Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne muscular dystrophy DMD Oligonucleotides, Antisense Exon skipping
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
This is a phase I/II study to evaluate the safety, tolerability, efficacy, and pharmacokinetic (PK) profile of DS-5141b in patients with Duchenne muscular dystrophy (DMD) amenable to exon 45 skipping and to determine the dosage for subsequent studies.

Detailed description:

Arms:
arm 1: DS-5141b, Subcutaneous injection

Part 1: DS-5141b will be injected subcutaneously once a week for 2 weeks at the following dose levels. Dose escalation will be performed. DS-5141b will be administered at dose levels 1 and 3 in Cohort 1 and at dose levels 2 and 4 in Cohort 2.

* Level 1: 0.1 mg/kg
* Level 2: 0.5 mg/kg
* Level 3: 2.0 mg/kg
* Level 4: 6.0 mg/kg

Part 2: Two doses of DS-5141b will be selected based on the results obtained in Part 1. Each selected dose will be administered subcutaneously once a week for 12 weeks.

Part 2-Extension-2: Two doses, 2.0 mg/kg or 6.0 mg/kg, of DS-5141b will be administered subcutaneously once a week for 48 weeks.

Interventions: intervention 1: DS-5141b
Intervention descriptions: intervention 1: DS-5141b, Subcutaneous injection

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
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Pr ot o c ol N u m b er:  D S 5 1 4 1- A-J 1 0 1 
 
 
 
 
 
 
 
 
S t u d y Pr ot oc ol 
 
A P hase 1/ 2 St u d y of D S - 5 1 4 1 b 
- O p e n -la bel St u d y of D S-5 1 4 1 b i n Patie nts wit h D uc he n ne M us c ular D ystr o p h y - 
 
 
 
 
 
 
 
 
N ot e o n c o nfi d e nti al i nf or m ati o n  
 
T his cli ni cal st u d y pr ot o c ol  is c o nfi d e nti al i nf or mati o n, a n d is pr o vi d e d t o t h e 
i n v esti g at ors, s u bi n v esti g at ors, st u d y st aff, st u d y dr u g m a n a g ers, st u d y sit es a n d 
i nstit uti o n al r e vi e w b o ar ds parti ci p ati n g i n t his st u d y.   T his cli ni cal st u d y pr ot o c ol  
ma y n ot b e dis cl os e d t o a n y t hir d p art y, or us e d f or a n y p ur p os e ot h er t h a n t his st u d y, 
wit h o ut t h e writt e n c o ns e nt of D aii c hi S a n k y o C o m p a n y, Li mit e d , e x ce pt t o e x pl ai n t h e 
c o nt e nts of t his st u d y t o s u bj ects a n d t h eir l e g all y acce pt a bl e re pres e nt ati v es.  
 
S p o ns or : Daiic hi Sa n k y o C o m p a n y, Li mite d  
 
Ve rs i o n  0 3. 0 4 . 0 0 0/D at e of re p ort : 1 1 J u n 2 0 2 0  


 
 
 
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P R O T O C O L S Y N O P SI S  
 
Pr ot o c ol N u m b er  
D S 5 1 4 1 - A-J 1 0 1 
I n v esti g ati o n al s u bst a n ce c o d e D S - 5 1 4 1 b 
G e n eri c N a m e  
re n adirs e n (I N N)  
St u d y Titl e  
A P h as e 1/ 2 St u d y of D S -5 1 4 1 b ‐ O p e n -l a b el St u d y of 
D S -5 1 4 1 b i n P ati e nts wit h D u c h e n n e M us c ul ar 
D ystr o p h y ‐ 
St u d y P h as e  
P h as e 1/ 2  
I n di cati o n u n d er I n v esti g ati o n D u c h e n n e m us c ul ar d ystr o p h y ( D M D)  
St u d y O bj ecti v es  
T h e o bj ecti v e of t h e st u d y is t o ass ess t h e s afet y, 
t ol era bilit y, effi cac y, a n d p h ar m ac o ki n eti cs of D S -5 1 4 1 b 
i n D M D p ati e nts.   T h e st u d y is als o i nt e n d e d t o ass ess 
t h e d os e t o b e us e d i n t h e n e xt-p h as e st u di es.  
St u d y D esi g n  
A m ulti ce nt er, u n c o ntr oll e d, o p e n -l a b el st u d y 
St u d y D urati o n  
0 1 O ct 2 0 1 5 t o 3 1 D ec 2 0 2 0  
St u d y Sit es  
2  sit es 
Pl a n n e d S a m pl e Si ze  
6 s u bj ects i n eac h p art  
S u bj ect Eli gi bilit y Crit eria  
[I n cl usi o n Crit eri a] 
1)  P ati e nts w h o h a v e b ee n c o nfir m e d t o h a v e a n 
o ut- of -fra m e d el eti o n t h at ca n b e c orrect e d b y e x o n 
4 5 s ki p pi n g of t h e d ystr o p hi n g e n e, t o t h us rest ore 
t h e i n-fra m e d el eti o n. 
2)  T h os e w h o h a v e b ee n c o nfir m e d t o h a v e a D N A 
s e q u e n ce t h at f or ms a d o u bl e stra n d wit h D S -5 1 4 1 b 
i n t h e e x o n 4 5 of t h e d ystr o p hi n g e n e.  
3)  T h os e w h o h a v e i nt act m us cl es of a d e q u at e q u alit y 
f or bi o ps y t o all o w e v al u ati o n of t h e effi cac y o f t h e 
st u d y dr u g. 
4)  B o ys a g e d fr o m 5 t o < 1 1 y ears at t h e ti m e of 
re gistrati o n. 
5)  T h os e w h o are a bl e t o w al k at l east 3 2 5 m et ers i n 
t h e 6-mi n ut e w al k t est.  
6)  St er oi d -n ai v e p ati e nts or p ati e nts w h o h a v e b ee n 
treat e d wit h st er oi ds f or at l east 6 m o nt hs pri or t o 


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re gistrati o n i n t h e st u d y wit h o ut a d os a g e c h a n g e f or 
at l east 3 m o nt hs pri or t o re gistrati o n. 
7)  T h os e w h o are a bl e t o f oll o w t h e i nstr u cti o ns o n t h e 
s c h e d ul e d a d missi o n, visits, treat m e nt pl a n, 
tests/ o bs er v ati o ns, a n d ot h er st u d y pr o ce d ures s et i n 
t he pr ot o c ol w hil e  p arti ci p ati n g i n t h e st u d y.  
8)  T h os e w h o h a v e v ol u nt aril y pr o vi d e d writt e n 
i nf or m e d c o ns e nt or h a v e recei v e d a d e q u at e 
e x pl a n ati o ns a b o ut t h e st u d y i n v ol vi n g t h eir 
d ecisi o n -m a ki n g a b o ut p arti ci p ati o n i n t h e st u d y.  
9)  T h os e w h os e l e g al re pres e nt ati v es h a v e v ol u nt aril y 
pr o vi d e d writt e n i nf or m e d c o ns e nt i n a n a p pr o pri at e 
ma n n er.  
 
[ E x cl usi o n Crit eri a] 
1)  P ati e nts wit h a g e n e m ut ati o n w hi c h is n ot e x p ect e d 
t o pr o d u ce  t h e d ystr o p hi n pr ot ei n b y e x o n 4 5 
s ki p pi n g. 
2)  C o n c urre nt ill n ess ot h er t h a n D M D t h at ca n ca us e 
m us cl e w ea k n ess a n d/ or i m p air m e nt of m ot or 
f u n cti o n. 
3)  C urre nt or pre vi o us s e v ere dis or d er i n v ol vi n g t h e 
li v er, ki d n e ys, bl o o d, h y p ers e nsiti vit y, res pirat or y 
s yst e m, g astr oi nt esti n al s yst e m, circ ul at or y s yst e m, 
ce ntral n er v o us s yst e m, e t c. 
4)  L eft v e ntri c ul ar ej ecti o n frac ti o n < 5 5 % o n t h e 
ec h o car di o gra m.  
5)  Fri d eri ci a -c orrect e d Q T i nt er v al ( Q Tc) > 0. 4 5 
s ec o n ds o n t h e 1 2-l ea d electr o car di o gra m. 
6)  T h os e w h o re q uire treat me nt of t h e res pirat or y 
s yst e m, e g, res pirat or y p h ysi cal t h era p y or 
mec h a ni cal res pirat or y s u p p ort. 
7)  T h os e w h o h a v e a p ositi v e res ult f or t h e h e p atitis B 
s urface ( H Bs) a nti g e n, h e p atitis C vir us ( H C V) 
a nti b o d y, or h u m a n i m m u n o d efi ci e n c y vir us ( HI V) 


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a nti b o d y t ests.  
8)  T h os e w h o h a v e p arti ci p at e d i n a n ot h er cli ni cal 
st u d y a n d h a v e recei v e d a n i n v esti g ati o n al pr o d u ct 
wit hi n  3 m o nt hs pri or t o re gistrati o n i n t his st u d y. 
9)  T h os e  w h o are c o nsi d ere d i n eli gi bl e f or t h e st u d y b y 
t h e i n v esti g at or or s u bi n v esti g at or. 
D os e a n d R o ut e of 
A d mi nistr a ti o n 
< P art 1 >  
D S -5 1 4 1 b will b e s u b c ut a n e o usl y a d mi nist ere d at t h e 
f oll o wi n g d os e l e v els o nce w ee kl y f or 2 w ee ks .   T h e 
d os e l e v el will b e i n creas e d st e p wis e .   D S -5 1 4 1 b  will 
b e a d mi nist ere d  at  D os e L e v el 1 a n d D os e L e v el 3 i n 
C o h ort 1 a n d at D o s e L e v el 2 a n d D os e L e vel  4 i n 
C o h ort 2.  
• 
D os e L e v el 1 : 0. 1  m g/ k g  
• 
D o s e L e v el 2 : 0. 5  m g/ k g  
• 
D os e L e v el 3 : 2 . 0 m g/ k g  
• 
D os e L e v el 4 : 6. 0  m g/ k g  
< P art 2 >  
D S -5 1 4 1 b will b e s u b c ut a n e o usl y a d mi nist ere d at 2 d os e 
le v els, d et er mi n e d b as e d o n t h e res ults of P art 1, o n ce 
w ee kl y f or 1 2 w ee ks.  
< P a rt 2-E xt e nsi o n >  
Bas e d o n t h e res ults of P a rt 2, D S-5 1 4 1 b will b e 
s u b c ut a n e o usl y a d mi nist ere d at 2 d os e l e v els ( 2. 0  m g / k g 
a n d 6. 0 m g / k g) t h at h a d b ee n ad mi nist ere d  i n P art 2, 
o n ce w ee kl y f or 4 8 w ee ks.  
Bas e d o n t h e res ults of n o n cli ni cal st u di es i n mi ce, t h e 
st u dy d r u g a d mi nistrati o n w as t e m p oraril y dis c o nt i n u e d. 
< P art 2 -E xt e nsi o n -2 >  
B as e d o n t h e res ults of P art 2, D S -5 1 4 1 b will b e 
s u b c ut a n e o usl y a d mi nist ere d at 2 d os e l e v els ( 2. 0 m g / k g 
a n d 6. 0 m g / k g) t h at h a d b ee n ad mi nist ere d  i n P art 2, 
o n ce w ee kl y f or 4 8 w ee ks (a t ot a l of 4 8 d os es).  
Pr o hi bit e d C o n c o mit a nt Dr u gs  C o n c o mit a nt us e of t h e f oll o wi n g dr u gs is pr o hi bit e d 
d uri n g t h e p eri o d fr o m re gistrati o n i n t h e st u d y t o t h e 


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e n d of t h e f oll o w -u p p eri o d i n P art 2,  a n d d uri n g t h e 
p e ri o d fr o m t h e d ay of i nf or m e d c o ns e nt f or P ar t 
2 - E xt e nsi o n t o t h e e n d of t h e f oll o w-u p p eri o d i n P art 
2 - E xt e nsi o n-2 ( d uri n g t h e p eri o d fr o m re gistrati o n i n t h e 
st u d y t o t h e e n d of t h e f oll o w-u p p eri o d i n P art 
2 - E xt e nsi o n-2 f or s u bj ects p arti ci p ati n g i n t h e  st u d y 
fr o m P art 2 -E xt e nsi o n or P art 2 - E xt e nsi o n- 2; a n d t o  t h e 
st art of st u d y dr u g a d mi nistrati o n f or s u bj ects 
p arti ci p ati n g i n t h e l o n g -ter m e xt e nsi o n st u d y ). 
1)  O t h er a nti-D M D dr u gs t h a n t h e st u d y dr u g us e d i n 
t his st u d y a n d st er oi ds 
2)  O t h er i n v esti g ati o n al pr o d u cts  
3)  C hl or o q ui n e a n d h y dr o x y c hl or o q ui n e  
Pr o hi bit e d C o n c o mit a nt 
T h er a p y  
T h e us e of t h e f oll o wi n g t h era p y is p r o hi bit e d fr o m 
r e gistrati o n i n t his st u d y t o th e e n d of t h e f oll o w- u p 
p eri o d  i n P art 2- E xt e nsi o n- 2 ( or t o t h e st art of st u d y 
dr u g a d mi nistrati o n i n t h e l o n g- t er m e xt e nsi o n st u d y f or 
s u bj ects p arti ci p ati n g i n t h e l o n g-t er m e xt e nsi o n st ud y) . 
1)  H A L ®  (H y bri d Ass isti v e Li m b® ) 
St u d y Pr o ce d ur es  
See A p p e n di x 3.  
St u d y E n d p oi nts  
[ S afet y E n d p oi nts] 
A d v ers e e v e nts, l a b orat or y d at a, b o d y w ei g ht, vit al 
si g ns, 1 2- l ea d el ectr o car di o gra m, a n d  
. 
[ P h ar m ac oki n eti c E n d p oi nts]  
P h ar m ac o ki n eti c p ara m et ers  
[ M aj or Effi cac y En d p oi nts]  
• 
E x pressi o n of t h e d ystr o p hi n pr ot ei n i n t h e m us cl e 
tiss u e 
• 
P r o d u cti o n of e x o n 4 5-s ki p p e d d ystr o p hi n m R N A i n 
t h e m us cl e tiss u e 
St atist i cal A n al ys es 
[ S afet y E n d p oi nts] 
T h e i n ci d e n c e of a d v ers e e v e nts will b e cal c ul at e d b y 
d os e l e v el.   T h e fre q u e n c y  of a d v ers e e v e nts will als o 
b e c o u nt e d b y e v e nt .   F or l a b orat or y d at a, b o d y w ei g ht, 
vit al si g ns, 1 2 -l ea d el ectr o car di o gra m res ults, a n d  
 
C CI
C CI


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 fi n di n gs, s u m m ar y st atisti cs will b e cal c ul at e d a nd 
fr e q u e n c y will b e c o u nt e d b y t h e d os e l e v el. 
[ P h ar m ac o ki n eti c E n d p oi nts] 
F or p h ar m ac o ki n eti c p ara m et ers, s u m m ar y st atistics will 
b e cal c ul at e d b y t h e d os e l e v el.  
[ Effi cac y E n d p oi nts] 
T h e d ystr o p hi n pr ot ei n l e v els i n t h e m us cl e tiss ue 
r el ati v e t o t h e n or m al  m us cl e a n d t h eir c h a n g e  will b e 
cal c ul at e d f or eac h s u bj ect.  
 
C CI


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T A B L E O F C O N T E N T S  
 
P R O T O C O L S Y N O P SI S  .................................................................................................. 3 
T A B L E O F C O N T E N T S  ................................................................................................... 8 
LI S T O F T A B L E S  ............................................................................................................ 1 0 
LI S T O F FI G U R E S  ......................................................................................................... 1 0 
L I S T OF A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  ................................ 11  
1.  I N T R O D U C TI O N ...................................................................................................... 1 3 
1. 1  Bac k gr o u n d t o D e v el o p me nt  ..................................................................................... 1 3 
1. 2  S u m m ar y of Si g nifi ca nt Fi n di n gs O bt ai n e d fr o m N o n cli ni cal St u di es a n d  Cli ni cal 
St u di es ........................................................................................................................ 1 4  
2.  S T U D Y O B J E C TI V E S  .............................................................................................. 2 4 
3.  S T U D Y D E SI G N  ........................................................................................................ 2 5 
4.  T A R G E T S U B J E C T S  ................................................................................................ 2 8 
4. 1  Sel ecti o n of S u bj ects  .................................................................................................. 2 8 
4. 2  Re gistr ati o n of S u bj ects  ............................................................................................. 3 0 
4. 3  Wit h dr a w al Crit eri a of I n di vi d u al S u bj ects a n d A cti o n o n Wit h dra w al  ................... 3 1 
5.  M E T H O D O L O G Y  ..................................................................................................... 3 2 
5. 1  S t u d y Dr u g ................................................................................................................. 3 2 
5. 2  St u d y Dr u g A d mi nistr ati o n M et h o d  .......................................................................... 3 3 
5. 3  M et h o d of A d mi nistr ati o n  .......................................................................................... 3 5 
5. 4  Part 1 a n d P art 2  ......................................................................................................... 3 6 
5. 5  Ra n d o mi zati o n a n d Bli n di n g  ..................................................................................... 3 9 
5. 6  C o n c o mit a nt M e di cati o ns a n d C o n c o mit a nt T h era p y, a n d O t h er R estri cti o ns ........ 3 9 
5. 7  S u bj ect M a n a g e m e nt  .................................................................................................. 4 0 
5. 8  A d dit i o n of S u bj ects .................................................................................................. 4 2 
6.  S T U D Y P R O C E D U R E S  ............................................................................................ 4 3 
6. 1  Listi n g of E x a mi n ati o ns, O bs er v ati o ns a n d  Tests  ..................................................... 4 3 
6. 2  It e mi zati o n of Vit al Si g ns, Cli ni cal Fi n di n gs a n d L a b orat or y Tests  ......................... 4 3 
6. 3  It e ms a n d Ti mi n g of Tests B ef ore R e gistrati on of S u bj ects  ...................................... 4 7 
6. 4  It e ms a n d Ti mi n g of Tests Aft er R e gistrati o n ........................................................... 4 8 
6. 5  Test It e ms o n Wit h dr a w al fr o m t h e St u d y a n d t h eir Ti mi n g  ..................................... 6 3 
6. 6  F oll o w- u p Aft er Wit h dr a w al fr o m t h e St u d y  ............................................................ 6 6 
6. 7  P h ar m ac o ki n eti cs ( Bl o o d C oll ecti o n [ Pl as m a])  ........................................................ 6 7 


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6. 8  C h ec ki n g t h e DN A S e q u e n ce of t h e Sit e of D S -5 1 4 1 b D o u bl e -Stra n d F or mati o n 
( Bl o o d C ollecti o n [ W h ol e Bl o o d])  ............................................................................ 6 9 
6. 9  E x pr essi o n of D ystr o p hi n Pr ot ei n a n d Pr o d u cti o n of E x o n 4 5 -S ki p p e d D ystr o p hi n 
m R N A i n M us cl e Tiss u e ( M us cl e Bi o ps y) ................................................................ 6 9 
6. 1 0  M eas ur e m e nt of A nti -D ystr o p hi n A nti b o d y ( Bl o o d C oll ecti o n [ S er u m])  ................ 7 0 
6. 1 1  M eas ur e m e nt of A nti -D S -5 1 4 1 b A nti b o d y ( Bl o o d C oll ecti o n [ Pl as m a])  ................ 7 0 
6. 1 2  E x pl or at or y Bi o m ar k er Res ear c h  .............................................................................. 7 1 
6 . 1 3 St or a g e a n d Dis p os al of S p eci m e ns f or G e n eti c A n al ysis a n d Bi o m ar k er R es earc h  7 3 
6. 1 4  L o n g -Ter m St or a g e ( B a n ki n g) of Cli ni cal S p eci m e ns f or G e n o mi c a n d G e n eti c 
A n al ysis  ...................................................................................................................... 7 4 
7.  P H A R M A C O KI N E TI C E N D P OI N T S  .................................................................... 7 6 
8.  E F FI C A C Y  E N D P OI N T S  ......................................................................................... 7 7 
8. 1  Pri m ar y E n d p oi nt  ....................................................................................................... 7 7 
8. 2  Sec o n d ar y E n d p oi nt  ................................................................................................... 7 7 
9.  S A F E T Y E N D P OI N T S  .............................................................................................. 7 8 
9. 1  D efi niti o n of A d v ers e E v e nt ...................................................................................... 7 8  
9. 2  D efi niti o n of S eri o us A d v ers e E v e nt  ......................................................................... 7 8 
9. 3  H a n dli n g of A b n or m al C h a n g es i n L a b orat or y D ata  ................................................ 7 8 
9. 4  A d v ers e E v ent C oll ecti o n P eri o d  .............................................................................. 7 9 
9. 5  It e ms t o I n v esti g at e f or A d v ers e E v e nts .................................................................... 7 9 
9. 6  D efi nit i o n of A d v ers e Dr u g R eacti o n ........................................................................ 8 1 
9. 7  A cti o n If a n A d v ers e E v e nt O cc urs  ........................................................................... 8 1 
1 0.  Ot h er E n d p oi nts  ......................................................................................................... 8 3 
11.  St atisti c al A n a l ysis ..................................................................................................... 8 7 
1 1. 1  O bj ecti v e of A n al ysis  ................................................................................................. 8 7 
1 1. 2  A n al ysis S ets  .............................................................................................................. 8 7 
1 1. 3  D at a  H a n d li n g ............................................................................................................ 8 8 
1 1. 4  St atisti cal A n al ysis It e ms a n d M et h o ds of A n al ysis  ................................................. 8 8 
1 1. 5  C h a n g es t o  t h e A n al ysis Pl a n ..................................................................................... 9 2 
1 1. 6  I nt eri m A n al ysis ......................................................................................................... 9 2 
1 1. 7  Pl a n n e d S a m pl e Si ze  .................................................................................................. 9 2 
1 2.  Q u alit y C o nt r ol a n d Q u alit y Ass u r a n ce .................................................................. 9 4  
1 3.  P a y m e nt f o r P a rti ci p ati o n, C o m p e n s ati o n f o r St u d y-R el ate d I nj u ri es a n d 
I ns u r a n ce ..................................................................................................................... 9 5 
1 3. 1  Pa y m e nt f or P arti ci p ati o n  .......................................................................................... 9 5 


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1 3. 2  C o m p e ns ati o n f or St u d y -R el at e d I nj uri es  ................................................................. 9 5 
1 3. 3  I ns ur a n ce .................................................................................................................... 9 6 
1 4.  P u bli c ati on P oli c y  ....................................................................................................... 9 7 
1 5.  S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N ..................................................... 9 8 
1 5. 1  Et hi cs  .......................................................................................................................... 9 8 
1 5. 2  S u bj ect C o nfi d e nti alit y  .............................................................................................. 9 8 
1 5. 3  O bt ai ni n g I nf or m e d C o ns e nt  ..................................................................................... 9 8 
1 5. 4  I nf or m e d C o nse nt f or P h ar m ac o g e n o mi cs a n d Bi o m ar k er R es earc h  ..................... 1 0 1 
1 5. 5  Pr o visi o n of N e w I nf or m ati o n A ffecti n g t h e C o n d u ct of t h e St u d y ....................... 1 0 2 
1 5. 6  Pl a n n e d St u d y P eri o d  ............................................................................................... 1 0 2 
1 5. 7  Pr ot o c ol A m e n d m e nt  ............................................................................................... 1 0 2 
1 5. 8  Ter mi n ati o n a n d Te m p or ar y Dis c o nti n u ati o n of t h e St u d y  ..................................... 1 0 3 
1 5. 9  Pr o ce d ur es f or Pr e p ari n g t h e C as e R e p ort F or m a n d R e m ar ks  .............................. 1 0 3 
1 5. 1 0  St or a g e of S o ur ce D o c u me nts a n d Ot h er R ec or ds  .............................................. 1 0 5 
1 5. 1 1  S o u r ce Do c u m e nt Verifi cati o n  ............................................................................. 1 0 6 
1 5. 1 2  Or g a ni zati o n  ......................................................................................................... 1 0 7 
1 5. 1 3  D e p art m e nt R es p o nsi bl e f or A u dit ....................................................................... 1 1 3  
1 5. 1 4  E m er g e n c y C o nt act I nf or m ati o n  ........................................................................... 1 1 3  
1 5. 1 5  C o m p a n y C o n d u cti n g J oi nt D e v el o p m e nt  ............................................................ 1 1 4  
1 6.  R ef ere n ces  .................................................................................................................. 11 5  
1 7.  A p p e n di ces  ................................................................................................................. 11 7  
Att a c h m e nts  ..................................................................................................................... 11 8  
 
 
L I S T O F T A B L E S 
Ta bl e 9. 5 -1 It e ms t o I n v esti g at e W h e n a n A d v ers e E v e nt O cc urs  .................................... 8 0 
Ta bl e 1 5. 9 -1 E D C S yst e m  ................................................................................................ 1 0 4 
 
 
L I S T O F FI G U R E S  
Fi g ur e 3 -1 St u d y D esi g n  .................................................................................................... 2 5 
 


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LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
 
List of A b b re vi ati o ns  
A b br e viati o n  
U na b br e viate d ter m  
A/ G  
al b u mi n/ gl o b uli n  
A L P  
al kali n e p h os p hatase  
A L T ( G P T)  
L -ala nin e a mi n otra nsf er ase ( gl uta mic p yr u vic a ci d tr a nsa mi nas e)  
A O N  
a ntis e nse  oli g o n ucle oti d e  
A P T T  
acti v ate d p artial t hr o m b o plasti n ti me  
A S T ( G O T)  
L -as p artate a mi n otr a nsferas e ( gl uta mic o x al oa cetic aci d tr a nsa m i n as e) 
B M D  
Bec k er  m usc ular d ystr o p h y  
B U N  
bl o o d u r ea nitr o g e n 
C K ( C P K)  
cr eati n e ki n as e (cr eat i n e p h os p h o ki nase) 
C P F  
c o u g h pe a k fl o w  
C R P  
C -rea cti ve pr otei n  
C T  
c o m p uterize d t o m o gra p h y  
D M D  
D uc h e n n e  m usc ular d ystr o p h y  
D N A  
d e o x y ri b o n u cleic a ci d 
E/ A  
earl y diast olic filli n g  v el o cit y/atrial filli n g v el o cit y  
E D C  
electr o nic d ata ca pt uri n g  
E N A  
2’ -O , 4’-C -e t h yle ne bri d ge d n ucleic aci ds  
F E V 1  
f orc e d e x pirat or y v ol u me i n 1 sec o n d 
F V C  
f orc e d vital c a p acit y 
G C P  
g o o d cli nic al pr actic e  
g a m ma-G T  
ga m ma -gl uta m yl tra nsf er as e  
H Bs  
he p at itis B s urfa ce  
H C V  
he p atitis C vir us  
H E D  
h u ma n e q ui v ale nt d os e  
h E R G  
h u ma n et her -a -g o -g o relate d ge ne  
HI V  
h u ma n i m m u n o deficie nc y vir us  
H P F  
hi g h p o w er fiel d  
I C H 
i nter nati o nal c o nfer e nc e o n har m o nisati o n  
I H C 
i m m u n o hist oc he mistr y  
I R B 
I nstit uti o nal Re vie w B o ar d 
L D H  
la ctic a ci d (lactate) de hy dr o ge n as e  
L P F  
l o w p o w er fiel d 
M C H  
me a n cell h e m o gl o bi n  
M C H C  
me a n cell h e m o gl o bi n c o nc e ntr ati o n  
M C V  
me a n cell v ol u me  
Me d D R A  
Me dica l Dicti o n ar y f or Re g ulat or y Acti vities 
mi R - 
micr o -R N A - 
M RI  
m a g netic res o na nc e ima gi n g  


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A b br e viati o n  
U na b br e viate d ter m  
M T D  
ma xi m u m t oler ate d d os e  
m R N A  
m esse n ger ri b o n ucleic aci d 
N A G  
N -a cet yl -β -D -gl u c osa mi ni d ase  
N O A E L  
n o -o bser ve d -a d v ers e -effe ct  
n o n -T g  
n o n -tra ns ge nic 
P E F  
pea k e x pir at or y fl o w  
P T  
pr ef err e d ter m  
P T -I N R 
pr ot hr o m bi n ti me -i nter nati o nal n or maliz e d r ati o 
Q Tc  
c orr ecte d Q T i nter v al  
Q Tc B  
c orr ecte d Q T i nter v al usi n g Bazett's f or m ula  
Q Tc F  
c orr ecte d Q T i nte r v al usi n g Fri d ericia's f or m ula 
R N A  
ri b o n u cleic a ci d 
R T -P C R  
re verse tr a nscri pti o n-p ol y mer as e c h ai n r ea cti o n  
S O C  
s yste m or g a n class 
W B  
wester n bl ot  
– : N o a p plic a ble n otati o n  
 
L ist of P h a r m a c o ki n eti c P a r a m et ers 
A b br e viati o n  
U na b br e viate d ter m  
A R  
o bs er v e d ac c u m ulati o n rati o  
A U C 1 6 8 h  
ar ea u n der t he plas ma c o n ce ntr ati o n-ti me c ur v e u p  t o 1 6 8 h o urs  
A U Ci nf  
ar ea u n der t he plas ma c o n ce ntr ati o n-ti me c ur v e u p  t o i nfi nit y 
A U Clast  
ar ea u n der t he plas ma c o n ce ntr ati o n -ti me c ur v e u p t o t he last q ua ntifia ble 
ti me 
A U Cta u  
ar ea u n der t he plas ma c o n ce ntr ati o n -ti me c ur v e d uri n g  d osi n g i nter v al  
Ca v g  
a ver a ge  plas ma c o n ce ntr ati o n  
C L/ F  
a p p ar e nt t otal b o d y cleara nc e  
C Lss/ F  
ap p ar e nt t otal b o d y cleara nc e at stea d y  state 
C ma x  
ma xi m u m plas ma c o n ce ntr ati o n  
Kel  
eli mi n ati o n rate  c o nsta nt ass ociate d wit h t h e ter mi nal p h as e  
M R Ti nf  
me a n r esi de nce ti me  u p  t o i nfi nit y 
t 1/ 2 
ter mi n al eli mi n ati o n h alf-lif e 
T ma x  
ti me t o r ea c h ma xi m u m plas ma c o nc e ntrati o n 
Vz/ F  
ap p ar e nt v ol u me of distri b uti o n base d o n t he ter mi nal p h as e  


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1.  
I N T R O D U C TI O N 
1. 1  
B a c k g r o u n d t o D e v el o p m e nt  
D u c h e n n e m us c ul ar d ystr o p h y  (D M D ) is a s eri o us, rare, X-li n k e d re gressi v e g e n eti c 
dis eas e ca us e d b y  a m ut ati o n  (s u ch as d el eti o n or d u pli cati o n)  i n t h e d ystr o p hi n g e n e, 
lea di n g t o d ystr o p hi n d efic i e n c y.    I n its cli ni cal c o urs e, p ati e nts at  3 t o 5 y ears ol d  fall 
o v er easil y, a n d ar e oft e n u n a bl e t o r u n, a n d th eir m ot or f u n cti o n reac h es a p ea k ar o u n d 
t h e a g e of 5 y ears.   A ft er t his, m us cl e atr o p h y a n d m us cl e w ea k n ess gra d u all y 
pr o gr ess, a n d i n m a n y cas es, p a ti e nts l os e a m b ul ati o n  at ar o u n d t h e a g e of 1 0 y ears .   
As m ot or f u n cti o n d ecr eas es, joi nt c o ntract ure or s c oli osis a p p ears, an d g e n erall y, fr o m 
t h e a g e of 1 0 y ears o n w ar ds, res pir at or y fail ure a n d car di o m y o p at h y st art t o a p pear.   
D u e t o r ece nt a d v a n ces i n m e di cal t ec h n ol o g y s u c h as res pirat or y m a n a g e me nt, 
p ati e nts n o w h a v e a lif e e x p ect a n c y of o v er 3 0  y ears .1 
St er oi d t h er a p y  is t h e o nl y p h ar m ac ot h era p y f or D M D wit h a v ail a b l e e vi d e n ce f or t h e 
pr e v e nti o n of pr o gr essi o n , a n d h as b ee n s h o w n t o i m pr o v e m us cl e stre n gt h a n d 
f u n cti o n i n a p eri o d of 6 m o nt hs t o 2 y ears .   H o w e v er, its m ec h a nis m of acti o n is 
u n k n o w n, a n d si d e eff ects ar e c o m m o nl y re p ort e d.  In a d diti o n, t h ere is i ns uffi ci e nt 
e vi d e n ce a b o ut eff ects of st er oi d o n p ara m et ers s u c h as res pirat or y f u n cti o n or car di ac 
f u n cti o n i n l o n g-t er m us e aft er l oss of a m b ul ati o n.2  As a n o n - p har m ac ot h era p y, 
r e h a bilit ati o n t o m ai nt ai n m ot or f u n cti o n, res pirat or y care s u c h as res pirat or y 
p h ysi ot h er a p y  a n d tr eat me nt of m y o car di al dis or d er, et c . are a v ail a bl e, b ut c urre nt 
t h er a p y i n cl u di n g st er oi ds is s y m pt o m ati c treat m e nt, a n d is n ot b as e d o n t h e ca us e of 
D M D . T her ef or e , m or e eff ecti v e, n e w t h era pi es are d esire d . 
I n 20 0 6 , it w as dis c o v er e d t h at a n a ntis e ns e oli g o n u cl e oti d e (A O N ) i n d u ce d e x o n 
s ki p pi n g, r es ulti n g i n t h e s ynt h esis  of d ystr o p hi n pr ot ei n i n D M D  p ati e nts .3  At 
pr e s e nt, m ulti pl e m o difi e d A O Ns s u c h as 2’- O -met h yl R N A  a n d m or p h oli n o n u cl ei c 
aci d t h at s ki p a n e x o n s u c h as e x o n 5 1, 5 3 or  4 5 of t h e 7 9 e x o ns i n t h e d ystr o p hi n g e n e 
ar e b ei n g  d e v el o p e d  bot h i n J a p a n a n d o v ers eas .    T h e e x o n 5 1 s ki p pi n g dr u g 
et e plirs e n  w as a p pr o v e d i n 2 0 1 6 , an d t h e ex o n 5 3  s ki p pi n g dr u g g ol odirs e n  w as 
a p pr o v e d i n 2 0 1 9 , i n t h e U S, b ut t h eir  tar g et p o p ulati o ns are differe nt fr o m t h at of 
D S - 5 1 4 1 b, w hi c h is a n A O N t h at i n d u ces d ystr o p hi n e x o n 4 5 s ki p pi n g.   D S- 5 1 4 1 b is 
a m o difi e d oli g o n u cl e oti d e c o nsisti n g of 2’- O , 4’-C -et h yl e n e -bri d g e d n u cl ei c aci ds  
(E N A ) a n d 2’-O -m et h yl R N A , a n d w as dis c o v ere d a n d f or m ul at e d i n J a p a n  b y  D aii c hi  
Sa n k y o C o m p a n y, Li mit e d  i n c oll a b orati o n wit h 
 of t h e 
, K o b e U ni v ersit y Gra d u at e S c h o ol of M e di ci n e (
 
, K o b e G a k ui n U ni v ersit y), et c. .   M o difi e d  
P P D
P P D
P P D


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oli g o n u cl e o ti d es c o nt ai ni n g E N A s ha v e dra m ati call y i n creas e d affi nit y f or 
c o m pl e m e nt ar y str a n d s of n u cl ei c aci d c o m p are d wit h  c o n v e nti o n al m o difie d n u cl ei c 
aci ds s u c h as  2’-O -m et h yl R N A  or m or p h oli n o n u cl ei c aci d , a n d h a v e s u peri or 
n u cl ea s e r esist a n ce4.   Th er ef or e , E N A- c o nt ai ni n g m o dif i e d oli g o n u cl e oti d es  are 
e x p ect e d t o b e us ef ul f or tr eati n g D M D b y i n d u ci n g s ki p pi n g m ore str o n gl y.  
To c o nfir m  t h e p h ar m ac ol o gi cal acti vit y of D S- 5 1 4 1 b , d ystr o p hi n m R N A  w as 
a n al y zed i n a n i n vitr o st u d y usi n g m y ot u b es d eri v e d fr o m a D M D  pati e nt, a n d 
D S - 5 1 4 1 b w as c o nfir m e d t o i n d u ce e x o n 4 5  s ki p pi n g.    A n d th e  e x pressi o n of  
d ystr o p hi n pr ot ei n w as c o nfir m e d  b y West er n bl ot.    I n a n i n vi v o  st u d y usi n g a 
m uri n e m o d el of m us c ul ar d ystr o p h y ( m d x  mi ce), D S -5 1 4 1 b  i n d u ce d e x o n 4 5 s ki p pi n g 
of d ystr o p hi n m R N A i n t h e a nt e ri or ti bi al m us cl e, d i a p hra g m, a n d h e art . 
G i v e n t h e a b o v e, it is p ossi bl e t h at, b y i n d u ci n g s ki p pi n g of e x o n 4 5, D S - 5 1 4 1 b ca us es 
e x pr essi o n of d ystr o p hi n pr ot ei n i n D M D p ati e nts wit h g e n eti c a b n or m aliti e s a m e n a bl e 
t o ex o n 4 5 s ki ppi n g t h er a p y.   As D S -5 1 4 1 b  h as a differe nt m ec h a nis m of acti o n fr o m 
ot h er t h era p e uti c dr u gs, w e c o nsi d er t h at if it is c o-a d mi nist ere d wit h e xisti n g t h era pi es, 
D S - 5 1 4 1 b is e x p ect e d t o m ai nt ai n m ot o r f u n cti o n, res pirat ory f u n cti o n a n d car di ac 
f u n cti o n in D M D  p ati e nts o v er a l o n g p eri o d, a n d t h eref ore , w e d eci d e d t o p urs u e 
d e v el o p m e n t of D S - 5 1 4 1 b. 
 
1. 2  
S u m m a r y of Si g nifi c a nt Fi n di n gs O bt ai n e d fr o m N o n cli ni c al St u di es a n d 
Cli ni c al St u di es  
1. 2. 1  
P h a r m a c ol o gi c al A cti o n  
E x o n 4 5  ski p pi n g  w as o bs er v e d  at c o n ce ntrati o ns  
 a n d t h e e x pressi o n of 
d ystr o p hi n pr ot ei n w a s c o nfir m e d  at a c o n ce ntrati o n of 
 wh e n  c ult ure d 
m y ot u b es d eri v e d fr o m a D M D p ati e nt  w ere tra nsfe ct e d wit h D S -5 1 4 1 b .   E x o n  4 5 
s ki p pi n g w as c o nfi r m ed i n t h e a nt eri or ti bi al m us cl e, di a p hra g m , a n d h eart b y re v erse 
tr a ns cri pti o n-p ol y m er as e c h ai n r ea cti o n  (R T -P C R ) of m R N A  aft er s u b c ut a n e o us 
a d mi nistr a ti o n of D S -5 1 4 1 b  t o m d x mi ce o n ce w ee kl y f or 4 w ee ks .   T h e  e x o n 
4 5- s ki p pe d b a n ds  wer e d et ect e d  in a p pr o xi m at el y h alf of t h e a ni m als at 
a n d i n  
all a ni m als at 
  A cc or di n g t o t h es e res ults, D S- 5 1 4 1 b  is e x p ect e d t o ca us e 
e x o n 4 5 s ki p pi n g als o i n h u m a ns. 
 
1. 2. 2  
S af et y P h a r m a c ol o g y  
F or i n vitr o s af et y p h ar m ac ol o g y st u d y i n t h e car di o v as c ul ar s yst e m , t h e h u m a n 
et h er- a-g o -g o r el at e d g e n e  (h E R G ) c urre nt  st u d y w as c o n d u ct e d usi n g 
C CI
C CI
C CI
C CI


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h E R G- tr a nsf ect e d h u m a n e m b r y o ni c ki d n e y 2 9 3  cells .  D S - 5 1 4 1 b di d n ot affect 
h E R G c urr e nts at c o n ce ntr ati o ns u p t o 
 b ut mil dl y re d u ce d h E R G c urre nts 
at 
 ( corr ect e d s u p pr essi o n rat e  
).   H o w e v er , i n a 1- m o nt h i nt er m itt e nt 
s u b c ut a n e o us d os e ( o n ce  w ee kl y ) t o xi city st u d y wit h a 3- m o nt h rec o v er y p eri o d i n 
c y n o m ol g us m o n k e ys a n d a 9- m o nt h i nt er mitt e nt s u b c ut a n e o us d os e  (o n ce  w ee kl y ) 
t o xi cit y st u d y wit h a 3-m o nt h r ec o v er y p er i od i n c y n om ol g us m o n k e ys , D S -5 1 4 1 b h a d 
n o eff ect s o n t h e car di o v as c ul ar s yst e m i ncl u di n g  bl o o d press ure a n d 
el ectr o car di o gr a ms at d os e s u p t o 
  In a 1- m o nt h i nt er mi tt e nt s u b c ut a ne o us 
d os e (t wi ce  w ee kl y ) t o xicity st u d y wit h  a 3-m o nt h rec o v er y p eri o d i n mice, D S -5 1 4 1 b 
h a d n o eff ect s o n t h e ce ntr al n er v o us s yst e m or res pirat or y s yst e m  u p t o t h e m a xi m u m 
d os e of 
   In a 1- m o nt h i nt er mitt e nt s u b c ut a n e o us d os e (o n ce  w ee kl y ) 
t o xi cit y st u d y wit h a 3-m o nt h r ec o v er y p eri o d i n c y n o m ol g us m o n k e ys, D S -5 1 4 1 b h a d 
n o eff ect s o n t h e ce ntr al n er v o us s yst e m u p t o t h e m a xi m u m d os e of  
  
T h us, D S -5 1 4 1 b h a s n o cli ni call y r el e v a nt s afet y p h ar m ac ol o gi cal effects o n t h e 
ce nt r al n er v o us s yst e m, r es pir at or y s yst e m, or  car di o v as c ul ar  s yst e m. 
 
1. 2. 3  
P h a r m a c o ki n eti cs a n d D r u g Met a b olis m  
Aft er  a si n gl e s u b cut a n e o us  a d mi nistrati o n t o cy n o m ol g us m o n k e ys , D S - 5 1 4 1 b w as 
r a pi dl y a bs or b e d, an d t h e m ea n T m a x  of pl as m a D S -5 1 4 1 a c o n ce ntrati o n r a n g e d fr o m 
.   T h e n,  t h e pl as m a  D S -5 1 4 1 a c o n ce ntrati o n d e creas e d i n a 
bi p h asi c m a n n er .   T h e mea n A U Cl as t i n creas e d wit h  d os e i n cre m e nt a n d t e n d e d t o 
i n cr ease m or e t h a n d os e pr o p or ti on a ll y.   T h e a bs ol ut e bi o a v ail a bilit y  w as 
 at 
 a n d D S -5 1 4 1 b w as a bs or b e d w ell aft er s u b c ut a n e o u s a d mi nistrati o n. 
Af t er a si n gl e su b c ut a n e o us a dmi ni strati o n of [1 4C] D S - 5 1 4 1 b at 
 t o al bi n o 
mi ce , th e r a di o activit y w as d et ect e d br o a dl y t hr o u g h o ut t h e e ntire b o d y e x ce pt t h e 
ce ntr al n er v o us s yst e m at  
 aft er a d mi ni stratio n .   H i gh ra di o acti vi ty w as  
d et ect e d  es p eci a ll y i n t h e ki d n e y a n d bl a d d er (i n cl u di n g t h e u ri n e), s u g g esti n g t he 
uri n ar y e x cr eti o n  as t h e maj or eli mi n ati o n p at h w a y.   W hil e ra di o activit y i n t h e blo o d 
w as  eli mi n at e d b el o w t h e l o w e r li mit of qu a ntit ati o n at  
 aft er a d mi nistrati o n , 
t h e i n cr eas e d r adi o acti vit y w as d et ect e d o v er ti m e i n m a n y tiss u es, s u g g esti n g 
D S - 5 1 4 1 b w as cl ear e d fr o m cir c ul ati o n b y distr i b uti o n t o tiss u es d uri n g t his  p eri o d .   
T h e r e m ai ni n g  r a di o acti vit y i n t h e w h ol e-b o d y  at  
 aft er 
a d mi nistr ati o n  w er e 
 of t h e a d mi nist ere d  d os e, res p ecti v el y, 
i n di catin g t h at D S- 5 1 4 1 b is sl o wl y eli mi n at e d o v er  ti m e.   R a di o acti vit y re m ai n e d i n 
ma n y tiss u es , i ncl u d i n g t h e m us cl e tiss u es t h at are t h e t ar g et of t h e p h ar m ac ol o gi cal  
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eff ect (th e s k el et al m us cl es , d i a p hr a g m, an d h eart ), at 
 aft er a d mi nistrati o n .  
In pi g m e nt e d mi ce, t h e distr i b uti o n to t h e s ki n a n d ey e b alls w as o bs er v e d .   H o w e v er , 
si mil ar distri b uti o n w as als o o bs er v e d i n al bi n o mi ce, s u g g esti n g th at t h e distri b uti o n 
of r a di o acti vit y t o t h e s ki n a n d e y e b alls is n ot d e p e n d e nt o n m e l a ni n bi n di n g. 
Pl as m a prot ei n bi n di n g w as hi g h ,  
, i n eac h s p eci es, mi ce , c y n o m ol g us m o n k e ys, 
a n d h u m a ns, a n d n o diff er e n ce b et w ee n s p eci es or co n ce ntrati o n d e p e n d e n c y w ere 
n ot e d . 
N o m et a b olit es w er e d et ect e d e it h er i n a n i n vitr o m et a b ol is m st u d y usi n g 
cr y o pr es er v e d  h e p at o c yt es  fr o m mi ce, c y n o m ol g us m o n k e ys, a n d h u m a ns or i n 
a n al ysis of uri n e s a m pl es  aft er a si n gl e s u b c ut a n e o us a d mi nistratio n  t o mi ce , 
s u g g esti n g D S -5 1 4 1 b  w a s m et a b oli call y st a bl e.   T h e m aj or  c o m p o n e nt i n pl as m a a n d 
uri n e s a m pl es aft er a s u bc ut a n e o us a d mi nistrati o n of D S -5 1 4 1 b  t o h u m a ns was t he 
u n c h a n g e d dr u g , an d n o p ea ks w hi c h c orres p o n d e d t o m et a b olit es w ere d et ect e d.  
I n a n e x creti o n st u d y  i n mi ce, a ft er a si n gl e s u b cut a n e o us a dmi nistra ti o n of  1 0 m g / k g 
of [1 4C] D S - 5 1 4 1 b t o m al e al bi n o mi ce, t h e ra di oacti vit y i n t h e uri n e , feces, a n d 
e x pi r e d air w as m eas ur e d o v er ti m e.   T h e c u m ulati v e ra di o acti vit y e xcrete d i n t h e 
uri n e, f eces, a n d e x pir e d air w er e 
of t h e d os e , res p ecti v el y, u p 
t o 
 aft er a d mi nistr ati o n, su g g est i ng t h at ur i n ar y e x creti o n is t h e maj or  
eli mi n ati o n p at h w a y.   E x cr eti o n w as sl o w, a n d  ap pr o xi m at el y  
 of t h e 
a d mi nist er e d r a di o acti vit y r e m ai n e d i n t h e b o d y  e v e n at 
 aft er a d mi nistrati o n .  
D S- 5 1 4 1 b s h ow e d  n o  m aj or  i n hi bitor y  or i n d u ci n g effect  on t h e c yt o c hr o me P 4 5 0  
(C Y P ) iso f or ms.   D S -5 1 4 1 b  als o s ho w e d n o i n hi bit or y effect  o n t h e m aj or  
tr a ns p ort ers. 
 
