Conditions: Muscular Atrophy, Spinal
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 62
Healthy volunteers: no

Brief summary:
Open-label, multi-center clinical study is to assess the safety, tolerability, pharmacokinetic (PK), pharmacodynamics (PD), and efficacy of Risdiplam (RO7034067) in infants with Type 1 spinal muscular atrophy (SMA). The study consists of two parts, an exploratory dose finding part (Part 1) and a confirmatory part (Part 2) which will investigate Risdiplam (RO7034067) for 24-months at the dose selected in Part 1.

Detailed description:

Arms:
arm 1: Participants will receive multiple ascending doses of risdiplam (RO7034067), administered orally once daily for a minimum of 4 weeks to select the dose for Part 2. During the first year of treatment, most participants will switch to the Part 2 dose. During the second year of treatment, all Part 1 participants will be receiving the Part 2 dose. They will thereafter enter a 3-year open-label extension phase and continue to receive risdiplam at the same dose. arm 2: Participants will receive risdiplam (RO7034067), administered orally once daily at the dose defined in Part 1 of the study, for a duration of 24 months. They will thereafter enter a 3-year open-label extension phase and continue to receive risdiplam at the same dose.

Interventions: intervention 1: Risdiplam
Intervention descriptions: intervention 1: Risdiplam will be administered orally.

Protocol document:
Prot_000.pdf: 
FI N A L P R O T O C O L A M E N D M E N T A P P R O V A L  
C O N FI D E N TI A L  
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt, e s p e ci all y a n y u n p u bli s h e d d at a, i s t h e pr o p ert y of 
F. H off m a n n -L a R o c h e Lt d ( or u n d er it s c o ntr ol) a n d t h er ef or e i s pr o vi d e d t o y o u i n c o nfi d e n c e a s
a n I n v e sti g at or, p ot e nti al I n v e sti g at or, or c o n s ult a nt, f or r e vi e w b y y o u, y o ur st aff, a n d a n
a p pli c a bl e Et hi c s C o m mitt e e or I n stit uti o n al R e vi e w B o ar d. It i s u n d er st o o d t h at t hi s i nf or m ati o n 
will n ot b e di s cl o s e d t o ot h er s wit h o ut writt e n a ut h ori z ati o n fr o m R o c h e e x c e pt t o t h e e xt e nt 
n e c e s s ar y t o o bt ai n i nf or m e d c o n s e nt fr o m p er s o n s t o w h o m t h e dr u g m a y b e a d mi ni st er e d.  
R O 7 0 3 4 0 6 7 — F. H off m a n n -L a  R o c h e Lt d 
Pr ot o c ol B P 3 9 0 5 6, V er si o n 7 
P R O T O C O L  
TI T L E:  
A T W O P A R T S E A M L E S S, O P E N -L A B E L, 
M U L TI -C E N T E R S T U D Y T O I N V E S TI G A T E T H E 
S A F E T Y, T O L E R A BI LI T Y, P H A R M A C O KI N E TI C S, 
P H A R M A C O D Y N A MI C S A N D E F FI C A C Y O F RI S DI P L A M  
(R O 7 0 3 4 0 6 7 ) I N I N F A N T S WI T H T Y P E 1 S PI N A L 
M U S C U L A R A T R O P H Y  
P R O T O C O L N U M B E R:  B P 3 9 0 5 6  
V E R SI O N:  
7  
E U D R A C T N U M B E R:  
2 0 1 6 -0 0 0 7 7 8 -4 0  
I N D N U M B E R: 
1 2 8 9 7 2  
N C T N U M B E R:  
N C T 0 2 9 1 3 4 8 2  
T E S T P R O D U C T:  
Ri s di pl a m  (R O 7 0 3 4 0 6 7 ) 
M E DI C A L M O NI T O R:  
, M. D., P h. D. 
S P O N S O R:  
D A T E FI N A L:  
D A T E S A M E N D E D:  
F. H off m a n n -L a R o c h e  Ltd
V er si o n 1:   2 2  J u n e 2 0 1 6  
V er si o n 2:   1 0 F e br u ar y  2 0 1 7 
V er si o n 3:   2 2 M a y  2 01 7  
V er si o n 4:   6 A pril  20 1 8  
V er si o n 5:   2 7 J a n u ar y  2 0 19 
V er si o n 6 :  1 8 M a y  2 0 2 0 
V er si o n  7 :  S e e el e ctr o ni c  d ate st a m p b el o w . 
 
1 7- J u n- 2 0 2 0 1 6: 1 3: 1 3
Titl e
A p pr o v er' s N a m e
C o m p a n y Si g n at or y
D at e a n d Ti m e ( U T C)


R O 7 0 3 4 0 6 7 — F. H off m a n n -L a R o c h e Lt d  
2/ Pr ot o c ol B P 3 9 0 5 6, V er si o n 7 
P R O T O C O L  A M E N D M E N T, V E R SI O N  7: 
R A TI O N A L E 
Pr ot o c ol  BP 3 9 0 5 6  V er si o n 6 w a s  r el e a s e d b ut i s n ot eff e cti v e; thi s  V er si o n 7 r e pr e s e nt s 
c h a n g e s  m a d e  to  Ver si o n 5 of  t h e pr ot o c ol. T h e prot o c ol  h a s  b e e n a m e n d e d  to  ma k e 
th e  f oll o wi n g c ha n g e s  t o t h e stu d y: 
•
Gi v e n  t h e a b s e n c e of a n y ri s di pl a m-i n d u c e d o p ht h al m ol o gi c al fi n di n g s t o d at e i n
4 7 1  p ati e nt s e x p o s e d t o ri s di pl a m f or u p t o 3 y e ar s, t h e fr e q u e n c y of o p ht h al m ol o g y
a s s e s s m e nt s h a s b e e n r e d u c e d t o e v er y 6  m o nt h s a n d c ol or f u n d u s p h ot o gr a p h y
will n o l o n g er b e p erf or m e d ( S e cti o n 1. 3. 2, 4. 6. 1. 8, A p p e n di x 1, A p p e n di x 2, a n d
A p p e n di x 5).
•
T h e l e n gt h of t h e o p e n -l a b el e xt e n si o n p h a s e h a s b e e n d efi n e d a s 3 y e ar s f or e a c h
p ati e nt t o all o w f or a l o n g er s af et y f oll o w -u p p eri o d. C o nti n u e d a c c e s s t o  ri s di pl a m
will b e pr o vi d e d u ntil t h e e n d of st u d y, pr o vi d e d t h at ri s di pl a m i s n ot c o m m er ci all y
a v ail a bl e i n t h e p ati e nt' s c o u ntr y . T h e l e n gt h of t h e st u d y h a s b e e n m o difi e d a n d will
n ot e x c e e d 5  y e ar s aft er t h e l a st p ati e nt i s e nr oll e d i n t h e st u d y ( S e cti o n s 3. 1. 1. 1,
3. 1. 1. 2, a n d 3. 1. 5).
•
C a uti o n ar y l a n g u a g e o n t h e c o n c o mit a nt u s e of C Y P 3 A 4 s u b str at e s h a s b e e n
r e m o v e d, b a s e d o n t h e r e c e nt r e s ult s of t h e cli ni c al dr u g-dr u g i nt er a cti o n
St u d y  B P 4 1 3 6 1 a n d s u b s e q u e nt  p h y si ol o gi c all y -b a s e d p h ar m a c o ki n eti c m o d eli n g
f or e xtr a p ol ati o n t o c hil dr e n a n d i nf a nt s. T h e st u d y s h o w e d t h at c o a d mi ni str ati o n
wit h ri s di pl a m l e d t o o nl y a s m all i n cr e a s e i n e x p o s ur e of t h e s e n siti v e C Y P 3 A
s u b str at e mi d a z ol a m , w hi c h i s n ot c o n si d er e d t o b e cli ni c all y r el e v a nt
( S e cti o n s 1. 2. 1. 2, 1. 2. 2, a n d 4. 5. 1) .
•
T h e s af et y m o nit ori n g p eri o d h a s b e e n m o difi e d t o e xt e n d fr o m s cr e e ni n g t hr o u g h
t h e o p e n-l a b el e xt e n si o n, t h e st u d y c o m pl eti o n/ e arl y wit h dr a w al vi sit, a n d f oll o w-u p
( p h o n e c all). L a n g u a g e r el at e d t o t h e st u d y c o m pl eti o n/ e arl y wit h dr a w al vi sit a n d
f oll o w-u p h a s b e e n cl arifi e d t o e n s ur e t h at all a s s e s s m e nt s ar e p erf or m e d at t h e l a st
vi sit f or e a c h p ati e nt, a n d t h at t h e f oll o w-u p  s h o ul d o c c ur 3 0  d a y s aft er t h at vi sit
( S e cti o n s 1. 3. 2, 3. 3. 1, a n d 4. 5. 1; A p p e n di x 1 a n d A p p e n di x 2).
•
S af et y m o nit ori n g a n d st o p pi n g r ul e s f or a d v er s e e v e nt s aff e cti n g t h e s ki n, m o ut h,
p h ar y n x, a n d l ar y n x h a v e b e e n r e m o v e d t o ali g n wit h c urr e nt d at a o n p ot e nti al ri s k s
u p d at e d i n t h e Ri s di pl a m I n v e sti g at or' s Br o c h ur e, V er si o n 7 ( S e cti o n s 3. 3. 1, 4. 6. 1. 4,
5. 2. 1, 5. 2. 2, 5. 2. 3 , a n d 5. 2. 4. 1; T a bl e 4, A p p e n di x 1 , a n d A p p e n di x 2).
•
T h e a d v er s e e v e nt r e p orti n g p eri o d h a s b e e n r e d u c e d t o 3 0 d a y s aft er t h e st u d y
c o m pl eti o n/ e arl y wit h dr a w al vi sit (i. e., at l e a st 3 0 d a y s aft er t h e l a st d o s e of st u d y
dr u g ), t o r efl e ct t h at a d v er s e e v e nt s ar e n ot e x p e ct e d b e y o n d t hi s r e p orti n g p eri o d;
t h e eli mi n ati o n h alf-lif e of ri s di pl a m will n ot e x c e e d 3 0 d a y s ( S e cti o n 5. 3. 1).
A d diti o n al c h a n g e s t o t h e pr ot o c ol, al o n g wit h a r ati o n al e f or e a c h c h a n g e, ar e 
s u m m ari z e d b el o w:  
•
B a c k gr o u n d i nf or m ati o n o n c o m pl et e d a n d o n g oi n g st u di e s of ri s di pl a m h a s b e e n
u p d at e d ( S e cti o n  1. 2. 2).



D o si n g i n str u cti o n s h a v e b e e n pr o vi d e d f or p ati e nt s 2 y e ar s of a g e a n d wit h b o d y
w e i g ht 2 0 k g t o ali g n wit h t h e d o si n g r e gi m e n i n St u d y B P 3 9 0 5 5 of ri s di pl a m
i n p ati e nt s 2 y e ar s ol d wit h T y p e 2 a n d T y p e 3 s pi n al m u s c ul ar atr o p h y
(S e cti o n s 3. 1. 1 . 2 a n d 3. 2. 1) .

L a n g u a g e r e g ar di n g o p ht h al m ol o gi c al a s s e s s m e nt s h a s b e e n a m e n d e d t o cl arif y
t h e r e q uir e m e nt s f or op ht h al m ol o gi c al a s s e s s or s a n d t er mi n ol o g y r el at e d t o t h e
o p ht h al m ol o g y m a n u al. I n a d diti o n, t h e c o v er/ u n c o v er t e st h a s b e e n r ei n st at e d a s
a n a s s e s s m e nt ( err o n e o u sl y o mitt e d i n pr e vi o u s pr ot o c ol v er si o n s ) a n d r e d u n d a nt
l a n g u a g e r e g ar di n g o p ht h al m ol o gi c al a s s e s s m e nt s h a s b e e n r e m o v e d
( S e cti o n s 3. 3. 1, 4. 6. 1. 8, a n d 5. 2. 2 ; A p p e n di x 5).

It h a s b e e n cl arifi e d t h at ni a ci n i s per mitt e d if u s e d a s a n utriti o n al s u p pl e m e nt
( S e cti o n 4. 5. 2).

L a n g u a g e r el at e d t o h o m e vi sit s h a s b e e n m o difi e d f or c o n si st e n c y wit h t h e
s c h e d ul e s of a s s e s s m e nt s a n d f or fl e xi bilit y t o all o w a d diti o n al a s s e s s m e nt s if
n e e d e d ( S e cti o n 4. 6. 1).

A nt hr o p o m etri c m e a s ur e m e nt a s s e s s m e nt s h a v e b e e n r e vi s e d t o r efl e ct a p pr o pri at e
m et h o d s f or p ati e nt s a s t h e y gr o w ( S e cti o n 4. 6. 1. 3) .

Effi c a c y a s s e s s m e nt s p erf or m e d d uri n g t h e o p e n -l a b el e xt e n si o n p h a s e h a v e b e e n
r e d u c e d t o i m pr o v e p ati e nt e x p eri e n c e, i n cl u di n g r e m o vi n g re s pir at or y
p l et h y s m o gr a p h y a n d c o m p o u n d m u s cl e a cti o n p ot e nti al a n d r e d u ci n g t h e B a yl e y
S c al e s of I nf a nt a n d T o d dl er D e v el o p m e nt a s s e s s m e nt s ( S e cti o n 4. 6. 1. 1 4,
A p p e n di x 1, a n d A p p e n di x 2).

S p e cifi c d et ail s of t h e c o m p o u n d m u s cl e a cti o n p ot e nti al a s s e s s m e n t h a ve b e e n
cl arifi e d ( S e cti o n 4. 6. 1. 1 6).

T h e ti mi n g of a s s e s s m e nt s d uri n g tr e at m e nt h a s b e e n a m e n d e d t o all o w fl e xi bilit y if
t h e p ati e nt i s u n c o o p er ati v e a n d t o cl arif y a s s e s s m e nt s p erf or m e d u p t o a n d
i n cl u di n g We e k 1 0 4 a n d d uri n g t h e o p e n -l a b el e xt e n si o n p h a s e ( S e cti o n 4. 6. 2. 2).

A f o ot n ot e t o T a bl e 5 ( A d v er s e E v e nt S e v erit y Gr a di n g S c al e) t h at h a d i n a d v ert e ntl y
b e e n r et ai n e d i n pr ot o c ol a m e n d m e nt V er si o n 5 h a s b e e n r e m o v e d ( S e cti o n 5. 3. 3).

T h e s t ati sti c al a n al y si s d e s cri pti o n f or t h e e x pl or at or y effi c a c y e n d p oi nt s ,
cli ni ci a n -r e p ort e d r e s pir at or y f u n cti o n a n d a bilit y t o s w all o w, h a s b e e n r e m o v e d
( S e cti o n 6. 6. 3).

T h e M e di c al M o nit or a n d a p pli c a bl e c o nt a ct i nf or m ati o n h a s b e e n c h a n g e d
t hr o u g h o ut t h e pr ot o c ol.

T h e st u d y dr u g n a m e h a s b e e n u p d at e d fr o m R O 7 0 3 4 0 6 7 t o ri s di pl a m t hr o u g h o ut
t h e pr ot o c ol.
A d diti o n al mi n or c h a n g e s h a v e b e e n m a d e t o i m pr o v e cl arit y a n d c o n si st e n c y.  
S u b st a nti v e n e w i nf or m ati o n a p p e ar s i n it ali c s.  T hi s a m e n d m e nt  r e pr e s e nt s c u m ul ati v e 
c h a n g e s t o t h e ori gi n al pr ot o c ol.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
3/ P r ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H offm a n n - La R o c h e Lt d  
4/ P r ot o c ol B P 3 9 0 5 6, V er si o n 7
T A B L E O F C O N T E N T S
P R O T O C O L A M E N D M E N T A C C E P T A N C E F O R M .......................................... 1 1
P R O T O C O L S Y N O P SI S .................................................................................... 1 2
1.
B A C K G R O U N D A N D R A TI O N A L E ............................................................ 2 6
1. 1
B a c k gr o u n d o n Di s e a s e ......................................................... 2 6
1. 2
B a c k gr o u n d o n Ri s di pl a m ...................................................... 2 7
1. 2. 1 
Pr e vi o u s N o n cli ni c al St u di e s ................................................. 2 7
1. 2. 1. 1
P h ar m a c ol o g y ........................................................................ 2 7
1. 2. 1. 2
P h ar m a c o ki n eti c s .................................................................. 2 8
1. 2. 1. 3
T o xi c ol o g y a n d S af et y P h ar m a c ol o g y ................................... 2 8
1. 2. 2
Pr e vi o u s a n d O n g oi n g Cli ni c al St u di e s .................................. 3 0
1. 2. 2. 1
Cli ni c al S u m m ar y St u d y B P 2 9 8 4 0 ......................................... 3 1
1. 2. 2. 2
Cli ni c al S u m m ar y St u d y B P 3 9 0 5 5 ( P art 1) ............................ 3 2
1. 2. 2. 3
Cli ni c al S u m m ar y St u d y B P 3 9 0 5 6 ( P art 1) ............................ 3 3
1. 3
St u d y R ati o n al e a n d B e n efi t – Ri s k A s s e s s m e nt..................... 3 3
1. 3. 1 
St u d y R ati o n al e ..................................................................... 3 3
1. 3. 2
B e n efit -Ri s k A s s e s s m e nt ....................................................... 3 5
2.
O B J E C TI V E S .............................................................................................. 3 8
2. 1
Pri m ar y O bj e cti v e s ................................................................ 3 8
2. 2
S e c o n d ar y O bj e cti v e s ............................................................ 3 8
2. 3
E x pl or at or y O bj e cti v e s ........................................................... 3 9
3.
S T U D Y D E SI G N ......................................................................................... 4 0
3. 1
D e s cri pti o n of St u d y .............................................................. 4 0
3. 1. 1
O v er vi e w of St u d y D e si g n ..................................................... 4 0
3. 1. 1. 1
E x pl or at or y P art 1 .................................................................. 4 1
3. 1. 1. 2
C o nfir m at or y P art 2 ............................................................... 4 2
3. 1. 2
I nt er n al M o nit ori n g C o m mitt e e............................................... 4 4
3. 1. 3 
I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e .............................. 4 4
3. 1. 4
P er m a n e nt V e ntil ati o n A dj u di c ati o n C o m mitt e e ..................... 4 5
3. 1. 5
E n d of St u d y .......................................................................... 4 6


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
5/ P r ot o c ol B P 3 9 0 5 6, V er si o n 7
3. 2
R ati o n al e f or St u d y D e si g n.................................................... 4 6
3. 2. 1
R ati o n al e f or D o s a g e S el e cti o n ............................................. 4 7
3. 2. 2
R ati o n al e f or St u d y P o p ul ati o n .............................................. 5 1
3. 2. 3
R ati o n al e f or C o ntr ol Gr o u p ................................................... 5 2
3. 2. 4
R ati o n al e f or Bi o m ar k er A s s e s s m e nt s ................................... 5 2
3. 3
O ut c o m e M e a s ur e s ............................................................... 5 2
3. 3. 1
S af et y O ut c o m e M e a s ur e s .................................................... 5 2
3. 3. 2
P h ar m a c o ki n eti c ( P K) a n d P h ar m a c o d y n a mi c 
( P D) O ut c o m e M e a s ur e s ....................................................... 5 3
3. 3. 2. 1
P h ar m a c o ki n eti c O ut c o m e M e a s ur e s .................................... 5 3
3. 3. 2. 2
P h ar m a c o d y n a mi c O ut c o m e M e a s ur e s ................................. 5 3
3. 3. 3
Effi c a c y O ut c o m e M e a s ur e s .................................................. 5 4
3. 3. 4
P ar e nt/ C ar e gi v er -R e p ort e d O ut c o m e M e a s ur e s ................... 5 4
4.
M A T E RI A L S A N D M E T H O D S .................................................................... 5 4
4. 1
C e nt er .................................................................................... 5 4
4. 2
St u d y P o p ul ati o n ................................................................... 5 4
4. 2. 1
R e cr uit m e nt Pr o c e d ur e s ........................................................ 5 5
4. 2. 2
I n cl u si o n Crit eri a.................................................................... 5 5
4. 2. 3
E x cl u si o n Crit eri a ................................................................... 5 6
4. 3
M et h o d of Tr e at m e nt A s si g n m e nt .......................................... 5 9
4. 4
St u d y Tr e at m e nt .................................................................... 5 9
4. 4. 1
F or m ul ati o n, P a c k a gi n g, a n d H a n dli n g .................................. 5 9
4. 4. 1. 1
P art 1 F or m ul ati o n – Ri s di pl a m ( P o w d er a n d 
s ol v e nt f or or al s ol uti o n, 2 0 m g a n d 1 2 0
m g) ......................... 5 9
4. 4. 1. 2
P art 2 F or m ul ati o n – Ri s di pl a m ( P o w d er f or or al 
s ol uti o n, 2 0 m g a n d 6 0
m g) ................................................... 5 9
4. 4. 1. 3
P a c k a gi n g a n d H a n dli n g ........................................................ 6 0
4. 4. 2
D o s a g e, A d mi ni str ati o n, a n d C o m pli a n c e .............................. 6 0
4. 4. 2. 1
Ri s di pl a m ............................................................................... 6 0
4. 4. 3
I n v e sti g ati o n al M e di ci n al Pr o d u ct A c c o u nt a bilit y ................... 6 1
4. 4. 4
P o st -Tri al A c c e s s t o Ri s di pl a m .............................................. 6 2
4. 5
C o n c o mit a nt T h er a p y a n d F o o d ............................................ 6 3
4. 5. 1
P er mitt e d T h er a p y ................................................................. 6 3
4. 5. 2
Pr o hi bit e d T h er a p y ................................................................ 6 4


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
6/ P r ot o c ol B P 3 9 0 5 6, V er si o n 7
4. 5. 3 
Pr o hi bit e d F o o d ..................................................................... 6 5
4. 6
St u d y A s s e s s m e nt s ............................................................... 6 6
4. 6. 1
D e s cri pti o n of St u d y A s s e s s m e nt s ........................................ 6 6
4. 6. 1. 1
M e di c al Hi st or y a n d D e m o gr a p hi c D at a ................................ 6 6
4. 6. 1. 2
S pi n al M u s c ul ar Atr o p h y Hi st or y ............................................ 6 7
4. 6. 1. 3
A nt hr o p o m etri c M e a s ur e m e nt s .............................................. 6 7
4. 6. 1. 4
P h y si c al E x a mi n ati o n s ........................................................... 6 8
4. 6. 1. 5
Vit al Si g n s .............................................................................. 6 8
4. 6. 1. 6
El e ctr o c ar di o gr a m s ................................................................ 6 9
4. 6. 1. 7
L a b or at or y A s s e s s m e nt s ....................................................... 7 0
4. 6. 1. 8
O p ht h al m ol o gi c al A s s e s s m e nt s ............................................. 7 1
4. 6. 1. 9
N utriti o n al C h e c k ................................................................... 7 2
4. 6. 1. 1 0
Pl a s m a Pr ot ei n Bi n di n g ......................................................... 7 2
4. 6. 1. 1 1
P h ar m a c o ki n eti c A s s e s s m e nt s .............................................. 7 2
4. 6. 1. 1 2 
Fl ui d P h ar m a c o d y n a mi c A s s e s s m e nt s .................................. 7 3
4. 6. 1. 1 3
Cli ni c al G e n ot y pi n g S a m pl e s ................................................. 7 4
4. 6. 1. 1 4  
M ot or F u n cti o n a n d M ot or D e v el o p m e nt 
A s s e s s m e nt s ......................................................................... 7 4
4. 6. 1. 1 5
R e s pir at or y Pl et h y s m o gr a p h y ................................................ 7 7
4. 6. 1. 1 6
C o m p o u n d M u s cl e A cti o n P ot e nti al ....................................... 7 8
4. 6. 1. 1 7
Cli ni ci a n - R e p ort e d R e s pir at or y a n d S w all o wi n g 
It e m s...................................................................................... 7 9
4. 6. 1. 1 8
P ar e nt/ C ar e gi v er -R e p ort e d O ut c o m e s .................................. 7 9
4. 6. 2
Ti mi n g of St u d y A s s e s s m e nt s ............................................... 8 0
4. 6. 2. 1
S cr e e ni n g a n d Pr etr e at m e nt A s s e s s m e nt s ............................ 8 0
4. 6. 2. 2
A s s e s s m e nt s d uri n g Tr e at m e nt ............................................. 8 1
4. 6. 2. 3
A s s e s s m e nt s at St u d y C o m pl eti o n/ E arl y 
Wi t h dr a w al Vi sit..................................................................... 8 2
4. 6. 2. 4
F oll o w -U p -A s s e s s m e nt s ........................................................ 8 2
4. 6. 3
Pri oriti z ati o n Or d er f or Bl o o d S a m pl e s .................................. 8 3
4. 7
P ati e nt, St u d y, a n d Sit e Di s c o nti n u ati o n ................................ 8 3
4. 7. 1
P ati e nt Di s c o nti n u ati o n .......................................................... 8 3


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
7/ P r ot o c ol B P 3 9 0 5 6, V er si o n 7
4. 7. 1. 1
Di s c o nti n u ati o n fr o m St u d y Dr u g ........................................... 8 3
4. 7. 1. 2
Wi t h dr a w al fr o m St u d y........................................................... 8 4
4. 7. 2
St u d y a n d Sit e Di s c o nti n u ati o n .............................................. 8 4
5.
A S S E S S M E N T O F S A F E T Y ....................................................................... 8 5
5. 1
S af et y P ar a m et er s a n d D efi niti o n s ........................................ 8 5
5. 1. 1 
A d v er s e E v e nt s ..................................................................... 8 5
5. 1. 2
S eri o u s A d v er s e E v e nt s (I m m e di at el y R e p ort a bl e 
t o t h e S p o n s or)...................................................................... 8 5
5. 1. 3
N o n -S eri o u s A d v er s e E v e nt s of S p e ci al I nt er e st 
(I m m e di at el y R e p orta bl e t o t h e S p o n s or) .............................. 8 6
5. 2
S af et y Pl a n ............................................................................ 8 6
5. 2. 1
S af et y Pr e c a uti o n s ................................................................ 8 7
5. 2. 2
S af et y M o nit ori n g ................................................................... 8 7
5. 2. 3
M a n a g e m e nt of S p e cifi c A d v er s e E v e nt s .............................. 8 8
5. 2. 4
St o p pi n g R ul e s ...................................................................... 8 8
5. 2. 4. 1
I n di vi d u al P ati e nt St o p pi n g R ul e s.......................................... 8 8
5. 2. 4. 2
St o p pi n g R ul e s f or a C o h ort a n d D o s e -E s c al ati o n 
Crit eri a R ul e s i n P art 1 ........................................................... 8 9
5. 2. 4. 3
St o p pi n g R ul e s f or P art 2 ....................................................... 8 9
5. 3
M et h o d s a n d Ti mi n g f or C a pt uri n g a n d 
A s s e s si n g S af et y P ar a m et e r s................................................ 9 0
5. 3. 1
A d v er s e E v e nt R e p orti n g P eri o d ........................................... 9 0
5. 3. 2
Eli citi n g A d v er s e E v e nt I nf or m ati o n ....................................... 9 0
5. 3. 3
A s s e s s m e nt of S e v erit y of A d v er s e E v e nt s ........................... 9 1
5. 3. 4
A s s e s s m e nt of C a u s alit y of A d v er s e E v e nt s ......................... 9 1
5. 3. 5
Pr o c e d ur e s f or R e c or di n g A d v er s e E v e nt s ............................ 9 2
5. 3. 5. 1
Di a g n o si s v er s u s Si g n s a n d S y m pt o m s ................................. 9 2
5. 3. 5. 2
A d v er s e E v e nt s O c c urri n g S e c o n d ar y t o Ot h er 
E v e n t s.................................................................................... 9 2
5. 3. 5. 3
P er si st e nt or R e c urr e nt A d v er s e E v e nt s ................................ 9 2
5. 3. 5. 4
A b n or m al L a b or at or y V al u e s ................................................. 9 3
5. 3. 5. 5
A b n or m al Vit al Si g n V al u e s ................................................... 9 3
5. 3. 5. 6
A b n or m al Li v er F u n cti o n T e st s .............................................. 9 4
5. 3. 5. 7
D e at h s ................................................................................... 9 4


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
8/ P r ot o c ol B P 3 9 0 5 6, V er si o n 7
5. 3. 5. 8
Pr e e xi sti n g M e di c al C o n diti o n s .............................................. 9 5
5. 3. 5. 9
H o s pit ali z ati o n or Pr ol o n g e d H o s pit ali z ati o n .......................... 9 5
5. 3. 5. 1 0
O v er d o s e s ............................................................................. 9 6
5. 3. 5. 1 1
P ar e nt/ C ar e gi v er -R e p ort e d O ut c o m e D at a ........................... 9 6
5. 4
I m m e di at e R e p orti n g R e q uir e m e nt s fr o m 
I n v e sti g at or t o S p o n s or.......................................................... 9 6
5. 4. 1
E m er g e n c y M e di c al C o nt a ct s ................................................ 9 7
5. 4. 2
R e p orti n g R e q uir e m e nt s f or S eri o u s A d v er s e 
E v e nt s a n d N o n -S eri o u s - A d v er s e E v e nt s of 
S p e ci al I nt er e st ...................................................................... 9 7
5. 4. 3
R e p orti n g R e q uir e m e nt s f or M e di c al D e vi c e 
C o m pl ai nt s ............................................................................. 9 7
5. 5
F oll o w -U p of P ati e nt s aft er A d v er s e E v e nt s .......................... 9 7
5. 5. 1
I n v e sti g at or F oll o w-U p ........................................................... 9 7
5. 5. 2
S p o n s or F oll o w -U p ................................................................ 9 8
5. 6
P o st -St u d y A d v er s e E v e nt s ................................................... 9 8
5. 7
E x p e dit e d R e p orti n g t o H e alt h A ut h oriti e s, 
I n v e sti g at or s, I n stit uti o n al R e vi e w B o ar d s, a n d 
Et hi c s C o m mitt e e s ................................................................. 9 8
6.
S T A TI S TI C A L C O N SI D E R A TI O N S A N D A N A L Y S I S P L A N....................... 9 9
6. 1
D et er mi n ati o n of S a m pl e Si z e ............................................. 1 0 0
6. 2
S u m m ari e s of C o n d u ct of St u d y .......................................... 1 0 0
6. 3
A n al y si s P o p ul ati o n s ........................................................... 1 0 1
6. 3. 1
S af et y A n al y si s P o p ul ati o n .................................................. 1 0 1
6. 3. 2
P h ar m a c o ki n eti c A n al y si s P o p ul ati o n .................................. 1 0 1
6. 3. 3
Effi c a c y A n al y si s P o p ul ati o n ................................................ 1 0 1
6. 4
S u m m ari e s of Tr e at m e nt Gr o u p C o m p ar a bilit y ................... 1 0 1
6. 5
S af et y A n al y s e s ................................................................... 1 0 1
6. 5. 1 
A d v er s e E v e nt s ................................................................... 1 0 2
6. 5. 2
Cli ni c al L a b or at or y T e st R e s ult s .......................................... 1 0 2
6. 5. 3
Vit al Si g n s ............................................................................ 1 0 2
6. 5. 4
El e ctr o c ar di o gr a m D at a A n al y si s ......................................... 1 0 2
6. 5. 5
C o n c o mit a nt M e di c ati o n s .................................................... 1 0 2
6. 6
Effi c a c y A n al y s e s ................................................................ 1 0 3


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
9/ P r ot o c ol B P 3 9 0 5 6, V er si o n 7
6. 6. 1
Pri m ar y Effi c a c y E n d p oi nt .................................................... 1 0 3
6. 6. 2
S e c o n d ar y Effi c a c y E n d p oi nt s ............................................. 1 0 3
6. 6. 3
E x pl or at or y Effi c a c y E n d p oi nt s ............................................ 1 0 7
6. 6. 4
S u b gr o u p A n al y s e s ............................................................. 1 0 8
6. 7
P h ar m a c o d y n a mi c A n al y s e s
............................................... 1 0 9
6. 8
P h ar m a c o ki n eti c A n al y s e s ................................................... 1 0 9
6. 9
I nt eri m A n al y s e s.................................................................. 1 0 9
6. 1 0
C hi n a S u b p o p ul ati o n A n al y s e s ............................................ 1 1 0
7.
D A T A C O L L E C TI O N A N D M A N A G E M E N T ............................................. 1 1 0
7. 1
D at a Q u alit y A s s ur a n c e ....................................................... 1 1 0
7. 2
El e ctr o ni c C a s e R e p ort F or m s ............................................. 1 1 1
7. 3
S o ur c e D at a D o c u m e nt ati o n ................................................ 1 1 1
7. 4
U s e of C o m p ut eri z e d S y st e m s ............................................ 1 1 2
7. 5
R et e nti o n of R e c or d s ........................................................... 1 1 2
8.
E T HI C A L C O N SI D E R A TI O N S .................................................................. 1 1 2
8. 1
C o m pli a n c e wit h L a w s a n d R e g ul ati o n s .............................. 1 1 2
8. 2
I nf or m e d C o n s e nt................................................................ 1 1 3
8. 3
I n stit uti o n al R e vi e w B o ar d or Et hi c s C o m mitt e e .................. 1 1 3
8. 4
C o nfi d e nti alit y ...................................................................... 1 1 4
8. 5
Fi n a n ci a l Di s cl o s ur e ............................................................ 1 1 4
9.
S T U D Y D O C U M E N T A TI O N, M O NI T O RI N G, A N D
A D MI NI S T R A TI O N ................................................................................... 1 1 5
9. 1
St u d y D o c u m e nt ati o n .......................................................... 1 1 5
9. 2
Pr ot o c ol D e vi ati o n s .............................................................. 1 1 5
9. 3
Sit e I n s p e cti o n s ................................................................... 1 1 5
9. 4
A d mi ni str ati v e Str u ct ur e ....................................................... 1 1 5
9. 5
Di s s e mi n ati o n of D at a a n d Pr ot e cti o n of Tr a d e 
S e cr et s ................................................................................ 1 1 6
9. 6
Pr ot o c ol A m e n d m e nt s ......................................................... 1 1 7
1 0.
R E F E R E N C E S ......................................................................................... 1 1 8


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 0 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
LI S T O F T A B L E S
T a bl e 1
O v er vi e w of t h e M ar gi n s v er s u s K e y T o xi citi e s of Ri s di pl a m ...... 3 7
T a bl e 2  
Or d er a n d Bl o c k s of A s s e s s m e nt s at Vi sit s W h e n Effi c a c y 
M e a s ur e m e nt s Ar e P erf or m e d, u p t o a n d I n cl u di n g W e e k 
1 0 4 .............................................................................................. 8 2
T a bl e 3
Pri oriti z ati o n Or d er f or Bl o o d S a m pl e s ........................................ 8 3
T a bl e 4  
G ui d eli n e s f or M a n a gi n g S p e cifi c A d v er s e E v e nt s ...................... 8 8
T a bl e 5 
A d v er s e E v e nt S e v erit y Gr a di n g S c al e ....................................... 9 1
LI S T O F A P P E N DI C E S
A p p e n di x 1 
S c h e d ul e of A s s e s s m e nt s: P art 1 ............................................. 1 2 1
A p p e n di x 2
S c h e d ul e of A s s e s s m e nt s: P art 2 ............................................. 1 2 6
A p p e n di x 3
P K/ P D Bl o o d Dr a w s: P art 1 ...................................................... 1 3 0
A p p e n di x 4
P K/ P D Bl o o d Dr a w s: P art 2 ...................................................... 1 3 1
A p p e n di x 5
O p ht h al m ol o g y E x a mi n ati o n:  P art s 1 a n d 2 ............................. 1 3 2






R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 3 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7

T o e v al u at e t h e pr o p orti o n of i nf a nt s w h o a c hi e v e a s c or e of 4 0 or hi g h er i n t h e C hil dr e n' s
H o s pit al of P hil a d el p hi a I nf a nt T e st of N e ur o m u s c ul ar Di s or d er s ( C H O P -I N T E N D) at
1 2 m o nt h s of tr e at m e nt.

T o e v al u at e t h e pr o p orti o n of i nf a nt s w h o a c hi e v e a n i n cr e a s e of at l e a st 4 p oi nt s o n t h eir
C H O P -I N T E N D s c or e fr o m b a s eli n e at 8 a n d 1 2 m o nt h s of tr e at m e nt.

T o e v al u at e t h e pr o p orti o n of i nf a nt s w h o a c hi e v e h e a d c o ntr ol at 8, 1 2, a n d 2 4 m o nt h s of
tr e at m e nt ( d efi n e d a s a s c or e of 3 or hi g h er f or it e m 1 2 of t h e C H O P -I N T E N D).

T o a s s e s s t h e c h a n g e fr o m b a s eli n e i n t h e t ot al r a w s c or e of t h e B SI D -III gr o s s m ot or s c al e
at 1 2 a n d 2 4 m o nt h s of tr e at m e nt.

T o a s s e s s t h e pr o p orti o n of i nf a nt s w h o a c hi e v e a r e d u cti o n o f at l e a st 3 0 d e gr e e s i n p h a s e
a n gl e at 1 2 m o nt h s of tr e at m e nt m e a s ur e d b y r e s pir at or y pl et h y s m o gr a p h y ( R P).

T o e v al u at e t h e pr o p orti o n of i nf a nt s w h o d o n ot r e q uir e i n v a si v e or n o n -i n v a si v e r e s pir at ory
s u p p ort at 1 2 a n d 2 4 m o nt h s of tr e at m e nt.

T o a s s e s s a t 1 2 a n d 2 4 m o nt h s of tr e at m e nt t h e pr o p orti o n of i nf a nt s w h o ar e ali v e wit h o ut
p er m a n e nt v e ntil ati o n, a s d efi n e d b y 1 6 h o ur s of n o n -i n v a si v e v e ntil ati o n p er d a y or
i nt u b ati o n f or2 1 c o n s e c uti v e d a y s i n t h e a b s e n c e of, or f oll o wi n g t h e r e s ol uti o n of, a n
a c ut e r e v er si bl e e v e nt or tr a c h e o st o m y.

T o a s s e s s t h e i m p a ct of tr e at m e nt wit h ri s di pl a m o n ti m e -t o-e v e nt ( d e at h, p er m a n e nt
v e ntil ati o n).

T o e v al u at e t h e pr o p orti o n of i nf a nt s wit h t h e a bilit y t o f e e d or all y at 1 2 a n d 2 4 m o nt h s of
tr e at m e nt.
E x pl or at or y O bj e cti v e s
T h e e x pl or at or y o bj e cti v e s f or P art 2 of t hi s st u d y ar e a s f oll o w s:

T o e x pl or e t h e eff e ct of tr e at m e nt wit h ri s di pl a m o n p ar e nt/ c ar e gi v er -r at e d i nf a nt h e alt h
st at u s a n d i m p a ct o n t h e p ar e nt/ c ar e gi v er, a s m e a s ur e d b y t h e I nf a nt T o d dl er Q u ality of
Lif e Q u e sti o n n air e at 1 2 a n d 2 4 m o nt h s .

T o a s s e s s at 8, 1 2, a n d 2 4 m o nt h s of tr e at m e nt wit h ri s di pl a m t h e r ati o b et w e e n t h e c h e st
a n d h e a d cir c u mf er e n c e.

T o e x pl or e t h e tr e at m e nt eff e ct o n pr e -s p e cifi e d di s e a s e -r el at e d a d v er s e e v e nt s b y 1 2 a n d
2 4 m o nt h s of tr e at m e nt.

T o i n v e sti g at e t h e eff e ct at 1 2 a n d 2 4 m o nt h s of tr e at m e nt wit h ri s di pl a m o n m u s cl e
el e ctr o p h y si ol o g y , a s a s s e s s e d b y c o m p o u n d m u s cl e a cti o n p ot e nti al ( C M A P).

T o e x pl or e t h e eff e ct of tr e at m e nt wit h ri s di pl a m o n t h e n u m b er of h o s pit ali z ati o n s (f or a n y
r e a s o n) p er p ati e nt -y e ar a n d n u m b er of ni g ht s a d mitt e d t o h o s pit al p er i nf a nt at 1 2 a n d
2 4 m o nt h s of tr e at m e nt .

T o e v al u at e at 2 4 m o nt h s t h e eff e ct s of ri s di pl a m o n s u st ai n e d sitti n g f or t h o s e i nf a nt s
sitti n g at 1 2 m o nt h s ( d efi n e d a s sitti n g wit h o ut s u p p ort f or 5 s e c o n d s) .

T o e x pl or e at 2 4 m o nt h s t h e m ai nt e n a n c e of t h e eff e ct s of ri s di pl a m o n r e s pir at or y f u n cti o n
f or t h o s e i nf a nt s w h o a c hi e v e a r e d u cti o n of at l e a st 3 0 d e gr e e s i n p h a s e a n gl e at
1 2 m o nt h s.

T o e x pl or e at 1 2 m o nt h s t h e eff e ct of tr e at m e nt wit h ri s di pl a m o n cli ni ci a n -r e p ort e d c h a n g e s
i n i nf a nt s’ r e s pir at ory f u n cti o n a n d s w all o wi n g a bilit y, a s m e a s ur e d b y t h e cli ni c al d o m ai n
l e v el it e m s.

T o a s s e s s at 1 2 a n d 2 4 m o nt h s of tr e at m e nt wit h ri s di pl a m t h e c h a n g e fr o m b a s eli n e i n
w ei g ht a n d l e n gt h/ h ei g ht p er c e ntil e s.






R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 6 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
E x cl u si o n crit eri a:
I nf a nt s w h o m e et a n y of t h e f oll o wi n g crit eri a will b e e x cl u d e d fr o m st u d y e ntry:
1)
I n a bilit y t o m e et st u d y r e q uir e m e nt s.
2)
C o n c o mit a nt or pr e vi o u s p arti ci p ati o n i n a n y i n v e sti g ati o n al dr u g or d e vi c e st u d y wit hi n
9 0 d a y s pri or t o s cr e e ni n g or 5 h alf -li v e s, w hi c h e v er i s l o n g er.
3)
C o n c o mit a nt or pr e vi o u s a d mi ni str ati o n of a S M N 2 -t ar g eti n g a nti s e n s e oli g o n u cl e oti d e,
S M N 2 s pli ci n g m o difi er or g e n e t h er a p y eit h er i n a cli ni c al st u d y or a s p art of m e di c al c ar e.
4)
A n y hi st or y of c ell t h er a p y.
5)
H o s pit ali z ati o n f or p ul m o n ar y e v e nt wit hi n t h e l a st 2 m o nt h s, or pl a n n e d at t h e ti m e of
s cr e e ni n g.
6)
U n st a bl e g a str oi nt e sti n al , r e n al, h e p ati c, e n d o cri n e or c ar di o v a s c ul ar s yst e m di s e a s e s.
7)
I n t h e o pi ni o n of t h e I n v e sti g at or, i n a d e q u at e v e n o u s or c a pill ary bl o o d a c c e s s f or t h e st u d y
pr o c e d ur e s.
8)
P ati e nt s r e q uiri n g i n v a si v e v e ntil ati o n or tr a c h e o st o m y.
9)
P ati e nt s r e q uiri n g a w a k e n o n -in v a si v e v e ntil ati o n or wit h a w a k e h y p o x e mi a ( S a O 2 9 5 %)
wit h or wit h o ut v e ntil at or s u p p ort.
1 0) P ati e nt s wit h a hi st or y of r e s pir at or y f ail ur e or s e v er e p n e u m o ni a, a n d h a v e n ot f ull y
r e c o v er e d t h eir p ul m o n ar y f u n cti o n at t h e ti m e of s cr e e ni n g.
1 1) M ulti pl e or fi x e d c o ntr a ct ur e s a n d/ or hi p s u bl u x ati o n or di sl o c ati o n at birt h.
1 2) Pr e s e n c e of n o n -S M A -r el at e d c o n c urr e nt s y n dr o m e s or di s e a s e s.
1 3) C o nfir m e d ( 2 c o n s e c uti v e m e a s ur e m e nt s) s y st oli c bl o o d pr e s s ur e ( S B P) or di a st oli c bl o o d
pr e s s ur e ( D B P) o ut si d e t h e 9 5 t h p er c e ntil e f or a g e; r e sti n g h e art r at e 7 0 b p m or 1 7 0 b p m .
1 4) Pr e s e n c e of cli ni c all y r el e v a nt el e ctr o c ar di o gr a m ( E C G) a b n or m aliti e s b ef or e st u d y dr u g
a d m i ni str ati o n; c orr e ct e d Q T i nt er v al u si n g B a z ett’ s m et h o d ( Q T c B) 4 6 0 m s; p er s o n al or
f ami l y hi st or y (fir st d e gr ee r el ati v e s) of c o n g e nit al l o n g Q T s y n dr o m e i n di c ati n g a s af et y ri s k
f or p ati e nt s a s d et er mi n e d b y t h e I n v e sti g at or. Fir st-d e gr e e atri o v e ntri c ul ar bl o c k or i s ol at e d
ri g ht b u n dl e br a n c h bl o c k ar e all o w e d.
1 5) Hi st or y of m ali g n a n c y if n ot c o n si d er e d c ur e d.
1 6) A n y m aj or ill n e s s wit hi n o n e m o nt h b ef or e t h e s cr e e ni n g e x a mi n ati o n or a n y f e bril e ill n e s s
wit hi n o n e w e e k pri or t o s cr e e ni n g a n d u p t o fir st d o s e a d mi ni str ati o n.
1 7) T a ki n g a n y n utri e nt s k n o w n t o m o d ul at e C Y P 3 A a cti vit y ( e. g., gr a p efr uit j ui c e; S e vill e
or a n g e) wit hi n 2 w e e k s pri or t o a d mi ni str ati o n of st u d y dr u g s.
1 8) T h e i nf a nt ( a n d t h e m ot h er, if br e a stf e e di n g t h e p ati e nt):
a.
A n y i n hi bit or of C Y P 3 A 4 t a k e n wit hi n 2 w e e k s ( or wit hi n 5 ti m e s t h e eli mi n ati o n
h alf -lif e, w hi c h e v er i s l o n g er) pri or t o d o si n g, i n cl u di n g b ut n ot li mit e d t o:
k et o c o n a z ol e, mi c o n a z ol e, itr a c o n a z ol e, fl u c o n a z ol e, er yt hr o m y c i n, cl arit hr o my c i n,
r a niti di n e, ci m eti di n e.
b.
A n y i n d u c er of C Y P 3 A 4 t a k e n wit hi n 4 w e e k s ( or wit hi n 5 ti me s t h e eli mi n ati o n h alf -
lif e, w hi c h e v er i s l o n g er) pri or t o d o si n g, i n cl u di n g b ut n ot li mit e d t o: rif a m pi ci n,
rif a b uti n, gl u c o c orti c oi d s, c ar b a m a z e pi n e, p h e n y t oi n, p h e n o b ar bit al, St. J o h n' s w ort.
c.
A n y O C T - 2 a n d M A T E s u b str at e s s h all b e a v oi d e d (i n cl u di n g b ut n ot li mit e d t o:
a m a nt a di n e, ci m eti di n e, m e m a nti n e, a mil ori d e, f a m oti di n e, m etf or mi n, pi n d ol ol,
r a niti di n e, pr o c ai n a mi d e, v ar e ni cli n e, a c y cl o vir, g a n ci cl o vir, o x ali pl ati n, c e p h al e xi n,
c e p hr a di n e, f e x of e n a di n e).
d.
A n y k n o w n F M O 1 or F M O 3 i n hi bit or s or s u b str at e s.


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 7 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
1 9) Cli ni c all y si g nifi c a nt a b n or m aliti e s i n l a b or at or y t e st r e s ult s e. g., Gr a d e 1 a n e mi a, al a ni n e
a m i n otr a n sf er a s e ( A L T) v al u e s e x c e e di n g 1. 5 t h e u p p er li mit of n or m al ( U L N) u nl e s s t h e
el e v at e d A L T l e v el i s c o n si d er e d of m u s c ul ar ori gi n (i. e., i n t h e a b s e n c e of ot h er e vi d e n c e
of li v er di s e a s e w hi c h i s c o nfir m e d b y el e v at e d cr e ati n e ki n a s e a n d l a ct at e d e h y dr o g e n a s e
[ L D H]). O ut of r a n g e cr e ati n e ki n a s e l e v el s s h o ul d b e r e vi e w e d i n li g ht of t h e u n d erl yi n g
S M A p at h ol o g y of t h e p ati e nt; el e v at e d l e v el s p er s e d o n ot di s q u a lify t h e p ati e nt fr o m t h e
st u d y. I n t h e c a s e of u n c ert ai n or q u e sti o n a bl e r e s ult s, t e st s p erf or m e d d uri n g s cr e e ni n g
m a y b e r e p e at e d b ef or e e nr oll m e nt t o c o nfir m eli gi bilit y.
2 0) A s c ert ai n e d or pr e s u m pti v e h y p er s e n siti vit y ( e. g., a n a p h yl a cti c r e a cti o n) t o ri s dipl a m or t o
t h e c o n stit u e nt s of it s f or m ul ati o n
2 1) C o n c o mit a nt di s e a s e or c o n diti o n t h at c o ul d i nt erf er e wit h, or tr e at m e nt of w hi c h mi g ht
i nt erf er e wit h, t h e c o n d u ct of t h e st u d y, or t h at w o ul d, i n t h e o pi ni o n of t h e I n v e sti g at or,
p o s e a n u n a c c e pt a bl e ri s k t o t h e s u bj e ct i n t hi s st u d y.
2 2) T h er a p e uti c u s e, d efi n e d a s u s e f or 8 w e e k s or l o n g er, of t h e f oll o wi n g m e di c ati o n s wit hi n
9 0 d a y s pri or t o e nr oll m e nt: ril u z ol e, v al pr oi c a ci d, h y dr o x y ur e a, s o di u m p h e n yl b ut yr at e,
b ut yr at e d eri v ati v e s, cr e ati n e, c ar niti n e, gr o w t h h or m o n e, a n a b oli c st er oi d s, pr o b e n e ci d,
a g e nt s a nti ci p at e d t o i n cr e a s e or d e cr e a s e m u s cl e str e n gt h, a g e nt s wit h k n o w n or
pr e s u m e d hi st o n e d e a c et yl a s e ( H D A C) i n hi bit or y eff e ct, m e di c ati o n s k n o w n t o or s u s p e ct e d
of c a u si n g r eti n al t o xi cit y ( e. g. d ef er o x a m i n e, t o pir a m at e, l at a n o pr o st, ni a ci n, r o si glit a z o n e,
t a m o xif e n, c a nt h a x a nt hi n e, sil d e n afil, a n d i nt erf er o n) a n d m e di c ati o n s wit h k n o w n
p h ot ot o xi cit y li a biliti e s ( e. g., or al r eti n oi d s i n cl u di n g o v er -t h e-c o u nt er [ O T C] f or m ul ati o n s,
a m i o d ar o n e, p h e n ot hi a zi n e s a n d u s e of mi n o c y cli n e). S h ort er u s e of a n y of t h e s e dr u g s
wit hi n 9 0 d a y s pri or t o e nr oll m e nt will b e r e vi e w e d o n a c a s e -b y -c a s e b a si s a n d di s c u s s e d
b et w e e n t h e S p o n s or a n d t h e I n v e sti g at or, w h o will j oi ntl y m a k e t h e d e ci si o n if t h e p ati e nt
c a n b e e nr oll e d i n t h e st u d y. (I nf a nt s w h o ar e o n i n h al e d c orti c o st er oi d s, a d mi ni st er e d
eit h er t hr o u g h a n e b uli z er or a n i n h al er, will b e all o w e d i n t h e st u d y).
a.
I nf a nt s m u st n ot b e gi n tr e at m e nt wit h t h e a b o v e m e di c ati o n s aft er i niti ati n g st u d y
dr u g.
2 3) R e c e ntl y i niti at e d tr e at m e nt (wit hi n 6 w e e k s pri or t o e nr oll m e nt) wit h or al s al b ut a m ol or
a n ot h er 2- a dr e n er gi c a g o ni st t a k e n or all y i s n ot all o w e d. I nf a nt s w h o h a v e b e e n o n or al
s al b ut a m ol ( or a n ot h er 2- a dr e n er gi c a g o ni st) f or 6 w e e k s b ef or e s cr e e ni n g a n d h a v e
s h o w n g o o d t ol er a n c e ar e all o w e d. T h e d o s e of 2- a dr e n er gi c a g o ni st s h o ul d r e m ai n st a bl e
a s m u c h a s p o s si bl e f or t h e d ur ati o n of t h e st u d y. U s e of i n h al e d 2- a dr e n er gi c a g o ni st s
( e. g., f or t h e tr e at m e nt of a st h m a) i s all o w e d.
2 4) Pri or u s e ( at a n y ti m e i n t h e p ati e nt s ’ li v e s) a n d/ or a nti ci p at e d n e e d f or q ui n oli n e s
( c hl or o q ui n e a n d h y dr o xy c hl or o q ui n e), t hi ori d a zi n e, vi g a b atri n, r eti g a bi n e, or a n y ot h er dr u g
k n o w n t o c a u s e r eti n al t o xi cit y d uri n g t h e st u d y d o e s n ot all o w p arti ci p ati o n i n t h e tri al.
I nf a nt s e x p o s e d t o c hlor o q ui n e, h y dr o x y c h ol or o q ui n e, t hi ori d a zi n e, vi g a b atri n, r eti g a bi n e or
dr u g s wit h k n o w n r eti n al t o xi cit y gi v e n t o m ot h er s d uri n g pr e g n a n c y ( a n d l a ct ati o n) s h o ul d
n ot b e e nr oll e d.
2 5) R e c e nt hi st or y (l e s s t h a n 6 m o nt h s) of o p ht h al mi c di s e a s e s ( e. g., gl a u c o m a n ot c o ntr oll e d
b y  tr e at m e nt, c e ntr al s er o u s r eti n o p at h y, i nfl a m m at or y/i nf e cti o u s r eti niti s u nl e s s cl e arl y
i n a cti v e, r eti n al d et a c h m e nt, i ntr a o c ul ar tr a u m a, r eti n al d y str o p h y or d e g e n er ati o n, o pti c
n e ur o p at h y, or o pti c n e uriti s) t h at w o ul d i nt erf er e wit h t h e c o n d u ct of t h e st u d y a s a s s e s s e d
b y  a n o p ht h al m ol o gi st. A n y ot h er a b n or m aliti e s d et e ct e d wit h O C T at s cr e e ni n g
( e. g., r eti n al l a y er a b n or m aliti e s, e d e m a, c ysti c or atr o p hi c c h a n g e s) m u st b e di s c u s s e d
wit h t h e I n v e sti g at or, O p ht h al m ol o gi st, a n d wit h t h e S p o n s or, w h o will j oi ntl y m a k e t h e
d e ci si o n if t h e p ati e nt m a y b e e nr oll e d i n t h e st u d y. I nf a nt s i n w h o m O C T m e a s ur e m e nt of
s uffi ci e nt q u alit y c a n n ot b e o bt ai n e d at s cr e e ni n g will n ot b e e nr oll e d.
L E N G T H O F S T U D Y

T h e d ur ati o n of t h e st u d y f or e a c h i nf a nt e nr oll e d i n P art 1 ( n ot i n cl u di n g t h e e xt e n si o n
p h a s e) will b e di vi d e d a s f oll o w s:
S cr e e ni n g: U p t o 3 0 d a y s pri or t o fir st d o s e .


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 8 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
Tr e at m e nt P eri o d: mi ni m u m of 2 w e e k s at st e a d y st at e e x p o s ur e ( a s d e ci d e d b y t h e I nt er n al 
M o nit ori n g C o m mitt e e [I M C]).

T h e d ur at i o n of t h e st u d y f or e a c h i nf a nt e nr oll e d i n P art 2 ( n ot i n cl u di n g t h e e xt e n si o n
p h a s e) will b e u p t o 2 5 m o nt h s a s f oll o w s :
S cr e e ni n g: u p t o 3 0 d a y s pri or t o fir st d o s e.
Tr e at m e nt p eri o d: 2 4 m o nt h s fr o m t h e st art of d o si n g, wit h t h e pri m ar y a n al ysi s aft er t h e l a st
i nf a nt r e a c h e s a mi ni m u m of 1 2 m o nt h s of tr e at m e nt.
Aft er e a c h i nf a nt c o m pl et e s 2 4 m o nt h s of tr e at m e nt, h e or s h e will e nt er a n o p e n -l a b el
e xt e n si o n.
E N D O F S T U D Y
T h e e n d of t hi s st u d y i s d efi n e d a s t h e d at e w h e n t h e l a st p ati e nt l a st vi sit ( L P L V) o c c ur s. L P L V 
is ex pe cte d t o o c c ur at t he l atest w he n t he l ast p atie nt e nr olle d i n t he st u d y h as c o m plete d 
2 4 m o nt hs i n t he tre at me nt p h ase a n d 3 ye ars i n t he o pe n l a bel e xte nsi o n .
T h e st u d y will c o nti n u e u ntil t he E O S, or a s p er l o c al r e g ul ati o n, or p er t h e S p o n s or’ s d e ci si o n t o 
t er mi n at e ri s di pl a m d e v el o p m e nt. T h e le n gth of t he st u d y  will n ot e x c e e d 5 ye ars aft er t h e l a st 
p ati e nt i s e nr oll e d i n t h e st u d y.
After c o m pleti o n of 2 4 m o nt hs of tre at me nt, e a c h p atie nt will e nter t he o pe n -l a bel e xte nsi on 
p h ase f or a n a d diti o n al 3 ye ars. After a p atie nt h as c o m plete d 3 ye ars i n t he o pe n -l a bel 
e xte nsi o n, t he p atie nt m a y c o nti n ue i n t he st u d y u ntil E O S, pr o vi de d t h at ris di pl a m is n ot 
c o m mer ci all y a v ail a ble i n t he p atie nt's c o u ntr y .
O U T C O M E M E A S U R E S
S A F E T Y O U T C O M E M E A S U R E S
T h e s af et y  o ut c o m e m e a s ur e s f or t hi s st u d y ar e a s f oll o w s:

I n ci d e n c e a n d s e v erit y of a d v er s e e v e nt s.

I n ci d e n c e a n d s e v erit y of s eri o u s a d v er s e e v e nt s.

I n ci d e n c e of tr e at m e nt di s c o nti n u ati o n s d u e t o a d v er s e e v e nt s.

I n ci d e n c e of a b n or m al l a bor at or y v al u e s.

I n ci d e n c e of a b n or m al E C G v al u e s.

Vit al si g n s a b n or m aliti e s, i n cl u di n g b o d y  t e m p er at ur e, s yst oli c a n d di a st oli c bl o o d pr e s s ur e,
h e art r at e, r e s pir at or y r at e.

O p ht h al m ol o gi c al a s s e s s m e nt s a s a p pr o pri at e f or a g e.

P h y s i c al e x a mi n ati o n.

A nt hr o p o m etri c e x a mi n ati o n, i n cl u di n g w ei g ht, h ei g ht, h e a d, a n d c h e st cir c u mf er e n c e.
A d v er s e e v e nt s a n d c o n c o mit a nt m e di c ati o n s will b e m o nit or e d t hr o u g h o ut t h e e ntir e st u d y 
( s cr e e ni n g t hr o u g h o pe n -l a bel e xte nsi o n or t he st u d y c o m pleti o n/e arl y wit h dr a w al visit a nd 
f oll o w-u p).
P H A R M A C O KI N E TI C O U T C O M E M E A S U R E S
Bl o o d s a m pl e s f or d et er mi n ati o n of pl a s m a c o n c e ntr ati o n s of ri s di pl a m, a n d it s m et a b olit e( s) a s 
a p pli c a bl e, will b e c oll e ct e d a s d et ail e d i n t h e S o A. T h e f oll o wi n g p ar a m et er s will b e c al c ul at e d 
(if p o s si bl e, b a s e d o n t h e a v ail a bl e d at a):

C o n c e ntr ati o n p er ti m e -p oi nt li st e d.

P e a k pl a s m a c o n c e ntr ati o n ( C m a x ).

Ar e a u n d er t h e c ur v e ( A U C).

C o n c e ntr ati o n at t h e e n d of a d o si n g i nt er v al ( C tr o u g h) t o a s s e s s st e a d y-st at e.

Ot h er P K p ar a m et er s a s a p pr o pri at e


P H A R M A C O D Y N A M I C O U T C O M E M E AS U R E S
T h e fl ui d P D a s s e s s m e nt s ( S M N m R N A a n d S M N pr ot ei n i n bl o o d) will b e p erf or m e d a s 
d et ail e d i n t h e S o A.
E F FI C A C Y O U T C O M E M E A S U R E S
T h e effi c a c y  o ut c o m e m e a s ur e s f or t hi s st u d y ar e a s f oll o w s:

M ot or mi l e st o n e s a c hi e v e d a s a s s es s e d b y t h e Gr o s s M ot or S c al e of t h e B SI D -III.

M ot or mil e st o n e s a c hi e v e d a s a s s e s s e d b y H a m m er s mit h I nf a nt N e ur ol o gi c al E x a mi n ati o n
M o d ul e
2 ( HI N E -2).

C H O P -I N T E N D.

R P.

Di s e a s e -r el at e d a d v er s e e v e nt s.

C M A P.

L e v el of r e s pir at or y s u p p ort.

V e ntil ati o n fr e e -s ur vi v al.

A bilit y t o s w all o w a n d t o f e e d or all y.

Cli ni ci a n -r e p ort e d r e s pir at or y f u n cti o n a n d a bilit y t o s w all o w it e m s.

C h a n g e i n h ei g ht a n d w ei g ht.
P A R E N T/ C A R E GI V E R R E P O R T E D O U T C O M E M E A S U R E S
T h e p ar e nt/ c ar e gi v er -r e p ort e d o ut c o m e m e a s ur e f or t hi s st u d y i s a s f oll o w s:

P ar e nt/ c ar e gi v er -rat e d i nf a nt h e alt h st at u s a n d i m p a ct o n t h e p ar e nt/ c ar e gi v er, a s
m e a s ur e d b y t h e I nf a nt T o d dl er Q u alit y of Lif e (I T Q O L) Q u e sti o n n air e.
BI O M A R K E R/ G E N O T Y PI N G S A M P L E C O L L E C TI O N
Cli ni c al G e n ot y pi n g ( C G) S a m pl e s
A si n gl e m a n d at or y w h ol e bl o o d s a m pl e will b e t a k e n fr o m e v er y p ati e nt at s cr e e ni n g f or D N A 
e xtr a c ti o n. T h e D N A will b e u s e d t o d et er mi n e t h e n u m b er of c o pi e s of t h e S M N 2  g e n e a n d t o 
c o nfir m S M N 1  g e n e m ut ati o n or d el eti o n.
A m a n d at or y w h ol e bl o o d s a m pl e wi ll b e t a k e n f or D N A e xtr a cti o n fr o m e v er y p ati e nt o n c e 
e nr oll e d o nt o t h e st u d y a n d m a y  b e u s e d f or a d diti o n al c o nfir m at or y  t e sti n g of S M N 1
d el eti o n/ S M N 2  c o p y  n u m b er.
S a m pl e s m a y  b e u s e d f or e x pl or at or y a n al y si s/ a s s a y d e v el o p m e nt r el at e d t o S M A, i n c l u di n g, 
b ut n ot li mit e d t o, mit o c h o n dri al D N A a n d g e n e s r el at e d t o S M N f u n cti o n or tr e at m e nt r e s p o n s e.
I N V E S TI G ATI O N A L M E DI CI N A L P R O D U C T
E x pl or at or y P art 1:
T h e I n v e sti g ati o n al M e di ci n al Pr o d u ct (I M P) will b e s u p pli e d i n  b ottl e s c o nt ai ni n g 2 0 m g  or 
1 2 0  m g  of ri s dipl a m d r u g s u b st a n c e ( n o e x ci pi e nt). B ef or e a d mi ni str ati o n, t h e dr u g su b st a n c e 
will b e c o n stit ut e d wit h a s ol v e nt, w hi c h i s pr e p ar e d b y di s s ol vi n g a pr o vi d e d e x ci pi e nt bl e n d 
wit h w at er f or i nj e cti o n. F or t h e fir st i nf a nt( s), a f urt h er di l uti o n st e p i s f or e se e n t o e n a bl e t h e 
a d m i ni str ati o n of a l o w st arti n g d o s e.
C o nfir m at or y  P art 2:
T h e I M P will c h a n g e t o a n e w f or m ul ati o n w hi c h i s s u p pli e d i n b ottl e s fill e d wit h p o w d er bl e n d s 
c o nt ai ni n g 2 0 m g or 6 0 m g of  ri s di pl a m dr u g s u b st a n c e a s w ell a s all e x ci pi e nt s. T h e dr u g 
s ol uti o n c a n b e dir e ctl y c o n stit ut e d wit h p urifi e d w at er i n t h e  b ottl e of t h e I M P.
ri s di pl a m s h o ul d b e t a k e n or all y o n c e d ail y. I n t h e c a s e of br e a stf e e di n g, t h e p ati e nt s h o ul d b e 
f e d pri or t o d o si n g, wi n d e d , a n d t h e st u d y m e di c ati o n a d mi ni st er e d. St u d y p arti ci p a nt s u n a bl e t o 
s w all o w t h e st u d y m e di c ati o n a n d w h o h a v e a  n a s o -g a stri c or g a str o st o m y t u b e i n sit u s h o ul d 
r e c ei v e t h e st u d y m e di c ati o n b y b ol u s vi a t h e t u b e.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
1 9 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


P R O C E D U R E S
S c h e d ul e of a s s e s s m e nt s t a bl e s ar e pr o vi d e d i n A p p e n di c e s.
S T A T I S TI C AL M E T H O D S
T h e a n al y s e s of t hi s s t u d y will b e str u ct ur e d i nt o t w o p art s; e x pl or at or y (P art  1)  t o s el e ct t h e 
d o s e a n d c o nfir m at or y ( P art  2) t o e v al u at e t h e tr e at m e nt eff e ct of ri s di pl a m.
F oll o wi n g t h e d o s e s el e cti o n f or P art  2, d at a fr o m t h e e x pl or at or y P art  1  of t hi s st u d y ( a n d t h e 
P art  1 e xt e n si o n p h a s e) m a y b e l o c k e d at i nt er v al s i n or d er t o a n al y z e a n d r e p ort t h e s af et y, 
P K/ P D , a n d e x pl or at or y effi c a c y of t h o s e p ati e nt s e nr oll e d i nt o P art  1 o nl y.
A d at a b a s e l o c k f or t h e p ur p o s e of t h e pri m ar y a n al y si s a n d a n al y s e s of t h e 1 2 - mo nt h 
s e c o n d ar y a n d e x pl or at or y e n d p oi nt s will o c c ur o n c e t h e l a st i nf a nt e nr oll e d i nt o P art  2 d uri n g 
t h e gl o b al e nr oll m e nt p h a s e h a s eit h er c o m pl et e d hi s/ h er 1 2- mo nt h a s s e s s m e nt or h a s b e e n 
wit h dr a w n. At t h e ti m e of t h e pri m ar y  a n al ysi s,  all a v ail a bl e effi c a c y  d at a p o st M o nt h  1 2 will b e 
r e p ort e d. All a v ail a bl e s af et y d at a i n b ot h p art s of t h e st u d y will b e r e p ort e d. A d at a b a s e l o c k f or 
t h e a n al y s e s of t h e 2 4- mo nt h s e c o n d ar y a n d e x pl or at or y e n d p oi nt s will o c c ur o n c e t h e l a s t 
i nf a nt e nr oll ed i nt o P art  2  d uri n g t h e gl o b al e nr oll m e nt p h a s e h a s eit h er c o m pl et e d hi s/ h e r 
2 4 - mo nt h a s s e s s m e nt or h a s b e e n wit h dr a w n.
T h e gl o b al p o p ul ati o n will i n cl u d e all i nf a nt s e nr oll e d d uri n g t h e gl o b al e nr oll m e nt p h a s e 
(i n cl u di n g i nf a nt s e nr oll e d at 
-re c o g ni z e d sit e s d uri n g t h e gl o b al p h a s e), a n d t h e C hi n a 
s u b p o p ul ati o n will i n cl u d e all i nf a nt s e nr oll e d at  
-re c o g ni z e d sit e s (i. e.,  d uri n g b ot h t h e 
gl o b al e nr oll m e nt p h a s e a n d t h e e xt e n d e d C hi n a e nr oll m e nt p h a s e ). S e p ar at e a n al ys e s will b e 
p erf or m e d f or t h e g l o b al p o p ul ati o n a n d t h e C hi n a s u b p o p ul ati o n.
E F FI C A C Y A N A L Y S E S
T h e i nt e nt -to -tr e at (I T T) p o p ul ati o n will b e t h e pri m ar y a n al y si s p o p ul ati o n for all effi c a c y 
a n al y s e s. T h e I T T p o p ul ati o n i s  d efi n e d a s all e nr oll e d i nf a nt s, r e g ar dl e s s of w h et h er t h e y 
r e c ei ve d tr e at m e nt or n ot.
T h e c o nfir m at or y  effi c a c y a n al y s e s will o nl y i n cl u d e d at a fr o m t h e i nf a nt s e nr oll e d i nt o P art  2 of 
t h e st u d y; it will n ot i n cl u d e d at a fr o m t h e P art  1  i nf a nt s w h o will b e a n al y z e d t o s el e ct t h e d o s e. 
Effi c a c y  d at a of t h e i nf a nt s e nr oll e d i nt o  P art  1  will b e s u m m ari z e d d e s cri pti v el y, u si n g i n di vi d u al 
p ati e nt pl ot s or li sti n g s ( a s a p pr o pri at e) a n d pr e s e nt e d s e p ar a t el y fr o m t h e c o nfir m at or y effi c a c y 
a n al y si s of  P art  2.
Pri m ar y Effi c a c y E n d p oi nt
T h e pri m ar y  e n d p oi nt f or t h e c o nfir m at or y  P ar t 2  of t h e st u d y i s t h e pr o p orti o n of i nf a nt s w h o ar e 
sitti n g wit h o ut s u p p ort  aft er  1 2  m o nt h s  of tr e at m e nt. I nf a nt s w h o d o n ot a c hi e v e sitti n g, or h a v e 
n ot m ai nt ai n e d sitti n g a c hi e v e d e arli er, or h a v e b e e n wit h dr a w n, or di e d, will b e cl a s sifi e d a s 
n o n -re s p o n d er s (i. e., n o n - sitt er s) f or t h e pri m ar y a n al ysi s. Sitti n g i s d efi n e d a s ‘ sit s wit h o ut 
s u p p ort f or 5  s e c o n d s’ a s a s s e s s e d i n It e m 2 2 of t h e  B SI D -III gr o s s m ot or s c al e. T h e 
a s s e s s m e nt of t h e i n d e p e n d e nt c e ntr al r e a d er s will b e u s e d f or t h e pri m ar y a n al y sis.
T h e pr o p orti o n of i nf a nt s w h o ar e ali v e a n d sitti n g aft er 1 2  m o nt h s of tr e at m e nt will b e 
pr e s e nt e d wit h a t w o - si d e d 9 0 % Cl o p p er- Pe ar s o n ( E x a ct) c o nfi d e n c e i nt er v al. A n e x a ct 
bi n o mi al t e st will b e p erf or m e d. T h e h y p ot h e si s t o b e t e st e d i s t h at t h e  pr o p orti o n of i nf a nt s w h o 
sit o n tr e at m e nt ( p) i s:
H o: p  5 % ( n ull) v er s u s H a: p  5 % ( alt er n ati v e). 
If t h e o n e- si d e d p- val u e i s  5 % t h e n, t h e n ull h y p ot h e si s will b e r ej e ct e d. If t h e l o w er li mit of t h e 
t w o- si d e d 9 0 % c o nfi d e n c e i nt er v al i s a b o v e t h e 5 % t hr e s h ol d, t h e pri m ar y o bj e cti v e of t h e st u d y 
will b e c o n si d er e d a c hi e v e d.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
2 0 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


S e c o n d ar y Effi c a c y E n d p oi nt s
T h e s e c o n d ar y effi c a c y  e n d p oi nt s i n P art 2 ar e a s f oll o w s:

M ot or F u n cti o n a n d D e v el o p m e nt Mil e st o n e s: Pr o p orti o n of i nf a nt s w h o a c hi e v e a s c or e
of 4 0 or hi g h er i n t h e C H O P -I N T E N D at M o nt h
1 2 ; pr o p orti o n of i nf a nt s w h o a c hi e v e a n
i n cr e a s e of at l e a st 4 p oi nt s i n t h eir C H O P -I N T E N D s c or e fr o m b a s eli n e at M o nt h 8 a n d
M o nt h
1 2; p r o p orti o n of i nf a nt s w h o a c hi e v e h e a d c o ntr ol at M o nt h 8, M o nt h
1 2, a n d
M o nt h
2 4 ( d efi n e d a s a s c or e of 3 or hi g h er f or it e m 1 2 of t h e C H O P -I N T E N D); c h a n g e fr o m
b a s eli n e i n t h e t ot al r a w s c or e of t h e B SI D -III gr o s s m ot or s c al e at M o nt h
1 2 a n d M o nt h
2 4;
pr o p orti o n of i nf a nt s w h o a c hi e v e t h e att ai n m e nt l e v el s of t h e m ot or mil e st o n e s a s a s s e s s e d
i n t h e HI N E-2 at M o nt h
8 ( h e a d c o ntr ol, a bilit y t o ki c k, r olli n g ), M o nt h
1 2, a n d M o nt h
2 4;
pr o p orti o n of m ot or mil e st o n e r e s p o n d er s a s a s s e s s e d b y HI N E -2 at M o nt h 1 2 a n d
M o nt h
2 4; hi g h e st m ot or mil e st o n e a c hi e v e d b y M o nt h
1 2 a n d M o nt h 2 4; pr o p orti o n of
i nf a nt s w h o ar e ali v e a n d sitti n g wit h o ut s u p p ort f or 5 s e c o n d s at M o nt h
2 4 ( d efi n e d a s p er
t h e pri m ar y e n d p oi nt); pr o p orti o n of i nf a nt s w h o ar e ali v e a n d sitti n g with o ut s u p p ort f or
3 0 s e c o n d s at M o nt h 2 4 ( d efi n e d a s “ Sit s wit h o ut s u p p ort f or 3 0 s e c o n d s” a s a s s e s s e d i n
It e m 2 6 of t h e B SI D -III gr o s s m ot or s c al e); pr o p orti o n of i nf a nt s w h o ar e ali v e a n d st a n di n g
at M o nt h
2 4 ( d efi n e d a s ‘ St a n d s Al o n e’ a s a s s e s s e d i n It e m 4 0 of t h e B SI D -III gr o s s m ot or
s c al e); pr o p orti o n of i nf a nt s w h o ar e ali v e a n d w al ki n g at M o nt h
2 4 ( d efi n e d a s ‘ Wal k s Al o n e’
a s a s s e s s e d i n It e m 4 2 of t h e B SI D -III gr o s s m ot or s c al e).

S ur vi v al a n d V e ntil ati o n -Fr e e S ur vi v al : Ti m e t o d e at h or p er m a n e nt v e ntil ati o n (d efi n e d
a s 1 6 h o ur s of n o n -i n v a si v e v e ntil ati o n p er d a y or i nt u b ati o n f or2 1 c o n s e c uti v e d a y s i n
t h e a b s e n c e of, or f oll o wi n g t h e r e s ol uti o n of, a n a c ut e r e v er si bl e e v e nt or tr a c h e o st o m y)
fr o m e nr oll m e nt, ti m e t o d e at h fr o m e nr oll m e nt, pr o p orti o n of i nf a nt s w h o ar e ali v e wit h o ut
p er m a n e nt v e ntil ati o n at M o nt h
1 2 a n d M o nt h
2 4, pr o p orti o n of i nf a nt s w h o ar e ali v e at
M o nt h
1 2 a n d M o nt h
2 4 .

R e s pir at or y: Ti m e t o p er m a n e nt v e ntil ati o n fr o m e nr o ll me nt, pr o p orti o n of i nf a nt s w h o ar e
wit h o ut p er m a n e nt v e ntil ati o n at M o nt h 1 2 a n d M o nt h
2 4, pr o p orti o n of i nf a nt s w h o a c hi e v e
a r e d u cti o n of at l e a st 3 0 d e gr e e s i n t h eir p h a s e a n gl e fr o m b a s eli n e, a s m e a s ur e d b y R P,
at M o nt h
1 2, pr o p orti o n of i nf a nt s w h o d o n ot r e q uir e i n v a si v e or n o n -i n v a si v e r e s pir at ory
s u p p ort at M o nt h 1 2 a n d M o nt h 2 4 .

N utriti o n: Pr o p orti o n of i nf a nt s wit h t h e a bilit y t o f e e d or all y at M o nt h 1 2 a n d M o nt h 2 4.
S A F E T Y A N A L Y S E S
All i nf a nt s w h o r e c ei v e at l e a st o n e d o s e of st u d y m e di c ati o n  (ri s di pl a m) will b e i n cl u d e d i n t h e 
s af et y p o p ul ati o n.
S af et y d at a will b e s u m m ari z e d d e s cri pti v el y u si n g t h e s af et y p o p ul ati o n. I n  P art  1,  s af et y d at a 
will b e pr e s e nt e d i n s u m m ari e s, li sti n g s or i n di vi d u al p ati e nt pl ot s ( a s a p pr o pri at e) b y 
d o s e/ e x p o s ur e l e v el. F or  P art  2,  t h e s af et y d at a will b e s u m m ari z e d d e s cri pti v el y f or t h e fir st 1 2 -
m o nt h p eri o d (i. e., 1 2 - mo nt h d at a f or e a c h i n di vi d u al i nf a nt) a n d f or  all a v ail a bl e s af et y d at a  
c oll e ct e d at t h e ti m e of t h e a n al y si s. Si mil ar s u m m ari e s f or t h e fir st 2 4 - mo nt h p eri o d will b e  
pr e s e nt e d at t h e ti m e of t h e 2 4 - mo nt h a n al y si s r e p orti n g e v e nt.
S A M P L E SI Z E J U S TI FI C A TI O N
I n P art  1,  t h e t ar g et s a m pl e si z e i s 8  i nf a nt s, 4 e nr oll e d t o e a c h d o s e l e v el. Wit h 8 i nf a nt s 
e x p o s e d t o  ri s di pl a m, t h er e i s o v er a n 8 0 % c h a n c e to d et e ct a n A E i n at l e a st o n e i nf a nt, gi v e n 
t h at t h e tr u e u n d erl yi n g a d v er s e e v e nt r at e i s 2 0 %. Wi t h 4  i nf a nt s e x p o s e d at e a c h d o s e l e v el, 
t h e pr o b a bilit y t o d et e ct a n A E i n at l e a st o n e i nf a nt, gi v e n th at t h e tr u e u n d erl yi n g a d v er s e 
e v e nt r at e i s 3 0 %, i s  7 6 %.
I n P art  2,  t h e t ar g et s a m pl e si z e i s 4 0  i nf a nt s. T hi s s a m pl e si z e pr o vi d e s at l e a st 9 0 % p o w er t o 
t e st t h e n ull h y p ot h e si s H o: p 5 % v er s u s alt er n ati v e h y p ot h e si s H a: p  5 %, if t h e tr u e 
pr o p orti o n of i nf a nt s  w h o w o ul d sit o n tr e at m e nt i s 2 0 %. T hi s is b a s e d o n a n e x a ct bi n o mi al t e st 
wit h a o n e si d e d 5 % si g nifi c a n c e l e v el. T h e mi ni m u m n u m b er of i n f a nt s n e e d e d t o b e o b s er v e d 
sitti n g i s 5 o ut of 4 0 f or a st ati sti c all y si g nifi c a nt r e s ult.  If m or e t h a n 4 0 i nf a nt s ar e e nr oll e d, t h e 
n u m b er of b a bi e s r e q uir e d  t o m e et t h e pri m ar y e n d p oi nt will i n cr e a s e. F urt h er d et ail s ar e 
pr o vi d e d i n t h e S A P . If i n P art 2, 5 o ut of 4 0 i nf a nt s sit t h e l o w er li mit of t h e  -tw o si d e d - 9 0 % 
Cl o p p er- P e ar s o n ( E x a ct) c o nfi d e n c e i nt er v al w o ul d b e a b o v e  5 %.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
2 1 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


N o all o w a n c e h a s b e e n m a d e f or i nf a nt s w h o wit h dr a w e arl y a s t h e s e i nf a nt s will b e cl a s sifi e d 
a s a n o n -r e s p o n d er/ n o n-sitt er a n d i n cl u d e d wit hi n t h e pri m ar y a n al y si s.
I nt eri m An al y s e s
A s t hi s st u d y i s o p e n -l a b el, o n c e at l e a st 5 i nf a nt s e nr oll e d i nt o t h e c o nfir m at or y P art 2 d uri n g 
t h e gl ob al e nr oll m e nt p h a s e h a v e m et t h e pri m ar y  e n d p oi nt of sitti n g wit h o ut s u p p ort at 
M o nt h
1 2 ( a s a s s e s s e d b y t h e i n d e p e n d e nt c e ntr al r e a d er s), t h e mi ni m u m n u m b er of i nf a nt s 
n e e d e d f or a st ati sti c all y si g nifi c a nt r e s ult will h a v e b e e n a c hi e v e d a n d t h e pri m ar y o bj e cti v e of 
t h e st u d y will b e c o n si d er e d a c hi e v e d at t hi s e arli er ti m e-p oi nt. T h e st u d y will n ot b e st o p p e d 
a n d all 4 0 i nf a nt s e nr oll e d wit hi n t h e c o nfir m at or y P art 2 will c o nti n u e t o r e c ei v e 1 2 m o nt h s of 
tr e at m e nt i n or d er t o pr o vi d e a n u n bi a s e d e sti m at e of t h e pr o p orti o n of i nf a nt s sitti n g at 
M o nt h
1 2.
I n a d diti o n, a f utilit y a s s e s s m e nt f or effi c a c y will b e c o n d u ct e d aft er t h e fir st 1 4 i nf a nt s e nr oll e d 
i nt o t h e c o nfir m at or y P art 2 of t h e st u d y r e a c h 1 2 m o nt h s of tr e at m e nt or h a v e b e e n wit h dr a w n. 
If t h e pr e di cti v e pr o b a bilit y of “ s u c c e s s” ( d efi n e d a s o b s er vi n g 5 o ut of 4 0 sitti n g) i s l e s s t h a n 1 0 % 
( c orr e s p o n di n g t o n o i nf a nt h a s m et t h e pri m ar y e n d p oi nt of sitti n g wit h o ut s u p p ort at M o nt h 1 2 
i n t h e fir st 1 4 i nfa nt s e nr oll e d i n P art 2) t h e n t h e S p o n s or m a y  c o n si d er st o p pi n g t h e st u d y.
I nt eri m a n al y s e s f or effi c a c y a n d f utilit y will b e p erf or m e d b y t h e S p o n s or a n d t h e r e s ult s 
pr e s e nt e d t o t h e i D M C. T h e i D M C will b e r e q u e st e d t o r e vi e w all a v ail a bl e s af et y d at a a n d
a s k e d t o pr o vi d e a n i n d e p e n d e nt a s s e s s m e nt of t h e b e n efit ri s k pr ofil e of ri s di pl a m i n t h e Ty p e 1 
S M A p o p ul ati o n at t hi s e arli er ti m e p oi nt. T h e fi n al d e ci si o n b a s e d o n t h e 
i D M C- r e c o m m e n d ati o n will b e m a d e b y t h e S p o n s or.
LI S T O F P R O HI BI T E D M E DI C A TI O N S
T h e f oll o wi n g m e di c ati o n i s e x pli citl y pr o hi bit e d f or t h e p ati e nt s a n d t h e m ot h er if br e a stf e e di n g 
t h e i nf a nt:

A n y i n hi bit or of C Y P 3 A 4, i n cl u di n g b ut n ot li mit e d t o: k et o c o n a z ol e, mi c o n a z ol e,
itr a c o n a z ol e, fl u c o n a z ol e, er yt hr o my c i n, cl arit hr o my c i n, r a niti di ne, ci m eti di n e.

