Clinical trial NCT02618408
Conditions: Attention Deficit Hyperactivity Disorder (ADHD)
Sponsor: Supernus Pharmaceuticals, Inc.
Start date: 2016-01-25; Completion date: 2019-10-24
Enrollment: 333 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to demonstrate the efficacy, safety, and tolerability of SPN-810 in the treatment of Impulsive Aggression (IA) in subjects with Attention-Deficit/Hyperactivity Disorder (ADHD) in conjunction with standard ADHD treatment. Approximately 426 subjects aged 6 to 12 years with ADHD and comorbid impulsive aggression will be recruited in this study. The frequency of impulsive aggression behaviors will be assessed as a primary outcome. Additionally, the severity and improvement in impulsive aggression and quality of life measures for the subject and caregiver will be assessed using validated scales.

Detailed description:
This is a multicenter, randomized, double-blind, placebo-controlled, 3-arm, parallel-group study, to assess the efficacy, safety, and tolerability of SPN-810 in the treatment of IA in subjects 6 to 12 years old with ADHD, in conjunction with standard ADHD treatment.

Arms: arm 1: Oral arm 2: Oral arm 3: Oral
Interventions: intervention 1: SPN-810 (18 mg) intervention 2: SPN-810 (36 mg) intervention 3: Placebo
Intervention descriptions: intervention 1: Subjects were randomized to receive SPN-810 low dose (18 mg) twice each day (BID) with or without food, in the morning and in the evening, in addition to the stable dose of the optimized ADHD medication determined from the lead-in period. If initiating treatment before noon, patients should start with the morning dose; if after noon, the evening dose. intervention 2: Subjects were randomized to receive SPN-810 high dose (36 mg) twice each day (BID) with or without food, in the morning and in the evening, in addition to the stable dose of the optimized ADHD medication determined from the lead-in period. If initiating treatment before noon, patients should start with the morning dose; if after noon, the evening dose. intervention 3: Subjects were randomized to receive Placebo twice each day (BID) with or without food, in the morning and in the evening, in addition to the stable dose of the optimized ADHD medication determined from the lead-in period. If initiating treatment before noon, patients should start with the morning dose; if after noon, the evening dose.

Protocol documents:
Prot_000.pdf: 
S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
TI TL E P A G E 
Pr ot oc ol N u m b er:  
8 1 0 P 3 0 1  
Titl e:  
A R a n d o miz e d, D o u bl e -Bli n d, Pl ac e b o -C o ntr oll e d St u dy t o Ev al u at e t h e 
Effic ac y a n d S af ety of M oli n d o n e Hy dr oc hl ori d e Ext e n d e d -R el e as e T a bl ets 
f or t h e Tr e at m e nt of I m p ulsi v e A g gr essi o n i n P e di atric P ati e nts wit h 
Att e nti o n D eficit/ Hy p er activit y  Dis or d er ( A D H D ) i n C o nj u ncti o n wit h 
S t a n d ar d A D H D T r e at m e nt 
S p o ns or:  
S u p er n us P h ar m ac e utic als, I nc.  
  
 
 
 
 
I N D n u m b er: 
1 0 6, 5 1 5  
I nv esti g ati o n al 
M e dici n al Pr o d uct:  
M oli n d o n e Hy dr oc hl ori d e Ext e n d e d -R el e as e T a bl ets (S P N -8 1 0)  
I n dic ati o n: 
Tr e at m e nt of I m p ulsiv e A g gr essi o n i n p ati e nts wit h Att e nti o n 
D eficit/ Hy p er activity  Dis or d er ( A D H D) i n c o nj u ncti o n wit h st a n d ar d A D H D 
tr e at m e nt 
Cli nic al C R O:  
 
 
 
M e dic al M o nit or  
 
 
 
 
                      
 
 
P h as e:  
3  
Pr ot oc ol V ersi o n:  
9 .0  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
R el e as e D at e:  
0 1 N o v  2 0 1 8  
G o o d Cli nic al Pr actic e 
( G C P) St at e m e nt: 
T his st u dy is t o b e p erf or m e d i n f ull c o m pli a nc e wit h I nt er n ati o n al 
C o nf er e nc e o n H ar m o niz ati o n (I C H) G C P a n d all a p plic a bl e l oc al r e g ul ati o ns.  
All r e q uir e d st u dy d oc u m e nt ati o n will b e arc hiv e d as r e q uir e d b y r e g ul at ory 
a ut h oriti es.  
 
I, t h e u n d ersi g n e d, h a v e r e a d t his pr ot oc ol a n d a gr e e t o c o n d uct t his tri al i n acc or d a nc e wit h all 
sti p ul ati o ns of t h e pr ot oc ol a n d i n acc or d a nc e wit h I C H G C P a n d all a p plic a bl e l oc al g ui d eli n es, 
i ncl u di n g t h e D ecl ar ati o n of H elsi n ki a n d all its acc e pt e d a m e n d m e nts t o d at e. 
 
 
 
 
 
 
Pri nci p al I n v esti g at or  
 
Si g n at ur e  
 
D at e  
 
  
 




S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
S U M M A R Y O F C H A N G E S 
T his s u m m ary t a bl e lists all cl arific ati o ns, a d mi nistr ativ e c h a n g es or a m e n d m e nts t o S u p er n us pr ot oc ol 
8 1 0 P 3 0 1. A d diti o ns ar e d e n ot e d by b ol d l ett ers a n d d el eti o ns b y stri k et hr o u g h. 
 
 
S ecti o n  
P a g e  
D escri pti o n of C h a n g e  
R ati o n al e  
C h a n g es t o 8 1 0 P 3 0 1 V 5. 0 D at e d 2 1 D ec 2 0 1 5  
Titl e P a g e  
1  
Pr ot oc ol v ersi o n a n d d at e w as u p d at e d  
A d mi nistr ati v e  
Si g n at ur e 
p a g e  
3  
T h e a ut h ors hi p f or r e vis e d  
F or cl arific ati o n  
S y n o psis  
1 0  
T h e f oll o wi n g w as a d d e d:  
 
 
 
 
 
 
T o u n d erst a n d ex p os ur e 
of m et a b olit es i n 
c hil dr e n 
S y n o psis  
1 1  
T h e f oll o wi n g w as c h a n g e d:  
T ot al s u bj ect d ur ati o n o n st u d y:  A p pr oxi m at el y 1 3  1 0 1 2  
w e e ks  
•  
Pr e -tr e at m e nt p h as e: U p t o 4 5 d a ys  4 6 w e e ks  
o  
Scr e e ni n g p eri o d:  U p t o 3 0 d a ys  2 - 4 w e eks  
o  
B as eli n e p eri o d:  At l e ast 1 5 d a ys  2 w e eks  
T o f acilit at e st u d y 
c o n d uct 
S y n o psis  
1 2  
T h e f oll o wi n g w as a d d e d:  
 
 
 
 
T o u n d erst a n d ex p os ur e 
of m et a b olit es i n 
c hil dr e n 
S y n o psis  
1 3  
T h e f oll o wi n g w as a d d e d:  
 
 
 
 
T o u n d erst a n d ex p os ur e 
of m et a b olit es i n 
c hil dr e n 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 
 
List of 
A b br evi ati o ns  
1 9  
List of A b br e vi ati o ns w as u p d at e d t o i ncl u d e A d v ers e E v e nt 
of S p eci al I nt er est ( A E SI)  
F or cl arific ati o n  
2. 3  
2 5  
T h e f oll o wi n g w as c h a n g e d:  
 
 
 
 
 
 
T o u n d erst a n d ex p os ur e 
of m et a b olit es i n 
c hil dr e n 
3. 2  
2 6  
T h e f oll o wi n g w as c h a n g e d:  
F oll o wi n g scr e e ni n g, eli gi bl e s u bj ects will e nt er a t w o w e ek  
fl e xi bl e b as eli n e p eri o d, at w hic h ti m e t h e I A di ar y will b e 
iss u e d t o t h e s u bj ect’s pri m ar y c ar e gi v er.  At t h e e n d of t h e 
t w o w e e k  b as eli n e p eri o d, eli gi bl e s u bj ects w h os e pri m ar y 
c ar e gi v er h as m ai nt ai n e d at l e ast 8 0 % c o m pli a nc e wit h t h e I A 
di ar y will b e r a n d o miz e d 1: 1: 1 t o 1 8  m g/ d a y S P N -8 1 0, 
3 6  m g/ d a y S P N -8 1 0, or pl ac e b o.    
T o gi v e c ar e gi v ers t h e 
o p p ort u nit y t o i m pr o v e 
di ar y c o m pli a nc e  
3. 2. 1. 1  
2 6  
T h e f oll o wi n g w as c h a n g e d:  
Scr e e ni n g will t a k e pl ac e f or u p t o 2 8  4 5  d a ys pri or t o 
r a n d o miz ati o n a n d m a y b e c arri e d o ut o v er m or e t h a n o n e 
visit if n ec ess ar y.   
T o f acilit at e st u d y 
c o n d uct 
3. 2. 1. 1  
2 6  
T h e f oll o wi n g w as a d d e d:  
St aff at st u d y sit es ar e e nc o ur a g e d t o c o m pl et e scr e e ni n g 
pr oc e d ur es as e arl y as p ossi bl e t o pr o vi d e m or e fl e xi bilit y i n 
t h e B as eli n e P eri o d f or t h e c ar e gi v ers t o ac hi e v e I A di ar y 
c o m pli a nc e (s e e S ecti o n 3. 2. 1. 2).  
F or cl arific ati o n  
3. 2. 1. 2  
2 7  
T h e f oll o wi n g w as c h a n g e d:  
S u bj ects w h o m e et st u d y e ntr y r e q uir e m e nts will pr oc e e d t o 
t h e t w o w e e k  fl e xi bl e 1 5-d a y  b as eli n e p eri o d.  At Visit 2  
pri m ar y a n d ( if assi g n e d) s ec o n d ar y c ar e gi v ers will r ec ei v e 
tr ai ni n g o n t h e us e of t h e I A di ar y.  Aa n I A di ar y d evic e 
(L o g P a d) will b e iss u e d t o t h e pri m ar y c ar e gi v er.  T h e pri m ar y 
a n d (if assi g n e d) s ec o n d ar y c ar e gi v ers will r ec ei v e tr ai ni n g 
o n t h e us e of t h e I A di ar y.  E v er y eff ort will b e m a d e t o 
pr o vi d e a d e q u at e c ar e gi v er tr ai ni n g o n t h e us e of t h e I A 
di ar y at Visit 2 a n d ac k n o wl e d g e m e nt of tr ai ni n g will b e 
c a pt ur e d o n t h e d e vic e. T h e c ar e gi v er will b e i nstr uct e d t o 
T o gi v e c ar e gi v ers t h e 
o p p ort u nit y t o i m pr o v e 
di ar y c o m pli a nc e  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
m ai nt ai n t h e di ar y f or t w o w e eks.  At t h e e n d of t hi s p eri o d, 
c ar e gi v er c o m pli a nc e wit h t h e I A di ar y will b e ass ess e d.   
F oll o wi n g at l e ast 1 5 d a ys of I A di ar y us e, c ar e gi v er 
c o m pli a nc e wit h t h e I A di ar y will b e ass ess e d.  C o m pli a nc e 
will b e c alc ul at e d as t h e p erc e nt a g e of d a ys o v er t h e p ast 1 5 
d a ys  d uri n g t h e b as eli n e p eri o d f or w hic h a n e v e ni n g di ar y 
w as c o m pl et e d.  C o m pli a nc e of at l e ast 8 0 % m ust b e 
d e m o nstr at e d t o c o nti n u e i nt o t h e titr ati o n p eri o d a n d t o b e 
eli gi bl e f or r a n d o miz ati o n. C o m pli a nc e will b e m e as ur e d b y 
t h e p erc e nt a g e of e v e ni n g di ar y e ntri es c o m pl et e d d uri n g t h e 
b as eli n e p eri o d. S u bj ects w h os e c ar e gi v ers d e m o nstr at e at 
l e ast 8 0 % c o m pli a nc e will b e eli gi bl e f or r a n d o miz ati o n a n d 
c o nti n u e i nt o t h e titr ati o n p eri o d.  
S u bj ects w h os e c ar e gi v ers d o n ot r e ac h 8 0 % c o m pli a nc e 
d uri n g t h e first 1 5 d a ys of t h e B as eli n e P eri o d m a y b e 
all o w e d t o c o nti n u e t o us e t h e di ar y f or u p t o 1 5 a d diti o n al 
d a ys.  F or t h es e s u bj ects, c ar e gi v ers will r ec ei v e r e m e di al 
tr ai ni n g o n t h e us e of t h e I A di ar y.  D uri n g t his ti m e, 
c ar e gi v er c o m pli a nc e wit h t h e I A di ar y will b e m o nit or e d 
d ail y b y st u d y sit e p ers o n n el o v er t h e p ast 1 5 -d a ys as a 
“r olli n g wi n d o w”.  W h e n t h e c ar e gi v ers’ p erf or m a nc e wit h 
t h e I A di ar y i m pr o v es s uc h t h at t h e c ar e gi v ers ar e a bl e t o 
d e m o nstr at e at l e ast 8 0 % c o m pli a nc e o v er t h e p ast 1 5 -d a y 
r olli n g wi n d o w, t he s u bj ect will b e eli gi bl e f or 
r a n d o miz ati o n a n d all o w e d t o c o nti n u e i nt o t h e titr ati o n 
p eri o d.  
Alt h o u g h t h er e ar e u p t o 3 0 d a ys a v ail a bl e f or e ac h of t h e 
scr e e ni n g a n d t h e b as eli n e P eri o d, t h e t ot al d ur ati o n of 
scr e e ni n g a n d bas eli n e p eri o ds m a y n ot e xc e e d 4 5 d a ys.  
R escr e e ni n g  
As a g e n er al r ul e, r escr e e ni n g of s u bj ects is n ot all o w e d.  
T h e o nl y e xc e pti o n t o t his will b e f or s u bj ects w h o h a d 
f ail e d scr e e ni n g d u e t o c ar e gi v er n o n-c o m pli a nc e wit h t h e 
I A di ar y u n d er pr ot oc ol v ersi o n 5. 0. T h es e s u bj ects m a y be 
r escr e e n e d t o p artici p at e i n t h e st u d y u n d er pr ot oc ol 6. 0. 
T h es e s u bj ects will b e assi g n e d a n e w s u bj ect I D n u m b er 
a n d will c o m pl et e all st u d y scr e e ni n g pr oc e d ur es.  
3. 2. 4  
2 8  
T h e f oll o wi n g w as c h a n g e d:  
S u bj ects will r et ur n t o t h e st u d y sit e f or a fi n al visit, aft er 
c o m pl eti n g t h e 1 -w e ek T a p er/ C o n v ersi o n P eri o d.  T h os e 
F or cl arific ati o n  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
s u bj ects w h o el ect t o c o nti n u e i n t h e OL E st u d y will h a v e 
pr oc e d ur es p erf or m e d f or t h at st u d y as w ell.  All s u bj ects 
w h o disc o nti n u e e arl y will r et ur n t o t h e st u d y sit e f or a fi n al 
visit.  A n y  sS u bj ects w h o disc o nti n u e s fr o m t h e st u d y d uri n g 
t h e m ai nt e n a nc e p eri o d will b e off er e d a T a p er kit a n d will 
r et ur n t o t h e st u d y sit e f or a f oll o w-u p visit ( E O S).  S u bj ects 
w h o disc o nti n u e  d uri n g t h e titr ati o n p eri o d will n ot r ec ei v e 
a t a p er kit a n d will o nl y c o m pl et e t h e E O S pr oc e d ur es.   
Fi g ur e 1 a n d 
2  
2 9,  
3 0  
T h es e fi g ur es w er e u p d at e d wit h t h e n e w visit wi n d o ws a n d 
scr e e ni n g p eri o d 
U p d at e d as p er c h a n g es 
i n t h e pr ot oc ol 
4. 1. 1  
3 1  
T h e f oll o wi n g w as a d d e d:   
8 . 
α 2 - a dr e n er gic a g o nists ( e. g. cl o ni di n e a n d 
g u a nf aci n e) us e d f or a n y ot h er r e as o n e xc e pt f or 
m o n ot h er a p y tr e at m e nt f or A D H D ( e. g. a g gr essi o n or 
i ns o m ni a) m ust b e disc o nti n u e d at l e ast t w o w e e ks pri or t o 
Visit 2.  
T o  f acilit at e st u d y 
c o n d uct 
T a bl e 1  
3 3,  
3 4  
T a bl e 1 w as u p d at e d wit h t h e n e w visit wi n d o ws , scr e e ni n g 
p eri o d , b as eli n e p eri o d, a n d f o ot n ot es. D u e t o t h e a d diti o n of 
a n e w f o ot n ot e, t his s ecti o n h a d t o b e r e n u m b er e d  
U p d at e d as p er c h a n g es 
i n t h e pr ot oc ol 
T a bl e 1  
3 3,  
3 4  
T h e f oll o wi n g n e w f o ot n ot e “c” w as a d d e d f or Visit 3 
wi n d o w d a ys:  Visit 3 will occ ur at l e ast 1 5 d a ys f oll o wi n g 
Visit 2.  
 
F o ot n ot e “ g ” w as r e n u m b er e d t o “ h” a n d c h a n g e d as f oll o ws:  
g h       T ot al of 5 P K bl o o d s a m pl es will b e  o bt ai n e d o v er  o n e 
or t w o visits ( Visit 4 a n d/ or Visit 5)  t o b e di vi d e d b et w e e n 
Visit 4 a n d Visit 5.  
 
F o ot n ot e “ d ” w as r e n u m b er e d t o “ e” a n d c h a n g e d as f oll o ws:  
d e  
Di ar y c o m pli a nc e m ust b e at l e ast 8 0 % ( mi ni m u m of 
1 2 d a ys o ut of 1 4 1 5 ) t o q u alif y f or r a n d o miz ati o n. 
U p d at e d as p er c h a n g es 
i n t h e pr ot oc ol 
4. 2. 1  
3 5  
T h e f oll o wi n g w as c h a n g e d:  
S u bj ect scr e e ni n g pr oc e d ur es will b e p erf or m e d wit hi n 2 8  4 5  
d a ys pri or t o Visit 3 a n d m a y b e d o n e o n m or e t h a n o n e d ay.   
T o f acilit at e st u d y 
c o n d uct 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
4. 2. 2  
3 5  
T h e f oll o wi n g w as c h a n g e d:   
Visit 2 will occ ur at l e ast 1 4  1 5  d a ys pri or t o Visit 3.   
T o f acilit at e st u d y 
c o n d uct 
4. 2. 2  
3 5  
T h e f oll o wi n g w as a d d e d :   
Pl e as e n ot e t h at, p er pr ot oc ol a n d wit hi n t h e E D C, Visit 1 
a n d Visit 2 m a y occ ur o n t h e s a m e d a y.  
F or cl arific ati o n  
4. 2. 3  
3 5  
T h e f oll o wi n g w as c h a n g e d:  
Visit 3 will occ ur at l e ast 1 4 1 5  d a ys f oll o wi n g Visit 2 acc or di n g 
t o t h e Sc h e d ul e of Visits a n d Pr oc e d ur es.  
T o f acilit at e st u d y 
c o n d uct 
4. 2. 3  
3 6  
T h e f oll o wi n g w as c h a n g e d:  
1 0.  
C oll ect uri n e s a m pl es f or uri n al ysis, uri n e dr u g 
scr e e n ( all s u bj ects), a n d pr e g n a nc y t est ( F O C P o nl y) 
F or cl arific ati o n  
4. 2. 4  
3 6  
T h e f oll o wi n g w as c h a n g e d:  
Visit 4 will occ ur 7 ( ± 1 2 ) d a ys f oll o wi n g Visit 3 acc or di n g t o 
t h e Sc h e d ul e of Visits a n d Pr oc e d ur es. 
T o f acilit at e st u d y 
c o n d uct 
4. 2. 5  
3 6  
T h e f oll o wi n g w as c h a n g e d:  
Visit 5 will occ ur 1 4 ( ± 1 2 ) d a ys f oll o wi n g Visit 3 acc or di n g t o 
t h e Sc h e d ul e of Visits a n d Pr oc e d ur es. 
T o f acilit at e st u d y 
c o n d uct 
4. 2. 6  
3 7  
T h e f oll o wi n g w as c h a n g e d:  
Visit 6 will occ ur 2 1 ( ± 1 3 ) d a ys f oll o wi n g Visit 5 acc or di n g t o 
t h e Sc h e d ul e of Visits a n d Pr oc e d ur es.   
T o f acilit at e st u d y 
c o n d uct 
4. 2. 8  
3 8  
T h e f oll o wi n g w as c h a n g e d:  
T h es e will i ncl u d e pr e a n d p ost -d os e s a m pl es o bt ai n e d o v er 
o n e visit ( Visit 4 or Visit 5) or c a n b e o bt ai n e d o v er t w o 
visits ( Visit 4 a n d Visit 5)  Bl o o d will b e dr a w n f or q u a ntit ati v e 
P K a n al ysis at Visit 4 a n d Visit 5.     
If t h e s u bj ect d eci d es t o c o m pl et e t h e P K s a m pli n g o v er o n e 
visit t h e n h e/s h e will arri v e at t h e cli nic i n t h e m or ni n g pri or 
t o t a ki n g t h e m or ni n g d os e.   
A P K s a m pl e  will b e dr a w n pr e -d os e; t h e n t h e d os e will b e 
o bs er v e d i n t h e cli nic.  P ost -d os e P K s a m pl es will b e t a k e n 
at a p pr o xi m at el y 1 h o ur,  2 h o urs, 4 h o urs a n d 6 h o urs aft er 
t h e ti m e of t h e o bs er v e d d os e.  P K s a m pl es s h o ul d b e 
o bt ai n e d wit hi n 1 5 mi n ut es of t h e 1 h o ur a n d 2 h o ur 
T o f acilit at e st u d y 
c o n d uct 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
ti m e p oi nts a n d wit hi n 3 0 mi n ut es of t h e 4 h o ur a n d 6 h o ur 
ti m e p oi nt. At o n e of t h es e visits, s u bj ects will arri v e at t h e 
cli nic i n t h e m or ni n g, pri or t o t a ki n g t h eir m or ni n g d os e.  A P K 
s a m pl e will b e dr a w n pr e d os e; t h e n t h e d os e will b e 
o bs er v e d i n t h e cli nic.  P ost d os e P K s a m pl es will b e t a k e n at 
a p pr oxi m at el y 1 h o ur a n d 2 h o urs aft er t h e ti m e of t h e 
o bs er v e d d os e.  P K s a m pl es s h o ul d b e o bt ai n e d wit hi n 1 5 
mi n ut es of t h e t ar g et e d ti m e p oi nts.   
If t h e s u bj ect d eci d es t o c o m e f or t h e P K s a m pli n g o v er t w o 
visits, t h e n o n o n e visit t h e s u bj ect will arri v e at t h e cli nic i n 
t h e m or ni n g, pri or t o t a ki n g t h eir m or ni n g d os e. A P K 
s a m pl e will b e dr a w n pr e-d os e; t h e n t h e d os e will b e 
o bs er v e d i n t h e cli nic .  P ost-d os e P K s a m pl es will b e t a k e n 
at a p pr o xi m at el y 1 h o ur a n d 2 h o urs aft er t h e ti m e of t h e 
o bs er v e d d os e. P K s a m pl es s h o ul d b e o bt ai n e d wit hi n 1 5 
mi n ut es of t h e t ar g et e d ti m e p oi nts.   
4. 4  
4 1  
T h e f oll o wi n g w as a d d e d:  
4. 4  
Pr o hi bit e d M e dic ati o ns:  
S u bj ects m a y  n ot b e o n a n y pr o hi bit e d m e dic ati o n w hil e o n 
st u d y as i n dic at e d i n t h e I ncl usi o n/ E xcl usi o n Crit eri a. T h es e 
m e dic ati o ns i ncl u d e:  
•  
α 2 - a dr e n er gic a g o nists ( e. g. cl o ni di n e a n d 
g u a nf aci n e) us e d f or a n y ot h er r e as o n e xc e pt 
f or m o n ot h er a p y tr e at m e nt f or A D H D  
•  
A nti -ps yc h otics i ncl u di n g ari pi pr az ol e,  
ris p eri d o n e, q u eti a pi n e, a n d zi pr asi d o n e  
•  
A ntic o n v uls a nts i ncl u di n g c ar b a m az e pi n e a n d 
v al pr oic aci d, a nti d e pr ess a nts, m o o d 
st a biliz ers i ncl u di n g lit hi u m, b e nz o di az e pi n es, 
c h oli n est er as e i n hi bit ors or a n y dr u g k n o w n 
t o i n hi bit C Y P 2 D 6 acti vit y 
•  
H er b al s u p pl e m e nts  
F or cl arific ati o n  
4. 5  
4 1  
T h e f oll o wi n g w as d el et e d:  
S u bj ects m a y n ot b e o n a n y pr o hi bit e d m e dic ati o n as 
i n dic at e d i n t h e I ncl usi o n/ Excl usi o n Crit eri a.  
F or cl arif ic ati o n 
5. 2. 1  
4 3  
T h e f oll o wi n g w as c h a n g e d:  
F or cl arific ati o n  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
•  
C GI -I, r el ati v e t o t h e c o n diti o n at b as eli n e  Visit 3 , 
will b e e v al u at e d b y t h e c ar e gi v er a n d b y t h e I n v esti g at or at 
e ac h p ost -b as eli n e visit o n a 7 -p oi nt sc al e wit h 1 = V er y m uc h 
i m pr o v e d, 2 = M uc h i m pr o v e d, 3 = Mi ni m all y i m pr o v e d, 4 = N o 
c h a n g e, 5 = Mi ni m all y w ors e, 6 = M uc h w ors e, a n d 7 = V er y 
m uc h w ors e.  
5. 3  
4 4  
T h e f oll o wi n g w as a d d e d:  
 
 
 
 
T o u n d erst a n d ex p os ur e 
of m et a b olit es i n 
c hil dr e n 
5. 3. 2  
4 4  
T h e f oll o wi n g w as a d d e d:  
 
 
T o u n d erst a n d ex p os ur e 
of m et a b olit es i n 
c hil dr e n 
5. 4. 2. 1  
4 7  
T h e f oll o wi n g w as c h a n g e d:  
All S A Es m ust b e r e p ort e d t o t h e Dr u g S af et y C o nt act wit hi n 
2 4 h o urs of first b ec o mi n g a w ar e of t h e S A E.  T h e I n v esti g at or 
m ust c o m pl et e a n S A E e C R F i n E D C  F or m  a n d i ncl u d e a 
d et ail e d d escri pti o n of t h e S A E, as w ell as ot h er a v ail a bl e 
i nf or m ati o n p erti n e nt t o t h e c as e ( e. g., h os pit al r ec or ds, 
a ut o psy r e p orts a n d ot h er r el ev a nt d oc u m e nts).  S h o ul d t h e 
sit e b e u n a bl e t o acc ess E D C, a p a p er S A E f or m  m ust b e 
c o m pl et e d a n d s e nt t o  
 Dr u g S af et y b y e m ail or f a x.  T h e 
i n v esti g at or will k e e p a c o p y of t his S A E R e p ort f or m o n fil e at 
t h e st u d y sit e. O nc e E D C b ec o m es a v ail a bl e, t h e sit e m ust 
c o m pl et e t h e S A E e C R F i n E D C.  
F or Cl arific ati o n  
5. 4. 2. 1  
4 8  
T h e E -m ail  a d dr ess f or dr u g s af et y c o nt act w as u p d at e d:  
 
A d mi nistr ati v e  
5. 4. 2. 2.  
4 8  
T h e f oll o wi n g w as a d d e d:  
T h e I n v esti g at or m ust c o m pl et e a Pr e g n a nc y O utc o m e F or m 
as a f oll o w u p.  
F or Cl arific ati o n  
5. 4. 2. 2  
4 8  
T h e f oll o wi n g w as c h a n g e d:  
Tr e at m e nt -e m er gi n g E P S ( e. g. a k at hisi a, d yst o ni a, 
P ar ki ns o nis m, t ar di v e d yski n esi a) a n d n e ur ol e ptic m ali g n a nt 
sy n dr o m e s h o ul d b e r e p ort e d t o t h e Dr u g S af et y C o nt act 
p ers o n(s) b y  c o m pl eti n g t h e A d v ers e E v e nt S p eci al I nt er est 
(A E SI ) e C R F i n E D C.  S h o ul d t h e sit e b e u n a bl e t o acc ess E D C, 
F or  Cl arific ati o n  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 
 
a p a p er A E SI f or m m ust b e c o m pl et e d a n d s e nt t o  
 Dr u g 
S af et y b y e m ail or f a x f axi n g or sc a n ni n g t h e a p pr o pri at e 
s o urc e d oc u m e nt ati o n wit hi n 2 4 h o urs of first b ec o mi n g 
a w ar e of t h e e v e nt.  O nc e E D C b ec o m es a v ail a bl e t h e sit e 
m ust c o m pl et e A E SI e C R F i n E D C. E P S i nci d e nc e will b e 
s u m m ariz e d a n d s h ar e d wit h st u d y I n v esti g at ors t hr o u g h o ut 
t h e tri al.   
5. 4. 4  
4 9  
T h e f oll o wi n g w as a d d e d:  
A s u bj ect will b e e xcl u d e d if t h e Scr e e ni n g bl o o d t est r es ults 
i n dic at es > 2 ti m es t h e u p p er li mit of n or m al ( UL N) of 
al a ni n e a mi n otr a nsf er as e ( AL T), as p art at e a mi n otr a nsf er as e 
( A S T), g a m m a gl ut a m yl tr a ns pe pti d as e ( G G T), a n d/ or s er u m 
cr e ati ni n e. L a b or at or y t ests will n ot b e r e p e at e d f or t h es e 
s u bj ects. 
A n y r e p e at l a b or at or y t esti n g will b e c o n d uct e d u n d er 
f asti n g c o n diti o n. 
F or Cl arific ati o n  
6. 5  
5 4  
T h e f oll o wi n g w as a d d e d:  
O nl y o n e ( pri m ar y) r e as o n f or st u d y disc o nti n u ati o n will b e 
r ec or d e d f or e ac h s u bj ect. 
F or Cl arific ati o n  
 
 
6. 9. 2  
5 6  
T h e f oll o wi n g w as c h a n g e d:  
T h e s ec o n d ar y e n d p oi nts ar e:  
1 . 
Act u al C ar e gi v er  C GI -I sc or e at Visit 6   
2.  
Act u al I n v esti g at or C GI -I sc or e at Visit 6 
2. 3.  
C h a n g e fr o m Visit 3 t o Visit 6 i n I n v esti g at or C GI -S 
sc or e 
3. 4.  
C h a n g e fr o m Visit 3 t o Visit 6 i n C H Q -2 8 sc or e 
5.  
C h a n g e fr o m Visit 3 t o Visit 6 i n P SI -4 -S F sc or es i n: 
a.  
P ar e nt al Distr ess  
b.  
P ar e nt -C hil d D ysf u ncti o n al I nt er acti o n  
a .c. 
Diffic ult C hil d  
4.  
C h a n g e fr o m Visit 3 t o Visit 6 i n C ar e gi v er c o m pl et e d 
C GI I  
F or Cl arific ati o n  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
5. 6.  
C h a n g e fr o m Visit 3 t o Visit 6 i n S N A P -I V A D H D 
sc or es i n: 
a.  
I n att e nti o n r ati n gs 
b.  
H y p er acti vit y/I m p ulsi vit y r ati n gs  
c. 
C o m bi n e d Sc al e r ati n gs  
6. 1 3  
6 0  
 T h e f oll o wi n g w as a d d e d:  
 
 
 
 
 
 
 
 
T o u n d erst a n d ex p os ur e 
of m et a b olit es i n 
c hil dr e n 
7. 4. 4  
6 4  
T h e f oll o wi n g w as a d d e d:  
 
 
 
T o u n d erst a n d ex p os ur e 
of m et a b olit es i n 
c hil dr e n 
C h a n g es t o 8 1 0 P 3 0 1 V 6 . 0 D at e d 2 1 J ul 2 0 1 6 
Titl e P a g e  
1  
Pr ot oc ol v ersi o n a n d d at e w as u p d at e d  
A d mi nistr ati v e  
Si g n at ur e 
P a g e  
3  
T h e si g n at ur e p a g e w as u p d at e d  
A d mi nistr ati v e  
S y n o psis  
1 5  
N u m b er of S u bj ects:  A p pr oxi m at el y 3 7 8 s u bj ects a g e d 6 -1 2  
1 7    y e ars (i ncl usi v e) will b e scr e e n e d t o ac hi e v e 2 9 1 s u bj ects  
r a n d o miz e d; 9 7 p er tr e at m e nt ar m 
Pr oc e d ur al  
S y n o psis  
1 5  
Crit eri a f or I ncl usi o n:  
Ot h er wis e h e alt h y m al e or f e m al e s u bj ects, a g e 6 t o  1 2  1 7 
y e ars  at t h e ti m e of scr e e ni n g wit h a pri m ar y di a g n osis o f 
A D H D a n d c urr e ntl y r ec ei vi n g m o n ot h er a p y tr e at m e nt wit h 
a n o pti miz e d F D A -a p pr o v e d A D H D m e dic ati o n.  I A will b e 
c o nfir m e d at scr e e ni n g usi n g R -M O A S a n d Viti ell o A g gr essi o n 
Sc al e.  
Pr oc e d ur al  
List of 
A b br evi ati o n  
2 5  
F O C P c h a n g e d t o F O C B P  
T o Cl arif y  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
3. 1  
3 1  
T h e pr es e nt st u d y is d esi g n e d t o e v al u at e t h e effic ac y, s af et y, 
a n d t ol er a bilit y of S P N -8 1 0 i n p ati e nts a g e d 6 t o 1 2  1 7 y e ars 
wit h A D H D a n d c o m or bi d I A, w h e n t a k e n i n c o nj u ncti o n wit h 
a st a n d ar d A D H D tr e at m e nt.  
Pr oc e d ur al  
3. 2  
3 2  
Pr ot oc ol 8 1 0 P 3 0 1 is a r a n d o miz e d, pl ac e b o-c o ntr oll e d, 
d o u bl e bli n d, m ultic e nt er, p ar all el gr o u p, fix e d d os e st u d y t o 
d e m o nstr at e t h e effic ac y, s af et y, a n d t ol er a bilit y of S P N -8 1 0 
i n t h e tr e at m e nt of I A i n p ati e nts a g e d 6-1 2  1 7  y e ars wit h 
A D H D i n c o nj u ncti o n wit h st a n d ar d A D H D t r e at m e nt. 
Pr oc e d ur al  
3. 2. 1. 1  
3 2  
T h e Viti ell o A g gr essi o n Sc al e will b e us e d t o e v al u at e s u bt y p e 
of a g gr essi o n ( pl a n n e d vs. i m p ulsi v e); o nl y t h os e c hil dr e n a n d 
a d ol esc e nts  w h o sc or e as pr e d o mi n a ntl y i m p ulsi v e will b e 
i ncl u d e d. 
Pr oc e d ur al  
3. 2. 1. 2  
3 3  
T h es e s u bj ects m a y b e r escr e e n e d t o p artici p at e i n t h e st u d y 
u n d er pr ot oc ol 6. 0 c urr e nt pr ot oc ol . 
T o Cl arif y  
4. 1  
3 7  
T h e t ar g et p o p ul ati o n will b e m al e a n d f e m al e s u bj ects a g e d 
6 t o 1 2  1 7  y e ars wit h I A a n d A D H D.  
Pr oc e d ur al  
4. 1. 1  
3 7  
1 . 
H e alt h y m al e or f e m al e s u bj ects, a g e 6 t o 1 2  1 7 
y e ars at t h e ti m e of scr e e ni n g.  
1 0. W ei g ht of at l e ast 2 0 k g  f or 6-1 2 y e ar ol d s u bj ects . 
Pr oc e d ur al  
4. 1. 2  
3 7, 3 8  
1.      B o d y M ass I n d ex ( B MI) i n l ess t h a n 2 5t h a n d a b o v e 9 9 t h 
p erc e ntil e or a b o v e  f or 1 3-1 7 y e ar ol d s u bj ects o nl y . 
9.  
Pr e g n a nc y or r ef us al t o pr actic e c o ntr ac e pti o n 
d uri n g t h e st u d y (f or f e m al e s u bj ects of c hil d b e ari n g 
p ot e nti al ) a n d s e x u all y acti v e m al es ). 
9. 1 0 . 
Cri mi n al arr est or r e p ort at l e ast 6 m o nt hs pri or t o 
Visit 2.  
 
T a bl e 1  
4 0  
f 
T o b e p erf or m e d f or f e m al e s u bj ects of c hil d b e ari n g 
p ot e nti al pri or t o a d mi nistr ati o n of first d os e of S M a n d will 
h a v e t o b e t est e d as n e g ati v e f or t h e s u bj ect t o c o nti n u e i n 
t h e st u d y. 
 
4. 2. 1. 4. 2. 3 
a n d 4. 2. 7  
4 1, 4 2, 
4 3  
F O C P c h a n g e d t o F O C B P  
T o Cl arify  
4. 2. 8  
4 4  
T h e f oll o wi n g p ar a gr a p h i n S ecti o n 4. 2. 8 w as d e pict e d as 
d el et e d b y a stri k et hr o u g h i n err or  i n t h e s u m m ar y of 
c h a n g es; t h e stri k et hr o u g h w as r e m o v e d:  
A d mi nistr ati v e  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
If t h e s u bj ect d eci d es t o c o m pl et e t h e P K s a m pli n g o v er o n e 
visit t h e n h e/s h e will arri v e at t h e cli nic i n t h e m or ni n g pri or 
t o t a ki n g t h e m or ni n g d os e. 
T a bl e 3  
5 6  
F O C P c h a n g e d t o F O C B P  
T o Cl arify  
C h a n g es t o 8 1 0 P 3 0 1 V 7. 0 D at e d 2 4 J ul 2 0 1 7  
Titl e P a g e  
1  
Pr ot oc ol v ersi o n a n d d at e w as u p d at e d  
A d mi nistr ati v e  
Si g n at ur e 
P a g e  
3  
T h e si g n at ur e p a g e w as u p d at e d a n d r evis e d  
A d mi nistr ati v e  
S y n o psis  
1 8  
N u m b er of S u bj ects:  A p pr oxi m at el y 3 7 8 s u bj ects a g e d 6 -1 7  
1 2   y e ars (i ncl usi v e) will b e scr e e n e d t o ac hi e v e 2 9 1 s u bj ects  
r a n d o miz e d; 9 7 p er tr e at m e nt ar m 
Pr oc e d ur al  
S y n o psis  
1 8  
Crit eri a f or I ncl usi o n: 
Ot h er wis e h e alt h y m al e or f e m al e s u bj ects, a g e 6 t o  1 7  1 2 
y e ars at t h e ti m e of scr e e ni n g wit h a pri m ar y di a g n osis of 
A D H D a n d c urr e ntl y r ec ei vi n g m o n ot h er a p y tr e at m e nt wit h 
a n o pti m iz e d F D A-a p pr o v e d A D H D m e dic ati o n.  I A will b e 
c o nfir m e d at scr e e ni n g usi n g R-M O A S a n d Viti ell o 
A g gr essi o n Sc al e.  
Pr oc e d ur al  
S y n o psis  
1 9  
Pri m ar y Effic ac y E n d p oi nt  
T h e pri m ar y effic ac y e n d p oi nt is t h e p erc e nt c h a n g e ( P C H M T) 
i n t h e fr e q u e nc y ( u n w ei g ht e d sc or e) of I A b e h a vi ors p er 7 
d a ys i n t h e M ai nt e n a nc e  Tr e at m e nt ( Titr ati o n a n d 
M ai nt e n a nc e)   p eri o d r el ati v e t o t h e B as eli n e p eri o d 
c alc ul at e d o v er t h e n u m b er of d a ys wit h n o n -missi n g I A 
di ar y d at a.    
T h e pri m ar y effic ac y e n d p oi nt P C H M T will b e c alc ul at e d b y 
P C H M T= 1 0 0 *( M T –  B)/ B, w h er e M T  a n d B ar e I A b e h a vi or 
fr e q u e nci es p er 7 d a ys d uri n g t h e m ai nt e n a nc e  Tr e at m e nt  
p eri o d a n d b as eli n e p eri o d , r es p ecti v el y. 
T o cl arify  
S y n o psis  
2 0  
H y p ot h es es:  
L et 1, 2, a n d 3 r e pr es e nt t h e m e di a n p erc e nt c h a n g e i n 
t h e fr e q u e nc y of I A b e h a vi ors p er 7 d a ys i n t h e M ai nt e n a nc e  
Tr e at m e nt  p eri o d r el ati v e t o t h e B as eli n e p eri o d i n t h e I T T 
p o p ul ati o n f or s u bj ects tr e at e d wit h Pl ac e b o, 1 8 m g a n d 3 6 
m g d os es of S P N -8 1 0, r es p ecti v el y.  T h e n ull ( H 0) a n d t h e 
alt er n ati v e ( H a) h y p ot h es es ar e as i n t h e f oll o wi n g. 
T o cl arify  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
S y n o psis  
2 0  
H a n dli n g Missi n g D at a:  
F or t h e pri m ary effic acy e n d p oi nt, t h e fr e q u e ncy of I A 
b e h a vi ors d uri n g t h e  m ai nt e n a nc e  tr e at m e nt p eri o d will 
b e c alc ul at e d o v er t h e n u m b er of d a ys wit h n o n -missi n g I A 
di ar y d at a i n t h e m ai nt e n a nc e  tr e at m e nt p eri o d.  
T o cl arify  
S y n o psis  
2 1  
St atistic al M et h o ds:  
T h e pri m ar y effic ac y a n al ysis will b e b as e d o n t h e I T T 
p o p ul ati o n.  T h e pri m ar y effic ac y e n d p oi nt is t h e p erc e nt 
c h a n g e i n t h e fr e q u e nc y  ( u n w ei g ht e d sc or e) of I A b e h a vi ors 
p er 7 d a ys i n t h e M ai nt e n a nc e  Tr e at m e nt   p eri o d r el ati v e t o 
t h e B as eli n e p eri o d i n t h e I T T p o p ul ati o n c alc ul at e d o v er t h e 
n u m b er of d a ys wit h n o n -missi n g I A di ar y d at a.  
T o cl arify  
3. 1  
3 4  
T h e pr es e nt st u d y is d esi g n e d t o e v al u at e t h e effic ac y, 
s af et y, a n d t ol er a bilit y of S P N-8 1 0 i n p ati e nts a g e d 6 t o 1 7  
1 2 y e ars wit h A D H D a n d c o m or bi d I A, w h e n t a k e n i n 
c o nj u ncti o n wit h a st a n d ar d A D H D  tr e at m e nt. 
Pr oc e d ur al  
3. 2  
3 5  
Pr ot oc ol 8 1 0 P 3 0 1 is a r a n d o miz e d, pl ac e b o-c o ntr oll e d, 
d o u bl e bli n d, m ultic e nt er, p ar all el gr o u p, fix e d d os e st u d y t o 
d e m o nstr at e t h e effic ac y, s af et y, a n d t ol er a bilit y of S P N -8 1 0 
i n t h e tr e at m e nt of I A i n p ati e nts a g e d 6-1 7  1 2  y e ars wit h 
A D H D i n c o nj u ncti o n wit h st a n d ar d A D H D t r e at m e nt. 
Pr oc e d ur al  
3. 2. 1. 1  
3 5  
T h e Viti ell o A g gr essi o n Sc al e will b e us e d t o e v al u at e 
s u bt y p e of a g gr essi o n ( pl a n n e d vs. i m p ulsi v e); o nl y t h os e 
c hil dr e n a n d a d ol esc e nts  w h o sc or e as pr e d o mi n a ntl y 
i m p ulsi v e will b e i ncl u d e d. 
Pr oc e d ur al  
4. 1  
4 0  
T h e t ar g et p o p ul ati o n will b e m al e a n d f e m al e s u bj ects a g e d 
6 t o 1 7  1 2  y e ars wit h I A a n d A D H D.  
Pr oc e d ur al  
4. 1. 1  
4 0  
1 . 
H e alt h y m al e or f e m al e s u bj ects, a g e 6 t o 1 7  1 2  
y e ars at t h e ti m e of scr e e ni n g.  
1 0. W ei g ht of at l e ast 2 0 k g  f or 6 1 2 y e ar ol d s u bj ects . 
Pr oc e d ur al  
4. 1. 2  
4 0, 4 1  
1.      B o d y M ass I n d ex ( B MI) i n l ess t h a n 2 5t h a n d a b o v e 9 9 t h 
p erc e ntil e or  a b o v e  f or 1 3 1 7 y e ar ol d s u bj ects o nl y . 
 9. 1 0.  
Cri mi n al arr est or r e p ort at l e ast 6 m o nt hs pri or t o 
Visit 2.  
Pr oc e d ur al  
6. 2  
6 2  
F or t h e pri m ar y effic ac y e n d p oi nt, t h e fr e q u e nc y of I A 
b e h a vi ors d uri n g t h e m ai nt e n a nc e  tr e at m e nt p eri o d will b e 
T o cl arify  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
c alc ul at e d o v er t h e n u m b er of d a ys wit h n o n -missi n g I A 
di ar y d at a i n t h e m ai nt e n a nc e  tr e at m e nt p eri o d.  
6. 9. 1  
6 4  
T h e pri m ar y effic ac y e n d p oi nt is t h e p erc e nt c h a n g e ( P C H M T) 
i n t h e fr e q u e nc y ( u n w ei g ht e d sc or e) of I A b e h a vi ors p er 7 
d a ys i n t h e M ai nt e n a nc e  Tr e at m e nt ( Titr ati o n a n d 
M ai nt e n a nc e)   p eri o d r el ati v e t o t h e B as eli n e p eri o d 
c alc ul at e d o v er t h e n u m b er of d a ys wit h n o n -missi n g I A 
di ar y d at a.    
T h e pri m ar y effic ac y e n d p oi nt P C H M T will b e c alc ul at e d b y 
P C H M T= 1 0 0 *( M T –  B)/ B, w h er e M T  a n d B ar e I A b e h a vi or 
fr e q u e nci es p er 7 d a ys d uri n g t h e m ai nt e n a nc e Tr e at m e nt  
p eri o d a n d b as eli n e p eri o d , r es p ecti v el y.  
L et 1, 2, a n d 3 r e pr es e nt t h e m e di a n p erc e nt c h a n g e i n 
t h e fr e q u e nc y of I A b e h a vi ors p er 7 d a ys i n t h e M ai nt e n a nc e  
Tr e at m e nt  p eri o d r el ati v e t o t h e B as eli n e p eri o d i n t h e I T T 
p o p ul ati o n f or s u bj ects tr e at e d wit h Pl ac e b o, 1 8 m g a n d 3 6 
m g d os es of S P N -8 1 0, r es p ecti v el y.   
T o cl arify  
6. 1 1  
6 7  
H o w e v er, t h e pri m ar y e n d p oi nt f or t his st u d y is p erc e nt 
c h a n g e i n t h e fr e q u e nc y  of I A i nci d e nc e p er 7 d a ys i n t h e 
M ai nt e n a nc e  Tr e at m e nt  ( Titr ati o n a n d M ai nt e n a nc e) 
p eri o d ( P C H M T) r el ati v e t o t h e B as eli n e p eri o d i n t h e I T T 
p o p ul ati o n c alc ul at e d o v er t h e n u m b er of d a ys wit h n o n -
missi n g I A di ar y d at a  
T o cl arify  
C h a n g es t o 8 1 0 P 3 0 1 V 8. 0 D at e d 0 7 N o v 2 0 1 7  
Titl e P a g e  
1, 2  
Pr ot oc ol v ersi o n a n d d at e w er e  u p d at e d  
A d mi nistr ati v e  
Si g n at ur e 
P a g e  
3  
T h e si g n at ur e p a g e w as u p d at e d  
A d mi nistr ati v e  
Pr ot oc ol 
S y n o psis  
1 9  
N u m b er of S u bj ects:  
A p pr oxi m at el y 4 2 6  3 7 8  s u bj ects a g e d 6-1 2 y e ars (i ncl usi v e) 
will b e scr e e n e d t o ac hi ev e 2 9 1  3 3 0  s u bj ects r a n d o miz e d; 9 7 
p er tr e at m e nt ar m  
R evis e d f oll o wi n g r e-
esti m ati o n of s a m pl e 
siz e 
Pr ot oc ol 
S y n o psis  
2 0  
S a m pl e siz e:  
B as e d o n r es ults fr o m t h e P h as e 2 st u d y, it is ass u m e d t h at 
t h e a v er a g e tr e at m e nt diff er e nc e b et w e e n S P N-8 1 0 d os e 
gr o u ps a n d pl ac e b o is 1 1. 5 1  1 5  wit h a c o m m o n st a n d ar d 
d evi ati o n of 2 7. 3.  A s a m pl e siz e of 1 3 2  7 7  s u bj ects p er ar m 
(2 6 4  2 3 1  s u bj ects f or 3  ar ms) will yi el d 9 0 % p o w er t o d et ect 
R evis e d f oll o wi n g r e-
esti m ati o n o f s a m pl e 
siz e 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
a n o n -z er o diff er e nc e b et w e e n t h e m e di a n of 1 8 m g or  3 6 
m g d os e gr o u p a n d t h e pl ac e b o usi n g t h e Wilc ox o n r a n k -
s u m t est wit h a 2-si d e d si g nific a nc e l e v el al p h a = 0. 0 5. 
It is ass u m e d t h at a p pr oxi m at el y 2 0 % of  s u bj ects will 
dr o p o ut b ef or e t h e c o m pl eti o n of t h e st u d y a n d h e nc e, a n 
a dj ust e d t ot al of 3 3 0  2 9 1  s u bj ects will b e r a n d o miz e d i n a 
1: 1 :1  r ati o t o o bt ai n 2 6 4  2 3 1  s u bj ects i n t h e I T T p o p ul ati o n 
at t h e c o m pl eti o n of t h e st u d y.  
4. 1  
4 1  
A p pr oxi m at el y 3 3 0 2 9 1  s u bj ects will b e r a n d o miz e d i n t his 
cli nic al i n v esti g ati o n.  
R evis e d f oll o wi n g r e-
esti m ati o n of s a m pl e 
siz e 
5. 2. 2  
5 3  
 
A D H D -C o m bi n e d s u bsc al e: t h e first t w o s u bsc al e s it e ms 
ar e c o m bi n e d  
E ac h s u bsc al e sc or e is t h e s u m a v er a g e  of t h e sc or es f or t h e 
i n di vi d u al it e ms i ncl u d e d i n t h e s u bsc al e. 
Cl arific ati o n  
6. 1 0  
6 8  
B as e d o n r es ults fr o m t h e P h as e 2 st u d y, it is ass u m e d t h at 
t h e a v er a g e tr e at m e nt diff er e nc e b et w e e n S P N -8 1 0 d os e 
gr o u ps a n d pl ac e b o is 1 1. 5 1  1 5  wit h a c o m m o n st a n d ar d 
d evi ati o n of 2 7. 3 . A s a m pl e siz e of 7 7  1 3 2  s u bj ects p er ar m 
(2 3 1  2 6 4  s u bj ects f or 3  ar ms) will yi el d 9 0 % p o w er t o d et ect 
a n o n -z er o diff er e nc e b et w e e n t h e m e di a n of 1 8 m g or  3 6 
m g d os e gr o u p a n d t h e pl ac e b o usi n g t h e Wilc ox o n r a n k -
s u m t est wit h a 2-si d e d si g nific a nc e l e v el al p h a = 0. 0 5. 
It is ass u m e d t h at a p pr oxi m at el y 2 0 % of  s u bj ects will 
dr o p o ut b ef or e t h e c o m pl eti o n of t h e st u d y a n d h e nc e, a n 
a dj ust e d t ot al of 2 9 1  3 3 0 s u bj ects will b e r a n d o miz e d i n a 
1: 1 :1  r ati o t o o bt ai n 2 3 1  2 6 4  s u bj ects i n t h e I T T p o p ul ati o n 
at t h e c o m pl eti o n of t h e st u d y.  
R evis e d f oll o wi n g r e-
esti m ati o n of s a m pl e 
siz e 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
CLI NI C AL P R O T O C OL S Y N O P SI S 
N a m e of C o m p a n y:  
S u p er n us P h ar m ac e utic als, I nc.  
I N D N u m b er:   1 0 6, 5 1 5  
N a m e of Pr o d uct:  M oli n d o n e Hy dr oc hl ori d e 
Ext e n d e d -R el e as e T a bl ets (S P N -8 1 0)  
N a m e of Acti v e I n gr e di e nt:  
M oli n d o n e Hy dr oc hl ori d e  
Pr ot oc ol N u m b er:  8 1 0 P 3 0 1  
P h as e of D e v el o p m e nt:  3  
F ull Titl e of St u d y:  A R a n d o miz e d, D o u bl e -Bli n d, Pl ac e b o -C o ntr oll e d St u dy t o Ev al u at e t h e Effic ac y 
a n d S af et y of M oli n d o n e Hy dr oc hl ori d e Ext e n d e d -R el e as e T a bl ets f or t h e Tr e at m e nt of I m p ulsiv e 
A g gr essi o n i n P e di atric P ati e nts wit h Att e nti o n D eficit/ Hy p er activity  Dis or d er ( A D H D ) i n 
C o nj u ncti o n wit h St a n d ar d A D H D T r e at m e nt 
I n v esti g at or(s) / C e nt er(s):  A p pr oxi m at el y 2 5 U S c e nt ers  
O bj ecti v es:  
Pri m ar y  
T h e pri m ar y o bj ecti v e is t o ass ess t h e effic acy a n d s af et y  of S P N -8 1 0 i n r e d uci n g t h e fr e q u e ncy of 
i m p ulsiv e a g gr essi o n (I A) b e h a vi ors i n p e di atric p ati e nts wit h A D H D w h e n t a k e n i n c o nj u ncti o n wit h 
st a n d ar d A D H D tr e at m e nt 
S ec o n d ar y  
T h e s ec o n d ary o bj ectiv es of t h e st u dy ar e t o ass ess t h e f oll o wi n g:  
 
t h e eff ect of S P N-8 1 0 o n t h e I n v esti g at or -r at e d Cli nic al Gl o b al I m pr essi o n –  I m pr ov e m ent 
Sc al e ( C GI -I)  
 
t h e eff ect of S P N-8 1 0 o n t h e Cli nic al Gl o b al I m pr essi o n –  S ev erity Sc al e ( C GI -S)  
 
t h e eff ect of S P N-8 1 0 o n t h e c hil d’s o v er all h e alt h as m e as ur e d b y t h e C hil d H e alt h 
Q u esti o n n air e P ar e nt F or m 2 8 -it e m ( C H Q-P F 2 8)  
 
t h e eff ect of tr e ati n g t h e c hil d wit h S P N-8 1 0 o n t h e p ar e nt -c hil d r el ati o ns hi p as m e as ur e d 
by t h e P ar e nti n g Str ess I n d ex –  S h ort F or m ( P SI -4 -S F)   
 
t h e eff ect of S P N-8 1 0 o n t h e C ar e giv er -r at e d C GI-I 
 
t h e eff ect of S P N-8 1 0 o n i n att e nti o n a n d h y p er activit y -i m p ulsivity m e as ur e d b y t h e S N A P-
I V R ati n g Sc al e  
T erti ary  
 
 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
St u d y D esi g n:  D o u bl e -bli n d, pl ac e b o -c o ntr oll e d, r a n d o miz e d, p ar all el gr o u p st u dy 
N u m b er of S u bj ects:  A p pr oxi m at ely 4 2 6 s u bj ects a g e d 6 -1 2 y e ars (i ncl usi v e) will b e scr e e n e d t o 
ac hi e v e 3 3 0  s u bj ects r a n d o miz e d 
Crit eri a f or I ncl usi o n:  
Ot h er wis e h e alt h y m al e or f e m al e s u bj ects, a g e 6 t o 1 2  y e ars at t h e ti m e of scr e e ni n g  wit h a 
pri m ar y d i a g n osis of A D H D a n d c urr e ntl y r ec eivi n g m o n ot h er a py t r e at m e nt wit h a n  o pti miz e d F D A -
a p pr o v e d A D H D m e dic ati o n .  I A will b e c o nfir m e d at scr e e ni n g usi n g R-M O A S a n d Viti ell o 
A g gr essi o n Sc al e.  
Crit eri a f or E xcl usi o n:  
C urr e nt or lif eti m e di a g n osis of e pil e ps y, m aj or d e pr essi v e dis or d er, bi p ol ar dis or d er, sc hiz o p hr e ni a 
or r el at e d dis or d er, p ers o n alit y dis or d er, T o ur ett e’s dis or d er, or psyc h osis n ot ot h er wis e s p ecifi e d.   
C urr e ntl y m e eti n g D S M crit eri a f or a utis m s p ectr u m dis or d er, p er v asi v e d ev el o p m e nt al dis or d er, 
o bs essiv e c o m p ulsiv e dis or d er, p ost -tr a u m atic str ess dis or d er, or a ny ot h er a nxi et y dis or d er as 
pri m ar y di a g n osis.   K n o w n or s us p ect e d i nt elli g e nc e q u oti e nt (I Q) < 7 0, s uici d ality, pr e g n a ncy, or 
s u bst a nc e or alc o h ol a b us e. 
Tr e at m e nt, D os e, a n d M o d e of A d mi nistr ati o n:  
M oli n d o n e h y dr oc hl ori d e e xt e n d e d-rel e as e ta bl et d os a g e f or ms of 3 m g  a n d 9 m g  wit h  m atc hi n g 
pl ac e b o t a bl ets.  Tr e at m e nt t o b e a d mi nist er e d or all y t wic e d ail y  wit h or wit h o ut f o o d .  S u bj ects 
will b e f orc e -titr at e d o v er a p eri o d of 2 w e eks t o t h e ir fi n al r a n d o miz e d d os e. 
 
