Clinical trial NCT02760277
Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne muscular dystrophy vamorolone
Sponsor: ReveraGen BioPharma, Inc.
Start date: 2016-07-28; Completion date: 2018-04-26
Enrollment: 48 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main purposes of this study are to see if it is safe to use a new medication called vamorolone for more than two weeks in children with Duchenne muscular dystrophy (DMD), to see if vamorolone works for the treatment for DMD, and to see how any potential side effects compare to those seen in boys using steroids.

Detailed description:
This study will evaluate if it is safe to use a new medication called vamorolone for more than two weeks in children with DMD, if boys with DMD who take the study medication have improved muscle function compared to boys with DMD in other studies who did not take any type of steroid, and to see if boys with DMD who take the study medication gain less weight compared to boys with DMD in a prior study who took another type of steroid called prednisone. Enrolled participants will take the study medication for 24 weeks.

Arms: arm 1: Participants enrolled in Dose Level Group 1 will receive vamorolone 0.25 mg/kg/day. arm 2: Participants enrolled in Dose Level Group 2 will receive vamorolone 0.75 mg/kg/day. arm 3: Participants enrolled in Dose Level Group 3 will receive vamorolone 2.0 mg/kg/day. arm 4: Participants enrolled in Dose Level Group 4 will receive vamorolone 6.0 mg/kg/day.
Interventions: intervention 1: Vamorolone 0.25 mg/day/day intervention 2: Vamorolone 0.75 mg/day/day intervention 3: Vamorolone 2.0 mg/day/day intervention 4: Vamorolone 6.0 mg/day/day
Intervention descriptions: intervention 1: Oral administration of 0.25 mg/kg/day daily for 24 weeks. intervention 2: Oral administration of 0.75 mg/kg/day daily for 24 weeks. intervention 3: Oral administration of 2.0 mg/kg/day daily for 24 weeks. intervention 4: Oral administration of 6.0 mg/kg/day daily for 24 weeks.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
P a ge 1 of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
R E VI S E D  C LI NI C A L S T U D Y P R O T O C O L 
 
D oc u me nt Title:  
Re vis e d Cli nic al Pr ot o c ol # 2 f or a P h ase II O pe n-l a bel, 
 
M ultice nter E xte nsi o n St u d y t o Assess t he L o n g-ter m S afet y 
 
a n d  Effic ac y of V a m or ol o ne in B o ys wit h D uc he n ne M usc ul ar 
 
D ystr o p h y ( D M D ) 
 
Pr ot oc ol N u m be r:  
V B P 1 5- 0 0 3 
D oc u me nt N u m ber:   
V B P 1 5- 0 0 3- R 2 
 
F D A I N D N o.:  
 
1 1 8, 9 4 2 
 
I n vesti g ati o n al Pr o d uct:  
Va m or ol o ne  ( V B P 1 5) 
 
 
S p o ns or: 
 
Re vera Ge n Bi o P har ma, I nc.  
  
1 5 5 Gi b bs Street 
S uite 4 3 3 
R oc k ville, M D. 2 0 8 5 0 
 
St u d y C h air:   
 
Pa ula R. Cle me ns, M D 
  
  
  
  
P h o ne: ( 4 1 2) 3 8 3- 7 2 0 7 
  
 
  
  
E mail: cle m pr @ u p mc.e d u 
 
Me dic al M o nit or:  
 
Be nja mi n D. Sc h wartz, M. D., P h. D. 
 
  
P h o ne: ( 3 1 4) 2 2 0- 7 0 6 7 
 
  
E mail: b dsc h w @ca m de n gr o u p.c o m 
 
 
D oc u me nt D ate:  
 
2 2 Fe br u ar y 2 0 1 7 
 
 
T hi s d oc u me nt re prese nts pr o priet ar y i nf or m ati o n bel o n gi n g t o 
Re ver a Ge n Bi o P h ar m a, I nc.  
U n a ut h orize d re pr o d ucti o n of t he w h ole or p art of t he d oc u me nt b y a n y me a ns is strictl y pr o hi bite d.  
T his pr ot oc ol is pr o vi de d t o y o u as a Pri nci p al I n vesti g at or, p ote nti al I n vesti g at or or c o ns ult a nt f or 
re vie w b y y o u, y o ur st aff a n d I nstit uti o n al Re vie w B o ar d or I n de pe n de nt Et hics C o m mittee .  T he 
i nf or m ati o n c o nt ai ne d i n t his d oc u me nt is pri vile ge d a n d c o nfi de nti al a n d, e xce pt t o t he e xte nt 
necess ar y t o o bt ai n i nf or me d c o nse nt, m ust n ot be discl ose d u nless s uc h discl os ure is re q uire d b y 
fe der al or st ate l a w or re g ul ati o ns.  Pers o ns t o w h o m t he i nf or m ati o n is discl ose d i n c o nfi de nce m ust be 
i nf or me d t h at t he i nf or m ati o n is c o nfi de nti al a n d m ust n ot be discl ose d b y t he m t o a t hir d p art y. 


Va m or ol o ne 
Re vise d Cli nical Pr ot oc ol # 2 
Pr ot oc ol N o. V B Pl 5- 0 0 3 
2 2 Fe br uar y 2 0 1 7 
D o c u m e nt N o. V B P 1 5- 0 0 3- R 2 
I N D 1 1 8. 9 4 2 
SI G N A T U R E S O F A G R E E M E N T F O R V B PI S- 0 0 3- Rl 
Re vise d Cli ni c al Pr ot o c ol # 2 f or a P h as e II O p e n-l a b el, M ulti c e nt er E xt e nsi o n St u d y 
t o Assess t h e L o n g-t er m S af et y a n d Efficac y of V a m or ol o n e i n B o ys wit h D u c h e n n e 
M us c ul ar D ystr o p h y ( D M D) 
Re vie we d a n d A p pr o v e d b y: 
Eric H off ma n, P h. D. 
C hief E xec uti ve Officer 
Re vera Ge n Bi o P har ma, I nc. 
Pa ula R. Cle me ns, M. D. 
St u d y C hair 
U ni versit y of Pitts b ur g h Sc h o ol of Me dici ne 
C o ns ulti n g Me dical M o nit or 
T he Ca m de n Gr o u p, L L C 
La urel J. Me n gle- Ga w, P h. D. 
C o ns ulti n g Cli nical M o nit or 
T he Ca m de n Gr o u p .. L L C 
A vital C naa n, P h. D. 
T Ri N D S, L L C 
2 5 F e br u ar y 2 0 1 7 
Date 
2 4 Fe br uar y 2 0 1 7 
Date 
2 4 F e br u ar y 2 0 1 7 
Date 
2 M ar c h 
2 0 1 7 
Date 
Re vera Ge n Bi o P ha n na. I nc. - C O N FI D E N TI A L 
Pa ge 2 of 1 3 7 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 3 of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
I N V E S TI G A T O R R E VI S E D P R O T O C O L A G R E E M E N T 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Re vise d Cli nic al Pr ot o c ol # 2 f or a P h ase II O pe n-l a bel, M ultice nter E xte nsi o n St u d y 
t o Assess the L o n g-ter m S afet y a n d Effic ac y of V a m or ol o ne i n B o ys wit h D uc he n ne 
M usc ul ar D ystr o p h y ( D M D) 
Pr ot oc ol N u m ber:    
V B P 1 5- 0 0 3 
D oc u me nt N u m ber:    
V B P 1 5- 0 0 3- R 2 
S p o ns or: 
Re ver a Ge n Bi o P h ar m a, I nc. 
D oc u me nt D ate:  
2 2 Fe br u a r y 2 0 1 7 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
By m y si g n at ure, I c o nfir m t h at m y st aff a n d I h ave c ar ef ully re a d a n d u n derst a n d t his 
pr ot oc ol, pr ot oc ol a m e n d m e nt, a m e n de d pr ot oc ol, or revise d pr ot oc ol a n d a gree t o 
c o m ply wit h t he c o n d uct a n d ter ms of t he st u dy s pecifie d herei n a n d wit h a ny ot her 
st u dy c o n d uct pr oce d ures pr ovi de d by Rever a Ge n Bi o P h ar m a, I nc.  
I a gree t o c o n d uct t he st u dy acc or di n g t o t his pr ot oc ol a n d t he o bli g ati o ns a n d 
re q uire m e nts of cli nic al I nvesti g at ors a n d all ot her re q uire m e nts liste d i n 2 1 C F R p art 
3 1 2 a n d all a p plic a ble l oc al, st ate, a n d fe der al re g ul ati o ns a n d I C H g ui deli nes.  I will 
n ot i niti ate t his st u dy wit h o ut t he a p pr ov al of a n I nstit uti o n al Revie w B o ar d (I R B ) or 
I n de pe n de nt Et hics C o m mittee (I E C). 
I un derst a n d t h at, s h o ul d t he decisi o n be m a de by Rever a Ge n Bi o P h ar m a, I nc. t o 
ter min ate pre m at urely or s us pe n d t he st u dy at a ny ti m e f or w h atever re as o n, s uc h 
decisi o n will be c o m m u nic ate d t o m e i n writi n g.  C o nversely, s h o ul d I deci de t o 
wit h dr a w fr o m e xec uti o n of t he st u dy, I will c o m m u nic ate i m m e di ately s uc h decisi o n i n 
writi n g t o Rever a Ge n Bi o P h ar m a, I nc. 
F or pr ot oc ol a m e n d m e nts a n d a m e n de d pr ot oc ols, I a gree n ot t o i m ple m e nt t he 
a m e n d m e nt 
wit h o ut 
a gree m e nt fr o m 
Rever a Ge n 
Bi o P h ar m a, I nc. 
a n d pri or 
s u bmissi o n t o a n d writte n a p pr ov al ( w here re q uire d) fr o m t he I R B/I E C, e xce pt w he n 
necess ary t o eli mi n ate a n i m m e di ate h az ar d t o t he s u bjects, or f or a d mi nistr ative 
as pects of t he st u dy ( w here per mitte d by all a p plic a ble re g ul at ory re q uire m e nts). 
 
 
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I n v esti gat or’s Si g n at ure   
  
  
  
  
Date  
 
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I n v esti gat or’s N a me ( Ple ase pri nt)  
A d dress ( Pleas e pri nt): 
 
R E T U R N T H E O RI GI N A L SI G N E D C O P Y T O R E V E R A G E N BI O P H A R M A, I N C. O R 
D E SI G N E E A N D K E E P A X E R O X C O P Y A T Y O U R SI T E. 
 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 4 of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
S E RI O U S A D V E R S E E V E N T C O N T A C T I N F O R M A TI O N 
I n t he e ve nt of a seri o us a d verse e ve nt ( S A E) (see Secti o n 7. 2. 6. 1 ), t he I n vesti g at or 
wil l c o m plete t he S A E electr o nic c ase re p ort f o r m wit hi n 2 4 h o urs of first a w are ness 
of t he e ve nt.  I n t he u nli kel y e ve nt t h at t he electr o nic st u d y d at a b ase is i n accessi ble 
a n d t he I n vesti g at or is u n a ble t o c o m plet e t he S A E electr o nic c as e re p ort f or m 
wit hi n 2 4 h o urs, t he S A E N otific ati o n F or m ( p df) s h o ul d be c o m plete d a n d e m aile d 
or pri nte d/f a xe d t o t he P R A s afet y m a n a ge me nt te a m wit hi n 2 4 h o urs, usi n g t he 
c o nt act i nf or m ati o n bel o w :  
E m ail C H O S afet y @ pr a hs.c o m 
Dr u g S afet y F a x: 1- 8 8 8- 7 7 2- 6 9 1 9 or 1- 4 3 4- 9 5 1- 3 4 8 2 
  
S A E Q uesti o ns: Dr u g S afet y H otli ne: 1- 8 0 0- 7 7 2- 2 2 1 5 or 1 - 4 3 4- 9 5 1- 3 4 8 9 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 5 of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
P R O T O C O L A M E N D M E N T T R A C KI N G 
D oc u me nt  
D oc u me nt N u m ber  
A p pr o v al D ate  
Ori gi nal Pr ot oc ol  
V B P 1 5 -0 0 3  
0 7 Marc h 2 0 1 6  
A me n de d Pr ot oc ol # 1  
V B P 1 5 -0 0 3 -A 1  
3 1  Ma y  2 0 1 6  
Re vise d Pr ot oc ol # 1  
V B P 1 5 -0 0 3 -R 1  
0 1 A u g ust 2 0 1 6  
A me n de d Pr ot oc ol # 2  
V B P 1 5 -0 0 3 -A 2  
2 1 Fe br u ar y 2 0 1 7  
Re vise d Pr ot oc ol # 2  
V B P 1 5 -0 0 3 -R 2  
2 2 Fe br u ar y 2 0 1 7  
N ote: A me n de d pr ot oc ols s h o w all c h a n ges fr o m pre vi o us versi o n i n 
b ol d/stri ke-t hr o u g h f or m at. 
Re as o n f or Re vise d Pr ot oc ol # 2: 
1.  t o i nc or p orate all c ha n ges fr o m A me n de d Pr ot oc ol # 2 i nt o a ne w pr ot oc ol 
d oc u me nt. 
Re as o n s f or A me n de d Pr ot oc ol # 2: 
1.  t o u p date t he n o ncli nical t o xic ol o g y i nf or mati o n wit h res ults of a 2 6- wee k 
t o xic ol o g y st u d y i n mice; 
2.  t o u p date t he st u d y me di cati o n dis pe nsi n g sc he d ule t o reflect a 1 2- wee k s u p pl y t o 
be dis pe nse d at e ac h Treat me nt Peri o d dis pe nsi n g visit;  
3.  t o re m o ve t he re q uire me nt t hat Q Tc m ust be calc ulate d usi n g Fre d ericia’s 
f or m ula;  
4.  t o clarif y t he r ole of t he D S M B i n s afet y dat a re vi e w, i ncl u di n g re m o val of t he 
req uire me nt t hat S A E i nf or mati o n be f or war de d t o t he D S M B wit hi n 2 4 h o urs of 
first a ware ness; 
5.  t o u p date t he bl o o d v ol u mes re q uire d f or cli nical la b orat or y a n d P D bi o mar ker 
a nal ysis; a n d 
6.  t o c orrect t y p o gra p hical err ors. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 6 of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
S T U D Y S Y N O P SI S 
Pr ot oc ol Title  
A  P hase II O pe n-la bel, M ultic e nter E xte nsi o n St u d y t o Assess t he L o n g -ter m 
Safet y  a n d  Efficac y of Va m or ol o ne  i n B o ys wit h D uc he n ne M usc ular 
D ystr o p h y ( D M D)  
Pr ot oc ol N u m ber  
V B P 1 5 -0 0 3  
N a me of S p o ns or  
Re vera Ge n Bi o P har ma , I nc. 
Dr u g S u bst a nce  
delta -1, 4, 9( 1 1) -pre g natrie ne -1 7 -al p ha, 2 1 -di h y dr o x y -1 6 -al p ha -met h yl -3, 2 0 -
di o ne  
I n vesti g ati o n al Dr u g 
Pr o d uct  
Va m or ol o ne , 4 % s us pe nsi o n f or oral d osi n g 
P h ase of 
De v el o p me nt  
P hase II 
I n dic ati o n 
Treat me nt of D uc he n ne m usc ular d ystr o p h y  ( D M D) 
O bjecti ves  
Pri m ary : 
1.  T o e val uate t he 
l o n g-ter m safet y a n d t olera bilit y of va m or ol o ne , 
a d mi nistere d orall y at dail y d oses u p t o 6 . 0 m g/ k g o ver a 
2 4 -wee k 
Treat me nt P eri o d, i n b o ys a ges 4-7  years wit h D M D ;  
2.  T o c o m pare t he efficac y, as meas ure d b y t he T i me t o Sta n d T est 
( T T S T A N D), of va m or ol o ne  a d mi nistere d orall y at dail y d os es u p t o 
6. 0  m g/ k g  o ver a 2 4 -wee k  Treat me nt P eri o d vs. u ntreate d D M D hist orical 
c o ntr ols i n b o ys a ges 4 -7  years wit h D M D; a n d  
3.  T o c o m pare t he safet y, as me as ure d b y b o d y mass i n de x ( B MI) z -sc ore, of 
va m or ol o ne  a d mi nistere d orall y at dail y d oses u p t o 6 . 0 m g/ k g o ver a 
2 4 -wee k  Treat me nt P eri o d vs. pre d nis o ne -treate d hist oric al c o ntr ols i n 
b o ys a ges 4 -7  years wit h D M D . 
Sec o n d ary : 
1.  T o i n vesti gate t he effects of va m or ol o ne , a d mi nistere d ora ll y at dail y d oses 
u p t o 6. 0  m g/ k g  o ver a 2 4 -wee k  Treat me nt P eri o d vs. pre d nis o ne -treate d 
hist orical c o ntr ols , o n ser u m p har mac o d y na mic ( P D) bi o mar kers o f safet y 
(i ns uli n resista nce, a dre nal a xis s u p pressi o n, a n d b o ne t ur n o ver);  
2.  T o i n vesti gate  t he effects of va m or ol o ne , a d mi nistere d orall y at dail y d oses 
u p t o 6. 0  m g/ k g  o ver a 2 4 -wee k  treat me nt peri o d vs. u ntr eate d hist orical 
c o ntr ols, o n ser u m P D bi o mar kers of efficac y (i nfla m mat or y pr otei n 
s u p pressi o n); a n d  
3.  T o i n vesti gate t he effects of va m or ol o ne , a d mi nistere d orall y at dail y d oses 
u p t o 6. 0  m g/ k g  o ver a 2 4 -wee k T reat me nt P eri o d , o n m uscle stre n gt h, 
m o bilit y a n d f u ncti o nal e xercise ca pacit y vs. hist oric al c o ntr ols as 
meas ure d b y Q ua ntitati ve M uscle T esti n g ( Q M T),  Ti me t o R u n/ W al k T est 
( T T R W), N ort h Star A m b ul at or y A ssess me nt ( N S A A), Ti me t o C li m b 
T est ( T T C LI M B) , a n d 6-mi n ute 
Wal k T est ( 6 M W T) i n b o ys a ges 
4 -7  years wit h D M D . 
Ex pl or at ory : 
1.  T o i n vesti gate t he effects of va m or ol o ne  a d mi nistere d orall y at dail y d oses 
u p t o 6. 0  m g/ k g o ver a 2 4 -we e k Treat me nt P er i o d o n a n e xte n de d pa nel of 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 7 of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
P D  bi o mar kers usi n g S o ma Sc a n a pta mer arra ys, a n d pr ote o mic pr ofili n g.  
St u d y Desi g n  
T his P hase II a e xte nsi o n st u d y is a n o pe n -la bel, m ultice nter st u d y t o e val uate 
t he l o n g-ter m safet y, t olera bilit y, cli nical efficac y, a n d P D  of va m or ol o ne  at 
d ose le vels u p t o 6. 0  m g/ k g a d mi nistere d dail y b y li q ui d oral s us pe nsi o n o ver a 
Treat me nt P eri o d of 2 4 wee k s t o b o ys a ges 4-7  years wit h D M D.  S u bj ects w h o 
ha ve c o m plete d t he 
P hase IIa 
V B P 1 5 -0 0 2 
St u d y 
Wee k  4  F oll o w -u p 
assess me nts wit hi n 8 wee ks pri or t o e nr oll me nt are eli gi ble .  
T he st u d y is c o m prise d of a Pretreat me nt Baseli ne P eri o d of u p t o 2 4  h o urs, 
w hic h be gi ns wit h t he si g ni n g of t he e xte nsi o n st u d y -s pecifi c i nf or me d c o nse nt 
f orm (I C F) , a 2 4-wee k Treat me nt P eri o d, a n d a 2 - t o 5-wee k D ose -ta peri n g 
P eri o d f or s u bj ects w h o elect t o tra nsiti o n off va m or ol o ne treat me nt at t he e n d 
of t he st u d y.  
S u bj ects are e nr olle d at t he ti me of I C F si g ni n g.  P are nts or g uar dia ns of 
eli gi ble s u bj ects ma y  pr o vi de 
writte n i nf or me d c o nse nt f or 
V B P 1 5 -0 0 3 
e xte nsi o n st u d y partici pati o n , a n d s u bj ects ma y u n der g o Baseli ne assess me nts, 
at t he fi nal V B P 1 5 -0 0 2 Wee k  4 Visit, f oll o wi n g c o m pleti o n of all V B P 1 5-0 0 2 
W ee k 4 assess me nts .  
Pl a n ne d S a m ple Size  
U p t o a p pr o xi matel y 4 8  s u bj ects w h o c o m plete t he V B P 1 5-0 0 2 c ore st u d y will 
be e nr oll e d; a p pr o xi matel y 1 2 s u bj ects ma y be eli gi ble f or e xte nsi o n st u d y 
d osi n g  at eac h of t he d ose le vels t olerate d i n t he P hase IIa c ore st u d y.   
P o p ul ati o n  
I ncl usi o n Criteri a: 
1.  S u bj ect’s pare nt or le gal g uar dia n has pr o vi de d 
writte n i nf or me d 
c o nse nt/ HI P A A a ut h orizati o n pri or t o a n y e xte nsi o n st u d y-s pecifi c 
pr oce d ures;  
2.  S u bj ect has pre vi o usl y c o m pl ete d st u d y V B P 1 5 -0 0 2 u p t o a n d i ncl u di n g 
t he W ee k 4 F oll o w -u p assess me nts  wit hi n 8 wee ks pri or t o e nr oll me nt ; a n d 
3.  S u bj ect a n d pare nt/ g uar dia n are willi n g  a n d a ble t o c o m pl y wit h sc he d ule d 
visits, st u d y dr u g a d mi nistrati o n pla n, a n d st u d y pr oce d ures.  
E xcl usi o n Criteri a:  
1.  S u bj ect ha d a seri o us or se vere a d verse e ve nt i n st u d y V B P 1 5 -0 0 2 t hat, i n 
t he o pi ni o n of t he I n vesti gat or, was pr o ba bl y or defi nit el y relate d t o 
va m or ol o ne  use a n d precl u des safe use of va m or ol o ne  f or t he s u bj ect i n 
t his st u d y; 
2.  S u bj ect has c urre nt or hist or y of 
maj or re nal or he patic i m pair me nt, 
dia betes mellit us or i m m u n os u p pressi o n;  
3.  S u bj ect has c urre nt or hist or y of c hr o nic s yste mic f u n gal  or viral 
i nfecti o ns; 
4.  S u bj ect has use d mi neral oc ortic oi d rece pt or a ge nts, s uc h as spir o n olact o ne, 
eplere n o ne, ca nre n o ne (ca nr e n oate p otassi u m), p r ore n o ne ( pr ore n oate 
p otassi u m), m e xre n o ne ( me xre n oate p otassi u m) wit hi n 4 wee ks pri or t o 
t he first d ose of st ud y me dicati o n;  
5.  S u bj ect 
has 
e vi de nce 
of 
s y m pt o matic 
car di o m y o p at h y.  [ N ote: 
As y m pt o matic car diac a b n or malit y o n i n vesti gati o n 
w o ul d n ot be 
e xcl usi o nar y];  
6.  S u bj ect is c urre ntl y bei n g tre ate d or has recei ve d pre vi o us treat me nt wit h 
oral gl uc oc ortic oi ds or ot he r i m m u n os u p pressi ve a ge nts.  [ N otes: P ast 
tra nsie nt use of oral gl uc oc ortic oi ds or ot her oral i m m u n os u p pressi ve 
a ge nts f or n o l o n ger t ha n 3 m o nt hs c u m ulati ve, wit h last use at least 
3  m o nt hs pri or t o first d ose of st u d y me dicati o n, will be c o nsi dere d f or 
eli gi bilit y o n a case-b y -case basis.  I n haled  a n d/ or t o pical c ortic oster oi ds 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 8 of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
prescri be d f or  a n i n dicati o n ot her t ha n D M D are per mitt e d b ut m ust be 
a d ministere d at sta ble d ose f or at least 3 m o nt hs pri or t o st u d y dr u g 
a d mi nistrati o n];  
7.  S u bj ect has use d i de be n o ne wit hi n 4 wee ks pri or t o t he first d ose of st u d y 
me dicati o n;  
8.  S u bj ect has a n aller g y or h y perse nsiti vit y t o t he st u d y me dic ati o n or t o a n y 
of its  c o nstit ue nts;  
9.  S u bj ect has se vere be ha vi oral or c o g niti ve pr o ble ms t hat precl u de 
partici pati o n i n t he st u d y,  i n t he o pi ni o n of t he I n vesti gat or; 
1 0.  S u bj ect has pre vi o us or o n g oi n g 
me dical c o n diti o n, 
me dical hist or y, 
p h ysical fi n di n gs or la b orat or y a b n or malities t hat c o ul d affe ct safet y, ma ke 
it u nli kel y t hat treat me nt a n d f oll o w-u p will be c orrectl y c o m plete d or 
i mpair t he assess me nt of st u d y res ults, i n t he o pi ni o n of t he I n vesti gat or;  or  
1 1.  S u bj ect is c urre ntl y ta ki n g a n y i n vesti gati o nal dr u g, or has ta ke n a n y 
i n vesti gati o nal dr u g ot her t ha n va m or ol o ne  wit hi n 3 m o nt hs pri or t o t he 
start of st u d y treat me nt. 
N ote : S u bj ects ma y be re -e val uate d  if i neli gi ble d ue t o a tra nsie nt c o n diti o n 
w hic h w o ul d pre ve nt t he s u bj ect fr o m partici pati n g . 
N u m ber of Ce nters  
T he st u d y wi ll be c o n d ucte d at a p pr o xi matel y 1 0  U nite d States ( U S ) a n d 
n o n -U S  st u d y sites. 
St u d y Peri o d  
First s u bj ec t e nr olle d: 2 Q 2 0 1 6  
Last s u bj ect last visit: 4 Q 2 0 1 7  
St u d y D ur ati o n  
U p t o a p pr o xi mate l y 2 4  m o nt hs  t otal d urati o n 
I n di vi d u al S u bject 
St u d y D ur ati o n  
A p pr o xi matel y  2 4 -2 9  wee ks:  
 
B aseli ne P eri o d: u p t o 2 4 h o urs i m me diatel y pri or t o a d mi nistrati o n of 
first d ose of st u d y me dicatio n i n V B P 1 5 -0 0 3 e xte nsi o n st u d y  
 
Treat me nt P eri o d: 2 4  wee k s 
 
D ose -ta peri n g P eri o d: 2-5 we e ks ( o nl y f or s u bj ects w h o will tra nsiti o n 
off va m or ol o ne at e n d of st u d y)  
St u d y Dr u g 
F or m ul ati o n, D os a ge 
& A d mi nistr ati o n  
Va m or ol o ne  4 % oral s us pe n si o n will be a d mi nistere d o nce dail y o ver a 
2 4 -wee k  Treat me nt 
P eri o d , at the 
f oll o wi n g 
pla n ne d 
d ose le vels: 
0. 2 5  m g/ k g / da y, 0. 7 5  m g/ k g/ da y, 2. 0  m g/ k g / da y, or 6 . 0 m g/ k g / da y.  S u bj ects 
will recei ve va m or ol o ne t hr o u g h o ut t he 2 4-wee k Treat me nt P eri o d i n  t his st u d y 
at t he sa me d ose le vel t he y re cei ved i n t he P hase IIa V B P 1 5 -0 0 2 st u d y.  
S u bj ects w h o elect t o tra nsiti o n off va m or ol o ne treat me nt at t he e n d of t he 
Treat me nt P eri o d 
will recei ve va m or ol o ne f or a n a d diti o nal 1 -4 
wee ks 
acc or di n g t o a d ose -ta peri n g pr ot oc ol f oll o wi n g t he e n d of t he Treat me nt 
P eri o d.  
T he 
W ee k 1 2 a n d 
Wee k 2 4 d oses will be a d mi nistere d at t he st u d y site; all 
ot her d oses, i ncl u di n g t he first d ose a d mi nistere d o n St u d y Da y  1, will be 
a d mi nistere d at h o me u n der t he s u per v isi o n of t he pare nt or g uar dia n .  St u d y 
dr u g will be a d mi nistere d b y  m o ut h usi n g a  v ol u metric s yri n ge .  F oll o wi n g 
a d mi nistrati o n of t he d ose of st u d y dr u g, t he s yri n ge will be fille d o nce wit h 
water a n d t he water will b e a d mi nistere d b y m o ut h usi n g t he v ol u metric 
s yri n ge.  T he su bj ect will t he n dri n k  a p pr o xi matel y 5 0  m L (a p pr o xi matel y 2 
o u nces) of water  t o e ns ure t he f ull d ose has bee n i n geste d.   
T he dail y d ose of st u d y me dicati o n s h o ul d be ta ke n wit h 8 o u nces of w h ole  
mil k.   If w h ole  mil k is n ot t ol era ble t o t he s u bj ect, a ser v i n g of a n ot her hi g h fat 
f o o d ca n be s u bstit ute d. .  T here are n o f o o d or dri n k restricti o ns b ef ore or after 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 9 of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
d osi n g .   
St u d y S u m m a r y  
T his P hase IIa e xte nsi o n st u d y is a n o pe n -la bel, m ulti ple-d os e st u d y t o e val uate 
t he l o n g-ter m safet y, t olera bilit y, efficac y a n d P D of va m or ol o ne a d mi nistere d 
o nce dail y b y li q ui d oral s us pe nsi o n o ver a Treat me nt P eri o d of 2 4  wee ks t o 
b o ys a ges 4 -7  years wit h D M D.   
O nl y s u bj ects w h o ha ve c o m plete d P hase IIa c ore st u d y V B P 1 5-0 0 2 Wee k  4 
F oll o w -u p Visit assess me nts will be eli g i ble f or partici pati o n i n t his o pe n-la bel 
e xte nsi o n st u d y.  P artici pati o n i n t his e xte nsi o n st u d y will be disc usse d wit h t he 
s u bj ect’s pare nt or g uar dia n pri or t o t he V B P 1 5 -0 0 2 Wee k 4 Visit.  Sta n dar d of 
care treat me nt ( gl uc o c orticoi ds) f or D M D 
ma y be offe r e d t o t he s u bj ect 
f oll o wi n g c o m pleti o n of t he P hase IIa V B P 1 5-0 0 2 st u d y, if t he s u bj ect’s pare nt 
or g uar dia n d oes n ot wis h t o e nr oll t he s u bj ect i n t he e xte nsi o n st u d y a n d/ or t he 
I n vesti gat or feels it t o be i n t he best i nterest of t he s u bj ect.  A t otal of u p t o 
a p pr o xi matel y 4 8  s u bj ects will be e nr olle d i nt o t his e xte nsi o n st u d y.  
T he pare nts or le gal g uar dia ns of s u bj ects w h o c h o ose t o e nr oll i n t his 
e xte nsi o n st u d y will gi ve writte n i nf or me d c o nse nt f or t he e xte nsi o n st u d y at 
t he V B P 1 5-0 0 3 Baseli ne Da y -1  Visit.  T he Baseli ne Da y -1 Visit, i ncl u di n g 
si g ni n g of t he I C F, ma y occ ur at t he c o ncl usi o n of t he V B P 1 5 -0 0 2 
Wee k  4 
Visit f oll o wi n g c o m pleti o n of all 
Wee k 4 assess me nts; a lter nati vel y, t he 
B aseli ne Da y -1 Visit a n d V B P 1 5 -0 0 3 -s pecific I C F si g ni n g ma y occ ur u p t o 8 
wee ks after t he  date of  t he fi nal V B P 1 5-0 0 2 Wee k 4 Visit, at t he c o n ve nie nce 
of t he s u bj ect’s pare nt or le gal g uar dia n a n d discreti o n of t he I n vesti gat or.  
S u bj ects are c o nsi dere d t o be e nr olle d i n t he V B P 1 5 -0 0 3 e xte nsi o n st u d y after 
t he pare nt o r g uar dia n has si g ne d t he V B P 1 5-0 0 3 -s pecific I C F at t he Baseli ne 
Da y  -1 Visit.  Eac h s u bj ect will retai n t he st u d y i de ntificati o n n u m ber assi g ne d 
t o hi m at t he start of t he P hase IIa c ore st u d y. 
F or s u bj ects w h o e nr oll i n t he V B P 1 5 -0 0 3 e xte nsi o n st u d y wit h i n 2 8 da ys after 
c o m pleti o n of all fi nal V B P 1 5 -0 0 2 Wee k 4 assess me nts, ma n y of t he safet y, 
efficac y, a n d P D assess me nts perf or me d f or t he V B P 1 5 -0 0 2 st u d y at t he fi nal 
W ee k  4 Visit will be use d t o deter mi ne e xte nsi o n st u d y eli gi bilit y or t o pr o vi de 
baseli ne  st u d y data f or t he e xt e nsi o n st u d y a n d d o n ot nee d t o be re peate d at t he 
V B P 1 5 -0 0 3 Baseli ne Visit.  F or t hese s u bj e cts, a d diti o nal e xte nsi o n st u d y  
pr oce d ures will still be perf or me d at t he Baseli ne Da y  -1 Visit, wit hi n 2 4 h o urs 
pri or t o a d mi nistrati o n of t he first d ose of st u d y dr u g i n t he e xte nsi o n st u d y.  
S u bj ects w h o e nr oll i n t he V B P 1 5-0 0 3 e xte nsi o n st u d y > 2 8 da ys after t he date 
of t he fi nal V B P 1 5 -0 0 2 Wee k  4 Visit m ust ha ve all sc he d ul e d Baseli ne Da y  -1 
assess me nts perf or me d.  
S u bj ects 
will be gi n d osi n g  i n t his st u d y o n St u d y 
Da y 1 at t he sa me 
va m or ol o ne d ose le vel t he y re cei ve d i n t he P hase IIa c ore st u d y.  S u bj ects will 
c o nti n ue t o recei ve va m or ol o ne at t he d ose recei ve d i n t he P hase IIa c ore st u d y 
f or t he d urati o n of t he 2 4 -wee k Treat me nt P eri o d, u nl e ss ne w safet y data 
i n dicate t he d ose le vel s h o ul d be de-escalate d.   
T he pla n ne d d ose le vels are 0. 2 5  m g / k g ( D ose Le vel Gr o u p 1), 0. 7 5  m g/ k g 
( D ose Le vel 2), 2. 0  m g/ k g ( D ose Le vel Gr o u p 3 ), a n d 6 . 0 m g/ k g ( D ose Le vel 
Gr o u p  4).  A t otal of a p pr o xi matel y 4 8  s ubj ects will be e nr olle d; a  ma xi m u m of 
1 2 s u bj ects ma y be eli gi ble f or e xte nsi o n st u d y d osi n g  at eac h of t he d ose 
le vels t olerate d i n t he P hase II a st u d y.   
If d ose li miti n g t o xicities ar e i de ntifie d i n t he P hase IIa c ore st u d y w hic h 
precl u de c o nfir mati o n o f safet y of  all f o ur pla n ne d d ose le vels, t he d ose le vels 
i n t his e xte nsi o n st u d y will be m o difie d, as nee de d. 
I n t he e ve nt an y cli nical o bser vati o n s u g gests a n i nt olera bilit y f or a n i n di vi d ual 
s u bj ect t o t he st u d y me dicati o n, i n t he o pi ni o n of t he I n vesti gat or, t he s u bj ect’s 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 0  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
d ose le vel ma y be decrease d t o t he ne xt l o wer d ose le vel (e. g., a s u bj ect ta ki n g 
6 . 0 m g/ k g/ da y decrease d t o 2. 0  m g/ k g/ da y) a n d mai ntai ne d at t hat l o wer d ose 
le vel t hr o u g h o ut t he d urati o n of t he Treat me nt P eri o d .  I n t he e ve nt t he ne xt 
l o wer d ose le vel is als o n ot t olerate d a n d is c o nsi dere d a safet y ris k t o t he 
s u bj ect, i n t he o pi ni o n of t he I n vesti gat or, St u d y C hair, a n d Me dical M o nit or,  
t he s u bj ect s h o ul d be wit h dra w n fr o m t he st u d y.   
S u bj ects will be assesse d f or s afet y a n d t olera bi lit y, cli nical efficac y, a n d P D at 
sc he d ule d visits t hr o u g h o ut t he 2 4-wee k Treat me nt P eri o d.  Treat me nt P eri o d 
st u d y visits will occ ur at 
Wee k 2, 
Wee k  4, a n d e ver y 4 wee ks t hereafter 
t hr o u g h 
Wee k 2 4 .  A d verse e ve nts ( A Es), i ncl u di n g seri o us a d verse e ve nts 
(S A Es ), a n d c o nc o mita nt me dicati o ns will be rec or de d t hr o u g h o ut t he st u d y.   
O nce dail y Treat me nt P eri o d st u d y dr u g d osi n g will occ ur fr o m Da y  1 u ntil t he 
W ee k  2 4 Visit.  St u d y dr u g d osi n g will occ ur at h o me o n all da ys e xce pt t he 
da ys of t he Wee k 1 2 a n d W ee k 2 4 Visits, w he n d osi n g will occ ur at t he st u d y 
site.   
S u bj ect diaries will be dis pe nse d at Baseli ne Da y -1 a n d at eac h m o nt hl y st u d y 
visit t o rec or d A Es a n d c o nc o mita nt me dicati o ns ta ke n d uri n g t he st u d y.  
All s u bj ects will ret ur n t o t he cli nical site f or Wee k 2 4 assess me nts.  F oll o wi n g 
c o m pleti o n of t he 2 4 -wee k Treat me nt P eri o d, s u bj ects ma y be offere d f urt her 
e xte n de d treat me nt wit h va m or ol o ne i n a se parate e xte nsi o n st u d y, or s witc h t o 
sta n dar d of care treat me nt (e. g., gl uc oc ortic oids) f or 
D M D, as de e me d 
a p pr o priate f or eac h s u bj ect.  Alter nati vel y, s u bj ects ma y c h o ose t o disc o nti n ue 
va m or ol o ne a n d n ot be gi n sta n dar d of care gl uc oc ortic oi d treat me nt f or D M D.  
S u bj ects w h o s witc h t o sta n dar d of care gl uc o c ortic oi ds f or  D M D or w h o 
disc o nti n ue treat me nt will partici pate i n a D ose -ta peri n g P eri o d of 2-5 wee ks i n 
d urati o n, f oll o wi n g t he e n d of t he Treat me nt P eri o d a n d pri or t o disc har ge fr o m 
t he st u d y; s u bj ects w h o elect t o recei ve f urt her va m or ol o ne treat me nt will be 
disc har ge d fr o m t he V B P -0 0 3 st u d y after  c o m pleti o n of fi nal V B P -0 0 3 st u d y 
assess me nts at t he Wee k 2 4 Visit, pri or t o e nr oll me nt i n a s u bse q ue nt e xte nsi o n 
st u d y.  S u bj ects will be disc har ge d fr o m t he st u d y f oll o wi n g c o m pleti o n of all 
fi nal W ee k 2 4 or D ose -ta peri n g P eri o d assess me nts , as a p pr o priate.   
I n t he e ve nt t hat a n y cli nical or la b orat or y para meters re mai n a b n or mal at t he 
ti me of disc har ge fr o m t he st u d y, t he s u bj ect will be f oll o we d me dicall y as 
cli nicall y i n dicate d.  A n y s u bj ect w h o disc o nti n ues t he st u d y pri or t o t he 
W ee k  2 4 Visit s h o ul d ret ur n t o t he st u d y u nit f or fi nal 
Wee k  2 4 safet y a n d 
efficac y assess me nts at t he ti me of earl y disc o nti n uati o n.  
S afet y M e as ures  
 
P h ysical e xa mi nati o n  
 
W ei g ht  
 
B o d y Mass I n de x ( B MI)   
 
Vital si g ns (s u pi ne bl o o d press ure, heart rate , res pirat or y rate, oral 
te m perat ure) 
 
Cli nical la b orat or y tests  
o  H e mat ol o g y a n d bi oc he mistr y   
o  Uri nal ysis  ( b y di pstic k a n d mi cr osc o pic a nal ysis ) 
o  Li pi d pr ofile (tri gl yceri des, t otal c h olester ol, l o w de nsit y li p o pr otei n 
[L D L ], hi g h de nsit y li p o pr otei n [ H D L ]) 
 
1 2 -lea d electr ocar di o gra m (E C G ) 
 
Cli nical si g ns a n d s y m pt o ms ( A Es a n d S A Es)  
 
Gra di n g of cli nical a n d cli nic al la b orat or y A Es  will be acc or di n g t o t he 
C o m m o n T er mi n ol o g y Criteri a f or A d verse E ve nts  (C T C A E ), v 4. 0. 3  
P h ar m ac o d y n a mic 
M e as ures  
 
Bl o o d will be dra w n f or a ser u m P D bi o mar ke r pa nel at Da y -1, Wee k 8, 
W ee k 1 2, Wee k 1 6,  Wee k 2 4 , a n d at t he e n d of t he D ose-ta peri n g P eri o d, 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 1  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
if a p plica ble, t o e x pl ore t he effect of va m or ol o ne  o n bi o mar kers of 
a dre nal a xis s u p pressi o n, b o ne t ur n o ver, a n d i ns uli n resista nce. 
Cli nic al Effic ac y  
M e as ur es  
 
Q ua ntitati ve M uscle T esti n g ( Q M T)  
 
Ti me t o Sta n d T est ( T T S T A N D)  
 
Ti me t o Cli m b T est ( T T C LI M B)  
 
Ti me t o R u n/ Wal k  T est ( T T R W)  
 
N ort h Star A m b ulat or y Assess me nt ( N S A A)  
 
Si x -mi n ute Wal k  T est ( 6 M W T)  
E x pl or at or y 
M e as ures   
 
Meas ures of ser u m pr otei ns ( S o ma Sca n a pta mer pa nel; pr ote o mics 
pr ofili n g)  
St atistic al M et h o ds  
S a m ple Size:  
T his is a n o pe n -la bel e xte nsi o n st u d y wit h n o place b o ar m.  Hist orical c o ntr ol 
data are a vaila ble f or t he sa me a ge ra n ge ( 4 -7 years), lar gel y c ollecte d at t he 
sa me st u d y sites, wit h t he sa me o utc o me meas ures.  U ntre ate d nat ural hist or y 
c o ntr ol p o p ulati o n data are fr o m t he o n g oi n g 
C o o perati ve I nter nati o nal 
Ne ur o m usc ular Researc h Gr o u p (CI N R G ) D uc he n ne Nat ural Hist or y St u d y of 
a p pr o xi matel y 4 0 0 D M D b o ys.  Pre d nis o ne -treate d hist orical c o ntr ol data are 
fr o m a cli nical trial of pre d nis o ne carrie d o ut b y t he CI N R G gr o u p ( CI N R G 
Pre d nis o ne st u d y) .  V a m or ol o ne is a d mi nistere d dail y i n t his P hase IIa 
e xte nsi o n trial.  T o m ore acc uratel y deter mi ne t he sa m pl e size necessar y t o 
detect a gl uc oc ortic oi d ef fect o n efficac y, sa m ple size calc ulati o ns were li mite d 
t o t he dail y pre d nis o ne tre at me nt ar m of t he CI N R G Pre d nis o ne st u d y 
( n =  1 1 -1 3), at 6 or 1 2 
m o nt hs, f or t hree cli nical efficac y o utc o mes 
( T T S T A N D, T T R W, T T C LI M B) (S y n o psis T a ble 1 ).  S a m ple size was als o 
calc ulate d ass u mi n g t he o bser ve d effect of va m or ol o ne was 1 0 0 %, 8 0 % or 6 0 % 
of t hat o bser ve d wit h dail y gl uc oc ortic oi ds ( S y n o psis T a ble 1 ).   
T he pri mar y p har mac ol o gic al safet y o utc o me pr o p ose d i n t he P hase IIa 
exte nsi o n trial is c ha n ge i n B MI  z-sc ore.  Dail y gl uc oc ortic oi ds s h o w a 
relati vel y  ra pi d  i ncrease  i n  
B MI  
z-sc ore 
( 6-m o nt h 
c ha n ge  i n 
n o n -treate d =  -0. 1 4; 6 -m o nt h c ha n ge i n pre d nis o ne -treate d =  + 0. 5 4) ( S y n o psis 
T a ble 1 ).  Va m or ol o ne is n ot a ntici pate d t o s h o w a n i ncreas e i n B MI. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 2  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
 
S y n o psis T a ble 1.  6 -m o nt h  a n d 1 2 -m o nt h c h a n ges i n o utc o mes i n 
4 -< 7  ye a rs ol d ( at st u d y st art).   
 
N otes:  a) Data f or u ntreate d s u bjects fr o m t h e CI N R G  D uc he n ne Nat ural Hist or y 
St u d y; data f or pre d nis o ne -treate d s u bjects fr o m t h e CI N R G Pre d nis o ne 
st u d y.   
b) All c o m paris o ns are of dail y d ose pre d nis o ne -treate d patie nts t o u ntreate d 
patie nts.  
c) All calc ulati o ns  ass u me a re pe ate d meas ures A N O V A m o del wit h o ne pre -
a n d o ne p ost -meas ure me nt.  C orrelati o n bet wee n re peate d meas ures  was  use d 
as f oll o ws:  0. 7 5 f or hei g ht c ha n ges, 0. 7 0 f or 6 m o nt h B MI c ha n ges, a n d 0. 6 5 
f or 1 2 m o nt h B MI z-sc ore c ha n ges, a n d 0. 5 7 5 f or 6 a n d 1 2 m o nt h vel o cit y 
c ha n ges.  P o wer  =  0. 8 0 a n d al p ha  =  0. 0 2 5 f or all calc ulati o ns t o acc o u nt f or 
m ulti ple gr o u p c o m paris o ns (i.e. t w o va m or ol o ne  d oses, eac h c o m pare d  t o 
pre d nis o ne f or safet y a n d place b o f or effic ac y).  
^ C o nser vati ve c ha n ge esti mat es wer e defi n e d as f oll o ws: F or B MI  z-sc ore, t he 
e x pecte d c ha n ge i n va m or ol o ne  was set t o 0. 0 rat h er t h a n t h e o bser ve d decre ase.  F or 
ti me d tests, t h e e x pecte d c ha n ge i n va m o r ol o ne was set t o 8 0 % of t h e o bser ve d c ha n ge 
i n t he pre d nis o ne gr o u p.   
^ ^ C o nser vati ve c ha n ge esti mates were defi n e d as f oll o ws: F or ti me d tests, t h e e x pecte d 
c ha n ge i n va m or ol o ne  was set t o 6 0 % of t h e o bser ve d c ha n ge i n t h e pre d nis o ne gr o u p 
( wit h S D at 80 %).  
A n al ysis P o p ul ati o ns:   
All a nal yses will be base d o n t he act ual treat me nt eac h s u bj ect recei ve d.  F o ur  
p o p ulati o ns will be defi ne d f or data a nal ysis: t he Safet y P o p ulati o n , t he F ull 
A nal ysis Set , t he co ntr ol p o p ulati o n CI N R G D uc he n ne Nat ural Hist or y  S t u d y, 
a n d t he co ntr ol p o p ulati o n CI N R G P re d nis o ne st u d y. 
Safet y P o p ulati o n  
All s u bj ects w h o recei ve at le ast o ne d ose of va m or ol o ne  st u d y me dicati o n i n 
t he e xte nsi o n st u d y will be i ncl u de d i n t he Safet y P o p ulati o n.  T he Safet y 
P o p ulati o n is t he pri mar y a nal ysis p o p ulati o n f or safet y assess me nts.   T his is 
als o t he m o difie d I nte nti o n t o Treat ( mI T T) p o p ulati o n. 
F ull A nal ysis Set ( F A S)  
All s u bj ects w h o recei ve at le ast o ne d ose of va m or ol o ne  st u d y me dicati o n i n 
t he e xte nsi o n st u d y a n d ha ve at least o ne p ost-b aseli ne assess me nt will be 
i ncl u de d i n t he F A S.  T he F A S is t he pri mar y a nal ysis p o p ulati o n f or cli nical 
efficac y a n d P D assess me nts.   T his is t he mI T T p o p ulati o n, wit h t he a d diti o nal 
restricti o n of ha vi n g at least o ne p ost-baseli ne assess me nt.   S u bj ects w h o 
recei ve at least o ne d ose o f va m or ol o ne b ut ne ver ha ve p ost-baseli ne 
assess me nts will be e xcl u de d.   
C o ntr ol P o p ulati o n CI N R G D uc he n ne Nat ural Hist or y  S t u d y 
T he c o ntr ol p o p ulati o n fr o m t he CI N R G D uc he n ne Nat ural Hist or y S t u d y will 
i ncl u de all s u bj ects wh o were o bser ve d as part of t he st u d y i n a ges ≥ 4 years 
a n d < 7 years of a ge at a start of a n i nter val of o bser vati o n ; o bser ve d f or at least 
o ne year  wit h  at least t w o visits i n a ti me i nter val of n o m ore t ha n 1 5 m o nt hs  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 3  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
wit h T T S T A N D, T T C LI M B, T T R W, N S A A, 6 M W T a n d Q M T meas ure d; 
re mai ne d gl uc oc ortic oi d-nai ve d uri n g t he e ntire o bser vati o n peri o d; a n d w ere  
a ble t o wal k i n de pe n de n tl y wit h o ut assisti ve de vices, a b le t o c o m plete t he 
T T S T A N D ; a n d lac ke d a n y hist or y of disease , i m pair me nt, or me dicati o ns t hat 
w o ul d h a ve ma de t he m i neli gi ble t o recei ve t he va m or ol o ne i nter ve nti o n as 
defi ne d b y t he  P hase IIa  st u d y e xcl usi o n criteria  at t he start of t he i nter val .  
C o ntr ol P o p ulati o n CI N R G Pre d nis o ne St u d y  
T he c o ntr ol p o p ulati o n fr o m t he CI N R G P re d nis o ne st u d y will i ncl u de all 
s u bj ects w h o were y o u n ger t ha n 7 years ol d at e ntr y a n d w h o were ra n d o mize d 
t o t he dail y pre d nis o ne  ar m.  
Ge ner al St atistic al C o nsi der ati o ns :   
All meas ure me nts will be a nal yze d base d u p o n t he t y pe of distri b uti o n a n d 
descri pti ve statistics prese nt e d b y treat me nt gr o u p a n d ti me p oi nt, as 
a p pr o priate.  N o i nteri m statistical a nal yses are pla n ne d.  Missi n g val ues f or 
safet y a n d e x pl orat or y o utc o mes will be treate d as missi n g.   
B aseli ne meas ure me nt is defi ne d as t he last n o n -missi n g val ue pri or t o t he fi rst 
d ose of st u d y dr u g i n t he e xte nsi o n st u d y.   
Effic ac y  A n al yses:  
T he pri mar y efficac y o utc o me is T T S T A N D .  Sec o n dar y efficac y o utc o mes are 
t he N S A A assess me nt, T T C LI M B, T T R W, Q M T , a n d t he 6 M W T .  T he 
pri mar y o utc o me 
will be c o m pare d bet wee n va m or ol o ne  a n d  hist orical 
u ntreate d c o ntr ols usi n g a mi xe d -effects li near m o del wit h treat me nt gr o u p.  
A ge at st u d y e ntr y will be i ncl u de d as a c o variate.  T he i nitial m o del will 
c o m bi ne va m or ol o ne  d oses a n d a s u bse q ue nt sec o n dar y m o del will l o o k at eac h 
d ose i n c o m pari s o n t o u ntreate d nat ural hi st or y c o ntr ols.  T his will all o w t he 
testi n g of w het her va m or ol o ne  i n ge neral a n d va m or ol o ne  at i n di vi d ual d oses 
ha ve si g nifica nt effects o n t he sl o pe of t he vel ocit y.  A d diti o nal h y p ot heses of 
efficac y will i ncl u de si milar li nea r m o delli n g wit h t he se c o n dar y o utc o mes.  
T he y will als o i ncl u de c o m paris o n gr o u ps i ncl u di n g pr e d nis o ne -treate d or 
u ntreate d nat ural hist or y c o ntr ols.  
P h ar m ac o d y n a mics A n al yses:  
Ser u m P D bi o mar kers of a dre nal  a xis s u p pressi o n, i ns uli n resista nce, a n d b o ne  
t ur n o ver will be assesse d.  L o n git u di nal a nal ysis of P D bi o mar kers will be 
st u die d as a f u ncti o n of treat me nt, wit h c o m paris o n t o pre d nis o ne -treate d a n d 
u ntreate d hist orical c o ntr ols , as a p pr o priate.   
S afet y  A n al yses:  
All e val uati o ns of cli nical safet y w ill be liste d wit h descri pti ve statistics b y 
treat me nt gr o u p prese nte d.  T he pri mar y safet y varia ble will be B MI z-sc ore 
a n d will be assesse d usi n g t he sa me t y pe of statistical m o dels use d f or efficac y.  
A d diti o nal sec o n dar y safet y data will i ncl u de hei g ht  z -sc ore, bl o o d press ure, 
a n d E C G res ults.  As n o c ha n ge i n bl o o d press ure or car diac res ults  is e x pecte d, 
t hese data will be a nal yze d usi n g a n a nal ysis of c o varia nce ( A N C O V A) 
a p pr oac h 
w hic h i ncl u des t he baseli ne val ue f or eac h 
meas ure me nt as a 
c o variate.  C ha n ges i n hei g ht z -sc ores, f or w hic h a n o bser ve d c ha n ge is 
e x pecte d , will be m o del le d usi n g a li near mi xe d effects m o del.  C o nti n u o us, 
q ua ntitati ve la b orat or y val ues will be a nal yze d si milar t o B MI z -sc ores.  
Cate g orize d la b orat or y val ues a n d prese nce or  a bse nc e of 
A Es 
will be 
c o m pare d usi n g a n e xact c hi -s q uare test.  A d verse e ve nts  will be s u m marize d 
o verall a n d b y d ose le vel, s yste m or ga n class ( S O C) a n d preferre d ter m ( usi n g 
t he Me dical Dicti onar y f or Re g ulat or y Acti vities [ Me d D R A ]); b y d ose le vel 
a n d relati o ns hi p t o st u d y me dicati o n;  a n d b y d ose le vel a n d i nte nsit y ( C T C A E 
gra d e).  A d diti o nal h y p ot heses of safet y will i ncl u de si mil ar li near m o delli n g 
wit h t he sec o n dar y a n d e x pl orat or y o utc o mes.   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 4  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
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 T R A C KI N G.................................................................... 5  
S T U D Y S Y N O P SI S ................................ ........................................................................... 6 
LI S T O F T A B L E S ................................ ........................................................................... 1 8 
LI S T O F FI G U R E S ................................ ......................................................................... 1 9 
LI S T O F A B B R E VI A TI O N S ......................................................................................... 2 0  
1  
I N T R O D U C TI O N................................................................................................... 2 4 
1. 1  B A C K G R O U N D A N D U N M E T N E E D ........................................................................ 2 4 
1. 2  N O N C LI NI C A L E X P E RI E N C E  ................................................................................. 2 6 
1. 2. 1  
S afety P h ar m ac ol o gy ................................................................................ 2 6  
1. 2. 2  
P h ar m ac o ki netics a n d Met a b olis m .......................................................... 2 8  
1. 2. 3  
T o xic ol o gy ................................................................................................. 3 2  
1. 3  C LI NI C A L E X P E RI E N C E  ........................................................................................ 4 2 
1. 3. 1  
P h ase I St u dy i n He alt hy A d ult V ol u nteers ............................................. 4 2  
1. 4  R A TI O N A L E F O R S T U D Y D E SI G N .......................................................................... 5 5 
1. 5  O V E R A L L B E N E FI T / RI S K ..................................................................................... 5 7 
2  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S ......................................................... 5 8  
2. 1  S T U D Y O B J E C TI V E S  .............................................................................................. 5 8 
2. 1. 1  
Pri m ary O bjectives .................................................................................... 5 8  
2. 1. 2  
Sec o n d ary O bjectives ................................................................................ 5 9  
2. 1. 3  
E x pl or at ory O bjective ............................................................................... 5 9  
2. 1. 4  
A ncill ary St u dy .......................................................................................... 5 9  
2. 2  S T U D Y E N D P OI N T S  ............................................................................................... 6 0 
2. 2 . 1 
S afety E n d p oi nts ....................................................................................... 6 0  
2. 2. 2  
Cli nic al Effic acy E n d p oi nts ...................................................................... 6 1  
2. 2. 3  
P h ar m ac o dy n a mic E n d p oi nts................................................................... 6 2  
2. 2. 4  
E x pl or at ory E n d p oi nts .............................................................................. 6 2  
2. 2. 5  
E n d p oi nts f or S u bject Re p orte d O utc o m es .............................................. 6 2  
3  
S T U D Y D E SI G N ..................................................................................................... 6 2  
3. 1  O V E R A L L S T U D Y D E SI G N  .................................................................................... 6 2 
3. 2  S T U D Y S U M M A R Y  ................................................................................................. 6 5 
4  
S E L E C TI O N A N D WI T H D R A W A L O F S T U D Y S U B J E C T S ......................... 6 6  
4. 1  S U B J E C T S C R E E NI N G , E N R O L L M E N T , A N D ID E N TI FI C A TI O N L O G  ..................... 6 6 
4. 2  IN C L U SI O N C RI T E RI A  ........................................................................................... 6 6 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 5  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
4. 3  E X C L U SI O N C RI T E RI A  .......................................................................................... 6 7 
4. 4  W
I T H D R A W A L O F S U B J E C T S F R O M S T U D Y  ......................................................... 6 8 
4. 5  R E P L A C E M E N T O F W
I T H D R A W N S U B J E C T S  ........................................................ 6 9 
4. 6  T E R MI N A TI O N O F S T U D Y  ..................................................................................... 6 9 
5  
T R E A T M E N T O F S T U D Y S U B J E C T S .............................................................. 7 0  
5. 1  S T U D Y M
E DI C A TI O N A D MI NI S T E R E D  .................................................................. 7 0 
5. 2  ID E N TI T Y O F IN V E S TI G A TI O N A L P R O D U C T  ......................................................... 7 0 
5. 3  D O S A G E S C H E D U L E A N D A D MI NI S T R A TI O N O F S T U D Y M
E DI C A TI O N  ................ 7 0 
5. 4  R A TI O N A L E F O R D O S E S E L E C TI O N  ..................................................................... 7 2 
5. 5  T R E A T M E N T C O M P LI A N C E  .................................................................................. 7 3 
5. 6  S T U D Y D R U G  D O S E IN T E R R U P TI O N , D E -E S C A L A TI O N , O R D I S C O N TI N U A TI O N . 7 3 
5. 7  P RI O R A N D C O N C O MI T A N T M
E DI C A TI O N S A N D T H E R A PI E S  .............................. 7 4 
5. 7. 1  
Pri or T her a py ............................................................................................ 7 4  
5. 7. 2  
C o nc o mit a nt T her a py ............................................................................... 7 4  
5. 7. 3  
Pr o hi bite d T her a pies ................................................................................. 7 5  
5. 7. 4  
Per mitte d T her a pies .................................................................................. 7 5  
5. 8  S T U D Y M
E DI C A TI O N M
A N A G E M E N T  ................................................................... 7 6 
5. 8. 1  
P ac k a gi n g a n d L a beli n g of St u dy Me dic ati o n ......................................... 7 6  
5. 8. 2  
St or a ge of St u dy Me dic ati o n..................................................................... 7 7  
5. 8. 3  
St u dy Me dic ati o n S hi p pi n g a n d H a n dli n g ............................................... 7 7  
5. 8. 4  
St u dy Me dic ati o n Acc o u nt a bility.............................................................. 7 8  
5. 9  P R O C E D U R E S F O R A S SI G NI N G S U B J E C T S T U D Y N U M B E R S  ................................. 7 8 
6  
S T U D Y S C H E D U L E .............................................................................................. 7 9  
6. 1  T I M E A N D E V E N T S S C H E D U L E  ............................................................................. 7 9 
6. 2  IN F O R M E D C O N S E N T / HI P A A A U T H O RI Z A TI O N  ................................................. 8 3 
6. 3  V I SI T S C H E D U L E A N D P R O C E D U R E S  .................................................................... 8 4 
6. 3. 1  
B aseli ne Peri o d ( D ay - 1) ........................................................................... 8 4  
6. 3. 2  
Tre at m e nt Peri o d D ay 1 ............................................................................ 8 7  
6. 3. 3  
Tre at m e nt Peri o d Wee ks 2- 2 4................................................................... 8 7  
6. 3. 4  
D ose T a peri n g Peri o d ( Wee ks 2 5- 2 9) ....................................................... 8 9  
6. 4  S U B J E C T D IS C O N TI N U A TI O N  ................................................................................ 9 0 
6. 5  S T U D Y C O M P L E TI O N  ............................................................................................ 9 0 
7  
S T U D Y A S S E S S M E N T S A N D M E A S U R E M E N T S .......................................... 9 0  
7. 1  D E M O G R A P HI C A S S E S S M E N T S  ............................................................................. 9 0 
7. 2  S A F E T Y A N D T O L E R A BI LI T Y A S S E S S M E N T S  ........................................................ 9 1 
7. 2. 1  
I nteri m Me dic al Hist ory............................................................................ 9 1 
7. 2. 2  
P hysic al E x a mi n ati o n, Wei g ht, a n d Hei g ht ............................................. 9 1  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 6  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
7. 2. 3  
Vit al Si g ns ................................................................................................. 9 2  
7. 2. 4  
Cli nic al L a b or at ory Tests.......................................................................... 9 2  
7. 2. 5  
1 2- Le a d E C G ............................................................................................. 9 5  
7. 2. 6  
A dverse Eve nts a n d Seri o us A dverse Eve nts ........................................... 9 6  
7. 2. 7  
St u dy Me dic ati o n Acce pt a bility Assess m e nt .......................................... 1 0 3  
7. 3  C LI NI C A L E F F I C A C Y A N D P H A R M A C O D Y N A MI C A S S E S S M E N T S  ...................... 1 0 4 
7. 3. 1  
Q u a ntit ative M uscle Testi n g ( Q M T) ...................................................... 1 0 4  
7. 3. 2  
Ti m e t o St a n d Test ( T T S T A N D) ............................................................. 1 0 4  
7. 3. 3  
Ti m e t o Cli m b Test ( T T C LI M B) ............................................................. 1 0 4  
7. 3. 4  
Ti m e t o R u n/ W al k Test ( T T R W) ............................................................ 1 0 5  
7. 3. 5  
N ort h St ar A m b ul at ory Assess m e nt ( N S A A) ......................................... 1 0 5  
7. 3. 6  
Si x- mi n ute W al k Test ( 6 M W T)............................................................... 1 0 6  
7. 3. 7  
P h ar m ac o dy n a mic Bi o m ar k er P a nel ..................................................... 1 0 6  
7. 3. 8  
Pe di atric O utc o m es D at a C ollecti o n I nstr u m e nt ................................... 1 0 7  
7. 4  T O T A L B L O O D V O L U M E R E Q UI R E D  .................................................................. 1 0 8 
8  
D A T A C O L L E C TI O N ......................................................................................... 1 0 8  
8. 1  S O U R C E D O C U M E N T S  ......................................................................................... 1 0 8 
8. 2  E L E C T R O NI C C A S E  R E P O R T F O R M C O M P L E TI O N  ............................................ 1 0 9 
8. 3  D A T A P R O C E S SI N G  ............................................................................................. 1 1 0 
8. 4  S U B J E C T D IA RI E S  ............................................................................................... 1 1 0 
9  
S T A TI S TI C A L M E T H O D S A N D P L A N N E D A N A L Y S E S ............................ 1 1 0  
9. 1  S A M P L E S IZ E D E T E R MI N A TI O N  ......................................................................... 1 1 0 
9. 2  S T A TI S TI C A L A N D A N A L Y TI C A L P L A N ( S A P) ................................................... 1 1 2 
9. 2. 1  
Devi ati o ns fr o m t he St atistic al A n alysis Pl a n ........................................ 1 1 2  
9. 3  A N A L Y SI S P O P U L A TI O N S .................................................................................... 1 1 3 
9. 3. 1  
S afety P o p ul ati o n .................................................................................... 1 1 3  
9. 3. 2  
F ull A n alysis Set ( F A S) .......................................................................... 1 1 3  
9. 3. 3  
C o ntr ol P o p ul ati o n D N H S St u dy ........................................................... 1 1 3  
9. 3. 4  
C o ntr ol P o p ul ati o n Pre d nis o ne St u dy .................................................... 1 1 4  
9. 4  M
E A S U R E S T A K E N T O A V OI D / MI NI MI Z E B I A S ................................................. 1 1 4 
9. 5  IN T E RI M A N A L Y S I S ............................................................................................ 1 1 4 
9. 6  M
I S SI N G, U N U S E D , A N D S P U RI O U S D A T A  .......................................................... 1 1 4 
9. 7  S T A TI S TI C A L A N A L Y S I S ..................................................................................... 1 1 4 
9. 7. 1  
Ge ner al C o nsi der ati o ns .......................................................................... 1 1 4  
9. 7. 2  
S u bject Dis p ositi o n, De m o gr a p hics, a n d B aseli ne C h ar acteristics ...... 1 1 5  
9. 7. 3  
S afety A n alyses ........................................................................................ 1 1 5  
9. 7. 4  
Cli nic al Effic acy a n d P h ar m ac o dy n a mic A n alyses ............................... 1 1 6  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 7  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
9. 7. 5  
C o nc urre nt Me dic ati o ns ......................................................................... 1 1 7  
1 0  
S T U D Y M A N A G E M E N T A N D E T HI C A L A N D R E G U L A T O R Y 
R E Q UI R E M E N T S................................................................................................ 1 1 7  
1 0. 1  R E G U L A T O R Y A P P R O V A L A N D G O O D C LI NI C A L P R A C TI C E  ............................ 1 1 7 
1 0. 2  IN V E S TI G A T O R R E S P O N SI BI LI TI E S  .................................................................... 1 1 8 
1 0. 2. 1  
S u bject I nf or m ati o n a n d I nf or m e d C o nse nt .......................................... 1 1 8  
1 0. 2. 2  
I nstit uti o n al Revie w B o ar d/I n de pe n de nt Et hics C o m mittee A p pr ov al 
a n d Ot her I nstit uti o n al Re q uire m e nts ................................................... 1 1 9  
1 0. 2. 3  
St u dy D oc u m e nt ati o n .............................................................................. 1 2 0  
1 0. 2. 4  
Dele g ati o n of I nvesti g at or Res p o nsi bilities ............................................ 1 2 1  
1 0. 3  P R O T O C O L D E VI A TI O N S A N D V I O L A TI O N S ....................................................... 1 2 2 
1 0. 3. 1  
Pr ot oc ol Devi ati o n a n d Vi ol ati o n Defi niti o ns ....................................... 1 2 2  
1 0. 3. 2  
Re p orti n g Devi ati o ns/ Vi ol ati o ns............................................................. 1 2 2  
1 0. 4  S T U D Y R E C O R D S R E T E N TI O N A N D D I R E C T A C C E S S T O S O U R C E D O C U M E N T S 1 2 2  
1 0. 5  S T U D Y M
O NI T O RI N G  .......................................................................................... 1 2 4 
1 0. 6  Q U A LI T Y A S S U R A N C E  ........................................................................................ 1 2 5 
1 0. 7  S T U D Y T E R MI N A TI O N A N D S I T E C L O S U R E ........................................................ 1 2 5 
1 0. 8  S I T E T E R MI N A TI O N  ............................................................................................ 1 2 6 
1 0. 9  D I SC O N TI N U A TI O N O F S T U D Y  ............................................................................ 1 2 7 
1 1  
DI S C L O S U R E O F D A T A .................................................................................... 1 2 7  
1 1. 1  C O N FI D E N TI A LI T Y  ............................................................................................. 1 2 7 
1 1. 2  P U B LI C A TI O N  ..................................................................................................... 1 2 8 
1 2  
I N V E S TI G A T O R’ S P R O T O C O L A G R E E M E N T ........................................... 1 2 9 
1 3  
R E F E R E N C E S ...................................................................................................... 1 3 0  
1 4  
A P P E N DI C E S ....................................................................................................... 1 3 4  
A P P E N DI X 1 4. 1  V A M O R O L O N E D O S E C A L C U L A TI O N W
O R K S H E E T A N D B U L K  
D I S P E N SI N G G UI D E  ...................................................................................................... 1 3 5 
 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 8  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
LI S T O F T A B L E S 
T a ble 1  
S u m m ar y of p h ar m ac o ki netic p ar a meters f or v a m o r ol o ne after or al 
a d mi nistr ati o n of si n gle d oses of 0. 1, 0. 3, 1. 0, 3. 0, 8. 0, a n d 2 0. 0 m g/ k g t o 
he alt h y s u bjects u n der f aste d c o n diti o ns ................................................. 4 5  
T a b le 2 
S u m m ar y of p h ar m ac o ki netic p ar a meters f or v a m o r ol o ne after si n gle 
d ose or al a d mi nistr ati o n of 8 m g/ k g t o he alt h y s u bjects u n der fe d a n d 
f aste d c o n diti o ns ......................................................................................... 4 7 
T a b le 3 
S u m m ar y of p h ar m ac o ki netic p ar a meters f or v a m o r ol o ne d uri n g or al 
a d mi nistr ati o n of 1, 3, 9, a n d 2 0 m g/ k g d oses o nce d ail y f or 1 4 d a ys t o 
he alt h y s u bjects u n der f aste d c o n diti o ns ................................................. 4 8  
T a b le 4 
Bi o m ar kers pre vi o usl y defi ne d t o be res p o nsi ve t o c hr o nic d oses of 
gl u c oc ortic oi ds i n D M D b o ys .................................................................... 5 6  
T a b le 5 
Pl a n ne d D ose Le vel C o m p ositi o n .............................................................. 6 4  
T a b le 6 
Sc he d ule of St u d y Acti vities ...................................................................... 8 1  
T a b le 7 
V a m or ol o ne D ose T a peri n g ....................................................................... 8 9  
T a b le 8 
He m at ol o g y, C he mist r y, a n d Li pi ds Cli nic al L a b or at or y Tests ............ 9 4  
T a b le 9 
Uri n al ysis Cli nic al L a b or at or y Tests ........................................................ 9 4  
T a b le 1 0 
P h ar m a c o d y n a mi c Bi o m a r kers .............................................................. 1 0 7  
T a b le 1 1 
Bl o o d S a m ple N u m ber a n d V ol u me ....................................................... 1 0 8  
T a b le 1 2 
6- m o nt h a n d 1 2- m o nt h C h a n ges i n O utc o mes i n 4- < 8 ye ar- ol d D M D 
B o ys  ............................................................................................................ 1 1 2 
 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 9  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
LI S T O F FI G U R E S 
Fi g ure 1  
Arit h metic me a n ± st a n d ar d err or pl as m a c o nce ntr ati o ns of 
v a m o r ol o ne ( V B P 1 5) after or al a d mi nistr ati o n of si n gle d oses of 0. 1, 
0. 3, 1, 3, 8, a n d 2 0 m g/ k g t o he alt h y s u bjects u n der f aste d c o n diti o ns - 
li ne ar pl ot (t o p); se mi-l o g arit h mi c pl ot ( b ott o m) .................................... 4 4  
Fi g u re 2  
Rel ati o ns hi p bet wee n i n di vi d u al s u bject v a m or ol o ne A U C( i nf) a n d d ose 
after or al a d mi nistr ati o n of si n gle d oses of 0. 1, 0. 3, 1, 3, 8, a n d 2 0 m g/ k g 
t o he alt h y s u bjects u n der f aste d c o n diti o ns ............................................. 4 5 
Fi g u re 3  
Arit h metic me a n ± st a n d ar d err or pl as m a c o nce ntr ati o ns of 
v a m o r ol o ne ( V B P 1 5) after si n gle d ose or al a d mi nistr ati o n of 8 m g/ k g t o 
he alt h y s u bjects u n der fe d a n d f aste d c o n diti o ns - li ne ar (t o p p a nel) 
a n d  se mi-l o g arit h mic ( b ott o m p a nel) a xes ............................................... 4 6 
Fi g u re 4  
Arit h metic me a n ± st a n d ar d err or pl as m a c o nce ntr ati o ns of 
v a m o r ol o ne ( V B P 1 5) o n D a ys 1 a n d 1 4 d uri n g or al a d mi nistr ati o n of 
1, 3, 9, a n d 2 0 m g/ k g d oses o nce d ail y f or 1 4 d a ys t o he alt h y s u bjects 
u n der f aste d c o n diti o ns (li ne ar a xes) ................................ ........................ 4 9 
Fi g u re 5  
M or ni n g c ortis ol me as u res i n t he v a m or ol o ne P h ase I M A D 
v ol u nteers. * ................................ ................................................................. 5 1 
Fi g u re 6  
F asti n g ser u m gl uc ose d uri n g t he P h ase I M A D peri o d (t w o wee ks d ail y 
tre at me nt) .................................................................................................... 5 3 
 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 2 0  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
LI S T O F A B B R E VI A TI O N S 
A b bre vi ati o n  
Defi niti o n/ Ter m  
 
