Clinical trial NCT01557400
Conditions: Duchenne Muscular Dystrophy Becker Muscular Dystrophy Dystrophinopathy
Keywords: Duchenne muscular dystrophy Becker muscular dystrophy Nonsense mutation Premature stop codon DMD BMD nmDBMD DBMD Ataluren PTC124
Sponsor: PTC Therapeutics
Start date: 2012-05-20; Completion date: 2018-01-19
Enrollment: 94 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Duchenne/Becker muscular dystrophy (DBMD) is a genetic disorder that develops in boys. It is caused by a mutation in the gene for dystrophin, a protein that is important for maintaining normal muscle structure and function. Loss of dystrophin causes muscle fragility that leads to weakness and loss of walking ability during childhood and teenage years. A specific type of mutation, called a nonsense (premature stop codon) mutation, is the cause of DBMD in approximately 10-15% of boys with the disease. Ataluren is an orally delivered, investigational drug that has the potential to overcome the effects of the nonsense mutation. This study comprises a Phase 3, open-label study of ataluren in participants with nmDBMD who previously received ataluren at an Investigator site in a prior PTC-sponsored clinical study. A separate open-label study (PTC124-GD-016-DMD; NCT01247207) is being conducted for nmDBMD participants who previously received ataluren at an Investigator site in the United States (US).

Detailed description:
All participating sites must have had at least 1 participant that received ataluren treatment in prior PTC-sponsored clinical studies in DBMD (Phase 2b double-blind, placebo-controlled study \[PTC124-GD-007-DMD; NCT00592553\] and the subsequent open-label extension study \[Study PTC124-GD-007e-DMD; NCT00847379\]). It is planned that up to \~96 participants will be enrolled.

It is also planned that participants will receive ataluren 3 times per day (TID) at respective morning, midday, and evening doses of 10 milligrams/kilograms (mg/kg), 10 mg/kg, and 20 mg/kg for approximately 336 weeks. Study assessments will be performed at clinic visits during screening, on the first day of ataluren dosing, and then every 48 weeks during the ataluren treatment period, except for weight, which will be measured every 24 weeks at a primary care physician (PCP).

Arms: arm 1: Ataluren will be provided as a vanilla-flavored powder to be mixed with water, milk, fruit juice (except apple juice) fruit punch, or in semi-solid food (for example, yogurt, pudding, or applesauce). The dose level for ataluren will be 10 milligrams/kilograms (mg/kg) in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening. Administration within 30 minutes after a meal will be recommended. Study drug dosing will be based on milligrams of drug per kilogram of body weight. Because of potential changes in participant body weight over time, weight-based dose adjustment can occur every 24 weeks as required. Study drug will be taken for up to 240 weeks.
Interventions: intervention 1: Ataluren
Intervention descriptions: intervention 1: Oral powder for suspension

Protocol documents:
Prot_000.pdf: 
C LI NI C A L P R O T O C O L 
A N O P E N -L A B E L  S T U D Y F O R P R E VI O U S L Y T R E A T E D A T A L U R E N  
( P T C 1 2 4®) 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
Pr ot o c ol N u m b er P T C 1 2 4
-G D
G D -0 1 9
0 1 9 -D M D
D M D  
1 8 N o v e m b er 
1 8 N o v e m b er 2 0 1 5
2 0 1 5  
V er si o n 
V er si o n 5 . 0
. 0 
P T C T h er a p e uti c s, I n c.
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
1 0 0 C or p or at e C o urt
 
S o ut h 
S o ut h Pl ai nfi el d, N J 0 7 0 8 0 U S A
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 h i 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 pt l y. 
N C T #: N C T 0 1 5 5 7 4 0 0


Protocol Number PTC124-GD-019-DMD  
18 November 2015  
Version 5.0 
 
 
PTC Therapeutics, Inc.  – Confidential 
Page 2 of 86 
 
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 
2011-004853-18 
Included in clinical trials.gov Database 
Yes 
Protocol Number 
 
PTC124-GD-019-DMD 
Protocol Version 
Version 5.0 
Protocol Version Date 
18 November 2015 
Protocol Phase 
Phase 3 
Protocol Title 
An Open-Label Study for Previously Treated Ataluren 
(PTC124) Patients with Nonsense Mutation 
Dystrophinopathy 
PTC Medical Monitor 
  
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
 
  
PTC Biostatistician 
  
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
 
 
 
PTC Clinical Program Scientist 
 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
 
 
 


Protocol Number PTC124-GD-019-DMD  
18 November 2015  
Version 5.0 
 
 
PTC Therapeutics, Inc.  – Confidential 
Page 3 of 86 
 
PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________ 
 
 
 
___________________________ 
 
PTC Therapeutics, Inc. 
 
 
 
 
 
 
Date 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 


Protocol Number PTC124-GD-019-DMD  
18 November 2015  
Version 5.0 
 
 
PTC Therapeutics, Inc.  – Confidential 
Page 4 of 86 
 
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 1 9 -D M D  
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Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 5  of 8 6  
 
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 2  
2.  
I N T R O D U C TI O N ............................................................................................................................................ 1 2  
2. 1.  
D I S E A S E IN DI C A TI O N  ................................................................................................................................. 1 2  
2. 2.  
A T A L U R E N ( P T C 1 2 4) ................................................................................................................................ 1 3  
2. 2. 1.  
T her a pe utic C o nce pt  ............................................................................................................................ 1 3  
2. 2. 2.  
C he mic al Descri pti o n  .......................................................................................................................... 1 4  
2. 2. 3.  
Cli nic al St u dies  .................................................................................................................................... 1 4  
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 8  
3. 1.  
P RI M A R Y O BJ E C TI V E  ................................................................................................................................. 1 8  
3. 2.  
S E C O N D A R Y O BJ E C TI V E S  .......................................................................................................................... 1 8  
3. 3.  
C LI NI C A L E N D P OI N T S  ................................................................................................................................ 1 8  
4.  
S U B J E C T S E L E C TI O N C R I T E RI A ............................................................................................................. 1 9  
4. 1.  
O V E R VI E W ................................................................................................................................................. 1 9  
4. 2.  
IN C L U SI O N C RI T E RI A  ................................................................................................................................. 1 9  
4. 3.  
E X C L U SI O N C RI T E RI A  ................................................................................................................................ 2 0  
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 S U BJ E C 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 1  
6. 1.  
IN V E S TI G A TI O N A L P R O D U C T  ..................................................................................................................... 2 1  
6. 1. 1.  
At al ure n ( P T C 1 2 4)  .............................................................................................................................. 2 1  
6. 1. 2.  
Dr u g S o urce  ......................................................................................................................................... 2 1  
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 2  
6. 1. 7.  
St u dy Dr u g Acc o u nt a bility  ................................................................................................................... 2 2  
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 3  
6. 2. 1.  
D ur ati o n of T her a py  ............................................................................................................................ 2 3  
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 4  
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 7  
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 .......................................................... 2 7  
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 .................................................... 2 8  
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  


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P T C T hera pe utics, I nc.  –  C o nfi de ntial  
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6. 4. 1.  
A mi n o glyc osi des or Ot her P ote nti ally Ne p hr ot oxic A ge nts  ................................................................. 2 9  
6. 4. 2.  
Hy dr ati o n  ............................................................................................................................................. 2 9  
6. 4. 3.  
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. 4.  
Dr u gs Met a b olize d by Cyt oc hr o me  P 4 5 0 E nzy mes  ............................................................................. 3 0  
6. 4. 5.  
Ot her P ote nti al Dr u g I nter acti o ns  ....................................................................................................... 3 0  
6. 4. 6.  
Ot her C o nc o mit a nt Me dic ati o ns  .......................................................................................................... 3 1  
6. 5.  
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. 6.  
D I E T A R Y R E S T RI C TI O N S  ............................................................................................................................ 3 2  
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.  
Pretre at me nt, Tre at me nt, a n d F oll o w -U p Peri o ds  .............................................................................. 3 4  
7. 2. 2.  
I nf or me d C o nse nt ................................................................................................................................. 3 5  
7. 2. 3.  
Cli nic al/ Me dic ati o n Hist ory  ................................................................................................................ 3 5  
7. 2. 4.  
He p atitis Scree n  ................................................................................................................................... 3 5  
7. 2. 5.  
Vit al Si g ns  ............................................................................................................................................ 3 5  
7. 2. 6.  
Br o oke U p per Extre mity F u ncti o n al R ati n g Sc ale  .............................................................................. 3 5  
7. 2. 7.  
Hei g ht/ Ul n a Le n gt h/ Ar m S p a n  ............................................................................................................ 3 5  
7. 2. 8.  
P hysic al Ex a mi n ati o n  .......................................................................................................................... 3 6  
7. 2. 9.  
Wei g ht  .................................................................................................................................................. 3 6  
7. 2. 1 0.  
He m at ol o gy L a b or at ory Assess me nt  ............................................................................................... 3 6  
7. 2. 1 1.  
Ser u m Bi oc he mistry L a b or at ory Assess me nt  .................................................................................. 3 6  
7. 2. 1 2.  
A dre n al  L a b or at ory  Assess me nts  .................................................................................................... 3 7  
7. 2. 1 3.  
Uri n alysis  ........................................................................................................................................ 3 7  
7. 2. 1 4.  
1 2 -Le a d E C G  .................................................................................................................................. 3 7  
7. 2. 1 5.  
Ec h oc ar di o gr a m  ............................................................................................................................. 3 7  
7. 2. 1 6.  
6 -Mi n ute W alk Tes t ......................................................................................................................... 3 8  
7. 2. 1 7.  
Ti me d F u ncti o n Tests  ...................................................................................................................... 3 8  
7. 2. 1 8.  
N ort h St ar A m b ul at ory Assess me nt  ................................................................................................. 3 8  
7. 2. 1 9.  
E ge n Kl assifik ati o n Sc ale  ................................................................................................................ 3 8  
7. 2. 2 0.  
S pir o metry  ....................................................................................................................................... 3 8  
7. 2. 2 1.  
Dise ase St at us S urvey  ..................................................................................................................... 3 9  
7. 2. 2 2.  
St u dy Dr u g A d mi nistr ati o n  ............................................................................................................. 3 9  
7. 2. 2 3.  
St u dy Dr u g C o m pli a nce  .................................................................................................................. 3 9  
7. 2. 2 4.  
A dver se Eve nts ................................................................................................................................ 3 9  
7. 2. 2 5.  
C o nc o mit a nt Me dic ati o ns  ............................................................................................................... 4 0  
7. 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 1  
8. 1.  
A D V E R S E E V E N T D E FI NI TI O N S  .................................................................................................................. 4 1  
8. 1. 1.  
A dverse Eve nts  ..................................................................................................................................... 4 1  
8. 1. 2.  
Seri o us A dverse Eve nts ( S A Es)  ............................................................................................................ 4 2  
8. 1. 3.  
U nex pecte d A dverse Eve nts  ................................................................................................................. 4 3  
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 4  
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 5  
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 6  
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 6  
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  


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P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 7  of 8 6  
 
9.  
WI T H D R A W A L O F P A TI E N T S  ................................................................................................................... 4 8  
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 F O R T H E P RI M A R Y E N D P OI N T  ....................................................................... 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 9  
1 0. 2. 1.  
As -Tre ate d P o p ul ati o n  .................................................................................................................... 4 9  
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 9  
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 9  
1 0. 4. 1.  
St u dy C o n d uct a n d S u bject Dis p ositi o n  .......................................................................................... 4 9  
1 0. 4. 2.  
B aseli ne C h ar acteristics  ................................................................................................................. 4 9  
1 0. 4. 3.  
St u dy Tre at me nt A d mi nistr ati o n  ..................................................................................................... 4 9  
1 0. 4 . 4. 
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 9  
1 0. 4. 5.  
Pri m ary V ari a bles  ........................................................................................................................... 5 0  
1 0. 4. 6.  
Sec o n d ary V ari a bles  ....................................................................................................................... 5 0  
1 0. 4. 7.  
Ex pl or ati o n of C orrel ati o ns  ............................................................................................................ 5 2  
1 1.  
S T U D Y C O M MI T T E E  ................................................................................................................................... 5 2  
1 1. 1.  
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 5  
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 6  
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 8  
1 3. 1.  
P A TI E N T S E L E C TI O N  .................................................................................................................................. 5 8  
1 3. 1. 1.  
Ge ner al  ........................................................................................................................................... 5 8  
1 3. 1. 2.  
Re q uire d L a b or at ory V al ues  ........................................................................................................... 5 8  
1 3. 1. 3.  
Re pr o d uctive C o nsi der ati o ns  .......................................................................................................... 5 8  
1 3. 1. 4.  
Pri or a n d C o nc o mit a nt T her a pies  .................................................................................................. 5 8  
1 3. 2.  
T R E A T M E N T R A TI O N A L E  ........................................................................................................................... 5 9  
1 3. 2. 1.  
At al ure n Sc he d ule a n d D ose Selecti o n  ........................................................................................... 5 9  
1 3. 2. 2.  
D ur ati o n of T her a py  ....................................................................................................................... 6 0  
1 3. 2. 3.  
S afety M o nit ori n g  ............................................................................................................................ 6 0  
1 3. 2. 4  
Ot her A b n or m alities  ........................................................................................................................ 6 8  
1 3. 2. 5  
Acti o ns t o be T ake n i n Res p o nse t o  S afety Si g n als  ......................................................................... 6 8  
1 3. 2. 6  
Effic acy Me as ure me nts  ................................................................................................................... 6 9  
1 4
1 4  
B E N E FI T S A N D RI S K S
B E N E FI T S A N D RI S K S  ................................................................................................................................. 7 0  
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  ...................................................................................................... 7 0  
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 2  
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 3  
1 4. 4  
B E N E FI T / RI S K C O N C L U SI O N S  .................................................................................................................... 7 4  


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P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 8  of 8 6  
 
BI B LI O G R A P H Y  ...................................................................................................................................................... 7 5  
A P P E N DI X A.  
D E C L A R A TI O N O F H E L SI N KI  ........................................................................................... 8 3  
 
LI S T O F T A B L E S  
T A B L E  1.   R E Q UI R E D S C R E E NI N G L A B O R A T O R Y V A L U E S  ......................................................................................... 2 0  
T A B L E  2.   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 3.   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  4.   S C H E D U L E O F E V E N T S  ................................................................................................................................. 3 3  
T A B L E  5.   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  6.   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  7.   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 5  
T A B L E  8.   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  
  


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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 
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 
BID 
Bis in die (2 times per day) 
BMD 
Becker muscular dystrophy 
BUN 
Blood urea nitrogen 
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 
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 
EK 
Egen Klassifikation 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
FDAMA 
Food and Drug Modernization Act of 1997 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 


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Abbreviation 
Definition 
HDL 
High-density lipoprotein 
hERG 
Human ether-à-go-go-related gene 
HPA 
Hypothalamic-pituitary-adrenal 
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  
IWR 
Interactive Web Response 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LLN 
Lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
nmDBMD 
Nonsense mutation Duchenne and Becker muscular dystrophy 
NSAA 
North Star Ambulatory Assessment 
PK 
Pharmacokinetic(s) 
QT 
Ventricular depolarization-repolarization interval on ECG 
SAE 
Serious adverse event 
SD 
Standard deviation 
t1/2 
Plasma half-life 
TID 
Ter in die (3 times per day) 
Tx 
Treatment 
UE 
Upper extremity 
ULN 
Upper limit of normal 
US 
United States  
WHODRUG 
World Health Organization Drug Dictionary 
WNL 
Within normal limits 


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1. 
OVERVIEW 
1.1. Background 
Duchenne muscular dystrophy (DMD) is a disabling and life-threatening X-linked genetic 
disorder affecting males.  A small subset of boys and men (1 out of 10) are classified as having 
Becker muscular dystrophy (BMD), a phenotypically milder form of the dystrophic muscle 
disease that is associated with later manifestation of symptoms.  In essence, DMD and BMD 
represent a continuum of the same disease caused by mutations in the gene for dystrophin, a 
protein that stabilizes muscle cell membranes.  Boys with DBMD (Duchenne and Becker 
muscular dystrophy) develop progressive proximal muscle weakness that leads to deterioration of 
ambulation, wheelchair dependency, and eventual respiratory and cardiac failure.  Only chronic 
administration of corticosteroids has slowed progression of the disease.  However, because of 
serious side effects, corticosteroids are not always employed, especially in nonambulatory 
patients.  There is no current therapy for the underlying cause of DBMD.  
In ~10 to 15% of boys and men with DBMD, the causative defect in the dystrophin gene is a 
nonsense mutation that truncates dystrophin protein production by introducing a premature stop 
codon into the dystrophin messenger ribonucleic acid (mRNA).  Ataluren (PTC124) is a novel, 
orally bioavailable, small-molecule drug that promotes ribosomal readthrough of mRNA 
containing a premature stop codon.  Through this mechanism of action, ataluren has the potential 
to overcome the genetic defect in patients with nonsense mutation DBMD (nmDBMD). 
A previous Phase 2a study (PTC124-GD-004-DMD) enrolled 38 boys with nmDMD, including 
ambulatory and nonambulatory patients, to receive 28 days of ataluren treatment.  The study 
demonstrated ataluren-related increases in in vitro and in vivo dystrophin expression and 
statistically significant reductions in serum concentrations of muscle-derived creatine kinase 
(CK).  Of the 38 patients, 36 patients subsequently enrolled into a Phase 2a open label extension 
study (PTC124-GD-004e-DMD).  These patients received the 20-, 20-, 40-mg/kg dose level of 
ataluren for a median [range] of 70 [53 to 81] weeks.  
A Phase 2b, international, multicenter, randomized, double-blind, placebo-controlled, 
dose-ranging, efficacy, and safety study (Study PTC124-GD-007-DMD; Study 007) evaluating 
ataluren in patients with nmDBMD was conducted.  Patients were 5 to 20 years of age and were 
ambulatory at baseline.  They were randomized 1:1:1 to receive placebo; ataluren at a low dose 
of 10 mg/kg (morning), 10 mg/kg (midday), 20 mg/kg (evening); or ataluren at a high dose of 
20 mg/kg (morning), 20 mg/kg (midday), 40 mg/kg (evening).  Patients completing this study 
continued to receive high-dose ataluren in an open-label extension to this study (PTC124-GD-
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 low-dose 
ataluren experienced a slower loss of walking ability relative to patients receiving placebo.  
Efficacy in the high-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 lower 
dose of ataluren, the data monitoring committee (DMC) for the ataluren DBMD program 
recommended discontinuation of ongoing studies evaluating high-dose ataluren.  Consequently, 
ataluren administration in the open-label extension studies (004e and 007e) and in an additional 


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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 low-dose ataluren 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 low-dose ataluren 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 high-dose 
ataluren and placebo in change in 6MWD over 48 weeks.   
Positive trends in muscle function, as measured by timed function tests, were observed at 
Week 48 in patients treated with low-dose ataluren when compared to patients treated with 
placebo.  In addition, over the 48-week study, patients treated with low-dose ataluren had a 
reduction in the frequency of accidental falls compared to patients treated with placebo.  Mean 
changes in other secondary outcome measures were generally small; the meaningfulness of these 
results is unclear given the lack of prior experience in DBMD and/or other known limitations 
associated with these evaluations. 
1.2. Study Design 
This study comprises a Phase 3, open-label study of ataluren in patients with nmDBMD who 
previously received ataluren at an investigator site in a prior PTC-sponsored clinical study.  A 
separate open-label study (PTC124-GD-016-DMD) is being conducted for nmDBMD patients 
who previously received ataluren at an investigator site in the United States (US). 
All participating sites must have had at least 1 patient that received ataluren treatment in a prior 
PTC-sponsored clinical study in DBMD.  It is planned that up to ~96 patients will be enrolled. 
Subjects will receive ataluren 3 times per day (TID) at respective morning, midday, and evening 
doses of 10 mg/kg, 10 mg/kg, and 20 mg/kg, for approximately 240 weeks.  Study assessments 
will be performed at clinic visits during screening, on the first day of ataluren dosing, and then 
every 12 weeks during the ataluren treatment period.    
2. 
INTRODUCTION 
2.1. Disease Indication 
DBMD is an X-linked disorder caused by defects in the gene for dystrophin, a protein that is 
critical to the structural stability of myofibers in skeletal, diaphragmatic, and cardiac muscle 
[Worton 2001, Khurana 2003].  The prevalence is estimated at ~13,000 males in the US and 
~17,000 boys in the European Union (EU) [Hirawat 2004a, Hirawat 2004b]. 
Dystrophin is a high-molecular-weight cytoskeleton protein localized at the inner surface of the 
muscle membrane [Worton 2001].  It is part of a dystrophin-glycoprotein complex that also 
includes dystroglycan and sarcoglycans.  This complex provides a bridge across the muscle 
membrane; dystrophin couples actin in the cytoplasm with dystroglycan.  Dystrophin deficiency 
destabilizes the dystrophin-glycoprotein complex, impairing localization of the dystroglycan and 
sarcoglycans to the muscle membrane, and compromising the structural integrity of the 


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membrane.  The absence of normally functioning dystrophin results in sarcolemmal breakdown, 
calcium ion influx, phospholipase activation, oxidative muscle injury, and, ultimately, 
myonecrosis.  As muscle damage progresses, connective tissue and fat replace muscle fibers. 
DBMD usually first manifests in boys ~3 to 7 years of age when they are noted to develop 
lordosis, a waddling gait, and the Gowers’ sign (a characteristically abnormal method of rising 
from a supine to a standing position) [Brooke 1989, McDonald 1995, Boland 1996, Worton 
2001].  Inexorable progressive weakness is seen, particularly in the proximal musculature.  
Ambulation becomes increasingly abnormal.  By the age of 8 years, most boys have difficulty 
rising from the floor and ascending stairs and they often fall while walking.  Boys with the 
disease spend less time walking and walk more slowly than healthy boys [McDonald 2005a] and 
are significantly less active than normal boys of similar age [McDonald 2002, McDonald 2005b].  
By 10 to 14 years of age, most are wheelchair-bound.  In ambulatory DMD boys, the most 
frequent cardiac abnormality is sinus tachycardia and heart rate variability, occurring from 
childhood and persisting throughout life [Finsterer 2003, Gulati 2005].  Pulmonary function is 
usually normal before 10 years of age and is well maintained into adolescence in boys receiving 
corticosteroids [Mendell 1989, Griggs 1991, Phillips 2001, Tangsrud 2001, Biggar 2001, 
Biggar 2006].  Later in adolescence, cardiac and diaphragmatic muscles become progressively 
weaker and patients require treatment for cardiac insufficiency and ventilatory support.  Patients 
usually die of cardiac or pulmonary failure by 15 to 22 years of age [Brooke 1989, 
McDonald 1995, Simonds 1998, Worton 2001, Eagle 2002].   
2.2. Ataluren (PTC124) 
2.2.1. Therapeutic Concept 
Among the several types of disease-causing mutations, a nonsense mutation is a single-point 
alteration in one of the nucleotides of deoxyribonucleic acid (DNA) that, when copied to mRNA, 
is interpreted as a stop signal by the ribosomal cellular translational machinery.  The presence of 
such a premature stop signal within the protein-coding region of the mRNA for dystrophin tells 
the ribosomes to halt production of the protein before the full-length protein is completed.  The 
resulting truncated dystrophin is too short to serve its necessary function and causes disease.  It is 
estimated that ~10-15% of all boys with DMD and BMD have a nonsense mutation as the basis 
for the disorder [Dent 2005], resulting in a prevalence of nmDBMD of ~1700 boys in the United 
States and ~2200 boys in Europe.   
It has been known for some time that drugs with translation-modifying mechanisms of action, 
such as the aminoglycoside antibiotics (eg, gentamicin), can ameliorate the effects of nonsense 
mutations in experimental systems.  By binding to the ribosomes, such agents permit the 
ribosomes to reinterpret the nonsense mutation stop signal in mRNA such that they can move 
through the obstruction by inserting an amino acid and continuing the translation process to 
produce a full-length functional protein.  In experimental animal systems and in pilot studies in 
nmDBMD, treatment with high concentrations of gentamicin has restored production of 
functional dystrophin [Barton-Davis 1999, Politano 2003].  Similarly, nonclinical and clinical 
studies in cystic fibrosis (CF) have demonstrated restoration of the cystic fibrosis transmembrane 
conductance regulator (CFTR), the epithelial chloride channel that is defective in that disease 


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[Clancy 2001, Du 2002, Wilschanski 2003].  Current data suggest that the geometry of mRNA 
and associated initiation-termination proteins is critically different at a premature stop than at a 
normal stop.  This may explain why a drug can permit the ribosomes to selectively read through 
the premature stop codon, but will not allow the ribosomes to read through the normal stop 
codon at the end of the mRNA protein-coding region [Sachs 2000, Welch 2000, Amrani 2004].  
Because serious renal and otic toxicities and the need for parenteral administration preclude the 
long-term clinical use of gentamicin, there has been considerable interest in the identification of 
safer and more conveniently administered, low-molecular-weight, synthetic compounds with the 
ability to promote readthrough of disease-causing nonsense mutations.   
Ataluren as an orally bioavailable, small molecule with potential clinical utility in treating 
genetic disorders through induction of readthrough of nonsense mutations and production of 
full-length, functional proteins.  Ataluren does not promote readthrough of normal stop codons, 
alter mRNA levels, or affect the process of nonsense-mutation-mediated mRNA decay.  In the 
subset of patients whose disease is mediated by a nonsense mutation, clinical development of 
ataluren may offer a definitive therapy by overcoming the basic cause for DBMD and other 
disabling and life-threatening genetic disorders. 
2.2.2. Chemical Description 
Ataluren is a new chemical entity with a chemical formula of C15H9FN2O3 and a molecular 
weight of 284.2 Daltons.  Ataluren is a Biopharmaceutical Classification System Case 2 
compound, possessing low aqueous solubility (<31 µg/mL) but high permeability across 
gastrointestinal epithelium, consistent with its high oral bioavailability.  The drug has been 
manufactured and formulated under current Good Manufacturing Practices (cGMP) and is 
provided as a vanilla-flavored, white to off-white powder for suspension. 
2.2.3. Clinical Studies 
2.2.3.1. 
Phase 1 Studies 
Two Phase 1 safety and pharmacokinetic (PK) studies of ataluren were conducted in 62 healthy 
adult male and female volunteers ranging in age from 18 to 30 years [Hirawat 2007].  Single 
doses of ataluren administered orally at dose levels ranging from 3 to 100 mg/kg were palatable 
and generally well tolerated.  Mild adverse events of mild headache, dizziness, nausea, vomiting, 
diarrhea, and abdominal pain at dose levels of 150 and 200 mg/kg appeared to be coincident with 
achieving the maximum concentration (Cmax).  Elevations of serum alanine aminotransferase 
(ALT) and aspartate aminotransferase (AST) were observed in 1 subject receiving a single dose 
of 200 mg/kg.  With repeated doses through 50 mg/kg/dose 2 times per day (BID), reversible, 
low-grade (<2 times the upper limit of normal [ULN]) transaminase elevations were observed in 
some patients.  No bilirubin increases were observed.  In addition, no notable BUN, creatinine, or 
urinalysis abnormalities were observed.  PK analyses indicated rapid oral absorption, generally 
dose-proportional PK, an effective plasma half-life (t1/2) in the range of 2 to 6 hours, and no 
relevant drug accumulation with repeated dosing.  The data also demonstrated that ataluren can 
be given with or without food and that trough plasma concentrations exceeding the ~2-µg/mL to 
~10-µg/mL target values active in the mdx mouse model of DMD might best be achieved with 
TID dosing after meals. 