Tr e at m e nt 1:  pl ac e b o  
 
Tr e at m e nt 2:  1 8 m g  
 
Tr e at m e nt 3:  3 6 m g  
D ur ati o n of Tr e at m e nt a n d St u d y D ur ati o n:  
T ot al s u bj ect d ur ati o n o n st u dy:  A p pr oxi m at el y 1 3  w e e ks  
 
Pr e -tr e at m e nt p h as e: U p t o 4 5 d ays   
o  Scr e e ni n g p eri o d:  U p t o 3 0 d a ys  
o  B as eli n e p eri o d :  At l e ast 1 5 d a ys   
 
Tr e at m e nt p h as e:  5 w e e ks  
o  Titr ati o n  p eri o d :  2 w e e ks  
o  M ai nt e n a nc e  p eri o d :  3 w e e ks  
 
C o nv ersi o n/t a p er p h as e :  1  w e e k  
E n d p oi nts:  
Pri m ar y Effic acy E n d p oi nt  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
T h e pri m ar y effic acy e n d p oi nt is t h e p erc e nt c h a n g e  ( P C HT) i n t h e fr e q u e ncy ( u n w ei g ht e d sc or e) of 
I A b e h avi ors p er 7 d ays i n t h e Tr e at m e nt ( Titr ati o n a n d M ai nt e n a nc e)   p eri o d r el ati v e t o t h e 
B as eli n e p eri o d c alc ul at e d o v er t h e n u m b er of d a ys wit h n o n -missi n g I A di ary d at a.    
T h e pri m ar y effic acy e n d p oi nt P C H T will b e c alc ul at e d by P C H T= 1 0 0 *( T –  B) / B, w h er e T a n d B ar e I A 
b e h a vi or fr e q u e nci es p er 7 d a ys d uri n g t h e Tr e at m e nt p eri o d a n d b as eli n e p eri o d , r es p ecti v el y. T h e 
I A b e h avi or fr e q u e ncy p er 7 d a ys is d efi n e d as ( S U M/ D A Y) x 7, w h er e S U M  is  t h e t ot al of t h e I A 
b e h a vi ors  r e p ort e d i n t h e s u bj ect I A di ary, a n d D A Y is t h e n u m b er of d a ys wit h n o n-missi n g I A 
sc or e  i n t h e s u bj ect I A di ary d uri n g t h e s p ecifi e d st u dy p eri o d .  
 S ec o n d ary Effic ac y E n d p oi nts   
1.  I nv esti g at or-r at e d C GI-I 
2.  C GI -S  
3.  C H Q -P F 2 8  
4.  P SI -4 -S F  
5.  C ar e gi v er -r at e d C GI-I 
6.  S N A P -I V R ati n g Sc al e  
 
S af et y a n d T ol er a bilit y E n d p oi nts  
1.  A dv ers e ev e nts ( A E) 
2.  E xtr apyr a mi d al sy m pt o ms ( E P S) sc al es ( Si m ps o n -A n g us Sc al e, B ar n es Ak at hisi a Sc al e, 
A b n or m al I nv ol u nt ary M o v e m e nt Sc al e)  
3.  Cli nic al l a b or at ory t ests ( H e m at ol o gy, C h e mistry a n d Uri n al ysis)  
4.  E C Gs  
5.  Vit al si g ns  
6.  C ol u m bi a S uici d e S ev erity R ati n g Sc al e ( C -S S R S)  
7.  I nfr e q u e nt B e h avi ors C h ecklist 
 
S a m pl e siz e:  
B as e d o n r es ults fr o m t h e P h as e 2 st u dy, it is ass u m e d t h at t h e  a v er a g e tr e at m e nt diff er e nc e 
b et w e e n S P N -8 1 0 d os e gr o u ps a n d pl ac e b o is  1 1. 5 1 wit h a c o m m o n st a n d ar d d e vi ati o n of 2 7. 3. A 
s a m pl e siz e of 1 3 2  s u bj ects p er ar m (2 6 4  s u bj ects f or 3 ar ms) will yi el d 9 0 % p o w er t o d et ect a n o n-
z er o diff er e nc e b et w e e n t h e m e di a n of 1 8 m g or 3 6 m g d os e gr o u p a n d t h e pl ac e b o usi n g t h e 
Wilc ox o n r a nk -s u m t est wit h a 2-si d e d si g nific a nc e l e v el al p h a = 0. 0 5.  
It is ass u m e d t h at a p pr oxi m at el y 2 0 % of s u bj ects will dr o p o ut b ef or e t h e c o m pl eti o n of t h e st u dy 
a n d h e nc e, a n a dj ust e d t ot al of 3 3 0  s u bj ects will b e r a n d o miz e d i n a 1: 1: 1 r ati o t o o bt ai n 26 4  
s u bj ects i n t h e I T T p o p ul ati o n at t h e c o m pl eti o n of t h e st u dy.   
T h e s a m pl e siz e w as c alc ul at e d usi n g t h e n Q u er y A dvis or S oft w ar e, V ersi o n 7.    


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
A n al ysis P o p ul ati o ns:  
S af et y P o p ul ati o n :  will i n cl u d e all r a n d o miz e d s u bj ects w h o r ec ei v e d at l e ast 1 d os e of st u dy dr u g.  
I nt e nt-t o-Tr e at (I T T) P o p ul ati o n :  will i ncl u d e all s u bj ects w h o r ec eiv e d at l e ast 1 d os e of st u dy dr u g 
a n d h a v e a b as eli n e a n d at l e ast 1 v ali d p ost -r a n d o miz ati o n ass ess m e nt of fr e q u e nc y of I A  
b e h a vi ors b as e d o n I A  di ary e ntry.  
P er -Pr ot oc ol ( P P) P o p ul ati o n :  will i ncl u d e all of t h e s u bj ects i n t h e I T T p o p ul ati o n w h o c o m pl et e d 
t h e tr e at m e nt p eri o d wit h 8 0 % di ary c o m pl eti o n c o m pli a nc e a n d w h o di d n ot h av e m aj or pr ot oc ol 
d e vi ati o ns.  
P K p o p ul ati o n :  will i ncl u d e all s u bj ects i n t h e s af et y p o p ul ati o n w h o h a d at l e ast o n e P K s a m pl e 
dr a w n w hic h h a d a q u a ntit at a bl e c o nc e ntr ati o n f or at l e ast o n e a n alyt e of i nt er est . 
H y p ot h es es:  
L et 1, 2, a n d 3 r e pr es e nt t h e m e di a n p erc e nt c h a n g e i n t h e fr e q u e ncy of I A b e h a vi ors p er 7 d a ys 
i n t h e Tr e at m e nt  p eri o d r el ati v e t o t h e B as eli n e  p eri o d i n t h e I T T p o p ul ati o n f or s u bj ect s tr e at e d 
wit h Pl ac e b o, 1 8 m g a n d 3 6 m g d os e s of S P N -8 1 0 , r es p ecti v el y.  T h e n ull ( H 0) a n d t h e alt er n ativ e 
( Ha) hy p ot h es es ar e as i n t h e f oll o wi n g. 
 
H 0 1: 2= 1, (t h er e is n o diff er e nc e b et w e e n t h e m e di a n of t h e 1 8 m g d os e S P N -8 1 0  a n d t h e 
m e di a n of pl ac e b o) vs. H
a 1: 2≠ 1,(t h er e is a diff er e nc e b et w e e n t h e m e di a n of t h e 1 8 m g 
d os e S P N -8 1 0   a n d t h e m e di a n of pl ac e b o)  
 
H 0 2: 3= 1, (t h er e is n o diff er e nc e b et w e e n t h e m e di a n of t h e 3 6 m g d os e S P N -8 1 0  a n d t h e 
m e di a n of pl ac e b o) vs. H
a 2: 3≠ 1,(t h er e is a diff er e nc e b et w e e n t h e m e di a n of t h e 3 6 m g 
d os e  S P N -8 1 0   a n d t h e m e di a n of pl ac e b o)  
H a n dli n g Missi n g D at a:  
F or t h e pri m ary effic acy e n d p oi nt, t h e fr e q u e ncy of I A b e h a vi ors d uri n g t h e tr e at m e nt p eri o d will 
b e c alc ul at e d ov er t h e n u m b er of d ays wit h n o n -missi n g I A di ary d at a i n t h e tr e at m e nt p eri o d. N o 
ex plicit i m p ut ati o n of missi n g d at a will b e us e d, b ut t his a p pr o ac h is i m plicitl y e q ui v al e nt t o usi n g 
t h e fr e q u e ncy of I A b e h avi ors d uri n g t h e d a ys wit h n o n-missi n g I A di ary d at a t o i m p ut e t h e 
fr e q u e nc y f or d ays aft er st u dy disc o nti n u ati o n a n d d ays wit h missi n g I A di ary d at a.  
P h ar m ac o ki n etic M et h o ds:  
S a m pli n g : 
5  bl o o d s a m pl e s di vi d e d b et w e e n 2  visits.  
Bi o a n al ytic al A n al ysis:  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 
 
 
P h ar m ac oki n etic  A n al ysis:  
  
 
 
 
   
 
 
 
St atistic al M et h o ds:  
S u m m ari es f or c o nti n u o us v ari a bl es will i ncl u d e t h e s a m pl e siz e, m e a n, a n d st a n d ar d d e vi ati o n, 
m e di a n, mi ni m u m, a n d m axi m u m. S u m m ari es f or discr et e v ari a bl es  w ill i ncl u d e t h e t a b ul ati o n of 
fr e q u e nci es a n d p erc e nt a g es.  
T h e pri m ar y effic acy a n alysis will b e b as e d o n t h e I T T p o p ul ati o n.  T h e pri m ar y effic ac y e n d p oi n t is 
t h e p erc e nt c h a n g e i n t h e fr e q u e nc y  ( u n w ei g ht e d sc or e) of I A b e h avi ors p er  7 d ays i n t h e 
Tr e at m e nt  p eri o d r el ati v e t o t h e B as eli n e  p eri o d i n t h e I T T p o p ul ati o n c alc ul at e d ov er t h e n u m b er 
of d a ys wit h n o n -missi n g I A di ar y d at a.  
T h e pri m ar y effic acy a n alysis will b e p erf or m e d usi n g t h e Wilc ox o n r a n k -s u m t est t o c o m p ar e t h e 
m e di a ns of e ac h of t h e t w o d os es of S P N -8 1 0 ( 1 8 m g a n d 3 6 m g) wit h t h e m e di a n of t h e Pl ac e b o.  
T h e H o d g es -L e h m a n n esti m at e a n d t h e ass oci at e d 9 5 % c o nfi d e nc e i nt erv al ( CI) will b e c al c ul at e d. 
T h e r o b ust n ess of t h e pri m ar y a n al ys es will b e c h ec k e d b y p erf or mi n g t w o s e nsitivit y a n al ys es .   
E ac h o n e of t h e  six s ec o n d ar y e n d p oi nts will b e a n alyz e d usi n g t h e a n al ysis of c ov ari a nc e m et h o d 
b as e d o n t h e I T T p o p ul ati o n wit h missi n g d at a i m p ut e d usi n g t h e L ast O bs er v ati o n C arri e d F or w ar d 
(L O C F) m et h o d. T h e m o d el i ncl u d es tr e at m e nt a n d b as eli n e as fix e d i n d e p e n d e nt c o v ari at es a n d 
c h a n g e fr o m b as eli n e t o fi n al m ai nt e n a nc e visit as a r es p o ns e v ari a bl e. T h e l e ast s q u ar es m e a n of 
e ac h tr e at m e nt gr o u p, t h e diff er e nc e i n t h e  l e ast s q u ar es m e a n ( 1 8 m g d os e mi n us pl ac e b o a n d 3 6 
m g d os e mi n us pl ac e b o), a n d t h e 2 -si d e d 9 5 % CI f or t h e diff er e nc e will b e o bt ai n e d.   
I nt eri m a n al ysis: 
A si n gl e i nt eri m a n alysis will b e p erf or m e d aft er a p pr oxi m at el y 5 0 % of t h e r a n d o miz e d s u bj ects 
c o m pl et e t h e st u dy. T h e m ai n p ur p os e of t h e i nt eri m a n al ysis is t o r e-esti m at e t h e s a m pl e siz e .  
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
S af et y a n a l ysis: 
S af et y  a n al ys es  will b e b as e d o n t h e s af et y p o p ul ati o n.   All A Es will b e c o d e d usi n g t h e M e dic al 
Dicti o n ar y f or R e g ul at or y Acti viti es ( M e d D R A) a n d will b e s u m m ariz e d usi n g discr et e s u m m ari es at 
t h e s u bj ect a n d ev e nt l ev el b y syst e m or g a n cl ass a n d pr ef err e d t er m f or e ac h tr e at m e nt gr o u p.  
Si mil arly, tr e at m e nt -e m er g e nt A Es will b e s u m m ariz e d b y s ev erit y a n d r el ati o ns hi p s e p ar at ely.  
Vit al si g ns will b e s u m m ariz e d usi n g d escri ptiv e st atistics by tr e at m e nt gr o u ps.  T h e s u m m ary 
i ncl u d es s a m pl e siz e, m e a n, a n d st a n d ar d d evi ati o n, m e di a n, mi ni m u m, a n d m axi m u m.  C o nti n u o us 
l a b or at or y p ar a m et ers will b e s u m m ariz e d si mil arly.  If a p plic a bl e, c at e g oric al l a b or at or y t ests will 
b e s u m m ariz e d usi n g n u m b er a n d p erc e nt of s u bj ects b y tr e at m e nt gr o u ps.   D at a o n i nfr e q u e nt 
b e h a vi ors will b e list e d.  
 
 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
T A BL E O F C O N T E N T S  
 
TI TL E P A G E ............................................................................................................................ 1 
S U M M A R Y O F C H A N G E S ........................................................................................................ 4 
CLI NI C AL P R O T O C OL S Y N O P SI S ............................................................................................ 1 8  
T A BL E O F C O N T E N T S ........................................................................................................... 2 4  
LI S T O F T A BL E S A N D FI G U R E S .............................................................................................. 2 8  
LI S T O F A B B R E VI A TI O N S ...................................................................................................... 2 9  
1  
I N T R O D U C TI O N ............................................................................................................ 3 1  
1. 1  
B ac k gr o u n d ................................................................................................................... 3 1  
1. 2  
S p o ns or’s P h as e 2 a St u d y  ............................................................................................... 3 2  
1. 3  
S p o ns or’s P h as e 2 b St u d y  ............................................................................................... 3 3  
1. 4  
I m p ulsi v e A g gr essi o n Di ar y (I A Di ar y) ............................................................................. 3 4  
1. 5  
St u d y R ati o n al e ............................................................................................................. 3 4  
2  
S T U D Y O BJ E C TI V E S ....................................................................................................... 3 4  
2. 1  
Pri m ar y O bj ecti v e .......................................................................................................... 3 4  
2. 2  
S e c o n d ar y O bj ecti v es ..................................................................................................... 3 5  
2. 3  
T erti ar y O bj ecti v e .......................................................................................................... 3 5  
3  
I N V E S TI G A TI O N AL PL A N ............................................................................................... 3 5  
3. 1  
R a ti o n al e f or St u d y D esi g n, I ncl u di n g C h oic e of Tr e at m e nt Gr o u ps, A p pr o pri at e n ess of 
M e as ur e m e nts ............................................................................................................................. 3 5  
3. 2  
O v er all St u d y D esi g n a n d Pl a n ........................................................................................ 3 6  
3. 2. 1  
Pr e- Tr e at m e nt P h as e .......................................................................................................... 3 6  
3. 2. 1. 1  
Scr e e ni n g P eri o d ........................................................................................................................... 3 6  
3. 2. 1. 2  
B as eli n e P eri o d .............................................................................................................................. 3 7  
3. 2. 2  
Tr e at m e nt P h as e ................................................................................................................. 3 8  
3. 2. 2. 1  
R a n d o miz ati o n .............................................................................................................................. 3 8  
3. 2. 2. 2  
Titr ati o n P eri o d ............................................................................................................................. 3 8  
3. 2. 2. 3  
M ai nt e n a nc e P eri o d ...................................................................................................................... 3 8  
3. 2. 3  
C o nv ersi o n/ T a p er P h as e ..................................................................................................... 3 8  
3. 2. 4  
E n d of St u dy / E arly T er mi n ati o n ........................................................................................ 3 8  
4  
S T U D Y M E T H O D S .......................................................................................................... 4 1  
4. 1  
S el ecti o n of St u d y P o p ul ati o n ......................................................................................... 4 1  
4. 1. 1  
I ncl usi o n Crit eri a ................................................................................................................. 4 1  
4. 1. 2  
Excl usi o n Crit eri a ................................................................................................................. 4 1  
4. 2  
Sc h e d ul e of Visits a n d Pr oc e d ur es .................................................................................. 4 2  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
4. 2. 1  
Visit 1 ................................................................................................................................... 4 5  
4. 2. 2  
Visit 2 ................................................................................................................................... 4 5  
4. 2. 3  
Visit 3 ................................................................................................................................... 4 5  
4. 2. 4  
Visit 4 ................................................................................................................................... 4 6  
4. 2. 5  
Visit 5 ................................................................................................................................... 4 6  
4. 2. 6  
Visit 6 ................................................................................................................................... 4 7  
4. 2. 7  
Visit 7 ................................................................................................................................... 4 7  
4. 2. 8  
P h ar m ac o ki n etic S a m pl e C oll ecti o n .................................................................................... 4 8  
4. 3  
Tr e at m e nts .................................................................................................................... 4 8  
4. 3. 1  
Tr e at m e nts A d mi nist er e d ................................................................................................... 4 8  
4. 3. 2  
I d e ntit y of I nv esti g ati o n al Pr o d uct(s) ................................................................................. 4 8  
4. 3. 3  
St u dy M e dic ati o n H a n dli n g a n d Acc o u nt a bility .................................................................. 4 9  
4. 3. 4  
M et h o d of Assi g ni n g S u bj ects t o Tr e at m e nt Gr o u ps .......................................................... 4 9  
4. 3. 5  
Tr e at m e nt R e pl ac e m e nt ..................................................................................................... 5 0  
4. 3. 6  
D osi n g Sc h e d ul e .................................................................................................................. 5 0  
4. 3. 7  
M et h o d of A d mi nistr ati o n .................................................................................................. 5 0  
4. 3. 8  
Bli n di n g ............................................................................................................................... 5 0  
4. 4  
Pr o hi bit e d M e dic ati o ns: ................................................................................................. 5 1  
4. 5  
C o nc o mit a nt M e dic ati o n ................................................................................................ 5 1  
4. 6  
C o m pl eti o n of St u d y a n d Disc o nti n u ati o n of S u bj ects ..................................................... 5 2  
5  
A N AL Y SI S V A RI A BL E S .................................................................................................... 5 2  
5. 1  
Pri m ar y Effic ac y V ari a bl e ................................................................................................ 5 2  
5. 2  
S ec o n d ar y Effic ac y V ari a bl es .......................................................................................... 5 3  
5. 2. 1  
Cli nic al Gl o b al I m pr essi o n ( C GI) Sc al es ............................................................................... 5 3  
5. 2. 2  
S w a ns o n, N ol a n, P el h a m R ati n g Sc al e- R e vis e d ( S N A P- I V) ................................................. 5 3  
5. 2. 3  
C hil d H e alt h Q u esti o n n air e P ar e nt F or m 2 8- It e m ( C H Q- P F 2 8) ......................................... 5 4  
5. 2. 4  
P ar e nti n g Str ess I n d ex- S h ort F or m ( P SI- 4- S F)  ..................................................................... 5 4  
5. 3  
P h ar m ac o ki n etic M e as ur e m e nts .................................................................................... 5 4  
5. 3. 1  
P h ar m ac o ki n etic V ari a bl es .................................................................................................. 5 4  
5. 3. 2  
Ex pl or at ory P h ar m ac o ki n etic V ari a bl es .............................................................................. 5 4  
5. 4  
S af et y Ass ess m e nts ........................................................................................................ 5 5  
5. 4. 1  
A dv ers e E v e nts .................................................................................................................... 5 5  
5. 4. 1. 1  
C a us alit y ........................................................................................................................................ 5 5  
5. 4. 1. 2  
R ec or di n g a n d E v al u ati o n of A d v ers e E v e nts ................................................................................ 5 5  
5. 4. 1. 3  
Crit eri a f or Ass essi n g S e v erit y ....................................................................................................... 5 6  
5. 4. 1. 4  
Crit eri a f or Ass essi n g C a us alit y ..................................................................................................... 5 6  
5. 4. 2  
S eri o us A dv ers e Ev e nts ( S A E) .............................................................................................. 5 7  
5. 4. 2. 1  
I n v esti g at or R es p o nsi biliti es f or R e p orti n g S A Es .......................................................................... 5 7  
5. 4. 2. 2  
Ot h er E v e nts R e q uiri n g I m m e di at e R e p orti n g .............................................................................. 5 8  
5. 4. 2. 3  
S p o ns or R es p o nsi biliti es f or Ex p e dit e d R e p orti n g of S A Es ........................................................... 5 9  
5. 4. 3 
M a n a g e m e nt of Tr e at m e nt- E m er gi n g E P S ......................................................................... 5 9  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
5. 4. 4  
L a b or at ory M e as ur e m e nts ................................................................................................. 5 9  
5. 4. 5  
Vit al Si g n a n d H ei g ht/ W ei g ht M e as ur e m e nts .................................................................... 6 0  
5. 4. 6  
M e dic al Hist ory ................................................................................................................... 6 0  
5. 4. 7  
P hysic al Ex a mi n ati o ns a n d El ectr oc ar di o gr a ms ( E C Gs) ...................................................... 6 0  
5. 4. 8  
Ot h er S p eci al T ests .............................................................................................................. 6 1  
5. 4. 8. 1  
K- S A D S- PL 2 0 1 3 Di a g n ostic I nt er vi e w ........................................................................................... 6 1  
5. 4. 8. 2  
Si m ps o n- A n g us Sc al e .................................................................................................................... 6 1  
5. 4. 8. 3  
B ar n es A k at hisi a Sc al e ................................................................................................................... 6 1  
5. 4. 8. 4  
A b n or m al I n v ol u nt ar y M o v e m e nt Sc al e ( AI M S) ........................................................................... 6 1  
5. 4. 8. 5  
Viti ell o A g gr essi o n Sc al e ............................................................................................................... 6 2  
5. 4. 8. 6  
R etr os p ecti v e- M o difi e d O v ert A g gr essi o n Sc al e ( R- M O A S) .......................................................... 6 2  
5. 4. 8. 7  
C ol u m bi a S uici d e S e v erit y R ati n g Sc al e ( C- S S R S) .......................................................................... 6 2  
5. 4. 8. 8  
I nfr e q u e nt B e h a vi ors C h ec klist ..................................................................................................... 6 2  
6  
S T A TI S TI C AL M E T H O D S ................................................................................................. 6 2  
6. 1  
St atistic al a n d A n al ytic al Pl a ns ....................................................................................... 6 2  
6. 2  
H a n dli n g Missi n g D at a ................................................................................................... 6 3  
6. 3  
A n al ysis P o p ul ati o ns ...................................................................................................... 6 3  
6. 4  
D e m o gr a p hic a n d B as eli n e C h ar act eristics ...................................................................... 6 4  
6. 5  
S u bj ect Dis p ositi o n ........................................................................................................ 6 4  
6. 6  
Pr ot oc ol D e vi ati o ns ........................................................................................................ 6 4 
6. 7  
St u d y M e dic ati o n E x p os ur e a n d C o m pli a nc e ................................................................... 6 5  
6. 8  
C o nc o mit a nt M e dic ati o ns .............................................................................................. 6 5  
6. 9  
Effic ac y A n al ys es ............................................................................................................ 6 5  
6. 9. 1  
Pri m ar y Effic acy A n al ysis ..................................................................................................... 6 5  
6. 9. 2  
S ec o n d ar y Effic ac y A n alys es ............................................................................................... 6 6  
6. 9. 3  
S e nsiti vity A n al ysis .............................................................................................................. 6 7  
6. 9. 3. 1  
M ulti pl e i m p ut ati o n u n d er  Missi n g at R a n d o m ( M A R) ................................................................ 6 7  
6. 9. 3. 2  
M ulti pl e i m p ut ati o n u n d er Missi n g N ot at R a n d o m ( M N A R) ....................................................... 6 8  
6. 9. 3. 3  
P er Pr ot oc ol A n al ysis ..................................................................................................................... 6 8  
6. 1 0  
S a m pl e Siz e a n d P o w er C o nsi d er ati o ns ........................................................................... 6 8  
6. 1 1  
I nt eri m A n al ysis ............................................................................................................. 6 8  
6. 1 2  
Ass ess m e nt of M CI C ....................................................................................................... 6 8  
6. 1 3  
P h ar m ac o ki n etic A n al ys es .............................................................................................. 7 0  
6. 1 4  
S af et y A n al ys es .............................................................................................................. 7 0  
6. 1 4. 1  
A dv ers e E v e nts .................................................................................................................... 7 0  
6. 1 4. 2  
L a b or at ory V al u es ............................................................................................................... 7 1  
6. 1 4 . 3  
Vit al Si g ns, H ei g ht a n d W ei g ht ............................................................................................ 7 1  
6. 1 4. 4  
E C G R es ults ......................................................................................................................... 7 1  
6. 1 4. 5  
P hysic al Ex a mi n ati o ns ......................................................................................................... 7 2  
6. 1 4. 6  
C ol u m bi a S uici d e S ev erity R ati n g Sc al e ( C- S S R S) ................................................................ 7 2  
6. 1 4. 7  
I nfr e q u e nt B e h avi ors C h ecklist ........................................................................................... 7 2  
6. 1 4. 8  
Ot h er S p eci al T ests .............................................................................................................. 7 2  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
7  
D O C U M E N T A TI O N ........................................................................................................ 7 2  
7. 1  
A d h er e nc e t o t h e Pr ot oc ol ............................................................................................. 7 2  
7. 2  
C h a n g es t o t h e Pr ot oc ol ................................................................................................. 7 2  
7. 3  
Pr ot oc ol D e vi ati o ns ........................................................................................................ 7 3  
7. 4  
D at a Q u alit y Ass ur a nc e .................................................................................................. 7 3  
7. 4. 1  
D at a C oll ecti o n .................................................................................................................... 7 3  
7. 4. 2  
Cli nic al D at a M a n a g e m e nt .................................................................................................. 7 4  
7. 4. 3  
D at a b as e Q u ality Ass ur a nc e ............................................................................................... 7 4  
7. 4. 4  
Bi o a n al ytic al D at a M a n a g e m e nt a n d Q u ality C o ntr ol ........................................................ 7 4  
7. 5  
R et e nti o n of R ec or ds ..................................................................................................... 7 4  
7. 6  
A u diti n g Pr oc e d ur es ....................................................................................................... 7 5  
7. 7  
P u blic ati o n of R es ults ..................................................................................................... 7 5  
7. 8  
Fi n a nci n g a n d I ns ur a nc e ................................................................................................. 7 5  
7. 9  
Discl os ur e a n d C o nfi d e nti alit y ........................................................................................ 7 5  
7. 1 0  
Disc o nti n u ati o n of St u d y ................................................................................................ 7 6  
8  
E T HI C S .......................................................................................................................... 7 6  
8. 1  
I nstit uti o n al R e vi e w B o ar ds / I n d e p e n d e nt Et hics C o m mitt e es ........................................ 7 6  
8. 2  
Et hic al C o n d uct of t h e St u d y ........................................................................................... 7 6  
8. 3  
I n v esti g at ors a n d St u d y P ers o n n el .................................................................................. 7 7  
8. 4  
S u bj ect I nf or m ati o n a n d C o ns e nt/ Ass e nt ........................................................................ 7 7  
9  
R E F E R E N C E LI S T ............................................................................................................ 7 7  
1 0  
A P P E N DI C E S .............................................................................................................. 8 1  
1 0. 1  
A d a pti v e D esi g n Pl a n ..................................................................................................... 8 1  
1 0 . 1. 1  
I ntr o d ucti o n ........................................................................................................................ 8 1  
1 0. 1. 2  
Tri al D esi g n .......................................................................................................................... 8 1  
1 0. 1. 3  
D ecisi o n R ul es at I nt eri m A n al ysis ...................................................................................... 8 2  
1 0. 1. 4  
A d a pti v e D esi g n .................................................................................................................. 8 3  
1 0. 1. 5  
I m p ort a nt I nt eri m A n alysis C o nsi d er ati o ns ........................................................................ 8 6  
1 0. 1. 5. 1  R es p o nsi bl e P art y .......................................................................................................................... 8 6  
1 0. 1. 5. 2  C o nfi d e nti alit y ............................................................................................................................... 8 6  
1 0. 2  
R etr os p ecti v e M o difi e d O v ert A g gr essi o n Sc al e ( R- M O A S) .............................................. 8 7  
1 0. 3  
Cli nic al Gl o b al I m pr essi o n ( C GI) Sc al e ............................................................................. 8 9  
1 0. 4  
Viti ell o Sc al e .................................................................................................................. 9 0  
1 0 . 5 
Ki d di e- S a ds- Pr es e nt a n d Lif eti m e V ersi o n ( K- S A D S- PL) 2 0 1 3 ............................................ 9 1  
1 0. 6  
C ol u m bi a- S uici d e S e v erit y R ati n g Sc al es ( C- S S R S) .......................................................... 2 0 2 
1 0. 7  
S w a ns o n, N ol a n a n d P el h a m R ati n g Sc al e- R e vis e d ( S N A P I V) ......................................... 2 0 9 
1 0. 8  
Si m ps o n- A n g us R ati n g Sc al e ......................................................................................... 2 1 0 
1 0. 9  
B ar n es A k at hisi a R ati n g Sc al e ( B A R S) ............................................................................ 2 1 4 
1 0. 1 0  
A b n or m al I n v ol u nt ar y M o v e m e nt Sc al e ( AI M S) ............................................................ 2 1 6 
1 0. 1 1  
C hil d H e alt h Q u esti o n n air e P ar e nt F or m 2 8-it e m ( C H Q- P F 2 8) ........................................ 2 2 1 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 1 2  
P ar e nti n g Str ess I n d e x- S h ort F or m ( P SI- 4- S F) ................................................................ 2 2 5 
 
LI S T O F T A BL E S A N D FI G U R E S 
 
T a bl e 1:  Sc h e d ul e of Visits a n d Pr oc e d ur es ............................................................................................... 4 3  
T a bl e 2: D osi n g Sc h e d ul e ( T ot al D aily D os e) ............................................................................................... 5 0  
T a bl e 3: Cli nic al L a b or at or y T ests ............................................................................................................... 6 0  
 
Fi g ur e 1: Tr e at m e nt Sc h e d ul e ( C o nv ersi o n) ............................................................................................... 3 9  
Fi g ur e 2: Tr e at m e nt Sc h e d ul e ( T a p er) ........................................................................................................ 4 0  
 
 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
LI S T O F A B B R E VI A TI O N S 
 
A D H D  
Att e nti o n -D eficit Hy p er activit y Dis or d er  
A E  
A dv ers e E v e nt  
A E SI  
A dv ers e E v e nt of S p eci al I nt er est  
AI M S  
A b n or m al I nv ol u nt ary M o v e m e nt Sc al e  
A S D  
A utis m S p ectr u m Dis or d er  
BI D  
T wic e a D a y  
C F R  
C o d e of F e d er al R e g ul ati o ns  
C GI -S  
Cli nic al Gl o b al I m pr essi o n –  S e v erit y of Ill n ess  
C GI -I 
Cli nic al Gl o b al I m pr essi o n –  Gl o b al I m pr ov e m e nt  
C H Q -P F 2 8  
CL/ F  
C hil d H e alt h Q u esti o n n air e P ar e nt F or m 2 8 -it e m  
A p p ar e nt Cl e ar a nc e  
C R A  
Cli nic al R es e arc h Ass oci at e  
C R O  
C o ntr act R es e arc h Or g a niz ati o n  
C -S S R S  
C ol u m bi a S uici d e S ev erity R ati n g Sc al e  
e C R F  
El ectr o nic C as e R e p ort F or m  
E P S  
Extr a pyr a mi d al Sy m pt o ms  
F O C B P  
F e m al es of C hil d b e ari n g P ot e nti al  
I A 
I m p ulsiv e A g gr essi o n  
I A F 
I nf or m e d A ss e nt F or m  
I C F 
I nf or m e d C o ns e nt For m  
I C H 
I nt er n ati o n al C o nf er e nc e o n H ar m o niz ati o n 
I E C 
I n d e p e n d e nt Et hics C o m mitt e e 
I R B 
I nstit uti o n al R evi e w B o ar d 
I T T 
I nt e nt t o Tr e at 
K BI T -2  
K a uf m a n Bri ef I nt elli g e nc e T est, S ec o n d E diti o n  
K -S A D S -PL  2 0 1 3  
Sc h e d ul e f or Aff ecti v e Dis or d ers a n d Sc hiz o p hr e ni a f or Sc h o ol -a g e d 
C hil dr e n –  Pr es e nt a n d Lif eti m e V ersi o ns  2 0 1 3  
L S M 
L e ast-s q u ar e M e a ns  
M A R  
Missi n g at R a n d o m  
M e d D R A  
M e dic al Dicti o n ary f or R e g ul at or y Activiti es  
MI  
M ulti pl e I m p ut ati o n  
M N A R  
Missi n g  N ot at R a n d o m  
O D D  
O p p ositi o n al D efi a nt Dis or d er  
P K  
P SI -4 -S F 
P h ar m ac o ki n etic(s)  
P ar e nti n g Str ess I n d ex –  S h ort F or m  
Q D  
O nc e a D ay  
R -M O A S  
R etr os p ectiv e M o difi e d O v ert A g gr essi o n Sc al e  
S A E  
S eri o us A dv ers e E v e nt 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 3 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
S A P  
St atistic al A n alysis Pl a n  
S M  
St u dy M e dic ati o n  
S N A P -I V 
S w a ns o n, N ol a n a n d P el h a m R ati n g Sc al e - R evis e d  
T D D  
T ot al D aily D os e  
UL N  
U p p er Li mit of N or m al  
V/ F  
A p p ar e nt V ol u m e of Distri b uti o n  
   
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 3 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1  I N T R O D U C TI O N 
1. 1  B ac k gr o u n d 
B e h a vi or wit h t h e i m m e di at e i nt e nt t o c a us e h ar m –  w h et h er t o s elf, ot h ers, o bj ects, or pr o p ert y –  
c o nstit ut es a g gr essi o n. A g gr essi v e b e h avi or b ec o m es m al a d a ptiv e w h e n it p ersists, occ urs o utsi d e a n 
acc e pt a bl e s oci al c o nt ext, a n d is of a n i nt e nsity, fr e q u e nc y, s e v erity a n d/ or d ur ati o n d etri m e nt al t o t h e 
c hil d’s i nt er ests ( C o n n or 2 0 0 6; J e ns e n 2 0 0 7). M al a d a pti v e a g gr essi o n is a n ex pr essi o n of c e ntr al n erv o us 
s yst e m d ysf u ncti o n a n d m ay t h er ef or e b e a m e n a bl e t o tr e at m e nts t ar g eti n g its n e ur o bi ol o gic s u bstr at e.  
A g gr essi o n c a n b e c at e g oriz e d i nt o t w o br o a d s u bt y p es b as e d o n t h e a g gr e ss or’s m otiv ati o n – 1) 
r e activ e or i m p ulsiv e a n d 2) pr o acti v e or i nstr u m e nt al ( Viti ell o 1 9 9 7). I m p ulsiv e a g gr essi o n (I A) is a n gr y, 
r et ali at or y a g gr essi o n arisi n g o ut of fr ustr ati o n, a n n oy a nc e, or h ostilit y t o r e al or p erc eiv e d pr o v oc ati o ns 
–  str ess ors t h at y o ut h of t h e s a m e a g e ty pic all y ex p eri e nc e wit h e q u a ni mit y. I A is t h er ef or e a n 
u n pl a n n e d a n d i m m e di at e r es p o ns e r efl ecti n g o ut- of -c o ntr ol e m oti o n alit y t h at s atisfi es i m m e di at e 
e m oti o n al pr ess ur es, al b eit wit h n e g ati v e c o ns e q u e nc es t o t h e a g gr ess or. I n c o ntr ast, i nstr u m e nt al 
a g gr essi o n is c o nsci o usly pl a n n e d, g o al- ori e nt e d b e h avi or wit h t h e s p ecific i nt e nt of b e n efiti n g t h e 
a g gr ess or (J e ns e n 2 0 0 7).   
I A is a c o m m o n c o m or bi dity i n att e nti o n- d eficit/ h y p er acti vity dis or d er ( A D H D) a n d is oft e n r efr act or y t o 
pri m ar y A D H D t h er a py. I n t h e M ulti m o d al Tr e at m e nt of C hil dr e n wit h A D H D ( M T A) st u dy ( M T A 1 9 9 9), 
5 4 % of pr e a d ol esc e nt st u dy p artici p a nts wit h A D H D C o m bi n e d s u bt y p e dis pl a y e d cli nic all y si g nific a nt 
a g gr essi o n at b as eli n e. Of t h es e, 4 4 % r e m ai n e d si g nific a ntl y sy m pt o m atic i n t er ms of a g gr essi v e 
b e h a vi or aft er 1 4 m o nt hs of o pti m al m e dic ati o n (sti m ul a nts) wit h/ wit h o ut b e h a vi or al t h er a py (J e ns e n, 
2 0 0 7).  
I A a m plifi es t h e psyc h ol o gic al, ac a d e mic, e m oti o n al, a n d s oci al pr o bl e ms ass oci at e d wit h A D H D 
( S h elt o n, 1 9 9 8), m ar k e dly i ncr e asi n g t h e ris k of p e rsist e nt b e h avi or al pr o bl e ms, c o n d uct dis or d er, 
e nc o u nt ers wit h t h e j ustic e s yst e m, d eficits i n ac a d e mic ac hi ev e m e nt, b e h avi or al a n d disci pli n ar y 
pr o bl e ms at sc h o ol, a n d s u bst a nc e ex p eri m e nt ati o n/ a b us e. E arly- o ns et, p erv asi v e a n d u nr e mitti n g I A i n 
t h e c o nt ext of i m p ulsiv e t h o u g hts, e m oti o n al l a bilit y, a n d i m p ulsiv e b e h avi or is t h o u g ht t o r e pr es e nt a 
hi g h-ris k pr ofil e f or pr o gr essi o n fr o m c hil d h o o d A D H D t o a d ult a ntis oci al dis or d ers ( Mc K a y, 2 0 0 1). I n t h e 
c o nt ext of A D H D it r e pr es e nts a s eri o us cli nic al a n d p u blic h e alt h c o nc er n a n d w arr a nts eff ectiv e a n d 
ti m ely i nt er v e nti o n. 
Si nc e pri m ary A D H D t h er a py h as li mit e d eff ect o n I A, a st e p p e d-c ar e a p pr o ac h h as b e e n r ec o m m e n d e d, 
wit h a g gr essi o n-t ar g et e d t h er a py s uc h as a n a nti psyc h otic a d d e d t o A D H D t h er a py t o m a n a g e r esi d u al 
a g gr essi v e b e h avi ors ( Sc ott o- R os at o 2 0 1 2). R is p eri d o n e a n d ot h er “ aty pic al” a nti ps yc h otics h av e 
hist oric ally b e e n at t h e f or efr o nt of tr e at m e nt r ec o m m e n d ati o ns r e g ar di n g c o m bi n ati o n t h er a py f or 
m a n a gi n g c o m or bi d a g gr essi o n i n c hil dr e n wit h A D H D ( P a p p a d o p ul os et al. 2 0 0 3; Plisz k a et al. 2 0 0 6; 
Plisz k a et al. 2 0 0 7). H o w ev er, o nly t w o d o u bl e- bli n d r a n d o miz e d pl ac e b o-c o ntr oll e d tri als of ris p eri d o n e 
as a dj u ncti v e t h er a py i n c hil dr e n wit h A D H D a n d a g gr essi o n r efr act or y t o sti m ul a nts h a v e b e e n 
p u blis h e d –  1) a pil ot st u dy i n 2 5 c hil dr e n t h at w as li k el y u n d er p o w er e d a n d di d n ot d et ect a si g nific a nt 
tr e at m e nt eff ect ( Ar m e nt er os 2 0 0 7; A m a n 2 0 1 4) a n d 2) t h e r ec e ntl y c o m pl et e d T O S C A ( Tr e at m e nt of 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 3 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
S e v er e C hil d h o o d A g gr essi o n) st u dy ( F ar m er et al. 2 0 1 1; A m a n 2 0 1 4; G a d o w 2 0 1 4). T h e eff ect siz e f or 
ris p eri do n e’s eff ect o n I A w as s m all ( 0. 2 9), ev e n t h o u g h t h e d os a g e c o ul d b e a dj ust e d t o o pti m al eff ect. 
T h e T O S C A st u dy pr ovi d es i niti al e m piric al evi d e nc e s u p p orti n g a st e p p e d-c ar e a p pr o ac h i n w hic h A D H D 
c hil dr e n wit h s e v er e a g gr essi o n ar e i niti ally tr e at e d wit h pri m ar y A D H D t h er a py f oll o w e d b y a dj u nctiv e 
a nti ps yc h otic t h er a py t ar g et e d t o I A .  H o w e v er, t h e l o n g-t er m eff ects of ris p eri d o n e a n d si mil ar 
a nti ps yc h otics i n t er ms of m et a b olic d er a n g e m e nts pr e dicti v e of di a b et es a n d c ar di o v asc ul ar dis e as e, 
h a v e b ec o m e c a us e f or c o nsi d er a bl e c o nc er n, es p eci all y i n t h e f ac e of v er y li mit e d e vi d e nc e of effic ac y 
as a g gr essi o n-t ar g et e d t h er a py i n A D H D.   T h e T O S C A st u dy c o nfir m e d t h at sti m ul a nt c o-t h er a py d o es 
n ot att e n u at e t h e a d v ers e eff ects of ris p eri d o n e or si mil ar a g e nts o n b o dy c o m p ositi o n, m et a b olic 
p ar a m et ers, pr ol acti n, or s e d ati o n ( C al ar g e 2 0 0 9; P e nz n er 2 0 0 9). 
M oli n d o n e hy dr oc hl ori d e ( m oli n d o n e) is a m e di u m p ot e nc y a nti ps yc h otic, a n d is c urr e ntl y u n d er 
d e v el o p m e nt by t h e S p o ns or as a n ext e n d e d-r el e as e f or m ul ati o n ( S P N- 8 1 0), f or its p ot e nti al utilit y i n 
tr e ati n g I A i n c hil dr e n wit h A D H D.  
I n a n o p e n-l a b el st u dy, m oli n d o n e i m pr ov e d a g gr essi v e b e h a vi or i n c hil dr e n ( N = 6, 6- 1 1 y e ars of a g e) 
wit h u n d ers oci aliz e d c o n d uct dis or d er, a g gr essi v e ty p e ( Gr e e n hill 1 9 8 1).  T h e o pti m u m d os e w as 0. 5 
m g/k g/ d a y.  M oli n d o n e w as als o s h o w n t o b e eff ecti v e i n tr e ati n g a g gr essiv e b e h a vi or i n a d o u bl e- bli n d, 
8- w e e k, i n p ati e nt st u dy of 3 1  c hil dr e n, a g es 6 t o 1 1, wit h u n d ers oci aliz e d c o n d uct dis or d er, a g gr essiv e 
t y p e ( Gr e e n hill 1 9 8 5).  
Pri or t o its wit h dr a w al fr o m t h e U S m ar k et f or c o m m erci al r e as o ns, I m m e di at e- R el e as e M oli n d o n e 
( M o b a n ®) w as a p pr o v e d f or t h e tr e at m e nt of sc hiz o p hr e ni a i n a d ults a n d a d ol esc e nts. Its us e w as als o 
e v al u at e d i n a p e di atric p o p ul ati o n wit h e arly- o ns et sc hiz o p hr e ni a a n d sc hiz o aff ecti v e dis or d er w h e n it 
w as s el ect e d as t h e first- g e n er ati o n a nti ps yc h otic o n t h e b asis of its m or e f a v or a bl e s af ety pr ofil e f or 
c o m p aris o n wit h s ec o n d- g e n er ati o n a g e nts (ris p eri d o n e, ol a nz a pi n e) i n a n NI H-s p o ns or e d st u dy ( T E O S S, 
Tr e at m e nt of E a rl y- O ns et Sc hiz o p hr e ni a S p ectr u m Dis or d ers St u dy) ( Mc Cl ell a n 2 0 0 7). At a n a v er a g e 
d os e of 6 0 m g/ d a y (r a n g e, 1 0- 1 4 0 m g/ d ay), m oli n d o n e w as s h o w n t o b e s af e a n d w ell-t ol er at e d ( Sikic h 
2 0 0 8). M oli n d o n e ( 1 0- 1 4 0 m g/ d ay) w as n ot ass oci at e d wit h si g nific a nt i ncr e as es i n w ei g ht/ B MI (i n 
c o ntr ast t o ol a nz a pi n e). M oli n d o n e w as als o n ot ass oci at e d wit h m or e dyst o nic or p ar ki ns o ni a n 
s y m pt o ms w h e n giv e n wit h b e nztr o pi n e, alt h o u g h ak at hisi a w as r e p ort e d by m or e m oli n d o n e-tr e at e d 
s u bj ects. R es ults of r a n d o miz e d c o ntr oll e d tri als s uc h as T E O S S sti m ul at e d i nt er est i n t h e p ot e nti al 
us ef ul n ess of m oli n d o n e as a w ei g ht- a n d m et a b olic ally- n e utr al D 2-r ec e pt or a nt a g o nist i n c hil dr e n wit h 
A D H D a n d c o m or bi d I A. 
1. 2  S p o ns or’s P h as e 2 a St u d y  
St u dy 8 1 0 P 2 0 1, w as a pr o of- of -c o nc e pt, m ultic e nt er, o p e n-l a b el, p ar all el- gr o u p, r a n d o miz e d, d os e-
r a n gi n g, s af et y, a n d t ol er a bilit y st u dy of m oli n d o n e a d mi nist er e d as ex p eri m e nt al M oli n d o n e I m m e di at e 
R el e as e ( I R) c a ps ul es i n c hil dr e n wit h A D H D a n d p ersist e nt s eri o us c o n d uct pr o bl e ms ( St oc ks 2 0 1 2). 
T ar g et s u bj ects w er e h e alt hy m al e or f e m al e c hil dr e n a g e d 6 t o 1 2 y e ars, i ncl usiv e, wit h a di a g n osis of 
A D H D acc o m p a ni e d b y p ersist e nt s eri o us c o n d uct pr o bl e ms. A t ot al of 7 8 s u bj ects ( 1 9- 2 0 p er tr e at m e nt 
gr o u p) i n t e n U. S sit es w er e r a n d o miz e d. T h e pri m ar y o bj ecti v e w as t o e v al u at e t h e s af ety a n d 
t ol er a bility of f o ur w ei g ht- b as e d d os a g es of M oli n d o n e I R d os e d t hr e e ti m es d aily i n c hil dr e n wit h A D H D 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 3 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
a n d p ersist e nt s eri o us c o n d uct pr o bl e ms ( < 3 0 k g: 
/ d a y; ≥3 0 k g: 
 
m g/ d ay). T h e s ec o n d ary o bj ectiv es w er e t o 1) ex pl or e t h e r el ati o ns hi p b et w e e n m oli n d o n e pl as m a 
c o nc e ntr ati o n ex p os ur e a n d s af ety/t ol er a bilit y e n d p oi nts a n d 2) ass ess t h e eff ect of M oli n d o n e I R aft er 
6 w e e ks of m ai nt e n a nc e tr e at m e nt i n r e d uci n g p ersist e nt s eri o us c o n d uct pr o bl e ms as m e as ur e d b y t h e 
C o n d uct Pr o bl e m S u bsc al e of t h e Nis o n g er C hil d B e h avi or R ati n g F or m- T y pic al I nt elli g e nc e Q u oti e nt 
( N C B R F- TI Q). 
 
 
 
1. 3  S p o ns or’s P h as e 2 b St u d y 
S p o ns or c o m pl et e d a P h as e 2 b m ultic e nt er, r a n d o miz e d, d o u bl e- bli n d, pl ac e b o-c o ntr oll e d tri al i n t h e 
U nit e d St at es i n p e di atric s u bj ects 6 t o 1 2 y e ars of a g e di a g n os e d wit h A D H D a n d I A t h at w as n ot 
c o ntr oll e d b y o pti m al sti m ul a nt a n d b e h avi or al t h er a py ( S p o ns or St u dy 8 1 0 P 2 0 2).  T h e pri m ary o bj ectiv e 
of t h e st u dy w as t o ass ess t h e eff ect of a n ext e n d e d-r el e as e t a bl et f or m ul ati o n of m oli n d o n e 
hy dr oc hl ori d e ( S P N- 8 1 0) ( 1 2 t o 5 4 m g/ d a y) i n r e d uci n g I A as m e as ur e d b y t h e R etr os p ecti v e- M o difi e d 
O v ert A g gr essi o n Sc al e ( R- M O A S) aft er at l e ast t hr e e w e eks of assi g n e d tr e at m e nt. S ec o n d ary e n d p oi nts 
i ncl u d e d t h e r at e of r e missi o n of I A a n d m e as ur e m e nt of t h e eff ectiv e n ess of S P N- 8 1 0 o n Cli nic al Gl o b al 
I m pr essi o n ( C GI) a n d A D H D sc al es as w ell as ev al u ati o n of t h e s af et y a n d t ol er a bilit y of t h e 
dr u g.  P ati e nts w h o c o m pl et e d t h e st u dy w er e off er e d t h e o p p ort u nity t o c o nti n u e i nt o a n o p e n-l a b el 
p h as e of six m o nt hs d ur ati o n.   
S P N- 8 1 0 d os e wit hi n tr e at m e nt gr o u ps w as str atifi e d by w ei g ht ( b el o w/ a b ov e 2 0 k g).  B ot h t h e m e di u m 
( 2 4/ 3 6 m g) a n d l o w ( 1 2/ 1 8 m g) d os e gr o u ps s h o w e d st atistic ally si g nific a nt diff er e nc e fr o m t h e pl ac e b o 
gr o u p i n t h e c h a n g e fr o m b as eli n e t o Visit 1 0 i n R- M O A S b ut t h e hi g h ( 3 6/ 5 4 m g) d os e gr o u p w as n ot 
si g nific a ntl y diff er e nt fr o m t h e pl ac e b o gr o u p. F urt h er m or e, b ot h t h e l o w d os e a n d m e di u m d os e gr o u ps 
w er e si g nific a ntl y diff er e nt fr o m t h e hi g h d os e b as e d o n p air- wis e c o m p aris o n a m o n g t h e d os e gr o u ps.  
 
