Conditions: Muscular Dystrophy, Duchenne Muscular Dystrophies Muscular Disorders, Atrophic Muscular Diseases Musculoskeletal Diseases Neuromuscular Diseases Nervous System Diseases Genetic Diseases, X-Linked Genetic Diseases, Inborn
Keywords: Duchenne muscular dystrophy Dystrophinopathy Nonsense mutation Premature stop codon Becker muscular dystrophy DMD/BMD PTC124 Ataluren
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 219
Healthy volunteers: no

Brief summary:
The primary objective of this study is to obtain long term safety data of ataluren in male participants with nonsense mutation dystrophinopathy (who participated and completed a previous Phase 3 study of ataluren \[PTC124-GD-020-DMD {NCT01826487}\]) to augment the overall safety database. Screening and baseline procedures are structured to avoid a gap in treatment between the double-blind study (PTC124-GD-020-DMD) and this extension study.

This study may be further extended by amendment until either ataluren becomes commercially available or the clinical development of ataluren in duchenne muscular dystrophy (DMD) is discontinued.

Detailed description:

Arms:
arm 1: Participants will receive ataluren suspension orally 3 times a day (TID), 10 milligrams/kilogram (mg/kg) at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for up to 144 weeks.

Interventions: intervention 1: Ataluren
Intervention descriptions: intervention 1: Ataluren will be administered per the dose and schedule specified in the arm.

Protocol document:
Prot_000.pdf: 
C LI NI C A L P R O T O C O L 
A P H A S E 3 E X T E N SI O N S T U D Y O F A T A L U R E N ( P T C 1 2 4) I N 
P A TI E N T S  WI T H N O N S E N S E  M U T A TI O N D Y S T R O P HI N O P A T H Y  
Pr ot o c ol N u m b er P T C 1 2 4 - G D-0 2 0 e- D M D  
1 9  N o v e m b er 2 0 1 5  
V er si o n 2. 0 
P T C T h er a p e uti c s, I n c.  
1 0 0 C or p or at e C o urt  
S o ut h Pl ai nfi el d, N J 0 7 0 8 0 U S A  
N oti c e  of  Pr o pri et ar y  I nf or m ati o n:  T hi s  d o c u m e nt  c o nt ai n s  c o nfi d e nti al  i nf or m ati o n  b el o n gi n g  t o  
P T C  T h er a p e uti c s, I n c.  E x c e pt a s m a y ot h er wi s e b e p er mitt e d i n writi n g, b y a c c e pti n g or r e vi e wi n g 
t h e s e  m at eri al s,  y o u  a gr e e  t h at  t hi s  i nf or m ati o n  s h o ul d  n ot  b e  di s cl o s e d  t o  ot h er s  ( e x c e pt  w h er e  
r e q uir e d b y a p pli c a bl e l a w) a n d s h o ul d n ot b e u s e d f or u n a ut h ori z e d p ur p o s e s.  I n t h e e v e nt of a n 
a ct u al or s u s p e ct e d br e a c h of t hi s o bli g ati o n, P T C T h er a p e uti c s, I n c. s h o ul d b e n otifi e d pr o m ptl y.  
N C T #: N C T 0 2 0 9 0 9 5 9


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
Version 2.0 
 
PTC Therapeutics, Inc.  – Confidential 
Page 2 of 91 
 
PROTOCOL IDENTIFIERS AND STUDY PERSONNEL 
Project Code 
PTC124-GD 
Therapeutic Area 
Genetic Disorders – Duchenne Muscular Dystrophy 
PTC Therapeutics Substance Identifier 
Ataluren (PTC124) 
IND Number 
68,431 
EudraCT Number 
2013-005489-20 
Included in clinical trials.gov Database 
Yes 
Protocol Number 
 
PTC124-GD-020e-DMD 
Protocol Version 
Version 2.0 
Protocol Version Date 
18 November 2015 
Protocol Phase 
Phase 3 
Protocol Title 
A Phase 3 Extension Study of Ataluren (PTC124) in 
Patients with Nonsense Mutation Dystrophinopathy 
PTC Medical Monitor 
  
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Telephone (office): 
 
Facsimile: 
 
E-mail: 
 
PTC Biostatistician 
 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Telephone: 
 
Facsimile: 
 
E-mail: 
 
PTC Clinical Program Scientist 
 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Telephone: 
 
Facsimile: 
 
E-mail: 
 
 


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
Version 2.0 
 
PTC Therapeutics, Inc.  – Confidential 
Page 3 of 91 
 
PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
Version 2.0 
 
PTC Therapeutics, Inc.  – Confidential 
Page 4 of 91 
 
PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE 
 
I have read the protocol document and, on behalf of my institution, agree to comply with the 
protocol and all applicable regulations. 
 
 
 
 
Principal Investigator 
Institution: 
Address: 
City: 
State/Province: 
Country: 
Phone: 
Fax: 
E-mail: 
 
Date 
 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 5  of 9 1  
 
T A B L E O F C O N T E N T S   
1.  
O V E R VI E W  ..................................................................................................................................................... 1 1  
1. 1.  
B A C K G R O U N D  ........................................................................................................................................... 1 1  
1. 2.  
S T U D Y D E SI G N  .......................................................................................................................................... 1 3  
2.  
I N T R O D U C TI O N ............................................................................................................................................ 1 3  
2. 1.  
D I S E AS E IN DI C A TI O N  ................................................................................................................................. 1 3  
2. 2.  
A T A L U R E N ( P T C 1 2 4) ................................................................................................................................ 1 4  
2. 2. 1.  
T her a pe utic C o nce pt  ............................................................................................................................ 1 4  
2. 2. 2.  
C he mic al Descri pti o n  .......................................................................................................................... 1 5  
2. 2. 3.  
Cli nic al St u dies  .................................................................................................................................... 1 5  
3.  
S T U D Y O B J E C TI V E A N D E N D P OI N T S  ..................................................................................................... 1 9  
3. 1.  
P RI M A R Y O BJ E C TI V E  ................................................................................................................................. 1 9  
3. 2.  
S E C O N D A R Y O BJ E C TI V E S  .......................................................................................................................... 1 9  
3. 3.  
C LI NI C A L E N D P OI N T S  ................................................................................................................................ 1 9  
4.  
P A TI E N T S E L E C TI O N C R I T E RI A ............................................................................................................. 2 0  
4. 1.  
O V E R VI E W ................................................................................................................................................. 2 0  
4. 2.  
IN C L U SI O N C RI T E R I A ................................................................................................................................. 2 0  
4. 3.  
E X C L U SI O N C RI T E RI A  ................................................................................................................................ 2 1  
5.  
E N R O L L M E N T P R O C E D U R E S  ................................................................................................................... 2 1  
5. 1 . 
S O U R C E A N D N U M B E R O F P A TI E N T S  ......................................................................................................... 2 1  
5. 2.  
S C R E E NI N G A N D S T U D Y D R U G A L L O C A TI O N  ............................................................................................. 2 1  
6.  
S T U D Y D R U G A D MI NI S T R A TI O N  ............................................................................................................ 2 2  
6. 1.  
IN V E S TI G A TI O N A L P R O D U C T  ..................................................................................................................... 2 2  
6. 1. 1.  
At al ure n ( P T C 1 2 4)  .............................................................................................................................. 2 2  
6. 1. 2.  
Dr u g Kits  ............................................................................................................................................. 2 2  
6. 1. 3.  
St u dy Dr u g P ack a gi n g a n d L a beli n g  ................................................................................................... 2 2  
6. 1. 4.  
St u dy Dr u g Dis pe nsi n g  ........................................................................................................................ 2 2  
6. 1. 5.  
Ret ur n of St u dy Dr u g  ........................................................................................................................... 2 2  
6. 1. 6.  
St or a ge a n d St a bility ............................................................................................................................ 2 3  
6. 1. 7.  
St u dy Dr u g Acc o u nt a bility  ................................................................................................................... 2 3  
6. 1. 8.  
Over d ose Prec a uti o ns  .......................................................................................................................... 2 3  
6. 1. 9.  
I n a dverte nt Ex p os ure a n d S pill Prec a uti o ns ....................................................................................... 2 3  
6. 2.  
S T U D Y D R U G T R E A T M E N T  ........................................................................................................................ 2 4  
6. 2. 1.  
D ur ati o n of Tre at me nt  ......................................................................................................................... 2 4  
6. 2. 2.  
Sc he d ule of A d mi nistr ati o n  .................................................................................................................. 2 4  
6. 2. 3.  
I nstr ucti o ns f or Del ays i n D osi n g ........................................................................................................ 2 4  
6. 2. 4.  
St u dy Dr u g Pre p ar ati o n a n d St or a ge  .................................................................................................. 2 5  
6. 3 . 
S A F E T Y M O NI T O RI N G A N D S T U D Y D R U G D O S E IN T E R R U P TI O N / MO DI FI C A TI O N  ........................................ 2 5  
6. 3. 1.  
L a b or at ory A b n or m alities a n d A dverse Eve nts Re q uiri n g Ev al u ati o n a n d P ote nti al Dr u g 
I nterr u pti o n/ M o dific ati o n .................................................................................................................................. 2 5  
6. 3. 2.  
Ev al u ati o n of A dverse Eve nts or L a b or at ory A b n or m alities  ............................................................... 2 6  
6. 3. 3.  
I nstr ucti o ns f or Res u mi n g St u dy Dr u g A d mi nistr ati o n after a n I nterr u pti o n f or S afety C o ncer ns  ..... 2 7  
6. 3. 4.  
I nstr ucti o ns f or Disc o nti n u ati o n of St u dy Dr u g A d mi nistr ati o n f or S afety C o ncer ns ......................... 2 8  
6. 4.  
C O N C O MI T A N T A N D S U P P O R TI V E T H E R A P Y  .............................................................................................. 2 8  
6. 4. 1.  
C ortic oster oi ds ..................................................................................................................................... 2 8  
6. 4. 2.  
A mi n o glyc osi des  .................................................................................................................................. 2 9  


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 6  of 9 1  
 
6. 4. 3.  
Hy dr ati o n  ............................................................................................................................................. 2 9  
6. 4. 4.  
C ar di ac Dr u gs f or C H F Pr o p hyl axis/ Tre at me nt  ................................................................................. 2 9  
6. 4. 5.  
Dr u gs Met a b o lize d by Cyt oc hr o me P 4 5 0 E nzy mes ............................................................................. 3 0  
6. 4. 6.  
P ote nti al dr u g i nter acti o ns  .................................................................................................................. 3 0  
6. 4. 7.  
Ot her C o nc o mit a nt Me dic ati o ns  .......................................................................................................... 3 0  
6. 5.  
A S SI S TI V E D E VI C E S  ................................................................................................................................... 3 1  
6. 6.  
P H Y SI C A L A N D R E S PI R A T O R Y T H E R A P Y  .................................................................................................... 3 1  
6. 7.  
D I E T A RY R E S T RI C TI O N S  ............................................................................................................................ 3 1  
7.  
S C H E D U L E O F E V E N T S A N D S T U D Y P A R A M E T E R S  .......................................................................... 3 2  
7. 1.  
S C H E D U L E O F E V E N T S  ............................................................................................................................... 3 2  
7. 2.  
E X P L A N A TI O N O F S T U D Y P R O C E D U R E S  ..................................................................................................... 3 4  
7. 2. 1.  
Tr a nsiti o n fr o m t he P h ase 3 St u dy, At al ure n Tre at me nt, a n d F oll o w -u p Peri o ds  ............................... 3 4  
7. 2. 2.  
Scree ni n g/ B aseli ne Visit ( Visit 1)  ........................................................................................................ 3 4  
7. 2. 3.  
Tre at me nt Visits d uri n g St u dy ( Visits 2 t hr o u g h 1 2)  ............................................................................ 3 4  
7. 2. 4.  
E n d of Tre at me nt  ................................................................................................................................. 3 5  
7. 2. 5.  
P ost -Tre at me nt Visits  ........................................................................................................................... 3 5  
7. 3.  
IN F O R M E D C O N S E N T  ................................................................................................................................. 3 5  
7. 4.  
V I T A L S I G N S .............................................................................................................................................. 3 5  
7. 5.  
H EI G H T , W
EI G H T , A N D P H Y SI C A L E X A MI N A TI O N  ...................................................................................... 3 5  
7. 6.  
H E M A T O L O G Y L A B O R A T O R Y A S S E S S M E N T  ............................................................................................... 3 6  
7. 7.  
S E R U M B I O C H E MI S T R Y L A B O R A T O R Y A S S E S S M E N T  ................................................................................. 3 6  
7. 8.  
U RI N A L Y SI S  ............................................................................................................................................... 3 6  
7. 9.  
R E N A L U L T R A S O U N D  ................................................................................................................................ 3 7  
7. 1 0.  
1 2 -L E A D E C G  ........................................................................................................................................... 3 7  
7. 1 1.  
S T U D Y D R U G A D MI NI S T R A TI O N  ................................................................................................................ 3 7  
7. 1 2.  
S T U D Y D R U G C O M P LI A N C E  ....................................................................................................................... 3 7  
7. 1 3.  
A D V E R S E E V E N T S  ..................................................................................................................................... 3 8  
7. 1 4.  
C O N C O MI T A N T M E DI C A TI O N S  ................................................................................................................... 3 8  
7. 1 5.  
6 -M I N U T E W
A L K T E S T  .............................................................................................................................. 3 8  
7. 1 6.  
T I M E D F U N C TI O N T E S T S  ............................................................................................................................ 3 8  
7. 1 7.  
N O R T H S T A R A M B U L A T O R Y A S S E S S M E N T  ................................................................................................ 3 8  
7. 1 8.  
P E R F O R M A N C E O F U P P E R L I M B A S S E S S M E N T ( P U L) ................................................................................ 3 9  
7. 1 9.  
A C TI VI TI E S O F D AI L Y L I VI N G/ DI S E A S E S Y M P T O M S U R V E Y  ....................................................................... 3 9  
7. 2 0.  
P O D CI  Q U E S TI O N N AI R E  ........................................................................................................................... 3 9  
7. 2 1.  
S PI R O M E T R Y  ............................................................................................................................................. 3 9  
7. 2 2.  
B L O O D F O R A N A L Y SI S O F P H A R M A C O KI N E TI C S  ......................................................................................... 3 9  
7. 2 3.  
B L O O D C O L L E C TI O N S U M M A R Y  ................................................................................................................ 4 0  
8.  
A D V E R S E E V E N T A S S E S S M E N T S  ............................................................................................................. 4 0  
8. 1.  
A D V E R S E E V E N T D E FI NI TI O N S  .................................................................................................................. 4 0  
8. 1. 1.  
A dverse Eve nts  ..................................................................................................................................... 4 0  
8. 1. 2.  
Seri o us A dverse Eve n ts ( S A Es) ............................................................................................................ 4 1  
8. 1. 3.  
U nex pecte d A dverse Eve nts  ................................................................................................................. 4 2  
8. 2.  
E LI CI TI N G A D V E R S E E V E N T IN F O R M A TI O N  ............................................................................................... 4 3  
8. 3.  
A D V E R S E E V E N T R E C O R DI N G  ................................................................................................................... 4 3  
8. 4.  
D E S C RI BI N G A D V E R S E E V E N T R E L A TI O N S HI P T O S T U D Y D R U G  ................................................................ 4 3  
8. 5.  
G R A DI N G O F S E V E RI T Y O F A D V E R S E E V E N T S  ........................................................................................... 4 4  
8. 6.  
P R E G N A N C Y O F F E M A L E P A R T N E R S  .......................................................................................................... 4 4  
8. 7.  
F O L L O W -U P O F U N R E S O L V E D A D V E R S E E V E N T S  ...................................................................................... 4 5  
8. 8.  
A D V E R S E E V E N T R E P O R TI N G P E RI O D  ....................................................................................................... 4 5  
8. 9.  
IN V E S TI G A T O R S I T E A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S  .......................................................... 4 5  
8. 1 0.  
P T C  T H E R A P E U TI C S A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S  ......................................................... 4 7  


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 7  of 9 1  
 
9.  
WI T H D R A W A L O F P A TI E N T S  ................................................................................................................... 4 7  
1 0.  
S T A TI S TI C S A N D D A T A M A N A G E M E N T ................................................................................................ 4 8  
1 0. 1.  
S A M P L E S I Z E C A L C U L A TI O N  ...................................................................................................................... 4 8  
1 0. 2.  
S T U D Y P O P U L A TI O N D E FI NI TI O N  ............................................................................................................... 4 8  
1 0. 2. 1.  
S afety P o p ul ati o n  ............................................................................................................................ 4 8  
1 0. 2. 2.  
Ev al u a ble P o p ul ati o ns  .................................................................................................................... 4 8  
1 0. 3.  
G E N E R A L S T A TI S TI C A L  C O N SI D E R A TI O N S  ................................................................................................. 4 8  
1 0. 4.  
S P E CI FI C S T A TI S TI C A L A N A L Y S E S  ............................................................................................................. 4 8  
1 0. 4. 1.  
St u dy C o n d uct a n d P atie nt Dis p ositi o n  .......................................................................................... 4 8  
1 0. 4. 2.  
Use of C o nc o mit a nt Me dic ati o n a n d S u p p ortive T her a py  .............................................................. 4 8  
1 0. 4. 3.  
Pri m ary V ari a bles –  S afety  ............................................................................................................. 4 9  
1 0. 5.  
S E C O N D A R Y E N D P OI N T S  ........................................................................................................................... 5 0  
1 0. 5. 1.  
6 Mi n ute W alk Test  ......................................................................................................................... 5 0  
1 0. 5. 2.  
Ti me d F u ncti o n Tests ( T F Ts)  .......................................................................................................... 5 0  
1 0. 5. 3.  
N ort h St ar A m b ul at ory Assess me nt ( N S A A)  .................................................................................... 5 0  
1 0. 5. 4.  
Pe di atric O utc o mes D at a C ollecti o n I nstr u me nt ( P O D CI) Tr a nsfers/ B asic M o bility a n d  
S p orts/ P hysic al F u ncti o ni n g sc ores  ................................................................................................................... 5 1  
1 0. 5. 5.  
Perf or m a nce U p per Li m b ( P U L) Assess me nt  ................................................................................. 5 1  
1 0. 5. 6.  
Activities of D aily Livi n g/ Dis e ase St at us S urvey  ............................................................................ 5 1  
1 0. 5. 7.  
S pir o metry  ....................................................................................................................................... 5 1  
1 0. 5. 8.  
At al ure n Pl as m a C o nce ntr ati o ns  .................................................................................................... 5 1  
1 0. 5. 9.  
Ex pl or ati o n of C orrel ati o ns  ............................................................................................................ 5 1  
1 1.  
S T U D Y C O M MI T T E E S  ................................................................................................................................. 5 2  
1 1. 1.  
S T U D Y S T E E RI N G C O M MI T T E E  .................................................................................................................. 5 2  
1 1. 2.  
D A T A M O NI T O RI N G C O M MI T T E E  ............................................................................................................... 5 2  
1 2.  
O B LI G A TI O N S O F T H E I N V E S TI G A T O R A N D T H E S P O N S O R  ......................................................... 5 3  
1 2. 1.  
C O M P LI A N C E WI T H E T HI C A L A N D R E G U L A T O R Y G UI D E LI N E S  ................................................................... 5 3  
1 2. 2.  
IN S TI T U TI O N A L R E VI E W B O A R D /IN D E P E N D E N T E T HI C S C O M MI T T E E  ........................................................ 5 3  
1 2. 3.  
IN F O R M E D C O N S E N T / AS S E N T  .................................................................................................................... 5 3  
1 2. 4.  
C A S E R E P O R T F O R M S  ................................................................................................................................ 5 4  
1 2. 5.  
S T U D Y R E C O R D S  ....................................................................................................................................... 5 4  
1 2. 6.  
C O N FI D E N TI A LI T Y  ..................................................................................................................................... 5 5  
1 2. 7.  
R E T E N TI O N O F R E C O R D S  ........................................................................................................................... 5 5  
1 2. 8.  
M O NI T O RI N G A N D A U DI TI N G  ..................................................................................................................... 5 6  
1 2. 9.  
T E R MI N A TI O N O F T H E S T U D Y  .................................................................................................................... 5 6  
1 2. 1 0.  
P U B LI C N O TI FI C A TI O N O F S T U D Y C O N D U C T  ......................................................................................... 5 6  
1 2. 1 1.  
D I S S E MI N A TI O N O F R E S U L T S  ................................................................................................................ 5 7  
1 2. 1 2.  
C O M M U NI C A TI O N WI T H R E G U L A T O R Y A U T H O RI TI E S  ............................................................................ 5 7  
1 3.  
R A TI O N A L E F O R S T U D Y D E SI G N F E A T U R E S  ...................................................................................... 5 7  
1 3. 1.  
P A TI E N T S E L E C TI O N  .................................................................................................................................. 5 7  
1 3. 1. 1.  
Overvie w  ......................................................................................................................................... 5 7  
1 3. 1. 2 . 
Re pr o d uctive C o nsi der ati o ns  .......................................................................................................... 5 8  
1 3. 1. 3.  
C o nc o mit a nt T her a pies  ................................................................................................................... 5 8  
1 3. 1. 4.  
S afety Pr ofili n g  ............................................................................................................................... 5 8  
1 3. 1. 5.  
St u dy Dr u g C o m pli a nce  .................................................................................................................. 5 8  
1 3. 1. 6.  
Tr o u g h At al ure n Pl as m a C o nce ntr ati o ns  ....................................................................................... 5 8  
1 3. 1. 7.  
Ti mi n g o f Assess me nts..................................................................................................................... 5 8  
1 3. 2.  
T R E A T M E N T A N D S A F E T Y M O NI T O RI N G P L A N  .......................................................................................... 5 9  
1 3. 2. 1.  
Sc he d ule a n d D ose Selecti o n  .......................................................................................................... 5 9  


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 8  of 9 1  
 
1 3. 2. 2.  
D ur ati o n of T her a py  ....................................................................................................................... 5 9  
1 3. 2. 3.  
S afety M o nit ori n g  ............................................................................................................................ 5 9  
1 3. 2. 4.  
Re n al M o nit ori n g Pl a n  ................................................................................................................... 6 1  
1 3. 2. 5.  
He p atic M o nit ori n g Pl a n  ................................................................................................................ 6 4  
1 3. 2. 6.  
Li pi d Pr ofile  .................................................................................................................................... 6 4  
1 3. 2. 7.  
Bl o o d Press ure Assess me nt  ............................................................................................................. 6 4  
1 3. 2. 8.  
Ot her N o ncli nic al Fi n di n gs  ............................................................................................................ 6 4  
1 3. 2. 9.  
Ot her A b n or m alities  ........................................................................................................................ 6 5  
1 3. 2. 1 0.  
Acti o ns t o be T ake n i n Res p o nse t o S afety Si g n als  ......................................................................... 6 5  
1 3. 2. 1 1.  
C o nc o mit a nt T her a pies  ................................................................................................................... 6 5  
1 3. 3.  
S T U D Y C O M MI T T E E S  ................................................................................................................................. 6 6  
1 3. 4.  
E F FI C A C Y M E A S U R E M E N T S ........................................................................................................................ 6 6  
1 3. 4. 1.  
6 -Mi n ute W alk Test  ......................................................................................................................... 6 6  
1 3. 4. 2.  
Ti me d F u ncti o n Tests  ...................................................................................................................... 6 7  
1 3. 4. 3.  
N ort h St ar A m b ul at ory Assess me nt  ................................................................................................. 6 7  
1 3. 4. 4.  
Perf or m a nce of U p per Li m b Assess me nt ( P U L)  ............................................................................. 6 7  
1 3. 4. 5.  
S pir o metry  ....................................................................................................................................... 6 7  
1 3. 4. 6.  
Pe di atric Q u ality of Life I nstr u me nt  ............................................................................................... 6 8  
1 3. 4. 7.  
Activities of D aily Livi n g a n d Dise ase Sy m pt o m S urvey  ................................................................. 6 8  
1 4.  
B E N E FI T S A N D RI S K S  ................................................................................................................................. 6 9  
1 4. 1.  
B E N E FI T S A N D R I S K S: N O N C LI NI C A L  ......................................................................................................... 6 9  
1 4. 2.  
B E N E FI T S A N D R I S K S: C LI NI C A L E F FI C A C Y  ................................................................................................ 7 0  
1 4. 3.  
B E N E FI T S A N D R I S K S: C LI NI C A L S A F E T Y  ................................................................................................... 7 2  
1 4. 4.  
B E N E FI T / RI S K C O N C L U SI O N S  .................................................................................................................... 7 2  
BI B LI O G R A P H Y  ...................................................................................................................................................... 7 4  
A P P E N D I X A. 
M A N A G E M E N T O F C O R TI C O S T E R OI D S  ....................................................................... 8 3  
A P P E N DI X B.  
D E C L A R A TI O N O F H E L SI N KI  ........................................................................................... 8 8  
 LI S T O F T A B L E S  
T A B L E 1.   S U G G E S T E D D AI L Y D O SI N G S C H E D U L E  ........................................................................................................ 2 4  
T A B L E 2.   S A F E T Y M O NI T O RI N G P A R A M E T E R S A N D A C TI O N S T O B E T A K E N  ............................................................... 2 6  
T A B L E 3.  S C H E D U L E O F E V E N T S  ................................................................................................................................ 3 3  
T A B L E 4.   B L O O D D R A WI N G R E Q UI R E M E N T S ............................................................................................................. 4 0  
T A B L E 5.   R E L A TI O N S HI P O F S T U D Y D R U G T O A D V E R S E E V E N T  .................................................................................. 4 4  
T A B L E 6.   G R A DI N G O F A D V E R S E E V E N T S E V E RI T Y  ..................................................................................................... 4 4  
T A B L E 7 .  IN V E S TI G A T O R  S I T E R E P O R TI N G R E Q UI R E M E N T S F O R A D V E R S E E V E N T S  ..................................................... 4 6  
  


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
Version 2.0 
 
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Page 9 of 91 
 
ABBREVIATIONS 
Abbreviation 
Definition 
6MWD 
6-minute walk distance 
6MWT 
6-minute walk test 
99m-Tc-DTPA 
99m-diethylenetriamine pentaacetic acid  
ACE 
Angiotensin converting enzyme (inhibitor) 
ACTH 
Adrenocorticotropic hormone 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
ARB 
Angiotensin receptor blocker 
AST 
Aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical 
AUC 
 
Area under the concentration versus time curve 
AUC0-24 
Area under the concentration versus time curve from time 0 to 24 hours 
BCRP 
Breast Cancer Resistant Protein 
BID 
Bis in die (2 times per day) 
BMD 
Becker muscular dystrophy 
BUN 
Blood urea nitrogen 
CAP 
College of American Pathologists 
CF 
Cystic fibrosis 
CFR 
Code of Federal Regulations 
CFTR 
Cystic fibrosis transmembrane conductance regulator 
cGMP 
Current Good Manufacturing Practices 
CHF 
Congestive heart failure 
CI 
Confidence Interval 
CK 
Creatine kinase 
CLIA 
Clinical Laboratory Improvement Act/Amendment 
Cmax 
Maximum plasma concentration 
CRF 
Case report form 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
D/C 
Discontinuation 
DMC 
Data monitoring committee 
DBMD 
Duchenne and Becker muscular dystrophy 
DMD 
Duchenne muscular dystrophy 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRFs 
Electronic case report forms 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
FDAMA 
Food and Drug Administration Modernization Act of 1997 


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
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PTC Therapeutics, Inc.  – Confidential 
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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
HDL 
High-density lipoprotein 
HPLC/MS-MS 
High-performance liquid chromatography with tandem mass spectrometry 
HRQL 
Health-related quality of life 
ICH 
International Conference on Harmonisation 
ICJME 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug (Application) 
IRB/IEC 
Institutional Review Board/Institutional Ethics Committee 
IV 
Intravenous  
IVR 
Interactive voice response 
IWR 
Interactive Web Response 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LLN 
Lower limit of normal 
LOAEL 
Lowest observed adverse effect level 
MCID 
Minimal clinically important difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intention-to-treat 
MPS 
Mucopolysaccharidosis 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
nmDBMD 
Nonsense mutation Duchenne and Becker muscular dystrophy 
NOAEL 
No-observed-adverse-effect level 
NSAA 
North Star Ambulatory Assessment 
OAT 
Organic Anion Transporter 
PedsQL 
Pediatric Quality of Life Inventory 
PK 
Pharmacokinetic(s) 
PODCI 
Pediatric Outcomes Data Collection Instrument 
PUL 
Performance of Upper Limb Assessment 
QD 
Once a day 
SAE 
Serious adverse event 
SD 
Standard deviation 
SSC 
Study steering committee 
t1/2 
Plasma half-life 
TEAE 
Treatment-emergent adverse event 
TFT 
Timed function test 
TID 
Ter in die (3 times per day) 
Tx 
Treatment 
ULN 
Upper limit of normal 
US 
United States  
WHODRUG 
World Health Organization Drug Dictionary 
 
 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 1 1  of 9 1  
 
1.  O V E R VI E W  
1. 1.  B a c k gr o u n d  
D uc he n ne m usc ular d ystr o p h y ( D M D) is a disa bli n g a n d life -t hreate ni n g X-li n ke d ge netic 
dis or der [ W ort o n 2 0 0 1 , K h ura na 2 0 0 3 ] ca use d b y defects i n t he ge ne f or d ystr o p hi n, a pr otei n 
t hat sta bilizes m uscle cell me m bra nes [La pi d os 2 0 0 4 ].  D ue t o m uscle fra gilit y, b o ys wit h D M D  
de vel o p m uscle wea k ness t hat lea ds t o deteri orati o n of a m b ulati o n, w heelc hair de pe n de nc y, a n d  
e ve nt ual res pirat or y a n d car diac fail ure wit h deat h b y 1 5 t o 2 2 years of a ge [ Br o o ke 1 9 8 9 , 
Mc D o nal d 1 9 9 5 , W ort o n 2 0 0 1 ].  M ost patie nts are c haracterize d as ha vi n g D uc he n ne m usc ular  
d ystr o p h y a n d e x perie nce o nset of s y m pt o ms d u ri n g earl y c hil d h o o d [Ciafal o ni 2 0 0 9 ].  A s mall  
s u bset ( ~ 1 0 %) of b o ys is classifie d as ha vi n g Bec ker m usc ular d ystr o p h y ( B M D), a 
p he n ot y picall y mil der f or m of d ystr o p hi n o pat h y t hat is ass ociate d wit h later ma nifestati o n of  
s y m pt o ms [E mer y 1 9 9 1 ].  O nl y c hr o nic a d mi nistrati o n of c ortic oster oi ds has sl o we d pr o gressi o n  
of d ystr o p hi n o pat h y.  H o we ver, c ortic oster oi ds d o n ot a d dress t he u n derl yi n g ca use of 
d ystr o p hi n o pat h y, are t y picall y ass ociate d wit h seri o us se q uelae, a n d are n ot al wa ys e m pl o ye d.  
T here is n o c urre nt t hera p y f or t he u n derl yi n g ca use of d ystr o p hi n o pat h y.   I n ~ 1 3 % of b o ys wit h 
D uc he n ne/ Bec ker m usc ular d ystr o p h y ( D B M D ) , t he ca usati ve defect i n t he d ystr o p hi n ge ne is a 
n o nse nse m utati o n t hat tr u ncates d ystr o p hi n pr otei n pr o d ucti o n b y i ntr o d uci n g a pre mat ure st o p 
c o d o n i nt o t he d ystr o p hi n messe n ger ri b o n ucleic aci d ( m R N A) [ De nt 2 0 0 5 ].  N o nse nse m utati o n 
D B M D ( n m D B M D) is esti mate d t o affect ~ 1 7 0 0 b o ys i n t he U nite d States a n d ~ 2 2 0 0 b o ys i n 
E ur o pe [ Hira wat 2 0 0 4a , Hira wat 2 0 0 4 b ].   
Atal ure n is a n orall y  bi oa vaila ble, i n vesti gati o nal ne w dr u g t hat pr o m otes ri b os o mal rea dt hr o u g h 
of pre mat ure st o p c o d o ns [ Welc h 2 0 0 7 , D u 2 0 0 8 , Wa n g 2 0 1 0 , G ol d ma n n 2 0 1 1 , Ta n 2 0 1 1 , 
Ka yali 2 0 1 2 ].  I n re p orter assa ys, as well as i n n o ncli nical m o dels of ge netic disease, atal ure n 
de m o nstrates t he a bilit y t o s pecificall y a n d selecti vel y e na ble ri b os o mal rea dt hr o u g h of m R N A 
c o ntai ni n g a pre mat ure st o p c o d o n, i n d uci n g pr o d ucti o n of pr otei n t hat l ocalizes t o t he 
a p pr o priate cell ular l ocati o n a n d is f u ncti o nall y acti ve [ Welc h 2 0 0 7 , D u 2 0 0 8 , Wa n g 2 0 1 0 , 
G ol d ma n n 2 0 1 1 , Ta n 2 0 1 1 , Ka yali 2 0 1 2 ].  I n vitr o a n d i n vi v o st u dies i n n m D B M D ha ve s h o w n 
t hat atal ure n ca n rest ore pr o d ucti o n of t he missi n g d ystr o p hi n [Welc h 2 0 0 7 , Ka yali 2 0 1 2 ]. 
A pre vi o us P hase 2a st u d y ( P T C 1 2 4 -G D -0 0 4 -D M D ; St u d y 0 0 4) e nrolle d 3 8 b o ys wit h n m D M D, 
i ncl u di n g a m b ulat or y a n d n o na m b ulat or y patie nts , t o recei ve 2 8 da ys of atal ure n treat me nt.  I n 
t his st u d y, i ncreases i n i n vitr o a n d i n vi v o m uscle d ystr o p hi n e x pressi o n a n d re d ucti o ns i n ser u m 
c o nce ntrati o ns of m uscle -deri ve d cre ati ne ki nase ( C K) were o bser ve d.  Of t he 3 8  patie nt s, 3 6 
patie nts  s u bse q ue ntl y e nr olle d i nt o a P hase 2a o pe n la bel e xte nsi o n st u d y ( P T C 1 2 4 -G D -0 0 4e -
D M D ; St u d y 0 0 4e).  T hese patie nts recei ve d t he 2 0 -, 2 0-, 4 0-m g/ k g d ose le vel of atal ure n f or a 
me dia n [ra n ge] of 7 0 [ 5 3 t o 8 1] wee ks .  
A P hase 2 b, i nter nati o nal, m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, 
d ose -ra n gi n g, efficac y, a n d safet y st u d y ( St u d y P T C 1 2 4-G D -0 0 7 -D M D; St u d y 0 0 7) e val uati n g 
atal ure n i n patie nts wit h n m D B M D was c o n d ucte d.  Patie n ts were 5 t o 2 0 years of a ge a n d were 
a m b ulat or y at baseli ne.  T he y were ra n d o mize d 1: 1: 1 t o recei ve place b o; a tal ure n at a l o w d ose 
of  1 0 m g/ k g ( m or ni n g), 1 0 m g/ k g ( mi d da y), 2 0 m g/ k g (e ve ni n g); or atal ure n  at a hi g h d ose of  
2 0  m g/ k g ( m or ni n g), 2 0 m g/ k g ( m i d da y), 4 0 m g/ k g (e ve ni n g).  Patie nts c o m pleti n g t his st u d y 
c o nti n ue d t o recei ve hi g h -d ose atal ure n i n a n o pe n -la bel e xte nsi o n t o t his st u d y ( P T C 1 2 4-G D -


Protocol Number PTC124-GD-020e-DMD  
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007e-DMD; Study 007e).  The safety data from Study 007 revealed a favorable ataluren safety 
profile across both ataluren dose levels.  Efficacy data indicated that patients receiving the 10, 10, 
20 mg/kg dose experienced a slower loss of walking ability relative to patients receiving placebo.  
Efficacy in the 20, 20, 40 mg/kg-dose ataluren arm was not better than observed in the placebo 
arm.  Given these data suggesting the potential for an inverse dose-response relationship favoring 
the 10, 10, 20 mg/kg dose of ataluren, the data monitoring committee (DMC) for the ataluren 
DBMD program recommended discontinuation of ongoing studies evaluating 20, 20, 40 mg/kg 
dose of ataluren.  Consequently, ataluren administration in the open-label extension studies 
(Studies 004e and 007e) and in an additional open-label study assessing the safety and exposure 
profiles of ataluren in nonambulatory patients with nmDBMD (Study PTC124-GD-008-DMD; 
Study 008) was halted in March 2010.   
At the end of Study 007 (Week 48), the mean change from baseline in 6-minute walk distance 
(6MWD) was ~30 meters greater in patients treated with the 10, 10, 20 mg/kg dose than in 
patients treated with placebo, consistent with the 30-meter change specified in the study protocol 
as being clinically relevant.  The improvement among patients treated with the 10, 10, 20 mg/kg 
dose compared to patients treated with placebo was generally consistent regardless of age, use of 
corticosteroids, or walking ability at the beginning of the study.  There was no difference 
between the 20, 20, 40 mg/kg-dose and placebo in change in 6MWD over 48 weeks.   
Timed function tests of muscle function (stair climbing, stair descending, and walking/running 
10 meters) revealed supportive trends for ataluren relative to placebo, as evidenced by less 
decline over 48 weeks. These changes were clinically relevant at the 10, 10, 20 mg/kg dose. 
Patient/parent-reported data showed that the frequency of accidental falls over 48 weeks was 
lower in both ataluren treatment arms relative to placebo.  Positive trends favoring ataluren 10, 
10, 20 mg/kg vs placebo were also seen for various other measures of physical functioning, 
including activity and wheelchair use in the community setting, patient-reported physical 
functioning as measured by the PedsQL, and myometric evaluation of muscle strength.  
Mean changes in other secondary outcome measures were generally small; the meaningfulness of 
these results is unclear given the lack of prior experience in dystrophinopathy and/or other known 
limitations associated with these evaluations. 
These encouraging data led to the conduct of a Phase 3, international, multicenter, randomized, 
double-blind, placebo-controlled, efficacy and safety study (Study PTC124-GD-020-DMD).  
This ongoing Phase 3 study includes a treatment period of 48 weeks and an estimated recruitment 
period of ~18 months at ~50 investigational sites worldwide.  The first patient in study 
PTC124-020-DMD initiated study drug treatment on 10 April 2013.   
All patients who successfully complete the Phase 3 double-blind, placebo-controlled study 
(PTC124-GD-020-DMD) will be eligible for this Phase 3 open-label, extension study 
(PTC124-GD-020e-DMD).  This Phase 3 extension study will evaluate the long-term safety and 
efficacy of ataluren 10-, 10-, and 20-mg/kg.  
 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 1 3  of 9 1  
 
1. 2.  St u d y D e si g n  
T he pri mar y o bjecti ve  of t his P hase 3 e xte nsi o n st u d y will be t o o btai n  l o n g-ter m safet y data t o 
a u g me nt t he o verall safet y data base.  T he sec o n dar y o bjecti ves will be t o a u g me nt t he efficac y 
data  c ollecte d i n t he d o u ble -bli n d st u d y  (P T C 1 2 4 -G D -0 2 0 -D M D ).   
Scree ni n g a n d baseli ne pr oce d ures are str uct ure d t o a v oi d a ga p i n tre at me nt bet wee n t he 
d o u ble -bli n d st u d y ( P T C 1 2 4 -G D -0 2 0 -D M D ) a n d t his e xte nsi o n st u d y.  W he n p ossi ble, 
Scree ni n g/ Baseli ne ( Visit 1) f or t his e xte nsi o n st u d y s h o ul d occ ur o n t he sa me da y as t he 
E n d -of -St u d y visit f or t he d o u ble -bli n d st u d y ( P T C 1 2 4 -G D -0 2 0 -D M D ).  D uri n g t he treat me nt 
peri o d, st u d y assess me nts will be perf or me d at cli nic visits at Wee k 1 2 a n d t hereafter  e ver y 1 2 
wee ks u ntil t he e n d of t he st u d y.   
2.  I N T R O D U C TI O N 
2. 1.  Di s e a s e  I n di c ati o n 
D B M D  is a n X-li n ke d dis or der ca use d b y defects i n t he ge ne f or d ystr op hi n, a pr otei n t hat is 
critical t o t he str uct ural stabilit y of m y ofi bers i n s keletal, dia p hra g matic, a n d car diac m uscle 
[W ort o n  2 0 0 1 , K h ura na 2 0 0 3 ].  T he pre vale nce is esti mate d at ~ 1 3, 0 0 0  males  i n t he 
U nite d  States ( U S ) a n d ~ 1 7, 0 0 0  b o ys i n t he E ur o pea n Uni o n ( E U)  [Hira wat 2 0 0 4a , 
Hira wat  2 0 0 4 b ]. 
D ystr o p hi n is a hi g h -m olec ular -wei g ht c yt os kelet o n pr otei n l ocalize d at t he i n ner s urface of t he 
m uscle me m bra ne [ W ort o n 2 0 0 1 ].  It is part of a d ystr o p hi n-gl yc o pr otei n c o m ple x t hat als o 
i ncl u des d ystr o gl yca n a n d sarc o gl yca ns.  T his c o m ple x pr o vi des a bri d ge acr oss t he m uscle 
me m bra ne; d ystr o p hi n c o u ples acti n i n t he c yt o plas m wit h d ystr o gl yca n.  D ystr o p hi n deficie nc y 
desta bilizes t he d ystr o p hi n -gl yc o pr otei n c o m ple x, i m pairi n g l ocalizati o n of t he d ystr o gl yca n a n d 
sarc o gl yca ns t o t he m uscle me m bra ne, a n d c o m pr o misi n g t he str uct ural i nte grit y of t he 
me m bra ne.  T he a bse nce of n or mall y f u ncti o ni n g d ystr o p hi n res ults i n sarc ole m mal brea k d o w n, 
calci u m i o n i nfl u x, p h os p h oli pase acti vati o n, o xi dati ve m uscle i nj ur y, a n d, ulti matel y, 
m y o necr osis.  As m uscle da ma ge pr o gresses, c o n necti ve tiss ue a n d fat re place m uscle fi bers.  
M ost patie nts wit h d ystr o p hi n o pat h y are c haracterize d as ha vi n g D M D ; t hese patie nts e x perie nce 
o nset of s y m pt o ms d uri n g earl y c hil d h o o d [ Ciafal o ni 2 0 0 9 ].  A s mall s u bset ( ~ 1 0 %) of b o ys is 
classifie d as ha vi n g B M D, a p he n ot y picall y mil der f or m of d ystr o p hi n o pat h y t hat is ass ociate d 
wit h later ma nifestati o n of s y m pt o ms [ E mer y 1 9 9 1 ].  DM D  us uall y first ma nifests i n b o ys ~ 3 t o 
7 years of a ge w he n t he y are n ote d t o de vel o p l or d osis, a wa d dli n g gait, a n d t he G o wers’ si g n (a 
c haracteristicall y a b n or mal met h o d of risi n g fr o m a s u pi ne t o a sta n di n g p ositi o n) [ Br o o ke 1 9 8 9 , 
Mc D o nal d 1 9 9 5 , B ola n d 1 9 9 6 , W ort o n  2 0 0 1 ].  I ne x ora ble pr o gressi ve wea k ness is see n, 
partic ularl y i n t he pr o xi mal m usc ulat ure.  A m b ulati o n bec o mes i ncreasi n gl y a b n or mal.  B y t he 
a ge of 8 years, m ost b o ys ha ve diffic ult y risi n g fr o m t he fl o or a n d asce n di n g stairs a n d t he y ofte n 
fall w hile wal ki n g.  B o ys wit h t he disease s pe n d less ti me wal ki n g a n d wal k more sl o wl y t ha n 
healt h y b o ys [ Mc D o nal d  2 0 0 5a ] a n d are si g nifica ntl y less acti ve t ha n n or mal b o ys of si milar a ge 
[Mc D o nal d  2 0 0 2 , Mc D o nal d 2 0 0 5 b ].  B y 1 0 t o 1 4 years of a ge, m ost are w heelc hair-b o u n d.  I n 
a m b ulat or y D M D b o ys, t he m ost fre q ue nt car diac a b n or m alit y is si n us tac h ycar dia a n d heart rate 
varia bilit y, occ urri n g fr o m c hil d h o o d a n d persisti n g t hr o u g h o ut life [ Fi nsterer 2 0 0 3 , 
G ulati  2 0 0 5 ].  P ul m o nar y f u ncti o n is us uall y n or mal bef ore 1 0 years of a ge a n d is well 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 1 4  of 9 1  
 
mai ntai ne d i nt o a d olesce nce i n b o ys recei vi n g c ortic oster oi ds [ Me n dell 1 9 8 9 , Gri g gs 1 9 9 1 , 
P hilli ps 2 0 0 1 , Ta n gsr u d 2 0 0 1 , Bi g gar 2 0 0 1 , Bi g gar  2 0 0 6 ].  Later i n a d olesce nce, car diac a n d 
dia p hra g matic m uscles bec o me pr o gressi vel y wea ker a n d patie nts re q uire treat me nt f or car diac 
i ns ufficie nc y a n d ve ntilat or y s u p p ort.  Patie nts us uall y die of car diac or p ul m o nar y fail ure b y 
1 5  t o 2 2 years of a ge [Br o o ke 1 9 8 9 , Mc D o nal d  1 9 9 5 , Si m o n ds 1 9 9 8 , W ort o n 2 0 0 1 , Ea gle 2 0 0 2 ].   
2. 2.  At al ur e n ( P T C 1 2 4) 
2. 2. 1.  T h er a p e uti c C o n c e pt  
A m o n g t he se veral t y pes of disease -ca usi n g m utati o n s, a n o nse nse m utati o n is a si n gle-p oi nt 
alterati o n i n o ne of t he n ucle oti des of de o x yri b o n ucleic aci d ( D N A) t hat, w he n c o pie d t o m R N A, 
is i nter prete d as a st o p si g nal b y t he ri b os o mal cell ular tra nslati o nal mac hi ner y.  T he prese nce of 
s uc h a pre mat ure st op si g nal wit hi n t he pr otei n -c o di n g re gi o n of t he m R N A f or d ystr o p hi n tells 
t he ri b os o mes t o halt pr o d ucti o n of t he pr otei n bef ore t he f ull-le n gt h pr otei n is c o m plete d.  T he 
res ulti n g tr u ncate d d ystr o p hi n is t o o s h ort t o ser ve its necessar y f u ncti o n a n d ca uses disease.  It is 
esti mate d t hat ~ 1 0 -1 5 % of all b o ys wit h D M D a n d B M D ha ve a n o nse nse m utati o n as t he basis 
f or t he dis or der [De nt  2 0 0 5 ], res ulti n g i n a pre vale nce of n mD B M D  of ~ 1 7 0 0 b o ys i n t he U nite d 
States a n d ~ 2 2 0 0 b o ys i n E ur o pe.   
It has bee n k n o w n f or s o me ti me t hat dr u gs wit h tra nslati o n-m o dif yi n g mec ha nis ms of acti o n, 
s uc h as t he a mi n o gl yc osi de a nti bi otics (e g, ge nta mici n), ca n a meli orate t he effects of n o nse nse 
m utati o ns i n e x peri me ntal s yste ms.  B y bi n di n g t o t he ri b os o mes, s uc h a ge nts per mit t he 
ri b os o mes t o rei nter pret t he n o nse nse m utati o n st o p si g nal i n m R N A s uc h t hat t he y ca n m o ve 
t hr o u g h t he o bstr ucti o n b y i nserti n g a n a mi n o aci d a n d c o nti n ui n g t he tra nslati o n pr ocess t o 
pr o d uce a f ull -le n gt h f u ncti o nal pr otei n.  I n e x peri me ntal a ni mal s yste ms a n d i n pil ot st u dies i n 
n m D B M D , treat me nt wit h hi g h c o nce ntrati o ns of ge nta mici n has rest ore d pr o d ucti o n of 
f u ncti o nal d ystr o p hi n [ Bart o n -Da vis 1 9 9 9 , P olita n o 2 0 0 3 ].  Si milarl y, n o n cli nical a n d cli nical 
st u dies i n c ystic fi br osis ( C F ) ha ve de m o nstrate d rest orati o n of t he c ystic fi br osis tra ns me m bra ne 
c o n d ucta nce re g ulat or ( C F T R), t he e pit helial c hl ori de c ha n nel t hat is defecti ve i n t hat disease 
[Cla nc y 2 0 0 1 , D u 2 0 0 2 , Wilsc ha ns ki 2 0 0 3 ].  C urre nt data s u g gest t hat t he ge o metr y of m R N A 
a n d ass ociate d i nit iati o n-ter mi nati o n pr otei ns is criticall y differe nt at a pre mat ure st o p t ha n at a 
n or mal st o p .  T his ma y e x plai n w h y a dr u g ca n per mit t he ri b os o mes t o selecti vel y rea d t hr o u g h 
t he pre mat ure st o p c o d o n, b ut will n ot all o w t he ri b os o mes t o rea d t hr o u g h t he n or mal st o p 
c o d o n at t he e n d of t he m R N A pr otei n -c o di n g re gi o n [Sac hs 2 0 0 0 , Welc h 2 0 0 0 , A mra ni  2 0 0 4 ].  
Beca use seri o us re nal a n d otic t o xicities a n d t he nee d f or pare nteral a d mi nistrati o n precl u de t he 
l o n g-ter m cli nical use of ge nta mici n, t here has bee n c onsi dera ble i nterest i n t he i de ntificati o n of 
safer a n d m ore c o n ve nie ntl y a d mi nistere d, l o w-m olec ular -wei g ht, s y nt hetic c o m p o u n ds wit h t he 
a bilit y t o pr o m ote rea dt hr o u g h of disease -ca usi n g n o nse nse m utati o ns.   
A tal ure n as a n orall y bi oa vaila ble, s mall m olec ule wit h p ote ntial cli nical utilit y i n treati n g 
ge netic dis or ders t hr o u g h i n d ucti o n of rea dt hr o u g h of n o nse nse m utati o ns a n d pr o d ucti o n of 
f ull-le n gt h, f u ncti o nal pr otei ns.  Atal ure n d oes n ot pr o m ote rea dt hr o u g h of n or mal st o p c o d o ns, 
alter m R N A le vels, o r affect t he pr ocess of n o nse nse-m utati o n -me diate d m R N A deca y.  I n t he 
s u bset of patie nts  w h ose disease is me diate d b y a n o nse nse m utati o n, cli nical de vel o p me nt of 
atal ure n ma y offer a defi niti ve t hera p y b y o verc o mi n g t he basic ca use f or D B M D  a n d ot her 
dis a bli n g a n d life-t hreate ni n g ge netic dis or ders. 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 1 5  of 9 1  
 
2. 2. 2.  C h e mi c al D e s cri pti o n  
Atal ure n is a ne w c he mical e ntit y wit h a c he mical f or m ula of C 1 5H 9F N 2O 3 a n d a m olec ular 
wei g ht of 2 8 4. 2 Dalt o ns.  Atal ure n is a Bi o p har mace utical Classificati o n S yste m Class  2 
c o m p o u n d, p o ssessi n g l o w a q ue o us s ol u bilit y ( < 3 1 µ g/ m L) b ut h ig h per mea bilit y acr oss 
gastr oi ntesti nal e pit heli u m, c o nsiste nt wit h its oral bi oa vaila bilit y.   
2. 2. 3.  Cli ni c al St u di e s  
P h a s e 1 St u di e s  
T w o P hase 1 safet y a n d p har mac o ki netic ( P K ) st u dies of atal ure n were c o n d ucte d i n 6 2  healt h y 
a d ult male a n d fe male v ol u nteers ra n gi n g i n a ge fr o m 1 8 t o 3 0 years [ Hira wat 2 0 0 7 ].  S i n gle 
d oses of atal ure n a d mi nistere d orall y at d ose le vels ra n gi n g fr o m 3 t o 1 0 0  m g/ k g  were palata ble 
a n d ge nerall y well t olerate d .  Mil d a d verse e ve nts o f mil d hea dac he, dizzi ness, na usea, v o miti n g, 
diarr hea, a n d a b d o mi nal pai n  at d ose le vels of 1 5 0 a n d 2 0 0  m g/ k g a p peare d t o be c oi nci de nt wit h 
ac hie vi n g t he ma xi m u m c o nce ntrati o n ( C ma x ).  Ele vati o ns of ser u m ala ni ne a mi n otra nsferase 
( A L T) a n d as partate a mi notra nsferase ( A S T) were o bser ve d i n 1  s u bject recei vi n g a si n gle d ose 
of 2 0 0  m g/ k g .  Wit h re peate d d oses t hr o u g h 5 0  m g/ k g/ d ose 2 ti mes per da y ( BI D), re versi ble, 
l o w-gra de ( < 2 ti mes t he u p per li mit of n or mal  [ U L N]) tra nsa mi nase ele vati o ns were o bser ve d i n 
s o me patie nts.  N o bilir u bi n i ncreases were o bser ve d.  I n a d diti o n, no n ota ble B U N, creati ni ne, or 
uri nal ysis a b n or malities  were o bser ve d .  P K a nal yses i n dicate d ra pi d oral a bs or pti o n, ge nerall y 
d ose -pr o p orti o nal P K, a n effecti ve plas ma half -life (t1/ 2) i n t he ra n ge of 2 t o 6 h o urs, a n d n o 
rele va nt dr u g acc u m ulati o n wit h re peate d d osi n g.  T he data als o de m o nstrate d t hat atal ure n ca n 
be gi ve n wit h or wit h o ut f o o d a n d t hat tr o u g h plas ma c o nce ntrati o ns e x cee di n g t he ~ 2 -µ g/ m L t o 
~ 1 0 -µ g/ m L tar get val ues acti ve i n t he m dx m o use m o del of D M D mi g ht best be ac hie ve d wit h 
TI D d osi n g after meals.  
T he mass bala nce, a bs or pti o n, meta b olis m, a n d e x creti o n pr ofiles of atal ure n after a si n gle d ose 
of u nla bele d a n d  [ 1 4C] -la bele d atal ure n oral s us pe nsi o n were deter mi ne d i n 7 healt h y male 
s u bjects in a n a d diti o nal  P hase 1  st u d y.  Eac h s u bject recei ve d 1 3 7 5 m g [ 1 8. 5 m g/ k g] of 
u nla bele d atal ure n a n d 9 6. 6 µ Ci of [ 1 4C]atal ure n ( ~ 0. 5 m g).  W h ole bl o o d a n d plas ma sa m ples, 
a n d uri ne a n d feces were c ollecte d u p t o 2 6 4 h o urs after d osi ng.  T he res ults s h o we d t hat t he 
maj orit y of circ ulati n g t otal ra di oacti vit y i n plas ma was ass ociate d wit h u nc ha n ge d atal ure n.  
Atal ure n was n ot hi g hl y ass ociate d wit h re d bl o o d cells.  T he o nl y meta b olite detecte d i n plas ma 
after oral a d mi nistrati o n of ata l ure n was atal ure n ac yl gl uc ur o ni de, w hic h re prese nte d ~ 8 %, o n 
a vera ge, of t he e x p os ure ( area u n der t he c o nce ntrati o n -ti me c ur ve [A U C ]) relati ve t o atal ure n.  
T he t otal mea n rec o ver y of t he a d mi nistere d ra di oacti ve d ose was c o m plete ( ~ 1 0 2 %), wit h 5 5 % 
rec o ver y i n uri ne a n d 4 7 % i n feces.  Base d o n t he mea n uri nar y rec o ver y of ra di oacti vit y, t he 
a bs ol ute bi oa vaila bilit y of atal ure n is esti mate d t o be ≥5 5 %.  T he maj orit y of t he ra di oacti vit y 
rec o vere d i n uri ne re prese nte d atal ure n ac yl gl uc ur o ni de ( ~ 4 9 % of t he a d mi nistere d d ose); 
u nc ha n ge d atal ure n i n uri ne re prese nte d < 1 % of t he a d mi nistere d d ose.  T he pri mar y dr u g -relate d 
m oiet y i n feces was a meta b olite ( M 2) f or me d as a res ult of a re d ucti ve clea va ge of t he 
o x a diaz ole ri n g of atal ure n, f oll o we d b y h y dr ol ysis; u nc ha n ge d atal ure n i n feces re prese nte d 
~ 0. 4 % of t he ra di oacti ve d ose.  M 2 is pres u ma bl y t he pr o d uct of meta b olis m of atal ure n b y fecal 
micr o or ga nis ms.  T he eli mi nati o n of atal ure n is li kel y de pe n de nt o n he patic gl uc ur o ni dati o n of 
atal ure n f oll o we d b y re nal e x creti o n of t he res ulti n g gl uc ur o ni de meta b oli te.  