A n y i n d u c er of C Y P 3 A 4, i n cl u di n g b ut n ot li mit e d t o: rif a m pi ci n, rif a b uti n, gl u c o c orti c oi d s,
c ar b a m a z e pi n e, p h e n yt oi n, p h e n o b ar bit al, St. J o h n' s w ort.

A n y O C T 2 a n d M A T E s u b str at e s s h all b e a v oi d e d, i n cl u di n g b ut n ot li mit e d t o: a m a nt a di n e,
ci m eti di n e, m e m a nti n e, a mil ori d e, f a m oti di n e, m etf or mi n, pi n d ol ol, r a niti di n e, pr o c ai n a mi d e,
v ar e ni cli n e, a c y cl o vir, g a n ci cl o vir, o x ali pl ati n, c e p h al e xi n, c e p hr a di n e, f e x of e n a di n e.

A n y k n o w n F M O 1 or F M O 3 i n hi bit or s or s u b str at e s.
U s e of t h e f oll o wi n g t h er a pi e s i s pr o hi bit e d f or at l e a st 9 0 d a y s pri or t o e nr oll m e nt ( u nl e s s t h e 
I n v e sti g at or h a s c o n s ult e d wit h t h e S p o n s or d uri n g t h e s cr e e ni n g p eri o d a n d b ot h h a v e a gr e e d 
t h at t h e pri or u s e will n ot c o n stit ut e a ri s k t o t h e p ati e nt), a n d d uri n g t h e st u d y:

M e di c ati o n s i nt e n d e d f or t h e tr e at m e nt of S M A:  ril u z ol e, v al pr oi c a ci d, h y dr o xy ur e a,
s o di u m p h e n yl b ut yr at e, b ut yr at e d eri v ati v e s, cr e ati n e, c ar niti n e, gr o wt h h or m o n e, a n a b oli c
st er oi d s, pr o b e n e ci d, b ort e z o mi n, q u er c eti n, c hr o ni c or al or p ar e nt er al u s e of c orti c o st er oi d s
(i n h al e d c orti c o st er oi d u s e i s all o w e d, s e e a b o v e), a g e nt s a nti ci p at e d t o i n cr e a s e or
d e cr e a s e m u s cl e str e n gt h or a g e nt s wit h k n o w n or pr e s u m e d H D A C i n hi biti o n a cti v ity, a n d
a n y pri or u s e of S pi nr a z a T M or a n y ot h er S M N 2 -t ar g eti n g a nti s e n s e oli g o n u cl e oti d e, S M N-2
s pli ci n g m o difi er or g e n e t h er a p y ar e pr o hi bit e d.

M e di c ati o n s wit h k n o w n r eti n al t o xi cit y li a biliti e s: A mi o d ar o n e, p h e n ot hi a zi n e s, a n d
c hr o ni c u s e of mi n o c y c li n e.

P ati e nt s s h o ul d n ot h a v e r e c ei v e d t h e f oll o wi n g dr u g s at a n y ti m e i n t h eir li v e s a n d ar e
pr o hi bit e d d uri n g t h e st u d y: q ui n oli n e s ( c hl or o q ui n e a n d h y dr o x y c hl or o q ui n e), t hi ori d a zi n e,
vi g a b atri n a n d r eti g a bi n e at a n y ti m e i n t h eir li v e s
U s e of t h e f oll o wi n g t h er a pi e s i s pr o hi bit e d  f or t h e p ati e nt s , a n d f or t h e m ot h er if br e a stf e e di n g 
t h e i nf a nt d uri n g t h e st u d y a n d i n t h e pr e c e di n g 9 0  d a y s of e nr oll m e nt: d ef er o x a mi n e, 
t o pir a m at e, l at a n o pr o st, ni a ci n ( n ot a p pli c a ble if use d as a n utriti o n al s u p ple me nt), 
r o si glit a z o n e, t a m o xif e n, c a nt h a x a nt hi n e, sil d e n afil, i nt erf er on or a n y ot h er dr u g s k n o w n t o 
c a u s e r eti n al t o xi cit y.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
2 2 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
2 3 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S
A b br e vi ati o n
D efi niti o n
A E
A d v er s e e v e nt s
A L T
Al a ni n e a mi n otr a n sf er a s e
a P T T
A cti v at e d p arti al t hr o m b o pl a sti n ti m e
A S T
A s p art at e a mi n otr a n sf er a s e
A U C
Ar e a u n d er t h e c ur v e
A U C 0 2 4 h
Ar e a u n d er t h e c ur v e fr o m ti m e 0 t o 2 4 h o ur s
A U C 0 2 4 h, s s
Ar e a u n d er t h e c ur v e fr o m ti m e 0 t o 2 4 h o ur s at st e a d y 
st at e
A U C 0 l a st
Are a u n der c ur ve fr o m ti me 0 t o l ast me as ur a ble 
c o n ce ntr ati o n
B P
Bl o o d pr e s s ur e
B SI D -III
B a yl e y s c al e s of i nf a nt a n d t o d dl er d e v el o p m e nt – t hir d 
e diti o n
C D C
C e nt er s f or di s e a s e c o ntr ol a n d pr e v e nti o n
C H O P -I N T E N D
C hil dr e n’ s h o s pit al of P hil a d el p hi a i nf a nt t e st of 
n e ur o m u s c ul ar di s or d er s
C M A P
C o m p o u n d m u s cl e a cti o n p ot e nti al
C m a x
P e a k pl a s m a c o n c e ntr ati o n
C N S
C e ntr al n er v o u s s y st e m
C R O
C o ntr a ct r e s e ar c h or g a ni z ati o n
C T C A E
C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s
C tr o u g h
C o n c e ntr ati o n at t h e e n d of a d o si n g i nt er v al
C Y P
C y t o c hr o m e P 4 5 0
D B P
Di a st oli c bl o o d pr e s s ur e
D DI
Dr u g -dr u g i nt er a cti o n
D N A
D e o x yri b o n u cl ei c a ci d
D T R
D e e p t e n d o n r efl e x
E C
Et hi c s C o m mitt e e
E C G
El e ctr o c ar di o gr a m s
e C R F
El e ctr o ni c C a s e R e p ort F or m
E D C
El e ctr o ni c d at a c a pt ur e
E E A
E ur o p e a n E c o n o mi c Ar e a
E R G
El e ctr or eti n o gr a m
E S F
Eli gi bilit y S cr e e ni n g F or m
E U
E ur o p e a n C o m mi s si o n
F D A
F o o d a n d Dr u g A d mi ni str ati o n
F L
F ull l e n gt h




R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
2 5 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
A b br e vi ati o n
D efi niti o n
Q T c
Q T c orr e ct e d f or h e art r at e
Q T c B
Q T c orr e ct e d f or h e art r at e u si n g t h e B a z ett’ s 
c orr e cti o n f a ct or
R B C
R e d bl o o d c ell
R N A
Ri b o n u cl ei c a ci d
R P
R e s pir at or y pl et h y s m o gr a p h y
R R
R R i nt er v al
S A D
Si n gl e a s c e n di n g d o s e
S A E
S eri o u s a d v er s e e v e nt
S A P
St ati sti c al a n al y si s pl a n
S B P
S y st oli c bl o o d pr e s s ur e
S D -O C T
S p e ctr al d o m ai n -o pti c al c o h er e n c e t o m o gr a p h y
S M A
S pi n al m u s c ul ar atr o p h y
S M N
S ur vi v al of m ot or n e ur o n
S M N 1
S M N 1 g e n e
S o A
S c h e d ul e of a s s e s s m e nt s
tm a x
Ti m e  of m a xi m u m c o n c e ntr ati o n
U L N
U p p er li mit of n or m al
U S
U nit e d St at e s
W B C
W h it e bl o o d c ell


1.
B A C K G R O U N D A N D R A TI O N A L E
1. 1
B A C K G R O U N D O N DI S E A S E
S pi n al m u s c ul ar atr o p h y  ( S M A) i s a n a ut o s o m al r e c e s si v e n e ur o m u s c ul ar di s or d er 
c h ar a ct eri z e d b y t h e pr o gr e s si v e l o s s of pr o xi m al m ot or n e ur o n s  l e a di n g t o m u s cl e 
w e a k n e s s a n d pr of o u n d n e ur o m ot or di s a bilit y b e gi n ni n g i n  i nfa n c y ( Cr a wf or d et al 1 9 9 6; 
L u n n  et al 2 0 0 8). It i s t h e l e a di n g g e n eti c c a u s e of m ort alit y i n i nf a nt s a n d y o u n g 
c hil dr e n, wit h a n i n ci d e n c e of 1 i n ~ 1 1, 0 0 0  li v e birt h s a n d a c arri er fr e q u e n c y e sti m at e d at 
1 i n 
5 0 7 0 i n di vi d u al s ( S u g ar m a n et al 2 0 1 2).
Cli ni c all y, S M A r a n g e s i n di s e a s e s e v erit y. F or cl a s sifi c ati o n p ur p o s e s, p ati e nt s ar e 
u s u all y c at e g ori z e d i nt o f o ur m ai n  s u bt y p e s b a s e d o n cli ni c al crit eri a, i n cl u di n g a c hi e vi n g 
( or f aili n g t o a c hi e v e) p h y si c al m ot or mil e st o n e s, a g e of o n s et a n d lif e s p a n ( M u n s at et al 
1 9 9 2):  T y p e  1 S M A or W e r d ni g- Hoff m a n n di s e a s e ( s e v er e i nf a ntil e t y p e, o n s et b ef or e 
6  m o nt h s of a g e, p ati e nt s n e v er sit wit h o ut s u p p ort, wit h d e at h d u e t o r e s pir at or y di str e s s 
u s u all y wit hi n  2  y e ar s ), T y p e 2 S M A (i nt er m e di at e c hr o ni c i nf a ntil e t y p e wit h o n s et aft er 
t h e a g e of 6 m o nt h s, u n a bl e t o st a n d or w al k wit h o ut s u p p ort),  T y p e  3  S M A or K u g el b er g -
W e l a n d er di s e a s e ( c hr o ni c j u ve nil e t y p e wit h o n s et ar o u n d t h e a g e of 
1 8  m o nt h s, c hil dr e n ar e a bl e t o w al k u ntil t h e di s e a s e pr o gr e s s e s) a n d  T y p e  4  S M A 
( ad ult o n s et). A fift h t y p e, d e n ot e d a s  T y p e  0,  h a s b e e n pr o p o s e d f or e xtr e m el y s e v er e 
S M A t h at m a nif e st s d uri n g f et al lif e a n d r e s ult s i n d e at h wit hi n a f e w w e e k s aft er birt h 
( K ol b et al 2 0 1 1). T hi s clini c al tri al will e nr oll  T y p e  1  S M A p ati e nt s o nl y.
S M A i s c a u s e d b y a h o m o z y g o u s d el et i o n ( 9 5 % of c a s e s) or m ut ati o n of t h e S ur vi v al of 
M ot or N e ur o n ( S M N ) 1 g e n e o n c hr o m o s o m e 5 q (l o c u s 5 q 1 3 ), w hi c h e n c o d e s S M N, a n 
e s s e nti al pr ot ei n e x pr e s s e d i n b ot h n e ur o n al a n d n o n - ne ur o n al c ell s ( L ef e b vr e et al 
1 9 9 5 ). I n hu m a n s, t h er e ar e t w o S M N g e n e s,  t h e S M N 1 g e n e a n d it s p ar al o g  S M N 2 . 
S p e ci e s ot h er t h a n h u m a n h a v e o nl y o n e S M N g e n e, w hi c h i s e q ui v al e nt t o t h e h u m a n 
S M N 1 g e n e. D u e t o a tr a n sl ati o n all y s y n o n y m o u s C  t o T m ut ati o n at  n u cl e oti d e  6  i n e x o n  
7, t h e  S M N 2 pr e - mR N A u n d er g o e s alt er n ati v e  s pli ci n g, w hi c h e x cl u d e s e x o n  7 fr o m 
8 5 - 90 % of m at ur e  S M N 2 tr a n s cri pt s pr o d u ci n g a n u n st a bl e S M N 7 pr ot ei n t h at i s r a pi dl y 
d e gr a d e d ( L or s o n et al 1 9 9 9 ; C h o et al 2 0 1 0 ). A c c or di n gl y, f ull-le n gt h S M N 2 m R N A i s 
g e n er at e d i n o nl y 1 0 - 15 % of s pli ci n g e v e nt s. Si n c e S M A p ati e nt s o nl y h a v e t h e S M N 2 
g e n e, t h eir S M N pr ot ei n l e v el s ar e si g nifi c a ntl y  d e cr e a s e d ( K ol b et al 2 0 1 1 ).
I n all t y p e s of S M A, a s t h e di s e a s e pr o gr e s s e s, cli ni c al s y m pt o m s i n cl u d e h y p ot o ni a, 
s y m m etri c al m u s cl e w e a k n e s s a n d atr o p h y ( pr e d o mi n a ntl y of  t h e pr o xi m al m u s cl e s of t h e 
s h o ul d er a n d p el vi c gir dl e), di mi ni s h e d or a b s e nt d e e p t e n d o n r efl e x e s ( D T R s), tr e m or of 
fi n g er s a n d h a n d s, f a s ci c ul ati o n of t h e t o n g u e m u s cl e s, a n d h y por efl e xi a wit h ort h o p e di c 
d ef or miti e s ( c o ntr a ct ur e s, s c oli o si s). Pr o gr e s si v e  r e s pir at or y f ail ur e a n d fr e q u e nt 
p ul m o n ar y i nf e cti o n s  a n d s u p er-inf e cti o n s ar e c o m m o n i n  T y p e s  1  a n d 2 S M A. Ot h er 
c o m m o n c o m or bi diti e s i n cl u d e f ail ur e t o t hri v e, sl e e p diffi c ult i e s, p n e u m o ni a, o st e o p e ni a 
a n d o st e o p or o si s wit h p at h ol o gi c al fr a ct ur e s, p o or  c o u g h a n d s e cr eti o n 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
2 6 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


cl e ar a n c e, r e d u c e d vit al c a p a cit y, g a str o e s o p h a g e al d y s m otilit y, uri n ar y i n c o nti n e n c e, 
hi p di sl o c ati o n, a n d j oi nt a n d m u s cl e p ai n.
A s t h e m e di c al n e e d i n S M A i s v er y hi g h, s e v er al dr u g c a n di d at e s ar e c urr e ntl y u n d er 
i n v e sti g ati o n i n t h e n o n cli ni c al a n d cli ni c al s etti n g ( L e w elt et al 2 0 1 2; d’ Y d e w all e et al 
2 0 1 5). T h e S M N 2 -t ar g eti n g a nti s e n s e oli g o n u cl e oti d e, n u si n er s e n ( S pi nr a z a ™), h a s 
b e e n a p pr o v e d b y h e alt h a ut h oriti e s i n t h e U nit e d St at e s, E ur o p e a n U ni o n, C a n a d a, a n d 
ot h er j uri s di cti o n s f or t h e tr e at m e nt of S M A i n p e di atri c a n d a d ult p ati e nt s, a n d m ar k eti n g 
a p pli c ati o n s h a v e b e e n s u b mitt e d t o ot h er r e g ul at or y a ut h oriti e s f or a p pr o v al.
Alt er n ati v e m a n a g e m e nt str at e gi e s f o c u s o n pr e v e nti o n a n d tr e at m e nt of c o m or bi diti e s, 
s u c h a s f ail ur e t o t hri v e, s ur gi c al a n d n o n -s ur gi c al tr e at m e nt of s c oli o si s a n d 
c o ntr a ct ur e s, p ul m o n ar y h y gi e n e, n o n -i n v a si v e v e ntil ati o n, m o bilit y a n d s e ati n g s u p p ort, 
a n d p h y si c al a n d o c c u p ati o n al t h er a p y. 
1. 2
B A C K G R O U N D O N RI S DI P L A M
O n e of t h e pr o mi si n g p h ar m a c ol o gi c al str at e gi e s c urr e ntl y b ei n g  p ur s u e d i s t o r e st or e 
S M N pr ot ei n l e v el s i n S M A p ati e nt s b y m o d ul ati n g  S M N 2  s pli ci n g t o f a v or t h e i n cl u si o n of 
e x o n  7 i nt o t h e m R N A tr a n s cri pt, t h er e b y i n cr e a si n g e x pr e s si o n of st a bl e f ull -le n gt h 
pr ot ei n fr o m t h e  S M N 2  g e n e  ( K ol b et al 2 0 1 1 ; N ur p utr a et al  2 0 1 3 ). O n e s u c h c o m p o u n d 
c urr e ntl y b ei n g d e v el o p e d i s  ri s di pl a m, w hi c h dir e ctl y t ar g et s t h e u n d erl yi n g m ol e c ul ar 
d ef i ci e n c y of t h e di s e a s e a nd pr o m ot e s t h e i n cl u si o n of e x o n  7 t o g e n er at e f ull -le n gt h 
S M N 2 m R N A, w hi c h i n cr e a s e s t h e pr o d u cti o n of f u n cti o n al S M N pr ot ei n. S M N pr ot ei n 
i n cr e a s e aft er tr e at m e nt wit h ri s di pl a m h a s b e e n s h o w n i n fi br o bl a st s a n d m ot or n e ur o n s 
d eri v e d fr o m p ati e nt s wit h S M A.
Ri s di pl a m  i s a f oll o w- up c o m p o u n d t o R O 6 8 8 5 2 4 7, a n ot h er  S M N 2 m R N A s pli ci n g 
m o difi er w hi c h i n S M A p ati e nt s i n cr e a s e d l e v el s of f ull l e n gt h ( F L) S M N 2 m R N A, a n d 
r e d u c e d l e v el s of S M N 7  m R N A. S M N pr ot ei n i n bl o o d i n cr e a s e d b y u p t o  2-f ol d  
c o m p ar e d t o b a s eli n e i n t h e s e p ati e nt s. T h e st u d y, B P 2 9 4 2 0, f urt h er s h o w e d t h at t h e 
c o m p o u n d R O 6 8 8 5 2 4 7 w a s w ell  t ol er at e d i n 9  a d ol e s c e nt  a n d a d ult S M A p ati e nt s at t h e 
1 0  m g d o s e/ d a y f or 1 2 - we e k tr e at m e nt, wit h n o d e at h s, s eri o u s a d v er s e e v e nt s ( S A E s), 
or  wit h dr a w al s d u e t o a d v er s e e v e nt s ( A E s). T h e m ai n A E s r e p ort e d w er e i nfl u e n z a 
(t hr e e p ati e nt s) a n d di arr h e a (t w o p ati e nt s).
S e e t h e  Ri s di pl a m I n v e sti g at or’ s Br o c h ur e f or d et ail s o n n o n cli ni c al a n d cli ni c al st u di e s.
1. 2. 1  
Pr e vi o u s N o n c li ni c al St u di e s
1. 2. 1. 1  
P h ar m a c ol o g y
Ri s di pl a m  eff e cti v el y c orr e ct s t h e d y sf u n cti o n al s pli c i n g of h u m a n S M N 2 pr e - mR N A i n 
c ult ur e d c ell s b y s hifti n g t h e b al a n c e of t h e alt er n ati v e s pli ci n g r e a cti o n c o m pl et el y 
t o w ar d s t h e i n cl u si o n of S M N 2 e x o n  7  a n d t h e pr o d u cti o n of t h e  f ull-le n gt h  m R N A a n d 
f u n cti o n al S M N pr ot ei n. I n vi v o, ri s di pl a m eff e cti v el y c orr e ct s t h e d y sf u n cti o n al s pli ci n g of 
t h e h u m a n S M N 2 pr e - mR N A  i n S M A m o u s e m o d el s (t h e se v er e S M N 7 m o d el a n d t h e 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
2 7 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


mil d er C/ C- a ll el e m o d el) c arr yi n g h u m a n S M N 2 tr a n s g e n e s. T hi s c orr e cti o n r es ult s i n a 
si g nifi c a nt i n cr e a s e i n S M N  pr ot ei n l e v el s a n d a pr of o u n d pr ol o n g ati o n of a ni m al 
s ur vi v al, pr ot e cti o n of t h e n e ur o m u s c ul ar cir c uit, a n d i m pr o v e m e nt of m ot or f u n cti o n i n 
t h e S M N 7 m o u s e m o d el of s e v er e S M A.
1. 2. 1. 2  
P h ar m a c o ki n eti c s
Ri s di pl a m i s w ell- ab s or b e d i n r at s a n d m o n k e y s f oll o wi n g or al a d mi ni str ati o n. T h e 
c o m p o u n d h a s v er y l o w i ntri n si c cl e ar a n c e i n vitr o a n d i n vi v o,  a n d h a s fr e e-fra cti o n 
v al u e s of 1 1, 1 5, 1 6, a n d 1 0 % i n h u m a n, m o n k e y, r at a n d m o u s e pl a s m a, r e s p e cti v el y. 
I n h u m a n pl a s m a, ri s dipl a m  i s pr e d o mi n a ntl y b o u n d t o s er u m al b u mi n, wit h n o bi n di n g t o 
al p h a - 1 a ci d gl y c o pr ot ei n. T hi s r e s ult s i n l o w s y st e mi c cl e ar a n c e i n a ni m al s a n d a l o w 
pr e di ct e d s y st e mi c cl e ar a n c e i n h u m a n s. B a s e d o n p h y si c o c h e mi c al pr o p erti e s a n d i n 
vi v o st u di e s i n r at s,  mi c e a n d m o n k e y s,  ri s di pl a m i s pr e di ct e d t o e nt er t h e c e ntr al 
n er v o u s s y st e m ( C N S) i n h u m a n s.  Ri s di pl a m  i s hi g hl y b o u n d t o m el a ni n i n vitr o a n d 
a c c u m ul at e s i nt o m el a ni n - co nt ai ni n g str u ct ur e s of t h e e y e i n pi g m e nt e d r at s a n d 
m o n k e y s.
Ri s di pl a m  i s cl e ar e d in a ni m al s pri m aril y t hr o u g h m et a b oli s m wit h mi n or c o ntri b uti o n 
fr o m r e n al cl e ar a n c e. T h e e n z y m e s i n v ol v e d i n h u m a n m et a b oli s m of  ri s di pl a m ar e fl a vi n 
m o n o o x y g e n a s e ( F M O) 1 a n d 3 a n d m ulti pl e m e m b er s of t h e c yt o c hr o m e 
P 4 5 0  s u p erf a mil y  ( C Y P), e s p e ci all y C Y P 3A i s o e n z y m e s.  Ri s di pl a m  i s n ot a s u b str at e f or 
h u m a n P- g l y c o pr ot ei n ( P- gp ). T h e p ot e nti al f or i nt er a cti o n wit h ot h er dr u g s t h at i n hi bit or 
i n d u c e m et a b oli zi n g e n z y m e s or a cti v e tr a n s p ort pr ot ei n s c a n n ot b e r ul e d o ut at t hi s 
st a g e of d e v el o p m e nt.
Ri s di pl a m  i s n ot a n i n hi bit or of h u m a n m ulti dr u g r e si st a n c e pr ot ei n 1 ( M D R 1), or g a ni c 
a ni o n -tr a n s p orti n g p ol y p e pti d e ( O A T P) 1 B 1, O A T P 1 B 3, or g a ni c a ni o n tr a n sp ort er ( O A T) 1 
or O A T 3. It i s t h er ef or e u nli k el y t h at c o - ad mi ni str ati o n wit h  ri s di pl a m will alt er t h e 
p h ar m a c o k i n eti c s ( P K) of ot h er dr u g s w h o s e di s p o siti o n i s i nfl u e n c e d b y t h e s e 
tr a n s p ort er s. H o w e v er, ri s di pl a m i s a n i n hi bit or of or g a ni c c ati o n tr a n s p ort er 2 ( O C T 2), 
m ulti dr u g a n d t o xi n e xtr u si o n ( M A T E) 1 a n d  M A T E 2 - K a n d t h e p ot e nti al f or i nt er a cti o n 
wit h ot h er dr u g s t h at ar e s u b str at e s of t h o s e tr a n s p ort pr ot ei n s c a n n ot b e r ul e d o ut at 
t hi s st a g e. S u c h dr u g s ar e t h er ef or e pr o hi bit e d f or p ati e nt s p arti ci p ati n g i n t hi s st u d y 
( Se cti o n  4. 5. 2 ).
1. 2. 1. 3  
T o xi c ol o g y  a n d S af et y P h ar m a c ol o g y
A t o xi c ol o g y a n d s af et y p h ar m a c ol o g y pr o gr a m u si n g  ri s di pl a m h a s b e e n c o n d u ct e d 
a c c or di n g t o t h e I C H g ui d eli n e s, wit h all pi v o t al st u di e s c o n d u ct e d i n c o m pli a n c e wit h 
G L P r e g ul ati o n s. Pi v ot al t o xi cit y st u di e s wit h o n c e d ail y or al g a v a g e a d mi ni str ati o n of 
ri s di pl a m of u p t o 2 6 w e e k s i n d ur ati o n w er e c o n d u ct e d i n t h e j u v e nil e a n d a d ult r at a n d 
u p t o 3 9 w e e k s i n y o u n g c y n o m ol g u s m o n k e y. I n a d diti o n, v ari o u s g e n ot o xi cit y a n d 
s af et y p h ar m a c ol o g y st u di e s h a v e b e e n c o n d u c t e d a n d, b e c a u s e of t h e a b s or pti o n of 
ri s di pl a m i n t h e U V r a n g e, t h e p ot e nti al f or p h ot ot o xi cit y w a s al s o st u die d i n vitr o. 
M e c h a ni sti c i n v e sti g ati o n s i n vitr o a n d i n vi v o t o el u ci d at e m e c h a ni s m s of t o xi cit y b a s e d 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
2 8 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


o n p h y si c o c h e mi c al pr o p erti e s a n d s e c o n d ar y s pli c e t ar g et i d e ntifi c ati o n w er e c o n d u ct e d. 
A s ri s di pl a m i s b ei n g d e v el o p e d t o c hr o ni c all y tr e at S M A, w hi c h i n it s m o st s e v er e f or m 
m a nif e st s it s elf s o o n aft er birt h,
t h e t o xi cit y t e sti n g str at e g y i n cl u d e s a 3 9-w e e k t o xi cit y 
st u d y t h at w a s st art e d wit h y o u n g, 2 -y e ar ol d m o n k e y s ( wit h a ni m al s still b ei n g pr e -or 
p eri -p u b ert al at t h e e n d of 3 9 w e e k s of tr e at m e nt a n d aft er t h e 2 2 -w e e k r e c o v er y p h a s e), 
a n d t w o r e p e at -d o s e G L P j u v e nil e t o xi cit y st u di e s i n r at s: i) a 1 3 -w e e k r at j u v e nil e st u d y 
wit h tr e at m e nt i m m e di at el y p o st -w e a ni n g ( P N D 2 3 -2 4), a n d ii) a 4 -w e e k r at j u v e nil e 
st u d y wit h a ni m al s d o s e d fr o m P N D 4 u ntil P N D 3 2. T h e s e st u di e s i n cl u d e d d e di c at e d 
a s s e s s m e nt s of criti c al d e v el o pi n g or g a n s y st e m s a c c or di n g t o t h e a v ail a bl e g ui d eli n e s 
i s s u e d b y F D A a n d C H M P. I n a d diti o n, a 1 3/ 2 6-w e e k t o xi cit y st u d y i n pi g m e nt e d r at s h a s 
b e e n c o n d u ct e d t o st u d y t h e o n s et, if a n y, a n d pr o gr e s si o n of c h a n g e s i n t h e r eti n a 
u si n g li g ht/ el e ctr o n mi cr o s c o p y, s d O C T a n d E R G a s s e s s m e nt s. I n t hi s st u d y, 
hi st o p at h ol o gi c al e v al u ati o n of ot h er or g a n s of i nt er e st ( br ai n, p a n cr e a s a n d a dr e n al s) 
w a s i n cl u d e d t o c o m p ar e r e s ult s of t h e 2 6 -w e e k c hr o ni c t o xi cit y st u d y i n al bi n o r at s 
a cr o s s r at str ai n s.
S af et y p h ar m a c ol o g y st u di e s i n vitr o a n d i n vi v o c o n d u ct e d wit h ri s di pl a m di d n ot 
d e m o n str at e a n y n ot e w ort h y eff e ct s.
Fi n di n g s of t o xi c ol o gi c al si g nifi c a n c e f or ri s di pl a m w er e o b s er v e d i n or g a n s wit h r a pi d 
c ell t ur n o v er i n mi c e, r at s, a n d m o n k e y s a n d i n cl u d e d:

M i cr o n u cl e u s i n d u cti o n i n vitr o i n m o u s e c ell li n e s a n d i n r at b o n e m arr o w
er yt hr o bl a st s.

Fi n di n g s i n g a str oi nt e sti n al ( GI) e pit h eli a (i n cr e a s e d a p o pt o si s/ si n gl e c ell n e cr o si s)
a n d l a mi n a pr o pri a ( v a c u ol ati o n) i n m o u s e, r at, a n d/ or m o n k e y.

P ar a k er at o si s/ h y p er pl a si a/ d e g e n er ati o n of t h e s ki n, t o n g u e a n d l ar y n x e pit h eli a wit h
a s s o ci at e d i nfl a m m ati o n i n m o n k e y.

D e g e n er ati o n of g er m c ell s i n m o n k e y a n d r at t e st e s.

F urt h er t e st it e m -r el at e d fi n di n g s w er e o b s er v e d i n h e m at ol o g y (r e d a n d w hit e c ell s)
wit h c orr el at e s i n s m all t h y m u s a n d t h y m u s atr o p h y i n m o n k e y s b ut wit h o ut
hi st o p at h ol o gi c al c h a n g e s i n b o n e m arr o w.
R i s di pl a m-r el at e d fi n di n g s w er e a s s o ci at e d wit h a cl e ar n o -o b s er v e d -a d v er s e -eff e ct  l e v el 
( N O A E L) a n d/ or a cl e ar st ati sti c al t hr e s h ol d u si n g a b e n c h m ar k d os e a p pr o a c h 
(for  mi cr o n u cl e u s i n d u cti o n i n r at b o n e m arr o w).
E vi d e n c e s u g g e st s t h at t h e s e eff e ct s of  ri s di pl a m o n pr olif er ati n g c ell s a n d ti s s u e ar e 
r el at e d t o alt er n ati v e s pli ci n g eff e ct s o n s e c o n d ar y t ar g et s s uc h a s t h e F or k h e a d  b o x 
pr ot ei n M 1 ( F o x M 1), a m aj or c ell c y cl e r e g ul ati n g f a ct or, a n d M A P ki n a s e a cti v ati n g 
d e at h d o m ai n ( M A D D), a g e n e wit h v ari o u s s pli c e v ari a nt s i n v ol v e d i n a p o pt o si s. F urt h er 
s e c o n d ar y s pli c e t ar g et s h a v e b e e n i d e ntifi e d b ut i n s uffi ci e nt d at a ar e p u bli s h e d o n t h e 
bi ol o gi c al i m p a ct of c h a n g e s i n s pli c e v ari a nt e x pr e s si o n.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
2 9 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


A f urt h er fi n di n g of t o xi c ol o gi c al si g nifi c a n c e f or ri s di pl a m w a s n ot e d i n t h e r eti n a fr o m t h e 
3 9 - we e k  t o xi cit y st u d y i n m o n k e y s. M ultif o c al p eri p h er al r eti n a d e g e n er ati o n i n t h e 
p h ot or e c e pt or l a y er a n d mi cr o c y sti c s p a c e s i n t h e i n n er r eti n al l a y er s i n m o n k e y s w a s 
d et e ct e d b y s p e ctr al d o m ai n - opti c al c o h er e n c e t o m o gr a p h y ( O C T). T hi s w a s a s s o ci at e d 
wit h d e pr e s s e d s c ot o pi c (r o d)  B- w a v e  a n d s o m e w h at l e s s aff e ct e d p h ot o pi c ( c o n e)  B-
w a v e  i n t h e el e ctr or eti n o gr a m ( E R G). T h e s e fi n di n g s w er e c o nfir m e d b y  hi st o p at h ol o g y. 
O C T a n d E R G ar e i n di c ati v e of p arti al/ sl o w r e c o v er y of s o m e p ar a m et er s i n t h e  2 2 - we e k  
r e c o v er y p h a s e. T h e eff e ct o n t h e r eti n a i s t h o u g ht t o b e c o n n e ct e d wit h e vi d e n c e of hi g h 
m el a ni n bi n di n g a n d ti s s u e r et e nti o n i n t h e r eti n a a n d i m p air m e nt of l y s o s o m al f u n cti o n/
a ut o p h a g o s o m al a c c u m ul ati o n i n r eti n al pi g m e nt e d e pit h eli al c el l s.
F urt h er n ot e w ort h y o b s er v ati o n s w er e m aj or diff er e n c e s i n t ol er a bilit y wit h r e p e at e d or al 
d o si n g i n y o u n g ( pr e - a n d p o st - we a ni n g ) a n d a d ult r at s wit h m u c h hi g h er s u s c e pti bilit y of 
y o u n g er r at s t o t o xi c eff e ct s of  ri s di pl a m t h a n ol d er r at s at c o m p ar a bl e d o s e s. H o w e v er, 
w h e n fr e e e x p o s ur e t o  ri s di pl a m i s c o m p ar e d b et w e e n s p e ci e s a n d a g e s, n o m aj or 
diff er e n c e s i n e x p o s ur e a s s o ci at e d wit h s u b a c ut e d o s e -li miti n g t o xi cit y ar e r e cor d e d.
I n t er m s of c hr o ni c tr e at m e nt of S M A p ati e nt s, it i s pr o p o s e d t o e v al u at e d o s e s n ot 
e x c e e di n g t h e e x p o s ur e at t h e N O A E L/ N O E L of t h e  3 9 - we e k  t o xi cit y st u d y i n m o n k e y s 
wit h a n  ar e a u n d er t h e c ur v e  fr om ti m e 0 t o 2 4  h o ur s  ( AU C 0- 2 4 h ) of 1 8 7 0/ 2 0 6 0  n g  h/ m L 
i n m al e s a n d f e m al e s, r e s p e cti v el y. Y o u n g/ v er y  y o u n g r at s di s pl a y e d a hi g h er d o s e -
b a s e d s u s c e pti bilit y t o t h e s u b a c ut e, lif e -thr e at e ni n g t o xi cit y of  ri s di pl a m t h a n ol d er r at s 
li k el y b a s e d o n a hi g h er fr e e fr a cti o n a n d l o n g er h alf-lif e. T h u s, i n t h e u p c o mi n g cli ni c al 
st u di e s, c ar ef ul e v al u ati o n of t h e fr e e  fr a cti o n of ri s di pl a m i n pl a s m a of i nf a nt s a n d 
c hil dr e n i s w arr a nt e d, wit h  s p e cifi c a d a pt ati o n of t h e d o s e s t o b e t e st e d if diff er e n c e s i n 
pl a s m a pr ot ei n bi n di n g si mil ar t o t h o s e s e e n i n r at s of diff er e nt a g e s s h o ul d b e f o u n d.
S e e t h e  Ri s di pl a m  I n v e sti g at or’ s Br o c h ur e f or d et ail s o n n o n cli ni c al  a n d cli ni c al st u di e s.
1. 2. 2  
Pr e vi o u s a n d O n g oi n g  Cli ni c al St u di e s
A s of  M arc h 2 0 2 0 , ri s di pl a m h a s b e e n i n v e sti g at e d i n  fi ve cli ni c al p h ar m a c ol o g y st u di e s: 
St u d y  B P 2 9 8 4 0 ( S A D, e ntr y -int o - hu m a n st u d y i n h e alt h y m al e a d ult s); St u d y  N P 3 9 6 2 5 ( a 
P K  st u d y i n h e alt h y J a p a n e s e a d ult s); St u d y  B P 3 9 1 2 2 ( a m a s s b al a n c e st u d y i n h e alt h y 
m al e a d ult s) ; St u d y B P 4 1 3 6 1 ( a dr u g - dr u g i nter a cti o n [ D DI] st u d y wit h t he C Y P 3 A 
s u bstr ate mi d a z ol a m , a n d St u d y B P 4 0 9 9 5 ( he p ati c i m p air me nt st u d y). All f o ur st u di e s 
( B P 2 9 8 4 0, N P 3 9 6 2 5, B P 3 9 1 2 2 a n d  B P 4 1 3 6 1 ) h a v e b e e n c o m pl et e d; St u d y B P 4 0 9 9 5 is 
cli ni c all y c o m plete b ut t he Cli ni c al St u d y Re p ort is pe n di n g  ( s e e t h e Ri s di pl a m  
I n v e sti g at or’ s Br o c h ur e f or a v ail a bl e d at a). 
I n St u d y B P 4 1 3 6 1, it w as o bser ve d t h at a d mi nistr ati o n of ris di pl a m o n ce d ail y f or 
2  wee ks i n he alt h y a d ult  s u bjects sli g htl y i n cre ase d t he e x p os ure of mi d a z ol a m, a 
se nsiti ve C Y P 3 A s u bstr ate, b y 1 1 % f or a re a u n der c ur ve fr o m ti me 0 t o l ast me as ur a ble 
c o nce ntr ati o n  ( A U C0-l a st) a n d 1 6 % f or pe a k pl as m a c o n ce ntr ati o n ( Cm a x) . H o we ver, t he 
o bser ve d m a g nit u de of t his effe ct is n ot c o nsi d ere d cli ni c all y rele v a nt.  B ase d o n 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
3 0 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


p h ysi ol o gi c all y - base d p h ar m a c o ki neti c ( P B P K)  m o deli n g , a si mil ar m a g nit u de of t he 
effect is e x pe cte d i n c hil dre n a n d i nf a nts as y o u n g as 2 m o nt hs ol d.
A d diti o n all y, t h er e ar e  f o ur o n g oi n g st u di e s i n p a ti e nt s wit h S M A: St u d y  B P 3 9 0 5 4 ( a n 
o p e n -la b el s af et y a n d P K/ p h ar m a c o d y n a mi c ( P D) st u d y i n  n o n- nai v e  p ati e nt s  wit h S M A 
T y p e  2 or  3); St u d y  B P 3 9 0 5 5 ( a st u d y t o e v al u at e s af et y, P K/ P D, a n d effi c a c y i n p ati e nt s 
wit h T y p e  2 a n d  3 S M A) ; St u d y B N 4 0 7 0 3 ( a n o pe n -la bel st u d y i n i nf a nts wit h 
ge neti c all y di a g n ose d a n d pres y m pt o m ati c S M A);  a n d t h e pr e s e nt st u d y ( B P 3 9 0 5 6). 
C u rre nt d at a f or o n g oi n g st u dies  is pr o vi de d i n t he Ri s di pl a m I n vesti g at or's Br oc h ure.
1. 2. 2. 1  
Cli ni c al S u m m ar y  St u d y B P 2 9 8 4 0
St u d y B P 2 9 8 4 0 c o n si s t e d of a si n gl e a s c e n di n g d o s e ( S A D) p art, i n cl u di n g a n 
e x pl or at or y i n v e sti g ati o n of t h e eff e ct of f o o d, i n 2 5  h e alt h y m al e s u bj e ct s of w h o m 1 8 
r e c ei v e d ri s di pl a m at d o s e s r a n gi n g fr o m 0. 6  m g t o 1 8  m g, a n d a n itr a c o n a z ol e 
i nt er a cti o n p art i n 8  s u bj e ct s.
Ri s di pl a m  w a s r a pi dl y a b s or b e d wit h a m e di a n t m a x  b et w e e n 2  a n d 3  h o ur s u n d er f a st e d 
c o n diti o n s. C m a x  a n d t ot al pl a s m a e x p o s ur e ( ar e a u n d er t h e c ur v e; A U C) i n cr e a s e d i n a 
d o s e - pr o p orti o n al m a n n er. T h e eli mi n ati o n h alf-lif e w a s a p pr o xi m at el y 4 0  t o 5 0  h o ur s. 
O n a v er a g e, a s m all fr a cti o n ( 1 0 %) of t h e a d mi ni st er e d d o s e w a s e x cr et e d u n c h a n g e d 
i nt o uri n e. F o o d h a d n o r el e v a nt eff e ct o n t h e P K of  ri s di pl a m; o nl y t h e m e di a n tm a x  w a s 
d el a y e d t o 5  h o ur s .
T h e c o - ad mi ni str ati o n of  ri s di pl a m wit h itr a c o n a z ol e r e s ult e d i n a sli g ht ( 1 1 %) i n cr e a s e 
i n A U C 0- 1 2 0 h  a n d a sli g ht d e cr e a s e i n C m a x .
Ri s di pl a m  h a d a d o s e- d e p e n d e nt eff e ct o n S M N 2 s pli ci n g, a s s h o w n b y a c h a n g e i n t h e 
r ati o of f ull-le n gt h S M N 2 m R N A t o S M N Δ  7 m R N A w hi c h i s i nt er pr et e d a s pr o of of 
m e c h a ni s m  i n t er m s of t h e e x p e ct e d P D eff e ct.
Ri s di pl a m  w a s w ell -tol er at e d i n t hi s st u d y at all d o s e l e v el s. T h er e w er e n o d e at h s , 
s eri o u s a d v er s e e v e nt s ( S A E s) or wit h dr a w al s d u e t o a d v er s e e v e nt s ( A E s). N o cli ni c all y 
r el e v a nt c h a n g e s i n l a b or at or y s af et y p ar a m et er s, vit al si g n s, A E s, el e ctr o c ar di o gr a m 
( E C G) p ar a m et er s or o p ht h al m ol o gi c al a s s e s s m e nt s w er e o b s er v e d.
A t ot al of 2 7 A E s w er e r e p ort e d i n t h e S A D a n d itr a c o n a z ol e i nt er a cti o n p art s. All A E s 
w er e of mil d i nt e n sit y a n d r e s ol v e d wit hi n a s h ort p eri o d of ti m e  wit h o ut s e q u el a e. All 
A E s w er e c o n si d er e d t o b e n ot r el at e d t o  ri s di pl a m b y t h e I n v e sti g at or wit h t h e e x c e pti o n 
of  p oll a ki uri a ( pl a c e b o) a n d h e a d a c h e ( ri s di pl a m 1 8  m g).
T h e m o st fr e q u e ntl y aff e ct e d S y st e m Or g a n Cl a s s w a s GI di s or d er s ( 9 A E s) f oll o w e d b y 
n er v o u s s y st e m di s or d er s ( 4  A E s). T h e m o st fr e q u e ntl y r e p ort e d A E s w er e h e a d a c h e 
( 4 s u bj e ct s) a n d di arr h e a, a b d o mi n al p ai n a n d n a s o p h ar y n giti s ( 3  s u bj e ct s e a c h).
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
3 1 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


T h er e w a s n o d o s e -rel at e d i n cr e a s e i n t h e i n ci d e n c e or s e v erit y of r e p ort e d A E s a n d n o 
cl u st er  of A E s i n di c ati v e of a t o xi c eff e ct of t h e c o m p o u n d o n a gi v e n or g a n s y st e m.
M ore re ce nt a n d  d et ail e d  i nfor m ati o n i s pr o vi d e d i n t h e  Ri s di pl a m  I n v e sti g at or’ s 
Br o c h ur e.
1. 2. 2. 2  
Cli ni c al S u m m ar y  St u d y B P 3 9 0 5 5 ( P art  1)
A s of S e pt e m b er 2 0 1 7, 5 1  p ati e nt s h a v e b e e n e nr oll e d i n P art  1 of St u d y  B P 3 9 0 5 5, 
e v al u ati n g t h e s af et y, t ol er a bilit y, P K a n d P D of  ri s di pl a m i n p ati e nt s wit h T y p e 2 a n d 
T y p e  3 ( a m b ul a nt or n o n - am b ul a nt) S M A, wit h t h e o bj e cti v e t o s el e ct t h e d o s e f or P art  2 
of  t h e st u d y. 
T h e s e 5 1  p ati e nt s w er e e nr oll e d  i n fi v e c o h ort s a n d r a n d o mi z e d i n a 2: 1 r ati o t o a cti v e 
tr e at m e nt or pl a c e b o. P ati e nt s w er e i niti all y a s si g n e d t o t h e f oll o wi n g d o s e l e v el s: 3 m g 
a n d 5  m g o n c e d ail y i n p ati e nt s a g e d 1 2 2 5  y e ar s  ol d ; a n d 0. 0 2 m g/ k g, 0. 0 5  m g/ k g, a n d 
0. 2 5  m g/ k g i n p ati e nt s  a g e d 2 1 1  y e ar s  ol d .
A n o v er vi e w of c urr e nt d at a c a n b e f o u n d i n t h e  Ri s di pl a m  I n v e sti g at or' s Br o c h ur e.
A cr o s s t h e s e d o s e l e v el s,  ri s di pl a m P K w a s li n e ar (i. e.,  t h er e w a s a c orr e s p o n di n g 
i n cr e a s e i n ri s di pl a m pl a s m a c o n c e ntr ati o n s wit h i n cr e a s e i n d o s e). St e a d y st at e w a s 
att ai n e d aft er 7 1 4  d a y s of tr e at m e nt wit h  ri s di pl a m o n c e d ail y.
A d o s e r el at e d i n cr e a s e i n S M N pr ot ei n w a s o b s er v e d a cr o s s all d o s e l e v el s a n d a g e 
gr o u p s u p o n tr e at m e nt wit h  ri s di pl a m, wit h a m e di a n S M N pr ot ei n i n cr e a s e of 1 5 1 % 
(r a n g e 4 9 %2 5 1 %) v er s u s b a s eli n e at 5  m g i n t h e a g e gr o u p of 1 2 2 5  y e ar s  ol d , a n d a 
9 6 % (r a n g e 1 7 % 1 5 0 %) i n cr e a s e at 0. 2 5  m g/ k g i n t h e a g e gr o u p of 2 1 1  y e ar s  ol d .
A r e vi e w of all a v ail a bl e s af et y l a b or at or y r e s ult s, vit al si g n s, E C G s, a n d 
o p ht h al m ol o gi c al a s s e s s m e nt s di d n ot s h o w a n y cli ni c all y si g nifi c a nt a d v er s e fi n di n g s 
a s c o m p ar e d wit h b a s eli n e or t h e pl a c e b o gr o u p.
Ri s di pl a m  w a s w ell t ol er at e d a cr o s s all d o s e l e v el s t e st e d i n b ot h a g e c a t e g ori e s a n d n o 
st o p pi n g r ul e s w er e m et. T h er e h a v e b e e n n o d e at h s  a n d n o di s c o nti n u ati o n s fr o m t h e 
st u d y f or a n y r e a s o n.
B a s e d o n t h e s e d at a, a d o si n g r e gi m e n of 5  m g f or p ati e nt s wit h a b o d y w ei g ht  2 0  k g 
a n d 0. 2 5  m g/ k g f or p ati e nt s wit h a  b o d y w ei g ht  2 0  k g w a s s el e ct e d f or P art  2 of St u d y  
B P 3 9 0 5 5 .
M ore re ce nt a n d d et aile d i nf or m ati o n is pr o vi de d i n t he  Ri s di pl a m I n vesti g at or’s 
Br oc h ure.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
3 2 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


1. 2. 2. 3
Cli ni c al S u m m ar y  St u d y B P 3 9 0 5 6 ( P art 1)
T h e fi n al d o s e l e v el s s el e ct e d f or P art 2 of t hi s st u d y ar e 0. 0 8 m g/ k g a n d 0. 2
m g/ k g, 
b a s e d o n t h e P K d at a o bt ai n e d u ntil F e br u ar y 2 0 1 8 i n 1 6 i nfa nt s . T h e m e a n A U C 0 2 4 h, s s
w a s 1 7 0 0 n g• h / m L wit h 0. 0 8 m g/ k g i n i nf a nt s 5 m o nt h s ol d at e nr oll m e nt, 7 4 7
n g• h/ m L 
wit h 0. 0 8 m g/ k g i n i nf a nt s 5 m o nt h s ol d at e nr oll m e nt, a n d 2 0 4 0
n g• h/ m L wit h 
0. 2 m g/ k g i n i nf a nt s 5 m o nt h s ol d at e nr oll m e nt .
L o w er cl e ar a n c e a n d gr e at er e x p o s ur e w a s o b s er v e d i n 3 i nfa nt s 5 m o nt h s ol d at t h e 
ti m e of e nr oll m e nt, a n d t h er ef or e t h e d o s e i n t h e s e i nf a nt s w a s r e d u c e d t o 0. 0 8 m g/ k g 
w h er e a s i nf a nt s 5 m o nt h s ol d at t h e ti m e of e nr oll m e nt r e c ei v e d a fi n al d o s e of 
0. 2 m g/ k g . P er t h e pr ot o c ol, t h e fir st 3 i nf a nt s e nr oll e d i n t h e st u d y r e m ai n e d at t h e d o s e 
of  0. 0 8 m g/ k g f or a t ar g et e x p o s ur e of 7 0 0
n g• h /m L.
A m e di a n 2- f ol d i n cr e a s e (r a n g e 1. 05. 4) i n S M N pr ot ei n i n bl o o d v er s u s b a s eli n e w a s 
o b s er v e d f or i nf a nt s wit h a n e x p o s ur e ( A U C 0 2 4 h ) 1 0 0 0 n g• h/ m L , a n d a m e di a n 3. 2 -f ol d 
i n cr e a s e (r a n g e 1. 66. 5) w a s o bt ai n e d i n i nf a nt s wit h a n e x p o s ur e ( A U C 0 2 4 h ) 
1 0 0 0 n g• h /m L.
A r e vi e w of all a v ail a bl e s af et y l a b or at or y r e s ult s, vit al si g n s, E C G s, a n d 
o p ht h al m ol o gi c al a s s e s s m e nt s di d n ot s h o w a n y cli ni c all y si g nifi c a nt a d v er s e fi n di n g s a s 
c o m p ar e d wit h b a s eli n e.
T w o p ati e nt s h a d di s c o nti n u e d fr o m t h e st u d y d u e t o f at al pr o gr e s si o n of S M A di s e a s e. 
E v e nt s wit h a f at al o ut c o m e r e p ort e d i n t h e s e p ati e nt s w er e vir al r e s pir at or y tr a ct 
i nf e cti o n i n 1 p ati e nt, a n d c ar di a c arr e st a n d r e s pir at or y arr e st i n a n ot h er p ati e nt 
( all c o n si d er e d t o b e u nr el at e d t o st u d y tr e at m e nt).
Fi v e a d diti o n al p ati e nt s e x p eri e n c e d S A E s: p n e u m o ni a ( 2 e v e nt s i n 1 p ati e nt), a c ut e 
r e s pir at or y f ail ur e, at el e ct a si s, h y p o xi a, p n e u m o ni a a s pir ati o n, r e s pir at or y di str e s s, 
n e utr o p e ni a, i nfl u e n z a, a n d u p p er r e s pir at or y tr a ct i nf e cti o n.  All b ut o n e S A E 
( n e utr o p e ni a, r e s ol v e d) w er e c o n si d er e d a s u nr el at e d t o st u d y tr e at m e nt.  T h er e h a v e 
b e e n n o A E s l e a di n g t o m o difi c ati o n or p er m a n e n t wit h dr a w al of st u d y tr e at m e nt.
O v er all, ri s di pl a m w a s w ell t ol er at e d a cr o s s all d o s e l e v el s t e st e d a n d n o st o p pi n g r ul e s 
w er e m et.
M ore re ce nt a n d d et ail e d i nfor m ati o n i s pr o vi d e d i n t h e R i s di pl a m I n v e sti g at or’ s 
Br o c h ur e.
1. 3
S T U D Y R A TI O N A L E A N D B E N E FI T – RI S K A S S E S S M E N T
1. 3. 1
St u d y R ati o n al e
S M A i s  t h e l e a di n g g e n eti c c a u s e of d e at h i n i nf a nt s a n d y o u n g c hil dr e n. It i s a 
d e v a st ati n g di s e a s e:  T y p e  1  S M A r e s ult s i n al m o st i n e vit a bl e m ort alit y wit hi n a f e w y e ar s 
of  di a g n o si s. O n e dr u g w a s r e c e ntl y a p pr o v e d i n t h e  U nit e d St at e s, E ur o p e a n U ni o n, 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
3 3 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


C a n a d a, a n d ot h er j uri s di cti o n s  f or t h e tr e at m e nt of S M A i n p e di atri c a n d a d ult p ati e nt s 
(t h e a nti s e n s e oli g o n u cl e oti d e n u si n er s e n [ S pi nr a z aT M ]) b ut, t h e m e di c al n e e d i n S M A i s 
still v er y hi g h. T h er e i s c urr e ntl y n o or al tr e at m e nt  f or S M A t h at pr o vi d e s st a bili z ati o n or 
i m pr o v e m e nt of m ot or f u n cti o n a n d d e v el o p m e nt, w hi c h w o ul d b e of i m m e n s e v al u e f or 
p ati e nt s a n d p ar e nt s/ c ar e gi v er s .
S m all m ol e c ul e  S M N 2  s pli ci n g m o difi er s s u c h a s  ri s di pl a m r e pr e s e nt a p ot e nti al 
tr e at m e nt o pti o n f or p ati e nt s wit h S M A, a s t h e y i n cr e a s e t h e a m o u nt of S M N pr ot ei n. 
D efi ci e n c y of S M N pr ot ei n i s t h e f u n d a m e nt al p at h o p h y si ol o gi c al m e c h a ni s m of S M A. 
T h er e i s  i n cr e a si n g pr e cli ni c al e vi d e n c e t o s u g g e st t h at S M N r e st or ati on i n t h e C N S 
r e s ult s i n si g nifi c a nt i m pr o v e m e nt s i n s ur vi v al, m ot or f u n cti o n a n d di s e a s e p at h ol o g y b ut 
i s i n s uffi ci e nt t o f ull y a m eli or at e t h e S M A p h e n ot y p e ( P or e n s k y et al 2 0 1 2; P a s si ni et al 
2 0 1 1). B y r e st ori n g S M N pr ot ei n l e v el s i n b ot h t h e C N S a n d i n p eri p h er al ti s s u e, or all y 
a d mi ni st er e d S M N 2 s pli ci n g m o difi er s ar e a c c or di n gl y h y p ot h e si z e d t o pr o vi d e i m pr o v e d 
effi c a c y o v er c o m p o u n d s c urr e ntl y i n d e v el o p m e nt a d mi ni st er e d t o t h e C N S o nl y ( H u a 
et  al 2 0 1 1).
R i s di pl a m h a s d e m o n str at e d eff e cti v e c orr e cti o n of s pli ci n g of t h e h u m a n  S M N 2 g e n e. 
T h e c o m p o u n d s hift s t h e b al a n c e of alt er n ati v e s pli ci n g c o m pl et el y t o w ar d s i n cl u si o n of 
S M N 2 e x o n  7  a n d pr o d u cti o n of f u n cti o n al S M N pr ot ei n i n h u m a n c ult ur e d c ell s a n d i n 
S M A m o u s e m o d el s (f or d et ail s, s e e t h e  R i s di pl a m I n v e sti g at or’ s Br o c h ur e). Pr oof  of  
m e c h a ni s m f or t h e c h a n g e i n  S M N 2  s pli ci n g i n t er m s of  S M N 2  m R N A w a s e st a bli s h e d 
wit h ri s di pl a m i n a si n gl e a s c e n di n g d o s e st u d y i n h e alt h y s u bj e ct s. Pr o of of m e c h a ni s m 
i n t er m s of a n i n cr e a s e i n S M N pr ot ei n w a s pr e vi o u sl y d e m o n str at e d wit h a n ot h er 
c o m p o u n d h a vi n g a si mil ar m e c h a ni s m  of  a cti o n, R O 6 8 8 5 2 4 7, wit h a n u p t o 2 -f ol d 
i n cr e a s e i n S M N pr ot ei n o b s er v e d u p o n tr e at m e nt wit h R O 6 8 8 5 2 4 7.
T hi s st u d y i s d e si g n e d t o a s s e s s t h e s af et y, t ol er a bilit y, P K a n d P D of  ri s di pl a m i n 
p ati e nt s wit h  T y p e  1  S M A a g e d  1 t o  7  m o nt h s  at e nr oll m e nt, a cr o s s t h e e x p o s ur e r a n g e 
t h at i s e x p e ct e d t o pr o vi d e t h er a p e uti c b e n efit: P art  1 , t e sti n g t w o d o s e/ e x p o s ur e l e v el s 
of  ri s di pl a m i n a d o s e-e s c al ati o n - m a n n er , a n d i n P art  2 , t o a s s e s s t h e effi c a c y a n d 
s af et y of tr e at m e nt wit h  ri s di pl a m at t h e d o s e -l e v el s el e ct e d fr o m P art  1 . T h e 
d o s e -s el e cti o n  a p pr o a c h f or P art  2 ai m s at m a xi mi zi n g effi c a c y a n d t h er a p e uti c b e n efit 
b y t ar g eti n g t h e m a xi m u m S M N pr ot ei n bl o o d l e v el t h at c a n b e s a f el y a c hi e v e d i n T y p e 1 
S M A p ati e nt s, a s d et er mi n e d i n P art  1  ( S e cti o n 2  a n d S e cti o n  3. 2. 2 ).
A s t hi s i s t h e fir st st u d y wit h  ri s di pl a m i n i nf ant s wit h  T y p e  1  S M A, s af et y a n d t ol er a bilit y, 
P D a n d P K of  ri s di pl a m will b e a s s e s s e d i n d et ail i n  P art  1 , t o e n a bl e d o s e-s el e cti o n f or 
P art  2 . P h ar m a c o d y n a mi c eff e ct s of ri s di pl a m will b e m e a s ur e d i n t er m s of S M N pr ot ei n 
a n d S M N  m R N A s pli c e f or m s i n bl o o d . Effi c a c y will b e a s s e s s e d i n t er m s of m ot or 
f u n cti o n a n d m ot or d e v el o p m e nt mil e st o n e s wit h t h e Gr o s s M ot or S c al e of t h e B a yl e y 
S c al e s of I nf a nt a n d T o d dl er d e v el o p m e nt  –  T hir d E diti o n ( B SI D -III; B a yl e y 2 0 0 6 ) a n d 
t h e C hil dr e n' s H o s pit al of P hil a d el p hi a I n f a nt T e st of N e ur o m u s c ul ar Di s or d er s 
(C H O P -I N T E N D; Gl a n z m a n et al 2 0 1 0 ; Gl a n z m a n et al 2 0 1 1 ). R e s pir at or y f u n cti o n will 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
3 4 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


b e m e a s ur e d b y r e s pir at or y pl et h y s m o gr a p h y ( R P). Ot h er tr e at m e nt eff e ct s will b e 
m e a s ur e d b y a s s e s si n g q u alit y of lif e a n d r el e v a nt bi o m ar k er s ( S e cti o n
4. 6. 1. 1 5 ).
1. 3. 2
B e n efit -Ri s k A s s e s s m e nt
I n t h e S A D st u d y ( B P 2 9 8 4 0; S e cti o n 1. 2. 2 ), ri s di pl a m w a s s h o w n t o b e s af e a n d w ell  
t ol er at e d u p t o a si n gl e d o s e of 1 8  m g.  T hi s st u d y e st a bli s h e d pr o of of m e c h a ni s m i n 
h e alt h y s u bj e ct s t h at, at s af e a n d t ol er a bl e d o s e s,  ri s di pl a m i s a bl e t o m o d ul at e t h e 
s pli ci n g of  S M N 2 m R N A, l e a di n g t o a n e x p o s ur e - de p e n d e nt i n cr e a s e i n t h e a m o u nt of 
f ull-le n gt h S M N 2 ( F L-S M N 2 ) m R N A a n d a c orre s p o n di n g d e c r e a s e i n t h e a m o u nt of 
S M N 2  m R N A l a c ki n g  e x o n  7.  I n P art  1 of St u di e s  B P 3 9 0 5 5 a n d B P 3 9 0 5 6 ( s e e i nt eri m 
d at a s u m m ari z e d i n S e cti o n  1. 2. 2 ), tr e at m e nt wit h ri s di pl a m w a s s af e a n d w ell t ol er at e d, 
a n d a n e x p o s ur e d e p e n d e nt i n cr e a s e i n S M N pr ot ei n w a s o b s er v e d c o nfir mi n g pr o of of 
m e c h a ni s m i n p ati e nt s wit h S M A. A c c or di n gl y, a v ail a bl e d at a t o d at e  s u g g e st t h at 
ri s di pl a m m a y pr o vi d e b e n efit f or p ati e nt s wit h S M A.
I n vi e w of t h e a d v er s e fi n di n g s i n t h e a ni m al t o xi c ol o g y st u di es, t h e m a xi m u m e x p o s ur e 
i n t h e fir st cli ni c al tri al i n h e alt h y v ol u nt e er s ( H V) w a s li mit e d t o a n i n di vi d u al pl a s m a 
e x p o s ur e ( A U C 0- 2 4 h ) of 1 5 0 0 h  n g / m L, t o e n s ur e t h e s af et y of t h e p arti ci p ati n g h e alt h y 
s u bj e ct s  w hil e a s s e s si n g s af et y a n d t ol er a bilit y u p t o a t h er a p e uti c ally r el e v a nt e x p o s ur e 
l e v el, a n d t o d et er mi n e e s s e nti al P K a n d P D i nf or m ati o n t o s u p port m o d eli n g a cti viti e s 
a n d s el e cti o n of t h e st arti n g d o s e f or t h er a p e uti c tri al s i n i nf a nt s.
I n t hi s st u d y, a sli g htl y hi g h er e x p o s ur e c a p of 2 0 0 0  h  n g/ m L ( m e a n A U C 0- 2 4 h ,S S ) 
c orr e s p o n di n g t o t h e o v er all N O A E L of t h e 3 9 - we e k t o xi c ol o g y st u d y i n 
c y n o m ol g u s - m o n k e y, al o n g wit h a t h or o u g h cli ni c al s af et y m o nit ori n g pl a n i s j u stifi e d, 
c o n si d eri n g t h e p ot e nti al b e n efit f or T y p e  1 S M A p ati e nt s e nr oll e d. At t h e d o si n g r e gi m e n 
s el e ct e d f or P art  2 of t h e st u d y, t h e pr e di ct e d e x p o s ur e i s a m e a n A U C 0 2 4 h, s s  of 
1 6 5 0  n g• h/ m L i n i nf a nt s 3 5  m o nt h s ol d at e nr oll m e nt  wit h a d o s e of 0. 0 8  m g/ k g, a n d a 
pr e di ct e d m e a n A U C 0 2 4 h, s s  of  2 0 2 0 n g• h/ m L i n i nf a nt s  5  m o nt h s ol d at e nr oll m e nt wit h a 
d o s e of 0. 2  m g/ k g. B e c a u s e t hi s pr e di cti o n i s b a s e d o n a s m all n u m b er of p a ti e nt s fr o m 
P art  1, e x p o s ur e will b e m o nit or e d i n all i nf a nt s e nr oll e d i n P art  2 a n d t h e d o s e a dj u st e d if 
n e c e s s ar y, t o e n s ur e t h at i nf a nt s ar e i n t h e t ar g et e d e x p o s ur e r a n g e.
E a c h d o s e  l e vel t o b e t e st e d i n t hi s st u d y h a s t h e p ot e nti al t o pr o vi d e t h er a p e uti c b e n efit 
t o S M A p ati e nt s. A v ail a bl e d at a s u g g e st t h at a 1 0 0 % i n cr e a s e i n S M N pr ot ei n l e v el s (t h e 
t ar g et f or t h e l o w er d o s e l e v el t e st e d i n P art 1) c o ul d t ur n s e v er e S M A p h e n ot y p e s i nt o 
mil d er f or m s, w hil e f urt h er i n cr e a s e m a y pr o vi d e e v e n gr e at er b e n efit ( S e cti o n  3. 2. 1 ). I n 
P art  1 of t h e st u d y,  a  m e di a n 2-f ol d i n cr e a s e (r a n g e 1. 0 5. 4) i n S M N pr ot ei n i n bl o o d 
v er s u s b a s eli n e w a s o b s er v e d f or i nf a nt s wit h a n e x p o s ur e ( A U C 0 2 4 h ) 1 0 0 0  n g• h / m L, 
a n d a  m e di a n 3. 2 -fol d i n cr e a s e (r a n g e 1. 6 6. 5) w a s o bt ai n e d i n i nf a nt s wit h a n e x p o s ur e 
( A U C0 2 4 h ) 1 0 0 0  n g• h / mL .
S af et y pr e c a uti o n s ar e  pr o vi d e d a n d a t h or o u g h s af et y m o nit ori n g pl a n f o c u si n g o n 
li a biliti e s i d e ntifi e d i n t h e n o n cli ni c al t o xi c ol o g y s t u di e s will b e i m pl e m e nt e d t o a d dr e s s 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
3 5 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7





I m pl e m e nt ati o n of a n I M C ( P art 1; S e cti o n 3. 1. 2 ) a n d a n e xt er n al i n d e p e n d e nt D at a
M o nit ori n g C o m mitt e e (i D M C; P art 2; S e cti o n
3. 1. 3 ), w h o will r e vi e w s af et y, P K a n d
P D d at a o n a r e g ul ar a n d a d -h o c b a si s t hr o u g h o ut t h e st u d y.

A p pr o pri at e i n cl u si o n/ e x cl u si o n crit eri a a n d g ui d a n c e r e g ar di n g pr o hi bit e d t h er a p y
(i n cl u di n g C Y P 3 A 4 i n hi bit or s/i n d u c er s, or g a ni c c ati o n tr a n s p ort er [ O C T]- 2 a n d
M A T E s u b str at e s, F M O i n hi bit or s a n d s u b str at e s, a n d m e di c ati o n s wit h p ot e nti al
r eti n al t o xi cit y; S e cti o n 4. 5 ).
T h e str a t e g y a n d r ati o n al e f or d o s e-s el e cti o n i s d e s cri b e d i n S e cti o n 3. 2. 1 . T a bl e 1 gi v e s 
a n o v er vi e w of t h e m ar gi n s v er s u s k e y t o xi citi e s of ri s di pl a m at t h e st arti n g e x p o s ur e of 
t hi s st u d y a n d at t h e e x p o s ur e c a p. T h e s af et y m ar gi n s f or t h e t ar g et e d e x p o s ur e i n 
P art 2 ar e t h e s a m e a s f or t h e e x p o s ur e c a p, b e c a u s e t h e hi g h e st p o s si bl e d o s e at t h e 
e x p o s ur e c a p h a s b e e n s el e ct e d t o m a xi mi z e t h e i n cr e a s e i n S M N pr ot ei n a n d 
s u b s e q u e ntl y t h e c h a n c e f or cli ni c al effi c a c y i n i nf a nt s wit h T y p e 1 S M A.
B a s e d o n a d v er s e fi n di n g s o n t e s t e s o b s er v e d i) i n b ot h s p e ci e s ii) at e x p o s ur e m at c hi n g 
cli ni c al t ar g et e x p o s ur e, t h e p ot e nti al f or ri s di pl a m t o aff e ct m al e g er m c ell s
a n d f ertilit y i n 
h u m a n i s p o s si bl e. H o w e v er, fr o m a ni m al st u di e s, t h er e i s e vi d e n c e t h at t h e st u d y dr u g 
aff e ct s t h e j u v e nil e p a c h yt e n e s p er m at o c yt e s wit h n o e vi d e n c e of t ar g eti n g t h e st e m 
c ell s. H e n c e, r e v er si bilit y of t h e eff e ct w o ul d b e e x p e ct e d if tr e at m e nt wit h ri s di pl a m i s 
di s c o nti n u e d.
T a bl e 1
O v er vi e w  of t h e M ar gi n s v er s u s K e y T o xi citi e s of R i s di pl a m
T y p e of T o xi cit y
M a r gi n at N O AE L v s St arti n g 
E x p o s ur e of 7 0 0 n g h/ m L
( AU C 0- 2 4 h )
M a r gi n at N O AE L v s C a p 
E x p o s ur e of 2 0 0 0 n g h/ m L
( AU C 0- 2 4 h )
Mi cr o n u cl e u s i n d u cti o n i n r at 
b o n e m arr o w
~ 5
~ 1. 5
T e sti s t o xi cit y i n r at s a n d 
m o n k e y s
~ 1
n o
E pit h eli al fi n di n g s ( s ki n, e y eli d, 
l ar y n x) i n m o n k e ys
1 0
2. 5
H e m at ol o g y c h a n g e s ( R B C 
a n d l y m p h o c y t e s) i n m o n k e y s
1 0
4
R eti n a c h a n g e s i n m o n k e y s
~ 3
~ 1
O v er all N O A E L ( 1 3 w e e k s of 
tr e at m e nt: j u v e nil e r at)
~ 1 0
3
O v er all N O A E L ( 3 9 w e e k s of 
tr e at m e nt: m o n k e y)
~ 3
~ 1
N O A E L: n o -o b s er v e d -a d v er s e -e v e nt l e v el; R B C: r e d bl o o d c ell.
T h e p ot e nti al b e n efit of tr e at m e nt wit h  ri s di pl a m f or T y p e  1  S M A p ati e nt s w o ul d b e a n 
i n cr e a s e i n S M N pr ot ei n l e v el s, i n t h e c e ntr al n er v o u s s y st e m an d p eri p h er al ti s s u e s, 
s u c h a s m u s cl e s a n d e n d ot h eli al c ell s. T hi s p h ar m a c ol o gi c al eff e ct i s h y p ot h e si z e d t o 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
3 7 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
3 8 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
tr a n sl at e i nt o a n i m pr o v e m e nt of p ati e nt s’ m ot or mil e st o n es a c hi e v e d, p ul m o n ar y 
f u n cti o n a n d o v er all, a b ett er h e alt h st at u s. F oll o wi n g t hi s h y p ot h e si s, b y t h e e n d of t h e 
st u d y, m aj or mil e st o n e s, li k e sitti n g wit h o ut s u p p ort i n s o m e p ati e nt s a n d at l e a st st o p or 
sl o wi n g of di s e a s e pr o gr e s si o n a n d it s a s s o ci at e d c o- m or bi diti e s, ar e h y p ot h e si z e d t o b e 
a c hi e v e d. I n s o m e p ati e nt s, b e n efi ci al eff e ct s i n p ul m o n ar y f u n cti o n a n d n or m ali z ati o n i n 
m ot or mil e st o n e d e v el o p m e nt ar e al s o h y p ot h e si z e d t o b e s e e n.
O v er all, c o n si d eri n g t h e di s e a s e s e v erit y of S M A p ati e nt s a n d t h e p ot e nti al f or t h e s e 
p ati e nt s t o b e n efit fr o m tr e at m e nt wit h ri s di pl a m, R o c h e c o n si d er s t h e s af et y m ar gi n s i n 
t hi s st u d y a p pr o pri at e, a n d d at a fr o m P art 1 of t h e st u d y c o nti n u e t o j u stif y t h e b e n efit-
ri s k of tr e at m e nt wit h ri s di pl a m f or 1- t o 7-m o nt h ol d p ati e nt s ( at e nr oll m e nt) wit h T y p e 1
S M A.
2.
O B J E C TI V E S
2. 1
P RI M A R Y O B J E C TI V E S
T h e pri m ar y o bj e cti v e s f or t h e st u d y ar e a s f oll o w s:

P art 1
T o e v al u at e t h e s af et y, t ol er a bilit y, p h ar m a c o ki n eti c s, a n d p h ar m a c o d y n a mi c s of
ri s di pl a m i n i nf a nt s wit h T y p e 1 S M A, a n d t o s el e ct t h e d o s e f or P art 2.

P art 2
T o a s s e s s t h e effi c a c y of ri s di pl a m m e a s ur e d a s t h e pr o p orti o n of i nf a nt s sitti n g
wit h o ut s u p p ort aft er 1 2 m o nt h s
of tr e at m e nt, a s a s s e s s e d i n t h e Gr o s s M ot or S c al e
of  t h e B a yl e y S c al e s of I nf a nt a n d T o d dl er d ev el o p m e nt – T hir d E diti o n ( B SI D -III)
( d efi n e d a s sitti n g wit h o ut s u p p ort f or 5 s e c o n d s).
2. 2
S E C O N D A R Y O B J E C TI V E S
T h e s e c o n d ar y o bj e cti v e s f or P art 2 of t hi s st u d y ar e a s f oll o w s:

T o a s s e s s t h e s af et y a n d t ol er a bilit y of or al tr e at m e nt wit h ri s di pl a m.

T o a s s e s s t h e p h ar m a c o ki n eti c s of ri s di pl a m.

T o a s s e s s t h e p h ar m a c o d y n a mi c eff e ct s of ri s di pl a m (S M N 2 m R N A , S M N pr ot ei n).

T o e v al u at e at 1 2 m o nt h s
of tr e at m e nt wit h ri s di pl a m t h e eff e ct o n m ot or
d e v el o p m e nt mil e st o n e s, s u c h a s h e a d c o ntr ol a n d r olli n g, a s m e a s ur e d i n t h e
B SI D -III gr o s s m ot or s c al e.

T o e v al u at e at 2 4 m o nt h s
of tr e at m e nt wit h ri s di pl a m t h e eff e ct o n sitti n g wit h o ut
s u p p ort f or 5 s e c o n d s a n d f urt h er m ot or d e v el o p m e nt mil e st o n e s, s u c h a s sitti n g
wit h o ut s u p p ort f or 3 0 s e c o n d s, cr a wli n g, st a n di n g al o n e, a n d w al ki n g, a s m e a s ur e d
i n t h e B SI D -III gr o s s m ot or s c al e.


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
3 9 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7

T o a s s e s s t h e a c hi e v e m e nt of m ot or mil e st o n e s at 1 2 a n d 2 4 m o nt h s of tr e at m e nt
wit h ri s di pl a m, a s m e a s ur e d b y t h e H a m m er s mit h I nf a nt N e ur ol o gi c al E x a mi n ati o n
( HI N E) M o d ul e 2.

T o e v al u at e t h e pr o p orti o n of i nf a nt s w h o a c hi e v e a s c or e of 4 0 or hi g h er i n t h e
C hil dr e n' s H o s pit al of P hil a d el p hi a I nf a nt T e st of N e ur o m u s c ul ar Di s or d er s
( C H O P-I N T E N D) at 1 2 m o nt h s of tr e at m e nt.

T o e v al u at e t h e pr o p orti o n of i nf a nt s w h o a c hi e v e a n i n cr e a s e of at l e a st 4 p oi nt s o n
t h eir C H O P -I N T E N D s c or e fr o m b a s eli n e at 8 a n d 1 2 m o nt h s of tr e at m e nt.

T o e v al u at e t h e pr o p orti o n of i nf a nt s w h o a c hi e v e h e a d c o ntr ol at 8, 1 2, a n d
2 4 m o nt h s of tr e at m e nt ( d efi n e d a s a s c or e of 3
or hi g h er f or it e m 1 2 of t h e
C H O P -I N T E N D).

T o a s s e s s t h e c h a n g e fr o m b a s eli n e i n t h e t ot al r a w s c or e of t h e B SI D -III gr o s s
m ot or s c al e at 1 2
a n d 2 4 m o nt h s of tr e at m e nt.

T o a s s e s s t h e pr o p orti o n of i nf a nt s w h o a c hi e v e a r e d u cti o n of at l e a st 3 0 d e gr e e s
i n p h a s e a n gl e at 1 2 m o nt h s
of tr e at m e nt m e a s ur e d b y r e s pir at or y
pl et h y s m o gr a p h y ( R P).

T o e v al u at e t h e pr o p orti o n of i nf a nt s w h o d o n ot r e q uir e i n v a si v e or n o n -i n v a si v e
r e s pir at or y s u p p ort at 1 2 a n d 2 4 m o nt h s of tr e at m e nt.

T o a s s e s s at 1 2 a n d 2 4 m o nt h s
of tr e at m e nt t h e pr o p orti o n of i nfa nt s w h o ar e ali v e
wit h o ut p er m a n e nt v e ntil ati o n, a s d efi n e d b y 1 6 h o ur s of n o n -i n v a si v e v e ntil ati o n
p er d a y or i nt u b ati o n f or 2 1 c o n s e c uti v e d a y s i n t h e a b s e n c e of, or f oll o wi n g t h e
r e s ol uti o n of, a n a c ut e r e v er si bl e e v e nt or tr a c h e o st o m y.

T o a s s e s s t h e i m p a ct of tr e at m e nt wit h ri s di pl a m o n ti m e -t o-e v e nt ( d e at h,
p er m a n e nt v e ntil ati o n).

T o e v al u at e t h e pr o p orti o n of i nf a nt s wit h t h e a bilit y t o f e e d or all y at 1 2 a n d
2 4
m o nt h s of tr e at m e nt.
2. 3
E X P L O R A T O R Y O B J E C TI V E S
T h e e x pl or at or y o bj e cti v e s f or P art 2 of t hi s st u d y ar e a s f oll o w s:

T o e x pl or e t h e eff e ct of tr e at m e nt wit h ri s di pl a m o n p ar e nt/ c ar e gi v er -r at e d i nf a nt
h e alt h st at u s a n d i m p a ct o n t h e p ar e nt/ c ar e gi v er, a s m e a s ur e d b y t h e I nf a nt
T o d dl er Q u alit y of Lif e Q u e sti o n n air e at 1 2 a n d 2 4 m o nt h s .

T o a s s e s s at 8, 1 2, a n d 2 4 m o nt h s
of tr e at m e nt wit h ri s di pl a m t h e r ati o b et w e e n t h e
c h e st a n d h e a d cir c u mf er e n c e.

T o e x pl or e t h e tr e at m e nt eff e ct o n pr e -s p e cifi e d di s e a s e -r el at e d a d v er s e e v e nt s b y
1 2 a n d 2 4 m o nt h s
of tr e at m e nt.

T o i n v e sti g at e t h e eff e ct at 1 2 a n d 2 4 m o nt h s
of tr e at m e nt wit h ri s di pl a m o n m u s cl e
el e ctr o p h y si ol o g y, a s a s s e s s e d b y c o m p o u n d m u s cl e a cti o n p ot e nti al ( C M A P).

T o e x pl or e t h e eff e ct of tr e at m e nt wit h ri s di pl a m o n t h e n u m b er of h o s pit ali z ati o n s
(for a n y r e a s o n) p er p ati e nt -y e ar a n d n u m b er o f ni g ht s a d mitt e d t o h o s pit al p er
i nf a nt at 1 2 a n d 2 4 m o nt h s of tr e at m e nt .



T o e v al u at e at 2 4 m o nt h s
t h e eff e ct s of ri s di pl a m o n s u st ai n e d sitti n g f or t h o s e
i nf a nt s sitti n g at 1 2 m o nt h s ( d efi n e d a s sitti n g wit h o ut s u p p ort f or 5
s e c o n d s) .

T o e x pl or e at 2 4 m o nt h s t h e m ai nt e n a n c e of t h e eff e ct s of ri s di pl a m o n r e s pir at or y
f u n cti o n f or t h o s e i nf a nt s w h o a c hi e v e a r e d u cti o n of at l e a st 3 0 d e gr e e s i n p h a s e
a n gl e at 1 2 m o nt h s .

T o e x pl or e at 1 2 m o nt h s t h e eff e ct of tr e at m e nt wit h ri s di pl a m o n cli ni ci a n -r e p ort e d
c h a n g e s i n i nf a nt s ’ r e s pir at or y f u n cti o n a n d s w all o wi n g a bilit y, a s m e a s ur e d b y t h e
cli ni c al d o m ai n l e v el it e m s.