1. 2. 4  
T o xi cit y  
1. 2. 4. 1  
R e p e at e d -D os e To xi cit y St u di es  
In a 1- m o nt h i nt er mitt e n t s u b c ut a n e o us d os e t oxi cit y st ud y wit h  a 3- m o nt h rec o v er y 
p eri o d i n mi ce ( dos es : 1 0 , 3 0, 1 0 0, a n d 3 0 0 m g / k g, t wi ce w ee kl y ), 
 
 w as o bs er v ed at 1 h o ur aft er a d mi nistrati o n o n D a ys 1 1,  1 5 , 
a n d 1 8, b ut dis a p p ear e d at 4 h o urs aft er a d mi nistrati o n  at ≥1 0 0 m g / k g.   I n t h e 
hist o p at h ol o gi cal e x a mi n ati o n , 
 
 at ≥3 0 m g / k g, a n d 
 
≥1 0 0 m g / k g wer e o bs er v e d .   E ac h of t h e fi n din gs s ho w e d rev ersi bilit y after a 
3- m o nt h r ec o v er y p eri od .   T h er ef ore , t h e n o -o bs er v e d -a d v er s e-effect  l e v el (N O A E L ) 
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w as d et er mi n e d  t o b e 1 0 m g / k g.   I n a 6- m o nt h i nter mitt e nt s u b c ut a n e o us d os e t o xi cit y 
st u d y with a 3- m o nt h r ec o v er y p eri o d i n mi ce ( d os es: 1 , 3 , 1 0, a n d 1 0 0 m g / k g, t wi ce 
w ee kl y ), i n t h e hist o p at h ol o gi cal e x a mi n ati o n , 
 
 
 at d os e  l e v els of  ≥1 0 m g / k g 
w er e o bs er v e d .   At 1 0 0 m g / k g, 
 w ere 
o bs er v e d 
, a n d i n t h e hist o p at h ol ogi cal e x a mi n a ti o n, 
 
 w as o bs er v e d.   All  of t h e fi n di n gs 
te n d e d t o r ec o v er aft e r a 3- m o nt h r ec o v er y peri o d .   T h eref ore , t h e N O A E L  w as 
d et er mi n e d t o b e 3 m g / k g.   In a 1- m o n t h i nt er mitt e nt s u b c ut a n e o us d os e t o xi cit y 
st u d y wit h  a 3-m o nt h r ec o v er y p e rio d i n c y n o m ol g us m o n k e ys ( d os es: 1 0 , 3 0, a n d 
1 0 0  m g / k g, o n ce  w ee kl y ), n o t o x i cit y fi n di n gs w ere o bs er v e d u p t o 1 0 0  m g / k g, a n d t h e 
N O A E L  w as  d et er mi n e d to b e 1 0 0 m g / k g.   I n a 9- m o nt h i nt er mitt e nt s u b c ut a n e o us 
d os e t o xi cit y st u d y wit h a 3- m o nt h r ec o v er y p eri o d i n c y n o m ol g us m o n k e ys ( d os es: 1 0 , 
3 0 , a n d 1 0 0 m g / k g, o n ce w ee kl y ), 
 
 was o bs er v e d at ≥3 0  m g / k g.   At 1 0 0 m g / k g, 
 
 w as o bs er v e d , a n d 
 
, wh i c h w ere c o nsi d ere d  t o b e s ec on d ar y c h a n g e s 
r el at e d t o 
, were  als o n ot e d .   All  t h e fi n di ng s s h o w ed 
r ev er sibilit y  aft er a 3- m o nt h r ec o v er y p eri o d.   T h eref ore , t h e N O A E L w as d et er mi n e d  
to b e 1 0 m g / k g. 
 
1. 2. 4. 2  
G e not o xi cit y St u di es  
In g e n ot o xi cit y st u di es,  a b act eri al r e v ers e m ut ati o n st u d y, a c hr o m os o m e a b errati o n 
st ud y usi n g C hi n es e h a mst er l u n g  cells, a n d a m o us e b o n e m arr o w m i cr o n u cl e us st u d y 
h a d n e g ati v e r es ults.   T h er ef or e,  D S - 5 1 4 1 b is d eter mi n e d  t o h a v e n o p ot e n ti al t o 
i n d uce g e n ot o x i cit y.   In t h e m o us e b o n e m arr o w mi cr o n u c l e us st u d y, d ecreas e d 
at ≥1 2 5 m g/ k g , a n d 
 
 at ≥5 0 0 m g / k g w er e o bs er v e d .    A n d aft er 4 8  h o ur s aft er a d mi nistrati o n  in 
t h e 1 0 0 0  m g / k g gr o u p, 
 w as si g nifi ca ntl y l o w er t h a n t h at i n t he 
n e g ati v e c o ntr ol gr o u p. 
 
1. 2. 4. 3  
R e p r o d u cti v e a n d D e v el o p m e nt al To xi cit y St u di es  
I n a f ertilit y a n d earl y e m br y o ni c d e v e l o p m e nt st u d y i n mal e mi ce (d os es: 3 0 , 1 0 0, a n d  
3 0 0 m g / k g) d e cr eas e d 
w as o bs er v e d at 
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a p pr o xi m at el y 3 0 mi n ut es a ft er a d mi nistrati o n i n t h e 3 0 0 m g / k g gr o u p, b ut t h es e 
fi n di n gs al w ays  dis a p p ear e d at 1 t o 2 h o urs af t er a d mi nistrati on.   N o t o xi c ol o g i cally 
si g nifi ca nt c h a n g es w er e n ot e d i n b o d y w ei g ht, b o d y w ei g ht g ai n , f o o d c o ns u m pti o n, 
c o p ul ati o n r at e , c o p ul at or y i nt er v al, fertilit y rat e, n ecr o ps y, o r g a n w ei g ht (test es  or  
e pi di d y mi d es) , or s pe r m e x a mi n ati o n .   At  1 0 0 a n d 3 0 m g / k g gr o u ps , n o t est 
arti cl e -r el at e d c h a n g es  w er e n ot e d i n t h e a b o v e t est it e ms, i n cl u di n g cli ni cal sig ns .   I n 
a d diti o n , no t est arti cl e-r el at e d c h a n g es w ere n ot e d i n t h e n u m b er of c or p ora l ut ea, 
n u m b er of i m pl a nt ati o ns, i m pl a nt ati o n rat e, pre i m pl a nt ati o n l oss rat e, n u m b er  of li ve 
e m br yos , e m br y o ni c vi a bilit y  r at e, n u m b er of p ost i m pl a nt ati o n l oss es, or 
p ost i m pl a nt ati o n l oss r at e, in all t est arti cl e gr o u p s.   T h eref ore , t h e N O A E Ls w e re 
d et er mi n e d t o b e 1 0 0  m g/ k g  f or g e n eral t o xi cit y a n d 3 0 0 m g/ k g  f or re pr o d u cti v e 
f u n cti o n a n d earl y e m br y o ni c d e v el o p m e nt. 
 
1. 2. 4. 4  
D os e R a n g e Fi n d i n g St u d y f o r C a rci n o g e ni cit y St u d y  
In a 1- m o nt h i nt er mitt e nt s u b c ut a n e o us d os e t o xi cit y st u d y i n n o n- tra ns g e ni c ( n o n-T g ) 
litt er m at es of Ji c: C B 6 F 1-T g r as H 2 @J cl  (ras H 2-/-, n o n-T g ) mi ce ( d os es: 0 , 3 0, 1 0 0, 
a n d 3 0 0 m g/ k g , t wi ce w ee kl y ), 
 
 at ≥3 0 m g / k g, 
 
 at 1 0 0 m g / k g, a n d 
 
 
 at 3 0 0  m g/ k g  w ere n ot e d .    Th e m a xi m u m t ol erat e d d o s e (M T D ) 
w as d et er m i n e d t o b e 3 0 m g / k g.   I n t h e cli ni cal si g ns, 
 
 at ≥1 0 0  m g/ k g  a n d  
 at 3 0 0 m g/ k g  w e re n ot e d .   
I n a 3- m o nt h i nt er mi tt e nt s u b c ut a n e o us d os e t o xi cit y st u d y i n rats ( d os es: 3 0 , 1 0 0 a n d 
3 0 0 m g / k g, o n ce  w ee kl y ), 
 at 
≥3 0  m g/ k g  a n d 
 
 at ≥1 0 0 m g / k g, a n d 
 at 3 0 0 m g / k g w ere n ot e d.    T h e  M T D w as d et er mi n e d  t o b e 
1 0 0 m g / k g. 
 
1. 2. 5  
S y n o psis of I n v esti g ati o n of 
 O bs er v e d i n N o n cli ni c al 
St u di es  
1. 2. 5. 1  
St u d y t o Fi n d t h e Mec h a nis m of O cc u rre n ce of 
 i n Mi ce 
T h e m ec h a nis ti c st u di es f or 
 were c o n d u ct e d , b eca us e  
 w ere 
o bs er v e d i n a d os e r a n g e fi n di n g st u d y f or  carci n o g e ni cit y st ud y u si ng n o n -T g  mi ce  (a 
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1- m o nt h i nt er mitt e nt s u b c ut a n e o us d os e t o xi cit y st u d y). 
 
1. 2. 5. 1. 1  
T i m e of O cc u rre n ce of 
 i n Mi ce 
I n a si n gl e s u b c ut a n e o us d os e st u d y i n n o n-T g  mi ce ( d os e : 3 0 0 m g / k g), 
 
 aft er a d mi nistrati o n, 
 
 aft er a d mi nistrati o n, a n d 
als o 
 aft er a dmi nistr ati o n 
w er e o bs er v e d .   In a  2-w ee k -m a xi m u m i nt er mitte nt s u b c ut a n e o us d os e st u d y i n 
n o n- T g  mi ce  ( d os e: 3 0 0 m g / k g, twi ce w ee kl y ), si mil ar c h a n g es w ere als o o bs er v e d i n 
a ni m als i n 
 aft er th e st art of a d mi nistrati o n, b ut n o m aj or 
diff er e n ces w er e n ot e d 
 
I n a si n gl e s u b c ut a n e o us d os e st u d y i n Crl: C D 1 (I C R) mi ce ( I C R mi c e) (d os es : 5 0 0  a n d 
1 0 0 0 m g/ k g ), 
 w er e o bs er v e d at ≥5 0 0  m g/ k g , a n d 
 
 aft er a si n gl e a d mi nistrati o n , 
a n d 
 
aft er  a d mi nistr ati o n  wer e  o bs er v e d at 1 0 0 0  m g / k g.   I n a 2- w ee k -m a xi m u m 
i nt er mitt e nt s u b c ut a n e o us d os e st u d y i n I C R mi ce ( d os es: 5 0 0 a n d 1 0 0 0  m g / k g, twi ce  
w ee kl y ), si mil ar 
w ere  o bs er v e d i n a ni m als i n 
 
 aft er t h e st ar t of a d mi nistr ati o n (
 aft er t h e st art of a d mi nistrati o n 
at 1 0 0 0  m g/ k g ), a n d n o maj or diff er e n ces w ere n ot e d 
 
.   T h e  
 
o bs er v e d a t ≥5 0 0  m g / k g of D S -5 1 4 1 b i n I C R mi ce w ere q u alit ati v el y c o m p a ra bl e t o 
t h os e o bs er v e d i n n o n-T g  mi ce.  
 
1. 2. 5. 1. 2  
 Distri b uti o n 
T h e c o n ce ntr ati o ns  of i n t h e 
 w ere m eas ure d  
 aft er a 
si n gl e s u bc ut a n e o us a dmi ni str ati o n ( dos es : 3 0  a n d 3 0 0 m g / k g) t o n o n -T g  mi ce .   At  
t h e 3 0  m g / k g, t h e D S - 51 4 1 a  c o nce ntrati o n  
 w as b el o w t h e li mit of 
q u a ntit ati o n 
.   
 D S -5 1 4 1 a w as o bs er v e d  at  
3 0 0 m g / k g, alt h o u g h t h e 
w as e xtre m el y l o w.  
T h e D S -5 1 4 1 a  c o n ce ntr ati o ns i n t h e 
w ere m eas ure d 
 
aft er  a si n gl e s u b c ut a n e o us a d mi nistrati o n  t o I C R mi ce ( d os es: 3 0, 3 0 0 , 5 0 0, a n d 
1 0 0 0 m g/ k g ).   T h e D S -5 1 4 1 a  c o nce ntrati o ns i n t he 
 i n creas ed 
wit h d os e i n cr e m e nt.   
D S -5 1 4 1 b i n IC R mi ce w as  c o m p ara bl e t o 
t h at i n n o n-T g  mi ce at  t h e s a m e d os es, a n d t h us n o m aj or  differe n ce is n ot ed  
 
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 b et w ee n m uri n e str ai ns. 
To ass ess  t h e 
 of DS- 5 1 4 1 b , 
 
 o bt ai n e d b y 
 w as c o n d u ct e d  usi n g 
sa m pl es fr o m a 1 -m o nt h i nt er mitt e nt s u b c ut a n e o us d os e st u d y i n n o n -T g  mi c e (a d os e 
r a n g e fi n di n g st u d y f or car ci n o g e ni ci t y stu d y ) a n d a 1-m o nt h i nt er mitt e nt 
s u b c ut a n e o us d os e t o xi cit y st u d y i n I C R mi ce .   I n n o n-T g  mi ce , 
 
 w ere  
 at ≥3 0  m g/ k g, a n d t h e 
br o a d e n e d wit h d o s e i n cre me nt.   T h e 
 was  als o o bs er v ed i n 
 at 3 0 0 m g / k g.   In 
I C R mi ce, 
w as  als o o bs er v e d  i n 
 at 
≥1 0 0 m g / k g, a n d als o i n 
at 3 0 0  m g/ k g .   N o 
maj or  str ai n diff er e n ce w as n o t e d f or t h e 
 of D S -5 1 4 1 a 
b e t w ee n no n -T g mi c e a n d I C R  mi ce .   B e ca us e 
 of  D S -5 1 4 1 b 
w as o bs er v e d fr o m t h e d os e l e v els t h at 
w ere n ot n ot e d  at , an d  th e 
of  D S - 5 1 4 1 b di d n ot n ecess aril y c o rres p o n d t o 
 
D S - 5 1 4 1 b-
w as c o nsi dere d n ot t o b e ca us e d b y 
of D S - 5 1 4 1 a 
 
 
1. 2. 5. 1. 3  
(In V it ro) 
To ass ess  t h e 
 of D S- 5 1 4 1 b, D S - 5 1 4 1 b was tra nsfect e d t o m o us e  pri m ar y 
  T h e 
w as ass ess e d b y m eas uri n g t h e 
 of t h e cells at 4 8 h o urs aft er tra nsfecti o n of D S -5 1 4 1 b ( 5, 1 5, 5 0, a n d 
1 5 0 n m ol/ L ) usi n g tr a nsfecti o n r ea g e nt  t o 
 d eri v e d fr o m 2 
str ai ns of mi ce ( C 5 7 BL a n d I C R) s ee d e d o n a 9 6- w ell pl at e at c o n ce ntrati o ns ≥8. 3 × 
1 0 4 cells/ w ell .    N o 
 
w as o bs er v e d i n a n y of t h e 
 
 
1. 2. 5. 1. 4  
A ss o ci ati o n B et w ee n M uri n e 
 a n d 
 
 
I n b ot h no n -T g  a n d I C R mi ce , at d os e  l e v els t h at led t o t h e 
 ( n o n-T g  mi ce:  
≥1 0 0 m g / k g; I C R mi ce:  ≥5 0 0 m g / k g), t h e 
 of d ecreas e d  
w ere 
o bs er v e d i m m e di at el y after a d mi nistrati o n of D S - 5 1 4 1 b 
 
 aft er a d mi nistr ati o n).   
 
 di d n ot n ecess aril y c orres p o n d t o t h e o cc urre n ce  
 b ut in 
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i n di vi d u als wit h 
 
 w as o bs er v e d. 
 
1. 2. 5. 1. 5  
O t h er St u di es R el ati n g to 
 
Aft er  a si n gl e s u b c ut a n e o us a d mi nistrati o n  of 1 0 0 0  m g / k g of D S -5 1 4 1 b  t o IC R mi ce , 
t h e 
 w as ass es s e d b y 
  
o bs er v e d i n  2 of 4 a ni m als  at 
 aft er a d mi nistr ati o n.   In a n al ysis of 
 of I C R 
mi ce , 
 i n t h e gr o u p of 
 rel at e d t o 
 
, w hi c h is re p ort e d t o b e acti v at e d 
 
, w as o bs er v e d 
 aft er a si n gl e s u b c ut a n e o us 
a d mi nistr ati o n o f 5 0 0 a n d 1 0 0 0  m g/ k g.  
 aft er 
a d mi nistr ati o n t o I C R mi ce, 
 
, w as o bs er v e d  
 
 w as o bs er v e d .   In a d diti o n, w h e n t h e 
 
 t o I C R mi ce , f oll o w e d b y a si n gl e 
s u b c ut a n e o us a d mi nistr ati o n of 5 0 0 m g/ k g  of D S - 5 1 4 1 b, 
 w ere  
o bs er v e d i n a n y a ni m als .  In a d diti o n, 
 
 w er e o bs er v e d.  
F r o m t h e a b o v e, b as e d o n t h e f oll o wi n g; 
 
 oft e n o cc urr e d  
 t h e res ults of 
a n al ysis  a n d 
 a n d c o m pl et e  s u p pressi o n 
 
, D S - 5 1 4 1 b-i n du ce d  
 
 
.   B eca us e  
 di d n ot affect  t h e 
t o D S - 5 1 4 1 b, t h e 
 of D S -5 1 4 1 b -i n d u ce d 
 
 was c o nsi d e r e d t o b e r el at e d t o t h e 
 
. 
 
1. 2. 5. 2  
D iff ere n ces B et w ee n S p eci es 
Af t er a si n gl e su b c ut a n e o us a d mi nistr at i o n of 3 0 0  m g/ k g  of D S -5 1 4 1 b t o rats a n d 
1 0 0 m g / k g of D S -5 1 4 1 b t o c y n o m ol g us m o n k e ys, t h e D S -5 1 4 1 a c o n ce ntrati o ns i n th e 
w er e m eas ur e d 
 aft er a dmi nistra ti o n, res p ecti v el y 
.   In b ot h r ats a n d c y no m ol g us m o n k e ys , 
of D S - 5 1 4 1 b 
w as o bs er v e d , b ut t h e 
 w as l o w. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
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C CI
C CI
C CI
C CI
C CI
C CI
C CI
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C CI
C CI
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C CI
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C CI
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C CI
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 usi n g s a m pl es fr o m a 3-m o nt h 
i nt er mitt e nt s u b c ut a n e o us a d mi nistr ati o n d os e t o xicit y st u d y i n rats (a d os e fi n di n g 
st u d y f or car ci n o g e ni cit y st u d y) a n d a 9 -m o nt h i nter mitt e nt s u b c ut a n e o us d os e t o xi cit y 
st u d y i n c y n o m ol g us m o n k e ys  w as c o n d u c t e d.    In b ot h rats a n d c y n o m ol g us m o n k e ys , 
 w as  o bs er v e d i n t h e 
 at 
≥3 0  m g/ k g , a n d t h e 
 br o a de n e d wit h d os e 
i n cr e m e nt. 
T o i n v esti g at e w h et h er t h e 
 o bs er v e d i n mi ce are s p ecifi c t o mi ce, 
 
 wer e  e x a mi n e d  a n d 
 a n d 
 were  m eas ure d 
    Aft er a si n gl e s u b c uta n e o us 
a d mi nistr ati o n of 1 0 0 0  a n d 2 0 0 0 m g / k g t o u n a n est h eti ze d  u n c o nstrai n e d rats , n ecr o ps y 
w as c o n d u ct e d at 2 4 h o urs aft er ad mi nistrati o n a n d p at h ol o gi cal t e sts  
were 
c on d u ct e d .   A t d os es u p t o 2 0 0 0  m g / kg, n o effect w as o bs er v e d  i n 
 
 or 
 a n d 
 w as 
o bs er v e d . 
Bas e d o n t h e a b o v e,  D S -5 1 4 1 b tr a nsferred t o  
 a n d distri b ut e d  als o i n rats a n d 
c yn o m ol g us m o n k e ys li k e in m i ce.   H o w e v er, D S - 5 1 4 1 b-i n d u ce d 
 are  
c o nsi d er e d t o b e m o us e -s p ecifi c, b eca us e n o p at h ol o g i cal fi n di n gs were  o bs er v e d i n 
u p t o 2 0 0 0 m g/ k g i n r ats a n d 1 0 0 m g/ k g i n c y n o m olg us m o n k e ys.  
 
1. 2. 5. 3  
S af et y M a r gi n  
Bas e d o n t h at 
 o bs er v e d i n mi ce aft er  a 
s u b c ut a n e o us a d mi nistr ati o n of DS- 5 1 4 1 b is 
a n d 
d o es n ot w ors e n b y 
 C ma x is c o nsi d ere d a p pr o pri at e f or 
cal c ul ati n g t h e s af et y m a rgi n i n h u m a ns .    
I n c o m p aris o n of t h e e x p os ur e ( C m a x ) t o D S-5 1 4 1 a  at t h e N O A E L f or 
 i n 
eac h a ni m al str ai ns/s p eci es wi t h t h at at 6 m g/ k g i n h u m a n s, t h e s afet y m ar g i n is 
 i n th e m ost s e nsiti v e m uri n e strai n , n o n- T g  mi ce,  a n d  
 i n I C R mi ce , 
rats , a n d c y n o m ol g us m o n k e ys. 
 
1. 2. 6  
C li ni cal St u di es  
As of 3 0 A u g 2 0 1 9 , n o cli ni cal st u di es h a v e b ee n c o m pl et e d, a n d 1 st u d y  (t his st u d y) is 
i n pr o gr ess. 
As of 1 9 M ar 2 0 1 8 , P art 2 is c o m pl et e, an d a t ot al of 7 s u bj ects h a v e recei v e d 
D S - 5 1 4 1 b. 
C CI
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T h e p rim ar y effi cac y e n d p oi nt, ex pr essi o n of d ystr o p hi n pr ot ei n i n m us cl e tiss u e, w as 
p ositi v e i n 1 of 7 s u bj ects, an d t h e s ec o n d ar y effi cac y e n d p oi nt , pr o d u cti o n of e x o n 
4 5- s ki p p e d d ystr o p hi n m R N A  i n mus cl e tiss u e , w as o bs er v e d i n all s u bj ects.  
D uri n g  t h e Part  2-E xt e nsi o n , b as e d o n t h e res ult of n o n cli ni cal st u di es usi n g mi ce 
s h o w n i n S ecti o n 1. 2. 4. 4 , t h e st u d y dr u g a d mi nistrati o n a n d t h e P art 2- E xt e nsi o n  w ere 
te m p or aril y dis c o nti n u e d. 
As of 3 0 A u g 2 0 1 9 , P art 2- E xt e nsi o n- 2 is i n pr o gress.   A s eri o us a d v ers e e v e nt, 
a p p e n di citis, h as b ee n o bs er v e d i n 1 of 7 s u bj ects .   T h e s e v erit y w as mil d, a n d t h e 
e v e nt w as c o nsi d er e d u nr el at e d t o t h e st u d y dr u g an d w as c o nfir m e d  t o b e res ol v e d.   
N o a d v ers e e v e nts l ea di n g t o wit h dr a w al f r om a d mi nistrati o n of t h e st u d y dr u g or a 
c h a n g e i n t h e d os e of t h e st u d y dr u g w ere o bs er v e d .   C o m m o n a d v ers e e v e nts (t h os e 
t h at o cc urr e d i n 3 or m or e s u bj ects ) w ere inj ecti o n sit e reacti o n  ( 7 s u bjects), 
n as o p h ar y n gitis ( 6 s u bj ects), al p h a 1 mi cr o gl o b uli n i ncreas e d a n d b et a 2 mi cr o gl o b uli n 
uri n e i n cr eas e d  ( 4 s u bj ects eac h) a n d i nfl u e n za a n d p yre xi a ( 3 s u bj ects eac h).   T h e 
s e v erit y of eac h of t h es e w as mil d. 
Bas e d o n a n al ysis of t h e s af et y i nf or m ati o n fr o m s o urces i n cl u di n g n o n cli ni cal st u di es, 
cli n i cal st u d y a n d p u bli cati o ns a b o ut ot h er n u cl ei c aci d m e di cati o ns, w e n e wl y 
s el ect e d “i nj ecti o n sit e r eacti o n” a n d “al p h a 1 mi cr o gl o b uli n uri n e i n creas e d ” as ot h er 
i d e ntifi e d ris ks.   B as e d o n t h e fi n di n gs o b s er v e d i n t h e carci n o g e ni cit y a n d d os e 
fi n di n g st ud y i n mi c e,  we n e wl y s el ect e d 
 as a n i m p ort a nt 
p ot e nti al ris k a n d 
 as a n ot h er p ot e nti al ris k. 
C CI
C CI


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2.  
S T U D Y O B J E C TI V E S  
T h e o bj ecti v e of t h e st u d y is t o ass ess t h e s afet y, t ol era bilit y, effi cac y, a n d 
p h ar m ac o ki n eti cs of D S - 5 1 4 1 b i n D M D p ati e nts.    T h e st u d y is als o i nt e n d e d t o ass ess 
t h e d os e t o b e us e d i n t h e n e xt-p h as e st u di es.  
 




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< P art 2 > 
D S - 5 1 4 1 b will b e a d mi nist er e d s u b c ut a n e o usl y o n ce w ee kl y f or 1 2 w ee ks (a t ot al of 
1 2 d os es) at 2 d os e l e v els d et er mi n e d b as e d o n t h e res ults of P art 1.    S u bjects w h o 
h a v e fi nis h e d P art 1 m a y p arti ci p at e, an d 3 s u bj ects will  be assi g n e d t o eac h d os e l e v el .  
A n y n e w s u bj ects will b e a d d e d acc or di n g t o t h e pr o ce d ure i n 5. 8 . 
D S - 5 1 4 1 b w as a d mi nist er e d at 2 d os e l e v els  ( 2. 0 m g / k g a n d 6. 0 m g / k g) b as e d o n t h e 
r es ults of P art 1. 
 
< P art 2- E xt e n si o n > 
D S -5 1 4 1 b will b e a d mi nist er e d s u b c ut a n e o usl y o n ce w ee kl y f or 4 8 w ee ks (a t ot al of 
4 8 d os es) at 2 d os e l e v els ( 2. 0 m g / k g a n d 6. 0 m g / k g) b as e d o n t h e res ults of P art 2.   
S u bj ects w h o h a v e fi n is h e d P art 2 m a y p arti ci p at e, a n d 3 s u bj ects will b e assi g n e d  t o 
eac h d os e l e v el .   A n y  n e w  s u bj ects will b e a d d e d acc or di n g t o t h e pr o ce d ure i n 5. 8 . 
Bas e d o n t h e r es ults of n o n cli ni cal st u di es i n mi ce, t h e st u d y dr u g a d mi nistrati o n w as 
te m p or aril y dis c o nti n u e d. 
 
< P art 2- E xt e nsi o n - 2 > 
D S -5 1 4 1 b will b e a d mi nist er e d s u b c ut a n e o usl y o n ce w ee kl y f or 4 8 w ee ks (a t ot al of 
4 8 d os es) at t h e 2 d os e l e v els of D S -5 1 4 1 b a d mi nist ere d i n P art 2 ( 2. 0  m g / k g a n d 
6. 0 m g / k g) b as e d o n t he r es ults of P art 2.    S u bj ects w h o h a v e fi nis h e d P art 2 m a y  
p arti ci p at e, a n d 3 s u bj ects will b e assi g n e d t o eac h d os e l e v el .    A n y n e w s u bj ects will 
b e a d d e d acc or di n g t o t h e pr o ce d ur e i n 5. 8 . 
A s a m eas ur e t o pr e v ent t h e s pr ea d of t h e n o v el c or o n a vir us, ad mi nistra ti o n b y a 
g u ar di a n at h o m e ( “s elf -a d mi nistr ati o n ”) will b e all o w e d.   C o ns e nt f or 
s elf-a d mi nistr ati o n will b e o bt ai n e d fr o m t h e l e g all y acce pt a bl e re pres e nt ati v e, a n d t h e 
g u ar di a n p erf or mi n g s elf -a d mi nistr at i o n will b e gi v e n trai ni n g i n t h e m et h o d of st ori ng 
t h e st ud y  dr u g, th e m et h o d of a d mi nist eri n g t h e st u d y dr u g  a n d t h e m et h o d f or 
r ec or di n g i nf or m ati o n i n t h e “ S elf-I nj ecti o n Di ar y ” b ef ore s elf-a d mi nistrati o n st arts.  
 
< R ati o n al e > 
Si n ce t h e n u m b er of t ar g et  p ati e nts i n t his st u d y is s m all, we s el ect e d a d e si g n t h at 
all o ws as m u c h i nf or m ati o n f or ass essi n g D S-5 1 4 1 b as p ossi bl e t o b e o bt ai n e d fr o m a 
li mit e d n u m b er of p ati e nts.   W e s el ect e d 4 w ee ks as t h e d urati o n of st u d y dr u g 
a d mi nistr ati o n  f or eac h s u bj ect in P art 1 , si n ce t his is t h e p eri o d f or w hi c h s afety w as 
c o n fir m e d i n t h e n o n cli nical t o xi c ol o g y st u d y.   S p ecifi call y, w e d eci d e d t o a d mi nist er 


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eac h d os e l e v el t o a s u bj ect o n ce w ee kl y f or 2 w ee ks (a t ot al of 2 d os es), s o t h at 2 d os e 
le v els ar e a d mi nist er e d , wit h a t ot al of 4 d os es o v er 4 w ee ks.  We s el ect e d 1 2 d os es  i n 
1 2 w ee ks as t h e d ur ati o n of st u d y dr u g a d mi nistrati o n  i n P art 2 i n or d er t o c o nfir m t h e 
e x pr essi o n of d ystr o p hi n pr ot ei n.   We pl a n t o st art P art 2 aft er s afet y h as b ee n 
c o nfir m e d i n a n o n cli n i cal t o xi c ol o g y st u d y wit h l o n g-t er m re p eat e d d osin g. 
We s e l ect e d 4 8 d os es i n 4 8 w ee ks as t h e d urati o n of st u d y dr u g a d mi nistrati o n  i n Part 
2- E xt e nsi o n a n d  P art 2- E xt e nsi o n- 2 , i n or d er t o c o nfir m t h e e x pressi o n of d ystr o p hi n 
p r ot ei n d u e t o l o n g-t er m a d mi nistr ati o n of D S-5 1 4 1 b . 
 


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4.  
T A R G E T S U B J E C T S  
4. 1  
S el ecti o n o f S u bj ects 
D M D p ati e nts w h o m eet all of t h e f oll o wi n g i n cl usi o n crit eri a a n d d o n ot meet a n y of 
t h e e x cl usi o n crit eri a at t h e ti m e of re gistrati o n i n t his st u d y will b e i n cl u d e d i n t h e 
st u d y. 
 
4. 1. 1  
In cl usi o n C ri t eri a 
1)  Pati e nts w h o h a v e b ee n c o nfir m e d t o h a v e a n o ut- of- fra m e d el eti o n t h at ca n b e 
c orr ect e d b y e x o n 4 5 s ki p pi n g of t h e d ystr o p hi n g e n e, t o t h us rest ore t h e i n -fra m e 
d el eti o n.  
2)  T h os e w h o h a v e b ee n c o nfir m e d t o h a v e a D N A s e q u e n ce t h at f or ms a d o u bl e 
str a n d wit h D S -5 1 4 1 b i n t h e e x o n 4 5 of t h e d ystr o p hi n g e n e.  
3)  T h os e  w h o h a v e i nt act m us cl es of a d e q u at e q u alit y f or bi o ps y t o all o w e v al u ati o n 
of t h e effi cac y of t h e st u d y dr u g.  
4)  B o ys a g e d fr o m 5 t o < 1 1 y ears at t h e ti m e of re gistrati o n.  
5)  T h os e w h o ar e a bl e t o  w al k at l east 3 2 5 m et ers i n t h e 6 -mi n ut e w al k t est.  
6)  St er oi d -n ai v e p ati e nts or p ati e nts w h o h a v e b ee n treat e d wit h st er oi ds f or at l east 6 
m o nt hs pri or t o r e gistr ati o n i n t h e st u d y wit h o ut a d os a g e c h a n g e f or at l east 3 
m o nt hs pri or t o r e gistr ati o n. 
7)  T h os e w h o ar e a bl e t o f oll o w t h e i nstr u cti o ns o n  t h e s c h e d ul e d a d missi on, visits, 
tr eat m e nt pl a n, t ests/ o bs er v ati o ns, a n d ot h er st u d y pr o ce d ures s et i n t h e pr ot o c ol 
w hil e p arti ci p ati n g i n t h e st u d y.  
8)  T h os e w h o h a v e v ol u nt aril y pr o vi d e d writt e n i nf or m e d c o ns e nt or  h a v e recei v e d 
a d e q u at e e x pl a n ati o ns a b o ut  t h e st u d y i n v ol vi ng t h eir d ecisi o n -m a ki n g a b o ut 
p arti ci p ati o n i n t h e st u d y.  
9)  T h os e w h os e l e g al r e pr es e nt ati v es h a v e v ol u nt aril y pr o vi d e d writt e n i nf or me d 
c o ns e nt i n a n a p pr o pri at e m a n n er.  
 
< R ati o n al e > 
1), 2), 3) T h es e w er e s el ect e d t o a p pr o pri at el y ass ess t h e effi cac y of t h e  st ud y dr u g.  
4) L o w er a g e li mit  ( 5 y ears or ol d er) : T h e l o w er a g e li mit w as s el ect e d t o b e a n a g e 
w h er e t h e s u bj ect ca n f oll o w t h e st u d y pr o ce d ures pl a n n e d i n t his st u d y wit h t h e 
c o o p er ati o n of t h eir f a mili es or g u ar di a ns.  U p p er a g e li m it (y o u n g er  t h a n 1 1  y ea rs): 
D uri n g t h e cli ni cal c o urs e of D M D , m a n y p ati e nts l os e t h e a bilit y t o w al k at ar o u n d t h e 
a g e of 1 0 y ears .1  T h e u p p er a g e li mit w as s el ect e d b eca us e it is n ot feasi bl e t o 


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p erf or m m us cl e bi o ps y i n  p ati e nt s w ho h a v e l ost t h e a bilit y t o w al k . 
5) It h as b ee n r e p ort e d t h at p ati e nts wit h a res ult l ess t h a n 3 2 5 m i n t h e 6- mi n ut e w al k 
test ar e li k el y t o l os e t h e a bilit y t o w al k wit hi n 1 y ear.5  T his w as s el ect e d b eca us e it 
is n ot f easi bl e t o p erf or m m us cl e bi o ps y i n p ati e nts w h o h a v e l ost t h e a bilit y t o w al k. 
6), 7) T h es e w er e s el ect e d t o a p pr o pri at el y ass ess t h e effi cac y a n d s afet y of t h e st u d y 
dr u g.  
8), 9) T h es e w er e s el ect e d d u e t o et hi cal c o nsi d er ati o ns a b o u t t h e h an dli n g of s u bj ects.  
 
4. 1. 2  
E x cl usi o n C rit eri a  
1)  Pati e nts wit h a g e n e m ut ati o n w hi c h is n ot e x p ect e d t o pr o d u ce t h e d ystr o p hi n 
pr ot ei n b y e x o n 4 5 s ki p pi n g . 
2)  C o n c urr e nt ill n ess o t h er t h a n D M D t h at ca n ca us e m us cl e w ea k n ess a n d/ or 
i m p air m e nt of m ot or f u n cti o n. 
3)  C urr e nt or pr e vi o us s e v er e dis or d er i n v ol vi n g t h e li v er, ki d n e ys, bl o o d, 
h y p ers e nsiti vit y, r es pir at or y s yst e m, g astr oi nt esti n al s yst e m, circ ul at or y s yst e m, 
ce ntr al n er v o us s y st e m, et c. 
4)  L eft v e ntr i c ul ar ej ecti o n fr acti o n < 5 5 % o n t h e ec ho car di o gra m.  
5)  Fri d eri ci a -c orr ect e d Q T i nt er v al ( Q Tc) > 0. 4 5 s ec o n ds o n t h e 1 2 -l ea d 
el ectr o car di o gr a m.  
6)  T h os e w h o r e q uir e tr eat me nt of t h e res pirat or y s yst e m, e g, res pirat or y p h ysi cal 
t h er a p y or m ec ha ni cal r es pir at or y s u p p ort.  
7)  T h os e w h o h a v e a p ositi v e r es ult f or t h e h e p atitis B s urface ( H Bs) a nti g e n, 
h e p atitis C vir us ( H C V) a nti b o d y, or 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 ests.  
8)  T h os e w h o h a v e p arti ci p at e d i n a n ot h er cli ni cal st u d y a n d h a v e r ecei v e d a n  
i n v esti g ati o n al pr o d u ct wit hi n 3 m o nt hs pri or t o re gistrati o n  i n t his st u d y. 
9)  Ot h er  p ati e nts w h o ar e c o nsi d er e d i n eli gi bl e f or t h e st u d y b y t h e i n v esti g at or or 
s u bi n v esti g at or. 
 
< R ati o n al e > 
1), 2), 8) T h es e w er e s el ect e d t o a p pr o pri at el y ass ess t h e effi cac y a n d s afet y of t h e 
st u d y dr u g. 
3), 4), 5) , 6) , 7)  T h es e w er e s el ect e d o ut of c o nsi d erati o n f or t h e s afet y of s u bj ects.  
9 ) T his w as s el ect e d s o t h at t h e i n v esti g at or or s u bi n v esti g at or ca n t a k e ot h er g e n eral 
f act ors i nt o acc o u nt. 


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4. 2  
R e gist r ati o n of  S u bj ects  
4. 2. 1  
S u bj ect R e g ist r ati o n P r o ce d u re 
Aft er o bt ai ni n g writ t e n i nf or m e d c o ns e nt (c o nfir mati o n of i nt e nt ) fr o m a s u bj ects or 
his l e g all y acce pt a bl e r e pr es e nt ati v e (s ee 1 5. 3 ), t h e i n v esti g at or or s u bi n v esti g at or will  
assi g n a s u bj ect i d e ntifi cati o n c o d e, pre p are a s u bject s cree ni n g list a n d c o nfir m t h e 
eli gi bilit y of t h e s u bj ect.   Th e i n v esti g at or or s u bi n v esti g at or will fill o ut t h e 
n ecess ar y it e ms o n t h e s u bj ect r e gistrati o n f or m ( A p p e n di x 1) f or a s u bj ect d et er mi n e d 
t o be eli gi bl e a n d s e n d it t o t h e s p o ns or b y fa x.  
T h e s p o ns or will cr oss -c h ec k t h e c o nte nts of t h e s u bj ect re gistrati o n f or m recei v e d  
wit h t h e i n cl usi o n crit eri a a n d e x cl usi o n crit eri a f or t his st u d y an d c h ec k t h e eli gi bilit y 
of t h e r el e v a nt s u bj ect.  If t h e sp o ns or h as a n y q u eri es a b o ut t h e c o nt e nts of t h e 
s ubj ect r e gistr ati o n f or m , t h e s p ons or will i m m e diat el y co nt act t h e i n v esti g at or or 
s u bi n v esti g at or an d c h ec k t h e c o nt e nts.   If t h e s u bj ect is c o nfir m e d t o b e eli gi bl e, h e 
will b e r e gist er e d a n d as si g n e d a su bj ect n u m b er.   T h e  s p o ns or w ill i m m e di at el y 
i nf or m t h e i n v esti g at or etc. of i nf or m ati o n i n cl u di n g t h e eli gi bilit y ass ess me nt res ult , 
re gistr ati o n d at e, s u bj ect n u m b er a n d st u d y dr u g d os e l e v el, f or e x a m pl e b y fa x.  If 
t h e s p o ns or d et er mi n es t h at  a s u bj ect  is i n eli gibl e, t h e s p o ns or will i m m e diat el y i nf or m  
t h e i n v esti g at or or s u bi n v esti gat or o f t h e reas o n f or t his.    Th e i n v esti g at or or 
s u bi n v esti g at or must n ot pr es cri b e t h e st u d y dr u g u ntil t h e s u bj ect is re gist ere d. 
If a n y s u bj ect w as n ot r e gist er e d, t h e in v esti g at or  or s u bi n v esti g at or  will e x pl ai n t h e 
r eas o n f or t his.   L at er , if t h e i n vesti g at or or s u bi n v esti g at or d et er mi n es t h at t h e 
s u bj ect is s uit a bl e f or t his st u d y, h e or s h e will o btai n writt e n i nf or m e d c o ns e nt fr o m 
th e s u bj ect or l e g all y acce pt a bl e r epr es e nt ati v e a g ai n a n d p erf or m re gistrati o n of t h e 
s u bj ect acc or di n g t o t h e pr o ce d ur e s p ecifi e d i n t his s ecti o n.   T h e i n v esti g at or et c. w ill 
r ec or d i nf or m ati o n i n cl u di n g t h e r e gistrati o n d at e, s u bj ect n u m b er a n d st u d y dr u g d os e 
le v el i n t h e cas e r e p ort f orm.  
 
4. 2. 2  
N otifi c ati o n If a S u bj ect Is R ecei vi n g Tre at m e n t fr o m A n ot h er P h ysi ci a n 
T h e i n v esti g at or or s u bi n v esti g at or will c h ec k w h et h er s u bj ects are recei vi n g treat m e nt 
fr o m a n ot h er p h ysi ci a n (a n ot h er d e p art m e nt at t h e st u d y sit e or a n ot h er m e di cal 
i nstit uti o n).   If a s u bj ect is r ecei vi n g treat m e nt fr o m a n ot h er p h ysi ci a n, wit h t h e 
c o ns e nt of t h e s u bj ect a n d his l e g all y acce pt a bl e re pres e nt ati v e, t h e i n v esti g at or or 
s u bi n v esti g at or will n otif y t h e p h ysi ci a n t h at t h e s u bj ect is p arti ci p ati n g i n t h e st u d y.   
T h e f ac t t h at t his n otifi cati o n h as b ee n m a d e will b e rec o r d e d i n m e di cal rec or ds or t h e 


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li k e. 
 