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
Version 2.0 
 
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Page 16 of 91 
 
Phase 2 Clinical Studies in Duchenne/Becker Muscular Dystrophy 
 
 
Phase 2a Study 
The initial evaluation of ataluren in nmDMD was a Phase 2a, open-label, sequential 
dose-ranging, activity, safety, and PK study PTC124-GD-004-DMD (Study 004) conducted at 
3 centers in the United States.  Participants in the study were 38 boys with nmDMD ranging in 
age from 5 to 17 years.  Cohorts received sequential, escalating dose levels of ataluren in a single 
56-day cycle, comprising 28 days of drug administration and 28 days of follow-up.  The first 
cohort of 6 patients received drug TID at morning, midday, and evening doses of 4-, 4-, and 
8-mg/kg.  A second cohort of 20 patients received drug TID at doses of 10-, 10-, and 20-mg/kg.  
Thereafter, a further cohort of 12 patients received drug TID at doses of 20-, 20-, and 40-mg/kg.   
The primary outcome measure was muscle dystrophin expression.  As assessed by quantitative 
immunohistochemistry, ataluren induced a mean [SD] 11.1 [24.3] % increase in muscle 
dystrophin expression over the 28 days of treatment, with 23/38 (61%) of patients showing a 
response (positive change).  Serum CK reductions were observed in 92% (35/38) of patients 
during ataluren administration.  With cessation of ataluren treatment, mean serum CK 
concentrations reverted toward baseline.  Changes in myometry scores and timed function tests 
were small and not statistically significant with 28 days of ataluren treatment.  However, parents 
and teachers of several boys noted evidence of greater activity, increased endurance, and less 
fatigue during ataluren administration; these effects waned after the cessation of ataluren.  The 
timing of the onset and reversion of CK and symptomatic effects provided additional support for 
ataluren pharmacological activity.  
Mild treatment-emergent adverse events of transient headache and gastrointestinal complaints 
were observed at all 3 dose levels and appeared consistent with background symptoms 
commonly observed in clinical trials.  No clearly dose-dependent increases in frequency or 
severity were evident.  Episodes of nausea and vomiting were primarily related to anesthesia 
administered at the time of muscle biopsies.  No drug-related serious adverse events (SAEs) were 
reported.  There were no safety concerns identified in patients’ physical examinations, vital sign 
measurements, or electrocardiograms (ECGs), and none of the patients had clinically concerning 
laboratory abnormalities.  Consistent with this safety profile, compliance was excellent; on 
average, boys received >99% of the planned ataluren doses and no patient discontinued ataluren 
due to an adverse event.   
Mean values for Cmax and area under the concentration-time curve through 24 hours (AUC0-24) 
for ataluren plasma concentrations on Days 1 and 28 showed no drug accumulation and no 
change in ataluren exposures in boys receiving or not receiving corticosteroids as treatment for 
DMD.  At the 10-, 10-, 20-mg/kg and 20-, 20-, 40-mg/kg dose levels, mean trough plasma 
concentrations exceeding target values active in the mdx mouse model of DMD were achieved. 
 
Phase 2b Study  
Based on the Phase 2a results, a Phase 2b, randomized, double-blind, placebo-controlled study 
PTC124-GD-007-DMD (Study 007) of ataluren in nmDBMD was conducted at 37 centers in 
11 countries.  Participants in the study were 174 boys with nmDBMD ranging in age from 
5 to 20 years.  Patients were randomized 1:1:1 so that 57 received placebo, 57 received the 


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
Version 2.0 
 
PTC Therapeutics, Inc.  – Confidential 
Page 17 of 91 
 
low-dose the ataluren 10-, 10-, 20-mg/kg dose, and 60 received the ataluren 20-, 20-, 40-mg/kg 
dose for a duration of 48 weeks.   
At the end of Study 007 (Week 48), the mean change from baseline in 6-minute walk distance 
(6MWD) was ~30 meters greater in patients treated with the 10, 10, 20 mg/kg dose than in 
patients treated with placebo, consistent with the 30-meter change specified in the study protocol 
as being clinically relevant.  The improvement among patients treated with the 10, 10, 20 mg/kg 
dose compared to patients treated with placebo was generally consistent regardless of age, use of 
corticosteroids, or walking ability at the beginning of the study.  There was no difference 
between the 20, 20, 40 mg/kg-dose and placebo in change in 6MWD over 48 weeks.   
Timed function tests of muscle function (stair climbing, stair descending, and walking/running 
10 meters) revealed supportive trends for ataluren relative to placebo, as evidenced by less 
decline over 48 weeks. These changes were clinically relevant at the 10, 10, 20 mg/kg dose. 
Patient/parent-reported data showed that the frequency of accidental falls over 48 weeks was 
lower in both ataluren treatment arms relative to placebo.  Positive trends favoring ataluren 
10, 10, 20 mg/kg vs placebo were also seen for various other measures of physical functioning, 
including activity and wheelchair use in the community setting, patient-reported physical 
functioning as measured by the PedsQL, and myometric evaluation of muscle strength. Mean 
changes in other secondary outcome measures were generally small; the meaningfulness of these 
results is unclear given the lack of prior experience in dystrophinopathy and/or other known 
limitations associated with these evaluations. 
Measurement of muscle dystrophin expression was included in this study as an exploratory 
secondary endpoint.  However, the data are compromised by poor sample quality and 
inadequacies in currently available methods.  Consequently, no conclusions can be drawn from 
the analyses of muscle dystrophin expression. 
Ataluren was well tolerated at both the low- and high-dose levels.  The majority of 
treatment-emergent adverse events were mild (Grade 1) to moderate (Grade 2).  The most 
frequent adverse events were vomiting (46.6%), headache (29.3%), and diarrhea (24.1%).  The 
only adverse event that showed potential dose-relatedness was abdominal pain, occurring in 7% 
of patients receiving placebo, 12.3% of patients receiving low-dose ataluren, and 16.7% of 
patients receiving high–dose ataluren.  Investigators’ attributions of drug-relatedness were 
similar across the placebo- and ataluren-treated groups.  None of the patients prematurely 
discontinued treatment because of adverse events.  No ataluren-related SAEs were reported.  
There were no safety concerns identified in patients’ physical examinations, vital sign 
measurements, or ECGs, and none of the patients had clinically concerning laboratory 
abnormalities.     
Median study drug compliance was >97% in each treatment arm.  Ataluren plasma 
concentrations were obtained prior to the morning dose (trough) and 2 hours after the morning 
dose at each visit.  These plasma concentrations were dose-proportional and well-maintained 
over time. 
 
Other Completed Studies 
Patients completing Study 007 were eligible to enroll in an open-label extension trial PTC124-
GD-007e-DMD (Study 007e).  Of the 174 patients participating in the blinded Phase 2b study, 


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
Version 2.0 
 
PTC Therapeutics, Inc.  – Confidential 
Page 18 of 91 
 
173 patients enrolled in this study.  These patients received the 20-, 20-, 40-mg/kg dose level of 
ataluren for a median [range] of 22 [11 to 57] weeks before the study was discontinued on 
03 March 2010.  The safety findings from this study confirmed that ataluren was well tolerated; 
there were no concerning safety signals evident in the patients participating in this trial.   
Patients completing Study 004 were eligible to enroll in an open-label extension trial.  Of the 
38 patients participating in the prior Phase 2a study, 36 patients enrolled in an open-label 
extension study PTC124-GD-004e-DMD (Study 004e).  These patients received the 20-, 20-, 
40-mg/kg dose level of ataluren for a median [range] of 70 [53 to 81] weeks before the study was 
discontinued on 03 March 2010.  The safety results from this trial also documented good 
tolerability for ataluren; there were no worrisome ataluren-related adverse events reported for the 
patients participating in this trial.   
In addition, an open-label Phase 2a study PTC124-GD-008-DMD (Study 008) was conducted in 
nonambulatory patients with nmDBMD; this study was discontinued on 03 March 2010.  At the 
time of discontinuation, 6 patients had received the 20, 20, 40 mg/kg dose level of ataluren for 
periods ranging from1 week to 6 weeks.  While no safety concerns were identified during this 
study, with the small number of patients and short duration of dosing, no definitive conclusions 
can be drawn from this study regarding the safety profile of ataluren 20, 20, and 40 mg/kg in 
nonambulatory boys with nmDBMD. 
The results of the nmDBMD program were reviewed by an independent DMC on 
24 February 2010.  It was the DMC opinion that there were no safety concerns based on the 
available data.     
 
 
Ongoing Study PTC124-GD-016-DMD 
A Phase 3 open-label, study PTC124-GD-016-DMD (Study 016) to assess the safety of ataluren 
in patients who participated in one of the 5 previous ataluren nmDBMD studies at an investigator 
site in the US is ongoing.  As of 01 September 2015, this study had enrolled 108 patients who 
received ataluren for a median of 124 weeks (range, 4 to 249 weeks).   
 
Ongoing Study PTC124-GD-019-DMD 
A Phase 3 open-label, study PTC124-GD-019-DMD (Study 019) to assess ataluren in patients 
who participated in one of the 5 previous ataluren nmDBMD studies at an investigator site in 
Europe, Israel, Australia and Canada is ongoing.  As of 11 November 2015, this study has 
enrolled 95 patients who received ataluren for a median of 128 weeks (range, 16 to 166 weeks).   
Safety Experience in Other Indications 
Ataluren is currently being evaluated in children and adults with nonsense mutation cystic 
fibrosis. Detailed descriptions of these studies and safety information from them are provided in 
the Ataluren Investigator Brochure. 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 1 9  of 9 1  
 
3.  
S T U D Y O B J E C TI V E  A N D E N D P OI N T S  
3. 1.  Pri m ar y O bj e cti v e  
T o e val uate t he l o n g -ter m safet y of atal ure n i n b o ys wit h n o nse nse m utati o n d ystr o p hi n o pat h y, as 
deter mi ne d b y a d verse e ve nts a n d la b orat or y a b n or malities.  
3. 2.  S e c o n d ar y O bj e cti v e s  
T he se c o n dar y o bjecti ves , w hic h e val uate t he effects of atal ure n o n maj or cli nical ma nifestati o ns 
of D M D, a re: 
P hysic al  
•  T o deter mi ne t he effect of atal ure n o n a m b ulati o n  i n patie nt s w h o are a m b ulat or y .  
•  T o e val uate t he effect of atal ure n o n pr o xi mal m uscle f u ncti o n i n patie nt s w h o are a ble t o 
perf or m ti me d f u ncti o n tests . 
•  T o e val uate t he effect of atal ure n o n p h ysical f u ncti o n i n patie nt s w h o are a ble t o perf or m t he 
N ort h Star A m b ulat or y Assess me nt . 
•  T o e val uate t he effect of atal ure n o n u p per li m b f u ncti o n.   
P ul m o n ary f u ncti o n  
•  T o e val uate t he effect of atal ure n o n p ul m o nar y f u ncti o n . 
P atie nt -re p orte d o utc o mes 
•  T o deter mi ne t he effect of atal ure n o n healt h -relate d q ualit y of life ( H R Q L) as re p orte d b y 
patie nt s a n d pare nts/care gi vers. 
•  T o assess t he effect of atal ure n o n acti vities of dail y li vi n g .  
Ex p os ure  
•  T o assess l o n g -ter m atal ure n plas ma e x p os ure. 
3. 3.  Cli ni c al E n d p oi nt s  
Pri m ary  
•  Safet y pr ofile c haracterize d b y t y pe, fre q ue nc y, se verit y, ti mi n g, a n d relati o ns hi p t o 
atal ure n of a n y a d verse e ve nts or la b orat or y a b n or ma lities 
Sec o n d ary  
P h ysic al  
•  C ha n ge i n a m b ulati o n as meas ure d b y t he 6 M W T  
•  C ha n ge i n pr o xi mal m uscle f u ncti o n as assesse d b y ti me d f u ncti o n tests (ti me t o rise fr o m 
s u pi ne p ositi o n, ti me t o r u n 1 0 meters, a n d ti me t o cli m b / desce n d 4  stairs) 
•  C ha n ge i n p h ysical f u ncti o n as assesse d b y t he N ort h Star A m b ulat or y Assess me nt 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 2 0  of 9 1  
 
•  C ha n ge i n m ot or perf or ma nce of t he u p per li m b as meas ure d b y t he Perf or ma nce U p per Li m b 
( P U L) 
P ul m o n ar y f u ncti o n  
C ha n ge i n p ul m o nar y f u ncti o n as meas ure d b y s pir o metr y  (e g. F V C, F E V 1) 
P atie nt -Re p orte d O utc o mes  
•  C ha n ge i n patie nt - a n d pare nt/care gi ver -re p orte d H R Q L as meas ure d b y t he P O D CI 
Tra nsfer/ Basic M o bilit y a n d S p orts/ P h ysical F u ncti o ni n g sc ores  
•  C ha n ge i n patie nt  a n d pare nt/care gi ver re p orte d acti vities of dail y li vi n g  
E x p os ure  
•  Pre -d ose atal ure n plas ma c o nce ntrati o ns pri or t o m or ni n g atal ure n a d mi nistrati o n at eac h 
cli nic visit as assesse d b y a vali date d bi oa nal ytical met h o d   
S af et y  
•  C ha n ge fr o m baseli ne i n ot her safet y para meters (e g, vital si g ns)  
 
4.  
P A TI E N T  S E L E C TI O N C RI T E RI A  
4. 1.  O v er vi e w  
T his cli nical st u d y ca n f ulfill its o bjecti ves o nl y if a p pr o priate patie nts  are e nr olle d.  T he 
f oll o wi n g eli gi bilit y criteria are desi g ne d t o select patie nts  f or w h o m st u d y partici pati o n is 
c o nsi dere d a p pr o priate.  All rele va nt me dical a n d n o n -me dical c o n diti o ns s h o ul d be ta ke n i nt o 
c o nsi derati o n w he n deci di n g w het her t his pr ot oc ol is s uita ble f or a partic ular patie nt .  Eli gi bilit y 
criteria ma y n ot be wai ve d a n d c o nf or ma nce t o t he eli gi bilit y criteria is s u bject t o re vie w i n t he 
case of a G o o d Cli nical Practice ( G C P) or a re g ulat or y a ut h orit y a u dit.  A n y q uesti o ns re gar di n g 
a patie nt ’s eli gi bilit y s h o ul d be disc usse d wit h t he P T C T hera pe utics me d ical m o nit or pri or t o 
e nr oll me nt.  
4. 2.  I n cl u si o n Crit eri a 
Patie nt s m ust meet all of t he f oll o wi n g c o n diti o ns t o be eli gi ble f or e nr oll me nt i nt o t he st u d y:  
1.  C o m pleti o n of st u d y treat me nt i n t he pre vi o us P hase  3, d o u ble -bli n d st u d y pr ot oc ol ( Pr ot oc ol 
P T C 1 2 4 -G D -0 2 0 -D M D).  
2.  E vi de nce of si g ne d a n d date d i nf or me d c o nse nt/asse nt d oc u me nt(s) i n dicati n g t hat t he patie nt  
(a n d/ or his pare nt/le gal g uar dia n) has bee n i nf or me d of all perti ne nt as pects of t he trial.  
N ote: If t he st u dy c a n di d ate is c o nsi dere d a c hil d u n der l oc al re g ul ati o n, a p are nt or le g al 
g u ar di a n m ust pr ovi de writte n c o nse nt pri or t o i niti ati o n of st u dy scree ni n g pr oce d ures 
a n d t he st u dy c a n di d ate m ay be re q uire d t o pr ovi de writte n asse nt.  T he r ules of t he 
res p o nsi ble I nstit uti o n al Revie w B o ar d/I n de pe n de nt Et hic C o m mittee (I R B/I E C) 
re g ar di n g w het her o ne or b ot h p are nts m ust pr ovi de c o nse nt a n d t he a p pr o pri ate a ges f or 
o bt ai ni n g c o nse nt a n d asse nt fr o m t he p atie nt  s h o ul d be f oll o we d.   


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
Version 2.0 
 
PTC Therapeutics, Inc.  – Confidential 
Page 21 of 91 
 
3. In patients who are sexually active, willingness to abstain from sexual intercourse or employ 
a barrier or medical method of contraception during the study drug administration and 
6-week follow-up period. 
4. Willingness and ability to comply with scheduled visits, ataluren administration plan, study 
procedures, laboratory tests, and study restrictions.   
4.3. Exclusion Criteria 
Prior to treatment with study drug, it will be confirmed that the patient meets none of the 
following conditions: 
1. Known hypersensitivity to any of the ingredients or excipients of the study drug (Litesse® 
UltraTM [refined polydextrose], polyethylene glycol 3350, Lutrol® micro F127 [poloxamer 
407], mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, vanilla, Cab-O-Sil® M5P 
[colloidal silica], magnesium stearate). 
2. Ongoing participation in any other therapeutic clinical trial.  
3.    Prior or ongoing medical condition (eg, concomitant illness, psychiatric condition, 
behavioral disorder, alcoholism, drug abuse), medical history, physical findings, ECG 
findings, or laboratory abnormality that, in the investigator’s opinion, could adversely affect 
the safety of the patient, makes it unlikely that the course of treatment or follow-up would be 
completed, or could impair the assessment of study results. 
5. 
ENROLLMENT PROCEDURES 
5.1. Source and Number of Patients 
Patients for this Phase 3 extension study are derived only from those who completed blinded 
study drug in the Phase 3 study (PTC124-GD-020-DMD). 
5.2. Screening and Study Drug Allocation 
The investigator must inform each prospective patient of the nature of the study, explain the 
potential risks, and obtain written informed consent/assent from the patient and/or the 
parent/legal guardian prior to performing any study related screening procedures.   
The patient number used in the prior Phase 3 study (Protocol Number PTC124-GD-020-DMD) 
shall be retained for use in this study.  This patient number must be used for patient identification 
on all study-related documents (case report forms [CRFs], clinic notes, laboratory samples, etc).  
The user will need to supply the Interactive Voice Response/Interactive Web Response 
(IVR/IWR) system with the information required by the system (eg, site number, patient 
number).


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
Version 2.0 
 
PTC Therapeutics, Inc.  – Confidential 
Page 22 of 91 
 
6. 
STUDY DRUG ADMINISTRATION 
6.1. Investigational Product 
6.1.1. Ataluren (PTC124) 
Ataluren will be provided as a white to off-white powder for oral suspension.  The drug has been 
manufactured under cGMP conditions.  The formulation includes matrix and suspending agents, 
surfactants, and various excipients that aid in the manufacturing process.  The powder for oral 
suspension are packaged in aluminum-foil, child-resistant sachets (packets) and supplied in dose 
strengths containing 125, 250, or 1000 mg of the active drug substance.  For administration, the 
powder in the sachet may be mixed with water, milk (skim, 1% fat, 2% fat, whole milk, 
chocolate milk, or lactose-free milk), or in semi-solid food (yogurt, pudding, or applesauce). 
6.1.2. Drug Kits 
Drug kits will be provided, each of which contains 90 sachets of one of the dose strengths 
(125, 250, or 1000 mg.). 
6.1.3. Study Drug Packaging and Labeling 
Sachets and cartons will be color coded to indicate dosage strength (125 mg – yellow, 250 mg – 
pink, 1000 mg – blue).   
Labels will be provided in appropriate languages as required by each country in which the study 
is conducted.  The content of the labeling will be in accordance with local regulatory 
specifications and requirements.  
6.1.4. Study Drug Dispensing 
Dosing of ataluren will be based on milligrams of drug per kilogram of patient body weight at 
Screening/Baseline (Visit 1) and will be adjusted to allow for dosing with the available sachet 
dose strengths.  The sachet dosage strengths and number of sachets to be taken per dose will be 
provided by the IVR/IWR system.   
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing study 
drug according to the IVR/IWR system directions.  Sufficient study drug will be provided for 
each study period at the beginning of the period.  
Because of potential changes in patient body weight over time, weight-based dose adjustments 
will occur every 6 months.  Depending upon the magnitude of change in patient body weight 
since baseline, the number and type of sachets to be used by the patient may remain the same or 
may be adjusted.   
 
6.1.5. Return of Study Drug 
Patients should return all remaining study drug (all unused sachets) to the study site at the end of 
each 12-week treatment period for inventory.  The Study Drug Administration Record will serve 
as the source document for drug supply to the patients and will document the return of any 
unused drug for compliance assessments.   


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 2 3  of 9 1  
 
6. 1. 6.  St or a g e a n d St a bilit y  
Kits c o ntai ni n g sac hets of st u d y dr u g will be s hi p pe d a n d st ore d at r o o m t e m perat ure 
( ~ 1 5 t o 3 0 °C).  T he a vaila ble sta bilit y data fr o m re prese ntati ve sa m ple s s u p p ort t he use of t he 
dr u g pr o d uct f or 4 8  m o nt hs w he n st ore d at r o o m te m perat ure.  T he sta bilit y of t he cli nical st u d y 
sa m ples or re prese ntati ve sa m ples will be m o nit ore d t o s u p p ort t he cli nical st u d y.   
6. 1. 7.  St u d y Dr u g A c c o u nt a bilit y  
St u d y pers o n nel m ust e ns ure t hat all st u d y dr u g s u p plies are te m perat ure m o nit ore d a n d ke pt i n a 
sec ure l oc ke d area wit h access li mite d t o a ut h orize d pers o n nel.  T his st u d y pr o d uct m ust n ot be 
use d o utsi de t he c o nte xt of t his pr ot oc ol.  U n der n o circ u msta nces s h o ul d t he i n vesti gat or or site 
pers o n nel s u p pl y st u d y pr o d uct t o ot her i n vesti gat ors or cli nics, or all o w t he s u p plies t o be use d 
ot her t ha n as directe d b y t his pr ot oc ol.  
T he i n vesti gat or a n d/ or t he res p o nsi ble site pers o n nel m ust mai ntai n acc urate rec or ds of t he 
recei pt of all st u d y dr u g s hi p pe d b y P T C T hera pe utics or its desi g nee, i ncl u di n g, b ut n ot li mite d 
t o, t he date recei ve d, l ot n u m ber, a m o u nt recei ve d, a n d t he dis p ositi o n of all st ud y dr u g.  C urre nt 
rec o nciliati o n a n d dis pe nsi n g rec or ds m ust als o be mai ntai ne d t hat i ncl u de t he date a n d a m o u nt 
of dr u g dis pe nse d, a n d patie nt ’s assi g ne d st u d y n u m ber.   
De pe n di n g u p o n t he decisi o n of P T C  T hera pe utics, u n use d cli nical s u p plies m ust be des tr o ye d or 
m ust be ret ur ne d t o P T C  T hera pe utics or its desi g nee after t he st u d y is c o m plete d.  
Acc o u nta bilit y m ust be verifie d b y t he site m o nit or pri or t o ret ur n or destr ucti o n.  Rec or ds 
d oc u me nti n g t he date of st u d y dr u g destr ucti o n or s hi p pi n g, rele va nt sac het n u m bers, a n d a m o u nt 
destr o ye d or s hi p pe d s h o ul d be ke pt i n t he i n vesti gat or site st u d y file.  
6. 1. 8.  O v er d o s e Pr e c a uti o n s  
F or a n y patie nt  e x perie nci n g a n o ve r d ose (a d mi nistrati o n of a st u d y dr u g d ose  > 4  ti mes t he 
hi g hest i nte n de d t otal dail y d ose le vel  f or t his pr ot oc ol [ >1 6 0  m g/ k g/ da y]) , o bser vati o n f or a n y 
s y m pt o matic si de effects s h o ul d be i nstit ute d, a n d vital si g ns a n d bi oc he mical a n d he mat ol o gical 
para meters s h o ul d be f oll o we d cl osel y (c o nsiste nt wit h t he pr ot oc ol or m ore fre q ue ntly, as 
nee de d).  A p pr o priate s u p p orti ve ma na ge me nt t o miti gate a d verse effects s h o ul d be i nitiate d.  
Pe n di n g t he ac q uisiti o n of s ufficie nt h u ma n e x perie nce wit h t he dr u g, use of gastric la va ge or 
i n d ucti o n of e mesis is n ot s pecificall y rec o m me n de d n or c o ntrai n dicate d.   
T he P T C  T hera pe utics me dical m o nit or m ust be c o ntacte d if a n o ver d ose occ urs.  U n der 
a p plica ble re g ulati o ns, o ver d osi n g ma y be c o nsi dere d a n S A E a n d s h o ul d be re p orte d 
acc or di n gl y (see Secti o ns 8. 1. 1  a n d 8. 1. 2 ).   
6. 1. 9.  I n a d v ert e nt E x p o s ur e a n d S pill Pr e c a uti o n s 
Refere nce ca n be ma de t o t he Atal ure n I n vesti gat or Br oc h ure f or c urre nt i nf or mati o n o n 
i na d verte nt e x p os ures a n d s pill preca uti o ns.   


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 2 4  of 9 1  
 
6. 2.  St u d y Dr u g Tr e at m e nt  
6. 2. 1.  D ur ati o n of Tr e at m e nt  
I n t his st u d y, treat me nt will c o m prise c o nti n u o us dail y treat me nt wit h atal ure n f or u p t o 
1 4 4  wee ks ( ~ 3  years).  T his st u d y ma y be f urt her e xte n de d b y a me n d me nt u ntil eit her atal uren  
bec o mes c o m merciall y a vaila ble or t he cli nical de vel o p me nt of atal ure n i n D M D is disc o nti n ue d.   
6. 2. 2.  S c h e d ul e of A d mi ni str ati o n  
As n ote d i n  Ta ble 1 , 3 d oses s h o ul d be ta ke n per da y –  t he 1st d ose i n t he m or ni n g, t he 2 n d d ose 
d uri n g t he mi d dle of t he da y ( mi d -da y), a n d t he 3 r d d ose i n t he e ve ni n g.  I deall y eac h d ose s h o ul d 
be ta ke n wit hi n ~ 3 0  mi n utes after a meal (e g, ~ 7: 0 0 A M after brea kfast, ~ 1: 0 0 P M after l u nc h, 
a n d ~ 7: 0 0  P M after di n ner) .  I nter vals f or d osi n g s h o ul d be ~ 6 h o urs (± 1  h o ur ) bet wee n m or ni n g 
a n d mi d-da y d oses, ~ 6  h o urs (± 1  h o ur ) bet wee n mi d -da y a n d e ve ni n g d oses, a n d ~ 1 2  h o urs 
(± 1  h o ur ) bet wee n e ve ni n g d oses a n d t he m or ni n g d ose o n t he ne xt da y .  W hile it is realize d t hat 
variati o ns i n d osi n g sc he d ule ma y occ ur i n t he o ut patie nt setti n g, t he prescri be d re gi me n 
(i ncl u di n g d osi n g i nter vals a n d t he relati o ns hi p of d osi n g t o meals) s h o ul d be f oll o we d cl osel y o n 
t he da y prece di n g P K sa m ple c ollecti o n i n t he cli nic.    
T a bl e 
T a bl e 1 .  S u g g est e d D ail y D osi n g Sc h e d ul e
.  S u g g est e d D ail y D osi n g Sc h e d ul e 
D o s e D e si g n ati o n  
Pr e c e di n g M e al  
E x a m pl e D o si n g Ti m e s a  
M or ni n g  
Br e a kf a st  
~ 7: 0 0 A M  –   0 7 0 0 h o ur s ( ± 1 h o ur)  
 
 
↑ 
 
 
~ 6 h o ur s  
 
 
↓ 
Mi d -d a y  
L u n c h  
~ 1: 0 0  P M  –  1 3 0 0 h o ur s  (± 1 h o ur)  
 
 
↑ 
 
 
~ 6 h o ur s  
 
 
↓ 
E v e ni n g  
Di n n er  
~ 7: 0 0 P M  –  1 9 0 0 h o ur s ( ± 1 h o ur)  
 
 
↑ 
 
 
~ 1 2 h o ur s  
 
 
↓ 
N e xt D a y M or ni n g  
Br e a kf a st  
7: 0 0 A M  –   0 7 0 0 h o ur s ( ± 1 h o ur)  
a  
D o si n g ti m e s ar e e x a m pl e s a n d m a y b e v ari e d t o s uit e a c h p ati e nt ’ s s c h e d ul e.  
H o w e v er, t h e ti m e b et w e e n m or ni n g a n d mi d d a y d o s e s a n d b et w e e n mi d d a y 
a n d e v e ni n g d o s e s s h o ul d b e m ai nt ai n e d at ~ 6 h o ur i nt er v al s, w hil e t h e ti m e 
b e t w e e n t h e e v e ni n g a n d n e xt m or ni n g d o s e s h o ul d b e m ai nt ai n e d at a n ~ 1 2 
h o ur i nt er v al.   
 
 
6. 2. 3.  I n str u cti o n s f or D el a y s i n D o si n g 
If a patie nt  e x perie nces a dela y i n t he a d mi nistrati o n of st u d y dr u g of ≤1  h o ur, t he pla n ne d d ose 
s h o ul d be ta ke n wit h n o c ha n ges t o t he s u bse q ue nt d ose sc he d ules.  F or a patie nt  w h o has a dela y 
of > 1  h o ur b ut ≤4  h o urs, t he pla n ne d d ose s h o ul d be ta ke n; h o we ver, all f ut ure d oses f or t hat da y 
s h o ul d be s hifte d later b y a n a p pr o xi matel y c orres p o n di n g a m o u nt.  F or a patie nt  w h o has a de la y 
i n a d mi nistrati o n of st u d y dr u g of > 4  h o urs, t he d ose s h o ul d n ot be ta ke n.  St u d y dr u g 
a d mi nistrati o n ma y c o nti n ue b ut t he misse d d ose s h o ul d n ot be ma de u p a n d t he pla n ne d ti mi n g 
of s u bse q ue nt st u dy  dr u g d osi n g s h o ul d n ot be altere d.    


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 2 5  of 9 1  
 
6. 2. 4.  St u d y Dr u g Pr e p ar ati o n a n d St or a g e  
St u d y dr u g sac hets s h o ul d be st ore d a n d m o nit ore d at r o o m te m perat ure , a wa y fr o m t he reac h of 
c hil dre n u ntil ti me of rec o nstit uti o n.  T he p o w der i n t he sac het ma y be mi x e d wit h water, mil k 
(s ki m, 1 % fat, 2 % fat, w h ole mil k, c h oc olate m il k, or lact ose free mil k)  o r i n se mi-s oli d f o o d 
( y o g urt, p u d di n g, or a p plesa uce).  T he n u m ber of sac hets t o be ta ke n f or a d ose s h o ul d be 
se parate d fr o m t he t otal n u m ber of sac hets dis pe nse d f or t he patie nt .  T he f ull c o nte nts of t he 
sac hets s h o ul d be mi xe d wit h at least 3 0 m L ( 1 o u nce) of li q ui d, or 3  ta bles p o o ns of se mi-s oli d 
f o o d.  T he pre pare d d ose s h o ul d be mi x e d well bef ore a d mi nistrati o n.  T he a m o u nt of t he li q ui d 
or se mi -s oli d f o o d ca n be i ncrease d base d o n patie nt prefere nce. 
T he cli nic staff will  i nstr uct eac h patie nt  or pare nt/care gi ver o n t he s pecific n u m ber of sac hets t o 
be ta ke n fr o m eac h kit at eac h d ose a n d will pr o vi de detaile d oral directi o ns re gar di n g dr u g 
pre parati o n.  I n a d diti o n, detaile d writte n dr u g mi xi n g a n d d osi n g i nstr ucti o ns wil l be pr o vi de d t o 
t he patie nt  or pare nt/care gi ver w he n dr u g s u p plies are dis pe nse d.  T he cli nic staff s h o ul d atte m pt 
t o f oll o w u p wit h t he patie nt /care gi ver re gar di n g t he dr u g pre parati o n a n d d osi n g pr oce d ures 
wit hi n a n a p pr o priate i nter val (e g, 1 wee k) aft er i nitiati o n of st u d y treat me nt.   
6. 3.  S af et y M o nit ori n g a n d St u d y Dr u g D o s e 
I nt err u pti o n/ M o difi c ati o n 
6. 3. 1.  L a b or at or y A b n or m aliti e s a n d A d v er s e E v e nt s R e q uiri n g E v al u ati o n 
a n d P ot e nti al Dr u g I nt err u pti o n/ M o difi c ati o n  
Patie nt s m ust be m o nit ore d cl osel y f or a d verse e ve nts or la b orat or y a b n or malities d uri n g t he 
c o urse of t he st u d y.   
F or a d verse e ve nts or la b orat or y a b n or malities, t he i n vesti gat or will use j u d g me nt i n deter mi ni n g 
w het her t he e ve nt or a b n or malit y is cli nicall y si g nifica nt, w het her dia g n ostic e val uati o n is 
warra nte d, a n d w het her p ote ntial i nterr u pti o n of st u d y dr u g treat me nt is a p pr o priate.  I n ge neral, 
life-t hreate ni n g ( Gra de 4) or se vere ( Gra de 3) a d verse e ve nts or la b orat or y a b n or malities s h o ul d 
be c o nsi dere d cli nicall y si g nifica nt, alt h o u g h rec urre n t or persiste nt m o derate e ve nts ( Gra de 2) 
ma y als o be c o nsi dere d cli nicall y si g nifica nt i n certai n circ u msta nces.  Refere nce s h o ul d be ma de 
t o t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E), Versi o n 3. 0 (see  
htt p://cte p.c a ncer. g ov/ pr ot oc ol Devel o p me nt/electr o nic _ a p plic ati o ns/ d ocs/ctc aev 3. p df f or gra di n g 
t he se verit y of a d verse e ve nts a n d la b orat or y a b n or malities.   
Ta ble 2  pr o vi des i nf or mati o n o n acti o ns t o be ta ke n i n t he e ve nt t hat a b n or malities are n ote d i n 
s pecifie d la b orat or y para meters.  T hres h ol ds are pr o vi de d f or i nterr u pti n g st u d y dr u g 
i m me diatel y, f or i nterr u pti n g st u d y dr u g after c o nfir mati o n of a val ue be y o n d t he t hres h ol d, or 
f or c o nti n ui n g st u d y dr u g w hile e val uati n g f or p ote ntial dr u g -relate d t o xicit y.  F or a d verse e ve nts 
or la b orat or y a b n or malities n ot liste d i n Ta ble 2 , t he i n vesti gat or s h o ul d use his/ her j u d g me nt i n 
deter mi ni n g w het her t he e ve nt or a b n or malit y is cli nicall y si g nifica nt, w het her dia g n ostic 
e val uati o n is warra nte d, a n d w het her p ote ntial i nterr u pti o n of st u d y dr u g is a p pr o priate.  


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 2 6  of 9 1  
 
T a bl e 
T a bl e 2 . .  S af et y M o nit ori n g P ar a m et ers a n d Acti o ns T o B e T a k e n
S af et y M o nit ori n g P ar a m et ers a n d Acti o ns T o B e T a k e n   
Or g a n S y st e m a n d  
L a b or at or y P ar a m et er  
St o p St u d y Dr u g 
I m m e di at el y, C onfir m 
A b n or m al V al u e,  
a n d T h e n St art W or k -U p  
St o p St u d y Dr u g Aft er  
C o nfir mi n g a  A b n or m al V al u e,  
a n d T h e n St art W or k -U p  
C o nti n u e St u d y Dr u g,  
C o nfir m A b n or m al V al u e,  
a n d t h e n St art W or k -U p a  
H e p ati c  
 
 
 
S er u m t ot al bilir u bi n  
≥Gr a d e 3 ( ≥3. 0 x U L N)  
Gr a d e 2 ( 1. 5 –  3. 0 x U L N)  
--- 
S er u m G G T  
≥Gr a d e 3 ( ≥5. 0 x U L N)  
Gr a d e 2 ( > 2. 5 –  5. 0 x U L N)  
--- 
S er u m A L T  
 
 
↑ of > 1 5 0 U/ L wit h st a bl e 
or  
↓ C K  
R e n al  
 
 
 
