Clinical trial NCT04622254
Conditions: Moderate to Severe Upper Facial Lines (Horizontal Forehead Lines, Glabellar Frown Lines, and Lateral Canthal Lines)
Sponsor: Merz North America, Inc.
Start date: 2020-11-12; Completion date: 2022-07-08
Enrollment: 368 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 24 U NT 201: placebo injection both in the GFL and HFL area, and 24 U NT 201 injection in the LCL area (12 U per side) 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% Sodium Chloride (NaCl). intervention 2: Solution for injection prepared by reconstitution of powder with percent (%) Sodium Chloride (NaCl).

Protocol documents:
Prot_000.pdf: 
Merz P har mace uticals G m b H  
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Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1  of 2 1 0  
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 fro 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 me nt p h ase:  
P hase 3  
St u d y i de ntifier  
E u dr a C T  
I N D 
M 6 0 2 0 1 1 0 7 0  / N C T 0 4 6 2 2 2 5 4
2 0 1 9- 0 0 4 1 1 3- 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 b ellar 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:  
First s u bject first visit:  
Q 4 2 0 2 0  
Last pri mar y o utc o me visit:   Q 2 2 0 2 1 
Last s u bject last visit:   
Q 3  2 0 2 2  
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 u r 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:  
Merz P har mace uticals G m b H  
Ec ke n hei mer La n dstr. 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 n si 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: 
Cli nical Pr oject Ma na ger : 
  
Lea d Me dical E x pert: 
 
Bi 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 d e ntial a n d pr o prietar y t o Merz P har mace uticals G m b H . 
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 writt e n c o nse nt of 
Merz P har mace uticals  G m b H . 
P P D
P P D
C CI
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Merz P har mace uticals G m b H  
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C o nfi de ntial  
P a ge 2  of 2 1 0  
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 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, i ncl u di n g 
E U  ( Dir ecti ve  2 0 0 1/ 2 0/ E G;  Ge neral  D ata  Pr ot ecti o n  Re g ulati o n)  a n d  Ger ma n  la ws  
( Ger ma n Me di ci nes Act [ A M G]; G C P-or di na nce [ G C P -V] a n d a p plica ble data pr otecti o n 
re q uire me nts). I n a d diti o n, t he cli nical st u d y pr ot oc ol a n d i nf or me d c o ns e nt f or m (I C F) 
are  ali g ne d  wit h  t he  re q uire me nts  of  t he  u pc o mi n g  E U  re g ulati o n  N o.  5 3 6/ 2 0 1 4,  as  
rec o m me n de d b y t he E M A. 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)  
 
Si g nat ure  
T he f oll o wi n g i n di vi d uals als o si g nifi ca 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 >  
P P D
P P D
P P D
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 0  
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C o nfi de ntial  
P a ge 3  of 2 1 0  
St at e m e nt of C o m pli a n c e  
I ha v e t h or o u g hl y r ea 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 orm 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  Decl arati o n  of  Helsi n ki,  a n d  re g ulat or y  a ut h orit y  re q uire me nts,  as  well  as  E U  
( Directi ve 2 0 0 1/ 2 0/ E G; Ge ner al Data Pr otecti o n Re g ulati o n) a n d Ger ma n la ws ( Ger ma n 
Me dici nes  A ct  [ A M G];  G C P -or di na nce  [ G C P -V]  a n d  a p plica bl e  d ata  pr otecti o n  
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 o c h ure. Ha vi n g bee n a d e q u atel y i nf or m e 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: 
•  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.  
•  Wait u ntil I ha v e r ecei ve d a p ositi ve o pi ni o n fr o m t he res p o nsi ble I E C bef ore 
e nr olli n g a n y s u bj ect i n t his st u d y. 
•  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.  
•  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 h a ve bee n f ulfille d. 
•  Per mit st u d y -rel ate d m o nit ori n g, a u dits, I E C re vi e w, a n d re g ulat or y i ns pecti o ns. 
•  Pr o vi de direct access t o all st u d y -relat e 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, or re g ulat or y a ut h orit y u p o n re q u est. 
•  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.  
•  Re p ort t o t he safet y de p art me nt of t he C R O, 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 s eri o us a d vers e e v e nt i m me diatel y a n d u n der n o 
circ u msta nces later t ha n 2 4 h o urs after l ear ni n g of t he e ve nt , w het h er c o nsi dere d 
treat me nt relat e d or n ot. 
•  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.  
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C o nfi de ntial  
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F urt her m ore, I u n d ersta n d t hat: 
•  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 pro priate I E C a n d r e g ulat or y a ut h orit y. 
•  T he c o nte nt of t he cli nical st u d y pr ot oc ol is c o nfi d e ntial a n d pr o priet ar y t o Merz. 
•  A n y d e viati o n fr o m t h e cli nical st u d y pr ot oc ol ma y l ea 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 >  
< St u d y site sta m p (if 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 5  of 2 1 0  
List of a b br e vi ati o n s a n d d e fi 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 nter est  
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  
E u dr a C T  
E ur o pea n U ni o n Dr u g Re g ulati n g A ut h orities Cl i nical Trials Data base 
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 
Nee dle ga uc he  
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 
L C L  
L ateral ca nt hal li nes  
M A S  
Merz Aest hetics Scale  
M e d D R A  
Me dical Dicti o nar y f or Re g ul at or y Acti vities  
M P  
Mai n peri o d  
C CI
C CI
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Merz P har mace uticals G m b H  
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C o nfi de ntial  
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N 
N u m ber of s u bj ects  
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  
P er pr ot oc ol set  
P R O  
P atie 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  
S O C  
S yste m or ga n class  
S O P  
Sta n dar d o perati n g pr oce d ure  
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 ad v erse e ve nt of s pecial i nte rest 
T E S A E  
Treat me nt -e mer ge nt seri o us ad v erse e ve nt  
U 
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 mi cal classificati o n  
 
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Merz P har mace uticals G m b H  
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T a bl e of C o nt e nt s  
1  
S Y N O P SI S  ................................................................................................................. 1 2 
2  
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 
2. 1  
I nter nal r es p o nsi bilities .......................................................................................... 1 8 
2. 2  
E xter nal res p o nsi bilities  ......................................................................................... 1 9 
2. 3  
C o m mittees  ............................................................................................................ 2 1 
3  
E T HI C S  ..................................................................................................................... 2 2 
3. 1  
I n d e pe n de nt Et hics C o m mittee (I E C) .................................................................... 2 2 
3. 2  
Et hical c o n d uct of t he st u d y ................................................................................... 2 2  
3. 3  
S u bject i nf or mati o n a n d i nf or me d c o ns e nt ............................................................ 2 3  
3. 3. 1  
S u bject i nf or mati o n  .......................................................................................... 2 3 
3. 3. 2  
I nf or me d c o ns e nt ............................................................................................. 2 3 
3. 3. 3  
S u b ject car d ...................................................................................................... 2 4 
3. 3. 4  
P ost- st u d y tr eat me nt......................................................................................... 2 4 
3. 3. 5  
S u bject pri vac y................................................................................................. 2 5  
3. 3. 6  
C o ntact p oi nt .................................................................................................... 2 5  
3. 4  
I ns ura nce ................................................................................................................ 2 5 
3. 5  
Fi na nci n g ................................................................................................................ 2 6 
4  
I N T R O D U C TI O N .................................................................................................... 2 7 
4. 1  
St u d y b ac k gr o u n d .................................................................................................. 2 7  
4. 2  
St u d y rati o nale  ....................................................................................................... 2 9 
4. 3  
Ris k -be nefit assess me nt  ......................................................................................... 3 0 
5  
S T U D Y O B J E C TI V E S  ............................................................................................ 3 2 
6  
I N V E S TI G A TI O N A L P L A N .................................................................................. 3 3 
6. 1  
O verall  st u d y desi g n .............................................................................................. 3 3 
6. 1. 1  
E n d of st u d y ..................................................................................................... 3 3  
6. 1. 2  
St u d y fl o w c h art  ............................................................................................... 3 4 
6. 2  
Disc ussi 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 4  
7  
S T U D Y P O P U L A TI O N  ........................................................................................... 3 6 
7. 1  
Selecti o n of st u d y p o p ulati o n................................................................................. 3 6  
7. 2  
I n cl usi o n criteria .................................................................................................... 3 6 
7. 3  
E x cl usi o n criteria  ................................................................................................... 3 7 
7. 4  
Re m o val of s u bjects fr o m treat me nt or assess me nt  ............................................... 4 2 
7. 4. 1  
Disc o nti n uati o n of s u bject’s st u d y p artici pati o n .............................................. 4 2 
7. 4. 2  
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 3  
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7. 4. 3  
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 4  
8  
T R E A T M E N T S  ........................................................................................................ 4 5 
8. 1  
I n v esti gati o nal pr o d uct(s) ...................................................................................... 4 5 
8. 1. 1  
Descri pti o n of i n vesti gati o nal pr o d uct(s)......................................................... 4 5  
8. 1. 1. 1  
I nstr ucti o ns f or pre p ar ati o n ....................................................................... 4 5 
8. 1. 1. 2  
I nstr ucti o ns f or a d mi nistr ati o n .................................................................. 4 6 
8. 1. 2  
Pac ka gi n g a n d la b eli n g  .................................................................................... 4 8 
8. 1. 3  
St ora ge of i n vesti gati o nal pr o d uct(s) ............................................................... 4 8  
8. 1. 4  
Acc o u nta bilit y f or i n vesti gati o nal pr o d u ct(s) .................................................. 4 9  
8. 1. 5  
Destr ucti o n of i n vesti gati o nal pr o d uct(s)......................................................... 4 9  
8. 2  
Treat me nts a d mi nistere d  ........................................................................................ 5 0 
8. 2. 1  
Met h o ds of assi g ni n g s u bjects t o treat me nt gr o u ps ......................................... 5 1  
8. 2. 2  
Selecti o n of d oses i n t he st u d y ......................................................................... 5 2  
8. 2. 3  
Selecti o n a n d ti mi n g of d oses f or eac h s u bject ................................................ 5 2  
8. 2. 4  
D urati o n of treat me nt per s u bject .................................................................... 5 3  
8. 2. 5  
Treat me nt c o m plia nce  ...................................................................................... 5 3 
8. 2. 6  
Treat me nt of o v er d ose ..................................................................................... 5 3  
8. 3  
Pre vi o us a n d c o nc o mita nt t hera pies....................................................................... 5 4  
8. 4  
Restricti o ns d uri n g t he st u d y ................................................................................. 5 6  
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  ............................................ 5 8 
9. 1  
Assess me nts  ........................................................................................................... 5 8 
9. 1. 1  
Cli nical assess me nts ......................................................................................... 5 8 
9. 1. 1. 1  
Effic acy assess me nts  .................................................................................. 5 8 
9. 1. 1. 2  
Ge ner al assess me nts  .................................................................................. 6 2 
9. 1. 2  
La b orat or y e val uati o ns ..................................................................................... 6 3 
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 3  
9. 1. 3  
P har mac o d y na mics  .......................................................................................... 6 4 
9. 1. 4  
P har mac o ki netics  ............................................................................................. 6 4 
9. 1. 5  
P har mac o ge n etics  ............................................................................................ 6 4 
9. 1. 6  
Ta ble of bl o o d v ol u me ..................................................................................... 6 5  
9. 1. 7  
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 5  
9. 2  
Visit sc he d ule  ......................................................................................................... 6 5 
9. 2. 1  
M o difie d visit sc he d ule d uri n g a p a n de mic ..................................................... 6 6  
1 0  S A F E T Y A S S E S S M E N T S  ....................................................................................... 7 2 
1 0. 1  
Defi niti o n of a n a d v erse e ve nt ............................................................................... 7 2  
1 0. 1. 1  
Defi niti o n of i nte nsit y  ...................................................................................... 7 3 
1 0. 1. 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 4  
1 0. 1. 4  
Cate g ories of o utc o me  ..................................................................................... 7 4 
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C o nfi de ntial  
P a ge 9  of 2 1 0  
1 0. 2  
Defi niti o n of a seri o us a d verse e v e nt  ..................................................................... 7 5 
1 0. 3  
A E SIs / al ert ter ms  ................................................................................................. 7 6 
1 0. 4  
E x pecte d a d verse e ve nts  ........................................................................................ 7 8 
1 0. 5  
U ne x pecte d a d verse e v e nts  .................................................................................... 7 9 
1 0. 6  
Pre g n a nc y  ............................................................................................................... 7 9 
1 1  D A T A Q U A LI T Y A S S U R A N C E  ............................................................................ 8 0 
1 1. 1  
Sta n dar dizati o n pr oce d ures .................................................................................... 8 0  
1 1. 2  
S o urce d oc u me ntati o n re q uire me nts ...................................................................... 8 0  
1 1. 3  
Data ma na ge me nt ................................................................................................... 8 1 
1 1. 4  
M o nit ori n g ............................................................................................................. 8 2  
1 1. 5  
A u diti n g ................................................................................................................. 8 3  
1 2  S T A TI S TI C A L M E T H O D S  .................................................................................... 8 4 
1 2. 1  
Deter mi nati o n of sa m ple size  ................................................................................. 8 4 
1 2. 2  
A nal ysis sets ........................................................................................................... 8 5 
1 2. 3  
E n d p oi nts a n d mai n esti ma n ds f or a nal ysis ........................................................... 8 5  
1 2. 3. 1  
Efficac y e n d p oi nts a n d mai n efficac y esti ma n ds ............................................. 8 5  
1 2. 3. 1. 1  
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  
1 2. 3. 1. 2  
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.................................................................................................... 9 0  
1 2. 3. 2  
P har mac o d y na mic e n d p oi nts  ........................................................................... 9 3 
1 2. 3. 3  
P har mac o ki netic e n d p oi nts .............................................................................. 9 3  
1 2. 3. 4  
P har mac o ge n etic e n d p oi nts  ............................................................................. 9 3 
1 2. 3. 5  
Safet y e n d p oi nts  ............................................................................................... 9 3 
1 2. 3. 5. 1  
Pri m ary s afety e n d p oi nt ............................................................................. 9 3  
1 2. 3. 5. 2  
Sec o n d ary s afety e n d p oi nts ........................................................................ 9 4  
1 2. 4  
Statistical a nal ysis met h o ds  ................................................................................... 9 4 
1 2. 4. 1  
Efficac y e n d p oi nts a n d efficac y esti ma n ds ...................................................... 9 4  
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 5  
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 7  
1 2. 4. 2  
P har mac o d y na mic e n d p oi nts  ........................................................................... 9 8 
1 2. 4. 3  
P har mac o ki netic e n d p oi nts .............................................................................. 9 9  
1 2. 4. 4  
P har mac o ge n etic e n d p oi nts  ............................................................................. 9 9 
1 2. 4. 5  
Safet y e n d p oi nts  ............................................................................................... 9 9 
1 2. 4. 5. 1  
Pri m a ry s afety e n d p oi nt ............................................................................. 9 9 
1 2. 4. 5. 2  
Sec o n d ary s afety e n d p oi nts ........................................................................ 9 9  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 0  of 2 1 0  
1 2. 4. 7  
S pecial statistical/a nal yti cal iss ues  ................................................................ 1 0 0 
1 2. 4. 7. 1  
Disc o nti n u ati o ns a n d missi n g d at a .......................................................... 1 0 0  
1 2. 4. 7. 2  
I nteri m a n alyses ....................................................................................... 1 0 0 
1 2. 4. 7. 3  
C o m mittees  ............................................................................................... 1 0 0 
1 2. 4. 7. 4  
M ulti ple c o m p aris o ns/ m ulti plicity  ........................................................... 1 0 1 
1 2. 4. 7. 5  
Ex a mi n ati o n of s u b gr o u ps ....................................................................... 1 0 1  
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 3 
1 3. 1  
C orrecti o ns t o data ............................................................................................... 1 0 3  
1 3. 2  
Rec or d kee pi n g ..................................................................................................... 1 0 3  
1 3. 3  
Destr ucti o n of st u d y d oc u me nts........................................................................... 1 0 4  
1 4  P U B LI C A TI O N P O LI C Y  ...................................................................................... 1 0 5 
1 5  R E F E R E N C E S  ....................................................................................................... 1 0 6 
1 6  A P P E N DI C E S  ......................................................................................................... 1 0 9 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 1  of 2 1 0  
 