 
A C T H  
a dre n oc ortic otr o pic h or m o ne  
A D L  
acti vities of dail y li vi n g  
A E  
ad verse eve nt  
A L P  
al kali ne p h os p hatase  
A L T  
ala ni ne ami n otra nsfer as e  
A N C O V A  
a nal ysis of c o varia nce  
A S T  
as partate ami n otra nsferas e  
A U C  
area u n d er t he c o nce ntrati o n -ti me c ur ve 
A U C 0 -2 4 hr 
area u n der t he  c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 2 4 h o urs  
A U C 0 -t 
area u n der t he  c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o ti me t 
A U C i nf 
area u n der t he  c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o i nfi nit y 
A U C last 
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 
t he last o bser ve d meas ura ble c o nce ntrati o n 
B MI  
b o d y mass i n de x  
B U N  
bl o o d urea nitr o ge n  
C  
Celsi us  
C D 2 3  
cl uster desi g nati o n 2 3 
C F R  
C o de of Fe d eral Re g ul ati o ns  
CI N R G  
C o o perati ve I nter nati o nal Ne ur o m usc ular Res earc h Gr o u p  
C K  
creati ne ki n ase  
C L  
cleara nce  
C o n A  
co nc an a vali n A  
c m 
ce nti meter  
C ma x  
ma xi m u m o bser ve d plas ma c o nce ntr ati o n  
C Q M S  
CI N R G Q u a ntitati ve Meas u re me nt S yste m 
C T C A E  
C o m m o n Ter mi n ol o g y Criteria  f or A d verse E ve nts 
C T M  
Cli nical Trial Material  
C T X  
car b o x y-t er mi nal tel o pe pti de 
C Y P  
cyt o c hr o me P 4 5 0  
d L  
deciliter  
D M D  
D uc he n ne m us c ular d ystr o p h y  
D S M B  
Data a n d Safet y M o nit ori n g B oar d  
E C G  
electr ocar di ogra m  
e C R F 
electr o nic case re p ort f or m  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 2 1  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
A b bre vi ati o n  
Defi niti o n/ Ter m  
 
 
E D C  
electr o nic d ata ca pt ure 
F  
Fa hre n heit  
F, F %  
bi oa vaila bilit y, perce nt bi oa vaila bilit y  
F A S  
F ull A nal ysis Set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
G G T  
g a m ma g l uta m yl tra nsferase 
G L P  
G o o d  La b orat or y Practice  
H b A 1c  
h e m o gl o bi n A 1 c  
H D L  
hi g h de nsit y li p o pr otei n  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
hr  
h o ur  
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I E C 
I n d e pe n de nt Et hics C o m mittee  
I G F B P-2  
i ns uli n-li ke gr o wt h f act or-bi n di n g pr otei n 2  
I G F B P-5  
i ns uli n-li ke gr o wt h f act or-bi n di n g pr otei n 5  
I L-2 2 B P  
i nterle u ki n-2 2 bi n di n g pr otei n  
I N D 
I n v esti gati o nal Ne w Dr u g 
I R B 
I nstit uti o nal Re vie w B oar d 
K 2-E D T A  
d i p otassi u m et h yl e ne dia mi netetraacetic aci d 
k g  
kil o gra m  
λ z 
eli mi nati o n rate c o nsta nt  
L  
liter 
L L C  
Li mite d Lia bilit y C o m pa n y  
L C -M S  
Li q ui d C hr o mat o gra p h y –  Mass S pec tr o metr y 
L D H  
lactate de h y dr o ge nas e 
L D L  
l o w de nsit y li p o pr otei n 
m  
meter  
M A D  
m ulti ple asce n di n g d os e (st u d y)  
m dx  
m o use m o del lac ki n g d ystr o p hi n  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
m g  
milli gra m  
mi n  
mi n ute  
MI S T  
Meta b olites i n Safet y Testi n g  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 2 2  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
A b bre vi ati o n  
Defi niti o n/ Ter m  
 
 
mI T T  
m o difie d I nt e nti o n t o Treat  
m L  
milliliter  
M M P -3  
matri x metall o pr otei nase -3  
M M P -1 2  
matri x metall o pr otei nase -1 2  
M S Ba n d  
Micr os oft Ba n d  
N A D P H  
nic oti na mi de a de ni ne di n ucle oti de p h os p hate  
N F -κ B  
n uclear fact or k a p pa -li g ht-c hai n -e n h a ncer of acti vate d B cells  
n g  
na n o gra m  
N o. , n 
n u m ber  
N O A E L  
n o o bser ve d a d v erse effect le vel  
N S A A  
N ort h Star A m b ulat or y Assess me nt  
O T C  
o ver -t he-co u nter ( n o n -prescri pti o n me dicati o n)  
% C V  
perce nt a ge c o effi cie nt of variati o n  
P 1 N P  
ser u m a mi n oter mi nal pr o pe pti de of t y p e I c olla ge n  
P B L  
peri p heral bl o o d le u k oc ytes  
P D  
p har mac o d y n a mics  
P HI  
Pr otecte d Healt h I nf or mati o n  
P K  
p har mac o ki netics  
P R [ P Q]  
i nter val fr o m o nset of P wa ve t o start of t he Q R S c o m ple x 
Q  
q uarter  
Q M T  
Q ua ntitati ve M uscle Testi n g  
Q R S  
i n electr ocar di o gra p h y, t he c o m ple x c o nsisti n g of Q, R, a n d S 
wa ves, c orres p o n di n g t o de p olarizati o n of ve ntricl es [c o m ple x]  
Q S A R  
q ua ntitati ve str uct ure -acti vit y relati o ns hi p  
Q T  
i n car di ol o g y, t h e i nter val bet wee n t he start of t he Q wa ve a n d 
e n d of t he T wa ve  
Q T c 
correcte d Q T i nter val  
R B C  
Re d Bl o o d Cell  
R R  
i n electr ocar di o gra p h y, t he i nter val bet wee n s uccessi ve R 
wa ve s ( pea ks of Q R S c o m ple x es) 
6 M W T  
Si x -mi n ute Wal k Test  
S A D  
si n gle as ce n di n g d ose (st u d y) 
S A E  
Ser i o us A d verse E v e nt 
S A P  
statistical a nal ysis pla n 
S D  
sta n dar d de viati o n 
S O C  
s yste m or ga n class 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 2 3  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
A b bre vi ati o n  
Defi niti o n/ Ter m  
 
 
S O P  
sta n dar d o perati n g pr oce d ures 
S S L  
sec ure s o c ket la yers 
t1/ 2 
ter mi nal half-life 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T ma x  
ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n 
T T C LI M B  
Ti me t o Cli m b ( Test)  
T T S T A N D  
Ti me t o Sta n d ( Test)  
T T R W  
Ti me t o R u n/ Wal k ( Test)  
U S  
U nite d States  
vs.  
vers us  
V ss 
v ol u me of distri b uti o n at stea d y st ate  
V z 
ter mi nal p hase v ol u me of distri b uti o n 
W B C  
W hite Bl o o d Cell  
W H O  
W orl d  Healt h Or ga nizati o n  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 2 4  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
1  
I N T R O D U C TI O N 
1. 1  
B ac k gr o u n d a n d U n met Nee d 
D uc he n ne m us c ular d ystr o p h y ( D M D) is a ra pi dl y pr o gressi ve f or m of m usc ular 
d ystr o p h y t hat occ urs pri maril y i n males a n d ma nifests pri or t o t he a ge of si x years.  
D uc he n ne m us c ular d ystr o p h y affects a p pr o xi matel y 1 i n 3, 6 0 0 t o 9, 3 0 0 male birt hs 
w orl d wi de. 1  Duc he n ne m usc ular d ystr o p h y is ca use d b y m utati o ns i n t he d ystr o p hi n 
ge n e w hic h c o des f or a pr otei n t hat pr o vi des str uct ural sta bilit y t o t he d ystr o gl yca n 
c o m ple x o n m uscle cell me m bra nes. 2  T he lac k of d ystr o p hi n r e d uces plas ma me m bra ne 
sta bility.  M e m bra ne d est a biliz ati o n res ults i n altere d mec ha ni cal pr o perties a n d a berra nt 
si g nali n g, w hic h c o ntri b ute t o me m bra ne fra gilit y, necr osis, i nfla m mati o n, a n d 
pr o gre ssi ve m uscle wasti n g. 3 
I n a d diti o n t o t he si g nifica nt c o ntri b uti o n of me m bra ne dest a bilizati o n a n d mec ha nical 
i nj ur y i n D M D, a b erra nt i ntracell ular si g nali n g casca des t hat re g ulate i nfla m mat or y a n d 
i m m u ne pr ocesses als o c o ntri b ute t o D M D pat h o p h ysi ol o g y.  U p-re g ulate d i nfla m mat or y 
ge n e e x pressi o n a n d acti vate d i m m u ne cell i nfiltrates, at least partiall y me diate d b y 
n uclear fact or k a p pa-li g ht-c hai n-e n h a ncer of acti vate d B cells (N F -κ B ) acti vati o n, are 
e vi de nt d uri n g earl y dise ase sta ges a n d pla y a si g nifica nt r ole i n m uscle wasti n g. 3  N F - κ B 
ha s bee n s h o w n t o r e g ulate t he e x pressi o n of n u mer o us i nfla m mat or y ge n es i n i m m u ne 
cells a n d m uscle fi bers, 4 ,5 ,6 ,7 a n d t he i nfiltrati o n a n d acti vati o n of t hese cells ca n tri g ger 
m uscle f i ber deat h.8 ,9 
Alt h o u g h si g nifica nt a d v a nces ha ve bee n ma de i n u n dersta n di n g t he eti ol o g y of D M D, a 
c ure has n ot b ee n f o u n d, a n d c urre nt treat me nt o pti o ns are all me dicati o ns use d “ off-
la bel” t o alle viate t he s y m pt o ms of D M D.  Des pite scie ntific a d va n ces, o nl y 
gl uc o c ortic oi ds, s uc h as pre d nis o ne, ha v e c o nsiste ntl y de m o nstr ate d efficac y i n cli nical 
trials.1 0  F urt her, ma n y disease m o dif yi n g tec h n ol o gies t h at are c urre ntl y i n de vel o p me nt 
f oc us o n s u bsets of dystr o p hi n m utati o ns a n d t heref ore d o n ot a d dress t he u n met nee d i n 
all pers o ns wit h D M D.  H o we ver, it is li kel y t hat gl uc oc ortic oi ds will nee d t o be 
c o-a d mi nistere d wit h ma n y of t hes e c o m p o u n ds f or ma xi m u m effect a n d gl uc oc ortic oi ds 
ha ve e xte nsi ve si de effect pr ofiles, ofte n li miti n g l o n g-ter m a d mi nistrati o n.  T he c urre nt 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 2 5  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
g oal of D M D researc h is t o fi n d a m utati o n-i n de pe n de nt treat me nt t hat matc hes or 
e x cee ds t he efficac y of gl uc oc ortic oi ds wit h a si g nifica ntl y l o w er si de effect pr ofile. 
Va m or ol o ne is a first ge n erati o n delta- 9, 1 1 c he mi cal c o m p o u n d bel o n gi n g t o t he 
str uct ural class of s y nt hetic ster oi dal dr u gs, w hic h i ncl u des t he gl u c ortic oi ds pre d nis o ne, 
met h yl pre d nis o n e, a n d d e x a met has o ne. 1 1  T he c he mical str uct ure of va m or ol o ne has 
o pti mi ze d f o ur s u bacti vities of tra diti o nal gl u c oc ortic oi d dr u gs, n a mel y tra nsacti vati o n, 
tra nsrepressi o n, p h ysi o c h e mical me m bra n e pr o perties, a n d mi neral oc ortic oi d rece pt or 
a nta g o nis m. 1 1  B y re d u ci n g tra ns acti vati o n s u b pr o perties, retai ni n g tr a nsre pressi o n, 
i m parti n g me m bra ne sta bilizi n g pr o perties, a n d i n hi biti n g t he mi neral oc orti c oi d rece pt or 
pat h wa y, va m or ol o ne h as fa v ora ble effi cac y a n d si de effect pr ofiles relati v e t o classic 
gl uc o c ortic oi ds i n n o ncli nical m o dels a n d is a ntici pate d t o be a n attracti ve ca n di date f or 
t he treat me nt of D M D i n pe diatric patie nts. 
I n vitr o a n d n o ncli nical d ata t o date s u g gest t hat v a m or ol o ne ma y offer a m u c h nee d e d 
alter nati ve t o t he c urre nt gl uc o c ortic oi ds w hic h are sta n dar d of care f or D M D, 1 2 wit h 
a d ministrati o n be gi n ni n g ar o u n d t he a ge of 5 years i n m ost de vel o pe d c o u ntries, or e ve n 
earlier i n s o me cases. 
T he si g nifica nt effects of gl uc o c ortic oi ds o n gr o wt h a n d de vel o p me nt, h o w e ver, pre ve nt 
t heir r o uti ne a d mi nistrati o n i n i nfa nc y or ‘t o d dler’ years, des pite e vi de nce t hat t he earlier 
t he a d mi nistrati o n, t he better t he o verall f u ncti o nal o utc o me.1 3  T he c u m ulati ve si de 
effects of gl uc oc ortic oi ds, i ncl u di n g e x cess wei g ht, dela ye d p u bert y, fra gile s ki n, l oss of 
b o ne mi neral de nsit y, br uisi n g, a n d C us hi n g oi d a p peara n ce c o nti n ue t o ne gati vel y i m pact 
o n t he q ualit y of lif e of t he i n di vi d ual, lea di n g t o si g nifica nt v ariati o ns i n cli nical 
practice. 1 4  Gl uc oc ortic oi ds als o c o ntri b ute t o f urt her m uscle da m a ge wit h l o n g-ter m 
a d ministrati o n.   Va m or ol o ne has s h o w n fe w if a n y of t he si de effects of tr a diti o nal 
gl uc o c ortic oi ds i n m o use m o dels of D M D. 1 1 ,1 5 ,1 6 
T his st u d y is tar gete d t o e x pl ore w het her va m or ol o ne will s h o w at least e q ual effic ac y t o 
gl uc o c ortic oi d s wit h a m ore fa v ora ble si de effect pr ofile, t here b y i m pr o vi n g t he q ualit y 
of life f or D M D patie nts.  T his pr ofile w o ul d e na ble use of va m or ol o ne i n D M D b o ys 
w h o are at a y o u n ger a ge t ha n w he n gl uc oc ortic oi d  treat me nt is c urre ntl y i nitiate d.  I n 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 2 6  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
a d diti o n, va m or ol o ne c o ul d be prescri b e d i n later sta ge n o n -a m b ula nt y o u n g me n wit h 
D M D a n d f or a l o n ger peri o d of ti me, w here t h e ris k: be nefit bala nce of gl u c oc ortic oi d s is 
ofte n less fa v ora ble.  
Efficac y ma y als o be i m pr o ve d o ver classic gl uc oc ortic oi d s i n t he l o n ger t er m.  I n 
a d diti o n t o t he a nti -i nfla m mat or y pr o perties of v a m or ol o ne as a res ult of N F-B pat h wa y 
i n hi biti o n, va m or ol o ne ma y als o i m pr o ve efficac y o ver c o n ve nti o nal gl uc oc ortic oi d s d ue 
t o t he lac k of i nterfere nce i n t he A K T 1/ F O X O pat h wa y, a ke y feat ure of gl uc oc ortic oi d  
t hera p y w hic h le a ds i n t he l o n g ter m t o m uscle wasti n g a n d atr o p h y.1 7  F urt her, 
va m or ol o ne has bee n rece ntl y de m o nstr ate d t o i m pr o ve as y nc hr o n o us re m o deli n g, 
belie ve d t o be a c o m p o ne nt of pr o gressi ve m uscle wea k ness a n d wasti n g i n D M D 1 8 a n d 
ma y als o pre ve nt m uscle me m bra ne da m a ge, t here b y del a yi n g pr o gressi o n of t he disease 
f urt her.  V a m or ol o ne is a n a nta g o nist t o t he mi neral oc ortic oi d rece pt or, w hereas 
gl uc o c ortic oi ds are t y pi call y a g o nists.  A n a nt a g o nist f or t he mi neral oc orti c oi d rece pt or, 
e pler o n o ne, w as r ece ntl y s h o w n t o si g nifica ntl y i m pr o ve D M D heart f u n cti o n. 1 9  Fi nall y, 
va m or ol o ne i m parts p h ysical sta bilit y t o m y ofi b er plas ma me m bra nes, w h ereas 
pre d nis o ne desta biliz es me m bra nes.  T his pr o pert y a d dresses t he pri mar y defect of 
me m bra ne i nsta bilit y i n d ystr o p hi n deficie nt m y ofi bers i n D M D. 1 5 
P ote ntiall y,  t h e a d mi nistrati o n of va m or ol o ne t o a D M D patie nt ma y be gi n s o o n after 
birt h t o sl o w t he d ystr o p hic pr ocess of m us cle, ret ai ni n g re ge nerati ve ca pacit y a n d 
s u bsta ntiall y i m pr o vi n g p atie nt q ualit y of life. 
1. 2  
N o ncli nic al E x perie nce 
T he safet y p h ar mac ol o g y, p har mac o ki netics ( P K) a n d meta b olis m, a n d t o xic ol o g y of 
va m or ol o ne ha ve b ee n e val uate d i n m ulti ple n o ncli nical st u dies i n vitr o a n d i n mice, rats, 
bea gle d o gs, a n d c y n o m ol g us m o n ke ys i n viv o.  
1. 2. 1  
S afety P h ar m ac ol o gy 
St u nte d gr o wt h is a si g nifica nt si de effect of c hr o nic gl uc oc ortic oi d use i n c hil dre n. 2 0 ,2 1  
C hr o nic treat me nt wit h gl uc oc ortic oi ds ne gati vel y affects b o ne gr o wt h a n d de vel o p me nt 
a n d ca n ca use oste o p or osis. 2 2 ,2 3 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 2 7  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T he effect of v a m or ol o ne as c o m pare d t o pre d nis ol o ne o n b o ne gr o wt h a n d de vel o p me nt 
was e val uat e d i n t he m dx m o use m o del of D M D t hat lac ks d ystr o p hi n d ue t o a pre mat ure 
c hai n-ter mi nati n g m utati o n i n t he m o use h o m ol o g ue of t he d ystr o p hi n ge ne.  I n t he pre-
s y m pt o matic m dx  st u d y, ti bia le n gt h was me as ure d t o deter mi ne if va m or ol o ne i n hi bite d 
b o ne gr o wt h.  Pre d nis ol o ne si g nifica ntl y d ecreas e d ti bia le n gt h w hereas v a m or ol o ne di d 
n ot affect ti bia le n gt h at a n y c o nce ntrati o n teste d.  Micr o-c o m p ute d t o m o gra p h y was 
perf or me d o n fe m urs t o e x a mi ne b o ne de nsit y a n d str uct ure.  C o m paris o n of ve hicle, 
pre d nis ol o ne, a n d t he hi g hest va m or ol o ne d ose s h o we d pre d nis ol o ne t o si g nifica ntl y 
re d uce tra bec ular t hic k n ess c o m pare d t o ve hicl e, w hile va m or ol o ne di d n ot.1 5 
I n n or mal, male C D- 1®  mice, t hese effects were re pr o d uce d.  U nli ke C D- 1 mice treate d 
wit h pre d nis ol o ne, C D- 1 mice recei vi n g v a m or ol o ne di d n ot e x perie nce ti bia le n gt h 
s h orte ni n g.1 6  H o we ver, at t he hi g h est va m or ol o n e d ose teste d, mice di d h a ve 
si g nifica ntl y re d uce d b o d y le n gt h, t h o u g h t o a less er e xte nt as c o m pare d t o pre d nis ol o ne. 
D uc he n ne m us c ular d ystr o p h y is ass oci ate d wit h car di o m y o p at h y t h at ca n b ec o me life 
t hreate ni n g, a n d i ncreas e d fi br osis wit h pre d nis o ne treat me nt i n heart m uscle of t he m dx  
m o use has bee n re p orte d. 2 4  Hist ol o gicall y, clear fi br osis was e vi de nt i n 5 0 % of y o u n g 
( 8- wee k) pre d nis ol o ne-tr eate d m o use hearts c o m p are d t o n o i nci de nce of fi br osis 
i de ntifie d i n t he ot her gr o u ps ( wil d t y pe; m dx  ve hi cle, a n d va m or ol o n e -treate d). 
P ha r mac ol o gicall y, gl uc o c ortic oi ds s h o w i m m u n os u p pressi ve a n d i m m u n ot o xic 
pr o pe rties t hat li mit t hera pe utic wi n d o ws a n d l o n g-ter m use.  Va m or ol o ne ( 5, 1 5, 3 0 
m g/ k g/ da y) was be nc h m ar ke d a gai nst pre d nis ol o ne ( 5 m g/ k g/ da y) t o deter mi ne if si milar 
pr o perties were o bs er ve d. 1 5  U ntreate d m dx  mice s h o we d i ncrease d n u m bers of peri p heral 
bl o o d le u k oc yt es ( P B L) a n d e nlar ge d s plee ns res ulti n g fr o m o n g oi n g m uscle da ma ge 
c o m pare d t o wil d t y pe mice.  Va m or ol o ne treat me nt re d uce d s plee n mass a n d P B L 
c o u nts i n a d ose- de p e n de nt ma n ner.  T his fi n di n g is attri b ute d t o a re d ucti o n i n m uscle 
da ma ge b y va m or ol o n e t hat decreases s plee n size t o le vels rese m bli n g t h os e i n wil d t y pe 
mice.  Pre d nis ol o ne re d u ce d t hese meas ures b el o w wil d t y pe, s u g gesti n g 
i m m u n os u p pressi ve a n d/ or i m m u n ot o xic pr o perties.  F urt her, pre d nis ol o ne si g nifica ntl y 
dec rease d via bl e s ple n oc yt es per gra m of tiss ue ( p0. 0 0 5), w hereas t his decreas e was n ot 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 2 8  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
o bser ve d f or a n y va m or ol o ne d ose teste d ( Re v era Ge n Re p ort N o. M D X- R B P- V B P 1 5-
0 2). 1 5 
T o f urt her q u er y t he p ote ntial i m m u ne m o d ulati o n, t he effects of va m or ol o ne a n d 
pre d nis ol o ne o n c o u nts of s ple nic B a n d T-l y m p h oc yt es is olate d fr o m treat e d m dx  mice 
were  e x a mi ne d.  C D 4 + T-cell acti vati o n was assa ye d b y sti m ulati o n of s ple n oc yt es wit h 
t he T-cell mit o ge n, c o nca na vali n A ( C o n A).  S ple n oc yt es o btai ne d fr o m pre d nis ol o ne-
treate d mice dis pla ye d a si g nifica nt r e d ucti o n of t he perce nta ge of s ple nic acti vate d 
C D 4 + C D 2 5 + T-cells u p o n C o n A sti m ulati o n w hile s ple n oc ytes deri ve d fr o m 
va m or ol o ne-treate d mice di d n ot ( Re vera Ge n Re p ort N o. M D X- R B P- V B P 1 5- 0 2). 
Ta ke n t o get her, t hese fi n di n gs s u g gest t hat w hile pre d nis ol o ne treat me nt lea ds t o a 
re d ucti o n i n T-cell n u m ber a n d acti vati o n stat us, va m or ol o ne m o d ulates i nfla me d m dx  
i m m u ne s yste ms t o war ds a wil d t y pe st at e wit h o ut c o m pr o misi n g T-cell acti vati o n stat us. 
1. 2. 2  
P h ar m ac o ki netics a n d Met a b olis m 
1. 2. 2. 1  
Si n gle  D ose 
Va m or ol o ne P K pr ofiles were d eter mi ne d i n male C D- 1 mice, S pra g ue Da wle y rats a n d 
bea gle d o gs after a si n gle i ntra ve n o us i njecti o n of 1 0 m g/ k g a n d after a si n gle oral d ose 
of 5 0 m g/ k g i n mice a n d rats a n d 3 0 m g/ k g i n d o gs. 
P ha r mac o ki netic res ults f or va m or ol o ne f oll o wi n g a si n gle i ntr a ve n o us a d mi nistrati o n of 
1 0 m g/ k g i n Crl: C D 1(I C R) mice de m o nstrate d a cleara n ce ( C L) of 1 8. 8 m L/ mi n/ k g.  T h e 
ter minal half-life (t ½ ) was 0. 3 5 h o urs.  V ol u me of distri b uti o n at stea d y stat e ( Vss) was 
0. 7 6 L/ k g.  F oll o wi n g oral a d mi nistrati o n of 5 0 m g/ k g i n mice, t he ma xi m u m o bser ve d 
plas ma c o nce ntrati o n ( C ma x ) of 6 7 8 7 n g/ m L was o bser ve d at 2 h o urs (ti me t o ma xi m u m 
o bser ve d plas ma c o nce ntrati o n [ T ma x ]) after dr u g a d mi nistrati o n, a n d perce nt 
bi oa vaila bilit y ( F %) was 7 4. 5 %.  F oll o wi n g oral a d mi nistrati o n of 1 5 m g/ k g via c herr y 
s yr u p, t he Cma x  of 1 5 2 7 n g/ m L was o bs er ve d at 2 h o urs after dr u g a d mi nistrati o n a n d 
bi oa vail a bilit y was 4 7. 7 % ( Re vera Ge n Re p ort N o. P H- D P M K- V B P- 1 0- 0 0 4). 
P har mac o ki netic res ults f or va m or ol o ne f oll o wi n g a si n gle i ntr a ve n o us a d mi nistrati o n of 
5 0  m g/ k g i n S pra g ue D a wle y rats i n dicate d a C L of 2 0. 2 m L/ mi n/ k g. T h e t
½  was 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 2 9  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
0. 5 8  h o urs.  V ss was 0. 7 7 L/ k g, w hic h was si milar t o t hat o bser ve d i n mice.  After oral 
a d ministrati o n of 5 0 m g/ k g i n rats, a C ma x  of 2 5 4 3 n g/ m L was o bs er ve d at 4 h o urs after 
d ose a d mi nistrati o n, a n d bi oa vaila bilit y was 4 7. 8 % ( Re vera Ge n Re p ort N o. P H- D P M K-
V B P- 1 0- 0 0 7). 
I n bea gle d o gs, v a m or ol o ne ha d a C L  of 2 4. 7 m L/ mi n/ k g.  T he t½  was 5. 4 2 h o urs a n d Vss 
was 1. 9 3 L/ k g.  After oral a d mi nistrati o n of 3 0 m g/ k g i n d o gs, a C ma x  of 8 1 4 n g/ m L was 
o bser ve d at 6 h o urs after d ose a d mi nistrati o n a n d bi oa vaila bilit y was 5 3. 2 % ( Re vera Ge n 
Re p ort N o. 4 8 5 0 4- 1 0- 4 6 4). 
Va m or ol o ne cle ara nce w as t heref ore c o m para bl e i n all 3 s pecies st u die d 
( 1 9- 2 5 m L/ mi n/ k g).  Bi oa vaila bilit y ra n ge d fr o m a p pr o xi matel y 5 0 % i n m o use (c herr y 
s yr u p), rat, a n d d o g t o 7 5 % i n t he m o use ( 3 0 % La brafil) ( Re v era Ge n Re p ort N os. 
P H - D P M K- V B P- 1 0- 0 0 4, P H- D P M K- V B P- 1 0- 0 0 7, 4 8 5 0 4- 1 0- 4 6 4). 
1. 2. 2. 2  
M ulti ple D ose 
C rl: C D 1(I C R) mice w ere a d mi nistere d va m or ol o n e or ve hicle o n ce d ail y f or 
2 8 c o nsec uti ve da ys.  Va m or ol o ne e x p os ure (as assesse d b y t he C ma x  a n d area u n der t h e 
c o nce ntr ati o n-ti me c ur ve [ A U C ]) i ncrease d wit h i ncreasi n g d os e o n St u d y Da ys 1 a n d 2 8.  
Re peate d d osi n g of va m or ol o ne o ver a 2 8- da y d urati o n was ass ociate d wit h decreases i n 
mea n va m or ol o ne A U C last val ues i n t he 3 0 a n d 1 0 0 m g/ k g d ose gr o u ps c o m pare d t o 
Da y  1, i n dicati n g p ossi ble e nz y me i n d u cti o n.  O n St u d y Da y 2 8, mea n A U Clast val ues 
were  1. 8 1-f ol d a n d 5. 0 2-f ol d l o wer c o m pare d t o St u d y Da y 1 f or t he 3 0 a n d 1 0 0 m g/ k g 
d ose gr o u ps, res p ecti vel y.  T he o bser ve d differe nce i n e x p os ure relati ve t o Da y 1 
i ncreas e d wit h t he i ncrease i n a d mi nistere d d ose of va m or ol o ne ( Re v era Ge n Re p ort N o. 
1 9 9 8- 0 0 9). 
Be a gl e d o gs were eit her a d mi nistere d va m or ol o ne or ve hicle o nce dail y f or 2 8 
c o nsecuti ve da ys.  Va m or ol o ne e x p os ure i n d o gs (as assesse d b y C ma x  a n d A U Clast) 
ge n erall y i ncreas e d wit h i ncreasi n g d ose o n St u d y Da ys 1 a n d 2 8.  F or t h e 2 a n d 1 0 
m g/ k g d ose gr o u ps, e x p os ure o n Da y 2 8 was ge n erall y hi g her t ha n o n Da y 1, i n dicati n g 
p ossi ble i n hi biti o n of meta b olis m of va m or ol o ne at t hese d ose le vels.  O n Da y 2 8, mea n 
A U C last val ues were 2. 3 5-f ol d a n d 2. 4 3-f ol d ( males) a n d 3. 0 3-f ol d a n d 3. 2 3-f ol d 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 3 0  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
(fe males) hi g h er c o m p are d t o St u d y Da y 1 f or t he 2 a n d 1 0 m g/ k g/ da y d os e gr o u ps, 
res pecti vel y.  F or t he 5 0 m g/ k g d ose gr o u p, e x p os ure o n Da y 2 8 was si milar t o t hat o n 
Da y 1.  At t he 5 0 m g/ k g d ose, A U C last val ues i n males were 1. 7 1-f ol d l o w er w hereas 
fe males w ere 1. 2 2 hi g her o n Da y 2 8 c o m pare d t o Da y 1 ( Re vera Ge n Re p ort N o. 
0 3 1 3 0 2). 
N o n- naï ve c y n o m ol g us m o n ke ys w ere a d mi nistere d va m or ol o ne ( 3 0 0 a n d 
6 0 0 m g/ k g/ da y) or v e hicl e o nce d ail y f or 7 c o nsec uti ve da ys.  Va m or ol o ne e x p os ure (as 
assessed b y C ma x  a n d A U Clast) ge nerall y i ncrease d wit h i ncreasi n g d ose o n St u d y Da ys 1 
a n d 7 wit h t he e x ce pti o n of male m o n ke ys o n Da y 7, w hic h s h o we d n o cl ear i ncrease i n 
e x p os ure bet wee n t he 3 0 0 a n d 6 0 0 m g/ k g/ da y d os e le vels.  Re peate d d osi n g o ver t he 
7- da y st u d y d urati o n was ass ociate d wit h decreases i n mea n plas ma va m or ol o ne A U C last 
val ues f or fe male a n d male m o n ke ys i n dicati n g p ossi ble meta b olic i n d ucti o n.  O n Da y 7, 
mea n A U C last val ues were 1. 6 0-f ol d, 2. 1 9-f ol d, a n d 2. 0 2-f ol d l o wer i n fe males a n d 
1. 2 0-f ol d, 2. 0 9-f ol d, a n d 2. 8 8-f ol d l o wer i n males c o m pare d t o St u d y Da y 1 f or t he 1 0 0, 
3 0 0 a n d 6 0 0 m g/ k g/ da y d ose gr o u ps, res p ecti vel y ( Re vera Ge n Re p ort N os. 1 9 9 8- 0 0 1, 
S W 1 1- 0 4 1 8). 
1. 2. 2. 3  
Distri b uti o n 
In t he pl as ma pr otei n bi n di n g st u dies, perce nt b o u n d was si milar i n h u ma n a n d m o use 
cells i n c ult ure ( 8 8. 0 6 % a n d 8 6. 7 1 %, res p ecti vel y).  I n t he bl o o d partiti o n e x peri me nt 
d o ne ex viv o, t he bl o o d t o plas ma rati o was si milar bet wee n h u m a n a n d m o use ( 0. 8 7 a n d 
0. 6 8, res pecti vel y), b ut t h e re d bl o o d cell t o plas ma rati o f or t he m o us e ( 0. 3 3) was less 
t ha n half t hat of t he h u m a n ( 0. 7 4).  H u ma n i n viv o data are pres e nte d i n Secti o n 1. 3  
( V B P 1 5- 0 0 1).  I n t he bl o o d/ brai n c o nce ntrati o n m o use e x peri me nt i n viv o, t he plas ma 
c o nce ntr ati o ns of va m or ol o ne were hi g h er t ha n brai n c o nce ntrati o ns wit h t h e A U C a n d 
C ma x  a p pr o xi matel y 2-f ol d hi g her i n plas m a t ha n i n brai n ( Re vera Ge n Re p ort N os. 
A D M E - N C G-P P B - N C 1 3 5, A D M E- V B P-P P B - V 0 0 2, A D M E- N C G-B P - N C 1 3 4, N C A T S 
2 0 1 3- 3 8). 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 3 1  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
1. 2. 2. 4  
Met a b olis m 
T he i n vitr o a n d i n viv o d ata de m o nstrate t h at va m or ol o ne ca n b e meta b olize d via 
m ulti ple me ta b olic pat h wa ys, i ncl u di n g gl uc ur o ni dati o n, h y dr o x ylati o n, a n d re d ucti o n.  
Gl uc ur o ni dati o n a p peare d t o be t he maj or meta b olic pat h wa y i n h u ma n cells i n vitr o.  All 
meta b olites o bser ve d i n h u ma n i n vitr o were o bser ve d i n m o n ke y i n vitr o.  M ost h u ma n 
meta b olites i de ntifie d i n vitr o were als o f o u n d i n m o use a n d d o g.  T h us, t here is n o 
u ni q ue h u ma n meta b olite i de ntifie d f or va m or ol o n e. 
T he meta b olic sta bilit y of va m or ol o ne was assess e d i n n o n- G o o d La b orat or y Practice 
( G L P) st u dies.  Bas e d o n t he data ge n erate d, va m or ol o ne was hi g hl y sta ble f or u p t o 
6 0 mi n utes i n h u ma n, m o n ke y, d o g, a n d m o use li ver micr os o mes i n t he prese nce or 
a bse nce of nic oti na mi de a de ni ne di n ucle oti de p h os p hate ( N A D P H) a n d sta ble f or u p t o 
6 0 mi n utes i n rat li ver i n t he a bse nce of N A D P H.  M o derate met a b olis m was a p pare nt i n 
rat li ver micr os o mes i n t he prese n ce of N A D P H sti m ulati o n ( 3 5 % re mai ni n g), s u g gesti n g 
t hat rat was a hi g h met a b olizer of va m or ol o ne rel ati ve t o ot her s pecies ( m o use, d o g, 
h u ma n) ( Re vera G e n Re p ort N os. NI H- R 2 5 2 6, a n d A D M E- V B P- L M - V 0 0 3). 
Va m or ol o ne di d n ot si g nifica ntl y i n hi bit a n y of t h e c yt oc hr o me P 4 5 0 ( C Y P) e nz y m e 
is of or ms teste d ( C Y P 1 A 2, 2 B 6, 2 C 8, 2 C 9, 2 C 1 9, 2 D 6, a n d 3 A 4).  Va m or ol o ne 
m o deratel y i n d uce d C Y P 3 A 4 ( 2 4 % t o 4 2 %), i n dicati n g t hat va m or ol o n e is a p ote ntial 
i n d ucer of C Y P 3 A 4 ( Re v era G e n Re p ort N os. A D M E- V B P-I n hi biti o n- V 0 0 5, A D M E-
V B P-I n d u cti o n- V 0 0 6, A D M E- V B P-I n d ucti o n- V 0 0 9). 
1. 2. 2. 5  
E xcreti o n 
Va m or ol o ne s h o we d hi g h plas ma cleara nce i n rats b ut, c o nsiste nt wit h t he e xte nsi ve 
meta b olis m i n he pat oc yt es fr o m t his s pecies, t he biliar y a n d uri nar y e x creti o n of t he 
pare nt c o m p o u n d w as l o w wit h a n a vera ge of < 0. 0 5 % of t he d ose rec o v ere d i n bile a n d 
a p pr o xi matel y 0. 1 % i n uri ne.  O verall, va m or ol o ne s h o we d hi g h plas ma cl eara n ce a n d 
e xtre mel y l o w biliar y a n d uri nar y e x creti o n ( Re v era Ge n Re p ort N o. N C A T S 2 0 1 3- 4 4). 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 3 2  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
1. 2. 3  
T o xic ol o gy 
1. 2. 3. 1  
Si n gle D ose 
Crl: C D 1(I C R) mice w ere a d mi nistere d va m or ol o n e o nce via oral ga v a ge at 5 0, 1 2 5, 2 5 0, 
a n d 5 0 0 m g/ k g a n d o bs er ve d f or a b n or malities.  All a ni mals s ur vi ve d t o t heir sc he d ule d 
ter minati o n, a n d t here were n o si g nifica nt a b n or malities o bser ve d.  T here was a sli g ht 
decrease i n b o d y w ei g ht attri b ute d t o va m or ol o ne i n b ot h males a n d fe males at d oses 
a b o ve 1 2 5 m g/ k g.  A d os e de pe n d e nt decreas e i n f o o d c o ns u m pti o n relate d t o 
va m or ol o ne was als o o bser ve d i n males a n d fe mal es.  N o ot her a b n or malities were 
o bser ve d i n e x peri me ntal mice ( Re vera Ge n R e p ort N o. 1 9 9 8- 0 0 2). 
Bea gl e d o gs recei ve d si n gle 6 0, 1 8 0, 3 6 0, a n d 7 5 0 m g/ k g d oses of va m or ol o ne usi n g a n 
escalati o n st u d y desi g n wit h a 4- da y was h o ut peri o d bet wee n d oses.  All a ni mals 
s ur vi ve d d ose escalati o n.  Cli nical si g ns attri b ute d t o va m or ol o ne ( 7 5 0 m g/ k g) i ncl u d e d 
re d disc ol orati o n of t he ears a n d face.  T his effect occ urre d wit hi n a fe w h o urs of d osi n g 
a n d was tra nsi e nt.  T he hi g hest d ose als o res ulte d i n i ncrease d w hite bl o o d cell c o u nt 
(i ncrease d ne utr o p hils a n d m o n oc ytes [fe mal e o nl y] a n d decrease d l y m p h o c yt es a n d 
e osi n o p hils [ male a n d fe male]).  At t he 3 6 0 a n d 7 5 0 m g/ k g d ose le vels, sli g ht ele v ati o ns 
i n al b u mi n were o bser ve d.  A mil d ele vati o n i n c h olester ol at t he 7 5 0 m g/ k g (a n d 
p ossi bl y 3 6 0 m g/ k g) d os e le vel was als o o bser ve d ( Re vera Ge n Re p ort N o. 1 3 7 8 8. 0 1. 0 1). 
I n c y n o m ol g us m o n ke ys, si n gle oral d oses of u p t o 5 0 0 m g/ k g were well t olerate d wit h 
n o si g nifica nt a b n or malities o bser ve d ( R e vera Ge n Re p ort N o. 1 9 9 8- 0 0 1). 
1. 2. 3. 2  
M ulti ple D ose 
Va m or ol o ne or v e hicle w as a d mi nistere d t o Crl: C D 1(I C R) mice o nce dail y f or 2 8 
c o nsecuti ve da ys at d oses of 1 0, 3 0 a n d 1 0 0 m g/ k g/ da y.  All a ni mals s ur vi ve d t o t heir 
sc he d ule d necr o ps y wit h t he e x ce pti o n of a fe m ale m o use ( 1 0 0 m g/ k g/ da y d ose gr o u p) 
t hat was f o u n d dea d o n Da y 1 6.  T he ca use of deat h was c o nsi dere d i nci d e ntal a n d 
attri b ute d t o a d osi n g i nj ur y b ase d o n t he a m o u nt of re d fl ui d i n t he t h oraci c ca vit y. 
N o effects attri b uta ble t o va m or ol o ne were o bser ve d i n f o o d c o ns u m pti o n, o p ht hal mic 
e x a mi nati o n, or uri nal ysis d uri n g t he st u d y.  D ose- de pe n de nt d ecrease i n b o d y wei g ht 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 3 3  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
gai n w as o bser v e d at all d oses; h o we ver, wei g ht was f ull y re gai n e d d uri n g t he rec o v er y 
peri o d.  A dre n al gla n d wei g hts were v aria ble bet wee n gr o u ps a n d ge nerall y decrease d, 
b ut wit h o ut a d ose res p o nse relati o ns hi p, a n d c orrelate d micr osc o pi call y wit h mi ni mal t o 
m o derate vac u olar d e ge n erati o n a n d c ortical atr o p h y.  After t he 2- wee k rec o ver y peri o d 
t here was e vi de nce of vac u olar de ge nerati o n of t he a dre n al gla n d.  Li ver wei g hts were 
si g nifica ntl y i ncreas e d at t he 1 0 0 m g/ k g/ da y d ose le vel.  He pat o cell ular h y pertr o p h y, 
i ncreas e d vac u ol ati o n, a n d necr osis (si n gle cell) were see n i n a fe w male mi ce at 
3 0 m g/ k g/ da y.  T here w as e vi de nce of li pi d a n d gl yc o ge n acc u m ulati o n.  Ser u m ala ni ne 
a min otra nsferase a n d as p artate a mi n otra nsferase l e vels were hi g her wit h ass ociate d 
micr osc o pic h y pertr o p h y/ vac u olati o n/ necr osis at 1 0 0 m g/ k g/ da y.  S plee n wei g hts 
decrease d i n a d os e- de p e n de nt ma n ner a n d c orrelate d wit h a decreas e d n u m ber of 
l y m p h oc ytes i n s plee n.  T h y m us wei g hts de creas e d i n a d ose de p e n de nt m a n ner a n d were 
ass ociate d micr os c o picall y wit h l y m p h oi d atr o p h y.  Mice ha d d ose- de pe n d e nt re d ucti o ns 
i n ser u m l y m p h oc ytes w hic h were si g nifica nt i n t he 1 0 0 m g/ k g d ose gr o u p.  After t he 
rec o ver y peri o d, all para meters ret ur n e d t o n or mal ( u ntreate d) e x ce pt f or t h y m us wei g hts, 
w hic h were i ncrease d. 
Base d o n t he li ver-relat e d fi n di n gs i n t his st u d y, t he n o o bser ve d a d verse effect le vel 
( N O A E L) f or va m or ol o ne i n mice is 3 0 m g/ k g/ da y ( Re v era Ge n Re p ort N o. 1 9 9 8- 0 0 9). 
A G L P- c o m plia nt st u d y was carrie d o ut t o e val u ate t he t o xicit y of t he t est article, 
va m or ol o ne, i n Crl: C D 1 ® (I C R) mice after a d mi nistrati o n f or 2 6 wee ks, i ncl u di n g 
e val uati o n of t he re versi bilit y, pr o gressi o n, or del a ye d a p peara n ce of a n y o bser ve d 
c ha n ges f oll o wi n g a 4- w ee k p ost- d ose o bser vati o n peri o d.  Assess me nt of t o xicit y was 
base d o n m ortalit y, cli nical o bser vati o ns, b o d y wei g ht, a n d f o o d c o ns u m pti o n; 
o p ht hal m osc o pic e x a mi nati o ns; a n d cli nical a n d a nat o mic pat h ol o g y.  T o xic o ki netic 
assess me nt was c o n d u cte d f or t he test articl e. 
T here w ere n o v a m or ol o ne-rel ate d effects o n m ortalit y, detaile d cli nical o bser vati o ns, 
f o o d c o ns u m pti o n, o p ht hal m ol o g y, s per m e val uati o ns, or b o ne le n gt hs (fe m ur or ti bi a). 
Fi ve test articl e-treate d mice were u nsc he d ul e d d eat hs (e ut ha nize d i n extr e mis or f o u n d 
dea d) d uri n g t he d osi n g p hase.  T hree of t hes e were c o nsi dere d t o be p ote ntiall y d ue t o 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 3 4  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
d osi n g i nj ur y base d o n micr osc o pic fi n di n gs i n me diasti n u m, e picar di u m, or l u n g.  O ne 
of t hese u nsc h e d ule d deat hs was attri b ute d t o m o derate pr o gressi ve n e p hr o pat h y; a 
s p o nta ne o us bac k gr o u n d fi n di n g.  T he d eat h of o n e male at t he 5 m g/ k g/ da y d ose was 
u n deter mi ne d si nce t h ere were n o maj or pat h ol o gic fi n di n gs t o e x plai n t he u nsc he d ule d 
deat h of t his a ni mal; t here was n o tar get or ga n t o xicit y i n t he m o use.  Tar get or ga n 
t o xicit y was n ot c o nsi dere d a c o ntri b ut or t o t he d eat h of t hese a ni mals a n d t here was n o 
d ose-relati o ns hi p i n i nci d e nce. 
A va m or ol o ne-relate d i n creas e i n b o d y wei g ht gai n was o bser v e d relati ve t o c o ntr ols i n 
males ( + 1 4 %) a n d fe mal es ( + 2 3 %) at t he 4 5 m g/ k g/ da y d os e.  I ncreas es i n b o d y wei g hts 
at 4 5 m g/ k g/ da y w ere n ot c o nsi dere d t o be a d verse d ue t o t he ge neral healt h of t he 
a ni mals o verall.  D uri n g t he rec o v er y p has e, b o d y wei g hts i n males ret ur ne d t o 
c o m para ble l e vels as c o ntr ols, h o we ver fe male b o d y wei g hts r e mai ne d i ncrease d 
c o m pare d t o f e male c o ntr ols. 
E vi de nce of a mi ni mal t o mil d va m or ol o ne-relate d he patic effects were o bser ve d i n males 
at d oses ≥5 m g/ k g/ da y a n d fe males at 4 5 m g/ k g/ da y, i n dicat e d b y mil d t o m o derate 
i ncreas es i n al kali ne p h os p hatase, ala ni n e a mi n otr a nsferase, as p artate a mi n otra nsferase 
acti vities, a n d/ or t otal bilir u bi n, as relate d t o micr osc o pic he pat ocell ular vac u olati o n, 
i nfla m mati o n, a n d/ or necr osis i n males at ≥ 1 5 m g/ k g/ da y a n d fe males at 4 5 m g/ k g/ da y; 
t hese cha n ges ha d ge n erall y res ol ve d at rec o ver y c ollecti o ns wit h t he e x ce pti o n of 
mi ni mal i ncreases i n ala ni ne a mi n otra nsferase acti vit y i n fe males at 4 5 m g/ k g/ da y, w hi c h 
ma y  h a ve c orrel ate d t o micr osc o pic li ver p at h ol o g y. 
A mil d va m or ol o ne-relat e d i ncrease i n ne utr o p hil c o u nts was o bser v e d i n b ot h se xes at 
4 5 m g/ k g/ da y wit h c o nc urre nt decreases i n l y m p h oc yt e c o u nts i n fe mal es at 
4 5  m g/ k g/ da y c o nsiste nt wit h a gl uc oc ortic oi d-li k e effect, as relate d t o micr osc o pic 
l y m p h oi d de pleti o n.  H o we ver, a n i nfla m mat or y sti m ul us ma y h a ve c o ntri b ute d t o 
i ncreas es i n ne utr o p hil c o u nts, as relate d t o micr osc o pic li ver i nfla m mati o n; t hese 
c ha n ges ha d ge nerall y res ol ve d at rec o v er y c ollecti o ns. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 3 5  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
A mil d va m or ol o ne -relat e d decreas e i n c hl ori de was o bser ve d i n males at d oses 
≥ 5 m g/ k g/ d a y a n d fe mal es at d oses ≥ 1 5 m g/ k g/ d a y t h at lac ke d c orrelati ve fi n di n gs 
a m o n g ot her st u d y e n d p oi nts; res ol uti o n f or t his o bser vati o n c o ul d n ot be d eter mi ne d. 
A mil d va m or ol o ne -relat e d i ncrease i n al b u mi n was o bser ve d i n males at d oses 
≥ 5 m g/ k g/ d a y a n d fe mal es at 4 5 m g/ k g/ da y wit h c o nc urre nt mil d i ncreas es i n gl o b uli n i n 
fe males at 4 5 m g/ k g/ da y; t hese c ha n ges ha d res ol ve d at rec o ver y c ollecti o ns. 
A mi n or va m or ol o ne -rel ate d alterati o n i n li pi d meta b olis m was o bser ve d i n b ot h se x es at 
t he 4 5 m g/ k g/ da y d ose a n d fe males at t he 1 5 m g/ k g/ da y d os e i n dicate d b y i ncreas es i n 
tri glyceri de a n d/ or c h olester ol; t hese c ha n ges ha d res ol ve d at rec o ver y c ollecti o ns. 
Va m or ol o ne-relate d ma cr osc o pic fi n di n gs occ urre d i n t he li ver of mice at t he 
4 5 m g/ k g/ da y d ose.  T a n disc ol orati o n occ urre d i n o ne fe male a n d f o ur m ales at t his d ose 
i n t he d osi n g p hase.  T his c orrel ate d wit h micr o vesic ular/ macr o vesic ular he pat oc yt e 
vac u olati o n.  T here were n o test article-relate d macr osc o pic fi n di n gs i n rec o ver y a ni mals. 
Test article-relate d micr osc o pic fi n di n gs o cc urre d i n a dre nal gla n d (c ortical atr o p h y wit h 
c orrel ati n g d ecreases i n a dre nal wei g hts i n fe m ales), li ver (i ncrease d s e verit y of 
ce ntril o b ular h y pertr o p h y; he p at oc yte vac u olati o n; a n d i nfla m mati o n/ necr osis), l y m p h oi d 
tiss ues (t h y m us, s plee n, ma n di b ular l y m p h n o de, mese nteric l y m p h n o de, a n d g ut 
ass ociate d l y m p h oi d tiss ue [ G A L T]) s ki n, a n d pa ncreatic islets ( mi ni mal t o mil d 
h y pertr o p h y).  O bs er ve d c ha n ges i n t hese tiss ues are c o nsi dere d 
p har ma c ol o gic all y- m e diate d a n d n ot a d verse. 
A n i ncreas e d i nci de n ce of decrease d a na ge n hair f ollicles occ urre d i n mice at t he 
4 5 m g/ k g/ da y d ose.  D ecrease d a na ge n hair f ollicl es were d oc u me nte d f or i n di vi d u al 
a ni mals w he n t here were n o a na ge n h air f ollicles i n t he secti o n of s ki n.  I nci de nce i n 
c o ntr ols a n d mice at t he 5 a n d 1 5 m g/ k g/ da y d oses were si milar.  A s e verit y sc ore was 
n ot gi ve n t o t he de crease as t his ma y ha v e bee n s o me w hat de pe n d e nt o n size of s ki n 
sa m ple.  T his c ha n ge is n ot c o nsi dere d a d v erse. 
T here w as f ull re v ersi bilit y of l y m p h oi d c ha n ges i n t h y m us, s plee n, mese nt eric l y m p h 
n o de, ma n di b ular l y m p h n o de, a n d G A L T.  T here n o mea ni n gf ul differe nces bet wee n 
treate d a ni mals a n d c o ntr ols at t he e n d of t he rec o ver y tiss ues f or t hes e l y m p h oi d tiss ues.  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 3 6  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T here w as rec o ver y of a dre nal gla n d fi n di n gs i n fe males a n d partial rec o v er y of a dre n al 
gla n d fi n di n gs i n males.  I n a d diti o n, t here was partial re versi bilit y of li ver fi n di n gs f or 
males a n d fe m ales.  Mi n or c ha n ges p ersiste d i n t he pa ncreas a n d s ki n. 
S yste mic e x p os ure t o va m or ol o ne a p peare d t o be se x- de pe n de nt o n Da y 1 ( males > 
fe males) a n d a p peare d t o be i n de pe n de nt of s e x o n Da y 1 7 9.  F oll o wi n g dail y 
a d mi nistrati o n of va m or ol o ne i n fe males a n d m ales, s yste mic e x p os ure ( A U C 0- 2 4 hr) a n d 
C ma x  val ues of va m or ol o ne i ncrease d wit h i ncreasi n g d ose i n a great er t ha n 
d ose- pr o p orti o nal ma n ner o n Da y 1 a n d i n a n a p pr o xi matel y d ose- pr o p orti o nal ma n ner 
o n Da y 1 7 9.  S yste mic e x p os ure t o va m or ol o ne i n fe males a p peare d t o i ncrease f oll o wi n g 
re peat e d a d mi nistrati o n of va m or ol o ne at 5 m g/ k g/ da y, di d n ot a p p ear t o c h a n ge 
f oll o wi n g re peat e d a d mi nistrati o n of va m or ol o ne at 1 5 m g/ k g/ da y, a n d a p p eare d t o 
dec rease f oll o wi n g re peate d a d mi nistrati o n of va m or ol o ne at 4 5 m g/ k g/ da y.  S yste mic 
e x p os ure t o va m or ol o ne i n males a p peare d t o decrease f oll o wi n g re peat e d a d mi nistrati o n 
of va m or ol o ne. 
T he o nce d ail y a d mi nistrati o n of va m or ol o ne via oral ga va ge t o mice f or 2 6 wee ks at 5, 
1 5, a n d 4 5 m g/ k g/ da y di d n ot pr o d uce a n y a d verse effects.  T heref ore, t he N O A E L is 
c o nsidere d t o be 4 5 m g/ k g/ da y u n d er t he c o n diti o ns of t his st u d y. 
Va m or ol o ne or v e hicle w as a d mi nistere d t o bea gl e d o gs o nce dail y f or 2 8 c o nsec uti ve 
da y s at d oses of 2, 1 0 a n d 5 0 m g/ k g/ da y.  All a ni mals s ur vi ve d t o t heir sc he d ule d 
ter mi nati o n a n d n o effect of va m or ol o ne was n ote d o n gr oss vis ual i ns pecti o n, b o d y 
wei g ht, b o d y te m p erat ur e, f o o d c o ns u m pti o n, o p ht hal m ol o g y, electr ocar di o gra p h y or 
uri nal ysis para meters at necr o ps y.  A d os e- de p e n de nt decrease i n t he e x pecte d n or mal 
b o d y w ei g ht gai n was o bser ve d at all d oses b ut wei g hts ge n erall y i ncreas e d t o a n or mal 
le vel d uri n g t h e rec o ver y peri o d. 
A dre nal gla n d wei g hts decrease d wit h va m or ol o n e treat me nt, w hic h c orrel ate d wit h mil d 
or m o derate diff use bilat eral atr o p h y of t he a dre n al c orte x, mil d m ultif ocal bilateral 
vac u olati o n of t he a dre n al c orte x, i ncrease d w hite bl o o d cell a n d ne utr o p hil c o u nts, a n d 
decrease d e osi n o p hil c o u nts.  Li ver wei g hts i ncrease d i n t he 5 0 m g/ k g/ da y d ose gr o u p, 
w hic h c orrelate d wit h diff use h y pertr o p h y a n d va c u olati o n a n d i ncreas e d le vels of 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 3 7  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
al kali ne p h os p hatase a n d ga m ma gl uta m yltra nsferase.  S plee n wei g hts de crease d, w hic h 
c orrel ate d wit h l y m p h oi d de pleti o n.  T h y m us w ei g hts decrease d, w hic h c orres p o n de d t o 
diff use l y m p h oi d de pl eti o n.  Wit h t he e x ce pti o n of diff use de pl eti o n of l y m p h oc yt es i n 
t h y m us i n t he 5 0 m g/ k g gr o u p, all a b n or mal para meters ret ur n e d t o n or mal d uri n g t he 
reco ver y peri o d. 
T he N O A E L was c o nsi d ere d b y t he st u d y direct or t o be 1 0 m g/ k g/ da y.  Alt h o u g h 
re versi ble, t he li ver c h a n ges were c o nsi der e d a d v erse at 5 0 m g/ k g/ da y beca use t he 
se verit y sc ore was m o derate a n d t he c ha n ges w ere diff use i n nat ure i n all a ni mals treate d 
at t he hi g h d ose.  T his deter mi nati o n is i n c o ntrast t o t he c o ncl usi o n dra w n b y t he st u d y 
pat h ol o gist, w h o c o nsi dere d t he N O A E L t o be 5 0 m g/ k g/ da y d ue t o r e versi bilit y 
f oll o wi n g cessati o n of d osi n g ( Re v era Ge n Re p ort N o. 3 1 3 0 2). 
Va m or ol o ne or v e hicle w as a d mi nistere d t o bea gl e d o gs o nce dail y f or 3 9 wee ks at d oses 
of 2, 1 0 a n d 5 0 m g/ k g/ da y.  Si x d o gs of eac h se x recei ve d eac h d ose or place b o, a n d t w o 
of t he si x d o gs of eac h se x at eac h d ose or place b o were f oll o we d f or a n a d diti o nal 
4 wee ks t o e v al uate re versi bilit y, pr o gressi o n, or d ela ye d a p p eara nce of a n y o bser ve d 
c han ges.  O n e male d o g t hat recei ve d 5 0 m g/ k g/ d a y was e ut ha nize d i n e xtre mis o n Da y 
2 7 3 d ue t o par a p hi m osis (a n e xte n de d pe nis).  All ot her a ni mals s ur vi ve d t o t heir 
sc hed ule d ter mi nati o n.   
Detaile d c li nical o bser vati o ns c o nsi dere d test articl e-rel ate d at 5 0 m g/ k g/ da y, a n d 
re versi ble, i ncl u d e d decrease d acti vit y (c o nsi d ere d a d verse), str u g gli n g d uri n g d osi n g, 
feces s oft, li m b f u ncti o n i m paire d, i nter di gital c ysts, a n d u n ke m pt a p peara n ce 
(c o nsi dere d a d verse).  T est article-relate d, d ose- de pe n de nt i ncreases i n b o d y wei g ht gai ns 
c orrel ati n g wit h i ncreas es i n f o o d c o ns u m pti o n were o bser ve d relati ve t o c o ntr ols i n 
males at a ll d ose le vels a n d i n fe males at 1 0 a n d 5 0 m g/ k g/ da y.  Test article-rel ate d, 
re versi ble i ncreases i n a v era ge m ea n f o o d c o ns u m pti o n, relati ve t o c o ntr ols, o ver t he 
c o urse of t he 3 9- wee k d ose p hase were o bs er ve d i n b ot h se x es at 1 0 a n d 5 0 m g/ k g/ da y.   
N o test ar ticle-relate d o p ht hal m ol o gical effects were n ote d.  N o test-articl e-relate d 
c han ges w ere n ot e d i n res pirat or y rates or rectal te m perat ures.  T h ere m a y ha ve bee n a 
mil d d os e-relate d re versi ble i ncreas e i n t he heart rate at t he ter mi nal p ost- d ose i nter val 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 3 8  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
t hat was si g nifica ntl y differe nt fr o m ve hicle i n b ot h se xes f oll o wi n g t he 5 0 m g/ k g/ da y 
d ose.  S e me n a nal ysis/e v al uati o n f or test article affects c o ul d n ot be c o n d ucte d as t here 
were  n ot e n o u g h via ble s a m ples c ollecte d. 
Test article-relate d effects o n cli nical pat h ol o g y e n d p oi nts wit h micr osc o pic c orrelates 
i ncl u de d t he f oll o wi n g: 
 A he pat oc ell ular a n d he p at o biliar y effect i n males at 1 0 m g/ k g/ da y a n d b ot h se xes 
at 5 0 m g/ k g/ da y, w hic h i ncl u de d i ncrease d al kali ne p h os p hatase, ga m ma 
gl ut a m yltra nsf eras e, ala ni ne a mi n otra nsferase, a n d as partate a mi n otra nsferase 
acti vit y.  T hes e c h a n ges c orrel ate d wit h micr osc o pic c ha n ges i n t he li ver, bile 
d uct , a n d gall bla d der.  T his s pectr u m of c ha n ges was c o nsi dere d a d v erse i n b ot h 
se xes at 5 0 m g/ k g/ d a y.   
 T here w as als o e vi de n ce of a n i nfla m mat or y res p o nse i n b ot h se xes at 
5 0 m g / k g/ da y, w hic h i ncl u de d i ncrease d t otal le u k oc yt e, ne utr o p hil, a n d 
m o n oc y te c o u nts, a n d i ncrease d fi bri n o ge n a n d/ or gl o b uli n c o nce ntrati o ns.  T he 
i nflam mat or y res p o nse was li kel y sec o n dar y t o i nfla m mati o n i n t he li ver 
ass ociate d wit h he p at ocell ular necr osis.  Platelet c o u nts were als o i ncreas e d i n 
b ot h se x es at 5 0 m g/ k g/ d a y a n d ma y ha v e bee n sec o n dar y t o t he i nfla m mat or y 
res p o nse. 
F oll o wi n g a 4- w ee k rec o ver y peri o d, all n ote d cli nical pat h ol o gi cal c ha n ges res ol ve d, 
wit h t he e x ce pti o ns of i ncreas e d ala ni n e a mi n otra nsferas e acti vit y i n b ot h se xes at 
5 0 m g/ k g/ da y, a n d i ncrease d gl o b uli n i n males at 5 0 m g/ k g/ da y. 
Re versi ble, test article-relate d macr osc o pic fi n di n gs i ncl u de d mil dl y t o m o deratel y 
e nlar ge d li vers i n males a n d fe males at 5 0 m g/ k g/ d a y, w hic h c orrelat e d micr osc o picall y 
wit h pa nl o b ular he pat oc ell ular h y pertr o p h y a n d/ or he pat ocell ular v ac u olati o n; 
he m orr ha ge i n t he gall bla d der of o n e 5 0 m g/ k g/ d a y fe male, t h at was ass o ciate d wit h 
m o derate ac ute i nfla m mati o n a n d mil d vasc ular necr osis, a n d c o nsi dere d t o be a d vers e; 
re d f ocus/f o ci wit hi n t he p yl or us of t h e st o mac h of o ne 5 0 m g/ k g/ da y fe mal e a n d o ne 
male a t 1 0 m g/ k g/ da y, w hic h c orrelate d micr osc o picall y wit h mil d ac ute i nfla m mati o n i n 
t he female.   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 3 9  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
Test article-relate d or ga n wei g ht c ha n ges at t he ter mi nal necr o ps y i ncl u de d decreases i n 
a dre nal gla n d wei g hts i n b ot h se x es at ≥ 2 m g/ k g/ da y ( micr osc o pic c orrelat e of bilateral 
c ortical atr o p h y); i n creas es i n li ver wei g hts i n b ot h se x es at ≥ 1 0 m g/ k g/ da y ( micr osc o pic 
c orrel ates of pa nl o b ular he pat ocell ular h y p ertr o p h y a n d/ or he pat ocell ular vac u olati o n); 
i ncreas es i n ki d ne y wei g hts i n fe males at ≥ 1 0 m g/ k g/ da y a n d m ales at 5 0 m g/ k g/ da y 
( micr osco pic c orrel ate of bilateral t u b ular vac u olati o n); decreases i n pr ostate gla n d 
wei g hts i n males at 5 0 m g/ k g/ da y ( micr osc o pic c orrelate of decrease d secret or y pr o d u ct).  
T he se or ga n wei g ht c ha n ges were all re v ersi ble, e x ce pt f or t he decreas es i n t he pr ostate 
gla n d.   Micr osc o pic e v al uati o n re veal e d t he f oll o wi n g test article-relate d c ha n ges: 
a dre nal gla n ds (atr o p h y of t he z o na fascic ul ata a n d z o na retic ularis a n d 
h y pertr o p h y/ h y per plasi a of t he z o n a gl o mer ul osa i n b ot h se xes at ≥ 1 0 m g/ k g/ da y a n d 
atr o p h y was c o nsi d ere d a d verse); es o p h a g us a n d p yl or us of t h e st o mac h 
(er osi o n/ ulcerati o n i n a fe w a ni mals of b ot h se x es at 5 0 m g/ k g/ da y); gall bl a d der 
( h yp ertr o p h y/ h y per plasia of t he m uc osal e pit heli u m i n b ot h se x es at ≥ 1 0 m g/ k g/ da y a n d 
c yt o plas mic v ac u olati o n of t he m uc osal e pit heli u m i n males at ≥ 1 0 m g/ k g/ da y a n d 
fe males at ≥ 2 m g/ k g/ da y); li ver ( he pat o cell ular vac u olati o n i n males at ≥ 1 0 m g/ k g/ da y 
a n d females at ≥ 2 m g/ k g/ da y, p a nl o b ular h y pertr o p h y i n males at 5 0 m g/ k g/ da y a n d 
fe males at ≥ 1 0 m g/ k g/ da y, a n d i nfl a m mati o n/ necr osis i n b ot h se x es at 5 0 m g/ k g/ da y a n d 
c o nsidere d a d vers e, bile d uct h y p er plasia i n b ot h se x es at 5 0 m g/ k g/ d a y, bile d uct 
h y pertr o p h y i n males at 5 0 m g/ k g/ da y a n d fe males at ≥ 1 0 m g/ k g/ da y, a n d c yt o plas mic 
vac u olati o n of t he bile d u ct e pit heli u m i n b ot h se xes at ≥ 1 0 m g/ k g/ da y); ki d ne ys 
( bilateral t u b ular v ac u olati o n i n males at 5 0 m g/ k g/ da y a n d fe mal es at ≥ 1 0 m g/ k g/ da y 
a n d an i ncrease d i n ci de n ce of bilateral bas o p hilic t u b ules i n males a n d fe m ales at 
5 0  m g/ k g/ da y); l y m p h oi d de pleti o n i n b ot h se x es at 5 0 m g/ k g/ d a y i n ma n di b ular a n d 
mese nter ic l y m p h n o des, t h y m us a n d s plee n ( wit h e xtra me d ullar y h e mat o p oiesis i n 
5 0 m g/ k g/ da y fe m ales); b o ne marr o w i n t he ster n u m (i ncreas e d a di p oc ytes i n males at 
≥ 2 m g / k g/ d a y a n d fe m al es at 5 0 m g/ k g/ da y); t estes (s per mat o c yt e/s per mati d 
de ge nerati o n i n males at 5 0 m g/ k g/ da y); e pi di d y mi des ( oli g os per mia/ ger m cell de bris i n 
males at 5 0 m g/ k g/ da y); o varies (a bs e nt c or p ora l utea i n fe males at ≥ 2 m g/ k g/ da y a n d 
c o nsidere d a d vers e); t he ma m mar y gl a n d a n d ot her tiss ues i n t he fe male re pr o d ucti ve 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 4 0  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
tract ( uter us, cer vi x, a n d va gi n a) of t hes e a ni mals were c o nsiste nt wit h a ni mals t hat ha ve 
n ot o v ulate d; vac u olati o n i n t he e pit heli u m of t he ma m mar y gl a n d d uct i n fe males at 
5 0 m g/ k g/ da y; par oti d sali var y gla n d (c yt o plas mic alterati o n i n b ot h se xes at 
≥ 1 0 m g / k g/ d a y); bice ps fe m oris (atr o p h y of t he s keletal m uscle i n b ot h se x es at 
5 0 m g/ k g/ da y); s ki n (atr o p h y a n d al o peci a/ h y p otri c h osis i n males at 5 0 m g/ k g/ da y a n d 
fe males at ≥ 1 0 m g/ k g/ da y); pr ostat e gla n d ( d ecrease d secret or y pr o d u ct i n males at 
5 0 m g/ k g/ da y); t h yr oi d gla n ds ( bilateral i ncreas e d c oll oi d i n males at ≥ 1 0 m g/ k g/ da y). 
Ma n y  of t he fi n di n gs were felt b y t he St u d y Direct or t o be c o nsiste nt wit h t he 
p har mac ol o g y of t h e test article i ncl u di n g c ortical atr o p h y of t he a dre nal gl a n ds (affecti n g 
t he z o na fascic ulata a n d retic ularis), ge n eralize d l y m p h oi d de pleti o n i n l y m p h oi d tiss ues 
(t h y m us, s plee n, a n d l y m p h n o des), i ncrease d a di p oc yt es i n t he b o ne marr o w, atr o p h y of 
t he s keletal m uscle, al o p ecia/ h y p otric h osis a n d atr o p h y of t he s ki n (t hi n ni n g of t he 
der ma l c olla ge n a n d atr o p h y of h air f ollicles a n d a d ne x a), a n a bs e nce of c or p ora l utea i n 
t he o vary (li kel y i n dicati ve of dela ye d p u bert y), decrease d secret or y pr o d u ct i n t he 
pr ostate  gla n d, a n d m ulti ple c ha n ges i n t he li ver.  T he li ver ha d p a nl o b ular h y pertr o p h y 
a n d vac u olati o n of h e pat oc yt es c o nsiste nt wit h gl yc o ge n acc u m ulati o n.  D ue t o t he 
ma g nit u de of h y p ertr o p h y a n d v ac u olati o n, t here were (li kel y s ec o n dar y) f oci of 
he pat ocell ular n ecr osis a n d i nfla m mati o n. 
Test article-relate d micr osc o pic fi n di n gs at t he rec o ver y necr o ps y were prese nt i n t he 
a dre nal gla n ds, li ver, gall bla d der, ki d ne ys, st o mac h ( p yl or us), fe m ale re pr o d ucti ve tract 
( o varies), m ale re pr o d ucti ve tract (testes, e pi di d y mi des, pr ostate gl a n d), m ese nteric  
l ym p h n o de, s kelet al m uscle ( bice ps fe m oris), a n d par oti d sali var y gla n d. 
T he N o  O bser ve d A d v erse Effect Le vel was 2 m g/ k g/ da y f or males; a N o O bser ve d 
A d verse  Effect Le vel w as n ot o bser ve d f or fe males ( Re vera Ge n Re p ort N o. 1 9 9 8- 0 1 4).  
N o n- nai ve c y n o m ol g us m o n ke ys w ere a d mi nistere d va m or ol o ne or ve hicl e o nce d ail y f or 
7 c o nsec uti ve da ys at d oses of 1 0 0, 3 0 0, a n d 6 0 0 m g/ k g.  All a ni mals s ur vi ve d u ntil t he 
e n d of t he st u d y peri o d.  T here were effects o n cli nical o bser vati o ns, f o o d c o ns u m pti o n, 
a n d uri nal ysis attri b uta ble t o va m or ol o ne t hat are descri be d b el o w. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 4 1  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T here w as a d ose pr o p orti o nal decrease i n b o d y wei g ht gai n o bser ve d i n m ales a n d 
fe males at eac h d os e ( u p t o 1 1 % a n d 9 % res pecti v el y) relat e d t o va m or ol o n e.  A 
cessati o n of t he b o d y w ei g ht l oss i n treat me nt was o bser ve d d uri n g t he rec o ver y p hase 
b ut n o rec o ver y of b o d y wei g ht l ost d uri n g t he 7 da ys of d osi n g was o bser ve d. 
At ter mi nati o n t here w ere n o nsi g nifica nt i ncreases i n re d cell mass a n d d ecreases i n 
l y m p h oc ytes ( u p t o 5 6 %) i n t he 6 0 0 m g/ k g/ da y d ose gr o u p.  H o we v er, m ost i n di vi d ual 
a ni mals, i ncl u di n g c o ntr ols, ha d decreases i n l y m p h oc yt es ( u p t o 8 1 %) at ter mi nati o n 
relati ve t o t heir res pecti v e pretest.  T he y h a d res ol ve d b y t h e rec o ver y i nter val i n b ot h 
se x es. 
I n b ot h se x es recei vi n g ≥ 3 0 0 m g/ k g/ da y, t here was i ncrease d urea nitr o ge n ( u p t o 1 4 1 %), 
creati ni ne ( u p t o 5 8 %), t otal pr otei n ( u p t o 1 5 %), al b u mi n ( u p t o 1 1 %), gl o b uli n ( u p t o 
2 5 %), a n d/ or p otassi u m ( u p t o 3 9 %) wit h c o nc urre nt decreases i n s o di u m ( u p t o 1 0 %) 
a n d c hl ori de ( u p t o 1 0 %) relati ve t o c o ntr ols.  At t he rec o v er y i nter v al, t he maj orit y of 
t hese effects ha d res ol ve d ( Re vera Ge n Re p ort N o. 1 9 9 8- 0 0 1). 
1. 2. 3. 3  
Ge n ot o xicity 
T he  m uta ge nic a n d ge n ot o xic p ote ntial of va m or ol o ne was ass esse d i n se veral assa ys.  A 
n o n- G L P A m es scree n w as ne gati ve f or bact erial m utati o ns ( Re vera Ge n Re p ort N o. 
BI O- V B P- 0 0 1- A M E S).  I n a G L P A mes test, n o b ac k gr o u n d la w n t o xicit y was o bser v e d; 
h o we ver, a re d u cti o n i n re verta nt c o u nts w as o bser ve d ( Re vera Ge n Re p ort N o. 
A D 7 9 D T. 5 0 2I C H. B T L).  Va m or ol o ne was ne gati ve f or i n d uci n g c hr o m os o mal 
a berrati o ns i n c ult ure d m o use l y m p h oc ytes wit h o ut a n d wit h meta b olic acti vati o n 
( Re vera Ge n Re p ort N o. A D 7 9 D T. 7 0 4. B T L). 
Fe m oral b o n e marr o w was micr osc o picall y e v al u ate d f or t he prese n ce of p ol yc hr o m atic 
er yt hr oc ytes ( P C Es) c o ntai ni n g micr o n uclei.  N o si g nifica nt re d ucti o ns i n t he P C Es/ E C 
(t otal eryt hr oc ytes) rati o were o bs er ve d i n t he v a m or ol o ne gr o u ps c o m pare d t o t he 
ve hicle c o ntr ol gr o u p.  Alt h o u g h statisticall y si g nifica nt i ncreases i n t he i nci de nce of 
micr o n ucleate d P C Es i n t he va m or ol o ne tr eate d gr o u ps were o bs er ve d, n o d ose res p o nse 
was o bser v e d wit h res pect t o ot her gr o u ps a n d t he val ues of micr o n ucl ei f or t he 
i n di vi d ual a ni mals were wit hi n t he hist orical ra n ge.  T heref ore, t he statisticall y 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 4 2  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
si g nifica nt i ncreas e was c o nsi dere d as bi ol o gicall y i nsi g nifica nt ( Re vera Ge n Re p ort N o. 
A D 7 6 B K. 1 2 3 0 1 2I C H. B T L). 
A st u d y w as perf or me d t o e val uate t he p ot e ntial m uta ge ni cit y of t w o t h e oretical e p o xi de 
i m p urities relate d t o t he dr u g s u bsta n ce v a m or ol o ne (f or merl y V B P 1 5), w hic h is a 
ster oi d-li ke str uct ure c o ntai ni n g a d elta 9, 1 1 d o u ble b o n d.  T he delta 9, 1 1 e p o xi de 
str uct ures e val uate d w ere V B P 1 5- B- 3, w hic h is str uct urall y si milar t o va m or ol o ne e x ce pt 
f or t he e p o xi de m oiet y, a n d V B P 1 5- B- 2, w hic h h as a 2 1-acetate s u bstit uti o n ( va m or ol o ne 
a n d V B P 1 5- B- 3 c o ntai n a 2 1- h y dr o x y m oiet y).  T w o vali date d a n d c o m ple me ntar y 
i n silic o pre dicti o n met h o d ol o gies were us e d f or assessi n g m uta ge nic p ote ntial.  T he 
statistics- base d q ua ntitati ve str uct ure-acti vit y relati o ns hi p ( Q S A R) pr o gra m M ulti C A S E 
C A S E Ultra was use d, e m pl o yi n g f o ur differe nt m o d ules ( G T 1 _ A 7 B, G T 1 _ A T _ E C O LI, 
P H A R M _ E C O LI, a n d P H A R M _ S A L) desi g n e d t o c o ver a wi de ra n ge of m olec ular 
s u bstr uct ures c ollect e d fr o m b ot h pr o prietar y a n d p u blic c o m p o u n ds.  I n a d diti o n, t he 
e x pert r ule- base d S A R pr o gra m Dere k Ne x us was use d t o deter mi ne if t he t he oretical 
i m p urities c o ntai ne d str uct ural alerts ass ociate d wit h k n o w n ge n ot o xica nts.  C A S E Ultra 
pre dicte d b ot h V B P 1 5- B- 2 a n d V B P 1 5- B- 3 as ne gati ve f or m uta ge ni cit y [ Re vera Ge n 
Re p ort “I n Silic o M uta ge nicit y E val uati o n of Delta 9, 1 1 E p o xi de Str uct ures of V B P 1 5: 
V B P 1 5- B- 2 ( 2 1- Acet ate) a n d V B P 1 5- B- 3 ( 2 1- H y dr o x y)”]. 
Ta ke n t o get her, t hes e data i n dicate va m or ol o ne has n ot ge nerate d a m uta ge nic si g n al 
base d o n t hese si m ulati o ns. 
1. 3  
Cli nic al E x perie nce 
1. 3. 1  
P h ase I St u dy i n He alt hy A d ult V ol u nteers 
Cli nical e x perie nce is li mite d t o a si n gle P hase I cli nical trial of va m or ol o ne i n healt h y 
a d ult v ol u nteers ( V B P 1 5 -0 0 1).  T his st u d y e val uate d t he safet y, t olera bilit y, a n d P K of  
va m or ol o ne i n a P hase I ra n d o mize d, place b o -c o ntr olle d, d o u ble -bli n d, si n gle asce n di n g 
d ose ( S A D) a n d m ulti ple asce n di n g d ose ( M A D) st u d y.  I n t he S A D p orti o n of t he st u d y, 
C o h orts 1 t hr o u g h 5 a n d C o h ort 7 we re c o m prise d of ei g ht s u bjects eac h; si x s u bjects i n 
eac h c o h ort recei ve d  a si n gle oral d ose of v a m or ol o ne ( 0. 1  m g/ k g, 0. 3  m g/ k g, 1. 0  m g/ k g, 
3. 0  m g/ k g, 8. 0 m g/ k g , a n d 2 0 m g/ k g, res p ecti vel y) a n d t w o s u bjects i n eac h c o h ort 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 4 3  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
recei v e d place b o u n der faste d c o n diti o ns.  I n C o h ort 6, si x s u bjects recei ve d a si n gle oral 
d ose of  8. 0 m g/ k g v a m or ol o ne wit hi n 3 0 mi n utes of be gi n ni n g a hi g h fat/ hi g h cal orie 
meal.  T he M A D p orti o n of t he st u d y h a d f o ur c o h orts ( 6 dr u g, 2 place b o i n eac h ) 
recei vi n g 1 4 dail y d oses of va m or ol o ne ( 1. 0, 3. 0, 9. 0 a n d 2 0. 0 m g/ k g/ da y).  T he cli nical 
c o n d uct f or all se ve n S A D c o h orts, a n d all f o ur M A D c o h orts has b ee n c o m plete d; data 
a nal ysis is o n g oi n g. 
T he pri mar y o bje cti ves of t he P hase I st u d y were t o e val uate t he s afet y a n d t olera bilit y of 
si n gle an d m ulti ple oral d oses of va m or ol o ne, a n d t o e val uate t he P K of si n gle d oses a n d 
m ulti ple d oses of va m or ol o ne.  A sec o n d ar y o bjecti ve was t o e val uat e t h e effect of f o o d 
o n t he a bs or pti o n a n d P K of va m or ol o ne.  Ot her o bjecti ves were t o o btai n sa m ples fr o m 
s u bjects o n Da y 1 ( pre- d ose) a n d Da y 1 4 of t he M A D c o h orts f or us e i n Meta b olites i n 
Safet y Testi n g ( MI S T) assess me nts, a n d t o test bac k- u p P K sa m ples fr o m a s u bset of 
M A D s u bjects f or p h ar m ac o d y na mic ( P D) bi o mar kers. 
1. 3. 1. 1  
S A D C o h orts  
1. 3. 1. 1. 1  
S A D C o h orts –  P h ar m ac oki netics F aste d 
Va m or ol o ne  P K data s h o ws str o n g a d here nce t o d ose li nearit y a n d d ose pr o p orti o nalit y, 
wit h relati vel y little s u bject -s u bject v ariati o n (Fi g ure 1 , T a ble 1 , Fi g ure 2 ).  T he half-life 
wa s a b o ut 2 h o urs f or d oses 0. 1- 1. 0 m g/ k g.  D os es at 3. 0, 8. 0 a n d 2 0. 0 m g/ k g s h o w e d a n 
e x te n de d tail, i ncreasi n g half-life t o 2. 5, 3. 8 a n d 3. 8 h o urs, res pecti vel y (Fi g ure 1 ). 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 4 4  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
Fi g ure 1  
Arit h metic me a n ± st a n d ar d err or pl as m a c o nce ntr ati o ns of 
v a m o r ol o ne ( V B P 1 5) after or al a d mi nistr ati o n of si n gle d oses of 0. 1, 0. 3, 
1, 3, 8, a n d 2 0 m g/ k g t o he alt h y s u bjects u n der f aste d c o n diti o ns - li ne ar 
pl ot ( t o p); se mi-l o g arit h mic pl ot ( b ott o m) 
 