S er u m c y st ati n C  
> 2. 0 0 m g/ L  
> 1. 3 3 –  2. 0 0 m g/ L  
--- 
S er u m cr e ati ni n e  
≥ Gr a d e 2 ( ≥1. 5 x U L N f or 
a g e)  
Gr a d e 1 ( > U L N –  1. 5 x U L N f or 
a g e)  
--- 
S er u m B U N  
≥3. 0 x U L N  
≥1. 5 –  3. 0 x U L N  
--- 
Uri n e pr ot ei n: uri n e 
cr e ati ni n e ( s p ot)  
--- 
> 0. 4 0 m g: m g  
--- 
Uri n e pr ot ei n: uri n e 
o s m ol alit y ( s p ot)  
--- 
> 0. 3 0 m g/ L: m O s m/ k g  
--- 
Uri n e bl o o d ( b y 
di p sti c k)  
4 +  ( L ar g e) 
3 +  ( M o d er at e) 
2 +  ( S mall)  
S er u m el e ctr ol yt e s  
Gr a d e 3 -4  
Gr a d e 2  
Gr a d e 1  
S er u m N a +, hi g h  
> 1 5 5 m m ol/ L  
> 1 5 0 –  1 5 5 m m ol/ L  
--- 
S er u m N a +, l o w  
< 1 3 0 m m ol / L 
--- 
--- 
S er u m K +, hi g h  
> 6. 0 m m ol/ L  
> 5. 5 –  6. 0 m m ol/ L  
--- 
S er u m K +, l o w  
< 3. 0 m m ol/ L  
--- 
--- 
S er u m M g 2 + , hi g h 
> 1. 2 3  m m ol/ L  
--- 
--- 
S er u m M g 2 + , l o w 
< 0 . 4 m m ol/ L  
< 0. 5  –  0. 4  m m ol/ L  
--- 
T ot al s er u m C a 2 + , hi g h 
> 3. 1  m m ol/ L  
> 2. 9  –  3. 1  m m ol/ L  
--- 
T ot al s er u m C a 2 + , l o w 
< 1. 7 5  m m ol/ L  
< 2. 0 –  1. 7 5  m m ol/ L  
--- 
S er u m p h o s p h or o u s  
< 0. 6  m m ol/ L  
< 0. 8 –  0. 6  m m ol/ L  
--- 
S er u m H C O 3 - 
< 1 1 m m ol/ L  
< 1 6 –  1 1 m m ol/ L  
--- 
 
 
a     
L a b or at or y a b n or m aliti e s m a y b e c o nfir m e d i m m e di at el y or at t h e n e xt s c h e d ul e d cli ni c vi sit b a s e d o n i n v e sti g at or j u d g m e nt . 
A b br e vi ati o n s:  A C T H = a dr e n o c orti c otr o pi c h or m o n e, A L T = al a ni n e a mi n otr a n sf er a s e, B U N = bl o o d ur e a nitr o g e n, C a 2 +  = c al ci u m,  
C K =  cr e ati n e ki n a s e, G G T = g a m m a gl ut a m yl tr a n sf er a s e, H C O 3 - = bi c ar b o n at e, K + = p ot a s si u m,  
M g 2 +  = m a g n e si u m, N a + = s o di u m, U L N = u p p er li mit of n or m al  
6. 3. 2.  E v al u ati o n of A d v er s e E v e nt s or L a b or at or y A b n or m aliti e s  
W hile s pecific m o nit or i n g, dia g n ostic testi n g, a n d s u p p orti ve care meas ures m ust be i nstit ute d 
base d o n t he cli nical j u d g me nt of t he i n vesti gat or, i n vesti gat ors are e nc o ura ge d t o c o ntact eit her 
t he P T C T hera pe utics me dical m o nit or ( or desi g nee) t o o btai n g ui da nce a n d t o ascertai n w het her 
si milar e ve nts are bei n g see n at ot her i n vesti gat or sites.  T he P T C T hera pe utics me dical m o nit or 
s h o ul d be n otifie d of a n y a d verse e ve nt or la b orat or y a b n or malit y t hat lea ds t o d ose i nterr u pti o n 
a n d s h o ul d be a p prise d of a ncillar y la b orat or y or ot her dia g n ostic fi n di n gs a n d t he e v ol vi n g data 
fr o m a n y w or k-u p of t he i nitial a b n or malit y.  T he P T C  T hera pe utics me dical m o nit or ma y 
s u g gest re vie w of t he case wit h gastr oe nter ol o g y o r ne p hr ol o g y c o ns ulta nts or wit h ot her e x perts 
(eit her at t he site or retai ne d b y P T C  T hera pe utics).   
Cli nical e val uati o ns f or p ote ntial he patic a n d re nal t o xicities ma y i ncl u de t he f oll o wi n g:  
•  He p atic:   T he me dical hist or y, all cli nical bl o o d val ues ( partic ularl y ser u m bilir u bi n, C K, 
G G T, A S T, a n d A L T val ues), a n d all c o nc o m ita nt me dicati o ns s h o ul d be re vie we d.  
De pe n di n g u p o n c ha n ges o bser ve d, t he rec o m me n de d dia g n ostic w or k u p ma y i ncl u de m ore 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 2 7  of 9 1  
 
fre q ue nt m o nit ori n g or f urt her e val uati o ns f or viral he patitis a n d i m m u ne dis or ders; tests f or 
c h olelit hiasis; or a b d o mi nal ultras o u n d, c o m p ute d t o m o gra p h y ( C T), ma g netic res o na nce 
i ma gi n g ( M RI), or ot her i ma gi n g met h o ds. 
•  Re n al:   T he me dical hist or y , baseli ne ultras o u n d data, all cli nical bl o o d a n d uri ne re nal 
val ues, ser u m electr ol ytes, me dicati o ns, a n d p ote ntial pre - or p ost re nal c o n diti o ns s h o ul d be 
re vie we d.  De pe n di n g u p o n t he c ha n ges o bser ve d, rec o m me n de d dia g n ostic w or k u p ma y 
i ncl u de f urt her e val uati o ns of bl o o d or uri ne; tests of gl o mer ular filtrati o n rate ( G F R), 
c o nce ntrati n g a bilit y, or ot her re nal f u ncti o ns; C T, M RI, or ot her  i ma gi n g met h o ds; a n d/ or 
re nal bi o ps y. 
6. 3. 3.  I n str u cti o n s f or R e s u mi n g St u d y Dr u g A d mi ni str ati o n aft er a n 
I nt err u pti o n f or S af et y C o n c er n s 
I n deci di n g w het her t o rei nstit ute st u d y dr u g after a d ose i nterr u pti o n f or a n y cli nicall y si g nifica nt 
safet y c o ncer n, t he i n vesti gat or s h o ul d c o nsi der fact ors s uc h as t he t y pe a n d se verit y of t he 
a d verse e ve nt or la b orat or y a b n or malit y, t he p ote ntial ca usal relati o ns hi p of st u d y dr u g, t he 
patie nt ’s stat us i n ter ms of d ystr o p hi n o pat h y  or ot her healt h c o n diti o ns, a n d t he a bilit y t o m o nit or 
f or rec urre nce of t he e ve nt. 
F or he patic  o r re nal e ve nts (refer t o  Ta ble 2 ), t he le vel of i n vesti gat or certai nt y t hat a n 
a b n or malit y lea di n g t o dr u g i nterr u pti o n is dr u g -relate d s h o ul d be c o nsi dere d str o n gl y i n deci di n g 
w het her or n ot t o rei nstit ute st u d y dr u g treat me nt.  If t he i n vesti gat or c o nsi ders t he he patic or 
re nal e ve nt t o t hat le d t o st u d y dr u g i nterr u pti o n t o be pr o ba bl y relate d t o st u d y dr u g, restarti n g 
st u d y dr u g is n ot a d vise d.  I n t his case, t he patie nt  s h o ul d be disc o nti n ue d fr o m t he st u d y (see 
Secti o ns 6. 3. 4  a n d 9 ).  If t he i n vesti gat or c o nsi ders t he he patic  or re nal e ve nt  t hat pr o m pte d st u d y 
dr u g  i nterr u pti o n t o be p ossi bl y relate d or u nli kel y relate d t o st u d y dr u g, t he i n vesti gat or s h o ul d 
use best j u d g me nt i n deter mi ni n g w het her t o restart st u d y dr u g.  If t he he patic or re nal e ve nt is 
c o nsi dere d u nrelate d t o st u d y dr u g, rei nstit uti o n of st u d y dr u g is rec o m me n de d.   
If t he i n vesti gat or belie ves it is a p pr o priate t o d o s o a n d t he P T C T hera pe utics me dical m o nit or 
has bee n c o ns ulte d, st u d y dr u g ma y be re -i nitiate d.  If t he e ve nt was deter mi ne d t o be u nrelate d 
t o st u d y dr u g, t he st u d y dr u g ma y be res u me d at f ull d ose.  Ot her wise, if t he dr u g is res u me d, it 
s h o ul d be rei nitiate d at half of t he ori gi nal d ose.  I n t he e ve nt t hat c o nti n ui n g at a re d uce d d ose is 
a p pr o priate, t he i n vesti gat or will call t he I V R/I W R s yste m, e nter t he patie nt   n u m ber, a n d i nf or m 
t he I V R/I W R s yste m of t he nee d f or d ose re d ucti o n.  T he I V R/I W R s yste m will pr o vi de details 
re gar di n g t he re vise d n u m ber of st u d y dr u g sac hets t o be use d per d ose.  T he a p pr o priate cli nic 
staff s h o ul d i nstr uct t he patie nt /care gi ver a b o ut t he re vise d n u m ber of st u d y dr u g sac hets t o be 
use d per d ose acc or di n g t o t he ne w sc he d ule pr o vi de d b y t he I V R/I W R s yste m.   
I n ge neral, after d ose re d ucti o n, t he d ose s h o ul d n ot be ret ur ne d t o t he ori gi nal d ose le vel.  
H o we ver, if f urt her e val uati o n re veals t hat t he a d verse e ve nt t hat le d t o d ose re d ucti o n was n ot 
relate d t o t he st u d y dr u g, t he d ose ma y be escalate d t o t he ori gi nal d ose le vel.  I n t he e ve nt t hat a 
ret ur n t o t he ori gi nal d ose le vel is warra nte d, t he i n vesti gat or will call t he I V R/I W R s yste m, e nter 
t he patie nt   n u m ber a n d i nf or m t he I V R/I W R s yste m of t he nee d f or ret ur ni n g t o t he ori gi nal 
d ose.  T he I V R/I W R s yste m will pr o vi de details re gar di n g t he re vise d n u m ber of st u d y dr u g 
sac hets t o be use d per d ose.  T he a p pr o priate cli nic staff s h o ul d i nstr uct t he patie nt /care gi ver 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 2 8  of 9 1  
 
a b o ut t he re vise d n u m ber of st u d y dr u g sac hets t o be use d per d ose acc or di n g t o t he sc he d ule 
pr o vi de d b y t he I V R/I W R s yste m.    
If after d ose re d ucti o n, t he patie nt  e x perie nces a rec urre nce of a pre vi o us a b n or malit y t hat le d t o 
st u d y dr u g d ose i nterr u pti o n or e x perie nces t he ne w occ urre nce of a n u nacce pta ble a d verse e ve nt 
or la b orat or y a b n or malit y, t he i n vesti gat or s h o ul d i nterr u pt st u d y dr u g a n d c o nfer wit h t he 
P T C  T hera pe utics me dical m o nit or re gar di n g t he p ote ntial nee d t o disc o nti n ue st u d y dr u g 
per ma ne ntl y.  
6. 3. 4.  I n str u cti o n s f or Di s c o nti n u ati o n of St u d y Dr u g A d mi ni str ati o n f or 
S af et y C o n c er n s  
If after a p pr o priate c o nsi derati o n of st u d y dr u g i nterr u pti o n/ m o dificati o n a n d c o ns ultati o n wit h 
t he P T C T hera pe utics me dical m o nit or, it is n ot a p pr o priate f o r a patie nt  t o c o nti n ue wit h st u d y 
treat me nt, t he n st u d y dr u g s h o ul d be per ma ne ntl y disc o nti n ue d.  After per ma ne nt disc o nti n uati o n 
of st u d y dr u g f or a safet y c o ncer n, a n d if t he i nitial e ve nt was re p orte d as a S A E, t he n a 
f oll o w-u p S A E re p ort f or m s h o ul d b e c o m plete d.  I n t he case of a treat me nt disc o nti n uati o n d ue 
t o a n e ve nt t hat is n ot a n S A E, t he P T C  T hera pe utics me dical m o nit or s h o ul d be n otifie d (see 
Secti o n 9 ).  I n a d diti o n, details re gar di n g t he reas o ns f or disc o nti n ua ti o n a n d t he a d verse e ve nts 
leadi n g t o t he disc o nti n uati o n s h o ul d be rec or de d i n t he s o urce d oc u me nts a n d i n t he a p pr o priate 
C R F.  T he E n d of Treat me nt  Visit C R F s h o ul d be c o m plete d a n d a p pr o priate f oll o w -u p (at 
~ 6  wee ks as per pr ot oc ol or u ntil rec o ver y fr o m or sta bilizati o n of t he a d v erse e ve nt, w hic he ver 
c o mes last) s h o ul d be i nstit ute d.  
6. 4.  C o n c o mit a nt a n d S u p p orti v e T h er a p y  
Ot her t ha n t he st u d y dr u g, a n y treat me nts (i ncl u di n g prescri pti o n a n d n o n -prescri pti o n dr u gs, 
healt h f o o ds, her bal re me dies, self -prescri be d dr u gs, street dr u g s, t o bacc o pr o d ucts, or alc o h ol) t hat 
are ta ke n b y a patie nt  d uri n g t he scree ni n g peri o d, d uri n g st u d y dr u g a d mi nistrati o n, a n d f or 
6  wee ks after disc o nti n uati o n of st u d y dr u g are c o nsi dere d c o nc o mita nt me dicati o ns.  
I nf or mati o n re gar di n g a n y c o nc o mita nt me dicati o ns will be c ollecte d a n d d oc u me nte d i n t he 
c o nc o mita nt me dicati o n C R F pa ge a n d i n t he s o urce d oc u me nts b y t he cli nic staff.  
6. 4. 1.  
C orti c o st er oi d s  
T o date, c ortic oster oi ds use is t he o nl y p har mac ol o gical i nter ve nti o n t hat has de m o nstrate d 
be nefit i n D M D [Me n del l 1 9 8 9, Fe nic hel  1 9 9 1a , Fe nic hel 1 9 9 1 b , Gri g gs 1 9 9 1 , Bi g gar 2 0 0 1 , 
Bee na k ker 2 0 0 5a , Bi g gar 2 0 0 6 , Pra d ha n 2 0 0 6 ].  T o mi ni mize p ote ntial c o nf o u n di n g effects of 
c ha n ges i n c ortic oster oi d t hera p y o n t he i nter pretati o n of st u d y res ults , t he use of t hese 
me dicati o ns m ust be sta n dar dize d as m uc h as p ossi ble d uri n g t he st u d y.   
A  sta ble a n d sta n dar dize d c ortic oster oi d re gi me n s h o ul d be mai ntai ne d d uri n g t he 1 4 4 wee ks of 
st u d y dr u g treat me nt.  A dj ust me nts i n c ortic oster oi d d osa ge f or i ncreases i n b o d y wei g ht are 
per m itte d b ut are n ot ma n dat or y.  U p war d a dj ust me nts i n c ortic oster oi d d ose f or i ncreases i n 
b o d y wei g ht or ot her reas o ns s h o ul d f oll o w rec o m me n dati o ns pr o vi de d i n A p pe n di x A . 
If a patie nt  e x perie nces a c o ncer ni n g c ortic oster oi d -relate d a d verse e ve nt  (e g. h y perte nsi o n), 
i nter ve nti o ns or p ote ntial a dj ust me nts i n t he c ortic oster oi d d osa ge ma y  be c o nsi dere d, as detaile d 
i n A p pe n di x A .  It s h o ul d be e m p hasize d t hat re d ucti o ns i n c ortic oster oi d d osa ge f or c osmetic or 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
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Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 2 9  of 9 1  
 
ot her mi n or reas o ns s h o ul d be a v oi de d.  Patie nt s w h o re q uire c ortic oster oi d i nterr u pti o n, d ose 
m o dificati o n, or rei nstit uti o n ma y re mai n o n  st u d y dr u g t hera p y.  
6. 4. 2.   A mi n o gl y c o si d e s  
Re nal a b n or malities were o bser ve d i n  a n i nter nati o nal, m ultice nter, d o u ble -bli n d, place b o -
c o ntr olle d P hase 3 trial e val uati n g atal ure n i n patie nts ≥6 years of a ge wit h n o nse nse m utati o n 
c ystic fi br osis i n patie nts recei vi n g c o nc o mita nt atal ure n a n d i ntra ve n o us (I V) a mi n o gl yc osi des 
(as descri be d i n t he Atal ure n I n vesti gat or Br oc h ure).  In patie nts  w h o re q uire treat me nt f or 
seri o us i nfecti o ns, in vesti gat ors s h o ul d s u bstit ute ot her a nti bi otics f or s yste mic a mi n o gl yc osi des 
w he n cli nicall y a p pr o priate .  If I V a mi n o gl yc osi des or ot her ne p hr ot o xic a nti bi otics (e g, 
va nc o m yci n) are a d mi nistere d, st u d y dr u g m ust be i nterr u pte d d uri n g t he c o urse of t hese 
a nti bi otics.  Patie nts re q uiri n g I V a mi n o gl yc osi de or va nc o m yci n t hera p y s h o ul d be cl osel y 
m o nit ore d i n a n a p pr o priate setti n g, s uc h as a h os pital.  I n patie nts recei vi n g p ote ntiall y 
ne p hr ot o xic a ge nts s uc h as I V a mi n o gl yc osi des or va nc o m yci n, a nti bi otic dr u g le vels a n d ser u m 
creati ni ne a n d B U N s h o ul d be f oll o we d cl osel y.  T he a nti bi otic tr o u g h le vel a n d creati ni ne a n d 
B U N s h o ul d be meas ure d wit hi n 2 4 t o 4 8 h o urs of a d mi nistrati o n of t he first a nt i bi otic d ose, a n d 
f urt her a nti bi otic d osi n g s h o ul d be base d o n t hese res ults.  Tr o u g h le vels s h o ul d be meas ure d at 
i nter vals d uri n g t he c o urse of a nti bi otic treat me nt.  Creati ni ne a n d B U N s h o ul d be meas ure d 
pri or t o i nitiati n g I V a mi n o gl yc osi de or va nc o m yc i n t hera p y a n d at least t wice a wee k d uri n g t he 
c o urse of a nti bi otic treat me nt.  
6. 4. 3.  H y dr ati o n  
Beca use of t he p ote ntial ris k of re nal d ysf u ncti o n d uri n g peri o ds of de h y drati o n i n patie nts 
recei vi n g st u d y dr u g, it is i m p orta nt t o e nc o ura ge st u d y patie nts t o mai ntai n a de q uate h y drati o n 
t hr o u g h o ut t he st u d y.  Patie nts s h o ul d be a de q uatel y h y drate d pri or t o recei vi n g p ote ntiall y 
ne p hr ot o xic a ge nts s uc h as a mi n o gl yc osi des or va nc o m yci n, a n d h y drati o n stat us s h o ul d be 
caref ull y m o nit ore d t hr o u g h o ut t he a d mi nistrati o n of t hese a ge nts.  I n vesti gat ors s h o ul d be 
partic ularl y vi gila nt wit h patie nts w h o are e x perie nci n g na usea, v o miti n g, diarr hea, or fe ver, or 
w h o ha ve la b orat or y e vi de nce of de h y drati o n.  
6. 4. 4.  C ar di a c Dr u g s f or C H F Pr o p h yl a xi s/ Tr e at m e nt  
Car diac dr u gs (e g, A C E i n hi bit ors, A R Bs, beta -bl oc kers , etc) ma y be use d i n t he treat me nt of 
C H F i n  n o na m b ulat or y a d olesce nts wit h D M D / B M D a n d ma y i ncreasi n gl y be c o nsi dere d f or use 
as pr o p h yla xis a gai nst s y m pt o matic car diac d ysf u ncti o n i n y o u n ger b o ys wit h t he disease [B osser 
2 0 0 4 , A merica n Aca de m y of Pe diatrics 2 0 0 5 , D u b oc 2 0 0 5 , Kaji m ot o 2 0 0 6 , Ra maci otti  2 0 0 6 ].  I n 
a d diti o n, rece nt st u dies of l osarta n i n t he m dx  m o use m o del of D M D ha ve s u g geste d sal utar y 
effects o n s keletal m uscle re ge nerati o n [ C o h n 2 0 0 7 ], pr o m pti n g use of l osarta n wit h t he h o pe of 
disease palliati o n.   
F or patie nt s w h o are o n car diac dr u gs, a sta ble re gi me n s h o ul d be mai ntai ne d d uri n g t he1 4 4  
st u d y dr u g treat me nt peri o d .  A dj ust me nts i n d osa ge or t y pe of dr u g are per mitte d t o a v oi d 
s y m pt o ms (e g, c o u g h ass ociate d with A C E i n hi bit ors) b ut atte m pts s h o ul d be ma de t o a v oi d 
e ntirel y re m o vi n g patie nt s fr o m C H F pr o p h yla xis/treat me nt.  Patie nt s w h o re q uire i nitiati o n, 
i nterr u pti o n, d ose m o dificati o n, or rei nstit uti o n of C H F pr o p h yla xis/treat me nt ma y re mai n o n  
st u d y dr u g t hera p y. 


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
Version 2.0 
 
PTC Therapeutics, Inc.  – Confidential 
Page 30 of 91 
 
6.4.5. Drugs Metabolized by Cytochrome P450 Enzymes 
As the primary route of ataluren metabolism is via glucuronidation by UGT1A9, clinically 
significant interactions between ataluren and co-administered drugs metabolized by cytochrome 
P450 enzymes (CYPs) are unlikely. In particular, ataluren is not an inhibitor of CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, and does not have induction 
potential on the major CYP enzymes. Based on in vitro studies, ataluren is also not expected to 
be an inhibitor or a substrate of p-gp mediated transport.   
As an added measure of safety, investigators should pay specific attention to use of drugs that are 
known substrates of this enzyme, particularly when such drugs may have a low therapeutic index.   
Drugs that are metabolized by CYP2C8 or CYP2C9 that have low therapeutics indices (in 
particular, paclitaxel for CYP2C8 and coumarin anticoagulants [eg, warfarin], phenytoin, or 
tolbutamide for CYP2C9) may be of particular concern.  Coumarin anticoagulants are cleared by 
CYP2C9 and increases in plasma concentrations of coumarin anticoagulants may result in 
serious clinical consequences.  For patients who require anticoagulation during the study, use of 
an alternative form of anticoagulation (eg, fractionated heparin) should be considered.  Phenytoin 
is metabolized by CYP2C9 and concomitant use with ataluren may be of potential concern.  For 
patients who require anticonvulsant therapy during the study, use of alternative anticonvulsant 
drugs should be considered.  
The metabolism of losartan to its active metabolite may, in part, be mediated by CYP2C9.  
However, concomitant use of losartan and inhibitors of CYP2C9 have not been examined.  
Because this drug does not have a narrow therapeutic window, the potential for mild to moderate 
changes in activity does not require a dose modification. 
 
6.4.6. Potential drug interactions 
Based on in vitro studies, ataluren is a substrate of UGT1A9 and breast cancer resistant protein 
(BCRP).  Caution should be exercised when ataluren is co-administered with drugs that are 
inducers of UGT1A9 (eg, mycophenolate mofetil), or inhibitors of BCRP (eg, cyclosporine). 
In vitro data indicate that ataluren is an inhibitor of UGT1A9, organic anion transporter 1 
(OAT1), organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 1B3 
(OATP1B3).  Caution should be exercised when ataluren is co-administered with drugs that are 
substrates of UGT1A9 (eg, propofol, mycophenolate mofetil), OAT1, OAT3, or OATP1B3 (eg, 
oseltamivir, acyclovir, ciprofloxacin, captopril, furosemide, bumetanide, valsartan, pravastatin, 
rosuvastatin, atorvastatin, pitavastatin) because of the risk of increased concentration of these 
drugs. 
6.4.7. Other Concomitant Medications 
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study medication should be minimized during the study period.  Patients should be 
discouraged from use of “health supplements” (eg, creatine, glutamine, coenzyme Q), herbal 
remedies, growth hormone, self-prescribed drugs, street drugs, tobacco products, or alcohol at any 
time during clinical studies of ataluren.   


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If c o nsi dere d necessar y f or t he patie nt ’s well bei n g , dr u gs f or c o nc o mita nt me dical c o n diti o ns or f or 
s y m pt o m ma na ge me nt ma y be gi ve n at t he discreti o n of t he i n vesti gat or.  T he decisi o n t o a ut h orize 
t he use of a n y ot her dr u g(s) s h o ul d ta ke i nt o acc o u nt patie nt  safet y, t he me dical nee d, t he 
p ote ntial f or dr u g i nteracti o ns, t he p ossi bilit y f or mas ki n g s y m pt o ms of a m ore rele va nt 
u n derl yi n g e ve nt , a n d w het her use of a c o nc o mita nt me dicati o n will c o m pr o mise t he o utc o me or 
i nte grit y of t he st u d y.   
Patie nt s s h o ul d be i nstr ucte d a b o ut t he i m p orta nce of t he nee d t o i nf or m t he cli nic staff of t he use 
of a n y dr u gs or re me dies ( w het her prescri be d, o ver -the -c o u nter, or illicit) bef ore a n d d uri n g t he 
c o urse of t he st u d y.  I nf or mati o n re gar di n g an y c o nc o mita nt dr u gs ta ke n b y a patie nt  d uri n g t he 
c o urse of t he st u d y a n d t he reas o n f or use will be rec or de d i n t he s o urce d oc u me nts a n d i n t he 
c o nc o mita nt me dicat i o n C R F. 
6. 5.  
A s si sti v e D e vi c e s  
D uri n g st u d y -s pecifie d 6 M W Ts, ti me d f u ncti o n tests, N ort h Star A m b ulat or y Assess me nts,  a n d 
P U L assess me nts, patie nt s m ust n ot use assisti ve de vices.   
6. 6.  P h y si c al a n d R e s pir at or y T h er a p y  
T here are neit her restricti o ns n or prescri pti o ns f or p h ysical or res pirat or y t hera p y d uri n g t he 
st u d y.  Sites s h o ul d use l ocal best practices i n pr o vi di n g p h ysical t hera p y s u p p ort f or patie nt s 
partici pati n g i n t he st u d y.  Res pirat or y care g ui deli nes as s u g geste d b y t he A merica n T h oracic 
S ociet y s h o ul d be f oll o we d [ A T S 2 0 0 4 ].  S ites are e nc o ura ge d t o mai ntai n t he sa me ge neral le vel 
of s u p p ort t hr o u g h o ut t he d urati o n of t he st u d y.  
6. 7.  Di et ar y R e stri cti o n s  
T here are n o s pecific dietar y restricti o ns i n t he st u d y.   


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7.  
S C H E D U L E O F E V E N T S A N D S T U D Y P A R A M E T E R S  
7. 1.  S c h e d ul e of E v e nt s  
T he pr o p ose d t y pes a n d ti mi n g of data t o be rec or de d are descri be d i n  Ta ble 3 .  Please see 
Secti o n 7. 2  f or cr oss-refere nce d e x pla nati o ns of t he st u d y pr oce d ures descri be d i n t he ta bles.  
 


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Table 3. Schedule of Events 
 
 
 
 
Study 
Period 
Screening/
Baseline 
Treatment Period 
Post-Treatment     
Post Treatment 
Study Week 
(±7 days) 
Day 
1 
12 
24 
36 
48 
60 
72 
84 
96 
108 
120 
132 
144 
6 
Weeks 
Post-Tx 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Informed 
consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
Xa 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Hematology  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal 
ultrasound 
Xa 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
12-lead ECG  
Xa 
 
 
 
X 
 
 
  
X 
 
 
 
X 
X 
Study drug 
assignment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug 
Dispensed 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug 
compliance  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse 
events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6-minute 
walk test  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Timed 
function tests  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
North Star 
Ambulatory 
Assessment 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Activities of 
Daily 
Living/Diseas
e Status 
Survey  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PODCI 
Questionnair
e 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Spirometry 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PUL 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokin
etics 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a 
Study procedure need not be performed if Day 1 is within 14 days of the end-of-study 
evaluations at Week 48 (Visit 8) of the preceding Phase 3 double-blind study 
(PTC124-GD-020-DMD). 
 
 
 
 
Abbreviations:; D/C = discontinuation; ECG = electrocardiogram; F/U = follow-up; PUL = 
Performance of Upper Limb, Tx = treatment 
 
 
 
 
 
 


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7. 2.  E x pl a n ati o n of St u d y Pr o c e d ur e s  
7. 2. 1.  Tr a n siti o n fr o m t h e P h a s e 3 St u d y, At al ur e n Tr e at m e nt, a n d 
F oll o w -u p P eri o d s  
E ver y eff ort s h o ul d be ma de t o c o n d uct t he Scree ni n g/ Baseli ne visit ( Visit 1) o n Da y 2 of t he 
E n d -of -Treat me nt visit ( Visit 8/ Wee k 4 8) of t he P hase 3 d o u ble -bli n d st u d y 
( P T C 1 2 4-G D -0 2 0 -D M D) t o a v oi d i nterr u pti o n i n treat me nt wit h st u d y dr u g.  Si g nat ure of t he 
i nf or me d c o nse nt/asse nt d oc u me nt(s) f or t his st u d y s h o ul d be o btai ne d after c o m pleti o n of t he 
Da y 2 st u d y pr oce d ures at t he E n d -of -Treat me nt visit ( Visit 8/ Wee k 4 8) of t he P hase 3 d o u ble -
bli n d st u d y ( P T C 1 2 4 -G D -0 2 0 -D M D).    
I n t his P hase 3 e xte nsi o n st u d y, cli nic visits ha ve bee n si m plified fr o m 2 -da y t o 1 -da y visits t o 
re d uce b ur de n f or t he patie nt s a n d st u d y sites.  F or patie nt s o n a n i nter mitte nt treat me nt re gi me n 
of a c ortic oster oi d, cli nic visits s h o ul d be sc he d ule d s uc h t hat st u d y -relate d e val uati o ns are 
perf or me d at t he sa me a p pr o xi m ate ti me p oi nt wit hi n a patie nt ’s c ortic oster oi d re gi me n i n or der 
t o a v oi d c o nf o u n di n g effects d ue t o t he c ortic oster oi ds. 
7. 2. 2.  S cr e e ni n g/ B a s eli n e Vi sit ( Vi sit 1)  
F oll o wi n g si g nat ure of t he i nf or me d c o nse nt/asse nt d oc u me nt(s), t he  patie nt  will c o m plete  t he 
neces sar y scree ni n g e val uati o ns.  It s h o ul d be n ote d t hat res ults fr o m safet y la b orat or y tests fr o m 
E n d -of -Treat me nt visit ( Visit 8/ Wee k 4 8) of t he P hase 3  st u d y ( P T C 1 2 4-G D -0 2 0 -D M D) are n ot 
re q uire d t o deter mi ne eli gi bilit y.  Patie nt s w h o ha ve bee n c o nfir me d t o  be eli gi ble b y t he 
i n vesti gat or f or t his e xte nsi o n st u d y s h o ul d c o m plete all Scree ni n g/ Baseli ne  (Visit 1 ) st u d y 
pr oce d ures.  M ost of t he data c ollecte d d uri n g t he E n d -of -Treat me nt visit ( Visit 8/ Wee k 4 8) of 
t he P hase 3  st u d y ( P T C 1 2 4-G D -0 2 0 -D M D) ca n be uti lize d f or t he baseli ne assess me nts (see 
f o ot n ote “a” of Ta ble 3 .  If t he Baseli ne visit ( Visit 1) is n ot c o m plete d wit hi n 1 4 da ys of t he 
E n d -of -Treat me nt visit ( Visit 8 / Wee k 4 8) of t he P hase 3  st u d y ( P T C 1 2 4-G D -0 2 0 -D M D), all 
st u d y pr oce d ures s h o ul d be perf or me d.   
After t he c o m pleti o n of t he baseli ne st u d y pr oce d ures, a site re prese ntati ve s h o ul d access t he 
I V R/I W R s yste m a n d s u p pl y t he necessar y i nf or mati o n t o o btai n atal ure n d osi n g i nstr ucti o ns .  
T he patie nt  will r e mai n at t he cli nic u ntil atal ure n s u p pl y f or t he ne xt 1 2  wee ks has bee n 
dis pe nse d a n d t he patie nt /care gi ver has bee n i nstr ucte d re gar di n g atal ure n st ora ge, pre parati o n , 
a n d a d mi nistrati o n . 
7. 2. 3.  Tr e at m e nt Vi sit s d uri n g St u d y ( Vi sit s 2 t hr o u g h 1 2 ) 
Eac h patie nt  w ill s u bse q ue ntl y ret ur n t o t he cli nical researc h facilit y d uri n g Wee k 1 2 ( Visit 2), 
Wee k  2 4  ( Visit 3), Wee k 3 6 ( Visit 4), Wee k 4 8 ( Visit 5), Wee k 6 0 ( Visit 6), Wee k 7 2 ( Visit 7), 
Wee k 8 4 ( Visit 8), a n d Wee k 9 6 ( Visit 9) , Wee k 1 0 8 ( Visit 1 0), Wee k 1 2 0 ( Visit 1 1), a n d Wee k 
1 3 2 ( Visit 1 2) .  Beca use of p ote ntial c ha n ges i n patie nt  b o d y wei g ht o ver ti me, a site 
re prese ntati ve s h o ul d e nter t he patie nt ’s c urre nt b o d y wei g ht i nt o t he I V R/I W R s yste m at Wee k 
2 4 ( Visit 3), Wee k 4 8 ( Visit 5) Wee k 7 2 ( Visit 7) , a n d Wee k 1 2 0 ( Visit 1 1)  t o a p pr o priatel y 
m o dif y atal ure n d osi n g i nstr ucti o ns.    


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7.2.4. End of Treatment  
 The patient will return to the clinical research facility at Week 144 (Visit  13) for the 
End-of-Treatment visit.  If the patient discontinues prematurely (ie, before Week  144), and the 
procedures that would normally be performed at Week  144 should be performed as a 
Premature-Discontinuation Visit before the patient leaves the study.   If the patient terminates the 
study early because ataluren is commercially available in that country then the patient does not 
need to come in for the 6-week Post-Treatment Follow-up Visit. 
 
7.2.5. Post-Treatment Visits 
 All patients who discontinue study drug, except patients switching to commercial ataluren, must 
return for a Post-Treatment Visit at the investigator site 6 weeks (±7 days) after the last dose of 
study drug and the End of Treatment Visit, for final study-related evaluations.  If the End-of-
Treatment Visit occurs >6 weeks after the last dose of study drug, the Post-Treatment Visit does 
not need to be performed. 
7.3. Informed Consent 
The investigator or sub-investigator must inform each prospective patient of the nature of the 
study, explain the potential risks, and obtain written informed consent/assent from the patient 
and/or the parent/legal guardian prior to performing any study-related screening procedures.  
Patients will be re-consented with the appropriate age-related documents as needed, if required 
by local regulations. 
7.4. Vital Signs 
Vital signs (including systolic and diastolic blood pressure, pulse rate, and body temperature) 
will be monitored at Screening/Baseline on Visit 1, Week 12 (Visit 2), Week 24 (Visit 3), Week 
36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), Week 84 (Visit 8), Week 
96 (Visit 9)  Week 108 (Visit 10), Week 120 (Visit 11), Week 132 (Visit 12), Week 144 (Visit 
13- End-of-Treatment/Premature Discontinuation), and at the Post-Treatment visit (6 weeks post 
discontinuation of study drug).  The pulse rate and blood pressure determinations will be 
performed with the patient in a sitting position after a 5-minute rest.   
7.5. Height, Weight, and Physical Examination  
Standing height (in cm) will be measured at Screening/Baseline on Visit 1, Week 12 (Visit 2), 
Week 24 (Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), 
Week 84 (Visit 8), Week 96 (Visit 9) Week 108 (Visit 10), Week 120 (Visit 11), Week 132 
(Visit 12), Week 144 (Visit 13- End-of-Treatment/Premature Discontinuation), and at the 
Post-Treatment visit (6 weeks post discontinuation of study drug).   
For nonambulatory patients, due to the difficulty in obtaining an accurate standing height 
measurement, ulna length and arm span will be used as a surrogate measure for height (see Study 
Manual). Ulna length and arm span (in cm) will be measured at Screening/Baseline on Visit 1, 
Week 12 (Visit 2), Week 24 (Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), 
Week 72 (Visit 7), Week 84 (Visit 8), Week 96 (Visit 9)  Week 108 (Visit 10), Week 120 (Visit 


Protocol Number PTC124-GD-020e-DMD  
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PTC Therapeutics, Inc.  – Confidential 
Page 36 of 91 
 
11), Week 132 (Visit 12), Week 144 (Visit 13 - End-of-Treatment/Premature Discontinuation), 
and at the Post-Treatment visit (6 weeks post discontinuation of study drug).   
Weight (in kg) will be measured at Screening/Baseline on Visit 1, Week 12 (Visit 2), Week 24 
(Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), Week 84 
(Visit 8), Week 96 (Visit 9)  Week 108 (Visit 10), Week 120 (Visit 11), Week 132 (Visit 12), 
Week 144 (Visit 13- End-of-Treatment/Premature Discontinuation), and at the Post-Treatment 
visit (6 weeks post discontinuation of study drug).  
A full physical examination (including evaluation of cardiovascular system, chest and lungs, 
thyroid, abdomen, nervous system, skin and mucosae, musculoskeletal system, eyes, ears, nose, 
mouth, throat, spine, lymph nodes, extremities, and genitourinary) will be conducted at 
Screening/Baseline (Visit 1), Week 48 (Visit 5), and Week 96 (Visit 9) and Week 144 (Visit 13 – 
End of Treatment/Premature Discontinuation) visit. 
Physical exams may also be performed at any time during the study as clinically indicated. 
7.6. Hematology Laboratory Assessment 
Hematology laboratory assessments will include white blood cell count with differential, 
hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, total red cell count with morphology, and platelet count.  
These parameters will be measured at Screening/Baseline on Visit 1, Week 12 (Visit 2), Week 24 
(Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), Week 84 
(Visit 8), Week 96 (Visit 9) Week 108 (Visit 10), Week 120 (Visit 11), Week 132 (Visit 12), 
Week 144 (Visit 13- End-of-Treatment/Premature Discontinuation), and at the Post-Treatment 
visit (6 weeks post discontinuation of study drug).  Hematology parameters will be analyzed by 
the central laboratory.  The Central Laboratory Manual should be consulted for collection, 
processing, and shipping details. 
7.7. Serum Biochemistry Laboratory Assessment 
Biochemistry laboratory assessments will include sodium, potassium, chloride, bicarbonate, 
blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total 
protein, albumin, globulin, albumin:globulin ratio, bilirubin (total, direct and indirect), AST, 
ALT, GGT, CK, lactate dehydrogenase (LDH), alkaline phosphatase, total cholesterol, high-
density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, and cystatin C.  These 
parameters will be measured at Screening/Baseline on Visit 1, Week 12 (Visit 2), Week 24 (Visit 
3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), Week 84 (Visit 
8), Week 96 (Visit 9) Week 108 (Visit 10), Week 120 (Visit 11), Week 132 (Visit 12), Week 144 
(Visit 13 - End-of-Treatment/Premature Discontinuation), and at the Post-Treatment visit (6 
weeks post discontinuation of study drug).  Patients should have fasted for at least 8 hours prior 
to blood collection.  Biochemistry parameters will be analyzed by the central laboratory.  The 
Central Laboratory Manual should be consulted for collection, processing, and shipping details. 
7.8. Urinalysis 
Urinalysis will include analysis for pH, specific gravity, glucose, ketones, blood, protein, 
urobilinogen, bilirubin, nitrite, and leukocytes.  These parameters will be measured at 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
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Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 3 7  of 9 1  
 
Scree ni n g / Baseli ne o n Visit  1 , Wee k 1 2 ( Visit 2), Wee k 2 4 ( Visit 3), Wee k 3 6 ( Visit 4), Wee k 
4 8 ( Visit 5), Wee k 6 0 ( Visit 6), Wee k 7 2 ( Visit 7), Wee k 8 4 ( Visit 8), Wee k 9 6 ( Visit 9 ) Wee k 
1 0 8 ( Visit 1 0), Wee k 1 2 0 ( V isit 1 1), Wee k 1 3 2 ( Visit 1 2), Wee k 1 4 4 ( Visit 1 3 - 
E n d -of -Treat me nt/ Pre mat ure Disc o nti n uati o n), a n d at t he P ost -Treat me nt visit ( 6 wee ks p ost 
disc o nti n uati o n of st u d y dr u g) .  T hese para meters will be a nal yze d b y t he ce ntral la b orat or y.  
Uri ne sa m ples will  als o be c ollecte d a n d s hi p pe d t o ce ntral la b orat or y f or assess me nt of uri ne 
pr otei n, creati ni ne, os m olalit y, a n d uri nal ysis.  T he Ce ntral  L a b orat or y M a n ual s h o ul d be 
c o ns ulte d f or c ollecti o n, pr ocessi n g, a n d s hi p pi n g details.    
7. 9.  R e n al Ultr a s o u n d  
A n ultras o u n d t o e x a mi ne t he ki d ne ys a n d c ollecti n g s yste m will be perf or me d at  
Scree ni n g/ Baseli ne ( Visit 1), Wee k 4 8 ( Visit 5), a n d Wee k 9 6  ( Visit 9 ) a n d Wee k 14 4  ( Visit 1 3 –  
E n d of Treat me nt/ Pre mat ure Disc o nti n uati o n)  visit.  T he ultras o u n d e x a mi nati o n will be 
perf or me d acc or di n g t o l ocal sta n dar ds a n d a fi nal i nter pretati o n a n d re p ort will be pr o vi de d b y  a 
l ocal q ualifie d e x pert.  T he fi n di n gs will be ca pt ure d i n s o urce d oc u me nts a n d wit h t he C R F.   
A f oll o w -u p re nal ultras o u n d ma y als o be perf or me d at a n y ti me d ur i n g t he st u d y as cli nicall y 
i n dicate d at t he discreti o n of t he i n vesti gat or.  T he P T C me dical m o nit or m ust be i nf or me d via e-
mail t hat a n a d diti o nal re nal ultras o u n d was o btai ne d a n d t he seri o us a d verse e ve nt re p orti n g 
pr ocess s h o ul d be f oll o we d, if a p plic a ble. 
7. 1 0.  1 2 -L e a d E C G  
A 1 2 -lea d E C G will be o btai ne d at Scree ni n g/ Baseli ne ( Visit 1), Wee k 4 8 ( Visit 5), Wee k 9 6  
( Visit 9 )  Wee k 1 4 4  ( Visit 13 – –  E n d of Treat me nt/ Pre mat ure Disc o nti n uati o n)  visit, a n d at t he 
P ost -Treat me nt Visit ( 6 wee ks p ost disc o nti n uati o n of  st u d y dr u g).  T he E C G  will be perf or me d 
a n d i nter prete d l ocall y.  T he fi n di n gs will be ca pt ure d i n s o urce d oc u me nts a n d wit h t he C R F.   
A f oll o w -u p E C G ma y als o be perf or me d at a n y ti me d uri n g t he st u d y as cli nicall y i n dicate d at 
t he discreti o n of t he i n vesti gat or.  T he P T C me dical m o nit or m ust be i nf or me d via e -mail t hat a n 
a d diti o nal E C G was o btai ne d a n d t he seri o us a d verse e ve nt re p orti n g pr ocess s h o ul d be f oll o we d, 
if a p plica ble. 
7. 1 1.  St u d y Dr u g A d mi ni str ati o n  
Patie nt s s h o ul d ta ke st u d y dr u g TI D as descri be d i n Secti o n  6. 2. 2   St u d y dr u g s u p pl y s ufficie nt 
f or eac h 1 2 -wee k  treat me nt peri o d will be s u p plie d t o t he patie nt  at Screei n g/ Baseli ne  ( Visit 1 ), 
Wee k 1 2  ( Visit 2 ), Wee k 2 4  ( Visit 3 ), Wee k 3 6  ( Visit 4 ), Wee k 4 8  ( Visit 5), Wee k 6 0 ( Visit 6), 
Wee k 7 2  ( Visit 7 ), a n d Wee k 8 4  ( Visit 8 ) Wee k 9 6 ( Visit 9)  Wee k 1 0 8 ( Visit 1 0), Wee k 1 2 0 
( Visit 1 1), Wee k 1 3 2 a n d Wee k 1 3 2 ( Visit 1 2).  S ufficie nt dr u g f or 9 0  da ys ( 1 2  wee ks + 6 da ys ) 
will be pr o vi de d at eac h of t hese visits s o lesse n t he li keli h o o d t hat patie nt s will e x perie nce dr u g 
s h orta ges d ue t o i na d verte nt l oss of s o me of t he sac hets or sc he d uli n g dela ys f or ret ur n visits.  
7. 1 2.  St u d y Dr u g  C o m pli a n c e  
St u d y dr u g  c o m plia nce will be assesse d usi n g a St u d y Dr u g  A d mi nistrati o n Rec o r d (t o be 
c o m plete d b y t he i n vesti gati o nal site p har macist  or dele gate site staff ), w hic h will d oc u me nt t he 
ret ur n of u n use d sac hets f or c o m plia nce assess me nts.   


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Patie nt s or care gi vers will ret ur n all u n use d sac hets of st u d y dr u g t o t he st u d y site f or f ull 
c o m plia nce assess me nt s usi n g t he St u d y Dr u g A d mi nistrati o n Rec or d.  Cli nic staff will rec or d 
t he st u d y dr u g d osi n g i nf or mati o n i ncl u di n g t he act ual cl oc k ti me of eac h d ose w he n  t he patie nt  
is d ose d  i n t he cli nic.   
7. 1 3.  A d v er s e E v e nt s  
A d verse e ve nts m ust be a ssesse d a n d d oc u me nte d at eac h cli nic visit .  T his i nf or mati o n will be 
c ollecte d at Scree ni n g/ Baseli ne ( Visit 1)  –  f oll o wi n g i nitiati o n of st u d y dr u g, Wee k 1 2  ( Visit 2 ), 
Wee k 2 4  ( Visit 3 ), Wee k 3 6  ( Visit 4 ), Wee k 4 8 ( Visit 5), Wee k 6 0 ( Visit 6), Wee k 7 2  ( Visit 7 ), 
Wee k 8 4 ( Visit 8), Wee k 9 6 ( Visit 9) Wee k 1 0 8 ( Visit 1 0), Wee k 1 2 0 ( Visit 1 1), Wee k 1 3 2  
( Visit 1 2), Wee k 1 4 4 ( Visit 1 3)a n d at t he P ost -Treat me nt Visit ( 6 wee ks p ost disc o nti n uati o n of 
st u d y dr u g).  I n a d diti o n, patie nts /care gi vers will be e nc o urage d t o re p ort a d verse e ve nts of 
c o ncer n at a n y ti me i n t he i nter vals bet wee n visits.  
7. 1 4.  C o n c o mit a nt M e di c ati o n s  
I nf or mati o n re gar di n g a n y c o nc o mita nt me dicati o ns a d mi nistere d, as well as i nf or mati o n 
re gar di n g all n o n-dr u g t hera pies,  will be c ollecte d t hr o u g h o ut t he st u d y.   T his i nf or mati o n will be 
c ollecte d at Scree ni n g/ Baseli ne ( Visit 1)  –  f oll o wi n g i nitiati o n of st u d y dr u g, Wee k 1 2  ( Visit 2 ), 
Wee k 2 4  ( Visit 3 ), Wee k 3 6  ( Visit 4 ), Wee k 4 8 ( Visit 5), Wee k 6 0 ( Visit 6), Wee k 7 2  ( Visit 7 ), 
Wee k 8 4 ( Visit 8), Wee k 9 6 ( Visit 9) Wee k 1 0 8 ( Visit 1 0), Wee k 1 2 0 ( Visit 1 1), Wee k 1 3 2 
( Visit 1 2), Wee k 1 4 4 ( Visit 1 3) a n d at t he P ost -Treat me nt Visit ( 6 wee ks p ost disc o nti n uati o n of 
st u d y dr u g).   
7. 1 5.  6 -Mi n ut e W al k T e st  
A m b ulati o n will be assesse d via t he 6 M W T f oll o wi n g sta n dar d ize d pr oce d ures (see St u d y 
Ma n ual f or detaile d i nstr ucti o ns).  T he 6 M W T will be perf or me d d uri n g Scree ni n g / Baseli ne o n 
Visit  1 , Wee k 1 2 ( Visit 2), Wee k 2 4 ( Visit 3), Wee k 3 6 ( Visit 4), Wee k 4 8 ( Visit 5), Wee k 6 0 
( Visit 6), Wee k 7 2 ( Visit 7), Wee k 8 4 ( Visit 8), a n d Wee k 9 6 ( Visit 9 )  Wee k 1 0 8 ( Visit 1 0), 
Wee k 1 2 0 ( Visit 1 1), Wee k 1 3 2 ( Visit 1 2), Wee k 1 4 4 ( Visit 1 3 - E n d -of -Treat me nt/ Pre mat ure 
Disc o nti n uati o n).  
7. 1 6.  Ti m e d F u n cti o n T e st s  
Ti me d f u ncti o n tests will  perf or me d a n d will i ncl u de t he ti me ta ke n t o r u n/ wal k 1 0 meters , ti me 
t o sta n d fr o m a s u pi ne p ositi o n , ti me t o cli m b 4 stairs, a n d ti me t o desce n d 4 stairs  [Me n dell 
1 9 8 9 , Gri g gs 1 9 9 1 , Bee na k ker 2 0 0 5a , Pra d ha n 2 0 0 6 ] (see St u d y Ma n ual f or detaile d 
i nstr ucti o ns).  T hese para meters will be m o nit ore d at Scree ni n g / Baseli ne o n Visit  1 , Wee k 1 2 
( Visit 2), Wee k 2 4 ( Visit 3), Wee k 3 6 ( Visit 4), Wee k 4 8 ( Visit 5), Wee k 6 0 ( Visit 6), Wee k 7 2 
( Visit 7), Wee k 8 4 ( Visit 8), a n d Wee k 9 6 ( Visit 9)  Wee k 1 0 8 ( Visit 1 0), Wee k 1 2 0 ( Visit 1 1), 
Wee k 1 3 2 ( Visit 1 2), Wee k 1 4 4 ( Visit  1 3 - E n d -of -Treat me nt/ Pre mat ure Disc o nti n uati o n).  
7. 1 7.  N ort h St ar A m b ul at or y A s s e s s m e nt  
T he N S A A will be use d t o e val uate  p h ysical f u ncti o n, usi n g sta n dar dize d pr oce d ures (see St u d y 
Ma n ual  f or detaile d i nstr ucti o ns).  T he N S A A will be perf or me d at Scree ni n g / Baseli ne o n 
Visit  1 , Wee k 1 2 ( Visit 2), Wee k 2 4 ( Visit 3), Wee k 3 6 ( Visit 4), Wee k 4 8 ( Visit 5), Wee k 6 0 


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(Visit 6), Week 72 (Visit 7), Week 84 (Visit 8), and Week 96 (Visit 9) Week 108 (Visit 10), 
Week 120 (Visit 11), Week 132 (Visit 12), Week 144 (Visit 13-End-of-Treatment/Premature 
Discontinuation). 
7.18. Performance of Upper Limb Assessment (PUL) 
The PUL assessment will be performed to evaluate upper limb function.  The PUL assessment 
will be performed at Screening/Baseline on Visit 1, Week 12 (Visit 2), Week 24 (Visit 3), Week 
36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), Week 84 (Visit 8), and 
Week 96 (Visit 9) Week 108 (Visit 10), Week 120 (Visit 11), Week 132 (Visit 12), Week 144 
(Visit 13- End-of-Treatment/Premature Discontinuation). 
7.19. Activities of Daily Living/Disease Symptom Survey  
A survey will be administered at Screening/Baseline on Visit 1, Week 12 (Visit 2), Week 24 
(Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), Week 84 
(Visit 8), and Week 96 (Visit 9) Week 108 (Visit 10), Week 120 (Visit 11), Week 132 (Visit 12), 
Week 144 (Visit 13- End-of-Treatment/Premature Discontinuation) to collect prospective 
information on patient and/or parent-reported changes in activities of daily living and disease 
symptoms.  The survey will be available in all languages relevant for this study and will be 
administered by the site staff to the parent/caregiver and/or patient. 
7.20. PODCI Questionnaire 
HRQL will be measured via the Pediatric Outcomes Data Collection Instrument (PODCI) 
domains of Transfers/Basic Mobility and Sports/Physical Functioning.  The PODCI 
questionnaire will be available in all languages relevant for this study and will be completed by 
the parent/caregiver.  If possible, the same parent/caregiver should complete the questionnaire 
each time.  The PODCI questionnaire will be completed during Screening/Baseline on Visit 1, 
Week 12 (Visit 2), Week 24 (Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), 
Week 72 (Visit 7), Week 84 (Visit 8), and Week 96 (Visit 9) Week 108 (Visit 10), Week 120 
(Visit 11), Week 132 (Visit 12), Week 144 (Visit 13 - End-of-Treatment/Premature 
Discontinuation).  Please refer to the Study Manual for further details on how to administer the 
PODCI questionnaire. 
7.21. Spirometry 
Spirometry will be conducted in a standardized fashion (see Study Manual for details) and will 
be performed at Screening/Baseline on Visit 1, Week 24 (Visit 3), Week 48 (Visit 5), Week 72 
(Visit 7), and Week 96 (Visit 9), Week 120 (Visit 11), Week 144 (Visit 13- 
End-of-Treatment/Premature Discontinuation.   
7.22. Blood for Analysis of Pharmacokinetics  
Blood for trough ataluren concentrations will be collected at Week 12 (Visit 2), Week 24 (Visit 
3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), Week 84 (Visit 
8), and Week 96 (Visit 9) Week 108 (Visit 10), Week 120 (Visit 11), Week 132 (Visit 12), Week 
144 (Visit 13-End-of-Treatment/Premature Discontinuation immediately prior to the morning 


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d ose of st u d y dr u g .  T he Ce ntral  L ab orat or y M a n ual s h o ul d be c o ns ulte d f or c ollecti o n, 
pr ocessi n g, a n d s hi p pi n g details.  
Sa m ples will be st ore d at t he bi oa nal ytical la b f or a nal ysis of atal ure n pare nt dr u g usi n g a 
vali date d h i g h perf or ma nce li q ui d c hr o mat o gra p h y wit h ta n de m mass s pectr o metry  
(H P L C /M S -M S ) met h o d .  T hereafter, sa m ples will be retai ne d at t he bi oa nal ytical la b f or 
p ote ntial f oll o w -u p a n al yses of atal ure n meta b olites or c ortic oster oi d pare nt dr u g a n d 
meta b olites.     
7. 2 3.  Bl o o d C oll e cti o n S u m m ar y  
I nf or mati o n re gar di n g t he t y pes a n d a ppr o xi mate a m o u nts of bl o o d sa m ples t o be c ollecte d i n t he 
st u d y is pr o vi de d i n Ta ble 4 .  Ass u mi n g a 1 4 4 -wee k treat me nt of atal ure n, t he ma xi m u m a m o u nt 
of bl o o d t o be dra w n at a visit is  ~ 1 2  m L  a n d t he t otal a m o u nt  of bl o o d t o be dra w n o ver t he 
e ntire 1 4 4 -wee k st u d y peri o d (i ncl u di n g t he Scree ni n g visit, t he 9 6 -wee k treat me nt peri o d, a n d 
t he 6-wee k f oll o w -u p peri o d) is a p pr o xi matel y 1 5 2  m L.    
T a bl e 4 .  Bl o o d Dr a wi n g R e q uir e m e nt s  
T e st  
S a m pl e  
T y p e  
T u b e  
T y p e  
T u b e 
T o p  
( C ol or) 
T u b e 
Si z e  
( m L) 
Bl o o d 
P er 
T u b e 
( m L) 
N u m b er  
of T u b e s  
T ot al 
Bl o o d  
( m L) 
P er  
Vi sit  
T ot al  
H e m at ol o g y  
W h ol e 
bl o o d  
E D T A  
L a v e n d er  
3  
3  
1  
 1 4  
4 2  
Bi o c h e mi str y  
S er u m  
Cl ot  
G ol d  
5  
5  
1  
1 4  
7 0  
Bl o o d f or tr o u g h P K  
Pl a s m a  
K 3 -E D T A  
L a v e n d er  
4  
4  
1  
1 0  
4 0  
M a xi m u m T ot al  
 
 
 
 
 
 
 
 1 5 2  
A b br e vi ati o n s: K 3  =  tri p ot a s si u m, E D T A = et h yl e n e di a mi n et e tr a a c et at e 
 
8.  
A D V E R S E E V E N T A S S E S S M E N T S  
8. 1.  A d v er s e E v e nt D efi niti o n s  
8. 1. 1.  A d v er s e E v e nt s  
A n a d verse e ve nt is a n y u nt o war d me dical occ urre nce ass ociate d wit h t he use of a dr u g 
(i n vesti gati o nal me dici nal pr o d uct) i n h u ma ns, w het her or n ot it is c o nsi dere d relate d t o t he dr u g.  
A n a d verse e ve nt c a n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease i n a st u d y patie nt  w h o is a d mi nistere d st u d y dr u g i n t his 
st u d y.   
F or t his pr ot oc ol, u nt o war d me dical occ urre nces t hat s h o ul d be re p orte d as a d verse e ve nts 
i ncl u de t he f oll o wi n g: 
•  All a d verse e ve nts t hat are s us pecte d t o be d ue t o st u d y dr u g.   
•  O ver d ose ( a d ministrati o n of a  st u d y dr u g d ose > 4 ti mes  t he hi g hest i nte n de d t otal dail y d ose 
le vel f or t his pr ot oc ol [ > 1 6 0 m g/ k g/ da y] ) of st u d y dr u g. 
•  All reacti o ns fr o m me dicati o n mis use, a b use, wit h dra wal, se nsiti vit y, or t o xicit y.  


