Single Center, Open Label, Repeat Intramuscular Administration, 270 Days, Phase I/2a Clinical Trial to Evaluate Safety, Tolerability of Investigational Product (Engensis: VM202) With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
Phase: PHASE1
Conditions: CMT
Sponsor: Helixmith Co., Ltd.



 
 
 
 
 
 
 
 
 
Ta bl e of C o nt e nt s  
SI G N A T U R E P A G E  ....................................................................................................................................... 1 
C O N S E N T F O R M F O R I N V E S TI G A T O R  .................................................................................................... 2 
S Y N O P SI S ..................................................................................................................................................... 3 
S U M M A R Y O F S T U D Y S C H E D U L E  ......................................................................................................... 1 2  
G L O S S A R Y O F A B B R E VI A TI O N S  ............................................................................................................. 1 6  
1  
TI T L E A N D P H A S E O F C LI NI C A L S T U D Y  ....................................................................................... 1 9  
1. 1  
T I T L E O F C LI NI C A L S T U D Y : P H A S E 1/ 2 A  ............................................................................................................. 1 9  
2  
I N F O R M A TI O N O F S P O N S O R A N D C R O, N A M E A N D TI T L E O F P RI N CI P A L I N V E S TI G A T O R ............... 2 0  
2. 1  
S P O N S O R  ...................................................................................................................................................................... 2 0  
2. 2  
P RI N CI P A L IN V E S TI G A T O R A N D O T H E R C LI NI C A L S T U D Y P A R TI CI P A N T S  ..................................................... 2 0  
2. 3  
C O N T R A C T R E S E A R C H O R G A NI Z A TI O N  ................................................................................................................ 2 0  
3  
I N T R O D U C TI O N................................................................................................................................. 2 1  
3. 1  
IN CI D E N C E A N D P R E V A L E N C E O F C H A R C O T - MA RI E - TO O T H D I S E A S E .......................................................... 2 1  
3. 2  
P A T H O P H Y SI O L O G Y O F C H A R C O T - MA RI E - TO O T H D I S E A S E ............................................................................ 2 1  
3. 3  
L A T E S T T R E A T M E N T M
E T H O D S F O R C H A R C O T - MA RI E - TO O T H D I S E A S E .................................................... 2 3  
3. 4  
L I MI T A TI O N S O F E XI S TI N G T H E R A PI E S A N D N E C E S SI T Y F O R N E W T H E R A PI E S ........................................... 2 5  
3. 5  
T R E A T M E N T O F C H A R C O T - MA RI E - TO O T H D I S E A S E U SI N G H E P A T O C Y T E G R O W T H F A C T O R ( H G F) ... 2 6  
3. 6  
E N G E N SI S ; V M 2 0 2  ................................................................................................................................................... 2 9  
3. 7  
N O N C LI NI C A L S T U D Y D A T A ..................................................................................................................................... 3 1  
3. 8  
R E S U L T S O F P R E VI O U S L Y C O N D U C T E D C LI NI C A L S T U DI E S  .............................................................................. 3 4  
3. 8. 1  
P h a s e 1 Cli ni c al St u d y i n P ati e nt s wit h Criti c al Li m b I s c h e mi a  ........................................ 3 4  
3. 8. 2  
P h a s e 2 Cli ni c al St u d y o n Criti c al Li m b I s c h e mi a  .................................................................... 3 6  

 
 
 
 
 
 
 
 
 
3. 8. 3  
P h a s e 1/ 2 Cli ni c al St u d y o n P ai nf ul Di a b eti c P eri p h er al N e ur o p at h y  .......................... 3 8  
3. 8. 4  
P h a s e 2 Cli ni c al St u d y o n P ai nf ul Di a b eti c P eri p h er al N e ur o p at h y  ............................... 3 9  
3. 8. 5  
P h a s e 1/ 2 Cli ni c al St u d y o n A m y otr o p hi c L at er al S cl er o si s  ............................................... 4 1  
3. 8. 6  
P h a s e 1 Cli ni c al St u d y o n A n gi n a P e ct ori s  .................................................................................. 4 2  
3. 9  
R A TI O N A L E F O R E S T A B LI S HI N G D O S E O F IN V E S TI G A TI O N A L P R O D U C T  ....................................................... 4 3  
4  
G O O D C LI NI C A L P R A C TI C E  ............................................................................................................. 4 7  
5  
C LI NI C A L S T U D Y P L A N  .................................................................................................................... 4 8  
5. 1  
P U R P O S E O F C LI NI C A L S T U D Y  ................................................................................................................................ 4 8  
5. 2  
C LI NI C A L S T U D Y D E SI G N  ......................................................................................................................................... 4 9  
5. 3  
S U BJ E C T S  ...................................................................................................................................................................... 4 9  
5. 3. 1  
Tar g et N u m b er of S u bj e ct s a n d R ati o n al e f or C al c ul ati o n  ................................................. 4 9  
5. 3. 2  
I n cl u si o n Crit eri a ......................................................................................................................................... 5 0  
5. 3. 3  
E x cl u si o n Crit eri a  ........................................................................................................................................ 5 0  
5. 3. 4  
A s si g n m e nt of S u bj e ct N u m b er s  ....................................................................................................... 5 2  
5. 4  
C O N T R AI N DI C A T E D M
E DI C A TI O N S ......................................................................................................................... 5 3  
5. 5  
T E R MI N A TI O N O F C LI NI C A L S T U D Y  ....................................................................................................................... 5 8  
5. 5. 1  
St u d y Ter mi n ati o n f or S u bj e ct s  .......................................................................................................... 5 8  
5. 5. 2  
S u bj e ct Dr o p -o ut  ........................................................................................................................................ 5 8  
5. 5. 3  
E arl y Ter mi n ati o n of Cli ni c al St u d y ................................................................................................... 5 9  
5. 6  
IN F O R M A TI O N A B O U T A N D M
A N A G E M E N T O F IN V E S TI G A TI O N A L P R O D U C T  ............................................ 6 1  
5. 6. 1  
I nf or m ati o n A b o ut a n d M a n a g e m e nt of I n v e sti g ati o n al Pr o d u ct ................................. 6 1  
5. 6. 2  
D o s e, A d mi ni str ati o n R o ut e, a n d A d mi ni str ati o n M et h o d  ................................................. 6 1  
5. 6. 3  
L a b eli n g a n d P a c k a gi n g  .......................................................................................................................... 6 2  
5. 6. 4  
H a n dli n g a n d Pr e p ar ati o n of I n v e sti g ati o n al Pr o d u ct  .......................................................... 6 3  
5. 6. 5  
A c c o u nt a bilit y M a n a g e m e nt, C oll e cti o n a n d Di s p o s al of I n v e sti g ati o n al Pr o d u ct  ................... 6 3  
5. 7.  M A N A G E M E N T O F C O R O N A VI R U S D I S E A S E-1 9  ( C O VI D-1 9)  ................................................................................. 6 4  

 
 
 
 
 
 
 
 
 
5. 7. 1 S el e cti o n a n d e nr oll m e nt of cli ni c al st u d y s u bj e cts  ............................................................................ 6 4  
5. 7. 2 M a n a g e m e nt of cli ni c al st u d y s u bj e cts  ..................................................................................................... 6 4  
5. 7. 3 R e c or ds of C or o n a vir us Dis e as e -1 9 ( C O VI D -1 9)  ................................................................................... 6 5  
5. 8  R E T R O S P E C TI V E B I O M A R K E R S T U D Y  ............................................................................................................................... 6 5  
5. 8. 1 P ur p os e of t h e st u d y  ......................................................................................................................................... 6 5  
5. 8. 2 M et h o d of t h e st u d y  .......................................................................................................................................... 6 5  
5. 8. 3 M e t h o ds f or a n o n y mi zi n g h u m a n m at eri als a n d m e as ur es t o pr ot e ct p er s o n al i nf or m ati o n ............... 6 6  
6  
C LI NI C A L S T U D Y P R O C E D U R E S A N D A S S E S S M E N T S  ................................................................ 6 7  
6. 1  
V I SI T S C H E D U L E A N D O B S E R V A TI O N IT E M S  ........................................................................................................ 6 7  
6. 1. 1  
Vi sit 1 ( s cr e e ni n g, fr o m D a y -3 0 t o D a y -1)  ............................................................................... 7 1  
6. 1. 2  
Vi sit 2 ( A d mi ni str ati o n 1, D a y 0)  ....................................................................................................... 7 6  
6. 1. 3  
Vi sit 3 ( S e c o n d A d mi ni str ati o n, D a y 1 4 ± 5)  .............................................................................. 8 1  
6. 1. 4  
D a y 3 0 ± 7 ( s h all b e p erf or m e d o nl y if f oll o w -u p t e sti n g i s r e q uir e d)  ...................... 8 4  
6. 1. 5  
Vi sit 4 ( T hir d A d mi ni str ati o n, D a y 9 0 ± 7)  .................................................................................. 8 7  
6. 1. 6  
Vi sit 5 ( F o urt h A d mi ni str ati o n, D a y 1 0 4 ± 7)  ............................................................................ 9 2  
6. 1. 7  
Vi sit 6 (I nt eri m Vi sit, D a y 1 8 0 ± 7)  .................................................................................................. 9 5  
6. 1. 8  
Vi sit 7 ( Ter mi n ati o n Vi sit, D a y 2 7 0 ± 7) a n d E arl y T er mi n ati o n  ...................................... 9 8  
6. 1. 9  
U n s c h e d ul e d Vi sit s  ................................................................................................................................... 1 0 3  
6. 2  
A S S E S S M E N T IT E M S  ................................................................................................................................................. 1 0 5  
7  
A D V E R S E E V E N T  .............................................................................................................................. 1 0 6  
7. 1  
D E FI NI TI O N  ................................................................................................................................................................ 1 0 6  
7. 2  
E X P E C T E D A D V E R S E E V E N T  ................................................................................................................................... 1 0 7  
7. 2. 1  
A d v er s e e v e nt s t h at m a y b e c a u s e d b y C h ar c ot -M ari e -T o ot h, t h e u n d erl yi n g di s e a s e  ...... 1 0 8  
7. 2. 2  
A d v er s e e v e nt s t h at m a y b e c a u s e d b y a d mi ni str ati o n of i n v e sti g ati o n al pr o d u ct  .............. 1 0 9  
7. 2. 3  
S u m m ar y of A E s t h at o c c urr e d i n cli ni c al st u di e s o n ot h er i n di c ati o n s u si n g t h e i n v e sti g ati o n al pr o d u ct  .................... 1 1 1  
7. 3  
P R E C A U TI O N S  ............................................................................................................................................................ 1 1 4  

 
 
 
 
 
 
 
 
 
7. 4  
C RI T E RI A A N D M E T H O D S F O R A S S E S SI N G A E S  ................................................................................................. 1 1 4  
7. 4. 1  
C a u s alit y wit h i n v e sti g ati o n al pr o d u ct  ......................................................................................... 1 1 5  
7. 4. 2  
S e v erit y of A E  ............................................................................................................................................. 1 1 6  
7. 4. 3  
R e p orti n g, c oll e cti o n, a n d r e c or di n g of A E s  ............................................................................. 1 1 7  
7. 4. 3. 1 C oll e cti o n, a n d r e c or di n g of A E SI( A d v er s e E v e nt s of S p e ci al I nt er e st)  ....................... 1 1 8  
7. 4. 4  
R e p orti n g a n d r e c or di n g of S A E s .................................................................................................... 1 1 8  
7. 4. 5  
H a n dli n g A E  ................................................................................................................................................. 1 2 0  
7. 4. 6  
H a n dli n g r el at e d t o i n v e sti g ati o n al pr o d u ct  ............................................................................ 1 2 1  
7. 4. 7  
Pr e g n a n c y r e p ort  ...................................................................................................................................... 1 2 2  
8  
S T A TI S TI C A L M E T H O D  ................................................................................................................... 1 2 3  
8. 1  
A N A L Y SI S S E T  ............................................................................................................................................................ 1 2 3  
8. 1. 1  
S u bj e ct S et t o B e I n cl u d e d i n S af et y a n d T ol er a bilit y A s s e s s m e nt A n al ys e s: S af et y s et  .... 1 2 3  
8. 1. 2  
S u bj e ct S et t o B e I n cl u d e d i n Effi c a c y A s s e s s m e nt A n al ysi s: I nt e nti o n -t o-tr e at (I T T) s et . 1 2 3  
8. 1. 3  
S u bj e ct S et t o B e I n cl u d e d i n Effi c a c y A s s e s s m e nt A n al ysi s: P er -pr ot o c ol ( P P) s et  .............. 1 2 3  
8. 1. 4  
S u b gr o u p A n al y si s P o p ul ati o n  .......................................................................................................... 1 2 3  
8. 2  
H A N D LI N G O F M
I S SI N G V A L U E S  .......................................................................................................................... 1 2 4  
8. 3  
C L A S SI FI C A TI O N O F S U BJ E C T S  ............................................................................................................................... 1 2 4  
8. 4  
S T A TI S TI C A L A N A L Y SI S M
E T H O D  .......................................................................................................................... 1 2 4  
8. 4. 1  
G e n er al Pri n ci pl e s of St ati sti c al A n al y si s  .................................................................................... 1 2 5  
8. 4. 2  
B a si c I nf or m ati o n o n S u bj e ct s a n d Di s e a s e  .............................................................................. 1 2 5  
8. 4. 3  
Pri m ar y E n d p oi nt s  .................................................................................................................................... 1 2 5  
8. 4. 4  
S e c o n d ar y E n d p oi nt s  .............................................................................................................................. 1 2 6  
9.  
D O C U M E N T M A N A G E M E N T  ......................................................................................................... 1 2 8  
9. 1  
C A S E R E P O R T F O R M  ............................................................................................................................................... 1 2 8  
9. 2  
R E C O R DI N G A N D C O L L E C TI N G  .............................................................................................................................. 1 2 8  
9. 3  
A C C E S S T O , P R O T E C TI O N O F , A N D S T O R A G E O F R E C O R D S ............................................................................ 1 2 9  

 
 
 
 
 
 
 
 
 
1 0  Q U A LI T Y C O N T R O L A N D A S S U R A N C E  ....................................................................................... 1 3 1  
1 1  I N F O R M E D C O N S E N T .................................................................................................................... 1 3 2  
1 2  A P P R O V A L O F C LI NI C A L S T U D Y P R O T O C O L  ............................................................................. 1 3 3  
1 3  C O N FI D E N TI A LI T Y O F S U BJ E C T S’ R E C O R D S .............................................................................. 1 3 4  
1 4  M O NI T O RI N G O F C LI NI C A L S T U D Y ............................................................................................. 1 3 5  
1 5  M E A S U R E S F O R P R O T E C TI O N O F S U BJ E C T S’ S A F E T Y  ............................................................. 1 3 6  
1 6  A M E N D M E N T O F C LI NI C A L S T U D Y P R O T O C O L ........................................................................ 1 3 7  
1 7  C LI NI C A L S T U D Y R E P O R T ( C S R) ................................................................................................... 1 3 8  
1 8  P R E S E N T A TI O N A N D P U B LI C A TI O N O F C LI NI C A L S T U D Y R E P O R T  ...................................... 1 3 9  
1 9  R E F E R E N C E S  ..................................................................................................................................... 1 4 0  
 
 

 
 
 
 
 
 
 
 
 
A P P E N DI X 1. I N F O R M A TI O N O F S P O N S O R, N A M E A N D TI T L E O F P RI N CI P A L I N V E S TI G A T O R  
A P P E N DI X 2. C O N T R AI N DI C A T E D D R U G S  
A P P E N DI X 3. A D MI NI S T R A TI O N M E T H O D O F I N V E S TI G A TI O N A L P R O D U C T  
A P P E N DI X 4. C M T N S -V 2  
A P P E N DI X 5. O N L S L E G S C A L E  
A P P E N DI X 6. 1 0 -M E T E R W A L K T E S T ( 1 0 M W T)  
A P P E N DI X 7. N E R V E C O N D U C TI O N S T U D Y ( N C S)  
A p p e n di x 8. Al g orit h m f or C a u s al R el ati o n s hi p  A s s e s s m e nt M et h o d  
A p p e n di x 9. S u m m ar y of A d v er s e E v e nt s T h at O c c urr e d i n Pr e vi o u s Cli ni c al St u di e s  
 
 

 
 
 
 
 
 
 
 
 
Li st of Ta bl e s  
 
Ta b l e  1 Pl a s mi d c o m p o n e nt f a ct or s  ...................................................................................... 3 1  
Ta b l e  2 S u m m ar y of Cli ni c al St u di e s C o n d u ct e d o n E n g e n si s ( V M 2 0 2) ......................... 3 4  
Ta bl e 3. T o xi cit y st u d y r e s ult s  ................................................................................................. 4 4  
Ta bl e 4. A d mi ni str ati o n d o s e p er vi sit i n p a st cli ni c al st u di e s  ......................................... 4 5  
Ta bl e 5. C o ntr ai n di c at e d m e di c ati o n s  ................................................................................... 5 3  
Ta bl e 6. I nf or m ati o n a b o ut a n d st or a g e c o n diti o n s of i n v e sti g ati o n al pr o d u ct  .......... 6 1  
T a bl e 7. T ot al n u m b er of i n v e sti g ati o n al pr o d u ct vi al s, d o s e s, a n d i nj e cti o n s p er s u bj e ct at e a c h vi sit  ....... 6 2  
T a bl e 8. N u m b er of i nj e cti o n s a n d a d mi ni str ati o n d o s e p er t ar g et m u s cl e (i nj e cti o n sit e)  ........ 6 2  
Ta bl e 9. N e ur ol o gi c e x a m it e m s a n d pr o c e d ur e s f or C M T N S -v 2 m e a s ur e m e nt  .......... 7 4  
Ta bl e 1 0. N e ur ol o gi c e x a m it e m s a n d pr o c e d ur e s f or C M T N S -v 2 m e a s ur e m e nt  ........ 7 8  
Ta bl e 1 1. N e ur ol o gi c e x a m it e m s a n d pr o c e d ur e s  ............................................................. 8 3  
Ta bl e 1 2. N e ur ol o gi c e x a m it e m s a n d pr o c e d ur e s  ............................................................. 8 6  
Ta bl e 1 3. N e ur ol o gi c e x a m it e m s a n d pr o c e d ur e s  ............................................................. 9 0  
Ta bl e 1 4. N e ur ol o gi c e x a m it e m s a n d pr o c e d ur e s  ............................................................. 9 3  
Ta bl e 1 5. N e ur ol o gi c e x a m it e m s a n d pr o c e d ur e s  ............................................................. 9 8  
Ta b l e  1 6  A d v er s e e v e nt s t h at m a y b e c a u s e d b y C h ar c ot - M ari e-T o ot h  ....................... 1 0 8  
Ta b l e  1 7  A d v er s e e v e nt s c a u s e d b y i ntr a m u s c ul ar i nj e cti o n  [ 7 8-8 3]  ............................ 1 1 0  
Ta bl e 1 8 Pr e di ct e d a d v er s e e v e nt s d e s cri b e d i n t h e I n v e sti g at or’s Br o c h ur e  ............. 1 1 0  
Ta b l e  1 9   A E s t h at w er e r e p ort e d a s h a vi n g c a u s alit y i n C LI p h a s e 1  .......................... 1 1 1  
Ta b l e  2 0   A E s t h at w er e r e p ort e d a s h a vi n g c a u s alit y i n C LI p h a s e 2  .......................... 1 1 2  
Ta bl e 2 1   A E s t h at w er e r e p ort e d a s h a vi n g c a u s alit y i n p ai nf ul D P N p h a s e 1/ 2  ...... 1 1 3  
Ta bl e 2 2. A E s t h at w er e r e p ort e d a s h a vi n g c a u s alit y i n p ai nf ul D P N p h a s e 2  .......... 1 1 3  
Ta b l e  2 3   A E s t h at w er e r e p ort e d a s h a vi n g c a u s alit y i n A L S p h a s e 1/ 2  .................... 1 1 4  
Ta bl e 2 4 C a u s alit y wit h i n v e sti g ati o n al pr o d u ct  ............................................................... 1 1 5  

 
 
 
 
 
 
 
 
 
Ta bl e 2 5 G e n er al cl a s sifi c ati o n i n N CI -C T C A E V 5. 0  .......................................................... 1 1 7  
 
 

 
 
 
 
 
 
 
 
 
Li st of Fi g ur e s  
 
Fi g ur e 1. St u d y s c h e m ati c di a gr a m  ......................................................................................... 6 
Fi g ur e 2 P at h o p h y si ol o g y of C M T  ......................................................................................... 2 3  
Fi g ur e 3 M ol e c ul ar m e c h a ni s m of n e ur o pr ot e cti v e eff e ct of H G F  .................................. 2 9  
Fi g ur e 4 Str u ct ur e of E n g e n si s ( V M 2 0 2)  ............................................................................... 3 0  
Fi g ur e 5 E n g e n si s ( V M 2 0 2) pl a s mi d m a p  ............................................................................. 3 1  
Fi g ur e 6 T o xi cit y st u d y d at a ( s e e I B)  ..................................................................................... 3 3  
Fi g ur e 7. A s c h e m ati c di a gr a m of cli ni c al st u d y  ................................................................. 4 9  
Fi g ur e 8. S u m m ar y of i n v e sti g ati o n al pr o d u ct p a c k a gi n g  ................................................ 6 3  
Fi g ur e 9 A E s t h at m a y o c c ur d uri n g cli ni c al st u d y  ........................................................... 1 0 8  
 
 
 

 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
V ersi o n : 4 . 0 
 1  / 2  
 
 
 
SI G N A T U R E P A G E  
 
S p o n s or’s A p pr o v al:  
T h e V M C M T -0 0 1 cli ni c al st u d y pr ot o c ol h as b e e n a p pr o v e d b y H eli x mit h C o., Lt d.  
 
R e s p o n si bl e M e di c al Offi c er:  
 
Cli ni c al D e v el o p m e nt  
H eli x mit h C o., Lt d.  
 
S p o n s or’s A ut h ori z e d Offi c er:  
R e vi e w:  
 
 
Cli ni c al D e v el o p m e nt  
H eli x mit h C o., Lt d.  
 
D at e  
 
A p pr o v al:  
 
 
Cli ni c al D e v el o p m e nt  
H eli x mit h C o., Lt d.  
 
D at e  

 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
V ersi o n : 4 . 0 
 2  / 3  
 
 
 
C o n s e nt F or m f or I n v e sti g at or  
I s h all p erf or m all of m y r es p o nsi biliti es w hil e c o n d u cti n g t his cli ni c al st u d y at t his i nstit uti o n, a n d I 
h er e b y a gr e e t o c o m pl y wit h t h e f oll o wi n g d et ails:  
• 
I a m w ell a w ar e t h at t his cli ni c al st u d y pr ot o c ol is c o nfi d e nti al. I s h all n ot dis cl os e t h e 
i nf or m ati o n c o nt ai n e d i n t his d o c u m e nt t o a n y o n e wit h o ut a pri or writt e n p er missi o n of t h e 
s p o ns or, H eli x mit h C o., Lt d., e x c e pt f or t h e p ur p os e of c o n d u cti n g t his cli ni c al st u d y or 
o bt ai ni n g a p pr o v al f or t his cli ni c al st u d y fr o m t h e I nstit uti o n al R e vi e w B o ar d or ot h er 
c o m mitt e es a n d I h er e b y a gr e e t o t h e a b o v e.  
• 
I h a v e g ai n e d f ull k n o wl e d g e of t h e d et ails of t his cli ni c al st u d y pr ot o c ol. I s h all c o n d u ct t his 
cli ni c al st u d y i n a c c or d a n c e wit h t h e a p pr o v e d cli ni c al st u d y pr ot o c ol, d et ails of pr ot o c ol 
a m e n d m e nts, t h e I nt er n ati o n al C o nf er e n c e o n H ar m o nis ati o n -G o o d Cli ni c al Pr a cti c e (I C H -
G C P), all r e q uir e m e nts of r e g ul at or y a g e n ci es r el at e d t o cli ni c al st u di es, a n d d o m es ti c l a ws. 
• 
E x c e pt f or t h e p ur p os e of t a ki n g a cti o ns a g ai nst e m er g e n c y sit u ati o ns t h at h a v e o c c urr e d i n 
t h e s u bj e cts, I s h all n ot ar bitr aril y c h a n g e t h e d et ails of t his cli ni c al st u d y pr ot o c ol wit h o ut a 
pri or writt e n p er missi o n of H eli x mit h C o., Lt d. or a pr eli mi n ar y r e vi e w a n d writt e n a p pr o v al of 
t h e I nstit uti o n al R e vi e w B o ar d or a n ot h er s e p ar at e c o m mitt e e. 
• 
I h a v e g ai n e d f ull k n o wl e d g e of t h e d et ails of t h e i n v esti g at or’s br o c h ur e. 
• 
F or t h e d ur ati o n of t h e cli ni c al st u d y, w hi c h h as b e e n a gr e e d u p o n wit h  H eli x mit h C o., Lt d., I 
s h all c o n d u ct a n d c o m pl et e t his cli ni c al st u d y i n a c c or d a n c e wit h r e g ul ati o ns. I c o nstit ut e t h e 
a ut h ori z e d p ers o n w h o is q u alifi e d t o c o n d u ct t his cli ni c al st u d y pr o p erl y a n d s af el y, a n d s h all 
s et u p t h e r el e v a nt e q ui p m e nt.  
• 
I s h all e ns ur e t h at a p pr o pri at e tr ai ni n g i n h o w t o c o n d u ct t h e st u d y, t h e cli ni c al st u d y 
pr ot o c ol, a n d t h e d uti es of e a c h i n v esti g at or is p erf or m e d f or all i n v esti g at ors r el at e d t o t his 
cli ni c al st u d y at t his i nstit uti o n. If a pr e vi o us i n v esti g at or is t o d el e g at e his/ h er d uti es t o a 
n e w i n v esti g at or, a l ett er of d el e g ati o n s h all b e pr o vi d e d t o H eli x mit h C o., Lt d.  
• 
If r e q uir e d f or t h e pr ot e cti o n of ri g hts a n d i nt er ests of t h e s u bj e cts e nr oll e d i n t h e cli ni c al 
st u d y, I a m w ell a w ar e t h at H eli x mit h C o., Lt d., t h e i nstit uti o n, or t h e pri n ci p al i n v esti g at or 
m a y t e m p or aril y st o p r e cr uiti n g s u bj e cts or t er mi n at e t h e cli ni c al st u d y.  
 
Pri n ci p al 
I n v esti g at or 
( N a m e) 
 
I nstit uti o n/ P ositi o n 
 
A d dr ess 
 
Si g n at ur e/ D at e  
 

 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
V ersi o n : 4 . 0 
 3  / 4  
 
 
 
S y n o p si s  
S p o n s or  
H eli x mit h C o., Lt d.  
2 1, M a g o kj u n g a n g 8 -r o 7-gil, G a n gs e o -g u, S e o ul 0 7 7 9 4, S o ut h K or e a  
St u d y titl e
St u d y titl e  
A Si n gl e -C e nt er, O p e n -L a b el, P h as e 1/ 2 a Cli ni c al St u d y t o E v al u at e t h e S af et y a n d 
T ol er a bilit y  f or  2 7 0  D a ys  F oll o wi n g  R e p e at e d  I ntr a m us c ul ar  A d mi nistr ati o n  of  
I n v esti g ati o n al Pr o d u ct ( E n g e nsis: V M 2 0 2) i n P ati e nts Wit h C h ar c ot-M ari e -T o ot h 
Dis e as e S u bt y p e 1 A ( C M T 1 A)  
St u d y 
d e si g n  
Si n gl e c e nt er, r e p e at d os e, o p e n l a b el, p h as e I/II A cli ni c al st u d y  
P h a s e s of 
st u d y  
P h as e I/II A cli ni c al st u d y  
Pri n ci p al 
i n v e sti g at o
r, 
i n stit uti o n 
Pri n ci p al i n v e sti g at or:    
Pr of. B y u n g O k C h oi / N e ur ol o g y  
I n stit uti o n:   
S a ms u n g M e di c al C e nt er / 8 1 Ir w o n -r o, G a n g n a m-g u, S e o ul, S o ut h K or e a  
D ur ati o n 
of st u d y  
4 8 m o nt hs aft er cli ni c al st u d y pr ot o c ol a p pr o v al b y t h e K or e a n Mi nistr y of F o o d 
a n d Dr u g S af et y a n d I R B ( St u d y c o m pl eti o n: d at e of l ast p ati e nt’s l ast visit)  
I n v e sti g ati
o n al 
pr o d u ct  
C o d e n a m e:  E n g e nsis ( V M 2 0 2)  
D o s a g e  f or m  a n d  a p p e ar a n c e :  W hit e  ( or  cl os e  t o  w hit e)  l y o p hili z e d  p o w d er  
c o nt ai n e d  i n  a  c ol orl ess,  cl e ar  vi al;  cl e ar  li q ui d  w h e n  diss ol v e d  wit h  w at er  f or  
i nj e cti o n  
St or a g e of i n v e sti g ati o n al pr o d u ct : r efri g er at e d st or a g e ( 2-8 ℃)  
St u d y 
s u bj e ct s  
C h ar c ot -M ari e -T o ot h dis e as e s u bt y p e 1 A ( C M T 1 A) p ati e nts wit h mil d -t o- m o d er at e 
dis e as e  s e v erit y  ass ess e d  b y  C h ar c ot -M ari e -T o ot h  N e ur o p at h y  S c or e  v ersi o n  2  
( C M T N S-v 2) wit h a s c or e > 2 a n d ≤2 0;  
N u m b er of 
s u bj e ct s  
1 2  
P ur p o s e  of  
st u d y  
T o  ass ess  t h e  s af et y  a n d  t ol er a bilit y  of  t h e  i n v esti g ati o n al  pr o d u ct  ( V M 2 0 2)  
i nj e ct e d i n t h e w e a k e n e d l o w er li m b m us cl es of C M T 1 A p ati e nts 

 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
V ersi o n : 4 . 0 
 4  / 5  
 
 
 
I n cl u si o n 
crit eri a  
S u bj e ct s  e nr oll e d  i n  t hi s  cli ni c al  st u d y  m u st  s ati sf y  all  of  t h e  f oll o wi n g  
i n cl u si o n crit eri a: 
1)  M al e or f e m al e, a g e d 1 9 t o 6 5 y e ars;  
2)  P ati e nts wit h c o nfir m e d di a g n osis of C M T 1 A b y g e n eti c t esti n g;  
3)  P ati e nts  wit h  mil d -t o-m o d er at e  s e v erit y  ass ess e d  b y  C h ar c ot -M ari e -T o ot h 
N e ur o p at h y S c or e v ersi o n 2 ( C M T N S -v 2) wit h a s c or e > 2 a n d ≤ 2 0;  
4)  I n di vi d u als  wit h  l o w er  li m b  m us cl e  w e a k n ess  wit h  mi ni m u m  d orsifl e xi o n  or  
m or e;  
5)  I n di vi d u als w h o v ol u nt aril y c o ns e nt t o p arti ci p at e i n t his st u d y a n d si g n t h e  
I R B-a p pr o v e d i nf or m e d  c o ns e nt f or m aft er u n d erst a n di n g  a d es cri pti o n o n  
t h e c h ar a ct eristi cs of t his cli ni c al st u d y pri or t o all s cr e e ni n g t ests; 
6)  I n di vi d u als w h o c a n c o m pl y wit h t h e r e q uir e m e nts i n t h e cli ni c al st ud y; 
7)  I n c as e of f e m al es of c hil d b e ari n g p ot e nti al, t h os e w h o t est n e g ati v e i n a uri n e 
or s er u m pr e g n a n c y t est at s cr e e ni n g;  
8)  I n di vi d u als  w h o  pr a cti c e  m e di c all y  a p pr o v e d  c o ntr a c e pti v e  m et h o ds* 
t hr o u g h o ut t h e cli ni c al st u d y.  
* D efi niti o n 
- Dr u gs:  Or al  c o ntr a c e pti v es,  s ki n  p at c h es,  or  pr o g esti n  f or m ul ati o ns  (i m pl a nts  or  
i nj e cti o ns) 
- B arri er  m et h o ds:  C o n d o ms,  di a p hr a g ms,  i ntr a ut eri n e  d e vi c es  (I U Ds),  v a gi n al  
s u p p osit ori es  
- A bsti n e n c es:  C o m pl et e  a bsti n e n c e  ( H o w e v er,  p eri o di c  a bsti n e n c e  ( e. g.,  c al e n d ar  
m et h o d,  o v ul ati o n  m et h o d,  a n d  s y m pt o -t h er m al  m et h o d)  a n d  s elf-r estr ai nt  ar e  n ot  
c o nsi d er e d as a c c e pt a bl e m et h o ds of c o ntr a c e pti o n.)  
E x cl u si o n 
crit eri a  
S u bj e ct s will b e e x cl u d e d fr o m t hi s cli ni c al st u d y if a n y o n e of t h e f oll o wi n g 
crit eri a i s m et:  
1) P ati e nts  wit h  si g nifi c a nt  r es pir at or y,  cir c ul at or y,  r e n al,  g astr oi nt esti n al,  h e p ati c,  
e n d o cri n e, h e m at ol o gi c, ps y c hi atri c dis or d er s or ot h er s e v er e dis e as es, or al c o h ol 
or  dr u g  a d di cti o n  w h o  m a y  d e v el o p  s af et y  iss u es  or  c a us e  c o nf usi o n  i n  t h e  
i nt er pr et ati on  of  t h e  cli ni c al  st u d y  r es ults  as  d et er mi n e d  b y  t h e  pri n ci p al  
i n v esti g at or; 
2)  P ati e nts  wit h  ot h er  n e ur o m us c ul ar  dis e as es  or  n e ur o p at h y -i n d u ci n g  f a ct ors:  
P ati e nts  wit h  c hr o ni c  al c o h ol  a d di cti o n,  u n d er g oi n g  a nti c a n c er  c h e m ot h er a p y,  or  
t a ki n g n e ur ot o xi c dr ugs; 
3) P ati e nts di a g n os e d wit h di a b et es;  
4) P ati e nts di a g n os e d wit h i nfl a m m at or y b o w el dis e as e;  
5) P ati e nts  wit h a hist or y  of str o k e or c er e br al is c h e mi c att a c k wit hi n 1 2  m o nt hs  
pri or t o t h e s cr e e ni n g d at e;  
6) P ati e nts wit h a hist or y of c or o n ar y art er y di s e as e, s u c h as m y o c ar di al i nf ar cti o n 

 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
V ersi o n : 4 . 0 
 5  / 6  
 
 
 
a n d u nst a bl e a n gi n a p e ct oris  wit hi n 1 2 m o nt hs pri or t o t h e s cr e e ni n g d at e;  
7) M or bi dl y o b es e p ati e nts wit h b o d y m ass i n d e x ( B MI) ≥ 3 7;  
8)  P ati e nts  w h o  u n d er w e nt  ort h o p e di c  s ur g er y  ( c orr e cti v e  s ur g er y  f or  b o n e  a n d  
li g a m e nt,  artifi ci al  j oi nt  i m pl a nt ati o n,  ost e os y nt h esis,  ost e ot o m y,  art hr os c o pi c  
s ur g er y) i n t h e l o w er li m bs wit hi n 6 m o nt hs pri or t o t h e s cr e e ni n g d at e;  
9) P ati e nts w h o m a y b e aff e ct e d b y t h e m us cl e str e n gt h m e as ur e m e nt t est d u e t o 
a n kl e c o ntr a ct ur e or s u r g er y; 
1 0) P ati e nts  wit h  u n c o ntr oll e d  h y p ert e nsi o n  (if  s yst oli c  bl o o d  pr ess ur e  is  ≥  1 6 0 
m m H g or di ast oli c bl o o d pr ess ur e is ≥ 1 0 0 m m H g at s cr e e ni n g) ; 
1 1)  P ati e nts  or  p ati e nt’s  i m m e di at e  f a mil y  m e m b er s  ( p ar e nts,  si bli n gs,  offs pri n g)  
wit h a hist or y of m ali g n a nt t u m ors wit hi n t h e l ast 5 y e ars pri or t o t h e s cr e e ni n g 
d at e, e x cl u di n g b as al c ell c ar ci n o m a or s q u a m o us c ell c ar ci n o m a t h at o c c urs o n t h e 
s ki n  (if  it  is  d et er mi n e d  t h at  t h er e  is  n o  p ossi bilit y  of  r el a ps e  aft er  r es e cti o n),  or  
wit h  a  f a mil y  hist or y  of  f a m ili al  a d e n o m at o us  p ol y p osis  ( F A P)  or  h er e dit ar y  
n o n p ol y p osis c ol or e ct al c a n c er ( H N P C C);  
1 2)  P ati e nts  w h o  h a v e  n ot  c o m pl et e d  a  n ati o n al  c a n c er  s cr e e ni n g  pr o gr a m  
a p pli c a bl e t o t h eir s e x a n d a g e (if it c a n n ot b e c o nfir m e d t h at t h e r el e v a nt t est w as 
r e c ei v e d at a n ati o n al c a n c er s cr e e ni n g c e nt er or a r e c o g ni z e d s cr e e ni n g c e nt er). 
H o w e v er, if it is c o nfir m e d t h at t h e r el e v a nt t est w as r e c ei v e d at a n ati o n al c a n c er 
s cr e e ni n g c e nt er or a r e c o g ni z e d s cr e e ni n g c e nt er d uri n g t h e s cr e e ni n g p eri o d, a n d 
t h at t h e r es ults w er e wit hi n n or m al r a n g e, t h e p ati e nts m a y p arti ci p at e i n t h e cli ni c al 
st u d y; 
C o m m o n t o m al es a n d f e m al es: If a p ati e nt is ≥ 5 0 y e ar s of a g e, t h e r es ults 
of a c ol o n os c o p y wit hi n 5 y e ar s pri or t o t h e s cr e e ni n g m ust b e d et er mi n e d 
as b ei n g wit hi n n or m al r a n g e, a n d if a d e n o m at o us p ol y ps ar e e vi d e nt, t h e 
r es ults of a c ol o n os c o p y wit hi n 1 y e ar m ust b e d et er mi n e d as b ei n g wit hi n 
n or m al  r a n g e  (i nfl a m m at or y  p ol y ps  or  h y p er pl asti c  p ol y ps  ar e  i n cl u d e d  i n  
t h e n or m al r a n g e). If a p ati e nt is ≥ 4 0 y e ar s of a g e,  t h e  r es ults  of  a  
g astr os c o p y  wit hi n  2  y e ar s  pri or  t o  t h e  s cr e e ni n g  m ust  b e  wit hi n  n or m al  
r a n g e. If a p ati e nt is ≥ 5 4 y e ar s of a g e a n d h as a 3 0 p a c k-y e ar hist or y of 
s m o ki n g or m or e, t h e r es ults of a l o w -d os e c h est C T wit hi n 2 y e ar s pri or t o 
t h e s cr e e ni n g m ust b e wit hi n n or m al r a n g e. I n c as e of li v er c a n c er, c arri ers 
of h e p atitis B or h e p atitis C vir us a n d p ati e nts wit h h e p ati c cirr h osis f all u n d er 
t h e e x cl usi o n crit eri a. 
   
F e m al es:  F or  f e m al es  ≥  4 0  y e ars  of  a g e,  n or m al  r a n g e  fi n di n gs  m ust  b e 
c o nfir m e d i n a  m a m m o gr a m wit hi n 2 y e ar s. F or f e m al es ≥ 2 0 y e ar s of a g e, 
n or m al r a n g e fi n di n gs m ust b e c o nfir m e d i n a P a p s m e ar wit hi n 2 y e ar s.  
 

 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
V ersi o n : 4 . 0 
 7  / 8  
 
 
 
 
If s u bj e cts w h o h a v e v ol u nt aril y si g n e d t h e st u d y c o ns e nt f or m ar e e nr oll e d i n t h e 
cli ni c al st u d y, t h e y ar e t est e d f or eli gi bilit y t o t his st u d y d uri n g t h e s cr e e ni n g p eri o d.  
T h os e w h o m e et t h e i n cl usi o n/ e x cl usi o n crit eri a ar e gi v e n a t ot al of 4 d os es of t h e 
i n v esti g ati o n al pr od u ct f or 1 0 4 d a ys ( 2 d os es o v er 2 w e e ks, f oll o w e d b y 3 - m o nt h 
s af et y  a n d  t ol er a bilit y  ass ess m e nt, a n d t h e n  a n ot h er 2  d os es  o v er 2  w e e ks).  T h e 
dr u g’s s af et y a n d t ol er a bilit y ar e ass ess e d at e a c h visit, a n d effi c a c y is ass ess e d at 
t h e 2n d  visit ( b as eli n e, D a y  0) a n d 7 t h visit (l ast visit, D a y 2 7 0).  
Alt h o u g h t his st u d y is a p h as e 1/ 2 a, c o nsi d eri n g t h at C M T 1 A ( C h ar c ot -M ari e -T o o t h )  
dis e as e is a r ar e dis e as e t h at h as n o tr e at m e nt y et, t his cli ni c al st u d y is d esi g n e d 
t o c o n d u ct a n ass ess m e nt of cli ni c all y m e a ni n gful f a ct ors i n r el ati o n t o effi c a c y.    
A d mi ni str a
ti o n of 
i n v e sti g ati
o n al 
pr o d u ct  
A d mi ni str ati o n of i n v e sti g ati o n al pr o d u ct:  I ntr a m us c ul ar i nj e cti o n 
Pr e p ar ati o n of i n v e sti g ati o n al pr o d u ct:    
E a c h  vi al  c o nt ai ns  2. 5  m g  of  
 t h e  m ai n  i n gr e di e nt  of  t h e  
i n v esti g ati o n al pr o d u ct, i n a st erili z e d/l y o p hili z e d c o n diti o n. T h e i n v esti g at or us es 
5. 0 m L of w at er f or i nj e cti o n t o dil ut e t h e i n v esti g ati o n al pr o d u ct ( 0. 5 m g/ m L) a n d 
t h e n a d mi nist ers a t ot al of 5 6 i ntr a m us c ul ar i nj e cti o ns i nt o t hr e e m us cl es e a c h i n 
t h e  l eft  a n d  ri g ht  l o w er  li m bs  of  t h e  st u d y  s u bj e ct.  T h e  q u a ntit y  of  t h e  
i n v esti g ati o n al pr o d u ct, t h e n u m b er  of i nj e cti o ns, d os a g e, a n d t ar g et  m us cl es  b y  
e a c h s u bj e ct at e a c h visit ar e s h o w n i n Ta bl e 4 a n d Ta bl e 5 b el o w.  
C a uti o n :  
E a c h dil ut e d vi al s h all b e us e d f or o n e s u bj e ct o nl y.  
Usi n g t hi n n e e dl es s uit a bl e f or i ntr a m us c ul ar i nj e cti o n ( e. g., 2 9 g a u g e, 1/ 2 i n c h or 
1i n c h i n l e n gt h a c c or di n g t o m us cl e t y p e a n d s u b c ut a n e o us f at t hi c k n ess), i nj e cti o ns 
s h all  b e  e v e nl y  distri b ut e d  o n  t h e  t ar g et  m us cl e  as  s h o w n  b el o w,  a v oi di n g  t h e  
f as ci a.  
 
Ta bl e 4. T ot al n u m b er of vi al s, d o s a g e, a n d n u m b er of i nj e cti o n s p er vi sit  
N u m b er of vi al s p er vi sit  
N u m b er of i nj e cti o n s p er 
vi sit  
T ot al d o s e p er vi sit  
7 
5 6  
1 4 m g/ 2 8 m L  
 
Ta bl e 5. N u m b er of i nj e cti o n s a n d d o s a g e f or e a c h m u s cl e (i nj e cti o n sit e)  
T ar g et m u s cl e  
D o s a g e  ( m g)  p er  t ar g et  m us cl e  ( n u m b er  of  
T ot al
 d o s a g e
 

 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
V ersi o n : 4 . 0 
 8  / 9  
 
 
 
i nj e cti o n s p er m u s cl e: l eft/ri g ht) 
( m g),
 (t ot al
 
n u m b er
 of
 
i nj e cti o n s: 
l eft/ri g ht) 
1st 
a d mi nis
tr ati o n 
2 n d 
a d mi nis
tr ati o n 
3r d 
a d mi nis
tr ati o n 
4t h 
a d mi nis
tr ati o n  
D 0  
D 1 4  
D 9 0  
D 1 0 4  
  
L o w er 
l e g  
P er o n e us 
l o n g us 
3, ( 6/ 6)  
3, ( 6/ 6)  
3, ( 6/ 6)  
3, ( 6/ 6)  
1 2, ( 2 4/ 2 4)  
G astr o c n e
mi us  
6, ( 1 2/ 1 2)  
6, ( 1 2/ 1 2)  
6, ( 1 2/ 1 2)  
6, ( 1 2/ 1 2)  
2 4, ( 4 8/ 4 8)  
Ti bi alis 
a nt eri or  
 5, ( 1 0/ 1 0)  
5, ( 1 0/ 1 0)  
5, ( 1 0/ 1 0)  
5, ( 1 0/ 1 0)  
2 0, ( 4 0/ 4 0)  
Fi n al d o s a g e 
( n u m b er of 
i nj e cti o n s: 
l eft/ri g ht) 
1 4, 
( 2 8/ 2 8) 
1 4, 
( 2 8/ 2 8) 
1 4, 
( 2 8/ 2 8) 
1 4, 
( 2 8/ 2 8) 
5 6 ( 1 1 2/ 1 1 2)  
 
Pri m ar y 
e n d p oi nt  
S af et y a n d t ol er a bilit y ar e e v al u at e d i n t h e f oll o wi n g it e m s, i n cl u di n g a d v er s e 
e v e nt s  c oll e ct e d  fr o m  st u d y  s u bj e ct s  f oll o wi n g  t h e  a d mi ni str ati o n  of  t h e  
i n v e sti g ati o n al pr o d u ct ( V M 2 0 2). 
 
* S af et y a n d t ol er a bilit y a s s e s s m e nt  
( 1) A d v ers e e v e nt  
- All  a d v ers e  e v e nts  t h at  m a nif est  aft er  a d mi nistr ati o n  of  t h e  i n v esti g ati o n al 
pr o d u ct s h all b e c oll e ct e d.  
- At  Visits  3,  4,  a n d  5  ( 2 n d,  3r d,  a n d  4t h  a d mi nistr ati o n  s essi o ns  of  t h e  
i n v esti g ati o n al pr o d u ct), a d v ers e e v e nts s h all b e ass ess e d a n d c oll e ct e d b ef or e 
a n d aft er a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct.  
( 2) L a b or ator y t ests ( c o m pl et e bl o o d c ell c o u nt/ g e n er al bl o o d c h e mistr y/ uri n al ysis 
t ests) 
( 3) Vit al si g ns  
S e c o n d ar y 
e n d p oi nt  
C o nsi d eri n g t h at C M T 1 A ( C h ar c ot -M ari e -T o ot h) dis e as e is a r ar e dis e as e t h at h as  
n o  tr e at m e nt  y et,  t his  cli ni c al  tri al  is  d esi g n e d  t o  e v al u at e  cli ni c all y  m e a ni n gf ul  
f a ct ors i n r el ati o n t o effi c a c y.: 
 
( 1) C h a n g e i n s e v erit y of dis e as e 
- C M T N S -v 2 ( C h ar c ot-M ari e -T o ot h N e ur o p at h y S c or e v ersi o n 2)  
- F D S (f u n cti o n al dis a bilit y s c al e)  
( 2) C h a n g es i n l o w er li m b f u n cti o n 
- O N L S ( o v er all n e ur o p at h y li mit ati o n s c or e) l e g s c al e  
- 1 0 M W T ( 1 0 -m et er w al k t est)  
( 3) C h a n g es i n f att y i nfiltr ati o n l e v el of l o w er li m b m us cl es 
- M RI l e g  
( 4) N er v e r e g e n er ati o n p ot e nti al 
- C M A P ( c o m p o u n d m ot or n er v e a cti o n p ot e nti al)  

 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
V ersi o n : 4 . 0 
 9  / 1 0  
 
 
 
- S N A P ( c o m p o u n d s e ns or y n er v e a cti o n p ot e nti al)  
- N C V ( n er v e c o n d u cti o n v el o cit y)  
( 5) H G F a nti b o d y g e n er ati o n b y V M 2 0 2 
St ati sti c al 
a n al y si s  of  
pri m ar y 
e n d p oi nt  
D efi niti o n of s u bj e ct s f or pri m ar y e n d p oi nt a n al y si s  
S af et y s et  
Of all s u bj e cts w h o w er e d e ci d e d s uit a bl e d uri n g s cr e e ni n g, t h e a n al ysis i n cl u d es 
t h os e w h o w er e a d mi nist er e d t h e i n v esti g ati o n al pr o d u ct a n d c a n b e ass ess e d f or 
s af et y.  T h e  st u d y  s u bj e cts  i n cl u d e d  i n  t h e  s af et y  a n d  t ol er a bilit y  a n al ysis  ar e  
a n al y z e d  b as e d  o n  i nf or m ati o n  o n  t h e  i n v esti g ati o n al  pr o d u ct  t h at  w as  a ct u all y  
a d mi nist er e d. F urt h er m or e, t h e s af et y s et is a n al y z e d f or d e m o gr a p hi c d at a ( g e n d er, 
a g e, et c.) a n d b a c k gr o u n d f a ct ors ( m e di c al hist or y, pr e vi o us dr u g tr e at m e nt, et c.)  
 
St ati sti c al a n al y si s m et h o d f or pri m ar y e n d p oi nt  
( 1) A d v er s e e v e nt: 
: S u m m ar y a n d a n al ysis of a d v ers e e v e nts ar e c o n d u ct e d o n Tr e at m e nt-E m er g e nt 
A d v ers e  E v e nts  ( T E A Es)  t h at  o c c ur  aft er  t h e  a d mi nistr ati o n  of  t h e  i n v esti g ati o n al  
pr o d u ct. 
Fr e q u e n c y  a n d  p er c e nt a g e  of  T E A Es,  a d v ers e  dr u g  r e a cti o ns  ( A D Rs),  a n d  s eri o us  
a d v ers e  e v e nts  ( S A Es),  o c c urri n g  aft er  i n v esti g ati o n al  pr o d u ct  a d mi nistr ati o n,  ar e  
pr o vi d e d.  
T E A Es, A D Rs, a n d S A Es ar e c o d e d usi n g M e d D R A ( M e di c al Di cti o n ar y f or R e g ul at or y 
A cti viti es, l at est v ersi o n) a c c or di n g t o  t h e S yst e m Or g a n Cl ass ( S O C) a n d Pr ef err e d 
Ter mi n al ( P T). T h e n u m b er of s u bj e cts wit h c o d e d a d v ers e e v e nts, t h e o c c urr e n c e 
r at e, a n d t h e n u m b er of t h e c as es ar e pr es e nt e d. 
 