 
 
 
 
 
 
 
 
 
 
 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 3 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 
 
 
  
1. 4  I m p ulsi v e A g gr essi o n Di ar y (I A Di ar y)  
S p o ns or h as d e v el o p e d a n d v ali d at e d a n e w m e as ur e m e nt t o ol t o ass ess b e h avi ors ass oci at e d wit h I A . 
T h e i m p ulsiv e a g gr essi o n di ar y ( I A di ary) is a n el ectr o nic o bs er v er-r e p ort e d o utc o m e ( e O bs R O) 
i nstr u m e nt t h at c o m pris es a n e pis o dic di ary (t o b e r e p ort e d as s o o n as p ossi bl e aft er t h e p ar e nt or ot h er 
g u ar di a n or o bs er v er wit n ess es t h e c hil d’s I A b e h a vi or) a n d a n ev e ni n g di ary (t o e n a bl e at a mi ni m u m, 
c o m pl eti o n of t h e di ar y o nc e e ac h d a y).  T h e I A di ary m o nit ors t h e fr e q u e ncy of occ urr e nc e of 1 5 IA 
b e h a vi ors: Y elli n g, Scr e a mi n g, T hr e at e ni n g, Scr atc hi n g, T hr o wi n g, Sl a m mi n g, Hitti n g S elf, Ar g ui n g, 
C ursi n g, N a m e C alli n g, S h ovi n g, H air P ulli n g, Fi g hti n g, Hitti n g Ot h ers, Kicki n g Ot h ers.  T h e d ev el o p m e nt 
pr oc ess f oll o w e d F D A’s “ G ui d a nc e f or I n d ustry P ati e nt - R e p ort e d O utc o m e M e as ur es: Us e i n M e dic al 
Pr o d uct D e v el o p m e nt t o S u p p ort L a b eli n g Cl ai ms. ”  T hr o u g h t his pr oc ess, t h e I A di ary w as d e m o nstr at e d 
t o b e a psyc h o m etric ally v ali d a n d r eli a bl e t o ol t o ass ess I A i n c hil dr e n ( S p o ns or St u dy 8 1 0 P 5 0 1).   
1. 5  St u d y R ati o n al e 
T h e r es ults of t h e P h as e 2 b st u dy i n dic at e d t h at d os es r a n gi n g fr o m  
/ d a y w er e s af e, eff ecti v e 
a n d w ell t ol er at e d.  T his P h as e 3 st u dy s e e ks t o d e m o nstr at e t h e effic acy, s af et y, a n d t ol er a bilit y of S P N-
8 1 0 i n t h e tr e at m e nt of I A i n p ati e nts wit h A D H D i n c o nj u ncti o n wit h st a n d ar d A D H D tr e at m e nt. St u dy 
m e dic ati o n ( S M) will b e giv e n as a divi d e d d os e t wic e d aily ( BI D) wit h or wit h o ut f o o d.  A r a n d o miz e d, 
pl ac e b o-c o ntr oll e d, d o u bl e bli n d, m ultic e nt er, p ar all el gr o u p, fix e d d os e st u dy d esi g n will b e us e d. 
Fr e q u e nc y of I A b e h a vi ors will s erv e as a pr oxy f or I A s e v erit y.  T h e I A di ary will b e us e d t o ass ess t h e 
fr e q u e nc y of I A b e h a vi ors.  T h e I A di ar y w as d e v el o p e d a n d v ali d at e d f or us e as a c o nt e m p or a n e o us, 
e v e nt- driv e n, o bs er v er-r e p ort e d o utc o m e m e as ur e.  It m o nit ors b e h avi ors t h at h a v e b e e n s p ecific ally 
li n k e d t o I A.  It d o es n ot r ely o n l o n g p eri o ds of r ec all or s u bj ecti v e w ei g hti n g of b e h a vi ors.  F or t h es e 
r e as o ns, t h e I A di ar y is u ni q u el y s uit e d t o d et ect c h a n g es i n t h e fr e q u e ncy I A b e h a vi ors, w hic h i n t ur n is 
i n dic ati v e of t h e s e v erit y of I A.    
A d diti o n ally, I A s ev erity a n d i m pr ov e m e nt will b e ass ess e d usi n g Cli nic al Gl o b al I m pr essi o n ( C GI) sc al es 
c o m pl et e d b y b ot h i nv esti g at or a n d c ar e giv er.  S u bj ect a n d c ar e gi v er q u ality of lif e will als o b e 
e v al u at e d.   
T h e eff ect of m oli n d o n e o n b o dy c o m p ositi o n, m et a b olic p ar a m et ers, a n d pr ol acti n will b e e v al u at e d.  
E m er g e nc e of extr a pyr a mi d al s y m pt o ms will b e m o nit or e d. 
2  S T U D Y O BJ E C TI V E S 
2. 1  Pri m ar y O bj ecti v e 
T h e pri m ar y o bj ecti v e is t o ass ess t h e effic acy a n d s af et y of S P N- 8 1 0 i n r e d uci n g t h e fr e q u e ncy of I A 
b e h a vi ors i n p e di atric p ati e nts wit h A D H D w h e n t a k e n i n c o nj u ncti o n wit h st a n d ar d A D H D tr e at m e nt. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 3 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
2. 2  S ec o n d ar y O bj ecti v es 
T h e s ec o n d ary o bj ectiv es of t h e st u dy ar e t o ass ess t h e f oll o wi n g:  
 
t h e eff ect of S P N- 8 1 0 o n t h e Cli nic al Gl o b al I m pr essi o n –  I m pr ov e m e nt Sc al e ( C GI-I)  
 
t h e eff ect of S P N- 8 1 0 o n t h e Cli nic al Gl o b al I m pr essi o n –  S ev erity Sc al e ( C GI-S)  
 
t h e eff ect of S P N-8 1 0 o n t h e c hil d’s o v er all h e alt h as m e as ur e d b y t h e C hil d H e alt h 
Q u esti o n n air e P ar e nt F or m 2 8-it e m ( C H Q- P F 2 8) 
 
t h e eff ect of tr e ati n g t h e c hil d wit h S P N- 8 1 0 o n t h e p ar e nt-c hil d r el ati o ns hi p as m e as ur e d b y t h e 
P ar e nti n g Str ess I n d ex –  S h ort F or m v ersi o n 4 ( P SI- 4-S F)   
 
t h e eff ect of S P N- 8 1 0 o n t h e c ar e giv er-c o m pl et e d C GI-I 
 
t h e eff ect of S P N- 8 1 0 o n i n att e nti o n a n d h y p er activit y-i m p ulsivity m e as ur e d b y t h e S N A P-I V 
R ati n g Sc al e 
2. 3  T erti ar y O bj ecti v e 
 
 
 
3  I N V E S TI G A TI O N AL PL A N 
3. 1  R ati o n al e f or St u d y D esi g n, I ncl u di n g C h oic e of Tr e at m e nt Gr o u ps, 
A p pr o pri at e n ess of M e as ur e m e nts 
T h e pr es e nt st u dy is d esi g n e d t o ev al u at e t h e effic acy, s af ety, a n d t ol er a bilit y of S P N- 8 1 0 i n p ati e nts 
a g e d 6 t o 1 2  y e ars wit h A D H D a n d c o m or bi d I A, w h e n t a k e n i n c o nj u ncti o n wit h a st a n d ar d A D H D 
tr e at m e nt.  I n t his p ati e nt p o p ul ati o n, I A b e h a vi ors p ersist, d es pit e m o n ot h er a py tr e at m e nt wit h a n 
F D A- a p pr o v e d A D H D m e dic ati o n, sti m ul a nt or n o n-sti m ul a nt, at a n F D A- a p pr o v e d o pti miz e d d os e. 
A titr ati o n sc h e d ul e will b e f oll o w e d t o e ns ur e a s af e esc al ati o n t o e ac h d os e l ev el.   T h e titr ati o n r at e 
a n d d os e r a n g e u n d er i nv esti g ati o n i n t h e pr es e nt st u dy w er e d e m o nstr at e d t o b e s af e, effic aci o us, a n d 
w ell t ol er at e d i n a si mil ar p ati e nt p o p ul ati o n i n t h e pr e vi o us P h as e 2 b st u dy.  A d mi nistr ati o n of st u dy 
m e dic ati o n will b e r ec or d e d usi n g a n el ectr o nic d osi n g di ar y. 
T h e I A di ar y will s er v e as t h e pri m ary ass ess m e nt t o ol f or effic ac y.  T h e I A di ary is a n e w el ectr o nic 
o bs erv er-r e p ort e d o utc o m e ( e O bs R O) i nstr u m e nt d ev el o p e d by t h e S p o ns or t o r ec or d b e h a vi ors 
ass oci at e d wit h I A.  S ec o n d ar y m e as ur es of effic ac y will i ncl u d e t h e eff ect of S P N- 8 1 0 o n t h e Cli nic al 
Gl o b al I m pr essi o n –  I m pr ov e m e nt Sc al e ( C GI-I), t h e eff ect of S P N- 8 1 0 o n t h e Cli nic al Gl o b al I m pr essi o n –  
S e v erit y Sc al e ( C GI- S), t h e eff ect of S P N- 8 1 0 o n t h e c hil d’s o v er all h e alt h as m e as u r e d by t h e C hil d 
H e alt h Q u esti o n n air e P ar e nt F or m 2 8-it e m ( C H Q- P F 2 8), a n d t h e eff ect of tr e ati n g t h e c hil d wit h S P N- 8 1 0 
o n t h e p ar e nt-c hil d r el ati o ns hi p as m e as ur e d b y t h e P ar e nti n g Str ess I n d ex –  S h ort F or m ( P SI- 4- S F).  T h e 
c hil d’s A D H D s y m pt o ms will b e m e as ur e d usi n g t h e S w a ns o n, N ol a n a n d P el h a m R ati n g Sc al e - R evis e d 
( S N A P-I V). 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 3 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
S af et y will b e ass ess e d b y t h e m o nit ori n g of A Es, c o nc o mit a nt m e dic ati o ns, vit al si g ns, cli nic al l a b or at or y 
t ests, p hysic al ex a mi n ati o ns, a n d E C Gs, as w ell as b y t h e Si m ps o n-A n g u s Sc al e, t h e B ar n es A k at hisi a 
Sc al e, a n d t h e A b n or m al I nv ol u nt ary M ov e m e nt Sc al e ( AI M S).  T h e sc al es w er e c h os e n t o s p ecific ally 
m o nit or E P S, si nc e y o ut h tr e at e d wit h a nti psyc h otics ar e at gr e at er ris k f or E P S si d e eff ects t h a n a d ults 
( Fi n dli n g 2 0 0 5).  T h es e sc al es w er e utiliz e d i n P h as e 2 st u di es a n d h a v e b e e n us e d i n ot h er cli nic al 
st u di es of aty pic al a nti psyc h otics i n c hil dr e n. 
3. 2  O v er all St u d y D esi g n a n d Pl a n 
Pr ot oc ol 8 1 0 P 3 0 1 is a r a n d o miz e d, pl ac e b o-c o ntr oll e d, d o u bl e bli n d, m ultic e nt er, p ar all el gr o u p, fix e d 
d os e st u dy t o d e m o nstr at e t h e effic acy, s af et y, a n d t ol er a bilit y of S P N- 8 1 0 i n t h e tr e at m e nt of I A i n 
p ati e nts a g e d 6- 1 2  y e ars wit h A D H D i n c o nj u ncti o n wit h st a n d ar d A D H D tr e at m e nt.   T h e st u dy is 
pr es e nt e d sc h e m atic ally i n Fi g ur e 1  a n d Fi g ur e 2 .  T h e st u dy is divi d e d i nt o t hr e e p h as es: Pr e- Tr e at m e nt, 
Tr e at m e nt, a n d C o nv ersi o n/ T a p er. 
F oll o wi n g scr e e ni n g, eli gi bl e s u bj ects will e nt er a fl exi bl e b as eli n e p eri o d, at w hic h ti m e t h e I A di ar y will 
b e iss u e d t o t h e s u bj ect’s pri m ar y c ar e giv er.  At t h e e n d of t h e b as eli n e p eri o d, eli gi bl e s u bj ects  w h os e 
pri m ar y c ar e giv er h as m ai nt ai n e d at l e ast 8 0 % c o m pli a nc e wit h t h e I A di ar y will b e r a n d o miz e d 1: 1: 1 t o 
1 8  m g/ d a y S P N- 8 1 0, 3 6 m g/ d a y S P N- 8 1 0, or pl ac e b o. A d os e titr ati o n sc h e d ul e will b e f oll o w e d, wit h 
d osi n g i n t h e activ e tr e at m e nt gr o u ps i niti at e d at 3 m g/ d a y a n d i ncr e as e d a p pr oxi m at el y ev er y 3 d a ys 
u ntil t h e t ar g et d os e is r e ac h e d.   Aft er c o m pl eti n g t h e t w o- w e e k titr ati o n p eri o d a n d t h e t hr e e - w e e k 
m ai nt e n a nc e p eri o d, s u bj ects will e nt er t h e c o nv ersi o n or t a p eri n g p h as e pri or t o disc o nti n ui n g S M, at 
w hic h ti m e s u bj ects will h av e t h e o pti o n t o e nt er a n o p e n l a b el ext e nsi o n ( OL E) st u dy.  A s u bj ect w h o 
disc o nti n u es d uri n g t h e m ai nt e n a nc e p eri o d pri or t o Visit 6 m ay b e all o w e d t o p artici p at e i n t h e OL E o n 
a c as e- by -c as e b asis o nl y aft er c o ns ult ati o n b et w e e n t h e I nv esti g at or, t h e M e dic al M o nit or a n d t h e 
S p o ns or.  T h e OL E st u dy will b e c o n d uct e d u n d er a s e p ar at e pr ot oc ol.  S u bj ects w h o c h o os e t o 
p artici p at e i n t h e OL E will e nt er t h at st u dy at a d os e of 1 8 m g/ d a y S P N- 8 1 0. 
 
3. 2. 1  
Pr e- Tr e at m e nt P h as e 
3. 2. 1. 1  Scr e e ni n g P eri o d 
Scr e e ni n g will t a k e pl ac e f or u p t o 4 5  d a ys pri or t o r a n d o miz ati o n a n d m ay b e c arri e d o ut ov er m or e 
t h a n o n e visit if n ec ess ary.  Pri or t o c o n d ucti n g a n y scr e e ni n g pr oc e d ur es, writt e n i nf or m e d 
c o ns e nt/ ass e nt m ust b e o bt ai n e d fr o m t h e p ar e nt or l e g al r e pr es e nt ativ e, a n d s u bj ect ( w h e n r e q uir e d). 
E ac h scr e e n e d s u bj ect will b e assi g n e d a s u bj ect n u m b er st arti n g fr o m 1 0 0 1 t o 1 9 9 9 i n a s e q u e nti al 
m a n n er. St aff at st u dy sit es ar e e nc o ur a g e d t o c o m pl et e scr e e ni n g pr oc e d ur es as e arl y as p ossi bl e t o 
pr o vi d e m or e fl exi bility i n t h e b as eli n e p eri o d f or t h e c ar e gi v ers t o ac hi ev e I A di ary c o m pli a nc e (s e e 
S ecti o n 3. 2. 1. 2 ). 
T h e R- M O A S a n d C GI - S will b e a d mi nist er e d t o d et er mi n e e ntry t o t h e b as eli n e p eri o d of t h e st u dy a n d 
als o t o d et er mi n e eli gi bilit y f or r a n d o miz ati o n t o tr e at m e nt.  T h e Viti ell o A g gr essi o n Sc al e will b e us e d t o 
e v al u at e s u bty p e of a g gr essi o n ( pl a n n e d vs. i m p ulsiv e); o nl y t h os e c hil dr e n w h o sc or e as pr e d o mi n a ntl y 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 3 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
i m p ulsiv e will b e i ncl u d e d. T h e di a g n osis of A D H D will b e c o nfir m e d wit h t h e Sc h e d ul e f or Aff ectiv e 
Dis or d ers a n d Sc hiz o p hr e ni a f or Sc h o ol- a g e d C hil dr e n — Pr es e nt  a n d Lif eti m e V ersi o ns 2 0 1 3 ( K- S A D S- PL 
2 0 1 3). T h e K- S A D S- PL 2 0 1 3 is a s e mi-str uct ur e d di a g n ostic i nt ervi e w d esi g n e d t o di a g n os e c urr e nt a n d 
p ast e pis o d es of psyc h o p at h ol o gy i n c hil dr e n a n d a d ol esc e nts acc or di n g t o D S M- 5 crit eri a.   T h e 
I ntr o d uct or y a n d Scr e e n I nt er vi e ws will b e c o m pl et e d.  T h e Scr e e n I nt er vi e w will ass ess t h e diff er e nt 
di a g n os es a n d d et er mi n e w hic h s u p pl e m e nts s h o ul d b e c o m pl et e d.  S u p pl e m e nt 4 ( N e ur o d e v el o p m e nt, 
Disr u pti v e a n d C o n d uct Dis or d ers) m ust b e c o m pl et e d t o ass ess A D H D, O D D, C D , Tic a n d A S D ( A utis m 
S p ectr u m Dis or d er).  If a n excl usi o n ary di a g n osis is c o nfir m e d, t h e r e m ai n d er of t h e di a g n ostic will n ot 
b e c o m pl et e d a n d t h e s u bj ect will b e d e e m e d a scr e e n f ail ur e.   
3. 2. 1. 2  B as eli n e P eri o d 
S u bj ects w h o m e et st u dy e ntr y r e q uir e m e nts will pr oc e e d t o t h e fl exi bl e b as eli n e p eri o d.  At Visit 2 a n I A 
di ary d evic e (L o g P a d) will b e iss u e d t o t h e pri m ar y c ar e giv er.  T h e pri m ary a n d (if assi g n e d) s ec o n d ary 
c ar e giv ers will r ec ei v e tr ai ni n g o n t h e us e of t h e I A di ar y. Ev er y eff ort will b e m a d e t o pr ovi d e a d e q u at e 
c ar e giv er tr ai ni n g o n t h e us e of t h e I A di ar y at Visit 2 a n d ac k n o wl e d g e m e nt of tr ai ni n g will b e c a pt ur e d 
o n t h e d e vic e.  
F oll o wi n g at l e ast 1 5 d a ys of I A di ary us e, c ar e giv er c o m pli a nc e wit h t h e I A di ary will b e ass ess e d.  
C o m pli a nc e will b e c alc ul at e d as t h e p erc e nt a g e of d ays o v er t h e p ast 1 5 d a ys d uri n g t h e b as eli n e p eri o d 
f or w hic h a n ev e ni n g di ar y w as c o m pl et e d. S u bj ects w h os e c ar e giv ers d e m o nstr at e at l e ast 8 0 % 
c o m pli a nc e will b e eli gi bl e f or r a n d o miz ati o n a n d c o nti n u e i nt o t h e titr ati o n p eri o d. 
S u bj ects w h os e c ar e giv ers d o n ot r e ac h 8 0 % c o m pli a nc e d uri n g t h e first 1 5 d ays of t h e b as eli n e p eri o d 
m a y b e all o w e d t o c o nti n u e t o us e t h e di ary f or u p t o 1 5 a d diti o n al d ays.  F or t h es e s u bj ects, c ar e giv ers 
will r ec ei v e r e m e di al tr ai ni n g o n t h e us e of t h e I A di ary.  D uri n g t his ti m e, c ar e giv er c o m pli a nc e wit h t h e 
I A di ar y will b e m o nit or e d d aily b y st u dy sit e p ers o n n el o v er t h e p ast 1 5-d a ys as a “r olli n g wi n d o w”.  
W h e n t h e c ar e giv ers’ p erf or m a nc e wit h t h e I A di ary i m pr ov es s uc h t h at t h e c ar e gi v ers ar e a bl e t o 
d e m o nstr at e at l e ast 8 0 % c o m pli a nc e o v er t h e p ast 1 5- d a y r olli n g wi n d o w, t h e s u bj ect will b e eli gi bl e 
f or r a n d o miz ati o n a n d all o w e d t o c o nti n u e i nt o t h e titr ati o n p eri o d.  
Alt h o u g h t h er e ar e u p t o 3 0 d a ys a v ail a bl e f or e ac h of t h e scr e e ni n g a n d t h e b as eli n e p eri o d, t h e t ot al 
d ur ati o n of scr e e ni n g a n d b as eli n e p eri o ds m a y n ot e xc e e d 4 5 d a ys.  
R escr e e ni n g 
As a g e n er al r ul e, r escr e e ni n g of s u bj ects is n ot all o w e d.  T h e o nl y exc e pti o n t o t his will b e f or s u bj ects 
w h o f ail e d scr e e ni n g d u e t o c ar e giv er n o n-c o m pli a nc e wit h t h e I A di ary u n d er pr ot oc ol v ersi o n 5. 0. 
T h es e s u bj ects m ay b e r escr e e n e d t o p artici p at e i n t h e st u dy u n d er c urr e nt pr ot oc ol. T h es e s u bj ects will 
b e assi g n e d a n e w s u bj ect I D n u m b er a n d will c o m pl et e all st u dy scr e e ni n g pr oc e d ur es.   


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 3 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
3. 2. 2  
Tr e at m e nt P h as e   
3. 2. 2. 1  R a n d o miz ati o n 
I ncl usi o n/ excl usi o n crit eri a will b e r e- ass ess e d t o v erify eli gi bilit y pri or t o st u dy r a n d o miz ati o n at t h e e n d 
of Visit 3 ( R a n d o miz ati o n).  Eli gi bl e s u bj ects w h os e pri m ar y c ar e giv er h as m ai nt ai n e d at l e ast 8 0 % 
c o m pli a nc e wit h t h e I A di ary will b e r a n d o miz e d.  Eli gi bl e s u bj ects w h o c o m pl et e t h e b as eli n e p eri o d 
a n d m e et t h e r e q uir e m e nts f or t h e d o u bl e bli n d st u dy will  b e r a n d o miz e d at Visit 3 ( D a y 1) i n a 1: 1: 1 
r ati o t o r ec ei v e 1 8 m g/ d ay, 3 6 m g/ d a y S P N- 8 1 0, or pl ac e b o a n d pr oc e e d t o t h e titr ati o n p eri o d, w hic h 
will b e t w o w e e ks.  
3. 2. 2. 2  Titr ati o n P eri o d 
S u bj ects will b e titr at e d t o m ai nt e n a nc e d os e ov er a p eri o d of 2 w e e ks. 
3. 2. 2. 3  M ai nt e n a nc e P eri o d 
F oll o wi n g d os e titr ati o n, s u bj ects o n acti v e tr e at m e nt will b e m ai nt ai n e d at t h eir d esi g n at e d d os e l e v el 
f or 3 w e e ks.   
3. 2. 3  
C o n v ersi o n/ T a p er P h as e 
All s u bj ects w h o c o m pl et e t h e r a n d o miz e d, d o u bl e bli n d p orti o n of st u dy 8 1 0 P 3 0 1 will h av e t h e o pti o n 
t o p artici p at e i n a n OL E st u dy (st u dy pr ot oc ol 8 1 0 P 3 0 4) i n w hic h all s u bj ects will r ec eiv e acti v e S M 
tr e at m e nt.  S u bj ects c h o osi n g t o p artici p at e will r ec eiv e bli n d e d c o nv ersi o n m e dic ati o n kits, a n d t h eir 
t ot al d ail y d os e f or t h e o p e n l a b el ext e nsi o n will b e c o nv ert e d t o 1 8 m g / d ay (Fi g ur e 1 ).  T h os e s u bj ects 
w h o d o n ot el ect t o p artici p at e i n t his ext e nsi o n will b e t a p er e d off S M ( Fi g ur e 2 ).   
3. 2. 4  
E n d of St u d y / E arl y T er mi n ati o n 
S u bj ects will r et ur n t o t h e st u dy sit e f or a fi n al visit, aft er c o m pl eti n g t h e 1- w e ek T a p er/ C o nv ersi o n 
P eri o d.  T h os e s u bj ects w h o el ect t o c o nti n u e i n t h e OL E st u dy will h av e pr oc e d ur es p erf or m e d f or t h at 
st u dy as w ell.   S u bj ects w h o disc o nti n u e fr o m t h e st u dy d uri n g t h e m ai nt e n a nc e p eri o d will b e off er e d a 
T a p er kit a n d will r et ur n t o t h e st u dy sit e f or a f oll o w- u p visit ( E O S).  S u bj ects w h o disc o nti n u e d uri n g 
t h e titr ati o n p eri o d will n ot r ec eiv e a t a p er kit a n d will o nl y c o m pl et e t h e E O S pr oc e d ur es. 






S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 4 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
4  S T U D Y M E T H O D S 
4. 1  S el ecti o n of St u d y P o p ul ati o n 
T h e t ar g et p o p ul ati o n will b e m al e a n d f e m al e s u bj ects a g e d 6 t o 1 2 y e ars wit h I A a n d A D H D.  S M will b e 
a d mi nist er e d i n c o nj u ncti o n wit h t h e s u bj ect’s st a n d ar d A D H D tr e at m e nt.  A p pr oxi m at el y 3 3 0 s u bj ects 
will b e r a n d o miz e d i n t his cli nic al i n v esti g ati o n.   
4. 1. 1  
I ncl usi o n Crit eri a 
1.  H e alt h y m al e or f e m al e s u bj ects, a g e 6 t o 1 2  y e ars at t h e ti m e of scr e e ni n g.  
2.  Di a g n osis of A D H D acc or di n g t o t h e Di a g n ostic a n d St atistic al M a n u al of M e nt al Dis or d ers- 5   
( D S M- 5 c o nfir m e d by  t h e Sc h e d ul e f or Aff ecti v e Dis or d ers a n d Sc hiz o p hr e ni a f or Sc h o ol- a g e d 
C hil dr e n –  Pr es e nt a n d Lif eti m e V ersi o n 2 0 1 3 ( K- S A D S-PL  2 0 1 3).  
3.  R etr os p ectiv e M o difi e d O v ert A g gr essi o n Sc al e ( R- M O A S) sc or e of 2 4 at scr e e ni n g. 
4.  C GI - S sc or e of at l e ast m o d er at ely ill at b ot h Scr e e ni n g a n d R a n d o miz ati o n.  
5.  Viti ell o A g gr essi o n Sc al e sc or e fr o m - 2 t o - 5 at Scr e e ni n g. 
6.  Fr e e of a nti psyc h otic m e dic ati o n f or at l e ast t w o w e eks pri or t o Visit 2.  
7.  M o n ot h er a py tr e at m e nt wit h F D A- a p pr ov e d o pti miz e d A D H D m e dic ati o n ( ps yc h osti m ul a nt or 
n o n-sti m ul a nt) at a n F D A- a p pr o v e d d os e f or at l e ast o n e m o nt h pri or t o Scr e e ni n g, a n d willi n g 
t o m ai nt ai n t h at d os e t hr o u g h o ut t h e B as eli n e a n d Tr e at m e nt p eri o d.   
8.  α 2 - a dr e n er gic a g o nists ( e. g. cl o ni di n e a n d g u a nf aci n e) us e d f or a n y ot h er r e as o n exc e pt f or 
m o n ot h er a py tr e at m e nt f or A D H D ( e. g. a g gr essi o n or i ns o m ni a) m ust b e disc o nti n u e d at l e ast 
t w o- w e e ks pri or t o Visit 2. 
9.  M e dic ally h e alt hy a n d wit h cli nic all y n or m al l a b or at ory pr ofil es, vit al si g ns, a n d 
el ectr oc ar di o gr a ms ( E C Gs). 
1 0.  W ei g ht of at l e ast 2 0 k g. 
1 1.  A bl e a n d willi n g t o s w all o w t a bl ets w h ol e a n d n ot c h e w e d, c ut or cr us h e d.  
1 2.  Writt e n I nf or m e d C o n s e nt o bt ai n e d fr o m t h e s u bj ect’s p ar e nt or l e g al r e pr es e nt ati v e, a n d 
writt e n I nf or m e d Ass e nt o bt ai n e d fr o m t h e s u bj ect if a p pr o pri at e. 
1 3.  M e as ur e m e nt of c o m pli a nc e ≥ 8 0 % f or c o m pl eti o n of I A Di ary d uri n g B as eli n e P eri o d.  
4. 1. 2  
E xcl usi o n Crit eri a 
1.  B o dy M ass I n d ex ( B MI) i n 9 9 t h p erc e ntil e or a b o v e. 
2.  C urr e nt or lif eti m e di a g n osis of e pil e ps y, m aj or d e pr essi v e dis or d er, bi p ol ar dis or d er, 
sc hiz o p hr e ni a or r el at e d dis or d er, p ers o n alit y dis or d er, T o ur ett e’s dis or d er, or psyc h osis n ot 
ot h er wis e s p ecifi e d. 
3.  C urr e ntl y m e eti n g D S M- 5 crit eri a f or a utis m s p ectr u m dis or d er, p er v asiv e d e v el o p m e nt al 
dis or d er, o bs essi v e c o m p ulsi v e dis or d er, p ost-tr a u m atic str ess dis or d er, or a ny ot h er a nxi ety 
dis or d er as pri m ary di a g n osis. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 4 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
4.  Us e of a ntic o nv uls a nts i ncl u di n g c ar b a m az e pi n e a n d v al pr oic aci d, a nti d e pr ess a nts, m o o d 
st a biliz ers i ncl u di n g lit hi u m, b e nz o di az e pi n es, c h oli n est er as e i n hi bit ors or a ny dr u g k n o w n t o 
i n hi bit C Y P 2 D 6 acti vity wit hi n t w o w e e ks of Visit 2.  
5.  Us e of h er b al s u p pl e m e nts wit hi n o n e w e e k of Visit 2. 
6.  K n o w n or s us p ect e d i nt elli g e nc e q u oti e nt (I Q) < 7 0. 
7.  U nst a bl e e n d ocri n ol o gic al or n e ur ol o gic al c o n diti o ns w hic h c o nf o u n d t h e di a g n osis or ar e a 
c o ntr ai n dic ati o n t o tr e at m e nt wit h a nti ps yc h otics. 
8.  S uici d alit y, d efi n e d as eit h er acti v e s uici d al pl a n/i nt e nt or acti v e s uici d al t h o u g hts i n t h e six 
m o nt hs b ef or e t h e Scr e e ni n g Visit or m or e t h a n o n e lif eti m e s uici d e att e m pt.   
9.  Pr e g n a nc y or r ef us al t o pr actic e c o ntr ac e pti o n d uri n g t h e st u dy (f or f e m al e s u bj ects of 
c hil d b e ari n g p ot e nti al a n d s ex u ally activ e m al es). 
1 0.  S u bst a nc e or alc o h ol us e d uri n g t h e l ast t hr e e m o nt hs. 
1 1.  Uri n e dr u g t est at scr e e ni n g t h at is p ositiv e f or alc o h ol or dr u gs of a b us e. 
1 2.  K n o w n all er g y or s e nsitivity t o m oli n d o n e h y dr oc hl ori d e.  
1 3.  A ny r e as o n w hic h, i n t h e o pi ni o n of t h e I n v esti g at or or t h e S p o ns or, w o ul d pr e v e nt t h e s u bj ect 
a n d s u bj ect’s c ar e giv er fr o m p artici p ati n g i n t h e st u dy or c o m plyi n g wit h t h e st u dy pr oc e d ur es.  
1 4.  Us e of a n i nv esti g ati o n al dr u g or p artici p ati o n i n a n i n v esti g ati o n al st u dy wit hi n 3 0 d a ys pri or t o 
Visit 2. 
4. 2  Sc h e d ul e of Visits a n d Pr oc e d ur es 
All s u bj ects w h o ar e r a n d o miz e d a n d t ak e a ny S M will b e f oll o w e d acc or di n g t o t h e pr ot oc ol r e g ar dl ess 
of t h e n u m b er of d os es of S M t a k e n, u nl ess c o ns e nt f or f oll o w- u p is wit h dr a w n.  T h e S p o ns or, or t h e 
S p o ns or’s d esi g n e e, m ust b e n otifi e d of all d evi ati o ns fr o m t h e pr ot oc ol visits or pr oc e d ur es, a n d t h es e 
pr oc e d ur es, if a p plic a bl e, will b e r esc h e d ul e d or p erf or m e d at t h e n e ar est p ossi bl e ti m e t o t h e ori gi n al 
sc h e d ul e.  S u bj ects will b e i nstr uct e d t o c all st u dy p ers o n n el t o r e p ort a n y a b n or m aliti es d uri n g t h e 
i nt er v als i n b et w e e n st u dy visits a n d t o c o m e t o t h e st u dy sit e if m e dic al e v al u ati o n is n e e d e d a n d as t h e 
ur g e nc y of t h e sit u ati o n i n dic at es.  U nsc h e d ul e d visits m ay b e c o n d uct e d at t h e discr eti o n of t h e 
i nv esti g at or t hr o u g h o ut all st u dy p eri o ds.  T h e m e dic al m o nit or m ust b e c o nt act e d pr o m ptl y i n t h e 
e v e nt t h at a n y cli nic ally si g nific a nt fi n di n gs or i nf or m ati o n ar e o bt ai n e d d uri n g t h e u nsc h e d ul e d visit. 
T his s h o ul d b e c a pt ur e d i n t h e a p pr o pri at e e C R F.  F or e m er g e nc y a n d ot h er u nsc h e d ul e d visits t o a 
m e dic al f acility ot h er t h a n t h e st u dy sit e, m e dic al r ec or ds will b e o bt ai n e d by t h e I nv esti g at or or 
q u alifi e d d esi g n e e as s o urc e d at a f or st u dy f oll o w- u p . 
T a bl e 1  pr es e nts t h e sc h e d ul e of visits a n d pr oc e d ur es f or t h e st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 4 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n 
writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
T a bl e 1:  Sc h e d ul e of Visits a n d Pr oc e d ur es 
P h as e  
Pr e -tr e at m e nt 
Tr e at m e nt  
C o n v ersi o n/  
T a p er  
P eri o d  
Scr e e ni n g  
B as eli n e  
Titr ati o n  
M ai nt e n a nc e  
VI SI T N U M B E R  
1  
2  
3  
4  
5  
6  
7  
D A Y  
-4 5  
-1 5  
1  
8  
1 5  
3 6  
4 3  
WI N D O W ( D A Y S)  
4 5 d pri or t o 
V isit 3  
≥1 5 d pri or t o  
V isit 3  
0 c 
7 d ± 2 d fr o m 
Visit 3  
1 4 d ± 2 d fr o m 
Visit 3  
2 1 d ± 3 d fr o m 
Visit 5  
7 d ± 1 d fr o m 
Visit 6  
I nf or m e d C o ns e nt/ Ass e nt a 
X  b 
 
 
 
 
 
 
R -M O A S, K -S A D S -PL 2 0 1 3 & Viti ell o 
A g gr essi o n Sc al e  
X  
 
 
 
 
 
 
M e dic al Hist or y  
X  
 
X d 
 
 
 
 
D e m o gr a p hics  
X  
 
 
 
 
 
 
P h ysic al Ex a mi n ati o n  
X  
 
 
 
 
X  
 
E C G ( 1 2 -l e a d) 
X  
 
 
X  
 
X  
 
I ncl usi o n/ Excl usi o n Crit eri a 
X  
 
 
 
 
 
 
R a n d o miz ati o n  
 
 
X b ,e 
 
 
 
 
Uri n e Dr u g Scr e e n  
X  
 
X  
 
 
 
 
Uri n e Pr e g n a nc y T est f 
X  
 
X  
 
 
 
X  
Di ar y Tr ai ni n g & Distri b uti o n or E v al u ati o n  
 
X  
X  e 
X  
X  
X  
 
Vit al Si g ns g 
X  
 
 
 
 
 
X  
W ei g ht, h ei g ht , B MI 
X  
 
X  
X  
X  
X  
X  
H e m at ol o gy/c h e mistry/ Uri n al ysis  
X  
 
X  
 
 
X  
X  
P K Bl o o d  S a m pli n g  
 
 
 
X h 
X h 
 
 
C ol u m bi a S uici d e S ev erit y R ati n g Sc al e 
( C S S R S) 
X  
 
X  
X  
X  
X  
X  
I nv esti g at or C GI -S  
X  
 
X  
X  
X  
X  
 
C ar e giv er a n d i nv esti g at or C GI -I 
 
 
 
X  
X  
X  
 
Effic ac y sc al es ( S N A P -I V, C H Q-P F 2 8, P SI -4 -S F ) 
 
 
X  
 
 
X  
 
S af ety Sc al es ( Si m ps o n -A n g us, B ar n es, AI M S)  
 
 
X  
X  
X  
X  
X  
I nfr e q u e nt B e h a vi ors C h ec klist 
 
 
X  
X  
X  
X  
 
A dv ers e E v e nts  
 
 
X  
X  
X  
X  
X  
C o nc o mit a nt M e dic ati o ns  
X  
X  
X  
X  
X  
X  
X  
Dr u g Dis p e ns ati o n  
 
 
X b 
 
X  
X  
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 4 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n 
writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
P h as e  
Pr e -tr e at m e nt 
Tr e at m e nt  
C o n v ersi o n/  
T a p er  
P eri o d  
Scr e e ni n g  
B as eli n e  
Titr ati o n  
M ai nt e n a nc e  
VI SI T N U M B E R  
1  
2  
3  
4  
5  
6  
7  
D A Y  
-4 5  
-1 5  
1  
8  
1 5  
3 6  
4 3  
WI N D O W ( D A Y S)  
4 5 d pri or t o 
V isit 3  
≥1 5 d pri or t o  
V isit 3  
0 c 
7 d ± 2 d fr o m 
Visit 3  
1 4 d ± 2 d fr o m 
Visit 3  
2 1 d ± 3 d fr o m 
Visit 5  
7 d ± 1 d fr o m 
Visit 6  
Dr u g R et ur n a n d C o m pli a nc e  
 
 
 
 
X  
X  
X  
Di ar y R et ur n  
 
 
 
 
 
 
X  
a  
Writt e n c o ns e nt m ust b e o bt ai n e d pri or t o p erf or mi n g a n y st u dy -r el at e d pr oc e d ur e. 
b  
Acc ess I W R S . 
c 
Visit 3 will occ ur at l e ast 1 5 d ays f oll o wi n g Visit 2  
d  
Ass ess f or a n y cli nic ally si g nific a nt c h a n g e i n M e dic al Hist ory si nc e scr e e ni n g . 
e  
Di ary c o m pli a nc e m ust b e at l e ast 8 0 % ( mi ni m u m of 1 2 d ays o ut of 1 5 ) t o q u alify f or 
r a n d o miz ati o n. 
 
f 
T o b e p erf or m e d f or f e m al e s u bj ects of c hil d b e ari n g p ot e nti al  pri or t o a d mi nistr ati o n of 
first d os e of S M a n d will h av e t o b e t est e d as n e g ativ e f or t h e s u bj ect t o c o nti n u e i n 
t h e st u dy. 
g  
H e art R at e ( H R), bl o o d pr ess ur e ( B P), t e m p er at ur e, a n d r es pir at or y r at e will b e 
m e as ur e d.  
h  
T ot al of 5 P K bl o o d s a m pl es will b e o bt ai n e d ov er o n e or t w o visits ( Visit 4 a n d/ or Visit 5)  
 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 4 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
4. 2. 1  
Visit 1 
Pri or t o c o n d ucti n g a n y scr e e ni n g pr oc e d ur es, writt e n I nf or m e d C o ns e nt m ust b e o bt ai n e d fr o m t h e 
p ar e nt or l e g al r e pr es e nt ati v e, a n d, if a p pr o pri at e, I nf or m e d Ass e nt fr o m t h e s u bj ect.  S u bj ect scr e e ni n g 
pr oc e d ur es will b e p erf or m e d wit hi n 4 5  d ays pri or t o Visit 3 a n d m ay b e d o n e o n m or e t h a n o n e d a y.  
A b n or m al r es ults o n scr e e ni n g l a b or at or y t ests m a y b e r e p e at e d at t h e discr eti o n of t h e I nv esti g at or .  
T h e f oll o wi n g pr oc e d ur es will b e p erf or m e d at Visit 1: 
1.  O bt ai n writt e n i nf or m e d c o ns e nt a n d ass e nt. 
2.  O bt ai n d e m o gr a p hic i nf or m ati o n, m e dic al hist ory 
3.  Acc ess I nt er activ e W e b R es p o ns e Syst e m (I W R S) f or s u bj ect n u m b er 
4.  A d mi nist er K- S A D S- PL  2 0 1 3 f or c o nfir m ati o n of A D H D di a g n osis 
5.  A d mi nist er Viti ell o A g gr essi o n Sc al e 
6.  A d mi nist er R- M O A S 
7.  A d mi nist er I nv esti g at or C GI- S 
8.  P erf or m p hysic al ex a mi n ati o n 
9.  R ec or d vit al si g ns ( H R, B P, t e m p er at ur e, a n d R R), h ei g ht, w ei g ht a n d B MI 
1 0.  P erf or m 1 2-l e a d E C G 
1 1.  C oll ect bl o o d s a m pl es f or h e m at ol o gy a n d c h e mistry 
1 2.  A d mi nist er C- S S R S 
1 3.  C oll ect uri n e s a m pl e f or uri n al ysis a n d uri n e dr u g scr e e n ( all s u bj ects), a n d pr e g n a nc y t est 
( F O C B P o nly) 
1 4.  Ass ess a n d r ec or d c o nc o mit a nt m e dic ati o ns 
1 5.  Ass ess i ncl usi o n/ excl usi o n crit eri a 
 
4. 2. 2  
Visit 2 
Visit 2 will occ ur at l e ast 1 5 d a ys pri or t o Visit 3.  Pl e as e n ot e t h at, p er pr ot oc ol a n d wit hi n t h e E D C, Visit 
1 a n d Visit 2 m ay occ ur o n t h e s a m e d ay. 
1.  Pr ovi d e tr ai ni n g f or I A di ary a n d d osi n g di ary m o d ul e 
2.  Distri b ut e d e vic e  
3.  Ass ess a n d r ec or d c o nc o mit a nt m e dic ati o ns 
4. 2. 3  
Visit 3 
Visit 3 will occ ur at l e ast 1 5 d a ys f oll o wi n g Visit 2 acc or di n g t o t h e Sc h e d ul e of Visits a n d Pr oc e d ur es. 
1.  A d mi nist er effic acy sc al es (S N A P-I V, C H Q- P F 2 8, P SI- 4- S F)  
2.  Ass ess I A di ary c o m pli a nc e / r evi e w tr ai ni n g as n ec ess ar y 
3.  C o nfir m eli gi bilit y t o r a n d o miz e t o st u dy m e dic ati o n tr e at m e nt 
4.  R a n d o miz e s u bj ect vi a I W RS 
5.  A d mi nist er I nv esti g at or C GI- S 
6.  A d mi nist er I nfr e q u e nt B e h a vi ors C h ecklist 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 4 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
7.  A d mi nist er s af ety sc al es ( Si m ps o n- A n g us, B ar n es A k at hisi a, AI M S) 
8.  R ec or d h ei g ht, w ei g ht, a n d B MI 
9.  C oll ect bl o o d s a m pl es f or h e m at ol o gy/c h e mistry 
1 0.  C oll ect uri n e s a m pl es f or uri n al ysis, uri n e dr u g scr e e n ( all s u bj ects), a n d pr e g n a ncy t est ( F O C B P 
o nl y)  
1 1.  A d mi nist er C- S S R S 
1 2.  R ec or d c o nc o mit a nt m e dic ati o n 
1 3.  Ass ess f or a ny cli nic ally si g nific a nt c h a n g e i n M e dic al Hist or y 
1 4.  Dis p e ns e S M vi a I W R S.   
1 5.  R e vi e w tr ai ni n g o n d osi n g di ary m o d ul e 
1 6.  Ass ess a dv ers e ev e nts ( p ost- d os e) 
4. 2. 4  
Visit 4 
Visit 4 will occ ur 7 ( ± 2) d a ys f oll o wi n g Visit 3 acc or di n g t o t h e Sc h e d ul e of Visits a n d Pr oc e d ur es. 
1.  A d mi nist er I nv esti g at or C GI- S 
2.  A d mi nist er c ar e giv er a n d i nv esti g at or-c o m pl et e d C GI-I 
3.  A d mi nist er I nfr e q u e nt B e h a vi ors C h ecklist 
4.  A d mi nist er s af ety sc al es ( Si m ps o n- A n g us, B ar n es A k at hisi a, AI M S) 
5.  R ec or d h ei g ht, w ei g ht, a n d B MI 
6.  P erf or m 1 2-l e a d E C G 
7.  C oll ect bl o o d s a m pl es f or P K a n al ysis 
8.  A d mi nist er C- S S R S 
9.  R ec or d c o nc o mit a nt m e dic ati o n 
1 0.  R e vi e w I A di ary c o m pli a nc e a n d pr o vi d e tr ai ni n g as r e q uir e d 
1 1.  C oll ect A Es 
1 2.  R e vi e w d osi n g di ar y c o m pli a nc e a n d pr ovi d e tr ai ni n g as r e q uir e d 
4. 2. 5  
Visit 5 
Visit 5 will occ ur 1 4 ( ± 2) d ays f oll o wi n g Visit 3 acc or di n g t o t h e Sc h e d ul e of Visits a n d Pr oc e d ur es. 
1.  A d mi nist er I nv esti g at or C GI- S 
2.  A d mi nist er c ar e giv er a n d i nv esti g at or-c o m pl et e d C GI-I 
3.  A d mi nist er I nfr e q u e nt B e h a vi ors C h ecklist 
4.  A d mi nist er s af ety sc al es ( Si m ps o n- A n g us, B ar n es A k at hisi a, AI M S) 
5.  R ec or d h ei g ht, w ei g ht, a n d B MI 
6.  C oll ect bl o o d s a m pl es f or P K a n al ysis 
7.  A d mi nist er C- S S R S 
8.  R ec or d c o nc o mit a nt m e dic ati o n 
9.  R e vi e w I A di ary c o m pli a nc e a n d pr o vi d e tr ai ni n g as r e q uir e d 
1 0.  C oll ect A Es 
1 1.  C oll ect r et ur n e d S M; ass ess tr e at m e nt c o m pli a nc e 
1 2.  R e vi e w d osi n g di ar y c o m pli a nc e a n d pr ovi d e tr ai ni n g as r e q uir e d  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 4 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 3.  Dis p e ns e S M 
4. 2. 6  
Visit 6 
Visit 6 will occ ur 2 1 ( ± 3) d ays f oll o wi n g Visit 5 acc or di n g t o t h e Sc h e d ul e of Visits a n d Pr oc e d ur es.   
1.  A d mi nist er effic acy sc al es (I nv esti g at or C GI- S, c ar e giv er a n d i n v esti g at or C GI-I, S N A P-I V, C H Q-
P F 2 8, P SI- 4- S F)  
2.  A d mi nist er I nfr e q u e nt B e h a vi ors C h ecklist 
3.  A d mi nist er s af ety sc al es ( Si m ps o n- A n g us, B ar n es A k at hisi a, AI M S) 
4.  R ec or d h ei g ht, w ei g ht, a n d B MI 
5.  P erf or m 1 2 -l e a d E C G 
6.  P erf or m p hysic al ex a mi n ati o n 
7.  C oll ect bl o o d s a m pl es f or h e m at ol o gy/c h e mistry 
8.  C oll ect uri n e s a m pl e f or uri n al ysis 
9.  A d mi nist er C- S S R S 
1 0.  R ec or d c o nc o mit a nt m e dic ati o n 
1 1.  R e vi e w I A di ary c o m pli a nc e a n d pr o vi d e tr ai ni n g as r e q uir e d 
1 2.  C oll ect A Es 
1 3.  C oll ect r et ur n e d S M; ass ess tr e at m e nt c o m pli a nc e 
1 4.  R e vi e w d osi n g di ar y c o m pli a nc e a n d pr ovi d e tr ai ni n g as r e q uir e d  
1 5.  D et er mi n e w h et h er s u bj ect wis h es t o p artici p at e i n o p e n-l a b el ext e nsi o n  
1 6.  Dis p e ns e S M ( eit h er C o nv ersi o n or T a p er b as e d u p o n s u bj ect’s d ecisi o n a b o ut p art ici p ati o n i n 
o p e n-l a b el ext e nsi o n) 
4. 2. 7  
Visit 7 
Visit 7 will occ ur 7 ( ± 1) d a ys f oll o wi n g Visit 6 acc or di n g t o t h e Sc h e d ul e of Visits a n d Pr oc e d ur es.  T h es e 
pr oc e d ur es will als o b e p erf or m e d f or p ati e nts w h o disc o nti n u e e arl y.  P ati e nts w h o disc o nti n u e e arl y 
aft er Visit 5 will b e off er e d a t a p er kit. 
1.  A d mi nist er s af ety sc al es ( Si m ps o n- A n g us, B ar n es A k at hisi a, AI M S) 
2.  R ec or d vit al si g ns ( H R, B P, t e m p er at ur e, a n d R R), h ei g ht, w ei g ht a n d B MI 
3.  C oll ect uri n e s a m pl e f or pr e g n a nc y t est ( F O C B P o nl y) 
4.  A d mi nist er C- S S R S 
5.  R ec or d c o nc o mit a nt m e dic ati o n 
6.  C oll ect A Es 
7.  C oll ect S M a n d ass ess tr e at m e nt c o m pli a nc e 
8.  C oll ect d evic e 
9.  C o m pl et e/ disc o nti n u e s u bj ect 
1 0.  C oll ect bl o o d s a m pl es f or h e m at ol o gy/c h e mistry 
1 1.  C oll ect uri n e s a m pl e f or uri n al ysis 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 4 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
4. 2. 8  
P h ar m ac o ki n etic S a m pl e C oll ecti o n 
All bl o o d s a m pl es f or P K a n al ysis will b e dr a w n at t h e cli nic al sit e.  A t ot al of 5 bl o o d s a m pl es ( 4 mL e ac h) 
will b e t a k e n f or P K a n alysis o v er t h e c o urs e of t h e st u dy.  T h es e will i ncl u d e pr e- a n d p ost- d os e s a m pl es 
o bt ai n e d o v er o n e visit ( Visit 4 or Visit 5) or o v er t w o visits ( Visit 4 a n d Visit 5).   
If t h e s u bj ect d eci d es t o c o m pl et e t h e P K s a m pli n g ov er o n e visit t h e n h e/s h e will arriv e at t h e cli nic i n 
t h e m or ni n g pri or t o t aki n g t h e m or ni n g d os e.  A P K s a m pl e will b e dr a w n pr e- d os e; t h e n t h e d os e will 
b e o bs er v e d i n t h e cli nic.  P ost- d os e P K s a m pl es will b e t a k e n at a p pr oxi m at el y 1 h o ur, 2 h o urs, 4 h o urs 
a n d 6 h o urs aft er t h e ti m e of t h e o bs er v e d d os e.  P K s a m pl es s h o ul d b e o bt ai n e d wit hi n 1 5 mi n ut es of 
t h e 1 h o ur a n d 2 h o ur ti m e p oi nts a n d wit hi n 3 0 mi n ut es of t h e 4 h o ur a n d 6 h o ur ti m e p oi nts.  
If t h e s u bj ect d eci d es t o c o m e f or t h e P K s a m pli n g o v er t w o visits, t h e n o n o n e visit t h e s u bj ect will 
arri v e at t h e cli nic i n t h e m or ni n g, pri or t o t a ki n g t h eir m or ni n g d os e. A P K s a m pl e will b e dr a w n pr e-
d os e; t h e n t h e d os e will b e o bs erv e d i n t h e cli nic.  P ost- d os e P K s a m pl es will b e t a k e n at a p pr oxi m at el y 
1 h o ur a n d 2 h o urs aft er t h e ti m e of t h e o bs erv e d d os e. P K s a m pl es s h o ul d b e o bt ai n e d wit hi n 1 5 
mi n ut es of t h e t ar g et e d ti m e p oi nts.  At t h e ot h er visit, s u bj ects will arri v e at t h e cli nic aft er t aki n g t h eir 
m or ni n g d os e.  P K s a m pl es will b e t a k e n at a p pr oxi m at el y 4 h o urs a n d 6 h o urs aft er t h e ti m e t h at t h e 
m or ni n g d os e w as t a k e n.  P K s a m pl es s h o ul d b e o bt ai n e d wit hi n 3 0 mi n ut es of t h e t ar g et e d ti m e p oi nts. 
Bl o o d s a m pl es will b e c oll ect e d a n d pr oc ess e d as p er i nstr ucti o ns i n t h e L a b or at or y M a n u al. 
4. 3  Tr e at m e nts 
4. 3. 1  
Tr e at m e nts A d mi nist er e d 
S u bj ects will t a k e m oli n d o n e hy dr oc hl ori d e ext e n d e d-r el e as e t a bl et ( S P N- 8 1 0) or pl ac e b o t wic e e ac h 
d a y ( BI D) wit h or wit h o ut f o o d, i n t h e m or ni n g a n d i n t h e ev e ni n g, i n a d diti o n t o t h e st a bl e d os e of t h e 
o pti miz e d A D H D m e dic ati o n d et er mi n e d fr o m t h e l e a d-i n p eri o d.  If i niti ati n g tr e at m e nt b ef or e n o o n, 
p ati e nts s h o ul d st art wit h t h e m or ni n g d os e; if aft er n o o n, t h e e v e ni n g d os e. 
S u bj ects will b e r a n d o miz e d t o o n e of t hr e e tr e at m e nts at Visit 3.  S u bj ects will b e titr at e d u p t o t h e fi n al 
r a n d o miz e d t ot al d ail y d os e ( T D D).   
 
R ef er e nc e tr e at m e nt 
o  Tr e at m e nt 1: Pl ac e b o t a bl ets, P O, BI D 
 
T est tr e at m e nts  
o  Tr e at m e nt 2: M oli n d o n e ext e n d e d- r el e as e t a bl ets, 1 8 m g T D D, P O, BI D 
o  Tr e at m e nt 3: M oli n d o n e ext e n d e d-r el e as e t a bl ets, 3 6 m g T D D, P O, BI D 
 
4. 3. 2  
I d e ntit y of I n v esti g ati o n al Pr o d uct(s) 
T est a n d r ef er e nc e ( m atc hi n g pl ac e b o) pr o d ucts ar e eit h er p ur pl e ( 3 m g) or y ell o w ( 9 m g) r o u n d t a bl ets 
pri nt e d o n o n e si d e wit h t h e t a bl et d os e str e n gt h (“ 3 ” or “9 ”) t h at will b e s u p pli e d i n l a b el e d blist er 
c ar ds b y t h e S p o ns or. T h e S p o ns or will p ack a g e t h e S M i n a d o u bl e- bli n d c o nfi g ur ati o n.   