 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 4 5  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T a ble 1   
S u m m ar y of p h ar m ac o ki netic p ar a meters f or v a m o r ol o ne after or al 
a d mi nistr ati o n of si n gle d oses of 0. 1, 0. 3, 1. 0, 3. 0, 8. 0, a n d 2 0. 0 m g/ k g t o 
he alt h y s u bjects u n der f aste d c o n diti o ns 
 
C ma x  = ma xi m u m o bser ve d plas ma c o nce ntrati o n; T ma x  = ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n; A U C ( 0-t) = 
area u n der c o nce ntrati o n -time c ur ve fr o m ti me 0 t o ti me t; A U C (i nf) = area u n der c o nce ntrati o n -ti me c ur ve fr o m ti me 0 
t o i nfi nit y; z = eli mi n ati o n rate c o nsta nt;  t½  = ter mi n al half -life; C L/ F = a p pare nt t otal cleara nce fr o m plas ma; Vz/ F = 
a p pare nt v ol u me of distri b uti o n d uri n g ter m i n al p hase. 
Fi g ure 2  
Rel ati o ns hi p bet wee n i n di vi d u al s u bject v a m or ol o ne A U C( i nf) a n d d ose 
after or al a d mi nistr ati o n of si n gle d oses of 0. 1, 0. 3, 1, 3, 8, a n d 2 0 m g/ k g 
t o he alt h y s u bjects u n der f aste d c o n diti o ns 
 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 4 6  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
1. 3. 1. 1. 2  
S A D C o h orts –  P h ar m ac oki netics Fe d 
F or t he f o o d effect gr o u p, a hi g h fat meal ( 4 5 gra ms fat) was gi ve n t o a c o h ort of P hase I 
S A D v ol u nteers wit h t he 8. 0 m g/ k g d ose of va m or ol o ne.  T hese dat a were t he n c o m pare d 
t o t he faste d 8. 0 m g/ k g c o h ort data.  T his s h o we d t hat a bs or pti o n was i ncrease d b y 2. 5-
f ol d b y t he hi g h fat meal, c o nsiste nt wit h t he li p o p hilic c haracter of va m or ol o ne (ster oi dal 
c o m p o u n d) ( Fi g ure 3 , T a ble 2 ). 
Fi g ure 3  
Arit h metic me a n ± st a n d ar d err or pl as m a c o nce ntr ati o ns of 
v a m o r ol o ne ( V B P 1 5) after si n gle d ose or al a d mi nistr ati o n of 8 m g/ k g t o 
he alt h y s u bjects u n der fe d a n d f aste d c o n diti o ns - li ne ar (t o p p a nel) a n d 
se mi-l o g arit h mic ( b ott o m p a nel) a xes 
 
 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 4 7  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T a ble 2   
S u m m ar y of p h ar m ac o ki netic p ar a meters f or v a m o r ol o ne after si n gle 
d ose or al a d mi nistr ati o n of 8 m g/ k g t o he alt h y s u bjects u n der fe d a n d 
f aste d c o n diti o ns 
 
* Ge o metric mea n ( % C V) ( N) e xce pt T ma x f or w hic h t h e me dia n ( N) is re p orte d. 
† Rati o of t h e ge o metric mea ns. 
C ma x  = ma xi m u m o bser ve d plas ma c o nce ntrati o n; T ma x  = ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n; A U C ( 0-t) = 
area u n der c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o ti me t; A U C(i nf) = area u n der c o nce ntrati o n -ti me c ur ve fr om ti me 0 
t o i nfi nit y; z = eli mi n ati o n rate c o nsta nt;  t½  = ter mi n al half -life; C L/ F = a p pare nt t otal cleara nce fr o m plas ma; Vz/ F = 
a p pare nt v ol u me of distri b uti o n d uri n g ter mi n al p hase.  
1. 3. 1. 1. 3  
S A D C o h orts –  A dverse Eve nts 
O ne s u bject i n t he S A D 8. 0 m g/ k g s h o we d a dela ye d mil d ele v ati o n of li ver e nz y m es.  
T his was n ot  felt t o be dr u g-relate d d u e t o ti mi n g of t he ele vati o ns, a n d it is n ot k n o w n if 
t his was a dr u g-tr eate d or place b o s u bject (st u d y re mai ns bli n de d).  T here were n o ot her 
a d verse e ve nts ( A Es) see n i n a n y d os e gr o u p. 
1. 3. 1. 2  
M A D C o h orts   
T he  P hase I M A D treat m e nt pla n was disc usse d i n li g ht of t he i nitial P K data.  T he 
relati vely s h ort half-life of va m or ol o ne ( 2- 4 h o urs), c o u ple d wit h t he pla n ne d dail y d os e 
sc hed ule, w o ul d be e x pecte d t o gi v e P K data o n eac h si n gl e d ose, n ot c u m ulati ve d ose, as 
t he d osi n g i nter val was > 5 × t½ .  T h us, t he M A D c o m p o ne nt w o ul d be a st u d y of 
i n di vi d ual dail y d oses, rat her t ha n d ose-relate d acc u m ulati o n a n d p har mac o distri b uti o n 
relate d t o c u m ulati ve dr u g e x p os ure.  I n ot h er w or ds, a t y pical g o al of a M A D st u d y is t o 
deter mi ne stea d y stat e dr u g le vels after m ulti ple d oses; yet wit h t he s h ort h alf-life of 
va m or ol o ne, usef ul i nf or mati o n w o ul d n ot be e x pecte d t o be gai ne d wit h t he c urre nt dail y 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 4 8  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
d osi n g sc he d ul e.  Safet y a n d t olera bilit y are a d diti o nal g o als of t he M A D st u d y, a n d t h ese 
re mai n i m p orta nt e n d p oi nts i n de pe n de nt of t he P K st u dies. 
1. 3. 1. 2. 1  
M A D C o h orts –  P h ar m ac oki netics F aste d  
T he  ori gi nal desi g n f or t h e P hase I  M A D was m o difie d t o re m o ve t he t w o l o west d oses 
( 0. 1, 0. 3 m g/ k g/ da y), a n d t o be gi n d osi n g at 1. 0 m g/ k g/ da y.  T he cli nical c o n d uct of all 
f o ur c o h orts has b ee n c o m plete d ( 1. 0 m g/ k g/ da y, 3. 0 m g/ k g/ da y, 9. 0 m g/ k g/ da y, 
2 0. 0  m g/ k g/ da y) f or t he M A D  st u d y (T a ble  3 ).    
T a ble  3  
S u m m ar y of p h ar m ac o ki netic p ar a meters f or v a m o r ol o ne d uri n g or al 
a d mi nistr ati o n of 1, 3, 9, a n d 2 0 m g/ k g d oses o nce d ail y f or 1 4 d a ys t o 
he alt h y s u bjects u n der f aste d c o n diti o ns  
 
V a m or ol o ne D ose  
1 m g/ k g  
3 m g/ k g  
9 m g/ k g  
2 0 m g/ k g  
Da y 1  
C ma x  ( n g/ m L) 
1 5 3  ( 1 5. 9) 
2 8 1 ( 3 6. 9)  
1, 0 8 2 ( 2 3. 3)  
2, 4 1 6 ( 5 1. 1)  
T ma x  ( hr) 
3. 0 4  
2. 0 1  
1. 7 5  
1. 0 0  
[ 1. 5 0 –  4. 0 0]  
[ 1. 0 0 –  3. 0 0]  
[ 1. 0 0 –  6. 0 0]  
[ 0. 5 0 –  3. 0 0]  
A U C ( 0-t) 
( hrxn g/ m L)  
6 8 6 ( 2 2. 4)  
1, 4 7 1 ( 2 3. 6)  
5, 7 0 9 ( 2 9. 9)  
1 0, 1 8 2 ( 2 8. 1)  
A U C ( 0-2 4) 
( hr× n g/ m L)  
6 8 6 ( 2 2. 4)  
1, 4 7 1 ( 2 3. 6)  
5, 7 0 9 ( 2 9. 9)  
1 0, 1 8 2 ( 2 8. 1)  
A U C (i nf) 
( hr× n g/ m L)  
6 9 5 ( 2 2. 1)  
1, 4 8 7 ( 2 3. 7)  
5, 7 4 5 ( 2 9. 5)  
1 0, 1 9 0 ( 2 7. 0)  
z ( 1/ hr) 
0. 3 8 4 8 ( 1 0. 9)  
0. 2 9 1 8 ( 1 8. 1)  
0. 2 3 1 7 ( 2 2. 6)  
0. 1 7 4 7 ( 4 4. 3)  
t½  ( hr) 
1. 8 0 ( 1 0. 9)  
2. 3 8 ( 1 8. 1)  
2. 9 9 ( 2 2. 6)  
3. 9 7 ( 4 4. 3)  
C L/ F ( L/ hr/ k g)  
1. 4 4 ( 2 2. 1)  
2. 0 2 ( 2 3. 7)  
1. 5 7 ( 2 9. 5)  
1. 9 6 ( 2 7. 0)  
V z/ F ( L/ k g) 
3. 7 4 ( 1 6. 9)  
6. 9 1 ( 3 4. 8)  
6. 7 6 ( 4 6. 9)  
1 1. 2 ( 7 7. 6)  
Da y 1 4  
C ma x  ( n g/ m L) 
2 0 3 ( 3 0. 1)  
2 7 6 ( 3 5. 6)  
9 3 5 ( 4 8. 3)  
2, 4 9 1 ( 2 7. 9)  
T ma x  ( hr) 
2. 9 6  
2. 5 0  
1. 2 5  
2. 0 0  
[ 1. 5 0 –  3. 0 0]  
[ 1. 0 0 –  4. 0 0]  
[ 0. 5 5 –  3. 0 0]  
[ 1. 0 0 –  2. 0 0]  
A U C ( 0-2 4) 
(hr × n g/ m L)  
7 9 4 ( 2 2. 3)  
1, 4 9 4 ( 1 8. 6)  
4, 3 6 6 ( 2 0. 2)  
9, 3 0 9 ( 3 8. 8)  
z ( 1/ hr) 
0. 3 9 9 3 ( 2 0. 4)  
0. 3 2 7 3 ( 2 5. 2)  
0. 1 6 2 9 ( 6 3. 5)  
0. 1 8 7 9 ( 3 1. 6)  
t½ ( hr) 
1. 7 4 ( 2 0. 4)  
2. 1 2 ( 2 5. 2)  
4. 2 5 ( 6 3. 5)  
3. 6 9 ( 3 1. 6)  
C L/ F ( L/ hr/ k g)  
1. 2 6 ( 2 2. 3)  
2. 0 1 ( 1 8. 6)  
2. 0 6 ( 2 0. 2)  
2. 1 5 ( 3 8. 8)  
V z/ F ( L/ k g) 
3. 1 5 ( 2 0. 6)  
6. 1 4 ( 3 9. 7)  
1 2. 7 ( 7 9. 9)  
1 1. 4 ( 4 9. 1)  
C ma x  = ma xi m u m o bser ve d plas ma c o nce ntrati o n; T ma x  = ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n; A U C ( 0-t) = 
area u n der c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o ti me t; A U C ( 0-2 4) = area u n der c o nce ntra ti o n-ti me c ur ve fr o m ti me 0 
t o 2 4 h o urs; A U C (i nf) = ar ea u n der c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o i nfi nit y; z = eli mi n ati o n rate c o nsta nt;  t½  = 
ter mi n al half-life; C L/ F = a p pare nt t otal cleara nce fr o m plas ma; Vz/ F = a p pare nt v ol u me of distri b uti o n d uri n g ter mi n al 
p hase.  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 4 9  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
Ta ki n g i nt o acc o u nt t he s mall n u m bers a n d differe nt s u bjects, t he ge o metric mea n val ues 
f or Cma x , A U C(0 -t), a n d A U C(i nf) are n ot differe nt f or t he S A D a n d M A D c o h orts.  Wit hi n 
t he M A D, t here is g o o d a gree me nt bet w ee n Da ys 1 a n d 1 4 at all d ose gr o u ps.  T here is n o 
acc u m ulati o n —  t he ge o metric mea n Cma x  a n d A U C ( 0-2 4 ) o n Da ys 1 a n d 1 4 are n ot 
differe nt, c o nsiste nt wit h t he t ½  ( ~ 2 h o ur) a n d d osi n g i nter val ( 2 4 h o urs) (F i g ure 4; 
T a ble  3 ).  
Fi g ure 4  
Arit h metic me a n ± st a n d ar d err or pl as m a c o nce ntr ati o ns of 
v a m o r ol o ne ( V B P 1 5) o n D a ys 1 a n d 1 4 d uri n g or al a d mi nistr ati o n of 
1, 3, 9, a n d 2 0 m g/ k g d oses o nce d ail y f or 1 4 d a ys t o he alt h y s u bj ects 
u n der f aste d c o n diti o ns (li ne ar a xes) 
 
 
1. 3. 1. 2. 2  
M A D C o h orts –  A dverse Eve nts  
T hre e s u bjects ha ve disc o nti n ue d d osi n g; o ne s u bject ( 1. 0 m g/ k g/ da y gr o u p) wit h dre w 
c o nse nt o n Da y 1 0 s o t hat he c o ul d recei ve care f or a n e x acer bati o n of a pre vi o usl y 
e xisti n g de ntal c o n diti o n.  D osi n g was disc o nti n ue d i n a sec o n d s u bject o n Da y 9 ( o n 
place b o i n t he 1. 0 m g/ k g/ da y c o h ort after c o m pleti n g 8 da ys of d osi n g) d ue t o a n i ncreas e 
i n ala ni ne ami n otra nsf erase ( A L T).  T h e s u bject’s baseli ne val ue was 4 0 ( n or mal ≤ 5 0); 
o n Da y s 7, 8, a n d 9, it was 7 0, 8 6, a n d 1 0 6, res pecti vel y.  F oll o wi n g cessati o n of d osi n g, 
t he A LT has sl o wl y decli ne d a n d is c o nti n ui n g t o be f oll o we d.  As partate 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 5 0  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
a mi n otra nsferase ( A S T) was wit hi n n or mal li mits wit h t he e x ce pti o n of a val ue of 4 7 o n 
Da y 9 ( n or ma l ≤ 4 5), w hic h was a gai n n or mal t he f oll o wi n g da y.  Al kali ne p h os p hatase, 
bilir u bi n, a n d c oa g ulati o n para meters ha ve re mai ne d wit hi n n or mal li mits a n d t he s u bject 
has re mai ne d as y m pt o matic.  A t hir d s u bject w h o was o n acti ve dr u g i n t he 2 0 m g/ k g 
d ose gr o u p was disc o nti n ue d after 9 da ys of d osi n g d ue t o a n i ncrease i n A L T.  T he 
s u bject’s baseli ne v al ue was 4 3 ( n or mal ≤ 5 0) at scree ni n g; o n D a ys 7, 8, a n d 9, it was 
5 6, 6 0, a n d 7 3, r es pecti vel y.  F oll o wi n g cessati o n of d osi n g, t he A L T i ncrease d t o 9 6 a n d 
1 0 4 o n Da ys 1 0 a n d 1 2; o n Da y 1 7, it ha d decli ne d t o 8 5.  T he s u bject c o nti n ues t o be 
f oll o we d an d has re mai n e d as y m pt o matic.  As part ate a mi n otra nsferas e was wit hi n 
n or mal l i mits wit h t he e xce pti o n of a val u e of 4 7 o n Da y 1 2 ( n or mal ≤ 4 5); t otal bilir u bi n 
was 0. 7  at scree ni n g ( n or mal 0. 2- 1. 2); it was i ncrease d at 1. 4, 1. 9, a n d 1. 4 o n Da ys 1, 2, 
a n d 3, res pecti vel y, a n d wit hi n n or mal li mits f or t he re mai n der of d osi n g a n d f oll o w- u p.  
N o s u bject i n t he 3. 0 or 9. 0 m g/ k g/ da y c o h orts h a d t o disc o nti n ue d osi n g f or a n A E. 
1. 3. 1. 2. 3  
P h ar m ac o dy n a mic S af ety Bi o m arkers 
Va m or ol o ne has s h o w n i m pr o ve d safet y pr ofiles relati ve t o pre d nis o ne i n n o ncli nical 
testi n g, b ot h i n vitr o a n d i n viv o.1 5 ,1 7  Safet y c o n cer ns wit h gl uc oc ortic oi ds i ncl u de 
s u p pressio n of t he a dre nal a xis a n d i ns uli n resista nce.  P har mac o d y na mic bi o mar ker 
assa ys of s u p pressi o n of t he a dre n al a xis (ser u m c ortis ol) a n d i ns uli n resista nce (ser u m 
gl uc ose) were me as ure d i n t he P hase I M A D st u di es of va m or ol o ne. 
S u p pressi o n of t he a dre n al a xis.  Pre d nis o ne directl y i m pi n ges o n c ortis ol r e g ul at or y 
pat h wa ys (a dre nal a xis) b ot h ac utel y a n d c hr o nicall y.  Ac ute s u p pressi o n of a dre n al 
f u ncti o n is see n wit hi n h o urs of d oses of a si n gle 0. 1 m g/ k g/ da y (a p pr o xi mate) d ose of 
pre d nis o ne, as e vi de nce d b y re d ucti o ns i n a dre n o c ortic otr o pic h or m o ne  (A C T H) le vels i n 
n or mal v ol u nteers. 2 5  M ore c hr o ni c s u p pressi o n of t he a dre n al a xis, c haract erize d as 
se vere, is t y picall y dia g n ose d w he n m or ni n g c ortis ol is < 1 0 0 n m ol/ L ( < 3. 6 
mic r o gra m/ d L) w h e n dra w n > 2 4 hrs after t he last d ose of p har m ac ol o gical ster oi ds. 
M or ni n g se r u m c ortis ol le vels were meas ure d i n t he va m or ol o ne P hase I M A D c o h orts, at 
baseli ne ( pri or t o dr u g a d mi nistrati o n), 2 4 h o urs after t he first d ose ( Da y 1), a n d 2 4 h o urs 
after t he 1 4- da y d ose ( Da y 1 5) ( Fi g ure 5 ).  Acti ve s u bsta nce v ol u nteers at f o ur M A D 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 5 1  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
d ose le vels are s h o w n ( 1. 0 m g/ k g/ da y; 3. 0 m g/ k g/ da y; 9. 0 m g/ k g/ d a y; 2 0. 0 m g/ k g/ da y); 
all s u bjects were treate d f or 1 4 da ys wit h dail y d osi n g.  T he re d hat c he d li ne o n eac h 
gra p h s h o ws a t y pic al t hres h ol d f or a dre nal a xis s u p pressi o n ( < 1 0 0 n m ol/ L, or 
< 3. 6 µ g/ d L).  P val ues s h o w n are f or pair e d T test, i n dicati n g si g nifica nce of t he 
c o nsiste nc y of l o n git u di nal c ha n ges of s u bjects rel ati ve t o t heir o w n i n di vi d ual baseli ne 
val ues.  Ac ute a dre n al a xis s u p pressi o n is meas ure d at 2 4 h o urs (aft er first d ose), w hereas 
c hr o nic a dre nal a xis s u p pressi o n is meas ure d after 1 4 da ys of dail y d osi n g ( 2 4 h o urs after 
last d ose).  
Fi g ure 5  
M or ni n g c ortis ol me as u res i n t he v a m or ol o ne P h ase I M A D 
v ol u n teers. * 
*  Place b o s u bj ects fr o m eac h of t he f o ur M A D c o h orts are gra p he d t o get her.   
Va m or ol o ne s h o we d little e vi de nce of eit her ac ut e ( 2 4 h o ur data), or c hr o nic ( Da y 1 5 
data) s u p pressi o n of t h e a dre nal a xis at d oses of eit her 1. 0 m g/ k g/ da y or 3. 0 m g/ k g/ da y.  
T he data s u g gest t hat va m or ol o ne i n d uces vari a ble, mil d, ac ute a n d c hr o ni c s u p pressi o n 
of t he a dre nal a xis at 9. 0 m g/ k g/ da y, a n d str o n ger e vi de nce of b ot h ac ute a n d c hr o nic 
a dre nal a xis s u p pressi o n at 2 0. 0 m g/ k g/ da y.  Pre d nis o ne t y picall y s h o ws b ot h ac ute a n d 
c hr o nic a dre nal a xis s u p pressi o n a p pr o xi matel y at 0. 1 m g/ k g/ da y, 2 5 s u g gesti n g t hat 
va m or ol o ne has a n i m pr o ve d safet y wi n d o w re gar di n g a dre nal a xis s u p pressi o n. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 5 2  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
Va m or ol o ne t h us s h o ws a p pr o xi matel y a 1 0 0-f ol d i m pr o ve me nt i n safet y wi n d o w 
c o m pare d t o pr e d nis o ne o n a m g/ k g c o m p arati ve basis.  T hese data are c o nsiste nt wit h i n 
vitr o a n d ex vi v o n o ncli nical m o use data c o m pari n g V B P 1 5/ va m or ol o ne t o pre d nis o ne f or 
a dre nal s u p pressi o n. 1 5 
I ns uli n resista n ce.  Pre d nis o ne i n d uces t he safet y si g nal of i ns uli n resista nce, w here 
gl uc ose is n ot efficie ntl y ta ke n u p fr o m t he bl o o d b y tar get tiss ues, s uc h as m uscle a n d 
li ver, lea di n g t o h y p er gl yce mia.2 5  I ns uli n resista nce ma y be a n i m p orta nt s afet y si g nal 
f or d ystr o p hic m uscle, w here t he d ysf u ncti o nal m y ofi bers ha ve bee n s h o w n t o ha ve 
i na de q uate e ner g y st or es,1 8 ,2 6 a n d i ns uli n resista nce li kel y li mits a vaila bilit y of gl yc o ge n 
s u bstrates f or gl yc ol ysis.  T he h y p er gl yce mia, i n t ur n, lea ds t o c hr o nic i n creases i n 
i ns uli n le vels ( h y peri ns uli ne mia).   
Le v els of fasti n g gl uc os e a n d i ns uli n are reas o na bl y se nsiti ve a n d relia ble m eas ures of 
i ns uli n resista nce i n n o n- dia betic i n di vi d uals.  Gl uc ose is ac utel y (si n gle d os e) a n d 
c hr o nicall y ( m ulti ple d oses) ele vate d aft er treat me nt wit h p har mac ol o gical 
gl uc o c ortic oi ds.  Gl uc ose is ele vate d 2 4 h o urs after a si n gl e a d mi nistrati o n of 
gl uc o c ortic oi ds ( 2. 0 m g/ k g). 2 7 ,2 8 
I n t he P h ase I M A D of va m or ol o ne, fasti n g ser u m gl uc ose was me as ure d at 1 0 ti me 
p oi nts d uri n g t he 2- w ee k st u d y; eac h sa m ple was ta ke n 2 4 h o urs after t he pre vi o us d ose 
of va m or ol o ne ( Fi g ure 6 ). 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 5 3  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
Fi g ure 6  
F asti n g ser u m gl uc ose d uri n g t he P h ase I M A D peri o d (t w o wee ks d ail y 
treat me nt)  
 
Gl uc ose le vels f or all va m or ol o ne d ose gr o u ps were si milar t o t h ose of t he place b o gr o u p.  
T here w as n o e vi de n ce of ele vati o ns of gl uc os e le vels at a n y ti me p oi nt or a n y d os e of 
va m or ol o ne, s u g gesti n g t hat t he si de effect of i ns uli n resista nce was n ot see n wit h 
va m or ol o ne.  T hese d ata are c o nsiste nt wit h a n o n cli nical st u d y i n a d ystr o p hi n- deficie nt 
m o use  m o del, w here c hr o nic treat me nt of pre d nis ol o ne ( 5 m g/ k g/ da y) vers us va m or ol o ne 
( 1 5 m g/ k g/ da y; 3 0 m g/ k g/ da y) s h o we d de v el o p me nt of i ns uli n resista nce wit h 
pre d nis ol o ne, b ut n ot va m or ol o ne. 2 9 
1. 3. 1. 3  
S u m m ary of P h ase I d at a 
In s u m mar y: 
 Va m or ol o ne P K data s h o w str o n g a d here nce t o d ose li nearit y a n d d ose 
pr o p orti o nalit y, wit h rel ati vel y little s u bject-s u bject variati o n ( b ot h S A D a n d 
M A D). 
 T he half-life was a b o ut 2 h o urs f or d oses 0. 1- 1. 0 m g/ k g.  D oses at 3. 0, 8. 0, a n d 
2 0. 0  m g/ k g s h o we d a n e xte n de d tail, i ncreasi n g h alf-life t o 2. 5, 3. 8, a n d 3. 8 h o urs, 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 5 4  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
res pecti vel y.  T h e P K f or t he M A D c o h orts was ver y si milar t o t he S A D c o h orts, 
s h o wi n g little if a n y dr u g acc u m ulati o n, c o nsiste nt wit h t he s h ort half-life a n d dail y 
d osi n g sc he d ul e. 
 F or t he f o o d effect gr o u p, a hi g h fat meal w as gi ve n t o a c o h ort of P has e I S A D 
v ol u nt eers wit h t he 8. 0 m g/ k g d ose of v a m or ol o ne.  T hese data were t he n c o m pare d 
t o t he faste d 8. 0 m g/ k g c o h ort data.  T he c o m paris o n s h o we d t hat a bs or pti o n was 
i ncreas e d b y 2. 5-f ol d b y t he hi g h fat meal, c o nsist e nt wit h t he li p o p hilic c haract er 
of va m or ol o ne (ster oi dal c o m p o u n d). 
 F or t he M A D c o h orts, t h ere were n o A Es precl u di n g f urt her es calati o ns i n d osi n g.  
 Re gar di n g t he pri mar y t ar get or ga n, li ver, o ne s u bject o n place b o  i n t he 1. 0 
m g/ k g/ da y c o h ort a n d o n e s u bject o n va m or ol o ne i n t he 2 0 m g/ k g/ da y c o h ort 
s h o we d mil d ele vati o ns of li ver e nz y m es, a n d dr u g d osi n g was h alte d.  N o s u bjects 
i n t he 3. 0 or 9. 0 m g/ k g/ d a y M A D c o h orts s h o w e d ele vati o ns of li ver e nz y mes. 
 Safet y P D bi o mar ker st u dies s h o we d t hat va m or ol o ne ha d a n i m pr o ve d s afet y 
wi n d o w f or a dre nal a xis s u p pressi o n ( 1 0 0-f ol d i ncrease i n t hera pe utic wi n d o w), a n d 
n o e vi de nce of i ns uli n resista nce, c o m pare d t o pre d nis o ne st u dies re p orte d i n t he 
literat ure. 
T he res ults s h o w t hat t he half-life of v a m or ol o ne is ver y si milar t o gl uc oc ortic oi ds, s uc h 
as pre d nis o ne.  D es pite t he s h ort half-life, pre d nis o ne is t y picall y gi ve n o nce per da y f or 
m ost i n dic ati o ns (i ncl u di n g D M D), a n d o nce dail y d osi n g is als o pr o p ose d f or 
va m or ol o ne.  Pre vi o us st u dies of i ncreasi n g t h e fre q ue nc y of dr u g a d mi nistrati o n of 
gl uc o c ortic oi ds ha ve s h o w n t hat t his has i ncreas e d si de effect pr ofiles wit h o ut a 
si g nifica nt gai n i n effic ac y.  T h us, t he mec ha nis m of acti o n of gl uc oc ortic oi ds ma y b e 
relate d t o t he s h ort-t er m ( p ulse d) dail y dr u g e x p os ure.  As va m or ol o n e is t h o u g ht t o s hare 
a si milar a nti-i nfla m mat or y me c ha nis m of acti o n as gl uc oc ortic oi ds ( N F- B i n hi biti o n), 
it is felt t hat t he dail y p ulse d e x p os ure i n t he P hase I M A D is m ost rele va nt t o t he pla n ne d 
clinical trials i n D M D i ncl u di n g t he P hase II M A D a n d P hase II efficac y/s afet y st u dies, 
w here d ail y d osi n g sc he d ules will be f oll o we d.  T he o pti o n of i ncreasi n g t h e d osi n g 
re gi me n i n t he P hase I M A D t o better st u d y dr u g acc u m ulati o n a n d stea d y state P D  was 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 5 5  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
c o nsi dere d, b ut t his was f elt t o be u nrelate d t o pla n ne d P hase II tri als, a n d dr u g 
mec ha nis m of acti o n. 
1. 4  
R ati o n ale f or St u d y Desi g n 
Va m or ol o ne  is u n der de v el o p me nt f or t he treat me nt of D M D.  T he first-i n- h u ma n cli nical 
assess me nt of va m or ol o n e is o n g oi n g i n t he S A D/ M A D st u d y ( V B P 1 5- 0 0 1) a n d is 
pr o vi di n g a n i nitial cli nic al assess me nt a n d ass ess me nt of t he P K c haracteristics of 
va m or ol o ne  f oll o wi n g a d mi nistrati o n of a n oral s us pe nsi o n of va m or ol o ne i n healt h y 
a d ult s u bjects.  W hile t here are li kel y t o be s o me differe n ces b et wee n a d ults a n d c hil dre n, 
a n d bet wee n healt h y a n d D M D s u bjects, t he data fr o m V B P 1 5- 0 0 1 ha v e est a blis he d t he 
2- 4 h o ur half-life of va m or ol o ne, f o o d effect, d ose pr o p orti o nalit y a n d vari a bilit y a m o n g 
s u bjects. 
A P hase IIa M ulti ple Asce n di n g D os e  st u d y ( V B P 1 5-0 0 2 ) w ill deter mi ne t he safe a n d 
t olera ble d ose(s) of va m or ol o ne  t o e na ble f ut ure st u dies wit h c hr o nic a d mi nistrati o n i n 
D M D s u bjects, a ge d 4 -7 years .  T he n arr o w a ge wi n d o w f or t his st u d y is dri ve n  b y 
se veral f act ors: 1) t h e a v era ge a ge of dia g n osis is still a p pro xi matel y 4. 8 years d ue t o lac k 
of scree ni n g pr o gra ms; 2) t he c urre nt sta n dar ds of cli nical care i n Wester n c o u ntries , 
w here gl uc o c ortic oi d  t hera p y is t y picall y i nitiate d be t wee n 5 a n d 7 years of a ge f or D M D 
patie nts; a n d 3) t he o bser vati o n t hat  pea k f u nct i o n f or D M D patie nts occ urs at ar o u n d 
7  years  of a ge  (after w hic h ti me m ost affecte d mal es wit h D M D  will be gi n t o decli ne ), all 
of w hic h res ult i n a narr o w a ge wi n d o w t o i de ntif y ster oi d -nai ve males wit h D M D.    
Ke y safet y p ara m eters i n c o nj u ncti o n wit h P K data are bei n g e val uate d d uri n g t he c o urse 
of t he P hase IIa st u d y t o assess va m or ol o ne  safet y a n d t olera bilit y.  E x pl ora t or y cli nical 
effic ac y para meters a n d P D b i o mar kers of tiss ue brea k d o w n a n d re p air are als o bei n g 
e val uate d. 
T he va m or ol o ne  d e vel o p me nt pr o gra m has ma de a d va nces i n bi o mar ker disc o ver y a n d 
de vel o p me nt i n D M D, wit h a s u bset of t hese st u dies rece ntl y p u blis he d. 3 0  A pa nel of 
bi o mar kers i n D M D pati e nt sera t hat s h o w res p o nse t o c hr o nic ( ~ 4 m o nt h) treat me nt wit h 
gl uc o c ortic oi ds has bee n i de ntifie d.  T hese c hr o nic pre d nis o ne P D bi o mar kers were 
disc o vere d t hr o u g h st u d y of ser u m sa m ples of D M D patie nts e nr olle d i n t he C o o perati ve 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 5 6  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
I nter nati o nal N e ur o m usc ular Researc h Gr o u p (CI N R G ) D uc he n n e Nat ural Hist or y St u d y  
( D N H S).  S o ma Sca n a pt a mer pa n els testi n g 1, 2 0 0 ser u m pr otei ns were use d t o disc o ver a 
ca n di date set of pre d nis o ne -res p o nsi ve bi o mar kers, wit h a s u bset of t hese vali dati n g i n a 
l o n git u di nal sa m ple set (i n di vi d ual D M D patie nts pre/ p ost ster oi d treat me nt).  T hese P D  
bi o mar kers were assi g n e d t o a safet y pa n el or effi cac y p a nel base d o n c o m paris o n t o 
n or mal c o ntr ols a n d i nf or mati o n c o ncer ni n g t he f u ncti o n of eac h pr otei n ( T a ble 4 ).  All 
safet y bi o mar kers were v ali date d i n a se parate c o h ort of pe diatric i nfl a m mat or y dise ase 
patie nts (l o n git u di nal pre/ p ost ster oi ds).  T he sa me S o ma Sca n assa y will b e use d o n t he 
c hr o nic sa m ples fr o m t he va m or ol o ne P hase IIa tri al (e ntr y, 2 wee ks treat me nt, 2 wee ks 
was h o ut), wit h i nitial data a nal yses li mite d t o t h ose vali date d bi o mar k ers s h o w n 
(T a ble  4 ). 
T a b le 4  
Bi o m ar kers pre vi o usl y defi ne d t o be res p o nsi ve t o c hr o nic d oses of 
gl uc oc ortic oi ds i n D M D b o ys 
C hr o nic s af et y  
Ass a y met h o d  
C hr o nic effic ac y  
Ass a y met h o d  
M M P -3   
S o ma Sca n  
C D 2 3  
S o ma Sca n  
Le pti n  
S o ma Sca n  
M D C  
S o ma Sca n  
I ns uli n  
S o ma Sca n  
I L-2 2 B P  
S o ma Sca n  
I G F B P-5  
S o ma Sca n  
L y m p h ot o xi n a 1/ b 2  
S o ma Sca n  
A n gi ote nsi n o ge n  
S o ma Sca n  
I G F B P-2  
S o ma Sca n  
Afa mi n  
S o ma Sca n  
I nte grin a 1 b 1; C D 4 9a  
S o ma Sca n  
1 7 -h y dr o x y pr o gester o ne  
L C -M S  
M M P -1 2  
S o ma Sca n  
C ortic oster o ne  
L C -M S  
 
 
T est oster o ne  
L C -M S  
 
 
1 1 -de o x yc ortis ol  
L C -M S  
 
 
 