( 2) L a b or at or y t e st s a n d vit al si g n s 
: F or c o nti n u o us v ari a bl es, d es cri pti v e st atisti cs ( a v er a g e, st a n d ar d d e vi ati o n, m e di a n 
v al u e, mi ni m u m v al u e, m a xi m u m v al u e) ar e pr es e nt e d f or e a c h visit. F or c at e g ori c al 
v ari a bl es,  fr e q u e n c y  a n d  p er c e nt a g e  ar e  pr es e nt e d.  F or  e a c h  visit, fr e q u e n c y  a n d  
p er c e nt a g e of n or m al c h a n g es, n ot cli ni c all y si g nifi c a nt ( N C S) a b n or m al c h a n g es, 
a n d  cli ni c all y  si g nifi c a nt  ( C S)  c h a n g es  ar e  pr es e nt e d  f or  e a c h  visit,  a n d  a  list  of  
s u bj e cts ass ess e d as a b n or m al ( C S) f or e a c h visit is pr es e nt e d.    
St ati sti c al 
a n al y si s  of  
s e c o n d ar y 
e n d p oi nt  
D efi niti o n of s u bj e ct s f or s e c o n d ar y e n d p oi nt a n al y si s  
I nt e nti o n-T o -Tr e at (I T T)  
R e g ar dl ess of w h et h er t h e pr ot o c ol w as br e a c h e d or t h e visit s c h e d ul e w as a d h er e d 
t o, all s u bj e cts w h o h a v e b e e n a d mi nist er e d wit h t h e i n v esti g ati o n al pr o d u ct o nc e 
or m or e a n d c a n b e ass ess e d f or effi c a c y ar e i n cl u d e d i n t h e I T T.  
 
P er -Pr ot o c ol S et ( P P S)  
P P S a p pli es t o t h e I T T s u bj e cts w h o h a v e c o m pl et e d t h e st u d y i n a c c or d a n c e wit h 

 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
V ersi o n : 4 . 0 
 1 0  / 1 1  
 
 
 
t h e pr ot o c ol wit h o ut a n y m aj or pr ot o c ol vi ol ati o n, a n d t h e s u bj e cts c orr es p o n di n g 
t o  t h e  f oll o wi n g  ar e  d efi n e d  as  P P S.  C o m pli a n c e  wit h  N o.  ① eli gi bilit y  s h all  b e  
d et er mi n e d i n a d at a r e vi e w m e eti n g pri or t o d at al o c k . 
① S u bj e cts  w h o  c o m pli e d  wit h  t h e  i n cl usi o n/ e x cl usi o n  crit eri a  ( eli gi bl e  
p ati e nts);  
② S u bj e cts w h o c o m pl et e d all visits . 
 
St ati sti c al a n al y si s m et h o d f or s e c o n d ar y e n d p oi nt  
Alt h o u g h  t his  st u d y  is  p h as e  1/ 2 a  t h at  is  n ot  i nt e n d e d  f or  effi c a c y  ass ess m e nt,  
c o nsi d eri n g t h at t his is a r ar e dis e as e t h at h as n o tr e at m e nt y et, ass ess m e nt will b e 
c o n d u ct e d o n cli ni c all y m e a ni n gf ul f a c t ors i n r el ati o n t o effi c a c y. 
 
( 1) S e v erit y of di s e a s e 
M e as ur e d  b y  C M T N S -v 2  ( C h ar c ot-M ari e -T o ot h  N e ur o p at h y  S c or e  v er si o n  2)  a n d  
F D S (f u n cti o n al dis a bilit y s c al e)  
 
( 2) W al ki n g f u n cti o n 
C h a n g e  i n  w al ki n g  f u n cti o n  is  ass ess e d  b y  O N L S  ( o v er all  n e ur o p at h y  li mit ati o n  
s c or e) l e g s c al e, a n d 1 0 M W T ( 1 0 -m et er w al k t est).  
 
( 3) F att y i nfiltr ati o n r at e i n l o w er li m b m u s cl e 
Usi n g  l e g  M RI  s c a ns,  t h e  d e gr e e  of  f att y  i nfiltr ati o n  of  t h e  l e g  m us cl e  t h at  h as 
r e c ei v e d t h e i n v esti g ati o n al pr o d u ct is m e as ur e d a n d e v al u at e d as t h e f at c o nt e nt 
v al u e ( %) at e a c h m us cl e l e v el.  
 
( 4) P ot e nti al of n er v e r e g e n er ati o n 
N er v e c o n d u cti o n t ests ar e c o n d u ct e d, i n cl u di n g C M A P ( c o m p o u n d m ot or n er v e  
a cti o n p ot e nti al), S N A P ( c o m p o u n d s e ns or y n er v e a cti o n p ot e nti al), a n d N C V ( n er v e 
c o n d u cti o n v el o cit y).  
 
( 5) F or m ati o n of H G F a nti b o d y c a u s e d b y E n g e n si s ( V M 2 0 2) 
T h e f or m ati o n of a nti -H G F A b i n t h e bl o o d is c h e c k e d. Pr eli mi n ar y ass ess m e nt is 
m a d e of w h et h er a nti b o d y pr o d u cti o n is c orr el at e d b et w e e n t h e s u bj e ct gr o u p w h o 
ar e c o nsi d er e d t o h a v e i n cr e as e d m us cl e m ass a n d i m pr o v e d f u n cti o n a n d t h os e 
w h o  ar e  n ot.  T h e  s u m m ar y  t a bl e  pr es e nts  t h e  fr e q u e n c y  a n d  r ati o  of  a nti b o d y  
g e n er ati o n i n t h e bl o o d.  
H o w e v er, if n o a nti b o d y i n t h e bl o o d is pr o d u c e d i n a n y si n gl e s u bj e ct, n o r es ults 
ar e pr es e nt e d.  
 
F or  t h e  s e c o n d ar y  e n d p oi nt,  f or  v al u es  b ef or e  a n d  aft er  tr e at m e nt,  c o nti n u o us 
v ari a bl es pr es e nt a v er a g e, st a n d ar d d e vi ati o n, m e di a n v al u e, mi ni m u m v al u e, a n d 

 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
V ersi o n : 4 . 0 
 1 1  / 1 2  
 
 
 
m a xi m u m  v al u e;  c at e g ori c al  v ari a bl es  pr es e nt  fr e q u e n c y  a n d  p er c e nt a g e.  T o  
c o m p ar e diff er e n c es of v al u es b ef or e a n d aft er tr e at m e nt, c o nti n u o us v ari a bl es us e 
a p air e d t -t est or Wil c o x o n si g n r a n k t est; c at e g ori c al v ari a bl es us e M c N e m ar’s t est.  
S m all 
gr o u p 
a n al y si s  
W h e n c o n d u cti n g t h e a d v ers e e v e nts  a n d effi c a c y ass ess m e nts, s m all gr o u p a n al ysis 
is c arri e d o ut c o nsi d eri n g t h e f oll o wi n g it e ms: 
 
• G e n d er ( m al e, f e m al e) 
• A g e ( ≤ m e di a n, > m e di a n) 
• B as eli n e B MI ( ≤ m e di a n, > m e di a n)  
• Pr es e n c e or a bs e n c e of m e di c al hist or y  
• Pr es e n c e or a bs e n c e of c o n c o mit a nt m e di c ati o ns  
• Dis e as e s e v erit y ( C M T N S v 2) ( mil d, m o d er at e)  
 
If t h e n u m b er of s u bj e cts t h at fit i nt o t h e a b o v e s u b gr o u ps is s m all i n e a c h gr o u p, 
t h e a n al ysis s h all n ot b e c o n d u ct e d o n t h at s u b gr o u p. F or e x a m pl e, if m al e s u bj e cts 
ar e l ess  t h a n  3 0 % of t h e t ot al s u bj e cts, n o  a n al ysis  is  p erf or m e d o n g e n d er a n d  
w h et h er t o a n al y z e s h all b e d et er mi n e d i n a d at a r e vi e w m e eti n g pri or t o d at al o c k. 
R etr o s p e ct
i v e 
bi o m ar k er  
st u d y ( T o  b e  
c o n d u ct e d 
s e p ar at el y) 
 
 
 
  

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1. 0 6 . 07 
V ersi o n : 4 . 0 
 1 4  / 1 5  
 
 
 
b e s ur v e y e d r e g ar dl ess of t h e ti m e p eri o d. Cli ni c all y si g nifi c a nt m e di c al c o n diti o ns or a b n or m aliti es o bs er v e d d uri n g t h e p er i o d fr o m t h e o bt ai n m e nt of t h e i nf or m e d c o ns e nt f or m 
u ntil t h e a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct s h all b e d e e m e d as m e di c al hist or y. It s h all b e s ur v e y e d w h et h er t h e n ati o n al c a n c er s cr e e ni n g ( g astri c c a n c er, c ol o n c a n c er, li v er 
c a n c er, l u n g c a n c er, c er vi c al c a n c er, br e ast c a n c er) e x a mi n ati o ns r el e v a nt t o t h e p ati e nt’s a g e ar e t a k e n a n d t h e r es ults ar e  wit hi n t h e n or m al r a n g e. I n c as e of c er vi c al c a n c er, if it 
c a n n ot b e c o nfir m e d t h at t h e n ati o n al c a n c er s cr e e ni n g e x a mi n ati o ns w er e t a k e n wit hi n 2 y e ars a n d t h e r es ults ar e wit hi n t h e n or m al r a n g e, a n e x a mi n ati o n a n d a p a p s m e ar s h all b e 
p erf or m e d at t h e i nstit uti o n t o v erif y n or m al r a n g e r es ults.  
3)  
P h ysi c al e x a mi n ati o n: I nf or m ati o n s h all b e c oll e ct e d f or e x a mi n ati o n it e ms c o nsisti n g of e xt er n al a p p e ar a n c e, s ki n, h e a d/ n e c k , c h est/l u n gs, h e art, a b d o m e n, uri n ar y/r e pr o d u cti v e s yst e m, 
li m bs, m us c ul os k el et al s yst e m, n er v o us s yst e m, l y m p h n o d es, a n d ot h er it e ms.  
4)  
B o d y m e as ur e m e nt ( w ei g ht m e as ur e m e nt): H ei g ht, w ei g ht, a n d B MI s h all b e m e as ur e d. H ei g ht a n d B MI s h all b e m e as ur e d o nl y at s c r e e ni n g ( Visit 1). 
5)  
Vir us s er ol o g y t est: HI V, H Bs A g, A nti -H Bs, A nti -H C V  
6)  
C o m pl et e bl o o d c ell c o u nt a n d g e n er al bl o o d c h e mistr y t ests: T h e l a b or at or y t est it e ms ar e as f oll o ws:  
- C o m pl et e bl o o d c ell c o u nt: W B C, R B C, H b, H ct, M C V, M C H, M C H C, P L T, E S R, M P V, diff er e nti al c o u nt of W B C ( B a n d n e utr o p hil, S e g m e nt e d n e utr o p hil, E osi n o p hil, B as o p hil, Ly m p h o c yt e, 
M o n o c yt e)    
- G e ner al bl o o d c h e mistr y t est: t ot al pr ot ei n, al b u mi n, gl o b uli n, A/ G r ati o, c h ol est er ol, t ot al bilir u bi n, A S T, A L T, f asti n g gl u c o s e, B U N, cr e ati ni n e, esti m at e d G F R, C a 2 + , p h os p h at e, N a+ , 
K + , Cl-, C R P, tri gl y c eri d e, H D L-c h ol est er ol, L D L -c h ol est er ol  
7)  
R etr os p e cti v e bi o m ar k er st u d y : Bl o o d s a m pl es ar e c oll e ct e d at  D a y 0, D a y 9 0, D a y 1 8 0  a n d  D a y 2 7 0 ( or e arl y t er mi n ati o n visit ) f or r etr os p e cti v e bi o m ar k er st u d y of C M T. C oll e ct e d 
s a m pl es will b e  pr o c ess e d a c c or di n g t o d et ail e d pr o c e d ur e i n a s e p ar at e pr ot o c ol.  C M T  
8)  
C h est X -r a y ( P A): At Visit 1 (s cr e e ni n g), c h est P A X-r a y s h all b e p erf or m e d t o v erif y w h et h er a cti v e t u b erc ul osis is pr es e nt. T h e r es ults wit hi n 1 m o nt h ( 3 0 d a ys) b ef or e Visit 1 m a y b e 
us e d.  
9)  
Uri n al ysis: T h e l a b or at or y t est it e ms ar e as f oll o ws:  
- C ol or, t ur bi dit y, s p e cifi c gr a vit y, p H, al b u mi n, gl u c os e, k et o n es, bilir u bi n, bl o o d, ur o bili n o g e n, nitrit e, l e u k o c yt e est er as e, mi cr os c o p y ( R B C, W B C, c asts)  
1 0)  Uri n e or s er u m pr e g n a n c y t est At Visit 1 (s cr e e ni n g), uri n e or s er u m pr e g n a n c y t ests s h all b e p erf or m e d i n f e m al es of c hil d b e ari n g p ot e nti al (fr o m p ost -m e n ar c h e f e m al es t o f e m al es 
≥ 5 0 y e ars of a g e wit hi n 1 y e ar of m e n o p a us e, or fr o m p ost -m e n arc h e f e m al es t o f e m al es < 5 0 y e ars of a g e wit hi n 2 y e ars of m e n o p a us e). H o w e v er, p ati e nts wi t h s ur gi c al m e n o p a us e 
( h yst er e ct o m y, bil at er al o o p h or e ct o m y, et c.) or w h o u n d er w e nt st erili z ati o n s ur g er y ( bil at er al t u b al li g ati o n, bil at er al t u b ect o m y) m a y b e e x cl u d e d. M e n o p a us e r ef ers t o t h e st at e aft er 
1 y e ar of a m e n orr h e a.  
1 1)  El e ctr o c ar di o gr a m: T h e el e ctr o c ar di o gr a m t o b e p erf or m e d at Visit 1 (s cr e e ni n g) m a y us e r es ults wit hi n 4 w e e ks b ef or e Visit 1 (s cr e e ni n g).  
1 2)  C o n c o mit a nt  m e di c ati o ns  s ur v e y:  All  m e di c ati o ns  a n d  tr e at m e nts  a d mi nist er e d  wit hi n  6  m o nt hs  b ef or e  Visit  1  (s cr e e ni n g)  s h all  b e  s ur v e y e d .  Pr e vi o us  m e di c ati o ns  a n d  pr e vi o us  
tr e at m e nts  s h all  b e  d efi n e d  as  all  pr e vi o usl y  c oll e ct e d  m e di c ati o ns  a n d  tr e at m e nts  b ef or e  Visit  2  (first  a d mi nistr ati o n  of  i n v esti g ati o n al  pr o d u ct).  C o n c o mit a nt  m e di c ati o ns  a n d  
tr e at m e nts s h all r ef er t o all m e di c ati o ns t h at h a v e b e e n a d mi nist er e d at l e ast o n c e st arti n g fr o m Visit 2 (first a d mi nistr ati o n of i n v esti g ati o n al pr o d u ct) a n d t hr o u g h o ut t h e cli ni c al 
st u d y. T h e c at e g ori es of c oll e ct e d m e di c ati o ns a n d tr e at m e nts s h all f oll o w t his d efi niti o n. W h et h er t h e m e di c ati o ns  a n d tr e at m e nts b ei n g a d mi nist er e d s h o ul d b e c o nti n u e d s h all b e 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1. 0 6 . 07 
V ersi o n : 4 . 0 
 1 5  / 1 6  
 
 
 
i n v esti g at e d at e a c h visit. 
1 3)  M RI l e g: T h e m us cl es of l o w er li m bs s h all b e i m a g e d, a n d t h e f att y i nfiltr ati o n l e v el of t h e l e g m us cl es i nj e ct e d wit h t h e i n v esti g ati o n al pr o d u ct s h all b e m e as ur e d a n d e v al u at e d as 
f at c o nt e nt v al u e ( %) at o n e l e v el f or e a c h m us cl e. C o nsi d eri n g t h e s c h e d ul e, et c., of t h e i nstit uti o n, it s h all b e p erf or m e d o pti o n all y at t h e e arl y t er mi n ati o n visit, a n d if it is n ot 
p erf or m e d, t h e r e as o ns s h all b e r e c or d e d i n t h e c as e r e p ort f or m.  
1 4)  A d v ers e e v e nt ass ess m e nt: At Visits 3, 4, a n d 5, a n ass ess m e nt of a d v ers e e v e nts t h at h a v e o c c urr e d si n c e t h e l ast visit s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al 
pr o d u ct, a n d l o c ali z e d a d v ers e e v e nts s h all b e ass e ss e d at 2 ± 1 h o urs aft er a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct, as w ell as o n t h e d a y aft er a d mi nistr ati o n.  
1 5)  H os pit ali z ati o n: S u bj e cts s h all b e h os pit ali z e d o n t h e d a y b ef or e a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct a n d t h eir vit al si g ns s h all b e m e as ur e d. If t h e y ar e n ot h os pit ali z e d, vit al 
si g ns m a y b e o mitt e d, a n d t h e h os pit ali z ati o n d a y i n t h e c as e r e p ort f or m s h all b e r e c or d e d t h e s a m e as t h e t est d a y pri or t o  a d mi nistr ati o n.  
1 6)  
Aft er a d mi nistr ati o n: Vit al si g ns a n d a d v ers e e v e nts s h all b e ass ess e d at 2 ± 1 h o urs aft er a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct. T h e pr es e n c e or a bs e n c e of l o c ali z e d a d v ers e 
e v e nts s h all b e v erifi e d o n t h e d a y aft er a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct.

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 1 6  / 1 7  
 
 
Gl o s s ar y of A b br e vi ati o n s  
A E  
A d v ers e E v e nt  
A E SI 
A d e v ers e E v e nt s of S p e ci al I nt er est  
A F O  
A n kl e F o ot Ort h osis  
A L S  
A m y otr o p hi c L at er al S cl er osis  
A L T  
Al a ni n e Tr a ns a mi n as e ( S G T P)  
A nti - H C V 
H e p atitis C A nti b o di es  
A S T  
As p art at e Tr a ns a mi n as e ( S G O P)  
B MI 
B o d y M ass I n d e x  
B U N  
Bl o o d Ur e a Nitr o g e n  
C B C 
C o m pl et e Bl o o d c ell C o u nt 
c D N A  
C o m pl e m e nt ar y D e o x y n u cl ei c A ci d  
C LI 
Criti c al Li m b Is c h e mi a  
C M A P 
C o m p o u n d M us cl e A cti o n P ot e nti al  
C M T 
C h ar c ot -M ari e -T o ot h dis e as e  
C M T 1 A 
C h ar c ot -M ari e -T o ot h dis e as e s u bt y p e 1 A  
C M T N S- v 2  
C h ar c ot -M ari e -T o ot h N e ur o p at h y S c or e V ersi o n 2  
C O X - 1 
C y cl o o x y g e n as e -1  
C O X - 2 
C y cl o o x y g e n as e -2  
C R F  
C as e R e p ort F or m  
C R O  
C o ntr a ct R es e ar c h Or g a ni z ati o n  
D M  
D at a M a n a g e m e nt  
D M P 
D at a M a n a g e m e nt Pl a n  
D N A  
D e o x yri b o n u cl ei c A ci d  
D P N 
Di a b eti c P eri p h er al N e ur o p at h y  
D S M B 
D at a S af et y M o nit ori n g B o ar d  
E D C  
El e ctr o ni c D at a C a pt ur e  
E K G  
El e ctr o c ar di o gr a m  
F D S  
F u n cti o n al Dis a bilit y S c al e  
G C P 
G o o d Cli ni c al Pr a cti c e  
H b c A b  
H e p atitis B c or e a nti b o d y  
H b s A b  
H e p atitis B s urf a c e a nti b o d y  
H b s A g  
H e p atitis B s urf a c e a nti g e n  
H B V  
H e p atitis B Vir us  
H C G 
H u m a n C h ori o ni c G o n a d otr o p hi n  
H C T 
H e m at o crit  

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 1 7  / 1 8  
 
 
H C V 
H e p atitis C Vir us  
H E D  
H u m a n E q ui v al e n c e D os e  
H g b  
H e m o gl o bi n  
H G F  
H e p at o c yt e Gr o wt h F a ct or  
HI V  
H u m a n I m m u n o d efi ci e n c y Vir us  
H M S N 
H er e dit ar y M ot or a n d S e ns or y N e ur o p at h y  
H T L V  
A nti- H u m a n T -C ell L y m p h otr o pi c Vir us  
I H D 
Is c h e mi c H e art Dis e as e 
I L- 6 
I nt erl e u ki n-6  
I N D 
I n v esti g ati o n al N e w Dr u g 
I R B 
I nstit uti o n al R e vi e w B o ar d 
I S R 
I nj e cti o n Sit e R e a cti o n 
I T T 
I nt e nt-t o-Tr e at  
K G C P 
K or e a G o o d Cli ni c al Pr a cti c e  
L O C F  
L ast O bs er v ati o n C arri e d F or w ar d A n al ysis  
M C H 
M e a n C or p us c ul ar H e m o gl o bi n  
M C H C 
M e a n C or p us c ul ar H e m o gl o bi n C o n c e ntr ati o n  
M C V 
M e a n C or p us c ul ar V ol u m e  
M e d D R A  
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti es  
M P V 
M e a n Pl at el et V ol u m e  
M RI  
M a g n eti c R es o n a n c e I m a gi n g  
m R N A  
M ess e n g er Ri b o n u cl ei c A ci d  
N CI -C T C A E  
N ati o n al C a n c er I nstit ut e -C o m m o n T er mi n ol o g y Crit eri a f or A d v ers e E v e nts  
N C V  
N er v e C o n d u cti o n V el o cit y  
N C A M  
N e ur al c ell a d h esi o n m ol e c ul e 1  
N O A E L  
N o -O bs er v e d -A d v ers e -Eff e ct L e v el  
O N L S  
O v er all N e ur o p at h y Li mit ati o n S c al e  
P A 
P ost eri or t o A nt eri or  
P N S  
P eri p h er al N er v o us S yst e m  
P P 
P er Pr ot o c ol  
P T 
Pr ef err e d T er m  
p 6 2  
p 6 2/s e q u est os o m e - 1 
p 7 5  
p 7 5 N e ur otr o p hi n r e c e pt or  
R B C  
R e d Bl o o d C ell  
S A E  
S eri o us A d v ers e E v e nt  
S N A P  
S e ns or y N er v e A cti o n P ot e nti al  
S O C  
S yst e m Or g a n Cl ass  
S O P  
St a n d ar d O p er ati n g Pr o c e d ur e  

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 1 8  / 1 9  
 
 
T E A E  
Tr e at m e nt -E m er g e nt A d v ers e E v e nt  
T N F  
T u m or N e cr osis F a ct or  
1 0 M W T  
1 0- m et er w al k t est  
W B C  
W hit e Bl o o d C ell  
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 1 9  / 2 0  
 
 
1 
Titl e a n d P h a s e of Cli ni c al St u d y  
1. 1  
Titl e of Cli ni c al St u d y: P h a s e 1/ 2 a  
Si n gl e  C e nt er,  O p e n  l a b el,  R e p e at  I ntr a m us c ul ar  A d mi nistr ati o n,  2 7 0 d a ys,  P h as e  I/ 2 a  Cli ni c al  
Tri al t o E v al u at e S af et y a n d T ol er a bilit y of I n v esti g ati o n al Pr o d u ct ( E n g e nsis: V M 2 0 2) i n P ati e nts 
wit h C h ar c ot -M ari e -T o ot h Dis e as e s u bt y p e 1 A ( C M T 1 A)  
 
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 2 0  / 2 1  
 
 
2 
I nf or m ati o n of S p o n s or a n d C R O, N a m e a n d Titl e of Pri n ci p al I n v e sti g at or 
2. 1  
S p o n s or  
 
H eli x mit h C o., Lt d.  
 
2 1, M a g o kj u n g a n g 8 -r o 7-gil, G a n gs e o -g u, S e o ul, S o ut h K or e a  
 
2. 2  
Pri n ci p al I n v e sti g at or a n d Ot h er Cli ni c al St u d y P arti ci p a nt s  
 
  
D e p art m e nt of N e ur ol o g y  
S a ms u n g M e di c al C e nt er  
8 1, Ir w o n -r o, G a n g n a m-g u, S e o ul, S o ut h K or e a  
 
S e e “ A p p e n di x  1. I nf or m ati o n of S p o ns or, N a m e a n d Titl e of Pri n ci p al I n v esti g at or” f or ot h er 
cli ni c al st u d y p arti ci p a nts.  
 
2. 3  
C o ntr a ct R e s e ar c h Or g a ni z ati o n  
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 2 1  / 2 2  
 
 
3 
I ntr o d u cti o n 
3. 1  
I n ci d e n c e a n d Pr e v al e n c e of C h ar c ot -M ari e -T o ot h Di s e a s e  
H er e dit ar y  n e ur o p at h y  i n cl u d es  a  v ari et y  of  p eri p h er al  n e ur o p at hi es  t h at  ar e  cli ni c all y  a n d  
g e n eti c all y diff er e nt. C h ar c ot -M ari e -T o ot h dis e as e ( h er ei n aft er C M T), als o k n o w n as h er e dit ar y 
m ot or  a n d  s e ns or y  n e ur o p at h y  ( H M S N),  is  t h e  m ost  c o m m o n  dis e as e  of  t h es e  h er e dit ar y  
n e ur o p at hi es. T h e pr e v al e n c e of C M T is a p pr o xi m at el y 1 p ers o n i n e v er y 2, 5 0 0. [1 ] 
It  is  k n o w n  t h at  t h er e  ar e  a p pr o xi m at el y  2. 9  milli o n  p ati e nts  w orl d wi d e,  a n d  t h e  n u m b er  of  
p ati e nts i n S o ut h K or e a is esti m at e d t o b e a p pr o xi m at el y 2 0, 0 0 0. C M T is di vi d e d i nt o s e v er al 
s u bt y p es, a n d t h e m ost c o m m o n is C M T s u bt y p e 1 A ( h er ei n aft er C M T 1 A), t h e t ar g et dis e as e 
of t his cli ni c al st u d y, w hi c h a c c o u nts f or 4 0 % of all C M T. T h er e ar e a p pr o xi m at el y 9, 0 0 0 p ati e nts 
wit h  C M T 1 A i n S o ut h K or e a, a n d 1. 4 milli o n C M T 1 A p ati e nts w orl d wi d e. C M T 1 A is c a us e d b y 
t h e d u pli c ati o n of t h e P M P 2 2 g e n e.[2 ]   
 
3. 2  
P at h o p h y si ol o g y of C h ar c ot -M ari e -T o ot h Di s e a s e  
C M T is a h er e dit ar y p eri p h er al n e ur o p at h y, w hi c h is a dis e as e c a us e d b y d a m a g e t o m ot or a n d 
s e ns or y  n er v es  b y  g e n e  m ut ati o ns.  V ari o us  cli ni c al  p att er ns  ar e  s h o w n  d e p e n di n g  o n  t h e  
c a us ati v e g e n e, a n d cli ni c al s y m pt o ms s u c h as a m y otr o p h y i n t h e u p p er a n d l o w er li m bs, f o ot 
d ef or mit y, s e ns or y l oss, bli n d n ess, h e ari n g l oss, a n d ar efl e xi a ar e c o m m o nl y o bs er v e d, w hi c h 
s h o w a p att er n of gr a d u all y pr o gr essi n g o v er ti m e. [3 ]   
T h e p eri p h er al n er v o us s yst e m ( P N S) e xt e n ds o ut fr o m t h e c e ntr al n er v es ( br ai n, s pi n al c or d) 
a n d is distri b ut e d t o e a c h p art of t h e b o d y. It s er v es t h e r ol e of tr a ns mitti n g  e xt er n al sti m uli t o 
t h e c e ntr al n er v o us s yst e m a n d d eli v eri n g c o m m a n ds of t h e c e ntr al n er v o us s yst e m t o m us cl es 
or e a c h or g a n. T h e p eri p h er al n er v o us  s yst e m is  g e n er all y di vi d e d i nt o t h e s o m ati c n er v o us 
s yst e m a n d t h e a ut o n o mi c n er v o us s yst e m. T h e s o m ati c  n er v o us s yst e m is f urt h er di vi d e d i nt o 
m ot or a n d s e ns or y n er v es. M ot or n er v es ar e eff er e nt, a n d t h e y i n d u c e m us cl e c o ntr a cti o n b y 
tr a ns mitti n g e x cit ati o n fr o m t h e c e nt er t o t h e p eri p h er y (s k el et al m us cl es). S e ns or y n er v es ar e 
aff er e nt, a n d t h e y i n d u c e s e n s ati o n b y tr a ns mitti n g si g n als fr o m t h e p eri p h er y (s e ns or y or g a ns) 
t o  t h e  c e nt er.  P eri p h er al  n er v es  t h at  e m a n at e  fr o m  t h e  c e ntr al  n er v es  gr a d u all y  di vi d e  a n d  
s pr e a d t hr o u g h o ut t h e b o d y t o r e a c h t h e p eri p h er al or g a ns, w hi c h ar e di vi d e d i nt o t h e cr a ni al 
n er v es ( 1 2 p airs) a n d t h e s pi n al n er v es ( 3 1 p airs) d e p e n di n g o n w h er e t h e y e m a n at e fr o m.    
E a c h a x o n  wit hi n  t h e p eri p h er al n er v es  e xists  i nsi d e  a t y p e of t u b e m a d e of m y eli n s h e at hs  
pr o d u c e d b y s p e ci al n e ur o gli a c all e d S c h w a n n c ells. A n a x o n a n d m y eli n s h e at hs c o m bi n e d ar e 
c all e d a n er v e fi b er. A n u m b er of n er v e fi b ers f or m a b u n dl e t o c o nstit ut e o n e n er v e, b ut t h e 
n u m b er of n er v e fi b ers v ari es. A p pr o xi m at el y 1/ 3 of all n er v e fi b ers ar e wr a p p e d q uit e w ell. I n 
t h e  gr o wt h  p h as e,  S c h w a n n  c ells  wr a p  ar o u n d  a n  a x o n  in  s e v er al  l a y ers.  T his  r es ults  i n  t h e  
f or m ati o n of a m y eli n s h e at h m a d e of a mi xt ur e of li pi ds a n d pr ot ei ns i n b et w e e n t h e a x o n 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 2 2  / 2 3  
 
 
a n d t h e S c h w a n n c ells. As s u c h, a cr oss -s e cti o n of a n er v e fi b er r es e m bl es a n el e ctri c al wir e 
s urr o u n d e d b y a t hi c k i ns ul ati o n l a y er. A n er v e fi b er i ns ul at e d i n t his w a y is c all e d a m y eli n at e d 
or m e d ull at e d fi b er. T h e n er v e c o n d u cti o n v el o cit y of a m y eli n at e d n er v e fi b er is m u c h f ast er 
t h a n t h at of a n u n m y eli n at e d n er v e fi b er.  
 
C M T c a n b e l ar g el y cl assifi e d i nt o t w o t y p es b as e d o n  n er v e c o n d u cti o n st u di es a n d hist ol o gi c al 
f e at ur es,  a n d  t h es e  ar e  C M T 1  c h ar a ct eri z e d  b y  d e m y eli n ati o n  a n d  C M T 2  c h ar a ct eri z e d  b y  
d a m a g es t o a x o n c ells. R e c e ntl y, m or e d et ail e d cl assifi c ati o ns h a v e b e c o m e p ossi bl e as m or e 
st u di es  o n  t h e  c a us ati v e  g e n e  h a v e  b e c o m e  a cti v e  d u e  t o  a d v a n c es  i n  m ol e c ul ar  g e n eti cs  
t e c h n ol o g y. Wit h o v er 9 0 g e n eti c m ut ati o ns dis c o v er e d t o d at e, t h e y h a v e b e e n a gr e at h el p 
t o  p at h o p h ysi ol o gi c al  st u di es  as  w ell  as  i n  t h e  cl assifi c ati o n  of  c o m pl e x  cli ni c al  t y p es  a n d  
g e n ot y p es. [4 ] 
C M T c a n b e di vi d e d i nt o s e v er al s u bt y p es b as e d o n t h e c a us ati v e g e n e, a n d t h e m ost c o m m o n 
a n d t y pi c al s u bt y p e is C M T 1 A, t h e t ar g et dis e as e of t his cli ni c al st u d y. C M T 1 A d e v el o ps d u e t o 
t h e  d u pli c ati o n  of  c hr o m os o m e  1 7 p 1 1. 2-p 2 2  t h at  c o nt ai ns  p eri p h er al  m y eli n  pr ot ei n  2 2  
( P M P 2 2), a n d it is a n a ut os o m al d o mi n a nt i n h erit a n c e.[5 ] I n el e ctr o p h ysi ol o g y t ests, C M T 1 A is 
c h ar a ct eri z e d  b y  a  u nif or m  d e cr e as e  i n  n er v e  c o n d u cti o n  v el o cit y.  T his  is  a  c h ar a ct eristi c  of  
h er e dit ar y d e m y eli n ati n g n e ur o p at h y t h at c o ntr asts wit h t h e c o n d u cti o n bl o c k a n d t e m p or al 
dis p ersi o n s h o w n i n i nfl a m m at or y d e m y eli n ati n g n e ur o p at h y. [6 ]   
T h e o ns et a g e of p ati e nts wit h C M T 1 A is us u all y b ef or e 1 0 y e ar s of a g e, a n d t h e s y m pt o ms 
st art i n dist al r e gi o ns of li m bs a n d pr o gr ess t o t h e pr o xi m al r e gi o ns. As t h e dis e as e pr o gr ess es 
aft er t y pi c all y m a nif esti n g first i n t h e l o w er li m bs, its s y m pt o ms ar e als o s h o w n i n t h e u p p er 
li m bs. S e ns or y l oss, w e a k e ni n g of m us cl e str e n gt h, a m y otr o p h y, et c., st art t o m a nif est i n b ot h 
f e et as w ell as i n t h e l e g b el o w t he k n e es, a n d aft er s e v er al y e ar s, t h e s y m pt o ms als o m a nif est 
i n t h e h a n ds a n d ar ms.[7 ] 
F ats  a c c u m ul at e  i n  t h e  atr o p hi e d  m us cl e  tiss u es,  a n d  t h e  f att y  i nfiltr ati o n  l e v el  wit hi n  t h e  
m us cl es c a n b e i d e ntifi e d usi n g M RI i m a gi n g. At t his ti m e, t h e f at c o nt e nt v al u e ( %) s h all b e 
m e as ur e d a n d e v al u at e d at o n e l e v el f or e a c h m us cl e. [8 ] 
T h e p at h o g e n esis of C M T 1 A is k n o w n t o b e d u e t o a n i n cr e as e d q u a ntit y of m R N A c a us e d b y 
t h e  d u pli c ati o n  of  t h e  P M P 2 2  g e n e,  w hi c h  i n  t ur n  pr o d u c es  a  str u ct ur all y  u nst a bl e  m y eli n  
s he at h. [9 ] It h as b e e n v erifi e d t h at t h e s y m pt o ms s h o w n i n m ut at e d r ats w h os e d u pli c ati o n of 
t h e P M P 2 2 g e n e h a d b e e n artifi ci all y i n d u c e d w er e si mil ar t o t h os e s h o w n i n h u m a ns.[1 0 ] [1 1 ]   
D e m y eli n ati o n of a n er v e fi b er o c c ur s d u e t o d a m a g es i n a str u ct ur all y  u nst a bl e m y eli n s h e at h, 
a n d t h e n er v e c o n d u cti o n v el o cit y d e cr e as es b e c a us e of t his.  
N u m er o us  n o n m y eli n ati n g  or  d ys m y eli n ati n g  S c h w a n n  c ells  ar e  pr o d u c e d  i n  C M T 1 A  d u e  t o  
a b n or m al  diff er e nti ati o n  of  i m m at ur e  S c h w a n n  c ells,  a n d  t h us  c a us e  a  d e m y eli n ati n g  
n e ur o p at h y.  A  r e c e nt  st u d y  h as  s h o w n  t h at  t h e  s er u m  c o n c e ntr ati o ns  of  p 7 5  n e ur otr o p hi n  
r e c e pt or ( p 7 5) a n d n e ur al c ell a d h esi o n m ol e c ul e 1 ( N C A M) a p p e ar diff er e nt d e p e n di n g o n t h e 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 2 4  / 2 5  
 
 
A st u d y t h at a d mi nist er e d O n a prist o n e, a pr o g est er o n e a nt a g o nist, s h o w e d p ot e nti al i n a ni m al 
e x p er i m e nts, b ut m e a ni n gf ul r es ults w er e n ot a c hi e v e d i n cli ni c al st u di es. W h e n pr o g est er o n e 
is a d mi nist er e d d ail y i n C M T 1 A r ats, t h e P M P 2 2 c o n c e ntr ati o n i n bl o o d i n cr e as es i n t h e s ci ati c 
n er v e, w hi c h r es ults i n d e m y eli n ati n g p at h ol o gi c c orr el ati o n. I n c o ntr ast, w h e n t h e pr o g est er o n e 
r e c e pt or  a nt a g o nist,  O n a prist o n e,  is  a d mi nist er e d,  it  w as  s h o w n  t h at  t h e C M T  p h e n ot y p e  of  
tr a ns g e ni c  r ats  i m pr o v e d  wit h o ut  si d e  eff e cts  as  t h e  o v er e x pr essi o n  of  t h e  P M P 2 2  m R N A  
q u a ntit y is r e d u c e d. [1 6 ] 
T h e s a m e w as tr u e i n a n as c or bi c a ci d st u d y. As c or bi c a ci d h as b e e n d e m o nstr at e d t o b e a n 
ess e nti al  s u bst a n c e  f or  t h e  f or m ati o n  of  m y eli n  s h e at hs  i n  t h e  p eri p h er al  n er v o us  s yst e m  
t hr o u g h e x p eri m e nts t h at w er e c ult ur e d S c h w a n n c ells al o n g wit h d ors al r o ot g a n gli o n c ells. 
W h e n  as c or bi c  a c i d  w as  a d mi nist er e d  i n  C M T 1 A  tr a ns g e ni c  r ats  b as e d  o n  t his  r ati o n al e,  r e-
f or m ati o n of m y eli n s h e at hs a n d i m pr o v e m e nt of t h e C M T p h e n ot y p e w er e o bs er v e d, a n d at 
t h e  s a m e  ti m e,  it  w as  v erifi e d  t h at  t h e  o v er e x pr essi o n  of  t h e  P M P 2 2  m R N A  q u a ntit y  w as  
i n hi bit e d t o t h e e xt e nt r e q uir e d f or i m pr o v e m e nt of s y m pt o ms.[1 7 ] H o w e v er, m e a ni n gf ul r es ults 
still c o ul d n ot b e o bt ai n e d i n a cli ni c al st u d y. [1 8 ] 
A c ur c u mi n st u d y als o s h o w e d effi c a c y i n a ni m al e x p eri m e nts. A p o pt osis o c c ur s w h e n m y eli n 
pr ot ei n z er o ( M P Z) m ut ati o n pr ot ei n, w hi c h h as b e e n i d e ntifi e d as t h e c a us e i n 1 0 % of C M T 1 B 
p ati e nts,  a c c u m ul at es  i n  t h e  e n d o pl as mi c  r eti c ul u m  ( E R),  b ut  t his  c a n  b e  pr e v e nt e d  wit h  a  
pr etr e at m e nt  of  c ur c u mi n.  C ur c u mi n,  a  c o m p o n e nt  of  t ur m eri c,  s er v es  as  a  s ar c o pl as mi c/ E R  
C a 2 +  A P Tas e  i n hi bit or  t h at  s u p pr ess es  w h at  r e m ai ns  i n  t h e  e n d o pl as mi c  r eti c ul u m.  W h e n  
c ur c u mi n  is  or all y  a d mi nist er e d,  t h e  p h e n ot y p e  of  tr e m bl er  J  ( TrJ)  m o us e,  w hi c h  h as  
s p o nt a n e o usl y o c c urri n g d e m y eli n ati o n, is p arti all y all e vi at e d. [1 9 ] 
I n a d diti o n, a st u d y h a d b e e n c o n d u ct e d o n w h et h er c ur c u mi n c a n b e a c a n di d at e dr u g f or t h e 
C M T s u bt y p e c a us e d b y t h e a c c u m ul ati o n of misf ol d e d pr ot ei n i n t h e e n d o pl as mi c r eti c ul u m 
b y or all y a d mi nist eri n g c ur c u mi n i n a n M P Z - m ut ati o n-g e n e k n o c k -i n C M T 1 B m o us e m o d el.[2 0 ] 
H o w e v er,  t his st u d y als o di d n ot l e a d t o a m e a ni n gf ul cli ni c al st u d y. 
T h er e h a v e als o b e e n e x p eri m e nts t h at e v al u at e d t h e eff e cts of n e ur otr o p hi n -3 ( N T -3). N T -3 is 
e x pr ess e d i n S c h w a n n c ells t h at f or m t h e m y eli n s h e at h i n p eri p h er al n er v es, a n d it pr o m ot es 
n er v e r e g e n er ati o n. N T -3 pr o m ot es t h e gr o wt h of S c h w a n n c ells i n n er v e e n di n gs i n C M T 1 A 
a n d cr e at es a f a v or a bl e e n vir o n m e nt f or n er v e r e g e n er ati o n, as w ell as s y n er gi zi n g wit h i ns uli n -
li k e gr o wt h f a ct or (I G F) a n d pl at el et-d eri v e d gr o wt h f a ct or -B B ( P D G F -B B). S c h w a n n c ells w hi c h 
h a d  m ut ati o ns  o c c urri n g  i n  a  x e n o gr aft  e x p eri m e nt  r es p o n d e d  t o  N T -3,  a n d  a x o n al  
r e g e n er ati o n as w ell as t h e m y eli n ati o n pr o c ess s h o w e d m e a ni n gf ul i m pr o v e m e nts. I n a st u d y 
t h at  e v al u at e d  t h e eff e cts  of  N T-3,  a x o n al r e g e n er ati o n w as pr o m ot e d i n  t h e  a ni m al m o d el,  
a n d s e ns or y s y m pt o ms i m pr o v e d i n t h e C M T 1 A p ati e nt gr o u p wit h a n i n cr e as e i n m y eli n at e d 
n er v e  fi b ers.  Si n c e  t his  w as  a  s m all -s c al e  st u d y  wit h  f o ur  s u bj e cts  e a c h  i n  t h e  p ati e nt  a n d  
c o ntr ol gr o u ps, f oll o w -u p st u di es ar e r e q uir e d. [2 1 ] 
T h e P X T 3 0 0 3 st u d y is t h e m ost r e c e nt st u d y t o d at e. P X T 3 0 0 3 is a c o m bi n ati o n of t hr e e dr u gs, 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 2 5  / 2 6  
 
 
n a m el y b a cl of e n, n altr e x o n e, a n d D -s or bit ol. B a cl of e n is a G A B A B r e c e pt or-s p e cifi c a g o nist, a n d 
it  r e d u c es  t h e  e x pr essi o n  of  P M P 2 2  b y  l o w eri n g  t h e  c o n c e ntr ati o n  of i ntr a c ell ul ar  c A M P  b y  
d e cr e asi n g t h e a cti vit y of a d e n yl at e c y cl as e. N altr e x o n e is a n o pi oi d r e c e pt or a nt a g o nist, a n d 
at  n o nt o xi c  l o w  d os es,  it  l o w ers  t h e  c o n c e ntr ati o n  of  i ntr a c ell ul ar  c A M P  b y  str e n gt h e ni n g  
c ell ul ar  si g n als  b y  bi n di n g  t o  i n hi bit or y  G  al p h a  pr ot ei n  s u b u nits.  D -s or bit ol  is  a  n at ur al  
m et a b olit e, a n d it s er v es a n i m p ort a nt r ol e i n e n er g y pr o d u cti o n/st or a g e. As a c o m bi n ati o n of 
t h es e dr u gs, P X T 3 0 0 3 is i n v ol v e d i n i n hi biti n g t h e o ns et of C M T 1 A, a n d t his is b as e d o n t h e 
h y p ot h esis t h at it i m pr o v e s m y eli n ati o n a n d n er v e f u n cti o ns b y r e d u ci n g t h e t o xi c a cti o ns d u e 
t o  t h e o v er e x pr essi o n  of t h e P M P 2 2  g e n e. I n a n a ni m al e x p eri m e nt  t h at  or all y  a d mi nist er e d  
P X T 3 0 0 3 i n a C M T 1 A tr a ns g e ni c r at m o d el, P M P 2 2 tr a ns cri pt w as d o w nr e g ul at e d i n t h e s ci ati c 
n er v e, a n d  i m pr o v e m e nts  w er e  s h o w n  i n  m ot or  f u n cti o ns  a n d  s e ns or y  f u n cti o ns  ( h e at  
s e nsiti vit y) as w ell as i n hist ol o gi c al a n d el e ctr o p h ysi ol o gi c al t est r es ults. P ositi v e r es ults w er e 
als o s h o w n i n a s u bs e q u e nt cli ni c al st u d y. T h e r es ults of c o n d u cti n g a p h as e 2 c li ni c al st u d y i n 
8 0  s u bj e cts  wit h  C M T 1 A  f or  1 2  m o nt hs  s h o w e d  i m pr o v e m e nts  of  8 %,  1 2. 1 %,  a n d  2 0. 1 %,  
r es p e cti v el y, i n C M T N S, O N L S, a n d s e ns or y n er v e c o n d u cti o n v el o cit y i n t h e hi g h-d os e gr o u p 
a m o n g f o ur gr o u ps ( a pl a c e b o gr o u p a n d t hr e e st u d y dr u g gr o u ps at diff er e nt d os es). A p h as e 
3 cli ni c al st u d y w as c o n d u ct e d i n 3 2 3 s u bj e cts f or 1 5 m o nt hs, a n d it w as s h o w n t h at t h e r es ults 
f or  O N L S  a n d  t h e  1 0-m et er  w al k  t est  w er e  i m pr o v e d. [2 2 ] Alt h o u g h  p ositi v e  r es ults  w er e  
o bt ai n e d  i n  t h e  cli ni c al  st u d y,  t h e  m e c h a nis m  b y  w hi c h  s y n er gisti c  eff e cts  ar e  s h o w n  w h e n  
t h es e t hr e e dr u gs ar e us e d i n c o m bi n ati o n is y et t o b e i d e ntifi e d, a n d it r e m ai ns as a t as k t o 
b e u n d ert a k e n i n t h e f ut ur e. [2 3 ] 
 
3. 4  
Li mit ati o n s of E xi sti n g T h er a pi e s a n d N e c e s sit y f or N e w T h er a pi e s  
D es pit e  t h e  f a ct  t h at  C M T  is  a  dis e as e  t h at  p ersists  t hr o u g h o ut  a  p ati e nt’s  lif eti m e  wit h  
w ors e ni n g  s y m pt o ms,  n o  t h er a p e uti c  dr u gs  h a v e  b e e n  d e v el o p e d  t o  d at e  t h at  c a n  i m pr o v e  
o ut c o m es i n C M T p ati e nts. Si n c e t h er e ar e n o a g gr essi v e tr e at m e nt m et h o ds, p ati e nts u n d er g o 
o nl y c o ns er v ati v e tr e at m e nts. [2 4 ] As ti m e p ass es, w al ki n g gr a d u all y b e c o m es m or e diffi c ult a n d 
li vi n g a n or m al d ail y lif e als o b e c o m es diffi c ult d u e t o w ors e ni n g p ai n.[2 5 ] T h e o nl y a v ail a bl e 
o pti o n is eit h er w e ari n g a n assisti v e d e vi c e f or w al ki n g, [2 6 ] or a v oi di n g a g gr a v ati n g f a ct ors t h at 
a c c el er at e t h e s p e e d of dis e as e pr o gr essi o n.  
N ot o nl y ar e v ari o us t y p es of dr u gs i n cl u d e d i n t h e a g gr a v ati n g f a ct ors of C M T, b ut r o uti n e 
e v e nts t h at c a n b e e x p eri e n c e d b y a n y o n e i n cl u di n g str ess s u c h as tr a u m a a n d s ur g er y ,[2 7 ] as 
w ell as r e m ai ni n g i n a st ati o n ar y p ositi o n f or a n e xt e n d e d d ur ati o n ar e als o i n cl u d e d. N u m er o us 
t y p es  of  a nti c a n c er  dr u gs  i n cl u di n g  vi n cristi n e,  a nti bi oti cs,  a nti arr h yt h mi c  dr u gs,  g o ut  
m e di c ati o ns, a nti vir al a g e nts, al c o h ol d e p e n d e n c y m e di c ati o ns,  a ntir h e u m ati c dr u gs, a n est h eti c 
g as es, f att y a ci d s y nt h as e i n hi bit ors, vit a mi n B 6, i m m u n e -m o d ul ati n g a g e nts, a n d t h e m e di ci n e 
f or Sl e e pi n g Si c k n ess c a n a g gr a v at e C M T, a n d t h us, C M T p ati e nts m a y fi n d it diffi c ult t o c h o os e 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 2 6  / 2 7  
 
 
m e di c ati o ns  w h e n  t h e y  c o ntr a ct  ot h er  dis e as es. [2 8 ] C a uti o n  is  n e c ess ar y  si n c e  e n d o cri n e  
dis e as es s u c h as di a b et es ar e als o i n cl u d e d i n t h e a g gr a v ati n g f a ct ors. [2 9 ] 
P ati e nts s uff eri n g fr o m t h e dis e as e e x p eri e n c e m or e diffi c ulti es si n c e m a n y el e m e nts s u c h as 
t h es e t h at c a n n ot b e a v oi d e d b y t h eir c ar ef ul n ess or eff ort al o n e ar e i n cl u d e d i n t h e a g gr a v ati n g 
f a ct ors. 
A d e q u at e e x er cis e, p h ysi c al t h er a p y, o c c u p ati o n al t h er a p y, et c., ar e h el pf ul i n pr es er vi n g t h eir 
a bilit y  t o  p erf or m  d ail y  a cti viti es,  b ut  s p e ci al  c a uti o n  is  n e c ess ar y  si n c e  e x c essi v e  e x er cis e  
a ct u all y a g gr a v at es t h e dis e as e.[ 2 6]  
 