4. 3  
W it h d r a w al C rit eri a of I n di vi d u al Su bject s a n d A cti o n o n Wit h d r a w al  
If a s u bj ect m eets a n y of t h e f oll o wi n g crit eri a, t h e i n v esti g at or or s u bi n v esti g at or will 
pr o m ptl y  wit h dr a w t h e r el e v a nt s u bj ect fr o m t h e st u d y a n d h a n dl e t h e s u bject 
a p pr o pri at el y.   T h e i n v esti g at or or s u bi n v esti g at or  will als o f oll o w u p a n y 
a b n or m aliti es o bs er v e d at t h e ti m e of wit h dra w al a n d , as far as t h e c o o p erati o n of t h e 
s u bj ect a n d hi s l e g all y acce pt a bl e r e pres e nt ati v e ca n b e o bt ai n e d , will p er f or m t h e 
p h ysi cal e x a mi n ati o ns a n d t ests s p ecifi e d i n “ 6. 5  T est It e ms o n Wit h dra w al fr o m t h e 
St u d y a n d t h eir Ti mi n g ” a n d m a k e eff orts  t o e ns ure t h e s afet y of t h e s u bj ect.   If a n 
a d v ers e e v e nt o cc urs , t h e pr o ce d ur es i n “9. 5  It e ms t o I n v esti g at e f or Ad v ers e E v e nts ” 
a n d “ 9. 7  A cti o n If a n A d v ers e E v e nt O cc urs ” will b e f oll o w e d . 
E ac h s u bj ect’s c o m pl eti o n of/ wit h dr a w al fr o m t h e st u d y, t h e d at e of st u d y c o m pl eti o n 
or wit h dr a w al/ dis c o nti n u ati o n , a n d t h e pri m ar y  reas o n f or earl y 
wit h dr a w al/ dis c o nti n u ati o n will b e rec or d e d o n t h e cas e re p ort f or m.  
• 
C o nti n u e d st u d y dr u g a d mi nistr ati o n b ec o m es diffi c ult d u e t o t h e o cc urre n ce of a n 
a d v ers e e v e nt  
• 
A m aj or d e vi ati o n fr o m t h e cli ni cal st u d y pr ot o c ol  is dis c o v ere d 
• 
T h e s u bj ect or l e g all y acce pt a bl e re pres e nt ati v e ma k es a re q u est t o w it h dra w 
• 
T h e st u d y is t er mi n at e d b y t h e s p o ns or  
• 
T h e i n v esti g at or or s u bi n v esti g at or d et er mi n e d t h at it is u ns uit a bl e t o c o nti n u e t h e 
s u bj ect’s p arti ci p ati o n i n t h e st u d y f or a n y ot h er reas o n 
 


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5.  
M E T H O D O L O G Y  
5. 1  
St u d y D r u g  
F o r d et ails of t h e st u d y dr u g a n d its h a n dli n g, see t h e “I n v esti g at or’s Br o c h ure” a n d 
“P h ar m ac y M a n u al . ” 
 
5. 1. 1  
In v esti g ati o n al D r u g  
1)  In v esti g ati o n al s u bst a n ce c o d e : D S - 5 1 4 1 b 
2)  G e n eri c n a m e: r e n adirs e n (I N N)  
3)  C o nt e nt a n d d os a g e f or m : 
• 
D S - 5 1 4 1 b f or i nj ecti o n 1 0 0 m g  is a l y o p hili ze d p o w d er i n a gl ass vi al.   It is 
w hit e t o li g ht y ell o wis h w hi t e ca k e -li k e m ass, an d eac h vi al c o nt ai ns 1 0 0  m g  
of D S - 5 1 4 1 b. 
• 
D S -5 1 4 1 b f or i nj ecti o n 1 5 0  m g  is a l y o p hili ze d p o w d er i n a gl ass vi al .   It  is  a  
w hit e  t o li g ht y ell o wis h w hit e ca k e -li k e m ass, a n d eac h vi al c o nt ai ns 1 5 0 m g  
of D S -5 1 4 1 b.  
• 
T h e acc o m p a n yi n g r ec o nst it uti o n dil u e nt f or DS- 5 1 4 1 b f or i nj ecti o n (f or 
1 0 0 m g / mL) is a cl ear c ol orl ess li q ui d , a n d eac h vial ( 1. 1 m L ) c o nt ai ns 3 1  m g  
of gl u c os e . 
• 
T h e acc o m p a n yi n g r ec o nstit uti o n dil u e nt  f or DS- 5 1 4 1 b f or i nj ecti o n (f or 
3 0 m g / m L) is a cl ear c ol orl ess li q ui d, a n d eac h vi al ( 5. 4 m L) c o nt ai ns 2 2 7  m g 
of gl u c os e . 
• 
T h e ac c o m p a n yi n g r ec o nstit uti o n dil u e nt  f or DS- 5 1 4 1 b f or i nj ecti o n (f or 
1 5 0 m g / m L) is a cl ear c ol orl ess li q ui d, a n d eac h vial ( 5. 4 m L) c o nt ai ns 3 9  m g  
of gl u c os e . 
4)  L ot n u m b er : S h o w n i n “ P h ar m ac y M a n u al . ” 
 
5. 1. 2  
L a b eli n g a n d P a c k a gi n g 
S h o w n i n  “P h ar m ac y M a n u al . ” 
 
5. 1. 3  
S t o r a g e of t h e St u d y D r u g 
Aft e r a c o ntr act h as b ee n c o n cl u d e d, th e s p o ns or w ill s u p pl y t h e st u d y dr u g t o t h e 
st u d y sit e.   T h e st u d y dr u g m a n a g er will st ore “ D S - 5 1 4 1 b f or i nj ecti o n 1 0 0 m g , ” 
“ D S - 5 1 4 1 b f or i nj ectio n 1 5 0 m g , ” “ac co m p a n yi n g  rec o nstit uti o n dil u e nt f or D S - 5 1 4 1 b 
f or i nj ecti o n (f or 1 0 0 m g / m L), ” “acc o m p a n yi n g rec o nstit uti o n dil u e nt  f or D S-5 1 4 1 b 
f or i nj ecti o n (f or 3 0  m g/ m L ) ” a n d “ acc o m p a n yi n g rec o nstit uti o n dil u e nt  f or DS- 5 1 4 1 b 


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f or i nj ecti o n (f or 1 5 0 m g / m L)” i n a refri g erat or ( 2° C t o 8° C).   T h e st u d y dr u g wil l b e 
ma n a g e d a n d c oll ect e d acc or di n g t o t h e “P h ar m ac y M a n u al . ” 
If s elf-a d mi nistr ati o n is p erf or m e d as a m eas ure t o pre v e nt  t h e s prea d of t h e n o v el 
c or o n a vir us, b ef or e  distri b uti n g t h e st ud y dr u g, t h e st u d y  dr u g m a n a g er will p er f or m 
vis u al i ns p ecti o n t o c h ec k w h et h er t h ere are f orei g n o bj ects or dis c ol orati o n i n a n y 
vi als .   If f or ei g n o bj ects or dis c ol orati o n are o bs er v e d  i n a st u d y dr u g, it m ust n ot b e 
distri b ut e d .   T h e st u d y dr u g m a n a g er w ill c h ec k t h e q u a ntiti es of st u d y dr u g 
distri b ut e d to eac h s u bj ect o n eac h visit d a y a n d t h e d at es, t h e q u a ntiti es of us e d a n d 
u n us e d vi als r et ur n e d b y s u bj ects, a n d t h e “S elf -I nj ecti o n Di ari es, ” a n d will rec or d 
t h es e i n t h e Dr u g A cc o u nt a bilit y  R ec or d .   If s elf-i nj ecti o n is p erf or m e d, t h e st u d y 
dr u g will b e st or e d i n t h e s u bj ects’ h o m es acc or di n g t o t h e “ S elf -I nj ecti o n G ui d e. ” 
 
5. 2  
St u d y D r u g  A d mi nist r ati o n Met h o d  
5. 2. 1  
D os e  
D os es will b e cal c ul at e d b a s e d o n t h e s u bj ect’s b o d y w ei g ht .   If t h e s ub j ect’s b o d y 
w ei g ht h as c h a n g e d b y ≥1 0 % si n ce t h e l ast d os e, t h e d os e will b e recal c ul at e d. 
 
< P art 1 > 
T his p art will c o nsist of t h e f oll o wi n g d os e l e v els.  
L e vel  
D ose  
N u m b er of d os es , ro ute of a d mi nistrati o n  
1  
0. 1  m g / k g 
O nce wee kl y f or 2 we e ks  (a t otal of 2 d os es ) 
S u b c uta ne o u s ad mi nistr ati o n  
2  
0. 5  m g / k g 
3  
2. 0  m g /k g  
4  
6. 0  m g / k g 
 
< P art 2 > 
T h e 2 d os e  l e v els of D S - 5 1 4 1 b d eci d e d b as e d o n t h e res ults of P art 1 will b e 
a d mi nist er e d s u b c ut a n e o us l y o n ce w ee kl y f or 1 2 w ee ks (a t ot al of 1 2 d os es ). 
 
< P art 2- E xt e ns i o n > 
Bas e d o n t h e r es ults of Part 2 , t h e 2 d os e l e v els of D S -5 1 4 1 b  a d mi nist ere d i n P art 2  
( 2. 0 m g / k g, 6. 0 m g / k g) will b e a d mi nist ere d s u b c ut a n e o usl y o n ce w ee kl y f or 4 8  w ee ks 
(a t ot al of 4 8 d os es ). 
Bas e d o n t h e r es ults of n o n cli ni cal st u di es i n mi ce, t h e stu d y dr u g  a d mi nistrati o n w as 
te m p or aril y dis c o nti n u e d. 
 


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< P art 2- E xt e nsi o n - 2 > 
Bas e d o n t h e r es ults of P art 2, t h e 2 d os e  l e v els of D S-5 1 4 1 b a d mi nist ere d i n P art 2 
( 2. 0 m g / k g, 6. 0 m g / k g) will b e a d mi nist ere d s u b c ut a n e o usl y o n ce w ee kl y f or 4 8 w ee ks 
( a t ot al of 4 8 d os e s). 
 
< R ati o n al e > 
We s el ect e d t h e first d os e of 0. 1  m g/ k g  wit h refere n ce t o  “ G ui d a n ce f or Esta blis hi n g 
Saf et y i n First -i n-H u m a n St u di es d uri n g Dr u g D e v el o p m e nt ,6” b y cal c ul ati n g t h e 
h u m a n e q ui v al e nt d os e ( H E D) f or t h e N O A E L in m uri n e t o xi cit y st u di es , a n d t a ki n g 
t h e s af et y f act or i nt o c o nsi d er ati o n. 
I n a t wi ce-w ee kl y 1- m o nt h i nt er mitt e nt  s u b c ut a n e o us a d mi nistrati o n t o xi cit y st u d y  i n 
mi ce, v ac u oli zati o n of t h e bl a d d er tr a nsiti o n al e pit h eli u m a n d t hi c k e ni n g of  t h e bl ad d er 
m u c os a w er e o bs er v e d i n gr o u ps a d mi n ist ere d d os es ≥3 0 m g / k g, a n d t h eref ore, w e 
d et er mi n e d t h at t h e  N O A E L w as 1 0 m g / k g.  T a ki n g i nt o acc o u nt t h es e t o xi cit y 
fi n di n gs a n d t h e s e v erit y a n d r arit y of D M D , w e s el ect e d 1 0 as t h e s afet y fact or.   
Si n ce d os es w er e a d mi nist er e d t wi ce w ee kl y i n t h e m urin e t o xi cit y st u d y, th e d os e p er 
w ee k at t h e N O A E L  i n mi ce w as 1 0  m g / k g × 2 = 2 0  m g / k g p er w ee k , a n d t h e H E D 
aft er b o d y s urf ace ar ea c o n v ersi o n ( co n v ersi o n fact or 0. 0 9  [ass u mi n g a c hil d’s b o d y 
w ei g ht t o b e 3 0 k g ])7 w as cal c ul a t e d t o b e 1. 8 m g / k g p er w ee k.  
B as e d o n t h e a b o v e , a n d ta ki n g i nt o acc o u nt t h at D S - 5 1 4 1 b is a n o v el n u clei c aci d 
c o m p o u n d, w e s el ect e d 0. 1 m g / k g, a d os e n o great er t h a n 1. 8 m g / k g × 1/ 1 0 = 
0. 1 8  m g/ k g , as t h e first d os e l e v el.   We s el ect e d 0 . 5 m g / k g, 5 ti m es t h e first d os e l e v el, 
as t h e s ec o n d d os e  l e v el, 2 m g/ k g , 4 ti m es t h e s ec o n d d os e l e v el, as t h e t hir d d os e l e v el, 
a n d 6 m g/ k g , 3 ti m es t h e t hir d d os e l e v el, as t h e f o urt h d os e l e v el.   T h e t hir d d os e 
le v el of 2 m g / k g is al m ost t h e s a m e as 1. 8 m g / k g, t h e H E D of t h e d os e p er w ee k at t h e 
N O A E L  i n mi ce, 2 0  m g / k g p er w ee k, an d t h e m a xi m u m d os e of 6 m g / k g is cl os e t o 
5. 4 m g / k g, t h e H E D of t h e d os e p er w ee k t h at w as a t o xi c d os e i n mi ce, 6 0  m g/ k g  p er 
w ee k .   T h us, si n ce t h e t hir d d os e l e v el a n d f o urt h d os e l e v el are b et w ee n t h e N O A E L  
a n d t o xi c d os es, t h e d os es will b e titrat e d ca uti o usl y, wit h caref ul m o nit ori n g t o e ns ure 
t h e s af et y of s u bj ects. 
Si n ce n o n e of t h e 4 d os e le v els a d mi nist ere d i n P art 1 w as ass o ci at e d wit h a n y 
pr o bl e ms wit h s u bj ect t oler a bilit y, t h e st u d y dr u g w as a d mi nist ere d at d os e  l e v els of 
2. 0 m g / k g a n d 6. 0 m g/ k g  i n P art 2.   I n P art 2- E xt e nsi o n a n d  P art 2- E xt e nsi o n - 2, it 
will b e a d mi nist er e d at t h e s a m e d os e  l e v els as i n P art 2. 
 


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5. 3  
M et h o d of A d mi nist r ati o n  
T h e s t u d y dr u g will b e a d mi nist er e d  o n ce w ee kl y  b y s u b c ut a n e o us inj ecti o n .   I n P art 
2 , P art 2- E xt e nsi o n a n d  Part 2- E xt e nsi o n - 2, if it ca n n ot b e a d mi nist ere d o n ce w ee kl y, 
f or e x a m pl e b eca us e of t h e cir c u mst a n ces of t h e s u bj ect, t h e a d mi nistrati o n d a y is 
all o w e d t o b e wit hi n ± 2 d a ys of t h e s p ecifi e d d at e .   T h ere will b e i nt er v als of at l east 
3 d a ys b et w ee n d os es .   T h e t e m p er at ure of t h e s ol uti o n f or a d mi nistrati o n will b e 
a dj ust e d t o a p pr o xi m at el y b et w ee n r o o m t e m p erat ure a n d b o d y t e m p erat ure b ef ore 
a d mi nistr ati o n .   If 1 d os e is a d mi nist ere d at multi pl e l o cati o ns, t h ere will b e dist a n ces 
of ≥4 c m  b et w ee n l o cati o ns .   T h e st u d y dr u g will n ot b e a d mi nist ere d t o t h e s a m e 
l o cati o n i n c o ns ec uti v e w ee ks. 
If s elf-a d mi nistr ati o n is p erf or m e d as a m eas ure t o pre v e nt t h e s prea d of t h e n o v el 
c or o n a virus, t h e g u ar di a n p erf or mi n g s elf -a d mi nistrati o n will rec or d t h e d os e a n d 
d at e/ti m e of a d mi nistr ati o n  i n a “S elf -I nj ecti o n Diar y . ”  T h e i n v esti g at or or 
s u bi n v esti g at or will c h ec k t h e “S elf -I nj ecti o n Di ar y ” o n eac h visit d a y an d pr o vi d e 
r etr ai ni n g if n ecess ar y. 
 
5. 3. 1  
M eth o d f o r Pre p a ri n g t he S ol uti o n  f o r A d mi nistr ati o n 
T h e d os e of t h e s t u d y dr u g will b e cal c ul at e d b as e d o n t h e s u bj ect’s b o d y w ei g ht .   
T h e sol uti o n  f or i nj ecti o n will b e pr e p are d acc or di n g t o t h e rel e v a nt pr o ce d ure i n o n e 
of 1) to 3) b el ow, d e p e n di n g  o n t h e d os e .   If t h e t ot al d os e ca n n ot b e o bt ai n e d b y 
p erf or mi n g  t h e pr o ce d ur e o n ce, th e s a m e pr o ce d ure will b e re p eat e d u ntil t h e t ot al d os e 
is o bt ai n e d.   T h e pr e p ar e d sol uti o n  f or a d mi nistrati o n will b e a d mi nist ere d pr o m ptl y 
aft er pr e p a r ati o n. 
1)  If th e d os e is < 3 m g  
A n a m o u nt of 5. 4  m L of t h e “ acc o m p a n yi n g rec o nstit uti o n dil u e nt  f or D S - 5 1 4 1 b 
f or i nj ecti o n (f or 3 0 m g/ m L) ” will b e a d d e d t o “D S - 5 1 4 1 b f or i nj ecti o n 1 5 0 m g ” 
t o r ec o nstit ut e it.   Aft er t his, 1. 0 m L  of t h e o bt ai n e d s ol uti o n f or a d mi nistrati o n 
( 3 0 m g / m L) a n d 9. 0  m L  of J a p a n es e P h ar m ac o p o ei a gl u c os e f or i nj ecti o n w ill b e 
mi x e d i n a st erili ze d vi al t o pr e p are 1 0 m L of 3 m g / m L sol uti o n  f or a d mi nistrati o n. 
2)  If t h e d os e is ≥3 m g  a n d < 3 0 m g  
A n a m o u nt of  5. 4  m L of t h e “ acc o m p a n yi n g rec o nstit uti o n dil u e nt  for D S - 5 1 4 1 b 
f or i nj ecti o n (f or 3 0 m g/ m L) ” will b e a d d e d t o “ D S- 5 1 4 1 b f or i nj ecti o n 1 5 0 m g ” 
t o r ec o nstit ut e it, a n d 5. 4 m L of 3 0  m g/ m L sol uti o n  f or a d mi nistrati o n will b e 
p r e p ar e d. 
3)  If t h e d os e is ≥3 0  m g  


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A n a m o u nt of 1. 0  m L of t h e “ ac c o m p a n yi n g rec o nstit uti o n dil u e nt  f or D S- 51 4 1 b 
f or i nj ecti o n (f or 1 5 0 m g / m L)” will b e a d d e d t o “D S -5 1 4 1 b f or  i nj ecti o n 1 5 0 m g ” 
t o r ec o nstit ut e it, a n d 1 5 0 m g / m L s ol uti o n f or ad mi nistrati o n will b e pre p are d.   
Alt er n ati v el y, a n a m o u nt of 1. 1  m L of t h e “acc o m p a n yi n g rec o nstit uti o n dil u e nt  
f or D S-5 1 4 1 b f or i nj ecti o n (f or 1 0 0  m g/ m L) ” will b e a d d e d t o “D S -5 1 4 1 b f or 
i nj ecti o n 1 0 0 m g ” t o r ec o nstit ut e it, a nd 1 0 0  m g / m L sol uti o n  f or a d mi nistrati o n 
will b e pr e p ar e d.  
 
5. 4  
P a rt 1 a n d P a rt 2 
5. 4. 1  
St a rt Ti m e of A d mi nist r ati o n i n P a rt 1 
A d mi nistr ati o n of t h e st u d y dr u g t o t h e s ec o n d s u bj ect at eac h d os e l e v el i n Part 1 w ill 
b e st art e d aft er t h e s ec o n d d os e of t h e s tu d y dr u g h as b ee n a d mi nist ere d t o t h e first 
s u bj ect.   If a d mi nistr ati o n at D os e L e v el 3 ( or 4) is st art e d i n a s u bj ect w h o h as 
fi nis h ed D os e L e v el 1 ( or 2) i n P a rt 1 , t h ere will b e a n i nt er v al ≥1 2 w ee ks b et w ee n t h e 
st o p d at e of a d mi nistr ati o n of t h e st u d y dr u g  at D os e L e v el 1 ( or 2) a n d t h e st art d at e 
of a d mi nistr ati o n of t h e st u d y dr u g at D os e L e v el 3 ( or 4). 
 
5. 4. 2  
Tr a nsiti o n B et w ee n D os e L e v els i n P a rt 1 
Tr a nsiti o ns b et w ee n d os e l e v els i n P art 1 will b e ma d e acc or di n g t o t h e f oll o wi n g 
pr o ce d ur e.  
1)  T h e i n v esti g a tor  will pr o m ptl y re p ort d at a rel ati n g t o t h e s afet y a n d t ol era bilit y i n 
eac h s u bj ect t o t h e s p o ns or. 
2)  W h et h er t o tr a nsiti o n t o t h e n e xt d os e l e v el will b e c o nsi d ere d b a s e d o n t h e d at a 
f or 3 s u bj ects at t h e ti m e p oi nt 7 d a ys aft er t h e s ec o n d d os e of t h e st ud y dr u g t o 
t h e t hir d s u bj ect at t h e d os e l e v el b ei n g ass ess e d.   T h e s p o ns or will pr o vi d e t h e 
d at a t o a s af et y ass ess m e nt c o m mitt ee m e m b er an d re q u est t h at t h e c o m mitt ee  
me m b er c o nsi d ers w h et h er it is p ossi bl e t o tra nsiti o n t o t h e n e xt d os e l e v el .   
Bas e d o n  t h e o p i ni o n of t h e s af et y ass ess m e nt c o m mitt ee m e m b er, t h e s p o ns or w ill 
c o nsi d er w h et h er it is p ossi bl e t o tra nsiti o n t o t h e n e xt d os e l e v el, a n d m a k e a 
d ecisi o n .   D ur i n g c o nsi d er ati o n, th e d et ails of a d v ers e e v e nts o bs er v e d at t his 
d os e l e v el, th eir ass o ci atio n wit h t h e st u d y dr u g, d os e d e p e n d e n ce , th eir d e gree  
(se v erit y), rec o v er a bilit y, an d r es ults s u c h as p h ar mac o ki n eti c res ults a n d t h e 
r es ults of n o n cli ni cal t o xici t y st u di es will b e t a k e n i nt o acc o u nt.   R efere n ce will 
b e m a d e t o “ 5. 4. 4  Crit eri a f or C o nsi d eri n g W h et h er t o Tra nsiti o n B et w ee n  D os e 
L e v els i n P art 1 , ” a n d t h e i n v esti g at or or m e di cal e x p ert will b e c o ns ult e d as 


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n ecess ar y.  
3)  W h e n tr a nsiti o ni n g t o t h e n e xt d os e l e v el, t o e ns ure t h e s afet y of s u bj ects if acti o n 
s u c h as c h a n gi n g t h e c o nte nts or fre q u e n ci es of t ests or o bs er v ati o ns is n ecess ar y, 
t h e s p o ns or will c h a n g e d o c u m e nts s uc h as t h e cli ni cal st u d y pr ot o c ol  a n d 
i nf or m e d c o ns e nt f or m. 
4)  T h e s p o ns or w ill i nf or m t h e i n v esti g at or of t h e res ults of c o nsi d erati o n a b o ut 
tr a nsiti o ni n g t o t h e n e xt d os e l e v el. 
 
5. 4. 3  
Tr a nsiti o ni n g f r o m P a rt 1 t o P a rt 2 
Tr a nsiti o ni n g fr o m P art 1 t o P art 2 will b e p erf or me d acc or di n g t o t h e f oll o wi n g 
pr o ce d ur e.  
1)  T h e i n v esti g at or w ill pr o m ptl y re p ort d at a  rel ati n g t o s afet y a n d t ol era bilit y i n 
eac h s u bj ect t o t h e s p o ns or. 
2)  W h et h er t o tr a nsiti o n t o t h e n e xt d os e l e v el a n d t h e d os es t o us e i n P art 2 will b e 
c o nsi d er e d  b as e d o n t h e d at a f or all d os e l e v els at t h e ti m e p oi nt 7 d a ys aft er t h e 
s ec o n d d os e of t h e stu d y dr u g t o t h e t hir d s u bj ect at t h e hi g h est d os e l e v el ass ess e d 
i n P art 1.  T h e s p o ns or will pr o vi d e t h e d at a t o a s afet y ass ess m e nt c o m mitt ee 
me m b er a n d r e q u es t t h at t h e c o m mitt ee m e m b er c o nsi d ers w h et h er it is p ossi bl e t o 
tr a nsiti o n t o P art 2 a n d t h e d o s es t o us e i n P art 2.  B as e d o n t h e o pi ni o n of t h e 
s af et y ass ess m e nt c o m mitt ee m e m b er, t h e s p o ns or will c o nsi d er w h et h er it is 
p ossi bl e t o tr a nsiti o n t o Part 2 a n d t h e d os es t o us e i n P art 2, a n d m a k e a d ecisi o n.   
D uri n g c o nsi d er ati o n, t h e d et ails o f a d ver s e e v e nts o bs er v e d i n P art 1, t h eir 
ass o ci ati o n wit h t h e st u d y dr u g, d os e d e p e n d e n ce, t h eir d e gree (s e v erit y), 
r ec o v er a bilit y, a n d r es ults s u c h as p h ar m ac o ki n eti c res ults a n d t h e res ults of 
n o n cli ni cal t o xi cit y st u di es will b e t a k e n i nt o acc o u nt.   R eferen c e will b e m a d e t o 
“ 5. 4. 4  Crit eri a f or C o nsi d eri n g W h et h er t o Tra nsiti o n B et w ee n  D os e L e v els i n P art 
1 ,” a n d t h e i n v esti g at or or m e di cal e x p ert will b e c o ns ult e d as n e cess a r y. 
3)  W h e n tr a nsiti o ni n g t o P art 2 , t o e ns ure t h e s afet y of s u bj ects if acti o n s u c h as 
c h a n gi n g t h e c o nt e nts or fr e q u e n ci es of t ests or o bs er v ati o ns is n ecess ar y, t h e 
s p o ns or will c h a n g e d o c u m e nts s u c h as t h e cli ni cal st u d y pr ot o c ol  a n d i nf or m e d 
c o ns e nt  f or m. 
4)  T h e s p o ns or will i nf or m t h e i n v esti g at or of t h e res ults of c o nsi d erati o n a b o ut 
tr a nsiti o ni n g t o P art 2.   If t h e st u d y will tra nsiti o n t o P art 2 , t h e s p o ns or will 
d eci d e t h e d os e l e v els a d mi nist ere d t o eac h s u bj ect i n P art 2 a n d i nf or m t h e 
i n v esti g ator. 


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5. 4. 4  
C r it eri a f o r C o nsi d eri n g W h et h er t o Tr a nsiti o n B et w ee n  D os e L e v els i n 
P a rt 1 
If t h e f oll o wi n g fi n di n gs ar e o bs er v e d at a d os e l e v el b ei n g ass ess e d i n Part 1 , w h et h er 
t o tr a nsiti o n b et w ee n d os e l e v els i n P art 1 will b e c o nsi d ere d . 
1)  A d v ers e r eacti o ns c or res p o n d i n g t o Gra d e 3 i n “ S eri o us n ess Gra di n g Crit eri a f or 
A d v ers e R eacti o ns t o P h ar m ace uti cals ”  (N otifi cati o n N o. 8 0 of t h e S afet y 
Di visi o n, P A B d at e d 2 9 J u n 1 9 9 2 , A p p e n di x 2 ) (i n ≥1 s u bj ect) 
F or a d v ers e r eacti o ns of t h e li v er a n d k i d n e ys, t h es e crit eri a will n o t b e us e d. 
2)  S e v ere a d v ers e r eacti o n s (i n ≥2 s u bj ects) 
 
If fi n di n gs m eeti n g a n y of t h e f oll o wi n g crit eri a are o bs er v e d at a d os e l e v el b ei n g 
ass ess e d i n P art 1 , w h et h er t o t r a nsiti o n b et w ee n d os e l e v els i n P art 1 will b e 
c o nsi d er e d, t a ki n g a c o m pr e h e ns i v e vi e w of i nf or mati o n i n cl u di n g t h e b as eli n e v al u e, 
o t h er t est fi n di n gs a n d cli ni cal fi n di n gs. 
< L i v er> 
1)  A L T  ≥1 0 ti m es t h e sit e’s u p p er li mit of refere n ce ra n g e a n d al s o tot al b ilir u bi n ≥2 
ti m es t h e sit e’s u p p er li mit of r efere n ce ra n g e 
2)  A L T  ≥1 0 ti m es t h e s it e’s u p p er li mit of refere n ce ra n g e a n d als o P T -I N R > 1. 5 
3)  A L T >t wi ce t h e b as eli n e v al u e a n d als o t ot al bilir u bi n > t wi ce t h e sit e’s u p p er li mit 
of r ef er e n ce r a n g e  
4)  A L T  >t wi ce t h e b as eli n e v al u e a n d als o P T -I N R > 1. 5 
5)  A L T ≥1 0 ti m es t h e sit e’s u p p er li mit of ref ere n ce ra n g e a n d als o s y m pt o ms of 
h e p atitis  or h y p ers e nsiti vit y  
 
< Ki d n e ys > 
1)  U ri ne pr ot ei n/ cr eati ni n e r ati o > 0. 5 g/ g Cr  o n 2 c o ns ec uti v e o ccasi o ns  
2)  S er u m c yst ati n C c o n ce n tr ati o n ≥th e sit e’s u p p er l i mit of refere n ce ra n g e a n d als o 
≥1. 5 ti m es t h e b as eli n e v al u e  
3)  Uri n e  pr ot ei n i n 2 4- h o ur p o ol e d uri n e > 3 0 0  m g / da y a n d als o > t wi ce t h e b as eli n e 
v al u e  
4)  Uri n e al b u mi n i n 2 4 -h o ur p o ol e d uri n e > 5 0  m g / d a y a n d als o >t wi ce t h e b as eli n e 
v al u e  
5)  N e wl y o cc urri n g casts ot h er t h a n h y ali n e casts i n uri n e s e di m e nt at ≥1 cast / L P F, or 
n e wl y o c c urri n g h y ali n e casts at ≥2 1  casts / L P F 


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6)  N e wl y o cc urri n g uri n e r e d bl o o d cells at ≥5 cells/ H P F 
 
5. 5  
R a n d o mi z ati o n a n d B li n di n g 
R a n d o mi zati o n a n d bli n di n g will n ot b e p erf or m e d i n t his st u d y. 
 
5. 6  
C o n c o mit a nt Me di c ati o ns a n d C o n c o mit a nt T h er a p y , a n d Ot h er 
R estr i ctio ns 
If c o n c o mit a nt m e di cati o ns ar e us e d d uri n g t h e p eri o d fr o m re gistrati o n i n t h e st u d y t o 
t h e e n d of t h e f oll o w-u p p eri o d  i n P art 2, a n d d uri n g t h e p eri o d fr o m t h e d a y of 
i nf or m e d c o ns e nt f or P art 2-E xt e nsi o n t o t h e e n d of t h e f oll o w-u p p eri o d  i n P art 
2- E x t e nsi o n-2 ( d uri n g t h e p eri o d fr o m re gistrati o n i n t h e st u d y t o t h e e n d of t h e 
f oll o w-u p p eri o d  i n P art 2- E xt e nsi o n-2 f or s u bj ects p arti ci p ati n g i n t h e st u d y fr o m  P art 
2- E x t e nsi o n or P art 2-E xte nsi o n - 2; a n d t o t h e st art of st u d y dr u g a d mi nistrati o n f or 
s ubj ects p arti ci p ati n g i n t h e l o n g -t er m e xt e nsi o n st u d y), t h e dr u g n a m e, a d mi nistrati o n 
met h o d , d os e, st art d at e, st o p d at e, a n d i n di cati o n i nt e n d e d f or w ill b e rec or d e d o n t he 
cas e r e p ort f or m.   If c o n c o mit a nt t h era p y is p erf or m e d, th e treat m e nt/ pr o ce d ure n a m e, 
st art d at e, st o p d at e, fr e q u e n c y a n d i n di cati o n i nt e n d e d f or will b e rec or d e d o n t h e cas e 
r e p ort f or m. 
 
5. 6. 1  
P r o hi bit e d C o n c o mit a nt D r u gs 
C o n c o mit a nt us e of t h e f oll o wi n g dr u gs is pr o hi bit e d d uri n g t h e p eri o d fr o m 
r e gistr ati o n i n t h e st u d y t o t h e e n d of t he f oll o w-u p p eri o d i n P art 2,  a n d d uri n g t h e 
p eri o d fr o m t h e d a y of i nf or m e d c o ns e nt f or P art 2 - E xt e nsi o n t o t h e e n d of t h e 
f oll o w-u p p eri o d i n P art 2 - E xt e nsi o n- 2 (d uri n g t h e p eri o d fr o m re gistrati o n i n t h e 
st u d y t o t h e e n d of t h e f oll o w- u p p eri o d i n Part 2- E xt e nsi o n -2 f or s u bj ects p arti ci p ati n g 
i n t h e st u d y fr o m P art 2 -E xt e nsi o n or P art 2 - E xt e nsi o n- 2; a n d t o t h e st art of st u d y dr u g 
a d mi nistr ati o n  f or s u bj ects p artici p ati n g i n t h e l o n g -t er m e xt e nsi o n st u d y ). 
1)  Ot h er a nti -D M D dr u gs t h a n t h e st u d y dr u g us e d  i n t his st u d y a n d st er oi ds 
2)  Ot h er i n v esti g ati o n al pr o d u cts  
3)  C hl or o q ui n e a n d h y dr o x y c hl or o q ui n e  
 
< R ati o n al e > 
1)  T his w as s el ect e d b eca us e it m a y affect ass ess m e nt of effi ca c y a n d s af et y.  
2)  T his w as s el ect e d b eca us e t h e s afet y of ot h er i n v esti g ati o n al pr o d u cts i n 
d e v e l op m e nt h as n ot b ee n est a blis h e d, a n d t h eref ore , c o n c o mit a nt us e wit h t h e 


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st u d y dr u g is a s af et y pr o bl e m. 
3)  T his w as s el ect e d b eca us e it m a y affect ass ess m e nt of s af et y a n d effi cac y.  It w as 
s el ect e d b eca us e, wit h t h e s pr ea d of t h e n o v el c or o n a vir us, c o nc o mi t ant us e of 
t h es e dr u gs h as b ec o m e m or e li k el y. 
 
5. 6. 2  
P r o hi bit e d C o n c o mit a nt T h er a p y  
T h e us e of t h e f oll o wi n g t h er a p y is pr o hi bit e d fr o m re gistrati o n i n t his st u d y t o t h e e n d 
of t h e f oll o w-u p p eri o d  i n P art 2-E xt e nsi o n -2 ( or t o t h e st art of st u d y dr u g 
a d mi n istrati o n i n t h e l o n g-t er m e xt e nsi o n st u d y f or s u bj ects p arti ci p ati n g i n t h e 
l o n g-t er m e xt e nsi o n  st u d y). 
1)  H A L ®  (H y bri d Assisti v e Li m b ® ) 
 
< R ati o n al e > 
1)  T his w as s el ect e d b eca us e it m a y affect ass ess m e nt of effi cac y a n d s afet y.  
 
5. 6. 3  
O t h er R est ri cti o ns 
D uri n g t h e p e ri o d fr o m r e gistr ati o n i n t h e st u d y t o t h e e n d of t h e f oll o w-u p p eri o d  i n 
Part 2, a n d d uri n g t h e p eri o d fr o m t h e d a y of i nf or m e d c o ns e nt f or P art 2 -E xt e nsi o n t o 
t h e e nd of t h e f oll o w-u p p eri o d  i n P art 2- E xt e nsi o n-2 ( d uri n g t h e p eri o d fr o m 
r e gistr ati o n i n th e s t ud y t o t h e e n d of t h e f oll o w-u p p eri o d  i n P art 2- E xt e nsi o n-2 f or 
s u bj ects p arti ci p ati n g i n t h e st u d y fr o m P art 2-E xte nsi o n or P art 2 -E xt e nsi o n -2, a n d 
fr o m t h e st art of st u dy dr u g a d mi nistrati o n f or s u bj ects p arti ci p ati n g i n t h e l o n g-t er m 
e xt e nsi o n st ud y), e x ce pt i n t h e f oll o wi n g cas es, n e wl y st arti n g st er oi ds or c h a n gi n g t h e 
fr e q u e n c y or d os e of st er oi ds is pr o hi bit e d. 
• 
T e m p or ar y dis c o nti n u ati o n or dis c o nti n u ati o n d u e t o t h e o cc urre n ce of a d v ers e 
r eacti o ns t o st er oi ds 
• 
C h a n g es i n d os e d u e t o v ari ati o ns i n b o d y  w ei g ht 
• 
L o cali ze d a d mi nistr ati o n (s u c h as t h e us e of e y e dr o ps or i n h al ati o n) f or p ur p os es 
ot h er t h a n tr eat m e nt of D M D  
 
< R ati o n al e > 
T his w as s el ect e d b eca us e it m a y aff ect  ass ess m e nt of effi cac y.  
 
5. 7  
S u bj ect M a n a g e m e nt 
T h e d ur ati o n of h os pit ali zati o n wi ll be as f oll o ws.  


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1)  F r o m t h e d a y b ef or e  a d mi nistr ati o n of t h e first d os e of t h e st u d y dr u g  at eac h d os e 
le v el i n P art 1 (D a y 0 ) t o 3 d a ys aft er st u d y dr u g a d mi nistrati o n (D a y  4) 
2)  F r o m t h e d at e of a d mi nistr ati o n of t h e s ec o n d d os e of t h e st u d y dr u g at eac h d os e 
lev e l i n P art 1 ( D a y 8) t o 3 d a ys aft er st u d y dr u g a d mi nistrati o n ( D a y 1 1 ) 
3)  F r o m t h e d a y b ef or e a d mi nistr ati o n of t h e first d os e of t h e st u d y dr u g i n Part 2 
(D a y 0 ) to t h e d a y aft er a d mi nistrati o n  (D a y  2) 
4)  Fr o m t h e d a y b ef or e a d mi nistr ati o n of t h e l ast d os e of  th e st u d y dr u g i n Part 2 
( D a y 7 7) t o t h e d a y aft er a d mi nistrati o n of t h e l ast d os e of t h e st u d y dr u g ( D a y 7 9) 
5)  Fr o m t h e d a y b ef or e a d mi nistr ati o n of t h e first d os e  of t h e st u d y dr u g i n Part 
2- E xt e nsi o n ( Wee k  0/ D a y  0) t o t h e d a y aft er a d mi nistrati o n ( Wee k  1/  D a y  2)  
6)  Fr o m t h e d a y b ef or e a d mi nistr ati o n of t h e st u d y dr u g i n Wee k  1 3 of P art 
2- E xt e nsi o n ( Wee k  1 2/ D a y  8 4), t h e d a y b ef ore a d mi nistrati o n of t h e st u d y dr u g i n  
Wee k  2 5 ( Wee k  2 4/ D a y  1 6 8) a n d t h e d a y b ef ore a d mi nistrati o n of t h e st u d y dr u g 
i n Wee k 37 ( Wee k 3 6/ D a y  2 5 2) t o t h e d a y of a d mi nistrati o n  
7)  Fr o m t h e d a y b ef or e a d mi nistr ati o n of t h e l ast d os e of t h e st u d y dr u g i n Wee k 4 8 
of P art 2 -E xt e nsi o n ( Wee k  4 7/ D a y  3 2 9) t o t h e d a y aft er a d mi nistrati o n of t h e l ast 
d os e of t h e st u d y dr u g ( Wee k  4 8/ D a y  3 3 1)  
8)  Fr o m t h e d a y b ef or e a d mi nistr ati o n of t h e first d os e of t h e st u d y dr u g i n Part 
2- E xt e nsi o n- 2 ( Wee k  0/  D a y  0) t o t h e d a y aft er a d mi nistrati o n ( Wee k  1/ D a y  2)  
9)  Fr o m t h e d a y b ef or e a d mi nistr ati o n of t h e st u d y dr u g i n Wee k  1 3 of P art 
2- E xt e nsi o n- 2 ( Wee k  1 2/ D a y  8 4) , t h e d a y b ef ore a d mi nistrati o n of t h e st u d y dr u g 
i n Wee k 2 5 ( Wee k  2 4/ D a y  1 6 8) a n d t h e d a y b ef ore a d mi nistrati o n of t h e st u d y 
dr u g i n Wee k  3 7 ( Wee k  3 6/ D a y  2 5 2) t o t h e d a y of a d mi nistrati o n  
1 0)  Fr o m t h e d a y b ef or e a d mi nistr ati o n of t h e l ast d os e of t h e st u d y dr u g i n Wee k 4 8 
of P art 2 -E xt e nsi o n -2 ( Wee k  4 7/ D a y  3 2 9) t o t h e d a y aft er a d mi nistrati o n of t h e 
last d os e of t h e st u d y dr u g ( Wee k 4 8/ D a y  3 3 1)  
 
F or 5 ) t o 7) a n d 9) t o 1 0), hos pit ali zati o n is n ot c o m p uls or y if t ests a n d ass ess m e nt ca n 
b e p erf or m e d a p pr o pri a t el y, b ut i n t h e cas e of s u bj ects p arti ci p at i n g i n t h e st u d y fr o m 
Part 2- E xt e nsi o n , h os pit ali zati o n f or 5)  is c o m p uls or y. 
 
If a n a d v ers e e v e nt t h at o cc urs d uri n g hos pit ali za ti o n c o nti n u es u ntil t h e pla n n e d 
dis c h ar g e d at e, t h e i n v esti g at or or s u bi n v estig at o r w ill d et er mi n e w h et h er it is 
n ecess ar y t o c o nti n u e h os pit ali zati o n, t a ki n g i nt o acc o u nt t h e n ee d t o e ns ure t h e 
s u bj ect’s s af et y. 


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5. 8  
A d diti o n of S u bj ect s 
I n t h e f oll o wi n g cases , s u bj ects m a y b e n e wl y a d d e d i n P art 1 , P art 2 , P art 2- E xt e nsi o n 
or P art 2- E xt e n sio n - 2.   T h e s p o ns or will c o ns ult t h e m e di cal e x p ert if n ecess ar y 
b ef or e d eci di n g w h et h er it is n ecess ar y t o a d d a s u bj ect. 
1)  T h er e is a s u bj ect w h o is f o u n d n ot t o m eet t h e e li gi bilit y re q uire m e nts aft er 
r e gistr ati o n 
2)  T h er e is a s u bj ect w h o w as n ot a d mi n ist ered t h e s t u d y dr u g or i n w h o m 
a d mi nistr ati o n of t h e st u d y dr u g w as n ot c o m pl et e d  
3)  It is c o nsi d er e d n ecess ar y t o a d d a s u bj ect f or a n y ot h er reas o n i n or d er t o ass ess 
t h e s af et y a n d effi cac y of st u d y dr u g 
 


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6.  
S T U D Y P R O C E D U R E S  
6. 1  
Listi n g of E x a mi n ati o ns , O bs er vati o ns  a n d T ests  
T h e ti mi n g of e x a mi n ati o ns , o bs er v ati o ns a n d t ests  i n t his st u d y is s h o w n i n A p p e n di x 
3 .   T h e i n v esti g at or or s u bi n v esti g at or w ill rec or d t h e res ults of e x a mi n a ti o ns, 
o bs er v ati o ns  a n d t ests a n d i nf or m ati o n s u c h as t h e ti m e of s a m pl e c oll ec ti o n on t h e 
cas e r e p ort f or m.   I n t his st u d y, t h e p eri o d fr o m t h e d at e of i nf or m e d c o ns e nt t o t h e 
e n d of t h e f oll o w -u p p eri o d i n P art 2, a n d d uri n g t h e p eri o d fr o m t h e  d a y of i n f or m e d 
c o ns e nt f or P art 2 -E xt e nsi o n t o t h e e n d of t h e f oll o w -u p p eri o d i n P art 2- E x t ensi o n- 2 
( d uri n g t h e p eri o d fr o m t h e d at e of i nf or m e d c o ns e nt f or P art 2- E xt e nsi o n-2 t o t h e e n d 
of t h e f oll o w -u p p eri o d i n P art 2 -E xt e nsi o n -2 f or s u bj ects p arti ci p ati n g i n t h e st u d y 
fr o m P art 2- E xt e nsi o n- 2) will b e t h e “st u d y d urati o n ” f or eac h su bj ec t.   S u bj ects w h o 
c o m pl et e 4 8 w ee ks of st u d y dr u g a d mi nistrati o n i n P art 2- E xt e nsi o n- 2 of t his st u d y 
a n d c o m pl et e effi cac y ass ess m e nt aft er a d mi nistrati o n m a y p arti ci p a t e i n t h e l o n g-t er m 
e xt e nsi o n st u d y.   F or s u bj ects w h o p arti ci p at e i n t h e l o n g -t er m e xt e n si o n st u d y, Wee k 
5 2/ D a y  3 5 8 will n ot b e carri e d o ut , a n d t h e p eri o d u ntil t h e st art of st u d y dr u g 
a d mi nistr ati o n  i n t h e l o n g-t er m e xt e nsi o n st u d y will b e t h e “st u d y d urati o n ” f or t his 
st u d y.   H o w e v er , if it is diffi c ult f or a s u bj ect t o c o nti n u e t h e st u d y, f or e x a m pl e 
b eca us e t h e s u bj ect is u n a bl e t o m a k e visits, t h e st u d y d urati o n will e n d as of t h e 
r el e v a nt d at e, a n d will n ot c o nti n u e u ntil t h e e n d of t h e f oll o w-u p p eri o d. 
 
6. 2  
Ite mi z ati o n of Vit al Si g ns , Cli ni c al Fi n di n gs a n d L a b o r at o r y Tests  
1)  V it al si g ns 
B o d y t e m p er at ur e  (a xill ar y t e m p erat ure ), b l o o d press ure (syst oli c bl o o d press ure , 
di ast oli c  bl o o d pr ess ur e ) a n d p uls e rat e will b e m eas ure d , a n d t h e res ult a n d 
d at e/ti m e of m eas ur e m e nts will b e rec or d e d o n t h e cas e re p ort f or m.   Bl o o d 
pr ess ur e  a n d p uls e r at e  wil l b e m eas ure d i n t h e sitti n g p ositi o n.  
2)  C li ni cal fi n di n gs 
A p h ysi cal e x a mi n ati o n i n cl u di n g m e di cal i nt er vi e w, v is u al e x a mi n ati o n, 
a us c ult ati o n  a n d p al p ati o n will b e  p erf or m e d , a n d t h e res ult a n d d at e/ti m e of t h e 
e x a mi n ati o n  will b e r ec or d e d o n t h e cas e re p ort f or m.   In p arti c ul ar , n e ur ol o gi cal 
fi n di n gs will b e o bs er v e d car ef ull y, wit h refere n ce t o t h e “ P e di atri c N e ur ol o gi cal 
Test C h art .8” 
3)  B l o o d t ests a n d uri n al ysis 
T h e f oll o wi n g it e ms will b e m eas ure d , a n d t h e t est res ult, bl o o d ( or uri n e) 
c oll ecti o n d at e  a n d f e d/f ast e d st at e (bl o o d c h e mistr y t ests a n d uri n al ysis o nl y)  will 


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b e r ec or d e d o n t h e cas e r e p ort f or m .   T h e refere n ce ra n g es at t h e m eas uri n g sit e 
will b e us e d as r ef er e n ce r a n g es f or l a b orat or y d ata .   O n D a y 1 ( pre- d os e), D a y  4 
a n d D a y  1 1  of eac h d os e le v el i n P art 1 , D a y  1 ( pre- d os e) a n d D a y  7 8  ( pre- d os e) 
of P art 2 , Wee k  1/  D a y  1 ( pr e- d os e), Wee k  1 3 / D a y  8 5  ( pre- d os e), 
Wee k  2 5 / Da y  1 6 9  ( pr e- d os e), Wee k  3 7 / D a y  2 5 3 ( pre- d os e), a n d 
Wee k  4 8 / D a y  3 3 0  ( pr e- d os e) of P a rt 2- E xt e nsi o n, a n d Wee k  1/ D a y  1 ( pre- d os e), 
Wee k  1 3/ D a y  8 5  ( pr e- d os e), Wee k  2 5 / D a y  1 6 9 ( pre- d os e), Wee k  3 7/ D a y  2 5 3 
( pr e- d os e), a n d Wee k  4 8 / D a y  3 3 0  ( pre- d ose)  of P art  2- E xt e nsi o n- 2, 2 4- h o ur uri n e 
p o oli n g will b e p erf or m e d, st arti n g o n t h e pre vi o us d a y.   O n ot h er s p ecifie d d at e s, 
sp ot uri n e will b e us e d .   S p ot uri n e b ef ore st u d y dr u g a d mi nistrati o n, o n t h e d a y 
aft er st u d y dr u g a d mi nistr ati o n, a n d d uri n g t h e f oll o w-u p p eri o d will b e c oll ect e d 
i n t h e m or ni n g, as f ar as p ossi bl e.   S p ot uri n e o n Wee k  1/ Da y  1 (fr o m 4 h o urs 
p ost- d os e), Wee k  1 3/ D a y  8 5  (fr o m 4 h o urs p ost- d os e), Wee k  2 5 / D a y  1 6 9 (fr o m 4 
h o urs p ost - d os e), Wee k  3 7/ D a y  2 5 3 (fr o m 4 h o urs p ost- d os e), a n d 
Wee k  4 8 / Da y  3 3 0  (fr o m 4 h o urs p ost- d os e) of P art 2 -E xt e nsi o n a n d  
Wee k  1/ D a y  1 (fr o m 4 ho urs p ost- d os e) , Wee k  1 3/ D a y  8 5  (fr o m 4 h o urs 
p ost- d os e), Wee k  2 5 / D a y  1 6 9 (fr o m 4 h o urs p ost- d os e), Wee k  3 7 / D a y  2 5 3  (fr o m 
4 h o urs p ost - d os e), a n d Wee k  4 8 / D a y  3 3 0  (fr o m 4 h o urs p ost- d os e) of P art 
2- E xt e nsi o n- 2 will b e s a m pl e d o n t h e d at e of st u d y dr u g ad mi n istrati o n, ≥4 h o urs 
aft er st u d y dr u g a d mi nistr ati o n, as far as p ossi bl e. 
 