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The mass balance, absorption, excretion, and metabolism profiles of ataluren after a single dose 
of unlabeled and  [14C]-labeled ataluren oral suspension were determined in 7 healthy male 
subjects in an additional Phase 1 study.  Each subject received 1375 mg [18.5 mg/kg] of 
unlabeled ataluren and 96.6 µCi of [14C]ataluren (~0.5 mg).  Whole blood and plasma samples, 
and urine and feces were collected up to 264 hours after dosing.  The results showed that the 
majority of circulating total radioactivity in plasma was associated with unchanged ataluren.  
Ataluren was not highly associated with red blood cells.  The only metabolite detected in plasma 
after oral administration of ataluren was ataluren acyl glucuronide, which represented ~8%, on 
average, of the exposure (area under the concentration-time curve [AUC]) relative to ataluren.  
The total mean recovery of the administered radioactive dose was complete (~102%), with 55% 
recovery in urine and 47% in feces.  Based on the mean urinary recovery of radioactivity, the 
absolute bioavailability of ataluren is estimated to be ≥55%.  The majority of the radioactivity 
recovered in urine represented ataluren acyl glucuronide (~49% of the administered dose); 
unchanged ataluren in urine represented <1% of the administered dose.  The primary drug-related 
moiety in feces was a metabolite (M2) formed as a result of a reductive cleavage of the 
oxadiazole ring of ataluren, followed by hydrolysis; unchanged ataluren in feces represented 
~0.4% of the radioactive dose.  M2 is presumably the product of metabolism of ataluren by fecal 
microorganisms.  The elimination of ataluren is likely dependent on hepatic glucuronidation of 
ataluren followed by renal excretion of the resulting glucuronide metabolite.  
2.2.3.2. 
Phase 2 Clinical Studies in Duchenne/Becker Muscular Dystrophy 
2.2.3.2.1.  
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 


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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. 
2.2.3.2.2. 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 low-dose 
level of ataluren (10-, 10-, 20-mg/kg), and 60 received the high-dose level of ataluren (20-, 20-, 
40-mg/kg) for a duration of 48 weeks.   
At the end of Study 007 (Week 48), the mean change from baseline in 6MWD was ~30 meters 
greater in patients treated with low-dose ataluren 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 low-dose ataluren 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 high-dose ataluren and placebo in 
change in 6MWD over 48 weeks.   
Positive trends in muscle function, as measured by timed function tests, were observed at  
Week 48 in patients treated with low-dose ataluren when compared to patients treated with 
placebo.  In addition, over the 48-week study, patients treated with low-dose ataluren had a 
reduction in the frequency of accidental falls compared to patients treated with placebo.  Mean 
changes in other secondary outcome measures were generally small; the meaningfulness of these 
results is unclear given the lack of prior experience in DBMD 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 


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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. 
2.2.3.2.3. Other Completed Studies 
Subjects 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, 
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.   
Subjects 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.    
2.2.3.2.4. Ongoing Studies  
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 


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received ataluren for a median of 227 weeks (range, 4 to 249 weeks).  To date in this study, 
ataluren has been well tolerated.  Further details on the safety results are found in the IB. 
A Phase 3 extension study (Study 020e) of ataluren (PTC124) in patients with nonsense mutation 
dystrophinopathy, that is being conducted at 54 sites in 18 countries.  As of 31 July, 2015, this 
study had enrolled 199 patients who received ataluren for a median of 24 weeks (range, 0.2 to 71 
weeks).  To date in this study, ataluren has been well tolerated.  Further details on the safety 
results are found in the IB.  
2.2.3.3. 
Safety Experience in Other Indications 
Ataluren is also being evaluated in children and adults with other nonsense mutation genetic 
disorders  Safety information from other indications are provided in the Ataluren Investigator 
Brochure. 
3. 
STUDY OBJECTIVE AND ENDPOINTS 
3.1. Primary Objective 
The primary objective of this study is to assess the long-term safety and tolerability of 10, 10, 
20 mg/kg ataluren in patients with nmDBMD who had prior exposure to ataluren in a 
PTC-sponsored clinical trial.   
3.2. Secondary Objectives 
Secondary objectives include the following: 
• Ambulatory patients (able to run/walk 10 meters in ≤30 seconds) - To determine the effect of 
ataluren on ambulation and other aspects of physical function 
• Nonambulatory patients (unable to run/walk 10 meters in ≤30 seconds) - To assess the effect 
of ataluren on activities of daily living, upper limb function, and pulmonary function 
• All patients – To assess patient and/or parent/caregiver reports of changes in disease status: 
o Retrospectively during and after participation in previous studies (Studies 007 and 
007e) 
o Prospectively during the current study  
3.3. Clinical Endpoints 
Primary 
• Safety profile characterized by type, frequency, severity, timing, and relationship to ataluren 
of any adverse events or laboratory abnormalities  
Secondary 
• In ambulatory patients, change from baseline in 6MWD as measured by the 6-minute walk 
test (6MWT) 


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• In ambulatory patients, change from baseline in physical function as measured by the North 
Star Ambulatory Assessment (NSAA)  
• In ambulatory patients, change from baseline in timed function tests (time to stand from 
supine and time to run/walk 10 meters) 
• In nonambulatory patients, change from baseline in pulmonary function as measured by 
spirometry 
• In nonambulatory patients, change from baseline in patient and parent/caregiver-reported 
activities of daily living, as measured by the Egen Klassifikation (EK) scale 
• In all patients, changes in patient and/or parent/caregiver reports of disease status as 
measured by a standardized survey administered by site personnel 
4. 
SUBJECT SELECTION CRITERIA 
4.1. Overview 
This clinical study can fulfill its objectives only if appropriate patients are enrolled.  The 
following eligibility criteria are designed to select patients for whom study participation is 
considered appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.  Eligibility 
criteria may not be waived by the investigator and conformance to the eligibility criteria is 
subject to review in the case of a Good Clinical Practice (GCP) or a regulatory authority audit.  
Any questions regarding a subject’s eligibility should be discussed with the MAPI medical 
monitor or the PTC Therapeutics medical monitor prior to enrollment. 
4.2. Inclusion Criteria 
Subjects must meet all of the following conditions to be eligible for enrollment into the study: 
1. Evidence of signed and dated informed consent/assent document(s) indicating that the subject 
(and/or his parent/legal guardian) has been informed of all pertinent aspects of the trial.  
Note: If the study candidate is considered a child under local regulation, a parent or legal 
guardian must provide written consent prior to initiation of study screening procedures 
and the study candidate may be required to provide written assent.  The rules of the 
responsible Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
regarding whether one or both parents must provide consent and the appropriate ages for 
obtaining consent and assent from the subject should be followed.   
2. History of exposure to ataluren in a prior PTC study in nmDBMD .  Note: Patients are 
considered eligible only if they received ataluren during their participation in one or more 
prior PTC-sponsored studies of ataluren in nmDBMD.  Note: Subjects who have 
participated in a prior or ongoing PTC study with ataluren in nmDBMD at a trial site in 
the US or Canada, but reside outside of the US and Canada, may be eligible for this study 
(with the approval of the PTC Therapeutics Medical Monitor).  
3. Male sex. 


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4.  C o nfir me d scree ni n g la b orat or y val ues wit hi n t he ce ntral la b orat or y ra n ges s pecifie d i n 
Ta ble  1  bel o w.  N ote: C o nfir m ati o n s h o ul d be perf or m e d f or o ut -of -r a n ge v al ues t o 
deter mi ne if t he a b n or m ality is re al or artif act u al.  V al ues use d t o est a blis h eli gi bilit y 
s h o ul d be t he l ast m e as ure m e nts o bt ai ne d wit hi n t he scree ni n g peri o d. 
T a bl e  1 .  R e q uir e d S cr e e ni n g L a b or at or y V al u e s 
Or g a n S y st e m  
P ar a m et er  
R e q uir e d V al u e  
H e p ati c  
S er u m t ot al bilir u bi n  
≤1. 5 x U L N  
S er u m G G T  
≤1. 5 x U L N  
H e p atit i s B c or e a nti b o d y a n d H e p atiti s C a nti b o d y  N e g ati v e  
R e n al  
S er u m cr e ati ni n e  
≤U L N  
S er u m B U N  
≤U L N  
Uri n e bl o o d ( b y di p sti c k)  
≤1 +  
S er u m  
El e ctr ol yt e s  
S er u m s o di u m ( N a + )  
< Gr a d e 2  
S er u m p ot a s si u m  ( K+ ) 
< Gr a d e 2  
S er u m bi c ar b o n at e ( H C O 3 -) 
< Gr a d e 2  
S e r u m m a g n e si u m ( M g2 + ) 
< Gr a d e 2  
S er u m c al ci u m ( C a 2 + ) 
< Gr a d e 2  
S er u m p h o s p h or u s  
< Gr a d e 2  
A b br e vi ati o n s : B U N = bl o o d ur e a nitr o g e n, G G T = g a m m a gl ut a m yl tr a n sf er a s e, U L N = u p p er 
li mit of n or m al 
 
5.  I n patie nts  w h o are se x uall y acti ve, willi n g ness t o a bsta i n fr o m se x ual i nterc o urse or e m pl o y 
a barrier or me dical met h o d of c o ntrace pti o n d uri n g atal ure n a d mi nistrati o n a n d t he 6-wee k 
f oll o w-u p peri o d.  
6.  Willi n g ness a n d a bilit y t o c o m pl y wit h sc he d ule d visits, dr u g a d mi nistrati o n pla n, st u d y 
pr oce d ures, la b orat or y tests, a n d st u d y restricti o ns .  N ote: Psyc h ol o gic al, s oci al, f a mili al, or 
ge o gr a p hic al f act ors t h at mi g ht precl u de a de q u ate st u dy p artici p ati o n s h o ul d be 
c o nsi dere d . 
4. 3.  E x cl u si o n Crit eri a  
Pri or t o treat me nt wit h atal ure n, it will be c o nfir me d t hat t he patie nt meets n o ne of t he f oll o wi n g 
c o n diti o ns:  
1.  E x p os ure t o a n ot her i n vesti gati o nal dr u g wit hi n 1 m o nt h pri or t o start of st u d y treat me nt.  
2.  Eli gi bilit y f or a n ot her atal ure n cli nical trial t hat is acti vel y e nr olli n g st u d y partici pa nts.  
3.  K n o w n h y perse nsiti vit y t o a n y of t he i n gre die nts or e x ci pie nts of atal ure n ( Litesse ® UltraT M  
[refi ne d p ol y de xtr ose], p ol yet h yle ne gl yc ol 3 3 5 0, L utr ol ® micr o F 1 2 7 [ p ol o x a mer 4 0 7], 
ma n nit ol 2 5 C, cr os p o vi d o ne X L 1 0, h y dr o x yet h yl cell ul ose, va nilla, Ca b -O -Sil ® M 5 P 
[ c oll oi dal silica], ma gnesi u m stearate).  
4.  O n g oi n g use of t he f oll o wi n g me dicati o ns:  
a. C o u mari n -base d a ntic oa g ula nts (e g, warfari n), p he n yt oi n, t ol b uta mi de, or paclita x el. 
b.  S yste mic a mi n o gl yc osi de t hera p y  
5.  O n g oi n g u nc o ntr olle d me dical/s ur gical c o n diti o n, E C G fi n di n gs, or la b orat or y a b n or malit y 
t hat, i n t he i n vesti gat or’s o pi ni o n, c o ul d a d versel y affect t he safet y of t he patie nt or ma ke it 
u nli kel y t hat f oll o w -u p w o ul d be c o m plete d.  


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5. 
ENROLLMENT PROCEDURES 
5.1. Source and Number of Subjects 
Up to ~96 patients with nmDBMD each received ataluren treatment in a prior PTC-sponsored 
clinical trial; these patients are all potential candidates for this study.  
It is anticipated that patients will be enrolled from investigator sites in countries including 
Belgium, France, Germany, Italy, Spain, United Kingdom, Sweden, Israel, and Australia.  
5.2. Screening and Study Drug Allocation 
The investigator or sub-investigator must inform each prospective subject of the nature of the 
study, explain the potential risks, and obtain written informed consent/assent from the subject 
and/or the parent/legal guardian prior to performing any study-related screening procedures.   
The subject number used in the prior ataluren DBMD study shall be retained for use in this study.  
This subject number must be used for subject identification on all study-related documents (case 
report forms [CRFs], laboratory samples, etc).  
Any questions regarding the eligibility of a subject should be discussed with the PTC 
Therapeutics medical monitor.   
The relevant site staff will need to supply the Interactive Web Response (IWR) system with the 
information required by the system (eg, site number, subject number, subject weight in 
kilograms) to permit study drug allocation. 
6. 
STUDY DRUG ADMINISTRATION 
6.1. Investigational Product 
6.1.1. Ataluren (PTC124) 
Ataluren will be provided as a vanilla-flavored, white to off-white powder for oral suspension.  
The drug has been manufactured and formulated under cGMP conditions.  The formulation 
includes matrix and suspending agents, surfactants, and various minor excipients that aid in the 
manufacturing process.  The powder for oral suspension is packaged in aluminum-foil, 
child-resistant sachets and is 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, or lactose-free milk), fruit juice (except apple juice), 
fruit punch, or in semi-solid food (yogurt, pudding, or applesauce). 
6.1.2. Drug Source 
Ataluren will be supplied free of charge to the investigator site by PTC Therapeutics for 
appropriate distribution to the patients/caregivers.  It is intended that ataluren will be provided in 
sufficient supply for a 12-week study period.  However, in the event of pending commercial 
availability of ataluren, drug may be supplied for a treatment period of less than 12 weeks.  
Resupply may be obtained via the IWR system.    


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6.1.3. Study Drug Packaging and Labeling 
Sachets will be color-coded to indicate dosage strength (125 mg – yellow, 250 mg – pink, 1000 
mg – blue).  The labeling will bear the text “CAUTION – New Drug – limited by Federal (USA) 
law to investigational use.” 
6.1.4. Study Drug Dispensing  
Dosing of ataluren will be based on milligrams of drug per kilogram of subject 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 EDC system.   
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing study 
drug according to the EDC system directions.   
Because of potential changes in subject body weight over time, weight-based dose adjustment  
will occur every 6 months.  Depending upon the magnitude of change in subject body weight 
since baseline, the number and type of sachets to be used by the subject may remain the same or 
may be adjusted.   
6.1.5. Return of Study Drug 
Subjects should return all unused sachets of ataluren to the investigator site at the end of each 
visit for inventory.  The case report forms will serve as the source document for drug supply to 
the patients and will document the return of any unused drug for compliance assessments.   
6.1.6. Storage and Stability 
Sachets containing ataluren will be shipped and stored at room temperature (~15 to 30°C).  The 
available stability data from representative sample support the use of the drug product for 
48 months when stored at room temperature.   
6.1.7. Study Drug Accountability 
Study personnel must ensure that all ataluren supplies are temperature-monitored and kept in a 
secure locked area with access limited to authorized personnel.  This study product must not be 
used outside the context of this protocol.  Under no circumstances should the investigator or 
other site personnel supply study product to other investigators or clinics, or allow the supplies to 
be used other than as directed by this protocol. 
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all ataluren shipped by PTC Therapeutics or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all ataluren.  Current 
reconciliation and dispensing records must also be maintained that include the date and amount 
of drug dispensed, relevant batch and sachet numbers, and subject’s assigned study number.   
Depending upon the decision of PTC Therapeutics, unused clinical supplies must be destroyed or 
must be returned to PTC Therapeutics or its designee after the study is completed. 


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P a ge 2 3  of 8 6  
 
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 s u bject e x perie nci n g a n o ve r d ose (a d mi nistrati o n of an  atal ure n 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 ntl y, 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 ni tiate 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 s h o ul d be c o ntacte d if a n o ver d ose occ ur s.  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.   
6. 2.  St u d y Dr u g Tr e at m e nt  
6. 2. 1.  
D ur ati o n of T h er a p y  
Treat me nt wit h atal ure n i n t he c o nte xt of t his pr ot oc ol is a ntici pate d t o occ ur f or 2 4 0  wee ks.  T he 
act ual d urati o n of atal ure n treat me nt u n der t his pr ot oc ol will be s u bject t o t he f oll o wi n g 
c o n diti o ns:  
•  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 atal ure n 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 atal ure n treat me nt, 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 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 atal ure n treat me nt, 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.   
•  T he patie nt will be wit h dra w n fr o m treat me nt if he is u na b le t o t olerate atal ure n. 
•  T he patie nt ma y be wit h dra w n fr o m t his st u d y if he is eli gi ble t o partici pate i n a n ot her 
atal ure n - n m D B M D cli nical st u d y or pr o gra m.  
•  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 ny 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.  


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P a ge 2 4  of 8 6  
 
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  2  bel o w, 3  d oses s h o ul d be ta ke n per da y –  t he first d ose i n t he m or ni n g 
( 1 0 m g/ k g), t he sec o n d d ose d uri n g t he mi d dle of t he da y ( mi d -da y –  1 0  m g/ k g), a n d t he t hir d 
d ose i n t he e ve ni n g ( 2 0  m g/ k 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) .  If 
p ossi ble, 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.   
T a bl e  2 .  S u g g e st e d D ail y D o si n g S c 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 s u bj e ct’ 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 et 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 s u bject e x p erie nces a dela y i n t he a d mi nistrati o n of atal ure n 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 s u bject 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 s u bject w h o has a dela y 
i n a d mi nistrati o n of atal ure n of > 4  h o urs, t he d ose s h o ul d n ot be ta ke n.  Atal ure n 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 o t 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 
atal ure n d osi n g s h o ul d n ot be altere d.    
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 s us pe nsi o n ( 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, or lact ose free mil k), fr uit j uice  (e x ce pt a p ple 
j uice), fr uit p u nc h, or 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 s u bject.  T he f ull c o nte nts of eac h pac ket s h o ul d be mi x e d wit h at least 3 0 m L ( 1 o u nce) of 


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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.  
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  
S u bjects 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 atal ure n 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 nt 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) 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.    
If t he patie nt e x perie nces a d ose-li mitin g a d verse e ve nt relate d t o atal ure n, t he n dr u g a d mi nistrati o n 
ca n be i nterr u pte d, as necessar y, u ntil t he a d verse e ve nt res ol ves or sta bilizes t o a n acce pta ble 
de gree.  If f urt her e val uati o n re veals t hat t he a d verse e ve nt is n ot relate d t o atal ure n, treat me nt will 
be c o nti n ue d at t he ori gi nal d ose le vel.  Alter nati vel y, u ntil f ull res ol uti o n of t he atal ure n relate d 
a d verse e ve nt, atal ure n ma y be c o nti n ue d at a re d uce d d ose le vel of 5  m g/ k g i n t he m or ni n g, 
5  m g/ k g at mi d da y, a n d 1 0  m g/ k g i n t he e ve ni n g.  If  t he patie nt c o nti n ues t o e x perie nce d ose-
li miti n g a d verse e ve nts at t his l o wer d ose le vel, atal ure n will be disc o nti n ue d.  If t he atal ure n 
a d verse e ve nt is f ull y res ol ve d, t he atal ure n d ose ma y be i ncrease d bac k t o 1 0  m g/ k g i n t he 
m or ni n g, 1 0  m g/ k g at mi d da y, a n d 2 0  m g/ k g i n t he e ve ni n g.  T he P T C T hera pe utics me dical 
m o nit or will be n otifie d of a n y S A E or a n y a d verse e ve nt t hat lea ds t o d ose re d ucti o n , 
i nterr u pti o n, or treat me nt disc o nti n uati o n.   I n a d diti o n, the M A PI  Safet y De part me nt  will be 
n otifie d a n y  S A Es.  
Ta ble 3  bel o w 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 atal ure n 
i m me diatel y, f or i nterr u pti n g atal ure n 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 atal ure n 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 3  bel o w, 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 atal ure n t hera p y is a p pr o priate.  


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Table 3.  Safety Monitoring Parameters and Actions To Be Taken
  
Organ System and 
Laboratory Parameter 
Stop Study Drug 
Immediately, Confirm 
Abnormal Value, 
and Then Start Work-Up 
Stop Study Drug After  
Confirminga Abnormal Value,  
and Then Start Work-Up 
Continue Study Drug,  
Confirm Abnormal Value,  
and then Start Work-Upa 
Hepatic 
 
 
 
Serum total bilirubin 
≥Grade 3 (≥3.0 x ULN) 
Grade 2 (1.5 – 3.0 x ULN) 
--- 
Serum GGT 
≥Grade 3 (≥5.0 x ULN) 
Grade 2 (>2.5 – 5.0 x ULN) 
--- 
Serum ALT 
 
 
↑ of > 150 U/L with stable 
or  
↓ CK 
Adrenal 
 
 
 
Plasma ACTH 
--- 
>ULN (and plasma cortisol 
<LLN) 
>ULN (and cortisol WNL) 
Renal 
 
 
 
Serum cystatin C 
>2.00 mg/L 
>1.33 – 2.00 mg/L 
--- 
Serum creatinine 
≥ Grade 2 (≥1.5 x ULN for 
age) 
Grade 1 (>ULN – 1.5 x ULN for 
age) 
--- 
Serum BUN 
≥3.0 x ULN 
≥1.5 – 3.0 x ULN 
--- 
Urine protein: urine 
creatinine (spot) 
--- 
>0.40 mg:mg 
--- 
Urine protein: urine 
osmolality (spot) 
--- 
>0.30 mg/L:mOsm/kg 
--- 
Urine blood (by 
dipstick) 
4+ (Large) 
3+ (Moderate) 
2+ (Small) 
Serum electrolytes 
Grade 3-4 
Grade 2 
Grade 1 
Serum Na+, high 
>155 mmol/L 
>150 – 155 mmol/L 
--- 
Serum Na+, low 
<130 mmol/L 
--- 
--- 
Serum K+, high 
>6.0 mmol/L 
>5.5 – 6.0 mmol/L 
--- 
Serum K+, low 
<3.0 mmol/L 
--- 
--- 
Serum Mg2+, high 
>1.23 mmol/L 
--- 
--- 
Serum Mg2+, low 
<0.4 mmol/L 
<0.5 – 0.4 mmol/L 
--- 
Total serum Ca2+, high 
>3.1 mmol/L 
>2.9 – 3.1 mmol/L 
--- 
Total serum Ca2+, low 
<1.75 mmol/L 
<2.0 – 1.75 mmol/L 
--- 
Serum phosphorous 
<0.6 mmol/L 
<0.8 – 0.6 mmol/L 
--- 
Serum HCO3- 
<11 mmol/L 
<16 – 11 mmol/L 
--- 
 
 
a    
Laboratory abnormalities may be confirmed immediately or at the next scheduled clinic visit based on investigator judgment. 
Abbreviations: ACTH = adrenocorticotropic hormone, ALT = alanine aminotransferase, BUN = blood urea nitrogen, Ca2+ = calcium,  
CK =  creatine kinase, GGT = gamma glutamyl transferase, HCO3- = bicarbonate, K+ = potassium,   
Mg2+ = magnesium, Na+ = sodium, ULN = upper limit of normal, WNL = within normal limits 
It should be noted that blood samples for renin and aldosterone determinations will also be 
obtained at screening, and, as necessary, for patients with treatment-emergent evidence of adrenal 
dysfunction.  Changes in these laboratory parameters alone will not be exclusionary or reason for 
study drug discontinuation because renin and aldosterone values are markedly affected by age 
and normal reference ranges are too narrow to reliably use as guidance for treatment 
discontinuation in this study population.  In addition, renin and aldosterone values may be 
affected by angiotensin-converting enzyme (ACE) inhibitors, and angiotensin-receptor blockers 
(ARBs).  Changes in renin and aldosterone will be viewed in context with other laboratory 
findings. 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 2 7  of 8 6  
 
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 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 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, e n d ocri n ol o g y, or 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 dre nal, 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, he patitis scree ni n g res ults, all cli nical bl o o d val ues 
( partic ularl y ser u m bilir u bi n, G G T, A S T, a n d A L T val ues), a n d all c o nc o mita 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 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. 
•  A dre n al:   T he me dical a n d  fa mil y hist or y, all cli nical bl o o d val ues ( partic ularl y pre vi o us 
a dre n oc ortic otr o pic h or m o ne ( A C T H ), c ortis ol, re ni n, a n d al d oster o ne val ues a n d ser u m 
p otassi u m a n d s o di u m c o nce ntrati o ns), a n d all c o nc o mita nt me dicati o ns ( partic ularl y 
c ortic oster oi ds, A C E i n hi bit ors, a n d A R Bs) 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 
plas ma A C T H, c ortis ol, a n d al d oster o ne le vels; ser u m electr ol ytes; A C T H sti m ulati o n 
testi n g; reassess me nt of plas ma re ni n a n d al d oster o ne after i nterr u pti o n of A C E i n hi bit or or 
A R B treat me nt; C T, M RI, or ot her i ma gi n g met h o ds; a n d/ or a dre nal bi o ps y.  
•  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, s er 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 ud 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 t hera py 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 atal ure n t hera p y, t he 
s u bject’s stat us i n ter ms of DB M D  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, a dre nal, or re nal  e ve nts (refer t o  Ta ble 3 ), t he le vel of i n vesti gat or certai nt y t hat a n 
a b n or malit y l ea 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 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 2 8  of 8 6  
 
w het her or n ot t o rei nstit ute atal ure n treat me nt.  If t he i n vesti gat or c o nsi ders t he he patic, a dre nal, 
or re nal e ve nt t o t hat le d t o atal ure n i nterr u pti o n t o be pr o ba bl y relate d t o atal ure n, restarti n g t he 
atal ure n is n ot a d vise d.  I n t his case, t he s u bject 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, a dre nal, or re nal e ve nt  t hat 
pr o m pte d atal ure n i nterr u pti o n t o be p ossi bl y relate d or u nli kel y relate d t o atal ure n, 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 atal ure n.  If t he he patic, 
a dre nal, or re nal e ve nt is c o nsi dere d u nrelate d t o atal ure n, rei ns tit uti o n of atal ure n 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, atal ure n 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 
atal ure n, 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 ( 5 -, 5-, 1 0-m g/ k g).  T he a p pr o priate cli nic staff s h o ul d 
i nstr uct t he s u bject/care gi ver a b o ut t he re vise d n u m ber of atal ure n sac hets to be use d per d ose 
acc or di n g t o t he ne w sc he d ule .   
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 the atal ure n, t he d ose ma y be ret ur ne d t o t he ori gi nal d ose le vel.  T he a p pr o priate cli nic 
staff s h o ul d i nstr uct t he s u bject/care gi ver a b o ut t he re vise d n u m ber of atal ure n 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 W R s yste m.  
If after d ose re d ucti o n, t he s u bject 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 
atal ure n 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 atalure n 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 atal ure n 
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 atal ure n 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 or a s u bject t o c o nti n ue wit h st u d y 
treat me nt, t he n atal ure n 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 
atal ure n 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 be 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 lea di 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 b e 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 verse 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 atal ure n, a n y treat me nts (i ncl u di n g p rescri 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, t o bacc o pr o d ucts, or alc o h ol) t hat are 