3. 5  
Tr e at m e nt of C h ar c ot - M ari e-T o ot h Di s e a s e U si n g H e p at o c yt e Gr o wt h F a ct or ( H G F)  
T h e h e p at o c yt e gr o wt h f a ct or ( H G F) is a s e cr et or y pr ot ei n d eri v e d fr o m m es e n c h y m e, a n d c -
M et  is  k n o w n  as  its  u ni q u e  r e c e pt or.  T h e  c -M et  r e c e pt or  a cti v at e d  b y  H G F  s h o ws  v ari o us  
f u n cti o ns. H G F is k n o w n as a str o n g a n gi o g e ni c gr o wt h f a ct or a n d a nti-a p o pt osis f a ct or, a n d 
pr o m ot es t h e gr o wt h of v as c ul ar e n d ot h eli al c ells a n d t h e mi gr ati o n of v as c ul ar s m o ot h m us cl e 
c ells. [3 0 ][3 1 ][3 2 ][3 3 ]   It is k n o w n t h at H G F/ c-M et p at h w a y a cts d os e -d e p e n d e ntl y t o sti m ul at e 
t h e  s y nt h esis  of  D N A,  R N A,  a n d  pr ot ei n  i n  t h e  v as c ul ar  e n d ot h eli al  c ells,  a n d  h el ps  i n  
a n gi o g e n esis b y i n cr e asi n g t h e e x pr essi o n of v ari o us s e cr et or y pr ot ei ns i n cl u di n g t h e v as c ul ar 
e n d ot h eli al  gr o wt h  f a ct or  ( V E G F).  F urt h er m or e,  it  is  k n o w n  t h at  H G F  c o ntri b ut es  t o  tiss u e  
r e g e n er ati o n wit h its a nti-i nfl a m m at or y a n d a ntifi br oti c a cti viti es.[3 4 ][3 5 ] 
H G F h as b e e n t h o u g ht of as a n a n gi o g e ni c f a ct or, b ut it h as b e e n r e c e ntl y i d e ntifi e d as s er v i n g 
t h e  r ol e  of  a  n e ur otr o p hi c  f a ct or.[3 6 ][3 7 ][3 8 ][3 9 ][4 0 ][4 1 ][4 2 ] M or e o v er,  it  h as  b e e n  r e p ort e d  
t h at  it  c a n  c o ntri b ut e  t o  m us cl e  tiss u e  r e g e n er ati o n  b y  t ar g eti n g  o n  m us cl es.[ 4 3 ][ 4 4 ] 
C o nsi d eri n g t h e p at h ol o gi c m e c h a nis m of C M T, t h e p ot e nti al of t h e bi ol o g i c al m e c h a nis m of 
H G F t o s h o w t h er a p e uti c eff e cts is q uit e hi g h f or t h e f oll o wi n g r e as o ns:  
a)  Tar g eti n g o n p eri p h er al n er v e tiss u es  
A c c or di n g  t o  t h e r es ults  of a r e c e nt  st u d y, t h e e x pr essi o n/ a cti vit y  of H G F a n d  c -M et 
r e c e pt or i n cr e as es si g nifi c a ntl y w h e n d a m a g es t o p eri p h er al n er v es o c c ur. If t h e a cti vit y 
of  c -M et  is  i m p e d e d  i n  mi c e  aft er  p eri p h er al  n er v e  d a m a g e,  t h e  s p o nt a n e o us  
r e g e n er ati o n pr o c ess of n er v e tiss u e is gr e atl y hi n d er e d, a n d it c a n b e o bs er v e d t h at 
t h e c o n diti o ns of m y eli n s h e at h tiss u e a n d a x o n ar e a g gr a v at e d m or e i n p arti c ul ar. T his 
s u g g ests  t h at  H G F/ c-M et  m a y  b e  i n v ol v e d  i n  t h e  r e g e n er ati o n pr o c ess  of  p eri p h er al  
n er v es.  
T o  dis c o v er  m or e  d et ail e d  m e c h a nis m,  t h e  r ol e  of  H G F/ c -M et  i n  e a c h  c ell  t h at  
c o nstit ut es p eri p h er al n er v e tiss u es h as b e e n st u di e d.  
First,  S c h w a n n  c ells  ar e  i m p ort a nt  c ells  t h at  f or m  t h e  m y eli n  s h e at h  t h at  s urr o u n d  
p eri p h er al  n er v es,  a n d  t h e y  s er v e  a  cr u ci al  r ol e  i n  m ai nt ai ni n g  t h e  f u n cti o ns  of  
p eri p h er al n er v es. [4 5 ] T h e c -M et r e c e pt or is pr es e nt i n a S c h w a n n c ell, a n d if H G F is 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 2 7  / 2 8  
 
 
b o u n d t o t his, t h e S c h w a n n c ell c h a n g es t o b e a bl e t o r e p air t h e d a m a g e d n er v e. T h e 
a cti vit y of k e y tr a ns cri pti o n f a ct ors i n cr e as es i n t his pr o c ess, a n d i m pr o v e d e x pr essi o n 
of f a ct ors r el at e d t o n e ur o pr ot e cti o n, s u c h as t h e gli al c ell-d eri v e d n e ur otr o p hi c f a ct or 
( G D N F),  w as  i d e ntifi e d.  T hr o u g h  t his,  it  c o ul d  b e  s e e n  t h at  H G F  c o ntri b ut es  t o  t h e  
r e c o nstr u cti o n pr o c ess of t h e m y eli n s h e at h b y t ar g eti n g o n t h e S c h w a n n c ells.  
N e xt,  t h e  eff e cts  o n  p eri p h er al  n er v es  w er e  i n v esti g at e d.  T h e  c -M et  r e c e pt or  is  als o  
pr es e nt  i n  p eri p h er al  n er v es,  a n d  it  w as  v erifi e d  t h at  a x o n al  gr o wt h  is  pr o m ot e d  
si g nifi c a ntl y w h e n H G F is b o u n d t o t his. N ot o nl y di d t h e a cti vit y of k e y tr a ns cri pti o n 
f a ct ors i n cr e as e i n t his pr o c ess as i n S c h w a n n c ells, b ut t h e mit o c h o n dri al a cti vit y als o 
i n cr e as e d, w hi c h s h o w e d t h at c o ntri b uti o n is m a d e t o e n er g y m et a b olis m.  
b)  Tar g eti n g o n m us cl e tiss u es  
O n e of t h e m aj or s y m pt o ms of C M T dis e as e is m us cl e atr o p h y. Atr o p h y o c c ur s i n t h e 
m us cl es if t h e n er v e si g n als tr a ns mitt e d t o m us cl es ar e r e d u c e d d u e t o a b n or m aliti es 
i n n er v e f u n cti o ns, a n d t his i n t ur n l e a ds t o d e cr e as e d m us cl e f u n cti o n, b ut H G F a n d 
c- M et r e c e pt or c a n a ct t o w ar d all e vi ati n g m us cl e atr o p h y u n d er t h es e cir c u mst a n c es. 
T h e e x pr essi o n/ a cti vit y of H G F a n d c -M et r e c e pt or i n cr e as es w h e n a m y otr o p h y o c c urs, 
a n d t h e i n cr e as e d H G F/ c -M et c o ntri b ut es t o t h e all e vi ati o n of a m y otr o p h y. I n p arti c ul ar, 
it  h as  b e e n  v erifi e d  t h at  H G F  i n cr e as es  mi cr o R N A  c all e d  mi R-2 0 6  i n  m y o c yt es,  a n d  
t h er e b y i n hi bits  t h e  e x pr essi o n  of  k e y  a m y otr o p h y  g e n es.  I n  a d diti o n,  H G F  i n d u c es  
r e g e n er ati o n  of m us cl e fi b ers  b y  h a vi n g a n i m p a ct  als o  o n t h e m us cl e s at ellit e c ells,  
w hi c h  ar e  st e m  c ells  pr es e nt  i n  m us cl es.  Fi n all y,  H G F  c a n  r e g ul at e  t h e  i nfl a m m at or y  
r es p o ns e s ho w n aft er m us cl e d a m a g e, a n d it c a n s h o w a nti -i nfl a m m at or y a cti vit y b y  
r e d u ci n g t h e s e cr eti o n of i nfl a m m at or y c yt o ki n es i n p arti c ul ar.  
c)  P ai n r e d u cti o n eff e cts  
H G F c a n r e d u c e p ai n b y t ar g eti n g o n t h e p eri p h er al n er v es. I n n e ur o p at hi c p ai n -i n d u c e d 
a ni m al m o d els, p ai n -i n d u ci n g f a ct ors s u c h as C S F 1, A T F 3, a n d c al ci u m c h a n n el s u b u nit 
α 2 δ 1 ar e e x pr ess e d i n hi g h l e v els i n t h e s pi n al n er v e d ors al r o ot g a n gli a ( D R G), a n d it 
h as b e e n v erifi e d t h at H G F i n hi bits t h e e x pr essi o n of t h es e p ai n f a ct ors. F urt h er m or e, 
it h as  b e e n  v erifi e d  t h at  H G F  s er v es  t h e  r ol e  of  i n hi biti n g  di visi o n  a n d  a cti v ati o n  of  
mi cr o gli a  a n d  astr o c yt es  t h at  ar e  i n v ol v e d  i n  n e ur oi nfl a m m at or y  r es p o ns e.  
N e ur oi nfl a m m at or y r es p o ns e m ai nl y c a us es n e ur o p at hi c p ai n. T h us, n ot o nl y h as t h e  
m e c h a nis m of H G F  i n r e d u ci n g n e ur o p at hi c p ai n b e e n r e v e al e d i n t er ms of m ol e c ul ar 
bi ol o g y a n d hist o p at h ol o g y, b ut it h as als o b e e n r e v e al e d t h at t h e E n g e nsis ( V M 2 0 2) 
i ntr a m us c ul ar  i nj e cti o n  c a n  e v e n  r e m o d el  t h e  c e ntr al  n er v o us  s yst e m  cir c uit  f or  
n e ur o p at hi c p ai n. [4 6 ]   
d) 
Ot h er a cti o ns  
T h e n e ur o pr ot e cti v e a cti o ns of H G F h a v e alr e a d y b e e n r e v e al e d i n a st u d y o n a n A L S 
a ni m al  m o d el.  W.  S u n  et  al.  ( 2 0 0 2)  h a v e  dis c o v er e d  t h at  H G F  w hi c h  is  c o nti n u o usl y  

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 2 8  / 2 9  
 
 
pr o d u c e d l o c all y i n  t h e  n er v e  tiss u es  of S O D G 9 3 A mi c e,  t h e  tr a ns g e ni c  a m y otr o p hi c 
l at er al s cl er osis ( A L S) e x p eri m e nt m o d el, all e vi at es t h e s y m pt o ms of A L S b y a cti v ati n g 
a dir e ct n e ur otr o p hi c a cti o n o n t h e m ot or n er v es a n d h a vi n g a n i n dir e ct a cti o n o n t h e 
gli al c ells. [4 7 ] I n ot h er w or ds, t h e t h e y h a v e f o u n d t h at H G F p erf or ms n e ur o prot e cti v e 
a cti o ns.  
 
T h e m ot or f u n cti o n i m pr o v e d i n mi c e w h os e H G F w as c o nti n u o usl y pr o d u c e d, a n d c o m p ar e d 
wit h mi c e t h at di d n ot pr o d u c e it, t h eir p ar esis st art e d l at er a n d t h eir s ur vi v al w as l o n g er. T h es e 
r es ults s u g g est t h at H G F c a n h el p m ai nt ai n t h e f u n cti o n of m ot o n e ur o ns. T h us, t his s h o ws t h at 
H G F h as t h e p ot e nti al t o c o ntri b ut e t o t h e i m pr o v e m e nt of m ot o n e ur o n f u n cti o n e v e n u n d er 
C  M T. [4 8 ][4 9 ][5 0 ] 
W h e n s o m e a x o n c ells di e, t h e s ur vi vi n g n er v e fi b ers cr e at e a n et w or k t o a g ai n d o mi n at e t h e 
m ot or u nit ( m us cl e gr o u p) w h os e n et w or k h a d b e e n l ost d u e t o t h e d e a d c ells. As a r es ult, a 
l ar g er  m ot or  u nit  is  cr e at e d.  H G F  sl o ws  t h e  pr o gr essi o n  of  dis e as e  b y  pr o m oti n g  t h e  n er v e  
r e c o n n e cti o n pr o c ess. H G F pr o m ot es n e ur o g e n esis, a n gi o g e n esis, a n d s y n a ps e f or m ati o n, a n d 
bl o c ks t h e o c c urr e n c e of fi br osis  at is c h e mi c sit es. [5 1 ] I n a d diti o n, H G F als o h as a d ef e nsi v e 
eff e ct a g ai nst e x cit ot o xi c d a m a g e. It is k n o w n t o w e a k e n a x o n al d e g e n er ati o n as e x cit ot o xi cit y 
is r e d u c e d b y r e g ul ati n g t h e e x pr essi o n of s c aff ol di n g pr ot ei n of t h e N M D A r e c e pt or, a n d t his 
s u g g ests  t h at  H G F  c a n  i m p e d e  n e ur o n al  d e g e n er ati o n  u n d er  t h e  p at h ol o gi c  c o n diti o ns  of  
C  M T. [5 2 ] 
Fi n all y, H G F pr e v e nts c ell d e at h i n m ot o n e ur o ns, a n d st o ps c as c a di n g d a m a g e of n ei g h b ori n g 
c ells b y dir e ctl y i n hi biti n g c as p as e si g n als.[ 5 2 ][5 3 ] Si n c e c as p as e r e m ai ns a cti v e i n e a c h n e ur o n 
f or  a n  e xt e n d e d  l e n gt h  of  ti m e  ( c a n  b e  fr o m  s e v er al  w e e ks  t o  s e v er al  m o nt hs),  c ell ul ar  
d ysf u n cti o n c a n b e r e d u c e d a n d c ell d e at h c a n b e d el a y e d if c as p as e is i n hi bit e d u n d er t h es e 
c o n diti o ns.[ 5 4 ]   
Fi g ur e 3 s h o ws t h e m e c h a nis m of H G F o n m ot o n e ur o ns. H G F bi n ds t o c -M et o n t h e c ell s urf a c e, 
a n d i n d u c es t h e a ut o p h os p h or yl ati o n r es p o ns e of i ntr a c ell ul ar t yr osi n e r esi d u es of c -M et.    
S u bs e q u e ntl y,  H G F  i n hi bits  t h e  a cti v ati o n  of  c as p as e -1,  a n d  eff e cti v el y  pr e v e nts  t h e  c as p as e  
c as c a di n g r e a cti o ns t h at f oll o w, s u c h as c as p as e -3, -7, a n d -9, b y i n d u ci n g x -li n k e d i n hi bit or of 
a p o pt osis pr ot ei n ( XI A P). T h us, at l e ast a p art of t h e n e ur otr o p hi c a cti o n of H G F i n m ot o n e ur o ns 
is  pr o m ot e d  b y  pr e v e nti n g  c as p as e-m e di at e d  c ell  d e at h  si g n als.  C o nsi d eri n g  t his  s eri es  of  
a cti o ns,  if  H G F  is  a p pli e d  t o  C M T,  t h er e  is  s uffi ci e nt  p ot e nti al  f or  H G F  t o  s h o w  t h er a p e uti c  
eff e cts b y aff e cti n g d e g e n er ati n g n e ur o ns.  
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 2 9  / 3 0  
 
 
 
3. 6  
E n g e n si s; V M 2 0 2  
H e p at o c yt e gr o wt h f a ct or is k n o w n t o bi n d t o t h e c -M et r e c e pt or o n t h e c ell m e m br a n e h a vi n g 
t yr osi n e ki n as e a cti vit y a n d pr o m oti n g v ari o us c ell di visi o n, mi gr ati o n, a n d a n gi o g e n esis, as w ell 
as i n hi biti n g a p o pt osis. [5 5 ] 
T w o  diffi c ulti es  m ust  b e  o v er c o m e  t o  d eli v er  a  t ar g et  q u a ntit y  of  e x o g e n o us  H G F.  T h e  first  
diffi c ult y  is  t h at  H G F  is  u nst a bl e  i n  t h e  bl o o dstr e a m,  a n d  t h e  s e c o n d  is  t h at  it  is  r a pi dl y  
m et a b oli z e d i n t h e li v er; t h e i n vi v o h alf -lif e of H G F is 1 5 mi n ut es.[5 6 ][5 7 ] 
T h us, a w a y t o i n cr e as e t h e a v ail a bl e H G F i n n e ur o ns is t o d e v el o p a g e n e d eli v er y str at e g y 
t h at all o ws c o nti n u o us e x pr essi o n of H G F pr ot ei n i n vi v o. Alt h o u g h pl as mi d D N A h as t h e l o w est 
effi ci e n c y  a m o n g  t h e  g e n e  tr a nsf er  s yst e ms  t h at  h a v e  r e c e ntl y  us e d,  usi n g  l o c al  t ar g et e d  
d eli v er y  is  a  hi g hl y  attr a cti v e  c h oi c e  ( es p e ci all y  i n  s k el et al  m us cl es)  d u e  t o  t h e  f a cts  t h at  its  
p ersist e n c e i n vi v o is li mit e d a n d t h at g e n e i ns erti o n is u n n e c ess ar y.  
E n g e nsis ( V M 2 0 2) is t h e dr u g d e v el o p e d t o a c hi e v e t his v er y o bj e cti v e, a n d it is t h e st u d y dr u g 
t h at will b e us e d i n t his cli ni c al st u d y. E n g e nsis ( V M 2 0 2) is a D N A pl as mi d c o nt ai ni n g a n e w 
r e c o m bi n a nt H G F g e n e ( H G F-X 7 ) t h at h as b e e n m a d e t o si m ult a n e o usl y e x pr ess t w o is of or ms 
( H G F7 2 3 , H G F7 2 8 ) of t h e h e p at o c yt e gr o wt h f a ct or ( H G F). 
T h e m ai n f e at ur e of H G F -X 7 is t h at it h as b e e n d esi g n e d t o effi ci e ntl y e x pr ess t w o is of or ms of 
H G F si m ult a n e o usl y i n t h e s a m e w a y as i n t h e h u m a n b o d y b y i ns erti n g a p orti o n of t h e i ntr o n 
b as e s e q u e n c e i nt o a s p e cifi c sit e of H G F c D N A. I n a d diti o n, si n c e t h er e ar e n o c h a n g es i n t h e 
c o di n g r e gi o ns of H G F, t h e H G F pr ot ei ns e x pr ess e d b y E n g e nsis ( V M 2 0 2) ar e i d e nti c al t o t h e 
pr ot ei ns pr o d u c e d i n v i v o.  

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 3 0  / 3 1  
 
 
E n g e nsis ( V M 2 0 2) is effi ci e ntl y d eli v er e d t o e v e n t h os e c ells t h at h a v e c o m pl et e d di visi o n s u c h 
as s k el et al m us cl es or n e ur o ns. T h e H G F pr ot ei n is e x pr ess e d l o c all y o nl y at t h e a d mi nistr ati o n 
sit e, a n d ot h er or g a ns ar e n ot aff e ct e d. T h es e f a cts h a v e b e e n d e m o nstr at e d i n t h e pr e vi o us 
st u d y.  T h us,  eff e cti n g  n e ur otr o p hi c  f a ct or  a cti o ns  b y  d eli v eri n g  t h e  H G F  g e n e  t o  t h e  t ar g et  
m us cl e tiss u e b y usi n g t h e pl as mi d a n d t h e n e x pr essi n g pr ot ei ns is a hi g hl y attr a cti v e a n d s af e 
tr e at m e nt m et h o d. M or e o v er, si n c e t h e E n g e nsis ( V M 2 0 2) pl as mi d r e m ai ni n g i n vi v o aft er t h e 
i ntr a m us c ul ar i nj e cti o n e xists o utsi d e t h e c hr o m os o m e, t h e pr o b a bilit y of it b ei n g i ns ert e d i nt o 
t h e c hr o m os o m e of t h e p ati e nt is al m ost n e gli gi bl e.[ 2 8-3 0] T h es e l o c al eff e cts of pl as mi ds ar e 
alr e a d y  w ell k n o w n fr o m pr e vi o us st u di es t h at i nj e ct e d pl as mi d D N A. [5 8 ][5 9 ] 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 3 2  / 3 3  
 
 
I n n o n cli ni c al st u di es, t h e s af et y of E n g e nsis ( V M 2 0 2) w as ass ess e d wit h a n i ntr a m us c ul ar 
si n gl e-d os e  t o xi cit y  st u d y  i n  r ats  as  w ell  as  a n  i ntr a v e n o us  si n gl e -d os e  t o xi cit y  st u d y.  
A d diti o n all y,  s af et y  w as  als o  ass ess e d  i n  i nt er mitt e nt  i ntr a m us c ul ar  r e p e at - dos e  t o xi cit y  
st u di es ( w e e kl y or m o nt hl y) i n r a b bits a n d r ats us e d.  
T h e p ossi bilit y of g e n o mi c i nt e gr ati o n at t h e i nj e cti o n sit e or t h e p ossi bilit y of distri b uti o n 
a n d p ersist e n c e of E n g e nsis ( V M 2 0 2) i n r e pr o d u cti v e tiss u es w er e e v al u at e d i n e x p eri m e nts 
c o n d u ct e d i n r ats. I n t h e i ntr a m us c ul ar a d mi nistr ati o n of mi c e, t h e p ossi bilit y of E n g e nsis 
( V M 2 0 2) t o i n d u c e h u m or al i m m u n e r es p o ns e w as e v al u at e d t hr o u g h a n e x p eri m e nt t h at 
eit h er a d mi nist er e d or di d n ot a d mi nist er a n a dj u v a nt c o n c o mit a ntl y.  
I n  c o n cl usi o n,  t h e  r es ults  of  v ari o us  t o xi cit y  st u di es  s h o w e d  t h at  E n g e nsis  ( V M 2 0 2)  w as  
w ell -t ol er at e d  i n  all  st u di es,  a n d  t h e  o nl y  t o xi cit y  w as  mil d  a n d  tr a nsi e nt  i nj e cti o n  sit e  
irrit ati o n. E vi d e n c e of s yst e mi c t o xi cit y w as n ot s h o w n at all i n a n y of t h e st u di es, a n d t h er e 
w as  als o  n o  e vi d e n c e  of  h u m a n  H G F  d et e ct e d  i n  t h e  s er u m  of  r ats  or  r a b bits  aft er  
i ntr a m us c ul ar  i nj e cti o ns.  [l o w er  li mit  of  q u a ntit ati o n  ( L L O Q)  =  1 2 5  p g/ m L].  G e n o mi c  
i nt e gr ati o n, g er m c ell tr a ns missi o n, i m m u n osti m ul at or y eff e cts, et c., w er e n ot s h o w n at all 
w h e n E n g e nsis ( V M 2 0 2) w as a d mi nist er e d i ntr a m us c ul arl y.  
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 3 3  / 3 4  
 
 
 
Fi g ur e 6 T o xi cit y st u d y d at a ( s e e I B)  
 
( 2) Effi c a c y st u d y  
Aft er a d mi nist eri n g E n g e nsis, t h e f oll o wi n g effi c a c y ass ess m e nts w er e p erf or m e d.  
- N er v e r e g e n er ati o n eff e cts: Aft er a d mi nist eri n g E n g e nsis ( V M 2 0 2), t h e r e c o nstr u cti o n 
of m y eli n s h e at h b y S c h w a n n c ells w as pr o m ot e d, a n d r e g e n er ati o n of t h e d e g e n er at e d 
a x o n w as pr o m ot e d as w ell.  
-  Mus cl e  r e g e n er ati o n  eff e cts:  Aft er  a d mi nist eri n g  E n g e nsis  ( V M 2 0 2),  n er v e  d a m a g e -
i n d u c e d  a m y otr o p h y  w as  i m pr o v e d.  T h e  m us cl e  r e g e n er ati o n  pr o c ess  aft er  m us cl e  

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 3 5  / 3 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 3 6  / 3 7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
  
 
  
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 3 7  / 3 8  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 3 8  / 3 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
s
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 3 9  / 4 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 4 0  / 4 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 4 1  / 4 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
  
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 4 3  / 4 4  
 
 
 
R es ults of s af et y ass ess m e nt: T h e t ol er at e d d os e of E n g e nsis ( V M 2 0 2) a d mi nist er e d i n t h e 
is c h e mi c m y o c ar di u m of s u bj e cts wit h a n gi n a p e ct oris w as 2 m g. A t ot al of 1 1 2 c as es of 
a d v ers e  e v e nts  o c c urr e d  i n  t h e  ni n e  s u bj e cts  t h at  p arti ci p at e d  i n  t h e  cli ni c al  st u d y,  b ut  
t h er e w er e n o a d v ers e e v e nts dir e ctl y r el at e d t o E n g e nsis ( V M 2 0 2), a n d m ost w er e t y pi c al 
a d v ers e e v e nts t h at w er e d u e t o t h e w ors e ni n g of u n d erl yi n g dis e as es or t h at o c c ur aft er 
c or o n ar y art er y b y p ass s ur g er y. T h e q u a ntit y of H G F pr ot ei n i n bl o o d w as m ai nt ai n e d at 
a st a bl e l e v el wit h o ut a n y s p e ci al c h a n g es d uri n g t h e f oll o w -u p p eri o d, a n d it w as v erifi e d 
t h at a nti b o di es f or t h e H G F pr ot ei n e x pr ess e d b y E n g e nsis ( V M 2 0 2) w er e n ot pr o d u c e d.  
 
Ass ess m e nt  of  pr eli mi n ar y  effi c a c y:  T h e  r es ults  of  pr eli mi n ar y  effi c a c y  ass ess m e nt  usi n g  
m y o c ar di al MI BI -S P E C T, c ar di a c M RI, a n d e c h o c ar di o gr a p h y s h o w e d st atisti c all y si g nifi c a nt 
i m pr o v e m e nt eff e cts o n t h e i ntr a m y o c ar di al p erf usi o n ( b ef or e a d mi nistr ati o n vs. at t hr e e 
or si x m o nt hs aft er a d mi nistr ati o n, p < 0. 0 5) of t h e E n g e nsis ( V M 2 0 2) a d mi nistr ati o n sit e, 
t h e m y o c ar di al t hi c k n ess at e n d s yst oli c p h as e a n d e n d di ast oli c p h as e of t h e l eft v e ntri cl e 
( b ef or e  a d mi nistr ati o n  vs.  at  t hr e e  m o nt hs  aft er  a d mi nistr ati o n,  p  <  0. 0 5),  a n d  t h e  
m y o c ar di al w all m oti o n i n d e x ( b ef or e a d mi nistr ati o n vs. at si x m o nt hs aft er a d mi nistr ati o n, 
p < 0. 0 5).  
I n  t h e  p h as e  1  cli ni c al  st u d y  o n  s u bj e cts  wit h  a n gi n a  p e ct oris,  it  w as  v erifi e d  t h at  t h e  
t ol er at e d  d os e  of  E n g e nsis  ( V M 2 0 2)  w as  2  m g,  a n d  a d v ers e  e v e nts  t h at  w er e  dir e ctl y  
r el at e d t o E n g e nsis ( V M 2 0 2) w er e n ot o bs er v e d. T h es e r es ults s h o w t h at t h e m et h o d of 
a d mi nist eri n g  E n g e nsis  ( V M 2 0 2)  i nt o  t h e  is c h e mi c  m y o c ar di u m  is  s af e  f or  p ati e nts  wit h  
a n gi n a  p e ct oris  w h o  u n d er g o  c or o n ar y  art er y  b y p ass  s ur g er y,  a n d  t h at  it  i m pr o v es  t h e  
bl o o d  fl o w  b y  i n d u ci n g  a n gi o g e n esis  wit hi n  t h e  i nj e ct e d  m y o c ar di u m.  I n  a d diti o n,  t h e  
r es ults als o s h o w t h e p ot e nti al of t h e dr u g t o f u n d a m e nt all y i m pr o v e c ar di a c f u n cti o ns b y 
r e c o v eri n g  t h e  t hi c k n ess  of  is c h e mi c  m y o c ar di u m  t hr o u g h  pr ot e cti v e  eff e cts  o n  t h e  
m y o c ar di u m. 
 
3. 9  
R ati o n al e f or E st a bli s hi n g D o s e of I n v e sti g ati o n al Pr o d u ct  
T h e  a d mi nistr ati o n  d os e  of  V M 2 0 2,  t h e  i n v esti g ati o n al  pr o d u ct  of  t his  st u d y,  h as  b e e n  
est a blis h e d b as e d o n t h e r es ults of n o n cli ni c al st u di es, as w ell as t h e a d mi nistr ati o n d os es a n d 
p h ar m a c o d y n a mi c ass ess m e nts i n p ast cli ni c al st u di es.  
 
R ati o n al e 1. N o n c li ni c al St u d y R e s ult s 
( 1) Si n gl e -d os e t o xi cit y st u d y  
A si n gl e i ntr a m us c ul ar d os e t o xi cit y st u d y a n d a si n gl e i ntr a v e n o us d os e t o xi cit y st u d y w er e 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 4 6  / 4 7  
 
 
m g p er a d mi nistr ati o n, f or a t ot al of 5 6 m g. C o nsi d eri n g t h e r esi d u al q u a ntit y r es ults i n t h e 
p h as e 1/ 2  cli ni c al st u d y  i n  p ati e nts  wit h a m y otr o p hi c l at er al s cl er osis, a n i nt er v al of 9 0  d a ys  
w as pl a c e d b et w e e n t h e 1st d os e a n d t h e 3r d d os e.  
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 4 7  / 4 8  
 
 
4 
G o o d Cli ni c al Pr a cti c e  
T his  st u d y  s h all  b e  c o n d u ct e d  i n  c o m pli a n c e  wit h  t h e  a p pr o v al  of  S a ms u n g  M e di c al  C e nt er  
I nstit uti o n al R e vi e w B o ar d (I R B) a n d r el e v a nt r e g ul ati o ns s u c h as t h e D e cl ar ati o n of H elsi n ki, Arti cl e 
3 0 of t h e R e g ul ati o n o n S af et y of M e di ci n al Pr o d u cts, et c. [i m pl e m e nt e d o n M ar c h 2 3, 2 0 1 3], a n d 
t h e K or e a n G o o d Cli ni c al Pr a cti c e f or M e di ci n al Pr o d u cts. T h er ef or e, t h e p ur p os e of t h e st u d y a n d 
t h e  c h ar a ct eristi cs  of  t h e  i n v esti g ati o n al  pr o d u ct  s h all  b e  d es cri b e d  t o  t h e  s u bj e cts  t hr o u g h  a n  
i nf orm ati o n  s h e et.  O nl y  t h os e  v ol u nt e ers  w h o  h a v e  c o m pl et e d  t h e  c o ns e nt  f or m,  k n o wi n g  t h e  
p ur p os e of t h e st u d y, its ris ks, et c., s h all p arti ci p at e i n t h e st u d y. F urt h er m or e, it s h all b e e x pl ai n e d 
t o t h e s u bj e cts t h at t h e y m a y wit h dr a w t h eir c o ns e nt f or st u d y p arti ci p ati o n, if t h e y wis h, at a n y  
ti m e  t hr o u g h o ut  t h e  st u d y.  T h e  r es ults  o bt ai n e d  d uri n g  t h e  st u d y  s h all  b e  r e c or d e d  i n  t h e  c as e  
r e p ort f or m, a n d c o nfi d e nti alit y s h all b e e ns ur e d f or all i nf or m ati o n. If a n a d v ers e e v e nt o c c ur s, it 
s h all b e i m m e di at el y r e p ort e d t o t h e p ers o n i n c h ar g e of t h e cli ni c al st u d y. If n e c ess ar y, t h e s u bj e ct 
s h all b e all o w e d t o r e c ei v e i n p ati e nt t ests a n d tr e at m e nt, a n d f oll o w -u ps s h all b e p erf or m e d u ntil 
t h e s y m pt o ms dis a p p e ar.    
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 4 8  / 4 9  
 
 
5 
Cli ni c al St u d y Pl a n  
5. 1  
P ur p o s e of Cli ni c al St u d y 
T o e v al u at e t h e s af et y a n d t ol er a bilit y of t h e i n v esti g ati o n al pr o d u ct ( V M 2 0 2) i nj e ct e d i n t h e 
w e a k e n e d l o w er li m b m us cl es of C M T 1 A p ati e nts.  
Pri m ar y O bj e cti v e  
T o  e v al u at e  s af et y  a n d  t ol er a bilit y  f oll o wi n g  r e p e at e d  d os es  of  t h e  i n v esti g ati o n al  pr o d u ct  
( V M 2 0 2). 
 
S e c o n d ar y O bj e cti v e s  
T o e v al u at e effi c a c y f oll o wi n g r e p e at e d d os es of t h e i n v esti g ati o n al pr o d u ct ( V M 2 0 2).  
( 1) C h a n g es i n s e v erit y of dis e as e  
- C M T N S -v 2 ( C h ar c ot-M ari e -T o ot h N e ur o p at h y S c or e v ersi o n 2)  
- F D S (f u n cti o n al dis a bilit y s c al e)    
( 2) C h a n g es i n l o w er li m b f u n cti o n:  
- O N L S ( o v er all n e ur o p at h y li mit ati o n s c or e) l e g s c al e  
- 1 0 M W T ( 1 0 -m et er w al k t est)  
( 3) C h a n g es i n f att y i nfiltr ati o n l e v el of l o w er li m b m us cl es:  
- M RI l e g  
( 4) N er v e r e g e n er ati o n  p ot e nti al:  
- C M A P ( c o m p o u n d m ot or n er v e a cti o n p ot e nti al)  
- S N A P ( c o m p o u n d s e ns or y n er v e a cti o n p ot e nti al)  
- N C V ( n er v e c o n d u cti o n v el o cit y)  
( 5) H G F a nti b o d y g e n er ati o n b y V M 2 0 2  
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 5 0  / 5 1  
 
 
of t h e i n di c ati o n a n d t h e pr o gr essi o n of C M T 1 A is sl o w alt h o u g h t his cli ni c al st u d y als o 
t ar g ets si mil ar s y m pt o ms. 
5. 3. 2  
I n cl u si o n Crit eri a 
S u bj e cts e nr oll e d i n t his cli ni c al st u d y m ust s atisf y all of  t h e f oll o wi n g i n cl usi o n crit eri a:    
1)  
M al es or f e m al es ≥ 1 9 y e ars of a g e a n d ≤ 6 5 y e ars of a g e 
 
2)  
P ati e nts wit h c o nfir m e d di a g n osis of C M T 1 A b y g e n eti c t esti n g  
3)  
P ati e nts  wit h  mil d -t o-m o d er at e  s e v erit y  ass ess e d  b y  C h ar c ot -M ari e -T o ot h 
N e ur o p at h y S c or e v ersi o n 2 ( C M T N S -v 2) wit h a s c or e > 2 a n d ≤ 2 0  
4)  
I n di vi d u als wit h l o w er li m b m us cl e w e a k n ess wit h mi ni m u m d orsifl e xi o n or m or e 
5)  
I n di vi d u als w h o v ol u nt aril y c o ns e nt e d t o p arti ci p at e i n t his st u d y a n d si g n e d t h e 
I R B-a p pr o v e d  i nf or m e d  c o ns e nt  f or m  aft er  lis t e ni n g  t o  a  d es cri pti o n  o n  t h e  
c h ar a ct eristi cs of t his cli ni c al st u d y pri or t o all s cr e e ni n g t ests  
6)  
I n di vi d u als w h o c a n c o m pl y wit h t h e r e q uir e m e nts i n t h e cli ni c al st u d y 
7)  
I n c as e of f e m al es of c hil d-b e ari n g p ot e nti al, t h os e w h o t est n e g ati v e i n a uri n e or 
s er u m pr e g n a n c y t est at s cr e e ni n g  
8)  
I n di vi d u als w h o pr a cti c e m e di c all y a p pr o v e d c o ntr a c e pti v e m et h o ds*  t hr o u g h o ut 
t h e cli ni c al st u d y 
 
5. 3. 3  
E x cl u si o n Crit eri a  
S u bj e ct s will b e e x cl u d e d fr o m t hi s cli ni c al st u d y if a n y o n e of t h e f oll o wi n g 
crit eri a i s m et:  
 
1)  P ati e nts wit h si g nifi c a nt r es pir at or y, cir c ul at or y, r e n al, g astr oi nt esti n al, h e p ati c, 
e n d o cri n e, h e m at ol o gi c, ps y c hi atri c dis or d ers or ot h er s e v er e dis e as es, or al c o h ol or 
dr u g a d di cti o n w h o m a y d e v el o p s af et y iss u es or c a us e c o nf usi o n i n t h e i nt er pr et ati o n 
of t h e cli ni c al st u d y r es ults as d et er mi n e d b y t h e pri n ci p al i n v esti g at or  
2)  P ati e nts wit h ot h er n e ur o m us c ul ar dis e as es or n e ur o p at h y -i n d u ci n g f a ct ors: P ati e nts 
wit h c hr o ni c al c o h ol a d di cti o n, u n d er g oi n g a nti c a n c er c h e m ot h er a p y, or t a ki n g 
n e ur ot o xi c dr u gs 
* Defi niti o ns  
• 
Dr u gs: Oral c o ntrace pti v es, s ki n p atc h es, or pr o g esti n f or m ulati o ns (i m pla nts or i njecti o ns) 
• 
Barrier met h o ds: C o n d o ms, dia p hra g ms, i ntra uteri n e d e vices (I U Ds), v a gi n al s u p p osit ories  
• 
A bsti n e n ces:  C o m plete  a bsti n e nce  ( H o we v er,  p eri o dic  a bsti n e nce  (e. g.,  cale n d ar  met h o d,  
o v ulati o n met h o d, a n d s y m pt o -t her mal met h o d) a n d self-restrai nt are n ot c o nsi d ere d as 
acce pta ble met h o ds of c o ntrace pti o n.)  
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 5 1  / 5 2  
 
 
3)  P ati e nts di a g n os e d wit h di a b et es  
4)  P ati e nts di a g n os e d wit h i nfl a m m at or y b o w el dis e as e  
5)  P ati e nts wit h a hist or y of str o k e or c er e br al is c h e mi c att a c k wit hi n 1 2 m o nt hs pri or 
t o t h e s cr e e ni n g d at e 
6)  P ati e nts wit h a hist or y of c or o n ar y art er y dis e as e , s u c h as m y o c ar di al i nf ar cti o n a n d 
u nst a bl e a n gi n a p e ct oris, wit hi n 1 2 m o nt hs pri or t o t h e s cr e e ni n g d at e  
7)  M or bi dl y o b es e p ati e nts wit h b o d y m ass i n d e x ( B MI) ≥ 3 7 
 
8)  P ati e nts w h o u n d er w e nt ort h o p e di c s ur g er y ( c orr e cti v e s ur g er y f or b o n e a n d 
li g a m e nt, artifi ci al j oi nt i m pl a nt ati o n, ost e os y nt h esis, ost e ot o m y, art hr os c o pi c 
s ur g er y) i n t h e l o w er li m bs wit hi n 6 m o nt hs pri or t o t h e s cr e e ni n g d at e  
9)  P ati e nts w h o m a y b e aff e ct e d b y t h e m us cl e str e n gt h m e as ur e m e nt t est d u e t o 
a n kl e c o ntr a ct ur e or s ur g er y  
1 0)  P ati e nts wit h u n c o ntr oll e d h y p ert e nsi o n (if s yst oli c bl o o d pr ess ur e is ≥ 1 6 0 m m H g 
or di ast oli c bl o o d pr ess ur e is ≥ 1 0 0 m m H g at s cr e e ni n g)  
1 1)  P ati e nts or p ati e nt’s i m m e di at e f a mil y m e m b ers ( p ar e nts, si bli n gs, offs pri n g) wit h a 
hist or y of m ali g n a nt t u m ors wit hi n t h e l ast 5 y e ars pri or t o t h e s cr e e ni n g d at e, 
e x cl u di n g b as al c ell c ar ci n o m a or s q u a m o us c ell c ar ci n o m a t h at o c c urs o n t h e s ki n 
(if it is d et er mi n e d t h at t h er e is n o p ossi bilit y of r el a ps e aft er r es e cti o n), or wit h a 
f a mil y hist or y of f a mili al a d e n o m at o us p ol y p osis ( F A P) or h er e dit ar y n o n p ol y p osis 
c ol or e ct al c a n c er ( H N P C C)  
1 2)  P ati e nts w h o h a v e n ot c o m pl et e d a n ati o n al c a n c er s cr e e ni n g pr o gr a m a p pli c a bl e 
t o t h eir s e x a n d a g e (if it c a n n ot b e c o nfir m e d t h at t h e r el e v a nt t est w as r e c ei v e d at 
a n ati o n al c a n c er s cr e e ni n g c e nt er or a r e c o g ni z e d s cr e e ni n g c e nt er)  
 
H o w e v er, if it is c o nfir m e d t h at t h e r el e v a nt t est w as r e c ei v e d at a n ati o n al c a n c er 
s cr e e ni n g c e nt er or a r e c o g ni z e d s cr e e ni n g c e nt er d uri n g t h e s cr e e ni n g p eri o d, a n d 
t h at t h e r es ults w er e wit hi n n or m al r a n g e, t h e p ati e nts m a y p arti ci p at e i n t h e cli ni c al 
st u d y. 
 
C o m m o n t o m al es a n d f e m al es: If a p ati e nt is ≥ 5 0 y e ars of a g e, t h e r es ults of a 
c ol o n os c o p y wit hi n 5 y e ar s pri or t o t h e s cr e e ni n g m ust b e d et er mi n e d as b ei n g 
wit hi n n or m al r a n g e, a n d if a d e n o m at o us p ol y ps ar e e vi d e nt, t h e r es ults of a 
c ol o n os c o p y wit hi n 1 y e ar m ust b e d et er mi n e d as b ei n g wit hi n n or m al r a n g e 
(i nfl a m m at or y p ol y ps or h y p er pl asti c p ol y ps ar e i ncl u d e d i n t h e n or m al r a n g e). If a 
p ati e nt is ≥ 4 0 y e ars of a g e, t h e r es ults of a g astr os c o p y wit hi n 2 y e ars pri or t o t h e 
s cr e e ni n g m ust b e wit hi n n or m al r a n g e. If a p ati e nt is ≥ 5 4 y e ars of a g e a n d h as a 
3 0 p a c k -y e ar hist or y of s m o ki n g or m or e, t h e r es ults  of a l o w -d os e c h est C T wit hi n 
2 y e ars pri or t o t h e s cr e e ni n g m ust b e wit hi n n or m al r a n g e. I n c as e of li v er c a n c er, 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 5 2  / 5 3  
 
 
c arri ers of h e p atitis B or h e p atitis C vir us a n d p ati e nts wit h h e p ati c cirr h osis f all 
u n d er t h e e x cl usi o n crit eri a.    
F e m al es: F or f e m al es ≥ 4 0 y e ars of a g e, n or m al r a n g e fi n di n gs m ust b e c o nfir m e d 
i n a m a m m o gr a m wit hi n 2 y e ars. F or f e m al es ≥ 2 0 y e ars of a g e, n or m al r a n g e 
fi n di n gs m ust b e c o nfir m e d i n a P a p s m e ar wit hi n 2 y e ars.    
1 3)  P ati e nts di a g n os e d wit h a cti v e p ul m o n ar y t u b er c ul osis  
1 4)  P ati e nts wit h H B V or H C V  
1 5)  P ati e nts w h o t est p ositi v e i n h u m a n i m m u n o d efi ci e n c y vir us ( HI V) a nti b o d y t est  
1 6)  P ati e nts i n a n i m m u n os u p pr essi v e st at e d u e t o tr e at m e nts s u c h as 
i m m u n os u p pr ess a nts, c h e m ot h er a p y, a n d r a di ot h er a p y  
1 7)  P ati e nts wit h a hist or y of m e nt al dis e as e wit hi n 6 m o nt hs pri or t o t h e s cr e e ni n g 
d at e, w hi c h m a y i nt erf er e wit h p arti ci p ati o n i n t h e st u d y  
1 8)  P ati e nts w h o  m ust t a k e m e di c ati o ns , t h at ar e  k n o w n t o h a v e si g nifi c a nt dr u g 
i nt er a cti o ns wit hi n 1 4 d a ys aft er t h e first a d mi nistr ati o n of t h e i n v esti g ati o n al 
pr o d u ct or d e e m e d u ns uit a bl e b y t h e i n v esti g at or's j u d g m e nt  
1 9)  I n di vi d u als w h o p arti ci p at e d i n a n ot h er cli ni c al st u d y* wit hi n 6 m o nt hs b ef or e t h e 
ti m e of s cr e e ni n g 
 
2 0)  I n di vi d u als w h o h a v e s h o w n si g nifi c a nt a d v ers e e v e nts s u c h as h y p ers e nsiti vit y 
r e a cti o ns t o t h e i n v esti g ati o n al pr o d u ct 
2 1)  Pr e g n a nt or br e astf e e di n g f e m al es  
2 2)  Ot h e r i n di vi d u als d et er mi n e d i n eli gi bl e b y t h e pri n ci p al i n v esti g at or t o p arti ci p at e 
i n t h e cli ni c al st u d y d u e t o ot h er r e as o ns i n cl u di n g cli ni c al l a b or at or y t est r es ults 
 
5. 3. 4  
A s si g n m e nt of S u bj e ct N u m b er s  
S u bj e cts  t h at  will  b e  v ol u nt aril y  p arti ci p ati n g  i n  t his  cli ni c al  st u d y  s h all  b e  assi g n e d  
s cr e e ni n g  n u m b ers  ( c o m pl eti o n  of  i nf or m e d  c o ns e nt  f or m  - c h e c ki n g  eli gi bilit y  wit h  
i n cl usi o n/ e x cl usi o n  crit eri a), a n d s h all b e assi g n e d all o c ati o n n u m b ers  if t h e y  s atisf y t h e 
i n cl usi o n/ e x cl usi o n crit eri a.  
 
* Defi niti o ns  
• Dr u g: T h ose w h o p artici p ate d i n a n ot h er cli nical st u d y wit hi n 6 m o nt hs b ef ore t h e ti me of 
scree ni n g s h all b e e x cl u d e d.  
• Me dical d e vice: T h ose w h o p artici p ate d i n a n o ni n v asi v e cli nical st u d y ma y p artici p ate i n t his 
cli nical  st u d y  if  t h e  pri n ci p al  i n v esti g at or  d eter mi n es  t h at  t h e  safet y  or  
p h ar mac o d y n a mic assess m e nt will n ot b e affecte d.  

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 5 9  / 6 0  
 
 
5. 5. 3  
E arl y Ter mi n ati o n of Cli ni c al St u d y  
T h e  s p o ns or  h as  t h e  ri g ht  t o  dis c o nti n u e  t h e  cli ni c al  st u d y  at  a n y  ti m e  t hr o u g h o ut  t h e  
cli ni c al st u d y f or r e as o ns s u c h as s af et y, et hi cs, or m a n a g e m e nt iss u es.  
 
( 1) E arl y di s c o nti n u ati o n b y t h e s p o n s or or i n v e sti g at or 
T his  cli ni c al  st u d y  m a y  b e  dis c o nti n u e d  e arl y  at  a n y  ti m e  f or  s af et y,  b e h a vi or al,  or  
a d mi nistr ati v e r e as o ns d e p e n di n g o n t h e d e cisi o n of t h e i n v esti g at or or t h e s p o ns or.  
T h e c as es i n w hi c h t h e i n v esti g at or or t h e s p o ns or e arl y dis c o nti n u es t h e cli ni c al st u d y ar e 
as f oll o ws:  
1)  If t h e i nstit uti o n f ails t o e nr oll t h e t ar g et n u m b er of s u bj e cts; 
2)  If effi c a c y a n d s af et y i nf or m ati o n t h at c a n si g nifi c a ntl y i m p a ct t h e c o nti n u ati o n of t h e 
cli ni c al st u d y e m er g es;  
3)  If it is diffi c ult t o c o n d u ct a n a p pr o pri at e cli ni c al st u d y b e c a us e t h e i nstit uti o n or t h e 
i n v esti g at or h as vi ol at e d t h e K or e a G o o d Cli ni c al Pr a cti c e ( K G C P), t h e cli ni c al st u d y 
pr ot o c ol, c o ntr a ct u al m att ers, et c.;  
4)  If t h er e ar e ot h er a d mi nistr ati v e r e as o ns t h at  c a n h a v e a si g nifi c a nt i m p a ct  o n t h e 
c o nti n u ati o n of t h e cli ni c al st u d y.  
 