T o a s s e s s at 1 2 a n d 2 4 m o nt h s of tr e at m e nt wit h ri s di pl a m t h e c h a n g e fr o m
b a s eli n e i n w ei g ht a n d l e n gt h/ h ei g ht p er c e ntil e s.
3.
S T U D Y D E SI G N
3. 1
D E S C RI P TI O N O F S T U D Y
3. 1. 1
O v er vi e w  of St u d y D e si g n
T hi s i s a s e a ml e s s o p e n -l a b el, si n gl e-ar m, m ulti -c e nt er cli ni c al st u d y t o i n v e sti g at e t h e 
s af et y, t ol er a bilit y, p h ar m a c o ki n eti c s, p h ar m a c o d y n a mi c s a n d effi c a c y of  ri s di pl a m i n 
T y p e  1 S M A i nf a nt s.  T h e st u d y will b e c o n d u ct e d i n t w o p art s a n d f oll o w e d b y a n 
o p e n -l a b el e xt e n si o n p h a s e :
E x pl or at or y  P art 1:  P art  1  i s a n o p e n-l a b el, d o s e e s c al ati o n st u d y i n i nf a nt s wit h T y p e 1 
S M A a g e d 1 t o  7  m o nt h s  ( at ti m e of e nr oll m e nt). T hi s e x pl or at or y p art will c o n si st of at 
l e a st 8 i nf a nt s a n d u p t o 2 4  i nfa nt s  (if r e q uir e d) t o a s s e s s t h e s af et y, P K a n d P D pr ofil e 
of  ri s di pl a m i n i nf a nt s a n d d et er mi n e t h e d o s e f or P art  2.
C o nfir m at or y  P art 2:  P art  2  i s a n o p e n-l a b el, si n gl e-ar m st u d y i n  4 0  i nfa nt s  wit h T y p e  1 
S M A a g e d 1 t o  7  m o nt h s  ( at ti m e of e nr oll m e nt) t o a s s e s s t h e effi c a c y of ri s di pl a m at t h e 
d o s e s el e ct e d i n  P art  1  o v er a 2 4 -m o nt h tr e at m e nt p eri o d, wit h t h e pri m ar y e n d p oi nt 
a n al y z e d at  1 2  m o nt h s  of tr e at m e nt.
I n b ot h P art 1 a n d P art 2, aft er 2 4 m o nt h s  of tr e at m e nt  p ati e nt s will e nt er a n o p e n -l a b el 
e xt e n si o n p h a s e.
I n b ot h P art 1 a n d P art 2, aft er a p ati e nt c o m pl et e s We e k 1 0 4 it m a y b e p o s si bl e f or t h e 
p ati e nt t o b e all o c at e d t o a n ot h er sit e, f oll o wi n g di s c u s si o n a n d a gr e e m e nt b y t h e 
S p o n s or. If t hi s o c c ur s, t h e r e all o c ati o n will n ot b e c o n si d er e d a n e w e nr oll m e nt i n t h e 
st u d y.
T h e st u d y will pr o gr e s s i n a n o p er ati o n all y s e a ml e s s m a n n er fr o m P art  1  i nt o P art  2  aft er 
t h e d o s e s el e cti o n d e ci si o n h a s  b e e n t a k e n ( s e e S e cti o n  3. 2. 1 ).
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
4 0 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


3. 1. 1. 1  
E x pl or at or y  P art 1
I nf a nt s ( b et w e e n t h e a g e of 1 a n d 7  m o nt h s  at e nr oll m e nt) will b e e nr oll e d i n a st a g g er e d 
m a n n er i n t hi s d o s e  e s c al ati o n st u d y.
T h e fir st i nf a nt will r e c ei v e a si n gl e  d o s e of t h e st u d y dr u g  ri s di pl a m t o a s s e s s s af et y a n d 
t ol er a bilit y, a n d P K ( S e cti o n 3. 2. 1 ). If t hi s si n gl e d o s e of t h e st u d y dr u g i s s af e a n d w ell 
t ol er at e d i n t hi s fir st i nf a nt, a n d aft er t h e P K h a s b e e n a s s e ss e d a n d e v al u at e d, t hi s 
i nf a nt will c o nti n u e tr e at m e nt wit h ri s di pl a m a n d st art a p pr o xi m at el y  2  w e e k s  l at er t h e 
st u d y a s p er t h e S c h e d ul e of A s s e s s m e nt s ( S o A) at t h e d o s e l e v e l (D o s e L e v el  1 ; t ar g et 
A U C 0- 2 4 h, s s  7 0 0  n g • h/ m L) s el e ct e d b a s e d o n t h e P K d at a o bt ai n e d fr o m t h e fir st si n gl e 
d o s e. If t h e st u d y dr u g i s w ell  t ol er at ed i n t hi s fir st i nf a nt f or at l e a st o n e w e e k aft er 
r e a c hi n g a p pr o xi m at e st e a d y-st at e ( or a mi ni m u m of 2 -w e e k tr e at m e nt),  a n a d diti o n al 
2  i nfa nt s will b e e nr oll e d ( 5 t o 7 m o nt h s of a g e) t o r e c ei v e t hi s d o s e/ e x p o s ur e l e v el. P K, 
s af et y a n d t ol er a bilit y will b e a s s e s s e d pri or t o e nr olli n g 2 a d diti o n al p ati e nt s
( 1 t o 7  m o nt h s). S af et y a n d t ol er a bilit y, P K a n d P D will b e cl o s el y a s s e s s e d, a n d t h e 
d o s e a dj u st e d a s r e q uir e d b a s e d o n a ct u al m e a s ur e d P K v er s u s t h e pr e di ct e d t ar g et 
e x p o s ur e.
I n t h e u nli k el y c a s e t h at P K m e a s ur e m e nt s ar e b el o w t h e li mit of q u a ntifi c ati o n ( B L Q) 
af t er a d mi ni str ati o n of t h e fir st si n gl e d o s e, t hi s fir st i nf a nt will r e p e at t h e si n gl e d o s e 
a d mi ni str ati o n wit h a hi g h er d o s e w hi c h i s pr e di ct e d t o b e q u a ntifi a bl e b ut b el o w t h e 
e x p o s ur e c a p.
If u p o n r e vi e w of s af et y a n d t ol er a bilit y i n t h e fir st 5 i nf a nt s f or at l e a st 7  d a y s at 
a p pr o xi m at e st e a d y -st at e ( or a mi ni m u m of 2 -w e e k tr e at m e nt), t hi s d o s e/ e x p o s ur e l e v el 
d o e s n ot m e et a n y of t h e d o s e  e s c al ati o n st o p pi n g r ul e s ( S e cti o n  5. 2. 4 ), t h e d o s e of t h e 
5 t h i nf a nt will b e i n cr e a s e d t o r e a c h t h e hi g h er t ar g et e x p o s ur e ( D o s e L e v el  2 ; t h e 
e x p o s ur e wit h m a xi m u m e x p e ct e d S M N pr ot ei n i n c r e a s e, b ut b el o w t h e e x p o s ur e c a p). 
A s s u mi n g d o s e e s c al ati o n st o p pi n g r ul e s r e m ai n u n m et aft er a d mi ni str ati o n  of ri s di pl a m 
i n all 5 e nr oll e d i nf a nt s (f or a mi ni m u m of  1  w e e k  i n t h e l a st i nf a nt r e c ei vi n g Do s e L e v el  2 , 
a n d l o n g er tr e at m e nt d ur ati o n i n all pr e vi o u sl y e nr oll e d i nf a nt s at D o s e L e v el  1), 3  
a d diti o n al i nf a nt s will b e e nr oll e d a n d r e c ei v e  ri s di pl a m at t hi s hi g h er t ar g et e x p o s ur e. 
Aft er a mi ni m u m tr e at m e nt d ur ati o n of  4  w e e k s  at D o s e  L e v el  2  ( or 2  w e e k s  at t h e fi n al 
a p pr o xi m at e st e a d y -st at e e x p o s ur e) i n all  4  i nfa nt s , all s af et y, P K, a n d P D d at a will b e 
r e vi e w e d t o s el e ct t h e d o s e t o b e e v al u at e d i n P art  2.
Si n c e P art  1  of t h e st u d y  i s e x pl or at or y i n n at ur e, it m a y b e d e ci d e d t o e x pl or e a d diti on al 
o r i nt er m e di at e d o s e/ e x p o s ur e l e v el s, or t o e nr oll a d diti o n al i nf a nt s ( u p t o a m a xi m u m 
t ot al n u m b er of 2 4 i nfa nt s i n  P art  1 ), if r e q uir e d t o b ett er c h ar a ct eri z e t h e s af et y a n d 
t ol er a bilit y or P K of ri s di pl a m i n i nf a nt s, a n d t o b e a bl e t o s el e ct t h e a p pr o priat e d o s e f or 
P art  2.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
4 1 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


O n c e t h e d o s e f or P art 2 h a s b e e n s el e ct e d, u p o n a p pr o pri at e s af et y a n d t ol er a bilit y, 
a n d wit h o ut a n y i nt err u pti o n of tr e at m e nt, all i nf a nt s (i n cl u di n g t h e fir st 4 i nf a nt s e nr oll e d 
at D o s e L e v el 1) will b e gi v e n t h e p o s si bilit y t o c o nti n u e r e c ei vi n g ri s di pl a m at t h e d o s e 
s el e ct e d f or P art 2 a s p art of a n e xt e n si o n p h a s e. T h e o p e n -l a b el e xt e n si o n p h a s e ,
b e gi n ni n g aft er 2 4 m o nt h s of tr e at m e nt , will i n cl u d e r e g ul ar m o nit ori n g of s af et y, 
t ol er a bilit y a n d effi c a c y will c o nti n u e f or a n a d diti o n al 3 ye ars f or e a c h p atie nt , as 
o utli ne d bel o w .
A s t h e i nf a nt s gr o w a n d d e v el o p, t h e d o s e m a y n e e d t o b e a dj u st e d b a s e d o n b o d y 
w e i g ht, a g e, or ot h er p ar a m et er s i d e ntifi e d, i n or d er t o m ai nt ai n t h e e x p o s ur e l e v el o v er
ti m e i n a n i n di vi d u al gr o wi n g i nf a nt (i. e., t h e d o s e a d mi ni st er e d m a y b e hi g h er t h a n t h e 
d o s e l e v el s e x pli citl y li st e d i n t h e pr ot o c ol, pr o vi d e d t h e m e a s ur e d a n d o b s er v e d P K 
e x p o s ur e i s i n c o m pli a n c e wit h t h e e x p o s ur e c a p of a m e a n A U C 0- 2 4 h ,s s of 2 0 0 0 n g• h / m L).
T h e d ur ati o n of t h e st u d y f or e a c h i nf a nt e nr oll e d i n P art 1 will b e di vi d e d a s f oll o w s:

S cr e e ni n g: U p t o 3 0 d a y s pri or t o fir st d o s e

Tr e at m e nt P eri o d: mi ni m u m of 2 w e e k s at st e a d y st at e e x p o s ur e ( a s d e ci d e d b y t h e
I nt er n al M o nit ori n g C o m mitt e e [I MC]) , f oll o we d b y tre at me nt f or 2 4 m o nt hs fr o m t he
st art of d osi n g

O pe n -l a bel e xte nsi o n: f or a n a d diti o n al 3 ye ars, after c o m pleti o n of 2 4 m o nt hs of
tre at me nt. After a p atie nt h as c o m plete d 3 ye ars i n t he o pe n -l a bel e xte nsi o n, t he
p atie nt m a y c o nti n ue i n t he st u d y u ntil t he e n d of st u d y ( E O S ), pr o vi de d
t h at ris di pl a m is n ot c o m mer ci all y a v ail a ble i n t he p atie nt's c o u ntr y
(see Se cti o n 3. 1. 5 ).
3. 1. 1. 2
C o nfir m at or y P art 2
A t ot al of 4 0 i nfa nt s will b e e nr oll e d t o r e c ei v e ri s di pl a m at t h e d o s e s el e ct e d fr o m P art 1. 
I nf a nt s fr o m P art 1 will n ot b e e nr oll e d i nt o P art 2.
O n t h e b a si s of a v ail a bl e d at a fr o m P art 1, t h e f oll o wi n g st arti n g d o s e l e v el s h a v e b e e n 
s el e ct e d f or P art 2:

I nf a nt s > 1 m o nt h a n d b el o w 3 m o nt h s ol d at e nr oll m e nt: 0. 0 4
m g/ k g.

I nf a nt s at l e a st 3 m o nt h s b ut b el o w 5
m o nt h s ol d at e nr oll m e nt: 0. 0 8
m g/ k g.

I nf a nt s 5 m o nt h s ol d or ol d er at e nr oll m e nt: 0. 2 m g/ k g.
P ati e nt s will r e m ai n o n t h eir i niti all y a s si g n e d d o s e l e v el (i. e.,  t h e d o s e will n ot c h a n g e 
o n c e a p ati e nt r e a c h e s 3  m o nt h s a n d 5 m o nt h s of a g e, r e s p e cti v el y) u nl e s s a c h a n g e of 
d o s e i s r e q u e st e d b y t h e Cli ni c al P h ar m a c ol o gi st u p o n r e vi e w of t h e P K d at a. T h e P K i n 
all i nf a nt s will b e r e g ul arl y m o nit or e d ( d at a r e vi e w e v er y 2  w e e k s, b ut t hi s m a y b e 
a dj u st e d o n t h e b a si s of t h e d at a) b y t h e Cli ni c al P h ar m a c ol o gi st, a n d t h e d o s e of all or 
i n di vi d u al i nf a nt s m a y b e a dj u st e d t o e n s ur e t h at i nf a nt s ar e in t h e t ar g et e d e x p o s ur e 
r a n g e a n d i n c o m pli a n c e wit h t h e e x p o s ur e c a p.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
4 2 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7




3. 1. 2
I nt er n al M o nit ori n g C o m mitt e e
T h e I nt er n al M o nit ori n g C o m mitt e e (I M C) will c o n si st of s el e ct e d R o c h e r e pr e s e nt ati v e s: 
Cli ni c al P h ar m a c ol o gi st, Tr a n sl ati o n al M e di ci n e L e a d er, S af et y S ci e n c e L e a d er, 
St ati sti ci a n, a n d St ati sti c al Pr o gr a m m er. T h e I M C will b e r e s p o n si bl e f or m o nit ori n g t h e 
s af et y of i nf a nt s, f or s el e cti n g t h e d o s e f or P art 2 a n d f or m a ki n g t h e f oll o wi n g d e ci si o n s 
d uri n g P art 1:

D e ci si o n t o pr o c e e d wit h d ail y a d mi ni str ati o n f oll o w i n g a si n gl e a d mi ni str ati o n i n t h e
fir st p ati e nt. D at a p a c k a g e r e vi e w e d f or t hi s d e ci si o n: all a v ail a bl e P K, s af et y a n d
t ol er a bilit y d at a (i n cl u di n g A E s, E C G s, vit al si g n s).

D e ci si o n s t o pr o c e e d wit h e nr oll m e nt of f urt h er p ati e nt s at e a c h d o s e l e v el o n c e t h e
fir st p ati e nt at t h at d o s e l e v el h a s r e a c h e d st e a d y-st at e ( mi ni m u m of 2 w e e k s),
d o s e -e s c al ati o n d e ci si o n s (t o a hi g h er d o s e -l e v el), a n d a s s o ci at e d d o s e -s el e cti o n
d e ci si o n s. D at a p a c k a g e r e vi e w e d f or t hi s d e ci si o n: all P K, a v ail a bl e P D ( S M N
m R N A, S M N pr ot ei n), s af et y a n d t ol er a bilit y d at a (i n cl u di n g A E s, E C G s, vit al si g n s,
cli ni c al l a b or at or y t e st r e s ult s, o p ht h al m ol o g y m o nit ori n g) i n all i nf a nt s tr e at e d f or at
l e a st 2 w e e k s ( s o m e i nf a nt s will h a v e l o n g er tr e at m e nt d ur ati o n) at t h e pr e vi o u s
d o s e -l e v el( s).

T h e I M C m a y al s o d e ci d e t o i n cr e a s e t h e n u m b er of i nf a nt s at a n y of t h e pl a n n e d
d o s e l e v el s or t o i niti at e a d diti o n al d o s e / e x p o s ur e l e v el s, u p t o a m a xi m u m of
2 4 i nfa nt s i n t ot al f or P art 1. D at a p a c k a g e r e vi e w e d f or t hi s d e ci si o n: all P K,
a v ail a bl e P D ( S M N m R N A, S M N pr ot ei n), s af et y a n d t ol er a bilit y d at a (i n cl u di n g A E s,
E C G s, vit al si g n s, cli ni c al l a b or at or y t e st r e s ult s, o p ht h al m ol o g y m o nit ori n g) i n all
i nf a nt s.
T h e r ol e s, r e s p o n si biliti e s, m e m b er s hi p, s c o p e of a cti viti e s, ti m e of m e eti n g s a n d 
c o m m u ni c ati o n pl a n f or t h e I M C will b e d o c u m e nt e d i n a n a p pr o pri at e c h art er pri or t o t h e 
i niti ati o n of t h e st u d y.
3. 1. 3
I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e
A n e xt er n al i n d e p e n d e nt D at a M o nit ori n g C o m mitt e e (i D M C) will b e e st a bli s h e d t o 
m o nit or p ati e nt s af et y d uri n g P art  2  of t h e st u d y. T h e i D M C will m e et t o r e vi e w d at a fr o m 
P art  1 a n d c o nfir m t h e d o s e  s el e cti o n d e ci si o n of t h e I M C.  T h e i D M C will pr o vi d e a 
r e c o m m e n d ati o n t o t h e S p o n s or w h et h er t h e st u d y c a n c o nti n u e a s pl a n n e d, i. e., t h at 
t h e st u d y c a n m o v e i nt o P art  2  wit h t h e s el e ct e d d o s e fr o m  P art  1  a s r e c o m m e n d e d b y 
t h e I M C. T h e fi n al d e ci si o n b a s e d o n t h e i D M C r e c o m m e n d ati o n will b e m a d e b y t h e 
S p o n s or. T h e i D M C will m e et o n a r e g ul ar b a si s o v er t h e c o ur s e of  P art  2  of t h e st u d y 
a n d m a y al s o m e et o n a n a d -h o c b a si s a s r e q uir e d, e. g., if a n y u n e x p e ct e d s af et y 
c o n c er n s ari s e. Aft er e v er y m e eti n g, t h e i D M C will m a k e a r e c o m m e n d ati o n t o t h e 
S p o n s or f or t h e st u d y c o n d u ct, i n cl u di n g ( b ut n ot li mit e d t o) c o nti n u ati o n, h alti n g or 
a m e n di n g t h e pr ot o c ol.
W h il st t h e i nt eri m a n al y s e s f or effi c a c y a n d f utilit y d uri n g P art  2  of t h e st u d y will b e 
p erf or m e d b y t h e S p o n s or a n d pr e s e nt e d t o t h e i D M C, t h e i D M C wi ll b e r e q u e st e d t o 
r e vi e w all a v ail a bl e s af et y d at a a n d b e a s k e d t o pr o vi d e a n i n d e p e n d e nt a s s e s s m e nt of 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
4 4 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


t h e b e n efit-ri s k pr ofil e of ri s di pl a m i n t h e T y p e 1 S M A p o p ul ati o n at t hi s e arli er 
ti m e-p oi nt. T h e fi n al d e ci si o n b a s e d o n t h e i D M C r e c o m m e n d ati o n will b e m a d e b y t h e 
S p o n s or.
A S p o n s or Cli ni c al P h ar m a c ol o gi st ( w h o i s n ot a m e m b er of t h e i D M C) will r e g ul arl y 
r e vi e w t he P K a n d P D d at a fr o m P art 2 i n or d er t o b e a bl e t o a dj u st t h e d o s e of 
i n di vi d u al i nf a nt s if r e q uir e d, a s s uri n g n ot t o e x c e e d t h e e x p o s ur e c a p, t o c o nti n u e 
tr e at m e nt at t h e t ar g et e d e x p o s ur e l e v el ( a s i nf a nt s gr o w a n d t h eir b o d y s y st e m s 
m at ur e), a n d t o e n s ur e t ar g et e d e x p o s ur e f or n e wl y e nr oll e d p ati e nt s. D o s e a dj u st m e nt s 
f or i n di vi d u al or all p ati e nt s m a y o c c ur, a s r e q uir e d. T h e i D M C will b e i nf or m e d of a n y 
i n di vi d u al d o s e c h a n g e s r e q uir e d at t h e n e xt s c h e d ul e d i D M C m e eti n g.
T h e r ol e s, r e s p o n si biliti e s, m e m b er s hi p, s c o p e of a cti viti e s, ti m e of m e eti n g s a n d 
c o m m u ni c ati o n pl a n f or t h e i D M C will b e d o c u m e nt e d i n t h e C h art er pri or t o t h e i niti ati o n 
of  t h e st u d y. T h e e xt er n al i D M C will b e c h air e d b y a m e di c all y q u alifi e d i n di vi d u al wit h 
e x p eri e n c e wit h S M A a n d w ill i n cl u d e at l e a st o n e ot h er P h y si ci a n e x p eri e n c e d i n 
N e ur ol o g y, a Cli ni c al P h ar m a c ol o gi st, a n O p ht h al m ol o gi c E x p ert a n d a Bi o st ati sti ci a n. 
N o m e m b er of t h e i D M C will p arti ci p at e i n t h e st u d y a s a n I n v e sti g at or or 
s u b -I n v e sti g at or.
3. 1. 4
P er m a n e nt V e ntil ati o n A d j u di c ati o n C o m mitt e e
Ti m e t o p er m a n e nt v e ntil ati o n will b e d et er mi n e d b y a c e ntr al, i n d e p e n d e nt P er m a n e nt 
V e ntil ati o n A dj u di c ati o n C o m mitt e e .  T hi s c o m mitt e e will m e et p eri o di c all y t o r e vi e w all 
p erti n e nt d at a f or i nf a nt s t h at m a y m e e t t h e d efi niti o n of p er m a n e nt v e ntil ati o n 
(1 6 h o ur s of n o n -i n v a si v e v e ntil ati o n p er d a y or i nt u b ati o n f or2 1 c o n s e c uti v e d a y s i n
t h e a b s e n c e of, or f oll o wi n g t h e r e s ol uti o n of, a n a c ut e r e v er si bl e e v e nt or
tr a c h e o st o m y).
A n a c ut e r e v er si bl e e v e nt will i n cl u d e a n y of t h e f oll o wi n g e v e nt s t h at o c c ur b et w e e n 
7 d a y s pri or a n d 7 d a y s aft er t h e o n s et of 1 6 h o ur s of n o n -i n v a si v e v e ntil ati o n p er d a y 
or i nt u b ati o n:

F e v er.

L a b or at or y di a g n o si s of a vir al, b a ct eri al, or f u n g u s i nf e cti o n eit h er b y dir e ct
e x a mi n ati o n of a s a m pl e ( e. g., s p ut u m, ti s s u e et c.), c ult ur e, s er ol o g y, or p ol y m er a s e
c h ai n r e a cti o n.

L e u k o c yt o si s.

I m a gi n g st u di e s d e m o n str ati n g a n a cti v e i nf e cti o n.

S ur gi c al pr o c e d ur e.
T h e i nf a nt will b e gi v e n a p eri o d of 7  d a y s a ft er t h e e v e nt t o r e c o v er a n d b e gi n 
e xt u b ati o n or w e a ni n g off v e ntil ati o n s u p p ort b ef or e t h e e n d p oi nt of p er m a n e nt 
v e ntil ati o n c a n b e c o nfir m e d (i. e.,  t h e e n d p oi nt will n ot b e m et u ntil t h e i nf a nt r e q uir e s 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
4 5 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


1 6 h o ur s of n o n -i n v a si v e v e ntil ati o n p er d a y or i nt u b ati o n f or2 1 c o n s e c uti v e d a y s
st arti n g 7 d a y s aft er t h e r e s ol uti o n of t h e a c ut e r e v er si bl e e v e nt).
T h e i n d e p e n d e nt P er m a n e nt V e ntil ati o n A dj u di c ati o n C o m mitt e e will d et er mi n e if t hi s 
e n d p oi nt h a s b e e n m et a n d pr o vi d e r e c o m m e n d ati o n s t o t h e S p o n s or. 
T h e pr o c e d ur e s f or r e vi e wi n g a n d a dj u di c ati n g e v e nt s, a n d t h e g o v er ni n g a n d o p er ati o n 
of  t h e i n d e p e n d e nt P er m a n e nt V e ntil ati o n A dj u di c ati o n C o m mitt e e will b e d e s cri b e d i n a 
c h art er.
3. 1. 5
E n d of St u d y
T h e E O S i s d efi n e d a s t h e d at e w h e n t h e l a st p ati e nt l a st vi sit ( L P L V) o c c ur s. L P L V is 
e x pe cte d t o o c c ur at t he l atest w he n t he l ast p atie nt e nr olle d i n t he st u d y h as c o m plete d 
2 4 m o nt hs i n t he tre at me nt p h ase a n d 3 ye ars i n t he o pe n l a bel e xte nsi o n .
T h e st u d y will c o nti n u e u ntil t he E O S, or a s p er l o c al r e g ul ati o n, or p er t h e S p o n s or’ s 
d e ci si o n t o t er mi n at e ri s di pl a m d e v el o p m e nt. T h e le n gth of t he st u d y w ill n ot e x c e e d 
5 ye ars aft er t h e l a st p ati e nt i s e nr oll e d i n t h e st u d y .
After c o m pleti o n of 2 4 m o nt hs of tre at me nt, e a c h p atie nt will e nter t he o pe n -l a bel 
e xte nsi o n p h ase f or a n a d diti o n al 3 ye ars. After a p atie nt h as c o m plete d 3 ye ars i n t he 
o pe n -l a bel e xte nsi o n, t he p atie nt m a y c o nti n ue i n t he st u d y u ntil E O S, pr o vi de d t h at 
ris di pl a m is n ot c o m mer ci all y a v ail a ble i n t he p atie nt's c o u ntr y.
S e e S e cti o n 4. 4. 4 f or c o n diti o n s r e g ar di n g p o st-tri al a c c e s s t o ri sdi pl a m .
3. 2
R A TI O N A L E F O R S T U D Y D E SI G N
T hi s st u d y i s d e si g n e d t o a s s e s s t h e effi c a c y a n d s af et y of  ri s di pl a m tr e at m e nt i n i nf a nt s 
wit h T y p e  1  S M A w h o ar e a g e d 1 t o  7  m o nt h s  at t h e ti m e of e nr oll m e nt.
A si n gl e -ar m st u d y d e si g n i s c o n si d er e d j u stifi e d i n t h e c o n t e xt of t h e c h oi c e of t h e 
pri m ar y e n d p oi nt t h at i s  mi ni m all y s u bj e ct t o bi a s a n d t h e k n o w n n at ur al hi st or y of t hi s 
e n d p oi nt wit hi n t h e st u d y p o p ul ati o n ( s e e b el o w), a s d efi n e d b y t h e i n cl u si o n a n d 
e x cl u si o n crit eri a f or t hi s st u d y.
T h e pri m ar y e n d p oi nt wil l b e t h e pr o p orti o n of i nf a nt s w h o ar e sitti n g aft er 1 2-m o nt h 
tr e at m e nt. T hi s e n d p oi nt c a n b e o bj e cti v el y m e a s ur e d, i n c or p or at e s s ur vi v al a n d i s a 
cli ni c all y m e a ni n gf ul e n d p oi nt. F urt h er m or e, t h e e v al u ati o n of t h e gr o s s m ot or s c al e, 
i n cl u di n g sitti n g, will b e vi d e o -r e c or d e d i n a st a n d ar di z e d m a n n er a n d c e ntr all y r e vi e w e d 
b y t w o i n d e p e n d e nt r e a d er s , u p t o a n d i ncl u di n g t he Wee k 1 0 4 assess me nt. T h e 
a s s e s s m e nt of t h e c e ntr al r e a d er s will b e u s e d f or t h e pri m ar y a n al y si s.
T h e n at ur al hi st or y  of t h e di s e a s e i s well -d ef i n e d i. e., T y p e  1  S M A i nf a nt s n e v er a c hi e v e 
sitti n g wit h o ut s u p p ort  (C o b b e n et al 2 0 0 8 ; Fi n k el et al 2 0 1 4 ), t h e pri m ar y e n d p oi nt i n t hi s 
st u d y. T hi s n at ur al hi st or y c a n t h er ef or e b e u s e d t o d efi n e t h e  p erf or m a n c e crit eri a f or 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
4 6 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


s u c c e s s, i. e., a t hr e s h ol d of a c hi e v e m e nt f or t h e ri s di pl a m-tr e at e d i nf a nt s t o b e a s s e s s e d 
a g ai n st wit hi n t hi s st u d y. T h e pr e -d ef i n e d p erf or m a n c e crit eri a f or t h e pri m ar y e n d p oi nt 
will b e 5 %.
3. 2. 1
R ati o n al e f or D o s a g e S el e cti o n
St u d y B P 3 9 0 5 6 will e nr oll i nf a nt s wit h T y p e 1 S M A, a g e d 1 t o 7 m o nt h s at ti m e of 
e nr oll m e nt. T h e s e T y p e 1 i nf a nt s r e pr e s e nt t h e S M A p o p ul ati o n wit h t h e hi g h e st u n m et 
m e di c al n e e d w h o m a y p ot e nti all y h a v e t h e gr e at e st b e n efit fr o m e arl y i niti ati o n of 
tr e at m e nt wit h ri s di pl a m. Gi v e n t h e s e verit y a n d t h e hi g h m ort alit y a n d m or bi dit y i n T y p e 
1 i nf a nt s, all d o s e l e v el s i n t hi s st u d y ar e ai mi n g t o pr o vi d e t h er a p e uti c b e n efit t o i nf a nt s. 
I n P art 1 of t h e st u d y, t w o d o s e/ e x p o s ur e l e v el s ar e pl a n n e d t o b e a s s e s s e d i n a d o s e -
e s c al ati n g m a n n er t o e n s ur e t h e s af et y of all i nf a nt s. T h e o bj e cti v e s of P art 1 ar e t o 
a s s e s s s af et y a n d t ol er a bilit y of ri s di pl a m i n i nf a nt s, a n d P K a n d P D t o i d e ntif y t h e m o st 
a p pr o pri at e d o s e f or P art 2 of t h e st u d y.
Gi v e n t h e li mit e d d e gr e e of e xtr a p ol ati o n p o s si bl e fr o m ol d e r a g e, e nr oll m e nt of i nf a nt s 
i nt o t hi s st u d y will n ot b e d e p e n d e nt o n t h e a v ail a bilit y of d at a fr o m ol d er c hil dr e n. 
E xtr a p ol ati o n fr o m ol d er c hil dr e n wit h T y p e 2 a n d 3 S M A ( w h o ar e u s u all y ol d er t h a n 
2 y e ar s of a g e) w o ul d n ot b e a d e q u at e d u e t o diff er e n c e s i n t h eir p h y si ol o g y, a n d 
m et a b oli c p at h w a y s f or t h e diff er e nt a g e r a n g e s, a n d t h e diff eri n g pr ofil e of 
c o- m or bi diti e s i n t h e T y p e 1 v er s u s t h e T y p e 2 a n d 3 S M A p o p ul ati o n s.
P B P K m o d eli n g
h a s b e e n c o n d u ct e d t o pr e di ct t h e P K pr ofil e i n i nf a nt s, t o h el p wit h t h e 
s el e cti o n of t h e st arti n g d o s e, a n d t o d efi n e t h e d o si n g str at e g y o n c e P K d at a i s 
a v ail a bl e i n t hi s a g e gr o u p. A P B P K m o d el w a s d e v el o p e d u si n g Si m C Y P v er si o n 1 5
b a s e d o n p h y si c o c h e mi c al pr o p erti e s, i n vitr o, pr e cli ni c al, a n d cli ni c al ( P K aft er si n gl e 
d o s e i n h e alt h y s u bj e ct s, i n cl u di n g f o o d eff e ct a s s e s s m e nt) st u d y r e s ult s f or ri s di pl a m. 
A b s or pti o n i s m o d el e d b y a m e c h a ni sti c a p pr o a c h u si n g t h e A d v a n c e d Di s s ol uti o n, 
A b s or pti o n a n d M et a b oli s m (A D A M) m o d el of Si m C Y P; al m o st c o m pl et e a b s or pti o n 
(9 0 %) i s pr e di ct e d. Ti s s u e di stri b uti o n i s d e s cri b e d a c c or di n g t o ti s s u e t o pl a s m a
c o n c e ntr ati o n r ati o s d et er mi n e d i n m o n k e y s. Eli mi n ati o n i n t h e P B P K m o d el i s a s s u m e d
m o stl y b y h e p ati c m et a b oli s m ( 9 5 %) t hr o u g h C Y P 3 A 4 a n d F M O 3 e n z y m e s, a n d mi n or
( 5 %) r e n al e x cr eti o n. T hi s P B P K m o d el a d e q u at el y d e s cri b e d pl a s m a-c o n c e ntr ati o n
pr ofil e s aft er si n gl e d o s e of 0. 6 t o 1 8 m g i n h e alt h y a d ult s u bj e ct s i n b ot h f a st e d a n d f e d
st at e, a n d pr e di ct e d w ell t h e e xt e nt of t h e D DI wit h itr a c o n a z ol e i n h e alt h y m al e
i n di vi d u al s ( 1 4 % v s 1 2 % i n cr e a s e i n A U C
0- 1 2 0 h b y t h e pr e di cti o n a n d t h e o b s er v ati o n,
r e s p e cti v el y). T hi s P B P K m o d el w a s tr a n sf err e d t o t h e Si m C Y P P e di atri c M o d ul e t o
pr e di ct P K i n i nf a nt s a n d c hil dr e n wit h c o n si d er ati o n of gr o wt h i n b o d y si z e, or g a n
m at ur ati o n, o nt o g e n y of m et a b oli c e n z y m e s, a n d pr ot ei n bi n di n g.
T h e st arti n g d o s e f or t h e fir st i nf a nt e nr oll e d w a s s el e ct e d b a s e d o n t h e m o st 
c o n s er v ati v e p e di atri c P B P K m o d el pr e di cti o n. N e v ert h el e s s, t h e r e i s u n c ert ai nt y i n t h e 
pr e di cti o n a n d e xtr a p ol ati o n, a n d t h er ef or e,  P art  1  will st art wit h t h e a d mi ni str ati o n of a 
si n gl e  d o s e o nl y t o a si n gl e i nf a nt. T o e n s ur e t h e s af et y of t hi s fir s t e nr oll e d i nf a nt, a 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
4 7 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
4 8 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
s af et y f a ct or of 1 0 will b e a p pli e d t o t h e d o s e s el e ct e d b a s e d o n t h e m o st c o n s er v ati v e 
P B P K m o d el s c e n ari o. P K will b e m e a s ur e d aft er a d mi ni str ati o n of t h e si n gl e d o s e, a n d 
s af et y a n d t ol er a bilit y will b e c ar ef ull y a s s e s s e d, a n d t h e P B P K m o d el u p d at e d wit h t h e 
o bt ai n e d P K d at a, i n or d er t o s el e ct t h e d o s e f or D o s e L e v el 1 i n t hi s fir st i nf a nt ( a n d 
s u b s e q u e nt i nf a nt s).
I n a d diti o n, t h e fr e e fr a cti o n (f u) of ri s di pl a m will b e m e a s ur e d i n all i nf a nt s at s cr e e ni n g 
wit h a n i n vitr o a s s a y. I n c a s e t h e m e a s ur e d fr e e fr a cti o n i n i nf a nt s i s diff er e nt fr o m t h e 
fr e e fr a cti o n i n a d ult s, t h e st arti n g d o s e ( a n d s u b s e q u e nt d o s e l e v el s a n d th e e x p o s ur e 
c a p) will b e a dj u st e d f or t hi s diff er e n c e.
T h e d o s e -s el e cti o n will t ar g et i n P art 1:

St arti n g d o s e: A si n gl e i nf a nt will b e e nr oll e d i niti all y a n d will r e c ei v e a si n gl e d o s e of
0. 0 0 1 0 6 m g / k g ri s di pl a m (i. e., 0. 0 0 74 m g f or a 7 k g i nf a nt, a s s u mi n g fr e e
fr a cti o n 0. 2 5; t h e a ct u al d o s e i s t o b e c o nfir m e d wit h t h e S p o n s or b ef or e a n y dr u g
a d mi ni str ati o n a n d c a n b e a dj u st e d u p o n r e vi e w of all eli gi bilit y crit eri a of t h e fir st
i nf a nt, i n cl u di n g fr e e fr a cti o n at s cr e e ni n g). T hi s d o s e i s pr e di ct e d t o r e s ult i n a n
e x p o s ur e ( A U C i nf) at l e a st 1 0-f ol d b el o w t h e t ar g et e x p o s ur e of A U C0- 2 4 h, s s 
7 0 0 n g h / m L (r e s p e cti v el y A U C, fr e e fr a cti o n 7 7 n g h/ m L) f or D o s e L e v el 1 . T hi s
d o s e w a s s el e ct e d b a s e d o n t h e m o st c o n s er v ati v e P B P K m o d eli n g
s c e n ari o a s
d e s cri b e d a b o v e, pl u s a n a d diti o n all y a p pli e d s af et y f a ct or of 1 0. T hi s will e n s ur e a
s af e a d mi ni str ati o n of t hi s c o m p o u n d f or t h e fir st ti m e t o i nf a nt s, i n c a s e t h e a ct u al
o b s er v e d e x p o s ur e d e vi at e s fr o m t h e P K pr ofil e pr e di ct e d wit h t h e P B P K m o d el.

D o s e L e v el 1, t ar g et e x p o s ur e of A U C 0- 2 4 h, s s 7 0 0 n g h/ m L: a n e x p o s ur e pr e di ct e d t o
r e s ult i n a d o u bli n g of S M N pr ot ei n l e v el s (i. e., a 1 0 0 % i n cr e a s e v er s u s t h e p ati e nt’ s
b a s eli n e). T h e a ct u al d o s e t o a c hi e v e t hi s t ar g et e x p o s ur e will b e c al c ul at e d b a s e d
o n t h e P K d at a o bt ai n e d i n t h e fir st i nf a nt, a n d will b e li k el y b a s e d o n b ot h a g e a n d
b o d y w ei g ht. T h e P B P K m o d el will b e c o nti n u o u sl y u p d at e d wit h t h e e m er gi n g P K
d at a fr o m all e nr oll e d i nf a nt s, a n d t h e d o s e a dj u st e d if r e q uir e d. A 1 0 0 % S M N
pr ot ei n i n cr e a s e i s e x p e ct e d t o l e a d t o a s u b st a nti al cli ni c al b e n efit i n S M A p ati e nt s,
t ur ni n g m or e s e v er e p h e n ot y p e s i nt o mil d er f or m s, b a s e d o n S M N pr ot ei n l e v el s
m e a s ur e d i n S M A p ati e nt s ( K ol b et al 2 0 0 6 ; S u m n er et al 2 0 0 6 ; N g u y e n et al 2 0 0 8 )
a n d o n d at a o bt ai n e d i n a ni m al S M A m o d el s r e g ar di n g effi c a c y a n d t h e a s s o ci at e d
S M N pr ot ei n i n cr e a s e ( R i s di pl a m I n v e sti g at or’ s Br o c h ur e). A n A U C 0- 2 4 h e x p o s ur e of
u p t o 1 4 7 0 n g h/ m L w a s w ell -t ol er at e d i n t h e S A D st u d y i n h e alt h y s u bj e ct s, wit h o ut
a n y cli ni c all y r el e v a nt s af et y fi n di n g s. T hi s e x p o s ur e of A U C 0- 2 4 h, s s 7 0 0 n g h/ m L i s a
f a ct or of a p pr o xi m at el y 3 ( 2. 8) b el o w t h e N O A E L l e v el i n t h e 3 9 -w e e k m o n k e y st u d y
(i. e., 2. 8 -f ol d b el o w t h e e x p o s ur e l e v el at w hi c h n o a d v er s e fi n di n g s w er e o b s er v e d).
O nl y eff e ct s o n t h e t e st e s w er e o b s er v e d at t h o s e e x p o s ur e l e v el s i n r at s. Eff e ct s o n
t e st e s at l ow e x p o s ur e a n d t h eir r e v er si bilit y c o ul d n ot b e a s s e s s e d i n c y n o m ol g u s
m o n k e y d u e t o s e x u al i m m at urit y of t h e a ni m al s ( s e e R i s di pl a m I n v e sti g at or’ s
Br o c h ur e ); p ar e nt s of m al e s u bj e ct s will b e i nf or m e d a c c or di n gl y.



D o s e L e v el 2 : a hi g h er e x p o s ur e, l e a di n g to t h e m a xi m u m p o s si bl e S M N pr ot ei n
i n cr e a s e ( pr o vi d e d all cli ni c al a n d n o ncli ni c al s af et y d at a a v ail a bl e at t h e ti m e of t h e
d o s e e s c al ati o n d e ci si o n s u p p ort t hi s), w hi c h i s pr e di ct e d t o pr o vi d e gr e at er b e n efit
b a s e d o n pr e cli ni c al d at a a s w ell a s p u bli s h e d cli ni c al d at a wit h t h e a nti s e n s e
oli g o n u cl e oti d e n u si n er s e n (C hiri b o g a et al 2 0 1 6 ). P arti c ul arl y i n t hi s l et h al di s e a s e
of  T y p e 1 S M A, it i s c o n si d er e d i m p ort a nt t o stri v e f or m a xi m u m p o s si bl e effi c a c y.
T h e hi g h e st p o s si bl e i n cr e a s e i s c urr e ntl y a s s u m e d t o b e at m a xi m u m a 2 0 0 % S M N
pr ot ei n i n cr e a s e, b a s e d o n a ni m al a n d i n vitr o c ell c ult ur e d at a wit h S M A p ati e nt
fi br o bl a st s a n d m ot or n e ur o n s ( s e e R i s di pl a m I n v e sti g at or’ s Br o c h ur e). B a s e d o n
c urr e nt pr e di cti o n s, t hi s t ar g et m a y b e r e a c h e d at a n e x p o s ur e n ot e x c e e di n g t h e
e x p o s ur e c a p of 2 0 0 0 n g h/ m L A U C 0- 2 4 h, s s . U n d er n o cir c u m st a n c e s will a d o s e b e
s el e ct e d t h at l e a d s t o a n e x p o s ur e a b o v e a m e a n A U C 0- 2 4 h, s s of 2 0 0 0 n g h/ m L or a
m e a n C
m a x of  4 0 0 n g/ m L ( or e q ui v al e nt fr e e fr a cti o n, if t h e fr e e fr a cti o n i n i nf a nt s i s
diff er e nt fr o m v al u e s i n a d ult s).
T h e d o s e f or P art 2 will b e s el e ct e d b y t h e I M C b a s e d o n t h e r e s ult s o bt ai n e d fr o m 
P art 1, a n d will b e a d o s e t h at:

I s j u d g e d t o b e w ell t ol er at e d a n d wit h o ut a n y k n o w n s af et y si g n al, b a s e d o n all
a v ail a bl e d at a fr o m P art 1 a n d a s c o nfir m e d b y t h e e xt er n al i D M C.

R e s ult s i n a n e x p o s ur e at st e a d y -st at e b el o w t h e e x p o s ur e c a p ( m e a n v al u e) of
A U C 0- 2 4 h, s s 2 0 0 0 n g h/ m L ( a dj u st e d f or fr e e fr a cti o n, if r e q uir e d). T o a c c o u nt f or
c h a n g e s i n P K i n diff er e nt a g e -gr o u p s, a diff er e nt d o s e i s li k el y t o b e s el e ct e d f or t h e
v ari o u s a g e gr o u p s. T h e d o s e will li k el y b e a b o d y w ei g ht -a dj u st e d d o s e, b ut ot h er
crit eri a, e. g., b o d y s urf a c e ar e a ( B S A) or a g e, m a y b e u s e d, d e p e n di n g o n t h e
r e s ult s of t h e a n al y si s of t h e P K d ata o bt ai n e d i n P art 1.

R e s ult s i n a n S M N pr ot ei n i n cr e a s e t h at i s e x p e ct e d t o b e cli ni c all y r el e v a nt i n t er m s
of  effi c a c y.
O v er all t h e a p pr o a c h i s t o t ar g et t h e hi g h e st S M N pr ot ei n i n cr e a s e t h at c a n b e s af el y 
a c hi e v e d wit h ri s di pl a m; h o w e v er, t h e s h a p e of t h e P K/ P D c ur v e will b e t a k e n i nt o 
a c c o u nt t o d et er mi n e t h e m o st a p pr o pri at e t ar g et e x p o s ur e ( a n d t h er ef or e, d o s e), 
c o n si d eri n g s af et y a n d t ol er a bilit y d at a a cr o s s e x p o s ur e l e v el s i n P art 1, a n d t h e 
a b o v e -m e nti o n e d e x p o s ur e c a p t hr e s h ol d. Cli ni c al j u d g m e nt
will pr e v ail.
B a s e d o n t h e crit eri a li st e d a b o v e a n d c urr e ntl y a v ail a bl e d at a fr o m P art 1, t h e f oll o wi n g 
st arti n g d o s e l e v el s h a v e b e e n s el e ct e d f or P art 2:

I nf a nt s > 1 m o nt h a n d b el o w 3 m o nt h s ol d at e nr oll m e nt: 0. 0 4
m g/ k g.

I nf a nt s at l e a st 3 m o nt h s b ut b el o w 5 m o nt h s ol d at e nr oll m e nt: 0. 0 8
m g/ k g.

I nf a nt s 5 m o nt h s ol d or ol d er at e nr oll m e nt: 0. 2 m g/ k g.
P ati e nt s will r e m ai n o n t h eir i niti all y a s si g n e d d o s e l e v el (i. e.,  t h e d o s e will n ot c h a n g e 
o n c e a p ati e nt r e a c h e s 3  m o nt h s a n d 5 m o nt h s of a g e, r e s p e cti v el y) u nl e s s a c h a n g e of 
d o s e i s r e q u e st e d b y t h e Cli ni c al P h ar m a c ol o gi st u p o n r e vi e w of t h e P K d at a. T h e P K i n 
all i nf a nt s will b e r e g ul arl y m o nit or e d ( d at a r e vi e w e v er y 2  w e e k s, b ut t hi s m a y b e 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
4 9 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


a dj u st e d o n t h e b a si s of t h e d at a) b y t h e Cli ni c al P h ar m a c ol o gi st, a n d t h e d o s e of all or 
i n di vi d u al i nf a nt s m a y b e a dj u st e d t o e n s ur e t h at i nf a nt s ar e i n t h e t ar get e d e x p o s ur e 
r a n g e a n d i n c o m pli a n c e wit h t h e e x p o s ur e c a p.
At t h e d o si n g r e gi m e n s el e ct e d f or P art 2 of t h e st u d y, t h e pr e di ct e d e x p o s ur e i s a m e a n 
A U C 0 2 4 h, s s of 1 6 5 0 n g• h/ m L i n i nf a nt s 3 5 m o nt h s ol d at e nr oll m e nt wit h a d o s e of 
0. 0 8 m g/ k g, a n d a pr e di ct e d m e a n A U C 0 2 4 h, s s of 2 0 2 0 n g• h/ m L i n i nf a nt s 5 m o nt h s ol d 
at e nr oll m e nt wit h a d o s e of 0. 2 m g/ k g. T h e pr e di ct e d m e a n A U C
0 2 4 h, s s of 2 0 2 0 n g• h/ m L 
i s c o n si d er d i n c o m pli a n c e wit h t h e e x p o s ur e c a p of a m e a n A U C 0 2 4 h, s s of 2 0 0 0 n g• h/ m L, 
si n c e it i s o nl y n u m eri c all y m ar gi n all y gr e at er a n d t h e P K will b e m o nit or e d i n all i nf a nt s 
t o e n s ur e t h at t h e a ct u al o b s er v e d P K v al u e s ar e i n c o m pli a n c e wit h t h e c a p.
Gi v e n t h e s e v erit y of t h e di s e a s e i n p ati e nt s wit h T y p e
1 S M A a n d t h e o b s er v e d 
c orr el ati o n of S M N pr ot ei n i n cr e a s e v er s u s i n di vi d u al P K, t hi s t ar g et e x p o s ur e h a s b e e n 
s el e ct e d t o m a xi mi z e t h e li k eli h o o d of cli ni c al b e n efit w hil e still b ei n g c o m pli a nt wit h t h e 
e x p o s ur e c a p.
T h e d o s e of 0. 0 8 m g/ k g w a s c h o s e n f or i nf a nt s 3 5 m o nt h s ol d. T hi s d o s e i s pr e di ct e d t o 
r e s ult i n a s o m e w h at l o w er A U C; h o w e v er, t hi s pr e di cti o n i s c urr e ntl y b a s e d o n o nl y 
4 i nfa nt s i n t hi s a g e gr o u p a n d t h er ef or e a s s o ci at e d wit h s o m e u n c ert ai nt y. N o d at a i s 
c urr e ntl y a v ail a bl e f or i nf a nt s b et w e e n 2 8 d a y s ( 1 m o nt h) a n d 3 m o nt h s of a g e; t h er ef or e,
a n a d diti o n al s af et y m ar gi n h a s b e e n a p pli e d , a n d a st arti n g d o s e of 0. 0 4 m g/ k g h a s 
b e e n s el e ct e d f or P art 2. T hi s d o s e m a y b e a dj u st e d o n c e P K d at a i n t hi s a g e gr o u p h a s 
b e e n o bt ai n e d.
A v ail a bl e pr e -cli ni c al a n d n at ur al hi st o y d at a s u g g e st t h at a 1 0 0 % i n cr e a s e i n S M N 
pr ot ei n l e v el s c o ul d t ur n s e v er e S M A p h e n ot y p e s i nt o mil d er f or m s, w h er e a s f urt h er 
i n cr e a s e m a y pr o vi d e e v e n gr e at er b e n efit ( S e cti o n 3. 2. 1 ). I n P art 1 of t h e st u d y, a 
m e di a n 2- f ol d i n cr e a s e (r a n g e 1. 05. 4) i n S M N pr ot ei n i n bl o o d v er s u s b a s eli n e w a s 
o b s er v e d f or i nf a nt s wit h a n e x p o s ur e ( A U C 0 2 4 h ) 1 0 0 0 n g• h/ m L, a n d a m e di a n 3. 2 -f ol d 
i n cr e a s e (r a n g e 1. 66. 5) w a s o bt ai n e d i n i nf a nt s wit h a n e x p o s ur e ( A U C 0 2 4 h ) 
1 0 0 0 n g• h /m L . T h er ef or e t h e s el e ct e d d o s e l e v el s f or P art 2 ar e i n d e e d e x p e ct e d t o
l e a d t o cli ni c all y r el e v a nt effi c a c y i n p ati e nt s wit h T y p e 1 S M A .
R ef er t o S e cti o n 1. 2. 2 f or t h e d at a s u m m ar y fr o m P art 1 s u p p orti n g t h e d o s e s el e cti o n 
f or P art 2.
O nce t he  fi n al d osi n g re gi me n h as bee n sele cte d f or t his st u d y ( 0. 2 m g/ k g f or i nf a nts 
2 ye ars of a ge), n o f urt her d ose a dj ust me nts are f oresee n i n a n y i nf a nt i n P art 1 or
P art 2.
O nce a p atie nt re a c hes 2 ye ars of a ge, t he d ose m a y be a dj uste d t o 0. 2 5 m g/ k g, at t he 
re q uest of t he S p o ns or a n d u p o n re vie w of a v ail a ble P K a n d s afet y d at a f or e ac h 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
5 0 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


i n di vi d u al i nf a nt. T he d ose of 0. 2 5 m g/ k g w as i de ntifie d as t he a p pr o pri ate d ose f or 
c hil dre n 2 ye ars of a ge i n St u d y B P 3 9 0 5 5 i n p atie nts wit h S M A T y pe 2 a n d T y pe 3.
T he sele cte d m g/ k g d osi n g re gi me n (i.e., 0. 2 m g/ k g f or i nf a nts 2 ye ars of a ge, w hi c h 
m a y be i n cre ase d t o 0. 2 5 m g/ k g f or i nf a nts 2 ye ars of a ge u p o n re vie w of t he 
i n di vi d u al i nf a nt’s d at a) will be a p plie d w he n a p atie nt’s b o d y wei g ht is 2 0 k g. A fl at 
d ose of 5 m g will be a d mi nistere d w he n a p atie nt’s b o d y wei g ht is 2 0 k g. T he d ose of 
5 m g w as i de ntifie d as t he a p pr o pri ate d ose f or p atie nts a ge d 2 ye ars wit h 2 0 k g 
b o d y wei g ht i n St u d y B P 3 9 0 5 5 i n p atie nts wit h S M A T y pe 2 a n d T y pe 3.
3. 2. 2
R ati o n al e f or St u d y  P o p ul ati o n
St u d y B P 3 9 0 5 6 h a s b e e n d e si g n e d a s t h e fir st st u d y i n T y p e 1 S M A i nf a nt s wit h 
ri s di pl a m:

Aft er ri s di pl a m w a s s h o w n t o b e s af e a n d w ell t ol er at e d aft er si n gl e d o s e
a d mi ni str ati o n i n h e alt h y a d ult v ol u nt e er s ( B P 2 9 8 4 0), it i s e s s e nti al t o st u d y it s
s af et y a n d t ol er a bilit y pr ofil e i n t h e T y p e 1 t ar g et p o p ul ati o n, e s p e ci all y giv e n t h e
v ari o u s c o m or bi diti e s S M A p ati e nt s pr e s e nt wit h t h eir a g e a n d di s e a s e s e v erit y.

T h e P K pr ofil e of ri s di pl a m n e e d s t o b e s p e cifi c all y e v al u at e d i n T y p e 1 S M A
p ati e nt s of t h e t ar g et e d a g e -r a n g e (i nf a nt s) si n c e P K will b e diff er e nt i n i nf a nt s
c o m p ar e d t o ol d er s u bj e ct s, a s w ell a s it s P D eff e ct s i n t er m s of i n cr e a s e of
f ull-l e n gt h S M N 2 m R N A a n d S M N pr ot ei n l e v el s.

T h e ri s k -b e n ef it of ri s di pl a m i n T y p e 1 S M A p ati e nt s i s c o n si d er e d f a v or a bl e a s it
h a s t h e p ot e nti al t o a d dr e s s t h e u n m et n e e d i n t hi s s e v er el y aff e ct e d p o p ul ati o n.
T h er ef or e, it i s i m p ort a nt t o d et er mi n e t h e effi c a c y a n d s af et y of ri s di pl a m,
s p e cifi c all y i n T y p e 1 S M A p ati e nt s.
T y p e  1  S M A p ati e nt s h a v e a m or e s e v er e cli ni c al pr e s e nt ati o n a n d r e d u c e d s ur vi v al r at e 
c o m p ar e d t o  T y p e  2  a n d 3 S M A  p ati e nt s. T h e cli ni c al pr o gr e s si o n of t h e di s e a s e i s m or e 
pr o n o u n c e d t h a n i n  T y p e  2  a n d 3 S M A p ati e nt s a n d t h eir c o m or bi diti e s a n d 
c o m pli c ati o n s ( e. g.,  s w all o wi n g a n d br e at hi n g f u n c ti o n) ar e u s u all y m or e s e v er e. T hi s 
p o p ul ati o n u s u all y h a s l e s s t h a n t hr e e  S M N 2  c o p y n u m b er s a n d t h eir  S M N  m R N A 
e x pr e s si o n i n ti s s u e i s c o n si d er e d t o b e l o w. E arl y i niti ati o n of tr e at m e nt i n t hi s e arl y 
o n s et p o p ul ati o n wit h a s pli ci n g m o difi er, a s pr o p o s e d i n t hi s st u d y , m a y l e a d t o a 
si g nifi c a nt i n cr e a s e i n S M N pr ot ei n e x pr e s si o n t h at c o ul d r e s c u e p artl y or c o m pl et el y t h e 
c hr o ni c S M N pr ot ei n d efi ci e n c y d uri n g t h e m ot or f u n cti o n d e v el o p m e nt p h a s e of t h e s e 
i nf a nt s. T hi s i s e x p e ct e d t o l e a d t o a cli ni call y r el e v a nt o ut c o m e i n m ot or a n d r e s pir at or y 
f u n cti o n of tr e at e d p ati e nt s, e. g., a c hi e v e m e nt of sitti n g mil e st o n e aft er 1 2 m o nt h s of 
c o nti n u o u s tr e at m e nt. T h er ef or e, t ar g eti n g p ati e nt s wit h  T y p e  1  S M A b ef or e t h e a g e of 
7  m o nt h s  i n cr e a s e s t h e c h a n c e t o i n d u c e b e n efi ci al eff e ct i n m ot or-mil e st o n e s t h at ar e 
d e v el o p e d aft er t h e a g e of  7  m o nt h s . A v er y e arl y i niti ati o n of a n eff e cti v e tr e at m e nt i s 
a nti ci p at e d t o c o u nt er a ct t h e d el et eri o u s eff e ct s of c hr o ni c S M N pr ot ei n d efi ci e n c y i n t h e 
b o d y.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
5 1 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
5 2 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
3. 2. 3
R ati o n al e f or C o ntr ol Gr o u p
T hi s i s a n o p e n -l a b el st u d y. A pl a c e b o c o ntr ol gr o u p will n ot b e i n cl u d e d i n t hi s st u d y a s 
it i s et hi c all y d e b at a bl e t o tr e at a T y p e 1 S M A p ati e nt wit h pl a c e b o, c o n si d eri n g t h e r a pi d 
d e cli n e a n d s h ort lif e -e x p e ct a n c y of t h e s e p ati e nt s. T h e o p e n -l a b el d e si g n i s c o n si d er e d 
j u stifi e d i n t h e c o nt e xt of t h e c h oi c e of t h e pri m ar y e n d p oi nt t h at i s mi ni m all y s u bj e ct t o 
bi a s a n d t h e k n o w n n at ur al hi st or y of t hi s e n d p oi nt ( a n d d e v el o p m e nt al mil e st o n e s) 
wit hi n t h e st u d y p o p ul ati o n, a s d efi n e d b y t h e i n cl u si o n a n d e x cl u si o n crit eri a f or t hi s 
st u d y.
O n e dr u g w a s r e c e ntl y a p pr o v e d i n t h e U nit e d St at e s, E ur o p e a n U ni o n, C a n a d a, a n d 
ot h er j uri s di cti o n s f or t h e tr e at m e nt of S M A i n p e di atri c a n d a d ult p ati e nt s (t h e a nti s e n s e 
oli g o n u cl e oti d e n u si n er s e n [ S pi nr a z a T M ]) b ut, t h e m e di c al n e e d i n S M A i s still v er y hi g h. 
T h er e i s c urr e ntl y n o or al tr e at m e nt f or S M A t h at pr o vi d e s st a bili z ati o n or i m pr o v e m e nt 
of  m ot or f u n cti o n a n d d e v el o p m e nt; a c c or di n gl y, n o a cti v e c o ntr ol c a n b e u s e d i n t hi s 
st u d y. H o w e v er, all p ati e nt s m u st r e c ei v e t h e l o c al cli ni c al st a n d ar d of c ar e f or S M A 
p ati e nt s, a s d efi n e d b y e a c h sit e I n v e sti g at or, e x c e pt f or t h e a d mi ni str ati o n of S M N 2 -
t ar g eti n g oli g o n u cl e oti d e s, w hi c h i s n ot all o w e d.
3. 2. 4
R ati o n al e f or Bi o m ar k er A s s e s s m e nt s
T h e p ut ati v e t ar g et ti s s u e s f or S M A tr e at m e nt ar e s pi n al c or d a n d m u s cl e, ti s s u e s t h at 
c a n n ot b e e a sil y s a m pl e d m ulti pl e ti m e s t o e v al u at e dr u g eff e ct s. A s S M A i s d u e t o 
d e cr e a s e d l e v el s of S M N pr ot ei n, c h a n g e s i n S M N m R N A a n d S M N pr ot ei n l e v el s 
(r el ati n g t o c h a n g e s i n t h e s pi n al c or d a n d m u s cl e) will b e m e a s ur e d i n bl o o d. I n a d diti o n 
t o t h e S M N 2 c o p y n u m b er a n al y sis d o n e at s cr e e ni n g, a d diti o n al g e n eti c m ar k er s w hi c h 
i nfl u e n c e t h e pr o gr e s si o n a n d s e v erit y of t h e di s e a s e or tr e at m e nt r e s p o n s e m a y b e 
st u di e d i n t h e p ati e nt s.
T h e f oll o wi n g bl o o d s a m pl e s will b e c oll e ct e d a c c or di n g t o t h e S o A
(A p p e n di x 1 -A p p e n di x 4 ) f or bi o m ar k er a n al y s e s:

Cli ni c al g e n ot y pi n g ( S e cti o n 4. 6. 1. 1 3 ).
I n a d diti o n a n d a s d e s cri b e d i n S e cti o n 4. 6. 1. 1 3 , t h e f oll o wi n g bl o o d s a m pl e s will b e 
c oll e ct e d a c c or di n g t o t h e S o A ( A p p e n di x 1 -A p p e n di x 4 ) t o a s s e s s t h e P D eff e ct s of 
ri s di pl a m:

I n vi v o s pli ci n g m o difi c ati o n of S M N 2 m R N A i n bl o o d.

S M N pr ot ei n l e v el s.
3. 3
O U T C O M E M E A S U R E S
3. 3. 1
S af et y  O ut c o m e M e a s ur e s
T h e s af et y o ut c o m e m e a s ur e s f or t hi s st u d y ar e a s f oll o w s:

I n ci d e n c e a n d s e v erit y of a d v er s e e v e nt s.

I n ci d e n c e a n d s e v erit y of s eri o u s a d v er s e e v e nt s.


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
5 3 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7

I n ci d e n c e of tr e at m e nt di s c o nti n u ati o n s d u e t o a d v er s e e v e nt s.

I n ci d e n c e of a b n or m al l a b or at or y v al u e s.

I n ci d e n c e of a b n or m al E C G v al u e s.

Vit al si g n s a b n or m aliti e s, i n cl u di n g b o d y t e m p er at ur e, s y st oli c a n d di a st oli c bl o o d
pr e s s ur e, h e art r at e, r e s pir at or y r at e.

O p ht h al m ol o gi c al a s s e s s m e nt s a s a p pr o pri at e f or a g e (see Se cti o n 4. 6. 1. 8  f or
det ails) .

P h y si c al e x a mi n ati o n

A nt hr o p o m etri c e x a mi n ati o n, i n cl u di n g w ei g ht, h ei g ht, h e a d, a n d c h e st
cir c u mf er e n c e.
A d et ail e d m e di c al hi st or y a n d a c o m pl et e p h y si c al e x a mi n ati o n wi ll b e p erf or m e d at t h e 
ti m e-p oi nt s i n di c at e d i n t h e S o A (A p p e n di x 1 , A p p e n di x 2 ).
A d v er s e e v e nt s a n d c o n c o mit a nt m e di c ati o n s will b e m o nit or e d t hr o u g h o ut t h e e ntir e 
st u d y ( s cr e e ni n g t hr o u g h o pe n -l a bel e xte nsi on or t he st u d y c o m pleti o n/e arl y wit h dr a w al 
visit a n d f oll o w-u p ).
3. 3. 2
P h ar m a c o ki n eti c ( P K) a n d P h ar m a c o d y n a mi c ( P D) O ut c o m e 
M e a s ur e s
3. 3. 2. 1
P h ar m a c o ki n eti c O ut c o m e M e a s ur e s
Bl o o d s a m pl e s f or d et er mi n ati o n of pl a s m a c o n c e ntr ati o n s of ri s di pl a m, a n d it s 
m et a b olit e( s) a s
a p pli c a bl e, will b e c oll e ct e d a s d et ail e d i n t h e S o A ( A p p e n di x 1 , 
A p p e n di x 2 ).
Pl a s m a c o n c e ntr ati o n s of ri s di pl a m a n d it s m et a b olit e s a s a p pr o pri at e will b e m e a s ur e d 
b y a s p e cifi c a n d v ali d at e d li q ui d c hr o m at o gr a p h y -t a n d e m m a s s s p e ctr o m etr y ( L C-
M S/ M S) m et h o d. P K s a m pl e s m a y b e u s e d f or t h e e x pl or at or y i d e ntifi c ati o n of 
m et a b olit e s a s n e c e s s ar y. P ati e nt e x p o s ur e t o ri s di pl a m will b e a s s e s s e d a n d t h e 
f oll o wi n g p ar a m et er s c al c ul at e d (if p o s si bl e, b a s e d o n t h e a v ail a bl e d at a):

C o n c e ntr ati o n p er ti m e -p oi nt li st e d.

P e a k pl a s m a c o n c e ntr ati o n ( C m a x ).

Ar e a u n d er t h e c ur v e ( A U C).

C o n c e ntr ati o n at t h e e n d of a d o si n g i nt er v al ( C tr o u g h) t o a s s e s s st e a dy- st at e .

Ot h er P K p ar a m et er s a s a p pr o pri at e.
3. 3. 2. 2
P h ar m a c o d y n a mi c O ut c o m e M e a s ur e s
P D a s s e s s m e nt s will b e p erf or m e d a s d et ail e d i n t h e S o A (A p p e n di x 1 , A p p e n di x 2 ) a n d 
will i n cl u d e:

S M N m R N A i n bl o o d.

S M N pr ot ei n i n bl o o d.




R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
5 5 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
gl o b al e nr oll m e nt p h a s e a n d t h e e xt e n d e d C hi n a e nr oll m e nt p h a s e), i n d e p e n d e nt fr o m 
t h e t ar g et s a m pl e si z e of 4 0 i nfa nt s t h at ar e c urr e ntl y c o n si d er e d f or t h e pri m ar y a n al y si s.
4. 2. 1
R e cr uit m e nt Pr o c e d ur e s
I nf a nt s will b e r e cr uit e d pri m aril y fr o m sit e/ c o u ntr y cli ni c al d at a b a s e s, or vi a r ef err al s 
fr o m p ati e nt gr o u p s i n cl u di n g t h o s e o ut si d e t h e sit e’ s c o u ntr y; h o w e v er, i n s o m e c a s e s, 
p ot e nti al p ati e nt s m a y b e i d e ntifi e d pri or t o c o n s e nti n g t o t a k e p art i n t hi s st u d y u si n g 
pr e s cr e e ni n g e nr oll m e nt l o g s, I n d e p e n d e nt Et hi c s C o m mitt e e/I n stit uti o n al R e vi e w B o ar d 
(I E C/I R B)-a p pr o v e d n e w s p a p er/r a di o a d v erti s e m e nt s a n d m aili n g li st s.
4. 2. 2 
I n cl u si o n Crit eri a
I nf a nt s m u st me et t h e f oll o wi n g crit eri a f or st u d y e ntr y:
1)
M a l e s a n d f e m al e s a g e d b et w e e n 2 8 d a y s ( 1 m o nt h ) of life a n d 2 1 0 d a y s ( 7 m o nt h s)
(i n cl u si v e) at e nr oll m e nt. F or t h e fir st 3 i nfa nt s e nr oll e d i n P art 1 , a g e will b e
b et w e e n 1 5 0 d a y s ( 5 m o nt h s) a n d 2 1 0 d a y s ( 7 m o nt h s ) i n cl u si v e a n d a mi ni m u m
b o d y w ei g ht of 7 k g i s r e q uir e d f or t h e fir st i nf a nt o nl y. E nr oll m e nt i s d efi n e d a s t h e
m o m e nt w h e n p ati e nt s g et t h eir d o si n g n u m b er a s si g n e d.
2)
A l e g all y a ut h ori z e d r e pr e s e nt ati v e m u st b e a bl e t o c o n s e nt f or t h e p ati e nt
a c c or di n g t o I nt er n ati o n al C o nf er e n c e o n H ar m o ni s ati o n (I C H) a n d l o c al r e g ul ati o n s.
3)
G e st ati o n al a g e of 3 7 t o 4 2 w e e k s .
4)
C o nfir m e d di a g n o si s of 5 q -a ut o s o m al r e c e s si v e S M A, i n cl u di n g:
a.
G e n eti c c o nfir m ati o n of h o m o z y g o u s d el eti o n or c o m p o u n d h et er o z y g o sit y
pr e di cti v e of l o s s of f u n cti o n of t h e S M N 1 g e n e.
b.
Cli ni c al hi st or y, si g n s or s y m pt o m s attri b ut a bl e t o T y p e 1 S M A,
i. e., h y p ot o ni a, a b s e nt ( D T R) a n d/ or t o n g u e f a s ci c ul ati o n s wit h o n s et aft er
t h e a g e of 2 8 d a y s, b ut pri or t o t h e a g e of 3 m o nt h s (i n cl u si v e), a n d i n a bilit y
t o sit i n d e p e n d e ntl y ( wit h o ut s u p p ort) at t h e ti m e of s cr e e ni n g.
5)
I nf a nt h a s t w o S M N 2 g e n e c o pi e s, a s c o nfir m e d b y c e ntr al t e sti n g.
6)
B o d y w ei g ht 3 r d p er c e ntil e f or a g e, u si n g a p pr o pri at e c o u ntr y -s p e cifi c g ui d eli n e s
(for t h e fir st i nf a nt o nl y:7 k g) .
7)
R e c e i vi n g a d e q u at e n utriti o n a n d h y dr ati o n ( wit h or wit h o ut g a str o st o m y) at t h e ti m e
of  s cr e e ni n g, i n t h e o pi ni o n of t h e I n v e sti g at or.
8)
A d e q u at el y r e c o v er e d fr o m a n y a c ut e ill n e s s at t h e ti m e of s cr e e ni n g a n d
c o n si d er e d w ell -e n o u g h t o p arti ci p at e i n t h e o pi ni o n of t h e I n v e sti g at or.
9)
M e di c al c ar e m e et s, i n t h e o pi ni o n of t h e I n v e sti g at or, l o c al a c c e pt e d st a n d ar d of
c ar e.
1 0)
A bl e a n d e x p e ct e d t o b e a bl e t o s af el y tr a v el t o t h e st u d y sit e f or t h e w h ol e d ur ati o n
of  t h e st u d y a n d a c c or di n g t o t h e fr e q u e n c y of r e q uir e d st u d y vi sit s, i n t h e o pi ni o n of
t h e I n v e sti g at or. Air tr a v el i s str o n gl y di s c o ur a g e d. T h e o v er all c o n diti o n a n d
sit u ati o n (i n cl u di n g g e o gr a p hi c al) of t h e p ati e nt s h o ul d b e e v al u at e d a n d t h e
d e ci si o n t a k e n b y t h e I n v e sti g at or pri or t o e nr oll m e nt.


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
5 6 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
1 1)
H a v e a st a bl e h o m e sit u ati o n wit h a c o n si st e nt c ar e gi v er.
1 2)
W o ul d b e a bl e t o c o m pl et e all st u d y pr o c e d ur e s, m e a s ur e m e nt s a n d vi sit s, a n d t h e
p ar e nt or c ar e gi v er of t h e p ati e nt, i n t h e o pi ni o n of t h e I n v e sti g at or, h a s a d e q u at el y
s u p p orti v e p s y c h o s o ci al cir c u m st a n c e s.
1 3)
If n ot alr e a d y i n pl a c e at t h e ti m e of s cr e e ni n g, p ar e nt or c ar e gi v er of p ati e nt i s
willi n g t o c o n si d er n a s o g a stri c, n a s o -j ej u n al or g a str o st o m y t u b e pl a c e m e nt d uri n g
t h e st u d y t o m ai nt ai n s af e h y dr ati o n, n utriti o n a n d tr e at m e nt d eli v er y, a s
r e c o m m e n d e d b y t h e I n v e sti g at or.
1 4)
If n ot alr e a d y i n pl a c e at t h e ti m e of s cr e e ni n g, p ar e nt or c ar e gi v er of i nf a nt i s willi n g
t o c o n si d er t h e u s e of n o n-i n v a si v e v e ntil ati o n d uri n g t h e st u d y, a s r e c o m m e n d e d
b y t h e I n v e sti g at or.
4. 2. 3
E x cl u si o n Crit eri a
I nf a nt s w h o m e et a n y of t h e f oll o wi n g crit eri a will b e e x cl u d e d fr o m st u d y e ntr y:
1)
I n a bilit y t o m e et st u d y r e q uir e m e nt s.
2)
C o n c o mit a nt or pr e vi o u s p arti ci p ati o n i n a n y i n v e sti g ati o n al dr u g or d e vi c e st u d y
wit hi n 9 0 d a y s pri or t o s cr e e ni n g or 5 h alf -li v e s, w hi c h e v er i s l o n g er.
3)
C o n c o m it a nt or pr e vi o u s a d mi ni str ati o n of a S M N 2-t ar g eti n g a nti s e n s e
oli g o n u cl e oti d e, S M N 2 s pli ci n g m o difi er or g e n e t h er a p y eit h er i n a cli ni c al st u d y or
a s p art of m e di c al c ar e.
4)
A n y hi st or y of c ell t h er a p y.
5)
H o s pit ali z ati o n f or p ul m o n ar y e v e nt wit hi n t h e l a st 2 m o nt h s , or pl a n n e d at t h e ti m e
of  s cr e e ni n g.
6)
U n st a bl e g a str oi nt e sti n al, r e n al, h e p ati c, e n d o cri n e or c ar di o v a s c ul ar s y st e m
di s e a s e s.
7)
I n t h e o pi ni o n of t h e I n v e sti g at or, i n a d e q u at e v e n o u s or c a pill ar y bl o o d a c c e s s f or
t h e st u d y pr o c e d ur e s.
8)
R e q uiri n g i n v a si v e v e ntil ati o n or tr a c h e o st o m y.
9)
R e q uiri n g a w a k e n o n -i n v a si v e v e ntil ati o n or wit h a w a k e h y p o x e mi a ( S a O2 9 5 %)
wit h or wit h o ut v e ntil at or s u p p ort.
1 0)
A hi st or y of r e s pir at or y f ail ur e or s e v er e p n e u m o ni a, a n d h a v e n ot f ull y r e c o v er e d
t h eir p ul m o n ar y f u n cti o n at t h e ti m e of s cr e e ni n g.
1 1)
M u lti pl e or fi x e d c o ntr a ct ur e s a n d/ or hi p s u bl u x ati o n or di sl o c ati o n at birt h.
1 2)
Pr e s e n c e of n o n -S M A -r el at e d c o n c urr e nt s y n dr o m e s or di s e a s e s.
1 3)
C o nfir m e d ( 2 c o n s e c uti v e m e a s ur e m e nt s) s y st oli c bl o o d pr e s s ur e ( S B P) or di a st oli c
bl o o d pr e s s ur e ( D B P) o ut si d e t h e 9 5 t h p er c e ntil e f or a g e; r e sti n g h e art r at e 7 0 b p m
or 1 7 0 b p m .


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
5 7 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
1 4)
Pr e s e n c e of cli ni c all y r el e v a nt E C G a b n or m aliti e s b ef or e st u d y dr u g a d mi ni str ati o n;
c orr e ct e d Q T i nt er v al u si n g B a z ett’ s m et h o d ( Q T c B) 4 6 0 m s; p er s o n al or f a mil y
h i st or y (fir st d e gr e e r el ati v e s) of c o n g e nit al l o n g Q T s y n dr o m e i n di c ati n g a s af et y
ri s k f or p ati e nt s a s d et er mi n e d b y t h e I n v e sti g at or. Fir st -d e gr e e atri o v e ntri c ul ar bl o c k
or i s ol at e d ri g ht b u n dl e br a n c h bl o c k ar e all o w e d.
1 5)
Hi st or y of m ali g n a n c y if n ot c o n s i d er e d c ur e d.
1 6)
A n y m aj or ill n e s s wit hi n o n e m o nt h b ef or e t h e s cr e e ni n g e x a mi n ati o n or a n y f e bril e
ill n e s s wit hi n o n e w e e k pri or t o s cr e e ni n g a n d u p t o fir st d o s e a d mi ni str ati o n.
1 7)
T a ki n g a n y n utri e nt s k n o w n t o m o d ul at e C Y P 3 A a cti vit y ( e. g., gr a p efr uit j ui c e;
S e vill e or a n g e) wit hi n 2 w e e k s pri or t o a d mi ni str ati o n of st u d y dr u g s.
1 8)
T h e i nf a nt ( a n d t h e m ot h er, if br e a stf e e di n g t h e i nf a nt):
a.
A n y i n hi bit or of C Y P 3 A 4 t a k e n wit hi n 2 w e e k s ( or wit hi n 5 ti m e s t h e
eli mi n ati o n h alf -life, w hi c h e v er i s l o n g er) pri or t o d o si n g, i n cl u di n g b ut n ot
li mit e d t o: k et o c o n a z ol e, mi c o n a z ol e, itr a c o n a z ol e, fl u c o n a z ol e,
er yt hr o m y ci n, cl arit hr o m y ci n, r a niti di n e, ci m eti di n e.
b.
A n y i n d u c er of C Y P 3 A 4 t a k e n wit hi n 4 w e e k s ( or wit hi n 5 ti m e s t h e
eli mi n ati o n h alf -life, w hi c h e v er i s l o n g er) pri or t o d o si n g, i n cl u di n g b ut n ot
li mit e d t o: rif a m pi ci n, rif a b uti n, gl u c o c orti c oi d s, c ar b a m a z e pi n e, p h e n yt oi n,
p h e n o b ar bit al, St. J o h n' s w ort.
c.
A n y O C T -2 a n d M A T E s u b str at e s s h all b e a v oi d e d (i n cl u di n g b ut n ot li mit e d
t o: a m a nt a di n e, ci m eti di n e, m e m a nti n e, a mil ori d e, f a m oti di n e, m etf or mi n,
pi n d ol ol, r a niti di n e, pr o c ai n a mi d e, v ar e ni cli n e, a c y cl o vir, g a n ci cl o vir,
o x ali pl ati n, c e p h al e xi n, c e p hr a di n e, f e x of e n a di n e).
d.
A n y k n o w n F M O 1 or F M O 3 i n hi bit or s or s u b str at e s.
1 9)
Cli ni c all y si g nifi c a nt a b n or m aliti e s i n l a b or at or y t e st r e s ult s e. g., Gr a d e 1 a n e mi a,
al a ni n e a mi n otr a n sf er a s e ( A L T) v al u e s e x c e e di n g 1. 5 t h e u p p er li mit of n or m al
( U L N) u nl e s s t h e el e v at e d A L T l e v el i s c o n si d er e d of m u s c ul ar ori gi n (i. e., i n t h e
a b s e n c e of ot h er e vi d e n c e of li v er di s e a s e w hi c h i s c o nfir m e d b y el e v at e d cr e ati n e
ki n a s e a n d l a ct at e d e h y dr o g e n a s e [ L D H]). O ut of r a n g e cr e ati n e ki n a s e l e v el s
s h o ul d b e r e vi e w e d i n li g ht of t h e u n d erl yi n g S M A p at h ol o g y of t h e p ati e nt; el e v at e d
l e v el s p er s e d o n ot di s q u a lif y t h e p ati e nt fr o m t h e st u d y. I n t h e c a s e of u n c ert ai n or
q u e sti o n a bl e r e s ult s, t e st s p erf or m e d d uri n g s cr e e ni n g m a y b e r e p e at e d b ef or e
e nr oll m e nt t o c o nfir m eli gi bilit y.
2 0)
A s c ert ai n e d or pr e s u m pti v e h y p er s e n siti vit y ( e. g., a n a p h yl a cti c r e a cti o n) t o
ri s dipl a m or t o t h e c o n stit u e nt s of it s f or m ul ati o n ( s e e R i s di pl a m I n v e sti g at or’ s
Br o c h ur e ).
2 1)
C o n c o mit a nt di s e a s e or c o n diti o n t h at c o ul d i nt erf er e wit h, or tr e at m e nt of w hi c h
mi g ht i nt erf er e wit h, t h e c o n d u ct of t h e st u d y, or t h at w o ul d, i n t h e o pi ni o n of t h e
In v e sti g at or, p o s e a n u n a c c e pt a bl e ri s k t o t h e i nf a nt i n t hi s st u d y.


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
5 8 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
2 2)
T h er a p e uti c u s e, d efi n e d a s u s e f or 8 w e e k s or l o n g er, of t h e f oll o wi n g m e di c ati o n s
wit hi n 9 0 d a y s pri or t o e nr oll m e nt: ril u z ol e, v al pr oi c a ci d, h y dr o x y ur e a, s o di u m
p h e n yl b ut yr at e, b ut yr a t e d eri v ati v e s, cr e ati n e, c ar niti n e, gr o wt h h or m o n e, a n a b oli c
st er oi d s, pr o b e n e ci d, a g e nt s a nti ci p at e d t o i n cr e a s e or d e cr e a s e m u s cl e str e n gt h,
a g e nt s wit h k n o w n or pr e s u m e d hi st o n e d e a c et yl a s e ( H D A C) i n hi bit or y eff e ct,
m e di c ati o n s k n o w n t o or s u s p e ct e d of
c a u si n g r eti n al t o xi cit y ( e. g. d ef er o x a mi n e,
t o pir a m at e, l at a n o pr o st, ni a ci n, r o si glit a z o n e, t a m o xif e n, c a nt h a x a nt hi n e, sil d e n afil,
a n d i nt erf er o n) a n d m e di c ati o n s wit h k n o w n p h ot ot o xi cit y li a biliti e s ( e. g., or al
r eti n oi d s i n cl u di n g o v er-t h e-c o u nt er [ O T C] f or m ul ati o n s, a mi o d ar o n e,
p h e n ot hi a zi n e s a n d u s e of mi n o c y cli n e ). S h ort er u s e of a n y of t h e s e dr u g s wit hi n
9 0 d a y s pri or t o e nr oll m e nt will b e r e vi e w e d o n a c a s e -b y -c a s e b a si s a n d di s c u s s e d
b et w e e n t h e S p o n s or a n d t h e I n v e sti g at or, w h o will j oi ntl y m a k e t h e d e ci si o n if t h e
p ati e nt c a n b e e nr oll e d i n t h e st u d y. (I nf a nt s w h o ar e o n i n h al e d c orti c o st er oi d s,
a d mi ni st er e d eit h er t hr o u g h a n e b uli z er or a n i n h al er, will b e all o w e d i n t h e st u d y).
a.
I nf a nt s m u st n ot b e gi n tr e at m e nt wit h t h e a b o v e m e di c ati o n s aft er i niti ati n g
st u d y dr u g.
2 3)
R e c e ntl y i niti at e d tr e at m e nt ( wit hi n 6 w e e k s pri or t o e nr oll m e nt) wit h or al
s al b ut a m ol or a n ot h er 2- a dr e n er gi c a g o ni st t a k e n or all y  i s n ot all o w e d. I nf a nt s
w h o h a v e b e e n o n or al s al b ut a m ol ( or a n ot h er 2- a dr e n er gi c a g o ni st) f or 6 w e e k s
b ef or e s cr e e ni n g a n d h a v e s h o w n g o o d t ol er a n c e ar e all o w e d. T h e d o s e of
2- a dr e n er gi c a g o ni st s h o ul d r e m ai n st a bl e a s m u c h a s p o s si bl e f or t h e d ur ati o n of
t h e st u d y. U s e of i n h al e d 2- a dr e n er gi c a g o ni st s ( e. g., f or t h e tr e at m e nt of a st h m a)
i s all o w e d.
2 4)
Pri or u s e ( at a n y ti m e i n t h e p ati e nt s’ li v e s) a n d/ or a nti ci p at e d n e e d f or q ui n oli n e s
( c hl or o q ui n e a n d h y dr o x y c hl or o q ui n e), t hi ori d a zi n e, vi g a b atri n, r eti g a bi n e, or a n y
ot h er dr u g k n o w n t o c a u s e r eti n al t o xi cit y d uri n g t h e st u d y d o e s n ot all o w
p arti ci p at i o n i n t h e tri al. I nf a nt s e x p o s e d t o c hl or o q ui n e, h y dr o x y c h ol or o q ui n e,
t hi ori d a zi n e, vi g a b atri n, r eti g a bi n e or dr u g s wit h k n o w n r eti n al t o xi cit y gi v e n t o
m ot h er s d uri n g pr e g n a n c y ( a n d l a ct ati o n) s h o ul d n ot b e e nr oll e d.
2 5)
R e c e nt hi st or y (l e s s t h a n 6 m o nt h s) o f o p ht h al mi c di s e a s e s ( e. g., gl a u c o m a n ot
c o ntr oll e d b y tr e at m e nt, c e ntr al s er o u s r eti n o p at h y, i nfl a m m at or y/i nf e cti o u s r eti niti s
u nl e s s cl e arl y i n a cti v e, r eti n al d et a c h m e nt, i ntr a o c ul ar tr a u m a, r eti n al d y str o p h y or
d e g e n er ati o n, o pti c n e ur o p at h y, or o pti c n e uriti s) t h at w o ul d i nt erf er e wit h t h e
c o n d u ct of t h e st u d y a s a s s e s s e d b y a n o p ht h al m ol o gi st. A n y ot h er a b n or m aliti e s
d et e ct e d wit h O C T at s cr e e ni n g ( e. g., r eti n al l a y er a b n or m aliti e s, e d e m a, c y sti c or
atr o p hi c c h a n g e s) m u st b e di s c u s s e d wit h t h e I n v e sti g at or, O p ht h al m ol o gi st, a n d
wit h t h e S p o n s or, w h o will j oi ntl y m a k e t h e d e ci si o n if t h e i nf a nt m a y b e e nr oll e d i n
t h e st u d y. I nf a nt s i n w h o m O C T m e a s ur e m e nt of s uffi ci e nt q u alit y c a n n ot b e
o bt ai n e d at s cr e e ni n g will n ot b e e nr oll e d.


