -face, d o u ble-bli n d, pr o of -of -c o nce pt st u d y. 
Der mat ol S ur g. 2 0 1 0; 3 6 S u p pl 4: 2 1 5 5- 6 0. 
Ta m b uric S, Gra nt -R oss P, La be dz ka M, et al. E x pl ori n g t he effects of n o n-me dical vers us 
me dical a p pr oa c h es t o t h e ma na g e me nt of s ki n a gi n g i n w o me n o v er si xt y. I nt J C os met 
Sci. 2 0 1 2; 3 4( 5): 4 8 1- 8. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 0 7  of 1 2 4  
Tre vi dic P, C o n oll y S, Bi wer B, et al. I nc o b ot uli n u mt o xi n A is a n effecti ve a n d well -
t olerate d treat me nt f or u p per facial li nes: res ults fr o m a n o pe n-la b el e xte nsio n peri o d of a 
P hase III st u d y. D er mat ol S ur ger y. 2 0 1 7; 4 3: S 2 8 5- S 2 9 2. 
Xe o mi n  Hi g hli g hts  of  Prescri bi n g  I nf or mati o n.  Re vise d  Ma y  2 0 1 9.  A vaila ble  at:  
w w w. xe o mi n.c o m. Accesse d 0 9- D ec- 2 0 1 9. 
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Merz P har mace uticals G m b H  
Q- 0 0 0 7 5/ E N - C LI NI C A L S T U D Y P R O T O C O L  
M 6 0 2 0 1 1 0 7 1  
Versi o n 4. 0  Fi nal  (1 4 -J U N-2 0 2 1)  
C O N FI D E N TI A L  
Pa ge 1 0 8  of 1 2 4  
1 6   A P P E N DI C E S 
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SAP_001.pdf: 


Mer z P h ar m a ce uticals G m b H  
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
Pa ge 2  of 9 2  
SI G N A T U R E P A G E  
I c o nfir m t hat t his St atistic al A nal ysis Pla n acc uratel y descri bes t he pla n ne d st atistic al a nal ys es t o 
t he best of m y k n o wle d ge a n d was fi naliz e d bef ore brea ki n g t he bli n d. 
 
A ut h or ( pri nt n a me) , 
 
Date ( d d -m m m -y y y y)  
Si g n at ur e  
 
Bi ost atisti ci a n Mer z ( pri nt na me)  
 
Date ( d d -m m m -y y y y)  
Si g n at ur e  
 
Me di cal E x pert Merz ( pri nt na me)  
Date ( d d -m m m -y y y y)  
Si g n at ur e  
P P D
P P D
P P D
P P D
P P D


Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 3  of 9 2  
 
T a bl e of C o nt e nt s  
SI G N A T U R E P A G E .............................................................................................................. 2  
List of A b bre viati o ns  .................................................................................................................. 5  
1  
Ge neral a n d T ec h nic al As p ects  ............................................................................................ 6  
2  
Cli nical Trial Desi g n a n d O bje cti ves  .................................................................................... 6  
3  
Det er mi nati o n of Sa m ple Size .............................................................................................. 7  
4  
A nal ysis Sets  ....................................................................................................................... 7  
5  
E n d p oi nts a n d M ai n Esti ma n ds f or A nal ysis  ........................................................................ 8  
5. 1  
Efficac y E n d p oi nts a n d Mai n Effic ac y Esti ma n ds  ......................................................... 8  
5. 1. 1  Pri mar y Effic ac y E n d p oi nts a n d Mai n Pri mar y Efficac y Esti ma n ds ........................ 8  
5. 1. 2  Sec o n dar y Effic ac y E n d p oi nts a n d Mai n Sec o n d ar y Effic ac y Esti ma n ds  .............. 1 2  
5. 2  
Safet y E n d p oi nts/ Varia bles  ......................................................................................... 1 5  
5. 2. 1  Pri mar y Safet y E n d p oi nt  ...................................................................................... 1 5  
5. 2. 2  Sec o n dar y Safet y E n d p oi nts  ................................................................................. 1 5  
6  
St atis tical A nal ysis Met h o ds .............................................................................................. 1 8  
6. 1  
Efficac y E n d p oi nts a n d Effic ac y Esti ma n ds  ................................................................ 1 8  
6. 1. 1  Pri mar y Effic ac y E n d p oi nts a n d Esti ma n ds  .......................................................... 1 8  
6. 1. 2  Sec o n dar y Effic ac y E n d p oi nts a n d Esti ma n ds  ...................................................... 2 2  
6. 2  
Safet y E n d p oi nts  ......................................................................................................... 2 7  
6. 2. 1  Pri mar y Safet y E n d p oi nts  ..................................................................................... 2 9  
6. 2. 2  Sec o n dar y Safet y E n d p oi nts  ................................................................................. 3 0  
6. 4  
S pecial St atistical/ A nal ytical Iss ues  ............................................................................ 3 3  
6. 4. 1  Dis c o nti n u ati o ns a n d Missi n g Dat a  ...................................................................... 3 3  
6. 4. 2  I nt eri m A nal yses .................................................................................................. 3 5  
6. 4. 3  M ulti ple C o m paris o ns/ M ulti plicit y  ...................................................................... 3 5  
6. 4. 4  E xa mi nati o n of S u b gr o u ps  ................................................................................... 3 5  
6. 4. 5  P o oli n g of Sit es  .................................................................................................... 3 6  
6. 4. 6  I nt erc urre nt E ve nts ............................................................................................... 3 6  
8  
Refere nc es  ......................................................................................................................... 3 9  
9  
A p pe n dic es  ........................................................................................................................ 4 0  
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 4  of 9 2  
 
 
 
 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 5  of 9 2  
 
Li st of A b br e vi ati o n s  
A Da M  
A nal ysis Dat a M o del  
A E SI  
A d vers e E ve nt of S pecial I nt erest  
A T C  
A nat o mical T hera pe utic C he mic al classificati o n  
B MI  
B o d y mass i n de x  
B o N T  
B ot uli n u m ne ur ot o xi n  
B P  
Bl o o d press ure  
CI  
C o nfi de nce i nt er val  
C S P  
Cli nical St u d y Pr ot o c ol  
C S R  
Cli nical St u d y Re p ort  
e C R F  
electr o nic Case Re p ort F or m  
C R O  
C o ntract Researc h Or ga niz ati o n  
F A S  
F ull A nal ysis S et 
G F L  
Gla bellar fr o w n li nes  
H F L  
H oriz o nt al f ore hea d li nes  
H R  
Heart rat e  
I C E 
I nt erc urre nt e ve nt 
I P  
I n vesti gati o nal pr o d uct 
I R P 
I n de pe n de nt rat er pa nel 
K M  
Ka pla n -M eier  
L C L  
Lat eral ca nt hal li nes  
L S  
Least s q uares  
M A S  
Merz Aest hetic Scales  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M N A R  
Missi n g n ot at ra n d o m  
M P  
Mai n peri o d  
n  
Val ues a nal yze d  
n i m p  
n u m ber of i m p ut e d val ues  
N T 2 0 1  
Cl ostri di u m b ot uli n u m ne ur ot o xi n t y pe A ( 1 5 0 K D, free of c o m ple xi n g pr ot ei ns) 
p o w der f or s ol uti o n f or i nje cti o n  
O L E X  
O pe n -la bel e xt e nsi o n  
P P S  
Per P r ot o c ol S et 
P T  
Preferre d t er m  
S A P  
St atistical A nal ysis Pla n  
S A S  
St atistical A nal ysis S yst e m ®  
S D T M  
St u d y Dat a T a b ulati o n M o del  
S E S  
Safet y E val uati o n S et 
S O C  
S yst e m or ga n class  
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt  
T E A E SI  
Treat me nt -e mer ge nt a d verse e ve nt of s pecial i n t er est 
T E S A E  
Treat me nt -e mer ge nt seri o us a d verse e ve nt  
T F L  
T a ble, Fi g ures, a n d Listi n gs  
T ot al N T  2 0 1  Gr o u p  U a n d Gr o u p  G & H  p o ole d  
U  
U nit  
U F L  
U p per facial li nes  
W H O  
W orl d Healt h Or ga nizati o n  
 