A dre nal a xis s u p pressi o n is a well-d oc u me nte d s afet y si g nal wit h c hr o nic use of 
gl uc o c ortic oi ds .  As n ote d a b o ve,  n o n cli nical d ata s u g ge st t hat va m or ol o n e  ma y n ot ca use 
a dre nal a xis s u p pressi o n.  T o test w het her va m or ol o ne  treat me nt ca uses c hr o nic a dre n al 
a xis s u p pressi o n, f o ur ster oi d h or m o nes will be teste d b y L C-M S i n t he va m or ol o ne -
treate d D M D b o ys ( 1 7-h y dr o x y pr o gester o n e, c ortisc oster o ne, test oster o ne, 
1 1 -de o x yc ortis ol) ( T a ble 4 ).  All f o ur ster oi d h or m o nes s h o we d si g nifi ca nt re d ucti o ns 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 5 7  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
after gl uc o c ortic oi d treat me nt i n D M D b o ys i n t h e cr oss -s ecti o nal a n d l o n git u di nal 
CI N R G D N H S partici pa nts . 
T he c urre nt st u d y is desi g ne d t o pr o vi de l o n g -ter m safet y, efficac y, a n d P D  data f or t h e 
va m or ol o ne  d o se(s) t hat are rec o g nize d as safe a n d well -t olerate d i n Phase IIa st u d y 
V B P 1 5 -0 0 2 testi n g a n d w hic h are a ntici pate d t o be teste d i n a fut ur e  P has e II b st u d y.  
E nr oll me nt i n t he Phase IIa e xte nsi o n st u d y will be offere d t o s u bjects w h o c o m plete t he 
P hase IIa st u d y, i n or d er t o e xte n d t he treat me nt d urati o n a n d i ncrease t he p ote ntial f or 
direct be nefit of st u d y tr eat me nt t o t hese pe diatr ic D M D patie nts.   Eac h s u bject  will 
recei ve va m or ol o ne tr eat me nt i n t his P hase IIa e xte nsi o n st u d y at t he sa m e d ose le vel he 
recei v e d i n t he Phase IIa  st u d y.  It is a ntici pate d t h at s u bjects will e nr oll i n t his st u d y o n 
o ne of f o ur d os e le v els (0. 2 5 , 0. 7 5,  2. 0 , or 6 . 0 m g/ k g/ da y ) a n d c o nti n ue o n t hat d ose le vel 
f or t he d urati o n of t h e 2 4 -wee k st u d y .  E v al uati o n of u p t o f o ur d ose le vels  i n t his l o n g-
ter m st u d y will all o w c o m paris o n of t he d ose le vels f or c ha n ge fr om B as eli ne i n safet y 
para meters, m uscle stre n gt h a n d f u ncti o n effi cac y para me ters, a n d P D bi o mar ker le v els 
o ver 2 4 wee k s of treat me nt; i n partic ular, f or t he P D bi o mar kers, e val uati o n of c ha n ge 
fr o m B as eli ne o ver a l o n ger (2 4 -wee k) peri o d ma y ai d i n t he cli nical vali dati o n of 
bi o mar kers  w hic h  e x hi bi t s mall c ha n ges o ver ti me.  C o m paris o ns of  efficac y a n d s afet y 
para meters wit h hist orical nat ural hist or y ( u ntreat e d) 3 1 ,3 2 ,3 3 ,3 4 a n d pre d nis o ne-treate d 
c o ntr ol gr o u ps 3 5 will be perf or me d as pri mar y o ut c o mes of t his st u d y.  
T his tria l will be c o n d ucte d i n c o m plia nce wit h t his pr ot oc ol, G o o d Cli nical Practice 
( G CP), a p plica ble F o o d a n d Dr u g A d mi nistrati o n ( F D A) re q uir e me nts, a n d t he rece ntl y 
iss ued F D A g ui da n ce o n de vel o pi n g dr u gs f or tr eat me nt f or D uc he n n e m usc ular 
d y str o p h y a n d relate d d ystr o p hi n o pat hies. 3 6 
It is o bli gat or y t hat t he I n vesti gat or b ec o me fa miliar wit h all secti o ns of t he Va m or ol o ne 
I n v esti gat or’s Br oc h ure.2 9 
1. 5  
O ver all  Be nefit/ Ris k 
T he c urre nt st u d y is a l o n g-ter m safet y a n d efficac y st u d y i n y o u n g b o ys wit h D M D.  It is 
a ntici pate d t hat t he a d v erse effect pr ofile of t he i n vesti gati o nal pr o d u ct will be m ore 
fa v orabl e t ha n sta n dar d of care gl uc oc ortic oi ds i n t he l o n g ter m.  T he a d v erse effects of 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 5 8  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
va m or ol o ne o ver a 2 4- w ee k treat me nt peri o d are n ot c urre ntl y k n o w n.  I n t he P hase I 
S A D/ M A D st u d y i n he alt h y a d ults, n o seri o us a d v erse e v e nts were o bser ve d i n a n y 
c o h ort.  C o h orts t este d i n t he P hase I M A D st u d y were 1. 0, 3. 0, 9. 0 a n d 2 0. 0 m g/ k g/ da y 
f or 1 4 days.  I n t he P has e I M A D cli nical trial i n a d ult v ol u nteers, va m or ol o ne s h o we d 
s u p pressi o n of t he a dre nal a xis at hi g her d oses ( 9. 0 m g/ k g/ da y a n d 2 0. 0 m g/ k g/ da y i n t he 
faste d state).2 9  I nstr u cti o ns f or detecti n g a dre n al crisis a n d t he circ u msta nces i n w hic h 
stress d ose ster oi ds s h o ul d be pr o vi de d will be i ncl u de d i n t he i nf or me d c o nse nt f or m 
(I C F).   
S u bjec ts ma y or m a y n ot recei v e direct healt h be n efit fr o m partici pati n g i n t he st u d y.  
S u bjec ts will recei ve v a m or ol o ne at o ne of f o ur pla n ne d d ose le vels ( 0. 2 5 m g/ k g/ da y, 
0. 7 5 m g/ k g/ da y, 2. 0 m g/ k g/ da y, or  6. 0 m g/ k g/ da y) o ver t he c o urse of t he 2 4 - wee k tri al.  
W hile it is a ntici pate d fr o m n o ncli nical st u dies t hat t hese d ose le vels ma y b e  effi caci o us 
i n t he treat me nt of D M D, t here are n o cli nical effi cac y d ata yet a v aila ble t o vali date t his 
h y p ot hesis.  I n vie w of t h e i nitial cli nical e vi de nce of safet y a n d t h e m o nit ora ble nat ur e of 
ke y  n o n cli nical t o xic ol o gical fi n di n gs, d ata s u p p ort a n acce pta ble ris k pr ofile f or 
va m or ol o ne. 
2  
S T U D Y O B J E C TI V E S A N D  E N D P OI N T S 
2. 1  
St u d y O bjecti ves 
2. 1. 1  
Pri m ary O bjectives 
T he pri mar y o bje cti ves of t his st u d y are: 
1.  T o e val uate t he l o n g-ter m safet y a n d t olera bilit y of va m or ol o ne, a d mi nistere d 
ora ll y at dail y d os es u p t o 6. 0 m g/ k g o ver a 2 4- wee k Treat me nt Peri o d, i n b o ys 
a ges 4- 7 years wit h D M D;  
2.  T o c o m pare t h e efficac y, as meas ure d b y t he Ti me t o Sta n d Test ( T T S T A N D), of 
va m or ol o ne  a d mi nistere d orall y at dail y d os es u p t o 6. 0 m g/ k g o ver a 2 4- wee k 
Tre at me nt Peri o d vs. u ntreate d D M D hist orical c o ntr ols i n b o ys a ges 4- 7 years 
wit h D M D; a n d 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 5 9  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
3.  T o c o m pare t h e safet y, as meas ure d b y b o d y mass i n de x ( B MI) z-sc ore, of 
va m or ol o ne a d mi nistere d orall y at dail y d os es u p t o 6. 0 m g/ k g o ver a 2 4- wee k 
Tre at me nt Peri o d vs. pre d nis o ne-treate d hist orical c o ntr ols i n b o ys a ges 4- 7 years 
wit h D M D. 
2. 1. 2  
Sec o n d ary O bjectives 
T he sec o n d ar y o bjecti ves of t his st u d y are: 
1.  T o i n vesti gate t h e effects of va m or ol o ne, a d mi nistere d orall y at dail y d oses u p t o 
6. 0 m g / k g o ver a 2 4- w ee k Treat me nt Peri o d vs. pre d nis o ne-treate d hist orical 
c o ntr ols , o n ser u m p har m ac o d y na mic ( P D) bi o mar kers of safet y (i ns uli n 
resista nce, a dre n al a xis s u p pressi o n, a n d b o ne t ur n o ver);  
2.  T o i n vesti gate t h e effects of va m or ol o ne, a d mi nistere d orall y at dail y d oses u p t o 
6 . 0 m g/ k g o ver a 2 4- w ee k Treat me nt Peri o d vs. u ntreate d hist orical c o ntr ols, o n 
ser u m PD bi o mar kers of efficac y (i nfl a m mat or y pr otei n s u p pressi o n ); a n d 
3.  T o i n vesti gate t h e effects of va m or ol o ne, a d mi nistere d orall y at dail y d oses u p t o 
6 . 0 m g/ k g o ver a 2 4- w ee k Treat me nt Peri o d, o n m uscle stre n gt h, m o bilit y a n d 
f u nctio nal e x ercise ca pacit y vs. hist orical c o ntr ols as meas ure d b y Q ua ntitati ve 
M uscle Testi n g ( Q M T), Ti me t o R u n/ Wal k Test ( T T R W), N ort h Star A m b ulat or y 
Assess m e nt ( N S A A), Ti me t o Cli m b Test ( T T C LI M B), a n d 6- mi n ute Wal k Test 
( 6 M W T) i n b o ys a ges 4- 7 years wit h D M D. 
2. 1. 3  
E x pl or at ory O bjective 
T he e x pl orat or y o bj ecti v e of t his st u d y is: 
1.  T o i n vesti gate t h e effects of va m or ol o ne a d mi nistere d orall y at dail y d oses u p t o 
6. 0 m g / k g o ver a 2 4- w ee k Treat me nt Peri o d o n a n e xte n de d pa nel of P D  
bi o mar kers usi n g S o ma Sca n a pta m er arra ys, a n d pr ote o mic pr ofili n g. 
2. 1. 4  
A ncill ary St u dy  
A n o pti o nal a ncillar y st u d y title d “ Use of Micr os oft Ba n ds as a n O utc o me Meas ure i n 
B o ys wit h D M D - Parallel st u d y t o Cli nical St u d y Pr ot oc ol V B P 1 5- 0 0 3” will be 
u n derta ke n i n parallel t o t his V B P 1 5- 0 0 3 st u d y, a n d e nr olli n g partici pa nts fr o m 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 6 0  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
V B P 1 5- 0 0 3.  T he o bj ecti ves of t he a n cillar y st u d y are t o de m o nstrat e t hat 
c o m m u nit y- bas e d acti vit y m o nit ori n g t hr o u g h t he use of a Micr os oft Ba n d ( M S Ba n d) is 
feasi ble a n d relia ble; t o d eter mi ne t he relati o ns hi p of data c ollecte d t hr o u g h t he M S Ba n d 
a n d cli nical assess me nt meas ures of f u ncti o n; a n d t o deter mi ne t he a bilit y of t he M S 
Ba n d t o meas ure dail y acti vit y p atter ns a n d e x pl ore c ha n ges i n patter ns t hat occ ur o ver 
ti me.  Data c ollecte d as p art of V B P 1 5- 0 0 3 will be s hare d wit h t his st u d y f or data 
a nal ysis p ur p oses if t he s u bject’s pare nt/le gal g uar dia n c o nse nts f or his partici pati o n i n 
b ot h st u di es. 
2. 2  
St u d y E n d p oi nts 
2. 2. 1  
S afety E n d p oi nts 
2. 2. 1. 1  
Pri m ary S afety E n d p oi nt 
1.  B MI z-sc ore: C o m paris o n wit h a pre d nis o ne-tr eat e d hist orical c o ntr ol gr o u p f or 
cha n ge fr o m Baseli ne t o Wee k 2 4. 
2. 2. 1. 2  
A d diti o n al S afety E n d p oi nts 
1.  B MI z-sc ore: C ha n ge fr o m Baseli ne t o eac h of t h e sc he d ule d o n-tr eat me nt a n d 
p ost- treat me nt assess me nt ti me p oi nts. 
2.  Treat me nt- e mer ge nt a d v erse e v e nts ( T E A Es) a n d seri o us a d verse e v e nts ( S A Es) 
b y s yste m or ga n class ( S O C): O verall b y treat me nt, b y treat me nt a n d relati o ns hi p, 
a n d b y tr eat me nt a n d i nte nsit y (see Se cti o n 7. 2. 6 );  
3.  Vital si g ns [ bl o o d press ure, heart rate, res pir at or y rate, b o d y te m perat ure] : 
C ha n ge fr o m Baseli ne t o eac h of t h e sc he d ul e d o n-treat me nt a n d p ost-tr eat me nt 
assess me nt ti me p oi nts;   
4.  B o d y wei g ht: C ha n ge fr o m Baseli ne t o eac h of t h e sc he d ule d o n-tr eat me nt a n d 
p ost -treat me nt assess me nt ti me p oi nts; 
5.  Cli nical la b orat or y val ues ( he mat ol o g y a n d bi oc he mistr y ): C ha n ge fr o m Baseli ne 
t o eac h of t he s c he d ule d o n-treat me nt a n d p ost-tr eat me nt assess me nt ti me p oi nts; 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 6 1  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
6.  Li pi d pr ofile (tri gl yceri d es, t otal c h olester ol, l o w de nsit y li p o pr otei n [ L D L], hi g h 
de nsit y li p o pr otei n [ H D L]): C ha n ge fr o m Bas eli ne t o eac h of t he s c he d ule d o n-
treat me nt a n d p ost-tr eat me nt assess me nt ti me p oi nts; 
7.  Uri nal ysis b y di pstic k a n d micr osc o pic a n al ysis : C ha n ge fr o m Baseli ne t o eac h of 
t he sc hed ule d o n-tr eat me nt a n d p ost-treat me nt ass ess me nt ti me p oi nts;  
8.  1 2 -lea d ele ctr ocar di o gra m ( E C G): C ha n ge fr o m Baseli ne t o eac h of t he sc he d ule d 
o n-treat me nt a n d p ost-tr eat me nt assess me nt ti me p oi nts; 
Data f or t h e f oll o wi n g a d diti o nal safet y o ut c o mes will be liste d o nl y: 
1.  P h ysical e x a mi nati o n fi n di n gs at Pretr eat me nt a n d Wee k 2 4. 
2. 2. 2  
Cli nic al Effic acy E n d p oi nts 
2. 2. 2. 1  
Pri m ary Cli nic al Effic acy E n d p oi nt 
1.  Ti me t o Sta n d Test ( T T S T A N D) vel o cit y (rise/sec o n d) : C o m paris o n wit h a 
hist orical nat ural hist or y ( u ntreate d) c o ntr ol gr o u p f or c ha n ge fr o m Bas eli ne t o 
We e k 2 4. 
2. 2. 2. 2  
Sec o n d ary Effic acy E n d p oi nt s 
1.  Ti me t o Sta n d Test ( T T S T A N D) vel o cit y (rise/sec o n d): C ha n ge fr o m Baseli ne t o 
eac h of t h e sc he d ul e d o n-treat me nt a n d p ost-tr eat me nt assess me nt ti me p oi nts; 
2.  Ti me t o Cli m b ( 4 Ste ps ) Test ( T T C LI M B): C ha n ge fr o m Baseli ne t o eac h of t he 
sc he d ule d o n-tr eat me nt a n d p ost-treat me nt assess me nt ti me p oi nts; 
3.  
N ort h Star A m b ulat or y Assess me nt ( N S A A): C h a n ge i n ti me d assess me nts a n d 
t otal sc ore fr o m Bas eli ne t o eac h of t he s c he d ule d o n-treat me nt a n d p ost-
treat me nt assess me nt ti me p oi nts;  
4.  
Q ua ntitati ve M uscle Testi n g ( Q M T): C ha n ge fr o m Baseli ne t o eac h of t he 
sche d ule d o n-tr eat me nt a n d p ost-treat me nt assess me nt ti me p oi nts;  
5.  
T otal dista nce tra v ele d, i n meters, i n c o m pleti n g t he Si x- mi n ute Wal k Test 
( 6 M W T): C ha n ge fr o m Baseli ne t o eac h of t he sc he d ule d o n-treat me nt a n d p ost-
treat me nt assess me nt ti me p oi nts; a n d 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 6 2  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
6.  
Ti me t o R u n/ W al k Test ( T T R W) : C ha n ge fr o m Baseli ne t o eac h of t he sc he d ule d 
o n-treat me nt a n d p ost-tr eat me nt assess me nt ti me p oi nts. 
2. 2. 3  
P h ar m ac o dy n a mic E n d p oi nts 
1.  C o nce ntrati o ns of ser u m P D bi o mar kers: oste ocal ci n, A C T H, i ns uli n, gl uc ose, 
1 7- h y dr o x y pr o gester o ne, car b o x y-t er mi nal tel o pe pti de ( C T X), ser u m 
ami n oter mi nal pr o pe pti de of t y p e I c olla ge n ( P 1 N P), c ortis ol, test oster o ne, 
c ortic oster o ne, 1 1- de o x yc ortis ol, a n d he m o gl o bi n A 1c ( H b A 1 c).  
2. 2. 4  
E x pl or at ory E n d p oi nts 
1.  Le v els of a n e xte n de d pa nel of P D  bi o mar kers usi n g S o ma Sca n a pta mer arra ys 
a n d prote o mic pr ofili n g. 
2. 2. 5  
E n d p oi nts f or S u bject Re p orte d O utc o m es 
Sa fet y e n d p oi nts base d o n s u bject re p orts of A Es are liste d i n Se cti o n 2. 2. 1. 2 .  S u bjects 
will be as ke d t o assess acce pta bilit y of v a m or ol o n e b y a 5- p oi nt he d o nic s cale (see 
Se cti o n 7. 2. 7 ).  A d diti o nall y, s u bjects’ p are nts/le gal g u ar dia ns will be as k e d t o c o m plete 
t he Pe diatric O utc o mes Data C ollecti o n I nstr u me nt (see Secti o n 7. 3. 8 ).  N o ot her s u bject-
re p orte d o utc o m es are pla n ne d.   
3  
S T U D Y D E SI G N 
3. 1  
O ver all  St u d y Desi g n 
T his P hase IIa e xte nsi o n st u d y is a n o pe n-la bel, m ulti ple- d ose st u d y t o e val uate t he 
l o n g-ter m safet y, t olera bilit y, effi cac y a n d P D of v a m or ol o ne a d mi nistere d o nce dail y b y 
li q uid oral s us pe nsi o n o ver a Treat me nt Peri o d of 2 4 wee ks t o b o ys a ges 4- 7 years wit h 
D M D.   
O nl y  s u bjects w h o ha ve c o m plete d P hase IIa c ore st u d y V B P 1 5- 0 0 2 Wee k 4 F oll o w- u p 
Visit asse ss me nts will be eli gi ble f or partici pati o n i n t his o pe n-la bel e xte nsi o n st u d y.  
Partici pati o n i n t his e xte nsi o n st u d y will be disc usse d wit h t he s u bject’s pare nt or 
g uar dia n pri or t o t he V B P 1 5- 0 0 2 Wee k 4 Visit.  Sta n dar d of care treat me nt 
( gl uc o cortic oi ds) f or D M D ma y b e offere d t o t he s u bje ct f oll o wi n g c o m pleti o n of t he 
P hase IIa V B P 1 5- 0 0 2 st u d y, if t he s u bject’s pare nt or g u ar dia n d o es n ot wis h t o e nr oll t he 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 6 3  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
s u bject i n t he e xte nsi o n st u d y a n d/ or t he I n vesti gat or feels it t o be i n t he best i nterest of 
t he s u bject.  A t otal of u p t o a p pr o xi matel y 4 8 s u bj ects will be e nr olle d i nt o t his 
e x te nsi o n st u d y. 
T he pare nts or le gal g uar dia ns of s u bjects w h o c h o ose t o e nr oll i n t his e xte nsi o n st u d y 
will gi ve writte n i nf or m e d c o nse nt f or t he e xte nsi o n st u d y at t he V B P 1 5- 0 0 3 Baseli ne 
Da y  - 1 Visit.  T he Baseli ne Da y - 1 Visit, i ncl u di n g si g ni n g of t he I C F, ma y occ ur at t he 
c o ncl usi o n of t he V B P 1 5- 0 0 2 Wee k 4 Visit f oll o wi n g c o m pleti o n of all Wee k 4 
assess me nts; alter nati vel y, t he Bas eli ne Da y - 1 Visit a n d V B P 1 5- 0 0 3-s pecific I C F 
si g ni ng ma y occ ur u p t o 8 wee ks after t he fi nal V B P 1 5- 0 0 2 Wee k 4 Visit, at t he 
c o n venie nce of t he s u bject’s pare nt or le gal g uar dia n a n d discreti o n of t he I n v esti gat or.  
S u bjects are c o nsi dere d t o be e nr olle d i n t he V B P 1 5- 0 0 3 e xte nsi o n st u d y after t he pare nt 
or g u ar dia n h as si g n e d t he V B P 1 5- 0 0 3-s pecifi c I C F at t he Baseli ne Da y - 1 Visit.  Eac h 
s u bject will retai n t he st u d y i de ntificati o n n u m ber assi g ne d t o hi m at t he start of t he 
P hase IIa c ore st u d y. 
F or  s u bjects w h o e nr oll i n t he V B P 1 5- 0 0 3 e xte nsi o n st u d y wit hi n 2 8 da ys after 
c o m pleti o n of all fi nal V B P 1 5- 0 0 2 Wee k 4 assess me nts, ma n y of t h e safet y, efficac y, a n d 
P D  assess me nts perf or m e d f or t he V B P 1 5- 0 0 2 st u d y at t he fi nal Wee k 4 Visit will be 
use d t o dete r mi ne e xte nsi o n st u d y eli gi bilit y or t o pr o vi de baseli ne st u d y data f or t he 
e x te nsi o n st u d y a n d d o n ot nee d t o be re p eat e d at t he V B P 1 5- 0 0 3 Baseli ne Da y - 1 Visit 
(see T a ble 6 ).  F or t hese s u bjects, a d diti o nal e xte nsi o n st u d y pr oce d ures will still be 
perf or me d at t he Baseli n e Da y - 1 Visit, wit hi n 2 4 h o urs pri or t o a d mi nistrati o n of t he first 
d ose of  st u d y dr u g i n t he e xte nsi o n st u d y.  S u bjects w h o e nr oll i n t he V B P 1 5- 0 0 3 
e x te nsi o n st u d y > 2 8 d a ys after t he date of t he fi nal V B P 1 5- 0 0 2 Wee k 4 Visit m ust ha ve 
all Baseli ne Da y - 1 assess me nts perf or me d, acc or di n g t o t he sc he d ul e i n T a b le 6. 
S u bjec ts will be gi n d osi n g i n t his st u d y o n St u d y Da y 1 at t he sa me v a m or ol o ne d ose 
le vel the y recei ve d i n t he P hase IIa c ore st u d y.  S u bjects will c o nti n ue t o recei ve 
va m or ol o ne at t he d ose recei ve d i n t he P has e IIa c ore st u d y f or t he d urati o n of t he 
2 4- wee k Treat me nt Peri o d, u nless ne w safet y d ata i n dicate t he d ose le vel s h o ul d be 
de- escalate d. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 6 4  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T he pla n ne d d ose l e vels are 0. 2 5  m g/ k g ( D os e Le vel Gr o u p 1), 0. 7 5 m g/ k g ( D ose Le v el 
Gr o u p  2), 2. 0 m g/ k g ( D ose Le vel Gr ou p  3), a n d 6 . 0 m g/ k g ( D ose Le vel Gr o u p 4) (see 
T a b le 5).  A p pr o xi matel y 1 2 s u bjects ma y b e eli gi ble f or e xte nsi o n st u d y d osi n g at eac h 
of t he d ose  le vels t olerate d i n t he P hase IIa st u d y.   
T a b le 5  
Pl a n ne d D ose Le vel C o m p ositi o n 
Pl a n ne d D ose L e vel 
G r o u p 
N o. S u bjects 
i n D ose 
L e vel G r o u p  
V a m or ol o ne  
D ose  Le vel  
1  
1 2  
0. 2 5 m g/ k g  
2  
1 2  
0. 7 5 m g/ k g  
3  
1 2  
2. 0 m g. k g  
4  
1 2  
6. 0 m g/ k g  
If d ose li miti n g t o xicities are i de ntifie d i n t he P has e IIa c ore st u d y w hi c h precl u de 
c o nfirmati o n of safet y of all f o ur pla n ne d d ose l e v els, t he d ose le vels i n t his e xte nsi o n 
st u d y will be m o difie d, as nee de d. 
I n t he e ve nt a n y cli nical o bser vati o n s u g gests a n i nt olera bilit y f or a n i n di vi d ual s u bject t o 
t he st u d y me dicati o n, i n t he o pi ni o n of t he I n vesti gat or, t h e s u bject’s d ose l e vel ma y be 
decrease d t o t he n e xt l o wer d ose le vel (e. g., a s u bj ect ta ki n g 6. 0 m g/ k g/ da y decrease d t o 
2. 0 m g/ k g/ da y) a n d m ai ntai ne d at t hat l o wer d ose le vel t hr o u g h o ut t he d urati o n of t he 
Tre at me nt Peri o d.  I n t h e e ve nt t he ne xt l o wer d ose le vel is als o n ot t olerate d a n d is 
c o nsidere d a safet y ris k t o t he s u bject, i n t he o pi ni o n of t he I n vesti gat or, St u d y C hair, a n d 
Me dical M o nit or, t he s u bject s h o ul d be wit h dra w n fr o m t he st u d y.  Details of d ose 
i nterr u pti o n, de-es calati o n, a n d disc o nti n uati o n are prese nt e d i n Secti o n 5. 6 . 
S u bjec ts will be assesse d f or safet y a n d t olera bilit y, cli nical efficac y, a n d P D at 
sc he d ule d visits t hr o u g h o ut t he 2 4- wee k Treat me nt P eri o d (see Secti o n 6  f or a sc he d ul e 
of st u d y ass ess me nts).  Treat me nt Peri o d st u d y visits will occ ur at Wee k 2, Wee k 4, a n d 
e ver y 4 w ee ks t hereafter t hr o u g h Wee k 2 4 (T a ble 6 ).  A d verse e ve nts, i ncl u di n g S A Es, 
a n d co nc o mita nt me dicati o ns will be rec or de d t hr o u g h o ut t he st u d y.   
O nce dail y Treat me nt Peri o d st u d y dr u g d osi n g will occ ur fr o m Da y 1 u ntil t he Wee k 2 4 
Visit  (Secti o n 5. 3 ).  St u d y dr u g d osi n g will occ ur at h o me o n all da ys e xce pt t he da ys of 
t he Wee k 1 2 a n d Wee k 2 4 Visits, w he n d osi n g will occ ur at t he st u d y site.   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 6 5  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
S u bject diaries will be dis pe nse d at Baseli ne Da y - 1 a n d at eac h m o nt hl y st u d y visit t o 
rec or d A Es a n d c o n c o mita nt me dicati o ns ta ke n d uri n g t he st u d y. 
All s u bjects will ret ur n t o t he cli nical site f or Wee k 2 4 assess me nts.  F oll o wi n g 
c o m pleti o n of t he 2 4- wee k Treat me nt Peri o d, s u bjects ma y b e offere d f urt her e xte n de d 
treat me nt wit h va m or ol o ne i n a se parate e xte nsi o n st u d y, or s witc h t o sta n dar d of care 
treat me nt (e. g., gl u c oc ortic oi ds) f or D M D, as dee me d a p pr o priat e f or eac h s u bject.  
Alter na ti vel y, s u bjects m a y c h o ose t o disc o nti n ue va m or ol o ne a n d n ot be gi n 
gl uc o c ortic oi d treat me nt f or D M D.  S u bjects w h o s witc h t o sta n dar d of care 
gl uc o c ortic oi ds f or D M D or w h o disc o nti n ue treat me nt will partici pate i n a 
D ose- ta peri n g Peri o d of 2- 5 wee ks i n d urati o n, f oll o wi n g t he e n d of t h e Treat me nt Peri o d 
a n d pri or t o disc har ge fr o m t he st u d y (see Secti o n 6. 3. 4 ); s u bjects w h o elect t o recei ve 
f urt her va m or ol o ne treat me nt will be disc har ge d fr o m t he V B P- 0 0 3 st u d y after 
c o m pleti o n of fi nal V B P- 0 0 3 st u d y assess me nts at t he Wee k 2 4 Visit, pri or t o e nr oll me nt 
i n a s u bse q uent e xte nsi o n stu d y.  S u bjects will be disc har ge d fr o m t he st u d y f oll o wi n g 
c o m pl eti o n of all fi nal Wee k 2 4 or D os e-ta p eri n g Peri o d assess me nts, as a p pr o priate.   
I n t he e ve nt t hat a n y cli nical or la b orat or y para met ers re mai n a b n or mal at t h e ti me of 
disc har ge fr o m t he st u d y, t he s u bject will be f oll o we d me dicall y as cli nicall y i n dicate d.  
A n y s u bject w h o disc o nti n ues t he st u d y pri or t o t he Wee k 2 4 Visit s h o ul d ret ur n t o t he 
st u d y u nit f or fi nal Wee k 2 4 safet y a n d efficac y assess me nts at t he ti me of earl y 
disc o nti n ua ti o n. 
I n vie w of t he ti me sc he d ule f or i nter nati o nal, n ati o nal a n d l ocal a p pr o vals, t his P hase IIa 
e xte nsi o n st u d y pr ot oc ol a n d relate d d o c u me ntati o n will be s u b mitte d f or re g ulat or y 
a p pr o val c o n c urre nt wit h P hase IIa c ore st u d y V B P 1 5- 0 0 2 .  
3. 2  
St u d y S u m m ar y 
T his P has e IIa e xte nsi o n st u d y is a n o pe n-la bel, m ultice nter st u d y t o e val uate t he 
l o n g-ter m safet y, t olera bilit y, cli nical efficac y, a n d P D  of va m or ol o ne at d ose le vels u p t o 
6. 0 m g/ k g a d mi nistere d d ail y b y li q ui d oral s us pe nsi o n o ver a Treat me nt Peri o d of 
2 4 wee ks t o b o ys a ges 4- 7 years wit h D M D.  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 6 6  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T he st u d y is c o m prise d of a Pretreat me nt Baseli ne Peri o d of u p t o 2 4 h o urs i n d urati o n, 
w hic h be gi ns at t he si g ni n g of t he e xte nsi o n st u d y-s pecific i nf or me d c o ns e nt, a 2 4- wee k 
Tre at me nt Peri o d, a n d a 2- t o 5- wee k D ose- tap e ri n g Peri o d f or s u bjects w h o elect t o 
tra nsiti o n off va m or ol o ne treat me nt at t he e n d of t he st u d y. 
4  
S E L E C TI O N A N D WI T H D R A W A L O F S T U D Y S U B J E C T S 
4. 1  
S u bject Scree ni n g, E nr oll me nt, a n d I de ntific ati o n L o g 
All s u bjec ts w h o c o m plete t he Wee k 4 F oll o w- u p assess me nts i n t he V B P 1 5- 0 0 2 c ore 
st u d y will be eli gi ble f or e nr oll me nt i n t his V B P 1 5- 0 0 3 e xte nsi o n st u d y, pr o vi de d t he y 
meet all V B P 1 5- 0 0 3 st u d y e ntr y criteri a.  Li mite d data will be c ollecte d f or s u bjec ts w h o 
d o n ot q ualif y  f or e nr oll me nt i nt o t he e xte nsi o n st u d y, or w h o are n ot i ntereste d i n 
partici pa ti n g i n t he st u d y, i ncl u di n g date of birt h a n d reas o n f or e x cl usi o n fr o m t he st u d y.  
S u bjec ts are c o nsi dere d t o be e nr olle d i n t he V B P 1 5- 0 0 3 e xte nsi o n st u d y after t he pare nt 
or g u ar dia n h as si g n e d t he V B P 1 5- 0 0 3-s pecifi c I C F at t he Baseli ne Da y - 1 Visit.  T he 
Ba seli ne Da y - 1 Visit, i ncl u di n g si g ni n g of t he I C F, ma y occ ur at t he c o ncl usi o n of t he 
V B P 1 5- 0 0 2 Wee k 4 Visit f oll o wi n g c o m pleti o n of all Wee k 4 assess me nts; alter nati vel y, 
t he Bas eli ne Da y - 1 Visit a n d V B P 1 5- 0 0 3-s pecifi c I C F si g ni n g ma y o cc ur u p t o 8 wee ks 
after t he fi nal V B P 1 5- 0 0 2 Wee k 4 Visit, at t he c o n ve nie nce of t he s u bject’s pare nt or 
le gal g u ar dia n a n d discreti o n of t he I n v esti gat or. 
S u bject e nr oll me nt a n d i de ntificati o n l o gs will be mai ntai ne d f or all s u bje ct s e nr olle d i n 
t he st u d y.  T hes e l o gs will be re vie we d d uri n g r o uti ne m o nit ori n g calls a n d/ or visits. 
4. 2  
I ncl usi o n Criteri a 
T o q ua lif y f or e nr oll me nt i n t his e xte nsi o n st u d y, t he s u bject m ust satisf y t h e f oll o wi n g 
i ncl usi o n criteria: 
1.  S u bject’s pare nt or l e gal g uar dia n has pr o vi de d writte n i nf or me d c o nse nt/ HI P A A 
a ut h orizati o n pri or t o a n y e xte nsi o n st u d y-s p ecific pr oce d ures; 
2.  S u bject has pre vi o usl y c o m plete d st u d y V B P 1 5- 0 0 2 u p t o a n d i ncl u di n g t h e 
Wee k 4 F oll o w- u p ass ess me nts wit hi n 8 wee ks pri or t o e nr oll me nt; a n d 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 6 7  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
3.  S u bject a n d pare nt/ g uar dia n are willi n g a n d a bl e t o c o m pl y wit h sc he d ul e d visits, 
st u d y dr u g a d mi nistrati o n pla n, a n d st u d y pr oce d ures. 
4. 3  
E xcl usi o n Criteri a 
A s u bject will be e x cl u de d fr o m e nr oll me nt i n t his e xte nsi o n st u d y if he m eets a n y of t he 
f oll o wi n g e x cl usi o n criteria: 
1.  S u bject ha d a seri o us or s e vere a d verse e v e nt i n st u d y V B P 1 5- 0 0 2 t hat, i n t he 
o pi ni o n of t he I n v esti gat or, was pr o ba bl y or defi nitel y rel ate d t o va m or ol o ne use 
a n d precl u d es safe use of va m or ol o ne f or t he s u bj ect i n t his st u d y; 
2.  S u bject has c urre nt or hist or y of m aj or re n al or he patic i m pair me nt, dia betes 
melli t us or i m m u n os u p pressi o n;  
3.  S u bject has c urre nt or hist or y of c hr o nic s yste mic f u n gal or viral i nfecti o ns; 
4.  S u bject has use d mi neral oc ortic oi d rece pt or a ge nts, s uc h as s pir o n olact o ne, 
eplere n o n e, ca nre n o n e (ca nre n oat e p otassi u m), pr ore n o ne ( pr ore n o ate p otassi u m), 
me xre n o ne ( me xre n oate p otassi u m) wit hi n 4 wee ks pri or t o t he first d ose of st u d y 
me dica ti o n; 
5.  S u bject has e vi de nce of s y m pt o matic car di o m y o p at h y.  [ N ote: As y m pt o matic 
car diac a b n or m alit y o n i n vesti gati o n w o ul d n ot b e e x cl usi o nar y]; 
6.  S u bject is c urre ntl y bei n g treate d or h as recei ve d pre vi o us treat me nt wit h oral 
g l uc o c ortic oi ds or ot her i m m u n os u p pressi ve a ge nts.  [ N otes: Past tra nsie nt use of 
oral gl u c oc ortic oi ds or ot her oral i m m u n os u p pressi ve a ge nts f or n o l o n ger t ha n 3 
m o nt hs c u m ulati ve, wit h last use at least 3 m o nt hs pri or t o first d ose of st u d y 
me dicati o n, will be c o nsi dere d f or eli gi bilit y o n a case- b y -cas e basis.  I n hal e d 
a n d/ or t o pi cal c ortic oster oi ds prescri be d f or a n i n dicati o n ot her t ha n D M D are 
per mitt e d b ut m ust be a d mi nistere d at sta ble d ose f or at least 3 m o nt hs pri or t o 
st u d y dr u g a d mi nistrati o n]; 
7.  S u bject has use d i de be n o ne wit hi n 4 wee ks pri or t o t he first d ose of st u d y 
me dic ati o n; 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 6 8  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
8.  S u bject has a n a ller g y or h y perse nsiti vit y t o t he st u d y me dicati o n or t o a n y of its 
c o nstit ue nts;  
9.  S u bject has se vere be ha vi oral or c o g niti ve pr o ble ms t hat precl u de partici pati o n i n 
t he st u dy, i n t he o pi ni o n of t he I n vesti gat or; 
1 0.  S u bject has pre vi o us or o n g oi n g me dical c o n diti o n, me dical hist or y, p h ysic al 
fi n di n gs or la b orat or y a b n or malities t hat c o ul d affect safet y, m a ke it u nli kel y t hat 
treat me nt a n d f oll o w- u p will be c orrectl y c o m plete d or i m pair t he ass ess me nt of 
st u d y res ults, i n t he o pi ni o n of t he I n vesti gat or; or 
1 1.  S u bject is c urre ntl y ta ki n g a n y i n v esti gati o nal dr u g, or has ta ke n a n y 
i n vesti gati o nal dr u g ot her t ha n va m or ol o ne wi t hi n 3 m o nt hs pri or t o t he start of 
st u dy treat me nt. 
N ote : S u bjects ma y be re- e val u ate d if i neli gi ble d u e t o a tra nsie nt c o n diti o n w hic h 
w o ul d pre ve nt t he s u bje ct fr o m partici pati n g. 
4. 4  
Wit h d r a w al of S u bjec ts fr o m St u d y 
A s u bject ma y wit h dra w fr o m t he st u d y, or ma y b e wit h dra w n b y his pare nt or g uar dia n 
at a n y ti me wit h o ut t h e nee d t o j ustif y t h e decisi o n. 
T h e  I n v esti gat or has t h e ri g ht t o ter mi n at e partici pati o n of a s u bj ect i n t h e st u d y f or a n y 
of t h e f oll o wi n g reas o ns:  
 T h e s u bje ct’s p are nt/le gal g u ar dia n is u n c o o p erati ve/ n o nc o m pli a nt a n d d o es n ot 
ad here t o st u d y res p o nsi biliti es, i n cl u di n g fail ure t o a p pear at st u d y visits; 
 Diffi c ult y i n o bt ai ni n g bl o o d s a m pl es fr o m t h e s u bject f or safet y m o nit ori n g; 
 T h e s u bje ct e x peri e n ces a n u n ma n a gea bl e or n o n-t ol era bl e A E/ S A E w hi c h is 
co nsi dere d t o b e p ossi bl y, pr o b a bl y, or d efi nit el y rel at e d t o st u d y dr u g, i n t he 
o pi ni o n of t h e I n v esti gat or; 
 T h e S p o ns or ter mi n at es t he st u d y ; 
 A n y ot h er reas o n relati n g t o s u bj ect s afet y or i nte grit y of t he st u d y d at a.   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 6 9  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
I n t he e ve nt a s u bj ect is wit h dra w n fr o m t he st u d y, t he S p o ns or or d esi g n ee (e. g., 
C o or di nati n g Ce nter) will be i nf or me d wit hi n o ne b usi ness da y.  If t here is a me dical 
reas o n f or wit h dra w al, t he s u bject will re mai n u n d er t he s u per visi o n of t he I n v esti gat or 
u ntil res ol uti o n of t he e ve nt. 
All s u bjects w h o wit h dra w fr o m t he st u d y pri or t o t he Wee k 2 4 Visit s h o ul d ret ur n t o 
t he st u d y site f or Wee k 2 4  assess me nts at t he ti me of earl y wit h dr a wal, ass u mi n g t he 
s u bject has n ot wit h dra w n c o nse nt.  I n t he e v e nt a s u bject wit h dra ws i nf or m e d 
c o nse nt, n o f urt her st u d y pr oce d ures s h o ul d be perf or me d a n d n o a d diti o nal data 
s h o ul d be c ollecte d.  A n y data c ollecte d u p t o t he p oi nt of wit h dra wal of i nf or me d 
c o nse nt ma y be use d b y t he S p o ns or. 
4. 5  
Re pl ace me nt of Wit h dr a w n S u bjec ts 
O nl y s u bje cts w h o ha ve c o m plete d t he P hase IIa st u d y are eli gi ble t o e nr oll i n t his 
e xte nsi o n st u d y.  S u bjects pre mat urel y disc o nti n u e d fr o m t he V B P 1 5- 0 0 3 e xte nsi o n 
st u d y will n ot be re pla ce d.  
4. 6  
Ter mi n ati o n of St u d y 
T his s t u d y ma y be pre mat urel y ter mi nate d if, i n t h e o pi ni o n of t he S p o ns or, t here is 
s ufficient reas o na ble ca use.  A n e x a m ple of a cir c u msta nce t hat ma y warra nt ter mi nati o n 
is deter minati o n of u ne x pecte d, si g nifica nt, or u n acce pta ble ris ks t o partici pa nts.   
If t he st u d y is pre mat urel y ter mi nat e d or s us pe n d e d, t he S p o ns or will pr o m ptl y i nf or m t he 
site I n v esti gat ors a n d t he re g ulat or y a ut h orit y(i es) of t he ter mi nati o n or s us pe nsi o n a n d 
t he reas o n(s) f or t h e ter mi nati o n or s us pe nsi o n.  T he I nstit uti o nal Re vie w B oar d(s) 
(IR B[s])/I n de p e n de nt Et hics C o m mittee(s) (I E C[s ]) will als o be i nf or me d pr o m ptl y b y 
t he I n v esti gat or/i nstit uti o n or t he S p o ns or a n d pr o vi de d t he reas o n(s) f or t he ter mi nati o n 
or s us pe nsi o n . 
S u bjec t e nr oll me nt at a gi ve n site ma y b e ter mi nat e d b y t h e S p o ns or.  P ossi ble reas o ns 
f or ter mi nati o n of t he st u d y at a gi ve n site i ncl u de, b ut are n ot li mite d t o: 
1.  U nsatisfact or y e nr oll me nt wit h res pect t o q ua ntit y or q ualit y 
2.  I n acc urate or i nc o m plete data c ollecti o n 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 7 0  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
3.  Falsificati o n of rec or ds 
4.  Fail ure t o a d h ere t o t he pr ot oc ol.  
5  
T R E A T M E N T O F S T U D Y S U B J E C T S  
5. 1  
St u d y Me dic ati o n A d mi nistere d 
V a m or ol o ne will be a d mi nistere d t o all s u bjects as a n oral li q ui d s us pe nsi o n. 
Pla n ne d va m or ol o ne d os e le vels: 0. 2 5 m g/ k g, 0. 7 5 m g/ k g/ da y, 2. 0 m g/ k g, a n d 6. 0 m g/ k g.   
Va m or ol o ne will be a d mi nistere d t o all s u bjects o nce dail y f or 2 4 wee ks, fr o m St u d y 
Da y  1 u ntil t he Wee k 2 4 Visit.  At t he e n d of t he 2 4- wee k Treat me nt Peri o d, a s u bset of 
s u bjects ma y recei ve a d diti o nal va m or ol o ne treat me nt i n a d ose-ta peri n g ma n ner d uri n g a 
2- t o 5- wee k D ose-ta p eri n g Peri o d, pri or t o disc har ge fr o m t he st u d y (see S ecti o n 6. 3. 4 ). 
5. 2  
I de ntit y of I n vesti g ati o n al Pr o d uct 
R e vera G e n Bi o P har ma, I nc. will s u p pl y t he f oll o wi n g i n vesti gati o nal st u d y me dicati o n: 
Na me : 
 
Va m or ol o ne 
Acti ve S u bsta nce:  
V B P 1 5 
Stre n gt h:  
 4 % b y wei g ht 
D osa ge F or m:  
 
Oral s us pe nsi o n 
Ma n ufact ur er:  
 
Velesc o P har m a 
5. 3  
D os a ge Sc he d ule a n d A d mi nistr ati o n of St u d y Me dic ati o n 
S u bjects w h o ha ve c o m plete d t he P hase IIa V B P 1 5- 0 0 2 c ore st u d y a n d w h o meet all 
ot her eli gi bilit y criteri a (see Secti o n 4. 2  a n d Secti o n 4. 3 ) will be e nr olle d i nt o t his 
exte nsi o n st u d y o n Baseli ne Da y - 1, f oll o wi n g si g ni n g of t he e xte nsi o n-st u d y-s p ecific 
I CF.  S u bjects will retai n t he e nr oll me nt n u m bers assi g ne d t o t he m f or t he P hase IIa 
V B P 1 5- 0 0 2 c ore st u d y.   
S u bjec ts will recei ve v a m or ol o ne 0. 2 5  m g/ k g, 0. 7 5 m g/ k g/ da y, 2. 0 m g/ k g, or 6. 0  m g/ k g, 
a d mi nistere d orall y o nce dail y fr o m St u d y Da y 1 t o Wee k 2 4.  A s u bset of s u bjects ma y 
als o recei ve va m or ol o ne f or a n a d diti o nal 1- 4 wee ks acc or di n g t o a d os e-ta peri n g 
pr ot oc ol f oll o wi n g t he e n d of t he Treat me nt Peri o d (see Secti o n 6. 3. 4 ). 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 7 1  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T he site p har macist or desi g nate d site st u d y staff will dis pe nse st u d y me di cati o n i n 
1 0 0 m L b ottles t o eac h s u bject e nr olle d i n t he st u d y (see Secti o n 5. 8. 1  a n d A p pe n di x  
1 4. 1 ).  All s u bjects will recei ve v a m or ol o ne 4 % oral s us pe nsi o n.  B ottles will be fitte d 
wit h a da pt ors b y t he site p har macist or desi g n ate d site st u d y staff pri or t o dis pe nsi n g.   
St u d y m e dicati o n s uffici e nt f or 1 2 wee ks of d osi n g ( pl us o vera ge) will be dis pe nse d b y 
trai ne d st u dy staff o n St u d y D a y - 1 a n d at t he Wee k 1 2 Visit.  S u bjects w h o partici pate i n 
t he D ose-ta p eri n g Peri o d will be dis pe nse d st u d y me dicati o n at t he Wee k 2 4 Visit 
s ufficie nt f or t he 4- wee k D ose-ta peri n g Peri o d.  E ac h s u bject’s d os e (i n m g) will be 
calc ulate d b ase d o n t he wei g ht of t he s u bject (i n k g) rec or de d at t he dis p e nsi n g visit (see 
A p pe n di x 1 4. 1  f or a d ose calc ul ati o n w or ks heet).   
E nr olle d s u bjects will recei ve a ll d oses of va m or ol o ne u n der t he s u p er visi o n of pare nt or 
le gal g u ar dia n or trai ne d st u d y staff.  T he d oses a d mi nistere d o n t he dates of t he Wee k 1 2 
a n d W ee k 2 4 Visits will be a d mi nistere d at t he st u d y site; all ot her d oses, i n cl u di n g t he 
first d ose a d mi nistere d o n St u d y Da y 1, will be a d mi nistere d at h o me.  St u d y dr u g will be 
a d ministere d b y m o ut h usi n g a v ol u metric s yri n ge s u p plie d b y t he site.  F oll o wi n g 
a d ministrati o n of t he d ose of st u d y dr u g, t he s yri n ge will be fille d o nce wit h water a n d 
t he water will be a d mi nistere d b y m o ut h usi n g t he v ol u metric s yri n ge.  T he s u bject will 
t he n dri n k a p pro xi matel y 5 0 m L of water t o e ns ure t he f ull d ose has bee n i n geste d.  
S u bjec ts s h o ul d recei ve eac h d ose of st u d y me dicati o n at a p pr o xi matel y t h e sa me ti me of 
da y .   
T he dail y d os e of st u d y me dicati o n s h o ul d be ta ke n wit h 8 o u nces of w h ol e mil k ( or 
e q ui vale nt hi g h fat f o o d p orti o n).  At t he Wee k 1 2 a n d Wee k 2 4 Visits, t he s u bject will 
be a s ke d t o c o ns u me a n 8- o u nce glass of w h ole mil k ( or e q ui vale nt hi g h fat f o o d p orti o n) 
a n d 1 c u p of cereal at t he st u d y site wit hi n a p pr o xi matel y 3 0 mi n utes pri or t o 
a d mi nistrati o n of t he d ose of st u d y m e dicati o n.  T here are n o ot her f o o d or dri n k 
restricti o ns bef ore or after d osi n g d uri n g t he st u d y. 
T he dis pe nse d st u d y me dicati o n b ottle( s) will be ret ur ne d t o t he st u d y site at eac h 
s u bse q ue nt sc hed ule d m o nt hl y visit.   St u d y me di cati o n ret ur ne d at t he Wee ks 4, 8, 1 6, 
a n d 2 0 Visits will be re dis pe nse d t o s u bjects at t he e n d of eac h visit, after i nteri m 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 7 2  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
c o m plia nce m o nit ori n g, f or c o nti n ue d d osi n g t hr o u g h t he re mai n der of t he 1 2- wee k 
dis pe nsi n g i nter val.  Dr u g pr o d u ct ret ur n e d at t he Wee ks 1 2 a n d 2 4 Visits, a n d e n d of t he 
D ose - Ta p eri n g Peri o d, if a p plica ble, will be retai n e d at t he cli nical st u d y site f or 
i n vesti gati o nal dr u g acc o u nta bilit y m o nit ori n g. 
5. 4  
R ati o n ale f or D ose Selecti o n 
D ose  le vels were c h ose n f or t his st u d y t o e ns ure t he safet y of s u bj ects e nr oll e d i n t he 
st u d y, t o all o w de m o nstr ati o n of efficac y a n d P D  effects, a n d t o e ns ure a de q uate safet y i n 
f ut ure cli nical st u dies a n d i n t he patie nt p o p ulati o n after F D A re g ulat or y a p pr o val.  All 
d osi n g  will be d o ne i n t h e m or ni n g wit h a gl ass of w h ole mil k ( 8 o u nces or 2 3 0 m L) or 
si milar fat e q ui vale nt me al (a p pr o xi matel y 8 gra ms fat). 
Eac h s u bject will e nr oll i n t his e xte nsi o n st u d y t o recei v e t he sa me d os e t hat he recei ve d 
d uri n g t he V B P 1 5- 0 0 2 c ore st u d y.  T he pla n ne d d ose le vels i n t his st u d y are 0. 2 5 m g/ k g, 
0. 7 5 m g/ k g, 2. 0 m g/ k g, a n d 6. 0 m g/ k g.  If d ose-li miti n g t o xicities are o bser ve d i n t he 
P ha se 2a c ore st u d y at d oses bei n g us e d i n t his st u d y, d ose l e vel(s) will be de-escalate d, 
as a p pr o priat e. 
T he rati o nale f or t he l o w est d ose of 0. 2 5 m g/ k g/ d a y, a d mi nistere d wit h a glass of w h ole  
mil k is as f oll o ws:  As P hase II d osi n g i n 4- 7 y ear ol d D M D c hil dre n will be d o ne at 
h o me i n t he m or ni n g, c h alle n ges were c o nsi dere d wit h s u bject a n d pare nt c o m plia nce 
wit h eit her f asti n g i n t he m or ni n g ( pri or t o sc h o ol or ot her acti vities), or a ri gi d pres cri be d 
diet of k n o w n fat c o nt e nt.  T o bala nce c o m plia nce wit h a p pr o priate assess me nts of 
bi oa vaila bilit y a n d m o nit ori n g of safet y, it was d eci de d t o a d mi nister m or ni n g d oses at 
h o me wit h a gl ass of w h ole mil k ( ~ 8 gra ms of fat) or si milar fat c o nte nt m eal.  
Fr o m t he P hase I st u d y i n a d ult v ol u nteers, a hi g h fat diet ( 4 0 gra ms) i n crease d 
bi oa vail a bilit y of va m or ol o ne ( 8 . 0 m g/ k g/ da y) b y 2 5 0 % c o m pare d t o t he faste d c o h ort at 
t his d ose.  As a f or mal f o o d effect st u d y h as n ot bee n d o ne, we m ust ass u me t hat a n y fat 
i ntake wit h dr u g d eli ver y has t he p ote ntial t o ha ve a 2 5 0 % i ncrease i n bi oa v aila bilit y vs. 
t he faste d state.  T h us, a c o nser vati ve a p pr o xi mati o n of va m or ol o ne dr u g e x p os ure i n 
D M D c hil dre n w h e n ta ke n wit h a glass of w h ole mil k is 2 5 0 % of t he faste d 
bi oa va ila bilit y.  A starti n g d ose of 0. 2 5 m g/ k g/ da y wit h a glass of mil k w o ul d be 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 7 3  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
e q ui vale nt t o 0. 6 2 5 m g/ k g/ da y fast e d, a n d t his starti n g d ose is 3. 1 % of t he hi g hest safe 
d ose teste d i n a d ults ( 2 0. 0 m g/ k g/ da y fast e d). 
T he hi g h est d ose t o be a d mi nistere d, 6. 0 m g/ k g/ da y, will si milarl y b e a d mi nistere d wit h a 
glass of  mil k, wit h a n e x pecte d i ncreas e d bi oa vail a bilit y of 2 5 0 %, or e q ui v ale nt t o 1 5. 0 
m g/ k g/ da y fast e d.  As 2 0. 0 m g/ k g/ da y fast e d i n a d ult v ol u nteers was s h o w n t o be safe i n 
t he P hase I a d ult v ol u nteer st u d y, t h e pr o p ose d hi g hest d ose i n 4- 7 yea r ol d c hildre n is 
a p pr o xi matel y 7 5 % of t h e safe hi g h est a d ult d ose.  Base d o n t h e P hase I P D  bi o mar ker 
safet y data prese nt e d i n Secti o n 1. 3 , safet y si g nals reflecti ve of i ns uli n resista nce are n ot 
a ntici pate d at a n y of t he pla n ne d P hase 2a e xte nsi o n d ose le vels.  Als o bas e d o n t he 
P hase I data, re gar di n g t h e s afet y si g nal of s u p pressi o n of t he a dre n al a xis, n o e vi de nce of 
a dre nal s u p pressi o n is a ntici pate d at t he pla n ne d 0. 2 5 m g/ k g/ da y, 0. 7 5 m g/ k g/ da y a n d 
2. 0 m g/ k g/ da y d ose le v els i n t he P hase IIa e xte nsi o n st u d y; s u p pressi o n of t he a dre n al 
a x is ma y b e o bser ve d at 6. 0 m g/ k g/ da y.   
5. 5  
Tre at me nt C o m pli a nce 
S u bject c o m plia nce wit h t he d osi n g sc he d ule will be assesse d b y site mai nt e na nce of 
acc urate st u d y dr u g dis pe nsi n g a n d ret ur n rec or ds.  T he I n vesti gat or is r es p o nsi ble f or 
e ns uri n g t h at d osi n g is a d mi nistere d i n c o m plia nce wit h t he pr ot oc ol.  T he I n vesti gat or or 
desi g nee will i nstr uct t he s u bject’s pare nt or g uar dia n wit h re gar d t o pr o p er d osi n g of 
st u d y me dicati o n, a n d will rei nf orce t h e i m p orta nce of ta ki n g all st u d y m e dicati o n per 
pr ot oc ol i nstr ucti o ns.  T he v ol u me of u n use d st u d y me dicati o n re mai ni n g i n eac h b ottle 
ret ur ne d will be d o c u me nte d i n t he s o urce d o c u me nts a n d o n t he a p pr o priate electr o nic 
case re p ort f or m (e C R F).  
5. 6  
St u d y Dr u g D ose I nterr u pti o n, De-esc al ati o n, or Disc o nti n u ati o n 
A d mi nistra ti o n of st u d y dr u g t o i n di vi d ual s u bjects s h o ul d be i nterr u pte d, a n d t he cas e 
disc usse d wit h t he St u d y C hair a n d Me dical M o nit or wit hi n 2 4 h o urs, i n t he e ve nt a n y 
clinical o bser vati o n s u g gests a n i nt olera bilit y of a n i n di vi d ual s u bject t o t he st u d y 
me dica ti o n, i n t he o pi ni o n of t he I n vesti gat or.  I n s uc h a n e ve nt, t he s u bj ect’s d ose le vel 
ma y  b e decreas e d t o t he ne xt l o wer d ose le vel (e. g., a s u bj ect ta ki n g 6. 0  m g/ k g/ da y 
dec rease d t o 2. 0 m g/ k g/ da y) a n d mai ntai ne d at t hat l o wer d ose le vel t hr o u g h o ut t he 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 7 4  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
d urati o n of t he st u d y.  I n t he e ve nt t he ne xt l o wer d ose le vel is als o n ot t olerate d a n d is 
c o nsi dere d a safet y ris k t o t he s u bject, i n t he o pi ni o n of t he I n vesti gat or, St u d y C hair a n d 
Me dical M o nit or, t he s u bject s h o ul d be wit h dra w n fr o m t he st u d y.   
I n t he eve nt t hat d ose-li miti n g t o xicities are o bser ve d i n t he V B P 1 5- 0 0 2 P hase IIa st u d y 
t hat req uire d e-es calati o n of d ose i n t he e xte nsi o n st u d y, s u bjects will be de-escal ate d as 
dictate d b y safet y res ults i n t he V B P 1 5- 0 0 2 st u d y. 
5. 7  
Pri o r a n d C o nc o mit a nt Me dic ati o ns a n d T her a pies 
5. 7. 1  
Pri or T her a py 
A n y c ha n ges i n n o n-st u d y me dicati o n/t hera p y, i ncl u di n g a d mi nistrati o n of ne w 
me dicati o n(s), c h a n ge of d ose, or disc o nti n uati o n of me dicati o n, t hat occ ur after 
c o m pl eti o n of t he V B P 1 5- 0 0 2 c ore st u d y Wee k 4 assess me nts a n d pri or t o a d mi nistrati o n 
of t he first d ose of st u d y me dicati o n i n t he e xte nsi o n st u d y will be ca pt ure d as pri or 
me dica ti o ns ( Me dicati o n Hist or y) i n t he e xte nsi o n st u d y e C R F. 
5. 7. 2  
C o nc o mit a nt T her a py 
A n y me di cati o ns t hat are starte d after a d mi nistrati o n of t he first d ose of st u d y me dicati o n 
i n t he e xte nsi o n st u d y will be rec or d e d as c o nc o mita nt me dicati o ns o n t he a p pr o priate 
e C R F.  S u bject diaries will be pr o vi de d t o s u bjects t o rec or d a n y c o nc o mit a nt me dicati o n 
c han ges d uri n g t he st u d y (see Se cti o n 8. 4 ).  
A ll me dicati o ns ( prescri pti o n a n d o ver-t he-c o u nter [ O T C]) ta ke n d uri n g t he st u d y m ust 
be  rec or de d i n t he s o ur ce d oc u me nts a n d i n t he e C R F, i ncl u di n g t he na me of t he 
me dica ti o n ( or de vi ce or pr oce d ure), d osa ge a n d re gi me n, reas o n f or t hera p y, a n d 
treat me nt start a n d st o p d ates.  F urt h er m ore, eac h c ha n ge i n c o nc o mita nt me dicati o n 
(e.g., ne w treat me nt, disc o nti n uati o n of treat me nt, or c ha n ge i n d os a ge/re gi me n) d uri n g 
t he st u d y m ust be d oc u m e nte d i n t he sa me ma n ner.  Details of a n y n o n- p h ar mac ol o gi cal 
t herapies (e. g., de vic es, pr oce d ures), i ncl u di n g na me, reas o n f or t hera p y, a n d dates of 
t hera p y, will als o be rec or de d.  Site pers o n nel will re vie w t he i nf or mati o n wit h t he 
s u bject a n d/ or his pare nt or g u ar dia n, if a p plica ble, f or c o m plete ness a n d acc urac y at eac h 
st u d y visit. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 7 5  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
5. 7. 3  
Pr o hi bite d T her a pies 
S u bjects m ust disc o nti n ue use of t he f oll o wi n g me dicati o ns pri or t o partici p ati o n i n t he 
st u d y, as i n dicat e d, a n d refrai n fr o m usi n g t hes e me dicati o ns t hr o u g h o ut t he d urati o n of 
t he st u d y: 
 Mi neral oc ortic oi d r ece pt or a ge nts, s uc h as s pir o n olact o ne, e plere n o ne, ca nre n o ne 
(ca nre n oate p ot assi u m), pr ore n o ne ( pr ore n oate p otassi u m), me xre n o ne 
( me xre n oate p otassi u m); use m ust be disc o nti n ue d at least 4 wee ks pri or t o t he 
first d ose of st u d y m e dicati o n; 
 Oral gl uc oc ortic oi ds or ot he r oral i m m u n os u p pressi ve a ge nts.  S u bjects w h o ha ve 
recei v e d m ore t ha n 3 m o nt hs c u m ulati ve treat me nt wit h oral i m m u n os u p pressi ve 
a ge nts or last treat me nt wit hi n 3 m o nt hs pri or t o first d ose of st u d y m e dicati o n are 
i neli gi ble f or st u d y e ntr y.  [ N ote: I n hale d a n d/ or t o pical c ortic oster oi ds pres cri be d 
f or a n i n dicati o n ot her t h a n D M D are per mitte d b ut m ust be a d mi nistere d at sta ble 
d ose f or at least 3 m o nt hs pri or t o st u d y dr u g a d mi nistrati o n]; 
 I d e be n o ne ( use m ust be disc o nti n ue d at least 4 wee ks pri or t o first d ose of st u d y 
me dic ati o n); 
 Li ve atte n uate d v acci n es ( use m ust be a v oi de d f or t he d urati o n of partici p ati o n i n 
t he st u dy); 
 A n y i n vesti gati o nal me di cati o ns ot her t ha n va m or ol o ne ( use m ust be disc o nti n ue d 
at least 3 m o nt hs pri or t o t he first d ose of st u d y me dicati o n). 
T he I n vesti gat or s h o ul d c o ntact t he St u d y C hair c o ncer ni n g i n di vi d ual me dicati o ns or 
t herapies n ot liste d t hat ma y b e of c o n cer n. 
5. 7. 4  
Per mitte d T her a pies 
E ver y eff ort s h o ul d be m a de N O T t o ta k e a n y pres cri pti o n or O T C me dicati o ns d uri n g 
t he st u dy.  C o nc o mita nt me dicati o ns s h o ul d be mai ntai ne d o n t he sa me d ose a n d re gi me n 
t hr o u g h o ut the st u d y w he ne ver p ossi ble.  H o we ver, all ot her me dicati o ns ot her t ha n t h ose 
s pecificall y pr o hi bite d a b o ve ma y be ta ke n d uri n g t he st u d y, if cli nicall y i n dicate d, 
pr o vi de d t he y are rec or d e d i n t he s o urce d o c u me nts a n d i n t he e C R F.   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 7 6  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
5. 8  
St u d y Me dic ati o n M a n a ge me nt 
5. 8. 1  
P ac k a gi n g a n d L a beli n g of St u dy Me dic ati o n 
T he site p har macist or desi g nate d st u d y staff will r ecei ve cli nical trial m aterial ( C T M) 
w he n all re g ulat or y re q uire me nts ha ve b ee n c o m plete d b y t he site.  A d diti o nal C T M will 
be a vaila ble u p o n re q uest.  Re vera Ge n Bi o P har ma, I n c. or desi g n ee will pr o vi de C T M i n 
b ul k q ua ntities s uf ficie nt t o satisf y t he pr ot o c ol re q uire me nt.  Cli nical trial material will 
be s hi p pe d i n b ul k t o t he st u d y site’s re gistere d p h ar macist or desi g n ate d st u d y staff i n 
s uita bl y la bele d st u d y cart o ns.  Cart o ns will c o ntai n st u d y me dicati o n pac ka ge d i n sterile 
1 0 0 m L glass b ottles; eac h b ottle will c o ntai n 4 gra ms of va m or ol o ne as a 4 % s us pe nsi o n 
i n sterile water.  B ul k dr u g s u p plies will be la bel e d wit h t he na me of S p o ns or, pr ot oc ol 
n u m ber, l ot  n u m ber, e x pirati o n or retest d ate, a n d ot her a p pr o pri ate st u d y i nf or mati o n.  
B ott le la bels will i ncl u de t he f oll o wi n g state m e nt: “ Ca uti o n: Ne w Dr u g – Li mite d b y 
Fe deral La w t o I n vesti gati o nal Use” or c o m p ara bl e state me nt, as re q uire d b y e x- U S 
re gulat or y a ut h orities.   
1 0 0 m L  b ottles of 4 % v a m or ol o ne oral s us pe nsi o n will be dis pe nse d t o t he s u bject’s 
pare nt or le gal g uar dia n at t he Baseli ne Da y - 1 Visit a n d at 1 2- wee k i nter vals (see 
A p pe n di x 1 4. 1  f or i nstr ucti o ns o n calc ulati n g t he n u m ber of va m or ol o ne b ottles t o be 
dis pe nse d a t eac h visit); dis pe nse d b ottle(s) of st u d y me dicati o n will be ret ur ne d at e ac h 
s u bse q ue nt m o nt hl y visit f or i nteri m c o m plia nce m o nit ori n g ( Wee ks 4, 8, 1 6, a n d 2 0) or 
pri or t o di s pe nsi n g b ottle(s) f or t he ne xt d osi n g i nter val ( Wee ks 1 2 a n d 2 4).  B ottles will 
be fitte d wit h a da pt ors b y t he site p har macist or desi g nate d site st u d y staff pri or t o 
dis pe nsi n g.   Eac h va m or ol o ne st u d y me dicati o n b ottle ma y be us e d f or a si n gle s u bject 
o nl y .  T he v ol u me p er d ose t o be a d mi nistere d t o eac h s u bject de p e n ds o n t he s u bject 
wei g ht calc ulate d at t he dis pe nsi n g visit; see A p pe n di x 1 4. 1  f or c o m plete i nstr ucti o ns o n 
calc ulati n g d ose v ol u me.  Cli nical s u p plies dis pe nse d b y t h e st u d y site staff a n d rea d y f or 
a d ministrati o n t o s u bjects will be la bele d wit h t he dis pe nse date, pr ot oc ol n u m ber, 
va m or ol o ne d ose le v el, a n d v ol u me t o be a d mi nistere d per d ose.   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 7 7  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
5. 8. 2  
St or a ge of St u dy Me dic ati o n 
All C T M f or use i n t he trial m ust be st ore d i n a l oc ke d c o ntai n er/ca bi n et free fr o m 
e n vir o n me ntal e xtre mes, u n der t he res p o nsi bilit y of t he i nstit uti o nal p har macist or 
Pri nci pal I n v esti gat or.  B ul k st u d y me dicati o n s h o ul d be st ore d at refri gerat e d 
te m perat ur e ( 2oC – 8 oC; 3 6 oF – 4 6 oF) .  E x c ursi o ns t o a m bie nt te m perat ure are all o we d.  
Acc ess t o st u d y me dicati o n st ore d at t he st u d y site m ust be li mite d t o a ut h orize d cli nic 
pers o n ne l. 
5. 8. 3  
St u dy Me dic ati o n S hi p pi n g a n d H a n dli n g 
Cli nical trial material will be s hi p pe d t o t he st u d y sites o nl y after recei pt of re q uire d 
d oc u me nts i n acc or da nce wit h a p plica ble re g ul at or y re q uire m e nts a n d S p o ns or 
pr oce d ures.   
Cli nical trial material will o nl y be dis pe nse d o n ce a s u bject has ( 1) a si g ne d I C F/ HI P A A 
a ut h oriz ati o n o n file, a n d has bee n e nr olle d i n t he e xte nsi o n st u d y; ( 2) m et all eli gi bilit y 
criteria f or e ntr y i nt o t he e xte nsi o n st u d y, ( 3) c o m plete d all Pretreat me nt re q uire me nts.   
It is esse ntial t o t his st u d y t hat all C T M be acc o u nte d f or d uri n g t he st u d y p eri o d.  All 
u n use d st u d y me dicati o n will be retai ne d at t he st u d y site f or rec o nciliati o n a n d c ollecti o n 
b y  t he S p o ns or's st u d y m o nit ors ( or desi g nees) d uri n g r o uti ne m o nit ori n g visits.  St u d y 
site pers o n nel s h o ul d n ot dis p ose of a n y C T M.  Fi nal dis p ositi o n of all u n use d C T M will 
be c o or di nate d b y t h e S p o ns or's st u d y m o nit ors ( or desi g n ees) at t he e n d of t he st u d y (s ee 
Sec ti o n 5. 8. 4 ).   
Cli nical trial material m ust be dis pe nse d a n d a d mi nistere d acc or di n g t o t he pr oce d ures 
desc ri be d i n t his pr ot oc ol.  O nl y s u bjects e nr olle d i n t he st u d y ma y recei v e st u d y 
me dicati o n, i n acc or da nce wit h all a p plica ble re g ulat or y re q uire m e nts.  O nl y a ut h orize d 
st u d y pers o n n el ma y s u p pl y C T M.  A ut h orize d st u d y pers o n nel r efers t o t he I n vesti gat or 
( or desi g nee), i n acc or da nce wit h all a p plica ble re g ulat or y re q uire m e nts a n d t he Site 
Si g nat ure L o g/ D ele gati o n of A ut h orit y.  O nl y a ut h orize d st u d y pers o n nel or t he s u bject’s 
pare nt or le gal g uar dia n ma y a d mi nister C T M. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 7 8  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
5. 8. 4  
St u dy Me dic ati o n Acc o u nt a bility 
T he I n vesti gat or is r es p o nsi ble f or t he c o ntr ol of dr u gs u n d er i n vesti gati o n.  A de q uate 
recor ds of t he recei pt (e. g., Dr u g Recei pt Rec or d) a n d dis p ositi o n (e. g., Dr u g Dis pe nsi n g 
L o g) of t he st u d y dr u g m ust be mai ntai ne d.  T he Dr u g Dis pe nsi n g L o g m ust be ke pt 
c urre nt a n d s h o ul d c o ntai n t he f oll o wi n g i nf or m ati o n: 
 T he i de ntificati o n of t he s u bject t o w h o m t he st u d y dr u g was dis pe nse d 
 T he date(s) a n d q ua ntit y of t he st u d y dr u g dis pe ns e d t o t he s u bject 
 T he date(s) a n d q ua ntit y of t he st u d y dr u g ret ur n e d b y t he s u bject. 
All rec or ds a n d dr u g s u p plies m ust be a vaila ble f or i ns pecti o n b y t h e St u d y M o nit or at 
e ver y m o nit ori n g visit.  U n use d me dicati o n will be ret ur n e d t o Re vera Ge n or its desi g nee 
at the e n d of t he st u d y.  T he c o m plete d Dr u g Dis pe nsi n g L o g a n d Dr u g Ret ur n Rec or d(s) 
will be  ret ur ne d t o Re vera Ge n or its desi g nee.  T h e I n vesti gat or’s c o p y of t he Dr u g 
Re t ur n Rec or d(s) m ust acc urat el y d o c u me nt t he ret ur n of all st u d y dr u g s u p plies t o 
Re vera G e n or its desi g nee. 
5. 9  
Pr o ce d ures f or Assi g ni n g S u bject St u d y N u m b ers 
T his is a n o pe n-la bel st u d y.  S u bjects e nr olle d i n t his e xte nsi o n st u d y will retai n t he 
e nroll me nt n u m bers assi g ne d t o t he m at t he start of t he V B P 1 5- 0 0 2 c ore st u d y.  All data 
f or all s u bjects w h ose p are nt or g u ar dia n si g ns t he I C F f or t he e xte nsi o n st u d y will be 
i de ntifie d usin g t he u ni q ue s u bject i de ntificati o n n u m ber.  S u bjects are c o nsi dere d t o be 
e nrolle d i n t his e xte nsi o n st u d y w he n t h e pare nt or g uar dia n si g ns t he e xte nsi o n 
st u d y-s pecific I C F at t he Baseli ne Da y - 1 Visit.  T he Site I n v esti gat or will kee p a rec or d 
relati n g t h e na mes of t h e s u bjects t o t heir e nr oll me nt n u m bers ( S u bject I de ntificati o n 
L o g) t o p er mit effici e nt verificati o n of d ata s u bject files, w he n re q uire d.  T his rec or d will 
als o i ncl u de t he dates of s u bject e nr oll me nt a n d c o m pleti o n/ter mi nati o n.   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 7 9  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
6  
S T U D Y S C H E D U L E 
6. 1  
Ti me a n d E ve nts Sc he d ule 
T he  st u d y pr oce d ures t o be c o n d ucte d f or eac h s u bject are di vi de d i nt o t he f oll o wi n g 
st u d y peri o ds:  
 Pretre at me nt B aseli ne Peri o d:   T he 2 4- h o ur peri o d i m me diatel y pri or t o 
a d ministrati o n of t he first d ose of st u d y m e dicati o n ( St u d y Da y - 1), w hic h 
i ncl u des si g ni n g of t he e xte nsi o n st u d y-s pecific I C F a n d e nr oll me nt i nt o t he 
e x te nsi o n st u d y.  T he Baseli ne Da y - 1 Visit ma y c oi nci de wit h t he fi nal Wee k 4 
F oll o w- u p Visit i n t he V B P 1 5- 0 0 2 c ore st u d y.  Alter nati vel y, s u bjects ma y ret ur n 
t o t he st u d y site u p t o 8 wee ks after c o m pleti o n of t he V B P 1 5- 0 0 2 Wee k 4 
assess me nts  f or Baseli ne Da y - 1 I C F si g ni n g a n d c o m pleti o n of Baseli ne 
assess m e nts. 
 Tre at me nt Peri o d:   T he 2 4- wee k i nter val starti n g wit h a d mi nistrati o n of t he first 
d ose of  st u d y m e dicati o n o n St u d y Da y 1a n d c o nti n ui n g t hr o u g h t he ti me of t he 
We e k 2 4 Visit a n d a d mi nistrati o n of t he fi nal d ose of Treat me nt Peri o d st u d y 
me dicati o n.  S u bjects electi n g t o c o nti n ue va m or ol o ne t hera p y u n der a s u bs e q ue nt 
e x te nsi o n pr ot oc ol will be disc har ge d fr o m t he V B P 1 5- 0 0 3 st u d y f oll o wi n g 
c o m pleti o n of all Wee k 2 4 safet y, efficac y, a n d P D assess me nts. 
 D ose-t a peri n g Peri o d:  T he 2- t o 5- wee k i nter val f oll o wi n g t he e n d of t he 
2 4- wee k Treat me nt Peri o d d uri n g w hi c h s u bjects w h o elect t o eit her s witc h t o 
sta n dar d of care gl uc oc ortic oi ds f or D M D, or disc o nti n ue va m or ol o ne a n d n ot 
be g i n sta n d ar d of care gl uc oc ortic oi d treat me nt, at t he e n d of t he st u d y will ha ve 
t heir vam or ol o ne d ose ta pere d t o 0 m g/ k g/ d a y.  T he le n gt h of ti me re q uir e d f or 
t his ta peri n g will de p e n d u p o n t he d ose recei ve d d uri n g t he Treat me nt Peri o d (see 
Secti o n 6. 3. 4 ).  S u bjects w h ose d ose is ta pere d d uri n g t he D ose-ta p eri n g Peri o d 
will be disc har ge d fr o m t he st u d y f oll o wi n g c o m pleti o n of all fi nal D ose-ta peri n g 
Peri o d assess me nts.   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d  Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 8 0  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T he pr oce d ures t o be c o m plete d d uri n g eac h st u d y peri o d are pres e nte d i n t he Sc he d ule 
of  St u d y Assess me nts i n T a ble 6  a n d i n t he secti o ns t hat f oll o w.  Detaile d descri pti o ns of 
t he assess me nts an d t he d efi niti o ns of st u d y e n d p oi nts are pr o vi de d i n Se cti o n 7  a n d 
Se cti o n 2. 2 .  A n y d e viati o n fr o m st u d y pr oce d ures s h o ul d be n ote d i n t he s o urce 
d oc u me nts a n d i n t he e C R F, a n d si g nifica nt de viati o ns s h o ul d be re p orte d i m me diatel y t o 
t he S p o ns or.   
O vera ll, a p pr o xi matel y 2 4 - 2 9 wee ks are all ocate d f or ea c h s u bject t o c o m pl ete t he st u d y, 
i ncl u di n g a 1- d a y Pretr eat me nt Baseli ne Peri o d a n d a 2 4- wee k Treat me nt Peri o d f or all 
s u bjects.  F or s u bjects w h o elect t o eit her s witc h t o sta n dar d of care gl uc oc oc ortic oi ds f or 
D M D, or d isc o nti n ue va m or ol o ne a n d n ot be gi n gl uc oc ortic oi d treat me nt at t he e n d of t he 
st u d y, a n a d diti o nal 2- 5 wee ks are all ocate d f or va m or ol o ne d ose ta peri n g. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
P a ge 8 1  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T a ble 6   
Sc he d ule of St u d y Acti vities 
 
Pr etr e at m e nt 
P eri o d  
Tr e at m e nt P eri o d  
D o s e -
t a p eri n g 
P eri o d  
B a s eli n e  
 
D a y  
W e e k  
St u d y D a y or 
W e e k/ Vi sit  
-1 a  
 
1 b  
 
2  
(1 d)  
4  
(2 d)  
8  
(5 d)  
1 2  
(1 w)  
1 6  
(1 w)  
2 0  
(1 w)  
2 4 c  
(1 w)  
2 6 -2 9 d  
(1 w)  
I n cl u si o n/ E x cl u si o n 
Crit eri a  
X  
 
 
 
 
 
 
 
 
 
I nf or m e d C o n s e nt 
X e  
 
 
 
 
 
 
 
 
 
E nr oll m e nt  
X  
 
 
 
 
 
 
 
 
 
I nt eri m M e di c al 
Hi st or y  
X f 
 
 
 
 
 
 
 
 
 
M e di c at i o n Hi st or y 
X g  
 
 
 
 
 
 
 
 
 
P h y si c al E x a mi n ati o n  
X h  
 
 
 
 
 
 
 
X  
 
H ei g ht  
X  
 
 
 
 
X  
 
 
X  
 
W ei g ht  
X  
 
 
X  
X  
X  
X  
X  
X  
 
Vit al Si g n s i 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
Bl o o d f or Cli ni c al L a b s j 
X h  
 
 
X  
X  
 
X  
 
X  
X  
Uri n al y si s k 
X h  
 
 
X  
X  
 
X  
 
X  
 
Bl o o d f or S er u m P D 
Bi o m ar k er P a n el l 
X h  
 
 
 
X  
 
X  
 
X  
X  
F a sti n g bl o o d f or 
i n s uli n, gl u c o s em  
 
 
 
 
 
X  
 
 
X  
 
1 2 -l e a d E C Gn  
X h  
 
 
 
 
X  
 
 
X  
 
Di s p e n s e St u d y 
M e di c ati o n  
X  
 
 
 
 
X  
 
 
X o  
 
R et ur n St u d y 
M e di c ati o n/ 
C o m pli a n c e 
M o nit ori n g  
 
 
 
X  
X  
X  
X  
X  
X  
X  
St u d y M e di c ati o n 
D o si n g p  
 
X  
 
 
 
 
 
 
X  
 
V a m or ol o n e d o s e 
t a p eri n gq  
 
 
 
 
 
 
 
 
 
X  
Ti m e t o St a n d T e st 
( T T S T A N D) 
X h  
 
 
 
 
X  
 
 
X  
 
Ti m e t o Cli m b T e st 
( T T C LI M B) 
X h  
 
 
 
 
X  
 
 
X  
 
Ti m e t o R u n/ W al k 
T e st ( T T R W)  
X h  
 
 
 
 
X  
 
 
X  
 
N S A A r 
X h  
 
 
 
 
X  
 
 
X  
 
Q u a ntit ati v e M u s cl e 
T e sti n g ( Q M T)  
X h  
 
 
 
 
X  
 
 
X  
 
Si x -mi n ut e W al k T e st  
( 6 M W T) 
X h  
 
 
 
 
X  
 
 
X  
 
P e di atri c O ut c o m e s 
D at a C oll e cti o n 
I n str u m e nt 
X  
 
 
 
 
X  
 
 
X  
 
St u d y M e d i c ati o n 
A c c e pt a bilit y 
A s s e s s m e nt s 
 
 
 
 
 
X  
 
 
X  
 
Di s p e n s e S u bj e ct 
Di ari e s t 
X  
 
 
X  
X  
X  
X  
X  
X p  
 
R et ur n S u bj e ct Di ari e s  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
A E/ S A E R e c or di n g u 
X  
 
 
 
 
 
 
 
X  
X  
C o n c o mit a nt 
M e di c a ti o n s 
 
X  
 
 
 
 
 
 
X  
X  
Di s c h ar g e fr o m St u d y  
 
 
 
 
 
 
 
 
X v 
X w  
d = da y(s); w = wee k.  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 8 2  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
a. 
Baseli ne Da y - 1, wit hi n 2 4 h o urs pri or t o a d mi nistrati o n of t h e first d ose of st u d y dr u g.   T he Baseli ne Visit 
f or St u d y V B P 1 5- 0 0 3 ca n c oi nci de wit h t h e fi n al Wee k 4 F oll o w- u p Visit f or St u d y V B P 1 5- 0 0 2 or occ ur u p 
t o 8 wee ks after t he date of t h e V B P 1 5- 0 0 2 Wee k 4 Visit. 
b.  
Treat me nt Da y 1 be gi ns at t he ti me of a d mi nistrati o n of t h e first d ose of V B P 1 5- 0 0 3 st u d y me dicati o n at 
h o me.  N o sc he d ule d st u d y visit will occ ur o n Da y 1. 
c. 
S u bjects w h o pre mat urel y disc o nti n ue fr o m t h e st u d y pri or t o Wee k 2 4 s h o ul d c o m plete t h e Wee k 2 4 
assess me nts at t h e ti me of earl y disc o nti n uati o n. 
d.  
All s u bjects E X C E P T t h ose w h o elect t o c o nti n ue va m or ol o ne t h era p y i n a f urt h er e xte nsi o n st u d y m ust 
c o nti n ue i n t he D ose-ta peri n g P eri o d a n d ha ve t h eir va m or ol o ne d ose ta pere d at wee kl y i nter vals o ver a 1- 4 
we e k peri o d pri or t o disc har ge fr o m t his st u d y.  S u bjects partici p ati n g i n t he D ose-ta peri n g P eri o d will ha ve 
o ne st u d y site visit d uri n g t his peri o d, at t h e e n d of d ose ta peri n g ( Wee ks 2 5- 2 9)  (see Secti o n 6. 3. 4 ).  
e. 
I nf or me d C o nse nt f or t his e xte nsi o n st u d y ma y be o btai ne d at t h e St u d y V B P 1 5- 0 0 2 Wee k 4 F oll o w- u p Visit, 
after c o m pleti o n of all fi n al V B P 1 5- 0 0 2 st u d y assess me nts a n d pri or t o a n y e xte nsi o n st u d y-s pecific 
pr oce d ures. 
f. 
I nteri m Me dical Hist or y will be c ollecte d o n Baseli ne Da y -1 f or all s u bjects, a n d will i n cl u de a n y A Es t h at 
occ urre d d uri n g t h e V B P 1 5- 0 0 2 c ore st u d y a n d are o n g oi n g at t he ti me of e ntr y i nt o V B P 1 5- 0 0 3 (see 
Secti o n 7. 2. 1 ). 
g.  
A n y c ha n ges i n me dicati o n/t hera p y i n cl u di n g a d mi nistrati o n of ne w me dicati o n(s), c ha n ge of d ose, or 
disc o nti n uati o n of me dicati o n aft er c o m pleti o n of t h e V B P 1 5- 0 0 2 c ore st u d y a n d pri or t o a d mi nistrati o n of 
t h e first d ose of st u d y me dicati o n i n V B P 1 5- 0 0 3 will be ca pt ure d as Pri or Me dicati o ns.  
h.  
If t h e Baseli ne Da y - 1 Visit occ urs ≤ 2 8 da ys after t he date of t h e fi n al V B P 1 5- 0 0 2 c ore st u d y Wee k 4 Visit, 
t h ese assess me nts d o n ot nee d t o be re peate d f or t h e V B P 1 5- 0 0 3 st u d y.  Cli nical la b orat or y a n d uri nal ysis test 
res ults fr o m t h e V B P 1 5- 0 0 2 Wee k 2 or Wee k 4 Visit ( w hic he ver is a vaila ble a n d later) ma y be use d a n d 
s h o ul d be re vie we d b y t h e Site I n vesti gat or t o deter mi n e eli gi bilit y f or Baseli ne Da y - 1 e nr oll me nt i nt o t he 
e xte nsi o n st u d y. 
i. 
S u pi ne bl o o d press ure, oral te m perat ure, res pirat or y rate, a n d he art rate. 
j. 
Bl o o d f or he mat ol o g y , c he mistr y, a n d li pi ds. 
k.  
Uri n al ysis b y di pstic k a n d micr osc o pic a nal ysis. 
l. 
Bl o o d c ollecte d f or c ortis ol, P 1 N P, oste ocalci n, 1 7- h y dr o x y pr o gester o ne, test oster o ne, c ortic oster o ne, 
1 1- de o x yc ortis ol, C T X, A C T H, H b A 1c ( n ot c ollecte d at Baseli ne), S o ma Sca n, a n d pr ote o mic testi n g. 
m.  Bl o o d will be c ollecte d f or i ns uli n a n d gl u c ose deter mi n ati o n i n t he m or ni n g after s u bjects ha ve fast e d f or ≥ 6 
h o urs, pri or t o t he dail y d ose of st u d y me dicati o n. 
n.  
E C G rec or de d after s u bject has reste d q uietl y i n a s u pi ne p ositi o n f or at l east 5 mi n utes. 
o.  
O nl y f or s u bjects w h o will partici pate i n t he D ose-ta peri n g P eri o d. 
p.  
T he d ose of st u d y me dicati o n o n t he da ys of t h e We e k 1 2 a n d Wee k 2 4 Visits will be a d mi nistere d after 1) a 
fasti n g bl o o d dra w f or i ns uli n a n d gl u c ose; a n d 2) brea kfast pr o vi d e d b y t h e st u d y site.  All ot h er d oses will 
be ta ke n at h o me. 
q.  
S u bjects w h o elect t o s witc h t o sta n dar d of care gl u c oc ortic oi ds, or disc o nti n ue va m or ol o ne a n d n ot be gi n 
gl u c oc ortic oi d treat me nt f or D M D at t h e e n d of t h e st u d y will ha ve t h eir va m or ol o ne d ose ta pere d at wee kl y 
i nter vals t o a d ose of 0 m g/ k g/ d a y pri or t o fi n al st u d y assess me nts (see Secti o n 6. 3. 4 ). 
r. 
N ort h Star A m b ulat or y Assess me nt; i ncl u des t h e Ti me t o Sta n d Test ( T T S T A N D). 
s. 
St u d y me dicati o n acce pta bilit y assesse d i m me diatel y bef ore (s mell) a n d after (taste) d osi n g at t he Wee k 1 2 a n d 
Wee k 2 4 Visits. 
t. 
S u bject diaries use d t o rec or d a n y c o nc o mita nt me dicati o ns ta ke n a n d a n y A Es e x perie nce d d uri n g t he st u d y. 
u.  
All A Es a n d S A Es m ust b e c ollecte d i n t h e s o urce d oc u me nts a n d e C R F fr o m t h e date of t h e s u bject’s writte n 
i nfor me d c o nse nt u ntil t he Wee k 2 4 Visit or t h e s u bject’s partici pati o n i n t he st u d y is c o m plete d.  O n g oi n g A Es 
will be f oll o we d t o res ol uti o n, sta bilizati o n, or u ntil s uc h ti me t h e I n vesti gat or a grees f oll o w- u p is n ot necessar y. 
v.  
S u bjects w h o elect t o c o nti n ue va m or ol o ne t h era p y i n a s u bse q ue nt e xte nsi o n st u d y ma y be disc har ge d fr o m 
t h e st u d y f oll o wi n g c o m pleti o n of all fi n al Wee k 2 4 pr oce d ures. 
w.  S u bjects w h o partici p ate i n t h e D ose-ta peri n g P eri o d ma y be disc har ge d fr o m t h e st u d y f oll o wi n g c o m pleti o n 
of all fi n al D ose-ta peri n g Visit assess me nts (see Secti o n 6. 3. 4 ). 
 