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•  All reacti o ns t hat res ult fr o m me dica ti o n err ors or uses of t he st u d y dr u g o utsi de w hat is 
descri be d i n t he pr ot oc ol.  
•  A p pare ntl y u nrelate d ill nesses, i ncl u di n g t he w orse ni n g of a pree xisti n g ill ness.  
•  I nj ur y or acci de nts.  N ote t hat if a me dical c o n diti o n is k n o w n t o ha ve ca use d t he i nj ur y or 
acci de nt (a fall sec o n dar y t o dizzi ness), t he me dical c o n diti o n ( dizzi ness) a n d t he acci de nt 
(fall) s h o ul d be re p orte d as 2 se parate a d verse e ve nts.  The o utc o me of t he acci de nt 
( hi p fract ure sec o n dar y t o t he fall) s h o ul d be rec or de d i n s o urce d oc u me nts. 
•  A b n or malities i n p h ysi ol o gical testi n g or p h ysical e x a mi nati o n fi n di n gs t hat re q uire cli nical 
i nter ve nti o n or f urt her i n vesti gati o n ( be y o n d or deri n g a re peat [c o nfir mat or y] test). 
•  La b orat or y or E C G a b n or malities t hat re q uire cli nical i nter ve nti o n or f urt her  i n vesti gati o n 
( be y o n d or deri n g a re peat [ c o nfir mat or y] test) u nless t he y are ass ociate d wit h a n alrea d y 
re p orte d cli nical e ve nt.  La b orat or y a b n or malities ass ociate d wit h a cli nical e ve nt 
(e g, ele vate d li ver e nz y mes i n a patie nt  wit h ja u n dice) s h o ul d be c a pt ure d i n t he s o urce 
d oc u me nts.  La b orat or y a b n or malities n ot re q uiri n g cli nical i nter ve nti o n or f urt her 
i n vesti gati o n will be ca pt ure d as part of o verall la b orat or y m o nit ori n g, a n d s h o ul d n ot be 
re p orte d as a d verse e ve nts. 
•  A pree xisti n g c o n diti o n (e g, al ler gic r hi nitis) m ust be n ote d o n t he a p pr o priate electr o nic 
C R F (e C R F) f or Visit 1, b ut s h o ul d n ot be re p orte d as a n a d verse e ve nt u nless t he c o n diti o n 
w orse ns or e pis o des i ncrease i n fre q ue nc y d uri n g t he a d verse e ve nt re p orti n g peri o d.  
Dia g n ostic a n d t h era pe utic n o n -i n vasi ve a n d i n vasi ve pr oce d ures, s uc h as s ur ger y, s h o ul d n ot 
be re p orte d as a d verse e ve nts.  H o we ver, t he me dical c o n diti o n f or w hic h t he pr oce d ure was 
perf or me d s h o ul d be re p orte d if it meets t he defi niti o n of a n a d verse e ve nt.  F or e x a m ple , a n 
ac ute a p pe n dicitis t hat be gi ns d uri n g t he a d verse e ve nt re p orti n g peri o d s h o ul d be re p orte d as 
t he a d verse e ve nt a n d t he res ulti n g a p pe n dect o m y s h o ul d be rec or de d i n t he s o urce 
d oc u me nts.  If a s ur gical pr oce d ure was pla n ne d pri or t o e ntr y i nt o t he st u d y, a n d t he s ur ger y 
is n ot perf or me d beca use of a w orse ni n g of a baseli ne c o n diti o n, t his s h o ul d n ot be re p orte d 
as a n a d verse e ve nt.  N ote t hat, as descri be d i n Secti o n 8. 1. 2 , a n y i n patie nt h os pitalizati o n 
occ u rri n g as t he c o nse q ue nce of a n a d verse e ve nt d uri n g t he st u d y peri o d s h o ul d be re p orte d 
as a n S A E.  
Eac h a d verse e ve nt is t o be classifie d as seri o us or n o nseri o us  b y t he i n vesti gat or usi n g me dical 
a n d scie ntific j u d g me nt .   
8. 1. 2.  S eri o u s A d v er s e E v e nt s ( S A E s)  
A seri o us a d verse e ve nt ( S A E) is a n u nt o war d me dical occ urre nce  or effect ass ociate d wit h t he 
use of a st u d y dr u g  at a n y d ose, re gar dless of w het her it is c o nsi dere d t o be relate d t o t he st u d y 
dr u g , w hic h res ults i n o ne of t he f oll o wi n g : 
•  Deat h (ie, all deat hs o n treat me nt or wit hi n 6  wee ks  after last st u d y dr u g a d mi nistrati o n ), 
i ncl u di n g deat hs d ue t o disease pr o gressi o n.  A n y deat h occ urri n g later t ha n 6 wee ks 
f oll o wi n g t he last d ose nee d n ot be re p orte d as a seri o us a d verse e ve nt u nless it is a res ult of 
a n e ve nt t hat starte d wit hi n t he peri o d c o vere d b y t he o n -st u d y defi niti o n.  T he re p orte d 
a d verse e ve nt s h o ul d be t he e ve nt t hat ca use d t he deat h.  I n a d diti o n, a n y a d verse e ve nt 


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res ulti n g i n deat h t hat occ urs s u bse q ue nt t o t he a d verse e ve nt-re p orti n g peri o d a n d t hat t he 
i n vesti gat or assesses as p ossi bl y relate d t o t he st u d y dr u g s h o ul d als o be re p orte d as seri o us.   
•  Life -t hreate ni n g a d verse e ve nt .  T his is a n eve nt t hat, i n t he vie w of eit her t he i n vesti gat or or 
t he s p o ns or, places t he patie nt  at i m me diate ris k of deat h.  It d oes n ot i ncl u de a n e ve nt t hat, 
ha d it occ urre d i n a m ore se vere f or m, h y p ot heticall y mi g ht ha ve ca use d deat h.   
•  I n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n (e g. e x cl u di n g 
h os pitalizati o ns f or a d mi nistrati o n of the st u d y dr u g , pr oce d ures re q uire d b y t he st u d y 
pr ot oc ol, or D B M D -relate d dia g n ostic pr oce d ures; ot her pla n ne d h os pitalizati o ns; or 
h os pitalizati o ns relate d o nl y t o pr o gressi o n of disease).  Treat me nts i n t he e mer ge nc y r o o m 
f or pr oce d ures s uc h as h y drati o n t hat d o n ot re q uire a d mitti n g t he patie nt  t o t he h os pital a n d 
o bser vati o nal d urati o ns i n t he e mer ge nc y r o o m f or less t ha n 2 4  h o urs are n ot c o nsi dere d 
seri o us. 
•  Persiste nt or si g nifica nt disa bilit y or i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o 
co n d uct n or mal life f u ncti o ns, n ot relate d t o d ystr o p hi n o pat h y . 
•  A n y ot her me dicall y i m p orta nt e ve nt t hat t he i n vesti gat or or t he s p o ns or j u d ges t o be seri o us 
or w hic h is defi ne d as seri o us b y t he re g ulat or y a ge nc y i n t he l ocal c o u ntr y.  Me dical 
j u d g me nt s h oul d be e x ercise d i n deci di n g w het her a reacti o n is seri o us i n ot her sit uati o ns.  
I m p orta nt me dical e ve nts  t hat d o n ot res ult i n deat h, are n ot i m me diatel y life-t hreate ni n g, a n d 
d o n ot re q uire  h os pitalizati o n ma y be c o nsi dere d seri o us w he n, base d o n a p pr o pr iate me dical 
j u d g me nt, t he y ma y je o par dize t he patie nt  a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt a n y of t he o utc o mes liste d a b o ve.  E x a m ples of s uc h me dical e ve nts i ncl u de aller gic 
br o nc h os pas m re q uiri n g i nte nsi ve treat me nt a d mi nistrati o n  i n a n e mer ge nc y r o o m or at 
h o me, ne wl y dia g n ose d mali g na nc y, or bl o o d d yscrasias, or c o n v ulsi o ns t hat d o n ot res ult i n 
i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n de nc y or dr u g a b use. 
A n e ve nt nee d n ot be re p orte d as a S A E if it e x cl usi vel y  re prese nts a rela pse or a n e x pecte d 
c ha n ge or pr o gressi o n of t he baseli ne d ystr o p hi n o pat h y .  T his t y pe of e ve nt nee d o nl y t o be 
re p orte d as a n a d verse e ve nt.   
N ote t hat a n y S A Es occ urri n g after t he e n d of t he patie nt’s partici pati o n i n t he st u d y s h o ul d b e 
re p orte d t o t he s p o ns or if t he i n vesti gat or bec o mes a ware of t he m. 
8. 1. 3.  U n e x p e ct e d A d v er s e E v e nt s  
U ne x pecte d  a d verse e ve nts are defi ne d as t h ose e ve nts t hat were n ot pre vi o usl y re p orte d wit h 
st u d y dr u g as refere nce d i n t he m ost c urre nt i n vesti gat or br oc h ure, or t hat are s y m pt o maticall y 
a n d pat h o p h ysi ol o gicall y relate d t o a k n o w n t o xicit y b ut differ beca use of greater se verit y or 
s pecificit y.  F or e x a m ple , u n der t his defi niti o n, he patic necr osis w o ul d be u ne x pecte d ( b y virt ue 
of greater se verit y) if t he i n vesti gat or br oc h ure o nl y referre d t o ele vate d he patic e nz y mes or 
he patitis .  Si milarl y, cere bral t hr o m b oe m b olis m a n d cere bral vas c ulitis w o ul d be u ne x pecte d 
( b y virt ue of greater s pecificit y) if t he i n vesti gat or br oc h ure o nl y liste d cere bral vasc ular 
acci de nts .  “ U ne x pecte d,” as use d i n t his defi niti o n, als o refers t o a n a d verse e ve nt t hat is 
me nti o ne d i n t he  m ost c urre nt i n vesti gat or br oc h ure  as occ urri n g wit h t he class of dr u gs or as 
a ntici pate d fr o m t he p har mac ol o gical pr o perties of t he st u d y dr u g, b ut is n ot s pecificall y 
me nti o ne d as occ urri n g wit h t he me dici nal pr o d uct.   


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F or t he p ur p oses of c o nsi deri n g e x pecte d ness, t he atal ure n in vesti gat or b r oc h ure pr o vi des a 
s u m mar y of t he safet y pr ofile of atal ure n base d o n a vaila ble cli nical i nf or mati o n  (als o referre d t o 
as t he refere nce safet y i nf or mati o n) .   
8. 2.  Eli citi n g A d v er s e E v e nt I nf or m ati o n  
T he i n vesti gat or is t o re p ort all directl y o bser ve d a d verse e ve nts a n d all a d verse e ve nts 
s p o nta ne o usl y re p orte d b y t he st u d y patie nt  or pare nt/ g uar dia n i n case of a c hil d.  I n  a d diti o n, 
eac h st u d y patie nt  will be q uesti o ne d a b o ut a d verse e ve nts at eac h sc he d ule d cli nic visit after 
st u d y dr u g a d mi nistrati o n or d uri n g a n y tele p h o ne c o ntact wit h t he patie nt  or pare nt/ g uar dia n i n 
case of a c hil d.  T he t y pe of q uesti o n as ke d s h o ul d be o pe n -e n de d, e g, “ H o w h as y o ur c hil d bee n 
feeli n g ? ” or a si milar t y pe of q uer y.   
8. 3.  A d v er s e E v e nt R e c or di n g  
All a d verse e ve nts ( b ot h seri o us a n d n o nseri o us)  t hat occ ur i n patie nts  d uri n g t he a d verse e ve nt 
re p orti n g peri o d m ust be rec or de d, w het her or n ot the e ve nt is c o nsi dere d dr u g relate d.  I n 
a d diti o n, a n y k n o w n u nt o war d e ve nt t hat occ urs s u bse q ue nt t o t he a d verse e ve nt re p orti n g peri o d 
t hat t he i n vesti gat or assesses as p ossi bl y relate d t o t he i n vesti gati o nal dr u g/ pr o d uct s h o ul d als o 
be rec or de d as a n a d verse e ve nt.  
All a d verse e ve nts are t o be rec or de d i n t he s o urce d oc u me nts a n d o n t he C R F usi n g c o ncise 
me dical ter mi n ol o g y; w he ne ver p ossi ble ter ms c o ntai ne d i n Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A) s h o ul d be e m pl o ye d.  I n a d diti o n, t he f o ll o wi n g i nf or mati o n s h o ul d be 
rec or de d: 
•  I n dicati o n of w het her t he e ve nt is seri o us or n o nseri o us (see Secti o n 8. 1. 2 ) 
•  Relati o ns hi p t o st u d y dr u g (see Secti o n 8. 4 ) 
•  Se ve rit y of t he e ve nt (see Secti o n 8. 5 ) 
•  O nset date  
•  Res ol uti o n date, or date of deat h  
•  Acti o n ta ke n  
•  O utc o me of t he e ve nt  
Classificati o n of t he e ve nt as seri o us or n o nseri o us deter mi nes t he re p orti n g pr oce d ures t o be  
f oll o we d.   
8. 4.  D e s cri bi n g A d v er s e E v e nt R el ati o n s hi p t o St u d y Dr u g  
Base d o n t he c o nsi derati o ns o utli ne d i n Ta ble 5 , t he i n vesti gat or s h o ul d pr o vi de a n assess me nt of 
t he relati o ns hi p of t he a d verse e ve nt t o t he st u d y dr u g, ie, w het her t here is a reas o na ble 
p o ssi bilit y t hat t he st u d y dr u g ca use d t he a d verse e ve nt.  


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T a bl e 
T a bl e 5 .  R el ati o ns hi p of St u d y Dr u g 
.  R el ati o ns hi p of St u d y Dr u g to A d v ers e E v e nt
o A d v ers e E v e nt  
R el ati o n s hi p  
D e s cri pti o n  
Pr o b a bl e  
A cli ni c al e v e nt i n w hi c h a r el ati o n s hi p t o t h e st u d y dr u g  s e e m s pr o b a bl e b e c a u s e of s u c h 
f a ct or s a s c o n si st e n c y wit h k n o w n eff e ct s of t h e dr u g; a cl e ar t e m p or al a s s o ci ati o n wit h t h e 
u s e of t h e dr u g; i m pr o v e m e nt u p o n wit h dr a w al of t h e dr u g; r e c urr e n c e u p o n r e c h all e n g e wit h 
t h e dr u g; l a c k of alt er n ati v e e x pl a n ati o n s f or t h e e v e nt.   
P o s si bl e  
A cli ni c al e v e nt o c c urri n g c oi n ci d e nt wit h a d mi ni str ati o n of t h e st u d y dr u g  a n d w hi c h m a y or 
m a y n ot b e e x pl ai n e d b y c o n c urr e nt di s e a s e or ot h er dr u g s or c h e mi c al s.  I nf or m ati o n o n 
dr u g wit h dr a w al or r e c h all e n g e m a y b e l a c ki n g.   
U nli k el y  
A cli ni c al e v e nt wit h a t e m p or al r el ati o n s hi p t o t h e st u d y dr u g e x p o s ur e t h at d o e s n ot 
pr e cl u d e c a u s alit y b ut f or w hi c h t h er e i s a cl e ar alt er n at e c a u s e t h at i s m or e li k el y t o h a v e 
c a u s e d t h e a d v er s e e v e nt t h a n st u d y dr u g .  S u c h alt er n ati v e s i n cl u d e a c o n c o mit a ntl y 
a d mi ni st er e d dr u g, t h e p ati e nt ’ s di s e a s e st at e, ot h er m e di c al c o n diti o n s, or e n vir o n m e nt al 
f a ct or s. 
U nr el at e d  
A cli ni c al e v e nt, f or w hi c h a r el ati o n s hi p t o t h e st u d y dr u g s e e m s i m pr o b a bl e b e c a u s e of 
f a ct or s s u c h a s i n c o n si st e n c y wit h k n o w n eff e ct s of t h e st u d y dr u g , l a c k of a t e m p or al 
a s s o ci ati o n wit h st u d y dr u g a d mi ni str ati o n, l a c k of a s s o ci ati o n of t h e e v e nt wit h st u d y dr u g 
wit h dr a w al or r e c h all e n g e, a n d/ or pr e s e n c e of alt er n ati v e e x pl a n ati o n s f or t h e e v e nt.  
Alt er n ati v e e x pl a n ati o n s mi g ht i n cl u d e a k n o w n r e l ati o n s hi p of t h e a d v er s e e v e nt t o a 
c o n c o mit a nt dr u g, m e di c al hi st or y of a si mil ar e v e nt, t h e p ati e nt ’ s di s e a s e st at e, ot h er 
m e di c al c o n diti o n s, or e n vir o n m e nt al f a ct or s.  
 
8. 5.  Gr a di n g of S e v erit y of A d v er s e E v e nt s  
T he se verit y of a d verse e ve nts will be gra d e d usi n g t he C T C A E, Versi o n 3. 0 (refer t o St u d y 
Ma n ual or t o  htt p://cte p.ca ncer. g o v/f or ms/ C T C A E v 3. p df ).  F or eac h e pis o de, t he hi g hest se verit y 
gra de attai ne d s h o ul d be re p orte d   
If a C T C A E criteri on d oes n ot e xist, t he i n vesti gat or s h o ul d use t he gra de or a djecti ves: Gra de 1 
( mil d), Gra de 2 ( m o derate), Gra de 3 (se vere), Gra de 4 (life-t hreate ni n g), or Gra de 5 (fatal) t o 
descri be t he ma xi m u m i nte nsit y of t he a d verse e ve nt.  F or p ur p oses of c o nsiste nc y  wit h t he 
C T C A E, t hese i nte nsit y gra des are defi ne d i n Ta ble 6 . 
T a bl e 
T a bl e 6 .  Gr a di n g
.  Gr a di n g of A d v ers e E v e nt S e v erit y
of A d v ers e E v e nt S e v erit y  
Gr a d e  
A dj e cti v e  
D e s cri pti o n  
Gr a d e 1  
Mil d  
Si g n or s y m pt o m i s pr e s e nt, b ut it i s e a sil y t ol er at e d, i s n ot e x p e ct e d t o h a v e a  cli ni c all y 
si g nifi c a nt eff e ct o n t h e p ati e nt ’ s o v er all h e alt h a n d w ell b ei n g, d o e s n ot i nt erf er e wit h 
t h e p ati e nt ’ s u s u al f u n cti o n, a n d i s n ot li k el y t o r e q uir e m e di c al att e nti o n 
Gr a d e 2  
M o d er at e  
Si g n or s y m pt o m c a u s e s i nt erf er e n c e wit h u s u al a cti vit y or  aff e ct s  cli ni c al st at u s, a n d 
m a y r e q uir e m e di c al i nt er v e nti o n  
Gr a d e 3  
S e v er e  
Si g n or s y m pt o m i s i n c a p a cit ati n g or si g nifi c a ntl y aff e ct s cli ni c al st at u s a n d li k el y 
r e q uir e s m e di c al i nt er v e nti o n a n d/ or cl o s e f oll o w-u p  
Gr a d e 4  
Lif e -t hr e at e ni n g Si g n or s y m p t o m r e s ult s i n a p ot e nti al t hr e at t o lif e 
Gr a d e 5  
F at al  
Si g n or s y m pt o m r e s ult s i n d e at h  
 
N ote t he disti ncti o n bet wee n t he seri o us ness a n d t he se verit y of a n a d verse e ve nt.  Se vere is a 
meas ure of i nte nsit y; t h us, a se vere reacti o n is n ot necessaril y a seri o us reacti o n.  F or e x a m ple, a 
hea dac he ma y be se vere i n i nte nsit y, b ut w o ul d n ot be classifie d as seri o us u nless it met o ne of 
t he criteria f or seri o us e ve nts liste d i n Secti o n 8. 1. 2 .   
8. 6.  Pr e g n a n c y  of F e m al e P a rt n er s  
P T C  T hera pe utics s h o ul d be n otifie d  i n t he e ve nt t hat a fe male part ner of a patie nt  bec o mes 
pre g na nt at a n y ti me after t he patie nt ’s first d ose of st u d y dr u g.  A n y s uc h pre g na nc y occ urri n g 
o n -st u d y or wit hi n 6 0 da ys of t he last a d mi nistrati o n of stu d y dr u g  m ust be re p orte d o n  a 


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Pre g na nc y N otificati o n  F or m  (see St u d y Ma n ual f or details) .  T his m ust be d o ne w het her or n ot 
a n a d verse e ve nt has occ urre d a n d wit hi n 2 4 h o urs of a ware ness of t he pre g na nc y.  T he 
i nf or mati o n s u b mitte d s h o ul d i ncl u de t he a ntici pate d date of birt h or pre g na nc y ter mi nati o n .  
Writte n c o nse nt is re q uire d pri or t o c ollecti n g a n d re p orti n g a n y i nf or mati o n o n a fe male part ner 
of a patie nt .   
If p ossi ble, t he i n vesti gat or s h o ul d f oll o w t he pre g na nt fe male part ner of t he patie nt  u ntil 
c o m pleti o n of t he pre g na nc y a n d n otif y t he P T C  T hera pe utics me dical m o nit or of t he o utc o me 
wit hi n 5 da ys or as s pecifie d bel o w.  T he i n vesti gat or will pr o vi de t his i nf or mati o n as a f oll o w u p 
t o t he i nitial Pre g na nc y N otificati o n  F or m  via t he Pre g na nc y O utc o me F or m  (see St u d y Ma n ual 
f or details).   
If t he o utc o me of t he pre g na nc y meets t he criteria f or i m me diate classificati o n as a seri o us 
a d verse e ve nt (ie, s p o nta ne o us a b orti o n, still birt h, ne o natal deat h, or c o n ge nital a n o mal y 
[i ncl u di n g t hat i n a n a b orte d fet us]), t he i n vesti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g 
seri o us a d verse e ve nts, ie, re p ort t he e ve nt t o t he P T C  T hera pe utics Safet y De part me nt a n d 
f oll o w u p b y s u b missi o n of a p pr o priate a d verse e ve nt C R Fs (see Secti o n 8. 9 ). 
8. 7.  F oll o w -U p of U nr e s ol v e d A d v er s e E v e nt s  
All a d verse e ve nts s h o ul d be f oll o we d u p b y t he i n vesti gat or u ntil t he y are res ol ve d, or t he 
i n vesti gat or assesses t he m as c hr o nic or sta ble.  F oll o w-u p of a n y S A E t hat is fatal or 
life-t hreate ni n g s h o ul d be pr o vi de d wit hi n o ne a d diti o nal cale n dar wee k.  T he i n vesti gat or s h o ul d 
c o nsi der pr ot oc ol g ui deli nes a n d use his/ her discreti o n i n or deri n g a d diti o nal tests as necessar y t o 
m o nit or t he res ol uti o n of s uc h e ve nts.  I n t he e ve nt of a d diti o na l i n vesti gati o ns, t he P T C 
T hera pe utics  Safet y De part me nt  s h o ul d be i nf or me d via e-mail  or fa x .  A patie nt  wit h dra w n fr o m 
t he st u d y beca use of a n a d verse e ve nt m ust be f oll o we d b y t he i n vesti gat or u ntil cli nical rec o ver y 
is c o m plete a n d la b orat or y res ults ha ve ret ur ne d t o n or mal, or u ntil pr o gressi o n has bee n 
sta bilize d.  F oll o w-u p ma y nee d t o c o nti n ue after t he patie nt  has disc o nti n ue d fr o m t he st u d y, a n d 
a d diti o nal i n vesti gati o ns ma y be re q ueste d b y t he me dical m o nit ori n g tea m.   
8. 8.  A d v er s e E v e nt R e p orti n g P e ri o d 
T he first da y of a d verse e ve nt re p orti n g will c oi nci de wit h t he da y t he first d ose of st u d y dr u g is 
a d mi nistere d .  T he a d verse e ve nt re p orti n g peri o d f or t his st u d y e n ds wit h t he 6 -wee k ( ±  7  da ys) 
P ost -Treat me nt Visit, e x ce pt as descri be d i n Secti o n 8. 7 .  I n a d diti o n, S A Es occ urri n g i n a 
patie nt  after t he st u d y peri o d s h o ul d be re p orte d t o t he s p o ns or if t he i n vesti gat or bec o mes a ware 
of t he m.  
8. 9.  I n v e sti g at or Sit e A d v er s e E v e nt R e p orti n g R e q uir e m e nt s  
Classificati o n of a n e ve nt  as seri o us or n o nseri o us (see Secti o n 8. 1. 2 ) deter mi nes t he re p orti n g 
pr oce d ures t o be f oll o we d .  I n vesti gat or site re p orti n g re q uire me nts f or a d verse e ve nts are 
s u m marize d i n Ta ble 7 .  


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
Version 2.0 
 
PTC Therapeutics, Inc.  – Confidential 
Page 46 of 91 
 
Table 7.  Investigator Site Reporting Requirements for Adverse Events 
Classification 
Reporting Time 
Reporting Action 
Serious 
Within 24 hours 
Telephone call, fax, or e-mail to the PTC Therapeutics Safety 
Department  
Within 24 hours 
Fax report or document scan on designated SAE report form to 
the PTC Therapeutics Safety Department and to site IRB/IEC, 
as per local IRB/IEC requirements 
Within 5 calendar days 
Photocopies or document scan of relevant CRFs (eg, adverse 
event form, medical history form, concomitant drug/therapy 
form) and source documentsa (eg, progress notes, nurses’ 
notes, laboratory and diagnostic test results, discharge 
summaries) to the PTC Therapeutics Safety Department 
Per CRF submission procedure 
Record and submit information on appropriate CRFs 
Nonserious 
Per CRF submission procedure 
Record and submit information on appropriate CRFs 
a 
Patient name, address, and other personal identifiers should be obscured. 
Abbreviations:  CRF = case report form, IRB/IEC = Institutional Review Board/Independent Ethics Committee,  
SAE = Serious Adverse Event 
 
For SAEs, in addition to completing the adverse event portion of the CRF, the SAE report form 
must also be completed.  The SAE report form should be signed by the investigator; however, if 
the investigator is unable to sign at the time of the event or within 24 hours, the form should be 
signed by the clinical staff member reporting the SAE (eg, the study coordinator).  The SAE 
report form must be faxed or emailed to the PTC Therapeutics Safety Department and to the site 
IRB/IEC (if required by local regulations) within 24 hours.  Follow up information to the SAE 
should be clearly documented as “follow up” in the SAE report form and must also be faxed or 
emailed to the same party.  All follow up SAE report forms for the event must be signed by the 
investigator.  Any source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic 
test results, discharge summaries) provided to the sponsor should be redacted so that the patient’s 
name, address, and other personal identity information are obscured.  Only the patient’s study 
number and initials are to be provided (in regions where the provision of such information is 
permitted).  The information in the adverse event portion of the CRF and the SAE report form(s) 
must match or be reconciled.  Where the same data are collected, the forms must be completed in 
a consistent manner.  For example, the same adverse event term should be used on both forms.   
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (for example, if a patient initially seeks treatment elsewhere), the investigator is to 
report the event within 24 hours after learning of it and to document his/her first awareness of the 
adverse event.  
The PTC Therapeutics Safety Department contact information for reporting serious adverse 
events is provided below.  This information is also provided in the Study Manual and in the SAE 
report form.   
PTC Therapeutics Safety Department 
Attention: 
 
Telephone (office): 
 
Facsimile: 
 
E-mail: 
 


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8. 1 0.  P T C  T h er a p e uti c s A d v er s e E v e nt R e p orti n g R e q uir e m e nt s  
As t he s p o ns or of t he st u d y, P T C  T hera pe utics is res p o nsi ble f or re p orti n g certai n safet y 
i nf or mati o n, partic ularl y S A Es a n d patie nt  deat hs relate d t o partici pati o n i n t he st u d y , t o eac h 
i n vesti gat or i n a n e x pe dite d ma n ner.  If n otificati o n of a n a d verse e ve nt re q uiri n g e x pe dite d 
re p orti n g t o i n vesti gat ors is recei ve d, P T C T hera pe utics or its desi g nate d re prese ntati ve will 
c o ntact eac h i n vesti gat or  site partici pati n g i n t his st u d y b y e -mail, fa x, a n d/or o ver ni g ht mail suc h 
t hat t he i n vesti gat or ca n pr o m ptl y n otif y t he site I R B/I E C per t heir  l ocal re q uire me nts.  T he 
i nitial e x pe dite d safet y re p ort will be pr o vi de d as re q uire d acc or di n g t o l ocal re g ulati o ns 
(e g, wit hi n 1 5 da ys) after t he earliest date P T C  T hera pe utics or a n a ge nt of P T C T hera pe utics 
(e g, a site m o nit or) bec o mes a ware of a n a d verse e ve nt.  T his a ware ness date is t he date t he 
re g ulat or y re p orti n g cl oc k be gi ns a n d t he date is c o nsi dere d Da y 0 . 
9.  
WI T H D R A W A L O F P A TI E N T S   
All patie nts  w h o recei ve st u d y dr u g s h o ul d re mai n i n t he st u d y w he ne ver p ossi ble.  H o we ver : 
•  T he patie nt has t he ri g ht t o wit h dra w c o nse nt a n d disc o nti n ue st u d y dr u g at a n y ti me. 
•  If t he patie nt’s c o n diti o n s u bsta ntiall y w orse ns after i nitiati n g st u d y dr u g, t he patie nt will be 
caref ull y e val uate d b y t he i n vesti gat or i n c o ns ultati o n wit h t he P T C T hera pe utics me dical 
m o nit or.  T his w orse ni n g ma y i ncl u de car diac e ve nts s uc h as Q Tc i nter val li mits, ne w 
e vi de nce of s y m pt o matic car di o m y o pat h y a n d si g nifica nt decrease i n left ve ntric ular ejecti o n 
fracti o n.  T he patie nt will be wit h dra w n fr o m treat me nt if c o nti n ui n g w o ul d place t he m at 
ris k. 
•  U p o n c o ns ultati o n wit h t he P T C T hera pe utics me dical m o nit or, t he i n vesti gat or ma y 
wit h dra w t he patie nt fr o m st u d y dr u g, if, i n t he i n vesti gat or’s cli nical j u d g me nt, it is n ot i n 
t he patie nt’s best i nterest t o c o nti n ue.   
•  If t he patie nt bec o mes si g nifica ntl y n o nc o m plia nt wit h st u d y dr u g a d mi nistrati o n, st u d y 
pr oce d ures, or st u d y re q uire me nts .  I n t his e ve nt, t he patie nt s h o ul d be wit h dra w n fr o m st u d y 
treat me nt w he n t he circ u msta nces s urr o u n di n g n o nc o m plia nce i ncrease ris k t o t he patie nt  or 
are antici pate d t o s u bsta ntiall y c o m pr o mise t he i nter pretati o n of st u d y res ults. 
•  T he patie nt will be wit h dra w n fr o m treat me nt if he is u na ble t o t olerate st u d y dr u g. 
•  T his st u d y ma y be disc o nti n ue d b y t he rele va nt re g ulat or y a ut h orit y a n d/ or P T C T hera pe utics 
at a n y ti me. 
•  T his st u d y ma y be st o p pe d u p o n atal ure n mar keti n g a ut h orizati o n wit hi n t he rele va nt  c o u ntr y. 
T he date st u d y dr u g  is disc o nti n ue d a n d t he reas o n f or disc o nti n uati o n will be rec or de d i n t he 
s o urce d oc u me nts a n d i n t he eC R F.  T he P T C  me dical m o nit or  (a n d desi g nee) s h o ul d be 
i nf or me d via e-mail of w he n a patie nt  is disc o nti n ues st u d y dr u g.  
W he n st u d y dr u g  is disc o nti n ue d (re gar dless of t he reas o n), t he i n vesti gat or s h o ul d e nc o ura ge 
t hat all of t he e val uati o ns re q uire d at t he E n d of Treat me nt Visit  be perf or me d a n d t hat a n y 
a d diti o nal e val uati o ns be c o m plete d t hat ma y be necessar y t o e ns ure t hat t he patie nt  is free of 


Protocol Number PTC124-GD-020e-DMD  
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untoward effects.  The patient should be encouraged to seek appropriate follow-up for any 
continuing health problems.   
10. STATISTICS AND DATA MANAGEMENT  
10.1. Sample Size Calculation  
The sample size for this extension study is not based upon any formal statistical hypothesis, but 
its upper bound is determined by the requirement that patients must have participated in the 
previous Phase 3 study of PTC124 (PTC124-GD-020-DMD) in which ~ 220 patients are 
expected to be enrolled. 
10.2. Study Population Definition 
10.2.1. Safety Population 
The safety population consists of all patients who took at least one dose of ataluren.  This 
population will be used to analyze safety and treatment administration. 
10.2.2. Evaluable Populations 
In general, evaluable populations consist of all as-treated patients who have sufficient data to 
assess the measure of interest (eg, ataluren plasma concentrations, Activities of Daily 
Living/Disease Status Survey).  These populations may be evaluated in the analysis of other 
secondary endpoints. 
10.3. General Statistical Considerations 
By-patient listings will be created for each CRF module.  Summary tables for continuous 
variables will contain the following statistics: n, mean, standard deviation, standard error, 95% 
confidence intervals (CIs) on the mean, median, minimum, and maximum.  Summary tables for 
categorical variables will include N, n, percentage, and 95% CIs on the percentage.  Where 
applicable, the summary data (mean, standard error) will be presented in graphical form of 
against  time of visit.   
Unless otherwise specified, all analyses will be 2-sided at the 0.05 level of significance. 
10.4. Specific Statistical Analyses  
10.4.1. Study Conduct and Patient Disposition 
The number of patients in each of the analyzed study populations and the patients completing all 
planned assessments during the study will be described.  Patients who discontinue study drug or 
are removed from the study prematurely will also be reported.   
10.4.2. Use of Concomitant Medication and Supportive Therapy 
Concomitant medications will be coded by means of the World Health Organization Drug 
Dictionary (WHODRUG) dictionary into Anatomical-Therapeutic-Chemical classification 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 4 9  of 9 1  
 
(A T C ) c o des.  T he t y pe a n d ti mi n g of use of s pecific c o nc o mita nt me dicati o ns will be liste d a n d 
s u m marize d.   
S pecific atte nti o n will be f oc use d o n c ortic oster oi d use.  T he t y pe a n d d urati o n of pre -st u d y use 
will be descri be d .  T he t y pe, d ose, sc he d ule, d urati o n of use, d ose m o dificati o ns, d ose o missi o ns, 
a n d reas o ns f or de viati o ns fr o m i nitial t hera p y will be descri be d .   
1 0. 4. 3.  Pri m ar y V ari a bl e s –  S af et y  
Vital si g ns ( hei g ht, wei g ht, s yst olic a n d diast olic bl o o d press ure, ra dial p ulse rate, a n d b o d y 
te m perat ure) a n d p h ysical e x a mi nat i o n data will be liste d a n d s u m marize d b y visit a n d o verall.  
W here a p pr o priate, c ha n ges fr o m baseli ne at eac h visit will be s u m marize d a n d teste d b y mea ns 
of t he paire d t -test or a n o n para metric alter nati ve. 
A d verse e ve nts will be classifie d usi n g t he Me d D R A classificati o n s yste m.  T he se verit y of 
a d verse e ve nts will be gra de d acc or di n g t o t he C T C A E, Versi o n 3. 0, w he ne ver p ossi ble.   
T he fre q ue nc y of patie nt s e x perie nci n g a s pecific a d verse e ve nt will be ta b ulate d b y treat me nt 
peri o d a n d f or t he w h ole st u d y, cate g orizi n g e ve nts b y b o d y s yste m, a n d Me d D R A ter m.  I n t he 
b y -patie nt  a nal ysis, a patie nt  ha vi n g t he sa me e ve nt m ore t ha n o nce will be c o u nte d o nl y o nce.  
A d verse e ve nts will be s u m marize d b y w orst C T C A E gra de wit hi n a patie nt . 
A d verse e ve nts classifi e d as C T C A E Gra de 3 or hi g her; st u d y-dr u g -relate d e ve nts; a dre nal, 
he patic, a n d re nal e ve nts lea di n g t o s pecial dia g n ostic e val uati o ns; e ve nts lea di n g t o 
disc o nti n uati o n fr o m treat me nt; a n d S A Es will be c o nsi dere d wit h s pecial atte nti o n.  
N o atte m pt will be  ma de t o rec o ncile data c ollecte d fr o m t he patie nt /care gi ver-re p orte d o utc o me 
i nstr u me nts wit h a d verse e ve nt re p orti n g. 
He mat ol o gical data will be s u m marize d b y treat me nt peri o d a n d o verall.  He mat ol o gical data 
will be gra de d acc or di n g t o C T C A E se verit y gr a de.  T he fre q ue ncies of t he w orst se verit y gra de 
o bser ve d will be dis pla ye d b y w orst C T C A E gra de wit hi n a patie nt . 
Ser u m bi oc he mistr y a n d uri ne data (i ncl u di n g para meters f or assess me nt of a dre nal, he patic, a n d 
re nal m o nit ori n g –  see Secti o n 6. 3. 1 ) will be s u m marize d b y treat me nt peri o d a n d o verall.  
Val ues will be gra de d acc or di n g t o C T C A E se verit y gra de, w he n a p plica ble.  F or varia bles 
gra de d acc or di n g t o C T C A E se verit y gra de, t he fre q ue ncies of t he w orst se ve rit y gra de o bser ve d 
will be dis pla ye d wit hi n a patie nt .  F or para meters f or w hic h a C T C A E scale d oes n ot e xist, t he 
fre q ue nc y of patie nt s wit h val ues bel o w, wit hi n, a n d a b o ve t he n or mal ra n ges will be 
s u m marize d. 
Uri nal ysis data will be liste d a n d s u m mariz e d b y treat me nt peri o d a n d o verall, a n d will be 
c hec ke d f or c ha n ges fr o m baseli ne o ver ti me.    
T he res ults of a n ultras o u n d t o e x a mi ne t he ki d ne ys a n d c ollecti n g s yste m will be liste d a n d 
a b n or mal res ults will be n ote d a n d i n vesti gate d i n ter ms of t heir r elati o n t o ot her rele va nt patie nt 
o utc o me meas ure me nt.  
E C G data will be liste d a n d s u m marize d b y treat me nt peri o d a n d o verall, a n d will be c hec ke d f or 
c ha n ges fr o m baseli ne o ver ti me.    


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 5 0  of 9 1  
 
1 0. 5.  S e c o n d ar y E n d p oi nt s  
1 0. 5. 1.  6 Mi n ut e W al k T e st  
T he 6 mi n ute wal k dista nce ( 6 M W D) res ults, as well as t heir c ha n ges fr o m baseli ne will be 
descri be d b y patie nt  a n d visit a n d s u m marize d b y visit.  T he wit hi n patie nt  c ha n ges fr o m baseli ne 
will be teste d f or eac h a p plica ble visit usi n g t he paire d t test.  
S u p p orti ve a nal yses will  i ncl ude:  
•  A n or di nar y A N C O V A (a gai n after m ulti ple i m p utati o n f or missi n g val ues) will be 
a p plie d.  T he m o del will i ncl u de t he stratificati o n fact ors as strata a n d baseli ne as a 
c o variate. 
•  A n a nal ysis of ti me t o persiste nt 1 0 % w orse ni n g usi n g Ka pla n -Meier met h o d  a n d C o x 
re gressi o n 
•  A re peat of t he pri mar y A N C O V A a nal ysis o n t he 6 M W D after it has bee n c o n verte d t o 
perce nt -pre dicte d 6 M W D b y mea ns of a rele va nt refere nce e q uati o n [ Gei ger 2 0 0 7 ] 
•  A c o m paris o n of t he perce nta ge of res p o n ders ( < 1 0 % w orse ni n g of 6 M W D at We e k 4 8) 
a n d pr o gress ors ( ≥ 1 0 % w orse ni n g of 6 M W D at Wee k 4 8)  
•  A n e x pl orati o n of t he treat me nt effect i n 6 M W D i n t he c o nte xt of t he f oll o wi n g:  
o  t he pr ot oc ol-s pecifie d stratificati o n fact ors  
o  baseli ne hei g ht,  baseli ne wei g ht, a n d baseli ne B MI  
o  St o p c o d o n t y pe  
o  E x o n l ocati o n  
I n all rele va nt a nal yses, c o m plia nt patie nt s w h o bec o me n o na m b ulat or y ( u na ble t o perf or m t he 
1 0 meter r u n/ wal k test i n ≤3 0 sec o n ds) d uri n g t he st u d y will be assi g ne d a 6 M W D of zer o fr o m 
t he ti me p oi nt at w hic h t he patie nt bec o mes n o na m b ulat or y.  
1 0. 5. 2.  Ti m e d F u n cti o n T e st s ( T F T s)   
T he res ults of t he ti me d f u ncti o n tests (t he ti me ta ke n t o sta n d fr o m a s u pi ne p ositi o n, ti me ta ke n 
t o r u n/ wal k 1 0 meters, a n d ti me ta ke n t o cli m b/ desce n d 4 sta n dar d-size d stairs ) i n t h ose patie nt s 
w h o ha ve t he a bilit y, as well as t he  c ha n ges fr o m baseli ne will be descri be d b y patie nt  a n d visit 
a n d s u m marize d b y visit a n d o verall.  T he wit hi n patie nt  c ha n ges fr o m baseli ne will be teste d f or 
eac h a p plica ble visit usi n g t he paire d t -test.  Patie nt s w h o ca n n ot perf or m a test wit hi n 3 0 
seco n ds will be assi g ne d 3 0 sec o n ds as t heir res ult.  
1 0. 5. 3.  N ort h St ar A m b ul at or y A s s e s s m e nt ( N S A A)  
T he N S A A c o nsists of 1 7 acti vities, eac h sc ore d as 0, 1, or 2.  T he s u m of t hese 1 7 sc ores will be 
use d t o f or m a t otal sc ore.   T he c ha n ges fr o m baseli ne will be des cri be d b y patie nt  a n d visit a n d 
s u m marize d b y visit a n d o verall.   


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10.5.4. Pediatric Outcomes Data Collection Instrument (PODCI) 
Transfers/Basic Mobility and Sports/Physical Functioning scores   
The two PODCI domains (transfers/mobility and sports participation) each provide a numerical 
score from 0-100.  Changes from baseline will be described by patient and visit and summarized 
by visit and overall.   
10.5.5. Performance Upper Limb (PUL) Assessment 
The PUL assessment includes 22 items (with an entry item to define starting functional level to 
avoid testing functional dimensions in which the patient lacks the lower limit of function, and 21 
items subdivided into shoulder level (4 items), elbow level (9 items), and distal level (8 items) 
dimensions. Scoring varies across the scale between 0-1 to 0-6 according to performance.  Each 
dimension will be scored separately with a maximum score of 16 for shoulder level, 34 for elbow 
level, and 24 for distal level. Total score will be calculated by adding the 3 level scores 
(maximum global score of 74).  Changes from baseline will be described by patient and visit and 
summarized by visit and overall.   
10.5.6. Activities of Daily Living/Disease Status Survey 
Disease status survey data will be listed by patient and visit. Changes from baseline to each 
scheduled visit and to the final visit will be summarized descriptively. 
10.5.7. 
Spirometry 
Pulmonary function parameters (adjusted as appropriate for gender, age, and height (using ulna 
length and arm span) and their changes from baseline will be described by patient and visit and 
summarized by visit. Ulna length and arm span will be used for separate calculation of %- 
predicted parameters. The within-patient changes from baseline will be tested for each 
applicable visit using the t-test. Repeated measure analysis may also be used to estimate the 
effect of treatment duration on pulmonary function parameters. 
10.5.8. 
 Ataluren Plasma Concentrations 
Ataluren plasma concentrations collected prior to the morning dose will be summarized.  The 
relationship between ataluren plasma concentrations and selected efficacy and safety outcomes 
will be explored.  Results will be placed into context with PK data from previous studies. 
If needed, data regarding concentrations of major and/or active metabolites in retained plasma 
samples will be summarized and potential correlations with safety variables will be investigated.   
10.5.9. 
Exploration of Correlations 
Correlations between patient characteristics and outcome measures and correlations among 
outcomes measures may be explored using regression models or other appropriate techniques.   


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 5 2  of 9 1  
 
1 1.  S T U D Y C O M MI T T E E S  
1 1. 1.  St u d y St e eri n g C o m mitt e e  
A st u d y steeri n g co m mittee ( S S C) will be res p o nsi ble f or pr ot oc ol de vel o p me nt, re vie w of a n y 
st u d y a me n d me nts, a n d c o or di nati o n of stu d y c o n d uct a n d inter pretati o n of res ults.  T he S S C 
c o m prises t he P T C T hera pe utics me dical m o nit or a n d bi ostatisticia n f or t he st u d y, t he P T C 
T hera pe utics c hief me dical officer  a n d e x perts i n D M D .  Ot her s pecialists ma y be i n vite d t o 
partici pate as me m bers of t he S S C at a n y ti me if a d diti o nal e x pertise is desire d.  T he acti vities of 
t his c o m mittee are descri be d i n a c harter.   
1 1. 2.  D at a M o nit ori n g C o m mitt e e  
A D M C, o perati n g a ut o n o m o usl y fr o m t he s p o ns or, t he cli nical i n vesti gat ors , a n d t he S S C, will 
be res p o nsi ble f or pr o vi di n g i n de pe n de nt rec o m me n dati o ns t o P T C T hera pe utics a b o ut e v ol vi n g 
ris k-be nefit o bser ve d i n t he c o urse of t he st u d y a n d a n y m o dificati o ns re q uire d d uri n g t he c o urse 
of t he st u d y.  T he D M C will c o m prise at least 2 p h ysicia ns e x perie nce d i n treati n g  patie nts wit h 
d ystr o p hi n o pat h y , a ne p hr ol o gist, a car di ol o gist a n d a bi ostatisticia n.  T he D M C will be c haire d 
b y o ne of t hese i n di vi d uals.  D M C me m bers m ust n ot be acti vel y i n v ol ve d i n st u d y desi g n, 
c o n d uct, or dail y ma na ge me nt of t his st u d y a n d m ust n ot ha ve fi na ncial, pr o priet ar y, 
pr ofessi o nal, or ot her i nterests t hat ma y affect i m partial, i n de pe n de nt  decisi o n -ma ki n g.  
S pecialists ma y be i n vite d t o partici pate as n o n -v oti n g me m bers at a n y ti me if a d diti o nal 
e x pertise is desire d.  T he D M C  will f or mall y i nteract wit h t he S S C  t hr ou g h t he s hari n g of 
meeti n g mi n utes .  I nf or mal i nteracti o ns bet wee n t he D M C a n d S S C will be li mite d.  
T he D M C will o perate u n der a charter de vel o pe d as a c olla b orati ve d oc u me nt bet wee n t he D M C  
a n d P T C  T hera pe utics .  T he pri mar y res p o nsi bilit y of t he D M C  is t o pr otect t he safet y a n d 
welfare of patie nt s partici pati n g i n t his cli nical st u d y a n d t o e ns ure t he i nte grit y of t he cli nical 
st u d y.   
I n ge neral, t he D M C will be res p o nsi ble f or: 
•  E x a mi ni n g acc u m ulate d data at pres pecifie d p oi nts d uri n g t he c o urse of t he st u d y i n or der 
t o ma ke rec o m me n dati o ns c o ncer ni n g c o nti n uati o n, ter mi nati o n, or m o dificati o n of t he 
st u d y 
•  Re vie wi n g maj or st u d y desi g n m o dificati o ns pr o p ose d b y t he S S C pri or t o 
i m ple me ntati o n of t h ose m o dificati o ns 
•  Re vie wi n g t he ge neral pr o gress of t he st u d y as re gar ds s uc h iss ues as patie nt  accr ual, 
st u d y c o n d uct, a n d pr ot oc ol vi olati o ns 
•  Pr o vi di n g e x pert a d vice t o t he P T C  T hera pe utics me m bers of t he S S C o n a n a d h oc basis 
re gar di n g matters s uc h as safet y c o ncer ns or dia g n ostic e val uati o ns i n i n di vi d ual pa tie nts 
Base d o n t he res ults of its deli berati o ns, t he D M C ca n rec o m me n d c o nti n uati o n of t he st u d y 
u nc ha n ge d, st u d y i nterr u pti o n , st u d y ter mi nati o n, m o dificati o n of t he st u d y, or alterati o n i n t he 
D M C m o nit ori n g pla n.   