( 2) P er m a n e nt di s c o nti n u ati o n of a d mi ni str ati o n of i n v e sti g ati o n al pr o d u ct  
T h e  c as es  i n  w hi c h  a d mi nistr ati o n  of  t h e  i n v esti g ati o n al  pr o d u ct  is  p er m a n e ntl y  
dis c o nti n u e d ar e as f oll o ws b ut ar e n ot li mit e d t h er et o:  
1)  If t h e s u bj e ct or his or h er r e pr es e nt ati v e wit h dr a ws c o ns e nt;  
2)  If it is diffi c ult t o c o nti n u e t h e cli ni c al st u d y d u e t o a d v ers e e v e nts; 
3)  If vi ol ati o ns  of t h e i n cl usi o n a n d  e x cl usi o n  crit eri a ar e  f o u n d  w hil e  c o n d u cti n g t h e  
cli ni c al st u d y;  
4)  If  it  is  d et er mi n e d  t h at  t a ki n g  c o ntr ai n di c at e d  m e di c ati o ns  or  tr e at m e nt  wit h  
c o ntr ai n di c at e d p h ar m a c e uti c als is n e c ess ar y;  
5)  If c o ntr ai n di c at e d t h er a pi es w er e p erf or m e d, or if it is d et er mi n e d t h at p erf or mi n g 
c o ntr ai n di c at e d t h er a pi es is n e c ess ar y;  
6)  If s u bj e ct f oll o w-u p is n ot p ossi b l e; 
7)  If s eri o us vi ol ati o ns of t h e pr ot o c ol ar e f o u n d;  
8)  If a n ot h er dis e as e is f o u n d i n t h e s u bj e ct t h at m a k es it i m p ossi bl e t o c o n d u ct t h e 
t ests a n d pr o c e d ur es p erf or m e d at r e g ul ar visits; 
9)  If  t h e  i n v esti g at or  d et er mi n es  t h at  c o nti n ui n g  t h e  cli ni c al  st u d y  is  diffi c ult  d u e  t o  
ot h er r e as o ns.  
 
I n  or d er  n ot  t o  miss  t h e  o c c urr e n c e  of  a d v ers e  e v e nts  w hi c h  t h e  i n v esti g at or  d o es  n ot  
k n o w a b o ut, all m et h o ds s u c h as p h o n e c alls, l ett er s, a n d dir e ct visits s h all b e utili z e d t o 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 6 0  / 6 1  
 
 
dir e ctl y c o nt a ct t h e s u bj e cts w h o r ef us e t o visit. T h e r e as o ns f or e arl y dis c o nti n u ati o n or 
t er mi n ati o n of a d mi nistr ati o n s h all b e r e c or d e d i n t h e c as e r e p ort f or m. S u bj e cts w h o h a v e 
e arl y dis c o nti n u e d or h a v e t er mi n at e d a d mi nistr ati o n m a y n ot p arti ci p at e a g ai n.  
 
F or  s u bj e cts  w h o  h a v e  e arl y  t er mi n at e d  t h e  st u d y,  t h e  t ests  f or  e arl y  t er mi n ati o n  i n  
“S u m m ar y of St u d y S c h e d ul e ” s h all b e p erf or m e d. 
If t h e cli ni c al st u d y h as b e e n e arl y dis c o nti n u e d, t h e f oll o wi n g s h all b e p erf or m e d:  
 
1)  If  t h e  pri n ci p al  i n v esti g at or  h as  e arl y  t er mi n at e d  or  s us p e n d e d  t h e  cli ni c al  st u d y  
wit h o ut  a  pri or  a gr e e m e nt  wit h  t h e  s p o ns or,  t h e  pri n ci p al  i n v esti g at or  s h all  
i m m e diat el y i nf or m t his f a ct t o t h e s p o ns or a n d t h e I nstit uti o n al R e vi e w B o ar d, a n d 
s h all s u b mit a d et ail e d st at e m e nt of r e as o ns f or t h e e arl y t er mi n ati o n a n d s us p e nsi o n.  
2)  If  t h e  s p o ns or  h as  e arl y  t er mi n at e d  or  s us p e n d e d  t h e  cli ni c al  st u d y,  t h e  pri n ci p al  
i n v esti g at or s h all i m m e di at el y i nf or m t his f a ct t o t h e I nstit uti o n al R e vi e w B o ar d, a n d 
s h all s u b mit a d et ail e d st at e m e nt of r e as o ns f or t h e e arl y t er mi n ati o n a n d s us p e nsi o n.  
3)  If t h e I nstit uti o n al R e vi e w B o ar d h as e arl y t er mi n at e d or s us p e n d e d t h e cli ni c al st ud y, 
t h e pri n ci p al i n v esti g at or s h all i m m e di at el y i nf or m t his f a ct t o t h e s p o ns or, a n d s h all 
s u b mit a d et ail e d st at e m e nt of r e as o ns f or t h e e arl y t er mi n ati o n a n d s us p e nsi o n.  
4)  If t h e r el e v a nt cli ni c al st u d y h as b e e n e arl y t er mi n at e d or s us p e n d e d as i n 1) thr o u g h 
3) i n a c c or d a n c e wit h r e g ul ati o ns, t h e pri n ci p al i n v esti g at or s h all i m m e di at el y i nf or m 
t his f a ct t o t h e s u bj e cts, a n d s h all e ns ur e t h at a p pr o pri at e m e as ur es ar e t a k e n a n d 
f oll o w-u ps ar e c o n d u ct e d.  
 
F or  s u bj e cts  w h o  h a v e  b e e n  dis c o nti n u e d  d u e  t o  a d v ers e  e v e nts,  f oll o w -u ps  s h all  b e  
c o n d u ct e d  u ntil  t h e  i n v esti g at or  d et er mi n es  t h at  t h e  c orr es p o n di n g  a d v ers e  e v e nts  ar e  
r es ol v e d or t h e s u bj e cts ar e m e di c all y st a bl e. F or t h es e s u bj e cts, H eli x mit h C o., Lt d. a n d t h e 
i n v esti g at ors s h all tr y t h eir b est t o pr o vid e st a n d ar d cli ni c al tr e at m e nt. H eli x mit h C o., Lt d. 
s h all pr o vi d e i n d e m nifi c ati o n, if a p pli c a bl e, i n a c c or d a n c e wit h t h e s u bj e ct i n d e m nifi c ati o n 
p oli c y. I n a d diti o n, t h e t ests ( 1 0 it e ms) m e nti o n e d a b o v e s h all b e p erf or m e d f or t h e s af et y 
of t h e s u bj e cts.  
 
If a s u bj e ct c a n n ot  b e c o nt a ct e d i n f oll o w-u ps, t h e i n v esti g at or s h all att e m pt t o c o nt a ct  
( p h o n e c all, e m ail, et c.) t h e s u bj e ct at l e ast t hr e e ti m es. If t h er e is n o r es p o ns e fr o m t h e 
s u bj e ct d es pit e t his, t h e i n v esti g at or s h all c o nt a ct a f a mil y m e m b er of t h e s u bj e ct or his or 
h er pri m ar y p h ysi ci a n. T h e e vi d e n c e of s u c h att e m pt e d c o nt a ct  s h all b e r e c or d e d i n t h e 
s o ur c e d at a, a n d t h e c o nfir m ati o n of r e c ei pt of l ett ers s e nt t o t h e s u bj e ct c a n b e a n e x a m pl e 
of s u c h pr o of.  
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 6 4  / 6 5  
 
 
T h e cli ni c al tri al p h ar m a cist or a d esi g n at e d i n di vi d u al s h all a c c ur at el y r e c or d t h e d at e of 
r e c ei pt a n d d etails w h e n r e c ei vi n g t h e i n v esti g ati o n al pr o d u ct.  
As  t h e  cli ni c al  tri al  p h ar m a cist  s h all  st or e  a n d  m a n a g e  t h e  i n v esti g ati o n al  pr o d u cts  b y  
r e c or di n g  t h e  all o c ati o n  n u m b er,  pr es cri pti o n  d at e,  r el e as e d  q u a ntit y,  et c.,  i n  t h e  dr u g  
a c c o u nt a bilit y l o g, t h e cli ni c al tri al p h ar m a cist s h all v erif y t h e us a g e st at us a n d st or e a list 
of  r e c ei pt,  iss u a n c e,  a n d  r et ur n  r e c or ds  f or  t h e  dr u g  us e d  i n  t h e  cli ni c al  st u d y.  T his  
a c c o u nt a bilit y l o g of t h e i n v esti g ati o n al pr o d u ct m ust b e v erifi a bl e at a n y ti m e, a n d t h e 
cli ni c al tr i al p h ar m a cist s h all pr o vi d e a c o p y of t his r e c or d t o t h e st u d y s p o ns or w h e n t h e 
st u d y is t er mi n at e d.  
A cli ni c al st u d y m o nit or s h all r e g ul arl y vi e w t h e m a n a g e m e nt l o g t o v erif y t h e us a g e d et ails 
of all i n v esti g ati o n al pr o d u cts.  
E v e n aft er t er mi n ati o n of t h e cli ni c al st u d y, t h e cli ni c al tri al p h ar m a cist s h all v erif y 
t h e i n v e nt or y of all i n v esti g ati o n al pr o d u cts i n cl u di n g t h e i n v esti g ati o n al pr o d u cts 
u s e d  i n  t h e  cli ni c al  st u d y,  u n us e d  i n v esti g ati o n al  pr o d u cts,  a n d  p arti all y  us e d  
i n v esti g ati o n al  pr o d u ct s,  a n d  if  t h er e  ar e  u n u s e d  i n v esti g ati o n al  pr o d u cts  
r e m ai ni n g,  t h e y  s h all  b e  r et ur n e d  t o  t h e  st u d y  s p o n s or,  a n d  t h e  st u d y  s p o n s or  
s h all v erif y t h e t ot al q u a ntit y i n writi n g.  
 
5 . 7. M a n a g e m e nt of C or o n a vir u s Di s e a s e -1 9  (C O VI D -1 9 ) 
5 . 7. 1 S el e cti o n a n d e nr oll m e nt of cli ni c al st u d y s u bj e ct s  
N ot  a p pli c a bl e  b e c a u s e  e nr oll m e nt  of  a ll  s u bj e cts  h as b e e n  c o m pl et e d  f or  t his  
st u d y.  
 
5 . 7. 2 M a n a g e m e nt of cli ni c al st u d y s u bj e ct s  
R e g ar di n g C O VI D -1 9, t his cli ni c al st u d y is m a n a g e d as f oll o ws:  
• S u bj e cts w h o  h a v e  b e e n  c o nfir m e d  t o  h a v e  C O VI D -1 9  or  w h o  h a v e  b e e n  i n  cl os e 
c o nt a ct  wit h  C O VI D -1 9 p ati e nts, m ust  b e  q u ar a nti n e d f or  1 4  d a ys  w h et h er  or  n ot  
s y mt o ns h a v e o c c urr e d. A ft er b ei n g r el e as e d fr o m q u ar a nti n e, t h e s u bj e ct c o nti n u es  
wit h t h e pr o c e d ur es f or t h e  visit  p eri o d .  
• S u bj e cts w h o h a v e b e e n c o nfir m e d t o h a v e C O VI D -1 9 p ati e nts aft er d osi n g b ut h a v e 
r e c o v er e d pri or t o t h eir n e xt visit m a y c o nti n u e t o p arti ci p at e i n t h e st u d y.  
• S u bj e cts w h o h a v e b e e n c o nfir m e d t o h a v e C O VI D -1 9 p ati e nts aft er d osi n g b ut h a v e 
n ot r e c o v er e d pri or t o t h eir n e xt visit  m ust s us p e n d t h eir p arti ci p ati o n i n t h e st u d y 
a n d c o nti n u e wit h t h e pr o c e d ur es f or t h e visit p eri o d aft er r e c o v eri n g. S u bj e cts w h o 
h a v e  n ot  r e c o v er e d  u ntil  D a y  2 7 0  ±  7   s h o ul d  dis c o nti n u e t h eir p arti ci p ati o n  i n  t h e  

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 6 5  / 6 6  
 
 
st u d y.  All  r e as o ns  f or  dis c o nti n u ati o n  s h o ul d  b e  r e c or d e d  i n  t h e  st u d y  t er mi n ati o n  
f or m of t h e C as e R e p ort F or m.  
• If it is d e e m e d b y t h e i n v esti g at or t h at t h e s u bj e ct c o nfir m e d wit h C O VI D -1 9 is n o 
l o n g er  a bl e  t o  p arti ci p at e  i n  t h e  st u d y d u e  t o  a n y  r e as o n,  t h e  i n v esti g at or s h all 
dis c o nti n u e t h e p ati e nt’s st u d y. All r e as o ns f or dis c o nti n u ati o n s h o ul d b e r e c or d e d i n 
t h e st u d y t er mi n ati o n f or m of t h e C as e R e p ort F or m.  
• T h e f a ct t h at s u bj e cts of t his cli ni c al st u d y h a v e b e e n c o nfir m e d t o h a v e C O VI D -1 9 is 
r e c or d e d  as  a n  a d v er s e  e v e nt  o n  t h e  C as e  R e p ort  F or m  a n d  cl assifi e d  as  A d v ers e  
E v e nts of S p e ci al I nt er est ( A E SI).  
 
5 . 7. 3 R e c or d s of C or o n a vir u s Di s e a s e -1 9  ( C O VI D-1 9)  
If t h e pr ot o c ol  is  n ot  c o m pli e d  wit h  d u e t o  c or o n a vir u s  Dis e as e -1 9  ( C O VI D-1 9), 
C O VI D -1 9 s h all b e cl e arl y r e c or d e d a n d m a n a g e d as a r e as o n f or n o n -c o m pli a n c e 
o n t h e r el e v a nt f or m of t h e c as e r e p ort f or m. 
• A d e v ers e E v e nt F or m  
• S t u d y Ter mi n ati o n Fr o m 
• D at e of visit a n d E v al u ati o n F or m  
• O t h er 
 
5 . 8 R etr o s p e cti v e Bi o m ar k er St u d y  
Bl o o d s a m pl es ar e c oll e ct e d at D a y 0, D a y 9 0, D a y 1 8 0 a n d D a y 2 7 0 ( or e arl y t er mi n ati o n visit) 
f or r etr os p e cti v e bi o m ar k er st u d y  of C M T. C oll e ct e d s a m pl es will b e pr o c ess e d a c c or di n g  t o  
d et ail e d pr o c e d ur e i n a s e p ar at e pr ot o c ol.  
5 . 8. 1 P ur p o s e of t h e st u d y  
C h a n g e s i n p eri p h er al n e ur o p at h y bi o m ar k er ( p 6 2, p 7 5, N C A M)  
- S er u m p 6 2 ( p 6 2/ s e q u est o s o m e -1) c o n c e ntr ati o n  
- S er u m p 7 5 ( p 7 5 n e ur otr o p hi n r e c e pt or) c o n c e ntr ati o n  
- S er u m N C A M ( n e ur al c ell a d h esi o n m ol e c ul e 1) c o n c e ntr ati o n  
5. 8. 2 M et h o d of t h e st u d y  
Aft er e x pl ai ni n g t h e p ur p o s e of t h e bi o m ar k er st u d y a n d pr es er v ati o n p eri o d of 
bl o o d s a m pl es t o t h e s u bj e ct, t h e bl o o d of t h e s u bj e ct w h o v ol u nt aril y si g n e d t h e 
c o n s e nt f or m  f or r es e ar c h o n h u m a n m at eri als, w hi c h is a 3 4t h a p p e n di x f or m  i n 
t h e E nf or c e m e nt R ul e of Bi o et hi cs a n d S af et y A ct , is r etr o s p e cti v el y a n al y z e d.   
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi d e nti al  
2 0 2 1 .0 6 . 07  
V ersi o n : 4 . 0 
 6 6  / 6 7  
 
 
5. 8. 3 M et h o d s  f or  a n o n y mi zi n g  h u m a n  m at eri al s a n d  m e a s ur e s  t o  pr ot e ct  p er s o n al  
i nf or m ati o n 
Aft er t h e s u bj e ct's v ol u nt ar y c o n s e nt, t h e c oll e ct e d bl o o d s a m pl es ar e st or e d wit h 
u ni q u e n u m b er s af t er all p er s o n al i nf or m ati o n is d el et e d. T h e pr es er v ati o n  p eri o d  
of h u m a n m at eri als is i n a c c or d a n c e wit h t h e c o n s e nt f or m f or r es e ar c h o n h u m a n 
m at eri als.  
 

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi de nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 6 9  / 7 0  
 
 
1)  
S u bj e ct b a c k gr o u n d s ur v e y: A s ur v e y s h all b e p erf or m e d o n d e m o gr a p hi c i nf or m ati o n a n d hist or y of al c o h ol a n d t o b a c c o us e, et c.  
2)  
M e di c al hist or y s ur v e y: A s ur v e y s h all b e p erf or m e d o n m e di c al hist or y wit hi n 6 m o nt hs b ef or e Visit 1 (s cr e e ni n g). H o w e v er, m e di c al hist or y/tr e at m e nt hist or y r el at e d t o c a n c er s h all 
b e s ur v e y e d r e g ar dl ess of t h e ti m e p eri o d. Cli ni c all y si g nifi c a nt m e di c al c o n diti o ns or a b n or m aliti es o bs er v e d d uri n g t h e p er i o d fr o m t h e o bt ai n m e nt of t h e i nf or m e d c o ns e nt f or m 
u ntil t h e a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct s h all b e d e e m e d as m e di c al hist or y. It s h all b e s ur v e y e d w h et h er t h e n ati o n al c a n c er s cr e e ni n g ( g astri c c a n c er, c ol o n c a n c er, 
li v er c a n c er, l u n g c a n c er, c er vi c al c a n c er, br e ast c a n c er) e x a mi n ati o ns r el e v a nt t o t h e p ati e nt’s a g e ar e t a k e n a n d t h e r es ults ar e wit hi n t h e n or m al r a n g e. I n c as e of c er vi c al c a n c er, if 
it c a n n ot b e c o nfir m e d t h at t h e n ati o n al c a n c er s cr e e ni n g e x a mi n ati o ns w er e t a k e n wit hi n 2 y e ars a n d t h e r es ults ar e wit hi n t h e n or m al r a n g e, a n e x a mi n ati o n a n d a p a p s m ear s h all 
b e p erf or m e d at t h e i nstit uti o n t o v erif y n or m al r a n g e r es ults.  
3)  
P h ysi c al e x a mi n ati o n: I nf or m ati o n s h all b e c oll e ct e d f or e x a mi n ati o n it e ms c o nsisti n g of e xt er n al a p p e ar a n c e, s ki n, h e a d/ n e c k , c h est/l u n gs, h e art, a b d o m e n, uri n ar y/r e pr o d u cti v e s yst e m, 
li m bs, m us c ul os k el et al s yst e m, n er v o us s yst e m, l y m p h n o d es, a n d ot h er it e ms.  
4)  
B o d y m e as ur e m e nt ( w ei g ht m e as ur e m e nt): H ei g ht, w ei g ht, a n d B MI s h all b e m e as ur e d. H ei g ht a n d B MI s h all b e m e as ur e d o nl y at s c r e e ni n g ( Visit 1). 
5)  
Vir us s er ol o g y t est: HI V, H Bs A g, A nti -H Bs, A nti -H C V  
6)  
C o m pl et e bl o o d c ell c o u nt a n d g e n er al bl o o d c h e mistr y t ests: T h e l a b or at or y t est it e ms ar e as f oll o ws:  
- C o m pl et e bl o o d c ell c o u nt: W B C, R B C, H b, H ct, M C V, M C H, M C H C, P L T, E S R, M P V, diff er e nti al c o u nt of W B C ( B a n d n e utr o p hi l, S e g m e nt e d n e utr o p hil, E osi n o p hil, B as o p hil, 
L y m p h o c yt e, M o n o c yt e)    
- G e n er al bl o o d c h e mistr y t est: t ot al pr ot ei n, al b u mi n, gl o b uli n, A/ G r ati o, c h ol est er ol, t ot al bilir u bi n, A S T, A L T, f asti n g gl u c os e, B U N, cr e ati ni n e, esti m at e d G F R, C a 2 + , p h os p h at e, N a+ , 
K + , Cl-, C R P, tri gl y c eri d e, H D L-c h ol est er ol, L D L -c h ol est er ol  
7)  
R etr os p e cti v e bi o m ar k er st u d y : Bl o o d s a m pl e s ar e  c oll e ct e d at  D a y 0, D a y 9 0, D a y 1 8 0  a n d  D a y 2 7 0 ( or e arl y t er mi n ati o n visit ) f or r etr os p e cti v e bi o m ar k er st u d y of C M T. C oll e ct e d 
s a m pl es will b e  pr o c ess e d a c c or di n g t o d et ail e d pr o c e d ur e i n a s e p ar at e pr ot o c ol. C M T 질환의 후향적 생물학적 표지자 연구를 위하여 D a y 0, D a y 9 0, D a y 1 8 0, D a y 2 7 0 ( 또는 조기
종료 방문)에 혈액을 수집한다. 수집된 혈액은 별도의 연구계획서에서 구체적인 연구방법에 따라서 진행될 것이다. 
8)  
C h est X -r a y ( P A): At Visit 1 (s cr e e ni n g), c h est P A X-r a y s h all b e p erf or m e d t o v erif y w h et h er a cti v e t u b er c ul osis is pr es e nt. T h e r es ults wit hi n 1 m o nt h ( 3 0 d a ys) b ef or e Visit 1 m a y b e 
us e d.  
9)  
Uri n al ysis: T h e l a b or at or y t est it e ms ar e as f oll o ws:  
- C ol or, t ur bi dit y, sp e cifi c gr a vit y, p H, al b u mi n, gl u c os e,  k et o n e s, bilir u bi n, bl o o d, ur o bili n o g e n, nitrit e, l e u k o c yt e  est er as e, mi cr os c o p y ( R B C, W B C, c asts)  
1 0)  Uri n e or s er u m pr e g n a n c y t est At Visit 1 (s cr e e ni n g), uri n e or s er u m pr e g n a n c y t ests s h all b e p erf or m e d i n f e m al es of c hil d b e ari n g p ot e nti al (fr o m p ost -m e n ar c h e f e m al es t o f e m al es 
≥ 5 0 y e ars of a g e wit hi n 1 y e ar of m e n o p a us e, or fr o m p ost -m e n ar c h e f e m al es t o f e m al es < 5 0 y e ars of a g e wit hi n 2 y e ars of m e n o p a us e). H o w e v er, p ati e nts wit h s ur gi c al m e n o p a us e 
( h yst er e ct o m y, bil at er al o o p h or e ct o m y, et c.) or w h o u n d er w e nt st erili z ati o n s ur g er y ( bil at er al t u b al li g ati o n, bil at er al t u b e ct o m y) m a y b e e x cl u d e d. M e n o p a us e r ef ers t o t h e st at e aft er 
1 y e ar of a m e n orr h e a.  
1 1)  El e ctr o c ar di o gr a m: T h e el e ctr o c ar di o gr a m t o b e p erf or m e d at Visit 1 (s cr e e ni n g) m a y us e r es ults wit hi n 4 w e e ks b ef or e Visit 1 (s cr e e ni n g).  
1 2)  C o n c o mit a nt  m e di c ati o ns  s ur v e y:  All  m e di c ati o ns  a n d  tr e at m e nts  a d mi nist er e d  wit hi n  6  m o nt hs  b ef or e  Visit  1  (s cr e e ni n g)  s h all  b e  s ur v e y e d.  Pr e v i o us  m e di c ati o ns  a n d  pr e vi o us  
tr e at m e nts  s h all  b e  d efi n e d  as  all  pr e vi o usl y  c oll e ct e d  m e di c ati o ns  a n d  tr e at m e nts  b ef or e  Visit  2  (first  a d mi nistr ati o n  of  i n v esti g ati o n al  pr o d u ct).  C o n c o mit a nt  m e di c ati o ns  a n d  

 
 
 
 
 
 
 
P R T N O: V M C M T -0 0 1  
C o nfi de nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 7 0  / 7 1  
 
 
tr e at m e nts s h all r ef er t o all m e di c ati o ns t h at h av e b e e n a d mi nist er e d at l e ast o n c e st arti n g fr o m Visit 2 (first a d mi nistr ati o n of i n v esti g ati o n al pr o d u ct) a n d t hr o u g h o ut t h e  cli ni c al 
st u d y. T h e c at e g ori es of c oll e ct e d m e di c ati o ns a n d tr e at m e nts s h all f oll o w t his d efi niti o n. W h et h er t h e m e di c ati o ns a n d tr e at m e nts b ei n g a d mi nist er e d s h o ul d b e c o nti n u e d s h all b e 
i n v esti g at e d at e a c h visit. 
1 3)  M RI l e g: T h e m us cl es of l o w er li m bs s h all b e i m a g e d, a n d t h e f att y i nfiltr ati o n l e v el of t h e l e g m us cl es i nj e ct e d wit h t h e i n v esti g ati o n al pr o d u ct s h all b e m e as ur e d a n d e v al u at e d as 
f at c o nt e nt v al u e ( %) at o n e l e v el f or e a c h m us cl e. C o nsi d eri n g t h e s c h e d ul e, et c., of t h e i nstit uti o n, it s h all b e p erf or m e d o pti o n all y at t h e e arl y t er mi n ati o n visit, a n d if it is n ot 
p erf or m e d, t h e r e as o ns s h all b e r e c or d e d i n t h e c as e r e p ort f or m.  
1 4)  A d v ers e e v e nt ass ess m e nt: At Visits 3, 4, a n d 5, a n ass ess m e nt of a d v ers e e v e nts t h at h a v e o c c urr e d si n c e t h e l ast visit s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al 
pr o d u ct, a n d l o c ali z e d a d v ers e e v e nts s h all b e ass ess e d at 2 ± 1 h o urs aft er a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct, as w ell as o n t h e d a y aft er a d mi nistr ati o n.  
1 5)  H os pit ali z ati o n: S u bj e cts s h all b e h os pit ali z e d o n t h e d a y b ef or e a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct a n d t h eir vit al si g ns s h all b e m e as ur e d. If t h e y  ar e n ot h os pit ali z e d, vit al 
si g ns m a y b e o mitt e d, a n d t h e h os pit ali z ati o n d a y i n t h e c as e r e p ort f or m s h all b e r e c or d e d t h e s a m e as t h e t est d a y pri or t o  a d mi nistr ati o n.  
1 6)  Aft er a d mi nistr ati o n: Vit al si g ns a n d a d v ers e e v e nts s h all b e ass ess e d at 2 ± 1 h o urs aft er a d mi nist eri n g t h e i n v esti g ati o n al  pr o d u ct. T h e pr es e n c e or a bs e n c e of l o c ali z e d a d v ers e 
e v e nts s h all b e v erifi e d o n t h e d a y aft er a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct.  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 7 1
7 1  / 7 2
7 2  
 
 
6. 1. 1  
Vi sit 1 ( s cr e e ni n g, fr o m D a y -3 0 t o D a y -1)  
T h e f oll o wi n g it e ms s h all b e p erf or m e d o n o nl y t h os e s u bj e cts t h at m a d e t h e s cr e e ni n g 
visit a n d pr o vi d e d v ol u nt ar y c o ns e nt.  
• 
C o m pl eti o n of i nf or m e d c o n s e nt f or m  
T h e r es p o nsi biliti es t h at s h o ul d b e c o m pli e d wit h b y a s u bj e ct t hr o u g h o ut t h e st u d y s h all b e 
e x pl ai n e d. If a s u bj e ct d e ci d es t o v ol u nt aril y p arti ci p at e i n t h e st u d y a n d c o ns e nts t o t h e v ari o us 
t ests a n d pr o c e d ur es t h at t h e s u bj e ct will b e r e c ei vi n g t hr o u g h o ut t h e cli ni c al st u d y, t h e s u bj e ct’s 
h a n d writt e n  si g n at ur e  s h all  b e  o bt ai n e d  o n  a n  alr e a d y  pr e p ar e d  i nf or m e d  c o ns e nt  f or m.  T h e  
s u bj e ct a n d t h e i n v esti g at or s h all si g n t h e i nf or m e d c o ns e nt f or m a n d fill i n t h e d at e. T h e ori gi n al 
si g n e d i nf or m e d c o ns e nt f or m s h all b e st or e d wit h t h e s u bj e ct’s r e c or ds, a n d o n e c o p y s h all b e 
pr o vi d e d t o t h e s u bj e ct.  
 
• 
A s si g n m e nt of s u bj e ct s cr e e ni n g n u m b er  
S e e s e cti o n 5. 3. 4 Assi g n m e nt of S u bj e ct N u m b er s  
 
• 
B a c k gr o u n d s ur v e y  
At Visit 1 (s cr e e ni n g), a s ur v e y s h all b e p erf or m e d o n d e m o gr a p hi c i nf or m ati o n (s e x, a g e, et c.), 
s m o ki n g hist or y, al c o h ol c o ns u m pti o n hist or y, et c.  
 
• 
M e di c al hi st or y s ur v e y  
M e di c al r e c or ds o n t h e m e di c al hist or y wit hi n 6 m o nt hs b ef or e Visit 1 (s cr e e ni n g) s h all 
b e o bt ai n e d, a n d all p ositi v e/ n e g ati v e r es ults s h all b e r e c or d e d i n d et ail i n t h e c as e 
r e p ort  f or m.  H o w e v er,  m e di c al  hist or y/tr e at m e nt  hist or y  r el at e d  t o  c a n c er  s h all  be 
s ur v e y e d r e g ar dl ess of t h e ti m e p eri o d. N e w r es ults f o u n d at Visit 1 (s cr e e ni n g) a n d 
Visit 2 ( b ef or e a d mi nistr ati o n of i n v esti g ati o n al pr o d u ct) s h all b e c o nsi d er e d a p art of 
m e di c al  hist or y  a n d  s h all  n ot  b e  r e c or d e d  as  a d v er s e  e v e nts.  T h e  i n v esti g at or  s h all 
v erif y w h et h er t h e di a g n osis of C M T 1 A h as b e e n g e n eti c all y c o nfir m e d f or t h e p ati e nt.  
   
• 
P h y si c al e x a mi n ati o n  
T his  s h all  b e  p erf or m e d  at  Visit  1  (s cr e e ni n g),  a n d  it  s h all  i n cl u d e  e xt er n al  a p p e ar a n c e,  s ki n,  
h e a d/ n e c k,  c h est/l u n gs,  h e art,  a b d o m e n,  uri n ar y/r e pr o d u cti v e  s yst e m,  li m bs,  m us c ul os k el et al  
s yst e m, n er v o us s yst e m, l y m p h n o d es, a n d ot h er it e ms. All a b n or m al fi n di n gs s h all b e r e c or d e d 
i n t h e c as e r e p ort f or m, a n d t h e cli ni c al si g nifi c a n c e of e a c h fi n di n g s h all b e ass ess e d.  
 
• 
B o d y m e a s ur e m e nt  
T hi s s h all i n cl u d e h ei g ht, w ei g ht, a n d B MI ( o bt ai n e d fr o m h ei g ht i n m et er s a n d w ei g ht i n k g t h at 
h as b e e n r o u n d e d u p t o 1 d e ci m al pl a c e fr o m 2 d e ci m al pl a c es).  
 
• 
Vir u s s er ol o g y t e st  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 7 2
7 2  / 7 3
7 3  
 
 
At Visit 1 (s cr e e ni n g), s er ol o g y t ests f or t h e f oll o wi n g i nf e cti v e vir al dis e as es s h all b e p erf or m e d:  
HI V, H Bs A g, A nti -H Bs, A nti -H C V  
 
• 
C o m pl et e bl o o d c ell c o u nt  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. T h e c o m pl et e bl o o d c ell 
c o u nt it e ms ar e as f oll o w s:  
 
W B C, R B C, H b, H ct, M C V, M C H, M C H C, P L T, E S R, M P V, diff er e nti al c o u nt of W B C ( B a n d n e utr o p hil, 
S e g m e nt e d n e utr o p hil, E osi n o p hil, B as o p hil, L y m p h o c yt e, M o n o c yt e)  
 
• 
G e n er al bl o o d c h e mi str y t e st  
 
T his  s h all  b e  p erf or m e d  e v er y  ti m e  a  s u bj e ct  m a k es  a  visit  (s h all  b e  p erf or m e d  pri or  t o 
a d mi nist eri n g  t h e  i n v esti g ati o n al  pr o d u ct  at  Visits  2,  3,  4,  a n d  5).  H o w e v er,  if  t h er e  is  a  
s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 ( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt 
a n d a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d at D a y 3 0 d e p e n d i n g o n t h e d e cisi o n 
of t h e pri n ci p al i n v esti g at or. Si n c e a bl o o d gl u c os e t est is i n cl u d e d, t h e s u bj e ct s h all m ai nt ai n 
a n  8 -h o ur  f asti n g  st at e  pri or  t o  t h e  t est.  T h e  g e n er al  bl o o d  c h e mistr y  t est  it e ms  ar e  as  
f oll o ws:  
 
t ot al pr ot ei n, al b u mi n, gl o b uli n, A/ G r ati o, c h ol est er ol, t ot al bilir u bi n, A S T, A L T, f asti n g gl u c os e, 
B U N, cr e ati ni n e, esti m at e d G F R, C a 2 + , p h os p h at e, N a+ , K+ , Cl-, C R P, tri gl y c eri d e, H D L-c h ol est er ol, 
L D L- c h ol est er ol  
 
• 
C h e st X -r a y ( P A) 
At Visit 1 (s cr e e ni n g), c h est P A X -r a y s h all b e p erf or m e d t o v erif y w h et h er a cti v e t u b er c ul osis is 
pr es e nt. T h e r es ults wit hi n 1 m o nt h ( 3 0 d a ys) b ef or e Visit 1 (s cr e e ni n g) m a y b e us e d.  
 
• 
Uri n al y si s wit h mi cr o s c o p y  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), uri n al ysis wit h mi cr os c o p y m a y b e p erf or m e d at D a y 3 0 d e p e n di n g o n t h e d e cisi o n 
of t h e pri n ci p al i n v esti g at or.  
T h e uri n al ysis it e ms ar e as f oll o ws:  
 
C ol or, t ur bi dit y,  s p e cifi c  gr a vit y,  p H,  al b u mi n,  gl u c os e, k et o n e s,  biliru bi n, bl o o d, ur o bili n o g e n, 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 7 3
7 3  / 7 4
7 4  
 
 
nitrit e, l e u k o c yt e  est er as e, mi cr os c o p y ( R B C, W B C, c asts)  
 
• 
Uri n e H C G t e st f or f e m al e s u bj e ct s  
At  Visit  1, f e m al e s u bj e cts of c hil d b e ari n g p ot e nti al s h all u n d er g o a uri n e pr e g n a n c y t est  
( uri n e β-H C G, b et a -h u m a n c h ori o ni c g o n a d ot r o pi n). At Visit 1 (s cr e e ni n g), uri n e pr e g n a n c y 
t ests s h all b e p erf or m e d i n f e m al es of c hil d b e ari n g p ot e nti al (fr o m p ost-m e n ar c h e f e m al es 
t o f e m al es ≥ 5 0 y e ar s of a g e wit hi n 1 y e ar of m e n o p a u s e, or fr o m p ost-m e n ar c h e f e m al es 
t o f e m al es < 5 0 y e ar s of a g e wit hi n 2 y e ar s of m e n o p a us e). A s er u m pr e g n a n c y t est m a y 
s er v e as a s u bstit ut e if c oll e cti o n of uri n e f ails. H o w e v er, p ati e nt s wit h s ur gi c al m e n o p a us e 
( h yst er e ct o m y, bil at er al o o p h or e ct o m y, et c.) or w h o u n d er w e nt st erili z ati o n s ur g er y ( bil at er al 
t u b al li g atio n, bil at er al t u b e ct o m y) m a y b e e x cl u d e d. M e n o p a us e r ef er s t o t h e st at e aft er 1 
y e ar  of  a m e n orr h e a.  T h e  t est  r es ult  m ust  b e  n e g ati v e,  a n d  eff e cti v e  m et h o ds  of  
c o ntr a c e pti o n s h all b e d o c u m e nt e d. T h e s a m pl es s h all b e i m m e di at el y dis c ar d e d w h e n t h e 
t est is c om pl et e d. A c c e pt a bl e m et h o ds of c o ntr a c e pti o n ar e as f oll o ws:  
 
• 
El e ctr oc ar di o gr a m  
A 1 2 -l e a d el e ctr o c ar di o gr a m s h all b e p erf or m e d at Visit 1 (s cr e e ni n g). If t h er e ar e r es ults fr o m 
a  t est  p erf or m e d  at  t h e  s a m e  i nstit uti o n  wit hi n  4  w e e ks  b ef or e  Visit  1  (s cr e e ni n g),  t h e y  m a y  
s er v e as a s u bstit ut e.  
 
• 
Vit al si g n s  
Vit al  si g ns  i n cl u di n g  bl o o d  pr ess ur e  ( m e as ur e m e nt  s h all  b e  t a k e n  wit h  t h e  s u bj e ct  i n  a  
sitti n g  p ositi o n  aft er  r esti n g  f or  at  l e ast  1 0  mi n ut es  pri or  t o  m e as ur e m e nt),  t e m p er at ur e,  
h e art r at e p er mi n ut e, a n d r es pir at or y r at e p er mi n ut e s h all b e m e as ur e d. T h e m e as ur e m e nt 
r es ults s h all b e r e c or d e d i n t h e s u bj e cts’ c as e r e p ort f or ms. T his s h all b e p erf or m e d at Visit 
1 (s cr e e ni n g) a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a s u bj e ct m a k es a visit ( o n t h e 
dr u g a d mi nistr ati o n d a ys c o nsisti n g of Visits 2, 3, 4, a n d 5, it s h all b e p erf or m e d b o t h pri or 
t o a d mi nistr ati o n a n d 2 ± 1 h o ur s aft er a d mi nistr ati o n). H o w e v er, if t h er e is a s u bj e ct wit h 
a b n or m al fi n di n gs i n t h e t est at Visit 3 ( D a y 1 4), a f oll o w -u p t est m a y b e p erf or m e d at D a y 
3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
 
• 
C o n c o mit a nt m e di c ati o n s s ur v e y  
T h e br a n d n a m es a n d i n gr e di e nt n a m es of c o n c o mit a nt m e di c ati o ns s h all b e s ur v e y e d at e v er y 
visit a n d r e c or d e d i n t h e c as e r e p ort f or m. All m e di c ati o ns a n d tr e at m e nts a d mi nist er e d wit hi n 
6 m o nt hs b ef or e Visit 1 (s cr e e ni n g) s h all b e s ur v e y e d. Pr e vi o us dr u gs a n d pr e vi o us tr e at m e nts 
s h all  b e  d efi n e d  as  all  pr e vi o usl y  c oll e ct e d  m e di c ati o ns  a n d  tr e at m e nts  b ef or e  Visit  2  (fir st  
• 
Dr u g: Oral c o ntrace pti v es, s ki n patc h es, or pr o g esti n f or m ulati o ns (i m pla nts or i njecti o ns)  
• 
Barrier met h o d: C o n d o ms, dia p hra g ms, i ntra uteri n e d e vices (I U Ds), v a gi n al s u p p osit ories 
• 
A bsti n e n ce:  C o m plete  a bsti n e n ce  ( H o we v er,  p eri o dic  a bsti n e n ce  (e. g.,  cale n d ar  met h o d,  o v ulati o n  
met h o d, a n d s y m pt o -t h er mal met h o d) a n d self-restrai nt are n ot c o nsi d ere d as acce pta ble met h o ds 
of c o ntrace pti o n.)  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 7 5
7 5  / 7 6
7 6  
 
 
 
• 
C M T N S- v 2  
C h ar c ot -M ari e -T o ot h  N e ur o p at h y  S c or e -v ersi o n  2  ( C M T N S -v 2)  is  a  m e as ur e m e nt  t o ol  f or  
e v al u ati n g t h e s e v erit y of dis e as e. [6 6 ] M e as ur e m e nts s h all b e t a k e n f or 9 it e ms w hi c h i n cl u d e 3 
it e ms f or dis e as e s y m pt o ms, 4 it e ms f or si g ns, a n d 2 it e ms f or n e ur o p h ysi ol o gi c al t esti n g. T h e 
s e v erit y of dis e as e s h all b e cl assifi e d a c c or di n g t o s c or es as mil d ( ≤1 0), m o d er at e ( 1 1  t o 2 0), 
a n d  s e v e r e  ( > 2 0).  T his  cli ni c al  st u d y  s h all  t ar g et  mil d  t o  m o d er at e  p ati e nts.  T his  s h all  b e  
p erf or m e d at Visit 1 (s cr e e ni n g), Visit 2 ( D a y 0), a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) (s h all b e 
p erf or m e d pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0]). S e e “ A p p e n di x 4 . C M T N S-v 2” f or d et ails.  
 
• 
U s e of a s si sti v e d e vi c e s a n d t y p e s  
T h e assisti v e d e vi c es us e d b y t h e s u bj e cts s h all b e s ur v e y e d at Visit 1 (s cr e e ni n g) a n d at Visit 7 
(t er mi n ati o n visit, D a y 2 7 0). S p e ci ali z e d s h o es, br a c es f or l o w er li m bs, cr ut c h es, c a n es, w al ker s, 
w h e el c h air s, et c., f all u n d er t h es e d e vi c es. E v e n if n e w a d diti o n al assisti v e d e vi c es ar e us e d d uri n g 
t h e cli ni c al st u d y, t h e y s h all n ot b e i n cl u d e d i n a d v er s e e v e nts.    
 
• 
C o nfir m ati o n of i n cl u si o n/ e x cl u si o n crit eri a  
 
• 
S c h e d ul e d M RI  
T h e m us cl es of l o w er li m bs s h all b e i m a g e d, a n d t h e f att y i nfiltr ati o n l e v el of t h e l e g m us cl es 
i nj e ct e d wit h t h e i n v esti g ati o n al pr o d u ct s h all b e m e as ur e d a n d e v al u at e d as f at c o nt e nt v al u e 
( %) at o n e l e v el f or e a c h m us cl e.[6 7 ]   
T h e t est d a ys s h all b e at Visit 2 ( D a y 0) a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) (s h all b e p erf or m e d 
pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0]).  
 
6. 1. 1. 1  S cr e e ni n g F ail ur e  
S u bj e cts w h os e s cr e e ni n g t est r es ults f ail t o s atisf y t h e i n cl usi o n/ e x cl usi o n crit eri a of t his 
cli ni c al st u d y m a y n ot p arti ci p at e i n t h e cli ni c al st u d y. T h e r e as o ns f or s cr e e ni n g f ail ur e of 
t h es e s u bj e cts w h o ar e i n eli gi bl e t o p arti ci p at e i n t h e cli ni c al st u d y s h all b e r e c or d e d i n 
t h e s cr e e ni n g l o g. If s cr e e ni n g f ails, s cr e e ni n g c o nti n u es u ntil t h e t ar g et n u m b er is m et. 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 7 6
7 6  / 7 7
7 7  
 
 
6. 1. 2  
Vi sit 2 ( A d mi ni str ati o n 1, D a y 0)  
 
6. 1. 2. 1  B ef or e A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct  
T h e f oll o wi n g s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct.  
• 
H os pit aliz ati o n (if a p pli c a bl e)  
S u bj e cts s h all b e h os pit ali z e d o n t h e d a y b ef or e a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct 
a n d t h eir vit al si g ns s h all b e m e as ur e d. If t h e y ar e n ot h os pit ali z e d, vit al si g ns m a y b e o mitt e d, 
a n d t h e h os pit ali z ati o n d a y i n t h e c as e r e p ort f or m s h all b e r e c or d e d t h e s a m e as t h e t est d a y 
pri or t o a d mi nistr ati o n.  
 
• 
Fi n al c o nfir m ati o n of i n cl u si o n/ e x cl u si o n crit eri a  
 
• 
A s si g n m e nt of all o c ati o n n u m b er s * w h e n i n cl u si o n / e x cl u si o n crit eri a ar e s ati sfi e d  
*: S e e s e cti o n 5. 3. 4 Assi g n m e nt of S u bj e ct N u m b er s  
 
• 
B o d y m e as ur e m e nt ( w ei g ht m e as ur e m e nt)  
A s u bj e ct’s w ei g ht s h all b e m e as ur e d at Visit 1 a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a 
s u bj e ct m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at 
Visits 2, 3, 4, a n d 5).  
 
• 
C o m pl et e bl o o d c ell c o u nt  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. T h e c o m pl et e bl o o d c ell 
c o u nt it e ms ar e as f oll o w s:  
   
W B C, R B C, H b, H ct, M C V, M C H, M C H C, P L T, E S R, M P V, diff er e nti al c o u nt of W B C ( B a n d n e utr o p hil, 
S e g m e nt e d n e utr o p hil, E osi n o p hil, B as o p hil, L y m p h o c yt e, M o n o c yt e)  
 
• 
G e n er al bl o o d c h e mi str y t e st  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct 
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h emistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. Si n c e a bl o o d gl u c os e 
t est  is  i n cl u d e d,  t h e  s u bj e ct  s h all  m ai nt ai n  a n  8-h o ur  f asti n g  st at e  pri or  t o  t h e  t est.  T h e  
g e n er al bl o o d c h e mistr y t est it e ms ar e as f oll o ws:  
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 7 7
7 7  / 7 8
7 8  
 
 
t ot al pr ot ei n, al b u mi n, gl o b uli n, A/ G r ati o, c h ol est er ol, t ot al bilir u bi n, A S T, A L T, f asti n g gl u c os e, 
B U N, cr e ati ni n e, esti m at e d G F R, C a 2 + , p h os p h at e, N a+ , K+ , Cl-, C R P, tri gl y c eri d e, H D L-c h ol est er ol, 
L D L- c h ol est er ol  
 
• 
S a m pl e c oll e cti o n f or r etr o s p e cti v e bi o m ar k er st u d y    
T h e s er u m of s u bj e cts s h all b e c oll e ct e d a n d st or e d fr o z e n at -7 0° C. All bl o o d s a m pl es ar e st or e d 
wit h u ni q u e n u m b er s f or r etr os p e cti v e bi o m ar k er st u d y aft er all p er s o n al i nf or m ati o n is d el et e d . 
 
• 
Uri n al y si s wit h mi cr o s c o p y  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u b j e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), uri n al ysis wit h mi cr os c o p y m a y b e p erf or m e d at D a y 3 0 d e p e n di n g o n t h e d e cisi o n 
of t h e pri n ci p al i n v esti g at or.  
T h e uri n al ysis it e ms ar e as f oll o ws:  
 
C ol or, t ur bi dit y,  s p e cifi c  gr a vit y,  p H,  al b u mi n,  gl u c os e,  k et o n e s,  bilir u bi n,  bl o o d, ur o bili n o g e n, 
nitrit e, l e u k o c yt e  est er as e, mi cr os c o p y ( R B C, W B C, c asts)  
 
• 
Vit al si g ns  
Vit al si g ns i n cl u di n g bl o o d pr ess ur e ( m e as ur e m e nt s h all b e t a k e n wit h t h e s u bj e ct i n a sitti n g 
p ositi o n aft er r esti n g f or at  l e ast 1 0 mi n ut es pri or t o m e as ur e m e nt), t e m p er at ur e, h e art r at e 
p er  mi n ut e,  a n d  r es pir at or y  r at e  p er  mi n ut e  s h all  b e  m e as ur e d.  T h e  m e as ur e m e nt  r es ult s  
s h all  b e  r e c or d e d  i n  t h e  s u bj e cts’  c as e  r e p ort  f or ms.  T his  s h all  b e  p erf or m e d  at  Visit  1  
(s cr e e ni n g) a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a s u bj e ct m a k es a visit ( o n t h e dr u g 
a d mi nistr ati o n d a ys  c o nsisti n g of  Visits  2, 3, 4, a n d 5,  it s h all  b e p erf or m e d b ot h pri or  t o 
a d mi nistr ati o n  a n d  2  ±  1  h o ur s  aft er  a d mi nistr ati o n).  H o w e v er,  if  t h er e  is  a  s u bj e ct   wit h 
a b n or m al fi n di n gs i n t h e t est at Visit 3 ( D a y 1 4), a f oll o w -u p t est m a y b e p erf or m e d at D a y 
3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
 
• 
C o n c o mit a nt m e di c ati o n s s ur v e y  
T h e br a n d n a m es a n d i n gr e di e nt n a m es of c o n c o mit a nt m e di c ati o ns s h all b e s ur v e y e d at e v er y 
visit a n d r e c or d e d i n t h e c as e r e p ort f or m. All m e di c ati o ns a n d tr e at m e nts a d mi nist er e d wit hi n 
6  m o nt hs  b ef or e  Visit  1  (s cr e e ni n g)  s h all  b e  s ur v e y e d.  Pr e vi o us  m e di c a ti o ns  a n d  pr e vi o us  
tr e at m e nts s h all b e d efi n e d as all pr e vi o usl y c oll e ct e d m e di c ati o ns a n d tr e at m e nts b ef or e Visit 
2 (fir st a d mi nistr ati o n of i n v esti g ati o n al pr o d u ct). C o n c o mit a nt m e di c ati o ns a n d tr e at m e nts s h all 
r ef er  t o  all m e di c ati o ns  t h at  h a v e  b e e n  a d mi nist er e d  at  l e ast  o n c e  st arti n g  fr o m  Visit  2  (fir st 
a d mi nistr ati o n of i n v esti g ati o n al pr o d u ct) a n d t hr o u g h o ut t h e cli ni c al st u d y. T h e c at e g ori es of 
c oll e ct e d  m e di c ati o ns  a n d  tr e at m e nts  s h all  f oll o w  t his  d efi niti o n.  T h e  f oll o wi n g  s h all  als o  b e  
s ur v e y e d f or  e a c h m e di c ati o n:  
• 
Br a n d n a m e  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 7 9
7 9  / 8 0
8 0  
 
 
e v al u ati n g t h e s e v erit y of dis e as e. [ 6 6]   M e as ur e m e nts s h all b e t a k e n f or 9 it e ms w hi c h i n cl u d e 
3 it e ms f or dis e as e s y m pt o ms, 4 it e ms f or si g ns, a n d 2 it e ms f or n e ur o p h ysi ol o gi c al t esti n g. T h e 
s e v erit y of dis e as e s h all b e cl assifi e d a c c or di n g t o s c or es as mil d ( ≤1 0), m o d er at e ( 1 1  t o 2 0), 
a n d  s e v e r e  ( > 2 0).  T his  cli ni c al  st u d y  s h all  t ar g et  mil d  t o  m o d er at e  p ati e nts.  T his  s h all  b e  
p erf or m e d at Visit 1 (s cr e e ni n g), Visit 2 ( D a y 0), a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) (s h all b e 
p erf or m e d pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0]). S e e “ A p p e n di x 4 . C M T N S-v 2” f or d et ails.  
 