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taken by a subject during the screening period, during ataluren administration, and for ≥6 weeks 
after discontinuation of ataluren are considered concomitant medications.  Information regarding 
any concomitant medications will be recorded in the source documents and in the concomitant 
medication CRF. 
6.4.1. 
Aminoglycosides or Other Potentially Nephrotoxic Agents 
Renal abnormalities were observed in an international, multicenter, double-blind, placebo-
controlled Phase 3 trial evaluating ataluren in patients ≥6 years of age with nonsense mutation 
cystic fibrosis in patients receiving concomitant ataluren and intravenous (IV) aminoglycosides 
(as described in the Ataluren Investigator Brochure).  In patients who require treatment for 
serious infections, investigators should substitute other antibiotics for systemic aminoglycosides 
when clinically appropriate.  
 If IV aminoglycosides are administered, study drug must be interrupted during the course of 
these antibiotics.  Study drug interruption should be considered with concomitant use of other 
potentially nephrotoxic antibiotics (eg, vancomycin).  Caution should be exercised during 
concomitant use of other potentially nephrotoxic agents.    Patients requiring IV aminoglycoside 
or other potentially nephrotoxic antibiotic should be closely monitored in an appropriate setting.  
In patients receiving potentially nephrotoxic antibiotics such as IV aminoglycosides or 
vancomycin, antibiotic drug levels and serum creatinine and BUN should be followed closely.  
The antibiotic trough level and creatinine and BUN should be measured within 24 to 48 hours of 
administration of the first antibiotic dose, and further antibiotic dosing should be based on these 
results.  Trough levels should be measured at intervals during the course of antibiotic treatment.  
Creatinine and BUN should be measured prior to initiating IV aminoglycoside or vancomycin 
therapy and at least twice a week during the course of antibiotic treatment. 
6.4.2. 
Hydration 
Because of the potential risk of renal dysfunction during periods of dehydration in patients 
receiving ataluren, it is important to encourage study patients to maintain adequate hydration 
throughout the study.  Patients should be adequately hydrated prior to receiving potentially 
nephrotoxic agents such as aminoglycosides or vancomycin, and hydration status should be 
carefully monitored throughout the administration of these agents.  Investigators should be 
particularly vigilant with patients who are experiencing nausea, vomiting, diarrhea, or fever, or 
who have laboratory evidence of dehydration. 
6.4.3. 
Cardiac Drugs for CHF Prophylaxis/Treatment 
Cardiac drugs (eg, ACE inhibitors, ARBs, beta-blockers, etc) may be used in the treatment of 
congestive heart failure (CHF) in nonambulatory patients with DMD and may increasingly be 
considered for use as prophylaxis against symptomatic cardiac dysfunction in younger boys with 
the disease [Bosser 2004, American Academy of Pediatrics 2005, Duboc 2005, Kajimoto 2006, 
Ramaciotti 2006].   
In patients who are receiving an ACE inhibitor or ARB, monitoring of plasma renin and 
aldosterone values in patients with treatment-emergent evidence of adrenal dysfunction should be 
conducted with the understanding that high renin values or low aldosterone values may not 


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represent definitive evidence of adrenal toxicity.  In patients on these drugs who develop other 
evidence for primary adrenal insufficiency (eg, elevated plasma ACTH concentration), 
reassessment of plasma renin and aldosterone after interruption of ACE inhibitor or ARB 
treatment may be warranted.   
Subjects who require initiation, interruption, dose modification, or reinstitution of CHF 
prophylaxis/treatment may continue ataluren dosing. 
6.4.4. 
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, CYP2C19, CYP2D6, and CYP3A4/5, and does not have induction potential on the 
major CYP enzymes.  
In vitro, ataluren is a weak inhibitor of CYP2C8 and CYP2C9, but in vivo drug-drug interactions 
mediated by these enzymes are not expected according to the criteria described in the EMA 
guideline on the investigation of drug interactions [EMA 2012].  As an added measure of safety, 
investigators should pay specific attention to use of drugs that are known substrates of these 
enzymes, particularly when such drugs may have a low therapeutic index.  The study manual 
includes a list of clinically available drugs that are metabolized by CYP2C8 or CYP2C9 so that 
investigators may use appropriate judgment in deciding how to monitor patients who may be 
receiving such substrates.  
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 and patients who require the use of these 
drugs will not be enrolled to the study.  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; thus, 
investigators should be aware that administration of ataluren may hypothetically change losartan 
effectiveness.  However, concomitant use of losartan and inhibitors of CYP2C9 has not been 
examined. 
 
6.4.5.   Other 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, phenobarbital, rifampin), or inhibitors of BCRP (eg, cyclosporine, 
eltrombopag, gefitinib), as these drugs may affect ataluren plasma concentrations. 


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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 concentrations of these 
drugs. 
Based on in vitro studies, ataluren is not expected to be an inhibitor or a substrate of p-gp 
mediated transport.   
Pharmacokinetic data indicate that no ataluren dose adjustment is required when ataluren is 
co-administered with systemic corticosteroids (deflazacort, prednisone, or prednisolone), and no 
corticosteroid dose adjustments are required when they are co-administered with ataluren.  
Co-administration of systemic corticosteroids with ataluren may cause more frequent instances of 
hypertension than does systemic corticosteroid use alone (without ataluren).  However, the blood 
pressure data available to date are not unequivocal about any contributory role of ataluren in 
development of hypertension in patients who are taking corticosteriods.   
6.4.6. 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.  Subjects should be 
discouraged from use of “health supplements” (eg, creatine, glutamine, coenzyme Q), herbal 
remedies, self-prescribed drugs, street drugs, tobacco products, or alcohol at any time during 
clinical studies of ataluren.   
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator.  The decision to 
authorize the use of any drug other than ataluren should take into account subject safety, the 
medical need, the potential for drug interactions, the possibility for masking symptoms of a more 
relevant underlying event, and whether use of a concomitant medication will compromise the 
outcome or integrity of the study.   
Subjects should be instructed about the importance of the need to inform the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during 
the course of the study.  Information regarding any concomitant drugs taken by a subject during 
the course of the study and the reason for use will be recorded in the source documents and in the 
concomitant medication CRF. 
6.5. Physical and Respiratory Therapy 
There are neither restrictions nor prescriptions for physical or respiratory therapy during the 
study.  Investigator sites should use local best practices in providing physical therapy support for 
patients participating in the study.  Respiratory care guidelines as suggested by the American 
Thoracic Society should be followed [ATS 2004].   


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6. 6.  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.   
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  4  b el o w.  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.  
 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
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P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 3 3  of 8 6  
 
a  
At al ur e n m a y b e i niti at e d a s s o o n a s  t h e in v e sti g at or c o nfir m s p ati e nt eli g i bilit y.  B a s eli n e pr o c e d ur e s ( e x cl u di n g dr u g a d mi ni str ati o n) 
d o n ot n e e d t o b e p erf or m e d if S cr e e ni n g pr o c e d ur e s h a v e b e e n p erf or m e d wit hi n 7 d a y s of a nti ci p at e d i niti ati o n of at al ur e n 
tr e at m e nt.  
b  
O nl y a p pli e s t o p ati e nt s w h o di s c o nti n u e t h e st u d y aft e r 2 4 0  w e e k s of tr e at 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 , D/ C = di s c o nti n u ati o n, E C G = el e ctr o c ar di o gr a m, T x = tr e at m e nt, U E = u p p er 
 
 
                       
                                
         T a bl e
T a bl e  4 .  S c h e d ul e of E v e nt s
.  S c h e d ul e of E v e nt s  
 
 
P eri o d  
S cr e e ni n g a  
B a s eli n e
a  
At al ur e n Tr e at m e nt  
P o st -Tr e at m e nt  
St u d y W e e k  
( ± 7 d a y s) 
-4 t o -1  
W e e k 1  
 
 
E v er y 6 0 
W e e k s  
E v er y 1 2 
W e e k s  
E v er y 2 4 
W e e k s  
E v er y 4 8 
W e e k s  
 
E n d of T x 
W e e k 2 4 0  
6 W e e k P o st D/ C  
I nf or m e d C o n s e nt 
{ 7. 2. 2} 
X  
 
 
 
 
 
 
 
Cli ni c al/ m e di c ati o n 
hi st or y { 7. 2. 3 } 
X  
 
 
 
 
 
 
 
H e p atiti s s cr e e n 
{7. 2. 4 } 
X  
 
 
 
 
 
 
 
Vit al si g n s { 7. 2. 5 } 
X  
X  
 
X  
 
 
X  
X  
Br o o k e U E 
F u n cti o n al R ati n g 
S c al e { 7. 2. 6 } 
X  
 
 
 
 
 
 
 
H ei g ht/ Ul n a 
l e n gt h/ Ar m S p a n 
{7. 2. 7 } 
X  
 
 
 
X  
 
X  
 
 
P h y si c al 
e x a mi n ati o n { 7. 2. 8 } 
X  
 
 
 
 
X  
X  
 
 
W ei g ht { 7. 2. 9 } 
X  
X  
 
X  
 
 
X  
X  
H e m at ol o g y 
{7. 2. 1 0 } 
X  
X  
 
X  
 
 
X  
 
X  
Bi o c h e mi str y 
{7. 2. 1 1 } 
X  
X  
 
X  
 
 
X  
 
X  
A C T H a n d c orti s ol 
{7. 2. 1 2 } 
X  
X  
 
X  
 
 
X  
X  
R e ni n a n d 
al d o st er o n e 
{7. 2. 1 2 } 
X  
                                                                              A s I n di c at e d  
Uri n al y si s { 7. 2. 1 3 } 
X  
X  
 
X  
 
 
X  
X  
1 2 -l e a d E C G 
{7. 2. 1 4 } 
X  
                                                                              A s I n di c at e d  
E c h o c ar di o gr a m 
{7. 2. 1 5 } 
X  
 
X  
 
 
X  
 
X b  
6 -mi n ut e w al k t e st 
{7. 2. 1 6 } 
X  
 
 
 
X  
 
X   
 
Ti m e d F u n cti o n 
T e st s { 7. 2. 1 7 } 
X  
 
 
 
 
 X  
X   
 
N ort h St ar 
A m b ul at or y 
A s s e s s m e nt 
{7. 2. 1 8 } 
X  
 
 
 
 
 X  
X   
 
E g e n Kl a s sifi k ati o n 
S c al e  { 7. 2. 1 9 } 
X  
 
 
 
 
X  
X   
 
S pir o m etr y { 7. 2. 2 0 } 
X  
 
 
 
X   
 
X   
 
Di s e a s e st at u s 
s ur v e y { 7. 2. 2 1 } 
X  
X  
 
X   
 
 
X   
 
Dr u g a d mi ni str ati o n 
{7. 2. 2 2 } 
 
X  
 
X   
 
 
 
 
Dr u g c o m pli a n c e 
{7. 2. 2 3 } 
 
 
 
X   
 
 
X   
 
A d v er s e e v e nt s 
{7. 2. 2 4 } 
 
X  
 
X   
 
 
X   
X  
C o n c o mit a nt 
m e di c ati o n s 
{7. 2. 2 5 } 
X  
X  
 
X   
 
 
X   
X  


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P a ge 3 4  of 8 6  
 
e xtr e mit y  
 
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.  Pr etr e at m e nt, Tr e at m e nt, a n d F oll o w -U p P eri o d s  
7. 2. 1. 1.  
S cr e e ni n g/ B a s eli n e P eri o d  
N o st u d y -relate d pr oce d ures s h o ul d be perf or me d pri or t o t he 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 hereafter, st u d y ca n di dates s h o ul d u n der g o t he i nitial set of  
scree ni n g pr oce d ures as n ote d i n Ta ble 4.  If a s u bject has s uccessf ull y c o m plete d t he necessar y 
scree ni n g assess me nts a n d has bee n c o nfir me d t o be eli gi ble b y t he i n vesti gat or, t he baseli ne visit 
f or t he s u bject ca n be c o n d ucte d a n d atal ure n treat me nt ma y be i nitiate d.  Atal ure n ma y be 
i nitiate d as s o o n as t he in ves ti gat or c o nfir ms patie nt eli gi bilit y.  Baseli ne pr oce d ures d o n ot nee d 
t o be perf or me d if scree ni n g pr oce d ures ha ve bee n perf or me d wit hi n 7  da ys of a ntici pate d 
i nitiati o n of atal ure n treat me nt.  T he s u bject  will re mai n at t he cli nic u ntil after st u d y dr u g f or t he 
ne xt 1 2  wee ks has bee n dis pe nse d a n d t he s u bject/care gi ver has bee n i nstr ucte d re gar di n g st u d y 
dr u g st ora ge , c o m plia nce, a n d a d mi nistrati o n . 
7. 2. 1. 2 . 
Tr e at m e nt Vi sit s d uri n g St u d y   
Eac h s u bject will s u bse q ue ntl y ret ur n t o t he cli nical researc h faci lit y d uri n g Wee k 1 2 ( Visit 3), 
Wee k 2 4 ( Visit 4), Wee k 3 6 ( Visit 5) , Wee k 4 8  ( Visit 6 ), Wee k 6 0 ( Visit 7), Wee k 7 2 ( Visit 8), 
Wee k 8 4 ( Visit 9) ,  Wee k 9 6 ( Visit 1 0) , Wee k 1 0 8 ( Visit 1 1), Wee k 1 2 0 ( Visit 1 2), Wee k 1 3 2 
( Visit 1 3),Wee k 1 4 4 ( Visit 1 4) , Wee k 1 56 ( Visit 1 5), Wee k 1 6 8 ( Visit 1 6), Wee k 1 8 0 ( Visit 1 7) ,  
Wee k 1 9 2 ( Visit 1 8) , Wee k 2 0 4 ( Visit 1 9), Wee k 2 1 6 ( Visit 2 0), Wee k 2 2 8 ( Visit 2 1)  a n d Wee k 
2 4 0 ( Visit 2 2) . 
7. 2. 1. 3 . 
E n d of Tr e at m e nt   
It is pla n ne d t hat eac h s u bject will ret ur n t o t he cli nical researc h facilit y at Wee k  2 4 0  ( Visit 2 2 ) 
f or t he E n d-of -Treat me nt Visit.  H o we ver, t his st u d y d urati o n ma y be altere d per t he c o n diti o ns 
n ote d i n Secti o n 6. 2. 1 .  I n t his case, t he ti mi n g of t he E n d-of -Treat me nt Visit , will be a dj u ste d 
a p pr o priatel y.   If t he patie nt ter mi nates t he st u d y earl y beca use atal ure n is c o m merciall y a vaila ble 
i n t hat c o u ntr y, t he n t he patie nt o nl y nee ds t o ret ur n f or t he E n d-of -Treat me nt Visit . 
If t he s u bject disc o nti n ues pre mat urel y, e x ce pt patie nts s witc hi n g t o c o m mercial atal ure n (ie, 
bef ore Wee k  2 4 0 ) a n d t he last visit t o t he i n vesti gator  site occ urre d > 3 wee ks pre vi o usl y, t he 
pr oce d ures t hat w o ul d n or mall y be perf or me d at Wee k  2 4 0  s h o ul d be perf or me d as a Pre mat ure 
Disc o nti n uati o n Visit bef ore t he s u bje ct lea ves t he st u d y.  
7. 2. 1. 4  
P o st -Tr e at m e nt Vi sit s  
All patie nts  w h o disc o nti n ue atal ure n m ust ret ur n f or a P ost -Treat me nt Visit at t he i n vesti gat or 
site 6 wee ks ( ± 7  da ys) after t he last d ose of atal ure n f or fi nal st u d y -relate d e val uati o ns.  If t he 
E n d -of -T reat me nt Visit occ urs > 6 wee ks after t he last d ose of atal ure n, t he P ost-Treat me nt Visit 
d oes n ot nee d t o be perf or me d.   F or patie nts disc o nti n ui n g t he st u d y t o tra nsiti o n t o c o m mercial l y 
a vaila ble atal ure n , a n E n d-of -Treat me nt visit s h o ul d be perf or me d f o r t hat patie nt. H o we ver, a 6-
Wee k P ost -Treat me nt Visit is n ot re q uire d f or t hese patie nts.  


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7.2.2. 
Informed Consent 
The investigator or sub-investigator must inform each prospective subject of the nature of the 
study, explain the potential risks, and obtain written informed consent/assent from the subject 
and/or the parent/legal guardian prior to performing any study-related screening procedures.  
Subjects will be re-consented with the appropriate age-related documents as needed, if required 
by local regulations. 
7.2.3. 
Clinical/Medication History 
The investigator should review the study candidate’s clinical history, including details relating to 
DBMD and any other medical conditions.  Information regarding current medications must be 
recorded in the source documents and on the concomitant medication CRF.   
7.2.4. 
Hepatitis Screen 
Tests include hepatitis A antibody, hepatitis B core antibody, and hepatitis C antibody.  The 
Central Laboratory Manual should be consulted for collection, processing, and shipping details.  
Note: Only hepatitis B and C results are required for eligibility determination. 
7.2.5. 
Vital Signs 
Vital signs (including systolic and diastolic blood pressure, pulse rate, and body temperature) 
will be monitored at Screening (Visit 1), Week 1 (Visit 2), Week 12 (Visit 3), Week 24 (Visit 4), 
Week 36 (Visit 5), Week 48 (Visit 6), Week 60 (Visit 7), Week 72 (Visit 8), Week 84 (Visit 9), 
Week 96 (Visit 10), Week 108 (Visit 11), Week 120 (Visit 12), Week 132 (Visit 13), Week 144 
(Visit 14), Week 156 (Visit 15), Week 168 (Visit 16), Week 180 (Visit 17), Week 192 (Visit 18), 
Week 204 (Visit 19), Week 216 (Visit 20), Week 228 (Visit 21) and Week 240 (Visit 22 End-of-
Treatment/Premature Discontinuation) and at the Post-Treatment Visit (6 weeks post 
discontinuation of ataluren).  The pulse rate and blood pressure determinations will be performed 
with the subject in a sitting position after a 5-minute rest.   
7.2.6. 
Brooke Upper Extremity Functional Rating Scale 
Upper extremity function will be assessed in all patients who are nonambulatory at study entry 
using the Brooke Upper Extremity Functional Rating Scale [Brooke 1981, Lue 2006, Florence 
1984]; this evaluation will be performed at Screening (Visit 1).  The Study Manual provides 
additional information regarding the performance of this procedure. 
7.2.7. 
Height/Ulna Length/Arm Span 
Height (in cm) will be measured at Screening (Visit 1), at Week 24 (Visit 4), Week 48 (Visit 6), 
and Week 72 (Visit 8), Week 96 (Visit 10), Week 120 (Visit 12), Week 144, Week 168 (Visit 
16), Week 192 (Visit 18), Week 216 (Visit 20) and Week 240 (Visit 22 End-of-
Treatment/Premature Discontinuation) in ambulatory patients. 
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 (Visit 1),Week 


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24 (Visit 4), Week 48 (Visit 6), and Week 72 (Visit 8), Week 96 (Visit 10), Week 120 (Visit 12), 
Week 144, Week 168 (Visit 16), Week 192 (Visit 18), Week 216 (Visit 20)  and Week 240 (Visit 
22 End-of-Treatment/Premature Discontinuation). 
7.2.8. 
Physical Examination  
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 
(Visit 1), at Week 48 (Visit 6 ), Week 96 (Visit 10), Week 144 (Visti 14), Week 192 (Visit 18),  
and Week 240 (Visit 22 End-of-Treatment/Premature Discontinuation). 
Physical exams may also be performed at any time during the study as clinically indicated. 
7.2.9. 
Weight 
Weight (in kg) will be measured at Screening (Visit 1), Week 1 (Visit 2), Week 12 (Visit 3), 
Week 24 (Visit 4), Week 36 (Visit 5), Week 48 (Visit 6), Week 60 (Visit 7), Week 72 (Visit 8), 
Week 84 (Visit 9), Week 96 (Visit 10), Week 108 (Visit 11), Week 120 (Visit 12), Week 132 
(Visit 13), Week 144 (Visit 14), Week 156 (Visit 15), Week 168 (Visit 16), Week 180 (Visit 17), 
Week 192 (Visit 18), Week 204 (Visit 19), Week 216 (Visit 20), Week 228 (Visit 21), Week 240 
(Visit 22 End-of-Treatment/Premature Discontinuation) and at the Post-Treatment Visit (6 weeks 
post discontinuation of ataluren). 
7.2.10. 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 (Visit 1), Week 1 (Visit 2), Week 12 (Visit 3), 
Week 24 (Visit 4), Week 36 (Visit 5), Week 48 (Visit 6), Week 60 (Visit 7), Week 72 (Visit 8), 
Week 84 (Visit 9), Week 96 (Visit 10), Week 108 (Visit 11), Week 120 (Visit 12), Week 132 
(Visit 13), Week 144 (Visit 14),Week 156 (Visit 15), Week 168 (Visit 16), Week 180 (Visit 17), 
Week 192 (Visit 18), Week 204 (Visit 19), Week 216 (Visit 20), Week 228 (Visit 21), Week 240 
(Visit 22 End-of-Treatment/Premature Discontinuation) and at the Post-Treatment Visit (6 weeks 
post discontinuation of ataluren).  Hematology parameters will be analyzed by the central 
laboratory.  The Covance Central Laboratory Manual should be consulted for collection, 
processing, and shipping details. 
7.2.11. 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 (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 (Visit 1), Week 1 (Visit 2), Week 12 (Visit 3), 
Week 24 (Visit 4), Week 36 (Visit 5), Week 48 (Visit 6), Week 60 (Visit 7), Week 72 (Visit 8), 
Week 84 (Visit 9), Week 96 (Visit 10), Week 108 (Visit 11), Week 120 (Visit 12), Week 132 


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(Visit 13), Week 144 (Visit 14), Week 156 (Visit 15), Week 168 (Visit 16), Week 180 (Visit 17), 
Week 192 (Visit 18), Week 204 (Visit 19), Week 216 (Visit 20), Week 228 (Visit 21), Week 240 
(Visit 22 End-of-Treatment/Premature Discontinuation) and at the Post-Treatment Visit (6 weeks 
post discontinuation of ataluren).  Subjects should have fasted for at least 8 hours prior to blood 
collection.  Biochemistry parameters will be analyzed by the central laboratory.  The Covance 
Central Laboratory Manual should be consulted for collection, processing, and shipping details. 
7.2.12. Adrenal Laboratory Assessments 
A plasma sample for ACTH and cortisol assessments will be collected.  These parameters will be 
measured at Screening (Visit 1), Week 1 (Visit 2), Week 12 (Visit 3), Week 24 (Visit 4), 
Week 36 (Visit 5), Week 48 (Visit 6), Week 60 (Visit 7), Week 72 (Visit 8), Week 84 (Visit 9) , 
Week 96 (Visit 10), Week 108 (Visit 11), Week 120 (Visit 12), Week 132 (Visit 13), Week 144 
(Visit 14, Week 156 (Visit 15), Week 168 (Visit 16), Week 180 (Visit 17), Week 192 (Visit 18), 
Week 204 (Visit 19), Week 216 (Visit 20), Week 228 (Visit 21), Week 240 (Visit 22 End-of-
Treatment/Premature Discontinuation) and at the Post-Treatment Visit (6 weeks post 
discontinuation of ataluren).  These parameters will be analyzed by the central laboratory.  The 
Central Laboratory Manual should be consulted for collection, processing, and shipping details. 
Aldosterone and renin pre-treatment values will be measured at Screening (Visit 1), and, as 
necessary, for patients with treatment emergent evidence of adrenal dysfunction.  These 
parameters will be analyzed by the central laboratory.  The Covance Central Laboratory Manual 
should be consulted for collection, processing, and shipping details. 
7.2.13. Urinalysis 
Urinalysis will include analysis for pH, specific gravity, glucose, ketones, blood, protein, 
urobilinogen, bilirubin, nitrite, and leukocytes.  These parameters will be measured at Screening 
(Visit 1), Week 1 (Visit 2), Week 12 (Visit 3), Week 24 (Visit 4), Week 36 (Visit 5), Week 48 
(Visit 6), Week 60 (Visit 7), Week 72 (Visit 8), Week 84 (Visit 9), Week 96 (Visit 10), Week 
108 (Visit 11), Week 120 (Visit 12), Week 132 (Visit 13), Week 144 (Visit 14), Week 156 (Visit 
15), Week 168 (Visit 16), Week 180 (Visit 17), Week 192 (Visit 18), Week 204 (Visit 19), Week 
216 (Visit 20), Week 228 (Visit 21), Week 240 (Visit 22 End-of-Treatment/Premature 
Discontinuation) and at the Post-Treatment Visit (6 weeks post discontinuation of ataluren).  
These parameters will be analyzed by the central laboratory.  Urine samples will also be collected 
and shipped to central laboratory for assessment of urine protein, creatinine, osmolality and 
urinalysis.  The Covance Central Laboratory Manual should be consulted for collection, 
processing, and shipping details.   
7.2.14. 12-Lead ECG 
A 12-lead ECG will be obtained at Screening (Visit 1) to establish a baseline tracing.  Thereafter 
during the study, ECGs should be obtained as clinically indicated.   
7.2.15. Echocardiogram 
An echocardiogram will be obtained at Screening (Visit 1), Week 60 (Visit 7), Week 108 (Visit 
11), Week 156 (Visit 15) and Week 216 (Visit 20).  In addition, an echocardiogram will be 


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obtained at the Post-Treatment Visit (6 weeks post discontinuation of ataluren) in patients who 
discontinue the study after 240 weeks of treatment. 
7.2.16. 6-Minute Walk Test 
6MWD will be assessed in those patients who are ambulatory (able to run/walk 10 meters in 
≤30 seconds) at study entry, using standardized procedures [McDonald 2010] (see Study 
Manual).  The 6MWT will be performed at Screening (Visit 1), Week 24 (Visit 4), Week 48 
(Visit 6), Week 72 (Visit 8), Week 96 (Visit 10), Week 120 (Visit 12), Week 144 (Visit 14), 
Week 168 (Visit 16), Week 192 (Visit 18), Week 216 (Visit 20) and Week 240 (Visit 22 End-of-
Treatment/Premature Discontinuation). 
7.2.17. Timed Function Tests 
Timed function tests will performed in those patients who are ambulatory at study entry, and 
include the time taken to stand from supine and time taken to run/walk 10 meters [Mendell 1989, 
Griggs 1991, Beenakker 2005a, Pradhan 2006] (see Study Manual).  These parameters will be 
monitored at Screening (Visit 1), Week 48 (Visit 6), Week 96 (Visit 10), Week 144 (Visit 14), 
Week 192 (Visit 18) and Week 240 (Visit 22 End-of-Treatment/Premature Discontinuation). 
 