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 4 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
E ac h S M blist er c ar d will c o nt ai n c o m bi n ati o ns of m oli n d o n e ext e n d e d-r el e as e a n d/ or pl ac e b o t a bl ets, 
w hic h will s u p pl y a s u bj ect wit h 6 (six) t o 8 ( ei g ht) d a ys of d osi n g as w ell as s o m e extr as f or l ost pr o d uct 
a n d/ or t o acc o u nt f or visit d el a ys ass oci at e d wit h p ati e nt/sit e sc h e d ul es.  T h e S M blist er c ar d t y p es 
i ncl u d e: Titr ati o n (t w o blist er c ar ds), M ai nt e n a nc e (t hr e e blist er c ar ds), T a p er ( o n e blist er c ar d), a n d 
C o nv ersi o n ( o n e blist er c ar d).   
A si n gl e S M kit c o nt ai ns a t ot al of 7 pr e- p ack a g e d blist er c ar ds (t w o Titr ati o n blist er c ar ds, t hr e e 
M ai nt e n a nc e blist er c ar ds, o n e T a p eri n g blist er c ar d a n d o n e C o nv ersi o n blist er c ar d) a n d is m ar k e d wit h 
a u ni q u e 4- di git S M kit n u m b er.   
4. 3. 3  
St u d y M e dic ati o n H a n dli n g a n d Acc o u nt a bilit y 
All S M will b e s u p pli e d t o t h e I nv esti g at or b y t h e S p o ns or.  S M s u p pli es m ust b e k e pt i n a n a p pr o pri at e 
s ec ur e ar e a ( e. g., l oc k e d c a bi n et) a n d st or e d acc or di n g t o t h e c o n diti o ns s p ecifi e d o n t h e S M l a b els.  S M 
m ust b e st or e d b et w e e n 5 9 ° F –  8 6 ° F ( 1 5° C –  3 0 ° C). 
F oll o wi n g S p o ns or i nstr ucti o ns a n d i n c o m pli a nc e wit h I C H E 6 as w ell as l oc al, st at e, a n d f e d er al 
r e g ul ati o ns, t h e I nv esti g at or a n d st u dy st aff will b e r es p o nsi bl e f or t h e acc o u nt a bilit y of all cli nic al 
s u p pli es (r ec ei vi n g, s hi p m e nt, dis p e nsi n g, i n v e nt ory, a n d r ec or d k e e pi n g) i n a S M acc o u nt a bility l o g, a 
c o py of w hic h will b e c oll ect e d b y t h e S p o ns or at t h e e n d of t h e st u dy. 
U n d er n o circ u mst a nc es will t h e I nv esti g at or all o w t h e S M t o b e us e d ot h er t h a n as dir ect e d b y t his 
pr ot oc ol.  Cli nic al s u p pli es will n ot b e dis p e ns e d t o a ny i n di vi d u al w h o is n ot r a n d o miz e d i nt o t h e st u dy. 
A n acc ur at e a n d ti m el y r ec or d of t h e r ec ei pt of all cli nic al s u p pli es; dis p e nsi n g of S M t o t h e s u bj ect; 
c oll ecti o n of u n us e d s u p pli es r et ur n e d b y t h e s u bj ect; a n d s u bs e q u e nt r et ur n of u n us e d S M t o t h e 
S p o ns or m ust b e m ai nt ai n e d wit h d at es.  T his S M acc o u nt a bilit y l o g i ncl u d es, b ut m a y n ot b e li mit e d t o: 
( a) d oc u m e nt ati o n of r ec ei pt of cli nic al s u p pli es, ( b) S M i n v e nt ory l o g, (c) S M acc o u nt a bilit y l o g, a n d ( d) 
all s hi p pi n g s er vic e r ec ei pts.  All f or ms will b e pr ovi d e d b y t h e S p o ns or.  A ny c o m p ar a bl e f or ms t h at t h e 
st u dy sit e wis h es t o us e m ust b e a p pr o v e d b y t h e S p o ns or. 
T h e s u p pli es a n d i nv e nt or y r ec or ds m ust b e m a d e a v ail a bl e, u p o n r e q u est, f or i ns p ecti o n by t h e 
d esi g n at e d r e pr es e nt ati v e of t h e S p o ns or, a r e pr es e nt ati v e of t h e F D A, or a r e pr es e nt ativ e of a n o n- U S 
h e alt h a ut h orit y.  T h e assi g n e d Cli nic al R es e arc h Ass oci at e ( C R A) will r evi e w t h es e d oc u m e nts al o n g wit h 
all ot h er st u dy c o n d uct d oc u m e nts at e ac h a n d ev ery visit t o t h e st u dy sit e o nc e S M h as b e e n r ec ei v e d 
by t h e st u dy sit e.  All us e d, p artl y us e d, a n d u n us e d cli nic al s u p pli es, i ncl u di n g e m pt y c o nt ai n ers, ar e t o 
b e r et ur n e d t o t h e I nv esti g at or by t h e s u bj ect a n d ulti m at el y t o t h e S p o ns or at t h e c o ncl usi o n of t h e 
st u dy, u nl ess pr ovisi o n is m a d e by t h e S p o ns or f or d estr ucti o n of s u p pli es a n d c o nt ai n ers at t h e st u dy 
sit e.  U p o n c o m pl eti o n of S M acc o u nt a bility a n d r ec o ncili ati o n pr oc e d ur es b y st u dy sit e p ers o n n el a n d 
d oc u m e nt ati o n pr oc e d ur es b y S p o ns or p ers o n n el, S M is t o b e r et ur n e d t o t h e S p o ns or wit h a c o py of 
t h e c o m pl et e d S M dis p ositi o n f or m as o utli n e d i n t h e St u dy M e dic ati o n M a n u al. 
4. 3. 4  
M et h o d of Assi g ni n g S u bj ects t o Tr e at m e nt Gr o u ps 
All oc ati o n of st u dy dr u g will b e c o m pl et e d c e ntr ally t hr o u g h t h e us e of a n i nt er acti v e w e b r es p o ns e 
s yst e m (I W R S) t h at will d et er mi n e w hic h kit t o assi g n t o t h e s u bj ect. T h e r a n d o miz ati o n sc h e d ul es will 




S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 5 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
c o n d uct of t h e st u dy, a n d will n ot r ev e al t o a n y cli nic al p ers o n n el i n v ol v e d i n t h e st u dy t h e tr e at m e nt t o 
w hic h a s u bj ect is assi g n e d.    R a n d o miz ati o n sc h e d ul e d at a will b e k e pt strictl y c o nfi d e nti al, fil e d 
s ec ur el y b y t h e I W R S v e n d or, a n d acc essi bl e o nly t o a ut h oriz e d p ers o ns u ntil t h e ti m e of u n bli n di n g. 
T h e t est t a bl ets h av e m atc hi n g pl ac e b o t a bl ets.  T h e bli n d is m ai nt ai n e d pri m arily t hr o u g h t h e I W R S.  
T h e bli n d will b e m ai nt ai n e d t hr o u g h t h e e n d of t h e C o nv ersi o n/ T a p er p eri o d. 
T h e I nv esti g at or m ust tr y t o av oi d br e a ki n g t h e bli n d.  T h e d ec o di n g i nf or m ati o n will n ot b e vi e w e d 
u nl ess a n act u al m e dic al or m e dic ati o n s af et y e m er g e nc y occ urs.  T h e I nv esti g at or c a n acc ess t h e 
s u bj ect’s r a n d o miz e d tr e at m e nt i nf or m ati o n vi a I W R S o nl y if k n o wl e d g e of t h e tr e at m e nt r e gi m e n will 
i nfl u e nc e or assist wit h m e dic al m a n a g e m e nt of t h e s u bj ect i n a n ac ut e e m er g e nc y.  B ef or e br e aki n g t h e 
bli n d, e v ery eff ort m ust b e m a d e t o c o nt act t h e M e dic al M o nit or t o asc ert ai n t h e n ec essity of br e aki n g 
t h e c o d e.  If t h e I nv esti g at or is u ns ucc essf ul i n c o nt acti n g t h e M e dic al M o nit or, h e/s h e will c o nt act t h e 
b ac k u p M e dic al M o nit or ( or ot h er a p pr o pri at e d esi g n e e if t h e b ack u p M e dic al M o nit or is u n a v ail a bl e).  
If it is n ot p ossi bl e t o c o nt act t h e M e dic al M o nit or or t h e b ac k u p M e dic al M o nit or ( or d esi g n e e), a n d t h e 
sit u ati o n is a n e m er g e nc y, t h e I n v esti g at or m a y br e a k t h e bli n d a n d c o nt act t h e M e dic al M o nit or as 
s o o n as p ossi bl e.  T h e I nv esti g at or is t o m a k e a c ar ef ul n ot e of t h e d at e a n d ti m e of d ec o di n g, t h e r e as o n 
t h at n ec essit at e d br e aki n g t h e c o d e, a n d t h e si g n at ur e of t h e p ers o n w h o br ok e t h e c o d e.  U p o n 
br e a ki n g t h e r a n d o miz ati o n c o d e, t h e s u bj ect s h o ul d b e wit h dr a w n fr o m t h e st u dy b ut s h o ul d b e 
f oll o w e d u p f or s af ety p ur p os es. 
4. 4  Pr o hi bit e d M e dic ati o ns: 
S u bj ects m a y n ot b e o n a ny pr o hi bit e d m e dic ati o n w hil e o n st u dy as i n dic at e d i n t h e I ncl usi o n/ Excl usi o n 
Crit eri a. T h es e m e dic ati o ns i ncl u d e:  
 
α 2 - a dr e n er gic a g o nists ( e. g. cl o ni di n e a n d g u a nf aci n e) us e d f or a n y ot h er r e as o n exc e pt f or 
m o n ot h er a py tr e at m e nt f or A D H D  
 
A nti- ps yc h otics i ncl u di n g ari pi pr az ol e,  ris p eri d o n e, q u eti a pi n e, a n d zi pr asi d o n e  
 
A ntic o nv uls a nts i ncl u di n g c ar b a m az e pi n e a n d v al pr oic aci d, a nti d e pr ess a nts, m o o d st a biliz ers 
i ncl u di n g lit hi u m, b e nz o di az e pi n es, c h oli n est er as e i n hi bit ors or a ny dr u g k n o w n t o i n hi bit 
C Y P 2 D 6 acti vity 
 
H er b al s u p pl e m e nts 
4. 5  C o nc o mit a nt M e dic ati o n 
T h e d os e of t h e o n g oi n g A D H D m e dic ati o n wi ll n ot b e a dj ust e d d uri n g t h e st u dy, st arti n g at Visit 1. N o 
a d diti o n al c o nc o mit a nt m e dic ati o ns ar e all o w e d d uri n g t h e st u dy, wit h t h e f oll o wi n g exc e pti o ns: 
 
C hr o nic m e dic ati o n f or c o n diti o ns n ot r el at e d t o A D H D or I A t h at ar e all o w e d by I nv esti g at or at 
Scr e e ni n g 
 
N utriti o n al s u p pl e m e nts ( e. g. m ulti vit a mi ns, fis h oil) 
 
E ml a or ot h er n u m bi n g cr e a m f or P K v e ni p u nct ur e 
 
B e nztr o pi n e is p er mitt e d f or t h e tr e at m e nt of e m er gi n g E P S at a st arti n g d os e of 0. 5 m g BI D u p 
t o a r a n g e of 1 t o 4 m g/ d a y.  L or az e p a m ( 1 t o 2 m g p er d os e n ot t o exc e e d t hr e e ti m es d ail y) a n d 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 5 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
cl o n az e p a m ( 0. 2 5 t o 1 m g p er d os e n ot t o exc e e d t wic e d aily) will als o b e p er mitt e d t o tr e at 
e m er gi n g E P S.    
 
C o m m o n o v er-t h e-c o u nt er ( O T C) t h er a pi es f or mi n or tr a nsi e nt ail m e nts ( e. g. ac et a mi n o p h e n f or 
h e a d ac h e, i b u pr of e n f or f ev er) will b e all o w e d wit h o ut exc e pti o n. 
 
Tr e at m e nt f or A Es ot h er t h a n E P S or mi n or tr a nsi e nt ail m e nts is o nl y p er mitt e d i n c o ns ult ati o n 
wit h t h e M e dic al M o nit or.  
All c o nc o mit a nt m e dic ati o ns will b e r ec or d e d i n t h e e C R F. 
4. 6  C o m pl eti o n of St u d y a n d Disc o nti n u ati o n of S u bj ects  
S u bj ects will b e c o nsi d er e d t o h av e c o m pl et e d t h e st u dy if t h ey c o m pl et e all visits u p t o a n d i ncl u di n g 
Visit 6.  All s u bj ects w h o disc o nti n u e e arl y will c o m pl et e Visit 7.  A ny s u bj ect w h o disc o nti n u es fr o m t h e 
st u dy aft er Visit 5 will b e off er e d a T a p er kit.  
T h e I nv esti g at or(s) or s u bj ects t h e ms el v es m a y st o p S M tr e at m e nt at a ny ti m e f or s af ety or p ers o n al 
r e as o ns.  A s u bj ect is fr e e t o wit h dr a w fr o m t h e st u dy at a ny ti m e f or a n y r e as o n wit h o ut pr ej u dic e t o 
t h eir f ut ur e m e dic al c ar e by t h e p hysici a n or at t h e i nstit uti o n.  T h e I nv esti g at or or S p o ns or m ay als o 
wit h dr a w t h e s u bj ect at a ny ti m e i n t h e i nt er est of s u bj ect s af ety.  T h e wit h dr a w al of a s u bj ect fr o m t h e 
st u dy s h o ul d b e disc uss e d w h er e p ossi bl e wit h t h e M e dic al M o nit or a n d/ or C R A  b ef or e t h e s u bj ect st o ps 
S M.  S u bj ects r e m o v e d fr o m t h e st u dy f or a n y r e as o n will n ot b e r e pl ac e d. 
R e as o ns f or wit h dr a w al m ay i ncl u d e b ut ar e n ot li mit e d t o s u bj ect wit h dr a w al of c o ns e nt, occ urr e nc e of 
u n m a n a g e a bl e A Es, or if it is i n t h e b est i nt er est of t h e s u bj ect as p er I nv esti g at or’s discr eti o n . 
T h e pri m ar y r e as o n f or wit h dr a w al m ust b e r ec or d e d i n t h e s u bj ect’s m e dic al r ec or d a n d o n t h e e C R F.  If 
a s u bj ect is wit h dr a w n f or m or e t h a n o n e r e as o n, e ac h r e as o n s h o ul d b e d oc u m e nt e d i n t h e s o urc e 
d oc u m e nt a n d t h e m ost m e dic ally si g nific a nt  r e as o n s h o ul d b e e nt er e d o n t h e e C R F. 
5  A N AL Y SI S V A RI A BL E S 
5. 1  Pri m ar y Effic ac y V ari a bl e 
T h e pri m ar y effic acy e n d p oi nt will b e b as e d o n a c h ec klist of 1 5 I A b e h avi ors c oll ect e d i n a n el ectr o nic I A 
di ary.  T h e I A di ary c o m pris es t w o p arts:  1) A n e pis o dic di ary t h at will b e us e d b y t h e pri m ar y c ar e giv er 
( or alt er n at e) t o e nt er e v e nts as s o o n as p ossi bl e aft er t h e y ar e o bs erv e d; a n d 2) a n e v e ni n g di ary t h at 
will pr o m pt t h e c ar e giv er t o r evi e w ev e nts f or t h e d a y a n d t o e nt er a n y e v e nts t h at w er e n ot pr e vi o usl y 
c a pt ur e d.  Ev e nts c a n b e dir ectl y o bs er v e d b y t h e c ar e gi v er or c o ul d b e r e p ort e d t o t h e c ar e giv er by 
a n ot h er o bs erv er s uc h as a t e ac h er.   E ac h ev e nt will b e c h ar act eriz e d b y a c h ec klist of 1 5 o bs erv e d 
b e h a vi ors:  Y elli n g, Scr e a mi n g, T hr e at e ni n g, Scr atc hi n g, T hr o wi n g, Sl a m mi n g, Hitti n g S elf, Ar g ui n g, 
C ursi n g, N a m e C alli n g, S h ovi n g, H air P ulli n g, Fi g hti n g, Hitti n g Ot h ers, Kicki n g Ot h ers.  T h e c h ecklist will 
i n dic at e w h et h er e ac h b e h a vi or w as o bs er v e d (c o d e d 1) or w as n ot o bs erv e d (c o d e d 0) d uri n g t h e 
i nci d e nc e of a n ev e nt.  E ac h d a y c a n h av e m ulti pl e ev e nts.  A d ay c a n h av e n o e v e nt, as c a n b e att est e d 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 5 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
i n t h e ev e ni n g di ar y.  I n t his c as e, if n o ev e nt is r e p ort e d d uri n g a d a y, a n d t h e e v e ni n g di ar y c o nfir ms 
t his, t h e d aily ev e nt sc or e f or t h at s u bj ect will b e 0.  B e h a vi ors n ot o n t his list will n ot b e c a pt ur e d.   
5. 2  S ec o n d ar y Effic ac y V ari a bl es 
T h e f oll o wi n g effic acy sc al es will b e a d mi nist er e d at visits d esi g n at e d i n t h e Sc h e d ul e of Visits a n d 
Pr oc e d ur es ( T a bl e 1 ). 
5. 2. 1  
Cli nic al Gl o b al I m pr essi o n ( C GI) Sc al es 
T h e C GI sc al e w as d e v el o p e d t o pr ovi d e a bri ef, st a n d- al o n e ass ess m e nt of t h e cli nici a n’s vi e w of a 
s u bj ect’s gl o b al f u ncti o ni n g pri or t o a n d aft er a d mi nistr ati o n of a S M ( G uy 1 9 7 6).  S e v erit y of ill n ess ( C GI-
S) a n d gl o b al i m pr ov e m e nt ( C GI- I) ar e b ot h r at e d o n a sc al e of 1 t o 7 wit h 7 b ei n g “ extr e m ely ill” or “ v ery 
m uc h w ors e”, r es p ectiv el y.  S ucc essf ul t h er a py is i n dic at e d b y a l o w er ov er all sc or e i n s u bs e q u e nt 
t esti n g.  I nv esti g at ors s h o ul d c o nsi d er t h eir t ot al cli nic al ex p eri e nc e wit h c hil dr e n w h o h a v e I A c o m or bi d 
wit h A D H D a n d r at e h o w s e v er e t h e s u bj ect’s c o n diti o n is at t h e ti m e.   
 
C GI - S will b e e v al u at e d b y t h e I nv esti g at or at e ac h visit o n a 7- p oi nt sc al e wit h 1 = N or m al,    
2 = B or d erli n e ill, 3 = Mil dl y ill, 4 = M o d er at el y ill, 5 = M ark e dly ill, 6 = S ev er el y ill, a n d 7 = Extr e m ely ill.    
 
C GI -I, r el ativ e t o t h e c o n diti o n at Visit 3, will b e ev al u at e d b y t h e c ar e gi v er a n d b y t h e 
I nv esti g at or at e ac h p ost- b as eli n e visit o n a 7- p oi nt sc al e wit h 1 = V er y m uc h i m pr o v e d, 2 = M uc h 
i m pr ov e d, 3 = Mi ni m ally i m pr o v e d, 4 = N o c h a n g e, 5 = Mi ni m ally w ors e, 6 = M uc h w ors e, a n d 7 = V ery 
m uc h w ors e.    
C GI - S will b e ass ess e d b y t h e I nv esti g at or at Visit 1, Visit 3, Visit 4, Visit 5 a n d Visit 6.  C GI-I will b e 
ass ess e d b y t h e c ar e giv er a n d t h e I nv esti g at or at Visit 4, Visit 5 a n d Visit 6.   
5. 2. 2  
S w a ns o n, N ol a n, P el h a m R ati n g Sc al e- R e vis e d ( S N A P-I V) 
T h e S N A P-I V r ati n g sc al e i ncl u d es 1 8 A D H D a n d 8 o p p ositi o n al d efi a nt dis or d er ( O D D) sy m pt o ms as 
s p ecifi e d i n t h e D S M-I V- T R a n d I nt er n ati o n al St atistic al Cl assific ati o n of Dis e as es a n d H e alt h R el at e d 
Pr o bl e ms 1 0t h R e visi o n (I C D- 1 0) Cl assific ati o n of M e nt al a n d B e h avi or al Dis or d ers.  T h e s y m pt o ms ar e 
sc or e d b y assi g ni n g a s ev erit y esti m at e f or e ac h s y m pt o m o n a 4- p oi nt sc al e ( S w a ns o n 2 0 0 1).  T h e S N A P-
I V r ati n g s h o ul d b e p erf or m e d by t h e s a m e p ar e nt or l e g al r e pr es e nt ati v e at e ac h visit w h e n p ossi bl e. 
T h e r ati n gs fr o m t h e S N A P-I V sc al e ar e gr o u p e d i nt o t h e f oll o wi n g 4 s u bsc al es:   
 
A D H D-I n att e nti o n (it e ms # 1- 9),  
 
A D H D- Hy p er activity/I m p ulsivit y (it e ms # 1 0- 1 8)  
 
O D D (it e ms # 1 9- 2 6)   
 
A D H D- C o m bi n e d s u bsc al e: t h e first t w o s u bsc al e it e ms ar e c o m bi n e d   
E ac h s u bsc al e sc or e is t h e av er a g e of t h e sc or es i ncl u d e d i n t h e s u bsc al e. 
T h e S N A P-I V r ati n g sc al e will b e a d mi nist er e d at Visit 3 a n d Visit 6. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 5 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
5. 2. 3  
C hil d H e alt h Q u esti o n n air e P ar e nt F or m 2 8- It e m ( C H Q- P F 2 8) 
T h e C hil d H e alt h Q u esti o n n air e P ar e nt F or m 2 8-it e m ( C H Q- P F 2 8) is a s h ort g e n eric m e as ur e of h e alt h 
st at us a n d h e alt h r el at e d q u alit y of lif e (L a n d gr af 1 9 9 6).  C H Q- P F 2 8 it e ms h a v e f o ur, fi v e, or six r es p o ns e 
o pti o ns, di vi d e d ov er ei g ht m ulti-it e m sc al es ( p hysic al f u ncti o ni n g, g e n er al b e h avi or, m e nt al h e alt h, s elf-
est e e m, g e n er al h e alt h p erc e pti o ns, p ar e nt al i m p act: e m oti o n al, p ar e nt al i m p act: ti m e, a n d f a mily 
acti viti es) a n d fiv e si n gl e it e m c o nc e pts (r ol e f u ncti o ni n g: e m oti o n al/ b e h a vi or, r ol e f u ncti o ni n g: p hysic al, 
b o dily p ai n, f a mily c o h esi o n, a n d c h a n g e i n h e alt h). T h e C H Q- P F 2 8 s h o ul d b e p erf or m e d b y t h e pri m ary 
c ar e giv er w h e n p ossi bl e.   
T h e C H Q- P F 2 8 will b e a d mi nist er e d at Visit 3 a n d Visit 6. 
5. 2. 4  
P ar e nti n g Str ess I n d e x- S h ort F or m ( P SI- 4- S F) 
R e d ucti o n i n str ess is c o nsi d er e d i m p ort a nt f or p ar e nts of c hil dr e n wit h disr u pti v e b e h a vi or pr o bl e ms, 
d e v el o p m e nt al dis a biliti es, a n d c hr o nic ill n ess ( H as k ett 2 0 0 6).  T h e P ar e nti n g Str ess I n d ex –  S h ort F or m 
( P SI- 4- S F) is a 3 6-it e m s elf-r e p ort m e as ur e of p ar e nti n g str ess ( A bi di n 1 9 9 5). T hr e e s u bsc al es ( P ar e nt al 
Distr ess, P ar e nt- C hil d D ysf u ncti o n al I nt er acti o n, a n d Diffic ult C hil d) c o nsist of 1 2 it e ms e ac h.  P ar e nts 
us e a 5- p oi nt sc al e t o i n dic at e t h e d e gr e e t o w hic h t h e y a gr e e wit h e ac h st at e m e nt.   
T h e P SI- 4- S F will b e a d mi nist er e d at Visit 3 a n d Visit 6. 
5. 3  P h ar m ac o ki n etic M e as ur e m e nts 
 
 
 
 
5. 3. 1  
P h ar m ac o ki n etic V ari a bl es 
T h e p h ar m ac o ki n etic v ari a bl es ar e: 
 
A p p ar e nt cl e ar a nc e ( CL/ F) of m oli n d o n e i n t h e p e di atric p o p ul ati o n 
 
A p p ar e nt v ol u m e of distri b uti o n ( V/ F) of m oli n d o n e i n p e di atric p o p ul ati o n 
 
Eff ect o n m oli n d o n e a p p ar e nt cl e ar a nc e ( CL/ F) of c o- a d mi nistr ati o n of a m p h et a mi n es, 
m et hyl p h e ni d at e, cl o ni di n e, g u a nf aci n e a n d at o m ox eti n e  
5. 3. 2  
E x pl or at or y P h ar m ac o ki n etic V ari a bl es 
 
 
 
 
 
 
 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 5 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
5. 4  S af et y Ass ess m e nts 
S af et y ass ess m e nts will c o nsist of m o nit ori n g of a n d r ec or di n g of all c o nc o mit a nt m e dic ati o ns a n d A Es, 
cli nic al l a b or at ory t ests, m e as ur e m e nt of vit al si g ns a n d 1 2-l e a d E C Gs, s uici d alit y m o nit ori n g, a n d t h e 
p erf or m a nc e of p hysic al ex a mi n ati o ns at visits d esi g n at e d i n t h e Sc h e d ul e of Visits a n d Pr oc e d ur es 
(T a bl e 1 ). 
Ass ess m e nt of p ossi bl e n e ur ol o gic al si d e eff ects a n d E P S will b e p erf or m e d usi n g t h e Si m ps o n- A n g us 
sc al e, t h e B ar n es A k at hisi a sc al e a n d t h e AI M S.  A p ositi v e r ati n g or fi n di n g o n t h e s af ety sc al e will b e 
c a pt ur e d as a n A E at t h e discr eti o n of t h e I nv esti g at or. 
5. 4. 1  
A d v ers e E v e nts 
As d efi n e d b y t h e I C H G ui d eli n e f or G C P, a n a d v ers e e v e nt ( A E)  is a ny u nt o w ar d m e dic al occ urr e nc e i n a 
p ati e nt or cli nic al i nv esti g ati o n s u bj ect a d mi nist er e d a p h ar m ac e utic al pr o d uct a n d w hic h d o es n ot 
n ec ess arily h a v e t o h av e a c a us al r el ati o ns hi p wit h tr e at m e nt. 
A n A E c a n b e: 
 
A ny u nf a v or a bl e a n d u ni nt e n d e d si g n (i ncl u di n g a n a b n or m al l a b or at ory fi n di n g), s y m pt o m, or 
dis e as e t e m p or ally ass oci at e d wit h t h e us e of a m e dici n al pr o d uct, w h et h er or n ot c o nsi d er e d 
r el at e d t o t h e m e dici n al pr o d uct. 
 
A ny n e w dis e as e, i nt erc urr e nt i nj uri es, or ex ac er b ati o n of a n existi n g dis e as e. 
 
A ny d et eri or ati o n i n a l a b or at ory v al u e or ot h er cli nic al t est ( e. g., E C G) t h at r es ults i n s y m pt o ms, 
a c h a n g e i n tr e at m e nt, or disc o nti n u ati o n fr o m S M. 
 
R ec urr e nc e of a n i nt er mitt e nt m e dic al c o n diti o n ( e. g., h e a d ac h e) n ot pr es e nt at b as eli n e. 
S ur gic al pr oc e d ur es ar e n ot A Es; t h ey ar e t h er a p e utic m e as ur es f or c o n diti o ns t h at r e q uir e s ur g er y.  T h e 
c o n diti o n f or w hic h t h e s ur g er y is r e q uir e d is a n A E, if it occ urs or is d et ect e d d uri n g t h e st u dy p eri o d. 
5. 4. 1. 1  C a us alit y 
A Es m ay b e c at e g oriz e d as eit h er A dv ers e Dr u g R e acti o ns or S us p ect e d A dv ers e Dr u g R e acti o ns b as e d 
o n t h eir r el ati o ns hi p t o S M a n d t h e d e gr e e of c ert ai nty a b o ut c a us alit y.  
S us p ect e d a d v ers e dr u g r e acti o ns  ( S A D Rs) ar e a s u bs et of a d v ers e ev e nts f or w hic h t h er e is evi d e nc e t o 
s u g g est a c a us al r el ati o ns hi p b et w e e n t h e dr u g a n d t h e A E, i. e., t h er e is a r e as o n a bl e p ossi bility t h at t h e 
dr u g c a us e d t h e a dv ers e e v e nt.   
A d v ers e dr u g r e acti o ns  ( A D Rs) ar e a s u bs et of all S A D Rs f or w hic h t h er e is r e as o n t o c o ncl u d e t h at t h e 
dr u g c a us e d t h e e v e nt. 
5. 4. 1. 2  R ec or di n g a n d E v al u ati o n of A d v ers e E v e nts 
All s u bj ects w h o ar e e nr oll e d (st arti n g at Visit 3) will b e q u esti o n e d r e g ar di n g t h e occ urr e nc e of A Es.  At 
e ac h c o nt act wit h t h e s u bj ect, t h e i n v esti g at or m ust s e e k i nf or m ati o n o n A Es by s p ecific q u esti o ni n g 
a n d, as a p pr o pri at e, by ex a mi n ati o n.  I nf or m ati o n o n all A Es s h o ul d b e r ec or d e d i m m e di at ely i n t h e 
s o urc e d oc u m e nt, a n d als o i n t h e a p pr o pri at e a dv ers e e v e nt m o d ul e of t h e e C R F.  All cl e arly r el at e d 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 5 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
si g ns, s y m pt o ms, a n d a b n or m al di a g n ostic pr oc e d ur es r es ults s h o ul d b e r ec or d e d i n t h e s o urc e 
d oc u m e nt, t h o u g h t h ey m ay b e gr o u p e d u n d er o n e di a g n osis.  F or ex a m pl e, f ev er, el ev at e d W B C, c o u g h, 
a b n or m al c h est X- r ay, etc., c a n all b e r e p ort e d as “ p n e u m o ni a”. 
All A Es occ urri n g aft er e nr oll m e nt a n d t hr o u g h o ut t h e st u dy p eri o d m ust b e r ec or d e d.  A tr e at m e nt-
e m er g e nt a dv ers e ev e nt ( T E A E) is d e fi n e d as a n A E wit h a st art d at e o n or aft er t h e first d os e of st u dy 
dr u g, or t h at w ors e n e d f oll o wi n g first a d mi nistr ati o n of st u dy dr u g. F or s u bj ects w h o r ec eiv e S M, T E A Es 
will b e c oll ect e d st arti n g fr o m t h e first d os e of S M.  T h e cli nic al c o urs e of e ac h A E s h o ul d b e f oll o w e d 
u ntil r es ol uti o n or u ntil, i n t h e m e dic al j u d g m e nt of t h e I nv esti g at or, t h e ev e nt h as st a biliz e d or is 
ass ess e d as c hr o nic.   
A n i ncr e as e i n t h e C S S R S, Si m ps o n A n g us Sc al e, B ar n es A k at hisi a Sc al e, or t h e AI M S will n ot n ec ess arily 
b e r at e d as a n A E u nl ess t h e ev e nt m e ets A E crit eri a. 
T h e I nv esti g at or is r es p o nsi bl e f or e v al u ati n g A Es a n d d et er mi ni n g t h e f oll o wi n g: 
 
S eri o us vs. N o n-s eri o us:  Is t h e ev e nt a S eri o us A dv ers e E v e nt ( S A E) ? 
 
C a us alit y:  W as A E r el at e d or p ossi bl y r el at e d t o t h e S M ? 
 
S e v erit y:  H o w pr o n o u nc e d is t h e i nc a p acit y/ disc o mf ort c a us e d by a n A E ? 
5. 4. 1. 3  Crit eri a f or Ass essi n g S e v erit y 
T h e I nv esti g at or will ev al u at e t h e c o m m e nts of t h e s u bj ect a n d t h e r es p o ns e t o tr e at m e nt i n or d er t h at 
h e or s h e m a y j u d g e t h e tr u e n at ur e a n d s e v erity of t h e A E.  S ev erit y r ef ers t o t h e acc u m ul at e d i nt e nsity 
of disc o mf ort/i m p air m e nt of h e alt h si nc e t h e l ast r ec or di n g of A Es a n d will b e ass ess e d acc or di n g t o t h e 
f oll o wi n g crit eri a: 
 
Mil d:   A w ar e n ess of si g n, sy m pt o m, or e v e nt, b ut e asil y t ol er at e d 
 
M o d er at e : Disc o mf ort e n o u g h t o i nt erf er e wit h us u al acti vity a n d m ay w arr a nt i nt er v e nti o n 
 
S e v er e:  I nc a p acit ati n g wit h i n a bility t o d o us u al acti viti es or si g nific a ntl y aff ects cli nic al st at us 
a n d w arr a nts i nt er v e nti o n 
T h e crit eri a f or ass essi n g s ev erity ar e diff er e nt fr o m t h os e us e d f or s eri o us n ess. 
5. 4. 1. 4  Crit eri a f or Ass essi n g C a us alit y 
T h e I nv esti g at or is r es p o nsi bl e f or d et er mi ni n g t h e r el ati o ns hi p b et w e e n t h e a d mi nistr ati o n of S M a n d 
t h e occ urr e nc e of a n A E as n ot s us p ect e d  or as a s us p ect e d r e acti o n t o S M.  T h es e ar e d efi n e d as 
f oll o ws: 
N ot s us p ect e d:  T h e t e m p or al r el ati o ns hi p of t h e A E t o S M a d mi nistr ati o n m a k es a c a us al r el ati o ns hi p 
u nli k el y , or ot h er dr u gs, t h er a p e utic i nt er v e nti o ns, or u n d erl yi n g c o n diti o ns pr o vi d e a s uffici e nt 
ex pl a n ati o n f or t h e o bs erv e d e v e nt.  
 
N ot r el at e d:   T e m p or al r el ati o ns hi p t o S M a d mi nistr ati o n is missi n g or i m pl a usi bl e, or t h er e is a n 
e vi d e nt ot h er c a us e. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 5 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 
U nli k el y r el at e d :  T e m p or al r el ati o ns hi p t o S M a d mi nistr ati o n m ak es a c a us al r el ati o ns hip 
i m pr o b a bl e; a n d ot h er dr u gs, c h e mic als, or u n d erlyi n g dis e as e pr o vi d e pl a usi bl e ex pl a n ati o ns. 
S us p ect e d:  T h e t e m p or al r el ati o ns hi p of t h e A E t o S M a d mi nistr ati o n m a k es a c a us al r el ati o ns hi p 
p ossi bl e , a n d ot h er dr u gs, t h er a p e utic i nt erv e nti o ns, or u n d erl yi n g c o n diti o ns d o n ot pr o vi d e a s uffici e nt 
ex pl a n ati o n f or t h e o bs erv e d e v e nt.  
 
P ossi bl y r el at e d:   T e m p or al r el ati o ns hi p t o S M a d mi nistr ati o n is pl a usi bl e, b ut c o nc urr e nt 
dis e as e or ot h er dr u gs or c h e mic als c o ul d als o ex pl ai n e v e nt.  I nf or m ati o n o n dr u g wit h dr a w al 
m a y b e l acki n g or u ncl e ar.  T his will b e r e p ort e d as a S us p ect e d A d v ers e Dr u g R e acti o n ( S A D R) . 
 
D efi nit el y r el at e d:  T e m p or al r el ati o ns hi p t o S M a d mi nistr ati o n is pl a usi bl e, a n d c o nc urr e nt 
dis e as e or ot h er dr u gs or c h e mic als c a n n ot ex pl ai n e v e nt.   T h e r es p o ns e t o wit h dr a w al of t h e 
m e dic ati o n ( d ec h all e n g e) s h o ul d b e cli nic ally pl a usi bl e.   T h e e v e nt m ust b e d efi niti v e 
p h ar m ac ol o gic ally or p h e n o m e n ol o gic all y, usi n g a s atisf act ory r ec h all e n g e pr oc e d ur e if 
n ec ess ary.   T his will b e r e p ort e d as a n A d v ers e Dr u g R e acti o n ( A D R). 
5. 4. 2  
S eri o us A d v ers e E v e nts ( S A E) 
A Es ar e cl assifi e d as s eri o us or n o n-s eri o us.  A n A E or A D R is c o nsi d er e d “s eri o us” if, i n t h e vi e w of eit h er 
t h e i n v esti g at or or S p o ns or, it r es ults i n o n e of t h e f oll o wi n g o utc o m es:  
 
d e at h 
 
lif e-t hr e at e ni n g A E (i. e., t h e s u bj ect w as at i m m e di at e ris k of d e at h fr o m t h e A E as it occ urr e d.  
T his d o es n ot i ncl u d e a n e v e nt t h at, h a d it occ urr e d i n a m or e s ev er e f or m or w as all o w e d t o 
c o nti n u e, mi g ht h av e c a us e d d e at h.) 
 
i n- p ati e nt h os pit aliz ati o n or pr ol o n g ati o n of existi n g h os pit aliz ati o n 
 
p ersist e nt or si g nific a nt dis a bilit y or i nc a p acity or s u bst a nti al disr u pti o n of t h e a bilit y t o c o n d uct 
n or m al lif e f u ncti o ns 
 
a c o n g e nit al a n o m aly or birt h d ef ect 
 
a n i m p ort a nt m e dic al ev e nt 
I m p ort a nt m e dic al e v e nts ar e t h os e t h at m a y n ot b e i m m e di at ely lif e t hr e at e ni n g or r es ult i n d e at h or 
h os pit aliz ati o n, b ut ar e cl e arly of m aj or cli nic al si g nific a nc e.   T h ey m a y j e o p ar diz e t h e s u bj ect, a n d m ay 
r e q uir e i nt erv e nti o n t o pr ev e nt o n e of t h e ot h er s eri o us o utc o m es n ot e d a b ov e.  F or ex a m pl e, dr u g 
d e p e n d e nc e or a b us e, bl o o d d yscr asi as, a s eiz ur e t h at di d n ot r es ult i n i n- p ati e nt h os pit aliz ati o n, or 
i nt e nsi v e tr e at m e nt f or all er gic br o nc h os p as m i n a n e m er g e nc y d e p art m e nt w o ul d t y pic ally b e 
c o nsi d er e d s eri o us. 
5. 4. 2. 1  I n v esti g at or R es p o nsi biliti es f or R e p orti n g S A Es 
T h e I nv esti g at or m ust i m m e di at el y r e p ort t o t h e S p o ns or all S A Es, r e g ar dl ess of w h et h er t h e I nv esti g at or 
b eli e v es t h ey ar e dr u g r el at e d. 
All S A Es m ust b e r e p ort e d t o t h e Dr u g S af et y C o nt act wit hi n 2 4 h o urs of first b ec o mi n g a w ar e of t h e 
S A E.  T h e I nv esti g at or m ust c o m pl et e a n S A E e C R F i n E D C a n d i ncl u d e a d et ail e d d escri pti o n of t h e S A E, 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 5 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
as w ell as ot h er a v ail a bl e i nf or m ati o n p erti n e nt t o t h e c as e ( e. g., h os pit al r ec or ds, a ut o psy r e p orts a n d 
ot h er r el ev a nt d oc u m e nts).  S h o ul d t h e sit e b e u n a bl e t o acc ess E D C, a p a p er S A E f or m m ust b e 
c o m pl et e d a n d s e nt t o  
Dr u g S af et y b y e m ail or f ax. T h e i nv esti g at or will k e e p a c o py of t his S A E 
R e p ort f or m o n fil e at t h e st u dy sit e. O nc e E D C b ec o m es a v ail a bl e, t h e sit e m ust c o m pl et e t h e S A E e C R F 
i n E D C.  
T h e I nv esti g at or or st u dy p hysici a n, aft er t h or o u g h c o nsi d er ati o n of all f acts t h at ar e a v ail a bl e, m ust 
i ncl u d e a n ass ess m e nt of c a us alit y of a n A E t o S M i n t h e r e p ort t o t h e S p o ns or.   
F oll o w- u p i nf or m ati o n, or n e w i nf or m ati o n av ail a bl e aft er t h e i niti al r e p ort, s h o ul d b e activ el y s o u g ht 
a n d r e p ort e d t o t h e S p o ns or as it b ec o m es a v ail a bl e usi n g t h e S A E R e p ort F or m.   
T h e Dr u g S af ety C o nt act f or S A E r e p orti n g is: 
 
 
 
 
 
5. 4. 2. 2  Ot h er E v e nts R e q uiri n g I m m e di at e R e p orti n g 
T h e I nv esti g at or m ust r e p ort a pr e g n a nc y  t h at occ urs i n a s u bj ect d uri n g a cli nic al st u dy t o t h e Dr u g 
S af et y C o nt act wit hi n 2 4 h o urs of first b ec o mi n g a w ar e of t h e e v e nt.   Pr e g n a ncy s h o ul d b e r e p ort e d o n a 
Pr e g n a nc y R e p ort F or m.   T h e I nv esti g at or s h o ul d disc uss t h e c as e wit h t h e M e dic al M o nit or; t h e 
I nv esti g at or m ust f oll o w a ny pr e g n a nt s u bj ect f or 3 m o nt hs aft er t h e c hil d is b or n.  T h e I nv esti g at or 
m ust c o m pl et e a Pr e g n a nc y O utc o m e F or m as a f oll o w u p. A ny A E s c o nc er ni n g t h e pr e g n a nc y of t h e 
s u bj ect d uri n g pr e g n a nc y or t h e c hil d aft er birt h m ust b e d oc u m e nt e d a n d r e p ort e d t o t h e S p o ns or. 
Tr e at m e nt- e m er gi n g E P S  ( e. g. a k at hisi a, dyst o ni a, P arki ns o nis m, t ar div e d ys ki n esi a) a n d n e ur ol e ptic 
m ali g n a nt sy n dr o m e s h o ul d b e r e p ort e d t o t h e Dr u g S af et y C o nt act p ers o n(s) by c o m pl eti n g t h e A dv ers e 
E v e nt of S p eci al I nt er est ( A E SI) e C R F i n E D C.  S h o ul d t h e sit e b e u n a bl e t o acc ess E D C, a p a p er A E SI f or m 
m ust b e c o m pl et e d a n d s e nt t o  
 Dr u g S af ety b y e m ail or f ax wit hi n 2 4 h o urs of first b ec o mi n g a w ar e 
of t h e ev e nt.   O nc e E D C b ec o m es a v ail a bl e t h e sit e m ust c o m pl et e A E SI e C R F i n E D C. E P S i nci d e nc e will 
b e s u m m ariz e d a n d s h ar e d wit h st u dy I nv esti g at ors t hr o u g h o ut t h e tri al.   
O v er d os a g e  of m oli n d o n e pr es u m a bl y m a y b e m a nif est e d b y s ev er e E P S a n d s e d ati o n.  C o m a wit h 
r es pir at ory d e pr essi o n a n d s e v er e hy p ot e nsi o n r es ulti n g i n a s h ock-li k e s y n dr o m e c o ul d occ ur. I n t he 
e v e nt of a s us p ect e d ov er d os e, t h e p ar e nt or l e g al r e pr es e nt ativ e s h o ul d b e i nstr uct e d t o c all 9 1 1 or 
t h eir l oc al p ois o n c o ntr ol c e nt er at 
. 
S y m pt o m atic, s u p p ortiv e t h er a py s h o ul d b e t h e r ul e.  G astric l av a g e is i n dic at e d f or t h e r e d ucti o n of 
a bs or pti o n of m oli n d o n e w hic h is fr e ely s ol u bl e i n w at er. Si nc e t h e a ds or pti o n of m oli n d o n e by 
acti v at e d c h arc o al h as n ot b e e n d et er mi n e d, t h e us e of t his a nti d ot e m ust b e c o nsi d er e d of t h e or etic al 
v al u e. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 5 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
E m esis i n a c o m at os e p ati e nt is c o ntr ai n dic at e d. A d diti o n ally, w hil e t h e e m etic eff ect of a p o m or p hi n e is 
bl oc k e d b y m oli n d o n e i n a ni m als, t his bl ocki n g eff ect h as n ot b e e n d et er mi n e d i n h u m a ns. 
5. 4. 2. 3  S p o ns or R es p o nsi biliti es f or E x p e dit e d R e p orti n g of S A Es 
T h e S p o ns or will i nf or m I nv esti g at ors a n d r e g ul at ory a ut h oriti es of r e p ort a bl e e v e nts, i n c o m pli a nc e 
wit h a p plic a bl e r e g ul at ory r e q uir e m e nts, o n a n ex p e dit e d b asis (i. e., wit hi n s p ecific ti m efr a m es).  F or 
t his r e as o n, it is i m p er ativ e t h at st u dy sit es s u b mit S A E i nf or m ati o n t o t h e S p o ns or i n t h e m a n n er 
d escri b e d a b o v e.  
I nv esti g at ors m ust c o m ply wit h t h e a p plic a bl e r e g ul at or y r e q uir e m e nts r el at e d t o t h e r e p orti n g of S A Es 
t o t h e I R B/I E C.  I nv esti g at ors m ust als o s u b mit t h e s af et y i nf or m ati o n pr ovi d e d by t h e S p o ns or t o t h e 
I R B/I E C u nl ess t h e c o u ntr y l e g al r e g ul ati o n r e q uir es t h at t h e S p o ns or s h o ul d b e r es p o nsi bl e f or t h e 
s af et y r e p orti n g t o t h e I R B/I E C. 
It is t h e r es p o nsi bilit y of t h e S p o ns or t o n otif y all p artici p ati n g i n v esti g at ors, i n a writt e n I N D s af ety 
r ep ort, of a n y S A D R t h at is b ot h s eri o us a n d u n ex p ect e d.  T h e S p o ns or will als o n otif y p artici p ati n g 
i nv esti g at ors of a ny fi n di n gs fr o m ot h er s o urc es ( ot h er st u di es, a ni m al a n d i n vitr o t esti n g, etc.) t h at 
s u g g est a si g nific a nt ris k f or h u m a n s u bj ects.  S uc h fi n di n gs will t y pic ally l e a d t o s af et y-r el at e d c h a n g es 
i n t h e st u dy pr ot oc ol, I nf or m e d C o ns e nt, a n d/ or I nv esti g at or’s Br oc h ur e. 
5. 4. 3  
M a n a g e m e nt of Tr e at m e nt- E m er gi n g E P S 
If a s u bj ect ex p eri e nc es tr e at m e nt- e m er gi n g E P S (i ncl u di n g a k at hisi a, dyst o ni a, P ar ki ns o nis m, or t ar di v e 
dys ki n esi a), b e nztr o pi n e will b e p er mitt e d at a st arti n g d os e of 0. 5 m g BI D u p t o a r a n g e of 1 t o 
4 m g/ d a y.  L or az e p a m ( 1 t o 2 m g p er d os e n ot t o exc e e d t hr e e ti m es d ail y) a n d cl o n az e p a m ( 0. 2 5 t o 1 
m g p er d os e n ot t o exc e e d t wic e d ail y) will als o b e p er mitt e d t o tr e at e m er gi n g E P S. 
A p ositiv e fi n di n g o n a n E P S s af ety ass ess m e nt sc al e ( B ar n es A k at hisi a, Si m ps o n- A n g us, AI M S) d o es n ot 
n ec ess arily e q u at e t o a n E P S e v e nt.  I nv esti g at ors s h o ul d e v al u at e p ositi v e fi n di n gs o n t h e E P S s af et y 
ass ess m e nt sc al es a n d i nt e gr at e t h e m i nt o a gl o b al cli nic al o bs erv ati o n t o d et er mi n e if a n A E of E P S 
s h o ul d b e r ec or d e d. 
5. 4. 4  
L a b or at or y M e as ur e m e nts 
Wit h t h e exc e pti o n of uri n e pr e g n a nc y t est, cli nic al l a b or at or y t ests will b e p erf or m e d by a c e ntr al 
l a b or at or y as s p ecifi e d i n t h e r ef er e nc e bi n d er. 
D et ails f or c oll ecti n g, h a n dli n g, a n d s hi p pi n g s a m pl es (i ncl u di n g s hi p m e nt a d dr ess es) will b e d et ail e d i n a 
s e p ar at e l a b or at ory m a n u al.  T h e Sc h e d ul e of Visits a n d Pr oc e d ur es ( T a bl e 1 ) s h o ws t h e ti m e p oi nts at 
w hic h uri n e s a m pl es will b e c oll ect e d f or uri n al ysis a n d bl o o d s a m pl es will b e c oll ect e d f or cli nic al 
l a b or at or y t ests a n d pl as m a c o nc e ntr ati o n l ev els.   
T a bl e 3  pr es e nts t h e cli nic al l a b or at or y t ests t o b e p erf or m e d.  M et a b olic p ar a m et ers (i ncl u di n g i ns uli n, 
gl uc os e, tri gl yc eri d es, a n d c h ol est er ol) a n d pr ol acti n will b e m e as ur e d. A s u bj ect will b e excl u d e d if t h e 
Scr e e ni n g bl o o d t est r es ults i n dic at es > 2 ti m es t h e u p p er li mit of n or m al ( UL N) of al a ni n e 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 6 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
a mi n otr a nsf er as e ( AL T), as p art at e a mi n otr a nsf er as e ( A S T), g a m m a gl ut a myl tr a ns p e pti d as e ( G G T), 
a n d/ or s er u m cr e ati ni n e. L a b or at or y t ests will n ot b e r e p e at e d f or t h es e s u bj ects. 
All l a b or at or y t ests will b e r e vi e w e d i n a ti m ely m a n n er b y q u alifi e d sit e p ers o n n el t o e ns ur e s af ety.  
A b n or m al l a b fi n di n gs m ay b e c o nfir m e d if n ec ess ary by o n e r e p e at e d t esti n g at t h e discr eti o n of t h e 
I nv esti g at or.  A ny r e p e at l a b or at or y t esti n g will b e c o n d uct e d u n d er f asti n g c o n diti o n. A ny l a b or at or y 
a b n or m alit y m ay q u alif y as a n A E i n t h e I nv esti g at or’s j u d g m e nt.  
A t ot al of a p pr oxi m at el y 4 2 mL of bl o o d p er s u bj ect will b e dr a w n d uri n g t h e st u dy: 2 2 mL is f or cli nic al 
l a b or at or y t ests a n d 2 0 mL is f or P K s a m pli n g. 
 
T a bl e 3: Cli nic al L a b or at or y T ests 
C at e g or y  
P ar a m et ers  
H e m at ol o gy  
R B C , W B C, H g b, H C T, M C H, M C H C, M C V, pl at el et c o u nt, a n d W B C wit h 
diff er e nti al ( n e utr o p hils, l y m p h ocyt es, m o n ocyt es, e osi n o p hils, b as o p hils , 
l ar g e u nst ai n e d c ells) 
C h e mistr y  
 
 
 
El ectr ol yt es:  N a +, K+, c hl ori d e, bic ar b o n at e 
Li v er f u ncti o n t ests: al k ali n e p h os p h at as e, A S T, AL T, t ot al bilir u bi n, dir ect 
bilir u bi n  ,i n dir ect bilir u bi n 
R e n al f u ncti o n p ar a m et ers:  B U N, cr e ati ni n e  
Ot h er:  gl uc os e, C a + 2, al b u mi n, p h os p h or us, l act at e d e h y dr o g e n as e, t ot al 
pr ot ei n, C K/ C P K, gl o b uli n , uric aci d, tri gl yc eri d es, i ns uli n, pr ol acti n , 
c h ol est er ol –  t ot al, H DL a n d L DL  
A m yl as e, g a m m a G T ( G G T), Ir o n, Li p as e, M a g n esi u m  
Uri n e  
Uri n al ysis  
Uri n e Dr u g Scr e e n  
Uri n e pr e g n a ncy t est ( F O C B P o nl y)  
 