V B P 1 5 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3 
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 8 3  of 1 3 7 
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
6. 2  
I nf or me d C o nse nt/ HI P A A A ut h oriz ati o n 
T he pare nts or g uar dia ns of s u bjects w h o c h o ose t o e nr oll i n t his e xte nsi o n st u d y will 
gi ve writte n i nf or me d c o nse nt f or t his st u d y at t he Baseli ne Da y - 1 Visit.  If t he Baseli ne 
Da y  - 1 Visit c oi nci des wit h t he V B P 1 5- 0 0 2 Wee k 4 Visit, t he pare nts or g u ar dia ns of 
s u bjects will gi ve writte n i nf or me d c o nse nt f or t his st u d y at t he P hase IIa V B P 1 5- 0 0 2 
We e k 4 Visit, f oll o wi n g c o m pleti o n of all V B P 1 5- 0 0 2 Wee k 4 assess me nts.  T he 
I n vesti gat or ( or d esi g n ate d staff) will o btai n t he writte n i nf or me d c o nse nt a n d HI P A A 
a ut h orizati o n, if a p plica ble, fr o m t he s u bject’s p are nt or g u ar dia n pri or t o a n y e xte nsi o n 
st u d y-s pecific pr oce d ures.  Eac h s u bject’s p a re nt or g u ar dia n will recei ve a n e x pla nati o n 
of t he na t ure a n d p ur p oses of t he st u d y fr o m t he I n vesti gat or or desi g nee.  T he 
I n vesti gat or or desi g nee will e ns ure t he st u d y is a p pr o priate f or t he s u bject.  Reas o ns f or 
e x cl usi o n will be d oc u me nte d f or s u bjects f o u n d i neli gi ble d uri n g t he Pr etr eat me nt 
Peri o d.  T he s u bject’s pare nt or g uar di a n will be as ke d if s/he u n de rsta n ds t hat t he st u d y 
is f or researc h p ur p oses o nl y a n d t hat it ma y n ot pr o vi de a n y t hera p e utic be nefit t o t he 
s u bject.  Eac h s u bject’s p are nt or g u ar dia n will be as ke d if s/ he u n dersta n ds t hat t he 
s u bject is free t o wit h dra w fr o m t he st u d y at a n y ti me wit h o ut prej u dice.  T he I n vesti gat or 
or de si g n ee will re vi e w t he ele me nts of t he HI P A A a n d Pr otecte d Healt h I nf or mati o n 
( P HI) wit h eac h s u bject’s pare nt or g u ar dia n a n d eac h s u bject’s p are nt or g uar dia n will be 
as ke d if s/ he u n dersta n ds HI P A A a ut h orizati o n a n d P HI.  E ac h s u bject’s parent or 
g ua r dia n will be re q uire d t o si g n a st u d y I C F (a n d HI P A A a ut h orizati o n, if a p plica ble) 
bef or e a n y pr oce d ures are perf or me d f or t h e e xte nsi o n st u d y.  T he writte n asse nt of 
c hildre n will be o btai ne d per i n di vi d ual site g ui deli nes. 
T he I n vesti gat or or d esi g nee will o btai n writte n i nf or me d c o nse nt fr o m eac h s u bject’s 
pare nt or g u ar dia n pri or t o s u bject’s partici pati o n i n t he e xte nsi o n st u d y o n I nf or me d 
C o nse nt F or ms a p pr o ve d b y t he a p pr o priat e I R B/I E C at eac h site.  C o nse nt m ust be 
o btai ne d i n acc or da nce wit h t he pri nci ples o utli ne d i n t he c urre nt v ersi o n of t he 
De clar ati o n of Helsi n ki.  I nf or me d C o nse nt F or ms m ust be date d a n d si g ne d b y t he 
I n vesti gat or or desi g nee a n d t he s u bject’s le gal re prese ntati ve a n d t he ori gi nal si g ne d 
c o nse nt f or m m ust be ke pt b y t he I n v esti gat or i n t he st u d y s u bject’s file.  “ Le gal 
re pres e ntati ve” me a ns a n i n di vi d ual w h o m a j u dicial or ot her b o d y a ut h orize d u n der 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 8 4  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
a p plica ble la w t o c o nse nt o n be half of a pr os pecti ve st u d y s u bject t o t he s u bjec t’s 
partici pati o n i n t he pr oce d ure(s) i n v ol ve d i n t he researc h.  T h e St u d y M o nit or will e ns ure 
t hat t he I C F has bee n si g ne d b y t h e s u bject’s le gal re pres e ntati ve.  T he st u d y s u bject’s 
legal re prese ntati ve will recei ve a c o p y of t h e si g n e d c o nse nt f or m. 
6. 3  
Visit Sc he d ule a n d Pr oce d ures 
D uri n g t h e st u d y, t here will be a t otal of u p t o 9 st u d y site visits : Pretreat m e nt Bas eli ne 
Visit ( Da y - 1); Tr eat me nt Peri o d Wee ks 2, 4, 8, 1 2, 1 6, 2 0, a n d 2 4; a n d a fi nal D ose-
ta peri n g Peri o d Visit f or s u bjects w h ose va m or ol o ne d ose is ta pere d at t he e n d of t he 
Treat me nt Peri o d.  E ac h s u bject will recei v e t he i n vesti gati o nal pr o d u ct at sta ble d ose f or 
a peri o d of 2 4 w ee ks.  S u bjects w h o partici pat e i n t he D ose-ta peri n g Peri o d will recei ve 
a d diti o nal va m or ol o ne at decreasi n g d ose o ver a 1- t o 4- wee k i nter val, a n d will ret ur n t o 
t he st u d y site f or fi nal st u d y ass ess me nts at t he e n d of t he 2- t o 5- wee k D ose-ta peri n g 
Pe ri o d.  T he Baseli ne D a y - 1 Visit ma y ta ke place o n t he sa me da y as t h e fi nal P hase IIa 
V B P 1 5- 0 0 2 Wee k 4 Visit.  I n t his cas e, Baseli ne Da y - 1 pr o ce d ures s ho ul d be perf or me d 
after c o m pleti o n of all fi nal V B P 1 5- 0 0 2 Wee k 4 assess me nts.  See Secti o n 7  f or a 
detaile d descri pti o n of t he safet y, cli nical effi cac y, a n d P D assess me nts t o be perf or me d 
i n t his st u d y. 
6. 3. 1  
B aseli ne Peri o d ( D ay - 1) 
F or  all s u bjects, t he Bas eli ne Da y - 1 Visit will occ ur after c o m pleti o n of all V B P 1 5- 0 0 2 
Wee k 4 pr oce d ures a n d wit hi n 2 4 h o urs pri or t o a d mi nistrati o n of t he first d ose of st u d y 
me dicati o n i n t he V B P 1 5- 0 0 3 e xte nsi o n st u d y.   
Pare nts or g uar di a ns of s u bjects w h o ha ve c o m plete d all V B P 1 5- 0 0 2 st u d y assess me nts 
will si g n t he I C F f or t he V B P 1 5- 0 0 3 e xte nsi o n st u d y at t he Bas eli ne Da y - 1 Visit.  If t he 
V B P 1 5- 0 0 2 Wee k 4 Visit will ser ve as t he Baseli ne Visit f or V B P 1 5- 0 0 3 , t he 
V B P 1 5- 0 0 3-s pecific I C F m ust be si g ne d after c o m pleti o n of all fi nal V B P 1 5- 0 0 2 Wee k 4 
assess me nts  a n d pri or t o t he perf or m a nce of a n y e xte nsi o n st u d y-s pecific pr oce d ures 
(Se cti o n 6. 2 ).   
S u bjec ts w h ose V B P 1 5- 0 0 3 Baseli ne Da y - 1 Visit occ urs ≤ 2 8 da ys after t h e fi nal 
V B P 1 5- 0 0 2 Wee k 4 Visit d o n ot nee d t o re peat, at t he Bas eli ne Da y - 1 Visit,  t he p h ysical 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 8 5  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
e x a mi nati o n, cli nical la b orat or y tests, P D bi o mar ker bl o o d dra w, 1 2-lea d E C G, a n d 
clinical efficac y assess m e nts perf or m e d at t he V B P 1 5- 0 0 2 Wee k 4 Visit.  
V B P 1 5- 0 0 2 Wee k 2 or Wee k 4 ( w hic he v er is a v aila ble a n d later) cli nical la b orat or y 
bl o o d ( he mat ol o g y, c he mistr y, a n d li pi ds) a n d uri nal ysis test res ults s h o ul d be recei ve d 
b y  t he site a n d re vie we d b y t he I n vesti gat or t o det er mi ne eli gi bilit y f or Bas eli ne Da y - 1 
e nroll me nt i nt o t he e xte nsi o n st u d y.   
S u bjects will retai n t he s u bject i de ntificati o n n u m ber assi g ne d f or t he P has e IIa 
V B P 1 5- 0 0 2 c ore st u d y. 
A n y  n e w me dic ati o ns ta ke n fr o m t he ti me of c o m pleti o n of t he V B P 1 5- 0 0 2 st u d y t o 
a d ministrati o n of t he first d ose of st u d y m e dicati o n i n t he V B P 1 5- 0 0 3 st u d y, or a n y 
c ha n ges t o me dic ati o ns ta ke n d uri n g t he c ore st u d y, will be rec or d e d as Pri or Me dicati o ns 
o n t he a p pr o priat e e C R F.  See Secti o n 7  f or d etaile d descri pti o ns a n d i nstr ucti o ns f or 
c o m pl eti o n of eac h s afet y, efficac y, a n d P D assess me nt. 
T he f oll o wi n g pr oce d ures will be perf or me d at t he Bas eli ne Da y - 1 Visit (see T a ble 6 ): 
 
Re vie w of I ncl usi o n a n d E x cl usi o n Criteria (see Secti o n 4. 2  a n d Secti o n 4. 3 )  
 
Writte n i nf or me d c o nse nt f or e xte nsi o n st u d y (see Secti o n 6. 2 ) 
 
E nr oll me nt (see Secti o n 5. 9 ) 
 
Re c or di n g of I nteri m Me dical Hist or y (see Secti o n 7. 2. 1 ) 
 
Re c or di n g of Me dic ati o n Hist or y (s ee Secti o n 5. 7. 1 ) 
 
Re c or di n g of A Es a n d S A Es be gi n ni n g at t he ti me writte n i nf or me d c o nse nt is 
o btai ne d (se e Secti o n 7. 2. 6 ) 
 
C o m plete p h ysical e x a mi nati o n ( n ot t o be re pe ate d if B aseli ne D a y - 1 is 
≤ 2 8 d a ys after t he V B P 1 5- 0 0 2 Wee k 4 Visit ass ess me nt d ate)  (see Secti o n 
7. 2. 2 ). 
 
Meas ure me nt of hei g ht a n d wei g ht (see Secti o n 7. 2. 2 ) 
 
Re c or di n g of vital si g ns (s u pi ne bl o o d press ure, h eart rate, oral te m perat ure, 
res pirat or y rate) (see Secti o n 7. 2. 3 ) 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 8 6  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
 
Cli nical la b orat or y e val u ati o n i ncl u di n g he mat ol o g y, cli nical c he mistr y, li pi ds, 
a n d uri nal ysis tests ( n ot t o be re pe ate d if B aseli ne D a y - 1 is ≤ 2 8 d a ys after t he 
V B P 1 5- 0 0 2 W ee k 4 Visit assess me nt d ate)  (see Secti o n 7. 2. 4 )  
 
Bl o o d s a m ples f or P D bi o mar kers i ncl u di n g A C T H, oste ocalci n, 
1 7- h y dr o x y pr o gester o ne, C T X, P 1 N P, c ortis ol, test oster o ne, c ortic oster o ne, a n d 
1 1- de o x yc ortis ol.  Bl o o d will als o be c ollecte d a n d st ore d f or f ut ur e pr ote o mics 
pr of ili n g a n d S o ma Sc a n st u dies.  ( N ot t o be re pe ate d if B aseli ne D a y - 1 is ≤ 2 8 
d a ys af ter t he V B P 1 5- 0 0 2 Wee k 4 Visit assess me nt d ate.)  (see Secti o n 7. 3. 7 )  
 
1 2-lea d E C G ( n ot t o be re pe ate d if B aseli ne D a y - 1 is ≤ 2 8 d a ys after t he 
V B P 1 5- 0 0 2 W ee k 4 Visit assess me nt d ate)  (see Secti o n 7. 2. 5 ) 
 
Q ua nti tati ve M uscle Testi n g ( Q M T) ( n ot t o be re pe ate d if B aseli ne D a y - 1 is 
≤ 2 8 d a ys after t he V B P 1 5- 0 0 2 Wee k 4 Visit ass ess me nt d ate)  (see 
Secti o n 7. 3. 1 ) 
 
Ti me t o R u n/ W al k Test ( T T R W) ( n ot t o be re pe ate d if B aseli ne D a y - 1 is 
≤ 2 8 d a ys after t he V B P 1 5- 0 0 2 Wee k 4 Visit ass ess me nt d ate)  (see 
Secti o n 7. 3. 4 ) 
 
Ti me t o S ta n d Test ( T T S T A N D) ( n ot t o be re pe ate d if B aseli ne D a y - 1 is 
≤ 2 8 d a ys after t he V B P 1 5- 0 0 2 Wee k 4 Visit ass ess me nt d ate)  (see 
Secti o n 7. 3. 2 )  
 
Ti me t o Cli m b Test ( T T C LI M B) ( n ot t o be re pe ate d if B aseli ne D a y - 1 is 
≤ 2 8 d a ys after t he V B P 1 5- 0 0 2 Wee k 4 Visit ass ess me nt d ate)  (see 
Secti o n 7. 3. 3 ) 
 
N or t h Star A m b ulat or y Assess me nt ( N S A A) ( n ot t o be re pe ate d if B aseli ne 
D a y - 1 is ≤ 2 8 d a ys after t he V B P 1 5- 0 0 2 Wee k 4 Visit assess me nt d ate)  (see 
Se cti o n 7. 3. 5 ) 
 
Si x- mi n ute Wal k Test ( 6 M W T) ( n ot t o be re pe ate d if B aseli ne D a y - 1 is 
≤ 2 8  d a ys after t he V B P 1 5- 0 0 2 Wee k 4 Visit ass ess me nt d ate)  (see 
Secti o n 7. 3. 6 ) 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 8 7  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
 
Pe diatric O utc o mes Data C ollecti o n I nstr u me nt c o m plete d b y p are nt/le gal 
g uar dia n (see Secti o n 7. 3. 8 ). 
 
Dis pe ns i n g of st u d y me dicati o n a n d s u bject diaries (see Secti o n 5. 3  a n d 
Se cti o n 8. 4 ) 
6. 3. 2  
Tre at m e nt Peri o d D ay 1 
Treat me nt Peri o d Da y 1 be gi ns wit h a d mi nistrati o n of t he first d ose of st u d y me dicati o n.  
T here  is n o sc he d ule d cli nic visit o n Da y 1.   
S u bjects will ta ke t he first d ose of st u d y me dicati o n at h o me o n t he m or ni n g of t he d a y 
after t he Da y - 1 Visit, o n St u d y Da y 1, u n der t he s u per visi o n of a pare nt or g uar dia n 
(Se cti o n 5. 3 ).   
6. 3. 3  
Tre at m e nt Peri o d Wee ks 2- 2 4  
S u bjec ts will ret ur n t o t he st u d y site f or safet y, efficac y, a n d P D assess me nts be gi n ni n g at 
We e k 2 a n d c o nti n ui n g t hr o u g h Wee k 2 4, acc or di n g t o t he sc h e d ule of visits i n T a b le 6.   
S u bjec ts will c o nti n ue t o recei v e dail y oral a d mi nistrati o n of va m or ol o ne t hr o u g h o ut t he 
2 4- wee k Treat me nt Peri o d, ta ke n f oll o wi n g i n gesti o n of 8 o u nces of w h ole mil k.  If 
w h ole mi l k is n ot t olera ble t o t he s u bject, a ser vi n g of a n ot her hi g h fat f o o d ma y b e 
s u bstitute d.   
D osi n g is t o occ ur at h o me t hr o u g h o ut t he 2 4- wee k Treat me nt Peri o d, e x ce pt at t he 
Wee k 1 2 a n d Wee k 2 4 Visits w he n d osi n g will occ ur at t he st u d y site.  S u bjects m ust 
ha ve  fast e d ≥ 6 h o urs pri or t o arri val at t he st u d y site f or Wee k 1 2 a n d Wee k 2 4 
pr oc e d ures a n d ass ess me nts.  T he pre- d os e bl o o d dra ws f or P D (i ns uli n a n d gl uc ose o nl y ) 
deter mi nati o n m ust be c ollecte d after s u bjects ha v e faste d f or ≥ 6 h o urs.  Brea kfast (a n 
8- o u nce glass of w h ole mil k [ or e q ui vale nt hi g h fat f o o d p orti o n] a n d 1 c u p of cereal) 
will be  ser ve d at t he st u d y site after t he bl o o d dr a w f or i ns uli n a n d gl uc ose, a n d wit hi n 
a p pr o x i matel y 3 0 mi n utes pri or t o a d mi nistrati o n of t he d ose of st u d y me di cati o n.  St u d y 
me dica ti o n acce pta bilit y will be assesse d b y a 5- p oi nt he d o nic scale i m me diatel y b ef ore 
(s mell) a n d aft er (taste) a d mi nistrati o n of t he dail y d ose of st u d y m e dicati o n at t he 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 8 8  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
Wee k 1 2 a n d Wee k 2 4 Visits.  All ot her Wee k 1 2 a n d Wee k 2 4 assess me nts s h o ul d be 
perf or me d after a d mi nistrati o n of t he fi nal d ose of st u d y me dicati o n.   
Cli nical efficac y assess m e nts ( Q M T, T T S T A N D, T T R W, T T C LI M B, N S A A, a n d 
6 M W T) a n d t he Pe diatric O utc o mes D ata C ollecti o n I nstr u me nt will be c o n d ucte d at 
1 2- wee k i nter vals ( Wee ks 1 2 a n d 2 4 ).  Wei g ht will be rec or de d e v er y 4 wee ks a n d hei g ht 
will be  meas ure d at 1 2- w ee k i nter vals.  Vital si g ns will be rec or d e d at eac h st u d y visit.  A 
p h ysical e x a mi nati o n will be perf or m e d at Wee k 2 4.  A 1 2-lea d E C G will b e rec or de d at 
We e ks 1 2 a n d 2 4.  Bl o o d a n d uri ne sa m ples f or cli nical la b orat or y tests a n d bl o o d f or t he 
ser u m PD bi o mar ker pa n el i ncl u di n g S o masca n a n d pr ote o mics pr ofili n g will be 
c ollecte d at sc h e d ule d visits t hr o u g h o ut t he st u d y (see  T a ble 6 ).  A d verse e ve nts, 
i ncl u di n g SA Es, a n d c o n c o mita nt me dicati o ns will be assesse d at eac h st u d y visit a n d 
rec or d e d t hr o u g h o ut t he st u d y.   
St u d y m e dicati o n will be dis pe nse d at 1 2- wee k i nter vals a n d ret ur ne d f or d osi n g 
c o m plia nce m o nit ori n g at 1- m o nt h i nter vals f or all s u bjects.  St u d y m e dicati o n ret ur ne d 
at the Wee k 4, 8, 1 6, a n d 2 0 Visits will be re dis pe nse d t o t he s u bject at t he e n d of eac h 
visit , after i nteri m c o m plia nce m o nit ori n g, f or c o nti n ue d d osi n g t hr o u g h t he e n d of t he 
1 2- wee k dis pe nsi n g i nter val.  S u bjects will recei v e s u bject diaries at eac h 1- m o nt h 
i nter val visit a n d ret ur n t he diaries at eac h s u bs e q ue nt visit.  Diaries will be re vie we d 
wit h t he  s u bject’s pare nt or g u ar dia n b y t he st u d y staff t o assess A Es a n d c ha n ges t o 
c o nco mita nt me dicati o ns/t hera pies.  
Li mite d safet y assess me nts a n d re vie w of t he s u bject diar y are c o n d ucte d at t he Wee k 2 
Visit.  
S u bjects w h o will n ot partici pate i n t he D ose-ta peri n g Peri o d (s ee Secti o n 6. 3. 4 ) will be 
disc har ge d fr o m t he st u d y f oll o wi n g c o m pleti o n of all Wee k 2 4 assess me nts.  S u bjects 
w h o d o partici pa te i n t he D ose-ta peri n g Peri o d will be dis pe nse d va m or ol o ne (a n d 
sta n dar d of care gl uc oc ortic oi d at t he discreti o n of t he I n v esti gat or f or s u bj ects w h o elect 
t o transiti o n t o sta n dar d of care gl uc oc ortic oi d treat me nt) at t he Wee k 2 4 Visit, as well as 
i nstr ucti o ns f or ta peri n g t he d ose of va m or ol o ne d uri n g t he D ose-ta peri n g Peri o d.   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 8 9  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
6. 3. 4  
D ose T a peri n g Peri o d ( Wee ks 2 5- 2 9) 
S u bjects w h o elect t o tra nsiti o n t o sta n dar d of care gl u c oc ortic oi d treat me nt f or D M D, or 
disc o nti n ue va m or ol o ne a n d n ot be gi n sta n dar d of care gl u c oc ortic oi d tr eat me nt f or 
D M D at t he e n d of t h e st u d y will ha ve t h eir va m or ol o ne d ose ta pere d pri or t o disc har ge 
fr o m t he st u d y.  S u bjects w h o disc o nti n ue st u d y m e dicati o n pri or t o c o m pleti o n of Wee k 
2 4 assess me nts will als o partici pate i n t he D os e-ta peri n g Peri o d if p ossi ble a n d if, i n t he 
o pi ni o n of t he I n v esti gat or, it is safe t o d o s o.  D ose ta peri n g will be perf or me d i n a 
ste p wise man ner, acc or di n g t o t he s u bject’s va m or ol o ne d ose d uri n g t he 2 4- wee k 
Treat me nt Peri o d, as o utli ne d i n T a ble 7 .  S u bjects w h o elect t o tra nsiti o n t o a sta n dar d 
of c are gl uc oc ortic oi d will ha ve t heir va m or ol o ne d ose ta pere d as i n T a ble 7 , a n d will 
be g i n treat me nt wit h a st a n dar d of care gl uc oc ortic oi d o n t he da y d ose ta peri n g be gi ns.  
T hese  s u bjects will c o nti n ue t o recei ve sta n dar d of care gl uc oc ortic oi d treat me nt, wit h 
dr u g  a n d d ose at t he discreti o n of t he I n vesti gat or, t hr o u g h o ut t he d urati o n of t he 
D ose- ta peri n g Peri o d a n d after disc h ar ge fr o m t he st u d y. 
T he s u bject’s w ei g ht r ec or de d at t he Wee k 2 4 Visit will be use d t o calc ulat e d ose v ol u me 
f or all d ose de-escalati o ns d uri n g t he D os e-ta peri n g Peri o d (see A p pe n di x 1 4. 1 ) 
T a b le 7  
V a m or ol o ne D ose T a peri n g 
Tre at me nt Peri o d 
V a m or ol o ne D ose 
Le v el  
Wee k 2 5 D ose 
Le v el  
Wee k 2 6 D ose 
Le vel  
Wee k 2 7 D ose 
Le vel  
Wee k 2 8 D ose 
Le vel  
Wee k 2 9 
D ose Le v el  
0. 2 5 m g/ k g/ d a y  
0. 1 2 5  m g/ k g/ d a y  
0  m g/ k g/ d a y  
 
 
 
0. 7 5 m g/ k g/ d a y  
0. 3 7 5  m g/ k g/ d a y  0. 1 2 5  m g/ k g/ d a y  
0 m g/ k g/ d a y  
 
 
2. 0 m g/ k g/ d a y  
1 m g/ k g/ d a y  
0. 5 m g/ k g/ d a y  
0. 2 5 m g/ k g/ d a y  
0 m g/ k g/ d a y  
 
6. 0 m g/ k g/ d a y  
3 m g/ k g/ d a y  
1. 5 m g/ k g/ d a y  
0. 7 5 m g/ k g/ d a y  
0. 2 5 m g/ k g/ d a y  
0 m g/ k g/ d a y  
 
All s u bjects partici pati n g i n t he D ose-ta peri n g Peri o d will ret ur n t o t he st u d y site f or fi nal 
st u d y assess me nts a p pr o xi matel y o ne wee k after t he fi nal d ose de-escalati o n (i.e., 
a p pr o x i matel y o ne w ee k after t he s u bject has recei ve d his last d ose of va m or ol o ne).  T he 
d urati o n of t he D ose-ta peri n g Peri o d will t heref ore var y de pe n di n g u p o n t he va m or ol o ne 
d ose recei ve d b y t he s u bj ect d uri n g t he Treat me nt Peri o d, fr o m a t otal d urati o n of t w o 
wee ks (f or s u bjects r ecei vi n g 0. 2 5 m g/ k g/ d a y va m or ol o ne; fi nal st u d y visit at W ee k 2 6) 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 9 0  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
t o fi ve wee ks (f or s u bjects recei vi n g va m or ol o n e 6. 0 m g/ k g/ da y; fi nal st u d y visit at Wee k 
2 9). 
At t he f i nal st u d y visit, s u bjects partici pati n g i n t he D ose-ta peri n g Peri o d will ha ve vital 
si g ns rec or de d, a n d bl o o d c ollecte d f or cli nical la b orat or y tests a n d P D bi o mar ker pa nel.  
St u d y m e dicati o n will be ret ur ne d f or c o m plia nce m o nit ori n g.  A d verse e ve nts, i ncl u di n g 
S A Es, a n d c o nc o mita nt me dicati o ns will be assesse d.  S u bject diaries will be ret ur n e d 
a n d re vie we d wit h site staff.   
S u bjects will be disc har ge d fr o m t he st u d y f oll o wi n g c o m pleti o n of all fi nal D ose-
ta peri ng Peri o d assess me nts. 
6. 4  
S u bject Disc o nti n u ati o n 
In t he e ve nt t hat a s u bj ect wit h dra ws earl y fr o m t he st u d y pri or t o t he Wee k 2 4 Visit, t he 
reas o n f or disc o nti n uati o n m ust be f ull y d oc u me nt e d i n t he s o urce d o c u me nts a n d t he 
e C R F.  F or s u bjects w h o wit h dra w earl y, fi nal Wee k 2 4 assess me nts s h o ul d be perf or me d 
at the ti me of earl y disc o nti n uati o n (s ee Secti o n 6. 3. 3 ).  Site pers o n nel will d oc u me nt all 
assess me nts, i ncl u di n g a n y A Es, i n t he s o urce d o c u me nts a n d e C R F.  S u bj ects w h o 
disc o nti n ue  st u d y me dicati o n s h o ul d f oll o w va m or ol o ne d ose ta peri n g pr oce d ures 
desc ri be d i n Secti o n 6. 3. 4  a n d detaile d i n t he Ma n ual of O perati o ns. 
6. 5  
St u d y C o m pleti o n 
A c o m plete d s u bject is d efi ne d as a s u bject w h o h as c o m plete d t he 2 4- wee k Treat me nt 
Pe ri o d a n d D ose-t a peri n g Peri o d, if a p plica ble, a n d has n ot pre mat urel y wit h dra w n fr o m 
t he st u d y f or a n y reas o n. 
7  
S T U D Y A S S E S S M E N T S A N D M E A S U R E M E N T S 
7. 1  
De m o gr a p hic Assess me nts 
D e m o gra p hic i nf or mati o n ( birt h date, race, a n d et h nicit y) c ollecte d d uri n g t he 
V B P 1 5- 0 0 2 st u d y will be use d f or t his st u d y; c ollecti o n of data will n ot be re peate d 
d uri n g t hi s st u d y.   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 9 1  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
7. 2  
S afet y a n d T oler a bilit y Assess me nts 
7. 2. 1  
I nteri m Me dic al Hist ory 
At t he Bas eli ne Da y - 1 Visit, i nteri m me dical hist or y will be rec or de d f or eac h s u bject, 
i ncl u di n g me dical hist or y mi grate d fr o m t he V B P 1 5- 0 0 2 c ore st u d y a n d a n y me dical 
hist or y t hat occ urre d i n t he peri o d bet w ee n c o m pl eti o n of V B P 1 5- 0 0 2 a n d e nr oll me nt 
i nt o t he VB P 1 5- 0 0 3 e xte nsi o n st u d y.  Mi grate d m e dical hist or y will i ncl u de a n y 
c o n diti o n t hat was rec or de d as me dical hist or y f or t he V B P 1 5- 0 0 2 c ore st u d y.  Me dical 
hist or y occ urri n g bet w ee n c o m pleti o n of V B P 1 5- 0 0 2 a n d V B P 1 5- 0 0 3 e nr oll me nt will 
i ncl u de s urgical hist or y a n d c o nc urre nt diseases, i ncl u di n g a n y c ha n ges fr o m t he c ore 
st u d y.  All A Es t hat are rec or de d d uri n g t he V B P 1 5- 0 0 2 c ore st u d y a n d are o n g oi n g at 
t he ti me of e nr oll me nt i nt o t he V B P 1 5- 0 0 3 st u d y will be rec or d e d as me di cal hist or y i n 
t he V BP 1 5- 0 0 3 st u d y. 
I nteri m me dical hist or y will be rec or d e d i n t he s o urce d oc u m e nts a n d i n t he e C R F. 
7. 2. 2  
P hysic al E x a mi n ati o n,  Wei g ht, a n d Hei g ht 
A c o m plete p h ysical e x a mi nati o n will be perf or m e d at t he Baseli ne Da y - 1 a n d Wee k 2 4 
Visit s, a n d will i ncl u d e e x a mi n ati o n of t h e f oll o wi n g: h e a d, e yes, ears, n ose, a n d t hr oat, 
nec k (i ncl u di n g a n e x a mi n ati o n of t he t hyr oi d), heart, l u n gs, a b d o me n (i ncl u di n g a n 
ex a mi n ati o n of t he liver a n d s plee n),  l y m p h n o d es, e xtre mities, ner v o us s yste m, a n d s ki n.  
If t he Baseli ne D a y - 1 Visit occ urs ≤ 2 8 da ys aft er t he date of t he fi nal V B P 1 5- 0 0 2 c ore 
st u d y Wee k 4 Visit, t he Baseli ne Da y - 1 p h ysic al e x a mi nati o n d oes n ot nee d t o be 
re peat e d (res ults fr o m t he V B P 1 5- 0 0 2 Wee k 4 Visit will be use d).  
A d diti o na l u nsc he d ule d s y m pt o m- directe d p h ysical e xa mi nati o ns ma y b e c o n d ucte d at 
a n y ti me at t he I n vesti gat or’s discreti o n.   
Hei g ht (i n c m) will be rec or de d at Bas eli ne Da y - 1, a n d Wee ks 1 2 a n d 2 4.  Wei g ht 
(i n k g) will be rec or de d at Baseli ne Da y - 1, Wee k 4, a n d eac h sc he d ule d m o nt hl y visit 
t hereafter t hr o u g h Wee k 2 4.  Wei g ht rec or de d at eac h m o nt hl y visit will be use d t o 
calc ulate t he v a m or ol o ne d ose v ol u me f or eac h s u bse q ue nt m o nt h’s d osi n g (see 
A p pe n di x 1 4. 1 ).   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 9 2  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
Res ults will be rec or de d i n t he s o urce d o c u me nts a n d o n t he a p pr o priat e e C R F. 
7. 2. 3  
Vit al Si g ns 
Vital si g ns (s u pi ne bl o o d press ure, h eart rate, res pirati o n rate, a n d oral te m perat ur e ) will 
be  rec or de d at Bas eli ne Da y - 1, Wee k 2, Wee k 4, a n d eac h sc he d ule d m o nt hl y visit 
t hereafter t hr o u g h Wee k 2 4 , a n d at t he fi nal Wee k 2 6- 2 9 st u d y visit f or s u bjects w h ose 
d ose is ta pere d d uri n g t h e D ose-ta peri n g Peri o d.  Vital si g ns s h o ul d be rec or de d aft er t he 
s u bject has bee n resti n g f or at least 5 mi n utes.   
Re s ults will be rec or de d i n t he s o urce d o c u me nts a n d o n t he a p pr o priat e e C R F. 
If vital si g ns ass ess me nt is perf or me d at t he sa me st u d y visit as bl o o d sa m pli n g a n d E C G 
rec or di n g, t he f oll o wi n g se q ue nce s h o ul d b e f oll o we d: 1) E C G rec or di n g; 2) vital si g ns 
assess me nt; a n d 3) bl o o d sa m pli n g.  
7. 2. 4  
Cli nic al L a b or at ory Tests 
Eac h s u bject will ha v e bl o o d dra w n a n d uri ne c oll ecte d f or t he he mat ol o g y, c he mistr y, 
li pi ds, a n d uri nal ysis cli nical la b orat or y tests liste d i n T a ble 8  a n d T a ble 9 , bel o w, at t he 
B aseli ne Da y - 1, a n d Wee k 4, 8, 1 6, a n d 2 4 Visits.  S u bjects w h ose d ose is ta pere d will 
als o ha ve cli nical la b orat or y tests p erf or m e d at t he fi nal Wee k 2 6- 2 9 Visit at t he e n d of 
t he D ose-ta p eri n g Peri o d.  If t he Baseli ne Da y - 1 Visit occ urs ≤ 2 8 da ys after t he date of 
t he fi nal V BP 1 5- 0 0 2 c ore st u d y Wee k 4 Visit, cli nical la b orat or y tests d o n ot nee d t o be 
re peat e d o n Baseli ne D a y - 1 f or t he V B P 1 5- 0 0 3 st u d y (res ults fr o m t he V B P 1 5- 0 0 2 c ore 
st u d y will be use d as b as eli ne meas ure me nts f or t he V B P 1 5- 0 0 3 st u d y).   
F or  all s u bjects, t he cli nical la b orat or y test res ults o btai ne d at t he V B P 1 5- 0 0 2 Wee k 2 
Visit wil l be use d t o assess e xte nsi o n st u d y eli gi bilit y, u nl ess V B P 1 5- 0 0 2 Wee k 4 Visit 
cli nical la b orat or y test r es ults are a vaila ble: if t he V B P 1 5- 0 0 2 Wee k 4 Visit cli nical 
la b orat or y test r es ults are a vaila ble pri or t o V B P 1 5- 0 0 3 e nr oll me nt, V B P 1 5- 0 0 2 Wee k 4 
res ults will be use d t o assess e xte nsi o n st u d y eli gi bilit y.  Re vie w of V B P 1 5- 0 0 2 Wee k 2 
res ults ( or V B P 1 5- 0 0 2 Wee k 4 res ults if a vaila bl e) is re q uir e d pri or t o e nr oll me nt of t he 
s u bject i nt o t his e xte nsi o n st u d y. 
All bl o o d a n d uri ne sa m ples will be se nt t o t he desi g nate d ce ntr al la b orat or y f or testi n g. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 9 3  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
F or t he h e mat ol o g y,  c he mistr y, a n d li pi ds la b orat or y tests, bl o o d will be c ollecte d b y 
direct ve ni p u nct ur e of peri p heral vei ns.  A p pr o xi matel y 4. 5 m L ( 7 m L at n o n- U S sites) of 
bl o o d will be o bta i ne d f or cli nical la b orat or y tests at eac h s c he d ule d visit.  A t otal of 
a p pr o xi matel y 1 8- 2 7 m L ( 2 8- 4 2 m L at n o n- U S sites) of bl o o d will be c ollecte d o ver t he 
c o urse of t his st u d y f or cli nical la b orat or y e val uati o n (see Secti o n 7. 4  f or d etails of bl o o d 
v ol u me s t o be c ollecte d).   
If bl o o d sa m pli n g is perf or me d at t he sa me st u d y visit as vital si g ns assess me nt a n d E C G 
rec or di n g, t he f oll o wi n g se q ue nce s h o ul d b e f oll o we d: 1) E C G rec or di n g; 2) vital si g ns 
assess me nt; a n d 3) bl o o d sa m pli n g.  
A n y a b n or mal he mat ol o g y, c h e mistr y, li pi d, or uri nal ysis test res ult dee me d cli nicall y 
si g nifica nt b y t he I n vesti gat or or me di call y q u alifie d s u b-i n vesti gat or ma y be re peate d, 
i ncl u di n g test res ults o bt ai ne d o n t he fi nal st u d y d a y.   
A n y  tr eat me nt- e mer ge nt a b n or mal la b orat or y test res ult t hat is cli nicall y si g nifica nt, i.e., 
meeti n g o n e or m ore of t he f oll o wi n g c o n diti o ns, s h o ul d be rec or de d as a si n gle dia g n osis 
o n t he A E se cti o n of t he e C R F: 
 Acc o m pa nie d b y cli nical s y m pt o ms  
 Re q uiri n g a c ha n ge i n c o nc o mita nt t hera p y (e. g. , a d diti o n of, i nterr u pti o n of, 
disc o nti n uati o n of, or a n y ot her c ha n ge i n a c o n c o mita nt me dicati o n, t hera p y, or 
treat me nt)  
 Is ot her wise c o nsi d ere d cli nicall y si g nifica nt b y t h e I n vesti gat or 
A n y cli nicall y si g nifica nt test a b n or malit y as defi n e d a b o ve s h o ul d be rec or de d as a n A E 
( u nless it was c o nsi dere d s p uri o us), a n d re p eat a nal ysis perf or me d u ntil res ol uti o n or 
u ntil t he I n vesti gat or or me dicall y q u alifie d s u b-i n vesti gat or d eter mi nes t h at res ol uti o n of 
t he a b n or malit y is n ot e x pecte d.   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 9 4  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T a ble 8   
He m at ol o g y, C he mist r y, a n d Li pi ds Cli nic al L a b or at or y Tests 
He m at ol o g y  
Re d Bl o o d Cells ( R B C ) 
N u merical platelet c o u nt (esti mate n ot acce pta ble)  
He m o gl o bi n  
W hite Bl o o d Cells ( W B C ) wit h differe ntial ( perce nt)  
He mat ocrit  
 
 
 
C he mistr y  
S o di u m  
T otal Bilir u bi n a 
P otassi u m  
Uric Aci d  
C hl ori de  
Gl uc ose  
Calci u m  
Al kali ne p h os p hatase ( A L P)  
I n or ga nic P hos p h or us  
Ga m ma Gl uta m yl Tra nsferase ( G G T)  
Bl o o d Urea Nitr o ge n ( B U N ) 
As partate a mi n otra nsferase  ( A S T) 
Creati ni ne  
Ala ni ne a mi n otra nsferase  ( A L T) 
T otal Pr otei n  
Creati ne ki nase ( C K)  
Al b u mi n  
Li pase  
Bicar b o nate  
A m ylase  
Lactate De h y dr o ge nase ( L D H)  
 
 
 
Li pi ds  
Tri gl yceri des  
L o w De nsit y Li p o pr otei n ( L D L)  
T otal c h olester ol  
Hi g h de nsit y Li p o pr otei n ( H D L)  
a. If o utsi de n or mal ra n ge, direct bilir u bi n will be meas ure d a n d re p orte d. 
Uri ne will be c ollect e d f or r o uti ne a nal ysis, b y di pstic k a n d micr osc o pic a n al ysis, f or t h e 
tests descri bed i n T a ble 9 .  Uri ne will be a nal yze d b y di pstic k a n d micr osc o pic a nal ysis 
b y  t he ce ntral la b orat or y at all assess me nt ti me p oi nts. 
T a ble 9  
Uri n al ysis Cli nic al L a b or at or y Tests 
Uri n al ysis (i ncl u di n g micr osc o pic e x a mi n ati o n) 
Di pstic k a 
Micr osc o pic A n al ysis  
Pr otei n  
W B C/ h pf  
Gl uc ose  
R B C/ h pf  
Ket o nes  
Casts  
p H  
Bacteria  
Le u k oc yte esterase  
 
Bl o o d  
 
aA mi dstrea m clea n -catc h uri ne s peci me n will be c ollecte d f or di pstic k a nal ysis.   
Cli nical la b orat or y tests will be perf or me d b y a ce ntral la b orat or y; res ults will be re p orte d 
t o t he st u d y site a n d tra nsferre d electr o nicall y i nt o t he cli nical st u d y d ata bas e. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 9 5  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T he pr oce d ures f or t he c ollecti o n, ha n dli n g, a n d s hi p pi n g of la b orat or y sa m ples will be 
s pecifie d i n t he La b orat or y M a n ual(s) pr o vi de d t o t he cli nical ce nter. 
7. 2. 4. 1  
F oll o w- u p of A b n or m al L a b or at ory Test Res ults 
In t he e ve nt of a me dicall y si g nifica nt, u n e x plai ne d, or a b n or mal cli nical la b orat or y test 
val ue, t he test(s) ma y b e re peat e d, e val u ate d b y t h e I n vesti gat or f or s ustai na bilit y a n d 
re pro d uci bilit y t o d eter mi ne if t he a b n or malit y re prese nts a n A E, a n d f oll o we d- u p u ntil 
t he res ults ha ve ret ur ne d t o t he n or mal ra n ge, sta bilize d, a n d/ or a n a de q uat e e x pla nati o n 
f or t he a b n or m alit y is f o u n d.  If a cl ear e x pla nati o n is esta blis he d, it s h o ul d be rec or de d i n 
t he s o urce d o c u me nts a n d e C R F.  T he cli nical la b orat or y will clearl y m ar k all la b orat or y 
test val ues t hat are o utsi d e t he n or mal ra n ge a n d t h e I n vesti gat or will i n dicate w hic h of 
t hese de viati o ns are cli nicall y si g nifica nt.  T hese cli nicall y si g nifica nt d e viati n g 
la b orat or y res ults will t he n be f urt h er des cri be d as A Es, a n d t he rel ati o ns hi p t o t he 
treat me nt, i n t he I n vesti gat or’s o pi ni o n, will be i n dicate d (see Se cti o n 7. 2. 6 ).  
7. 2. 5  
1 2 - Le a d E C G 
1 2-lea d E C Gs will be c ollecte d at t he Ba seli ne Da y - 1, Wee k 1 2, a n d Wee k 2 4 Visits.  If 
t he Bas eli ne Da y -1 Visit occ urs ≤ 2 8 da ys after t h e date of t he fi nal V B P 1 5- 0 0 2 c ore 
st u d y Wee k 4 Visit, t he Baseli ne Da y - 1 1 2-lea d E C G d oes n ot nee d t o be re peat e d 
(res ults fr o m t he V B P 1 5- 0 0 2 Wee k 4 Visit will be use d).  All E C G rec or di n gs m ust be 
perf or me d usi n g a sta n dar d hi g h- q u alit y, hi g h-fi delit y m ac hi ne e q ui p pe d wit h c o m p uter-
base d i nter val meas ure m e nts.  Di gital E C G rec or di n g is rec o m me n de d.  A ut o mate d E C G 
i nter vals ( Q R S d urati o n, P R [ PQ] i nter val, R R i nter val [i nter beat i nter v al], Q T i nter val, 
Q Tc , a n d heart rate) will be ca pt ur e d or calc ulate d.   
1 2-lea d E C Gs will be o bt ai ne d o ver a 3- t o 5- mi n ute peri o d aft er t he s u bject has bee n 
restin g q uietl y i n a s u pi n e p ositi o n f or at least 5 mi n utes.  
If bl o o d sa m pli n g, vital si g ns assess me nt, a n d E C G rec or di n gs are s c he d ul e d at t he sa me 
st u d y visits, t he f oll o wi n g se q ue nce s h o ul d b e f oll o we d: 1) E C G rec or di n g; 2) vital si g ns 
assess me nt; a n d 3) bl o o d sa m pli n g. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 9 6  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
E C G  res ults will be rea d l ocall y.  Res ults m ust be i nter prete d a n d rec or de d o n t he 
a p pr o priate e C R F. 
7. 2. 6  
A dverse Eve nts a n d Seri o us A dverse Eve nts 
T he c o n diti o n of t he s u bjects will be m o nit ore d t hr o u g h o ut t he d urati o n of t he st u d y b y 
t he clinical site st u d y te a m a n d b y rec or di n g of A Es i n s u bject diaries.  A n A E is a n y 
u nt o war d me dical o cc urre nce i n a s u bject w hic h d oes n ot necess aril y h a ve t o ha ve a 
ca usal relati o ns hi p wit h t he i nter ve nti o n.  A n A E ca n t heref ore be a n y u nfa v or a ble a n d 
u ni nte n de d si g n (i n cl u di n g a n a b n or mal la b orat or y fi n di n g, f or e x a m ple), s y m pt o m, or 
disease te m p orall y ass o ciate d wit h t he use of a n i n vesti gati o nal pr o d u ct, w h et her or n ot 
c o nsi dere d relate d t o t he pr o d uct.  Pre-e xisti n g c o n diti o ns t hat w orse n d uri n g a st u d y are 
t o be re p orte d as A Es. 
A d verse e ve nts will be rec or de d fr o m t he date of i nf or me d c o ns e nt a n d t hr o u g h t he ti me 
of t he s u bject’s last st u d y visit (st u d y c o m pleti o n or earl y disc o nti n uati o n).  Seri o us 
a d verse e ve nts will be rec or de d fr o m t he date of i nf or me d c o ns e nt, t hr o u g h o ut t he 
clinical trial, a n d f or u p t o 3 0 da ys after t he fi nal a d mi nistrati o n of st u d y dr u g.  S u bjects 
w h o e nr oll i n t he V B P 1 5- 0 0 3 e xte nsi o n st u d y will ha ve a n y A Es w hic h i nitiate d d uri n g 
V B P 1 5- 0 0 2 partici pati o n a n d w hic h are o n g oi n g at t he ti me of e nr oll me nt i nt o 
V B P 1 5- 0 0 3 rec or d e d i n t he V B P 1 5- 0 0 3 e C R F a n d f oll o we d d uri n g V B P 1 5- 0 0 3 
partici pati o n.  I n a d diti o n, s u bjects (a n d t heir p are nt or le gal g u ar dia n) will be q uesti o ne d 
b y st u d y staff at eac h st u d y visit f or a n y n e w si g ns or s y m pt o ms or c h a n ges i n e xisti n g 
si g ns or s y m pt o ms. 
All A Es a n d S A Es t hat are s p o nta ne o usl y re p orte d, i de ntifie d d uri n g q u esti o ni n g, or are 
a p pare nt fr o m a partici pa nt’s p h ysic al a p peara n ce will be rec or d e d i n t he s o urce 
d oc u me nts a n d i n t he s u bject’s e C R F.  T he d ate a n d ti me of o nset will be rec or de d.  A n y 
la b orat or y a b n or malit y t h at is o utsi de t he n or mal r a n ge a n d is c o nsi dere d a n A E (see 
Secti o n 7. 2. 4 ) s h o ul d be rec or d e d as a n A E o n t he a p pr o priate e C R F.  T he details 
recor d e d s hall i ncl u de t h e nat ure, d ate of o nset, fi nal o utc o me a n d its date, i nte nsit y 
assess me nt ( C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts [ C T C A E] gra de), a n d a 
deter mi nati o n of t he relati o ns hi p of t he e ve nt t o a d mi nistrati o n of t he st u d y dr u g (i.e., 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 9 7  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
ca usalit y).  All A Es will be gra de d b y C T C A E, Versi o n 4. 0 3.  Details of a n y me dicati o ns 
gi ve n t o t he s u bject t o a b ate t he A E s h o ul d be rec or de d i n t he a p pr o priate e C R F. 
I nte nsit y 
All cli nical A Es e nc o u nt ere d d uri n g t he cli nical st u d y will be rec or d e d i n t he e C R F.  
I nte nsit y of A Es will be gra de d usi n g t he m ost c urre nt versi o n of t he C o m m o n 
Ter mi n ol o g y Criteri a f or A d verse E v e nts ( C T C A E), versi o n 4. 0 3, 5- p oi nt s cale, a n d 
re p orte d i n det ail as i n dicate d o n t he e C R F.  A des cri pti o n of t he i nte nsit y s cales ca n be 
f o u n d bel o w: 
Mil d ( Gra de 1):  As y m pt o matic or mil d s y m pt o ms: cli nical or dia g n ostic o bser vati o ns 
o nl y; i nter ve nti o n n ot i n dicate d. 
M o derate ( Gra d e 2) :  Mi ni mal, l ocal, or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g 
a ge-a p pr o priate i nstr u me ntal acti vities of dail y li vi n g ( A D L). 
Se vere ( Gra d e 3):  Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life-
t hreate ni n g: h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; 
li miti n g self-care A D L; i nca pacitati n g wit h i na bilit y t o w or k or p erf or m n or mal dail y 
acti vit y. 
Lif e- T hreate ni n g ( Gra d e 4):  Ur ge nt i nter ve nti o n i n dicate d. 
Deat h ( Gra de 5):  Deat h relate d t o A E. 
Rel ati o ns hi p 
Relati o ns hi p t o st u d y dr u g will be gra de d o n a 5- p oi nt scale ( defi nite, pr o ba ble, p ossi ble, 
re m ote, or u nrelate d).  A descri pti o n of t he relati o ns hi p scale ca n b e f o u n d bel o w: 
Defi nite:  T his cate g or y a p plies t o a n A E t hat meets at least criteria 1, 2, a n d 4 of t he 
“ Pr o ba ble‟ cate g or y. 
Pr o ba ble:  T his cate g or y a p plies t o t h ose A Es t hat are c o nsi d ere d, wit h a hi g h de gree 
of cert ai nt y, t o be relate d t o t he st u d y dr u g.  A n A E ma y b e c o nsi dere d pr o ba ble, if 
( m ust i ncl u de first 3): 
1.  It f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of t he st u d y 
dr u g. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 9 8  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
2.  It c a n n ot be reas o na bl y e x plai ne d b y t h e k n o w n c haract eristics of t he 
s u bject’s cli nical state, e n vir o n me ntal or t o xic fact ors, or ot her m o des of 
t hera p y a d mi nistere d t o t he s u bject. 
3.  It disa p p ears or decreas es after d osi n g is c o m plete.  ( T here are i m p orta nt 
ex ce pti o ns w he n a n A E d oes n ot disa p pear u p o n disc o nti n uati o n of st u d y 
dr u g, yet dr u g relate d ness clearl y e xists, e. g., [ 1] b o ne marr o w d e pressi o n 
a n d [ 2] tar di ve d ys ki nesia.)  
4.  It f oll o ws a k n o w n patter n of res p o nse t o t he s us p ecte d st u d y dr u g. 
P ossi ble:  T his cate g or y a p plies t o t h ose A Es f or w hic h t he c o n necti o n wit h st u d y 
dr u g a d mi nistrati o n a p pears u nli kel y b ut ca n n ot b e r ule d o ut wit h certai nt y.  A n A E 
ma y b e c o nsi dere d p ossi bl y rel ate d t o st u d y dr u g if or w he n ( m ust i ncl u de first 2): 
1.  It f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of t he st u d y 
dr u g. 
2.  It ma y h a ve bee n pr o d u ce d b y t h e s u bject’s cli nical state, e n vir o n me ntal or 
t o xic fact ors, or ot her m o des of t hera p y a d mi nistere d t o t he s u bject. 
3.  It f oll o ws a k n o w n patter n of res p o nse t o t he s us p ecte d st u d y dr u g. 
Re m ote: I n ge neral, t his cate g or y is a p plica ble t o a n A E t hat meets t he f oll o wi n g 
criteria ( m ust i ncl u de t he first 2): 
1.  It d oes n ot f oll o w a reas o na ble te m p oral se q u e nce fr o m a d mi nistrati o n of 
t he st u d y dr u g. 
2.  It ma y rea dil y ha v e bee n pr o d uce d b y t he s u bject’s cli nical state, 
en vir o n me ntal or t o xic fact ors, or ot her m o des of t hera p y a d mi nistere d t o 
t he s u bject. 
3.  It d oes n ot f oll o w a k n o w n patter n of res p o nse t o t he s us pecte d st u d y dr u g. 
U nrelate d: T his c ate g or y is a p plica ble t o t h ose A Es w hic h are j u d ge d t o be clearl y 
a n d i nc o ntr o verti bl y d ue o nl y t o e xtra ne o us ca uses ( disease, e n vir o n me nt, etc.) a n d 
d o n ot meet t he criteria f or st u d y dr u g relati o ns hi p liste d u n der re m ote, p ossi ble, or 
pr o ba ble. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 9 9  of 1 3 7 
Re v era Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
Cli nic al L a b or at or y Test A b n or m alities 
Cli nical la b orat or y test res ults will be rec or de d i n t he desi g n ate d e C R F.  T h e i nte nsit y of 
a b n or mal cli nical la b orat or y test res ults t hat are A Es will als o be gra de d usi n g t he m ost 
c urre nt v ersi o n of t he C T C A E, versi o n 4. 0 3, 5- p oi nt scale a n d re p orte d i n d etail as 
i n dicate d i n t he e C R F.  A descri pti o n of t he i nte nsit y scal e ca n b e f o u n d a b o ve. 
A n y tr eat me nt- e mer ge nt a b n or mal cli nical la b orat or y test res ult t hat is cli nicall y 
si g nifica nt, i.e., m eeti n g o ne or m ore of t he f oll o wi n g c o n diti o ns, s h o ul d be rec or de d as a 
si n gle diag n osis o n t he A E secti o n of t he e C R F: 
 Acc o m pa nie d b y cli nical s y m pt o ms 
 Re q uiri n g a c ha n ge i n c o nc o mita nt t hera p y (e. g., a d diti o n of, i nterr u pti o n of, 
disc o nti n uati o n of, or a n y ot her c ha n ge i n a c o n c o mita nt me dicati o n, t hera p y, or 
treat me nt) 
 Is ot her wise c o nsi d ere d cli nicall y si g nifica nt b y t h e I n vesti gat or 
T his a p plies t o a n y pr ot oc ol a n d n o n- pr ot oc ol-s p ecifie d safet y la b orat or y res ult fr o m 
tests perf orme d after t h e first d ose of st u d y dr u g, w hic h falls o utsi de t he la b orat or y 
refere nce ra n ge a n d m eets t he cli nical si g nifica nce criteria per I n v esti gat or sta n dar d 
o perati n g pr oce d ures ( S O Ps). 
T his d oes n ot a p pl y t o a n y a b n or mal la b orat or y res ult t hat falls o utsi de t he la b orat or y 
refere nce ra n ge, b ut d oes n ot meet t he cli nical si g nifica nce criteri a ( w hic h will be 
a nal yze d a n d re p orte d as la b orat or y a b n or malities); t h ose t hat are c o nsi dere d A Es of t he 
t y pe e x plicitl y e x e m pte d b y t he pr ot oc ol; or t h ose t hat are t he res ult of a n A E w hic h h as 
alrea d y b ee n re p orte d. 
Ple as e N ote : a n y cli nical la b orat or y a b n or malit y f ulfilli n g t he criteri a f or a n S A E s h o ul d 
be re p ort e d as s uc h, i n a d diti o n t o bei n g rec or de d as a n A E i n t he e C R F. 
F oll o w- U p of A d verse E ve nts 
A d verse e ve nts will be f oll o we d u ntil t he y ha v e ret ur ne d t o baseli ne stat us, sta bilize d, or 
t he I n v esti gat or, St u d y C hair, Me dical M o nit or a n d S p o ns or a gree t h at f oll o w- u p is n o 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 0 0  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
l o n ger nee d e d.  If a cle ar e x pla nati o n of ca use is esta blis he d, it s h o ul d be rec or de d i n t he 
s o urce d oc u m e nts a n d e C R F.  I n t h e e ve nt of u n e x plai ne d a b n or mal la b orat or y test 
val ues, t he te sts ma y be re peate d as s o o n as p ossi ble a n d f oll o we d u p u ntil t he y h a ve 
ret ur ne d t o t he n or m al ra n ge or baseli ne v al ue a n d/ or a n a de q u ate e x pla nati o n of t he 
a b n or malit y is f o u n d.  I n case of o n g oi n g A Es at t he ti me of data bas e cl os ure, t he data 
o btai ne d at t he ti me of data base cl os ur e will be use d i n t he statistical a nal ysis.  T he 
f oll o w- u p of A Es will be d oc u me nte d i n t he s o urce d oc u me nts a n d will be descri be d i n 
t he fi nal re p ort o nl y if c o nsi dere d rel e va nt b y t he I n vesti gat or, t h e St u d y C h air, t he 
Me dical M o nit or a n d/ or t he S p o ns or. 
I n a d diti o n, t he Me dical M o nit or ma y re q uest a d diti o nal bl o o d tests, dia g n ostic i ma gi n g 
st u dies, or s pecialist p h ysicia n c o ns ultati o ns i n or der t o f urt her e val u ate a n y A E or test 
a b n or malit y c o nsi dere d t o be cli nicall y si g nifica nt b y t he St u d y S p o ns or. 
D osi n g Err or 
F or t he p ur p os es of t his st u d y, a d osi n g err or is defi ne d as a d os e e x cee di n g or less t ha n 
t he sc he d ule d d ose of 0. 2 5 m g/ k g, 0. 7 5 m g/ k g, 2. 0 m g/ k g, or 6. 0 m g/ k g s pecifie d f or 
eac h d ose l e vel gr o u p.  S uc h occ urre n ces s h o ul d b e re p ort e d a n d rec or d e d i n t he d osi n g 
pa ge  of t he eC R F  a n d as f oll o ws: 
 Use of st u d y me dicati o n i n d oses i n e x cess of t hat s pecifie d i n t he pr ot oc ol s h o ul d 
n ot be r ec or de d as a n A E u nless t here are ass o ciat e d si g ns or s y m pt o ms. 
 A d osi n g err or wit h ass o ciate d n o n-seri o us A Es s h o ul d be rec or de d as A Es o n t he 
rele va nt A E f or ms i n t he e C R F. 
 A d osi n g err or wit h a n ass ociate d S A E s h o ul d be rec or de d as a n S A E. 
 Details of all d osi n g err ors, i ncl u di n g act ual d ose a d mi nistere d, s h o ul d be 
d oc u me nte d i n t he s o urce d oc u me nts a n d rec or d e d o n t he Pr ot oc ol De viati o ns 
e CR F. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 0 1  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
7. 2. 6. 1  
Seri o us A dverse Eve nts  
F or  treat me nt-eli gi ble s u bjects, S A Es will be c ollecte d a n d re p ort e d d uri n g t he st u d y 
fr o m t he ti me i nf or me d c o nse nt is o btai ne d t hr o u g h 3 0 da ys after t he fi nal d ose of st u d y 
me dicati o n, acc or di n g t o t he pr ot oc ol a n d a p plica ble re g ulati o ns. 
All S A Es, i nc l u di n g t h ose t hat c o nti n ue be y o n d t h e n or mal A E c ollecti o n peri o d (i.e., are 
o n g oi n g at t he s u bject’s last st u d y visit), will be f oll o we d u ntil res ol uti o n or u ntil 
sta bilize d wit h o ut se q uelae.  Seri o us a d v erse e ve nts t hat be gi n after t he s u bject’s 
partici pati o n i n t he st u d y is c o m plete b ut t hat t he I n vesti gat or c o nsi ders t o be relate d t o 
st u d y dr u g will be re p ort e d t o t he S p o ns or wit hi n 2 4 h o urs or disc o ver y b y t he 
I n v esti gat or. 
D uri n g t h e S A E c ollecti o n peri o d, t he I n vesti gat or or cli nical site pers o n nel s h o ul d n otif y 
t he P R A safet y ma na ge m e nt tea m of all S A Es, re gar dless of relati o ns hi p t o t he 
i n vesti gati o nal dr u g, wit hi n 2 4 h o urs of cli nical staff bec o mi n g a ware of t h e e ve nt; 
n otificati o n t o t he P R A safet y ma na ge me nt tea m will tri g ger alerts t o t he C o or di nati n g 
Ce nter, St u d y C hair, t he S p o ns or, a n d t he Me dical M o nit or.  T he I n vesti gat or will 
pr o vi de t he i nitial n otificati o n b y c o m pleti n g t he S A E e C R F i n t he electr o nic data ca pt ure 
( E D C), whic h m ust i ncl u de t he I n vesti gat or’s assess me nt of t he relati o ns hi p of t he e ve nt 
t o i n vesti gati o nal dr u g.  I n t he u nli kel y e v e nt t hat t he electr o ni c st u d y d ata base is 
i naccessi ble a n d t he I n vesti gat or is u na ble t o c o m plete t he S A E e C R F wit hi n 2 4 h o urs, 
t he S A E N otificati o n F or m ( p df) s h o ul d be c o m pl ete d a n d e m aile d or pri nt e d/fa x e d t o t he 
P R A safet y m a na ge me nt tea m. 
I n a d diti o n, n otificati o n is se nt b y t he I n vesti gat or t o t he I R B a n d t he s u bject’s Pri mar y 
Care P h ysi cia n. 
F oll o w- u p i nf or mati o n, or ne w i nf or mati o n r e gar di n g a n o n g oi n g S A E, m ust be pr o vi de d 
pr o m ptl y t o t he P R A safet y ma na ge me nt tea m wit hi n 2 4 h o urs of k n o wle d ge of t he ne w 
or f oll o w- u p i nf or mati o n, w hic h will f or war d t he i nf or mati o n t o t he C o or di nati n g Ce nter, 
St u d y C h air, t he S p o ns or, a n d t he Me dical M o nit or. 
All S A E re p orts s h o ul d be c o m plete d wit hi n t he E D C. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 0 2  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T he Data a n d Safet y M o nit ori n g B o ar d ( D S M B) will re vie w S A Es a n d ot her perti ne nt 
safet y data at re g ular i nter vals d uri n g t he st u d y. 
A n A E or s us pect e d a d verse reacti o n is c o nsi dere d seri o us if, i n t he vie w of eit her t he 
I n v esti gat or or S p o ns or, it res ults i n a n y of t h e f oll o wi n g o utc o mes: 
 Is fatal (res ults i n t he o utc o me of deat h) 
 Is life-t hreate ni n g  
 Re q uires i n- patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
 Res ults i n persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he 
a bilit y t o c o n d uct n or mal life f u ncti o ns 
 Is a c o n ge nital a n o mal y or birt h defect 
 Is a n i m p orta nt me dical e ve nt t hat ma y j e o par dize t he s u bject a n d ma y re q uire 
me dic al or s ur gic al i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o v e. 
T he ter m “s u d de n d eat h” s h o ul d o nl y be use d w he n t he ca use is of a car diac ori gi n as pe r 
sta n dar d defi niti o n. 
T he ter ms deat h a n d s u d de n deat h are cl earl y disti nct a n d m ust n ot be use d 
i nterc ha n gea bl y. 
A n y A E or cli nicall y si g nifica nt a b n or mal la b orat or y test v al ue, as det er mi ne d b y t h e 
I n v esti gat or, t hat is seri o us a n d w hic h occ urs d uri n g t he c o urse of t he st u d y (as defi ne d 
a b o ve) m ust be re p orte d t o t he P R A safet y ma na ge me nt tea m, w h o will n otif y t he 
C o or di nati n g Ce nter, St u d y C hair, t he S p o ns or, a n d t he Me dical M o nit or wit hi n 2 4 h o urs 
of t he I n vesti gat or b ec o mi n g a ware of t he e v e nt.  A d diti o nal i nf or mati o n t hat bec o mes 
a vaila ble f or a n S A E after t he i nitial re p ort is s u b mitte d will be re p orte d t o t he P R A 
safet y ma na ge me nt tea m, w h o will n otif y t he C o or di nati n g Ce nter, St u d y C hair, t he 
S p o ns or, a n d t he Me dical M o nit or wit hi n 2 4 h o urs of t he I n vesti gat or b ec o mi n g a ware of 
t he ne w i nf or mati o n. 
Re late d S A Es M U S T be c ollecte d a n d re p orte d re gar dless of t he ti me el a pse d fr o m t he 
last a d mi nistrati o n of st u d y dr u g, e ve n if t he st u d y has bee n cl os e d.  U nrelate d S A Es 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 0 3  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
m ust be c ollecte d a n d re p orte d d uri n g t he st u d y fr o m t he ti me of i nf or me d c o nse nt 
t hr o u g h 3 0 d a ys after t he fi nal d ose of st u d y me di cati o n. 
If, at a n y ti me d uri n g t he st u d y, a s u bject e x perie n ces a n S A E, a p pr o priate care s h o ul d b e 
i nstit ute d. 
I n t he e ve nt of a n S A E, t he I n vesti g at or will c o m plete t he S A E e C R F wit hi n 2 4 
h o urs of first a w are ness of t he e ve nt.  I n t he u nli kel y e ve nt t h at t he electr o nic st u d y 
d at a b ase is i n accessi ble a n d t he I n vesti g at or is u n a ble t o c o m plete t he S A E e C R F 
wit hi n 2 4 h o urs, t he S A E N otific ati o n F or m ( p df) s h o ul d be c o m plete d a n d e m aile d 
or pri nte d/f a xe d t o t he P R A s afet y m a n a ge me nt te a m wit hi n 2 4 h o urs, usi n g t he 
c o nt act i nf or m ati o n bel o w : 
E m ail C H O S afet y @ pr a hs.c o m 
Dr u g S afet y F a x: 1- 8 8 8- 7 7 2- 6 9 1 9 or 1- 4 3 4- 9 5 1- 3 4 8 2 
 