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9 N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  – C o nfi de ntial  
P a ge 5 3  of 9 1  
 
1 2.  O B LI G A TI O N S O F T H E I N V E S TI G A T O R A N D T H E S P O N S O R  
1 2. 1.  C o m pli a n c e wit h Et hi c al a n d R e g ul at or y G ui d eli n e s  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat t he cli nical st u d y is perf or me d i n acc or da nce 
wit h t he Declarati o n of Helsi n ki a n d t he I nter nati o nal C o u ncil o n Har m o nisati o n (I C H) G C P 
g ui da nce d oc u me nts.  
1 2. 2.  I n stit uti o n al R e vi e w B o ar d/I n d e p e n d e nt Et hi c s C o m mitt e e 
Pri or t o e nr oll me nt of patie nts  i nt o t he st u d y, as re q uire d b y t he F o o d a n d Dr u g A d mi nistrati o n 
(F D A ) a n d ot her re g ulat or y a ut h orities, t he pr ot oc ol a n d i nf or me d c o nse nt d oc u me nt will be 
re vie we d a n d a p pr o ve d b y a n a p pr o priate I R B/I E C.  B y si g ni n g t he State me nt of I n vesti gat or 
F or m ( F D A F or m 1 5 7 2), t he i n vesti gat or ass ures t hat a p pr o val of t he st u d y pr ot oc ol will be 
o btai ne d fr o m t he I R B/I E C a n d t hat all as pects of t he I R B/I E C re vie w will be c o n d ucte d i n 
acc or da nce wit h c urre nt re g ulati o ns.  A me n d me nts t o t he pr ot oc ol will be patie nt  t o t he sa me 
I R B/I E C re vie w re q uire me nts as t he ori gi nal pr ot oc ol.  O nl y c ha n ges necessar y t o eli mi nate 
a p pare nt i m me diate hazar ds t o t he patie nts  ma y be i nitiate d  pri or t o I R B/I E C a p pr o val.  I n t hat 
e ve nt, t he i n vesti gat or m ust n otif y t he I R B/I E C a n d P T C T hera pe utics i n writi n g wit hi n 
5 w or ki n g da ys after i m ple me ntati o n.  T he i n vesti gat or will als o pr o m ptl y n otif y t he I R B/I E C of 
a n y seri o us, u ne x pecte d a d verse e ve n ts, or a n y ot her i nf or mati o n t hat ma y affect t he safe use of 
t he dr u g d uri n g t he c o urse of t he st u d y.   
A letter d oc u me nti n g t he I R B/I E C a p pr o val a n d a list of t he na mes a n d titles of t he I R B/I E C 
me m bers m ust be recei ve d b y P T C T hera pe utics pri or t o t he i n itiati o n of t he st u d y.  All 
c orres p o n de nce wit h t he I R B/I E C s h o ul d be retai ne d i n t he i n vesti gat or’s st u d y file.   
T he i n vesti gat or s hall s u b mit a pr o gress re p ort, at least o nce yearl y, t o t he I R B/I E C, a n d m ust 
pr o vi de a c o p y t o P T C T hera pe utics.  As s o o n as p ossi ble after c o m pleti o n or ter mi nati o n of t he 
st u d y, t he i n vesti gat or will s u b mit a fi nal re p ort t o t he I R B/I E C a n d t o P T C T hera pe utics.  T his 
re p ort s h o ul d i ncl u de t he dates of i nitiati o n a n d c o m pleti o n of t he st u d y, a descri pti o n of a n y 
c ha n ges i n s t u d y pr oce d ures or a me n d me nts t o t he pr ot oc ol, a n y de viati o ns fr o m t he pr ot oc ol, t he 
n u m ber a n d t y pe of patie nts  e val uate d, t he n u m ber of patie nts  w h o disc o nti n ue d (a n d t he reas o ns 
f or disc o nti n uati o n), t he n u m ber of patie nts  w h o c o m plete d t he st u d y, a n d t he res ults of t he 
st u d y, i ncl u di n g a descri pti o n of a n y a d verse e ve nts.  P T C T hera pe utics will assist t he 
i n vesti gat or i n t he pre parati o n of t his re p ort, as nee de d. 
If t his st u d y is perf or me d u n der a gra nt fr o m t he U S g o ver n me nt, P T C T hera pe utics will als o 
s u b mit t he pr ot oc ol a n d i nf or me d c o nse nt d oc u me nts t o t he c o m pa n y’s I R B of rec or d 
(
).  P T C T hera pe utics will be 
res p o nsi ble f or all i nteracti o ns wit h t he  
 relati n g t o t he st u d y, i ncl u di n g s u b missi on of 
pr ot oc ol d oc u me nts, c o nse nt f or ms, a n d a me n d me nts; s u b missi o n of a d verse e ve nt re p orts a n d 
a n n ual re p orts; recei pt of a p pr o val n otices; a n d e x c ha n ge of ot her c orres p o n de nce.   
1 2. 3.  I nf or m e d C o n s e nt/ A s s e nt 
B y si g ni n g t he State me nt of I n vesti gat or ( F D A F or m 1 5 7 2), t he i n vesti gat or ass ures t hat 
i nf or me d c o nse nt/asse nt will be o btai ne d fr o m eac h patie nt  a n d/ or pare nt/le gal g uar dia n pri or t o 


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study entry and that the informed consent/assent will be obtained in accordance with current 
regulations.   
The investigator or sub-investigator will give each patient and/or parent/guardian full and 
adequate verbal and written information regarding the objectives and procedures of the study and 
the possible risks involved.  An informed consent/assent document will be provided to each 
patient and/or parent/guardian in a language in which the patient or parent/guardian is fluent.  
This information must be provided to the patient or parent/guardian prior to undertaking any 
study-related procedure.  Adequate time should be provided for the patient and/or 
parent/guardian to read the informed consent, to understand the risks and benefits of participating 
in the study, and to ask any questions that the patient and/or parent/guardian may have about the 
study.  The patient and/or parent/guardian should be able to ask additional questions as and when 
needed during the conduct of the study.  The patient’s and/or parent/guardian signature on the 
informed consent form should be obtained at the investigator site in the presence of the 
investigator or a qualified representative (eg, sub-investigator).  Where applicable, the patient 
will sign an age-appropriate assent form. 
Each patient or parent/guardian will be given a copy of the signed consent/assent form.  The 
original signed informed consent forms will be retained by the investigator with the study 
records.   
The written patient information must not be changed without prior approval by PTC Therapeutics 
and the IRB/IEC.   
12.4. Case Report Forms  
An eCRF is required and must be completed for each enrolled patient, with all required study 
data accurately recorded such that the information matches the data contained in medical records 
(eg, physicians’ notes, nurses’ notes, clinic charts, and other study-specific source documents).  
The eCRFs exist within a Web-based electronic data capture (EDC) system managed by the data 
management contract research organization (CRO) for this study.  After the investigator or the 
investigator’s designees (eg, research coordinators) have been appropriately trained, they will be 
given access to the EDC system and will enter the data required by the protocol into the EDC 
system.  Any change of data will be made via the EDC system, with all changes tracked by the 
system to provide an audit trail.   
With an electronic signature, the investigator certifies that the data are complete and accurate 
prior to database lock.  This electronic signature serves to attest that the information contained in 
the eCRFs is true.  After database lock, the investigator will receive a CD-ROM and/ or paper 
copies of the patient data for archiving at the investigator site.  At all times, the principal 
investigator has final responsibility for the accuracy and authenticity of all clinical data entered 
onto the eCRFs and/or reported to PTC Therapeutics from the investigator site.   
12.5. Study Records 
During the study, the investigator will maintain adequate records for the study, including medical 
records, source document records detailing the progress of the study for each patient, laboratory 
reports, a CD-ROM or paper copy of the data that have been captured in the EDC for each 
patient (electronic equivalents of CRFs), paper CRFs, signed informed consent forms, study drug 


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P a ge 5 5  of 9 1  
 
dis p ositi o n rec or ds, c orres p o n de nce wit h t he I R B/I E C, a d verse e ve nt re p orts, a n d i nf or mati o n 
re gar di n g patie nt  disc o nti n uati o n a n d c o m pleti o n of t he st u d y.  C urre nt re g ulati o ns re q uire 
P T C  T hera pe utics ( or a n a ut h orize d desi g nee) t o i ns pect all d oc u me nts a n d rec or ds re q uire d t o be 
mai ntai ne d b y t he i n vesti gat or, i ncl u di n g b ut n ot li m ite d t o me dical rec or ds ( office, cli nic, or 
h os pital) f or t he patie nts  e nr olle d i n t his st u d y.  T hese re g ulati o ns als o all o w t he sa me rec or ds t o 
be i ns pecte d b y a ut h orize d re prese ntati ves of t he F D A or ot her re g ulat or y a ut h orities.   
1 2. 6.  C o nfi d e nti alit y  
Resear c h rec or ds will be c ollecte d a n d st ore d i n a ma n ner t hat pr otects  t he c o nfi de ntialit y of 
patie nt  i nf or mati o n.  T he na mes a n d i de ntities of all researc h patie nts  will be ke pt i n strict 
c o nfi de nce a n d will n ot a p pear o n  e C R Fs, pa per C R Fs , or ot her rec or ds pr o vi de d t o or retai ne d 
b y P T C T hera pe utics ( or its a ut h orize d desi g nee).  T he na mes a n d i de ntities of t he patie nts  nee d 
n ot be di v ul ge d; h o we ver, t he rec or ds m ust ne vert heless be i ns pecte d.  T his will be acc o m plis he d 
b y bla n ki n g o ut t he patie nt ’s na me a n d re placi n g t he na me wit h t he patie nt ’s st u d y i de ntificati o n 
n u m ber o n a n y rec or d pr o vi de d t o or retai ne d b y P T C T hera pe utics .  T he i nf or me d c o nse nt f or m 
m ust i ncl u de a p pr o priate state me nts e x plai ni n g t hese re q uire me nts .   
Atte nti o n is dra w n t o t he re g ulati o n s pr o m ul gate d b y t he F D A u n der t he Free d o m of I nf or mati o n 
Act or l ocal re g ulat or y a ut h orities pr o vi di n g, i n part, t hat i nf or mati o n f ur nis he d t o cli nical 
i n vesti gat ors a n d t he I R B/I E C will be ke pt c o nfi de ntial b y t he F D A o nl y if mai ntai ne d i n 
c o nfi de nce b y t he cli nical i n vesti gat or a n d t he I R B/I E C.  B y si g ni n g t his pr ot oc ol, t he 
i n vesti gat or affir ms t o P T C T hera pe utics t hat t he i n vesti gat or will mai ntai n, i n c o nfi de nce, 
i nf or mati o n f ur nis he d b y P T C T hera pe utics a n d will di v ul ge s uc h i nf or mati o n t o t he I R B/I EC 
u n der a n a p pr o priate u n dersta n di n g of c o nfi de ntialit y wit h s uc h b oar d.  
1 2. 7.  R et e nti o n of R e c or d s  
T o e na ble e val uati o ns a n d/ or a u dits fr o m re g ulat or y a ut h orities or P T C T hera pe utics, t he 
i n vesti gat or a grees t o kee p acc urate a n d c o m plete rec or ds, i ncl u di n g t he i de ntit y of all 
partici pati n g patie nts  (s ufficie nt i nf or mati o n t o li n k e C R Fs a n d cli nic rec or ds), all ori gi nal si g ne d 
i nf or me d c o nse nt f or ms, C D-R O M or pa per c o pies  of t he data t hat ha ve bee n ca pt ure d i n t he 
E D C f or eac h patie nt  (electr o nic e q ui vale nts of C R Fs), a n d detaile d rec or ds of  st u d y dr u g 
dis p ositi o n .  All rec or ds a n d d oc u me nts pertai ni n g t o  t he st u d y (i ncl u di n g b ut n ot li mite d t o t h ose 
o utli ne d i n Secti o n 1 2. 5 ) will be mai ntai ne d b y t he i n vesti gat or u ntil n otificati o n is recei ve d fr o m 
P T C T hera pe utics t hat t he rec or ds n o l o n ger nee d t o be retai ne d.   
T he i n vesti gat or m ust o btai n writte n per missi o n fr o m P T C T hera pe utics bef ore dis p osi n g of a n y 
rec or ds.  I n or der t o a v oi d a n y p ossi ble err ors, t he i n vesti gator will c o ntact P T C T hera pe utics 
pri or t o t he destr ucti o n of a n y st u d y rec or ds.  T he i n vesti gat or will pr o m ptl y n otif y 
P T C  T hera pe utics i n t he e ve nt of acci de ntal l oss or destr ucti o n of a n y st u d y rec or ds.  If t he 
i n vesti gat or rel ocates, retires, or f or a n y reas o n wit h dra ws fr o m t he st u d y, t he st u d y rec or ds ma y 
be tra nsferre d t o a n acce pta ble desi g nee, s uc h as a n ot her i n vesti gat or, a n ot her i nstit uti o n, or t o 
P T C T hera pe utics.   


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
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P a ge 5 6  of 9 1  
 
1 2. 8.  M o nit ori n g a n d A u diti n g  
I n acc or da nce wit h 2 1 C o de of Fe deral Re g ulati o ns ( C F R ) Part 3 1 2. 5 6 a n d/ or rele va nt I C H 
g ui deli nes, P T C T hera pe utics or a desi g nee will peri o dicall y i ns pect all e C R Fs (see 
Secti o n  1 2. 4 ), st u d y d oc u me nts, researc h facilities, a n d cli nical la b orat or y facilities ass ociate d 
wit h t his st u d y at m ut uall y c o n ve nie nt ti mes, bef ore, d uri n g, a n d after c o m pleti o n of t he st u d y.  
As re q uire d b y a p plica ble re g ulati o ns ( Res p o nsi bilities of S p o ns ors a n d I n vesti gat ors), t he 
m o nit ori n g visits pr o vi de P T C  T hera pe utics wit h t he o p p ort u nit y t o e val uate t he pr o gress of t he 
st u d y; verif y t he acc urac y a n d c o m plete ness of data i n t he e C R Fs; e ns ure t hat all pr ot oc ol 
re q uire me nts, a p plica ble F D A a n d ot her rele va nt re g ulati o ns, a n d i n vesti gat or’s o bli gati o ns are 
bei n g f ulfille d; a n d res ol ve a n y i n c o nsiste ncies i n t he st u d y rec or ds.  T his i ncl u des i ns pecti o n of 
all d oc u me nts a n d rec or ds re q uire d t o be mai ntai ne d b y t he i n vesti gat or, i ncl u di n g b ut n ot li mite d 
t o me dical rec or ds ( office, cli nic, or h os pital) f or t he patie nts  i n t his st u d y.  T he na mes a n d 
i de ntities of all researc h patie nts  will be ke pt i n strict c o nfi de nce a n d will n ot a p pear o n e C R Fs 
or ot her rec or ds pr o vi de d t o or retai ne d b y P T C  T hera pe utics.  T he i n vesti gat or/i nstit uti o n 
g uara ntees direct access t o s o urce d oc u me nts b y P T C  T hera pe ut ics a n d a p pr o priate re g ulat or y 
a ut h orities.  
T he i n vesti gat or site ma y als o be s u bject t o re vie w b y t he I R B/I E C, t o q ualit y ass ura nce a u dits 
perf or me d b y P T C T hera pe utics or a desi g nee, a n d/ or t o i ns pecti o n b y t he F D A a n d/ or ot her 
re g ulat or y a ut h orities.  The I n vesti gati o nal Ne w Dr u g (I N D) re g ulati o ns als o re q uire t he 
i n vesti gat or t o all o w a ut h orize d re prese ntati ves of t he F D A t o i ns pect a n d ma ke c o pies of t he 
sa me rec or ds.   
It is i m p orta nt t hat t he i n vesti gat or a n d rele va nt i nstit uti o nal pers o n nel are a vaila ble d uri n g t he 
m o nit ori n g visits a n d p ossi ble a u dits or i ns pecti o ns a n d t hat s ufficie nt ti me is de v ote d t o t he 
pr ocess.   
1 2. 9.  T er mi n ati o n of t h e St u d y  
P T C T hera pe utics reser ves t he ri g ht t o disc o nti n ue t he st u d y pri or t o i ncl usi o n of t he i nte n de d 
n u m ber of p atie nts.  T he i n vesti gat or, after c o ns ultati o n wit h t he P T C T hera pe utics me dical 
m o nit or, reser ves t he ri g ht t o disc o nti n ue t he st u d y at t he i n vesti gat or site f or safet y reas o ns at 
a n y ti me.   
After a decisi o n t o ter mi nate t he st u d y, i n vesti gat ors m ust c o n tact all patie nts  w h o are c o nti n ui n g 
t heir partici pati o n i n t he st u d y a n d m ust d o s o wit hi n a ti me-peri o d set b y P T C  T hera pe utics.  As 
directe d b y P T C T hera pe utics, all st u d y materials m ust be c ollecte d a n d all electr o nic data e ntr y 
f or ms c o m plete d t o t he greatest e xte nt p ossi ble.  
1 2. 1 0.  P u bli c N otifi c ati o n of St u d y C o n d u ct  
C o nsiste nt wit h S ecti o n 1 1 3 of t he F o o d a n d Dr u g M o der nizati o n Act of 1 9 9 7 ( F D A M A)  a n d 
wit h re q uire me nts of t he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors (I CJ M E) as a 
c o n diti o n of c o ns i derati o n f or p u blicati o n of st u d y res ults, P T C  T hera pe utics will be res p o nsi ble 
f or e ns uri n g t hat t his pr ot oc ol is liste d at t he Cli nical Trials. g o v we bsite a n d t hat i nf or mati o n at 
t he we bsite relati n g t o st u d y desi g n a n d c o n d uct is a p pr o priatel y u p date d duri n g t he c o urse of t he 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
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P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 5 7  of 9 1  
 
st u d y.  I n or der t o facilitate t his pr ocess, i n vesti gat ors will nee d t o s u p pl y P T C T hera pe utics wit h 
a p pr o priate c o ntact i nf or mati o n f or i n vesti gat or site pers o n nel. 
1 2. 1 1.  Di s s e mi n ati o n of R e s ult s  
T he i nf or mati o n de vel o pe d d uri n g t he c o n d uct of t his cli nical st u d y is c o nsi dere d c o nfi de ntial b y 
P T C T hera pe utics.  T his i nf or mati o n ma y be discl ose d as dee me d necessar y b y 
P T C  T hera pe utics.  
T o all o w f or t he use of t he i nf or mati o n deri ve d fr o m t his cli nical st u d y a n d t o i ns ure c o m plia nce 
wit h c u rre nt re g ulati o ns, t he i n vesti gat or is o bli ge d t o pr o vi de P T C T hera pe utics wit h c o m plete 
test res ults a n d all data de vel o pe d i n t his st u d y.  T he i nf or mati o n o btai ne d d uri n g t his st u d y ma y 
be ma de a vaila ble b y P T C T hera pe utics t o ot her p h ysicia ns w h o are c o n d ucti n g si milar st u dies 
a n d t o t he F D A or ot her re g ulat or y a ut h orities.  S uc h i nf or mati o n ma y be discl ose d as dee me d 
necessar y b y P T C  T hera pe utics.  
P T C T hera pe utics i nte n ds t hat t he data fr o m t his st u d y will be prese nte d a n d p u blis he d.  T he 
P T C  T hera pe uti cs staff u n der t he directi o n of t he P T C T hera pe utics c hief me dical officer i n 
c olla b orati o n wit h t he i n vesti gat or will be res p o nsi ble f or writi n g prese ntati o ns a n d ma n uscri pts 
f or p u blicati o n.  I n vesti gat ors will n ot be all o we d t o p u blis h or prese nt t he data fr o m t his st u d y 
wit h o ut pri or a gree me nt wit h P T C T hera pe utics.   
1 2. 1 2.  C o m m u ni c ati o n wit h R e g ul at or y A ut h oriti e s  
P T C  T hera pe utics will ass u me res p o nsi bilit y f or re g ulat or y i nteracti o ns wit h t he F D A, t he 
E ur o pea n Me dici nes A ge nc y ( E M A) , a n d/ or ot her re g ulat or y a ut h orities.  I n t his re gar d, 
P T C  T hera pe utics will mai ntai n a n I N D f or atal ure n i n s u p p ort of t he st u d y.  I n f ulfilli n g t his 
res p o nsi bilit y, P T C T hera pe utics ( or a desi g nee) will c ollect, asse m ble, a n d c o m m u nicate all 
re q uire d re g ulat or y d oc u me nts (e g, For m  F D A 1 5 7 2, i n vesti gat or fi na ncial discl os ure f or ms, 
pr ot oc ol a n d pr ot oc ol a me n d me nts, i n vesti gat or br oc h ures, i nf or me d c o nse nt d oc u me nts, a n n ual 
re p orts) as re q uire d b y re g ulati o n.  P T C T hera pe utics ( or a desi g nee) will als o ass u me 
res p o nsi bilit y f or a dverse e ve nt re p orti n g t o re g ulat or y a ut h orities as descri be d i n Secti o n 8. 1 0 . 
1 3.  R A TI O N A L E F O R S T U D Y D E SI G N F E A T U R E S  
1 3. 1.  P ati e nt  S el e cti o n  
1 3. 1. 1.  O v er vi e w  
Si nce t his pr ot oc ol descri bes a n o pe n -la bel e xte nsi o n st u d y, e nr oll ment is li mite d t o t he patie nt s 
w h o s uccessf ull y c o m plete t he d o u ble -bli n d, place b o -c o ntr olle d P hase 3 st u d y 
( P T C 1 2 4-G D -0 2 0 -D M D).  T he eli gi bilit y criteria are desi g ne d t o e na ble e nr oll me nt of patie nt s 
w h o are s ufficie ntl y well ( b ot h i n ter ms of D M D a n d i n t er ms of c o nc o mita nt ill ness) t o safel y 
partici pate i n st u d y pr oce d ures a n d pr o vi de i nter preta ble res ults.  C o nsiste nt wit h G C P 
g ui deli nes, pare nts a n d patie nt s m ust pr o vi de i nf or me d c o nse nt/asse nt bef ore i nitiati o n of a n y 
st u d y pr oce d ures.  T o mi ni mize missi n g data a n d pre mat ure disc o nti n uati o ns, patie nt s m ust ha ve 
t he pers o nal a n d fa mil y res o urces t o c o m pl y wit h st u d y pr oce d ures a n d restricti o ns.  I n a d diti o n, 
patie nt s m ust n ot ha ve seri o us c o nc o mita nt c o n diti o ns t hat w o ul d c o m pr o mise safet y, 
c o m plia nce, o r e val uati o n. 


Protocol Number PTC124-GD-020e-DMD  
19 November 2015 
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PTC Therapeutics, Inc.  – Confidential 
Page 58 of 91 
 
13.1.2.   Reproductive Considerations 
When tested in animals, ataluren did not affect male fertility in rats and was not teratogenic in 
rats and rabbits.  In addition, lack of sexual maturity in most of the patients likely to be enrolled 
in this study limits reproductive risks.  However, restriction on eligibility relating to willingness 
to avoid unprotected sexual intercourse in any patients known to be sexually active is included as 
a general precaution. 
13.1.3. Concomitant Therapies 
Ataluren has not proved allergenic in studies performed to date, but review of known allergies to 
excipients contained in the formulation is prudent.  The restriction on concurrent involvement in 
other therapeutic clinical trials is intended to avoid confounding effects.   
13.1.4. Safety Profiling  
As is conventional, safety will be characterized in terms of the type, incidence, timing, severity, 
drug-relatedness, and seriousness of adverse events and laboratory abnormalities.  For 
consistency of interpretation, adverse events will be coded using the MedDRA, the severity of 
these events and laboratory abnormalities will be graded using the well-defined CTCAE, Version 
3.0, and concomitant medications will be coded with the WHODRUG dictionary.   
13.1.5. Study Drug Compliance  
Evaluation of study drug compliance provides context for assessments of pharmacological 
activity, safety, and PK, and may offer a general indication of patient acceptance of therapy, 
integrating factors of tolerability, palatability, and convenience.  The compliance of the patient 
will be verified by counting unused drug study sachets.   
13.1.6. Trough Ataluren Plasma Concentrations 
Collection of plasma for ataluren concentrations is important for confirming maintenance of 
exposure over time.  Having these data may allow correlations of exposure with measures of 
efficacy and toxicity.  Because the ataluren PK profile has been well characterized in existing 
Phase 2a studies in patients with DMD, plasma sampling will be limited to before dosing relative 
to the morning dose at each clinic visit.  This will provide information regarding ataluren trough 
concentrations.  The high performance liquid chromatography with tandem mass spectrometry 
(HPLC/MS-MS) method that will be used to quantify ataluren plasma concentrations has been 
fully validated in the context of the prior Phase 1 and Phase 2 studies.  Plasma samples will be 
retained for potential later analyses of ataluren metabolites or corticosteroid parent drug and 
metabolites.    
13.1.7. Timing of Assessments 
The timing of study assessments is appropriate in the context of a chronic study, permitting 
inclusion of 8 post-baseline evaluations during the study period, ensuring that time trends can be 
adequately assessed and that sporadically missing data do not have a substantial impact on data 
analysis.  The visit frequency also give consideration the need for many patients to travel 
considerable distances to study sites and that sites may achieve limiting capacity to accomplish 


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P a ge 5 9  of 9 1  
 
st u d y visits a n d data fl o w o nce m ulti ple patie nts are bei n g f oll o we d si m ulta ne o usl y at a si n gle 
site.   
St u d y acti vities ha ve bee n ma p pe d acr oss t he st u d y as o utli ne d i n t he Sc he d ule of E ve nts (see 
Ta ble 3 ). 
1 3. 2.  Tr e at m e nt a n d S af et y M o nit ori n g Pl a n  
1 3. 2. 1.  S c h e d ul e a n d D o s e S el e cti o n  
D osi n g base d o n b o d y wei g ht will c o nti n ue t o be e m pl o ye d.  S uc h d osi n g is c o m m o n i n 
pe diatrics a n d re d uces varia bilit y i n e x p os ure b y acc o m m o dati n g differe nces i n patie nt size 
acr oss t he s pa n of a ges of t he b o ys w h o will partici pate i n t he cli nical st u d y pr o gra m.   
T he sc he d ule of dr u g a d mi nistrati o n is deri ve d directl y fr o m P hase 1 P K m o deli n g a n d fr o m 
P hase  2 e x p os ure i nf or mati o n.  T he i nte nt of a d mi nisteri n g 2 s maller d oses at 6 -h o ur i nter vals 
d uri n g t he da y a n d a lar ger d ose at a 1 2 -h o ur i nter val o ver ni g ht (e g, at 7: 0 0 A M, 1: 0 0 P M, a n d 
7: 0 0 P M) is t o o pti mall y s ustai n tar get plas ma c o nce ntrati o ns w hile mi ni mizi n g t otal e x p os ures.  
T his a d mi nistrati o n pla n ca pitalizes o n t he effect of f o o d i n mai ntai ni n g atal ure n plas ma 
c o nce ntrati o ns a n d o n n oct ur nal i ncrease i n plas m a e x p os ures o bser ve d i n t he P hase 1 st u dies 
[Hira wat 2 0 0 7 ].  T his sc he d ule is li kel y t o fit well wit h dail y patter ns of li vi n g f or patie nts, t h us 
e n ha nci n g c o m plia nce.  As c o nfir mati o n of t hat pre mise, c o m plia nce wit h atal ure n d osi n g i n 
P hase 2a a n d P hase 2 b testi n g has bee n e x celle nt.  
1 3. 2. 2.  D ur ati o n of T h er a p y  
T his o pe n -la bel st u d y is e x pecte d t o ge nerate at least 1 4 4 wee ks of safet y i nf or mati o n.  T his 
i nf or mati o n will s u p ple me nt safet y data o btai ne d fr o m t he ra n d o mize d, place b o-c o ntr olle d, 
d o u ble -bli n d st u d y (P T C 1 2 4 -G D -0 2 0 -D M D ), w hic h has a pla n ne d treat me nt d urati o n of 4 8  
wee ks.  
1 3. 2. 3.  S af et y M o nit ori n g  
I n res p o nse t o t he occ urre nce re nal t o xic ol o g y fi n di n gs i n t he m o use a n d re nal la b orat or y 
a b n or malities i n pri or atal ure n st u dies , a s pecific re nal safet y m o nit ori n g pla n has bee n 
esta blis he d i n t his st u d y.  I n a d diti o n, t hres h ol ds f or e val uati o n a n d i nter ve nti o n ha ve bee n 
esta blis he d f or ot her t y pes of a d verse e ve nts or la b orat or y a b n or malities o bser ve d i n t he st u d y , 
i ncl u di n g he patic a b n or malities.  T he i nte nt is t o pr otect patie nts, o btai n a t h or o u g h assess me nt 
of a n y cli nicall y rele va nt a d verse e ve nts or la b orat or y a b n or malities, a n d t o offer 
rec o m me n dati o ns f or i nterr u pti o n a n d d ose m o dificati o n of st u d y dr u g i n res p o nse t o p ote ntial 
safet y si g nals.  T he nat ure of t hese ris ks a n d t he  
meas ures t o m o nit or f or t he m are t o be reflecte d i n t he i nf or me d c o nse nt f or m.  
As n ote d i n Secti o n 6. 3. 1  patie nts m ust be m o nit ore d cl osel y f or a d verse e ve nts or la b orat or y 
a b n or malities d ur i n g t he c o urse of t he st u d y.  Secti o n 6. 3. 1  pr o vi des i nf or mati o n o n acti o ns t o be 
ta ke n i n t he e ve nt t hat a b n or malities are n ote d o n s pecifie d m o nit ori n g st u dies.  T hres h ol ds are 
pr o vi de d f or i nterr u pti n g st u d y dr u g i m me diatel y, f or i nterr u pti n g st u d y dr u g after c o nfir mati o n 
of a val ue be y o n d t he t hres h ol d, or f or c o nti n ui n g st u d y dr u g w hile e val uati n g f or p ote ntial 
dr u g -relate d t o xicit y.   


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R e n al A b n or m aliti e s  
 
O v er vi e w  
Re nal fi n di n gs were see n i n mice recei vi n g 1  or 2 d oses t hr o u g h 2 6 wee ks of d oses of atal ure n.  
A N O A E L f or t he re nal t o xicit y fi n di n gs i n mice has n ot bee n i de ntifie d; t he l o west o bser ve d 
a d verse effect le vel ( L O A E L) = 7 5 m g/ k g/ da y.  E x p os ure i n mice at 7 5 m g/ k g/ da y is 0. 3 -f ol d t he 
e x p os ure i n  pat ie nts a d mi nistere d atal ure n at t he m or ni n g, mi d da y, a n d e ve ni n g d oses of 1 0, 1 0 
a n d 2 0 m g/ k g/ da y, res pecti vel y.  T he re nal fi n di n g was see n pri maril y i n t he distal ne p hr o n a n d 
i n v ol ve d s o me de ge nerati ve c ha n ges (a p o pt osis) a n d pr oliferati o n of re nal e pit heli u m.  Re nal 
t u b ular dilatati o n a n d pr otei nace o us material wit hi n t he t u b ules als o were see n.  T he str uct ural 
i nte grit y of t he ne p hr o n was mai ntai ne d, as de ge nerati ve/ necr otic c ha n ges of lar ge n u m bers of 
cells were n ot see n.  A fe w gl o mer uli i n t he u p per c orte x were s hr u n ke n b ut t he o verall lesi o n di d 
n ot pri maril y i n v ol ve t he gl o mer uli.  T he fi n di n g was occasi o nall y acc o m pa nie d b y i n di vi d ual 
i ncreases i n ser u m bl o o d urea nitr o ge n ( B U N) a n d/ or creati ni ne, h o we ver, a d ose relati o ns hi p f or 
t hese para meters was n ot o bser ve d.  T he ki d ne y fi n di n gs were partiall y t o c o m pletel y re versi ble 
as s o o n as 2 wee ks after cessati o n of d osi n g.  T he re nal t o xicit y was o bser ve d i n mice o nl y, a n d 
has n ot bee n see n i n rats d ose d f or 2 4  m o nt hs or i n d o gs d ose d f or 5 2  wee ks des pit e ac hie ve me nt 
of e x p os ures i n rats a n d d o gs t hat were c o m para ble t o or greater t ha n t h ose o bser ve d i n mice.   I n 
P hase 1 st u dies i n healt h y v ol u nteers a n d P hase 2 st u dies i n patie nts wit h D M D a n d c ystic 
fi br osis, re nal la b orat or y a b n or malities ha ve bee n i nfre q ue nt.  
D uri n g t he P hase 2 b d o u ble -bli n d st u d y of atal ure n i n n m D M D ( P T C 1 2 4 -G D -0 0 7 -D M D),  small 
i ncreases i n mea n ser u m creati ni ne, B U N, a n d c ystati n C were o bser ve d.  T he val ues te n de d t o 
sta bilize earl y i n t he st u d y a n d di d n ot i ncrease f urt her wit h c o nti n ue d treat me nt. 
Re nal a b n or malities were o bser ve d i n  a n i nter nati o nal, m ultice nter, d o u ble -bli n d, place b o -
c o ntr olle d P hase 3 trial e val uati n g atal ure n i n patie nts ≥6 years of a ge wit h n o nse nse m utati o n 
c ystic fi br osis i n patie nts recei vi n g c o nc o mita nt atal ure n a n d i ntra ve n o us ( I V) a mi n o gl yc osi des 
(as descri be d i n t he Atal ure n I n vesti gat or Br oc h ure).  In patie nts  w h o re q uire treat me nt f or 
seri o us i nfecti o ns, in vesti gat ors s h o ul d s u bstit ute ot her a nti bi otics f or s yste mic a mi n o gl yc osi des 
w he n cli nicall y a p pr o priate .  If I V a mi n o gl yc osi des or ot her ne p hr ot o xic a nti bi otics (e g, 
va nc o m yci n) are a d mi nistere d, st u d y dr u g m ust be i nterr u pte d d uri n g t he c o urse of t hese 
a nti bi otics.  Patie nts re q uiri n g I V a mi n o gl yc osi de or va nc o m yci n t hera p y s h o ul d be cl osel y 
m o nit or e d i n a n a p pr o priate setti n g, s uc h as a h os pital.  I n patie nts recei vi n g p ote ntiall y 
ne p hr ot o xic a ge nts s uc h as I V a mi n o gl yc osi des or va nc o m yci n, a nti bi otic dr u g le vels a n d ser u m 
creati ni ne a n d B U N s h o ul d be f oll o we d cl osel y.  T he a nti bi otic tr o u g h le vel a n d creati ni ne a n d 
B U N s h o ul d be meas ure d wit hi n 2 4 t o 4 8 h o urs of a d mi nistrati o n of t he first a nti bi otic d ose, a n d 
f urt her a nti bi otic d osi n g s h o ul d be base d o n t hese res ults.  Tr o u g h le vels s h o ul d be meas ure d at 
i nter vals d uri n g t he c o urse of a nti bi otic treat me nt.  Creati ni ne a n d B U N s h o ul d be meas ure d 
pri or t o i nitiati n g I V a mi n o gl yc osi de or va nc o m yci n t hera p y a n d at least t wice a wee k d uri n g t he 
c o urse of a nti bi otic treat me nt.  
O verall, t he re nal m o nit ori n g pr o gra m i ncl u de d i n t his pr ot oc ol c o nsi ders n o ncl i nical a n d cli nical 
fi n di n gs wit h atal ure n, past e x perie nce wit h k n o w n ne p hr ot o xica nts, a n d ma nifestati o ns of 
D M D .  A f oc us is place d o n well-esta blis he d cli nical i n dict ors of re nal d ysf u ncti o n f or ma ki n g 
dia g n ostic decisi o ns a n d pr o m pti n g treat me nt i nterr u pti o ns/ m o dificati o ns i n i n di vi d ual patie nts.  
T he rati o nale f or eac h of t he decisi o n -ma ki n g para meters is disc usse d bel o w.     


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1 3. 2. 4.  R e n al M o nit ori n g Pl a n  
•  Ser u m C yst ati n C :  G F R  is a re q uisite c o m p o ne nt of re nal testi n g t o e val uate gl o mer ular 
a n d ne p hr o n i nte grit y.  W hile “ g ol d sta n dar d” met h o ds of deter mi ni n g G F R (e g, i nf usi o ns of 
i n uli n, i o he x ol, i ot hala mate, or tec h neti u m 9 9 m -diet h yle netria mi ne pe ntaacetic aci d 
[9 9 m-Tc -D T P A] wit h ti me d bl o o d a n d uri ne assess me nts) ca n be e m pl o ye d, t hese met h o ds are 
c u m bers o me a n d are ofte n reser ve d f or re nal p h ysi ol o g y la b orat ories at s pecialize d ce nters 
[G ui g nar d 2 0 0 4 , Ste ve ns 2 0 0 7 ].  I n cli nical practice, assess me nts of G F R ha ve m ore t y picall y 
relie d u p o n deter mi nati o n of creati ni ne cleara nce d uri n g 2 4-h o ur uri ne c ollecti o ns or 
calc ulati o n base d o n n o m o gra ms usi n g o nl y ser u m creati ni ne.  It is ge nerall y ac k n o wle d ge d 
t hat 2 4-h o ur uri ne c ollecti o n i n c hil dre n is i nacc urate a n d i m practical d ue t o c o m plia nce 
iss ues [G ui g nar d 2 0 0 4 ].  Calc ulati o n of G F R usi n g o nl y meas ure me nt of ser u m creati ni ne has 
l o n g bee n sta n dar dize d f or c hil dre n [Sc h wartz 1 9 8 7 ].  H o we ver, beca use it is b ot h filtere d 
a n d secrete d b y t he ki d ne y, ser u m creati ni ne is ac k n o wle d ge d t o be relati vel y i m precise a n d 
i nse nsiti ve mar ker of re nal da ma ge [Her get -R ose nt hal  2 0 0 7 , Sc h wartz 2 0 0 7 ].  M ore o ver, 
ser u m creati ni ne is s u bject t o variati o n base d o n e n d o ge n o us a n d e x o ge n o us fact ors.  T his 
pr o ble m is partic ularl y c o ncer ni n g i n b o ys wit h D M D beca use t he maj orit y of creati ni ne i n 
ser u m is deri ve d fr o m m uscle [Wa n g 1 9 9 6 ] an d b o ys wit h D M D ha ve decrease d ser u m 
creati ni ne c o nce ntrati o ns d ue t o re d uce d m uscle mass .  A re vie w of baseli ne ser u m creati ni ne 
val ues a m o n g t he 3 8  b o ys wit h D M D partici pati n g i n t he atal ure n P hase  2a st u d y i n dicates 
l o w ser u m creatini ne val ues ( me dia n  0. 3, ra n ge 0. 1 -0. 5 m g/ d L) .  A d diti o nal s o urces of  
varia bilit y f or b o ys wit h D M D ma y i ncl u de i n gesti o n of creati ne (a s u bstrate f or creati ni ne 
pr o d ucti o n) [ Esc olar 2 0 0 5 ] a n d treat me nt-me diate d alterati o ns i n m uscle fra gilit y 
[Me n dell  1 9 8 9 ].   
As a n alter nat i ve t o assessi n g G F R base d o n ser u m creati ni ne, ser u m c ystati n C offers 
s u bsta ntial a d va nta ges i n t he c o nte xt of t his pr ot oc ol.  C ystati n C is a l o w-m olec ular -wei g ht 
[ ~ 1 3 k Da] pr otei nase i n hi bit or deri ve d fr o m all cells t hat is filtere d b y t he gl o mer ul us an d 
de gra de d i n t he re nal t u b ules [ Her get -R ose nt hal 2 0 0 7 ].  T he ser u m c ystati n C c o nce ntrati o n 
is al m ost s olel y de pe n de nt u p o n G F R a n d a p pears relati vel y u naffecte d b y m uscle mass or 
ot her c o n diti o ns.  A n a d diti o nal a d va nta ge is t hat circ ulati n g c ystati n C c ha n ges m ore ra pi dl y 
i n res p o nse t o m ulti ple t y pes of re nal i nj ur y t ha n creati ni ne [Her get -R ose nt hal 2 0 0 7 ].  
Met h o ds f or meas uri n g c ystati n C are sta n dar dize d a n d t he c orrelati o ns bet wee n ser u m 
c ystati n C a n d G F R ha ve bee n deri ve d a n d c o nfir me d i n lar ge st u dies i n v ol vi n g healt h y 
c hil dre n a n d a d ults a n d t h ose wit h re nal d ysf u ncti o n [ D har ni d har ka 2 0 0 2 , Gr u b b 2 0 0 5 , 
Za p pitelli 2 0 0 7 ].  Base d o n t hese c o nsi derati o ns, val ues of ser u m c ystati n a b o ve 1. 3 3 m g/ L 
s h o ul d pr o m pt dia g n ostic e val uati o n a n d i nterr u pti o n/ m o dificati o n of st u d y dr u g if re q uire d 
per pr ot oc ol.  
•  Ser u m Cre ati ni ne :  Gi ve n t he wi des prea d cli nical fa miliarit y wit h ser u m creati ni ne as a 
mar ker of re nal d ysf u ncti o n a n d as a m o nit ori n g t o ol f or ne p hr ot o xi ns i n cli nical practice 
[Gilea d 2 0 0 2 , Gilea d 2 0 0 6 , N o vartis 2 0 0 5 ], c haracterizati o n of ser u m creati ni ne pr o vi des a n 
a p pr o priate fra me of refere nce relati ve t o ot her e x perie nces.  Beca use m ost partici pati n g b o ys 
wit h D M D are e x pecte d t o ha ve l o w n or mal val ues of ser u m creati ni ne d ue t o re d uce d 
m uscle mass, a n y val ues hi g her t ha n t he n or mal ra n ge ma y be ca use f or c o ncer n.  Ca veats 
re gar di n g i nter pretati o n of ser u m creati ni ne i n b o ys wit h D M D ( partic ularl y if t here are 


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f o o d- or treat me nt -i n d uce d c ha n ges i n ser u m creati ni ne val ues) dictate t hat a n i ncrease i n 
ser u m creati ni ne a b o ve t he a ge -s pecific n or mal ra n ge s h o ul d pr o m pt ree val uati o n of ot her 
safet y para meters a n d p ote ntial i nterr u pti o n/ m o dificati o n of st u d y dr u g d osi n g.  
•  Ser u m Bl o o d Ure a Nitr o ge n : C o nsi deri n g its r ole i n mai ntai ni n g uri ne -c o nce ntrati n g 
a bilit y, urea has maj or i m p orta nce i n re nal p h ysi ol o g y a n d its cli nical meas ure me nt as a 
mar ker of re nal d ysf u ncti o n is l o n g esta blis he d.  I n t he c o nte xt of ne p hr ot o xicit y, ele vati o ns 
i n B U N s u g gest disr u pti o n of t u b ular i nte grit y [V o n dersc her 2 0 0 7 ].  I n t he n oncli nical m o use 
st u dies of atal ure n i n w hic h ne p hr osis was o bser ve d, B U N was ele vate d i n s o me of t he 
affecte d a ni mals, c o nfir mi n g t hat t his mar ker s h o ul d als o be meas ure d i n cli nical st u dies of 
atal ure n.  M o nit ori n g ser u m B U N, li ke m o nit ori n g creati ni ne, p r o vi des a n a d diti o nal fra me of 
refere nce relati ve t o ot her mar kers assesse d wit hi n t his st u d y a n d i n ot her st u dies of k n o w n 
ne p hr ot o xica nts.  H o we ver, a n ele vati o n i n B U N is n ot a s pecific si g nal of re nal t u b ular 
i nj ur y, b ut als o ma y reflect c o m pr o mise d renal t u b ular bl o o d fl o w d ue t o de presse d car diac 
o ut p ut, me dicati o ns, or de h y drati o n [ G ui g nar d 2 0 0 4 , Ste ve ns 2 0 0 7 ].  F or t hese reas o ns, a 
B U N i ncrease ≥1. 5 x U L N s h o ul d pr o m pt a re vie w of p ote ntial pre -re nal, re nal, a n d 
p ost -re nal ca uses f or t he a b n or malit y as well as c o nsi derati o n of p ote ntial 
i nterr u pti o n/ m o dificati o n of st u d y dr u g d osi n g.  
•  Uri ne Pr otei n: Cre ati ni ne a n d Uri ne Pr otei n: Os m ol alit y R ati o: Pr otei n uria ca n be a n earl y 
mar ker f or re nal i nj ur y i n e x peri me ntal m o dels [ A mi n 2 0 0 4 ] a n d is c o m m o nl y o bserve d wit h 
e ve n m o dest cli nical decreases i n re nal f u ncti o n [ Nati o nal Ki d ne y F o u n dati o n 2 0 0 2 ].  
Gl o mer ular disease (e g, dia betic ne p hr o pat h y) is ofte n ass ociate d wit h  al b u mi n uria d ue t o 
defects i n e x cl usi o n of plas ma pr otei ns i n t he gl o mer ular filtrate.  T u b ular i nj ur y (e g, as 
o bser ve d i n mice recei vi n g atal ure n) m ore ofte n lea ds t o i ncreases i n l o w -m olec ular -wei g ht 
pr otei ns (e g, beta -2 micr o gl o b uli n, β 2 -micr o gl o b uli n, α 1 -micr o gl o b uli n reti n ol -bi n di n g 
pr otei n, l ys oz y me) as t u b ular pr otei n cata b olis m is c o m pr o mise d or pr otei ns of i nj ur y are 
pr o d uce d [ G ui g nar d 2 0 0 4 , Ste ve ns 2 0 0 7 ].  Beca use mice t hat de vel o pe d ne p hr osis w hile 
recei vi n g atal ure n ha d pr otei nace o us material i n t he re nal t u b ules o n hist ol o gical 
e x a mi nati o n, m o nit ori n g of uri ne pr otei n i n h u ma ns recei vi n g atal ure n is a d diti o nall y 
warra nte d.   
Tra diti o nal met h o ds of uri ne pr otei n scree ni n g are o nl y se mi q ua ntitati ve, are relati vel y 
i nse nsiti ve, a n d are c o nf o u n de d b y e x o ge n o us s u bsta nces a n d s u bjecti ve i nter pretati o n 
[Ki m  2 0 0 7 ].  T he prese nce of uri nar y pr otei n ma y be mas ke d i n dil ute uri ne or e x a g gerate d i n 
c o nce ntrate d uri ne.  F or t heses reas o ns, a q ua ntitati ve met h o d of accessi n g pr otei n uria is 
pla n ne d i n t his st u d y.  T w o met h o ds will be assesse d: uri nar y pr otei n c o nce ntrati o n relati ve 
t o uri nar y creatini ne c o nce ntrati o n [ Gi ns ber g 1 9 8 3 , Sc h wa b 1 9 8 7 ] a n d uri nar y pr otei n 
c o nce ntrati o n relati ve t o uri ne os m olalit y [ Wils o n 1 9 9 3 , M or ge nster n 2 0 0 3 ].  T hese met h o ds 
of scree ni n g, usi n g s p ot uri ne sa m ples, ha ve bee n f o u n d t o be as acc urate as a n d m ore 
practical t ha n q ua ntificati o n of uri ne pr otei n d uri n g a 2 4 -h o ur c ollecti o n.  Val ues f or 
pr otei n:creati ni ne of ≥0. 2 m g/ d L: m g/ d L a n d of pr otei n: os m olalit y of ≥0. 1 5  m g/ L: m Os m/ k g 
ha ve bee n esta blis he d as a b n or mal  [M or ge nster n 2 0 0 3 ].  W hile meas ure me nt of 
pr otei n:creati ni ne is ge nerall y t he preferre d met h o d i n c hil dre n [ M or ge nster n 2 0 0 3 ], it is 
p ossi ble t hat l o w uri nar y creati ni ne e x creti o n i n b o ys wit h D M D ma y falsel y ele vate 
pr otei n:creati ni ne rati os.  F or t his reas o n, c o nfir me d e vi de nce t hat b ot h meas ures are 