T est c o nte nts  
T est ite ms  
He mat ol o g y test  
R e d bl o o d cell c o u nt , he m o gl o bi n , he mat ocrit , w hite bl o o d c ell c o u nt , w hite 
bl o o d c ell differe ntial c o u nt  (n e utr o p hil, l y m p h oc yte , m o n oc yte , e osi n o p hil, 
bas o p hil ), p latelet c o u nt, retic ul o c yte c o u nt , M C V , M C H , M C H C , A P T T , P T -I N R 
B l o o d c h e mistr y 
test 
Total pr otei n , al b u mi n, A/ G rati o , t otal bilir u bi n, dire ct bilir u bi n , A S T , A L T , A L P , 
ga m ma -G T , L D H , C K , B U N , cr eati ni ne , uric aci d , N a , K, Cl , Ca , P, M g , t otal 
c h olester ol, tri gl y ceri d e, gl u c ose, C R P , ir o n, t otal ir o n bi n di n g c a p acit y, ferriti n, 
cystati n C , c ar dia c tr o p o ni n T  
Uri nal ysis 
Q ualitati v e  (g l uc os e, p r otei n, o cc ult bl o o d , ket o n e b o d ies, bilir u bi n, ur o bili n o ge n, 
s p ecific gra vit y, p H), uri nar y se di me nt (re d bl o o d cell, w hite bl o o d c ell, casts , 
e pit h elial cell s, cr ystals, bacteria), uri ne pr otei n ,* 1 uri n e cr eati ni ne,* 1 uri n e 
al b u mi n ,* 1 N A G ,* 1 al p ha-1 micr o gl o b uli n ,* 1 beta-2 micr o gl o b uli n ,* 1 vol u me of 
uri n e * 1 
* 1: To be m eas ur e d usi n g 2 4 -h o ur p o ole d uri n e o n D a y  1 ( pr e-d os e) , D a y  4 a n d  Da y  1 1  of Part 1 , 
Da y  1 ( pre-d ose ) a n d Da y  7 8  ( pre-d os e)  of P art 2 , We e k  1/  D a y  1 ( pr e-d ose), We e k  1 3/ Da y  8 5 
( pre-d ose), Wee k  2 5/ D a y  1 6 9 ( pr e-d ose) , We e k  3 7/ Da y  2 5 3 ( pr e- d os e) a n d Wee k  4 8/ Da y  3 3 0 
( pre-d ose)  of P art 2 -E x te nsi o n, a n d Wee k  1/  Da y  1 ( pre- d os e), Wee k  1 3/  D a y  8 5 ( pre-d os e) , 
Wee k  2 5 / Da y  1 6 9 ( pre-d ose), Wee k  3 7/ D a y  2 5 3 ( pr e-d ose ) a n d We e k  4 8/ Da y  3 3 0 ( pr e-d ose)  of 
Part 2 -E xte nsi o n - 2. 
 


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4)  1 2- l ea d el ectr o car di o gr a m 
A st a n d ar d 1 2- l ea d el ectr o car di o gra m will b e rec ord e d aft er t h e s u bj ect h as b ee n 
r est e d f or ≥5 mi n ut es i n t h e d ec u bit us p ositi o n.   T h e i n v esti g at or or 
s u bi n v esti g at or will j u d g e t h e o v erall t est res ult as “ n or m al, ” “ a b n or m al, n o t 
cli ni call y si g nifi ca nt ” or “cli ni call y si g nifi ca nt fi n di n g” a n d rec or d t his o n t h e cas e 
r e p ort f orm.   If t h e j u d g me nt is “cli ni call y si g nifica nt fi n di n g , ” this will b e 
h a n dl e d as a n a d v ers e e v e nt, a n d d et ails will b e rec or d e d o n th e cas e re p ort f or m.   
H o w e v er, a b n or m aliti es alr ea d y o bs er v e d b ef ore st u d y dr u g a d mi nistrati o n t h at 
h a v e n ot w ors e n e d aft er st u d y dr u g a d mi nistrati o n will n ot b e h a n dl e d as a d v ers e 
e v e nts . 
 
< 1 2- l ea d el ectr o car di o gr a m o bs er v ati o n p oi nts > 
• 
Part 1 
D a y 1  (pr e -d os e, 2 h o urs a n d 6 h o urs p ost - d os e), D a y 2 , D a y 4 , D a y 8  
( pr e-d os e, 2 h o urs a n d 6 h o urs p ost - d os e), D a y 9 , D a y 1 1 , D a y 1 5 , D a y 2 2, 
D a y 3 6 , D a y 6 4 
• 
Part 2 
D a y 1  (pr e -d os e, 2 h o urs a n d 6 h o urs p ost - d os e), D a y 2 , D a y 2 2  ( pre- d os e), 
D a y 5 0  ( pr e- d os e), D a y 7 8  (pre -d os e, 2 h o urs, 4 h o urs, 6 h o urs, a n d 8 h o urs 
p ost- d os e), D a y 7 9 , D a y 8 5 , D a y 9 2, D a y 1 0 6 , D a y 1 3 4 , D a y 1 6 2  
• 
Part 2- E xt e nsi o n 
Wee k  1/ D a y  1 (pr e -d os e a n d 4 h o urs p ost - d os e), Wee k  1/ D a y  2, 
Wee k  5/ D a y  2 9 ( pr e- d os e), Wee k  9/  D a y  5 7  ( pre- d os e), Wee k  1 3/ D a y  8 5 
( pr e- d os e), Wee k  1 7/ D a y  1 1 3  ( pre- d os e), Wee k  2 1/ D a y  1 4 1  ( pre-d os e), 
Wee k  2 5/ D a y  1 6 9  ( pr e- d os e), Wee k  2 9/ D a y  1 9 7 ( pre- d os e), 
Wee k  3 3/ D a y  2 2 5  ( pr e- d os e), Wee k  3 7/ D a y  2 5 3 ( pre- d os e), 
Wee k  4 1/ D a y  2 8 1  ( pr e- d os e), Wee k  4 5/ D a y  3 0 9 ( pre- d os e), 
Wee k  4 8/ D a y  3 3 0  (pr e -d os e, 2 h o urs, 4 h o urs, 6 h o urs, a n d 8 h o urs p ost - d os e), 
Wee k  4 8/ D a y  3 3 1, Wee k  4 9/ D a y  3 3 7, Wee k  5 2/ D a y  3 5 8  
• 
Part 2- E xt e nsi o n - 2 
Wee k  1/ D a y  1 (pr e -d os e a n d 4 h o urs p ost - d os e), Wee k  1/ D a y  2, 
Wee k  5/ D a y  2 9 ( pr e- d os e), Wee k  9/  D a y  5 7  ( pre- d os e), Wee k  1 3/ D a y  8 5 
( pr e- d os e), Wee k  1 7/ D a y  1 1 3  ( pre- d os e), Wee k  2 1/ D a y  1 4 1  ( pre-d os e), 
Wee k  2 5/ D a y  1 6 9  ( pr e- d os e), Wee k  2 9/ D a y  1 9 7 ( pre- d os e), 
Wee k  3 3/ D a y  2 2 5  ( pr e- d os e), Wee k  3 7/ D a y  2 5 3 ( pre- d os e), 


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Wee k  4 1/ D a y  2 8 1  ( pr e- d os e), Wee k  4 5/ D a y  3 0 9 ( pre- d os e), 
Wee k  4 8/ D a y  3 3 0  (pr e -d os e, 2 h o urs, 4 h o urs, 6 h o urs, a n d 8 h o urs p ost - d os e), 
Wee k  4 8/ D a y  3 3 1, Wee k  4 9/ D a y  3 3 7, W ee k 5 2/ D a y  3 5 8  
 
F or eac h s u bj ect, at t h e first d os e of t h e st u d y dr u g (D a y 1 ),* 2 pre -d os e a n d 2 
h o urs, 4 h o urs, 6 h o urs, 8 h o urs, a n d 2 4 h o urs p ost - d os e (D a y 2 ), at t h e s ec o n d 
d os e at D os e L e v el 3  a n d  D os e L e v el 4  of P art 1  (D a y 8 ), pre-d os e a n d 2 
h o urs, 4 h o urs, 6 h o urs, 8 h o urs, a n d 2 4 h o urs p ost - d os e (D a y 9 ), at t h e 1 2t h 
d os e of t h e st u d y dr u g i n P art 2 ( D a y 7 8 ), pre-d os e a n d 2 h o urs, 4 h o urs, 6 
h o urs, 8 h o urs, a n d 2 4 h o urs p ost - d os e (D a y 7 9 ), i n P art 2- E xt e nsi o n , o n 
Wee k  1/ D a y  1 (pr e -d os e a n d 4 h o urs p ost - d os e), 2 4 h o urs p ost - d os e 
(Wee k  1/ D a y 2) a n d Wee k  4 8/ D a y  3 3 0  (pre -d os e, 2 h o urs, 4 h o urs, 6 h o urs, 
a n d 8 h o urs p ost - d os e), 2 4 h o urs p ost - d os e (Wee k  4 8/ D a y  3 3 1 ), an d i n P art 
2- E xt e nsi o n- 2 , o n Wee k  1/ D a y  1 (pre -d os e a n d 4 h o urs p ost -d os e), 2 4 h o urs 
p ost- d os e ( Wee k  1/  D a y  2) a n d Wee k  4 8/ D a y  3 3 0 (pre -d os e, 2 h o urs, 4 h o urs, 
6 h o urs, a n d 8 h o urs p ost - d os e), 2 4 h o urs p ost - d os e (Wee k  4 8/ D a y  3 3 1 ), 
meas ur e m e nt will b e p erf or m e d 3 ti m es at eac h pla n n e d ti m e p oi nt , a n d t h e 
el ectr o car di o gr a m will b e s e nt el e ctr o ni call y t o a n el ectr o car di o gra m a n al ysis 
la b or at or y t o m eas ur e t h e P R  i nt er v al, Q R S  i nt er v al, Q T  i nt er v al, R R  i nt er v al, 
a n d Q Tc . 
 
* 2 : I n cl u di n g t h e first d os e of t h e st u d y dr u g i n s u bj ects p arti ci p ati n g i n t h e 
st u d y fr o m D os e L e v el 3  or  D os e L e v el 4  of  P art 1 , P art 2, P art 2- E xt e nsi o n or  
Part 2- E xt e nsi o n - 2 
 
5)  
 
 
  T h e i n v esti g at or or 
s u bi n v esti g at or will j u d g e t h e o v erall t est result  as “ n or m al, ” “a b n or m al, n ot 
cli ni call y si g nifi ca nt ” or “cli ni call y si g nifi ca nt fi n di n g ” a n d rec or d t his o n t h e cas e 
r e p ort f or m.    If t h e j u d g me nt is “cli ni call y si g nifica nt fi n di n g, ” t his will b e 
h a n dl e d as a n a d v ers e e v e nt, a n d d et ails will b e rec or d e d o n t h e cas e re p ort f or m.   
H o w e v er, a b n or m aliti es alr ea d y o bs er v e d b ef ore st u d y dr u g a d mi nistrati o n t h at 
h a v e n ot w ors e n e d aft er st u d y dr u g a d mi nistrati o n will n ot b e h a n dl e d as a d v ers e 
e v e nts.  
C CI


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6. 3  
It e ms a n d Ti mi n g of Tests B ef o re R e gistr ati o n of S u bject s 
1)  Ite ms c h ec k e d aft er i nf or me d c o ns e nt  a n d b ef ore re gistrati o n  
T h e f oll o wi n g i n v esti g ati o ns, e x a mi n ati o ns, a n d t ests will b e p erf or m e d, a n d t h e 
r es ults will b e r ec or d e d o n t h e cas e r e p ort f or m . 
• 
D a y of i nf or m e d c o ns e nt ( or c o nfir m ati o n of i nt e nt ) b y t h e s u bj ect f or 
p arti ci p ati o n i n t his st u d y  
• 
D a y of i nf or m e d c o ns e nt b y t h e l e g all y acce pt a bl e re pres e nt ati v e f or 
p arti ci p ati o n i n t his st u d y  
• 
S u bj ect i d e ntifi cati o n c o d e  
• 
Bas eli n e s u bj ect c h ar act eristi cs  
R ace , c o u ntr y of r esi d e n ce at i nf or m e d c o ns e nt , se x, d at e of birt h 
• 
M e di cal hist or y a n d c o m pli cati o ns 
W h et h er t h es e ar e pr es e nt or a bs e nt , w h et h er t h e y are o n g oi n g  (if o n g oi n g: 
c o m pli cati o ns ), an d t h e fi n di n gs a n d di a g n os es will b e c h ec k e d .   T h e m e dical 
hist or y will list t h e s y m pt o ms a n d dis eas es fr o m w hi c h t h e s u bj ect has rec o v ere d 
b ef or e st u d y dr u g a d mi nistr ati o n is st art e d t h at t h e i n v esti g at or or 
s u bi n v esti g at or d et er mi n es ar e n ecess ar y t o re p ort . 
• 
H ist or y of p arti ci p ati o n i n ot h er st u di es 
• 
M e di cal i nt er v e nti o ns b y ot h er p h ysi ci a ns  
• 
M et h o d of g e n eti c di a g n osis  
• 
Ty p e of d ystr o p hi n g e n e m ut ati o n  (f or e x a m pl e, t h e re gi o n of t h e missi n g e x o n) 
• 
D N A  s e q u e n ce of t h e sit e of D S -5 1 4 1 b  d o u bl e -stra n d f or m ati o n i n t h e 
d ystr o p hi n g e n e  
• 
H ist or y of m us cl e bi o ps y 
• 
Hist or y of st er oi d us e  
2)  It e ms p erf or m e d aft er i nf or m e d c o ns e nt  a n d wit hi n a p eri o d of 2 8 d a ys b ef ore 
r e gistr ati o n 
T h e f oll o wi n g i n v esti g ati o ns, e x a mi n ati o ns, a n d t ests will b e p erf or m e d .   D at a 
o bt ai n e d b ef or e i nf or m e d c o ns e nt m a y als o b e us e d .   F or M RI  or C T , m ot or f u n cti o n 
ass ess m e nt  ( 6-mi n ut e w al k t est ), a n d car di ac f u n cti o n ass ess m e nt ( l eft v e ntri c ul ar 
ej ecti o n fracti o n ), i nf or mati o n s u c h as t h e d a y of m eas ure m e nts will b e rec or d e d o n t h e 
cas e r e p ort f or m . 
• 
M RI  or C T  
< L o cati o n of i m a gi n g > 


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U p p er ar m : M RI or C T  (t o c o nfir m t h e l o cati o n of m us cl e bi o ps y) 
T hi g h : M RI* 3 
• 
M ot or f u n cti o n ass ess m e nt ( 6 -mi n ut e w al k t est ) 
• 
Car di ac f u n cti o n ass ess me nt (l eft v e ntri c ul ar ej ecti o n fracti o n)  
• 
1 2- l ea d el ectr o car di o gr a m 
• 
H Bs a nti g e n,  h e p atitis C vir us a nti b o d y,  HI V  a nti b o d y t est 
 
* 3: M RI  of t h e t hi g h will b e p erf or m e d aft er i nf or m e d c o ns e nt  an d b ef ore t h e  st art of 
st u d y dr u g a d mi nistr ati o n. 
 
6. 4  
It e ms a n d Ti mi n g of Tests After R e gistr ati o n  
T h e f oll o wi n g i n v esti g ati o ns, e x a mi n ati o ns, a n d t ests will b e p erf or m e d, a n d t h e 
r es ults will b e r ec or d e d o n t h e cas e r e p ort f or m . 
 
6. 4. 1  
It e ms to B e P erf o r m e d  Aft er R e gistr ati o n u p t o t h e D a y B ef o re t h e Fi rst 
D os e of S t u d y D r u g  (D a y 0 ) 
T h es e will b e p erf or m e d aft er r e gistrati o n u p t o t h e d a y b ef ore t h e first d os e of t h e 
st u d y dr u g i n eac h s u bj ect (D a y 0 ).   T h es e it e ms will als o b e p erf or m e d i n s u bj ects 
p arti ci p ati n g i n t h e st u d y f r o m D os e L e v el 3 or D os e L e v el 4 of P art 1, P art 2, P art 
2- E xt e nsi o n or P art 2- E xte nsi o n - 2 
< It e ms p erf or m e d u p t o 2 8 d a ys b ef ore t h e first d os e of t h e st u d y dr u g> 
• 
M us cl e bi o ps y, ski n bi o ps y * 4 
< It e ms p erf or m e d fr o m 1 4 d a ys b ef ore t h e first d os e of t h e st u d y dr u g u p t o t h e d a y 
b ef or e  t h e first d os e of t h e st u d y dr u g (D a y 0 ) > 
1)  C h ec ki n g c o n c o mit a nt m e di cati o ns a n d c o n c o mit a nt  t h era p y 
2)  H ei g ht a n d b o d y w ei g ht  
3)  V it al si g ns a n d cli ni cal fi n di n gs 
4)  B l o o d t ests a n d uri n al ysis 
5)  1 2- l ea d el ectr o car di o gr a m 
6)  
* 5 
7)  M ot or f u n cti o n ass ess m e nt * 6 
8)  R es pir at or y f u n cti o n ass ess m e nt * 7 
9)  C ar di ac f u n cti o n ass ess me nt * 7 
1 0)  Q u a ntit ati v e m us cl e str e n gt h ass ess m e nt * 6 
1 1)  B l o o d c oll ecti o n 
C CI


P r ot oc ol: D S 5 1 4 1- A-J 1 0 1 
Versi o n  0 3. 0 4. 0 0 0  
Pa ge   4 9 of 1 1 8  
• 
A nti -d ystr o p hi n a nti b o d y 
• 
A nti -D S - 5 1 4 1 b a nti b o d y 
• 
B l o o d cell d ystr o p hi n m R N A * 4 
1 2)  U ri n e c oll ecti o n 
• 
U ri n e pr ot ei n 
• 
U ri n e D S -5 1 4 1 b  m et a b olit es * 8 
 
* 4: N ot n ecess ar y i n s u bjects p arti ci p ati n g i n t h e st u d y fr o m P art 2- E xt e nsi o n or  P art 
2- E xt e nsi o n- 2. 
* 5 : To b e p erf or m e d i n s u bj ects p arti ci p ati n g i n t h e st u d y fr o m P art 2- E xt e nsi o n - 2.   
will b e p erf or me d aft er r e gistrati o n  a n d b ef ore t h e first d os e of t h e st u d y 
dr u g . 
* 6: To b e p erf or m e d t wi ce, at l east 2 8 d a ys aft er m us cl e bi o ps y. 
* 7: To b e p erf or m e d at l east 2 8 d a ys aft er m us cl e bi o ps y. 
* 8 : N ot n ecess ar y i n s u bjects p arti ci p ati n g i n t h e st u d y fr o m P art 2 , P art 2- E xt e nsi o n 
or  P art 2- E xt e nsi o n - 2. 
 
6. 4. 2  
P a rt 1 
6. 4. 2. 1  
It e ms to B e P e rf o r m e d  Bef o re t h e Fi rst D os e of t h e St u d y D r u g at t h e 
Sec o n d D os a g e  
If s u bj ects w h o h a v e fi nis h e d D os e L e v el 1  or 2 t o c o nti n u e t o p arti ci p at e i n D os e 
L e v el 3 or 4 of P art 1, t h e f oll o wi n g will b e p erf or m e d fr o m 1 4 d a ys b ef ore t h e first 
d os e of t h e st u d y dr u g  u p t o t h e d a y b ef ore  t h e first d os e of t h e st u d y dr u g (D a y 0 ). 
1)  C h ec ki n g c o n c o mit a nt m e di cati o ns a n d c o n c o mit a nt  t h era p y 
2)  H ei g ht a n d b o d y w ei g ht  
3)  Vit al si g ns a n d cli ni cal fi n di n gs  
4)  Bl o o d t ests a n d uri n al ysis  
5)  1 2- l ea d el ectr o car di o gr a m 
6)  Bl o o d c oll ecti o n  
• 
Bl o o d cell d ystr o p hi n m R N A  
7)  Uri n e c oll ecti o n  
• 
Uri n e pr ot ei n  
 
C CI


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6. 4. 2. 2  
It e ms to B e P erf o r m e d  D u ri n g t h e Tre at m e nt P eri o d  (D a y  1 t o D a y 1 4 ) 
a n d F oll o w- U p P eri o d  (D a y  1 5  t o D a y 6 4 ) f o r E a c h D os e L e v el 
T h e visit wi n d o w  f or it e ms perf or m e d o n D a y 1 5 a n d  D a y 2 2  is ± 2 d a ys, a n d t h e visit 
wi n d o w  f or it e ms p erf or me d o n D a y 3 6 a n d  D a y  6 4 is ± 7 d a ys. 
1)  C h ec ki n g t h e a d mi nistr ati o n st at us of t h e st u d y dr u g  
W h et h er t h e s t u d y dr u g w as a d mi nist ere d , d at e/ti me of st u d y dr u g a d mi nistrati o n, 
d os e l e v el , act u al d os e ( m g ) 
2)  I n v esti g ati n g c o n c o mit a nt m e di cati o ns a n d c o n c o mit a nt  t h era p y 
3)  I n v esti g ati n g a d v ers e e v e nts 
4)  B o d y w ei g ht  
< O bs er v ati o n p oi nt >  
D a y  1 5 
5)  Vit al si g ns a n d cli ni cal fi n di n gs  
< O bs er v ati o n p oi nt >  
D a y  1 (pr e -d os e  a n d 1 h o ur, 2 h o urs, a n d 6 h o urs p ost- d os e ), D a y  2, D a y  4, D a y  8 
( pr e- d os e a n d  1 h o ur, 2 h o urs, a n d 6 h o urs p ost - d os e), D a y  9, D a y  1 1 , D a y  1 5, D a y  
2 2 , D a y  3 6 , D a y  6 4  
6)  Bl o o d t ests a n d uri n al ysis  
< O bs er v ati o n p oi nt >  
D a y  1 ( pr e-d os e) ,* 8 D a y  2, D a y  4,* 8 D a y  8 ( pre- d os e), D a y  9, D a y  1 1 ,* 8 D a y  1 5, 
D a y  3 6, D a y  6 4  
7)  1 2- l ea d el ectr o car di o gr a m 
< O bs er v ati o n p oi nt >  
S ee 6. 2  
8)  Bl o o d c oll ecti o n  
• 
P h ar m ac o ki n eti cs  
< Bl o o d c oll ecti o n p oi nt >  
S ee 6. 7  
• 
A nti -d ystr o p hi n a nti b o d y  
< Bl o o d  c oll ecti o n p oi nt >  
D a y 1 5  
• 
A nti -D S -5 1 4 1 b a nti b o d y  
< Bl o o d c oll ecti o n p oi nt >  
D a y 1 5  
• 
Bl o o d cell d ystr o p hi n m R N A  


P r ot oc ol: D S 5 1 4 1- A-J 1 0 1 
Versi o n  0 3. 0 4. 0 0 0  
Pa ge   5 1 of 1 1 8  
< Bl o o d c oll ecti o n p oi nt >  
D a y 1 5  
9)  Uri n e c oll ecti o n  
• 
Uri n e pr ot ei n  
< Uri n e c oll ecti o n p oi nt >  
D a y 1 5  
• 
Uri n e D S -5 1 4 1 b m et a b olit es  
< Uri n e c oll ecti o n p oi nt >  
D a y 9  
* 8 : 2 4 -h o ur uri n e p o oli n g will b e p erf or m e d, st arti n g o n t h e pre vi o us d a y . 
 
6. 4. 3  
P a rt 2 
6. 4. 3. 1  
It e ms to B e P erf o r m e d  Bef o re t h e Fi rst D os e of St u d y D r u g i n P a rt 2 
If s u bj ects w h o h a v e fi nis h e d P art 1 c o nti n u e t o p arti ci p at e, t h e f oll o wi n g will b e 
p erf or m e d fr o m 1 4 d a ys b ef or e t h e first d os e of t h e st u d y dr u g u p t o t h e d a y b ef ore  t h e 
first d os e of t h e st u d y dr u g (D a y 0 ).  F or s u bj ects p arti ci p ati n g fr o m P art 2, “ 6. 4. 1  
It e ms t o B e P erfor m e d Aft er R e gistr ati o n u p t o t h e D a y B ef ore t h e First D os e of St u d y 
D r u g (D a y 0 )” will b e p erf or m e d, a n d t h es e t ests will n ot b e n ecess ar y.  
1)  C h ec ki n g c o n c o mit a nt m e di cati o ns a n d c o n c o mit a nt  t h era p y 
2)  H ei g ht a n d b o d y w ei g ht  
3)  Vit al si g ns a n d cli ni cal fi n di n gs  
4)  Bl o o d t ests a n d uri n al ysis  
5)  1 2- l ea d el ectr o car di o gr a m 
6)  M RI  (o nl y f or s u bj ects i n w h o m M RI ca n b e p erf or m e d a p pr o pri at el y ) 
< L o cati o n of i m a gi n g >  
M RI: T hi g h  
7)  M ot or f u n cti o n ass ess m e nt
* 9 
8)  Res pir at or y f u n cti o n ass ess m e nt  
9)  Car di ac f u n cti o n ass ess me nt  
1 0)  Q u a ntit ati v e m us cl e str e n gt h ass ess m e nt * 9 
1 1)  Bl o o d c oll ecti o n  
• 
A nti -d ystr o p hi n a nti b o d y  
• 
A nti -D S -5 1 4 1 b a nti b o d y  
• 
Bl o o d cell d ystr o p hi n m R N A  
1 2)  Uri n e c oll ecti o n  


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• 
Uri n e pr ot ei n  
 
* 9 : To b e p erf or m e d t wi ce. 
 
6. 4. 3. 2  
It e ms to B e P erf o r m e d  D u ri n g t h e Tre at m e nt P eri o d  (D a y  1 t o D a y 8 4 ) 
a n d F oll o w- U p P eri o d (D a y  8 5  t o D a y 1 6 2) 
T h e visit wi n d o w  f or it e ms p erf or m e d o n D a y  8 t o D a y 9 2  is ± 2 d a ys , a n d t h e visit 
wi n d o w  f or it e ms p erf or me d o n D a y  1 0 6, D a y  1 3 4, a n d D a y  1 6 2 is ± 7 d a ys . 
1)  A d mi nistr ati o n st at us of t h e st u d y dr u g  
W h et h er t h e st u d y dr u g w as a d mi nist ere d, d at e/ti me of st u d y dr u g a d mi nistrati o n, 
d os e l e v el, act u al d os e ( m g)  
2)  I n v esti g ati n g c o n c o mit a nt m e di cati o ns a n d c o n c o mit a nt  t h era p y 
3)  I n v esti g ati n g a d v ers e e v e nts 
4)  B o d y w ei g ht  
< O bs er v ati o n p oi nt >  
D a y  2 9, D a y  5 7 , D a y  8 5  
5)  Vit al si g ns a n d cli ni cal fi n d i n gs 
< O bs er v ati o n p oi nt >  
D a y  1 (pr e - d os e a n d 1 h o ur, 2 h o urs, a n d 6 h o urs p ost - d os e), D a y  2, D a y  8, D a y  1 5 , 
D a y  2 2, D a y  2 9 , D a y  3 6, D a y  4 3 , D a y  5 0, D a y  5 7, D a y  6 4, D a y  7 1, D a y  7 8  
( pr e- d os e a n d 1 h o ur, 2 h o urs, a n d 6 h o urs p ost - d os e), D a y 7 9 , D a y 8 5 , D a y  9 2, 
D a y  1 0 6, D a y  1 3 4, D a y  1 6 2 (t o b e p erf or m e d pre -d os e o n D a y  8 t o D a y  7 8 ) 
6)  Bl o o d t ests a n d uri n al ysis  
< O bs er v ati o n p oi nt >  
D a y  1,* 1 0  D a y  2, D a y  2 2, D a y  5 0 , D a y  7 8 ,* 1 0  D a y  8 5, D a y  1 0 6, D a y  1 3 4, D a y  1 6 2 
(t o b e p erf or m e d pr e -d os e o n D a y  1 t o D a y 7 8 ) 
7)  1 2- l ea d el ectr o car di o gr a m  
< O bs er v ati o n p oi nt >  
See 6. 2  
8)  M RI or  C T  
< L o cati o n of i m a gi n g >  
U p p er ar m: M RI or C T (t o c o nfir m t h e l o cati o n of m us cl e bi o ps y)  
T hi g h: M RI  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce i n t h e p eri o d fr o m D a y 8 5 t o D a y 9 9.  


P r ot oc ol: D S 5 1 4 1- A-J 1 0 1 
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Pa ge   5 3 of 1 1 8  
9)  M us cl e bi o ps y  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce i n t h e p eri o d fr o m D a y 8 5 t o D a y 9 9.   To b e p erf or me d  
aft er M RI or C T, m ot or f u n cti o n ass ess m e nt, res pirat or y f u n cti o n ass ess m e nt, 
car di ac f u n cti o n ass ess m e nt, a n d q u a ntit ati v e m us cl e stre n gt h ass ess m e nt . 
1 0)  M ot or f u n cti o n ass ess m e nt  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  t wi ce i n t h e p eri o d fr o m D a y 8 5 t o D a y 9 9. 
1 1)  Res pir at or y f u n cti o n ass ess m e nt  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce i n t h e p eri o d fr o m D a y 8 5 t o D a y 9 9.  
1 2)  Car di ac f u n cti o n ass ess me nt  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce i n t h e p eri o d fr o m D a y 8 5 t o D a y 9 9.  
1 3)  Q u a ntit ati v e m us cl e str e n gt h ass ess m e nt  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  t wi ce i n t h e p eri o d fr o m D a y 8 5 t o D a y 9 9. 
1 4)  Bl o o d c oll ecti o n  
• 
P h ar m ac o ki n eti cs  
< Bl o o d c oll ecti o n p oi nt >  
See 6. 7  
• 
A nti -d ystr o p hi n a nti b o d y  
< Bl o o d c oll ecti o n p oi nt >  
D a y  8 5 
• 
A nti -D S -5 1 4 1 b a nti b o d y  
< Bl o o d c oll ecti o n p oi nt >  
D a y 8 5  
• 
Bl o o d cell d ystr o p hi n m R N A  
< Bl o o d c oll ecti o n p oi nt >  
D a y 8 5  
1 5)  Uri n e c oll ecti o n  
• 
Uri n e pr ot ei n  
< Uri n e c oll ecti o n p oi nt >  
D a y 8 5  
* 1 0 : 2 4- h o ur uri n e p o oli n g will b e p erf or m e d, st arti n g o n t h e pre vi o us d a y.  


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6. 4. 4  
P a rt 2- E xt e nsi o n 
6. 4. 4. 1  
It e ms to B e P erf o r m e d  Bef o re t h e Fi rst D os e of St u d y D r u g i n P a rt 
2- E xt e nsi o n 
If s u bj ects w h o h a v e fi nis h e d P art 2 c o nti n u e t o p arti ci p at e, t h e f oll o wi n g will b e 
p erf or m e d fr o m 1 4 d a ys b ef or e t h e first d os e of t h e st u d y dr u g u p t o t h e d a y b ef ore  t h e 
first d os e of t h e st u d y dr u g (D a y 0 ).    F or s u bj ects p arti ci p ati n g fr o m P art 2- E xt e nsi o n, 
“ 6. 4. 1  It e ms t o B e P erf or me d Aft er R e gistrati o n u p t o t h e D a y B ef ore t h e First D os e of 
S t u d y D r u g (D a y 0 )” will b e p erf or m e d, a n d t h es e t ests will n ot b e n ecess ar y.  
1)  D a y of i nf or m e d c o ns e nt ( or c o nfir m ati o n  of i nt e nt) b y t h e s u bj ect f or 
p arti ci p ati o n i n P art 2 - E xt e nsi o n 
2)  D a y of i nf or m e d c o ns e nt b y t h e l e g all y acce pt a bl e re pres e nt ati v e f or p arti ci p ati o n 
i n P art 2- E xt e nsi o n 
3)  C h ec ki n g c o n c o mit a nt m e di cati o ns a n d c o n c o mit a nt  t h era p y 
4)  H ei g ht a n d b o d y w ei g ht  
5)  Vit al si g ns a n d cli ni cal fi n di n gs  
6)  Bl o o d t ests a n d uri n al ysis  
7)  1 2- l ea d el ectr o car di o gr a m 
8)  M RI  (o nl y f or s u bj ects i n w h o m M RI ca n b e p erf or m e d a p pr o pri at el y ) 
< L o cati o n of i m a gi n g >  
M RI: T hi g h  
9)  M ot or f u n cti o n ass ess m e nt
* 1 1 
1 0)  Res pir at or y f u n cti o n ass ess m e nt  
1 1)  Car di ac f u n cti o n  ass ess me nt  
1 2)  Q u a ntit ati v e m us cl e str e n gt h ass ess m e nt * 1 1 
1 3)  Bl o o d c oll ecti o n  
• 
A nti -d ystr o p hi n a nti b o d y  
1 4)  Uri n e c oll ecti o n  
• 
Uri n e pr ot ei n  
 
* 1 1 : To b e p erf or m e d t wice.  
 


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6. 4. 4. 2  
It e ms to B e P erf o r m e d  D u ri n g t h e Tre at m e nt P eri o d  (Wee k 1/  D a y 1  t o 
Wee k  4 8/ D a y  3 3 6) a n d F oll o w - Up P eri o d (Wee k 4 9/ D a y  3 3 7 t o Wee k 
5 2/ D a y  3 5 8) 
T h e visit wi n d o w  f or it e ms p erf or m e d o n Wee k 2/ D a y 8 t o Wee k 5 0/ D a y 3 4 4 is ± 2 
d a ys, a n d t h e visit wi n d o w  f or it e ms p erf or m e d o n Wee k 5 2/ D a y 3 5 8 is ± 7 d a ys. 
1)  A d mi nistr ati o n st at us of t h e st u d y dr u g  
W h et h er t h e st u d y dr u g w as a d mi nist ere d, d at e/ti me of st u d y dr u g a d mi nistrati o n, 
d os e l e v el, act u al d os e ( m g)  
2)  I n v esti g ati n g c o n c o mit a nt m e di cati o ns a n d c o n c o mit a nt  t h era p y 
3)  I n v esti g ati n g a d v ers e e v e nts 
4)  H ei g ht a n d b o d y w ei g ht  
< O bs er v ati o n p oi nt >  
Wee k 1 3/ D a y 8 5 , Wee k  2 5/ D a y 1 6 9 , Wee k 3 7/ D a y 2 5 3 , Wee k 4 8/ D a y 3 3 0  
5)  Vit al si g ns a n d cli ni cal fi n di n gs  
< O bs er v ati o n p oi nt >  
Wee k  1/ D a y  1 (pr e -d os e a n d 4 h o urs p ost - d os e), Wee k  1/ D a y  2, Wee k  2/ D a y  8, 
Wee k  3/ D a y  1 5, Wee k  4/  D a y  2 2, Wee k  5/ D a y  2 9, Wee k  6/ D a y  3 6, 
Wee k  7/ D a y  4 3, Wee k  8/  D a y  5 0, Wee k  9/ D a y  5 7, Wee k  1 0/ D a y  6 4 , 
Wee k  1 1/  D a y  7 1, Wee k  1 2/ D a y  7 8, Wee k  1 3/ D a y  8 5  (pre -d os e a n d 4 h o urs 
p ost- d os e), Wee k  1 4 / D a y  9 2, Wee k  1 5 / D a y  9 9 , Wee k  1 6 / D a y  1 0 6, 
Wee k  1 7 / D a y  1 1 3 , Wee k  1 8/ D a y  1 2 0, Wee k  1 9 / D a y  1 2 7, Wee k  2 0 / D a y  1 3 4, 
Wee k  2 1 / D a y  1 4 1, Wee k  2 2 / D a y  1 4 8, Wee k  2 3/ D a y  1 5 5, Wee k  2 4/ D a y  1 6 2, 
Wee k  2 5 / D a y  1 6 9  (pr e -d os e a n d 4 h o urs p ost -d os e), Wee k  2 6/ Da y  1 7 6, 
Wee k  2 7 / Da y  1 8 3, Wee k  2 8 / D a y  1 9 0, Wee k  2 9/ D a y  1 9 7, Wee k  3 0 / D a y  2 0 4, 
Wee k  3 1/ D a y  2 1 1 , Wee k  3 2/ D a y  2 1 8, W ee k 3 3/ D a y  2 2 5, Wee k  3 4/ D a y  2 3 2, 
Wee k  3 5/ D a y  2 3 9, Wee k  3 6/ D a y  2 4 6, Wee k  3 7 / D a y  2 5 3  (pre -d os e a n d 4 h o urs 
p ost- d os e), Wee k  3 8 / D a y  2 6 0, Wee k  3 9/ D a y  2 6 7, Wee k  4 0/ D a y  2 7 4, 
Wee k  4 1/ D a y  2 8 1, Wee k  4 2/ D a y  2 8 8, Wee k  4 3/ D a y  2 9 5 , Wee k  4 4/ D a y  3 0 2, 
Wee k  4 5/ D a y  3 0 9, Wee k  4 6/ D a y  3 1 6, Wee k  4 7/ D a y  3 2 3, Wee k  4 8/ D a y  3 3 0  
( pr e-d os e a n d 4 h o urs p ost - d os e), Wee k  4 8/ D a y  3 3 1, Wee k  4 9/ D a y  3 3 7, 
Wee k  5 2/ D a y  3 5 8  (t o b e p erf or m e d pre -d os e fr o m Wee k  2/  D a y  8 t o 
Wee k  1 2/ D a y  7 8 , fr o m Wee k  1 4 / D a y  9 2  t o Wee k 2 4/ D a y  1 6 2 , fr o m 
Wee k  2 6/ D a y  1 7 6  t o Wee k 3 6/ D a y  2 4 6, a n d fr o m Wee k  3 8 / D a y  2 6 0 t o 
Wee k  4 7/ D a y  3 2 3 ) 


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6)  Bl o o d t ests  
< O bs er v ati o n p oi nt >  
Wee k  1/ D a y  1, Wee k  1/ D a y  2, Wee k  5/  D a y  2 9, Wee k  9/ D a y  5 7, 
Wee k  1 3/ D a y  8 5 , Wee k  1 7/ D a y  1 1 3 , Wee k  2 1/ D a y  1 4 1, Wee k  2 5/ D a y  1 6 9, 
Wee k  2 9/ D a y  1 9 7, Wee k  3 3/ D a y  2 2 5, Wee k  3 7/ D a y  2 5 3, Wee k  4 1/ D a y  2 8 1, 
Wee k  4 5/ D a y  3 0 9, Wee k  4 8/ D a y  3 3 0, Wee k  4 9/ D a y  3 3 7, Wee k  5 2/ D a y  3 5 8  (t o 
b e p erf or m e d  pr e -d os e o n Wee k  1/  D a y  1 a n d  fr o m Wee k  5/  D a y  2 9  t o 
Wee k  4 8/ D a y  3 3 0 ) 
7)  Uri n al ysis  
< O bs er v ati o n p oi nt > 
Wee k  1/ D a y  1 ( pr e-d os e ,* 1 2 fr o m 4 h o urs p ost-d os e) , Wee k  1/ D a y  2, 
Wee k  5/ D a y  2 9, Wee k  9/  D a y  5 7, Wee k  1 3/ D a y  8 5 ( pre- d os e,* 1 2 fr o m 4 h o urs 
p ost- d os e), Wee k  1 7/ D a y  1 1 3 , Wee k  2 1/ D a y  1 4 1, Wee k  2 5/ D a y  1 6 9  ( pre- d os e,* 1 2  
fr o m 4 h o urs p ost- d os e), Wee k 2 9/ D a y  1 9 7, Wee k  3 3/ D a y  2 2 5, 
Wee k  3 7/ D a y  2 5 3  ( pr e- d os e,* 1 2  fr o m 4 h o urs p ost- d os e), Wee k  4 1/ D a y  2 8 1, 
Wee k  4 5/ D a y  3 0 9, Wee k  4 8/ D a y  3 3 0  ( pre- d os e,* 1 2  fr o m 4 h o urs p ost- d os e), 
Wee k  4 9/ D a y  3 3 7, Wee k  5 2/ D a y  3 5 8  (t o b e p erf or m e d pre -d os e o n 
Wee k  5/ D a y  2 9, Wee k  9/  D a y  5 7, Wee k  1 7/ D a y  1 1 3 , Wee k  2 1/ D a y  1 4 1, 
Wee k  2 9/ D a y  1 9 7, Wee k  3 3/ D a y  2 2 5, Wee k  4 1/ D a y  2 8 1, Wee k  4 5/ D a y  3 0 9 ) 
8)  1 2- l ea d el ectr o car di o gr a m 
< O bs er v ati o n p oi nt >  
See 6. 2  
9)  M RI  
< L o cati o n of i m a gi n g >  
U p p e r ar m: M RI or C T (t o c o nfir m t h e l o cati o n of m us cl e bi o ps y) 
T hi g h: M RI  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce i n t h e p eri o d fr o m Wee k  4 9/  D a y  3 3 7 t o Wee k 5 1 / D a y  3 5 1. 
1 0)  M us cl e bi o ps y  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d o n ce i n t h e p eri o d fr o m Wee k  4 9/  D a y  3 3 7 t o Wee k 5 1 / D a y  3 5 1.   
To b e p erf or m e d  aft er M RI or C T, m ot or f u n cti o n ass ess m e nt, res pirat or y f u n cti o n 
ass ess m e nt, car di ac f u n cti o n ass ess m e nt, a n d q u a ntit ati v e m us cl e stre n gt h 
ass ess m e nt . 


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1 1)  M ot or f u n cti o n ass ess m e nt  
<I n v esti g ati o n p oi nt >  
To b e p erf o r m e d o n ce eac h i n t h e p eri o d fr o m Wee k  1 2/ D a y  8 4  t o 
Wee k  1 3/ D a y  8 5  ( pr e- d os e), t h e p eri o d fr o m Wee k  2 4 / D a y  1 6 8  t o 
Wee k  2 5/ D a y  1 6 9  ( pr e- d os e), a n d t h e p eri o d fr o m Wee k  3 6/ D a y  2 5 2 t o 
Wee k  3 7/ D a y  2 5 3  ( pr e- d os e), a n d t wi ce i n t h e p eri o d fr o m Wee k  4 9/ D a y  3 3 7 t o 
Wee k  5 1 / D a y  35 1 . 
1 2)  Res pir at or y f u n cti o n ass ess m e nt  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d o n ce eac h i n t h e p eri o d fr o m Wee k  1 2/ D a y  8 4  t o 
Wee k  1 3/ D a y  8 5  ( pr e- d os e), t h e p eri o d fr o m Wee k  2 4 / D a y  1 6 8  t o 
Wee k  2 5/ D a y  1 6 9  ( pr e- d os e), t h e p eri o d fr o m Wee k 3 6/ D a y  2 5 2  t o 
Wee k  3 7/ D a y  2 5 3  ( pr e- d os e), a n d t h e p eri o d fr o m Wee k  4 9/ D a y  3 3 7 t o 
Wee k  5 1 / D a y  35 1 . 
1 3)  Car di ac f u n cti o n ass ess me nt  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d o n ce eac h i n t h e p eri o d fr o m Wee k  1 2/ D a y  8 4  t o 
Wee k  1 3/ D a y  8 5  ( pr e- d os e), t h e p eri o d fr o m Wee k  2 4 / D a y  1 6 8  t o 
Wee k  2 5/ D a y  1 6 9  ( pr e- d os e), t h e p eri o d fr o m Wee k  3 6/ D a y  2 5 2  t o 
Wee k  3 7/ D a y  2 5 3  ( pr e- d os e), a n d t h e p eri o d fr o m Wee k  4 9/ D a y  3 3 7 t o 
Wee k  5 1 / D a y  35 1 . 
1 4)  Q u a ntit ati v e m us cl e str e n gt h ass ess m e nt  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce eac h i n t h e p eri o d fr o m Wee k  1 2/ D a y  8 4  t o 
Wee k  1 3/ D a y  8 5  ( pr e- d os e), t h e p eri o d fr o m Wee k  2 4 / D a y  1 6 8  t o 
Wee k  2 5/ D a y  1 6 9  ( pr e- d os e), a n d t h e p eri o d fr o m Wee k  3 6/ D a y  2 5 2 t o 
Wee k  3 7/ D a y  2 5 3  ( pr e- d os e), a n d p erf or m e d t wi ce i n t h e p eri o d fr o m 
Wee k  4 9 / D a y  3 3 7  t o Wee k 5 1 / D a y  35 1 . 
1 5)  Bl o o d c oll ecti o n  
• 
P h ar m ac o ki n eti cs  
< Bl o o d c oll ecti o n p oi nt >  
See 6. 7  
• 
A nti -d ystr o p hi n a nti b o d y  
< Bl o o d c oll ecti o n p oi nt >  
Wee k  4 9/ D a y  3 3 7  


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• 
A nti -D S -5 1 4 1 b a nti b o d y  
< Bl o o d c oll ecti o n p oi nt >  
Wee k  4 9/ D a y  3 3 7  
1 6)  Uri n e c oll ecti o n  
• 
Uri n e pr ot ei n  
< Uri n e c oll ecti o n p oi nt >  
Wee k  1 3/ D a y  8 5 , Wee k  2 5/ D a y  1 6 9, Wee k  3 7/ D a y  2 5 3, Wee k  4 9/ D a y  3 3 7 
 
* 1 2 : 2 4- h o ur uri n e p o oli n g will b e p erf or m e d, st arti n g o n t h e pre vi o us d a y.  
 
6. 4. 5  
P a rt 2- E xt e nsi o n- 2 
6. 4. 5. 1  
It e ms to B e P erf o r m e d  Bef o re t h e Fi rst D os e of St u d y D r u g i n P a rt 
2- E xt e nsi o n- 2 
If s u bj ects w h o h a v e fi nis h e d P art 2-E xt e nsi o n c o nti n u e t o p arti ci p at e, t h e f oll o wi n g 
will b e p erf or m e d fr o m 1 4 d a ys b ef ore t h e first d os e of t h e st u d y dr u g u p t o t h e d a y 
b ef or e t h e first d os e of t h e st u d y dr u g ( D a y 0 ).    F or s u bj ects p arti ci p ati n g fr o m P art 
2- E xt e nsi o n- 2, “ 6. 4. 1  It e ms t o B e P erf or m e d Aft er R e gistrati o n u p t o t h e D a y B ef ore 
t h e First D os e of St u d y D r u g (D a y 0 )” will b e p erf or m e d, a n d t h es e t ests will n ot b e 
n ecess ar y.  
1)  D a y of i nf or m e d c o ns e nt ( or c o nfir m ati o n of i nt e nt ) b y t h e s u bj ect f or 
p arti ci p ati o n i n P art 2 - E xt e nsi o n- 2 
2)  D a y of i nf or m e d c o ns e nt b y t h e l e g all y acce pt a bl e re pres e nt ati v e f or p arti ci p ati o n 
i n P art 2- E xt e nsi o n- 2 
3)  C h ec ki n g c o n c o mit a nt m e di cati o ns a n d c o n c o mit a nt  t h era p y 
4)  H ei g ht a n d b o d y w ei g ht  
5)  Vit al si g ns a n d cli ni cal fi n di n gs  
6)  Bl o o d t ests a n d uri n al ysis  
7)  1 2- l ea d el ectr o car di o gr a m 
8)  
 
9)  M RI  (o nl y f or s u bj ects i n w h o m M RI ca n b e p erf or m e d  a p pr o pri at el y ) 
< L o cati o n of i m a gi n g >  
M RI: T hi g h  
1 0)  M ot or f u n cti o n ass ess m e nt
* 1 3 
1 1)  Res pir at or y f u n cti o n ass ess m e nt  
1 2)  Car di ac f u n cti o n ass ess me nt  
C CI


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1 3)  Q u a ntit ati v e m us cl e str e n gt h ass ess m e nt * 1 3 
1 4)  Bl o o d c oll ecti o n  
• 
A nti -d ystr o p hi n a nti b o d y  
1 5)  Uri n e c oll ecti o n  
• 
Uri n e pr ot ei n  
 
* 1 3 : To b e p erf or m e d t wice. 
 