5. 4. 5  
Vit al Si g n a n d H ei g ht/ W ei g ht M e as ur e m e nts 
Vit al si g n m e as ur e m e nts ( e. g., bl o o d pr ess ur e, h e art r at e, t e m p er at ur e, a n d r es pir at ory r at e) a n d h ei g ht, 
w ei g ht a n d B MI will b e o bt ai n e d at visits d esi g n at e d o n t h e Sc h e d ul e of Visits a n d Pr oc e d ur es ( T a bl e 1 ).  
Bl o o d pr ess ur e a n d h e art r at e will b e m e as ur e d aft er t h e s u bj ect h as b e e n sitti n g f or 5 mi n ut es. Vit al 
si g ns m ay b e t a k e n at a ny ot h er ti m e, as d e e m e d n ec ess ar y b y t h e I nv esti g at or. 
5. 4. 6  
M e dic al Hist or y  
M e dic al hist ory will b e c oll ect e d at visits d esi g n at e d o n t h e Sc h e d ul e of Visits a n d Pr oc e d ur es ( T a bl e 1 ).   
5. 4. 7  
P h ysic al E x a mi n ati o ns a n d El ectr oc ar di o gr a ms ( E C Gs) 
A p hysic al ex a mi n ati o n a n d a 1 2 -l e a d E C G will b e o bt ai n e d at visits d esi g n at e d o n t h e Sc h e d ul e of Visits 
a n d Pr oc e d ur es ( T a bl e 1 ).  A d diti o n al E C Gs m ay b e p erf or m e d at ot h er ti m es if d e e m e d n ec ess ary b y t h e 
I nv esti g at or. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 6 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
T h e E C G will b e r ec or d e d w hil e t h e s u bj ect is r esti n g i n a s u pi n e p ositi o n.  T h e E C G will el ectr o nic ally 
m e as ur e t h e P R, Q R S, Q T, a n d Q Tc i nt er v als, a n d h e art r at e. 
All E C G tr aci n gs will b e r evi e w e d wit hi n 2 4 h o urs b y t h e I nv esti g at or or q u alifi e d S u b -I nv esti g at or.  P R 
i nt er v als will b e d et er mi n e d f or e ac h of t h es e E C Gs fr o m a si n gl e r e a di n g.  I nv ali d m e as ur e m e nts will b e 
r e p e at e d.  Q Tc will b e r e p ort e d as Q Tc F ( Q T c orr ect e d usi n g Fri d erici a's m et h o d).  
5. 4. 8  
Ot h er S p eci al T ests 
T h e f oll o wi n g s p eci al t ests will b e a d mi nist er e d i n t h e cli nic at visits d esi g n at e d i n t h e Sc h e d ul e of Visits 
a n d Pr oc e d ur es ( T a bl e 1 ).   
5. 4. 8. 1  K- S A D S- PL 2 0 1 3 Di a g n ostic I nt er vi e w 
T h e K- S A D S- PL 2 0 1 3 is a s e mi-str uct ur e d di a g n ostic i nt er vi e w d esi g n e d t o di a g n os e c urr e nt a n d p ast 
e pis o d es of ps yc h o p at h ol o gy i n c hil dr e n a n d a d ol esc e nts acc or di n g t o D S M- 5 crit eri a ( K a uf m a n 1 9 9 7). 
W e will us e a v ersi o n of K- S A D S 2 0 1 3 t h at w as r evis e d t o b e c o m p ati bl e t o t h e D S M- 5 crit eri a.  It 
i ncl u d es  t h e p ar e nt a n d c hil d D S M- 5 cr oss-c utti n g s y m pt o ms m e as ur es  ( D S M- 5 C C- S M); a n 
u nstr uct ur e d I ntr o d uct ory I nt er vi e w; t h e Di a g n ostic Scr e e ni n g I nt ervi e w; t h e S u p pl e m e nt C o m pl eti o n 
C h ec klist; t h e Di a g n ostic S u p pl e m e nts a n d t h e S u m m ar y Lif eti m e Di a g n ostic C h ecklist.  T h e K- S A D S- PL 
2 0 1 3 will b e us e d at scr e e ni n g t o c o nfir m t h e di a g n osis of A D H D, as w ell as t o r ul e o ut excl usi o n ary 
di a g n os es.  T h e Scr e e n I nt er vi e w will ass ess t h e diff er e nt di a g n os es a n d d et er mi n e w hic h s u p pl e m e nts 
s h o ul d b e c o m pl et e d.  S u p pl e m e nt 4 ( N e ur o d e v el o p m e nt, Disr u ptiv e a n d C o n d uct Dis or d ers) m ust b e 
c o m pl et e d t o ass ess A D H D, O D D, C D Tic a n d A S D.  If a n excl usi o n ar y di a g n osis is c o nfir m e d, t h e 
r e m ai n d er of t h e di a g n ostic will n ot b e c o m pl et e d.  T his ass ess m e nt will b e a d mi nist er e d at Visit 1. 
5. 4. 8. 2  Si m ps o n- A n g us Sc al e 
T h e Si m ps o n- A n g us sc al e is a 1 0-it e m r ati n g sc al e t h at is wi d el y us e d f or ass ess m e nt of n e ur ol e ptic-
i n d uc e d P ar ki ns o nis m ( Si m ps o n 1 9 7 0).  It c o nsists of 1 it e m m e as uri n g g ait, 6 it e ms m e as uri n g ri gi dit y, 
a n d t hr e e it e ms m e as uri n g gl a b ell a t a p, tr e m or a n d s ali v ati o n, r es p ectiv ely.  T his ass ess m e nt will b e 
a d mi nist er e d at Visit 3 a n d all s u bs e q u e nt visits. 
5. 4. 8. 3  B ar n es A k at hisi a Sc al e 
T h e B ar n es A k at hisi a sc al e is a r ati n g sc al e f or dr u g-i n d uc e d a k at hisi a a n d i ncl u d es c o m p o n e nts f or 
r ati n g t h e o bs erv a bl e, r estl ess m ov e m e nts c h ar act eristic of a k at hisi a, t h e a w ar e n ess of r estl ess n ess, a n d 
a ny distr ess ass oci at e d wit h t h e c o n diti o n ( B ar n es 1 9 8 9).  T his ass ess m e nt will b e a d mi nist er e d at Visit 3 
a n d all s u bs e q u e nt visits. 
5. 4. 8. 4  A b n or m al I n v ol u nt ar y M o v e m e nt Sc al e ( AI M S) 
T h e AI M S t est is a r ati n g sc al e us e d t o m e as ur e t ar di v e dys ki n esi a ( M u n etz 1 9 8 8).  T h er e ar e 1 2 it e ms 
t h at r at e i nv ol u nt ar y m ov e m e nts of v ari o us ar e as of t h e s u bj ect’s b o dy.  T his ass ess m e nt will b e 
a d mi nist er e d at Visit 3 a n d all s u bs e q u e nt visits.  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 6 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
5. 4. 8. 5  Viti ell o A g gr essi o n Sc al e 
T h e Viti ell o A g gr essi o n Sc al e is a 1 0-it e m r ati n g sc al e t h at us es a cl ust er a n al ysis t o c at e g oriz e a g gr essi o n 
i nt o t w o s u bt y p es, pr e d at or y ( or pl a n n e d) a n d aff ectiv e ( or i m p ulsiv e) ( Viti ell o 1 9 9 0).  T his ass ess m e nt 
will b e a d mi nist er e d at Visit 1. 
5. 4. 8. 6  R etr os p ecti v e- M o difi e d O v ert A g gr essi o n Sc al e ( R- M O A S) 
T h e R etr os p ectiv e- M o difi e d O v ert A g gr essi o n Sc al e ( R- M O A S) w as d ev el o p e d t o g a u g e t h e s e v erit y of 
a g gr essi v e b e h avi or ( Bl a d er 2 0 1 0).   P ar e nts r at e t h e fr e q u e nc y ov er t h e p ast w e ek of 1 6 a g gr essiv e 
b e h a vi ors i n f o ur ar e as: v er b al a g gr essi o n; p hysic al a g gr essi o n t o w ar d ot h ers; a g gr essi o n t o w ar d 
o n es elf; a n d d estr ucti o n or h ostil e mis us e of pr o p erty.  N u m eric w ei g hti n g a m plifi es t h e s eri o us n ess of 
m or e h ar mf ul b e h avi ors i n t h e t ot al sc or e.  T his ass ess m e nt will b e a d mi nist er e d at Visit 1. 
5. 4. 8. 7  C ol u m bi a S uici d e S e v erit y R ati n g Sc al e ( C- S S R S) 
T h e C- S S R S is a q u esti o n n air e t h at pr os p ecti v el y ass ess es  s uici d al i d e ati o n a n d b e h a vi or usi n g a s e mi-
str uct ur e d i nt er vi e w t o pr o b e p ati e nt r es p o ns es ( P os n er 2 0 1 1).  T h e C- S S R S v ersi o ns a p plic a bl e t o t h e 
c urr e nt st u dy ar e t h e B as eli n e v ersi o n a n d t h e Si nc e L ast Visit v ersi o n. 
T h e B as eli n e v ersi o n of t h e sc al e ass ess es lif eti m e s uici d al i d e ati o n a n d b e h avi or.  T his v ersi o n is s uit a bl e 
as p art of a s u bj ect’s first i nt er vi e w a n d will b e us e d at Visit 1 t o i d e ntif y v ol u nt e ers w h o m ust n ot 
p artici p at e i n t h e tri al d u e t o t h eir s uici d al t e n d e nci es. 
T h e Si nc e L ast Visit v ersi o n of t h e sc al e ass ess es a n y s uici d al t h o u g hts or b e h a vi ors t h e s u bj ects m ay 
h a v e h a d si nc e t h e l ast a d mi nistr ati o n of t h e C- S S R S.  T his v ersi o n will b e us e d f or t h e ot h er st u dy visits. 
5. 4. 8. 8  I nfr e q u e nt B e h a vi ors C h ec klist 
T h e i nfr e q u e nt b e h avi ors c h ec klist is a c h ec klist of 1 5 b e h a vi ors t h at ( al o n g wit h t h e 1 5 I A Di ary 
b e h a vi ors) w er e q u alit ati v el y li n k e d t o I A d uri n g t h e d e v el o p m e nt of t h e I A di ary.  T h es e b e h avi ors 
i ncl u d e t e asi n g, s pitti n g, biti n g, w e a p o ns, ri p pi n g, br e a ki n g, v a n d alizi n g, d estr oyi n g, fir e s etti n g, hitti n g 
a ni m al, kic ki n g s elf, kicki n g a ni m al, s e v er e i nj ury s elf, s e v er e i nj ur y ot h ers, s e v er e i nj ur y a ni m al.  
C ar e gi v ers will b e ask e d w hic h, if a n y, of t h es e b e h avi ors h av e b e e n o bs erv e d si nc e t h e p ati e nt’s l ast 
visit.  T his ass ess m e nt will b e a d mi nist er e d at Visit 3, Visit 4, Visit 5, a n d Visit 6. 
6  S T A TI S TI C AL M E T H O D S 
6. 1  St atistic al a n d A n al ytic al Pl a ns 
T a b ul ar s u m m ari es of t h e d at a c oll ect e d d uri n g t h e st u dy will b e pr es e nt e d t o pr ovi d e a g e n er al 
d escri pti o n of t h e s u bj ects st u di e d a n d a n ov ervi e w of t h e Effic ac y, P K a n d s af ety r es ults.  D at a fr o m all 
sit es will b e c o m bi n e d i n t h e c o m p ut ati o n of t h es e s u m m ari es a n d s u m m ari es will b e pr es e nt e d b y 
tr e at m e nt gr o u p.  C o nti n u o us v ari a bl es will b e s u m m ariz e d usi n g d escri ptiv e st atistics ( n u m b er of 
s u bj ects, m e a n, st a n d ar d d e vi ati o n [ S D], m e di a n, a n d mi ni m u m a n d m axi m u m v al u es).  C at e g oric al 
( n o mi n al) v ari a bl es will b e s u m m ariz e d usi n g fr e q u e nc y t a bl es ( n u m b er a n d p erc e nt a g e of s u bj ects i n 
e ac h c at e g ory). 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 6 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
I n a d diti o n t o t a b ul ar s u m m ari es, s u bj ect d at a listi n gs, as s p ecifi e d i n S ecti o ns 1 6. 2 a n d 1 6. 4 of I C H 
G ui d a nc e E 3, will b e pr ovi d e d.  A d diti o n al s u bj ect d at a listi n gs t o b e pr ovi d e d f or t his st u dy ar e list e d 
u n d er t h e r el e v a nt s u bs ecti o ns b el o w. All d at a a n alys es will b e p erf or m e d b y t h e C R O aft er t h e st u dy is 
c o m pl et e d a n d t h e d at a b as e is r el e as e d.  St atistic al pr o gr a m mi n g a n d a n alys es will b e p erf or m e d usi n g 
S A S ® a n d/ or ot h er v ali d at e d st atistic al s oft w ar e as r e q uir e d. 
C o m pl et e d et ails of t h e st atistic al a n alysis will b e pr o vi d e d i n a s e p ar at e st atistic al a n al ysis pl a n ( S A P), 
w hic h will b e writt e n, fi n aliz e d, a n d a p pr o v e d pri or t o d at a b as e l oc k a n d will b e i ncl u d e d i n t h e Cli nic al 
St u dy R e p ort ( C S R) f or t his pr ot oc ol.  T h e st atistic al a n al ysis pl a n will s u p ers e d e t h e st atistic al a n alysis 
m et h o ds d escri b e d i n t his cli nic al pr ot oc ol . A ny d e vi ati o n fr o m t h e st atistic al pl a n will b e d oc u m e nt e d 
a n d d escri b e d i n t h e fi n al r e p ort.  If c h a n g es t o pri nci p al f e at ur es st at e d i n t h e pr ot oc ol ar e r e q uir e d, 
t h es e will b e d oc u m e nt e d i n a pr ot oc ol a m e n d m e nt.  T h e fi n al S A P will t a k e i nt o acc o u nt a ny 
a m e n d m e nt t o t h e pr ot oc ol. 
I n g e n er al, t h e b as eli n e v al u e f or a v ari a bl e is d efi n e d as t h e l ast o bs erv ati o n pri or t o t h e first d os e of 
d o u bl e- bli n d st u dy m e dic ati o n, i d e ally Visit 3, b ut i ncl u di n g t h e scr e e ni n g v al u e, if n ec ess ary. 
6. 2  H a n dli n g Missi n g D at a 
F or t h e pri m ary effic acy e n d p oi nt, t h e fr e q u e ncy of I A b e h a vi ors d uri n g t h e tr e at m e nt p eri o d will b e 
c alc ul at e d o v er t h e n u m b er of d ays wit h n o n- missi n g I A di ary d at a i n t h e tr e at m e nt p eri o d. N o ex plicit 
i m p ut ati o n of missi n g d at a will b e us e d, b ut t his a p pr o ac h is i m plicitl y e q ui v al e nt t o usi n g t h e fr e q u e ncy 
of I A b e h avi ors d uri n g t h e d a ys wit h n o n- missi n g I A di ar y d at a t o i m p ut e t h e fr e q u e nc y f or d a ys aft er 
st u dy disc o nti n u ati o n a n d d a ys wit h missi n g I A di ary d at a. 
6. 3  A n al ysis P o p ul ati o ns 
T h e p o p ul ati o n of “ a ll e nr oll e d s u bj ects” c o nsists of all t h os e scr e e n e d s u bj ects w h o m e et t h e 
r e q uir e m e nts f or st u dy p artici p ati o n a n d ar e e nt er e d i n t h e B as eli n e p eri o d of t h e st u dy.  T h e 
p o p ul ati o n of “ a ll r a n d o miz e d su bj ects” c o nsists of all t h os e e nr oll e d s u bj ects w h o c o m pl et e t h e 
B as eli n e P eri o d, m e et t h e i ncl usi o n/ excl usi o n crit eri a a n d ar e r a n d o miz e d. 
S af et y P o p ul ati o n:  will i ncl u d e all r a n d o miz e d s u bj ects w h o r ec ei v e d at l e ast 1 d os e of st u dy dr u g. 
I nt e nt-t o- Tr e at (I T T) P o p ul ati o n:  will i ncl u d e all s u bj ects w h o r ec eiv e d at l e ast 1 d os e of st u dy dr u g a n d 
h a v e a b as eli n e a n d at l e ast 1 v ali d p ost-r a n d o miz ati o n ass ess m e nt of fr e q u e ncy of I A b e h avi ors b as e d 
o n I A di ary e ntry. 
P er- Pr ot oc ol ( P P) P o p ul ati o n:  will i ncl u d e all of t h e s u bj ects i n t h e I T T p o p ul ati o n w h o c o m pl et e d t h e 
tr e at m e nt p eri o d wit h 8 0 % di ar y c o m pl eti o n c o m pli a nc e a n d w h o di d n ot h av e m aj or pr ot oc ol 
d e vi ati o ns. 
P K p o p ul ati o n:  will i ncl u d e all s u bj ects i n t h e s af et y p o p ul ati o n w h o h a d at l e ast o n e P K s a m pl e dr a w n 
w hic h h a d a q u a ntifi a bl e c o nc e ntr ati o n f or at l e ast o n e a n al yt e of i nt er est. 
T h e s af et y, I T T, P P , a n d P K p o p ul ati o ns ar e b as e d o n r a n d o miz e d tr e at m e nt r ec eiv e d. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 6 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
6. 4  D e m o gr a p hic a n d B as eli n e C h ar act eristics 
D e m o gr a p hic/ b as eli n e v ari a bl es i ncl u d e a g e, s ex, et h nicit y, r ac e, a n d h ei g ht at scr e e ni n g, w ei g ht at 
scr e e ni n g a n d b as eli n e, a n d m e dic al hist or y. T a b ul ar s u m m ari es of t h e d e m o gr a p hic/ b as eli n e v ari a bl es 
will b e pr es e nt e d f or t h e s af et y, I T T, a n d P P  p o p ul ati o ns, exc e pt f or m e dic al hist or y, w hic h will b e 
s u m m ariz e d f or t h e s af et y p o p ul ati o n o nl y. 
6. 5  S u bj ect Dis p ositi o n 
A dis p ositi o n of s u bj ects will i ncl u d e t h e n u m b er a n d p erc e nt a g e of s u bj ects i n e ac h of t h e f oll o wi n g 
c at e g ori es: 
 
S u bj ects i n t h e r a n d o miz e d p o p ul ati o n 
 
S u bj ects i n t h e I T T p o p ul ati o n 
 
S u bj ects tr e at e d (s af et y p o p ul ati o n) 
 
S u bj ects i n t h e P P st u dy p o p ul ati o n 
 
Wit hi n e ac h of t h e pr evi o us c at e g ori es, t h e n u m b er a n d p erc e nt a g e of s u bj ects w h o c o m pl et e d a n d 
disc o nti n u e d fr o m t h e st u dy will b e s u m m ariz e d. T h e r e as o ns f or st u dy disc o nti n u ati o n will als o b e 
s u m m ariz e d. T h e r e as o n f or disc o nti n u ati o n m a y i ncl u d e a ny of t h e f oll o wi n g:  
 
S u bj ect wit h dr e w c o ns e nt 
 
L ost t o f oll o w-u p  
 
A d mi nistr ativ e r e as o n 
 
A dv ers e ev e nt 
 
I nv esti g at or d ecisi o n 
 
F ail ur e t o f oll o w r e q uir e d st u dy pr oc e d ur es 
 
Ot h er 
O nly o n e ( pri m ar y) r e as o n f or st u dy disc o nti n u ati o n will b e r ec or d e d f or e ac h s u bj ect.  
6. 6   Pr ot oc ol D e vi ati o ns 
Pr ot oc ol d e vi ati o ns will b e pr es e nt e d i n listi n gs. If a p plic a bl e, t h e n u m b er a n d p erc e nt of s u bj ects wit hi n 
e ac h ty p e of pr ot oc ol d e vi ati o n will b e pr es e nt e d usi n g discr et e s u m m ary st atistics. Pr ot oc ol d evi ati o ns 
will i ncl u d e, b ut ar e n ot li mit e d t o: 
 
N o n-c o m pli a nc e wit h a ny sc h e d ul e d st u dy visit 
 
N o n-c o m pli a nc e wit h st u dy tr e at m e nt 
 
Dis all o w e d c o nc o mit a nt m e dic ati o ns 
 
N o n-c o m pli a nc e wit h st u dy i ncl usi o n or excl usi o n crit eri a 
 
N o n-c o m pli a nc e wit h st u dy ass ess m e nt pr oc e d ur es 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 6 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
6. 7  St u d y M e dic ati o n E x p os ur e a n d C o m pli a nc e 
D ur ati o n of ex p os ur e is d efi n e d as t h e t ot al n u m b er of d a ys a s u bj ect is ex p os e d t o a n y st u dy tr e at m e nt. 
T his will b e c alc ul at e d f or e ac h s u bj ect b y t a ki n g t h e diff er e nc e b et w e e n t h e d at e of l ast d os e mi n us t h e 
d at e of t h e first d os e, pl us 1 ( d at e of l ast d os e –  d at e of first d os e + 1).  
D ur ati o n of Tr e at m e nt ex p os ur e will als o b e s u m m ariz e d usi n g d escri pti v e st atistics ( n, m e a n, S D, 
m e di a n, mi ni m u m, a n d m axi m u m). 
P erc e nt of st u dy dr u g c o m pli a nc e is d efi n e d as {( n u m b er of t a bl ets dis p e ns e d – n u m b er of t a bl ets 
r et ur n e d) / 2 * ( d at e of l ast d os e – d at e of first d os e + 1)} * 1 0 0 %.  
F or e ac h tr e at m e nt, S M c o m pli a nc e will b e s u m m ariz e d b y c o m pli a nc e c at e g or y ( < 8 0 %, 8 0- 1 2 0 %, a n d 
> 1 2 0 %) a n d n u m b er of s u bj ects i n e ac h c o m pli a nc e c at e g ory.  St u dy m e dic ati o n c o m pli a nc e will als o b e 
s u m m ariz e d as a c o nti n u o us v ari a bl e usi n g d escri ptiv e st atistics ( n, m e a n, st a n d ar d d e vi ati o n, m e di a n, 
mi ni m u m, a n d m axi m u m) f or e ac h tr e at m e nt.    
S u m m ari es of tr e at m e nt c o m pli a nc e a n d ex p os ur e will b e pr es e nt e d s e p ar at ely f or t h e Titr ati o n P eri o d, 
M ai nt e n a nc e P eri o d, a n d c o m bi n e d Titr ati o n a n d M ai nt e n a nc e P eri o ds. 
6. 8  C o nc o mit a nt M e dic ati o ns 
C o nc o mit a nt m e dic ati o ns will b e assi g n e d a n 1 1- di git c o d e usi n g t h e W orl d H e alt h Or g a niz ati o n Dr u g 
Dicti o n ar y ( W H O D D) dr u g c o d es.  C o nc o mit a nt m e dic ati o ns will b e f urt h er c o d e d t o t h e a p pr o pri at e 
A n at o mic al- T h er a p e utic- C h e mic al ( A T C) c o d e i n dic ati n g t h er a p e utic cl assific ati o n.  A t a b ul ar s u m m ar y of 
c o nc o mit a nt m e dic ati o ns b y dr u g cl ass will b e pr es e nt e d f or t h e s af ety p o p ul ati o n. 
6. 9  Effic ac y A n al ys es 
6. 9. 1  
Pri m ar y Effic ac y A n al ysis 
T h e pri m ar y effic acy e n d p oi nt is t h e p erc e nt c h a n g e ( P C H T) i n t h e fr e q u e ncy ( u n w ei g ht e d sc or e) of I A 
b e h a vi ors p er 7 d ays i n t h e Tr e at m e nt ( Titr ati o n a n d M ai nt e n a nc e)  p eri o d r el ativ e t o t h e B as eli n e 
p eri o d c alc ul at e d o v er t h e n u m b er of d a ys wit h n o n- missi n g I A di ary d at a.   T h e fr e q u e nc y of I A 
b e h a vi ors p er 7 d ays is t h e s u m of sc or es f or all e v e nts i n a giv e n p eri o d of s e q u e nti al d a ys, a dj ust e d t o 7 
d a ys. 
T h e pri m ar y effic acy e n d p oi nt P C H T will b e c alc ul at e d by P C H T= 1 0 0 *( T –  B)/ B, w h er e T a n d B ar e I A 
b e h a vi or fr e q u e nci es p er 7 d a ys d uri n g t h e Tr e at m e nt p eri o d a n d b as eli n e p eri o d, r es p ecti v el y. T h e I A 
b e h a vi or fr e q u e ncy p er 7 d a ys is d efi n e d as ( S U M/ D A Y) x 7, w h er e S U M  is  t h e s u m of t h e I A b e h avi ors  
r e p ort e d i n t h e s u bj ect I A di ary, a n d D A Y is t h e n u m b er of d ays wit h n o n- missi n g I A fr e q u e nc y d at a i n 
t h e s u bj ect I A di ar y d uri n g t h e s p ecifi e d st u dy p eri o d. 
L et 1, 2, a n d 3 r e pr es e nt t h e m e di a n p erc e nt c h a n g e i n t h e fr e q u e ncy of I A b e h a vi ors p er 7 d a ys i n 
t h e Tr e at m e nt p eri o d r el ativ e t o t h e B as eli n e p eri o d i n t h e I T T p o p ul ati o n f or s u bj ects tr e at e d wit h 
Pl ac e b o, 1 8 m g a n d 3 6 m g d os es of S P N- 8 1 0, r es p ectiv el y.  T h e n ull ( H 0) a n d t h e alt er n ativ e ( Ha) 
hy p ot h es es ar e as i n t h e f oll o wi n g. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 6 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 
H 0 1: 2= 1, (t h er e is n o diff er e nc e b et w e e n t h e m e di a n of t h e 1 8 m g d os e S P N- 8 1 0 a n d t h e 
m e di a n of pl ac e b o) vs. H
a 1: 2≠ 1,(t h er e is a diff er e nc e b et w e e n t h e m e di a n of t h e 1 8 m g d os e 
S P N- 8 1 0   a n d t h e m e di a n of pl ac e b o) 
 
H 0 2: 3= 1, (t h er e is n o diff er e nc e b et w e e n t h e m e di a n of t h e 3 6 m g d os e S P N- 8 1 0 a n d t h e 
m e di a n of pl ac e b o) vs. H
a 2: 3≠ 1,(t h er e is a diff er e nc e b et w e e n t h e m e di a n of t h e 3 6 m g d os e  
S P N- 8 1 0   a n d t h e m e di a n of pl ac e b o) 
T h e pri m ar y effic acy a n alysis will b e p erf or m e d usi n g t h e Wilc ox o n r a n k-s u m t est t o c o m p ar e t h e 
m e di a ns of e ac h of t h e t w o d os es of S P N- 8 1 0 ( 1 8 m g a n d 3 6 m g) wit h t h e m e di a n of t h e Pl ac e b o.  T h e 
H o d g es-L e h m a n n esti m at e a n d t h e ass oci at e d 9 5 % c o nfi d e nc e i nt erv al ( CI) will b e c alc ul at e d. T o 
pr es er v e t h e o v er all Ty p e I err or-r at e at 0. 0 5 0 f or t h e pri m ar y effic acy e n d p oi nt, m ulti plicity a dj ust m e nt 
d u e t o i nt eri m a n alysis a n d t w o c o m p aris o ns of S P N- 8 1 0 d os e gr o u p ( 1 8 m g a n d 3 6 m g) wit h t h e 
Pl ac e b o will b e p erf or m e d as d escri b e d i n S ecti o n 1 0. 1. 4 .  
6. 9. 2  
S ec o n d ar y Effic ac y A n al ys es 
T h e s ec o n d ary e n d p oi nts ar e: 
1.  Act u al C ar e giv er C GI-I sc or e at Visit 6   
2.  Act u al I nv esti g at or C GI-I sc or e at Visit 6 
3.  C h a n g e fr o m Visit 3 t o Visit 6 i n I nv esti g at or C GI- S sc or e 
4.  C h a n g e fr o m Visit 3 t o Visit 6 i n C H Q- 2 8 sc or e 
5.  C h a n g e fr o m Visit 3 t o Visit 6 i n P SI- 4- S F sc or es i n: 
a.  P ar e nt al Distr ess 
b.  P ar e nt- C hil d D ysf u ncti o n al I nt er acti o n 
c. Diffic ult C hil d 
6.  C h a n g e fr o m Visit 3 t o Visit 6 i n S N A P-I V A D H D sc or es i n: 
a.  I n att e nti o n r ati n gs 
b.  Hy p er activity/I m p ulsivity r ati n gs 
c. C o m bi n e d Sc al e r ati n gs  
E ac h o n e of t h e six s ec o n d ar y e n d p oi nts will b e a n alyz e d usi n g t h e a n al ysis of c ov ari a nc e m et h o d b as e d 
o n t h e I T T p o p ul ati o n wit h missi n g d at a i m p ut e d usi n g t h e L ast O bs erv ati o n C arri e d F or w ar d (L O C F) 
m et h o d. T h e m o d el i ncl u d es tr e at m e nt a n d b as eli n e as fix e d i n d e p e n d e nt c o v ari at es a n d c h a n g e fr o m 
b as eli n e t o fi n al m ai nt e n a nc e visit as a r es p o ns e v ari a bl e. T h e l e ast s q u ar es m e a n of e ac h tr e at m e nt 
gr o u p, t h e diff er e nc e i n t h e l e ast s q u ar es m e a n ( 1 8 m g d os e mi n us pl ac e b o a n d 3 6 m g d os e mi n us 
pl ac e b o), a n d t h e 2-si d e d 9 5 % CI f or t h e diff er e nc e will b e o bt ai n e d.   
T o pr es erv e t h e o v er all ty p e I err or r at e at 0. 0 5 f or t h e s ec o n d ar y e n d p oi nts, a s e q u e nti al t esti n g 
pr oc e d ur e will b e us e d wit h t h e f oll o wi n g f e at ur es. First o nly d os e or d os es t h at ar e si g nific a ntl y 
diff er e nt fr o m pl ac e b o f or t h e pri m ar y e n d p oi nt will b e t est e d f or s ec o n d ar y e n d p oi nts. T h e first of t h e 
s ec o n d ary e n d p oi nts will b e c o m p ar e d t o pl ac e b o usi n g t h e H oc h b er g st e p u p pr oc e d ur e b ut o nl y usi n g 
t h os e d os es r et ai n e d as a r es ult of t esti n g t h e pri m ary e n d p oi nt ( H oc h b er g 1 9 8 8). T h e s ec o n d s ec o n d ar y 
e n d p oi nt will b e t est e d i n t h e s a m e m a n n er b ut o nly usi n g t h os e d os es t h at w er e r et ai n e d fr o m t h e 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 6 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
pri m ar y a n d t h e first s ec o n d ar y e n d p oi nt a n d s o f ort h. As t h e e n d p oi nts ar e g o n e t hr o u g h i n t h e pr e-
d efi n e d or d er d os es will o nl y b e r et ai n e d if si g nific a nt f or all e n d p oi nts t est e d s o f ar a n d at t h e gi v e n 
st a g e t h e H oc h b er g st e p- u p pr oc e d ur e will b e a p pli e d. 
T h e or d eri n g of t h e  6 s ec o n d ar y e n d p oi nts fr o m first t o b e t est e d t o sixt h is: I nv esti g at or Cli nic al Gl o b al 
I m pr essi o n –  I m pr o v e m e nt Sc al e ( C GI-I)( E n d p oi nt 1), Cli nic al Gl o b al I m pr essi o n –  S e v erit y Sc al e ( C GI-S)  
( E n d p oi nt 2), C hil d H e alt h Q u esti o n n air e ( C H Q- 2 8) ( E n d p oi nt 3), P ar e nti n g Str ess I n d ex ( P SI- 4-S F ) 
( E n d p oi nt 4), C ar e giv er-c o m pl et e d C GI-I ( E n d p oi nt 5) a n d S N A P-I V R ati n g Sc al e ( E n d p oi nt 6).      
6. 9. 3  
S e nsiti vit y A n al ysis 
I n t h e pr es e nc e of a hi g h dr o p- o ut r at e, p erf or m a nc e of s e nsitivit y a n alysis is cr uci al.  T h e p ur p os e of 
s e nsiti vit y a n alysis is t o s e e w h et h er diff er e nt m et h o ds of h a n dli n g missi n g d at a pr o vi d e c o nsist e nt a n d 
si mil ar r es ults f or t h e pri m ar y effic ac y a n alysis.  T o t his e n d, t h e t hr e e s e nsiti vity a n al ys es will b e 
p erf or m e d: 
1.  M ulti pl e i m p ut ati o n u n d er M A R  usi n g av ail a bl e d at a o n t h e pri m ar y e n d p oi nt  
2.  Pl ac e b o-  b as e d i m p ut ati o n u n d er M N A R  
3.  P er Pr ot oc ol A n al ysis 
6. 9. 3. 1  M ulti pl e i m p ut ati o n u n d er Missi n g at R a n d o m ( M A R) 
T h e m ulti pl e i m p ut ati o n ( MI) m et h o d ass u m es t h at t h e missi n g d at a ar e missi n g at r a n d o m ( M A R), t h at 
is, t h e pr o b a bilit y t h at a n o bs er v ati o n is missi n g m ay d e p e n d o n t h e o bs erv e d v al u es b ut n ot t h e missi n g 
v al u es. F or ex a m pl e, if a s u bj ect’s Di ary v al u es ar e av ail a bl e o n D a y 1 a n d D ay 2 b ut missi n g o n D a y 3, 
t h e n t h e missi n g v al u e o n D a y 3 is r el at e d t o t h e n o n- missi n g  v al u e o n D a y 1 a n d D a y 2. 
MI is i m pl e m e nt e d usi n g t h e f oll o wi n g t hr e e st e ps.  
 
 
1)  S A S P R O C MI is a p pli e d wit h i n p ut d at as et c o nt ai ni n g s o m e missi n g v al u es f or all d a ys d uri n g t h e 
titr ati o n a n d m ai nt e n a nc e p eri o d t o cr e at e 1 0 0 d at as ets. T h e d at a s ets will i ncl u d e s e p ar at e 
c ol u m ns f or t h e fr e q u e ncy of i nci d e nc es d uri n g e ac h d a y st arti n g fr o m b as eli n e. T h e M ark ov 
C h ai n M o nt e C arl o ( M C M C) m et h o d will b e us e d t o c o m pl et e t h e missi n g n ess p att er n t o a 
m o n ot o n e p att er n s e p ar at el y b y tr e at m e nt ar m.  T h e m o n ot o n e p att er ns will b e ac hi e v e d b y 
a p pl yi n g s e q u e nti al i m p ut ati o n b as e d o n B a y esi a n r e gr essi o n wit h t h e tr e at m e nt ar m i ncl u d e d 
as a c o v ari at e.  All c o pi es c o nt ai n i d e ntic al v al u es of t h e n o n- missi n g d at a it e ms, b ut diff er e nt 
v al u es i m p ut e d f or missi n g v al u es.  
2)  F or e ac h of t h es e MI d at a s ets, t h e p erc e nt c h a n g e will b e c o m p ut e d as i n t h e o bs er v e d d at a s et 
a n d t h e pri m ar y a n alysis b as e d o n t h e Wilc ox o n r a n k-s u m t est will b e c o n d uct e d a n d as y m pt otic 
9 5 % c o nfi d e nc e i nt erv als will b e c o nstr uct e d. 
3)  T o pr o d uc e a si n gl e c o nfi d e nc e i nt erv al f or e ac h d os e pl ac e b o c o m p aris o n ( e. g., D os e 1 v ers us 
pl ac e b o), P R O C MI A N AL Y Z E will b e us e d a n d R u bi n’s c o m bi n ati o n r ul es will b e a p pli e d t o t h e 
tr e at m e nt eff ect esti m at es a n d ass oci at e d asy m pt otic st a n d ar d err ors fr o m t h e MI d at a s ets.  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 6 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
T h e tr e at m e nt eff ect esti m at es will b e d efi n e d as t h e mi d p oi nts of t h e as y m pt otic c o nfi d e nc e 
i nt er v als a n d t h e st a n d ar d err ors will b e d efi n e d as t h e as y m pt otic st a n d ar d err ors ( b as e d o n 
t h e wi dt h of t h e ass oci at e d 9 5 % c o nfi d e nc e i nt erv als) fr o m t h e H o d g es-L e h m a n n esti m at e of 
t h e i n di vi d u al d at as ets ( R u bi n 1 9 8 7). 
6. 9. 3. 2  M ulti pl e i m p ut ati o n u n d er Missi n g N ot at R a n d o m ( M N A R) 
T his a p pr o ac h c a n b e l a b el e d “ w orst -c as e” s e nsitivity a n al ys es as it ass u m es t h at aft er disc o nti n u ati o n 
s u bj ects fr o m t h e d osi n g ar ms w o ul d a d o pt t h e o utc o m e m o d el esti m at e d fr o m t h e pl ac e b o ar m.  T o 
g e n er at e missi n g v al u es fr o m t his “ pl ac e b o -b as e d” i m p ut ati o n m o d el, P R O C MI wit h t h e M N A R 
st at e m e nt ( av ail a bl e i n S A S 9. 3 a n d l at er v ersi o ns) will b e us e d or, alt er n ativ el y, S A S m acr os av ail a bl e at 
t h e DI A Missi n g D at a W or ki n g Gr o u p sit e ( R atitc h et al., 2 0 1 3; Ay el e et al., 2 0 1 4) c a n b e us e d. 
6. 9. 3. 3  P er Pr ot oc ol A n al ysis 
T his a n al ysis will b e c o n d uct e d b y r e p e ati n g t h e pri m ar y a n al ysis o n t h e p er pr ot oc ol p o p ul ati o n. 
6. 1 0  S a m pl e Siz e a n d P o w er C o nsi d er ati o ns 
B as e d o n r es ults fr o m t h e P h as e 2 st u dy, it is ass u m e d t h at t h e a v er a g e tr e at m e nt diff er e nc e b et w e e n 
S P N- 8 1 0 d os e gr o u ps a n d pl ac e b o is 1 1. 5 1 wit h a c o m m o n st a n d ar d d evi ati o n of 2 7. 3. A s a m pl e siz e of 
1 3 2 s u bj ects p er ar m ( 2 6 4  s u bj ects f or 3 ar ms) will yi el d 9 0 % p o w er t o d et ect a n o n-z er o diff er e nc e 
b et w e e n t h e m e di a n of 1 8 m g or 3 6 m g d os e gr o u p a n d t h e pl ac e b o usi n g t h e Wilc ox o n r a n k-s u m t est 
wit h a 2-si d e d si g nific a nc e l e v el al p h a = 0. 0 5.  
It is ass u m e d t h at a p pr oxi m at el y 2 0 % of  s u bj ects will dr o p o ut b ef or e t h e c o m pl eti o n of t h e st u dy a n d 
h e nc e, a n a dj ust e d t ot al of 3 3 0  s u bj ects will b e r a n d o miz e d i n a 1: 1: 1 r ati o t o o bt ai n 2 6 4 s u bj ects i n t h e 
I T T p o p ul ati o n at t h e c o m pl eti o n of t h e st u dy.   
T h e s a m pl e siz e w as c alc ul at e d usi n g t h e n Q u er y A dvis or S oft w ar e, V ersi o n 7.    
6. 1 1  I nt eri m A n al ysis 
T h e m ai n p ur p os e of t h e i nt eri m a n al ysis is t o r e- esti m at e t h e s a m pl e siz e. T h e s a m pl e siz e esti m at e 
d escri b e d i n t h e s a m pl e siz e S ecti o n  6. 1 0  is b as e d o n eff ect siz e ass u m pti o ns fr o m t h e P h as e 2 d at a i n 
w hic h t h e pri m ary e n d p oi nt w as t h e c h a n g e fr o m b as eli n e t o e n d p oi nt i n R- M O AS r ati n gs. H o w e v er, t h e 
pri m ar y e n d p oi nt f or t his st u dy is p erc e nt c h a n g e i n t h e fr e q u e ncy  of I A i nci d e nc e p er 7 d ays i n t h e 
Tr e at m e nt ( Titr ati o n a n d M ai nt e n a nc e) p eri o d ( P C H T) r el ativ e t o t h e B as eli n e p eri o d i n t h e I T T 
p o p ul ati o n c alc ul at e d ov er t h e n u m b er of d a ys wit h n o n- missi n g I A di ar y d at a. H e nc e, t h er e is 
u nc ert ai nt y as t o w h at m a g nit u d e of alt er n ativ e h y p ot h esis tr e at m e nt diff er e nc e a n d b et w e e n-s u bj ect 
v ari a bilit y is a p pr o pri at e t o pr e-s p ecify. T o t his e n d, a si n gl e i nt eri m a n alysis is pl a n n e d aft er 
a p pr oxi m at ely 5 0 % of s u bj ects c o m pl et e t h e st u dy. T h e a d a pti v e d esi g n pl a n f or t h e i nt eri m a n alysis 
pl a n is pr es e nt e d i n t h e A p p e n dix 1 0. 1 . 
6. 1 2  Ass ess m e nt of M CI C 
B as e d o n u n bli n d e d d at a av ail a bl e at st u dy cl os e, t h e a bilit y of a p erc e nt c h a n g e ( P C H) e n d p oi nt t o 
d et ect c h a n g e will b e e v al u at e d usi n g t hr e e a nc h or- b as e d mi ni m al cli nic ally i m p ort a nt c h a n g e ( M CI C) 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 6 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
esti m at es o bt ai n e d fr o m t w o gl o b al i m pr essi o n of c h a n g e ( C GI-I) v ari a bl es a n d o n e gl o b al i m pr essi o n of 
s e v erit y ( C GI- S) v ari a bl e. C o nsist e nt wit h t h e r ec o m m e n d ati o ns of H ays ( H ays et al., 2 0 0 5), t h e 
ass ess m e nt of d et ecti o n of cli nic all y m e a ni n gf ul c h a n g e will e m p h asiz e u nst a n d ar diz e d a nc h or- b as e d 
esti m at es “ s o t h at us ers of t h e m e as ur e will b e a bl e t o i nt er pr et diff er e nc es i n t h e r a w m etric.” 
T h e a nc h or- b as e d M CI C v al u es will b e o bt ai n e d b y esti m ati n g t h e av er a g e P C H f or mi ni m al 
i m pr ov e m e nt gr o u ps d efi n e d b y r ati n gs fr o m t w o r at ers f or t w o c o nc e pts. I n v esti g at ors a n d c ar e giv ers 
will e ac h r at e gl o b al i m pr essi o n of c h a n g e.  T h es e will b e k n o w n as I nv esti g at or-r at e d C GI-I a n d 
C ar e gi v er-r at e d C GI-I, r es p ecti v el y.  H o w ev er, o nly i n v esti g at ors will r at e gl o b al i m pr essi o n of s e v erit y 
( C GI- S). T h es e C GI-I/ C GI- S m e as ur es will b e o bt ai n e d at m ulti pl e sit e visits ( Visit 3, Visit 4, Visit 5, a n d 
Visit 6) t hr o u g h o ut t h e st u dy p eri o d t o r e d uc e r ec all err or a n d q u a ntif y i ncr e m e nt al c h a n g e o v er ti m e . 
I nv esti g at or-r at e d C GI-I a n d C ar e gi v er-r at e d C GI-I will b e ass ess e d o n a 7- p oi nt sc al e wit h 1 = V er y m uc h 
i m pr ov e d, 2 = M uc h i m pr ov e d, 3 = Mi ni m ally i m pr o v e d, 4 = N o c h a n g e, 5 = Mi ni m ally w ors e, 6 = M uc h w ors e, 
a n d 7 = V ery m uc h w ors e. C GI S will b e e v al u at e d o n a 7- p oi nt sc al e wit h 1 = N or m al, 2 = B or d erli n e ill, 
3 = Mil dly ill, 4 = M o d er at ely ill, 5 = M ar k e dl y ill, 6 = S e v er ely ill, a n d 7 = Extr e m ely ill. Mi ni m al i m pr ov e m e nt 
gr o u ps (r ati n g of 3) f or a fix e d ass ess m e nt c o ntr ast ( e. g. Visit 3 vs. Vis it 4, Visit 3 vs. Visit 5, a n d Visit 3 vs. 
Visit 6) d efi n e t h e M CI C a nc h or o n I nv esti g at or-r at e d C GI-I a n d C ar e gi v er-r at e d C GI-I. T o d efi n e a n M CI C 
a nc h or o n C GI- S, t h e diff er e nc e i n s e v erity r ati n gs acr oss ass ess m e nt i nt erv al ( e. g. Visit 4 mi n us Visit 3, 
Visit 5 mi n us Visit 3, a n d Visit 6 mi n us Visit 3) will b e c alc ul at e d wit h t h os e ex hi biti n g mi ni m al 
i m pr ov e m e nt i n s ev erit y acr oss i nt er v als us e d t o d efi n e t h e M CI C a nc h or. Mi ni m al i m pr ov e m e nt o n C GI-
S is c alc ul at e d as a o n e c at e g or y c h a n g e of i m pr ov e m e nt, e. g. c h a n gi n g fr o m a v al u e of mil dl y ill at 
b as eli n e t o b or d erli n e ill at titr ati o n or m ar k e dly ill at b as eli n e t o m o d er at el y ill at m ai nt e n a nc e. 
T o c alc ul at e M CI C f or e ac h of t h e C GI-I/ C GI- S a nc h ors d efi n e d a b ov e, P C H sc or es will b e c alc ul at e d by 
visit: Visit 4, Visit 5, a n d Visit 6. Wit h t hr e e visits at w hic h M CI C will b e c alc ul at e d, t h e t hr e e P C H 
v ari a bl es m ay b e ex pr ess e d as P C H 3, 4= 1 0 0 ∗(
V 4 −B
B
) , P C H3, 5= 1 0 0 ∗(
V 5 −B
B
) , a n d P C H3, 6= 1 0 0 ∗(
V 6 −B
B
) , 
w h er e V 4- B, V 5- B, a n d V 6- B ar e t h e diff er e nc e i n u n w ei g ht e d sc or es a dj ust e d t o 7 d a ys b et w e e n Visit 4 
a n d b as eli n e, Visit 5 a n d b as eli n e, a n d Visit 6 a n d b as eli n e, r es p ecti v el y. T h e M CI C v al u es will b e 
o bt ai n e d fr o m a n A N O V A esti m at e d usi n g S A S’ GL M pr oc e d ur e wit h P C H as o utc o m e a n d t h e a nc h ors: 
I nv esti g at or-r at e d C GI-I, C ar e giv er-r at e d C GI-I, a n d c h a n g e i n C GI- S sc or es as fix e d i n d e p e n d e nt 
cl assific ati o n v ari a bl es. Wit h t hr e e ass ess m e nt occ asi o ns ( Visit 4, Visit 5 a n d Visit 6) f or w hic h P C H will 
b e c alc ul at e d a n d t hr e e a nc h ors (I nv esti g at or-r at e d C GI-I, C ar e gi v er-r at e d C GI-I, a n d C GI- S )  at e ac h 
occ asi o n t h er e will b e a t ot al of 9 P C H a n d a nc h or c o m bi n ati o ns.  A S e p ar at e o n e- w a y A N O V A will b e fit 
f or e ac h of t h e 9 P C H a n d a nc h or c o m bi n ati o ns.  Wit hi n a gi v e n P C H a n d a nc h or c o m bi n ati o n, t h e 
a v er a g e P C H v al u e f or e ac h l e v el of t h e a nc h or will b e esti m at e d, wit h t h e M CI C esti m at e c orr es p o n di n g 
t o t h e av er a g e P C H v al u e f or t h e mi ni m al i m pr o v e m e nt gr o u p.  C o nsist e nt wit h c urr e nt b est pr actic e f or 
M CI C r e p orti n g, ( H a ys et al., 2 0 0 5) t h e A N O V A esti m at e d 9 5 % c o nfi d e nc e i nt er v al f or t h e M CI C 
esti m at es will als o b e pr o vi d e d. M CI C esti m at es will b e tri a n g ul at e d i n a n att e m pt t o est a blis h t h e a bilit y 
of t h e I A di ary sc or e t o d et ect cli nic ally m e a ni n gf ul c h a n g e.  
I n a d diti o n, t h e c u m ul ati v e distri b uti o n f u ncti o ns ( C D Fs) f or P C H fr o m b as eli n e t o e ac h visit will b e 
ex pl or e d gr a p hic all y.  T h e C D Fs f or e ac h a nc h or c at e g or y str at u m will b e pl ott e d f or e ac h ass ess m e nt 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 7 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
c o m bi n ati o n ( visit 3 vs. 4, visit 3 vs. 5, a n d visit 3 vs. 6), a n d wit hi n e ac h ass ess m e nt c o m bi n ati o n t hr e e 
a nc h or-s p ecific C D F pl ots will b e g e n er at e d.  Gi v e n t h at t h e C GI-I a n d C GI- S e ac h h a v e s e v e n c at e g ori es, 
C D Fs f or t h e C GI-I a n d C GI-S m e as ur es will dis pl a y s ev e n t ot al C D Fs.  Giv e n t h at t h e C GI- S h as s e v e n 
c at e g ori es b ut t h e a nc h or will b e c o nv ert e d t o o n e-c at e g ory c h a n g e v al u es f or M CI C esti m ati o n, a n 
a d diti o n al C GI- S pl ot will b e pr o d uc e d dis pl a yi n g six C D Fs, o n e f or e ac h o n e-c at e g or y c h a n g e v al u e ( 1 t o 
2, 2 t o 3, . . ., 6 t o 7) at e ac h ass ess m e nt c o m bi n ati o n i n or d er t o ass ess t h e u nif or mity of P C H acr oss 
e ac h p ossi bl e o n e- p oi nt c h a n g e c o m bi n ati o n.  I n a d diti o n, t h e C D Fs f or e ac h tr e at m e nt ar m will b e 
pl ott e d.  T o a u g m e nt t h e i nt er pr et ati o n of t h e I A di ary’s a bilit y t o d et ect m e a ni n gf ul c h a n g e, t h e M CI C 
esti m at es will b e d e m arc at e d i n t h e tr e at m e nt-str atifi e d C D F pl ots a n d t h e tr e at m e nt- ar m s p ecific 
pr o p orti o ns ac hi e vi n g t h e M CI C esti m at es will b e r e p ort e d a n d c o m p ar e d. 
6. 1 3  P h ar m ac o ki n etic A n al ys es 
 
 
 
 
 
 
 
 
 
   
 
 
 
6. 1 4  S af et y A n al ys es 
E v al u ati o n of s af et y will b e p erf or m e d f or t h e s af et y p o p ul ati o n.  S af ety d at a t h at will b e e v al u at e d 
i ncl u d e c o nc o mit a nt m e dic ati o ns, A Es, cli nic al l a b or at or y r es ults, vit al si g ns, E C Gs, a n d fi n di n gs fr o m t h e 
p hysic al ex a mi n ati o ns.  T h e occ urr e nc e of n e ur ol o gic al si d e eff ects will b e ass ess e d b y l o o ki n g at a ny 
w ors e ni n g i n sc or es fr o m Visit 3 t o e ac h s u bs e q u e nt visit f or e ac h of t h e Si m ps o n- A n g us sc al e, B ar n es 
A k at hisi a sc al e, a n d AI M S. S uici d al i d e ati o n a n d s uici d al b e h a vi or will b e m e as ur e d b y C- S S R S. 
All s u m m ar y t a bl es r el at e d t o s af ety a n alys es will us e t h e s af ety p o p ul ati o n. 
6. 1 4. 1  A d v ers e E v e nts 
A Es will b e cl assifi e d i nt o st a n d ar diz e d m e dic al t er mi n ol o gy fr o m t h e v er b ati m d escri pti o n (I nv esti g at or 
t er m) usi n g t h e M e dic al Dicti o n ary f or R e g ul at ory Activiti es ( M e d D R A).  A Es will b e s u m m ariz e d usi n g 
discr et e s u m m ari es at t h e s u bj ect a n d ev e nt l ev el by s yst e m or g a n cl ass a n d pr ef err e d t er m f or e ac h 
tr e at m e nt gr o u p.  Si mil arly, tr e at m e nt- e m er g e nt A Es will b e s u m m ariz e d b y s ev erit y a n d r el ati o ns hi p 
s e p ar at ely.  V er b ati m d escri pti o n a n d all M e d D R A l ev el t er ms, i ncl u di n g t h e l o w er l e v el t er ms, f or all A Es 
will b e c o nt ai n e d i n t h e s u bj ect d at a listi n gs. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 7 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
All A Es occ urri n g aft er r a n d o miz ati o n a n d t hr o u g h o ut t h e st u dy p eri o d will b e r ec or d e d.  F or s u bj ects 
w h o r ec eiv e S M, tr e at m e nt- e m er g e nt A Es ( T E A Es) will b e c oll ect e d st arti n g aft er t h e first d os e of S M 
( Visit 3) t o t h e e n d of t h e st u dy.  T h es e A Es i ncl u d e t h os e t h at e m er g e d uri n g tr e at m e nt or w ors e n i n 
s e v erit y d uri n g tr e at m e nt. T h es e A Es will b e t a b ul at e d, list e d a n d a n alyz e d. 
S e p ar at e T E A E i nci d e nc e t a bl es will b e pr es e nt e d f or t h e t hr e e tr e at m e nt gr o u ps.  T h e i nci d e nc e r at es 
f or all S A D Rs will als o b e s u m m ariz e d as d escri b e d f or all T E A Es. 
I n a d diti o n, t h es e s a m e t a bl es will b e pr es e nt e d by tr e at m e nt p eri o d ( Titr ati o n, M ai nt e n a nc e, a n d 
c o m bi n e d Titr ati o n a n d M ai nt e n a nc e).  F or t h e c o m bi n e d Titr ati o n a n d M ai nt e n a nc e P eri o ds, t h e 
i nci d e nc e of T E A Es will als o b e pr es e nt e d by hi g h est s ev erity r e p ort e d a n d t h e d os e of S M at first 
occ urr e nc e.   
Listi n gs ( a n d t a b ul ar s u m m ari es, if w arr a nt e d) of d e at hs, ot h er S A Es, a n d ot h er si g nific a nt T E A Es, 
i ncl u di n g T E A Es r es ulti n g i n tr e at m e nt disc o nti n u ati o n, will b e pr ovi d e d. 
6. 1 4. 2  L a b or at or y V al u es 
Cli nic al l a b or at ory v al u es will b e s u m m ariz e d b y visit by tr e at m e nt gr o u p usi n g d escri pti v e st atistics f or 
h e m at ol o gy a n d bi oc h e mistr y.  F or q u a ntit ati v e l a b or at or y p ar a m et ers, b ot h act u al v al u es a n d c h a n g e 
fr o m b as eli n e v al u es will b e s u m m ariz e d.   
L a b or at ory t est r es ults will b e assi g n e d a l o w, n or m al, hi g h (L N H) cl assific ati o n acc or di n g t o w h et h er t h e 
v al u es w er e b el o w (L), wit hi n ( N), or a b ov e ( H) t h e l a b or at or y p ar a m et ers’ r ef er e nc e r a n g es p r o vi d e d b y 
t h e c e ntr al l a b or at or y.  Wit hi n-tr e at m e nt c o m p aris o ns will b e b as e d o n t hr e e by t hr e e t a bl es (s hift 
t a bl es) t h at, f or a p artic ul ar l a b or at or y t est, c o m p ar e t h e L N H cl assific ati o n at b as eli n e t o t h e L N H 
cl assific ati o n at visit.  By s u bj ect-listi n gs of all a b n or m al l a b or at or y v al u es, i. e., t h os e wit h L or H 
cl assific ati o n will b e pr o vi d e d. 
6. 1 4. 3  Vit al Si g ns, H ei g ht a n d W ei g ht 
Vit al si g ns will b e s u m m ariz e d b y visit by tr e at m e nt gr o u p usi n g d escri ptiv e st atistics.  B ot h act u al v al u es 
c h a n g es fr o m b as eli n e t o visit will b e s u m m ariz e d.  D escri pti v e s u m m ary st atistics ( m e a n, S D, m e di a n, 
a n d r a n g e) f or vit al si g n d at a, h ei g ht, w ei g ht a n d B MI will b e e v al u at e d b y tr e at m e nt gr o u p. 
6. 1 4. 4  E C G R es ults 
B y -visit t a b ul ar s u m m ari es of t h e q u a ntit ativ e E C G p ar a m et ers a n d t h e o v er all E C G fi n di n gs ( n or m al, 
a b n or m al n ot cli nic all y si g nific a nt, or a b n or m al cli nic all y si g nific a nt) will b e pr es e nt e d.   T h e Q T will b e 
c orr ect e d usi n g Fri d erici a’s m et h o d. 
E C G r es ults will b e s u m m ariz e d b y visit b y tr e at m e nt gr o u p usi n g d escri ptiv e st atistics (f or q u a ntit ati v e 
E C G p ar a m et ers) a n d fr e q u e nc y t a bl es (f or q u alit ati v e E C G p ar a m et ers, i ncl u di n g t h e o v er all E C G 
fi n di n g).  F or q u a ntit ativ e E C G p ar a m et ers, b ot h act u al v al u es a n d c h a n g e fr o m scr e e ni n g v al u es will b e 
s u m m ariz e d.   


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 7 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
6. 1 4. 5  P h ysic al E x a mi n ati o ns 
Fi n di n gs fr o m t h e p hysic al ex a mi n ati o ns will b e list e d f or e ac h s yst e m or ar e a ex a mi n e d. 
6. 1 4. 6  C ol u m bi a S uici d e S e v erit y R ati n g Sc al e ( C- S S R S) 
C- S S R S o utc o m es will b e s u m m ariz e d usi n g n u m b er a n d p erc e nt of s u bj ects b y c at e g ori es f or s uici d al 
i d e ati o n o nl y, s uici d al b e h avi or o nl y a n d s uici d ality (i d e ati o n a n d b e h avi or c o m bi n e d). T h e s u m m ar y will 
b e pr es e nt e d by tr e at m e nt gr o u ps.  T h e pr o p orti o n of s u bj ects i n e ac h tr e at m e nt gr o u p will b e 
c o m p ar e d wit h t h e pr o p orti o n of s u bj ects i n t h e pl ac e b o gr o u p usi n g Fis h er’s ex act t est or C hi -s q u ar e 
t est as a p plic a bl e if a p pr o pri at e.  
6. 1 4. 7  I nfr e q u e nt B e h a vi ors C h ec klist 
I nfr e q u e nt b e h a vi ors will b e list e d f or e ac h s u bj ect by tr e at m e nt gr o u p. 
6. 1 4. 8  Ot h er S p eci al T ests 
T h e occ urr e nc e of n e ur ol o gic al si d e eff ects will b e ass ess e d by l o o ki n g at t h e c h a n g es i n sc or es fr o m 
b as eli n e t o p ost- b as eli n e visits f or e ac h of t h e Si m ps o n- A n g us sc al e, B ar n es A k at hisi a sc al e, a n d AI M S.  
F or e ac h it e m o n e ac h of t h es e sc al es, t h e n u m b er ( a n d p erc e nt a g e) of s u bj ects wit h a w ors e sc or e at 
a ny p ost- b as eli n e visit, c o m p ar e d t o b as eli n e, will b e pr es e nt e d.  A listi n g of t h es e s u bj ects will als o b e 
pr o vi d e d.  
7  D O C U M E N T A TI O N 
7. 1  A d h er e nc e t o t h e Pr ot oc ol 
T h e I nv esti g at or a gr e es, w h e n si g ni n g t h e pr ot oc ol, t o a d h er e t o t h e i nstr ucti o ns a n d pr oc e d ur es 
d escri b e d i n t h e pr ot oc ol a n d t o a d h er e t o t h e pri nci pl es of I C H G C P t o w hic h t h e pr ot oc ol c o nf or ms as 
w ell as all g ov er ni n g l oc al r e g ul ati o ns a n d pri nci pl es f or m e dic al r es e arc h. 
T h e pr ot oc ol, I C F, a n d a p pr o pri at e r el at e d d oc u m e nts m ust b e r evi e w e d a n d a p pr o v e d b y a n I R B 
c o nstit ut e d a n d f u ncti o ni n g i n acc or d a nc e wit h I C H E 6 a n d a n y l oc al r e g ul ati o ns. D oc u m e nt ati o n of I R B 
c o m pli a nc e wit h t h e I C H a n d a n y l oc al r e g ul ati o ns r e g ar di n g c o nstit uti o n a n d r e vi e w c o n d uct will b e 
pr o vi d e d t o t h e S p o ns or. 
A si g n e d l ett er of st u dy a p pr o v al fr o m t h e I R B C h air m a n m ust b e s e nt t o t h e I nv esti g at or wit h a c o py t o 
t h e S p o ns or pri or t o st u dy st art a n d t h e r el e as e of a n y S M t o t h e sit e by t h e S p o ns or or its d esi g n e e.  If 
t h e I R B d eci d es t o s us p e n d or t er mi n at e t h e st u dy, t h e I nv esti g at or will i m m e di at el y s e n d t h e n otic e of 
st u dy s us p e nsi o n or t er mi n ati o n b y t h e I R B t o t h e S p o ns or. 
St u dy pr o gr ess is t o b e r e p ort e d t o I R B a n n u ally ( or as r e q uir e d) by t h e I nv esti g at or or S p o ns or, 
d e p e n di n g o n l oc al r e g ul at or y o bli g ati o ns.  If t h e I n v esti g at or is r e q uir e d t o r e p ort t o t h e I R B, h e/s h e will 
f or w ar d a c o py t o t h e S p o ns or at t h e ti m e of e ac h p eri o dic r e p ort.   
7. 2  C h a n g es t o t h e Pr ot oc ol 
T h er e ar e t o b e n o c h a n g es t o t h e pr ot oc ol wit h o ut writt e n a p pr ov al fr o m t h e S p o ns or.   