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a b n or mal s h o ul d sti m ulate f urt her e val uati o n a n d i nter ve nti o n.  F oll o w -u p met h o ds s uc h as 
uri ne electr o p h oresis ma y be  usef ul i n discri mi nati n g a m o n g t he t y pes of pr otei ns prese nt a n d 
ma y s u g gest a site of i nj ur y (e g, a n al b u mi n -s pecific patter n wit h gl o mer ular da mage vers us a 
diff use m ulti ple l o w -m olec ular -wei g ht pr otei n patter n wit h t u b ular da ma ge) [ Ste ve ns 2 0 0 7 ].  
C o nfir me d pr otei n uria s h o ul d pr o m pt c o nsi derati o n of i nterr u pti o n/ m o dificati o n of st u d y 
dr u g d osi n g.  
•  Uri ne Bl o o d :  Bl o o d i n t he uri ne ma y i n dicate pat h o l o g y of t he re nal pare nc h y ma or of t he 
uri nar y c ollecti n g s yste m (e g, ureters, bla d der, a n d uret hra).  Li ke pr otei n uria, he mat uria is 
c o m m o nl y f o u n d i n patie nts wit h mi ni mal c ha n ges i n G F R d ue t o re nal ( partic ularl y 
gl o mer ular) d ysf u ncti o n [ Nati o nal Ki d ne y  F o u n dati o n 2 0 0 2 ].  C o nfir me d, persiste nt e vi de nce 
of uri nar y bl o o d b y di pstic k a n d/ or micr osc o pic e x a mi nati o n will pr o m pt f urt her e val uati o n.  
Ultras o u n d or ot her i ma gi n g ca n e val uate f or a p ote ntial re nal ca use f or blee di n g.  Ur ol o g y 
c o ns ultati o n ca n be o btai ne d t o assess f or p ost -re nal s o urces of he mat uria.  Cl otti n g f u ncti o n 
a n d use of dr u gs t hat ma y i m pair platelet f u ncti o n will be re vie we d.  C o nfir me d, persiste nt 
he mat uria i n t he a bse nce of a p ost -re nal s o urce of blee di n g or a blee di n g diat hesis will 
pr o m pt p ote ntial i nterr u pti o n/ m o dificati o n of st u d y dr u g d osi n g.  
•  Ser u m Electr ol ytes : Assess me nts of ser u m electr ol ytes (s o di u m, c hl ori de, p otassi u m, 
bicar b o nate, ma g nesi u m, calci u m, a n d p h os p h or us) pr o vi de i nf or mati o n re gar di n g re nal 
f u ncti o n t hat ma y s u p ple me nt m ore pri mar y assess me nts.  Dera n ge me nts i n ser u m 
c o nce ntrati o ns ma y reflect altere d t u b ular ha n dli n g of t hese i o ns.  Wit h w orse ni n g re nal 
f u ncti o n, h y per p h os p hate mia a n d h y p ocalce mia ma y de vel o p a n d re d ucti o ns i n ser u m 
bicar b o nate or ele vati o ns i n p otassi u m ma y s u g gest a n i m paire d a bilit y of pr o xi mal t u b ules or 
c ollecti n g d ucts t o mai ntai n aci d -base bala nce [ Nati o nal Ki d ne y F o u n dati o n 2 0 0 2 ].  Gi ve n 
t he car di o vasc ular a n d ne ur ol o gical c o nse q ue nces of se vere dera n ge me nts of ser u m 
p otassi u m, calci u m, or  ma g nesi u m, e val uati o n of t hese i o ns is i m p orta nt t o a v oi d p ote ntial 
sec o n dar y c o m plicati o ns.  Beca use tra nsie nt Gra de 1 alterati o ns i n t he c o nce ntrati o ns of 
electr ol ytes are ver y u nli kel y t o be ass ociate d wit h si g nifica nt sec o n dar y si de effects, 
alterati ons t o ≥Gra de  2 are c o nsi dere d a p pr o priate t o pr o m pt p ote ntial 
i nterr u pti o n/ m o dificati o n of st u d y dr u g d osi n g.  
•  Re n al Ultr as o u n d : I n c o nsi deri n g t he mar kers t o be use d f or decisi o n-ma ki n g wit hi n t he 
st u d y, re nal ultras o u n d is pr o p ose d beca use it is t he ce ntral i ma gi n g m o dalit y f or assessi n g 
t he a nat o m y of t he ki d ne ys a n d uri nar y tract i n c hil dre n.  T he test ca n detect c ha n ges i n 
ki d ne y size, assess pare nc h y mal c ystic or mass lesi o ns, e val uate t he re nal vasc ulat ure, a n d 
assess t he c ollecti n g s yste m [ A v ni 2 0 0 4 ].  Re nal ultras o u n d is a r o uti ne c o m p o ne nt of 
dia g n ostic al g orit h ms f or f oll o w -u p of ser u m or uri nar y a b n or malities s u g gesti n g re nal 
d ysf u ncti o n [ Barratt 2 0 0 4 ] a n d will be a m o n g t he dia g n ostic testi n g perf or me d f or t his 
pr ot oc ol as part of t he assess me nt f or s uc h fi n di n gs.  It is safe, pai nless a n d c o n ve nie nt, 
pr o vi di n g a d va nta ges o ver c o ntrast -e n ha nce d c o m p ute d t o m o gra p h y ( C T) sca n ni n g ( w hic h 
has c o ntrast -me diate d ne p hr ot o xicit y a n d ra diati o n ris ks) a n d ma g netic res o na nce i ma gi n g 
( M RI) ( w hic h re q uires c o ntrast a d mi nistrati o n a n d p ote ntial se dati o n i n y o u n g c hil dre n).  
O btai ni n g a baseli ne ultras o u n d e n ha nces t he se nsiti vit y of s u bse q ue nt ultras o n o gra p h y, 
offeri n g c o nte xt f or a n y p ote ntial a b n or malities e mer gi n g d uri n g st u d y dr u g treat me nt.  A n 


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e n d-of -st u d y ultras o u n d offers f urt her reass ura nce t hat t he ki d ne ys re mai n a nat o micall y 
n or mal at t he c o m pleti o n of t his pr ot oc ol.  
1 3. 2. 5.  H e p ati c M o nit ori n g Pl a n  
M uscle brea k d o w n res ults i n A L T a n d A S T val ues t hat are c o m m o nl y 1 0 - t o 2 0-f ol d > U L N 
( Gra de 3-4) i n patie nts wit h  D B M D.  C o nse q ue ntl y, it is n ot practical t o e x cl u de patie nts wit h 
hi g h ser u m A S T or A L T c o nce ntrati o ns fr o m e nr oll me nt i n t his st u d y, a n d m o nit ori n g f or 
he pat ot o xicit y m ust rel y pri maril y o n f oll o wi n g patie nts f or i ncreases i n bilir u bi n or G G T.  
C o nsiste n t wit h well-esta blis he d g ui deli nes [ A b b o u d 2 0 0 7 ] a p plie d i n t his disease setti n g, e ve n 
m o dest ( Gra de 2) alterati o n i n bilir u bi n or G G T val ues s h o ul d pr o m pt i nterr u pti o n of st u d y dr u g.  
W hile ser u m A L T or A S T val ues ca n n ot r o uti nel y ser ve as meas ures of he p atic i nj ur y i n b o ys 
wit h D B M D, si g nifica nt i ncreases i n A L T ( > 1 5 0  U/ L) i n c o nj u ncti o n wit h a sta ble or falli n g C K 
s h o ul d pr o m pt i ncrease d fre q ue nc y of la b orat or y m o nit ori n g a n d p ossi bl y a n e val uati o n f or 
p ote ntial he pat ot o xicit y.  
1 3. 2. 6.  Li pi d Pr ofil e  
D uri n g t he P hase 2 b d o u ble -bli n d st u d y of atal ure n i n n m D M D ( P T C 1 2 4 -G D -0 0 7 -D M D) , mea n 
t otal c h olester ol a n d tri gl yceri des were i n t he u p per ra n ge of n or mal at baseli ne a n d i ncrease d o n 
st u d y, reac hi n g b or derli ne hi g h or hi g h val ues.  Alt h o u g h t he val ues te n de d t o sta bilize earl y i n 
t he trial a n d di d n ot i ncrease f urt her wit h c o nti n ue d use of atal ure n, m o nit ori n g t he c ha n ges i n 
patie nts’ li pi d pr ofile is warra nte d.  F or t his reas o n, total c h olester ol, L D L, H D L, a n d 
tri gl yceri des will be e val uate d at eac h visit t o m o ni t or f or c ha n ges i n li pi d pr ofile val ues.  
1 3. 2. 7.  Bl o o d Pr e s s ur e A s s e s s m e nt  
D uri n g t he P hase 2 b d o u ble -bli n d st u d y of atal ure n i n n m D M D ( P T C 1 2 4 -G D -0 0 7 -D M D),  6 
patie nts –  all recei vi n g c ortic oster oi ds –  ha d h y perte nsi o n ( or i ncrease d bl o o d press ure) re p orte d 
as a dverse e ve nts ( 0 f or atal ure n 2 0, 2 0, 4 0 m g/ k g, 5 f or atal ure n 1 0, 1 0, 2 0 m g/ k g, a n d 1 f or 
place b o).  F or t his reas o n, b l o o d press ure will be m o nit ore d via sta n dar dize d pr oce d ures at eac h 
visit.   
1 3. 2. 8.  Ot h er N o n cli ni c al Fi n di n g s  
Si n gle li p o mat o us, n o n -metastatic  t u m ors, deter mi ne d t o be mali g na nt hi ber n o mas ori gi nati n g i n 
br o w n a di p ose tiss ue were i de ntifie d i n 6 rats d uri n g a 2 6 wee k t o xicit y st u d y.  I n a sec o n d 2 6 
wee k rat st u d y, n o mali g na nt hi ber n o mas were o bser ve d i n a n y d ose gr o u p, i ncl u di n g t he hi g h 
d ose g r o u p ( 1 2 0 0 m g/ k g/ da y).  T he e x act c orrelati ve rele va nce of t his fi n di n g is u nclear gi ve n t he 
lac k of re pr o d uci bilit y i n rats, t he differe nt p h ysi ol o g y of br o w n fat i n rats relati ve t o h u ma ns 
[ Ca n n o n 2 0 0 4, Iatr o p o ul os 2 0 0 4], t he ver y y o u n g a ge of t he rats use d i n t hese st u dies, t he lac k of 
atal ure n ge n ot o xicit y, a n d t he e xtre me rarit y a n d ge nerall y be ni g n c o urse of hi ber n o mas i n 
h u ma ns [ F url o n g 2 0 0 1].   
Uri nar y bla d der t u m ors were o bser ve d i n 3/ 6 0 fe males at t he hi g h d ose of 3 0 0 m g/ k g/ da y i n t he 
2 4 -m o nt h car ci n o ge nicit y st u d y i n rats.  T his d ose e x cee de d t he ma xi m u m t olerate d d ose ( M T D), 
base d o n a n a vera ge 2 3 % re d ucti o n i n b o d y wei g ht gai n i n c o m paris o n t o ve hicle c o ntr ols 
t hr o u g h o ut t he st u d y.  I n a d diti o n, t he pr o p ose d m o de of uri nar y bla d der t u m or f or matio n 
( prese nce of calc uli) i n rats is n ot c o nsi dere d  rele va nt t o h u ma ns.  Mea n stea d y state e x p os ures i n 


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fe male rats at t he mi d-d ose of 1 0 0 m g/ k g/ da y a n d i n male rats at t he hi g h -d ose of 3 0 0 m g/ k g/ da y 
were 4 a n d 6 ti mes, res pecti vel y, t he stea d y state e x p os u re i n patie nts a d mi nistere d atal ure n at t he 
m or ni n g, mi d da y a n d e ve ni n g d oses of 1 0, 1 0 a n d 2 0 m g/ k g/ da y, res pecti vel y.  
L o n g -ter m p ost-treat me nt f oll o w-u p safet y data c urre ntl y a vaila ble fr o m t he patie nts d ose d wit h 
atal ure n t o date i n t he cli nical st u dies , s o me f or o ver 7 years i n dicate n o i ncrease d ris k of t u m ors. 
1 3. 2. 9.  Ot h er A b n or m aliti e s  
Rec o m me n dati o ns f or i nterr u pti o n of d osi n g are pr o vi de d i n Secti o n 6. 3. 1 , wit h t he ge neral 
i nte nt t hat a Gra de 4 (life-t hreate ni ng) e ve nt s h o ul d res ult i n i m me diate cessati o n of st u d y dr u g 
w hile a waiti n g c o nfir mati o n of t he a b n or mal la b orat or y val ue, a Gra de 3 (se vere) e ve nt ma y 
re q uire c o nfir mati o n of t he a b n or mal la b orat or y val ue bef ore cessati o n of d osi n g, a n d a Gra de 2 
( m o derate) e ve nt ma y pr o m pt f urt her e val uati o n w hile st u d y dr u g d osi n g c o nti n ues.  It is 
i nte n de d t hat t hese rec o m me n dati o ns be vie we d fle xi bl y; t he t y pe a n d c o nte xt f or a n y a d verse 
e ve nt or la b orat or y a b n or malit y m ust be c o nsi dere d i n ta ki n g acti o n.   
1 3. 2. 1 0.  A cti o n s t o b e T a k e n i n R e s p o n s e t o S af et y Si g n al s  
T he i nte nt of t he rec o m me n dati o ns t o i n vesti gat ors re gar di n g res p o nse t o safet y si g nals is t o 
e nc o ura ge a me dicall y a p pr o priate a n d c o nsiste nt a p pr oac h t o a d verse e ve nts a n d la b orat or y 
a b n or malities.  W hile s pecific m o nit ori n g, dia g n ostic testi n g, a n d s u p p orti ve care meas ures m ust 
be i nstit ute d base d o n t he cli nical j u d g me nt of t he i n vesti gat or, i n vesti gat ors are e nc o ura ge d t o 
c o ntact t he P T C T hera pe utics me dical m o nit or ( or q ualifie d desi g nee) t o o btai n g ui da nce a n d t o 
ascertai n w het her si milar e ve nts are bei n g see n at ot her  i n vesti gat or sites.  T he a vaila bilit y of 
a d vice fr o m he pat ol o g y a n d ne p hr ol o g y e x perts retai ne d b y P T C  T hera pe utics is i nte n de d t o 
pr o vi de a u nif or ml y hi g h le vel of c o ns ultati o n i n s u p p ort of t he i n vesti gat ors a n d t he P T C 
me dical m o nit or.   
T he d ose i nterr u pti o n a n d m o dificati o n pr o visi o ns  are desi g ne d t o bala nce a pri mar y c o ncer n f or 
patie nt safet y wit h t he p ote ntial f or o bser vi n g efficac y i n circ u msta nces u n der w hic h a patie nt 
e x perie nci n g a n a d ver se e ve nt ma y still be a ble t o c o nti n ue o n t hera p y at a l o wer st u d y dr u g d ose.  
I nterr u pti o n of t hera p y is a d v ocate d as t he pri mar y res p o nse i n or der t o deter mi ne re versi bilit y of 
t he a d verse fi n di n g.  Rec halle n ge per mits a patie nt t o pr ocee d wit h p ote ntiall y be neficial 
treat me nt a n d e n ha nces u n dersta n di n g of t he relate d ness of t he a d verse e ve nt t o st u d y dr u g.  
I nstit uti n g t he d ose m o dificati o n t hr o u g h t he I V R/I W R s yste m e ns ures t hat t he c ha n ge i n d osi n g 
is trac ke d a n d t hat a p pr o priate dis pe nsi n g occ urs. 
1 3. 2. 1 1.  C o n c o mit a nt T h er a pi e s  
As s u bsta ntial m o dificati o n of c ortic oster oi d d osi n g  d ue t o ma nifestati o n of u n desira ble si de 
effects s uc h as oste o p or osis  d uri n g t he st u d y ma y c o nf o u n d st u d y res ults , i n vesti gat ors a n d 
patie nt s are e nc o ura ge d t o mai ntai n c ortic oster oi d d osi n g as u nif or ml y as p ossi ble.  S pecific 
rec o m me n dati o ns f or mai ntai ni n g, m o dif yi n g, or disc o nti n ui n g c ortic oster oi ds are pr o vi de d wit h 
t he pr ot oc ol (see A p pe n di x A ).   
As t he pri mar y r o ute of atal ure n meta b olis m is via gl uc u r o ni dati o n b y U G T 1 A 9, cli nicall y 
si g nifica nt i nteracti o ns bet wee n atal ure n a n d c o-a d mi nistere d dr u gs meta b olize d b y c yt oc hr o me 
P 4 5 0 e nz y mes ( C Y Ps) are u nli kel y. I n partic ular, atal ure n is n ot a n i n hi bit or of C Y P 1 A 2, 


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CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, and does not have induction 
potential on the major CYP enzymes. Based on in vitro studies, ataluren is also not expected to 
be an inhibitor or a substrate of p-gp mediated transport.   
As an added measure of safety, investigators should pay specific attention to use of drugs that are 
known substrates of this enzyme, particularly when such drugs may have a low therapeutic index. 
Drugs that are metabolized by CYP2C8 or CYP2C9 that have low therapeutics indices (in 
particular, paclitaxel for CYP2C8 and coumarin anticoagulants [eg, warfarin], phenytoin, or 
tolbutamide for CYP2C9) may be of particular concern.  Coumarin anticoagulants are cleared by 
CYP2C9 and increases in plasma concentrations of coumarin anticoagulants may result in 
serious clinical consequences.  For patients who require anticoagulation during the study, use of 
an alternative form of anticoagulation (eg, fractionated heparin) should be considered.  Phenytoin 
is metabolized by CYP2C9 and concomitant use with ataluren may be of potential concern.  For 
patients who require anticonvulsant therapy during the study, use of alternative anticonvulsant 
drugs should be considered.  
The metabolism of losartan to its active metabolite may, in part, be mediated by CYP2C9.  
However, concomitant use of losartan and inhibitors of CYP2C9 have not been examined.  
Because this drug does not have a narrow therapeutic window, the potential for mild to moderate 
changes in activity does not require a dose modification. 
Based on in vitro studies, ataluren is a substrate of UGT1A9 and breast cancer resistant protein 
(BCRP).  Caution should be exercised when ataluren is co-administered with drugs that are 
inducers of UGT1A9 (eg, mycophenolate mofetil), or inhibitors of BCRP (eg, cyclosporine). 
In vitro data indicate that ataluren is an inhibitor of UGT1A9, organic anion transporter 1 
(OAT1), organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 1B3 
(OATP1B3).  Caution should be exercised when ataluren is co-administered with drugs that are 
substrates of UGT1A9 (eg, propofol, mycophenolate mofetil), OAT1, OAT3, or OATP1B3 (eg, 
oseltamivir, acyclovir, ciprofloxacin, captopril, furosemide, bumetanide, valsartan, pravastatin, 
rosuvastatin, atorvastatin, pitavastatin) because of the risk of increased concentration of these 
drugs. 
The investigator is encouraged to consult the PTC medical monitor with questions relating to 
specific drugs and their potential for interactions with ataluren. 
13.3. Study Committees 
Inclusion of both an SSC comprising PTC Therapeutics clinical/biostatistical personnel and 
committed disease experts and a DMC of independent experts incorporates a high level of 
collaborating skill in the conduct of the study with a high level of impartial oversight in analysis 
of study results.  Interaction between the external members of the SSC and the members of the 
DMC will be limited to avoid inadvertent or inappropriate disclosure of information. 
13.4. Efficacy measurements 
13.4.1. 6-Minute Walk Test 
Loss of ambulation is one of the most serious complications of DBMD. The 6MWT is an 
established outcome measure reflecting the global status of all the systems involved in walking, 


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i ncl u di n g t he ne ur o m usc ular, p ul m o nar y, a n d car di o vasc ular s yste ms [Ta ke uc hi 2 0 0 8 ]. 
Base d o n prece de nt i n ot her ne ur o m usc ular dis or ders [ R u bi n 2 0 0 2 , Wrait h 2 0 0 4 , M ue nzer 2 0 0 6 ], 
t he 6 M W T re prese nts a n a p pr o priate a p pr oac h t o assessi n g a m b ulat or y a bilit y i n b o ys wit h 
D B M D. A c ha n ge i n perf or ma nce o n t he 6 M W T c o nstit utes a cli nicall y mea ni n gf ul e n d p oi nt  
a n d i m pr o ve me nts w o ul d be a d irect reflecti o n of be nefit t o b o ys wit h D B M D. T he 6 M W T is 
feasi ble, acc urate, a n d re pr o d uci ble i n t he tar get p o p ulati o n [Mc D o nal d 2 0 1 0 ]. 
1 3. 4. 2.  
Ti m e d F u n cti o n T e st s  
C o m m o nl y e m pl o ye d o ver ma n y years [ Br o o ke 1 9 8 9 , Mc D o nal d 1 9 9 5 ], t hese tests 
are rele va nt t o t he d isease i n t hat t he y assess f u ncti o nal as pects of pr o xi mal m uscle stre n gt h 
re q uire d f or e ver y da y a m b ulati o n. Ti me d f u ncti o n tests are s u bsta ntiall y a b n or mal i n b o ys wit h 
D M D c o m pare d t o healt h y b o ys [ Bee na k ker 2 0 0 5 b ]. W orse ni n g val ues ha ve bee n c orrelate d 
w it h ti me t o w heelc hair de pe n de nc y [Br o o ke 1 9 8 9 , Mc D o nal d 1 9 9 5 ]. T hese tests ca n be 
se nsiti ve t o me dical i nter ve nti o n; c ortic oster oi d t hera p y has d oc u me nte d i m pr o ve me nts i n all 3 
para meters [ Me n dell 1 9 8 9 , Gri g gs 1 9 9 1 , Bee na k ker 2 0 0 5a ]. Gi ve n t heir l o n g-sta ndi n g use a n d  
si m plicit y, t here is s u bsta ntial e x perie nce wit h t he c o n d uct of t he tests a n d t he a nal yses of t he 
data a n d ver y hi g h re pr o d uci bilit y has bee n de m o nstrate d [ Ma y he w 2 0 0 7 ]. 
1 3. 4. 3.  
N ort h St ar A m b ul at or y A s s e s s m e nt  
T he N S A A is a f u ncti o nal scale s pecifica ll y desi g ne d f or a m b ula nt D M D b o ys.  T he scale has 
bee n de vel o pe d a n d pil ote d i n t he U nite d Ki n g d o m b y t he N ort h Star Cli nical Net w or k f or 
Pae diatric Ne ur o m usc ular Disease Ma na ge me nt wit h g o o d i ntra a n d i nter o bser ver relia bilit y a n d 
has rece ntl y bee n use d i n a lar ge m ultice nter st u d y [Mazz o ne 2 0 1 1 ]. 
T he scale i ncl u des ite ms assessi n g a bilities t hat are necessar y t o re mai n f u ncti o nall y a m b ula nt, 
ie, a bilit y t o rise fr o m t he fl o or, a bilit y t o get fr o m l yi n g t o sitti n g a n d sitti n g t o sta n di n g, a n d t hat 
are k n ow n t o pr o gressi vel y deteri orate i n u ntreate d D M D patie nts.  T he scale als o i ncl u des ite ms 
assessi n g hea d raise a n d sta n di n g o n heels t hat ca n be partl y prese nt i n t he earl y sta ges of t he 
disease a n d a n u m ber of acti vities s uc h as h o p pi n g, j u m pi n g, a n d r u n n i n g [Mazz o ne 2 0 1 0 ]. 
1 3. 4. 4.  
P erf or m a n c e of U p p er Li m b A s s e s s m e nt  ( P U L) 
T he P U L is a scale desi g ne d t o meas ure m ot or perf or ma nce of t he u p per li m bs i n D M D. T he 
P U L was create d wit hi n a c o nce pt ual fra me w or k reflecti n g t he pr o gressi o n of wea k ness a n d 
nat ural hist or y of f u ncti o nal decli ne e vi de nt i n b ot h t he a m b ula nt a n d n o n-a m b ula nt sta ges of 
D M D .  M o der n ps yc h o metric met h o ds were use d t o create a scale wit h r o b ust i nter nal relia bilit y, 
vali dit y, a n d hierarc hical scala bilit y; males wit h D M D a n d t heir fa milies were i n v ol ve d 
iterati vel y t hr o u g h o ut t he pr ocess of t he cli nicia n-re p orte d o utc o me assess me nt t o ol de vel o p me nt 
t o esta blis h cli nical mea ni n gf ul ness a n d rele va nce of i n di vi d ual P U L ite ms t o acti vities of dail y 
li vi n g [Ma y he w 2 0 1 3 ].  T he P U L i ncl u des 2 2 ite ms ( wit h a n e ntr y ite m t o defi ne starti n g 
f u ncti o nal le vel t o a v oi d testi n g f u ncti o nal di me nsi o ns i n w hic h t he patie nt  lac ks t he l o wer li mit 
of f u ncti o n, a n d 2 1 ite ms s u b di vi de d i nt o s h o ul der le vel ( 4 ite ms), el b o w le vel ( 9 ite ms), a n d 
distal le vel ( 8 ite ms) di me ns i o ns. 
1 3. 4. 5.  S pir o m etr y  
Pr o gressi ve p ul m o nar y d ysf u ncti o n is a maj or s o urce of disa bilit y a n d s h orte ne d s ur vi val  


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ass ociate d wit h D M D a n d re prese nts a n i m p orta nt tar get f or t hera pe utic i nter ve nti o n. Nat ural  
hist or y data i n D M D s h o w t hat p ul m o nar y val ues decli ne m o re preci pit o usl y o nce patie nts l ose 
a m b ulati o n [ Steffe nse n 2 0 0 2 ]. 
Base d o n e x perie nce at meas uri n g p ul m o nar y f u ncti o n i n ra n d o mize d trials [ Me n dell 1 9 8 9 , 
Gri g gs 1 9 9 1 ], it is clear t hat s pir o metr y testi n g ca n be perf or me d practicall y i n m ultice nter 
st u dies e nr olli n g st u d y p o p ulati o ns c o m para ble t o t h ose t o be e nr olle d i nt o t his st u d y. Sta n dar d  
o perati n g pr oce d ures f or s pir o metr y perf or ma nce, re q uiri n g t hat s pir o metric eff ort is s ufficie nt  
a n d t hat eac h test is c o nsiste nt wit h A merica n T h oracic S ociet y/ E ur o pe a n Res pirat or y S ociet y 
g ui deli nes [ Miller 2 0 0 5a , Miller 2 0 0 5 b ] will be use d. 
1 3. 4. 6.  
P e di atri c Q u alit y of Lif e I n str u m e nt  
H ealt h-relate d q ualit y of life meas ure me nt has bee n i ncreasi n gl y use d as a n esse ntial healt h 
o utc o me meas ure i n cli nical trials i n v ol vi n g c hil dre n wit h ne ur o m usc ular dis or ders.  Ge neric 
healt h -relate d q ualit y of life i nstr u me nts ha ve bee n use d m ost fre q ue ntl y as patie nt-re p orte d 
o utc o me meas ures; h o we ver, t hese meas ures ma y be i na de q uate i n ter ms of se nsiti vit y f or 
detecti o n of c ha n ge i n d uce d b y  a treat me nt [ Mc D o nal d 2 0 1 0c ].  F or t his st u d y, t he P O D CI 
d o mai ns of tra nsfers/ basic m o bilit y a n d s p orts/ p h ysical f u ncti o n ha ve bee n selecte d t o o btai n 
pare nt/care gi ver i nf or mati o n relati n g t o H R Q L.  I n a st u d y b y Mc D o nal d 2 0 1 0c, t hese  d o mai ns 
were s h o w n t o ha ve a cl ose ass ociati o n wit h disease pr o gressi o n a n d cli nical o utc o me meas ures 
hist oricall y e m pl o ye d i n cli nical trials of a m b ulat or y b o ys wit h D M D.  
T he P O D CI q uesti o n naire will be a vaila ble i n all la n g ua ges rele va nt f or t his st u d y a n d will be 
c o m pleted b y t he pare nt/care gi ver.  If p ossi ble, t he sa me pare nt/care gi ver s h o ul d c o m plete t he 
q uesti o n naire eac h ti me.   
1 3. 4. 7.  A cti viti e s of D ail y Li vi n g a n d Di s e a s e S y m pt o m  S ur v e y  
T here has bee n gr o wi n g  i nterest i n see ki n g direct patie nt re p orti n g of c ha n ges i n s y m pt oms a n d 
f u ncti o ni n g d uri n g a cli nical st u d y [F D A 2 0 0 9 ].  S uc h i nf or mati o n ma y hel p t o c o nfir m m ore 
o bjecti ve meas ures of patie nt be nefit, a n d d oc u me nt h o w dr u g acti vit y tra nslates t o i m pr o ve d 
well -bei n g o utsi de of t he cli nic.  A nec d otal re p orts fr o m pare nts  a n d teac hers of b o ys 
partici pati n g i n pri or st u dies of atal ure n i n n m D M D s u g geste d t hat b o ys ha ve e x perie nce d 
ps yc h ol o gical, s ocial a n d be ha vi oral be nefits (e g, less fr ustrati o n wit h p h ysical tas ks, i m pr o ve d 
a bilit y t o pla y wit h ot her c hil dre n) i n ass ocia ti o n wit h i m pr o ve d e n d ura nce a n d re d uce d fati g ue 
w hile recei vi n g atal ure n.  T o f or mall y ca pt ure s uc h re p orts, a  disease s y m pt o m s ur ve y will be 
utilize d t o ca pt ure i n di vi d ualize d patie nt a n d pare nt/care gi ver-re p orte d c ha n ges i n acti vities of 
dail y li vi n g a nd disease s y m pt o ms t hat are s pecific t o d ystr o p hi n o pat h y a n d are n ot assesse d i n 
sta n dar dize d q uesti o n naires.  T his s ur ve y has bee n de vel o pe d b y P T C T hera pe utics base d u p o n 
re p orts fr o m partici pa nts i n pre vi o us atal ure n st u dies.  T he s ur ve y will be a vaila ble i n all 
la n g ua ges rele va nt f or t his st u d y a n d will be a d mi nistere d b y t he site staff t o t he pare nt/care gi ver 
a n d/ or patie nt.    


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1 4.  B E N E FI T S A N D RI S K S  
1 4. 1.  B e n efit s a n d Ri s k s: N o n cli ni c al  
Atal ure n is a n orall y bi oa vaila ble s mall m olec ule i nte n de d f or t he treat me n t of n o nse nse m utati o n 
D uc he n ne m usc ular d ystr o p h y ( n m D M D) res ulti n g fr o m a n o nse nse m utati o n i n t he d ystr o p hi n 
ge ne.  I n cell ular assa ys a n d a ni mal m o dels of ge netic disease, atal ure n de m o nstrate d t he a bilit y 
t o s pecificall y a n d selecti vel y e na ble rea dt hro u g h of m R N A c o ntai ni n g a pre mat ure st o p c o d o n, 
i n d uci n g pr o d ucti o n of f ull-le n gt h pr otei n t hat l ocalizes t o t he a p pr o priate cell ular l ocati o n a n d is 
f u ncti o nall y acti ve.  Atal ure n c o nsiste ntl y e na ble d m R N A rea dt hr o u g h a n d f u ncti o nal f ull-le n gt h 
pr otei n pr o d ucti o n fr o m m R N As t hat c o ntai n a pre mat ure st o p c o d o n wit h o ut pr o m oti n g 
rea dt hr o u g h of n or mal st o p c o d o ns.   
Atal ure n was s h o w n t o be selecti ve f or tra nslati o n.  Atal ure n di d n ot alter le vels of m R N A wit h 
pre mat ure st o p c o d o ns or wil d t y pe m R N A de m o nstra ti n g t hat atal ure n d oes n ot m o dif y 
tra nscri pti o n or m R N A sta bilit y.  I n cell-free tra nslati o n assa ys, atal ure n f u ncti o ns at t he le vel of 
tra nslati o n a n d n ot tra nscri pti o n.  Atal ure n d oes n ot pr o d uce a f u ncti o nal pr otei n b y pr o m oti n g 
rea dt hr o u g h of pre mat ur e st o p c o d o ns d ue t o fra mes hift m utati o ns (i nserti o ns or deleti o ns) or of 
m R N As har b ori n g m ulti ple se q ue ntial pre mat ure st o p c o d o ns.  Atal ure n is selecti ve f or 
pre mat ure st o p c o d o ns a n d d oes n ot pr o m ote rea dt hr o u g h of n or mal st o p c o d o ns.  I n cell ular 
m o del s of n o nse nse m utati o n ge netic diseases, atal ure n e x hi bite d a bell-s ha pe d c o nce ntrati o n 
res p o nse wit h ma xi mal acti vit y at 1 0 μ g/ m L.  At atal ure n c o nce ntrati o ns a b o ve 2 0 µ g/ m L a 
re d ucti o n i n acti vit y is o bser ve d, i n dicati n g a bell-s ha pe d d ose res p o nse.  C yt ot o xicit y was n ot 
o bser ve d at a n y c o nce ntrati o n teste d.  I n a ni mal m o dels, atal ure n e x hi bite d a bell -s ha pe d 
d ose -res p o nse.  In vitr o a n d i n vi v o n o ncli nical efficac y p har mac ol o g y data i n dicate t hat 
c o nce ntrati o ns t hat ra n ge fr o m ~ 1 t o 2 0 μ g/ m L were ass ocia te d wit h p har mac o d y na mic acti vit y.  
S pecificall y, i n t he m dx  m o use m o del, efficac y was ass ociate d wit h c o nce ntrati o ns ra n gi n g fr o m 
2 t o 1 0 μ g/ m L.   
T o xic o ki netic data were o btai ne d i n t o xicit y st u dies c o n d ucte d i n mice, rats, ra b bits a n d d o gs.  
C o nsiste nt wit h t he s h ort t ½, t here was n o acc u m ulati o n of dr u g i n plas ma u p o n re peate d dail y 
d osi n g.  I n all s pecies, atal ure n e x p os ure i ncrease d wit h i ncreasi n g d ose, b ut t he i ncrease was 
ge nerall y less t ha n d ose pr o p orti o nal.  T here were n o se x -relate d differe nces i n atal ure n e x p os ure 
i n d o gs, b ut i n rats a n d mice, e x p os ure was sli g htl y hi g her i n fe males t ha n i n males.  T he maj or 
meta b olite see n i n mice, rats a n d d o gs was atal ure n ac yl gl uc ur o ni de; e x p os ure t o t his meta b olite 
i n t he t o xic ol o g y s pecies at L O A E Ls, N OA E Ls, a n d N E Ls i n t he t o xic ol o g y pr o gra m was greater 
t ha n t he e x p os ure o bser ve d i n h u ma ns a d mi nistere d t he cli nical d ose of 1 0, 1 0 a n d 2 0 m g/ k g/ da y 
at m or ni n g, mi d da y, a n d e ve ni n g, res pecti vel y.  Atal ure n is hi g hl y b o u n d ( > 9 7 %) t o plas ma 
pr otei ns i n all s pecies, i ncl u di n g h u ma n.  Atal ure n is neit her a s u bstrate f or n or a n i n hi bit or of p -
gl yc o pr otei n. E nz y me i n hi biti o n st u dies wit h h u ma n li ver micr os o mes s h o we d t hat atal ure n has a 
ver y wea k p ote ntial f or direct i n hi biti o n of C Y P 2 C 8 a n d C Y P 2 C 9. E nz y me i n d uct i o n 
e val uati o ns i n h u ma n he pat oc ytes s h o we d t hat atal ure n di d n ot i n d uce t he acti vities of C Y P 4 5 0 
e nz y mes.  H o we ver, t here were sli g ht i ncreases i n t he acti vities of C Y P 2 B 6 a n d C Y P 2 C 9 o nl y 
wit h t he hi g hest i nc u bate d atal ure n c o nce ntrati o n of 4 0 0 μ M.  It wa s c o ncl u de d t hat t he i ncrease d 
acti vities of C Y P 2 B 6 a n d C Y P 2 C 9 were n ot cli nicall y si g nifica nt or rele va nt.  T heref ore, 


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ataluren is not expected to decrease exposure to drugs that are eliminated via metabolism by 
these CYP enzymes. 
Based on in vitro studies, ataluren is a substrate of UGT1A9 and breast cancer resistant protein 
(BCRP).  Caution should be exercised when ataluren is co-administered with drugs that are 
inducers of UGT1A9 (eg, mycophenolate mofetil), or inhibitors of BCRP (eg, cyclosporine). 
In vitro data indicate that ataluren is an inhibitor of UGT1A9, organic anion transporter 1 
(OAT1), organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 1B3 
(OATP1B3).  Caution should be exercised when ataluren is co-administered with drugs that are 
substrates of UGT1A9 (eg, propofol, mycophenolate mofetil), OAT1, OAT3, or OATP1B3 (eg, 
oseltamivir, acyclovir, ciprofloxacin, captopril, furosemide, bumetanide, valsartan, pravastatin, 
rosuvastatin, atorvastatin, pitavastatin) because of the risk of increased concentration of these 
drugs. 
Ataluren was evaluated in safety pharmacology studies and found to have no effects on the 
cardiovascular system, respiratory system, or central nervous system.  In the toxicology program, 
the major findings observed were species-specific, ie, observed in one toxicology species only.  
These findings included kidney findings in mice (nephrosis, predominantly in the distal nephron, 
reversible following cessation of dosing) and adrenal gland cortical findings in dogs 
(lymphohistiocytic infiltrates with focal parenchymal cell degeneration in regions responsible for 
synthesis of glucocorticoids).  Chronic studies were conducted in weanling rats and dogs to 
support dosing in children as young as 2 years of age.  Ataluren was not genotoxic, and was not 
teratogenic in rats and rabbits.   In rats and rabbits, fetal toxicity was observed only at materno-
toxic doses.  Ataluren had no effect on the fertility of male and female rats.  In rats, postnatal 
developmental effects were observed only at materno-toxic doses.  Maternal administration of 
ataluren in rats had no effect on F1 reproduction or F2 embryo/fetal development.  Ataluren did 
not increase the incidence of tumors in a 26-week carcinogenicity study in Tg.rasH2 mice. 
Tumors observed in rats in the toxicology program occurred at exposures that exceeded clinical 
exposure and/or were not considered relevant to humans.  The structurally identified process 
impurities of the ataluren drug substance were qualified in rats at doses 29- to 33-fold higher  
than would be administered in the clinic at the proposed morning, midday, and evening doses of 
10, 10 and 20 mg/kg/day, respectively.  Ataluren is a small molecular weight compound, and 
therefore, is not expected to produce anti-drug antibodies.  Ataluren had no effect on the immune 
system in the toxicology program and in the clinical trials; therefore, immunotoxicity studies 
were not performed with ataluren. 
Nonclinical safety pharmacology and toxicology studies indicate that ataluren has an acceptable 
safety profile. The findings seen pose a low human safety risk and the program supports chronic 
administration of ataluren in patients as young as 2 years of age. 
The nonclinical evaluation of ataluren presented in this summary support its use for the treatment 
of nmDMD. 
14.2. Benefits and Risks: Clinical Efficacy 
Duchenne muscular dystrophy (DMD) is a rare (1 in 3500 male births) disabling, relentlessly 
progressive, and ultimately fatal X-linked genetic disorder that primarily affects males.  


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C urre ntl y, treat me nt is palliati ve.  N o t hera pies t hat a d dress t he u n derl yi n g ca use of t he disease 
are a vaila ble.  
Decli ne i n a m b ulati o n is t he hall mar k of D M D, a n d t he maj or g oal of i nter ve nti o n d uri n g t he 
a m b ulat or y p hase of D M D is t o mai ntai n a m b ulati o n f or as l o n g as p ossi ble.  Atal ure n at a d ose 
of 1 0, 1 0, 2 0  m g/ k g sl o we d  t he decli ne i n a m b ulati o n i n n o nse nse m utati o n D M D patie nts.  I n 
t he place b o-c o ntr olle d st u d y, St u d y 0 0 7, t he tar gete d differe nce of 3 0  meters bet wee n atal ure n 
1 0, 1 0, 2 0 m g / k g a n d place b o i n t he 6 -mi n ute wal k dista nce ( 6 M W D ) was ac hie ve d ( Δ = 3 1. 3 
meters, a dj uste d p = 0. 0 5 6 1, cI T T a nal ysis).   T he 3 0 -meter dista nce meets t he t hres h ol d f or 
mi ni mal cli nicall y i m p orta nt differe nce i n D M D a n d ot her diseases , a n d is i n t he ra n ge of t he 
6 M W D res ults f or a p pr o ve d t hera pies i n a variet y of c o n diti o ns .  T he 3 0-meter dista nce is 
mea ni n gf ul t o D M D patie nts, pr o vi di n g  greater a bilit y t o wal k i n t heir dail y li ves, f or e x a m ple, 
wal ki n g t o a n d fr o m t he sc h o ol b us a n d ta ki n g part i n s ocial acti vi ties. 
T he ti me -t o-e ve nt a nal ysis of 6 M W D pr o gressi o n f urt her s h o we d t hat atal ure n 1 0, 1 0, 2 0 m g/ k g 
sl o we d disease pr o gressi o n i n patie nts wit h n m D M D.  O nl y 2 6 % of patie nts w h o recei ve d 
atal ure n 1 0, 1 0, 2 0  m g/ k g, c o m pare d wit h 4 4 % of t he patie nts w h o recei v e d place b o, ha d 
persiste nt 1 0 % w orse ni n g i n t he 6 M W D at Wee k  4 8  (a dj uste d p = 0. 0 6 5 2, cI T T a nal ysis).  
Dela yi n g a m b ulat or y decli ne pr o vi des direct cli nical be nefit b y  aff or di n g b o ys wit h n m D M D a 
l o n ger peri o d of self-s ufficie nc y bef ore tra nsiti o ni n g t o f ull-ti me w heelc hair use.  Mai nte na nce of 
a m b ulat or y ca pacit y ca n pre ve nt, dela y t he o nset of, or re d uce t he se verit y of sc oli osis, a 
de bilitati n g c o m plicati o n of D M D , a n d is be neficial t o t he patie nt’s p ul m o nar y stat us.   
P ositi ve tre n ds i n sec o n dar y e n d p oi nts  i n St u d y 0 0 7 s u p p ort t he 6 M W D res ults.  Patie nts w h o 
were treate d wit h atal ure n 1 0, 1 0, 2 0  m g/ k g tre n de d t o war d less decli ne i n m uscle f u ncti o n t ha n 
patie nts w h o were treate d wit h place b o a n d met t he t hres h ol d ( ~ 1. 5 sec o n ds) f or cli nicall y 
mea ni n gf ul diff ere nces .  A m o n g t he T F Ts, t he lar gest effect f or atal ure n 1 0, 1 0, 2 0 m g/ k g was 
see n i n stair cli m bi n g, w hic h is o ne of t he m ost diffic ult acti vities of daily li vi n g f or patie nts wit h 
D M D .  P ositi ve tre n ds, fa v ori n g atal ure n 1 0, 1 0, 2 0 m g/ k g o ver place b o, w ere als o o bser ve d f or 
ti me d f u ncti o n test met h o d gra di n g, acci de ntal fall fre q ue nc y, acti vit y a n d w heelc hair use i n t he 
c o m m u nit y setti n g, m y o metr y, a n d patie nt -re p orte d p h ysical f u ncti o ni n g d o mai n of t he Pe ds Q L.  
T he c o nsiste nc y of t hese fi n di n gs  acr oss outc o me meas ures  s u p p orts a treat me nt effect of 
atal ure n 1 0, 1 0, 2 0 m g/ k g i n patie nts wit h n m D M D.  
T he hi g her d ose i n St u d y 0 0 7, 2 0, 2 0, 4 0 m g/ k g, di d n ot differe ntiate fr o m place b o i n t he pri mar y 
e n d p oi nt, 6 M W D.  T he i n verse d ose res p o nse pr o m pte d a n a nal ys is of efficac y meas ures b y 
atal ure n plas ma c o nce ntrati o n i n t he atal ure n cli nical trials.  Acr oss 3 cli nical trials ( place b o -
c o ntr olle d St u d y 0 0 7 a n d o pe n -la bel St u dies 0 0 7e a n d 0 0 4e), atal ure n c o nce ntrati o n-res p o nse 
a nal yses i n patie nts w h o were treate d w it h atal ure n 2 0, 2 0, 4 0 m g/ k g s h o we d better res ults f or t he 
6 M W T a n d ti me d f u ncti o n tests (T F Ts ) i n patie nts w h ose plas ma atal ure n c o nce ntrati o ns were i n 
t he ra n ge of t h ose o bser ve d wit h atal ure n 1 0, 1 0, 2 0  m g/ k g, t ha n i n patie nts wit h hi g her plas ma 
c o nce ntrati o ns.  T his i n verse c o nce ntrati o n -res p o nse relati o ns hi p is s u p p orte d b y t he p o p ulati o n 
P K -P D m o del of 6 M W T data.  T hese cli nical fi n di n gs are c o nsiste nt wit h n o ncli nical st u dies of 
atal ure n (i n t he D M D m o use m o del a n d ot her disease m o dels) as well as o t her n o nse nse m utati o n 
rea d-t hr o u g h dr u gs, w hic h s h o w a bell-s ha pe d c o nce ntrati o n-res p o nse relati o ns hi p.  T hese 
a nal yses e x plai n t he i n verse d ose -res p o nse see n i n St u d y 0 0 7 a n d s u p p ort t he pr o p ose d d ose of 
atal ure n 1 0, 1 0, 2 0  m g/ k g.    


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Collectively, the 6MWD data in Study 007, supported by secondary outcome measures, and the 
concentration-response analyses across nmDMD studies, demonstrate the beneficial effect of 
ataluren 10, 10, 20 mg/kg in patients with nmDMD.  Ataluren thus offers an important advance 
in the genetic-based treatment of nmDMD in patients aged 5 years and older. 
14.3. Benefits and Risks: Clinical Safety 
Ataluren was well tolerated by patients with nmDMD at the proposed recommended dose of 
10, 10, 20 mg/kg, as well as at the higher dose of 20, 20, 40 mg/kg, when taken daily for 
48 weeks in the Phase 2b placebo controlled study (Study 007).  Most adverse events were mild 
or moderate, transient, and did not require medical intervention.  None of the patients 
discontinued treatment because of adverse events.  Few serious adverse events were reported, 
none was attributed to ataluren, and no deaths occurred. 
The adverse-event profile of ataluren was comparable to that of placebo.  Vomiting, headache, 
diarrhea, nasopharyngitis, pyrexia, cough, and upper abdominal pain were the most commonly 
reported adverse events in the placebo, ataluren 10, 10, 20 mg/kg, and ataluren 20, 20, 40 mg/kg 
treatment arms.  Many of the reported adverse events were those that are typically associated 
with pediatric illnesses. 
In Study 007, no clinically meaningful effects of ataluren, at either dose level, were observed in 
clinical laboratory assessments, vital signs, physical examinations, or ECGs.  Six patients – all 
receiving corticosteroids - had hypertension (or increased blood pressure) reported as adverse 
events (0 for ataluren 20, 20, 40 mg/kg, 5 for ataluren 10, 10, 20 mg/kg, and 1 for placebo).  In 
this study, mean total cholesterol and triglycerides were in the upper range of normal at baseline 
and increased, reaching borderline high or high values.  The values tended to stabilize early in the 
study and did not increase further with continued treatment.  Small increases in mean serum 
creatinine, BUN, and cystatin C were observed.  Similarly, the values tended to stabilize early in 
the study and did not increase further with continued treatment.  
The safety profiles observed in other nmDMD studies and in nmCF studies were generally 
similar to that observed in Study 007.  Renal adverse reactions, primarily creatinine elevations, 
occurred more frequently in nmCF than in nmDMD, in particular with concomitant 
administration of IV aminoglycosides. 
Based on evidence of decreased renal function in patients with nmCF who received 
coadministration of ataluren and IV aminoglycosides, ataluren should not be coadministered with 
IV aminoglycosides.  Since some of the cases of decreased renal function were also associated 
with dehydration, patients receiving ataluren are encouraged to maintain adequate hydration. 
Collectively, the safety data from clinical trials demonstrate that ataluren has a favorable safety 
profile for the treatment of patients with nmDMD. 
14.4. Benefit/Risk Conclusions 
An urgent unmet medical need exists for a therapy that addresses the underlying cause of 
nmDMD, a condition for which no approved treatment exist.  Ataluren 10, 10, 20 mg/kg 


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represents the first disease-modifying therapy for this severely disabling, progressive, and, 
ultimately fatal disease.   
Study 007 was one of the largest studies ever conducted in DMD.  Moreover, Study 007 was a 
well designed placebo controlled study conducted with excellent compliance and with high 
quality.  The pre-specified and clinically meaningful target of a 30 meter difference in the 
primary endpoint, 6MWD, was achieved.  The study approached statistical significance in the 
primary endpoint after necessary correction of baseline data and refinement of the statistical 
analysis.  Furthermore, ataluren demonstrated slowing of disease progression in several outcome 
measures.  The positive trends in the analysis of percent of patients whose 6MWD progressed by 
Week 48, as well as in many secondary endpoints, support the clinical benefit of ataluren 
treatment in nmDMD. 
The unmet medical need in this devastating disease, in which there is no available therapy that 
addresses its underlying cause, justifies clinical treatment with this novel treatment.  Given that 
ataluren has a favorable safety profile, the benefit-risk profile of ataluren is positive.  The current 
trial (020e) is feasible and will provide additional safety and efficacy data of ataluren in 
nmDMD. 