6. 4. 5. 2  
It e ms to B e P erf o r m e d  D u ri n g t h e Tre at m e nt P eri o d  (Wee k 1/  D a y 1  t o 
Wee k  4 8/ D a y  3 3 6) a n d F oll o w -U p P eri o d ( Wee k 4 9/ D a y  3 3 7 t o Wee k 
5 2/ D a y  3 5 8) 
T h e visit wi n d o w  f or it e ms p erf or m e d o n Wee k 2/ D a y 8 t o Wee k 5 0/ D a y 3 4 4 is ± 2 
d a ys, a n d t h e visit wi n d o w  f or it e ms p erf or m e d o n Wee k 5 2/ D a y 3 5 8 is ± 7 d a ys. 
S u bj ects w h o c o m pl et e 4 8 w ee ks of st u d y dr u g a d mi nistrati o n i n P art 2-E xte nsi o n - 2 
a n d c o m pl et e effi cac y ass ess m e nt aft er a d mi nistrati o n m a y p arti ci p at e i n t h e l o n g -t er m 
e xt e nsi o n st u d y.  F or s u bj ects w h o p arti ci p at e i n t h e l o n g -t er m e xt e nsi o n st u d y, 
Wee k  5 2/ D a y  3 5 8  will n ot b e p erf or m e d . 
As a m eas ur e t o pr e v e nt t h e s pr ea d of t h e n o v el c or o n a vir us, s elf -a d mi nistrati o n  will 
b e all o w e d.    C o ns e nt f or s elf -a d mi nistrati o n will b e o bt ai n e d fr o m t h e l e g all y 
acce pt a bl e r e pr es e nt ati v e, a n d t h e g u ar di a n p erf or mi n g s elf -a d mi nistrati o n will b e 
gi v e n tr ai ni n g i n t h e m et h o d of st ori n g t h e st u d y dr u g a n d t h e m et h o d of a d mi nist eri n g 
t h e st u d y dr u g b ef or e s elf-a d mi nistr ati o n st arts.  
1)  A d mi nistr ati o n s t at us of t h e st u d y dr u g 
W h et h er t h e st u d y dr u g w as a d mi nist ere d, d at e/ti me of st u d y dr u g a d mi nistrati o n, 
d os e l e v el, act u al d os e ( m g) , a n d c h ec ki n g t h e “Self -I nj ecti o n Di ar y” if 
s elf-a d mi nistr ati o n w as p erf or m e d  
< Ti m e p oi nts at w hi c h s elf -a d mi nistrati o n is  p ossi bl e > 
Wee k  2 8/ D a y  1 9 0, Wee k  3 0/ D a y  2 0 4, Wee k  3 1 / D a y  2 1 1 , Wee k  3 2/ D a y  2 1 8, 
Wee k  3 4 / D a y  2 3 2, Wee k  3 5 / D a y  2 3 9, Wee k  3 6 / D a y  2 4 6, Wee k  3 8 / D a y  2 6 0, 
Wee k  3 9 / D a y  2 6 7, Wee k  4 0 / D a y  2 7 4, Wee k  4 2 / D a y  2 8 8, Wee k  4 3 / D a y  2 9 5, 
Wee k  4 4 / D a y  3 0 2, Wee k  4 6 / D a y 3 1 6, Wee k  4 7 / D a y  3 2 3  
2)  I n v esti g ati n g c o n c o mit a nt m e di cati o ns a n d c o n c o mit a nt  t h era p y 
3)  I n v esti g ati n g a d v ers e e v e nts 
4)  H ei g ht a n d b o d y w ei g ht  
< O bs er v ati o n p oi nt >  


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Wee k 1 3/ D a y 8 5 , Wee k 2 5/ D a y 1 6 9 , Wee k 3 7/ D a y 2 5 3 , Wee k 4 8/ D a y 3 3 0  
5)  Vit al si g ns a n d cli ni cal fi n di n gs  
If s elf-i nj ecti o n is p erf or me d, vit al si g ns will b e meas ure d t o t h e e xt e nt p ossi bl e .   
Cli ni cal fi n di n gs will b e c h ec k e d b y a m et h o d s u c h as m a ki n g a t el e p h o n e call.  
< O bs er v ati o n p oi nt >  
Wee k  1/ D a y  1 (pr e -d os e a n d 4 h o urs p ost - d os e), Wee k  1/ D a y  2, We e k 2/ D a y  8 
( pr e-d os e a n d 4 h o urs p ost - d os e), Wee k  3/ D a y  1 5  (pre -d os e a n d 4 h o urs 
p ost- d os e), Wee k  4/  D a y  2 2  (pr e -d os e a n d 4 h o urs p ost - d os e), Wee k  5/  D a y  2 9, 
Wee k  6/ D a y  3 6, Wee k  7/  D a y  4 3, Wee k  8/ D a y  5 0, Wee k  9/ D a y  5 7, 
Wee k  1 0/ D a y  6 4 , Wee k  1 1/  D a y  7 1 , Wee k  1 2/ D a y  7 8, Wee k  1 3/ D a y  8 5  (pre - d os e 
a n d 4 h o urs p ost - d os e), Wee k  1 4 / D a y  9 2 , Wee k  1 5/ D a y  9 9, Wee k  1 6 / D a y  1 0 6, 
Wee k  1 7 / D a y  1 1 3 , Wee k  1 8/ D a y  1 2 0, Wee k  1 9 / D a y  1 2 7, Wee k  2 0 / D a y  1 3 4, 
Wee k  2 1 / D a y  1 4 1, Wee k  2 2 / D a y  1 4 8, Wee k  2 3/ D a y  1 5 5, Wee k  2 4/ D a y  1 6 2, 
Wee k  2 5/ D a y  1 6 9  (pr e -d os e a n d 4 h o urs p ost -d os e), Wee k  2 6/ D a y  1 7 6, 
Wee k  2 7 / D a y  1 8 3, Wee k  2 8 / D a y  1 9 0, Wee k  2 9/ D a y  1 9 7, Wee k  3 0/ D a y  2 0 4, 
Wee k  3 1/ D a y  2 1 1 , Wee k  3 2/ D a y  2 1 8, Wee k  3 3/ D a y  2 2 5, Wee k  3 4/ D a y  2 3 2, 
Wee k  3 5/ D a y  2 3 9, Wee k  3 6/ D a y  2 4 6, Wee k  3 7 / D a y  2 5 3  (pre -d os e a n d 4 h o urs 
p ost- d os e), Wee k  3 8 / D a y  2 6 0, Wee k  3 9/ D a y  2 6 7, Wee k  4 0/ D a y  2 7 4, 
Wee k  4 1/ D a y  2 8 1, W ee k 4 2/ D a y  2 8 8, Wee k  4 3/ D a y  2 9 5, Wee k  4 4/ D a y  3 0 2, 
Wee k  4 5/ D a y  3 0 9, Wee k  4 6/ D a y  3 1 6, Wee k  4 7/ D a y  3 2 3, Wee k  4 8/ D a y  3 3 0  
( pr e- dos e a n d 4 h o urs p ost - d os e), Wee k  4 8/ D a y  3 3 1, Wee k  4 9/ D a y  3 3 7, 
Wee k  5 2/ D a y  3 5 8  (t o b e p erf or m e d pre -d os e o n Wee k  2/ D a y  8 t o 
Wee k  1 2/ D a y  7 8 , Wee k  1 4/ D a y  9 2  t o Wee k 2 4/ D a y  1 6 2, Wee k  2 6/ D a y  1 7 6 t o 
Wee k  3 6/ D a y  2 4 6, a n d Wee k  3 8 / D a y  2 6 0  t o Wee k 4 7/ D a y  3 2 3 ) 
6)  Bl o o d t ests  
< O bs er v ati o n p oi nt >  
Wee k  1/ D a y  1, Wee k  1/ D a y  2, Wee k  5/  D a y  2 9, Wee k  9/ D a y  5 7, 
Wee k  1 3/ D a y  8 5 , Wee k  1 7/ D a y  1 1 3 , Wee k  2 1/ D a y  1 4 1, Wee k  2 5/ D a y  1 6 9, 
Wee k  2 9/ D a y  1 9 7, Wee k  3 3/ D a y  2 2 5, Wee k  3 7/ D a y  2 5 3, Wee k  4 1/ D a y  2 8 1, 
Wee k  4 5/ D a y  30 9, Wee k  4 8/ D a y  3 3 0, Wee k  4 9/ D a y  3 3 7, Wee k  5 2/ D a y  3 5 8  (t o 
b e p erf or m e d  pr e -d os e o n Wee k  1/  D a y  1 a n d  Wee k  5/ D a y  2 9 t o 
Wee k  4 8/ D a y  3 3 0 ) 
7)  Uri n al ysis  
< O bs er v ati o n p oi nt >  
Wee k  1/ D a y  1 ( pr e-d os e ,* 1 4 fr o m 4 h o urs p ost-d os e) , Wee k  1/ D a y  2, 


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Wee k  5/ D a y  2 9, W ee k  9/  D a y  5 7, Wee k  1 3/ D a y  8 5 ( pre- d os e,* 1 4 fr o m 4 h o urs 
p ost- d os e), Wee k  1 7/ D a y  1 1 3 , Wee k  2 1/ D a y  1 4 1, Wee k  2 5/ D a y  1 6 9  ( pre- d os e,* 1 4 
fr o m 4 h o urs p ost- d os e), Wee k  2 9/ D a y  1 9 7, Wee k  3 3/ D a y  2 2 5, 
Wee k  3 7/ D a y  2 5 3  ( pr e- d os e,* 1 4 fr o m 4 h o urs p ost- d os e), We e k 4 1/ D a y  2 8 1, 
Wee k  4 5/ D a y  3 0 9, Wee k  4 8/ D a y  3 3 0  ( pre- d os e,* 1 4 fr o m 4 h o urs p ost- d os e), 
Wee k  4 9/ D a y  3 3 7, Wee k  5 2/ D a y  3 5 8  (t o b e p erf or m e d pre -d os e o n 
Wee k  5/ D a y  2 9, Wee k  9/  D a y  5 7, Wee k  1 7/ D a y  1 1 3 , Wee k  2 1/ D a y  1 4 1, 
Wee k  2 9/ D a y  1 9 7, Wee k  3 3/ D a y  2 2 5, Wee k  4 1/ D a y  2 8 1, Wee k  4 5/ D a y  3 0 9 ) 
8)  1 2- l ea d el ectr o car di o gr a m 
< O bs er v ati o n p oi nt >  
See 6. 2  
9)  
 
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d o n ce eac h i n t h e p eri o d fr o m Wee k 4/ D a y  2 2 t o Wee k 6/ D a y  3 6 
a n d t h e p eri o d fr o m Wee k  4 9/ D a y  3 3 7  t o Wee k 5 1/ D a y  3 5 1 . 
1 0)  M RI  
< L o cati o n of i m a gi n g >  
U p p er ar m: M RI or C T (t o c o nfir m t h e l o cati o n of m us cl e bi o ps y)  
T hi g h: M RI  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce i n t h e p eri o d fr o m Wee k  4 9/  D a y  3 3 7 t o Wee k 5 1 / D a y  3 5 1. 
1 1)  M us cl e bi o ps y  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce i n t h e p eri o d fr o m Wee k  4 9/  D a y  3 3 7 t o Wee k 5 1 / D a y  3 5 1.   
To b e p erf or m e d  aft er M RI or C T, m ot or f u n cti o n ass ess m e nt, res pirat or y f u n cti o n 
ass ess m e nt, car di ac f u n cti o n ass ess m e nt, a n d q u a ntit ati v e m us cl e stre n gt h 
ass ess m e nt . 
1 2)  M ot or f u n cti o n ass ess m e nt  (l o w er li m bs) 
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce eac h i n t h e p eri o d fr o m Wee k  1 2/ D a y  8 4  t o 
Wee k  1 3/ D a y  8 5  ( pr e- d os e), t h e p eri o d fr o m Wee k  2 4 / D a y  1 6 8  t o 
Wee k  2 5/ D a y  1 6 9  ( pr e- d os e), a n d t h e p eri o d fr o m Wee k  3 6/ D a y  2 5 2 t o 
Wee k  3 7/ D a y  2 5 3  ( pr e- d os e), a n d p erf or m e d t wi ce i n t h e p eri o d fr o m 
Wee k  4 9/ D a y  3 3 7  t o Wee k 5 1 / D a y  35 1 . 
C CI


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1 3)  M ot or f u n cti o n ass ess m e nt  ( u p p er li m bs) 
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce eac h i n t h e p eri o d fr o m Wee k  2 4 / D a y  1 6 8  t o 
Wee k 2 5/ D a y  1 6 9  ( pr e- d os e) a n d t h e p eri o d fr o m Wee k  3 6/ D a y  2 5 2 t o 
Wee k  3 7/ D a y  2 5 3  ( pr e- d os e), a n d p erf or m e d t wi ce i n t h e p eri o d fr o m 
Wee k  4 9/ D a y  3 3 7  t o Wee k 5 1 / D a y  35 1 .  N ot e t h at  m eas ure m e nt will b e st art e d 
w h e n p ossi bl e, at a ti mi n g t h at s uits t h e s u bj ect’s s c h e d ul e . 
1 4)  Res pir at or y f u n cti o n ass ess m e nt  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce eac h i n t h e p eri o d fr o m Wee k  1 2/ D a y  8 4  t o 
Wee k  1 3/ D a y  8 5  ( pr e- d os e), t h e p eri o d fr o m Wee k  2 4 / D a y  1 6 8  t o 
Wee k  2 5/ D a y  1 6 9  ( pr e- d os e), t h e p eri o d fr o m Wee k  3 6/ D a y  2 5 2  t o 
Wee k  3 7/ D a y  2 5 3  ( pr e- d os e), a n d t h e p eri o d fr o m Wee k  4 9/ D a y  3 3 7 t o 
Wee k  5 1 / D a y  35 1 . 
1 5)  Car di ac f u n cti o n ass ess me nt  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce eac h i n t h e p eri o d fr o m Wee k  1 2/ D a y  8 4  t o 
Wee k  1 3/ D a y  8 5  ( pr e- d os e), t h e p eri o d fr o m Wee k  2 4 / D a y  1 6 8  t o 
Wee k  2 5/ D a y  1 6 9  ( pr e- d os e), t h e p eri o d fr o m Wee k  3 6/ D a y  2 5 2  t o 
Wee k  3 7/ D a y  2 5 3  ( pr e- d os e), a n d t h e p eri o d fr o m Wee k  4 9/ D a y  3 3 7 t o 
Wee k  5 1 / D a y  35 1 . 
1 6)  Q u a ntit ati v e m us cl e str e n gt h ass ess m e nt  
<I n v esti g ati o n p oi nt >  
To b e p erf or m e d  o n ce eac h i n t h e p eri o d fr o m Wee k  1 2/ D a y  8 4  t o 
Wee k  1 3/ D a y  8 5  ( pr e- d os e), t h e p eri o d fr o m Wee k  2 4 / D a y  1 6 8  t o 
Wee k  2 5/ D a y  1 6 9  ( pr e- d os e), a n d t h e p eri o d fr o m Wee k  3 6/ D a y  2 5 2 t o 
Wee k  3 7/ D a y  2 5 3  ( pr e- d os e), a n d p erf or m e d t wi ce i n t h e p eri o d fr o m 
Wee k  4 9/ D a y  3 3 7  t o Wee k 5 1 / D a y  35 1 . 
1 7)  Bl o o d c oll ecti o n  
• 
P h ar m ac o ki n eti cs  
< Bl o o d c oll ecti o n p oi nt >  
See 6. 7  
• 
A nti -d ystr o p hi n a nti b o d y  
< Bl o o d c oll ecti o n p oi nt >  
Wee k  4 9/ D a y  3 3 7  


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A nti -D S -5 1 4 1 b a nti b o d y  
< Bl o o d c oll ecti o n p oi nt >  
Wee k  4 9/ Da y  3 3 7  
1 8)  Uri n e c oll ecti o n  
• 
Uri n e pr ot ei n  
< Uri n e c oll ecti o n p oi nt >  
Wee k  1 3/ D a y  8 5 , Wee k  2 5/ D a y  1 6 9, Wee k  3 7/ D a y  2 5 3, Wee k  4 9/ D a y  3 3 7 
1 9)  W h et h er t h e s u bj ect ca n p arti ci p at e i n t h e l o n g -t er m e xt e nsi o n st u d y 
< Ti mi n g of c o nfir m ati o n > 
Wee k  4 9/ D a y  3 3 7  t o Wee k 5 1/ D a y  3 5 1  ( A n e x pl a n ati o n of t h e l o n g-t er m 
e xt e nsi o n st u d y m a y b e pr o vi d e d t o s u bj ects w h o c o m pl et e 4 8 w ee ks of st u d y dr u g 
a d mi nistr ati o n i n P art 2- E xt e nsi o n - 2.) 
 
* 1 4 : 2 4- h o ur uri n e p o oli n g will b e p erf or m e d, st arti n g o n t h e pre vi o us d a y.  
 
6. 5  
T est It e ms o n Wit h d r a w al f r o m t h e St u d y a n d t h ei r Ti mi n g  
Wit hi n 7 d a ys fr o m t h e d at e w h e n t h e i n v esti g at or or s u bi n v esti g at or d eci d es t h at t h e 
s u bj ect s h o ul d b e wit h dr a w n fr o m t h e st u d y, th e f oll o wi n g i n v esti g ati o ns, 
e x a mi n ati o ns, a n d t ests will b e p erf or m e d, as far as p oss i bl e. 
 
6. 5. 1  
F o r Wit h d r a w al i n t h e P eri o d fr o m D a y 1 t o D a y 1 5  of A n y D os e L e v el i n 
P a rt 1  
1)  I n v esti g ati n g c o n c o mit a nt m e di cati o ns a n d c o n c o mit a nt  t h era p y 
2)  I n v esti g ati n g a d v ers e e v e nts 
3)  B o d y w ei g ht  
4)  Vit al si g ns a n d cli ni cal fi n di n gs  
5)  Bl o o d t ests a n d uri n al ysis  
6)  1 2- l ea d el ectr o car di o gr a m  
7)  Bl o o d c oll ecti o n  
• 
P h ar m ac o ki n eti cs  
• 
A nti -d ystr o p hi n a nti b o d y  
• 
A nti -D S -5 1 4 1 b a nti b o d y  
• 
Bl o o d cell d ystr o p hi n m R N A  
8)  Uri n e c oll ecti o n  
• 
Uri n e pr ot ei n  


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• 
Uri n e D S -5 1 4 1 b m et a b olit es  
 
6. 5. 2  
F o r Wit h d r a w al i n t h e P eri o d fr o m D a y 1 t o D a y 8 5  of P a rt 2  
1)  I n v esti g ati n g c o n c o mit a nt m e di cati o ns a n d c o n c o mit a nt  t h era p y 
2)  I n v esti g ati n g a d v ers e e v e nts 
3)  B o d y w ei g ht  
4)  Vit al si g ns a n d cli ni cal fi n di n gs  
5)  Bl o o d t ests a n d uri n al ysis  
6)  1 2- l ea d el ectr o car di o gr a m 
7)  M RI or C T  
< L o cati o n of i m a gi n g >  
U p p er ar m: M RI or C T (t o c o nfir m t h e l o cati o n of m us cl e bi o ps y)  
T hi g h: M RI  
8)  M us cl e bi o ps y  
9)  M ot or f u n cti o n ass ess m e nt  
1 0)  Res pir at or y f u n cti o n ass ess m e nt  
1 1)  Car di ac f u n cti o n ass ess me nt  
1 2)  Q u a ntit ati v e m us cl e str e n gt h ass ess m e nt  
1 3)  Bl o o d c oll ecti o n  
• 
P h ar m ac o ki n eti cs  
• 
A nti -d ystr o p hi n a nti b o d y  
• 
A nti -D S -5 1 4 1 b a nti b o d y  
• 
Bl o o d cell d ystr o p hi n m R N A  
1 4)  Uri n e c oll ecti o n  
• 
Uri n e pr ot ei n  
 
6. 5. 3  
F o r Wit h d r a w al i n t h e P eri o d fr o m Wee k  1/ D a y 1 t o Wee k  4 9/ D a y  3 3 7 of 
P a rt 2 - E xt e nsi o n o r f r o m Wee k  1/  D a y  1 t o Wee k  4 9/ D a y 3 3 7 of P a rt 
2- E xt e nsi o n- 2 
1)  I n v esti g ati n g c o n c o mit a nt m e di cati o ns a n d c o n c omit a nt  t h era p y 
2)  I n v esti g ati n g a d v ers e e v e nts 
3)  H ei g ht a n d b o d y w ei g ht  
4)  Vit al si g ns a n d cli ni cal fi n di n gs  
5)  Bl o o d t ests  
6)  Uri n al ysis  


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7)  1 2- l ea d el ectr o car di o gr a m 
8)  
* 1 5  
9)  M RI or C T  
< L o cati o n of i m a gi n g >  
U p p er ar m: M RI or C T (t o c o nfir m t h e l o cati o n of m us cl e bi o ps y ) 
T hi g h: M RI  
1 0)  M us cl e bi o ps y  
1 1)  M ot or f u n cti o n ass ess m e nt (l o w er li m bs a n d up p er li m bs )* 1 6  
1 2)  Res pir at or y f u n cti o n ass ess m e nt  
1 3)  Car di ac f u n cti o n ass ess me nt  
1 4)  Q u a ntit ati v e m us cl e str e n gt h ass ess m e nt  
1 5)  Bl o o d c oll ecti o n  
• 
P h ar m ac o ki n eti cs  
• 
A nti -d ystr o p hi n a nti b o d y  
• 
A nti -D S - 5 1 41 b a nti b o d y  
1 6)  Uri n e c oll ecti o n  
• 
Uri n e pr ot ei n  
 
* 1 5 : To b e p erf or m e d if t h e s u bj ect is wit h dra w n i n t h e p eri o d fr o m Wee k  1/ D a y  1 t o 
Wee k  4 9/ D a y 3 3 7  of P art 2 - E xt e nsi o n- 2. 
* 1 6 : N ot n ecess ar y if mot or f u n cti o n ass ess m e nt ( u p p er li m bs ) w as n ot p erf or m e d 
e v e n o n ce i n t h e p eri o d fr o m Wee k  2 4/ D a y  1 6 8 t o Wee k  3 7/ D a y  2 5 3 ( pre - d os e) of 
Part 2 -E xt e nsi o n - 2. 
 
6. 5. 4  
F o r Wit h d r a w al i n t h e P eri o d fr o m D a y 1 6 t o D a y 6 4  of P a rt 1 , fr o m D a y 
8 6 t o D a y 1 6 2  of P a rt 2 , f r o m Wee k  4 9/ D a y  3 3 8 t o Wee k 5 2/ D a y  3 5 8 of 
P a rt 2 - E xt e nsi o n, o r f r o m Wee k  4 9/ D a y  3 3 8 t o Wee k 5 2/ D a y  3 5 8 of P a rt 
2- E xt e nsi o n- 2 
1)  I n v esti g ati n g c o n c o mit a nt m e di cati o ns a n d c o n c o mit a nt  t h era p y 
2)  I n v esti g ati n g a d v ers e e v e nts 
3)  H ei g ht a n d b o d y w ei g ht  
4)  Vit al si g ns a n d cli ni cal fi n di n gs  
5)  Bl o o d t ests a n d uri n al ysis  
6)  1 2- l ea d el ectr o car di o gr a m 
7)  
* 1 7  
C CI
C CI


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8)  M RI or C T
* 1 8 
< L o cati o n of i m a gi n g >  
U p p er ar m: M RI or C T (t o c o nfir m t h e l o cati o n of m us cl e bi o ps y)  
T hi g h: M RI  
9)  M us cl e bi o ps y * 1 8  
1 0)  M ot or f u n cti o n ass ess m e nt (l o w er li m bs a n d up p er li m bs )* 1 8, 1 9  
1 1)  Res pir at or y f u n cti o n ass ess m e nt * 1 8 
1 2)  Car di ac f u n cti o n ass ess me nt * 1 8  
1 3)  Q u a ntit ati v e m us cl e str e n gt h ass ess m e nt * 1 8 
 
* 1 7: To b e p erf or m e d f or s u bj ects w h o p arti ci p at e d i n P art 2 - E xt e nsi o n- 2, b ut n ot 
n ecess ar y if p erf or m e d o n Wee k  4 9/ D a y  3 3 7 of P art 2 - E xt e nsi o n- 2 i n s u bj ects 
wit h dr a w n i n t h e p eri o d fr o m Wee k 4 9/ D a y  3 3 8 t o Wee k  5 2/ D a y  3 5 8 of Part 
2- E xt e nsi o n- 2. 
* 1 8: N ot n ecess ar y i n s u bj ects wit h dra w n i n t h e p eri o d fr o m D a y  8 6 t o D a y  1 6 2 of 
Part 2  if p erf or m e d o n D a y 8 5  of P art 2 .   N ot n ecess ar y f or s u bj ects wit h dra w n i n t h e 
p eri o d fr o m Wee k  4 9/  D a y  3 3 8 t o Wee k  5 2/ D a y  3 5 8 of P art 2 - E xt e nsi o n if p erf or m e d 
o n Wee k  4 9/ D a y  3 3 7  of Part 2 -E xt e nsi o n , a n d n ot n ecess ar y f or s u bj ects wit h dra w n i n 
t h e p eri o d fr o m Wee k  4 9/  D a y  3 3 8 t o Wee k  5 2/ D a y  3 5 8 of P art 2 - E xt e nsi o n- 2 if 
p erf or m e d o n Wee k  4 9/ D a y  3 3 7 of P art 2 - E xt e nsi o n- 2. 
 
* 1 9 : N ot n ecess ar y if mot or f u n cti o n ass ess m e nt ( u p p er li m bs ) w as n ot p erf or m e d 
e v e n o n ce i n t h e p eri o d fr o m  Wee k  2 4/ D a y  1 6 8 t o Wee k  3 7/ D a y  2 5 3 ( pre - d os e) of 
Part 2 -E xt e nsi o n - 2. 
 
6. 6  
F oll o w -u p Aft er Wit h d r a w al fr o m t h e St u d y  
At 2 8 d a ys aft er t h e l ast d os e of t h e s t u d y dr u g (acce pt a bl e li mit : ± 7 d a ys), t h e 
f oll o wi n g i n v esti g ati o ns, e x a mi n ati o ns, a n d t ests will b e p erf or m e d, as far as p ossi bl e.   
T h e c o nt e nts of t h e t ests will b e t h e s a m e as t h os e d uri n g t h e st u d y p eri o d . 
1)  I n v esti g ati n g c o n c o mit a nt m e d i cati o ns a n d c o n c o mit a nt  t h era p y 
2)  I n v esti g ati n g a d v ers e e v e nts 
3)  Vit al si g ns a n d cli ni cal fi n di n gs  
4)  Bl o o d t ests a n d uri n al ysis  
5)  1 2- l ea d el ectr o car di o gr a m 
 


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6. 7  
P h a r m a c o ki n eti cs  ( Bl o o d C oll ecti o n [ Pl as m a]) 
A t t h e ti m e of bl o o d c oll ecti o n f or p h ar m ac o ki n etics, 1 m L of bl o o d will b e c oll ect e d 
i n a bl o o d c oll ecti o n t u b e pr e p ar e d b y t h e s p o ns or or ce ntral l a b orat or y.   Aft er 
c oll ecti o n, t h e bl o o d will b e pr o m ptl y mi x e d b y i n v ersi o n mi xi n g.   T h e plas m a 
o bt ai n e d b y ce ntrif u g al s e p ar ati o n will b e st ore d fr o ze n (set t e m p erat ur e: ≤−7 0° C) 
u ntil it is s u b mitt e d t o t h e cli ni cal s p eci m e n st ora g e facilit y c o ntract e d b y t h e s p o ns or.   
D et ails ar e s p ecifi e d i n a s e p ar at e pr o ce d ure.  
T h e i n v esti g at or or s u bi n v esti g at or will rec or d w h et h er bl o o d w as c oll ect e d a n d t h e 
d at e/ti m e of bl o o d c oll e cti o n o n t h e cas e re p ort f or m.  
< B l o o d c oll ecti o n p oi nt> 
• 
Part 1 ( eac h d os e l e v el ) 
F irst d os e: 
D a y 1 ( pr e -d os e  a n d 0. 5 h o urs, 1 h o ur, 2 h o urs, 4 h o urs, 6 h o urs, a n d 8 h o urs  
p ost- d os e ), D a y 2 ( 2 4 h o urs p ost -d os e ), D a y 4 ( 7 2 h o urs p ost- d os e) 
S ec o n d d os e: 
D a y 8  ( pr e-d os e), D a y 9 ( 2 4 h o urs  p ost - d os e), D a y 1 1 ( 7 2 h o urs p ost- d os e), D a y 
1 5 ( 7 d a ys p ost - d os e), D a y 3 6 ( 4 w ee ks p ost- d os e), D a y 6 4 ( 8 w ee ks p ost- d os e) 
• 
Part 2 
F irst d os e: 
D a y 1 ( pr e -d os e  a n d 0. 5 h o urs, 1 h o ur, 2 h o urs, 4 h o urs, 6 h o urs, a n d 8 h o urs  
p ost- d o s e), D a y 2 ( 2 4 h o urs p ost -d os e ) 
S ec o n d d os e, f o urt h d os e , si xt h d os e, ei g ht h d os e, 1 0t h d os e: 
D a y 8 ( pr e -d os e), D a y 2 2 ( pr e -d os e), D a y 3 6 ( pre -d os e), D a y 5 0 ( pre -d os e), D a y 
6 4 ( pr e - d os e) 
1 2 t h d os e: 
D a y 7 8 ( pr e -d os e, 0. 5 h o urs, 1 h o ur, 2 h o urs, 4 h o urs, 6 h o urs, a n d 8 h o urs  
p ost- d os e ), D a y 7 9 ( 2 4 h o urs p ost- d os e), D a y 8 5 ( 7 d a ys p ost -d os e ), D a y 1 0 6 ( 4 
w ee ks p ost- d os e ), D a y 1 3 4 ( 8  w ee ks p ost - d os e), D a y 1 6 2 ( 1 2 w ee ks p ost - d os e) 
• 
Part 2- E xt e nsi o n a n d P art 2- E xt e nsi o n- 2 ( s u bj ects c o nti n ui n g p arti ci p ati o n fr o m 
Par t 2 a n d P art 2- E xt e nsi o n) 
F irst d os e: 
Wee k  1/ D a y  1 ( pr e-d os e a n d 4 h o urs p ost -d os e), Wee k  1/ D a y  2 ( 2 4 h o urs  
p ost- d os e) 
S ec o n d d os e: 
Wee k 2/ D a y 8 ( pr e - d os e) 


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F ift h d os e, ni nt h d os e, 1 3t h d os e, 1 7t h d os e, 2 1st d os e, 2 5t h d os e, 2 9t h d os e, 3 3 r d 
d os e, 3 7t h d os e, 4 1 st d os e, 4 5t h d os e : 
Wee k  5/ D a y  2 9 ( pr e -d os e), Wee k  9/  D a y  5 7 ( pre -d os e), Wee k  1 3/ D a y  8 5 
( pr e-d os e), Wee k  1 7/ D a y  1 1 3 ( pre -d os e), Wee k  2 1/ D a y  1 4 1 ( pre -d os e), 
Wee k  2 5/ D a y  1 6 9 ( pr e -d os e), Wee k  2 9/ D a y  1 9 7 ( pre -d os e), Wee k  3 3/ D a y  2 2 5 
( pr e-d os e), Wee k  3 7/ D a y  2 5 3 ( pre -d os e), Wee k  4 1/ D a y  2 8 1 ( pre -d os e), 
Wee k  4 5/ D a y  3 0 9 ( pr e - d os e) 
4 8t h d os e : 
Wee k  4 8/ D a y  3 3 0  ( pr e- d os e a n d 1 h o ur, 2 h o urs, 4 h o urs, 6 h o urs,  a n d 8 h o urs  
p ost- d os e ), Wee k 4 8/ D a y  3 3 1 ( 2 4 h o urs  p ost-d os e ), Wee k 4 9/ D a y  3 3 7 ( 7 d a ys 
p ost- d os e ), Wee k 5 2/ D a y  3 5 8 ( 4 w ee ks p ost -d os e ) 
• 
Part 2 -E xt e nsi o n a n d P art 2 - E xt e nsi o n-2 ( s u bj ects p arti ci p ati n g fr o m P art 
2- E xt e nsi o n a n d P art 2 - E xt e nsi o n- 2) 
F irst d os e: 
Wee k 1/ D a y 1 ( pr e -d os e  a n d  0. 5 h o urs, 1 h o ur, 2 h o urs, 4 h o urs, 6 h o urs, a n d 8 
h o urs  p ost- d os e), Wee k 1/ D a y 2 ( 2 4 h o urs p ost - d os e) 
S ec o n d d os e: 
Wee k 2/ D a y 8 ( pr e -d os e)  
F ift h d os e, ni nt h d os e, 1 3t h d os e, 1 7t h d os e, 2 1 st d os e, 2 5t h d os e, 2 9t h d os e, 3 3r d 
d os e, 3 7t h d os e, 4 1 st d os e, 4 5t h d os e : 
Wee k 5/ D a y 2 9 ( pr e -d os e), Wee k 9/ D a y 5 7 ( pre -d os e), We e k 1 3/ D a y 8 5 
( pr e-d os e), Wee k 1 7/ D a y 1 1 3 ( pre -d os e), Wee k 2 1/ D a y 1 4 1 ( pre -d os e), Wee k 
2 5/ D a y 1 6 9 ( pr e -d os e), Wee k 2 9/ D a y 1 9 7 ( pre -d os e), Wee k 3 3/ D a y 2 2 5 
( pr e-d os e), Wee k 3 7/ D a y 2 5 3 ( pre -d os e), Wee k 4 1/ D a y 2 8 1 ( pre -d os e), Wee k 
4 5/ D a y 3 0 9 ( pr e - d os e) 
4 8t h d os e : 
Wee k  4 8/ D a y  3 3 0  ( pr e- d os e a n d 1 h o ur, 2 h o urs, 4 h o urs, 6 h o urs,  a n d 8 h o urs  
p ost- d os e ), Wee k 4 8/ D a y  3 3 1 ( 2 4 h o urs  p ost-d os e ), Wee k 4 9/ D a y  3 3 7 ( 7 d a ys 
p ost- d os e ), Wee k 5 2/ D a y  3 5 8 ( 4 w ee ks p ost -d os e ) 
 
< A cce pt a bl e li mits > 
• 
0. 5 h o urs , 1 h o ur p o st- d os e 
: ± 5 mi n ut es  
• 
2 h o urs, 4 h o urs, 6 h o urs, 8 h o urs  p ost- d os e 
: ± 1 0 mi n ut es  
• 
2 4 h o urs  p ost - d os e 
: ± 1 h o ur  
• 
7 2 h o urs  p ost - d os e 
: ± 3 h o urs  


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< R ati o n al e >  
A cc or di n g t o t h e r es ult of a n o n cli ni cal st u d y i n w hi c h D S -5 1 4 1 b w as a d mi nist ere d t o 
m o n k e ys at 1 0 m g/ k g , t h e T m a x  of D S -5 1 4 1 b  w as 4. 0 0  ± 2. 0 0 ( m ea n ± S D)  a n d t h e 
ter mi n al h alf -lif e, as a r ef er e n ce, w as  2 9 6 h o urs .   T h e ter mi n al h alf -life of ot h er  A O N  
w as 2 9 d a ys. 9  B as e d o n t h es e p h ar m ac o ki n eti cs res ults  an d wit h refere n ce t o 
“ Cli ni cal P h ar m ac o ki n etic St u di es of P h ar m ace uticals, 1 0” o n e  bl o o d c oll ecti o n p oi nt 
dir ectl y  b ef or e a d mi nistr ati o n , at l e ast 1 p oi nt b ef ore reac hi n g t h e pre di ct e d C m a x , at 
least 2 p oi nts cl os e t o T ma x , a n d at l east 3 p oi nts i n eli mi n ati o n p h as e as t h e ti m e 
p oi nts  wer e s el ect e d si nce t hes e w er e c o nsi d ere d n ecess ar y f orp h ar m ac o ki n eti c  
ass ess m e nt. 
 
6. 8  
C h ec ki n g t h e D N A S e q ue n ce of t h e Site of D S- 5 1 4 1 b D o u bl e- Str a n d 
F o r m ati o n  ( Bl o o d Coll ecti o n [ W h ol e Bl o o d ]) 
T o c h ec k t h e D N A s e q u e n ce of t h e sit e of D S - 5 1 4 1 b d o u bl e-stra n d f or m ati o n i n t h e 
d ystr o p hi n g e n e , aft er i nf or m e d c o ns e nt  a n d b ef ore re gist rati o n, 2 m L of bl o o d will b e 
c oll ect e d i n a bl o o d c oll ecti o n t u b e pre p are d b y t h e s p o ns or or ce ntral l a b orat or y.   
Aft e r c oll ecti o n, t h e bl o o d will b e pr o m ptl y mi x e d b y i n v ersi o n, an d t h e n tra nsferre d 
t o a st or a g e c o nt ai n er pr e p ar e d b y t h e s p o ns or, a n d st ore d fr o ze n (s et t e m p erat ure: 
≤−2 0° C) u ntil it is s u b mitt e d t o t h e cli ni cal s p eci me n st ora g e f acilit y c o ntract e d b y t h e 
s p o ns or.  D et ails ar e s p ecifi e d i n a s e p arat e pr o ce d ure.  
T h e i n v esti g at or or s u bi n v esti g at or w ill rec or d w h et h er bl o o d w as c oll ect e d, t h e d at e 
of c oll ecti o n , a n d th e r es ult o n t h e cas e re p ort f or m.  
 
6. 9  
E x p ressi o n of D yst r o p hi n P r otei n a n d P r o d u cti o n of E x o n 4 5- S ki p p e d 
D yst r o p hi n m R N A  i n M us cl e Tiss u e ( Mus cl e Bi o ps y ) 
T o m eas ur e t h e d ystr o p hi n pr ot ei n i n m us cl e tiss u e a n d  t h e d ystr o p hi n m R N A i n du ce d  
b y e x o n 4 5 s ki p pi n g, aft er r e gistr ati o n, b ef ore t h e first d os e of t h e st u d y  dr u g  i n eac h 
s u bj ect, aft er t h e l ast dos e of t h e st u d y dr u g  ( D a y 8 5 t o D a y 9 9, or at wit h dra w al) i n 
Part 2 , aft er t h e l ast d os e of t h e st ud y dr u g  ( Wee k 4 9/ D a y  3 3 7 to Wee k  5 1/  D a y  3 5 1, 
or at wit h dr a w al) i n P art 2- E xt e nsi o n, a n d aft er t h e l ast d os e of t h e st u d y dr u g 
( Wee k 4 9/ D a y  3 3 7  t o Wee k 5 1 / D a y  3 5 1 , or at wit h dra w al) i n P art 2- E xt e nsi o n- 2, 
m us cl e tiss u e will b e  c ollect e d  fr o m, i n pri n ci pl e,  t h e bi ce ps brac hii m us cl e b y o p e n 
m us cl e bi o ps y .   T h e l o cati o n of c oll ecti o n will b e d eci d e d aft er c h ec ki n g t h e 
c o n diti o n of t h e m us cl e b y M RI or C T  p er f or m e d i n a d v a n ce.   Aft er c ollecti o n, t h e 


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s p eci m e n will b e pr o cess e d pr o m ptl y, a n d st ore d fr o ze n (s et t e m p erat ure: ≤−7 0° C) i n a 
c o nt ai n er pr e p ar e d b y t h e s p o ns or or ce ntral l a b orat or y u ntil it is s u b mitt e d t o t h e 
cli ni cal s p eci m e n st or a g e f acilit y c o ntract e d b y t h e s p o ns or.   D et ails are s p ecifi e d i n a 
s e p ar ate pr o ce d ur e.  
T h e i n v esti g at or or s u bi n v esti g at or will rec or d w h et h er a m us cl e bi o ps y w as 
p erf or m e d , th e d at e of bi o ps y , a n d th e re gi on of t h e c oll ect e d m us cl e  o n t he cas e re p ort 
f or m. 
 
6. 1 0  Me as u re m e nt of A n ti- D yst r o p hi n Anti b o d y ( B l o o d C oll ecti o n [S er u m] ) 
To m eas ur e a nti- d ystr o p hi n a nti b o d y , 2. 0 m L of bl o o d will b e c oll ect e d i n a bl o o d 
c oll ecti o n t u b e pr e p ar e d b y t h e s p o ns or or ce ntral l a b orat or y, b ef ore t h e first d os e of 
t h e st u d y dr u g a n d aft er t h e l ast d os e of t h e st u d y dr u g at eac h d os e l e v el ( Da y 1 5  or at 
wit h dr a w al)  i n P art 1, b ef or e t h e first d os e of t h e st u d y dr u g a n d aft er t h e l ast d os e of 
t h e st u d y dr u g ( D a y 8 5 or at wit h dr a w al) i n P art 2, b ef ore t h e first d os e of t h e st u d y 
dr u g a n d aft er t h e l ast d os e of t h e st u d y dr u g  ( Wee k 4 9/ D a y  3 3 7 or  at wit h dra w al) i n 
Part 2 -E xt e nsi o n , an d b ef o r e t h e first d os e of t h e st u d y dr u g a n d aft er t h e l ast d os e of 
t h e st u d y dr u g ( Wee k 4 9/ D a y  3 3 7 or at wit h dra w al) i n P art 2- E xt e nsio n - 2.   Aft er 
c oll ecti o n, t h e bl o o d wil l b e l eft f or 3 0 mi n ut es at r o o m t e m p erat ure a n d t h e n 
ce ntrif u g al s e p ar ati o n will b e p e rf or m e d wit hi n 1 h o ur of c oll ecti o n, an d t h e o bt ai n e d 
s er u m will b e di vi d e d i nt o 3 st or a g e c o nt ai n ers.   Th e o bt ai n e d s er u m will b e st ore d 
fr o ze n (s et t e m p er at ur e: ≤−7 0° C) u ntil it is s u b mitt e d t o t h e cli ni cal s p eci me n st ora g e 
f acilit y c o ntr act e d b y t h e sp o ns or.   D et ails are s p ecifi e d i n a s e p arat e pr o ce d ure.  
T h e i n v esti g at or or s u bi n v esti g at or w ill rec or d w h et h er bl o o d w as c oll ect e d an d t h e 
bl o o d c oll ecti o n d a y o n t h e cas e r e p ort f or m.  
 
6. 1 1  Me as u re m e nt of A nti -D S - 5 1 4 1 b Anti b o d y ( Bl o o d C oll ecti o n [ Pl as m a] ) 
To m eas ur e a nti- D S -5 1 4 1 b a nti b o d y, 1. 0 m L of bl o o d will b e c oll ect e d i n a bl o o d 
c oll ecti o n t u b e pr e p ar e d b y t h e s p o ns or or ce ntral l a b orat or y, b ef ore t h e first d os e of 
t h e stu d y dr u g i n P art 1 a n d aft er t h e l ast d os e of t h e st u d y dr u g at eac h d os e l e v el 
( D a y 1 5 or at wit h dr a w al)  i n P art 1, b ef ore t h e first d os e of t h e st u d y dr u g a n d aft er t h e 
last d os e of t h e st u d y dr u g ( D a y 8 5 or at wit h dra w al) i n P art 2, aft er t h e l ast d os e of t h e 
st u d y dr u g ( Wee k 4 9/ D a y  3 3 7 or  at wit h dra w al) i n P art 2 -E xt e nsi o n, a n d aft er t h e l ast 
d os e of t h e st u d y dr u g  ( Wee k 4 9/ D a y  3 3 7 or  at wit h dra w al) i n P art 2-E xte nsi o n - 2.   
F or s u bj ects p arti ci p ati n g fr o m P art 2 -E x t e nsi o n, bl o o d will als o b e c oll ecte d b ef ore 
t h e first d os e of t h e st u d y dr u g i n P art 2-E xt e nsi o n, a n d f or s u bj ects p arti ci p ati n g fr o m 


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Part 2 -E xt e nsi o n - 2, bl o o d will als o b e c oll ect e d b ef ore t h e first d os e of t h e st u d y dr u g 
in P art 2 - E xt e nsi o n- 2.   Aft er blo o d is c oll ect e d , i n v ersi o n mi xi n g will pr o m ptl y b e 
p erf or m e d a n d it will b e c o ol e d wit h i ce.   T h e pl as m a o bt ai n e d fr o m ce n trif u g al 
s e p ar ati o n will b e st or e d fr o ze n (s et t e m p erat ure: ≤−7 0° C) u ntil it is s u b mitt e d t o t h e 
cli ni cal s p eci m e n st or a g e f acilit y c o ntract e d b y t h e s p o ns or.   D et ails are  s p ecifi e d i n a 
s e p ar at e pr o ce d ur e. 
If a nti-D S -5 1 4 1 b a nti b o d y is p ositi v e i n t h e f oll o w -u p p eri o d ( or at wit h dra w al), 
a d diti o n al bl o o d will b e c oll ect e d 
 t o i n v esti g ate 
a nti- D S -5 1 4 1 b a nti b o d y.   A d diti o n al bl o o d c oll ecti o n will b e p erf or m e d 
 
, u ntil a nti -D S -5 1 4 1 b a nti b o d y is f o u n d t o b e n e g ati v e, 
u nt il t h e a nti -D S -5 1 4 1 b a nti b o d y tit er is f o u n d t o h a v e d ecreas e d b el o w b as eli n e  (if 
a nti- D S -5 1 4 1 b a nti b o d y w as f o u n d at b as eli n e ), u ntil t h e s u bj ect e nt ere d i n  a n e w 
st u d y, or u ntil t h e s u bj ect wit h dr a ws c o ns e nt, w hi c h e v er is earli est . 
T h e i n v esti g at o r or s u bi n vesti g at or will rec or d w h et h er bl o o d w as c oll ect e d a n d th e 
d at e of bl o o d c oll ecti o n o n t h e cas e re p ort f or m.  
 