• 
A nti -H G F A b t est  
T h e a nti b o d y t est f or h e p at o c yt e gr o wt h f a ct or s h all b e p erf or m e d at Visit 2 ( D a y 0) a n d Visit 7 
(t er mi n ati o n visit, D a y 2 7 0) (s h all b e p erf or m e d pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0]). T h e 
s er u m of s u bj e cts s h all b e c oll e ct e d a n d st or e d fr o z e n at -7 0° C. W h e n t h e c oll e cti o n of bl o o d 
fr o m all s u bj e cts is c o m pl et e d, t h e s a m pl es s h all b e s e nt t o t h e c e ntr al l a b or at or y all at o n c e f or 
a n al ysis.  
 
• 
M RI l e g  
T h e  m us cl es  of  l o w er  li m bs  s h all  b e  i m a g e d,  a n d  t h e  f att y  i nfiltr ati o n  l e v el  of  t h e  l e g  m us cl es  
i nj e ct e d wit h t h e i n v esti g ati o n al pr o d u ct s h all b e m e as ur e d a n d e v al u at e d as f at c o nt e nt v al u e ( %) 
at o n e l e v el f or e a c h m us cl e.[ 6 7 ]  
T h e t est d a ys s h all b e at Visit 2 ( D a y 0) a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) (s h all b e p erf or m e d 
pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0]).  
 
• 
F D S  
T h e  f u n cti o n al  dis a bilit y  s c al e  ( F D S)  ass ess es  a  p ati e nt  fr o m  0  t o  8  p oi nts  as  s h o w n  b el o w  
d e p e n di n g o n t h e p ati e nt’s m o bilit y. [6 8 ] T h e ass ess m e nt d a ys s h all b e at Visit 2 ( D a y 0), Visit 4 
( D a y 9 0), Visit 6 ( D a y 1 8 0), a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) ( ass ess m e nt s h all b e p erf or m e d 
pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0] a n d Visit 4 [ D a y 9 0]).  
0 = n or m al;  
1 = cr a m ps a n d f ati g a b ilit y;  
2 =i n a bilit y t o r u n;  
3 = p ossi bl e u n ai d e d;  
4 = wit h c a n e;  
5 = wit h cr ut c h;  
6 = wit h w al k er;  
7 = w h e el c h air;  
8 = b e dri d d e n.  
 
• 
O N L S l e g sc al e  
T h e o v er all n e ur o p at h y li mit ati o n s c al e ( O N L S) is a t o ol f or m e as uri n g t h e a cti vit y l e v el of p ati e nts 
wit h  p eri p h e r al  n e ur o p at h y.[ 6 9 ] It  is  s c or e d  b y  s e p ar at el y  c at e g ori zi n g  ar ms  a n d  l e gs.  
M e as ur e m e nt s h all b e p erf or m e d o nl y o n l e gs i n t his cli ni c al st u d y. T h e m e as ur e m e nt d a y s h all 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 8 0
8 0  / 8 1
8 1  
 
 
b e at Visit 2 ( D a y 0), Visit 4 ( D a y 9 0), Visit 6 ( D a y 1 8 0), a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) 
( m e asur e m e nt s h all b e p erf or m e d pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0] a n d Visit 4 [ D a y 9 0]).  
S e e “ A p p e n di x 5. O N L S L e g s c al e” f or d et ails.  
 
• 
1 0 M W T  
T his is a t est t h at m e as ur es t h e ti m e r e q uir e d f or a s u bj e ct t o w al k 1 0 m et er s. [7 0 ] A s u bj e ct s h all 
b e m a d e t o w al k at a d esir e d s p e e d w hil e w e ari n g s h o es. T h e s u bj e ct s h all b e all o w e d t o us e a n 
assisti v e d e vi c e t h at t h e s u bj e ct n or m all y us es, if a n y. T h e s u bj e ct s h all b e m a d e t o w al k a c orri d or 
t h at is 1 4 m et er s l o n g, a n d t h e ti m e t a k e n t o w al k 1 0 m et er s s h all b e m e as ur e d wit h a st o p w at c h 
pr o vi d e d b y t h e s p o ns or (ti m e t a k e n t o p ass 1 0 m et er s e x cl u di n g 2 m et er s e a c h f or t h e st arti n g 
a n d e n di n g p orti o ns). T h e ass ess m e nt d a y s h all b e at Visit 2 ( D a y 0), Visit 4 ( D a y 9 0), Visit 6 ( D a y 
1 8 0),  a n d  Visit  7  (t er mi n ati o n  visit,  D a y  2 7 0)  ( ass ess m e nt  s h all  b e  p erf or m e d  pri or  t o  
a d mi nistr ati o n at Visit 2 [ D a y 0] a n d Visit 4 [ D a y 9 0]).  
T h e st arti n g p oi nt at 2 m et er s, t h e p oi nt f or e n di n g m e as ur e m e nt at 1 2 m et er s, a n d t h e p oi nt 
f or e n d of w al ki n g at 1 4 m et er s s h all b e m ar k e d i n a d v a n c e al o n g t h e c orri d or.  
S e e “ A p p e n di x 6. 1 0 M W T ( 1 0 -m et er w al k t est)” f or d et ails.  
 
• 
El e ctr o n e ur o gr a p h y ( C M A P, S N A P, N C V)  
T h e t est d a ys s h all b e at Visit 2 ( D a y 0) a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) (s h all b e p erf or m e d 
pri or t o a d mi nistr ati o n a t Visit 2 [ D a y 0]). 
S e e “ A p p e n di x 7. N er v e C o n d u cti o n St u d y ( N C S)” f or d et ails.  
 
6. 1. 2. 2  A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct ( b a s eli n e, D a y 0)  
T h e i n v esti g at or s h all a d mi nist er t h e i n v esti g ati o n al pr o d u ct ( V M 2 0 2) o n t h e f oll o wi n g 
sit es of a s u bj e ct’s b ot h l o w er li m bs. T h e n u m b er of i nj e cti o ns d e p e n di n g o n t h e 
a d mi nistr ati o n sit e of V M 2 0 2 s h all b e 5 6 i ntr a m us c ul ar i nj e cti o ns i n t ot al wit h 2 8 
i nj e cti o ns f or 3 sit es o n t h e l eft a n d ri g ht l o w er li m bs, r es p e cti v el y. S e e “ A p p e n di x 3. 
A d mi nistr ati o n  M et h o d of I n v esti g ati o n al Pr o d u ct” f or d et ails.  
• 
P er o n e us l o n g us m us cl e – 6 i nj e cti o ns f or l eft p er o n e us l o n g us m us cl e a n d 6 
i nj e cti o ns f or t h e ri g ht p er o n e us l o n g us m us cl e 
• 
G astr o c n e mi us m us cl e – 1 2 i nj e cti o ns f or t h e l eft g astr o c n e mi us m us cl e a n d 1 2 
inj e cti o ns f or t h e ri g ht g astr o c n e mi us m us cl e  
• 
Ti bi alis a nt eri or m us cl e – 1 0 i nj e cti o ns f or t h e l eft ti bi alis a nt eri or m us cl e a n d 1 0 
i nj e cti o ns f or t h e ri g ht ti bi alis a nt eri or m us cl e 
 
6. 1. 2. 3  Aft er A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct ( b a s eli n e, D a y 0 ) 
T h e f oll o wi n g s h all b e p erf or m e d aft er a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct.  
• 
Vit al si g ns  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 8 1
8 1  / 8 2
8 2  
 
 
Vit al  si g ns  i n cl u di n g  bl o o d  pr ess ur e  ( m e as ur e m e nt  s h all  b e  t a k e n  wit h  t h e  s u bj e ct  i n  a  
sitti n g  p ositi o n  aft er  r esti n g  f or  at  l e ast  1 0  mi n ut es  pri or  t o  m e as ur e m e nt), t e m p er at ur e,  
h e art r at e p er mi n ut e, a n d r es pir at or y r at e p er mi n ut e s h all b e m e as ur e d. T h e m e as ur e m e nt 
r es ults s h all b e r e c or d e d i n t h e s u bj e cts’ c as e r e p ort f or ms. T his s h all b e p erf or m e d at Visit 
1 (s cr e e ni n g) a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a s u bj e ct m a k es a visit ( o n t h e 
dr u g a d mi nistr ati o n d a ys c o nsisti n g of Visits 2, 3, 4, a n d 5, it s h all b e p erf or m e d b ot h pri or 
t o a d mi nistr ati o n a n d 2 ± 1 h o ur s aft er a d mi nistr ati o n). H o w e v er, if t h er e is a s u bj e ct wit h 
a b n or m al fi n di n gs i n t h e t est at Visit 3 ( D a y 1 4), a f oll o w-u p t est m a y b e p erf or m e d at D a y 
3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
 
• 
A d v ers e e v e nt ass ess m e nt  
L o c ali z e d a d v ers e e v e nts s h all b e c h e c k e d at 2 ± 1 h o urs aft er a d mi nist eri n g t h e i n v esti g ati o n al 
pr o d u ct a n d o n t h e d a y aft er a d mi nistr ati o n.  
 
• 
S c h e d ul e d M RI a n d el e ctr o n e ur o gr a p h y  
T his s h all b e s c h e d ul e d t o b e p erf or m e d o n t h e s a m e d a y as Visit 7 ( D a y 2 7 0) pri or t o dis c h ar g e. 
 
6. 1. 3  
Vi sit 3 ( S e c o n d A d mi ni str ati o n, D a y 1 4 ± 5)  
 
6. 1. 3. 1  B ef or e A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct  
T h e f oll o wi n g s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct.  
• 
A d v er s e e v e nt a s s e s s m e nt  
I nf or m ati o n o n n e wl y d e v el o p e d or w or s e n e d a d v ers e e v e nts, or a d v ers e e v e nts t h at 
dis a p p e ar e d si n c e t h e l ast visit s h all b e c oll e ct e d.  
 
• 
B o d y m e as ur e m e nt ( w ei g ht m e as ur e m e nt)  
A s u bj e ct’s w ei g ht s h all b e m e as ur e d at Visit 1 a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a 
s u bj e ct m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at 
Visits 2, 3, 4, a n d 5).  
 
• 
C o m pl et e bl o o d c ell c o u nt  
T his  s h all b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est  at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. T h e c o m pl et e bl o o d c ell 
c o u nt it e ms ar e as f oll o w s:  
 
W B C, R B C, H b, H ct, M C V, M C H, M C H C, P L T, E S R, M P V, diff er e nti al c o u nt of W B C ( B a n d n e utr o p hil, 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 8 2
8 2  / 8 3
8 3  
 
 
S e g m e nt e d n e utr o p hil, E osi n o p hil, B as o p hil, L y m p h o c yt e, M o n o c yt e)  
 
• 
G e n er al bl o o d c h e mi str y t e st  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. Si n c e a bl o o d gl u c os e 
t est  is  i n cl u d e d,  t h e  s u bj e ct  s h all  m ai nt ai n  a n  8-h o ur  f asti n g  st at e  pri or  t o  t h e  t est.  T h e  
g e n er al bl o o d c h e mistr y t est it e ms ar e as f oll o ws:  
 
t ot al pr ot ei n, al b u mi n, gl o b uli n, A/ G r ati o, c h ol est er ol, t ot al bilir u bi n, A S T, A L T, f asti n g gl u c os e, 
B U N, cr e ati ni n e, esti m at e d G F R, C a 2 + , p h os p h at e, N a+ , K+ , Cl-, C R P, tri gl y c eri d e, H D L - c h ol est er ol, 
L D L- c h ol est er ol  
 
• 
Uri n al y si s wit h mi cr o s c o p y  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), uri n al ysis wit h mi cr os c o p y m a y b e p erf or m e d at D a y 3 0 d e p e n di n g o n t h e d e cisi o n 
of t h e pri n ci p al i n v esti g at or.  
T h e uri n al ysis it e ms ar e as f oll o ws:  
 
C ol or, t ur bi dit y,  s p e cifi c  gr a vit y,  p H,  al b u mi n,  gl u c os e, k et o n e s,  biliru bi n, bl o o d, ur o bili n o g e n, 
nitrit e, l e u k o c yt e  est er as e, mi cr os c o p y ( R B C, W B C, c asts)  
 
• 
Vit al si g ns  
Vit al  si g ns  i n cl u di n g  bl o o d  pr ess ur e  ( m e as ur e m e nt  s h all  b e  t a k e n  wit h  t h e  s u bj e ct  i n  a  
sitti n g  p ositi o n  aft er  r esti n g  f or  at  l e ast  1 0  mi n ut es  pri or  t o  m e as ur e m e nt), t e m p er at ur e,  
h e art r at e p er mi n ut e, a n d r es pir at or y r at e p er mi n ut e s h all b e m e as ur e d. T h e m e as ur e m e nt 
r es ults s h all b e r e c or d e d i n t h e s u bj e cts’ c as e r e p ort f or ms. T his s h all b e p erf or m e d at Visit 
1 (s cr e e ni n g) a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a s u bj e ct m a k es a visit ( o n t h e 
dr u g a d mi nistr ati o n d a ys c o nsisti n g of Visits 2, 3, 4, a n d 5, it s h all b e p erf or m e d b ot h pri or 
t o a d mi nistr ati o n a n d 2 ± 1 h o ur s aft er a d mi nistr ati o n). H o w e v er, if t h er e is a s u bj e ct wit h 
a b n or m al fi n di n gs i n t h e t est at Visit 3 ( D a y 1 4), a f oll o w-u p t est m a y b e p erf or m e d at D a y 
3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
 
• 
C o n c o mit a nt m e di c ati o n s s ur v e y  
T h e br a n d n a m es a n d i n gr e di e nt n a m es of c o n c o mit a nt m e di c ati o ns s h all b e s ur v e y e d at e v er y 
visit a n d r e c or d e d i n t h e c as e r e p ort f or m. All m e di c ati o ns a n d tr e at m e nts a d mi nist er e d wit hi n 
6  m o nt hs  b ef or e  Visit  1  (s cr e e ni n g)  s h all  b e  s ur v e y e d.  Pr e vi o us  m e di c a ti o ns  a n d  pr e vi o us  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 8 4
8 4  / 8 5
8 5  
 
 
t h e fir st s e ns ati o n l ost i n p eri p h er al n er v e dis or d er s. 
 
6. 1. 3. 2  A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct  
T h e i n v esti g at or s h all a d mi nist er t h e i n v esti g ati o n al pr o d u ct ( V M 2 0 2) o n t h e f oll o wi n g 
sit es of a s u bj e ct’s b ot h l o w er li m bs. T h e n u m b er of i nj e cti o ns d e p e n di n g o n t h e 
a d mi nistr ati o n sit e of V M 2 0 2 s h all b e 5 6 i ntr a m us c ul ar i nj e cti o ns i n t ot al wit h 2 8 
i nj e cti o ns f or 3 sit es o n t h e l eft a n d ri g ht l o w er li m bs, r es p e cti v el y. S e e “ A p p e n di x 3. 
A d mi nistr ati o n M et h o d of I n v esti g ati o n al Pr o d u ct” f or d et ails.  
• 
P er o n e us l o n g us m us cl e – 6 i nj e cti o ns f or l eft p er o n e us l o n g us m u s cl e a n d 6 
i nj e cti o ns f or t h e ri g ht p er o n e us l o n g us m us cl e 
• 
G astr o c n e mi us m us cl e – 1 2 i nj e cti o ns f or t h e l eft g astr o c n e mi us m us cl e a n d 1 2 
i nj e cti o ns f or t h e ri g ht g astr o c n e mi us m us cl e 
• 
Ti bi alis a nt eri or m us cl e – 1 0 i nj e cti o ns f or t h e l eft ti bi alis a nt eri or m us cl e a n d 1 0 
i nj e cti o ns f or t h e ri g ht ti bi alis a nt eri or m us cl e 
 
6. 1. 3. 3  Aft er A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct  
T h e f oll o wi n g s h all b e p erf or m e d aft er a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct.  
• 
Vit al si g ns  
Vit al si g ns i n cl u di n g bl o o d pr ess ur e ( m e as ur e m e nt s h all b e t a k e n wit h t h e s u bj e ct i n a sitti n g 
p ositi o n aft er r esti n g f or at l e ast 1 0 mi n ut es pri or t o m e as ur e m e nt), t e m p er at ur e, h e art r at e 
p er  mi n ut e,  a n d  r es pir at or y  r at e  p er  mi n ut e  s h all  b e  m e as ur e d.  T h e  m e as ur e m e nt  r es ult s  
s h all  b e  r e c or d e d  i n  t h e  s u bj e cts’  c as e  r e p ort  f or ms.  T his  s h all  b e  p erf or m e d  at  Visit  1  
(s cr e e ni n g) a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a s u bj e ct m a k es a visit ( o n t h e dr u g 
a d mi nistr ati o n d a ys  c o nsisti n g of  Visits  2, 3, 4, a n d 5, it s h all b e p erf or m e d b o t h pri or  t o 
a d mi nistr ati o n  a n d  2  ±  1  h o ur s  aft er  a d mi nistr ati o n).  H o w e v er,  if  t h er e  is  a  s u bj e ct  wit h  
a b n or m al fi n di n gs i n t h e t est at Visit 3 ( D a y 1 4), a f oll o w -u p t est m a y b e p erf or m e d at D a y 
3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
 
• 
A d v er s e e v e nt a s s e s s m e nt  
L o c ali z e d a d v er s e e v e nts s h all b e c h e c k e d at 2 ± 1 h o ur s aft er a d mi nist eri n g t h e 
i n v esti g ati o n al pr o d u ct a n d o n t h e d a y aft er a d mi nistr ati o n.  
 
6. 1. 4  
D a y 3 0 ± 7 ( s h all b e p erf or m e d o nl y if f oll o w -u p t e sti n g i s r e q uir e d)  
T his s h all b e p erf or m e d o nl y f or s u bj e cts w h o ar e d et er mi n e d b y t h e pri n ci p al 
i n v esti g at or t o t a k e s h ort-t er m f oll o w-u p t esti n g d u e t o a b n or m al fi n di n gs i n t h e 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 8 5
8 5  / 8 6
8 6  
 
 
h e m at ol o g y t est at Visit 2 ( D a y 1 4).  
• 
A d v er s e e v e nt a s s e s s m e nt  
I nf or m ati o n o n n e wl y d e v el o p e d or w or s e n e d a d v ers e e v e nts, or a d v ers e e v e nts t h at 
dis a p p e ar e d si n c e t h e l ast visit s h all b e c oll e ct e d.  
 
• 
B o d y m e as ur e m e nt ( w ei g ht m e as ur e m e nt)  
A s u bj e ct’s w ei g ht s h all b e m e as ur e d at Visit 1 a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a 
s u bj e ct m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at 
Visits 2, 3, 4, a n d 5).  
 
• 
C o m pl et e bl o o d c ell c o u nt  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. T h e c o m pl et e bl o o d c ell 
c o u nt it e ms ar e as f oll o w s:  
 
W B C, R B C, H b, H ct, M C V, M C H, M C H C, P L T, E S R, M P V, diff er e nti al c o u nt of W B C ( B a n d n e utr o p hil, 
S e g m e nt e d n e utr o p hil, E osi n o p hil, B as o p hil, L y m p h o c yt e, M o n o c yt e)  
 
• 
G e n er al bl o o d c h e mi str y t e st  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct 
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a nd a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. Si n c e a bl o o d gl u c os e 
t est  is  i n cl u d e d,  t h e  s u bj e ct  s h all  m ai nt ai n  a n  8-h o ur  f asti n g  st at e  pri or  t o  t h e  t est.  T h e  
g e n er al bl o o d c h e mistr y t est it e ms ar e as f oll o ws:  
 
t ot al pr ot ei n, al b u mi n, gl o b uli n, A/ G r ati o, c h ol est er ol, t ot al bilir u bi n, A S T, A L T, f asti n g gl u c os e, 
B U N, cr e ati ni n e, esti m at e d G F R, C a 2 + , p h os p h at e, N a+ , K+ , Cl-, C R P, tri gl y c eri d e, H D L-c h ol est er ol, 
L D L- c h ol est er ol    
 
• 
Uri n al y si s wit h mi cr o s c o p y  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u b j e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), uri n al ysis wit h mi cr os c o p y m a y b e p erf or m e d at D a y 3 0 d e p e n di n g o n t h e d e cisi o n 
of t h e pri n ci p al i n v esti g at or.  
T h e uri n al ysis it e ms ar e as f oll o ws:  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 8 7
8 7  / 8 8
8 8  
 
 
( C 8-T 1, ul n ar n er v e), a n d o p p ositi o n of t h u m b ( C 8 -T 1, m e di a n n er v e) s h all b e 
t est e d i n t h e u p p er li m bs. F or t h e str e n gt h of i ntri nsi c h a n d m us cl es, o nl y t h e 
t w o  m us cl es  of  t h e  a b d u ct or  p olli cis  br e vis  ( A P B)  a n d  t h e  fir st  d or s al  
i nt er oss e o us  ( F DI)  s h all  b e  e v al u at e d,  a n d  t h e  str o n g er  of  t h e  t w o  s h all  b e  
s c or e d. 
I n t h e l o w er li m bs, t h e fl e xi o n ( L 2-L 4), a d d u cti o n ( L 2 -L 4), a n d e xt e nsi o n ( S 1) of 
hi p  j oi nt,  t h e  e xt e nsi o n  ( L 2 -L 4)  a n d  fl e xi o n  ( L 4 -S 2)  of  k n e e,  as  w ell  as  t h e  
d or sifl e xi o n ( L 4 -5)  a n d pl a nt ar fl e xi o n ( S 1) of a n kl e s h all b e t est e d.  
 
T h e r es ults of p erf or mi n g a m us cl e str e n gt h t est of t h e li m bs i n a s u bj e ct s h all 
b e i n di c at e d usi n g t h e M e di c al R es e ar c h C o u n cil ( M R C) gr a d e*.  
* M R C gr a d e ( M ot or p o w er) 
0: C o m pl et e p ar al ysis  
I: Fli c k er of c o ntr a cti o n p ossi bl e  
II: M o v e m e nt p ossi bl e if gr a vit y eli mi n at e d 
III: M o v e m e nt a g ai nst gr a vit y b ut n ot r esist a n c e  
I V: M o v e m e nt p ossi bl e a g ai nst s o m e r esist a n c e  
V: P o w er n or m al (it is n ot n or m all y p ossi bl e t o o v erc o m e a n or m al a d ult’s p o w er)  
N o ci c e pti o n  
Sti m ul ati o n s h all b e a p pli e d b y alt er n at el y usi n g t o ols wit h a d ull e n d a n d a 
s h ar p e n d, a n d it s h all b e v erifi e d w h et h er t h es e c a n b e disti n g uis h e d. W h e n 
c o m p ari n g t h e l eft a n d ri g ht si d es of t h e b o d y, sti m ul ati o n s h all b e a p pli e d t o 
t h e s a m e sit es. T h e n, t h e s u bj e ct s h all b e as k e d w h et h er t h e s e ns ati o ns ar e t h e 
s a m e. 
P all est h esi a  
Vi br ati o n s h all b e a p pli e d t o a l o w -pit c h e d t u ni n g f or k ( a R y d el -S eiff er  t u ni n g 
f or k s h all b e us e d), a n d t his s h all b e pl a c e d o n t h e dist al j oi nts of t h e h a n ds 
a n d f e et t o v erif y t h at t h e s u bj e ct f e els t h e vi br ati n g s e ns ati o n. P all est h esi a is 
t h e fir st s e ns ati o n l ost i n p eri p h er al n er v e dis or d er s. 
 
6. 1. 5  
Vi sit 4 ( T hir d A d mi ni str ati o n, D a y 9 0 ± 7)  
 
6. 1. 5. 1  B ef or e A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct  
T h e f oll o wi n g s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct.  
• 
A d v er s e e v e nt a s s e s s m e nt  
I nf or m ati o n o n n e wl y d e v el o p e d or w or s e n e d a d v ers e e v e nts, or a d v ers e e v e nts t h at 
dis a p p e ar e d si n c e t h e l ast visit s h all b e c oll e ct e d.  
 
• 
B o d y m e as ur e m e nt ( w ei g ht m e as ur e m e nt)  
A s u bj e ct’s w ei g ht s h all b e m e as ur e d at Visit 1 a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a 
s u bj e ct m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at 
Visits 2, 3, 4, a n d 5).  
 
• 
C o m pl et e bl o o d c ell c o u nt  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 8 8
8 8  / 8 9
8 9  
 
 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
T h e c o m pl et e bl o o d c ell c o u nt it e ms ar e as f oll o ws:  
 
W B C, R B C, H b, H ct, M C V, M C H, M C H C, P L T, E S R, M P V, diff er e nti al c o u nt of W B C ( B a n d n e utr o p hil, 
S e g m e nt e d n e utr o p hil, E osi n o p hil, B as o p hil, L y m p h o c yt e, M o n o c yt e)  
 
• 
G e n er al bl o o d c h e mi str y t e st  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct 
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h emistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. Si n c e a bl o o d gl u c os e 
t est is i n cl u d e d, t h e s u bj e ct s h all m ai nt ai n a n 8-h o ur f asti n g st at e pri or t o t h e t est.  
T h e g e n er al bl o o d c h e mistr y t est it e ms ar e as f ol l o ws:  
 
t ot al pr ot ei n, al b u mi n, gl o b uli n, A/ G r ati o, c h ol est er ol, t ot al bilir u bi n, A S T, A L T, f asti n g gl u c os e, 
B U N, cr e ati ni n e, esti m at e d G F R, C a 2 + , p h os p h at e, N a+ , K+ , Cl-, C R P, tri gl y c eri d e, H D L-c h ol est er ol, 
L D L- c h ol est er ol    
 
• 
S a m pl e c oll e cti o n f or r etr o s p e cti v e bi o m ar k er st u d y    
T h e s er u m of s u bj e cts s h all b e c oll e ct e d a n d st or e d fr o z e n at -7 0° C. All bl o o d s a m pl es ar e st or e d 
wit h u ni q u e n u m b er s f or r etr os p e cti v e bi o m ar k er st u d y aft er all p er s o n al i nf or m ati o n is d el et e d.  
 
• 
Uri n al y si s wit h mi cr o s c o p y  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u b j e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), uri n al ysis m a y b e p erf or m e d at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al 
i n v esti g at or. 
T h e uri n al ysis it e ms ar e as f oll o ws:   
 
C ol or, t ur bi dit y,  s p e cifi c  gr a vit y,  p H,  al b u mi n,  gl u c os e,  k et o n e s,  bilir u bi n,  bl o o d, ur o bili n o g e n, 
nitrit e, l e u k o c yt e  est er as e, mi cr os c o p y ( R B C, W B C, c asts)  
 
• 
Vit al si g ns  
Vit al si g ns i n cl u di n g bl o o d pr ess ur e ( m e as ur e m e nt s h all b e t a k e n wit h t h e s u bj e ct i n a sitti n g 
p ositi o n aft er r esti n g f or at l e ast 1 0  mi n ut es pri or t o m e as ur e m e nt), t e m p er at ur e, h e art r at e 
p er  mi n ut e,  a n d  r es pir at or y  r at e  p er  mi n ut e  s h all  b e  m e as ur e d.  T h e  m e as ur e m e nt  r es ult s  
s h all  b e  r e c or d e d  i n  t h e  s u bj e cts’  c as e  r e p ort  f or ms.  T his  s h all  b e  p erf or m e d  at  Visit  1  
(s cr e e ni n g) a n d t hr o u g h out t h e cli ni c al st u d y e v er y ti m e a s u bj e ct m a k es a visit ( o n t h e dr u g 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 8 9
8 9  / 9 0
9 0  
 
 
a d mi nistr ati o n d a ys  c o nsisti n g of  Visits  2, 3, 4, a n d 5,  it s h all  b e p erf or m e d b ot h pri or  t o 
a d mi nistr ati o n  a n d  2  ±  1  h o ur s  aft er  a d mi nistr ati o n).  H o w e v er,  if  t h er e  is  a  s u bj e ct  wit h  
a b n or m al fi n di n gs i n t h e t est at Visit 3 ( D a y 1 4), a f oll o w -u p t est m a y b e p erf or m e d at D a y 
3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
 
• 
C o n c o mit a nt m e di c ati o n s s ur v e y  
T h e br a n d n a m es a n d i n gr e di e nt n a m es of c o n c o mit a nt m e di c ati o ns s h all b e s ur v e y e d at e v er y 
visit a n d r e c or d e d i n t h e c as e r e p ort f or m. All m e di c ati o ns a n d tr e at m e nts a d mi nist er e d wit hi n 
6  m o nt hs  b ef or e  Visit  1  (s cr e e ni n g)  s h all  b e  s ur v e y e d.  Pr e vi o us  m e di c a ti o ns  a n d  pr e vi o us  
tr e at m e nts s h all b e d efi n e d as all pr e vi o usl y c oll e ct e d m e di c ati o ns a n d tr e at m e nts b ef or e Visit 
2 (fir st a d mi nistr ati o n of i n v esti g ati o n al pr o d u ct). C o n c o mit a nt m e di c ati o ns a n d tr e at m e nts s h all 
r ef er  t o  all m e di c ati o ns  t h at  h a v e  b e e n  a d mi nist er e d  at  l e ast  o n c e  st arti n g  fr o m  Visit  2  (fir st 
a d mi nistr ati o n of i n v esti g ati o n al pr o d u ct) a n d t hr o u g h o ut t h e cli ni c al st u d y. T h e c at e g ori es of 
c oll e ct e d  m e di c ati o ns  a n d  tr e at m e nts  s h all  f oll o w  t his  d efi niti o n.  T h e  f oll o wi n g  s h all  als o  b e  
s ur v e y e d f or  e a c h m e di c ati o n:  
• 
Br a n d n a m e  
• 
I n di c ati o ns f or m e di c ati o n a d mi nistr ati o n (r e as o n f or a d mi nistr ati o n) 
• 
D os e/str e n gt h, a d mi nistr ati o n r o ut e, n u m b er of a d mi nistr ati o ns  
• 
St art a n d dis c o nti n u ati o n d at es of a d mi nistr ati o n ( w h et h er t o c o nti n u e w h e n t h e 
cli ni c al st u d y is t er mi n at e d)  
 
• 
F D S  
T h e  f u n cti o n al  dis a bilit y  s c al e  ( F D S)  ass ess es  a  p ati e nt  fr o m  0  t o  8  p oi nts  as  s h o w n  b el o w  
d e p e n di n g o n t h e p ati e nt’s m o bilit y.[ 6 8 ] T h e ass ess m e nt d a ys s h all b e at Visit 2 ( D a y 0), Visit 4 
( D a y 9 0), Visit 6 ( D a y 1 8 0), a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) ( ass ess m e nt s h all b e p erf or m e d 
pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0] a n d Visit 4 [ D a y 9 0]).  
0 = n or m al;  
1 = cr a m ps a n d f ati g a bilit y;  
2 =i n a bilit y t o r u n;  
3 = p ossi bl e u n ai d e d;  
4 = wit h c a n e;  
5 = wit h cr ut c h;  
6 = wit h w al k er;  
7 = w h e el c h air;  
8 = b e dri d d e n.  
 
• 
O N L S l e g s c al e  
T h e o v er all n e ur o p at h y li mit ati o n s c al e ( O N L S) is a t o ol f or m e as uri n g t h e a cti vit y l e v el of p ati e nts 
wit h  p eri p h er al  n e ur o p at h y.[ 6 9 ]  It  is  s c or e d  b y  s e p ar at el y  c at e g ori zi n g  ar ms  a n d  l e gs.  
M e as ur e m e nt s h all b e p erf or m e d o nl y o n l e gs i n t his cli ni c al st u d y. T h e m e as ur e m e nt d a y s h all 
b e at Visit 2 ( D a y 0), Visit 4 ( D a y 9 0), Visit 6 ( D a y 1 8 0), a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 9 1
9 1  / 9 2
9 2  
 
 
c o m p ari n g t h e l eft a n d ri g ht si d es of t h e b o d y, sti m ul ati o n s h all b e a p pli e d t o 
t h e s a m e sit es. T h e n, t h e s u bj e ct s h all b e as k e d w h et h er t h e s e ns ati o ns ar e t h e 
s a m e. 
P all est h esi a  
Vi br ati o n s h all b e a p pli e d t o a l o w -pit c h e d t u ni n g f or k ( a R y d el -S eiff er  t u ni n g 
f or k s h all b e us e d), a n d t his s h all b e pl a c e d o n t h e dist al j oi nts of t h e h a n ds 
a n d f e et t o v erif y t h at t h e s u bj e ct f e els t h e vi br ati n g s e ns ati o n. P all est h esi a is 
t h e fir st s e ns ati o n l ost i n p eri p h er al n er v e dis or d er s. 
 
6. 1. 5. 2  A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct  
T h e i n v esti g at or s h all a d mi nist er t h e i n v esti g ati o n al pr o d u ct ( V M 2 0 2) o n t h e f oll o wi n g 
sit es of a s u bj e ct’s b ot h l o w er li m bs. T h e n u m b er of i nj e cti o ns d e p e n di n g o n t h e 
a d mi nistr ati o n sit e of V M 2 0 2 s h all b e 5 6 i ntr a m us c ul ar i nj e cti o ns i n t ot al wit h 2 8 
i nj e cti o ns f or 3 sit es o n t h e l eft a n d ri g ht l o w er li m bs, r es p e cti v el y. S e e “ A p p e n di x 3. 
A d mi nistr ati o n M et h o d of I n v esti g ati o n al Pr o d u ct” f or d et ails.  
• 
P er o n e us l o n g us m us cl e – 6 i nj e cti o ns f or l eft p er o n e us l o n g us m us cl e a n d 6 
i nj e cti o ns f or t h e ri g ht p er o n e us l o n g us m us cl e 
• 
G astr o c n e mi us m us cl e – 1 2 i nj e cti o ns f or t h e l eft g astr o c n e mi us m us cl e a n d 1 2 
i nj e cti o ns f or t h e ri g ht g astr o c n e mi us m us cl e 
• 
Ti bi alis a nt eri or m us cl e – 1 0 i nj e cti o ns f or t h e l eft ti bi alis a nt eri or m us cl e a n d 1 0 
i nj e cti o ns f or t h e ri g ht ti bi alis a nt eri or m us cl e 
 
6. 1. 5. 3  Aft er A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct  
T h e f oll o wi n g s h all b e p erf or m e d aft er a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct.  
• 
Vit al si g ns  
Vit al si g ns i n cl u di n g bl o o d pr ess ur e ( m e as ur e m e nt s h all b e t a k e n wit h t h e s u bj e ct i n a sitti n g 
p ositi o n aft er r esti n g f or at l e ast 1 0 mi n ut es pri or t o m e as ur e m e nt), t e m p er at ur e, h e art r at e 
p er  mi n ut e,  a n d  r es pir at or y  r at e  p er  mi n ut e  s h all  b e  m e as ur e d.  T h e  m e as ur e m e nt  r es ult s 
s h all  b e  r e c or d e d  i n  t h e  s u bj e cts’  c as e  r e p ort  f or ms.  T his  s h all  b e  p erf or m e d  at  Visit  1  
(s cr e e ni n g) a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a s u bj e ct m a k es a visit ( o n t h e dr u g 
a d mi nistr ati o n d a ys  c o nsisti n g of  Visits  2, 3, 4, a n d 5,  it s h all  b e p erf or m e d b ot h pri or  t o 
a d mi nistr ati o n  a n d  2  ±  1  h o ur s  aft er  a d mi nistr ati o n).  H o w e v er,  if  t h er e  is  a  s u bj e ct  wit h  
a b n or m al fi n di n gs i n t h e t est at Visit 3 ( D a y 1 4), a f oll o w -u p t est m a y b e p erf or m e d at D a y 
3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. 
 
• 
A d v er s e e v e nt a s s e s s m e nt  
L o c ali z e d a d v er s e e v e nts s h all b e c h e c k e d at 2 ± 1 h o ur s aft er a d mi nist eri n g t h e 
i n v esti g ati o n al pr o d u ct a n d o n t h e d a y aft er a d mi nistr ati o n.  
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 9 2
9 2  / 9 3
9 3  
 
 
6. 1. 6  
Vi sit 5 ( F o urt h A d mi ni str ati o n, D a y 1 0 4 ± 7)  
 
6. 1. 6. 1  B ef or e A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct  
T h e f oll o wi n g s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct.  
• 
A d v er s e e v e nt a s s e s s m e nt  
I nf or m ati o n o n n e wl y d e v el o p e d or w or s e n e d a d v ers e e v e nts, or a d v ers e e v e nts t h at 
dis a p p e ar e d si n c e t h e l ast visit s h all b e c oll e ct e d.  
 
• 
B o d y m e as ur e m e nt ( w ei g ht m e as ur e m e nt)  
A s u bj e ct’s w ei g ht s h all b e m e as ur e d at Visit 1 a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a 
s u bj e ct m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at 
Visits 2, 3, 4, a n d 5).  
 
• 
C o m pl et e bl o o d c ell c o u nt  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
T h e c o m pl et e bl o o d c ell c o u nt it e ms ar e as f oll o ws:  
 
W B C, R B C, H b, H ct, M C V, M C H, M C H C, P L T, E S R, M P V, diff er e nti al c o u nt of W B C ( B a n d n e utr o p hil, 
S e g m e nt e d n e utr o p hil, E osi n o p hil, B as o p hil, L y m p h o c yt e, M o n o c yt e)  
 
• 
G e n er al bl o o d c h e mi str y t e st  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct 
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h emistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. Si n c e a bl o o d gl u c os e 
t est is i n cl u d e d, t h e s u bj e ct s h all m ai nt ai n a n 8-h o ur f asti n g st at e pri or t o t h e t est.  
T h e g e n er al bl o o d c h e mistr y t est it e ms ar e as f ol l o ws: 
 
t ot al pr ot ei n, al b u mi n, gl o b uli n, A/ G r ati o, c h ol est er ol, t ot al bilir u bi n, A S T, A L T, f asti n g gl u c os e, 
B U N, cr e ati ni n e, esti m at e d G F R, C a 2 + , p h os p h at e, N a+ , K+ , Cl-, C R P, tri gl y c eri d e, H D L-c h ol est er ol, 
L D L- c h ol est er ol    
 
• 
Uri n al y si s wit h mi cr o s c o p y  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 9 4
9 4  / 9 5
9 5  
 
 
str e n gt h 
str e n gt h is r ef err e d t o as p ar al ysis.  
T o m e as ur e t h e m us cl e str e n gt h of li m bs, t h e fl e xi o n ( C 5 -6) a n d e xt e nsi o n of 
wrist j oi nt, e xt e nsi o n of wrist ( C 6 -8), gr as pi n g t est ( C 7 -T 1), a b d u cti o n of fi n g er 
( C 8-T 1, ul n ar n er v e), a n d o p p ositi o n of t h u m b ( C 8 -T 1, m e di a n n er v e) s h all b e 
t est e d i n t h e u p p er li m bs. F or t h e str e n gt h of i ntri nsi c h a n d m us cl es, o nl y t h e 
t w o m us cl es  of  t h e  a b d u ct or  p olli cis  br e vis  ( A P B)  a n d  t h e  fir st  d or s al  
i nt er oss e o us  ( F DI)  s h all  b e  e v al u at e d,  a n d  t h e  str o n g er  of  t h e  t w o  s h all  b e  
s c or e d. 
I n t h e l o w er li m bs, t h e fl e xi o n ( L 2-L 4), a d d u cti o n ( L 2 -L 4), a n d e xt e nsi o n ( S 1) of 
hi p  j oi nt,  t h e  e xt e nsi o n  ( L 2 -L 4)  a n d  fl e xi o n  ( L 4 -S 2)  of  k n e e,  as  w ell  as  t h e  
d or sifl e xi o n ( L 4 -5) a n d pl a nt ar fl e xi o n ( S 1) of a n kl e s h all b e t est e d.  
 
T h e r es ults of p erf or mi n g a m us cl e str e n gt h t est of t h e li m bs i n a s u bj e ct s h all 
b e i n di c at e d usi n g t h e M e di c al R es e ar c h C o u n cil ( M R C) gr a d e*.  
* M R C gr a d e ( M ot or p o w er) 
0: C o m pl et e p ar al ysis  
I: Fli c k er of c o ntr a cti o n p ossi bl e 
II: M o v e m e nt p ossi bl e if gr a vit y eli mi n at e d 
III: M o v e m e nt a g ai nst gr a vit y b ut n ot r esist a n c e  
I V: M o v e m e nt p ossi bl e a g ai nst s o m e r esist a n c e  
V: P o w er n or m al (it is n ot n or m all y p ossi bl e t o o v erc o m e a n or m al a d ult’s p o w er)  
N o ci c e pti o n  
Sti m ul ati o n s h all b e a p pli e d b y alt er n at el y usi n g t o ols wit h a d ull e n d a n d a 
s h ar p e n d, a n d it s h all b e v erifi e d w h et h er t h es e c a n b e disti n g uis h e d. W h e n 
c o m p ari n g t h e l eft a n d ri g ht si d es of t h e b o d y, sti m ul ati o n s h all b e a p pli e d t o 
t h e s a m e sit es. T h e n, t h e s u bj e ct s h all b e as k e d w h et h er t h e s e ns ati o ns ar e t h e 
s a m e. 
P all est h esi a  
Vi br ati o n s h all b e a p pli e d t o a l o w -pit c h e d t u ni n g f or k ( a R y d el -S eiff er t u ni n g 
f or k s h all b e us e d), a n d t his s h all b e pl a c e d o n t h e dist al j oi nts of t h e h a n ds 
a n d f e et t o v erif y t h at t h e s u bj e ct f e els t h e vi br ati n g s e ns ati o n. P all est h esi a is 
t h e fir st s e ns ati o n l ost i n p eri p h er al n er v e dis or d er s.  
 
6. 1. 6. 2  A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct  
T h e i n v esti g at or s h all a d mi nist er t h e i n v esti g ati o n al pr o d u ct ( V M 2 0 2) o n t h e f oll o wi n g 
sit es of a s u bj e ct’s b ot h l o w er li m bs. T h e n u m b er of i nj e cti o ns d e p e n di n g o n t h e 
a d mi nistr ati o n sit e of V M 2 0 2 s h all b e 5 6 i ntr a m us c ul ar i nj e cti o ns i n t ot al wit h 2 8 
i nj e cti o ns f or 3 sit es o n t h e l eft a n d ri g ht l o w er li m bs, r es p e cti v el y. S e e “ A p p e n di x 3. 
A d mi nistr ati o n M et h o d of I n v esti g ati o n al Pr o d u ct” f or d et ails.  
• 
P e r o n e us l o n g us m us cl e – 6 i nj e cti o ns f or l eft p er o n e us l o n g us m us cl e a n d 6 
i nj e cti o ns f or t h e ri g ht p er o n e us l o n g us m us cl e 
• 
G astr o c n e mi us m us cl e – 1 2 i nj e cti o ns f or t h e l eft g astr o c n e mi us m us cl e a n d 1 2 
i nj e cti o ns f or t h e ri g ht g astr o c n e mi us m us cl e 
• 
Ti bi alis a nt eri or m us cl e – 1 0 i nj e cti o ns f or t h e l eft ti bi alis a nt eri or m us cl e a n d 1 0 
i nj e cti o ns f or t h e ri g ht ti bi alis a nt eri or m us cl e 
 
6. 1. 6. 3  Aft er A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct  
T h e f oll o wi n g s h all b e p erf or m e d aft er a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct.  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 9 5
9 5  / 9 6
9 6  
 
 
• 
Vit al si g ns  
Vit al si g ns i n cl u di n g bl o o d pr ess ur e ( m e as ur e m e nt s h all b e t a k e n wit h t h e s u bj e ct i n a sitti n g 
p ositi o n aft er r esti n g f or at l e ast 1 0 mi n ut es pri or t o m e as ur e m e nt), t e m p er at ur e, h e art r at e 
p er  mi n ut e,  a n d  r es pir at or y  r at e  p er  mi n ut e  s h all  b e  m e as ur e d.  T h e  m e as ur e m e nt  r es ult s  
s h all  b e  r e c or d e d  i n  t h e  s u bj e cts’  c as e  r e p ort  f or ms.  T his  s h all  b e  p erf or m e d  at  Visit  1  
(s cr e e ni n g) a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a s u bj e ct m a k es a visit ( o n t h e dr u g 
a d mi nistr ati o n d a ys  c o nsisti n g of  Visits  2, 3, 4, a n d 5,  it s h all  b e p erf or m e d b ot h pri or  t o 
a d mi nistr ati o n  a n d  2  ±  1  h o ur s  aft er  a d mi nistr ati o n).  H o w e v er,  if  t h er e  is  a  s u bj e ct  wit h  
a b n or m al fi n di n gs i n t h e t est at Visit 3 ( D a y 1 4), a f oll o w -u p t est m a y b e p erf or m e d at D a y 
3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
 
• 
A d v er s e e v e nt a s s e s s m e nt  
L o c ali z e d a d v er s e e v e nts s h all b e c h e c k e d at 2 ± 1 h o ur s aft er a d mi nist eri n g t h e 
i n v esti g ati o n al pr o d u ct a n d o n t h e d a y aft er a d mi nistr ati o n. 
 
6. 1. 7  
Vi sit 6 (I nt eri m Vi sit, D a y 1 8 0 ± 7)  
• 
A d v er s e e v e nt a s s e s s m e nt  
I nf or m ati o n o n n e wl y d e v el o p e d or w or s e n e d a d v ers e e v e nts, or a d v ers e e v e nts t h at 
dis a p p e ar e d si n c e t h e l ast visit s h all b e c oll e ct e d.  
 
• 
C o m pl et e bl o o d c ell c o u nt  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
T h e c o m pl et e bl o o d c ell c o u nt it e ms ar e as f oll o ws:  
 
W B C, R B C, H b, H ct, M C V, M C H, M C H C, P L T, E S R, M P V, diff er e nti al c o u nt of W B C ( B a n d n e utr o p hil, 
S e g m e nt e d n e utr o p hil, E osi n o p hil, B as o p hil, L y m p h o c yt e, M o n o c yt e)  
 
• 
G e n er al bl o o d c h e mi str y t e st  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct 
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a nd a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. Si n c e a bl o o d gl u c os e 
t est is i n cl u d e d, t h e s u bj e ct s h all m ai nt ai n a n 8-h o ur f asti n g st at e pri or t o t h e t est.  
T h e g e n er al bl o o d c h e mistr y t est it e ms ar e as f oll o ws:  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 9 6
9 6  / 9 7
9 7  
 
 
 
t ot al pr ot ei n, al b u mi n, gl o b uli n, A/ G r ati o, c h ol est er ol, t ot al bilir u bi n, A S T, A L T, f asti n g gl u c os e, 
B U N, cr e ati ni n e, esti m at e d G F R, C a 2 + , p h os p h at e, N a+ , K+ , Cl-, C R P, tri gl y c eri d e, H D L-c h ol est er ol, 
L D L- c h ol est er ol    
 
• 
S a m pl e c oll e cti o n f or r etr o s p e cti v e bi o m ar k er st u d y  
T h e s er u m of s u bj e cts s h all b e c oll e ct e d a n d st or e d fr o z e n at -7 0° C. All bl o o d s a m pl es ar e st or e d 
wit h u ni q u e n u m b er s f or r etr os p e cti v e bi o m ar k er st u d y aft er all p er s o n al i nf or m ati o n i s d el et e d.  
 
• 
B o d y m e a s ur e m e nt ( w ei g ht m e a s ur e m e nt)  
A s u bj e ct’s w ei g ht s h all b e m e as ur e d at Visit 1 a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a 
s u bj e ct m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at 
Visits 2, 3, 4, a n d 5).  
 
• 
Uri n al y si s wit h mi cr o s c o p y  
T his s h al l b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t e st at Visit 3 
( D a y 1 4), uri n al ysis m a y b e p erf or m e d at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al 
i n v esti g at or. T h e uri n al ysis it e ms ar e as f oll o ws: 
 
C ol or, t ur bi dit y,  s p e cifi c  gr a vit y,  p H,  al b u mi n,  gl u c os e, k et o n e s,  bilir u bi n,  bl o o d, ur o bili n o g e n, 
nitrit e, l e u k o c yt e  est er as e, mi cr os c o p y ( R B C, W B C, c asts)  
 
• 
Vit al si g ns  
Vit al si g ns i n cl u di n g bl o o d pr ess ur e ( m e as ur e m e nt s h all b e t a k e n wit h t h e s u bj e ct i n a sitti n g 
p ositi o n aft er r esti n g f or at l e ast 1 0 mi n ut es pri or t o m e as ur e m e nt), t e m p er at ur e, h e art r at e 
p er  mi n ut e,  a n d  r es pir at or y  r at e  p er  mi n ut e  s h all  b e  m e as ur e d.  T h e  m e as ur e m e nt  r es ult s  
s h all  b e  r e c or d e d  i n  t h e  s u bj e cts’  c as e  r e p ort  f or ms.  T his  s h all  b e  p erf or m e d  at  Visit  1  
(s cr e e ni n g) a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a s u bj e ct m a k es a visit ( o n t h e dr u g 
a d mi nistr ati o n d a ys  c o nsisti n g of  Visits  2, 3, 4, a n d 5,  it s h all  b e p erf or m e d b ot h pri or  t o 
a d mi nistr ati o n  a n d  2  ±  1  h o ur s  aft er  a d mi nistr ati o n).  H o w e v er,  if  t h er e  is  a  s u bj e ct  wit h  
a b n or m al fi n di n gs i n t h e t est at Visit 3 ( D a y 1 4), a f oll o w -u p t est m a y b e p erf or m e d at D a y 
3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
 
• 
C o n c o mit a nt m e di c ati o n s s ur v e y  
T h e br a n d n a m es a n d i n gr e di e nt n a m es of c o n c o mit a nt m e di c ati o ns s h all b e s ur v e y e d at e v er y 
visit a n d r e c or d e d i n t h e c as e r e p ort f or m. All m e di c ati o ns a n d tr e at m e nts a d mi nist er e d wit hi n 
6  m o nt hs  b ef or e  Visit  1  (s cr e e ni n g)  s h all  b e  s ur v e y e d.  Pr e vi o us  m e di c a ti o ns  a n d  pr e vi o us  
tr e at m e nts s h all b e d efi n e d as all pr e vi o usl y c oll e ct e d m e di c ati o ns a n d tr e at m e nts b ef or e Visit 
2 (fir st a d mi nistr ati o n of i n v esti g ati o n al pr o d u ct). C o n c o mit a nt m e di c ati o ns a n d tr e at m e nts s h all 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 9 7
9 7  / 9 8
9 8  
 
 
r ef er  t o  all m e di c ati o ns  t h at  h a v e  b e e n  a d mi nist er e d  at  l e ast  o n c e  st arti n g  fr o m  Visit  2  (fir st 
a d mi nistr ati o n of i n v esti g ati o n al pr o d u ct) a n d t hr o u g h o ut t h e cli ni c al st u d y. T h e c at e g ori es of 
c oll e ct e d  m e di c ati o ns  a n d  tr e at m e nts  s h all  f oll o w  t his  d efi niti o n.  T h e  f oll o wi n g  s h all  als o  b e  
s ur v e y e d f or  e a c h m e di c ati o n:  
• 
Br a n d n a m e  
• 
I n di c ati o ns f or m e di c ati o n a d mi nistr ati o n (r e as o n f or a d mi nistr ati o n) 
• 
D os e/str e n gt h, a d mi nistr ati o n r o ut e, n u m b er of a d mi nistr ati o ns  
• 
St art a n d dis c o nti n u ati o n d at es of a d mi nistr ati o n ( w h et h er t o c o nti n u e w h e n t h e 
cli ni c al st u d y is t er mi n at e d)  
 
• 
F D S  
T h e  f u n cti o n al  dis a bilit y  s c al e  ( F D S)  ass ess es  a  p ati e nt  fr o m  0  t o  8  p oi nts  as  s h o w n  b el o w  
d e p e n di n g o n t h e p ati e nt’s m o bilit y.[ 6 8 ] T h e ass ess m e nt d a ys s h all b e at Visit 2 ( D a y 0), Visit 4 
( D a y 9 0), Visit 6 ( D a y 1 8 0), a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) ( ass ess m e nt s h all b e p erf or m e d 
pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0] a n d Visit 4 [ D a y 9 0]).  
0 = n or m al;  
1 = cr a m ps a n d f ati g a bilit y;  
2 =i n a bilit y t o r u n;  
3 = p ossi bl e u n ai d e d;  
4 = wit h c a n e;  
5 = wit h cr ut c h;  
6 = wit h w al k er;  
7 = w h e el c h air;  
8 = b e dri d d e n.  
 