4. 3
M E T H O D O F T R E A T M E N T A S SI G N M E N T
T hi s i s a n o p e n -l a b el st u d y a n d all i nf a nt s will r e c ei v e ri s di pl a m.
I n P art 1 , i nf a nt s will b e e nr oll e d i nt o t w o m ulti pl e-a s c e n di n g d o s e c o h ort s. I n P art 2 , all 
i nf a nt s will b e e nr oll e d t o r e c ei v e ri s di pl a m at t h e d o s e (t ar g et e x p o s ur e l e v el) s el e ct e d i n 
P art 1.
A n I nt er a cti v e ( v oi c e/ w e b) R e s p o n s e S y st e m (I x R S) will b e u s e d t o m a n a g e p ati e nt 
s cr e e ni n g, e nr oll m e nt a n d dr u g s u p pl y. T h e p ati e nt n u m b er will b e all o c at e d b y I x R S a n d 
will b e u s e d i n t h e cli ni c al d at a b a s e a n d f or r e c or di n g d at a i n t h e el e ctr o ni c c a s e r e p ort 
f or m ( e C R F). Sit e s s h o ul d c all t h e I x R S t o e nt er t h e p ati e nt i nt o s cr e e ni n g a n d t o r e gi st er 
a s cr e e n f ail ur e. T h e e nr oll m e nt c all t o t h e I x R S s h o ul d o c c ur o n D a y 1 aft er t h e 
p ati e nt’ s eli gi bilit y (i. e., i n cl u si o n/ e x cl u si o n crit eri a) h a s b e e n c o nfir m e d.
4. 4
S T U D Y T R E A T M E N T
4. 4. 1
F or m ul ati o n, P a c k a gi n g, a n d H a n dli n g
4. 4. 1. 1
P art 1 F or m ul ati o n – R i s di pl a m ( P o w d er a n d s ol v e nt f or or al 
s ol uti o n, 2 0 m g a n d 1 2 0
m g)
R i s di pl a m cli ni c al f or m ul ati o n f or P art 1 i s a p o w d er a n d s ol v e nt f or c o n stit uti o n t o a n 
or al s ol uti o n. R i s di pl a m dr u g pr o d u ct i s c o m p o s e d of t w o b ottl e s; o n e c o nt ai ni n g 2 0 m g 
or 1 2 0 m g of ri s di pl a m s u b st a n c e ( n o e x ci pi e nt s) a n d a n ot h er wit h e x ci pi e nt s bl e n d 
( p o w d er f or s ol v e nt f or r e c o n stit uti o n). T h e e x ci pi e nt bl e n d b ottl e i s c o n stit ut e d wit h 
w at er f or i nj e cti o n a n d e ntir el y tr a n sf err e d t o t h e dr u g s u b st a n c e b ottl e t o yi el d a n or al 
s ol uti o n c o nt ai n i n g 0. 2 5 m g/ m L a n d 1. 5 m g/ m L of ri s di pl a m. F or t h e fir st i nf a nt( s), a 
f urt h er dil uti o n st e p i s f or e s e e n t o e n a bl e t h e a d mi ni str ati o n of a l o w st arti n g d o s e w hi c h 
h a s b e e n d efi n e d a s b ei n g a bl e t o e n s ur e t h e s af et y of t h e fir st e nr oll e d i nf a nt. 
T h e e x ci pi e nt bl e n d u s e d f or c o n stit uti o n of t h e dr u g s u b st a n c e c o n si st s of m a n nit ol, 
t art ari c a ci d, s o di u m b e n z o at e, a s c or bi c a ci d, p ol y et h yl e n e gl y c ol 6 0 0 0 , di s o di u m 
e d et at e di h y dr at e, s u cr al o s e a n d str a w b err y fl a v or. All e x ci pi e nt s s el e ct e d f or t h e p o w d er 
f or or al s ol uti o n f or m ul ati o n c o m pl y wit h p h ar m a c o p ei a r e q uir e m e nt s ( U nit e d St at e s 
P h ar m a c o p ei a – N ati o n al F or m ul ar y [ U S P/ N F] a n d/ or t h e E ur o p e a n P h ar m a c o p o ei a 
[ P h. E ur] a n d E U F o o d r e g ul ati o n).
4. 4. 1. 2
P art 2 F or m ul ati o n – R i s di pl a m ( P o w d er f or or al s ol uti o n, 2 0 m g 
a n d 6 0 m g)
R i s di pl a m cli ni c al f or m ul ati o n f or P art 2 i s a p o w d er f or c o n stit uti o n t o a n or al s ol uti o n. 
E a c h b ottl e c o nt ai n s 2 0  m g or 6 0  m g of  ri s di pl a m s u b st a n c e wit h e x ci pi e nt s. T h e p o w d er 
i s c o n stit ut e d wit h p urifi e d w at er t o yi el d a n or al s ol uti o n c ont ai ni n g 0. 2 5  m g/ m L or 
0. 7 5  m g/ m L of  ri s di pl a m, r e s p e cti v el y.
T h e e x ci pi e nt s u s e d i n t h e P art 2 cli ni c al f or m ul ati o n ar e t h e s a m e a s f or P art 1 
f or m ul ati o n ( p o w d er a n d s ol v e nt f or or al s ol uti o n), e x c e pt f or i s o m alt a d d e d a s dil u e nt. 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
5 9 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


I nf a nt s p arti ci p ati n g i n t h e P art 1 e xt e n si o n of t h e st u d y s h all c o nti n u e t o u s e t h e P art  1 
ri s di pl a m cli ni c al f or m ul ati o n u ntil s wit c h t o t h e P art 2  ri s di pl a m cli ni c al f or m ul ati o n u p o n 
a v ail a bilit y of t h e n e w f or m ul ati o n. I nf a nt s i n P art 2 of t h e s t u d y will r e c ei v e t h e P art 2 
f or m ul ati o n t hr o u g h o ut t h eir p arti ci p ati o n i n t h e st u d y.
4. 4. 1. 3  
P a c k a gi n g a n d H a n dli n g
T h e c o n stit uti o n of t h e st u d y  m e di c ati o n will b e c arri e d o ut at t h e cli ni c al st u d y sit e 
a ut h ori z e d p h ar m a c y b y q u alifi e d p h ar m a c e uti c al p er s o n n el. F urt h er d et ail e d 
i n str u cti o n s f or t h e c on stit uti o n pr o c e d ur e will b e pr o vi d e d i n a s e p ar at e p h ar m a c y 
m a n u al. Aft er c o n stit uti o n, t h e p h ar m a c e uti c al p er s o n n el will i n s ert a pr e s s -i n-b ottl e -
a d a pt er i nt o t h e b ottl e n e c k a n d cl o s e wit h a c hil d -r e si st a nt cl o s ur e. T h e b ottl e a d a pt er 
all o w s i n s erti o n o f or al/ e nt er al di s p e n s er s i nt o t h e b ottl e f or wit h dr a w al of t h e c o n stit ut e d 
s ol uti o n. T h e b ottl e t h at c o nt ai n s t h e or al s ol uti o n will b e i n s ert e d i nt o a l a b el e d c art o n 
pr o vi d e d b y R o c h e Cli ni c al Tri al s S u p pli e s d e p art m e nt. T h e cli n i c al st u d y sit e will 
pr o v i d e or al/ e nt er al di s p e n s er s t o t h e p ar e nt/ c ar e gi v er t o a d mi ni ster t h e s ol uti o n. A di ar y 
will b e pr o vi d e d t o t h e p ar e nt/ c ar e gi v er wit h i n str u cti o n s o n s t u d y dr u g a d mi ni str ati o n at 
h o m e.
F or e a c h i nf a nt a n d f or all o c c a si o n s of di s p e n s ati o n of st u d y dr u g, it  s h all b e r e c or d e d 
b y t h e P h ar m a ci st or p er s o n n el u n d er t h eir s u p er vi si o n w hi c h f o r m ul ati o n str e n gt h a n 
i nf a nt r e c ei v e d. 
St u d y dr u g p a c k a gi n g will b e o v er s e e n b y t h e R o c h e Cli ni c al Tri al S u p pli e s d e p art m e nt 
a n d will b e ar a l a b el wit h t h e i d e ntifi c ati o n r e q uir e d b y l o c al l a w, t h e pr ot o c ol n u m b er, 
dr u g i d e ntifi c ati o n a n d d o s a g e. T h e p a c k a gi n g a n d l a b elli n g of t h e st u d y m e di c ati o n will 
b e i n a c c or d a n c e wit h R o c h e st a n d ar d a n d l o c al r e g ul ati o n s. T h e  q u alifi e d i n di vi d u al 
r e s p o n si bl e f or di s p e n si n g t h e st u d y dr ug w ill pr e p ar e t h e c orr e ct dr u g pr o d u ct a c c or di n g 
t o t h e i n di vi d u al s p e cifi c d o s e all o c at e d t o a n i n di vi d u al p atie nt. 
U p o n arri v al of i n v e sti g ati o n al pr o d u ct s at t h e sit e, sit e p er s o n n el s h o ul d c h e c k f or 
d a m a g e a n d v erif y pr o p er i d e ntit y, q u a ntit y, i nt e grit y of s e al s a n d t e m p er at ur e c o n diti o n s, 
a n d r e p ort a n y d e vi ati o n s or pr o d u ct c o m pl ai nt s t o t h e M o nit or u p o n di s c o v er y. All dr u g 
s u p pli e s s h o ul d b e st or e d i n a s e c ur e, t e m p er at ur e -c o ntr oll e d ar e a wit h li mit e d a c c e s s. 
ri s di pl a m i n v e sti g ati o n al pr o d u ct m u st b e st or e d a c c or di n g t o t h e d et ail s o n t h e pr o d u ct 
l a b el.
F or f urt h er d et ail s, s e e t h e  R i s di pl a m I n v e sti g at or’ s Br o c h ur e a n d B P 3 9 0 5 6 P h ar m a c y 
M a n u al.
4. 4. 2  
D o s a g e, A d mi ni str ati o n, a n d C o m pli a n c e
4. 4. 2. 1  
R i s di pl a m
T h e q u alifi e d i n di vi d u al r e s p o n si bl e f or di s p e n si n g t h e st u d y dr u g will pr e p ar e t h e c orr e ct 
d o s e a c c or di n g t o t h e e nr oll m e nt s c h e d ul e. T hi s i n di vi d u al will  writ e t h e d at e di s p e n s e d 
a n d p ati e nt n u m b er a n d i niti al s o n t h e st u d y dr u g vi al l a b el a n d o n t h e Dr u g 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
6 0 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
6 1 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
A c c o u nt a bilit y R e c or d. T hi s i n di vi d u al will al s o r e c or d t h e M E D N O/ st u d y dr u g b at c h 
n u m b er r e c ei v e d b y e a c h p ati e nt d uri n g t h e st u d y. T hr o u g h o ut t h e st u d y, t h e st u d y 
m e di c ati o n ( ri s di pl a m) s h o ul d b e t a k e n or all y o n c e d ail y. I n t h e c a s e of br e a stf e e di n g, 
th e p ati e nt s h o ul d b e f e d pri or t o d o si n g, wi n d e d, a n d t h e st u d y m e di c ati o n a d mi ni st er e d. 
I n p ati e nt s a bl e t o s w all o w, st u d y dr u g will b e a d mi ni st er e d wit h a s yri n g e i n s ert e d 
b et w e e n b a b y' s g u m a n d c h e e k a s d e s cri b e d i n t h e st u d y dr u g a d mi ni str ati o n 
i n str u cti o n s f or u se. T h er e aft er, w at er ( a p pr o x. 1 0 – 2 0 m L) s h o ul d b e a d mi ni st er e d wit h a 
b a b y’ s b ottl e t o pr e v e nt pr ol o n g e d c o nt a ct of st u d y dr u g wit h b u c c al m u c o s a. Si mil arl y, 
t h e p eri b u c c al- ar e a of t h e S M A i nf a nt will b e w a s h e d wit h w at er i n c a s e of dr u g dr o ol i n g 
or s pitti n g. Br e a stf e e di n g s h o ul d b e a v oi d e d wit hi n o n e h o ur aft er st u d y dr u g 
a d mi ni str ati o n. W o m e n br e a stf e e di n g will b e a d vi s e d t o ri n s e t h eir br e a st s wit h w at er 
w h e n br e a stf e e di n g o c c ur s s h ortl y aft er ( 1 h) ri s di pl a m a d mi ni str ati o n.
If a p ar e nt or c ar e gi v er d o e s n ot a d mi ni st er t h e d o s e at t h e r e g ul ar ti m e, b ut r e ali z e s 
pri or t o 1 2: 0 0 ( n o o n) l o c al ti m e, t h e y will b e i n str u ct e d t o a d mi ni st er t h e r e g ul ar d o s e at 
t h at ti m e. If a p ar e nt or c ar e gi v er r e ali z e s a mi s s e d a d mi ni str ati o n o nl y aft er 
1 2: 0 0 ( n o o n) l o c al ti m e, t hi s will b e c o n si d er e d a mi s s e d d o s e a n d p ar e nt s or c ar e gi v er s 
will b e i n str u ct e d t o n ot a d mi ni st er st u d y dr u g f or t h at d a y. T h e y s h o ul d gi v e t h e r e g ul ar 
a m o u nt at t h e n e xt s c h e d ul e d ti m e o n t h e s u b s e q u e nt d a y, b ut n ot d o u bl e -u p t h e d o s e, 
a n d r e p ort t h e e v e nt i n t h e m e di c ati o n di ar y.
St u d y p arti ci p a nt s u n a bl e t o s w all o w t h e st u d y m e di c ati o n a n d w h o h a v e a n a s o -g a stri c 
or g a str o st o m y t u b e i n sit u s h o ul d r e c ei v e t h e st u d y m e di c ati o n b y b ol u s vi a t h e t u b e. 
T hi s s h o ul d b e f oll o w e d b y a b ol u s fl u s h of w at er t hr o u g h t h e t u b e.
T h e fir st d o s e of st u d y m e di c ati o n will b e a d mi ni st er e d at t h e cli ni c al sit e o n D a y 1 aft er 
all pr e -d o s e a s s e s s m e nt s h a v e b e e n c o n d u ct e d.
A s u bj e ct di ar y will b e r e q uir e d t h at will c a pt ur e i nf or m ati o n r el at e d t o dr u g a d mi ni str a ti o n 
f or all d o s e s t hr o u g h o ut st u d y. All b ottl e s a n d u n u s e d dr u g a n d dr u g s u p pli e s will b e 
r et ur n e d t o t h e sit e d uri n g a st u d y vi sit or c oll e ct e d d uri n g a h o m e vi sit.
G ui d eli n e s f or d o s a g e m o difi c ati o n a n d tr e at m e nt i nt err u pti o n or di s c o nti n u ati o n ar e 
pr o v i d e d i n S e cti o n 4. 7 .
4. 4. 3
I n v e sti g ati o n al M e di ci n al Pr o d u ct Ac c o u nt a bilit y
All I M P ( ri s di pl a m) r e q uir e d f or c o m pl eti o n of t hi s st u d y will b e pr o vi d e d b y t h e S p o n s or. 
T h e i n v e sti g ati o n al sit e will a c k n o wl e d g e r e c ei pt of I M P, t o c o nfir m t h e s hi p m e nt c o n diti o n 
a n d c o nt e nt. A n y d a m a g e d s hi p m e nt s will b e r e pl a c e d.


T h e I n v e sti g at or i s r e s p o n si bl e f or t h e c o ntr ol of dr u g s u n d er i n v e sti g ati o n. A d e q u at e 
r e c or d s of t h e r e c ei pt ( e. g., Dr u g R e c ei pt R e c or d) a n d di s p o siti o n ( e. g., Dr u g Di s p e n si n g 
L o g) of t h e st u d y dr u g m u st b e m ai nt ai n e d. T h e Dr u g Di s p e n si n g L o g m u st b e k e pt 
c urr e nt a n d s h o ul d c o nt ai n t h e f oll o wi n g i nf or m ati o n:

T h e i d e ntifi c ati o n of t h e p ati e nt t o w h o m t h e st u d y dr u g w a s di s p e n s e d (f or e x a m pl e
p ati e nt i niti al s a n d d at e of birt h).

T h e d at e( s), q u a ntit y of t h e st u d y dr u g di s p e n s e d t o t h e p ati e nt.

T h e d at e( s) a n d q u a ntit y of t h e st u d y dr u g r et ur n e d b y t h e p ati e nt.

All r e c or d s a n d dr u g s u p pli e s m u st b e a v ail a bl e f or i n s p e cti o n b y t h e R o c h e M o nit or
[ at e v er y m o nit ori n g vi sit].
I MP s will eit h er b e di s p o s e d of at t h e st u d y sit e a c c or di n g t o t h e st u d y sit e’ s i n stit uti o n al 
st a n d ar d o p er ati n g pr o c e d ur e or r et ur n e d t o t h e S p o n s or wit h t h e a p pr o pr i at e 
d o c u m e nt ati o n. T h e sit e' s m et h o d of I M P d e str u cti o n m u st b e a gr e e d u p o n b y t h e 
S p o n s or. L o c al or i n stit uti o n al r e g ul ati o n s m a y r e q uir e i m m e di at e d e str u cti o n of u s e d 
i n v e sti g ati o n al m e di ci n al pr o d u ct f or s af et y r e a s o n s. I n t h e s e c a s e s, it m a y b e 
a c c e pt a bl e f or i n v e sti g ati o n al st u d y sit e st aff t o d e str o y di s p e n s e d i n v e sti g ati o n al 
pr o d u ct b ef or e a m o nit ori n g i n s p e cti o n pr o vi d e d t h at s o ur c e d o c u m e nt v erifi c ati o n i s 
p erf or m e d o n t h e r e m ai ni n g i n v e nt or y a n d r e c o n cil e d a g ai n st t h e d o c u m e nt ati o n of 
q u a ntit y s h i p p e d, di s p e n s e d, r et ur n e d, d e str o y e d a n d pr o vi d e d t h at a d e q u at e st or a g e 
a n d i nt e grit y of dr u g h a s b e e n c o nfir m e d.
T h e sit e m u st o bt ai n writt e n a ut h ori z ati o n fr o m t h e S p o n s or b ef or e a n y I M P i s d e str o y e d, 
a n d I M P d e str u cti o n m u st b e d o c u m e nt e d o n t h e a p pr o p ri at e f or m.
Wr itt e n d o c u m e nt ati o n of d e str u cti o n m u st c o nt ai n t h e f oll o wi n g:

I d e ntit y of i n v e sti g ati o n al pr o d u ct[ s] d e str o y e d.

Q u a ntit y of i n v e sti g ati o n al pr o d u ct[ s] d e str o y e d.

D at e of d e str u cti o n.

M et h o d of d e str u cti o n.

N a m e a n d si g n at ur e of r e s p o n si bl e p er s o n [ or c o m p a n y] w h o d e str o y e d
i n v e sti g ati o n al pr o d u ct[ s].
A c c ur at e r e c or d s of all I M P s r e c ei v e d at, di s p e n s e d fr o m, r et ur n e d t o, a n d di s p o s e d of 
b y t h e st u d y sit e s h o ul d b e r e c or d e d o n t h e Dr u g I n v e nt or y L o g.
4. 4. 4
P o st -Tri al A c c e s s t o R i s di pl a m
T h e S p o n s or will off er p o st -tri al a c c e s s t o t h e st u d y dr u g (ri s di pl a m) fr e e of c h ar g e t o 
eli gi bl e p ati e nt s i n a c c or d a n c e wit h t h e R o c h e Gl o b al P oli c y o n C o nti n u e d A c c e s s t o 
I n v e sti g ati o n al M e di ci n al Pr o d u ct, a s o utli n e d b el o w.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
6 2 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


A p ati e nt will b e eli gi bl e t o r e c ei v e st u d y dr u g aft er t h e e n d of t h e st u d y if all of t h e 
f oll o wi n g c o n diti o n s ar e m et:

T h e p ati e nt h a s a lif e -t hr e at e ni n g or s e v er e m e di c al c o n diti o n a n d r e q uir e s
c o nti n u e d st u d y dr u g tr e at m e nt f or hi s or h er w ell -b ei n g .

T h er e ar e n o a p pr o pri at e alt er n ati v e tr e at m e nt s a v ail a bl e t o t h e p ati e nt.

T h e p ati e nt a n d hi s or h er d o ct or c o m pl y wit h a n d s ati sf y a n y l e g al or r e g ul at or y
r e q uir e m e nt s t h at a p pl y t o t h e m.
A p ati e nt will n ot b e eli gi bl e t o r e c ei v e st u d y dr u g aft er t h e e n d of t h e st u d y if a n y of t h e 
f oll o wi n g c o n diti o n s ar e m et:

T h e st u d y dr u g i s c o m m er ci all y m ar k et e d i n t h e p ati e nt' s c o u ntr y a n d i s r e a s o n a bl y
a c c e s si bl e t o t h e p ati e nt ( e. g., i s c o v er e d b y t h e p ati e nt' s i n s ur a n c e or w o ul d n't
ot h er wi s e cr e at e a fi n a n ci al h ar d s hi p f or t h e p ati e nt).

T h e S p o n s or h a s di s c o nti n u e d d e v el o p m e nt of t h e st u d y dr u g or d at a s u g g e st t h at
t h e st u d y dr u g i s n ot eff e cti v e f or S M A.

T h e S p o n s or h a s r e a s o n a bl e s af et y c o n c er n s r e g ar di n g t h e st u d y dr u g a s tr e at m e nt
f or S M A.

Pr o vi si o n of st u d y dr u g i s n ot p er mitt e d u n d er t h e l a w s a n d r e g ul ati o n s of t h e
p ati e nt' s c o u ntr y.
T h e R o c h e Gl o b al P oli c y o n C o nti n u e d A c c e s s t o I n v e sti g ati o n al M e di ci n al Pr o d u ct i s 
a v ail a bl e at t h e f oll o wi n g W e b sit e:
htt p:// w w w.r o c h e. c o m/ p oli c y _ c o nti n u e d _ a c c e s s _t o _i n v e sti g ati o n al _ m e di ci n e s. p df
4. 5
C O N C O MI T A N T T H E R A P Y A N D F O O D
4. 5. 1
P er mitt e d T h er a p y
C o n c o mit a nt t h er a p y i n cl u d e s a n y m e di c ati o n, e. g., v a c ci n e s, pr e s cri pti o n dr u g s, 
o v er -t h e-c o u nt er dr u g s, a p pr o v e d di et ar y a n d h er b al s u p pl e m e nt s, n utriti o n al 
s u p pl e m e nt s a n d a n y n o n -m e di c ati o n i nt er v e nti o n s ( e. g., i n di vi d u al p h y si ot h er a p y, 
p h y si c al t h er a p y a n d r e h a bilit ati v e t h er a p y) u s e d b y a p ati e nt wit hi n  3 0  d a y s  of s cr e e ni n g 
u ntil t h e  st u d y c o m pleti o n/ e arl y wit h dr a w al visit , u nl e s s st at e d ot h er wi s e, s e e 
e x cl u si o n crit eri a. All c o n c o mit a nt m e di c ati o n s s h o ul d b e r e p ort e d t o t h e I n v e sti g at or a n d  
r e c or d e d o n t h e Pr e vi o u s a n d C o n c o mit a nt Tr e at m e nt s e C R F.
P h y si ot h er a p y, o c c u p ati o n al t h er a p y a n d ot h er f or m s of e x er ci s e t h er a p y ar e 
e n c o ur a g e d b ut t h e fr e q u e n c y s h o ul d r e m ai n t h e s a m e d uri n g  t h e cli ni c al st u d y. All 
c o n c o mit a nt t h er a p y s h o ul d b e r e p ort e d t o t h e I n v e sti g at or a n d r e cor d e d o n t h e Pr e vi o u s 
a n d C o n c o mit a nt Tr e at m e nt s e C R F.
All t h er a p y a n d/ or m e di c ati o n a d mi ni st er e d t o m a n a g e a d v er s e e v e nt s s h o ul d b e 
r e c or d e d o n t h e A d v er s e E v e nt e CR F.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
6 3 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


U nl e s s s p e cifi e d diff er e ntl y b el o w, f or a n y c hr o ni c tr e at m e nt, p ati e nt s s h o ul d b e o n 
st a bl e r e gi m e n f or 6 w e e k s pri or t o s cr e e ni n g a n d s h o ul d r e m ai n o n st a bl e r e gi m e n 
t hr o u g h o ut t h e st u d y.
E x a m pl e s of all o w e d m e di c ati o n s i n cl u d e t h e f oll o wi n g, u nl e s s p r o hi bit e d p er
S e cti o n 4. 5. 2 :

I n h al e d c orti c o st er oi d s.

Ot h er i n h al e d dr u g s f or o b str u cti v e air w a y s di s e a s e s ( e. g., a nti c h oli n er gi c s a n d
a nti -all er gi c a g e nt s).

Ot h er s y st e mi c dr u g s f or o b str u cti v e air w a y s di s e a s e s ( e. g., l e u k otri e n e r e c e pt or
a nt a g o ni st s).

L a x ati v e s a n d ot h er dr u g s f or f u n cti o n al g a str oi nt e sti n al di s or d er s.

O c c a si o n al u s e of a n al g e si c s, i n cl u di n g o pi oi d s ( e. g.,
h y dr o m or p h o n e or c o d ei n e).

A n y a nti bi oti c s.

A nti hi st a mi n e s.

Pr ot o n p u m p i n hi bit or s.

A n y v a c ci n e c o n si d er e d a s p art of t h e l o c al st a n d ar d of c ar e f or t h e p ati e nt.
4. 5. 2
Pr o hi bit e d T h er a p y
All m e di c ati o n s ( pr e s cri pti o n a n d O T C) t a k e n wit hi n 3 0 d a y s of st u d y s cr e e ni n g will b e 
r e c or d e d o n t h e a p pr o pri at e e C R F.
T h e f oll o wi n g m e di c ati o n i s e x pli citl y pr o hi bit e d f or t h e p ati e nt s a n d t h e m ot h er if 
br e a stf e e di n g t h e p ati e nt:

A n y i n hi bit or of C Y P 3 A 4, i n cl u di n g b ut n ot li mit e d t o: k et o c o n a z ol e, mi c o n a z ol e,
itr a c o n a z ol e, fl u c o n a z ol e, er yt hr o m y ci n, cl arit hr o m y ci n, r a niti di n e, ci m eti di n e.

A n y i n d u c er of C Y P 3 A 4, i n cl u di n g b ut n ot li mit e d t o: rif a m pi ci n, rif a b uti n,
gl u c o c orti c oi d s, c ar b a m a z e pi n e, p h e n yt oi n, p h e n o b ar bit al, St. J o h n' s w ort.

A n y O C T- 2 a n d M A T E s u b str at e s s h all b e a v oi d e d, i n cl u di n g b ut n ot li mit e d t o:
a m a nt a di n e, ci m eti di n e, m e m a nti n e, a mil ori d e, f a m oti di n e, m etf or mi n, pi n d ol ol,
r a niti di n e, pr o c ai n a mi d e, v ar e ni cli n e, a c y cl o vir, g a n ci cl o vir, o x ali pl ati n, c e p h al e xi n,
c e p hr a di n e, f e x of e n a di n e.

A n y k n o w n F M O 1 or F M O 3 i n hi bit or s or s u b str at e s.
U s e of t h e f oll o wi n g t h er a pi e s i s pr o hi bit e d f or at l e a st 9 0  d a y s pri or  t o e nr oll m e nt 
( u nl e s s t h e I n v e sti g at or h a s c o n s ult e d wit h t h e S p o n s or d uri n g t h e s cr e e ni n g p eri o d a n d 
b ot h h a v e a gr e e d t h at t h e pri or u s e will n ot c o n stit ut e a ri s k t o t h e p ati e nt), a n d d uri n g 
t h e st u d y:
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
6 4 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
6 5 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
M e di c ati o n s i nt e n d e d f or t h e tr e at m e nt of S M A

Ril u z ol e

V al pr oi c a ci d

H y dr o x y ur e a

S o di u m p h e n yl b ut yr at e

B ut yr at e d eri v ati v e s

Cr e ati n e

C ar niti n e

Gr o wt h h or m o n e

A n a b oli c st er oi d s

Pr o b e n e ci d

B ort e z o mi n

Q u er c eti n

C hr o ni c or al or p ar e nt er al u s e of c orti c o st er oi d s (i n h al e d c orti c o st er oi d u s e i s
all o w e d, s e e a b o v e).

A g e nt s a nti ci p at e d t o i n cr e a s e or d e cr e a s e m u s cl e str e n gt h or a g e nt s wit h k n o w n or
pr e s u m e d H D A C i n hi biti o n a cti vit y.

A n y pri or u s e of S pi nr a z a or a n y ot h er S M N 2 -t ar g eti n g a nti s e n s e oli g o n u cl e oti d e,
S M N- 2 s pli ci n g m o difi er or g e n e t h er a p y i s pr o hi b it e d.
M e di c ati o n s wit h k n o w n r eti n al t o xi cit y  li a biliti e s

A mi o d ar o n e, p h e n ot hi a zi n e s, a n d c hr o ni c u s e of mi n o c y cli n e.
P ati e nt s s h o ul d n ot h a v e r e c ei v e d t h e f oll o wi n g dr u g s at a n y ti m e i n t h eir li v e s a n d ar e 
pr o hi bit e d d uri n g t h e st u d y :

Q ui n oli n e s ( c hl or o q ui n e a n d h y dr o x y c hl or o q ui n e), t hi ori d a zi n e, vi g a b atri n a n d
r eti g a bi n e
U s e of t h e f oll o wi n g t h er a pi e s i s pr o hi bit e d f or t h e p ati e nt s, a n d f or t h e m ot h er if 
br e a stf e e di n g t h e i nf a nt d uri n g t h e st u d y a n d i n t h e pr e c e di n g 9 0 d a y s of e nr oll m e nt:

D ef er o x a mi n e, t o pir a m at e, l at a n o pr o st, ni a ci n ( n ot a p pli c a ble if use d as a
n utriti o n al s u p ple me nt ), r o si glit a z o n e, t a m o xif e n, c a nt h a x a nt hi n e, sil d e n afil,
i nt erf er o n or a n y ot h er dr u g s k n o w n t o c a u s e r eti n al t o xi cit y
4. 5. 3
Pr o hi bit e d F o o d
S u bj e ct s ar e t o a v oi d gr a p efr u it j ui c e a n d S e vill e or a n g e (j ui c e) st arti n g at l e a st 2 w e e k s 
pri or t o st u d y dr u g a d mi ni str ati o n.


Br e a stf e e di n g of t h e p ati e nt i s all o w e d if t h e m ot h er i s n ot c o n s u mi n g a n y pr o hi bit e d 
m e di c ati o n s ( s e e S e cti o n
4. 5. 2 ). Br e a stf e e di n g i s n ot p er mitt e d f or o n e h o ur aft er st u d y 
dr u g a d mi ni str ati o n i n or d er t o a v oi d dir e ct c o nt a ct b et w e e n t h e m ot h er’ s s ki n a n d t h e 
dr u g pr o d u ct i m m e di at el y aft er a d mi ni str ati o n.
4. 6
S T U D Y A S S E S S M E N T S
4. 6. 1
D e s cri pti o n of St u d y  As s e s s m e nt s
All e x a mi n ati o n s li st e d b el o w will b e p erf or m e d a c c or di n g t o t h e s c h e d ul e of 
a s s e s s m e nt s o utli n e d i n  A p p e n di x 1 -A p p e n di x  4 .
Pri oriti z ati o n of bl o o d s a m pl e s i s d e s cri b e d i n  S e cti o n  4. 6. 3 .
F oll o w -u p p h o n e c all s ar e pl a n n e d i n t hi s st u d y. P ar e nt s ( or c ar e gi v er s of p ati e nt s, a s 
a p pr o pri at e) will b e c all e d b y t h e I n v e sti g at or or d e si g n e e t o m o nit or s af et y a n d 
tol er a bilit y w h e n n ot att e n di n g t h e cli ni c. A s s e s s m e nt s will i n cl u d e a d v er s e e v e nt s, 
c o n c o mit a nt m e di c ati o n r e vi e w, a n d si g nifi c a nt lif e e v e nt s  (A p p e n di x 1 , A p p e n di x  2 ).
H o m e vi sit s ar e pl a n n e d i n t hi s st u d y ( s e e S o A,  A p p e n di x 1 , A p p e n di x  2 ) t o s u p pl y t he 
p atie nt wit h st u d y me di c ati o n a n d c he c k p atie nt di ar y f or c o m pli a n ce. Alter n ati vel y, 
t he p atie nts m a y  visit t he cli ni c o n t he d ates s c he d ule d f or h o me visits.  If ne e de d, t he 
f oll o wi n g assess me nts c o ul d be perf or me d d uri n g h o me visits: bl o o d s a m pl e s, vit al 
si g n s, wei g ht , a d v er s e e v e nt s, c o n c o mit a nt m e di c ati o n r e vi e w, a n d  si g nifi c a nt lif e  e v e nt  
d at a c olle cti o n . 
T h e e x a ct ti mi n g of all st u d y a s s e s s m e nt s ( e. g., P K or P D bl o o d  s a m pli n g) m a y b e 
s hift e d d e p e n di n g o n e m er g e nt d at a, b ut t h e  t ot al n u m b er of a s s e s s m e nt s will n ot 
c h a n g e.
4. 6. 1. 1  
M e di c al Hi st or y  a n d D e m o gr a p hi c D at a
M e di c al hi st or y i n cl u d e s cli ni c all y si g nifi c a nt di s e a s e s a n d al l m e di c ati o n s 
( e. g., pr e s cri pti o n dr u g s, O T C dr u g s, h er b al or h o m e o p at hi c r e m e di e s, n utr iti o n al 
s u p pl e m e nt s) or  p h y si c al/ o c c u p ati o n al/ e x er ci s e t h er a p y a p pli e d t o t h e p ati e nt w it hi n 
3 0  d a y s pri or t o t h e s cr e e ni n g vi sit.
D e m o gr a p hi c d at a will i n cl u d e a g e, s e x, a n d p ar e nt/ c ar e gi v er -r e p ort e d p ati e nt 
r a c e/ et h ni cit y ( coll e cti n g t hi s i nf or m ati o n i s e s s e nti al t o b e a bl e t o e v al u at e t h e r e s ult s of 
t hi s st u d y, e. g., i n c a s e of P K o utli er s or i m p ort a nt b et w e e n-s u bj e ct s diff er e n c e s i n t er m s 
of  tr e at m e nt eff e ct).
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
6 6 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
6 7 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
4. 6. 1. 2
S pi n al M u s c ul ar A tr o p h y Hi st or y
S M A hi st or y will b e c oll e ct e d a s a v ail a bl e i n t h e p ati e nt’ s m e di c al r e c or d s. T h e c oll e ct e d 
p ar a m et er s will i n cl u d e (li st i s n ot e x h a u sti v e, pl e a s e r ef er t o t h e e C R F):

A g e of o n s et.

Pr e vi o u s s c or e o n f u n cti o n al m ot or s c al e ( e. g., C H O P -I N T E N D, B SI D -III).

C urr e nt l e v el of f u n cti o n a n d hi g h e st m ot or f u n cti o n a c hi e v e d (i. e., r olli n g, cr a wlin g).
S M A hi st or y will b e r e c or d e d o n t h e e C R F at t h e ti m e-p oi nt s s p e cifi e d i n t h e S o A 
(A p p e n di x 1 , A p p e n di x 2 ).
4. 6. 1. 3
A n t hr o p o m etri c M e a s ur e m e nt s
A nt hr o p o m etri c m e a s ur e m e nt s i n cl u d e w ei g ht, h ei g ht, h e a d a n d c h e st cir c u mf er e n c e 
a n d will b e m e a s ur e d at t h e ti m e -p oi nt s s p e cifi e d i n t h e S o A s ( A p p e n di x 1 , A p p e n di x 2 ).
B o d y W ei g ht

B o d y w ei g ht will b e m e a s ur e d t o t h e n e ar e st 1 0 0 g.
H ei g ht

H ei g ht ( or l e n gt h) will b e m e a s ur e d t o t h e n e ar e st c e nti m et er wit h t h e c hil d i n l yi n g
p o siti o n u si n g a n i nfl e xi bl e l e n gt h b o ar d wit h fi x e d h e a d b o ar d a n d m o v e a bl e
f o ot b o ar d.

F or all p atie nts w h o are a ble t o st a n d, hei g ht will be me as ure d w hile st a n di n g
usi n g a st a di o meter u nless t he y prese nt wit h s c oli osis/ c o ntr a ct ures.

W he n a p atie nt’s hei g ht c a n n o l o n ger be assesse d b y a fi xe d b o ar d a n d t he p atie nt
is u n a ble t o st a n d (e. g., be c a use t he p atie nt is l o n ger t h a n t he fi xe d b o ar d or d ue t o
s c olisis/ c o ntr a ct ures), t he p atie nt’s hei g ht will be deri ve d fr o m ul n a le n gt h t o t he
ne arest ce nti meter b y t he f oll o wi n g met h o d:
-
Ul n a r le n gt h (fr o m t he ti p of t he ole cr a n o n pr ocess t o t h at of t he st yl oi d
pr o cess) will be me as ure d usi n g a n a nt hr o p o meter wit h t he p a tie nt i n sitti n g
p ositi o n, t he left f ore ar m resti n g c o mf ort a bl y o n a t a ble, el b o w be nt 9 0 t o
1 1 0 , p al m f a ci n g d o w n w ar ds a n d fi n gers e xte n de d b ut t o get her.

Met h o d of hei g ht me as ure me nt s h o ul d be ke pt c o nsiste nt f or as l o n g as p ossi ble.
H e a d a n d C h e st C irc u mf er e n c e

H e a d a n d c h e st cir c u mf er e n c e will b e m e a s ur e d t o t h e n e ar e st c e nti m et er u si n g a n
a ut o m at e d fl e xi bl e, n o n -str et c h a bl e t a p e d e vi c e a s f oll o w s:
-
H e a d cir c u mf er e n c e ( or o c ci pit al -fr o nt al cir c u mf er e n c e [ O F C]) will b e m e a s ur e d
at t h e l e v el of t h e pl a n e p a s si n g a b o v e t h e gl a b ell a (t h e m o st a nt eri or
pr otr u si o n of t h e f or e h e a d) a n d o v er t h e o pi st hr o cr a ni o n - (t h e m o st p o st eri or
pr otr u si o n fr o m gl a b ell a o n t h e b a c k of t h e h e a d), p er p e n di c ul ar t o t h e
mi d -s a gitt al pl a n e. T h e i nf a nt' s h e a d s h o ul d b e s u p p ort e d a w a y fr o m t h e t a bl e
s urf a c e. T h e m e a s uri n g t a p e s h o ul d r e m ai n a b o v e t h e e ar s a n d f ull y c o m pr e s s
a n y h air ( h air or n a m e nt s s h o ul d b e r e m o v e d a n d l ar g e pl ait s or br ai d s


l o o s e n e d). T h e m e a s ur e m e nt s h o ul d b e t a k e n t o t h e n e ar e st milli m et er a n d 
r e p e at e d t hr e e ti me s wit h t h e l ar g e st m e a s ur e m e nt b ei n g r e c or d e d.
-
C h e st cir c u mf er e n c e will b e m e a s ur e d wit h t h e i nf a nt l yi n g o n t h e b a c k, u n d er
t h e a xill a a n d o v er t h e ni p pl e li n e. T h e m e a s ur e m e nt s h o ul d b e t a k e n t o t h e
n e ar e st milli m et er a n d r e p e at e d t hr e e ti m e s wit h t h e l ar g e st m e a s ur e m e nt
b ei n g r e c or d e d.
H e a d t o c h e st cir c u mf er e n c e r ati o will b e d eri v e d t hr o u g h o ut t h e st u d y ( S e cti o n  6. 6. 3 ).
4. 6. 1. 4  
P h y si c al E x a mi n ati o n s
A f ull p h y s i c al e x a mi n ati o n s h o ul d i n cl u d e a n e v al u ati o n of t h e h e a d, e y e s, e ar s, n o s e, 
t hr o at, n e c k a n d l y m p h n o d e s, a n d t h e c ar di o v a s c ul ar, d er m at ol o gi c al, m u s c ul o s k el et al, 
r e s pir at or y, g a str oi nt e sti n al, g e nit o uri n ar y, a n d n e ur ol o gi c al s y st e m s. F ull p h y si c al 
e x a mi n ati o n will b e c arri e d o ut at ti m e -p oi nt s s p e cifi e d i n t h e S o A  (A p p e n di x 1 , 
A p p e n di x  2 ). T h e p h y si c al e x a m will n ot i n cl u d e p el vi c or r e ct al e x a m s u nl e s s d e e m e d 
n e c e s s ar y b y t h e st u d y sit e p h y si ci a n.
A n e ur ol o gi c al e x a mi n ati o n will b e p erf or m e d d uri n g t h e p h y si c al e x a mi n ati o n. A s t h e 
m ot or a s s e s s m e nt s ar e p erf or m e d i n t h e ot h er e x a m s t hi s will f o c u s o n m e nt al st at u s, 
b e h a vi or a n d c o g niti v e a s s e s s m e nt s. T h e e x a mi n ati o n will b e p erf or m e d b y a s ki n g 
p ar e nt s/ c ar e gi v er s a b o ut t h e i nf a nt’ s d e v el o p m e nt, o v er a ll b e h a vi o ur, sl e e p a n d m o o d 
s u c h a s n u m b er of t a ntr u m s a n d v o c ali z ati o n. T h e I n v e sti g at or will  o b s er v e a n d i nt er a ct 
wit h t h e i nf a nt u si n g t a s k s or p ar a di g m s a d a pt e d t o t h e i nf a nt’ s a g e a n d m ot or a bilit y, f or 
e x a m pl e o b s er vi n g i nf a nt’ s r e a cti o n t o a s o u n d,  s p e e c h d e v el o p m e nt, s hifti n g att e nti o n 
t o a n e wl y i ntr o d u c e d t o y, o b s er vi n g t h e p ati e nt i nt er a ct wit h t h e p ar e nt/ c ar e gi v er.
A n y a b n or m alit y i d e ntifi e d at b a s eli n e s h o ul d b e r e c or d e d o n t h e G e n er al M e di c al 
Hi st or y a n d B a s eli n e C o n diti o n s e C R F.
C h a n g e s fr o m  b a s eli n e a b n or m aliti e s s h o ul d b e r e c or d e d i n p ati e nt’ s n ot e s. N e w or 
w or s e n e d cli ni c all y si g nifi c a nt a b n or m aliti e s s h o ul d b e r e c or d e d a s a d v er s e e v e nt s o n 
t h e A d v er s e E v e nt e C R F.
4. 6. 1. 5  
Vit al Si g n s
Bl o o d pr e s s ur e ( B P), p ul s e r at e, r e s pir at or y r at e a n d b o d y t e m p er at ur e (or al or t y m p a ni c) 
will b e r e c or d e d at t h e ti m e -p oi nt s s p e cifi e d i n S o A  (A p p e n di x 1 , A p p e n di x  2 ).
M e a s ur e m e nt s s h o ul d b e o bt ai n e d i n a q ui et r o o m at a c o mf ort a bl e t e m p er at ur e, wit h 
t h e p ati e nt p o siti o n e d i n a s e mi-s u pi n e/ s u pi n e p o siti o n wit h t h e ar m s u n c o n str ai n e d b y 
cl ot hi n g or ot h er  m at eri al. M e a s ur e m e nt s s h o ul d b e t a k e n pri or t o bl o o d dr a w or a t l e a st 
1 0  mi n ut e s aft er t h e l a st bl o o d dr a w a n d aft er t h e p ati e nt h a s b e e n r e sti n g f or at l e a st 
5  mi n ut e s.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
6 8 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


T hr o u g h o ut t h e st u d y all bl o o d pr e s s ur e m e a s ur e m e nt s will b e o bt ai n e d fr o m t h e s a m e 
ar m ( w h e n n ot p o s si bl e t o m e a s ur e it fr o m t h e ar m t h e l o w er l e g m a y b e u s e d ) a n d wit h 
t h e a p pr o pri at e c uff si z e,  u si n g a w ell - cali br at e d a ut o m ati c i n str u m e nt wit h a di git al 
r e a d o ut (t h e “i d e al” c uff s h o ul d h a v e a bl a d d er l e n gt h t h at i s 8 0 % a n d a wi dt h t h at i s at 
l e a st 4 0 % of ar m cir c u mf er e n c e [ a l e n gt h-to - wi dt h r ati o of 2: 1]). A n y cl ot hi n g t h at c o v er s 
t h e l o c ati o n of t h e c uff pl ac e m e nt s h o ul d b e r e m o v e d.
At s cr e e ni n g a n d at e v er y bl o o d pr e s s ur e a s s e s s m e nt t hr o u g h o ut t h e st u d y, S B P a n d 
D B P p er c e ntil e s f or a g e s h o ul d b e d et er mi n e d u si n g t h e C e nt er s f or Di s e a s e C o ntr ol 
a n d Pr e v e nti o n ( C D C) t a bl e s, w hi c h r e q uir e t o fir st d et er mi n e p at i e nt’ s p er c e ntil e f or 
st at ur e u si n g t h e C D C gr o wt h c h art s.
B ot h t h e C D C bl o o d pr e s s ur e p er c e ntil e s t a bl e s a n d gr o wt h c h art s will b e pr o vi d e d t o 
t h e sit e s pri or t o st u d y st art.
4. 6. 1. 6  
El e ctr o c ar di o gr a m s
At e a c h s p e cifi e d  ti m e- poi nt  (A p p e n di x 1 , A p p e n di x  2 ), 1 2-le a d E C G r e c or di n g s m u st b e 
o bt ai n e d i n tri pli c at e (i. e., t hr e e u s ef ul E C G s wit h o ut artif a ct s 2 - 3 mi n ut e s a p art). T h e 
a v er a g e of t h e t hr e e r e a di n g s will b e u s e d t o d et er mi n e E C G i nt er v al s ( e. g., P R, Q R S, 
Q T). W h e n e v er p o s si bl e, t h e s a m e br a n d/ m o d el of a st a n d ar d hi g h - qu alit y, hi g h -fi d elit y 
el e ctr o c ar di o gr a p h m a c hi n e e q ui p p e d wit h c o m p ut er - ba s e d i nt er v al m e a s ur e m e nt s 
s h o ul d b e u s e d f or e a c h p ati e nt. T h e c o n diti o n s s h o ul d b e a s cl o s e a s p o s si bl e t o 
pr e - do s e ti m e - poi nt s; t hi s i n cl u d e s b ut i s n ot li mit e d t o f o o d i nt a k e, a cti vit y l e v el, 
str e s s or s a n d r o o m t e m p er at u r e.
T o mi ni mi z e v ari a bilit y, it i s i m p ort a nt t h at t h e i nf a nt b e i n a r el a xi n g p o siti o n 
f or 1 0  mi n ut e s pri or t o e a c h E C G e v al u ati o n. B o d y p o siti o n s h o ul d b e c o n si st e ntl y 
m ai nt ai n e d f or e a c h E C G e v al u ati o n t o pr e v e nt c h a n g e s i n h e art r at e. E n vir o n m e nt al 
di str a cti o n s ( e. g., t el e vi si o n, r a di o, c o n v er s ati o n) s h o ul d b e a v oi d e d d uri n g t h e pr e - EC G 
r e sti n g p eri o d a n d d uri n g E C G r e c or di n g. E C G s s h o ul d b e p erf or m e d pri or t o a n y 
s c h e d ul e d  vit al si g n m e a s ur e m e nt s a n d bl o o d dr a w s.  If a n E C G  i s p erf or m e d aft er vit al 
si g n m e a s ur e m e nt s a n d bl o o d dr a w s, t h e p ati e nt s h o ul d b e pr o vi d e d wit h e n o u g h ti m e 
t o r e st i n or d er t o mi ni mi z e v ari a bilit y. I n s o m e c a s e s, it m a y b e a p pr o pri at e t o r e p e at 
a b n or m al E C G s t o r ul e o ut i m pr o p er l e a d pl a c e m e nt a s c o ntri b u ti n g t o t h e E C G 
a b n or m alit y.
F or s af et y m o nit ori n g p ur p o s e s, t h e I n v e sti g at or or d e si g n e e m u st r e vi e w, si g n, a n d d at e 
all E C G tr a ci n g s. P a p er or el e ctr o ni c c o pi e s will b e k e pt a s p a rt of t h e p ati e nt’ s 
p er m a n e nt st u d y fil e at t h e sit e. If c o n si d er e d a p pr o pr i at e b y R o c h e, E C G s m a y b e 
a n al y z e d r etr o s p e cti v el y at a c e ntr al r e a d er.
E C G c h ar a ct eri sti c s, i n cl u di n g h e art r at e, Q R S d ur ati o n, P R, Q T  a n d R R i nt er v al s, will 
b e r e c or d e d o n t h e e C R F. Q T c B ( B a z ett’ s c orr e cti o n;  P h a n et al 2 0 1 5 ), Q T c F
( Fri d eri ci a’ s c orr e cti o n) will b e c al c ul at e d b y t h e S p o n s or. B ot h c orr e cti o n s of Q T c will b e 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
6 9 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
7 0 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
t a b ul at e d a n d a n al y z e d; alt h o u g h, i n c hil dr e n, B a z ett’ s f or m ul a a p p e ar s t o pr o vi d e a 
b ett er c orr e cti o n of t h e Q T i nt er v al. C h a n g e s i n T ‑ w a v e a n d U -w a v e m or p h ol o g y a n d 
o v er all E C G i nt er pr et ati o n will b e d o c u m e nt e d o n t h e e C R F, a d diti o n all y a s a n A E a s 
a p pr o pri at e. T- w a v e i nf or m ati o n will b e c a pt ur e d a s n or m al or a b n or m al, U- w a v e
i nf or m ati o n will b e c a pt ur e d i n t w o c at e g ori e s: a b s e nt/ n or m al or a b n or m al.
4. 6. 1. 7
L a b or at or y  As s e s s m e nt s
N or m al r a n g e s f or t h e st u d y l a b or at or y p ar a m et er s m u st b e s u p pli e d t o t h e S p o n s or 
b ef or e t h e st u d y st art s. L a b or at or y s af et y t e st s s h all b e c oll e ct e d at ti m e -p oi nt s s p e cifi e d 
i n t h e S o A (A p p e n di x 1 , A p p e n di x 2 ).
At a n y ti m e a n d a s d e s cri b e d i n S e cti o n 4. 6. 3 , s af et y l a b or at or y s a m pl e s will b e gi v e n 
t h e pri orit y o v er a n y ot h er s a m pl e, s u c h t h at t h e v ol u m e of bl o o d t a k e n at a n y si n gl e 
ti m e-p oi nt will n ot e x c e e d 1. 5 m L/ k g, a n d t h e v ol u m e c oll e ct e d o v er a n y 8 -w e e k p eri o d 
t hr o u g h o ut t h e st u d y will n ot e x c e e d 4. 5 m L/ k g.
A d diti o n al bl o o d s a m pl e s m a y b e t a k e n at t h e di s cr eti o n of t h e I n v e sti g at or if t h e r e s ult s 
of  a n y t e st f all o ut si d e t h e r ef er e n c e r a n g e s, or cli ni c al s y m pt o ms n e c e s sit at e a d diti o n al 
t e sti n g t o m o nit or p ati e nt s af et y. F or s af et y l a b or at or y s a m pl e s o nl y, u s e of 
mi cr o c oll e cti o n m et h o d s h o ul d al w a y s b e f a v or e d i n or d er t o li mit t h e a m o u nt of bl o o d 
c oll e ct e d. W h er e t h e cli ni c al si g nifi c a n c e of a b n or m al l a b r e s ult s i s c o n si d er e d u n c ert ai n, 
s cr e e ni n g l a b t e st s m a y b e r e p e at e d b ef or e e nr ol m e nt t o c o nfir m eli gi bilit y.
I n t h e e v e nt of u n e x pl ai n e d a b n or m al cli ni c all y si g nifi c a nt l a b or at or y t e st v al u e s, t h e 
t e st s s h o ul d b e r e p e at e d i m m e di at el y a n d f oll o w e d u p u ntil t h e y h av e r et ur n e d t o t h e 
n or m al r a n g e a n d/ or a n a d e q u at e e x pl a n ati o n of t h e a b n or m alit y i s f o u n d. R e s ult s of 
cli ni c al l a b or at or y t e sti n g will b e r e c or d e d o n t h e e C R F or b e r e c ei v e d a s el e ctr o ni c all y 
pr o d u c e d l a b or at or y r e p ort s s u b mitt e d dir e ctl y fr o m t h e l o c al o r c e ntr al l a b or at or y.
S a m pl e s will b e c oll e ct e d f or t h e f oll o wi n g a n al y si s:

H e m at ol o g y: h e m o gl o bi n, h e m at o crit, er yt hr o c yt e s ( R B C), pl at el et s, l e u k o c yt e s
( WB C), diff er e nti al s ( c o u nt s): n e utr o p hil s, e o si n o p hil s, l y m p h o c yt e s, m o n o c yt e s,
b a s o p hil s, r eti c ul o c y t e.

S er u m c h e mi str y: a s p art at e a mi n otr a n sf er a s e ( A S T), al a ni n e a mi n otr a n sf er a s e
( A L T), t ot al a n d c o nj u g at e d bilir u bi n, al b u mi n, cr e ati ni n e, ur e a nitr o g e n, s o di u m,
c hl ori d e, p ot a s si u m, gl u c o s e.
B a s e d o n c o nti n u o u s a n al y si s of t h e d at a i n t hi s st u d y a n d ot h er st u di e s, a n y s a m pl e 
t y p e n ot c o n si d er e d t o b e criti c al f or s af et y m a y b e st o p p e d at a n y ti m e if t h e d at a fr o m 
t h e s a m pl e s c oll e ct e d d o e s n ot pr o d u c e u s ef ul i nf or m ati o n.


4. 6. 1. 8
O p ht h al m ol o gi c al A s s e s s m e nt s
O p ht h al m ol o gi c al a s s e s s m e nt s will b e p erf or m e d at ti m e p oi nt s s p e cifi e d i n t h e S o As 
(A p p e n di x 1 , A p p e n di x 2 , a n d A p pe n di x 5 ). E x a mi n ati o n s will b e c arri e d o ut b y a 
p e di atri c o p ht h al m ol o gi st , n e ur o o p ht h al m ol o gi st , or p e di atri c o p ht h al m ol o g y i m a gi n g 
s p e ci ali st tr ai ne d a n d certifie d t o perf or m t he st u d y-s pe cifi c o p ht h al m ol o gi c al 
assess me nts . O p ht h al m ol o gi c e x a mi n ati o n a n d r eti n al i m a gi n g i n cl u d e:
1.
Vi s u al D e v el o p m e nt.
2.
R e d r efl e x: P erf or m e d wit h a n o p ht h al m o s c o p e or r eti n o s c o p e fr o m a p pr o xi m at el y
3 0 c m / 1 f o ot i n a s e mi-d ar k e n e d r o o m, e x a mi n ati o n will a s s e s s bri g ht n e s s of p u pil
r efl e x ( c ol or a n d h o m o g e n eit y, s y m m etr y of t h e fi n di n g s, a b s e n c e, w hit e, o p a cifi e d).
3.
E xt er n al O c ul ar E x a mi n ati o n: i n cl u di ng, b ut n ot li mite d t o, e y eli d s, c o nj u n cti v a,
s cl er a.
4.
P u pill ar y R e s p o n s e: U si n g a bri g ht li g ht, p u pill ar y r e s p o n s e of e a c h e y e will b e
a s s e s s e d f or dir e ct a n d c o n s e n s u al r e s p o n s e a n d w h e n a c hi e v a bl e a c c o m m o d ati v e
r e s p o n s e will b e t e st e d.
5.
C o ver/ U n c o ver Test.
6.
Fi x a n d f oll o w t e st: F ail ur e t o fi x a n d f oll o w will b e a s s e s s e d i n t h e c o nt e xt of t h e
p ati e nt’ s m e di c al c o n diti o n s a n d a g e.
7.
O c ul ar e x a mi n ati o n u n d er m a g nifi c ati o n ( i ncl u di n g slit l a m p / o p ht h al m o s c o p e of
a nt eri or a n d p o st eri or s e g m e nt s i n cl u di n g a s s e s s m e nt ( wit h dil ati o n or n ot) of t h e
r eti n a a n d o pti c n er v e).
8.
O C T i m a gi n g will b e r e c or d e d wit h t h e E n vi s u h a n d -h el d d e vi c e fr o m Bi o pti g e n I n c.
( or ot h er h a n d -h el d d e vi c e O C T a v ail a bl e a p pr o v e d b y t h e c e ntr al o p ht h al mi c
l a b or at or y), alt er n ati v e m et h o d m a y i n cl u d e t h e u s e of a S p e ctr ali s ( H ei d el b er g
E n gi n e eri n g) c o n v ert e d t o a h a n d -h el d s y st e m f or s u pi n e i m a gi n g. E v er y att e m pt
s h o ul d b e m a d e t o c a pt ur e a d diti o n al i m a g e s aft er u p, d o w n, l eft, a n d ri g ht g a z e.
9.
C ol or F u n d u s P h ot o gr a p h y.
T h e d et ail s of t h e v i s u al t e st s will b e i n cl u d e d i n a s e p ar at e Ce ntr al Re a di n g Ce nter  
m a n u al.
W h e n e v er f e a si bl e, a d diti o n al o p ht h al mi c a s s e s s m e nt s s u c h a s d ar k  a d a pt ati o n 
t hr e s h ol d t e sti n g, el e ctr o-r eti n o gr a p h y mi g ht b e c arri e d o ut a s n e e d e d i n c a s e of 
a b n or m aliti e s or u p o n r e c o m m e n d ati o n fr o m t h e sit e or c e ntr al O p ht h al m ol o gi st.
C e ntr al R e a di n g
T h e C e ntr al R e a di n g C e nt er will pr o vi d e sit e s wit h t h e C e ntr al R e a di n g C e nt er M a n u al 
a n d tr ai ni n g m at eri al s f or st u d y m a n d at e d o c ul ar i m a gi n g. B ef or e st u d y i m a g e s ar e 
o bt ai n e d, sit e p e r so n n el, t e st i m a g e s, a n d s y st e m s a n d s oft w ar e ( w h er e a p pli c a bl e)  will 
b e c ertifi e d b y t h e r e a di n g c e nt er a s s p e cifi e d i n t h e C e ntr al R e a d i n g C e nt er M a n u al. 
All  o c ul ar i m a g e s will b e o bt ai n e d o nl y b y tr ai n e d a n d C e ntr al R e a d i n g C e nt er−c ertifi e d 
p er s o n n el a t t h e st u d y sit e s a n d f or w ar d e d t o t h e C e ntr al R e a di n g C e nt er f or st or a g e 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
7 1 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


a n d f or i n d e p e n d e nt a n al y si s, i n cl u di n g c o nfir m ati o n of eli gi bilit y f or d efi n e d i m a gi n g 
crit eri a.
4. 6. 1. 9
N utriti o n al C h e c k
N utriti o n al a s s e s s m e nt will b e p erf or m e d f or all p ati e nt s at t h e ti m e-p oi nt s i n di c at e d i n 
t h e S o A (A p p e n di x 1 , A p p e n di x 2 ) a n d will i n cl u d e:

H e a d t o c h e st cir c u mf er e n c e r ati o fr o m a nt hr o p o m etri c m e a s ur e m e nt s
( S e cti o n 4. 6. 1. 3 ).

N utriti o n al st at u s i nt er vi e w of t h e p ar e nt/ c ar e gi v er i n cl u di n g q u e sti o n s a b o ut a bilit y
t o s w all o w a n d l e v el of s oli d f o o d i nt a k e.

A s p e e c h l a n g u a g e p at h ol o gi st or ot h er s uit a bl y q u alifi e d i n di vi d u al will p erf or m a
st a n d ar d s w all o wi n g a s s e s s m e nt a c c or di n g t o l o c al pr a cti c e at t h e b a s eli n e vi sit,
a n d t h e n, a c c or di n g t o t h e S o A. T hi s will i n cl u d e a s s e s si n g t h e a bilit y of t h e p ati e nt
t o s w all o w a g e a p pr o pri at e f o o d s.
B a s e d o n t hi s a s s e s s m e nt, s p e cifi c n utriti o n al a d vi c e m a y b e gi v e n i n di vi d u all y t o t h e 
p ati e nt’ s p ar e nt s/ c ar e gi v er s b y t h e I n v e sti g at or or N utriti o ni st.
4. 6. 1. 1 0  
Pl a s m a Pr ot ei n Bi n di n g
A v e n o u s bl o o d s a m pl e will b e c oll e ct e d fr o m all p ati e nt s at s cr e e ni n g  i n or d er t o 
m e a s ur e pl a s m a pr ot ei n bi n di n g, i. e.,  t o m e a s ur e t h e fr e e fr a cti o n of t h e st u d y dr u g 
( S e cti o n 3. 2. 1 ). R e s ult s f or a p ati e nt m u st b e a v ail a bl e a n d c h e c k e d b y t h e Sp o n s or 
b ef or e a n y st u d y dr u g i s a d mi ni st er e d t o t hi s s p e cifi c p ati e nt.
Pl a s m a pr ot ei n bi n di n g (i. e.,  fr e e fr a cti o n, f u) m a y al s o b e m e a s ur e d fr o m t h e P K 
s a m pl e s c oll e ct e d d uri n g t h e st u d y.
T h e pl a s m a pr ot ei n bi n di n g a s s e s s m e nt at s cr e e ni n g m a y n ot b e r e q uir e d i n  P art  2  of 
t hi s st u d y, d e p e n di n g o n t h e d at a c oll e ct e d i n P art  1.
4. 6. 1. 1 1  
P h ar m a c o ki n eti c A s s e s s m e nt s
Bl o o d f or d et er mi n ati o n of pl a s m a c o n c e ntr ati o n s of  ri s di pl a m, a n d it s m et a b olit e( s) a s 
a p pli c a bl e, will b e c oll e ct e d a s d et ail e d i n  t h e S o A (A p p e n di x  3 , A p p e n di x  4 ).
A d diti o n al P K s a m pl e s m a y b e t a k e n if r e q uir e d f or s af et y r e a s o n s, e. g., u p o n a 
r e q u e st e d d o s e c h a n g e t o c o nfir m t h e n e w t ar g et e x p o s ur e, or t o c o nfir m u n u su al P K 
fi n di n g s b ef or e r e q u e sti n g a d o s e c h a n g e  (s e e A p p e n di x 1  a n d A p p e n di x  2 ).
V e n o u s bl o o d s h all b e c oll e ct e d f or P K s a m pl e s. T h e p o s si bilit y of c a pill ar y bl o o d 
s a m pli n g f or P K d et er mi n ati o n m a y b e a s s e s s e d d uri n g t h e st u d y b y p ar all el v e n o u s a n d 
c a pill ar y s a m pli n g, u p o n s p e cifi c r e q u e st b y t h e S p o n s or. D e p e n di n g o n t h e e m er gi n g 
d at a fr o m t h e c o m p ari s o n of v e n o u s a n d c a pill ar y bl o o d c oll e cti o n, t h e S p o n s or m a y gi v e 
p er mi s si o n f or c a pill ar y bl o o d c oll e cti o n s u b s e q u e ntl y.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
7 2 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


Pl a s m a c o n c e ntr ati o n s of ri s di pl a m will b e m e a s ur e d b y a s p e cifi c v ali d at e d L C -M S/ M S 
a s s a y. M et a b olit e s m a y b e m e a s ur e d b y a s p e cifi c v ali d at e d L C -M S / MS a s s a y, or ot h er 
m et h o d s a s a p pr o pri at e, a n d P K s a m pl e s m a y al s o b e u s e d f or e x pl or at or y m et a b olit e 
i d e ntifi c ati o n.
A ct u al P K s a m pli n g ti m e s m u st b e d o c u m e nt e d i n t h e e C R F. A ct u al d at e a n d ti m e of 
d o si n g o n t h e d a y of P K s a m pli n g ( a n d t h e t w o pr e c e di n g d o si n g o c c a si o n s if p o s si bl e) 
m u st b e d o c u m e nt e d i n t h e e C R F.
P K s a m pl e s will b e d e str o y e d n o l at er t h a n 5 y e ar s aft er t h e d at e of fi n al l o c k of t h e 
cli ni c al d at a b a s e.
4. 6. 1. 1 2
Fl ui d P h ar m a c o d y n a mi c A s s e s s m e nt s
T h e f oll o wi n g fl ui d P D a s s e s s m e nt s will b e p erf or m e d a s d et ail e d i n t h e S o A 
(A p p e n di x 3 , A p p e n di x 4 ).
H o w e v er, s h o ul d t h e t ot al bl o o d v ol u m e t o b e c oll e ct e d at a n y ti m e -p oi nt a c c or di n g t o 
t h e S c h e d ul e of A s s e s s m e nt s e x c e e d 1.5 m L / k g, or t h e v ol u m e c oll e ct e d o v er a n y 
8- w e e k p eri o d t hr o u g h o ut t h e st u d y e x c e e d s 4.5 m L / k g, t h e bl o o d s a m pl e pri oriti z ati o n
d e s cri b e d i n S e cti o n 4. 6. 3 s h o ul d b e f oll o w e d.

I n vi v o s pli ci n g m o difi c ati o n of S M N 2 m R N A
i n bl o o d
W h ol e bl o o d s a m pl e s will b e t a k e n fr o m e v er y p ati e nt at t h e ti m e -p oi nt s s p e cifi e d i n t h e 
S o A ( A p p e n di x 1 , A p p e n di x 2 ) t o m e a s ur e i n vi v o s pli ci n g m o difi c ati o n of S M N 1, S M N 2 
F L, a n d S M N Δ 7 m R N A d uri n g t h e c o ur s e of t h e st u d y. I n a d diti o n, h o u s e k e e pi n g g e n e s 
f or t h e q u a ntit ati v e a n al y si s of R N A will b e m e a s ur e d. A d diti o n al m R N A m a y b e u s e d f or 
e x pl or at or y a n al y si s/ a s s a y d e v el o p m e nt r el at e d t o S M A i n cl u di n g, b ut n ot li mit e d t o, 
p at h w a y s r el at e d t o S M N f u n cti o n a n d tr e at m e nt r e s p o n s e.

S M N pr ot ei n l e v el s
V e n o u s bl o o d f or S M N pr ot ei n a n al y si s will b e c oll e ct e d fr o m e v er y p ati e nt.
B a s e d o n c o nti n u o u s a n al y si s of t h e d at a i n t hi s st u d y a n d ot h er st u di e s,  a n y s a m pl e 
t y p e n ot c o n si d er e d t o b e c riti c al f or s af et y m a y b e st o p p e d at a n y ti m e if t h e d at a fr o m 
t h e s a m pl e s c oll e ct e d d o e s n ot pr o d u c e u s ef ul i nf or m ati o n.
T h e s e s a m pl e s will b e d e str o y e d n o l at er t h a n  5  y e ar s  af t er t h e d at e of fi n al l o c k of t h e 
cli ni c al d at a b a s e a n d m a y b e u s e d f or a d diti o n al e x pl or at or y a n al y si s/ a s s a y 
d e v el o p m e nt r el at e d t o S M A i n cl u di n g, b ut n ot li mit e d t o, p at h w a y s r el at e d t o S M N 
f u n cti o n or tr e at m e nt r e s p o n s e.
F or s a m pli n g pr o c e d ur e s, st or a g e c o n diti o n s, a n d s hi p m e nt i n s tr u cti o n s, s e e t h e S a m pl e 
H a n dli n g a n d L o gi s ti c s M a n u al.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
7 3 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


4. 6. 1. 1 3
Cli ni c al G e n ot y pi n g S a m pl e s
A si n gl e m a n d at or y w h ol e bl o o d s a m pl e will b e t a k e n fr o m e v er y p ati e nt at s cr e e ni n g f or 
D N A e xtr a cti o n ( A p p e n di x 1 , A p p e n di x 2 ). T h e D N A will b e u s e d t o d et er mi n e t h e 
n u m b er of c o pi e s of t h e S M N 2 g e n e ( s e e I n cl u si o n crit eri a i n S e cti o n 4. 2 ) a n d t o c o nfir m 
S M N 1 g e n e m ut ati o n or d el eti o n.
A m a n d at or y w h ol e bl o o d s a m pl e will b e t a k e n f or D N A e xtr a cti o n fr o m e v er y p ati e nt 
o n c e e nr oll e d o nt o t h e st u d y a n d m a y b e u s e d f or a d diti o n al c o nfir m at or y t e sti n g of 
S M N 1 d el eti o n/ S M N 2 c o p y n u m b er .
S a m pl e s m a y b e u s e d f or e x pl or at or y a n al y si s/ a s s a y d e v el o p m e nt r el at e d t o S M A, 
i n cl u di n g, b ut n ot li mit e d t o, mit o c h o n dri al D N A, a n d g e n e s r el at e d t o S M N f u n cti o n or 
tr e at m e nt r e s p o n s e.
T h e cli ni c al g e n ot y pi n g s a m pl e s will b e d e str o y e d n o l at er t h a n 5 y e ar s aft er t h e d at e of 
fi n al l o c k of t h e cli ni c al d at a b a s e. D at a ari si n g fr o m cli ni c al g e n ot y pi n g will b e s u bj e ct t o 
t h e c o nfi d e nti alit y st a n d ar d s d e s cri b e d i n S e cti o n 8. 4 .
F or s a m pli n g pr o c e d ur e s, st or a g e c o n diti o n s, a n d s hi p m e nt i n str u cti o n s, s e e t h e S a m pl e 
H a n dli n g a n d L o gi sti c s M a n u al.
4. 6. 1. 1 4
M ot or F u n cti o n a n d M ot or D e v el o p m e nt A s s e s s m e nt s
A s s e s s m e nt s of m ot or f u n cti o n a n d m ot or d e v el o p m e nt will  b e p erf or m e d a s d et ail e d i n 
t h e S o A (A p p e n di x 1 , A p p e n di x  2 ).
B a y l e y S c al e s of I nf a nt a n d T o d dl er D e v el o p m e nt  –  T hir d E diti o n
T h e B a yl e y S c al e s of I nf a nt a n d T o d dl er D e v el o p m e nt  –  T hir d E diti o n ( B SI D -III) i s t h e 
c urr e nt v er si o n of t h e m o st e xt e n si v el y u s e d m e a s ur e of i nf a nt a n d t o d dl er d e v el o p m e nt 
i n cli ni c al a n d r e s e ar c h pr a cti c e. T h e B SI D w er e fir st p u bli s h e d b y N a n c y B a yl e y i n T h e 
B a yl e y S c al e s of I nf a nt D e v el o p m e nt  ( 1 9 6 9) a n d h a v e b e e n u s e d e xt e n si v ely w orl d wi d e 
s i n c e t h e n t o a s s e s s t h e d e v el o p m e nt of i nf a nt s. C o m p ar e d t o t h e pr e vi o u s v er si o n, t h e 
T hir d E diti o n of t h e B SI D, p u bli s h e d i n 2 0 0 6 ( B a yl e y  2 0 0 6), w a s i m pr o v e d b y u p d ati n g 
n or m ati v e d at a, str e n gt h e ni n g p s y c h o m etri c q u aliti e s a n d c h a n gi n g s o m e i t e m s t o m a k e 
a d mi ni str ati o n a n d s c ori n g e a si er a n d m or e m e a ni n gf ul.
B SI D d at a r efl e ct t h e U. S. p o p ul ati o n i n t er m s of r a c e, et h ni ci t y, i nf a nt g e n d er, e d u c ati o n 
l e v el of p ar e nt s, a n d d e m o gr a p hi c l o c ati o n of t h e i nf a nt. T h e B SI D w a s st a n d ar di z e d i n 
1, 7 0 0  i nfa nt s , t o d dl er s, a n d pr e s c h o ol er s  b et w e e n o n e a n d  4 2  m o nt h s  of a g e. A 
s u p pl e m e nt al st u d y h a s al s o d e m o n str at e d str o n g m e a s ur e m e nt pr o p erti e s f or t h e 
B SI D -III i n 2 2 1  i nf a nt s i n t h e U nit e d Ki n g d o m a n d Ir el a n d. T h e n or m e d-s c or e s d eri v e d 
fr o m t h e B SI D -III ar e u s e d i n cli ni c al pr a cti c e t o d et e ct i nf a nt s wit h d e v el o p m e nt al 
d el a y s, a s w ell a s t o e v al u at e d e v el o p m e nt al pr o gr e s s a n d t h e i m p a ct of t h er a p e uti c 
i nt er v e nti o n s. I n a d diti o n, t h e g e n er at e d T- s c or e s  a n d p er c e ntil e s f or d e v el o p m e nt al 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
7 4 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
7 5 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
a c hi e v e m e nt all o w dir e ct cli ni c al c o m p ari s o n of a n y st a bili z ati o n of d e cli n e or 
i m pr o v e m e nt a g ai n st n or m all y d e v el o pi n g c hil dr e n.
T h e B SI D c o n si st s of a c or e b att er y of fi v e s c al e s. T hr e e s c al e s ( c o g niti v e, m ot or, 
l a n g u a g e) ar e a d mi ni st er e d wit h c hil d i nt er a cti o n a n d t w o s c al e s (s o ci al -e m oti o n al , 
a d a pti v e b e h a vi or) ar e c o n d u ct e d wit h p ar e nt q u e sti o n n air e s. T h e B SI D -III al s o i n cl u d e s 
a B e h a vi or O b s er v ati o n I n v e nt or y, a s e p ar at e s c al e f or v ali d ati n g e x a mi n er a n d p ar e nt 
p er c e pti o n s of t h e c hil d’ s r e s p o n s e s.
I n t hi s st u d y, t h e Gr o s s M ot or s c al e of t h e B SI D -III will b e u s e d a s a n o ut c o m e m e a s ur e 
t o a s s e s s att ai n m e nt of m ot or mil e st o n e s; ot h er B SI D -III s c al e s will n ot b e u s e d. T h e 
t e st, w hi c h i s e x p e ct e d t o t a k e a b o ut 2 5 mi n ut e s t o b e a d mi ni st er e d i n t hi s p o p ul ati o n, i s 
a s s e s si n g t h e f oll o wi n g: st ati c p o siti o ni n g ( e. g., h e a d c o ntr ol, sitti n g), d y n a mi c 
m o v e m e nt i n cl u di n g l o c o m oti o n ( e. g.,
cr a wli n g), q u alit y of m o v e m e nt ( e. g., ki c ki n g), 
b al a n c e a n d m ot or pl a n ni n g.
C o n si d eri n g t h e p o p ul ati o n of t hi s st u d y, t h e t e st will b e a d mi ni st er e d i n a m o difi e d w a y 
c o m p ar e d t o t h e st a n d ar d a d mi ni str ati o n of t h e B SI D -III a s d e s cri b e d i n t h e B SI D -III
m a n u al, e. g., p ati e nt’ s a g e will n ot b e u s e d a s t h e st arti n g crit eri a f or t e sti n g a n d t h e 
or d er of it e m a d mi ni str ati o n m a y b e c h a n g e d. T h e st a n d ar di z e d i n str u m e nt kit will b e 
u s e d a n d t h e t e st will b e a d mi ni st er e d b y a n e x p eri e n c e d cli ni ci a n s p e cifi c all y tr ai n e d t o 
t h e t e st pr o c e d ur e s, w hi c h will b e d e s cri b e d i n a s e p ar at e m a n u al. If p o s si bl e, t h e s a m e 
a s s e s s or s h o ul d f oll o w t h e p ati e n t at all vi sits u p t o a n d i n cl u di n g W e e k 1 0 4.
All B SI D -III a s s e s s m e nt s p erf or m e d u p t o a n d i n cl u di n g Wee k 1 0 4 will b e 
vi d e o -r e c or d e d i n a st a n d ar di z e d m a n n er a n d c e ntr all y r e vi e w e d b y t w o i n d e p e n d e nt 
ce ntr al r e a d er s. T h e a s s e s s m e nt of t h e c e ntr al r e a d er s will b e u s e d f or t h e pri m ar y 
a n al y si s. T h e vi d e o s m a y al s o b e u s e d f or tr ai ni n g p ur p o s e s, if t h e p ar e nt s pr o vi d e 
c o n s e nt i n t h e I nf or m e d C o n s e nt F or m.
D uri n g t he o pe n -l a bel e xte nsi o n p h ase of t he st u d y, vi de o re c or di n g is o pti o n al. T he site 
e v al u at or will c o nti n ue t o assess t he p atie nts o n t he B SI D -III. Vi de o-re c or di n g is 
hi g hl y e n c o ur a ge d w he n a p atie nt a c hie ves ne w milest o nes. 
D uri n g t he o pe n -l a bel e xte nsi o n p h ase of t he st u d y, o nl y t he f oll o wi n g ite ms fr o m t he 
BI S D -III f ull gr oss m ot or s c ale will be assesse d:

He a d c o ntr ol:
–
Ite m 9 – C o ntr ols he a d w hile u pri g ht, 1 5 sec o n ds

R olli n g:
–
Ite m 1 4 – R olls fr o m si de t o b a c k
–
Ite m 2 0 – R olls fr o m b a c k t o si de



Sitti n g:
–
Ite m 1 6 – Sits wit h s u p p ort briefl y
–
Ite m 1 9 – Sits wit h s u p p ort 3 0 sec o n ds
–
Ite m 2 2 – Sits wit h o ut s u p p ort 5 sec o n ds
–
Ite m 2 6 – Sits wit h o ut s u p p ort 3 0 sec o n ds

St a n di n g
–
Ite m 3 3 – S u p p orts wei g ht
–
Ite m 4 0 – St a n ds al o ne

W al ki n g
–
Ite m 3 7 – W al ks wit h s u p p ort
–
Ite m 4 2 - W al ks al o ne
C hil dr e n' s H o s pit al of P hil a d el p hi a I nf a nt T e st of N e ur o m u s c ul ar Di s or d er s  
T h e C H O P -I N T E N D i s a m e a s ur e of m ot or f u n cti o n t h at w a s d e v el o p e d fr o m t h e T e st of 
I nf a nt M ot or P erf or m a n c e ( TI M P) s p e cifi c all y f or w e a k i nf a nt s wit h n e ur o m u s c ul ar 
di s e a s e. It i n cl u d e s b ot h a cti v e a n d eli cit e d r efl e xi v e m o v e m e nt ( 1 6  it e m s i n t ot al e a c h 
s c o r e d fr o m 0  t o 4 ), s u c h a s s p o nt a n e o u s m o v e m e nt of u p p er a n d l o w er e xtr e mit y, h a n d 
gr a s pi n g, r olli n g, h e a d c o ntr ol, a n d ot h er s. A t ot al s c or e i s c al c ul at e d b y s u m mi n g t h e 
it e m s c or e s wit h l o w er s c or e s i n di c ati n g gr e at er s e v erit y. T h e C H O P -I N T E N D 
d e m o n str at e s g o o d i ntr a - a n d i nt er-r at er r eli a bilit y i n T y p e  1  S M A p ati e nt s ( Gl a n z m a n 
et  al 2 0 1 0 ; Gl a n z m a n et al 2 0 1 1 ).
T h e C H O P -I N T E N D h a s b e e n u s e d i n s e v er al st u di e s i n  T y p e  1  S M A p ati e nt s, i n cl u di n g 
b ot h n o n- dr u g l o n git u di n al st u di e s, s u c h a s t h e P e di atri c N e ur o m u s c ul ar Cli ni c al 
R e s e ar c h n et w or k ( P N C R) ( Gl a n z m a n et al 2 0 1 0 ) a n d t h e N ati o n al I n stit ut e of 
N e ur ol o gi c al Di s e a s e s a n d Str o k e ( NI N D S) N e ur o N e xt n at ur al hi st or y st u di e s  i n c hil dr e n 
wit h T y p e  1  S M A ( K ol b et al 2 0 1 6 ), a n d i nt er v e nti o n al m e di ci n al pr o d u ct st u di e s, s u c h a s 
t h e I O NI S’ st u d y [ Cli ni c al Tri al s. g o v I d e ntifi er N C T 0 1 8 3 9 6 5 6]. Sc or e s o n t h e 
C H O P -I N T E N D ar e c orr el at e d wit h cli ni c al d e cli n e o v er ti m e, r e q uir e me nt f or v e ntil ati o n 
a n d a s s o c i ati o n wit h S M N 2 c o p y n u m b er ( Gl a n z m a n et al 2 0 1 1 ).
I n t hi s st u d y, t h e C H O P -I N T E N D will b e a d mi ni st er e d b y a n e x p eri e n c e d a n d s p e cifi c all y 
tr ai n e d cli ni ci a n. Pl e a s e r ef er t o t h e C H O P -I N T E N D t e st a d mi ni str ati o n m a n u al f or 
s p e cifi c i n str u c ti o n r e g ar di n g a d mi ni str ati o n. T h e a s s e s s m e nt will b e vi d e o -r e c or d e d f or 
q u alit y c o ntr ol p ur p o s e s a s  i n di c at e d i n t h e Tr ai ni n g a n d Q u alit y a s s ur a n c e m et h o d ol o g y 
m a n u al.  If p o s si bl e, t h e s a m e a s s e s s or s h o ul d f oll o w t h e p ati e nt at all vi sits  u p t o a n d 
i n cl u di n g W e e k 1 0 4.  T h e vi d e o s m a y al s o b e u s e d f or tr ai ni n g p ur p o s e s, if t h e p ar e nt s 
pr o vi d e c o n s e nt  i n t h e Inf or m e d C o n s e nt F or m .
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
7 6 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