Li st of Fi g ur e s  
Li st of T a bl e s  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 2  of 2 1 0  
1 
S Y N O P SI S  
St u d y title  
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 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 b ellar 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  ( h oriz o ntal f ore hea d li nes, gla bellar fr o w n li nes, a n d l ateral ca nt hal 
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 xcl 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 hea 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 h e i n vesti gat or a n d s u bject acc or di n g t o  
Merz Aest hetics Scale  [ M A S]. T he rati n gs of t he i n vesti 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 derate 
or se ver e.  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 3  of 2 1 0  
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 la st 1 2 m o nt hs bef ore i njecti o n. 
•  
A n y f acial 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 h era p y,  laser  treat me nt,  ultras o u n d  treat me nt,  tatt o o i 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 pr e vi o us i nserti o n of per ma ne nt mat erial i n t he face  i ncl u di n g a n y i nserti o n 
of trea ds i n  t he u p per fac e or at c hee ks (re gar dless of t he ti me bet wee n pre vi o us 
treat me 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. 
St u d y desi g n  
T his  will  be  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 nter  
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 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 h e  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), L C L  treat me nt  ( Gr o u p  L ),  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 2 4 U N T  2 0 1 i n t he L C L area a n d place b o i n t he G F L a n d H F L area 
( Gr o u p L), or wit h  place b o i n all t hre e facial 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 ycl e  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  
(if re q uire d). 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 01  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 val uate d b ef or e eac h 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 4  of 2 1 0  
Pl a n ne d st u d y peri o d  
First s u bject first visit:   
Q 4 2 0 2 0 
Last pri mar y o utc o me visit:   Q 2 2 0 2 1 
Last s u bject last visit:    
Q 3 2 0 2 2 
D ur ati o n of t re at me nt per s u bject  
S u bjects will recei ve i n v esti gati o nal pr o d u ct (I P) 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 
Pri 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 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 nd  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 -r es 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 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 h e s u bject. 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 5  of 2 1 0  
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 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 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 v esti 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 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. 
•  
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  bas eli 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 vesti 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  bas eli 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 ntract i o n as assesse d b y t he  
i n vesti 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  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 t he i n vesti gat or  
•  
G AI S  as assess e d b y t he i n vesti gat or at D a 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. 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
 