7.2.18. North Star Ambulatory Assessment 
The NSAA will be used to evaluate physical function in those patients who are ambulatory at 
study entry, using standardized procedures (see Study Manual).  The NSAA will be performed at 
Screening (Visit 1), Week 48 (Visit 6), Week 96 (Visit 10), Week 144 (Visit 14), Week 192 
(Visit 18) and Week 240 (Visit 22 End-of-Treatment/Premature Discontinuation). 
7.2.19. Egen Klassifikation Scale 
Activities of daily living will be measured using the EK scale [Steffensen 2001] in 
nonambulatory patients (unable to run/walk 10 meters in ≤30 seconds).  The EK scale will be 
completed at Screening (Visit 1), Week 48 (Visit 6), Week 96 (Visit 10), and Week 144 (Visit 
14), Week 192 (Visit 18), and Week 240 (Visit 22 End-of-Treatment/Premature 
Discontinuation). 
 
Please refer to the Study Manual for further details on how to administer the EK scale. 
7.2.20. Spirometry 
Spirometry will be conducted in nonambulatory patients.  Spirometry will be performed at 
Screening (Visit 1), Week 24 (Visit 4), Week 48 (Visit 6), Week 72 (Visit 8), Week 96 
(Visit 10), Week 120 (Visit 12), Week 144 (Visit 14), Week 168 (Visit 16), Week 192 (Visit 18), 
Week 216 (Visit 20) and Week 240 (Visit 22 End-of-Treatment/Premature Discontinuation). 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
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7. 2. 2 1.  Di s e a s e St at u s S ur v e y  
F or all patie nts, a  disease stat us s ur ve y will be a d mi nistere d at Scree ni n g ( Visit 1) t o c ollect 
retr os pecti ve i nf or mati o n o n patie nt a n d/ or pare nt-re p orte d c ha n ges i n disease stat us d uri n g a n d 
after t heir partici pati o n i n t he pri or P T C  T hera pe utics  St u dies 0 0 7 a n d 0 0 7e.  
A se parate s ur ve y will be a d mi nistere d at Wee k 1 ( Visit 2), Wee k 1 2 ( Visit 3), Wee k 2 4 ( Visit 
4), Wee k 3 6  ( Visit 5 ), Wee k 4 8  ( Visit 6 ), Wee k 6 0 ( Visit 7), Wee k 7 2 ( Visit 8), Wee k 8 4 ( Visit 
9) , Wee k 9 6 ( Visit 1 0) , Wee k 1 0 8 ( Visit 1 1), Wee k 1 2 0 ( Vis it 1 2), Wee k 1 3 2 ( Visit 1 3), Wee k 
1 4 4 ( Visit 1 4 ),  Wee k 1 5 6 ( Visit 1 5), Wee k 1 6 8 ( Visit 1 6), Wee k 1 8 0 ( Visit 1 7) , Wee k 1 9 2 
( Visit 1 8), Wee k 2 0 4 ( Visit 1 9), Wee k 2 1 6 ( Visit 2 0), Wee k 2 2 8 ( Visit 2 1), Wee k 2 4 0 ( Visit 2 2 
E n d -of -Treat me nt/ Pre mat ure Disc o nti n uat i o n)   t o c ollect pr os pecti ve i nf or mati o n o n patie nt 
a n d/ or pare nt -re p orte d c ha n ges i n disease stat us. 
7. 2. 2 2.  St u d y Dr u g A d mi ni str ati o n  
S u bjects s h o ul d ta ke atal ure n TI D as descri be d i n Secti o n 6. 2. 2 .  Atal ure n  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 s u bject or care gi ver , as a p pr o priate.  T he 
patie nt is still re q uire d t o be at t he site f or t he 2 4 -wee k ( 6 -m o nt h) re -wei g h visit.  T he a m o u nt of 
st u d y dr u g s u p plie d t o t he s u bject ma y be a ltere d i n t he e ve nt of pe n di n g c o m mercial a vaila bilit y 
or ot her reas o ns as n ote d i n Secti o n 6. 2. 1 .  S ufficie nt dr u g will be pr o vi de d at eac h of t hese visits 
t o lesse n t he li keli h o o d t hat patie nts  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.   
Beca use of p ote ntial c ha n ges i n s u bject b o d y wei g ht o ver ti me, a n i n vesti gat or  site re prese ntati ve 
s h o ul d e nter t he s u bject’s c urre nt b o d y wei g ht i nt o t he I W R s yste m at Wee k 2 4, Wee k 4 8, Wee k 
7 2 , Wee k 9 6, Wee k 1 2 0 , Wee k 1 4 4, Wee k 1 6 8 , Wee k 1 9 2 a n d Wee k 2 1 6 t o o btai n st u d y dr u g 
d osi n g i nstr ucti o ns.  De pe n di n g u p o n t he ma g nit u de of c ha n ge i n s u bject b o d y wei g ht si nce 
baseli ne, t he n u m ber a n d t y pe of sac hets t o be use d b y t he s u bject ma y re mai n t he sa me or ma y 
be a dj uste d.   
7. 2. 2 3.  St u d y Dr u g C o m pli a n c e  
Atal ure n  c o m plia nce will be assesse d usi n g t he electr o nic case re p ort f or ms.  T he s yste m will 
d oc u me nt t he ret ur n of a n y u n use d dr u g sac hets f or c o m plia nce assess me nts.  
S u bjects or  care gi vers will ret ur n all u n use d sac hets of atal ure n t o t he i n vesti gat or site f or f ull 
c o m plia nce assess me nts.   
7. 2. 2 4.  A d v er s e E v e nt s  
A d verse e ve nts m ust be assesse 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 Wee k 1 ( Visit 2), Wee k 1 2 ( Visit 3), Wee k 2 4 ( Visit 4), Wee k 3 6 ( Visit 5), Wee k 4 8  
( Visit 6 ), Wee k 6 0 ( Visit 7), Wee k 7 2 ( Visit 8), Wee k 8 4 ( Visit 9), Wee k 9 6 ( Visit 1 0) , Wee k 
1 0 8 ( Visit 1 1), Wee k 1 2 0 ( Visit 1 2), Wee k 1 3 2 ( Visit 1 3), Wee k 1 4 4 ( Visit 1 4 ), Wee k 1 5 6 ( Visit 
1 5),  Wee k 1 6 8 ( Visit 1 6), Wee k 1 8 0 ( Visit 1 7), Wee k 1 9 2 ( Visit 1 8 ), Wee k 2 0 4 ( Visit 1 9), Wee k 
2 1 6 ( Visit 2 0),  Wee k 2 2 8 ( Visit 2 1), Wee k 2 4 0 ( Visit 2 2 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 atal ure n).  I n 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 4 0  of 8 6  
 
a d diti o n, patie nts /care gi vers will be e nc o ura ge 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. 
I n a d diti o n, a d verse e ve nts s h o ul d be e val uate d after t he P ost-Treat me nt Visit ( 6  wee ks p ost 
disc o nti n uati o n of atal ure n) u ntil a n y dr u g-relate d a d verse e ve nts a n d/ or o n g oi n g S A Es ha ve 
res ol ve d or bec o me sta ble, w hic he ver occ urs later.   
7. 2. 2 5.  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-d r 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 ( Visit 1), Wee k 1 ( Visit 2), Wee k 1 2 ( Visit 3), Wee k 2 4 ( Visit 4), 
Wee k  3 6  ( Visit 5 ), Wee k 4 8  ( Visit 6 ), Wee k 6 0 ( Visit 7), Wee k 7 2 ( Visit 8), Wee k 8 4 (Visit 9) , 
Wee k 9 6 ( Visit 1 0) , Wee k 1 0 8 ( Visit 1 1), Wee k 1 2 0 ( Visit 1 2), Wee k 1 3 2 ( Visit 1 3), Wee k 1 4 4 
( Visit 1 4), Wee k 1 5 6 ( Visit 1 5), Wee k 1 6 8 ( Visit 1 6), Wee k 1 8 0 ( Visit 1 7), Wee k 1 9 2 ( Visit 1 8 ), 
Wee k 2 0 4 ( Visit 1 9), Wee k 2 1 6 ( Visit 2 0),  Wee k 2 2 8 ( Visit 2 1), Wee k 2 4 0 ( Visit 2 2 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 atal ure n).  
7. 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 p pr o xi mate a m o u nts of bl o o d sa m ples t o be c ollect e d i n t he 
st u d y is pr o vi de d i n Ta ble  5 .  Ass u mi n g a 2 4 0 -wee k treat me nt of atal ure n, t he a p pr o xi mate 
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 2 2. 5 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 2 4 0 -wee k st u d y  peri o d (i ncl u di n g t he Scree ni n g visit, t he 2 4 0 -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 2 6 4. 5  m L.   A d diti o nal 
bl o o d c ollecti o n ma y be re q uire d i n t he e ve nt of a n a d verse e ve nts or la b orat or y a b n or malit y.     
T a bl e
T a bl e  5 .  Bl o o d Dr a wi n g R e q uir e m e nt s 
.  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  
2  
2  
1  
2 3  
4 6  
H e p atiti s s cr e e n  
S e r u m 
Cl ot  
G ol d  
3. 5  
3. 5  
1  
1  
3. 5  
Bi o c h e mi str y  
S er u m  
Cl ot  
G ol d  
5  
5  
1  
2 3  
1 1 5  
A C T H  
Pl a s m a  
E D T A  
L a v e n d er  
2  
2  
1  
2 3  
4 6  
C orti s ol  
Pl a s m a  
E D T A  
L a v e n d er  
2  
2  
1  
2 3  
4 6  
Al d o st er o n e a n d R e ni n  
Pl a s m a  
E D T A  
L a v e n d er  
8  
8  
1  
1  
8  
M a xi m u m T ot al  
 
 
 
 
 
 
 
2 6 4. 5  
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,  E D T A = et h yl e n e di a mi n et e tr a a c et at e 
 


Protocol Number PTC124-GD-019-DMD  
18 November 2015  
Version 5.0 
 
 
PTC Therapeutics, Inc.  – Confidential 
Page 41 of 86 
 
8. 
ADVERSE EVENT ASSESSMENTS 
8.1. 
Adverse Event Definitions 
8.1.1. 
Adverse Events 
An adverse event is any untoward medical occurrence associated with the use of a drug 
(investigational medicinal product) in humans, whether or not it is considered related to the drug.  
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease in a study subject who is administered ataluren in this 
study.   
For this protocol, untoward medical occurrences that should be reported as adverse events 
include the following: 
• All adverse events that are suspected to be due to ataluren.   
• Overdose (administration of an ataluren dose >4 times the highest intended total daily dose 
level for this protocol [>160 mg/kg/day]) of ataluren. 
• All reactions from medication misuse, abuse, withdrawal, sensitivity, or toxicity. 
• All reactions that result from medication errors or uses of the study drug outside what is 
described in the protocol. 
• Apparently unrelated illnesses, including the worsening of a preexisting illness. 
• Injury or accidents.  Note that if a medical condition is known to have caused the injury or 
accident (a fall secondary to dizziness), the medical condition (dizziness) and the accident 
(fall) should be reported as 2 separate adverse events.  The outcome of the accident (hip 
fracture secondary to the fall) should be recorded in source documents. 
• Abnormalities in physiological testing or physical examination findings that require clinical 
intervention or further investigation (beyond ordering a repeat [confirmatory] test). 
• Laboratory or ECG abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an already 
reported clinical event.  Laboratory abnormalities associated with a clinical event (eg, 
elevated liver enzymes in a subject with jaundice) should be captured in the source 
documents.  Laboratory abnormalities not requiring clinical intervention or further 
investigation will be captured as part of overall laboratory monitoring, and should not be 
reported as adverse events. 
• A preexisting condition (eg, allergic rhinitis) must be noted on the appropriate electronic 
CRF (eCRF) for Visit 1, but should not be reported as an adverse event unless the condition 
worsens or episodes increase in frequency during the adverse event reporting period.  
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 4 2  of 8 6  
 
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 urri 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 u rre 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 atal ure n a dmi nistrati o n ), 
i ncl u di n g deat hs d ue t o pr o gressi o n of DB M D .  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 
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 to atal ure n 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 s u bject 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 urr e 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 x cl u di n g 
h os pitalizati o ns f or a d mi nistrati o n of atal ure n, 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 s u bject t o t he h os pital a n d o bser vati onal 
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 
c o n d uct n or mal life f u ncti o ns, n ot relate d t o D B M D . 
•  A n y ot her me dicall y i mp 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 o ul 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 priate me dical 
j u d g me nt, t he y ma y je o par dize t he s u bject 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. 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 4 3  of 8 6  
 
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 B M D.  T hi s 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 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. 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 
atal ure n 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 us e 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 vasc 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 the  
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 
atal ure n.   
F or t he p ur p oses of c o nsi deri n g e x pecte d ness , Secti o n  9 of 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 s u bject 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 s u bject 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 visi t after 
atal ure n 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 s u bject 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 t he 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 nci se 
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 oll 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 ) 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 4 4  of 8 6  
 
•  Relati o ns hi p t o atal ure n (see Secti o n 8. 4 ) 
•  Se verit 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  6  be l o w, 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 ossi bilit y t hat t he st u d y dr u g ca use d t he a d verse e ve nt.  
T a bl e
T a bl e  6 .  R el ati o n s hi p of St u d y Dr u g 
.  R el ati o n s hi p of St u d y Dr u g 
to A d v er s e E v e nt
o A d v er s 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 por 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 o t 
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 s u bj e ct’ 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, o r 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 el 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 s u bj e ct’ 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 de 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 o n 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  7 . 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 4 5  of 8 6  
 
T a bl e
T a bl e  7 .  Gr a di n g
.  Gr a di n g  of A d v er s e E v e nt S e v erit y
of A d v er s 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 s u bj e c t’ 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 s u bj e ct’ 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 pt o m r e s ult s i n a p ot e nti al t hr e at t o lif e  
G r 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 m a 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  a b o ve.   
8. 6.  Pr e g n a n c y  of F e m al e P art n er s   
P T C  T hera pe utics s h o ul d be n otifie d  i n t he e vent t hat a fe male part ner of a s u bject bec o mes 
pre g na nt at a n y ti me after t he s u bject’s first d ose of atal ure n .  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 atal ure n  m ust be re p orte d o n  a 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 s u bject.   
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 s u bject  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 utic s 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 v erse 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 nal 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 s u bject 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 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 4 6  of 8 6  
 
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 s u bject 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 eri 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 atal ure n 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  a b o ve.  I n a d diti o n, S A Es occ urri n g i n a 
s ubject 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  8  bel o w . 
T a bl e
T a bl e  8 .  
.  I n v e sti g at or
I n v e sti g at or  Sit e R e p orti n g R e q uir e m e nt s 
Sit e R e p orti n g R e q uir e m e nt s 
foror  A d v er s e E v e nt s
A d v er s e E v e nt s
 
Cl a s sifi c ati o n  
R e p orti n g Ti m e  
R e p orti n g A cti o n  
S eri o u s  
Wit hi n 2 4 h o ur s  
T el e p h o n e c all , f a x, or e -m ail t o t h e P T C T h er a p e uti c s  S af et y 
D e p art m e nt  
Wit hi n 2 4 h o ur s  
F a x r e p ort or d o c u m e nt s c a n o n d e si g n at e d S A E r e p ort f or m t o 
t h e P T C T h er a p e uti c s  S af et y D e p art m e nt  a n d t o sit e I R B/I E C, 
a s p er l o c al I R B/I E C r e q uir e m e nt s  
Wit hi n 5 c al e n d ar d a y s  
P h ot o c o pi e s or d o c u m e nt s c a n of r el e v a nt C R F s ( e g, a d v er s e 
e v e nt f or m, m e di c al hi st or y f or m, c o n c o mit a nt dr u g/t h er a p y 
f or m) a n d s o ur c e d o c u m e nt sa  ( e g, pr o gr e s s n ot e s, n ur s e s’ 
n ot e s, l a b or at or y a n d di a g n o sti c t e st r e s ult s, di s c h ar g e 
s u m m ari e s) t o t h e P T C T h er a p e uti c s  S af et y D e p art m e nt  
P er C R F s u b mi s si o n pr o c e d ur e  
R e c or d a n d s u b mit i nf or m ati o n o n a p pr o pri at e C R F s  
N o n s eri o u s  
P er C R F s u b mi s si o n pr o c e d ur e  
R e c or d a n d s u b mit i nf or m ati o n o n a p pr o pri at e C R F s  
a  
S u bj e ct n a m e, a d dr e s s, a n d ot h er p er s o n al i d e ntifi er s s h o ul d b e o b s c ur e d.  
A b br e vi ati o n s:  C R F = c a s e r e p ort f or m, I R B/I E C = 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,  
S A E = S eri o u s A d v e r s e E v e nt 
 
F or S A Es, i n a d diti o n t o c o m pleti n g t he a d verse e ve nt p orti o n of t he C R F, t he S A E re p ort f or m 
m ust als o be c o m plete d.  T he S A E re p ort f or m s h o ul d be si g ne d b y t he i n vesti gat or; h o we ver, if 
t he i n vesti gat or is u na ble t o si g n at t he ti me of t he e ve nt or wit hi n 2 4  h o urs, t he f or m s h o ul d be 
si g ne d b y t he cli nical staff me m ber re p orti n g t he S A E (e g, t he st u d y c o or di nat or).  T he S A E 
re p ort f or m m ust be fa x e d or e maile d t o t he P T C T hera pe utics  Safet y De part me nt  a n d t o t he site 
I R B/I E C (if re q uire d b y l ocal re g ulati o ns) wit hi n 2 4 h o urs.  F oll o w u p i nf or mati o n t o t he S A E 
s h o ul d be clearl y d oc u me nte d as “f oll o w u p” i n t he S A E re p ort f or m a n d m ust als o be fa x e d or 
e maile d t o t he sa me part y.  All f oll o w u p S A E re p ort f or ms f or t he e ve nt m ust be si g ne d b y the 
i n vesti gat or.  A n y s o urce d oc u me nts (e g, pr o gress n otes, n urses’ n otes, la b orat or y a n d dia g n ostic 
test res ults, disc har ge s u m maries) pr o vi de d t o t he s p o ns or s h o ul d be re dacte d s o t hat t he patie nt’s 
na me, a d dress, a n d ot her pers o nal i de ntit y i nf or mati o n are o bsc ure d.  O nl y t he patie nt’s st u d y 
n u m ber a n d i nitials are t o be pr o vi de d.  T he i nf or mati o n i n t he a d verse e ve nt p orti o n of t he C R F 
a n d t he S A E re p ort f or m(s) m ust matc h or be rec o ncile d.  W here t he sa me data are c ollecte d, t he 


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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 subject 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.   
 
 
 
 
 
 
8.10. PTC Therapeutics Adverse Event Reporting Requirements 
As the sponsor of the study, PTC Therapeutics is responsible for reporting certain safety 
information, particularly SAEs and subject deaths related to participation in the study, to each 
investigator in an expedited manner.  If notification of an adverse event requiring expedited 
reporting to investigators is received, PTC Therapeutics or its designated representative will 
contact each investigator site participating in this study by e-mail, fax, and/or overnight mail such 
that the investigator can promptly notify the site IRB/IEC per their local requirements.  The 
initial expedited safety report will be provided as required according to local regulations (eg, 
within 15 days) after the earliest date PTC Therapeutics or an agent of PTC Therapeutics (eg, a 
site monitor) becomes aware of an adverse event.  This awareness date is the date the regulatory 
reporting clock begins and the date is considered Day 0. 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 4 8  of 8 6  
 
 
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 atal ure n s h o ul d re mai n i n t he st u d y w he ne ver p ossi ble.   Treat me nt wit h 
atal ure n i n t he c o nte xt of t his pr ot oc ol is a ntici pate d t o occ ur f or 2 4 0  wee ks.  T he act ual d urati o n 
of atal ure n treat me nt u n der t his pr ot oc ol will be s u bject t o t he f oll o w i n g c o n diti o ns: 
•  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 atal ure n 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 atal ure n treat me nt, 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 ult ati 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 atal ure n treat me nt, 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.   
•  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 atal ure n.  
•  T he patie nt ma y be wit h dra w n fr o m t his st u d y if he is eli gi ble t o partici pate i n a n ot her 
atal ure n - n m D B M D cli nical st u d y or pr o gra m.  
•  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 treat me nt is disc o nti n ue d a n d t he reas o n f or disc o n ti 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 M A PI  me dical m o nit or a n d t he P T C me dical 
m o nit or  s h o ul d be i nf or me d via e-mail of w he n a s u bject is disc o nti n ues st u d y treat me nt .   
W he n st u d y treat me nt 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 
u nt o war d effects .  T he patie nt  s h o ul d be e nc o ura ge d t o see k a p pr o priate f oll o w-u p f or a n y 
c o nti n ui n g healt h pr o ble ms .   
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  
1 0. 1.  S a m pl e Si z e C al c ul ati o n f or t h e Pri m ar y E n d p oi nt  
T he p o ol of patie nts p ote ntiall y eli gi ble f or t his st u d y is descri be d b y  i ncl usi o n criteri o n 2 of  
Secti o n  4. 2 .  He nce t he sa m ple size is deter mi ne d b y h o w ma n y s uc h patie nts satisf y all 
i ncl usi o n/e x cl usi o n criteria w he n a p pl yi n g f or partici pati o n i n t his st u d y a n d n ot b y  a n y f or mal 
statistical h y pot hesis.   


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10.2. Study Population Definition 
10.2.1. As-Treated Population 
The as-treated population consists of all patients who receive at least 1 dose of ataluren.  This 
population will be evaluated in the analyses of safety (the primary endpoint) and treatment 
administration.  
10.3. General Statistical Considerations 
By-patient listings will be created for each CRF module. 
Summary tables for continuous variables, overall and by corticosteroid use, will contain the 
following statistics: n, mean, standard deviation, standard error, 95% confidence intervals (CIs) 
on the mean, median, minimum, and maximum.  In addition, changes from baseline will be 
likewise summarized.  
Summary tables for categorical variables, overall and by corticosteroid use, will include N, n, and 
percentages.   
In addition to a stand-alone analysis of data from this study, the data may be interpreted in 
conjunction with corresponding data from other alaluren studies. 
10.4. Specific Statistical Analyses  
10.4.1. Study Conduct and Subject Disposition 
Subjects who discontinue ataluren prematurely or are removed from the study prematurely will 
be reported.  Reasons for screening failures and early discontinuations, and time of withdrawal 
from study will be described. 
10.4.2. Baseline Characteristics  
Subject characteristics at entry into the study will be summarized in frequency tables and 
descriptive statistics will be provided for quantitative variables.   
10.4.3. Study Treatment Administration 
For each patient, ataluren administration will be described in terms of the total duration of 
therapy, dose modifications, dose delays, and dose omissions; and reasons for deviations from 
planned therapy.   
10.4.4. Use of Concomitant Medication and Supportive Therapy 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHODRUG) dictionary into Anatomical-Therapeutic-Chemical classification (ATC) codes.  
The type and timing of use of specific concomitant medications will be listed and summarized.   
Specific attention will be focused on corticosteroid use and use of drugs for 
prophylaxis/treatment of CHF.  The type and duration of pre-study use will be described.  The 
type, dose, schedule, duration of use, dose modifications, dose omissions, and reasons for 
deviations from initial therapy will be described. 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 5 0  of 8 6  
 
1 0. 4. 5.  Pri m ar y V ari a bl e s  
1 0. 4. 5. 1.  A d v er s e E v e nt s  
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 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 treat me nt -e mer ge nt a d verse e ve nt is defi n e d as a n a d verse e ve 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 patie nt’s first atal ure n d ose i n t his st u d y t o 6 
wee ks after t he last atal ure n d ose i n t his st u d y.  
T he fre q ue nc y of patie nts  e x perie nci n g a s pecific a d verse e ve nt will be ta b ulate d b y visit, 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 usi n g t he w orst C T C A E gra de. 
A d verse e ve nts classifie 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.  
1 0. 4. 5. 2.  L a b or at or y D at a  
He mat ol o gical, ser u m bi oc he mistr y, a dre nal la b orat o ries, a n d uri ne data 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.  He mat ol o gical, 
ser u m bi oc he mistr y, a dre nal la b orat ories, a n d uri ne data 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 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 nts  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.  S u m mar y ta bles will be prese nte d f or eac h rele va nt assa y t o s h o w t he n u m ber of 
patie nts  b y se verit y gra de wit h c orres p o n di n g perce nta ges.  S u bjects will be c haracterize d o nl y 
o nce f or a gi ve n assa y, base d o n t heir w orst se verit y gra de o bser ve d d uri n g t he ti me peri o d of 
i nterest.   
S hift ta bles f or he mat ol o g y, ser u m bi oc he mistr y, a dre nal la b ora t ories, a n d uri ne data will als o be 
prese nte d s h o wi n g c ha 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 hic 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 ha 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]).  
Se parate listi n gs a n d ta bles will be create d f or para meters f or assess me nt of a dre nal, he patic, a n d 
re nal m o nit ori n g base d o n t he c o n diti o ns liste d i n Secti o n  6. 3 .   
1 0. 4. 5. 3.  P h y si c al Fi n di n g s  
P h ysical fi n di n gs ( wei g ht, p h ysical e x a mi nati o n data, 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 ) will be liste d a n d s u m marize d b y visit.  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 usi n g t he paire d t -test or a 
n o n para metric alter nati ve.    
1 0. 4. 6.  S e c o n d ar y V ari a bl e s  
1 0. 4. 6. 1.  6 -Mi n ut e W al k T e st  
T he dista nce wal ke d at eac h visit a n d t he c ha n ge fr o m baseli ne i n t he dista nce wal ke d at eac h  


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postbaseline visit, as obtained from the 6MWT, will be summarized descriptively. Only the 
results of the patient’s best valid test at each visit will be included in the analysis.  Changes from 
baseline in 6MWD at each postbaseline visit will be analyzed using paired t-tests.  All data from 
the 6MWTs, valid or invalid, will be listed by patient and visit, with invalid results flagged. 
The 6MWD at each visit will be converted into a percent-predicted 6MWD value through the use 
of a relevant reference equation.  The percent-predicted 6MWD value at each visit and the 
change from baseline in the percent-predicted 6MWD value will be summarized descriptively.  
Only the results of the patient’s best valid test at each visit will be included in the analysis.  
Changes from baseline at each postbaseline visit will be analyzed using paired t-tests.  All 
percent-predicted 6MWD values, valid or invalid, will be listed by patient and visit, with invalid 
results flagged. 
10.4.6.2. Timed Function Tests 
Timed function test data (time taken to stand from supine and time taken to run/walk 10 meters) 
will be summarized by visit and the changes in the variable from baseline to each post-baseline 
visit and summarized descriptively.  The changes from baseline to each postbaseline visit will be 
analyzed using paired t-tests. 
10.4.6.3. North Star Ambulatory Assessment 
Data from the North Star Ambulatory Assessment will be summarized by visit and the changes in 
the variable from baseline to each postbaseline visit and will be summarized descriptively.  The 
changes from baseline to each postbaseline visit will be analyzed using paired t-tests. 
10.4.6.4. Egen Klassifikation Scale 
EK scale results will be summarized by visit and the changes in the variable from baseline to 
each postbaseline visit and will be summarized descriptively.  The changes from baseline to each 
postbaseline visit will be analyzed using paired t-tests.  
10.4.6.5. 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 subject and visit and 
summarized by visit.  Ulna length and arm span will be used for separate calculation of %-
predicted parameters.  The within-subject 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. 
10.4.6.6. Disease Status Survey 
Disease status survey data will be listed by subject and visit; these data will be summarized by 
visit.  For the prospective survey data, changes from baseline to each scheduled visit and to the 
final visit will be summarized descriptively. Data from the retrospective survey will be 
summarized and compared with other subject characteristic and outcome measure data generated 
from this study and Studies 007 and 007e. 