H a m m er s mit h I nf a nt N e ur ol o gi c al E x a mi n ati o n –  M o d ul e 2
T h e H a m m er s mit h I nf a nt N e ur ol o gi c al E x a mi n ati o n ( HI N E) i s a n e u r ol o gi c e x a mi n ati o n 
i niti all y d e si g n e d t o e v al u at e i nf a nt s b et w e e n 2  m o nt h s  a n d 2 4  m o nt h s  of a g e. It i s a 
si m pl e a n d s c or a bl e m et h o d t h at i n cl u d e s  2 6  it e m s a s s e s si n g diff er e nt a s p e ct s of 
n e ur ol o gi c al e x a mi n ati o n s s u c h a s cr a ni al n er v e s, p o st ur e, m o v e m e nt s, t o n e, a n d 
r efl e x e s. T h e pr o f or m a pr o vi d e s i n str u cti o n s f or p erf or mi n g t he i n di vi d u al it e m s a n d 
di a gr a m s t o ai d r e c or di n g. T h e HI N E i s e a sil y p erf or m e d a n d a c c e s si bl e t o all cli ni ci a n s; 
it c a n b e c o m pl et e d i n  5  t o 1 0  mi n ut e s. It h a s s h o w n g o o d  i nt er- ob s er v er  r eli a bilit y, e v e n 
i n i n e x p eri e n c e d st aff.
I n t hi s st u d y, o nl y M o d ul e  2  of t h e HI N E, w hi c h e v al u at e s  8  d e v el o p m e nt  mil e st o n e s, will 
b e a s s e s s e d.
4. 6. 1. 1 5  
R e s pir at or y  Pl et h ys m o gr a p h y
R e s pir at or y I n d u c ti v e Pl et h y s m o gr a p h y ( R P) will b e u s e d t o m e a s ur e t h e d e gr e e of 
s y n c hr o n y b et w e e n di a p hr a g m ati c ( a b d o mi n al) br e at hi n g a n d t h or a ci c c a g e - dri v e n 
br e at hi n g.
I n c hil dr e n wit h S M A, t h e w e a k n e s s of i nt er c o st al m u s cl e s l e a d s t o a s y n c hr o n y of t h e 
t h or a x wit h t h e di a p hr a g m (t h e m ot or i n n er v ati o n t o t h e p hr e ni c n er v e i s r el ati v el y s p ar e d 
i n S M A) a n d e v e nt u all y i n effi ci e nt a n d cli ni c all y e vi d e nt p ar a d o xi c al br e at hi n g p att er n s. 
T h e d e gr e e of s y n c hr o n y b et w e e n t h e m o v e m e nt of t h e c h e st w all a n d a b d o m e n d uri n g 
t h e r e s pirat or y c y cl e c a n b e e x pr e s s e d a s t h e p h a s e a n gl e b et w e e n t h e t w o 
c o m p art m e nt s a n d m e a s ur e d i n a n o n -in v a si v e m a n n er b y pl a ci n g t w o R P b a n d s ar o u n d 
t h e t h or a x a n d a b d o m e n.
I n p ar a d o xi c al br e at hi n g, t h e p h a s e a n gl e () i s r e v er s e d c o m p ar e d t o t h e n or m al 
v e nti l ati o n c y cl e. I n a d diti o n t o , R P all o w s e sti m ati o n of a n u m b er of ot h er cli ni c all y 
si g nifi c a nt p ar a m et er s i n cl u di n g ti d al v ol u m e, w or k of br e at hi n g a n d e pi s o d e s of 
h y p o p n e a or a p n e a. I m pr o v e m e nt i n t h e s e p ar a m et er s w o ul d i n di c a t e 
tr e at m e nt- as s o ci at e d i m p r o v e m e nt i n i nt er c o st al, s u b c o st al a n d tr a n s v er s e t h or a ci c 
m u s cl e s, a s w ell a s t h e s err at u s a n d p ar a s pi n al m u s cl e s. T h e s e m e a s ur e s w o ul d b e 
e x p e ct e d t o pr e di ct a cli ni c all y si g nifi c a nt i m p a ct i n r e s pir at or y m or bi dit y a n d m ort alit y, 
a s w e ll a s a m eli or ati n g pr o gr e s si o n of ort h o p e di c  d ef or mit y ( s c oli o si s, t h or a ci c c a g e 
c oll a p s e).
I n t hi s st u d y, R P will b e a d mi ni st er e d b y tr ai n e d p er s o n n el f oll o wi n g i n str u cti o n s i n t h e 
R P m a n u al. T h e d at a will b e r e vi e w e d, pr o c e s s e d a n d a n al y z e d b y a c e ntr al r e a d er a n d 
t h e o ut co m e u s e d f or a n al y si s.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
7 7 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


4. 6. 1. 1 6  
C o m p o u n d M u s cl e A cti o n P ot e nti al
El e ctr o p h y si ol o gi c al o ut c o m e m e a s ur e s o bt ai n e d t hr o u g h n er v e c o n d u cti o n st u di e s, i n 
p arti c ul ar C M A P, pr o vi d e u ni q u e i nf or m ati o n r e g ar di n g t h e f u n cti o n of t h e m ot or u nit, 
w h i c h i s c e ntr al i n t h e p at h o ph y si ol o gi c al pr o c e s s i n S M A.
C M A P, w hi c h i s  t h e m e a s ur e of t h e t ot al o ut p ut of t h e m ot or u nit s t h at s u p pl y a p arti cul ar 
m u s cl e, h a s b e e n e xt e n si v el y u s e d t o m o nit or di s e a s e pr o gr e s si o n i n a m y otr o p hi c l at er al 
s cl er o si s ( A L S) a n d S M A; a n u m b er of st u di e s h a v e s h o w n t h at it c orr el at e s wit h di s e a s e 
s e v erit y, f u n cti o n al st at u s,  S M N 2 c o p y n u m b er, a n d a g e ( L e w elt et al 2 0 1 0; Fi n k el  2 0 1 3; 
K ol b et al 2 0 1 6). A c c or di n gl y, C M A P m a y h a v e p ot e nti al a s a pr e di cti v e a n d pr o g n o st i c 
bi o m ar k er of cli ni c al d e cli n e i n S M A, a n d p o s si bl y a s a n e arl y m e a s ur e of m u s cl e 
r ei n n er v ati o n i n S M A cli ni c al tri al s.
I n P art 1, m a xi m u m ul n ar C M A P a m plit u d e a n d ar e a will b e o bt ai n e d b y r e c or di n g fr o m 
t h e a b d u ct or di giti mi ni mi  m u s cl e f oll o wi n g ul n ar n er v e sti m ul ati o n at t h e wri st. I n P art  2, 
m a xi m u m ul n ar C M A P a m plit u d e a n d ar e a will b e o bt ai n e d b y sti m u l ati n g t h e ul n ar n er v e 
at t h e el b o w  or wrist  a n d r e c or di n g f r o m t h e a b d u ct or di giti mi ni mi m u s cl e. T h e 
sti m ul ati o n l o c ati o n f or e a c h p atie nt s h o ul d re m ai n c o nsiste nt t hr o u g h o ut t he st u d y. 
T h e l at er alit y of m u s cl e gr o u p s st u di e d wit h C M A P m u st r e m ai n c o n si s t e nt f or e a c h 
s u bj e ct t hr o u g h o ut t h e st u d y.
M a xi m u m v al u e s f or b ot h n e g ati v e p e a k ( N P) a m plit u d e a n d N P ar e a will b e  o bt ai n e d 
fr o m a t ot al of 3 – 5  G 1 el e ctr o d e pl a c e m e nt s, u si n g t h e s u p pli e d di s p o s a bl e s urf a c e 
el e ctr o d e s.
I nf a nt s will b e di str a ct e d u si n g st a n d ar d t e c h ni q u e s r e g ul arl y u s e d at t h e sit es f or 
p e di atri c el e c tr o m y o gr a p h y st u di e s. 
Ori gi n al C M A P w a v ef or m s will b e pri nt e d a n d f a x e d/ e m ail e d t o t h e  d at a - co or di n ati n g  
c e nt er wit h t h e c o m pl et e d cli ni c al r e s e ar c h f or m f or i n d e p e n d e n t r e vi e w. C M A P 
a m plit u d e a n d N P ar e a d at a fr o m all sit e s will b e s cr e e n e d b y a  si n gl e r e vi e w er t o e n s ur e 
stri ct a d h er e n c e t o pr ot o c ol a n d a s c ert ai n a c c ur a c y of pl a c e m e nt of m ar k er s f or 
a m plit u d e a n d ar e a m e a s ur e m e nt s.
C M A P d at a will b e e x cl u d e d f or o n e or m or e of t h e f oll o wi n g r e a s o n s: 1 ) 3 t e c h ni c all y 
a d e q u at e w a v ef or m s a s s o ci at e d wit h u ni q u e G 1 el e ctr o d e pl a c e m e nt, 2)  el e ctri c al artif a ct 
t h at pr e cl u d e s a c c ur at e a m plit u d e a n d/ or ar e a m e a s ur e m e nt s, a n d/ or 3) i niti al p o siti v e 
d efl e cti o n t h at e x c e e d s o n e -thir d of t h e n e g ati v e p e a k a m plit u d e.
C M A P will b e p erf or m e d  b y a n el e c tr o p h y si ol o gi st e x p eri e n c e d i n t h e a s s e s s m e nt of 
p e di atri c p ati e nt s. A s m u c h a s p o s si bl e, t h e s a m e  p er s o n s h o ul d p erf or m all t h e 
a s s e s s m e nt s f or e a c h p ati e nt t hr o u g h o ut t h e st u d y.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
7 8 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


4. 6. 1. 1 7  
Cli ni ci a n - Re p ort e d R e s pir at or y  a n d S w all o w i n g It e m s 
I n or d er t o c a pt ur e c h a n g e s i n  a n i nf a nt’ s r e s pir at or y f u n cti o n a n d a bilit y t o s w all o w, a 
r a n g e of cli ni c al d o m ai n l e v el  it e m s will b e c o m pl et e d b y  t h e I n v e sti g at or. T h e fir st it e m i s 
a cli ni c al gl o b al i m pr e s si o n of c h a n g e ( C GI - C), w hi c h i s a si n gl e it e m m e a s ur e of c h a n g e 
u si n g s e v e n r e s p o n s e o pti o n s: “ V er y m u c h i m pr o v e d”, “ M u c h i m pr o v e d”, “ Mi ni m all y 
i m pr o v e d”, “ N o c h a n g e”, “ Mi ni m all y w or s e”, “ M u c h w or s e”, “ V er y m u c h w or s e”. It i s a 
wi d el y u s e d e n d p oi nt i n cli ni c al tri al s a cr o s s a v ari et y of di s e a s e ar e a s.  T h e I n v e sti g at or  
will s c or e p ati e nt s u si n g t hi s s c al e i n P art 2 at  t h e W e e k 5 2  vi sit b a s e d o n t h eir 
i m pr e s si o n of c h a n g e i n t h e p ati e nt’ s r e s pir at or y f u n cti o n si n c e b a s eli n e. T h e I n v e sti g at or 
will al s o s c or e t h e  i n di vi d u al’ s s w all o wi n g a bilit y i n t h e s a m e m a n n er. I n v e sti g at ors will 
al s o b e a s k e d t o r at e h o w t h e i n di vi d u al’ s r e s pir at or y f u n cti o n a n d s w all o wi n g a bilit y 
c o m p ar e t o a si mil arl y a g e d u ntr e at e d i nf a nt wit h  T y p e 1 S M A  a n d t y pi c all y d e v el o pi n g 
i nf a nt s, o n a 7 - poi nt s c al e r a n gi n g fr o m “ v er y m u c h b ett er” t o “ v er y m u c h w or s e” . Fi n all y, 
t h e I nv e sti g at or  will b e a s k e d t o r at e t h e i nf a nt’ s c urr e nt r e s pir at or y f u n cti o n a n d 
s w all o wi n g a bilit y  u si n g a 0 1 0 n u m eri c al r e s p o n s e r ati n g s c al e.
4. 6. 1. 1 8  
P ar e nt/ C ar e gi v er - Re p ort e d O ut c o m e s
T h e i nf a nt/t o d dl er q u alit y of lif e  q u e sti o n n air e  - s h ort  f or m 4 7 -it e m v er si o n  (IT Q O L - SF 4 7 ) 
i s a p ar e nt - co m pl et e d  m e a s ur e t h at w a s d e v el o p e d t o a s s e s s h e alt h st at u s a n d 
h e alt h -rel at e d q u alit y of lif e ( H R Q o L) of c hil dr e n b et w e e n  2  m o nt h s  a n d 5  y e ar s  ol d 
( La n d gr af et al 2 0 1 3 ). It al s o a s s e s s e s t h e H R Q o L of t h e p ar e nt. It w a s a d a pt e d fr o m t h e 
l o n g er 9 7 -it e m d u e t o c o n c er n s a b o ut t h e l e n gt h of t h e q u e sti o n n air e a n d t h e s u b s e q u e nt 
b ur d e n o n t h e r e s p o n d e nt. F a ct or a n al y si s, st e p wi s e r e gr e s si o n a n d m ultitr ait  it e m-
s c ali n g a n al y si s  w er e c o n d u ct e d t o i nf or m it e m r e d u cti o n. T h e c o n c e pt u al r el e v a n c e a n d 
fit t o t h e c o n c e pt u al fr a m e w or k w er e al s o c o n si d er e d. T h e I T Q O L- SF 4 7  c o nt ai n s t hr e e 
si n gl e -it e m s c or e s ( O v er all H e alt h, C h a n g e i n H e alt h, a n d F a mil y C o h e si o n) a n d ei g ht 
m ulti -it e m d o m ain s ( P h y si c al A biliti e s [ 6 it e m s] , Gr o wt h a n d D e v el o p m e nt [ 5], B o dil y P ai n 
[ 2], T e m p er a m e nt a n d M o o d s [ 6], B e h a vi or [ 1 2], G e n er al H e alt h Per c e pti o n [ 5], P ar e nt -
E m oti o n al H e alt h [ 4] a n d P ar e nt - Tim e Li mit ati o n s [ 4]). It e m s ar e s c or e d u si n g a Li k ert -
t y p e s c al e wit h fi v e l e v el s ( e x c e pt P ar e nt - Ti m e li mit ati o n s w hi c h h a s 4  r e s p o n s e o pti o n s). 
W h er e a p pli c a bl e, it e m s c or e s ar e r e v er s e d s o t h at hi g h er s c or e s i n di c at e b ett er h e alt h. 
F or e a c h d o m ai n, it e m s ar e s u m m e d a n d c o n v ert e d t o a 0 ( w or st h e alt h)  - 1 0 0 ( b e st 
h e al t h) s c al e.
T h e I T Q O L h a s b e e n u s e d t o a s s e s s t h e p ar e nt -re p ort e d H R Q o L of y o u n g c hil dr e n wit h 
a v ari et y of c o n diti o n s, i n cl u di n g r e s pir at or y di s e a s e s, p ai n, a n d T y p e  1 
n e ur ofi br o m at o si s ( R a at et al 2 0 0 7 ; M o h a n g o o et al 2 0 1 2 ; O o st e n bri n k et al 2 0 0 7 ; 
S p uij br o e k et al 2 0 1 1). G o o d e vi d e n c e of r eli a bilit y a n d v ali dit y h a s b e e n d e m o n str at e d 
f or t h e I T Q O L- SF 4 7 ( u si n g s a m pl e s of h e alt h y i n di vi d u al s, p ati e nt s wit h b ur n i nj ur y, a n d 
p ati e nt s wit h a b d o mi n al p ai n) ( L a n d gr af et al 2 0 1 3 ).
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
7 9 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


T hr o u g h o ut t h e st u d y, t h e  s a m e p a r e nt/ c ar e gi v er s h o ul d c o m pl et e t h e I T Q O L-S F 4 7.  If 
t h e p ar e nt/ c ar e gi v er d o e s n ot s p e a k t h e l a n g u a g e s p o k e n at t h e sit e, t h e I T Q O L-S F 4 7 
will b e tr a n sl at e d i nt o t h e p ar e nt/ c ar e gi v er ’s l a n g u a g e. A tr a n s l at or s h o ul d n ot b e u s e d t o 
a d mi ni st er t h e I T Q O L -S F 4 7.
4. 6. 2  
Ti mi n g of St u d y  As s e s s m e nt s
4. 6. 2. 1  
S cr e e ni n g a n d Pr etr e at m e nt A s s e s s m e nt s
Pri or t o o bt ai ni n g p ati e nt i nf or m e d c o n s e nt f or p arti ci p ati o n i nt o t h e st u d y, i n v e sti g ati o n al 
sit e s will b e r e q uir e d t o c o m pl et e a n d s u b mit t o t h e S p o n s or or  t h e c o ntr a ct e d C o ntr a ct 
R e s e ar c h Or g a ni z ati o n ( C R O) a S cr e e ni n g N otifi c ati o n F or m. B a s e d o n t h e a v ail a bilit y 
of  s cr e e ni n g/ e nr oll m e nt all o c ati o n s i n t h e c urr e nt c o h ort, t h e S p o n s or or C R O will n otif y 
t h e sit e a s t o w h et h er t h e p ati e nt s cr e e ni n g c a n or c a n n ot pr o c e e d at t h at curr e nt ti m e.  
T hi s will e n s ur e t h at t h e r e cr uit m e nt t ar g et s f or e a c h c o h ort a r e a d h er e d t o a s p er t hi s 
pr ot o c ol.
Wr itt e n i nf or m e d c o n s e nt f or p arti ci p ati o n i n t h e st u d y m u st b e o bt ai n e d ( b y t h e p ar e nt or 
l e g all y a ut h ori z e d r e pr e s e nt ati v e) b ef or e p erf or mi n g a n y st u d y -s p e cifi c  s cr e e ni n g t e st s 
or e v al u ati o n s. I nf or m e d C o n s e nt F or m s f or e nr oll e d p ati e nt s a n d f or p ati e nt s w h o ar e 
n ot s u b s e q u e ntl y e nr oll e d ( s cr e e n f ail ur e s) will b e m ai nt ai n e d at t h e st u d y sit e.
All s cr e e ni n g a n d pr e -tr e at m e nt a s s e s s m e nt s m u st b e c o m pl et e d a n d r e vi e w e d t o 
c o nfir m t h at p ati e nt s m e et all eli gi bilit y crit eri a. T h e I n v e st i g at or will m ai nt ai n a s cr e e ni n g 
l o g t o r e c or d d et ail s of all p ati e nt s s cr e e n e d a n d t o c o nfir m eli gi bilit y or r e c or d r e a s o n s 
f or s cr e e ni n g f ail ur e.
I n P art 1, a n Eli gi bilit y S cr e e ni n g F or m ( E S F) d o c u m e nti n g t h e I n v e sti g at or’ s 
a s s e s s m e nt of e a c h s cr e e n e d p ati e nt wit h r e g ar d t o t h e pr ot o c ol’ s i n cl u si o n a n d 
e x cl u si o n crit eri a i s t o b e c o m pl et e d b y t h e I n v e sti g at or, s e nt t o t h e S p o n s or a n d k e pt at 
t h e i n v e sti g ati o n al sit e.
S cr e e ni n g a n d  pr e -tr e at m e nt a s s e s s m e nt s will b e p erf or m e d wit hi n 3 0 d a y s  pri or t o 
D a y  1. A b br e vi at e d r e s cr e e ni n g ( writt e n i nf or m e d c o n s e nt, m e di c al hi st or y, p h y si c al 
e x a mi n ati o n, b o d y w ei g ht, s af et y l a b or at or y t e st s, a n d i n cl u si o n/ e x cl u si o n crit eri a) m a y 
b e all o w e d u n d er cir c u m st a n c e s w h er e t h e p ati e nt h a s p a s s e d s cr e e ni n g b ut c o ul d n ot 
b e e nr oll e d wit hi n t h e 3 0 -d a y s cr e e ni n g wi n d o w d u e t o a st u d y h alt, l o gi sti c al, p er s o n al, 
or t e c h ni c al r e a s o n s. At n o ti m e s h o ul d t h e d ur ati o n b et w e e n t h e ori gi n al s cr e e ni n g vi sit 
a n d t h e a b br e vi at e d r e s cr e e ni n g vi sit e x c e e d 3  m o nt h s. A b br e vi at e d r e s cr e e ni n g will 
o nl y b e p er mitt e d i n c a s e s w h er e t hi s p o s e s n o s af et y ri s k t o t h e p ati e nt.
P ati e nt s c a n n ot c o m m e n c e e nr ol m e nt pr o c e d ur e u ntil all t h e e ntr y crit eri a h a v e b e e n 
f ulfill e d. Wh er e t h e cli ni c al si g nifi c a n c e of a n a b n or m al s cr e e ni n g t e st r e s ult (l a b or at or y  
or a n y ot h er t e st s) i s  c o n si d er e d u n c ert ai n, t h e t e st s h o ul d b e r e p e at e d t o c o nfir m th e 
r e s ult.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
8 0 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


4. 6. 2. 2  
A s s e s s m e nt s d uri n g Tr e at m e nt
U n d er n o cir c u m st a n c e s will  p ati e nt s w h o e nr oll i n t hi s st u d y a n d h a v e c o m pl et e d 
tr e at m e nt a s s p e cifi e d, b e p er mitt e d t o b e all o c at e d a n e w p ati e nt n u m b er an d r e -e nr oll 
i n t h e st u d y.
T h e p ati e nt st u d y vi sit s w h e n effi c a c y a s s e s s m e nt s ar e p erf or m e d ( s e e S o A f or 
ti m e-p oi nt s; A p p e n di x 1 , A p p e n di x  2 ) will b e t h e m o st e xt e n si v e vi sit s, i n cl u di n g all 
effi c a c y a s s e s s m e nt s i n a d diti o n t o p h ar m a c o ki n eti c s, p h ar m a c o d y n a mi c s, f ull p h y si c al 
e x a mi n ati o n, a n d s af et y a s s e s s m e nt s. A c c or di n gl y, t h e s e vi sit s  m a y b e c o n d u ct e d eit h er 
a s a o n e -d a y  vi sit or o v er  t w o d a y s, w hi c h e v er i s pr ef err e d b y t h e p ar e nt s or c ar e gi v er 
a n d p o s si bl e f or t h e cli ni c al sit e. F or t h e s e vi sit s,  t hr e e bl o c k s of a s s e s s m e nt s h a v e b e e n 
i d e ntifi e d t h at s h o ul d i d e all y b e c o n d u ct e d i n t h e or d er d e s cri b e d i n  T a bl e  2 , fl e xi bilit y 
b ei n g gi v e n t o t h e sit e t o, wit hi n e a c h of t h e s e bl o c k s, p erf or m t h e a s s e s s m e nt s i n a n y 
or d er. S h o ul d t hi s n ot b e p o s si bl e, w h at i s  criti c al i s t h at i n Bl o c k s  1  a n d 2, t h e B SI D -III 
a n d C H O P -I N T E N D ar e al w a y s pr e c e d e d b y a br e a k of at l e a st 1 5  mi n ut e s . A d diti o n al 
br e a k s ar e r e c o m m e n d e d at a n y ot h er ti m e a s a p pr o pri at e f or e a c h p ati e nt. T h e br e a k s 
c a n i n cl u d e n ur si n g/f e e di n g of t h e p ati e nt. It i s al s o r e c o m m e n d e d t h at f or a si n gl e 
p ati e nt, a s s e s s m e nt s ar e c o n d u ct e d i n t h e s a m e or d er t hr o u g h o ut t h e tri a l.
Bl o c k  3  m a y b e p erf or m e d t h e m or ni n g of t h e d a y pr e c e di n g Bl o c k  1 or t h e n e xt d a y if 
t h e I n v e sti g at or d et er mi n e s t h at t hi s i s r e q uir e d f or t h e p ati e nt or i s pr ef err e d b y t h e 
p ar e nt s/ c ar e gi v er s. H o w e v er, t h e or d er of a s s e s s m e nt s s h o ul d b e m ai nt ai n e d f or t h e 
e ntir e t y of t h e st u d y. 
M ot or f u n cti o n a n d m ot or milest o ne assess me nts ( B SI D -III, C H O P-I N T E N D, HI N E-2) 
m a y be del a ye d t o a n ot her ti me or d a y wit hi n t he visit wi n d o w if, i n t he o pi ni o n of t he 
i n vesti g at or or p h ysi ot her a pist, t he p atie nt is u n c o o per ati ve.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
8 1 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


T a bl e 2
Or d er a n d Bl o c k s of A s s e s s m e nt s at Vi sit s W h e n Effi c a c y  
M e a s ur e m e nt s Ar e P erf or m e d , u p t o a n d I n cl u di n g W e e k 1 0 4 a
Bl o c k 1

E C G, vit al si g n s, p h y si c al e x a mi n ati o n (i n cl u di n g w ei g ht)
B R E A K

B SI D -III
B R E A K

C H O P -I N T E N D

HI N E - 2
B R E A K

Bl o o d s a m pl e ( or i n s erti o n of c at h et er)

D o s e a d mi ni str ati o n
B R E A K
Bl o c k 2

R P

I nf a nt T o d dl er Q u alit y of Lif e Q u e sti o n n air e
B R E A K

C M A P
B R E A K
Bl o c k 3
O p ht h al m ol o gi c al e x a mi n ati o n
a
After t he Wee k 1 0 4 visit, i n t he o pe n -l a bel e xte nsi o n p h ase of t he st u d y, R P a n d C M A P are 
n ot perf or me d , a n d o nl y sele cte d ite ms of t he B SI D-III are perf or me d. C o nti n ue t o use t he 
Bl o c k 1 or der as a re c o m me n d ati o n.
W h e n bl o o d s a m pl e s ar e s c h e d ul e d f or t h e s a m e n o mi n al ti m e a s ot h er a s s e s s m e nt s 
t h e f oll o wi n g or d er s h o ul d b e f oll o w e d:
1. 
1 2 -l e a d E C G s
2.
bl o o d pr e s s ur e
3.
bl o o d s a m pl e s.
4. 6. 2. 3  
A s s e s s m e nt s at  St u d y C o m pl eti o n/ E arl y  Wit h dr a w al Vi sit  
P ati e nt s w h o  c o m pl et e t h e st u d y or  di s c o nti n u e st u d y dr u g e arl y will b e a s k e d t o r et ur n 
t o t h e cli ni c f or a st u d y c o m pleti o n/e arl y wit h dr a w al visit  a s s h o w n i n t h e S o A
(A p p e n di x 1 , A p p e n di x  2 ).
4. 6. 2. 4  
F oll o w -U p -A s s e s s m e nt s
A  f oll o w-u p p h o ne c all s h o ul d occ ur 3 0 d a ys  a ft er t h e st u d y c o m pl eti o n/ e arl y 
wit h dr a w al visit  t o c olle ct i nf or m ati o n o n a d v er s e e v e nt s  a n d use of res pir at or y 
s u p p ort a s o utli n e d i n S e cti o n s  5. 5  a n d 5. 6  a n d t he  S o A ( A p pe n di x 1 , A p pe n di x  2 ).
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
8 2 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


4. 6. 3
Pri oriti z ati o n Or d er f or Bl o o d S a m pl e s
Ti m e -p oi nt s f or bl o o d s a m pl e s ar e i n di c at e d i n t h e S o A ( A p p e n di x 1 , A p p e n di x 2 ). 
H o w e v er, s h o ul d t h e t ot al bl o o d v ol u m e t o b e c oll e ct e d at a n y ti m e -p oi nt a c c or di n g t o 
t hi s S o A e x c e e d 1. 5 m L/ k g or t h e v ol u m e c oll e ct e d o v er a n y 8- w e e k p eri o d t hr o u g h o ut 
t h e st u d y e x c e e d 4.5 m L/ k g, t h e pri oriti z ati o n or d er i n di c at e d i n T a bl e 3 b el o w s h o ul d b e 
f oll o w e d.
T a bl e 3
Pri oriti z ati o n Or d er f o r Bl o o d S a m pl e s
1
A n y s af et y l a b or at or y s a m pl e s ( s c h e d ul e d or u n s c h e d ul e d a n d p erf or m e d at 
t h e di s cr eti o n of t h e I n v e sti g at or).
2
P K s a m pl e s, i n cl u di n g a s s e s s m e nt of fr e e fr a cti o n.
3
S a m pl e s f or S M N pr ot ei n l e v el s.
4
S a m pl e s f or i n vi v o s pli ci n g m o difi c ati o n of S M N 2 m R N A.
4. 7
P A TI E N T, S T U D Y, A N D SI T E DI S C O N TI N U A TI O N
4. 7. 1
P ati e nt Di s c o nti n u ati o n
T h e I n v e sti g at or h a s t h e ri g ht t o di s c o nti n u e a p ati e nt fr o m ri s di pl a m or wit h dr a w a 
p ati e nt fr o m t h e st u d y at a n y ti m e. I n a d diti o n, t h e p ar e nt( s) or c ar e gi v er h a v e t h e ri g ht t o 
v ol u nt aril y di s c o nti n u e st u d y dr u g or wit h dr a w t h e p ati e nt fr o m t h e st u d y at a n y ti m e f or 
a n y r e a s o n. R e a s o n s f or di s c o nti n u ati o n of st u d y dr u g or wit h dr a w al fr o m t h e st u d y m a y 
i n cl u d e, b ut ar e n ot li mit e d t o, t h e f oll o wi n g:

T h e p ar e nt or c ar e gi v er’ s wit h dr a w al of c o n s e nt at a n y ti m e.

A n y m e di c al c o n diti o n t h at t h e I n v e sti g at or or S p o n s or d et er mi n e s m a y j e o p ar di z e
t h e p ati e nt’ s s af et y if h e or s h e c o nti n u e s i n t h e st u d y.

I n v e sti g at or or S p o n s or d et er mi n e s it i s i n t h e b e st i nt er e st of t h e p ati e nt.

P ati e nt n o n -c o m pli a n c e (i n cl u di n g st u d y dr u g a d mi ni str ati o n a s r e c or d e d i n t h e
p ati e nt’ s di ar y).
4. 7. 1. 1
Di s c o nti n u ati o n fr o m St u d y  Dr u g
P ati e nt m u st di s c o nti n u e st u d y dr u g if t h e y e x p eri e n c e a n y of t h e f oll o wi n g:

O p ht h al m ol o g i c al or ot h er e v e nt s a s d e s cri b e d i n S e cti o n 5. 2. 3 .

U n a bl e t o c o nti n u e t o c o m pl y wit h st u d y r e q uir e m e nt s .
F or p ati e nt s w h o di s c o nti n u e st u d y dr u g pr e m at ur el y, t h eir p ar e nt s or c ar e gi v er will b e 
a s k e d t o r et ur n wit h t h e p ati e nt t o t h e cli ni c f or a  st u d y c o m pl eti o n/ e arl y wit h dr a w al vi sit 
( S e cti o n 4. 6. 2. 3 ). T h e pri m ar y r e a s o n f or pr e m at ur e st u d y dr u g di s c o nti n u ati o n s h o ul d 
b e d o c u m e nt e d o n t h e a p pr o pri at e e C R F .
P ati e nt s w h o di s c o nti n u e st u d y dr u g pr e m at ur el y will n ot b e r e pl a c e d i n P art  2, b ut  m a y 
b e r e pl a c e d i n  P art  1 , if t h e r e a s o n f or wit h dr a w al i s n ot r el at e d t o a s af et y fi n din g.
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8 4 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
If a p ati e nt n e e d s t o st o p a d mi ni str ati o n of st u d y dr u g ( e. g., i m m e di at e n e e d f or s ur g er y, 
r e q uir e d tr e at m e nt wit h a dr u g k n o w n t o or s u s p e ct e d t o h a v e a n i nt er a cti o n wit h 
ri s di pl a m, et c.), t h e i n v e sti g at or m u st di s c u s s t h e sit u ati o n wit h t h e S p o n s or t o d et er mi n e 
w h et h er t h e p ati e nt s h o ul d wit h dr a w fr o m t h e st u d y or t e m p or aril y di s c o nti n u e st u d y dr u g. 
4. 7. 1. 2
Wit h dr a w al fr o m St u d y
E v er y eff ort s h o ul d b e m a d e t o o bt ai n i nf o r m ati o n o n p ati e nt s w h o wit h dr a w fr o m t h e 
st u d y. T h e pri m ar y r e a s o n f or wit h dr a w al fr o m t h e st u d y s h o ul d b e d o c u m e nt e d o n t h e 
a p pr o pri at e e C R F.
P ati e nt s will n ot b e f oll o w e d f or a n y r e a s o n aft er c o n s e nt h a s b e e n wit h dr a w n.
P ati e nt s w h o wit h dr a w fr o m t h e st u d y f or s af et y r e a s o n s will n ot b e r e pl a c e d. P ati e nt s 
w h o wit h dr a w fr o m t h e st u d y f or ot h er r e a s o n s will n ot b e r e pl a c e d i n P art 2 , b ut m a y b e 
r e pl a c e d i n P art 1.
W h e n t h e p ar e nt s or c ar e gi v er v ol u nt aril y wit h dr a w s t h e p ati e nt fr o m t h e st u d y, or i s 
wit h dr a w n b y t h e I n v e sti g at or, s a m pl e s c oll e ct e d u ntil t h e d at e of wit h dr a w al will b e 
a n al y z e d, u nl e s s t h e p ar e nt s or c ar e gi v er s p e cifi c all y r e q u e st s f or t h e s e t o b e di s c ar d e d 
or l o c al l a w s r e q uir e t h eir i m m e di at e d e str u cti o n.
4. 7. 2
St u d y a n d Sit e Di s c o nti n u ati o n
T h e S p o n s or h a s t h e ri g ht t o t er mi n at e t hi s st u d y at a n y ti m e. R e a s o n s f or t er mi n ati n g 
t h e st u d y m a y i n cl u d e, b ut ar e n ot li mit e d t o, t h e f oll o wi n g:

T h e i n ci d e n c e or s e v erit y of a d v er s e e v e nt s i n t hi s or ot h er st u di e s i n di c at e s a
p ot e nti al h e alt h h a z ar d t o p ati e nt s.

P ati e nt e nr oll m e nt i s u n s ati sf a ct or y.
T h e S p o n s or will n otif y t h e I n v e sti g at or a n d H e alt h A ut h oriti e s if t h e st u d y i s pl a c e d o n 
h ol d, or if t h e S p o n s or d e ci d e s t o di s c o nti n u e t h e st u d y or d e v el o p m e nt pr o gr a m.
T h e S p o n s or h a s t h e ri g ht t o cl o s e d o w n a n d/ or r e pl a c e a sit e at a n y ti m e. R e a s o n s f or 
r e pl a ci n g a sit e m a y i n cl u d e, b ut ar e n ot li mit e d t o, t h e f oll o wi n g:

E x c e s si v el y sl o w r e cr uit m e nt.

P o or pr ot o c ol a d h er e n c e.

I n a c c ur at e or i n c o m pl et e d at a r e c or di n g.

N o n -c o m pli a n c e wit h t h e I nt er n ati o n al C o nf er e n c e o n H ar m o ni s ati o n (I C H) g ui d eli n e
f or G o o d Cli ni c al Pr a cti c e.


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5.
A S S E S S M E N T O F S A F E T Y
5. 1
S A F E T Y P A R A M E T E R S A N D D E FI NI TI O N S
S af et y a s s e s s m e nt s will c o n si st of m o nit ori n g a n d r e c or di n g a d v er s e e v e nt s, i n cl u di n g 
s eri o u s a d v er s e e v e nt s a n d n o n -s eri o u s a d v er s e e v e nt s of s p e ci al i nt er e st; 
m e a s ur e m e nt of pr ot o c ol -s p e cifi e d s af et y l a b or at or y a s s e s s m e nt s; m e a s ur e m e nt of 
pr ot o c ol -s p e cifi e d vit al si g n s, E C G s; a n d ot h er pr ot o c ol -s p e cifi e d t e st s t h at ar e d e e m e d 
criti c al t o t h e s af et y e v al u ati o n of t h e st u d y.
C ert ai n t y p e s of e v e nt s r e q uir e i m m e di at e r e p orti n g t o t h e S p o n s or, a s o utli n e d i n 
S e cti o n 5. 4 .
5. 1. 1
A d v er s e E v e nt s
A c c or di n g t o t h e I C H g ui d eli n e f or G o o d Cli ni c al Pr a cti c e, a n a d v er s e e v e nt i s a n y 
u nt o w ar d m e di c al o c c urr e n c e i n a cli ni c al i n v e sti g ati o n s u bj e ct a d mi ni st er e d a 
p h ar m a c e uti c al pr o d u ct, r e g ar dl e s s of c a u s al attri b uti o n. A n a d v er s e e v e nt c a n t h er ef or e 
b e a n y of t h e f oll o wi n g:

A n y u nf a v or a bl e a n d u ni nt e n d e d si g n (i n cl u di n g a n a b n or m al l a b or at or y fi n di n g),
s y m pt o m, or di s e a s e t e m p or all y a s s o ci at e d wit h t h e u s e of a m e di ci n al pr o d u ct,
w h et h er or n ot c o n si d er e d r el at e d t o t h e m e di ci n al pr o d u ct.

A n y n e w di s e a s e or e x a c er b ati o n of a n e xi sti n g di s e a s e ( a w or s e ni n g i n t h e
c h ar a ct er, fr e q u e n c y, or s e v erit y of a k n o w n c o n diti o n), e x c e pt a s d e s cri b e d i n
S e cti o n 5. 3. 5. 8 .

R e c urr e n c e of a n i nt er mitt e nt m e di c al c o n diti o n ( e. g., h e a d a c h e) n ot pr e s e nt at
b a s eli n e.

A n y d et eri or ati o n i n a l a b or at or y v al u e or ot h er cli ni c al t e st ( e. g., E C G, X ‑ r a y) t h at i s
a s s o ci at e d wit h s y m pt o m s or l e a d s t o a c h a n g e i n st u d y tr e at m e nt or c o n c o mit a nt
tr e at m e nt or di s c o nti n u ati o n fr o m st u d y dr u g.

A d v er s e e v e nt s t h at ar e r el at e d t o a pr ot o c ol -m a n d at e d i nt er v e nti o n, i n cl u di n g t h o s e
t h at o c c ur pri or t o a s si g n m e nt of st u d y tr e at m e nt ( e. g., s cr e e ni n g i n v a si v e
pr o c e d ur e s, s u c h a s bi o p si e s).
5. 1. 2
S eri o u s A d v er s e E v e nt s (I m m e di at el y  R e p ort a bl e t o t h e 
S p o n s or)
A s eri o u s a d v er s e e v e nt i s a n y a d v er s e e v e nt t h at m e et s a n y of t h e f oll o wi n g crit eri a:

F at al (i. e., t h e a d v er s e e v e nt a ct u all y c a u s e s or l e a d s t o d e at h).

Lif e -t hr e at e ni n g (i. e., t h e a d v er s e e v e nt, i n t h e vi e w of t he I n v e sti g at or, pl a c e s t h e
p ati e nt at i m m e di at e ri s k of d e at h).
T hi s d o e s n ot i n cl u d e a n y a d v er s e e v e nt t h at h a d it o c c urr e d i n a m or e s e v er e f or m or 
w a s all o w e d t o c o nti n u e mi g ht h a v e c a u s e d d e at h.

R e q uir e s or pr ol o n g s i n p ati e nt h o s pit ali z ati o n ( s e e S e cti o n 5. 3. 5. 9 ).



R e s ult s i n p er si st e nt or si g nifi c a nt di s a bilit y/i n c a p a cit y (i. e ., t h e a d v er s e e v e nt
r e s ult s i n s u b st a nti al di sr u pti o n of t h e p ati e nt’ s a bilit y t o c o n d u ct n or m al lif e
f u n cti o n s).

Si g nifi c a nt m e di c al e v e nt i n t h e I n v e sti g at or' s j u d g m e nt ( e. g., m a y j e o p ar di z e t h e
p ati e nt or m a y r e q uir e m e di c al/ s ur gi c al i nt er v e nti o n t o pr e v e nt o n e of t h e o ut c o m e s
li st e d a b o v e).
T h e t er m s “ s e v er e” a n d “ s eri o u s” ar e n ot s y n o n y m o u s. S e v erit y r ef er s t o t h e i nt e n sit y of 
a n a d v er s e e v e nt (r at e d a s mil d, m o d er at e, or s e v er e, or a c c or di n g t o a pr e -d ef i n e d 
gr a di n g crit eri a ( e. g., N ati o n al C a n c er I n stit ut e C o m m o n T er mi n ol o g y Crit eri a f or 
A d v er s e E v e nt s [ N CI C T C A E] crit eri a; S e cti o n 5. 3. 3 ); t h e e v e nt it s elf m a y b e of r el ati v el y 
mi n or m e di c al si g nifi c a n c e ( s u c h a s s e v er e h e a d a c h e wit h o ut a n y f urt h er fi n di n g s).
S e v erit y a n d s eri o u s n e s s n e e d t o b e i n d e p e n d e ntl y a s s e s s e d f or e a c h a d v er s e e v e nt 
r e c or d e d o n t h e e C R F.
S eri o u s a d v er s e e v e nt s ar e r e q uir e d t o b e r e p ort e d b y t h e I n v e sti g at or t o t h e S p o n s or 
i m m e di at el y (i. e., n o m or e t h a n 2 4 h o ur s aft er l e ar ni n g of t h e e v e nt; s e e S e cti o n 5. 4. 2 f or 
r e p orti n g i n str u cti o n s).
5. 1. 3
N o n -S eri o u s A d v er s e E v e nt s of S p e ci al I nt er e st (I m m e di at el y  
R e p ort a bl e t o t h e S p o n s or)
N o n -s eri o u s a d v er s e e v e nt s of s p e ci al i nt er e st ar e r e q uir e d t o b e r e p ort e d b y t h e 
I n v e sti g at or t o t h e S p o n s or i m m e di at el y (i. e., n o m or e t h a n 2 4 h o ur s af t er l e ar ni n g of t h e 
e v e nt; s e e S e cti o n 5. 4. 2 f or r e p orti n g i n str u cti o n s). A d v er s e e v e nt s of s p e ci al i nt er e st f or 
t hi s st u d y i n cl u d e t h e f oll o wi n g:

C a s e s of a n el e v at e d A L T or A S T i n c o m bi n ati o n wit h eit h er a n el e v at e d bilir u bi n or
cli ni c al j a u n di c e, a s d efi n e d i n S e cti o n 5. 3. 5. 6 .

S u s p e ct e d tr a n s mi s si o n of a n i nf e cti o u s a g e nt b y t h e st u d y dr u g, a s d efi n e d b el o w:
A n y or g a ni s m, vir u s, or i nf e cti o u s p arti cl e ( e. g., pri o n pr ot ei n tr a n s mitti n g
tr a n s mi s si bl e s p o n gif or m e n c e p h al o p at h y), p at h o g e ni c or n o n-p at h o g e ni c, i s
c o n si d er e d a n i nf e cti o u s a g e nt. A tr a n s mi s si o n of a n i nf e cti o u s a g e nt m a y b e
s u s p e ct e d fr o m cli ni c al s y m pt o m s or l a b or at or y fi n di n g s t h at i n di c at e a n i nf e cti o n i n
a p ati e nt e x p o s e d t o a m e di ci n al pr o d u ct. T hi s t er m a p pli e s o nl y w h e n a
c o nt a mi n ati o n of t h e st u d y dr u g i s s u s p e ct e d.
5. 2
S A F E T Y P L A N
T h e S af et y Pl a n c o n si d er s o b s er v ati o n s m a d e i n  n o n cli ni c al  i n v e sti g ati o n s, i n cl u di n g 
G o o d L a b or at or y Pr a cti c e ( G L P) t o xi c ol o g y st u di e s  i n r at s a n d c y n o m ol g u s m o n k e y s , a n d 
t h e o b s er v ati o n s m a d e i n cli ni c al tri al s. H y p ot h eti c al c o n si d erati o n s ar e i n cl u d e d i n t h e 
i nt er pr et ati o n of n o n cli ni c al  a n d cli ni c al d at a.  T h e e x p o s ur e c a p of  a m e a n A U C 0- 2 4 h , s s 
2 0 0 0  n g  h/ m L  c orr e s p o n d s t o t h e N O A E L i n t h e 3 9 - we e k t o xi c ol o g y st u d y i n 
c y n o m ol g u s - m o n k e y, i. e.,  t h e e x p o s ur e l e v el at w hi c h n o a d v er s e e v e nt s w er e o b s er v e d. 
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O nl y eff e ct s o n t h e t e st e s w er e o b s er v e d at t h o s e e x p o s ur e l e v el s i n a n ot h er st u d y i n 
r at s ( eff e ct s o n t e st es c o ul d n ot b e a s s e s s e d i n c y n o m ol g u s m o n k e y d u e t o s e x u al 
i m m at urit y of t h e a ni m al s ( Ri s di pl a m I n v e sti g at or’ s Br o c h ur e); p ar e nt s of m al e s u bj e ct s 
will b e i nf or m e d a c c or di n gl y. I n h u m a n s, t h e p a c h yt e n e st a g e of m ei o si s i s c o m pl et e d 
t o w ar d s t h e e n d of f et al d e v el o p m e nt. I n t hi s st u d y, eff e ct s o n t h e o o c yt e ar e n ot 
e x p e ct e d b e c a u s e pr e m at ur e i nf a nt s will n ot b e i n cl u d e d. I n j u v e nil e a n d a d ult r at t o xi cit y 
st u di e s a n d i n m o n k e y t o xi cit y st u di e s, t h er e w a s n o eff e ct o n f e m al e r e pr o d u cti v e 
or g a n s or f e m al e f erti lit y. A n y eff e ct s o n m ei o si s a n d o o c yt e m at ur ati o n will b e f urt h er 
i n v e sti g at e d i n a pr e-p o st n at al t o xi cit y st u d y i n r at s ( Ri s di pl a m I n v e sti g at or’ s Br o c h ur e).
T h e st o p pi n g r ul e s d et ail e d i n S e cti o n 5. 2. 4 will b e a p pli e d i n c a s e of s p e cifi c a d v er s e 
e v e nt s.
5. 2. 1
S af et y  Pr e c a uti o n s
B a s e d o n o b s er v e d t o xi cit y i n n o n cli ni c al st u di e s ( s e e R i s di pl a m I n v e sti g at or’ s Br o c h ur e
f or d et ail s), t h e f oll o wi n g s af et y pr e c a uti o n s s h o ul d b e f oll o w e d f or t hi s st u d y:

Eff e ct s o n h e m at ol o g y p ar a m et er s: r e g ul ar m o nit ori n g of h e m at ol o gi c al p ar a m et er s
will b e p erf or m e d .

P ar e nt s or c ar e gi v er will b e i nf or m e d t h at i n c a s e of vi s u al i m p air m e nt s , i nf a nt s
c o ul d pr e s e nt wit h e. g., s q ui nt, b e h a vi or al c h a n g e s ( e. g., f oll o w f a c e s or fi x ati o n
l o s s e s, n ot r e a c hi n g/ gr a b bi n g o bj e ct s, r u b bi n g of t h e e y e s).
5. 2. 2
S af et y  M o nit ori n g
B a s e d o n o b s er v e d t o xi cit y i n n o n cli ni c al st u di e s ( s e e R i s di pl a m I n v e sti g at or’ s Bro c h ur e 
f or d et ail s), t h e f oll o wi n g s af et y m o nit ori n g pl a n h a s b e e n c o m pil e d:

S p e ci alt y m e di c al d o ct or s ( o p ht h al m ol o gi st,) will b e i d e ntifi e d w h o will b e tr ai n e d i n
ri s di pl a m o b s er v e d n o n cli ni c al t o xi c ol o gi c al fi n di n g s pri or t o st u d y st art t o f oll o w -u p
q ui c kl y i n c a s e of a n y s u s pi ci o u s or a ct u al a d v er s e t o xi cit y e v e nt.

O p ht h al m ol o gi c al a s s e s s m e nt s (see Se cti o n 4. 6. 1. 8 f or det ails)

St o p pi n g r ul e s f or i n di vi d u al p ati e nt s h a v e b e e n d efi n e d t h at i n cl u d e crit eri a f or
tr e at m e nt di s c o nti n u ati o n i n c a s e of o p ht h al mi c e v e nt s ( S e cti o n 5. 2. 4 ).

F oll o w -u p p h o n e c all s ( a s p er t h e ti m e-p oi nt s i n t h e S o A; A p p e n di x 1 , A p p e n di x 2 ):
p ar e nt s or c ar e gi v er will b e c all e d b y t h e I n v e sti g at or or d e si g n e e t o m o nit or s af et y
a n d t ol er a bilit y w h e n n ot att e n di n g t h e cli ni c. A s s e s s m e nt s will i n cl u d e a d v er s e
e v e nt s, c o n c o mit a nt m e di c ati o n r e vi e w a n d si g nifi c a nt lif e e v e nt s.


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8 8 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
5. 2. 3
M a n a g e m e nt of S p e cifi c A d v er s e E v e nt s
S p e cifi c a d v er s e e v e nt s r el at e d t o o p ht h al m ol o gi c al a d v er s e e v e nt s s h o ul d b e m a n a g e d 
a s d e s cri b e d i n T a bl e 4 .
T a bl e 4
G ui d eli n e s f or M a n a gi n g S p e cifi c A d v er s e E v e nt s
E v e nt 
A cti o n t o t a k e
O p ht h al m ol o gi c al e v e nt
C o n s ult a n O p ht h al m ol o gi st a s q ui c kl y  a s p o s si bl e f or 
o p ht h al mi c e x a mi n ati o n a n d pr o vi d e a c o p y of t h e I C F 
a n d c o nt a ct pr o m ptl y t h e st u d y I n v e sti g at or. If fi n di n g s 
ar e u n u s u al, di s c o nti n u e st u d y tr e at m e nt u ntil t h e 
st u d y -tr ai n e d O p ht h al m ol o gi st at st u d y sit e a n d t h e 
st u d y I n v e sti g at or h a v e b e e n c o n s ult e d a n d t h e r e s ult s 
of a f ull o p ht h al mi c e x a mi n ati o n h a v e b e e n r e vi e w e d.
5. 2. 4
St o p pi n g R ul e s
5. 2. 4. 1
I n di vi d u al P ati e nt St o p pi n g R ul e s
W h il e t h e I n v e sti g at or s, t h e R o c h e Cli nic al Scie nce Le a der , t h e R o c h e S af et y S ci e n c e 
L e a d er, t h e I MC i n P art 1, a n d t h e e xt er n al i D M C i n P art 2 ( a n d a n y ot h er pr of e s si o n al 
c o n si d er e d n e c e s s ar y t o c o n s ult) will r e vi e w t h e b e n efit -ri s k pr ofil e f or t h e i n di vi d u al 
p ati e nt s o n a n o n g oi n g b a si s, t h e f oll o wi n g s p e cifi c s af et y st o p pi n g r ul e s f or a n i n di vi d u al 
s u bj e ct ar e d efi n e d a pri ori:

F u n cti o n al or str u ct ur al e y e a b n or m aliti e s.
-
Cli ni c all y r el e v a nt a b n or m aliti e s o n s p e ctr al d o m ai n ( S D) -O C T c o n si d er e d t o
b e r el at e d t o st u d y dr u g a s a s s e s s e d b y a n o p ht h al m ol o gi st, i. e., c h a n g e s i n
r eti n al t hi c k n e s s, pr e s e n c e of e d e m a, c y st oi d or atr o p hi c c h a n g e s – i n c a s e
of  e q ui v o c al o b s er v ati o n s r eti n al i m a gi n g c a n b e r e p e at e d t o c o nfir m or r ef ut e
t h e i niti al r e s ult s. I n c a s e of r eti n al fi n di n g s, e a c h i n di vi d u al c a s e will b e
di s c u s s e d b et w e e n t h e I n v e sti g at or, t h e O p ht h al m ol o gi st e x a mi ni n g t h e
p ati e nt a n d t h e S p o n s or t o d e ci d e 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.
-
Cli ni c all y r el e v a nt i m p air m e nt of vi si o n d et e ct e d b y t h e o p ht h al m ol o gi c al
e x a mi n ati o n.

Si g nifi c a nt a n d cli ni c all y r el e v a nt c h a n g e s i n l a b or at or y p ar a m et er s, E C G, or vit al
si g n s w hi c h p o s e a n u n a c c e pt a bl e ri s k f or t h e p ati e nt.

P ati e nt s wit h a n y el e v at e d A L T of 3 U L N, al k ali n e p h o s p h at a s e ( A L P) 2 U L N,
a n d a s s o ci at e d wit h a n i n cr e a s e i n bilir u bi n ( 2 u p p er li m it of n or m al) (i. e., a
s u s p e ct e d “ H y’ s l a w” w hi c h i n di c at e s ri s k of s e v er e/ s eri o u s li v er i m p air m e nt) i n t h e
a b s e n c e of a diff er e nt e x pl a n ati o n.

Ot h er fi n di n g s s u c h a s a S A E or a n y ot h er s e v er e A E t h at, at t h e j oi nt di s cr eti o n of
R o c h e Cli ni c al S cie n ce Le a d er, R o c h e S af et y S ci e n c e L e a d er, a n d t h e I n v e sti g at or,
i n di c at e t h at d o si n g s h o ul d b e h alt e d.


5. 2. 4. 2
St o p pi n g R ul e s f or a C o h ort a n d D o s e -E s c al ati o n Crit eri a 
R ul e s i n P art 1
St o p pi n g R ul e s f or a C o h ort
T h e I M C will r e vi e w t h e s af et y of t h e p ati e nt s at pr e d efi n e d ti m e-p oi nt s or o n a n a d -h o c 
b a si s ( a s d et ail e d i n t h e C h art er) a n d c a n r e c o m m e n d t er mi n ati o n of a c ert ai n c o h ort at 
a n y ti m e. I n a d diti o n, a c o h ort m a y b e t er mi n at e d at t h e j oi nt di s cr eti o n of t h e R o c h e 
Tr a n sl ati o n al M e di ci n e L e a d er, Cli ni c al P h ar m a c ol o gi st a n d S af et y S ci e n c e L e a d er.
S af et y  Crit eri a f or D o s e-E s c al ati o n
T h e d o s e c a n b e e s c al at e d i n P art 1 if  n o n e of t h e f oll o wi n g cir c u m st a n c e s o c c ur s i n a 
c o h ort of p ati e nt s at t h e s a m e d o s e l e v el ( or at t h e s a m e t ar g et e x p o s ur e l e v el) u nl e s s 
t h e s e e v e nt s are cl e arl y n ot r el at e d t o t h e a d mi ni str ati o n of t h e st u d y dr u g:

Gr a d e 2 s ki n or s u b c ut a n e o u s r e a cti o n s of t h e s a m e t y p e i n m or e t h a n 2 o ut of t h e
fir st 5 i nf a nt s ( or4 0 % of all i nf a nt s at t h e s a m e e x p o s ur e l e v el).

Gr a d e 2 p h ar y n g e al/l ar y n g e al or m u c o s al r e a cti o n s of t h e s a m e t y p e i n m or e t h a n
2 o ut of fir st 5 i nfa nt s ( or 4 0 % of all i nf a nt s at t h e s a m e e x p o s ur e l e v el).

A b n or m al o p ht h al m ol o gi c al e x a mi n ati o n or r eti n al fi n di n g s f or O C T i n m or e t h a n
2 o ut of fir st 5 i nfa nt s ( or 4 0 % of all i nf a nt s at t h e s a m e e x p o s ur e l e v el, a s
a s s e s s e d b y a st u d y tr ai n e d O p ht h al m ol o gi st.

Gr a d e 3 a d v er s e dr u g r e a cti o n ( ot h er t h a n t h o s e d e s cri b e d a b o v e) of t h e s a m e
t y p e i n m or e t h a n 2 o ut of fir st 5 i nf a nt s ( or4 0 % of  all i nf a nt s at t h e s a m e e x p o s ur e
l e v el).

Cli ni c a ll y si g nifi c a nt l a b or at or y a b n or m aliti e s of t h e s a m e t y p e i n m or e t h a n 2 o ut of
fir st 5 i nf a nt s ( or4 0 % of all i nf a nt s at t h e s a m e e x p o s ur e l e v el).

Cli ni c all y si g nifi c a nt c h a n g e s i n vit al si g n s of t h e s a m e t y p e i n m or e t h a n 2 o ut of
fir st 5 i nf a nt s ( or4 0 % of all i nf a nt s at t h e s a m e e x p o s ur e l e v el).

Cli ni c all y si g nifi c a nt c h a n g e s i n E C G s of t h e s a m e t y p e i n m or e t h a n 2 o ut of  fir st
5 i nfa nt s ( or 4 0 % of all i nf a nt s at t h e s a m e e x p o s ur e l e v el).
If a n y of t h e a b o v e cir c u m st a n c e s ar e m et, d o s e-e s c al ati o n  will n ot pr o c e e d b ut l o w er or 
i nt er m e di at e d o s e s c a n b e t e st e d t o s el e ct a n a d e q u at e d o s e f or t h e c o nfir m at or y p art of 
t h e tri al. D o s e-e s c al ati o n c a n pr o gr e s s wit h t h e a p pr o v al of t h e I M C w h e n n o n e of t h e 
a b o v e cir c u m st a n c e s ar e m et .
5. 2. 4. 3  
St o p pi n g R ul e s f or  P art 2
Cli ni c al s af et y d at a will b e r e vi e w e d b y t h e e xt er n al i D M C, s u p p ort e d b y a n e xt er n al 
st ati sti c al gr o u p, at pr e d efi n e d ti m e -p oi nt s or o n a n a d -h o c b a si s ( a s d et ail e d i n t h e 
C h art er) a n d t h e i D M C c a n r e c o m m e n d t er mi n ati o n of t h e st u d y.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
8 9 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
9 0 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
5. 3
M E T H O D S A N D TI M I N G F O R C AP T U RI N G A N D A S S E S SI N G 
S A F E T Y P A R A M E T E R S
T h e I n v e sti g at or i s r e s p o n si bl e f or e n s uri n g t h at all a d v er s e e v e nt s ( s e e S e cti o n 5. 1. 1 f or 
d ef i niti o n) ar e r e c or d e d o n t h e A d v er s e E v e nt e C R F a n d r e p ort e d t o t h e S p o n s or i n 
a c c or d a n c e wit h i n str u cti o n s pr o vi d e d i n t hi s s e cti o n a n d i n S e cti o n s 5. 4 -5. 6 .
F or e a c h a d v er s e e v e nt r e c or d e d o n t h e A d v er s e E v e nt e C R F, t h e I n v e sti g at or will m a k e 
a n a s s e s s m e n t of s eri o u s n e s s ( S e cti o n 5. 1. 2 f or s eri o u s n e s s crit eri a), s e v erit y 
( S e cti o n 5. 3. 3 ), a n d c a u s alit y ( S e cti o n 5. 3. 4 ).
5. 3. 1
A d v er s e E v e nt R e p orti n g P eri o d
I n v e sti g at or s will s e e k i nf or m ati o n o n a d v er s e e v e nt s at e a c h p ati e nt c o nt a ct. All a d v er s e 
e v e nt s, w h et h er r e p ort e d b y t h e p ati e nt or n ot e d b y st u d y p er s o n n el , will b e r e c or d e d i n 
t h e p ati e nt’ s m e di c al r e c or d. A d v er s e e v e nt s will t h e n b e r e p ort e d o n t h e A d v er s e E v e nt 
e C R F a s f oll o w s:
Af t er i nf or m e d c o n s e nt h a s b e e n o bt ai n e d b ut pri or t o i niti ati o n of st u d y  dr u g, o nl y 
s eri o u s a d v er s e e v e nt s c a u s e d b y a pr ot o c ol -m a n d at e d i nt er v e nti o n s h o ul d b e r e p ort e d 
( e. g., s eri o u s a d v er s e e v e nt s r el at e d t o i n v a si v e pr o c e d ur e s s u c h a s bi o p si e s). A n y 
ot h er a d v er s e e v e nt s h o ul d n ot b e r e p ort e d.
Af t er i niti ati o n of st u d y dr u g, all a d v er s e e v e nt s, r e g ar dl e s s of r el ati o n s hi p t o st u d y
dr u g, will b e r e p ort e d u ntil 3 0 d a ys after t he st u d y c o m pleti o n/e arl y wit h dr a w al visit 
(i.e., at le ast 3 0 d a ys aft er t h e l a st d o s e of st u d y dr u g).
I n str u cti o n s f or r e p orti n g a d v er s e e v e nt s t h at o c c ur aft er t h e a d v er s e e v e nt r e p orti n g 
p eri o d ar e pr o vi d e d i n S e cti o n 5. 6 .
5. 3. 2
Eli citi n g A d v er s e E v e nt I nf or m ati o n
A c o n si st e nt m et h o d ol o g y of n o n -dir e cti v e q u e sti o ni n g s h o ul d b e a d o p t e d f or eli citi n g 
a d v er s e e v e nt i nf or m ati o n at all p ati e nt e v al u ati o n ti m e ‑ p oi nt s. E x a m pl e s of 
n o n -dir e cti v e q u e sti o n s i n cl u d e t h e f oll o wi n g:
“ H o w h a s y o ur c hil d f elt si n c e it s l a st cli ni c vi sit ?”
“ H a s s h e/ h e h a d a n y n e w or c h a n g e d h e alt h pr o bl e m s si n c e s h e/ h e w a s l a st h er e ?”


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
9 1 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
5. 3. 3
A s s e s s m e nt of S e v erit y  of Ad v er s e E v e nt s
T h e a d v er s e e v e nt s e v erit y gr a di n g s c al e f or t h e N CI C T C A E ( v 4. 0 3) will b e u s e d t o 
a s s e s s a d v er s e e v e nt s e v erit y. T a bl e 5 will b e u s e d f or a s s e s si n g s e v erit y f or a d v er s e 
e v e nt s t h at ar e n ot s p e cifi c all y li st e d i n t h e N CI C T C A E .
T a bl e 5
A d v er s e E v e nt S e v erit y Gr a di n g S c al e
Gr a d e
S e v erit y
1
Mil d; a s y m pt o m ati c or mil d s y m p t o m s; cli ni c al or di a g n o sti c o b s er v ati o n s o nl y;
or i nt er v e nti o n n ot i n di c at e d.
2
M o d er at e; mi ni m al, l o c al, or n o n -i n v a si v e i nt er v e nti o n i n di c at e d; or li miti n g a g e-
a p pr o pri at e i n str u m e nt al a cti viti e s of d ail y li vi n g.
3
S e v er e or m e di c all y si g nifi c a nt, b ut n ot i m m e di at el y lif e -t hr e at e ni n g; 
h o s pit ali z ati o n or pr ol o n g ati o n of h o s pit ali z ati o n i n di c at e d; di s a bli n g; or li miti n g 
s elf -c ar e a cti viti e s of d ail y li vi n g a .
4
Lif e -t hr e at e ni n g c o n s e q u e n c e s or ur g e nt i nt er v e nti o n i n di c at e d b .
5
D e at h r el at e d t o a d v er s e e v e nt
b .
N CI C T C A E = N ati o n al C a n c er I n stit ut e C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s.
N ot e: B a s e d o n t h e N CI C T C A E ( v 4. 0 3), w hi c h c a n b e f o u n d at: 
htt p:// e v s. n ci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3 _ 2 0 1 0 -0 6 -1 4 _ Q ui c k R ef er e n c e _ 8. 5 x 1 1. p df
a
If a n e v e nt i s a s s e s s e d a s a " si g nifi c a nt m e di c al e v e nt", it m u st b e r e p ort e d a s a s eri o u s 
a d v er s e e v e nt ( S e cti o n 5. 4. 2 f or r e p orti n g i n str u cti o n s), p er t h e d efi niti o n of s eri o u s a d v er s e 
e v e nt i n S e cti o n 5. 1. 2 .
b
Gr a d e 4 a n d 5 e v e nt s m u st b e r e p ort e d a s s eri o u s a d v er s e e v e nt s ( S e cti o n 5. 4. 2 f or r e p orti n g 
i n str u cti o n s), p er t h e d efi niti o n of s eri o u s a d v er s e e v e nt i n S e cti o n 5. 1. 2 .
5. 3. 4
A s s e s s m e nt of C a u s alit y  of A d v er s e E v e nt s
I n v e sti g at or s s h o ul d u s e t h eir k n o wl e d g e of t h e p ati e nt, t h e cir c u m st a n c e s s urr o u n di n g 
t h e e v e nt, a n d a n e v al u ati o n of a n y p ot e nti al alt er n ati v e c a u s e s t o d et er mi n e w h et h er or 
n ot a n a d v er s e e v e nt i s c o n si d er e d t o b e r el at e d t o t h e st u d y dr u g, i n di c ati n g " y e s" or 
" n o" a c c or di n gl y. T h e f oll o wi n g g ui d a n c e s h o ul d b e t a k e n i nt o c o n si d er ati o n:

T e m p or al r el ati o n s hi p of e v e nt o n s et t o t h e i niti ati o n of st u d y dr u g.

C o ur s e of t h e e v e nt, c o n si d eri n g e s p e ci all y t h e eff e ct s of d o s e -r e d u cti o n,
di s c o nti n u ati o n of st u d y dr u g, or r ei ntr o d u cti o n of st u d y dr u g.

K n o w n a s s o ci ati o n of t h e e v e nt wit h t h e st u d y dr u g or wit h si mil ar tr e at m e nt s.

K n o w n a s s o ci ati o n of t h e e v e nt wit h t h e di s e a s e u n d er st u d y.

Pr e s e n c e of r i s k f a ct or s i n t h e p ati e nt or u s e of c o n c o mit a nt m e di c ati o n s k n o w n t o
i n cr e a s e t h e o c c urr e n c e of t h e e v e nt.

Pr e s e n c e of n o n -tr e at m e nt-r el at e d f a ct or s t h at ar e k n o w n t o b e a s s o ci at e d wit h t h e
o c c urr e n c e of t h e e v e nt.


5. 3. 5
Pr o c e d ur e s f or R e c or di n g A d v er s e E v e nt s
I n v e sti g at or s s h o ul d u s e c orr e ct m e di c al t er mi n ol o g y/ c o n c e pt s w h e n r e c or di n g a d v er s e 
e v e nt s o n t h e A d v er s e E v e nt e C R F. A v oi d c oll o q ui ali s m s a n d a b br e vi ati o n s.
O nl y o n e a d v er s e e v e nt t er m s h o ul d b e r e c or d e d i n t h e e v e nt fi el d o n t h e A d v er s e E v e nt 
e C R F.
5. 3. 5. 1
Di a g n o si s v er s u s Si g n s a n d S y m pt o m s
F or A E s, a di a g n o si s (if k n o w n) s h o ul d b e r e c or d e d o n t h e A d v er s e E v e nt e C R F r at h er 
t h a n i n di vi d u al si g n s a n d s y m pt o m s ( e. g., r e c or d o nl y li v er f ail ur e or h e p atiti s r at h er t h a n 
j a u n di c e, a st eri xi s, a n d el e v at e d tr a n s a mi n a s e s). H o w e v er, if a c o n st ell ati o n of si g n s 
a n d/ or s y m pt o m s c a n n ot b e m e di c all y c h ar a ct eri z e d a s a si n gl e di a g n o si s or s y n dr o m e 
at t h e ti m e of r e p orti n g, e a c h i n di vi d u al e v e nt s h o ul d b e r e c or d e d o n t h e A d v er s e E v e nt 
e C R F. If a di a g n o si s i s s u b s e q u e ntl y e st a bli s h e d, all pr e vi o u sl y r e p ort e d a d v er s e e v e nt s 
b a s e d o n si g n s a n d s y m pt o m s s h o ul d b e n ullifi e d a n d r e pl a c e d b y o n e a d v er s e e v e nt 
r e p ort b a s e d o n t h e si n gl e di a g n o si s, wit h a st arti n g d at e t h at c orr e s p o n d s t o t h e st arti n g 
d at e of t h e fir st s y m pt o m of t h e e v e nt u al di a g n o si s.
5. 3. 5. 2
A d v er s e E v e nt s O c c urri n g S e c o n d ar y  t o Ot h er E v e nt s
I n g e n er al, a d v er s e e v e nt s o c c urri n g s e c o n d ar y t o ot h er e v e nt s ( e. g., c a s c a d e e v e nt s or 
cli ni c al s e q u el a e) s h o ul d b e i d e ntifi e d b y t h eir pri m ar y c a u s e, wit h t h e e x c e pti o n of 
s e v er e or s eri o u s s e c o n d ar y e v e nt s. H o w e v er, m e di c all y si g nifi c a nt a d v er s e e v e nt s 
o c c urri n g s e c o n d ar y t o a n i niti ati n g e v e nt t h at ar e s e p ar at e d i n ti m e s h o ul d b e r e c or d e d 
a s i n d e p e n d e nt e v e nt s o n t h e A d v er s e E v e nt e C R F. F or e x a m pl e:

If v o miti n g r e s ult s i n mil d d e h y dr ati o n wit h n o a d diti o n al tr e at m e nt i n a h e alt h y a d ult,
o nl y v o miti n g s h o ul d b e r e p ort e d o n t h e e C R F.

If v o miti n g r e s ult s i n s e v er e d e h y dr ati o n, b ot h e v e nt s s h o ul d b e r e p ort e d s e p ar at el y
o n t h e e C R F.

If a s e v er e g a str oi nt e sti n al h e m orr h a g e l e a d s t o r e n al f ail ur e, b ot h e v e nt s s h o ul d b e
r e p ort e d s e p ar at el y o n t h e e C R F.

If di z zi n e s s l e a d s t o a f all a n d s u b s e q u e nt fr a ct ur e, all t hr e e e v e nt s s h o ul d b e
r e p ort e d s e p ar at el y o n t h e e C R F.
All a d v er s e e v e nt s s h o ul d b e r e c or d e d s e p ar at el y o n t h e A d v er s e E v e nt  e C R F if it i s 
u n cl e ar a s t o w h et h er t h e e v e nt s ar e a s s o ci at e d.
5. 3. 5. 3  
P er si st e nt or R e c urr e nt A d v er s e E v e nt s
A p er si st e nt a d v er s e e v e nt i s o n e t h at e xt e n d s c o nti n u o u sl y, wit h o ut r e s ol uti o n, b et w e e n 
p ati e nt e v al u ati o n ti m e -p oi nt s. S u c h e v e nt s s h o ul d o nl y b e r e c or d e d o n c e o n t h e 
A d v er s e E v e nt e C R F. T h e i niti al s e v erit y of t h e e v e nt s h o ul d b e  r e c or d e d, a n d t h e 
s e v erit y s h o ul d b e u p d at e d t o r efl e ct t h e m o st e xtr e m e s e v erit y a n y ti m e t h e e v e nt 
w or s e n s. If t h e e v e nt b e c o m e s s eri o u s , t h e A d v er s e E v e nt e C R F s h o ul d b e u p d at e d t o 
r efl e ct t hi s.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
9 2 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
9 3 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
A r e c urr e nt a d v er s e e v e nt i s o n e t h at r e s ol v e s b et w e e n p ati e nt e v al u ati o n ti m e -p oi nt s 
a n d s u b s e q u e ntl y r e c ur s. E a c h r e c urr e n c e of a n a d v er s e e v e nt s h o ul d b e r e c or d e d 
s e p ar at el y o n t h e A d v er s e E v e nt e C R F .
5. 3. 5. 4
A b n or m al L a b or at or y V al u e s
N ot e v er y l a b or at or y a b n or m alit y q u alifi e s a s a n a d v er s e e v e nt. A l a b or at or y t e st r e s ult 
s h o ul d b e r e p ort e d a s a n a d v er s e e v e nt if it m e et s a n y of t h e f oll o wi n g crit eri a:

A c c o m p a ni e d b y cli ni c al s y m pt o m s.

R e s ult s i n a c h a n g e i n st u d y tr e at m e nt ( e. g., d o s a g e m o dif i c ati o n, tr e at m e nt
i nt err u pti o n, or tr e at m e nt di s c o nti n u ati o n).

R e s ult s i n a m e di c al i nt er v e nti o n ( e. g., p ot a s si u m s u p pl e m e nt ati o n f or h y p o k al e mi a)
or a c h a n g e i n c o n c o mit a nt t h er a p y.

Cli ni c all y si g nifi c a nt i n t h e I n v e sti g at or’ s j u d g m e nt.
It i s t h e I n ve sti g at or’ s r e s p o n si bilit y t o r e vi e w all l a b or at or y fi n di n g s. M e di c al a n d 
s ci e ntifi c j u d g m e nt s h o ul d b e e x er ci s e d i n d e ci di n g w h et h er a n i s ol at e d l a b or at or y 
a b n or m alit y s h o ul d b e cl a s sifi e d a s a n a d v er s e e v e nt.
If a cli ni c all y si g nifi c a nt l a b or at or y a b n or malit y i s a si g n of a di s e a s e or s y n dr o m e 
( e. g., al k ali n e p h o s p h at a s e a n d bilir u bi n 5 ti m e s t h e U L N a s s o ci at e d wit h c h ol e c y stiti s), 
o nl y t h e di a g n o si s (i. e., c h ol e c y stiti s) s h o ul d b e r e c or d e d o n t h e A d v er s e E v e nt e C R F.
If a cli ni c all y si g nifi c a nt l a b or at or y a b n or m alit y i s n ot a si g n of a di s e a s e or s y n dr o m e, 
t h e a b n or m alit y it s elf s h o ul d b e r e c or d e d o n t h e A d v er s e E v e nt e C R F, al o n g wit h a 
d e s cri pt or i n di c ati n g if t h e t e st r e s ult i s a b o v e or b el o w t h e n or m al r a n g e ( e. g., " el e v at e d 
p ot a s si u m", a s o p p o s e d t o " a b n or m al p ot a s si u m"). If t h e l a b or at or y a b n or m alit y c a n b e 
c h ar a ct eri z e d b y a pr e ci s e cli ni c al t er m p er st a n d ar d d efi niti o n s, t h e cli ni c al t er m s h o ul d 
b e r e c or d e d a s t h e a d v er s e e v e nt. F or e x a m pl e, a n el e v at e d s er u m p ot a s si u m l e v el of 
7. 0 m E q/ L s h o ul d b e r e c or d e d a s “ h y p er k al e mi a”.
O b s er v ati o n s of t h e s a m e cli ni c all y si g nifi c a nt l a b or at or y a b n or m alit y fr o m vi sit t o vi sit 
s h o ul d n ot b e r e p e at e dl y r e c or d e d o n t h e A d v er s e E v e nt e C R F, u nl e s s t h e eti ol o g y 
c h a n g e s. T h e i niti al s e v erit y of t h e e v e nt s h o ul d b e r e c or d e d, a n d t h e s e v erit y or 
s eri o u s n e s s s h o ul d b e u p d at e d a n y ti m e t h e e v e nt w or s e n s.
5. 3. 5. 5
A b n or m al Vit al Si g n V al u e s
N ot e v er y vit al si g n a b n or m alit y q u alifi e s a s a n a d v er s e e v e nt. A vit al si g n r e s ult s h o ul d 
b e r e p ort e d a s a n a d v er s e e v e nt if it m e et s a n y of t h e f oll o wi n g crit eri a:

A c c o m p a ni e d b y cli ni c al s y m pt o m s.

R e s ult s i n a c h a n g e i n st u d y tr e at m e nt ( e. g., d o s a g e m o difi c ati o n, tr e at m e nt
i nt err u pti o n, or tr e at m e nt di s c o nti n u ati o n).



R e s ult s i n a m e di c al i nt er v e nti o n or a c h a n g e i n c o n c o mit a nt t h er a p y.

Cli ni c all y si g nifi c a nt i n t h e I n v e sti g at or’ s j u d g m e nt.
It i s t h e I n v e sti g at or’ s r e s p o n si bilit y t o r e vi e w all vit al si g n fi n di n g s. M e di c al a n d s ci e ntifi c 
j u d g m e nt s h o ul d b e e x er ci s e d i n d e ci di n g w h et h er a n i s ol at e d vit al si g n a b n or m alit y 
s h o ul d b e cl a s sifi e d a s a n a d v er s e e v e nt.
If a cli ni c all y si g nifi c a nt vit al si g n a b n or m alit y i s a si g n of a di s e a s e or s y n dr o m e 
( e. g., hi g h bl o o d pr e s s ur e), o nl y t h e di a g n o si s (i. e., h y p ert e n si o n) s h o ul d b e r e c or d e d o n 
t h e A d v er s e E v e nt e C R F.
O b s er v ati o n s of t h e s a m e cli ni c all y si g nifi c a nt vit al si g n a b n or m alit y fr o m vi sit t o vi sit 
s h o ul d n ot b e r e p e at e dl y r e c or d e d o n t h e A d v er s e E v e nt e C R F, u nl e s s t h e eti ol o g y 
c h a n g e s. T h e i niti al s e v erit y of t h e e v e nt s h o ul d b e r e c or d e d, a n d t h e s e v erit y or 
s eri o u s n e s s s h o ul d b e u p d at e d a n y ti m e t h e e v e nt w or s e n s.
5. 3. 5. 6
A b n or m al Li v er F u n cti o n T e st s
T h e fi n di n g of a n el e v at e d A L T or A S T ( 3 U L N) i n c o m bi n ati o n wit h eit h er a n el e v at e d 
t ot al bilir u bi n (2 U L N) or cli ni c al j a u n di c e i n t h e a b s e n c e of c h ol e st a si s or ot h er 
c a u s e s of h y p er bilir u bi n e mi a i s c o n si d er e d t o b e a n i n di c at or of s e v er e li v er i nj ur y. 
T h er ef or e, i n v e sti g at or s m u st r e p ort a s a n a d v er s e e v e nt t h e o c c urr e n c e of eit h er of t h e 
f oll o wi n g:

Tr e at m e nt -e m er g e nt A L T or A S T 3 U L N i n c o m bi n ati o n wit h t ot al
bilir u bi n 2 U L N

Tr e at m e nt -e m er g e nt A L T or A S T 3 U L N i n c o m bi n ati o n wit h cli ni c al j a u n di c e.
T h e m o st a p pr o pri at e di a g n o si s or (if a di a g n o si s c a n n ot b e e st a bli s h e d) t h e a b n or m al 
l a b or at or y v al u e s s h o ul d b e r e c or d e d o n t h e A d v er s e E v e nt e C R F ( S e cti o n 5. 3. 5. 1 ) a n d 
r e p ort e d t o t h e S p o n s or i m m e di at el y (i. e., n o m or e t h a n 2 4  h o ur s  aft er l e ar ni n g of t h e 
e v e nt), eit h er a s a s eri o u s a d v er s e e v e nt or a n o n -s eri o u s a d v er s e e v e nt of s p e ci al 
i nt er e st ( S e cti o n 5. 4. 2 ).
5. 3. 5. 7  
D e at h s
D e at h s h o ul d b e c o n si d er e d a n o ut c o m e a n d n ot a di sti n ct e v e nt. T h e e v e nt or c o n diti o n 
t h at c a u s e d or c o ntri b ut e d t o t h e f at al o ut c o m e s h o ul d b e r e c or d e d a s t h e si n gl e m e di cal 
c o n c e pt o n t h e A d v er s e E v e nt e C R F. G e n er all y, o nl y o n e s u c h e v e nt s h o ul d b e r e p ort e d. 
If t h e c a u s e of d e at h i s u n k n o w n a n d c a n n ot b e a s c ert ai n e d at t h e ti m e of r e p orti n g, 
“u n e x pl ai n e d d e at h ” s h o ul d b e r e c or d e d o n t h e A d v er s e E v e nt e C R F. If t h e c a u s e of 
d e at h l at er b e c o m e s a v ail a bl e ( e. g.,  aft er a ut o p s y), “ u n e x pl ai n e d d e at h” s h o ul d b e 
r e pl a c e d b y t h e e st a bli s h e d ca u s e of d e at h. T h e t e r m " s u d d e n d e at h "  s h o ul d n ot b e 
u s e d u nl e s s c o m bi n e d wit h t h e pr e s u m e d c a u s e of d e at h ( e. g., " s u d d e n c ar di a c d e at h").
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
9 4 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
9 5 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
If t h e d e at h i s attri b ut e d t o pr o gr e s si o n of S M A di s e a s e a n d/ or a s s o ci at e d c o m pli c ati o n s 
or c o m or bi diti e s, t h e D e at h Attri b ut e d t o Pr o gr e s si v e Di s e a s e e C R F s h o ul d b e 
c o m pl et e d. 
5. 3. 5. 8
Pr e e xi sti n g M e di c al C o n diti o n s
A pr e e xi sti n g m e di c al c o n diti o n i s o n e t h at i s pr e s e nt at t h e s cr e e ni n g vi sit f or t hi s st u d y. 
S u c h c o n diti o n s s h o ul d b e r e c or d e d o n t h e G e n er al M e di c al Hi st or y a n d B a s eli n e 
C o n diti o n s e C R F.
A pr e e xi sti n g m e di c al c o n diti o n s h o ul d b e r e c or d e d a s a n a d v er s e e v e nt o nl y if t h e 
fr e q u e n c y, s e v erit y, or c h ar a ct er of t h e c o n diti o n w or s e n s d uri n g t h e st u d y. W h e n 
r e c or di n g s u c h e v e nt s o n t h e A d v er s e E v e nt e C R F, it i s i m p ort a nt t o c o n v e y t h e c o n c e pt
t h at t h e pr e e xi sti n g c o n diti o n h a s c h a n g e d b y i n cl u di n g a p pli c a bl e d e s cri pt or s 
( e. g., “ m or e fr e q u e nt h e a d a c h e s”).
5. 3. 5. 9
H o s pit ali z ati o n or Pr ol o n g e d H o s pit ali z ati o n
A n y a d v er s e e v e nt t h at r e s ult s i n h o s pit ali z ati o n or pr ol o n g e d h o s pit ali z ati o n s h o ul d b e 
d o c u m e n t e d a n d r e p ort e d a s a s eri o u s a d v er s e e v e nt ( p er t h e d efi niti o n of s eri o u s 
a d v er s e e v e nt i n S e cti o n 5. 3. 5. 9 ), e x c e pt a s o utli n e d b el o w.
A n e v e nt t h at l e a d s t o h o s pit ali z ati o n u n d er t h e f oll o wi n g cir c u m st a n c e s s h o ul d n ot b e 
r e p ort e d a s a n a d v er s e e v e nt or a s eri o u s a d v er s e e v e nt:

H o s pit ali z ati o n f or r e s pit e c ar e.