P a ge 1 6  of 2 1 0  
Sec o n d ary s afety e n d p oi nts 
•  
I n ci de nce of r elate d treat me nt-e mer ge 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 Ger ma n y. 
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 u p t o 1 2 sites i n Ger ma n y. 
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 visits), 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 v e  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 met 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 ys es f or pri mar y efficac y e n d p oi nts will  be  base 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 “ Male 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 derate (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 assesse d b y t he i n v esti 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 tr eat 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 mize d treat me nt 
assi g n me nt.”  F urt her  e fficac 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 bjects, 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 ns zel 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 . 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 7  of 2 1 0  
T he fa mil y -wise t w o -si d e d t y p e 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 
vers us P will be c o n d u cte 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 h e test 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. 
Gr o u p L will  n ot be part of t he pri 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 nc i de n ces 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 M e dical Dicti o nar y f or Re g ulat or y A cti vities  (Me d D R A ) s yst e m or ga n class 
a n d pref err e d ter m b y ra n d o mize 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 he  a nal ys es  b y  treat me nt  c ycl e,  t he  de n o mi nat or  f or  t he  
i nci de nces will be a dj ust e d t o all s u bjects bei n g treate d i n t hat treat me nt c ycle. 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 2 1  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 2 2  of 2 1 0  
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) 
T he f oll o wi n g d oc u me nts m ust be s u b mitte d t o t he res p o nsi ble I E C a n d p ositi ve o pi ni o n 
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 o c 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  w ell  as  u p dat es  (if  
a p plica ble).  
•  
S u bject car d  
•  
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). 
•  
I ns ura nce state me nt/certificate a n d c o n diti o ns 
•  
F or ms/ Q uesti o n naires  f or  assess me nts  t o  be  c o m p lete d  b y  t he  s u bj ect  (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 b e 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 parat e 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 his st u d y will be c o n d ucte d i n acc or da n ce wit h t he et hical pri n ci ples t hat ha ve t heir 
ori gi n i n t he D eclarati o n of H elsi n ki 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 uir e me nts, i ncl u di n g E U ( Directi v e 2 0 0 1/ 2 0/ E G; Ge neral Data Pr otecti o n 
Re g ulati o n) a n d G er ma n la ws ( Ger ma n M e dici nes Act [ A M G]; G C P -or di na nce [ G C P -V] 
a n d a p plica ble d ata pr ot ecti o n 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 vals, f a v ora ble o pi ni o ns, or a d diti o nal re q uire me nts of t he a p pr o priat e IE 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 ges i n pr ot o c ol c o n d uct necessar 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 2 3  of 2 1 0  
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).  
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  
3. 3. 1  
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 n ce,  e x pecte d  b e nefits,  p ote ntial  ris ks,  a n d  e x pecte d  
c o nse q ue nces of t he st u d y. T he s u bject will be  i nf or me d t hat t he treat me nt wit h N T 2 0 1 
is n ot per ma ne nt a n d r es ults i n a te m p orar y i m pr o ve me nt of wri n kles f or 4 – 6 m o nt hs, i n 
i n di vi d ual  patie nts  e ve n  l o n ger,  a n d  t hat  s u bjects  will  ret ur n  t o  t heir  baseli ne  stat us  
after w ar ds. T his ver bal a n d writte n i nf or mati o n will be pr o vi de d b y t he 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 D eclarati o n of H elsi n ki. 
T he o bli gati o ns of t he i n vesti gat or are set f ort h i n t he cli nical st u d y pr ot oc ol, t he I C H -
G C P pri nci ples (eff ecti v e 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  n ati 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, i ncl u di n g E U ( Directi ve 2 0 0 1/ 2 0/ E G; Ge neral Data Pr otecti o n Re g ulati o n) a n d 
Ger ma n la ws ( Ger ma n Me dici ne s Act [ A M G]; G C P-or di na nce [ G C P -V] a n d a p plica ble 
data pr otecti o n re q uir e m e nts).  Eac h s u bject  will  ha ve t he o p p ort u nit y t o q uesti o n t he 
i n vesti gat or ( or a ut h orize 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. 
3. 3. 2  
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 orize d d esi g n ee 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  was 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 plie d t he i nf or mati o n. 
T he 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 dates (if a p plica bl e).  
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  m a n ner  if  
i nf or mati o n  bec o mes  a vaila ble  t hat  ma y  be  rele va 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 v erse e ve nts ( A Es), or p o or t olera bilit y t o 
t he i n vesti gati o nal pr o d u ct (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 ke a j u d g me nt w het her c o nti n ui n g i n t h e st u d y ser ves t he s u bject’s b est i nterests. T he 
s u bject, h o we ver, is free t o wit h dra w c o nse nt at a n y ti me a n d f or a n y reas o n, w het her 
e x presse d or n ot. F or c o u ntr y -s p ecific re q uire me nts, see Secti o n  1 6. 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 2 4  of 2 1 0  
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 nifi ca nt c h a n ges 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 v er bal 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 d ate 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 urier t o o btai n a re -c o nse nt. 
•  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 w a 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 su bjects are a ble t o ret ur n t o t he sites, if a p plica ble.  
3. 3. 3  
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 b ject’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 p art 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.  
•  1 2 U per si de i n t he lat eral or bic ularis oc uli m uscle a n d place b o i n t he c orr u gat or 
a n d pr ocer us. 
•  Place b o i n all t hree area s. 
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. 
3. 3. 4  
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 u ati 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 . 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 2 5  of 2 1 0  
3. 3. 5  
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 mize d)  o nl y  t o  a ut h orize d  
i n divi 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 m er ge ncies) will be 
p ossi ble b y t he s pecific 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 dat a will be all o w e d s olel y t o c hec k v ali dit y, a n d s u c 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 orize d b y 
t he s p o ns or ( e. g. ( m e 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) w h o h a ve bee n b o u n d t o c o nfi de ntialit y. If t he 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 d e ntial. 
3. 3. 6  
C o nt a ct p oi nt  
All  s u bjects  will  be pr o vi de d wit h t he s u bject  i nf or me d c o nse nt  f or m  wit h a c o ntact  
a d dress w her e t he y m a y o btai n f urt her ge n eral i nf or mati o n re gar di n g cli ni cal st u dies  a n d 
data pr otecti o n ri g hts . T h e s u bject car d will als o c o ntai n t he c o ntact p oi nt of t he st u d y site 
a n d t he res p o nsi ble PI.  
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 r e g ulati 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 v esti 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 h e 
i ns ura nce d o c u me nt c o n diti o ns will be ha n de d o ut t o t he s u bject. 
A n y me di cal 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 o c ol. T he s p o ns or 
is als o us uall y not lia ble f or e ve nts res ulti n g fr o m ne gli ge n ce of t he i n vesti gat or, cli nical 
st u d y  st aff,  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 h e cli nical st u d y pr ot o c ol. 
F or deta ile d c o u ntr y-s p ecific (i.e. Ger ma n y-s pecifi c) re q uire me nts, see Secti o n  1 6. 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 2 6  of 2 1 0  
3. 5  
Fi n a n ci n g  
T he  fi na n cial  as p ects  of  t he  st u d y will  be  d o c u me nte d  i n  a n  a gree me nt  bet wee n  t he  
S p o ns or, t he C R O, eac h PI  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 h e st u d y c o m me n ces.  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 2 8  of 2 1 0  
Me dic al b ac k gr o u n d 
A y o ut hf ul a n d aest h eticall y pl easa nt a p peara nce is i ncreasi n gl y i n -f o c us all o ver t he 
w orl d. Eff ecti ve ma na ge me nt of facial li nes re q uires a p pr oac h es t hat i n cl u de aest hetic 
a n d der mat ol o gical treat me nts , s uc h as peels, laser res urfaci n g, a n d fill ers, as well as  
s ur gical  treat me nts, s uc h  as  r h yti d ect o m y,  e ye br o w  lift,  a n d  ble p har o plast y  
[Cat her  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 t ec h ni q ues ma y n ot ac hi e 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 pres e 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 1 8 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 ]. I n Ger m a n y, t he B o N T-A treat me nt is t he m ost fre q u e nt 
a n d fa v ore d n o n -s ur gical mi ni mall y i n vasi ve c os metic pr oce d ure [De utsc he Ges ellsc haft 
f ür Äst hetisc he- Plastisc he C hir ur gi e 2 0 1 8, Statista 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 [Carr 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 os e. T he a p pr o ve d sta n dar d d ose of N T 2 0 1 i n t his 
i n dicati o n is 2 0 u nits [ U]  [B oc o ut ure E U S u m mar y of Pr o d u ct C haracteristics ] b ut t he 
d ose ma y be i ncr ease 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 uscl e a n d te n d t o b e dee per i n s u bjects w ho 
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 nse 
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 x cessi ve br o w pt osis s h o ul d n ot ge t 
i njecte d i n t he fr o ntalis m uscle t o a v oi d e x cessi 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 h er d ose ca n be us e d t ha n d uri n g a 
si n gle  tr eat 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 ha nce  of br o w  pt osis  de vel o p i n g  [Carr ut hers  2 0 0 4, 
Kee 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 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 2 9  of 2 1 0  
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 si n gle s u bj ect, a n d c o nse q ue ntl y h olistic treat me nt is bec o mi n g i n creasi 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  [Blitzer  1 9 9 7, C arr ut hers  2 0 0 7, 
Carr ut hers  2 0 0 9 a, Carr ut hers  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]. The 
c o m bi ne d treat me nt of differe nt u p p er f aci 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 has 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  tr eat me nt  of  wri n kles  i n  t h e  u p per  face  pr o d uces  a  y o u n ger,  m ore  
refr es he d, nat ur al a n d m ore rela x e d a p peara n ce a n d is bec o mi n g i ncreasi n gl y p o p ular. 
Treat me nt wit h B o N T - A i n t he u p per face offers pre dicta ble res ults, has fe w a d vers e 
effects, a n d is ass ociate d  wit h hi g h patie nt satisfacti o n . T he E U a ut h orities a gree d t o 
m ut uall y a p pr o v e 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 -Mar c h -2 0 1 6. 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 treat me nt 
of m o derate  t o se ver e G F L i n 2 0 1 1. T he s p o ns or i nte n ds t o br oa de n t he e xisti n g U S 
aest hetic la bel f or Xe o mi n (c urre 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 ar ea s ( G F L, H F L, a n d L C L) 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 3 0  of 2 1 0  
T he pla n ne d st u d y will a d d t o a n u m ber of cli ni cal st u dies t hat ha v e bee n c o n d ucte d i n 
t he 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 urre 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 h er t ha n tr eati n g si n gle f ol ds or mi mic m uscle gr o u ps i n or der t o ac hie ve a 
m ore nat ural aes t 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 eff ects, a n d is ass ociate d wit h hi g h p atie nt satisfacti o n . 
N T  2 0 1  was  safe  a n d  well  t olerate d  w he n  all  t hree  facial  areas  w ere  treate d  i n 
c o m bi nati o n, a n d n o ne w saf et y c o n cer 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 or e o ver, t her e w as n o e vi de nce of a n i ncrease d i nci de nce of treat me nt-e mer ge nt 
A Es [ T E A Es ], a n d es peci all y t h ose of s pecial i nterest [treat me nt-e mer ge nt A E SIs], i n 
s u bjects u n der g oi n g re p eat-d ose treat me nt.  
T o date, a ll cli nical st u dies wit h N T 2 0 1 i n s u bjects wit h m o derate -t o-se v ere 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, h a ve s h o w n a g o o d efficac y a n d c o m para ble safet y 
pr ofile , wit h  n o  e vi de n ce  of ne w  safet y  c o ncer ns.  N o  ne w  safet y  iss ues  ha ve  bee n  
detecte d i n t h e o ver all s afet y dat a base.  T he s afet y res ults are c o nsiste n t 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 nce fr o m t he c o m pre h e nsi ve o verall 
safet y data b ase. 
I n  ge n eral,  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 desira ble effects af ter N T 2 0 1 i njecti o n i ncl u de l ocal, ge nerali ze d, or pr oce d ural A Es 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 3 1  of 2 1 0  
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 osis. 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 nal 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 
e ns 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 x a m ple, fr o m q uara nti nes, site cl os ures, tra vel li mitati o ns, 
i nterr 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 bjects 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-s pecifie 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 ef er t o Secti 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 3 2  of 2 1 0  
5 
S T U D Y O BJ 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  s e 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 e fficac 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 3 3  of 2 1 0  
6 
I N V E S TI G A TI O N A L P L A N 
6. 1  
O v er all st u d y d e si g n  
T his  will  be  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 ulti ce 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 ycl e 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: t he U F L treat me nt gr o u p ( Gr o u p U) , t he L C L treat me nt gr o u p ( Gr o u p L), a n d t he 
place b o gr o u p ( 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 h e M P, s u bjects will 
be treate d eit her wit h a t otal d ose of 6 4  U N T  2 0 1 ( U F L), or wit h 2 4  U N T 2 0 1 i n t he 
L C L area  a n d place b o i n t he G F L a n d H F L area, or wit h place b o i n all 3 facial areas.  F or 
f urt her  det ails,  see  
 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 b ef or e t he y ma y e nter i n t o t he O L E X p eri o d. T he d urati o n of t he M P ( C ycle  1) 
will t heref ore b e 1 2 0  d a ys pl us t he d urati o n of i n di vi d ual scree ni n g ( s cree ni n g: D a ys - 1 4 
t o - 3). 
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 ycl es, C ycle  2 a n d C ycl e  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 m e nts per c ycle. 
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  furt h er  details  see  
 F or  det ails  o n  t he  pla n ne d  visits,  see  
Secti o n  9. 2 . 
T he  o ver all  st u d y  d urati o n  will  be  a b o ut  3 6 0  da ys  pl us  t he  i n di vi d ual  d urati o n  of  
scree ni n g ( Da y -1 4 t o  -3)  at st u d y start pl us a m a xi m u m of 3 0  da ys after C ycle 1 a n d 
C ycle 2 f or eli gi bilit y r eassess me nt f or e nteri n g t he ne xt treat me nt c ycl e, as a p plica ble. 
Eli gi ble s u bjects will recei ve o ne i njecti o n sessi o n wit h st u d y treat me nt eac h at D a y 1 of 
t he res pecti ve treat me nt c ycle. 
T his st u d y will be c o n d u cte d i n u p t o 1 2 sites i n Ger ma n y. 
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.  
6. 1. 1  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 3 4  of 2 1 0  
6. 2  
Di s c u s si o n of st u d y d e si g n, i n cl u di n g c h oi c e of c o ntr ol gr o u p s  
T he 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 desi g n of t he 
M P  of  t his  P hase  3  st u d y  w as  c h os e 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 mize 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 r es ults are e x pecte 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 3 5  of 2 1 0  
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 f irst 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 4 2  of 2 1 0  
7. 4  
R e m o v al of s u bj e ct s fr o m tr e at m e nt or a s s e s s m e nt  
7. 4. 1  
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 nce  wit h  t he  Declarati o n  of  Helsi 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 partici 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 nefits  t o w hic h t he s u bject 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 h e s u bject’s partici pati o n i n t he st u d y was pre mat urel y dis c o nti n ue d m ust 
be  rec or de d  i n  t he  s o urce  d oc u me nt ati o n  (e. g. s u bject’s  me dical  rec or ds)  a n d  t he  
electr o nic  Case  Re p ort  F or m  (e C R F).  Dat e  a n d  mai n  disc o nti n uati o n  circ u msta n ces 
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 p artici 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 n a nc y  pri or  t o  i njecti o n  of  I P.  I n  cas e  of  pre g n a nc y  after  a  s u bj ect  has  
recei v e 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 v asi 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 o ce 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. 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 4 3  of 2 1 0  
•  
I nta k e of a n y ot her i n vesti gati o nal dr u g. 
•  
A d mi nistrati o n of b ot uli n u m t o xi n of a n y ser ot y p e i n t he face e x ce pt f or I P. 
•  
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, m es ot hera p y, p h ot o d y n a mic t h era 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 x cl usi o n  criteria  
esta blis he d i n Secti o n  7. 3  t hat arise after t h e s u bj ect has bee n i ncl u de d i n t he st u d y m a 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 nt e 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 pl a n ne d miti gati o ns t o 
pr otect  t he  saf et 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  recr 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 ha 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 
site is cl ose d e. g. d u e 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 q uire 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).  
7. 4. 2  
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 sit e 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 bjects. 
•  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 4 4  of 2 1 0  
•  
T he i n vesti gat or or st u d y site e x hi bits 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 re q uire me nts , i ncl u di n g E U ( Directi ve 2 0 0 1/ 2 0/ E G; Ge neral 
Data Pr otecti o n Re g ulati o n) a n d G er ma n la ws ( Ger ma n M e dici nes A ct [ A M G]; 
G C P - or di na nce [ G C P- V] a n d a p plica ble d ata pr ot ecti o n re 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 he st u d y ma y be pre mat urel y e n d e d if t he re g ulat or y a ut h orit y or t he I E C  
has  deci de d  t o  wit h dr a w  or  s us pe n d  a p pr o val  f or  t he  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 t er 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, 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 r eas 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 heal t 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 nte na nce of data v ali dit y.  
7. 4. 3  
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. 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 4 5  of 2 1 0  
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) 
8. 1. 1  
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 u n der t he bra n d na mes B oc o ut ure ( E U/ E E A o nl y) a n d Xe o mi n i n t he 
U S  (acti ve  i n gr e die nt:  N T  1 0 1,  B o N T -A  free  fr o m  c o m ple xi n g  pr ot ei ns;  U S A N:  
i nc o b otuli 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 r ec 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 d er  f or  rec o nstit uti o n,  e x ci pie nts  o nl y (s u cr ose,  
h u ma n ser u m al b u mi n) wit h o ut N T  1 0 1. Place b o vi als 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  M erz  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 ea se d  b y  Merz  
P har mace uticals G m b H, Alfre d -We ge n er - Stra ße 2, 6 0 4 3 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 is a vac u u m i n t he vial w hic h e ns ures t hat t he l y o p hili ze 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 n etrate 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 be rel e ase d a n d 
t he p o w der dis perse 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 h e 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 n ee dle 
is rec o m me n d e d f or r ec o nstit uti o n. After re m o val of t he s yri n ge fr o m t he vial t he pr o d u ct 
is mi x e d wit h t he s ol ve nt b y caref ull y s wirli n g a n d i n verti n g t he vi al a n d s h o ul d n ot be 
s ha ke n vi g or o usl y. If nee de d, t he n ee 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 uir e 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 he  I P(s)  s h o ul d  be  rec o nstit ute d  s h ortl y  b ef ore  
i njecti o n. H o we 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 ger at or at 2° C t o 8° C.  
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 4 6  of 2 1 0  
A n y de vi ati o n t o t his will be d oc u me nte 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 I P  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 ges, 
s pilla ges, or ot h er materials t hat ha ve bee n i n c o ntact wit h t he test or refere nce pr o d u ct 
m ust be a ut ocla ve d. A n y ( partiall y) use d or u n use d I P will be destr o ye d a p pr o priatel 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  trai ne d  a n d  
dele gate d st u d y tea m me m ber. 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 ups, 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 
 n ee dles m ust be use d f or i njecti o ns. 
O nl y t he pr o vi de d st u d y mater ial is all o we d t o 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 perie n ce d i n aest hetic B o N T treat me nt are all o we d t o 
i nject. T he n u m ber of i n vesti gat ors res p o nsi ble f or t hese tas ks 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.  I n e x ce pti o nal cases, a n i n vesti gati o nal site ma y 
trai n a t hir d i nject or as a preca uti o n t o o verc o me e ve nt ual staff s h orta ge d uri n g t h e ne w 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 4 7  of 2 1 0  
C O VI D -1 9 pa n de mic o ut brea k. I n a n y case, a t hir d i nject or at  a n i n vesti gati o nal  site m ust 
be a n n o u nce d t o a n d a gr ee d b y t h e s p o ns or i n a d va nce. 
Bef ore  i njecti o ns,  t he  area  t o  be  treate d  will  be  clea n e 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  s afet y  reas o ns,  
e mer ge n c y e q ui p me nt f or treat me nt of a na p h ylactic reacti o ns will be a vail a ble at site. 
. 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 d a nce wit h t his 
cli nical st u d y pr ot o c 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 4 8  of 2 1 0  
8. 1. 2  
 