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P a ge 7 4  of 9 1  
 
BI B LI O G R A P H Y  
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Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
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P a ge 7 5  of 9 1  
 
B osser G, L ucr o n H, Let h or J P, B ur ger G, Beltra m o F, Marie P Y, Marc o n F.  E vi de nce of earl y 
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1 0 5 ( 6): 2 0 6 4-9.  


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
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Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
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P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 7 7  of 9 1  
 
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1 9  N o ve m ber 2 0 1 5  
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Sc h wartz GJ, Bri o n L P, S pitzer A .  T he use of pl as ma creati ni ne c o nce ntrati o n f or esti mati n g 
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A P P E N DI X A.  M A N A G E M E N T O F C O R TI C O S T E R OI D S  
A.  I niti ati n g Alt er n at e C orti c o st er oi d s D uri n g t h e St u d y  
If a patie nt  d oes re q uire i nitiati o n of a n alter nate c ortic oster oi d t hera p y (ie. s witc hi n g fr o m 
pre d nis o ne t o deflazac ort or vice -versa) d uri n g t he st u d y, t otal d oses s h o ul d n ot e x cee d 0. 7 5 
m g/ k g f or pre d nis o ne a n d 0. 9 m g/ k g f or deflazac ort.  Ge neral rec o m me n dati o ns f or 
c ortic oster oi d d osi n g are pr o vi de d i n Ta ble A bel o w.  
T a bl e A. 
T a bl e A. G ui d a nc e f or I niti ati n g 
G ui d a nc e f or I niti ati n g Alt er n at e 
Alt er n at e C orti c ost er oi d Tr e at m e nt
C orti c ost er oi d Tr e at m e nt  
W ei g ht R a n g e  
Pr e d ni s o n e D o s e  
( 0. 7 5 m g/ k g) 
D efl a z a c ort D o s e  
( 0. 9 m g/ k g) 
1 5 -1 9 k g  
1 2 m g  
1 5 m g  
2 0 -2 5 k g  
1 7 m g  
2 1 m g  
2 6 -3 2 k g  
2 2 m g  
2 7 m g  
3 3 -3 9 k g  
2 7 m g  
3 3 m g  
4 0 k g +  
3 0 m g  
3 6 m g  
 
Patie nt s w h o re q uire alter nate c ortic oster oi d i nitiati o n ma y re mai n o n st u d y dr u g.  C ha n gi n g t he 
t y pe of c ortic oster oi d or t he c ortic oster oi d sc he d ule d uri n g t he st u d y is str o n gl y disc o ura ge d.   
B . M ai nt ai ni n g C orti c o st er oi d D o s a g e D uri n g t h e St u d y  
A dj ust me nts i n c ortic oster oi d d osa ge f or i ncreases i n b o d y wei g ht are per mitte d b ut are n ot 
ma n dat or y.  If it is t he practice of  t he i n vesti gat or t o a dj ust patie nt s’ c ortic oster oi d d oses f or 
c ha n ges i n b o d y wei g ht, t otal d oses s h o ul d n ot e x cee d 0. 7 5 m g/ k g f or pre d nis o ne a n d 0. 9 m g/ k g 
f or deflazac ort (see Ta ble A a b o ve).   
I n a d diti o n, c o nsiste nt wit h t he sta n dar ds pr o p ose d f or t he pla n ne d i nter nati o nal c ortic oster oi d 
o pti mizati o n st u d y [ B us h b y 2 0 0 7 ], i ncreases i n t otal d ose f or a n y reas o ns s h o ul d n ot e x cee d 5 m g 
f or pre d nis o ne or 6 m g f or deflazac ort.  F or e x a m ple, if a patie nt  is recei vi n g 2 2 m g Q D of 
pre d nis o ne a n d it is electe d t o i ncrease t he d ose, t he t otal pre d nis o ne d ose s h o ul d n ot be 
i ncrease d be y o n d 2 7 m g Q D.  I n a d diti o n, f or patie nt s ≥4 0 k g, t otal d oses s h o ul d be ca p pe d at 3 0 
m g of pre d nis o ne or 3 6  m g of deflazac ort u nless t he patie nt  was alrea d y recei vi n g a hi g her d ose 
of  c ortic oster oi ds t ha n t hese li mits at st u d y e ntr y [ B us h b y 2 0 0 7 ].   
Patie nt s w h o re q uire c ortic oster oi d i ncreases ma y re mai n o n st u d y dr u g.  
C.   M o dif yi n g C orti c o st er oi d D o s a g e D uri n g t h e St u d y  
Disc o nti n uati o n of c ortic oster oi d t hera p y d uri n g t he st u d y s h o u l d be a v oi de d u nless cli nicall y 
necessar y.  I n t he case of t he de vel o p me nt of pre dicta ble c ortic oster oi d -relate d si de effects, 
a p pr o priate s u p p orti ve care s h o ul d be pr o vi de d a n d c ortic oster oi d d osa ge ca n be mai ntai ne d ( ie, 
n ot i ncrease d f or t he n or mal i ncr ease i n b o d y wei g ht).  If u nacce pta ble c ortic oster oi d si de effects 
persist, t he d osa ge ca n be re d uce d i n decre me nts of ≤5 m g t otal d ose f or pre d nis o ne ( ≤6 m g t otal 
d ose f or deflazac ort).  Fi nall y, c ortic oster oi d a d mi nistrati o n ca n be st o p pe d alt o get her.  S pecific 
rec o m me n dati o ns f or preca uti o nar y i nter ve nti o ns f or s pecific c ortic oster oi d-relate d a d verse 
e ve nts are gi ve n bel o w.  


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A c n e  
I n t he e ve nt of b ot hers o me ac ne t hat ma y be attri b uta ble t o c ortic oster oi ds, t he f oll o wi n g 
i nter ve nti o ns are rec o m me n de d : 
•  C orti c oster oi ds s h o ul d n ot t o be i ncrease d t o a dj ust f or i ncreases i n b o d y wei g ht  a n d t he 
patie nt  s h o ul d be pr o vi de d wit h c o ns ultati o n fr o m a der mat ol o gist f or i nstit uti o n of 
a p pr o priate c o n ve nti o nal t hera p y f or ac ne.  
•  If t he ac ne is s o se vere it ca n n ot be ma na ge d wit h a p pr o priate a nti -ac ne meas ures, d osa ge 
re d ucti o ns of ≤5  m g t otal d ose f or pre d nis o ne ( ≤6  m g t otal d ose f or deflazac ort) at ~  
6 -8 -wee k i nter vals ca n be c o nsi dere d.  
•  E ver y atte m pt s h o ul d be ma de t o a v oi d st o p pi n g c ortic oster oi ds  s olel y f or ac ne; if t he 
patie nt /fa mil y de ma n ds t hat c ortic oster oi ds be st o p pe d, see Secti o n D  bel o w f or pr oce d ures 
f or wit h dra wal of c ortic oster oi ds.   
B e h a vi or  C h a n g e s  
W here be ha vi or c ha n ges are disr u pti ve t o fa mil y/sc h o ol life, t he f oll o wi n g i nter ve nti o ns are 
rec o m me n de d: 
•  T he  patie nt  a n d t he fa mil y s h o ul d be pr o vi de d wit h be ha vi oral s u p p ort fr o m a c hil d 
ps yc h ol o gist.  
•  If t he patie nt  is alrea d y recei vi n g be ha vi oral a d vice u n der t he g ui da nce of a c hil d 
ps yc h ol o gist , t he c ortic oster oi d d osa ge s h o ul d n ot t o be i ncrease d t o a dj ust for i ncreases i n 
b o d y wei g ht .  Co nsi der ati o n ca n be gi v en  t o a d mi nisteri n g t he c ortic oster oi d d ose at ni g ht 
i nstea d of i n t he m or ni n g. 
•  If t here is n o i m pr o ve me nt des pite be ha vi oral a d vice u n der t he g ui da nce of a c hil d 
ps yc h ol o gist , d osa ge re d ucti o ns of ≤5  m g t otal d ose f or pre d nis o ne ( ≤6  m g t otal d ose f or 
deflazac ort) at ~ 6 -8 -wee k i nter vals ca n be c o nsi dere d.  
•  If t he se vere be ha vi oral pr o ble ms c o nti n ue t o ca use u nacce pta ble disr u pti o n t o sc h o ol/ fa mil y 
life, c ortic oster oi ds ma y be st o p pe d.  See Secti o n D  bel o w f or pr oce d ures f or wit h dra wal of 
c ortic oster oi ds.  
B o n e F r a ct ur e s D u e t o O st e o p or o si s  
Patie nt s w h o e x perie nce li m b fract ures s h o ul d ha ve fi x ati o n as directe d b y a n ort h o pe dic 
s ur ge o n.  Patie nt s w h o de vel o p verte bral fract ures ca n be treate d wit h bis p h os p ha nates (e g, 
pa mi dr o nate, 0. 5 t o 1 m g/ k g/ da y i ntra ve n o usl y f or 3 da ys e ver y 4 m o nt hs).  Patie nt s s h o ul d n ot 
ha ve a c ortic oster oi d d osa ge a dj ust me nt d ue t o t he occ urre nce of fract ures.  
C at ar a ct s  
T he de vel o p me nt of cataracts s h o ul d pr o m pt referral t o a n o p ht h al m ol o gist f or e val uati o n.  
Patie nt s s h o ul d n ot ha ve a c ortic oster oi d d osa ge a dj ust me nt d ue t o t he occ urre nce of cataracts.   
C u s hi n g oi d A p p e ar a n c e  
If t he patie nt  de vel o ps a C us hi n g oi d a p peara nce, t hat is u nacce pta ble t o t he patie nt /fa mil y, t he 
f oll o wi n g acti o ns are rec o m me n de d : 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 8 5  of 9 1  
 
•  C ortic oster oi d  d osa ge s h o ul d n ot be i ncrease d t o a dj ust f or i ncreases i n b o d y wei g ht  
•  Reass ura nce a n d s u p p ort s h o ul d be pr o vi de d.  C o u nseli n g fr o m a c hil d ps yc h ol o gist s h o ul d 
be c o nsi dere d.  
•  If t he C us hi n g oi d a p peara nce re mai ns u nacce pta ble t o c hil d/fa mil y, d osa ge re d ucti o ns of 
≤5  m g t otal d ose f or pre d nis o ne ( ≤6  m g t otal d ose f or deflazac ort) at ~ 6 -8 -wee k i nter vals ca n 
be c o nsi dere d.  
•  E ver y atte m pt s h o ul d be ma de t o a v oi d st o p pi n g c ortic oster oi ds  s olel y f or C us hi n g oi d 
a p peara nce; if t h e patie nt /fa mil y de ma n ds t hat c ortic oster oi ds be st o p pe d, see Secti o n D  
bel o w f or pr oce d ures f or wit h dra wal of c ortic oster oi ds.    
G a str oi nt e sti n al Irrit ati o n  
I n t he e ve nt of t he de vel o p me nt of s y m pt o ms c o nsiste nt wit h es o p ha gitis, gastritis, or d u o de nitis, 
t he f oll o wi n g i nter ve nti o ns are rec o m me n de d : 
•  T reat me nt wit h s u p p orti ve care ( H2 a nta g o nists, pr ot o n p u m p i n hi bit ors, a ntaci ds)  s h o ul d be 
i nitiate d a n d c ortic os ter oi d d osa ge s h o ul d n ot be i ncrease d t o a dj ust f or i ncreases i n b o d y 
wei g ht . 
•  If s y m pt o ms persist f or ≥6 wee ks des pite s u p p orti ve care ( H 2 a nta g o nists, pr ot o n p u m p 
i n hi bit ors, a ntaci ds), a gastr oe nter ol o g y c o ns ultati o n s h o ul d be o btai ne d .  
•  If s y m pt o ms persist des pite c o nti n ue d s u p p orti ve care ( H2 a nta g o nists, pr ot o n p u m p 
i n hi bit ors, a ntaci ds) a n d gastr oe nter ol o g y e val uati o n, d osa ge re d ucti o ns of ≤5  m g t otal d ose 
f or pre d nis o ne (≤6  m g t otal d ose f or deflazac ort) at ~ 6 -8 -wee k i nter vals ca n be c o nsi dere d.  
•  If t he gastr oe nter ol o gist rec o m me n ds disc o nti n uati o n of c ortic oster oi ds f or fra n k 
gastr oi ntesti nal u lcerati o n, blee di n g, etc, c ortic oster oi ds ma y be st o p pe d.  See Secti o n D  
bel o w f or pr oce d ures f or wit h dra wal of c ortic oster oi ds.  
H ei g ht G ai n I n hi biti o n   
I n t he e ve nt of a n i n hi biti o n of b o d y hei g ht i ncreases t hat is u nacce pta ble t o t he patie nt /fa mil y, 
t he f oll o wi n g i nter ve nti o ns are rec o m me n de d : 
•  C ortic oster oi d  d osa ge s h o ul d n ot be i ncrease d t o a dj ust f or i ncreases i n b o d y wei g ht  
•  Reass ura nce a n d s u p p ort s h o ul d be pr o vi de d.  C o u nseli n g fr o m a c hil d ps yc h ol o gist s h o ul d 
be c o nsi dere d.  
•  If t he fail ure t o gai n heig ht re mai ns u nacce pta ble t o c hil d/fa mil y, d osa ge re d ucti o ns of ≤5  m g 
t otal d ose f or pre d nis o ne (≤6  m g t otal d ose f or deflazac ort) at ~ 6 -8 -wee k i nter vals ca n be 
c o nsi dere d.  
•  E ver y atte m pt s h o ul d be ma de t o a v oi d st o p pi n g c ortic oster oi ds  s olel y f or fail ure t o gai n 
hei g ht; if t he patie nt /fa mil y de ma n ds t hat c ortic oster oi ds be st o p pe d, see Secti o n D  bel o w f or 
pr oce d ures f or wit h dra wal of c ortic oster oi ds.    


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 8 6  of 9 1  
 
H y p er gl y c e mi a or Gl y c o s uri a  
E vi de nce of fasti n g h y per gl yce mia or ≥1 + gl yc os uria persisti n g f or ≥6 wee ks s h o ul d pr o m pt t he 
f oll o wi n g i nter ve nti o ns: 
•  I nstit ute m o nit ori n g of gl yc os ylate d he m o gl o bi n ( he m o gl o bi n A 1c) t o e val uate f or e vi de nce 
of c hr o nic h y per gl yce mia.  
•  If h y per gl yce mia or gl uc os uria is o nl y e pis o dic a n d c hr o nic h y per gl yce mia is n ot prese nt b y 
he m o gl o b i n A 1c, c ortic oster oi ds s h o ul d n ot t o be i ncrease d t o a dj ust f or i ncreases i n b o d y 
wei g ht .   
•  If c hr o nic h y per gl yce mia is prese nt b y he m o gl o bi n A 1c, c o ns ultati o n s h o ul d be arra n ge d wit h 
a n e n d ocri n ol o gist re gar di n g dia g n ostic e val uati o n a n d p ote ntial i nter v e nti o n f or 
h y per gl yce mia  
•  If h y per gl yce mia persists a n d c ortic oster oi d d ose re d ucti o n is warra nte d, d osa ge re d ucti o ns of 
≤5  m g t otal d ose f or pre d nis o ne ( ≤6  m g t otal d ose f or deflazac ort) at ~ 6 -8 -wee k i nter vals ca n 
be c o nsi dere d.  
•  If t he e n d ocri n ol o gist rec om me n ds c ortic oster oi d disc o nti n uati o n, c ortic oster oi ds ma y be 
st o p pe d.  See Secti o n D  bel o w f or pr oce d ures f or wit h dra wal of c ortic oster oi ds.  
H y p ert e n si o n  
E vi de nce of s u bsta ntial h y perte nsi o n ( bl o o d press ure ele vati o n at 9 9 t h per ce ntile f or a ge) 
persisti n g f or ≥6 wee ks s h o ul d pr o m pt t he f oll o wi n g i nter ve nti o ns:  
•  C ortic oster oi ds s h o ul d n ot t o be i ncrease d t o a dj ust f or i ncreases i n b o d y wei g ht .  Dietar y 
rec o m me n dati o ns ( wei g ht re d ucti o n/s o di u m re d ucti o n) s h o ul d be c o nsi dere d.  
•  If s u bsta ntial h y perte nsi o n persists, a p pr o priate bl o o d press ure ma na ge me nt (e g, di uretics, 
beta bl oc kers, calci u m c ha n nel bl oc kers) ca n be c o nsi dere d.  If t he y ca n be a v oi de d, 
a n gi ote nsi n c o n verti n g e nz y me i n hi bit ors or a n gi ote nsi n rece pt or bl oc kers  s h o ul d n ot be 
i nstit ute d d uri n g st u dy dr u g t hera p y beca use s uc h dr u gs ma y ele vate plas ma re ni n val ues a n d 
o bsc ure m o nit ori n g f or p ote ntial P T C 1 2 4 h y p oal d oster o nis m.  
•  If h y perte nsi o n persists des pite c o nti n ue d a nti h y perte nsi ve t hera p y, d osa ge re d ucti o ns of 
≤5  m g t otal d ose f or pre d nis o ne ( ≤6  m g t otal d ose f or deflazac ort) at ~ 6 -8 -wee k i nter vals ca n 
be c o nsi dere d.  
•  If h y perte nsi o n persists des pite c o nti n ue d a nti h y perte nsi ve s u p p ort a n d c ortic oster oi d d osa ge 
re d ucti o ns, c ortic oster oi ds ma y be st o p pe d.  See Secti o n D  bel o w f or pr oce d ures f or 
wit h dr a wal of c ortic oster oi ds.    
I nf e cti o n s P ot e nti all y R el at e d t o C orti c o st er oi d-M e di at e d I m m u n o s u p pr e s si o n  
U n us ual o p p ort u nistic i nfecti o ns or u n us ual res p o nses t o i nfecti o n p ote ntiall y c o nsiste nt wit h  
c ortic oster oi d -me diate d i m m u n os u p pressi o n s h o ul d pr o m pt t h e f oll o wi n g i nter ve nti o ns:  
•  C ortic oster oi ds s h o ul d n ot t o be i ncrease d t o a dj ust f or i ncreases i n b o d y wei g ht  a n d 
c o ns ultati o n wit h a n i nfecti o us disease e x pert s h o ul d be o btai ne d.  


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 2 0e -D M D  
1 9  N o ve m ber 2 0 1 5  
Versi o n 2. 0  
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 8 7  of 9 1  
 
•  If i nfecti o ns ca n n ot be ma na ge d wit h a p pr o priate a nti bi otic pr o p h yla xis or treat me nt, d osa ge 
re d ucti o ns of ≤5  m g t otal d ose f or pre d nis o ne ( ≤6  m g t otal d ose f or deflazac ort) at ~ 6 -8 -wee k 
i nter vals ca n be c o nsi dere d. 
•  If i nfecti o ns are cli nicall y se vere a n d/ or persiste nt des pite c ortic oster oi d d osa ge re d ucti o ns, 
c ortic oster oi ds ma y be st o p pe d .  See Secti o n D  bel o w f or pr oce d ures f or wit h dra wal of 
c ortic oster oi ds.  
W ei g ht G ai n  
I n t he e ve nt of a b o d y wei g ht i ncrease t hat is u nacce pta ble t o t he patie nt /fa mil y, t he f oll o wi n g 
i nter ve nti o ns are rec o m me n de d : 
•  C ortic oster oi d  d osa ge s h o ul d n ot be i ncrease d t o a dj ust f or i ncreases i n b o d y wei g ht  
•  Reass ura nce a n d s u p p ort s h o ul d be pr o vi de d.  C o u nseli n g fr o m a n utriti o nist s h o ul d be 
c o nsi dere d.  
•  If t he b o d y wei g ht i ncrease re mai ns u nacce pta ble t o c hil d/fa mil y, d osa ge re d ucti o ns of ≤5  m g 
t otal d ose f or pre d nis o ne (≤6  m g t otal d ose f or deflazac ort) at ~ 6 -8 -wee k i nter vals ca n be 
c o nsi dere d.  
•  E ver y atte m pt s h o ul d be ma de t o a v oi d st o p pi n g c ortic oster oi ds  s olel y f or fail ure t o gai n 
hei g ht; if t he patie nt /fa mil y de ma n ds t hat c ortic oster oi ds be st o p pe d, see S ecti o n D bel o w f or 
pr oce d ures f or wit h dra wal of c ortic oster oi ds.  
D.  Wit h dr a w al of C orti c o st er oi d s  
C ortic oster oi ds s h o ul d n ot be st o p pe d s u d de nl y.  A ta pere d re d ucti o n i n d osa ge is re q uire d t o 
a v oi d ris ks of a dre nal i ns ufficie nc y.  Ta peri n g of dr u g d osa ge s h o ul d f oll o w t he n or mal cli nical 
practice of ta ki n g ½ t he re g ular d ose  f or t he first wee k, ¼ t he re g ular d ose  f or t he sec o n d wee k, 
1/ 8  t he re g ular d ose  f or t he t hir d wee k a n d n o st u d y dr u gs t hereafter.  All a d verse effects p ossi bl y 
d ue t o c ortic oster oi d  sh o ul d  be m o nit ore d u ntil res ol ve d  a n d patie nt s s h o ul d be f oll o we d cl osel y 
f or s y m pt o ms c o nsiste nt wit h a dre nal i ns ufficie nc y.  Patie nt s w h o re q uire c ortic oster oi d 
disc o nti n uati o n ma y re mai n o n st u d y dr u g.  
E .  R ei n stit uti o n of C orti c o st er oi d s  
I n patie nt s wh o disc o nti n ue c ortic oster oi ds after f oll o wi n g t he rec o m me n de d i nter ve nti o ns a n d 
c ortic oster oi d d osa ge m o dificati o n pr oce d ures, rei nstit uti o n of c ortic oster oi ds is n ot ge nerall y 
rec o m me n de d u nless a dre nal i ns ufficie nc y is detecte d.  H o we ver, if rei nstit utio n of 
c ortic oster oi ds is dee me d necessar y, t he c ortic oster oi d d osa ge s h o ul d be l o wer t ha n t he l o west 
t otal d ose t hat pre vi o usl y pr o ve d i nt olera ble.  Patie nt s w h o re q uire c ortic oster oi d rei nstit uti o n 
ma y re mai n o n st u d y dr u g. 
 
 


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APPENDIX B. DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI  
Ethical Principles for Medical Research Involving Human Subjects  
Adopted by the 18th World Medical Association General Assembly Helsinki, Finland, June 1964 
and amended by the 29th World Medical Association General Assembly, Tokyo, Japan, October 
1975 35th World Medical Association General Assembly, Venice, Italy, October 1983 41st 
World Medical Association General Assembly, Hong Kong, September 1989 48th World 
Medical Association General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 52nd World Medical Association General Assembly, Edinburgh, Scotland, October 2000  
A. Introduction 
1. The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical research 
involving human subjects.  Medical research involving human subjects includes research on 
identifiable human material or identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the people.  The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty.   
3. The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my patient will be my first consideration," and the International Code 
of Medical Ethics declares that, "A physician shall act only in the patient's interest when 
providing medical care which might have the effect of weakening the physical and mental 
condition of the patient."  
4. Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects.   
5. In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society.   
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the etiology and 
pathogenesis of disease.  Even the best proven prophylactic, diagnostic, and therapeutic 
methods must continuously be challenged through research for their effectiveness, efficiency, 
accessibility and quality.   
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights.  Some research populations are vulnerable and need special 
protection.  The particular needs of the economically and medically disadvantaged must be 
recognized.  Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will 


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not benefit personally from the research and for those for whom the research is combined 
with care.   
9. Research investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this Declaration.   
B. Basic Principles for All Medical Research 
1. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject.   
2. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and on adequate laboratory and, where appropriate, animal 
experimentation.   
3. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected.   
4. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol.  This protocol should be submitted 
for consideration, comment, guidance, and where appropriate, approval to a specially 
appointed ethical review committee, which must be independent of the investigator, 
PTC Therapeutics, or any other kind of undue influence.  This independent committee should 
be in conformity with the laws and regulations of the country in which the research 
experiment is performed.  The committee has the right to monitor ongoing trials.  The 
researcher has the obligation to provide monitoring information to the committee, especially 
any SAEs.  The researcher should also submit to the committee, for review, information 
regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and 
incentives for subjects.   
5. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in this 
Declaration.   
6. Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  The 
responsibility for the human subject must always rest with a medically qualified person and 
never rest on the subject of the research, even though the subject has given consent.   
7. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 
subject or to others.  This does not preclude the participation of healthy volunteers in medical 
research.  The design of all studies should be publicly available.   
8. Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed.  Physicians should cease any investigation if the risks are found to 


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outweigh the potential benefits or if there is conclusive proof of positive and beneficial 
results.   
9. Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject.  This is especially 
important when the human subjects are healthy volunteers.   
10. Medical research is only justified if there is a reasonable likelihood that the populations in 
which the research is carried out stand to benefit from the results of the research.   
11. The subjects must be volunteers and informed participants in the research project. 
12. The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
patient's information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject.   
13. In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations 
of the researcher, the anticipated benefits and potential risks of the study and the discomfort it 
may entail.  The subject should be informed of the right to abstain from participation in the 
study or to withdraw consent to participate at any time without reprisal.  After ensuring that 
the subject has understood the information, the physician should then obtain the subject's 
freely-given informed consent, preferably in writing.  If the consent cannot be obtained in 
writing, the non-written consent must be formally documented and witnessed.   
14. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or may 
consent under duress.  In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship.   
15. For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent 
from the legally authorized representative in accordance with applicable law.  These groups 
should not be included in research unless the research is necessary to promote the health of 
the population represented and this research cannot instead be performed on legally 
competent persons.   
16. When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition 
to the consent of the legally authorized representative.   
17. Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 
informed consent is a necessary characteristic of the research population.  The specific 
reasons for involving research subjects with a condition that renders them unable to give 
informed consent should be stated in the experimental protocol for consideration and 
approval of the review committee.  The protocol should state that consent to remain in the 


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research should be obtained as soon as possible from the individual or a legally authorized 
surrogate.   
18. Both authors and publishers have ethical obligations.  In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results.  Negative as 
well as positive results should be published or otherwise publicly available.  Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared in 
the publication.  Reports of experimentation not in accordance with the principles laid down 
in this Declaration should not be accepted for publication.   
C. Additional Principles for Medical Research Combined with Medical Care  
19. The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic or therapeutic value.  When 
medical research is combined with medical care, additional standards apply to protect the 
patients who are research subjects.   
20. The benefits, risks, burdens and effectiveness of a new method should be tested against those 
of the best current prophylactic, diagnostic, and therapeutic methods.  This does not exclude 
the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or 
therapeutic method exists.   
21. At the conclusion of the study, every patient entered into the study should be assured of 
access to the best proven prophylactic, diagnostic and therapeutic methods identified by the 
study.   
22. The physician should fully inform the patient which aspects of the care are related to the 
research.  The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship.   
23. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods 
do not exist or have been ineffective, the physician, with informed consent from the patient, 
must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in 
the physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering.  Where possible, these measures should be made the object of research, designed to 
evaluate their safety and efficacy.  In all cases, new information should be recorded and, 
where appropriate, published.  The other relevant guidelines of this Declaration should be 
followed.   
 

SAP_001.pdf: 
P T C T h er a p e uti c s, I n c. – C o nfi d e nti al  
P a g e 1 of 2 3  
P T C 1 2 4- G D - 0 2 0 e D M D 
A P H A S E 3 E X T E N SI O N S T U D Y O F A T A L U R E N ( P T C 1 2 4) I N 
P A TI E N T S WI T H  N O N S E N S E M U T A TI O N 
D Y S T R O P HI N O P A T H Y 
St ati sti c al A n al y si s Pl a n 
V er si o n 2 . 0   
J a n. 2 3 , 2 0 1 9  
P T C T hera pe utics, I n c.  
1 0 0 C or p orate C o urt 
S o ut h Plai nfiel d, NJ 0 7 0 8 0, U S A 
N oti c e of Pr o pri et ar y I nf or m ati o n: T hi s d o c u m e nt c o nt ai n s c o nfi d e nti al i nf or m ati o n b el o n gi n g t o  
P T C T h er a p e uti c s, I n c. e x c e pt a s m a y ot h er wi s e b e p er mitt e d i n writi n g, b y  a c c e pti n g or r e vi e wi n g t h e s e 
m at eri al s, y o u a gr e e t h at t hi s i nf or m ati o n s h o ul d n ot b e di s cl o s e d t o ot h er s ( e x c e pt w h er e r e q uir e d b y 
a p pli c a bl e l a w) a n d s h o ul d n ot b e u s e d f or u n a ut h ori z e d p ur p o s e s. I n t h e e v e nt of a n a ct u al or s u s p e ct e d 
br e a c h of t hi s o bli g ati o n, P T C T h er a p e uti c s, I n c. s h o ul d b e n otifi e d pr o m ptl y.  
N C T #: N C T 0 2 0 9 0 9 5 9


PTC124-GD-020e-DMD  
 23 January 2019  
SAP v2.0 
         
PTC Therapeutics, Inc. – Confidential 
Page 2 of 23 
 
APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
  
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 


P T C 1 2 4 -G D -0 2 0 e -D M D  
 2 3 J a n u ar y 2 0 1 9  
S A P  v 2. 0  
         
P T C T h er a p e uti c s, I n c. –  C o nfi d e nti al  
P a g e 3  of 2 3  
 
 
T A B L E O F C O N T E N T S  
1.  
O V E R VI E W  ....................................................................................................................................................... 7  
2.  
S T U D Y D E SI G N  ................................................................................................................................................ 7  
3.  
S T U D Y O B J E C TI V E S A N D  E N D P OI N T S  .................................................................................................... 9  
3. 1.  
P RI M A R Y O BJ E C TI V E  ................................................................................................................................... 9  
3. 2.  
S E C O N D A R Y O BJ E C TI V E S  ............................................................................................................................ 9  
3. 3.  
S T U D Y E N D P OI N T S  ...................................................................................................................................... 9  
3. 4.  
S A M P L E S I Z E ............................................................................................................................................. 1 0  
4.  
S T U D Y P O P U L A TI O N ................................................................................................................................... 1 0  
5.  
S T A TI S TI C A L A N A L Y SI S  ............................................................................................................................ 1 0  
5. 1.  
G E N E R A L S T A TI S TI C A L C O N SI D E R A TI O N S  ................................................................................................ 1 0  
5. 2.  
S U BJ E C T D I S P O SI TI O N ............................................................................................................................... 1 1  
5. 3.  
D E M O G R A P HI C A N D B A S E LI N E C H A R A C T E RI S TI C S  ................................................................................... 1 1  
5. 4.  
C LI NI C A L H I S T O R Y ................................................................................................................................... 1 1  
5. 5.  
C O N C O MI T A N T M E DI C A TI O N S A N D P R O C E D U R E S  ..................................................................................... 1 1  
5. 6.  
S T U D Y D R U G E X P O S U R E A N D C O M P LI A N C E  ............................................................................................. 1 2  
5. 7.  
P RI M A R Y V A RI A B L E S  ................................................................................................................................ 1 2  
5. 7. 1.  
A dverse Eve nts  ................................................................................................................................ 1 2  
5. 7. 2.  
L a b or at ory Tests  ............................................................................................................................. 1 3  
5. 8.  
O T H E R V A RI A B L E S  .................................................................................................................................... 1 5  
5. 8. 1.  
Vit al Si g ns  ....................................................................................................................................... 1 5  
5. 8. 2.  
E C G s ............................................................................................................................................... 1 5  
5. 8. 3.  
6 -Mi n ute W alk Test  ......................................................................................................................... 1 5  
5. 8. 4.  
Ti me d F u ncti o n Tests  ...................................................................................................................... 1 5  
5. 8. 5.  
N ort h St ar A m b ul at ory Assess me nt  ................................................................................................. 1 6  
5. 8. 6.  
Pe di atric O utc o mes D at a C ollecti o n I nstr u me nt ( P O D CI)  ............................................................ 1 6  
5. 8. 7.  
S pir o metry  ....................................................................................................................................... 1 6  
5. 8. 8.  
Perf or m a nce U p per Li m b ( P U L) Assess me nt  ................................................................................. 1 6  
5. 8. 9.  
Activities of D aily Livi n g/ Dise ase St at us S urvey  ............................................................................ 1 6  
5. 8. 1 0.  
Re n al Ultr a S o u n d  ........................................................................................................................... 1 7  
5. 8. 1 1.  
P hysic al Ex a mi n ati o n  ..................................................................................................................... 1 7  
5. 8. 1 2.  
At al ure n Pl as m a C o nce ntr ati o ns  .................................................................................................... 1 7  
6.  
D A T A H A N D LI N G  ......................................................................................................................................... 1 7  
6. 1.  
A N A L Y SI S V I SI T S B A S E D O N V I SI T W
I N D O W S ........................................................................................... 1 7  
6. 2.  
B A S E LI N E  .................................................................................................................................................. 1 7  
6. 3.  
A B S O L U T E A N D R E L A TI V E C H A N G E F R O M B A S E LI N E  ............................................................................... 1 8  
6. 4.  
M I S SI N G D A T E S O F A E  A N D P RI O R A N D C O N C O MI T A N T M E DI C A TI O N S  .................................................... 1 8  
6. 4. 1.  
Missi n g D ate I nf or m ati o n f or A dverse Eve nts  ................................................................................ 1 8  
6. 4. 2.  
Missi n g D ate I nf or m ati o n f or Pri or or  C o nc o mit a nt Me dic ati o ns  ................................................. 1 8  
7.  
A N A L Y SI S C H A N G E S F R O M P R O T O C O L  .............................................................................................. 2 0  
8.  
CI N R G D A T A  .................................................................................................................................................. 2 0  
8. 1.  
O V E R VI E W O F CI N R G  D A T A  .................................................................................................................... 2 0  
8. 2.  
M A T C H E D P O P U L A TI O N S  ........................................................................................................................... 2 0  
8. 3.  
A N A L Y S E S B A S E D O N M A T C H E D P O P U L A TI O N S O F CI N R G  A N D S T U D Y 0 2 0 E  ......................................... 2 1  
9.  
BI B LI O G R A P H Y  ............................................................................................................................................ 2 2  


P T C 1 2 4 -G D -0 2 0 e -D M D  
 2 3 J a n u ar y 2 0 1 9  
S A P  v 2. 0  
         
P T C T h er a p e uti c s, I n c. –  C o nfi d e nti al  
P a g e 4  of 2 3  
1 0.  
D O C U M E N T HI S T O R Y  ............................................................................................................................ 2 2  


P T C 1 2 4 -G D -0 2 0 e -D M D  
 2 3 J a n u ar y 2 0 1 9  
S A P  v 2. 0  
         
P T C T h er a p e uti c s, I n c. –  C o nfi d e nti al  
P a g e 5  of 2 3  
  
T A B L E S  
T A B L E 1.  
S C H E D U L E O F E V E N T S  .......................................................................................................................... 8  
T A B L E 2:  
S A F E T Y M O NI T O RI N G P A R A M E T E R S A N D A C TI O N S T O B E T A K E N  .................................................... 1 4  


PTC124-GD-020e-DMD  
 23 January 2019  
SAP v2.0 
         
PTC Therapeutics, Inc. – Confidential 
Page 6 of 23 
ABBREVIATIONS 
Abbreviation 
Definition 
6MWD 
6-minute walk distance 
6MWT 
6-minute walk test 
ACTH 
adrenocorticotropic hormone 
ALT 
alanine aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical classification 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CINRG 
Cooperative International Neuromuscular Research Group 
CK 
blood urea nitrogen 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
D/C 
discontinuation 
DBP 
diastolic blood pressure 
DMD 
Duchenne muscular dystrophy 
ECG 
electrocardiogram 
EK 
Egen Klassifikation  
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GGT 
gamma glutamyl transferase 
LOCF 
last observation carried forward 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid  
MMRM 
mixed model repeated measures 
nmDMD 
nonsense mutation Duchenne muscular dystrophy 
NSAA 
North Star Ambulatory Assessment 
PCF 
peak cough flow 
PEF 
peak expiratory flow 
SAP 
statistical analysis plan 
SOC 
System Organ Class 
SBP 
systolic blood pressure  
TEAE 
treatment-emergent adverse event  
TFT 
Timed function test 
TID 
ter in die (3 times per day) 
Tx 
treatment 
UE   
upper extremity 
ULN 
upper limit of normal  
WHODRUG 
World Health Organization Drug Dictionary 
WNL 
within normal limits 
 


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P T C T h er a p e uti c s, I n c. –  C o nfi d e nti al  
P a g e 7  of 2 3  
1.  O V E R VI E W  
T his statistical a nal ysis pla n ( S A P) details t he statistical met h o ds t o be use d i n t he a nal ys es a n d 
prese ntati o n of t he d ata c ollecte d i n St u d y P T C 1 2 4 -G D -0 2 0e -D M D, als o referre d t o as St u d y 
0 2 0e . P re par ati o n of t his S A P i nc or p orates statistical desi g n ele me nts prese nt i n t he pr ot oc ol 
a me n d me nt versi o n  2 . 0 ( date d 18  N o ve m ber 2 0 1 5 ). Details are d oc u me nte d i n secti o ns 1 -7.    
I n a d diti o n t o t he pr ot oc ol defi ne d a nal ys es, a  nat ural hist or y c o ntr ol usi n g t he C o o perati ve 
I nter nati o nal N e ur o m usc ular Researc h Gr o u p ( CI N R G) will be utilize d  i n or der t o hel p t o better 
u n dersta n d  t he l o n g-ter m atal ure n dat a. Alt h o u g h t he pla n ne d a n al ysis will n ot be i ncl u de d i n t he 
C S R it will be prese nte d i n Secti o n 8  f or c o m plete ness.  
W here c o nflicts e xist bet wee n t his S A P a n d t he st u d y pr ot o c ol s, t he i nf or m ati o n c o ntai ne d i n this 
S A P s u perse des t he pr ot oc ol.  
2.  
S T U D Y D E SI G N  
All patie nts w h o s uccessf ull y c o m plete d t he P has e 3 d o u ble bli n d, p lace b o c o ntr olle d st u d y 
( P T C 1 2 4-G D -0 2 0 -D M D) wer e eli gi ble f or t his P hase 3 o pe n  la b el, e xte nsi o n st u d y ( P T C 1 2 4-
G D -0 2 0e -D M D).  T his P hase 3 e xte nsi o n st u d y will e val uate t he l o n g t er m safet y  of at al ure n 1 0, 
1 0 , a n d 2 0 m g/ k g.  
T he pri mar y o bjecti ve  of t his P hase 3 e xte nsi o n st u d y will be t o o btai n  l o n g-ter m safet y d ata t o 
a u g m e nt t he o ver all safet y dat a base.  T h e sec o n d ar y o bjecti ves will be t o a u g me nt t he efficac y 
data  c ollecte d i n t he d o u ble -bli n d st u d y  (P T C 1 2 4 -G D -0 2 0 -D M D ).   
Scree ni n g a n d b aseli ne pr oce d ur es ar e str uct ure d t o a v oi d a ga p i n treat me nt bet wee n t he 
d o u ble -bli n d st u d y ( P T C 1 2 4 -G D -0 2 0 -D M D ) a n d t his e xte nsi o n st ud y.  W he n p ossi ble, 
Scree ni n g/ Baseli ne ( Visit 1) f or t his e xte nsi o n st u d y s h o ul d occ ur o n t he sa me da y as t he 
E n d -of -St u d y visit f or t h e d o u ble -bli n d st u d y ( P T C 1 2 4 -G D -0 2 0 -D M D ).  D uri n g t h e treat me nt 
peri o d, st u d y assess me nts will be perf or me d at cli nic vis its at Wee k 1 2 a n d t hereafter e v er y 1 2 
wee ks u ntil t he e n d of t h e st u d y.   
T he pr o p ose d t y pes a n d ti mi n g of data t o be rec or de d are d escri b e d i n  Ta bl e 1 f or a m e n d me nt 
2. 0 ( date d 1 9 N o v e m ber 2 0 1 5).  
 
 
 
 
 
 
 
 
 
 
 


PTC124-GD-020e-DMD  
 
 23 Jan. 2019 
SAP v2.0 
 
PTC Therapeutics, Inc. – Confidential 
Page 8 of 23 
  Table 1. 
Schedule of Events 
Study 
Period 
Screenin
g/Baseli
ne 
Treatment Period 
Post-Treatment     
Study Week 
(±7 days) 
Day 
1 
12 
24 
36 
48 
60 
72 
84 
96 
108 
120 
132 
144 
6 Weeks 
Post-Tx 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Informed 
consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
Xa 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Hematology  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal 
ultrasound 
Xa 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
12-lead ECG  
Xa 
 
 
 
X 
 
 
  
X 
 
 
 
X 
X 
Study drug 
assignment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug 
Dispensed 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug 
compliance  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse 
events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6-minute 
walk test  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Timed 
function tests  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
North Star 
Ambulatory 
Assessment 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Activities of 
Daily 
Living/Diseas
e Status 
Survey  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PODCI 
Questionnair
e 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Spirometry 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PUL 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokin
etics 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a 
Study procedure need not be performed if Day 1 is within 14 days of the 
end-of-study evaluations at Week 48 (Visit 8) of the preceding Phase 3 double-
blind study (PTC124-GD-020-DMD). 
 
 
 
 
Abbreviations:; D/C = discontinuation; ECG = electrocardiogram; F/U = follow-up; PUL = 
Performance of Upper Limb, Tx = treatment 
 
 
 
 
 
 
 
 
 


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3.  
S T U D Y O B J E C TI V E S A N D  E N D P OI N T S  
3. 1.  
Pri m ar y O bj e cti v e  
T he pri mar y o bjecti ve of t his st u d y is t o e val u ate t he l o n g-t er m safet y of at al ure n i n b o ys wit h 
n o nse nse m utati o n d ystr o p hi n o pat h y, as d eter mi ne d b y a d v erse e ve nts a n d l a b orat or y 
a b n or malities.  
3. 2.  S e c o n d ar y O bj e cti v e s  
T he sec o n d ar y o bjecti ves , w hic h e val uat e t he effects of atal ure n o n m aj or cli nical ma nifestati o ns 
of D M D, a r e: 
P hysic al  
•  T o deter mi ne t he effect of atal ure n o n a m b ulati o n  i n patie nt s w h o are a m b ulat or y.  
•  T o e val uate t he eff ect of atal ure n o n pr o xi mal m uscle f u ncti o n i n patie nts w h o are a ble t o 
perf or m ti me d f u n cti o n tests.  
•  T o e val uate t he eff ect of atal ure n o n p h ysical f u ncti o n i n patie nts w h o are a ble t o perf or m t he 
N ort h Sta r A m b ulat or y Assess me nt. 
•  T o e val uate t he eff ect of atal ure n o n u p per li m b f u ncti o n.   
P ul m o n ary f u ncti o n  
•  T o e val uate t he eff ect of atal ure n o n p ul m o nar y f u ncti o n.  
P atie nt -re p orte d o utc o m es 
•  T o deter mi ne t he effect of atal ure n o n h ealt h -relat e d q ualit y of life ( H R Q L) as re p orte d b y 
patie nt s a n d par e nts/car e gi vers. 
•  T o assess t he effect of at al ure n o n acti vities of dail y li vi n g.  
Ex p os ure  
•  T o assess l o n g -ter m atal ure n plas ma e x p os ure. 
 
3. 3.  
St u d y E n d p oi nt s  
Pri m ar y : 
•  Safet y pr ofile c h ar acteriz e d b y t y p e, fre q ue nc y, s e verit y, ti mi n g, a n d relati o ns hi p t o atal ure n 
of a n y a d verse e v e nts or la b orat or y a b n or malities  
Sec o n d ar y : 
P h ysic al  
•  C ha n ge i n a m b ulati o n as meas ure d b y t he 6 M W T  
•  C ha n ge i n pr o xi mal m uscle f u ncti o n as assesse d b y ti me d f u ncti o n tests (ti me t o rise fr o m 
s u pi ne p ositi o n, ti me t o r u n 1 0  meters, a n d ti me t o cli m b / desce n d 4  stairs) 


P T C 1 2 4 -G D -0 2 0 e -D M D  
 
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P T C T h er a p e uti c s, I n c. –  C o nfi d e nti al  
P a g e 1 0  of 2 3  
•  C ha n ge i n p h ysical f u ncti o n as assesse d b y t he N ort h Star A m b ulat or y Ass ess me nt  
•  C ha n ge i n m ot or p erf or m a nce of t h e u p per li m b as meas ure d b y t he Perf or ma nce U p p er 
Li m b ( P U L)  
P ul m o n ar y f u ncti o n  
C ha n ge i n p ul m o nar y f u ncti o n as meas ure d b y s pir o metr y (e g. F V C, F E V 1)  
P ati e nt -Re p orte d O utc o mes  
•  C ha n ge i n p atie nt - a n d p are nt/care gi ver -re p orte d H R Q L as meas ure d b y t h e P O D CI 
Tra nsfer/ Basic M o bilit y a n d S p orts/ P h ysi cal F u n cti o ni n g sc ores  
•  C ha n ge i n p atie nt a n d pare nt/car e gi ver re p orte d acti vities of dail y li vi n g  
E x p os ure  
•  Pre -d ose atal ure n plas ma c o nce ntr ati o ns pri or t o m or ni n g atal ure n a d mi nistrati o n at eac h 
cli nic visit as assesse d b y a vali date d bi oa n al ytical met h o d  
S af et y  
•  C ha n ge fr o m bas eli ne i n ot her safet y p ara m eters (e g, vital si g ns)  
 
3. 4.  S a m pl e Si z e  
T he sa m ple size f or t his e xte nsi o n st u d y is n ot base d u p o n a n y f or m al statistical h y p ot hesis, b ut 
its u p per b o u n d is deter mi ne d b y t he re q uire me nt t hat patie nts m ust ha ve partici pate d i n t he 
pre vi o u s P hase 3 st u d y of P T C 1 2 4 ( P T C 1 2 4-G D -0 2 0 -D M D) i n w hic h ~ 2 2 0 patie nts are 
e x pecte d t o be e nr olle d.  
 
4.  
S T U D Y P O P U L A TI O N  
•  As -Treate d p o p ulati o n: All s u bjects w h o recei ve at least 1 d ose of at al ure n treat me nt i n t he 
e xte nsi o n p hase. T his p o p ulati o n will be e val uate d i n t he a nal ys es of safet y a n d effi cac y.  
•  P K p o p ulati o n: All s u bjects w h o has at least o ne P K c o nce ntrati o n data. T his p o p ulati o n 
will use d f or t he P K c o nce ntrati o n a n d para meter s u m mar y.  
 
5.  
S T A TI S TI C A L A N A L Y SI S  
5. 1.  
G e n er al St ati sti c al C o n si d er ati o n s  
S u m mar y t a bles f or c o nti n u o us varia bles will c o nt ai n t he f oll o wi n g statistics: n, mea n, sta n dar d 
de viati o n, sta n dar d err or, 9 5 % c o nfi de n ce i nter v als ( CIs) o n t h e mea n, me dia n, mi ni m u m, a n d 
ma xi m u m.  S u m mar y t a bles f or cate g orical varia bl es  will i ncl u de N, n , a n d perce nt a ges. I n b y-
visit s u m maries, t he a nal ysis visits will be deri ve d via visit ma p pi n g wi n d o ws.  
F or des cri pti ve s u m mar y ta bles, t he all data will b e a nal yz e d a n d dis pla ye d  b y a m b ulat or y st at us 
(a m b ulat or y or n o n -a m b ulat or y) at baseli ne, u nl ess s pe cifie d ot her wise. W here a p plica ble, t he 
s u m mar y d ata ( mea n, sta n dar d err or) will be prese nte d i n gra p hical f or m of a gai nst ti me of visit.  


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B y -patie nt listi n gs will b e create d f or eac h C R F m o d ule. T he data  will be liste d b y ce nt er/s u bject 
I D a n d visit. 
5. 2.  
S u bj e ct D i s p o siti o n 
A s u m mar y of s u bjects w h o disc o nti n ue d  atal ure n treat me nt pre mat urel y or were  re m o ve d fr o m 
t he st u d y pr e mat urel y will be re p orte d f or o verall s u bjects a n d a s u b gr o u p of a m b ulat or y/ n o n -
a m b ulat or y s u bj ects at st u d y e ntr y.  Reas o ns f or treat me nt earl y disc o nti n uati o ns will be 
descri be d.   
Si nce t he s p o ns or has deci de d t o disc o nti n ue t he St u d y 0 2 0 e , s u bjects w h o disc o nti n ue t he st u d y 
d ue t o t his reas o n or c o m plete t he st u d y p er pr ot oc ol will be c o nsi dere d as ce ns ore d i n t he ti me 
t o disc o nti n uati o n a nal ysis. T he ti me t o disc o nti n uati o n (i n wee ks) is calc ul ate d as 
( disc o nti n uati o n date - first d ose date + 1)/ 7 f or s u bjects w h o disc o nti n ue fr o m t he st u d y d ue t o 
reas o ns ot her t h a n s p o ns or’s decisi o n of ter mi nati o n t he st u d y or tra nsiti o ni n g t o c o m mercial 
dr u g. F or s u bjects w h o disc o nti n ue d ue t o t hese reas o ns or c o m plete t he st u d y, t he ce ns or ti me is 
( disc o nti n uati o n date - first d ose date + 1)/ 7 a n d (st u d y c o m pleti o n dat e –  first d ose date + 1)/ 7, 
res pecti vel y. Ti me t o dis c o nti n uati o n will be assesse d usi n g K a pla n -Mei er met h o ds a n d t he 
Ka pla n -Mei er c ur ve will be dis pla ye d.  
T he p r ot oc ol de viati o ns will be s u m marize d b y t y pe. A listi n g of pr ot oc ol de viati o ns will be 
pr o vi de d.  
 