6. 1 2  E x pl o r at o r y Bi o m a r k er R es e a rc h 
6. 1 2. 1  I m a gi n g A n al ysis of  s k elet al m us cl e 
T o e x a mi n e  t h e dis eas e pr o gr ess i o n a n d fat re pl ace m e nt i n s k el et al m us cl e, M RI will 
b e p erf or m e d i n t h e t hi g h b ef or e t h e first d os e of t h e st u d y dr u g  i n eac h s u bj ect , b ef ore 
t h e first d os e of t h e st u d y dr u g a n d aft er th e l ast d os e of t h e st u d y dr u g  ( D a y 8 5 t o D a y 
9 9, or at w it h dr a w al) i n Part 2, b ef ore t h e first d os e of t h e st u d y dr u g i n P art 
2- E xt e nsi o n , an d b ef or e t h e first d os e of t h e st u d y dr u g a n d af t er t h e l ast d os e of t h e 
st u d y dr u g ( Wee k 4 9/ D a y  3 3 7 t o Wee k 5 1/ D a y  3 5 1, or at wit h dra w al) i n Part 
2- E xt e nsi o n- 2 , a n d t h e d at a will b e s u b mitt e d t o t h e s p o ns or.   Det ails of pr o ce d ures 
a n d t h e d at a a n al ysis f acilit y will b e s p ecifi e d s e p arat el y.   This e x p l orat or y bi o m ar k er 
r es ear c h will o nl y b e p erf or m e d f or s u bj ects i n w h o m M RI ca n b e p erf or me d 
a p pr o pri at el y. 
T h e i n v esti g at o r or s u bi n v esti g at or will rec or d w h et h er M RI w as p erf or m e d, t h e d at e 
of i m a gi n g , a n d t h e l o cati o n of i m a gi n g o n t h e cas e re p ort f or m.  
 
6. 1 2. 2  Me as u re m e nt of I n V it r o D ystr o p hi n Pr otei n a n d D ystr o p hi n m R N A 
( Ski n Bi o ps y ) 
To i n v esti g at e t h e r eacti vit y of t h e m us cl e cells of eac h s u bj ect  to D S - 5 1 4 1 b, i n vitr o 
st u di es usi n g s ki n fi br o blasts w ill b e p erf or m e d.   F or s u bj ects p arti ci p ati n g i n t his 
C CI
C CI


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st ud y fr o m P art 1 or P art 2,  a s ki n s a m pl e will b e c o ll ect e d at t h e ti m e of m us cl e 
bi o ps y b ef or e t h e first d os e of t h e st u d y d r u g a n d st ore d (set t e m p erat ure : 4° C) i n a 
st or a g e c o nt ai n er pr e p ar e d b y t h e s p o ns or or ce ntral l a b orat or y until it is s u b mitt e d t o 
th e ce ntr al l a b or at or y .    D et ails ar e s p ecifi e d i n a s e p arat e pr o ce d ure. 
T h e i n v esti g at or or s u bi n v esti g at or w ill rec or d w h eth er s ki n bi o ps y w as p erf or m e d a n d 
th e d at e of bi o ps y o n t h e cas e r e p ort f or m.  
 
6. 1 2. 3  Me as u re m e nt of B l o o d Cell D ystr o p h i n m R N A ( Bl o o d C oll ecti o n [ W h ol e 
Bl o o d]) 
T o m eas ur e t h e d ystr o p hi n m R N A i n d u ce d b y e x on 4 5 s ki p pi n g i n bl o o d cells, b ef ore 
t h e first d os e of t h e st u d y dr u g a n d aft er t h e l ast d os e of t h e st u d y dr u g at eac h d os e 
lev el ( D a y 1 5 or at wit h dr a w al) i n P art 1 a n d b ef ore t h e first d os e of t h e st u d y dr u g a n d 
aft er t h e l ast d os e of t h e st u d y dr u g ( D a y 8 5 or at wit h dra w al)  i n P art 2, 2. 5 m L of  
bl o o d will b e c oll ect e d i n t h e bl o o d c oll ecti o n t u b e pre p are d b y t h e s p o ns or or ce ntral 
la b or at or y a n d st or e d fr o ze n (s et t e m p erat ure: ≤−2 0° C) u ntil it i s s u b mitt e d t o t h e 
cli ni cal s p eci m e n st or a g e f acilit y c o ntract e d b y t h e s p o ns or.    D et ails are s p ecifi e d i n a 
s e p ar at e pr o ce d ur e. 
T h e i n v esti g at or or s u bi n v esti g at or will rec or d w h et h er bl o o d w as c oll ect e d a n d th e 
bl o o d c oll ecti o n d a y o n t h e cas e r e p ort f or m.  
 
6. 1 2. 4  M e as u re m e nt of Mi cr o R N A ( B l o o d C oll ecti o n [ S er u m]) 
M i cr o R N A i n bl o o d (s u c h as mi R -1, mi R -1 3 3, a n d mi R -2 0 6) will b e m eas ure d .   P art 
of t h e s er u m o bt ai n e d f or m eas ur e m e nt of a nti-d ys tr o p hi n a nti b o d y (s ee 6. 1 0 ) will b e 
us e d as t h e s p eci m e n .    D et ails ar e s p ecifi e d i n a s e p arat e pr o ce d ure. 
 
6. 1 2. 5  Me as u re m e nt of U ri n e P r otei n ( U ri n e C oll ecti o n)  
T o m eas ure uri n e pr ot ei n (s u c h as titi n ), w hi c h is a n i n dicat or of m us cl e d ec o m p ositi o n , 
b ef or e t h e first d os e of t h e st u d y dr u g a n d aft er t h e l ast d os e of t h e st u d y dr u g at eac h 
d os e l e v el ( D a y 1 5 or at wit h dr a w al) i n P art 1, b ef ore t h e first d os e of t h e st u d y dr u g 
a n d aft er t h e l ast d os e of t h e st u d y dr u g ( D a y 8 5 or at wit h dra w al) i n P art 2, b ef ore t h e 
first d os e of t h e st u d y dr u g, o n Wee k  1 3/ D a y  8 5 , Wee k 2 5/ D a y  1 6 9, a n d 
Wee k  3 7 / D a y  2 5 3  i n P art 2- E xt e nsi o n, a n d b ef ore t h e first d os e of t h e st u d y dr u g, o n 
Wee k  1 3/ D a y  8 5 , Wee k 2 5/ D a y  1 6 9, Wee k 3 7/ D a y  2 5 3 a n d  aft er t h e l ast d os e of t h e 
st u d y dr u g ( Wee k 4 9/ D a y  3 3 7 or  at wit h dra w al) i n P art 2-E xt e nsi o n - 2, 1 0 m L of uri n e 
will b e c oll ect e d i n t h e uri n e c oll ecti o n t u b e pre p are d b y t h e s p o ns or or ce ntral 


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la b or at or y a n d  st or e d fr o ze n (s et t e m p erat ure: ≤−7 0° C) u ntil it is s u b mitt e d t o t h e 
cli ni cal s p eci m e n st or a g e f acilit y c o ntract e d b y t h e s p o ns or.   D et ails of t h e pr o ce d ure  
a n d t h e m eas ur e m e nt f acilit y ar e s p ecifi e d s e p arat el y. 
T h e i n v esti g at or or s u bi n v esti g at or w ill rec or d w h et h er uri n e w as c oll ect e d a n d t h e 
uri n e c oll ecti o n d a y o n t h e cas e r e p ort f or m.  
 
6. 1 2. 6  M e as u re m e nt of Bl o o d D S - 5 1 4 1 b Met a b olites ( Bl o o d C oll ecti o n [ Pl as m a]) 
U n k n o w n m et a b olit es of D S- 5 1 4 1 b will b e e x pl orat ori l y i n v esti g at e d.   P art of t h e 
pl as m a o bt ai n e d f or p h ar mac o ki n eti cs  (s ee 6. 7 ) will b e us e d as a s p ecim e n .   D et ails  
ar e s p ecifi e d i n a s e p ar at e pr o ce d ur e.  
 
6. 1 2. 7  Me as u re m e nt of U ri n e D S - 5 1 4 1 b Met a b olites ( U ri n e C oll ecti o n ) 
To e x pl or at ori l y i n v esti g at e u n k n o w n m et a b olit es of DS- 5 1 4 1 b, b ef ore t h e first d os e of 
t h e st u d y dr u g i n P art 1  a n d on t h e d a y aft er t h e l ast d os e of t h e st u d y dr u g at eac h d os e 
le v el ( D a y 9 or at wit h dr a w al), 5. 0 m L of uri n e will b e c oll ect e d i n a uri n e c oll ecti o n 
t u b e pr o vi d e d b y t h e s p o ns or or ce ntral l a b orat or y.    Th e s p eci m e n will b e st ore d 
fr o ze n (s et t e m p er at ur e: ≤−2 0° C) u ntil it is s u b mitt e d t o t h e cli ni cal s p eci me n st ora g e 
f acilit y c o ntr act e d b y t h e s p o ns or.  D et ails are s p ecifi e d i n a s e p arat e pr o ce d ure.  
T h e i n v esti g at or or s u bi n v esti g at or will rec or d w h et h er uri n e w as c oll ect e d a n d t h e 
u ri n e c oll ecti o n d a y o n t h e cas e r e p ort f or m. 
 
6. 1 3  St o r a g e a n d Dis p os al of S p eci me ns f o r G e n eti c A n al ysis a n d B i o m a r k er 
R es e a rc h  
6. 1 3. 1  S t o r a g e of S p eci m e ns 
I n vi e w of t h e p ossi bilit y t h at, b as e d o n n e wl y o bt ai n e d k n o wl e d g e, a d diti o n al 
e x a mi n ati o ns  of t h e  r el ati o ns hi p b et w ee n t h e effi cac y or s afet y of t h e st u d y dr u g a n d 
t h e bi o m ar k ers will b e p erf or m e d, a n d t h at t h e a b o v e bi o m ar k ers will b e meas ure d 
a g ai n, t h e s u b mitt e d s p eci m e ns will b e st ore d at t h e res p ecti v e m eas ure m e nt faciliti es 
f or u p t o 1 0 y ears fro m t h e ti m e o f t h e n otifi cati o n of t h e st u d y pl a n f or t his st u d y. 
 
6. 1 3. 2  D is p os al of S p eci m e ns 
All s p eci m e ns t h at r eac h t h e e n d of t h eir st ora g e p eri o d will b e dis p os e d of b y t h e 
bi o m ar k er m eas ur e m e nt f acilit y acc or di n g t o t h e i nstr u cti o ns of t h e s p o ns or . 
If a s u bj ect wit h dr a ws c o ns e nt f or bi o m ar k er res earc h, s p eci m e ns will b e dis p os e d of 
acc or di n g t o t h e f oll o wi n g pr o ce d ur es, d e p e n di n g o n t h e l o cati o n of t h e s p eci m e ns at 


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t h at ti m e.   If bi o m ar k er a n al ysis w as p erf or m e d at t h e m eas ure m e nt facilit y b ef ore t h e 
s u bj ect wi t h dr e w co ns e nt, t his d at a will n ot b e dis p os e d of . 
1)  If s p eci m e ns ar e b ei n g t e m p or aril y st ore d at st u d y sit e 
T h e i n v esti g at or or s u bi n v esti g at or w ill i d e ntif y t h e s p eci m e ns fr o m t h e rele v a nt 
s u bj ect an d dis p os e of t h e m . 
2)  If s p eci m e ns ar e b ei n g st or e d at t h e cli ni cal s p eci me n st ora g e facilit y 
T h e i n v esti g at or or s u bi n v esti g at or w ill i nf or m t h e s p o ns or of t h e s u bj ect 
i d e ntifi cati o n c o d e of t h e r el e v a nt s u bj ect.   T h e s p o ns or will i nstr u ct t h e cli ni cal 
s p eci m e n st or a g e f acilit y to dis p os e of t h e rel e v a nt  s u bject ’s s p eci m ens. 
 
6. 1 4  L o n g- Ter m St o r a g e ( B a n ki n g) of Cli ni c al S p eci m e ns f o r G e n o mi c a n d 
Ge n eti c A n al ysis  
L o n g -t er m st or a g e ( b a n ki n g) of D N A s p eci m e ns e xtract e d fr o m t h e s u bj ects’ bl o o d 
will b e p erf or m e d, t o e n a bl e g e n o mi c or g e n eti c a n al ysis rel ati n g t o, f or e x a m pl e, t h e 
e ffi cac y or s af et y of DS- 5 1 4 1 b.   I f res earc h is p erf or m e d usi n g t h es e D N A  s p eci m e ns, 
a r es ear c h pl a n will b e n e wl y pr e p ar e d.  
 
6. 1 4. 1  Sc o p e 
A t st u d y sit es w h er e b a n ki n g is a p pr o v e d, an e x pla n ati o n of b a n ki n g will b e pr o vi d e d, 
a n d s a m pl es o bt ai n e d fr o m s u bj ects w h o pr o vi d e i nf or m e d c o ns e nt b as e d o n t his 
e x pl a n ati o n will b e i n cl u d e d i n t h e s c o p e of b a n ki n g .   F or s u bj ects w h o pr o vi d e 
i nf or m e d c o ns e nt f or b a n ki n g, th e i n v esti g at or or s u bi n v esti g at or w ill rec or d t h e d at e 
of i nf or m e d c o ns e nt  o n t h e cas e r e p ort f orm.   If th ere is a n y i nf or m ati o n s u c h as 
me di cal hist or y t h at m a y aff ect g e n o mi c or g e n eti c i nf or m ati o n  (for e x a m ple, 
all o g e n ei c b o n e m arr o w tr a ns pl a nt ati o n ), t his will b e rec or d e d o n t h e cas e re p ort f or m.  
 
6. 1 4. 2  B a n ki n g S p eci m e ns  ( D N A) 
D N A will b e e xtr act e d  fr o m s o m e of t h e bl o o d c oll ect e d f or c h ec ki n g t h e D N A 
s e q u e n ce of t h e sit e of DS- 5 1 4 1 b d o u bl e- stra n d f or m ati o n (s ee 6. 8 ), a n d t his will b e 
us e d as t h e b a n ki n g s p eci m e n . 
 
6. 1 4. 3  S t o r a g e P eri o d 
T h e st or a g e p eri o d of t h e b a n ki ng s p eci m e ns will b e a m a xi m u m of 1 5 y ears fr o m t h e 
d at e of s u b missi o n of t h e n otifi cati o n of t h e st u d y pl a n f or t his st u d y . 
 


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6. 1 4. 4  D is cl os u re of t h e R es ult of G e n o mi c a n d G e n etic A n al ysis Usi n g B a n ki n g 
S p eci m e ns  
A t pr es e nt, t h e ti mi n g of p h ar m ac o g e n o mi c i n vesti g ati o n usi n g ba n ki n g s p eci m e ns, t h e 
met h o d of g e n o mi c or g e n eti c a n al ysis, a n d w h et h er dis cl os ure will b e n ecess ar y are 
u n d et er mi n e d .   Acc or di n gl y, w e d o n ot pl a n t o dis cl os e t h e res ult of g e n eti c a n al ysis 
t o t h e i n v esti g at or et c. a n d s u bj ects. 
 
6. 1 4. 5  Dis p os al of  B a n ki n g  S p eci m e ns  
A ft er t h e e n d of t h e st or a g e p eri o d, o r if a s u bj ect wit h dra ws c o ns e nt d uri n g t h e 
st or a g e p eri o d, b a n ki n g s p eci m e ns will b e pr o m ptl y dis p os e d of .   H o w e v er, if g e n eti c 
a n al ysis w as p erf or m e d b ef or e t h e e n d of t h e st ora g e p eri o d or b e f ore c o ns e nt w as 
wit h dr a w n, th es e d at a will n ot b e dis p os e d of.  


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7.  
P H A R M A C O KI N E TI C E N D P OI N T S  
T h e f oll o wi n g p h ar m ac o ki n eti c p ar a m et ers will b e cal c ul at e d fr o m t h e pl as m a 
D S -5 1 4 1 a (t h e fr ee f or m of D S -5 1 4 1 b ) c o n ce ntrati o n  i n Part  1, P art 2, P art 
2- E xt e nsi o n, a n d P art  2-E xt e nsi o n - 2 usi n g a  n o n-c o m p art m e nt  m o d el .   D et ails of 
p h ar m ac o ki n eti c a n al ysis will b e s p ecifi e d i n t h e St atisti cal A n al ysis Pl a n . 
 
< P h ar m ac o ki n eti c p ar a m et ers > 
• 
Part 1 a n d P art 2 (f irst d os e) 
C m a x, A U C 1 6 8 h, A U Ci nf, T m a x, K el, t 1/ 2, M R Ti nf, C L/ F, V z/ F 
• 
Part 2 ( 1 2t h d os e ) 
C m a x, C a v g, A U Ct a u, T ma x, K el, t 1/ 2 
• 
Part 2 -E xt e nsi o n ( 4 8t h d os e) a n d P art 2 - E xt e nsi o n- 2 ( 4 8t h d os e) 
C m a x, C a v g, A U Ct a u, T ma x, K el, t 1/ 2, M R Ti nf, C Lss/ F, V z/ F, A R  
• 
Part 2 -E xt e nsi o n (first d os e i n s u bj ects p arti ci p ati n g i n t h e st u d y fr o m P art 
2- E xt e nsi o n *) a n d P art 2 -E xt e nsi o n - 2 (first d os e i n s u bj ects p arti ci p ati n g i n t h e 
st u d y fr o m P art 2 -E xt e nsi o n - 2*)  
C m a x, A U C 1 6 8 h, A U Ci nf, T m a x, K el, t1/ 2, M R Ti nf, C L/ F, V z/ F  
* T h e 4 8t h d os e will b e  h a n dl e d i n t h e s a m e w a y as f or su bj ects c o n ti n ui n g 
p arti ci p ati o n fr o m P art 2  
S i n ce a d mi nistr ati o n of t h e st u d y dr u g w as t e m p oraril y dis c o nti n u e d i n P art 
2- E xt e nsi o n, p h ar m ac o ki n eti c p ara m et ers f or t h e 4 8 t h d os e will b e cal c ul ate d 
o nl y i n ca s es wh er e cal c ul ati o n is p ossi bl e . 
 
< R ati o n al e >  
T h es e p h ar m ac o ki n eti c p ar a m et ers w ere s p ecifi e d t o ass ess  t h e p h ar m ac o ki n eti cs of 
si n gl e d os es a n d r e p eat e d d os es of DS- 5 1 4 1 b, w it h refere n ce t o “ Cli ni cal 
P h ar m ac o ki n eti c St u di es of P h ar m ace uti cal s.1 0” 
 


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8.  
E F FI C A C Y E N D P OI N T S  
8. 1  
P ri m a r y E n d p oi nt  
8. 1. 1  
E x p ress i o n of D yst r o p hi n P r otei n i n M us cl e Tiss u e 
D ystr o p hi n pr ot ei n will b e m eas ur e d b y i m m u n ost ai ni n g, usi n g fr o ze n sli ces of m us cl e 
tiss u e.    T h e e x pr essi o n of d ystr o p hi n prot ei n will als o b e m eas ure d b y t h e W est er n 
bl ot m et h o d usi n g pr ot ei n e xtr act e d fr o m t h e m us cl e tiss u e.  
 
8. 2  
S ec o n d a r y E n d p oi nt  
8. 2. 1  
P r o d u cti o n of E x o n 4 5- S ki p p e d D ystr o p hi n m R N A i n M us cl e Tiss u e 
U si n g t h e t ot al R N A e xtr act e d fr o m m us cl e tiss u e, w h et h er  d ystr o p hi n m R N A i n d u ce d 
b y e x o n 4 5 s ki p pi n g is pr o d u ce d will b e m eas ure d wit h R T -P C R.  
 
< R ati o n al e  a n d A p pr o pri at e n ess of E n d p oi nt > 
D M D is a s eri o us dis eas e t h at o cc urs as a res ult of l oss of d ystr o p hi n pr ot ei n d u e t o 
m ut ati o n of t h e d ystr o p hi n g e n e .   Bec k er m us c ular d ystr o p h y ( B M D),  li k e D M D,  
o cc urs d u e  t o m ut ati o n of t h e d ystr o p hi n g e n e, b ut a s h ort er dystr o p hi n pr ot ei n t h o u g ht 
li k el y t o h a v e p arti al f u n cti o n is e x press e d, an d t h us it is a dis eas e t y p e wit h mil d er 
s y mpt o ms a n d pr o gr essi o n .   D S-5 1 4 1 b is e x p ecte d t o bi n d t o t h e t ar g et s e q u e n ce of 
t h e pr e -m R N A  of t h e d ystr o p hi n g e n e, pr o d u c e e x o n 4 5 -s ki p p e d m R N A, ca usi n g t h e 
pr o d u cti o n of s h ort er, b ut f u n cti o n al d ystr o p hi n pr ot ei n li k e B M D, a n d t h us d el a y  t h e 
pr o gr essi o n of D M D.   T h us, ex pr essi o n of d ystr o p hi n pr ot ei n i n m us cl e tiss u e is 
li k ely t o l ea d t o d el a y th e pr o gr essi o n of D M D.   At t h e s a m e ti m e , d et e cti o n of e x o n 
4 5- s ki p p e d m R N A  is li k el y t o b e a us ef ul i n d e x s h o wi n g t h at t his dr u g is e x erti n g a n 
acti o n.  
 


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9.  
S A F E T Y E N D P OI N T S  
T h e s af et y e n d p oi nts will b e a d v ers e e v e nts, l a b orat or y d at a, b o d y w ei g ht, vit al si g ns, 
1 2- l ea d el ectr o car di o gr a m, a n d 
 
 
9. 1  
D efi niti o n of A d v ers e E v e nt  
A n a d v ers e e v e nt is a n y u nt o w ar d or u ni nt e n d e d si g n (i n cl u di n g a b n or m al c h a n g es i n 
la b or at or y d at a a n d a b n or m al c h a n g es i n vit al si g ns), sy m pt o m or dis eas e t h at o cc urs 
i n a s u bj ect, w h et h er or n ot t h e y h a v e a rel ati o ns hi p wit h t h e st u d y dr u g. 
S y m pt o ms or dis eas es t h at o cc ur b ef ore a d mi nistrati o n of t h e s t u d y dr u g will b e 
c o nsi d er e d c o m pli cati o ns, a n d will n ot b e h a n dl e d as ad v ers e e v e nts .   Ho w e v er, if a 
c o m pli cati o n w ors e ns d uri n g a d mi nistrati o n of t h e st u d y dr u g, it will b e h a n dle d as a n 
a d v ers e e v e nt , a n d t h e d at e w h e n w ors e ni n g w as o bs er v e d will b e c o nsi d ere d t h e d at e 
of o ns et of t h e a d v ers e  e v e nt. 
 
9. 2  
D efi niti o n of S eri o us A d v ers e E v e nt  
A s eri o us a d v ers e e v e nt is a n a d v ers e e v e nt t h at meets t h e f oll o wi n g crit eri a. 
• 
R es ults i n d eat h  
• 
Is lif e-t hr eat e ni n g 
• 
R e q uir es a d missi o n t o a h os pit al or cli ni c  or pr ol o n g ati o n of t h e d urati o n of t h e 
e xisti n g h os p it ali zati o n 
• 
R es ults i n dis a bilit y  
• 
Is ass o ci at e d wit h a ris k of dis a bilit y 
• 
Is m e di call y si g nifi ca nt i n a w a y si mil ar t o t h e a b o v e 
• 
Is a c o n g e nit al a n o m al y or birt h d efect  
 
9. 3  
H a n dli n g of A b n o r m al C h a n g es i n L a b o r at o r y D at a  
L a b or at or y t est fi n di n gs a n d t est r es u lts t h at m eet t h e f oll o wi n g crit eri a (in cl u di n g 
b l o o d t ests, uri n al ysis, v ital si g ns, a n d ot h er t est res ults) will b e h a n dl e d as a d v ers e 
e v ents . 
• 
S us p e nsi o n (or p o st p o n e me nt of a d mi nistrati o n ), or dis c o nti n u ati o n of t h e st u d y 
dr u g is n ecess ar y  
• 
N e w m e di cal o r s ur gi cal i nt er v e nti o n is n ecess ar y 
• 
T h e i n v esti g at or or s u bi n v esti g at or d et er mi n es t h at t h e fi n di n g is cli ni call y 
si g nifi ca nt f or a n y ot h er r eas o n 
 
C CI


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9. 4  
A d v ers e E v e nt  C oll ecti o n P eri o d  
T h e a d v ers e e v e nt c oll ecti o n p eri o d will b e as f oll o ws . 
• 
F r o m t h e first d os e of t h e st u d y dr u g at eac h d os e l e v el i n P art 1 to t h e e n d of t h e 
f oll o w-u p p eri o d  
• 
Fr o m t h e first d os e of t h e st u d y dr u g i n P art 2 t o t h e e nd of t h e f oll o w -u p p er i o d 
• 
Fr o m t h e first d os e of t h e st u d y dr u g i n P art 2 -E xte nsi o n t o t h e e n d of t h e 
f oll o w-u p p eri o d i n P art 2 - E xt e nsi o n-2 ( f or s u bj ects p arti ci p ati n g i n t h e st u d y fr o m 
Part 2 -E xt e nsi o n - 2, fr o m t h e first d os e of t h e st u d y dr u g i n P art 2 - Ext e nsi o n - 2 t o 
t h e e n d of t h e f oll o w -u p p eri o d i n P art 2 - E xt e nsi o n-2.   F or s u bj ects p arti ci p ati n g 
i n t h e l o n g-t er m e xt e nsi o n st u d y, u ntil t h e first d os e of t h e st u d y dr u g i n t h e 
l o n g-t er m e xt e nsi o n  st u d y.) 
 
A ll a d v ers e e v e nts t h at o cc ur d uri n g t his p eri o d will b e rec or d e d o n t h e cas e re p ort 
f or m.   E v e n o utsi d e t h e c oll ecti o n p eri o d , a d v ers e e v e nts t h at t h e i n v esti g at or or 
s u bi n v esti g at or d et er mi n es h a v e a r el ati o ns hi p wit h t h e st u d y dr u g will b e re p ort e d t o 
t h e s p o ns or i n t h e s a m e w a y as d uri n g t h e c oll ecti o n p eri o d. 
 
9. 5  
It e ms t o I nv esti g at e f o r A d v ers e E v e nts  
If a n a d v ers e e v e n o cc urs d uri n g t h e st u d y, t h e it e ms s h o w n i n T a bl e 9. 5 - 1 will b e 
i n v esti g at e d a n d r ec or d e d o n t h e cas e re p ort f or m  or a n ot h er d o c u m e nt . 
 


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T a bl e 9. 5- 1 It e ms t o I n v esti g at e W h e n a n A d v ers e E v e nt O cc urs 
Ite m t o i n vesti gate  
D etails of i n v esti g ati o n  
D etails of a d verse 
e ve nt  
A d vers e e v e nt ter m , date of o ns et  
Acti o n ta k e n f or 
ad v ers e e ve nt  
Details of s t u d y dru g a cti o n ta ke n, detai ls of ot h er a cti o n ta k e n 
O utc o me  
O utc o me classificati o n , da y of o utc o me assess me nt , st o p date 
 
O utc o me 
classific ati o n  
Rec o vere d/r es ol v e d  
T he ad verse e v e nt disa p pe ars a n d t h e s u bject ret ur ns t o 
t h e c o n diti o n b ef ore t he a d v erse e ve nt o cc urr e d  
Rec o veri n g /r es ol vi n g T he a d verse e v e nt a l m ost disa p pe ars, a n d t h e s u bje ct 
ret ur ns t o a c o n diti o n cl ose t o t h at b ef ore t h e a d v ers e 
e ve nt occ urr e d  
N ot r ec o v er e d/ n ot 
res ol ve d 
T he a d verse e v e nt d o es n ot disa p p ear , a n d t h e s u bje ct 
re mai ns i n a c on diti o n si milar t o w he n t h e a d vers e 
e ve nt occ urr e d  ( un c h a n g e d ) 
Rec o vere d/r es ol v e d 
wit h s e q u ela e  
T he a d verse e v e nt  h as disa p pear e d , b ut t h e s u bje ct has 
se q uelae 
D eat h  
T h is i n dicates t hat t h e i n vesti g at or etc. co nsi d ers t h at 
t h e a d vers e e v e nt has a r el ati o ns hi p wit h t h e de a t h, or 
t h at a relati o ns hi p ca n n ot b e r ule d o ut, a n d i n cases of 
deat h d ue t o c a uses s u c h as w o rse ni n g of t he 
u n d erl yi n g dise as e, t his classific ati o n d o es n ot a p pl y  
U n k n o w n  
T here is n o i nf or mati o n , a n d t he o utc o me is u n k n o w n  
S e v eri t y 
M il d 
A t olera ble le v el, wit h n o i m pair me nt t o acti vities of 
dail y lif e  
M o d er ate  
A le v el wit h s o me i m p air me nt of  acti vities of d ail y life  
S e v er e  
A  le v el at w hic h acti vities of dail y life are i m p ossi ble  
S eri o us n ess  
S eri o us/ n o nseri o us  
Ca usalit y  
C a usa lit y classificati o n (as p er t h e f oll o wi n g ca us alit y classificati o n), reas o n 
f or j u d g me nt 
 
C a usalit y 
classific ati o n  
R elate d  
• 
T here is a r eas o na ble te m p oral r elati o ns h i p 
bet we e n t he o cc urre nc e of t he a d vers e e v e nt a n d 
t h e a d mi nistr ati o n of t he st u d y dr u g, it is n ot 
a p pr o priate t o  deter mi ne t hat t he a d verse e ve nt is 
d ue t h e s u bject’s c o n diti o n o r fa ct ors ot her t ha n 
t h e st ud y dr u g ( s uc h as t h e u n derl yi n g dis eas e, 
c o m plic ati o ns or c o n c o mita nt  me dicati o ns) , a n d 
a n ass ociati o n wit h t h e st u d y dr u g ca n n ot b e r ule d 
o ut  
• 
T here is a r eas o na ble te m p oral r elati o ns hi p 
bet we e n t he o cc urre nc e of t he a d vers e e v e nt a n d 
t h e a d mi nistr ati o n of t he st u d y dr u g, a n d t h e 
a d v ers e e ve nt ca n b e e x p lai n e d as a k n o w n 
re acti o n t o t h e st u d y dr u g or s i milar c o m p o u n ds, 
or bas e d o n its p har mac o l o gic al acti o n 
  
U nre late d 
• 
T here is n o re as o n a ble te m p or al relati o ns hi p 
bet we e n t he o cc urre nc e of t he a d vers e e v e nt  a n d 
a d mi nistr ati o n of t he st u d y dr u g, or it is 


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Ite m t o i n vesti gate  
D etails of i n v esti g ati o n  
ap pr o priate t o deter mi ne t hat t he o cc urre nc e of t h e 
a d v ers e e ve nt i s d u e t o t h e s u bje ct’s c on diti o n or 
fa ct ors ot h er t ha n t h e st u d y dr u g (s u c h as t he 
u n d erl yi n g dise as e, c o m plic ati o ns or c o n c o mita nt  
me dicati o ns), a n d a n ass ociati o n wit h t he st u d y 
dr u g ca n b e r ule d o ut  
 
9. 6  
D efi niti o n of A d v ers e D r u g R e a cti o n  
A d v ers e e v e nt s f or w hi c h t h e r el ati o ns hi p wit h t h e st u d y dr u g is d et er mi n e d t o b e 
“r el at e d ” will b e h a n dl e d as a d v ers e dr u g reacti o ns . 
 
9. 7  
A cti o n If a n A d v ers e E v e nt O cc u rs  
9. 7. 1  
R ec o m m e n d e d A cti o n f o r A d v ers e E v e nt s 
If a n a d v ers e e v e nt o cc urs, th e i n v esti g at or or s u bi n v esti g at or w ill t a k e t h e n ecess ar y 
a cti o n, will r e p ort it t o t h e s p o ns or if n ecess ar y, a n d, as far as p ossi bl e, w ill o bs er v e t h e 
c o urs e of t h e a d v ers e e v e nt u ntil t h e s u bj ect rec o v ers a n d t h e a d v ers e ev e nt dis a p p ears 
or  is r eli e v e d (e v e n aft er t h e e n d of t h e s p ecifi e d o bs er v ati o n p eri o d ).   Ho w e v er , e v e n 
i n a sit uati o n w h er e t h e a d v ers e e v e nt d o es n ot dis a p p ear a n d is n ot reli e v e d , if it ca n 
b e d et er mi n e d t h at t h e s u bj ect’s c o n diti o n is st a bl e a n d his s afet y is e ns ure d, t h e 
i n v esti g at or or s u bi n v esti g at or will e n d o bs er v ati o n i n t h e st u d y, after pr o vi di n g a n 
e x pl a n ati o n t o t h e s u bj ect a n d his l e g all y acce pt a bl e re pres e nt ati v e (h o w e v er, treat m e nt 
of t h e r el e v a nt s y m pt o ms will c o nti n u e ). 
In n o n cli ni cal t o xi cit y st u di es, 
 
 
 w ere o bs er v e d 
i n t h e t o xi c r a n g e i n a n i nt er mitt e nt s u b c ut a n e o us ad mi nistrati o n t o xi cit y st u d y i n mi ce .   
T h er ef or e , 
 
 will b e k e pt i n mi n d.   I n rel ati o n t o  
 
 
will b e ca uti o u sl y o bs er v e d.   I n p arti c ul ar, if s y m pt o ms s u c h as 
 
o bs er v e d , i n a d diti o n t o tr eat m e nt of s y m pt o ms, dia g n osti c t ests will b e c o nsi d ere d.   
Si n ce D S - 5 1 4 1 b is a d mi nist er e d s u b c ut a n e o usl y, reacti o ns t o t h e l o cati o n of 
a d mi nistr ati o n will b e k e pt i n mi n d .   Als o, i n si n g l e-d os e st u di es a n d i nt er mitt e nt 
a d mi nistr ati o n st u di es i n mi ce, 
 
 
, 
C CI
C CI
C CI
C CI
C CI


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 w ere o bs er v e d .   In a n i nt er m itt e nt 
a d mi nistr ati o n st u d y i n mi ce, 
 w as als o o bs er v e d.   Bas e d o n t h es e 
fi n di n gs, w e n e wl y s el ecte d 
 as a n i m p ort ant p ot e nti al ris k 
a n d 
 as a n ot h er p ot e nti al ris k.   
 
 
  
 
 
 
 
  
 
 
If it is d et er mi n e d t h at d et aile d r e p orti n g of a n a d v ers e e v e nt i s n ecess ar y, i nf or m ati o n 
i n cl u di n g t h e o bs er v e d si g ns a n d sy m pt o ms , t h e c o nt e nts an d res ults of t ests , t h e 
tr eat m e nt gi v e n, an d t h e  te m p or al c o urs e of t h es e will b e rec or d e d o n t h e cas e re p ort 
f or m.   D et ails of t h e a b o v e a d v ers e e v e nts of 
 
 will b e rec or d e d o n t h e cas e re p ort f or m.  
 
9. 7. 2  
A cti o n If a S eri o us A d v ers e E v e nt O cc u rs  
If a s eri o us a d v ers e e v e nt o cc urs, th e i n v esti g at or or s u bi n v esti g at or will pr o vi d e 
a p pr o pri at e tr eat m e nt, a n d  als o pr o m ptl y re p ort i nf or m ati o n a b o ut t h e a d v ers e e v e nt t o 
t h e s p o ns or, f or e x a m pl e b y t el e p h o n e or fa x.    T h e i n v esti g at or will als o re p ort th e 
d et ails in writi n g t o t h e s p o ns or a n d t h e direct or of t h e st u d y sit e.   T h e writt e n re p or t 
t o t h e dir ect or of th e st u d y sit e will b e m a d e acc or di n g t o t h e pr o ce d ures a n d f or m at  of 
t h e r el e v a nt m e di cal i nst it uti o n. 
C CI
C CI
C CI
C CI
C CI
C CI


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1 0.  O t h er E n d p oi nts 
1)  M ot or f u n cti o n ass ess m e n t it e ms (lo w er li m bs a n d u p p er li m bs) 
M ot or f u n cti o n ass ess m e nt will b e p erf or m e d b ef ore t h e first d os e of t h e st u d y dr u g  i n 
Part 1, b ef or e t h e first d os e of t h e st u d y dr u g a n d aft er t h e l ast d os e of t h e st u d y dr u g 
( D a y 8 5 t o D a y 9 9, or at wit h dr a w al) i n Part 2 , b ef ore t h e first d os e of t h e st u d y dr u g, 
aft er t h e 1 2t h d os e ( Wee k  1 2 / D a y  8 4 t o Wee k 1 3/  D a y  8 5 pri or t o st u d y dr u g 
a d mi nistr ati o n), aft er t h e 2 4t h d os e ( Wee k  2 4/ D a y  1 6 8 t o Wee k  2 5/ D a y  1 6 9 pri or t o  
st u d y dr u g a d mi nistr ati o n), aft er t h e 3 6t h d os e ( Wee k 3 6 / D a y  2 5 2 t o 
Wee k  3 7/ D a y  2 5 3 pri or t o st u d y dr u g a d mi nistrati o n), a n d aft er t h e l ast d os e of t h e 
st u d y dr u g ( Wee k 4 9/ D a y  3 3 7 t o Wee k  5 1/ D a y  3 5 1, or at wit h dra w al)  i n Part 
2- E xt e nsi o n , an d b ef or e t h e first d os e of t h e st u d y dr u g, aft er t h e 1 2t h d os e 
( Wee k 1 2/ D a y  8 4 t o Wee k  1 3/ D a y  8 5 pri or t o st u d y dr u g a d mi nistrati o n), aft er t h e 
2 4t h d os e ( Wee k  2 4/ D a y  1 6 8 t o Wee k  2 5/ D a y  1 6 9 pri or t o st u d y dr u g a d mi nistrati o n), 
aft er t h e 3 6t h d os e ( Wee k  3 6 / D a y  25 2 t o Wee k  3 7/ D a y  2 5 3 pri or t o st u d y dr u g 
a d mi nistr ati o n), a n d aft er t h e l ast d os e of t h e st u d y dr u g ( Wee k 4 9/ D a y  3 3 7 t o 
Wee k  5 1/ D a y 3 5 1,  or at wit h dr a w al)  i n P art 2 -E xte nsi o n - 2.   Ass ess m e nt will b e 
p erf or m e d t wi ce at eac h pl a n n e d ti m e p oi nt b ef ore t h e first d os e of t h e st u d y dr u g a n d 
aft er t h e l ast d os e of t h e st u d y dr u g i n P art 1, P art 2, P art 2-E xt e nsi o n, a n d P art 
2- E xt e nsi o n- 2 , a n d r ec o r d e d o n t h e cas e re p ort f or m.   T h e m a xi m u m v al u es will b e 
us e d as d at a .   At ot h er pl a n n e d ti m e p oi nts, ass ess m e nt will b e p erf or m e d o n ce, a n d 
will b e r ec or d e d o n t h e  cas e r e p ort f or m.   T h e m eas ure m e nt pr o ce d ure f or eac h it e m 
will b e s p ecifi e d i n a s e p ar at e  pr o ce d ure .   N ot e t h at  m eas ure m e nt of m ot or f u n cti o n 
ass ess m e nt it e ms ( u p p er li m bs ) will b e st art e d w h e n p ossi bl e, at a ti mi n g t h at s uits t h e 
s u bj ect’s s c h e d ul e. 
• 
6- m i n ut e w al k t est 
T h e dist a n ce a s u bj ect is a bl e t o w al k i n 6 m i n ut es, w al ki n g as fast as p ossi bl e, 
will b e m eas ur e d. 
• 
Ti m e d Fl o or t o St a n d  
T h e ti m e a s u bj ect t a k es w h e n g etti n g o ut of fl o or a n d st a n di n g u p as q ui c kl y as 
p ossi bl e will b e m eas ur e d . 
• 
Ti m e d u p a n d g o t est 
T h e ti m e a s u bj ect t a k es t o st a n d u p fr o m sitti n g o n a pl atf or m (a st o ol), w al k as 
q ui c kl y as p ossi bl e t o a c o n e 3 m  a h ea d a n d sit b ac k d o w n o n t h e s a m e pl atf or m 
will b e m eas ur e d . 


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• 
Ti m e t o r u n/ w al k 1 0 m    
T h e ti m e a s u bj ect t a k es t o r u n or w al k 1 0 m as q ui c kl y as p ossi bl e will b e 
meas ur e d . 
• 
N ort h St ar A m b ul at or y Ass ess m e nt  
M ot or f u n cti o ns  di vi d e d i nt o 1 7 it e ms, i n cl u di n g st a n di n g p ositi o n a n d w al ki n g, 
will b e ass ess e d .   A s c or e fr o m 0 p oi nts t o 2 p oi nt s will b e assi g n e d f or eac h 
it e m d e p e n di n g o n t h e s u bj ect’s f u n cti o n l e v el, a n d t h e t ot al p oi nt s c ore will b e 
us e d f or ass ess m e nt . 
• 
P erf or m a n ce of U p p er L i m b 
U p p er  li m b f u n cti o ns di vi d e d i nt o 2 2 it e ms, c o v eri n g t h e re gi o ns of t h e 
s h o ul d ers, el b o ws a n d h a n ds, will b e ass ess e d.   A 3 -st a g e s c ore of 0, 1 or 2 will 
b e assi g n e d f or eac h it e m, a n d t h e t ot al p oi nt s c ore will b e us e d f or ass ess m e nt . 
2)  Res pir at or y f u n cti o n ass e ss m e nt it e ms 
Res pir at or y f u n cti o n ass ess m e nt  will b e p erf or m e d f or s u bj ects a bl e t o u n d erst a n d  t h e 
i nstr u cti o ns i n t h e r es pir at or y f u n cti o n t est b ef ore t h e first d os e of t h e st u d y dr u g  i n 
Part 1 , b ef or e t h e first d os e of t h e st u d y dr ug a n d aft er t h e l ast d os e of t h e st u d y dr u g 
( D a y 8 5 t o D a y 9 9, or at wit h dr a w al) i n P art 2, b ef ore t h e first d os e of  t h e st u d y dr u g, 
aft er t h e 1 2t h d os e ( Wee k  1 2 / D a y 8 4 t o Wee k  1 3/  D a y  8 5 pri or t o st u d y dr u g 
a d mi nistr ati o n), aft er t h e 2 4t h d os e ( Wee k  2 4/ D a y  1 6 8 t o Wee k  2 5/ D a y 1 6 9 pri or t o 
st u d y dr u g a d mi nistr ati o n), aft er t h e 3 6t h d os e ( Wee k 3 6 / D a y  2 5 2 t o 
Wee k  3 7/ Da y  2 5 3 pri or t o st u d y dr u g a d mi nistrati o n), a n d aft er t h e l ast d os e of t h e 
st u d y dr u g ( Wee k 4 9/ D a y  3 3 7 t o Wee k  5 1/ D a y  3 5 1, or at wit h dra w a l) i n Part 
2- E xt e nsi o n , an d b ef or e t h e first d os e of t h e st u d y dr u g, aft er t h e 1 2t h d os e 
( Wee k 1 2/ D a y  8 4 t o Wee k  1 3 / D a y  8 5 pri or t o st u d y dr u g a d mi nistrati o n), aft er t h e 
2 4t h d os e ( Wee k  2 4/ D a y  1 6 8 t o Wee k  2 5/ D a y  1 6 9 pri or t o st u d y dr u g a d mi nistrati o n),  
aft er t h e 3 6t h d os e ( Wee k  3 6 / D a y  2 5 2 t o Wee k  3 7/ D a y  2 5 3 pri or t o st u d y dr u g 
a d mi nistr ati o n), a n d aft er t h e l ast d os e of t h e st u d y dr u g ( Wee k  4 9/ D a y  3 3 7 t o 
Wee k  5 1/ D a y 3 5 1, or at wit h dr a w al)  i n P art 2 -E xte nsi o n - 2.   A res pirat or y f u n cti o n 
test (spir o m et r y) will b e p erf or m e d , a n d f orce d vital ca p acit y (F V C), f orce d e x pirat or y 
v ol u m e i n 1 s ec o n d (F E V 1), p ea k e x pirat or y  fl o w (P E F), a n d c o u g h p ea k fl o w (C P F)  
will b e m e as ur e d .   T h e meas ur e m e nt pr o ce d ure f or eac h it e m will b e s p ecifi e d i n a 
s e p ar at e pr o ce d ur e. 
3)  Car di ac f u n cti o n ass e ss me nt it e ms 
Car di ac f u n cti o n ass ess me nt will b e p erf or m e d b ef ore t h e first d os e of t h e st u d y dr u g  
i n P art 1, b ef or e t h e first d os e of t h e st u d y dr u g a n d aft er t h e l ast d os e of t h e st u d y 


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dr u g ( D a y 8 5 t o D a y 9 9, or at wit h dr a w al)  i n P art 2, b ef ore t h e first d os e of t h e st u d y 
dr u g, aft er t h e 1 2t h d os e ( Wee k  1 2/ D a y  8 4 t o Wee k  1 3/ D a y  8 5 pri or t o st u d y dr u g 
a d mi nistr ati o n), aft er t h e 2 4t h d os e ( Wee k  2 4/ D a y  1 6 8 t o Wee k  2 5/ D a y  1 6 9 pri or t o 
st u d y dr u g a d mi nistr ati o n), aft er t h e 3 6t h d os e (Wee k  3 6 / D a y  2 5 2 t o 
We e k 3 7/ D a y  2 5 3 pri or t o st u d y dr u g a d mi nistrati o n), a n d aft er t h e l ast d os e of t h e 
st u d y dr u g ( Wee k 4 9/ D a y  3 3 7 t o Wee k  5 1/ D a y  3 5 1, or at wit h dra w al)  i n Part 
2- E xt e nsi o n , an d b ef or e t h e first d os e of t h e st u d y dr u g, aft er t h e 1 2t h d o s e 
( Wee k 1 2/ D a y  8 4 t o  Wee k  1 3/ D a y  8 5 pri or t o st u d y dr u g a d mi nistrati o n), aft er t h e 
2 4t h d os e ( Wee k  2 4/ D a y  1 6 8 t o  Wee k  2 5/ D a y  1 6 9 pri or t o st u d y dr u g a d mi nistrati o n), 
aft er t h e 3 6t h d os e ( Wee k  3 6 / D a y  2 5 2 t o Wee k  3 7/ D a y  2 5 3 pri or t o st u d y dr u g 
a d mi nistr ati o n), a n d aft er t he l ast d os e of t h e st u d y dr u g ( Wee k  4 9/ D a y  3 3 7 t o 
Wee k  5 1/ D a y 3 5 1, or at wit h dr a w al)  i n P art 2-E xte nsi o n - 2.   C ar di ac ultras o n o gra p h y  
(ec h o car di o gr a p h y) will b e p erf or m e d , a n d t h e l eft v e ntri c ul ar e n d -di ast oli c di m e nsi o n , 
left v e ntri c ul ar fr acti o n al s h ort e ni n g , l eft v e ntri c ular ej ecti o n rat e, E/A rati o, a n d 
E- w a v e d ecel er ati o n r at e  will b e m eas ure d .   T h e m eas ure m e nt pr o ce d ure f or eac h 
it e m will b e s p ecifi e d i n a s e p ar at e pr o ce d ure.  
4)  Q u a ntit ati v e m us cl e str e n gt h ass ess m e nt  
Q u a ntit ati v e m us cl e str e n gt h ass ess m e nt will b e p erf or m e d b ef ore t h e first d os e of t h e 
st u d y dr u g i n P art 1, b ef or e t h e first d ose of t h e st u d y dr u g a n d aft er t h e l ast d os e of 
t he st u d y dr u g ( D a y 8 5 t o D a y 9 9, or at wit h dra w al)  i n P art 2, b ef ore t h e first d os e of 
t h e st u d y dr u g, aft er t h e 1 2t h d os e ( Wee k 1 2 / D a y  8 4 t o Wee k  1 3/ D a y  8 5 pri or t o 
st u d y dr u g a d mi nistr ati o n), aft er t h e 2 4t h d os e ( Wee k 2 4/ D a y  1 6 8 t o 
Wee k  2 5/ D a y  1 6 9  pri or t o st u d y dr u g a d mi nistrati o n), aft er t h e 3 6t h d os e 
( Wee k 3 6/ D a y  2 5 2 t o Wee k  3 7/ D a y  2 5 3  pri or t o st u d y dr u g a d mi nistrati o n), a n d aft er 
t h e l ast d os e of t h e st u d y dr u g ( Wee k 4 9/ D a y  3 3 7 t o Wee k  5 1/ D a y  3 5 1, or at 
wit h dr a w al)  i n P art 2-E xte nsi o n , an d b ef ore t h e first d os e of t h e st u d y dr u g, aft er t h e 
1 2t h d os e ( Wee k  1 2 / D a y  8 4 t o Wee k  1 3/ D a y  8 5 pri or t o st u d y dr u g  a d mi nistrati o n), 
aft er t h e 2 4t h d os e ( Wee k  2 4/ D a y  1 6 8 t o Wee k  2 5/ D a y  1 6 9  pri or t o st u d y dr u g 
a d mi nistr ati o n), aft er t h e 3 6t h d os e ( Wee k  3 6/ D a y  2 5 2 t o Wee k  3 7/ D a y  2 5 3 pri or t o 
st u d y dr u g a d mi nistr ati o n), a n d aft er t h e l ast d os e of t h e st u d y dr u g ( Wee k 4 9/ D a y  3 3 7 
t o Wee k 5 1/ D a y  3 5 1, or at wit h dr a w al)  i n P art 2-E xt e nsi o n - 2.   Usi n g a h a n d h el d 
d y n a m o m et er , m us cl e str e n gt h i n hi p j oi nt fl e xi o n a n d e xt e nsi o n, i n k n ee j oi nt fl e xi o n 
a n d e xt e nsi o n, a n d i n a n kl e j oi nt d ors al fl e xi o n a n d pl a nt ar fl e xi o n w ill b e m eas ure d .   
Ass ess m e nt will b e p erf or m e d t wi ce at eac h pl a n n e d ti m e p oi nt b ef ore t h e first d os e  of 
t h e st u d y dr u g a n d aft er t h e l ast d os e of t h e st u d y dr u g i n P art 1, P art 2, a n d P art 


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2- E xt e nsi o n, a n d r ec or d e d o n t h e cas e re p ort f or m.  T h e m a xi m u m v al u es wi ll b e 
us e d as d at a.    At ot h er pl a n n e d ti m e p oi nts, ass ess m e nt will b e p erf or m e d o n ce, a n d 
will  b e r ec or d e d o n t h e cas e r e p ort f or m.    T h e m eas ur e m e nt pr o ce d ure f or eac h it e m 
will b e s p ecifi e d i n a s e p ar at e pr o ce d ure.  
5)  M eas ur e m e nt of a nti- d ystr o p hi n a nti b o d y  
6)  M eas ur e m e nt of a nti- D S -5 1 4 1 b a nti b o d y  
 


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1 1.  S t atisti c al A n al ysis 
T his is a s y n o psis of st atisti cal a n al ysis a n d p h ar mac o ki n eti c a n al ysis.    We will 
se p ar at el y pr e p ar e a St atisti cal A n al ysis Pl a n t o d es cri b e t h e a n al ysis m et h o ds i n m ore 
d et a il. 
 