 c o ntai ni n g N T 2 0 1 or place b o vials f or t he M P will be se nt t o t he 
sites. 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 
materials. 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 t he 
o pe n- la bel tr eat me nt peri o ds. 
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 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  I P  will  be  la bele d  
acc or di n g t o re g ulat or y r e q uire me nts i n t he partici pati n g c o u ntries. F or t h e d o u ble- bli n d 
part of t his st u d y, t he test pr o d uct a n d refere n ce pr o d uct(s) will ha ve t he sa me pri nte d 
la bel  i nf or mati o n  o n  t h e  o uter  me dicati o n  pac ka gi n g  ( b o x)  a n d  t he  i n ner  c o ntai n ers  
( vials). See Secti o n 8. 5  f or details of t he bli n di n g pr oce d ures pla n ne d f or t his st u d y. 
8. 1. 3  
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  will  be  
i ncl u de d i n t he s hi p me nt. U n o pe ne d vials s h o ul d be st ore d at a te m perat ure bet wee n 2 ° C 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 4 9  of 2 1 0  
a n d  2 5° C. D uri n g st or a 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 perat ur e l o g eac h w or ki n g da y b y a mi n-/ ma x-t her m o meter pr ovi de d b y t h e S p o ns or, 
C R O or ce ntral la b or at or y. 
8. 1. 4  
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 a p plica ble la w t o  
e ns ure t hat a c urre nt rec or d of i n ve nt or y/ dr u g acc o u nta bilit y is mai nta i ne d. I n v e nt or y 
rec or ds m ust be rea dil y a vaila 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 re g ulat or y a ut h orities at a n y ti me. E ac h s hi p me nt of materials f or t he st u d y 
will c o ntai n a n ‘I P deli v er y f or m’ t o assist t he i n vesti gat or i n m ai ntai ni n g u p -t o-date a n d 
acc ur ate i n ve nt or y rec or ds. T his f or m i ncl u des t h e f oll o wi n g i nf or mati o n: st u d y n u m ber, 
dates, q ua ntities, batc h n u m ber, e x pirati o n date, a n d t he me dicati 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 a p plica ble 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  d eli ver y  f or m’  will  be  c o m plet e d  a n d  si g n e 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 n al 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 ge 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 nter vals  b y  t h e  m o nit or  ( Cli nical  Researc h  Ass ociate). 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 orities) 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 p erf or m st u d y -acc o u nta bilit y pr o ce d ures re m otel y a n d 
ret ur n of u n use d s u p plies ma y b e dela ye d u ntil site pers o n nel are a ble t o safel y d o s o. 
8. 1. 5  
D e str u cti o n of i n v e sti g ati o n al pr o d u ct( s)  
A n y us e 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 n e of t he f oll o wi n g met h o ds: 
•  
A ut ocla vi 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 5 0  of 2 1 0  
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 
p le nt y of water 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 da ma ge d s ki n, t he area s h o ul d b e ri nse d t h or o u g hl y wit h ple nt y of w ater 
a n d a p pr o pri ate me dical ste ps acc or di n g t o t he d ose 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 us e 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 orize d part y. T he s p o ns or or a n ot her  
a ut h orize d part y will destr o y t h e I P(s) after c o m pleti o n of t he cli nical st u d y re p ort t a k i 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 orizati 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 ycl e 1)  s u bjects  will  be  ra n d o mi z e 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 Gr o u p L, s u bjects will recei v e place b o i n t he G F L area, pl ace b o 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 Gr o u p 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 ( C ycles 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 . 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 5 1  of 2 1 0  
I n case of a p u blic healt h e mer ge n c y treat me nts ma y b e halte d or p ost p o n e d. 
8. 2. 1  
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, 
L,  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 bers a n d date of ra n d o mizati o n will be rec or d e d i n t he e C R F . 
Ra n d o miz ati o n  will  be  stratifie d  b y  i n v esti gati o nal  site  a n d will  be  i n  bl oc ks  of  
a p pr o priate  size.  T his  will  e ns ure  a n  a p pr o xi matel y  e q ual  rati o  of  treat me nt  gr o u ps  
bet wee n sites.  T h e bl oc k size will n ot be discl ose d t o i n vesti gat ors u ntil t he st u d y is 
u n bli n de d. 
N o ot her criteria f or str ati ficati o n of ra n d o mizati o n will be a p plie d. 
If s u bj ects ar e disc o nti n ue d fr o m t he st u d y d uri n g t he M P, n o re place me nt of s u bjects is 
pla n ne 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 5 3  of 2 1 0  
8. 2. 4  
D ur a ti o n of tr e at m e nt p er s u bj e ct 
S u bjects will recei ve I P at u p t o t hree i njecti o n visits.  T he o verall st u d y d urati o n f or eac h 
s u bject will be a p pr o xi matel y 3 6 0 d a ys pl us t h e i n di vi d ual d urati o n of scree ni n g u ntil 
baseli ne  ( u p  t o  1 4  da ys)  pl u s  a  ma xi m u m  of  3 0 da ys  after  C ycle 1  a n d  C ycle  2, 
res pecti vel y, f or eli gi bilit y r eassess me nt as a p plica ble.  
I n case of a p u blic healt h e mer ge nc y t h e 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 b e m o difie d wit h i m pa ct to 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.  
8. 2. 5  
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. 
8. 2. 6  
Tr e at m e nt of o v er d o s e  
A n o ver d ose is defi ne d as a n y d e viati o n fr o m t he s pecifie d d ose i n t he pr ot oc ol ( d oses 
t hat ar e 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 secti o n, 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 m e nts. A n y case of o ver d ose lea di n g t o 
seri o us a d verse e v e 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 ner usi n g t h e a p pr o priat e re p orti n g f o r m (Secti o n  1 0. 1 ). 
As treat me nt wit h I P is perf or me d e x cl usi vel y i n a cli nical setti n g u n der t he s u per visi o n 
of trai ne d me dical pers o n nel, t he ris k of o ver d os e i n t his st u d y is esti mate d t o be ver y 
l o w. F or t he I P use d i n t his st u d y, n o a nti d ote has bee n i de ntifie d t o date, 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 v er d ose. 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 5 4  of 2 1 0  
T here is n o si g nifica nt i nf or mati o n re gar 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 ysici a n is a d vise d t o use 
best cli nical j u d g e me 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 x cess d ose. E x cessi 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 ut e  s y m metric,  desce n di n g  fl acci 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 o cc ur 1 2 t o 
7 2 h o urs after e x p os ure [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 ptosis, ge neralize 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 i atr o ge nic 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  w ere  c o nsiste nt  wit h  t h ose  of  
nat u rall y o cc 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 os e 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 bser v e d,  treat me nt  wit h  a ntit o xi n  will  n o  l o n ger  be  
effecti ve beca us e t he ne ur ot o xi n has alrea d y irre versi 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 u a ni di ne,  3, 4 -dia 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 perie nce wit h a s pecific a nti d ote t o 
B o N T i n cl 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 h e d case re p ort 
descri bes  t he  s uccessf ul  treat me nt  of  d ys p ha gi a  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 n c 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  o cc 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 x cessi 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 b e re q uire d 
w here e x cessi ve d oses ca use paral ysis of t he res pirat or y m uscl es. 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 pare nt  b y  t he  ti me  of  a ntit o xi n  
a d mi nistrati o n.  
8. 3  
Pr e vi o u s a n d c o n c o mit a nt t h er a pi e s  
Bef ore  e nr oll me nt,  t he  s u bject’s  me dical  hist or y  s h o ul d  i ncl u de  a  detaile d  list  of  all  
me dicati o ns (i ncl u di n g r esc ue me dicati o n) t hat t he s u bject was ta ki n g f or a peri o d of at 
least 3 0 da ys a n d f or a p eri o d of 1 2 m o nt hs f or n o n-dr u g t hera pies pre vi o us t o scree ni n g. 
T he rec or d s h o ul d i ncl u de t he dr u g na me (tra d e or ge neric), r o ute of a d mi nistrati o n (e. g., 
i ntra ve n o us, oral), t otal d ail y d ose/ u nit (e x presse d i n m g, m L, or I U), i n dicati o n, t he start 
a n d st o p date ( da y, m o nt h, a n d year) f or eac h me dicati o n. At t he e n d of t he st u d y , a n 
a d diti o nal state me nt will be e ntere d t o i n dicat e w het her t he i nta ke of t he me dicati o n is 
o n g oi n g at t he e n d of t he st u d y. 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 5 6  of 2 1 0  
a gai nst  acet yl c h oli ne  rece pt ors  (e. g.,  D -p e nicilla mi ne), wit hi n  1 4  da ys  bef ore  
i njecti o n a n d d uri n g t h e e ntire c o urse of t he st u d y8. 
•  
Reti n oi ds (e x cl usi o n criteri o n n o. 4) 
•  
B o N T treat me nt of a n y ser ot y p e f or a n y treat m e nt i n dicati o n d uri n g t h e 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 h e e ntire c o urse of t he st u d y. 
T hera p y c ha n ges (i ncl u di n g c h a n ges of re gi me n) d uri n g t he st u d y are t o b e d oc u me nte d 
i n t he s o urce d oc u m e 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 nj ecti 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 4).  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 5 7  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 5 8  of 2 1 0  
9 
S T U D Y A S S E S S  M E N T S  A N D VI S I 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 b e 
descri be d i n a res pecti ve o utc o me ma n ual ( pr o vi de d b y M erz). All  assess me nts will be 
p erf or me d  as  s c he d ule d  acc or di n g  t o  t he  st u d y  fl o w  c h art  pr o vi de d  i n  
 i n 
Secti o n  9. 2 . A n o verall d escri 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 . 
9. 1. 1  
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 nd st u d y st aff 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 ns ure 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 ni cal assess me nts 
a n d self-assess me nts. T he 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 uate  li g hti n g  a n d  wit h o ut  
dist ur ba nce at t he b e 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 b e 
pr o vi de d s o t hat s u bjects ca n c o ntr ol res pecti vel y f or t heir facial a p peara n ce. 
E ntries i n t he s o urce d o c u me nts 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. 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 5 9  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 6 0  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 6 1  of 2 1 0  
 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 6 2  of 2 1 0  
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 n c o mita nt  me dicati o n,  
pri or a n d c o n c o mita nt n o n- dr u g t hera pi es.  
•  
S u bject dis p ositi o n. 
•  
De m o gra p hic data.  
• 
B o d y h ei 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.  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 6 3  of 2 1 0  
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  b ef ore  scree ni n g)  a n d  all  
c urre nt a n d c o n c 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  faci al  c os metic  pr oce d ure  a n d   
 