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 7 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
A ny c h a n g e t o t h e pr ot oc ol r e q uir es a writt e n pr ot oc ol a m e n d m e nt or a d mi nistr ati v e c h a n g e t h at m ust 
b e a p pr ov e d b y t h e S p o ns or b ef or e i m pl e m e nt ati o n.  A m e n d m e nts s p ecific ally aff ecti n g t h e s af et y of 
s u bj ects, t h e sc o p e of t h e i nv esti g ati o n, or t h e sci e ntific q u alit y of t h e st u dy r e q uir e a d diti o n al a p pr ov al 
by t h e a p plic a bl e I R Bs a n d, i n s o m e c o u ntri es, by t h e r e g ul at ory a ut h orit y.  T h es e r e q uir e m e nts s h o ul d 
i n n o w ay pr ev e nt a ny i m m e di at e acti o n fr o m b ei n g t ak e n b y t h e I nv esti g at or, or by t h e S p o ns or, i n t he 
i nt er est of pr es ervi n g t h e s af et y of all s u bj ects i ncl u d e d i n t h e st u dy.  If a n i m m e di at e c h a n g e t o t h e 
pr ot oc ol is w arr a nt e d as p er t h e I n v esti g at or, f or s af ety r e as o ns, t h e M e dic al M o nit or a n d I R B m ust b e 
n otifi e d pr o m ptl y. 
C h a n g es aff ecti n g o nl y a d mi nistr ativ e as p ects of t h e st u dy d o n ot r e q uir e f or m al pr ot oc ol a m e n d m e nts 
or I R B a p pr ov al, b ut t h e I R B m ust b e k e pt i nf or m e d of s uc h c h a n g es.  I n t h es e c as es, t h e S p o ns or will 
s e n d a l ett er t o t h e I R B d et aili n g s uc h c h a n g es. 
7. 3  Pr ot oc ol D e vi ati o ns 
T h er e ar e t o b e n o I nv esti g at or-i niti at e d d evi ati o ns fr o m t h e pr ot oc ol.  A ny s u bj ect w h os e tr e at m e nt 
d e vi at es fr o m t h e pr ot oc ol or w h o is n ot q u alifi e d f or st u dy p artici p ati o n m a y b e i n eli gi bl e f or a n alysis 
a n d m a y c o m pr o mis e t h e st u dy.  T h e d at e of a n d r e as o n f or d evi ati o ns m ust b e d oc u m e nt e d i n all c as es. 
Si g nific a nt or m aj or pr ot oc ol d evi ati o ns i m p acti n g t h e s af ety of t h e s u bj ect or t h e i nt e grity of t h e st u dy 
m ust b e r e p ort e d b y t h e I nv esti g at or t o t h e I R B i m m e di at el y. R e p orti n g of all ot h er pr ot oc ol d e vi ati o ns 
m ust a d h er e t o t h e r e q uir e m e nts of t h e g ov er ni n g I R B. Pr ot oc ol ass ess m e nts will c o nti n u e u ntil t h e e n d 
of t h e st u dy, u nl ess t h e pr ot oc ol d evi ati o ns p ut t h e s u bj ect at ris k or t h e s u bj ect’s c o n diti o n r e q uir es 
t h at h e/s h e b e disc o nti n u e d fr o m t h e st u dy. 
7. 4  D at a Q u alit y Ass ur a nc e 
T his st u dy will b e or g a niz e d, p erf or m e d, a n d r e p ort e d i n c o m pli a nc e wit h t h e pr ot oc ol, st a n d ar d 
o p er ati n g pr oc e d ur es ( S O Ps), w or ki n g pr actic e d oc u m e nts, a n d a p plic a bl e r e g ul ati o ns a n d g ui d eli n es.  
Sit e visit a u dits m ay b e m a d e p eri o dic ally b y t h e S p o ns or’s Q u alit y Ass ur a nc e t e a m or q u alifi e d 
d esi g n e e, w hic h is a n i n d e p e n d e nt f u ncti o n fr o m t h e st u dy c o n d uct t e a m. 
7. 4. 1  
D at a C oll ecti o n 
T h e pri m ar y s o urc e d oc u m e nt will b e t h e s u bj ect’s m e dic al r ec or d.  If s e p ar at e r es e arc h r ec or ds ar e 
m ai nt ai n e d by t h e I nv esti g at or(s), b ot h t h e m e dic al r ec or d a n d t h e r es e arc h r ec or d will b e c o nsi d er e d 
t h e s o urc e d oc u m e nts f or t h e p ur p os es of m o nit ori n g a n d a u diti n g t h e st u dy. 
El ectr o nic d at a c oll ecti o n t ec h ni q u es will b e us e d t o c oll ect d at a dir ectly fr o m t h e st u dy sit es usi n g 
e C R Fs.  T h e el ectr o nic d at a will b e st or e d c e ntr ally i n a f ull y v ali d at e d cli nic al d at a b as e. 
 
 
 
/ pr o gr a ms. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 7 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
D at a r ec or d e d o n s o urc e d oc u m e nts will b e tr a nscri b e d i nt o t h e e C R Fs i n acc or d a nc e wit h t h e e C R F 
C o m pl eti o n I nstr ucti o ns t h at ar e pr ovi d e d t o t h e st u dy sit es.  T h e I nv esti g at or is r es p o nsi bl e f or e ns uri n g 
t h at all s ecti o ns of e ac h e C R F ar e c o m pl et e d c orr ectl y, a n d t h at e ntri es c a n b e v erifi e d a g ai nst s o urc e 
d oc u m e nts.  T h e e C R Fs will b e m o nit or e d f or c o m pl et e n ess a n d acc ur ac y a g ai nst t h e s o urc e d oc u m e nts 
by t h e C R A(s) o n a r e g ul ar b asis.  I nc o nsist e nci es b et w e e n t h e e C R Fs a n d s o urc e d oc u m e nts will b e 
r es olv e d i n acc or d a nc e wit h t h e pri nci pl es of G C P. 
C o m pl et e d e C R Fs will b e extr act e d fr o m t h e cli nic al d at a b as e, st or e d as P D F fil es o n a C D- R O M a n d s e nt 
t o t h e r es p ectiv e st u dy sit e f or arc hivi n g.  A C D- R O M c o nt ai ni n g all e C R Fs will b e k e pt by t h e S p o ns or i n 
t h e S p o ns or’s Tri al M ast er Fil e. 
7. 4. 2  
Cli nic al D at a M a n a g e m e nt 
D at a fr o m e C R Fs a n d ot h er ext er n al d at a ( e. g., l a b or at or y d at a) will b e e nt er e d i nt o or m er g e d wit h a 
cli nic al d at a b as e as s p ecifi e d i n t h e d at a m a n a g e m e nt pl a n.  Q u alit y c o ntr ol a n d d at a v ali d ati o n 
pr oc e d ur es will b e a p pli e d t o e ns ur e t h e v ali dit y a n d acc ur ac y of t h e cli nic al d at a b as e. 
7. 4. 3  
D at a b as e Q u alit y Ass ur a nc e 
I n acc or d a nc e wit h t h e v e n d or’s  pr oc e d ur es, t h e cli nic al d at a b as e will b e r evi e w e d a n d c h ec k e d f or 
o missi o ns, a p p ar e nt err ors, a n d v al u es r e q uiri n g f urt h er cl arific ati o n usi n g c o m p ut eriz e d a n d m a n u al 
pr oc e d ur es.    D at a q u eri es r e q uiri n g cl arific ati o n will b e d oc u m e nt e d a n d r et ur n e d t o t h e st u dy sit e f or 
r es ol uti o n.  O nly a ut h oriz e d p ers o n n el will m a k e c orr ecti o ns t o t h e cli nic al d at a b as e, a n d all c orr ecti o ns 
wi ll b e d oc u m e nt e d i n a n a u dit tr ail. 
7. 4. 4  
Bi o a n al ytic al D at a M a n a g e m e nt a n d Q u alit y C o ntr ol 
 
 
 
 
 
7. 5  R et e nti o n of  R ec or ds 
T h e I nv esti g at or h as t h e r es p o nsi bilit y t o r et ai n all st u dy “ ess e nti al d oc u m e nts”, as d escri b e d i n I C H E 6.  
Ess e nti al d oc u m e nts i ncl u d e b ut n ot li mit e d t o t h e  pr ot oc ol, c o pi es of p a p er C R Fs or e C R Fs, s o urc e 
d oc u m e nts, l a b or at ory t est r es ults, S M i nv e nt or y r ec or ds, I n v esti g at or's Br oc h ur e, r e g ul at or y a g e nc y 
r e gistr ati o n d oc u m e nts ( e. g., F D A f or m 1 5 7 2, I C Fs, a n d I R B/I E C c orr es p o n d e nc e).  T h e i nv esti g at or 
s h o ul d t a k e m e as ur es t o pr e v e nt acci d e nt al or pr e m at ur e d estr ucti o n of t h es e d oc u m e nts.  St u dy 
ess e nti al d oc u m e nts s h o ul d b e r et ai n e d u ntil at l e ast t w o y e ars aft er t h e l ast a p pr o v al of a m ar k eti n g 
a p plic ati o n or aft er f or m al disc o nti n u ati o n of cli nic al d e v el o p m e nt of t h e i nv esti g ati o n al pr o d uct.  T h es e 
d oc u m e nts s h o ul d b e r et ai n e d f or a l o n g er p eri o d, h o w e v er, if r e q uir e d b y t h e a p plic a bl e r e g ul at or y 
r e q uir e m e nts or by a n a gr e e m e nt wit h t h e S p o ns or.  T h e I nv esti g at or m ust o bt ai n writt e n p er missi o n 
fr o m t h e S p o ns or pri or t o t h e d estr ucti o n of a ny st u dy d oc u m e nt. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 7 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
It is r e q u est e d t h at at t h e c o m pl eti o n of t h e r e q uir e d r et e nti o n p eri o d, or s h o ul d t h e I n v esti g at or r etir e 
or r el oc at e, t h e I nv esti g at or c o nt act t h e S p o ns or, all o wi n g t h e S p o ns or t h e o pti o n of p er m a n e ntl y 
r et ai ni n g t h e st u dy r ec or ds. 
T h es e r ec or ds m ust b e m a d e a v ail a bl e at r e as o n a bl e ti m es f or i ns p ecti o n a n d d u plic ati o n, if r e q uir e d, by 
a pr o p erly a ut h oriz e d r e pr es e nt ativ e of t h e U S F D A i n acc or d a nc e wit h t h e U S 2 1 C F R 3 1 2. 6 8 or ot h er 
n ati o n al or f or ei g n r e g ul at or y a ut h oriti es i n acc or d a nc e wit h r e g ul at or y r e q uir e m e nts. 
7. 6  A u diti n g Pr oc e d ur es 
I n a d diti o n t o t h e r o uti n e m o nit ori n g pr oc e d ur es, t h e S p o ns or’s C or p or at e Q u alit y Ass ur a nc e 
d e p art m e nt or q u alifi e d d esi g n e e m a y c o n d uct a u dits of cli nic al r es e arc h acti viti es i n acc or d a nc e wit h 
t h e S p o ns or’s writt e n S O Ps t o e v al u at e c o m pli a nc e wit h t h e pri nci pl es of I C H G C P a n d all a p plic a bl e l oc al 
r e g ul ati o ns.  A g ov er n m e nt r e g ul at ory a ut h ority m a y als o wis h t o c o n d uct a n i ns p ecti o n ( d uri n g t h e 
st u dy or aft er its c o m pl eti o n).  If a n i ns p ecti o n is r e q u est e d by a r e g ul at ory a ut h orit y, t h e I nv esti g at or 
m ust i nf or m t h e S p o ns or a n d t h e C R O i m m e di at ely t h at t his r e q u est h as b e e n m a d e. 
T h es e r ec or ds m ust b e m a d e a v ail a bl e at r e as o n a bl e ti m es f or i ns p ecti o n a n d d u plic ati o n, if r e q uir e d, by 
a pr o p erly a ut h oriz e d r e pr es e nt ativ e of t h e U S F D A i n acc or d a nc e wit h t h e U S 2 1  C F R 3 1 2. 6 8 or ot h er 
n ati o n al or f or ei g n r e g ul at or y a ut h oriti es i n acc or d a nc e wit h r e g ul at or y r e q uir e m e nts. 
7. 7  P u blic ati o n of R es ults 
A ny pr es e nt ati o n or p u blic ati o n of d at a c oll ect e d as a dir ect or i n dir ect r es ult of t his tri al will b e 
c o nsi d er e d as a j oi nt p u blic ati o n b y t h e I nv esti g at or(s) a n d t h e a p pr o pri at e p ers o n n el at t h e S p o ns or’s 
sit e.  A ut h ors hi p will b e d et er mi n e d by m ut u al a gr e e m e nt.  All m a n uscri pts, a bstr acts or ot h er m o d es of 
pr es e nt ati o n arisi n g fr o m t h e r es ults of t h e st u dy m ust b e r evi e w e d a n d a p pr o v e d i n writi n g b y t h e 
S p o ns or, pri or t o s u b missi o n f or p u blic ati o n or pr es e nt ati o n.  N o p u blic ati o n or pr es e nt ati o n wit h 
r es p ect t o t h e st u dy s h all b e m a d e u ntil a ny S p o ns or c o m m e nts o n t h e pr o p os e d p u blic ati o n or 
pr es e nt ati o n h av e b e e n a d dr ess e d t o t h e S p o ns or’s s atisf acti o n.  
T h e d et ail e d o bli g ati o ns r e g ar di n g t h e p u blic ati o n of a ny d at a, m at eri al r es ults, or ot h er i nf or m ati o n, 
g e n er at e d or cr e at e d i n r el ati o n t o t h e st u dy s h all b e o utli n e d i n t h e a gr e e m e nt b et w e e n e ac h 
I nv esti g at or a n d t h e S p o ns or or d esi g n e e. 
7. 8  Fi n a nci n g a n d I ns ur a nc e 
Fi n a nci n g a n d I ns ur a nc e i nf or m ati o n will b e s et f ort h i n a s e p ar at e d oc u m e nt b et w e e n t h e I n v esti g at or 
a n d S p o ns or ( pr ovi d e d b y t h e S p o ns or or d esi g n e e). 
7. 9  Discl os ur e a n d C o nfi d e nti alit y 
T h e c o nt e nts of t his pr ot oc ol a n d a n y a m e n d m e nts a n d r es ults o bt ai n e d d uri n g t h e c o urs e of t his st u dy 
will b e k e pt c o nfi d e nti al b y t h e I nv esti g at or, t h e I nv esti g at or’s st aff, a n d I R B a n d will n ot b e discl os e d i n 
w h ol e or i n p art t o ot h ers or us e d f or a ny p ur p os e ot h er t h a n r evi e wi n g or p erf or mi n g t h e st u dy wit h o ut 
t h e writt e n c o ns e nt of t h e S p o ns or.  N o d at a c oll ect e d as p art of t his st u dy will a p p e ar i n a ny writt e n 
w or k, i ncl u di n g p u blic ati o ns, wit h o ut t h e writt e n c o ns e nt of S p o ns or. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 7 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
All p ers o ns assisti n g i n t h e p erf or m a nc e of t his st u dy m ust b e b o u n d b y t h e o bli g ati o ns of c o nfi d e nti alit y 
a n d n o n- us e s et f ort h i n t h e C o nfi d e nti alit y A gr e e m e nt b et w e e n t h e I nv esti g at or a n d S p o ns or. 
7. 1 0  Disc o nti n u ati o n of St u d y 
T h e S p o ns or r es erv es t h e ri g ht t o disc o nti n u e t h e st u dy f or m e dic al or a d mi nistr ati v e r e as o ns at a n y 
ti m e.  T h e I nv esti g at or will b e r ei m b urs e d f or r e as o n a bl e ex p e ns es c ov eri n g s u bj ects, us e of liv e-i n 
f aciliti es, l a b or at ory t ests, a n d ot h er pr of essi o n al f e es.  T h e I nv esti g at or will r ef u n d t h e exc ess of 
p a y m e nts m a d e i n a d v a nc e. 
T h e I nv esti g at or r es erv es t h e ri g ht t o disc o nti n u e t h e st u dy s h o ul d his/ h er j u d g m e nt s o dict at e.  T h e 
I nv esti g at or will n otif y t h e I R B i n c as e of st u dy disc o nti n u ati o n.  St u dy r ec or ds m ust b e r et ai n e d as n ot e d 
a b o v e. 
8  E T HI C S 
8. 1  I nstit uti o n al R e vi e w B o ar ds / I n d e p e n d e nt Et hics C o m mitt e es 
A list of t h e I nstit uti o n al R evi e w B o ar d(s) (I R B) a n d/ or I n d e p e n d e nt Et hics C o m mitt e e(s) (I E C) t h at 
a p pr o v e d t his st u dy a n d t h e a p pr ov al l ett ers will b e i ncl u d e d i n t h e cli nic al st u dy r e p ort f or t his pr ot oc ol. 
T h e pr ot oc ol, a n y pr ot oc ol a m e n d m e nts, a n d t h e i nf or m e d c o ns e nt f or m (I C F) will b e r evi e w e d a n d 
a p pr o v e d b y t h e a p pr o pri at e I R B b ef or e s u bj ects ar e scr e e n e d f or e ntr y.  V erific ati o n of t h e I R B 
u nc o n diti o n al a p pr o v al of t h e pr ot oc ol will b e tr a ns mitt e d t o t h e S p o ns or pri or t o t h e s hi p m e nt of st u dy 
m e dic ati o n t o t h e i nv esti g ati o n al sit e.  T h e I nv esti g at ors or S p o ns or will s u b mit, d e p e n di n g o n l oc al 
r e g ul ati o ns, p eri o dic r e p orts a n d i nf or m t h e I R B of a ny r e p ort a bl e a dv ers e ev e nts ( A Es) p er I nt er n ati o n al 
C o nf er e nc e o n H ar m o niz ati o n (I C H) g ui d eli n es a n d l oc al I R B st a n d ar ds of pr actic e. 
8. 2  Et hic al C o n d uct of t h e St u d y 
T his st u dy will b e c o n d uct e d i n acc or d a nc e wit h st a n d ar d o p er ati n g pr oc e d ur es (S O Ps) of t h e S p o ns or 
a n d  
 t h e C o ntr act R es e arc h Or g a niz ati o ns ( C R O) t h at will c o n d uct t h e st u dy.  T h es e S O Ps ar e 
d esi g n e d t o e ns ur e a d h er e nc e t o G o o d Cli nic al Pr actic e ( G C P) g ui d eli n es as r e q uir e d b y: 
 
D ecl ar ati o n of H elsi n ki, 1 9 6 4 (“ R ec o m m e n d ati o ns G ui di n g P hys ici a ns i n Bi o m e dic al R es e arc h 
I nv olvi n g H u m a n P ati e nts”), a n d all its acc e pt e d a m e n d m e nts t o d at e c o nc er ni n g m e dic al 
r es e arc h i n h u m a ns. 
 
I C H G ui d eli n e f or G C P ( C o m mitt e e f or Pr o pri et ary M e dici n al Pr o d ucts/I C H/ 1 3 5/ 9 5) of t h e 
E ur o p e a n A g e ncy f or t h e Ev al u ati o n of M e dici n al Pr o d ucts, C o m mitt e e f or Pr o pri et ar y M e dici n al 
Pr o d ucts, I C H of P h ar m ac e utic als f or H u m a n Us e. 
 
U nit e d St at es ( U S) C o d e of F e d er al R e g ul ati o ns ( C F R) d e ali n g wit h cli nic al st u di es ( 2 1 C F R, 
i ncl u di n g p arts 5 0 a n d 5 6 c o nc er ni n g P ati e nt I nf or m e d C o ns e nt a n d I R B r e g ul ati o ns). 
 
L oc al, n ati o n al l e g al g ui d eli n es. 




S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 7 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
Ar m e nt er os JL, L e wis J E, D av al os M. Ris p eri d o n e a u g m e nt ati o n f or tr e at m e nt-r esist a nt a g gr essi o n i n 
att e nti o n- d eficit/ hy p er activit y dis or d er: A pl ac e b o-c o ntr oll e d pil ot st u dy. J A m Ac a d C hil d A d ol esc 
Ps yc hi atr y 2 0 0 7; 4 6: 5 5 8- 6 5.  
A y el e B T, Li pk o vic h I, M ol e n b er g hs, G, M alli nc kr o dt, C H . A m ulti pl e i m p ut ati o n b as e d a p pr o ac h t o 
s e nsiti vit y a n alys es a n d eff ecti v e n ess ass ess m e nts i n l o n git u di n al cli nic al tri als. J o ur n al of 
Bi o p h ar m ac e utic al St atistics 2 0 1 4; 2 4, 2 1 1- 2 2 8. 
B ar n es T R E. A r ati n g sc al e f or dr u g-i n d uc e d a k at hisi a. Br. J. Psyc hi atr y 1 9 8 9; 1 5 4: 6 7 2- 6 7 6. 
Bl a d er J C, Plisz k a S R, J e ns e n P S, Sc h o ol er N R, K af a nt aris V. P e di atrics 2 0 1 0; 1 2 6( 4): e 7 9 6- 8 0 6. 
C al ar g e C A, Aci o n L, K u p er m a n S et al. W ei g ht g ai n a n d m et a b olic a b n or m aliti es d uri n g ext e n d e d 
ris p eri d o n e tr e at m e nt i n c hil dr e n a n d a d ol esc e nts. J C hil d A d ol esc Psyc h o p h ar m 2 0 0 9; 1 9: 1 0 1-9.  
C h e n Y H, D e M ets DL, L a n K K G. I ncr e asi n g t h e s a m pl e siz e w h e n t h e u n bli n d e d i nt eri m r es ult is 
pr o misi n g. St atistics i n M e dici n e 2 0 0 4; 2 3: 1 0 2 3- 1 0 3 8. 
C o n n or D F, Mc L a u g hli n TJ. A g gr essi o n a n d di a g n osis i n p yc hi atric ally r ef err e d c hil dr e n. C hil d Ps yc hi atr y 
H u m. D e v. 2 0 0 6; 3 7( 1): 1- 1 4. 
F ar m er C A, Ar n ol d L E, B u kst ei n O G, Fi n dli n g RL, G a d o w K D, Li X, B utt er E M, A m a n M G. T h e tr e at m e nt of 
s e v er e c hil d a g gr essi o n ( T OS C A) st u dy: D esi g n c h all e n g es.  C hil d a n d A d ol esc e nt Ps yc hi atry a n d M e nt al 
H e alt h 2 0 1 1; 5: 3 6. 
Fi n dli n g RL, St ei n er H, W ell er E B. Us e of a nti psyc h otics i n c hil dr e n a n d a d ol esc e nts. J. Cli n. Psyc hi atry 
2 0 0 5; 6 6: 2 9- 4 0. 
G a d o w K D, Ar n ol d L E, M oli n a B S et al. Ris p eri d o n e a d d e d t o p ar e nt tr ai ni n g a n d sti m ul a nt m e dic ati o n: 
Eff ects o n att e nti o n- d eficit/ hy p er acti vit y dis or d er, o p p ositi o n al d efi a nt dis or d er, c o n d uct dis or d er, a n d 
p e er a g gr essi o n. . J A m Ac a d C hil d A d ol esc Psyc hi atry 2 0 1 4; 5 3: 9 4 8- 5 9.  
Gr e e n hill LL, B ar m ack J E, S p alt e n D, A n d ers o n M, H al p er n F. M oli n d o n e hy dr oc h ol ori d e i n t h e tr e at m e nt 
of a g gr essiv e, h os pit aliz e d c hil dr e n.  Psyc h o p h ar m ac ol. B ull. 1 9 8 1; 1: 1 2 5- 1 2 7. 
Gr e e n hill LL, S ol o m o n M, Pl e a k R, A m br osi ni P.  M oli n d o n e hy dr oc hl ori d e tr e at m e nt of h os pit aliz e d 
c hil dr e n wit h c o n d uct dis or d er.  J. Cli n. Psyc hi atry 1 9 8 5; 4 6: 2 0- 2 5. 
G uy W.  Cli nic al gl o b al i m pr essi o ns. E C D E U Ass ess m e nt M a n u al f or Psyc h o p h ar m ac ol o gy.  R ock vill e, M D.  
U. S. N ati o n al I nstit ut e of H e alt h, Ps yc h o p h ar m ac ol o gy R es e arc h Br a nc h 1 9 7 6; 2 1 7 -2 2 2.  
H as k ett M E, A h er n L S, W ar d C S, All air e J C. F act or str uct ur e a n d v ali dit y of t h e p ar e nti n g str ess i n d ex-
s h ort fr o m. J. Cli n. C hil d A d ol esc. Psyc h ol. 2 0 0 6; 3 5( 2): 3 0 2- 3 1 2. 
H a ys R D, F ariv ar S S, Li u H. A p pr o ac h es a n d r ec o m m e n d ati o ns f or esti m ati n g mi ni m ally i m p ort a nt 
diff er e nc es f or h e alt h r el at e d q u alit y of lif e m e as ur es. C O P D 2 0 0 5; 2( 1): 6 3 – 6 7. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 7 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
H oc h b er g Y. A s h ar p er B o nf err o ni pr oc e d ur e f or m ulti pl e si g nific a nc e t esti n g. Bi o m etrik a 1 9 8 8; 
7 5( 4): 8 0 0- 8 0 2. 
J e ns e n P S, Y o u n gstr o m E A, St ei n er H, Fi n dli n g RL, M e y er R E, M al o n e R P, C arls o n G A, C occ ar o E F, A m a n 
M G, Bl air J, D o u g h erty D, F erris C, Fly n n L, Gr e e n E, H o a g w o o d K, H utc hi ns o n J, L a u g hr e n T, L e v e L D, 
N o vi ns D K, Viti ell o B. C o ns e ns us R e p ort o n I m p ulsiv e A g gr essi o n as a S y m pt o m Acr oss Di a g n ostic 
C at e g ori es i n C hil d Psyc hi atr y: I m plic ati o ns f or M e dic ati o n St u di es. J. A m. Ac a d. C hil d A d ol esc. Ps yc hi atr y 
2 0 0 7; 4 6 ( 3): 3 0 9- 3 2 2. 
K a uf m a n J, Bir m a h er B, Br e nt D, R a o U, Fly n n C, M or eci P, et al. Sc h e d ul e f or Aff ecti v e Dis or d ers a n d 
Sc hiz o p hr e ni a f or Sc h o ol -A g e C hil dr e n -Pr es e nt a n d Lif eti m e V ersi o n ( K -S A D S -PL): i niti al r eli a bility a n d 
v ali dit y d at a. J A m Ac a d C hil d A d ol esc Psyc hi atry 1 9 9 7; 3 6( 7): 9 8 0 -8.  
K a uf m a n, A S, Lic ht e n b er g er, E. Ass essi n g A d ol esc e nt a n d A d ult I nt elli g e nc e. 3r d E diti o n; 2 0 0 5. 
L a n d gr af J M, A b etz L, W ar e J E. T h e C H Q Us er’s M a n u al. B ost o n. First E diti o n B ost o n, M A: T h e H e alt h 
I nstit ut e, N e w E n gl a n d M e dic al C e nt er  1 9 9 6. 
 
Mc Cl ell a n J, Si kic h L, Fi n dli n g RL, Fr azi er J A, Viti ell o B, Hl ast al a S A, et al. Tr e at m e nt of e arl y -o ns et 
sc hiz o p hr e ni a s p ectr u m disor d ers ( T E O S S): R ati o n al e, d esi g n, a n d m et h o ds. J. A m. Ac a d. C hil d A d ol esc. 
Ps yc hi atr y 2 0 0 7; 4 6: 9 6 9 -9 7 8.  
Mc K ay K E, H al p eri n J M. A D H D, a g gr essi o n, a n d a ntis oci al b e h avi or acr oss t h e lif es p a n. A n n N Y Ac a d Sci 
2 0 0 1; 9 3 1: 8 4- 9 6 . 
M e ht a C R, P oc oc k SJ. A d a pti v e i ncr e as e i n s a m pl e siz e w h e n i nt eri m r es ults ar e pr o misi n g: a pr actic al 
g ui d e wit h e x a m pl es. St atistics i n M e dici n e 2 0 0 0; 0 0: 1- 6.  
T h e M T A C o o p er ativ e Gr o u p. A 1 4- m o nt h r a n d o miz e d cli nic al tri al of tr e at m e nt str at e gi es f or att e nti o n-
d eficit/ hy p er acti vity dis or d er. T h e M T A C o o p er ati v e Gr o u p. M ulti m o d al Tr e at m e nt St u dy of C hil dr e n 
wit h A D H D. Arc h G e n Ps yc hi atr y 1 9 9 9; 5 6: 1 0 7 3- 8 6 . 
M u n etz M R, B e nj a mi n S. H o w t o ex a mi n e p ati e nts usi n g t h e a b n or m al i nv ol u nt ary m ov e m e nt sc al e. 
H os p. C o m m u n. Ps yc hi atr y 1 9 8 8; 3 9: 1 1 7 2- 1 1 7 7. 
P a p p a d o p ul os E, M aci ntyr e II J C, Cris m o n ML et al. Tr e at m e nt r ec o m m e n d ati o ns f or t h e us e of 
a nti ps yc h otics f or a g gr essi v e y o ut h ( T R A A Y). P art II. J A m Ac a d C hil d A d ol esc Ps yc hi atr y 2 0 0 3; 4 2: 1 4 5- 6 1 . 
P e nz n er J B, D u d as M, S ait o E et al. L ac k of eff ect of sti m ul a nt c o m bi n ati o n wit h s ec o n d- g e n er ati o n 
a nti ps yc h otics o n w ei g ht g ai n, m et a b olic c h a n g es, pr ol acti n l e v els, a n d s e d ati o n i n y o ut h wit h cli nic all y 
r el e v a nt a g gr essi o n or o p p ositi o n alit y. J C hil d A d ol esc Psyc h o p h ar m 2 0 0 9; 1 9: 5 6 3-7 3 . 
Plisz k a S, A A C A P W or k Gr o u p o n Q u ality Iss u es. Pr actic e p ar a m et er f or t h e ass ess m e nt a n d tr e at m e nt of 
c hil dr e n a n d a d ol esc e nts wit h att e nti o n- d eficit/ hy p er acti vity dis or d er. J A m Ac a d C hil d A d ol esc 
Ps yc hi atr y 2 0 0 7; 4 6: 8 9 4- 9 2 1 . 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 8 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
Plisz k a S R, Cris m o n ML, H u g h es C W et al. T h e T ex as C hil dr e n's M e dic ati o n Al g orit h m Pr oj ect: R e visi o n of 
t h e al g orit h m f or p h ar m ac ot h er a py of att e nti o n- d eficit/ hy p er activit y dis or d er. J A m Ac a d C hil d A d ol esc 
Ps yc hi atr y 2 0 0 6; 4 5: 6 4 2- 5 7.  
P os n er K, Br o w n G K, St a nl ey B, Br e nt D A, Y ers h o v a K V, O q u e n d o M A, C urri er G W, M elvi n G A, Gr e e n hill 
L, S h e n S, M a n n JJ. T h e C ol u m bi a- S uici d e S ev erity r ati n g sc al e: i niti al v ali dit y a n d i nt er n al c o nsist e ncy 
fi n di n gs fr o m t hr e e m ultisit e st u di es wit h a d ol esc e nts a n d a d ults. A m J Psyc hi atry 2 0 1 1; 6 8: 1 2 6 6- 1 2 7 7. 
R atitc h B, O’ K elly , M, T osi ell o, R.  Missi n g d at a i n cli nic al tri als: fr o m cli nic al ass u m pti o ns t o st atistic al 
a n al ysis usi n g p att er n mixt ur e m o d els. P h ar m ac e utic al St atistics, 2 0 1 3; 1 2, 3 3 7- 3 4 7. 
R u bi n D. B.  M ulti pl e I m p ut ati o n f or N o nr es p o ns e i n S ur v e ys, N e w Y or k, Wil ey; 1 9 8 7. 
Sc ott o R os at o N, C orr ell C U, P a p p a d o p ul os E et al. Tr e at m e nt of m al a d a pti v e a g gr essi o n i n y o ut h: C ert 
g ui d eli n es ii. Tr e at m e nts a n d o n g oi n g m a n a g e m e nt. P e di atrics 2 0 1 2; 1 2 9: e 1 5 7 7- 8 6.  
S h elt o n TL, B ar kl ey R A, Cr oss w ait C et al. Ps yc hi atric a n d ps yc h ol o gic al m or bi dit y as a f u ncti o n of 
a d a pti v e dis a bility i n pr esc h o ol c hil dr e n wit h a g gr essiv e a n d hy p er acti v e-i m p ulsiv e-i n att e nti v e b e h avi or. 
J A b n or m C hil d Psyc h ol o gy 1 9 9 8; 2 6: 4 7 5-9 4 . 
Sikic h L, Fr azi er J A, Mc Cl ell a n J et al. D o u bl e- bli n d c o m p aris o n of first- a n d s ec o n d- g e n er ati o n 
a nti ps yc h otics i n e arl y- o ns et sc hiz o p hr e ni a a n d sc hiz o- aff ectiv e dis or d er: Fi n di n gs fr o m t h e tr e at m e nt of 
e arl y- o ns et sc hiz o p hr e ni a s p ectr u m dis or d ers ( T E O S S) st u dy. A m J Ps yc hi atr y 2 0 0 8; 1 6 5: 1 4 2 0- 3 1 . 
Si m ps o n G M, A n g us J W S. A r ati n g sc al e f or extr a pyr a mi d al si d e eff ects.  Act a Psyc hi atr. Sc a n d. S u p pl. 
1 9 7 0; 2 1 2: 1 1- 1 9  
St oc ks J D, T a n ej a B K, B ar ol di P et al. A p h as e 2 a r a n d o miz e d, p ar all el gr o u p, d os e-r a n gi n g st u dy of 
m oli n d o n e i n c hil dr e n wit h att e nti o n- d eficit/ hy p er activit y dis or d er a n d p ersist e nt, s eri o us c o n d uct 
pr o bl e ms. J C hil d A d ol esc Ps yc h o p h ar m 2 0 1 2; 2 2: 1 0 2- 1 1 . 
S w a ns o n J M, Kr a e m er H C, Hi ns h a w S P, Ar n ol d L E, C o n n ers C K, A bi k off H B, et al.  Cli nic al r el ev a nc e of t h e 
pri m ar y fi n di n gs of t h e M T A: S ucc ess r at es b as e d o n s e v erit y of A D H D a n d O D D sy m pt o ms at t h e e n d of 
tr e at m e nt.  J. A m er. Ac a d. C hil d A d ol esc. Psyc hi atry 2 0 0 1; 4 0: 1 6 8- 1 7 9. 
S u p er n us P h ar m ac e utic als, I nc. Si n gl e- C e nt er, Si n gl e- D os e, O p e n-L a b el, R a n d o miz e d, I nc o m pl et e 
Cr oss o v er Pil ot St u dy t o Ev al u at e t h e Si n gl e D os e P h ar m ac o ki n etics of C o ntr oll e d a n d I m m e di at e 
R el e as e F or m ul ati o ns of M oli n d o n e Hy dr oc hl ori d e i n H e alt h y A d ult V ol u nt e ers U n d er F e d a n d F ast e d 
C o n diti o ns 2 0 1 0 .  
S u p er n us P h ar m ac e utic als, I nc St u dy 8 1 0 P 2 0 2. A R a n d o miz e d, D o u bl e- Bli n d, Pl ac e b o- C o ntr oll e d, D os e-
R a n gi n g St u dy t o Ev al u at e t h e Effic acy a n d S af et y of M oli n d o n e Hy dr oc hl ori d e Ext e n d e d- R el e as e T a bl ets 
as A dj u ncti v e T h er a py i n C hil dr e n wit h I m p ulsiv e A g gr essi o n C o m or bi d wit h Att e nti o n-
D eficit/ Hy p er activity Dis or d er ( A D H D) 2 0 1 3. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 8 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
S u p er n us P h ar m ac e utic als, I nc St u dy 8 1 0 P 5 0 1. Ps yc h o m etric T esti n g of a n El ectr o nic O bs erv er- R e p ort e d 
O utc o m e M e as ur e of I m p ulsiv e A g gr essi o n of C hil dr e n wit h Att e nti o n D eficit H y p er activit y Dis or d er 
2 0 1 5. 
Viti ell o B, B e h ar D, H u nt, J, St off, D, Ricc uiti, A. S u bty pi n g A g gr essi o n i n C hil dr e n a n d A d ol esc e nts. J. 
N e ur o ps yc hi atr y Cli n. N e ur osci e nc es 1 9 9 0; 2: 1 8 9- 1 9 2. 
Viti ell o B, St off D M. S u bty p es of a g gr essi o n a n d t h eir r el e v a nc e t o c hil d ps yc hi atry. J. A m. Ac a d. C hil d 
Ps yc hi atr y 1 9 9 7; 3 6( 3): 3 0 7- 3 1 5. 
1 0  A P P E N DI C E S 
1 0. 1  A d a pti v e D esi g n Pl a n 
1 0. 1. 1  I ntr o d ucti o n 
T h e d oc u m e nt d efi n es t h e k ey el e m e nts of t h e a d a pti v e d esi g n f or Pr ot oc ol 8 1 0 P 3 0 1 ( A R a n d o miz e d, 
D o u bl e- Bli n d, Pl ac e b o- C o ntr oll e d St u dy t o Ev al u at e t h e Effic ac y a n d S af et y of M oli n d o n e Hy dr oc hl ori d e 
Ext e n d e d- R el e as e T a bl ets f or t h e Tr e at m e nt of I m p ulsi v e A g gr essi o n i n P e di atric S u bj ects wit h Att e nti o n 
D eficit/ Hy p er activity Dis or d er ( A D H D) i n C o nj u ncti o n wit h St a n d ar d A D H D Tr e at m e nt). 
1 0. 1. 2  Tri al D esi g n 
T h e tri al will b e d esi g n e d t o ev al u at e t h e effic ac y a n d s af et y pr ofil es of t w o d os es of S P N- 8 1 0 c o m p ar e d 
t o pl ac e b o.  F or c o m p act n ess, t h e d os es will b e d e n ot e d b y D os e 1 ( 1 8 m g) a n d D os e 2 ( 3 6 m g).  
A t w o-st a g e d esi g n wit h a si n gl e i nt eri m a n alysis a n d fi n al a n al ysis ( F A) will b e utiliz e d i n t his tri al: 
 
St a g e 1 will i ncl u d e s u bj ects w h o c o m pl et e t h e tri al pri or t o t h e I nt eri m A n alysis.   
 
St a g e 2 will i ncl u d e s u bj ects w h o c o m pl et e t h e tri al aft er t h e I nt eri m A n alysis. 
T h e I nt eri m A n alysis d at a will b e r e vi e w e d i n a n u n bli n d e d m a n n er t o p ot e nti all y i ncr e as e t h e n u m b er of 
s u bj ects i n St a g e 2.  T h e s a m pl e siz es i n e ac h st a g e of t h e tri al will b e d e n ot e d as f oll o ws: 
 
L et n 1 d e n ot e t h e t ot al n u m b er of s u bj ects w h o c o m pl et e t h e tri al pri or t o I nt eri m A n al ysis (i n 
ot h er w or ds, t his will b e t h e t ot al s a m pl e siz e i n St a g e 1).  T h e n u m b er of s u bj ects all oc at e d t o 
D os e 1, D os e 2 a n d Pl ac e b o i n St a g e 1 will b e d e n ot e d b y n 1 1, n 1 2 a n d n 1 3, r es p ecti v ely.  N ot e t h at 
n 1 1 + n 1 2 + n 1 3 = n 1 
 
L et n 2 d e n ot e t h e t ot al n u m b er of s u bj ects i n St a g e 2 wit h o ut s a m pl e siz e a dj ust m e nt at I nt eri m 
A n al ysis.  T h e n u m b er of s u bj ects all oc at e d t o D os e 1, D os e 2 a n d Pl ac e b o i n St a g e 2 will b e 
d e n ot e d b y n 2 1, n 2 2 a n d n 2 3, r es p ecti v el y.  N ot e t h at s o m e of t h es e s a m pl e siz es will b e s et t o 0 if 
a d ecisi o n t o dr o p a d osi n g ar m is m a d e at I A a n d n 2 1 + n 2 2 + n 2 3 = n 2. 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 8 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 1. 3  D ecisi o n R ul es at I nt eri m A n al ysis 
As i n dic at e d a b o v e, I nt eri m A n al ysis will b e c o n d uct e d m ai nl y t o s u p p ort a d ecisi o n t o i ncr e as e t h e 
n u m b er of s u bj ects i n St a g e 2 if t h e o bs er v e d tr e at m e nt diff er e nc e f or t h e pri m ar y e n d p oi nt is l ess t h a n 
a ntici p at e d.  It is i m p ort a nt t o n ot e t h at s u bj ect e nr oll m e nt will n ot b e t er mi n at e d i n eit h er d osi n g ar m 
at I nt eri m A n al ysis d u e t o ov er w h el mi n g effic acy a n d, as a c o ns e q u e nc e, n o α will b e s p e nt at I nt eri m 
A n al ysis.  H o w ev er, s u bj ect e nr oll m e nt m a y b e t er mi n at e d d u e t o f utilit y as ex pl ai n e d b el o w. 
I nt eri m A n alysis will b e p erf or m e d aft er a pr e- d efi n e d fr acti o n t h e t ot al n u m b er of s u bj ects c o m pl et e 
t h e tri al, i. e., a p pr oxi m at ely 5 0 % of s u bj ects c o m pl et e t h e fi n al visit. 
T h e f oll o wi n g s a m pl e siz e r e ass ess m e nt r ul e will b e a p pli e d at I nt eri m A n alysis.  L et C P d efi n e t h e d os e-
s p ecific c o n diti o n al p o w er at I nt eri m A n al ysis, i. e., t h e pr o b a bilit y of est a blis hi n g a si g nific a nt tr e at m e nt 
eff ect o n t h e pri m ar y e n d p oi nt c o n diti o n al u p o n t h e pri m ar y e n d p oi nt d at a av ail a bl e at I nt eri m A n al ysis 
u n d er t h e ori gi n al s a m pl e siz e ass u m pti o ns.  I n p artic ul ar, C P 1 is d efi n e d as c o n diti o n al p o w er b as e d o n 
t h e c o m p aris o n of D os e 1 t o pl ac e b o at I nt eri m A n alysis a n d C P 2 is d efi n e d as c o n diti o n al p o w er b as e d 
o n t h e c o m p aris o n of D os e 2 t o pl ac e b o at I nt eri m A n al ysis. 
T h e tri al’s d esi g n will b e m o difi e d at I nt eri m A n al ysis usi n g t h e f oll o wi n g t hr es h ol ds ( C P r ef ers t o eit h er 
C P 1 or C P 2): 
 
If C P < 0. 1, disc o nti n u e s u bj ect e nr oll m e nt i n t his p artic ul ar d osi n g ar m ( e. g., s u bj ects will b e 
all oc at e d t o D os e 2 or pl ac e b o i n St a g e 2 if C P 1 < 0. 1 a n d C P 2 ≥ 0. 1).  
 
If C P ≥ 0. 1 a n d C P ≤ 0. 3 6, r et ai n t h e ori gi n al s a m pl e siz e i n t h e d osi n g ar m. 
 
If C P ≥ 0. 3 6 a n d C P ≤ 0. 8, i ncr e as e t h e s a m pl e siz e i n t h e d osi n g ar m. 
 
If C P > 0. 8, r et ai n t h e ori gi n al s a m pl e siz e i n t h e d osi n g ar m.  
T h e s a m pl e siz e will b e i ncr e as e d i n a d osi n g ar m t o ac hi e v e t h e n o mi n al p o w er of 8 0 % b ef or e t h e 
m ulti plicity a dj ust m e nt or t h e s a m pl e siz e will b e d o u bl e d, w hic h ev er is s m all er. 
T h e f oll o wi n g r ul es will b e a p pli e d t o c o m p ut e t h e s a m pl e siz es acr oss t h e tr e at m e nt ar ms i n St a g e 2:  
 
If a d ecisi o n t o disc o nti n u e s u bj ect e nr oll m e nt is m a d e f or a p artic ul ar d osi n g ar m at I nt eri m 
A n al ysis, s u bj ects w h o w er e pl a n n e d t o b e e nr oll e d i n t h at ar m aft er I nt eri m A n al ysis will b e r e-
distri b ut e d t o t h e r e m ai ni n g tr e at m e nt ar ms.  F or ex a m pl e, if D os e 1 is dr o p p e d a n d D os e 2 is 
r et ai n e d, t h e s a m pl e siz es f or t h e t hr e e tr e at m e nt ar ms i n St a g e 2 will b e d efi n e d as f oll o ws:  
o  D os e 1: 0. 
o  D os e 2: n 2 2 + n 1 2 / 2. 
o  Pl ac e b o: n 2 3 + n 1 2 / 2.  
 
 
If a d ecisi o n is m a d e t o i ncr e as e t h e s a m pl e siz e i n at l e ast o n e d osi n g ar m, t h e m o difi e d s a m pl e 
siz e i n t h e pl ac e b o ar m will b e e q u al t o t h e l ar g er m o difi e d s a m pl e siz e i n t h e t w o d osi n g ar ms.  
F or ex a m pl e, if t h e m o difi e d s a m pl e siz es i n t h e t w o d osi n g ar ms i n St a g e 2 ar e n 3 1 a n d n 3 2, 
r es p ectiv ely, t h e m o difi e d s a m pl e siz e i n t h e pl ac e b o ar m i n St a g e 2 will b e s et t o m ax(n 3 1, n 3 2).  
H o w ev er, if t h e s a m pl e siz e is i ncr e as e d i n o n e d osi n g ar m, t h e s a m pl e siz e i n t h e ot h er d osi n g 
ar m will n ot b e a ut o m atic ally i ncr e as e d. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 8 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 1. 4  A d a pti v e D esi g n 
T his s ecti o n d efi n es t h e m at h e m atic al a p pr o ac h us e d i n t h e pr o p os e d a d a pti v e d esi g n wit h t w o st a g es 
a n d d at a- dri v e n d ecisi o n r ul es ( e. g., s a m pl e siz e m o dific ati o n at I nt eri m A n alysis).  T h e d eriv ati o n of t h e 
a d a pti v e d esi g n is b as e d o n t h e c o m bi n ati o n f u ncti o n a p pr o ac h a p pli e d i n c o nj u ncti o n wit h t h e cl os ur e 
pri nci pl e, s e e, f or ex a m pl e, W a n g et al. ( 2 0 0 1), Br a n n at h et al. ( 2 0 0 2) a n d H o m m el ( 2 0 0 5).  T his g e n er al 
a p pr o ac h is c o m m o nly us e d t o c o nstr uct a d a ptiv e d esi g ns i n c o nfir m at or y tri als a n d g u ar a nt e es t h at t h e 
o v er all Ty p e I err or r at e is pr ot ect e d i n t h e tri al at t h e n o mi n al l ev el (t w o-si d e d α = 0. 0 5) r e g ar dl ess of 
t h e ty p e of d esi g n m o dific ati o ns at a n I nt eri m A n alysis, i ncl u di n g d ecisi o ns t o dr o p a tr e at m e nt ar m or 
a dj ust t h e s a m pl e siz e i n o n e or m or e ar ms. 
L et H 1 a n d H 2 d e n ot e t h e n ull h y p ot h es es of n o tr e at m e nt eff ect f or t h e t w o d os e- pl ac e b o c o m p aris o ns 
( D os e 1 v ers us pl ac e b o a n d D os e 2 v ers us pl ac e b o).  Acc or di n g t o t h e c o m bi n ati o n f u ncti o n a p pr o ac h, 
t h e a m o u nt of e vi d e nc e t o r ej ect t h es e n ull h y p ot h es es will b e ev al u at e d s e p ar at el y i n e ac h i n di vi d u al 
st a g e of t h e tri al a n d t h e i nf er e nc es at F A will b e p erf or m e d by c o m bi ni n g t h e evi d e nc e acr oss t h e t w o 
st a g es.  F urt h er, t h e r ej ecti o n r ul es f or H 1 a n d H 2 will b e c h os e n t o ac hi e v e c o nsist e nc y wit h t h e 
H oc h b er g pr oc e d ur e ( D mitri e n k o a n d D’ A g osti n o, 2 0 1 3) t h at w as pr e- d efi n e d as m ulti plicity a dj ust m e nt 
t o ol i n t his tri al.  T o ac hi ev e t his c o nsist e nc y, t h e H oc h b er g pr oc e d ur e will b e a p pli e d wit hi n e ac h st a g e 
( H oc h b er g, 1 9 8 8). 
L et p i a n d q i d e n ot e t h e p-v al u es f or t esti n g t h e n ull h y p ot h esis H i, i = 1, 2, b as e d o n t h e d at a i n St a g es 1 
a n d 2, r es p ectiv ely.  T h e St a g e 2 p-v al u es ar e c o m p ut e d fr o m t h e s a m pl es o bt ai n e d aft er I nt eri m 
A n al ysis, i. e., t h e s a m pl e siz e i n a d osi n g ar m m ay b e a dj ust e d.  F urt h er, p ( 1) < p ( 2) will d e n ot e t h e 
or d er e d tr e at m e nt eff ect p-v al u es i n St a g e 1 a n d si mil arly q ( 1) < q ( 2) will d e n ot e t h e or d er e d tr e at m e nt 
eff ect p-v al u es i n St a g e 2.  T h es e p-v al u es will b e us e d t o c o nstr uct a cl os ur e- b as e d r e pr es e nt ati o n of 
t h e H oc h b er g pr oc e d ur e i n e ac h of t h e t w o st a g es.  T o d efi n e t h e cl os ur e- b as e d r e pr es e nt ati o n, a cl os e d 
f a mily of i nt ers ecti o n h y p ot h es es t h at i ncl u d es all p ossi bl e n o n- e m pty i nt ers ecti o ns of t h e t w o n ull 
hy p ot h es es will b e s et u p.  T a bl e 1 a n d T a bl e 2 dis pl ay t h e i nt ers ecti o n hy p ot h es es i n t h e cl os e d f a mily 
a n d ass oci at e d i nt ers ecti o n p-v al u es t h at d efi n e t h e H oc h b er g pr oc e d ur e i n St a g e 1 a n d St a g e 2 
r es p ectiv ely. 
T a bl e 1: I nt ers ecti o n h y p ot h esis a n d H oc h b er g i nt ers ecti o n p- v al u es i n St a g e 1. 
I nt ers ecti o n hy p ot h esis 
H oc h b er g i nt ers ecti o n p -v al u e  
H 1 ∩ H 2  
p 1 2 = mi n ( 2 p ( 1) , p ( 2)) 
H 1 
p 1 
H 2 
p 2 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 8 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
T a bl e 2: I nt ers ecti o n h y p ot h esis a n d H oc h b er g i nt ers ecti o n p- v al u es i n St a g e 2. 
I nt ers ecti o n hy p ot h esis 
H oc h b er g i nt ers ecti o n p -v al u e  
H 1 ∩ H 2  
q 1 2 = mi n ( 2 q ( 1) , q ( 2)) 
H 1 
q 1 
H 2 
q 2 
 
N ot e t h at, if a c ert ai n d os e is dr o p p e d d u e t o f utilit y at I nt eri m A n al ysis, t h e c orr es p o n di n g p-v al u es i n 
St a g e 2 is a ut o m atic ally s et t o 1 t o r e m ov e t h e d osi n g ar m fr o m c o nsi d er ati o n.  T his g u ar a nt e es t h at a 
n ull h y p ot h esis c a n n ot b e r ej ect e d at F A if t h e c orr es p o n di n g d os e w as dr o p p e d d u e t o f utilit y at I nt eri m 
A n al ysis.  F urt h er, t h e p-v al u es c o m p ut e d at I nt eri m A n al ysis ( St a g e 1 p-v al u es) ar e n ot us e d f or 
i nf er e nti al p ur p os es a n d t h er ef or e n o α will b e s p e nt at I nt eri m A n al ysis t o st o p t h e tri al e arl y d u e t o 
o v er w h el mi n g effic ac y. 
As a n ill ustr ati o n, if D os e 1 is dr o p p e d at I nt eri m A n alysis, t h e c orr es p o n di n g tr e at m e nt eff ect p-v al u e i n 
St a g e 2 ( q 1) will b e s et t o 1.  As a r es ult, t h e i nt ers ecti o n p- v al u es will b e d efi n e d i n St a g e 2 as s h o w n i n 
T a bl e 3 ( n ot e t h at t h e s m all er or d er e d p-v al u e will b e e q u al t o q 2 a n d t h e l ar g er or d er e d p-v al u e will b e 
e q u al t o 1). 
T a bl e 3: I nt ers ecti o n h y p ot h es es a n d H oc h b er g i nt ers ecti o n p- v al u es i n St a g e 2 if d os e 1 is dr o p p e d at 
I nt eri m A n al ysis. 
I nt ers ecti o n hy p ot h esis 
H oc h b er g i nt ers ecti o n p -v al u e  
H 1 ∩ H 2  
q 1 2 = mi n ( 2 q 2 , 1 ) 
H 1 
1  
H 2 
q 2 
 
T h e i nf er e nc es f or t h e t w o n ull h y p ot h es es will b e p erf or m e d at F A usi n g t h e c o m p osit e tr e at m e nt 
eff ect p-v al u es t h at will b e d efi n e d as f oll o ws.  L et w 1 a n d w 2 d efi n e t h e st a g e w ei g hts t h at ar e 
pr os p ectiv ely d efi n e d b as e d o n t h e ex p ect e d a m o u nt of i nf or m ati o n at I nt eri m A n al ysis.  Si nc e I nt eri m 
A n al ysis is pl a n n e d t o b e t ak e n aft er 5 0 % of t h e s u bj ects h a v e c o m pl et e d t h e tri al, 
n 1 (t ot al s a m pl e siz e i n St a g e 1) = n 2 (t ot al s a m pl e siz e i n St a g e 2 b ef or e s a m pl e siz e a dj ust m e nt), 
a n d t h us t h e pr e-s p ecifi e d st a g e w ei g hts ar e gi v e n b y  


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 8 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
w 1 =
n 1
n 1 + n 2
= 0. 5 , w 2 =
n 2
n 1 + n 23
= 0. 5 . 
Usi n g t h e st a g e w ei g hts, t h e c o m bi n ati o n f u ncti o n t o b e us e d at F A will b e d efi n e d as f oll o ws: 
 
 
w h er e (x) is t h e c u m ul ativ e distri b uti o n f u ncti o n of t h e st a n d ar d n or m al distri b uti o n.   
T his c o m bi n ati o n f u ncti o n will b e a p pli e d t o c o m p ut e c o m p osit e i nt ers ecti o n p-v al u es f or e ac h 
i nt ers ecti o n hy p ot h esis i n t h e cl os e d f a mily.  T h e r es ulti n g c o m p osit e i nt ers ecti o n p-v al u es ar e d e n ot e d 
by r1 2, r1, r2, a n d ar e d efi n e d i n T a bl e 4. 
T a bl e 4: I nt ers ecti o n h y p ot h esis a n d c o m p osit e i nt ers ecti o n p- v al u es at F A. 
I nt ers ecti o n hy p ot h esis 
C o m p osit e i nt ers ecti o n p -v al u e  
H 1 ∩ H 2  
r1 2 = c(p 1 2, q 1 2) 
H 1 
r1  = c(p 1, q 1) 
H 2 
r2 = c(p 2, q 2) 
 
Aft er t h at, t h e n ull h y p ot h esis H 1 will b e r ej ect e d at F A ( w hic h i m pli es a st atistic ally si g nific a nt tr e at m e nt 
eff ect at D os e 1) if t h e c o m p osit e p-v al u es f or all i nt ers ecti o n h y p ot h es es i n t h e cl os e d f a mily t h at 
c o nt ai n H 1 ar e si g nific a nt at  = 0. 0 5 (t w o-si d e d), i. e.,   
r1 2 ≤  a n d r1 ≤  
Si mil arly, t h e n ull hy p ot h esis H 2 will b e r ej ect e d at F A ( a n d a st atistic ally si g nific a nt tr e at m e nt eff ect will 
b e est a blis h e d at D os e 2) if t h e c o m p osit e p-v al u es f or all i nt ers ecti o n h y p ot h es es i n t h e cl os e d f a mily 
t h at c o nt ai n H 2 ar e si g nific a nt at  = 0. 0 5, i. e.,   
r1 2 ≤  a n d r2 ≤  
As i n dic at e d a b o v e, t h e r es ulti n g a p pr o ac h acc o u nts f or t w o s o urc es of m ulti plicit y i n t his cli nic al tri al 
( m ulti pl e d at a l o oks a n d m ulti pl e d os e- pl ac e b o c o m p aris o ns) a n d g u ar a nt e es T y p e I err or r at e c o ntr ol at 
α  = 0. 0 5.  T h e α  c o ntr ol is r et ai n e d ev e n if t h e s a m pl e siz e is a dj ust e d i n or m or e tr e at m e nt ar ms at 
I nt eri m A n alysis.  I n a d diti o n, it n e e ds t o b e e m p h asiz e d t h at a n ull h y p ot h esis c a n n ot b e r ej ect e d at F A 
if t h e c orr es p o n di n g d os e w as dr o p p e d d u e t o f utilit y at I nt eri m A n alysis. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 8 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 1. 5  I m p ort a nt I nt eri m A n al ysis C o nsi d er ati o ns 
1 0. 1. 5. 1  R es p o nsi bl e P art y 
T h e I nt eri m A n alysis will b e p erf or m e d b y a n i n d e p e n d e nt u n bli n d e d st atistici a n w h o is n ot affili at e d t o 
t h e tri al s p o ns or, tri al m a n a g e m e nt, d at a cl e a ni n g, a n d a n alysis. 
T h e H e a d of Cli nic al R es e arc h a n d Dir ect or of Bi ost atistics at S u p er n us (s p o ns or) will r ec ei v e 
r ec o m m e n d ati o n l ett er fr o m t h e i n d e p e n d e nt u n bli n d e d st atistici a n.  T h e y will m a k e t h e fi n al d ecisi o n 
f or t h e s a m pl e siz e a dj ust m e nt. 
1 0. 1. 5. 2  C o nfi d e nti alit y 
T h e i n d e p e n d e nt st atistici a n will si g n t h e c o nfi d e nti alit y a gr e e m e nt.  H e/s h e will n ot r ev e al a ny 
u n bli n d e d d at a/i nf or m ati o n t o a ny p ers o ns wit hi n his/ h er o w n or g a niz ati o n or t o t h e s p o ns or, wit h t h e 
exc e pti o n of s e n di n g r ec o m m e n d ati o n as d escri b e d i n S ecti o n 1 0. 1. 5. 1  a b o v e. 
R ef er e nc es 
Br a n n at h W, P osc h M, B a u er P. R ec ursiv e c o m bi n ati o n t ests. J o ur n al of t h e A m eric a n St atistic al 
Ass oci ati o n. 2 0 0 2; 9 7: 2 3 6- 2 4 4. 
D mitri e n k o, A., D’ A g osti n o, R. B. T ut ori al i n Bi ost atistics: Tr a diti o n al m ulti plicity a dj ust m e nt m et h o ds i n 
cli nic al tri als. St atistics i n M e dici n e. 2 0 1 3; 3 2: 5 1 7 2- 5 2 1 8. 
H o m m el, G. A d a ptiv e m o dific ati o ns of hy p ot h es es aft er a n i nt eri m a n al ysis. Bi o m etric al J o ur n al. 2 0 0 5; 5: 
5 8 1- 5 8 9. 
W a n g, SJ, H u n g H MJ, Ts o n g Y, C ui L. Gr o u p s e q u e nti al t est str at e gi es f or s u p eri orit y a n d n o n-i nf eri orit y 
hy p ot h es es i n activ e c o ntr oll e d cli nic al tri als. St atistics i n M e dici n e. 2 0 0 1; 2 0: 1 9 0 3- 1 9 1 2. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 8 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 2  R etr os p ecti v e M o difi e d O v ert A g gr essi o n Sc al e ( R- M O A S)  
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 8 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 8 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 3  Cli nic al Gl o b al I m pr essi o n ( C GI) Sc al e 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 9 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 4  Viti ell o Sc al e 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 9 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 5  Ki d di e- S a ds- Pr es e nt a n d Lif eti m e V ersi o n ( K- S A D S- PL) 2 0 1 3  
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 9 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 9 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 9 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 9 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 9 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 9 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 9 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 9 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 0 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 0 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 0 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 0 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 0 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 0 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 0 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 0 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 0 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 0 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 1 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 1 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 1 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 1 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 1 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 1 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 1 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 1 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 1 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 1 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 2 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 2 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 2 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 2 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 2 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 2 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 2 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 2 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 2 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 2 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 3 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 3 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 3 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 3 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 3 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 3 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 3 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 3 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 3 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 3 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 4 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 4 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 4 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 4 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 4 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 4 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 4 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 4 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 4 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 4 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 5 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 5 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 5 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 5 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 5 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 5 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 5 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 5 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 5 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 5 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 6 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 6 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 6 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 6 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 6 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 6 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 6 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 6 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 6 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 6 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 7 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 7 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 7 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 7 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 7 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 7 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 7 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 7 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 7 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 7 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 8 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 8 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 8 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 8 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 8 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 8 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 8 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 8 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 8 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 8 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 9 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 9 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 9 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 9 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 9 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 9 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 9 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 9 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 9 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 1 9 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 0 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 0 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 0 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 6  C ol u m bi a- S uici d e S e v erit y R ati n g Sc al es ( C- S S R S) 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 0 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 0 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 0 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 0 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 0 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 0 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 0 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 7  S w a ns o n, N ol a n a n d P el h a m R ati n g Sc al e- R e vis e d ( S N A P I V) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 1 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 8  Si m ps o n- A n g us R ati n g Sc al e 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 1 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 1 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 1 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 1 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 
1 0. 9  B ar n es A k at hisi a R ati n g Sc al e ( B A R S) 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 1 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 1 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 1 0  A b n or m al I n v ol u nt ar y M o v e m e nt Sc al e ( AI M S) 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 1 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 1 8  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 1 9  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 2 0  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 2 1  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 1 1  C hil d H e alt h Q u esti o n n air e P ar e nt F or m 2 8-it e m ( C H Q- P F 2 8) 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 2 2  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 2 3  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 2 4  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 2 5  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
1 0. 1 2  P ar e nti n g Str ess I n d e x- S h ort F or m ( P SI- 4- S F) 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 2 6  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 


S u p er n us ® P h ar m ac e utic als, I nc.  
C O N FI D E N TI AL 
 
8 1 0 P 3 0 1                                                                   V ersi o n 9. 0                                               P a g e 2 2 7  of 2 2 7  
 
T his d oc u m e nt is c o nfi d e nti al.  It c o nt ai ns pr o pri et ary i nf or m ati o n of S u p er n us ® P h ar m ac e utic als, I nc.  A ny vi e wi n g or discl os ur e 
of s uc h i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by t h e S p o ns or is strictly pr o hi bit e d.  S uc h i nf or m ati o n m a y b e us e d s ol ely 
f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy. 
 