 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 6  of 9 2  
 
1  G e n er al a n d T e c h ni c al A s p e ct s  
T he o bjecti ve of t his st atistic al a nal ysis pla n ( S A P) is t o s pecif y t he st atistical a nal ys es wit h 
a p pr o priat e det ail a n d precisi o n t o ser ve as a g ui d eli ne f or st atistical pr o gra m mi n g a n d creati o n of 
t a bles, fi g ures, a n d listi n gs f or cli nic al st u d y pr ot o c ol  ( C S P) M 6 0 2 0 1 1 0 7 1 ( versi o n 4. 0) , dat e d 
1 4J u n 2 0 2 1 . 
All pr o gra ms will be writt e n usi n g S A S versi o n 9. 4 or hi g her. A preferre d f o nt size of 1 0  p oi nts, 
mi ni m u m f o nt size of 9  p oi nts wit h a u ni q ue f o nt size f or t he w h ole d o c u me nt re q uire d will be 
use d f or t he t a bles a n d fi g ures i n Secti o n 1 4. F or listi n gs, a st a n dar d f o nt siz e of 9 p oi nts will be 
use d t o pr o d uce t he o ut p ut i n A 4 f or mat. I n di vi d u al S A S pr o gra ms will be writt e n f or all t a bles, 
fi g ures, a n d listi n gs. All o ut p uts will be tra nsferre d i nt o P D F files. T hese P D F files will be 
ge nerat e d as nee de d t o p o p ulat e t he s u bs ecti o ns of Secti o n  1 4 a n d Secti o n 1 6. 2 of t he cli nical st u d y 
re p ort ( C S R). E ac h o ut p ut file will i ncl u de t he c orres p o n di n g t a ble of c o nt e nts, prece di n g t he 
c o nt e nt of t he file.  
T he Merz st a n da r d T a ble, Fi g ures, a n d Listi n gs ( T F Ls) f or dr u gs, versi o n 7 . 0 will be a p plie d a n d 
a da pt e d t o trial s pecific re q uire me nts as lai d d o w n i n C S P M 6 0 2 0 1 1 0 7 1 ( versi o n 4. 0) . T hese m o c k 
T F Ls will s er ve as st u d y-s p ecific o ut p ut s pecific ati o ns f or st atistical pr o gra m mi n g  of T F Ls . T F L 
hea d ers are list e d i n 
  
S pecial att e nti o n will be pai d t o pla n ni n g a n d perf or ma nce of q ualit y c o ntr ol meas ures. Ris k sc ores 
base d o n assess me nts of c o m ple xit y a n d i m pa ct of err ors a n d q ualit y c o ntr ol meas ures f or 
st atistical pr o gra m mi n g (i ncl u di n g T F Ls, S D T Ms, a n d A Da Ms) will be d o c u me nt e d i n t he q ualit y 
c o ntr ol pla n s f or S D T Ms, A Da Ms, a n d T F Ls .  
2  Cli ni c al Tri al  D e si g n a n d O bj e cti v e s  
T his is a pr os pecti ve, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, m ultice nt er st u d y wit h  a 
place b o -c o ntr olle d mai n peri o d ( M P ) wit h o ne N T  2 0 1 i njecti o n c ycle f oll o we d b y a n o pe n -la bel 
e xt e nsi o n ( O L E X) peri o d wit h t w o N T  2 0 1 i njecti o n c ycles.  
I n t he M P ( C ycle 1), a t ot al of 3 6 0  s u bjects will be ra n d o mize d t o t hree differ e nt treat me nt gr o u ps: 
u p per facial li nes ( U F L ) treat me nt ( Gr o u p U), gla bellar fr o w n li nes ( G F L ) a n d h oriz o nt al f ore hea d 
li nes (H F L ) tr eat me nt ( Gr o u p G & H), a n d place b o ( Gr o u p  P) i n a ra n d o mizati o n rati o of 2: 1: 1. 
D uri n g t he M P, s u bjects will be treat e d eit her wit h a t ot al d ose of  6 4  U N T  2 0 1 as si m ult a ne o us 
i njecti o ns i n all t hree facial areas ( Gr o u p U), wit h a t ot al d ose of 4 0  U N T  2 0 1 i n t he G F L a n d H F L 
area a n d place b o i n t he lat eral ca nt hal li nes ( L C L ) area ( Gr o u p G & H), or wit h plac e b o i n all t hre e 
facial areas ( Gr o u p P). All ra n d o miz e d s u bjects will t he n be f oll o we d u p f or 1 2 0  da ys bef ore t he y 
ma y e nt er t he O L E X peri o d. T he d urati o n of t he M P ( C ycle  1) will t h us be 1 2 0  da ys pl us t he 
d urati o n of i n di vi d ual scree ni n g ( u p t o 1 4 da ys).  
T he O L E X peri o d will c o m prise t w o a d diti o nal tr eat me nt c ycles, C ycle  2 a n d C ycle  3 wit h 
d urati o ns of 1 2 0  da ys eac h pl us u p t o 3 0 da ys f or eli gi bilit y reassess me nts per c ycle. D uri n g eac h 
c ycle, eli gi ble s u bjects will recei ve si m ult a ne o us i njecti o ns of N T 2 0 1 at a t ot al d ose of 6 4  U i n all 
t hree facial areas. Eli gi bilit y crit eria will be e val uat e d bef ore rei nje cti o n. 
T he pri mar y o bjecti ve of t his st u d y is t o assess t he efficac y of si m ult a ne o us i ntra m us c ular 
i njecti o ns of N T 2 0 1  i n s u bje cts wit h m o derat e t o se vere U F L i n c o m paris o n t o plac e b o. 
T he sec o n dar y o bje cti ves are t o assess efficac y a n d safet y of si m ult a ne o us si n gle a n d re peat -d ose 
i ntra m usc ular i nje cti o ns of N T 2 0 1 i n s u bjects wit h m o derat e t o se vere U F L.  
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 7  of 9 2  
 