 m ust be rec or d e d re gar dless of ti me 
of a p plicati o n. F or pr o hi bite d pri or a n d c o nc o mita nt t hera pies, s ee Secti o n  8. 3 . A re vie w 
of t his i nf or mati o n will all o w t he i n vesti gat or t o assess w het her t he s u bj ect s h o ul d be 
e nr olle d. Ot h er d ata wil l 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 x a mi nati o ns a n d vital si g ns. If c o u ns eli n g of s u bjects is dee me d necess ar y, 
eit her bef ore e nr oll me nt or d uri n g t he st u d y, c o u nseli n g will be ma de  a vaila ble b y t h e 
i n vesti gat or i n v ol vi n g ot her me dical s p ecialists, if necessar y. 
9. 1. 2  
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 perf or me d as descri be d i n t he st u d y vi sit 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 n c y test i n g, will be a nal yz e 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 w ell 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 . 
I n cas e of p at h ol o gi cal l a b orat or y fi n din gs , t he i n vesti gat or will disc uss t hese wit h t he 
s u bject, if a gree d i n t he i nf or me d c o ns e nt f or m. 
If la b or at or y e v al uati o ns are missi n g or are u nrelia 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 dat a base. 
A n a d diti o nal safet y l a b orat or y assess me nt ca n be perf or m e 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  assess me nts  will  n ot  be  e ntere d  i n  t he  st u d y  
data base b ut ca n b e a d d e d t o t he safet y d ata bas e o pti o nall y if val ues are part of safet y 
re p orti n g. 
C CI
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 6 4  of 2 1 0  
9. 1. 3  
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.  
9. 1. 4  
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. 
9. 1. 5  
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.  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 6 5  of 2 1 0  
9. 1. 6  
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 na l bl o o d sa m pli n g ma y b e necessar y i n case of missi n g val ues e. g. d ue t o faile d 
a nal ysis.  
9. 1. 7  
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 mist r y, he 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 he 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 s it 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  s cree ni n g  visit  is  t o  d eter mi ne  s u bject  eli gi bilit y  f or  st u d y  
partici pati o n.  
Baseli ne  is d efi ne d as D a y 1, w hic h is t he d a y of ra n d o mi zati 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 saf et y a n d efficac y d ata 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 o r all t hree facial areas at t h e C ycle 2 baseli ne visit 
V 8. T he e n d - of-C ycl e  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 x cl usi o n 
criteria of t he O L E X peri o d  (Secti o n 7. 4 3 ) are met at V 7. Reassess me nt f or eli gi bilit y is 
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 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 6 6  of 2 1 0  
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 ycle  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 x cl usi o n 
criteria of t he O L E X p eri o d ( Secti o n 7. 4 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 ules 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 x ce pt V 3 w here o nl y a ±  3-da y 
wi n d o w is all o we d. T he I P(s) m ust be i njecte d b y t he i n v esti gat or, w h o is trai ne d a n d 
e x perie nce 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 h e i n vesti gat or if a n y A Es h a ve o cc urre d si nce a d mi nist rati 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  reass ess me nt  visit,  t he  
e n d- of-st u d y visit will be perf or m e 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 nsc he d ule d visits  ma y b e re q uire d i n t he 
case of A Es or pr e mat ur e disc o nti n uati o n of t he st u d y. I n t his cas e, t he fi n al 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 pe n di n g o n t he nat ure of t he f oll o w- u p re q uire d. 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 6 7  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 6 8  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 6 9  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 7 0  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 7 1  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 7 2  of 2 1 0  
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 a n d he mat ol o g y, 
vital  si g ns,  p h ysi cal  e x a mi nati o n,  p re 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   Defi 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 h a 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 ora 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 ill 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 v al 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 o ce d ure. 
C ha n g es i n efficac y e n d p oi nts (e. g., s u bject -re p orte d o utc o me e n d p oi nts ( q uesti o n naires 
a n 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  efficac y  e n d p oi nts.  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 gar d e d 
as A Es.  
F or  scree 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 mize d  
s u bjects t hat e x perie n ce d A Es d uri n g t he s cree ni n g p eri o d t h ese h a ve t o b e e nter e 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 w as  si g n e 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 E s 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 after 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 the e x pecte 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 k e 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 ule 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 nless t he c o n diti o n w orse ns or t he 
disease r e occ urs d uri n g t he o bser vati o n p eri o d. T o deter mi ne w het her a c o n diti o n has 
w orse ne d,  it  is  c o m par e 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  
la b orat or y  val u es  o btai n e d  d uri n g  t he  s u bject’s  scree ni n g  p eri o d  will  o nl y  meet  A E  
criteria if n e wl y detecte d a n d if c o nsi dere d cli nicall y si g nifica nt.  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 7 3  of 2 1 0  
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 re p ort, t hr o u g h i n vesti gat or i n q uir y, or disc o v ere d i n t he c o urse of 
e x a 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.  
•  
Dat e 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 a n 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 d escri 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 . 
1 0. 1. 1  
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 classi fie 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 ol erat 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 distract e 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 nterfer e  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  be  i g n ore d  a n d  d o  n ot  
disa p pear w h e n t he s u bject is distracte d.  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 7 4  of 2 1 0  
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 n ca pacitate 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  rel e va nt  
la b orat or y val u es t hat ar e d oc u me nte d a n d e v al uate 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 g me nt bas e d o n cli nical e x perie nce.  
1 0. 1. 2  
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 pressi 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 h at 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. ” 
1 0. 1. 4  
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 uelae 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. 
If t her e is m or e t ha n o ne A E, o nl y t he A E lea din 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.  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 7 5  of 2 1 0  
1 0. 2  D efi 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 w ar d me dical occ urre n ce, at a n y d ose, t h at:  
•  
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 xi sti n g h os pitalizati o n. 
•  
Res ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit 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  electi 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 hat occ ur d uri n g t he st u d y p eri 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 t elefa x, tele p h o ne or e mail . 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 File (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 m u m i nf or mati o n is a vaila ble: 
•  
A n i de ntifia ble s u bject ( n u m ber). 
•  
A s us pect pr o d uct. 
•  
A n i de nt ifia ble re p orti n g s o urce (i n vesti gat or/st u d y site i de ntificati o n). 
                                                          
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 bj ect 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 d i 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 j e o par dize t he 
patie nt/s u bj ect or ma y re q uir e i nter ve nti o n t o pr e 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.” 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 7 6  of 2 1 0  
•  
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  i n ves ti 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 n te gral  part  of  t his  
s u p p orti n g i nf or mati o n. F oll o w-u p re 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 k e d  as  a  “f oll o w -u p”  re p ort)  a n d  acc o m pa ni e d  b y  a p pr o priate  
s u p p orti n g d oc u m e ntati o n (e. g., h os pital re p orts). T he S A E is t o be f oll o w e 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  d ata base  after  fi nal  S A E  rec o nciliati o n  is  
c o m plete d.  
M ore o ver, S A Es ar e t o be d oc u me nte d o n t he ge n eral pa ge s 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 x e d/se 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 ud y visit ( V 1 7)  nee d o nl y be re p ort e d if t he i n vesti gat or 
c o nsi ders t he e v e 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 d ata bas e. T hese re p orts will be e ntere d i nt o t he Safet y D ata b ase.  
1 0. 3  A E SI s / al ert t er m s  
A Es  occ urri n g  aft er  tr eat 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 k e d b y t he i n vesti gat or at eac h visit after 
scree 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 urr e 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. 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 7 7  of 2 1 0  
A E SIs are c o nsi der e d t o ha ve a s pecial mea ni n g or i m p orta nce f or a p artic ular 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 t elefa x or e mail t o t he res p o nsi ble C R O wit hi n 2 4  h ours  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 m e nte d o n t he ge neral 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 dical  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 x e d/se nt al o n g wit h 
t he A E SI re p orti n g f or m. T he 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 7 8  of 2 1 0  
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 ar e t h ose descri be d i n Secti o n  7. 1 . ‘C o m pa n y C ore Safet y I nf or mati o n ’ of 
t he i n vesti gat or’s br oc h ure f or N T 2 0 1. 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 7 9  of 2 1 0  
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 pecte d  A Es  are  t h ose  n ot descri b e d  i n  Secti o n  7. 1 .  ‘C o m pa n y  C ore  Safet y  
I nf or mati o n’ of t he i n v esti gat or’s br oc 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 n a ncies  a n d  pr e g na nc y f oll o w -u p  s h o ul d  b e  re p orte d  o n  a  pre g na nc 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 n a nc y, i ncl u di n g a n y 
v ol u ntar y or s p o nta n e 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 n a 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 bef or e or d uri n g pr e 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  r e p orte d  as  S A E  ( o n  a n  S A E  f or m). I n  case  a  pre g na n c y o cc urs  pri or  t o  first  
i njecti o n, t he s u bject m ust n ot be ra n d o mize d. If a pre g na n c y occ urs after a s u bject has 
recei v e 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 he  c orres p o n di n g  c ycle  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 v er, 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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M 6 0 2 0 1 1 0 7 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 8 0  of 2 1 0  
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 r e g ulat or y a ut h orit y re prese nt ati ves a n d I E C are p ossi ble at a n y ti me, e v e n 
after t he e n d of st u d y. T he i n vesti gat or is t o n otif y t h e 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-relate d m o nit ori n g, a u dits, 
re vie ws b y t he I E C 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 ur ce d oc u m e 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 dizati o n pr oce d ur es will be i m ple me nte d t o e ns ure acc urate, c o nsiste nt, 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 ntralize d  
e val uati o ns, a n d vali dati o n met h o ds). 
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 
I C H- G C 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 pecti ve s o urce d oc u me ntati o n (e. g. s u bject file). T his i ncl u des a c o p y of 
t he letter se nt t o t he s u bject’s pri mar y p h ysi cia 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  has  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 ure  ( Secti o n  3. 3. 2 ).  T he  i n vesti gat or  m ust  als o  c o nfir m  b y  writte n  
state me nt i n t he s o ur ce d oc u me ntati o n t hat all i ncl usi o n criteria a n d all e x cl usi o n criteri a 
were c hec ke d pri or t o i n cl 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 x cl usi o n criteria a n d eli gi bilit y criteria h a ve t o be 
tracea ble o n t he basis of t he d oc 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 a n d t heir use d met h o d of birt h c o ntr ol m ust be n ote d i n t he s o urce 
d oc 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 hese dat a (e. g. s u bject file, s u bject di ar y, la b orat or y 
re p ort).  Scales  or  q uesti o n naires assesse d  b y  t h e  i n vesti gat ors  a n d  s u bj ects  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 h e 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  data  after  eac h  visit.  T he  p a 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 he 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 btai n  o verla p pi n g  pa per  pri nt -o uts,  t he  
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 8 1  of 2 1 0  
c o m plete ness of s o urce d at a m ust be e ns ure d b y ot her s uita ble mea ns. T he pri nt -o ut m ust 
be si g n e d a n d dat e d b y a me m ber of t h e site staff w h o ca n c o nfir m t he acc urac y a n d 
c o m plete ness of dat a 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 h e 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 he I S F. If s o urce d ata i nf or mati o n is e ntere d retr os pecti vel y, t his 
m ust be d o ne directl y o n t he pa per pri nt -o ut a n d s h o ul d be i nitiale d a n d date d. T he sa m e 
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 ur e [ E D C] s yste m) pr o vi de d b y t he C R O. All users w h o will e nter 
data i nt o t he e C R F will be pre vi o usl y trai ne d. S u ccessf ul c o m pleti o n of t he trai ni n g will 
be  a  prere q uisite  f or  t h e  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 part 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 nsiste 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 me 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 ges. E dit c he c ks 
ge n erat e a ut o matic q ueri es d uri n g d ata 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 data 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 plet e ness of t hese data. T he C R O’s da ta ma na ge me nt f u ncti o n (see 
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 d a nce  wit h  t he  
s p o ns or’s data ma n a ge m e nt pr oce d ures 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 yst e m). F urt her det ails will be s pecifie d i n 
t he Data Ma n a ge 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 ges  t o  t he  data  after  
data base cl ose, t hese c ha n ges will be d oc u me 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 8 2  of 2 1 0  
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, 
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 o cesses:  
•  Data  e ntr y  a n d  res p o nse  t o  data  clarificati o ns  will  pr ocee d  de pe n di n g  o n  
a vaila bilit y of st u d y n urs es, 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 he  necessit y  of  s o urce  data  
re vie w of t h e res p o ns e will be re-assess e 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 o c k).  
•  If a p plica ble, ris k-b ase d assess me nt of cl osi n g l o n g o p e n q ueries will b e d o ne 
c o nsi deri n g t heir i m p act 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 dele gati o n l o g is t o b e 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 h e  s o ur ce  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  D eclarati o n  of  Helsi n ki,  a n d  re g ul at or y  a ut h orit y  
re q uire me nts, i ncl u di n g E U ( Ric htli nie 2 0 0 1/ 2 0/ E G; Date nsc h utz gr u n d v er or d n u n g; t he 
u pc o mi n g E U re g ulati o n N o. 5 3 6/ 2 0 1 4) a n d Ger ma n la ws Arz nei mittel gesetz [ A M G]; 
G C P -Ver or d n u n g  Dat e nsc h utz besti m m u n ge n).  M o nit ori n g  will  als o  be  ai me d  at  
detecti n g a n y misc o n d u ct 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 , 
S A Es, A E SI s or pr e g na nci es ha v e bee n re p orte d a p pr o priat el y wit hi n t he ti me peri o ds 
re q uire d. T h e 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 n e ver p ossi ble. T he i n v esti gat or m ust be a v aila 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 dat a pr o perl y rec or de d i n t he s o urce d o c 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 vi sits. 
•  
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  be  s yste matic,  pri oritize d,  a n d  ris k- base d. 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 8 3  of 2 1 0  
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 u ate,  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 basis t hr o u g h o ut all sta ges of t he trial’s life- c ycl e.  
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, 
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 date d m o nit ori n g pl a 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 sit e 
cl os ures, re d u ce d staff a n d a n y ot h er 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 ge nc y.  
C urre nt l ocal re g ulati o ns, i ncl u di n g d ata pri v ac y re g ulati o ns will b e c o nsi dere d w h e n 
accessi n g s o ur ce 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 he  c orres p o n di n g  a u dit  pr o gra m,  w hic h  will  
i ncl u de t he p ossi bilit y t hat a me m b er of t he s p o ns or’s q ualit y ass ura nce f u ncti o n m a y 
arra n ge t o visit t he i n vesti gat or i n or der t o a u dit t he perf or m a 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 perf or me d b y 
c o ntract a u dit ors. In t his case, t h e s p o ns or’s q ualit y ass ura n ce f u ncti o n will a gree wit h t h e 
c o ntract a u dit or r e 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 h e a u dit or(s). 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 8 4  of 2 1 0  
1 2  S T A TI S TI C A L M E T H O D S  
T his  secti o n de scri 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  d e viati o ns  fr o m  pl a n ne d  a n al ys es,  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 ys es t hat ma y b e perf or me d bef ore data bas e cl ose 
or  u n bli n di n g,  res pecti v el y,  will  be  descri be 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/ or alterati o ns will be s u m marize d i n t he cli nical 
st u dy 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 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 date d statistical a nal ysis pla n: 
•  Descri be  c ha n ges  t o  pla n ne d  a n d  a d diti o nal  a nal yses  d u e  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 u c h  as  missi n g  v al ues  a n d  virt ual  i nstea d  of  li ve  ass ess 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 ha 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 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, L C 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 v ati ve 
ass u m pti o ns. F or pr o p orti o ns of 2 0 % L C L -res p on 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 x act  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 %. 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 8 5  of 2 1 0  
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 L a n d P, t he  st u d y will ha v e at least 9 0 % p o wer t o esta blis h efficac 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 -r es 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. 
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 af et y e v al u ati o n set ( 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 I P at least o nce. S u bjects  i n t he 
S E S a nal yses will be a n al yz e d as treate d.  
F ull a n al ysis set  ( F A 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 nal yses  will  be  
a nal yz e d as ra n d o miz e d. 
Per pr 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 h e 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 
1 2. 3. 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  
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 hr ee 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 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 8 6  of 2 1 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 -r es 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 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) d escri be t he treat me nt effects of i nterest 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  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
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 8 7  of 2 1 0  
 