Pl a n n e d h o s pit ali z ati o n r e q uir e d b y t h e pr ot o c ol ( e. g., f or st u d y dr u g a d mi ni str ati o n).

H o s pit ali z ati o n f or a pr e e xi sti n g c o n diti o n, pr o vi d e d t h at all of t h e f oll o wi n g crit eri a
ar e m et:
T h e h o s pit ali z ati o n w a s pl a n n e d pri or t o t h e st u d y o r w a s s c h e d ul e d d uri n g t h e 
st u d y w h e n el e cti v e s ur g er y b e c a m e n e c e s s ar y b e c a u s e of t h e e x p e ct e d 
n or m al pr o gr e s si o n of t h e di s e a s e.
T h e p ati e nt h a s n ot s uff er e d a n a d v er s e e v e nt.
A n e v e nt t h at l e a d s t o h o s pit ali z ati o n u n d er t h e f oll o wi n g cir c u m st a n c e s i s n ot 
c o n si d er e d t o b e a s eri o u s a d v er s e e v e nt, b ut s h o ul d b e r e p ort e d a s a n a d v er s e e v e nt 
i n st e a d:

H o s pit ali z ati o n f or a n a d v er s e e v e nt t h at w o ul d or di n aril y h a v e b e e n tr e at e d i n a n
o ut p ati e nt s etti n g h a d a n o ut p ati e nt cli ni c b e e n a v ail a bl e.

A d mi s si o n t o e m er g e n c y r o o m t h at d o e s n ot r e s ult i n h o s pit ali z ati o n will n ot
c o n stit ut e p er s e a s eri o u s a d v er s e e v e nt.

H o s pit ali z ati o n d u e s ol el y t o t h e pr o gr e s si o n of t h e u n d erl yi n g S M A di s e a s e, a s
p arti c ul arl y i n t hi s p ati e nt p o p ul ati o n, h o s pit ali z ati o n s ar e e x p e ct e d a n d fr e q u e ntl y
o c c urri n g d u e t o t h e n at ur e of t h e di s e a s e.


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
9 6 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
5. 3. 5. 1 0
O v er d o s e s
R i s di pl a m m a y h a v e a n arr o w t h er a p e uti c wi n d o w. B a s e d o n e x p o s ur e i n a ni m al st u di e s 
at t h e li mit s of t ol er a bilit y, t h er e i s e vi d e n c e t h at a c ut e or s h ort -t er m t o xi cit y of ri s di pl a m
i s dri v e n b y e x p o s ur e t o fr e e, n o n -pr ot ei n -b o u n d ri s di pl a m. C al c ul ati o n s of t h e fr e e
e x p o s ur e c o n c e ntr ati o n s c o m p ar e d wit h t h e e x p o s ur e a s s o ci at e d wit h t h e hi g h e st d o s e 
i n t hi s st u d y all o w e sti m ati n g t h at a p pr o xi m at el y 1 0-f ol d hi g h er fr e e c o n c e ntr ati o n s m a y 
b e a s s o ci at e d wit h lif e -t hr e at e ni n g si g n s.
T h er ef or e, t h e a d mi ni str ati o n of t h e pr e ci s e d o s a g e m u st al w a y s b e e n s ur e d.
St u d y dr u g o v er d o s e i s t h e a c ci d e nt al or i nt e nti o n al u s e of t h e dr u g i n a n a m o u nt hi g h er 
t h a n t h e d o s e b ei n g st u di e d. A n o v er d o s e or i n c orr e ct a d mi ni str ati o n of st u d y dr u g i s n ot 
a n a d v er s e e v e nt u nl e s s it r e s ult s i n u nt o w ar d m e di c al eff e ct s. 
A n y st u d y dr u g o v er d o s e or i n c orr e ct a d mi ni str ati o n of st u d y dr u g s h o ul d b e n ot e d o n 
t h e St u d y Dr u g A d mi ni str ati o n e C R F.
All a d v er s e e v e nt s a s s o ci at e d wit h a n y s p e ci al sit u ati o n s e v e nt a s d efi n e d a b o v e s h o ul d 
b e r e c or d e d o n t h e A d v er s e E v e nt e C R F. If t h e a s s o ci at e d a d v er s e e v e nt f ulfill s s eri o u s 
crit eri a, t h e e v e nt s h o ul d b e r e p ort e d t o t h e S p o n s or i m m e di at el y (i. e., n o m or e t h a n 
2 4 h o ur s aft er l e ar ni n g of t h e e v e nt; s e e S e cti o n 5. 4. 2 ).
5. 3. 5. 1 1
P ar e nt/ C ar e gi v er -R e p ort e d O ut c o m e D at a
A d v er s e e v e nt r e p ort s will n ot b e d eri v e d fr o m p ar e nt/ c ar e gi v er -r e p ort e d o ut c o m e d at a 
b y t h e S p o n s or, a n d s af et y a n al y s e s will n ot b e p erf or m e d u si n g t h e s e d at a. Alt h o u g h 
sit e s ar e n ot e x p e ct e d t o r e vi e w t h e s e d at a, it i s p o s si bl e t h at a n I n v e sti g at or c o ul d 
b e c o m e a w ar e of p ar e nt/ c ar e gi v er -r e p ort e d o ut c o m e d at a t h at m a y b e i n di c ati v e of a n 
A E. U n d er t h e s e cir c u m st a n c e s, t h e I n v e sti g at or will d et er mi n e w h et h er t h e crit eri a f or 
a n a d v er s e e v e nt h a v e b e e n m et a n d, if s o, will r e p ort t h e e v e nt o n t h e A d v er s e E v e nt 
e C R F f or m.
5. 4
I M M E DI AT E R E P O R TI N G R E Q UI R E M E N T S F R O M 
I N V E S TI G AT O R T O S P O N S O R
C ert ai n e v e nt s r e q uir e i m m e di at e r e p orti n g t o all o w t h e S p o n s or t o t a k e a p pr o pri at e 
m e a s ur e s t o a d dr e s s p ot e nti al n e w ri s k s i n a cli ni c al tri al. T h e I n v e sti g at or m u st r e p ort 
s u c h e v e nt s t o t h e S p o n s or i m m e di at el y; u n d er n o cir c u m st a n c e s s h o ul d r e p orti n g t a k e 
pl a c e m or e t h a n 2 4 h o ur s aft er t h e I n v e sti g at or l e ar n s of t h e e v e nt. T h e f oll o wi n g i s a li st 
of e v e nt s t h at t h e I n v e sti g at or m u st r e p ort t o t h e S p o n s or wit hi n 2 4 h o ur s af t er l e ar ni n g 
of  t h e e v e nt, r e g ar dl e s s of r el ati o n s hi p t o st u d y dr u g:

S eri o u s a d v er s e e v e nt s ( d efi n e d i n S e cti o n 5. 1. 2 ; s e e S e cti o n 5. 4. 2 f or d et ail s o n
r e p orti n g r e q uir e m e nt s)

N o n -s eri o u s a d v er s e e v e nt s of s p e ci al i nt er e st ( d efi n e d i n S e cti o n 5. 1. 3 ; s e e
S e cti o n 5. 4. 2 f or d et ail s o n r e p orti n g r e q uir e m e nt s)



M e di c al d e vi c e c o m pl ai nt s ( s e e S e cti o n
5. 4. 2 a n d 5. 4. 3 f or d et ail s o n r e p orti n g
r e q uir e m e nt s).
T h e I n v e sti g at or m u st r e p ort n e w si g nifi c a nt f oll o w -u p i nf or m ati o n f or t h e s e e v e nt s t o t h e 
S p o n s or i m m e di at el y (i. e., n o m or e t h a n 2 4 h o ur s aft er b e c o mi n g a w ar e of t h e 
i nf or m ati o n). N e w si g nifi c a nt i nf or m ati o n i n cl u d e s t h e f oll o wi n g:

N e w si g n s or s y m pt o m s or a c h a n g e i n t h e di a g n o si s.

Si g nifi c a nt n e w di a g n o sti c t e st r e s ult s.

C h a n g e i n c a u s alit y b a s e d o n n e w i nf or m ati o n.

C h a n g e i n t h e e v e nt’ s o ut c o m e, i n cl u di n g r e c o v er y.

A d diti o n al n arr ati v e i nf or m ati o n o n t h e cli ni c al c o ur s e of t h e e v e nt.
I n v e sti g at or s m u st al s o c o m pl y wit h l o c al r e q uir e m e nt s f or r e p orti n g s eri o u s a d v er s e 
e v e nt s t o t h e l o c al H e alt h A ut h orit y a n d I R B/ E C.
5. 4. 1
E m er g e n c y  M e di c al C o nt a ct s
T o e n s ur e t h e s af et y of st u d y p ati e nt s, a c c e s s t o t h e M e di c al M o nit or s i s a v ail a bl e 
2 4 h o ur s a d a y 7 d a y s a w e e k. C o u ntr y s pecific t oll -free n u m bers of t he e mer ge n c y 
me dic al c all ce nter are file d i n t he i n vesti g at or site file.
5. 4. 2
R e p orti n g R e q uir e m e nt s f or S eri o u s A d v er s e E v e nt s a n d 
N o n -S eri o u s - A d v er s e E v e nt s of S p e ci al I nt er e st
F or r e p ort s of s eri o u s a d v er s e e v e nt s a n d n o n -s eri o u s a d v er s e e v e nt s of s p e ci al i nt er e st 
( s e e S e cti o n s 5. 1. 2 a n d 5. 1. 3 ), i n v e sti g at or s s h o ul d r e c or d all c a s e d et ail s t h at c a n b e 
g at h er e d o n t h e S eri o u s A d v er s e R e p orti n g F or m a n d f or w ar d t hi s f or m t o t h e 
S A E R e s p o n si bl e wit hi n 2 4 h o ur s .
5. 4. 3
R e p orti n g R e q uir e m e nt s f or M e di c al D e vi c e C o m pl ai nt s
T h e I n v e sti g at or m u st r e p ort all m e di c al d e vi c e c o m pl ai nt s t o t h e S p o n s or. T h e 
I n v e sti g at or s h o ul d d o c u m e nt a s m u c h i nf or m ati o n a s p o s si bl e o n t h e M e di c al D e vi c e 
C o m pl ai nt i n cl u di n g t h e pr o d u ct b at c h n u m b er a n d e x pir ati o n d at e. If t h e m e di c al d e vi c e 
c o m pl ai nt r e s ult s i n a n a d v er s e e v e nt, t h e a d v er s e e v e nt m u st b e r e p ort e d o n t h e 
A d v er s e E v e nt e C R F. If t h e e v e nt i s s eri o u s, t h e A d v er s e E v e nt e C R F m u st b e 
c o m pl et e d a n d r e p ort e d t o t h e S p o n s or wit hi n 2 4 h o ur s aft er l e ar ni n g of t h e e v e nt 
( S e cti o n 5. 4. 2 ).
5. 5
F O L L O W -U P O F P A TI E N T S A F T E R A D V E R S E E V E N T S
5. 5. 1
I n v e sti g at or F oll o w-U p
T h e I n v e sti g at or s h o ul d f oll o w e a c h a d v er s e e v e nt u ntil t h e e v e nt h a s r e s ol v e d t o 
b a s eli n e gr a d e or b ett er,  t h e e v e nt i s a s s e s s e d a s st a bl e b y t h e I n v e sti g at or, t h e p ati e nt 
i s l o st t o f oll o w-u p, or t h e p ati e nt wit h dr a w s c o n s e nt. E v er y eff ort s h o ul d b e m a d e t o 
f oll o w all s eri o u s a d v er s e e v e nt s c o n si d er e d t o b e r el at e d t o st u d y dr u g or tri al-r el at e d 
pr o c e d ur e s  u ntil a fi n al o ut c o m e c a n b e r e p ort e d.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
9 7 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


D uri n g t h e st u d y p eri o d, r e s ol uti o n of a d v er s e e v e nt s ( wit h d at e s) s h o ul d b e d o c u m e nt e d 
o n t h e A d v er s e E v e nt e C R F a n d i n t h e p ati e nt’ s m e di c al r e c or d t o f a cilit at e s o ur c e d at a 
v erifi c ati o n. If, aft er f oll o w -u p, r et ur n t o b a s eli n e st at u s or st a bili z ati o n c a n n ot b e 
e st a bli s h e d, a n e x pl a n ati o n s h o ul d b e r e c or d e d o n t h e A d v er s e E v e nt e C R F.
5. 5. 2
S p o n s or F oll o w -U p
F or s eri o u s a d v er s e e v e nt s, n o n -s eri o u s a d v er s e e v e nt s of s p e ci al i nt er e st, t h e S p o n s or 
or a d e si g n e e m a y f oll o w -u p b y t el e p h o n e, f a x, el e ctr o ni c m ail, a n d/ or a m o nit ori n g vi sit 
t o o bt ai n a d diti o n al c a s e d et ail s a n d o ut c o m e i nf or m ati o n ( e. g., fr o m h o s pit al di s c h ar g e 
s u m m ari e s, c o n s ult a nt r e p ort s, a ut o p s y r e p ort s) i n or d er t o p erf or m a n i n d e p e n d e nt 
m e di c al a s s e s s m e nt of t h e
r e p ort e d c a s e.
5. 6
P O S T -S T U D Y A D V E R S E E V E N T S
T h e I n v e sti g at or i s n ot r e q uir e d t o a cti v el y m o nit or p ati e nt s f or a d v er s e e v e nt s aft er t h e 
e n d of t h e a d v er s e e v e nt r e p orti n g p eri o d ( a s d ef i n e d i n S e cti o n 5. 3. 1 ). If t h e I n v e sti g at or 
b e c o m e s a w ar e of a n y ot h er s eri o u s a d v er s e e v e nt o c c urri n g aft er t h e e n d of t h e 
a d v er s e e v e nt r e p orti n g p eri o d, if t h e e v e nt i s b eli e v e d t o b e r el at e d t o pri or st u d y dr u g 
tr e at m e nt, t h e e v e nt s h o ul d b e r e p ort e d dir e ctl y t o t h e S p o n s or or it s d e si g n e e, eit h er b y 
f a xi n g or b y s c a n ni n g a n d e m aili n g t h e S eri o u s A d v er s e E v e nt R e p orti n g F or m u si n g t h e 
f a x n u m b er or e m ail a d dr e s s pr o vi d e d t o i n v e sti g at or s.
5. 7
E X P E DI T E D R E P O R TI N G T O H E A L T H A U T H O RI TI E S,
I N V E S TI G AT O R S, I N S TI T U TI O N A L R E VI E W B O A R D S, A N D 
E T HI C S C O M MI T T E E S
T h e S p o n s or will pr o m ptl y e v al u at e all s eri o u s a d v er s e e v e nt s a n d n o n -s eri o u s a d v er s e 
e v e nt s of s p e ci al i nt er e st a g ai n st c u m ul ati v e pr o d u ct e x p eri e n c e t o i d e ntif y a n d 
e x p e diti o u sl y c o m m u ni c at e p o s si bl e n e w s af et y fi n di n g s t o i n v e sti g at or s, I R B s, E C s, a n d 
a p pli c a bl e H e alt h A ut h oriti e s b a s e d o n a p pli c a bl e l e gi sl ati o n.
T o d et er mi n e r e p orti n g r e q uir e m e nt s f or si n gl e a d v er s e e v e nt c a s e s, t h e S p o n s or will 
a s s e s s t h e e x p e ct e d n e s s of t h e s e e v e nt s u si n g t h e f oll o wi n g r ef er e n c e d o c u m e nt:

R i s di pl a m I n v e sti g at or’ s Br o c h ur e
T h e S p o n s or will c o m p ar e t h e s e v erit y of e a c h e v e nt a n d t h e c u m ul ati v e e v e nt 
fr e q u e n c y r e p ort e d f or t h e st u d y wit h t h e s e v erit y a n d fr e q u e n c y r e p ort e d i n t h e 
a p pli c a bl e r ef er e n c e d o c u m e nt.
R e p orti n g r e q uir e m e nt s will al s o b e b a s e d o n t h e I n v e sti g at or' s  a s s e s s m e nt of c a u s alit y 
a n d s eri o u s n e s s, wit h all o w a n c e f or u p gr a di n g b y t h e S p o n s or a s n e e d e d.
A n I M C a n d i D M C will m o nit or t h e i n ci d e n c e of t h e s e e x p e ct e d e v e nt s d ur i n g t h e st u d y. 
A n a g gr e g at e r e p ort of a n y cli ni c all y r el e v a nt i m b al a n c e s t h at d o n ot f a v or t h e t e st 
pr o d u ct will b e s u b mitt e d t o H e alt h A ut h oriti e s.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
9 8 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


6.  
S T A TI S TI C A L C O N SI D E R A T I O N S A N D A N A L Y SI S P L A N
T h e a n al y s e s of t hi s st u d y will b e str u ct ur e d i nt o t w o p art s;  e x pl or at or y ( P art  1 ) t o s el e ct 
t h e d o s e a n d c o nfir m at or y (P art  2 ) t o e v al u at e t h e tr e at m e nt eff e ct of ri s di pl a m. T h e 
c o nfir m at or y a n al y s e s will o nl y i n cl u d e t h e i nf a nt s  e nr oll e d i nt o P art  2  of t h e st u d y; it will 
n ot i n cl u d e t h e  P art  1  i nf a nt s w h o will b e a n al y z e d t o s el e ct t h e d o s e.
F oll o wi n g t h e d o s e s el e c ti o n f or P art 2, d at a fr o m t h e e x pl or at or y P art  1 of t hi s st u d y 
( a n d t h e P art 1 e xt e n si o n p h a s e) m a y b e l o c k e d at i nt er v al s i n or d er t o a n al y z e a n d 
r e p ort t h e s af et y, P K/ P D, a n d e x pl or at or y effi c a c y of t h o s e p ati e nt s e nr oll e d i nt o P art  1 
o nl y.
A d at a b a s e l o c k f or t h e p ur p o s e of t h e pri m ar y a n al y si s a n d a n a l y s e s of t h e 1 2-m o nt h 
s e c o n d ar y a n d e x pl or at or y e n d p oi nt s will o c c ur o n c e t h e l a st i nf a nt e nr oll e d i nt o P art  2 
d uri n g t h e gl o b al e nr oll m e nt p h a s e  h a s ei t h er c o m pl et e d hi s/ h er 1 2-m o nt h a s s e s s m e nt 
or h a s b e e n wit h dr a w n.  At t h e ti m e of t h e pri m ar y a n al y si s, all a v ail a bl e effi c a c y d at a 
p o st M o nt h  1 2 will b e r e p ort e d . All a v ail a bl e s af et y d at a i n b ot h p art s of t h e st u d y will b e 
r e p ort e d. A d at a b a s e l o c k f or  t h e a n al y s e s of t h e 2 4-m o nt h s e c o n d ar y a n d e x pl or at or y 
e n d p oi nt s will o c c ur o n c e t h e l a st i nf a nt e nr oll e d i nt o  P art  2  d uri n g t h e gl o b al e nr oll m e nt 
p h a s e h a s eit h er c o m pl et e d hi s/ h er 2 4 -m o nt h a s s e s s m e nt or h a s b e e n wit h dr a w n.  At t h e 
ti m e of t h e M o nt h 2 4 a n a l y si s, all a v ail a bl e effi c a c y d at a p o st M o nt h 2 4 c oll e ct e d a s p art 
of  t h e e xt e n si o n p eri o d will al s o b e r e p ort e d. All a v ail a bl e s af et y d at a i n b ot h p art s of t h e 
st u d y will b e r e p ort e d.
F oll o wi n g t h e pri m ar y a n al y si s, s u b s e q u e nt l o c k s of t h e d at a b a s e m a y o c c ur i n or d er t o 
p erf or m s af et y a n al y s e s of t h e d at a at f urt h er ti m e -p oi nt s d uri n g t h e st u d y. T h e fi n al 
d at a b a s e l o c k will o c c ur at st u d y e n d (i. e.,  l a st p ati e nt, l a st o b s er v ati o n).
F ull d et ail s of t h e st ati sti c al m et h o d s f or t h e c o nfir m at or y p art  h a v e b e e n  pr e -s p e cifi e d 
wit hi n t h e St ati sti c al A n al y si s Pl a n ( S A P) pri or t o t h e fir st i nf a nt e nr oll e d i nt o  P art  2 .
T h e gl o b al p o p ul ati o n will i n cl u d e all i nf a nt s e nr oll e d d uri n g t h e gl o b al e nr oll m e nt p h a s e 
(i n cl u di n g i nf a nt s e nr oll e d at  
-r e c o g ni z e d sit e s d uri n g t h e gl o b al p h a s e), a n d t h e 
C hi n a s u b p o p ul ati o n will i n cl u d e all i nf a nt s e nr oll e d at  
-r e c o g ni z e d sit e s 
(i. e., d uri n g b ot h t h e gl o b al e nr oll m e nt p h a s e a n d t h e e xt e n d e d C hi n a e nr oll m e nt p h a s e). 
S e p ar at e a n al y s e s will b e p erf or m e d f or t h e gl o b al p o p ul ati o n a n d t h e C hi n a 
s u b p o p ul ati o n ( s e e S e cti o n  6. 1 0  f or i nf or m ati o n o n t h e C hi n a su b p o p ul ati o n a n al y s e s).
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
9 9 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


6. 1
D E T E R MI N A TI O N O F S A M P L E SI Z E
E x pl or at or y  P art 1
T h e t ar g et s a m pl e si z e i s 8 i nfa nt s , 4 e nr oll e d t o e a c h d o s e l e v el. Wit h 8 i nf a nt s e x p o s e d 
t o ri s di pl a m, t h er e i s o v er a n 8 0 % c h a n c e t o d et e ct a n A E i n at l e a st o n e p ati e nt, gi v e n 
t h at t h e tr u e u n d erl yi n g a d v er s e e v e nt r at e i s 2 0 %. Wi t h 4 i nfa nt s e x p o s e d at e a c h d o s e 
l e v el, t h e pr o b a bilit y t o d et e ct a n A E i n at l e a st o n e p ati e nt, gi v e n t h at t h e tr u e u n d erl yi n g 
a d v er s e e v e nt r at e i s 3 0 %, i s 7 6 %.
I n or d er t o e n a bl e t h e d o s e s el e cti o n f or P art 2 ( e. g., t o t a k e i nt o a c c o u nt a n d a s s e s s 
v ari a bi lit y of P K wit h diff er e nt a g e or b o d y w ei g ht of t h e i nf a nt s), 1 6 a d diti o n al p ati e nt s 
m a y b e e nr oll e d i n P art 1 , f or u p t o a m a xi m u m t ot al n u m b er of 2 4 p ati e nt s .
C o nfir m at or y  P art 2
T h e p ur p o s e of t hi s p art of t h e st u d y i s t o e sti m at e t h e pr o p orti o n of i nf a nt s w h o ar e 
sitti n g wit h o ut s u p p ort at 1 2 m o nt h s
of tr e at m e nt a n d t o t e st w h et h er t hi s pr o p orti o n i s 
hi g h er t h a n a p erf or m a n c e crit eri o n s et at 5 %. T hi s 5 % t hr e s h ol d w a s c h o s e n b a s e d o n 
t h e n at ur al hi st or y of t h e di s e a s e, t y pi c all y t h at T y p e 1 S M A p ati e nt s n e v er a c hi e v e 
sitti n g wit h o ut s u p p ort b y d efi niti o n.
T h e t ar g et s a m pl e si z e i s 4 0 i nfa nt s . T hi s s a m pl e si z e pr o vi d e s at l e a st 9 0 % p o w er t o 
t e st t h e n ull h y p ot h e si s H o: p 5 % v er s u s alt er n ati v e h y p ot h e si s H a: p 5 %, if t h e tr u e 
pr o p orti o n of i nf a nt s w h o w o ul d sit o n tr e at m e nt i s 2 0 %. T hi s i s b a s e d o n a n e x a ct 
bi n o mi al t e st wit h a o n e -si d e d 5 % si g nifi c a n c e l e v el. T h e mi ni m u m n u m b er of i nf a nt s 
n e e d e d t o b e o b s er v e d sitti n g i s 5 o ut of 4 0 f or a st ati sti c all y si g nifi c a nt r e s ult . If m or e 
t h a n 4 0 i nf a nt s ar e e nr oll e d, t h e n u m b er of b a bi e s r e q uir e d t o m e et t h e pri m ar y e n d p oi nt 
will i n cr e a s e. F urt h er d et ail s ar e pr o vi d e d i n t h e S A P. If i n P art 2, 5 o ut of 4 0 i nf a nt s sit 
t h e l o w er li mit of t h e t w o-si d e d 9 0 % Cl o p p er -P e ar s o n ( E x a ct) c o nfi d e n c e i nt er v al w o ul d 
b e a b o v e 5 %.
N o all o w a n c e h a s b e e n m a d e f or i nf a nt s w h o wit h dr a w e arl y a s t h e s e i nf a nt s will b e 
cl a s sifi e d a s a n o n -r e s p o n d er/ n o n-sitt er a n d i n cl u d e d wit hi n t h e pri m ar y a n al y si s.
6. 2
S U M M A RI E S O F C O N D U C T O F S T U D Y
T h e n u m b er of i nf a nt s w h o w er e e nr oll e d, di s c o nti n u e d,  c o nti n ui n g tr e at m e nt at t h e ti m e 
of  t h e a n al y si s or h a v e c o m pl et e d t h e st u d y will b e s u m m ari z e d. R e a s o n s f or pr e m at ur e 
st u d y wit h dr a w al will b e li st e d a n d s u m m ari z e d. E nr oll m e nt a n d m aj or pr ot o c ol 
d e vi ati o n s will b e li st e d a n d e v al u at e d f or t h eir p ot e nti a l eff e ct s o n t h e i nt er pr et ati o n of 
st u d y r e s ult s . D at a will b e pr e s e nt e d f or e a c h p art of t h e st u d y s e p ar at el y a n d 
s u m m ari e s f or  P art  1  will b e pr e s e nt e d o v er all a n d b y d o s e/ e x p o s ur e l e v el.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
1 0 0 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 0 1 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
6. 3
A N A L Y SI S P O P U L A TI O N S
6. 3. 1
S af et y  An al y si s P o p ul ati o n
All i nf a nt s w h o r e c ei v e at l e a st o n e d o s e of st u d y m e di c ati o n ( ri s di pl a m) will b e i n cl u d e d 
i n t h e s af et y p o p ul ati o n. I nf a nt s will b e gr o u p e d a c c or di n g t o t h e d o s e/ e x p o s ur e l e v el 
a ct u all y r e c ei v e d i n P art 1.
6. 3. 2
P h ar m a c o ki n eti c A n al y si s P o p ul ati o n
All i nf a nt s wit h at l e a st o n e ti m e-p oi nt wit h a m e a s ur e a bl e c o n c e ntr ati o n will b e i n cl u d e d 
i n t h e P K a n al y si s d at a s et. I nf a nt s will b e e x cl u d e d fr o m t h e p h ar m a c o ki n eti c a n al y si s 
p o p ul ati o n if t h e y si g nifi c a ntl y vi ol at e t h e i n cl u si o n or e x cl u si o n crit eri a, d e vi at e 
si g nifi c a ntl y fr o m t h e pr ot o c ol or if d at a ar e u n a v ail a bl e or i n c o m pl et e w hi c h m a y 
i nfl u e n c e t h e p h ar m a c o ki n eti c a n al y si s. E x cl u d e d c a s e s will b e d o c u m e nt e d t o g et h er 
wit h t h e r e a s o n f or e x cl u si o n.
6. 3. 3
Effi c a c y  An al y si s P o p ul ati o n
T h e i nt e nt-t o-tr e at (I T T) p o p ul ati o n will b e t h e pri m ar y a n al y si s p o p ul ati o n f or all effi c a c y 
a n al y s e s. T h e I T T p o p ul ati o n i s d efi n e d a s all e nr oll e d i nf a nt s, r e g ar dl e s s of w h et h er 
t h e y r e c ei v e d tr e at m e nt or n ot.
6. 4
S U M M A RI E S O F T R E A T M E N T G R O U P C O M P A R A BI LI T Y
D e m o gr a p hi c a n d ot h er b a s eli n e c h ar a ct eri sti c s wil l b e s u m m ari z e d f or t h e I T T 
p o p ul ati o n u si n g d e s cri pti v e st ati sti c s, m e a n s, st a n d ar d d e vi ati o n s, m e di a n s, 
i nt er q u artil e r a n g e s a n d r a n g e s f or c o nti n u o u s v ari a bl e s a n d n u m b er a n d p er c e nt a g e s 
f or c at e g ori c al v ari a bl e s, a s a p pr o pri at e. B a s eli n e will b e d efi n ed a s t h e l a st 
m e a s ur e m e nt pri or t o e nr oll m e nt u nl e s s s p e cifi e d ot h er wi s e i n t h e S A P. D at a will b e 
pr e s e nt e d f or e a c h p art of t h e st u d y s e p ar at el y a n d s u m m ari e s f or P art 1 will al s o b e 
pr e s e nt e d b y d o s e/ e x p o s ur e l e v el.
6. 5
S A F E T Y A N A L Y S E S
T h e s af et y e n d p oi nt s i n cl u d e, b ut m a y n ot b e li mit e d t o, t h e f oll o wi n g:

I n ci d e n c e of a d v er s e e v e nt s ( o v er all, b y s e v erit y a n d b y r el ati o n s hi p t o st u d y
m e di c ati o n).

I n ci d e n c e of s eri o u s a d v er s e e v e nt s.

I n ci d e n c e of tr e at m e nt di s c o nti n u ati o n s d u e t o a d v er s e e v e nt s.

I n ci d e n c e of l a b or at or y a b n or m aliti e s.

I n ci d e n c e of E C G a b n or m aliti e s.

I n ci d e n c e of vit al si g n a b n or m aliti e s.

I n ci d e n c e of cli ni c all y si g nifi c a nt fi n di n g s o n o p ht h al m ol o gi c al e x a mi n ati o n.

A nt hr o p o m etri c e x a mi n ati o n i n cl u di n g w ei g ht, h ei g ht, h e a d, a n d c h e st
cir c u mf er e n c e.


S af et y d at a will b e s u m m ari z e d d e s cri pti v el y u si n g t h e s af et y p o p ul ati o n. I n P art 1 , 
s af et y d at a will b e pr e s e nt e d i n s u m m ari e s, li sti n g s or i n di vi d u al p ati e nt pl ot s 
( a s a p pr o pri at e) b y d o s e/ e x p o s ur e l e v el. F or P art 2 , t h e s af et y d at a will b e s u m m ari z ed 
d e s cri pti v el y f or t h e fir st 1 2 -m o nt h p eri o d (i. e.,
1 2 -m o nt h d at a f or e a c h i n di vi d u al i nf a nt) 
a n d f or all a v ail a bl e s af et y d at a c oll e ct e d at t h e ti m e of t h e a n al y si s. Si mil ar s u m m ari e s 
f or t h e fir st 2 4-m o nt h p eri o d will b e pr e s e nt e d at t h e ti m e of t h e 2 4 -m o nt h a n al y si s 
r e p orti n g e v e nt.
A n al y s e s r e q uir e d f or t h e I M C or i D M C’ s d at a r e vi e w will b e p erf or m e d a s d e s cri b e d i n 
t h e a s s o ci at e d I M C or i D M C C h art er.
6. 5. 1
A d v er s e E v e nt s
T h e ori gi n al t er m s r e c or d e d o n t h e e C R F b y t h e I n v e sti g at or f or a d v er s e e v e nt s will b e 
st a n d ar di z e d b y t h e S p o n s or. A d v er s e e v e nt s ( A E s) will b e s u m m ari z e d b y m a p p e d t er m 
a n d a p pr o pri at e t h e s a ur u s l e v el. A E s will al s o b e s u m m ari z e d b y s e v erit y a n d 
r el ati o n s hi p t o t h e st u d y dr u g. S eri o u s A E s a n d A E s l e a di n g t o tr e at m e nt di s c o nti n u ati o n 
will b e s u m m ari z e d s e p ar at el y.
6. 5. 2
Cli ni c al L a b or at or y  T e st R e s ult s
All cli ni c al l a b or at or y d at a will b e st or e d o n t h e d at a b a s e i n t h e u nit s i n w hi c h t h e y w er e 
r e p ort e d. P ati e nt s’ li sti n g s a n d s u m m ar y st ati sti c s at e a c h a s s e s s m e nt ti m e will b e 
pr e s e nt e d u si n g t h e I n t er n ati o n al S y st e m of U nit s ( SI u nit s; S y st è m e I nt er n ati o n al 
d’ U nit é s). L a b or at or y d at a n ot r e p ort e d i n SI u nit s will b e c o n v ert e d t o SI u nit s b ef or e 
pr o c e s si n g.
L a b or at or y d at a will b e li st e d f or p ati e nt s wit h v al u e s o ut si d e t h e n or m al r a n g e s. 
I n a d diti o n , s hift t a bl e s t o c o m p ar e t h e st at u s at b a s eli n e t o e a c h ti m e-p oi nt 
p o st -b a s eli n e a n d o v er all, will b e u s e d, a s a p pr o pri at e.
6. 5. 3
Vit al Si g n s
Vit al si g n s d at a will b e li st e d f or p ati e nt s wit h v al u e s o ut si d e t h e n or m al r a n g e s. 
I n a d diti o n, t a b ul ar s u m m ari e s will b e u s e d, a s a p pr o pri at e.
6. 5. 4
El e ctr o c ar di o gr a m D at a A n al y si s
E C G d at a will b e li st e d f or p ati e nt s wit h v al u e s o ut si d e t h e n or m al r a n g e s. I n a d diti o n, 
t a b ul ar s u m m ari e s will b e u s e d, a s a p pr o pri at e.
6. 5. 5
C o n c o mit a nt M e di c ati o n s
T h e ori gi n al t er m s r e c or d e d o n t h e p a ti e nt’ s e C R F b y t h e I n v e sti g at or f or c o n c o mit a nt 
m e di c ati o n s will b e st a n d ar di z e d b y t h e S p o n s or b y a s si g ni n g pr ef err e d t er m s. 
C o n c o mit a nt m e di c ati o n s will b e pr e s e nt e d i n s u m m ar y t a bl e s.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
1 0 2 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 0 3 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
6. 6
E F FI C A C Y A N A L Y S E S
T h e i nt e nt -t o-tr e at (I T T) p o p ul ati o n will b e t h e pri m ar y a n al y si s p o p ul ati o n f or all effi c a c y 
a n al y s e s. T h e c o nfir m at or y effi c a c y a n al y s e s will o nl y i n cl u d e d at a fr o m t h e i nf a nt s 
e nr oll e d i nt o P art 2 of t h e st u d y; it will n ot i n cl u d e d at a fr o m t h e P art 1 i nfa nt s w h o will b e 
a n al y z e d t o s el e ct t h e d o s e. E ffi c a c y d at a of t h e i nf a nt s e nr oll e d i nt o P art 1 will b e 
s u m m ari z e d d e s cri pti v el y, u si n g i n di vi d u al p ati e nt pl ot s or li sti n g s ( a s a p pr o pri at e) a n d 
pr e s e nt e d s e p ar at el y fr o m t h e c o nfir m at or y effi c a c y a n al y si s of P art 2.
6. 6. 1
Pri m ar y  Effi c a c y E n d p oi nt
T h e pri m ar y e n d p oi nt f or t h e c o nfir m at or y P art 2 of  t h e st u d y i s t h e pr o p orti o n of i nf a nt s 
w h o ar e sitti n g wit h o ut s u p p ort aft er 1 2 m o nt h s of tr e at m e nt. I nf a nt s w h o d o n ot a c hi e v e 
sitti n g, or h a v e n ot m ai nt ai n e d sitti n g a c hi e v e d e arli er, or h a v e b e e n wit h dr a w n, or di e d, 
will b e cl a s sifi e d a s n o n -r e s p o n d er s (i. e., n o n -sitt er s) f or t h e pri m ar y a n al y si s. Sitti n g i s 
d ef i n e d a s ‘ sit s wit h o ut s u p p ort f or 5 s e c o n d s’ a s a s s e s s e d i n It e m 2 2 of t h e B SI D -III
gr o s s m ot or s c al e. T h e a s s e s s m e nt of t h e i n d e p e n d e nt c e ntr al r e a d er s wi ll b e u s e d f or 
t h e pri m ar y a n al y si s.
T h e pr o p orti o n of i nf a nt s w h o ar e ali v e a n d sitti n g aft er 1 2 m o nt h s of tr e at m e nt will b e 
pr e s e nt e d wit h a t w o -si d e d 9 0 % Cl o p p er -P e ar s o n ( E x a ct) c o nfi d e n c e i nt er v al. A n e x a ct 
bi n o mi al t e st will b e p erf or m e d. T h e h y p ot h e si s t o b e t e st e d i s t h at t h e pr o p orti o n of 
i nf a nt s w h o sit o n tr e at m e nt ( p) i s:
H o: p 5 % ( n ull) v er s u s H a: p 5 % ( alt er n ati v e).
If t h e o n e-si d e d p- v al u e i s5 % ( T y p e 1 err or r at e) t h e n, t h e n ull h y p ot h e si s will b e 
r ej e ct e d. If t h e l o w er li mit of t h e t w o-si d e d 9 0 % c o nfi d e n c e i nt er v al i s a b o v e t h e 5 % 
t hr e s h ol d, t h e pri m ar y o bj e cti v e of t h e st u d y will b e c o n si d er e d a c hi e v e d.
6. 6. 2
S e c o n d ar y  Effi c a c y E n d p oi nt s
T h e s e c o n d ar y effi c a c y e n d p oi nt s i n P art 2 ar e a s f oll o w s:
M ot or F u n cti o n a n d D e v el o p m e nt Mil e st o n e s

Pr o p orti o n of i nf a nt s w h o a c hi e v e a s c or e of 4 0 or hi g h er i n t h e C H O P -I N T E N D at
M o nt h
1 2 .
I nf a nt s w h o d o n ot a c hi e v e a s c or e of at l e a st 4 0, or h a v e n ot m ai nt ai n e d t hi s s c or e
a c hi e v e d e arli er, or h a v e b e e n wit h dr a w n, or di e d, will b e cl a s sifi e d a s
n o n -r e s p o n d er s f or t h e a n al y si s.

Pr o p orti o n of i nf a nt s w h o a c hi e v e a n i n cr e a s e of at l e a st 4 p oi nt s i n t h eir
C H O P -I N T E N D s c or e fr o m b a s eli n e at M o nt h 8 a n d M o nt h 1 2.

Pr o p orti o n of i nf a nt s w h o a c hi e v e h e a d c o ntr ol at M o nt h 8, M o nt h
1 2, a n d M o nt h
2 4
( d efi n e d a s a s c or e of 3 or hi g h er f or it e m 1 2 of t h e C H O P -I N T E N D).

C h a n g e fr o m b a s eli n e i n t h e T ot al R a w S c or e of t h e B SI D -III gr o s s m ot or s c al e at
M o nt h
1 2 .


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 0 4 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7

C h a n g e fr o m b a s eli n e i n t h e T ot al R a w S c or e of t h e B SI D -III gr o s s m ot or s c al e at
M o nt h
2 4 .

Pr o p orti o n of i nf a nt s w h o a c hi e v e t h e att ai n m e nt l e v el s of t h e m ot or mil e st o n e s a s
a s s e s s e d i n t h e HI N E - 2* at M o nt h
8 ( s u b s et #), M o nt h
1 2 a n d M o nt h
2 4 .
*Mil e st o n e s of: h e a d c o ntr ol #, sitti n g, v ol u nt ar y gr a s p, a bilit y t o ki c k #, r olli n g #,
cr a wli n g, st a n di n g a n d w al ki n g.

Pr o p orti o n of m ot or mil e st o n e r e s p o n d er s a s a s s e s s e d b y HI N E -2 at M o nt h 1 2 a n d
M o nt h
2 4.

Hi g h e st m ot or mil e st o n e* a c hi e v e d b y M o nt h
1 2 a n d M o nt h
2 4 .
* Mil e st o n e s of: h e a d c o ntr ol (it e m 9 ‘ C o ntr ol s h e a d w hil e u pri g ht f or 1 5 s e c o n d s’ ),
r olli n g (it e m 1 4 ‘ R oll s fr o m si d e t o b a c k’), sitti n g wit h o ut s u p p ort ( pri m ar y e n d p oi nt),
cr a wli n g ( it e m 3 0 ‘ Cr a wl s o n st o m a c h’), st a n di n g (it e m 4 0 ‘ St a n d s Al o n e’) a n d
w a l ki n g (it e m 4 2 ‘ Wal k s Al o n e’) a s a s s e s s e d i n t h e B SI D -III gr o s s m ot or s c al e.

Pr o p orti o n of i nf a n t s w h o ar e ali v e a n d sitti n g wit h o ut s u p p ort f or 5 s e c o n d s at
M o nt h
2 4 ( d efi n e d a s p er t h e pri m ar y e n d p oi nt).

Pr o p orti o n of i nf a nt s w h o ar e ali v e a n d sitti n g wit h o ut s u p p ort f or 3 0 s e c o n d s at
M o nt h
2 4 ( d efi n e d a s “ Sit s wit h o ut s u p p ort f or 3 0 s e c o n d s” a s a s s e s s e d i n It e m 2 6
of  t h e B SI D-III gr o s s m ot or s c al e).

Pr o p orti o n of i nf a nt s w h o ar e ali v e a n d st a n di n g at M o nt h
2 4 ( d efi n e d a s ‘ St a n d s
Al o n e’ a s a s s e s s e d i n It e m 4 0 of t h e B SI D -III gr o s s m ot or s c al e).

Pr o p orti o n of i nf a nt s w h o ar e ali v e a n d w al ki n g at M o nt h
2 4 ( d efi n e d a s ‘W al k s
Al o n e’ a s a s s e s s e d i n It e m 4 2 of t h e B SI D -III gr o s s m ot or s c al e).
F or t h e a c hi e v e m e nt of sitti n g, st a n di n g a n d w al ki n g at M o nt h 2 4, i nf a nt s w h o d o n ot 
a c hi e v e t h e mil e st o n e, or h a v e n ot m ai nt ai n e d t hi s mil e st o n e a c hi e v e d e arli er, or h a v e 
b e e n wit h dr a w n or di e d, will b e cl a s sifi e d a s a n o n -r e s p o n d er f or t h e a n al y si s.
S ur vi v al a n d V e ntil ati o n -Fr e e S ur vi v al

Ti m e t o d e at h or p er m a n e nt v e ntil ati o n (fr o m e nr oll m e nt). P er m a n e nt v e ntil ati o n i s
d ef i n e d a s 1 6 h o ur s of n o n -i n v a si v e v e ntil ati o n p er d a y or i nt u b ati o n
f or2 1 c o n s e c uti v e d a y s i n t h e a b s e n c e of, or f oll o wi n g t h e r e s ol uti o n of, a n a c ut e
r e v er si bl e e v e nt or tr a c h e o st o m y.

Ti m e t o d e at h (fr o m e nr oll m e nt).

Pr o p orti o n of i nf a nt s w h o ar e ali v e wit h o ut p er m a n e nt v e ntil ati o n at M o nt h
1 2 .

Pr o p orti o n of i nf a nt s w h o ar e ali v e wit h o ut p er m a n e nt v e ntil ati o n at M o nt h
2 4.

Pr o p orti o n of i nf a nt s w h o ar e ali v e at M o nt h 1 2.

Pr o p orti o n of i nf a nt s w h o ar e ali v e at M o nt h 2 4.


R e s pir at or y

Ti m e t o p er m a n e nt v e ntil ati o n (fr o m e nr oll m e nt).

Pr o p orti o n of i nf a nt s w h o ar e wit h o ut p er m a n e nt v e ntil ati o n at M o nt h 1 2.

Pr o p orti o n of i nf a nt s w h o ar e wit h o ut p er m a n e nt v e ntil ati o n at M o nt h 2 4.

Pr o p orti o n of i nf a nt s w h o a c hi e v e a r e d u cti o n of at l e a st 3 0 d e gr e e s i n t h eir p h a s e
a n gl e fr o m b a s eli n e, a s m e a s ur e d b y R P, at M o nt h
1 2 .
I nf a nt s w h o d o n ot a c hi e v e a r e d u cti o n of at l e a st 3 0 d e gr e e s , or h a v e n ot
m ai nt ai n e d t hi s l e v el of r e d u cti o n if a c hi e v e d e arli er, or h a v e b e e n wit h dr a w n or di e d,
will b e cl a s sifi e d a s n o n -r e s p o n d er s f or t h e a n al y si s.

Pr o p orti o n of i nf a nt s w h o d o n ot r e q uir e i n v a si v e or n o n -i n v a si v e r e s pir at or y s u p p ort
at M o nt h 1 2 a n d M o nt h 2 4.
N utriti o n

Pr o p orti o n of i nf a nt s wit h t h e a bilit y t o f e e d or all y at M o nt h 1 2 a n d M o nt h 2 4.
A n al y s e s of t h e s e c o n d ar y effi c a c y e n d p oi nt s will b e p erf or m e d  o n all d at a a v ail a bl e i n 
P art  2  at t h e ti m e of t h e 1 2 - or 2 4 -m o nt h a n al y si s r e p orti n g e v e nt s.
All s e c o n d ar y e n d p oi nt s ( e x c e pt f or ti m e -t o-e v e nt) will b e s u m m ari z e d b y ti m e -p oi nt f or 
t h e I T T p o p ul ati o n u si n g d e s cri pti v e st ati sti c s. At M o nt h s 1 2 a n d 2 4, t w o -si d e d 9 0 % 
c o nfi d e n c e i nt er v al s will al s o b e pr e s e nt e d, a s a p pr o pri at e.
T h e hi g h e st m ot or mil e st o n e a c hi e v e d b y t h e i nf a nt at a n y ti m e d uri n g t h e fir st 
1 2  m o nt h s ( a n d fir st  2 4  m o nt h s ) of tr e at m e nt will b e s u m m ari z e d u si n g n u m b er a n d 
p er c e nt a g e s b a s e d o n t h e I T T p o p ul ati o n. T hi s i s r e g ar dl e s s of t h e m ai nt e n a n c e of eff e ct 
or s u b s e q u e nt s ur vi v al st at u s of t h e i nf a nt. I n a d diti o n, t h e n u m b er a n d p er c e nt a g e of 
i nf a nt s wit hi n e a c h att ai n m e nt r e s p o n s e c at e g or y of t h e HI N E-2  m ot or mil e st o n e s  at 
M o nt h  1 2 a n d  M o nt h  2 4  will b e pr e s e nt e d. T h e pr o p orti o n of m ot or mil e st o n e r e s p o n d er s  
( a s a s s e s s e d b y HI N E-2) will b e s u m m ari z e d at M o nt h  1 2 a n d M o nt h  2 4. F or t h e 
r e s p o n d er d efi niti o n a n i m pr o v e m e nt i n a m ot or mil e st o n e i s d efi n e d a s at l e a st a 2 -p oi nt 
i n cr e a s e i n a bilit y t o ki c k ( or m a xi m al s c or e) or a 1-p oi nt i n cr e a s e i n h e a d c o ntr ol, r olli n g, 
sitti n g, cr a wli n g, st a n di n g, or w al ki n g.  W o r s e ni n g i s si mil arl y d efi n e d a s a 2-p oi nt 
d e cr e a s e i n a bilit y t o ki c k ( or l o w e st s c or e) or a 1 -p oi nt d e cr e a s e i n h e a d c o ntr ol, r olli n g, 
sitti n g, cr a wli n g, st a n di n g, or w al ki n g. A n i nf a nt i s cl a s sifi e d a s a r e s p o n d er if m or e m ot or 
mil e st o n e s s h o w e d i m pr o v e m e nt t h a n s h o w e d w or s e ni n g; i nf a nt s w h o di e or wit h dr a w 
will b e cl a s sifi e d a s n o nr e s p o n d er s.
Ti m e -t o-d e at h or p er m a n e nt v e ntil ati o n a n d it s i n di vi d u al c o m p o n e nt s  will b e pr e s e nt e d 
gr a p hi c all y u si n g  K a pl a n -M ei er  c ur v e s. T h e m e di a n ti m e t o  v e ntil ati o n -fr e e s ur vi v al a n d 
t h e pr o p orti o n of i nf a nt s w h o ar e s ur vi vi n g v e ntil ati o n -fr e e at M o nt h s  1 2 a n d  2 4  will b e 
e sti m at e d u si n g  K a pl a n -M e i er m et h o d ol o g y, w h e n p o s si bl e. Ti m e -t o-d e at h or p er m a n e nt 
v e ntil ati o n i s d efi n e d a s t h e ti m e i n m o nt h s fr o m t h e d at e of e nr oll m e nt i nt o t h e st u d y 
u ntil t h e d at e of d e at h fr o m a n y c a u s e or d at e of p er m a n e nt v e ntil ati o n, w hi c h e v er e v e nt 
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
1 0 5 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


o c c ur s fir st. I nf a nt s wit h n o e v e nt r e p ort e d pri or t o t h e a n al y si s c ut - off d at e will b e 
c e n s or e d at t h e l at e st d at e b ef or e t h e c ut - off i n w hi c h t h e y w er e k n o w n t o b e ali v e a n d 
v e ntil ati o n -fr e e. T h e o c c urr e n c e of a p er m a n e nt v e ntil ati o n e v e nt will b e d et er mi n e d b y 
t h e i n d e p e n d e nt P er m a n e nt V e ntil ati o n A dj u di c ati o n C o m mitt e e .
T h e pr o p orti o n of i nf a nt s w h o at  2 4  m o nt h s  of tr e at m e nt ar e ali v e a n d ( 1)  sitti n g wit h o ut 
s u p p ort  f or 5 s e c o n d s, ( 2) sitti n g wit h o ut s u p p ort f or 3 0  s e c o n d s , (3)  st a n di n g, a n d 
( 4) w al ki n g will b e a n al y z e d a s f or t h e pri m ar y e n d p oi nt t e sti n g t h e s a m e n ull h y p ot h e si s  
t h at t h e pr o p orti o n of i nf a nt s w h o ar e ali v e a n d h a v e a c hi e v e d t h e m ot or mil e st o n e 5 %
( n ull) v er s u s p 5 % ( alt er n ati v e).
T h e r e s ult s of ot h er  s e c o n d ar y e n d p oi nt s will b e c o m p ar e d t o, a n d p ut i nt o c o nt e xt w it h, 
r e s ult s of si mil ar c o h ort s of u ntr e at e d T y p e  1  S M A i nf a nt s c o n str u ct e d fr o m r e al w orl d 
d at a s o ur c e s/ n at ur al hi st or y st u di e s a n d ot h er cli ni c al tri al s, w h e n d at a f or t h e e n d p oi nt i s 
a v ail a bl e.  W h e n p u bli cl y a v ail a bl e r e al w orl d p ati e nt l e v el d at a e xi st s, s u m m ar y d at a h a s 
b e e n g e n er at e d fr o m a c o h ort of p ati e nt s d efi n e d u si n g t h e st u d y i n cl u si o n/ e x cl u si o n 
crit eri a, w h e n e v er p o s si bl e. 
T h e hi st ori c al c o ntr ol d at a a v ail a bl e  t o d at e w a s u s e d t o d eri v e a n u m eri c al v al u e t o 
s er v e a s a pr e d efi n e d b e n c h m ar k (i. e.,  a n o bj e cti v e p erf or m a n c e crit eri a or p erf or m a n c e 
g o al) ( Fr e n c h et al 2 0 1 0; W i e n s et al 2 0 1 4) a g ai n st w hi c h t o  a s s e s s t h e effi c a c y of 
tr e at m e nt. If m ulti pl e s o ur c e s of d at a w er e a v ail a bl e f or a s e c o n d ar y e n d p oi nt, t h e c o h ort 
wit h t h e b a s eli n e c h ar a ct eri sti c s m o st si mil ar t o t h o s e t ar g et e d b y t h e st u d y i n cl u si o n a n d 
e x cl u si o n crit eri a w a s u s e d. T h e b e n c h m ar k i s b a s e d o n t h e a s s o ci at e d u p p er li mit of  t h e 
9 0 % c o nfi d e n c e i nt e r v al fr o m t h e hi st ori c al d at a. W h e n a pr e d efi n e d b e n c h m ar k c o ul d b e 
d et er mi n e d f or t h e s e c o n d ar y e n d p oi nt, h y p ot h e s i s t e sti n g will b e p erf or m e d.
T h e h y p ot h e si s t o b e t e st e d i s t h at t h e tr e at m e nt r e s p o n s e r at e ( p) i s:
H o: p pr e d efi n e d b e n c h m ar k ( n ull) v er s u s H a: p b e n c h m ar k ( alt er n ati v e).
If t h e o n e- si d e d p- v al u e  i s 5 % ( n o mi n al) t h e n t h e  n ull h y p ot h e si s  will b e r ej e ct e d.
T o c o ntr ol f or m ulti pli cit y a cr o s s t h e diff er e nt e n d p oi nt s, a h i er ar c hi c al t e sti n g a p pr o a c h 
will b e i m pl e m e nt e d.
T h e fir st s e c o n d ar y effi c a c y e n d p oi nt of t h e pr o p orti o n of i nf a nt s w h o a c hi e v e a s c or e of 
4 0 or hi g h er i n t h e  C H O P -IN T E N D  at M o nt h  1 2  will b e t e st e d if a n d o nl y if t h e pri m ar y 
e n d p oi nt h a s r e a c h e d t h e 5 % si g nifi c a nt l e v el (i. e.,  p- v al u e  ≤ 0. 0 5). Ot h er s e c o n d ar y 
e n d p oi nt s will b e t e st e d at a 5 % si g nifi c a n c e l e v el a c c or di n g t o  t h e hi er ar c h y t h at  h a s 
b e e n  pr e - sp e cifi e d i n t h e S A P a s l o n g a s t h e p - val u e i s  ≤ 0. 0 5 f or e n d p oi nt s hi g h er i n t h e 
hi er ar c h y.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
1 0 6 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 0 7 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
F ull d et ail s of t h e s e c o n d ar y a n al y si s i n cl u di n g t h e a v ail a bl e s o ur c e s t o b e u s e d a s t h e 
e xt er n al c o ntr ol a n d t h e b e n c h m ar k s/ p erf or m a n c e crit eri a t o b e u s e d i n t h e a n al y si s 
(i n cl u di n g t h e a ct u al n ull h y p ot h e si s r e s p o n s e r at e s t o b e t e st e d) h a v e b e e n pr e d efi n e d 
a n d j u stifi e d wit hi n t h e S A P, pri or t o t h e fir st p ati e nt e nr oll e d wit hi n t h e c o nfir m at or y 
P art 2.
6. 6. 3
E x pl or at or y  Effi c a c y E n d p oi nt s
T h e e x pl or at or y effi c a c y e n d p oi nt s i n P art 2 i n cl u d e, b ut m a y n ot b e li mit e d t o, t h e 
f oll o wi n g:
M ai nt e n a n c e of 1 2 -M o nt h Tr e at m e nt Eff e ct

Pr o p orti o n of i nf a nt s w h o m ai nt ai n e d sitti n g at M o nt h 2 4 (f or i nf a nt s sitti n g at
M o nt h
1 2; d efi n e d a s p er t h e pri m ar y e n d p oi nt).
I nf a nt s w h o h a v e n ot m ai nt ai n e d sitti n g, or h a v e b e e n wit h dr a w n or di e d, will b e
cl a s sifi e d a s n o n -r e s p o n d er s (i. e., n ot m ai nt a i n e d sitti n g) f or t h e a n al y si s.

Pr o p orti o n of i nf a nt s w h o m ai nt ai n e d ( or c o nti n u e d t o i m pr o v e) t h eir p h a s e a n gl e
r e d u cti o n at M o nt h
2 4 (f or i nf a nt s wit h a p h a s e a n gl e r e d u cti o n of at l e a st
3 0 d e gr e e s fr o m b a s eli n e at M o nt h
1 2 ).
M u s cl e El e ctr o p h y si ol o g y

Pr o p orti o n of i nf a nt s w h o a c hi e v e a n i n cr e a s e of at l e a st 0. 3 m V
fr o m b a s eli n e i n
t h eir C M A P n e g ati v e p e a k a m plit u d e at M o nt h
1 2 .

Pr o p orti o n of i nf a nt s w h o a c hi e v e a n i n cr e a s e of at l e a st 0 . 3 m V fr o m b a s eli n e i n
t h eir C M A P n e g ati v e p e a k a m plit u d e at M o nt h
2 4 .
I nf a nt s w h o d o n ot a c hi e v e a n i n cr e a s e of at l e a st 0. 3, or h a v e n ot m ai nt ai n e d t hi s
i m pr o v e m e nt if a c hi e v e d e arli er, or h a v e b e e n wit h dr a w n or di e d, will b e cl a s sifi e d
a s n o n -r e s p o n d er s f or t h e a n al y si s.
Di s e a s e -R el at e d A d v er s e E v e nt s

Pr o p orti o n of i nfa nt s w h o e x p eri e n c e at l e a st o n e di s e a s e -r el at e d a d v er s e e v e nt b y
M o nt h
1 2 a n d b y M o nt h
2 4 .

N u m b er of di s e a s e -r el at e d a d v er s e e v e nt s p er p ati e nt-y e ar at M o nt h 1 2 a n d 2 4.
Di s e a s e -r el at e d a d v er s e e v e nt s will b e c oll e ct e d t hr o u g h t h e a d v er s e e v e nt
r e p orti ng of t h e st u d y a n d e v e nt s will b e i d e ntifi e d b y a p pl yi n g  b a s k et s of M e di c al
Di cti o n ar y f or R e g ul at or y A cti viti e s ( M e d D R A) l o w e st l e v el t er m s t o t h e a d v er s e
e v e nt d at a s et. T h e b a s k et s h a v e b e e n pr e d efi n e d i n t h e S A P a n d fi n ali z e d pri or t o
e nr oll m e nt i nt o P art 2.

Pr o p orti o n of i nf a nt s w h o e x p eri e n c e at l e a st o n e di s e a s e -r el at e d a d v er s e e v e nt
r e s ulti n g i n h o s pit ali z ati o n b y M o nt h
1 2 a n d b y M o nt h
2 4 .

N u m b er of di s e a s e -r el at e d a d v er s e e v e nt s r e s ulti n g i n h o s pit ali z ati o n p er p ati e nt-
y e ar at M o nt h 1 2 a n d 2 4.


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 0 8 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
H e a lt h c ar e Utili z ati o n

N u m b er of h o s pit ali z ati o n s (f or a n y r e a s o n) p er p ati e nt -y e ar a n d n u m b er of  ni g ht s
a d mitt e d t o h o s pit al p er i nf a nt at M o nt h 1 2 a n d 2 4.
S w all o wi n g a n d N utriti o n

Pr o p orti o n of i nf a nt s wit h t h e a bilit y t o s w all o w at M o nt h 8, M o nt h 1 2, a n d M o nt h
2 4.
Gr o w t h M e a s ur e s

R ati o b et w e e n t h e c h e st a n d h e a d cir c u mf er e n c e at M o nt h
8, M o nt h
1 2, a n d
M o nt h
2 4 .
H e a d cir c u mf er e n c e will b e t h e d e n o mi n at or of t h e r ati o.

C h a n g e fr o m b a s eli n e i n w ei g ht p er c e ntil e s at M o nt h 1 2 a n d M o nt h 2 4.

C h a n g e fr o m b a s eli n e i n l e n gt h/ h ei g ht p er c e ntil e s at M o nt h 1 2 a n d M o nt h 2 4.
P ar e nt/ C ar e gi v er R e p ort e d O ut c o m e s

C h a n g e fr o m b a s eli n e i n t h e I T Q O L-S F 4 7 d o m ai n s* at M o nt h
1 2 a n d M o nt h
2 4 .
* p ar e nt-pr o x y d o m ai n s of: p h y si c al a biliti e s, gr o wt h a n d d e v el o p m e nt, b o dil y p ai n,
t e m p er a m e nt a n d m o o d s, g e n er al h e alt h p er c e pti o n; o v er all h e alt h a n d f a mil y
c o h e si o n si n gl e it e m s c al e s; a n d p ar e nt e m oti o n al i m p a ct, p ar e nt ti m e i m p a ct.
Cli ni ci a n -R e p ort e d R e s pir at or y  F u n cti o n a n d S w all o wi n g A bilit y It e m s

Pr o p orti o n of i nf a nt s wit h n o c h a n g e or i m pr o v e m e nt i n r e s pir at or y f u n cti o n a s
a s s e s s e d b y t h e cli ni ci a n -r e p ort e d C GI- C at M o nt h 1 2.

Pr o p orti o n of i nf a nt s wit h n o c h a n g e or i m pr o v e m e nt i n t h e a bilit y t o s w all o w  a s
a s s e s s e d b y t h e cli ni ci a n -r e p ort e d C GI-C at M o nt h 1 2.
St ati sti c al m et h o d s, d efi niti o n s a n d a n al y s e s f or all e x pl or at or y e n d p oi nt s h a v e b e e n f ull y 
s p e cifi e d i n t h e S A P.
6. 6. 4
S u b gr o u p A n al y s e s
S u b gr o u p a n al y s e s will b e p erf or m e d f or t h e pri m ar y effi c a c y e n d p oi nt of t h e pr o p orti o n 
of  i nf a nt s sitti n g wit h o ut s u p p ort f or 5 s e c o n d s at M o nt h 1 2 a n d t h e s e c o n d ar y effi c a c y 
e n d p oi nt of ti m e-t o-d e at h or p er m a n e nt v e ntil ati o n. A n al y s e s will b e pr e s e nt e d f or t h e 
f oll o wi n g s u b gr o u p s:

A g e at e nr oll m e nt ( 5 m o nt h s , 5 m o nt h s ).

S e x.

R a c e/ et h ni cit y.

R e gi o n ( E ur o p e, U nit e d St at e s/ C a n a d a, r e st of w orl d).

B a s eli n e C H O P -I N T E N D s c or e (m e di a n s c or e, m e di a n s c or e) .

B a s eli n e C M A P a m plit u d e ( 1 m V, 1 m V) .

Ti m e b et w e e n o n s et of s y m pt o m s a n d fir st tr e at m e nt (3 m o nt h s , 3 m o nt h s ).


T h e n u m b er a n d p er c e nt a g e of i nf a nt s sitti n g wit h o ut s u p p ort at M o nt h 1 2 a n d 
c orr e s p o n di n g 9 0 % Cl o p p er -P e ar s o n ( E x a ct) CI s will b e pr e s e nt e d f or e a c h s u b gr o u p 
u si n g f or e st pl ot s.
Ti m e -t o-d e at h or p er m a n e nt v e ntil ati o n will b e pr e s e nt e d gr a p hi c all y f or e a c h s u b gr o u p 
u si n g K a pl a n -M ei er c ur v e s. T h e m e di a n ti m e t o v e ntil ati o n -fr e e s ur vi v al a n d t h e 
pr o p orti o n of i nf a nt s w h o ar e s ur vi vi n g v e ntil ati o n -fr e e at M o nt h 1 2 will b e e sti m at e d 
u si n g K a pl a n -M ei er m et h o d ol o g y, w h e n p o s si bl e.
6. 7
P H A R M A C O D Y N A MI C A N A L Y S E S
All p h ar m a c o d y n a mi c p ar a m et er s will b e pr e s e nt e d b y li sti n g s a n d d e s cri pti v e s u m m ar y 
st ati sti c s, a s a p pr o pri at e. I n P art 1 , d at a will b e pr e s e nt e d b y d o s e/ e x p o s ur e l e v el.
6. 8
P H A R M A C O KI N E TI C A N A L Y S E S
All p h ar m a c o ki n eti c p ar a m et er s will b e pr e s e nt e d b y li sti n g s a n d d e s cri pti v e s u m m ar y 
st ati sti c s. I n di vi d u al a n d m e a n pl a s m a c o n c e ntr ati o n s of ri s di pl a m ( a n d m et a b olit e s, a s 
a p pr o pri at e) v er s u s ti m e d at a will b e t a b ul at e d.
N o n -li n e ar mi x e d eff e ct s m o d eli n g ( s oft w ar e N O N M E M) will b e u s e d t o a n al y z e t h e 
s p ar s e s a m pl e s of c o n c e ntr ati o n -ti m e d at a of ri s di pl a m ( a n d it s m et a b olit e s if d e e m e d 
n e c e s s ar y). P o p ul ati o n a n d i n di vi d u al p h ar m a c o ki n eti c p ar a m et er s will b e e sti m at e d a n d 
t h e i nfl u e n c e of v ari o u s c o v ari at e s ( s u c h a s a g e, g e n d er a n d b o d y w ei g ht) o n t h e s e 
p ar a m et er s will b e i n v e sti g at e d i n a n e x pl or at or y w a y. D at a m a y b e p o ol e d wit h d at a 
fr o m ot h er st u di e s wit h ri s di pl a m i n or d er t o i m pr o v e t h e p ar a m et er e sti m at e s fr o m t h e 
m o d el. S e c o n d ar y P K p ar a m et er s ( s u c h a s C m a x a n d A U C) m a y b e d eri v e d fr o m t h e 
m o d el f or e a c h i n di vi d u al i n cl u d e d i n t h e P K a n al y si s a n d will b e pr e s e nt e d d e s cri pti v el y. 
A d diti o n all y e x pl or at or y a n al y s e s o n e x p o s ur e a n d s af et y / effi c a c y r el ati o n s hi p m a y b e 
c o n d u ct e d if d e e m e d n e c e s s ar y. T h e d et ail s of t h e m o d eli n g
a n d e x pl or at or y a n al y s e s 
m a y b e r e p ort e d i n a d o c u m e nt s e p ar at e fr o m t h e cli ni c al st u d y r e p ort.
A s s e s s m e nt of pr ot ei n bi n di n g will b e p erf or m e d o n pr e -d o s e s a m pl e s ( a n d m a y a s w ell 
b e p erf or m e d o n P K s a m pl e s t hr o u g h o ut t h e st u d y, a s r e q uir e d) a n d r e p ort e d.
A d diti o n al P K a n al y s e s will b e c o n d u ct e d a s a p pr o pri at e.
6. 9
I N T E RI M AN A L Y S E S
A s t hi s st u d y i s o p e n -l a b el, o n c e at l e a st  5  i nfa nt s  e nr oll e d i nt o t h e c o nfir m at or y P art  2 
d uri n g t h e gl o b al e nr oll m e nt p h a s e h a v e m et t h e pri m ar y e n d p oi nt of sitti n g wit h o ut 
s u p p ort at M o nt h  1 2 ( a s a s s e s s e d b y t h e i n d e p e n d e nt c e ntr al r e a d er s), t h e mi ni m u m 
n u m b er of i nf a nt s n e e d e d f or a st ati sti c all y si g nifi c a nt r e s ult  will h a v e b e e n a c hi e v e d a n d 
t h e pri m ar y o bj e cti v e of t h e st u d y will b e c o n si d er e d a c hi e v e d at t hi s e arli er ti m e -p oi nt. 
T h e st u d y will n ot b e st o p p e d a n d all  4 0  i nfa nt s  e nr oll e d wit hi n t h e c o nfir m at or y  P art  2
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
1 0 9 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7




7. 2
E L E C T R O NI C C A S E R E P O R T F O R M S 
D at a f or t hi s st u d y will b e c a pt ur e d vi a a n o n li n e E D C s y st e m. T h e d at a c oll e ct e d i n t h e 
s o ur c e d o c u m e nt s i s e nt er e d o nt o t h e st u d y e C R F. A n a u dit tr ail will m ai nt ai n a r e c or d of 
i niti al e ntri e s a n d c h a n g e s m a d e; r e a s o n s f or c h a n g e; ti m e a n d d at e of e ntr y; a n d u s er 
n a m e of p er s o n a ut h ori zi n g e ntr y or c h a n g e. F or e a c h p ati e nt e nr oll e d, a n e C R F m u st 
b e c o m pl et e d a n d el e ctr o ni c all y si g n e d b y t h e Pri n ci p al I n v e sti g at or or a ut h ori z e d 
d el e g at e fr o m t h e st u d y st aff. If a p ati e nt wit h dr a w s fr o m t h e st u d y, t h e r e a s o n m u st b e 
n ot e d o n t h e e C R F. If a p ati e nt i s wit h dr a w n fr o m t h e st u d y b e c a u s e of a 
tr e at m e nt-li miti n g a d v er s e e v e nt, t h or o u g h eff ort s s h o ul d b e m a d e t o cl e arl y d o c u m e nt 
t h e o ut c o m e.
T h e I n v e sti g at or s h o ul d e n s ur e t h e a c c ur a c y, c o m pl et e n e s s a n d ti m eli n e s s of t h e d at a 
r e p ort e d t o th e S p o n s or/ C R O i n t h e e C R F s a n d i n all r e q uir e d r e p ort s.
e C R F s will b e s u b mitt e d el e ctr o ni c all y t o t h e S p o n s or/ C R O a n d s h o ul d b e h a n dl e d i n 
a c c or d a n c e wit h i n str u cti o n s fr o m t h e S p o n s or/ C R O.
At t h e e n d of t h e st u d y, t h e I n v e sti g at or will r e c ei v e p ati e nt d a t a f or hi s or h er sit e i n a 
r e a d a bl e f or m at o n a c o m p a ct di s c t h at m u st b e k e pt wit h t h e st u d y r e c or d s. 
A c k n o wl e d g e m e nt of r e c ei pt of t h e c o m p a ct di s c i s r e q uir e d.
7. 3
S O U R C E D A T A  D O C U M E N TA T I O N
St u d y m o nit or s will p erf or m o n g oi n g s o ur c e d at a v erifi c ati o n t o  c o nfir m t h at criti c al 
pr ot o c ol d at a (i. e.,  s o ur c e d at a) e nt er e d i nt o t h e e C R F s b y a ut h ori z e d sit e p er s o n n el ar e 
a c c ur at e, c o m pl et e, a n d v erifi a bl e fr o m s o ur c e d o c u m e nt s.
S o ur c e d o c u m e nt s ( p a p er or el e ctr o ni c) ar e t h o s e i n w hi c h p ati e nt d at a ar e r e c or d e d 
a n d d o c u m e nt e d f or t h e fir st ti m e. T h e y i n cl u d e, b ut ar e n ot li mit e d t o, h o s pit al r e c or d s, 
cli ni c al a n d offi c e c h art s, l a b or at or y n ot e s, m e m or a n d a, p ar e nt/ c ar e gi v er -r e p ort e d 
o ut c o m e s, e v al u ati o n c h e c kli st s, p h ar m a c y di s p e n si n g r e c or d s, r e c or d e d d at a fr o m 
a ut o m at e d i n str u m e nt s, c o pi e s of tr a n s cri pti o n s t h at ar e c ertif i e d aft er v erifi c ati o n a s 
b ei n g a c c ur at e a n d c o m pl et e, mi cr ofi c h e, p h ot o gr a p hi c n e g ati v e s , mi cr ofil m or m a g n eti c 
m e di a, X -r a y s, p ati e nt fil e s, a n d r e c or d s k e pt at p h ar m a ci e s, l a b or at orie s, a n d 
m e di c o - t e c h ni c al d e p art m e nt s i n v ol v e d i n a cli ni c al tri al.
B ef or e st u d y i niti ati o n, d at a t o b e e nt er e d dir e ctl y i nt o t h e e C R F s (i. e.,  n o pri or writt e n or 
el e ctr o ni c r e c or d of t h e d at a) a n d c o n si d er e d s o ur c e d at a m u st b e d efi n e d i n t h e Tri al 
M o nit ori n g Pl a n .
S o ur c e d o c u m e nt s t h at ar e r e q uir e d t o v erif y t h e v ali dit y a n d c o m pl et e n e s s of d at a 
e nt er e d i nt o t h e e C R F s m u st n ot b e o blit er at e d or d e str o y e d a n d  m u st b e r et ai n e d p er 
t h e p oli c y f or r et e nti o n of r e c or d s d e s cri b e d i n S e cti o n 7. 5 .
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
1 1 1 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


T o f a cilit at e s o ur c e d at a v erifi c ati o n, t h e i n v e sti g at or s a n d i n stit uti o n s m u st pr o vi d e t h e 
S p o n s or dir e ct a c c e s s t o a p pli c a bl e s o ur c e d o c u m e nt s a n d r e p ort s f or tri al -r el at e d 
m o nit ori n g, S p o n s or a u dit s, a n d I R B/ E C r e vi e w. T h e i n v e sti g ati o n al sit e m u st al s o all o w 
i n s p e cti o n b y a p pli c a bl e H e alt h A ut h oriti e s.
7. 4
U S E O F C O M P U T E RI Z E D S Y S T E M S
W h e n cli ni c al o b s er v ati o n s ar e e nt er e d dir e ctl y i nt o a n i n v e sti g ati o n al sit e’ s
c o m p ut eri z e d m e di c al r e c or d s y st e m (i. e., i n li e u of ori gi n al h ar d c o p y r e c or d s), t h e 
el e ctr o ni c r e c or d c a n s er v e a s t h e s o ur c e d o c u m e nt if t h e s y st e m h a s b e e n v ali d at e d i n 
a c c or d a n c e wit h H e alt h A ut h orit y r e q uir e m e nt s p ert ai ni n g t o c o m p ut eri z e d s y st e m s u s e d 
i n cli ni c al r e s e ar c h. A n a c c e pt a bl e c o m p ut eri z e d d at a c oll e cti o n s y st e m all o w s 
pr e s er v ati o n of t h e ori gi n al e ntr y of d at a. If ori gi n al d at a ar e m o difi e d, t h e s y st e m s h o ul d 
m ai nt ai n a vi e w a bl e a u dit tr ail t h at s h o w s t h e ori gi n al d at a a s w ell a s t h e r e a s o n f or t h e 
c h a n g e, n a m e of t h e p er s o n m a ki n g t h e c h a n g e, a n d d at e of t h e c h a n g e.
7. 5
R E T E N TI O N O F R E C O R D S
R e c or d s a n d d o c u m e nt s p ert ai ni n g t o t h e c o n d u ct of t hi s st u d y a n d t h e di stri b uti o n of 
I MP, i n cl u di n g e C R F s, I nf or m e d C o n s e nt F or m s, l a b or at or y t e st r e s ult s , a n d m e di c ati o n 
i n v e nt or y r e c or d s, m u st b e r et ai n e d b y t h e Pri n ci p al I n v e sti g at or f or 1 5 y e ar s aft er 
c o m pl eti o n or di s c o nti n u ati o n of t h e st u d y, or f or t h e l e n gt h of ti m e r e q uir e d b y r el e v a nt 
n ati o n al or l o c al H e alt h A ut h oriti e s, w hi c h e v er i s l o n g er. Aft er t h at p eri o d of ti m e, t h e 
d o c u m e nt s m a y b e d e str o y e d, s u bj e ct t o l o c al r e g ul ati o n s. N o r e c or d s m a y b e di s p o s e d 
of  wit h o ut t h e writt e n a p pr o v al of t h e S p o n s or. Writt e n n otifi c ati o n s h o ul d b e pr o vi d e d t o 
t h e S p o n s or pri or t o tr a n sf erri n g a n y r e c or d s t o a n oth er p art y or m o vi n g t h e m t o a n ot h er 
l o c ati o n.
R o c h e will r et ai n st u d y d at a f or 2 5 y e ar s aft er t h e fi n al Cli ni c al St u d y R e p ort h a s b e e n 
c o m pl et e d or f or t h e l e n gt h of ti m e r e q uir e d b y r el e v a nt n ati o n al or l o c al h e alt h 
a ut h oriti e s, w hi c h e v er i s l o n g er.
8.
E T HI C A L  C O N SI D E R ATI O N S
8. 1
C O M P LI A N C E WI T H L A W S
A N D R E G U L A TI O N S
T hi s st u d y will b e c o n d u ct e d i n f ull c o nf or m a n c e wit h t h e  I C H E 6  g ui d eli n e f or G o o d 
Cli ni c al Pr a cti c e a n d t h e pri n ci pl e s of t h e D e cl ar ati o n of H el si n ki,  or t h e  a p pli c a bl e  l a w s 
a n d r e g ul ati o n s of t h e c o u ntr y i n w hi c h t h e r e s e ar c h i s c o n d u ct e d, w hi c h e v er aff or d s t h e 
gr e at er pr ot e cti o n t o t h e i n di vi d u al. T h e st u d y will c o m pl y wit h t h e r e q uir e m e nt s of t h e 
I C H E 2 A  g ui d eli n e ( Cli ni c al S af et y D at a M a n a g e m e nt: D efi niti o n s a n d St a n d ar d s f or 
E x p e dit e d R e p orti n g). St u di e s c o n d u ct e d i n t h e U nit e d St at e s or  u n d er a U. S. 
I n v e sti g ati o n al N e w Dr u g (I N D) a p pli c ati o n will c o m pl y wit h U. S. F D A r e g ul ati o n s a n d 
a p pli c a bl e l o c al, st at e, a n d f e d er al l a w s. St u di e s c o n d u ct e d i n t h e E U/ E E A will c o m p l y 
wit h t h e E U Cli ni c al Tri al Dir e cti v e ( 2 0 0 1/ 2 0/ E C)  a n d a p pli c a bl e l o c al, r e gi o n al, a n d 
n ati o n al l a w s .
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
1 1 2 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


8. 2
I N F O R M E D C O N S E N T
T h e S p o n s or’ s s a m pl e C ar e gi v er' s I nf or m e d C o n s e nt F or m will b e pr o vi d e d t o e a c h sit e. 
If a p pli c a bl e, it will b e pr o vi d e d i n a c ertifi e d tr a n sl ati o n of t h e l o c al l a n g u a g e. T h e 
S p o n s or or it s d e si g n e e m u st r e vi e w a n d a p pr o v e a n y pr o p o s e d d e vi ati o n s fr o m t h e 
S p o n s or' s s a m pl e I nf or m e d C o n s e nt F or m s or a n y alt er n at e c o n s e nt f or m s pr o p o s e d b y 
t h e sit e ( c oll e cti v el y, t h e “ C o n s e nt F or m s”) b ef or e I R B/ E C s u b mi s si o n. T h e fi n al 
I R B/ E C-a p pr o v e d C o n s e nt F or m s m u st b e pr o vi d e d t o t h e S p o n s or f or H e alt h A ut h orit y 
s u b mi s si o n p ur p o s e s a c c or di n g t o l o c al r e q uir e m e nt s.
T h e C o n s e nt F or m s m u st b e si g n e d a n d d at e d b y t h e p ati e nt’ s l e g all y a ut h ori z e d 
r e pr e s e nt ativ e b ef or e hi s or h er p arti ci p ati o n i n t h e st u d y. T h e c a s e hi st or y or cli ni c al 
r e c or d s f or e a c h p ati e nt s h all d o c u m e nt t h e i nf or m e d c o n s e nt pr o c e s s a n d t h at writt e n 
i nf or m e d c o n s e nt w a s o bt ai n e d pri or t o p arti ci p ati o n i n t h e st u d y.
T h e C o n s e nt F or m s s h o ul d b e r e vi s e d w h e n e v er t h er e ar e c h a n g e s t o st u d y pr o c e d ur e s 
or w h e n n e w i nf or m ati o n b e c o m e s a v ail a bl e t h at m a y aff e ct t h e willi n g n e s s of t h e p ati e nt 
t o p arti ci p at e. T h e fi n al r e vi s e d I R B/ E C-a p pr o v e d C o n s e nt F or m s m u st b e pr o vi d e d t o 
t h e S p o n s or f or H e alt h A ut h orit y s u b mi s si o n p ur p o s e s.
P ati e nt s m u st b e r e -c o n s e nt e d t o t h e m o st c urr e nt v er si o n of t h e C o n s e nt F or m s ( or t o a 
si g nifi c a nt n e w i nf or m ati o n/fi n di n g s a d d e n d u m i n a c c or d a n c e wit h a p pli c a bl e l a w s a n d 
I R B/ E C p oli c y) d uri n g t h eir p arti ci p ati o n i n t h e st u d y. F or a n y u p d at e d or r e vi s e d 
C o n s e nt F or m s, t h e c a s e hi st or y or cli ni c al r e c or d s f or e a c h p ati e nt s h all d o c u m e nt t h e 
i nf or m e d c o n s e nt pr o c e s s a n d t h at writt e n i nf or m e d c o n s e nt w a s o bt ai n e d u si n g t h e 
u p d at e d/r e vi s e d C o n s e nt F or m s f or c o nti n u e d p arti ci p ati o n i n t h e st u d y.
A c o p y of e a c h si g n e d C o n s e nt F or m m u st b e pr o vi d e d t o t h e p ati e nt’ s l e g all y a ut h ori z e d 
r e pr e s e nt ati v e. All si g n e d a n d d at e d C o n s e nt F or m s m u st r e m ai n i n e a c h p ati e nt’ s st u d y 
fil e or i n t h e sit e fil e a n d m u st b e a v ail a bl e f or v erifi c ati o n b y st u d y M o nit or s at a n y ti m e.
F or sit e s i n t h e U nit e d St at e s, e a c h C o n s e nt F or m m a y al s o i n cl u d e p ati e nt’ s l e g all y 
a ut h ori z e d r e pr e s e nt ati v e a ut h ori z ati o n t o all o w u s e a n d di s cl o s ur e of p er s o n al h e alt h 
i nf or m ati o n i n c o m pli a n c e wit h t h e U. S. H e alt h I n s ur a n ce P ort a bilit y a n d A c c o u nt a bilit y 
A ct of 1 9 9 6 ( HI P A A). If t h e sit e utili z e s a s e p ar at e A ut h ori z ati o n F or m f or p ati e nt 
a ut h ori z ati o n f or u s e a n d di s cl o s ur e of p er s o n al h e alt h i nf or m ati o n u n d er t h e HI P A A 
r e g ul ati o n s, t h e r e vi e w, a p pr o v al, a n d ot h er pr o c e s s e s o utli n e d a b o v e a p pl y e x c e pt t h at 
I R B r e vi e w a n d a p pr o v al m a y n ot b e r e q uir e d p er st u d y sit e p oli ci e s.
8. 3
I N S TI T U TI O N AL R E VI E W B O A R D O R E T HI C S C O M MI T T E E
T hi s pr ot o c ol, t h e I nf or m e d C o n s e nt F or m s, a n y i nf or m ati o n t o b e gi v e n t o t h e p ati e nt, 
a n d r el e v a nt s u p p ort i n g i nf or m ati o n m u st b e s u b mitt e d t o t h e I R B/ E C b y t h e Pri n ci p al 
I n v e sti g at or a n d r e vi e w e d a n d a p pr o v e d b y t h e I R B/ E C b ef or e t h e st u d y i s i niti at e d. 
I n a d diti o n, a n y p ati e nt r e cr uit m e nt m at eri al s m u st b e a p pr o v e d b y  t h e I R B/ E C.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
1 1 3 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 1 4 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
T h e Pri n ci p al I n v e sti g at or i s r e s p o n si bl e f or pr o vi di n g writt e n s u m m ari e s of t h e st at u s of 
t h e st u d y t o t h e I R B/ E C a n n u all y or m or e fr e q u e ntl y i n a c c or d a n c e wit h t h e r e q uir e m e nt s, 
p oli ci e s, a n d pr o c e d ur e s e st a bli s h e d b y t h e I R B/ E C. I n v e sti g at o r s ar e al s o r e s p o n si bl e 
f or pr o m ptl y i nf or mi n g t h e I R B/ E C of a n y pr ot o c ol a m e n d m e nt s ( s e e S e cti o n 9. 6 ).
I n a d diti o n t o t h e r e q uir e m e nt s f or r e p orti n g all a d v er s e e v e nt s t o t h e S p o n s or, 
i n v e sti g at or s m u st c o m pl y wit h r e q uir e m e nt s f or r e p orti n g s eri o u s a d v er s e e v e nt s t o t h e 
l o c al H e alt h A ut h orit y a n d I R B/ E C. I n v e sti g at or s m a y r e c ei v e writt e n I N D s af et y r e p ort s 
or ot h er s af et y -r el at e d c o m m u ni c ati o n s fr o m t h e S p o n s or. I n v e sti g at or s ar e r e s p o n si bl e 
f or e n s uri n g t h at s u c h r e p ort s ar e r e vi e w e d a n d pr o c e s s e d i n a c c or d a n c e wit h H e alt h 
A ut h orit y r e q uir e m e nt s a n d t h e p oli ci e s a n d pr o c e d ur e s e st a bli s h e d b y t h eir I R B/ E C, a n d 
ar c hi v e d i n t h e sit e’ s st u d y fil e.
8. 4
C O N FI D E N TI A LI T Y
T h e S p o n s or m ai n t ai n s c o nfi d e nti alit y st a n d ar d s b y c o di n g e a c h p ati e nt e nr oll e d i n t h e 
st u d y t hr o u g h a s si g n m e nt of a u ni q u e p ati e nt i d e ntifi c ati o n n u m b er. T hi s m e a n s t h at 
p ati e nt n a m e s ar e n ot i n cl u d e d i n d at a s et s t h at ar e tr a n s mitt e d t o a n y S p o n s or l o c ati o n.
P ati e nt m e di c al i nf or m ati o n o bt ai n e d b y t hi s st u d y i s c o nfi d e nti al a n d m a y o nl y b e 
di s cl o s e d t o t hir d p arti e s a s p er mitt e d b y t h e I nf or m e d C o n s e nt F or m ( or s e p ar at e 
a ut h ori z ati o n f or u s e a n d di s cl o s ur e of p er s o n al h e alt h i nf or m ati o n) si g n e d b y t h e p ati e nt, 
u nl e s s p er mitt e d or r e q uir e d b y l a w.
M e di c al i nf or m ati o n m a y b e gi v e n t o a p ati e nt’ s p er s o n al p h y si ci a n or ot h er a p pr o pri at e 
m e di c al p er s o n n el r e s p o n si bl e f or t h e p ati e nt’ s w elf ar e, f or tr e at m e nt p ur p o s e s.
D at a g e n er at e d b y t hi s st u d y m u st b e a v ail a bl e f or i n s p e c ti o n u p o n r e q u e st b y 
r e pr e s e nt ati v e s of t h e U. S. F D A a n d ot h er n ati o n al a n d l o c al H e alt h A ut h oriti e s, S p o n s or 
M o nit or s, r e pr e s e nt ati v e s, a n d c oll a b or at or s, a n d t h e I R B/ E C f or e a c h st u d y sit e, a s 
a p pr o pri at e.
8. 5
FI N A N CI A L DI S C L O S U R E
I n v e sti g at or s will pr o vi d e t h e S p o n s or wit h s uffi ci e nt, a c c ur at e fi n a n ci al i nf or m ati o n i n 
a c c or d a n c e wit h l o c al r e g ul ati o n s t o all o w t h e S p o n s or t o s u b mit c o m pl et e a n d a c c ur at e 
fi n a n ci al c ertifi c ati o n or di s cl o s ur e st at e m e nt s t o t h e a p pr o pri at e H e alt h A ut h oriti e s. 
I n v e sti g at or s ar e r e s p o n si bl e f or pr o vi di n g i nf or m ati o n o n fi n a n ci al i nt er e st s d uri n g t h e 
c o ur s e of t h e st u d y a n d f or o n e y e ar aft er c o m pl eti o n of t h e st u d y (i. e., l a st p ati e nt, l a st 
o b s er v ati o n).