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10.4.7. Exploration of Correlations 
Correlations between subject characteristics and outcome measures and correlations among 
outcomes measures may be explored using regression models or other appropriate techniques.   
11. STUDY COMMITTEE 
11.1. Data Monitoring Committee 
A DMC, operating autonomously from the sponsor and the clinical investigators, will be 
responsible for providing independent recommendations to PTC Therapeutics about evolving 
risk-benefit observed in the course of the study and any modifications required during the course 
of the study.  The DMC will comprise physicians experienced in treating DMD and a 
biostatistician.  The DMC will be chaired by one of these individuals.  DMC members must not 
be actively involved in study design, conduct, or daily management of this study and must not 
have financial, proprietary, professional, or other interests that may affect impartial, independent 
decision-making.  Specialists may be invited to participate as non-voting members at any time if 
additional expertise is desired 
The DMC will operate under a charter developed as a collaborative document between the DMC 
and PTC Therapeutics.  The primary responsibility of the DMC is to protect the safety and 
welfare of subjects participating in this clinical study and to ensure the integrity of the clinical 
study.   
In general, the DMC will be responsible for: 
• Examining accumulated safety, efficacy, and other relevant data at prespecified points 
during the course of the study in order to make recommendations concerning 
continuation, termination, or modification of the study 
• Reviewing major study design modifications proposed prior to implementation of those 
modifications 
• Reviewing the general progress of the study  
• Providing expert advice to the PTC Therapeutics members on an ad hoc basis regarding 
matters such as safety concerns or diagnostic evaluations in individual subjects 
Based on the results of its deliberations, the DMC can recommend continuation of the study 
unchanged, study interruption, study termination, modification of the study, or alteration in the 
DMC monitoring plan.  
 


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12. OBLIGATIONS OF THE INVESTIGATOR AND THE SPONSOR 
12.1. Compliance with Ethical and Regulatory Guidelines 
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the Declaration of Helsinki and the International Council on Harmonisation (ICH) GCP 
guidance documents. 
12.2. Institutional Review Board/Independent Ethics Committee 
Prior to enrollment of patients into the study, as required by the FDA and other regulatory 
authorities, the protocol and informed consent document will be reviewed and approved by an 
appropriate IRB/IEC.  By signing the Statement of Investigator Form (FDA Form 1572), the 
investigator assures that approval of the study protocol will be obtained from the IRB/IEC and 
that all aspects of the IRB/IEC review will be conducted in accordance with current regulations.  
Amendments to the protocol will be subject to the same IRB/IEC review requirements as the 
original protocol.  Only changes necessary to eliminate apparent immediate hazards to the 
patients may be initiated prior to IRB/IEC approval.  In that event, the investigator must notify 
the IRB/IEC and PTC Therapeutics in writing within 5 working days after implementation.  The 
investigator will also promptly notify the IRB/IEC of any serious, unexpected adverse events, or 
any other information that may affect the safe use of the drug during the course of the study.   
A letter documenting the IRB/IEC approval and a list of the names and titles of the IRB/IEC 
members must be received by PTC Therapeutics prior to the initiation of the study.  All 
correspondence with the IRB/IEC should be retained in the investigator’s study file.   
The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to PTC Therapeutics.  As soon as possible after completion or termination of the 
study, the investigator will submit a final report to the IRB/IEC and to PTC Therapeutics.  This 
report should include the dates of initiation and completion of the study, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the protocol, the 
number and type of patients evaluated, the number of patients who discontinued (and the reasons 
for discontinuation), the number of patients who completed the study, and the results of the 
study, including a description of any adverse events.  PTC Therapeutics will assist the 
investigator in the preparation of this report, as needed. 
12.3. Informed Consent/Assent 
By signing the Statement of Investigator (FDA Form 1572), the investigator assures that 
informed consent/assent will be obtained from each patient and/or parent/legal guardian prior to 
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 


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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, ataluren 
disposition records, correspondence with the IRB/IEC, adverse event reports, and information 
regarding patient discontinuation and completion of the study.  Current regulations require 
PTC Therapeutics (or an authorized designee) to inspect all documents and records required to be 
maintained by the investigator, including but not limited to medical records (office, clinic, or 
hospital) for the patients enrolled in this study.  These regulations also allow the same records to 
be inspected by authorized representatives of the FDA or other regulatory authorities.   


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 5 5  of 8 6  
 
1 2. 6.  C o nfi d e nti alit y  
Researc 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 str ict 
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 n s 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 stat e 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 ns 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 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 E C 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 atal ure n 
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  a b o ve) 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 gat or 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.   
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 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 


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regulations, and investigator’s obligations are being fulfilled; and resolve any inconsistencies in 
the study records.  This includes inspection of all documents and records required to be 
maintained by the investigator, including but not limited to medical records (office, clinic, or 
hospital) for the patients in this study.  The names and identities of all research patients will be 
kept in strict confidence and will not appear on eCRFs or other records provided to or retained by 
PTC Therapeutics.  The investigator/institution guarantees direct access to source documents by 
PTC Therapeutics and appropriate regulatory authorities. 
The investigator site may also be subject to review by the IRB/IEC, to quality assurance audits 
performed by PTC Therapeutics or a designee, and/or to inspection by the FDA and/or other 
regulatory authorities.  The IND regulations also require the investigator to allow authorized 
representatives of the FDA to inspect and make copies of the same records.   
It is important that the investigator and relevant institutional personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.   
12.9. Termination of the Study 
PTC Therapeutics reserves the right to discontinue the study prior to inclusion of the intended 
number of patients.  The investigator, after consultation with the PTC Therapeutics medical 
monitor, reserves the right to discontinue the study at the investigator site for safety reasons at 
any time.   
After a decision to terminate the study, investigators must contact all patients who are continuing 
their participation in the study and must do so within a time-period set by PTC Therapeutics.  As 
directed by PTC Therapeutics, all study materials must be collected and all electronic data entry 
forms completed to the greatest extent possible. 
12.10. Public Notification of Study Conduct 
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICJME) as a 
condition of consideration for publication of study results, PTC Therapeutics will be responsible 
for ensuring that this protocol is listed at the ClinicalTrials.gov website and that information at 
the website relating to study design and conduct is appropriately updated during the course of the 
study.  In order to facilitate this process, investigators will need to supply PTC Therapeutics with 
appropriate contact information for investigator site personnel. 
12.11. Dissemination of Results 
The information developed during the conduct of this clinical study is considered confidential by 
PTC Therapeutics.  This information may be disclosed as deemed necessary by 
PTC Therapeutics. 
To allow for the use of the information derived from this clinical study and to insure compliance 
with current regulations, the investigator is obliged to provide PTC Therapeutics with complete 
test results and all data developed in this study.  The information obtained during this study may 
be made available by PTC Therapeutics to other physicians who are conducting similar studies 


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1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 5 7  of 8 6  
 
a n d t o t he F D A o r 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 utics 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 n t 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 p e 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, F or m F D A 1 5 7 2, i n vesti gat or fi na ncial disc l 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 d verse 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 . 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 5 8  of 8 6  
 
 
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.  G e n er al  
T his st u d y is a n o pe n -la bel safet y a n d t olera bilit y st u d y i n pre vi o usl y treate d atal ure n patie nts 
wit h n m D B M D .  C o nsiste nt wit h G C P g ui deli nes, pare nts/ g uar dia ns a n d patie nts  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 nts  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 nts  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, or e val uati o n.   
1 3. 1. 2.  R e q uir e d L a b or at or y V al u e s  
I n ge neral, t he re q uire d la b orat or y val ues f or eli gi bilit y are necessar y i n or der t o i m ple me nt t he 
safet y m o nit ori n g pla n descri be d i n Secti o n 6. 3. 1 . 
1 3. 1. 3.  R e pr o d u cti v e C o n si d er ati o n s  
Atal ure n is n ot ge n ot o xic, di d n ot affect fertilit y i n male a n d fe male rats, a n d was n ot terat o ge nic 
i n rats a n d ra bbits.  I n a d diti o n, lac k of se x ual mat urit y i n m ost of t he patie nts  li kel y t o be 
e nr olle d i n t his st u d y li mits re pr o d ucti ve ris ks.  H o we ver, restricti o n o n eli gi bilit y relati n g t o 
willi n g ness t o a v oi d u n pr otecte d se x ual i nterc o urse i n a n y patie nts  k n o w n t o  be se x uall y acti ve is 
i ncl u de d as a ge neral preca uti o n. 
1 3. 1. 4.  Pri or a n d C o n c o mit a nt T h er a pi e s  
C o n ve nti o nal s u p p orti ve t hera pies will be per mitte d; h o we ver, eff orts will be ma de t o a v oi d use 
of c o nc o mita nt me dicati o ns t hat mi g ht c o nf o u n d i nter pretati o n of st u d y res ults 
(e g, a mi n o gl yc osi des) or p ose a safet y ris k (i m m u n os u p pressi ve t hera p y ot her t ha n 
c ortic oster oi ds).  Atal ure n has n ot pr o ve d aller ge nic i n st u dies perf or me d t o date, b ut re vie w of 
k n o w n aller gies t o e x ci pie nts c o ntai ne d i n t he f or m ulati o n is pr u de n t. 
P har mac o ki netic data i n dicate t hat n o atal ure n d ose a dj ust me nt is re q uire d w he n atal ure n is c o-
a d mi nistere d wit h s yste mic c ortic oster oi ds  ( deflazac ort, pre d nis o ne, or pre d nis ol o ne), a n d n o 
c ortic oster oi d  d ose a dj ust me nt s are re q uire d w he n t he y are c o-a dmi nistere d wit h atal ure n.  
C o -a d mi nistrati o n of s yste mic c ortic oster oi ds wit h atal ure n ma y ca use m ore fre q ue nt i nsta nces of 
h y perte nsi o n t ha n d oes s yste mic c ortic oster oi d use al o ne ( wit h o ut atal ure n).  H o we ver, t he bl o o d 
press ure data a vaila ble t o date are  n ot u ne q ui v ocal a b o ut a n y c o ntri b ut or y r ole of atal ure n i n 
de vel o p me nt of h y perte nsi o n i n patie nts w h o are ta ki n g c ortic osteri o ds.   
As t he pri mar y r o ute of atal ure n meta b olis m is via gl uc ur 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, 
C Y P 2 B 6, C Y P 2 C 1 9, C Y P 2 D 6, a n d C Y P 3 A 4/ 5, a n d d oes n ot ha ve i n d ucti o n p ote ntial o n t he 
maj or C Y P e nz y mes.  


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In vitro, ataluren is a weak inhibitor of CYP2C8 and CYP2C9, but in vivo drug-drug interactions 
mediated by these enzymes are not expected according to the criteria described in the EMA 
guideline on the investigation of drug interactions [EMA 2012].  As an added measure of safety, 
consideration should be given when ataluren is administered concomitantly with drugs that have 
narrow therapeutic indices and are primarily metabolized by CYP2C8 (eg, paclitaxel) or 
CYP2C9 (eg, warfarin and phenytoin), to avoid any risk of increased concentrations of these 
drugs. 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 not expected to be an inhibitor or a substrate of p-gp 
mediated transport.   
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, phenobarbital, rifampin), or inhibitors of BCRP (eg, cyclosporine, 
eltrombopag, gefitinib), as these drugs may affect ataluren plasma concentrations. 
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 concentrations of these 
drugs.   
  Other restrictions relating to recent use of experimental drugs or surgery allow candidates 
sufficient time to recover before proceeding to ataluren dosing.  Restrictions against enrollment 
of patients expected to have major surgical procedures during the course of the study or who 
have substantial respiratory or cardiac compromise are intended to avoid safety problems or gaps 
in ataluren administration in patients who require intensive supportive care.   
13.2. Treatment Rationale 
13.2.1. Ataluren Schedule and Dose Selection 
Dosing based on body weight will continue to be employed.  Such dosing is common in 
pediatrics and reduces variability in exposure by accommodating differences in patient size 
across the span of ages of the boys who will participate in the clinical study program.   


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
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P a ge 6 0  of 8 6  
 
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 ge t 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 ma 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  
Beca use  atal ure n t hera p y will be a d mi nistere d c hr o nicall y if t he c o m p o u n d recei ves re g ulat or y 
a ut h orit y a p pr o val, it is i m p orta nt t o c o nti n ue t o c ollect l o n g-ter m safet y a n d efficac y data d uri n g 
t he atal ure n de vel o p me nt  pr o gra m .  This o pe n -la bel st u d y is e x pecte d t o ge nerate a d diti o nal 
l o n g-ter m safet y a n d efficac y i nf or mati o n at t he pla n ne d d ose d le vel.  T his i nf or mati o n will 
s u p ple me nt data o btai ne d i n patie nts wit h n mD B M D  w h o recei ve d atal ure n i n a pri or P T C 
cli nical st u d y.  
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 of mil d tra nsa mi nase ele vati o ns i n healt h y v ol u nteers partici pati n g 
i n P hase 1 st u dies, a n d a dre nal a n d re nal fi n di n gs i n i n di vi d ual t o xic ol o g y s pecies, a s pecific 
safet y m o nit ori n g pla n f or t he tar get or ga ns t hat t hese t y pes of a b n or malities re prese nt 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.  
T he i nte nt is t o pr otect patie nts , o btai n a th 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 atal ure n 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 uri n g t he c o urse of t he st u d y; safet y fi n di n gs deser vi n g partic ular atte nti o n  
i ncl u de he patic, a dre nal, re nal, a n d electr ol yte a b n or malities.  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 atal ure n i m me diatel y, f or i nterr u pti n g atal ure n 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 atal ure n w hile e val uati n g f or 
p ote ntial dr u g -relate d t o xicit y.   
1 3. 2. 3. 1.  H e p ati c A b n or m aliti e s  
1 3. 2. 3. 1. 1.   O v er vi e w  
W hile t o xic ol o g y st u dies i n  mice, rats, a n d d o gs di d n ot i n dicate a d verse c ha n ges i n he patic 
pat h ol o g y or ser u m a mi n otra nsferase le vels, atal ure n a d mi nistrati o n d uri n g P hase 1 st u dies i n 
healt h y v ol u nteers was ass ociate d wit h Gra de 1, re versi ble tra nsa mi nase ele vati o ns i n A L T a n d 
A S T [ Hira wat 2 0 0 7].  D uri n g P hase 2a testi n g, ser u m tra nsa mi nase le vels ha ve te n de d t o 
i m pr o ve i n b ot h D M D a n d c ystic fi br osis patie nts  ( per ha ps i n dicati n g e vi de nce of res p o nse t o 


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treatment).  Thus, while clinical risk appears low, specific follow-up of markers of liver injury in 
this study is warranted. 
13.2.3.1.2.  Hepatic Monitoring Plan 
Muscle breakdown results in ALT and AST values that are commonly 10- to 20-fold > ULN 
(Grade 3-4) in patients with DBMD.  Consequently, it is not practical to exclude patients with 
high serum AST or ALT concentrations from enrollment in this study, and monitoring for 
hepatotoxicity must rely primarily on following patients for increases in bilirubin or GGT.  
Consistent with well-established guidelines [Abboud 2007] applied in this disease setting, even 
modest (Grade 2) alteration in bilirubin or GGT values should prompt interruption of ataluren.  
While serum ALT or AST values cannot routinely serve as measures of hepatic injury in boys 
with DBMD, significant increases in ALT (>150 U/L) in conjunction with a stable or falling CK 
should prompt increased frequency of laboratory monitoring and possibly an evaluation for 
potential hepatotoxicity. 
13.2.3.2. Adrenal Abnormalities 
13.2.3.2.1.  Overview 
Adrenal findings were noted in dogs receiving ataluren for ≥20 weeks.  Anatomic findings 
included decreased adrenal weights and lymphohistiocytic infiltration with adjacent foci of 
parenchymal degeneration in the adrenal cortex.  The morphology was not consistent with an 
immune-mediated hypoadrenalism (Addison’s disease) and the dogs were asymptomatic 
throughout the entire study duration.  These findings did not reverse at the end of 4 and  
8 weeks of recovery following 20 and 52 weeks of dosing.  An increase in serum basal 
adrenocorticotropic hormone (ACTH) values was observed and ACTH stimulation testing  
indicated that all dogs showed responses with increases in serum cortisol levels.  However, 
because the magnitude of the cortisol response was not as great in animals receiving the mid- and 
high-dose of ataluren (500 and 1000 mg/kg/day) in comparison to controls, a no observed 
adverse effect level (NOAEL) for adrenal cortical function at the lowest ataluren dose level (250 
mg/kg/day) was established.  Consistent with lack of involvement of the zona glomerulosa, 
serum aldosterone values were unaffected and no serum electrolyte changes were seen.  Steady 
state exposure in dogs at 250 mg/kg/day is ~0.8-fold the exposure in patients administered 
ataluren at the morning, midday, and evening doses of 10, 10 and 20 mg/kg/day, respectively.  
No drug-related effects on the adrenal gland have been seen in mice dosed for 26 weeks or in rats 
dosed for 24 months. 
It is possible that patients participating in the ataluren studies could experience events similar to 
those occurring in animals.  Pending the acquisition of further clinical safety information, a 
program of adrenal monitoring for patients receiving ataluren is being instituted using 
well-established techniques.   
13.2.3.2.2. Adrenal Monitoring Plan 
Adrenal monitoring in boys with DBMD presents unique challenges given the prevalence of 
chronic corticosteroid use in this population.  While assessments of adrenal function in boys who 
are not using corticosteroids is straightforward, regular administration of prednisone or 
deflazacort to boys with DBMD is expected to induce secondary adrenal atrophy and reductions 


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in circulating glucocorticoids that may obscure the biochemical detection of potential 
ataluren-mediated adrenal toxicity.  While this situation might seem concerning, it should be 
realized that boys who are receiving supraphysiological doses of corticosteroids are protected 
against endogenous hypoproduction of cortisol due to any cause [Ten 2001, Kyriazopoulou 
2007].   
In this context, the proposed monitoring plan for adrenal toxicity relies upon repeated assessment 
of tandem plasma markers – ACTH and cortisol to assess functional changes in glucocorticoid 
production, and secondary assessments of renin and aldosterone to measure mineralocorticoid 
production.  Such use of these markers builds on evolving paradigms for semi-annual or annual 
monitoring adrenal function in individuals at high risk of primary autoimmune adrenal failure 
[Barker 2005, Coco 2006] and the well-established physiology of the adrenal gland and 
associated endocrine organs [Oelkers 1996].   
In the evaluation of glucocorticoid function, it is understood that progressive primary failure of 
the adrenal gland results in decreased cortisol production and diminished negative feedback on 
pituitary gland generation of ACTH.  In humans with an intact hypothalamic-pituitary-adrenal 
(HPA) axis, the pituitary gland compensates by progressively increasing plasma ACTH to 
maintain plasma cortisol levels.  Cortisol production is preserved until adrenal cortical reserves 
become so low that ACTH hyperstimulation is no longer sufficient and cortisol concentrations 
finally fall.  Thus, an early harbinger of a failure of primary glucocorticoid production is the 
detection of an elevated plasma ACTH concentration with a normal or falling cortisol level 
[Ketchum 1984, Oelkers 1992, De Bellis 1993, Blevins 1994].  Similar negative feedback loops 
exist for the renin-angiotensin-aldosterone system.  In this situation, primary loss of aldosterone 
production in the adrenal results in compensatory hyperproduction of renin by the kidney.  Thus, 
the earliest sign of a failure of mineralocorticoid production is the detection of an elevated 
plasma renin concentration with a normal or falling plasma aldosterone level [Ketchum 1984, 
De Bellis 1993, Betterle 2002].   
Based on the findings of ataluren-associated effects on the ACTH-cortisol axis in the dog, 
assessments of plasma ACTH and cortisol are clearly warranted, especially in patients who are 
not receiving exogenous corticosteroids.  In patients who are taking corticosteroids, endogenous 
plasma ACTH and cortisol levels will generally be low and the diagnostic sensitivity will be 
blunted.  However, abnormal elevations of ACTH in this circumstance would still be a specific 
indication of glucocorticoid insufficiency and so should be monitored during ataluren dosing 
[Ten 2001]. 
The dog toxicology data do not indicate an ataluren-related risk of compromised 
mineralocorticoid production.  Additionally, clinical measures of renin and aldosterone are 
markedly affected by age and normal reference ranges are very narrow.  In boys who are taking 
ACE inhibitors or ARBs as prophylaxis/treatment of CHF, plasma renin values may be elevated 
and plasma aldosterone levels may be low due to these drugs [Azizi 1997, Hansen 1999].  For 
such patients, plasma renin and aldosterone concentrations may not prove useful as adrenal 
monitoring tools.  Given these limitations, reliance will primarily be placed on monitoring of 
ACTH and cortisol values; routine assessment of the renin-aldosterone axis will only be 
performed if evidence of compromised corticosteroid production is observed.  To facilitate 


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assessment of the renin-aldosterone axis in patients with treatment-emergent evidence of adrenal 
dysfunction, baseline renin and aldosterone values will be obtained in all patients prior to 
initiating treatment with study drug.   
Based on these considerations, elevations of plasma ACTH should prompt confirmation of the 
elevated value, reassessment of cortisol levels, further diagnostic evaluation (potentially 
including ACTH stimulation testing [Dorin 2003]), and possible interruption of ataluren dosing.  
If patients who are not already receiving corticosteroids develop ataluren-related adrenal 
insufficiency, physiological replacement therapy with corticosteroids and/or mineralocorticoids 
can be instituted according to well-established protocols [Oelkers 1992, Ten 2001, 
Kyriazopoulou 2007].    
13.2.3.3. Renal Abnormalities 
13.2.3.3.1. Overview 
Renal findings were seen in mice receiving 1 or 2 doses through 26 weeks of doses of ataluren.  
A NOAEL for the renal toxicity findings in mice has not been identified; the lowest observed 
adverse effect level (LOAEL) = 75 mg/kg/day.  Exposure in mice at 75 mg/kg/day is 0.3-fold the 
exposure in  patients administered ataluren at the morning, midday, and evening doses of 10, 10 
and 20 mg/kg/day, respectively. The renal finding was seen primarily in the distal nephron and 
involved some degenerative changes (apoptosis) and proliferation of renal epithelium.  Renal 
tubular dilatation and proteinaceous material within the tubules also were seen.  The structural 
integrity of the nephron was maintained, as degenerative/necrotic changes of large numbers of 
cells were not seen.  A few glomeruli in the upper cortex were shrunken but the overall lesion did 
not primarily involve the glomeruli. The finding was occasionally accompanied by individual 
increases in serum blood urea nitrogen (BUN) and/or creatinine, however, a dose relationship for 
these parameters was not observed.  The kidney findings were partially to completely reversible 
as soon as 2 weeks after cessation of dosing.  The renal toxicity was observed in mice only, and 
has not been seen in rats dosed for 24 months or in dogs dosed for 52 weeks despite achievement 
of exposures in rats and dogs that were comparable to or greater than those observed in mice.  In 
Phase 1 studies in healthy volunteers and Phase 2 studies in patients with DMD and cystic 
fibrosis, renal laboratory abnormalities have been infrequent. 
During the Phase 2b double-blind study of ataluren in nmDMD (PTC124-GD-007-DMD), small 
increases in mean serum creatinine, BUN, and cystatin C were observed.  The values tended to 
stabilize early in the study and did not increase further with continued treatment. 
Renal abnormalities were observed in an international, multicenter, double-blind, placebo-
controlled Phase 3 trial evaluating ataluren in patients ≥6 years of age with nonsense mutation 
cystic fibrosis in patients receiving concomitant ataluren and IV aminoglycosides (as described in 
the Ataluren Investigator Brochure).  In patients who require treatment for serious infections, 
investigators should substitute other antibiotics for systemic aminoglycosides when clinically 
appropriate.  If IV aminoglycosides are administered, study drug must be interrupted during the 
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Study drug interruption should be considered with concomitant use of other potentially 
nephrotoxic antibiotics (eg, vancomycin).  Caution should be exercised during concomitant use 
of other potentially nephrotoxic agents. 
Patients requiring IV aminoglycoside or vancomycin therapy should be closely monitored in an 
appropriate setting.  In patients receiving potentially nephrotoxic antibiotics such as IV 
aminoglycosides or vancomycin, antibiotic drug levels and serum creatinine and BUN should be 
followed closely.  The antibiotic trough level and creatinine and BUN should be measured within 
24 to 48 hours of administration of the first antibiotic dose, and further antibiotic dosing should 
be based on these results.  Trough levels should be measured at intervals during the course of 
antibiotic treatment.  Creatinine and BUN should be measured prior to initiating IV 
aminoglycoside or vancomycin therapy and at least twice a week during the course of antibiotic 
treatment.   
Overall, the renal monitoring program included in this protocol considers nonclinical and clinical 
findings with ataluren, past experience with known nephrotoxicants, manifestations of DBMD, 
and current knowledge regarding exploratory renal toxicity biomarkers.  A focus is placed on 
well-established clinical indictors of renal dysfunction for making diagnostic decisions and 
prompting treatment interruptions/ modifications in individual patients.  The rationale for each of 
the decision-making parameters is discussed below.     
13.2.3.3.2. Renal Monitoring Plan  
• Serum Cystatin C:  GFR is a requisite component of renal testing to evaluate glomerular 
and nephron integrity.  While “gold standard” methods of determining GFR (eg, infusions of 
inulin, iohexol, iothalamate, or technetium 99m-diethylenetriamine pentaacetic acid 
[99m-Tc-DTPA] with timed blood and urine assessments) can be employed, these methods are 
cumbersome and are often reserved for renal physiology laboratories at specialized centers 
[Guignard 2004, Stevens 2007].  In clinical practice, assessments of GFR have more typically 
relied upon determination of creatinine clearance during 24-hour urine collections or 
calculation based on nomograms using only serum creatinine.  It is generally acknowledged 
that 24-hour urine collection in children is inaccurate and impractical due to compliance 
issues [Guignard 2004].  Calculation of GFR using only measurement of serum creatinine has 
long been standardized for children [Schwartz 1987].  However, because it is both filtered 
and secreted by the kidney, serum creatinine is acknowledged to be relatively imprecise and 
insensitive marker of renal damage [Herget-Rosenthal 2007, Schwartz 2007].  Moreover, 
serum creatinine is subject to variation based on endogenous and exogenous factors.  This 
problem is particularly concerning in boys with DMD because the majority of creatinine in 
serum is derived from muscle [Wang 1996] and boys with DMD have decreased serum 
creatinine concentrations due to reduced muscle mass.  A review of baseline serum creatinine 
values among the 38 boys with DMD participating in the ataluren Phase 2a study indicates 
low serum creatinine values (median 0.3, range 0.1-0.5 mg/dL).  Additional sources of 
variability for boys with DMD may include ingestion of creatine (a substrate for creatinine 
production) [Escolar 2005] and treatment-mediated alterations in muscle fragility [Mendell 
1989].   