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol Title 
A Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Molindone Hydrochloride 
Extended-Release Tablets for the Treatment of Impulsive 
Aggression in Pediatric Patients with Attention 
Deficit/Hyperactivity Disorder (ADHD) in Conjunction with 
Standard ADHD Treatment 
 
Protocol Number  
810P301  
 
Protocol Version 
V9.0  
 
Protocol Date: 
01 Nov 2018 
Study Drug 
Molindone Hydrochloride Extended-Release Tablets (SPN-810) 
 
Study Phase 
III 
 
IND Number 
106,515 
 
Sponsor  
Supernus Pharmaceuticals, Inc.  
  
 
  
 
 
SAP Version 
Final v3.0 
 
Date (v2.0)  
Final (v3.0) 
14 Mar 2019 
11 June 2019  




Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 3 
11 June 2019 
Table of Contents 
LIST OF ABBREVIATIONS .................................................................................................................... 5 
1 
INTRODUCTION ....................................................................................................................... 10 
2 
STUDY OBJECTIVES .................................................................................................................. 10 
2.1 
PRIMARY OBJECTIVE .......................................................................................................................................... 10 
2.2 
SECONDARY OBJECTIVES .................................................................................................................................... 10 
2.3 
TERTIARY OBJECTIVES ........................................................................................................................................ 11 
3 
STUDY DESIGN ........................................................................................................................ 11 
3.1 
GENERAL DESCRIPTION ...................................................................................................................................... 11 
3.2 
SCHEDULE OF VISITS AND PROCEDURES ................................................................................................................. 12 
3.3 
STUDY TREATMENT ........................................................................................................................................... 15 
3.3.1 
Treatment, Dose, and Mode of Administration .................................................................................. 15 
3.3.2 
Duration of Treatment and Study Duration ........................................................................................ 15 
3.3.3 
Methods of Assigning Subjects to Treatment Group ........................................................................... 15 
3.3.4 
Blinding ............................................................................................................................................... 15 
3.4 
HYPOTHESES .................................................................................................................................................... 16 
3.5 
DETERMINATION OF SAMPLE SIZE ........................................................................................................................ 16 
3.6 
CHANGES TO ANALYSES PLANNED IN THE PROTOCOL ............................................................................................... 16 
4 
DEFINITIONS AND DERIVED DATASETS ..................................................................................... 16 
5 
EFFICACY AND SAFETY VARIABLES ........................................................................................... 18 
5.1 
PRIMARY EFFICACY VARIABLE.............................................................................................................................. 18 
5.2 
SECONDARY EFFICACY VARIABLES ........................................................................................................................ 18 
5.3 
PHARMACOKINETIC VARIABLES ............................................................................................................................ 20 
5.4 
SAFETY VARIABLES ............................................................................................................................................ 20 
5.4.1 
Medical History and Adverse Events (AEs) .......................................................................................... 20 
5.4.2 
Prior, Concomitant, and Prohibited Medications ................................................................................ 20 
5.4.3 
Clinical Laboratory Tests (Hematology, Chemistry, and Urinalysis) .................................................... 21 
5.4.4 
Vital Signs, Height and Weight............................................................................................................ 21 
5.4.5 
12-Lead ECG ........................................................................................................................................ 21 
5.4.6 
Physical Examinations ......................................................................................................................... 21 
5.4.7 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................................. 21 
5.4.8 
Infrequent Behaviors Checklist ............................................................................................................ 22 
5.4.9 
Extrapyramidal symptoms (EPS) scales ............................................................................................... 22 
6 
STATISTICAL METHODS ........................................................................................................... 23 
6.1 
GENERAL METHODOLOGY .................................................................................................................................. 23 
6.2 
VISIT WINDOW AND UNSCHEDULED ASSESSMENTS ................................................................................................. 24 
6.3 
ADJUSTMENT FOR COVARIATES ........................................................................................................................... 24 
6.4 
HANDLING OF DROPOUTS, MISSING DATA, AND DATA DISCREPANCIES ...................................................................... 24 
6.5 
INTERIM ANALYSIS AND ADAPTIVE DESIGN ............................................................................................................ 25 
6.5.1 
Objective ............................................................................................................................................. 26 
6.5.2 
Responsible Party ................................................................................................................................ 26 
6.5.3 
Confidentiality ..................................................................................................................................... 26 
6.5.4 
Scope of Data Being Analyzed ............................................................................................................. 26 
6.5.5 
Procedures for Interim Analysis........................................................................................................... 26 
6.5.6 
Adaptation Rules ................................................................................................................................. 27 
6.5.7 
Adaptive Design .................................................................................................................................. 31 
6.5.8 
Communication of the Interim Analysis Results to the Trial Sponsor .................................................. 34 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 4 
11 June 2019 
6.6 
TIMING OF FINAL ANALYSES ................................................................................................................................ 35 
6.7 
MULTICENTER STUDY......................................................................................................................................... 35 
6.8 
MULTIPLE COMPARISONS/MULTIPLICITY ADJUSTMENT ........................................................................................... 35 
6.9 
EXAMINATION OF SUBGROUPS ............................................................................................................................ 35 
7 
STATISTICAL ANALYSIS ............................................................................................................ 35 
7.1 
ANALYSIS POPULATIONS..................................................................................................................................... 35 
7.1.1 
Safety Population ................................................................................................................................ 35 
7.1.2 
Intent-to-treat (ITT) Population........................................................................................................... 36 
7.1.3 
Per Protocol (PP) Population ............................................................................................................... 36 
7.2 
DISPOSITION OF SUBJECTS .................................................................................................................................. 36 
7.3 
PROTOCOL DEVIATIONS ..................................................................................................................................... 37 
7.4 
DEMOGRAPHICS AND BASELINE SUBJECT CHARACTERISTICS ...................................................................................... 37 
7.5 
BASELINE DISEASE CHARACTERISTICS .................................................................................................................... 38 
7.6 
TREATMENTS .................................................................................................................................................... 38 
7.6.1 
Treatment Compliance and Extent of Exposure .................................................................................. 38 
7.6.2 
Prior and Concomitant Medications ................................................................................................... 39 
7.7 
EFFICACY ANALYSES ........................................................................................................................................... 39 
7.7.1 
Primary Efficacy Analysis..................................................................................................................... 39 
7.7.2 
Sensitivity Analyses ............................................................................................................................. 40 
7.7.2.1 
Multiple Imputation Assuming Missing at Random ................................................................................... 40 
7.7.2.2 
Multiple Imputation Assuming Missing Not at Random ............................................................................ 41 
7.7.3 
Analysis of PCH Based on Data from Maintenance Period ................................................................. 42 
7.7.4 
Supplementary Analysis ...................................................................................................................... 42 
7.7.5 
Analysis Based on Adjustment of Covariates ...................................................................................... 42 
7.7.6 
Examination of Subgroups .................................................................................................................. 42 
7.7.7 
Secondary Efficacy Analyses ................................................................................................................ 42 
7.8 
SAFETY ANALYSES ............................................................................................................................................. 44 
7.8.1 
Adverse Events .................................................................................................................................... 44 
7.8.2 
Laboratory Test ................................................................................................................................... 45 
7.8.3 
Vital Signs, Height, Weight, and BMI .................................................................................................. 45 
7.8.4 
12-Lead ECG ........................................................................................................................................ 46 
7.8.5 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................................. 46 
7.8.6 
Infrequent Behaviors Checklist ............................................................................................................ 46 
7.8.7 
Other Special Tests .............................................................................................................................. 46 
8 
VALIDATION ............................................................................................................................ 46 
9 
REFERENCES ............................................................................................................................ 47 
APPENDIX 1. EXCLUSION CRITERIA FOR THE PER PROTOCOL POPULATIONS ...................................... 49 
APPENDIX 2. LIST OF TABLES, LISTINGS, AND FIGURES ...................................................................... 50 
APPENDIX 3. TABLE AND LISTING SHELLS ......................................................................................... 58 
 
 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 5 
11 June 2019 
LIST OF ABBREVIATIONS 
AE  
Adverse event 
BID  
Bis in die, twice daily 
CP 
Conditional Power 
CRO 
Contract Research Organization 
CRF  
Case report form 
ECG  
Electrocardiogram 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
IA 
Impulsive Aggression 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonisation  
IND  
Investigational New Drug Application 
IV  
Intravenous 
IWRS  
Interactive web-based randomization system 
kg  
kilogram  
mcg  
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg  
Milligram 
msec 
Millisecond 
PK  
Pharmacokinetic(s) 
PCH 
Percent Change in the frequency of IA behaviors per 7 days 
PO 
Oral 
PP 
Per Protocol 
PT 
Preferred term in MedDRA and WHODD 
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SM 
Study Medication 
SOC 
System Organ Class in MedDRA 
TEAE  
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
WHODD 
WHO Drug Dictionary 
 
 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 6 
11 June 2019 
Summary of Changes to the Version 1.0 SAP Submitted to FDA 
Section 
Page 
Description of Change 
Rationale 
Signature 
Page 
 
Updated signatory information 
Administrative 
1 
9 
a. The protocol version and date are 
updated  
b. The CRO name for MCIC determination 
is updated  
c. A sentence is added to state that this 
SAP does not cover the population PK 
analysis method 
Protocol amendment 
V8.0 
Administrative 
2.2 
9 
“Oppositional defiant disorder” is added 
to the SNAP-IV rating scale 
This subscale was 
omitted in the last 
version of SAP 
3.1 
10-13 a. Age range changed from “6-17” to “6-
12”. This update and removal of “13-
17”are found in multiple sections. This 
describption will not be repeated 
below 
b. Treatment schedule diagrams are 
updated to reflect the change/ 
correction in the study day ranges for 
the screening and baseline periods 
c. A brief paragraph is added to the end 
of the section to describe the planned 
interim analysis 
Protocol amendment 
V8.0 
3.2 
11 
A new section titled “Schedule of Visits 
and Procedures” is added  
Administrative 
3.5 
17 
A paragraph is added to describe the 
changes in the sample size and 
randomization scheme after the planned 
interim analysis and the new blinded SD 
estimate.   
Protocol amendment 
V9.0 
Note the effect of sample 
size increase on the type-
I error is controlled by 
the method of inverse 
normal p-value 
combination test (MINP) 
(Section 6.5.7)  
4 
18 
Added “Baseline Period”, “Titration 
Period”, “Maintenance Period”, and 
“Treatment Period” definitions 
Clarification 
5.1 
19 
A clarification of the visit range is added 
for the treatment period 
Clarification 
5.2 
20-21 a. Added “at Visit 6” to clarify  caregiver’s 
timing for CGI-I  
Clarification  


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 7 
11 June 2019 
 
b. Added “Oppositional defiant disorder” 
to SNAP-IV ADHD scores 
c. Protocol Appendix numbers are 
updated in this section and various 
sections thereafter. This same 
description will not repeated 
Descriptions for CHQ-PF28 is updated 
to include reference for the derivation 
of scores for individual items, multi-
item scales, and summaries 
Clarification and 
correction is made to the 
CHQ-PF28 scoring based 
on the published manual 
5.3 
22 
Previous Section “5.3 Pharmacokinetic 
Variables” is removed 
PK analysis is not the 
scope of this SAP 
5.4.7 
23 
Visit range for C-SSRS is corrected 
Administrative 
5.4.8 
24 
“by the site coordinator” is added to 
clarify the subjects who administer the 
caregivers’s assessment of patient’s IA 
daily activities 
Clarification 
5.4.9 
24 
Inserted sentences describing the ranges 
of the scale scores 
Clarification 
6.1 
25 
Respecified the number of decimal places 
for some summary statistics in the table 
presentation 
Administrative 
6.2 
26 
Clarified how unscheduled data points 
will be used in the analysis 
Clarification 
6.3 
26 
Updated the reference for the statistical 
method and added two more covariates 
for the adjustment of covariates: pooled 
site and baseline IA adjusted to 7 days 
Administrative 
6.4 
28 
Expanded text to include methods of 
deriving weekly IA frequency in the 
treatment and maintenance period when 
subject discontinued the study or date of 
last dose is missing; Replaced LOCF 
analysis with MMRM analysis for 
secondary endpoints 
To provide detail of how 
primary endpoint is 
calculated when diary 
and dosing data are 
incomplete   
replace LOCF method by 
MMRM with respect to 
secondary endpoints 
6.8 
37 
To add section number for where to find 
the multiplicity adjustment 
Clarification 
6.9 
35 
Deleted age subgroup of “13-17”  
Protocol amendment 
7.1.2 
37 
Added a sentence “Subjects will be 
analyzed according to the treatment they 
were randomized to” to the definition of 
“ITT Population”  
Clarification 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 8 
11 June 2019 
7.1.3 
38 
a. Changed diary completion compliance 
requirement from “80%” to “70%” for 
the per protocol population 
b. Added words “within the treatment 
period” in the diary compliance 
formula 
To allow more patients in 
the PP analysis 
Clarification 
7.2 
38-39 a. Corrected a typographic error 
b. Clarified what populations will be used 
for the disposition summary 
Administrative 
7.3 
39 
Added information for protocol deviation 
summary 
Clarification 
7.5 
39 
Specified analysis population for the 
baseline summary 
Clarification 
7.6.1 
40 
Added word “treatment” to read 
“treatment compliance” to differentiate 
from “diary compliance” 
Clarification 
7.7.2.1 
42-43 Expanded the section to provide further 
details for the imputation procedure  
Clarification for missing 
data imputation 
7.7.3 
44 
Analysis of the maintenance period is 
added 
Administrative 
7.7.4 
44 
Renumbered from previous Section 
7.7.2.3 
Administrative 
7.7.5 
44 
a. Renumbered from previous Section 
7.7.2.4 
b. Added 2 new covariates  
c. Updated the statistical reference 
Administrative 
7.7.6 
44 
Defined CGI-I from caregiver and PI as 
key secondary efficacy variable 
Clarification 
7.7.7 
44-47 a. Clarifies the visit numbers for the by-
visit analysis and change from baseline 
analysis  
b. MMRM is added for the CGI-I and CGI-
S analysis with detailed specifications 
and sample SAS code 
c. Clarified other secondary endpoints 
will be analyzed by ANCOVA 
d. Added a paragraph to clarify the 
multiplicity adjustment for the 
secondary endpoints 
Clarification 
7.8 (old) 
 
Removed Pharmacokinetic Analysis 
section 
out of the scope for this 
SAP but will be defined in 
separate document 
7.8.1 
48 
Added a few clarifications for AE 
summaries 
Clarification 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 9 
11 June 2019 
 
 
7.8.2 
49 
Added a clarifications for lab summaries 
Clarification 
Reference 
51 
a. Included HealthActCHQ as the 
reference for CHQ-PF28 scoring 
b. Reference for the covariate 
adjustment is updated from “Zink and 
Koch, 2012” to “Dmitrienko and Koch, 
2017” 
Administrative 
Appendix 
2 
54 
Various tables and listings numbers and 
titles are updated as a result of the SAP 
text change 
Administrative 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 10 
11 June 2019 
1 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to ensure the credibility of the study findings 
by specifying the statistical approaches to the analysis of the data prior to database lock. This SAP 
covers the planned analyses of all data collected on the eCRFs and diary pages, and will identify 
handling of data issues. The statistical analysis plan presented in this document will supersede 
the statistical analysis methods described in the clinical protocol. Any deviations/changes from 
the planned analyses described in this SAP will be identified, with justification, in the appropriate 
section of the clinical study report. This SAP is based on the clinical study protocol 810P301, 
version 9.0, dated 01 November 2018 and its associated electronic case report forms (eCRF).  
 
This SAP does not cover the analytic methods for the determination of Minimal Clinically 
Important Change (MCIC) in clinical efficacy. The assessment of MCIC will be performed by 
, which is a designated CRO to perform this analysis. This SAP also does not cover the 
methods for the population pharmacokinetic modeling and analysis. 
  
2 STUDY OBJECTIVES  
2.1 Primary Objective 
The primary objective is to assess the efficacy and safety of SPN-810 in reducing the frequency 
of IA behaviors in pediatric patients with ADHD when taken in conjunction with standard ADHD 
treatment.  
2.2 Secondary Objectives 
The secondary objectives of the study are to assess the following:  
• The effect of SPN-810 on the Clinical Global Impression – Improvement Scale (CGI-I)  
• The effect of SPN-810 on the Clinical Global Impression – Severity Scale (CGI-S)  
• The effect of SPN-810 on the child’s overall health as measured by the Child Health 
Questionnaire Parent Form 28-item (CHQ-PF28)  
• The effect of treating the child with SPN-810 on the parent-child relationship as measured 
by the Parenting Stress Index – Short Form version 4 (PSI-4-SF)  
• The effect of SPN-810 on the caregiver-completed CGI-I  
• The effect of SPN-810 on inattention, hyperactivity-impulsivity and oppositional defiant 
disorder measured by the SNAP-IV Rating Scale  
 






Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 13 
11 June 2019 
Table 1:  Schedule of Visits and Procedures 
 
Phase 
Pre-treatment 
Treatment 
Conversion/ 
Taper 
Period 
Screening 
Baseline 
Titration 
Maintenance 
VISIT NUMBER 
1 
2 
3 
4 
5 
6 
7 
DAY 
-45 
-15 
1 
8 
15 
36 
43 
WINDOW (DAYS) 
≤45d prior to Visit
3 
≤15d prior  
to Visit 3 
0c 
7d±2d from Visit 3 14d±2d from Visit 3 
21d±3d from 
Visit 5 
7d±1d from Visit 
6 
Informed Consent/Assent a 
X b 
 
 
 
 
 
 
R-MOAS, K-SADS-PL 2013 & Vitiello Aggression Scale 
X 
 
 
 
 
 
 
Medical History 
X 
 
X d 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Physical Examination  
X 
 
 
 
 
X 
 
ECG (12-lead) 
X 
 
 
X 
 
X 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Randomization 
 
 
X b,e 
 
 
 
 
Urine Drug Screen 
X 
 
X 
 
 
 
 
Urine Pregnancy Test f 
X 
 
X 
 
 
 
X 
Diary Training & Distribution or Evaluation 
 
X 
X e 
X 
X 
X 
 
Vital Signsg 
X 
 
 
 
 
 
X 
Weight, height, BMI 
X 
 
X 
X 
X 
X 
X 
Hematology/chemistry/Urinalysis 
X 
 
X 
 
 
X 
X 
PK Blood Sampling 
 
 
 
X h 
X h 
 
 
Columbia Suicide Severity Rating Scale (CSSRS) 
X 
 
X 
X 
X 
X 
X 
Investigator CGI-S 
X 
 
X 
X 
X 
X 
 
Caregiver and investigator CGI-I 
 
 
 
X 
X 
X 
 
Efficacy scales (SNAP-IV, CHQ-PF28, PSI-4-SF) 
 
 
X 
 
 
X 
 
Safety Scales (Simpson-Angus, Barnes, AIMS) 
 
 
X 
X 
X 
X 
X 
Infrequent Behaviors Checklist 
 
 
X 
X 
X 
X 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Drug Dispensation 
 
 
X b 
 
X 
X 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 14 
11 June 2019 
Phase 
Pre-treatment 
Treatment 
Conversion/ 
Taper 
Period 
Screening 
Baseline 
Titration 
Maintenance 
VISIT NUMBER 
1 
2 
3 
4 
5 
6 
7 
DAY 
-45 
-15 
1 
8 
15 
36 
43 
WINDOW (DAYS) 
≤45d prior to Visit
3 
≤15d prior  
to Visit 3 
0c 
7d±2d from Visit 3 14d±2d from Visit 3 
21d±3d from 
Visit 5 
7d±1d from Visit 
6 
Drug Return and Compliance 
 
 
 
 
X 
X 
X 
Diary Return 
 
 
 
 
 
 
X 
a Written consent must be obtained prior to performing any study-related procedure. 
b Access IWRS. 
c Visit 3 will occur at least 15 days following Visit 2 
d Assess for any clinically significant change in Medical History since screening. 
e Diary compliance must be at least 80% (minimum of 12 days out of 15) to qualify for randomization. 
f To be performed for female subjects of childbearing potential prior to administration of first dose of SM and will have to be tested as negative for the subject to continue in the study. 
g Heart Rate (HR), blood pressure (BP), temperature, and respiratory rate will be measured. 
h Total of 5 PK blood samples will be obtained over one or two visits (Visit 4 and/or Visit 5) 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 15 
11 June 2019 
3.3 Study Treatment 
3.3.1 Treatment, Dose, and Mode of Administration 
SPN-810 (molindone hydrochloride extended-release tablet) or matching placebo tablets will be 
administered orally (PO) twice daily (BID). Subjects will be force-titrated over a period of 2 weeks 
to their final randomized dose.  
• Treatment 1: placebo  
• Treatment 2: 
mg total daily dose (TDD) 
• Treatment 3: 
mg TDD 
3.3.2 Duration of Treatment and Study Duration 
Total subject duration on study is approximately 13 weeks. 
• Pre-treatment phase: 45 days  
o Screening period: up to 30 days  
o Baseline period: at least 15 days  
• Treatment phase: 5 weeks  
o Titration period: 2 weeks  
o Maintenance period: 3 weeks  
• Conversion/Tapering phase: 1 week  
3.3.3 Methods of Assigning Subjects to Treatment Group 
Allocation of study drug will be completed centrally through the use of an interactive web 
response system (IWRS) that will determine which kit to assign to the subject. Separate schedules 
for subject randomization and drug list will be created. The randomization scheme assigns 
treatment to each randomization number in a 1:1:1 allocation ratio.  
Upon admission to the study, subjects will be assigned site (
) numbers and subject 
numbers 
), in the sequence that they are entered. Subjects who complete the 
Baseline Period and continue to meet all eligibility criteria will be assigned kit numbers, according 
to the randomization schedule, by using the IWRS. 
3.3.4 Blinding 
Subjects, all site personnel, the Sponsor and its designated Contract Research Organizations 
(CROs) are blinded with the following exceptions.  The CRO and Sponsor personnel who are 
a 
 
 e
 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 16 
11 June 2019 
involved in the randomization generation, study drug supply, and PK concentration assays are 
unblinded.  However, they are not involved in the routine study monitoring, data cleaning and 
review, the design of this SAP or data analysis.   
3.4 Hypotheses  
 
The null and alternative hypotheses are: 
• H01: There is no difference between SPN-810 
mg and Placebo in the treatment of IA 
in subjects with ADHD in conjunction with standard ADHD treatment. 
• Ha1: There is a difference between SPN-810 
 mg and Placebo in the treatment of IA in 
subjects with ADHD in conjunction with standard ADHD treatment. 
 
• H02: There is no difference between SPN-810 
mg and Placebo in the treatment of IA 
in subjects with ADHD in conjunction with standard ADHD treatment. 
• 
Ha2: There is a difference between SPN-810
 mg and Placebo in the treatment of IA in 
subjects with ADHD in conjunction with standard ADHD treatment. 
3.5 Determination of Sample Size 
Based on results from the Phase 2 study, it is assumed that the average treatment difference 
between SPN-810 dose groups and placebo is 15 with a common standard deviation of 27.3 in 
the primary efficacy endpoint. A sample size of 77 subjects per arm (231 subjects for 3 arms) will 
yield 90% power to detect a non-zero difference between the median of active drug group 
 
mg or 
 mg dose) and the placebo group using the Wilcoxon rank-sum test with a 2-sided 
significance level α=0.05.  
It is assumed that approximately 20% subjects will dropout before the completion of the study 
and hence, an adjusted total of 291 subjects will be randomized in a 1:1:1 ratio to obtain 231 
subjects in the ITT population at the completion of the study.  
To estimate the variability for designing Study 810P503, the standard deviation (SD) of the 
primary endpoint for Study 810P301 was reviewed blindly.  This review indicates that the SD for 
interim data was actually 34.83 instead of the protocol-assumed 27.3 (see above).  This increase 
in the SD resulted in the increase in the sample size to 122 subjects per treatment.  Allowing for 
20% dropout, the final sample size for randomization is 153 subjects per treatment.  
The sample size was calculated using the nQuery Advisor Software, Version 7. 
3.6 Changes to Analyses Planned in the Protocol 
This SAP will be updated as necessary if any changes in the protocol occur due to the expected 
protocol amendment impacting the SAP.  
4 DEFINITIONS AND DERIVED DATASETS 
Table 1. Terminology and Definition 
 
 
d
 e
 
 
 
 
 


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Terminology 
Definition 
Study Medication 
SPN-810 or the matching placebo. 
Study Day 
The first dose date (Day 1) is defined as the date on which a subject 
took the first dose of double-blind study medication (SM), Other study 
days are defined relative to the Study Day 1.  For visits prior to the first 
dose of the SM, Study Day is calculated as Visit Date – Day 1.  For visits 
after the first dose, Study Day is calculated as Visit Date – Day 1 +1. 
Enrolled 
Subject has provided signed informed consent. 
Randomized 
Subject is assigned with the kit number for the SM. 
Completer for the 
Study 
Subject who completes the maintenance period (Visit 6). 
Baseline 
Unless specified otherwise, baseline is defined as the non-missing 
value collected most recent to and before the time of the very first 
dose of the SM. 
Baseline Period 
For subject daily IA diaries, on and prior to Visit 3 (inclusive, ≤Day 1). 
Prior Medication 
Medication collected on the Prior/Concomitant Medication CRF, with 
the start date prior to Study Day 1. 
Concomitant 
Medication 
Medication collected on the Prior/Concomitant Medication CRF, with 
end date on/after Study Day 1. 
Titration Period 
For subject daily IA diaries from Visit 3 through Visit 5 (v3< to ≤ V5) 
Maintenance Period 
For subject daily IA diaries from Visit 5 through Visit 6 (V5< to ≤ V6) 
Treatment Period 
Titration and Maintenance Periods combined 
Derived Dataset 
Derived dataset (analysis dataset) is any permanently stored collection 
of data containing raw and/or derived variables created to support the 
production of statistical summary tables. Derived variables will be 
created from the “raw” data.  Analysis datasets to be created will 
include ADEFF (efficacy analysis dataset), ADSL (subject-level analysis 
dataset), ADAE (Adverse event analysis dataset) and other as 
appropriate.  In deriving ADEFF, the source data include both the 
episodic diary and evening diary data files.  
Specifications for derived datasets will be developed which will include 
the names and definitions of derived variables in the derived SAS 
datasets. 
 


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5 EFFICACY AND SAFETY VARIABLES  
5.1 Primary Efficacy Variable 
The primary efficacy endpoint is percent change (PCHT) in the frequency (unweighted score) of IA 
behaviors per 7 days in the treatment (titration and maintenance) period relative to the Baseline 
period calculated over the number of days with non-missing IA diary data.  
PCHT will be calculated as 100 x (T – B)/B, where T and B are IA behavior frequencies per 7 days 
during the treatment period (from Day 2 through Visit 6, inclusive) and baseline period (Day ≤1), 
respectively. The IA behavior frequency per 7 days is defined as (SUM/DAY) x 7, where SUM is 
the total of the IA behaviors reported in the subject IA diary, and DAY is the number of days with 
non-missing IA score in the subject IA diary during the specified study period.  
This primary efficacy variable will be based on a checklist of 15 IA behaviors collected in an 
electronic IA diary. The IA diary comprises two parts: 1) An episodic diary that will be used by the 
primary caregiver (or alternate) to enter events as soon as possible after they are observed; and 
2) an evening diary that will prompt the caregiver to review events for the day and to enter any 
events that were not previously captured. Each event will be characterized by a checklist of 15 
observed behaviors: Yelling, Screaming, Threatening, Scratching, Throwing, Slamming, Hitting 
Self, Arguing, Cursing, Name Calling, Shoving, Hair Pulling, Fighting, Hitting Others, and Kicking 
Others. The checklist will indicate whether each behavior was observed (coded 1) or was not 
observed (coded 0) during the incidence of an event. Each day can have multiple events. A day 
can have no event, as can be attested in the evening diary. In this case, if no event is reported 
during a day, and the evening diary confirms this, the daily event score for that subject will be 0 
for each of the 15 IA variables. Behaviors not on this list will not be captured.   
5.2 Secondary Efficacy Variables 
1. 
Actual CGI-I (Investigator-rated Clinical Global Impression – Improvement Scale) score 
at Visit 6 
2. 
Change from Visit 3 to Visit 6 in CGI-S (Investigator-rated Clinical Global Impression – 
Severity) score 
3. 
CHQ-PF28 at Visit 6 (Overall Health Measured by Child Health Questionnaire Parent 
Form 28-item)  
4. 
PSI-4-SF at Visit 6 (Parenting Stress Index – Short Form)  
5. 
Caregiver-completed CGI-I at Visit 6 
6. 
SNAP-IV ADHD scores at Visit 6 (Swanson, Nolan and Pelham-IV Rating Scale for 
Inattention, hyperactivity-impulsivity and oppositional defiant disorder measured) in 
• Inattention  


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• Hyperactivity/Impulsivity  
• Oppositional Defiant Disorder 
• Combined subscale  
 
CGI-I (Protocol Appendix 10.3), relative to the condition at Visit 3, will be evaluated by the 
caregiver and by the Investigator at Visits 4 to 6 on a 7-point scale with 1=Very much improved, 
2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, 
and 7=Very much worse.  
CGI-S (Protocol Appendix 10.3) will be evaluated by the Investigator at Visits 1, 3 - 6 on a 7-point 
scale with 1=Normal, 2=Borderline ill, 3=Mildly ill, 4=Moderately ill, 5=Markedly ill, 6=Severely ill, 
and 7=Extremely ill.  
The Child Health Questionnaire Parent Form 28-item (CHQ-PF28) (Protocol Appendix 10.11) is 
evaluated by the primary caregiver at Visit 3 and Visit 6 for the subject’s health status and health 
related quality of life. CHQ-PF28 items have four, five, or six response options, divided over eight 
multi-item scales (Physical Functioning [PF, Q2.1a–2.1c], Behavior [BE, Q5.1a-5.1c, Q5.2], Mental 
Health [MH, Q6.1a–6.1c], Self-Esteem [SE, Q7.1a-7.1c], General Health Perceptions [GH, Q1.1, 
Q8.1a-8.1c], Parental Impact - Emotional [PE, Q9.1a-9.1b], Parental Impact - Time [PT, Q9.2a-
9.2b], and Family Activities [FA, Q9.3a-9.3b]) and five single item concepts (Global Health [GGH, 
Q1.1], Role/Social Limitations - Emotional/Behavior [REB, 3.1], Role/Social Limitations - Physical 
[RP, Q3.2], Bodily Pain/Discomfort [BP, Q4.1], Global Behavior [GBE, Q5.2], Family Cohesion [FC, 
Q9.4], and Change in Health [CH, Q8.2]).  In addition, the individual scale scores will be 
aggregated to derive 2 summary component scores: the physical functioning and psychosocial 
health summary scores. Range on subscales and the overall scale is 0–100, where 0 is the worst 
possible health state and 100 the best possible health state. Details for item and multi-item scale 
scoring, calculation of standardized scores and Aggregate Physical and Psychological Summary 
Scores can be found in the Child Health Questionnaire (CHQ) Scoring and Interpretation Manual 
(HealthActCHQ). 
The Parenting Stress Index – Short Form (PSI-4-SF) (Protocol Appendix 1.10) is a 36-item self-
report measure of parenting stress at Visit 3 and Visit 6. Three subscales (Parental Distress [PD: 
Q1-12], Parent-Child Dysfunctional Interaction [P-CDI: Q13-24], and Difficult Child [DC: Q25-36]) 
consist of 12 items each. Parents use a 5-point scale to indicate the degree to which they agree 
with each statement.  The subscale score is the sum of the respective item scores.  “Total Stress” 
score is the sum of the 3 subscale scores. The subscale will be set to missing if 2 or more (>1) item 
scores in the subscale are missing. Total Stress score is set to missing if 1 or more subscale score 
is missing. 


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The SNAP-IV (Protocol Appendix 10.7) rating scale includes 18 ADHD and 8 oppositional defiant 
disorder (ODD) symptoms as specified in the DSM-IV-TR and International Statistical 
Classification of Diseases and Health Related Problems 10th Revision (ICD-10) Classification of 
Mental and Behavioral Disorders. The symptoms are scored by assigning a severity estimate for 
each symptom on a 4-point scale. The SNAP-IV rating is performed by the parent or legal 
representative at each visit. The ratings from the SNAP-IV scale are grouped into the following 4 
subscales:  
o 
ADHD-Inattention (items #1-9),  
o 
ADHD-Hyperactivity/Impulsivity (items #10-18)  
o 
ODD (items #19-26)  
o 
ADHD-Combined subscale: (items #1 – 18)  
 
Each subscale score is the average of the available item scores in the subscale.  The SNAP-IV rating 
scale will be administered at Visit 3 and Visit 6. 
5.3 Pharmacokinetic Variables 
Analysis of pharmacokinetic variables will not be covered in this SAP.  
5.4 Safety Variables 
5.4.1 Medical History and Adverse Events (AEs) 
AEs that occur on/after signing ICF will be recorded on the AE CRF.  Medical history and AEs will 
be coded for preferred term (PT) and system organ class (SOC) using Medical Dictionary for 
Regulatory Activities (MedDRA) version 18.1.  AEs are evaluated by the investigators for 
seriousness, relationship, and severity.   
5.4.2 Prior, Concomitant, and Prohibited Medications  
Prior medications and concomitant medications will be extracted from the Prior/Concomitant 
Medication CRF.  Medications taken prior to Study Day 1 will be considered as prior medications 
and medications taken on or after Study Day 1 will be considered as concomitant medications.  
Prior and concomitant medications will be coded using WHO Drug Dictionary (WHODD)  version 
1 June, 2015 for PT and Anatomical Therapeutic Chemistry (ATC) classification.   
Prohibited medications include, but are not limited to, 
• α2- adrenergic agonists (e.g. clonidine and guanfacine) used for any other reason except 
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• Anti-psychotics including aripiprazole, risperidone, quetiapine, and ziprasidone  
• Anticonvulsants including carbamazepine and valproic acid, antidepressants, mood 
stabilizers including lithium, benzodiazepines, cholinesterase inhibitors or any drug 
known to inhibit CYP2D6 activity  
• Herbal supplements  
5.4.3 Clinical Laboratory Tests (Hematology, Chemistry, and Urinalysis) 
Laboratory tests will be converted to follow the International System (SI) units.  Laboratory tests 
will be collected at Visits 1, 3, 6, and 7.  The tests include hematology, serum chemistry and 
urinalysis panels.  Laboratory values will be categorized according to the appropriate laboratory 
reference ranges. 
5.4.4 Vital Signs, Height and Weight 
Vital signs include body temperature, heart rate, respiratory rate, systolic blood pressure, and 
diastolic blood pressure.  They will be collected at Visits 1 and 7.  Subject height, weight, and BMI 
will be collected at Visits 1 and 3 – 7. 
5.4.5 12-Lead ECG 
The following ECG variables will be collected at Visits 1, 4, and 6: HR (heart rate), PR (respiratory 
rate), QRS interval, QT interval, and QTcF (QT interval corrected using the Fridericia’s method). 
5.4.6 Physical Examinations 
Physical examinations will be conducted at Visit 1 and Visit 6.  Clinically significant findings will 
be reported as adverse events. 
5.4.7 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS (Protocol Appendix 10.6) is a questionnaire assessing suicidal ideation and behavior 
at baseline and since last visit. This assessment will be conducted at Visits 1, and 3 – 7. The 
following outcomes are C-SSRS categories and have binary responses (yes/no). 
Category 1 – Wish to be dead  
Category 2 – Non-specific Active Suicidal Thoughts  
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act  
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan  
Category 5 – Active Suicidal Ideation with Specific Plan and Intent  
Category 6 – Preparatory Acts or Behavior  


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Category 7 – Aborted Attempt  
Category 8 – Interrupted Attempt  
Category 9 – Actual Attempt (non-fatal)  
Category 10 – Completed Suicide 
Three composite binary endpoints and one severity score are derived from the above categories. 
Suicidal ideation: A “yes” answer at any time during treatment to any one of the five 
suicidal ideation questions (Categories 1-5) on the C-SSRS.  
Suicidal behavior: A “yes” answer at any time during treatment to any one of the five 
suicidal behavior questions (Categories 6-10) on the C-SSRS.  
Suicidal ideation or behavior: A “yes” answer at any time during treatment to any one of 
the ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS. 
Suicidal Ideation score: The maximum suicidal ideation category (1-5 on the C-SSRS) 
present at the assessment.  Assign a score of 0 if no ideation is present. 
5.4.8 Infrequent Behaviors Checklist 
The infrequent behaviors checklist is a checklist of 15 behaviors that (along with the 15 IA Diary 
behaviors) were qualitatively linked to IA during the development of the IA diary. These behaviors 
include teasing, spitting, biting, weapons, ripping, breaking, vandalizing, destroying, fire setting, 
hitting animal, kicking self, kicking animal, severe injury self, severe injury others, severe injury 
animal.  Caregivers will be asked which, if any, of these behaviors have been observed since the 
patient’s last visit. This assessment will be administered at Visits 3 – 6 by the site coordinator. 
5.4.9 Extrapyramidal symptoms (EPS) scales  
The EPS symptom and neuroleptic malignant syndrome will be evaluated using the Simpson-
Angus scale (Protocol Appendix 10.8), the Barnes Akathisia scale (Protocol Appendix 10.9), and 
the Abnormal Involuntary Movement scale (AIMS) (Protocol Appendix 10.10). The Simpson-
Angus scale is a 10-item rating scale, consisting of 1 item measuring gait, 6 items measuring 
rigidity, and 3 items measuring glabella tap, tremor and salivation. The Barnes Akathisia scale is 
a rating scale for drug-induced akathisia.  It includes Objective Akathisia, Subjective Awareness 
of Restlessness, Subjective Distress Related to Restlessness, and Global Clinical Assessment of 
Akathisia subscales.  Additionally, total score will be calculated by summing up the Objective and 
two Subjective scale scores (Barnes 1989). The objective and two subjective symptoms are rated 
on a 4-point scale ranging from 0 to 3.  The global clinical assessment is rated on a 5-point scale 
ranging from 0 to 4.  The AIMS test is a rating scale used to measure tardive dyskinesia (Munetz 


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1988).  It includes 12 items to rate involuntary movements of various areas of the subject’s body. 
These assessments will be administered at Visit 3 and all subsequent visits. 
 
6 STATISTICAL METHODS 
6.1 General Methodology  
All statistical analyses will be conducted using SAS Version 9.4 or later on the Microsoft® 
Windows Operating System. 
 
All tabulations of analysis results will include summaries for the three treatment groups: SPN810 
mg, SPN810 
mg and placebo.  
 
Continuous data will be summarized using n (number of subjects with non-missing observations), 
mean, median, standard deviation (SD), minimum value, and maximum value.  Categorical data 
will be summarized using the frequency count and percentage (n, %) of subjects in each category. 
Number of subjects with non-missing values or number of subjects with missing values (e.g., Not 
Done) will be presented, where appropriate.  Subjects with missing values will not contribute to 
the denominator of percentage calculations. Counts of zero in any category will be presented 
without percentage. 
 
Treatment differences will be evaluated as SPN-810 dose minus placebo. Unless otherwise 
specified, all statistical hypothesis tests will be 2-sided with a significance level of α=0.05.  All 
confidence interval will be calculated 2-sided from the unadjusted 5% significance level. P-values 
will be reported to 4 decimal places.  P-values <0.0001 will be presented as “<0.0001”.  Similarly, 
p-values >0.9999 will be presented as “>0.9999” 
 
The precision rules for the presentation of summary statistics will be: 
• Sample size (n, N) and number of missing responses (if displayed) – Integer 
• Mean, median, percentiles, and confidence interval – One additional decimal place than 
reported/collected 
• Standard deviation – Two additional decimal places than reported/collected 
• Minimum, maximum – Same number of decimal places as reported/collected 
• Ratios – two decimal places 
• Percentages – one decimal place generally, or two decimal places for <0.1% 
 
The data summaries will be accompanied by individual subject data listings. All data available 
from diary, eCRF, and external transfer (labs) will be listed and will include relevant and pertinent 
subject information, e.g., treatment, center, age/gender/race, and study day.  The listings will be 
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sorted in the order of treatment group, unique subject ID, and assessment date/time and 
assessment name. The unique subject ID consists of 3-digit study number followed by -digit site 
number 
and 
-digit 
subject 
number 
separated 
by 
hyphen  
(e.g., 
).  
 
For each summary table, a supporting listing will be identified in the footnote.   
 
Dates will be presented in the ISO-8601 format YYYY-MM-DD.  Times will be displayed in 24-hour 
clock format. Numbering for tables, figures and listings will follow ICH E3 Guidelines. 
 
Alternative methods of analysis of the data may be considered prior to un-blinding when some 
of the assumptions underlying the proposed analyses not be met.  However, the reason for any 
departure from the planned approach and methods will be fully documented as an amendment 
to the SAP or in the clinical study report. 
6.2 Visit Window and Unscheduled Assessments 
There is no visit window for the by visit analysis.  Data will be analyzed according to the visit they 
are associated with. Data collected at unscheduled time points will not be summarized at the 
unscheduled time points.  However, the unscheduled data will be used for analysis if data are 
missing at the next scheduled visit due to early termination. 
6.3 Adjustment for Covariates 
An exploratory analysis of the primary efficacy endpoint will be performed using a 
randomization-based approach (Dmitrienko and Koch 2017).  This analysis will include age 
(categorical and continuous), gender, pooled site and baseline IA adjusted to 7 days as covariates.   
6.4 Handling of Dropouts, Missing Data, and Data Discrepancies 
For the primary analysis of the primary efficacy endpoint, the frequency of IA behaviors during 
the treatment (titration + maintenance) period will be calculated over the number of days with 
non-missing IA diary data in the treatment period. No explicit imputation of missing data will be 
used, but this approach is implicitly equivalent to using the frequency of IA behaviors during the 
days with non-missing IA diary data to impute the frequency for days after study discontinuation 
or days with missing IA diary data. In addition to this implicit imputation, multiple imputations 
under the assumption of missing at random (MAR) and missing not at random (MNAR) will be 
used for handling missing data for sensitivity analysis. Details of imputation methods are 
specified in Section 7.7.2.  
 
 
 


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For analysis of frequency of IA behaviors during the treatment period (titration or maintenance), 
the following methods will be followed.  
1) If subjects discontinued the study during the maintenance period, their maintenance period 
will be counted from Visit 5 (exclusive) through the date of last dose as documented on the End 
of Study eCRF page (inclusive). If the date of last dose is not collected, it will be imputed by the 
subjects’ last visit for the study.  
2) If subjects have ≥7 daily diaries in the maintenance period, their maintenance IA frequencies 
will be based on maintenance daily diaries.  
3) If subjects have <7 daily diaries in the maintenance period, their maintenance IA frequencies 
will be calculated pooling the titration period diaries with the maintenance period diaries.   
4) If subjects do not have any maintenance diaries, their maintenance IA frequencies will be 
entirely derived from the titration period diaries. 
Missing data for secondary efficacy endpoints will be handled by using the Mixed Model for 
Repeated Measures method, which is implemented via SAS® PROC MIXED procedure. MMRM 
assumes data are “Missing At Random (MAR)”. That is, the probability that an observation is 
missing may depend on the observed values but not the missing values in the previously 
scheduled visits. 
AEs with incomplete information for start or stop dates (i.e., either day or month is missing) will 
be considered treatment-emergent (TEAE) unless the partial start date or the stop date confirms 
the AE started or ended prior to Study Day 1 (e.g., the day of the AE start date is unknown but 
the month and year indicate that the AE starts prior to Study Day 1).  AEs with missing relationship 
to study drug will be included in the “Related” category for the summary tables (Section 7.8.1). 
AEs with missing severity will not be included in the summary table but will be footnoted. 
When there is incomplete information regarding dosing dates for prior and concomitant 
medication, the medication will be considered as a concomitant medication unless it contradicts 
with the stop date.  For example, a medication will be considered a prior medication if the month 
and year of the end date indicates a date before Study Day 1 even though the start date could be 
missing.   
6.5 Interim Analysis and Adaptive Design 
The sample size estimation described in Section 3.5 is based on the effect size assumptions from 
the Phase 2 data in which the primary endpoint was the change from baseline to endpoint in R-
MOAS ratings. However, the primary endpoint for this study is percent change in the frequency 
of IA incidence per 7 days in the treatment period (PCHT) relative to the Baseline period in the 
ITT population. Hence, there is uncertainty as to what magnitude of alternative hypothesis 


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treatment difference and between-subject variability is appropriate for the sample size 
calculation. To this end, a single interim analysis is planned after approximately 50% of subjects 
complete the study for the purpose of the Stage 2 sample size adjustment.  
6.5.1 Objective  
The primary objective of this Interim Analysis is to re-evaluate the pre-specified power and 
sample size to consider sample size adjustment using adaptive statistical methods.  
6.5.2  Responsible Party  
This interim analysis will be performed by an independent unblinded statistician who is not 
affiliated to the trial sponsor, trial management, data cleaning, and analysis.  
The Senior Director of Biostatistics and Executive VP and Chief Medical Officer for Clinical 
Developmen at Supernus (sponsor) will receive recommendation letter from the independent 
unblinded statistician. They will make the final decision for the sample size adjustment.  
6.5.3 Confidentiality  
The independent statistician will sign the confidentiality agreement. He/she will not reveal any 
unblinded data/information to any persons within his/her own organization or to the sponsor, 
with the exception of sending recommendation as described in Section 6.5.8 below.  
6.5.4 Scope of Data Being Analyzed  
Primary efficacy endpoint – percent change in the frequency of impulsive aggression behaviors 
per 7 days in the treatment (PCHT) period relative to Baseline period in the ITT population. The 
primary efficacy analysis will be performed using the Wilcoxon rank-sum test to compare the 
medians of each of the two doses of SPN-810 (
mg and 
mg) with the median of the Placebo.  
6.5.5 Procedures for Interim Analysis  
a. Cutoff dates for collection of diary data for efficacy analysis is established based on 
an estimated target date of 50% of the randomized subjects completing/discontinuing 
the study.  
b. All data received by the cutoff date will be validated, queries generated and resolved 
or pending queries documented.  
c. A snapshot of the diary data will be taken and used for the interim analysis.  
d. From the data obtained at the time of the interim analysis, the independent 
statistician will calculate 
 
d
 
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o The Conditional Power (CPL) associated with SPN-810 
 mg/day  
o The Conditional Power (CPH) associated with SPN-810 
 mg/day  
Using the formula derived from Chang (2008a), Hintze (2013), (Chen, 2004), and 
Jennison and Turnbull (2005), 
𝐶𝐶𝐶𝐶൫𝑛𝑛2, 𝛼𝛼2,, 𝑝𝑝1ห𝛿𝛿, 𝜎𝜎൯= 1 −Ф ቆ1
√𝑤𝑤2
ൣ𝑍𝑍1−𝛼𝛼2−ඥ𝑤𝑤1𝑍𝑍1−𝑝𝑝1൧−𝛿𝛿
𝜎𝜎ට𝑛𝑛2
2 ቇ 
1 −Ф ൬
1
√𝑤𝑤2 ൣ𝑍𝑍1−𝛼𝛼2−√𝑤𝑤1𝑍𝑍1−𝑝𝑝1൧−𝑍𝑍1−𝑝𝑝1ට
𝑛𝑛2
𝑛𝑛1൰, 
where 𝛿𝛿𝜎𝜎
⁄  is the expected effect size (standardized treatment difference from 
placebo), 𝑤𝑤1 =
𝑛𝑛1
𝑛𝑛1+𝑛𝑛2 , 𝑤𝑤2 =
𝑛𝑛2
𝑛𝑛1+𝑛𝑛2 are the weights for the average of the Stage 1 and 
Stage 2 test statistic, 𝑛𝑛1 is the sample size at stage 1,  𝑛𝑛2 is the planned sample size 
per group at Stage 2 (increment from interim to final), 𝛼𝛼2 = 0.025 is the one-sided 
Type-I error for the final analysis, and 𝑍𝑍1−𝑝𝑝1 is the Wilcoxon Rank Sum Z statistic with 
continuity correction at the interim analysis (Stage 1). When the interim analysis is 
conducted with 50% subjects have completed the study, 𝑤𝑤1 = 𝑤𝑤2 = 1 2
⁄ .  For the 
sample size re-estimation, Stage 2 data are assumed to follow the trend observed in 
Stage 1. Hence, the effect size is calculated as 
𝛿𝛿
𝜎𝜎= 𝑍𝑍1−𝑝𝑝1ට
2
𝑛𝑛1. (Chang 2008b). 
6.5.6 Adaptation Rules  
Based on the conditional power calculated in Section 6.5.5, the independent statistician will use 
the following adaptation rules for sample size adjustment and make recommendation to the 
sponsor.  
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Table 2. Sample Size Adjustment Decision Rules 
 
Case 
Dose 1 (
 
mg) 
Dose 2 (
 
mg) 
Decision for Stage 2 Sample Size Adjustment 
Verbiage for 
Communication to Sponsor 
(Section 6.5.8) 
1 
CpL<10% 
CPH<10% 
Terminate the trial. 
CASE 1. Terminate the trial. 
2 
CpL<10% 
10%≤CPH≤36% 
or CPH>80% 
Subjects to be randomized to Dose 1 group in Stage 2 will be 
allocated to Dose 2 and Placebo groups; However, subjects 
who received dose 1 prior to the interim analysis will continue 
to receive dose 1 in Stage 2. 
CASE 2. Stop enrollment for 
mg group, allocate Stage 2 
planned 
mg sample size to 
mg and Placebo. 
3 
10%≤CPL≤36% 
or CPL>80% 
CPH<10% 
Subjects to be randomized to Dose 2 group in Stage 2 will be 
allocated to Dose 1 and Placebo groups; However, subjects 
who received Dose 2 prior to the interim analysis will continue 
to receive Dose 2 in Stage 2. 
CASE 3. Stop enrollment for 
mg group, allocate Stage 2 
planned 
mg sample size to 
mg and Placebo. 
4 
CpL<10% 
36%<CPH≤80% 
Enrollment for Dose 1 group will be terminated. Sample size in 
Dose 2 and Placebo groups will be increased to achieve the 
conditional power of at least 90% (before the multiplicity 
adjustment). This increase will include subjects allocated to 
Dose 2 and Placebo from Dose 1 termination 
The maximum increase will not result in the doubling of the 
total sample size.  In other words, suppose n1 and n2 are the 
sample sizes per arm at the interim analysis and n2adj is the 
calculated adjusted sample size.  If (n1+ n2adj) ≤ 2*(n1+ n2) then 
the adjusted sample size for Stage 2 will be n2adj as calculated.  
If ((n1+n2adj)> 2*(n1+n2)) then n2adj = 2*(n1+n2) - n1. 
CASE 4. Stop enrollment for 
mg group, increase Stage 
2 sample sizes for 
mg and 
Placebo to xxx/group. 
 
 
 e
 
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a 
 
 
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Case 
Dose 1 (
 
mg) 
Dose 2 
 
mg) 
Decision for Stage 2 Sample Size Adjustment 
Verbiage for 
Communication to Sponsor 
(Section 6.5.8) 
5 
36%<CPL≤80% CpH<10% 
Enrollment for Dose 2 group will be terminated. Sample size in 
Dose 1 and Placebo groups will be increased to achieve the 
conditional power of at least 90% (before the multiplicity 
adjustment). This increase will include subjects allocated to 
Dose 1 and Placebo from Dose 2 termination.  
The maximum increase will not result in the doubling of the 
total sample size. 
CASE 5. Stop enrollment for 
mg group, increase Stage 
2 sample sizes for 
mg and 
Placebo to xxx/group. 
6 
10%≤CPL≤36% 
or CPL>80% 
10%≤CPH≤36% 
or CPH>80% 
Retain the original sample sizes of each treatment group.  
CASE 6. No change in sample 
sizes. 
7 
36%<CPL≤80% 36%<CPH≤80% 
Increase the sample size in all treatment groups to achieve the 
conditional power of at least 90% (before the multiplicity 
adjustment) in both treatment groups.  
The maximum increase will not result in the doubling of the 
total sample size. 
CASE 7. Increase Stage 2 
sample sizes for 
mg to xxx 
mg to xxx, and Placebo to 
xxx. 
8 
10%≤CPL≤36% 
or CPL>80% 
36%<CPH≤80% 
Retain the original sample size in Dose 1 group and increase 
the sample size in Dose 2 and Placebo groups to achieve the 
conditional power of at least 90% (before the multiplicity 
adjustment).  
The maximum increase will not result in the doubling of the 
total sample size. 
CASE 8. Increase Stage 2 
sample sizes for 
mg and 
Placebo to xxx/group. 
 