• 
O N L S l e g sc al e  
T h e o v er all n e ur o p at h y li mit ati o n s c al e ( O N L S) is a t o ol f or m e as uri n g t h e a cti vit y l e v el of p ati e nts 
wit h  p eri p h er al  n e ur o p at h y.[ 6 9 ]  It  is  s c or e d  b y  s e p ar at el y  c at e g ori zi n g  ar ms a n d  l e gs.  
M e as ur e m e nt s h all b e p erf or m e d o nl y o n l e gs i n t his cli ni c al st u d y. T h e m e as ur e m e nt d a y s h all 
b e at Visit 2 ( D a y 0), Visit 4 ( D a y 9 0), Visit 6 ( D a y 1 8 0), a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) 
( m e as ur e m e nt s h all b e p erf or m e d pri or t o a d mi nistrati o n at Visit 2 [ D a y 0] a n d Visit 4 [ D a y 9 0]).  
S e e “ A p p e n di x 5. O N L S L e g s c al e” f or d et ails.  
 
• 
1 0 M W T  
T his is a t est t h at m e as ur es t h e ti m e r e q uir e d f or a s u bj e ct t o w al k 1 0 m et er s.[ 7 0 ] A s u bj e ct s h all 
b e m a d e t o w al k at a d esir e d s p e e d w hil e w e ari n g s h o e s. T h e s u bj e ct s h all b e all o w e d t o us e a n 
assisti v e d e vi c e t h at t h e s u bj e ct n or m all y us es, if a n y. T h e s u bj e ct s h all b e m a d e t o w al k a c orri d or 
t h at is 1 4 m et er s l o n g, a n d t h e ti m e t a k e n t o w al k 1 0 m et er s s h all b e m e as ur e d wit h a st o p w at c h 
pr o vi d e d b y t h e s p o ns or (ti m e t a k e n t o p ass 1 0 m et er s e x cl u di n g 2 m et er s e a c h f or t h e st arti n g 
a n d e n di n g p orti o ns). T h e ass ess m e nt d a y s h all b e at Visit 2 ( D a y 0), Visit 4 ( D a y 9 0), Visit 6 ( D a y 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 9 9
9 9  / 1 0 0
1 0 0  
 
 
I nf or m ati o n o n n e wl y d e v el o p e d or w or s e n e d a d v ers e e v e nts, or a d v ers e e v e nts t h at 
dis a p p e ar e d si n c e t h e l ast visit s h all b e c oll e ct e d.  
 
• 
C o m pl et e bl o o d c ell c o u nt  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h e mistr y test m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
T h e c o m pl et e bl o o d c ell c o u nt it e ms ar e as f oll o ws:  
 
W B C, R B C, H b, H ct, M C V, M C H, M C H C, P L T, E S R, M P V, diff er e nti al c o u nt of W B C ( B a n d n e utr o p hil, 
S e g m e nt e d n e utr o p hil, E osi n o p hil, B as o p hil, L y m p h o c yt e, M o n o c yt e)  
 
• 
G e n er al bl o o d c h e mi str y t e st  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. Si n c e a bl o o d gl u c os e 
t est is i n cl u d e d, t h e s u bj e ct s h all m ai nt ai n a n 8-h o ur  f asti n g st at e pri or t o t h e t est.  
T h e g e n er al bl o o d c h e mistr y t est it e ms ar e as f oll o ws:  
 
t ot al pr ot ei n, al b u mi n, gl o b uli n, A/ G r ati o, c h ol est er ol, t ot al bilir u bi n, A S T, A L T, f asti n g gl u c os e, 
B U N, cr e ati ni n e, esti m at e d G F R, C a 2 + , p h os p h at e, N a+ , K+ , Cl-, C R P, tri gl y c eri d e, H D L-c h ol est er ol, 
L D L- c h ol est er ol    
 
• 
S a m pl e c oll e cti o n f or r etr o s p e cti v e bi o m ar k er st u d y  
T h e s er u m of s u bj e cts s h all b e c oll e ct e d a n d st or e d fr o z e n at -7 0° C. All bl o o d s a m pl es ar e st or e d 
wit h u ni q u e n u m b er s f or r etr os p e cti v e bi o m ar k er st u d y aft er all p er s o n al i nf or m ati o n is d el et e d.  
 
• 
B o d y m e a s ur e m e nt ( w ei g ht m e a s ur e m e nt)  
A s u bj e ct’s w ei g ht s h all b e m e as ur e d at Visit 1 a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a 
s u bj e ct m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at 
Visits 2, 3, 4, a n d 5).  
 
• 
Uri n al y si s wit h mi cr o s c o p y  
T his s h al l b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t e st at Visit 3 
( D a y 1 4), uri n al ysis m a y b e p erf or m e d at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 0 1
1 0 1  / 1 0 2
1 0 2  
 
 
e xt e nsi o n of wrist j oi nt, e xt e nsi o n of wrist ( C 6 -8), gr as pi n g t est ( C 7 -
T 1) , a b d u cti o n of fi n g er ( C 8-T 1, ul n ar n er v e), a n d o p p ositi o n of t h u m b 
( C 8-T 1,  m e di a n  n er v e)  s h all  b e  t est e d  i n  t h e  u p p er  li m bs.  F or  t h e  
str e n gt h  of  i ntri nsi c  h a n d  m us cl es,  o nl y  t h e  t w o  m us cl es  of  t h e  
a b d u ct or p olli cis  br e vis ( A P B) a n d t h e first d or s al i nt er o ss e o us  ( F DI)  
s h all b e e v al u at e d, a n d t h e str o n g er of t h e t w o s h all b e s c or e d.  
I n  t h e  l o w er  li m bs,  t h e  fl e xi o n  ( L 2-L 4),  a d d u cti o n  ( L 2 -L 4),  a n d  
e xt e nsi o n ( S 1) of hi p j oi nt, t h e e xt e nsi o n ( L 2 -L 4) a n d fl e xi o n ( L 4 -S 2) 
of k n e e, as w ell as t h e d orsifl e xi o n ( L 4 -5) a n d pl a nt ar fl e xi o n ( S 1) of 
a n kl e s h all b e t est e d.  
 
T h e  r es ults  of  p erf or mi n g  a  m us cl e  str e n gt h  t est  of  t h e  li m bs  i n  a  
s u bj e ct s h all b e i n di c at e d usi n g t h e M e di c al R es e ar c h C o u n cil ( M R C) 
gr a d e*.  
* M R C gr a d e ( M ot or p o w er) 
0: C o m pl et e p a r al ysis 
I: Fli c k er of c o ntr a cti o n p ossi bl e 
II: M o v e m e nt p ossi bl e if gr a vit y eli mi n at e d 
III: M o v e m e nt a g ai nst gr a vit y b ut n ot r esist a n c e  
I V: M o v e m e nt p ossi bl e a g ai nst s o m e r esist a n c e  
V: P o w er n or m al (it is n ot n or m all y p ossi bl e t o o v erc o m e a n or m al a d ult’s p o w er)  
N o ci c e pti o n  
Sti m ul ati o n s h all b e a p pli e d b y alt er n at el y usi n g t o ols wit h a d ull e n d 
a n d  a  s h ar p  e n d,  a n d  it  s h all  b e  v erifi e d  w h et h er  t h es e  c a n  b e  
disti n g uis h e d. W h e n c o m p ari n g t h e l eft a n d ri g ht si d es of t h e b o d y, 
sti m ul ati o n s h all b e a p pli e d t o t h e s a m e sit es. T h e n, t h e s u bj e ct s h all 
b e as k e d w h et h er t h e s e ns ati o ns ar e t h e s a m e.  
P all est h esi a  
Vi br ati o n s h all b e a p pli e d t o a l o w -pit c h e d t u ni n g f or k ( a R y d el -S eiff er 
t u ni n g f or k s h all b e us e d), a n d t his s h all b e pl a c e d o n t h e dist al j oi nts 
of  t h e  h a n ds  a n d  f e et  t o  v erif y  t h at  t h e  s u bj e ct  f e els  t h e  vi br ati n g  
s e ns ati o n.  P all est h esi a  is  t h e  first  s e ns ati o n  l ost  i n  p eri p h er al  n er v e  
dis or d ers.  
 
• 
C M T N S- v 2  
C h ar c ot -M ari e -T o ot h  N e ur o p at h y  S c or e -v ersi o n  2  ( C M T N S -v 2)  is  a  m e as ur e m e nt  t o ol  f or  
e v al u ati n g t h e s e v erit y of dis e as e.[ 6 6 ] M e as ur e m e nts s h all b e t a k e n f or 9 it e ms w hi c h i n cl u d e 3 
it e ms f or dis e as e s y m pt o ms, 4 it e ms f or si g ns, a n d 2 it e ms f or n e ur o p h ysi ol o gi c al t esti n g. T h e 
s e v erit y of dis e as e s h all b e cl assifi e d a c c or di n g t o s c or es as mi l d ( ≤1 0), m o d er at e ( 1 1  t o 2 0), 
a n d  s e v er e  ( > 2 0).  T his  cli ni c al  st u d y  s h all  t ar g et  mil d  t o  m o d er at e  p ati e nts.  T his  s h all  b e  
p erf or m e d at Visit 1 (s cr e e ni n g), Visit 2 ( D a y 0), a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) (s h all b e 
p erf or m e d pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0]). S e e “ A p p e n di x 4. C M T N S -v 2” f or d et ails.  
 
• 
A nti -H G F A b t est  
T h e a nti b o d y t est f or h e p at o c yt e gr o wt h f a ct or s h all b e p erf or m e d at Visit 2 ( D a y 0) a n d Visit 7 
(t er mi n ati o n visit, D a y 2 7 0) (s h all b e p erf or m e d pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0]). T h e 
s er u m of s u bj e cts s h all b e c oll e ct e d a n d st or e d fr o z e n at -7 0° C. W h e n t h e c oll e cti o n of bl o o d 
fr o m  all  s u bj e cts  is  c o m pl et e d,  t h e  s a m pl es  s h all  b e  s e nt  t o  t h e  c e ntr al  l a b or at or y  f or  b at c h  
a n al ysis.  
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 0 2
1 0 2  / 1 0 3
1 0 3  
 
 
• 
M RI l e g  
T h e  m us cl es  of  l o w er  li m bs  s h all  b e  i m a g e d,  a n d  t h e  f att y  i nfiltr ati o n  l e v el  of  t h e  l e g  m us cl es  
i nj e ct e d wit h t h e i n v esti g ati o n al pr o d u ct s h all b e m e as ur e d a n d e v al u at e d as f at c o nt e nt v al u e ( %) 
at o n e l e v el f or e a c h m us cl e.[ 6 9]  
T h e t est d a ys s h all b e at Visit 2 ( D a y 0) a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) (s h all b e p erf or m e d 
pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0]).  C o nsi d eri n g t h e s c h e d ul e, et c., of t h e i nstit uti o n, it s h all 
b e  p erf or m e d  o pti o n all y  at  t h e  e arl y  t er mi n ati o n  visit  a n d  u ns c h e d ul e d  visits,  a n d  if  it  is  n ot 
p erf or m e d, t h e r e as o ns s h all b e r e c or d e d i n t h e c as e r e p ort f or m.  
 
• 
F D S  
T h e  f u n cti o n al  dis a bilit y  s c al e  ( F D S)  ass ess es  a  p ati e nt  fr o m  0  t o  8  p oi nts  as  s h o w n  b el o w  
d e p e n di n g o n t h e p ati e nt’s m o bilit y.[ 6 8 ] T h e ass ess m e nt d a ys s h all b e at Visit 2 ( D a y 0), Visit 4 
( D a y 9 0), Visit 6 ( D a y 1 8 0), a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) ( ass ess m e nt s h all b e p erf or m e d 
pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0] a n d Visit 4 [ D a y 9 0]).  
0 = n or m al;  
1 = cr a m ps a n d f ati g a bilit y;  
2 =i n a bilit y t o r u n;  
3 = p ossi bl e u n ai d e d;    
4 = wit h c a n e;  
5 = wit h cr ut c h;  
6 = wit h w al k er;  
7 = w h e el c h air;  
8 = b e dri d d e n.  
 
• 
O N L S l e g sc al e  
T h e o v er all n e ur o p at h y li mit ati o n s c al e ( O N L S) is a t o ol f or m e as uri n g t h e a cti vit y l e v el of p ati e nts 
wit h  p eri p h er al  n e ur o p at h y.[ 6 9 ]  It  is  s c or e d  b y  s e p ar at el y  c at e g ori zi n g  ar ms  a n d  l e gs.  
M e as ur e m e nt s h all b e p erf or m e d o nl y o n l e gs i n t his cli ni c al st u d y. T h e m e as ur e m e nt d a y s h all 
b e at Visit 2 ( D a y 0), Visit 4 ( D a y 9 0), Visit 6 ( D a y 1 8 0), a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) 
( m e as ur e m e nt s h all b e p erf or m e d pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0] a n d Visit 4 [ D a y 9 0]).  
S e e “ A p p e n di x 5. O N L S L e g s c al e” f or d et ails.  
 
• 
1 0 M W T  
T his is a t est t h at m e as ur es t h e ti m e r e q uir e d f or a s u bj e ct t o w al k 1 0 m et er s.[ 7 0 ] A s u bj e ct s h all 
b e m a d e t o w al k at a d esir e d s p e e d w hil e w e ari n g s h o es. T h e s u bj e ct s h all b e all o w e d t o us e a n 
assisti v e d e vi c e t h at t h e s u bj e ct n or m all y us es, if a n y. T h e s u bj e ct s h all b e m a d e t o w al k a c orri d or 
t h at is 1 4 m et er s l o n g, a n d t h e ti m e t a k e n t o w al k 1 0 m et er s s h all b e m e as ur e d wit h a st o p w at c h 
pr o vi d e d b y t h e s p o ns or (ti m e t a k e n t o p ass 1 0 m et er s e x cl u di n g 2 m et er s e a c h f or t h e st arti n g 
a n d e n di n g p orti o ns). T h e ass ess m e nt d a y s h all b e at Visit 2 ( D a y 0), Visit 4 ( D a y 9 0), Visit 6 ( D a y 
1 8 0),  a n d  Visit  7  (t er mi n ati o n  visit,  D a y  2 7 0)  ( ass ess m e nt  s h all  b e  p erf or m e d  pri or  t o  
a d mi nistr ati o n at Visit 2 [ D a y 0] a n d Visit 4 [ D a y 9 0]).  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 0 3
1 0 3  / 1 0 4
1 0 4  
 
 
T h e st arti n g p oi nt at 2 m et er s, t h e p oi nt f or e n di n g m e as ur e m e nt at 1 2 m et er s, a n d t h e p oi nt 
f or e n d of w al ki n g at 1 4 m et er s s h all b e m ar k e d i n a d v a n c e al o ng t h e c orri d or.  
S e e “ A p p e n di x 6. 1 0 M W T ( 1 0 -m et er w al k t est)” f or d et ails.  
 
• 
El e ctr o n e ur o gr a p h y ( C M A P, S N A P, N C V)  
T h e t est d a ys s h all b e at Visit 2 ( D a y 0) a n d Visit 7 (t er mi n ati o n visit, D a y 2 7 0) (s h all b e p erf or m e d 
pri or t o a d mi nistr ati o n at Visit 2 [ D a y 0]).  
S e e “ A p p e n di x 7. N er v e C o n d u cti o n St u d y ( N C S)” f or d et ails.  
 
• 
U s e of a s si sti v e d e vi c e s a n d t y p e s  
T h e assisti v e d e vi c es us e d b y t h e s u bj e cts s h all b e s ur v e y e d at Visit 1 (s cr e e ni n g) a n d at Visit 7 
(t er mi n ati o n visit, D a y 2 7 0). S p e ci ali z e d s h o es, br a c es f or l o w er li m bs, cr ut c h es, c a n es, w al k er s, 
w h e el c h air s, et c., f all u n d er t h es e d e vi c es. E v e n if n e w a d diti o n al assisti v e d e vi c es ar e us e d d uri n g 
t h e cli ni c al st u d y, t h e y s h all n ot b e i n cl u d e d i n a d v er s e e v e nts.    
 
6. 1. 9  
U n s c h e d ul e d Vi sit s  
• 
A d v er s e e v e nt a s s e s s m e nt  
I nf or m ati o n o n n e wl y d e v el o p e d or w or s e n e d a d v ers e e v e nts, or a d v ers e e v e nts t h at 
dis a p p e ar e d si n c e t h e l ast visit s h all b e c oll e ct e d.  
 
• 
C o m pl et e bl o o d c ell c o u nt  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct  at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. T h e c o m pl et e bl o o d c ell 
c o u nt it e ms ar e as f oll o w s:  
 
W B C, R B C, H b, H ct, M C V, M C H, M C H C, P L T, E S R, M P V, diff er e nti al c o u nt of W B C ( B a n d n e utr o p hil, 
S e g m e nt e d n e utr o p hil, E osi n o p hil, B as o p hil, L y m p h o c yt e, M o n o c yt e)  
 
• 
G e n er al bl o o d c h e mi str y t e st  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), a c o m pl et e bl o o d c ell c o u nt a n d a g e n er al bl o o d c h e mistr y t est m a y b e p erf or m e d 
at D a y 3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or. Si n c e a bl o o d gl u c os e 
t est  is  i n cl u d e d,  t h e  s u bj e ct  s h all  m ai nt ai n  a n  8-h o ur  f asti n g  st at e  pri or  t o  t h e  t est.  T h e  
g e n er al bl o o d c h e mistr y t est it e ms ar e as f oll o ws:  
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 0 4
1 0 4  / 1 0 5
1 0 5  
 
 
t ot al pr ot ei n, al b u mi n, gl o b uli n, A/ G r ati o, c h ol est er ol, t ot al bilir u bi n, A S T, A L T, f asti n g gl u c os e, 
B U N, cr e ati ni n e, esti m at e d G F R, C a 2 + , p h os p h at e, N a+ , K+ , Cl-, C R P, tri gl y c eri d e, H D L -c h ol est er ol, 
L D L- c h ol est er ol    
 
• 
B o d y m e a s ur e m e nt ( w ei g ht m e a s ur e m e nt)  
A s u bj e ct’s w ei g ht s h all b e m e as ur e d at Visit 1 a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a 
s u bj e ct m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at 
Visits 2, 3, 4, a n d 5).  
 
• 
Uri n al y si s wit h mi cr o s c o p y  
T his  s h all  b e p erf or m e d at Visit  1 a n d t hr o u g h o ut  t h e cli ni c al  st u d y e v er y ti m e a s u bj e ct  
m a k es a visit (s h all b e p erf or m e d pri or t o a d mi nist eri n g t h e i n v esti g ati o n al pr o d u ct at Visits 
2, 3, 4, a n d 5). H o w e v er, if t h er e is a s u bj e ct wit h a b n or m al fi n di n gs i n t h e t est at Visit 3 
( D a y 1 4), uri n al ysis wit h mi cr os c o p y m a y b e p erf or m e d at D a y 3 0 d e p e n di n g o n t h e d e cisi o n 
of t h e pri n ci p al i n v esti g at or.  
T h e uri n al ysis it e ms ar e as f oll o ws:  
 
C ol or, t ur bi dit y,  s p e cifi c  gr a vit y,  p H,  al b u mi n,  gl u c os e, k et o n e s,  bilir u bi n,  bl o o d, ur o bili n o g e n, 
nitrit e, l e u k o c yt e  est er as e, mi cr os c o p y ( R B C, W B C, c asts)  
 
• 
Vit al si g ns  
Vit al si g ns i n cl u di n g bl o o d pr ess ur e ( m e as ur e m e nt s h all b e t a k e n wit h t h e s u bj e ct i n a sitti n g 
p ositi o n aft er r esti n g f or at l e ast 1 0 mi n ut es pri or t o m e as ur e m e nt), t e m p er at ur e, h e art r at e 
p er  mi n ut e,  a n d  r es pir at or y  r at e  p er  mi n ut e  s h all  b e  m e as ur e d.  T h e  m e as ur e m e nt  r es ult s  
s h all  b e  r e c or d e d  i n  t h e  s u bj e cts’  c as e  r e p ort  f or ms.  T his  s h all  b e  p erf or m e d  at  Visit  1  
(s cr e e ni n g) a n d t hr o u g h o ut t h e cli ni c al st u d y e v er y ti m e a s u bj e ct m a k es a visit ( o n t h e dr u g 
a d mi nistr ati o n d a ys  c o nsisti n g of  Visits  2, 3, 4, a n d 5,  it s h all  b e p erf or m e d b ot h pri or  t o 
a d mi nistr ati o n  a n d  2  ±  1  h o ur s  aft er  a d mi nistr ati o n).  H o w e v er,  if  t h er e  is  a  s u bj e ct  wit h  
a b n or m al fi n di n gs i n t h e t est at Visit 3 ( D a y 1 4), a f oll o w -u p t est m a y b e p erf or m e d at D a y 
3 0 d e p e n di n g o n t h e d e cisi o n of t h e pri n ci p al i n v esti g at or.  
 
• 
C o n c o mit a nt m e di c ati o n s s ur v e y  
T h e br a n d n a m es a n d i n gr e di e nt n a m es of c o n c o mit a nt m e di c ati o ns s h all b e s ur v e y e d at e v er y 
visit a n d r e c or d e d i n t h e c as e r e p ort f or m. All m e di c ati o ns a n d tr e at m e nts a d mi nist er e d wit hi n 
6  m o nt hs  b ef or e  Visit  1  (s cr e e ni n g)  s h all  b e  s ur v e y e d.  Pr e vi o us  m e di c ati o ns  a n d  pr e vi o us  
tr e at m e nts s h all b e d efi n e d as all pr e vi o usl y c oll e ct e d m e di c ati o ns a n d tr e at m e nts b ef or e Visit 
2 (fir st a d mi nistr ati o n of i n v esti g ati o n al pr o d u ct). C o n c o mit a nt m e di c ati o ns a n d tr e at m e nts s h all 
r ef er  t o  all m e di c ati o ns  t h at  h a v e  b e e n  a d mi nist er e d  at  l e ast  o n c e  st arti n g  fr o m  Visit  2  (fir st 
a d mi nistr ati o n of i n v esti g ati o n al pr o d u ct) a n d t hr o u g h o ut t h e cli ni c al st u d y. T h e c at e g ori es of 
c oll e ct e d  m e di c ati o ns  a n d  tr e at m e nts  s h all  f oll o w  t his  d efi niti o n.  T h e  f oll o wi n g  s h all  als o  b e  
s ur v e y e d f or e a c h m e di c ati o n:  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 0 5
1 0 5  / 1 0 6
1 0 6  
 
 
• 
Br a n d n a m e  
• 
I n di c ati o ns f or m e di c ati o n a d mi nistr ati o n (r e as o n f or a d mi nistr ati o n)  
• 
D os e/str e n gt h, a d mi nistr ati o n r o ut e, n u m b er of a d mi nistr ati o ns  
• 
St art a n d dis c o nti n u ati o n d at es of a d mi nistr ati o n ( w h et h er t o c o nti n u e w h e n t h e 
cli ni c al st u d y is t er mi n at e d)  
 
6. 2  
A s s e s s m e nt It e m s  
1) S af et y a n d t ol er a bilit y a s s e s s m e nt it e m s  
( 1) A d v ers e e v e nts  
- 
All a d v ers e e v e nts t h at m a nif est aft er a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct 
s h all b e c oll e ct e d.  
- 
At Visits 3, 4, a n d 5 ( 2 n d, 3r d, a n d 4t h a d mi nistr ati o n s essi o ns of t h e i n v esti g ati o n al  
pr o d u ct),  a d v ers e  e v e nts  s h all  b e  ass ess e d  a n d  c oll e ct e d  b ef or e  a n d  aft er  
a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct.  
( 2) L a b or at or y t ests ( c o m pl et e bl o o d c ell c o u nt/ g e n er al bl o o d c h e mistr y/ uri n al ysis t ests)  
( 3) Vit al si g ns  
 
2) Effi c a c y a s s e s s m e nt it e m s 
( 1) C h a n g es i n s e v erit y of dis e as e  
- C M T N S -v 2 ( C h ar c ot-M ari e -T o ot h N e ur o p at h y S c or e v ersi o n 2)  
- F D S (f u n cti o n al dis a bilit y s c al e)  
( 2) C h a n g es i n l o w er li m b f u n cti o n  
- O N L S ( o v er all n e ur o p at h y li mit ati o n s c or e) l e g s c al e  
- 1 0 M W T ( 1 0 -m et er w al k t est)  
( 3) C h a n g es i n f att y i nfiltr ati o n l e v el of l o w er li m b m us cl es  
- M RI l e g  
( 4) N er v e r e g e n er ati o n p ot e nti al  
- C M A P ( c o m p o u n d m ot or n er v e a cti o n p ot e nti al)  
- S N A P ( c o m p o u n d s e ns or y n er v e a cti o n p ot e nti al)  
- N C V ( n er v e c o n d u cti o n v el o cit y)  
( 5) H G F a nti b o d y g e n er a ti o n b y V M 2 0 2 
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 0 6
1 0 6  / 1 0 7
1 0 7  
 
 
7 
A d v er s e E v e nt  
7. 1  
D efi niti o n  
 
A n a d v ers e e v e nt ( A E) is a n u nf a v or a bl e a n d u ni nt e n d e d s y m pt o m ( e. g., m oti o n si c k n ess), si g n 
( e. g., h e p at o m e g al y), or cli ni c all y m e a ni n gf ul a n o m al y ( e. g., a b n or m al l a b or at or y fi n di n g) t h at 
o c c urr e d d uri n g t h e cli ni c al st u d y, w h et h er or n ot c a us e d b y t h e st u d y i nt er v e nti o n.  
 
A d v er s e Dr u g R e a cti o n ( A D R)  
A n A d v ers e Dr u g R e a cti o n ( A D R) is a h ar mf ul a n d u ni nt e n d e d r e a cti o n t h at o c c urr e d at a n y 
d os e  of  t h e  i n v esti g ati o n al  pr o d u ct,  of  w hi c h  t h e  c a us alit y  wit h  t h e  i n v esti g ati o n al  pr o d u ct  
c a n n ot b e d e ni e d.  
 
A d v er s e E v e nt s of S p e ci al I nt er e st, A E SI  
A n  a d v ers e  e v e nt  of  s p e ci al  i nt er est  (s eri o us  or  n o ns eri o us)  is  o n e  of  s ci e ntifi c  a n d  m e di c al  
c o n c er n s p e cifi c t o t h e s p o ns or's pr o d u ct or pr o gr a m, f or w hi c h o n g oi n g m o nit ori n g a n d r a pi d 
c o m m u ni c ati o n b y t h e i n v esti g at or t o t h e s p o ns or c a n b e a p pr o pri at e. 
 
S eri o u s A E∙A D R  
A S eri o us A E∙A D R is a n A E or A D R t h at o c c urr e d at a n y d os e of t h e i n v esti g ati o n al pr o d u ct, 
w hi c h r es ults i n a n y of t h e f oll o wi n g:  
( 1) D e at h or lif e -t hr e at e ni n g; 
( 2) I n p ati e nt h os pit ali z ati o n or pr ol o n g ati o n of e xisti n g h os pit ali z ati o n;  
( 3) P er m a n e nt or si g nifi c a nt d is a bilit y/i n c a p a cit y; 
( 4) C o n g e nit al a n o m al y/ birt h d ef e ct;  
( 5) Ot h er m e di c all y si g nifi c a nt e v e nts i n cl u di n g dr u g d e p e n d e n c e/ a b us e or h e m at ol o gi c 
dis e as e, et c.  
 
T h e t er m “lif e -t hr e at e ni n g” r ef ers t o a n e v e nt i n w hi c h t h e s u bj e ct w as at ris k of i nst a nt d e at h 
at t h e ti m e of t h e e v e nt.  
 
W h e n  t h e  s u bj e ct  h as  b e e n  st a y e d  at  t h e  e m er g e n c y  r o o m  f or  tr e at m e nt  f or  m or e  t h a n  2 4 
h o urs, t h e crit eri a f or h os pit ali z ati o n ar e c o nsi d er e d t o b e m et. H os pit ali z ati o n s c h e d ul e d b ef or e 
t h e i niti al i n v esti g ati o n al pr o d u ct a d mi nistr ati o n or h os pit ali z ati o n for c os m eti c s ur g er y is n ot 
c o nsi d er e d  a n  A E  or  S A E.  El e cti v e  s ur g er y  d uri n g  w hi c h  n o  A Es  o c c ur,  s u bs e q u e nt  
h os pit ali z ati o n  fr o m  s u c h  s ur g er y,  a n d  h os pit ali z ati o n  i n  c ar e  h os pit als  f or  r e c o v er y  ar e  n ot  
c o nsi d er e d S A Es. H o w e v er, u ns c h e d ul e d h os pit ali z ati o ns or h os pit ali z ati o ns r es ulti n g fr o m A Es 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 0 7
1 0 7  / 1 0 8
0 8  
 
 
ar e c o nsi d er e d S A Es.  
 
If a n e v e nt o c c urs t h at is m e di c all y c o nsi d er e d t o h a v e a si g nifi c a nt eff e ct o n t h e s af et y a n d 
h e alt h of t h e s u bj e ct, e v e n if n ot list e d a b o v e, it s h o ul d b e d et er mi n e d w h et h er t o c o nsi d er it 
a n S A E a c c or di n g t o t h e m e di c al j u d g m e nt of t h e p h ysi ci a n i n c h ar g e a n d r el e v a nt e x p erts, a n d 
a p pr o pri at e i nt er v e nti o ns s h o ul d b e t a k e n a c c or di n gl y.  
 
U n e x p e ct e d A d v er s e E v e nt  
A n u n e x p e ct e d a d v ers e e v e nt r ef er s t o a n A E t h at diff er s fr o m or is n ot st at e d i n t er ms of t h e 
d e gr e e  or  as p e cts  of  t h e  A D R,  c o nsi d eri n g  a v ail a bl e  dr u g -r el at e d  i nf or m ati o n,  s u c h  as  t h e  
I n v esti g at or’s Br o c h ur e or att a c h m e nts of t h e i n v esti g ati o n al pr o d u ct.  
A n e x p e ct e d e v e nt r ef ers t o a c as e w h er e a n A E w hi c h o c c urr e d e v e n b ef or e t h e us e of  t h e 
i n v esti g ati o n al  pr o d u ct  is  o bs er v e d,  w hi c h  is  n ot  a c c o m p a ni e d  b y  m e di c al  hist or y  or  
c o n c o mit a nt m e di c ati o ns a n d is d es cri b e d i n t h e I n v esti g at or’s Br o c h ur e.  
 
E x p e ct e d A d v er s e E v e nt  
A n e x p e ct e d a d v ers e e v e nt r ef ers t o a n A E t h at h as b e e n o bs er v e d a n d c o nfir m e d i n pr e vi o us 
st u di es  a n d  d es cri b e d  i n  t h e  a v ail a bl e i nf or m ati o n  r el at e d  t o  t h e  pr o d u ct  s u c h  as  t h e 
I n v esti g at or’s Br o c h ur e, t h e pr ot o c ol or i ns ert, et c., w hi c h d o es n ot i n cl u d e cas es a c c o m p a ni e d 
b y p ast m e di c al hist or y or c o n c o mit a nt m e di c ati o ns, b ut i n cl u d es c as es w h er e pr e di ct e d A Es 
r e p e at e dl y o c c ur o v er ti m e d u e t o c ert ai n dis e as e c o n diti o ns. 
 
7. 2  
E x p e ct e d A d v er s e E v e nt  
I n  t his  cli ni c al  st u d y, pr e di ct e d  si d e eff e cts  c a n b e cl assifi e d  i nt o  t w o  c at e g ori es: “ A E  d u e t o  
C h ar c ot -M ari e -T o ot h,”  t h e  u n d erl yi n g  dis e as e;  a n d  “ A E  t h at  m a y  o c c ur  aft er  i n v esti g ati o n al  
pr o d u ct a d mi nistr ati o n.”    
 
Fi g ur e 9 is i nt e n d e d as r ef er e n c e f or t h e i n v esti g at or e v al u ati n g t h e c a us e or c a us alit y of A Es. 
T h e i n v esti g at or m ust t a k e a p pr o pri at e i nt er v e nti o ns a g ai nst A Es t h at o c c ur d uri n g t h e cli ni c al 
st u d y, e v al u at e t h e c a us alit y a c c or di n g t o t h e al g orit h m of “ A p p e n di x 8. M et h o d of ass essi n g 
c a us alit y of a d v ers e e v e nts,” a n d r e p ort t h e A E.  
 
A Es  s u c h  as  p ai n,  d ys p n e a,  s ki n  ul c er,  or  m us cl e  cr a m ps  m a y  b e  o bs er v e d  b ot h  aft er  t h e  
a d mi nistr ati o n  of  t h e  i n v esti g ati o n al  pr o d u ct  a n d  as  s y m pt o ms  of  t h e  u n d erl yi n g  dis e as e,  
C h ar c ot -M ari e -T o ot h. T h e i n v esti g at or m ust c ar ef ull y d et er mi n e w h et h er t h e A E is c a us e d b y 
t h e u n d erl yi n g dis e as e or b y a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct. 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 1 5
1 1 5  / 1 1 6
1 1 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
n al pr o d u ct c a n n ot b e e x cl u d e d (“r el at e d”). 
A p p e n di x 8 is a n a d a pt ati o n of Ta bl e 1 7 b el o w, w hi c h is t h e g e n er al st a n d ar d f or 
ass essi n g c a us alit y, f or t his cli ni c al st u d y, a n d t h e i n v esti g at or e v al u at es c a us alit y b y 
r ef erri n g t o t his al g orit h m. 
 
Ta b l e  2 4  C a u s alit y wit h i n v e sti g ati o n al pr o d u ct  
D efi nit el y r el at e d  
 
T h er e  is  e vi d e n c e  t h at  t h e  i n v esti g ati o n al  pr o d u ct  h as  b e e n  
a d mi nist er e d  a n d  t h e  ti m e  s e q u e n c e  of  t h e  A E  o ns et  is  
r e as o n a bl e; 
 
T h e A E is m ost pr o b a bl y c a us e d b y t h e i n v esti g ati o n al pr o d u ct 
c o m p ar e d wit h a n y ot h er r e as o n;  
 
T h e A E dis a p p e ars w h e n a d mi nistr ati o n of t h e i n v esti g ati o n al 
pr o d u ct is s us p e n d e d;  
 
R e -a d mi nistr ati o n ( p erf or m e d o nl y if p ossi bl e) r es ult is p ositi v e;  
 
T h e A E s h o ws a p att er n c o nsist e nt wit h t h e i nf or m ati o n alr e a d y 
k n o w n a b o ut t h e i n v esti g ati o n al pr o d u ct or dr u gs of t h e s a m e 
f a mil y. 
Pr o b a bl y r el at e d  
 
T h er e  is  e vi d e n c e  t h at  t h e  i n v esti g ati o n al  pr o d u ct  h as  b e e n  
a d mi nist er e d  a n d  t h e  ti m e  s e q u e n c e  of  t h e  A E  o ns et  is  
r e as o n a bl e; 
 
T h e A E is m or e pr o b a bl y c a us e d b y t h e i n v esti g ati o n al pr o d u ct 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 1 6
1 1 6  / 1 1 7
1 1 7  
 
 
t h a n f or a n y ot h er r e as o n; 
 
T h e A E dis a p p e ars w h e n a d mi nistr ati o n of t h e i n v esti g ati o n al 
pr o d u ct is s us p e n d e d.  
P ossi bl y r el at e d  
 
T h er e  is  e vi d e n c e  t h at  t h e  i n v esti g ati o n al  pr o d u ct  h as  b e e n  
a d mi nist er e d  a n d  t h e  ti m e  s e q u e n c e  of  t h e  A E  o ns et  is  
r e as o n a bl e; 
 
T h e A E  is  c a us e d b y  t h e i n v esti g ati o n al pr o d u ct  at  t h e s a m e  
l e v el as ot h er pr o b a bl e r e as o ns; 
 
T h e A E dis a p p e ars w h e n a d mi nistr ati o n of t h e i n v esti g ati o n al 
pr o d u ct is s us p e n d e d (if p erf or m e d);  
U nli k el y  
 
T h er e  is  e vi d e n c e  t h at  t h e  i n v esti g ati o n al  pr o d u ct  h as  b e e n  
a d mi nist er e d; 
 
T h er e  ar e  ot h er  c a us es  wit h  hi g h er  p ossi bilit y  t h a n  t h e  
i n v esti g ati o n al pr o d u ct; 
 
T h e a d mi nistr ati o n s us p e nsi o n (if p erf or m e d) r es ult is n e g ati v e 
or a m bi g u o us; 
 
T h e  r e -a d mi nistr ati o n  (if  p erf or m e d)  r es ult  is  n e g ati v e  or  
a m bi g u o us; 
N ot r el at e d  
 
T h e s u bj e ct h as n ot b e e n a d mi nist er e d wit h t h e i n v esti g ati o n al 
pr o d u ct; 
 
T h e ti m e s e q u e n c e of t h e a d mi nistr ati o n a n d t h e A E o ns et is 
n ot r e as o n a bl e;  
 
T h er e ar e ot h er o b vi o us c a us es f or t h e A E;  
U n ass ess a bl e  
 
T h er e is i ns uffi ci e nt e vi d e n c e t o d et er mi n e t h e r el ati o ns hi p;  
 
I nf or m ati o n  is  i ns uffi ci e nt  or  c o nfli cti n g  t o  d et er mi n e,  a n d  
c a n n ot b e s u p pl e m e nt e d or v erifi e d;  
 
 
7. 4. 2  
S e v erit y of A E  
S e v erit y of a n A E  is c at e g ori z e d a c c or di n g t o N CI -C T C A E v ersi o n 5. 0. A Es  t h at  c a n n ot b e 
c at e g ori z e d b y t h e N CI -C T C A E ar e ass ess e d b y t h e f oll o wi n g fi v e gr a d es:  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 1 8
1 1 8  / 1 1 9
1 1 9  
 
 
7. 4. 3. 1 C oll e cti o n, a n d r e c or di n g of A E SI( A d v er s e E v e nt s of S p e ci al I nt er e st) 
All A E SIs t h at o c c ur t hr o u g h o ut t h e cli ni c al tri al ar e c oll e ct e d, t h e f oll o wi n g e v e nts ar e 
cl assifi e d as  A E SI, a n d  t h e  H eli x mit h P V  t e a m  m a n a g es  t h e m as  s af et y  i nf or m ati o n  
d at a.  
1)  
C or o n a vir us Dis e as e -1 9  (C O VI D -1 9)  
2)  
Inj e cti o n Sit e R e a cti o ns  
 
7. 4. 4  
R e p orti n g a n d r e c or di n g of S A E s  
 
7. 4. 4. 1  
R e p orti n g of S A E s  
T h e  I n v esti g at or  pr e p ar es  a n d  s u b mits  t h e  “ S A E  R e p ort  F or m”  t hr o u g h  t h e  e C R F  
s yst e m  wit hi n  2 4  h o urs  of  r e c o g ni zi n g  a n y  S A Es  r e g ar dl ess  of  c a us alit y  wit h  t h e  
i n v esti g ati o n al pr o d u ct. W h e n t h e I n v esti g at or’s el e ctr o ni c si g n at ur e a n d s u b missi o n 
ar e c o m pl et e, a n otifi c ati o n e -m ail is s e nt t o Dt & S a n o M e di cs P V t e a m a n d H eli x mit h 
C o.,  Lt d.  If  t h e  S A E  R e p ort  c a n n ot  b e  pr e p ar e d  a n d  s u b mitt e d  t hr o u g h  t h e  e C R F  
s yst e m  d u e  t o  u n a v oi d a bl e  cir c u mst a n c es,  t h e  “ S A E  R e p ort  F or m”  is  pr e p ar e d  a n d  
s u b mitt e d t o t h e s af et y i nf or m ati o n c o nt a ct p ers o n b el o w b y f a x or e m ail:  
 
S af et y r e p orti n g c o nt a ct i nf or m ati o n  
C o nt a ct 
p ers o n  
Dt & S a n o M e di cs P V Te a m  
F a x  
+ 8 2 - 2-5 6 6 -3 2 2 2  
e- m ail  
p v @ dt ns m. c o m  
a d dr ess 
1 5 t h Fl o or, 1 2 6, Te h er a n -r o, G a n g n a m- g u, S e o ul, S o ut h K or e a  
 
T h e  i niti al  S A E  R e p ort  m ust  i n cl u d e  t h e  f oll o wi n g  f o ur  mi ni m al  el e m e nts  of  
i nf or m ati o n:  
1)  
A n i d e ntifi a bl e r e p ort er  
2)  
A n i d e ntifi a bl e p ati e nt  
3)  
A s us p e ct dr u g  
4)  
A s eri o us a d v ers e e v e nt  
 
T h e  f oll o wi n g  ar e t h e r es p o nsi biliti es  of e a c h p ers o n i n c h ar g e r e g ar di n g t h e S A Es 
o c c urri n g d uri n g t h e cli ni c al st u d y p eri o d:    
 
1)   Pri n ci p al I n v e sti g at or  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 1 9
1 1 9  / 1 2 0
1 2 0  
 
 
W h e n a n S A E o c c urs, t h e pri n ci p al i n v esti g at or i m m e di at el y r e p orts it t o t h e S p o ns or 
( wit hi n  2 4  h o urs  of  r e c o g ni zi n g).  W h e n  i m p ort a nt  a d diti o n al  i nf or m ati o n  r e g ar di n g  
t h e S A E is a v ail a bl e l at er, t h e pri n ci p al i n v esti g at or m ust s u b mit a n a d diti o n al r e p ort 
in cl u di n g  d et ails,  wit hi n  2 4  h o urs  of  r e c o g ni zi n g  t h e  a d diti o n al  i nf or m ati o n.  Or,  i n  
c as e  of  a  s us p e ct e d  u n e x p e ct e d  s eri o us  a d v ers e  r e a cti o n,  it  m ust  b e  e x p e diti o usl y  
r e p ort e d  t o  t h e  S p o ns or  a n d  I R B.  W h e n  a  d e at h  c as e  is  r e p ort e d,  t h e  pri n ci p al  
i n v esti g at or m ust pr o vi d e a d diti o n al i nf or m ati o n s u c h as t h e a ut o ps y r e p ort ( o nl y if 
a n a ut o ps y w as c o n d u ct e d) a n d d e at h c ertifi c at e t o t h e S p o ns or a n d I R B.  
 
2)   S u b-I n v e sti g at or( s) 
W h e n  a n  S A E  o c c urs,  t h e  s u b -i n v esti g at or(s)  m ust  i m m e di at el y  r e p ort  it  t o  t h e  
pri n ci p al i n v esti g at or a n d  S p o ns or a n d l at er s u b mit a n a d diti o n al r e p ort c o nt ai ni n g 
d et ails. Or, i n  c as e of a s us p e ct e d u n e x p e ct e d s eri o us  a d v ers e r e a cti o n, it  m ust  b e 
e x p e diti o u sl y r e p ort e d t o t h e pri n ci p al I n v esti g at or, S p o ns or, a n d I R B.  
 
3)  I n stit uti o n al R e vi e w B o ar d (I R B) 
T h e  I R B  r e q uir es  t h e  pri n ci p al  i n v esti g at or  t o  t a k e  n e c ess ar y  a cti o ns  if  t h er e  is  a  
s us p e ct e d  u n e x p e ct e d  s eri o us  a d v ers e  r e a cti o n  or  a n y  n e w  i nf or m ati o n  t h at  m a y 
n e g ati v el y aff e ct t h e s af et y of s u bj e cts or o p er ati o n of t h e cli ni c al st u d y.  
 
4)  S p o n s or  
( 1) T h e S p o ns or r e p orts a n y s us p e ct e d u n e x p e ct e d s eri o us a d v ers e r e a cti o ns t o ot h er 
r el e v a nt i n v esti g at ors, t h e I R B ( o nl y if t h e I n v esti g at or h as n ot r e p ort e d t h e m t o t h e 
I R B or t h er e is a n e e d t o c h a n g e c o nt e nt of t h e r e p ort), a n d t h e Mi nistr y of F o o d 
a n d  Dr u g  S af et y  ( M F D S)  wit hi n  1 5  d a ys  of  r e c ei vi n g  a  r e p ort  fr o m  t h e  pri n ci p al  
i n v esti g at or or s u b-i n v esti g at or(s) o n or r e c o g ni zi n g t h e m. Or, i n t h e e v e nt of d e at h 
or li f e-t hr e at e ni n g, t h e S p o ns or m ust r e p ort o n it wit hi n s e v e n d a ys of r e c ei vi n g a 
r e p ort  o n  or  r e c o g ni zi n g  it,  a n d  r e p ort  f urt h er  d et ail e d  i nf or m ati o n  wit hi n  ei g ht  
d a ys of t h e i niti al r e p orti n g. W h e n s u b mitti n g a S U S A R r e p ort, i nf or m ati o n r e c ei v e d 
fr o m t h e pri n ci p al i n v esti g at or or s u b-i n v esti g at or(s) s h all b e att a c h e d. 
( 2) T h e S p o ns or m ust p eri o di c all y r e p ort a d diti o n al s af et y i nf or m ati o n r el at e d t o t h e 
a b o v e  r e p ort  u ntil  t h e  S U S A R  is  c o n cl u d e d  (t h e  dis a p p e ar a n c e  of  t h e  S U S A R  or  
i n a bilit y t o f oll o w u p). T h e i n v esti g at or m ust a cti v el y c o o p er at e i n pr o vi di n g d at a 
a n d i nf or m ati o n r e g ar di n g t h e r e p ort.  
 
7. 4. 4. 2  
R e p orti n g S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n ( S U S A R)  
T h e S p o ns or h as t h e o bli g ati o n t o c o nti n u o usl y c o n d u ct ass ess m e nt o n t h e s af et y of 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 2 0
1 2 0  / 1 2 1
1 2 1  
 
 
t h e i n v esti g ati o n al pr o d u ct us e d i n t h e cli ni c al st u d y.  
 
T h e S p o ns or m ust e x p e diti o usl y r e p ort a n y S U S A Rs t o t h e ot h er r el e v a nt i n v esti g at ors, 
t h e I R B, a n d t h e M F D S wit hi n t h e p eri o d s p e cifi e d as f oll o ws:  
 
( 1) T h e  S p o ns or  m ust  e x p e diti o usl y  r e p ort  a n y  S U S A Rs  t o  t h e  ot h er  r el e v a nt  
i n v esti g at ors, t h e M F D S, a n d, w h e n n e c ess ar y, t h e I R B wit hi n t h e p eri o d s p e cifi e d 
as f oll o ws:  
A) D e at h or lif e -t hr e at e ni n g: Wit hi n s e v e n d a ys of r e c ei vi n g a r e p ort o n or  
r e c o g ni zi n g  t h e  e v e nt.  Or,  if  t h e  i niti al  r e p ort  l a c ks  a n y  of  t h e  i nf orm ati o n 
r e q uir e d i n t h e att a c h e d F or m 7 7, t h e A D R R e p ort, i n cl u di n g t h e n a m e of t h e 
A D R, fi n al o bs er v ati o n r es ult, a n d A D R s u m m ar y, a n a d diti o n al r e p ort m ust 
b e  s u b mitt e d  wit h  d et ail e d  i nf or m ati o n  o n  t h e  A D R  wit hi n  1 5  d a ys  of  
r e c ei vi n g r e p ort o n or r e c o g ni zi n g t h e e v e nt.  
B) Ot h ers: wit hi n 1 5 d a ys of t h e S p o ns or r e c ei vi n g r e p ort o n or r e c o g ni zi n g 
t h e e v e nt.  
( 2) If  t h er e  is  a d diti o n al  i nf or m ati o n  o n  t h e  a d v ers e  dr u g  r e a cti o n  r e p ort e d  u n d er  
s u bs e cti o n  ( 1),  t h e  S p o ns or  m ust  r e p ort  it  u ntil  t h e  a d v ers e  dr u g  r e a cti o n  is  
c o n cl u d e d (r ef erri n g t o t h e dis a p p e ar a n c e of t h e A D R or t h e i n a bilit y t o c o n d u ct a 
f oll o w-u p).  
( 3) W h e n t h e S p o ns or i nt e n ds t o r e p ort t h e A D R t o t h e Mi nist er of F o o d a n d Dr u g 
S af et y p urs u a nt t o s u bs e cti o n ( 1), a n A D R s u m m ar y, i n cl u di n g CI O M S -I f or m, m ust 
b e att a c h e d t o F or m 7 7, t h e A D R r e p ort.  
 