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As an alternative to assessing GFR based on serum creatinine, serum cystatin C offers 
substantial advantages in the context of this protocol.  Cystatin C is a low-molecular-weight 
[~13 kDa] proteinase inhibitor derived from all cells that is filtered by the glomerulus and 
degraded in the renal tubules [Herget-Rosenthal 2007].  The serum cystatin C concentration 
is almost solely dependent upon GFR and appears relatively unaffected by muscle mass or 
other conditions.  An additional advantage is that circulating cystatin C changes more rapidly 
in response to multiple types of renal injury than creatinine [Herget-Rosenthal 2007].  
Methods for measuring cystatin C are standardized and the correlations between serum 
cystatin C and GFR have been derived and confirmed in large studies involving healthy 
children and adults and those with renal dysfunction [Dharnidharka 2002, Grubb 2005, 
Zappitelli 2007].  Based on these considerations, values of serum cystatin above 1.33 mg/L 
should prompt diagnostic evaluation and interruption/modification of ataluren if required per 
protocol. 
• Serum Creatinine:  Given the widespread clinical familiarity with serum creatinine as a 
marker of renal dysfunction and as a monitoring tool for nephrotoxins in clinical practice 
[Gilead 2002, Gilead 2006, Novartis 2005], characterization of serum creatinine provides an 
appropriate frame of reference relative to other experiences.  Because most participating boys 
with DMD are expected to have low normal values of serum creatinine due to reduced 
muscle mass, any values higher than the normal range may be cause for concern.  Caveats 
regarding interpretation of serum creatinine in boys with DMD (particularly if there are 
food- or treatment-induced changes in serum creatinine values) dictate that an increase in 
serum creatinine above the age-specific normal range should prompt reevaluation of other 
safety parameters and potential interruption/modification of ataluren dosing. 
• Serum Blood Urea Nitrogen: Considering its role in maintaining urine-concentrating 
ability, urea has major importance in renal physiology and its clinical measurement as a 
marker of renal dysfunction is long established.  In the context of nephrotoxicity, elevations 
in BUN suggest disruption of tubular integrity [Vonderscher 2007].  In the nonclinical mouse 
studies of ataluren in which nephrosis was observed, BUN was elevated in some of the 
affected animals, confirming that this marker should also be measured in clinical studies of 
ataluren.  Monitoring serum BUN, like monitoring creatinine, provides an additional frame of 
reference relative to other markers assessed within this study and in other studies of known 
nephrotoxicants.  However, an elevation in BUN is not a specific signal of renal tubular 
injury, but also may reflect compromised renal tubular blood flow due to depressed cardiac 
output, medications, or dehydration [Guignard 2004, Stevens 2007].  For these reasons, a 
BUN increase ≥1.5 x ULN should prompt a review of potential pre-renal, renal, and 
post-renal causes for the abnormality as well as consideration of potential 
interruption/modification of ataluren dosing. 
• Urine Protein:Creatinine and Urine Protein:Osmolality Ratio: Proteinuria can be an early 
marker for renal injury in experimental models [Amin 2004] and is commonly observed with 
even modest clinical decreases in renal function [National Kidney Foundation 2002].  
Glomerular disease (eg, diabetic nephropathy) is often associated with albuminuria due to 
defects in exclusion of plasma proteins in the glomerular filtrate.  Tubular injury (eg, as 


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observed in mice receiving ataluren) more often leads to increases in low-molecular-weight 
proteins (eg, beta-2 microglobulin, β2-microglobulin, α1-microglobulin retinol-binding 
protein, lysozyme) as tubular protein catabolism is compromised or proteins of injury are 
produced [Guignard 2004, Stevens 2007].  Because mice that developed nephrosis while 
receiving ataluren had proteinaceous material in the renal tubules on histological 
examination, monitoring of urine protein in humans receiving ataluren is additionally 
warranted.   
Dipstick methods of protein screening are only semiquantitative, are relatively insensitive, 
and are confounded by exogenous substances and subjective interpretation [Kim 2007].  The 
presence of urinary protein may be masked in dilute urine or exaggerated in concentrated 
urine.  For these reasons, a quantitative method of accessing proteinuria is planned in this 
study.  Two methods will be assessed: urinary protein concentration relative to urinary 
creatinine concentration [Ginsberg 1983, Schwab 1987]. and urinary protein concentration 
relative to urine osmolality [Wilson 1993, Morgenstern 2003].  These methods of screening, 
using spot urine samples, have been found to be as accurate as and more practical than 
quantification of urine protein during a 24-hour collection.  Values for protein:creatinine of 
≥0.2 mg/dL:mg/dL and of protein:osmolality of ≥0.15 mg/L:mOsm/kg have been established 
as abnormal [Morgenstern 2003].  While measurement of protein:creatinine is generally the 
preferred method in children [Morgenstern 2003], it is possible that low urinary creatinine 
excretion in boys with DMD may falsely elevate protein:creatinine ratios.  For this reason, 
confirmed evidence that both measures are abnormal should stimulate further evaluation and 
intervention.  Follow-up methods such as urine electrophoresis may be useful in 
discriminating among the types of proteins present and may suggest a site of injury (eg, an 
albumin-specific pattern with glomerular damage versus a diffuse multiple 
low-molecular-weight protein pattern with tubular damage) [Stevens 2007].  Confirmed 
proteinuria should prompt consideration of interruption/modification of ataluren dosing. 
• Urine Blood:  Blood in the urine may indicate pathology of the renal parenchyma or of the 
urinary collecting system (eg, ureters, bladder, and urethra).  Like proteinuria, hematuria is 
commonly found in patients with minimal changes in GFR due to renal (particularly 
glomerular) dysfunction [National Kidney Foundation 2002].  Confirmed, persistent evidence 
of urinary blood by dipstick and/or microscopic examination will prompt further evaluation.  
Ultrasound or other imaging can evaluate for a potential renal cause for bleeding.  Urology 
consultation can be obtained to assess for post-renal sources of hematuria.  Clotting function 
and use of drugs that may impair platelet function will be reviewed.  Confirmed, persistent 
hematuria in the absence of a post-renal source of bleeding or a bleeding diathesis will 
prompt potential interruption/modification of ataluren dosing. 
• Serum Electrolytes: Assessments of serum electrolytes (sodium, chloride, potassium, 
bicarbonate, magnesium, calcium, and phosphorus) provide information regarding renal 
function that may supplement more primary assessments.  Derangements in serum 
concentrations may reflect altered tubular handling of these ions.  With worsening renal 
function, hyperphosphatemia and hypocalcemia may develop and reductions in serum 
bicarbonate or elevations in potassium may suggest an impaired ability of proximal tubules 
or collecting ducts to maintain acid-base balance [National Kidney Foundation 2002].  


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Given the cardiovascular and neurological consequences of severe derangements of serum 
potassium, calcium, or magnesium, evaluation of these ions is important to avoid potential 
secondary complications.  Because transient Grade 1 alterations in the concentrations of 
electrolytes are very unlikely to be associated with significant secondary side effects, 
alterations to ≥Grade 2 are considered appropriate to prompt potential 
interruption/modification of ataluren dosing. 
 
13.2.3.4 Lipid Profile 
During the Phase 2b double-blind study of ataluren in nmDMD (PTC124-GD-007-DMD), mean 
total cholesterol and triglycerides were in the upper range of normal at baseline and increased on 
study, reaching borderline high or high values.  Although the values tended to stabilize early in 
the trial and did not increase further with continued use of ataluren, monitoring the changes in 
patients’ lipid profile is warranted.  For this reason, total cholesterol, LDL, HDL, and 
triglycerides will be evaluated at each visit to monitor for changes in lipid profile values. 
 
13.2.3.5 Blood Pressure Assessment 
During the Phase 2b double-blind study of ataluren in nmDMD (PTC124-GD-007-DMD), 6 
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).  For this reason, blood pressure will be monitored via standardized procedures at each 
visit. 
   
13.2.3.6 Other Non-Clinical Findings 
Single lipomatous, non metastatic tumors, determined to be malignant hibernomas originating in 
brown adipose tissue were identified in 6 rats during a 26 week toxicity study.  In a second 26 
week rat study, no malignant hibernomas were observed in any dose group, including the high 
dose group (1200 mg/kg/day).  The exact correlative relevance of this finding is unclear given the 
lack of reproducibility in rats, the different physiology of brown fat in rats relative to humans 
[Cannon 2004, Iatropoulos 2004], the very young age of the rats used in these studies, the lack of 
ataluren genotoxicity, and the extreme rarity and generally benign course of hibernomas in 
humans [Furlong 2001].   
Urinary bladder tumors were observed in 3/60 females at the high dose of 300 mg/kg/day in the 
24-month carcinogenicity study in rats.  This dose exceeded the maximum tolerated dose (MTD), 
based on an average 23% reduction in body weight gain in comparison to vehicle controls 
throughout the study.  In addition, the proposed mode of urinary bladder tumor formation 
(presence of calculi) in rats is not considered relevant to humans.  Mean steady state exposures in 
female rats at the mid-dose of 100 mg/kg/day and in male rats at the high-dose of 300 mg/kg/day 
were 4 and 6 times, respectively, the steady state exposure in patients administered ataluren at the 
morning, midday and evening doses of 10, 10 and 20 mg/kg/day, respectively. 


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
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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 d ies, 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. 4  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 n g) e ve nt s h oul d res ult i n i m me diate cessati o n of d osi n 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 mpt f urt her e val uati o n w hile atal ure n 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. 5  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 ost ic 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 M A PI  or P T C T hera pe utics me dical m o nit or 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, e n d ocri n 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 h e 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 verse e ve nt ma y still  be a ble t o c o nti n ue wit h d osi n g at a l o wer atal ure n d ose.  
I nterr u pti o n of d osi n g 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 atal ure n.   


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13.2.6 
Efficacy Measurements 
13.2.6.1 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, 
including the neuromuscular, pulmonary, and cardiovascular systems [Takeuchi 2008].  
Based on precedent in other neuromuscular disorders [Rubin 2002, Wraith 2004, Muenzer 2006], 
the 6MWT represents an appropriate approach to assessing ambulatory ability in boys with 
DBMD.  A change in performance on the 6MWT constitutes a clinically meaningful endpoint 
and improvements would be a direct reflection of benefit to boys with DBMD. The 6MWT is 
feasible, accurate, and reproducible in the target population [McDonald 2010]. 
13.2.6.2 Timed Function Tests 
These tests provide additional measures of ambulatory capability in boys with DMD who can 
still walk.  Commonly employed over many years [Brooke 1989, McDonald 1995], these tests 
are relevant to the disease in that they assess functional aspects of proximal muscle strength 
required for everyday ambulation.  Timed function tests are substantially abnormal in boys with 
DMD compared to healthy boys [Beenakker 2005b].  Worsening values have been correlated 
with time to wheelchair dependency [Brooke 1989, McDonald 1995].  These tests can be 
sensitive to medical intervention; corticosteroid therapy has documented improvements in all 3 
parameters [Mendell 1989, Griggs 1991, Beenakker 2005a].  Given their long-standing use and 
simplicity, there is substantial experience with the conduct of the tests and the analyses of the 
data and very high reproducibility has been demonstrated [Mayhew 2007].  
13.2.6.3 North Star Ambulatory Assessment 
The NSAA is a functional scale specifically designed for ambulant DMD boys.  The scale has 
been developed and piloted in the United Kingdom by the North Star Clinical Network for 
Paediatric Neuromuscular Disease Management with good intra and interobserver reliability and 
has recently been used in a large multicenter study [Mazzone 2011]. 
The scale includes items assessing abilities that are necessary to remain functionally ambulant, 
ie, ability to rise from the floor, ability to get from lying to sitting and sitting to standing, and that 
are known to progressively deteriorate in untreated DMD patients.  The scale also includes items 
assessing head raise and standing on heels that can be partly present in the early stages of the 
disease and a number of activities such as hopping, jumping, and running [Mazzone 2010]. 
13.2.6.4 Egen Klassifikation 
For nonambulatory patients with DMD, the EK scale has been selected to assess functional 
ability after loss of ambulation [Steffensen 2001]. The EK scale has previously been shown to be 
highly reliable when tested for intra- and inter-rater reliability among patients with DMD 
[Steffensen 2002a, Steffensen 2002b]. 
13.2.6.5 Spirometry 
Progressive pulmonary dysfunction is a major source of disability and shortened survival 
associated with DMD and represents an important target for therapeutic intervention.  Natural 


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history data in DMD show that pulmonary values decline more precipitously once patients lose 
ambulation [Steffensen 2002b].   
Based on experience at measuring pulmonary function in randomized trials [Mendell 1989, 
Griggs 1991], it is clear that spirometry testing can be performed practically in multicenter 
studies enrolling study populations comparable to those to be enrolled into this study.  Standard 
operating procedures for spirometry performance, requiring that spirometric effort is sufficient 
and that each test is consistent with American Thoracic Society/European Respiratory Society 
guidelines [Miller 2005a, Miller 2005b] will be used.   
13.2.6.6 Disease Status Surveys 
Information on patient and/or parent-reported changes in disease status (eg. disease symptoms 
and activities of daily living) during and after their participation in the prior PTC Therapeutics 
Studies 007 and 007e will be collected retrospectively through the use of a standardized survey 
administered by site personnel.  
A separate survey will be administered by site personnel during the study to collect prospective 
information on patient and/or parent-reported changes in disease status. 
 
14 
BENEFITS AND RISKS 
14.1 Benefits and Risks – Non-Clinical 
Ataluren is an orally bioavailable small molecule intended for the treatment of nonsense 
Duchenne muscular dystrophy (nmDMD) resulting from a nonsense mutation in the dystrophin 
gene.  In cellular assays and animal models of genetic disease, ataluren demonstrated the ability 
to specifically and selectively enable readthrough of mRNA containing a premature stop codon, 
inducing production of full-length protein that localizes to the appropriate cellular location and is 
functionally active.  Ataluren consistently enabled mRNA readthrough and functional full-length 
protein production from mRNAs that contain a premature stop codon without promoting 
readthrough of normal stop codons.   
Ataluren was shown to be selective for translation.  Ataluren did not alter levels of mRNA with 
premature stop codons or wild type mRNA demonstrating that ataluren does not modify 
transcription or mRNA stability.  In cell-free translation assays, ataluren functions at the level of 
translation and not transcription.  Ataluren does not produce a functional protein by promoting 
readthrough of premature stop codons due to frameshift mutations (insertions or deletions) or of 
mRNAs harboring multiple sequential premature stop codons.  Ataluren is selective for 
premature stop codons and does not promote readthrough of normal stop codons.  In cellular 
models of nonsense mutation genetic diseases, ataluren exhibited a bell-shaped concentration 
response with maximal activity at 10 μg/mL.  At ataluren concentrations above 20 µg/mL a 
reduction in activity is observed, indicating a bell-shaped dose response.  Cytotoxicity was not 
observed at any concentration tested.  In animal models, ataluren exhibited a bell-shaped 
dose-response.  In vitro and in vivo nonclinical efficacy pharmacology data indicate that 
concentrations that range from ~1 to 20 μg/mL were associated with pharmacodynamic activity.  


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Specifically, in the mdx mouse model, efficacy was associated with concentrations ranging from 
2 to 10 μg/mL.   
Toxicokinetic data were obtained in toxicity studies conducted in mice, rats, rabbits and dogs.  
Consistent with the short t½, there was no accumulation of drug in plasma upon repeated daily 
dosing.  In all species, ataluren exposure increased with increasing dose, but the increase was 
generally less than dose proportional.  There were no sex-related differences in ataluren exposure 
in dogs, but in rats and mice, exposure was slightly higher in females than in males.  The major 
metabolite seen in mice, rats and dogs was ataluren acyl glucuronide; exposure to this metabolite 
in the toxicology species at LOAELs, NOAELs, and NELs in the toxicology program was greater 
than the exposure observed in humans administered the clinical dose of 10, 10 and 20 mg/kg/day 
at morning, midday, and evening, respectively.  Ataluren is highly bound (> 97%) to plasma 
proteins in all species, including human.  Ataluren is neither a substrate for nor an inhibitor of p-
glycoprotein.  Enzyme inhibition studies with human liver microsomes showed that ataluren has 
a weak potential for direct inhibition of CYP2C8 and CYP2C9.  As an added measure of safety, 
investigators should pay specific attention to use of drugs that are known substrates of these 
enzymes, particularly when such drugs may have a narrow therapeutic index.  Enzyme induction 
evaluations in human hepatocytes showed that ataluren did not induce the activities of CYP450 
enzymes.   Induction of metabolism by ataluren is not expected since slight increases in CYP2B6 
and CYP2C9 activity are observed only at an ataluren concentration that is 3- to 5-fold higher 
than the average peak concentration after a 20 mg/kg dose.     
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, phenobarbital, rifampin), or inhibitors of BCRP (eg, cyclosporine, 
eltrombopag, gefitinib). 
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 


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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 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.  
Currently, treatment is palliative.  No therapies that address the underlying cause of the disease 
are available. 
Decline in ambulation is the hallmark of DMD, and the major goal of intervention during the 
ambulatory phase of DMD is to maintain ambulation for as long as possible.  Ataluren at a dose 
of 10, 10, 20 mg/kg slowed the decline in ambulation in nonsense mutation DMD patients.  In 
the placebo-controlled study, Study 007, the targeted difference of 30 meters between ataluren 
10, 10, 20 mg/kg and placebo in the 6-minute walk distance (6MWD) was achieved (Δ=31.3 
meters, adjusted p=0.0561, cITT analysis).  The 30-meter distance meets the threshold for 
minimal clinically important difference in DMD and other diseases, and is in the range of the 
6MWD results for approved therapies in a variety of conditions.  The 30-meter distance is 
meaningful to DMD patients, providing greater ability to walk in their daily lives, for example, 
walking to and from the school bus and taking part in social activities. 
The time-to-event analysis of 6MWD progression further showed that ataluren 10, 10, 20 mg/kg 
slowed disease progression in patients with nmDMD.  Only 26% of patients who received 
ataluren 10, 10, 20 mg/kg, compared with 44% of the patients who received placebo, had 
persistent 10% worsening in the 6MWD at Week 48 (adjusted p=0.0652, cITT analysis).  
Delaying ambulatory decline provides direct clinical benefit by affording boys with nmDMD a 
longer period of self-sufficiency before transitioning to full-time wheelchair use.  Maintenance of 


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ambulatory capacity can prevent, delay the onset of, or reduce the severity of scoliosis, a 
debilitating complication of DMD, and is beneficial to the patient’s pulmonary status.   
Positive trends in secondary endpoints in Study 007 support the 6MWD results.  Patients who 
were treated with ataluren 10, 10, 20 mg/kg trended toward less decline in muscle function than 
patients who were treated with placebo and met the threshold (~1.5 seconds) for clinically 
meaningful differences.  Among the TFTs, the largest effect for ataluren 10, 10, 20 mg/kg was 
seen in stair climbing, which is one of the most difficult activities of daily living for patients with 
DMD.  Positive trends, favoring ataluren 10, 10, 20 mg/kg over placebo, were also observed for 
timed function test method grading, accidental fall frequency, activity and wheelchair use in the 
community setting, myometry, and patient-reported physical functioning domain of the PedsQL.  
The consistency of these findings across outcome measures supports a treatment effect of 
ataluren 10, 10, 20 mg/kg in patients with nmDMD. 
The higher dose in Study 007, 20, 20, 40 mg/kg, did not differentiate from placebo in the primary 
endpoint, 6MWD.  The inverse dose response prompted an analysis of efficacy measures by 
ataluren plasma concentration in the ataluren clinical trials.  Across 3 clinical trials (placebo-
controlled Study 007 and open-label Studies 007e and 004e), ataluren concentration-response 
analyses in patients who were treated with ataluren 20, 20, 40 mg/kg showed better results for the 
6MWT and timed function tests (TFTs) in patients whose plasma ataluren concentrations were in 
the range of those observed with ataluren 10, 10, 20 mg/kg, than in patients with higher plasma 
concentrations.  This inverse concentration-response relationship is supported by the population 
PK-PD model of 6MWT data.  These clinical findings are consistent with nonclinical studies of 
ataluren (in the DMD mouse model and other disease models) as well as other nonsense mutation 
read-through drugs, which show a bell-shaped concentration-response relationship.  These 
analyses explain the inverse dose-response seen in Study 007 and support the proposed dose of 
ataluren 10, 10, 20 mg/kg.   
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 


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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 
represents the first disease-modifying therapy for this severely disabling, progressive, and, 
ultimately fatal disease.   
This is 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. 


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administration in Duchenne patients with premature stop codon.  Preliminary results.  Acta Myol.  
2003 May;22(1):15-21. 
Pradhan S, Ghosh D, Srivastava NK, Kumar A, Mittal B, Pandey CM, Singh U.  Prednisolone in 
Duchenne muscular dystrophy with imminent loss of ambulation.  J Neurol.  2006 
Oct;253(10):1309-16. 
Ramaciotti C, Heistein LC, Coursey M, Lemler MS, Eapen RS, Iannaccone ST, Scott WA.  Left 
ventricular function and response to enalapril in patients with Duchenne muscular dystrophy 
during the second decade of life.  Am J Cardiol.  2006 Sep 15;98(6):825-7. 
Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, 
Leconte I, Landzberg M, Simonneau G.  Bosentan therapy for pulmonary arterial hypertension. N 
Engl J Med. 2002 Mar 21;346(12):896-903. Erratum in: N Engl J Med 2002 Apr 
18;346(16):1258.  