5. 3.  
D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s  
S u bject  de m o gr a p hic a n d disease c h aracteristics (a ge, a ge gr o u p (6 -1 1 , 1 2 -1 7, a n d ≥1 8  years), 
ge n d er, r ace, e t h nicit y, h ei g ht, w ei g ht, b o d y mass i n de x, si x mi n ute wal k  dista nce, si x mi n ute 
wal k  d ista nce gr o u ps (< 3 0 0  meters , ≥3 0 0 -< 4 0 0  m eters , ≥4 0 0  meters), ti me t o r u n/ wal k 1 0 meter, 
ti me t o sta n d fr o m s u pi ne, ti me t o sta n d fr o m s u pi ne ( < 5s,  ≥5s), p erf or m a n ce of U p p er Li m b 
Assess me nt ( P U L) , c orti c oster oi d use ( Y es/ N o), a n d a m b ulat or y/ n o n -a m b ulat or y) at st u d y e ntr y 
will be s u m marize d f or o verall s u bjects, a s u b gr o u p of s u bjects w it h c ortic oster oi d use d urati o n 
(< 1 2 m o nt hs,  ≥1 2 m o nt hs  ) at baseli ne, a s u b gr o u p of s u bjects w it h c ortic oster oi d t y pe 
(deflazac ort vs pre d nis o n e/ pre d nis ol o ne ) at b aseli ne, a n d a s u b gr o u p of a m b ulat or y/ n o n -
a m b ulat or y s u bj ects at st u d y e ntr y.   
5. 4.  
Cli ni c al Hi st or y  
N/ A.    
5. 5.  
C o n c o mit a nt M e di c ati o n s a n d Pr o c e d ur e s  
Pri or me dicati o ns a n d c o nc o mita nt me dicati o ns will be c o de d usi n g t he W orl d Healt h 
Or ga nizati o n Dr u g Dicti o nar y ( W H O D R U G) dicti o nar y d ate d  2 0 1 7 D E C 0 1  i nt o A nat o mical-
T hera p e utic -C he mical ( A T C) classificati o n c o d es. T he pri or me dicati o ns are defi ne d as a n y 
me dicati o ns t hat s u bjec ts starte d bef ore t he first d ose date.  C o nc o mita nt me dicati o ns are defi ne d 
as a n y me dicati o ns t hat s u bjects t o o k after/ o n t he first d ose date.  T he pri or a n d c o nc o mita nt 
me dicati o ns will be s u m marize d b y A T C le v el 3 a n d preferre d ter ms.  T he c o nc o mita nt car di ac 
me dicati o ns  will be s u m marize d si milarl y.  


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S pecific atte nti o n will be f oc use d o n c ortic oster oi d use.  T he n u m ber s of s u bjects rece i vi n g/ n ot-
recei vi n g c ortic oster oi ds at baseli ne or d uri n g t he st u d y, s witc hi n g i n differe nt t y pes of 
c ortic oster oi ds d uri n g t he st u d y,  a n d d urati o n of c ortic oster oi d use d uri n g t h e st u d y a n d b y t y p e  
will be s u m marize d.  
T he pri or a n d c o nc o mita nt n o n -dr u g t h era pies will be defi ne d si milar t o t he pri or a n d 
c o nc o mita nt me dicati o ns. T he y wi ll be c o de d b y Me d D R A versi o n 2 0. 1 a n d s u m marize d b y 
S O C a n d P T.  
5. 6.  
St u d y Dr u g E x p o s ur e a n d C o m pli a n c e  
St u d y dr u g c o m plia nce will be assesse d i n ter ms of t he perce nta ge of dr u g act uall y ta ke n relati ve 
t o t he a m o u nt t hat s h o ul d ha ve bee n ta ke n d uri n g t he st u d y. Treat me nt d urati o n  (wee ks ) will be 
calc ulate d as (last d ose d ate –  first d ose dat e + 1)/ 7, if date of last st ud y dr u g i nta ke was n ot 
k n o w n: (last visit date –  first d ose date + 1)/ 7. T h e s u m mar y of t he o verall c o m plia nce a n d 
treat me nt d urati o n will be re pr ese nte d f or o verall s u bjects a n d a s u b gr o u p of a m b ulat or y/ n o n -
a m b ulat or y s u bj ects at st u d y e ntr y.  
5. 7.  
Pri m ar y  V ari a bl e s  
5. 7. 1.  A d v er s e E v e nt s  
A d verse e ve nts will be cl assifie d usi n g  M e d D R A v ersi o n 2 0. 1  classificati o n s yste m. T he s e verit y 
of a d vers e e ve nts will be gr a de d b y t he i n vesti gat or acc or di n g t o t he C T C A E, Versi o n 3. 0 
w he ne ver p ossi ble. A t reat me nt-e mer ge nt a d verse e ve nt ( T E A E) is defi ne d as a n a d verse e v e nt 
t hat occ urs or w orse ns i n t he peri o d e xte n di n g fr o m t he da y of a s u bject’s first d ose of st u d y dr u g 
t o 6 wee ks aft er t he last d ose of st u d y dr u g i n t his st u d y.  
If a s u bject h as m ulti ple e ve nts u n der a n y gi ve n S O C a n d P T, t he s u bject will be c o u nte d o nl y 
o nce u n der t h at S O C a n d P T. If a s u bject has t he s a me A E o n m ulti ple occ asi o ns, t he hi g hest 
se verit y (f etal, life-thr eat e ni n g , sever e, m o derat e, a n d mil d) rec or d e d f or t h e e ve nt will be 
prese nte d a n d t he hi g hest dr u g relati o ns hi p ( 1 = ‘ U nrelate d’, 2 = ‘ U nli kel y’, 3 = ‘ P ossi bl y’, 4 = 
‘ Pr o ba bl y’, 5 = ‘ R elate d’), recl assifie d i nt o Relate d (‘ P ossi bl y Relate d’, ‘ Pr o ba bl y Relat e d’, 
‘ Relate d’) or N ot Relate d (‘ U nr elate d’ a n d ‘ U nli kel y’), will be prese nt e d o n t he res pecti ve 
ta bles.  
T otal n u m bers of A Es, T E A Es a n d seri o us A Es ( S A E) a n d t he n u m ber a n d perc e nt a ge of 
s u bjects e x perie nci n g ≥1 T E A E, ≥1 S A E, disc o nti n uati o n d ue t o A E, a n d d eat h will be ta b ulate d. 
T he n u m ber a n d p erce nta ge of s u bjects wit h T E A Es a n d S A Es will be b y r elati o ns hi p t o st u d y 
dr u g a n d C T C A E/se verit y, r es pecti vel y.  
T he n u m ber a n d p erce n ta ge of s u bjects e x perie n ci n g a s p ecific T E A E will be ta b ulate d  
1)  b y S O C, a n d P T  
2)  b y S O C, P T, a n d C T C A E/se verit y gra d e  
3)  b y S O C i n t he desce n di n g or d er of t he S O C fre q u e nc y o verall  gr o u p,  
4)  b y P T i n t he desce n di n g or der of t he P T fre q u e nc y i n o verall  gr o u p.  
T he f oll o wi n g T E A Es will be a nal yze d si milarl y:  
1)  b y S O C, a n d P T a n d  


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2)  b y S O C, P T, a n d C T C A E/se verit y gra d e.  
•  P ossi bl y or pr o ba bl y treat me nt -relate d T E A Es 
•  Seri o us T E A Es a n d p ossi bl y or pr o b a bl y treat me nt -relate d s eri o us T E A Es 
•  T E A Es lea di n g t o disc o nti n uati o n fr o m treat me nt 
•  A dre nal, h e p atic a n d re n al e ve nts lea di n g t o s pecial dia g n ostic e val uati o ns T E A Es 
a n d p ossi bl y or pr o b a bl y treat me nt -relate d he p atic  a n d re nal  T E A Es lea di n g t o 
s pecial dia g n osis e val uati o n  
•  T E A Es wit h C T C A E/se verit y gra de ≥3 a n d p ossi bl y or pr o b a bl y treat me nt -relate d 
T E A Es wit h C T C A E/se verit y gra de ≥3  
•  C o m m o n T E A Es (s u bject fre q ue n c y of ≥5 %)  
Listi n gs of deat h, seri o us A Es, A Es lea di n g t o disc o nti n uati o n fr o m treat m e nt, a n d he patic a n d 
re nal A Es lea di n g t o s p ecial dia g n ostic e v al uati o ns will be pr o vi de d.  
T he dr u g e x p os ure a dj ust e d T E A E i nci de n ce rate will be s u m marize d b y S O C a n d P T, w here t h e 
i nci de nce r ate of t he T E A E per 1 0 0 patie nt-year = ( n u m ber of e ve nts/ n u m ber of patie nt -years) 
* 1 0 0. T he n u m ber of p atie nt -years is defi ne d as t h e s u m of t he n u m ber of d a ys o n st u d y dr u g of 
all patie nts di vi de d b y 3 3 6 . T hat is, a year is d efi n e d as 4 8 wee ks.   
I n a d diti o n, t he n u m ber of s u bjects wit h cli nical la b orat or y a b n or malities, a b n or mal vital si g ns, 
a n d a b n or mal el ectr ocar di o gra m re p orte d as T E A E will be s u m marize d.  
N o n -seri o us T E A E will be dis pla ye d b y S O C a n d P T. T he c o m m o n n o n-seri o us T E A E (s u bject 
fre q ue n c y of ≥5 %) will als o be dis pla ye d b y S O C a n d P T. 
N u m bers of occ urr e nce of seri o us T E A E a n d t he n u m bers of occ urre nce of n o n -seri o us T E A E 
will be s u m marize d b y S O C a n d P T, se parat el y.  
5. 7. 2.  L a b or at or y T e st s  
He mat ol o gi cal, ser u m bi oc he mistr y, a dre n al la b orat ories, a n d uri ne d ata a n d t heir c ha n ges ( o nl y 
f or c o nti n u o us la b orat or y para meters) fr o m baseli ne will be s u m marize d b y visit.  
S hift ta bles f or he mat ol o g y  a n d bi o c he mistr y data will als o be prese nte d s h o wi n g c h a n ge i n 
C T C A E se verit y gra de fr o m baseli ne t o eac h visit. F or para meters f or w hi c h a C T C A E scale 
d oes n ot e xist, s hift ta bles will be prese nte d s h o wi n g c h a n ge i n res ults fr o m baseli ne ( n or mal, 
l o w a nd hi g h [ or a b n or mal]) t o eac h visit ( n or mal, l o w a n d hi g h [ or a b n or mal]).  
S u m mar y of a b n or malities i n la b orat or y varia bles pre -defi ne d f or s afet y m o nit ori n g will be d o ne 
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T a bl e 2 : 
S af et y M o nit ori n g P ar a m et er s a n d A cti o n s t o b e T a k e n  
Or g a n S y st e m a n d  
L a b or at or y 
P ar a m et er  
St o p St u d y Dr u g 
I m m e di at el y, C o nfir m 
A b n or m al V al u e,  
a n d T h e n St art 
W or k -U p  
St o p St u d y Dr u g Aft er 
C o nfir mi n g a  A b n or m al 
V al u e, a n d T h e n St art 
W or k -U p  
C o nti n u e St u d y 
Dr u g, C o nfir m 
A b n or m al V al u e, 
a n d t h e n St art 
W or k -U p a  
H e p ati c  
 
 
 
S er u m t ot al bilir u bi n  
≥Gr a d e 3 ( ≥3. 0 x U L N)  
Gr a d e 2 ( 1. 5 –  3. 0 x U L N)  
--- 
S er u m G G T  
≥Gr a d e 3 ( ≥5. 0 x U L N)  
Gr a d e 2 ( > 2. 5 –  5. 0 x U L N)  
--- 
S er u m A L T  
 
 
↑ of > 1 5 0 U/ L wit h 
st a bl e or  
↓ C K  
R e n al  
 
 
 
S er u m c y st ati n C  
> 2. 0 0 m g/ L  
> 1. 3 3 –  2. 0 0 m g/ L  
--- 
S er u m cr e ati ni n e  
≥Gr a d e 2  
( ≥1. 5 x U L N f or a g e) 
Gr a d e 1  
( > U L N –  1. 5 x U L N f or a g e)  
--- 
S er u m B U N  
≥3. 0 x U L N  
≥1. 5 –  3. 0 x U L N  
--- 
Uri n e pr ot ei n: uri n e 
cr e ati ni n e ( s p ot)  
--- 
> 0. 4 0 m g: m g  
--- 
Uri n e pr ot ei n: uri n e 
o s m ol alit y ( s p ot)  
--- 
> 0. 3 0 m g/ L: m O s m/ k g  
--- 
Uri n e bl o o d ( b y 
di p sti c k)  
4 + ( L ar g e)  
3 + ( M o d er at e)  
2 + ( S m all)  
S er u m el e ctr ol yt e s  
Gr a d e 3 -4  
Gr a d e 2  
Gr a d e 1  
S er u m N a +, hi g h  
> 1 5 5 m m ol/ L  
> 1 5 0 –  1 5 5 m m ol/ L  
--- 
S er u m N a +, l o w  
< 1 3 0 m m ol/ L  
--- 
--- 
S er u m K +, hi g h  
> 6. 0 m m ol/ L  
> 5. 5 –  6. 0 m m ol/ L  
--- 
S er u m K +, l o w  
< 3. 0 m m ol/ L  
--- 
--- 
S er u m M g 2 + , hi g h 
> 1. 2 3 m m ol/ L  
--- 
--- 
S er u m M g 2 + , l o w 
< 0. 4 m m ol/ L  
< 0. 5 –  0. 4 m m ol/ L  
--- 
T ot al s er u m C a 2 + , hi g h 
> 3. 1 m m ol/ L  
> 2. 9 –  3. 1 m m ol/ L  
--- 
T ot al s er u m C a 2 + , l o w 
< 1. 7 5 m m ol/ L  
< 2. 0 –  1. 7 5 m m ol/ L  
--- 
S er u m p h o s p h or o u s  
< 0. 6 m m ol/ L  
< 0. 8 –  0. 6 m m ol/ L  
--- 
S er u m H C O 3 - 
< 1 1 m m ol/ L  
< 1 6 –  1 1 m m ol/ L  
--- 
a La b orat or y a b n or malities ma y be c o nfir me d i m me diatel y or at t he ne xt sc he d ule d cli nic visit base d o n 
i n vesti gat or j u d g me nt. 
A b bre vi ati o ns : A L T = ala ni ne a mi n otra nsferase, B U N = bl o o d urea nitr o ge n, Ca 2 + = calci u m, C K = creati ne ki nase, 
G G T = ga m ma gl uta m yl tra nsferase, H C O 3 - = bicar b o nate, K +  = p otassi u m, M g 2 + = ma g nesi u m, Na + = s o di u m, 
U L N = u p per li mit of n or mal  
 


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5. 8.  
Ot h er  V ari a b l e s 
5. 8. 1.  Vit al Si g n s  
Vital si g ns  (s yst olic a n d diast olic bl o o d press ure, p ulse rate, b o d y w ei g ht, hei g ht, ul na le n gt h, 
ar m s pa n, a n d b o d y te m p erat ur e) will s u m marize d b y visit f or o verall s u bjects. 
N u m ber ( %)  of s u bjects wit h meeti n g hy perte nsi o n c riteria as t he f oll o wi n g will be s u m marize d.  
•  If a ge < 1 8 years ol d, t he h y perte nsi o n criteria are base d o n a ge, ge n der, a n d hei g ht-
a dj uste d s yst olic bl o o d press ure ( S B P) a n d diast olic bl o o d press ure ( D B P) perce ntile 
res ults ( H y pert e nsi ve: ≥ 9 5t h perce ntile; Pre -h y p erte nsi ve: 9 0  - <  9 5t h perce ntile; 
N or mal: <  9 0t h per ce ntile).  
•  If a ge ≥ 1 8 years ol d, h y perte nsi ve: S B P ≥ 1 4 0 m m H g or D B P ≥ 9 0 m m H g; pre -
h y perte nsi ve: S B P 1 2 0  - 1 3 9 m m H g or D B P 8 0  - 8 9 m m H g; N or mal: S B P 9 0  -1 1 9 
m m H g a n d D B P 6 0  - 7 9 m m H g.  
5. 8. 2.  E C G s  
N u m be r ( %) of s u bjects e x perie nci n g a n or mal/a b n or mal E C G assess me nt will be ta b ulate d b y 
visit f or  o verall s u bjects.  
5. 8. 3.  6 -Mi n ut e W al k T e st  
T he dista nce w al ke d at eac h visit a n d t he c ha n ge fr o m baseli ne at eac h p ost  baseli ne visit, as 
o btai ne d fr o m t he 6 -mi n ute wa l k test (6 M W T ), will be s u m marize d descri pti vel y f or a m b ulat or y 
s u bjects wit h n o n -missi n g bas eli ne 6 M W T assess me nts . T he dista nce w al ke d at eac h  will als o be 
s u m marize d f or eac h act ual a ge. 
5. 8. 4.  Ti m e d  F u n cti o n T e st s  
Ti me d f u ncti o n test data ( ie, ti me t o sta n d fr o m s u pi ne, ti me t o r u n/ wal k 1 0 meters, ti me t o cli m b 
4 stairs, a n d ti me t o desce n d 4 stairs ) a n d c ha n ge fr o m baseli ne t o eac h p ost baseli ne visit will be 
s u m marize d descri pti vel y  b y v isit f or a m b ulat or y s u bjects wit h n o n -missi n g bas eli ne ti me d 
f u ncti o n tests assess me nts. Si milarl y t he ti me t o st a n d fr o m s u pi ne , ti me t o r u n/ wal k 1 0 meters, 
ti me t o cli m b 4 stairs, a n d ti me t o desce n d 4 stairs will  als o be s u m marize d f or eac h act ual a ge. 
Ti me d f u ncti o n test ( T F T) data  i m p utati o n r ules as t he f oll o wi n g will be use d i n t he s u m mar y.  
•  If ti me t o r u n/ wal k 1 0 meters > 3 0 s ec, t he n set t o 3 0 sec.  
•  If ti me t o sta n d fr o m s u pi ne > 3 0 sec, t he n set t o 3 0 sec.  
 
T he Ka pla n -Meier m et h o d will be a p plie d t o t he a nal ysis of a ge at l oss of a m b ulati o n. The 
me dia n a ge at l oss of a m b ulati o n will be re p orte d b y treat me nt gr o u p i n st u dies 0 2 0/ 0 2 0e 
(atal ure n/ atal ure n, place b o/  atal ure n, a n d o v erall), c ortic oster oi d use d urati o n ( < 1 2 m o nt hs, ≥1 2 
m o nt hs  ), a n d c ortic oster oi d t y pe  (d eflazac ort vs pre d nis o ne/ pre d n is ol o ne) at baseli ne. T he 
Ka pla n -Mei er c ur ves will als o be dis pla ye d. T he  a ge at l oss of a m b ulati o n is defi ne d as a ge of 
t he disease pr o gressi o n r e p orte d as t he a d vers e e v e nt. T he s u bjects w h o are a m b ulat or y at t he 
e n d of st u d y or disc o nti n uati o n will be ce ns ore d o n t he last vali d visit  date. A ge o n t hat date will 
be use d i n t he a nal ysis.  


P T C 1 2 4 -G D -0 2 0 e -D M D  
 
 2 3 J a n. 2 0 1 9  
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P T C T h er a p e uti c s, I n c. –  C o nfi d e nti al  
P a g e 1 6  of 2 3  
5. 8. 5.  N ort h St ar  A m b ul at or y A s s e s s m e nt  
T he N S A A c o nsists of 1 7 acti vities, eac h s c ore d as 0, 1, or 2.  T he s u m of t hese 1 7 sc ores will be 
use d t o f or m a t otal sc or e.  If fe wer t ha n 1 3 of t he 1 7 acti vities are p erf or m e d, t he t otal sc ore will 
be c o nsi der e d missi n g.  If fr o m 1 3 t o 1 6 acti vities are perf or m e d, t he t otal sc ore will be 
calc ulate d b y m ulti pl yi n g t he s u m of t he sc ores i n t he x acti vities t hat were perf or me d b y 1 7/ x.  
If a n acti vit y ca n n ot be p erf or me d d u e t o disease pr o gressi o n/l oss of a m b ulati o n, a sc ore of zer o 
will be assi g ne d. T h e li near sc ore is a tra nsf or mati o n of t he N S A A sc ore t o a scale of 0 t o 1 0 0 
[Ma y he w 2 0 1 3 ]. 
 
T otal sc ores a n d li near sc ores  fr o m t he N ort h Star A m b ulat or y Assess me nt will be s u m marize d  
b y visit a n d c ha n ge  fr o m baseli ne t o eac h p ost bas eli ne visit  w ill be s u m marize d descri pti vel y f or 
a m b ulat or y s u bj ects wit h n o n -missi n g baseli ne N S A A  assess me nts .   Si milarl y t he t otal a n d 
li near sc or es will  als o be s u m marize d f or eac h act ual a ge.  
 
T he n u m ber a n d pr o p orti o n of l oss of f u ncti o n of eac h N ort h Star A m b ulat or y Assess me nt ite m 
at wee k 4 8 will be ta b ul ate d. T he f u n cti o n l oss defi ne d as a s hift fr o m n o n -zer o at baseli ne t o 
zer o at wee k 4 8.  T h e missi n g data will be ha n dle d b y last o bser vati o n carri e d f or w ar d ( L O C F).  
 
5. 8. 6.  P e di atri c O ut c o m e s D at a C oll e cti o n I n str u m e nt ( P O D CI)  
T he t w o P O D CI d o mai ns (tra nsfers/ m o bilit y a n d s p orts partici pati o n) eac h pr o vi de a n u meri cal 
sc ore fr o m 0-1 0 0.  T he P O D CI d o m ai n sc ores a n d c ha n ges fr o m baseli ne will be s u m marize d b y 
visit f or a m b ulat or y s u bj ects.  
5. 8. 7.  S pir o m etr y  
P ul m o nar y f u n cti o n para meters of %-pre dicate d F V C , % -pre dict e d F E V 1 (a dj uste d  usi n g ul na  
le n gt h a n d a ge), pea k e x pirat or y fl o w  (P E F ), a n d pea k c o u g h fl o w (P C F ) a n d t heir a bs ol ute a n d 
relati ve c h a n ges fr o m basel i ne will be s u m marize d b y visit.  Si milarl y t he o bser ve d val u es of t he 
e n d p oi nts will als o be s u m marize d f or eac h act u al a ge. 
5. 8. 8.  P erf or m a n c e U p p er Li m b ( P U L) A s s e s s m e nt  
T he P U L assess me nt i ncl u des 2 2 ite ms ( wit h a n e ntr y ite m t o defi n e starti n g f u n cti o nal le vel t o 
a v oi d testi n g f u n cti o nal di me nsi o ns i n w hic h t he s u bject lac ks t he l o wer li mit of f u ncti o n, a n d 2 1 
ite ms s u b di vi de d i nt o s h o ul der le vel ( 4 ite ms), el b o w le vel ( 9 ite ms), a n d distal le vel ( 8 ite ms) 
di me nsi o ns. Sc ori n g vari es acr oss t he s cale fr o m 0 -1 t o 0 -6 acc or di n g t o perf or ma n ce. E ac h 
di me nsi o n will be sc ore d se parat el y wit h a ma xi m u m sc ore of 1 6 f or s h o ul der le vel, 3 4 f or el b o w 
le vel, a n d 2 4 f or distal le vel. T he t otal sc ore will be calc ul ate d b y a d di n g t h e 3 le vel sc ores 
( ma xi m u m gl o bal sc ore of 7 4).  T he t otal sc ore a n d 3 di me nsi o n sc ores a n d t heir c ha n ges fr o m 
baseli ne will be s u m mari ze d b y visit f or n o n -a m b ulat or y s u bjects.  Si milarl y t he P U L assess me nt 
will als o be s u m marize d f or eac h act ual a ge.  
5. 8. 9.  A cti viti e s of D ail y Li vi n g /Di s e a s e St at u s S ur v e y  
F or c h a n ge i n acti vities of dail y l i vi n g/disease stat us of pr os pecti ve s ur v e y data,  n u m ber ( %) of 
s u bjects wit h c ha n ges fr o m baseli ne t o eac h  visit will be s u m marize d b y eac h cate g or y  f or 
o verall  s u bjects. If t h ere are m ulti ple s y m pt o ms u n der a cate g or y, th e hi g h est sc ore/ w ors e  cas e of 
all a vaila ble s y m pt o ms was selecte d f or t he cate g or y i n t he s u m mar y. 


P T C 1 2 4 -G D -0 2 0 e -D M D  
 
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S A P v 2. 0  
 
P T C T h er a p e uti c s, I n c. –  C o nfi d e nti al  
P a g e 1 7  of 2 3  
5. 8. 1 0.  R e n al Ultr a S o u n d  
S hift ta bles f or re nal ultr as o u n d res ults (“ n or m al”, “a b n or mal a n d  n ot cli nicall y si g nifica nt”, 
a b n or mal a n d  cli nicall y si g nifica nt ”) will be prese nte d at eac h visit. 
5. 8. 1 1.  P h y si c al E x a mi n ati o n  
Si nce a b n or mal fi n di n gs i n p h ysical e x a mi nati o n  nee d t o be re p orte d i n A E a n d vital si g ns, a 
data listi n g of p h ysical e x a mi nati o n  will be pr o vi de d.  
5. 8. 1 2.  At al ur e n Pl a s m a C o n c e ntr ati o n s  
Atal ure n plas ma c o nce ntrati o ns ( µ g/ m L) c ollecte d pri or t o t he m or ni n g d ose will be s u m marize d 
b y visit.   
 
6.  
D A T A H A N D LI N G  
6. 1.  
A n al y si s Vi sit s b a s e d o n  Vi sit Wi n d o w s  
Si nce s o me s u bjects ha d earl y ter mi nati o ns or u ns c he d ule d visits i n d uri n g , the deri ve d a n al ysis 
visits will be ge ner ate d b y visit wi n d o w defi ne d as f oll o ws.  F or t he 6 w ee ks p ost -treat me nt visit, 
assi g n A VI SI T N = 1 4 a n d A VI SI T = 6 -Wee ks P ost -Treat me nt.  
Let St u d y da y =assess me nt date – first d ose date + 1.   
St u d y D a y  
A VI SI T N  
A VI SI T   
St u d y  E ve nt =' S C R'  or  
. < st u d y d a y ≤ 1  
1  
Baseli ne  
1 <  st u d y d a y ≤ 1 2 6 
2  
Wee k 1 2  
1 2 6 < st u d y d a y ≤ 2 1 0  
3  
Wee k 2 4  
2 1 0 < st u d y d a y ≤ 2 9 4  
4  
Wee k 3 6  
2 9 4 < st u d y d a y ≤ 3 7 8  
5  
Wee k 4 8  
3 7 8 < st u d y d a y ≤ 4 6 2  
6  
Wee k 6 0  
4 6 2 < st u d y d a y ≤ 5 4 6  
7  
Wee k 7 2  
5 4 6 < st u d y d a y ≤ 6 3 0  
8  
Wee k 8 4  
6 3 0 < st u d y d a y ≤ 7 1 4  
9  
Wee k 9 6  
7 1 4 < st u d y d a y ≤ 7 9 8  
1 0  
Wee k 1 0 8  
7 9 8 < st u d y d a y ≤ 8 8 2  
1 1  
Wee k 1 2 0  
8 8 2 < st u d y d a y ≤ 9 6 6  
1 2  
Wee k 1 3 2  
9 6 6 < st u d y d a y  
1 3  
Wee k 1 4 4  
 
If t here ar e m ore t ha n 1 v ali d assess me nt wit hi n o ne visit wi n d o w, t he last o ne will be c h ose n as 
t he a nal ysis val ue. 
6. 2.  
B a s eli n e  
I n ge ner al, Baseli ne is defi ne d as t he last n o n-missi n g vali d assess me nt pri or t o or o n t he date of 
t he first d ose of t he st u d y . F or s pir o metr y test s, Visit 1 meas ure me nts ca n b e use d as bas eli ne 
e ve n if t he y are after t he first d ose.  


P T C 1 2 4 -G D -0 2 0 e -D M D  
 
 2 3 J a n. 2 0 1 9  
S A P v 2. 0  
 
P T C T h er a p e uti c s, I n c. –  C o nfi d e nti al  
P a g e 1 8  of 2 3  
6. 3.  
A b s ol ut e a n d R el ati v e C h a n g e fr o m B a s eli n e  
T he a bs ol ute c h a n ge fr o m baseli ne at eac h p ost -b aseli ne visit is calc ulate d as ( p ost -baseli ne 
val ue –  Baseli ne), w hile t he relati ve c ha n ge ( %) fr o m baseli ne at eac h p ost -baseli ne visit is 
calc ulate d as ( p ost -bas eli ne val ue –  Baseli ne)/ Baseli ne × 1 0 0.  
6. 4.  
Mi s si n g D at e s of A E a n d Pri or a n d C o n c o mit a nt M e di c ati o n s  
6. 4. 1.  
Mi s si n g D at e I nf or m ati o n f or A d v er s e E v e nt s  
T he f oll o wi n g i m p utati o n r ules o nl y a p pl y t o cases i n w hic h t he start date is i nc o m plete (ie, 
partiall y missi n g) f or a d v erse e v e nts.  
Missi n g d a y a n d m o nt h  
•  If t he year is sa me as t h e year of t h e date of t h e first d ose of d o u ble-bli n d st u d y dr u g, t h e n t he 
da y a n d m o nt h of t he dat e of t he first d ose of d o u ble -bli n d st u d y dr u g will be assi g n e d t o t he 
missi n g fiel ds.  
•  If t he year is pri or t o t he year of t h e date of t h e first d ose d o u ble-bli n d st u d y dr u g, t h e n 
Dece m b er 3 1 will be assi g ne d t o t he missi n g fiel d s. 
•  If t he year is after t he year of t he date of t he first d ose d o u ble-bli n d st u d y dr u g, t he n J a n uar y 
1 will be assi g ne d t o t he missi n g fiel ds.  
Missi n g m o nt h o nl y  
•  T he da y will be treate d as missi n g a n d b ot h m o nt h a n d da y will be re pl ace d acc or di n g t o t he 
a bo ve pr oce d ur e.  
Missi n g d a y o nl y  
•  If t he m o nt h a n d year are sa me as t he year a n d m o nt h of t he date of t he first d ose d o u ble-
bli n d st u d y dr u g, t he n t h e date of t he first d ose d o u ble -bli n d st u d y dr u g will be assi g n e d t o 
t he missi n g da y. 
•  If eit her t he year is bef or e t he year of t he d ate of t he first d ose of d o u ble -bli n d st u d y dr u g or 
if b ot h years are t he sa m e b ut t he m o nt h is bef ore t he m o nt h of t he date of t he first d ose of 
d o u ble -bli n d st u d y dr u g, t he n t he last da y of t he m o nt h will be assi g ne d t o t he missi n g da y.  
•  If eit her t he year is after t he year of t he dat e of t he first d ose of d o u ble-bli n d st u d y dr u g or if 
b ot h years ar e t he sa m e b ut t he m o nt h is after t he m o nt h of t he date of t he first d ose of 
d o u ble -bli n d st u d y dr u g, t he n t he first da y of t he m o nt h wi ll be assi g ne d t o t he missi n g da y. 
If t he st o p date is c o m plete a n d t he i m p ute d start d ate as a b o v e is after t he st o p date, t he start 
date will be i m p ute d b y t he st o p date.  
6. 4. 2.  
Mi s si n g D at e I nf or m ati o n f or Pri or or C o n c o mit a nt M e di c ati o n s  
F or pri or or c o nc o mita nt me dicati o ns, i ncl u di n g resc ue me dicati o ns, i nc o m plete (ie,  partial 
missi n g) start date a n d/ or st o p date will be i m p ute d. W he n t he start date a n d t he st o p date are 
b ot h i nc o m plete f or a s u bject, i m p ute t he start date first.  


P T C 1 2 4 -G D -0 2 0 e -D M D  
 
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S A P v 2. 0  
 
P T C T h er a p e uti c s, I n c. –  C o nfi d e nti al  
P a g e 1 9  of 2 3  
6. 4. 2. 1.  
I n c o m pl et e St art D at e 
T he f oll o wi n g r ules will be a p plie d t o i m p ute t he missi n g n u merical fi el ds. If t he st o p date is 
c o m plete a n d t he i m p ute d start date is after t he st o p date, t he n t he start d ate will be i m p ute d 
usi n g t he st o p date.  
Missi n g d a y a n d m o nt h  
•  If t he year of t he in c o m plete start date is t he s a me as t he year of t he dat e of t he first d ose of 
d o u ble -bli n d st u d y dr u g, t he n t he da y a n d m o nt h of t he date of t h e first d ose of d o u ble -bli n d 
st u d y dr u g will be assi g n e d t o t he missi n g fiel ds. 
•  If t he year of t he i n c o m plete start date is pri or t o t h e year of t he dat e of t he first d ose of 
d o u ble -bli n d st u d y dr u g, t he n Dece m ber 3 1 will b e assi g n e d t o t he missi n g fiel ds.  
•  If t he year of t he i n c o m plete start date is after t he year of t h e date of t h e first d ose of d o u ble-
bli n d st u d y d r u g, t he n J a n uar y 1 will be assi g ne d t o t he missi n g fiel ds. 
Missi n g m o nt h o nl y  
•  T he da y will be treate d as missi n g a n d b ot h m o nt h a n d da y will be re pl ace d acc or di n g t o t he 
a b o ve pr oce d ur e.  
Missi n g d a y o nl y  
•  If t he m o nt h a n d year of t he i nc o m plete start date are t he sa me as t he m o nt h a n d year of t he 
date of t he first d ose of d o u ble -bli n d st u d y dr u g, t he n t he da y of t he d ate of t he first d ose of 
d o u ble -bli n d st u d y dr u g will be assi g ne d t o t he missi n g da y.  
•  If eit her t he year is bef or e t he year of t he d ate of t he first d ose of d o u ble-bli n d st u d y dr u g or 
if b ot h years are t he sa m e b ut t he m o nt h is bef ore t he m o nt h of t he date of t he first d ose of 
d o u ble -bli n d st u d y dr u g, t he n t he last da y of t he m o nt h will be assi g ne d t o t he missi n g da y.  
•  If eit her t he year is after t he year of t he dat e of t he first d ose of d o u ble-bli n d st u d y dr u g or if 
b ot h years ar e t he sa m e b ut t he m o nt h is after t he m o nt h of t he date of t he first d ose of 
d o u ble -bli n d st u d y dr u g, t he n t he first da y of t he m o nt h will be assi g ne d t o t he missi n g da y.  
6. 4. 2. 2.  
I n c o m pl et e St o p D at e 
T he f oll o wi n g r ules will be a p plie d t o i m p ute t he missi n g n u merical fi el ds. If t he date of t he last 
d ose of d o u ble -bli n d st u d y dr u g is missi n g, re place it wit h t he last visit date or data c ut -off d ate 
if t he s u bject is o n-g oi n g. If t h e i m p ute d st o p date is bef ore t he start date (i m p ute d or n o n -
i m p ute d start date), t he n t he i m p ute d st o p date will be e q ual t o t he start dat e. 
Missi n g d a y a n d m o nt h  
•  If t he year of t he i n c o m plete st o p date is t he sa me as t he year of t he dat e of t he last d ose of 
d o u ble -bli n d st u d y dr u g, t he n t he da y a n d m o nt h of t he date of t h e last d ose of d o u ble -bli n d 
st u d y dr u g will be assi g n e d t o t he missi n g fiel ds. 
•  If t he year of t he i n c o m plete st o p date is pri or t o t h e year of t he dat e of t he l ast d ose of 
d o u ble -bli n d st u d y dr u g, t he n Dece m ber 3 1 will b e assi g n e d t o t he missi n g fiel ds.  


P T C 1 2 4 -G D -0 2 0 e -D M D  
 
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P T C T h er a p e uti c s, I n c. –  C o nfi d e nti al  
P a g e 2 0  of 2 3  
•  If t he year of t he i n c o m plete st o p date is after t he year of t h e date of t h e last d ose of d o u ble-
bli n d st u d y dr u g, t he n J a n uar y 1 will be assi g ne d t o t he missi n g fiel ds.  
Missi n g m o nt h o nl y  
•  T he da y will be treate d as missi n g a n d b ot h m o nt h a n d da y will be re pl ace d acc or di n g t o t he 
a b o ve pr oce d ur e.  
Missi n g d a y o nl y  
•  If t he m o nt h a n d year of t he i nc o m plete st o p date are t he sa me as t he m o nt h a n d year of t he 
date of t he last d ose of d o u ble -bli n d  st u d y dr u g, t he n t he da y of t he d ate of t he last d ose of 
d o u ble -bli n d st u d y dr u g will be assi g ne d t o t he missi n g da y.  
•  If eit her t he year is bef or e t he year of t he d ate of t he last d ose of d o u ble-bli n d st u d y dr u g or if 
b ot h years ar e t he sa m e b ut t he m o nt h  is bef ore t he m o nt h of t he date of t h e last d ose of 
d o u ble -bli n d st u d y dr u g, t he n t he last da y of t he m o nt h will be assi g ne d t o t he missi n g da y.  
•  If eit her t he year is after t he year of t he dat e of t he last d ose of d o u ble-bli n d st u d y dr u g or if 
b ot h years ar e t he sa m e b ut t he m o nt h is after t he m o nt h of t he date of t he l ast d ose of 
d o u ble -bli n d st u d y dr u g, t he n t he first da y of t he m o nt h will be assi g ne d t o t he missi n g da y.  
 
7.  
A N A L Y SI S C H A N G E S F R O M  P R O T O C O L  
T he s u p p orti ve a nal ys es o n  6 -mi n ute wal k test  ha ve bee n re m o ve d beca us e t he y are n ot of t he 
scie ntific i nterest a n y m ore aft er t he earl y ter mi nati o n of t he st u d y. All paire d t -tests ha ve bee n 
re m o ve d. 
8.  
CI N R G D A T A  
8. 1.  
O v er vi e w of CI N R G D at a  
CI N R G  is a n at ural hist or y re gistr y data b ase w hic h c ollects D M D data usi n g  c o ns orti u m of 
me dical a n d scie ntific i n vesti gat ors fr o m ac a de mi c a n d res earc h ce nters o n ne ur o m usc ular 
disease . De m o gra p hics  a n d baseli ne c haracteristics , c ortic oster oi ds m e dicati o n use  (a n d t y pe), 
efficac y e n d p oi nts i ncl u di n g  6 M W T, ti me ta ke n to sta n d fr o m s u pi ne, ti me ta ke n t o r u n/ wal k 1 0 
meters , N S A A, s pir o metr y, a n d E K will be a nal yz e d . Ot her e n d p oi nts c ollecte d b y CI N R G b ut 
n ot i n S t u d y 0 2 0e  will n ot be i ncl u de d i nt o t his a nal ysis pla n. T he CI N R G nat ural hist or y c o ntr ol 
(data tra nsferre d o n N o v e m ber 1 8, 2 0 1 6) will be c o m pare d t o at al ure n’s efficac y d ata t o assess 
t he atal ure n’s l o n g- ter m treat me nt be nefit. 
 
8. 2.  
M at c h e d P o p ul ati o n s  
T o c o m pare CI N R G wit h St u d y 0 2 0 e , t he matc h e d p o p ulati o ns are defi n e d i n t he f oll o wi n g ta ble 
f or differe nt e n d p oi nts a n d a nal ys es.  


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P T C T h er a p e uti c s, I n c. –  C o nfi d e nti al  
P a g e 2 1  of 2 3  
E n d p oi nt/ A n al ysis  
A g e  
( Ye ars) at 
St u d y 
E ntr y  
A g e  ( Ye ars) 
at 
Assess me nt  
Ster oi d 
Use  
A m b ul ati
o n st at us  
E x cl u de
E X O N  
5 1 a n d 
4 5  
B aseli ne 
v al ue  
Visit Ye ar  
A g e at l oss of a m b ul ati o n  
 7 -1 4  
N ot 
a p plic a bl e  
C u m ul ativ e 
St er oi d us e 
d ur ati o n at 
e ac h 
ass ess m e nt 
≥6  m o nt hs  
A m b ul at ory 
at st u dy 
e ntry  
Y es  
 
N ot 
a p plic a bl e  
Pi ec e -wis e r e gr essi o n b as e d o n F V C  
N ot 
a p plic a bl e  
≤ 1 9  
C u m ul ativ e 
St er oi d us e 
d ur ati o n at 
e ac h 
ass ess m e nt 
≥2 4 m o nt hs  
N o n -
a m b ul at ory 
at e ac h  
ass ess m e nt   
Y es  
N ot 
a p plic a bl e  
≥2 0 1 2  
% -pr e dict e d F V C  
7 -1 5  
N ot 
a p plic a bl e  
N ot 
a p plic a bl e  
N o n -
a m b ul at ory 
at st u dy 
e ntry  
Y es  
 
N ot 
a p plic a bl e  
% -pr e dict e d F E V 1  
7 -1 5  
N ot 
a p plic a bl e  
N ot 
a p plic a bl e  
N o n -
a m b ul at ory 
at st u dy 
e ntry  
Y es  
 
N ot 
a p plic a bl e  
P E F  
7 -1 5  
N ot 
a p plic a bl e  
N ot 
a p plic a bl e  
N o n -
a m b ul at ory 
at st u dy 
e ntry  
Y es  
 
N ot 
a p plic a bl e  
6 M W T  
7 -1 5  
N ot 
a p plic a bl e  
C u m ul ativ e 
St er oi d us e 
d ur ati o n at 
e ac h 
ass ess m e nt 
≥6  m o nt hs  
A m b ul at ory 
at st u dy 
e ntry  
Y es  
 
N ot 
a p plic a bl e  
ti m e t a k e n t o r u n/ w alk 1 0 m et ers 
7 -1 5  
N ot 
a p plic a bl e  
C u m ul ativ e 
St er oi d us e 
d ur ati o n at 
e ac h 
ass ess m e nt 
≥6  m o nt hs  
A m b ul at ory 
at st u dy 
e ntry  
Y es  
 
N ot 
a p plic a bl e  
ti m e t a k e n t o st a n d fr o m s u pi n e 
7 -1 5  
N ot 
a p plic a bl e  
C u m ul ativ e 
St er oi d us e 
d ur ati o n at 
e ac h 
ass ess m e nt 
≥6  m o nt hs  
A m b ul at ory 
at st u dy 
e ntry  
Y es  
 
N ot 
a p plic a bl e  
N S A A  
7 -1 5  
N ot 
a p plic a bl e  
C u m ul ativ e 
St er oi d us e 
d ur ati o n at 
e ac h 
ass ess m e nt 
≥6  m o nt hs  
A m b ul at ory 
at st u dy 
e ntry  
Y es  
 
N ot 
a p plic a bl e  
 
8. 3.  
A n al y s e s B a s e d o n M at c h e d P o p ul ati o n s of CI N R G a n d St u d y 
0 2 0 e  
De m o gra p hics a n d baseli ne c har acteristics (a ge, race, a m b ulati o n stat us, c ortic oster oi d use ( yes 
or n o), d urati o n of c ortic oster oi d use, c ortic oster oi d t y pe, bas eli ne 6 M W D, baseli ne  ti me t o 
r u n/ wal k 1 0 m eters, bas eli ne ti me t o  sta n d fr o m s u pi ne, baseli ne %-pre dict e d F E V 1, % -pre dicte d 
F V C, P E F, N S A A t otal s c ore) will be s u m marize d descri pti vel y f or CI N R G a n d St u d y 0 2 0e  


P T C 1 2 4 -G D -0 2 0 e -D M D  
  
 2 3 J a n. 2 0 1 9  
S A P v 2. 0  
 
P T C T h er a p e uti c s, I n c. – C o nfi d e nti al  
P a g e 2 2  of 2 3  
base d o n eac h matc h e d p o p ulati o n. T he s u m mar y will be dis pla ye d b y c orti c oster oi d use ( yes vs 
n o) a n d c u m ulati ve ster oi d use ( ≥1 2 m o nt hs vs < 1 2 m o nt hs) f or baseli ne a m b ulat or y a n d n o n-
a m b ulat or y s u bj ects se paratel y.  T he b aseli ne is defi ne d as t he first visit i n CI N R G d ata.  
T he c o m paris o n t o t he nat ural hist or y dat a (ie, CI N R G data) bas e d o n mat c he d s u bjects will be 
perf or me d i n F V C usi n g piece- wis e re gressi o n m o dels a n d a ge t o l oss of a m b ulati o n usi n g 
Ka pla n -Mei er met h o d .  
Piece - wise r e gr essi o n m o dels will be a p plie d t o l o g F V C i n CI N R G a n d st u d y 0 2 0e d ata, 
se parat el y, usi n g diff er e nt a ges as t he c h a n ge p oi nt. T he m ost p ossi ble c ha n ge p oi nt i n terms of 
a ge will be c h ose n at t he best m o del fit (ie, AI C C val ue is t he ma xi mal). Scatter pl ots of l o g F V C 
a n d t he m ost fitte d piece - wise re gr essi o n li ne will be ge nerate d f or CI N R G a n d st u d y 0 2 0 e, 
se parat el y. C o m paris o n bet wee n t he o bs er ve d a n d pre dicte d F V C i n st u d y 0 2 0e will be 
perf or me d u si n g re peate d meas ures an al ysis of v aria nce t o acc o u nt f or w it hi n-su bject correlati o n , 
w here t he pre dict e d val u es are b ase d o n t he re gressi o n e q uati o n esti mate d b y t he b est fit 
re gressi o n m o del bas e d o n CI N R G d ata. ` 
I n st u d y 0 2 0e, t h e l oss of a m b ulati o n is defi ne d as t he disease pr o gressi o n re p orte d as t he 
a d verse e ve nt  or t he ti me t o r u n/ wal k 1 0 meters > 3 0 sec o n ds, w hic he v er o cc urs earlier. T h e 
e ve nt a ge is t he o n e o n t he A E start date. T he s u bj ects w h o are a m b ulat or y at t he e n d of st u d y 
will be ce ns ore d o n t h e last vali d ti me d f u ncti o n tests assess me nt date. A ge o n t hat date will be 
use d i n t he a nal ysis. I n t h e CI N R G data, t he a ge at t he earliest re p ort of t he n o n- a m b ulati o n or 
t he ti me t o r u n/ wal k 1 0 meters > 3 0 sec o n ds, w hi c he ver earlier, will be pic ke d as t he e v e nt a ge. If 
s u bjects i n CI N R G d ata d o n ot re p ort n o n-a m b ulati o n, t he a ge at t he last re p ort of a m b ulati o n 
will be c h ose n as t he ce ns or a ge.  A s e nsiti vit y a nal ysis will be perf or mi n g base d o n t he l oss of 
a m b ulati o n defi ne d o nl y b y diseas e pr o gressi o n A E. 
F or CI N R G dat a o nl y, t h e o bser ve d v al ues w ill be s u m marize d descri pti vel y f or eac h act ual a ge 
o n 6 M W T, t i me t o r u n/ wal k 1 0 meters , ti me t o sta n d fr o m s u pi ne, N S A A  t otal a n d li near sc ores,  
%- pre dict e d F V C, %- pr e dicte d F E V 1, a n d P E F b y c ortic oster oi d use at baseli ne ( yes or n o) a n d 
o verall base d o n t h e matc he d p o p ulati o ns. 
N S A A  sc ore d eri vati o n al g orit h ms i n St u d y 0 2 0e will be a p plie d t o CI N R G data.  
9.  
BI B LI O G R A P H Y  
Ma y h e w  A. G. , Ca n o J. S., Sc ott  E. , Ea gle M. , B us h b y K. , M a nz ur A. , M u nt o ni F. , a n d O n be h alf 
of t he N ort h Star Cli nical Net w or k f or Ne ur o m us c ular Disease. Detecti n g mea ni n gf ul c ha n ge 
usi n g t he N ort h Star A m b ulat or y Assess me nt i n D uc he n ne m us c ular d ystr o p h y. D e vel o p me ntal 
Me dici ne & C hil d Ne ur ol o g y, 2 0 1 3 N o v; 5 5( 1 1): 1 0 4 6- 1 0 5 2 . 
1 0.  D O C U M E N T HI S T O R Y  
Versi o n N u m ber  
A ut h or  
Descri pti o n  
Versi o n 1  
Versi o n 2 
 
 
I nitial versi o n –  Se pt. 1 8, 2 0 1 8  
J a n. 2 3, 2 0 1 9 
Re m o ve d t he c o m me nts t hat 
acci de ntl y left i n t he d o c u me nt  
C orrecte d d o c u me nt date i n t he 
hea der.  


PTC124-GD-020e-DMD  
 
 23 Jan. 2019 
SAP v2.0 
 
PTC Therapeutics, Inc. – Confidential 
Page 23 of 23