7. 4. 5  
H a n dli n g A E  
All A Es w hi c h o c c ur d uri n g t h e st u d y p eri o d m ust b e r e c or d e d i n d et ail i n t h e C as e 
R e p ort F or m, i n cl u di n g s y m pt o ms a n d si g ns, st art d at e/ e n d d at e, d ur ati o n, s e v erit y, 
tr e at m e nt a n d r es ults, a n d c a us alit y wit h t h e i n v esti g ati o n al pr o d u ct e v e n if t h e y ar e n ot 
r el at e d t o t h e i n v esti g ati o n al pr o d u ct. I n a d diti o n, if p ossi bl e, t h e A E s h all b e o bs er v e d 
u ntil it is r e c o v er e d t o pr e -a d mi nistr ati o n or b as eli n e l e v el, or u ntil t h e i n v esti g at or  c a n 
d et er mi n e t h at t h e A E h as b e e n n or m ali z e d, or u ntil f urt h er o bs er v ati o n is d e e m e d 
u n n e c ess ar y. 
 
H a n dli n g of t h e A E is c at e g ori z e d as f oll o ws:  
1)  
Dr u g a d mi nistr ati o n m ai nt ai n e d  
2)  
Dr u g a d mi nistr ati o n i nt err u pt e d  
3)  
Dr u g a d mi nistr ati o n p er m a n e ntl y dis c o nti n u e d 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 2 1
1 2 1  / 1 2 2
1 2 2  
 
 
4)  
N/ A: T h e s u bj e ct h as d e c e as e d, or a d mi nistr ati o n is t er mi n at e d w h e n t h e A E o c c urs  
5)  
U n k n o w n 
 
Tr e at m e nts of t h e A E ar e c at e g ori z e d as f oll o ws:  
 
1)  
P erf or m dr u g tr e at m e nt of t h e A E  
2)  
P erf or m n o n -dr u g tr e at m e nt of t h e A E  
3)  
P erf or m dr u g/ n o n -dr u g tr e at m e nt of t h e A E  
4)  
N o dr u g/ n o n -dr u g tr e at m e nt of t h e A E  
 
R es ults of t h e A E ar e c at e g ori z e d as f oll o ws:  
 
1)  
R e c o v er e d (r es ol v e d)  
2)  
R e c o v eri n g ( b ei n g r es ol v e d)  
3)  
N ot r e c o v er e d ( n ot r es ol v e d)  
4)  
R e c o v er e d (r es ol v e d) wit h s e q u el a e  
5)  
D e at h p ossi bl y r el at e d t o t h e A E  
6)  
D e at h n ot r el at e d t o t h e A E  
7)  
U n k n o w n 
7. 4. 6  
H a n dli n g r el at e d t o i n v e sti g ati o n al pr o d u ct  
D uri n g t h e cli ni c al st u d y, t h e pri n ci p al i n v esti g at or a n d s u b -i n v esti g at or(s) m ust m a k e e v er y 
eff ort t o s e c ur e t h e s af et y of t h e s u bj e cts a n d t a k e pr o m pt a n d a p pr o pri at e i nt er v e nti o ns 
t o mi ni mi z e A Es w h e n S A Es o c c ur. T h e pri n ci p al i n v esti g at or m a y dis c o nti n u e t h e cli ni c al 
st u d y  i n  c o ns ult ati o n  wit h  t h e  S p o ns or.  E v e n  w h e n  n ot  r el at e d  t o  t h e  i n v esti g ati o n al  
pr o d u ct, all A Es t h at o c c ur d uri n g t h e cl i ni c al st u d y p eri o d m ust b e r e c or d e d i n d et ail i n 
t h e C as e R e p ort F or m, wit h t h e s y m pt o ms a n d si g ns, st art d at e/ e n d d at e of o c c urr e n c e, 
d ur ati o n, s e v erit y, tr e at m e nt a n d r es ults, a n d c a us alit y wit h t h e i n v esti g ati o n al pr o d u ct. I n 
a d diti o n,  if  p ossi bl e,  c as es  s h all  b e  o bs er v e d  u ntil  t h e  A E  is  r e c o v er e d  t o  t h e  pr e -
a d mi nistr ati o n  or  b as eli n e  l e v el,  or  u ntil  t h e  i n v esti g at or  c a n  d et er mi n e  t h at  t h e  A E  h as  
b e e n n or m ali z e d, or u ntil f urt h er o bs er v ati o n is d e e m e d u n n e c ess ar y.  
 
W h e n a n A E o c c urs, t h e f oll o wi n g i nt er v e nti o ns s h all b e t a k e n:  
1)  D os e m ai nt ai n e d  
2)  D os e i n cr e as e d  
3)  D os e r e d u c e d  
4)  Dr u g a d mi nistr ati o n i nt err u pt e d  
5)  Dr u g a d mi nistr ati o n p er m a n e ntl y dis c o nti n u e d  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 2 2
1 2 2  / 1 2 3
1 2 3  
 
 
6)  N/ A: T h e s u bj e ct h as d e c e as e d, or a d mi nistr ati o n is t er mi n at e d w h e n t h e A E o c c urs  
7)  U n k n o w n 
7. 4. 7  
Pr e g n a n c y r e p ort  
F e m al e s u bj e cts of c hil d b e ari n g p ot e nti al a n d m al e s u bj e cts w h o ar e s e x u all y a cti v e wit h 
w o m e n of c hil d b e ari n g p ot e nti al m ust pr a cti c e a p pr o pr i at e c o ntr a c e pti o n u ntil t h e 7t h visit 
(l ast visit, D a y 2 7 0) aft er t h e l ast a d mi nistr ati o n of t h e i n v esti g ati o n al pr o d u ct.  
T h e a p pr o pri at e c o ntr a c e pti o n m et h o ds a c k n o wl e d g e d i n t his cli ni c al st u d y ar e:  
 
H or m o n al c o ntr a c e pti v es  
 
I ns erti o n of a n I ntr a ut eri n e d e vi c e or s yst e m  
 
D o u bl e b arri er m et h o d*(s p er mi ci d e a n d c o n d o m wit h v a gi n al di a p hr a g m, v a gi n al 
s p o n g e, or c er vi c al c a p)  
* B ot h m al e ( c o n d o m) a n d f e m al e ( v a gi n al di a p hr a g m, v a gi n al s p o n g e or c er vi c al 
c a p) m ust us e c o ntr a c e pti v e d e vi c es t o g et h er wit h s p er mi ci d e.  
 
St erili z ati o n s ur g er y ( v as e ct o m y, bil at er al t u b al li g ati o n, et c.)  
 
C o m pl et e  a bsti n e n c e:  If  pr ef err e d  b y  t h e  s u bj e ct  a n d  m at c h e d  wit h  e v er y d a y  
lif est yl e.  [ P eri o di c  a bsti n e n c e  a n d  c oit us  i nt err u pt us  ar e  n ot  a c k n o wl e d g e d  as  
c o ntr a c e pti o n.]  
 
T h e S p o ns or h as t h e o bli g ati o n t o f oll o w u p o n t h e r es ults of pr e g n a n c y r e p ort e d b y f e m al e 
a n d m al e s u bj e cts d uri n g t h e cli ni c al st u d y. If it is n ot s us p e ct e d t h at t h e i n v esti g ati o n al 
pr o d u ct i nt erf er e d wit h t h e effi c a c y of a p pr o pri at e c o ntr a c e pti o n a n d c o ntr a c e pti v es, t h e 
pr e g n a n c y its elf is n ot c o nsi d er e d a n A E. I n a d diti o n, v ol u nt ar y i n d u c e d a b orti o n wit h o ut 
c o m pli c ati o ns, ot h er t h a n t h er a p e uti c a b orti o n, is n ot c o nsi d er e d a n A E.  
 
Wit hi n 2 4 h o urs of b e c o mi n g a w ar e of pr e g n a n c y, t h e I n v esti g at or s h all pr e p ar e a n i niti al 
pr e g n a n c y r e p ort a n d r e p ort it t o t h e S p o ns or. T h e I n v esti g at or s h all tr a c k a n d d o c u m e nt 
t h e  pr o c ess  a n d  r es ults  of  all  pr e g n a n ci es  e v e n  if  t h e  s u bj e ct  wit h dr a ws  c o ns e nt  or  
t er mi n at es t h e cli ni c al st u d y. I n a d diti o n, t h e i n v esti g at or s h all pr e p ar e a pr e g n a n c y r es ult 
r e p ort a n d r e p ort it t o t h e S p o ns or wit hi n 2 4 h o urs of b e c o mi n g a w ar e of t h e r es ults of 
a n y pr e g n a n c y ( e. g., s p o nt a n e o us l a b or, s p o nt a n e o us a b orti o n, et c.).  
 
All S A Es ( e. g., s e v er e m at er n al c o m pli c ati o ns, pr e m at ur e birt h, t h er a p e uti c a b orti o n, e ct o pi c 
pr e g n a n c y, still birt h, n e o n at al d e at h, c o n g e nit al a n o m al y, birt h d ef e cts, et c.) t h at o c c urr e d 
fr o m b e gi n ni n g of pr e g n a n c y t o f o ur w e e ks aft er c hil d birt h s h all b e r e c or d e d i n t h e S A E 
r e p ort a n d m ust b e r e p ort e d i m m e di at el y t o t h e P V A of D T & S a n o M e di cs C o., Lt d., f oll o wi n g 
t h e pr o c e d ur e i n 7. 4 A d v er s e E v e nts. 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 2 3
1 2 3  / 1 2 4
1 2 4  
 
 
  8 St ati sti c al M et h o d  
8. 1  
A n al y si s S et  
Effi c a c y ass ess m e nt s h all us e t h e i nt e nti o n -t o-tr e at (I T T) p o p ul ati o ns as t h e a n al ysis s ets, a n d 
a n al ysis  s h all  b e  p erf or m e d  a u xili aril y  i n  t h e  p er -pr ot o c ol  ( P P)  s ets.  T h e  d efi niti o n  of  e a c h  
a n al ysis s et f or t h e ass ess m e nt of s af et y, t ol er a bilit y, a n d effi c a c y is as f oll o ws:  
8. 1. 1  
S u bj e ct  S et  t o  B e  I n cl u d e d  i n  S af et y  a n d  T ol er a bilit y  A s s e s s m e nt  A n al y s e s:  
S af et y s et  
A m o n g  all  s u bj e cts  e v al u at e d  f or  t h eir  eli gi bilit y  d uri n g  t h e  s cr e e ni n g  p eri o d,  t h os e  
s u bj e cts w h os e s af et y c a n b e ass ess e d aft er b ei n g a d mi nist er e d t h e i n v esti g ati o n al pr o d u ct 
s h all b e i n cl u d e d i n t h e s af et y a n al ysis. T h e s u bj e cts i n cl u d e d i n t h e s af et y a n al ysis s h all 
b e a n al y z e d b as e d o n t h e i nf or m ati o n of t h e a ct u all y a d mi nist er e d i n v esti g ati o n al pr o d u ct. 
I n a d diti o n, t h e d e m o gr a p hi c d at a (s e x, a g e, et c.) a n d b a c k gr o u n d f a ct ors ( m e di c al hist or y, 
pr e vi o us dr u g tr e at m e nt hist or y, et c.) s h all b e a n al y z e d i n t h e s af et y s et.  
 
8. 1. 2  
S u bj e ct S et t o B e I n cl u d e d i n Effi c a c y A s s e s s m e nt A n al y si s: I nt e nti o n -t o-tr e at 
(I T T) s et 
S u bj e cts  w h o  h a v e  b e e n  a d mi nist er e d  t h e  i n v esti g ati o n al  pr o d u ct  a n d  h a v e  u n d er g o n e  
effi c a c y ass ess m e nt at l e ast o n c e s h all b e i n cl u d e d i n t h e I T T a n al ysis s et, r e g ar dl ess  of 
pr ot o c ol vi ol ati o ns, c o m pli a n c e wit h visit s c h e d ul e, et c.  
 
8. 1. 3  
S u bj e ct S et t o B e I n cl u d e d i n Effi c a c y A s s e s s m e nt A n al y si s: P er -pr ot o c ol ( P P) 
s et  
P P S  s h all  i n cl u d e  t h os e  s u bj e cts  i n  t h e  I T T  s et  w h o  h a v e  c o m pl et e d  t h e  cli ni c al  st u d y  
a c c or di n g t o t h e pr ot o c ol wit h o ut m aj or pr ot o c ol vi ol ati o ns. S u bj e cts w h o f all u n d er t h e 
f oll o wi n g s h all b e d efi n e d as P P S. C o m pli a n c e wit h N o. ① eli gi bilit y  s h all b e d et er mi n e d 
i n a d at a r e vi e w m e eti n g pri or t o d at al o c k. 
① 
S u bj e cts w h o h a v e n ot vi ol at e d t h e i n cl usi o n a n d e x cl usi o n crit eri a ( eli gi bl e 
p ati e nts)  
② 
S u bj e cts w h o h a v e c o m pl et e d all visits  
 
8. 1. 4   
S u b gr o u p A n al y si s P o p ul ati o n  
W h e n c o n d u cti n g t h e a d v ers e e v e nts a n d effi c a c y ass ess m e nts, s u b gr o u p a n al ysis s h all b e 
p erf or m e d b y c o nsi d eri n g t h e f oll o wi n g it e ms:  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 2 4
1 2 4  / 1 2 5
1 2 5  
 
 
 
• 
S e x ( m al e, f e m al e)  
• 
A g e ( ≤ m e di a n, > m e di a n)  
• 
B as eli n e B MI ( ≤ m e di a n, > m e di a n)  
• 
Pr es e n c e or a bs e n c e of m e di c al hist or y  
• 
Pr es e n c e or a bs e n c e of c o n c o mit a nt dr u gs  
• 
Dis e as e s e v erit y ( C M T N S -v 2) ( mil d, m o d er at e)  
 
If t h er e ar e o nl y a f e w s u bj e cts i n e a c h s et w h o c orr es p o n d t o t h e a b o v e s u b gr o u p, a n al ysis 
s h all n ot b e p erf or m e d f or t h e a p p li c a bl e s u b gr o u p. F or e x a m pl e, if ≤ 3 0 % of t h e t ot al 
n u m b er of s u bj e cts is m al e, n o s e p ar at e a n al ysis f or s e x s h all b e p erf or m e d, a n d w h et h er 
a s u b gr o u p a n al ysis s h o ul d b e p erf or m e d s h all b e d et er mi n e d i n a d at a r e vi e w m e eti n g 
pri or t o d at al o c k.  
 
8. 2  
H a n dli n g of Mi s si n g V al u e s  
F or missi n g v al u es d u e t o e arl y t er mi n ati o n of s u bj e cts, t h e y s h all n ot b e i m p ut e d a n d s h all b e 
a n al y z e d usi n g t h e a v ail a bl e d at a s et.  
 
8. 3  
Cl a s sifi c ati o n of S u bj e ct s  
S cr e e n F ail ur e  - T his  is  a  s u bj e ct  w h o  h as  si g n e d t h e i nf or m e d c o ns e nt f or m  i n t h e cli ni c al 
st u d y b ut f ail e d t o s atisf y t h e i n cl usi o n/ e x cl usi o n crit eri a i n t h e s cr e e ni n g pr o c ess. N o f oll o w -
u p  f or  s af et y  or  p h ar m a c o d y n a mi c  ass ess m e nt  s h all  b e  c o n d u ct e d,  n eit h er  s h all  a n y  ot h er  
cli ni c al st u d y pr o c e d ur e b e p erf or m e d.  
E v al u a bl e  S u bj e ct   - T h es e  ar e  all  of  t h e  s u bj e cts  w h o  h a v e  b e e n  a d mi nist er e d  t h e  
i n v esti g ati o n al pr o d u ct b y p arti ci p ati n g i n t h e cli ni c al st u d y. T h e y s h all b e cl assifi e d a c c or di n g 
t o t h e d efi niti o n of “ 8. 1 A n al ysis S et” a n d a n al y z e d. 
L o st t o F oll o w -u p  - T hi s is a s u bj e ct w h o h as b e e n a d mi nist er e d t h e i n v esti g ati o n al pr o d u ct, 
b ut h as n ot c o m pl et e d t h e pl a n n e d visits. T h es e i n cl u d e s u bj e cts w h o h a v e wit h dr a w n c o ns e nt 
as  w ell as  s u bj e cts  w h o  h a v e r ef us e d f urt h er  p arti ci p ati o n i n  t h e cli ni c al st u d y  a n d f ail e d t o  
r es p o n d t o all att e m pts at c o nt a cti n g t h e s u bj e cts. A n al ysis s h all b e p erf or m e d a c c or di n g t o 
“ 8. 2. H a n dli n g of Missi n g V al u es.” 
 
8. 4  
St ati sti c al A n al y si s M et h o d  
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 2 5
1 2 5  / 1 2 6
1 2 6  
 
 
8. 4. 1  
G e n er al Pri n ci pl e s of St ati sti c al A n al y si s  
Si n c e t his is a p h as e 1/ 2 a cli ni c al st u d y a n d t h e n u m b er of s u bj e cts is s m all, t h e d at a 
fr o m t h e tr e at m e nt p eri o d a n d t h e f oll o w-u p p eri o d s h all b e d es cri pti v el y c o m p ar e d a n d 
r e vi e w e d. F or c o nti n u o us v ari a bl es, d es cri pti v e st atisti cs (t h e n u m b er of s u bj e cts, m e a n, 
st a n d ar d d e vi ati o n, m e di a n, m a xi m u m, mi ni m u m) s h all b e pr es e nt e d, w hil e fr e q u e n c y 
a n d p er c e nt s h all b e pr es e nt e d f or c at e g ori c al v ari a bl es.  
If n e c ess ar y or if c o m p aris o ns ar e p ossi bl e, st atisti c al t esti n g s h all b e p erf or m e d. T h e p-
v al u e s h all b e pr es e nt e d wit h f o ur d e ci m al pl a c es w h e n t esti n g, a n d a t w o -t ail e d t est 
s h all b e p erf or m e d u n d er a si g nifi c a n c e l e v el of 0. 0 5. A d v ers e e v e nts s h all b e c o m p ar e d 
b y c al c ul ati n g t h e 9 5 % c o nfi d e n c e i nt er v al. I n a d diti o n, i n d es cri pti v e st atisti cs, v al u es 
b el o w t h e d e ci m al p oi nt s h all b e pr es e nte d wit h t w o d e ci m al pl a c es . 
 
8. 4. 2  
B a si c I nf or m ati o n o n S u bj e ct s a n d Di s e a s e  
T h e  d e m o gr a p hi c  i nf or m ati o n  ( e. g.,  a g e,  s e x,  et c.)  of  s u bj e cts  as  w ell  as  u n d erl yi n g  
c h ar a ct eristi cs pri or t o tr e at m e nt ( e. g., m e di c al hist or y, c o n c o mit a nt m e di c ati o ns, et c.) s h all 
b e s u m m ari z e d.  
M e di c al  hist or y  s h all  b e  e n c o d e d  usi n g  t h e  s yst e m  or g a n  cl a ss es  ( S O Cs)  a n d  pr ef err e
d  t er ms  ( P Ts)  a c c or di n g  t o  t h e  l at est  v ersi o n  of  t h e  m e di c al  di cti o n ar y  f or  r e g ul at or y  
a cti viti es  ( M e d D R A),  a n d  t h e  fr e q u e n ci es  a n d  p er c e nt a g es  s h all  b e  pr es e nt e d.   
Pr e vi o us  a n d  c o n c o mit a nt  m e di c ati o ns  s h all  b e  cl assifi e d  i nt o  t h e  a n at o mi c al  m ai n  gr
o u ps  a n d  t h er a p e uti c  s u b gr o u ps  a c c or di n g  t o  t h e  l at est  v ersi o n  of  t h e  a n at o mi c al  t h
er a p e uti c  c h e mi c al  s yst e m  ( A T C  C O D E),  a n d  t h e  fr e q u e n ci es  a n d  p er c e nt a g es  s h all  b e  
pr es e nt e d.  I n  a d diti o n,  pr e vi o us  t h er a pi es  a n d  c o n c o mit a nt  t h er a pi es  s h al l  b e  e n c o d e
d  usi n g  t h e  s yst e m  or g a n  cl ass es  ( S O Cs)  a n d  pr ef err e d  t er ms  ( P Ts)  a c c or di n g  t o  t h e  l
at est  v ersi o n  of  t h e  m e di c al  di cti o n ar y  f or  r e g ul at or y  a cti viti es  ( M e d D R A),  a n d  t h e  fr e
q u e n ci es  a n d  p er c e nt a g es  s h all  b e  pr es e nt e d.  
 
8. 4. 3  
Pri m ar y E n d p oi nt s  
 ( 1) 
A d v er s e e v e nt s  
: S u m m ari z ati o n a n d a n al ysis of a d v ers e e v e nts s h all b e p erf or m e d o n tr e at m e nt-
e m er g e nt a d v ers e e v e nts ( T E A Es).  
T h e fr e q u e n ci es a n d p er c e nt a g es s h all b e pr es e nt e d f or t h e o c c urr e n c e of tr e at m e nt -
e m er g e nt a d v ers e e v e nts ( T E A Es), a d v ers e dr u g r e a cti o ns ( A D Rs), s eri o us a d v ers e e v e nts 
( S A Es) a n d a d v ers e e v e nts of s p e ci al i nt er ests( A E SIs) , et c. 
T h e a d v ers e e v e nts, a d v ers e dr u g r e a cti o ns, a n d s eri o us a d v ers e e v e nts s h all b e e n c o d e d 
usi n g t h e s yst e m or g a n cl ass es ( S O Cs) a n d pr ef err e d t er ms ( P Ts) a c c or di n g t o t h e l at est 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 2 6
1 2 6  / 1 2 7
1 2 7  
 
 
v ersi o n of t h e m e di c al di cti o n ar y f or r e g ul at or y a cti viti es ( M e d D R A). T h e n u m b er of 
s u bj e cts wit h o ns et, t h e i n ci d e n c e, t h e n u m b er of c as es, et c., s h all b e pr es e nt e d f or t h e 
e n c o d e d a d v ers e e v e nts.  
 
( 2) 
L a b or at or y t e st s a n d vit al si g n s  
: F or c o nti n u o us v ari a bl es, d es cri pti v e st atisti cs ( m e a n, st a n d ar d d e vi ati o n, m e di a n, 
mi ni m u m, m a xi m u m) s h all b e pr es e nt e d f or e a c h visit. Fr e q u e n ci es a n d p er c e nt a g es s h all 
b e pr es e nt e d f or c at e g ori c al v ari a bl es. T h e fr e q u e n ci es a n d p er c e nt a g es f or n or m al s hifts, 
n ot cli ni c all y si g nifi c a nt ( N C S) a b n or m al s hifts, a n d cli ni c all y si g nifi c a nt ( C S) a b n or m al 
s hifts s h all b e pr es e nt e d f or e a c h visit. T h e s u bj e cts w h o h a v e b e e n ass ess e d as cli ni c all y 
si g nifi c a nt ( C S) at e a c h visit s h all b e pr es e nt e d  i n a list. 
 
8. 4. 4  
S e c o n d ar y E n d p oi nt s  
( 1) S e v erit y of di s e a s e  
T his  s h all  b e  m e as ur e d  usi n g  C h ar c ot -M ari e -T o ot h  N e ur o p at h y  S c or e  v ersi o n  2  
( C M T N S-v 2) a n d t h e f u n cti o n al dis a bilit y s c al e ( F D S).  
: D es cri pti v e st atisti cs (fr e q u e n c y, p er c e nt a g e) f or t h e c h a n g es i n C M T N S -v 2 a n d F D S 
at  t h e  t er mi n ati o n  visit  ( V 7)  c o m p ar e d  wit h  t h e  b as eli n e  ( V 2)  s h all  b e  pr es e nt e d.  A  
c o nti n g e n c y  t a bl e  s h all  b e  pr e p ar e d  f or  t h e  diff er e n c es  b ef or e  a n d  aft er  
a d mi nistr ati o n, a n d a n al ysis s h all b e p erf or m e d usi n g t h e M c N e m ar’s t est.  
I n  a d diti o n,  d es cri pti v e  st atisti cs  ( m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  
m a xi m u m) s h all b e pr es e nt e d f or t h e c h a n g es i n F D S at e a c h visit ( v 4, v 6, v 7) c o m p ar e d 
wit h t h e b as eli n e ( v 2), a n d a n al ysis s h all b e p erf or m e d usi n g a p air e d t -t est ( wil c o x o n 
si g n e d  r a n k  t est  if  t h e  ass u m pti o n  of  n or m al  distri b uti o n  is  n ot  s atisfi e d)  f or  t h e  
diff er e n c es at e a c h visit c o m p ar e d wit h t h e b as eli n e.  
 
 
( 2) L o w er li m b f u n cti o n  
C h a n g es  i n  l o w er  li m b  f u n cti o n  s h all  b e  ass ess e d  usi n g  t h e  o v er all  n e ur o p at h y  
li mit ati o n s c or e ( O N L S) a n d t h e 1 0-m et er w al k t est ( 1 0 M W T).  
: D es cri pti v e st atisti cs ( m e a n, st a n d ar d d e vi ati o n, m e di a n, mi ni m u m, m a xi m u m) s h all 
b e  pr es e nt e d  f or  t h e  c h a n g es  i n  l o w er  li m b  f u n cti o n  ( O N L S  l e g  s c al e,  1 0 M W T))  at  
e a c h visit ( V 4, V 6, V 7) c o m p ar e d wit h t h e b as eli n e ( V 2), a n d a n al ysis s h all b e p erf or m e d 
usi n g  a  p air e d  t -t est  ( Wil c o x o n  si g n e d  r a n k  t est  if  t h e  ass u m pti o n  of  n or m al  
distri b uti o n  is  n ot  s atisfi e d)  f or  t h e  diff er e n c es  at  e a c h  visit  c o m p ar e d  wit h  t h e  
b as eli n e.  
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 2 7
1 2 7  / 1 2 8
1 2 8  
 
 
( 3) D e gr e e of F att y i nfiltr ati o n of l o w er li m b m u s cl e s  
T h e m us cl es of l o w er li m bs s h all b e i m a g e d wit h M RI l e g s c a n, a n d t h e d e gr e e of f att y 
i nfiltr ati o n  of  t h e  l e g  m us cl es  i nj e ct e d  wit h  t h e  i n v esti g ati o n al  pr o d u ct  s h all  b e  
m e as ur e d a n d e v al u at e d as f at c o nt e nt v al u e ( %) at o n e l e v el f or e a c h m us cl e.  
: D es cri pti v e st atisti cs ( m e a n, st a n d ar d d e vi ati o n, m e di a n, mi ni m u m, m a xi m u m) s h all 
b e pr es e nt e d f or t h e c h a n g es i n t h e d e gr e e of f att y i nfiltr ati o n of l o w er li m b m us cl es 
at  t h e  t er mi n ati o n  visit  ( V 7) c o m p ar e d  wit h t h e b as eli n e  ( V 2),  a n d  a n al ysis  s h all  b e 
p erf or m e d f or t h e diff er e n c es b ef or e a n d aft er a d mi nistr ati o n b y usi n g a p air e d t -t est 
( Wil c o x o n si g n e d r a n k t est if t h e ass u m pti o n of n or m al distri b uti o n is not s atisfi e d).  
 
( 4) N er v e r e g e n er ati o n p ot e nti al  
N er v e c o n d u cti o n st u di es i n cl u di n g c o m p o u n d m ot or n er v e a cti o n p ot e nti al ( C M A P), 
c o m p o u n d  s e ns or y  n er v e  a cti o n  p ot e nti al  ( S N A P),  a n d  n er v e  c o n d u cti o n  v el o cit y  
( N C V) s h all b e p erf or m e d. 
: D es cri pti v e st atistics ( m e a n, st a n d ar d d e vi ati o n, m e di a n, mi ni m u m, m a xi m u m) s h all 
b e pr es e nt e d f or t h e c h a n g es i n n er v e c o n d u cti o n st u di es ( C M A P, S N A P, N C V) at t h e 
t er mi n ati o n visit ( V 7) c o m p ar e d wit h t h e b as eli n e ( V 2), a n d a n al ysis s h all b e p erf or m e d 
f or t h e diff er e n c es b ef or e a n d aft er a d mi nistr ati o n b y usi n g a p air e d t-t est ( Wil c o x o n 
si g n e d r a n k t est if t h e ass u m pti o n of n or m al distri b uti o n is n ot s atisfi e d).  
 
( 5) H G F a nti b o d y pr o d u cti o n b y E n g e n si s ( V M 2 0 2)  
T h e  pr es e n c e  or  a bs e n c e  of  H G F  a nti b o d y  ( a nti -H G F  A b)  i n  bl o o d  s h al l  b e  v erifi e d  
wit h  t h e  E LI S A  m et h o d.  A  pr eli mi n ar y  ass ess m e nt  s h all  b e  p erf or m e d  o n  w h et h er  
a nti b o d y  pr o d u cti o n  is  c orr el at e d  b et w e e n  t h e  s u bj e ct  gr o u p  d et er mi n e d  t o  h a v e  
i n cr e as e d m us cl e m ass a n d i m pr o v e d f u n cti o n, a n d t h e s u bj e ct gr o u p n ot d et er mi n e d 
as s u c h.   
H o w e v er, if a nti b o di es i n bl o o d w er e n ot pr o d u c e d i n a n y of t h e s u bj e cts, t h e r es ults 
s h all n ot b e pr es e nt e d.  
: D es cri pti v e st atisti cs (fr e q u e n c y, p er c e nt a g e) s h all b e pr es e nt e d f or t h e c h a n g es i n 
H G F  a nti b o d y  pr o d u cti o n  at  t h e  t er mi n ati o n  visit  ( V 7)  c o m p ar e d  wit h  t h e  b as eli n e  
( V 2).  A  c o nti n g e n c y  t a bl e  s h all  b e  pr e p ar e d  f or  t h e  diff er e n c es  b ef or e  a n d  aft er  
a d mi nistr ati o n, a n d a n al ysis s h all b e p erf or m e d usi n g t h e M c N e m ar’s t est.  
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 2 8
1 2 8  / 1 2 9
1 2 9  
 
 
9. 
D o c u m e nt M a n a g e m e nt  
9. 1  
C a s e R e p ort F or m  
R el e v a nt d o c u m e nts ( R Ds) r ef er t o t h e s u bj e ct’s r e c or ds t h at s h all b e st or e d at t h e i nstit uti o n. 
M ost  s o ur c e  d o c u m e nts  ar e  c h arts  of  t h e  i n v esti g at or,  a n d  all  i nf or m ati o n  r e c or d e d  i n  c as e  
r e p ort f or ms ( C R Fs) s h all b e c o nsist e nt wit h t h e c orr es p o n di n g r el e va nt d o c u m e nts.  
T his  cli ni c al st u d y  s h all us e el e ctr o ni c C R Fs ( e C R Fs), a n d t h e d e v el o p m e nt, m ai nt e n a n c e, a n d 
d at a  m a n a g e m e nt  of  t h e  e C R Fs  s h all  b e  p erf or m e d  b y  t h e  c o ntr a ct  r es e ar c h  or g a ni z ati o n  
d esi g n at e d b y H eli x mit h C o., Lt d. T h e e ntr y a n d r e visi o n of d at a s h all b e p erf or m e d b y a p er s o n 
a ut h ori z e d b y t h e pri n ci p al i n v esti g at or, a n d t h e fi n al r e vi e w a n d si g ni n g s h all b e p erf or m e d b y 
t h e  pri n ci p al  i n v esti g at or.  T h e  pri n ci p al  i n v esti g at or  s h all  g u ar a nt e e  t h at  t h e  i nf or m ati o n  
r e c or d e d i n t h e C R F is tr u e b y si g ni n g, a n d s h all b e r es p o nsi bl e f or t h e a c c ur a c y a n d r eli a bilit y 
of t h e  i nf or m ati o n  r e c or d e d  i n  t h e C R F i n  all  c as es. W h e n  t h e  e nt er e d  d at a  ar e  r e vis e d,  t h e  
r e visi o n d et ails s h all b e a ut o m ati c all y s a v e d a n d t h e d el eti o n of pr e vi o usl y e nt er e d d at a s h all 
n o t b e all o w e d. If n e c ess ar y, a c o p y of t h e e C R F s h all b e s u b mitt e d, a n d H E LI X MI T H C O., L T D. 
s h all st or e t h e ori gi n al e C R F f or t hr e e y e ars fr o m t h e t er mi n ati o n d at e of t h e cli ni c al st u d y.  
 
9. 2  
R e c or di n g a n d C oll e cti n g  
T h e el e ctr o ni c d at a c a pt ur e ( E D C) s yst e m  s h all c o m pl y wit h P art 1 1 of Titl e 2 1 of t h e C o d e of 
F e d er al  R e g ul ati o ns  ( 2 1  C F R  P art  1 1)  a n d  t h e  g ui d eli n es  f or  h a n dli n g  a n d  m a n a g e m e nt  of  
el e ctr o ni c d at a of cli ni c al st u di es. A d at a m a n a g e m e nt pl a n ( D M P) t h at d efi n es all pr o c e d ur es 
r el at e d  t o  D M  t as ks  an d  t h e  r ol es  of  r el e v a nt  st aff  s h all  b e  est a blis h e d  t o  d o c u m e nt  all  
pr o c e d ur es a n d o ut p ut.  
T h e E D C s yst e m s h all  b e a c c essi bl e o nl y  w h e n a ut h ori z e d,  a n d all a cti o ns s u c h as i n p utti n g,  
r e visi n g, st ori n g, a n d d el eti n g t h e el e ctr o ni c c as e r e p ort f or m ( e C R F) thr o u g h t h e E D C s yst e m 
s h all b e tr a c k e d a n d r e c or d e d. D at a v ali d ati o n t o r es ol v e o missi o ns of d at a, as w ell as i n v ali d, 
ill o gi c al, a n d i n c o nsist e nt d at a s h all b e p erf or m e d t hr o u g h c o m p ut er pr o gr a m mi n g a n d m a n u al 
c h e c ki n g.   
T h e  pri n ci p al  i n v esti g at or’s  el e ctr o ni c  si g n at ur e  s h all  g u ar a nt e e  t h at  t h e  d at a  e nt er e d  i n  t h e  
e C R F ar e a c c ur at e, c o m pl et e, i nt er pr et a bl e, a n d ti m el y. Aft er t er mi n ati o n of t h e st u d y, c o pi es of 
t h e e C R F s h all b e s a v e d i n el e ctr o ni c st or a g e m e di a a n d d eli v er e d t o e a c h i nstit uti o n, a n d t h e y 
sh all  b e  st or e d  i n  t h e  s a m e  m a n n er  as  ot h er  b asi c  d o c u m e nts.  T h e  fi n al  d at a b as e  s h all  b e  
o ut p ut i n t h e S A S f or m at a n d s e nt t o t h e p ers o n i n c h ar g e of st atisti cs.  
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 2 9
1 2 9  / 1 3 0
1 3 0  
 
 
9. 3  
A c c e s s t o, Pr ot e cti o n of, a n d St or a g e of R e c or d s  
All d at a r el at e d t o t his st u d y s h all b e st or e d i n a r estri ct e d ar e a, a n d o nl y t h e d el e g at e of t h e 
i nstit uti o n, t h e s p o ns or ( or d el e g at e), a n d d esi g n at e d p ers o ns of s u p er visi n g r e g ul at or y 
a ut h oriti es s h all b e all o w e d t o vi e w t h e m. F or c o nfi d e nti alit y of t h e  s u bj e cts’ i nf or m ati o n, o nl y 
t h e s u bj e cts’ i niti als a n d i d e ntifi c ati o n n u m b ers s h all b e r e c or d e d i n all r e p orts a n d d at a 
r el at e d t o t h e st u d y t o i d e ntif y t h e s u bj e cts. T h e i n v esti g at or s h all c o nti n u all y v erif y t h at t h e 
s u bj e ct i d e ntifi c ati o n n u m b ers ar e c o nsist e nt, a n d t his i nf or m ati o n s h all b e h a n dl e d i n 
a c c or d a n c e wit h pr of essi o n al c o nfi d e nti alit y st a n d ar ds.  
 
If t h er e is a r e q u est fr o m t h e I nstit uti o n al R e vi e w B o ar d or t h e Mi nistr y of F o o d a n d Dr u g S af et y, 
t h e  i n v esti g at or  s h all  all o w  vi e wi n g  of  t h e  d o c u m e nts  r el at e d  t o  t h e  cli ni c al  st u d y,  a n d  s h all  
a cti v el y  c o o p er at e  wit h  r e q u ests  s u c h  as  s u b missi o n  of  c o pi es  a n d  v erifi c ati o n  of  d et ails.  I n  
a d diti o n,  if  a  visit ati o n  h as  b e e n  n otifi e d  b y  t h e  I nstit uti o n al  R e vi e w  B o ar d  or  r e g ul at or y  
a ut h oriti es i n cl u di n g t h e Mi nistr y of F o o d a n d Dr u g S af et y, t h e i n v esti g at or s h all i m m e di at el y 
i nf or m t h e s p o ns or ( or d el e g at e), a n d m a y d el e g at e his/ h er a ut h orit y t o t h e s p o ns or.    
 
T h e i n v esti g at or s h all pr o vi d e t h e f oll o wi n g d o c u m e nts t o t h e s p o ns or ( or d el e g at e) pri or t o 
i niti ati n g t h e st u d y a n d t h e c o pi es s h all b e st or e d i n t h e tri al m ast er fil e.  
 
• 
C Vs  a n d  m e di c al  li c e ns es  ( wit hi n  t w o  y e ars)  of  t h e  pri n ci p al  i n v esti g at or  a n d  all  c o -
i n v esti g at ors 
• 
C o pi es  of  all  cli ni c al  st u d y  a p pr o v al  l ett ers  iss u e d  b y  t h e  I nstit uti o n al  R e vi e w  B o ar d  
( M att ers r el at e d t o t h e c h a n gi n g pr o gr ess w hil e c o n d u cti n g t his cli ni c al st u d y s h all b e 
r e g ul arl y s u b mitt e d t o t h e I nstit uti o n al R e vi e w B o ar d or s h all b e s u b mitt e d i n a c c or d a n c e 
wit h t h e p oli ci es of t h e I nstit uti o n al R e vi e w B o ar d.)  
• 
S u bj e ct i nf or m e d c o ns e nt f or ms a p pr o v e d b y t h e I nstit uti o n al R e vi e w B o ar d  
• 
T h e si g n at ur e p a g e of t his cli ni c al st u d y pr ot o c ol t h at h as b e e n d at e d a n d si g n e d b y t h e 
pri n ci p al i n v esti g at or  
 
All r e c or ds r el at e d t o t h e cli ni c al st u d y s h all b e st or e d f or t hr e e y e ars fr o m t h e t er mi n ati o n d at e 
of t h e cli ni c al st u d y.  
T h e s p o ns or s h all i nf or m t h e pri n ci p al i n v esti g at or a n d t h e dir e ct or of t h e i nstit uti o n i n writi n g 
r e g ar di n g t h e n e c essit y of d at a st or a g e a n d t h e st or a g e p eri o d. If it is d et er mi n e d t h at st or a g e 
is n o l o n g er r e q uir e d, t h e s p o ns or s h all i nf or m t his f a ct i n writi n g t o t h e pri n ci p al i n v esti g at or 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 3 0
1 3 0  / 1 3 1
1 3 1  
 
 
a n d t h e dir e ct or of t h e i nstit uti o n.  
T h e  i n v esti g at or  s h all  n ot  d estr o y  a n y  d o c u m e nt  wit h o ut  a  n otifi c ati o n  fr o m  t h e  s p o ns or.  If  
tr a nsf erri n g  fr o m  t h e  c urr e nt  i nstit uti o n  t o  a  diff er e nt  o n e,  t h e  pri n ci p al  i n v esti g at or  s h all  
d el e g at e d o c u m e nt m a n a g e m e nt t o a p ers o n w h o t a k es hi s/ h er pl a c e, a n d i nf or m t h e s p o ns or 
of t h e n a m e of t h e d el e g at e d p ers o n as w ell as i nf or m ati o n o n t h e d o c u m e nt st or a g e l o c ati o n. 
If  d o c u m e nts  r el at e d  t o  t h e  st u d y  ar e  d a m a g e d  or  l ost  d u e  t o  mist a k es  or  a c ci d e nts,  t h e  
i n v esti g at or s h all pr o m ptl y i nf or m t his t o t h e s p o ns or. 
 
 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 3 1
1 3 1  / 1 3 2
1 3 2  
 
 
1 0 Q u alit y C o ntr ol a n d A s s ur a n c e  
T h e  s p o ns or  a n d  t h e c o ntr a ct  r es e ar c h  or g a ni z ati o n  s h all  c o n d u ct  t h e  cli ni c al  st u d y  a n d  pr e p ar e 
d o c u m e nts c o nsist e ntl y i n a c c or d a n c e wit h st a n d ar di z e d m et h o ds b as e d o n t h e st a n d ar d o p er ati n g 
pr o c e d ur es ( S O Ps). Si n c e c o m pli a n c e wit h r e g ul ati o ns is cr u ci al i n cli ni c al st u di es, t h e r e g ul ati o ns of 
r el e v a nt r e g ul at or y a g e n ci es a n d t h e K or e a n G o o d Cli ni c al Pr a cti c e ( K G C P) s h all b e c o m pli e d wit h.  
A n a u dit of t h e r eli a bilit y of t his cli ni c al st u d y m a y  b e p erf or m e d b y t h e s p o ns or at a n y ti m e d uri n g 
t h e  cli ni c al  st u d y  or  aft er  its  c o m pl eti o n.  T h e  s p o ns or  s h all  n otif y  t his  f a ct  i n  a d v a n c e  t o  t h e  
i n v esti g at or  s el e ct e d  t o  b e  a u dit e d,  a n d  t h e  n otifi e d  i n v esti g at or  s h all  pr o vi d e  c o o p er ati o n  t o  
f a cilit at e t h e a u dit. A n a u dit s h all b e p erf or m e d t o est a blis h t h e r eli a bilit y of d at a c oll e ct e d i n t h e 
r el e v a nt cli ni c al st u d y. I nf or m ati o n r el at e d t o t h e cli ni c al st u d y i n cl u di n g t h e i nf or m e d c o ns e nt f or ms, 
c as e r e p ort f or ms, s o ur c e d o c u m e nts, m e di c al r e c or ds, a n d r e g u l at or y d o c u m e nts s h all b e r e vi e w e d, 
a n d w h et h er t h e cli ni c al st u d y is b ei n g c o n d u ct e d i n a c c or d a n c e wit h t h e cli ni c al st u d y pr ot o c ol,  
t h e  s p o ns or’s  S O Ps,  t h e  K G C P,  a n d  r el e v a nt  r e g ul ati o ns  s h all  b e  v erifi e d.  Aft er  a n  a u dit,  a  bri ef  
m e eti n g s h all b e h el d t o  i nf or m t h e i n v esti g at or of t h e iss u es f o u n d i n t h e a u diti n g pr o c ess, a n d a 
r e p ort s h all b e m a d e usi n g a st a n d ar di z e d r e p ort f or m. 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 3 2
1 3 2  / 1 3 3
1 3 3  
 
 
1 1 I nf or m e d C o n s e nt 
T h e i n v esti g at or of t h e cli ni c al st u d y h as t h e r es p o nsi bilit y t o d es cri b e t o t h e s u bj e ct all i nf or m ati o n 
o n t h e cli ni c al st u d y ( p ur p os e of t h e cli ni c al st u d y, t as ks t o p erf or m w h e n p arti ci p ati n g i n t h e cli ni c al 
st u d y, p ot e nti al b e n efits a n d ris ks, et c.), as w ell as t h e r es p o nsi bilit y t o o bt ai n t h e i nf or m e d c o ns e nt 
f or m  c o m pl et e d  v ol u nt aril y  b y  t h e  s u bj e ct.  If  t h er e  is  a  n e e d  t o  a m e n d  t h e  i n cl u d e d  i nf or m e d  
c o ns e nt  f or m,  it  s h all  first  b e  a p pr o v e d  b y  t h e  I nstit uti o n al  R e vi e w  B o ar d.  A cti o ns  r el at e d  t o  t h e  
cli ni c al st u d y m ust n ot b e p erf or m e d u ntil t h e s u bj e ct h as c ar ef ull y r e a d t h e i nf or m e d c o ns e nt f or m 
a n d  h as  d at e d  a n d  si g n e d  t h e  f or m  i n  his/ h er  o w n  h a n d writi n g.  T h e  si g n e d  ori gi n al  i nf or m e d  
c o ns e nt f or m s h all b e st or e d at t h e i nstit uti o n, a n d a c o p y of t h e i nf or m e d c o ns e nt f or m s h all b e 
iss u e d t o t h e s u bj e ct. All d et ails o n t his s u bj e ct c o ns e nt pr o c e d ur e s h all b e r e c or d e d i n a c h art. T h e 
i nf or m e d c o ns e nt f or m s h all b e writt e n i n a w a y t h at c a n b e e asil y u n d erst o o d b y t h e s u bj e cts.  
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 3 3
1 3 3  / 1 3 4
1 3 4  
 
 
1 2 A p pr o v al of Cli ni c al St u d y Pr ot o c ol  
T h e cli ni c al st u d y m a y st art aft er s u b mitti n g t h e cli ni c al st u d y pr ot o c ol a n d r el e v a nt d o c u m e nts t o 
t h e Mi nistr y of F o o d a n d Dr u g S af et y a n d t h e I nstit uti o n al R e vi e w B o ar d, a n d o bt ai ni n g a p pr o v al.  
 
B ef or e  st arti n g  t h e  cli ni c al  st u d y,  t h e  cli ni c al  st u d y  pr ot o c ol,  i nf or m e d  c o ns e nt  f or m,  a n d  
i n v esti g at or’s  br o c h ur e  s h all  b e  s u b mitt e d  t o  a n d a p pr o v e d b y  t h e  I nstit uti o n al R e vi e w B o ar d. I n  
a d diti o n, t h e cli ni c al st u d y i n v esti g at or s h all pr e p ar e a n d s u b mit d o c u m e nts r el at e d t o t h e pri n ci p al 
i n v esti g at or’s  st at e m e nt.  W h e n  t h e  pri n ci p al  i n v esti g at or  si g ns  t h e  d o c u m e nts  r el at e d  t o  his/ h er  
st at e m e nt, a pr o mis e t o k e e p t h e r es p o nsi bilit y of c o n d u cti n g t h e cli ni c al st u d y i n a c c or d a n c e wit h 
r el e v a nt r e g ul ati o ns is m a d e. W h e n a p pr o v al l ett ers f or t h e cli ni c al st u d y pr ot o c ol, i nf or m e d c o ns e nt 
f or m, a n d si g n at ur e p a g e of t h e cli ni c al st u d y pr ot o c ol ar e iss u e d b y t h e I nstit uti o n al R e vi e w B o ar d, 
t h e i n v esti g at or s h all s u b mit t h es e t o t h e s p o ns or b ef or e t h e i n v esti g ati o n al pr o d u ct is d eli v er e d t o 
t h e  i nstit uti o n.  T h e  i nstit uti o n  s h all  a c c ur at el y  r e c or d  a n d  st or e  all  d et ails  of  t h e  a p pr o v al  l ett ers  
i n cl u di n g t h e d o c u me nts  t h at  w er e pr e p ar e d a n d r e p ort e d  i n  r el ati o n t o  t h e  I nstit uti o n al  R e vi e w 
B o ar d. T h e s p o ns or s h all r e c ei v e i nf or m ati o n o n t h e m e m b ers ( n a m es, p ositi o ns or titl es, affili ati o ns, 
I R B n u m b er) of t h e I nstit uti o n al R e vi e w B o ar d b ef or e t h e i n v esti g ati o n al pr od u ct a n d r el at e d arti cl es 
ar e d eli v er e d t o t h e i nstit uti o n.  
 
I n a c c or d a n c e wit h t h e r e g ul ati o ns of t h e Mi nistr y of F o o d a n d Dr u g S af et y or h e alt h a ut h oriti es, 
t h e  d et ails  r el at e d  t o  s u bj e ct  r e cr uit m e nt  a d v ertis e m e nts  m ust  b e  a p pr o v e d  b y  t h e  I nstit uti o n al  
R e vi e w  B o ar d  b ef or e  st arti n g  t h e  cli ni c al  st u d y.  T h e  i n v esti g at or  s h all  s u b mit  t h es e  first  t o  t h e  
s p o ns or  f or  c o nfir m ati o n  b ef or e  s u b mitti n g  t h e m  t o  t h e  I nstit uti o n al  R e vi e w  B o ar d  t o  o bt ai n  
a p pr o v al.  
I n  a c c or d a n c e  wit h  t h e  r e g ul ati o ns  of  t h e  I nstit uti o n al  Re vi e w  B o ar d,  t h e  i n v esti g at or  h as  t h e  
r es p o nsi bilit y t o r e p ort s eri o us a d v ers e e v e nts t h at o c c ur i n t h e s u bj e cts t o t h e I nstit uti o n al R e vi e w 
B o ar d. O n c e a r e p ort is s u b mitt e d, a c o p y s h all b e d eli v er e d t o t h e s p o ns or a n d t h e c o ntr a ct r es e ar c h 
or g a ni z ati o n. 
 