9.
S T U D Y D O C U M E N T A TI O N, M O NI T O RI N G, A N D
A D MI NI S T R A TI O N
9. 1
S T U D Y D O C U M E N T A TI O N
T h e I n v e sti g at or m u st m ai nt ai n a d e q u at e a n d a c c ur at e r e c or d s t o e n a bl e t h e c o n d u ct of 
t h e st u d y t o b e f ull y d o c u m e nt e d, i n cl u di n g b ut n ot li mit e d t o t h e pr ot o c ol, pr ot o c ol 
a m e n d m e nt s, I nf or m e d C o n s e nt F or m s, a n d d o c u m e nt ati o n of I R B/ E C a n d 
g o v er n m e nt al a p pr o v a l. I n a d diti o n, at t h e e n d of t h e st u d y, t h e I n v e sti g at or will r e c ei v e 
t h e p ati e nt d at a, w hi c h i n cl u d e s a n a u dit tr ail c o nt ai ni n g a c o m pl et e r e c or d of all c h a n g e s 
t o d at a.
R o c h e s h all al s o s u b mit a n D e v el o p m e nt S af et y U p d at e R e p ort ( D S U R) o n c e a y e ar t o 
t he I E C a n d C A s a c c or di n g t o l o c al r e g ul at or y r e q uir e m e nt s a n d ti m eli n e s of e a c h 
c o u ntr y p arti ci p ati n g i n t h e st u d y.
I n U. S., it i s t h e u n d er st a n di n g of t h e S p o n s or t h at t hi s pr ot o c ol ( a n d a n y m o difi c ati o n s) 
a s w ell a s a p pr o pri at e c o n s e nt pr o c e d ur e s a n d a d v e rti s e m e nt s, will b e r e vi e w e d a n d 
a p pr o v e d b y a n I n stit uti o n al R e vi e w B o ar d (I R B). T hi s b o ar d m u st o p er at e i n a c c or d a n c e 
wit h t h e c urr e nt F e d er al R e g ul ati o n s. T h e S p o n s or will b e s e nt a l ett er or c ertifi c at e of 
a p pr o v al pri or t o i niti ati o n of t h e st u d y, a n d al s o w h e n e v er s u b s e q u e nt a m e n d m e nt s 
/ m o difi c ati o n s ar e m a d e t o t h e pr ot o c ol.
9. 2
P R O T O C O L D E VI A TI O N S
T h e i n v e sti g at or s h o ul d d o c u m e nt a n d e x pl ai n a n y pr ot o c ol d e vi ati o n s.
T h e i n v e sti g at or 
s h o ul d pr o m ptl y r e p ort a n y d e vi ati o n s t h at mi g ht h a v e a n i m p a ct o n p at i e nt s af et y a n d 
d at a i nt e grit y t o t h e S p o n s or a n d t o t h e I R B/ E C i n a c c or d a n c e wit h e st a bli s h e d I R B/ E C 
p oli ci e s a n d pr o c e d ur e s.  T h e S p o n s or will r e vi e w all pr ot o c ol d e vi ati o n s a n d a s s e s s 
w h et h er a n y r e pr e s e nt a s eri o u s br e a c h of G o o d Cli ni c al Pr a cti c e g ui d eli n e s a n d r e q uir e 
r e p orti n g t o h e alt h a ut h oriti e s.  A s p er t h e S p o n s or' s st a n d ar d o p er ati n g pr o c e d ur e s, 
pr o s p e cti v e r e q u e st s t o d e vi at e fr o m t h e pr ot o c ol, i n cl u di n g r e q u e st s t o w ai v e pr ot o c ol 
eli gi bilit y crit eri a, ar e n ot all o w e d.
9. 3
SI T E I N S P E C TI O N S
Sit e v i sit s will b e c o n d u ct e d b y t h e S p o n s or or a n a ut h ori z e d r e pr e s e nt ati v e f or 
i n s p e cti o n of st u d y d at a, p ati e nt s’ m e di c al r e c or d s, a n d e C R F s. T h e I n v e sti g at or will 
p er mit n ati o n al a n d l o c al H e alt h A ut h oriti e s, S p o n s or M o nit or s, r e pr e s e nt ati v e s, a n d 
c oll a b or at or s, a n d t h e I R B s/ E C s t o i n s p e ct f a ciliti e s a n d r e c or d s r el e v a nt t o t hi s st u d y.
9. 4
A D MI NI S T R A TI V E S T R U C T U R E
T h e S p o n s or of t h e tri al i s F. H off m a n n -L a R o c h e Lt d. T h e S p o n s or i s r e s p o n si bl e f or t h e 
m e di c al o v er si g ht, d at a m a n a g e m e nt, st ati sti c al a n al y si s, a n d  m e di c al writi n g f or t h e 
Cli ni c al St u d y R e p ort.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
1 1 5 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


A n I M C will b e r e s p o n si bl e f or r e vi e wi n g s af et y, P K a n d P D d at a a n d f or d o s e -e s c al ati o n 
d e ci si o n s i n P art 1 a n d t h e d o s e -s el e cti o n f or P art 2 . A n i D M C will r e vi e w all a v ail a bl e 
d at a fr o m P art 1 t o c o nfir m t h e d o s e -d e ci si o n t a k e n b y t h e I M C, a n d will r e vi e w s af et y, 
effi c a c y, P K a n d P D f or P art 2 . T h e s c o p e a n d r e s p o n si bilit y of t h e s e c o m mitt e e s will b e 
d et ail e d i n a s p e cifi c C h art er.
A n I x R S s y st e m will b e u s e d t o r e gi st er t h e s cr e e ni n g/ s cr e e ni n g f ail ur e s, e nr ol l m e nt, 
dr u g all o c ati o n, wit h dr a w al, di s c o nti n u ati o n, a n d t er mi n ati o n of p ati e nt s.
A C R O will b e r e s p o n si bl e f or st u d y m a n a g e m e nt, m o nit ori n g, a n d i n s o m e c a s e s, 
v e n d or o v er si g ht.
A n o p ht h al m ol o gi c al m o nit ori n g v e n d or will b e r e s p o n si bl e f or c e ntr al r e vi e w of 
o p ht h al m ol o gi c al a s s e s s m e nt s, a n d h el p s u p p ort a cti viti e s a s s o ci at e d wit h tr ai ni n g l o c al 
r e a d er s a n d pr o c uri n g e q ui p m e nt.
9. 5
DI S S E MI N A TI O N O F D A T A  AN D P R O T E C TI O N O F T R A D E 
S E C R E T S
R e g ar dl e s s of t h e o ut c o m e of a tri al, t h e S p o n s or i s d e di c at e d t o o p e nl y pr o vi di n g 
i nf or m ati o n o n t h e tri al t o h e alt h c ar e pr of e s si o n al s a n d t o t h e p u bli c, at s ci e ntifi c 
c o n gr e s s e s, i n cli ni c al tri al r e gi stri e s, a n d i n p e er -r e vi e w e d j o ur n al s. T h e S p o n s or will 
c o m pl y wit h all r e q uir e m e nt s f or p u bli c ati o n of st u d y r e s ult s.  St u d y d at a m a y b e s h ar e d 
wit h ot h er s w h o ar e n ot p arti ci p ati n g i n t hi s st u d y ( s e e S e cti o n  8. 4  f or d et ail s), a n d 
r e d a ct e d Cli ni c al St u d y R e p ort s a n d ot h er s u m m ar y r e p ort s will b e m a d e a v ail a bl e u p o n 
r e q u e st, pr o vi d e d t h e r e q uir e m e nt s of R o c h e' s gl o b al p oli c y o n d at a s h ari n g h a v e b e e n 
m et.  F or m or e i nf or m ati o n, r ef er t o t h e R o c h e Gl o b al P oli c y o n S h ari n g of Cli ni c al Tri al s 
D at a at t h e f oll o wi n g w e b sit e:
w w w.r o c h e. c o m/r o c h e _ gl o b al _ p oli c y _ o n _ s h ari n g _ of _ cli ni c al _ st u d y _i nf or m ati o n . p df
T h e r e s ult s of t hi s st u d y m a y b e p u bli s h e d or pr e s e nt e d  at s ci e ntifi c m e eti n g s. F or all 
cli ni c al tri al s i n p ati e nt s i n v ol vi n g a n I M P f or w hi c h a m ar k et i n g a ut h ori z ati o n a p pli c ati o n 
h a s b e e n fil e d or a p pr o v e d i n a n y c o u ntr y, t h e S p o n s or ai m s t o s u b mit a j o ur n al 
m a n u s cri pt r e p orti n g pri m ar y cli ni c al tri al r e s ult s  wit hi n 6 m o nt h s aft er t h e a v ail a bilit y of 
t h e r e s p e cti v e Cli ni c al St u d y R e p ort.  I n a d diti o n, f or all cli ni c al tri al s i n p ati e nt s i n v ol vi n g 
a n I M P f or w hi c h a m ar k eti n g a ut h ori z ati o n a p pli c ati o n h a s b e e n  fil e d or a p pr o v e d i n a n y 
c o u ntr y, t h e S p o n s or ai m s t o p u bli s h r e s ult s fr o m a n al y s e s of a d diti o n al e n d p oi nt s a n d 
e x pl or at or y d at a t h at ar e cli ni c all y m e a ni n gf ul a n d st ati sti c al l y s o u n d.
T h e i n v e sti g at or m u st a gr e e t o s u b mit all m a n u s cri pt s or a b str a ct s t o t h e S p o n s or pri or 
t o s u b mi s si o n f or p u bli c ati o n or pr e s e nt ati o n.  T hi s all o w s t h e S p o n s or t o pr ot e ct 
pr o pri et ar y i nf or m ati o n a n d t o pr o vi d e c o m m e nt s b a s e d o n i nf or m ati o n fr o m ot h er 
st u di e s t h at m a y n ot y et b e a v ail a bl e t o t h e i n v e sti g at or.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
1 1 6 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 1 7 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
I n a c c or d a n c e wit h st a n d ar d e dit ori al a n d et hi c al pr a cti c e, t h e S p o n s or will g e n er all y 
s u p p ort p u bli c ati o n of m ulti c e nt er tri al s o nl y i n t h eir e ntir et y a n d n ot a s i n di vi d u al c e nt er 
d at a.  I n t hi s c a s e, a c o or di n ati n g i n v e sti g at or will b e d e si g n at e d b y m ut u al a gr e e m e nt.
A ut h or s hi p will b e d et er mi n e d b y m ut u al a gr e e m e nt a n d i n li n e wit h I nt er n ati o n al 
C o m mitt e e of M e di c al J o ur n al E dit or s a ut h or s hi p r e q uir e m e nt s.  A n y f or m al p u bli c ati o n 
of  t h e st u d y i n w hi c h c o ntri b uti o n of S p o n s or p er s o n n el e x c e e d e d t h at of c o n v e nti o n al 
m o nit ori n g will b e c o n si d er e d a s a j oi nt p u bli c ati o n b y t h e i n v e sti g at or a n d t h e 
a p pr o pri at e S p o n s or p er s o n n el.
A n y i n v e nti o n s a n d r e s ulti n g p at e nt s, i m pr o v e m e nt s, a n d/ or k n o w -h o w ori gi n ati n g fr o m 
t h e u s e of d at a fr o m t hi s st u d y will b e c o m e a n d r e m ai n t h e e x cl u si v e a n d u n b ur d e n e d 
pr o p ert y of t h e S p o n s or, e x c e pt w h er e a gr e e d ot h er wi s e.
9. 6
P R O T O C O L A M E N D M E N T S
A n y s u b st a nti al pr ot o c ol a m e n d m e nt s will b e pr e p ar e d b y t h e S p o n s or. S u b st a nti al 
pr ot o c ol a m e n d m e nt s will b e s u b mitt e d t o t h e I R B/ E C a n d t o r e g ul at or y a ut h oriti e s i n 
a c c or d a n c e wit h l o c al r e g ul at or y r e q uir e m e nt s.
A p pr o v al m u st b e o bt ai n e d fr o m t h e I R B/ E C a n d r e g ul at or y a ut h oriti e s ( a s l o c all y 
r e q uir e d) b ef or e i m pl e m e nt ati o n of a n y c h a n g e s, e x c e pt f or c h a n g e s n e c e s s ar y t o 
eli mi n at e a n i m m e di at e h a z ar d t o p ati e nt s or a n y n o n -s u b st a nti al c h a n g e s, a s d efi n e d b y 
r eg ul at or y r e q uir e m e nt s.


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 1 8 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
1 0.
R E F E R E N C E S
B a yl e y N. B a yl e y S c al e s of I nf a nt a n d T o d dl er D e v el o p m e nt , T hir d E diti o n ( B a yl e y-III).
2 0 0 6.
C hiri b o g a C A, S w o b o d a K J, D arr a s B T, et al. R e s ult s fr o m a p h a s e 1 st u d y of 
n u si n er s e n (I SI S -S M N R X ) i n c hil dr e n wit h s pi n al m u sc ul ar atr o p h y. N e ur ol o g y. 
2 0 1 6; 8 6: 8 9 0 -8 9 7.
C h o S, Dr e yf u s s G. A d e gr o n cr e at e d b y S M N 2 e x o n 7 s ki p pi n i s a pri n ci p al c o ntri b ut or 
t o s pi n al m u s c ul ar atr o p h y s e v erit y. G e n e s D e v. 2 0 1 0; 2 4: 4 3 8-4 4 9.
C o b b e n J M, L e m mi n k H H, S n o e c k I, et al. S ur vi v al i n S M A t y p e I: A pr o s p e cti v e a n al y si s 
of  3 4 c o n s e c uti v e c a s e s. N e ur o m u s c ul Di s or d. 2 0 0 8; 1 8: 5 4 1-5 4 4.
Cr a wf or d T O, P ar d o C A. T h e n e ur o bi ol o g y of c hil d h o o d s pi n al m u s c ul ar atr o p h y. 
N e ur o bi ol Di s. 1 9 9 6; 3: 9 7 -1 1 0.
d’ Y d e w all e C, S u m n er C. S pi n al M u s c ul ar Atr o p h y T h er a p e uti c s : Wh er e d o w e St a n d ? 
N e ur ot h er a p e uti c s. 2 0 1 5; 1 2( 2): 3 0 3 -3 1 6.
Fi n k el R S, M er c uri E, D arr a s B T, et al. N u si n er s e n v er s u s s h a m c o ntr ol i n i nf a ntil e -o n s et 
s pi n al m u s c ul ar atr o p h y. N E n gl J M e d 2 0 1 7 ; 3 7 7: 1 7 2 33 2.
Fi n k el R S. El e ctr o p h y si ol o gi c al a n d m ot or f u n cti o n s c al e a s s o ci ati o n i n a pr e -
s y m pt o m ati c i nf a nt wit h s pi n al m u s c ul ar atr o p h y t y p e I. N e ur o m u s c ul Di s or d. 
2 0 1 3; 2 3: 1 1 2 -1 1 5.
Fi n k el R S, M c D er m ott M P, K a uf m a n n P, et al. O b s er v ati o n al st u d y of s pi n al m u s c ul ar 
atr o p h y t y p e I a n d i m pli c ati o n s f or cli ni c al tri al s. N e ur ol o g y. 2 0 1 4; 8 3: 8 1 0 -8 1 7.
Fr e n c h J A, W a n g S, W a r n o c k B, et al. Hi st ori c al c o ntr ol m o n ot h er a p y d e si g n i n t h e 
tr e at m e nt of e pil e p s y. E pil e p si a. 2 0 1 0; 5 1( 1 0): 1 9 3 6-1 9 4 3.
Gl a n z m a n A M, M a z z o n e E, M ai n M. T h e C hil dr e n’ s H o s pit al of P hil a d el p hi a I nf a nt T e st 
of  Ne ur o m u s c ul ar Di s or d er s ( C H O P I N T E N D): T e st d e v el o p m e nt a n d r eli a bilit y. 
N e ur o m u s c ul Di s or d. 2 0 1 0; 2 0: 1 5 5 -1 6 1.
Gl a n z m a n A M, M c D er m ott M P, M o nt e s J, et al. V ali d ati o n of t h e C hil dr e n’ s H o s pit al of 
P hil a d el p hi a i nf a nt T e st of N e ur o m u s c ul ar Di s or d er s ( C H O P I N T E N D). P e di atr 
P h y s T h er. 2 0 1 1; 2 3: 3 2 2 -3 2 6.
H u a Y, S a h a s hi K, Ri g o F, et al. P eri p h er al S M N r e st or ati o n i s e s s e nti al f or l o n g -t er m 
r e s c u e of a s e v er e s pi n al m u s c ul ar atr o p h y m o u s e m o d el. N at ur e. 
2 0 1 1; 4 7 8: 1 2 3 -1 2 6.
K ol b S J, G u bit z A K, Ol s z e w s ki R F, et al. A n o v el c ell i m m u n o a s s a y t o m e a s ur e s ur vi v al 
of  m ot or n e ur o n s pr ot ei n i n bl o o d c ell s. B M C N e ur ol o g y. 2 0 0 6; 6: 6.
K ol b S J, Ki s s el J T. S pi n al m u s c ul ar atr o p h y: a ti m el y r e vi e w. Ar c h N e ur ol. 
2 0 1 1; 6 8( 8): 9 7 9 -9 8 4.


K ol b S J, C off e y C S, Y a n k e y J W,  et al. B a s eli n e r e s ult s of t h e N e ur o N E X T s pi n al 
m u s c ul ar atr o p h y i nf a nt bi o m ar k er st u d y. A n n Cli n Tr a n sl N e ur ol. 2 0 1 6; 3: 1 3 2 -1 4 5.
L a n d gr af J M, V o g el I, O o st e n bri n k R, et al. P ar e nt -r e p ort e d h e alt h o ut c o m e s i n 
i nf a nt s/t o d dl er s: m e a s ur e m e nt pr o p erti e s a n d cli ni c al v ali dit y of t h e I TQ O L -S F 4 7. 
Q u alit y Lif e R e s. 2 0 1 3; 2 2( 3): 6 3 5 -6 4 6.
L ef e b vr e S, B ur gl e n L, R e b o ull et S, et al. I d e ntifi c ati o n a n d c h ar a ct eri z ati o n of a s pi n al 
m u s c ul ar atr o p h y -d et er mi ni n g g e n e. C ell. 1 9 9 5; 8 0: 1 5 5 -1 6 5.
L e w elt A, Kr o s s c h ell K J, S c ott C, et al. C o m p o u n d m u s cl e a c ti o n p ot e nti al a n d m ot or 
f u n cti o n i n c hil dr e n wit h s pi n al m u s c ul ar atr o p h y. M u s cl e N er v e. 2 0 1 0; 4 2: 7 0 3-7 0 8.
L e w elt A, N e w c o m b T M, S w o b o d a K J. N e w t h er a p e uti c a p pr o a c h e s t o s pi n al m u s c ul ar 
atr o p h y. C urr N e ur ol N e ur o s ci R e p. 2 0 1 2; 1 2( 1): 4 2 – 5 3.
L or s o n C L, H a h n e n E, A n dr o p h y E J, et al. A si n gl e n u cl e oti d e i n t h e S M N g e n e 
r e g ul at e s s pli ci n g a n d i s r e s p o n si bl e f or s pi n al m u s c ul ar atr o p h y. Pr o c N atl A c a d 
S ci U S A. 1 9 9 9; 9 6: 6 3 0 7 -6 3 1 1.
L u n n M R, W a n g C H. S pi n al m u s c ul ar atr o p h y. L a n c et. 2 0 0 8; 3 7 1: 2 1 2 0 -2 1 3 3.
M a o J, T a y S, K h oj a st e h C S, et al. E v al u ati o n of Ti m e D e p e n d e nt I n hi biti o n A s s a y s f or 
M ar k et e d O n c ol o g y Dr u g s: C o m p ari s o n of H u m a n H e p at o c yt e s a n d Li v er 
Mi cr o s o m e s i n t h e Pr e s e n c e a n d A b s e n c e of H u m a n Pl a s m a. P h ar m R e s. 
2 0 1 6; 3 3: 1 2 0 4 -1 9.  
M o h a n g o o A D, d e K o ni n g H J, d e J o n g st e J C, et al. A st h m a -li k e s y m pt o m s i n t h e fir st 
y e ar of lif e a n d h e alt h -r el at e d q u alit y of lif e at a g e 1 2 m o nt h s: t h e G e n er ati o n R 
st u d y. Q u alit y Lif e R e s. 2 0 1 2; 2 1( 3): 5 4 5 -5 5 4.
M u n s at T L, D a vi e s K E. I nt er n ati o n al S M A C o n s orti u m M e eti n g ( 2 6-2 8 J u n e 1 9 9 2, B o n n, 
G er m a n y). N e ur o m u s c ul Di s or d. 1 9 9 2; 2( 5 -6): 4 2 3 – 4 2 8.
N g u y e n T M, H u m p hr e y E, L a m L T, et al. A t w o -sit e E LI S A c a n q u a ntif y u pr e g ul ati o n of 
S M N pr ot ei n b y dr u g s f or s pi n al m u s c ul ar atr o p h y. N e ur ol o g y. 2 0 0 8; 7 1: 1 7 5 7 -1 7 6 3.
N ur p utr a D K, L ai P S, H ar a h a NI F, et al. S pi n al m u s c ul ar atr o p h y: fr o m g e n e di s c o v er y t o 
cli ni c al tri al s. A n n H u m G e n et. 2 0 1 3; 7 7: 4 3 5 -4 6 3.
O o st e n bri n k R, S p o n g K, d e G o e d e -B ol d er A, et al. P ar e nt al r e p ort s of h e alt h -r el at e d 
q u alit y of lif e i n y o u n g c hil dr e n wit h n e ur ofi br o m a t o si s t y p e 1: I nfl u e n c e of c o n diti o n 
s p e cifi c d et er mi n a nt s. J P e di atr. 2 0 0 7; 1 5 1( 2): 1 8 2 -1 8 6.
P a s si ni M A, et al.  A nti s e n s e Oli g o n u cl e oti d e s D eli v er e d t o t h e M o u s e C N S A m eli or at e 
S y m pt o m s of S e v er e S pi n al M u s c ul ar Atr o p h y. S ci Tr a n sl M e d. 2 0 1 1; 3( 7 2): 7 2r a 1 8.
P h a n D Q, Sil k a M J, L a n Y T, et al.  C o m p ari s o n of f or m ul a s f or c al c ul ati o n of t h e 
c orr e ct e d Q T i nt er v al i n i nf a nt s a n d y o u n g c hil dr e n. J P e di atr.  2 0 1 5; 1 6 6: 9 6 0-9 6 4.
P or e n s k y  P N, et al. A si n gl e a d mi ni str ati o n of m or p h oli n o a nti s e n s e olig o m er r e s c u e s 
s pi n al m u s c ul ar atr o p h y i n m o u s e. H M G. 2 0 1 2; 2 1( 7): 1 6 2 5 -1 6 3 8.
R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d
1 1 9 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7


R O 7 0 3 4 0 6 7 — F . H off m a n n - La R o c h e Lt d  
1 2 0 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
R a at H, L a n d gr af J M, O o st e n bri n k R, et al. R eli a bilit y a n d v ali dit y of t h e I nf a nt a n d 
T o d dl er Q u alit y of Lif e Q u e sti o n n air e (I T Q O L) i n a g e n er al p o p ul ati o n a n d 
r e s pir at or y di s e a s e s a m pl e. Q u alit y Lif e R e s. 2 0 0 7; 1 6( 3): 4 4 5-4 6 0.
Ri s di pl a m I n v e sti g at or’ s Br o c h ur e V er si o n 7 , M arc h 2 0 2 0 .
S p uij br o e k A T, O o st e n bri n k R, L a n d gr af J M, et al. H e alt h -r el at e d q u alit y of lif e i n 
pr e s c h o ol c hil dr e n i n fi v e h e alt h c o n diti o n s. Q u alit y Lif e R e s. 2 0 1 1; 2 0( 5): 7 7 9 -7 8 6.
S u g ar m a n E A, N a g a n N, Z h u H, et al. P a n -et h ni c c arri er s cr e e ni n g a n d pr e n at al 
di a g n o si s f or s pi n al m u s c ul ar atr o p h y: cli ni c al l a b or at or y a n al y si s of 
7 2, 4 0 0 s p e ci m e n s. E ur J H u m G e n et. 2 0 1 2; 2 0: 2 7 -3 2.
S u m n er C J, K ol b S J, H ar mi s o n G G, et al. S M N m R N A a n d pr ot ei n l e v el s i n p eri p h er al 
bl o o d: bi o m ar k er s f or S M A cli ni c al tri al s. N e ur ol o g y. 2 0 0 6; 6 6: 1 0 6 7 -1 0 7 3.
Wi e n s B L, L y sti g T C, B err y S M. R e c e nt St ati sti c al C o ntri b uti o n s t o M e di c al D e vi c e 
D e v el o p m e nt. T h er I n n o v R e g ul S ci. 2 0 1 4; 4 8( 1): 9 0 -9 7.
























R O 7 0 3 4 0 6 7 — F . H off m a n n- La R o c h e Lt d  
1 3 2 / Pr ot o c ol B P 3 9 0 5 6, V er si o n 7
A p p e n di x 5
O p ht h al m ol o g y  E x a mi n ati o n:  P art s 1 a n d 2
W e e k
s cr e e ni n g
W k
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SAP_001.pdf: 
 
Official Title: 
 
A TWO PART SEAMLESS, OPEN-LABEL, MULTI-CENTER STUDY 
TO INVESTIGATE THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, PHARMACODYNAMICS AND EFFICACY 
OF RISDIPLAM (RO7034067) IN INFANTS WITH TYPE 1 SPINAL 
MUSCULAR ATROPHY 
NCT Number: 
NCT02913482 
Document Date: 
SAP Version 4: 29-July-2019 
 
 
 




RO7034067—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan BP39056
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
This Statistical Analysis Plan (SAP) has been amended to incorporate the following 
changes:

The sources of natural history data used to derive the performance criteria have 
been re-evaluated, and the performance criteria defined for the secondary endpoints 
have been updated (
 and Section 4.4.2).

The interim analysis for efficacy has been removed due to the close proximity of this 
analysis to the primary analysis (Section 2.4 and Section 4.8).
Additional minor changes have been made to improve clarity and consistency.


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3/Statistical Analysis Plan BP39056
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 7
2.2
Outcome Measures ................................................................. 7
2.2.1
Primary Efficacy Endpoint........................................................ 7
2.2.2
Secondary Efficacy Endpoints................................................. 7
2.2.3
Exploratory Efficacy Endpoints................................................ 9
2.2.4
Pharmacokinetic Endpoints ................................................... 10
2.2.5
Pharmacodynamic Endpoints................................................ 10
2.2.6
Safety Endpoints ................................................................... 11
2.3
Determination of Sample Size ............................................... 11
2.4
Analysis Timing ..................................................................... 12
3.
STUDY CONDUCT..................................................................................... 14
3.1
Randomization....................................................................... 14
3.2
Independent Review Facility.................................................. 14
3.2.1
Modified BSID-III Gross Motor Scale..................................... 14
3.2.2
Ophthalmological Assessments............................................. 15
3.2.3
Permanent Ventilation ........................................................... 16
3.3
Data Monitoring ..................................................................... 16
4.
STATISTICAL METHODS FOR THE GLOBAL POPULATION .................. 17
4.1
Analysis Populations ............................................................. 17
4.1.1
Intent-to-Treat Population...................................................... 17
4.1.2
Pharmacokinetic-Evaluable Population ................................. 17
4.1.3
Safety Population .................................................................. 17
4.2
Analysis of Study Conduct..................................................... 17
4.2.1
Study Enrollment ................................................................... 17
4.2.2
Protocol Deviations................................................................ 18
4.2.3
Patient Disposition................................................................. 18
4.3
Analysis of Treatment Group Comparability .......................... 18
4.3.1
Demographics and Baseline Characteristics ......................... 19
4.3.2
SMA History and Disease Characteristics ............................. 19


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4.3.3
General Medical History and Baseline Conditions................. 20
4.3.4
Previous and Concomitant Medications................................. 20
4.3.5
Previous and Concomitant SMA Related 
Surgeries and Procedures..................................................... 21
4.4
Efficacy Analysis.................................................................... 21
4.4.1
Primary Efficacy Endpoint...................................................... 22
4.4.2
Secondary Efficacy Endpoints............................................... 23
4.4.2.1
Motor Function and Development Milestones........................ 24
4.4.2.2
Survival and Ventilation-Free Survival................................... 29
4.4.2.3
Respiratory ............................................................................ 31
4.4.2.4
Nutrition ................................................................................. 33
4.4.3
Exploratory Efficacy Endpoints.............................................. 33
4.4.3.1
Maintenance of Treatment Effect........................................... 33
4.4.3.2
Muscle Electrophysiology ...................................................... 34
4.4.3.3
Disease-Related Adverse Events.......................................... 35
4.4.3.4
Healthcare Utilization............................................................. 36
4.4.3.5
Swallowing and Nutrition ....................................................... 36
4.4.3.6
Growth Measures .................................................................. 37
4.4.3.7
Parent/Caregiver Reported Outcomes .................................. 37
4.4.3.8
Parent/Caregiver Reported Motor Milestones........................ 38
4.4.3.9
Clinician Reported Respiratory Function and
Swallowing Ability Items ........................................................ 39
4.4.4
Sensitivity Analyses............................................................... 40
4.4.4.1
Site Evaluation of Sitting without Support for 5 
Seconds................................................................................. 40
4.4.4.2
Alternative Definition of Sitting without Support..................... 40
.............................................................
4.4.4.4
Censoring .............................................................................. 40
4.4.4.5
Events Reported During Safety Follow-Up ............................ 40
4.4.4.6
Handling of Missing Data....................................................... 41
4.4.5
Subgroup Analyses ............................................................... 42
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 42
4.6
Safety Analyses..................................................................... 43




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1.
BACKGROUND
This Statistical Analysis Plan (SAP) documents the statistical methods for summarizing 
and analyzing efficacy and safety data from the confirmatory (pivotal) Part 2 of 
Study BP39056 collected from infants with Type 1 spinal muscular atrophy (SMA).  The 
purpose of this document is to describe the data handling rules, derivation rules, and 
statistical analysis methods.
The global population will include all infants enrolled during the global enrollment phase 
(including infants enrolled in China during that phase), and the China subpopulation will 
include all infants enrolled in China (i.e., during both the global enrollment phase and the 
extended China enrollment phase).  Separate analyses will be performed for the global 
population and the China subpopulation (see Section 5 for information on the China 
subgroup analyses).
The SAP language and analysis supersedes the language in the protocol and protocol 
synopsis.
2.
STUDY DESIGN
Study BP39056 is a seamless two-part, open-label, single-arm, multi-center clinical 
study to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and 
efficacy of RO7034067 in Type 1 SMA infants.  The study will be conducted in two parts 
and each part will be followed by an open-label extension phase:
Exploratory Part 1: Part 1 is an open-label, dose escalation study in infants with Type 1 
SMA aged 1 to 7 months (at time of enrollment).  This exploratory part will consist of at 
least 8 infants and up to 24 infants (if required) to assess the safety, pharmacokinetic 
(PK), and pharmacodynamic (PD) profile of RO7034067 in infants and determine the 
dose for Part 2.
An internal monitoring committee (IMC) consisting of selected Sponsor personnel will be 
responsible for monitoring the safety of infants and selecting the dose for the 
confirmatory Part 2.  The dose selected by the IMC will be confirmed by an external 
independent Data Monitoring Committee (iDMC).
Confirmatory Part 2: Part 2 is an open-label, single-arm study in 40 infants with Type 1 
SMA aged 1 to 7 months (at time of enrollment) to assess the efficacy of RO7034067 at 
the dose selected in Part 1 over a 24-month treatment period, with the primary analysis 
performed at 12 months.
The study will progress in an operationally seamless manner from Part 1 into Part 2 after 
the dose selection decision has been taken.  Infants from Part 1 will not be enrolled into 
Part 2, but all infants will be given the possibility to continue receiving RO7034067 as 
part of an open-label extension phase.  The extension phase will include regular 


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7/Statistical Analysis Plan BP39056
monitoring of safety, tolerability, PK/PD, and exploratory efficacy of those patients 
enrolled in Part 1.
The duration of the study for each infant enrolled in Part 2 (not including the open-label 
extension phase) will be up to 25 months as follows:

Screening: up to 30 days prior to first dose.

Treatment period: 24 months from the start of dosing, with the primary analysis after 
the last infant in the global population reaches 12 months of treatment.

After each infant completes 24-month treatment, he or she will enter an open-label 
extension phase.
As in Part 1, the open-label extension phase is planned to run until RO7034067 is 
commercially available in the country of the infants who participated or until the Sponsor 
ceases producing or studying RO7034067.  If an infant is withdrawn from the clinical 
study at any time, they will be asked to participate in the follow-up period of the study as 
described in the Schedule of Assessments (SoA).
The analyses of this study will be structured into two parts: exploratory (Part 1) to select 
the dose, and confirmatory (Part 2) to evaluate the treatment effect of RO7034067.  This 
analysis plan describes the methods that will be used for the analysis of Part 2.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments for Part 2 of the study in Appendix 2.
2.2
OUTCOME MEASURES
2.2.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of infants sitting without support after 
12 months of treatment as assessed by item 22 (‘Sits without support for 5 seconds’) of 
the modified Gross Motor Scale of the Bayley Scales of Infant and Toddler Development 
Third Edition (BSID-III).
2.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows below.  The subset of secondary 
endpoints that are included within the hierarchical testing approach are specified in 
Section 4.4.2.
Motor Function and Development Milestones

Proportion of infants who achieve a score of 40 or higher in the Children’s Hospital 
of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at 
Month 12 of treatment.

Proportion of infants who achieve an increase of at least 4 points in their 
CHOP-INTEND score from baseline at Month 8 and Month 12 of treatment.


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
Proportion of infants who achieve head control at Month 8, Month 12, and Month 24 
of treatment (defined as a score of 3 or higher for item 12 of the CHOP-INTEND).

Change from baseline in the total raw score of the modified BSID-III gross motor 
scale at Month 12 and Month 24 of treatment.

Proportion of infants who achieve the attainment levels of the motor milestones 
assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2)* 
at Month 8 (subset #), Month 12 and Month 24 of treatment.
*Milestones of: head control#, sitting, voluntary grasp, ability to kick#, rolling#, crawling, 
standing, and walking.

Proportion of motor milestone responders as assessed by HINE-2 at Month 12 and 
Month 24 of treatment.

Highest motor milestone* achieved by Month 12 and Month 24 of treatment.
*Milestones of: head control (item 9 ‘Controls head while upright for 15 seconds’), rolling 
(item 14 ‘Rolls from side to back’), sitting without support (primary endpoint), crawling 
(item 30 ‘Crawls on stomach’), standing (item 40 ‘Stands alone’) and walking (item 42 
‘Walks alone’) as assessed in the modified BSID-III gross motor scale

Proportion of infants sitting without support for 5 seconds at Month 24 of treatment 
(defined as per the primary endpoint).

Proportion of infants sitting without support for 30 seconds (defined as ‘Sits without 
support for 30 seconds’ as assessed in item 26 of the modified BSID-III gross motor 
scale) at Month 24 of treatment.

Proportion of infants standing at Month 24 of treatment (defined as ‘Stands alone’ as 
assessed in item 40 of the modified BSID-III gross motor scale).

Proportion of infants walking at Month 24 of treatment (defined as ‘Walks alone’ as 
assessed in item 42 of the modified BSID-III gross motor scale).
Survival and Ventilation-Free Survival

Time to death or permanent ventilation (from enrollment).  Permanent ventilation is 
defined as16 hours of non-invasive ventilation per day or intubation 
for21 consecutive days in the absence of, or following the resolution of, an acute 
reversible event; or tracheostomy.

Time to death (from enrollment).

Proportion of infants who are alive without permanent ventilation at Month 12 and 
Month 24 of treatment.

Proportion of infants who are alive at Month 12 and Month 24 of treatment.
Respiratory

Time to permanent ventilation (from enrollment).

Proportion of infants who are without permanent ventilation at Month 12 and 
Month 24 of treatment.


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9/Statistical Analysis Plan BP39056

Proportion of infants who achieve a reduction of at least 30 degrees in their phase 
angle from baseline, as measured by respiratory plethysmography (RP), at 
Month 12 of treatment.

Proportion of infants who do not require invasive or non-invasive respiratory support 
at Month 12 and Month 24 of treatment.
Nutrition

Proportion of infants with the ability to feed orally at Month 12 and Month 24 of 
treatment.
2.2.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are as follows:
Maintenance of 12-Month Treatment Effect

Proportion of infants who maintained sitting at Month 24 of treatment (for infants 
sitting at Month 12), as assessed by item 22 of the modified BSID-III gross motor 
scale.

Proportion of infants who maintained (or continued to improve) their phase angle 
reduction at Month 24 of treatment (for infants with a phase angle reduction of at 
least 30 degrees from baseline at Month 12), as measured by RP.
Muscle Electrophysiology

Proportion of infants who achieve an increase of at least 0.3mV from baseline in 
their compound muscle action potential (CMAP) negative peak amplitude at 
Month 12 and Month 24 of treatment.
Disease-Related Adverse Events

Proportion of infants who experience at least one disease-related adverse event by 
Month 12 and Month 24 of treatment.

Number of disease-related adverse events per patient-year at Month 12 and 
Month 24 of treatment.

Proportion of infants who experience at least one disease-related adverse event 
resulting in hospitalization by Month 12 and Month 24 of treatment.

Number of disease-related adverse events resulting in hospitalization per 
patient-year at Month 12 and Month 24 of treatment.
Healthcare Utilization

Number of hospitalizations (for any reason) per patient-year and number of nights 
admitted to hospital per infant at Month 12 and Month 24 of treatment.
Swallowing and Nutrition

Proportion of infants with the ability to swallow at Month 8, Month 12, and Month 24 
of treatment.


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10/Statistical Analysis Plan BP39056
Growth Measures

Ratio between the chest and head circumference at Month 8, Month 12, and 
Month 24 of treatment.

Change from baseline in weight percentiles at Month 12 and Month 24.

Change from baseline in length/height percentiles at Month 12 and Month 24.
Parent/Caregiver Reported Outcomes

Change from baseline in the Infant Toddler Quality of Life (ITQOL)-SF47
Questionnaire domains and single item scores* at Month 12 and Month 24 of 
treatment.
*Parent-proxy domains of physical abilities, growth and development, bodily 
pain/discomfort, temperament and moods, behavior, general health perception, parent 
emotional impact and parent time impact.  Single item scores include overall health, 
change in health and family cohesion.
Clinician Reported Respiratory Function and Swallowing Ability Items

Proportion of infants with no change or improvement in respiratory function as 
assessed by the clinician reported Clinical Global Impression of Change (CGI-C) at 
Month 12.

Proportion of infants with no change or improvement in the ability to swallow as 
assessed by the clinician reported CGI-C at Month 12.
2.2.4
Pharmacokinetic Endpoints
The PK endpoints are as follows:

Concentration per time-point listed.

Peak plasma concentration (Cmax).

Area under the curve (AUC).

Concentration at the end of a dosing interval (Ctrough).

Other PK parameters as appropriate.
2.2.5
Pharmacodynamic Endpoints
The PD endpoints are as follows:

Percent change from baseline in full-length SMN2 mRNA in blood at each time-point.

Percent change from baseline in Δ7 SMN2 mRNA in blood at each time-point.

Percent change from baseline in the ratio of full-length to Δ7 SMN2 mRNA in blood 
at each time-point.

Absolute SMN protein in blood at each time-point.

Percent change from baseline in SMN protein in blood at each time-point.


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2.2.6
Safety Endpoints
The safety endpoints are as follows:

Incidence of adverse events (overall, by severity and by relationship to study 
medication).

Incidence of serious adverse events.

Incidence of treatment discontinuations due to adverse events.

Incidence of laboratory abnormalities.

Incidence of electrocardiogram (ECG) abnormalities.

Incidence of vital sign abnormalities.

Incidence of clinically significant findings on ophthalmological examination.

Anthropometric examination, including weight, height, head circumference and 
chest circumference.
2.3
DETERMINATION OF SAMPLE SIZE
The purpose of Part 2 of the study is to estimate the proportion of infants who are sitting 
without support at 12 months of treatment and to test whether this proportion is higher 
than a performance criterion set at 5%. This 5% threshold was chosen based on the 
natural history of the disease, typically that Type 1 SMA patients never achieve sitting 
without support by definition.
The target sample size is 40 infants. This sample size provides at least 90% power to 
test the null hypothesis H0: p5% versus alternative hypothesis Ha: p5%, if the true 
proportion of infants who would sit on treatment is 20%. This is based on an exact 
binomial test with a one-sided 5% significance level. The minimum number of infants 
needed to be observed sitting is 5 out of 40 for a statistically significant result. If in 
Part 2, 5 out of 40 infants sit, the lower limit of the two-sided 90% Clopper-Pearson 
(exact) confidence interval (CI) would be above 5%.


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The power and minimum number of infants needed to be observed sitting for a 
statistically significant result (the critical value) if the number of infants enrolled in Part 2 
is less than or greater than 40 are presented below:
Number of infants enrolled in Part 2
Critical value
Power (%)
35
5
85.7
36
5
87.3
37
5
88.8
38
5
90.1
39
5
91.3
40
5
92.4
41
6
85.6
42
6
87.1
43
6
88.5
44
6
89.8
45
6
91.0
No allowance has been made for infants who withdraw early as these infants will be 
classified as a non-responder/non-sitter and included within the primary analysis.
Sample Size for the China Extension Period
Part 2 of this study will initially enroll 40 infants across all sites in a global enrollment 
phase.  After completion of the global enrollment phase, additional infants may be 
enrolled at sites in mainland China, Hong Kong, and Taiwan that are recognized by the 
 
in an extended China enrollment phase to ensure a total of 
approximately 10 infants in a China subpopulation.  With a sample size of 10 the 
probability of observing at least 1 infant sitting is 89% if the true proportion of infants who 
would sit on treatment is 20%.
The global population will include all infants enrolled during the global enrollment phase 
(including infants enrolled in China during that phase), and the China subpopulation will 
include all infants enrolled in China (i.e., during both the global enrollment phase and the 
extended China enrollment phase).
2.4
ANALYSIS TIMING
The primary analysis will be performed after the last infant in the global population has 
completed 12 months of treatment, or has been withdrawn from the study (and all other 
infants in the global population have either completed 12 months of treatment or have 
been withdrawn from the study). A database lock for the purpose of the primary analysis 
and analyses of the 12-month secondary and exploratory endpoints will occur once the 
last infant enrolled into Part 2 during the global enrollment phase has either completed 


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13/Statistical Analysis Plan BP39056
his or her 12-month assessment or has been withdrawn (and all other infants in the 
global population have either completed the 12-month assessment or have been 
withdrawn from the study). A fixed-cutoff data cut will be used with a clinical cutoff date 
based on the date of the Month 12 visit of the last infant enrolled in Part 2 of the study
during the global enrollment phase.  The clinical cutoff date will be the same for all 
infants, and all data collected on or before the clinical cutoff date will be included in the 
data cut.  At the time of the primary analysis, all available interim efficacy data from the 
global population post Month 12 will be reported. All available safety data from infants 
enrolled in Part 2 of the study will also be reported.
A database lock for the analyses of the 24-month secondary and exploratory endpoints 
will occur once the last infant enrolled into Part 2 during the global enrollment phase has 
either completed his or her 24-month assessment or has been withdrawn (and all other 
infants in the global population have either completed the 24-month assessment or have 
been withdrawn from the study). A fixed-cutoff data cut will be used with a clinical cutoff 
date based on the date of the Month 24 visit of the last infant enrolled in Part 2 of the 
study during the global enrollment phase.  At the time of the Month 24 analysis, all 
available interim efficacy data from the global population post Month 24 collected as part 
of the open-label extension period will be reported. All available safety data will also be 
reported.
Following the primary analysis, subsequent locks of the database may occur in order to 
perform safety analyses of the data at further time-points during the study. The final 
database lock will occur at study end (i.e., last patient, last observation).
In addition, a futility assessment for efficacy will be conducted after the first 14 infants 
enrolled into the confirmatory Part 2 of the study during the global enrollment phase 
have reached 12 months of treatment or have been withdrawn.
Analysis Timing for the China Subgroup Analysis
The China subgroup analyses (including infants from both the global enrollment phase 
and the extended China enrollment phase, if required) will be performed after the last 
infant in the China subpopulation has completed 12 (or 24) months of treatment, or has 
been withdrawn from the study (and all other infants in the China subpopulation have 
either completed 12 [or 24] months of treatment or have been withdrawn from the study), 
or at the time of the global primary (or Month 24) analysis, respectively, whichever is 
later.
Once at least 1 infant in the China subpopulation (from either the global enrollment 
phase or the extended China enrollment phase) has met the primary endpoint of sitting 
without support at Month 12 (as assessed by the independent central readers), and at 
least 5 infants in the global population have met the primary endpoint, the objective for 
the China subpopulation will be considered achieved.  All 10 infants in the China 


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14/Statistical Analysis Plan BP39056
subpopulation will continue to receive 12 months of treatment in order to provide an 
unbiased estimate of the proportion of infants sitting without support at Month 12.
3.
STUDY CONDUCT
3.1
RANDOMIZATION
Part 2 of Study BP39056 is a single arm, open-label study, and all infants will receive 
RO7034067 at the dose (target exposure level) selected in Part 1.
3.2
INDEPENDENT REVIEW FACILITY
3.2.1
Modified BSID-III Gross Motor Scale
The evaluation of the modified BSID-III gross motor scale, including sitting, will be 
video-recorded at study sites in a standardized manner and centrally reviewed by two 
independent readers (in addition to the site clinical evaluator assessment). The 
following items of the modified BSID-III gross motor scale will be video recorded:

Sitting items: items 16, 19, 22, 26, 27, and 28

Crawling and kneeling items: items 30, 31, 32, and 34

Standing items: items 29, 33, 35, 36, 40, 51, 52, 60, 61, 69, and 70

Walking items: items 37, 38, 42, 43, 48, 53, 56, 61, 63, and 71
The two independent central readers will review all recorded items of the modified 
BSID-III assessment, but will only complete scoring of items 22, 26, 30, 40, and 42. The 
assessment of the central readers will be used for the analysis of the primary endpoint 
(item 22 ‘Sits without support for 5 seconds’) and for the analysis of the other scored 
items. The role and process of the reading center will be written in a separate charter.
The scores provided by the two independent readers will be evaluated to determine 
concordance in the five scored items of the gross motor scale. These include: item 22: 
sitting without support for 5 seconds (primary endpoint, defined as ‘Sits without support 
for 5 seconds’), item 26: sitting without support for 30 seconds (‘Sits without support for 
30 seconds’), item 30: crawling (‘Crawls on stomach’), item 40: standing (‘Stands alone’),
and item 42: walking (‘Walks alone’).
For the primary endpoint of sitting without support for 5 seconds and the other items to 
be classified as confirmed, both independent central readers should classify the 
milestone (i.e., item) to have been achieved by the infant. If the independent central 
readers both classify the milestone as not being achieved, then the milestone will be 
classified as not confirmed, regardless of the site clinical evaluator’s own assessment. If 
the scores of the independent central readers are discordant for any of the scored items, 
then both central readers will be asked to re-score the infant. If the scores of the 
independent central readers are concordant on re-score, i.e., both central readers 
classify the item as (not) being achieved, those milestones will be classified as 
confirmed (or not confirmed). If the two independent central readers are not in 


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15/Statistical Analysis Plan BP39056
agreement after they have re-scored the infant, then the motor milestone will be 
classified as not confirmed.
Table 1
Central Reader Scoring – Analysis of Scored Item (Example: Item 
22 ‘Sits without Support for 5 Seconds’)
Site Clinical 
Evaluator
Reader 1
Reader 
2
Discordance/
Re-score 
Needed
Reader 
1
Re-
Score
Reader 
2
Re-
Score
Confirmed for 
Primary Endpoint
Yessitting 
achieved
Yes
Yes
No
N/A
N/A
Yes
Yes
No
No
No
N/A
N/A
No
Yes
Yes
No
Yes
Asked to re-score
Yes
No
No
Yes
Yes
Yes
No
No
No
No
Yes
No
Nositting not 
achieved
No
No
No
N/A
N/A
No
No
Yes
Yes
No
N/A
N/A
Yes
No
Yes
No
Yes
Asked to re-score
Yes
No
No
Yes
Yes
Yes
No
No
No
No
Yes
No
N/A Not applicable
If ‘Cannot Test (CNT)’ is recorded by one of the independent central readers (and the 
other central reader provides a score), or if the reasons for ‘CNT’ are discordant, then 
both central readers will be asked to re-score the infant. If the scores of the independent 
central readers are concordant on re-score, i.e., both central readers classify the item as 
(not) being achieved, those milestones will be classified as confirmed (or not confirmed). 
If upon re-score the two central readers are not in agreement, or if at least one ‘CNT’ is 
recorded, then the motor milestone will be classified as not confirmed.
3.2.2
Ophthalmological Assessments
Images obtained from the spectral domain optical coherence tomography (SD OCT) and 
fundus photography examinations will be reviewed by an independent reader from the 
 


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This includes an assessment of clinically significant 
changes from baseline in these examinations at each time-point. These assessments 
will be used to determine the incidence of clinically significant findings in the SD OCT 
and fundus photography examinations.  The role and process of the reading center will 
be written in a separate charter.
3.2.3
Permanent Ventilation
The occurrence of permanent ventilation events will be determined by an independent 
permanent ventilation adjudication committee.  This committee will review all pertinent 
data for infants who may meet the definition of permanent ventilation and confirm if this 
endpoint has been met.  The assessment of the committee will be used in the analysis of 
time-to-death or permanent ventilation and time to permanent ventilation.  The role and 
process of the committee will be written in a separate charter.
3.3
DATA MONITORING
An external iDMC will be established to monitor patient safety during Part 2 of the study. 
The iDMC will meet to review data from Part 1 and confirm the dose selection decision 
of the IMC. The iDMC will provide a recommendation to the Sponsor whether the study 
can continue as planned (i.e., that the study can move into Part 2 with the selected dose 
from Part 1 as recommended by the IMC). The final decision based on the iDMC 
recommendation will be made by the Sponsor. After the dose selection decision, the 
IMC will hand over responsibility for reviewing patient safety to the iDMC. The iDMC 
from this time-point on will review the data of all ongoing Part 1 patients (who will 
continue to be treated in the extension phase) and all Part 2 patients.
The iDMC will meet on a regular basis (approximately every 3 months once the dose 
selection is confirmed) over the course of Part 2 of the study to review emerging data, 
and may also meet on an ad-hoc basis as required (e.g., if any unexpected safety 
concerns arise). After every meeting, the iDMC will make a recommendation to the 
Sponsor for the study conduct. The iDMC can make any of the following 
recommendations to the Sponsor:

Recommend to continue the trial without modification.

Recommend increases or decreases to the dose of RO7034067.

Recommend to stop the trial.

Recommend to put enrollment on hold pending further safety evaluations.

Recommend a protocol amendment.
Analyses required for the iDMC’s safety data review will be performed as described in 
the iDMC Charter.  Data displays will be prepared by an independent Data Coordinating 
Center (iDCC).


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The interim analyses for efficacy and futility during Part 2 of the study will be performed 
by the Sponsor and presented to the iDMC. The iDMC will be requested to review all 
available safety data and be asked to provide an independent assessment of the benefit-
risk profile of RO7034067 in the Type 1 SMA population at this earlier time-point. The 
final decision based on the iDMC recommendation will be made by the Sponsor.
A Sponsor Clinical Pharmacologist (who is not a member of the iDMC) will regularly 
review the PK and PD data from Part 1 and Part 2 in order to be able to adjust the dose 
of individual infants if required, ensuring not to exceed the mean exposure cap, and to 
continue treatment at the targeted exposure level, as infants grow and their body
systems mature. The iDMC will be informed of any individual dose adjustments required 
at the next scheduled iDMC meeting.
The roles, responsibilities, membership, scope of activities, time of meetings, and 
communication plan for the iDMC were documented in the Charter prior to the initiation 
of Part 1 of the study. The external iDMC will be chaired by a medically qualified 
individual with experience with SMA and will include another physician experienced in 
neurology, a clinical pharmacologist, an ophthalmologic expert, and a biostatistician. No 
member of the iDMC will participate in the study as an investigator or sub-investigator.
4.
STATISTICAL METHODS FOR THE GLOBAL POPULATION
4.1
ANALYSIS POPULATIONS
4.1.1
Intent-to-Treat Population
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, 
regardless of whether they received treatment or not. The ITT population will be the 
primary analysis population for all efficacy analyses.
4.1.2
Pharmacokinetic-Evaluable Population
All infants with at least one time-point with a measureable concentration will be included 
in the PK-evaluable population. Infants will be excluded from the PK analysis population 
if they significantly violate the inclusion or exclusion criteria, deviate significantly from the 
protocol or if data are unavailable or incomplete which may influence the PK analysis. 
Excluded cases will be documented together with the reason for exclusion.
4.1.3
Safety Population
All infants who receive at least one dose of study medication (RO7034067) will be 
included in the safety population.
4.2
ANALYSIS OF STUDY CONDUCT
4.2.1
Study Enrollment
The number of infants in each of the ITT and safety populations will be summarized, and 
the number of infants excluded from each of the populations will be summarized by 
reason for exclusion. Infants excluded from the analysis populations will also be listed.


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The number of infants enrolled at each country and site will be summarized.
4.2.2
Protocol Deviations
The major protocol deviations will be identified according to the Procedures for 
Managing Protocol Deviations document. Major protocol deviations will be listed and 
evaluated for their potential effects on the interpretation of study results. The number 
and percentage of infants with major protocol deviations will be summarized by protocol 
deviation criterion.
4.2.3
Patient Disposition
The number of infants who were enrolled, discontinued, continuing treatment at the time 
of the analysis or have completed the study (completed the 24-month treatment period 
and the open-label extension phase) will be summarized. Reasons for premature study 
withdrawal will be listed and summarized. The number of infants entering the open-label 
extension will also be summarized. The number of infants discontinuing between 0 and 
12 months, between 12 and 24 months, and during the open-label extension period, and 
the reasons for discontinuation, will be summarized.
In addition, the number of infants entering and discontinuing from the safety follow-up 
period, and the reasons for discontinuation, will be summarized.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic and other baseline characteristics will be summarized for the ITT 
population using descriptive statistics, means, standard deviations, medians, 
interquartile ranges (IQRs) and ranges for continuous variables and number and 
percentages for categorical variables, as appropriate.
Baseline will be defined as the last measurement recorded prior to or on the day of first 
study drug administration. If an assessment is performed at both the screening visit and 
the baseline visit, the baseline assessment will be used, unless this is missing and the 
screening assessment is available.
General medical history and baseline conditions, and previous and concomitant 
medications and SMA related surgeries and procedures will be summarized for the 
safety population.


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4.3.1
Demographics and Baseline Characteristics
Summary statistics will be presented for the following demographic and baseline 
characteristics: age at enrollment (including the number and percentage of 
infants5 months old and5 months old), sex, race, ethnicity, country, weight, body 
length/height, head circumference, chest circumference, and chest to head 
circumference ratio (head circumference will be the denominator of the ratio). The 
number and percentage of infants enrolled in each of the following geographical regions: 
Europe, USA or Canada, rest of world, will be presented. The rest of world category 
may be further subdivided depending on the final recruitment pattern.
Growth charts will be used to track an infant’s growth over time and to monitor his or her 
growth in relation to a reference population of healthy children. An infant’s percentile on 
the growth chart indicates the percentage of the reference population that his or her 
value equaled or surpassed for a given growth parameter. The standard deviation score 
(SDS or z-score) indicates to what extent the infant’s value deviated from the median of 
the reference population. Because of the relationship between an infant’s z-score and 
percentile on the growth chart, a standard normal distribution table can be used to obtain 
an infant’s z-score from his or her growth chart percentile, and vice versa.
Baseline weight-for-age, length/height-for-age, weight-for-length/height, and head 
circumference-for-age percentiles will be summarized, and a scatterplot of individual
percentiles versus age (at enrollment) will be presented for weight-for-age. The number 
and percentage of infants in the 3rd, 5th, 10th, 25th, 50th and50th percentiles for 
weight-for-age, length/height-for-age, weight-for-length/height, and head 
circumference-for-age will also be presented.  Percentiles will be based on World Health 
Organization (WHO) Child Growth Standards (2006 and 2007).  z-scores will be 
calculated using the methods described in the WHO Child Growth Standards (2006 and 
2007), with percentiles derived directly from the z-score and standard normal cumulative 
distribution function.
4.3.2
SMA History and Disease Characteristics
Summary statistics will be presented for the following parameters: SMN2 copy number, 
age at onset of symptoms, age at diagnosis, initial SMA symptoms, tracheostomy 
(yes/no), time between first treatment and onset of symptoms (including the number and 
percentage of infants with time3 months and3 months), baseline CHOP-INTEND, 
modified BSID-III gross motor scale and HINE-2 scores, and baseline CMAP amplitude 
values (including the number and percentage of infants with values1mV and1mV).
The current level of motor function, motor functions achieved and maintained (including 
age function was achieved and age function was lost, if applicable) and highest motor 
function achieved will also be summarized.
The level of respiratory support required by the infants at baseline will be summarized. 
The number and percentage of infants who: do not require invasive or non-invasive 


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pulmonary care, require cough assistance (used daily for therapy or with an illness) or 
bilevel positive airway pressure (BiPAP) support (16 hours per day or16 hours per 
day) and have ventilation being provided prophylactically (including type of ventilation: 
awake assisted ventilation, night-time assisted ventilation,16 hours assisted ventilation 
or airway clearance through cough assistance, if applicable) will be presented. The 
number and percentage of infants who have been receiving BiPAP support for16 hours 
per day for21 consecutive days or have been intubated for21 consecutive days will 
also be presented.
The primary food intake type will also be summarized.  Food intake type includes solid 
food, modified oral food intake, nasogastric food intake, 100% gastrostomy tube fed, oral 
fluid (milk) food intake, or mixed (fluid/puréed food) oral food intake. The number and 
percentage of infants with the ability to swallow will be presented, and the age the ability 
to swallow was lost or regained (if applicable) will be summarized.  The number and 
percentage of infants fed orally, via a feeding tube, or via a combination of oral and tube 
feeding, and the number and percentage of infants who can swallow water, nectar (or 
similar), rice pudding (or similar), purées, and solid food will also be presented.
4.3.3
General Medical History and Baseline Conditions
For all medical conditions, the term entered by the investigator describing the condition 
(the ‘verbatim term’) will be assigned to a standardized term (the ‘preferred term’) and 
system organ class based on the most up-to-date version of the Medical Dictionary for 
Regulatory Activities (MedDRA). All analyses will be performed using these preferred 
terms and body systems.
The number and percentage of infants with previous conditions (including conditions with 
an onset date within 30 days of the screening visit) and conditions concurrent at baseline 
will be summarized. Multiple occurrences of the same condition in an individual patient 
(i.e., same coded term) will be counted only once in the calculation of the event 
frequency. The overall number of infants with at least one condition and the total 
number of conditions will also be presented.
Previous conditions (conditions with an end date before the first dose date) and 
conditions concurrent at baseline (conditions that start prior to the first dose date and 
have no end date or an end date after the first dose date) will be summarized separately.
4.3.4
Previous and Concomitant Medications
For all medications, the term entered by the investigator describing the medication (the 
‘verbatim term’) will be assigned to a standardized term (the ‘preferred term’) and drug 
class based on the Genentech Drug Thesaurus. All analyses will be performed using 
these preferred terms and medication classes.
The number and percentage of infants taking each medication will be presented. This 
includes all medications with a start date within 30 days of the screening visit. Multiple 


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occurrences of the same medication in an individual patient (i.e., same coded term) will 
be counted only once. The overall number of infants taking at least one medication and 
the total number of medications will also be presented.
Previous medications (medications with an end date before the first dose date), 
medications present at baseline (medications that start prior to the first dose date and 
have no end date or an end date after the first dose date) and concomitant medications 
(medications with a start date on or after the first dose date up to the date of study 
withdrawal/completion) will be summarized separately. Medications with a start date 
from 1 day up to 52 weeks after study withdrawal/completion will also be summarized 
separately.
Treatments given for prophylaxis and treatments given for an adverse event will be 
summarized separately.
4.3.5
Previous and Concomitant SMA Related Surgeries and 
Procedures
For all surgeries and procedures, the term entered by the investigator describing the 
event (the ‘verbatim term’) will be assigned to a standardized term (the ‘preferred term’) 
and system organ class based on the most up-to-date version of MedDRA. All analyses 
will be performed using these preferred terms and body systems.
The number and percentage of infants who had any relevant SMA related surgeries or 
procedures will be presented. This will include all surgeries or procedures performed 
within 30 days of the screening visit. Multiple occurrences of the same procedure in an 
individual patient (i.e., same coded term) will be counted only once. The overall number 
of infants who have undergone at least one procedure and the total number of 
procedures reported will also be presented.
Surgeries or procedures performed prior to the first dose date and those performed on or 
after the first dose date up to the date of study withdrawal/completion will be 
summarized separately. Surgeries or procedures performed from 1 day up to 52 weeks 
after study withdrawal/completion will also be summarized separately.
4.4
EFFICACY ANALYSIS
The ITT population will be the primary analysis population for all efficacy analyses.  The 
confirmatory efficacy analyses will only include data from infants enrolled into Part 2 of 
the study.  For consistency with the analysis methods described for the anthropometric 
measurements in Section 4.6.8, the analyses for weight-for-age and length/height-for-
age percentiles will be based on the safety population.
Results from Part 2 will be compared to, and put into context with, natural history data 
from untreated Type 1 SMA infants. Full details of the available sources to be used as 
the external control and the benchmarks/performance criteria to be used in the analysis 


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(e.g., the actual null hypothesis response rate to be tested for secondary endpoints) are 
provided in
A time window will be created for each study visit, starting midway between that visit and 
the previous study visit, and ending midway between that visit and the next study visit (if 
applicable). Post-baseline efficacy assessments, including assessments performed at 
an unscheduled visit or early discontinuation visit, will be assigned to a scheduled study 
visit based on these time windows, even if the assessment is not scheduled to be 
performed at that visit. If multiple valid values for a variable are recorded in the same 
time window, the assessment performed closest to the scheduled study day of the visit 
will be used for summary of the data, except for the growth measures, where the last
assessment will be used for summary of the data for consistency with the methods 
described for the anthropometric measurements in Section 4.6.
4.4.1
Primary Efficacy Endpoint
The primary endpoint for the confirmatory Part 2 of the study is the proportion of infants 
who are sitting without support after 12 months of treatment. Sitting is defined as ‘sits 
alone without support for at least 5 seconds’ as assessed in item 22 of the modified 
BSID-III gross motor scale. As per the scoring manual, item 22 will not be considered 
achieved if the infant sits alone for less than 5 seconds before losing balance and falling 
over, or if the infant uses his or her arms to prop him- or herself up. The assessment of 
the independent central readers will be used for the primary analysis (as described in 
Section 3.2). Both central readers should classify the milestone to have been achieved 
for the endpoint to be confirmed.  Infants who do not achieve sitting, or have not 
maintained sitting achieved earlier, or have been withdrawn, or died, will be classified as 
non-responders (i.e., non-sitters) for the primary analysis. Infants with a missing 
assessment at Month 12 will also be classified as non-responders.
The natural history of the disease is well-defined; Type 1 SMA infants never achieve 
sitting (Cobben et al., 2008; Finkel et al., 2014; 
). This natural 
history can therefore be used to define the performance criterion for success (i.e., a 
threshold of achievement for the RO7034067-treated infants to be assessed against 
within this study).  The pre-defined performance criterion for the primary endpoint will be 
5%.
The number and percentage of infants sitting after 12 months of treatment (i.e., at 
Month 12) will be presented. The proportion of infants sitting at Month 12 will be 
presented with a two-sided 90% Clopper-Pearson (exact) CI.  An exact binomial test will 
be performed. The hypothesis to be tested is that the proportion of infants who sit on 
treatment (p) is:
H0: p5% (null) versus Ha: p5% (alternative).


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If the one-sided p-value is5% (type 1 error rate), then the null hypothesis will be 
rejected. If the lower limit of the two-sided 90% CI is above the 5% threshold, the 
primary objective of the study will be considered achieved.
The number and percentage of infants sitting at each time-point will also be presented, 
using the same responder/non-responder definition described above. A listing of 
individual responses, including the assessment of the site clinical evaluator and each 
assessment made by the independent central readers and whether or not they are 
concordant, will be presented.
The results of the primary endpoint will also be compared to results from similar cohorts 
of untreated Type 1 SMA infants obtained from real world data sources/natural history 
studies and other clinical trials. The proportion of infants sitting without support in each 
of these sources will be reported together with the associated 60%, 80%, and 90% CIs 
(
).
4.4.2
Secondary Efficacy Endpoints
All secondary endpoints (except for time-to-event) will be summarized by time-point for 
the ITT population using descriptive statistics. At Month 12 and Month 24 of treatment, 
two-sided 90% CIs will also be presented, as appropriate.
The results of the secondary endpoints will be compared to, and put into context with, 
results of similar cohorts of untreated Type 1 SMA infants constructed from real world 
data sources/natural history studies and other clinical trials, when data for the endpoint 
is available. 
 
 
 When publicly available real world patient level data exists, summary data 
was generated from a cohort of patients defined using the study inclusion/exclusion 
criteria, whenever possible.
The historical control data available to date was used to derive a numerical value to 
serve as a pre-defined benchmark (i.e., an objective performance criteria or performance 
goal) against which to assess the efficacy of treatment. If multiple sources of data were 
available for a secondary endpoint, the cohort with the baseline characteristics most 
similar to those targeted by the study inclusion and exclusion criteria was used (
 
).  The benchmark is based on the associated upper limit of the 90% CI from 
the historical data. When a pre-defined benchmark could be determined for the 
secondary endpoint, hypothesis testing will be performed.
The hypothesis to be tested is that the treatment response rate (p) is:
H0: p ≤ pre-defined benchmark (null) versus Ha: p > benchmark (alternative).
If the one-sided p-value is5% (nominal) then the null hypothesis will be rejected.


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To control for multiplicity across the different endpoints, a hierarchical testing approach 
will be implemented.
The first secondary efficacy endpoint of the proportion of infants who achieve a score of 
40 or higher in the CHOP-INTEND at Month 12 will be tested if and only if the primary 
endpoint has reached the 5% significant level (i.e., p-value0.05). Other secondary 
endpoints will be tested at a 5% significance level according to the following hierarchy, 
as long as the p-value is0.05 for endpoints higher in the hierarchy:

Proportion of infants who achieve an increase of at least 4 points in their 
CHOP-INTEND score from baseline at Month 12.

Proportion of motor milestone responders as assessed by the HINE-2 at Month 12.

Proportion of infants who are alive without permanent ventilation at Month 12.

Proportion of infants sitting without support for 30 seconds (defined as ‘Sits without 
support for 30 seconds’ as assessed in item 26 of the modified BSID-III gross motor 
scale) at Month 24.

Proportion of infants standing at Month 24 (defined as ‘Stands alone’ as assessed in 
item 40 of the modified BSID-III gross motor scale).

Proportion of infants walking at Month 24 (defined as ‘Walks alone’ as assessed in 
item 42 of the modified BSID-III gross motor scale).
Any other endpoints for which hypothesis testing will be performed will be 
simultaneously tested at the 5% significance level without adjustment for multiplicity, as 
they are considered to provide supportive information.
The secondary efficacy endpoints in Part 2 are as follows:
4.4.2.1
Motor Function and Development Milestones
4.4.2.1.1
CHOP-INTEND
The number and percentage of infants who achieve a score of 40 or higher in the 
CHOP-INTEND at Month 12 will be presented with a two-sided 90% Clopper-Pearson 
(exact) CI for the proportion. Infants who do not achieve a score of at least 40, or have 
not maintained an earlier achieved score of at least 40, or have been withdrawn, or died, 
will be classified as non-responders for the analysis. Infants with a missing 
CHOP-INTEND assessment at Month 12 will also be classified as non-responders.
The CHOP-INTEND consists of 16 items scored from 0 to 4, with a higher score 
indicating better motor skills. Both the left and right sides are scored and the maximum 
score is selected for the final item score. The total score is calculated by summing the 
item scores to give a maximum possible score of 64. If an individual item is missing or 
‘Cannot Test (CNT)’ is recorded, the item score will be set to 0.
 


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 An exact binomial test will be performed. The hypothesis to be 
tested is that the proportion of infants who achieve a score of 40 or higher in the CHOP-
INTEND on treatment (p) is:
H0: p17% (null) versus Ha: p17% (alternative).
If the one-sided p-value is5%, then the null hypothesis will be rejected.
Bar graphs displaying the proportion of infants with each CHOP-INTEND score and 
change from baseline score at Month 12 and Month 24 will be presented. Each graph 
will present the proportion of infants who were withdrawn from the study and the 
proportion of infants who had died by Month 12 and Month 24. A supportive summary 
table will also be produced.
The number and percentage of infants who achieve a score of 40 or higher at each 
time-point and corresponding 90% CIs will be presented. The same 
responder/non-responder definition described above will be used for these analyses.
The CHOP-INTEND score and change from baseline score at each time-point will also 
be summarized using descriptive statistics. The mean absolute scores and change from 
baseline scores and corresponding 90% CIs over time will also be presented graphically. 
All observed assessments will be included in the analyses; no imputation for missing 
assessments will be performed.
The number and percentage of infants who achieve an increase of at least 4 points in 
their CHOP-INTEND score from baseline at Month 8 and Month 12 (and all other time-
points) will be presented with a two-sided 90% Clopper-Pearson (exact) CI for the 
proportion. Infants who do not achieve an increase of at least 4 points, or have not 
maintained an earlier increase of at least 4 points, or have been withdrawn, or died, will 
be classified as non-responders for the analysis. Infants with a missing CHOP-INTEND 
assessment at a visit will also be classified as non-responders.
 
 
An exact binomial test will be performed. 
The hypothesis to be tested is that the proportion of infants who achieve an increase of 
at least 4 points in their CHOP-INTEND score from baseline on treatment (p) is:
H0: p17% (null) versus Ha: p17% (alternative).
If the one-sided p-value is5%, then the null hypothesis will be rejected.


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Head Control
The number and percentage of infants who achieve head control (defined by a score of 
3 or higher for item 12 of the CHOP-INTEND) at Month 8, Month 12, and Month 24 (and 
all other time-points) will be presented with a two-sided 90% Clopper-Pearson (exact) CI 
for the proportion. Infants who do not achieve a score of at least 3 for item 12, or have 
not maintained an earlier achieved score of at least 3, or have been withdrawn, or died, 
will be classified as non-responders for the analysis. Infants with a missing assessment 
at a visit will also be classified as non-responders.
4.4.2.1.2
Modified BSID-III Gross Motor Scale
Further Motor Milestones
The number and percentage of infants (1) sitting without support for 5 seconds (defined 
as per the primary endpoint), (2) sitting without support for 30 seconds (defined as ‘Sits 
without support for 30 seconds’ as assessed in item 26 of the modified BSID-III gross 
motor scale), (3) standing (defined as ‘Stands alone’ as assessed in item 40 of the 
modified BSID-III gross motor scale), and (4) walking (defined as ‘Walks alone’ as 
assessed in item 42 of the modified BSID-III gross motor scale) at Month 24 will be 
presented with a two-sided 90% Clopper-Pearson (exact) CI for the proportion. Infants 
who do not achieve the milestone, or have not maintained this milestone achieved 
earlier, or have been withdrawn, or died, will be classified as non-responders for the 
analysis. Infants with a missing assessment at Month 24 will also be classified as 
non-responders.
The proportion of infants who at 24 months of treatment are (1) sitting without support for 
5 seconds, (2) sitting without support for 30 seconds, (3) standing, and (4) walking will 
be analyzed as for the primary endpoint (Section 4.4.1) testing the same null hypothesis 
that the proportion of infants who achieve the motor milestone (p) is5% (null) versus 
p5% (alternative). If the one-sided p-value is5%, then the null hypothesis will be 
rejected.
The assessment of the independent central readers will be used for the analysis of these 
further motor milestones (as described in Section 3.2). Both central readers should 
classify the milestone to have been achieved for the endpoint to be confirmed.
The number and percentage of infants who achieve each of these motor milestones at 
each time-point and corresponding 90% CIs will be presented.  The same 
responder/non-responder definitions described above will be used for these analyses.
The number and percentage of infants achieving other motor milestones, including items 
3 (‘Lifts head’), 4 (‘Controls head while upright for 3 seconds’), 9 (‘Controls head while 
upright for 15 seconds’), 14 (‘Rolls from side to back’), 20 (‘Rolls from back to sides’), 25 
(‘Rolls from back to stomach’), 16 (‘Sits with support briefly’), 19 (‘Sits with support for 30 


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seconds’) and 30 (‘Crawls on stomach’), at each time-point will be presented.  The 
number and percentage of infants with a missing BSID-III assessment at a visit 
(including withdrawals) and the number and percentage of infants who had died by that 
visit will also be presented. Percentages will be based on the ITT population.
Highest Motor Milestone
The highest motor milestone achieved by the infant at any visit during the first 12 months 
(and first 24 months) of treatment will be summarized using numbers and percentages 
based on the ITT population. This is regardless of the maintenance of effect or 
subsequent survival status of the infant. Milestones include head control (item 9 
‘Controls head while upright for 15 seconds’), rolling (item 14 ‘Rolls from side to back’), 
sitting without support for 5 seconds (primary endpoint), crawling (item 30 ‘Crawls on 
stomach’), standing (item 40 ‘Stands alone’) and walking (item 42 ‘Walks alone’) as 
assessed in the modified BSID-III gross motor scale.
Total Raw Score
Considering the population of this study, the BSID-III gross motor scale will be 
administered in a modified way compared to the standard administration described in the 
original BSID-III manual.  Infants’ age will not be used as the starting criteria for testing, 
the order of item administration will be changed, and the discontinuation rule will not be 
applied.  This modified way of administration has been discussed and agreed with the 
scale developers as acceptable for the study objectives and patient population.  As a 
result, only raw scores will be calculated in this study; scaled (transformed) scores will 
not be used.
The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) 
or 1 (criteria for item achieved).  The total raw score is calculated by summing the item 
scores to give a maximum possible score of 72.  If an individual item is missing or 
‘Cannot Test (CNT)’ is recorded, the item score will be set to 0.
The total raw score of the modified BSID-III gross motor scale and change from baseline 
score at Month 12 and Month 24 (and all other time-points) will be summarized using 
descriptive statistics. These scores will be based on the assessment of the site clinical 
evaluator. The mean absolute scores and change from baseline scores and 
corresponding 90% CIs over time will also be presented graphically. All observed 
assessments will be included in the analyses; no imputation for missing assessments 
will be performed.
In addition, bar graphs displaying the proportion of infants with different levels of change 
in the total raw score from baseline to Month 12 and Month 24 will be presented. Each 
graph will present the proportion of infants who were withdrawn from the study and the 


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proportion of infants who had died by Month 12 and Month 24. A supportive summary 
table will also be produced.
4.4.2.1.3
HINE-2
Motor Milestones
The number and percentage of infants within each attainment response category of the 
HINE-2 motor milestones at Month 8 (subset # only), Month 12 and Month 24 (and all 
other time-points) will be presented. ‘Cannot test (CNT)’ will be included as a separate 
response category for each milestone. Milestones include head control#, sitting, 
voluntary grasp, ability to kick#, rolling#, crawling, standing, and walking. The number 
and percentage of infants with a missing HINE-2 assessment at a visit (including 
withdrawals) and the number and percentage of infants who had died by that visit will 
also be presented. Percentages will be based on the ITT population.
Motor Milestone Responders
The number and percentage of motor milestone responders (as assessed by HINE-2) at 
Month 12 and Month 24 will be presented with a two-sided 90% Clopper-Pearson (exact) 
CI for the proportion. For the responder definition, an improvement in a motor milestone 
is defined as at least a 2-point increase in ability to kick (or maximal score) or a 1-point 
increase in head control, rolling, sitting, crawling, standing, or walking. Worsening is 
similarly defined as a 2-point decrease in ability to kick (or lowest score) or a 1-point 
decrease in head control, rolling, sitting, crawling, standing, or walking. Voluntary grasp 
is excluded from the definition.  An infant will be classified as a responder if more motor 
milestones show improvement than show worsening; infants who die or withdraw will be 
classified as non-responders. Infants with a totally missing HINE-2 assessment at 
Month 12 or Month 24 will also be classified as non-responders.
The HINE-2 evaluates 8 developmental milestones scored on a 3, 4, or 5-point scale, 
with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the 
task) indicating full milestone development. The total score is calculated by summing 
the item scores to give a maximum possible score of 26. If an individual item is missing 
or ‘Cannot Test (CNT)’ is recorded, the item score will be set to 0.
 
 
An exact binomial test will be performed.
The hypothesis to be tested is that the proportion of motor milestone responders on 
treatment (p) is:
H0: p12% (null) versus Ha: p12% (alternative).
If the one-sided p-value is5%, then the null hypothesis will be rejected.