3  D et er mi n ati o n o f S a m pl e Si z e 
O verall, 3 6 0  s u bjects are pla n ne d t o be ra n d o mize d t o t hree treat me nt gr o u ps ( U F L, G F L & H F L or 
Place b o) wit h a ra n d o mizati o n of 2: 1: 1 at baseli ne visit V 2.  
T he F D A re q uire d t hat t he cli nical de vel o p me nt pr o gra m i ncl u des at least 3 0 0  c o m plet e d s u bjects 
w h o are treat e d si m ult a ne o usl y i n all t hree a nat o mical areas ( G F L, H F L, L C L) u n der pla ce b o -
c o ntr olle d c o n diti o ns t o s u p p ort safet y. Si nc e t w o  pi v ot al st u dies are pla n ne d f or de m o nstrati o n of 
N T 2 0 1 efficac y a n d safet y i n t he c o m bi ne d G F L, H F L a n d L C L treat me nt a n d ass u mi n g t hat u p 
t o 1 5 % of t he s u bjects will n ot c o m plet e t he st u d y, 1 8 0 s u bjects will be ra n d o mize d per st u d y t o 
be treat e d i n all t hree  a nat o mic al areas ( Gr o u p  U). A ra n d o mizati o n rati o of 2: 1: 1 f or t he treat me nt 
gr o u ps i n t his st u d y re s ults i n 9 0 s u bjects f or Gr o u ps G & H a n d P res pecti vel y.  
T hese sa m ple sizes pr o vi de s ufficie nt p o wer als o t o assess effic ac y u n der c o nser vati ve 
ass u m pti o ns. F or pr o p orti o ns of 2 0 % L C L -res p o n ders i n Gr o u p U a n d 5 % i n Gr o u p  P, a p o wer of 
9 3 % is ac hie ve d f or o ne -si d e d Fis her’s e xact t est at α =  2. 5 %. M ore o ver, if pr o p orti o ns of H F L - 
a n d G F L-res p o n d ers of at least 4 0 % f or Gr o u p U a n d at m ost 5 % f or Gr o u p  P are ass u me d, t he 
sa m ples sizes pr o vi de p o wer cl ose t o 1 0 0 %. 
I n c o ncl usi o n, w he n ra n d o mizi n g 1 8 0 s u bje cts t o Gr o u p  U a n d 9 0  s u bjects eac h t o Gr o u ps G & H 
a n d P, t he st u d y will ha ve at le ast 9 0 % p o wer t o est a blis h efficac y of N T  2 0 1 usi n g a hierarc hical 
pr o ce d ure f or c o m paris o ns of pr o p orti o ns of G F L -, H F L-, a n d L C L-res p o n ders bet wee n Gr o u ps U 
a n d P. Ass u mi n g t hat a b o ut 1 5 % of s u bje cts will n ot c o m plet e t he M P peri o d, t he pr o p ose d sa m ple 
size will res ult i n m ore t ha n 1 5 0 c o m plet e d s u bje cts i n Gr o u p  U i n t his st u d y. T his n u m ber of 
c o m plet e d patie nts i n t his st u d y is c o nsi dere d s ufficie nt t o s u p p ort t he o verall safet y  pr ofile of 
N T  2 0 1 f or si m ult a ne o us tr eat me nt of U F L.  
4  A n al y si s S et s  
T he  f oll o wi n g a nal ysis sets are defi ne d f or t he st atistic al  a nal ysis of t his st u d y: 
S af et y E v al u ati o n S et ( S E S)  
T he S E S is t he s u bset of all s u bjects w h o were e x p ose d t o st u d y me dicati o n a t le ast o nce. S u bjects 
i n t he S E S a nal ys es will be a nal yze d as treat e d. 
N ot e: I n t he defi niti o n of t he S E S a b o ve, “as treat e d” relat es t o act ual st u d y treat me nt  i n M P. 
F ull A n al y si s S et ( F A S)  
T he F A S will c o nsist of all ra n d o mize d s u bje cts. S u bjects i n F A S  a nal ys es will be a nal yze d as 
ra n d o mize d. 
P er Pr ot o c ol S et ( P P S)  
T he P P S is t he s u bset of s u bje cts i n t he F A S wit h o ut maj or pr ot o c ol de viati o ns. Maj or pr ot o c ol 
de viati o ns will be defi ne d d uri n g t he bli n de d dat a re vie w meeti n g.  
N ot e: S u bject 
 was ra n d o mize d t wic e a n d o nl y treat e d aft er sec o n d ra n d o mizati o n. 
Acc or di n g t o I T T pri nci ple treat me nt gr o u p fr o m first ra n d o miz ati o n 
 will be use d f or 
a nal ys es bas e d o n t he F A S or P P S . A p art fr o m ra n d o m gr o u p assi g n me nt, n o dat a rec or de d f or 
 will be a nal yze d. Dat a rec or de d f or 
 (sec o n d ra n d o mizati o n) will be i ncl u de d i n a n y 
st atistical a nal yses. 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 8  of 9 2  
 
5  E n d p oi nt s  a n d M ai n E sti m a n d s  f or A n al y si s 
5. 1  Effi c a c y  E n d p oi nt s  a n d M ai n Effi c a c y E sti m a n d s  
5. 1. 1  Pri m ar y Effi c a c y E n d p oi nt s a n d M ai n Pri m ar y Effi c a c y E sti m a n d s  
T he f oll o wi n g t hree e n d p oi nts will be use d f or pri mar y efficac y a nal ysis d uri n g t he M P:  
•  
Pr o p orti o n of G F L -res p o n ders at Da y 3 0  ( Visit 4) 
G F L -res p o nse is defi ne d as a sc ore of 0 ( n o) or 1 ( mil d) a n d at least t w o-gra de i m pr o ve me nt 
fr o m baseli ne t o Da y  3 0 of M P o n Merz Aest hetic Scales ( M A S ) f or G F L at ma xi m u m 
c o ntracti o n as assesse d b y b ot h t he i n vesti gat or a n d t he s u bject.  
•  
Pr o p orti o n of H F L -res p o n ders at Da y 3 0  ( Visit 4) 
H F L -res p o nse is defi ne d as a sc ore of 0 ( n o) or 1 ( mil d) a n d at least t w o-gra d e i m pr o ve me nt 
fr o m baseli ne t o Da y 3 0 of M P o n M A S f or H F L at ma xi m u m c o ntracti o n as assesse d b y 
b ot h t he i n vesti gat or a n d t he s u bject.  
•  
Pr o p orti o n of L C L -res p o n ders at Da y 3 0  ( Visit 4) 
L C L -res p o nse is defi ne d as a sc ore of 0 ( n o) or 1 ( mil d) a n d at least tw o -gra de i m pr o ve me nt 
fr o m baseli ne t o Da y 3 0 of 
M P o n 
M A S f or b ot h left a n d ri g ht L C L at ma xi m u m 
c o ntracti o n as assesse d b y b ot h t he i n vesti gat or a n d t he s u bject.  
Mai n esti ma n ds f or pri mar y effic ac y e n d p oi nts (se e 
 f or G F L, 
 f or H F L, 
 f or 
L C L) des cri be t he treat me nt effects of i nt erest f or t he t hree treat me nt areas.  F or eac h mai n pri mar y 
esti ma n d, t he varia ble attri b ut e c orres p o n ds t o t he res pecti ve pri mar y e n d p oi nt.   
 
 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 9  of 9 2  
 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 1 0  of 9 2  
 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 1 1  of 9 2  
 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 1 2  of 9 2  
 
5. 1. 2  S e c o n d ar y Effi c a c y E n d p oi nt s  a n d M ai n S e c o n d ar y Effi c a c y E sti m a n d s  
Ke y se c o n dar y effic ac y e n d p oi nts:  
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or G F L at ma xi m u m 
c o ntracti o n as assesse d b y t he i n vesti gat or at Da y  3 0  ( Visit 4) of M P.  
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or H F L at ma xi m u m 
c o ntracti o n as as sesse d b y t he i n vesti gat or at Da y  3 0  ( Visit 4) of M P.  
•  
Pr o p orti o n of s u bje cts wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or b ot h left a n d ri g ht 
L C L at ma xi m u m c o ntracti o n as ass ess e d b y t he i n vesti g at or at Da y  3 0  ( Visit 4) of M P.  
•  
Pr o p orti o n of s u bjects wit h  a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or G F L at ma xi m u m 
c o ntracti o n as assesse d b y t he s u bject at Da y  3 0  ( Visit 4)  of M P.  
•  
Pr o p orti o n of s u bjects wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or H F L at ma xi m u m 
c o ntracti o n as assesse d b y t he s u bject at Da y  3 0  ( Visit 4)  of M P.  
•  
Pr o p orti o n of s u bje cts wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or b ot h left a n d ri g ht 
L C L at ma xi m u m c o ntracti o n as ass ess e d b y t he s u bject at Da y  3 0  ( Visit 4)  of M P.  
•  
Gl o bal Aest hetic I m pr o ve me nt Scale ( G AI S ) as assesse d b y t he s u bject  at Da y  3 0  ( Visit 4)  
of M P.  
 
Mai n esti ma n ds f or M A S -base d ke y sec o n dar y efficac y e n d p oi nts are s pecifie d i n f ull det ail i n  
 All ke y s ec o n dar y esti ma n ds per treat me nt area were deri ve d fr o m t he res pecti ve mai n 
pri mar y esti ma n d as s pecifie d i n Secti o n  5. 1. 1 . 
Defi niti o ns of attri b ut es tr eat me nt, t ar get 
p o p ul ati o n, ot her i nt erc urre nt e ve nts (I C Es) a n d p o p ulati o n le vel s u m mar y are i d e ntical. T he 
varia ble attri b ut es of ke y sec o n dar y esti ma n ds were a da pt e d acc or di n g t o t he a b o ve -defi ne d ke y 
sec o n dar y e n d p oi nts f or t he res pecti ve treat me nt area bas e d o n t he i n vesti gat or/ s u bject assess me nt 
o n t he M A S at  ma xi m u m c o ntracti o n. F or e xa m ple, t he varia ble attri b ut es of t he mai n esti ma n ds 
f or t he t w o ke y sec o n dar y effic ac y e n d p oi nts f or tr eat me nt area G F L are defi ne d as “ G F L res p o ns e 
defi ne d as a sc ore of 0 ( n o) or 1 ( mil d) o n M A S f or G F L at ma xi m u m c o ntracti o n  as assesse d b y 
t he i n vesti g at or at Da y  3 0 ” a n d “ G F L res p o nse defi ne d as a sc ore of 0 ( n o) or 1 ( mil d) o n M A S 
f or G F L at ma xi m u m c o ntracti o n as assesse d b y t he s u bject at Da y  3 0 ”, res pecti vel y.  
T he mai n esti ma n d f or t he ke y sec o n d ar y e n d p oi nt base d o n s u bj ect’s G AI S at Da y  3 0  of M P is 
prese nt e d i n  
  