S A E Q uesti o ns: Dr u g S afet y H otli ne: 1- 8 0 0- 7 7 2- 2 2 1 5 or 1- 4 3 4- 9 5 1- 3 4 8 9 
Se ri o us A d verse E v e nts will be rec or d e d fr o m t he ti me t he s u bject’s writte n i nf or me d 
c o nse nt is o btai ne d.  Seri o us a d verse e ve nts t hat o cc ur wit hi n 3 0 da ys of st u d y dr u g 
d osi n g m ust c o nti n ue t o be rec or de d a n d re p orte d t o t he St u d y S p o ns or or its desi g nee.  
S h o ul d t here be a n S A E t hat occ urs t hat s u g gests a n i ncreas e d ris k t o t he partici pa nts, t he 
f oll o wi n g ste ps will be c o nsi dere d, de p e n di n g o n t he n u m ber a n d se v erit y of t he S A E(s): 
m o dificati o n of t he pr ot o c ol, i n vesti gati o n of t he relati o ns hi p of t he S A E(s) t o st u d y dr u g, 
s us pe nsi o n of t he st u d y, a n d/ or disc o nti n uati o n of t he st u d y. 
7. 2. 7  
St u dy Me dic ati o n Acce pt a bility Assess m e nt 
Acce pt a bilit y of t he st u d y me dicati o n will be assesse d usi n g a 5- p oi nt he d o nic scale 
i m me diatel y bef ore (s mell) a n d after (taste) d osi n g at t he Wee k 1 2 a n d Wee k 2 4 Visits.  
T he assess me nts will be a d mi nistere d b y trai ne d st u d y staff.  Res ults will be rec or de d i n 
t he s o urce d o c u me nts a n d e C R F.  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 0 4  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
7. 3  
Cli nic al Effic ac y a n d P h ar m a c o d y n a mic Assess me nts  
7. 3. 1  
Q u a ntit ative M uscle Testi n g ( Q M T) 
Q ua ntitati ve M uscle Testi n g ( Q M T) will be a d mi nistere d t o s u bjects at t he Baseli ne 
Da y - 1, Wee k 1 2, a n d Wee k 2 4 Visits  usi n g t he CI N R G Q ua ntitati ve Meas ure me nt 
S y ste m ( C Q M S).3 7  If t h e Bas eli ne Da y -1 Visit occ urs ≤ 2 8 da ys after t h e date of t he 
fi nal V BP 1 5- 0 0 2 c ore st u d y Wee k 4 Visit, t he Baseli ne Da y - 1 Q M T d oes n ot nee d t o be 
re peat e d (res ults fr o m t he V B P 1 5- 0 0 2 Wee k 4 Visit will be use d). 
T he Q M T meas ures u nilateral stre n gt h of f o ur m uscle gr o u ps : el b o w fle xi o n/e xte nsi o n, 
a n d k nee fl e xi o n/e xte nsi o n. 3 7  C o m plete i nstr ucti o ns f or a d mi nisteri n g t h e Q M T are 
gi ve n i n t he st u d y  ma n ual t o be s u p plie d t o t he sites pri or t o st u d y start. 
Res ults will be c ollecte d usi n g t he C Q M S 3 s oft ware a n d tr a nsferre d i n t o t h e e C R F. 
7. 3. 2  
Ti m e t o St a n d Test ( T T S T A N D) 
T he Ti me t o Sta n d Test ( T T S T A N D) will be a d mi nistere d t o s u bjects at t he Baseli ne 
Da y  - 1, Wee k 1 2, a n d Wee k 2 4 Visits.  If t he Bas eli ne Da y -1 Visit occ urs ≤ 2 8 da ys 
after t he d ate of t he fi nal V B P 1 5- 0 0 2 c ore st u d y Wee k 4 Visit, t he Baseli ne Da y - 1 
T T S T A N D d oe s n ot nee d t o be re peate d (res ults fr o m t he V B P 1 5- 0 0 2 Wee k 4 Visit will 
be use d). 
T he T T S T A N D me as ures t he s pee d ( m/s; vel ocit y) wit h w hic h t he c hil d ca n sta n d t o a n 
erect p ositi o n fr o m s u pi n e (fl o or), a n d is a d mi nistere d as p art of t he N S A A (see 
Secti o n 7. 3. 5 ).  C o m plete i nstr ucti o ns f or a d mi nisteri n g a n d sc ori n g t he T T S T A N D are 
g i ve n i n t he st u d y ma n ual t o be s u p plie d t o t he sites pri or t o st u d y start. 
Res ults will be rec or de d i n t he s o urce d o c u me nts a n d i n t he e C R F. 
7. 3. 3  
Ti m e t o Cli m b Test ( T T C LI M B) 
T he Ti me t o Cli m b Test ( T T C LI M B) will be a d mi nistere d t o s u bjects at t he Bas eli ne 
Da y  - 1, Wee k 1 2, a n d Wee k 2 4 Visits.  If t he Bas eli ne Da y -1 Visit occ urs ≤ 2 8 da ys 
after t he d ate of t he fi nal V B P 1 5- 0 0 2 c ore st u d y Wee k 4 Visit, t he Baseli ne Da y - 1 
T T C L I M B d oes n ot nee d t o be re peate d (res ults fr o m t he V B P 1 5- 0 0 2 Wee k 4 Visit will 
be use d). 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 0 5  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T he T T C LI M B m eas ur es t he ti me (i n sec o n ds) re q uire d f or t he s u bject t o cli m b 
4 sta n dar d stairs, be gi n ni n g a n d e n di n g i n a sta n di n g p ositi o n wit h ar ms at t he si des .3 8  
C o m pl ete i nstr ucti o ns f or a d mi nisteri n g t he T T C LI M B are gi ve n i n t he st u d y ma n ual t o 
be s u p plie d t o t he sites pri or t o st u d y start.  
Res ults will be rec or de d i n t he s o urce d o c u me nts a n d i n t he e C R F. 
7. 3. 4  
Ti m e t o R u n/ W al k Test ( T T R W) 
T he T T R W will be a d mi nistere d t o s u bjects at t he Baseli ne Da y - 1, Wee k 1 2, a n d 
We e k 2 4 Visits .  If t he Baseli ne Da y -1 Visi t occ urs ≤ 2 8 da ys after t he dat e of t he fi nal 
V B P 1 5- 0 0 2 c ore st u d y Wee k 4 Visit, t he Baseli ne Da y - 1 T T R W d oes n ot nee d t o be 
re peat e d (res ults fr o m t he V B P 1 5- 0 0 2 Wee k 4 Visit will be use d).   
T he Ti me t o R u n/ W al k Test ( T T R W) meas ures t h e ti me (i n sec o n ds) t hat it ta kes a 
s u bject t o r u n or wal k 1 0 meters a n d is a d mi nistere d as part of t he N S A A (s ee 
Se cti o n 7. 3. 5 .  C o m plete i nstr ucti o ns f or a d mi nisteri n g a n d sc ori n g t he T T R W are gi ve n 
i n t he st u d y ma n ual t o be s u p plie d t o sites pri or t o st u d y start. 
Re s ults will be rec or de d i n t he s o urce d o c u me nts a n d i n t he e C R F. 
7. 3. 5  
N ort h St ar A m b ul at ory Assess m e nt ( N S A A) 
T he N ort h Star A m b ulat or y Assess me nt ( N S A A) is a cli nical assess me nt s cale 
s pecificall y desi g ne d t o meas ure f u n cti o nal a bilit y i n a m b ula nt b o ys wit h D M D.3 9  T he 
N S A A c o nsists of 1 7 sc ore d ite ms a n d 2 ti me d tests, i ncl u di n g t he T T R W a n d t he 
T T S T A N D (see Secti o n 7. 3. 2 ).  T he N S A A will b e c o n d ucte d at t he Baseli ne Da y - 1, 
We e k 1 2, a n d Wee k 2 4 Visits.  If t he Bas eli ne Da y - 1 Visit occ urs ≤ 2 8 d a ys after t h e 
date of  t he fi n al V B P 1 5- 0 0 2 c ore st u d y Wee k 4 Visit, t he Baseli ne Da y - 1 N S A A d oes 
n ot nee d t o be re p eate d (res ults fr o m t he V B P 1 5- 0 0 2 Wee k 4 Visit will be use d).  
S u bjects s h o ul d be baref o ot a n d wear c o mf orta bl e cl ot hi n g. C o m plete i nstr ucti o ns f or 
a d mi nisteri n g a n d s c ori n g t he N S A A are gi ve n i n t he st u d y ma n ual t o be s u p plie d t o t he 
sites pri or t o st u d y start. 
T he N S A A s h o ul d be a d mi nistere d B E F O R E t he 6 M W T at st u d y visits w h ere b ot h tests 
are a d mi nistere d.    


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 0 6  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
Res ults will be r ec or de d i n t he s o urce d o c u me nts a n d i n t he e C R F. 
7. 3. 6  
Si x- mi n ute W al k Test ( 6 M W T) 
F u ncti o nal e x ercise ca p acit y a n d m o bilit y will be assesse d i n all s u bjects b y mea ns of t he 
Si x- mi n ute Wal k Test ( 6 M W T) at t he Baseli ne Da y - 1, Wee k 1 2, a n d Wee k 2 4 Visits.  If 
t he Bas eli ne Da y -1 Visi t occ urs ≤ 2 8 da ys after t h e date of t he fi nal V B P 1 5- 0 0 2 c ore 
st u d y Wee k 4 Visit, t he Baseli ne Da y - 1 6 M W T d oes n ot nee d t o be re peate d (res ults 
fr o m t he V B P 1 5- 0 0 2 Wee k 4 Visit will be use d). 
T his e val uati o n is a m o difie d versi o n of t he 6 M W T, a da pte d f or use i n D M D patie nts. 4 0 
T he t otal dista nce tra v ele d, i n meters, s h o ul d be rec or de d al o n g wit h t he vali dit y of t he 
test as assesse d b y t he test a d mi nistrat or i n t he s o urce d oc u m e nts a n d i n t he e C R F.  If a 
s u bject ca n n ot c o m plete 6 mi n utes of wal ki n g, t he t otal meters a n d t he ti me u ntil 
disc o nti n ua ti o n of t he test s h o ul d be rec or d e d.  C o m plete i nstr ucti o ns f or a d mi nisteri n g 
t he 6 M W T are gi ve n i n t he st u d y ma n ual t o be s u p plie d t o t he sites pri or t o st u d y start. 
T he 6 M W T s h o ul d be a d mi nistere d A F T E R t he N S A A at st u d y visits w here b ot h tests 
are a d mi nistere d.   
Res ults will be rec or de d i n t he s o urce d o c u me nts a n d i n t he e C R F. 
7. 3. 7  
P h ar m ac o dy n a mic Bi o m ar ker P a nel 
Bl o o d s a m ples will be c ollecte d t o e x pl ore t he effect of va m or ol o ne o n bi o mar kers of 
m uscle c ell ular pat h ol o g y, bi o mar kers ass o ciate d wit h c hr o nic gl uc oc ortic oi d treat me nt, 
a n d bi o mar kers ass ociate d wit h i ns uli n resista nce, a dre nal s u p pressi o n, a n d b o ne 
t ur n o ver, as liste d i n T a ble 1 0 .  Bl o o d sa m ples will be c ollecte d at t he Baseli ne Da y - 1 
a n d W ee ks 8, 1 6, a n d 2 4 Visits, a n d at t he fi nal D ose-ta peri n g Peri o d Visit f or s u bjects 
w h ose va m or ol o ne d os e is ta pere d at t he e n d of t h e st u d y.  If t he Baseli ne Da y - 1 Visit 
occ urs ≤ 2 8 da ys after t h e date of t he fi nal V B P 1 5- 0 0 2 c ore st u d y Wee k 4 Visit, t he 
Ba seli ne Da y - 1 bl o o d dr a w f or t he P D bi o mar ker pa nel d oes n ot nee d t o b e re peat e d 
(res ults fr o m t he V B P 1 5- 0 0 2 Wee k 4 Visit will be use d).  T he bi o mar ker a nal ysis 
i ncl u des A C T H, oste ocal ci n, 1 7- h y dr o x y pr o gester o ne, C T X, P 1 N P, c ortis ol, H b A 1c 
(e xce pt Bas eli ne), test ost er o ne, c ortic oster o ne, a n d 1 1- de o x yc ortis ol.  Bl o o d will als o be 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 0 7  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
c ollecte d at eac h of t hese ti me p oi nts a n d st ore d f or f ut ure pr ot e o mics pr ofili n g a n d 
S o ma Sca n st u dies .   
Bl o o d  sa m ples will be c ollecte d at t he Wee ks 1 2 a n d 2 4 Visits f or meas ure me nt of 
gl uc ose  a n d i ns uli n, after t he s u bject has fast e d f or ≥ 6 h o urs a n d pri or t o a d mi nistrati o n 
of t he da il y d os e of st u d y me dicati o n.   
A t otal of 6 1- 9 3 m L  ( 58 - 89 m L at n o n- U S sites) of bl o o d will be c ollecte d f or P D  
bi o mar kers, i ncl u di n g bl o o d c ollecte d f or fasti n g gl uc ose a n d i ns uli n, o ver t he c o urse of 
t he 2 4-wee k t o 2 9- wee k st u d y (see Secti o n 7. 4 ).   
T a b le 1 0  
P h ar m a c o d y n a mi c Bi o m a r kers 
A dre n al S u p pressi o n  
C ortis ol  
1 7 - h y dr o x y pr o gester o ne  
A C T H  
T est oster o ne  
C ortic oster o ne  
1 1 - De o x yc ortis ol  
I ns uli n Resist a nce 
Gl uc ose  
I ns uli n 
H b A 1c  
B o ne T ur n o ver  
Oste o calci n  
P 1 N P  
C T X  
E x pl or at or y Bi o m ar kers  
S o ma Sca n a n d Pr ote o mics Pr ofili n g  
 
7. 3. 8  
Pe di atric O utc o m es D at a C ollecti o n I nstr u m e nt 
Q ualit y of lif e will be ass esse d b y c o m pleti o n of t he Pe diatri c O utc o mes Data C ollecti o n 
I nstr u me nt.  T he s u bject pare nt/le gal g uar dia ns will be as ke d t o c o m plete t his i nstr u me nt 
at the Bas eli ne Da y - 1, Wee k 1 2, a n d Wee k 2 4 Visits.   
Res ults will be rec or de d i n t he e C R F. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 0 8  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
7. 4  
T ot al Bl o o d V ol u me Re q uire d 
T he n u m ber a n d v ol u me of bl o o d sa m ples a n d t otal v ol u me of bl o o d t o be c ollecte d fr o m 
eac h s u bject t hr o u g h o ut t he d urati o n of t he 2 4- wee k t o 2 9- wee k st u d y are s u m marize d i n 
T a b le 1 1.  A t otal of 7 9- 1 2 0 m L ( 8 6- 1 3 1 m L at n o n- U S sites) of bl o o d will be c ollecte d 
fr o m eac h s u bject o ver t he c o urse of t he u p t o 2 9- wee k st u d y.   
T a ble 1 1  
Bl o o d S a m ple N u m ber a n d V ol u me 
 
T ot al m L of Bl o o d  
Test  
D a y -1 a Wee k 
4  
Wee k 
8  
Wee k 
1 2  
Wee k 
1 6  
Wee k 
2 4  
Wee k 2 6 -2 9 
( E n d of 
D ose -
t a per)b  
T ot al 
V ol u me  
Cli nical Safet y La bs c 
4. 5   
( 7. 0)d 
4. 5  
( 7. 0)d 
4. 5  
( 7. 0)d 
 
4. 5  
( 7. 0)d 
4. 5  
( 7. 0)d 
4. 5   
( 7. 0)d 
1 8 -2 7  
( 2 8-4 2) d 
P D Bi o mar ker Pa nel  
1 5 e 
 
1 7 f 
( 1 6)f, d 
 
1 7 f 
( 1 6)f, d 
1 7 f 
( 1 6)f, d 
1 7 f  
( 1 6)f, d 
5 1 -8 3  
(4 8 -7 9) d 
P D I ns uli n/ Gl uc ose  
 
 
 
5 g 
 
5 g 
 
1 0  
T otal V o l u me b y Visit 
( m L) 
1 9. 5  
( 2 2)d 
4. 5  
( 7. 0)d 
2 1. 5  
( 2 3)d 
5  
2 1. 5  
( 2 3)d 
2 6. 5  
( 2 8)d 
2 1. 5  
( 2 3)d 
7 9 -1 2 0  
( 8 6-1 3 1) d 
T ot al V ol u me:  7 9 -1 2 0  m L  ( 8 6-1 3 1 m L) d  
a Da y -1 bl o o d dra ws f or cli nical la bs a n d P D bi o mar kers will n ot be re peate d f or s u bjects w h ose Da y -1 Visit c oi nci d es 
wit h t h e fi n al V B P 1 5 -0 0 2 Wee k 4 Visit a n d w h o ha d bl o o d dra w n f or cli nical la bs a n d P D bi o mar kers f or t h e 
V B P 1 5 -0 0 2 Wee k 4 Visit.  
b O nl y s u bjects w h o partici p ate i n t h e D ose -ta peri n g P eri o d will ha ve bl o o ds dra w n. 
c He mat ol o g y, C he mistr y, Li pi ds . 
d Bl o o d  v ol u me t o be c ollecte d at n o n -U S sites.  
e c ortis ol, P 1 N P, oste ocalci n, 1 7 - h y dr o x y pr o gester o ne, test oster o ne, c ortic oster o ne, 1 1 -de o x yc ortis ol, C T X, A C T H, 
S o ma Sca n, a n d pr ote o mics testi n g .  
f c ortis ol, P 1 N P, oste ocalci n, 1 7 - h y dr o x y pr o gester o ne, test oster o ne, c ortic oster o ne, 1 1 -de o x yc ortis ol, C T X, A C T H, 
H b A 1c, S o ma Sca n, a n d pr ote o mics testi n g . 
g  S u bjects m ust h a ve faste d ≥ 6 h o urs pri or t o bl o o d dra ws.   Bl o o d will be dra w n pri or t o a d mi nistrati o n of t h e d ose of 
st u d y me dicati o n.   
 
8  
D A T A C O L L E C TI O N 
8. 1  
S o urce D oc u me nts 
S o urce d oc u me nts are defi ne d as ori gi nal d oc u me nts, data, a n d rec or ds.  T hese 
d oc u me nts ma y i n cl u de h os pital rec or ds, cli nical a n d office c harts, la b orat or y 
data/i nf or mati o n, s u bjects’ diaries or e val uati o n c hec klists, p har mac y dis p e nsi n g a n d 
ot her r ec or ds, rec or d e d d ata fr o m a ut o mate d i nstr u me nts, micr ofil m or ma g netic m e dia, 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 0 9  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
a n d/ or x-ra ys.  Data c ollecte d d uri n g t his st u d y m ust be rec or d e d o n t he a p pr o priate 
s o urce d oc u m e nts. 
A s u bjec t e nr oll me nt l o g is t o be c o m plete d at eac h st u d y site.  Data rec or de d o n t he 
e nroll me nt l o g are t o i ncl u de a s u bject i de ntifier, t he date of e nr oll me nt, a n d t he reas o n 
t he s u bject was n ot e ntere d (if a p plica ble).  All s u bjects i nitiall y c o nsi dere d f or 
e nr oll me nt are t o b e rec or de d i n t his l o g.  
T he i n vesti gat or(s)/i nstit uti o n(s) will per mit st u d y-relate d m o nit ori n g, a u dits, I R B/I E C 
re vie w, a n d re g ulat or y i ns pecti o n(s), pr o vi di n g dir ect access t o s o urce data d oc u me nts. 
8. 2  
Electr o nic C ase Re p ort F or m C o m pleti o n 
S u bject data will be c ollecte d i n t his st u d y usi n g a n E D C s yste m.  T he E D C a n d data base 
s yste m will be O pe n Cli nica b y A kaza Res earc h, L L C.  O pe n Cli nica is a we b- base d 
(htt ps:/ / w w w. o pe ncli nica.c o m) data e ntr y s yst e m utilizi n g a hi g h sec urit y e n vir o n me nt.  
T he u n derl yi n g st ora ge facilit y will be P ost gre S Q L, w h os e str uct ur e per mits t he li n ki n g 
of s u bject i nf or mati o n acr oss all ta bles i n relati o nal data bases.  O pe n Cli nica uses sec ure 
s oc ket la yers ( S S L) a n d i n its E nter prise versi o n use d i n t his st u d y is 2 1 C o de of Fe deral 
Re g ulati o ns ( C F R) Part 1 1 c o m plia nt.  O nce a n e C R F is create d i n t he data base, a dat a 
dicti o nar y  e xists a n d t he data tea m creat es c o m pati ble pa per s o urce d oc u m e ntati o n.  
T he C o or di nati n g Ce nt er will desi g n a n el ectr o nic data base i n O p e n Cli nica f or t his st u d y.  
Access ri g hts t o t he E D C s yste m f or t h e st u d y site tea m me m bers will nee d t o be 
re q ueste d.  E v er y user of t he s yste m will be ma d e a ware of t he fact t hat user na me a n d 
pass w or d s h o ul d ne ver be s hare d a n d t heir el ectr o nic si g nat ur e c o nstit utes t he le gall y 
bi n di n g e q ui vale nt of a h a n d- writte n si g nat ur e.  O nl y trai ne d pers o n nel certifie d b y t he 
C o or di nati n g Ce nter will recei v e a user na me a n d pass w or d. 
All data will be directl y e ntere d or c ollecte d o n a s o urce d oc u m e nt a n d t he n e ntere d i nt o 
O pe n Cl i nica or tra nsf erre d electr o nicall y t o t he st u d y dat a base (e. g., cli nical la b orat or y 
res ults, q ua ntitati ve m uscle testi n g).   
T he C o or di nati n g Ce nt er data ma na ge me nt tea m will m o nit or t he e C R Fs f or 
c o m pl ete ness a n d acce pt a bilit y t hr o u g h o ut t he c o urse of t he st u d y.  Re vera Ge n pers o n nel 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 1 0  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
( or t heir re pres e ntati ves) will be all o we d access t o all s o urce d oc u m e nts i n or der t o verif y 
e C R F e ntries. 
8. 3  
D at a Pr ocessi n g 
A cli nical st u d y d ata bas e will be c o nstr ucte d fr o m t he eC R F s a n d a n y d ata mer ge d 
electr o nicall y, a n d t he data will be vali date d b ot h ma n uall y a n d electr o nicall y.  
Clar ificati o n of data will be re q uest e d fr o m t he st u d y site as re q uire d.  T h e data base will 
be q ualit y ass ure d i n a cc or da nce t o t he d ata ma n a ge m e nt pla n a n d will be a vaila ble f or 
statistical a nal ysis acc or di n g t o t he met h o ds o utli ne d i n Secti o n 9. 7  a n d t he Statistical 
A nal ysis Pla n ( S A P).  
8. 4  
S u bject Di aries 
T he  pare nt or le gal g uar dia n of eac h s u bject will b e gi v e n a s u bject diar y at t he Bas eli ne 
Da y  - 1 Visit i n w hic h t o rec or d a n y ne w c o nc o mit a nt me dicati o ns a n d a n y c ha n ges t o 
e x isti n g c o nc o mita nt me dicati o ns ta ke n d uri n g t h e st u d y, as well as a n y A Es e x perie nce d 
b y t he s u bject d uri n g t he st u d y.  Pare nts/le gal g u a r dia ns will be i nstr ucte d i n h o w t o 
recor d i nf or mati o n i n t he diar y a n d will be i nstr ucte d t o bri n g t he diar y wit h t he m t o eac h 
st u d y visit f or re vie w b y st u d y staff f or c o m plet e n ess a n d acc urac y.  A ne w diar y will be 
dis pe nse d at eac h m o nt hl y visit f or use t hr o u g h t h e ti me of t he ne xt sc he d ule d m o nt hl y 
visit.  C ollecti o n of fi nal diaries will occ ur at t he Wee k 2 4 Visit, or at t he e n d of t he 
D ose- ta perin g Peri o d f or s u bjects w h ose va m or ol o ne d ose is ta pere d at t he e n d of t he 
st u d y.  T he i nf or mati o n rec or de d i n t he di ar y will be c o nsi dere d s o urce d oc u me ntati o n, 
a n d an y i nf or mati o n r ec or de d i n t he diar y s h o ul d be tra nscri b e d b y st u d y st aff t o t he 
a p pr o priate e C R F. 
9  
S T A TI S TI C A L M E T H O D S A N D P L A N N E D A N A L Y S E S 
9. 1  
S a m ple Size D eter mi n ati o n 
Eli g i ble s u bjects are t h os e w h o e nr olle d i n t he V B P 1 5- 0 0 2 st u d y a n d ha v e c o m plete d u p 
t o a n d i ncl u di n g t he F oll o w- u p Wee k 4 st u d y assess me nts, u p t o a p pr o xi matel y 
4 8 s u bjects ( n = 1 2 per va m or ol o ne d ose gr o u p).   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 1 1  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T his is a n o pe n-la bel e xte nsi o n st u d y wit h n o place b o c o ntr ol.  Hist orical c o ntr ol data are 
a vaila ble f or t he sa me a ge ra n ge ( 4- 7 y ears), at lar gel y t he s a me st u d y sites, wit h t he 
sa me o utco me meas ures.  U ntreate d nat ural hist or y c o ntr ol p o p ulati o n dat a is fr o m t he 
o n g oi n g CI N R G D N H S st u d y of ~ 4 0 0 D M D b o ys. 3 1 ,3 2 ,3 3 ,3 4  Pre d nis o ne-treate d hist orical 
c o ntr ol data is fr o m a cli nical trial of pre d nis o n e carrie d o ut b y t he CI N R G gr o u p. 3 5  T he 
va m or ol o ne  P hase IIa e xte nsi o n trial is carrie d o ut wit h dail y d osi n g.  T o m ore acc uratel y 
deter mi ne sa m ple size n u m bers t o detect a gl u c oc ortic oi d effect o n efficac y, sa m ple size 
calc ulati o ns were li mite d t o t he dail y pre d nis o ne treat me nt ar m of t he CI N R G 
gl uc o c ortic oi d cli nical tri al ( n = 1 1- 1 3), at 6 or 1 2 m o nt hs, f or t hree gr oss m ot or milest o ne 
o utc o mes ( T T S T A N D, T T R W, T T C LI M B) ( T a ble 1 2 ).  Sa m ple siz e was als o calc ulate d 
ass u m i n g t he o bser ve d effect of v a m or ol o ne was 1 0 0 %, 8 0 % or 6 0 % of t hat o bser ve d 
wit h dail y  gl uc oc ortic oi ds (T a ble 1 2 ).  
T he pri ma r y p har mac ol o gic al safet y o utc o m e pr o p ose d i n t he P hase IIa e xte nsi o n trial is 
c ha n ge i n B MI z-sc ore.  Dail y gl uc oc ortic oi ds s h o w a relati vel y ra pi d i ncrease i n B MI 
z-sc ore ( 6 m o nt h c ha n ge i n n o n-treate d = - 0. 1 4; 6 m o nt h c ha n ge i n 
pre d nis o ne-tr eate d = + 0. 5 4) ( T a ble 1 2 ).  Va m or ol o ne is n ot a ntici pate d t o s h o w a n 
i ncreas e i n B MI. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 1 2  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
T a ble 1 2   
6- m o nt h a n d 1 2- m o nt h C h a n ges i n O utc o mes i n 4- < 8 ye ar- ol d D M D 
B o ys  
 
N otes: a) All patie nts a re 4-< 8 years of a ge at st u d y start.  
b) D ata fr o m u ntreate d s u bjects i n t h e CI N R G D M D Nat ural hist or y st u d y;3 1 ,3 2 ,3 3 ,3 4 d ata fr o m tre ate d 
s u bjects i n t h e CI N R G Pre d nis o ne trial.3 5   
c) C o m pares all o nl y dail y d ose pre d nis o ne -treate d patie nts t o u ntreate d patie nts. 
d) All calc ulati o ns as s u me a re peate d me as ures A N O V A m o del wit h o ne pre - a n d o ne p ost -meas ure me nt .  
C orrelati o n bet wee n re peate d me as ures use d as f oll o ws:  0. 7 5 f or hei g ht c ha n ges, 0. 7 0 f or 6 m o nt h B MI 
c ha n ges, a n d 0. 6 5 f or 1 2 m o nt h B MI c ha n ges, a n d 0. 5 7 5 f or 6 a n d 1 2 m o nt h vel ocit y c ha n ges.  
P o wer  =  0. 8 0  a n d al p ha  =  0. 0 2 5 f or all calc ulati o ns t o acc o u nt f or m ulti ple gr o u p c o m paris o ns (i.e. t w o 
va m or ol o ne  d oses, eac h c o m pare d t o pre d nis o ne f or safet y a n d place b o f or efficac y).  
^  C o nser vati ve c ha n ge esti mates wer e defi n e d as f ol l o ws: F or B MI, t h e e x pecte d c ha n ge i n va m or ol o ne  was set t o 
0. 0 rat h er t ha n t he o bser ve d decrease.  F or ti me d tests, t h e e x pecte d c ha n ge i n va m or ol o ne  was set t o 8 0 % of t h e 
o bser ve d c ha n ge i n t he pre d nis o ne gr o u p.   
^ ^ C o nser vati ve c ha n ge esti mates were de fi n e d as f oll o ws: F or ti me d tests, t h e e x pecte d c ha n ge i n va m or ol o ne  
was set t o 6 0 % of t h e o bser ve d c ha n ge i n t h e pre d nis o ne gr o u p ( wit h S D at 8 0 %).  
 
9. 2  
St atistic al a n d A n al ytic al Pl a n ( S A P) 
T he secti o ns bel o w s u m mariz e t he i nte n de d statistical met h o ds a n d a nal ys es f or t he 
e xte nsi o n st u d y.  A m ore detaile d S A P will be writte n a n d fi nalize d pri or t o fi nalizati o n 
of t he cli nical st u d y data base.  T he S A P will gi ve a detaile d des cri pti o n of t he s u m maries 
a n d a nal yses t hat will be perf or me d a n d will clearl y des cri be w he n t hese a n al yses will 
ta ke place.  A n y c h a n ges t o t he pla n ne d met h o ds a n d a nal ys es will be descri be d a n d 
j ustifie d i n t he S A P a n d/ or i n t he fi nal cli nical st u d y re p ort, as a p pr o priate.  
9. 2. 1  
Devi ati o ns fr o m t he St atistic al A n alysis Pl a n 
A n S A P will be writte n a n d fi nalize d pri or t o a n y l oc k of t he st u d y data base.  T he S A P 
will gi ve a d etaile d descri pti o n of t he s u m maries a n d a nal ys es t hat will be perf or me d a n d 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 1 3  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
will clearl y descri be w he n t hese a nal yses will ta ke place.  A n y d e viati o n(s) fr o m t he 
ori gi nal S A P will be descri be d a n d j ustifie d i n t he cli nical st u d y re p ort. 
9. 3  
A n al ysis  P o p ul ati o ns 
All a nal ys es will be base d o n t he act ual treat me nt eac h s u bject recei ve d.  F o ur 
p o p ulati o ns will be defi ne d f or dat a a nal ysis.   
9. 3. 1  
S afety P o p ul ati o n  
All s u bjec ts w h o recei ve at least o ne d ose of v a m or ol o ne st u d y me di cati o n i n t he 
e x te nsi o n st u d y will be i ncl u de d i n t he Safet y P o p ulati o n.  T he Safet y P o p ulati o n is t he 
pri m ar y a nal ysis p o p ulati o n f or safet y assess me nts.  T his is als o t he m o difie d I nte nti o n t o 
Tre at ( mI T T) p o p ulati o n. 
9. 3. 2  
F ull A n alysis Set ( F A S) 
All s u bjects w h o recei ve at least o ne d ose of v a m or ol o ne st u d y me di cati o n i n t he 
e x te nsi o n st u d y a n d h a ve at least o ne p ost- bas eli ne assess me nt will be i ncl u de d i n t he 
F A S.  T he F A S is t he pri mar y a nal ysis p o p ulati o n f or efficac y a n d P D assess me nts.  T his 
is t he mI T T p o p ulati o n, wit h t he a d diti o nal re q uir e me nt t o ha ve at least o ne p ost- baseli ne 
assess me nt.  S u bjects w h o recei v e at least o ne d ose of va m or ol o ne b ut n e ver ha ve p ost-
base li ne assess me nts will be e x cl u de d.   
9. 3. 3  
C o ntr o l P o p ul ati o n D N H S St u dy 
T he c o ntr ol p o p ulati o n fr o m t he D N H S st u d y will i ncl u de all st u d y s u bjects w h o were 
o bser ve d as p art of t he st u d y i n a ges ≥ 4 years a n d < 7 years of a ge at a start of a n i nter val 
of o bse r vati o n a n d o bs er ve d f or at least o ne year.  F urt her, t h e s u bjects nee d t o ha ve ha d 
at least t w o visits i n a ti me i nter val of n o m ore t ha n 1 5 m o nt hs (e. g., M o nt h 2 4 a n d 
M o nt h 3 6 of o bser vati o n f or a s u bject w h o e ntere d at a ge 2 or 3).  T he s u bject s h o ul d 
ha ve  bee n a ble t o w al k i n de pe n de ntl y wit h o ut assisti ve de vices at t he start of t he i nter val 
a n d s h o ul d ha ve bee n a bl e t o c o m plete t he T T S T A N D.  T h e s u bject s h o ul d n ot ha ve ha d 
a n y hist or y of disease or i m pair me nt or me dicati o ns t hat w o ul d ha ve ma de hi m i neli gi ble 
t o recei ve t h e va m or ol o n e i nter ve nti o n as defi ne d b y t he P has e IIa st u d y e x cl usi o n 
criteria.  T h e s u bject s h o ul d ha ve bee n gl u c oc orti c oi d- naï ve f or t he e ntire i nter val 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 1 4  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
c o nsi dere d i n t he c o ntr ol p o p ulati o n f or t his st u d y a n d s h o ul d n ot ha ve be g u n a n y 
i n vesti gati o nal treat me nt f or t he i nter val c o nsi dere d f or t he c o ntr ol c o m p aris o n.  Fi nall y, 
t he c o ntr ol inter vals t o be c o nsi dere d s h o ul d ha v e t he st u d y o utc o mes of T T S T A N D, 
T T C LI M B, T T R W, N S A A, 6 M W T a n d Q M T meas ure d.  It is acce pt a ble if t he 
partici pa nt ha d pr o gressi ve disease a n d c o ul d n ot perf or m a m eas ure me nt at a later p oi nt 
i n t he i nter val; t his will be a vel ocit y zer o. 
9. 3. 4  
C o ntr ol P o p ul ati o n Pre d nis o ne St u dy 
T he c o ntr ol p o p ulati o n fr o m t he pre d nis o ne st u d y will i ncl u de all s u bjects w h o were 
y o u n ger t ha n 7 years ol d at e ntr y a n d w h o were ra n d o mize d t o t he dail y pre d nis o ne ar m. 
9. 4  
Me as ures T a ke n t o A v oi d/ Mi ni mize Bi as 
N ot a p plica ble. 
9. 5  
I nteri m A n al ysis 
N o i nteri m statistical a nal yses are pla n ne d. 
9. 6  
Missi n g, U n use d, a n d S p uri o us D at a 
T he  p ossi bilit y of bias fr o m missi n g data of s u bjects w h o pre mat urel y dis c o nti n ue will be 
a d dresse d i n t he cli nical st u d y re p ort.  Missi n g val ues f or safet y a n d e x pl orat or y 
o utc o mes will be treate d as missi n g; w hile t h ose f or efficac y meas ure m e nts will be 
i m p ute d usi n g met h o d ol o g y as d escri be d i n t he S A P.  
9. 7  
St atistic al A n al ysis 
9. 7. 1  
Ge ner al C o nsi der ati o ns 
Statistical a nal yses will b e perf or me d usi n g S A S ® . 
All meas ure me nts will be a nal yz e d base d u p o n t h e t y p e of distri b uti o n, a n d descri pti ve 
statistics will be prese nte d b y treat me nt gr o u p a n d assess me nt ti me p oi nt, as a p pr o priate.  
Descri pti ve statistics f or c o nti n u o us varia bles ( n u m ber [ N], mea n, me dia n, sta n dar d 
de viati o n [ S D], mi ni m u m, a n d ma xi m u m), descri pti ve statistics f or cate g orical vari a bles 
( N a n d perce nt a ge), a n d i n di vi d ual s u bject pr ofiles will be prese nte d, as a p pr o priate.   


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 1 5  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
Baseli ne m eas ur e me nt is defi ne d as t he l ast n o n- missi n g val ue pri or t o t he first d ose of 
st u d y dr u g i n t he e xte nsi o n st u d y.  
9. 7. 2  
S u bject Dis p ositi o n, De m o gr a p hics, a n d B aseli ne C h ar acteristics 
S u bjec t dis p ositi o n will be s u m marize d b y  a nal ysis p o p ulati o n.  T he n u m ber of s u bjects 
e nr olle d, t he n u m ber i n eac h p o p ulati o n, a n d t he reas o n f or disc o nti n uati o n fr o m t he 
st u d y will be s u m mariz e d. 
S u bjec t de m o gra p hics ( e. g., a ge, race, a n d et h nicit y ) a n d baseli ne c haracteristics (e. g., 
hei g ht, w ei g ht, a n d m o nt hs/ years si nce D M D dia g n osis ) will be  s u m marize d 
descri pti vel y b y  a nal ysis p o p ulati o n.  Listi n gs of i n di vi d ual s u bject data s orte d b y d ose 
gr o u p will be re vie we d f or a n y differe n ces a m o n g t he d ose gr o u ps. 
9. 7. 3  
S afety A n alyses 
All s u bjects w h o recei ve d at least o ne d ose of v a m or ol o ne ( Safet y P o p ulati o n) will be 
i ncl u de d i n the safet y a nal yses.  I n ge neral, descri pti ve st atistics f or eac h s afet y e n d p oi nt 
will be prese nte d b y d o se le vel, w hile i n di vi d ual s u bject listi n gs of safet y e n d p oi nts, 
s orte d by d os e gr o u p, will be re vie we d f or a n y e vi de nce of d os e-relate d differe n ces or 
tre n ds i n t he safet y pr ofile of va m or ol o ne. 
All safet y data will be liste d. 
Ba seli ne m eas ur e me nt is defi ne d as t he n o n- missi n g val u e of t he c ore st u d y V B P 1 5- 0 0 2 
F oll o w- u p Wee k 4 or last n o n- missi n g val ue pri or t o first a d mi nistrati o n of st u d y dr u g i n 
t he e xte nsi o n st u d y. 
All e val uati o ns of cli nical safet y will be liste d wit h descri pti ve statistics prese nte d b y 
treat me nt gr o u p.  T he pri mar y s afet y v aria ble will be B MI z-sc ore a n d will be assesse d 
usi n g t he sa me t y p e of st atistical m o dels use d f or efficac y.  A d diti o nal sec o n dar y safet y 
data will i ncl u de hei g ht z-sc ore, bl o o d pr ess ure, a n d E C G res ults.  As n o c ha n ge i n bl o o d 
pre ss ure or car diac res ults is e x pecte d, t hese data will be a nal yze d usi n g a n a nal ysis of 
c o varia n ce ( A N C O V A) a p pr oac h w hic h i ncl u des t he baseli ne val u e f or eac h 
meas ure me nt as a c o v ari ate.  C ha n ges i n hei g ht z-sc ores, f or w hic h a n o bs er ve d c ha n ge is 
e x pecte d, will be m o delle d usi n g a li near mi x e d effects m o del.  C o nti n u o us, q ua ntitati ve 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 1 6  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
la b orat or y val u es will be a nal yze d si milar t o B MI z-sc ores.  Cate g orize d la b orat or y 
val ues a n d prese nce or a bse nce of A Es will be c o m pare d usi n g a n e x act c hi-s q uare test.   
A d verse e ve nts will be c o de d usi n g t he M e dical Dicti o nar y f or Re g ul at or y Acti vities 
( Me d D R A).  T h e i nci de n ce of A Es will be s u m marize d o verall a n d b y d ose le vel, S O C 
a n d preferre d ter m; d ose le vel, S O C, preferre d ter m, a n d i nte nsit y ( C T C A E gra de); a n d 
d ose le ve l, S O C, preferre d ter m, a n d rel ati o ns hi p t o st u d y dr u g.  A d diti o nal A E a nal yses 
will be  at t he s u bject le vel: t he n u m ber of s u bjects w h o ha d a n y A E, t h e distri b uti o n of 
n u m ber of A Es per s u bject wit hi n a d ose le vel, w orst i nte nsit y i n a s u bject wit hi n a d ose 
le vel, hig h est le vel of relati o ns hi p t o st u d y tr eat m e nt f or eac h s u bject wit hi n a d ose le vel. 
A d diti o nal h y p ot heses of safet y will i ncl u de si milar li near m o d elli n g wit h t he sec o n dar y 
a n d e x pl orat or y o ut c o mes.   
P h ysical e x a mi nati o n res ults will be liste d o nl y.   
9. 7. 4  
Cli nic al Effic acy a n d P h ar m ac o dy n a mic A n alyse s  
T he e val uati o ns of cli nical efficac y a n d P D  will be perf or me d usi n g t he F A S P o p ulati o n. 
T he pri mar y effic ac y o ut c o me is t he ti me t o sta n d fr o m s u pi ne vel ocit y ( T T S T A N D).  
Sec o n dar y effic ac y o utc o mes are t he N S A A assess me nt, ti me t o cli m b f o ur stairs 
( T T C LI M B), ti me t o r u n/ wal k 1 0 meters ( T T R W), Q ua ntitati ve M uscle Testi n g ( Q M T), 
a n d t he dista nce w al ke d i n 6 mi n utes ( 6 M W T) .  T he pri mar y o utc o me will be c o m pare d 
bet we e n v a m or ol o ne a n d hist orical u ntreate d c o ntr ols usi n g a mi x e d-effects li near m o del 
wit h trea t me nt gr o u p.  A ge at st u d y e ntr y will be i ncl u de d as a c o vari ate.  T he i nitial 
m o del will c o m bi ne va m or ol o ne d oses a n d a s u bse q ue nt sec o n d ar y m o del will l o o k at 
eac h d ose i n c o m paris o n t o u ntreate d nat ur al hist or y c o ntr ols.  T his will all o w t he testi n g 
of w het her v a m or ol o ne i n ge n eral a n d va m or ol o n e at i n di vi d ual d oses ha v e si g nifica nt 
effects o n t he sl o pe of t h e vel ocit y.  A d diti o nal h y p ot heses of efficac y will i ncl u de 
si milar li near m o delli n g wit h t he sec o n dar y o ut c o mes.  T he y will als o i ncl u de differi n g 
c o m paris o n gr o u ps i ncl u di n g u ntreate d nat ur al hist or y c o ntr ols.  
Ser u m P D bi o mar kers of a dre nal a xis s u p pressi o n, i ns uli n resista nce, a n d b o ne t ur n o ver 
will be assesse d.  L o n git u di nal a nal ysis of P D bi o mar kers will be st u die d as a f u ncti o n of 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 1 7  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
treat me nt, wit h c o m paris o n t o pre d nis o ne-treate d a n d u ntreate d hist orical c o ntr ols, as 
a p pr o priate.   
I n di vi d ual cli nical effi cac y a n d P D  data will be liste d.   
9. 7. 5  
C o nc urre nt Me dic ati o ns 
A s u m mar y of all c o nc o mita nt me dicati o ns ta ke n d uri n g t he c o urse of t he st u d y will be 
prese nte d i n ta b ular f or m b y t hera pe utic dr u g class a n d ge neri c dr u g na m e usi n g t he 
W orl d Healt h Or ga niz ati o n ( W H O) Dr u g cl assificati o n ( Versi o n 4. 3).  All c o nc o mita nt 
me dica ti o ns will be detaile d i n t he s u bject data listi n gs.   
1 0  
S T U D Y M A N A G E M E N T A N D E T HI C A L A N D R E G U L A T O R Y 
R E Q UI R E M E N T S 
1 0. 1  
Re g ul at or y A p pr o v al a n d G o o d Cli nic al Pr acti ce 
T his s t u d y will be c o n d u cte d i n acc or da n ce wit h t he pri nci ples of t he 1 8t h W orl d Me dical 
Asse m bl y ( Helsi n ki, J u ne 1 9 6 4), a n d a m e n d me nts of t he 2 9 t h ( T o k y o, 1 9 7 5), 3 5t h 
( Venice, 1 9 8 3), 4 1 st ( H o n g K o n g, 1 9 8 9), 4 8t h ( S o merset West, 1 9 9 6), 5 2n d ( Edi n b ur g h, 
2 0 0 0), 5 3 r d ( Was hi n gt o n, 2 0 0 2), 5 5t h ( T o k y o, 2 0 0 4), 5 9t h ( Se o ul, 2 0 0 8), a n d 6 4t h 
( F ortal eza, 2 0 1 3) W orl d Me dical Asse m blies. 
F urt her, t h e trial will be c o n d ucte d i n acc or da n ce wit h: 
 I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) E 6 G ui deli ne f or G o o d Cli nical 
Practice ( G C P) 
 T he U nite d States ( U S) F D A C o de of Fe deral Re g ulati o ns, Title 2 1 C F R Part 3 1 2 
– I n v esti gati o nal Ne w Dr u g A p plicati o n, Part 5 0 – Pr otecti o n of H u ma n Patie nts 
wit h parti c ular f o c us i n S u b Part D, a n d/ or Part 5 6 – I nstit uti o nal Re vie w B oar ds 
 U S Healt h I ns ura n ce P orta bilit y a n d Acc o u nta bilit y Act of 1 9 9 6 ( HI P A A). 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 1 8  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
1 0. 2  
I n vesti g at or Res p o nsi bilities 
1 0. 2. 1  
S u bject I nf or m ati o n a n d I nf or m e d C o nse nt 
Bef ore bei n g a d mitte d t o t he e xte nsi o n st u d y, a pare nt/ g uar dia n m ust c o nse nt i n writi n g 
f or t he s u bject t o partici pate.  Writte n or ver bal asse nt will als o be o btai ne d fr o m eac h 
s u bject as re q uir e d per re g ulati o ns.  A n  a p pr o ve d I C F will be gi ve n t o eac h 
pare nt/ g uar di a n w hic h will c o ntai n all U S  fe derall y re q uire d ele me nts, all I C H-re q uire d 
ele me nts, a n d HI P A A a ut h orizati o n i nf or mati o n, if a p plica ble, i n la n g u a ge t hat is 
u n dersta n da ble t o t he p are nt/ g uar dia n.  T he c o nse nt s h o ul d n ote t hat t he I n vesti gat or is 
recei vi n g c o m p e nsati o n f or t he e x pe nses of c o n d u cti n g t he st u d y. 
T he pr ocess of o btai ni n g t he i nf or me d c o nse nt will be i n c o m plia nce wit h all fe deral 
re g ulati o ns, I C H re q uir e me nts, a n d l ocal la ws. 
T he I n vesti gat or or d esi g nee will re vie w t h e st u d y wit h t he pare nt/ g uar di a n of eac h 
s u bject.  T he re vi e w will i ncl u de t he nat ure, s c o pe, pr oce d ures, a n d p ossi ble 
c o nse q ue nces of t he s u bj ec t’s partici p ati o n i n t he st u d y.  T he c o nse nt, asse nt, a n d re vie w 
m ust be i n a f or m u n dersta n da ble t o t he pare nt/ g u ar dia n of t he s u bject.  T h e I n vesti gat or 
or de si g n ee a n d t he pare nt/ g uar dia n of t he s u bject m ust b ot h si g n a n d date t he I C F after 
re vie w a n d b ef ore t he s u bject ca n p artici pate i n t h e st u d y.  T h e pare nt/ g u ar dia n of t he 
s u bject will recei v e a c o p y of t he si g n e d a n d dat e d f or m, a n d t he ori gi nal will be retai ne d 
i n t he site st u d y files.  T h e I n vesti gat or or d esi g n ee m ust e m p hasize t o t he 
pare nt/ g uar di a n of t he s u bject t hat st u d y partici pati o n is e ntirel y v ol u ntar y a n d t hat 
c o nse nt re gar di n g st u d y partici pati o n ma y be wit h dra w n at a n y ti me wit h o ut pe nalt y or 
l oss of be nefits t o w hic h t he s u bject is ot her wise e ntitle d. 
If t he I C F is a me n de d d uri n g t he st u d y, t he I n v esti gat or m ust f oll o w all a p plica ble 
re g ulat or y re q uire me nts pertai ni n g t o all ne w s u bj ects a n d re peat t he c o nse nt pr ocess wit h 
t he a me n de d I C F f or a n y o n g oi n g s u bjects. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 1 9  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
1 0. 2. 2  
I nstit uti o n al Revie w B o ar d/I n de pe n de nt Et hics C o m mittee A p pr ov al a n d 
Ot her I nstit uti o n al Re q uire m e nts 
Bef ore t he start of t he st u d y, t he st u d y pr ot oc ol, I C F, a n d a n y ot h er a p pr o pri ate 
d oc u me nts will be s u b mitte d t o t he I R B/I E C f or re vie w a n d a p pr o val.  Per i nstit uti o nal 
re q uireme nts, t he st u d y pr ot oc ol a n d a n y ot her a p pr o priate d oc u m e nts will be s u b mitte d 
t o scie ntific c o m mittees f or a p pr o val. 
T he I n vesti gat or will f or war d t o t he S p o ns or, or d esi g nee ( C o or di nati n g Ce nter), a c o p y 
of t he I R B/I E C’s a p pr o val of t his pr ot oc ol, a me n d me nts, I C F a n d a n y c ha n ges t o t he I C F, 
base d o n t he F D A re g ulati o ns set f ort h i n Part 5 6 of Title 2 1 of t he C F R.  T he 
I n vesti gat or will als o kee p d oc u me ntati o n of st u d y a p pr o val b y i nter nal scie ntific 
c o m mittees per i nstit uti o nal re q uire m e nts.  
St u d y m e dicati o n ca n o nl y be s u p plie d t o t he I n vesti gat or after d oc u me ntati o n of all 
et hical a n d le gal re q uire me nts f or starti n g t h e st u d y has b ee n recei ve d b y t he S p o ns or or 
desi g nee ( C o or di nati n g Ce nter).  T his d oc u me ntati o n m ust als o i ncl u de a n I R B/I E C 
me m bers hi p list t hat c o ntai ns me m bers’ occ u pati o ns a n d q ualificati o ns.  If t he I R B/I E C 
wi ll n ot discl ose t he na mes of t he c o m mittee me m bers, it s h o ul d be as ke d t o iss ue a 
state me nt c o nfir mi n g t hat t he c o m p ositi o n of t he c o m mittee is i n acc or d a nce wit h G C P.  
T he I R B Ass ura nce N u m ber ma y be acce pte d as a s u bstit ute f or t he I R B me m bers hi p list.  
T he I n vesti gat or will ke e p t he I R B/I E C i nf or me d re gar di n g t he pr o gress of t he st u d y, per 
i nstit uti o nal re q uire me nts.  N o c ha n ges will be m a de i n t he st u d y wit h o ut I R B/I E C 
a p pr o val, e x ce pt w he n re q uire d t o eli mi nate a p pare nt i m me diate hazar ds t o t he s u bject s. 
W hile t he st u d y is o n g oi n g a n d at st u d y c o m pleti o n/ disc o nti n uati o n, t he I n vesti gat or m ust 
s u b mit t o t he I R B/I E C t h e f oll o wi n g i nf or mati o n i n acc or d a nce wit h U S Fe deral 
re g ulat or y re q uire me nts: 
1.  I nf or mati o n o n seri o us or u ne x pecte d A Es, s h o wi n g d ue dili ge n ce i n pr o vi di n g 
t his i nf or mati o n as s o o n as p ossi ble 
2.  Peri o dic re p orts o n t he pr o gress of t he st u d y 
3.  Fi nal St u d y S u m mar y u p o n st u d y c o m pleti o n or cl os ure. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 2 0  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
N otificati o n of t he e n d of t he trial will be se nt t o t he I R B/I E C wit hi n 3 0 da ys after 
c o m pleti o n of t he st u d y cl ose- o ut visit.  I n case t he st u d y is e n de d pre mat urel y, t he 
I R B/I E C will be n otifie d wit hi n 1 5 da ys, i ncl u di n g t he reas o ns f or t he pre mat ure 
ter mi nati o n.  T he e n d of t he trial is defi ne d as t h e date of fi nal a nal ysis of t he st u d y d ata 
acc or di n g t o t he S A P. 
1 0. 2. 3  
St u dy D oc u m e nt ati o n 
1 0. 2. 3. 1  
Bef ore t he St art of t he St u dy 
T he f oll o wi n g st u d y d o c u me ntati o n will be i n place at t he st u d y site pri or t o t he first 
a d mi nistrati o n of st u d y dr u g: 
 
F ull y si g ne d pr ot oc ol a n d pr ot oc ol-s u p p orti n g m a n uals 
 
I n v esti gat or’s Br oc h ure2 9 
 
Pr ot oc ol Acce pta n ce f or m si g ne d b y t he I n v esti gat or 
 
I R B/I E C-a p pr o ve d c o p y of t he I C F 
 
C urric ul u m vitae of t he I n vesti gat or a n d all s u b-i n vesti gat ors liste d o n t he F D A 
F or m 1 5 7 2 
 
A letter of I R B/I E C a p pr o val f or pr ot oc ol 
 
A list of me m bers of t he I R B/I E C a n d t heir affiliati o ns 
 
A c o p y of t he I n v esti gat or-si g n e d F D A 1 5 7 2 f or m 
 
A n I n vesti gat or-si g ne d fi na ncial discl os ure f or m. 
1 0. 2. 3. 2  
D uri n g t he St u dy 
T he f oll o wi n g d o c u me nt ati o n s h o ul d be a d de d t o t he site st u d y file d uri n g st u d y c o n d u ct: 
 
A n y p a per s o urce f or ms c o m plete d a n d s u bse q ue ntl y e ntere d i nt o t he st u d y 
data base.  A n e x pla nati o n s h o ul d be gi ve n f or all missi n g data a n d a n y pr ot oc ol 
de viati o ns d oc u me nte d i n t he site st u d y file 
 
A n y c ha n ges t o t he d o c u me ntati o n i de ntifie d a b o ve i n Secti o n 1 0. 2. 3. 1  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 2 1  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
 
S hi p pi n g d oc u me nts relati n g t o s hi p me nt of me dicati o n ( dr u g acc o u nta bilit y) a n d 
bi oa nal ytical sa m ples 
 