 
 
 e
 e
 
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Case 
Dose 1 (
 
mg) 
Dose 2 
 
mg) 
Decision for Stage 2 Sample Size Adjustment 
Verbiage for 
Communication to Sponsor 
(Section 6.5.8) 
9 
36%<CPL≤80% 10%≤CPH≤36% 
or CPH>80% 
Retain the original sample size in Dose 2 group and increase 
the sample size in Dose 1 and Placebo groups to achieve the 
conditional power of at least 90% (before the multiplicity 
adjustment). 
The maximum increase will not result in the doubling of the 
total sample size. 
CASE 9. Increase Stage 2 
sample sizes for 
 and 
Placebo to xxx/group. 
 
 
 
 


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Note the sample size to achieve the conditional power of CP=90% is calculated as follows (Chang 
2008a and 2008b, Hintze 2013, and Jennison and Turnbull 2000), 
𝑛𝑛2 =
2𝜎𝜎2
𝛿𝛿2 ቄ
1
√𝑤𝑤2 ൫𝑍𝑍1−𝛼𝛼2−√𝑤𝑤1𝑍𝑍1−𝑝𝑝1൯−Ф−1(1 −𝐶𝐶𝐶𝐶)ቅ
2
, 
=
𝑛𝑛1
𝑍𝑍1−𝑝𝑝1
2
ቄ
1
√𝑤𝑤2 ൫𝑍𝑍1−𝛼𝛼2−√𝑤𝑤1𝑍𝑍1−𝑝𝑝1൯−Ф−1(1 −𝐶𝐶𝐶𝐶)ቅ
2
. 
The following rules will be applied to compute the sample sizes across the treatment arms in 
Stage 2:  
• If a decision to discontinue subject enrollment is made for a particular dosing arm at 
Interim Analysis, subjects who were planned to be enrolled in that arm after Interim 
Analysis will be re-distributed to the remaining treatment arms. For example, if Dose 1 is 
dropped and Dose 2 is retained, the sample sizes for the three treatment arms in Stage 2 
will be defined as follows:  
o Dose 1: 0  
o Dose 2: n22 + n21 /2  
o Placebo: n23 + n21 /2  
where nij is the sample size allocated to Stage i for Treatment Group j. 
• If a decision is made to increase the sample size in at least one dosing arm, the modified 
sample size in the placebo arm will be equal to the larger modified sample size in the two 
dosing arms. For example, if the modified sample sizes in the two dosing arms in Stage 2 
are n31 and n32, respectively, the modified sample size in the placebo arm in Stage 2 will 
be set to max(n31, n32). However, if the sample size is increased in one dosing arm, the 
sample size in the other dosing arm will not be automatically increased.  
6.5.7 Adaptive Design  
This section defines the mathematical approach used in the proposed adaptive design with two 
stages and data-driven decision rules (e.g., sample size modification at Interim Analysis). The 
derivation of the adaptive design is based on the combination function approach applied in 
conjunction with the closure principle, see, for example, Wang et al. (2001), Brannath et al. (2002) 
and Hommel (2005). This general approach is commonly used to construct adaptive designs in 
confirmatory trials and guarantees that the overall Type I error rate is protected in the trial at the 
nominal level (two-sided α= 0.05) regardless of the type of design modifications at an Interim 
Analysis, including decisions to drop a treatment arm or adjust the sample size in one or more 
arms. 


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Let H1 and H2 denote the null hypotheses of no treatment effect for the two dose-placebo 
comparisons (Dose 1 versus placebo and Dose 2 versus placebo). According to the combination 
function approach, the amount of evidence to reject these null hypotheses will be evaluated 
separately in each individual stage of the trial and the inferences at the final analysis will be 
performed by combining the evidence across the two stages. Further, the rejection rules for H1 
and H2 will be chosen to achieve consistency with the Hochberg procedure (Dmitrienko and 
D’Agostino, 2013) that was pre-defined as multiplicity adjustment tool in this trial. To achieve 
this consistency, the Hochberg procedure will be applied within each stage (Hochberg, 1988).  
Let pi and qi denote the p-values for testing the null hypothesis Hi, i = 1, 2, based on the data in 
Stages 1 and 2, respectively. The Stage 2 p-values are computed from the samples obtained after 
Interim Analysis, i.e., the sample size in a dosing arm may be adjusted as explained above. 
Further, p(1) < p(2) will denote the ordered treatment effect p-values in Stage 1 and similarly q(1) < 
q(2) will denote the ordered treatment effect p-values in Stage 2. These p-values will be used to 
construct a closure-based representation of the Hochberg procedure in each of the two stages. 
To define the closure-based representation, a closed family of intersection hypotheses that 
includes all possible non-empty intersections of the two null hypotheses will be set up. Table 3 
and Table 4 display the intersection hypotheses in the closed family and associated intersection 
p-values that define the Hochberg procedure in Stage 1 and Stage 2 respectively.  
Table 3: Intersection hypothesis and Hochberg intersection p-values in Stage 1 
Intersection hypothesis  
Hochberg intersection p-value  
H1 ∩ H2  
p12 = min (2 p(1) , p(2)) 
H1  
p1  
H2  
p2  
 
Table 4: Intersection hypothesis and Hochberg intersection p-values in Stage 2 
Intersection hypothesis  
Hochberg intersection p-value  
H1 ∩ H2  
q12 = min (2 q(1) , q(2))  
H1  
q1  
H2  
q2  
 
Note that, if a certain dose is dropped due to futility at Interim Analysis, the corresponding p-
values in Stage 2 is automatically set to 1 to remove the dosing arm from consideration. This 
guarantees that a null hypothesis cannot be rejected at Final Analysis if the corresponding dose 
was dropped due to futility at Interim Analysis. Further, the p-values computed at Interim 
Analysis (Stage 1 p-values) are not used for inferential purposes and therefore no α will be spent 
at Interim Analysis to stop the trial early due to overwhelming efficacy.  


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As an illustration, if Dose 1 is dropped at Interim Analysis, the corresponding treatment effect p-
value in Stage 2 (q1) will be set to 1. As a result, the intersection p-values will be defined in Stage 
2 as shown in Table 5 (note that the smaller ordered p-value will be equal to q2 and the larger 
ordered p-value will be equal to 1).  
Table 5: Intersection hypotheses and Hochberg intersection p-values in Stage 2 if dose 1 is dropped at 
Interim Analysis 
Intersection hypothesis  
Hochberg intersection p-value  
H1 ∩ H2  
q12 = min (2 q2 , 1)  
H1  
1  
H2  
q2  
 
The inferences for the two null hypotheses will be performed at final analysis using the composite 
treatment effect p-values that will be defined as follows. Let w1 and w2 define the stage weights 
that are prospectively defined based on the expected amount of information at Interim Analysis. 
Since Interim Analysis is planned to be taken after 50% of the subjects have completed the trial, 
n1 (total sample size in Stage 1) and n2 (total sample size in Stage 2 before sample size 
adjustment), and thus the pre-specified stage weights are given by 
𝑤𝑤1 =
𝑛𝑛1
𝑛𝑛1 + 𝑛𝑛2
= 0.5, 𝑤𝑤2 =
𝑛𝑛2
𝑛𝑛1 + 𝑛𝑛2
= 0.5. 
Using the stage weights, the combination function to be used at Final Analysis will be defined as 
follows: 
𝑐𝑐(𝑥𝑥1, 𝑥𝑥2) = 1 −∅ൣඥ𝑤𝑤1∅−1(1 −𝑥𝑥1) + ඥ𝑤𝑤2∅−1(1 −𝑥𝑥2)൧, 
where Φ(x) is the cumulative distribution function of the standard normal distribution.  
This combination function will be applied to compute composite intersection p-values for each 
intersection hypothesis in the closed family. The resulting composite intersection p-values are 
denoted by r12, r1, r2, and are defined in Table 6.  
Table 6: Intersection hypothesis and composite intersection p-values at final analysis 
Intersection hypothesis  
Composite intersection p-value  
H1 ∩ H2  
r12 = c(p12, q12)  
H1  
r1 = c(p1, q1)  
H2  
r2 = c(p2, q2)  
 




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6.6 Timing of Final Analyses 
Data summary and statistical analysis will commence after all subjects have completed study Visit 
7 (or discontinued prior to Visit 7) and the study database is cleaned and locked. 
6.7 Multicenter Study 
This is a multicenter study. The primary analysis will have all sites pooled.  Where applicable, 
analysis adjusting for site effect or analysis evaluating homogeneity across sites may be carried 
out.  If conducted, small sites (defined as those with sample size <9 ITT subjects/site) will be 
pooled with larger sites based on the geographic proximity.   
6.8 Multiple Comparisons/Multiplicity Adjustment 
With respect to the primary endpoint, the details of this multiplicity adjustment in the context of 
the adaptive design employed in this trial are defined in Sections 6.5.7. Multiplicity adjustment 
for secondary endpoints is described in Section 7.7.7. 
6.9 Examination of Subgroups 
In addition to the analysis adjusted for the confounding effects by the covariates (see 
Section 6.3), primary and key secondary efficacy variables will be summarized by subgroup to 
explore the heterogeneity of the treatment effect across subgroups.  Subgroups are defined as 
follows: 
• Gender (Male, Female) 
• Age (6-9, 10-12) 
• Race (White, Black/African American, Other) 
 
7 STATISTICAL ANALYSIS 
7.1 Analysis Populations 
The population of “all enrolled subjects” consists of all those screened subjects who meet the 
requirements for study participation and are entered in the Baseline period (i.e., distributed IA 
diary) of the study. The population of “all randomized subjects” consists of all those enrolled 
subjects who complete the Baseline Period, meet the inclusion/exclusion criteria and are 
randomized. 
7.1.1 Safety Population 
The safety population will include all randomized subjects who received at least 1 dose of study 
drug and have at least one post-randomization safety measurements. 


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7.1.2 Intent-to-treat (ITT) Population  
The intent-to-treat population will include all subjects who received at least 1 dose of study drug 
and have a baseline and at least 1 valid post-randomization assessment of frequency of IA 
behaviors based on IA diary entry. Subjects will be analyzed according to the treatment to which 
they were randomized. 
7.1.3 Per Protocol (PP) Population 
The per protocol population will include all of the subjects in the ITT population who completed 
the treatment period (Completed Maintenance Visit 6) with 70% diary completion compliance 
and who did not have major protocol deviations.  Diary compliance is calculated as  
diary compliance = number of days diary completed within the treatment period 
Number of treatment days
× 100% 
Detailed specification of the PP population will be provided prior to the database lock for the 
final analysis. 
7.2 Disposition of Subjects 
Subject disposition and reasons for screening failure will be summarized for screen-failed 
subjects (Table 14.1.1). 
Subject randomization schedule will be listed.  Subjects whose randomization codes are 
unblinded during the conduct of the study will be listed along with the reason for un-blinding 
(Listing 16.1.7). 
The following summaries and listings will be based on all randomized subjects.   
Subjects (n and %) who completed and discontinued from the study will be tabulated by the 
treatment group for (1) Randomized, (2) ITT, (3) Safety, and (4) PP populations (Table 14.1.2a – 
Table 14.1.2d).  The primary reasons for study discontinuation will be included in the tabulation.  
The primary reasons may include any of the following: 
• Subject withdrew consent 
• Lost to follow-up 
• Administrative reason 
• Adverse event  
• Investigator decision 
• Failure to follow required study procedures 
• Other 


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In addition, subject disposition will be summarized by treatment period (combined titration and 
maintenance, titration, maintenance, and tapering) for (1) Randomized, (2) ITT, (3) Safety, and 
(4) PP populations  (Table 14.1.3a – Table 14.1.3d). 
In addition, subject’s enrollment will be summarized by study site among ITT population (Table 
14.1.4).   
A data listing will be presented for subjects who do not complete the treatment along with the 
reasons for discontinuation (Listing 16.2.1.1). 
7.3 Protocol Deviations 
Protocol deviations will include, but are not limited to 
• Non-compliance with any scheduled study visit  
• Non-compliance with study treatment  
• Prohibited medications  
• Non-compliance with study inclusion or exclusion criteria  
• Non-compliance with study assessment procedures  
Subjects with major protocol deviations will be listed based on all randomized subjects.  The 
listing will include a brief description of the deviation, deviation category, and if applicable, study 
day when deviation occurred along with other pertinent information (Listing 16.2.1.2). 
If warranted, subjects (n and %) with major protocol deviations will be tabulated by treatment 
group and deviation category (Table 14.1.5a). 
Additionally, subjects (n and %) in each analysis population with major protocol violations will 
be tabulated by treatment group (Table 14.1.5b).  Subject’s inclusion/exclusion from each 
analysis population will be listed along with the applicable reasons for exclusion (Listing 
16.2.1.3).  
Summary (n and %) of the analysis population will also be presented by treatment groups for the 
randomized population (Table 14.1.6). 
7.4 Demographics and Baseline Subject Characteristics 
Subject age, sex, ethnicity, race, height at screening, weight at screening and baseline will be 
summarized based on the ITT, Safety and PP populations by treatment group.  Age will be 
summarized as a continuous variable as well as a categorical variable (6 to 9 [i.e., <10], and 10 to 
12 [i.e., ≥10 and ≤ 12] years, inclusive) (Table 14.1.7a – Table 14.1.7c).   
All demographic and baseline characteristics will be included in the subject data listing (Listing 
16.2.1.4). 


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7.5 Baseline Disease Characteristics 
Summaries of baseline disease characteristics will be based on the ITT population, with the 
exception of medical history which will be presented for the Safety population. 
Subject incidence (n and %) of medical history will be tabulated by MedDRA System Organ Class 
(SOC) and Preferred Term (PT) for each treatment group as per Section 7.8.1 (Table 14.1.8).  
R-MOAS and Vitiello Aggression Scale will be summarized by treatment group as per Section 6.1 
(Tables 14.1.9 - 14.1.10). 
All baseline disease characteristics will be listed (Listing 16.2.1.5 – Listing 16.2.1.7). 
7.6 Treatments 
7.6.1 Treatment Compliance and Extent of Exposure 
Summaries of treatment compliance and exposure will be based on the ITT population. 
Duration of exposure is defined as the total number of days a subject is exposed to any study 
treatment. This will be calculated for each subject by taking the difference between the date of 
last dose minus the date of the first dose, plus 1 (date of last dose – date of first dose +1). 
Duration of Treatment exposure will be summarized using descriptive statistics (n, mean, SD, 
median, minimum, and maximum).  
Percent of SM compliance is defined as  
Treatment Compliance
= Number of Tablets Dispensed −Number of Tablets Returned
4x(Date of Last Dose −Date of First Dose + 1)
∙100%. 
Each subject is expected to take 4 tablets per day as in the following. Subjects randomized to 
placebo group will take 2 placebo tablets in the morning and 2 placebo tablets in the evening.  
Subjects randomized to SPN-810 
 mg will take one  mg active tablet and 1 placebo tablet in 
the morning and one  mg active tablet and 1 placebo tablet in the evening.  Subjects randomized 
to SPN-810 
 mg will take two  mg active tablets in the morning and two  mg active tablets in 
the evening. For each treatment, SM compliance will be summarized with number of subjects (n 
and %) by compliance category (<80%, 80-120%, and >120%). SM compliance will also be 
summarized as a continuous variable using descriptive statistics (n, mean, standard deviation, 
median, minimum, and maximum) for each treatment.  
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a 
a 
 
a 
 


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Summaries of treatment compliance and exposure will be presented separately for the Titration 
Period, Maintenance Period, and combined Titration and Maintenance Periods (Table 14.1.11 
and Listing 16.2.1.8). 
7.6.2 Prior and Concomitant Medications  
Prior and concomitant medications will be tabulated separately based on the Safety Population.  
The number (n and %) of subjects taking at least one medication and the number (%) of subjects 
taking each medication at the WHODD preferred term level will be tabulated by treatment group, 
Anatomical-Therapeutic-Chemical classification 3 (ATC3), and PT.  Subjects taking the same PT 
medication twice will only be counted once (Table 14.1.12.1 and Table 14.1.12.2). 
A subject data listing will be provided to include the reported medication name, the WHODD PT, 
ATC4, study day and pertinent subject information (Listing 16.2.1.9.1 and Listing 16.2.1.9.2). 
A separate data listing will include subjects who received prohibited medications (Listing 
16.2.1.9.3). 
7.7 Efficacy Analyses 
7.7.1 Primary Efficacy Analysis 
The primary analysis is based on the ITT population and the primary efficacy endpoint is the 
percent change (PCHT) in the frequency (unweighted score) of IA behaviors per 7 days in the 
treatment period relative to the Baseline period calculated over the number of days with non-
missing IA diary data.   
The primary efficacy analysis will be performed using the Wilcoxon rank-sum test to compare the 
medians of each of the two doses of SPN-810 (
 mg and 
 mg) with the median of the Placebo. 
The Hodges-Lehmann estimate of the difference (SPN-810 dose minus placebo) and the 
associated 95% confidence interval (CI) around the difference will be calculated.  To protect the 
overall Type-I error rate from inflation due to sample size re-estimation and multi-dose to 
placebo comparisons, p-values will be adjusted using the method described in Section 6.8.  The 
statistical analysis will be presented in the table along with the summary of the change from 
baseline frequency for Stage 1 and Stage 2 data (Table 14.2.1.1).  The daily IA behavior diary will 
be listed.  The daily frequency, the derived 7-day frequency for each week, and the derived 7-day 
frequency for the treatment period will be included (Listing 16.2.2.1.1 – Listing 16.2.2.1.2).  
Box plots of Wilcoxon scores will be created for 
 mg dose SPN-810 and Placebo, and 36 mg 
dose SPN-810 and Placebo, separately, using SAS PROC NPAR1WAY. 
  
 
 
 


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7.7.2 Sensitivity Analyses  
7.7.2.1 Multiple Imputation Assuming Missing at Random 
This sensitivity analysis assumes that the diary data are missing at random (MAR), that is, the 
probability that an observation is missing may depend on the observed values but not the missing 
values (e.g., the probability of missing Week 5 diary is related to the observed Week 4 or Week 
3 value but not the unobserved Week 5 value).  In this sensitivity analysis, missing data is imputed 
multiple times, thus creating the multiply-imputed diary data.  The final analysis incorporates the 
between-imputation variability with the within-imputation variability. 
The SAS MI procedure is implemented using the following four steps.  
1. Weekly IA total score is derived from the available Daily IA total scores (see Section 5.1).  
Weekly IA total score is set to missing if all Daily IA total scores are missing for the week. 
2. SAS PROC MI is applied to the input dataset containing all weekly IA total scores during 
the baseline, titration, and maintenance period.  The Markov Chain Monte Carlo (MCMC) 
method will be used for the multiple imputations.  One hundred (100) multiply-imputed 
datasets will be created. 
3. For each of the multiply-imputed data sets, PCHT will be computed.  The primary analysis 
based on the Wilcoxon rank-sum test will be conducted and the Hodges-Lehmann 
asymptotic 95% confidence intervals will be constructed.  
4. To produce a single confidence interval for each dose and placebo comparison 
mg 
versus placebo and 
 mg versus placebo), PROC MIANALYZE will be used and the Rubin’s 
combination rules will be applied to the treatment effect estimates and associated 
asymptotic standard errors from the MI data sets. The treatment effect estimates will be 
defined as the midpoints of the asymptotic confidence intervals and the standard errors 
will be defined as the asymptotic standard errors (based on the width of the associated 
95% confidence intervals) from the Hodges-Lehmann estimate of the individual datasets 
(Rubin 1987).  
A sample SAS code is as follows. 
PROC MI DATA=adqs NIMPUTE=100 SEED=123456789  MINIMUM=0 OUT=adqs_imp ; 
BY trtp ; 
VAR age sex bwk  twk1 twk2 twk3  twk4  twk5 ; 
MCMC CHAIN=multiple IMPUTE=full INITIAL=em PRIOR=jeffreys ; 
RUN ; 
where trtp is treatment group, bwk, twk1, twk2, twk3, twk4, and twk5 are variables of weekly IA 
scores during the baseline, and treatment (titration + maintenance) periods. These are derived 
as (SUM/DAY)*7, where SUM is the total of the IA scores reported on the IA diary in that analysis 
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week, and DAY is the number of days with non-missing IA score in the IA diary in that analysis 
week. Analysis week is defined as: 1st week is the 1st 7 days after visit 3 (exclusive) during titration, 
2nd week is the rest of the days up to Visit 5 (inclusive) in titration period, 3rd week is the 1st 7 
days after Visit 5 (exclusive), 4th week is the following 7 days after 3rd week, the 5th week is the 
rest of the days in maintenance period up to Visit 6 (inclusive). Adqs is the input data set with 
missing values, and adqs_imp is the complete imputed data set after 100 imputations. For the 
weekly IA score calculation, if the week has <3 daily diaries, the weekly IA score for this week will 
be set to missing and imputed using the above procedure. 
From the above multiply-imputed IA data, the Hodges-Lehmann confidence interval will be 
calculated for each imputed data set.  The point estimate for the between group difference and 
the associated standard error (SEM) will be derived from the confidence interval.  These point 
estimates and the SEMs will be summarized by the SAS MIANALYZE procedure.  A sample SAS 
code is as follows. 
PROC MIANALYZE DATA=PARMEST ; 
MODELEFFECTS estim ; 
STDERR sem ; 
ODS OUTPUT PARAMETERESTIMATES=parmest2(KEEP= paramcd label estimate 
stderr lclmean uclmean probt) ; 
RUN ; 
where estim and sem are the point estimate and SEM from each imputed set, estimate, stderr, 
lclmen, uclmean, and probt are the final summarized point estimate, standard error, lower and 
upper confidence limits, and the p-value for the between group comparison (Table 14.2.1.2.1). 
7.7.2.2 Multiple Imputation Assuming Missing Not at Random 
This sensitivity analysis assumes that the diary data are missing not at random (MNAR), that is, 
the probability that an observation is missing may depend on its underlying unobserved value. 
This approach may be considered “worst-case” sensitivity analyses as it assumes that after 
discontinuation subjects from the dosing arms would adopt the outcome model estimated from 
the placebo arm. To generate missing values from this “placebo-based” imputation model, PROC 
MI with the MNAR statement will be used (Table 14.2.1.2.2). A sample SAS code is as follows. 
PROC MI DATA=adqs NIMPUTE=100 SEED=123456789 MINIMUM=0 OUT=adqs_imp ; 
CLASS trtp ; 
VAR age sex  bwk twk1 twk2 twk3 twk4 twk5; 
FCS reg ; 
MNAR MODEL(bwk twk1 twk2 twk3 twk4 twk5 / MODELOBS=(trtp=’Placebo’)) ; 
RUN ; 


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where multivariate imputation is carried out by the fully conditional specification (fcs) method. 
7.7.3 Analysis of PCH Based on Data from Maintenance Period 
For this sensitivity analysis, the primary analysis will be repeated using data restricted to the 
maintenance period only (Table 14.2.1.2.3). 
7.7.4 Supplementary Analysis  
A supplementary analysis will be performed based on the Per Protocol population and will be 
presented in Table 14.2.1.2.4.  
7.7.5 Analysis Based on Adjustment of Covariates  
An exploratory analysis of the primary efficacy endpoint will be performed using a 
randomization-based approach (Dmitrienko and Koch 2017). Separate models will be produced 
for the following key prognostic baseline characteristics (age [categorical and continuous] and 
gender [categorical]) will be used in this analysis.  In addition, pooled site and baseline IA adjusted 
to 7 days will be used as covariates (Table 14.2.1.4).    
7.7.6 Examination of Subgroups  
The primary and key secondary efficacy (Caregiver CGI-I and Investigator CGI-I) variables will be 
summarized by subgroup to explore the heterogeneity of the treatment effect across subgroups.  
This analysis will be done for the following subgroups: gender (male, female), age (6-9 and 10-
12), and race (White, Black/African American, Other) (Table 14.2.1.5a - Table 14.2.1.5c). 
7.7.7 Secondary Efficacy Analyses  
All secondary analyses are based on the ITT population to compare the 
 mg dose with the 
Placebo. The secondary analysis variables are: 
1. 
Actual Caregiver CGI-I score at Visits 4, 5, and 6 (Table 14.2.2 and Listing 16.2.2.2) 
2. 
Actual Investigator CGI-I score at Visits 4, 5, and 6 (Table 14.2.3 and Listing 
16.2.2.2) 
3. 
Change from baseline (Visit 3) to Visits 4, 5 and 6 in Investigator CGI-S (Table 14.2.4 
and Listing 16.2.2.3) 
4. 
CHQ-PF28 Aggregate Physical and Psychological Scores will be summarized  at Visit 
6 (Table 14.2.5 and Listing 16.2.2.4a – Listing 16.2.2.4c) 
5. 
PSI-4-SFwill be summarized at Visit 6 (Table 14.2.6, Listing 16.2.2.5a, and 
16.2.2.5b) 
a. Parental Distress 
b. Parent-Child Dysfunctional Interaction 
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c. Difficult Child 
6. 
SNAP-IV ADHD scores will be summarized at Visit 6 in (Listing 16.2.2.6a and Listing 
16.2.2.6b):  
a. Inattention ratings (Table 14.2.7.1) 
b. Hyperactivity/Impulsivity ratings (Table 14.2.7.2) 
c. Oppositional Defiant Disorder (Table 14.2.7.3) 
d. Combined Scale ratings (Table 14.2.7.4) 
 
Scores of CGI-I and CGI-S will be analyzed using a Mixed-Effects Model for Repeated Measure 
(MMRM).  The model includes treatment, visit, and interaction between treatment and visit as 
fixed factors, baseline CGI-S as covariate for both CGI-I and CGI-S. The model parameters will be 
estimated using restricted maximum likelihood method with unstructured variance-covariance 
matrix and Kenward-Roger approximation to estimate denominator degrees of freedom.  In case 
there is a convergence problem in the MMRM model with the unstructured variance covariance 
matrix, the first (co)variance structure which does not have convergence problem will be used 
for the analysis from the following ordered list: 1) Toeplitz 2) Autoregressive of order 1 3) 
Compound symmetry. The least squares mean of each treatment group, the difference in the 
least squares mean (
mg dose minus placebo and
 mg dose minus placebo), and the 2-sided 
95% CI for the difference will be obtained. 
A sample SAS code is provided as follows. 
PROC MIXED DATA=XXXX ; 
CLASS trtp(ref=”P”)  usubjid visit; 
MODEL Response = base trtp visit trtp*visit / DDFM=kr ;  
REPEATED visit / SUBJECT=usubjid(trtp) TYPE=UN ; 
Lsmeans trtp*visit/Pdiff alpha=0.05;”  
RUN ; 
Note: usubjid is subject ID, trtp (“P” denotes placebo treatment) is treatment variable, visit is the 
nominal study visit, and Response is respective endpoints.  
Scores for CHQ-PF28, PSI-4-SF, and SNAP-IV will be analyzed using analysis of variance (ANOVA) 
at Visit 6.  
To preserve the overall type I error rate at 0.05 for the secondary endpoints, a sequential testing 
procedure will be used with the following features. First only dose or doses that are significantly 
different from placebo for the primary endpoint will be tested for secondary endpoints. If the 
primary endpoint analysis indicates only one dose is significant, no multiplicity adjustment is 
required. Otherwise, multiplicity adjustment will be performed as in the following.  The first of 
the secondary endpoints will be compared to placebo using the Hochberg step up procedure but 
only using those doses retained as a result of testing the primary endpoint. The second secondary 
endpoint will be tested in the same manner but only using those doses that were retained from 
the primary and the first secondary endpoint and so forth. As the endpoints are gone through in 
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the pre-defined order doses will only be retained if significant for all endpoints tested so far and 
at the given stage the Hochberg step-up procedure will be applied.  
If the null hypothesis for the primary analysis is not rejected, then no multiplicity adjustment will 
be done for the secondary endpoints. Otherwise, a sequential testing procedure to preserve the 
type I error rate at 0.05 will be conducted as described below.  
The ordering of the secondary endpoints follows the order in the list above.  
7.8 Safety Analyses 
Subject safety is assessed by AEs, labs, vital signs, 12-lead ECGs, and findings from the physical 
examinations. The occurrence of neurological side effects will be assessed by looking at any 
worsening in scores for each of the Simpson-Angus scale, Barnes Akathisia scale, and AIMS.  
Suicidal ideation and suicidal behavior will be measured by C-SSRS.  All summaries related to 
safety analyses will use the safety population and will be presented by treatment groups. 
7.8.1 Adverse Events 
AEs will be summarized using subject incidence table by treatment period (titration, 
maintenance, combined titration and maintenance, and tapering).  An overview of TEAE will be 
presented.  This table will include numbers and percentages of subjects experiencing at least 1 
TEAE, study drug-related TEAE, AE leading to study drug discontinuation, severe TEAE, serious 
TEAE, related TESAE, AESI, and TEAE with outcome of death (Table 14.3.1.1). 
Additionally, the number and percent (%) are calculated based on the number of unique subjects 
within each category (e.g., preferred term) by treatment group.  A subject reporting multiple 
events of the same category will be counted only once for that category.  For summary purpose, 
AE relationship to the study drug will be grouped into “Unrelated” for “unrelated” or “unlikely 
related” and “Related” for “possibly”, “probably”, or “definitely related”.  For subjects with more 
than one event coded to the same PT, the subjects will be counted for the categories with the 
strongest relationship and the greatest severity. The following subject incidence tables will be 
presented.  
• TEAEs by PT (Preferred Term) sorted by the decreasing order of subject incidence in the 
combined active dose group (Table 14.3.1.2.1 – Table 14.3.1.2.3) 
• TEAEs by SOC (System Organ Class) and PT sorted alphabetically (Table 14.3.1.3.1 – Table 
14.3.1.3.3) 
• Study Drug-Related TEAEs by SOC and PT (Table 14.3.1.4.1 – Table 14.3.1.4.3) 
• Severity of TEAEs by SOC and PT (Table 14.3.1.5.1 – Table 14.3.1.5.3) 
• TESAEs by SOC and PT when applicable (Table 14.3.1.6) 


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• Number and percent of patients reporting common AEs (≥5% in any group) by PT (Table 
14.3.1.7.1 – Table 14.3.1.7.3) 
• TEAEs leading to study drug discontinuation by SOC and PT (Table 14.3.1.8) 
• Treatment Emergent AESI by SOC and PT (Table 14.3.1.9) 
Where warranted by the subject incidence, these same tables may be presented by treatment 
period (Titration, Maintenance and Conversion/Tapering). 
A subject data listing will be provided for all adverse events (Listing 16.2.3.1.1).  Included in the 
listing are the reported term, PT, SOC, TEAE flag, study day when AE starts, duration, relationship, 
severity, action taken, outcome, and seriousness category.  
Data listings will be provided for subjects who die on study, experience SAEs, have TEAEs leading 
to study drug discontinuation, or AEs of special interest (Listing 16.2.3.1.2 – Listing 16.2.3.1.5). 
7.8.2 Laboratory Test 
Clinical laboratory values will be summarized by treatment group and visit using descriptive 
statistics for hematology, biochemistry, and urinalysis.  For quantitative laboratory parameters, 
both actual values and change from baseline values will be summarized (Table 14.3.2.1, Table 
14.3.3.1, and Table 14.3.4.1).  
Laboratory test result will be assigned a low, normal, high (LNH) classification according to 
whether the value is below (L), within (N), or above (H) the reference range provided by the 
laboratory. Within-treatment comparisons will be based on three by three tables (shift tables), 
that, for a particular laboratory test, compare the LNH classification at baseline to the LNH 
classification at visit. By subject-listings of all laboratory values will be provided for subjects who 
have L or H classification in any of their laboratory tests (Table 14.3.2.2, Table 14.3.3.2, and Table 
14.3.4.2).  
Note the summary and shift tables will only use the planned/scheduled tests.  However, both 
scheduled and repeat tests will be in the data listing. 
A complete lab data listing, including hematology, biochemistry, and urinalysis will be provided 
for all subjects.  Investigator assessment of clinical significance is based on the local laboratory 
reference ranges (Listing 16.2.3.2.1 – Listing 16.2.3.2.3). 
7.8.3 Vital Signs, Height, Weight, and BMI 
Vital signs (body temperature, heart rate, respiration rate, systolic blood pressure, and diastolic 
blood pressure), and their changes from baseline will be summarized by treatment group and 


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visit (Table 14.3.5, Listing 16.2.3.3).  Subject body size (weight, height, and BMI) will be 
summarized similarly (Table 14.3.6, Listing 16.2.3.4). 
7.8.4 12-Lead ECG 
By-visit tabular summaries of the quantitative ECG parameters and the overall ECG findings 
(normal, abnormal not clinically significant, or abnormal clinically significant) will be presented. 
The QT interval will be corrected using Fridericia’s method.  
ECG results will be summarized by visit by treatment group using descriptive statistics (for 
quantitative ECG parameters) and frequency tables (for qualitative ECG parameters, including 
the overall ECG finding). For quantitative ECG parameters, both actual values and change from 
screening values will be summarized (Table 14.3.7.1 and Table 14.3.7.2).  
Data listings will be presented for ECG parameters by visit.  QTcF meeting the criteria of >450 but 
≤480, >480 but ≤500 or >500 msec for the absolute value, or >30 msec or >60 msec increase from 
baseline will be identified (Listing 16.2.3.5.1 and Listing 16.2.3.5.2). 
7.8.5 Columbia Suicide Severity Rating Scale (C-SSRS) 
C-SSRS outcomes will be summarized using number and percent of subjects by categories for 
suicidal ideation only, suicidal behavior only and suicidality (ideation and behavior combined). 
The summary will be presented by treatment groups. The proportion of subjects in each 
treatment group will be compared with the proportion of subjects in the placebo group using the 
Fisher’s exact test (Table 14.3.8 and Listing 16.2.3.6).  
7.8.6 Infrequent Behaviors Checklist 
Infrequent behaviors will be listed for each subject by treatment group (Listing 16.2.3.7).  
7.8.7 Other Special Tests 
The occurrence of neurological side effects will be assessed by looking at the changes in scores 
from baseline to post-baseline visits for each of the Simpson-Angus scale (Listing 16.2.3.8), 
Barnes Akathisia scale (Listing 16.2.3.9), and AIMS (Listing 16.2.3.10). For each item on each of 
these scales, the number (and percentage) of subjects with a worse score at any post-baseline 
visit, compared to baseline, will be presented. A listing of these subjects will also be provided.  
 
8 VALIDATION  
The Clinical Operations, Clinical Research, and Statistics groups at Supernus will work with 
 
and 
 to ensure that the data collected for the study are of the highest quality possible. The 
 
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study monitor will be responsible for reviewing and verifying the accuracy of the data recorded 
on the electronic case report forms (eCRFs) direct from source documents at the investigative 
site. 
will be responsible for performing edit checks and reviewing all data entered into the 
electronic database to identify discrepant and/or inconsistent values and to send queries to the 
clinical sites. The Investigator will be responsible for answering queries about discrepant data 
and providing electronic signatures to confirm data integrity.  
The programming of Tables, Listings and Figures (TLFs) based on the clinical data is outsourced 
to 
. Supernus seeks to ensure the quality of the reports 
provided by 
 in the form of TLFs must pass a rigorous validation process involving the 
following processes.  
 
• Derived datasets must be independently reprogrammed by a second programmer. The 
separate datasets produced by the 2 programmers must match 100%.  
• Tables must be independently reprogrammed by a second programmer for and the 
results from both programs must match.  
• Figures must be checked for consistency against corresponding tables and listings, or 
independently reprogrammed if there are no corresponding tables or listings.  
• Listings must be checked for consistency against corresponding tables, figures, and 
derived datasets.  
 
The entire set of TLF must be checked for completeness and consistency prior to its delivery to 
Supernus.  
 
The above validation process must be repeated any time TLFs are redelivered using different 
data. Execution of this validation process must be documented through the study Table of 
Programs that will be provided to Supernus at study conclusion. 
 
9 REFERENCES 
Brannath W, M Posch, P Bauer. Recursive combination tests. Journal of the American Statistical 
Association. 2002; 97: 236-244.  
Chang, M. Adaptive Design Theory and Implementation Using SAS and R. Chapman & Hall/CRC, 
Boca Raton, Florida. 2008a. 
Change, M. Classical and Adaptive Clinical Trial Designs Using ExpDesign Studio. Wiley, New 
Jersey. 2008b. 
 
 
 


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Chen, YH, DL DeMets, and KKG Lan. “Increasing the sample size when the unblinded interim result 
is promising.” Statistics in Medicine, 2004. 23: 1023-1038. 
HealthActCHQ. The CHQ Scoring and Interpretation Manual. Boston, MA: HealthActCHQ, 2013.  
2013.   
Dmitrienko, A, RB D’Agostino. Tutorial in Biostatistics: Traditional multiplicity adjustment 
methods in clinical trials. Statistics in Medicine. 2013; 32:5172-5218.  
Dmitrienko A, AC Tamhane, and F bretz. Multiple Testing Problems in Pharmaceutical Statistics. 
Chapman & Hall/CRC, Boca Raton, Florida. 2010. 
Dmitrienko, A and GG Koch. Analysis of Clinical Trials Using SAS: A Practical Guide. 2nd Ed. Cary, 
NC: SAS Institute Inc. 2017. 
Hintze, J. PASS 12, NCSS, LLC. Kaysville, Utah, USA. 2013. 
Hommel, G. Adaptive modifications of hypotheses after an interim analysis. Biometrical Journal. 
2005; 5: 581-589.  
Jennison C and Turnbull BW. Group Sequential Methods with Applications to Clinical Trials. 
Chapman & Hall/CRC, Boca Raton, Florida. 2000. 
Mehta CR and SJ Pocock. “Adaptive increase in sample size when interim results are promising: 
a practical guide with examples.” Statistics in Medicine, 2000. 00:1-6. 
Wang, SJ, HMJ Hung, Y Tsong, L Cui. Group sequential test strategies for superiority and non-
inferiority hypotheses in active controlled clinical trials. Statistics in Medicine. 2001; 20: 1903-
1912.  
 
 
 


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Appendix 1. Exclusion Criteria for the Per Protocol Populations 
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Appendix 2. List of Tables, Listings, and Figures 
Table No. 
Title 
Population 
14.1.1 
Subject Demographics Characteristics, and Reason for Screening 
Failure 
Screening Failure 
Subjects 
14.1.2a 
Subject Disposition and Reason for Discontinuation  
Randomized 
Population 
14.1.2b 
Subject Disposition and Reason for Discontinuation  
ITT Population 
14.1.2c 
Subject Disposition and Reason for Discontinuation  
Safety Population 
14.1.2d 
Subject Disposition and Reason for Discontinuation  
PP Population 
14.1.3a 
Subject Disposition and Reason for Discontinuation by treatment 
period (combined titration and maintenance, titration, maintenance, 
and tapering) 
Randomized 
Population 
14.1.3b 
Subject Disposition and Reason for Discontinuation by treatment 
period (combined titration and maintenance, titration, maintenance, 
and tapering)  
ITT Population 
14.1.3c 
Subject Disposition and Reason for Discontinuation by treatment 
period (combined titration and maintenance, titration, maintenance, 
and tapering) 
Safety Population 
14.1.3d 
Subject Disposition and Reason for Discontinuation by treatment 
period (combined titration and maintenance, titration, maintenance, 
and tapering) 
PP Population 
14.1.4 
Subject Enrollment by Study Site 
ITT Population 
14.1.5a 
Summary of Major Protocol Deviations During the Study, by Treatment 
Group 
ITT Population 
14.1.5b 
Summary of Major Protocol Violations During the Study, by Treatment 
Group and Deviation Category 
Randomized 
Population 
14.1.6 
Summary of Analysis Population 
Randomized 
Population 
14.1.7a 
Demographics and Baseline Characteristics 
ITT Population 
14.1.7b 
Demographics and Baseline Characteristics 
Safety Population 
14.1.7c 
Demographics and Baseline Characteristics 
PP Population 


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14.1.8 
Medical History by System Organ Class and Preferred Term 
Safety Population 
14.1.9a 
Retrospective Modified Overt Aggression Scale at Baseline – Item 
Scores 
ITT Population 
14.1.9b 
Retrospective Modified Overt Aggression Scale at Baseline – Domain 
and Total Scores 
ITT Population 
14.1.10a 
Vitiello Aggression Scale at Baseline – Item Scores 
ITT Population 
14.1.10b 
Vitiello Aggression Scale at Baseline – Domain and Total Scores 
ITT Population 
14.1.11 
Exposure to Study Medication and Compliance 
ITT Population 
14.1.12.1 
Prior Medications by ATC Code and Preferred Term 
Safety Population 
14.1.12.2 
Concomitant Medications by ATC Code and Preferred Term 
Safety Population 
14.2.1.1 
Analyses of PCH in the Frequency of IA Behaviors During the 
Treatment Period - Primary Analysis  
ITT Population 
14.2.1.2.1 
Analyses of PCH in the Frequency of IA Behaviors During the 
Treatment Period - Sensitivity Analysis, Multiple Imputation with MAR 
Assumption 
ITT Population 
14.2.1.2.2 
Analyses of PCH in the Frequency of IA Behaviors During the 
Treatment Period - Sensitivity Analysis, Multiple Imputation with 
MNAR Assumption 
ITT Population 
14.2.1.2.3 
Analyses of PCH in the Frequency of IA Behaviors During the 
Maintenance Period - Sensitivity Analysis  
ITT Population 
14.2.1.2.4 
Analyses of PCH in the Frequency of IA Behaviors During the 
Treatment Period - Supplementary Analysis  
PP Population 
14.2.1.3 
Descriptive Statistics for Frequency of IA Behaviors Per 7 Days and 
Change from Baseline by Study Period 
ITT Population 
14.2.1.4 
Percent Change from Baseline to Treatment Period in Frequency of IA 
Behaviors: Adjustment for Covariates using Randomization-Based 
Approach of Dmitrienko and Koch 
ITT Population 
14.2.1.5a 
Analyses of PCH in the Frequency of IA Behaviors During the 
Treatment Period by Gender - Primary Analysis 
ITT Population 
14.2.1.5b 
Analyses of PCH in the Frequency of IA Behaviors During the 
Treatment Period by Age - Primary Analysis 
ITT Population 


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14.2.1.5c 
Analyses of PCH in the Frequency of IA Behaviors During the 
Treatment Period by Race - Primary Analysis 
ITT Population 
14.2.2 
Investigator Clinical Global Impression – Improvement (CGI-I) Score by 
Visit 
ITT Population 
14.2.3 
Caregiver Clinical Global Impression – Improvement (CGI-I) Score by 
Visit 
ITT Population 
14.2.4 
Investigator Clinical Global Impression – Severity (CGI-S) Score and 
Change from Baseline by Visit  
ITT Population 
14.2.5.1 
Child Health Questionnaire Parent Form 28 (CHQ-PF28) - Item Scores 
and Change from Baseline to Visit 6 
ITT Population 
14.2.5.2 
Child Health Questionnaire Parent Form 28 (CHQ-PF28)-Component 
Scores and Change from Baseline to Visit 6 
ITT Population 
14.2.6.1 
Parenting Stress Index – Short Form (PSI-4-SF) Total Score, Change 
from Baseline to Visit 6 
ITT Population 
14.2.6.2 
Parenting Stress Index – Short Form (PSI-4-SF) Parental Distress 
Subscale Scores, Change from Baseline to Visit 6 
ITT Population 
14.2.6.3 
Parenting Stress Index – Short Form (PSI-4-SF) Parent-Child 
Dysfunctional Interaction Subscale Scores, Change from Baseline to 
Visit 6 
ITT Population 
14.2.6.4 
Parenting Stress Index – Short Form (PSI-4-SF) Difficult Child Subscale 
Scores, Change from Baseline to Visit 6 
ITT Population 
14.2.7.1 
SNAP-IV ADHD Inattention Subscale Score and Change from Baseline 
to Visit 6 
ITT Population 
14.2.7.2 
SNAP-IV ADHD Hyperactivity/Impulsivity Subscale Score and Change 
from Baseline to Visit 6 
ITT Population 
14.2.7.3 
SNAP-IV ADHD oppositional defiant disorder Score and Change from 
Baseline to Visit 6 
ITT Population 
14.2.7.4 
SNAP-IV ADHD Combined Scale Rating Score and Change from Baseline 
to Visit 6 
ITT Population 
14.2.8.1a 
Subgroup Analysis of Investigator Clinical Global Impression – 
Improvement (CGI-I) Score by Visit (Age) 
ITT Population 
14.2.8.1b 
Subgroup Analysis of Investigator Clinical Global Impression – 
Improvement (CGI-I) Score by Visit (Gender) 
ITT Population 


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14.2.8.1c 
Subgroup Analysis of Investigator Clinical Global Impression – 
Improvement (CGI-I) Score by Visit (Race) 
ITT Population 
14.2.8.2a 
Subgroup Analysis of Caregiver Clinical Global Impression – 
Improvement (CGI-I) Score by Visit (Age) 
ITT Population 
14.2.8.2b 
Subgroup Analysis of Caregiver Clinical Global Impression – 
Improvement (CGI-I) Score by Visit (Gender) 
ITT Population 
14.2.8.2c 
Subgroup Analysis of Caregiver Clinical Global Impression – 
Improvement (CGI-I) Score by Visit (Race) 
ITT Population 
14.3.1.1 
Overall Incidence of Treatment-Emergent Adverse Events by Study 
Period 
Safety Population 
14.3.1.2.1 
Incidence of Treatment-Emergent Adverse Events by Preferred Term – 
Titration and Maintenance Period 
Safety Population 
14.3.1.2.2 
Incidence of Treatment-Emergent Adverse Events by Preferred Term – 
Titration Period 
Safety Population 
14.3.1.2.3 
Incidence of Treatment-Emergent Adverse Events by Preferred Term – 
Maintenance Period 
Safety Population 
14.3.1.3.1 
Incidence of Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term – Titration and Maintenance Period 
Safety Population 
14.3.1.3.2 
Incidence of Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term – Titration Period  
Safety Population 
14.3.1.3.3 
Incidence of Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term – Maintenance Period 
Safety Population 
14.3.1.4.1 
Incidence of Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, Treatment-Relatedness, and Treatment Group – 
Titration and Maintenance Period  
Safety Population 
14.3.1.4.2 
Incidence of Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, Treatment-Relatedness, and Treatment Group – 
Titration Period 
Safety Population 
14.3.1.4.3 
Incidence of Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, Treatment-Relatedness, and Treatment Group – 
Maintenance Period 
Safety Population 
14.3.1.5.1 
Incidence of Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, Severity, and Treatment Group – Titration and 
Maintenance Period 
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14.3.1.5.2 
Incidence of Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, Severity, and Treatment Group – Titration 
Period 
Safety Population 
14.3.1.5.3 
Incidence of Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, Severity, and Treatment Group – Maintenance 
Period 
Safety Population 
14.3.1.6 
Incidence of Treatment-Emergent Serious Adverse Events by System 
Organ Class and Preferred Term 
Safety Population 
14.3.1.7.1 
Number (%) of Patients Reporting Common AEs (Greater or Equal to 
5% in Any Group) by Preferred Term – Titration and Maintenance 
Period  
Safety Population 
14.3.1.7.2 
Number (%) of Patients Reporting Common AEs (Greater or Equal to 
5% in Any Group) by Preferred Term – Titration Period  
Safety Population 
14.3.1.7.3 
Number (%) of Patients Reporting Common AEs (Greater or Equal to 
5% in Any Group) by Preferred Term –Maintenance Period  
Safety Population 
14.3.1.8.1 
TEAEs leading to study drug discontinuation by SOC and Preferred 
Term – Titration and Maintenance Period  
Safety Population 
14.3.1.8.2 
TEAEs leading to study drug discontinuation by SOC and Preferred 
Term – Titration Period  
Safety Population 
14.3.1.8.3 
TEAEs leading to study drug discontinuation by SOC and Preferred 
Term –Maintenance Period  
Safety Population 
14.3.1.9.1 
Treatment Emergent AESI by SOC and Preferred Term – Titration and 
Maintenance Period  
Safety Population 
14.3.1.9.2 
Treatment Emergent AESI by SOC and Preferred Term – Titration 
Period  
Safety Population 
14.3.1.9.3 
Treatment Emergent AESI by SOC and Preferred Term –Maintenance 
Period  
Safety Population 
14.3.2.1 
Hematology: Change from Baseline by Visit 
Safety Population  
14.3.2.2 
Hematology: Shift from Baseline Classification by Visit 
Safety Population 
14.3.3.1 
Blood Chemistry: Change from Baseline by Visit 
Safety Population 
14.3.3.2 
Blood Chemistry: Shift from Baseline Classification by Visit 
Safety Population 
14.3.4.1 
Urinalysis: Change from Baseline by Visit 
Safety Population  


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14.3.4.2 
Urinalysis: Shift from Baseline Classification by Visit 
Safety Population  
14.3.5 
Vital Signs: Change from Baseline at End of Study 
Safety Population  
14.3.6 
Subject Body Size: Change from Baseline by Visit 
Safety Population  
14.3.7.1 
12-Lead ECG Intervals: Change from Baseline by Visit 
Safety Population  
14.3.7.2 
12-Lead ECG Overall Findings: Shift from Baseline Classification by Visit 
Safety Population  
14.3.8 
Columbia Suicidal Severity Rating Scale by Visit 
Safety Population  
 
Listing No. 
Title 
Population 
16.1.7 
Subject Randomization Schedule  
Randomized Population 
16.2.1.1 
Subject Disposition and Reason for Disposition 
Randomized Population 
16.2.1.2 
Subjects Who had Major Protocol Deviations  
Randomized Population 
16.2.1.3 
Subjects Inclusion and the Reason for Exclusion from Analysis 
Populations  
Randomized Population 
16.2.1.4 
Demographics and Baseline Characteristics 
Randomized Population 
16.2.1.5 
Medical History  
Randomized Population 
16.2.1.6 
R-MOAS Scale at Baseline  
Randomized Population 
16.2.1.7 
Viteillo Aggression Scale at Baseline 
Randomized Population 
16.2.1.8 
Study Drug Accountability and Compliance 
 
16.2.1.9.1 
Prior Medications  
Randomized Population 
16.2.1.9.2 
Concomitant Medications  
Randomized Population 
16.2.1.9.3 
Prohibited Medications 
Randomized Population 
16.2.2.1.1 
Impulsive Aggression Behavior Daily Diary  
ITT Population 
16.2.2.1.2 
Derived Primary Endpoint 
ITT Population 
16.2.2.2 
Investigator and Caregiver Clinical Global Impression -
Improvement (CGI-I) 
ITT Population 
16.2.2.3 
Investigator Clinical Global Impression – Severity (CGI-S) 
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16.2.2.4a 
Child Health Questionnaire Parent Form 28 (CHQ-PF28)– 
Question Text  
ITT Population 
16.2.2.4b 
Child Health Questionnaire Parent Form 28 (CHQ-PF28) – 
Individual Questions 
ITT Population 
16.2.2.4c 
Child Health Questionnaire Parent Form 28 (CHQ-PF28) – Items, 
Components and General Health Scores 
ITT Population 
16.2.2.5a 
Parenting Stress Index – Short Form (PSI-4-SF) – Individual 
Questions 
ITT Population 
16.2.2.5b 
Parenting Stress Index – Short Form (PSI-4-SF) – Domain and 
Total Scores 
ITT Population 
16.2.2.6a 
SNAP-IV Teacher and Parent Rating Scale – Individual Questions 
ITT Population 
16.2.2.6b 
SNAP-IV Teacher and Parent Rating Scale – Subscales 
ITT Population 
16.2.3.1.1 
All Adverse Events  
Safety Population 
16.2.3.1.2 
Serious Adverse Events  
Randomized Population 
16.2.3.1.3 
Adverse Events with Outcome of Death 
Randomized Population 
16.2.3.1.4 
Adverse Events Leading to Study Drug Discontinuation 
Randomized Population 
16.2.3.1.5 
Adverse Events of Special Interest 
Randomized Population 
16.2.3.2.1 
Clinical Laboratory Tests-Hematology 
Randomized Population 
16.2.3.2.2 
Clinical Laboratory Tests - Blood Chemistry 
Randomized Population 
16.2.3.2.3 
Clinical Laboratory Tests - Urinalysis 
Randomized Population 
16.2.3.3 
Vital Signs  
Randomized Population 
16.2.3.4 
Subject Body Size  
Randomized Population 
16.2.3.5.1 
12-Lead ECG Intervals  
Randomized Population 
16.2.3.5.2 
12-Lead ECG Overall Interpretation  
Randomized Population 
16.2.3.6 
Columbia Suicidal Severity Rating Scale  
Randomized Population 
16.2.3.7 
Infrequent Behaviors 
Randomized Population 
16.2.3.8 
Simpson-Angus Rating Scale 
Randomized Population 
16.2.3.9 
Barness Akathisia Rating Scale 
Randomized Population 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 57 
11 June 2019 
16.2.3.10 
Abnormal Involuntary Movement Scale 
Randomized Population 
 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P301 
 
SAP v3.0 
Page 58 
11 June 2019 
Appendix 3. Table and Listing Shells