 
 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 1 3  of 9 2  
 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 1 4  of 9 2  
 
F urt her sec o n dar y effic ac y e n d p oi nts:  
•  
Pr o p orti o n of s u bjects wit h at le ast o ne -g ra de i m pr o ve me nt fr o m baseli ne t o Da y  3 0  
( Visit 4)  of M P o n M A S f or G F L at ma xi m u m c o ntracti o n as ass esse d b y t he i n vesti gat or.  
•  
Pr o p orti o n of s u bjects wit h at le ast o ne -gra de i m pr o ve me nt fr o m baseli ne t o Da y  3 0  
( Visit 4)  of M P o n M A S f or H F L at ma xi m u m c o n tracti o n as ass esse d b y t he i n vesti gat or. 
•  
Pr o p orti o n of s u bjects wit h at le ast o ne -gra de i m pr o ve me nt fr o m baseli ne t o Da y  3 0  
( Visit 4)  of M P o n M A S f or b ot h left a n d ri g ht L C L at ma xi m u m c o ntracti o n as assesse d 
b y t he i n vesti g at or.  
•  
G AI S as ass ess e d b y t he i n vesti gat or at Da y  3 0  ( Visit 4)  of M P.  
N o esti ma n ds are defi ne d f or f urt her sec o n dar y e n d p oi nts.  
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 1 5  of 9 2  
 
5. 2  S af et y E n d p oi nt s/ V ari a b l e s 
5. 2. 1  Pri m ar y S af et y E n d p oi nt  
N o pri mar y safet y e n d p oi nt has bee n defi ne d.  
5. 2. 2  S e c o n d ar y S af et y E n d p oi nt s  
•  
I nci de nce of relat e d treat me nt-e mer ge nt a d verse e ve nts ( T E A Es ) i n M P. 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 1 6  of 9 2  
 
•  
I nci de nce of relat e d T E A Es i n O L E X peri o d 
F or t he defi niti o n of T E A Es, see  
 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 1 7  of 9 2  
 
 
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Merz Pharmaceuticals GmbH 
 
STATISTICAL ANALYSIS PLAN 
M602011071 
 
Version 1.0, 03-AUG-2022 
 
CONFIDENTIAL AND PROPRIETARY 
 
Page 18 of 92 
 
6 Statistical Analysis Methods 
Continuous endpoints (values and changes from baseline/ cycle baseline, where applicable) will 
be summarized by number of subjects in the respective analysis set/ population (N), number of 
values analyzed (n), mean, standard deviation, median, quartiles, minimum, and maximum. If 
relevant, the number of values imputed due to missingness (nimp) will be reported for efficacy 
variables (see Section 6.4.1). Mean, quartiles, and median will be reported to one decimal place 
more than the data were collected, for the standard deviation two decimal places more will be 
displayed; for derived data, an adequate number of decimal places will be chosen. 
For qualitative endpoints, absolute and percent frequencies (n, %) and, if applicable, shift tables 
will be displayed. Frequency tables will include the number of missing values, if applicable. 
Percentages will be calculated using the denominator of all subjects in a specified population or 
treatment group. The denominator will be specified in a footnote to the tables for clarification if 
not otherwise obvious. Percentages will be reported to one decimal place. In frequency tables based 
on observed cases, number of missing values will not be presented and percentages will be based 
on number of observed cases (Nobs).  
If not otherwise specified, statistical tests will be conducted two-sided at type I error rate 5%. P-
values will be reported to four decimal places (e.g., p=0.0375). P-values below 0.0001 will be 
presented as ‘<0.0001’. Confidence intervals (CIs) will be two-sided 95%. 
In general, values obtained at Visit 2 are defined as the baseline values. Where data is not recorded 
at Visit 2, the last measurement before start of treatment is defined as baseline value. These values 
will be analyzed as baseline (i.e. baseline flag is ‘yes’ for last record with non-missing value before 
first treatment in Study Data Tabulation Model [SDTM]). For cycle 2 values obtained at Visit 8 
and for cycle 3 values obtained at Visit 13 will be used as cycle baselines. 
6.1 Efficacy Endpoints and Efficacy Estimands 
Primary and sensitivity analyses of primary efficacy endpoints (see Section 6.1.1.1) and 
confirmatory analyses of key secondary endpoints will be based on the target population of main 
primary and key secondary efficacy estimands (see Section 5.1.1 and Section 5.1.2, respectively). 
It is defined as “Male and female adults (18 years of age or older) with HFL, GFL, and LCL of 
moderate (score of 2) to severe (score of 3) intensity at maximum contraction as assessed by the 
investigator and the subject according to MAS, as randomized in this study: Subset of subjects 
randomized to UFL treatment group or to Placebo treatment group, grouped by randomized 
treatment assignment.”. Further efficacy analyses will be based on the FAS if not otherwise 
specified. Statistical tests will be two-sided hypothesis tests for between treatment differences in 
general. Adequate descriptive statistics as specified at the beginning of Section 6 above will be 
provided for all endpoints.  
In case Visit 7/Visit 8 or Visit 12/Visit 13 is performed on same day MAS assessments from Visit 
7/Visit 12 will be duplicated to be also analysed and listed at Visit 8/Visit 13. 
6.1.1 Primary Efficacy Endpoints and Estimands 
The primary endpoints will be proportions of GFL-, HFL- and LCL-responders as defined in 
Section 5.1.1. These proportions will be compared for treatment groups U and P. It should be noted 
that Group G&H is not part of the primary efficacy analysis which has the objective to compare 
efficacy of simultaneous treatment of UFL with NT 201 versus placebo. Group G&H and Total 
NT 201 (Group U and Group G&H pooled) will be considered in the supplementary analyses of 
primary endpoints on the FAS, the PPS, observed cases in the FAS, observed cases in the PPS (see 
below), in supplementary analyses of key secondary endpoints, and in analyses of further 
secondary and other efficacy endpoints.  