1 1. 1  O bj ecti v e of A n al ysis 
T h e o bj ecti v e of t his st u d y is t o e x pl orat ori l y ass ess t h e s afet y, t ol era bilit y, effi cac y, 
a n d p h ar m ac o ki n eti cs of D S -5 1 4 1 b i n D M D p ati e nt s.   St atisti cal p o w er w as n ot t a k e n 
i nt o acc o u nt w h e n t h e pl a n n e d s a m pl e si ze of t his st u d y w as s el ect e d .   T h u s, t h e 
st atisti cal a n al ysis i n t his st u d y is d es cri pti v e, a n d st atisti cal h y p ot h esis t esti n g will n ot 
b e p erf or m e d.  
 
1 1. 2  A n al ysis S ets 
Bef or e t h e d at a b as e is l o c k e d, th e s p o ns or will d eci d e o n t h e h a n dli n g of eac h s u bj ect, 
h ol di n g dis c ussi o n s wit h t h e m e di cal e x p ert as n ecess ar y.   I n cas es w h ere t h e 
h a n dli n g of s u bj ects is n ot s p ecifi e d i n t h e cli ni cal st u d y pr ot o c ol, t h e s p o ns or will 
m a k e a d ecisi o n, a ft er r ecei vi n g a d vi ce fr o m t h e me di cal e x p ert. 
 
1 1. 2. 1  E ffi c a c y A n al ysis P o p ul ati o n 
T h e effi cac y a n al ysis p o p ul ati o n wil l b e t h e p o p ulati o n of s u bj ects re gist ere d i n t h e 
st u d y, ex cl u di n g t h e f oll o wi n g s u bj ects.  
1)  S u b j ects w h o d o n ot m eet t h e in cl usi o n crit eri a  
2)  S u bj ects w h o di d n ot r ecei v e at l east 1 d os e of t h e s t u d y dr u g 
3)  S u bj ects wit h o ut a n y effi cac y d a t a aft er st u d y dr u g a dmi nistrati o n  
 
1 1. 2. 2  P h a r m a c o ki n eti c A n al ysis P o p ul ati o n  
T h e p h ar m ac o ki n eti c a n al ysis p o p ul ati o n will  b e t h e p o p ul ati o n of s u bj ects re gist ere d 
i n t h e st u d y 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 an d w h o m eet t h e 
f oll o wi n g crit eri a. 
1)  S u bj ects w h o h a v e  r ecei v e d t h e st u d y dr u g at l east o n ce  
2)  S u bj ects wit h n o m aj or pr ot o c ol d e vi ati o ns  
3)  S u bj ects w h os e pl as m a dr u g c o n ce ntrati o n  d at a is av ail a bl e  
 
1 1. 2. 3  S af et y A n al ysis P o p ul ati o n  
T h e s af et y a n al ysis p o p ulati o n will b e t h e p o p ul ati o n of s u bj e cts regist ere d i n t his 


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st u d y, e x cl u di n g “s u bj ects w h o w er e n ot a d mi nist ere d t h e st u d y dr u g at l ea st o n ce. ” 
 
1 1. 3  D at a H a n dli n g  
T h e s p o ns or will d eci d e o n t h e h a n dli n g of all d at a, aft er dis c ussi o n wit h t h e m e di cal 
e x p ert as n ecess ar y, a n d b as e d o n t h e d at a h a n d li ng s t a n d ar d t o b e pre p are d s e p arat el y, 
b ef or e l o c ki n g t h e d at a.  
 
1 1. 3. 1  H a n dli n g of Ti mi n g of I n v esti g ati o ns a n d Me as u re m e nts  
T h e ti mi n g of i n v esti g ati o ns a n d m eas ure m e nts wil l b e h a n dl e d acc or di n g t o “6  
S T U D Y P R O C E D U R E S . ”  D at a n ot h a n dl e d acc or di n g t o t h e d at a h a n dli n g s t a n d ar ds 
will b e e x cl u d e d fr o m a n al ysis .   If n o d at a m eet t h e d at a h a n dlin g st a n d ar ds, t h e 
r el e v a nt v al u es will b e h a n dl e d as missi n g d at a. 
 
1 1. 3. 2  H a n dli n g of Missi n g D at a  
M issi n g d at a will n ot b e i m p ut e d. 
 
1 1. 4  S t atisti c al A n al ysis It e ms a n d M et h o ds of A n al ysis  
1 1. 4. 1  B as e li n e Su bj ect C h a r a ct eristi cs  
F or b as eli n e s u bj ect c h ar act eristi cs  (d e m o gr a p hi c v ari a bl es a n d b as eli n e v al u es ), 
fr e q u e n c y t a bl es will b e pr e p ar e d f or cat e g ori cal dat a , a n d su m m ar y st atisti cs will b e 
cal c ul at e d f or q u a ntit ati v e d at a . 
 
1 1. 4. 2  E ffi c a c y A n al ysis 
E ffi cac y a n al ysis will b e p erf or m e d i n t h e effi cac y a n al ysis s et.  
 
1 1. 4. 2. 1  
P ri m a r y E n d p oi nt  
• 
E x pr essi o n of t h e d ystr o p hi n pr ot ei n i n t h e m us cl e tiss u e  
T h e d ystr o p hi n pr ot ei n l e v els r el ati v e t o t h e n or mal m us cl e, cal c ul at e d b y eac h 
ass ess m e nt m et h o d (i m m u n o hist o c h e mistr y [I H C] a n d w est er n bl ot [ W B]) b ef ore t h e 
first d os e of t h e st u d y dr u g, aft er t h e l ast d os e of t h e st u d y dr u g i n P art 2, a n d aft er t h e 
last d os e of t h e st u d y dr u g i n P art 2 - E xt e nsi o n- 2, a n d t h eir c h a n g es will b e list e d b y 
s u bj ect, a n d t h eir ti m e c o urs e will b e pl ott e d. 
 
1 1. 4. 2. 2  
S ec o n d a r y E n d p oi nt  
• 
P r o d u cti o n of e x o n 4 5 -s ki p p e d d ystr o p hi n m R N A  i n t h e m us cl e tiss u e 


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A list b y s u bj ect of w h et h er e x o n 4 5-s ki p p e d d ystr o p hi n m R N A w as pres e nt b ef ore t h e 
first d os e of t h e st u d y dr u g, aft er t h e l ast d os e of t h e st u d y dr u g i n P art 2, a n d aft er t h e 
last d os e of t h e st u d y dr u g i n P art 2- E xt e nsi o n-2 will b e pre p are d . 
 
1 1. 4. 3  P h a r m a c o ki n eti c A n al ysi s 
S u m m ar y st atisti cs will b e cal c ul at e d  b y treat m e nt  gr o u p  f or pl as m a c o n ce ntrati o n a n d 
p h ar m ac o ki n eti c p ar a m eters .   T h e ti m e c o urs e of pl as m a c o n ce ntrati o n will als o b e 
pl ott e d .   Ad diti o n all y, t h e r el ati o ns hi p b et w ee n d os es a n d p h ar m ac o ki n eti c 
p ar a m et ers will b e i n v esti g at e d . 
To e x pl or at ori l y ass ess t h e r e l ati o ns hi p b et w ee n t h e p h ar m ac o ki n eti cs of D S - 5 1 4 1 b 
a n d r es p o ns e, m o d eli n g a n d si m ul ati o n will b e c o n d u ct e d usi n g t his st u d y d at a or 
p o ol e d d at a i n cl u di n g ot h er st u di es t o  b e c o n d u ct e d i n t h e f ut ure .   Th es e a n al ys es will 
i n cl u d e a p o p ul ati o n p h ar m ac o ki n eti c a n al ysis of D S - 5 1 4 1 b a n d a n e x p os ure -res p o ns e 
a n al ysis f or bi o m ar k ers, Q Tc i nt er v al, effi cac y i n di cat ors or s a fet y i nd i cat ors.   W h e n  
m o d eli n g a n d si m ul ati o n ar e c o n d u ct e d, th e res ult will b e re p ort e d s e p arat el y . 
 
1 1. 4. 4  S af et y  A n al ysis  
T his will b e c o n d u ct e d i n  t h e s af et y a n al ysis s et.   T h e M e di cal Di cti o n ar y f or 
Re g ul at or y A cti viti es ( M e d D R A) will b e us e d f o r c o di ng a d v ers e e v e nt s, or g a n 
cl assifi cati o n will b e p erf or m e d b y M e d D R A s yst e m or g a n cl ass  (S O C), a n d a d v ers e 
e v e nt t erms will b e t a b ul at e d b y pr ef erre d t er m  ( P T). 
 
1 1. 4. 4. 1  
A d v ers e E v e nt  
T h e i n ci d e n ce of a d v ers e e v e nt s will b e cal c ul at e d.   T h e fre q u e n ci es of a d v ers e 
e v e nts will als o b e t a b ul at e d b y e v e nt a n d b y s e v erit y .   Ad v ers e dr u g reacti o ns will b e 
a n al y ze d i n t h e s a m e w a y.   In t a b ul ati o n b y S O C ( or P T), if m ulti pl e a d v ers e e v e nts 
wit h t h e s a m e S O C ( or P T) o cc ur i n t h e s a m e s u bject, th e y will b e c o u nt e d as a si n gl e 
e v e nt.   S O Cs will b e dis pl a y e d i n t h e i nt er n ati o n all y a gree d or d er, a n d P T  will b e 
dis pl a y e d i n t h e or d er of c o di n g.  
 
1 1. 4. 4. 2  
L a b o r at o r y D at a  
S u m m ar y st atist i cs will b e cal c ul at e d f or h e m at ol o g y t ests, bl o o d c h e mistr y t ests a n d 
uri n al ysis ( qu a ntit ati v e v al u es ).   T h e c h a n g es (ti me c o urs e) i n eac h s u bj ect b ef ore a n d 
aft er a d mi nistr ati o n will als o b e pl ott e d .   For uri n al ysis ( q u alit ati v e v al u es) , t h e 
fr e q u e n c y of m eas ur e m e nt i n di cat ors at eac h o bs er v ati o n p oi nt will b e t a b ul at e d , a n d 


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s hift t a bl es f or eac h s u bj ect will  b e pr o d u ce d . 
 
1 1. 4. 4. 3  
Hei g ht , Bo d y W ei g ht  a n d V it al Si g ns 
S u m m ar y st atisti cs will b e cal c ul at e d, a n d t h e c h a n g es (ti m e c o urs e) i n eac h s u bj ect 
b ef or e a n d af t er a d mi nistr ati o n will b e pl ott e d. 
 
1 1. 4. 4. 4  
1 2- L e a d E l ect r o c a r di o g r a m 
A fr e q u e n c y t a bl e f or eac h o bs er v ati on p oi nt  will b e pre p ar e d f or t h e p h ysici a n’s 
j u d g m e nt o n t h e st a n d ar d 1 2 -l ea d el ectr o car di o gra m. 
S u m m ar y st atisti cs f or P R i nt er v al, Q R S i nt er v al, Q T i nt er val , R R i nt er v al, a n d Q Tc 
will b e cal c ul at e d f or eac h o bs er v ati o n p oi nt , a n d ti m e c o urs es will b e pl o tte d.   F or 
Q Tc, t h e Q T  i nt er v al c orr ect e d b y p uls e rat e, s u m mar y st atisti cs will b e calc ul at e d f or 
eac h o bs er v ati o n p oi nt  a n d ti m e c o urs es will b e pl ott e d, usi n g t h e f oll o wi n g 2 m et h o ds 
of c orr ecti o n . 
– B azett ’s c orr ecti o n f or m ul a: Q Tc B = Q T/ ( R R)1/ 2 
– Fri d eri ci a ’s c orr ecti o n for m ul a : Q Tc F = Q T/ ( R R)1/ 3  
C o n ce ntr ati o n -Q T  a n al ysis will als o b e p erf or m e d, t o e x pl orat ori l y i n v esti g at e t h e 
r el ati o ns hi p b et w ee n t h e c h a n g e i n Q Tc F fr o m b as eli n e (∆Q Tc F) a n d t h e bl o o d 
c o n ce ntr ati o n of D S -5 1 4 1 b.  
 
1 1. 4. 4. 5  
 
 
 
 
1 1. 4. 5  A n al ysis Met h o ds f o r Ot h er It e ms  
1 1. 4. 5. 1  
M ot o r F u n cti o n A ss ess me nt Ite ms ( Lo w er Li m bs a n d U p p er Li m bs ) 
F or t h e f oll o wi n g e n d p oi nts , s u m m ar y st atisti cs will b e cal c ul at e d f or t h e meas ure m e nt 
at eac h ti m e p oi nt  a n d t h e c h a n g e fr o m b ef ore t h e first d os e of t h e st u d y dr u g.    A 
listi n g b y s u bj ect an d ti me c o urs e pl ot will als o be pre p are d .   F or t h e 6- mi n ut e w al k 
test, th e r ati os of m eas ur e d v al u es t o e x p ect e d v al u es w ill b e cal c ul at e d a n d a n al y ze d 
i n t h e s a m e w a y as m eas ur e d v al u es. 
• 
6- mi n ut e w al k t est  
• 
Ti m e d Fl o or t o St a n d  
• 
Ti m e d u p a n d g o t est 
• 
Ti m e t o r u n/ w al k 1 0 m  
C CI


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• 
N ort h St ar A m b u l at or y Ass ess m e nt 
• 
Perf or m a n ce of U p p er Li m b  
 
1 1. 4. 5. 2  
R es pi r at o r y F u n cti o n A ss ess m e nt Ite ms 
F or t h e f oll o wi n g e n d p oi nts, s u m m ar y st atisti cs will b e cal c ul at e d f or t h e meas ure m e nt 
at eac h ti m e p oi nt a n d t h e c h a n g e fr o m b ef ore t h e firs t d os e of t h e st u d y dr u g.    A 
listi n g b y s u bj ect a n d ti me c o urs e pl ot will als o b e pre p are d.    F or f orce d vit al ca p acit y, 
f orce d e x pir at or y v ol u m e i n 1 s ec o n d, a n d p ea k e x pirat or y fl o w, t h e rati os of m eas ure d 
v al u es t o e x p ect e d v al u es will b e cal c ul at e d a n d a n al y ze d i n t h e s a m e w a y as m eas ure d 
v al u es.  
• 
F or ce d vit al ca p acit y  (F V C ) 
• 
F or ce d e x pir at or y v ol u m e i n 1 s ec o n d  (F E V 1 ) 
• 
Pea k e x pir at or y fl o w  (P E F ) 
• 
C o u g h p ea k fl o w  ( C P F) 
 
1 1. 4. 5. 3  
C a r di a c F u n cti o n A ss ess me nt Ite ms 
F or t h e f oll o wi n g e n d p oi nts, s u m m ar y st atisti cs will b e cal c ul at e d f or t h e meas ure m e nt 
at eac h ti m e p oi nt a n d t h e c h a n g e fr o m b ef ore t h e first d os e of t h e st u d y dr u g.    A 
listi n g b y s u bj ect a n d ti me c o urs e pl ot will als o b e pre p are d.  
• 
L eft v e ntri c ul ar e n d -di ast oli c di m e nsi o n  
• 
L eft v e ntri c ul ar fr acti o n al s h ort e ni n g  
• 
L eft v e ntri c ul ar ej ecti o n r at e  
• 
E/ A r ati o  
• 
E- w a v e d ecel er ati o n r at e  
 
1 1. 4. 5. 4  
Q u a ntit ati v e M us cl e S t re n gt h A ss ess m e nt 
F or t h e f oll o w i n g e n d p oi nts, s u m m ar y st atisti cs will b e cal c ul at e d f or t h e meas ure m e nt 
at eac h ti m e p oi nt a n d t h e c h a n g e fr o m b ef ore t h e first d os e of t h e st u d y dr u g.    A 
listi n g by s u bj ect a n d ti me c o urs e pl ot will als o b e pre p are d. 
• 
H i p j oi nt fl e xi o n a n d e xt e nsi o n 
• 
K n ee j oi nt fl e xi o n a n d e xt e nsi o n 
• 
A n kl e j oi nt d ors al fl e xi o n a n d pl a nt ar fl e xi o n  
 
1 1. 4. 5. 5  
Me as u re m e nt of A nti - D ystr o p hi n Anti b o d y  
A list b y s u bj ect of w h et h er a nti- d ystr o p hi n a nti b o d y w as pres e nt at eac h ti m e p oi nt 


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will b e pr e p ar e d.  
 
1 1. 4. 5. 6  
Me as u re m e nt of A nti -D S - 5 1 4 1 b Anti b o d y  
A list b y s u bj ect of w h et h er  a nti-D S -5 1 4 1 b a nti b o d y w as pres e nt at eac h ti m e p oi nt 
will b e pr e p ar e d.  
 
1 1. 5  C h a n g es t o t h e A n al ysis Pl a n  
If th er e ar e a n y c h a n g es t o t h e a n al ysis pl a n, f or e x a m pl e d u e t o c h a n g e t o t h e m et h o d 
of h a n dl i n g d at a or c o n v ersi o n of v ari a bl es, th e s p o ns or will c o nsi d er t h e 
a p pr o pri at e n ess of th e c o nt e nts of t h es e c h a n g es a n d th e effect o n ass ess m e nt i n t his 
st u d y, a n d th e n m a k e a d ecisi o n o n w h et h er t h e c h a n g e is p ossi bl e .   T h e s p o ns or will 
cl earl y r ec or d d et ails i n cl u di n g t h e c o nt e nts of t h e dis c ussi o n, w h et h er t h e c h a n g e w as 
ma d e a n d t h e r eas o n f or t his i n writi n g, a n d st ore t h es e d o c u m e nts .   If a c h a n g e is 
ma d e, t he c o nt e nts of t his a n d t h e r eas o n f or it will b e i n cl u d e d i n t h e cli ni cal st u d y 
r e p ort.   C h a n g es t o t h e mai n a n al ysis list e d i n t h e cli ni cal st u d y pr ot o c ol will b e m a d e 
as p er “ 1 5. 7  P r ot o c ol A me n d m e nt. ” 
 
1 1. 6  Int eri m A n al ysis  
Aft er P art 1 h as e n d e d , i nt eri m ass ess m e nt of t h e s afet y a n d p h ar m ac o ki n eti cs i n P art 1 
will b e p erf or m e d, t o d eci d e o n t h e d os es t o us e i n P art 2.  
 
1 1. 7  P l a n n e d S a m pl e Si ze 
Part 1: 3  s u bj ects p er c o h ort, f or a t otal of 6 s u bj ects 
Part 2: 3 s u bj ects eac h i n t h e hi g h -d os e gr o u p a n d t h e l o w-d os e gr o u p , f or a t ot al of 6 
s u bj ects 
Part 2 -E xt e nsi o n: 3 s u bj ects eac h i n t h e hi g h -d os e gr o u p a n d t h e l o w-d os e gr o u p , f or a 
t ot al of 6 s u bj ects 
Part 2 -E xt e nsi o n - 2: 3 s u bj ects e ac h  i n t h e hi g h-d os e gr o u p a n d t h e l o w -d os e gr o u p, f or 
a t ot al of 6 s u bj ects  
 
< R ati o n al e >  
T h e pl a n n e d s a m pl e si ze w as s el ect e d n ot fr o m t h e p ers p ecti v e of st atisti cal p o w er b ut 
fr o m t h e p ers p ecti v e of f easi bilit y. 
Beca us e D M D  is a r ar e dis eas e, a n d t h ere are s e v eral t y p es of d efects i n t h e ca us ati v e 
g e n e, t h e n u m b er of p ati e nts w h o ca n b e t ar g et e d b y a t h era p e uti c dr u g t h at s ki ps a 


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s p ecifi c e x o n is li mit e d.   A cc or di n g t o a p ati e nt re gistrati o n sit e f or n e ur o m us c ul ar 
dis eas e p ati e nts  ( R e m u d y), t h e n u m b er of D M D  p ati e nts re gist ere d as of t h e e n d of J u n 
2 0 1 5 w as 1 0 3 7, a n d of t h es e, it is esti m at e d t h at  t h e n u m b er of p ati e nts treat a bl e wit h 
t h e e x o n 4 5 s ki p pi n g tr eat m e nt of t his st u d y is a p pr o xi m at el y 9 % 1 1 , 1 2 (ap pr o xi m at el y 
9 3 p ati e nts ) of all D M D p ati e nts, a n d si n ce it is p ossi bl e t o ass ess effi cac y a n d s afet y 
a p pr o pri at el y i n o nl y s o me of t h es e t ar g et p ati e nts, o ut of c o nsi d erati o n f or feasi bilit y , 
w e s el ect e d 6 s u bj ects as t h e n u m b er of ass ess a bl e s u bj ects f or t h e pri m ar y e n d p oi nt of 
t his st u d y. 


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1 2.  Q u alit y C o nt r ol a n d Q u alit y Ass u r a n ce  
T h e s p o ns or will ass ur e t h at t h e c o n d u ct of t h e st u d y a n d t h e pre p arati o n, rec or di n g 
a n d r e p orti n g of d at a c o m pl y wit h t h e f oll o wi n g it e ms, b y f oll o wi n g t h e q u alit y 
ass ur a n ce a n d q u alit y c o ntr ol s yst e ms b as e d o n t h e st a n d ar d o p erati n g pr o ce d ures s et 
d o w n b y t h e s p o ns or. 
1)  Cli ni cal st u d y pr ot o c ol 
2)  T h e crit eri a s p ecifi e d i n Arti cl e 1 4 P ara gra p h 3 a n d Arti cl e 8 0 -2 of t h e L a w o n 
Sec uri n g Q u alit y, Effi cac y a n d S afet y of P h ar m ace uti cals, M e di cal D e vi ces, 
Re g e n er ati v e a n d C ell ul ar T h er a p y Pr o d u ct s, G e n e T h era p y Pr o d u cts, a n d 
C os m eti cs  (a b br e vi at e d n a m e : P h ar m ace uti cals a n d M e di cal D e vi ces L a w ) 
3)  T h e G C P Or di n a n ce  
T o ass ur e t h e r eli a bilit y of all d at a r el ati n g t o t h e st u d y a n d t o ass ure t h at d at a are 
pr o cess e d pr o p erl y, t h e s p o ns or will p erf or m q u alit y c o ntr ol at eac h st a g e w h e n d at a 
ar e h a n dl e d .   T h e m et h o ds of q u alit y c o ntr ol will b e pre p are d i n a d v a n ce acc or di n g t o 
th e st a n d ar d o p er ati n g pr o ce d ur es s et d o w n b y t h e s p o ns or, a n d rec or ds of t h e q u alit y 
c o ntr ol c o n d u ct e d will b e k e pt . 
T h e s p o ns or’s r esp o nsi bl e a u dit or  will c o n d u ct G C P a u dits as p art of q u alit y ass ura n ce 
acti viti es, t o ass ess w h et h er t his st u d y c o m pli es wit h G C P,  t h e cli ni cal st u d y pr ot o c ol, 
pr o ce dur es a n d t h e li k e, in d e p e n d e nt a n d s e p arat el y fr o m us u al m o nit ori n g a n d st u d y 
q u alit y c o ntr ol w or k . 
 


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1 3.  P a y m e nt f o r P a rti ci p ati o n, C o m p e ns ati o n f o r St u d y -R el ate d I nj u ri es a n d 
Ins u r a n ce  
1 3. 1  P a y m e nt f o r P a rti ci p ati o n  
Pa y m e nts s u c h as p a y m e nts t o r eli e v e t h e fi n a n ci al b ur d e n o n s u bj ects will b e m a d e t o 
s u bj ects fr o m t h e e x p e ns es p ai d b y t h e s p o ns or to t h e  st u d y sit e, acc or di n g t o t h e r ul es 
s et d o w n s e p ar at el y b y t h e st u d y sit e. 
 
1 3. 2  C o m p e ns ati o n f o r St u d y -R el ate d I nj u ri es  
If a s u bj ect e x p eri e n ces a n y st u d y -r el at e d i njur y  ca us e d b y t his st u d y, t h e i n v esti g at or 
or s u bi n v esti g at or w ill pr o vi d e tr eat m e nt a n d t a k e ot h er n ecess ar y acti o n .   If a s u bj ect 
r e q u ests a r es p o ns e t o a st u d y-r el at e d i nj ur y, t h e i n v esti g at or or s u bi n v esti g at or will 
p r o m ptl y c o nt act t h e s p o ns or.   T h e sp o n s or will s et d o w n pr o ce d ures f or 
c o m p e ns ati n g st u d y -r el at e d i nj uri es t o t h e s u bj ect, a n d t ak e m eas ures s u c h as 
p ur c h asi n g i ns ur a n ce .   T h e s p o ns or will b ear t h e p orti o n of t h e s u bj ect’s c o p a y m e nt 
f or t h e c osts of tr eat m e nt f or t h e st u d y-rel at e d i nj ur y, ex cl u di n g t h e a m o u nt c o v ere d b y 
p a y m e nts s u c h as h ealt h i ns ur a n ce .   If a n y li a bilit y f or d a m a g es aris es, f or e x a m pl e 
d u e t o s e q u el ae, c o m p e ns ati o n will b e p ai d, usi n g t h e p a y m e nts u n d er t h e A d v ers e 
Dr u g R eacti o n R eli ef S yst e m as g ui d eli n e a m o u nts .   Ho w e v er , t his d o es n ot 
n ecess aril y a p pl y if t h e ca us e of t h e st u d y -rel at e d i nj ur y m eets a n y of t h e f oll o wi n g 
c o n diti o ns. 
1)  It is pr o v e n t h at t h er e is a cl ear rel ati o ns hi p t o a n ot h er ca us e of t h e st u d y-rel at e d 
i nj ur y 
2)  T h e t e m p or al r el ati o ns hi p b et w ee n a d mi nistrati o n o f th e s t u d y dr u g a n d t h e 
st u d y-r el at e d i nj ur y is i m pl a usi bl e 
3)  T h er e is a p art y w h o cl earl y ca us e d h ar m, as i n t h e cas e of a r o a d traffi c acci d e nt  
4)  T h e s u bj ect di d n ot r ecei v e t h er a p e uti c b e n efits d u e t o t h e st u d y dr u g 
a d mi nistr ati o n b ei n g i n eff ecti v e  
5)  T h e s u bj ect or t h e s u bj ect’s p art n er b eca m e pre g n a nt d uri n g t h e st u d y p eri o d  
6)  T h e s u bj ect f ail e d t o c o m pl y wit h t h e cli ni cal st u d y pr ot o c ol, wit h o ut a v ali d 
r eas o n 
 
If t h e st u d y-r el at e d i nj ur y is d et er mi n e d t o b e d u e t o t h e d eli b erat e act or gr oss 
n e gli g e n ce of t h e st u d y sit e or t h e s u bj ect, c o m p e ns ati o n m a y n ot a p pl y, or th e a m o u nt 
of c o m p e ns ati o n m a y b e r e d u ce d. 
 


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1 3. 3  Ins u r a n ce  
T h e s p o ns or will p ur c h as e t h e n ecess ar y i ns ura n ce f or p a y m e nt of c o m p e ns ati o n f or 
st u d y-r el at e d i nj uri es.   T h e st u d y sit e will p urc h as e i ns uran ce  or t a k e ot h er n ecess ar y 
meas ur es i n cas e st u d y -r el at e d i nj ur y o cc urs d u e t o m e di cal err or. 
 


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1 4.  P u bli c ati o n P oli c y  
1)  T h e i nf or m ati o n o bt ai n e d i n t his st u d y m ust n ot b e p u blis h e d, i n p art or i n w h ol e, 
wit h o ut pri or dis c ussi o n wit h t h e s p o ns or.   T h e s p o ns or wi ll d eci d e t h e m et h o d of 
p u bli cati o n .   If i nf or m ati o n is p u blis h e d, t h e pri v ac y of s u bj ects wil l b e pr ot ect e d. 
2)  T h e s p o ns or w ill us e t h e i nf or m ati o n o bt ai n e d i n t his st u d y f or p ur p os es s u c h as 
a p pli cati o n f or m a n uf act uri n g a n d m ar k eti n g a p pr o v al f or t h e i n v e stig ati o n al 
pr o d u ct .   If t h e i n v esti g ati o n al pr o d u ct is a p pr o v e d, p art of t h e c o nt e nts of t his  
st u d y m a y b e m a d e p u bli c b as e d o n th e “ A ct o n A ccess t o I nf or m ati o n H el d b y 
A d mi nistr ati v e Or g a ns ( A ct N o. 4 2 of 1 4 M a y 1 9 9 9) , ” t h e “ A ct o n A ccess t o 
I nf or m ati o n H e l d b y I n c or p or at e d A d mi nistrati v e A g e n ci es ( A ct N o. 1 4 0 of 0 5 
D ec 2 0 0 1) ”  a n d “ P u bli cati o n o f I nf or m ati o n R el ati n g t o A p pr o v al R e vi e w of N e w 
P h ar m ace uti cals  (N otifi cati o n N o. 0 4 2 2 0 0 1 of t h e E v al u ati o n a n d Li ce nsi n g 
Di visi o n, P F S B, d at e d 2 2 A pr 2 0 0 5 ).”  If inf or mati o n is m a d e p u bli c, t h e pri v ac y 
of s u bj ects will b e pr ot ecte d . 
 


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1 5.  S T U D Y A D MI NI S T R A TI V E  I N F O R M A TI O N 
1 5. 1  E t hi cs 
1 5. 1. 1  E t hi c al C o n d u ct of t h e St u d y 
T his st u d y will b e c o n d u ct e d i n c o m pli a n ce wit h  t h e st a n d ar ds s et d o w n i n Arti cl e 1 4 
Par a gr a p h 3 a n d Arti cl e 8 0 - 2 of  t h e P h ar m ace uti cals a n d M e di cal D e vi ces L a w a n d 
M H W Or di n a n ce N o. 2 8  d at e d 2 7 M ar 1 9 9 7,  “ T h e Mi nist eri al Or di n a n ce o n G o o d 
Cli ni cal Pr acti ce”  (“t h e G C P Or di n a n ce” ).   It will b e c o n d u ct e d i n acc or d a n ce wit h 
t h e et hi cal pri n ci pl es of t h e D ecl ar ati o n of Hels i n ki, a n d t h e h u m a n ri g hts, w elfare a n d 
s af et y of s u bj ects will b e e ns ur e d t o t h e great est e xt e nt p ossi bl e.  
I n a d diti o n t o t h e a b o v e, t h e g e n o mi c a n d g e n eti c a n al ysis p erf or m e d d uri n g t h e st u d y, 
a n d t h e b a n ki n g of cli ni cal s p eci m e ns f or g e n o mi c a n d g e n e ti c a n al ysis a n d res earc h 
usi n g t h es e s a m pl es  will als o b e i n acc or d a n ce wit h th e “ Et hi cal G ui d eli n es f or H u m a n 
G e n o m e/ G e n e A n al ysis Res ear c h 1 3 ” an d t h e “ Et hical G ui d eli n es f or Cli ni cal 
Res ear c h .1 4” 
 
1 5. 1. 2  I nstit uti o n al R e vi e w B o a r d 
Bef or e t his st u d y is c o n d u ct e d, it will b e re vi e w e d a n d a p pr o v e d b y a n I nstit uti o n al 
Re vi e w B o ar d (I R B ) as s et d o w n i n Arti cl e 2 7 of t h e G C P Or di n a n ce .   O n ce p er y ear 
d uri n g t h e c o n d u ct of t h e st u d y, or m ore fre q u e ntl y if re q u est e d b y t h e I R B , t h e st u d y 
will b e r e vi e w e d t o d eci d e w h et h er it  ca n co nti n u e .   A re vi e w t o d eci d e w h et h er t h e 
st u d y will c o nti n u e will als o b e p erf or m e d if i nf or m ati o n t h at m a y affect t h e s afet y of 
s u bj ects or t h e c o n d u ct of t h e st u d y is o bt ai n e d. 
 
1 5. 2  S u bj ect C o nfi d e nti alit y  
T o pr ot ect t h e c o nfi d e nti alit y of in di vi d u al su bj ect s, d o c u m e nts s u b mitt e d t o a n 
e xt er n al p art y b y t h e st u d y sit e w ill i d e ntif y s u bj ects usi n g s u bj ect i d e ntificati o n c o d es, 
a n d will n ot us e i nf or m ati o n s u c h a s na m es or m e di cal rec or d n u m b er s t h at ca n b e 
us e d t o i d e ntif y s u bj ects.   P ers o ns w h o m a y l ear n c o nfi d e nti al i nf or m ati o n a b o ut 
s u bj ect d uri n g t h eir w or k will m ai nt ai n t h e c o nfi d e nti alit y of t his i nf or m ati o n.  
 
1 5. 3  O bt ai ni n g I nf o r m e d C o ns e nt  
Bef or e s cr ee ni n g t es ts ar e p erf or m e d, t h e i n v esti g at or or s u bi n v esti g at or will pr o vi d e 
a n easil y u n d erst a n d a bl e e x pl a n ati o n of t h e f oll o wi n g it e ms t o a l e g all y acce pt a bl e 
r e pr es e nt ati v e w h o ca n act i n t h e b est i nt erest of t h e s u bj ect, usi n g t h e i nf or m e d 
c o ns e nt f or m , a n d will o b t ai n writt e n i nf or m e d c o ns e nt f or t h e s u bj ect t o p arti ci p at e i n 


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t h e st u d y, gi v e n of t h e l e gall y acce pt a bl e re pres e nt ati v e ’s o w n free will.   W h e n 
i nf or m e d c o ns e nt is o bt ai n e d, t h e l e g all y acce pt a bl e re pres e nt ati v e will b e gi v e n 
s uffi ci e nt ti m e t o d eci d e w h e t h er t o all o w t h e s u bject t o p arti ci p at e i n t h e st u d y a n d t h e 
o p p ort u nit y t o as k q u esti o ns,  a n d will recei v e a d e q u at e a ns w ers t o t h es e q u esti o ns .   
T h e s u bj ect will als o r ecei v e a n e x pl a n ati o n a b o ut i nf or m ati o n i n cl u di n g t h e c o nt e nts 
of t h e st u d y usi n g t h e i nf or m e d c o ns e nt or c o nfir mati o n of i nt e nt f or m/ ass e nt f or m, as 
a p pr o pri at e f or his a bilit y  t o u n d erst a n d, a n d eff orts will b e m a d e t o e n a bl e t h e s u bj ect 
t o u n d erst a n d, a n d w h e n p ossi bl e, writt e n c o nfir m ati o n of i nt e nt will b e o btai n e d. 
T h e i n v esti g at or  or  s u bi n v esti g at or w h o pr o vi d es t h e l e g all y acce pt a bl e re pres e nt ati v e 
or t h e s u bj ect hi ms elf wit h a n e x pl a n ati o n a b o ut matt ers s u c h as t h e c o nt e nts of t h e 
st u d y will a d d his/ h er n a me a n d s eal t o, or si g n, t h e i nf or m e d c o ns e nt a n d c o nfir m ati o n 
of i nt e nt f o r m, a n d eac h p ers o n will e nt er t h e d at e .   If t h e st u d y st aff a p p oi nt e d b y t h e 
dir ect or of t h e st u d y sit e pr o vi d es a s u p pl e m e nt ar y e x pl a n ati o n, i n a d diti o n t o t h e 
i n v esti g at or or s u bi n v esti g at or, t h e m e m b ers of t h e st u d y st aff will als o a d d t h eir 
n a m es a n d s eals t o, or si g n, t h e inf or m e d c o ns e nt a n d c o nfir m ati o n of i nt e nt f or m , a n d 
e nt er t h e d at e .   T h e l e g all y acce pt a bl e re pres e nt ati v e will writ e t h e s u bj ect’s n a m e 
a n d his/ h er r el ati o ns hi p wit h t h e s u bj ect o n t h e i nf or m e d c o ns e nt a n d c o nfir m ati o n of 
i nt e nt for m , a n d t h e n si g n it a n d e nt er t h e d at e.   If p ossi bl e, t h e s u bj ect hi ms elf will 
als o si g n t h e  i nf or m e d c o ns e nt a n d c o nfir m ati o n of i nt e nt f or m an d e nt er t h e d at e . 
T h e i n v esti g at or or s u bi n v esti g at or w ill gi v e t h e l e g all y acce pt a bl e re pres e nt ati v e a 
c o p y o f th e i nf or m e d c o ns e nt f or m a n d w ritt e n e x pl a n ati o n, a c o p y of t h e c o nfir m ati o n 
of i nt e nt f or m , a n d t h e ass e nt f or m, a n d will st ore t h e ori gi n al i nf or m e d c o ns e nt for m 
a n d c o nfir m ati o n of i nt e nt f or m at t h e st u d y sit e.   T h e i n v esti g at or or s u bi n v esti g at or 
w ill m a k e a writt e n r ec or d (s u c h as t h e ori gi n al of t h e i nf or m e d c o ns e nt f or m or 
me di cal r ec or d s) of h a vi n g pr o vi d e d t h e l e g all y acce pt a bl e re pres e nt ati v e wit h a c o p y 
of t h e i nf or m e d c o ns e nt f or m a n d writt e n i nf or m ati o n , a c o p y of t h e c o nfir m ati o n of 
i nt e nt f or m, a n d t h e ass e nt f or m. 
S u bj ects fr o m w h o m c o ns e nt h as b ee n o bt ai n e d b y t h e a b o v e m et h o d w ill b e rec or d e d 
o n t h e s u bj ect s cr ee ni n g list an d assi g n e d s u bj ect i d e ntifi cati o n c o d e s. 
 
[It e ms t o b e e x pl ai n e d t o s u bj ects a n d t h eir l e g all y acce pt a bl e re pres e nt ati v es] 
1)  T h at t h e st u d y i n v ol v es r es ear c h  
2)  T h e st u d y o bj ecti v es  
3)  T h e st u d y m et h o ds (t h e e x p eri m e nt al as p ects of t h e st u d y a n d th e i n cl usi o n crit eri a 
f or s u bj ects) 


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4)  T h e pl a n n e d d ur ati o n of p arti ci p ati o n of s u bj ect s i n t h e st u d y 
5)  T h e pl a n n e d n u m b er of s u bj ects w h o will p arti ci p at e i n t h e st u d y  
6)  T h e e x p ect e d b e n efits t o t h e s u bj ect’s m e nt al a n d p h ysi cal h ealt h fr o m t h e st u d y 
dr u g  (or, if n o b e n efits ar e e x p ect e d, t his fact)  a n d t h e e x p ect e d dis a d v a nt a g es t o 
t h e s u bj ect 
7)  W h et h er ot h er t h er a p e uti c a p pr o ac h es are a v ail a bl e, a n d t h e e x p ect e d si g nifi ca nt 
b e n efits a n d ris ks of t h es e t h er a p e uti c a p pr o ac h es  
8)  T h e c o m p e ns ati o n a n d tr eat m e nt t h e s u bj ect ca n recei v e if h e s uffers a n y 
st u d y-r el at e d i nj ur y 
9)  T h at t h e s u bj ect or his l e g all y acce pt a bl e re pres e nt ati v e ca n d eci d e w h et h er t o 
p arti ci p at e i n t h e st u d y of t h eir o w n free will , a n d t h at t h e s u bj ect or h is l e g all y 
acce pt a bl e r e pr es e nt ati v e ca n r ef us e or wit h dra w c o ns e nt f or t h e s u bj ect t o 
p arti ci p at e i n t h e st u d y at a n y ti m e .   Als o , t h at t h e s u bj ect will n ot s uffer a n y 
dis a d v a nt a g e f or r ef usi n g or wit h dra wi n g c o ns e nt, an d will n ot l os e a n y b e n efits 
h e is e ntitl e d t o if h e d o es n ot p arti ci p at e i n t h e st u d y  
1 0)  T h at if a n y i nf or m ati o n t h at m a y affect t h e willi n g n ess of t h e s u bj ect or his l e g all y 
acce pt a bl e r e pr es e nt ati v e t o c o nti n u e t o p a rti ci p at e i n t h e st u d y is o bt ai n e d, th e 
s u bj ect will pr o m ptl y b e i nf or m e d of t his i nf or m atio n  
1 1)  T h e c o n diti o ns or r eas o ns f or w hi c h t h e s u bj ect ca n b e wit h dra w n fr o m 
p arti ci p ati o n i n t h e st u d y  
1 2)  T h at t h e cli ni cal r es ear c h ass o ci at e,  res p o nsi bl e a u dit or, I R B, an d re g ul at or y 
a ut h oriti es m a y vi e w ori gi n al m e di cal rec or ds, a n d t h at w h e n t h es e rec or ds ar e 
vi e w e d , t h e s u bj ect’s c o nfi d e nti alit y will b e pr ot e ct e d, a n d t h at b y writi n g his 
n a m e a n d a d di n g his s eal t o, or si g ni n g, t h e i nf or me d c o ns e nt f or m, t h e s u bj ect 
c ons e nts t o t h es e r ec or ds b ei n g vi e w e d  
1 3)  T h at e v e n if t h e r es ult of t h e st u d y is p u blis h e d,  t h e s u bj ect’s c o nfi d e nti alit y will 
b e pr ot ect e d  
1 4)  If it is n ecess ar y f or t h e su bj ect t o b ear e x p e ns es, d et ails of t h es e 
1 5)  If a n y p a y m e nt will b e m a d e t o t h e s u bj ect, d etail s of t his 
1 6)  T h e n a m e, p ositi o n, a n d c o nt act i nf or m ati o n of t h e i n v esti g at or or s u bi n v esti g at o r 
1 7)  T h e offi ce of t h e st u d y site t h at s h o ul d b e c o nt act e d if t h e s u bj ect or h is l e g all y 
acce pt a bl e r e pr es e nt ati v e w a nts m ore i nf or m ati o n a b o ut t h e st u d y a n d t h e 
s u bj ect’s ri g hts, or t o m a k e e n q uiri es a b o ut a st u d y-rel at e d i nj ur y 
1 8)  T h e r ul es t h at t h e s u bj ect s h o ul d f oll o w  
1 9)  T h e t y p e of I R B p erf or mi n g r e vi e ws of t h e acce pt a bilit y of t h e st u d y, t h e it e ms 


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r e vi e w e d b y eac h I R B a n d ot h er i nf or m ati o n rel ati n g t o t h e I R B f or t h e stu d y 
 
As a m eas ur e t o pr e v e nt t h e s pr ea d of t h e n o v el c or o n a vir us, s elf -a d mi nistrati o n will 
b e all o w e d.    C o ns e nt f or s elf -a d mi nistrati o n will b e o bt ai n e d fr o m t h e l e g all y 
acce pt a bl e r e pr es e nt ati v e, a n d t h e g u ar di a n p erf or mi n g s elf -a d mi nistrati o n will b e 
gi v e n tr ai ni n g i n t h e m et h o d of st ori n g t h e st u d y dr u g a n d t h e m et h o d of a d mi nist eri n g 
t h e st ud y dr u g b ef or e s elf -a d mi nistr ati o n st arts.  
 