Cli ni c al st u d y pr o gr ess r e p orts s h all b e s u b mitt e d f oll o wi n g t h e i nt er v al est a blis h e d b as e d o n t h e 
p oli c y  of  t h e  I nstit uti o n al  R e vi e w  B o ar d.  I n  a d diti o n,  if  t h e  cli ni c al  st u d y  h as  b e e n  c o m pl et e d  
(i n cl u di n g e arl y t er mi n ati o n), t h e pri n ci p al i n v esti g at or s h all r e p ort t his t o t h e I nstit uti o n al R e vi e w 
B o ar d. A cl os e -o ut r e p ort s h all b e s u b mitt e d wit hi n t h e ti m eli n e est a blis h e d b as e d o n t h e p oli c y of 
t h e I nstit uti o n al R e vi e w B o ar d aft er t er mi n ati o n of t h e st u d y. T h e cl os e-o ut r e p ort s h all b e pr e p ar e d 
b y i n cl u di n g cli ni c al st u d y pr ot o c ol vi ol ati o ns, n u m b er of r e cr uit e d s u bj e cts, n u m b er of e v al u at e d 
s u bj e cts, s u bj e cts w h o w er e s us p e n d e d or dr o p p e d o ut fr o m t h e st u d y a n d t h eir r e as o ns, a d v ers e 
e v e nt d et ails, a n d t h e pri n ci p al i n v esti g at or’s fi n al c o m m e nts o n t h e o ut c o m es.  
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 3 4
1 3 4  / 1 3 5
1 3 5  
 
 
1 3 C o nfi d e nti alit y of S u bj e ct s’ R e c or d s  
C o nfi d e nti alit y  f or  t h e  i nf or m ati o n  of  s u bj e cts  p arti ci p ati n g  i n  t his  cli ni c al  st u d y  s h all  stri ctl y  
m ai nt ai n e d b y all i n di vi d u als r el at e d t o t h e cli ni c al st u d y i n a c c or d a n c e wit h K G C P a n d t h e  P ers o n al 
I nf or m ati o n Pr ot e cti o n A ct.  
T h e s u bj e cts s h all b e i nf or m e d  t h at  all cli ni c al st u d y d at a will b e st or e d i n a c o m p ut er a n d k e pt  
stri ctl y c o nfi d e nti al. T h e si g n e d i nf or m e d c o ns e nt f or ms s h all b e k e pt b y t h e pri n ci p al i n v esti g at or. 
T h e  pri n ci p al  i n v esti g at or  s h all  st or e  r el e v a nt  r e c or ds  b y  k e e pi n g  a  list  of  s u bj e ct  n u m b ers  a n d  
s u bj e ct n a m es. T h e i nf or m e d c o ns e nt f or ms a n d t h e list of s u bj e cts s h all b e st or e d at t h e i nstit uti o n 
f or 3 y e ars fr o m t h e t er mi n ati o n d at e of t h e cli ni c al st u d y. 
T h e i n v esti g a t or s h all m ai nt ai n c o nfi d e nti alit y f or all i nf or m ati o n o n t h e cli ni c al st u d y, a n d m a y n ot, 
f or a n y r e as o n, pr o vi d e r el e v a nt i nf or m ati o n t o a t hir d p art y (i n di vi d u al n ot r el at e d t o t h e cli ni c al 
st u d y) wit h o ut a writt e n c o ns e nt of t h e s p o ns or. H o w e v er, i nf or m ati o n m a y b e dis cl os e d t o w or k -
r el at e d i n di vi d u als w h o h a v e a gr e e d t o m ai nt ai n c o nfi d e nti alit y. 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 3 5
1 3 5  / 1 3 6
1 3 6  
 
 
1 4 M o nit ori n g of Cli ni c al St u d y  
T h e s p o ns or m a y d el e g at e d uti es or r ol es r el at e d t o t his st u d y t o a c o ntr a ct r es e ar c h or g a ni z ati o n. 
T h e cli ni c al m o nit or a ut h ori z e d b y t h e s p o ns or h as t h e r es p o nsi bilit y t o s u p er vis e t h e pr o gr ess of 
t h e cli ni c al st u d y.    I n a d diti o n, t h e cli ni c al m o nit or s h all visit t h e i nstit uti o n b ef or e t h e e nr oll m e nt 
of s u bj e cts a n d als o m a k e r e g ul ar visits, a n d s h all h a v e a c c ur at e k n o wl e d g e o f t h e cli ni c al st u d y i n 
pr o gr ess t hr o u g h p h o n e c alls a n d c orr es p o n d e n c e.  
 
W hil e visiti n g t h e i nstit uti o n, t h e m o nit or s h all pr e p ar e t o c oll e ct c as e r e p ort f or ms b y r e vi e wi n g 
s o ur c e d o c u m e nts t o v erif y t h e a c c ur a c y a n d c o m pl et e n ess of t h e i nf or m ati o n us e d i n c o m pl eti n g 
t h e c as e r e p ort f or ms. All s o ur c e d o c u m e nts s h all c o nt ai n all of t h e i nf or m ati o n r e q uir e d t o 
c o m pl et e t h e c as e r e p ort f or ms. All d at a a n d s o ur c e d o c u m e nts r e c or d e d d uri n g t his cli ni c al st u d y 
ar e s u bj e ct t o a u dit b y t h e Mi nist r y of F o o d a n d Dr u g S af et y or ot h er r e g ul at or y a g e n ci es. 
 
T h e cli ni c al m o nit or s h all m a k e a cl os e -o ut visit f or t h e t er mi n ati o n of t h e cli ni c al st u d y. T h e cl os e -
o ut visit s h all b e p erf or m e d t o c o m pl et e pr e p ar ati o n of all r e g ul at or y r e c or ds a n d r e p orts, t o arr a n g e 
a n d  c oll e ct  t h e  i n v esti g ati o n al  pr o d u ct  a n d  st u d y -r el at e d  arti cl es,  a n d  t o  cl e arl y  d efi n e  t h e  
i n v esti g at or’s r es p o nsi biliti es aft er t h e t er mi n ati o n of t h e cli ni c al st u d y. 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 3 6
1 3 6  / 1 3 7
1 3 7  
 
 
1 5 M e a s ur e s f or Pr ot e cti o n of S u bj e ct s’ S af et y  
T his cli ni c al st u d y s h all b e c o n d u ct e d s ci e ntifi c all y a n d et hi c all y i n a c c or d a n c e wit h t h e K G C P as w ell 
as  t h e  r el e v a nt  l a ws  a n d  r e g ul ati o ns.  F urt h er m or e,  t his  cli ni c al  st u d y  s h all  b e  c o n d u ct e d  i n  
a c c or d a n c e wit h t h e D e cl ar ati o n of H elsi n ki t o r es p e ct t h e di g nit y as w ell as t h e ri g hts a n d i nt er ests 
of h u m a n b ei n gs a n d n ot t o c a us e dis a d v a nt a g es t o t h e s u bj e cts. T h e I nstit uti o n al R e vi e w B o ar d 
s h all e v al u at e/ a p pr o v e t his cli ni c al st u d y pr ot o c ol i n a c c or d a n c e wit h t h e K G C P, a n d s h all r e g ul arl y 
e v al u at e w h et h er t h e cli ni c al st u d y is b ei n g c o n d u ct e d a c c or di n g t o t h e cli ni c al st u d y pr ot o c ol. 
 
T h e i n v esti g at or s h all v erif y t h e eli gi bilit y f or st u d y p arti ci p ati o n b y c h e c ki n g t h e h e alt h st at us of 
e a c h s u bj e ct pri or t o e nr oll m e nt i n t h e cli ni c al st u d y. I n a d diti o n, t h e i n v esti g at or s h all  tr y his/ h er 
b est  t o  g ai n  s uffi ci e nt  k n o wl e d g e  of  t h e  i n v esti g ati o n al  pr o d u ct  a n d  e ns ur e  t h e  s af et y  of  t h e  
s u bj e cts.  
 
If a n a d v ers e e v e nt d u e t o t h e cli ni c al st u d y o c c urs, a p pr o pri at e m e di c al i nt er v e nti o ns s h all b e t a k e n 
u ntil  t h e  s u bj e ct  r e c o v er s.  T h e  s p o ns or  s h all  pr o vi d e  i n d e m nifi c ati o n  f or  i nj uri es  d u e  t o  t h e  
i n v esti g ati o n al pr o d u ct i n a c c or d a n c e wit h t h e s u bj e ct i n d e m nifi c ati o n p oli c y. 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 3 7
1 3 7  / 1 3 8
1 3 8  
 
 
1 6 A m e n d m e nt of Cli ni c al St u d y Pr ot o c ol  
N eit h er  t h e  pri n ci p al  i n v esti g at or  n or  H eli x mit h  C o.,  Lt d.  m a y  a m e n d  t h e  d et ails  of  t his  pr ot o c ol  
d uri n g t h e cli ni c al st u d y wit h o ut t h e c o ns e nt of t h e ot h er p art y. Aft er t h e st art of t h e cli ni c al st u d y, 
a m e n d m e nts s h all b e m a d e o nl y i n e x c e pti o n al c as es. If a n a m e n d m e nt is t o b e m a d e i n t h e cli ni c al 
st u d y pr ot o c ol, all p arti es c o n c er n e d s h all a gr e e i n writt e n f or m b y pr o vi di n g t h eir si g n at ur es.  
A m e n d m e nts  t h at  m a y  i m p a ct  t h e  s af et y  of  t h e  s u bj e cts  or  t h e  v ali dit y  of  t h e  st u d y  m a y  b e  
i m pl e m e nt e d o nl y if t h e y ar e a p pr o v e d b y t h e Mi nistr y of F o o d a n d Dr u g S af et y or t h e I nstit uti o n al 
R e vi e w B o ar d (I R B).  
 
If t h e pr ot o c ol is t o b e a m e n d e d t o i m m e di at el y r e m o v e ris k f a ct ors s h o w n i n a m e di c al e m er g e n c y 
t h at h as o c c urr e d i n a s u bj e ct, it is r e c o m m e n d e d t o dis c uss t h e m att er wit h H eli x mit h C o., Lt d. or 
a n i n di vi d u al d esi g n at e d b y H eli x mit h C o., Lt d. T h es e e v e nts s h all b e r e p ort e d t o t h e Mi nistr y of 
F o o d a n d Dr u g S af et y a n d t h e I nstit uti o n al R e vi e w B o ar d as q ui c kl y as p ossi bl e.  
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 3 8
1 3 8  / 1 3 9
1 3 9  
 
 
1 7 Cli ni c al St u d y R e p ort ( C S R)  
W h e n t h e cli ni c al st u d y is c o m pl et e d or e arl y t er mi n at e d, t h e i n v esti g at or s h all a c c ur at el y pr e p ar e 
a C S R a n d s u b mit it t o t h e I nstit uti o n al R e vi e w B o ar d a n d t h e s p o ns or wit hi n o n e y e ar. T h e C S R  
s h all b e s u b mitt e d aft er all m o nit ori n g iss u es h a v e b e e n r es ol v e d i n t h e E D C s yst e m.  
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 3 9
1 3 9  / 1 4 0
1 4 0  
 
 
1 8 Pr e s e nt ati o n a n d P u bli c ati o n of Cli ni c al St u d y R e p ort  
T h e  d at a  o bt ai n e d  fr o m  t h e  r es ults  of  t his  st u d y  ar e  i nt ell e ct u al  pr o p erti es  of  t h e  cli ni c al  st u d y  
s p o ns or, a n d t h e y m a y b e pr es e nt e d o nl y w h e n all d at a h a v e b e e n a n al y z e d a n d t h e st u d y r es ults 
ar e a v ail a bl e. All r es ults o bt ai n e d fr o m t his st u d y m a y n ot b e  pr es e nt e d or p u blis h e d b y t h e pri n ci p al 
i n v esti g at or  or  ot h er  i n v esti g at ors  wit h o ut  a  pri or  a p pr o v al  of  t h e  s p o ns or.  W h e n  t h e  st u d y  is  
t er mi n at e d,  t h e  s p o ns or  or  a  d el e g at e  d esi g n at e d  b y  t h e  s p o ns or  s h all  pr e p ar e  a  cli ni c al  st u d y  
r e p ort. 
 
 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 4 0
1 4 0  / 1 4 0
1 4 0  
 
 
1 9  R ef er e n c e s 
 
 
[ 1] S a p ort a A S, S ottil e S L, Mill er LJ, F e el y S M, Sis ki n d C E, S h y M E. C h ar c ot -M ari e -T o ot h dis e as e s u bt y p es a n d 
g e n eti c t esti n g str at e gi es. A n n N e ur ol  2 0 1 1; 6 9: 2 2 – 3 3.  
[ 2] Va n P a ass e n B W, v a n d er K o oi AJ, v a n S p a e n d o n c k -Z w arts K Y, V er h a m m e C, d e Viss er F B, d e Viss er M. 
P M P 2 2 r el at e d n e ur o p at hi es: C h ar c ot -M ari e -T o ot h dis e as e t y p e 1 A a n d H er e dit ar y N e ur o p at h y wit h li a bilit y 
t o Pr ess ur e P alsi es. Or p h a n et J R ar e Dis e as es 2 0 1 4; 9: 3 8  
[ 3] S zi g eti K, L u ps k J R. C h ar c ot – M ari e – T o ot h dis e as e. E ur o p e a n J H u m a n G e n eti cs  2 0 0 9; 1 7: 7 0 3 -7 1 0  
[ 4] N a m S H, C h oi B O. Cli ni c al a n d g e n eti c as p e cts of C h ar c ot -M ari e -T o ot h dis e as e s u bt y p es.   Pr e cisi o n a n d 
F ut ur e M e di ci n e  2 0 1 9; 3( 2): 4 3 -6 8.  
[ 5] L u ps ki J R, d e O c a -L u n a R M, Sl a u g e n h a u pt S, P e nt a o L, G u z z ett a V, Tr as k BJ, S a u c e d o -C ar d e n as O, B ar k er 
D F, Killi a n J M, G ar ci a C A, C h a kr a v arti A, P at el PI.  D N A d u pli c ati o n ass o ci at e d wit h C h ar c ot -M ari e -T o ot h 
dis e as e t y p e 1 A, C ell  1 9 9 1; 6 6( 2): 2 1 9 -2 3 2  
[ 6] D y c k PJ, L a m b ert E H. L o w er m ot or a n d pri m ar y s e ns or y n e ur o n dis e as es wit h p er o n e al m us c ul ar atr o p h y. 
I. N e ur ol o gi c, g e n eti c, a n d el e ctr o p h ysi ol o gi c fi n di n gs i n h er e dit ar y p ol y n e ur o p at hi es. Ar c h N e ur ol.  1 9 6 8; 
1 8( 6): 6 0 3 – 6 1 8.  
[ 7] J u n ej a M,  B ur ns  J, S a p ort a  M A, et al. C h all e n g es i n m o d elli n g t h e C h ar c ot -M ari e -T o ot h n e ur o p at hi es f or 
t h er a p y d e v el o p m e nt. J N e ur ol, N e ur os ur g & Ps y c hi atr y 2 0 1 9; 9 0: 5 8 -6 7.  
[ 8] Ki m H S, Y o o n Y C, C h oi B O, Ji n W, C h a J G. M us cl e f at q u a ntifi c ati o n usi n g m a g n et i c r es o n a n c e i m a gi n g: 
c as e -c o ntr ol st u d y of C h ar c ot-M ari e -T o ot h dis e as e p ati e nts a n d v ol u nt e er s.  J C a c h e xi a S ar c o p e ni a M us cl e. 
2 0 1 9; 1 0( 3): 5 7 4 -5 8 5.  
[ 9] Vall at J -M, Si n d o u P, Pr e u x P -M, Ta b ar a u d F, Mil or A -M, C o ur ati er P, L e g u er n E, Bri c e A . Ultr astr u ct ur al 
P M P 2 2 e x pr essi o n i n i n h erit e d d e m y eli n ati n g n e ur o p at hi es. A n n N e ur ol  1 9 9 6; 3 9: 8 1 3 -8 1 7.  
[1 0 ] R o a B B, G ar ci a C A, S ut er U, et al. C h ar c ot -M ari e -T o ot h Dis e as e Ty p e 1 A - Ass o ci ati o n wit h a 
S p o nt a n e o us P oi nt M ut ati o n i n t h e P M P 2 2 G e n e. N E n gl J M e d  1 9 9 3; 3 2 9: 9 6 -1 0 1  
[1 1 ] S a n c h o S, Y o u n g P, S ut er U, R e g ul ati o n of S c h w a n n c ell pr olif er ati o n a n d a p o pt osis i n P M P 2 2 -d efi ci e nt 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 4 1
1 4 1  / 1 4 1
1 4 1  
 
 
 
mi c e a n d m o us e m o d els of C h ar c ot – M ari e – T o ot h dis e as e t y p e 1 A,  Br ai n  2 0 0 1; 1 2 4( 1 1): 2 1 7 7 – 2 1 8 7  
[1 2 ] Ki m, Y H , Ki m, Y H , S hi n, Y K , J o Y R, P ar k D K, S o n g M Y, U o o n B A, N a m S H, Ki m J H, C h oi B O, S hi n H Y, Ki m 
S W, Ki m S h, H o n g Y B, Ki m J K, P ar k H T. p 7 5 a n d n e ur al c ell a d h esi o n m ol e c ul e 1 c a n i d e ntif y p at h ol o gi c 
S c h w a n n c ells i n p eri p h er al n e ur o p at hi es . A n n Cli n Tr a nsl N e ur ol  2 0 1 9 ; 6 : 1 2 9 2 – 1 3 0 1 . 
[1 3 ] P a bl o S á n c h e z -M artí n, Tets u y a S ait o, M as a a ki K o m ats u. p 6 2/ S Q S T M 1: 'J a c k of all tr a d es' i n h e alt h a n d 
c a n c er. F E B S J.  2 0 1 9, 2 8 6( 1): 8 -2 3  
[1 4 ] J e n n y F ort u n, Willi a m A. D u n n Jr, S h al e J o y, Ji e Li, a n d L u ci a N ott er p e k. E m er gi n g R ol e f or A ut o p h a g y i n 
t h e R e m o v al of A g gr es o m es i n S c h w a n n C ells. J. N e ur os ci. 2 0 0 3. 2 3( 3 3) 1 0 6 7 2 -1 0 6 8 0.  
[1 5 ] P a nt er a H, S h y M E, S v ar e n J. R e g ul ati n g P M P 2 2 e x pr essi o n as a d os a g e s e nsiti v e n e ur o p at h y g e n e. Br ai n 
R es e ar c h  2 0 2 0; 1 7 2 6, Arti cl e 1 4 6 4 9 1  
[1 6 ] S er e d a M W, M e y er z u H ör st e G, S ut er U, U z m a N, N a v e K A.  T h er a p e uti c a d mi nistr ati o n of pr o g est er o n e 
a nt a g o nist i n a m o d el of C h ar c ot -M ari e -T o ot h dis e as e ( C M T -1 A).  N at M e d,  2 0 0 3; 9 : 1 5 3 3– 1 5 3 7  
[1 7 ] P ass a g e E, N orr e el J, N o a c k -Fr aissi g n es P, S a n g u e d ol c e V, Pi z a nt J, T hiri o n X, R o b a gli a -S c h ul p p A, 
P ellissi er J F, F o nt és M.  As c or bi c a ci d tr e at m e nt c orr e cts t h e p h e n ot y p e of a m o us e m o d el of C h ar c ot -M ari e -
T o ot h dis e as e.  N at M e d  2 0 0 4; 1 0( 4):  3 9 6 – 4 0 1  
[1 8 ] P ar e ys o n D, R eill y M M, S c h e n o n e A, F a bri zi G M, C a v all ar o T, S a nt or o L, Vit a G, Q u attr o n e A, P a d u a L, 
G e mi g n a ni F, Visi oli F, L a ur à M, R a di c e D, C al a br es e D, H u g h es R A, S ol ari A; C M T -T RI A A L; C M T -T R A U K 
gr o u ps. As c or bi c a ci d i n C h ar c ot - M ari e-T o ot h dis e as e t y p e 1 A ( C M T -T RI A A L a n d C M T -T R A U K): a d o u bl e -bli n d 
r a n d o mi z e d tri al. L a n c et N e ur ol. 2 0 1 1; 1 0( 4): 3 2 0 -3 2 8.  
[1 9 ] K h aj a vi M, S hi g a K, Wis z ni e ws ki W, H e F, S h a w C A, Ya n J, W e ns el T G, S ni p es GJ, L u ps ki J R. Or al c ur c u mi n 
miti g at es t h e cli ni c al a n d n e ur o p at h ol o gi c p h e n ot y p e of t h e Tr e m bl er -J m o us e: a p ot e nti al t h er a p y f or 
i n h erit e d n e ur o p at h y. A m J H u m G e n et 2 0 0 7; 8 1( 3): 4 3 8 – 4 5 3.  
[2 0 ] P at z k ó A, B ai Y, S a p ort a M A, K at o n a I, W u X, Vi z z us o D, F eltri M L, W a n g S, Dill o n L M, K a m h ol z J, 
Kir s c h n er D, S ar k ar F H, Wr a b et z L, S h y M E.  C ur c u mi n d eri v ati v es pr o m ot e S c h w a n n c ell diff er e nti ati o n a n d 
i m pr o v e n e ur o p at h y i n R 9 8 C C M T 1 B mi c e. Br ai n 2 0 1 2; 1 3 5( Pt 1 2): 3 5 5 1 -3 5 6 6.  
[2 1 ] S a h e n k Z, N a g ar aj a H N, M c Cr a c k e n B S, Ki n g W M, Fr ei m er M L, C e d ar b a u m J M, M e n d ell J R.  N T -3 
pr o m ot es n er v e r e g e n er ati o n a n d s e ns or y i m pr o v e m e nt i n C M T 1 A m o us e m o d els a n d i n p ati e nts. N e ur ol  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 4 2
1 4 2  / 1 4 2
1 4 2  
 
 
 
2 0 0 5; 6 5: 6 8 1 -6 8 9.  
[2 2 ] Vit a G, Vit a G L, St a n c a n elli C, G e ntil e L, R u s s o M, M a z z e o A. G e n eti c n e ur o m us c ul ar dis or d ers: li vi n g 
t h e er a of a t h er a p e uti c r e v ol uti o n. P art 1: p eri p h er al n e ur o p at hi es. N e ur ol S ci  2 0 1 9; 4 0( 4): 6 6 1 -6 6 9  
[2 3 ] C h u m a k o v I, Mil et A, C h ol et N, Pri m as 1 G, B o u c ar d 1 A, P er eir a 1 Y, Gr a u d e ns 1 E, M a n d el 1 J,    L aff air e 1 J, 
F o u c q ui er 1 J, Gli b ert 1 F, B ertr a n d 1 V, N a v e K -A, S er e d a M W,  Vi al 1 E,    G u e dj 1 M, H ajj 1 R, N a bir ot c h ki n 1 S, 
C o h e n D P ol yt h er a p y wit h a c o m bi n ati o n of t hr e e r e p ur p os e d dr u gs ( P X T 3 0 0 3) d o w n -r e g ul at es P m p 2 2  o v er -
e x pr essi o n a n d i m pr o v es m y eli n ati o n, a x o n al a n d f u n cti o n al p ar a m et er s i n m o d els of C M T 1 A 
n e ur o p at h y.  Or p h a n e t J R ar e Dis 2 0 1 4; 9, 2 0 1  
[2 4 ] M c C or q u o d al e D, P u cill o E M, J o h ns o n N E. M a n a g e m e nt of C h ar c ot -M ari e -T o ot h dis e as e: i m pr o vi n g 
l o n g-t er m c ar e wit h a m ulti dis ci pli n ar y a p pr o a c h. J M ulti dis ci p H e alt h c. 2 0 1 6; 9: 7 – 1 9.  
[2 5 ] Cr os bi e J, B ur ns J, O u vri er R A. Pr ess ur e c h ar a ct eristi cs i n p ai nf ul p es c a v us f e et r es ulti n g fr o m C h ar c ot –
M ari e – T o ot h dis e as e, G ait & P ost ur e. 2 0 0 8; 2 8( 4): 5 4 5 -5 5 1   
[2 6 ] R a m d h arr y G M, D a y B L, R eill y M M, M ar s d e n J F. F o ot dr o p s pli nts i m pr o v e pr o xi m al as w ell as dist al l e g 
c o ntr ol d uri n g g ait i n C h ar c ot -M ari e -T o ot h Dis e as e. M us cl e N er v e  2 0 1 2; 4 6: 5 1 2 -5 1 9.  
[2 7 ] W ei m er L H, P o d w all D. M e di c ati o n -i n d u c e d e x a c er b ati o n of n e ur o p at h y i n C h ar c ot M ari e T o ot h Dis e as e. 
J of N e ur ol o gi c al S ci e n c es 2 0 0 6; 2 4 2( 1 – 2): 4 7 -5 4  
[2 8 ] S u n A P, Ta n g L, Li a o Q, Z h a n g H, Z h a n g Y S, Z h a n g J. C o e xist e nt C h ar c ot -M ari e -T o ot h t y p e 1 A a n d t y p e 2 
di a b et es m ellit us n e ur o p at hi es i n a C hi n es e f a mil y.  N e ur al R e g e n R es  2 0 1 5; 1 0( 1 0): 1 6 9 6 – 1 6 9 9.  
[2 9 ] S m a n A D, H a c k ett D, Fi at ar o n e Si n g h M, F or n us e k C, M e n e z es M P, B ur ns J. S yst e m ati c r e vi e w of e x er cis e 
f or C h ar c ot-M ari e -T o ot h dis e as e. J P eri p h er N er v S yst 2 0 1 5; 2 0: 3 4 7 -3 6 2.  
[3 0 ] B uss oli n o F, Di R e n z o M F, Zi c h e M, B o c c hi ett o E, Oli v er o M, N al di ni L, G a u di n o G, Ta m a g n o n e L, C off er 
A, C o m o gli o P M. H e p at o c yt e gr o wt h f a ct or is a p ot e nt a n gi o g e ni c f a ct or w hi c h sti m ul at es e n d ot h eli al c ell 
m otilit y a n d gr o wt h.  J C ell Bi ol 1 9 9 2 ; 1 1 9( 3): 6 2 9 -4 1  
[3 1 ] M ats u m ot o K, N a k a m ur a T. E m er gi n g m ulti p ot e nt as p e cts of h e p at o c yt e gr o wt h f a ct or. J Bi o c h e m 1 9 9 6; 
1 1 9: 5 9 1 -6 0 0.  
[3 2 ] J a y as a n k ar V, W o o YJ, Pir olli TJ, et al. I n d u cti o n of a n gi o g e n esis a n d i n hi biti o n of a p o pt osis b y 
h e p at o c yt e gr o wt h f a ct or eff e cti v el y tr e ats p ostis c h e mi c h e art f ail ur e. J C ar d S ur g  2 0 0 5; 2 0: 9 3 -1 0 1  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 4 3
1 4 3  / 1 4 3
1 4 3  
 
 
 
[3 3 ] N a k a g a mi H, K a n e d a Y, O gi h ar a T, M oris hit a R. H e p at o c yt e gr o wt h f a ct or as  p ot e nti al c ar di o v as c ul ar 
t h er a p y. E x p ert R e v C ar di o v as c T h er  2 0 0 5; 3: 5 1 3 -9.  
[3 4 ] N a k a m ur a T , S a k ai K , N a k a m ur a T , M ats u m ot o K . H e p at o c yt e gr o wt h f a ct or t w e nt y y e ar s o n: M u c h m or e 
t h a n a gr o wt h f a ct or. J G astr o e nt er ol H e p at ol 2 0 1 1; 2 6 S u p pl 1: 1 8 8 -2 0 2.  
[3 5 ] N a k a m ur a T , Mi z u n o S . T h e dis c o v er y of h e p at o c yt e gr o wt h f a ct or ( H G F) a n d its si g nifi c a n c e f or c ell 
bi ol o g y, lif e s ci e n c es a n d cli ni c al m e di ci n e. Pr o c J p n A c a d S er B P h ys Bi ol S ci  2 0 1 0; 8 6( 6): 5 8 8 -6 1 0  
[3 6 ] H as hi m ot o N, Y a m a n a k a H, F u k u o k a T, et al. E x pr essi o n of H G F a n d c -M et i n t h e p eri p h er al n er v o us 
s yst e m of a d ult r ats f oll o wi n g s ci ati c n er v e i nj ur y. N e ur or e p ort 2 0 0 1; 1 2: 1 4 0 3 -7.  
[3 7 ] Gi a c o bi ni P, M essi n a A, Wr a y S, et al. H e p at o c yt e gr o wt h f a ct or a cts as a m ot o g e n a n d g ui d a n c e si g n al 
f or g o n a d otr o pi n h or m o n e-r el e asi n g h or m o n e-1 n e ur o n al mi gr ati o n. J N e ur os ci 2 0 0 7; 2 7: 4 3 1 -4 5.  
[3 8 ] K at o N, N e m ot o K, N a k a nis hi K, et al. N o n vir al g e n e tr a nsf er of h u m a n h e p at o c yt e gr o wt h f a ct or 
i m pr o v es str e pt o z ot o ci n-i n d u c e d di a b eti c n e ur o p at h y i n r ats. Di a b et es  2 0 0 5; 5 4: 8 4 6 -5 4  
[3 9 ] K oi k e H, M oris hit a R, I g u c hi S, A o ki M, M ats u m ot o K, N a k a m ur a T, Y o k o y a m a C, Ta n a b e T, O g hi h ar a T, 
K a n e d a Y. E n h a n c e d a n gi o g e n esis a n d i m pr o v e m e nt of n e ur o p at h y b y c otr a nsf e cti o n of h u m a n h e p at o c yt e 
gr o wt h f a ct or a n d pr ost a c y cli n s y nt h as e g e n e. F A S E B J  2 0 0 3; 1 7: 7 7 9 -8 1.  
[4 0 ] Ts u c hi h ar a T, O g at a S, N e m ot o K, O k a b a y as hi T, N a k a nis hi K, K at o N, M oris hit a R, K a n e d a Y, U e n o y a m a 
M, S u z u ki S, A m a k o M, K a w ai T, Ari n o H. N o n vir al R etr o gr a d e G e n e Tr a nsf er of H u m a n H e p at o c yt e Gr o wt h 
F a ct or I m pr o v es N e ur o p at hi c P ai n -r el at e d P h e n o m e n a i n R ats. M ol T h er 2 0 0 9 J a n; 1 7( 1): 4 2 -5 0.  
[4 1 ] T ö n g es L, Ost e n d orf T, L a m b all e F, G e n esti n e M, D o n o R, K o c h J. -C, B ä hr M, M ai n a F, Li n g or P. 
H e p at o c yt e gr o wt h f a ct or pr ot e cts r eti n al g a n gli o n c ells b y i n cr e asi n g n e ur o n al s ur vi v al a n d a x o n al 
r e g e n er ati o n i n vitr o a n d  i n vi v o. J o ur n al of N e ur o c h e mistr y 2 0 1 1, 1 1 7: 8 9 2 -9 0 3  
[4 2 ] Kit a m ur a K, I w a n a mi A, N a k a m ur a M, Ya m a n e J, W at a n a b e K, S u z u ki Y, Mi y a z a w a D, S hi b at a S, F u n a k os hi 
H, Mi y at a k e S, C offi n R S, N a k a m ur a T, T o y a m a Y, O k a n o H. H e p at o c yt e gr o wt h f a ct or pr o m ot es e n d o g e n o us 
r e p air a n d f u n cti o n al r e c o v er y aft er s pi n al c or d i nj ur y. J N e ur os ci. R es 2 0 0 7; 8 5: 2 3 3 2 -2 3 4 2  
[4 3 ] S h e e h a n S M, Tats u mi R, Te m m -Gr o v e CJ, All e n R E. H G F is a n a ut o cri n e gr o wt h f a ct or f or s k el et al m us cl e 
s at ellit e c ells i n vitr o. M us cl e N er v e  2 0 0 0; 2 3: 2 3 9 -2 4 5.  
[4 4 ] G al- L e vi R, L es h e m Y, A o ki S, N a k a m ur a T, H al e v y O. H e p at o c yt e gr o wt h f a ct or pl a ys a d u al r o l e i n 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 4 4
1 4 4  / 1 4 4
1 4 4  
 
 
 
r e g ul ati n g s k el et al m us cl e s at ellit e c ell pr olif er ati o n a n d diff er e nti ati o n. Bi o c hi mi c a et Bi o p h ysi c a A ct a ( B B A) - 
M ol e c ul ar C ell R es e ar c h 1 9 9 8; 1 4 0 2 ( 1): 3 9 -5 1.  
[4 5 ] J ess e n K R, Mir s k y R. S c h w a n n C ell Pr e c ur s ors; M ulti p ot e nt Gli al C ells i n E m br y o ni c Ner v es. Fr o nti er s i n 
M ol e c ul ar N e ur os ci e n c e  2 0 1 9; 1 2: 6 9  
[4 6 ] N h o B, L e e J, L e e J, K o K R, L e e SJ, Ki m S. Eff e cti v e c o ntr ol of n e ur o p at hi c p ai n b y tr a nsi e nt e x pr essi o n of 
h e p at o c yt e gr o wt h f a ct or i n a m o us e c hr o ni c c o nstri cti o n i nj ur y m o d el.  F A S E B J  2 0 1 8 ; 3 2( 9): 5 1 1 9 -5 1 3 1.  
[4 7 ] S u n W, F u n a k os hi H, N a k a m ur a T. O v er e x pr essi o n of H G F r et ar ds dis e as e pr o gr essi o n a n d pr ol o n gs lif e 
s p a n i n a tr a ns g e ni c m o us e m o d el of A L S. T h e J o ur n al of  n e ur os ci e n c e: t h e offi ci al j o ur n al of t h e S o ci et y f or 
N e ur os ci e n c e  2 0 0 2; 2 2: 6 5 3 7 -4 8.  
[4 8 ] K a d o y a m a K, F u n a k os hi H, O h y a W, N a k a m ur a T. H e p at o c yt e gr o wt h f a ct or ( H G F) att e n u at es gli osis a n d 
m ot o n e ur o n al d e g e n er ati o n i n t h e br ai nst e m m ot or n u cl ei of a tr a ns g e ni c m o us e m o d el of A L S. 
N e ur os ci e n c e r es e ar c h  2 0 0 7; 5 9: 4 4 6 -5 6.  
[4 9 ] Ty n d all SJ, W ali k o nis R S. Si g n ali n g b y h e p at o c yt e gr o wt h f a ct or i n n e ur o ns is in d u c e d b y 
p h ar m a c ol o gi c al sti m ul ati o n of s y n a pti c a cti vit y. S y n a ps e  2 0 0 7; 6 1: 1 9 9 -2 0 4.  
[5 0 ] A kit a H, Ta k a gi N, Is hi h ar a N, Ta k a gi K, M ur ot o mi K, F u n a k os hi H, M ats u m ot o  K, N a k a m ur a T, i Ta k e o S. 
H e p at o c yt e gr o wt h f a ct or i m pr o v es s y n a pti c l o c ali z ati o n of t h e N M D A r e c e pt or a n d i ntr a c ell ul ar si g n ali n g 
aft er e x cit ot o xi c i nj ur y i n c ult ur e d hi p p o c a m p al n e ur o ns. E x p eri m e nt al N e ur ol o g y  2 0 0 8; 2 1 0( 1): 8 3 -9 4.  
[5 1 ] S h a n g J, D e g u c hi K, O ht a Y, Li u N, Z h a n g X, Ti a n F, Ya m as hit a T, I k e d a Y, M ats u ur a T, F u n a k os hi H, 
N a k a m ur a T, A b e K.  Str o n g n e ur o g e n esis, a n gi o g e n esis, s y n a pt o g e n esis, a n d a ntifi br osis of h e p at o c yt e 
gr o wt h f a ct or i n r at’s br ai n aft er tr a nsi e nt mi d dl e c er e br al art er y o c cl u si o n. J N e ur os ci e n c e R es 2 0 1 1; 8 9: 8 6 -
9 5.  
[5 2 ] Is hi h ar a N, Ta k a gi N, Nii m ur a M, Ta k a gi K, N a k a n o M, Ta n o n a k a K, F u n a k os hi H, M ats u m ot o K, 
N a k a m ur a T, Ta k e o S. I n hi biti o n of a p o pt osis -i n d u ci n g f a ct or tr a nsl o c ati o n is i n v ol v e d i n pr ot e cti v e eff e cts of 
h e p at o c y t e gr o wt h f a ct or a g ai nst e x cit ot o xi c c ell d e at h i n c ult ur e d hi p p o c a m p al n e ur o ns. J N e ur o c h e mistr y 
2 0 0 6; 9 5: 1 2 7 7 -8 6.  
[5 3 ] Is hi g a ki A, A o ki M, N a g ai M, W arit a H, K at o S, K at o M, N a k a m ur a T, F u n a k os hi H, It o y a m a Y. I ntr at h e c al 
D eli v er y of H e p at o c yt e Gr o wt h F a ct or Fr o m A m y otr o p hi c L at er al S cl er osis O ns et S u p pr ess es Dis e as e 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 4 5
1 4 5  / 1 4 5
1 4 5  
 
 
 
Pr o gr essi o n i n R at A m y otr o p hi c L at er al S cl er osis M o d el. J N e ur o p at h o & E x p eri m e nt al N e ur ol 2 0 0 7; 6 6 ( 1 1): 
1 0 3 7 – 1 0 4 4.  
[5 4 ] G e n esti n e M, C ari c ati E, Fi c o A, Ri c h el m e S, H ass a ni H, S u n y a c h C, L a m b all e F, P a n zi c a G C, P ett m a n n B, 
H el m b a c h er F, R a o ul C, M ai n a F, D o n o R. E n h a n c e d n e ur o n al M et si g n ali n g l e v els i n A L S mi c e d el a y dis e as e 
o ns et. C ell d e at h & dis e as e  2 0 1 1; 2: e 1 3 0.  
[5 5 ] B ott ar o D P, R u bi n J S, F al ett o D L, C h a n A M, K mi e ci k T E, V a n d e W o u d e G F, A ar o ns o n S A. I d e ntifi c ati o n of  
t h e h e p at o c yt e  gr o wt h  f a ct or r e c e pt or as t h e c-m et pr ot o -o n c o g e n e pr o d u ct. S ci e n c e  1 9 9 1; 2 5 1( 4 9 9 5): 8 0 2 -4.  
[5 6 ] K a w ai d a K, M ats u m ot o K, S hi m a z u H, N a k a m ur a T. H e p at o c yt e gr o wt h f a ct or pr e v e nts a c ut e r e n al f ail ur e 
a n d a c c el er at es r e n al r e g e n er ati o n i n mi c e. Pr o c  N atl  A c a d  S ci U S A  1 9 9 4; 9 1: 4 3 5 7 -6 1.  
[5 7 ] Li u M L, M ar s W M, Z ar n e g ar R, Mi c h al o p o ul os G K. U pt a k e a n d distri b uti o n of h e p at o c yt e gr o wt h f a ct or 
i n n or m al a n d r e g e n er ati n g a d ult r at li v er. A m J P at h ol  1 9 9 4; 1 4 4: 1 2 9 -4 0.  
[5 8 ] Gill e J, K h ali k M, K o ni g V, K a uf m a n n R. H e p at o c yt e gr o wt h f a ct or/s c att er f a ct or ( H G F/ S F) i n d u c es 
v as c ul ar p er m e a bilit y f a ct or ( V P F/ V E G F) e x pr essi o n b y c ult ur e d k er ati n o c yt es. J I n v est D er m at ol 1 9 9 8; 
1 1 1: 1 1 6 0 -5.  
[5 9 ] M oris hit a R, A o ki M, Y o Y, O gi h ar a T. H e p at o c yt e gr o wt h f a ct or as c ar di o v as c ul ar h or m o n e: r ol e of H G F 
i n t h e p at h o g e n esis of c ar di o v as c ul ar dis e as e. E n d o cr J  2 0 0 2; 4 9: 2 7 3 -8 4.  
[6 0 ] H e nr y T D, Hir s c h AT, G ol d m a n J, W a n g Y L, Li ps D L, M c Mill a n W D, D u v al S, Bi g gs T A, K e o H H. S af et y of a 
n o n -vir al pl as mi d- e n c o di n g d u al is of or ms of  h e p at o c yt e  gr o wt h  f a ct or i n criti c al  li m b is c h e mi a p ati e nts:  a 
p h as e  I st u d y. G e n e  t h er a p y 2 0 1 1; 1 8( 8): 7 8 8 -9 4  
[6 1 ] Ki b b e M R, Hir s c h AT, M e n d els o h n F O, D a vi es M G, P h a m H, S a u c e d o J, M ar st o n W, P y u n W B, Mi n S K, 
P et er s o n B G, C o m er ot a A, C h oi D, B all ar d J, B art o w R A, L os or d o D W, S h er m a n W, Dri v er V, P eri n E C. S af et y 
a n d effi c a c y of pl as mi d D N A e x pr essi n g t w o  is of or ms of  h e p at o c yt e  gr o wt h  f a ct or i n p ati e nts  wit h  criti c al  li m b 
is c h e mi a. G e n e  t h er a p y 2 0 1 6; 2 3( 3): 3 0 6 -1 2.  
[6 2 ] Ajr o u d -Driss S, C hristi a ns e n M, All e n J A, K essl er J A. P h as e 1/ 2 o p e n -l a b el d os e-es c al ati o n st u d y of 
pl as mi d D N A e x pr essi n g t w o is of or ms of h e p at o c yt e gr o wt h f a ct or i n p ati e nts wit h p ai nf ul di a b eti c p eri p h er al 
n e ur o p at h y. M ol e c ul ar t h er a p y  2 0 1 3; 2 1( 6): 1 2 7 9 -8 6.  
[6 3 ] K essl er J A, S mit h A G, C h a B S, C h oi S H, W y m er J, S h ai b a ni A, Ajr o u d -Driss S, Vi ni k A; V M 2 0 2 D P N -II 

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 4 6
1 4 6  / 1 4 6
1 4 6  
 
 
 
St u d y Gr o u p.  D o u bl e -bli n d, pl a c e b o -c o ntr oll e d st u d y of H G F g e n e t h er a p y i n di a b eti c n e ur o p at h y. A n n Cli n 
Tr a ns l  N e ur ol  2 0 1 5; 2( 5): 4 6 5 -7 8  
[6 4 ] S ufit R L, Ajr o u d -Driss S, C as e y P, K essl er J A. O p e n l a b el st u d y t o ass ess t h e s af et y of V M 2 0 2 i n s u bj e cts 
wit h a m y otr o p hi c l at er al s cl er osis. A m y otr o p hi c L at er al S cl er osis a n d Fr o nt ot e m p or al D e g e n er ati o n 2 0 1 7; 
1 8( 3 -4): 2 6 9 -2 7 8  
[6 5 ] Ki m J S, H w a n g H Y, C h o K R, P ar k E A, L e e W, P a e n g J C, L e e D S, Ki m H K, S o h n D W, Ki m K B.  
I ntr a m y o c ar di al tr a nsf er of h e p at o c yt e gr o wt h f a ct or as a n a dj u n ct t o C A B G:  p h as e   I cli ni c al  st u d y. G e n e  
t h er a p y 2 0 1 3; 2 0( 7): 7 1 7 -2 2.  
[6 6 ] M ur p h y S M, H err m a n n D N, M c D er m ott M P, S c h er er S S, S h y M E, R eill y M M, P ar e ys o n D.    R eli a bilit y of 
t h e C M T n e ur o p at h y s c or e (s e c o n d v er si o n) i n C h ar c ot-M ari e -T o ot h dis e as e. J P eri p h er N er v S yst 2 0 1 1; 1 6( 3): 
1 9 1 -1 9 8  
[6 7 ] Ki m H S, Y o o n Y C, C h oi B O, Ji n W, C h a J G. M us cl e f at q u a ntifi c ati o n usi n g m a g n eti c r es o n a n c e i m a gi n g: 
c as e – c o ntr ol st u d y of C h ar c ot – M ari e – T o ot h dis e as e p ati e nts a n d v ol u nt e er s.  J C a c h e xi a, S ar c o p e ni a a n d 
M us cl e  2 0 1 9; 1 0 : 5 7 4 – 5 8 5 . 
[6 8 ] Bir o u k N, G o ui d er R, L e G u er n E, G u g e n h ei m M, Tar di e u S, M ais o n o b e T, L e F or esti er N, A gi d Y, Bri c e A, 
B o u c h e P.  C h ar c ot -M ari e -T o ot h dis e as e t y p e 1 A wit h 1 7 p 1 1. 2 d u pli c ati o n. Cli ni c al a n d el e ctr o p h ysi ol o gi c al 
p h e n ot y p e st u d y a n d f a ct or s i nfl u e n ci n g dis e as e s e v erit y i n 1 1 9 c as es. Br ai n 1 9 9 7; 1 2 0: 8 1 3 - 8 2 3.  
[6 9 ] Gr a h a m R C,  H u g h es  R A C. A m o difi e d p eri p h er al n e ur o p at h y s c al e: T h e O v er all N e ur o p at h y Li mit ati o ns 
S c al e. J N e ur ol N e ur os ur g & Ps y c hi atr y 2 0 0 6; 7 7: 9 7 3 -9 7 6.  
[7 0 ] Gr a h a m J E, Ostir G V, K u o Y F, Fis h er S R, Ott e n b a c h er KJ. R el ati o ns hi p B et w e e n T est M et h o d ol o g y a n d 
M e a n V el o cit y i n Ti m e d W al k T ests: A R e vi e w. Ar c h P h ys M e d R e h a bil 2 0 0 8; 8 9( 5): 8 6 5 -8 7 2  
[7 1 ] P ar e ys o n D, M ar c h esi C. Di a g n osis, n at ur al hist or y, a n d m a n a g e m e nt of C h ar c ot – M ari e – T o ot h dis e as e. 
L a n c et N e ur ol  2 0 0 9; 8: 6 5 4 – 6 7  
[7 2 ] B a n c hs I, C as as n o v as C,  Al b ertí A , D e J or g e L , P o v e d a n o M , M o nt er o J , M a rtí n e z-M at os J A , V ol pi ni V . 
Di a g n osis of C h ar c ot -M ari e -T o ot h Dis e as e. J Bi o m e d a n d Bi ot e c h 2 0 0 9; 9 8 5 4 1 5  
[7 3 ] El -A b assi R, E n gl a n d J D, C art er G T. C h ar c ot -M ari e -T o ot h Dis e as e: A n O v er vi e w of G e n ot y p es, 
P h e n ot y p es, a n d Cli ni c al M a n a g e m e nt Str at e gi es. P h ys M e d & R e h a b  2 0 1 4; 6: 3 4 2 -3 5 5  

 
 
 
 
 
 
 
P R T N O: V M C M T-0 0 1  
C o nfi d e nti al
C o nfi d e nti al  
2 0 2 1. 0 6 . 07  
Versi o n : 4 . 0 
 1 4 7
1 4 7  / 1 4 7
1 4 7  
 
 
 
[7 4 ] B ass a m B A. C h ar c ot – M ari e – T o ot h Dis e as e V ari a nts — Cl assifi c ati o n, Cli ni c al, a n d G e n eti c F e at ur es a n d 
R ati o n al Di a g n osti c E v al u ati o n. J Cli n N e ur o m us c Dis 2 0 1 4; 1 5: 1 1 7 – 1 2 8  
[7 5 ] C as as n o v as C, C a n o L M, Al b erti A,  C és p e d es M , Ri g o G . C h ar c ot -M ari e -T o ot h Dis e as e. F o ot & A n kl e 
S p e ci alist  2 0 0 8;  1( 6): 3 5 0– 3 5 4.  
[7 6 ] V all at a J M, M at his S, F u n al ot B. T h e v ari o us C h ar c ot – M ari e – T o ot h dis e as es. C urr O pi n N e ur ol  2 0 1 3; 
2 6( 5): 4 7 3 -8 0  
[7 7 ] Y o u n g P, D e J o n g h e P, St ö g b a u er F , B utt erf ass -B a hl o ul T . Tr e at m e nt f or C h ar c ot -M ari e -T o ot h dis e as e 
( R e vi e w). C o c hr a n e D at a b as e S yst R e v  2 0 0 8; 2 0 0 8( 1): C D 0 0 6 0 5 2 . 
[7 8 ] Gr e e n bl att DJ, All e n M D. I ntr a m us c ul ar i nj e cti o n -sit e c o m pli c ati o ns. J A M A 1 9 7 8; 2 4 0: 5 4 2 -4.  
[7 9 ] M üll er -V a hl H. A d v ers e r e a cti o ns aft er i ntr a m us c ul ar i nj e cti o ns. L a n c et 1 9 8 3: 1 0 5 0.  
[8 0 ] Mis hr a P, Stri n g er M D. S ci ati c n er v e i nj ur y fr o m i ntr a m us c ul ar i nj e cti o n: a p ersist e nt a n d gl o b al pr o bl e m. 
I nt J Cli n Pr a ct 2 0 1 0; 6 4( 1 1): 1 5 7 3 -1 5 7 9.  
[8 1 ] T a k S R, D ar G N, H al w ai M A, Mir M R. P ost -i nj e cti o n n er v e i nj uri es i n K as h mir M e n a c e o v erl o o k e d. J 
R es e ar c h i n M e d S ci  2 0 0 8; 1 3( 5) 2 4 4 -2 4 7.  
[8 2 ] R o d g er M A, Ki n g L. Dr a wi n g u p a n d a d mi nist eri n g i ntr a m us c ul ar i nj e cti o ns: a r e vi e w of t h e lit er at ur e. J 
A d v N urs  2 0 0 0; 3 1( 3): 5 7 4 -8 2  
[8 3 ] C o c o m a n A, M urr a y J. I ntr al m us c ul ar i nj e cti o n: a r e vi e w of b est pr a cti c e f or m e nt al h e alt h n urs es. J 
Ps y c hi atr M e nt H e alt h N urs  2 0 0 8; 1 5( 5): 4 2 4 – 4 3 4  
[ 8 4]  Bl u m  L,  K or n er-Bit e ns k y  N.  Us ef ul n ess  of  t h e  B er g  B al a n c e  S c al e  i n  Str o k e  R e h a bilit ati o n:  A  S yst e m ati c  
R e vi e w.  P h ys  T h er  2 0 0 8; 8 8( 5): 5 5 9 – 5 6 6  
[ 8 5] P ar e ys o n D, S c ai oli V, L a ur à M. Cli ni c al a n d el e ctr o p h ysi ol o gi c al as p e cts of C h ar c ot-M ari e -T o ot h dis e as e. 
N e ur o m ol e c ul ar M e d  2 0 0 6; 8( 1 -2): 3 – 2 2