Mer z P h ar m a ce uticals G m b H  
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
Pa ge 2 0  of 9 2  
A si milar S A S c o de t o t he f oll o wi n g st at e me nts will be e m pl o ye d f or t his a nal ysis (e xa m ple f or 
c o m paris o n of G F L res p o n ders) : 
6. 1. 1. 3  S u b gr o u p A n al y s e s 
T he pri mar y a nal ysis of pri mar y e n d p oi nts will be c o n d uct e d f or t w o  s u b gr o u ps f or t he t ar get 
p o p ulati o n of mai n pri mar y esti ma n ds. S u b gr o u ps are defi ne d b y  B o N T pre -tr eat me nt st at us. 
S u bjects will be disti n g uis he d o n w het her t he y ha ve bee n treat e d wit h B o N T  of a n y s er ot y pe pri or  
t o ra nd o mizati o n at a n y ti me f or a n y treat me nt i n dicati o n or n ot (tr eat me nt naï ve).  T w o -si de d 9 5 % 
Wils o n CIs f or pr o p orti o ns a n d 9 5 % Ma nt el Hae nszel CIs f or strat u m -a dj ust e d differe nces i n 
pr o p orti o ns wit h Ma nt el Hae ns zel t est p -val ues will be pr o vi de d f or t he three re gi o ns . I C Es will 
be ha n dle d  as descri be d i n Secti o n 6. 4. 6 . 
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Mer z P h ar m a ce uticals G m b H  
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
Pa ge 2 1  of 9 2  
T he last t hree s u p ple me nt ar y a nal ys es descri be d bel o w i n Secti o n 6. 1. 1. 4  als o c o nstit ut e s u b gr o u p 
a nal ys es. T he y will be perf or me d f or t he t hree pri mar y effica c y e n d p oi nts o n s u bjects w h ose 
i n-pers o n att e n da nce of t he pri mar y e n dp oi nt visit was n ot affect e d b y C O VI D -1 9 pa n de mic. T he 
t ar get of esti mati o n is s pecifie d i n f ull det ail i n t he defi niti o ns of t hree s u p ple me nt ar y esti ma n ds 
(see 
 T he p o p ulati o n attri b ut e is a s u bset of t he p o p ulati o n defi ne d i n Secti o n  6. 1  f or 
mai n pri mar y esti ma n ds. F or m ore det ails see Secti o n 6. 1. 1. 4 . 
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Mer z P h ar m a ce uticals G m b H  
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
Pa ge 2 2  of 9 2  
6. 1. 2  S e c o n d ar y Effi c a c y E n d p oi nt s  a n d E sti m a n d s  
Sec o n dar y effic ac y e n d p oi nts a n d esti ma n ds f or ke y se c o n dar y e n d p oi nts are des cri be d i n 
Secti o n  5. 1. 2 . Defi niti o ns of M A S-base d ke y sec o n dar y esti ma n ds are pr o vi de d i n 
 a n d 
of t he s u bject’s G AI S -ba s e d ke y sec o n dar y esti ma n d i n 
 N o esti ma n ds are defi ne d f or 
f urt her sec o n dar y e n d p oi nts. 
6. 1. 2. 1  
K e y S e c o n d ar y E ffi c a c y E n d p oi nt s a n d K e y S e c o n d ar y E ffi c a c y E sti m a n d s  
Mai n esti mat ors f or ke y s ec o n dar y esti ma n ds will be calc ulat e d f or t he t ar get p o p ulati o n of mai n 
ke y se c o n dar y esti ma n ds a n d I C Es will be ha n dle d  as descri be d i n Secti o n 6. 4. 6 . 
Mai n esti mat ors f or 
mai n ke y sec o n dar y dic h ot o m o us 
M A S -base d efficac y esti ma n ds 
(Secti o n  5. 1. 2 ) c orres p o n d t o mai n esti mat ors f or mai n pri mar y esti ma n ds (see Secti o n 6. 1. 1. 1 ). 
Missi n g dat a will be  i m p ut e d as descri be d  i n Secti o n 6. 1. 1. 1 . F or all t hree a nat o mical re gi o ns a n d 
f or i n vesti gat or’s as well as s u bje ct’s assess me nts o n t he M A S, strat u m-a dj ust e d diffe re nces i n 
pr o p orti o ns f or o verall c o m paris o ns of treat me nt Gr o u p  U  vers us Gr o u p  P (refere nce) wit h 
c orres p o n di n g 9 5 % Ma nt el Hae nszel CIs a n d Ma nt el -Hae nszel t est p -val u es will be calc ulat e d . 
Res p o n der rat es wit h t w o -si de d 9 5 % Wils o n CIs will be pr o vi d e d as well.  
Mai n esti mat or f or t he mai n ke y sec o n dar y esti ma n d base d o n s u bject’s G AI S (see  
 will 
be a nal ysis of c o varia nc e wit h fact ors tr eat me nt gr o u p a n d sit e, a n d mea n of baseli ne M A S f or 
H F L, G F L, a n d L C L at ma xi m u m c o ntracti o n assesse d b y s u bject as c o variat e.  
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 2 3  of 9 2  
 
Acc or di n g t o t he defi n iti o n of t he ke y sec o n dar y esti ma n d bas e d o n s u bje ct’s G AI S 
 
s pecific I C Es will  be ha n dle d  b y a p pl yi n g t he c o m p osit e strat e g y . I n t hese cases, missi n g  s u bject’s 
G AI S rati n gs or rati n gs of "
 
(see Secti o n  6. 4. 6  o n I C Es ), re gar dless of w het her t he G AI S sc ore 
fr o m s u bject assess me nt at Da y  3 0  ( V 4) is a vaila ble or w het her it is missi n g f or t he res pecti ve 
s u bje ct.  
Least  s q uares ( L S) mea n s, st a n dar d err or, a n d t w o-si d e d 9 5 % CI per treat me nt gr o u p a n d L S mea n 
treat me nt differe nce (“ Gr o u p U” –  “ Gr o u p P”) wit h ass o ciat e d t w o -si d e d 9 5 % CI a n d t -T est p-
val ue will be pr o vi de d.  T h e n ull h y p ot hesis of t h is t-T est is t hat t he L S mea n treat me nt differe nc e 
is zer o. 
A si milar S A S c o de t o t he f oll o wi n g st at e me nts will be e m pl o ye d f or t his a nal ysis: 
T he res ulti n g v al ue will be r o u n de d t o t w o deci mal s.  
M ulti plicit y a dj ust me nt strat e g y f or c o m paris o ns of treat me nt gr o u ps U a n d P o n ke y sec o n dar y 
e n d p oi nts is des cri be d i n Secti o n 6. 4. 3 . 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 2 4  of 9 2  
 
Res ults f or Gr o u p  G & H  fr o m a n y a nal ys es will o nl y be i nt er pret e d descri pti vel y.  
6. 1. 2. 2  
F urt h er S e c o n d ar y E n d p oi nt s  
Si milar a nal ysis strat e g y b y re gi o n as descri be d f or s u p ple me nt ar y a nal ysis of pri mar y e n d p oi nts 
o n o bser ve d cases i n F A S/ P P S (see Secti o n  6. 1. 1. 4 ) will be a p plie d f or t he f urt her sec o n dar y 
dic h ot o m o us M A S -base d effic ac y e n d p oi nts defi ne d f or t he M P. I n partic ular, pr o p orti o ns of 
s u bje cts wit h at least o ne -gra de i m pr o ve me nt i n treat me nt gr o u ps U a n d P will be c o m p are d b y 
strat u m-a dj ust e d a n d u na dj ust e d differe nces i n pr o p orti o ns wit h c orres p o n di n g 9 5 % 
Ma nt el 
Hae nszel CIs a n d p -val ues. M ore o ver, 9 5 % CIs f or pr o p orti o ns a n d u na dj ust e d differe nc e i n 
pr o p orti o ns will be pr o vi d e d.  
Gr o u p  G & H will o nl y be c o nsi dere d f or st atistical a nal ys es of M A S of t he G F L a n d H F L re gi o ns 
b ut n ot of t he L C L re gi o n. A nal ysis of strat u m-a dj ust e d a n d u na dj ust e d differe nc es i n pr o p orti o ns 
will be perf or me d se p arat el y f or Gr o u p  U vs. Gr o u p  P , G r o u p G & H vs. Gr o u p  P , a n d T ot al N T  2 0 1  
vs. Gr o u p P . F or Gr o u p  G & H, p r o p orti o ns wit h t w o -si de d 9 5 % Wils o n CIs will be pr o vi de d f or 
all t hree re gi o ns, b ut differe nce i n pr o p orti o ns c o m pare d t o Gr o u p  P  o nl y f or G F L a n d H F L 
re gi o ns. F or G F L a n d H F L re gi o ns, pr o p orti o ns will als o be pr o vi de d f or T ot al N T  2 0 1 . 
G AI S as assesse d b y t he i n vesti gat or at Da y  3 0 of t he M P will be a nal yze d usi n g a nal ysis of 
c o varia nce wit h fact ors treat me nt gr o u p a n d sit e, a n d me a n of baseli ne M A S f or H F L, G F L, a n d 
L C L at 
ma xi m u m c o ntracti o n assesse d b y i n vesti g at or as c o variat e  (see Secti o n  6. 1. 2. 1 ). 
C o m paris o ns will be ma de f or Gr o u p U t o Gr o u p  P , Gr o u p G & H t o Gr o u p  P , a n d T ot al N T  2 0 1  t o 
Gr o u p P . T w o  se parat e A N C O V As, o ne f or Gr o u p  P , Gr o u p U a n d Gr o u p G & H a n d o ne f or 
Gr o u p  P a n d T ot al  N T  2 0 1 ( Gr o u p  U a n d Gr o u p  G & H  p o ole d) will be c o n d uct e d . 
Res ults f or all f urt her sec o n dar y e n d p oi nts i ncl u di n g a n y p -val ues a n d 9 5 % CIs will o nl y be 
i nt er pret e d descri pti vel y. N o t y pe I err or a dj ust me nt will be a p plie d. 
F or f urt her sec o n dar y e n d p oi nts o nl y o bser ve d cas es will be a nal yz e d. A nal ys es will be pr o vi de d 
f or F A S a n d P P S. 
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S T A TI S TI C A L A N A L Y SI S  P L A N  
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Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 2 5  of 9 2  
 