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Bar graphs displaying the proportion of infants with different levels of change in the 
HINE-2 score from baseline to Month 12 and Month 24 will be presented. Each graph 
will present the proportion of infants who were withdrawn from the study and the 
proportion of infants who had died by Month 12 and Month 24. A supportive summary 
table will also be produced.
The number and percentage of motor milestone responders at each time-point and 
corresponding 90% CIs will be presented. The same responder/non-responder 
definition described above will be used for these analyses.
The total score and change from baseline score at each time-point will also be 
summarized using descriptive statistics. The mean absolute scores and change from 
baseline scores and corresponding 90% CIs over time will also be presented graphically. 
All observed assessments will be included in the analyses; no imputation for missing 
assessments will be performed.
4.4.2.2
Survival and Ventilation-Free Survival
4.4.2.2.1
Ventilation-Free Survival
Time-to-death or permanent ventilation will be presented graphically using Kaplan-Meier 
curves. Permanent ventilation is defined as:

16 hours of non-invasive ventilation (e.g., BiPAP) per day or intubation 
for21 consecutive days in the absence of, or following the resolution of, an acute 
reversible event; or

tracheostomy.
An acute reversible event will include any of the following events that occur between 
7 days prior and 7 days after the onset of16 hours of non-invasive ventilation per day 
or intubation:

Fever

Laboratory diagnosis of a viral, bacterial or fungus infection either by direct 
examination of a sample (e.g., sputum, tissue etc.), culture, serology or polymerase 
chain reaction (PCR)

Leukocytosis

Imaging studies demonstrating an active infection

Surgical procedure
The infant will be given a grace period of 7 days after the event to recover and begin 
extubation or weaning off ventilation support before the endpoint can be confirmed, i.e., 
the endpoint will not be met until the infant requires16 hours of non-invasive ventilation
per day or intubation for21 consecutive days starting 7 days after the resolution of the 
acute reversible event.


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The occurrence of a permanent ventilation event and the date of the event will be 
determined by the independent permanent ventilation adjudication committee, and will 
be recorded on the permanent ventilation electronic case report form (eCRF).  
Non-invasive ventilation use during the study will be collected via a patient diary.
The median time to ventilation-free survival (and 90% CI) and the proportion of infants 
who are surviving without permanent ventilation at Month 12 and Month 24 of treatment 
will be estimated using Kaplan-Meier methodology, when possible. Ninety percent CIs 
for the proportion of infants surviving without permanent ventilation at Month 12 and 
Month 24 will be presented. CIs will be calculated using the complimentary log-log 
transformation for the estimated survivor function S(t), with standard errors computed via 
Greenwood’s formula.
Time-to-death or permanent ventilation is defined as the time in months from the date of 
enrollment into the study until the date of death from any cause or date of permanent 
ventilation, whichever event occurs first. The date of permanent ventilation will be the 
first of the21 days of non-invasive ventilation support or intubation required for the 
endpoint to be confirmed, or the date of tracheostomy.  Infants with no event reported 
prior to the analysis cutoff date will be censored at the latest date before the cutoff in 
which they were known to be alive and without permanent ventilation. Individual listings 
will also be presented for the time-to-death or permanent ventilation (and the individual 
components).
Note: the date of enrollment occurs at least one day before the first study drug 
administration.
A partial event date will be replaced by the first day of the month (assuming the month 
and year are known), unless there is evidence that the infant was event-free within that 
month, in which case the date the infant was last known to be event-free within that 
month will be used as the event date.  If the month is missing, the date the infant was 
last known to be event-free will be used.
Infants who have been withdrawn from the study with no event reported prior to 
withdrawal will be censored at the date of withdrawal.  For infants who have been 
withdrawn from the study and entered safety follow-up, all events reported from the date 
of enrollment up to the date of withdrawal will be included in the analysis. The patient 
diary will not be available to provide information about the use of non-invasive ventilation 
once an infant has been withdrawn from the study and is no longer receiving study drug.  
If an infant has reached16 hours of non-invasive ventilation support per day or has 
been intubated continuously within the last 21 days prior to withdrawal, he or she will be 
followed by telephone contact until the outcome of the endpoint is confirmed.
 
 


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For a fixed time-point, log(-log{S(t)}) is asymptotically normally 
distributed, so a Z-test will be performed. The hypothesis to be tested is that the 
proportion of infants who are alive without permanent ventilation on treatment (p) is:
H0: p42% (null) versus Ha: p42% (alternative).
The test statistic Z[log(-log{p0}) – log(-log{S(t*)})] / se[log(-log{S(t*)})], where p0 is the 
proportion under the null hypothesis (42%), t* is the time-point of interest (12 months) 
and se[log(-log{S(t*)})] is the standard error of log(-log{S(t*)}).  If the one-sided p-value 
is5%, then the null hypothesis will be rejected.
4.4.2.2.2
Survival
Time-to-death will be presented graphically using Kaplan-Meier curves. The median 
time to death (and 90% CI) and the proportion of infants who are alive at Month 12 and 
Month 24 of treatment will be estimated using Kaplan-Meier methodology, when possible.  
Ninety percent CIs for the proportion of infants alive at Month 12 and Month 24 will be 
presented.  Time-to-death is defined as the time in months from the date of enrollment 
until the date of death from any cause. Infants with no event reported prior to the 
analysis cutoff date will be censored at the latest date before the cutoff in which they 
were known to be alive.
Infants who have been withdrawn from the study with no event reported prior to 
withdrawal will be censored at the date of withdrawal.  For infants who have been 
withdrawn from the study and entered safety follow-up, all events reported from the date 
of enrollment up to the date of withdrawal will be included in the analysis.
 
 
  A Z-test will be performed.  
The hypothesis to be tested is that the proportion of infants who are alive on treatment (p) 
is:
H0: p60% (null) versus Ha: p60% (alternative).
If the one-sided p-value is5%, then the null hypothesis will be rejected.
4.4.2.3
Respiratory
4.4.2.3.1
Permanent Ventilation
Time to permanent ventilation will be presented graphically using Kaplan-Meier curves.  
The median time to permanent ventilation (and 90% CI) and the proportion of infants 
who are without permanent ventilation at Month 12 and Month 24 of treatment will be 
estimated using Kaplan-Meier methodology, when possible.  Ninety percent CIs for the 
proportion of infants who are without permanent ventilation at Month 12 and Month 24 
will be presented.  Time to permanent ventilation is defined as the time in months from 
the date of enrollment into the study until the date of permanent ventilation.  Infants with 


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no event reported prior to the analysis cutoff date will be censored at the latest date 
before the cutoff in which they were known to be without permanent ventilation.
Infants who have been withdrawn from the study with no event reported prior to 
withdrawal will be censored at the date of withdrawal.  For infants who have been 
withdrawn from the study and entered safety follow-up, all events reported from the date 
of enrollment up to the date of withdrawal will be included in the analysis.
 
 
  A Z-test will be performed.  The hypothesis to be tested is that the 
proportion of infants who are ventilation-free on treatment (p) is:
H0: p89% (null) versus Ha: p89% (alternative).
If the one-sided p-value is5%, then the null hypothesis will be rejected.
4.4.2.3.2
Respiratory Plethysmography
The number and percentage of infants who achieve a reduction of at least 30 degrees in 
their phase angle from baseline, as measured by RP, at Month 12 will be presented with 
a two-sided 90% Clopper-Pearson (exact) CI for the proportion.  Infants who do not 
achieve a reduction of at least 30 degrees, or have not maintained this level of reduction 
if achieved earlier, or have been withdrawn, or died, will be classified as non-responders 
for the analysis.  Infants with a missing assessment at Month 12 will also be classified as 
non-responders.  Two measurements will be taken at baseline to establish test-retest 
reliability data.  The first of these two planned measurements will be used for all 
analyses.  If only one measurement is available at baseline, this measurement will be 
used.
The number and percentage of infants who achieve a reduction of at least 30 degrees in 
their phase angle from baseline at each time-point and corresponding 90% CIs will be 
presented.  The same responder/non-responder definition described above will be used 
for these analyses.
The phase angle and change from baseline values at each time-point will be 
summarized using descriptive statistics.  The rib cage contribution to inspiratory volume, 
respiratory rate, peak expiratory flow and labored breathing index, and change from 
baseline values at each time-point will also be summarized.  Each variable will be 
calculated as the mean of all valid breaths observed within a 10-minute time window (as 
determined by Vivonoetics).  The mean will only be calculated if there are a minimum of 
8 valid breaths, otherwise the variable will be considered missing.  If there are fewer 
than 8 valid breaths for the first baseline measurement, the second measurement will be 
used, if available.  The mean absolute phase angles and change from baseline phase


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angles and corresponding 90% CIs over time will also be presented graphically.  All 
observed assessments will be included in the analyses; no imputation for missing 
assessments will be performed.
4.4.2.3.3
Level of Respiratory Support
The number and percentage of infants who do not require invasive or non-invasive 
respiratory support at Month 12 and Month 24 (and all other time-points) will be 
presented with a two-sided 90% Clopper-Pearson (exact) CI for the proportion.  Infants 
who have not maintained this outcome if achieved earlier, or have been withdrawn, or 
died, will be classified as non-responders for the analysis.  Infants with a missing 
assessment at Month 12 or Month 24 will also be classified as non-responders.
The number and percentage of infants who require cough assistance (used daily for 
therapy or with an illness) or BiPAP support (16 hours per day or16 hours per day) 
and have ventilation provided prophylactically (including type of ventilation, if applicable) 
at each time-point will be presented.  The number and percentage of infants with a 
missing assessment at a visit (including withdrawals) and the number and percentage of 
infants who had died by that visit will also be presented.  Percentages will be based on 
the ITT population.
4.4.2.4
Nutrition
The number and percentage of infants with the ability to feed orally (‘oral’ or 
‘combination of oral and tube feeding’) at Month 12 and Month 24 (and all other time-
points) will be presented with a two-sided 90% Clopper-Pearson (exact) CI for the 
proportion.  Infants who have not maintained the ability to feed orally if achieved earlier, 
or have been withdrawn, or died, will be classified as non-responders for the analysis.  
Infants with a missing assessment at a visit will also be classified as non-responders.
The number and percentage of infants fed orally, via a feeding tube, or via a combination 
of oral and tube feeding at each time-point will be presented.  The number and 
percentage of infants with a missing assessment at a visit (including withdrawals) and 
the number and percentage of infants who had died by that visit will also be presented.  
Percentages will be based on the ITT population.  The number and percentage of infants
who have experienced coughing/choking during or after eating/drinking will also be 
presented.  For infants fed via a combination of oral and tube feeding, the percentage of 
feedings delivered through the tube and the change from baseline value will be 
summarized at each time-point.
4.4.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints in Part 2 are as follows:
4.4.3.1
Maintenance of Treatment Effect
The number and percentage of infants who maintained sitting without support at 
Month 24 (for infants sitting without support at Month 12, defined as per the primary 
endpoint) will be presented.  Infants who have not maintained sitting, or have been 


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withdrawn, or died, will be classified as non-responders (i.e., not maintained sitting) for 
the analysis.  Infants with a missing assessment at Month 24 will also be classified as 
non-responders.  The assessment of the independent central readers will be used for 
this analysis (as described in Section 3.2).  Both central readers should classify the 
milestone to have been achieved for the endpoint to be confirmed.
The number and percentage of infants who maintained (or continued to improve) their 
phase angle reduction, as measured by RP, at Month 24 (for infants with a phase angle 
reduction of at least 30 degrees from baseline at Month 12) will also be presented.  
Infants who have not maintained a reduction of at least 30 degrees, or have been 
withdrawn, or died, will be classified as non-responders for the analysis.  Infants with a 
missing RP assessment at Month 24 will also be classified as non-responders.
4.4.3.2
Muscle Electrophysiology
The number and percentage of infants who achieve an increase of at least 0.3mV from 
baseline in their CMAP negative peak amplitude at Month 12 and Month 24 will be 
presented with a two-sided 90% Clopper-Pearson (exact) CI for the proportion.  Infants 
who do not achieve an increase of at least 0.3mV, or have not maintained this 
improvement if achieved earlier, or have been withdrawn, or died, will be classified as 
non-responders for the analysis.  Infants with a missing assessment at Month 12 or 
Month 24 will also be classified as non-responders.
 
 
 
  An exact binomial test will 
be performed.  The hypothesis to be tested is that the proportion who achieve an 
increase of at least 0.3mV from baseline in their CMAP negative peak amplitude on 
treatment (p) is:
H0: p18% (null) versus Ha: p18% (alternative).
If the one-sided p-value is5%, then the null hypothesis will be rejected.
The number and percentage of infants who achieve an increase of at least 0.3mV from 
baseline in their CMAP negative peak amplitude at each time-point and corresponding 
90% CIs will be presented.  The same responder/non-responder definition described 
above will be used for these analyses.
The CMAP negative peak amplitude and area, and change from baseline values at each 
time-point will also be summarized using descriptive statistics.  In addition, the mean 
absolute CMAP negative peak amplitudes and change from baseline amplitudes and 
corresponding 90% CIs over time will be presented graphically.  Scatterplots of the 
CMAP negative peak amplitude versus age (at enrollment) and the time between first 
treatment and onset of symptoms at Month 12 and Month 24 will be presented.  All 


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observed assessments will be included in the analyses; no imputation for missing 
assessments will be performed.
4.4.3.3
Disease-Related Adverse Events
Disease-related adverse events (AEs) will be collected through the AE reporting of the 
study and events will be identified by applying prospectively defined baskets of MedDRA 
lowest level terms to the AE dataset.  A basket of terms has been defined for each of the 
following medical concepts: gastro-intestinal disorders, lower respiratory tract infections, 
respiratory impairment, neuro-musculo-skeletal and connective tissues, nutrition and 
growth, cardiac not elsewhere classified (NEC), and other NEC.  The lowest level terms
included in each basket, coded using MedDRA version 20.0, are presented in
  These baskets will be updated twice a year due to MedDRA version 
upgrades.
Note: the same lowest level term may be applicable to more than one medical concept 
and will therefore be included in more than one basket.
The number and percentage of infants who experience at least one disease-related AE
by Month 12 and Month 24 and corresponding 90% Clopper-Pearson (exact) CIs will be 
presented overall and by medical concept.  The total number of disease-related AEs will 
also be presented overall and by medical concept.  A listing of all terms searched will be 
produced.
For each AE recorded, the term entered by the investigator describing the event (the 
‘verbatim term’) will be assigned to a standardized term, the ‘lowest level term,’ which 
will be mapped to a second higher level of standardized term, the ‘preferred term,’ based 
on the most up-to-date version of MedDRA.  Data displays of disease-related AEs for 
each medical concept will be performed using the lowest level terms.  For summaries of 
AE incidences, infants who experienced the same event on more than one occasion will 
be counted once in the calculation of the event frequency at the highest intensity 
reported.
The number of disease-related AEs per patient-year at Month 12 and Month 24 and 
corresponding exact 90% CIs will also be presented overall and by medical concept, 
where
Number of disease-related AEs per patient-yearnumber of events observed by 
Month 12 (or 24) / total patient-years at risk
and
Total patient-years at risksum across all patients of the time intervals (in years) 
between start of study therapy and the earliest date of {study withdrawal or 
completion of 12 (or 24) months of treatment}


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The number and percentage of infants who experience at least one disease-related AE
resulting in hospitalization by Month 12 and Month 24 and corresponding 90% 
Clopper-Pearson (exact) CIs will be presented overall and by medical concept.  The 
number of disease-related AEs resulting in hospitalization per patient-year at Month 12 
and Month 24 and corresponding exact 90% CIs will also be presented overall and by 
medical concept.
Hospitalizations will include all hospital admissions which span at least two days, and 
which are not due to study requirements.
4.4.3.4
Healthcare Utilization
The number of hospitalizations (for any reason) per patient-year and corresponding 
exact 90% CIs, and the total number of hospitalizations at Month 12 and Month 24 will 
be presented.  The number of nights admitted to hospital per infant at Month 12 and 
Month 24 will also be summarized.  The number of hospitalizations per patient-year is 
computed as:
Number of hospitalizations per patient-yearnumber of hospitalizations observed by 
Month 12 (or 24) / total patient-years at risk
and
Total patient-years at risksum across all patients of the time intervals (in years) 
between start of study therapy and the earliest date of {study withdrawal or 
completion of 12 (or 24) months of treatment}
Hospitalizations will include all hospital admissions which span at least two days, and 
which are not due to study requirements.
4.4.3.5
Swallowing and Nutrition
The number and percentage of infants with the ability to swallow (liquid or any food type)
at Month 8, Month 12, and Month 24 (and all other time-points) will be presented with a 
two-sided 90% Clopper-Pearson (exact) CI for the proportion.  Infants who have not 
maintained the ability to swallow, or have been withdrawn, or died, will be classified as 
non-responders for the analysis.  Infants with a missing assessment at a visit will also be 
classified as non-responders.
A shift table comparing the status of each infant at baseline (able to swallow, unable to 
swallow, missing) to each time-point post baseline (able to swallow, unable to swallow, 
missing [including deaths]) will be presented.
Time-to-loss of swallowing (for infants with the ability to swallow at baseline) will be 
presented graphically using Kaplan-Meier curves.  The median time to loss of 
swallowing (and 90% CI) and the proportion of infants with the ability to swallow at 
Month 12 and Month 24 will be estimated using Kaplan-Meier methodology, when 


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possible.  Ninety percent CIs for the proportion of infants with the ability to swallow at 
Month 12 and Month 24 will also be presented.
Time-to-loss of swallowing is defined as the time in months from the date of enrollment 
until the date of loss of swallowing.  Infants with no event reported prior to the analysis 
cutoff date will be censored at the latest date before the cutoff in which they were known 
to be event-free.
A partial date for loss of swallowing will be replaced by the first day of the month 
(assuming the month and year are known), unless there is evidence of an assessment 
where the infant was able to swallow within that month, in which case the date of the last 
assessment within that month will be used.  If the month is missing, the date the infant 
was last known to be able to swallow will be used.
The number and percentage of infants who can swallow water, nectar (or similar), rice 
pudding (or similar), purées, and solid food at each time-point will also be presented.
The primary food intake type at each time-point will be summarized using numbers and 
percentages.  The number and percentage of infants who have lost or regained the 
ability to swallow (if applicable) will be presented, and the age the ability to swallow is 
lost or regained will be summarized.
In each summary table, the number and percentage of infants with a missing 
assessment at a visit (including withdrawals) and the number and percentage of infants 
who had died by that visit will be presented.  Percentages will be based on the ITT 
population.
4.4.3.6
Growth Measures
The ratio between the chest and head circumference at Month 8, Month 12, and 
Month 24 will be summarized.  The chest to head circumference ratio and change from 
baseline ratio at each time-point will also be summarized.  All observed assessments will 
be included in the analyses; no imputation for missing assessments will be performed.
The change from baseline in the weight-for-age and length/height-for-age percentiles at
Month 12 and Month 24 will be summarized.  Actual values and change from baseline 
values at each time-point will also be summarized.  All observed assessments will be 
included in the analyses; no imputation for missing assessments will be performed.  For 
consistency with the analysis methods described for the anthropometric measurements 
in Section 4.6.8, these analyses will be based on the safety population.
4.4.3.7
Parent/Caregiver Reported Outcomes
The total score and change from baseline score in the ITQOL-SF47 domains and single 
item scores at Month 12 and Month 24 (and all other time-points) will be summarized.  
All observed assessments will be included in the analyses; no imputation for missing 
assessments will be performed.


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The ITQOL-SF47 contains three single-item scores (Overall Health, Change in Health, 
and Family Cohesion) and eight multi-item domains (Physical Abilities [6 items], Growth 
and Development [5], Bodily Pain/Discomfort [2], Temperament and Moods [6], Behavior 
[12], General Health Perceptions [5], Parent Impact-Emotional Health [4] and Parent 
Impact-Time Limitations [4]).  Items are scored using a Likert-type scale with five levels 
(except Parent Impact-Time Limitations which has 4 response options).  Where 
applicable, item scores are reversed so that higher scores indicate better health.
For each domain, items are summed and transformed to a 0 (worst health) to 100 (best 
health) scale as defined in the scoring manual.  Raw scores are calculated by computing 
the algebraic mean of the items completed.  Scores are imputed for those individuals 
with missing items, provided that the respondents answered at least half of the items in 
the scale.  This is done by using a denominator for each respondent based on the 
number of items in the scale that were completed.  As per the ITQOL-SF47 scoring 
manual, scale scores will not be calculated if more than half of the items within a scale 
are missing.  The transformed score is calculated as:
Transformed raw score[(actual raw score lowest possible raw score) / possible 
raw score range]100
The ‘actual raw score’ is the mean of the item responses in a scale (sum of item 
responses / number of completed items).  The ‘possible raw score range’ is the highest 
possible raw score minus the lowest possible raw score.
Behavior Scales and Change in Health items are not appropriate for infants younger 
than 12 months of age, so should not be assessed at the baseline visit (the maximum 
age at enrollment is 7 months).  Only summary scores will be presented for these 
domains.
In addition, bar graphs displaying the proportion of infants with different levels of change 
in the ITQOL-SF47 domains from baseline to Month 12 and Month 24 will be presented.  
Each graph will present the proportion of infants who were withdrawn from the study and 
the proportion of infants who had died by Month 12 and Month 24.  A supportive 
summary table will also be produced.
4.4.3.8
Parent/Caregiver Reported Motor Milestones
The number and percentage of infants who experience any significant life events (loss or 
achievement of the following: kicked legs upward vertically, head control in ventral 
suspension, head control whilst carried upright, rolled from side to back, rolled from back 
to side, rolled completely, sat supported, sat unsupported, crawled combat style, crawled 
4 point, stood with support, stood without support, walked with support, walked without 
support, other) by Month 12 and Month 24 will be presented.  This will be based on the 
report from the parent/caregiver.  The number and percentage of infants who were 
withdrawn from the study and the number and percentage of infants who had died by 


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Month 12 and Month 24 will be presented.  Percentages will be based on the ITT 
population.
Infants’ age at the attainment of a new motor milestone (or at the loss of a motor 
milestone gained during or before the study) will also be summarized.
If a partial date is provided for the attainment of a motor milestone, the day will be 
replaced with the last day of the month (assuming the month and year are known).  If a 
partial date is provided for the loss of a motor milestone, the day will be replaced with 
the first day of the month (assuming the month and year are known).
4.4.3.9
Clinician Reported Respiratory Function and Swallowing 
Ability Items
A range of clinical domain level items will be completed by a clinician in order to capture 
changes in an infant’s respiratory function and ability to swallow at Month 12.  The first 
item is a CGI-C, which is a single item measure of change using 7 response options 
ranging from “Very much improved” to “Very much worse” (Item 1).  The clinician will 
rate patients on this scale at the Month 12 visit based on their impression of change in 
the infant’s respiratory function or ability to swallow since baseline. Clinicians will also 
be asked to rate how the infant’s change in respiratory function and swallowing ability at 
Month 12 compare to a similarly aged untreated infant with Type 1 SMA on a 7-point 
scale ranging from “Very much better” to “Very much worse” (Item 2).  Finally, the 
clinician will be asked to rate the infant’s current respiratory function and swallowing 
ability using a 0-10 numerical response rating scale (Item 3).
Item 1 (CGI-C)
The number and percentage of infants with no change or improvement in respiratory 
function at Month 12 will be presented with a two-sided 90% Clopper-Pearson (exact) CI 
for the proportion.  Infants who have a worsening in respiratory function, or who have 
been withdrawn, or died, will be classified as non-responders for the analysis.  Infants 
with a missing assessment at Month 12 will also be classified as non-responders.
The number and percentage of infants in each response category of the CGI-C item will
be presented.  The number and percentage of infants with a missing assessment at 
Month 12 (including withdrawals) and the number and percentage of infants who had 
died by that visit will also be presented.  Percentages will be based on the ITT 
population.
Item 2
The number and percentage of infants in each response category for item 2 will be 
presented.  The number and percentage of infants with a missing assessment at Month
12 (including withdrawals) and the number and percentage of infants who had died by 
that visit will also be presented.  Percentages will be based on the ITT population.


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Item 3
The responses for item 3 will be summarized using descriptive statistics.  All observed 
assessments will be included in the analyses; no imputation for missing assessments 
will be performed.
Similar analyses will be performed for the swallowing items.
4.4.4
Sensitivity Analyses
4.4.4.1
Site Evaluation of Sitting without Support for 5 Seconds
For the primary efficacy endpoint of the proportion of infants sitting without support for 
5 seconds at Month 12, the analyses described in Section 4.4.1 will be performed using 
the assessment of the site clinical evaluator instead of the assessment of the two 
independent central readers.
4.4.4.2
Alternative Definition of Sitting without Support
Sensitivity analyses will be performed using an alternative definition of sitting without 
support.
The proportion of infants sitting without support at Month 12 will be analyzed as 
described in Section 4.4.1 with sitting defined by the HINE-2 categories of ‘Stable sit’ or 
‘Pivots (rotates).’  Infants within either of these response categories for the milestone of 
sitting at Month 12 will be classified as responders.
 
 
 
 
4.4.4.4
Censoring
To assess the impact of early withdrawals on the time-to-death or permanent ventilation, 
the analyses described in Section 4.4.2.2.1 will be performed with infants who have 
been withdrawn from the study without entering safety follow-up and have no event 
reported prior to withdrawal assumed to have an event on the date of withdrawal.
4.4.4.5
Events Reported During Safety Follow-Up
For the secondary efficacy endpoint of time-to-death, the analyses described in Section 
4.4.2.2.2 will be performed including all events reported up to 52 weeks after the date of 
withdrawal (for infants who are withdrawn from the study and enter safety follow-up).


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4.4.4.6
Handling of Missing Data
To assess the impact of missing data on the CHOP-INTEND outcomes at Month 12, 
analyses described in Section 4.4.2.1.1 will be performed using different rules for 
handling missing data.
If an item of the CHOP-INTEND is missing at baseline or at Month 12, or if ‘CNT’ is 
recorded for an item, the item score will be imputed as follows:

If an item is missing or ‘CNT’ is recorded at baseline, the item score will be imputed 
as the median of the non-missing values in the stratum to which the infant belongs.  
Infants will be classified into the following strata, based on the time between first 
treatment and onset of symptoms, for the purpose of identifying non-missing data 
for imputation:
o
Time between first treatment and onset of symptoms ≤3 months
o
Time between first treatment and onset of symptoms >3 months
If there is no data available in that stratum at baseline (i.e., no scores have been 
recorded), the item score will be set to 0.

If an item is missing or ‘CNT’ is recorded at Month 12, and the Month 12 visit is
flanked by visits where the item is available, the item score will be imputed using 
linear interpolation with the result rounded to the nearest integer score.
If an item is missing or ‘CNT’ is recorded at Month 12, and the Month 12 visit is not 
flanked by visits where the item is available (i.e., Month 12 is the infant’s last 
assessment, or the item is missing or ‘CNT’ is recorded either at the previous or 
subsequent visit), the item score will be imputed as the minimum of the non-missing 
values in the stratum to which the infant belongs.  If there is no data available in that 
stratum at Month 12, the item score will be set to 0.
These rules will not be applied for infants who have died or been withdrawn from the 
study before Month 12, unless the infant has an assessment that falls in the visit 
window for Month 12.
This imputation will be applied to the proportion of infants who achieve a score of 40 or 
higher in the CHOP-INTEND at Month 12, the proportion of infants who achieve an 
increase of at least 4 points in their CHOP-INTEND score from baseline at Month 12 and 
the proportion of infants who achieve head control at Month 12 (defined as a score of 3 
or higher for item 12 of the CHOP-INTEND).  The CHOP-INTEND score and change 
from baseline score at Month 12 will also be summarized after applying the imputation 
rules.


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4.4.5
Subgroup Analyses
Subgroup analyses will be performed for the primary efficacy endpoint of the proportion 
of infants sitting without support for 5 seconds at Month 12 and the secondary efficacy 
endpoint of time-to-death or permanent ventilation.  Analyses will be presented for the 
following subgroups:

Age at enrollment (5 months,5 months)

Sex

Race/ethnicity

Region (Europe, USA/Canada, rest of world)

Baseline CHOP-INTEND score (median score, median score)

Baseline CMAP amplitude (1mV, 1mV)

Time between first treatment and onset of symptoms (3 months, 3 months)
The number and percentage of infants sitting without support at Month 12 and 
corresponding 90% Clopper-Pearson (exact) CIs will be presented for each subgroup 
using forest plots.
Time-to-death or permanent ventilation will be presented graphically for each subgroup 
using Kaplan-Meier curves. The median time to ventilation-free survival (and 90% CIs) 
and the proportion of infants who are surviving ventilation-free at Month 12 and 
corresponding 90% CIs will be estimated using Kaplan-Meier methodology, when 
possible.
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Non-linear mixed effects modeling (using software NONMEM) will be used to analyze 
the sparse samples of concentration-time data of RO7034067 (and its metabolites if 
deemed necessary).  Population and individual PK parameters will be estimated and the 
influence of various covariates (such as age, sex, and body weight) on these parameters 
will be investigated in an exploratory way.  Data may be pooled with data from other 
studies with RO7034067 in order to improve the parameter estimates from the model.  
Secondary PK parameters (such as Cmax and AUC) may be derived from the model for 
each individual included in the PK analysis and will be presented descriptively.  All PK 
parameters will be presented using listings and descriptive summary statistics.  
Individual and mean plasma concentrations of RO7034067 (and metabolites as 
appropriate) versus time data will be tabulated.
Additional PK analyses and exploratory analyses on exposure versus selected safety 
and efficacy parameters may be conducted as deemed necessary.  This may include 
scatterplots of AUC versus change from baseline in the CHOP-INTEND score, modified 
BSID-III gross motor scale total raw score, HINE-2 total score and CMAP negative peak 
amplitude at Month 12 and Month 24; and boxplots of AUC for infants who achieve/do 
not achieve sitting and head control at Month 12 and Month 24, and infants who 


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achieve/do not achieve standing and walking at Month 24, as assessed by items 22, 9, 
40, and 42 of the modified BSID-III gross motor scale, respectively.  Depending on the 
adverse event profile, correlations between exposure and adverse events may be 
explored.
The details of the modeling and exploratory analyses may be reported in a document 
separate from the clinical study report.
All PD parameters (SMN mRNA and SMN protein in blood) will be presented by listings, 
descriptive summary statistics and mean or median plots over time, as appropriate.
Exploratory analyses on PD parameters versus selected efficacy parameters may also 
be performed as deemed necessary, including, e.g., scatterplots of absolute SMN 
protein level and percent change from baseline in SMN protein level versus change from 
baseline in the CHOP-INTEND score, modified BSID-III gross motor scale total raw 
score, HINE-2 total score and CMAP negative peak amplitude at Month 12 and 
Month 24; and boxplots of absolute SMN protein level and percent change from baseline 
in SMN protein level for infants who achieve/do not achieve sitting and head control at 
Month 12 and Month 24, and infants who achieve/do not achieve standing and walking 
at Month 24, as assessed by items 22, 9, 40, and 42 of the modified BSID-III gross 
motor scale, respectively.
4.6
SAFETY ANALYSES
Safety data will be summarized descriptively using the safety population.  For Part 2, the 
safety data will be summarized descriptively for the first 12-month period (i.e., 12-month 
data for each individual infant) and for all available interim safety data collected at the 
time of the analysis (i.e., all data up to the clinical cutoff date for the analysis).  Similar 
summaries for the first 24-month period will be presented at the time of the 24-month 
analysis reporting event.  Data collected during the safety follow-up period will be 
presented separately.
Safety analyses will use the same visit windows defined in Section 4.4.  If multiple valid 
values for a variable are recorded in the same time window (including assessments 
performed at an unscheduled visit or an early treatment discontinuation visit), the last 
record will be selected for summary of the data, except for laboratory data, where the
worst record will be selected for summary of the data.
4.6.1
Exposure of Study Medication
The following extent of exposure to study drug will be summarized: duration of treatment 
(including the number and percentage of infants with duration of treatment from 06 
months, 6-12 months, 12-18 months, 18-24 months etc.), number of doses 
taken, number of doses missed, number of partial doses taken (actual volume 
administered 90% of planned volume administered), number of overdoses (actual 


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volume administered 110% of planned volume administered), dose intensity, and 
cumulative dose.
The duration of total treatment intake will be calculated from the infant’s first day of study 
treatment to the last day of study treatment:
Duration of treatmentdate of the last dose# date of the first dose 1 day
#Note: for outputs displaying all available interim exposure data, if dose administration is 
ongoing at the time of the clinical cutoff date, the last dose date will be replaced by the 
clinical cutoff date for the analysis.
All dose records with a start date on or before the clinical cutoff date will be included in 
the data cut.
Dose intensity will be calculated as:
Dose intensitynumber of non-missing doses taken * 100 / number of doses 
expected to be taken
The number and percentage of infants with dose intensity < 80% and ≥ 80% will be 
presented.
The route of administration of study drug and the number of dose adjustments per infant 
(if applicable) will also be summarized.
4.6.2
Adverse Events
For each AE recorded, the term entered by the investigator describing the event (the 
‘verbatim term’) will be assigned to a standardized term (the ‘preferred term’) based on 
the most up-to-date version of MedDRA.  Data displays of AEs will be performed using 
the system organ class and preferred terms.  For summaries of AE incidences, patients 
who experienced the same event on more than one occasion will be counted once in the 
calculation of the event frequency at the highest intensity reported.  Each table will also 
present the overall number of patients experiencing at least one AE and the total number 
of AEs reported.
AEs will be summarized for the following analysis periods separately:
Treatment period: includes (a) the AEs for which the onset date is on or after the first 
day of the study drug up to the earliest date of {study withdrawal or completion of 12 (or 
24) months of treatment#}; or (b) the AEs for which the onset date is prior to the first 
dose day with the end date on or after the first dose day or the AE is unresolved, and the 
most extreme intensity is greater than the initial intensity.
#Note: for outputs displaying all available interim safety data collected at the time of the 
analysis, the date of completion of 12 (or 24) months of treatment will be replaced by the 
clinical cutoff date for the analysis.


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All AEs with an onset date on or before the clinical cutoff date will be included in the data 
cut, regardless of the end date.
All AEs, AEs resulting in death, serious AEs (SAEs), AEs leading to withdrawal of study 
treatment and AEs leading to dose modification or interruption will be summarized.  AEs 
will also be summarized by intensity/severity (National Cancer Institute-Common 
Terminology Criteria for Adverse Event [NCI-CTCAE] grade) and by relationship to study 
treatment (as assigned by the treating investigator).  Most common AEs (reported in5% 
of patients) will be summarized by preferred term.  AE outcomes (recovered/resolved 
[including recovered/resolved with sequelae, recovering/resolving], not recovered/not 
resolved, fatal, unknown) will also be summarized by preferred term, with counts based 
on the number of events.  In addition, an overall AE profile summary table will be 
presented.
AEs resulting in death will be summarized overall and by cause of death (AE as primary 
cause of death vs progressive disease specified as primary cause of death).
The AE and SAE rate adjusted for patient years (all occurrences, by preferred term) and 
corresponding exact 90% CIs for the event rate will also be presented.  The AE rate per 
100 patient-years is computed as follows:
AE rate(number of AEs observed by Month 12 [or 24]# / total patient-years at risk) 
* 100
where
Total patient-years at risksum across all patients of the time intervals (in years) 
between start of study therapy and the earliest date of {study withdrawal or 
completion of 12 (or 24) months of treatment#}
#Note: for outputs displaying all available interim AEs collected at the time of the analysis, 
the date of completion of 12 (or 24) months of treatment will be replaced by the clinical 
cutoff date for the analysis.
In addition, the overall AE profile summary table, the summary table of all AEs by 
preferred term and system organ class, and the AE rate tables adjusted for patient-years 
will be presented for the following subgroups: age at enrollment (5 months,5 months), 
sex, region and time between first treatment and onset of symptoms (3 
months,3 months).
Follow-up period: includes the AEs for which the onset date is from 1 day up to 
52 weeks after study withdrawal/completion.  All AEs and SAEs will be summarized for 
the follow-up period.  AEs will also be summarized by intensity/severity (NCI-CTCAE 
grade).


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The following AEs of special interest (pre-defined in the protocol) will be summarized 
separately (for the treatment period and follow-up period):

Cases of potential drug-induced liver injury that include an elevated alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) (3upper limit of 
normal [ULN]) in combination with either an elevated total bilirubin (2ULN) or 
clinical jaundice, as defined by Hy’s law.

Suspected transmission of an infectious agent by the study drug.
Individual listings will also be generated for AEs, SAEs and AEs leading to withdrawal of 
study treatment.
In addition, non-treatment emergent AEs, including the SAEs caused by a protocol-
mandated intervention (e.g., SAEs related to invasive procedures such as biopsies), for 
which the onset date is before the date of the start of study medication (after informed 
consent has been obtained but prior to initiation of study drug), will be listed.
The following rules will be applied for AEs with missing onset and/or end dates:

Events that are missing both onset and end dates will be considered treatment 
emergent, given that a patient had at least one dose of study drug.

If the onset date is missing and the end date is on or after the first dosing date, then 
the event will be considered treatment emergent.

If the end date is missing and the onset date is on or after the first dosing date, then 
the event will be considered treatment emergent.

If the end date is missing and the extreme intensity is worse than the initial intensity, 
and the onset date is prior to the first dosing date, then the event will be considered 
treatment emergent.

The duration will be set to missing.
4.6.3
Death
A summary table of patient deaths by death cause (progressive disease vs other causes) 
will be presented.  Patient listings will also be generated containing all details for each 
infant who died during the protocol-specified AE reporting period (up to 52 weeks after 
study withdrawal/completion).  If progressive disease is specified as the cause of death, 
the associated AE will also be reported.
4.6.4
Laboratory Data
Laboratory data will be listed for infants with values outside the normal ranges (based on 
local laboratory ranges).  In addition, shift tables to compare the status at baseline to 
each time-point post-baseline and overall will be presented.  A plot of total bilirubin/ULN 
versus ALT/ULN and AST/ULN at each time-point will also be presented.  The number 
and percentage of infants with elevated ALT or AST levels at any time-point post-
baseline will be presented.


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Data collected during safety follow-up will be summarized similarly.
4.6.5
Vital Signs
Vital signs, including body temperature, respiratory rate, pulse rate and blood pressure, 
will be measured throughout the study.  Vital signs data will be listed for infants with
values outside the normal ranges.  The normal ranges will be based on the age of the 
infant at the time of the assessment.  In addition, shift tables to compare the status at 
baseline to each time-point post-baseline and overall will be presented.
The following normal ranges will be used:
Age (months)
Heart/Pulse 
Rate (beats/min)
Respiratory Rate 
(breaths/min)
Systolic Blood 
Pressure (mmHg)
Diastolic Blood 
Pressure (mmHg)
0-≤3
100-150
35-55
65-85
45-55
>3-≤6
90-120
30-45
70-90
50-65
>6-≤12
80-120
25-40
80-100
55-65
>12-≤24
70-110
20-30
90-105
55-70
>24-≤72
70-130
>24-≤144
18-30
90-125
60-80
For temperature, the following normal ranges will be used:
Age (months)
Temperature (°C)
0-24
36.4-38.0
24-144
35.5-37.8
Data collected during safety follow-up will be summarized similarly.
4.6.6
Electrocardiogram
ECG data will be listed for infants with values outside the normal ranges.  The normal 
ranges will be based on the age of the infant at the time of the assessment.  Triplicate 
and average ECG results will be listed, where the average ECG result is defined as the 
average of the valid (non-missing and non-zero) triplicate measurements.
In addition, shift tables for each parameter (PR duration, QT duration, QRS duration, RR 
duration, QTc [Bazett] [QTcB], QTc [Fridericia] [QTcF], T-wave, U-wave and 
interpretation [ECG result]) to compare the status at baseline to each time-point 
post-baseline and overall will be presented.
If ECG assessments are also evaluated by a local cardiologist (clinician), data for these 
infants will be listed.


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The following normal ranges will be used:
Age (months)
PR 
Duration 
(ms)
QT 
Duration 
(ms)
QRS 
Duration 
(ms)
RR 
Duration 
(ms)
QTcF 
(ms)
QTcB 
(ms)
0-≤24
80-120
230-420
50-90
370-450
370-450
>24-≤144
80-160
260-390
40-90
380-450
380-450
0-≤3
400-600
>3-≤6
500-670
>6-≤12
500-750
>12-≤24
450-860
>24-≤72
460-860
The number and percentage of infants with PR duration, QRS duration, QTcB and QTcF 
in the following ranges at each time-point will be presented:
ECG Parameter
Raw Value
Increase from Baseline
PR duration (ms)
  0-≤24 months
≤ 120
> 120
  >24-≤144 months
≤ 160
> 160
QRS duration (ms)
≤ 90
> 90
QTcB (ms)
≤ 450
≤ 30
> 450 and ≤ 480
> 30 and ≤ 60
> 480 and ≤ 500
> 60
> 500
QTcF (ms)
≤ 450
≤ 30
> 450 and ≤ 480
> 30 and ≤ 60
> 480 and ≤ 500
> 60
> 500
Data collected during safety follow-up will be summarized similarly.
4.6.7
Ophthalmological Assessments
Ophthalmological assessments will be classified into three main categories:

Imaging (including SD OCT and fundus photography)

Ophthalmological examination (including fundus examination, ocular examination 
[slit lamp and visual testing] and intraocular pressure)

Visual function (including fix and follow assessment)


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An overall ophthalmology profile summary table showing the number and percentage of 
infants with an abnormal or potentially clinically significant result at any time-point (
 
) will be presented for each assessment.  The total number 
of abnormal or potentially clinically significant results will also be presented.
In addition, the number and percentage of infants with an abnormal or potentially 
clinically significant result and the total number of abnormal or potentially clinically 
significant results at each time-point will be presented for each assessment.  The 
number and percentage of infants with an abnormal or potentially clinically significant 
result in both eyes will also be presented.
Listings will be produced for all infants with an abnormal or potentially clinically 
significant result in any ophthalmological assessment.
Short patient summaries will be provided for patients with an abnormal or potentially 
clinically significant result in order to provide an assessment on whether the finding may 
constitute a sign of risdiplam-related retinal toxicity.
 
 


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Data collected for all ophthalmological assessments during safety follow-up will be 
summarized similarly.
4.6.8
Anthropometric Examinations
Actual values and change from baseline values for weight, length/height, head 
circumference, and chest circumference will be summarized at each time-point.  The 
weight-for-age, length/height-for-age, weight-for-length/height and head


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circumference-for-age percentiles, and change from baseline percentiles at each 
time-point will also be summarized.
The number and percentage of infants in the 3rd, 5th, 10th, 25 h, 50th, and > 50th
percentiles of the WHO growth charts will be presented.  Shift tables for each parameter 
to compare the infant’s percentile at baseline (≤3rd,3rd-≤5th,5th-≤10th,10th-≤25th
and 25th≤50th,50th) to each time-point post-baseline will be presented.
Mean percentiles for weight-for-age and length/height-for-age and corresponding 
90% CIs will be plotted over time.  Scatterplots of individual weight-for-age and 
length/height-for-age percentiles at Month 12 and Month 24 versus chronological age 
(age at Month 12 and Month 24) and versus baseline weight-for-age and baseline 
length/height-for-age percentiles will also be presented.
Individual growth charts will be presented for each infant in the ITT population.  One 
chart will present the weight and length/height of the infant over time, with reference 
lines for the 3rd, 10th, 25th, 50th, 75th, 90th and 97th percentiles for weight-for-age and 
length/height-for-age from the WHO growth charts displayed.  The following parameters 
will also be presented: age ability to swallow is lost or regained and age at time of 
feeding tube (gastrostomy, nasogastric tube or jejunostomy tube) placement.  This will 
include all procedures with a MedDRA preferred term of ‘gastrostomy,’ ‘gastrointestinal 
tube insertion,’ ‘jejunostomy,’ or ‘feeding tube user,’ or a MedDRA lowest level term of 
‘gastrojejunostomy.’
A second chart will display the weight of the infant over time with reference lines for 
weight-for-age, plus the following parameters: chest circumference, phase angle, age at 
onset of any respiratory infection (AEs with a MedDRA high level group term [HLGT] of 
‘respiratory tract infections’), and age at time of permanent ventilation.
Both charts will also present the age at onset of symptoms, age at diagnosis, age at first 
dose, age at treatment/study discontinuation and age at death (if applicable).
4.7
MISSING DATA
For responder/non-responder definitions, infants with a missing assessment at a visit (for 
any reason) will be classified as non-responders.
For the calculation of the CHOP-INTEND score, modified BSID-III gross motor scale 
total raw score, or HINE-2 total score, if any individual item score contributing to the total 
score is missing or ‘Cannot test (CNT)’ is recorded, then that item will be set to 0 if there 
is at least one non-missing item at the assessment.  If all items are missing, then the 
total score will be set to missing.
No imputation will be performed for missing safety variables.


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4.8
INTERIM ANALYSES
A futility assessment for efficacy will be conducted after the first 14 infants enrolled into 
the confirmatory Part 2 of the study have reached 12 months of treatment or have been 
withdrawn.  If the predictive probability of ‘success’ (defined as observing 5 out of 40 
sitting) is less than 10% (corresponding to no infant has met the primary endpoint of 
sitting without support at Month 12 in the first 14 infants enrolled in Part 2) then the 
Sponsor may consider stopping the study.  The predictive probabilities of success at the 
primary analysis given the number of infants sitting without support at the futility analysis 
are presented in Table 2.
Table 2
Predictive Probabilities of Success at Primary Analysis (Month 12) 
Given Result of Futility Analysis
Number of infants 
enrolled in Part 2 
sitting without 
support at futility 
analysis
Action to be taken
Predictive 
probability of 
success at primary 
analysis 
(Month 12) (%)
0
Consider stopping study
8.8
1
Continue
38.7
2
Continue
75.1
3
Continue
94.9
4
Continue
99.6
5
Continue/File
100.0
An interim analysis for futility will be performed by the Sponsor and the results presented 
to the iDMC.  The iDMC will be requested to review all available safety data and asked 
to provide an independent assessment of the benefit-risk profile of RO7034067 in the 
Type 1 SMA population at this earlier time-point.  The final decision based on the iDMC 
recommendation will be made by the Sponsor.
5.
CHINA SUBGROUP ANALYSIS
A separate analysis will be performed for the China subpopulation, where data from all 
infants enrolled in China (i.e., during both the global enrollment phase and the extended 
China enrollment phase) will be combined and summarized.  Data from the China 
extension cohort will not be included in the primary analysis of the main study.  China 
subgroup analyses will be documented in a separate Clinical Study Report.
All analyses described in this section will include all data from the China subgroup 
collected up to the clinical cutoff date for the China subgroup analysis as defined in 
Section 2.4.
The analysis populations will be defined as per Section 4.1, but will only be based on 
infants who are residents of China, Hong Kong, or Taiwan, and are of Chinese ancestry.  


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Analyses of study conduct will be performed as described in Section 4.2.  Summaries of 
demographics and baseline characteristics, SMA history and disease characteristics, 
and medical and treatment history will be produced as described in Section 4.3.  Efficacy 
data for the China subgroup will be analyzed as described in Section 4.4, as appropriate.  
However, no hypothesis testing will be performed.  Safety data for the China subgroup 
will be analyzed as described in Section 4.6.


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6.
REFERENCES
 
Cobben JM, Lemmink HH, Snoeck I, et al. Survival in SMA type I: A prospective analysis 
of 34 consecutive cases. Neuromuscul Disord. 2008;18:541-544.
 
Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular 
atrophy type I and implications for clinical trials. Neurology. 2014;83:810-817.
 
WHO Child Growth Standards: Length/height-for-age, weight-for-age, weight-for-length, 
weight-for-height and body mass index-for-age: Methods and development. 
Geneva: World Health Organization, 2006.
WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards: Head 
circumference-for-age, arm circumference-for-age, triceps skinfold-for-age and 
subscapular skinfold-for-age: Methods and development. Geneva: World Health 
Organization, 2007.


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Appendix 1
Protocol Synopsis
TITLE:
A TWO-PART SEAMLESS, OPEN-LABEL, MULTI-CENTER STUDY 
TO INVESTIGATE THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, PHARMACODYNAMICS AND EFFICACY 
OF RO7034067 IN INFANTS WITH TYPE 1 SPINAL MUSCULAR 
ATROPHY
PROTOCOL NUMBER:
BP39056
VERSION:
5
EUDRACT NUMBER:
2016-000778-40
IND NUMBER:
128972
TEST PRODUCT:
RO7034067
PHASE:
II
INDICATION:
Type 1 spinal muscular atrophy
SPONSOR:
F. Hoffmann-La Roche Ltd
OBJECTIVES
Primary Objectives
The primary objectives for the study are as follows:

Part 1: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 
RO7034067 in infants with Type 1 SMA, and to select the dose for Part 2.

Part 2: To assess the efficacy of RO7034067 measured as the proportion of infants sitting 
without support after 12 months of treatment, as assessed in the Gross Motor Scale of the 
Bayley Scales of Infant and Toddler development – Third Edition (BSID-III) (defined as 
sitting without support for 5 seconds).
Secondary Objectives
The secondary objectives for Part 2 of this study are as follows:

To assess the safety and tolerability of oral treatment with RO7034067.

To assess the pharmacokinetics of RO7034067.

To assess the pharmacodynamic effects of RO7034067 (SMN2 mRNA, SMN protein).

To evaluate at 12 months of treatment with RO7034067 the effect on motor development 
milestones, such as head control and rolling, as measured in the BSID-III gross motor scale.

To evaluate at 24 months of treatment with RO7034067 the effect on sitting without support 
for 5 seconds and further motor development milestones, such as sitting without support for 
30 seconds, crawling, standing alone, and walking, as measured in the BSID-III gross motor 
scale.

To assess the achievement of motor milestones at 12 and 24 months of treatment with 
RO7034067, as measured by the Hammersmith Infant Neurological Examination (HINE) 
Module 2.

To evaluate the proportion of infants who achieve a score of 40 or higher in the Children's 
Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at 
12 months of treatment.


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
To evaluate the proportion of infants who achieve an increase of at least 4 points on their 
CHOP-INTEND score from baseline at 8 and 12 months of treatment.

To evaluate the proportion of infants who achieve head control at 8, 12, and 24 months of 
treatment (defined as a score of 3 or higher for item 12 of the CHOP-INTEND).

To assess the change from baseline in the total raw score of the BSID-III gross motor scale 
at 12 and 24 months of treatment.

To assess the proportion of infants who achieve a reduction of at least 30 degrees in phase 
angle at 12 months of treatment measured by respiratory plethysmography (RP).

To evaluate the proportion of infants who do not require invasive or non-invasive respiratory 
support at 12 and 24 months of treatment.

To assess at 12 and 24 months of treatment the proportion of infants who are alive without 
permanent ventilation, as defined by16 hours of non-invasive ventilation per day or 
intubation for 21 consecutive days in the absence of, or following the resolution of, an 
acute reversible event or tracheostomy.

To assess the impact of treatment with RO7034067 on time-to-event (death, permanent 
ventilation).

To evaluate the proportion of infants with the ability to feed orally at 12 and 24 months of 
treatment.
Exploratory Objectives
The exploratory objectives for Part 2 of this study are as follows:

To explore the effect of treatment with RO7034067 on parent/ caregiver-rated infant health 
status and impact on the parent/ caregiver, as measured by the Infant Toddler Quality of 
Life Questionnaire at 12 and 24 months.

To assess at 8, 12, and 24 months of treatment with RO7034067 the ratio between the 
chest and head circumference.

To explore the treatment effect on pre-specified disease-related adverse events by 12 and 
24 months of treatment.

To investigate the effect at 12 and 24 months of treatment with RO7034067 on muscle 
electrophysiology, as assessed by compound muscle action potential (CMAP).

To explore the effect of treatment with RO7034067 on the number of hospitalizations 
(for any reason) per patient-year and number of nights admitted to hospital per infant at 
12 and 24 months of treatment.

To evaluate at 24 months the effects of RO7034067 on sustained sitting for those infants 
sitting at 12 months (defined as sitting without support for 5 seconds).

To explore at 24 months the maintenance of the effects of RO7034067 on respiratory 
function for those infants who achieve a reduction of at least 30 degrees in phase angle at 
12 months.

To explore at 12 months the effect of treatment with RO7034067 on clinician-reported 
changes in infants’ respiratory function and swallowing ability, as measured by the 
clinical domain level items. 

To assess at 12 and 24 months of treatment with RO7034067 the change from baseline in 
weight and length/height percentiles.


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STUDY DESIGN
Description of Study
This is a seamless open-label, single-arm, multi-center clinical study to investigate the safety, 
tolerability, pharmacokinetics, pharmacodynamics and efficacy of RO7034067 in Type 1 SMA 
infants. The study will be conducted in two parts and followed by an open-label extension 
phase:

Exploratory Part 1: Part 1 is an open-label, dose escalation study in infants with Type 1 
SMA aged 1 to 7 months (at time of enrollment).

The first infant will receive a single dose of RO7034067 to assess safety and tolerability, 
and the pharmacokinetics (PK). If this single dose is safe and well tolerated in this first 
infant, and after the PK has been assessed and evaluated, this infant will continue 
treatment with RO7034067 and start approximately 2 weeks later the study as per the 
Schedule of Assessments (SoA) at the dose level (Dose Level 1; target AUC0-24h,ss 
700 ng h/mL) selected based on the PK data obtained from the first single dose. If the 
study drug is well tolerated in this first infant for at least one week after reaching 
approximate steady-state (or a minimum of 2-week treatment), an additional 2 infants 
will be enrolled (5 to 7 months of age) to receive this dose/exposure level.

If upon review of safety and tolerability in the first 5 infants for at least 7 days at 
approximate steady-state (or a minimum of 2-week treatment), this dose/exposure level 
does not meet any of the dose escalation stopping rules, the dose of the 5th infant will 
be increased to reach the higher target exposure (Dose Level 2: the exposure with 
maximum expected SMN protein increase, but below the exposure cap). Assuming 
dose escalation stopping rules remain unmet after administration of RO7034067 in all 
5 enrolled infants (for a minimum of 1 week in the last infant receiving Dose Level 2, and 
longer treatment duration in all previously enrolled infants at Dose Level 1), 3 additional 
infants will be enrolled and receive RO7034067 at this higher target exposure. After a 
minimum treatment duration of 4 weeks at Dose Level 2 (or 2 weeks at the final 
approximate steady-state exposure) in all 4 infants, all safety, PK, and PD data will be 
reviewed to select the dose to be evaluated in Part 2.

Confirmatory Part 2: Part 2 is an open-label, single arm study in 40 infants with Type 1 
SMA aged 1 to 7 months (at time of enrollment) to assess the efficacy of RO7034067 at the 
dose selected in Part 1 over a 24-month treatment period, with the primary endpoint 
analyzed at 12 months of treatment.
On the basis of available data from Part 1, the following dose levels have been selected for 
Part 2:

Infants >1 month and below 3 months old at enrollment: 0.04 mg/kg.

Infants at least 3 months but below 5 months old at enrollment: 0.08 mg/kg.

Infants 5 months old or older at enrollment: 0.2 mg/kg.
Patients will remain on their initially assigned dose level (i.e., the dose will not change once 
a patient reaches 3 months and 5 months of age, respectively) unless a change of dose is 
requested by the Clinical Pharmacologist upon review of the PK data, to ensure that infants 
are in the targeted exposure range and in compliance with the exposure cap.
After the initial enrollment of 40 infants across all sites in a global enrollment phase, 
additional infants may be enrolled in an extended China enrollment phase at sites that are 
recognized 
 to ensure a total of 
approximately 10 infants in a China subpopulation.
NUMBER OF PATIENTS
The exploratory Part 1 will consist of at least 8 infants and up to 24 infants (if required) enrolled 
into two multiple ascending dose cohorts.
In Part 2, 40 infants with Type 1 SMA will be enrolled to receive RO7034067 at the dose (target 
exposure level) selected in Part 1.


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After completion of the global enrollment phase for Part 2, additional infants may be enrolled in 
an extended China enrollment phase at 
-recognized sites to ensure approximately 
10 infants in a China subpopulation (including infants enrolled in the global enrollment phase 
and the extended China enrollment phase).
TARGET POPULATION
This study will include both male and female Type 1 SMA infants aged ≥1 month 
and7 months at the time of enrollment.
INCLUSION/EXCLUSION CRITERIA
Inclusion criteria:
Infants must meet the following criteria for study entry:
1)
Males and females aged between 28 days (1 month) of life and 210 days (7 months) 
(inclusive) at enrollment. For the first 3 infants enrolled in Part 1, age will be between 
150 days (5 months) and 210 days (7 months) inclusive and a minimum body weight of 
7 kg is required for the first infant only. Enrollment is defined as the moment when infants 
get their dosing number assigned.
2)
A legally authorized representative must be able to consent for the patient according to 
International Conference on Harmonisation (ICH) and local regulations.
3)
Gestational age of 37 to 42 weeks.
4)
Confirmed diagnosis of 5q-autosomal recessive SMA, including:
a.
Genetic confirmation of homozygous deletion or compound heterozygosity 
predictive of loss of function of the SMN1 gene.
b.
Clinical history, signs or symptoms attributable to Type 1 SMA, i.e., hypotonia, 
absent deep tendon reflex (DTR) and/or tongue fasciculations with onset after the 
age of 28 days, but prior to the age of 3 months (inclusive), and inability to sit 
independently (without support) at the time of screening.
5)
Patient has two SMN2 gene copies, as confirmed by central testing.
6)
Body weight3rd percentile for age, using appropriate country-specific guidelines (for the 
first infant only:7 kg).
7)
Receiving adequate nutrition and hydration (with or without gastrostomy) at the time of 
screening, in the opinion of the Investigator.
8)
Adequately recovered from any acute illness at the time of screening and considered 
well-enough to participate in the opinion of the Investigator.
9)
Medical care meets, in the opinion of the Investigator, local accepted standard of care.
10) Able and expected to be able to safely travel to the study site for the whole duration of the 
study and according to the frequency of required study visits, in the opinion of the 
Investigator. Air travel is strongly discouraged. The overall condition and situation (including 
geographical) of the patient should be evaluated and the decision taken by the Investigator 
prior to enrollment.
11) Have a stable home situation with a consistent caregiver.
12) Would be able to complete all study procedures, measurements and visits, and the parent 
or caregiver of the patient, in the opinion of the Investigator, has adequately supportive 
psychosocial circumstances.
13) If not already in place at the time of screening, parent or caregiver of patient is willing to 
consider nasogastric, naso-jejunal or gastrostomy tube placement during the study to 
maintain safe hydration, nutrition and treatment delivery, as recommended by the 
Investigator.
14) If not already in place at the time of screening, parent or caregiver of patient is willing to 
consider the use of non-invasive ventilation during the study, as recommended by the 
Investigator.


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Exclusion criteria:
Infants who meet any of the following criteria will be excluded from study entry:
1)
Inability to meet study requirements.
2)
Concomitant or previous participation in any investigational drug or device study within 
90 days prior to screening or 5 half-lives, whichever is longer.
3)
Concomitant or previous administration of a SMN2-targeting antisense oligonucleotide, 
SMN2 splicing modifier or gene therapy either in a clinical study or as part of medical care.
4)
Any history of cell therapy.
5)
Hospitalization for pulmonary event within the last 2 months, or planned at the time of 
screening.
6)
Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system diseases.
7)
In the opinion of the Investigator, inadequate venous or capillary blood access for the study 
procedures.
8)
Patients requiring invasive ventilation or tracheostomy.
9)
Patients requiring awake non-invasive ventilation or with awake hypoxemia (SaO295%) 
with or without ventilator support.
10) Patients with a history of respiratory failure or severe pneumonia, and have not fully 
recovered their pulmonary function at the time of screening.
11) Multiple or fixed contractures and/or hip subluxation or dislocation at birth.
12) Presence of non-SMA-related concurrent syndromes or diseases.
13) Confirmed (2 consecutive measurements) systolic blood pressure (SBP) or diastolic blood 
pressure (DBP) outside the 95th percentile for age; resting heart rate70 bpm or170 bpm.
14) Presence of clinically relevant electrocardiogram (ECG) abnormalities before study drug 
administration; corrected QT interval using Bazett’s method (QTcB) 460 ms; personal or 
family history (first degree relatives) of congenital long QT syndrome indicating a safety risk 
for patients as determined by the Investigator. First-degree atrioventricular block or isolated 
right bundle branch block are allowed.
15) History of malignancy if not considered cured.
16) Any major illness within one month before the screening examination or any febrile illness 
within one week prior to screening and up to first dose administration.
17) Taking any nutrients known to modulate CYP3A activity (e.g., grapefruit juice; Seville 
orange) within 2 weeks prior to administration of study drugs.
18) The infant (and the mother, if breastfeeding the patient):
a.
Any inhibitor of CYP3A4 taken within 2 weeks (or within 5 times the elimination 
half-life, whichever is longer) prior to dosing, including but not limited to: 
ketoconazole, miconazole, itraconazole, fluconazole, erythromycin, clarithromycin, 
ranitidine, cimetidine.
b.
Any inducer of CYP3A4 taken within 4 weeks (or within 5 times the elimination half-
life, whichever is longer) prior to dosing, including but not limited to: rifampicin, 
rifabutin, glucocorticoids, carbamazepine, phenytoin, phenobarbital, St. John's wort.
c.
Any OCT-2 and MATE substrates shall be avoided (including but not limited to: 
amantadine, cimetidine, memantine, amiloride, famotidine, metformin, pindolol, 
ranitidine, procainamide, varenicline, acyclovir, ganciclovir, oxaliplatin, cephalexin, 
cephradine, fexofenadine).
d.
Any known FMO1 or FMO3 inhibitors or substrates.


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19) Clinically significant abnormalities in laboratory test results e.g., Grade 1 anemia, alanine 
aminotransferase (ALT) values exceeding 1.5 the upper limit of normal (ULN) unless the 
elevated ALT level is considered of muscular origin (i.e., in the absence of other evidence 
of liver disease which is confirmed by elevated creatine kinase and lactate dehydrogenase 
[LDH]). Out of range creatine kinase levels should be reviewed in light of the underlying 
SMA pathology of the patient; elevated levels per se do not disqualify the patient from the 
study. In the case of uncertain or questionable results, tests performed during screening 
may be repeated before enrollment to confirm eligibility.
20) Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction) to RO7034067 or 
to the constituents of its formulation
21) Concomitant disease or condition that could interfere with, or treatment of which might 
interfere with, the conduct of the study, or that would, in the opinion of the Investigator, 
pose an unacceptable risk to the subject in this study.
22) Therapeutic use, defined as use for 8 weeks or longer, of the following medications within 
90 days prior to enrollment: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, 
butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, 
agents anticipated to increase or decrease muscle strength, agents with known or 
presumed histone deacetylase (HDAC) inhibitory effect, medications known to or suspected 
of causing retinal toxicity (e.g. deferoxamine, topiramate, latanoprost, niacin, rosiglitazone, 
tamoxifen, canthaxanthine, sildenafil, and interferon) and medications with known 
phototoxicity liabilities (e.g., oral retinoids including over-the-counter [OTC] formulations, 
amiodarone, phenothiazines and use of minocycline).Shorter use of any of these drugs 
within 90 days prior to enrollment will be reviewed on a case-by-case basis and discussed 
between the Sponsor and the Investigator, who will jointly make the decision if the patient 
can be enrolled in the study. (Infants who are on inhaled corticosteroids, administered 
either through a nebulizer or an inhaler, will be allowed in the study).
a.
Infants must not begin treatment with the above medications after initiating study 
drug.
23) Recently initiated treatment (within 6 weeks prior to enrollment) with oral salbutamol or 
another 2-adrenergic agonist taken orally is not allowed. Infants who have been on oral 
salbutamol (or another 2-adrenergic agonist) for 6 weeks before screening and have 
shown good tolerance are allowed. The dose of 2-adrenergic agonist should remain stable 
as much as possible for the duration of the study. Use of inhaled 2-adrenergic agonists 
(e.g., for the treatment of asthma) is allowed.
24) Prior use (at any time in the patients’ lives) and/or anticipated need for quinolines 
(chloroquine and hydroxychloroquine), thioridazine, vigabatrin, retigabine, or any other drug 
known to cause retinal toxicity during the study does not allow participation in the trial. 
Infants exposed to chloroquine, hydroxycholoroquine, thioridazine, vigabatrin, retigabine or 
drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should 
not be enrolled.
25) Recent history (less than 6 months) of ophthalmic diseases (e.g., glaucoma not controlled 
by treatment, central serous retinopathy, inflammatory/infectious retinitis unless clearly 
inactive, retinal detachment, intraocular trauma, retinal dystrophy or degeneration, optic 
neuropathy, or optic neuritis) that would interfere with the conduct of the study as assessed 
by an ophthalmologist. Any other abnormalities detected with OCT at screening 
(e.g., retinal layer abnormalities, edema, cystic or atrophic changes) must be discussed 
with the Investigator, Ophthalmologist, and with the Sponsor, who will jointly make the 
decision if the patient may be enrolled in the study. Infants in whom OCT measurement of 
sufficient quality cannot be obtained at screening will not be enrolled.
LENGTH OF STUDY

The duration of the study for each infant enrolled in Part 1 (not including the extension 
phase) will be divided as follows:
Screening: Up to 30 days prior to first dose.


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Treatment Period: minimum of 2 weeks at steady state exposure (as decided by the Internal 
Monitoring Committee [IMC]).

The duration of the study for each infant enrolled in Part 2 (not including the extension 
phase) will be up to 25 months as follows:
Screening: up to 30 days prior to first dose.
Treatment period: 24 months from the start of dosing, with the primary analysis after the last 
infant reaches a minimum of 12 months of treatment.
After each infant completes 24 months of treatment, he or she will enter an open-label
extension.
END OF STUDY
The end of this study is defined as the date when the last patient last visit (LPLV) occurs.
The study will continue until RO7034067 is commercially available in the infant’s country, or as 
per local regulation, or per the Sponsor’s decision to terminate RO7034067 development. 
However, the study will not exceed 4 years (or less as per country specific requirements) after 
the last infant is enrolled in the study.
OUTCOME MEASURES
SAFETY OUTCOME MEASURES
The safety outcome measures for this study are as follows:

Incidence and severity of adverse events.

Incidence and severity of serious adverse events.

Incidence of treatment discontinuations due to adverse events.

Incidence of abnormal laboratory values.

Incidence of abnormal ECG values.

Vital signs abnormalities, including body temperature, systolic and diastolic blood pressure, 
heart rate, respiratory rate.

Ophthalmological examination as appropriate for age: red reflex, external ocular 
examination, pupillary examination/response, fix and follow test, corneal light reflex, fundus 
examination including ophthalmoscopy/slit lamp examination, OCT and fundus photography.

Physical examination, including detailed examination of the skin, mouth, pharynx and larynx.

Anthropometric examination, including weight, height, head, and chest circumference.
Adverse events and concomitant medications will be monitored throughout the entire study 
(screening through follow-up).
PHARMACOKINETIC OUTCOME MEASURES
Blood samples for determination of plasma concentrations of RO7034067, and its metabolite(s) 
as applicable, will be collected as detailed in the SoA. The following parameters will be 
calculated (if possible, based on the available data):

Concentration per time-point listed.

Peak plasma concentration (Cmax).

Area under the curve (AUC).

Concentration at the end of a dosing interval (Ctrough) to assess steady-state.

Other PK parameters as appropriate
PHARMACODYNAMIC OUTCOME MEASURES
The fluid PD assessments (SMN mRNA and SMN protein in blood) will be performed as 
detailed in the SoA.


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EFFICACY OUTCOME MEASURES
The efficacy outcome measures for this study are as follows:

Motor milestones achieved as assessed by the Gross Motor Scale of the BSID-III.

Motor milestones achieved as assessed by Hammersmith Infant Neurological Examination 
Module 2 (HINE-2).

CHOP-INTEND.

RP.

Disease-related adverse events.

CMAP.

Level of respiratory support.

Ventilation free-survival. 

Ability to swallow and to feed orally.

Clinician-reported respiratory function and ability to swallow items.

Change in height and weight.
PARENT/CAREGIVERREPORTED OUTCOME MEASURES
The parent/caregiver-reported outcome measure for this study is as follows:

Parent/caregiver-rated infant health status and impact on the parent/caregiver, as 
measured by the Infant Toddler Quality of Life (ITQOL) Questionnaire.
BIOMARKER/GENOTYPING SAMPLE COLLECTION
Clinical Genotyping (CG) Samples
A single mandatory whole blood sample will be taken from every patient at screening for DNA 
extraction. The DNA will be used to determine the number of copies of the SMN2 gene and to 
confirm SMN1 gene mutation or deletion.
A mandatory whole blood sample will be taken for DNA extraction from every patient once 
enrolled onto the study and may be used for additional confirmatory testing of SMN1
deletion/SMN2 copy number.
Samples may be used for exploratory analysis/assay development related to SMA, including, 
but not limited to, mitochondrial DNA and genes related to SMN function or treatment response.
INVESTIGATIONAL MEDICINAL PRODUCT
Exploratory Part 1:
The Investigational Medicinal Product (IMP) will be supplied in bottles containing 20 mg or 
120 mg of RO7034067 drug substance (no excipient). Before administration, the drug 
substance will be constituted with a solvent, which is prepared by dissolving a provided 
excipient blend with water for injection. For the first infant(s), a further dilution step is foreseen 
to enable the administration of a low starting dose.
Confirmatory Part 2:
The IMP will change to a new formulation which is supplied in bottles filled with powder blends 
containing 20 mg or 60 mg of RO7034067 drug substance as well as all excipients. The drug 
solution can be directly constituted with purified water in the bottle of the IMP.
RO7034067 should be taken orally once daily. In the case of breastfeeding, the patient should 
be fed prior to dosing, winded, and the study medication administered. Study participants 
unable to swallow the study medication and who have a naso-gastric or gastrostomy tube in situ 
should receive the study medication by bolus via the tube.
PROCEDURES
Schedule of assessments tables are provided in Appendices.


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STATISTICAL METHODS
The analyses of this study will be structured into two parts; exploratory (Part 1) to select the 
dose and confirmatory (Part 2) to evaluate the treatment effect of RO7034067.
Following the dose selection for Part 2, data from the exploratory Part 1 of this study (and the 
Part 1 extension phase) may be locked at intervals in order to analyze and report the safety, 
PK/PD, and exploratory efficacy of those patients enrolled into Part 1 only.
A database lock for the purpose of the primary analysis and analyses of the 12-month 
secondary and exploratory endpoints will occur once the last infant enrolled into Part 2 during 
the global enrollment phase has either completed his/her 12-month assessment or has been 
withdrawn. At the time of the primary analysis, all available efficacy data post Month 12 will be 
reported. All available safety data in both parts of the study will be reported. A database lock for 
the analyses of the 24-month secondary and exploratory endpoints will occur once the last 
infant enrolled into Part 2 during the global enrollment phase has either completed his/her 
24-month assessment or has been withdrawn.
The global population will include all infants enrolled during the global enrollment phase 
(including infants enrolled at 
-recognized sites during the global phase), and the China 
subpopulation will include all infants enrolled at 
-recognized sites (i.e., during both the 
global enrollment phase and the extended China enrollment phase). Separate analyses will be 
performed for the global population and the China subpopulation.
EFFICACY ANALYSES
The intent-to-treat (ITT) population will be the primary analysis population for all efficacy 
analyses. The ITT population is defined as all enrolled infants, regardless of whether they 
received treatment or not.
The confirmatory efficacy analyses will only include data from the infants enrolled into Part 2 of 
the study; it will not include data from the Part 1 infants who will be analyzed to select the dose. 
Efficacy data of the infants enrolled into Part 1 will be summarized descriptively, using individual 
patient plots or listings (as appropriate) and presented separately from the confirmatory efficacy 
analysis of Part 2.
Primary Efficacy Endpoint
The primary endpoint for the confirmatory Part 2 of the study is the proportion of infants who are 
sitting without support at 12 months of treatment. Infants who do not achieve sitting, or have not 
maintained sitting achieved earlier, or have been withdrawn, or died, will be classified as 
non-responders (i.e., non-sitters) for the primary analysis. Sitting is defined as ‘sits without 
support for 5 seconds’ as assessed in Item 22 of the BSID-III gross motor scale. The 
assessment of the independent central readers will be used for the primary analysis.
The proportion of infants who are alive and sitting after 12 months of treatment will be presented 
with a two-sided 90% Clopper-Pearson (Exact) confidence interval. An exact binomial test will 
be performed. The hypothesis to be tested is that the proportion of infants who sit on treatment 
(p) is:
Ho: p 5% (null) versus Ha: p 5% (alternative). 
If the one-sided p-value is 5% then, the null hypothesis will be rejected. If the lower limit of the 
two-sided 90% confidence interval is above the 5% threshold, the primary objective of the study 
will be considered achieved.


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Secondary Efficacy Endpoints
The secondary efficacy endpoints in Part 2 are as follows:

Motor Function and Development Milestones: Proportion of infants who achieve a score 
of 40 or higher in the CHOP-INTEND at Month 12; proportion of infants who achieve an 
increase of at least 4 points in their CHOP-INTEND score from baseline at Month 8 and 
Month 12; proportion of infants who achieve head control at Month 8, Month 12, and
Month 24 (defined as a score of 3 or higher for item 12 of the CHOP-INTEND); change from 
baseline in the total raw score of the BSID-III gross motor scale at Month 12 and Month 24;
proportion of infants who achieve the attainment levels of the motor milestones as assessed 
in the HINE-2 at Month 8 (head control, ability to kick, rolling), Month 12, and Month 24;
proportion of motor milestone responders as assessed by HINE-2 at Month 12 and 
Month 24; highest motor milestone achieved by Month 12 and Month 24; proportion of 
infants who are alive and sitting without support for 5 seconds at Month 24 (defined as per 
the primary endpoint); proportion of infants who are alive and sitting without support for 
30 seconds at Month 24 (defined as “Sits without support for 30 seconds” as assessed in 
Item 26 of the BSID-III gross motor scale); proportion of infants who are alive and standing 
at Month 24 (defined as ‘Stands Alone’ as assessed in Item 40 of the BSID-III gross motor 
scale); proportion of infants who are alive and walking at Month 24 (defined as ‘Walks Alone’ 
as assessed in Item 42 of the BSID-III gross motor scale).

Survival and Ventilation-Free Survival: Time to death or permanent ventilation (defined 
as 16 hours of non-invasive ventilation per day or intubation for 21 consecutive days in 
the absence of, or following the resolution of, an acute reversible event or tracheostomy) 
from enrollment, time to death from enrollment, proportion of infants who are alive without 
permanent ventilation at Month 12 and Month 24, proportion of infants who are alive at 
Month 12 and Month 24.

Respiratory: Time to permanent ventilation from enrollment, proportion of infants who are 
without permanent ventilation at Month 12 and Month 24, proportion of infants who achieve 
a reduction of at least 30 degrees in their phase angle from baseline, as measured by RP, 
at Month 12, proportion of infants who do not require invasive or non-invasive respiratory 
support at Month 12 and Month 24.

Nutrition: Proportion of infants with the ability to feed orally at Month 12 and Month 24.
SAFETY ANALYSES
All infants who receive at least one dose of study medication (RO7034067) will be included in 
the safety population.
Safety data will be summarized descriptively using the safety population. In Part 1, safety data 
will be presented in summaries, listings or individual patient plots (as appropriate) by 
dose/exposure level. For Part 2, the safety data will be summarized descriptively for the first 
12-month period (i.e., 12-month data for each individual infant) and for all available safety data 
collected at the time of the analysis. Similar summaries for the first 24-month period will be 
presented at the time of the 24-month analysis reporting event.
SAMPLE SIZE JUSTIFICATION
In Part 1, the target sample size is 8 infants, 4 enrolled to each dose level. With 8 infants 
exposed to RO7034067, there is over an 80% chance to detect an AE in at least one infant, 
given that the true underlying adverse event rate is 20%. With 4 infants exposed at each dose 
level, the probability to detect an AE in at least one infant, given that the true underlying adverse 
event rate is 30%, is 76%.
In Part 2, the target sample size is 40 infants. This sample size provides at least 90% power to 
test the null hypothesis Ho: p 5% versus alternative hypothesis Ha: p 5%, if the true 
proportion of infants who would sit on treatment is 20%. This is based on an exact binomial test 
with a onesided 5% significance level. The minimum number of infants needed to be observed 
sitting is 5 out of 40 for a statistically significant result. If more than 40 infants are enrolled, the 
number of babies required to meet the primary endpoint will increase. Further details are 
provided in the SAP. If in Part 2, 5 out of 40 infants sit the lower limit of the -twosided- 90% 
Clopper-Pearson (Exact) confidence interval would be above 5%.


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65/Statistical Analysis Plan BP39056
No allowance has been made for infants who withdraw early as these infants will be classified 
as a non-responder/non-sitter and included within the primary analysis.
Interim Analyses
As this study is open-label, once at least 5 infants enrolled into the confirmatory Part 2 during 
the global enrollment phase have met the primary endpoint of sitting without support at 
Month 12 (as assessed by the independent central readers), the minimum number of infants 
needed for a statistically significant result will have been achieved and the primary objective of 
the study will be considered achieved at this earlier time-point. The study will not be stopped 
and all 40 infants enrolled within the confirmatory Part 2 will continue to receive 12 months of 
treatment in order to provide an unbiased estimate of the proportion of infants sitting at 
Month 12.
In addition, a futility assessment for efficacy will be conducted after the first 14 infants enrolled 
into the confirmatory Part 2 of the study reach 12 months of treatment or have been withdrawn. 
If the predictive probability of “success” (defined as observing 5 out of 40 sitting) is less than 10% 
(corresponding to no infant has met the primary endpoint of sitting without support at Month 12 
in the first 14 infants enrolled in Part 2) then the Sponsor may consider stopping the study.
Interim analyses for efficacy and futility will be performed by the Sponsor and the results 
presented to the iDMC. The iDMC will be requested to review all available safety data and 
asked to provide an independent assessment of the benefit risk profile of RO7034067 in the 
Type 1 SMA population at this earlier timepoint. The final decision based on the 
iDMC- recommendation will be made by the Sponsor.
LIST OF PROHIBITED MEDICATIONS
The following medication is explicitly prohibited for the patients and the mother if breastfeeding 
the infant:

Any inhibitor of CYP3A4, including but not limited to: ketoconazole, miconazole, 
itraconazole, fluconazole, erythromycin, clarithromycin, ranitidine, cimetidine.

Any inducer of CYP3A4, including but not limited to: rifampicin, rifabutin, glucocorticoids, 
carbamazepine, phenytoin, phenobarbital, St. John's wort.

Any OCT2 and MATE substrates shall be avoided, including but not limited to: amantadine, 
cimetidine, memantine, amiloride, famotidine, metformin, pindolol, ranitidine, procainamide, 
varenicline, acyclovir, ganciclovir, oxaliplatin, cephalexin, cephradine, fexofenadine.

Any known FMO1 or FMO3 inhibitors or substrates.
Use of the following therapies is prohibited for at least 90 days prior to enrollment (unless the 
Investigator has consulted with the Sponsor during the screening period and both have agreed 
that the prior use will not constitute a risk to the patient), and during the study:

Medications intended for the treatment of SMA: riluzole, valproic acid, hydroxyurea, 
sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic 
steroids, probenecid, bortezomin, quercetin, chronic oral or parenteral use of corticosteroids 
(inhaled corticosteroid use is allowed, see above), agents anticipated to increase or 
decrease muscle strength or agents with known or presumed HDAC inhibition activity, and 
any prior use of SpinrazaTM or any other SMN2-targeting antisense oligonucleotide, SMN-2 
splicing modifier or gene therapy are prohibited. 

Medications with known phototoxicity and retinal toxicity liabilities: Oral or topical 
retinoids, including over-the-counter formulations, amiodarone, phenothiazines, and chronic 
use of minocycline.

Patients should not have received the following drugs at any time in their lives and are 
prohibited during the study: quinolines (chloroquine and hydroxychloroquine), thioridazine, 
vigabatrin and retigabine at any time in their lives
Use of the following therapies is prohibited for the patients, and for the mother if breastfeeding 
the infant during the study and in the preceding 90 days of enrollment: deferoxamine, 
topiramate, latanoprost, niacin, rosiglitazone, tamoxifen, canthaxanthine, sildenafil, interferon or 
any other drugs known to cause retinal toxicity.








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69/Statistical Analysis Plan BP39056
Appendix 2
Schedule of Assessments: Part 2 (cont.)
a
Assessments should be performed in the following order, adverse events, previous/concomitant 
medication, confirmation of eligibility, followed by the order of assessments in Section 4.6.2.2 of 
protocol, Table 2 in the protocol.
b
See protocol Table 2 (Section 4.6.2.2) for assessments order and blocks of assessments at visits 
when efficacy measurements are performed
c
Physical examination will include weight, height, head and chest circumference, plus examination of 
skin, head, ears, nose, mouth and throat (buccal cavity, mucosa and oropharynx), neck and lymph 
nodes, respiratory, cardiovascular, abdomen, musculoskeletal, neurological and genitourinary 
systems.
d
Starting at Week 6, home visits may be scheduled for drug dispensation, return of unused drug, and 
supplies and any required assessments. Resupply visits (site or home visits) will be performed to 
ensure the patient has adequate drug and supplies between scheduled site visits as necessary.
e
The Investigator must agree with the parent/ caregiver when to perform the mandatory follow-up 
phone calls at the most appropriate time (day) between study visits. After Week 12, follow-up phone 
calls are per Investigator decision. If a patient withdraws from the study and the parent(s)/guardian(s) 
agrees, follow up phone calls should occur every 2 weeks after the early withdrawal visit until the 
FollowUp- Visit 1 to collect information on AEs and use of respiratory support.
f
Only SAEs.
g
For the details of the ophthalmology assessments, see Appendix 5 of the protocol.
h
Only weight is required.
i
Home resupply visits (or site visits if preferred by parent/guardian) after Week 104 will be performed 
as necessary to ensure that the patient has adequate drug and supplies between scheduled site 
visits.
j
Additional PK samples may be taken if required for safety reasons.
k
Patients will have a 24-hour PK sample taken, prior to receiving the second dose of RO7034067.
l
The confirmatory clinical genotyping sample can be collected at this visit or any following visit that
includes blood sample collection.
m
A swallowing assessment will be performed at Day -1 and on Weeks 26, 52, 78 and 104 as outlined in 
Section 4.6.1.9 of the protocol.
n
This includes SMA related surgeries and procedures.