Pr ot oc ol N u m ber P T C 1 2 4 -G D -0 1 9 -D M D  
1 8 N o ve m ber  2 0 1 5   
Versi o n 5 . 0 
 
 
P T C T hera pe utics, I nc.  –  C o nfi de ntial  
P a ge 8 1  of 8 6  
 
Sac hs A B, Vara ni G. E u kar y otic tra nslati o n i nitiati o n: t here are (at leas t) t w o si des t o e ver y st or y. 
Nat Str uct Bi ol. 2 0 0 0 Ma y; 7( 5): 3 5 6 -6 1.  
Sc h wa b SJ, C hriste nse n R L, D o u g hert y K, Kla hr S.  Q ua ntitati o n of pr otei n uria b y t he use of 
pr otei n -t o-creati ni ne rati os i n si n gle uri ne sa m ples.  Arc h I nter n Me d .  1 9 8 7 Ma y 1 4 7( 5): 9 4 3 -4.  
Sc h wartz GJ, Bri o n L P, S pitzer A .  T he use of plas ma creati ni ne c o nce ntrati o n f or esti mati n g 
gl o mer ular filtrati o n rate i n i nfa nts, c hil dre n, a n d a d olesce nts .  Pe diatr Cli n N ort h A m.  1 9 8 7 
J u ne 3 4( 3): 5 7 1-5 9 0.  
Sc h wartz GJ, F urt h S L.  Gl o mer ular filtrati o n  rate meas ure me nt a n d esti mati o n i n c hr o nic ki d ne y 
disease.  Pe diatr Ne p hr ol 2 0 0 7 J a n 1 0.  e p u b a hea d of pri nt.  
Si m o n ds A K, M u nt o ni F, Heat her S, Fiel di n g S .  I m pact of nasal ve ntilati o n o n s ur vi val i n 
h y perca p nic D uc he n ne m usc ular d ystr o p h y .  T h ora x.  1 9 9 8 N o v; 5 3( 1 1): 9 4 9 -5 2.  C o m me nt i n: 
T h ora x .  1 9 9 9 J u n; 5 4( 6): 5 6 4.  
Steffe nse n B, H y de S, L ya ger S, Mattss o n E. Vali dit y of t he E K scale: a f u ncti o nal assess me nt of 
n o n -a m b ulat or y i n di vi d uals wit h D uc he n ne m usc ular d ystr o p h y or s pi nal m usc ular atr o p h y. 
P h ysi ot h er Res I nt. 2 0 0 1; 6( 3): 1 1 9 -3 4.  
Steffe nse n B F, H y de S A, B, Atter ma n n J, Mattss o n E. Relia bilit y of t he E K scale, a f u ncti o nal 
test f or n o n-a m b ulat or y pers o ns wit h D uc he n ne d ystr o p h y. A d va nces i n P h ysi ot hera p y 2 0 0 2a; 
4: 3 7 -4 7.  
Steffe nse n B F, L ya ger S, Wer ge B,  Ra h be k J, Mattss o n E. P h ysical ca pacit y i n n o n -a m b ulat or y 
pe o ple wit h D uc he n ne m usc ular d ystr o p h y or s pi nal m usc ular atr o p h y: a l o n git u di nal st u d y. De v 
Me d C hil d Ne ur ol. 2 0 0 2 b Se p; 4 4( 9): 6 2 3 -3 2.  
Ste ve ns L A, Lafa yette R A, Perr o ne R D, Le ve y A S. La b orat or y e v al uati o n of ki d ne y f u ncti o n. I n: 
Sc hreir R W, e d. Diseases of t he ki d ne y a n d uri nar y tract, 8t h e d. P hila del p hia, Li p pi nc ott 
Willia ms & Wil ki ns 2 0 0 7; 2 9 9 -3 3 6.  
Ta ke uc hi Y, Kats u n o M, Ba n n o H, S uz u ki K, Ka was hi ma M, Ats uta N, It o M, Wata na be H, 
Ta na ka F, S o b u e G. Wal ki n g ca pacit y e val uate d b y t he 6 -mi n ute wal k test i n s pi nal a n d b ul bar 
m usc ular atr o p h y. M uscle Ner ve. 2 0 0 8 A u g; 3 8( 2): 9 6 4 -7 1.  
Ta n gsr u d S, Peterse n I L, L o dr u p Carlse n K C, Carlse n K H .  L u n g f u ncti o n i n c hil dre n wit h 
D uc he n ne's m usc ular d ystr o p h y.  Re s pir Me d.  2 0 0 1 N o v; 9 5( 1 1): 8 9 8-9 0 3.  
Te n S, Ne w M, Maclare n N .  Cli nical re vie w 1 3 0: A d dis o n's disease 2 0 0 1 .  J Cli n E n d ocri n ol 
Meta b .  2 0 0 1 J ul; 8 6( 7): 2 9 0 9 -2 2.  
V o n dersc her J .  Bi o mar ker of dr u g-i n d uce d ki d ne y i nj ur y: q ualificati o n f or re g ulat or y 
decisi o n -ma ki n g.  I nstit ute of Me dici ne of t he Nati o nal Aca de mies: F or u m o n Dr u g Disc o ver y, 
De vel o p me nt, a n d Tra nslati o n W or ks h o p –  E mer gi n g Safet y Scie nce.  2 0 0 7 A pr .  A vaila ble 
at:.htt p:// w w w.i o m.e d u/ O bject. File/ Master/ 4 2/ 6 6 5/ V o n dersc her. p df  
Wa n g Z M, Galla g her D, Nels o n M E, Matt he ws D E, He y msfiel d S B.  T otal -b o d y s keletal m uscle 
mass: e val uati o n of 2 4 -h uri nar y c reati ni ne e x creti o n b y c o m p uterize d a xial t o m o gra p h y.  A m J 
Cli n N utr 1 9 9 6 J u n; 6 3( 6): 8 6 3 -9.  


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Welch EM, Wong W, Peltz, SP.  Translation termination: It’s not the end of the story.  In 
Sonenberg N, Hershey JWB, and Matthews M, eds.  Translational control of gene expression.  
2000 Cold Spring Harbor Press, New York: 467-485.   
Wilschanski M, Yahav Y, Yaacov Y, Blau H, Bentur L, Rivlin J, Aviram M, Bdolah-Abram T, 
Bebok Z, Shushi L, Kerem B, Kerem E.  Gentamicin-induced correction of CFTR function in 
patients with cystic fibrosis and CFTR stop mutations.  N Engl J Med.  2003 Oct 
9;349(15):1433-41. 
Wilson DM, Anderson RL.  Protein-osmolality ratio for the quantitative assessment of 
proteinuria from a random urinalysis sample.  Am J Clin Pathol.  1993 Oct;100(4):419-24.   
Worton RG, Molnar MJ, Brais B and Karpati G.  The muscular dystrophies.  In: Scriver CR , 
Beaudet AL, Sly WS, Valle D, eds.  The metabolic and molecular basis of inherited disease.  8th 
ed.  Vol.  4.  New York: McGraw-Hill, 2001:5493-523. 
Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer J, Rapoport DM, Berger 
KI, Swiedler SJ, Kakkis ED, Braakman T, Chadbourne E, Walton-Bowen K, Cox GF.  Enzyme 
replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-
controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J 
Pediatr. 2004 May;144(5):581-8. 
Zappitelli M, Joseph L, Gupta IR, Bell L, Paradis G.  Validation of child serum creatinine-based 
prediction equations for glomerular filtration rate.  Pediatr Nephrol.  2007 Feb;22(2):272-81. 


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APPENDIX A. 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: 
S T A TI S TI C A L A N A L Y SI S  P L A N  
A N O P E N -L A B E L S T U D Y F O R P R E VI O U S L Y T R E A T E D A T A L U R E N ( P T C 1 2 4 ® ) 
S U B J E C 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 H I N O P A T H Y 
P T C 1 2 4- G D - 0 1 9-D M D  
V ersi o n 1. 0 
A pril 1 7, 2 0 1 8 
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 otice  of  Pr o prietar y  I nf or mati o n:  T his  d oc u me nt  c o nt ai ns  c o nfi de ntial  i nf or mati o n  o w ne d  b y  or  i n  t he  
p ossessi o n/c o ntr ol of P T C T hera pe utics, I nc. E xce pt as ma y ot her wise be per mitte d i n writi n g, b y acce pti n g or 
re vie wi n g t hese materials, y o u a gree t hat t his i nf or mati o n s h o ul d n ot be discl ose d t o ot hers (e xce pt w here re q uire d 
b y a p plica ble la w) a n d s h o ul d n ot be use d f or u na ut h orize d p ur p oses. I n t he e ve nt of a n a ct ual or s us pecte d breac h 
of t his o bli gati o n, P T C T hera pe utics, I nc. s h o ul d be n otifie d pr o m ptl y.  
N C T #: N C T 0 1 5 5 7 4 0 0


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APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
 
 
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Date 
 
 
 
 
 
 
  
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 3  of 2 8  
T A B L E O F C O N T E N T S  
A P P R O V A L SI G N A T U R E S  ..................................................................................................2  
T A B L E O F C O N T E N T S  ........................................................................................................3  
1  
O V E R VI E W  ..............................................................................................................6  
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  
Pri m ar y O bjecti ve  ...................................................................................................9  
3. 2  
Sec o n d ar y O bjecti ves  ..............................................................................................9  
3. 3  
St u d y E n d p oi nts  ......................................................................................................9  
3. 4  
S a m ple Size  ............................................................................................................1 0  
4  
S T U D Y P O P U L A TI O N  ..........................................................................................1 1  
5  
S T A TI S TI C A L A N A L Y SI S  ...................................................................................1 2  
5. 1  
Ge ner al St atistic al C o nsi der ati o ns  ......................................................................1 2  
5. 2  
S u bject Dis p ositi o n  ................................................................................................1 2  
5. 3  
De m o gr a p hic a n d B aseli ne C h ar acteristics  ........................................................1 2  
5. 3. 1  
Br o o k U p per F u ncti o n R ati n g  ....................................................................1 3  
5. 4  
Cli nic al Hist or y  .....................................................................................................1 3  
5. 5  
C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures  .........................................................1 3  
5. 6  
St u d y Dr u g E x p os ure a n d C o m pli a nce  ...............................................................1 3  
5. 7  
Pri m ar y V a ri a bles  .................................................................................................1 3  
5. 7. 1  
A d verse E ve nts  .............................................................................................1 3  
5. 7. 2  
L a b or at or y Tests  .........................................................................................1 5  
5. 7. 3  
Vit al Si g ns  .....................................................................................................1 6  
5. 7. 4  
Electr oc a r di o gr a m  .......................................................................................1 6  
5. 8  
Sec o n d ar y V ari a bles  .............................................................................................1 7  
5. 8. 1  
6 -Mi n ute W al k Test  .....................................................................................1 7  
5. 8. 2  
Ti me d F u ncti o n Tests  ..................................................................................1 7  
5. 8. 3  
N ort h St ar A m b ul at or y Assess me nt  ..........................................................1 8  
5. 8. 4  
E ge n Kl assifi k ati o n Sc ale  ............................................................................1 8  
5. 8. 5  
S pir o met r y  ....................................................................................................1 8  
5. 8. 6  
Dise ase St at us S ur ve y  ..................................................................................1 8  
5. 8. 7  
Ec h oc ar di o gr a m  ..........................................................................................1 9  
5. 9  
S u b g r o u p a n al ysis .................................................................................................1 9  
5. 9. 1  
Si x mi n ute w al k dist a nce s u b gr o u ps  ..........................................................1 9  
5. 9. 2  
C ortic ost er oi ds t y pe s u b gr o u ps  ..................................................................1 9  
5. 9. 3  
C u m ul ati ve d ur ati o n of c ortic oster oi ds use s u b gr o u ps  ...........................1 9  
5. 9. 4  
Ot her s u b gr o u ps  ..........................................................................................1 9  
6  
D A T A H A N D LI N G  .................................................................................................2 0  
6. 1  
A n al ysis Visits b ase d o n Visit Wi n d o ws  ..............................................................2 0  
6. 2  
B aseli ne  ..................................................................................................................2 1  
6. 3  
A bs ol ute a n d Rel ati ve C h a n ge fr o m B aseli ne  ....................................................2 1  
6. 4  
Missi n g D ates of A E a n d Pri or a n d C o nc o mit a nt Me dic ati o ns  ........................2 1  
6. 4. 1  
Missi n g D ate I nf or m ati o n f or A d verse E ve nts  .........................................2 1  


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 4  of 2 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  .........2 2  
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 4  
8  
CI N R G D A T A  .........................................................................................................2 5  
8. 1  
O ver vie w of CI N R G D at a  ....................................................................................2 5  
8. 2  
M atc he d P o p ul ati o ns  ............................................................................................2 6  
8. 2. 1  
A n al yses B ase d o n M atc he d P o p ul ati o ns of CI N R G a n d St u d y 0 1 9  ......2 7  
9  
BI B LI O G R A P H Y  ....................................................................................................2 8  
 
 
LI S T  O F T A B L E S  
T a ble 1:  
Sc he d ule of E ve nts  ................................................................................................8  
T a ble 2:  
S af et y M o nit ori n g P ar a meters a n d Acti o ns t o be T a ke n  ................................1 5  
 


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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 
 


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 6  of 2 8  
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 nt ati 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 1 9 -D M D,  als o referre d t o as 
St u d y 0 1 9.   Pr e 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  Versi o n  5. 0 ( d ate d 1 8 N o ve m ber 2 0 1 5) . Details are d o c u me nte d i n Secti o n s 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 h e l o n g-ter m atal ure n data. T h e pla n ne d a nal ysis will be prese nte d i n 
Secti o n 8 .  
After t he i m ple me nt of pr ot oc ol Versi o n  5. 0, t he s p o ns or has de vel o p e d t he pr ot oc ol 
Versi o n  6. 1 ( dat e d 0 8 Marc h 2 0 1 7)  s p ecificall y f or Ca na dia n sites o nl y f or et hics a p pr o v al 
w he n t he y fi nis he d all visits per Versi o n  5. 0 a n d were waiti n g t o r oll i nt o a n ot her o pe n -la bel 
n m D M D St u d y  P T C 1 2 4 -G D -0 1 6 -D M D c o n d ucte d i n t he U nite d States ( U S). T he ma xi mal 
sc he d ule d visit i n Versi o n  5. 0 was e xt e n de d fr o m wee k 2 4 0 t o wee k 3 3 6 i n Versi o n  6. 1. All 
data c ollecte d b ase d o n b ot h Versi o n s will be s u m marize d t o get her. 
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 
t his S A P s u perse des t he pr ot oc ol. 


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 7  of 2 8  
2  
S T U D Y D E SI G N  
T his st u d y c o m prises a P hase 3, o pe n -l a bel st u d y of atal ure n i n s u bjects wit h n m D B M D w h o 
pre vi o usl y recei ve d atal ure n at a n i n vesti gat or site i n a pri or P T C -s p o ns ore d cli nical st u d y. A 
se parat e o pe n-la b el st u d y ( P T C 1 2 4-G D -0 1 6 -D M D) is bei n g c o n d ucte d f or  n m D B M D 
s u bjects w h o pre vi o usl y recei v e d atal ure n at a n i n vesti gat or site i n t he U S .  
All partici pati n g sites m ust ha ve ha d at least 1 s u bject t hat recei ve d atal ure n treat me nt i n a 
pri or  
P T C -s p o ns ore d cli nical st u d y i n D B M D. It is pla n ne d t hat u p t o ~ 9 6 s ubject s will be 
e nr olle d.  
S u bjects will recei ve atal ure n 3 ti mes per da y ( TI D) at res p ecti ve m or ni n g, mi d da y, a n d 
e ve ni n g d oses of 1 0 m g/ k g, 1 0 m g/ k g, a n d 2 0 m g/ k g, f or a p pr o xi matel y 2 4 0  wee ks. St u d y 
assess me nts will be perf or me d at cli nic visits d uri n g scr ee ni n g, o n t he first da y of atal ure n 
d osi n g, a n d t he n e ver y 1 2 wee ks d uri n g t he atal ure n treat me nt peri o d.  
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  bel o w bas e d 
o n pr ot oc ol Versi o n  5. 0.   
 
 


Ataluren 
 
Statistical Analysis Plan 
17APR2018 
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PTC Therapeutics, Inc. - Confidential 
Page 8 of 28 
Table 1: 
Schedule of Events 
a Ataluren may be initiated as soon as the investigator confirms patient eligibility.  Baseline procedures 
(excluding drug administration) do not need to be performed if Screening procedures have been performed 
within 7 days of anticipated initiation of ataluren treatment. 
b Only applies to patients who discontinue the study after 240 weeks of treatment. 
Abbreviations: ACTH = adrenocorticotropic hormone, D/C = discontinuation, ECG = electrocardiogram, 
Tx = treatment, UE = upper extremity 
Period 
Screeninga Baselinea 
Ataluren Treatment 
Post-
Treatment 
Study Week 
(±7 days) 
-4 to -1 
Week 1 
Every 
60 
Weeks 
Every 
12 
Weeks 
Every 
24 
Weeks 
Every 
48 
Weeks 
End 
of Tx 
Week 
240 
6 Week 
Post D/C 
Informed Consent 
{7.2.2} 
X 
 
 
 
 
 
 
 
Clinical/medication 
history 
X 
 
 
 
 
 
 
 
Hepatitis screen  
X 
 
 
 
 
 
 
 
Vital signs  
X 
X 
 
X 
 
 
X 
X 
Brooke UE 
Functional Rating 
Scale  
X 
 
 
 
 
 
 
 
Height/Ulna 
length/Arm Span  
X 
 
 
 
X 
 
X 
 
Physical 
examination  
X 
 
 
 
 
X 
X 
 
Weight  
X 
X 
 
X 
 
 
X 
X 
Hematology  
X 
X 
 
X 
 
 
X 
X 
Biochemistry  
X 
X 
 
X 
 
 
X 
X 
ACTH and cortisol 
X 
X 
 
X 
 
 
X 
X 
Renin and 
aldosterone  
X 
As Indicated 
Urinalysis  
X 
X 
 
X 
 
 
X 
X 
12-lead ECG   
X 
As Indicated 
Echocardiogram  
X 
 
X 
 
 
X 
 
Xb 
6-minute walk test  
X 
 
 
 
X 
 
X 
 
Timed Function 
Tests  
X 
 
 
 
 
X 
X 
 
North Star 
Ambulatory 
Assessment   
X 
 
 
 
 
X 
X 
 
Egen Klassifikation 
Scale   
X 
 
 
 
 
X 
X 
 
Spirometry  
X 
 
 
 
X 
 
X 
 
Disease status 
survey  
X 
X 
 
X 
 
 
X 
 
Drug 
administration  
 
X 
 
X 
 
 
 
 
Drug compliance  
 
 
 
X 
 
 
X 
 
Adverse events  
 
X 
 
X 
 
 
X 
X 
Concomitant 
medications  
X 
X 
 
X 
 
 
X 
X 


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 9  of 2 8  
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 bjecti ve  
T he pri mar y o bjecti ve of t his st u d y  is t o assess t he l o n g-ter m safet y a n d t olera bilit y of 1 0, 1 0, 
2 0 m g/ k g atal ur e n i n s u bjects wit h n m D B M D w h o ha d pri or e x p os ure t o atal ure n i n a 
P T C -s p o ns ore d cli nical trial.  
3. 2  
Sec o n d ar y O bjecti ves  
Sec o n dar y o bjecti ves i ncl u de t he f oll o wi n g:  
● 
A m b ulat or y s u bjects (a bl e t o r u n/ wal k 1 0 meters i n ≤3 0 sec o n ds) - T o d eter mi ne 
t he eff ect of at al ure n o n a m b ulati o n a n d ot her as p ects of p h ysical f u n cti o n  
● 
N o na m b ulat or y s u bjects ( u na ble t o r u n/ wal k 1 0 m eters i n ≤3 0 sec o n ds) - T o assess 
t he eff ect of at al ure n o n acti v ities of dail y li vi n g, u p per li m b f u ncti o n, a n d 
p ul m o nar y f u ncti o n  
● 
All s u bjects - T o assess s u bject a n d/ or pare nt/care gi ver re p orts of c ha n ges i n 
disease stat us:  
i. 
Retr os pecti vel y d uri n g a n d after p artici pati o n i n pre vi o us st u dies 
( St u dies 0 0 7 a n d 0 0 7e)  
ii. 
Pr os pecti vel y d uri n g t h e c urre nt st u d y  
3. 3  
St u d y E n d p oi nts  
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 vers e e ve nts or la b orat or y a b n or malities 
Sec o n d ar y:  
● 
I n a m b ulat or y s u bjects,  
i. 
c ha n ge fr o m baseli ne i n 6 M W D as meas ure d b y t he 6 -mi n ute wal k test 
( 6 M W T) 
ii. 
c ha n ge fr o m baseli ne i n p h ysical f u ncti o n as meas ure d b y t he N ort h  Star 
A m b ulat or y Assess me nt ( N S A A)  
iii. c ha n ge fr o m baseli ne i n ti me d f u ncti o n tests (ti me t o sta n d fr o m s u pi ne a n d 
ti me t o r u n/ wal k 1 0 meters)  
● 
I n n o n-a m b ulat or y s u bjects,  
i. 
c ha n ge fr o m baseli ne i n p ul m o nar y f u ncti o n test - % pre dicate d f orce d vital 
ca pacit y ( F V C ) a n d % pre dicte d  f orce d e x pirat or y v ol u me i n 1 sec o n d 
(F E V 1 ) as meas ure d b y s pir o metr y  
ii. 
c ha n ge fr o m baseli ne i n patie nt a n d par e nt/care gi ver-re p orte d acti vities of 
dail y li vi n g, as meas ure d b y t he E ge n Klassifi kati o n ( E K) scale  


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 1 0  of 2 8  
● 
All s u bjects,  
i. 
c ha n ges i n patie nt a n d/ or pare nt/care gi ver re p orts of disease stat us as 
meas ure d b y a sta n dar diz e d s ur ve y a d mi nistere d b y site pers o n nel  
3. 4  
S a m ple Size  
T he  sa m ple size, u p t o ~ 9 6 s u bjects, wa s deter mi ne d b y h o w ma n y s u bjects satisf y all 
i ncl usi o n/e x cl usi o n criteria w he n a p pl yi n g f or p artici pati o n i n t his st u d y a n d n ot b y a n y 
f or mal statistical h y p ot hesis. 


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 1 1  of 2 8  
4  
S T U D Y P O P U L A TI O N  
T he As - Tr eate d p o p ulati o n c o nsists of all s u bjects w h o recei ve at least 1 d ose of atal ure n 
treat me nt. 
T his p o p ulati o n will be e val uate d i n t he a n al ys es of safet y (t h e pri mar y e n d p oi nt). 
S u bject   
 will be e xcl u de d fr o m t he As- Treat e d p o p ulati o n i n t he a nal ys es of t he 
sec on dar y e n d p oi nts i ncl u di n g 6 M W T, 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 , N S A A, E K, s pir o metr y e n d p oi nts, disease stat us s ur ve y, a n d left ve ntric ular 
ejecti o n fr acti o n ( L V E F ) beca use s u bj ect  
 w as re-e nrolle d i nt o t he st u d y as 
s u bject  
 a b o ut 2 ye ars after t he disc o nti n uati o n fr o m t he st u d y. All data c ollecte d f or 
b ot h s u bject I Ds will be set t o get h er  c hr o n ol o gi call y.  
A m b ulati o n/ N o n- a m b ulati o n s u bjects at st u d y e ntr y are defi ne d as f oll o ws:  
● 
A m b ulati o n s u bjects: all s u bjects w h o ha d ≤3 0 sec f or r u n/ wal k 1 0 meters at 
scree ni n g. 
● 
N o n - A m b ulati o n s u bjects:  all s u bjects w h o ha d > 3 0 sec f or r u n/ wal k 1 0 m eters at 
scree ni n g. 


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 1 2  of 2 8  
5  
S T A TI S TI C A L A N A L Y SI S  
5. 1  
Ge ner al St atistic al C o nsi der ati o ns  
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 d ar d err or, 9 5 % c o nfi de n ce i nter vals ( CIs) o n t he m ea n, me dia n, 
mi ni m u m, a n d ma xi m u m.  S u m mar y ta bles f or cate g orical varia bles  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.  
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 nter/s u bject I D a n d visit . 
I n a d diti o n, all a nal yses will be perf or me d b y c ortic oster oi d use (y es or n o bef ore or d uri n g 
t he st u d y), b y a m b ulat or y stat us ( a m b ulat or y or n o n -a m b ulat or y) at b aseli ne , a n d o verall, 
u nless s pecifie d ot her wise .  
5. 2  
S u bject D is p ositi 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 pre mat ur el y will be re p orte d f or o v erall s u bjects, a s u b gr o u p of s u bjects wit h 
c ortic oster oi d use ( Yes/ N o), 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 bjects at st u d y 
e ntr y.  R eas o ns f or treat me nt earl y disc o nti n uati o ns will be descri be d.  T h e n u m ber of 
s u bjects fr o m P T C 1 2 4-0 0 7 ( St u d y  0 0 7) t o St u d y  0 1 9 will als o be re p orte 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 1 9 , s u bj ects 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 per 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 h e ti me t o disc o nti n uati o n (i n wee ks) is calc ulate 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 ha 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 
date  –  first d ose dat e + 1)/ 7, res pecti vel y. Ti me t o disc o nti n uati o n will be assesse d usi n g 
Ka pla n -Mei er met h o ds a n d t he Ka pla n -M eier 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  
De m o gr a p hic a n d B aseli ne C h ar acteristics  
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 der, race, et h nicit y, hei 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  di sta 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), 
c ortic oster oi d use ( Yes/ N o), a n d  a m b ulat or y/ n o n -a m b ulat or 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 wit h c ortic oster oi d use ( Yes/ N o), b aseli ne si x mi n ute wal k  
dista nce gr o u ps ( < 3 0 0 meters, ≥3 0 0 -< 4 0 0 m eters, ≥4 0 0 meters), baseli ne ti me t o sta n d fr o m 
s u pi ne gr o u ps  ( < 5s, ≥5s), 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 bjects at st u d y 
e ntr y.   


Ataluren 
 
Statistical Analysis Plan 
17APR2018 
V1.0 
PTC Therapeutics, Inc. - Confidential 
Page 13 of 28 
5.3.1 
Brook Upper Function Rating 
The number of subjects with each baseline Brook Upper Function Rating score will be 
tabulated by the corticosteroid use (Yes/No). Subjects’ mean age of each baseline score will 
be summarized as well. 
5.4 
Clinical History 
Clinical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA Version 20.1). The count and percentage of subjects under each history term, 
coded by system organ class (SOC) and preferred term (PT), will be summarized.   
5.5 
Concomitant Medications and Procedures 
Prior medications and concomitant medications will be coded using the World Health 
Organization Drug Dictionary (WHODRUG) dictionary dated 2017DEC01 into 
Anatomical-Therapeutic-Chemical (ATC) classification codes. The prior medications are 
defined as any medications that subjects started before the first dose date. Concomitant 
medications are defined as any medications that subjects took after/on the first dose date. The 
prior and concomitant medications will be summarized by ATC level 3 and preferred terms. 
The concomitant cardiac medications will be summarized similarly.  
Specific attention will be focused on corticosteroid use. The numbers of subjects 
receiving/not-receiving corticosteroids at baseline or during the study, switching from 
receiving to not receiving or vice versa, switching in different types of corticosteroids, and 
duration of corticosteroid use during the study and by type will be summarized. 
The prior and concomitant non-drug therapies will be defined similar to the prior and 
concomitant medications. They will be coded by MedDRA Version 20.1 and summarized by 
SOC and PT. 
5.6 
Study Drug Exposure and Compliance 
Study drug compliance will be assessed in terms of the percentage of drug actually taken 
relative to the amount that should have been taken during the study. Treatment duration 
(weeks) will be calculated as (last dose date – first dose date +1)/7, if date of last study drug 
intake was not known: (last visit date – first dose date +1)/7. For subject 
, the treatment 
gap between 
 will be excluded from the treatment duration. The summary of 
the overall compliance and treatment duration will be represented for overall subjects and a 
subgroup of ambulatory/non-ambulatory subjects at study entry. 
5.7 
Primary Variables 
5.7.1 
Adverse Events 
Adverse events will be classified using MedDRA Version 20.1 classification system. The 
severity of adverse events will be graded by the investigator according to the CTCAE, 
Version 3.0 whenever possible. A treatment-emergent adverse event (TEAE) is defined as an 
adverse event that occurs or worsens in the period extending from the day of a subject’s first 
dose of study drug to 6 weeks after the last dose of study drug in this study. 