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 8 8  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 8 9  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 9 0  of 2 1 0  
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 assesse d b y t he i n v esti 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 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 s ec o n d ar y esti ma n ds per treat me nt area were d eri 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  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 ve nts a n d p o p ulati o n le vel 
s u m mar y are i de ntical. T he varia ble attri b utes 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 nts 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 x a m ple, t he varia 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 nts f or tr eat me nt area G F L are defi n e d as “ 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 i n vesti gat or 
at Da y 3 0 ” a n d “ G F L res p o n se 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 9 1  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 9 2  of 2 1 0  
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  bas eli 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 vesti 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  bas eli 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 vesti 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  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 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 9 3  of 2 1 0  
1 2. 3. 2  
P h a r m a c o d y n a mi c e n d p oi nt s 
N ot a p plica ble.  
1 2. 3. 3  
P h ar m a c o ki n eti c e n d p oi nt s  
N ot a p plica ble.  
1 2. 3. 4  
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.  
1 2. 3. 5  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 9 4  of 2 1 0  
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 p eri 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 
1 2. 4. 1  
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 ys es 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 he tar get 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 ys es will be bas e d o n t h e F A S if n ot ot her wise 
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 ges 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 nts, a bs ol ute a n d perce nt fre q ue 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 9 5  of 2 1 0  
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 ne d i n Secti 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 L is n ot part of t he pri mar y 
efficac y a nal ysis w hic h has t he o bj ecti 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 L 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 mai n pri mar y efficac y esti ma n ds are d efi 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 mar y 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 nszel 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 n at o mical re gi o n, t he t he strat u m-a dj uste d (c o m m o n) differe nce i n res p o nse 
rates b et 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 % Ma ntel -Hae nszel c o nfi de nce i nter v al ( CI) . T h e  n ull h y p ot hesis of 
t he  Ma ntel-H ae nszel test  is t hat t he c o m m o n differe nce i n res p o nse rat es 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 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 as descri 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 9 6  of 2 1 0  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 9 7  of 2 1 0  
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 s ec 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 he s u bject’s G AI S- b ase d ke y sec o n dar y esti ma n d i n 
 
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 s ec 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 
G r o u p U vers us P (r ef ere nce) wit h c orres p o n di n g 9 5 % Ma ntel Hae nszel  CIs a n d p -val 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 nal ysis of c o varia n ce wit h fact ors treat me nt gr o u p a n d site, 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 variate. Missi n g data o n s u 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 ( s ee 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 g r 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. 4. 7. 4 . 
S u p ple me ntar y  a nal ys es  of  ke y  s ec o n dar y  e n d p oi nts  f or  all  t hree  re gi o ns  will  b e  
perf or me d usi n g t he sa m e met h o ds as des cri be d f or s u p ple me nt ar 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 ( 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  
Si milar  a nal ysis  strate g y  b y  re gi o n  as  descri b e d  f or  t he  s u p ple me ntar y  a n al 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  will  be  a p plie d  f or  t he  f urt her 
sec o n dar y di c 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, 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 9 8  of 2 1 0  
pr o p orti o ns of s u bjects 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 par e d b y strat u m-a dj uste d differe nces i n pr o p orti o ns wit h c orres p o n di n g 9 5 % 
Ma ntel 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 differe nce i n pr o p orti o ns will be pr o vi de d.  
Gr o u p L will o nl y be c o nsi dere d f or statistical a nal yses of M A S of t he L C L re gi o n b ut 
n ot of t he G F L a n d H F L re gi o ns. 
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 yz e d usi n g a n al ysis 
o f 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 all f urt her sec o n dar y e n d p oi nts will o nl y be i nter prete d d escri pti vel y. 
F or f urt her s ec o n dar y e n d p oi nts o nl y o bser v e 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. 
1 2. 4. 2  
P h ar m a c o d y n a mi c e n d p oi nt s  
N ot a p pli ca 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 9 9  of 2 1 0  
1 2. 4. 3  
P h ar m a c o ki n eti c e n d p oi nt s  
N ot a p plica ble.  
1 2. 4. 4  
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.  
1 2. 4. 5  
S af et y e n d p oi nt s  
All safet y a n al ys es will be perf or me d o n t h e S E S.  T he a nal ysis of s afet y e n d p oi nts 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 yze 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 n al y ze d, w hic h are d efi ne d as A Es wit h o nset or w orse ni n g o n or after 
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 a r 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 n ces 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 verall, f or t he 
t otal  st u d y  peri o d  a n d  b y  treat me nt  c ycl e.  F or  t he  a nal yses  b y  treat me nt  c ycl e,  t he  
de n o mi nat or  f or  t he  i n ci de nces  will  b e  a dj uste d  t o  all  s u bjects  b ei n g  treate d  i n  t hat  
treat me nt c ycl e. 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 0 0  of 2 1 0  
1 2. 4. 7  
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 marize 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  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 0 1  of 2 1 0  
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 p e  I  err or  l e 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 s ec o n d ar y e n d p oi nts will be c o ntr olle d b y a 
hierar c hical test pr oce d ur e base d o n t w o -si d e d tests wit h α =  0. 0 5.  
T he hierarc hical pr oce d ure f or pri mar y a nal ysis ( Secti o n  1 2. 4. 1. 1 ) will be perf or m e d as 
descri be d b el o w. First, usi n g t he Ma nt el -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 vers 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 ):  As  ne xt  
ste ps, Ma ntel -Hae nszel tests f or s u peri ority 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  of M P f or G F L, t he n H F L a n d 
fi nall y  L C L  a n at o mical  re gi o n.  T hereafter,  Ma nte l-Hae nszel  tests  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 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 n at o mical re gi o n. 
Fi nall y, G AI S as assess e 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  hier arc hical  test  pr oce d ure  will  st o p  o nce  statistical  si g nifica n ce  c o ul d  n ot  be  
reac h e d.  
F or a n y ot her statist ical 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  L 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 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 n al 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 
acc or di n g t o pre -treat me nt stat us. S u bjects will be disti n g uis he d o n w het her t he y h a ve 
bee n  tr eate d  wit h  B o N T -A  pri or  t o  ra n d 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 (treat me nt naï ve).  
Dic h ot o mize d e n d p oi nts w hic h are base d o n M A S 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 at rest as ass esse d 
b y b ot h s u bject a n d i n vesti gat or. Si nce sc ores at rest ar e i n ge n eral l o wer 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 n e) or 1 ( mil d) at bas eli ne 
o n  M A S  at  rest.  T hese  s u b gr o u p  a n al ys es  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 n al yses of t he t otal F A S as the y c o nsi der effects i n ‘s y m pt o matic’ 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 0 2  of 2 1 0  
s u bjects,  i.e.  s u bjects  wit h  0  ( n o ne)  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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 0 3  of 2 1 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 P I N G  
B y si g ni n g a n d d ati n g t h e 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 
be e 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 his 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 o c 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,  dir ect  e ntries  are  n ot  all o w e d;  data  m ust  be  tra nscri be d  fr o m  t he  
s o urce d oc u m e ntati o n (e. g., s u bject file) t o t he e C R F. 
If c orr ecti o ns are necess ar 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 -base d eC R F. T he a u dit trail i n t he electr o nic d ata 
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 h e err or, lea vi n g 
t he i nc orr ect  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 h a n ges t o t hese d oc u me nts. 
Data base cl osi 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 after t he last a p pr o val of a 
mar keti n g a p plicati o n ( w het her pe n di n g or c o nt e m plate d) i n a n I C H re gi o n, or at least 
t w o  years  ha ve  ela ps e d  si nce  t he  f or mal  disc o nti nuati o n  of  I P  cli nical  de vel o p me nt.  
T hese  d oc u me nts  ar e  t o  be  retai ne d  f or  a  l o n ger  peri o d,  h o we v er,  if  re q uire d  b y  
a p plica ble r e 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 me di cal rec or ds). 
•  
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 year 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. 
•  
C Ds/ D V Ds  wit h  P D F -files  c o ntai ni n g  s u bjects’  e C R F  data  a n d  a u dit  trail  
( pref era bl y pr o vi d e 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 -
relate d s o ur ce dat a ( or, w here a p plicable, a ut h oriz e d c o pies of s o urce d ata). 
•  
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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 0 4  of 2 1 0  
•  
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 n ce  wit h  t he  I E C  a n d  wit h  t he  re g ulat or y  
a ut h orit y(i es).  
•  
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 m ati o n  re p orte d  d uri n g  t h e  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 o c u me nts  ma y  n ot  be  destr o ye d  b y  st u d y  site  pers o n n el  bef ore  e n d  of  t he  
rete nti o n peri o d s p ecifie d a b o ve wit h o ut t he pri or writte n c o ns e nt of t he s p o ns or. T he PI 
m ust i nf or m t he s p o ns or i n d ue t i 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 0 5  of 2 1 0  
1 4  P  U B LI C A TI O N P  O LI C Y  
T he st u d y r es 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 ust  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 h a 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 u c h as cli nicaltrials . g o v a n d E u dra C T), i n acc or da nce 
wit h  nati o nal/i nter nati o nal  re g ul a ti 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 0 6  of 2 1 0  
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 -J a n- 2 0 2 0. 
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 de r WJ, A vi v J E, et al. T he ma n a ge me nt of h y perf u ncti o nal facial li nes 
wit h b ot 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 oc o ut ur e  E U  S u m mar y  of  Pr o d uct  C haract eristics.  A vaila ble  at:  htt ps:// mri.cts -
mr p.e u/ h u ma n/ d o w nl oa ds/ D E _ H _ 2 6 1 9 _ 0 0 1 _ Fi nal PI. p df. A ccess e d 2 0- Fe b - 2 0 2 0. 
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 p e 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 u t 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 f e 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 D er 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 aest hetics. Plast Rec o nstr S ur g. 2 0 0 4; 1 1 4( 6): 1- 2 2. 
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 d ate o n b ot uli n u m t o xi n f or faci al aest h etics. Der mat ol Cli n . 
2 0 0 2; 2 0( 4): 7 4 9- 7 6 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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 0 7  of 2 1 0  
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 w ee 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.  
De utsc he  Ges ellsc haft  f ür  Äst hetisc he -Plastisc he  C hir ur gi e  2 0 1 8.  A vaila ble  at:  
htt ps:// w w w. d g bt. de/filea d mi n/ _ mi grate d/c o nte nt _ u pl oa ds/ Facts heet - D G B T. p df. 
Access e d 2 0 -Fe b - 2 0 2 0. 
Fl y n n T C, Carr ut hers A, Carr ut hers J, et al. Vali date d assess me nt scales f or t he u p pe r 
face. Der m at 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, Graf e S. B ot uli n u m Ne ur ot o xi n T y p e 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, Pra ger W, T ur n b ull C, Tre vi dic P, I n glefi el 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 p er  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. D er 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 M e 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 o w e 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 p e 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. 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 0 8  of 2 1 0  
L o w e  NJ,  S ha h  A,  L o we  P L,  et  al.  D osi n g,  effi cac y  a n d  safet y  pl us  t he  use  of  
c o m p uterize d p h ot o gr a p h y f or b ot uli n u m t o xi ns t y pe A f or u p p er facial li nes. J C os met 
La s er T h er. 2 0 1 0; 1 2( 2): 1 0 6- 1 1 1. 
Marc hi ni  C.  I ntr a nasal  ne osti g mi ne  t h era p y  of  b ot uli n u m  t o xi n  ( B T X)  treat me nt  
d ys p ha gi a [letter]. Cli n Ne ur o p har m ac ol. 1 9 9 7; 2 0( 3): 2 7 9- 2 8 0. 
Matarass o S L, M atarass o A. Treat me nt g ui d eli nes f or b ot uli n u m t o xi n t y p e 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 mace uticals G m b H. I n vesti gat or´s br o c h ure N T  2 0 1 ( Cl ostri di u m B ot uli n u m 
Ne ur ot o x i 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 p e A). 
C urre nt E diti o n  
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 ble -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. 
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. 
Statista 2 0 1 8. A vaila ble 
at: htt ps:// de.statista.c o m/statisti k/ date n/st u die/ 5 8 3 0 7 4/ u mfra ge/ hae ufi gste - nic ht-
c hir ur gisc he-sc h oe n h eits o perati o ne n- n ac h -art-d es -ei n griffs/. Access e d 2 0-Fe b - 2 0 2 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 oac h es t o t he ma na ge me nt of s ki n a gi n g i n w o me n o ver si xt y. I nt J 
C os met Sci. 2 0 1 2; 3 4( 5): 4 8 1- 8. 
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 nsi o 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. 
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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 0  
Versi o n 4. 0 ( 2 4 -J U N-2 0 2 1)  
C o nfi de ntial  
P a ge 1 0 9  of 2 1 0  
1 6  A P P E N DI C E S  
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SAP_001.pdf: 


Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
SI G N A T U R E P A G E  
 
I c o nfir m t hat t his St atistical A nal ysis Pla n acc urat el y descri bes t he pla n ne d st atistical 
a nal ys es t o t he best of m y k n o wle d ge a n d was fi nalize 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 ostatisticia n 
Merz  
( pri nt  
n a me)  
 
 
Date ( d d -m m m -y y y y)   
Si g n at ur e  
 
  
  
Me dical 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 mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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 6  
6  
St atistical 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 9  
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 3  
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  .......................................................................... 3 0  
6. 2. 2  Sec o n dar y Safet y  E n d p oi nts  ...................................................................... 3 1  
6. 4  
S pecial St atistical/ A nal ytical Iss ues  ................................................................. 3 4  
6. 4. 1  Dis c o nti n u ati o ns a n d Missi n g Dat a  ........................................................... 3 4  
6. 4. 2  I nt eri m A nal yses ....................................................................................... 3 6  
6. 4. 3  M ulti ple C o m paris o ns/ M ulti plicit y ............................................................ 3 6  
6. 4. 4  E xa mi nati o n of S u b gr o u ps  ........................................................................ 3 6  
6. 4. 5  P o oli n g of Sit es  ......................................................................................... 3 7  
6. 4. 6  I nt erc urre nt E ve nts .................................................................................... 3 7  
8  
Refere nc es  .............................................................................................................. 4 0  
9  
A p pe n dic es  ............................................................................................................. 4 1  
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
 
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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 njecti 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 nt 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  L  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 mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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 bje cti ve of t his st atistical 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 deli ne f or st atistical pr o gra m mi n g 
a n d creati o n o f t a bles, fi g ures, a n d listi n gs f or cli nical st u d y pr ot o c ol ( C S P) M 6 0 2 0 1 1 0 7 0  
( versi o n 4. 0), dat e d 2 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 siz e 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 
size 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 ual 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 bse cti o ns of Secti o n  1 4 
a n d Secti o n 1 6. 2 of t he cli nic al st u d y re p ort ( C S R). E ac h o ut p ut file will i ncl u de the 
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 nte nt of t he file.  
T he Merz st a n dar 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 0  
( versi o n 4. 0). T he se m o c k T F Ls will ser ve as st u d y-s pecific 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 ders are list e d i n 
  
S pecial att e nti o n will be pa i 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 pact 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 miz e 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 pla ce b o -c o ntr olle d mai n peri o d ( M P ) wit h o ne N T  2 0 1 i nje cti 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 differe nt treat me nt 
gr o u ps: u p per facial li nes ( U F L ) tr eat me nt ( Gr o u p U), lat eral ca nt hal li nes  ( L C L) treat me nt 
(Gr o u p  L ), 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 bje cts 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 2 4  U N T  2 0 1 i n t he L C L  area a n d 
place b o i n t he G F L a n d h oriz o nt al f ore hea d li nes  ( H C L) areas ( Gr o u p L) , or wit h place b o 
i n all t hree facial 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 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 u al s cree 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 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 ycle. 
D uri n g eac h c ycle, eli gi ble s u bje cts 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 njecti o n. 
T he pri mar y o bjecti ve of t his st u d y is t o assess t h e effic ac y of si m ult a ne o us i ntra m usc 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 bjecti ves are t o assess effica c 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 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.  
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Merz Pharmaceuticals GmbH 
 
STATISTICAL ANALYSIS PLAN 
M602011070 
 
Version 1.0, 16-SEP-2022 
 
CONFIDENTIAL AND PROPRIETARY 
 
Page 7 of 93 
 
3 Determination of Sample Size 
Overall, 360 subjects are planned to be randomized to three treatment groups (UFL, LCL 
or Placebo) with a randomization of 2:1:1 at baseline visit V2. 
The FDA required that the clinical development program includes at least 300 completed 
subjects who are treated simultaneously in all three anatomical areas (GFL, HFL, LCL) 
under placebo-controlled conditions to support safety. Since two pivotal studies are 
planned for demonstration of NT 201 efficacy and safety in the combined GFL, HFL and 
LCL treatment and assuming that up to 15% of the subjects will not complete the study, 
180 subjects will be randomized per study to be treated in all three anatomical areas 
(Group U). A randomization ratio of 2:1:1 for the treatment groups in this study results in 
90 subjects for each of the L and P Groups. 
These sample sizes provide sufficient power also to assess efficacy under conservative 
assumptions. For proportions of 20% LCL-responders in Group U and 5% in Group P, a 
power of 93% is achieved for one-sided Fisher’s exact test at α = 2.5%. Moreover, if 
proportions of HFL- and GFL-responders of at least 40% for Group U and at most 5% for 
Group P are assumed, the samples sizes provide power close to 100%. 
In conclusion, when randomizing 180 subjects to Group U and 90 subjects each to 
Groups L and P, the study will have at least 90% power to establish efficacy of NT 201 
using a hierarchical procedure for comparisons of proportions of GFL-, HFL-, and 
LCL-responders between Groups U and P. Assuming that about 15% of subjects will not 
complete the MP period, the proposed sample size will result in more than 150 completed 
subjects in Group U in this study. This number of completed patients in this study is 
considered sufficient to support the overall safety profile of NT 201 for simultaneous 
treatment of UFL. 
4 Analysis Sets 
The following analysis sets are defined for the statistical analysis of this study: 
Safety Evaluation Set (SES) 
The SES is the subset of all subjects who were exposed to study medication at least once. 
Subjects in the SES analyses will be analyzed as treated. 
Note: In the definition of the SES above, “as treated” relates to actual study treatment in 
MP. 
Full Analysis Set (FAS) 
The FAS will consist of all randomized subjects. Subjects in FAS analyses will be analyzed 
as randomized. 
Per Protocol Set (PPS) 
The PPS is the subset of subjects in the FAS without major protocol deviations. Major 
protocol deviations will be defined during the blinded data review meeting. 
 
 


Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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 M erz Aest hetic Scales ( M A S ) f or 
G F L at ma xi m u m c o ntracti o n as ass ess e 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 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 asse sse 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 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 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 b ot h t he i n vesti g at or a n d t he s u bje ct.  
Mai n esti ma n ds f or pri mar y effica c 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 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 mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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 assesse d b y t he i n vesti ga t 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 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 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 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 ontracti o n as assesse 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 effic ac y e n d p oi nts are s pecifie d i n f ull 
det ail i n  
 All ke y sec o n dar y esti ma n ds per tr eat 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 
treat me nt, t ar get p o p ulati 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 de ntical. T he varia ble attri b ut es of ke y s ec o n dar y  esti ma n ds w ere a da pt e d 
acc or di n g t o t he a b o ve -defi ne d ke y s ec o n dar y e n d p oi nts 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 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 efficac 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 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 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 he ke y sec 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 nt e d i n  
  
 
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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 least 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 assess e d b y t he 
i n vesti 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  
( Visit 4)  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 assess e d b y t he 
i n vesti 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  
( 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 gat 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 mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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.  
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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. 
•  
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 mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 8  of 9 3  
 
6  St ati sti c al A n al y si s M et h o d s  
C o nti n u o us e n d p oi nts ( val ues a n d c ha n g es fr o m baseli ne / c ycle baseli ne, w here a p plica ble) 
will be s u m marize d b y  n u m ber of s u bjects i n t he res pecti ve a nal ysis s et/ p o p ulati o n ( N), 
n u m ber of val ues a nal yz e d ( n) , mea n, st a 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. If rele va nt, t he n u m ber of val ues i m p ut e d d ue t o missi n g ness ( ni m p) will be 
re p ort e d f or efficac y varia bles (se e Secti o n  6. 4. 1 ). Mea n, q uartiles, a n d me dia n will be 
re p ort e d t o o ne deci mal place m ore t ha n t he dat a were c ollect e d, f or t he st a n dar d de viati o n 
t w o deci mal plac es m ore will be dis pla ye d ; f or deri ve d dat a, an a de q uat e n u m ber of 
deci mal places will be c h ose n . 
F or q ualit ati ve e n d p oi nts, a bs ol ut e a n d perce nt fre q ue ncies ( n, %)  a n d, if a p plica ble, s hift 
t a bles will be dis pla ye d. Fre q ue nc y t a bles will i n cl u de t he n u m ber of missi n g val ues, if 
a p plica ble. P erce nt a ge s will be calc ulat e d usi n g t he de n o mi nat or of all s u bje cts i n a 
s pecifie d p o p ulati o n or tr eat me nt gr o u p. T he de n o mi nat or will be s pecifie d i n a f o ot n ot e 
t o t he t a bles f or clarific ati o n if n ot ot her wise o b vi o us. Perce nt a ges will be re p ort e d t o o ne 
deci mal p lace. I n fre q ue nc y t a bles base d o n o bser ve d cases, n u m ber of missi n g val ues will 
n ot be prese nt e d a n d perce nt a ges will be base d o n n u m ber of o bser ve d cases ( N o bs).    
If n ot ot her wise s pecifie d, st atistical t ests will be c o n d uct e d t w o-si d e d at t y pe I err or rat e 
5 %. P -val u es will be re p ort e d t o f o ur deci mal places (e. g., p = 0. 0 3 7 5). P -val ues bel o w 
0. 0 0 0 1 will be prese nt e d as ‘ < 0. 0 0 0 1’. C o nfi de nc e i nt er vals ( CIs) will be t w o -si de d 9 5 % . 
I n ge neral, val u es o bt ai ne d at Visit 2 are defi ne d as t he baseli ne val ues. W here dat a is n ot 
rec or de d at Visit 2, t he last me as ure me nt bef ore st art of treat me nt is defi ne d as baseli ne 
val ue. T hes e val ues will be a nal yze d as bas eli ne (i. e. baseli ne fla g is ‘ yes’ f or last rec or d 
wit h n o n -missi n g val ue bef ore first treat me nt i n St u d y Dat a T a b ulati o n M o del [ S D T M]) . 
F or c ycle 2 val u es o bt ai ne d at Visit 8 a n d f or c ycle 3 val ues o bt ai ne d at Visit 1 3 will be 
use d as c ycle baseli nes.  
6. 1  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 ys es of pri mar y effica c y e n d p oi nts (s ee Secti o n  6. 1. 1. 1 ) a n d 
c o n fir mat or y a nal ys es of ke y sec o n d ar y e n d p oi nts will be base d o n t he t ar get p o p ulati o n 
of 
mai n pri mar y a n d ke y sec o n d ar y eff ic ac 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). It is defi ne d as “ Male a n d fe male a d ults ( 1 8 ye ars 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 nt e nsit y at 
ma xi m u m c o ntracti o n as a ssesse 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 miz e 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 tr eat me nt gr o u p or t o 
Place b o tr eat me nt gr o u p, gr o u pe d b y ra n d o mize d treat me nt assi g n me nt. ” . F urt her effic ac y 
a nal ys es will be base d o n t he F A S if n ot ot her wise s pecifie d. St atistical t ests will be t w o -
si d e d h y p ot hesis t ests f or bet wee n treat me nt differ e nc es i n ge neral. A de q uat e descri pti ve 
st atistics as s pecifie d at t he be gi n ni n g of Secti o n  6  a b o ve will be pr o vi de d f or all e n d p oi nts.   
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 9  of 9 3  
 