1 5. 4  Inf o r m e d C o ns e nt f o r P h a r m a c o g e n o mi cs a n d Bi o m a r k er R es e a rc h 
If g e n o mi c or g e n eti c a n al ysis will b e p erf or m e d d uri n g th e st u d y, or if t h ere will b e 
l o n g-t er m st or a g e of s p eci m e ns ( b a n ki n g) f or g e n o mi c or g e n eti c a n al ysis wit h n o 
fi x e d ti mi n g, t h e i n v esti g at or or s u bi n v esti g at or will pr o vi d e t h e s u bj ects a n d l e g all y 
acce pt a bl e r e pr es e nt ati v e s w h o h a v e gi v e n c o ns e nt f or t his st u d y wit h a n easil y 
u n d erst a n d a bl e e x pl a n ati o n of t h e it e ms s h o w n b el o w , a n d o bt ai n writt e n i nf or m e d 
c o ns e nt s e p ar at e fr o m t h e c o ns e nt f or t his st u d y, gi v e n of t h eir o w n free will .   T his 
i nf or m e d c o ns e nt will b e o bt ai n e d b ef ore s p eci m e ns are c oll ect e d. 
1)  T h e  c h ar act eristi cs a n d n at ur e of g e n eti c i nf or m ati o n  
2)  T h e o bj ecti v es of t his r es ear c h  
3)  T h e m et h o ds of t his r es ear c h  
4)  T h e e x p ect e d b e n efits a n d e x p ect e d dis a d v a nt a g es t o  th e s u bj ect ’s m e nt al a n d 
p h ysi cal h ealt h fr o m t his r es ear c h 
5)  T h at t h e s u bj ect or his l e g al l y acce pt a bl e re pres e nt ati v e ca n d eci d e w h et h er t o 
p arti ci p at e i n t h e p h ar m ac o g e n o mi c i n v esti g ati o n of t h eir o w n free wi ll, a n d t h at 
t h e s u bj ect ca n r ef us e or wit h dr a w c o ns e nt t o p artici p at e i n t his res earc h at a n y 
ti m e.    Als o, t h at t h e s u bject will n ot s uffer a n y dis a d v a nt a g e f or wit h dra wi n g 
c o ns e nt, a n d t h at his p artici p ati o n i n t h e st u d y will n o t b e affect e d if h e d o es n ot 
p arti ci p at e i n t his r es ear c h.  
6)  H o w s p eci m e ns a n d d at a will b e h a n dl e d if c o ns e nt is wit h dra w n  
7)  Inf or m ati o n a b o ut h o w s p eci m e ns will b e h a n dl e d a n d t h e st ora g e p eri o d a n d 
dis p os al of s p eci m e ns  
8)  T h e c o m p e ns ati o n t h at t h e s u bj ect ca n  recei v e 
9)  T h e dis cl os ur e a n d o w n ers hi p of t h e res ult of t h e res earc h  
1 0)  If it is n ecess ar y f or t h e s u bj ect t o b ear e x p e ns es, d et ails of t h es e 
1 1)  T h at t h e s u bj ect will n ot b e r ecei v e re m u n erati o n f or pr o vi di n g s p eci m e ns  
1 2)  T h at t h e s u bj ect’s c o nfi d e nti alit y a n d ot h er  h u m a n ri g hts will b e pr ot ect e d  


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1 5. 5  P r o visi o n of N e w Inf o r m ati o n A ffecti n g t h e C o n d u ct of t h e S t u d y 
If th e i n v esti g at or or s u bi n v esti g at or o bt ai ns i nf or mati o n t h at m a y affect t h e 
willi n g n ess of t h e s u bj ects or t h eir l e g all y acce pt a bl e re pres e nt ati v es t o c o nti n u e t o 
p arti ci p at e i n t h e st u d y, h e/s h e will pr o m ptl y e x plai n t his i nf or m ati o n t o t h e s u bj ects 
a n d t h eir l e g all y acce pt a bl e r e pr es e nt ati v es a n d c o nfir m w h et h er t h e s u bj ects a n d t h eir 
le g all y acce pt a bl e r e pr es e nt ati v es ar e willi n g t o c o nti n u e t o p arti ci p at e i n t h e st u d y.   
T h e i n v esti g at or or s u bi n v esti g at or will als o rec or d t h e d at e of e x pl a n ati o n, t h e p ers o n 
pr o vi di n g t h e e x pl a n ati o n, t h e c o nt e nts of t h e e x pla n ati o n, t h e wis h es of t h e s u bj ects 
a n d l e g all y acce pt a bl e r e pr es e nt ati v e s a n d t h e d at e of c o nfir m ati o n i n d o c u m e nts s u c h 
as m e di cal r ec or ds .   In a d diti o n , if n ecess ar y, t h e i n v esti g at or will pr o m ptl y a m e n d 
t h e i nf or m e d c o ns e nt f or m a n d writt e n i nf or m ati o n, c o nfir mati o n of i nt e nt f or m a n d 
ass e nt f or m , s u b mit it t o t h e s p o ns or a n d re p ort t o t h e direct or of t h e st u d y sit e a n d 
o bt ai n a p pr o v al fr o m t h e I R B.   I nf or m e d c o ns e nt will n ot b e o bt ai n e d fr o m n e w 
s u bj ects u ntil a p pr o v al is r ecei v e d fr o m t h e I R B.   If t h e st u d y is alrea d y b ei n g 
c o n d u ct e d i n s o m e s u bj ects, i nf or m e d c o ns e nt f or c o nti n ui n g t o p arti ci p at e in t h e st u d y 
will b e o bt ai n e d fr o m t h es e s u bj ects a g ai n, b y t h e s a m e m et h o d of o bt ai ni n g i nf or m e d 
c o ns e nt as a b o v e, usi n g t h e a m e n d e d  i nf or m e d c o ns e nt f or m a n d writt en i nf or m ati o n, 
c o nfir m ati o n of i nt e nt f or m a n d ass e nt f or m , a n d t h e l e g all y acce pt a bl e re pr es e nt ati v e 
will b e pr o vi d e d wit h a c o p y of t h e i nf or m e d c o ns e nt f or m  a n d w ritt e n i nf or m ati o n, a 
c o p y of t h e c o nfir m ati o n of i nt e nt f or m a n d t h e ass e nt f or m.   T h e i n v esti g at or or 
s u bi n v esti g at or will m a k e a writt e n rec or d (s u c h as t h e ori gi n al of t h e i nf or me d 
c o ns e nt f or m or m e di cal r ec or ds) of h a vi n g pr o vi d e d t h e l e g all y acce pt a bl e 
r e pr es e nt ati v e wit h a c o p y of t h e i nf or m e d c o ns e nt f or m a n d writt e n i nf or mati o n, a 
c o p y of t h e c o nfir m ati o n of i nt e nt f or m a n d t h e ass e nt f or m.  
 
1 5. 6  Pl a n n e d St u d y P eri o d  
0 1 O ct 2 0 1 5 t o 3 1 D ec 2 0 2 0  
 
1 5. 7  P r ot o c ol A m e n d m e nt  
If t h e sp o ns or a m e n ds t h e cli ni cal st u d y pr ot o c ol  aft er t h e st art of t h e st u d y, t h e 
s p o ns or will dis c uss t h e a p pr o pri at e n ess of t he c h a n g es a n d t h e effect o n ass ess m e nt i n 
t h e st u d y w it h p ers o ns s u c h as t h e m e di cal e x p ert, as n ecess ar y, b ef ore m a ki n g a 
d ecisi o n o n a m e n d m e nt .   T h e s p o ns or will m a k e a writt e n rec or d of t h e c o nt e nts of 
t h e dis c ussi o n, w h et h er a me n d m e nts w ere m a d e a n d t he reas o n f or t his, a n d st ore it.  


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T h e s p o ns or w ill pr o m ptl y i nf or m t h e i n v esti g at or of t h e co nt e nts of t h e a me n d m e nt t o 
t h e cli ni cal st u d y pr ot o c ol .   If t h e v ersi o n n u m b er of t h e cli ni cal st u d y pr ot o c ol  h as 
b ee n a m e n d e d , t h e s p o ns or will o bt ai n writt e n agre e m e nt fr o m t h e i n v esti g at or a g ai n , 
a n d will carr y o ut t h e pr o ce d ur es s p ecifi e d b y t h e st u d y sit e. 
 
1 5. 8  Ter mi n ati o n a n d Te m p o r a r y Dis c o nti n u ati o n of t h e St u d y  
If a n y of t h e f oll o wi n g crit eri a is m et, a n d t h e s p o ns or d et er mi n es t h at it is n ot feasi bl e 
t o c o nti n ue t h e st u d y, t h e s p o ns or will t e m p oraril y dis c o nti n u e a p art or t h e w h ol e of 
t h e st u d y at t h at ti m e.   Aft er t his, t h e sp o ns or will d eci d e  w h et h er t o t er mi n at e a p art 
or t h e w h ol e of t h e st u d y , a n d m a k e a writt e n rec or d of t his d ecisi o n . 
1)  N e w s af et y i nf or m at i o n or s eri o us a d v ers e e v e nt i nf or m ati o n a b o ut t h e st u d y dr u g 
h as b ee n o bt ai n e d  
2)  T h er e h as b ee n a m aj or G C P vi ol ati o n a n d m aj or d e vi ati o n fr o m t h e cli ni cal st u d y 
pr ot o c ol  b y t h e s p o ns or, st u d y sit e  or i n v esti g at or 
3)  O t h er i nf or m ati o n h as b ee n o bt ai n e d d urin g t h e c o n d u ct of t h e st u d y  
 
If t h e sp o ns or , i n dis c ussi o n wit h p ers o ns s u c h as t h e m e di cal e xp ert, d eci d es t o 
ter mi n at e a p art or t h e w h ol e of t h e st u d y, th e s p o ns or will pr o m ptl y i nf or m t h e 
dir ect or of t h e st u d y sit e i n writi n g, i n cl u di n g t h e reas o n f or t his.   T h e direct or of t h e 
st u d y sit e will pr o m ptl y i nf or m t h e i n v esti g at or a n d I R B, i n cl u di n g t h e reas o n. 
If t h e st u d y is t er mi n at e d or t e m p or aril y dis c o nti n u e d f or a n y reas o n, th e i n v esti g at or 
w ill pr o m ptl y i nf or m t h e s u bj ects p arti ci p ati n g i n t h e st u d y a n d th eir l e g all y acce pt a bl e 
r e pr es e nt ati v es, t a k e a p pr o pri at e acti o n a n d p erf or m t ests or ot her i n v esti g ati o ns t o 
c o nfir m t h e s af et y of s u bjects . 
 
1 5. 9  P r o ce d u res f o r P re p a ri n g t h e C as e R e p o rt F o r m a n d R e m a r ks  
In t his st u d y, i n a d diti o n t o  cas e r e p ort f or m s ( pre pare d b y t h e i n v esti g at or), dr u g 
c o n ce ntr ati o n m eas ur e m e nt r e p orts  (pre p are d b y t h e ce ntral l a b orat or y) a n d 
el ectr o car di o gr a m r e p orts  (pr e p ar e d b y t h e ce ntral l a b orat or y ), re p orts of t h e 
bi o m ar k er m eas ur e m e nts i n eac h of  6. 8  t o 6. 1 2  (pre p are d b y t h e ce ntral l a b o rat or y) 
will als o b e pr e p ar e d .   D et ails s u c h as t h e m et h o d f or pre p ari n g t h e m eas ure m e nt 
r e p orts will b e s p ecifi e d s e p ar at el y. 
 
1 5. 9. 1  St yl e of t h e C as e R e p o rt F o r m  
In t his  st u d y, cas e r e p ort f or ms will b e fill e d o ut electr o ni call y, usi n g a s yste m f or 


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el ectr o ni ca ll y pr e p ari n g cas e r e p ort f or m s (a n E D C s yst e m, T a bl e 1 5. 9 - 1).   A cas e 
r e p ort f or m (in cl u di n g a n a u dit tr ail ) will b e pre pare d f or eac h s u bj ect, a n d t h e cas e 
r e p ort f or m si g n e d b y t h e i n v esti g at or will b e h a n dl e d as t h e ori gi n al.   A n E D C  
s yst e m t h at h as b ee n v ali d at e d will b e us e d. 
 
T a bl e 1 5. 9 - 1 E D C S yst e m 
Na me of E D C s yste m  
Me d i data Ra ve®  
De vel o per of t he E D C  s yste m 
Me di data S ol uti o ns , I n c. 
E ntr y met h o d  
We b -b as e d d ata  e ntr y  
E ntr y ter mi n als  
Pers o nal c o m p uters at t he me dic al i nstit uti o n  
Pr o hi bite d O S  
N o ne  
B r o wser 
Me di data Ra ve
®  s u p p orts br o wsers t hat ha n dle H T M L 5 a n d 
C S S 2.   T he  use of Ja va Scri pt m ust b e e n a ble d i n br o ws ers . 
R ec o m me n de d scr ee n 
res ol uti o n 
At least 1 0 2 4 ×  7 6 4  
R ec o m me n de d c o n ne cti o n 
s p ee d 
≥1 2 8 k b ps  
O t h er re q uire me nts 
A d o be Flas h Pla y er Ver.  1 0 or a b o v e  
 
1 5. 9. 2  P re p a ri n g C as e R e p o rt F o r m s 
Bef or e pr e p ari n g cas e r e p ort f or m s, t h e i n v esti g at or w ill recei v e trai ni n g o n el ectr o ni c 
si g n at ur es, a n d t h e r ec or d of t his tr ai ni n g will t a k e t h e pl ace of t h e list of si g n at ures 
a n d s eals . 
1)  C as e r e p ort f or m s will b e pr e p are d f or s u bj ects w h o h a v e pr o vi d e d c o ns e nt. 
2)  T h e i n v esti g at or or s u bi n v esti g at or will pre p are cas e re p ort f or ms acc or di n g t o t h e 
“C as e R e p ort F or m C o m pl eti o n G ui d eli n es ” pr o vi d e d b y t h e s p o ns or . 
3)  If m e m b ers of t h e st u d y st aff assist wit h t h e pre p arati o n of cas e re p ort f or m s, t h e y 
will f oll o w t h e dir ecti o ns of t h e i n v esti g at or or s u bi n v esti g at or.  
4)  T h e i n v esti g at or w ill s u b mit cas e re p ort f or m s to t h e s p o ns or a n d s t ore c o pi es of 
t h e m. 
5)  If t h er e is a n y dis cr e p a n c y b et w ee n t h e d at a e nt ere d o n t h e cas e re p ort f or m s a n d 
t h e s o ur ce d o c u m e nts, t h e i n v esti g at or will s e p aratel y pre p are rec or ds e x pl ai ni n g 
t h e r eas o n f or t his a n d s u b mit t h e m t o t h e s p o ns or, st ori n g a c o p y. 
 
1 5. 9. 3  E n t eri n g N a m es a n d S e als o r Si g n at u res on C as e R e p o rt F o r m s 
T h e i n v esti g at or w ill c h ec k t h e cas e re p ort f or ms pre p are d at t h e st u d y sit e a n d si g n 
t h e m el ectr o ni call y. 
 


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1 5. 9. 4  C h a n g es o r R e visi o ns t o C as e R e p o rt F o r m s 
1)  T h e i n v esti g at or, s u bi n v esti g at or or s t u d y st aff will re vis e cas e re p ort f or ms 
acc or di n g t o t h e “C as e R e p ort F or m  C o m pl etio n  G ui d eli n es ” pr o vi d e d b y t h e 
s p o ns or. 
2)  T h e i n v esti g at or w ill h a v e r es p o nsi bilit y f or t h e c o nt e nts e nt ere d o n t h e cas e re p ort 
f or ms, a n d will st or e c o pies of all rec or ds of c h a n g es a n d re visi o ns t o t h e m . 
 
1 5. 1 0  S t o r a g e of S o u rce D o c u m e nts a n d O t h er R ec o r ds 
1 5. 1 0. 1  D efi niti o n of S o u rce D o c u m e nts  
T his r ef ers t o t h e ori gi n al d o c u m e nt, d at a a n d rec or ds, or certifi e d c o pi es of t h e m 
s p ecifi e d b y IC H -G C P 1. 5 2, a n d i n cl u d es t h e rec or ds (s o urce d at a) n ecess ar y t o 
r e pr o d u ce a n d ass ess t h e n arr ati v e of t h e st u d y.   For e x a m pl e , hos pit al rec or ds , 
cli ni cal c h arts , la b or at or y n ot es , me m ora n d a, s u bject ’s di ari es or e v al u ati o n c h ec klists , 
p h ar m ac y dis p e nsi n g r ec or ds, r ec or d e d d at a fr o m a ut o m at e d i nstr u m e nts , c o pi es or 
tr a ns cri pti o ns certifi e d after v erifi cati o n as b ei n g acc urat e c o pi es, mi cr ofi c h es, 
p h ot o gr a p hi c n e g ati v es, mi cr ofil m or m a g n eti c m e di a, X- ra ys, s u bj ect fil es, a n d 
r ec or ds k e pt at t h e p h ar mac y, at t h e l a b orat ori es a n d at m e di c o-t ec h ni cal d e p art m e nts 
i n v ol v e d i n t h e cli ni cal trial. 
 
1 5. 1 0. 2  R ec o r d K e e pi n g  
1 5. 1 0. 2. 1  Instit uti o n al R e vi e w B o a r d  
T h e p ers o n w h o est a blis h e d t h e I R B will st ore st a n d ar d o p erati n g pr o ce d ures , 
c o m mitt ee m e m b er lists , s u b mitt e d d o c u m e nts, mi n ut es of m eeti n gs  a n d s u m m ari es of 
t h es e, a n d l ett ers , u ntil w hi c h e v er of t h e d at es 1)  a n d 2) b el o w  is l at er.   Ho w e v er , if 
t h e s p o ns or d eci d es t h at it is n ecess ar y t o st ore t h es e f or a l o n g er p eri o d, dis c ussi o ns 
will b e h el d wit h t h e s p o ns or a b o ut t h e st ora g e p eri o d a n d m et h o d of st ora g e . 
1)  T h e d at e of a p pr o v al of t his dr u g  (if d e v el o p m e nt is t er mi n at e d, t h e d at e 3 y ears 
aft er t h e d a y w h e n n otifi cati o n of t er mi n ati o n of d e v el o p m e nt is recei v e d fr o m t h e 
s p o ns or) 
2)  T h e d at e 3 y ears aft er t h e st u d y is t er mi n at e d or e n ds 
 
1 5. 1 0. 2. 2  S t u d y S it es 
T h e dir ect or of t h e st u d y sit e or p ers o n res p o nsi bl e f or st ora g e of rec or ds will st ore t h e 
“st u d y- r el at e d d o c u m e nts or r ec or ds ” t h at are t o b e st ore d at t h e st u d y sit e until 
w hi c h e v er of t h e d at es 1)  a n d 2) b el o w is l at er .   H o w e v er, if t h e s p o ns or d eci d es t h at 


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it is n ecess ar y t o st or e t h es e f or a l o n g er p eri o d, dis c ussi o ns will b e h el d wit h t h e 
s p o ns or a b o ut t h e st or a g e p eri o d a n d m et h o d of st ora g e.   F or eac h rec or d, a p ers o n 
r es p o nsi bl e f or st or a g e will b e s p ecifi e d, a n d t his p ers o n will st ore t h es e rec or ds. 
T h e dir ect or of t h e st u d y sit e or p ers o n res p o nsi bl e f or st ora g e of rec or ds will t a k e 
meas ur e t o e ns ur e t h at t h es e r ec or ds are n ot l ost or dis p os e d of d uri n g t h e p eri o d f or 
w hi c h t h e y h a v e a d ut y t o st or e t h e m, an d t h at t h e y ca n pres e nt t h e rec or ds if t h e y are 
r e q u est e d. 
1)  A d at e at l east 1 5 y ea rs aft er t h e st u d y e n ds, w h e n t h ere are n o l o n g er a n y 
mar k eti n g a p pli cati o ns u n d er r e vi e w or i n v esti g ati o n i n t h e I C H re gi o n 
2)  A d at e at l east 3 y ears aft er cli ni cal d e v el o p m e nt of t h e i n v esti g ati o n al pr o d u ct h as 
b ee n offi ci all y t er mi n at e d  
I n t h e cas e of l o ng- t er m st or a g e of s p eci m e ns f or g e n o mic a n d g e n eti c a n al ysis  
( ba n ki n g ), t o h a n dl e wit h dr a w al of c o ns e nt b y s u bj ects w h o h a v e e n d e d t h e st u d y, t h e 
st u d y sit e will st or e t h e s u bj ect s cr ee ni n g list f or u p t o 2 0 y ears aft er t h e st u d y h as 
e n d e d . 
 
1 5. 1 0. 2. 3  S p o ns o r 
T h e s p o ns or will st or e t h e  “st u dy- r el at e d d o c u m e nts or rec or ds ” t h at are t o b e st ore d 
u ntil w hi c h e v er of t h e d ates 1) a n d 2) b el o w is l at er.  
1)  A d at e at l east 1 5 y ears aft er t h e st u d y e n ds, w h e n t h ere are n o l o n g er a n y 
mar k eti n g a p pli cati o ns u n d er r e vi e w or i n v esti g ati o n i n t h e I C H re gi o n  
2)  A d at e at l e ast 3 y ears aft er cli ni cal d e v el o p m e nt of t h e i n v esti g ati o n al pr o d u ct h as 
b ee n offi ci all y t er mi n at e d  
 
1 5. 1 1  S o u rce D o c u m e nt Verific ati o n  
A t t h e ti m e of m o nit ori n g or a u diti n g b y t h e s p o ns or or i n v esti g ati o ns b y t h e 
re g ul at o r y a ut h oriti es or I R B, t h e dir ect or of t h e st u d y sit e a n d t h e i n v esti g at or will 
pr o vi d e dir ect access t o all s o ur ce d o c u m e nts a n d ot h er st u d y -rel at e d d o c u m e nts.   To 
c h ec k t h at th e st u d y is b ei n g c o n d u ct e d a p pr o pri at el y a n d t h at th e reli a bilit y of d at a is 
full y e ns ur e d, th e s p o ns or w ill c o n d u ct m o nit ori n g a n d a u dits, a n d will directl y access 
s o ur ce d o c u m e nts a n d ot h er st u d y-r el at e d d o c u m e nts at t h e st u d y sit e.   T h e s p o ns or 
w ill dis c uss t h e m et h o d f or dir ectl y accessi n g s o urce d o c u m e nts wit h t h e i n v esti g at or 
i n a d v a n ce. 
 


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1 5. 1 2  Or g a ni z ati o n 
T h e or g a ni zat i o n f or t h e st u d y is as f oll o ws.   E ac h assi g n e d p ers o n will p erf or m w or k 
i n acc or d a n ce wit h t h e st a n d ar d o p erati n g pr o ce d ures of D aii c hi S a n k y o C o ., Lt d. 
 
1 5. 1 2. 1  S p o ns o r 
D aii c hi S a n k y o C o ., Lt d. 
3- 5- 1 Ni h o n b as hi  H o n c h o, C h u o -k u, To k y o 1 0 3 -8 4 2 6  
Tel: 
 (m ai n li n e)  
 
 
 
 
 
 
 
 
Cli ni cal D e v el o p m e nt D e p art m e nt  
III 
 
 
 
, Cli nical 
D e v el o p m e nt D e p art m e nt  III 
1- 2- 5 8 Hir o m ac hi, S hi n a g a w a -k u, To k y o 1 4 0 -8 7 1 0  
Tel: 
 ( m ai n li n e) 
Fa x: 
 
 
 
 
 
 
 
C M C D e p art m e nt  
 
 
 
 
D at a I nt elli g e n ce Di visi o n  
 
 
 
 
Cli ni cal P h ar m ac ol o g y Di visi o n  
 
 
 
 
Cli ni cal P h ar m ac ol o g y Di visi o n  
 
 
Bi o m ar k e r Di visi o n 
 
 
 
 
Cli ni cal P h ar m ac ol o g y Di visi o n  
 
 
 
D at a I nt elli g e n ce Di visi o n  
 
 
 
R D/ P V  R eli a b ilit y Ass uran ce 
Di visi o n  
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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Safet y M a n a g e m e nt Di visi o n  
3- 5- 1 Ni h o n b as hi H o n c h o, C h u o -k u, To k y o 1 0 3 -8 4 2 6  
Tel: 
      Fa x: 
 
 
 
 
Saf et y M a n a g e m e nt Di visi o n  
 
 
 
Bi o m ar k er Di visi o n  
 
 
 
 
Bi o m ar k er Di visi o n  
C o nt act Offi ce f or B a n ki n g : 
Bi o m ar k er 
Di visi o n  
 
1- 2- 5 8 Hir o m ac hi,  S hi n a g a w a -k u, To k y o 1 4 0 -8 7 1 0  
Tel: 
      Fa x:
 
 
1 5. 1 2. 2  M e di c al E x p ert  
, D e v el o p m e nt of P h ysi cal T h era p y, 
Fac ult y of R e h a bilit ati o n, K o b e G a k ui n U ni v ersit y  
5 1 8 Aris e, I k a w a d a ni c h o, N is hi-k u, K o b e-s hi, H y o g o 6 5 1- 2 1 8 0  
Tel: 
 
C o nt e nts of w or k:  
Gi vi n g a d vi ce o n t h e pl a n ni n g a n d c o n d u ct of t h e st u d y a n d t h e pre p arati o n of t h e 
cli ni cal st u d y r e p ort  fr o m a m e di cal p ers p ecti v e.   As t h e a p pr o v er of t h e cli ni cal 
st u d y r e p ort, si g ni n g t h e cli ni cal st u d y re p ort if it is d et er mi n e d t o b e a p pr o pri at e f or 
a p pr o v al. 
 
1 5. 1 2. 3  E D C S yst e m D e v el o p m e nt  
M e di d at a S ol uti o ns, I n c.  
Pers o n r es p o nsi bl e:  
 
3 5 0 H u ds o n Str eet, 9t h Fl o or, N e w Yor k, N e w  Yor k  1 0 0 1 4, U S A  
Tel: 
 ( mai n li n e) 
C o nt e nts of w or k:  
A d mi nist eri n g a n d m ai nt ai ni n g t h e o p erati o n of t h e E D C s yst e m b as e d o n a n 
o uts o ur ci n g c o ntr act . 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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1 5. 1 2. 4  E D C S yst e m S u p p o rt  
F ujits u Li mit e d  
Pers o n r es p o nsi bl e: 
 
T o k y u R E I T K a m at a B uil di n g, 5 -1 3 -2 K a m at a, Ot a -k u, To k y o 1 4 4 -0 0 5 2  
Tel: 
 
C o nt e nts of w or k:  
S u p p orti n g t h e E D C s yst e m b as e d o n a n o uts o urci n g c o ntract . 
 
1 5. 1 2. 5  
S t u d y S it e a n d In v esti g at o r s 
S ee Att ac h m e nt 1 L ist of St u d y Sit es a n d In v esti g at or s 
C o nt e nts of w or k:  
Bas e d o n dis c ussi o ns wit h t h e sp o ns or, a greei n g o n t h e cli ni cal st u d y pr ot o c ol , 
pr e p ari n g a n d a m e n di n g t h e i nf or m e d c o ns e nt f or m  a n d c o nfir m ati o n of i nte nt 
for m/ ass e nt f or m , s el ecti n g s u bj ects a n d o bt ai ni n g i nf or m e d c o ns e nt, i nstr u cti n g 
a n d o v ers eei n g s u bi n v esti g at ors a n d th e st u d y  st aff, pr o v i di n g d o c u m e nts a n d 
i nf or m ati o n, c o o p er ati n g wit h m o nit ori n g  a n d au dits, re p orti n g d e vi ati o ns fr o m a n d 
c h a n g es t o t h e cli ni cal st u d y pr ot o c ol  a n d a d v ers e e v e nt s, pre p ari n g cas e re p ort 
f or ms, a n d st ori n g “ st u d y-r el at e d d o c u m e nts or rec or ds . ” 
 
1 5. 1 2. 6  C e nt r al L a b o r a t o ri es 
1 5. 1 2. 6. 1  E l ect r o c a r di o g r a m A n al ysis Site 
C o ntr act or  
S u z u k e n C o., Lt d.  
Pers o n r es p o nsi bl e: 
 
2 6 Hi m e w a k a -c h o, M eit o -k u, N a g o y a -s hi, Ai c hi 4 6 5- 0 0 4 5  
Tel: 
 
C o nt e nts of w or k:  
Perf or mi n g w or k i n cl u di n g pr oj ect m a n a g e m e nt, re nti n g o ut an d i nst alli n g 
el ectr o car di o gr a p hs, pr o vi di n g sit e trai ni n g a n d tra ns mitti n g d at a, b as e d o n a n 
o uts o ur ci n g c o ntr act . 
A n al ysis sit e  
Bi o Cli ni ca, I n c.  
Pers o n r es p o nsi bl e: 
 
2 1 1 C ar n e gi e C e nt er, Pri n cet o n, NJ 0 8 5 4 0  
P P D
P P D
P P D
P P D
P P D


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C o n t e nts of w ork:  
Perf or mi n g w or k s u c h as a n al y zi n g el ectr o car di o gra ms s e nt fr o m st u d y sites, dat a 
ma n a g e m e nt a n d r e p orti n g r es ults, b as e d o n a n o uts o urci n g c o ntract. 
 
1 5. 1 2. 6. 2  C li ni c al S p eci m e n S t o r a g e F a cilit y  
L SI M e di e n ce C or p or ati o n  
Pers o n r es p o nsi bl e: 
 
3- 3 0 - 1 S hi m ur a, It a b as hi -k u, To k y o 1 7 4 -8 5 5 5  
Tel: 
 
C o nt e nts of w or k:  
M a n a gi n g t h e r ec o v er y a n d st or a g e cli ni cal s p eci me ns s u c h as bl o o d a n d uri n e i n 
t his st u d y, a n d t h eir tr a ns p ort ati o n t o ce ntral l a b orat ori es, b as e d o n a n o uts o urci n g 
c o n tr act. 
 
1 5. 1 2. 6. 3  C o nt r a ct o r St o ri n g a n d M a n a gi n g Cli ni c al S p eci m e ns f o r C h ec ki n g t h e 
D N A S e q u e n ces of t h e D S- 5 1 4 1 b D o u bl e- Str a n d F o r m ati o n Site a n d 
Ge n o mi c/ G e n eti c A n al ysis  
L SI M e di e n ce C or p or ati o n  
M a n a g er s: 
 
3- 3 0 - 1 S hi m ur a, It a b as hi - k u, To k y o 1 7 4 - 8 5 5 5 
Tel: 
 
C o nt e nts of w or k:  
M eas uri n g a n d st ori n g s a m pl es s e nt fr o m t h e st u d y sit es, b as e d o n a n o uts o urci n g 
c o ntr act.  
P erf or mi n g w or k s u c h as st ori n g ( b a n ki n g) a n d dis p osi n g of cli ni cal s p eci me ns f or 
g e n o mi c/ g e n eti c a n al ysis  ( D N A s p eci m e ns). 
 
1 5. 1 2. 6. 4  D r u g C o n ce nt r ati o n Me as u re m e nts  
C MI C P h ar m a S ci e n ce C o., Lt d.  
1 7- 1 8 N a k a h at a -c h o, Nis hi w a ki -s hi, H y o g o 6 7 7-0 0 3 2  
C o nt e nts of w or k:  
M eas uri n g a n d st ori n g s a m pl es s e nt fr o m st u d y sit e s, b as e d o n a n o uts o urc i n g 
c o ntr act.  
 
P P D
P P D
P P D
P P D
P P D


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1 5. 1 2. 6. 5  M e as u re m e nt of M us cl e Ti ss u e D ystr o p hi n P r otei n a n d D ystr o p hi n 
m R N A, Me as u re m e nt of Bl o o d C ell D ystr o p hi n m R N A 
G e n eti c L a b C o., Lt d.  
S a p p or o I T Fr o nt B uil di n g  T hir d Fl o or , 2 8- 1 9 6, Nis hi 1 5, Kit a 9 J o, C h u o -k u, 
Sa p p or o -s hi, H o k k ai d o 0 6 0-0 0 0 9  
C o nt e nts of w or k:  
M eas uri n g a n d st ori n g s a m pl es s e nt fr o m st u d y sit es, b as e d o n a n o uts o urci n g 
c o ntr act.  
 
Bi o A gil yti x L a bs , L L C. 
2 3 0 0 E n gl ert Dr, D ur h a m, N C 2 7 7 1 3  U S A  
C o nt e nts of w or k:  
M eas uri n g a n d st ori n g s a m pl es s e nt fr o m st u d y sit es, b as e d o n a n o uts o ur ci n g 
c o ntr act.  
 
A G A D A Bi os c i e n ces I n c. 
1 3 4 4 S u m m er Str eet, H alif a x, N S B 3 H 0 A 8, C a n a d a  
C o nt e nts of w or k:  
M eas uri n g a n d st ori n g s a m pl es s e nt fr o m st u d y sit es, b as e d o n a n o uts o urci n g 
c o ntr act.  
 
1 5. 1 2. 6. 6  Me as u re m e nt of A nti -D S - 5 1 4 1 b Anti b o d y  
S hi n Ni p p o n Bi o m e di cal L a b or at ori es, Lt d.  
2 4 3 8  Mi y a n o ur a -c h o, K a g os hi m a -s hi, K a g os hi m a 8 9 1-1 3 9 4  
C o nt e nts of w or k:  
M eas uri n g a n d st ori n g s a m pl es s e nt fr o m st u d y sit es, b as e d o n a n o uts o urci n g 
c o ntr act.  
 
1 5. 1 2. 6. 7  Me as u re m e nt of A nti - D ystr o p hi n Anti b o d y  
S u mi k a C h e mi cal A n al ysis S er vi ce, Lt d.  
3- 1- 1 3 5 K as u g a d e n a k a , K o n o ha n a -k u, Os a k a- s hi, Os a k a 5 5 4-0 0 2 2  
C o nt e nts of w or k:  
M eas uri n g a n d st ori n g s a m pl es s e nt fr o m st u d y sit es, b as e d o n a n o uts o urci n g 
c o ntr act.  
 


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1 5. 1 2. 6. 8  Me as u re m e nt of I n V it r o D ystr o p hi n Pr otei n a n d D ystr o p hi n m R N A  
A C E L, I n c.  
Pers o n r es p o nsi bl e: 
 
R o o m 2 5 0 6, S a g a mi h ar a I n c u b ati o n C e nt er SI C - 2, 5- 4-3 0  Nis hi h as hi m ot o, Mi d ori -k u, 
Sa g a mi h ar a -s hi, K a n a g a w a 2 5 2-0 1 3 1  
Tel: 
 
C o nt e nts of w or k:  
M eas uri n g a n d st ori n g s a m pl es s e nt fr o m st u d y sit es, b as e d o n a n o uts o urci n g 
c o nt r act. 
 
Ta k ar a Bi o I n c.  
N oji hi g as hi 7- 4- 3 8, K us ats u -s hi, S hi g a 5 2 5- 0 0 5 8  
C o nt e nts of w or k:  
M eas uri n g a n d st ori n g s a m pl es s e nt fr o m A C E L, I n c. , b as e d o n a n o uts o urci n g 
c o ntr act.  
 
1 5. 1 2. 6. 9  M e as u re m e nt of Mi cr o -R N A  
T a k ar a Bi o I n c.  
N oji hi g as hi  7- 4-3 8 , K us ats u-s hi, S hi g a 5 2 5- 0 0 5 8  
C o nt e nts of w or k:  
M eas uri n g a n d st ori n g s a m pl es s e nt fr o m st u d y sit es, b as e d o n a n o uts o urci n g 
c o ntr act.  
 
1 5. 1 2. 6. 1 0  Me as u re m e nt of Bl o o d a n d U ri n e D S - 5 1 4 1 b Met a b olites  
Dr u g M et a b olis m & P h ar m ac o ki n eti cs R es earc h L a b orat ori es, D aii c hi S a n k y o 
C o m p a n y, Li mit e d  
1- 2- 5 8 Hir o m ac hi, S hi n a g a w a- k u, To k y o 1 4 0- 8 7 1 0  
 
1 5. 1 2. 6. 1 1  M us c ul os k el et al  I m a g e A n al ysis 
M i cr o n, I n c. 
Pers o n r es p o nsi bl e: 
 
Ni h o n b as hi Nis hi k a w a B uil di n g, 1 - 5-3 Ni h o n b as hi, C h u o -k u, To k y o 1 0 3 -0 0 2 7  
Tel: 
 
C o nt e nts of w or k:  
A n al ysis of i m a g es  s e nt fr o m st u d y sit es, b ase d o n a n o ut s o urci n g c o ntract. 
P P D
P P D
P P D
P P D


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1 5. 1 2. 6. 1 2  Me as u re m e nt of U ri n e P r otei n  
L SI M e di e n ce C or p or ati o n  
3- 3 0 -1 S hi m ur a, It a b as hi -k u, To k y o 1 7 4 -8 5 5 5  
C o nt e nts of w or k:  
M eas uri n g a n d st ori n g s a m pl es s e nt fr o m st u d y sit es, b as e d o n a n o uts o urci n g 
c o nt r act. 
 
1 5. 1 2. 7  S af et y Ass ess m e nt C o m mittee Me m b er  
, P h ar mas p ur I n c. 
T o y o B uil di n g, 1- 2- 1 0 Ni h o n b as hi, C h u o -k u, To k y o 1 0 3 -0 0 2 7  
C o nt e nts of w or k:  
Ass essi n g s af et y d at a as a n e utr al t hir d p art y i n d e p e n d e nt of t h e s p o ns or a n d t he 
i n v esti g at or, a n d pr o vi di n g a d vi ce t o  t h e s p o ns or o n m att ers s u c h as w h et h er t o 
c o nti n u e, c h a n g e or t er mi n at e t h e st u d y. 
 
1 5. 1 3  D e p a rt m e nt R es p o nsi bl e f o r A u dit  
Pers o n r es p o nsi bl e: 
 
, D aii c hi S a n k y o C o m p a n y, Li mit e d  
1- 2- 5 8 Hir o m ac hi, S hi n a g a w a -k u, To k y o 1 4 0 -8 7 1 0  
Tel: 
, Fa x: 
 
C o nt e nts of w or k:  
C o n d u cti n g G C P a u dits. 
 
1 5. 1 4  E m er g e n c y C o nt a ct I nf o r m ati o n  
1)  C o nt act i nf or m ati o n f or e v e ni n gs  ( 1 8: 0 0 t o 9: 0 0) a n d S at ur d a ys, S u n d a ys a n d 
h oli d a ys (all  d a y)  
E m er g e n c y c o nt act d es k  
Tel: 
 
 
2)  C o nt act i nf or m ati o n f or d a yti m e ( 9: 0 0 t o 1 8: 0 0) M o n d a ys t o Fri d a ys (e x ce pt 
h oli d a ys)  
, D aii c hi 
Sa n k y o C o m p a n y, Li mit e d  
Tel: 
 ( m ai n li n e), 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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1 5. 1 5  C o m p a n y C o n d u cti n g J oi nt D e v el o p m e nt  
Or p h a n Dis eas e Tr eat m e nt I nstit ut e  C o., Lt d.  
1- 2- 5 8 Hir o m ac hi, S hi n a g a w a -k u, To k y o 1 4 0 -8 7 1 0  
 


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1 6.  R ef ere n ces  
1.  “Pr acti cal  G ui d eli n e f or D u c h e n n e M us c ul ar D ystr o p h y ( D M D)” Pre p arati o n 
C o m mitt e e, E ds . D u c h en n e M us c ul ar D ystr o p h y Treat m e nt G ui d eli n es,  2 0 1 4  [I n 
J a p a n es e]. N a n k o d o; 2 0 1 4. p. 2. Av ail a bl e fr o m: 
htt p:// w w w. n e ur ol o g y- j p. or g/ g ui d eli n e m/ p df/ d m d _ 0 1. p df 
2.  “Pr acti cal  G ui d eli n e f or D u c h e n n e M us c ul ar D ystr o p h y ( D M D)” Pre p arati o n 
C o m mitt ee, E ds. D u c h e n n e M us cul ar D ystr o p h y Treat m e nt G ui d eli n es, 2 0 1 4  [I n 
J a p a n es e]. N a n k o d o; 2 0 1 4. p. 5 8-6 1. Av ail a bl e fr o m: 
htt p:// w w w. n e ur ol o g y- j p. or g/ g ui d eli n e m/ p df/ d m d _ 0 5. p df  
3.  Ta k es hi m a Y, Ya gi M, Wa d a H, et al. I ntra v e n o us i nf usi o n of a n a ntis e ns e 
oli g o n u cl e oti d e r e s ults i n e x on s ki p pi n g i n m us cl e d ystr o p hi n m R N A of D u c h e n n e 
m us c ul ar d ystr o p h y. P e diatr R es. 2 0 0 6; 5 9( 5): 6 9 0 - 4. 
4.  M orit a K, Ta k a gi M, H as e g a w a C, et al. S y nt h esis a n d pr o p erti es of 
2'- O , 4'-C -et h yl e n e -bri d g e d n u cl ei c aci ds ( E N A) as effecti v e a ntis e ns e 
oli g o n u cl e oti d es. B io or g M e d C h e m. 2 0 0 3; 1 1( 1 0): 2 2 1 1 - 2 6. 
5.  M c D o n al d C M, H e nri cs o n E K, A bres c h R T, et al. T h e 6 -mi n ut e w al k t est a n d 
ot h er e n d p oi nts i n D u c h e n n e m us c ul ar d ystr o p h y: l o n git u di n al n at ural hist or y 
o bs er v ati o ns o v er 4 8 w ee ks fr o m a m ulti ce nt er st u d y. M us c l e N er v e. 
2 0 1 3; 4 8( 3): 3 4 3- 5 6. 
6.  A b o ut “ G ui d a n ce f or Est a blis hi n g S afet y i n First -i n-H u m a n St u di es d uri n g Dr u g 
D e v el o p m e nt , ” N otifi cati o n N o. 0 4 0 2 - 1 of t h e E v al u ati o n a n d Li ce nsi n g Di visi o n, 
P F S B  (0 2 A pr 2 0 1 2 ) [I n J a p a n es e]. 
7.  Ce nt er f or Dr u g E v al u ati o n a n d R es e arc h ( C D E R).  G ui d a n ce f or i n d ustr y: 
esti m ati n g t h e m a xi m u m s af e st arti n g d os e i n i nitial cli ni cal tri als f or t h era p e uti cs 
i n a d ult h ealt h y v ol u nt eers. (J ul 2 0 0 5). 
8.  P r acti cal P oi nts t o N ot e A b o ut t h e P arti al R e visi o n of t h e C al c ul a ti o n M et h o d f or 
M e di cal Fee s, A tt ac h e d F or m 1 9 - 2 “ P e di atri c N e ur ol o gi cal Test C h art , ” 
N otifi cati o n N o. 0 3 0 5 -1 of t h e H ealt h I ns ura n ce B urea u (0 5 M ar 2 0 1 8 ) [I n 
J a p a n es e]. 
9.  G o e m a ns N M, T uli ni us M, v a n d e n A k k er J T, et al. S yst e mi c a d mi nistrati o n of 
P R O 0 5 1 i n  D u c h e n n e's m us c ul ar d ystr o p h y. N E n gl J  M e d. 2 0 1 1; 
3 6 4( 1 6): 1 5 1 3 -2 2.  
1 0.  Cli ni cal P h ar m ac o ki n eti c St u di es of P h ar m ace uti cals , N otifi cati o n N o. 7 9 6 of t h e 
E v al u ati o n a n d Li ce nsi n g Di visi o n, P M S B  (0 1 J u n 2 0 0 1 ) [I n J a p a n es e]. 
1 1.  Ta k es hi m a Y, Ya gi M, O ki z u k a Y, et al. M ut ati o n s p ectr u m of t h e d y str o p hi n g e ne 


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i n 4 4 2 D u c h e n n e/ B ec k er m us c ul ar d ystr o p h y cas es fr o m o n e J a p a n es e referral 
ce nt er. J H u m G e n et. 2 0 1 0; 5 5( 6): 3 7 9 -8 8.  
1 2.  A arts m a -R us A, F o k k e m a I, Vers c h u ure n J, et al. T h e oreti c a p pli ca bilit y of 
a ntis e ns e- m e di at e d e x o n s ki p pi n g f or D u c h e n n e m us c ul ar d ystr o p h y  m ut ati o ns. 
H u m M ut at. 2 0 0 9; 3 0( 3): 2 9 3 -9.  
1 3.  Mi nistr y of E d u cati o n, C ult ur e, S p orts, S ci e n ce a n d Tec h n ol o g y , Mi nistr y of 
H ealt h, L a b o ur a n d Welf ar e , Mi nistr y of E c o n o m y, Tra d e a n d I n d ustr y . Et hi cal 
G ui d eli n es f or H u m a n G e n o m e/ G e n e A n al ysis R es earc h  (creat e d o n  2 9 M ar 2 0 0 1, 
c o m pr e h e nsi v el y r e vis e d o n 2 8 D ec 2 0 0 4 , p arti all y re vis e d o n 2 9 J u n 2 0 0 5 , 
p arti all y r e vis e d o n 0 1 D ec 2 0 0 8, c o m pre h e nsi v el y re vis e d o n 0 8 Fe b 2 0 1 3) [ I n 
J a p a n es e]. 
1 4.  Mi nistr y of H ealt h, L a b o ur a n d Welfare . Et hi cal G ui d eli n es f or Cli n i cal Res earch 
(cr eat e d o n 3 0 J ul 2 0 0 3 , c o m pr e h e nsi v el y re vis e d o n 2 8 D ec 2 0 0 4 , 
c o m pr e h e nsi v el y r e vis e d o n 3 1 J ul 2 0 0 8 ) [I n J a p a n es e]. 
 


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1 7.  A p p e n di ces  
A p p e n di x 1 S u bj ect R e gistr ati o n F or m  
A p p e n di x 2 St a n d ar ds f or Cl assifi cati o n of S er i o us A d v ers e Dr u g R eacti o ns 
(N otifi cati o n N o. 8 0 of t h e S af et y Di visi o n, P M S B d at e d 2 9 J u n 1 9 9 2 ) 
A p p e n di x 3 Ti mi n g of E x a mi n ati o ns , O bs er v ati o ns a n d Tests  
 


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A tt a c h m e nts 
Att ac h m e nt 1 List of St u d y Sit es a n d I n v esti g at ors