C o pies of rele va nt c orres p o n de nce s uc h as letters, e mails, meeti n g n otes, a n d 
telep h o ne calls. 
1 0. 2. 3. 3  
After t he St u dy 
After c o m pleti o n or pre mat ure ter mi nati o n of t he trial, all of t he d oc u me nts i de ntifie d 
s h o ul d be i n t he file, t o get her wit h t he f oll o wi n g: 
 St u d y dr u g acc o u nta bilit y d oc u m e nts 
 A u dit certificates (if a p plica ble) 
 I n v esti gat or dele gati o n of res p o nsi bilities l o g 
 Site si g nat ure l o g 
 S u bject e nr oll me nt l o g 
 S u bsta nti ve c orres p o n de nce wit h t he S p o ns or a n d I R B/I E C 
 N otificati o n of t he e n d of t he trial t o t he I R B/I E C. 
1 0. 2. 4  
Dele g ati o n of I nvesti g at or Res p o nsi bilities 
T he I n vesti gat or m ust (a) e ns ure t hat a n y i n di vi d u al t o w h o m a tas k is dele gat e d is 
q uali fie d b y e d ucati o n, trai ni n g, a n d e x perie nce (a n d lice ns ure, if rele va nt) t o perf or m t he 
tas k; a n d ( b) pr o vi de a de q uate s u per visi o n.  T he I n vesti gat or s h o ul d mai nt ai n a list of 
s u b-i n vesti gat ors a n d ot her a p pr o priatel y q ualifie d pers o ns t o w h o m he or s he has 
dele gate d si g nifica nt st u d y-relate d d uties. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 2 2  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
1 0. 3  
Pr ot oc ol D e vi ati o ns a n d Vi ol ati o ns 
1 0. 3. 1  
Pr ot oc ol Devi ati o n a n d Vi ol ati o n Defi niti o ns 
1 0. 3. 1. 1  
Pr ot oc ol De vi ati o n 
A pr ot oc ol de viati o n is a n y c h a n ge, di ver ge nce, or d e part ure fr o m t he st u d y desi g n or 
pr oce d ures of a researc h pr ot oc ol t hat is u n der t he I n v esti gat or’s c o ntr ol a n d t hat has n ot 
bee n a p pr o ve d b y t he I R B/I E C. 
C ha n ges or alterati o ns i n t he c o n d uct of t he tri al w hic h d o n ot ha ve a maj or i m pact o n t he 
s u bject's ri g hts, safet y or well- bei n g, or t he c o m plete ness, acc urac y a n d reli a bilit y of t he 
st u d y data are c o nsi dere d mi n or pr ot oc ol de viati o ns. 
1 0. 3. 1. 2  
Pr ot oc ol  Vi ol ati o n 
A pr ot oc ol vi olati o n is a de viati o n fr o m t he I R B/I E C-a p pr o ve d pr ot oc ol t hat ma y affect 
t he s u bject's ri g hts, s afet y, or well- bei n g a n d/ or t h e c o m plete ness, acc urac y a n d relia bilit y 
of t he st u d y d ata. T his i ncl u des e x a m ples s uc h as i na p pr o priate c o nse nt, err ors i n dr u g 
d osi n g , or la c k of re p orti n g of safet y d ata. 
1 0. 3. 2  
Re p orti n g Devi ati o ns/ Vi ol ati o ns 
U p o n disc o ver y of a maj or pr ot oc ol de viati o n or vi olati o n, t he I n vesti gat or is res p o nsi ble 
f or re p orti n g pr ot oc ol de viati o ns or vi olati o ns t o t he I R B/I E C a n d S p o ns or or desi g n ee 
( C o or di nati n g Ce nter) wit hi n 2 4 h o urs of disc o ver y. 
All ot her de viati o ns m ust be re p ort e d i n writi n g wit hi n 7 da ys of t he e ve nt or its 
disc o ver y. 
1 0. 4  
St u d y Rec or ds Rete nti o n a n d Direct Access t o S o urce D oc u me nts 
F e deral r e g ulati o ns re q uire t hat, f oll o wi n g c o m pleti o n of a cli nical st u d y, a c o p y of all 
rec or ds of t hat st u d y b e mai ntai ne d b y t h e I n v esti gat or f or at least t he s h orter of t he 
f oll o wi n g t w o ti me peri o ds: 
 T w o years after F D A a p pr o val of t he dr u g f or t he i n dicati o n f or w hic h it was 
i n vestigate d, or 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 2 3  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
 I n sit uati o ns w here n o a p plicati o n is t o be s u b mitte d or a n a p plicati o n is n ot 
ap pr o ve d f or s uc h i n dicati o n, 2 years aft er t he I n v esti gati o nal Ne w Dr u g (I N D) 
A p plicati o n is disc o nti n ue d a n d t he F D A is n otifie d. 
T he I n vesti gat or m ust mai ntai n a c o p y of all data c ollecte d f or eac h s u bject treate d 
(i ncl u di n g e C R Fs a n d s o urce dat a).  I n or der t o ass ure t he acc urac y of data c ollecte d i n 
t he e C R F, it is ma n dat or y t hat re pres e ntati ves of t he S p o ns or, or desi g nee, as well as 
re pres e ntati ves of t he F D A or ot her healt h a ut h orities ha ve direct access t o ori gi nal 
s o urce d oc u m e nts (e. g., s u bject rec or ds, s u bject c harts, a n d la b orat or y re p orts).  D uri n g 
t he re vie w of t hese d oc u me nts, t he a n o n y mit y of t he s u bject will be res pecte d wit h strict 
a d here n ce t o pr ofessi o nal sta n dar ds of c o nfi de ntialit y. 
T he S p o ns or reser ves t he ri g ht t o ter mi nate t he st u d y f or ref usal of t he I n vesti gat or t o 
s u p pl y s o urce d oc u me ntati o n of w or k perf or me d i n t his cli nical st u d y. 
T he f oll o wi n g i n cl u des, b ut is n ot li mite d t o, t he rec or ds t hat m ust be retai ne d b y t h e 
I n v esti gat or: 
1.  Si g ne d i nf or me d c o nse nt d oc u me nts f or all s u bjects 
2.  S u bject e nr oll me nt l o g 
3.  Rec or d of all rele va nt c o m m u nicati o ns bet wee n t he I n vesti gat or a n d t h e I R B/I E C 
4.  C o m p ositi o n of t he I R B/I E C 
5.  Rec or d of all rele va nt c o m m u nicati o ns bet wee n t he I n vesti gat or a n d t h e S p o ns or 
( or desi g nee) 
6.  List of s u b-i n vesti gat ors a n d ot her a p pr o pri atel y q ualifie d pers o ns t o w h o m t he 
In v esti gat or has del e gate d si g nifica nt st u d y-relate d d uties, t o get her wit h t heir 
r oles i n t he st u d y a n d t h eir si g nat ur es 
7.  Dr u g acc o u nta bilit y rec or ds (see S ecti o n 5. 8. 4 ) 
8.  Rec or d of a n y b o d y fl ui ds or tiss ue sa m ples retai n e d 
9.  All ot her s o urce d o c u me nts (s u bject rec or ds, h os pital rec or ds, la b orat or y rec or ds, 
etc.) 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 2 4  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
1 0.  All ot her d oc u me nts as liste d i n Secti o n 8 of t he I C H c o ns oli date d g ui d eli ne o n 
G C P ( Esse ntial D oc u me nts f or t he C o n d uct of a Cli nical Trial). 
1 0. 5  
St u d y M o nit ori n g 
In acc or da n ce wit h a p pli ca ble re g ulati o ns, G C P, a n d t he pr oce d ures of t he S p o ns or or its 
desi g nees, t he St u d y M o nit or will peri o dicall y c o ntact t he site a n d c o n d u ct o n-site visits.  
T he e xte nt, nat ure, a n d fre q ue nc y of o n-site visits will be base d o n e nr oll m e nt rate a n d 
data q ualit y at t he site.  T hr o u g h fre q u e nt c o m m u nicati o ns (e. g., letter, e- mail, a n d 
tele p h o ne), t he St u d y M o nit or will e ns ure t hat t he i n vesti gati o n is c o n d ucte d acc or di n g t o 
pr ot oc ol a n d re g ul at or y re q uire me nts. 
D uri n g t h ese c o nta cts, t he m o nit ori n g acti vities will i ncl u de: 
1.  C hec ki n g a n d assessi n g t he pr o gress of t he st u d y 
2.  Re vie wi n g st u d y dat a c ollecte d t o date f or c o m plet e ness a n d acc urac y 
3.  Re vie wi n g c o m plia nce wit h pr ot oc ol assess me nts 
4.  C o n d ucti n g s o urce d oc u me nt verificati o n b y re vie wi n g e C R F data base dat a 
agai nst s o urce d o c u me nts w he n a vaila ble (e. g., m e dical rec or ds, s u bject diaries, 
I C F [a n d asse nt, if a p plica ble], la b orat or y res ult re p orts, ra w dat a c ollecti o n 
f or ms) 
5.  I d e ntif yi n g a n y iss ues a n d a d dressi n g res ol uti o ns. 
T he se acti vities will be d o ne i n or der t o verif y t hat t he: 
1.  Data are a ut he ntic, acc urate, a n d c o m plete 
2.  Safet y a n d ri g hts of t he s u bjects are b ei n g pr otect e d 
3.  St u d y is c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot o c ol (a n d a n y 
a me n d me nts), G C P, a n d all a p plica ble re g ulat or y re q uire me nts. 
T he I n vesti gat or will all o w t he St u d y M o nit or direct access t o all rele va nt d oc u me nts, 
a n d all ocate his/ her ti me a n d t he ti me of his/ her st aff t o t he St u d y M o nit or t o disc uss 
fi n di n gs a n d a n y rele v a nt iss ues. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 2 5  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
I n a d diti o n t o c o ntacts d uri n g t he st u d y, t he St u d y M o nit or will c o ntact t he site pri or t o 
t he start of t he st u d y t o disc uss t he pr ot oc ol a n d data c ollecti o n pr oce d ures wit h site 
pers o n nel. 
At st u d y cl os ur e, St u d y M o nit ors will c o n d uct all a cti vities as i n dicate d i n Secti o n 1 0. 7 . 
1 0. 6  
Q u alit y Ass ur a nce 
At it s discreti o n, t he S p o ns or or its desi g n ee ma y c o n d uct a q ualit y ass ur a n ce a u dit of t his 
st u d y.  A u diti n g pr oce d ures of t he S p o ns or a n d/ or its desi g n ee will be f oll o we d i n or der 
t o c o m pl y wit h G C P g ui deli nes a n d e ns ure acce pt a bilit y of t he st u d y data f or re gistrati o n 
p ur p oses.  If s uc h a n a u dit occ urs, t he I n v esti gat or will gi ve t he a u dit or dir ect access t o 
all rele va nt d oc u m e nts, a n d will all ocate his/ her ti me a n d t he ti me of his/ her staff t o t he 
a u dit or as ma y be re q uire d t o disc uss fi n di n gs a n d a n y rele va nt iss ues. 
I n a d diti o n, re g ulat or y a ut h orities a n d/ or t he I R B/I E C ma y c o n d u ct a n i ns pecti o n of t his 
st u d y.  If s u c h a n i ns pecti o n occ urs, t he I n vesti gat or will all o w t he i ns pect or direct access 
t o all s o urce d oc u me nts, e C R Fs, a n d ot her st u d y d oc u me ntati o n f or s o urce data c hec k 
a n d/ or o n-site a u dit i ns pe cti o n.  T he I n vesti gat or m ust all ocate his/ her ti me a n d t he ti me 
of his/ her staff t o t he i ns pect or t o disc uss fi n di n gs of a n y rel e va nt iss ues. 
A n e x pla nati o n will be gi ve n f or all missi n g, u n use d, a n d s p uri o us d ata i n t he rele va nt 
secti o n of t he st u d y re p ort. 
1 0. 7  
St u d y Ter mi n ati o n a n d Site Cl os ure 
U p o n c o m pleti o n of t he st u d y, t he f oll o wi n g acti vities, w he n a p plica ble, m ust be 
c o n d ucte d b y t he St u d y M o nit or i n c o nj u ncti o n wit h t he I n v esti gat or, as a p pr o priate: 
1.  Pr o visi o n of all st u d y d at a t o t he S p o ns or 
2.  Data clarificati o ns a n d/ or res ol uti o ns 
3.  Acc o u nti n g, rec o nciliati o n, a n d fi nal dis p ositi o n of use d a n d u n use d st u d y 
me dicati o n 
4.  Re vie w of site st u d y rec or ds f or c o m plete ness. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 2 6  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
I n a d diti o n, t he S p o ns or reser ves t he ri g ht t o te m p oraril y s us pe n d or pre mat urel y 
ter mi nate t his st u d y f or a n y reas o n. 
If t he st u d y is s us pe n de d or ter mi nate d f or safet y reas o n(s), t he S p o ns or will pr o m ptl y 
i nf or m the I n vesti gat or, a n d will als o i nf or m t he re g ulat or y a ut h orities of t h e s us pe nsi o n 
or ter mi nati o n of t he st u d y a n d t h e reas o n(s) f or t h e acti o n.  T he I n vesti gat or is 
res p o nsi ble f or pr o m ptl y i nf or mi n g t he I R B/I E C, a n d pr o vi di n g t he r eas o n(s) f or t he 
s us pe nsi o n or ter mi nati o n of t he st u d y. 
If t he st u d y is pre mat urel y ter mi nat e d, all st u d y d ata m ust be ret ur ne d t o t he S p o ns or.  I n 
a d diti o n, t he site m ust c o n d uct fi nal dis p ositi o n of all u n use d st u d y me dicati o ns i n 
acc or d a nce wit h t he S p o ns or pr oce d ures f or t he st u d y. 
1 0. 8  
Site Ter mi n ati o n 
T he  S p o ns or ma y at a n y ti me, at its s ole discreti o n, ter mi nate t he st u d y site f or vari o us 
reas o ns, i ncl u di n g, wit h o ut li mitati o n, t he f oll o wi n g: 
1.  Fail ure of t he I n vesti gat or t o e nr oll s u bjects i nt o t he st u d y at a reas o na ble rate 
2.  Fail ure of t he I n vesti gat or t o c o m pl y wit h a p plica ble la ws a n d/ or perti ne nt F D A 
reg ulati o ns 
3.  S u b missi o n of k n o wi n gl y false i nf or mati o n fr o m t he researc h facilit y t o t h e 
S p o ns or, St u d y M o nit or, F D A, or ot h er re g ulat or y a ut h orities 
4.  I ns ufficie nt a d h ere n ce t o pr ot oc ol re q uire m e nts. 
If partici pati o n of a st u d y site is ter mi nate d, t he S p o ns or an d St u d y C hair will iss ue a 
writte n n otice t o t he I n vesti gat or.  T he writte n n otice will c o ntai n t he reas o ns f or ta ki n g 
s uc h acti o n.  If t he st u d y site is ter mi nate d f or n o n c o m plia nce, a p pr o priate re g ulat or y 
a ut h orities will als o be n otifie d b y t he S p o ns or. 
St u d y t er mi nati o n a n d f oll o w- u p will be perf or m e d i n c o m plia nce wit h t he c o n diti o ns set 
f ort h i n 2 1 C F R 3 1 2. 5 0 a n d 2 1 C F R 3 1 2. 5 6. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 2 7  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
1 0. 9  
Disc o nti n u ati o n of St u d y 
T he S p o ns or reser ves t he ri g ht t o disc o nti n ue t he st u d y f or a n y reas o n at a n y ti me.  I n 
a d diti o n, t he st u d y ma y b e st o p pe d at a n y ti me if, i n t he o pi ni o n of t he S p o ns or a n d 
Me dical M o nit or, safet y data s u g gest t hat t he me dical safet y of s u bj ects is bei n g or m a y 
bec o me c o m pr o mise d. 
1 1  
DI S C L O S U R E O F D A T A 
1 1. 1  
C o nfi de nti alit y 
T he  ri g hts a n d pri va c y of partici pa nts i n t his st u d y will be pr otecte d at all ti mes.  All 
pers o nal details of s u bjects will be treate d as c o nfi de ntial b y t he I n vesti gat or a n d 
ha n dli n g of pers o nal dat a will be i n c o m plia nce wit h HI P A A.  All a p plica bl e data 
pr otecti o n la ws i n t he rel e va nt c o u ntries will be a d here d t o at all ti mes. 
S u bject na mes will re mai n c o nfi de ntial a n d will n ot be i ncl u de d i n t he data base.  O nl y 
e nr oll me nt n u m ber, a n d birt h date will be rec or de d o n t he e C R F.  If t he s u bject’s na me 
a p pears o n a n y ot her d o c u me nt c ollecte d (e. g., h os pital disc har ge s u m mar y), t he na me 
m ust be  o bliterate d bef ore t he d oc u me nt is tra ns mitte d t o t he S p o ns or or its desi g nee.  All 
st u d y fi n di n gs will be st ore d i n electr o nic data bases.  T he s u bjects’ pare nts or g u ar dia ns 
will gi ve e x plicit per missi o n f or re prese ntati ves of t he S p o ns or, re g ulat or y a ut h orities, 
a n d t he I R B/I E C t o i ns pect t he s u bjects’ me dical r ec or ds t o verif y t he i nf or mati o n 
c ollecte d.  T he s u bj ects’ pare nts or g uar dia ns will be i nf or me d t hat all pers o nal 
i nf or mati o n ma de a v aila ble f or i ns pecti o n will be ha n dle d i n t he strictest c o nfi de nce a n d 
i n acc or d a nce wit h all state, l ocal, a n d fe deral data pr otecti o n/ pri vac y la ws, i ncl u di n g, 
wit h o ut li mitati o n, t he HI P A A, as a p plica ble. 
T he pare nts or g uar dia ns of all partici pa nts i n t he U nite d States will pr o vi de writte n 
a ut h oriz ati o n t o discl ose pri vate healt h i nf or m ati o n eit her as a part of t he writte n I C F or 
as a se parate a ut h orizati o n f or m.  T he a ut h orizati o n will c o ntai n all re q uire d ele me nts 
s pecifie d b y 2 1 C F R 5 0, a n d will c o ntai n a wai v er of s u bject access t o st u d y-relate d 
pri vate  healt h i nf or m ati o n u ntil t he c o ncl usi o n of t he cli nical st u d y.  T h e a ut h orizati o n 
will re mai n vali d a n d i n f ull f orce a n d effect u ntil t he first t o occ ur of ( 1) t h e e x pirati o n of 
2 years after t he st u d y m e dicati o n is a p pr o ve d f or t he i n dicati o n bei n g st u di e d, or ( 2) t he 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 2 8  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
e x pirati o n of 2 years aft er t he researc h pr o gra m is disc o nti n ue d.  I n di vi d ual s u bjec t 
me dical i nf or mati o n o btai ne d d uri n g t his st u d y is c o nfi de ntial, a n d its discl os ure t o t hir d 
parties ( ot her t h a n t h ose me nti o ne d i n t his secti o n) is strictl y pr o hi bite d.  I n a d diti o n, 
me dical i nf or mati o n o btai ne d d uri n g t his st u d y ma y be pr o vi de d t o t he s u bj ect’s pers o n al 
p h ysicia n or t o ot her a p pr o priate me dical pers o n n el w he n re q uire d i n c o n necti o n wit h t he 
s u bject’s c o nti n ue d healt h a n d welfare. 
T he st u d y I n vesti gat or will mai ntai n a s u bject i de ntificati o n l o g ( e nr oll me nt n u m bers a n d 
c orres p o n di n g s u bject na mes) t o e na ble rec or ds t o be i de ntifie d. 
St u d y d ata will be s hare d wit h t he st u d y ‘ Us e of Micr os oft Ba n ds as a n O utc o me 
Meas ure i n B o ys wit h D M D  - Parallel st u d y t o Cli nical St u d y Pr ot oc ol V B P 1 5- 0 0 3’ if 
t he s u bject’s pare nt/le gal g uar dia n c o ns e nts f or his partici pati o n i n b ot h st u dies. 
1 1. 2  
P u blic ati o n 
R e vera G e n Bi o P har ma, I nc. retai ns t he o w ners hi p of all data a n d res ults c ollecte d d uri n g 
t his st u d y.  T h eref ore, t h e S p o ns or reser ves t he ri g ht t o use t he dat a fr o m t his prese nt 
st u d y, eit her i n t he f or m of e C R Fs ( or c o pies of t h ese), or i n t he f or m of a re p ort, wit h or 
wit h o ut c o m me nts a n d a nal ysis i n or der t o s u b mit t he m t o t he U S F D A or t he Healt h 
A ut h orities of a n y c o u ntr y. 
F urt her m ore, i n t he e v e nt t hat t he cli nical researc h lea ds t o pate nta ble res ults, t he 
I n v esti gat or ( or e ntit y acti n g o n his/ her be h alf acc or di n g t o l ocal re q uire m e nts) s hall 
refrai n fr o m fili n g pate nt a p plicati o n(s).  Pate nt a p plicati o ns will be file d b y Re vera Ge n 
Bi o P har ma, I n c. or a n ot h er e ntit y d ele gat e d b y Re vera Ge n Bi o P har ma, I nc. 
All i nf or mati o n c o ncer ni n g t he pr o d uct as well as a n y i nf or mati o n s uc h as cli nical 
i n dicati o ns f or t he dr u g, its f or m ula, met h o ds of ma n ufact ure a n d ot h er scie ntific data 
relati n g t o it, t hat ha v e bee n pr o vi de d b y t he S p o ns or or desi g nee, a n d are u n p u blis he d, 
are c o nfi de ntial a n d m ust re mai n t he s ole pr o p ert y of t he S p o ns or.  T he I n v esti gat or will 
a gree t o us e t he i nf or mati o n o nl y f or t h e p ur p oses of carr yi n g o ut t his st u d y a n d f or n o 
ot her p ur p ose u nless pri or writte n per missi o n fr o m t he S p o ns or is o btai ne d.  T he S p o ns or 
has f ull o w ners hi p of t he e C R Fs c o m plete d as p art of t he st u d y. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 2 9  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
B y si g ni n g t he st u d y pr ot oc ol, t he I n vesti gat or a grees t hat t he res ults of t he st u d y ma y be 
use d f or t he p ur p os es of nati o nal a n d i nter nati o nal re gistrati o n, p u blicati o n, a n d 
i nf or mati o n f or me dic al a n d p har mace utical pr ofessi o nals b y t he S p o ns or.  If necessar y, 
t he a ut h orities will be n otifie d of t he I n vesti gat or's na me, a d dress, q ualificati o ns, a n d 
e xte nt of i n v ol ve me nt. 
T he S p o ns or or desi g nee will pre pare a fi nal re p ort o n t he st u d y.  T h e I n vesti gat or ma y 
n ot p u blis h or prese nt a n y i nf or m ati o n o n t his st u d y wit h o ut t he e x press writte n a p pr o val 
of t he S p o ns or.  A d diti o nall y, t he S p o ns or, ma y, f or a n y reas o n, wit h h ol d a p pr o val f or 
p u blicati o n or prese ntati o n. 
1 2  
I N V E S TI G A T O R’ S P R O T O C O L A G R E E M EN T  
T he  I n vesti gat or's Pr ot oc ol A gree me nt at t he fr o nt of t his d oc u me nt m ust be si g ne d b y 
t he st u d y site Pri nci pal I n vesti gat or.  T he ori gi nal or a c o py  m ust be ke pt o n file b y  t he 
S p o ns or a n d t he I n vesti gat or m ust retai n t he ori gi nal or a c o py .  T he Pr ot o c ol A gree m e nt 
si g nifies r e vie w a n d acce pta nce of t he pr ot oc ol b y t he Pri nci pal I n vesti gat or pri or t o 
i nitiati o n of t he st u d y. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 3 0  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
1 3  
R E F E R E N C E S 
1.  Ma h J K, K or n g ut L, D y k e ma n J, Da y L, Pri n gs hei m T, J ette N. A s yst e mic 
revie w a n d m eta- a nal ysis o n t he e pi de mi ol o g y of D uc he n ne a n d Bec k er 
m usc ular d ystr o p h y. Ne ur o m usc ul Dis or d . 2 0 1 4; 2 4( 6): 4 8 2 - 9 1. 
2.  H off ma n E P, Br o w n R H a n d K u n kel L M. D ystr o p hi n: t he pr otei n pr o d uct of 
t he D uche n n e m usc ular d ystr o p h y l oc us. Cell . 1 9 8 7; 5 1: 9 1 9- 2 8. 
3.  E va ns N P, Mis ya k S A, R o berts o n J L, Bassa g an ya -Riera J, Gra n ge R W. 
I m m u ne me di ate d mec h a nis ms p ote ntiall y re g ulat e t he disease ti me c o urse of 
D uc he n ne m us c ular d ystr o p h y a n d pr o vi de tar gets f or t hera p e utic 
i nter ve nti o n. P M R . 2 0 0 9; 1( 8): 7 5 5-6 8.  
4.  K u mar A a n d  B ori e k A M. Mec ha nical stress acti vates t he n uclear fact or-
ka p pa B pat h wa y i n s kel etal m uscle fi bers: a p ossi ble r ole i n D uc he n n e 
m usc ular d ystr o p h y. F A S E B J . 2 0 0 3; 1 7( 3): 3 8 6- 9 6. 
5.  Ac har y ya S, Villalta S A, Ba k kar N, et al. Inter pla y of I K K/ N F -ka p p a B 
si g nali n g i n macr o p ha ges a n d m y ofi bers pr o m otes m uscle cell de ge n erati o n i n 
D uc he n ne m us c ular d ystr o p h y. J Cli n I nvest . 2 0 0 7; 1 1 7( 4): 8 8 9-9 0 1.  
6.  D o gra C, C ha n g otra H, Wer ge d al J E, K u mar A. Re g ulati o n of 
p h os p ha ti d yli n osit ol- 3- ki nase ( PI 3 K)/ A kt a n d n uclear fact or- k a p pa B 
si g nali n g pat h wa ys i n d ystr o p hi n- deficie nt s kelet al m uscle i n res p o nse t o 
mec ha nic al stretc h. J Cell P hysi ol . 2 0 0 6; 2 0 8( 3): 5 7 5- 8 5. 
7.  Pa hl H L. A cti vat ors a n d tar get ge nes of Rel/ N F- k a p pa B tra nscri pti o n fact ors. 
O nc o ge ne . 1 9 9 9; 1 8( 4 9): 6 8 5 3- 6 6. 
8.  S pe ncer MJ, M o nteci n o- R o dri g uez E, D ors h ki n d K, Ti d ball J G. Hel per 
( C D 4( +)) a n d c yt ot o xic ( C D 8( +)) T cells pr o m ote t he pat h ol o g y of 
d ystr o p hi n- d eficie nt m us cle. Cli n I m m u n ol . 2 0 0 1; 9 8( 2): 2 3 5- 4 3. 
9.  S pe ncer MJ a n d Ti d ball J G. D o i m m u ne cells pr o m ote t he pat h ol o g y of 
d ystr o p hi n- d eficie nt m y o pat hies? Ne ur o m usc ul Dis or d . 2 0 0 1; 1 1( 6- 7): 
5 5 6- 6 4. 
1 0.  Mali k V, R o di n o - Kla pac L a n d M e n dell J R. E mer gi n g dr u g f or D uc h e n ne 
m usc ular d ystr o p h y. Ex p ert O pi n E mer g Dr u gs . 2 0 1 2; 1 7( 2): 2 6 1- 7 7. 
1 1.  Ree ves E K, H off ma n E P, Na garaj u K, Da ms ker J M, Mc Call J M. V B P 1 5: 
p recli nical c h aracterizati o n of a n o vel a nti-i nfla m mat or y d elta 9, 1 1 ster oi d. 
Bi o or g Me d C he m . 2 0 1 3; 2 1( 8): 2 2 4 1- 9. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 3 1  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
1 2.  B us h b y K, Fi n k el R, Bir n kra nt DJ, et al. Dia g n osis a n d ma na ge me nt of 
D uc he n ne m us c ular d ystr o p h y, part 1: dia g n osis, a n d p har mac ol o gical a n d 
ps yc h os o cial ma na ge me nt. L a ncet Ne ur ol . 2 0 1 0; 9( 1): 7 7- 9 3. 
1 3.  Pa ne M, Mazz o ne E S, Si v o S, et al. L o n g ter m nat ural hist or y d ata i n 
a m b ula nt B o ys wit h D uc he n ne m usc ular d ystr o p h y: 3 6 -m o nt h c ha n ges. 
Pl os O ne . 2 0 1 4; 1 0: 1 3 7 1/j o ur nal. p o ne. 0 1 0 8 2 0 5.  
1 4.  Ma nz ur A Y, K u ntzer T, Pi ke M, S wa n A V. Gl uc oc ortic oi d c ortic oster oi ds f or 
D uc he n ne m us c ular d ystr o p h y.  C oc hr a ne D at a b ase Syst Rev. 2 0 0 8; ( 1): 
C D 0 0 3 7 2 5.  
1 5.  Heier C R, Da ms ker J M, Y u Q, et al. V B P 1 5, a n o vel a nti -i nfla m mat or y a n d 
me m bra ne -sta biliz er i m pr o ves m usc ular d ystr o p h y wit h o ut si de effects. 
E M B O M ol M e d . 2 0 1 3; 5( 1 0): 1 5 6 9-8 5.  
1 6.  Da ms ker J M, Dilli n g ha m B C, R ose M C, et al. V B P 1 5, a gl uc oc ortic oi d 
anal o g ue, is effecti ve at r e d uci n g aller gic l u n g i nfl a m mati o n i n mice. Pl os 
O ne . 2 0 1 3; 8( 5): e 6 3 8 7 1. 
1 7.  Dilli n g ha m B C, K n o blac h S M, Ma n y G M, et al. V B P 1 5, a n o vel a nti-
i nfla m mat or y, is effecti ve at re d u ci n g t h e se verit y of m uri ne e x peri me ntal 
a ut oi m m u ne e nce p h al o m yelitis. Cell M ol Ne ur o bi ol.  2 0 1 5; 3 5( 3): 3 7 7- 8 7. 
1 8.  Da d gar S, Wa n g Z, J o h nst o n H, et al. As y n c hr o n o us re m o deli n g is a dri ver of 
faile d re ge nerati o n i n D uc he n ne m usc ular d ystr o p h y. J Cell Bi ol . 2 0 1 4; 
2 0 7( 1): 1 3 9- 5 8.   
1 9.  Ra ma n S V, H or K N, Maz ur W, Hal n o n NJ, Kissel J T, He X, Tra n T, S mart S, 
Mc Ca rt h y B, T a yl or M D, J efferies J L, Rafael- F ort ne y J A, L o we J, R o ble S L, 
Cri pe L H. E plere n o n e f or earl y car di o m y o p at h y i n D uc he n ne m us c ular 
d ystr o p h y: a ra n d o mise d, d o u ble- bli n d, place b o-c o ntr olle d trial. L a ncet 
Ne ur ol.  2 0 1 5; 1 4( 2): 1 5 3- 6 1. 
2 0.  A vi oli L V. Gl uc o c ortic oi d effects o n stat ural gr o wt h. Br J  R he u m at ol. 1 9 9 3;  
3 2 S u p pl 2: 2 7- 3 0. 
2 1.  W olt hers O D a n d Pe derse n S. S h ort ter m li near gr o wt h i n ast h matic c hil dre n 
d uri n g tr eat me nt wit h pre d nis ol o ne. B MJ . 1 9 9 0; 3 0 1( 6 7 4 4): 1 4 5- 8. 
2 2.  Birca n Z, S ora n M, Yil diri m I, et al. T he effect of alter nate- da y l o w d ose 
pr e d nis ol o ne o n b o ne a ge i n c hil dre n wit h ster oi d de pe n de nt ne p hr otic 
s y n dr o me. I nt Ur ol Ne p hr ol. 1 9 9 7; 2 9( 3): 3 5 7- 6 1. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 3 2  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
2 3.  Ma n ola gas S C, Wei nstei n R S. Ne w de vel o p me nts i n t he pat h o ge nesis a n d 
treat me nt of ster oi d-i n d u ce d oste o p or osis. J B o n e Mi ner Res . 1 9 9 9; 1 4( 7): 
1 0 6 1- 6.  
2 4.  Sali A, G uerr o n A D, G or dis h- Dress ma n H, et al. Gl uc oc ortic oi d -tr eate d mice 
are a n i n a p pr o priat e p ositi ve c o ntr ol f or l o n g-ter m precli nical st u dies i n t he 
m d x m o use.  Pl os O ne. 2 0 1 2; 7( 4): e 3 4 2 0 4. 8 
2 5.  Ka u h E, Mi xs o n L, M alice M- P, Mese ns S, Ra mael S, B ur ke J, Re y n d ers T, 
Va n D yc k K, Beals C, R ose n ber g E, a n d R u d d y M. Pre d nis o ne affects 
i nfla m mati o n, gl uc ose t olera nce, a n d b o ne t ur n o ver wit hi n h o urs of tr eat me nt 
i n healt h y i n di vi d uals. E ur o pe a n J E n d ocri n ol.  2 0 1 2; 1 6 6: 4 5 9 – 6 7. 
2 6.  We hli n g- He nric ks M, Olt ma n n M, Ri nal di C, M y u n g K H, a n d Ti d ball J G. 
L oss of p ositi ve all osteri c i nteracti o ns bet w ee n n e ur o nal nitric o xi de s y nt hase 
a n d p h os p h ofr uct o ki nas e c o ntri b utes t o defects i n gl yc ol ysis a n d i ncreas e d 
fati ga bilit y i n m usc ular d ystr o p h y. H u m M ol Ge n et . 2 0 0 9; 1 8( 1 8): 3 4 3 9- 5 1. 
2 7.  Y o u nes M, Neffati F, T o uzi M, Hasse n- Zr o ur S, Fe n dri Y, Bejia I, Be n A m or 
A, Be r ga o ui N, a n d Najjar M F. S yst e mic effects of e pi d ural a n d i ntraartic ul ar 
gl uc o c ortic oi d i njecti o ns i n dia betic a n d n o n- dia betic patie nts. J oi nt B o ne 
S pi ne . 2 0 0 7; 7 4( 5): 4 7 2- 6. 
2 8.  M o o n HJ, C h oi K H, Lee SI, Lee OJ, S hi n J W, a n d Ki m T W. C ha n ges i n 
bl o o d gl uc ose a n d c ortis ol le vels after e pi d ural or s h o ul der i ntra-artic ular 
gl uc o c ortic oi d i njecti o ns i n dia betic or n o n dia betic patie nts. A m J P hys Me d 
Re h a bil . 2 0 1 4; 9 3( 5): 3 7 2- 8. 
2 9.  I n v esti gat or’s Br oc h ure, Versi o n 3, Va m or ol o n e ( 1 7 α, 2 1- di h y dr o x y- 1 6 α-
met h yl- pre g na- 1, 4, 9( 1 1)-trie ne- 3, 2 0- di o ne) 4 % Oral S us pe nsi o n,  Re vera Ge n 
Bi o P ha r ma, I n c., J a n uar y 2 3, 2 0 1 6. 
3 0.  Hat h o ut Y, Br o d y E, Cle me ns P R, et al. L ar ge-s cale ser u m pr otei n bi o mar ker 
disc o ver y i n D uc h e n ne m usc ular d ystr o p h y. Pr o c N atl Ac a d Sci U S A.  2 0 1 5; 
1 1 2( 2 3): 7 1 5 3 -8.  
3 1.  Bell o L, Kes ari A, G or dis h- Dress ma n H, et al. Ge netic m o difiers of 
am b ulati o n i n t he C o o perati ve I nter n ati o nal Ne ur o m usc ular Researc h Gr o u p 
D uc he n ne n at ural hist or y st u d y. A n n Ne ur ol . 2 0 1 5; 7 7( 4): 6 8 4- 6 9 6. 
3 2.  S p ur ne y C, S hi miz u R, M or ge nr ot h L P, et al. C o o perati ve I nt er nati o nal 
Ne ur o m usc ular Researc h Gr o u p D uc h e n ne Nat ural Hist or y St u d y 
de m o nstrates i ns ufficie nt dia g n osis a n d tr eat me nt of car di o m y o pat h y i n 
D uc he n ne m us c ular d ystr o p h y. M us cle Nerve . 2 0 1 4; A u g; 5 0( 2): 2 5 0- 2 5 6.  


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 3 3  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
3 3.  Mc D o nal d C M, He nrics o n E K, A bres c h R T, et al. T he C o o perati ve 
I nter nati o nal N e ur o m usc ular Researc h Gr o u p D uc he n ne nat ur al hist or y st u d y 
–  a l o n git u di nal i n vesti gati o n i n t he era of gl uc oc ortic oi d t hera p y: desi g n of 
pr ot oc ol a n d t he met h o ds use d. M uscle Ner ve.  2 0 1 3; 4 8( 1): 3 2- 5 4.  
3 4.  He nrics o n E K, A bres c h R T, C naa n A, et al. T he C o o perati ve I nter nati o nal 
Ne ur o m usc ular Researc h Gr o u p D uc h e n ne nat ur al hist or y st u d y: 
gl uc o c ortic oi d treat me nt preser ves cli nicall y mea ni n gf ul f u n cti o n milest o nes 
a n d re d uces rat e of disease pr o gressi o n as meas ure d b y m a n ual m uscle testi n g 
a n d ot her c o m m o nl y use d cli nical trial o utc o me meas ures. M us cle Nerve.  
2 0 1 3; 4 8( 1): 5 5- 6 7. 
3 5.  Esc olar D M, Hac he L P, Cle me ns P R, et al. Ra n d o mize d, bli n de d trial of 
we e ke n d vs. d ail y pre d nis o ne i n D uc he n n e m usc ular d ystr o p h y. Ne ur ol o gy.  
2 0 1 1; 7 7( 5): 4 4 4- 4 5 2. 
3 6.  F D A Draft G ui da n ce f or I n d ustr y: D u c he n n e m usc ular d ystr o p h y a n d relat e d 
d ystr o p hi n o pat hies: de v el o pi n g dr u gs f or treat me nt. J u ne 2 0 1 5. 
3 7.  Ma y h e w J E, Fl ore nce J M, Ma y h e w T P, et al. Relia ble s urr o gate o utc o m e 
meas ures i n m ultice nter cli nical trials of D uc h e n n e m usc ular d ystr o p h y. 
M uscle Nerve.  2 0 0 7; 3 5( 1): 3 6- 4 2. 
3 8.  Br o o ke M H, Gri g gs R C, Me n dell J R, et al. Cli nical trial i n D uc he n ne 
d ystr o p h y. I. T h e desi g n of t he pr ot oc ol. M uscl e & N erve.  1 9 8 1; 4( 3): 1 8 6- 9 7. 
3 9.  Mazz o ne E S, Messi na S, Vasc o G, et al. Relia bilit y of t he N ort h Star 
A m b ulat or y Assess me nt i n a m ultice ntric setti n g. Ne ur o m usc ul Dis or d . 2 0 0 9; 
1 9( 7): 4 5 8- 6 1. 
4 0.  Mc D o nal d C M, He nrics o n E K, Ha n JJ, et al. T he 6- mi n ute Wal k Test as a 
ne w o utc o me meas ure i n D uc he n ne m us c ular d ystr o p h y. M us cle Nerve.  2 0 1 0; 
4 1( 4):  5 0 0- 1 0. 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 3 4  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
1 4  
A P P E N DI C E S 
 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 3 5  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
A p pe n di x 1 4. 1  
V a m or ol o ne D ose C al c ul ati o n W or ks heet a n d B ul k Dis pe nsi n g 
G ui de 
Va m or ol o ne is a d mi nistere d o nce d ail y as a 4 % oral s us pe nsi o n.  T he v ol u me per d ose is 
deter mi ne d b y t he s u bject’s d osi n g le vel a n d b o d y wei g ht (i n k g) at eac h st u d y 
me dica ti o n dis pe nsi n g visit, as s h o w n b y E q uati o n 1: 
E q u ati o n 1  
S u bject Wei g ht ( k g) x D ose Le vel ( m g/ k g)  
= S u bject D ose (i n m L)  
4 0 m g/ m L  
S u bject wei g ht (i n k g) s h o ul d be r o u n de d t o t he nearest w h ole i nte ger f or t h e calc ul ati o n 
of v ol u me per d ose.  
Calc ulate d d ose v ol u me will be r o u n de d t o t he nearest 0. 0 1 m L ( 1 m L s yri n ge), 0. 1 m L 
( 3 m L s yri n ge), or 0. 2 m L ( 5 m L s yri n ge), de p e n di n g u p o n t he t otal d ose v ol u me a n d 
cali brati o n of t he v ol u metric s yri n ge t o be use d f or a d mi nistrati o n of d ose, as s h o w n i n 
t he e xa m ples bel o w: 
E x a m ple 1:  D ose v ol u me calc ulati o n f or a s u bject recei vi n g 0. 2 5 m g/ k g/ da y wit h a b o d y 
wei g ht of 2 7 k g:  
S u bject Wei g ht ( 2 7 k g) x  D ose Level (0. 2 5  m g/ k g)  
=  0. 1 6 9  m L  
4 0 m g/ m L  
T he s u bject will r ecei ve a d ose v ol u me of 0. 1 6 9 m L per d ose t hr o u g h o ut t he f oll o wi n g 
1 2 wee ks.  D ose will be a d mi nistere d usi n g a 1 m L v ol u metric s yri n ge r o u n de d t o t he 
nearest 0. 0 1 m L, or 0. 1 7 m L dail y. 
E x a m ple 2:  D ose v ol u me calc ulati o n f or a s u bject recei vi n g 6. 0 m g/ k g/ d a y wit h a b o d y 
wei g ht of 2 3 k g:  
S u bject Wei g ht ( 2 3 k g) x D ose Level ( 6 .0 m g/ k g)  
= 3. 4 5  m L  
4 0 m g/ m L  
T he s u bject will recei ve a d ose v ol u me of 3. 4 5 m L per d ose t hr o u g h o ut t he  f oll o wi n g 
1 2 wee ks.  D ose will be a d mi nistere d usi n g a 5 m L v ol u metric s yri n ge r o u n de d t o t he 
nearest 0. 2 m L, or 3. 4 m L dail y. 
 
V a m or ol o ne 4 % S us pe nsi o n Dis pe nsi n g G ui de 
Eac h s u bject e nr olle d i n t he st u d y will be dis pe nse d 1 0 0 ml b ottle(s) of va m or ol o ne 4 % 
s us pe nsi o n at t he Bas eli ne Da y - 1 Visit, s ufficie nt f or d osi n g t hr o u g h t h e ti m e of t he 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 3 6  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
Wee k 1 2  Visit.  A d diti o nal s u p plies will be dis pe nse d at Wee k 1 2, s uffici e nt f or d osi n g 
t hr o u g h Wee k 2 4.  S u bje cts w h ose va m or ol o ne d ose is ta pere d d uri n g t h e D ose-ta peri n g 
Pe ri o d will be dis pe nse d a d diti o nal va m or ol o ne 4 % s us pe nsi o n at t he Wee k 2 4 Visit, 
s ufficie nt f or d os e ta peri n g t o 0 m g/ k g/ d a y (see Se cti o n 6. 3. 4 ). 
T he n u m ber  of b ottles t o be dis pe nse d at eac h dis p e nsi n g visit f or t he f oll o wi n g 1 2- wee k 
d osi n g  peri o d is c alc ulate d b y m ulti pl yi n g t he s u bj ect’s dail y d ose (i n m L/ d a y) (as 
calc ulate d b y E q u ati o n 1) b y 9 1 d a ys ( 8 4 da ys i n t he d osi n g p eri o d + 7 da ys o vera ge) a n d 
di vi di n g  b y 1 0 0 m L, t he n u m ber of m L per b ottle, as s h o w n i n E q uati o n 2, bel o w: 
E q u ati o n 2  
D ail y D ose ( m L/ d a y)  x 9 1 D a ys  
= # B ottle s t o be Dis pe nse d 
1 0 0 m L  
 
E x a m ple 3 : Calc ulati o n of n u m ber of b ottles t o be dis pe nse d f or a s u bject ta ki n g a dail y 
d ose of 0. 1 7 m L (fr o m E xa m ple 1 a b o ve):  
D ail y D ose (0. 1 7  m L / d a y) x 9 1 D a ys  
= 0. 1 5 B ottles  
1 0 0 m L  
T he n u m ber of b ottles dis pe nse d is r ou n de d t o t he nearest w h ole i nte ger, or 1 b ottle t o be 
dis pe nse d. 
E x a m ple 4 : Calc ulati o n of n u m ber of b ottles t o be dis pe nse d f or a s u bject ta ki n g a dail y 
d ose of 3. 4 m L (fr o m E xa m ple 2 a b o ve):  
D ail y D ose ( 3. 4 m L/ d a y) x 9 1  D a ys  
=   3. 0 9 B ottles  
1 0 0 m L  
T h e n u m ber of b ottles dis pe nse d is r o u n de d t o t he nearest w h ole i nte ger, or 4 b ottles t o 
be dis pe nse d. 
Eac h b ul k b ottle s h o ul d be use d f or o n e s u bject o nl y.  Eac h b ottle dis pe nse d t o t he 
s u bject a n d rea d y f or a d mi nistrati o n t o s u bjects will be la bele d wit h s u bject n u m ber, 
dis pe nse date, pr ot oc ol n u m ber, d ose le vel, a n d v ol u me t o be a d mi nistere d per d ose.   
A n y u n us e d or partiall y use d dr u g pr o d uct s h o ul d be ret ur n e d at eac h m o nt hl y visit 
t hr o u g h Wee k 2 4 a n d at t he e n d of t he D ose-ta peri n g Peri o d, if a p plica bl e.  Dr u g pr o d uct 
ret ur ned at t he Wee ks 4, 8, 1 6, a n d 2 0 Visits will be re dis pe nse d t o s u bjects at t he e n d of 
t he visit, after i nteri m c o m plia nce m o nit ori n g; dr u g pr o d u ct ret ur n e d at t he Wee ks 1 2 a n d 


Va m or ol o ne 
2 2 Fe br uar y 2 0 1 7 
Re v ise d Cli nical Pr ot oc ol # 2 
D oc u me nt N o. V B P 1 5- 0 0 3 - R 2 
Pr ot oc ol N o. V B P 1 5- 0 0 3  
I N D 1 1 8, 9 4 2 
 
 
 
P a ge 1 3 7  of 1 3 7  
Re vera Ge n Bi o P har ma, I nc. – C O N FI D E N TI A L 
2 4 Visits, a n d e n d of t he D ose- Ta p eri n g Peri o d, if a p plica ble, will be retai n e d at t he 
clinical st u d y site f or i n vesti gati o nal dr u g acc o u nta bilit y m o nit ori n g. 

SAP_001.pdf: 
 
 
 
ReveraGen BioPharma, Inc. 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol Title: 
A Phase II Open-label, Multicenter Extension Study to Assess 
the Long-term Safety and Efficacy of Vamorolone in Boys with 
Duchenne Muscular Dystrophy (DMD) 
Protocol Number 
VBP15-003 
Phase: 
Phase II 
Sponsor: 
ReveraGen BioPharma, Inc. 
155 Gibbs Street  
 
Suite 433 
Rockville, MD  20850 
 
Author: 
Philip Shale, PhD 
Summit Analytical, LLC 
8354 Northfield Blvd., Bldg. G Suite 3700 
Denver, CO 80238 
SAP Date: 
2018-07-27 
Status: 
FINAL V1.0 
 
 
 


ReveraGen BioPharma, Inc.
Study VBP15-003 Statistical Analysis Plan
IND#:118,942
Sponsor:
Protocol:
ProtocolTitte:
SAP Version:
SAP Date:
Signature
Reviewer: Heather Gordish-Dressman, PhD
Associate Professor of Pediatrics
George Washington University School of Medicine
ctnd Health Sciences
FINAL Version 1.0
2018-07-27
SUMMITANAIY 
II(]AI
Statistical Analysis Plan Approval Form
The statistical analysis plan has been reviewed and approved.
Sponsor: ReveroGenBioPharmo,lnc.
Eric Hoffman
cEo
f- 
.,
_31July )01 R
Signature
Date
Author:
Summit Analytical LLC
Philip Shole, PhD
Director
3l TrL,77-. r V
Date
't r*,- Q-^arl- &'rrr^^^t
Signature
Page l2
CONFIDENTIAL
Date
31July 2018
ReveraGen BioPharma, lnc.
vBP15-003
A Phase ll Open-label, Multicenter Extension Study to Assess the Long-term
Safety and Efficacy of Vamorolone in Boys with Duchenne Muscular
Dystrophy (DMD)


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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ............................................................................................................................... 3 
2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS................................................................... 6 
3. 
INTRODUCTION ......................................................................................................................................... 9 
3.1. 
Preface .............................................................................................................................................. 9 
3.2. 
Purpose of Analyses .......................................................................................................................... 9 
3.3. 
Summary of Statistical Analysis Changes to the Protocol ................................................................ 9 
4. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................... 14 
4.1. 
Study Objectives ............................................................................................................................. 14 
4.1.1. 
Primary Objective ......................................................................................................... 14 
4.1.2. 
Secondary Objectives .................................................................................................... 14 
4.1.3. 
Exploratory Objectives .................................................................................................. 15 
4.2. 
Study Endpoints .............................................................................................................................. 15 
4.2.1. 
Primary Endpoints ......................................................................................................... 15 
4.2.2. 
Secondary and Additional Endpoints ............................................................................ 15 
4.2.3. 
Exploratory Endpoint .................................................................................................... 16 
4.2.4. 
Endpoints for Subject Reported Outcomes ................................................................... 16 
5. 
STUDY METHODS .................................................................................................................................... 17 
5.1. 
General Study Design and Plan....................................................................................................... 17 
5.2. 
Inclusion – Exclusion Criteria and General Study Population ........................................................ 21 
5.3. 
Randomization and Blinding........................................................................................................... 21 
5.4. 
Analysis Variables .......................................................................................................................... 21 
6. 
SAMPLE SIZE ............................................................................................................................................ 21 
7. 
GENERAL CONSIDERATIONS ............................................................................................................... 22 
7.1. 
Analysis Populations ....................................................................................................................... 22 
7.1.1. 
Safety Population .......................................................................................................... 22 
7.1.2. 
Full Analysis Set (FAS) ................................................................................................ 22 
7.1.3. 
Control Population DNHS Study .................................................................................. 22 
7.1.4. 
Control Population Prednisone Study ........................................................................... 23 
7.2. 
Covariates and Subgroups ............................................................................................................... 23 
7.2.1. 
Planned Covariates ........................................................................................................ 23 
7.2.2. 
Planned Subgroups ........................................................................................................ 23 
7.2.3. 
Post hoc Subgroups ....................................................................................................... 23 
7.3. 
Management of Analysis Data ........................................................................................................ 23 
7.3.1. 
Data Handling ............................................................................................................... 23 
7.3.2. 
Missing Data ................................................................................................................. 24 
7.3.3. 
Handling of Early Termination Visit Information ......................................................... 25 
7.3.4. 
Pooling of Investigational Sites ..................................................................................... 26 
7.3.5. 
Coding Conventions for Events and Medications ......................................................... 26 
7.3.6. 
Baseline Visits ............................................................................................................... 26 
7.3.7. 
Analysis Software ......................................................................................................... 26 
7.3.8. 
Study Data ..................................................................................................................... 26 
7.4. 
Planned Study Analyses .................................................................................................................. 28 
7.4.1. 
Statistical Summaries: Descriptive and Inferential ....................................................... 28 
7.4.2. 
Interim Analyses and Data Monitoring ......................................................................... 28 


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7.4.3. 
Final Analysis ............................................................................................................... 28 
7.5. 
Multiple Testing Procedures ........................................................................................................... 28 
8. 
SUMMARY OF STUDY DATA ................................................................................................................ 29 
8.1. 
Subject Summary Grouping ............................................................................................................ 29 
8.2. 
Subject Disposition ......................................................................................................................... 29 
8.3. 
Protocol Deviations ......................................................................................................................... 29 
8.4. 
Demographics and Baseline Characteristics ................................................................................... 29 
8.5. 
Medical History .............................................................................................................................. 29 
8.6. 
Prior and Concomitant Medications ................................................................................................ 30 
8.7. 
Treatment Compliance and Study Drug Exposure .......................................................................... 30 
9. 
EFFICACY ANALYSES ............................................................................................................................ 31 
10. SAFETY ANALYSES................................................................................................................................. 32 
10.1. 
Adverse Events ............................................................................................................................... 33 
10.2. 
Vital Signs, 12-Lead ECG, and Laboratory Outcomes ................................................................... 34 
10.3. 
Physical Exam ................................................................................................................................. 35 
10.4. 
Other Safety Measures .................................................................................................................... 35 
11. PHARMACODYNAMIC (PD) SERUM AND OTHER BIOMARKERS .................................................. 35 
12. REPORTING CONVENTIONS .................................................................................................................. 36 
12.1. 
General Reporting Conventions ...................................................................................................... 36 
11.1 
Population Summary Conventions .................................................................................................. 37 
12 
REFERENCES ............................................................................................................................................ 38 
13 
APPENDICES ............................................................................................................................................. 40 
13.1 
List of Planned Tables ..................................................................................................................... 40 
13.2 
List of Planned Listings .................................................................................................................. 46 
13.3 
List of Planned Figures ................................................................................................................... 49 
13.4 
Calculating BMI Z-Scores .............................................................................................................. 52 
13.5 
SAP Amendment Summary of Changes ......................................................................................... 53 
 
 


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LIST OF TABLES 
 
Table 1: 
Dose level group composition ....................................................................................... 17 
Table 2 
Schedule of Study Activities ......................................................................................... 18 
 
 
LIST OF FIGURES 
 
Figure 1 
SDTM, ADaM, and TFL Development and Validation ................................................ 27 
 
 
 


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2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Only abbreviations and terms relevant to the SAP are repeated herein. The reader is referred 
to the protocol for the complete and comprehensive list of abbreviations and definitions of 
terms for the study. 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BL 
baseline 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
celsius 
CD23 
cluster designation 23 
CDC 
Centers for Disease Control and Prevention 
CINRG 
Cooperative International Neuromuscular Research Group 
CK 
creatine kinase 
cm 
centimeter 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
carboxy-terminal telopeptide 
DHEA 
dehydroepiandrosterone 
dL 
deciliter 
DMD 
Duchenne muscular dystrophy 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
F 
fahrenheit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GLDH 
glutamate dehydrogenase 
GLP 
Good Laboratory Practice 


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HbA1c 
hemoglobin A1c 
HDL 
high density lipoprotein 
HEENT 
head, eyes, ears, nose and throat 
HIPAA 
Health Insurance Portability and Accountability Act 
hr 
hour 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IGFBP-2 
insulin-like growth factor-binding protein 2 
IGFBP-5 
insulin-like growth factor-binding protein 5 
IL-22BP 
interleukin-22 binding protein 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
L 
liter 
LLC 
Limited Liability Company 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
LS 
least squares 
m 
meter 
MAD 
multiple ascending dose (study) 
MD 
medical doctor (physician) 
MDC 
macrophage-derived chemokine 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minute 
MIST 
Metabolites in Safety Testing 
mL 
milliliter 
MMP-3 
matrix metalloproteinase-3 
MMP-12 
matrix metalloproteinase-12 
MMRM 
mixed model for repeated measures 
MTD 
maximum tolerated dose 
ng 
nanogram 
No., n 
number 
nmol 
nanomole 
NSAA 
North Star Ambulatory Assessment 
%CV 
percentage coefficient of variation 
PD 
pharmacodynamic(s) 


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P1NP 
serum aminoterminal propeptide of type I collagen 
PK 
pharmacokinetic(s) 
PODCI 
Pediatric Outcomes Data Collection Instrument 
PR [PQ] 
time from onset of P wave to start of the QRS complex 
QMT 
quantitative muscle testing 
QRS 
in electrocardiography, the complex consisting of Q, R, and S 
waves, corresponding to depolarization of ventricles [complex] 
QT 
in cardiology, the time between the start of the Q wave and end 
of the T wave 
QTc 
corrected QT interval  
QTcF 
QT corrected for HR using Fridericia's method 
6MWT 
Six-minute Walk Test 
REML 
restricted maximum likelihood 
RR 
in electrocardiography, the interval between successive Rs 
(peaks of QRS complexes) 
SAD 
single ascending dose (study) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCR 
screening 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TTCLIMB 
Time to Climb (Test) 
TTSTAND 
Time to Stand (Test) 
TTRW 
Time to Run/Walk (Test) 
ULN 
upper limit of normal 
US 
United States 
vs. 
versus 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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3. 
INTRODUCTION 
3.1. 
Preface 
This document presents a statistical analysis plan (SAP) for ReveraGen BioPharma, Inc. 
Protocol VBP15-003, (A Phase II Open-label, Multicenter Extension Study to Assess the 
Long-term Safety and Efficacy of Vamorolone in Boys with Duchenne Muscular Dystrophy 
(DMD)). This SAP will provide the details and methods for analysis and reporting of the 
subject characteristics, safety, and efficacy information.  
Reference materials for this statistical plan include the protocol VBP15-003 (Revision #2 
Dated: 22 February 2017) and Case Report Forms (Version 1.0). 
The SAP described hereafter is an a priori plan.  The SAP will be finalized and approved 
prior to database lock.  Statistical programming may occur as study data accumulate in order 
to have analysis programs ready at the time the study finishes.     
The conduct of the study in the field is to be considered independent of any study outcome 
that might materialize upon enactment of the currently proposed statistical plan.  
3.2. 
Purpose of Analyses 
The purposes of the planned analyses described in this SAP are to assess the long-term 
safety, tolerability, clinical efficacy, and pharmacodynamics (PD) of vamorolone at dose 
levels up to 6.0 mg/kg administered daily by liquid oral suspension over a Treatment Period 
of 24 weeks to boys ages 4-7 years with DMD. Results from the analyses completed will be 
included in the final clinical study report for VBP15-003, and may also be utilized for 
regulatory submissions, manuscripts, additional endpoint specific reports, or other clinical 
development activities.  Post-hoc exploratory analyses not identified in this SAP may be 
performed to further examine the study data and provide context for study results. These 
analyses will be clearly identified, where appropriate, in the final clinical study report.  
Additional analyses not prospectively identified in this SAP may also be completed for 
publications, additional endpoint specific reports, regulatory, or funding inquiries. These 
analyses, if performed, may not be reported in the clinical study report, but will be fully 
documented in the document containing the additional analyses. 
3.3. 
Summary of Statistical Analysis Changes to the Protocol 
The analyses described in this analysis plan are consistent with the analyses described in the 
study protocol with the exceptions noted below. 


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Change of Baseline comparator:   
In the VBP15-003 Protocol Synopsis, General Statistical Considerations, it is stated 
“Baseline measurement is defined as the last non-missing value prior to the first dose of 
study drug in the extension study.”  In this VBP15-003 SAP, we have changed the baseline 
comparator to the Baseline visit of the preceding study (VBP15-002), with the exception of 
the PODCI, which is not collected in the VBP15-002 trial and whose baseline comparator is 
therefore the Baseline visit of the VBP15-003 trial.  The rationale for this is as follows.  All 
subjects enrolled in this study (VBP15-003) were recruited from a previous study 
(VBP15-002). VBP15-002 was a multiple-ascending dose, 2-week treatment, 2-week 
washout study, and all subjects maintained on the same dose level in VBP15-003 as they 
received in VBP15-002.  During the conduct of the VBP15-002 trial, nearly all subjects 
(46/48) had the last visit of VBP15-002 commensurate with the first visit of VBP15-003.  As 
all subjects had received drug treatment for two weeks in VBP15-002, the short period of 
time between baseline in VBP15-002 and measures in VBP15-003 led the study staff to 
change the baseline comparator to the Baseline visit of the preceding trial, VBP15-002. 
External Comparator Databases: 
 
The Cooperative International Neuromuscular Research Group (CINRG) was established in 
2000 to enable robust clinical studies and clinical trials in pediatric neuromuscular disease 
via an international academic network with central coordinating center (Escolar et al. 2002).  
The CINRG group has become the leading neuromuscular clinical trial network, establishing 
outcome measures and training programs for clinical evaluators, and has recruited over 1,400 
subjects into studies over the last 15 years (Bello et al. 2015, 2016a, 2016b; McDonald et al. 
2018).  From 2000 - 2015 the CINRG Coordinating Center was housed at Children’s 
National Medical Center.  In 2016, the CINRG Coordinating Center spun off into a stake 
holder owned and led company, TRiNDS LLC (www.trinds.com).   
 
The CINRG group carried out the vamorolone Phase 2 studies VBP15-002 and VBP15-003, 
using established outcome measures, and well-trained evaluators and recruitment sites.   
In communications with the FDA and EMA, and in developing the design of the vamorolone 
clinical trials, two previous CINRG studies were used to carry out sample size calculations 
for different outcome measures.  These were: 
 
• CINRG Prednisone-treated comparator 
o Publication: Escolar DM, Hache LP, Clemens PR, Cnaan A, McDonald CM, 
Viswanathan V, Kornberg AJ, Bertorini TE, Nevo Y, Lotze T, Pestronk A, 
Ryan MM, Monasterio E, Day JW, Zimmerman A, Arrieta A, Henricson E, 
Mayhew J, Florence J, Hu F, Connolly AM. Randomized, blinded trial of 
weekend vs daily prednisone in Duchenne muscular dystrophy. Neurology. 
2011 Aug 2;77(5):444-52. 


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o Design:  64 steroid naïve DMD boys, ages 4 to <10 years, randomized to 
either daily or high dose weekend prednisone, 12 month treatment period 
o Subset used in vamorolone studies: We limited analysis to the subset with 
the same inclusion/exclusion criteria as the vamorolone studies (ages 4 to <7 
years) on daily prednisone (0.7 mg/kg/day), comparing the 12-week and 
24-week time points to the corresponding vamorolone trial time points.   
• CINRG Steroid-naïve natural history comparator (Duchenne Natural History Study; 
DNHS) 
o Publication: McDonald CM, Henricson EK, Abresch RT, Han JJ, Escolar 
DM, Florence JM, Duong T, Arrieta A, Clemens PR, Hoffman EP, Cnaan A; 
CINRG Investigators. The cooperative international neuromuscular research 
group Duchenne natural history study--a longitudinal investigation in the era 
of glucocorticoid therapy: design of protocol and the methods used. Muscle 
Nerve. 2013 Jul;48(1):32-54. 
o Design:  This is a natural history study that recruited 440 DMD children and 
100 healthy peers over a period of 10 years (Figure 1).  The outcome 
measures collected depended on the subject’s age.     
o Subset used in vamorolone studies: 
 Time to Stand (TTSTAND), Time to Climb (TTCLIMB), Time to 
Run/Walk (TTRW), and Quantitative Muscle Testing (QMT) 
endpoints (muscle strength testing):  A data cut from 2015 that was 
the same used for sample size calculations for the design of the 
vamorolone study was used in this SAP.  This same data cut was also 
used in regulatory documents for the FDA and EMA.  Note that only 
subjects who remained steroid-free through 24 weeks of the study 
were included.   
 6-minute Walk Test (6MWT) and North Star Ambulatory 
Assessment (NSAA):  The original CINRG DNHS protocol did not 
include 6MWT or NSAA as outcome measures. These outcomes were 
added later in the study (Figure 1) and were not used for sample size 
calculations or in FDA or EMA communications in the Phase 1 – 2 
transition meeting.  In 2012, the CINRG DNHS protocol was amended 
to begin collection of 6MWT and NSAA outcomes. As noted below, 
however, comparisons to vamorolone data on these two endpoints 
were not done.  
 
Efficacy Analyses:   
The primary comparisons for efficacy will be between each of the 4 vamorolone dose groups 
and the historical untreated controls (CINRG DNHS).  Additional exploratory analyses have 
been added and will include pairwise comparisons between the 4 vamorolone dose groups 


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within the VBP15-003 trial (0.25 mg/kg, 0.75 mg/kg, 2.0 mg/kg, and 6.0 mg/kg) for 
TTSTAND velocity and raw, TTRW velocity and raw, TTCLIMB velocity and raw, 6MWT, 
NSAA total score, and QMT.  These comparisons (pairwise contrasts) will be added to the 
mixed model for repeated measures (MMRM) analysis used for each variable.  Vamorolone 
dose groups will not be combined for any analyses. 
Also, the VBP15-003 protocol indicates that 6MWT and NSAA results will be compared to 
the historical untreated controls (CINRG DNHS).  The CINRG DNHS protocol enrolled 
DMD subjects from 2005-2014.  The original CINRG DNHS protocol did not include 
6MWT or NSAA as outcome measures.  In 2012, the CINRG DNHS protocol was amended 
to begin collection of 6MWT and NSAA outcomes.  Thus, while CINRG DNHS carried out 
subject assessments for 9 years for other outcomes (TTSTAND, TTRW, TTCLIMB, and 
QMT), only two years included 6MWT and NSAA assessments.  The number of subjects and 
assessments in this narrow time window were insufficient to use as a comparator for these 
two outcome measures, and thus comparisons to vamorolone data were not done. 
The VBP15-003 protocol also indicates that the effects of vamorolone, administered orally at 
daily doses up to 6.0 mg/kg over a 24-week Treatment Period vs. prednisone-treated 
historical controls, on serum pharmacodynamic (PD) biomarkers of safety (insulin resistance, 
adrenal axis suppression, and bone turnover) will be investigated, as will vamorolone, 
administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period vs. 
untreated historical controls, on serum PD biomarkers of efficacy (inflammatory protein 
suppression).  These comparisons will not be carried out in this SAP as PD biomarker data 
were not collected in either of the CINRG DNHS or CINRG prednisone-treated cohort 
comparator studies.  
SomaScan data, if available, will be presented in an addendum report. 
Proteomics profiling data will be collected for potential analysis in future studies. These data 
will not be included in any by subject listing or in the CSR for this study. Any analysis of the 
proteomics profiling information will be reported in separate reports. 
Serum creatine kinase will be analyzed as an exploratory efficacy biomarker. 
Safety Analyses:  
The protocol states, “The primary safety variable will be BMI z-score and will be assessed 
using the same type of statistical models used for efficacy.”  This SAP has been revised to 
make it clear that the BMI z-score comparator group will be the prednisone-treated subjects 
from the CINRG prednisone trial.   
Analyses of additional secondary safety data are as described in the protocol but will use 
Baseline of VBP15-002 for all baseline comparisons.  GLDH has been added as an 
exploratory clinical chemistry analyte for liver damage. 


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Height z-scores will not be analyzed, ANCOVA models will not be utilized for vital signs 
and ECG endpoints, linear modelling will not be utilized for any other safety variables, and 
AE rates will not be compared using exact tests. 
Ancillary Study: 
Ancillary MS Band Study was not performed and is not included in the study analyses. 


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4. 
STUDY OBJECTIVES AND ENDPOINTS 
Study objectives and endpoints defined in the protocol include safety, tolerability, clinical 
efficacy, and PD. These protocol listed objectives and pre-specified endpoints are as follows: 
4.1. 
Study Objectives 
4.1.1. 
Primary Objective 
• To evaluate the long-term safety and tolerability of vamorolone, administered orally 
at daily doses up to 6.0 mg/kg over a 24-week Treatment Period, in boys ages 4-7 
years with DMD; 
• To compare the efficacy, as measured by the Time to Stand Test (TTSTAND), of 
vamorolone administered orally at daily doses up to 6.0 mg/kg over a 24-week 
Treatment Period vs. untreated DMD historical controls in boys ages 4-7 years with 
DMD; and 
• To compare the safety, as measured by body mass index (BMI) z-score, of 
vamorolone administered orally at daily doses up to 6.0 mg/kg over a 24-week 
Treatment Period vs. prednisone-treated historical controls in boys ages 4-7 years 
with DMD. 
4.1.2. 
Secondary Objectives 
• To investigate the effects of vamorolone, administered orally at daily doses up to 
6.0 mg/kg over a 24-week Treatment Period vs. prednisone-treated historical controls, 
on serum pharmacodynamic (PD) biomarkers of safety (insulin resistance, adrenal 
axis suppression, and bone turnover); 
• To investigate the effects of vamorolone, administered orally at daily doses up to 
6.0 mg/kg over a 24-week Treatment Period vs. untreated historical controls, on 
serum PD biomarkers of efficacy (inflammatory protein suppression); and 
• To investigate the effects of vamorolone, administered orally at daily doses up to 
6.0 mg/kg over a 24-week Treatment Period, on muscle strength, mobility and 
functional exercise capacity vs. historical controls as measured by Quantitative 
Muscle Testing (QMT), Time to Run/Walk Test (TTRW), and Time to Climb Test 
(TTCLIMB). in boys ages 4-7 years with DMD. 
 
 


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4.1.3. 
Exploratory Objectives 
• To investigate the effects of vamorolone administered orally at daily doses up to 
6.0 mg/kg over a 24-week Treatment Period on an extended panel of PD biomarkers 
using SomaScan aptamer arrays, and proteomic profiling. 
4.2. 
Study Endpoints 
4.2.1. 
Primary Endpoints 
Primary endpoints from the protocol include the following: 
• Safety: BMI z-score: Comparison with a prednisone-treated historical control group 
for change from baseline to Week 24. 
• Clinical Efficacy: TTSTAND velocity (rise/second): Comparison with an historical 
natural history (untreated) control group for change from baseline to Week 24. 
4.2.2. 
Secondary and Additional Endpoints 
Secondary and additional endpoints from the protocol include the following: 
• Safety 
o BMI z-score: Change from baseline to each of the scheduled on-treatment and 
post-treatment assessment time points. 
o Treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) by system organ class (SOC): Overall by treatment, by treatment and 
relationship, and by treatment and intensity. 
o Vital signs [blood pressure, heart rate, respiratory rate, body temperature]: 
Change from baseline to each of the scheduled on-treatment and post-
treatment assessment time points. 
o Body weight: Change from baseline to each of the scheduled on-treatment and 
post-treatment assessment time points. 
o Clinical laboratory values (hematology and biochemistry): Change from 
baseline to each of the scheduled on-treatment and post-treatment assessment 
time points. 
o Glutamate dehydrogenase (GLDH):  Change from baseline to each of the 
scheduled on-treatment and post-treatment assessment time points.  
o Lipid profile (triglycerides, total cholesterol, low density lipoprotein [LDL], 
high density lipoprotein [HDL]): Change from baseline to each of the 
scheduled on-treatment and post-treatment assessment time points. 
o Urinalysis by dipstick and microscopic analysis: Change from baseline to each 
of the scheduled on-treatment and post-treatment assessment time points. 


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o 12-lead electrocardiogram (ECG): Clinical assessment and shift from baseline 
to each of the scheduled on-treatment and post-treatment assessment time 
points. 
• Clinical Efficacy 
o TTSTAND velocity (rise/second) and seconds: Change from baseline to each 
of the scheduled on-treatment and post-treatment assessment time points. 
o TTRW seconds and velocity: Change from baseline to each of the scheduled 
on-treatment and post-treatment assessment time points. 
o TTCLIMB seconds and velocity: Change from baseline to each of the 
scheduled on-treatment and post-treatment assessment time points. 
o NSAA: Change in timed assessments and total score from baseline to each of 
the scheduled on-treatment and post-treatment assessment time points. 
o QMT: Change from baseline to each of the scheduled on-treatment and post-
treatment assessment time points. 
o Total distance traveled, in meters, in completing the 6MWT: Change from 
baseline to each of the scheduled on-treatment and post-treatment assessment 
time points. 
• PD 
o Concentrations of serum PD biomarkers: osteocalcin, adrenocorticotropic 
hormone (ACTH), insulin, glucose, 17-hydroxyprogesterone, carboxy-
terminal telopeptide (CTX), serum aminoterminal propeptide of type I 
collagen (P1NP), cortisol, testosterone, corticosterone, 11-deoxycortisol, and 
hemoglobin A1c (HbA1c) 
4.2.3. 
Exploratory Endpoint 
• Levels of an extended panel of exploratory PD biomarkers are out of scope of the 
SAP and may be reported as addendum reports. 
4.2.4. 
Endpoints for Subject Reported Outcomes 
• Assessment of acceptability of vamorolone by a 5-point hedonic scale. 
• Pediatric Outcomes Data Collection Instrument (PODCI). 
 