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S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 2 6  of 9 2  
 
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S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 2 7  of 9 2  
 
6. 2  S af et y E n d p oi nt s  
All s afet y a nal yses will be perf or me d o n t he  S E S.  All safet y t a bles will be prese nt e d b y act ual 
treat me nt gr o u p (“ Gr o u p P ”, “ Gr o u p  U ”, “ Gr o u p  G & H ”)  at V 2 i n M P. I n T E A E t a bles f or t ot al 
O L E X peri o d, C ycle 2, a n d C ycle  3, t he c ol u m n hea ders f or t hese t hree treat me nt gr o u ps will be 
“ M P Gr o u p P ”, “ M P Gr o u p  U ”, “ M P Gr o u p G & H ”. T E A E t a bles f or M P will a d diti o nall y i ncl u d e 
a “T ot al N T  2 0 1 ” c ol u m n f or w hic h acti ve treat me nt gr o u ps (Gr o u p  U a n d Gr o u p G & H ) will be 
p o ole d . T E A E t a bles f or t ot al O L E X peri o d, C ycle 2, a n d C ycle 3  will pres e nt p o ole d res ults fr o m 
all t hree treat me nt gr o u ps i n t he f o urt h c ol u m n, w hic h will be la bele d “ T ot al”.  F or T E A E a nal yses 
o ver t ot al st u d y peri o d, t he c ol u m ns “ M P Gr o u p P - M P ”, “ M P Gr o u p P  - O L E X ”, “ M P Gr o u p U”, 
“ M P Gr o u p G & H”  a n d “M P T ot al N T  2 0 1 ” (“M P Gr o u p P –  O L E X, M P ”,  “Gr o u p U ” a n d “Gr o u p 
G & H ” p o ole d)  will be prese nt e d.  I n c ol u m n “ M P Gr o u p P - M P ” o nl y A Es w hic h o cc urre d d uri n g 
M P are c o u nt e d, i n c ol u m n “ M P Gr o u p P  - O L E X ” o nl y A Es w hic h o cc urre d i n O L E X peri o d are 
c o u nt e d . 
All a nal yses of la b orat or y val ues fr o m a n y ti me p oi nt ( Scree ni n g V 1 a n d e n d -of -st u d y visit V 1 7) 
will be perf or me d b y act ual treat me nt gr o u p at V 2 i n M P a n d i n t ot al.  All a nal ys es of vit al si g ns 
fr o m a n y ti me p oi nt will be perf or me d b y act ual treat me nt gr o u p at V 2 i n M P, T ot al N T  2 0 1  
(la bele d “ M P T ot al N T  2 0 1 ” f or a nal ysis of vit al si g ns fr o m visits t ot al O L E X  peri o d) a n d i n t ot al.   
 
A Es will be c o de d acc or di n g t o t he Me d D R A versi o n i n effe ct at t he ti me t he dat a base is cl ose d. 
O nl y T E A Es will be a nal yz e d, w hic h are defi ne d as A Es wit h o nset or w orse ni n g  o n or aft er dat e 
of t he first a d mi nistrati o n of i n vesti gati o nal pr o d uct (I P) u p t o a n d i ncl u di n g e n d of st u d y visit 
( V 1 7) . I n case n o e n d of st u d y visit ( V 1 7)  is perf or me d, all A Es re p ort e d d uri n g a ti me peri o d 
c orres p o n di n g t o t he e x pect e d c ycle le n gt h will be re gar de d as treat me nt -e mer ge nt. F urt her det ails 
f or se parati o n of T E A Es a n d n o n-T E A Es ca n be f o u n d i n  
 N o n -T E A Es will be list e d  
o nl y . 
All a nal yses of T E A Es  will be base d o n t he f oll o wi n g ti me peri o ds : 
•  
T ot al st u d y peri o d  
•  
M P  ( C ycle 1)  
•  
T ot al O L E X  peri o d ( C ycle 2 a n d C ycle  3)  
•  
C ycle  2  
•  C ycle  3 . 
T E A Es of t he M P are defi ne d as A Es wit h o ns et or w orse ni n g o n or aft er dat e a n d ti me of t he first 
a d mi nistrati o n of I P  at V 2 a n d bef ore dat e a n d ti me of a d mi nistrati o n of I P i n V 8  ( C ycle 2) or u p 
t o a n d i ncl u di n g e n d of st u d y visit ( V 1 7)  i n cas e of pre mat ure disc o nti n uati o ns pri or t o V 8. F or 
s u bje cts w h o d o n ot recei ve st u d y tr eat me nt d uri n g O L E X peri o d all A Es wit h o nset or w orse ni n g 
o n or aft er dat e a n d ti me of t he first a d mi nistrati o n of I P u p t o a n d i ncl u di n g e n d of st u d y visit 
( V 1 7) will be c o nsi dere d as T E A Es of M P. I n case n o e n d of st u d y visit ( V 1 7)  perf or me d, all A Es 
wit h o nset or w orse ni n g  u p t o a n d i ncl u di n g Da y 1 2 0 of M P will be re gar de d as T E A Es of M P.  
T E A Es of t he t ot al O L E X peri o d are defi ne d as A Es wit h o nset or w orse ni n g o n  or aft er dat e a n d 
ti me of t he first a d mi nistrati o n of I P d uri n g O L E X peri o d at V 8 a n d u p t o a n d e n d of st u d y visit 
( V 1 7) visit . In case n o e n d of st u d y visit ( V 1 7)  is perf or me d, all A Es wit h o nset or w orse ni n g at or 
aft er dat e a n d ti me of t he first a d mi nistrati o n of I P d uri n g O L E X peri o d at V 8  a n d u p t o a n d 
i ncl u di n g Da y 1 2 0 of last c ycle will be re gar de d as T E A Es of O L E X. T E A Es of C ycle  2 are defi ne d 
as A Es wit h o nset or w orse ni n g o n or aft er dat e a n d ti me of t he first a d mi nistrati o n of I P at V 8 a n d 
bef ore dat e a n d ti me of a d mi nistrati o n of I P at V 1 3 ( C ycle  3) or u p t o a n d i ncl u di n g e n d of st u d y 
visit ( V 1 7)  i n case of pre mat ure disc o nti n uati o ns pri or t o V 1 3 or i n case n o st u d y treat me nt is 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 2 8  of 9 2  
 
a d mi nist ere d at V 1 3 . I n case n o e n d of st u d y visit ( V 1 7)  is perf or me d, all A Es wit h o nset or 
w orse ni n g at  or aft er dat e a n d ti me of t he first a d mi nistrati o n of I P at V 8 a n d u p t o a n d i ncl u di n g 
Da y 1 2 0 of C ycle 2 will be re gar de d as T E A Es of C ycle 2.  T E A Es of C ycle 3 are defi ne d as A Es 
wit h o nset or w orse ni n g o n or aft er dat e a n d ti me of t he first a d mi nistrati o n of I P at V 1 3 a n d u p t o 
a n d i ncl u di n g e n d of st u d y visit ( V 1 7) . I n case n o e n d of st u d y visit ( V 1 7)  is perf or me d, all A Es 
wit h o nset or w orse ni n g at  or aft er dat e a n d ti me of t he first a d mi nistrati o n of I P at V 1 3 a n d u p t o 
a n d i ncl u di n g Da y 1 2 0 of C ycle 3 will be re gar de d as T E A Es of C ycle 3.  
F or a nal ysis o ver t he t ot a l st u d y peri o d, t he n u m ber of s u bjects i n t he S E S will ser ve as t he 
de n o mi nat or f or calc ulati o n of i nci de nces. F or t he a nal ys es b y treat me nt c ycle t he de n o mi nat or 
will be a dj ust e d t o all  s u bjects bei n g treat e d i n t hat tr eat me nt c ycle.  F or t he a nal ysis o ver  t he t ot al 
O L E X  peri o d , t he de n o mi nat or f or t he i nci de nces will be all s u bjects bei n g treat e d at least o nce  i n 
t ot al O L E X peri o d .  
If a n A E w orse ns bet wee n st art a n d e n d of t his A E it will be c o nsi dere d as ne w A E st arti n g w it h 
t he dat e of w orse ni n g. I n t his cas e t he i m p ut ati o n of e n d dat es wit hi n e pis o des of t he sa me A E will 
be d o ne b y setti n g t he e n d dat e/e n d ti me t o st art dat e/st art ti me of t he c o nsec uti ve w orse ni n g rec or d.   
F or a nal ysis, i nc o m plet el y rec or de d or c o m plet el y missi n g st art of A Es will be  esti mat e d acc or di n g 
r ules lai d d o w n i n 
 E n d dat es will n ot be i m p ut e d. I n t he A E listi n g, st art dat e as 
rec or de d a n d as i m p ut e d f or a nal ysis will be dis pla yed.  
Calc ulati o n of ti me t o o nset/ d ur ati o n of A Es ( da ys):  
•  Ti me t o o nset of a n A E is defi ne d as st art dat e of A E - dat e of first a d mi nistrati o n of st u d y 
dr u g i n res pecti ve treat me nt c ycle [ + 1 da y f or T E A E s] 
•  T he d urati o n of a n A E will be calc ulat e d as st o p dat e - o nset dat e + 1  da y .  
 