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 1 4  of 2 8  
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 hat S O C a n d P T. If a s u bject has t he sa me A E o n m ulti ple occ asi o ns, t he 
hi g hest se v erit y (fet al, life -t hreate ni n g, severe, m o derate, a n d mil d) rec or de d f or t he e v e 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 b a bl y’, 5 = ‘ Relat e d’), recl assifie d i nt o Relate d (‘ P ossi bl y R elated’, 
‘ Pr o ba bl y R elate d’, ‘ R elate d’) or N ot Relate d (‘ U nrelate d’ a n d ‘ U nli kel y’), will be prese nte 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 perce 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 nuati 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 perce nt a ge of s u bjects wit h T E A Es a n d S A Es will be b y 
relati o ns hi p t o st u d y dr u g a n d C T C A E/se v erit y, res pecti vel y. 
T he n u m ber a n d p erce nta ge of s u bjects e x perie n ci n g a s p ecific T E A E will be ta b u late d  
● 
b y S O C, a n d P T  
● 
b y S O C, P T, a n d C T C A E/se verit y gra d e  
● 
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 i n atal ure n gr o u p   
● 
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 atal ure n 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:  
● 
b y S O C, a n d P T a n d  
● 
b y S O C, P T, a n d C T C A E/se verit y gra d e.  
i. 
P ossi bl y or pr o ba bl y treat me nt -relate d T E A Es 
ii. 
P ossi bl y tr eat me nt -relate d T E A Es 
iii. Pr o ba bl y tr eat me nt -relate d T E A Es 
i v. 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 
v.  
T E A Es lea di n g t o  disc o nti n uati o n fr o m treat me nt  
vi.  H e patic a n d re nal 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  
vii.  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 CA E/se verit y gra d e ≥3  
viii.  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 pecial 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 he i nci de nce rate of t h e T E A E per 1 0 0 p atie nt-year = ( n u m b er of e ve nts/ n u m ber of 
patie nt -years) * 1 0 0. T he n u m ber of patie nt -years is defi ne d as t he s u m of t h e 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 defi ne 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 electr ocar di o gra m re p orte d as T E A E will be s u m marize d. 


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 1 5  of 2 8  
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 fr e q ue nc 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 paratel y.  
5. 7. 2  
L a b or at or y Tests  
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 mari ze 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 pr ese 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 n d 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 per t he f oll o wi n g T a ble 2 . 
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  
A dr e n al  
 
 
 
Pl a s m a A C T H  
--- 
> U L N  
( a n d pl a s m a c orti s ol < L L N)  
> U L N  
( a n d c orti s ol W N L) 
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)  


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 1 6  of 2 8  
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  
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 C T H = a dre n oc ortic otr o pic h or m o ne, 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, W N L = wit hi n n or mal 
li mits 
5. 7. 3  
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 h y perte nsi o n criteria 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 [U S D H H S 2 0 0 5 ] ( H y pert e nsi ve: ≥9 5t h perce ntile; 
Pre -h y perte nsi v e: 9 0 - < 9 5t h perce ntile; N or m al: < 9 0t h perce ntile).  
● 
If a ge ≥1 8  years ol d, h y p erte 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. 7. 4  
Electr oc a r di o gr a m  
N u m ber ( %) of s u bjects e x perie nci n g a n or mal/a b n or mal electr o car di o gra m ( E C G ) 
assess me nt will be ta b ulate d b y visit f or o verall s u bjects.  


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 1 7  of 2 8  
5. 8  
Sec o n d ar y V ari a bles  
S u bject  
 will be e xcl u de d fr o m t he As- Treat e d p o p ulati o n i n t he a nal ys es of all 
sec o n dar y e n d p oi nts. 
5. 8. 1  
6- Mi n ute W al k Test  
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 wal 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 bj ects wit h n o n-missi n g baseli ne 6 M W T assess me nts . T he dista nce wal ke d at 
eac h will als o be s u m marize d f or eac h act ual a ge.  
T he e n d p oi nt will als o be a nal yze d b y m ea ns of a mi x e d m o del re peate d meas ures ( M M R M).  
A n u nstr uct ure d v aria nce- c o vari a nce will be ass u me d a n d t he esti mati o n met h o d will be t he 
defa ult, Re M L . T he m o d el will i ncl u de t he fact ors f or  treat me nt, visit, a ge ( 6- 1 1, 1 2- 1 7, a n d 
≥1 8 years ), us e of c ortic oster oi ds at baseli ne (yes vs n o), a n d baseli ne 6 M W D cate g or y 
(< 3 0 0 meters, ≥3 0 0 -< 4 0 0 meters, ≥4 0 0 meters ), a n d baseli ne 6 M W D as a c o variate . Visit is 
c o nsi dere d as a cate g orical varia ble.  Fr o m t his  a n al ysis t he mea n c ha n ge at eac h visit will be 
e val uate d.  If t he m o del ca n n ot c o n ver ge, c o m p o u n d s y m metr y varia nce-c o varia nce str uct ure 
will be ass u me d . 
5. 8. 2  
Ti me d F u ncti o n Tests  
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 a n d ti me t o r u n/ wal k 1 0 meters) a n d 
c ha n ge fr o m baseli ne t o eac h p ost bas eli 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 bj ects wit h n o n-missi n g baseli ne ti me d f u ncti o n tests assess me nts . Si milarl y 
t he ti me t o sta n d fr o m s u pi ne a n d ti me t o r u n/ wal k 1 0 meters 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.  
Si milar t o 6 M W T, t he ti me t o sta n d fr o m s u pi ne a n d ti me t o r u n/ wal k 1 0 meters of will als o 
be a nal yz e d b y mea ns of a mi x e d m o del re peate d meas ures ( M M R M)  w h ere baseli ne is 
baseli ne ti me ta ke n t o sta n d fr o m s u pi ne a n d ti me ta ke n t o r u n/ wal k 1 0 met ers, res p ecti vel y.  
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. T he 
me dia n a ge at  l oss of a m b ulati o n will be re p orte d b y c ortic oster oi ds use at baseli ne . T he 
Ka pla n -Mei er c ur ves will als o be dis p la 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 re p orte d as t he a d verse e ve nt or a ge at t he ti me t o r u n/ wal k 
1 0 meters > 3 0 sec o n ds, w hic he ver o cc urs earlier . 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 h e last vali d ti me d f u ncti o n tests assess me nt 
date. A ge o n t hat d ate will be use d i n t he a nal ysis. A se 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 disease pr o gressi o n A E. 


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 1 8  of 2 8  
5. 8. 3  
N ort h St ar A m b u l at or y Assess me 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 ore.  If fe wer t h a n 1 3 of t he 1 7 acti vities are perf or me d, t h e  
t otal sc ore will be c o nsi d ere d missi n g.  If fr o m 1 3 t o 1 6 acti vities are perf or me d, t he t otal 
sc ore will be c alc 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 perf or me d d ue 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 n e d. T he li near sc ore is t he li near tra nsf or mati o n of  
t he N S A A sc ore t o a scal e of 0 t o 1 0 0 [Ma y h e 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 bjects wit h n o n -missi n g baseli ne N S A A  ass ess me nts . 
Si milarl y t he t otal a n d li near sc ores  will  als o be s u m marize d f or eac h act u al 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 t a b ulate d. T he f u ncti 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 he missi n g data will be ha n dle d b y last o bser vati o n car ri e d 
f or war d ( L O C F). 
5. 8. 4  
E ge n Kl assifi k ati o n Sc ale  
T he t otal sc ore of E K scale a n d c ha n ge fr o m b aseli ne t o eac h p ost bas eli ne visit  wil l be 
s u m marize d descri pti vel y  b y visit f or n o n - a m b ulat or y s u bj ects a n d As -Treate d p o p ulati o n . 
Si milar l y t he t otal sc ore will  als o be s u m marize d f or eac h act ual a ge. 
5. 8. 5  
S pir o met r 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 h eir 
a bs ol ute a n d rel ati ve c ha n ges fr o m  basel i ne will be s u m marize d b y visit f or n o n - a m b ulat or y 
s u bjects a n d As-Tr eate d p o p ulati o n .  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 ual a ge. 
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 F V C  < 1 liter. T he me dia n 
a ge at F V C < 1 liter will b e re p ort e d  b y c ortic oster oi ds use at baseli ne . T he Ka pla n -Mei er 
c ur ves will als o be dis pla ye d. T h e a ge at F V C < 1 liter is t he o ne at t he first ti me F V C < 1 liter. 
If s u bjects d o n ot ha ve F V C < 1 liter, t he a ge at the last n o n -missi n g F V C assess me nt will be 
c h ose n as t he ce ns or a ge.   
5. 8. 6  
Dise a se St at us S ur ve y 
F or c h a n ge i n diseas e stat us of pr os pecti ve s ur v e y data,  n u m ber ( %) of s u bj ects 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 a n d a 
s u b gr o u p of s u bjects wit h c ortic oster oi d use ( Yes/ N o). If t here are m ulti ple s y m pt o ms u n der 
a cate g or y, t he hi g hest sc ore/ w orse case of all a vaila ble s y m pt o ms was sel ecte d f or t he 
cate g or y i n t he s u m mar y.  
Data fr o m t he retr os pecti ve s ur ve y i n st u dies 0 0 7 a n d 0 0 7e will be  s u m marize d se paratel y.  


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 1 9  of 2 8  
5. 8. 7  
Ec h oc ar di o gr a m  
T he L V E F will be s u m marize d b y visit a n d c h a 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 f or o v erall s u bjects. Si mil arl y th e L V E F  will be 
s u m marize d f or eac h act ual a ge. 
5. 9  
S u b gr o u p a n al ysis  
5. 9. 1  
Si x mi n ute w al k  dist a nce s u b gr o u ps  
T he  b y -visit s u m mar y o n t he o bser ve d v al ues a n d c ha n ge fr o m baseli ne t o eac h p ost bas eli ne 
visit val ues will be perf or me d  descri pti vel y f or eac h 6 M W T  s u b gr o u p (< 3 0 0 meters, 
≥3 0 0 -< 4 0 0 meters, ≥4 0 0 meters ) o n 6 M W T, T F T , a n d N S A A e n d p oi nts .  
5. 9. 2  
C ortic ost er oi ds t y pe s u b gr o u ps  
T he b y -visit s u m mar y o n t he o bser ve d v al ues a n d c ha n ge fr o m baseli ne t o eac h p ost bas eli ne 
visit val ues will be perf or me d descri pti vel y  f or eac h c ortic oster oi d t y pe pri or t o st u d y e ntr y 
(deflazac ort vs pre d nis o n e/ pre d nis ol o ne) o n 6 M W T a n d T F Ts. T h e Ka pla n -Meier met 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 a n d a ge at F V C < 1 liter eac h 
s u b gr o u p. 
5. 9. 3  
C u m ul ati ve d ur ati o n of  c ortic oster oi ds use s u b gr o u ps 
T he c u m ulati ve d ur ati o n of c ortic oster oi d use pri or t o st u d y e ntr y will be cate g orize d as 
< 1 2  m o nt hs vs ≥1 2 m o nt hs. T he b y -visit s u m mar y o n t he o bser ve d v al ues a n d c ha n ge fr o m 
baseli ne t o eac h p ost bas eli ne visit val ues will be perf or me d d escri pti vel y f or eac h s u b gr o u p  
o n 6 M W T  a n d T F Ts. T h e Ka pla n -M eier met 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 a n d a ge at F V C < 1 liter f or eac h s u b gr o u p.  
5. 9. 4  
Ot her s u b gr o u ps  
C ortic oster oi ds use i n t he st u d y will be re vi e we d. If a n y ot her c ortic oster oi ds s u b gr o u p is 
cli nicall y mea ni n gf ul, t he s u b gr o u p a nal ys es o n it will be perf or me d o n all efficac y 
e n d p oi nts. 


Ataluren 
 
Statistical Analysis Plan 
17APR2018 
V1.0 
PTC Therapeutics, Inc. - Confidential 
Page 20 of 28 
6 
DATA HANDLING 
6.1 
Analysis Visits based on Visit Windows 
Since some subjects had early terminations or unscheduled visits in during, the derived 
analysis visits will be generated by visit window defined as follows. 
The derived visits will be generated by visit window defined as follows. 
Let ADY=assessment date –first dose date +1. 
IF .<= ADY <=1 THEN AVISIT= BASELINE AND AVISITN=1; 
IF 42<= ADY <=126 THEN AVISIT=WEEK 12 AND AVISITN=2; 
IF 126<ADY <=210 THEN AVISIT=WEEK 24 AND AVISITN=3; 
IF 210<ADY <=294 THEN AVISIT=WEEK 36 AND AVISITN=4; 
IF 294<ADY <=378 THEN AVISIT=WEEK 48 AND AVISITN=5; 
IF 378<ADY <=462 THEN AVISIT=WEEK 60 AND AVISITN=6; 
IF 462<ADY <=546 THEN AVISIT=WEEK 72 AND AVISITN=7; 
IF 546<ADY <=630 THEN AVISIT=WEEK 84 AND AVISITN=8; 
IF 630<ADY <=714 THEN AVISIT=WEEK 96 AND AVISITN=9; 
IF 714<ADY <=798 THEN AVISIT=WEEK 108 AND AVISITN=10; 
IF 798<ADY <=882 THEN AVISIT=WEEK 120 AND AVISITN=11; 
IF 882<ADY <=966 THEN AVISIT=WEEK 132 AND AVISITN=12; 
IF 966<ADY <=1050 THEN AVISIT=WEEK 144 AND AVISITN=13; 
IF 1050<ADY <=1134 THEN AVISIT=WEEK 156 AND AVISITN=14; 
IF 1134<ADY <=1218 THEN AVISIT=WEEK 168 AND AVISITN=15; 
IF 1218<ADY <=1302 THEN AVISIT=WEEK 180 AND AVISITN=16; 
IF 1302<ADY <=1386 THEN AVISIT=WEEK 192 AND AVISITN=17; 
IF 1470<ADY <=1554 THEN AVISIT=WEEK 216 AND AVISITN=19; 
IF 1554<ADY <=1638 THEN AVISIT=WEEK 228 AND AVISITN=20; 
IF 1638<ADY <=1722 THEN AVISIT=WEEK 240 AND AVISITN=21 
IF 1722<ADY <=1806 THEN AVISIT=WEEK 252 AND AVISITN=22 
IF 1806<ADY <=1890 THEN AVISIT=WEEK 264 AND AVISITN=23 
IF 1890<ADY <=1974 THEN AVISIT=WEEK 276 AND AVISITN=24 
IF 1974<ADY <=2058 THEN AVISIT=WEEK 288 AND AVISITN=25 
IF 2058<ADY <=2142 THEN AVISIT=WEEK 300 AND AVISITN=26 


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 2 1  of 2 8  
I F 2 1 4 2< A D Y < = 2 2 2 6 T H E N A VI SI T = W E E K 3 1 2 A N D A VI SI T N = 2 7  
I F 2 2 2 6< A D Y < = 2 3 1 0 T H E N A VI SI T = W E E K 3 2 4 A N D A VI SI T N = 2 8  
I F 2 3 1 0< A D Y < = 2 3 9 4 T H E N A VI SI T = W E E K 3 3 6 A N D A VI SI T N = 2 9 .  
If t here ar e m ore t ha n 1 v ali d assess me nt wit hi n one 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 aseli ne  
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.  
6. 3  
A bs ol ute a n d Rel ati ve C h a n ge fr o m B aseli ne  
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  
Missi n g D ates of A E a n d P ri or a n d C o nc o mit a nt Me dic ati o ns  
6. 4. 1  
Missi n g D ate I nf or m ati o n f or A d verse E ve nts  
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 h e start date is i nc o m plete 
(ie, partiall y missi n g) f or a d verse e ve 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 he n t he da y a n d 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 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 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 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 b o ve pr oce d ure.  
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 he 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 ne d t o t he missi n g da y.  
● 
If eit her t he year is bef ore 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 n e d t o t he missi n g da y.  


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 2 2  of 2 8  
● 
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 me b ut t he m o nt h is after t he m o nt h of t he d at 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 first da y of t he m o nt h will be 
assi g ne d t o t he missi n g d a 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  
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  
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.  
6. 4. 2. 1  
I nc o m plete St art D ate 
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 star t 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 i n 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 d a y a n d 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 will be assi g ne 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 h e n Dece m ber 3 1 will be assi g ne 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 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 fi el 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 ure.  
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 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 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 will be  assi g ne d t o t he missi n g 
da y.  
● 
If eit her t he year is bef ore 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 n e 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 me b ut t he m o nt h is after t he m o nt h of t he d at 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 first da y of t he m o nt h will be 
assi g ne d t o t he missi n g d a y.  


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 2 3  of 2 8  
6. 4. 2. 2  
I nc o m plete St o p D ate 
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 dat e 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 date. 
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 h e n t he da y a n d 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 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 h e n Dece m ber 3 1 will be assi g ne 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 after t he year of t h e date of t h e last d ose 
of d o u ble -bl i 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 fi el 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 ure.  
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 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 h e n t he da y 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 will be assi g ne d t o t he missi n g d a y.  
● 
If eit her t he year is bef ore 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 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 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 n e 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 me b ut t he m o nt h is after t he m o nt h of t he d at 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 first da y of t he m o nt h will be 
assi g ne d t o t he missi n g d a y.  


Ataluren 
 
Statistical Analysis Plan 
17APR2018 
V1.0 
PTC Therapeutics, Inc. - Confidential 
Page 24 of 28 
7 
ANALYSIS CHANGES FROM PROTOCOL 
The paired t-test is removed from the analysis on change from baseline in 6-minute walk test, 
timed function tests, North Star Ambulatory Assessment, Egen Klassifikation Scale, and 
spirometry endpoints. Subgroup analyses based on 6-minute walk test, corticosteroid type, 
and the cumulative duration of corticosteroid use are added.  


Ataluren 
 
Statistical Analysis Plan 
17APR2018 
V1.0 
PTC Therapeutics, Inc. - Confidential 
Page 25 of 28 
8 
CINRG DATA 
8.1 
Overview of CINRG Data 
CINRG is a natural history registry database which collects DMD data using consortium of 
medical and scientific investigators from academic and research centers on neuromuscular 
disease. Demographics and baseline characteristics, corticosteroids medication use (and 
type), efficacy endpoints including 6MWT, time taken to stand from supine, time taken to 
run/walk 10 meters, NSAA, spirometry, and EK will be analyzed. Other endpoints collected 
by CINRG but not in Study 019 will not be included into this analysis plan. The CINRG 
natural history control will be compared to ataluren’s efficacy data to assess the ataluren’s 
long- term treatment benefit. 
 
 


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 2 6  of 2 8  
8. 2  
M atc he d P o p ul ati o ns  
T o c o m pare CI N R G wit h St u d y 0 1 9, t h e matc he 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 diff ere nt e n d p oi nts a n d a nal yses. Matc hi n g criteria will be a dj uste d if i m bala nce 
de m o gr a p hics a n d b aseli ne c har acteristics are o bs er ve d.  
E n d p oi nt/ 
A n al y si s  
A g e 
( Y e ar s) at 
St u d y 
E ntr y  
A g e ( Y e ar s) 
at 
A s s e s s m e nt  
St er oi d U s e  
A m b ul ati o n 
st at u s  
E x cl u d e  
E X O N 5 1 
a n d 4 5  
B a s eli n e 
v al u e  
Vi sit 
Y e ar  
A g e at 
l o s s of 
a m b ul ati o n  
9 -1 8  
N ot 
a p pli c a bl e  
C u m ul ati v e 
St er oi d u s e 
d ur ati o n at st u d y 
e ntr y ≥1 2  m o nt h s  
A m b ul at or y 
at st u d y 
e ntr y  
Y e s  
ti m e 
t a k e n t o 
r u n/ w al k 
1 0 m et er s  
3. 5 -2 6. 4 
s e c o n d s 2  
N ot 
a p pli c a bl e  
A g e at F V C 
< 1  lit er 
9 -1 8  
N ot 
a p pli c a bl e  
N ot a p pli c a bl e  
N o n -
a m b ul at or y 
at st u d y 
e ntr y  
Y e s  
1 -3. 0 8  
N ot 
a p pli c a bl e  
Pi e c e -wi s e 
r e gr e s si o n 
b a s e d o n 
F V C  
N ot 
a p pli c a bl e  
≤2 2  
C u m ul ati v e 
St er oi d u s e 
d ur ati o n at e a c h 
a s s e s s m e nt 
≥2 4  m o nt h s  
N o n -
a m b ul at or y 
at e a c h 
a s s e s s m e nt  
Y e s  
N ot 
a p pli c a bl e  
≥2 0 1 2  
% -
pr e di ct e d 
F V C  
9 -2 1  
N ot 
a p pli c a bl e  
N ot a p pli c a bl e  
N o n -
a m b ul at or y 
at  st u d y 
e ntr y  
Y e s  
3 2. 6 -
1 1 0. 3  
N ot 
a p pli c a bl e  
% -
pr e di ct e d 
F E V 1  
9 -2 1  
N ot 
a p pli c a bl e  
N ot a p pli c a bl e  
N o n -
a m b ul at or y 
at st u d y 
e ntr y  
Y e s  
2 8. 1 -
1 0 4. 0  
N ot 
a p pli c a bl e  
P E F  
9 -2 1  
N ot 
a p pli c a bl e  
N ot a p pli c a bl e  
N o n -
a m b ul at or y 
at st u d y 
e ntr y  
Y e s  
1. 3 -2 1 8. 0  
N ot 
a p pli c a bl e  
E K  
9 -1 8  
N ot 
a p pli c a bl e  
N ot a p pli c a bl e  
A m b ul at or y 
at st u d y 
e ntr y  
Y e s  
S c or e 
0 -1 5  
N ot 
a p pli c a bl e  
6 M W T  
9 -1 8  
N ot 
a p pli c a bl e  
C u m ul ati v e 
St er oi d u s e 
d ur ati o n at st u d y 
e ntr y ≥1 2 m o nt h s 
s  
A m b ul at or y 
at st u d y 
e ntr y  
Y e s  
3 6 -5 5 3 
m et er s  
N ot 
a p pli c a bl e  
ti m e t a k e n 
t o 
r u n/ w al k 
1 0 m et er s  
9 -1 8  
N ot 
a p pli c a bl e  
C u m ul ati v e 
St er oi d u s e 
d ur ati o n at st u d y 
e ntr y ≥1 2 m o nt h s  
A m b ul at or y 
at st u d y 
e ntr y  
Y e s  
3. 5 -2 6. 4 
s e c o n d s  
N ot 
a p pli c 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  
9 -1 8  
N ot 
a p pli c a bl e  
C u m ul ati v e 
St er oi d u s e 
d ur ati o n at st u d y 
e ntr y ≥1 2  m o nt h s  
A m b ul at or y 
at st u d y 
e ntr y  
Y e s  
2. 3 -3 0 
s e c o n d s  
N ot 
a p pli c a bl e  
N S A A  
9 -1 8  
N ot 
a p pli c a bl e  
C u m ul ati v e 
St er oi d u s e  
d ur ati o n at st u d y 
e ntr y ≥1 2  m o nt h s 
s  
A m b ul at or y 
at st u d y 
e ntr y  
Y e s  
T ot al 
s c or e 
3 -3 4  
N ot 
a p pli c a bl e  


At al ure n  
 
St atistic al A n al ysis Pl a n  
1 7 A P R 2 0 1 8  
V 1 . 0 
P T C T her a pe utics, I nc. - C o nfi de nti al  
P a ge 2 7  of 2 8  
8. 2. 1  
A n al yses B ase d o n M atc he d P o p ul ati o ns of CI N R G a n d St u d y 0 1 9  
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, b aseli ne 6 M W D, baseli ne  ti me 
t o r u n/ wal k 1 0 m eters, baseli ne ti me t o  sta n d fr o m s u pi ne, baseli ne %-pre di cte d F E V 1, 
% -pre dict e d F V C, P E F, E K sc ore, N S A A t otal sc 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 1 9 b ase 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 ortic 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 bjects se parat el y.  I n ge neral, th e baseli ne is 
defi ne d as t he first visit i n CI N R G d ata.  T he  b aseli ne a ge i n t he F V C a nal ysis usi n g 
piece -wis e re gressi o n m o dels is t he a ge at t he first F V C assess me nts f or b ot h CI N R G a n d 
S t u d y 0 1 9. 
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 ge t o l oss of a m b ulati o n, a n d a ge 
t o F V C < 1 liter  usi n g Ka pla n -Meier 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 1 9 dat a, 
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 ter ms 
of a ge will be c h os e 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 gressi o n li ne will be ge n erat e d f or CI N R G a n d 
St u d y  0 1 9, s e par atel y. C o m paris o n bet wee n t h e  o bser ve d a n d pre dicte d F V C i n St u d y  0 1 9 
will be perf or me d usi n g r e peate d m eas ures a nal ysis of varia nce t o acc o u nt f or wit hi n -s u bject 
c orrel ati o n, w here t h e pr e dicte d val ues are b ase d o n t he re gressi o n e q uati o n esti mate d b y t he 
best fit re gressi o n m o del ba se d o n CI N R G data.  
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 t o l oss of a m b ulati o n a n d 
a ge t o F V C < 1 liter. T he me dia n a ge t o l oss of a m b ulati o n a n d me dia n a ge t o F V C < 1 liter 
will be re p orte d. T h e c o m paris o n bet wee n St u d y  0 1 9 a n d CI N R G will be c o n d ucte d via 
l o g-r a n k test b y c ortic ost er oi d use at bas eli ne ( yes or n o) a n d o verall . T he Ka pla n-Mei er 
c ur ves will als o be dis pla ye d.  
I n St u d y  0 1 9, t he 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 h e 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 he CI N R G d ata, 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 hic he v er earli er,  will be pic ke d 
as t he e ve nt a ge. If s u bj ects i n CI N R G dat a 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 h e ce ns or a ge. A se nsiti vit y a nal ysis will be 
perf or mi n g bas e 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.  
Si milarl y, t he a ge at F V C < 1 liter is t he o ne at t he first ti me F V C < 1 liter. If s u bjects d o n ot 
ha ve F V C < 1 liter, t he a ge at t he last n o n -missi n g F V C assess me nt will be c h ose n as t he 
ce ns or a ge.  
F or CI N R G dat a o nl y, t h e o bser ve d v al ues will be s u m marize d descri pti vel y f or eac h act ual 
a ge o n 6 M W T, ti me t o r u n/ wal k 1 0 mete rs, 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, % -pre dict e d F E V 1, P E F  a n d E K t otal sc ores  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 1 9 will be a p plie d t o CI N R G data.  


Ataluren 
 
Statistical Analysis Plan 
17APR2018 
V1.0 
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