I n case Visit 7/ Visit 8 or Visit 1 2/ Visit 1 3 is perf or me d o n sa me da y M A S assess me nts 
fr o m Visit 7/ Visit 1 2 will be d u plic at e d t o be als o a nal ys e d a nd list e d at Visit 8/ Visit 1 3.  
6. 1. 1  Pri m ar y Effi c a c y E n d p oi nt s  a n d 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 ne d 
i n Secti o n  5. 1. 1 . T hese pr o p orti o ns will be c o m p are d f or treat me nt gr o u ps U a n d  P . It 
s h o ul d be n ot e d t hat Gr o u p L  is n ot part of t he pri mar y effic ac y a nal ysis w hic h has t he 
o bjecti ve t o c o m pare effica c y of si m ult a ne o us tr eat me nt of U F L wit h N T  2 0 1  vers us 
place b o. Gr o u p L  a n d T ot al  N T  2 0 1 ( Gr o u p U a n d Gr o u p  L  p o ole d ) will be c o nsi d ere d i n 
t he s u p ple me nt ar y a nal ys es of pri mar y e n d p oi nts o n t he F A S, t he P P S, o bser ve d cases i n 
t he F A S, o bser ve d cases i n t he P P S (see bel o w), i n s u p ple me nt ar y a nal yses of ke y 
sec o n dar y e n d p oi nts, a n d i n a nal ys es of f urt her  sec o n dar y a n d ot her efficac y e n d p oi nts .  
T he t hree mai n pri mar y effica c y esti ma n ds are defi ne d i n Secti o n  5. 1. 1  (see 
 f or 
G F L, 
 f or H F L, 
 f or L C L). 
6. 1. 1. 1  Pri m ar y a n al y si s  
T he f oll o wi n g mai n esti mat ors f or mai n pri mar y esti ma n ds will ser ve as pri mar y a nal ysis: 
F or 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 d ers i n treat me nt gr o u ps U 
a n d P, Ma nt el-Hae nszel strat u m wei g hts a n d t he Sat o varia nce esti mat or will be us e d t o 
calc ulat e t he strat u m-a dj ust e d ris k differe nce, wit h st u d y sit e ser vi n g as strat u m va ria ble. 
F or eac h a nat o mic al re gi o n, t he strat u m -a dj ust e d (c o m m o n) differe nce i n res p o nse rat es 
bet wee n tr eat me nt Gr o u p U a n d Gr o u p P (refere nce) (“ Gr o u p U” –  “ Gr o u p P”) will be 
pr o vi de d wit h t w o -si de d p-val ue a n d 9 5 % Ma nt el -Hae nszel c o nfi d e nce i nt er val ( CI ). T he 
n ull h y p ot hesis of t he Ma nt el -Hae ns zel t est is t hat t he c o m m o n differe nce i n res p o nse rat es 
is zer o. T he fa mil y-wis e t w o -si de d t y p e I err or le vel α =  0. 0 5 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 as descri be d i n 
Secti o n  6. 4. 3 .  
S tr at e gies f or ha n dli n g of I C Es  are descri be d i n Secti o n 6. 4. 6 . 
Missi n g dat a will be i m p u t e d s o t hat all s u bje cts i n t he t ar get p o p ulati o n of mai n pri mar y 
esti ma n ds ca n be i ncl u de d i n t he a nal ysis. 
 
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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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
R es p o n der ra t es wit h t w o-si de d 9 5 % Wils o n CIs will be pr o vi de d as well f or b ot h treat me nt 
gr o u ps i ncl u de d i n t ar get p o p ulati o n of mai n pri mar y effica c y esti ma n ds , o verall a n d per 
st u d y sit e. 
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): 
                                               
1 I n t h e C S P, it was err o n e o usl y state d t h at t h e sc or e fr o m V 3 ( Da y 8) is li kel y l o wer t h a n t h e sc or e t o be 
e x pecte d at Da y 3 0. T his is n o c ha n ge t o pla n n e d a nal yses si n ce n o c h a n ge t o t h e i m p utati o n r ule is i m pli e d. 
O nl y t h e j ustificati o n f or i m p uti n g m o n ot o n o usl y missi n g dat a at V 4, V 5, V 6, a n d V 7 wit h V 3 dat a 
(c o nser vati ve a p pr oac h) was c orr ecte d.  
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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 -
treat me nt st at us. S u bje cts 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 ser ot y pe pri or  t o ra n d o miz ati 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 str at u m -a dj ust e d differe nces i n pr o p orti o ns wit h Ma nt el Hae nsz el t est 
p -val ues will be pr o vi de d f or t he t hree 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 . 
T he last t hree s u p ple me nt ar y a nal ys es des cri 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 bje cts 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 d efi niti o ns 
of t hree s u p ple me nt ar y esti ma n ds 
 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 se e 
Secti o n 6. 1. 1. 4 . 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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 s ec o n dar y e n d p oi nts are descri be d i n 
Secti o n  5. 1. 2 . Defi niti o ns of 
M A S-base d ke y s ec o n dar y esti ma n ds are pr o vi de d i n 
 a n d of t he s u bje ct’s G AI S -ba se d ke y sec o n d ar 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 ffic a c y 
E sti m a n d s  
Mai n esti mat ors f or ke y sec 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 sec 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 effic ac 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 Se cti 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 bject’s ass ess me nts o n t he M A S,  
strat u m-a dj ust e d differe 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  
v ers 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 p -val ues 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 de d as well.  
Mai n esti mat or f or t he mai n ke y sec o n d ar y esti ma n d bas e d o n s u bjec t’s G AI S 
 
will be a nal ysis of c o varia nce 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 bje ct as c o variat e.  
Acc or di n g t o t he defi niti o n of t he ke y sec o n d ar y esti ma n d bas e d o n s u bject’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 bje ct 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 bject .  
Least  s q uares ( L S) mea n s, st a n dar d err or, a n d t w o-si de d 9 5 % CI per treat me nt gr o u p a n d 
L S me a 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 de 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 nce is zer o.  
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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 str at e g y f or c o m p aris o ns of tr eat 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 Se cti o n 6. 4. 3 . 
Res ults f or Gr o u p  L  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 des cri 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 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
f urt her sec o n dar y dic h ot o m o us M A S-bas e 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 bjects wit h at le ast 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 nce i n pr o p orti o ns will be pr o vi d e d.  
Gr o u p  L  wil l o nl y be c o nsi dere d f or st atistical a nal ys es of M A S of t he L C L re gi o n b ut n ot 
of t he G F L a n d H F L re gi o ns. A nal ysis of 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 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 L  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  L , pr 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 L C L  re gi o n. F or L C L re gi o n , pr o p orti o ns will als o be pr o vi d e d f or T ot al N T  2 0 1 . 
G AI S as assesse d b y t he i n vesti g at 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 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 i n vesti gat or as c o variat e (see 
Secti o n  6. 1 . 2. 1). C o m paris o ns will be ma d e f or Gr o u p U t o Gr o u p  P , Gr o u p L  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 L  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  L  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 p e  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 cases will be a nal yze d. A nal yses will be 
pr o vi de d f or F A S a n d P P S.  
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
6. 2  S af et y E n d p oi nt s  
All safet y a nal ys es 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 L ”)  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 d ers 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 L ”. T E A E t a bles f or M P will 
a d diti o nall y i ncl u de 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 L ) will be p o ole d . T E A E t a bles f or t otal O L E X peri o d, C ycle 2, a n d C ycle 3  
will prese 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 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
be la bele d “ T ot al”.  F or T E A E a nal ys es 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 L ” 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 L ” 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 ora t or y val ues fr o m a n y ti me p oi nt ( Scree ni n g V 1 a n d en 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 effect 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 pe ct 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 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 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 case of pre mat ure 
dis c o nti n uati o ns pri or t o V 8. F or s u bjects w h o d o n ot recei ve st u d y treat 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) is 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 
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 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 t i 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 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 w it 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 
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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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
a d mi nistrati o n of I P at V 1 3 a n d u p t o a n d i n cl 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 al 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 yses b y treat me nt c ycle t he 
de n o mi nat or wi ll be a dj ust e d t o all s u bje cts bei n g tr eat e d i n t hat treat 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 d e 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 c ase 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 ye d.  
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 us al 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 de nc e rat es i n t he fre q ue nc y t a bles re p orti n g i nci de nces 
b y i nt e nsit y/ ca usal relati o ns hi p  t o treat me nt/ o utc o me. I nci d e 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  will o nl y be calc ulat e d 
o verall. T here b y, T E A Es wit h missi 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 le ast 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 treat me nt/ o ut c o me 
cat e g or y per s u bje ct will be c o u nt e d f or calc ulati n g i nci d e 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 d e 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 vacci 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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Mer z P h ar mace 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  
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Versi o n 1. 0 , 1 6 -S E P -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 3  
 
I n case of missi n g i nt e nsit y or missi n g ca usal relati o ns hi p of a n A E t o tr eat 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 s et 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 dise ase 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 eas e will be i g n ore d f or calc ulati o n of t he res p ecti 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 dise ase  will be i ncl u de 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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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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 nces 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 p eri 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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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
 
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 eas o ns f or pre mat ure disc o nti n uati o n of st u d y will be s u m mariz e 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 ue d 
s u bje cts will n ot be re place d.  
F or s u bje cts disc 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 , effic ac y dat a c olle ct e d at V 1 7 will be a nal yz e 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) baseli ne, a n d c o nsi d eri n g treat me nt recei ve d f or eac h c ycle, usi n g t he f oll o wi n g 
visit wi n d o ws.  
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 6  of 9 3  
 
F or se parati o n of T E A Es fr o m n o n -T E A Es i n cas e of c o m plet el y or partl y missi n g st art 
e n d 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 treat 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 pecifie 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 -wis e 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 tr eat 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 
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 nific a nce ca n be est a blis he d f or all t hree pri mar y effic ac 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 dar y e n d p oi nts (Secti o n 6. 1. 2. 1 ): As ne xt st e ps, 
Ma nt el -Hae nsz el 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 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 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 mic al 
re gi o n. T hereaft er, Ma nt el-Hae ns zel 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 u ct e d f or pr o p orti o n of s u bjects wit h a s c 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 bj ect 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 atistical si g nifica nce 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 s e c 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 L  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 ac c o u nts 
f or a n y st atistical a nal ys es 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  (assesse d b y i n vesti gat or a n d s u bje ct) 
f or G F L/ H F L/ L C L 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  f or G F L/ H F L/ L C L at rest as assess e d b y b ot h s u bje ct 
a n d i n vesti g at or. Si nc e sc ores at rest are i n g e neral l o wer t ha n sc ores at ma xi m u m 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
c o ntracti o n, s o me s u bjects  ma y ha ve a s c 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 ys es 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 bje cts, 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. 
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 bje cts wit h baseli n e 
sc ore of at least 2 o n t he c orres p o n di n g M A S as ass esse d b y all t hree rat ers . T hese s u b gr o u p 
a nal ys es will be m ore me a 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 ot al F A S as t he y c o nsi der effects i n ‘s y m pt o matic’ s u bje cts, 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. 
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 se c o n dar y effic ac 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 strat e gies descri be d i n 
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
I n case m ulti ple I C Es wit h rele va nce f or t he sa me esti ma n d o cc ur f or a s pecific s u bje ct, 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 use 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 bject is i ncl u de d 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 3  
 
i n t he t ar get 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 ys es 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 des, e. g., a nal ys es of pri mar y a n d ke y 
sec o n dar y efficac 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 ys es 
of f urt her sec o n da r y or ot her efficac y e n dp oi nts or a n y safet y or ot her e n d p oi nts.  
 
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Mer z P h ar mace 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 0  
 
Versi o n 1. 0 , 1 6 -S E P -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 0  of 9 3  
 
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 nical Trials t o 
t he G ui deli ne o n St atistical Pri nci ples f or Cli nical Trials, 2 0 N o ve m ber 2 0 1 9, a d opt e d 
b y C H M P, 3 0 Ja n u ar y 2 0 2 0, iss u e 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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