If a s u bje ct has m ore t ha n o ne i nt e nsit y/ ca usal relati o ns hi p t o treat me nt/ o ut c o me wit hi n a 
preferre d t er m ( P T) o nl y t he w orst i nt e nsit y/ ca usal relati o ns hi p t o treat me nt/ o ut c o me will be 
c o nsi dere d f or calc ulati o n of i nci d e nc e rat es i n t he fre q ue nc y t a bles re p orti n g i nci d e nces b y 
i nt e nsit y/ ca usal relati o ns hip  t o tr eat me nt/ o ut c o me. I nci de nce of T E A Es relat e d t o C O VI D-1 9 
dis ease  a n d T E A Es relat e d t o C O VI D -1 9 vacci nati o n  will o nl y be calc ulat e d o verall. T here b y, 
T E A Es wit h miss i n g relati o ns hi p will be i g n ore d b ut affect e d s u bjects will n ot  be re m o ve d fr o m 
t he de n o mi nat or. Als o,  f or t he a nal ysis o verall, i. e. f or s u bjects wit h at least o ne T E A E, o nl y t he 
w orst i nt e nsit y/ ca usal relati o ns hi p t o tr eat me nt/ o ut c o me cat e g or y per s u bj e ct will be c o u nt e d f or 
calc ulati n g i nci de nce rat es . T he sa me a p plies t o calc ulati o n of o verall i nci de nce of T E A Es relat e d 
t o C O VI D-1 9 dise ase  a n d T E A Es relat e d t o C O VI D -1 9 vacci nati o n .  
T he w orst o ut c o me is defi ne d i n t he f oll o wi n g or der  ( w orst o ut c o me t o best o ut c o me) :  
•  fat al 
•  u n k n o w n  
•  n ot rec o vere d/ n ot res ol ve d  
•  rec o veri n g/r es ol vi n g  
•  rec o vere d/r es ol ve d wit h se q uelae  
•  rec o vere d/r es ol ve d 
A Es c o de d as “ Im m u nisati o n reacti o n ” ( preferre d t er m) are defi ne d as A Es relat e d t o C O VI D -1 9 
vac ci nati o n.  
T he A Es list e d i n 
 are defi ne d as a d vers e e ve nt of s pecial i nt erest ( A E SIs ) f or t his st u d y. 
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S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
Pa ge 2 9  of 9 2  
I n case of missi n g i nt e nsit y or missi n g ca us al relati o ns hi p of a n A E t o treat me nt, t he w orst case 
pri nci ple will be a p plie d, i. e. , a missi n g i nt e nsit y will be set t o “se vere” a n d a missi n g ca usal 
relati o ns hi p will be set t o “relat e d”. Missi n g o ut c o me will be set t o “ u n k n o w n”.  Missi n g ca u sal 
relati o ns hi p t o C O VI D-1 9 disease will n ot be i m p ut e d.  T E A Es wit h missi n g relati o ns hi p t o 
C O VI D -1 9 dis ease will be i g n ore d f or calc ulati o n of t he res pecti ve i nci de nc e rat es b ut affect e d 
s u bje cts will be ke pt i n t he de n o mi nat or a n d o nl y T E A Es w hic h are d o c u me nt e d as relat e d t o 
C O VI D -1 9 dis ease  will be i ncl u d e d i n res pecti ve listi n g. N o 
missi n g ness is  e x pe ct e d f or 
relati o ns hi p of T E A Es t o C O VI D-1 9 vacci nati o n.   
6. 2. 1  Pri m ar y S af et y E n d p oi n t s 
N o pri mar y safet y e n d p oi nt has bee n defi ne d.  
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S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 3 0  of 9 2  
 
6. 2. 2  S e c o n d ar y S af et y E n d p oi nt s  
T a bles dis pla yi n g i nci de nc es of relat e d T E A Es will be pr o vi de d b y s yst e m or ga n class ( S O C) a n d 
P T  f or ti me peri o ds a n d wit h t a ble c ol u m ns as defi ne d at be gi n ni n g of Secti o n  6. 2  a b o ve. Relat e d 
T E A Es i n M P a n d O L E X will als o be list e d.    
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S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 3 1  of 9 2  
 
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S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 3 2  of 9 2  
 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 3 3  of 9 2  
 
6. 4  S p e ci al St ati sti c al/ A n al yti c al I s s u e s  
6. 4. 1  Di s c o nti n u ati o n s a n d Mi s si n g D at a  
Mai n r e as o ns f or pre mat ure disc o nti n uati o n of st u d y will be s u m marize d descri pti vel y. As st at e d 
i n Secti o n 6. 2. 3 , T E A Es lea di n g t o disc o nti n uati o n will be list e d. Disc o nti n u e d s u bje cts will n ot 
be re place d.  
F or s u bjects dis c o nti n ui n g t he st u d y pre mat urel y a n d f or w h o m e n d -of -st u d y visit V 1 7 was 
d o c u me nt e d , efficac y dat a c ollect e d at V 1 7 will be a nal yze d u n der t he st u d y visit w hic h is cl osest 
t o t he rec or de d V 1 7 dat e. T his will be base d o n t he assess me nt dat e relati ve t o (c ycle) bas eli ne, 
a n d c o nsi deri n g treat me nt recei ve d f or eac h c ycle, us i n g t he f oll o win g visit wi n d o ws.  
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Mer z P h ar m a ce uticals G m b H  
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
Pa ge 3 4  of 9 2  
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 3 5  of 9 2  
 