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5. 
STUDY METHODS 
5.1. 
General Study Design and Plan 
As background for the statistical methods presented below, this section provides an overview 
of the study design and plan of study execution.  The protocol is the definitive reference for 
all matters discussed in what follows. 
This extension study is an open-label, multicenter study to evaluate the long-term safety, 
tolerability, clinical efficacy, and PD of vamorolone at dose levels up to 6.0 mg/kg 
administered daily by liquid oral suspension over a Treatment Period of 24 weeks to boys 
ages 4-7 years with DMD. 
The study is comprised of a Pretreatment Baseline Period of up to 24 hours in duration, 
which begins at the signing of the VBP15-003 study-specific informed consent, a 24-week 
Treatment Period, and a 2- to 5-week Dose-tapering Period for subjects who elect to 
transition off vamorolone treatment at the end of the study. Only subjects who have 
completed study VBP15-002 Week 4 Follow-up Visit assessments will be eligible for 
participation in this open-label VBP15-003 extension study. Each subject will retain the 
study identification number assigned to him at the start of the VBP15-002 study. 
Subjects will begin dosing in this study on Study Day 1 at the same vamorolone dose level 
they received in VBP15-002. Subjects will continue to receive vamorolone at the dose 
received in VBP15-002 for the duration of the 24-week Treatment Period, unless new safety 
data indicate the dose level should be de-escalated. The planned dose levels are 0.25 mg/kg 
(Dose Level Group 1), 0.75 mg/kg (Dose Level Group 2), 2.0 mg/kg (Dose Level Group 3), 
and 6.0 mg/kg (Dose Level Group 4) (Table 1). Approximately 12 subjects may be eligible 
for extension study dosing at each of the dose levels tolerated in the VBP15-002 study. 
Table 1: 
Dose level group composition 
Planned Dose 
Level Group 
No. Subjects in 
Dose Level Group 
Vamorolone Dose 
1 
12 
0.25 mg/kg 
2 
12 
0.75 mg/kg 
3 
12 
2.0 mg/kg 
4 
12 
6.0 mg/kg 
 
Table 2 presents the schedule of study activities. 
 
 


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Table 2 
Schedule of Study Activities 
 
Pretreatment 
Period 
Treatment Period 
Dose-
tapering 
Period 
Baseline 
 
Day 
Week 
Study Day or 
Week/Visit 
-1a 
 
1b 
 
2 
(±1d) 
4 
(±2d) 
8 
(±5d) 
12 
(±1w) 
16 
(±1w) 
20 
(±1w) 
24c 
(±1w) 
26-29d 
(±1w) 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
Informed Consent 
Xe 
 
 
 
 
 
 
 
 
 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
Interim Medical 
History 
Xf 
 
 
 
 
 
 
 
 
 
Medication History 
Xg 
 
 
 
 
 
 
 
 
 
Physical Examination 
Xh 
 
 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
X 
 
 
X 
 
Weight 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Vital Signsi 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for Clinical Labsj 
Xh 
 
 
X 
X 
 
X 
 
X 
X 
Urinalysisk 
Xh 
 
 
X 
X 
 
X 
 
X 
 
Blood for Serum PD 
Biomarker Panell 
Xh 
 
 
 
X 
 
X 
 
X 
X 
Fasting blood for 
insulin, glucosem 
 
 
 
 
 
X 
 
 
X 
 
12-lead ECGn 
Xh 
 
 
 
 
X 
 
 
X 
 
Dispense Study 
Medication 
X 
 
 
 
 
X 
 
 
Xo 
 
Return Study 
Medication/ 
Compliance 
Monitoring 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Study Medication 
Dosingp 
 
X 
 
 
 
 
 
 
X 
 
Vamorolone dose 
taperingq 
 
 
 
 
 
 
 
 
 
X 
Time to Stand Test 
(TTSTAND) 
Xh 
 
 
 
 
X 
 
 
X 
 
Time to Climb Test 
(TTCLIMB) 
Xh 
 
 
 
 
X 
 
 
X 
 
Time to Run/Walk 
Test (TTRW) 
Xh 
 
 
 
 
X 
 
 
X 
 
NSAAr 
Xh 
 
 
 
 
X 
 
 
X 
 


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Quantitative Muscle 
Testing (QMT) 
Xh 
 
 
 
 
X 
 
 
X 
 
Six-minute Walk Test 
(6MWT) 
Xh 
 
 
 
 
X 
 
 
X 
 
Pediatric Outcomes 
Data Collection 
Instrument 
X 
 
 
 
 
X 
 
 
X 
 
Study Medication 
Acceptability 
Assessments 
 
 
 
 
 
X 
 
 
X 
 
Dispense Subject 
Diariest 
X 
 
 
X 
X 
X 
X 
X 
Xp 
 
Return Subject Diaries  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE Recordingu 
X 
 
 
 
 
 
 
 
X 
X 
Concomitant 
Medications 
 
X 
 
 
 
 
 
 
X 
X 
Discharge from Study 
 
 
 
 
 
 
 
 
Xv 
Xw 
d = day(s); w = week.  
a. 
Baseline Day -1, within 24 hours prior to administration of the first dose of study drug.  The Baseline Visit for Study VBP15-003 can coincide with the final Week 4 
Follow-up Visit for Study VBP15-002 or occur up to 8 weeks after the date of the VBP15-002 Week 4 Visit. 
b. 
Treatment Day 1 begins at the time of administration of the first dose of VBP15-003 study medication at home.  No scheduled study visit will occur on Day 1. 
c. 
Subjects who prematurely discontinue from the study prior to Week 24 should complete the Week 24 assessments at the time of early discontinuation. 
d. 
All subjects EXCEPT those who elect to continue vamorolone therapy in a further extension study must continue in the Dose-tapering Period and have their 
vamorolone dose tapered at weekly intervals over a 1-4 week period prior to discharge from this study.  Subjects participating in the Dose-tapering Period will have 
one study site visit during this period, at the end of dose tapering (Weeks 25-29).  
e. 
Informed Consent for this extension study may be obtained at the Study VBP15-002 Week 4 Follow-up Visit, after completion of all final VBP15-002 study 
assessments and prior to any extension study-specific procedures. 
f. 
Interim Medical History will be collected on Baseline Day -1 for all subjects, and will include any AEs that occurred during the VBP15-002 core study and are 
ongoing at the time of entry into VBP15-003. 
g. 
Any changes in medication/therapy including administration of new medication(s), change of dose, or discontinuation of medication after completion of the VBP15-
002 core study and prior to administration of the first dose of study medication in VBP15-003 will be captured as Prior Medications.  
h. 
If the Baseline Day -1 Visit occurs ≤ 28 days after the date of the final VBP15-002 core study Week 4 Visit, these assessments do not need to be repeated for the 
VBP15-003 study.  Clinical laboratory and urinalysis test results from the VBP15-002 Week 2 or Week 4 Visit (whichever is available and later) may be used and 
should be reviewed by the Site Investigator to determine eligibility for Baseline Day -1 enrollment into the extension study. 
i. 
Supine blood pressure, oral temperature, respiratory rate, and heart rate. 
j. 
Blood for hematology, chemistry, and lipids. 
k. 
Urinalysis by dipstick and microscopic analysis. 
l. 
Blood collected for cortisol, P1NP, osteocalcin, 17-hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol, CTX, ACTH, HbA1c (not collected at Baseline), 
SomaScan, and proteomic testing. 
m. Blood will be collected for insulin and glucose determination in the morning after subjects have fasted for ≥ 6 hours, prior to the daily dose of study medication. 
n. 
ECG recorded after subject has rested quietly in a supine position for at least 5 minutes. 
o. 
Only for subjects who will participate in the Dose-tapering Period. 


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p. 
The dose of study medication on the days of the Week 12 and Week 24 Visits will be administered after 1) a fasting blood draw for insulin and glucose; and 2) 
breakfast provided by the study site.  All other doses will be taken at home. 
q. 
Subjects who elect to switch to standard of care glucocorticoids, or discontinue vamorolone and not begin glucocorticoid treatment for DMD at the end of the study 
will have their vamorolone dose tapered at weekly intervals to a dose of 0 mg/kg/day prior to final study assessments. 
r. 
North Star Ambulatory Assessment; includes the Time to Stand Test (TTSTAND). 
s. 
Study medication acceptability assessed immediately before (smell) and after (taste) dosing at the Week 12 and Week 24 Visits. 
t. 
Subject diaries used to record any concomitant medications taken and any AEs experienced during the study. 
u. 
All AEs and SAEs must be collected in the source documents and eCRF from the date of the subject’s written informed consent until the Week 24 Visit or the subject’s 
participation in the study is completed.  Ongoing AEs will be followed to resolution, stabilization, or until such time the Investigator agrees follow-up is not necessary. 
v. 
Subjects who elect to continue vamorolone therapy in a subsequent extension study may be discharged from the study following completion of all final Week 24 
procedures. 
w. Subjects who participate in the Dose-tapering Period may be discharged from the study following completion of all final Dose-tapering Visit assessments. 


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5.2. 
Inclusion – Exclusion Criteria and General Study Population 
All subjects who complete the Week 4 Follow-up assessments in the VBP15-002 study will 
be eligible for enrollment in this VBP15-003 study, provided they meet all VBP15-003 study 
entry criteria (up to 48 subjects total).  The inclusion and exclusion criteria defined in the 
protocol apply to all subjects and are not repeated here in the SAP. 
5.3. 
Randomization and Blinding 
This is an open-label study, and no randomization schedule or blinding of study medication 
is applicable. In the VBP15-002 study, subjects were assigned to dosing cohort sequentially 
on enrollment and screening. 
5.4. 
Analysis Variables 
Variables to be analyzed include demographics and baseline characteristics, safety variables, 
clinical efficacy variables, PD variables, etc. as described throughout this SAP.  Derived 
variables from study endpoints are described with the sections presenting the analyses for 
these endpoints. 
Unless otherwise noted, baseline is defined as the last measurement taken prior to first 
exposure to study drug (Baseline visit of VBP15-002).  
6. 
SAMPLE SIZE 
Eligible subjects are those who enrolled in the VBP15-002 study and have completed up to 
and including the VBP15-002 Follow-up Week 4 study assessments, up to approximately 48 
subjects (n=12 per vamorolone dose group). The VBP15-003 trial is carried out with daily 
dosing.  The comparator group for efficacy consisted of 31 subjects from the CINRG DNHS 
study who met all entry criteria of VBP15-003 and remained untreated through a 24-week 
period.  The comparator group for safety consisted of 14 subjects who met the entry criteria 
of VBP15-003 and received daily prednisone therapy in the CINRG prednisone trial.   
The primary pharmacological safety outcome proposed in the VBP15-003 trial is change in 
BMI z-score. Daily glucocorticoids show a relatively rapid increase in BMI z-score (6 month 
change in non-treated = -0.14; 6 month change in prednisone-treated = +0.54). Vamorolone 
is not anticipated to show an increase in BMI. 
See Section 9.1 of the protocol for full details. 
 


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7. 
GENERAL CONSIDERATIONS 
7.1. 
Analysis Populations 
There will be four (4) analysis populations defined for this study.  
7.1.1. 
Safety Population 
All subjects who receive at least one dose of vamorolone study medication in the VBP15-003 
study will be included in the Safety Population.  The Safety Population is the primary 
analysis population for safety and PD assessments.  This is also the modified Intention to 
Treat (mITT) population. 
7.1.2. 
Full Analysis Set (FAS) 
All subjects who receive at least one dose of vamorolone study medication in the VBP15-003 
study and have at least one post-baseline assessment will be included in the FAS.  The FAS 
is the primary analysis population for efficacy assessments. This is the mITT population, 
with the additional requirement to have at least one post-baseline assessment.  Subjects who 
receive at least one dose of vamorolone but never have post-baseline assessments will be 
excluded. 
7.1.3. 
Control Population DNHS Study 
The control population from the DNHS study will include all study subjects who were 
observed as part of the study in ages ≥ 4 years and <7 years of age at a start of an interval of 
observation and observed for at least one year.  Further, the subjects need to have had at least 
two visits in a time interval of no more than 15 months (e.g., Month 24 and Month 36 of 
observation for a subject who entered at age 2 or 3).  The subject should have been able to 
walk independently without assistive devices at the start of the interval and should have been 
able to complete the TTSTAND.  The subject should not have had any history of disease or 
impairment or medications that would have made him ineligible to receive the vamorolone 
intervention as defined by the VBP15-002 and VBP15-003 study exclusion criteria.  The 
subject should have been glucocorticoid-naïve for the entire interval considered in the control 
population for this study and should not have begun any investigational treatment for the 
interval considered for the control comparison.  Finally, the control intervals to be considered 
should have the study outcomes of TTSTAND, TTCLIMB, TTRW, and QMT measured.  It 
is acceptable if the participant had progressive disease and could not perform a measurement 
at a later point in the interval; this will be imputed as a velocity zero for TTSTAND, 
TTCLIMB, and TTRW. 


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7.1.4. 
Control Population Prednisone Study 
The control population from the prednisone study will include all subjects who were 4 to <7 
years at entry and who were randomized to the daily prednisone arm at the low (daily) dose 
level. 
 
7.2. 
Covariates and Subgroups 
7.2.1. 
Planned Covariates 
Baseline response will be included in the MMRM statistical analyses of BMI.  
Baseline age and response will be included in the MMRM statistical analyses of efficacy 
endpoints.  For the vamorolone subjects, age is calculated as (date of informed consent – 
birthdate)/365.25.  For the prednisone and DNHS subjects, age is calculated as (date of 
Baseline visit used in this study – birthdate)/365.25.  Note that the Baseline visit for a DNHS 
subject is the first visit that the subject meets the comparison eligibility criteria and has a 
non-missing response for at least one endpoint of interest. 
7.2.2. 
Planned Subgroups 
None.   
7.2.3. 
Post hoc Subgroups 
No post-hoc subgroups are initially planned for this study. However, after all planned 
analyses are completed additional post-hoc subgroups may be defined to further explore 
study results. Any additional post-hoc subgroups will be fully detailed in the final CSR. 
 
7.3. 
Management of Analysis Data 
7.3.1. 
Data Handling 
For the summary of continuous values and laboratory shift tables, unscheduled tests will be 
included with the time of the nearest regularly scheduled test.  If there is a scheduled test and 
one or more unscheduled tests assigned to the same time point, the most conservative test 
(i.e., a test with low or high results) will be used.  Repeated tests will be included only if they 
reflect abnormal (low or high) results and the corresponding original results are normal. All 
laboratory values, for all visits, will be provided in by-subject listings. 
Scheduled visits will be utilized for all analyses for data collected in the VBP15-003 study.  
The historical control data will be handled as follows: 


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CINRG DNHS (historical untreated controls):  TTSTAND, TTRW, TTCLIMB using 
scheduled visits (baseline, 3 months (used for Week 12), and 6 months (used for Week 24)). 
CINRG Prednisone trial: BMI z-score using scheduled visits (baseline, 3 months (used for 
Week 12), and 6 months (used for Week 24)). 
7.3.2. 
Missing Data 
Every effort will be made to collect all data. However, despite best efforts, missing or 
incomplete data may be reported. All missing or partial data will be presented in the subject 
data listing, as they are recorded on the eCRF. 
Subjects lost to follow-up or withdrawn will be included in statistical presentations up to the 
point of their last evaluation. Unless otherwise specified, in general no imputation of values 
for missing data will be performed. 
7.3.2.1. 
Handling of Missing Date Values 
Partial or Missing Dates/Times 
The following conventions will be used to impute missing portions of dates for adverse events 
and concomitant medications, if warranted.  Note that the imputed values outlined here may 
not always provide the most conservative date.  In those circumstances, the imputed value may 
be replaced by a date that will lead to a more conservative analysis. 
A. 
Start Dates 
1) 
If the year is unknown, then the date will not be imputed and will 
be assigned a missing value.  
2) 
If the month is unknown, then: 
i) If the year matches the first dose date year, then impute 
the month and day of the first dose date. 
ii) Otherwise, assign ‘January.’  
3) 
 If the day is unknown, then: 
i) If the month and year match the first dose date month 
and year, then impute the day of the first dose date. 
ii) Otherwise, assign the first day of the month. 
B. 
Stop Dates 
1) 
If the year is unknown, then the date will not be imputed and will 
be assigned a missing value. 
2) 
If the month is unknown, then assign ‘December.’ 
3) 
If the day is unknown, then assign the last day of the month. 
 


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For AEs, partial or missing times will be imputed in the following manner: 
A. 
Start Times 
1) 
Day 1:  
i) If hour is missing on the CRF, hour will be imputed as 
hour of the first dose.  
ii) If minute is missing on the CRF, minute will be 
imputed as minute of the first dose.  
iii) If hour is missing for both start of the AE and for the 
time of the first dose on the CRF, hour will be imputed 
as 23.  
iv) If minute is missing for both start of the AE and for the 
time of the first dose on the CRF, minute will be 
imputed as 59.  
 
2) 
 Study days other than Day 1: 
i) If hour is missing on the CRF, hour will be imputed as 
00. 
ii) If minute is missing on the CRF, minute will be 
imputed as 00. 
B. 
Stop Times 
1) 
If hour is missing on the CRF, hour will be imputed as 23.  
2)  
If minute is missing on the CRF, minute will be imputed as 59. 
 
7.3.2.2. 
Imputation Methods 
Velocity scores for TTSTAND, TTRW, and TTCLIMB will be imputed as 0 only at the first 
response missing due to disease progression and left missing for the remaining study visits.  
Local lab responses that are missing a normal flag may have it imputed for by-subject 
listings. 
All other data will be observed cases only, without imputation.  
7.3.3. 
Handling of Early Termination Visit Information 
In the event that a subject is terminated early from this study, the early termination (ET) visit 
data will be analyzed at the closest scheduled visit.  If the closest visit has valid data, the 
early termination data will be assigned to the next available visit.  In instances where the next 
scheduled visit is too far in the future, from a clinical perspective, analyses may be presented 


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twice, once with the ET observation assigned to the next available visit, and once with the ET 
observation omitted. 
7.3.4. 
Pooling of Investigational Sites 
The data from all study centers will be pooled together for analyses. 
7.3.5. 
Coding Conventions for Events and Medications 
All adverse events, and medical history will be mapped to the Medical Dictionary for 
Regulatory Activities (MedDRA version 19.0) system for reporting (preferred term and 
system organ class). 
Prior and Concomitant medications will be coded using World Health Organization (WHO) 
Drug classification (Version June 1st, 2017). 
7.3.6. 
Baseline Visits  
Baseline for endpoints is defined as VBP15-002 Baseline or Screening Assessment, 
whichever is closer to the first dose of study medication in VBP15-003:  physical exam 
(VBP15-002 Screening); vital signs (VBP15-002 Baseline); height (VBP15-002 Screening), 
weight and BMI (VBP15-002 Baseline); blood for chemistry, hematology, lipids 
(VBP15-002 Screening); urinalysis by dipstick and microscopic analysis (VBP15-002 
Screening); 12-lead ECG (VBP15-002 Screening); PD biomarkers (VBP15-002 Baseline); 
and timed function tests (QMT, TTRW, TTSTAND, TTCLIMB, NSAA, and 6MWT) 
(VBP15-002 Baseline).  Pediatric Outcomes Data Collection Instrument will use the baseline 
from the VBP15-003 study as these data were not collected in VBP15-002.   
7.3.7. 
Analysis Software 
Data manipulation, tabulation of descriptive statistics, and graphical representations will be 
performed primarily using SAS (release 9.4 or higher) for Windows.  If the use of other 
software is warranted, the final clinical study report will detail what software was used and 
for what purposes. 
7.3.8. 
Study Data 
Study data identified in the schedule for time and events (Table 2) are collected, and source 
verified, on the electronic data capture tool OpenClinica v3.13.  Laboratory data, including 
PD test results, are not collected in the EDC tool and are provided from external laboratories.  
All study data will be formulated into regulatory compliant data sets to provide transparency, 
traceability, and integrity of trial analysis results from the collection source. Observed study 
data will be mapped to the CDISC Study Data Tabulation Model (SDTM) and serve as the 
source data from the trial.  All study analyses will be completed using analysis data sets that 


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are derived from the SDTM and follow the CDISC Analysis Data Model (ADaM) 
architecture.  
The methods for programming the CDISC SDTM and ADaM data sets are described in 
Figure 1. 
Figure 1 
SDTM, ADaM, and TFL Development and Validation 
 
Where: 
1. Development, Validation, and Maintenance of SDTM domains 
2. Development and Validation of Analysis Data Sets (ADaM), with input source the 
appropriate SDTM domains. 
3. Development and Validation of draft and then final Tables, Figures, and Listings 
(TFL), with input data source the SDTM domains and analysis specific ADaM data 
sets and randomization code (RC) applied. 
 


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7.4. 
Planned Study Analyses 
7.4.1. 
Statistical Summaries: Descriptive and Inferential 
All statistical tests will be two-sided and a resultant p-value of less than or equal to 0.05 will 
be considered statistically significant.  All p-values will be rounded to and displayed in four 
decimals.  If a p-value less than 0.0001 occurs, it will be shown in tables as <0.0001. 
Descriptive summaries of variables will be provided where appropriate.  In general, for 
continuous variables, the number of non-missing values (n) and the mean, standard deviation, 
median, minimum, and maximum will be tabulated.  For categorical variables, the counts and 
proportions of each value will be tabulated.   
All collected data will be presented in listings.  Data not subject to analysis according to this 
plan will not appear in any tables or graphs but will be included in the data listings. 
7.4.2. 
Interim Analyses and Data Monitoring 
No interim analyses are planned for this study. 
The DSMB will meet at regular intervals to review all pertinent safety data.  The DSMB may 
request summaries at other points in time.  In addition, the Medical Monitor may request at 
any time that the DSMB review safety data if the Medical Monitor has specific concerns. 
In all cases, data will be compiled by the Coordinating Center and presented to the DSMB in 
a format that allows for complete review of all compiled safety data.  The DSMB can 
recommend to the Sponsor altering or terminating the trial for safety or other study integrity-
related issues. 
The primary safety endpoints that the DSMB will review are safety labs and adverse events.  
Refer to the DSMB charter for complete details. Analysis and reporting of safety endpoint 
information is specified in the DSMB Charter, and not repeated herein. Note that all DSMB 
reports will be included in the final CSR. 
7.4.3. 
Final Analysis 
The final study analysis will be completed following complete enrollment and the database 
locked after all subjects have completed their final follow-up assessments.  Subjects who 
prematurely discontinue from the study prior to Week 24 should complete the Week 24 
procedures at the time of early discontinuation and enter the 4-week Dose-tapering Period.   
7.5. 
Multiple Testing Procedures 
No adjustments for multiplicity on inferential statistics will be presented in this SAP. 
 


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8. 
SUMMARY OF STUDY DATA 
8.1. 
Subject Summary Grouping 
In general, and unless otherwise noted, summaries of VBP15-003 data will be presented by 
study cohort: Dose Group 1 0.25 mg/kg/day, Dose Group 2 0.75 mg/kg/day, Dose Group 3 
2.0 mg/kg/day, or Dose Group 4 6.0 mg/kg/day. Data from the untreated and prednisone-
treated DMD historical control studies will be presented in separate columns when the data 
align with the VBP15-003 data. 
8.2. 
Subject Disposition 
The number of subjects at each cohort dose level, and the compliance and completion rates of 
dosing at each dose level will be summarized.  The number of discontinuations (if any) and 
reason for discontinuation will be summarized by dose level group. 
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be presented. 
8.3. 
Protocol Deviations 
A summary listing of protocol deviations will be provided by dose level group and by study 
site.  
All protocol deviations will be presented in a by-subject data listing.  
8.4. 
Demographics and Baseline Characteristics  
Subject demographics (age, race, and ethnicity) and baseline characteristics (height, weight, 
body mass index [BMI] and BMI percentile (see Appendix13.4 for a description and example 
of BMI percentile calculation given BMI score; see Centers for Disease Control and 
Prevention [CDC] webpage https://www.cdc.gov/growthcharts/percentile_data_files.htm for 
a detailed discussion on the derivation of the computational algorithm), and months/years 
since DMD diagnosis) are collected in VBP15-002 and will be displayed descriptively from 
this preceding study.  
All demographic and baseline information will be listed by subject. 
8.5. 
Medical History 
Subject medical, surgical, medication and treatment history were collected during the 
screening phase for the VBP15-002 study; interim medical history will be collected on 
Day -1 of the VBP15-003 study and will be merged with the initial VBP15-002 medical 
history data. The dates and descriptions of past events will be documented in source 


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documents and captured in the relevant eCRF.  Medical history will be coded using the 
MedDRA (version 19.0).  
Subject medical history data will be presented in a by-subject listing. 
8.6. 
Prior and Concomitant Medications  
A categorical summary of all prior and concomitant medications taken during the course of 
the study will be presented in tabular form by therapeutic drug class and generic drug name 
(brand name where generic name is unavailable) using the World Health Organization 
(WHO) Drug classification (June 1st, 20a7).   
All prior and concomitant medications will be detailed in the subject data listings. 
A concomitant medication is defined as any medication taken on or after the day of first 
exposure to study drug in the VBP15-003 study through the Dose-tapering Period ending on 
Week 29. 
Prior medications are defined as any changes in non-study medication/therapy, including 
administration of new medication(s), change of dose, or discontinuation of medication, that 
occur after completion of the VBP15-002 core study Week 4 assessments and prior to 
administration of the first dose of study medication in the VBP15-003 study.  Medications 
that start during the VBP15-002 study will be considered prior medications for the 
VBP15-003 study.  
All prior and concomitant medications will be presented in by-subject listings. 
8.7. 
Treatment Compliance and Study Drug Exposure 
Descriptive statistics (n, mean, median, min, max) for treatment compliance percentage will 
be summarized.   
A summary table will also include number and percentage of subjects with overall (Weeks 1-
24) treatment compliance 80-120% by dose level group.  The denominator for the treatment 
compliance calculation will be the number of subjects with reliable treatment compliance 
data. Treatment compliance is calculated as described in the equations below and following 
examples:  
Total scheduled dose (in mL) is calculated as subject weight (kg) at the dispensing visit x 
assigned daily dose in mg/kg/day x days in the dosing interval ÷ 40 mg/mL for each dosing 
interval (Day 1 through Week 12 and Week 12 through Week 24), using the following 
conventions:   
The actual visit dates for the Day 1, Week 12, and Week 24 visits will be used to calculate 
the number of days a subject should have been on a scheduled dose. The dispensed and 


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returned bottle dates will NOT be used as there are instances where they do not match the 
visit dates of interest.   
As an example, assume a subject weighed 15 kg at the start of the study and 18 kg at 
12 weeks and was to receive 2 mg/kg/day every day over each of the dosing intervals (dosing 
interval is the actual number of days between the Day 1 visit and the Week 12 visit, 
inclusive, and the actual number of days between the day after the Week 12 visit and the 
Week 24 visit, inclusive). Assume for this subject the actual number of days in the first 
dosing interval is 80 and in the second dosing interval is 82. For the Day 1 to Week 12 
interval, total scheduled mL in the dosing interval = (15 kg x 2.0 mg/kg/day x 80 days ÷ 
40 mg/mL) = 60 mL, and for the Week 12 to Week 24 interval, total scheduled mL in the 
dosing interval = (18 kg x 2.0 mg/kg/day x 82 days ÷ 40 mg/mL) = 73.8 mL. The total 
scheduled mL overall is 133.8 mL. 
Actual total dose taken in mL is calculated as (dispensed volume) – (returned volume). 
For illustrative purposes, assume the subject was dispensed 2 bottles (each bottle is filled 
with 110 mL) which gives the dispensed volume of 220 mL, and returned 100 mL.   The 
actual total dose taken = 120 mL. (Note that treatment compliance will not be calculated if 
any bottle is not returned or amount returned is not recorded for any bottle). 
% Compliance is calculated as actual total dose taken in mL ÷ total scheduled mL (Day 1 to 
Week 12 scheduled mL + Week 12 to Week 24 scheduled mL). 
In this example, % compliance is 120 mL ÷ 133.8 mL = 89.7.1% for Overall Compliance. 
Descriptive statistics (n, mean, median, min, max) for total study drug exposure (mg) (Weeks 
1 to 24) will be summarized.  Total exposure (mg) is calculated as a subject’s assigned daily 
actual total dose taken in mL x 40 mg/mL. 
Dosing compliance data, including a flag to indicate a percentage between 80% and 120%, 
and total exposure (mg) will be presented in by-subject listings.  
   
9. 
EFFICACY ANALYSES  
The evaluations of clinical efficacy will be performed using the FAS for VBP15-003 study 
subjects (including VBP15-002 baseline data), and the control populations from the DNHS 
study.  Data will be summarized by planned treatment. 
The primary efficacy outcome is TTSTAND velocity. The descriptive summaries will 
include continuous descriptive statistics on observed values and change from VBP15-002 
baseline values at each time point by dose level.    


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TTSTAND velocity change from baseline (VBP15-002 baseline) results will be compared 
between vamorolone dose groups and historical untreated controls (CINRG DNHS) using a 
restricted maximum likelihood (REML)-based mixed model for repeated measures (MMRM) 
analysis with treatment group, week of the visit, and the treatment-by-week interaction as 
factors, and age at study entry and baseline response as covariates.  Week will be included in 
the model as a categorical variable (Week 12 and 24) along with the treatment-by-week 
interaction.  An unstructured within-subject covariance matrix will be used.  If this analysis 
fails to converge, Akaike’s information criterion will be used to select the best covariance 
structure from compound symmetry and autoregressive-1 (AR(1)).  The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom.  The primary 
treatment comparison will be the LS means contrasts between the dose groups and historical 
untreated controls (CINRG DHNS) at Week 24. Additional exploratory analyses will include 
pairwise comparisons between the 4 vamorolone dose groups within the VBP15-003 trial 
(0.25 mg/kg/day, 0.75 mg/kg/day, 2.0 mg/kg/day, and 6.0 mg/kg/day). 
The same approach described for TTSTAND velocity will be taken for TTSTAND raw, 
TTRW velocity and raw, and TTCLIMB velocity and raw; 6MWT, except no comparison to 
DNHS will be done; NSAA total score (note that NSAA total score is only calculated if all 
subscores are non-missing), except no comparison to DNHS will be done; and QMT. The 
QMT measurements will be done unilaterally using the dominant side, if known. For each 
muscle group (knee extension/flexion, elbow extension/flexion) the better of two collected 
test results at each visit will be summarized.   
For TTSTAND, TTRW, and TTCLIMB, results will also be converted to velocities and 
analyzed as described above using the following transformation formulas: 
• TTSTAND velocity = 1 / TTSTAND and is expressed as rises/sec. 
 
• TTCLIMB velocity = 1 / TTCLIMB and is expressed as tasks/sec. 
• TTRW velocity = 10 / TTRW and is expressed as meters/sec.   
Subject data reliability over testing visits may be explored if necessary and would be 
presented in the CSR as post hoc.      
All efficacy data will be presented in by-subject listings. 
10. 
SAFETY ANALYSES 
Safety analyses will be performed using the Safety Population and will be completed using 
the actual treatment a subject received and will address the primary objective of the study. 
All safety data will be presented in by-subject listings as well as in tables and figures as 
described below. 


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10.1. 
Adverse Events  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 19.0.   
Treatment-emergent adverse events (TEAEs) are defined as any adverse event or worsening 
of an existing condition after initiation of the investigational product and through the 
subject’s last study visit (study completion or early termination).  Serious adverse events will 
be recorded from the date of informed consent, throughout the clinical trial, and for up to 30 days 
after the final administration of study drug.  If the onset of an AE is on Day 1 and its 
relationship to time of study drug administration is unknown, then the AE will be counted as 
treatment-emergent.  If the onset of the AE is on Day 1 but is known to have onset prior to 
the time of the first administration of study drug, the AE will not be considered treatment-
emergent. 
Adverse events that start during the VBP15-002 study and are ongoing at the end of the 002 
study will be placed in the Interim Medical History CRF for the VBP15-003 study−they will 
not be presented as AEs in the VBP15-003 study unless they worsen during the VBP15-003 
study, in which case they would be treated as new AEs. Similarly, events that occur after the 
VBP15-002 study and before initiation of the investigational product for the VBP15-003 
study will be counted as medical history in the VBP15-003 study. 
The number and percent of subjects with any TEAEs will be summarized by system organ 
class and preferred term by dose level (and overall).  At each level of tabulation (e.g., at the 
preferred term level) subjects will be counted only once if they had more than one such event 
reported during the AE collection period. 
 
Level of intensity will be assessed using the CTCAE grading.  
The following summary tables and subject level listings will be presented for TEAE data:  
• 
Overall summary of TEAEs  
• 
Summary table of TEAE by descending incidence by PT 
• 
Summary table of TEAEs by SOC and PT  
• 
Summary table of serious TEAEs by SOC and PT  
• 
Summary table of TEAEs by maximum relatedness to treatment by SOC and PT  
• 
Summary table of TEAEs by maximum intensity by SOC and PT 
• 
Summary table of TEAEs leading to study drug discontinuation by SOC and PT 
• 
Summary table of TEAEs by worst outcome (recovered/resolved vs. 
recovering/resolving vs. not recovered/not resolved vs. recovered/resolved with 
sequelae vs. fatal vs. unknown) by SOC and PT   
• 
Table listing of SAEs 
• 
Table listing of related SAEs 


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• 
Table listing of all AEs leading to death 
• 
Table listing of all AEs leading to study discontinuation 
 
10.2. 
Vital Signs, 12-Lead ECG, and Laboratory Outcomes  
Vital signs, including height, weight and BMI and BMI z-score, clinical laboratory test 
results, and other laboratory test results not detailed elsewhere in this SAP will be 
summarized at each time point by dose level (and overall) using descriptive statistics and 
presented for observed response as well as change from baseline.  Descriptive statistics will 
include the typical statistics for continuous endpoints described in this SAP as well as 
interquartile range.   
The primary safety variable will be BMI z-score.  BMI z-score change from baseline 
(VBP15-002 baseline) results will be compared between vamorolone dose groups and daily 
prednisone treated subjects (CINRG prednisone trial) using a restricted maximum likelihood 
(REML)-based mixed model for repeated measures (MMRM) analysis with treatment group, 
week of the visit, and the treatment-by-week interaction as factors, and baseline response as a 
covariate.  Week will be included in the model as a categorical variable (Week 12 and 24) 
along with the treatment-by-week interaction.  An unstructured within-subject covariance 
matrix will be used.  If this analysis fails to converge, Akaike’s information criterion will be 
used to select the best covariance structure from compound symmetry and autoregressive-1 
(AR(1)).  The Kenward-Roger approximation will be used to estimate denominator degrees 
of freedom.  The primary treatment comparison will be the LS means contrasts between the 
vamorolone dose groups and daily prednisone treated subjects (CINRG prednisone trial) at 
Week 24. Additional exploratory analyses will include pairwise comparisons between the 4 
vamorolone dose groups within the VBP15-003 trial (0.25 mg/kg/day, 0.75 mg/kg/day, 2.0 
mg/kg/day, and 6.0 mg/kg/day). 
Change from baseline in continuous clinical laboratory test results will be tested using one-
sample t-tests within each vamorolone treatment group.  Clinical laboratory test results will 
also be presented in shift tables for all laboratory parameters where low/normal/high or 
abnormal/normal status can be ascertained.  Abnormal clinical lab test results will be 
presented in a table listing where low/normal/high or abnormal/normal status can be 
ascertained. 
Except for lab results, data gathered at unscheduled visits will not be summarized but will be 
included in by-subject data listings.  See Section 7.3.1 for unscheduled or repeated lab tests. 
Lab results will be presented using U.S. conventional units.  
For by-subject listings, normal/abnormal flags will be imputed on local lab data only if the 
normal flag is missing and both a lower and upper normal range are provided in the raw data 


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for the observation so that the lab response can be assessed as normal or abnormal depending 
on whether it falls within the provided normal range. 
Also, for by-subject listings, clinically significant response (yes/no) will only be presented in 
the listings for local labs if the response is abnormal. 
Overall ECG interpretation will be summarized categorically by assessment response and via 
shift table presenting Normal/Abnormal Not Clinically Significant/Abnormal Clinically 
Significant and will also be presented in subject listings. 
10.3. 
Physical Exam  
CRF physical exam results will be presented in by-subject listings. 
 
10.4. 
Other Safety Measures 
Acceptability of the study medication will be assessed using a 5-point hedonic scale 
immediately before (smell) and after (taste) dosing at the Week 12 and Week 24 Visits. Drug 
acceptability will be summarized descriptively as a continuous endpoint by study cohort at 
each time point collected and presented in a by-subject listing. 
Quality of life will be assessed by completion of the Pediatric Outcomes Data Collection 
Instrument (PODCI). Two subscales (Upper Extremity and Physical Function; Transfer and 
Basic Mobility) will be summarized descriptively as a continuous endpoint by study cohort at 
each time point collected.  Observed scores and change from baseline will be presented. 
Standardized scores will be used for the analyses.  All PODCI data will be presented in a 
by-subject listing. 
11. 
PHARMACODYNAMIC (PD) SERUM AND OTHER 
BIOMARKERS 
The evaluations of PD will be performed using the Safety Population. The baseline values 
will come from the baseline assessment in the VBP15-002 study.   
The descriptive summaries will include continuous descriptive statistics on observed, change 
from baseline, and percent change from baseline responses at each time point by dose level.  
Continuous descriptive statistics will be provided along with interquartile range.  Percentage 
change is defined as 100*(change from baseline/baseline).  One sample t-tests will be 
provided to test if the change from baseline mean values are different from zero within the 
vamorolone dose groups. 
PD biomarker change from baseline (VBP15-002 baseline) results will be analyzed using 
restricted maximum likelihood (REML)-based mixed models for repeated measures 


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(MMRM) analysis with treatment group, week of the visit, and the treatment-by-week 
interaction as factors, and age at study entry and baseline response as a covariate.  Week will 
be included in the model as a categorical variable (Week 8, 12, 16, and/or 24) along with the 
treatment-by-week interaction.  An unstructured within-subject covariance matrix will be 
used.  If this analysis fails to converge, Akaike’s information criterion will be used to select 
the best covariance structure from compound symmetry and autoregressive-1 (AR(1)).  The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom.  
Pairwise comparisons of LS means between the 4 vamorolone dose groups within the 
VBP15-003 trial (0.25 mg/kg/day, 0.75 mg/kg/day, 2.0 mg/kg/day, and 6.0 mg/kg/day) will 
be presented. 
All PD biomarker data will be presented in by-subject listings.  The listings will include 
normal range data, where available.  Furthermore, a listing of out of range observations will 
be presented. 
SomaScan data, if available, will be presented in an addendum report. 
Proteomics profiling data will be collected for potential analysis in future studies. These data 
will not be included in any by subject listing or in the CSR for this study. Any analysis of the 
proteomics profiling information will be reported in separate reports. 
12. 
REPORTING CONVENTIONS 
The following reporting conventions will be adopted for the presentation of study data.  
These conventions will enhance the review process and help to standardize presentation with 
common notations 
12.1. 
General Reporting Conventions  
• 
All tables and data listings will be developed in Landscape Orientation, unless 
presented as part of the text in a CSR. 
• 
Figures will be presented in Landscape Orientation, unless presented as part of 
the text in a CSR. 
• 
Legends will be used for all figures with more than one variable or item 
displayed. 
• 
Figures will be in presented in color with treatment groups distinguished by 
different symbols and colors.  Lines in figures should be wide enough to view 
the line after being photocopied.  
• 
Specialized text styles, such as bolding, italics, borders, shading, superscripted 
and subscripted text will not be used in tables, figures, and data listings unless 
they add significant value to the table, figure, or data listing.  


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• 
Only standard keyboard characters should be used in tables and data listings. 
Special characters, such as non-printable control characters, printer specific, 
or font specific characters, will not be used on a table, figure, or data listing.  
Hexadecimal character representations are allowed (e.g.,µ,α,β). 
• 
All titles will be centered on a page.  The ICH numbering convention is to be 
used for all tables, figures, and data listings. 
• 
All footnotes will be left justified and the bottom of a page.  Footnotes must 
be present on the page where they are first referenced.  Footnotes should be 
used sparingly and must add value to the table, figure, or data listing.  If more 
than four footnote lines are planned then a cover page may be used to display 
footnotes. 
• 
Missing values for both numeric and character variables will be presented as 
blanks in a table or data listing.  A zero (0) may be used if appropriate to 
identify when the frequency of a variable is not observed. 
• 
All date values will be presented as YYYY-MM-DD (e.g., 2013-05-17) ISO 
8601 format. 
• 
All observed time values will be presented using a 24-hour clock HH:MM:SS 
format (e.g., 01:35:45 or 11:26).  Seconds should only be reported if they 
were measured as part of the study, also in ISO 8601 format. 
• 
Time durations will be reported in mixed HHh MMm SSs notation (e.g., 5h 
32m, or 27h 52m 31s).  The use of decimal notation to present (display) time 
durations should be avoided (e.g. 0.083h = 5m) unless it is necessary to show 
the computation of time differences in a table, figure, or data listing, in which 
case both notations may be used to display the time duration.  
• 
All tables, figures, and data listings will have the Table, Listing, or Graph 
status (DRAFT, FINAL), and a date/time stamp on the bottom of each output.  
• 
All analysis programs developed for a table, figure, or data listing display will 
be self-contained to facilitate transfer of programs to multiple computing 
environments and transfer to a regulatory agency (if requested).  
11.1 
Population Summary Conventions 
• 
Population(s) represented on the tables or data listings will be clearly 
identified in the last title of the Table as “Population: <name of population>” 
and will be identical in name to that identified in the protocol or SAP. 
• 
Consistent terminology will be used to define and identify a population.   
• 
Sub-population(s) or special population(s) descriptions will provide sufficient 
detail to ensure comprehension of the population (e.g., FAS Females, Per-
Protocol Males >60 years of age) used for analysis in a table or figure. 


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• 
Population sizes may be presented for each treatment or dosing category as 
totals in the column header as (N=xxxx), where appropriate.  
• 
Population sizes shown with summary statistics are the samples sizes (n) of 
subjects with non-missing values.  
• 
All population summaries for categorical variables will include all categories 
that were planned and for which the subjects may have had a response. 
Percentages corresponding to null categories (cells) will be suppressed.    
• 
All population summaries for continuous variables will include: N, mean, SD, 
median, minimum, and maximum.  Other summaries (e.g. number missing, 
quartiles, 5%, 95% intervals, CV or %CV) may be used as appropriate. 
• 
All percentages are rounded and reported to xx.x%. A percentage of 100% 
will be reported as 100%.  For categorical summaries presenting “n (%)”, a 
count of 0 will be presented as “0”.  For continuous results, an estimated % of 
0 will be presented as “0%”.  
• 
Population summaries that include p-values will report the p-value to 
four decimal places with a leading zero (e.g., 0.0001).  All p-values reported 
on default output from statistical software (i.e., SAS® Software version 9.2 or 
later) may be reported at the default level of precision.  P-values <0.0001 
should be reported as <0.0001 not 0.0000. 
 
12 
REFERENCES 
Bello L, Gordish-Dressman H, Morgenroth LP, Henricson EK, Duong T, Hoffman EP, 
Cnaan A, McDonald CM; CINRG Investigators. Prednisone/prednisolone and deflazacort 
regimens in the CINRG Duchenne Natural History Study. Neurology. 2015 Sep 
22;85(12):1048-55. doi: 10.1212/WNL.0000000000001950. Epub 2015 Aug 26. PubMed 
PMID: 26311750; PubMed Central PMCID: PMC4603595. 
 
Bello L, Morgenroth LP, Gordish-Dressman H, Hoffman EP, McDonald CM, Cirak S; 
CINRG investigators. DMD genotypes and loss of ambulation in the CINRG Duchenne 
Natural History Study. Neurology. 2016 Jul 26;87(4):401-9. doi: 
10.1212/WNL.0000000000002891. Epub 2016 Jun 24. PubMed PMID: 27343068; PubMed 
Central PMCID: PMC4977110. 
 
Bello L, Flanigan KM, Weiss RB; United Dystrophinopathy Project, Spitali P,Aartsma-Rus 
A, Muntoni F, Zaharieva I, Ferlini A, Mercuri E, Tuffery-Giraud S, Claustres M, Straub V, 
Lochmüller H, Barp A, Vianello S, Pegoraro E, Punetha J, Gordish-Dressman H, Giri M, 
McDonald CM, Hoffman EP; Cooperative International Neuromuscular Research Group. 
Association Study of Exon Variants in the NF-κB and TGFβ Pathways Identifies CD40 as a 


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Modifier of Duchenne Muscular Dystrophy. Am J Hum Genet. 2016 Nov 3;99(5):1163-1171. 
doi: 10.1016/j.ajhg.2016.08.023. Epub 2016 Oct 13. PubMed PMID: 27745838; PubMed 
Central PMCID: PMC5097949. 
 
Escolar DM, Henricson EK, Pasquali L, Gorni K, Hoffman EP. Collaborative 
translational research leading to multicenter clinical trials in Duchenne 
muscular dystrophy: the Cooperative International Neuromuscular Research Group 
(CINRG). Neuromuscul Disord. 2002 Oct;12 Suppl 1:S147-154. 
 
ICH E9 Expert Working Group. Statistical Principles for Clinical Trials: ICH Harmonized 
Tripartite Guideline, September 1998 
McDonald CM, Henricson EK, Abresch RT, Duong T, Joyce NC, Hu F, Clemens PR, 
Hoffman EP, Cnaan A, Gordish-Dressman H; CINRG Investigators. Long-term effects of 
glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular 
dystrophy: a prospective cohort study. Lancet. 2018 Feb 3;391(10119):451-461.  


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13 
APPENDICES 
13.1 
List of Planned Tables 
This list of planned tables includes all of the main tables to be presented for the study.  Other 
tables may be presented and will be described in a TLF shell document. 
NUMBER TITLES 
14.1.1.1 
Subject Disposition \ All Subjects 
14.1.2 
Demographic and Baseline Characteristics \ Safety Population 
14.1.4.1 
Prior Medications \ Safety Population 
14.1.4.2 
Concomitant Medications\ Safety Population 
14.2.4.1 
Summary of Time to Stand (TTSTAND) in Seconds \ Full Analysis Set 
14.2.4.1.1 Summary of Time to Stand (TTSTAND) in Seconds - w/o ET\ Full Analysis 
Set 
14.2.4.2 
Summary of Time to Stand (TTSTAND) Velocity in Rises/Second \ Full 
Analysis Set 
14.2.4.2.1 Summary of Time to Stand (TTSTAND) Velocity in Rises/Second - w/o ET\ 
Full Analysis Set 
14.2.4.3 
Time to Stand (TTSTAND) in Seconds Change from Baseline at Week 12 and 
Week 24 - MMRM Analysis\ Full Analysis Set 
14.2.4.3.1 Time to Stand (TTSTAND) in Seconds Change from Baseline at Week 12 and 
Week 24 - w/o ET - MMRM Analysis\ Full Analysis Set 
14.2.4.4 
Time to Stand (TTSTAND) Velocity in Rises/Second Change from Baseline at 
Week 12 and Week 24 - MMRM Analysis\ Full Analysis Set 
14.2.4.4.1 Time to Stand (TTSTAND) Velocity in Rises/Second Change from Baseline at 
Week 12 and Week 24 - w/o ET - MMRM Analysis\ Full Analysis Set 
14.2.5.1 
Summary of Time to Climb (TTCLIMB) in Seconds\ Full Analysis Set 


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14.2.5.1.1 Summary of Time to Climb (TTCLIMB) in Seconds - w/o ET\ Full Analysis 
Set 
14.2.5.2 
Summary of Time to Climb (TTCLIMB) Velocity in Tasks/Second \ Full 
Analysis Set 
14.2.5.2.1 Summary of Time to Climb (TTCLIMB) Velocity in Tasks/Second - w/o ET\ 
Full Analysis Set 
14.2.5.3 
Time to Climb (TTCLIMB) in Seconds Change from Baseline at Week 12 and 
Week 24 - MMRM Analysis\ Full Analysis Set 
14.2.5.3.1 Time to Climb (TTCLIMB) in Seconds Change from Baseline at Week 12 and 
Week 24 - w/o ET - MMRM Analysis\ Full Analysis Set 
14.2.5.4 
Time to Climb (TTCLIMB) Velocity in Tasks/Second Change from Baseline at 
Week 12 and Week 24 - MMRM Analysis \ Full Analysis Set 
14.2.5.4.1 Time to Climb (TTCLIMB) Velocity in Tasks/Second Change from Baseline at 
Week 12 and Week 24 - w/o ET - MMRM Analysis \ Full Analysis Set 
14.2.6.1 
Summary of Time to Run/Walk 10 Meters (TTRW) in Seconds\ Full Analysis 
Set 
14.2.6.1.1 Summary of Time to Run/Walk 10 Meters (TTRW) in Seconds - w/o ET\ Full 
Analysis Set 
14.2.6.2 
Summary of Time to Run/Walk 10 Meters (TTRW) Velocity in Meters/Second\ 
Full Analysis Set 
14.2.6.2.1 Summary of Time to Run/Walk 10 Meters (TTRW) Velocity in Meters/Second 
- w/o ET\ Full Analysis Set 
14.2.6.3 
Time to Run/Walk 10 Meters (TTRW) in Seconds Change from Baseline at 
Week 12 and Week 24 - MMRM Analysis\ Full Analysis Set 
14.2.6.3.1 Time to Run/Walk 10 Meters (TTRW) in Seconds Change from Baseline at 
Week 12 and Week 24 - w/o ET - MMRM Analysis\ Full Analysis Set 
14.2.6.4 
Time to Run/Walk 10 Meters (TTRW) Velocity in Meters/Second Change from 
Baseline at Week 12 and Week 24 - MMRM Analysis\ Full Analysis Set 


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14.2.6.4.1 Time to Run/Walk 10 Meters (TTRW) Velocity in Meters/Second Change from 
Baseline at Week 12 and Week 24 - w/o ET - MMRM Analysis\ Full Analysis 
Set 
14.2.7.1 
Summary of 6 Minute Walk Test (6MWT) in Meters\ Full Analysis Set 
14.2.7.1.1 Summary of 6 Minute Walk Test (6MWT) in Meters - w/o ET\ Full Analysis 
Set 
14.2.7.2 
Summary of 6 Minute Walk Test (6MWT) in Meters - MMRM Analysis\ Full 
Analysis Set 
14.2.7.2.1 Summary of 6 Minute Walk Test (6MWT) in Meters - w/o ET - MMRM 
Analysis\ Full Analysis Set 
14.2.8.1  
Summary of Quantitative Muscle Testing (QMT) Elbow Flexors in Pounds\ 
Full Analysis Set 
14.2.8.2  
Summary of Quantitative Muscle Testing (QMT) Elbow Extensors in Pounds \ 
Full Analysis Set 
14.2.8.3 
Summary of Quantitative Muscle Testing (QMT) Knee Flexors in Pounds \ Full 
Analysis Set 
14.2.8.4 
Summary of Quantitative Muscle Testing (QMT) Knee Extensors in Pounds \ 
Full Analysis Set 
14.2.8.5 
Quantitative Muscle Testing (QMT) Elbow Flexors in Pounds Change from 
Baseline at Week 12 and Week 24 - MMRM Analysis\ Full Analysis Set 
14.2.8.6 
Quantitative Muscle Testing (QMT) Elbow Extensors in Pounds Change from 
Baseline at Week 12 and Week 24 - MMRM Analysis\ Full Analysis Set 
14.2.8.7 
Quantitative Muscle Testing (QMT) Knee Flexors in Pounds Change from 
Baseline at Week 12 and Week 24 - MMRM Analysis\ Full Analysis Set 
14.2.8.8 
Quantitative Muscle Testing (QMT) Knee Extensors in Pounds Change from 
Baseline at Week 12 and Week 24 - MMRM Analysis\ Full Analysis Set 
14.2.9.1  
Summary of North Star Ambulatory Assessment (NSAA) Total Score \ Full 
Analysis Set 
14.2.9.2 
Summary of North Star Ambulatory Assessment (NSAA) Total Score - MMRM 
Analysis\ Full Analysis Set 


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14.2.10.1 
Summary of Pharmacodynamic Parameters - Bone Turnover\ Safety Population 
14.2.10.1.1 Summary of Pharmacodynamic Parameters - Bone Turnover - w/o ET \ Safety 
Population 
14.2.10.2 
Summary of Pharmacodynamic Parameters - Adrenal Axis Suppression Mass 
Spectrometry\ Safety Population 
14.2.10.2.1 Summary of Pharmacodynamic Parameters - Adrenal Axis Suppression Mass 
Spectrometry - w/o ET \ Safety Population 
14.2.10.3 
Summary of Pharmacodynamic Parameters - Insulin Resistance \ Safety 
Population 
14.2.10.3.1 Summary of Pharmacodynamic Parameters - Insulin Resistance - w/o ET \ 
Safety Population 
14.2.10.4 
Summary of Pharmacodynamic Parameters - Bone Turnover - MMRM 
Analysis\ Safety Population 
14.2.10.4.1 Summary of Pharmacodynamic Parameters - Bone Turnover - w/o ET - 
MMRM Analysis\ Safety Population 
14.2.10.5 
Summary of Pharmacodynamic Parameters - Adrenal Axis Suppression Mass 
Spectrometry - MMRM Analysis\ Safety Population 
14.2.10.5.1 Summary of Pharmacodynamic Parameters - Adrenal Axis Suppression Mass 
Spectrometry - w/o ET - MMRM Analysis\ Safety Population 
14.2.10.6 
Summary of Pharmacodynamic Parameters - Insulin Resistance - MMRM 
Analysis\ Safety Population 
14.2.10.6.1 Summary of Pharmacodynamic Parameters - Insulin Resistance - w/o ET - 
MMRM Analysis\ Safety Population 
14.3.1 
Study Drug Exposure\ Safety Population 
14.3.1.1 
Overall Summary of Adverse Events \ Safety Population 
14.3.1.2 
Summary of Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term\ Safety Population 
14.3.1.3 
Summary of Treatment Emergent Adverse Events by Descending Incidence of 
Preferred Term\ Safety Population 


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14.3.1.4 
Summary of Serious Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term\ Safety Population 
14.3.1.5 
Summary of Treatment Emergent Adverse Events by Maximum Relatedness to 
Treatment by System Organ Class and Preferred Term\ Safety Population 
14.3.1.6 
Summary of Treatment Emergent Adverse Events by Maximum Severity by 
System Organ Class and Preferred Term\ Safety Population 
14.3.1.7 
Summary of Treatment Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term\ Safety Population 
14.3.1.8 
Summary of Treatment Emergent Adverse Events by Worst Outcome by 
System Organ Class and Preferred Term\ Safety Population 
14.3.2.1 
Table Listing of Serious Treatment Emergent Adverse Events\ Safety 
Population 
14.3.2.2 
Table Listing of Related Serious Treatment Emergent Adverse Events \ Safety 
Population 
14.3.2.3 
Table Listing of Treatment Emergent Serious Adverse Events Leading to 
Death\ Safety Population 
14.3.2.4 
Table Listing of Treatment Emergent Adverse Events Leading to Study 
Discontinuation\ Safety Population 
14.3.3.1 
Summary of Laboratory Parameters: Hematology\ Safety Population 
14.3.3.2 
Laboratory Shift from Baseline: Hematology \ Safety Population 
14.3.3.3 
Summary of Laboratory Parameters: Chemistry\ Safety Population 
14.3.3.4 
Laboratory Shift from Baseline: Chemistry \ Safety Population 
14.3.3.5 
Summary of Laboratory Parameters: Urinalysis\ Safety Population 
14.3.3.6 
Laboratory Shift from Baseline: Urinalysis- Random Urine\ Safety Population 
14.3.3.7 
Summary of Laboratory Parameters: Lipid Profile\ Safety Population 
14.3.3.8 
Laboratory Shift from Baseline: Lipid Profile\ Safety Population 
14.3.3.9 
Table Listing of Abnormal Lab Results by Subject and Visit\ Safety Population 


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14.3.3.10 
Table of Normal Laboratory Ranges 
14.3.3.11 
Table of Normal Biomarker Ranges 
14.3.4.1 
Summary of Vital Signs\ Safety Population 
14.3.4.2 
Summary of Anthropometrics\ Safety Population 
14.3.4.3 
Summary of 12-Lead ECG Interpretation\ Safety Population 
14.3.4.4 
12-Lead ECG Interpretation Shift from Baseline\ Safety Population 
14.3.4.5 
Summary of Study Medication Acceptability \ Safety Population  
14.3.4.6 
Summary of Pediatric Outcomes Data Collection Instrument \Safety Population 
14.3.4.7 
Summary of BMI Z-score \ Safety Population 
14.3.4.7.1 Summary of BMI Z-score - w/o ET\ Safety Population 
14.3.4.8 
Summary of BMI Z-score Change from Baseline at Week 12 and Week 24 - 
MMRM Analysis\ Safety Population 
14.3.4.8.1 
Summary of BMI Z-score Change from Baseline at Week 12 and Week 24 - 
w/o ET - MMRM Analysis\ Safety Population 
 


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13.2 
List of Planned Listings 
This list of planned listings includes all of the main listings to be presented for the study.  
Other listings may be presented and will be described in a TLF shell document.  
NUMBER TITLES 
16.2.1 
Subject Disposition \ All Subjects 
16.2.2.1.1 Inclusion/Exclusion Criteria 
16.2.2.1.2 Inclusion/Exclusion Listing\ All Subjects 
16.2.2.2 
Protocol Deviations\ All Subjects 
16.2.4.1 
Demographic and Baseline Information\ All Subjects 
16.2.4.2 
Medical History\ All Subjects  
16.2.4.3 
DMD History\ All Subjects 
16.2.4.4 
Genetic Confirmation by Muscle Biopsy\ All Subjects 
16.2.4.5.1 Genetic Confirmation by DNA\ All Subjects 
16.2.4.5.2 Genetic Confirmation by DNA Continued\ All Subjects 
16.2.5.1 
Study Drug Administration\ All Subjects 
16.2.5.2 
Study Drug Exposure\ All Subjects 
16.2.5.3 
Study Drug Accountability\ All Subjects 
16.2.6.1 
Timed Tests\ All Subjects 
16.2.6.2 
Time to Stand (TTSTAND)\ All Subjects 
16.2.6.3 
Time to Climb (TTCLIMB)\ All Subjects 
16.2.6.4 
Time to Run/Walk (TTRW)\ All Subjects 
16.2.6.5 
Quantitative Muscle Testing (QMT)\ All Subjects 
16.2.6.6 
6 Minute Walk Test (6MWT) Pre-Test\ All Subjects 


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16.2.6.7 
6 Minute Walk Test (6MWT) \ All Subjects 
16.2.6.8 
6 Minute Walk Test (6MWT) Post-Test\ All Subjects 
16.2.6.9 
North Star Ambulatory Assessment (NSAA)\ All Subjects 
16.2.7.1 
Adverse Events\ All Subjects 
16.2.7.2 
Adverse Events by System Organ Class and Preferred Term\ All Subjects 
16.2.7.3 
Serious Adverse Events\ All Subjects 
16.2.7.4 
Serious Adverse Events Leading to Death\ All Subjects 
16.2.8.1 
Hematology Laboratory Evaluations by Subject and Visit\ All Subjects 
16.2.8.2 
Chemistry Laboratory Evaluations by Subject and Visit\ All Subjects 
16.2.8.3 
Urinalysis Laboratory Evaluations by Subject and Visit\ All Subjects 
16.2.8.4 
Biomarker Laboratory Evaluations by Subject and Visit\ All Subjects 
16.2.8.5 
Lipids Laboratory Evaluations by Subject and Visit\ All Subjects 
16.2.8.6 
Laboratory Evaluations collected on the CRF by Subject and Visit\ All Subjects 
16.2.9.1.1 Prior and Concomitant Medications\ All Subjects 
16.2.9.1.2 Prior and Concomitant Medications - Steroids\ All Subjects 
16.2.9.1.3 Concurrent Assistive, Orthotic, Night Splint, and Respiratory Devices\ All 
Subjects 
16.2.9.1.4 Concurrent Occupational and Physical Therapy\ All Subjects 
16.2.9.2 
Vital Signs\ All Subjects 
16.2.9.3 
Physical Examination\ All Subjects 
16.2.9.4.1 12-Lead Electrocardiogram (ECG) Results\ All Subjects 
16.2.9.4.2 12-Lead Electrocardiogram (ECG) Interpretation\ All Subjects 
16.2.10 
Study Drug Acceptability\ All Subjects 


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16.2.11.1 
Pediatric Outcomes Data Collection Instrument (PODCI) - Part 1 (Questions 1-
8)\ All Subjects 
16.2.11.2 
Pediatric Outcomes Data Collection Instrument (PODCI) - Part 2 (Questions 9-
14)\ All Subjects 
16.2.11.3 
Pediatric Outcomes Data Collection Instrument (PODCI) - Part 3 (Questions 
15-25) \ All Subjects 
16.2.11.4 
Pediatric Outcomes Data Collection Instrument (PODCI) - Part 4 (Questions 
26-33) \ All Subjects 
16.2.11.5 
Pediatric Outcomes Data Collection Instrument (PODCI) - Part 5 (Questions 
34-43) \ All Subjects 
16.2.11.6 
Pediatric Outcomes Data Collection Instrument (PODCI) - Part 6 (Questions 
44-51) \ All Subjects 
16.2.11.7 
Pediatric Outcomes Data Collection Instrument (PODCI) - Part 7 (Questions 
52-65) \ All Subjects 
16.2.11.8 
Pediatric Outcomes Data Collection Instrument (PODCI) - Part 8 (Questions 
66-76) \ All Subjects 
16.2.11.9 
Pediatric Outcomes Data Collection Instrument (PODCI) - Part 9 (Questions 
77-86) \ All Subjects 
16.2.11.10 Pediatric Outcomes Data Collection Instrument (PODCI) - Part 10 (Derived 
Standardized Scores) \ All Subjects 
 
 
 


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13.3 
List of Planned Figures 
This list of planned figures includes all of the main figures to be presented for the study.  
Other figures may be presented and will be described in a TLF shell document.  
NUMBER TITLES 
14.2.4.1.1 Time to Stand (TTSTAND) in Seconds\ Full Analysis Set 
14.2.4.1.2 Time to Stand (TTSTAND) Change from Baseline in Seconds\ Full Analysis 
Set 
14.2.4.2.1 Time to Stand (TTSTAND) Velocity \ Full Analysis Set 
14.2.4.2.2 Time to Stand (TTSTAND) Velocity Change from Baseline\ Full Analysis Set 
14.2.5.1.1 Time to Climb (TTCLIMB) in Seconds\ Full Analysis Set 
14.2.5.1.2 Time to Climb (TTCLIMB) Change from Baseline in Seconds\ Full Analysis 
Set 
14.2.5.2.1 Time to Climb (TTCLIMB) Velocity \ Full Analysis Set 
14.2.5.2.2 Time to Climb (TTCLIMB) Velocity Change from Baseline\ Full Analysis Set 
14.2.6.1.1 Time to Run/Walk 10 Meters (TTRW) in Seconds\ Full Analysis Set 
14.2.6.1.2 Time to Run/Walk 10 Meters (TTRW) Change from Baseline in Seconds\ Full 
Analysis Set 
14.2.6.2.1 Time to Run/Walk 10 Meters (TTRW) Velocity \ Full Analysis Set 
14.2.6.2.2 Time to Run/Walk 10 Meters (TTRW) Velocity Change from Baseline\ Full 
Analysis Set 
14.2.7.1.1 6 Minute Walk Test (6MWT) \ Full Analysis Set 
14.2.7.1.2 6 Minute Walk Test (6MWT) Change from Baseline\ Full Analysis Set 
14.2.8.1.1 Quantitative Muscle Testing (QMT) Elbow Flexors \ Full Analysis Set 
14.2.8.1.2 Quantitative Muscle Testing (QMT) Elbow Flexors Change from Baseline\ Full 
Analysis Set 
14.2.8.2.1  Quantitative Muscle Testing (QMT) Elbow Extensors \ Full Analysis Set 


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14.2.8.2.2  Quantitative Muscle Testing (QMT) Elbow Extensors Change from Baseline\ 
Full Analysis Set 
14.2.8.3.1 Quantitative Muscle Testing (QMT) Knee Flexors \ Full Analysis Set 
14.2.8.3.2 Quantitative Muscle Testing (QMT) Knee Flexors Change from Baseline\ Full 
Analysis Set 
14.2.8.4.1 Quantitative Muscle Testing (QMT) Knee Extensors\ Full Analysis Set 
14.2.8.4.2 Quantitative Muscle Testing (QMT) Knee Extensors Change from Baseline\ 
Full Analysis Set 
14.2.9.1.1 North Star Ambulatory Assessment (NSAA) Total Score \ Full Analysis Set 
14.2.9.1.2  North Star Ambulatory Assessment (NSAA) Total Score Change from 
Baseline\ Full Analysis Set 
14.2.10.1.1 Pharmacodynamic Parameters - Bone Turnover\ Safety Population 
14.2.10.1.2 Pharmacodynamic Parameters - Bone Turnover Change from Baseline\ Safety 
Population 
14.2.10.1.3 Pharmacodynamic Parameters - Bone Turnover Change from Baseline by 
Subject\ Safety Population 
14.2.10.2.1 Pharmacodynamic Parameters - Adrenal Axis Suppression Mass Spectrometry\ 
Safety Population 
14.2.10.2.2 Pharmacodynamic Parameters - Adrenal Axis Suppression Mass Spectrometry 
Change from Baseline\ Safety Population 
14.2.10.2.3 Pharmacodynamic Parameters - Adrenal Axis Suppression Mass Spectrometry 
Change from Baseline by Subject\ Safety Population 
14.2.10.3.1 Pharmacodynamic Parameters - Insulin Resistance\ Safety Population 
14.2.10.3.2 Pharmacodynamic Parameters - Insulin Resistance Change from Baseline\ 
Safety Population 
14.2.10.3.3 Pharmacodynamic Parameters - Insulin Resistance Change from Baseline by 
Subject\ Safety Population 
14.3.3.3.1 Serum Creatine Kinase\ Safety Population 


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14.3.3.3.2 Serum Creatine Kinase Change from Baseline\ Safety Population 
14.3.3.3.3 Serum Creatine Kinase Change from Baseline by Subject\ Safety Population 
14.3.4.1.1 Body Mass Index (BMI) \ Safety Population 
14.3.4.1.2 Body Mass Index (BMI) Change from Baseline\ Safety Population 
14.3.4.1.3 Body Mass Index Z-score \ Safety Population 
14.3.4.1.4 Body Mass Index Z-score Change from Baseline\ Safety Population 
 
 
 


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13.4 Calculating BMI Z-Scores 
The following example for computing BMI z-scores given age and sex for children aged 2 to 
20 years uses the computational algorithm presented on the Centers for Disease Control and 
Prevention (CDC) webpage “Percentile Data Files with LMS Values”.   For a detailed 
discussion on the derivation of the computational algorithm and reference materials, visit the 
webpage at https://www.cdc.gov/growthcharts/percentile_data_files.htm. 
To obtain the z-score (Z) for a given BMI measurement X, use the following equation: 
Z= [((X/M)^L) – 1] / (LS), where L≠0 
or 
Z = ln(X/M)/S, where L=0 
where L, M, and S are the values from the BMIAGE.xls reference table (growth chart 8  
linked to on the aforementioned CDC webpage). 
For example, for a 24 month old male (coded sex value = 1) who has a BMI of 17.2864, the 
BMIAGE.xls reference table presents values of L=-2.01118, M=16.57503, and S=0.080592.  
Plugging those parameter values into the Z formula above results in a Z-score of 0.5.  
 
 


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13.5 SAP Amendment Summary of Changes 
Page Number 
Section 
Description of Change