F or se parati o n of T E A Es fr o m n o n -T E A Es i n case of c o m plet el y or partl y missi n g st art dat e  a n d 
ti me see 
 R ules for i m p ut ati o n of st art dat es a n d st art ti mes of A Es are pr o vi de d i n 
 E n d dat es of A Es will n ot be i m p ut e d.  
F or w orst case i m p ut ati o n of missi n g ca usal relati o ns hi p  t o tr eat me nt, i nt e nsit y or o ut c o me of a n 
A E refer t o Secti o n  6. 2 . Ca usal relati o ns hi p t o C O VI D -1 9 dise ase will be list e d base d o n o bser ve d 
cases. 
If n ot ot her wise s pe cifie d, all T E A E a nal ys es will be perf or me d o n t he S E S a n d all f urt her safet y 
a nal ys es o n o bser ve d cases.  
6. 4. 2  I nt eri m A n al y s e s 
N ot a p plica ble.  
6. 4. 3  M ulti pl e C o m p ari s o n s/ M ulti pli cit y  
T he fa mil y -wise t w o -si de d t y p e I err or le vel α =  0. 0 5 f or c o m paris o ns of treat me nt gr o u ps U a n d 
P o n t he pri mar y a n d ke y sec o n dar y e n d p oi nts will be c o ntr olle d b y a hierarc hical t est pr o ce d ure 
base d o n t w o -si de d t ests wit h α =  0. 0 5.  
T he hierarc hical pr o ce d ure f or pri mar y a nal ysis ( Secti o n 6. 1. 1. 1 ) will be perf or me d as descri be d 
bel o w. First, usi n g t he Ma nt el -Hae nsz el t est of t he n ull h y p ot hesis t hat t he c o m m o n differe nce i n 
res p o nse rat es at Da y  3 0  is zer o, Gr o u p U vers us Gr o u p  P will be t est e d f or s u peri orit y f or 
pr o p orti o n of G F L -res p o n ders, sec o n d f or pr o p orti o n of H F L-res p o n ders, a n d t hir d f or pr o p orti o n 
of L C L -res p o n ders. T he t est pr o ce d ure will st o p o nce st atistical si g nifica nce c o ul d n ot be reac he d. 
I n case st atistical si g nifica nc e ca n be est a blis he d f or all t hree pri mar y efficac y e n d p oi nts, t he 
pr o ce d ure will pr o cee d t o ke y sec o n d ar y e n d p oi nts ( Secti o n 6. 1. 2. 1 ): As ne xt st e ps, Ma nt el-
Hae nszel t ests f or s u peri orit y of Gr o u p  U vers us Gr o u p  P will be c o n d uct e d f or pr o p orti o n of 
s u bje cts wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S at ma xi m u m c o ntr acti o n as assesse d b y t he 
i nvesti g at or at Da y  3 0  f or G F L, t he n H F L a n d fi nall y L C L a nat o mical re gi o n. T hereaft er, Ma nt el-
Hae nszel t ests f or s u peri orit y of Gr o u p  U vers us Gr o u p  P will be c o n d uct e d f or pr o p orti o n of 
s u bje cts wit h a sc ore of 0 ( n o) or 1 ( mil d) o n M A S at ma xi m u m c o ntracti o n as assesse d b y t he 
s u bject at Da y  3 0  f or G F L, t he n H F L a n d fi nall y L C L a nat o mical re gi o n. 
Fi nall y, G AI S as assesse d b y t he s u bje ct at Da y  3 0  of M P will be t est e d as descri be d i n Secti o n 
6. 1. 2. 1 .  
T he hierarc hical t est pr o ce d ure will st o p o nce st atistic al si g nifica nc e c o ul d n ot be reac he d.  
F or a n y ot her st atistical t ests o n pri mar y or ke y sec o n dar y e n d p oi nts (e. g. c o m paris o n of treat me nt 
gr o u ps G & H  a n d P), n o t y pe I err or a dj ust me nt will be perf or me d. T he sa me acc o u nts f or a n y 
st atistical a nal yses of f urt her sec o n dar y a n d ot her e n d p oi nts.   
6. 4. 4  E x a mi n ati o n of S u b gr o u p s  
S u b gr o u p a nal ys es f or t he pri mar y effic ac y e n d p oi nt s are s pecifie d i n Secti o n 6. 1. 1. 3 . 
Dic h ot o mize d e n d p oi nts w hic h are base d o n M A S  (ass ess e d b y i n vesti g at or a n d s u bject)  f or 
G F L/ H F L/ L C L at rest will be a nal yz e d i n s u b gr o u ps of s u bjects wit h baseli ne sc ore of at le ast 2 
o n t he c orres p o n di n g M A S  f or G F L/ H F L/ L C L at rest as assesse d b y b ot h s u bject a n d i n vesti gat or. 
Si nce s c ores at rest are i n ge neral l o wer t ha n sc ores at ma xi m u m c o ntracti o n, s o me s u bje cts  ma y 
ha ve a sc ore of 0 ( n o) or 1 ( mil d) at c ycle baseli ne o n M A S f or G F L/ H F L/ L C L at rest. T hese 
s u b gr o u p a nal ys es will be m ore mea ni n gf ul a n d se nsiti ve t o tr eat me nt effects t ha n a nal yses of t he 
t ot al F A S as t he y c o nsi der effects i n ‘s y m pt o matic’ s u bjects, i. e. s u bjects wit h 0 ( n o) or 1 ( mil d) 
o n c orres p o n di n g M A S will n ot be a nal yz e d.  
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S T A TI S TI C A L A N A L Y SI S  P L A N  
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Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
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Pa ge 3 6  of 9 2  
 
Dic h ot o mize d e n d p oi nts w hic h are base d o n I R P assess me nts o n M A S f or G F L/ H F L/ L C L at 
ma xi m u m c o ntracti o n a n d at rest will be a nal yze d i n s u b gr o u ps of s u bjects wit h baseli ne sc ore of 
at least 2 o n t he c orres p o n di n g M A S as assesse d b y all t hree rat ers . T hese s u b gr o u p a nal yses will 
be m ore mea ni n gf ul a n d se nsiti ve t o tr eat me nt effe cts t ha n a nal yses of t he t ot al F A S as t he y 
c o nsi der effe cts i n ‘s y m pt o matic’ s u bjects, i. e. s u bjects w it h 0 ( n o) or 1 ( mil d) o n c orres p o n di n g 
M A S will n ot be a nal yz e d.  
6. 4. 5  P o oli n g of Sit e s  
N o  p o oli n g of sit es is pla n ne d .  
6. 4. 6  I nt er c urr e nt E v e nt s 
IC Es  acc or di n g t o I C H E 9 ( R 1) [1 ] are pres pecifie d f or mai n pri mar y , s u p ple me nt ar y pri mar y, a n d 
mai n 
ke y sec o n dar y efficac y esti ma n ds (see Secti o n  5. 1. 1 , 
 a n d Secti o n  5. 1. 2 , 
res pecti vel y) a n d will be a d dresse d b y t he ha n dli n g str at e gies des cri be d i n 
 
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Mer z P h ar m a ce uticals G m b H  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 3 7  of 9 2  
 
I n case m ulti ple I C Es wit h rele va nc e f or t he sa me esti ma n d o cc ur f or a s pecific s u bject, a 
c o nser vati ve a p pr o ac h will be a d o pt e d f or t he res pecti ve esti ma nd. F or e xa m ple,  a c o m p osit e 
strat e g y will be use d if t his is i n v o ke d b y at least o ne of t he I C Es rele va nt f or t he res pecti ve 
esti ma n d a n d a treat me nt p olic y is us e d ot her wise . 
Ge nerall y, t he a b o ve strat e gies f or ha n dli n g of I C Es will o nl y be a p plie d t o est i mat ors f or affect e d 
esti ma n ds. A n esti ma n d ca n o nl y be affe ct e d b y a n I C E if t he s u bje ct is i ncl u d e d i n t he t ar get 
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S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 3 8  of 9 2  
 
p o p ulati o n of t he esti ma n d, a n d o nl y i n t his case a ha n dli n g strat e g y f or a n i de ntifie d I C E will be 
a p plie d.  
Li k e wise, ha n dli n g strat e gies f or I C Es will n ot  be a p plie d i n a nal yses t hat are n ot defi ne d as 
esti mat ors f or a n y effica c y esti ma n ds. T his i ncl u d es, e. g., a nal ys es of pri mar y a n d ke y sec o n dar y 
effic ac y e n d p oi nts o n F A S, P P S, o bser ve d cases i n F A S/ P P S a n d a n y a nal yses of f urt her sec o n da r y 
or ot her efficac y e n d p oi nts or a n y safet y or ot her e n d p oi nts.  
 
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S T A TI S TI C A L A N A L Y SI S  P L A N  
M 6 0 2 0 1 1 0 7 1  
 
Versi o n 1. 0 , 0 3 -A U G -2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 
Pa ge 3 9  of 9 2  
 
8  R ef er e n c e s  
[1 ] I C H E 9 ( R 1): A d de n d u m o n Esti ma n ds a n d Se nsiti vit y A nal ysis i n Cli nic al Trials t o t he 
G ui deli ne o n St atistic al Pri nci ples f or Cli nical Trials, 2 0 N o ve m ber 2 0 1 9, a d o pt e d b y C H M P, 
3 0 Ja n uar y 2 0 2 0, iss ue d as E M A/ C H M P/I C H/ 4 3 6 2 2 1/ 2 0 1 7  
 
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